Interrupted Curtius Rearrangements of Quaternary Proline Derivatives: A Flow Route to Acyclic Ketones and Unsaturated Pyrrolidines
- Marcus Baumann*Marcus Baumann*Email: [email protected]School of Chemistry, University College Dublin, Science Centre South, Belfield D04 N2E2, IrelandMore by Marcus Baumann
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- Thomas S. MoodyThomas S. MoodyDepartment of Technology, Almac Sciences, 20 Seagoe Industrial Estate, Craigavon BT63 5QD, United KingdomArran Chemical Company, Roscommon N37 DN24, IrelandMore by Thomas S. Moody
- ,
- Megan SmythMegan SmythDepartment of Technology, Almac Sciences, 20 Seagoe Industrial Estate, Craigavon BT63 5QD, United KingdomMore by Megan Smyth
- , and
- Scott WharryScott WharryDepartment of Technology, Almac Sciences, 20 Seagoe Industrial Estate, Craigavon BT63 5QD, United KingdomMore by Scott Wharry
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Abstract
Conversion of N-Boc-protected quaternary proline derivatives under thermal Curtius rearrangement conditions was found to afford a series of ring-opened ketone and unsaturated pyrrolidine products instead of the expected carbamate species. The nature of the substituent on the quaternary carbon thereby governs the product outcome due to the stability of a postulated N-acyliminium species. A continuous flow process with in-line scavenging was furthermore developed to streamline this transformation and safely create products on a gram scale.
This publication is licensed under
CC-BY 4.0.
License Summary*
You are free to share (copy and redistribute) this article in any medium or format and to adapt (remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
Creative Commons (CC): This is a Creative Commons license.
Attribution (BY): Credit must be given to the creator.
*Disclaimer
This summary highlights only some of the key features and terms of the actual license. It is not a license and has no legal value. Carefully review the actual license before using these materials.
License Summary*
You are free to share (copy and redistribute) this article in any medium or format and to adapt (remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
Creative Commons (CC): This is a Creative Commons license.
Attribution (BY): Credit must be given to the creator.
*Disclaimer
This summary highlights only some of the key features and terms of the actual license. It is not a license and has no legal value. Carefully review the actual license before using these materials.
License Summary*
You are free to share (copy and redistribute) this article in any medium or format and to adapt (remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
Creative Commons (CC): This is a Creative Commons license.
Attribution (BY): Credit must be given to the creator.
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SPECIAL ISSUE
This article is part of the
Since its first reports in the late 19th century, the Curtius rearrangement (1) has established itself as one of the most versatile transformations to convert ubiquitous carboxylic acids into valuable amine derivatives. (2) Acyl azide species (1a) are thereby the key intermediates in this process that release nitrogen upon rearranging into isocyanates that can be trapped with various nucleophiles (Scheme 1). Mechanistic studies support a concerted reaction pathway for thermal Curtius rearrangements, whereas photochemical alternatives proceed stepwise via nitrene intermediates. (3) The popularity of the thermal Curtius rearrangement is evident from its regular application in natural product syntheses and drug development programs. (4) Moreover, recent years have witnessed further developments by harnessing the salient features of continuous flow (5) processing to yield modern variants (6) that mitigate safety concerns due to the use of toxic azides, the release of nitrogen gas, and the potential for run-away phenomena related to the inherent exothermicity of this reaction sequence. Importantly, the exploitation of continuous flow processing has enabled several medicinal chemistry studies (7) culminating in the safe execution of Curtius rearrangements on scales of >40 kg. (8)
Scheme 1
Scheme 1. Overview of the Curtius Rearrangement
Despite these advances, essentially all studies on the Curtius rearrangement convert carboxylic acids into amines and amine derivatives such as carbamates, amides, and ureas (e.g., 3a–d), thus overlooking opportunities for new directions. To address this shortcoming, this Note reports the realization of an interrupted Curtius rearrangement process rendering a set of new products such as γ-amino ketones and unsaturated pyrrolidines from Boc-protected proline derivatives.
Expanding on prior studies that integrated enzymatic impurity tagging strategies with flow-based Curtius rearrangement reactions, (9) this work evaluated the use of Boc-protected proline species bearing substitution on the chiral carbon (e.g., 4). Generation and subsequent trapping of the intermediate isocyanate 5 were thereby anticipated to afford a selection of versatile α-amino pyrrolidine species 6 as novel and potentially useful amine building blocks (Scheme 2).
Scheme 2
Scheme 2. Intended Curtius Rearrangement Application for N-Boc Proline Derivatives
Commencing our study, the readily available proline derivative 4a (R1 = Me) (10) was subjected to standard Curtius rearrangement conditions using DPPA (diphenylphosporyl azide, 7) as the azide source, triethylamine as the base, and benzyl alcohol as the trapping agent. Upon heating the reaction mixture in acetonitrile to reflux, the evolution of nitrogen gas was observed within minutes, indicating the onset of the anticipated rearrangement process. However, upon analyzing the crude reaction mixture by 1H NMR spectroscopy, not the anticipated Cbz product (R2 = OBn, 6a), but a new ring-opened product was observed (entry 1, Table 1). This material was subsequently identified as ketone 9a and confirmed by comparison to literature NMR data. (11) As the evolution of nitrogen gas had indicated the generation of the anticipated isocyanate species, it was surmised that steric hindrance around the chiral center may have precluded nucleophilic attack by the modestly reactive benzyl alcohol. Reactions with other alcohols such as ethanol, methanol, and water (entries 2–4) resulted in the isolation of the same ketone product as the sole product in all three cases. Furthermore, alternative solvents such as toluene and dioxane did not alter the reaction outcome (entries 5 and 6). This outcome was reproduced even in the absence of an added alcohol nucleophile (entry 7). These results prompted consideration of an unprecedented reaction path that may be governed by the presence of the pyrrolidine ring as well as the quaternary center.
Table 1. Formation of Ketone 9a from N-Boc Proline Derivative 4a
| entry | solvent | nucleophile (Nuc) | yield (%) |
|---|---|---|---|
| 1 | MeCN | BnOH | 85 |
| 2 | MeCN | EtOH | 81 |
| 3 | MeCN | MeOH | 77 |
| 4 | MeCN | water | 75 |
| 5 | 1,4-dioxane | BnOH | 71 |
| 6 | toluene | BnOH | 84 |
| 7 | MeCN | none | 81 |
In view of the synthetic versatility of the 1,4-disubstitution pattern observed in this unexpected product and the desire to evaluate the generality of this process, a small selection of N-Boc-protected proline derivatives were subjected to these reaction conditions. Pleasingly, their syntheses were readily accomplished by lithiation of N-Boc proline methyl ester (10, 0.5 M in toluene, 1.0 equiv) with LiHMDS (1.0 M in THF, 1.1 equiv) as a base at −78 °C, followed by trapping the resulting carbanion with various electrophiles bearing alkyl and benzyl appendages (Scheme 3). Hydrolysis of the methyl ester (11) under alkaline conditions rendered the desired carboxylic acid building blocks 4 in high chemical yields.
Scheme 3
Scheme 3. Batch Synthesis of Substrates 4 by Lithiation of N-Boc Proline Methyl Ester 10
To streamline the following evaluation of the reaction scope, a flow reactor system was exploited to improve the process in view of safety, reproducibility, and scalability. (12) In addition, toluene was preferred as a solvent in view of its higher boiling point and lower propensity to introduce water that may quench the acyl azide or isocyanate intermediate. Alcohols as nucleophiles were not added as they were found to have little effect on the reaction outcome (Table 1, entry 7). A simple flow process was devised and exploited in which streams of the substrate (4a–g, 1 M, toluene) in the presence of triethylamine as a base (1.0 equiv) and DPPA (7, 0.95 M, toluene, 0.95 equiv) were mixed in a T-piece before entering a heated flow coil (10 mL, 1/16 in id, PFA, 100 °C) with a residence time of 20 min (Scheme 4). The reaction mixture passed a back-pressure regulator (100 psi, Kinesis (13)) to ensure the steady release of nitrogen gas before collection in a receiving flask. A glass column containing a mixture of scavenger resins (Amberlyst A-21 and Amberlyst A-15; (14) 2 g each per mmol of substrate 4a–g) was optionally placed at the end of the reaction sequence to remove acidic and basic byproducts (NEt3, substrate, and diphenyl phosphonic acid).
Scheme 4
Scheme 4. Flow Approach toward Evaluating the Reaction Scope of Interrupted Curtius Rearrangements
The resulting flow study confirmed that the initial substrate bearing a methyl substituent (4a) smoothly underwent the rearrangement process rendering methyl ketone 9a in high chemical yield. Pleasingly, the same result was obtained when performing this process on a gram scale (Figure 1). Equally, introducing an ethyl group as a modified alkyl appendage was well tolerated and gave product 9b in high yield. An interesting case was observed when subjecting cinnamyl analogue 4f to the flow rearrangement protocol. As before, the formation of a gaseous byproduct (e.g., N2) was observed, and analysis of the crude material by 1H NMR indicated product formation in high yield; however, during purification by silica flash column chromatography, this material decomposed. It is surmised that the delicate skipped keto styryl moiety thereby tautomerized to a Michael acceptor, thus triggering decomposition by aldol or cycloaddition pathways. To support this assumption, cinnamyl ester 11f was converted under transfer hydrogenation conditions (15) into its saturated counterpart, and pleasingly, the corresponding acid 4g furnished the anticipated ketone product (9g) in high yield and without any stability concerns. Furthermore, when subjecting unsubstituted N-Boc proline to the rearrangement process, decomposition of the labile aldehyde product (9h) was observed.
Figure 1
Figure 1. Reaction scope rendering acyclic products and unsaturated pyrrolidines.
In addition, several benzyl-substituted substrates (e.g., 4c–e) were subjected to the flow protocol to verify if the analogous ring-opening process would take place. Formation of a gaseous byproduct was observed as before when employing the previous flow reaction conditions for this interrupted Curtius rearrangement process. However, when analyzing the purified reaction products (9c–e) by various NMR techniques, it was apparent that no ketone product was obtained. As these products were solids, single crystals were successfully grown for product 9e, enabling X-ray diffraction experiments to unambiguously determine the correct connectivity of this product. (16) This clearly indicated the presence of a partially unsaturated pyrrolidine ring bearing an exocyclic, E-configured alkene instead of a ring-opened product. Comparison of the NMR data of the other benzyl-derived products (9c and 9d) indicated that the same product had formed as an exclusive E-isomer. Surprisingly relatively few mild and stereoselective methods for creating such unsaturated pyrrolidine scaffolds are reported in the literature. As these include examples that require transition metal catalysts and potentially render alternative alkene isomers or ring sizes, (17) the methodology presented herein may serve as an attractive alternative.
To account for the observed reaction products, the following mechanism is proposed (Scheme 5). Activation of the carboxylic acid functionality with DPPA forms acyl azide 12, which subsequently undergoes thermal rearrangement to an isocyanate (5) accompanied by the release of nitrogen gas. This quaternary isocyanate is assumed to be too hindered to undergo nucleophilic attack as anticipated in the regular Curtius rearrangement. In the absence of a strong base, it is proposed that a unimolecular process in which (iso)cyanate anion is expelled and cyclic acyliminium (18) species 13 is obtained. This highly electrophilic acyliminium ion then reacts with adventitious water to give ketones (9a,b,g). In the case of a neighboring benzylic methylene group, the corresponding acyliminium appears to tautomerize rapidly by loss of the benzylic proton giving unsaturated pyrrolidine structures 9c–e instead, which appear to be stable under the reaction conditions. (19) It is believed that conjugation of the exocyclic alkene into the benzene ring for products 9c–e imparts higher stability toward attack by nucleophiles such as water and thus accounts for the observed reaction outcome.
Scheme 5
Scheme 5. Proposed Reaction Mechanism Accounting for Bifurcated Pathway
In conclusion, a novel reaction pathway for quaternary N-Boc proline species under thermal Curtius rearrangement conditions is reported. Fragmentation of the intermediate isocyanate species thereby renders a proposed N-acyliminium species, which facilitates ring-opening by adventitious water to give γ-amino ketone products in the case of small aliphatic substituents, whereas benzylic appendages render unsaturated pyrrolidines via tautomerization of this proposed N-acyliminium intermediate. A continuous flow protocol was successfully established to enable the safe and scaled exploration of this transformation. In view of its simplicity, high yields, and the value of the generated reaction products, this interrupted Curtius rearrangement method may find future synthetic applications in both batch and flow mode.
Experimental Section
ARTICLE SECTIONS
Materials and Methods
Unless otherwise stated, all solvents were purchased from Fisher Scientific and used without further purification. Substrates and reagents were purchased from Fluorochem or Sigma-Aldrich and used as received.
The heating of reaction mixtures was achieved by using DrySyn metal heating blocks available from Asynt.
1H NMR spectra were recorded on 300, 400, and 500 MHz instruments and are reported relative to the residual solvent: CHCl3 (δ 7.26 ppm). 13C{1H} NMR spectra were recorded on the same instruments (100 and 125 MHz) and are reported relative to CHCl3 (δ 77.16 ppm). 19F NMR were recorded at 282 and 376 MHz. Data for 1H NMR are reported as follows: chemical shift (δ/ ppm) (integration, multiplicity, coupling constant (Hz)). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet, br s = broad singlet, app = apparent. Data for 13C{1H} NMR are reported in terms of chemical shift (δ/ppm) and multiplicity (C, CH, CH2, or CH3). COSY and HSQC experiments were used in the structural assignment.
IR spectra were obtained by use of a Bruker Platinum spectrometer (neat, ATR sampling) with the intensities of the characteristic signals being reported as weak (w, <20% of the tallest signal), medium (m, 21–70% of the tallest signal), or strong (s, >71% of the tallest signal).
High-resolution mass spectrometry was performed using the indicated techniques on a micromass LCT orthogonal time-of-flight mass spectrometer with leucine-enkephalin (Tyr-Gly-Phe-Leu) as an internal lock mass. GC–MS was performed on a Waters GCT Premier Agilent 7898 system (column Macherey–Nagel; Optima 5 MS, length 15 m, diameter 0.25 mm).
Melting points were recorded on a Stuart SMP10 melting point apparatus and are uncorrected.
Continuous flow experiments were performed on a Vaportec E-series system in combination with Omnifit glass columns (6.6 mm id, 150 mm length) filled with scavenging resins (A-15/A-21).
Synthetic Procedures and Spectroscopic Data
Synthesis of Substituted N-Boc Proline Derivatives 11b–h
For a reaction on 2 mmol scale, to a solution of the N-Boc proline methyl ester (10, 1.0 equiv, 2.0 mmol) in toluene (0.5 M, held at −78 °C) was added a solution of LiHMDS (1 M, THF, 1.1 equiv, 2.2 mmol) dropwise. The resulting mixture was allowed to warm to 0 °C within 20 min before cooling to −78 °C. A solution of alkyl bromide or iodide electrophile (0.5 M, toluene, 1.0 equiv, 2.0 mmol) was subsequently added dropwise, and the reaction mixture continued stirring for 12 h, eventually warming to rt. The reaction mixture was quenched by the addition of NH4Cl solution (sat. aq) and extracted (DCM/water). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give the crude product. Purification was achieved via silica gel chromatography using a cyclohexane/ethyl acetate (75:15) eluent system.
1-(tert-Butyl) 2-Methyl 2-ethylpyrrolidine-1,2-dicarboxylate (11b). (20)
Yield: 640 mg (3.6 mmol, 83%). Appearance: clear oil. Mixtures of Boc-rotamers were observed by NMR spectroscopy; please see copies of 1H and 13C NMR spectra in Supporting Information. 1H NMR (400 MHz, CDCl3): δ 3.75–3.69 (m), 3.66 (s), 3.63–3.55 (m), 3.42–3.31 (m), 2.37–2.25 (m), 2.20–2.10 (m), 2.06–1.94 (m), 1.92–1.74 (m), 1.42 (s), 1.37 (s), 0.88–0.80 (m). 13C{1H} NMR (101 MHz, CDCl3): δ 175.6, 175.4, 154.0, 153.8, 79.8, 79.3, 68.3, 67.8, 52.0, 51.9, 48.7, 48.6, 36.9, 35.6, 28.4, 28.3, 27.8, 26.6, 23.2, 22.7, 7.9. IR (neat): ν/cm–1 2974 (m), 2879 (w), 1741 (m), 1693 (s), 1455 (m), 1386 (s), 1234 (m), 1157 (s), 1130 (s), 1075 (m), 1002 (m), 772 (m). HRMS (TOF-ESI+): calcd for C13H23NO4Na, 280.1519; found, 280.1522 (M + Na+).
1-(tert-Butyl) 2-Methyl 2-benzylpyrrolidine-1,2-dicarboxylate (11c)
Yield: 870 mg (2.7 mmol, 91%). Appearance: clear oil. Mixtures of Boc-rotamers were observed by NMR spectroscopy; please see copies of 1H and 13C NMR spectra in Supporting Information. 1H NMR (500 MHz, CDCl3): δ 7.30–7.21 (m), 7.14 (td, J = 6.8, 5.9, 3.2 Hz), 3.77 (d, J = 14.0 Hz), 3.75 (s), 3.57 (d, J = 13.8 Hz), 3.48 (dt, J = 10.5, 7.5 Hz), 3.39 (dt, J = 10.4, 7.2 Hz), 3.05 (d, J = 13.8 Hz), 3.04 (d, J = 13.8 Hz), 2.99 (ddd, J = 10.5, 7.6, 5.3 Hz), 2.88 (ddd, J = 10.4, 7.6, 5.6 Hz), 2.12–1.97 (m), 1.58 (ddt, J = 18.2, 7.4, 5.2 Hz), 1.51 (s), 1.49 (s), 1.00–0.83 (m). 13C{1H} NMR (126 MHz, CDCl3): δ 175.3, 175.1, 154.1, 153.5, 137.3, 136.9, 130.8, 130.7, 128.2, 128.0, 126.6, 126.4, 80.3, 79.6, 68.3, 68.0, 52.3, 48.2, 39.7, 38.5, 36.6, 35.4, 28.5, 28.4, 22.8, 22.2. IR (neat): ν/cm–1 2975 (m), 2877 (w), 1741 (m), 1694 (s), 1454 (m), 1389 (s), 1366 (m), 1251 (m), 1168 (s), 1119 (m), 1020 (m), 704 (m). HRMS (TOF-ESI+): calcd for C18H25NO4Na, 342.1676; found, 342.1679 (M + Na+).
1-(tert-Butyl) 2-Methyl 2-(4-fluorobenzyl)pyrrolidine-1,2-dicarboxylate (11d)
Yield: 750 mg (2.3 mmol, 75%). Appearance: clear oil. Mixtures of Boc-rotamers were observed by NMR spectroscopy; please see copies of 1H and 13C NMR spectra in Supporting Information. 1H NMR (500 MHz, CDCl3): δ 7.11–7.06 (m), 6.98–6.92 (m), 3.74 (s), 3.73 (s), 3.54–3.45 (m), 3.40 (dt, J = 10.6, 7.2 Hz), 3.03 (d, J = 14.2 Hz), 3.01 (d, J = 14.2 Hz), 3.00–2.96 (m), 2.89 (ddd, J = 10.4, 7.4, 5.7 Hz), 2.09–1.98 (m), 1.65–1.55 (m), 1.49 (s), 1.47 (s), 1.05–0.87 (m). 13C{1H} NMR (126 MHz, CDCl3): δ 175.1, 175.0, 161.9 (CF, d, J = 246 Hz), 161.8 (CF, d, J = 246 Hz), 154.2, 153.5, 132.9 (d, J = 4 Hz), 132.6 (d, J = 4 Hz), 132.1 (d, J = 8 Hz), 132.0 (d, J = 8 Hz), 115.1 (d, J = 21 Hz), 114.8 (d, J = 21 Hz), 80.4, 79.7, 68.3, 67.9, 52.3, 52.3, 48.3, 48.2, 38.9, 37.7, 36.5, 35.3, 28.4, 28.4, 22.8, 22.2. IR (neat): ν/cm–1 2976 (m), 2877 (w), 1741 (s), 1693 (s), 1510 (s), 1388 (s), 1251 (m), 1221 (m), 1160 (s), 1131 (m), 1016 (m), 844 (m), 772 (m). HRMS (TOF-ESI+): calcd for C18H24FNO4Na, 360.1582; found, 360.1585 (M + Na+).
1-(tert-Butyl) 2-Methyl 2-(4-(trifluoromethyl)benzyl)pyrrolidine-1,2-dicarboxylate (11e)
Yield: 920 mg (2.4 mmol, 80%). Appearance: white solid. Melting range: 94–96 °C. Mixtures of Boc-rotamers were observed by NMR spectroscopy; please see copies of 1H and 13C NMR spectra in Supporting Information. 1H NMR (400 MHz, CDCl3): δ 7.48 (dd, J = 8.2, 4.3 Hz), 7.22 (d, J = 7.9 Hz), 3.78 (d, J = 13.8 Hz), 3.71 (s), 3.70 (s), 3.56 (d, J = 13.8 Hz), 3.47 (dt, J = 10.6, 7.3 Hz), 3.37 (dt, J = 10.5, 7.1 Hz), 3.08 (d, J = 13.8 Hz), 3.07 (d, J = 13.8 Hz), 2.95 (ddd, J = 10.5, 7.6, 5.5 Hz), 2.86 (ddd, J = 10.4, 7.4, 5.8 Hz), 2.10–1.94 (m), 1.64–1.54 (m), 1.45 (s), 1.43 (s), 1.01–0.86 (m). 13C{1H} NMR (101 MHz, CDCl3): δ 174.8, 174.7, 154.2, 153.4, 141.5, 141.2, 129.0 (q, J = 32 Hz), 128.8 (q, J = 32 Hz), 125.0 (q, J = 4 Hz), 124.8 (q, J = 4 Hz), 124.3 (CF3, q, J = 273 Hz), 124.2 (CF3, q, J = 273 Hz), 80.5, 79.8, 68.1, 67.8, 52.3, 48.2, 39.7, 38.4, 36.6, 35.3, 28.3, 28.3, 22.7, 22.2.IR (neat): ν/cm–1 2977 (w), 2880 (w), 1742 (m), 1694 (s), 1389 (s), 1324 (s), 1251 (m), 1163 (s), 1123 (s), 1111 (s), 1067 (s), 1019 (m), 851 (m). HRMS (TOF-ESI+): calcd for C19H24NF3O4Na, 410.1550; found, 410.1551 (M + Na+).
1-(tert-Butyl) 2-Methyl 2-cinnamylpyrrolidine-1,2-dicarboxylate (11f)
Yield: 550 mg (1.6 mmol, 81%). Appearance: clear oil. Mixtures of Boc-rotamers were observed by NMR spectroscopy; please see copies of 1H and 13C NMR spectra in Supporting Information. 1H NMR (300 MHz, CDCl3): δ 7.40–7.18 (m), 6.48 (app d, J = 15.7 Hz), 6.27–6.08 (m), 3.76 (s, 3H), 3.73–3.52 (m), 3.48–3.32 (m), 3.26 (dd, J = 14.1, 6.9 Hz), 3.08 (dd, J = 14.3, 6.3 Hz), 2.81 (d, J = 9.1 Hz), 2.76 (d, J = 8.6 Hz), 2.23–2.05 (m), 1.96–1.73 (m), 1.48 (s), 1.46 (s). 13C{1H} NMR (126 MHz, CDCl3): δ 175.1, 174.9, 154.0, 153.6, 137.6, 137.3, 133.9, 133.7, 128.6, 128.5, 127.3, 127.1, 126.3, 126.1, 125.3, 124.9, 80.2, 79.6, 67.9, 67.3, 52.2, 52.2, 48.5, 48.5, 38.9, 37.6, 37.1, 35.9, 28.4, 28.4, 23.2, 22.7. IR (neat): ν/cm–1 2975 (m), 2876 (w), 1741 (s), 1697 (s), 1390 (s), 1249 (m), 1164 (m), 1135 (m), 748 (w), 695 (w). HRMS (TOF-ESI+): calcd for C20H27NO4Na, 368.1832; found, 368.1835 (M + Na+).
1-(tert-Butyl) 2-Methyl 2-(3-phenylpropyl)pyrrolidine-1,2-dicarboxylate (11g)
To a solution of ester 11f (1 mmol, 1.0 equiv) in EtOAc (10 mL, 0.1 M) were added ammonium formate (5 mmol, 5.0 equiv) and Pd/C (10%, ca. 100 mg). This solution was then heated under reflux for 5 h when TLC indicated full conversion of the substrate. After cooling to room temperature, the mixture was filtered through a pad of Celite, washed with EtOAc (10 mL), and concentrated in vacuo to give the saturated product 11g (quant.).
Yield: 344 mg (1.0 mmol, 99%). Appearance: clear oil. Mixtures of Boc-rotamers were observed by NMR spectroscopy; please see copies of 1H and 13C NMR spectra in Supporting Information. 1H NMR (500 MHz, CDCl3): δ 7.32–7.24 (m), 7.19 (app dd, J = 8.2, 4.4 Hz), 3.75–3.71 (m), 3.70 (s), 3.69 (s), 3.64–3.56 (m), 3.42–3.30 (m), 2.74–2.56 (m), 2.38 (ddd, J = 14.0, 12.2, 4.8 Hz), 2.20 (td, J = 13.3, 4.4 Hz), 2.13–1.94 (m), 1.94–1.84 (m), 1.79 (tq, J = 12.6, 6.5 Hz), 1.71–1.60 (m), 1.60–1.51 (m), 1.45 (s), 1.33 (s). 13C{1H} NMR (126 MHz, CDCl3): δ 175.5, 175.3, 154.0, 153.8, 142.6, 142.1, 128.5, 128.4, 128.3, 128.3, 125.8, 125.7, 79.8, 79.4, 67.9, 67.4, 52.1, 52.0, 48.6, 48.5, 37.5, 36.2, 36.1, 34.7, 33.9, 28.4, 28.2, 25.9, 25.4, 23.2, 22.8. IR (neat): ν/cm–1 2974 (m), 2870 (w), 1741 (m), 1697 (s), 1454 (w), 1391 (s), 1366 (m), 1235 (m), 1163 (m), 1132 (m), 700 (w). HRMS (TOF-ESI+): calcd for C20H29NO4Na, 370.1989; found, 370.1994 (M + Na+).
Synthesis of Acid Products 4a–g
For a reaction on 2 mmol scale, to a solution of ester intermediate 11 (2 mmol, 1.0 equiv, 2 M, THF/MeOH, 50:50 vol) was added a solution of NaOH (1 M aqueous, 4 mL, 2.0 equiv). The resulting mixture was heated to reflux until TLC indicated full consumption of the substrate (ca. 3 h). The resulting solution was partitioned between EtOAc and water. The aqueous layer was subsequently acidified by the addition of 1 M HCl (ca. 5 mL) and extracted with DCM, giving the target acid products after drying of the organic layer over anhydrous Na2SO4, filtration, and final evaporation under reduced pressure.
1-(tert-Butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic Acid (4a). (21)
Yield: 2.5 g (10.9 mmol, 91%). Appearance: colorless crystalline solid. Melting range: 129–131 °C (CHCl3). Mixtures of Boc-rotamers were observed by NMR spectroscopy; please see copies of 1H and 13C NMR spectra in Supporting Information. 1H NMR (500 MHz, CDCl3): δ 11.67 (br s), 3.60–3.39 (m), 2.38–2.30 (m), 2.26–2.22 (m), 1.92 (app tt, J = 10.2, 5.4 Hz), 1.86–1.79 (m), 1.55 (s), 1.48 (s), 1.42 (s), 1.38 (s). 13C{1H} NMR (126 MHz, CDCl3): δ 180.7, 179.0, 154.9, 153.7, 80.4, 80.4, 65.6, 64.8, 48.2, 47.8, 40.3, 39.0, 28.4, 28.3, 23.0, 22.8, 22.7, 22.1. IR (neat): ν/cm–1 3200–2800 (br), 2977 (m), 2884 (m), 1731 (s), 1619 (s), 1446 (m), 1417 (s), 1392 (s), 1366 (s), 1248 (m), 1159 (s), 1138 (s), 1080 (m), 892 (m), 852 (m), 772 (m), 583 (m). HRMS (TOF-ESI+): calcd for C11H20NO4, 230.1387; found, 230.1388 (M + H+).
1-(tert-Butoxycarbonyl)-2-ethylpyrrolidine-2-carboxylic Acid (4b)
Yield: 0.5 g (2.1 mmol, 88%). Appearance: clear oil. Mixtures of Boc-rotamers were observed by NMR spectroscopy; please see copies of 1H and 13C NMR spectra in Supporting Information. 1H NMR (400 MHz, CDCl3): δ 3.73–3.67 (m), 3.54–3.46 (m), 3.37 (dt, J = 10.7, 7.5 Hz), 3.29 (dt, J = 10.3, 8.0 Hz), 2.65–2.48 (m), 2.21–2.03 (m), 2.03–1.85 (m), 1.81–1.71 (m), 1.45 (s), 1.38 (s), 0.84 (app t, J = 7.5 Hz). 13C{1H} NMR (101 MHz, CDCl3): δ 180.9, 175.4, 156.9, 153.9, 81.8, 80.2, 70.8, 67.7, 49.4, 48.6, 36.9, 34.5, 28.3, 28.3, 27.4, 27.1, 22.7, 8.1, 7.7. IR (neat): ν/cm–1 3400–2400 (br), 2974 (m), 2880 (w), 1741 (m), 1698 (s), 1391 (s), 1367 (s), 1161 (s), 931 (m), 858 (m), 773 (m). HRMS (TOF-ESI+): calcd for C12H21NO4Na, 244.1543; found, 244.1550 (M + Na+).
2-Benzyl-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic Acid (4c)
Yield: 0.7 g (2.3 mmol, 85%). Appearance: clear oil. Mixtures of Boc-rotamers were observed by NMR spectroscopy; please see copies of 1H and 13C NMR spectra in Supporting Information. 1H NMR (500 MHz, CDCl3): δ 7.31–7.22 (m,), 7.17–7.13 (m), 3.67 (d, J = 13.9 Hz), 3.61 (d, J = 13.8 Hz), 3.51 (dt, J = 10.5, 7.3 Hz), 3.40 (ddd, J = 10.7, 7.5, 5.0 Hz), 3.10 (d, J = 13.7 Hz), 3.03 (d, J = 14.0 Hz), 3.01–2.96 (m), 2.93 (dt, J = 10.7, 7.5 Hz), 2.36 (ddd, J = 13.0, 7.2, 5.6 Hz), 2.21–2.09 (m), 2.01 (ddd, J = 13.0, 8.3, 7.1 Hz), 1.68–1.59 (m), 1.54 (s), 1.52 (s), 1.19 (tdd, J = 12.4, 7.0, 5.3 Hz), 0.93 (dp, J = 12.3, 7.5 Hz). 13C{1H} NMR (126 MHz, CDCl3): δ 180.6, 177.1, 156.1, 153.6, 136.7, 136.2, 130.7, 130.6, 128.3, 128.2, 126.8, 126.7, 81.3, 80.8, 69.8, 68.0, 49.0, 48.3, 39.4, 38.6, 36.7, 34.7, 28.5, 28.4, 22.4, 22.2. IR (neat): ν/cm–1 3300–2700 (br), 2976 (m), 2878 (m), 1737 (m), 1697 (s), 1392 (s), 1368 (m), 1167 (s), 1139 (m), 994 (m), 703 (m). HRMS (TOF-ESI+): calcd for C17H24NO4, 306.1700; found, 306.1705 (M + H+).
1-(tert-Butoxycarbonyl)-2-(4-fluorobenzyl)pyrrolidine-2-carboxylic Acid (4d)
Yield: 0.5 g (1.5 mmol, 92%). Appearance: waxy white solid. Mixtures of Boc-rotamers were observed by NMR spectroscopy; please see copies of 1H and 13C NMR spectra in Supporting Information. 1H NMR (500 MHz, CDCl3): δ 7.16–7.09 (m), 7.01–6.94 (m), 3.67 (d, J = 13.9 Hz), 3.59–3.50 (m), 3.43 (ddd, J = 10.6, 7.5, 5.2 Hz), 3.08 (d, J = 14.0 Hz), 3.05–2.98 (m), 2.94 (dt, J = 10.7, 7.3 Hz), 2.30 (ddd, J = 13.2, 7.2, 5.9 Hz), 2.18 (dt, J = 13.5, 7.7 Hz), 2.11–1.95 (m), 1.73–1.63 (m), 1.53 (s), 1.51 (s), 1.29–1.18 (m), 0.99 (dp, J = 12.1, 7.5 Hz). 13C{1H} NMR (126 MHz, CDCl3): δ 180.8, 178.0, 161.9 (2xd, J = 247 Hz), 155.6, 153.6, 132.3 (2x), 132.0 (m), 115.2 (d, J = 21 Hz), 115.1 (d, J = 21 Hz), 81.0, 81.0, 69.2, 67.9, 48.8, 48.3, 38.6, 37.6, 36.7, 34.9, 28.5, 28.4, 22.5, 22.3. IR (neat): ν/cm–1 3300–2600 (br), 2977 (m), 2880 (w), 1737 (m), 1696 (s), 1510 (s), 1392 (s), 1368 (s), 1223 (s), 1160 (s), 1140 (m), 996 (m), 840 (m), 771 (m). HRMS (TOF-ESI+): calcd for C17H23FNO4, 324.1611; found, 324.1618 (M + H+).
1-(tert-Butoxycarbonyl)-2-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylic Acid (4e)
Yield: 0.6 g (1.6 mmol, 95%). Appearance: waxy solid. Mixtures of Boc-rotamers were observed by NMR spectroscopy; please see copies of 1H and 13C NMR spectra in Supporting Information. 1H NMR (400 MHz, CDCl3): δ 7.56–7.52 (m), 7.28–7.24 (m), 3.69 (d, J = 13.7 Hz), 3.62 (d, J = 13.9 Hz), 3.53 (dt, J = 10.5, 7.3 Hz), 3.46–3.39 (m), 3.18 (d, J = 13.6 Hz), 3.08 (d, J = 13.9 Hz), 3.03–2.91 (m), 2.37 (dt, J = 12.7, 6.6 Hz), 2.24–2.15 (m), 2.08–2.02 (m), 1.98–1.88 (m), 1.73–1.58 (m), 1.52 (s), 1.48 (s), 1.31–1.21 (m), 1.00 (dt, J = 12.5, 7.3 Hz). 13C{1H} NMR (101 MHz, CDCl3): δ 179.9, 176.3, 156.1, 153.5, 140.9, 140.3, 131.0, 130.8, 125.2, 125.1, 125.1, 81.6, 81.1, 49.0, 48.3, 39.4, 38.5, 36.7, 34.7, 28.4, 28.4, 22.4, 22.3, 20.6; some resonances were not observed clearly. IR (neat): ν/cm–1 3400–2700 (br), 2977 (m), 2882 (w), 1738 (m), 1696 (s), 1392 (s), 1324 (s), 1163 (s), 1124 (s), 1112 (s), 1068 (s), 851 (m). HRMS (TOF-ESI+): calcd for C18H22F3NO4Na, 396.1393; found, 396.1393 (M + Na+).
1-(tert-Butoxycarbonyl)-2-cinnamylpyrrolidine-2-carboxylic Acid (4f)
Yield: 0.6 g (1.8 mmol, 82%). Appearance: clear oil. Mixtures of Boc-rotamers were observed by NMR spectroscopy; please see copies of 1H and 13C NMR spectra in Supporting Information. 1H NMR (300 MHz, CDCl3): δ 7.44–7.21 (m), 6.53 (d, J = 15.7 Hz), 6.04 (dt, J = 15.5, 7.5 Hz), 3.59–3.48 (m), 3.38–3.28 (m), 3.09 (dd, J = 13.7, 7.9 Hz), 2.88 (dd, J = 13.9, 7.1 Hz), 2.80–2.67 (m), 2.27–2.17 (m), 2.05–1.92 (m), 1.85–1.74 (m), 1.51 (app s). 13C{1H} NMR (126 MHz, CDCl3): δ 180.3, 175.9, 156.5, 153.7, 137.2, 137.2, 134.8, 134.1, 128.6, 127.5, 127.4, 126.2, 126.2, 124.7, 123.3, 81.7, 80.7, 69.6, 67.3, 49.3, 48.5, 38.5, 37.3, 37.2, 34.9, 28.4, 28.4, 22.7, 22.7. IR (neat): ν/cm–1 3300–2700 (br), 2975 (m), 2879 (w), 1733 (m), 1695 (s), 1390 (s), 1367 (s), 1247 (m), 1164 (s), 998 (m), 969 (m), 734 (s), 694 (s). HRMS (TOF-ESI+): calcd for C19H25NO4Na, 354.1676; found, 354.1677 (M + Na+).
1-(tert-Butoxycarbonyl)-2-(3-phenylpropyl)pyrrolidine-2-carboxylic Acid (4g)
Yield: 0.4 g (1.2 mmol, 88%). Appearance: clear oil. Mixtures of Boc-rotamers were observed by NMR spectroscopy; please see copies of 1H and 13C NMR spectra in Supporting Information. 1H NMR (400 MHz, CDCl3): δ 7.29–7.23 (m), 7.20–7.12 (m), 3.75–3.65 (m), 3.54–3.45 (m), 3.37 (dt, J = 10.9, 7.4 Hz), 3.32–3.22 (m), 2.74–2.54 (m), 2.25–1.98 (m), 1.94–1.72 (m), 1.69–1.50 (m,), 1.47 (s), 1.31 (s). 13C{1H} NMR (101 MHz, CDCl3): δ 180.9, 175.7, 156.7, 153.8, 142.0, 141.9, 128.4, 128.3, 128.3, 125.9, 125.8, 81.8, 80.3, 70.0, 67.3, 49.2, 48.5, 37.5, 36.0, 35.8, 35.2, 34.3, 33.9, 28.4, 28.2, 26.0, 25.3, 22.7, 22.7. IR (neat): ν/cm–1 3250–2600 (br), 2973 (m), 2932 (m), 2873 (w), 1738 (m), 1694 (s), 1453 (m), 1389 (s), 1366 (s), 1244 (m), 1162 (s), 1136 (s), 856 (m), 749 (m), 698 (s). HRMS (TOF-ESI+): calcd for C19H28NO4 334.2013; found, 334.2017 (M + H+).
Synthesis of Products 9a–g
For a reaction on a 2 mmol scale, a solution containing substrate acid 4 (1 M, toluene, 2 mmol, 1.0 equiv) and NEt3 (2 mml, 1.0 equiv) was prepared and pumped using a Vaportec E-series flow reactor at a flow rate of 0.25 mL/min. A second solution containing DPPA (0.95 M, toluene, 1.9 mmol, 0.95 equiv) was pumped at the same flow rate and mixed with the substrate solution via a T-piece (1/16 in. id). The combined mixture was then directed into a heated coil reactor (10 mL volume, PFA tubing, 1/16 in. id) held at 100 °C resulting in a residence time of 20 min. Upon exiting this reactor coil, the mixture passed through a BPR (100 psi, Kinesis) before entering an Omnifit glass column containing A-15 and A-21 scavenger resins (mixed bed, ca. 2 equiv each) at an ambient temperature. The crude mixture was collected in a flask and evaporated under reduced pressure. Purification was performed via silica gel chromatography using EtOAc/cyclohexane (10–20% EtOAc) as an eluent system.
A scaled version of this procedure was used starting from acid 4a (1.55 g, 6.78 mmol) to prepare compound 9a (1.20 g, 5.97 mmol, 88%).
tert-Butyl (4-Oxopentyl)carbamate (9a). (11)
Yield: 1.20 g (5.97 mmol, 88%). Appearance: colorless oil. 1H NMR (400 MHz, CDCl3): δ/ppm 4.61 (br s, 1H), 3.08 (q, J = 6.6 Hz, 2H), 2.45 (t, J = 7.1 Hz, 2H), 2.11 (s, 3H), 1.72 (p, J = 7.0 Hz, 2H), 1.40 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ/ppm 208.4 (C), 156.0 (C), 79.1 (C), 40.7 (CH2), 39.9 (CH2), 29.9 (CH3), 28.4 (3CH3), 24.2 (CH2). IR (neat): ν/cm–1 3365 (br, m), 2976 (m), 2932 (m), 1688 (s), 1517 (m), 1449 (w), 1391 (m), 1365 (s), 1249 (s), 1162 (s). HRMS (TOF-ESI+): calcd for C10H19NO3Na, 224.1257; found, 224.1259 (M + Na+).
tert-Butyl (4-Oxohexyl)carbamate (9b)
Yield: 289 mg (1.3 mmol, 84%). Appearance: colorless oil. 1H NMR (500 MHz, CDCl3): δ/ppm 4.60 (s, 1H), 3.12 (q, J = 6.6 Hz, 2H), 2.47–2.41 (m, 4H), 1.77 (p, J = 7.0 Hz, 2H), 1.44 (s, 9H), 1.06 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 211.2 (C), 156.0 (C), 79.2 (C), 40.1 (CH2), 39.4 (CH2), 36.0 (CH2), 28.4 (3CH3), 24.1 (CH2), 7.8 (CH3). IR (neat): ν/cm–1 3362 (br), 2976 (m), 2936 (m), 1689 (s), 1517 (m), 1454 (m), 1365 (m), 1248 (s), 1165 (s), 1042 (m), 1023 (m), 980 (m), 875 (m), 780 (m). HRMS (TOF-ESI+): calcd for C11H21NO3Na 238.1414; found, 238.1415 (M + Na+).
tert-Butyl (E)-2-Benzylidenepyrrolidine-1-carboxylate (9c). (17a)
Yield: 380 mg (1.47 mmol, 88%). Appearance: white solid. Melting range: 78–81 °C. 1H NMR (500 MHz, CDCl3): δ/ppm 7.32–7.28 (m, 2H), 7.26–7.23 (m, 2H), 7.15–7.11 (m, 2H), 3.66 (t, J = 7.0 Hz, 2H), 2.82 (td, J = 7.4, 2.0 Hz, 2H), 1.86 (p, J = 7.2 Hz, 2H), 1.56 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 152.9 (C), 140.9 (C), 139.0 (C), 128.2 (2CH), 128.0 (2CH), 125.0 (CH), 108.3 (CH), 80.6 (C), 48.9 (CH2), 30.6 (CH2), 28.5 (3CH3), 22.1 (CH2). IR (neat): ν/cm–1 2975 (w), 2883 (w), 1702 (s), 1639 m), 1383 (s), 1323 (s), 1243 (m), 1159 (s), 1136 (s), 1076 (m), 1003 (m), 856 (m), 748 (m), 694 (s). HRMS (TOF-ESI+): calcd for C16H22NO2, 260.1645; found, 260.1647 (M + H+).
tert-Butyl (E)-2-(4-Fluorobenzylidene)pyrrolidine-1-carboxylate (9d)
Yield: 223 mg (0.81 mmol, 81%). Appearance: white solid. Melting range: 65–68 °C. 1H NMR (400 MHz, CDCl3): δ/ppm 7.14 (dd, J = 8.7, 5.6 Hz, 2H), 7.06 (br s, 1H), 6.94 (t, J = 8.8 Hz, 2H), 3.62 (t, J = 7.0 Hz, 2H), 2.72 (td, J = 7.4, 2.0 Hz, 2H), 1.82 (p, J = 7.2 Hz, 2H), 1.51 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ/ppm 160.6 (CF, d, J = 243 Hz), 152.8 (C), 140.7 (C), 134.9 (C, d, J = 4 Hz), 129.4 (2CH, d, J = 8 Hz), 114.8 (2CH, d, J = 21 Hz), 107.2 (CH), 80.6 (C), 48.8 (CH2), 30.4 (CH2), 28.4 (3CH3), 22.0 (CH2). 19F-NMR (376 MHz, CDCl3): δ/ppm δ −118 (s). IR (neat): ν/cm–1 2977 (m), 2934 (w), 1703 (s), 1645 (m), 1507 (s), 1386 (s), 1329 (s), 1228 (m), 1158 (m), 1140 (s), 1002 (m), 860 (m), 768 (m). HRMS (TOF-ESI+): calcd for C16H20NFO2, 278.1551; found, 278.1552 (M + H+).
tert-Butyl (E)-2-(4-(Trifluoromethyl)benzylidene)pyrrolidine-1-carboxylate (9e)
Yield: 457 mg (1.40 mmol, 85%). Appearance: white solid. Melting range: 86–88 °C. 1H NMR (500 MHz, CDCl3): δ/ppm δ 7.51 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 7.16 (br s, 1H), 3.66 (t, J = 6.9 Hz, 2H), 2.81 (td, J = 7.3, 2.0 Hz, 2H), 1.87 (p, J = 7.2 Hz, 2H), 1.54 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 152.7 (C), 143.0 (C), 142.8 (C), 128.0 (2CH), 126.6 (C, q, J = 32.3 Hz), 124.9 (2CH, q, J = 3.9 Hz), 124.5 (CF3, q, J = 270 Hz), 107.0 (CH), 81.0 (C), 49.0 (CH2), 30.7 (CH2), 28.3 (3CH3), 22.0 (CH2). 19F-NMR (282 MHz, CDCl3): δ/ppm δ −62.2 (s). IR (neat): ν/cm–1 2978 (w), 2889 (w), 1706 (m), 1637 (m), 1610 (m), 1386 (m), 1314 (s), 1244 (m), 1159 (s), 1140 (s), 1107 (s), 1066 (s), 1002 (m), 859 (s). HRMS (TOF-ESI+): calcd for C17H20F3NO2Na, 350.1338; found, 350.1338 (M + Na+). Crystal data: CCDC 2083011: C17H20F3NO2; monoclinic, a = 15.3119(2) Å, b = 10.2080(2) Å, c = 21.3592(3) Å, α = 90°, β = 92.8390(10)°, γ = 90°; Z = 8; space group P21/c; T = 100 K; R1 = 0.0872.
tert-Butyl (4-Oxo-7-phenylheptyl)carbamate (9g)
Yield: 238 mg (0.79 mmol, 79%). Appearance: clear oil. 1H NMR (500 MHz, CDCl3): δ/ppm 7.28 (t, J = 7.7 Hz, 2H), 7.22–7.14 (m, 3H), 4.58 (s, 1H), 3.10 (q, J = 6.7 Hz, 2H), 2.61 (t, J = 7.6 Hz, 2H), 2.41 (m, 4H), 1.90 (p, J = 7.4 Hz, 2H), 1.73 (p, J = 7.0 Hz, 2H), 1.43 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 210.3 (C), 156.0 (C), 141.5 (C), 128.5 (2CH), 128.4 (2CH), 125.9 (CH), 79.2 (C), 42.0 (CH2), 40.0 (CH2), 39.9 (CH2), 35.1 (CH2), 28.4 (3CH3), 25.2 (CH2), 24.0 (CH2). IR (neat): ν/cm–1 3368 (br, m), 2975 (m), 2931 (m), 1701 (s), 1513 (m), 1453 (m), 1391 (m), 1365 (m), 1248 (m), 1165 (s), 748 (m), 700 (s). HRMS (TOF-ESI+): calcd for C18H27NO3Na, 328.1883; found, 328.1886 (M + Na+).
Supporting Information
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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.1c01133.
Copies of 1H and 13C NMR spectra (PDF)
CCDC 2083011 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Author Information
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- Marcus Baumann - School of Chemistry, University College Dublin, Science Centre South, Belfield D04 N2E2, Ireland;
https://orcid.org/0000-0002-6996-5893;
- Thomas S. Moody - Department of Technology, Almac Sciences, 20 Seagoe Industrial Estate, Craigavon BT63 5QD, United Kingdom; Arran Chemical Company, Roscommon N37 DN24, Ireland;https://orcid.org/0000-0002-8266-0269
- Megan Smyth - Department of Technology, Almac Sciences, 20 Seagoe Industrial Estate, Craigavon BT63 5QD, United Kingdom;https://orcid.org/0000-0002-2771-0382
Acknowledgments
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We gratefully acknowledge support from Science Foundation Ireland through the SFI Industry Fellowship Program for the project entitled “Development of Continuous Biocatalysed Processes, Continuous Biocatalysed Chemicals (CATCH)” (19/IFA/7420 to M.B.) as well as the Infrastructure Call 2018 (18/RI/5702) and the European Regional Development Fund (12/RC2275_P2). We thank Conor Kelly and Helge Müller-Bunz (both UCD, School of Chemistry) for solving the X-ray structure reported herein.
References
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This article references 21 other publications.
- 1(a) Curtius, T. Ueber Stickstoffwasserstoffsäure (Azoimid) N3H. Ber. Dtsch. Chem. Ges. 1890, 23, 3023– 3033, DOI: 10.1002/cber.189002302232Google ScholarThere is no corresponding record for this reference.(b) Curtius, T. 20. Hydrazide und Azide organischer Säuren. J. Prakt. Chem. 1894, 50, 275– 294, DOI: 10.1002/prac.18940500125Google Scholar1bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaD28XosFCntQ%253D%253D&md5=6f94ff08c62ee2934f60c7db68874ecaHydrazides and azides of organic acidsCurtius, T.Journal fuer Praktische Chemie (Leipzig) (1894), 50 (2), 275-94CODEN: JPCEAO ISSN:.The author applies the term acid hydrazides to substances of the formula R.CO.NH.NH2, while the derivatives of azoimide are designated by the term acid azides and have the formula R.CO.N3. An account of the experimental researches, of the results of which, the foregoing is a general statement, will be shortly published.
- 2
For selected reports on complementary approaches, please see:
(a) Thomas, M.; Alsarraf, J.; Araji, N.; Tranoy-Opalinski, I.; Renoux, B.; Papot, S. The Lossen rearrangement from free hydroxamic acids. Org. Biomol. Chem. 2019, 17, 5420– 5427, DOI: 10.1039/C9OB00789JGoogle Scholar2ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXptFKht78%253D&md5=82fe98dc11251705e60bea6a39d84a22The Lossen rearrangement from free hydroxamic acidsThomas, Mikael; Alsarraf, Jerome; Araji, Nahla; Tranoy-Opalinski, Isabelle; Renoux, Brigitte; Papot, SebastienOrganic & Biomolecular Chemistry (2019), 17 (22), 5420-5427CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)A review. The Lossen rearrangement, that allows the conversion of hydroxamic acids into isocyanates, was discovered almost 150 years ago. For more than a century, this transformation was supposed to occur exclusively in the presence of stoichiometric amts. of activating reagents devoted to promoting the dehydration of primary hydroxamic acids. Very recently, it was demonstrated that the Lossen rearrangement can take place directly from free hydroxamic acids offering a renewal of interest for such a reaction. This short review summarizes advances in this field by describing successively the metal-assisted, the self-propagative and the promoted self-propagative Lossen rearrangement with a special emphasis on their mechanisms.(b) Wallis, E. S.; Lane, J. F. The Hofmann Reaction. Organic Reactions 2011, 267, DOI: 10.1002/0471264180.or003.07Google ScholarThere is no corresponding record for this reference.(c) Zagulyaeva, A. A.; Banek, C. T.; Yusubov, M. S.; Zhdankin, V. V. Hofmann Rearrangement of Carboxamides Mediated by Hypervalent Iodine Species Generated in Situ from Iodobenzene and Oxone: Reaction Scope and Limitations. Org. Lett. 2010, 12, 4644– 4647, DOI: 10.1021/ol101993qGoogle Scholar2chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFKmtLrN&md5=ec8a03d9b4bd8d8cdd4f74288536a5b9Hofmann Rearrangement of Carboxamides Mediated by Hypervalent Iodine Species Generated in Situ from Iodobenzene and Oxone: Reaction Scope and LimitationsZagulyaeva, Aleksandra A.; Banek, Christopher T.; Yusubov, Mekhman S.; Zhdankin, Viktor V.Organic Letters (2010), 12 (20), 4644-4647CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)Alkylcarboxamides can be converted to the resp. amines by Hofmann rearrangement using hypervalent iodine species generated in situ from PhI and Oxone in aq. acetonitrile. E.g., using hypervalent iodine species generated in situ from PhI and Oxone in aq. acetonitrile, Hofmann rearrangement of PhCH2CONH2 gave 95% PHCH2NH2 (as the HCl salt). On the basis of this reaction, a convenient exptl. procedure for the prepn. of alkylcarbamates using Oxone as the oxidant in the presence of iodobenzene in methanol has been developed. An efficient method for direct conversion of substituted benzamides to the resp. quinone derivs. by treatment with Oxone and iodobenzene in aq. acetonitrile has also been found. E.g., oxidn. of PhCONH2 gave 98% 1,4-benzoquinone.(d) Huang, X.; Seid, M.; Keillor, J. W. A Mild and Efficient Modified Hofmann Rearrangement. J. Org. Chem. 1997, 62, 7495– 7496, DOI: 10.1021/jo9708553Google Scholar2dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmvVamsbo%253D&md5=ace6c263e23fc08a1d814271340900c4A Mild and Efficient Modified Hofmann RearrangementHuang, Xicai; Seid, Mehran; Keillor, Jeffrey W.Journal of Organic Chemistry (1997), 62 (21), 7495-7496CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Amides RCONH2 [R = 4-MeOC6H4, 3,4-(MeO)2C6H3, 4-MeC6H4, Ph, 4-ClC6H4, 4-O2NC6H4, PhCH2, nonyl, pentadecyl, 2,4-(MeO)2C6H3, 4-Me2NC6H4] underwent Hofmann rearrangement on treatment with NBS and DBU in MeOH to give RNHCO2Me in good yields.(e) Wolff, H. The Schmidt Reaction. Organic Reactions 2011, 307– 336, DOI: 10.1002/0471264180.or003.08Google ScholarThere is no corresponding record for this reference.(f) Lang, S.; Murphy, J. A. Azide rearrangements in electron-deficient systems. Chem. Soc. Rev. 2006, 35, 146– 156, DOI: 10.1039/B505080DGoogle Scholar2fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xot1ajtg%253D%253D&md5=54a2aeae02e9d7ef0f8183bc997505c2Azide rearrangements in electron-deficient systemsLang, S.; Murphy, J. A.Chemical Society Reviews (2006), 35 (2), 146-156CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review discusses the rearrangement reactions of org. azides, particularly Schmidt reactions of azides with carboxylic acids, ketones, and ketals and their derivs. to provide lactams and nitrogen heterocycles. - 3(a) Wentrup, C.; Bornemann, H. The Curtius Rearrangement of Acyl Azides Revisited - Formation of Cyanate (R-O-CN). Eur. J. Org. Chem. 2005, 2005, 4521– 4524, DOI: 10.1002/ejoc.200500545Google ScholarThere is no corresponding record for this reference.(b) Eibler, E.; Sauer, J. Ein Beitrag zur Isocyanatbildung bei der Photolyse von Acylaziden. Tetrahedron Lett. 1974, 15, 2569– 2572, DOI: 10.1016/S0040-4039(01)92295-6Google ScholarThere is no corresponding record for this reference.
- 4(a) Ghosh, A. K.; Brindisi, M.; Sarkar, A. The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry. ChemMedChem 2018, 13, 2351– 2373, DOI: 10.1002/cmdc.201800518Google Scholar4ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVygs7zM&md5=da82f908635028b26540cbe25080ee63The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal ChemistryGhosh, Arun K.; Brindisi, Margherita; Sarkar, AnindyaChemMedChem (2018), 13 (22), 2351-2373CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)The Curtius rearrangement is the thermal decompn. of an acyl azide derived from carboxylic acid to produce an isocyanate as the initial product. The isocyanate can undergo further reactions to provide amines and their derivs. Due to its tolerance for a large variety of functional groups and complete retention of stereochem. during rearrangement, the Curtius rearrangement has been used in the synthesis of a wide variety of medicinal agents with amines and amine-derived functional groups such as ureas and urethanes. The current review outlines various applications of the Curtius rearrangement in drug discovery and medicinal chem. In particular, the review highlights some widely used rearrangement methods, syntheses of some key agents for popular drug targets and FDA-approved drugs. In addn., the review highlights applications of the Curtius rearrangement in continuous-flow protocols for the scale-up of active pharmaceutical ingredients.(b) Ghosh, A. K.; Sarkar, A.; Brindisi, M. The Curtius rearrangement: mechanistic insight and recent applications in natural product syntheses. Org. Biomol. Chem. 2018, 16, 2006– 2027, DOI: 10.1039/C8OB00138CGoogle Scholar4bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjtlKguro%253D&md5=242915726420c02b495c466675f713dcThe Curtius rearrangement: mechanistic insight and recent applications in natural product synthesesGhosh, Arun K.; Sarkar, Anindya; Brindisi, MargheritaOrganic & Biomolecular Chemistry (2018), 16 (12), 2006-2027CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)A review. The Curtius rearrangement is a versatile reaction in which a carboxylic acid can be converted to an isocyanate through an acyl azide intermediate under mild conditions. The resulting stable isocyanate can then be readily transformed into a variety of amines and amine derivs. including urethanes and ureas. There have been wide-ranging applications of the Curtius rearrangement in the synthesis of natural products and their derivs. Also, this reaction has been extensively utilized in the synthesis and application of a variety of biomols. In this review, we present mechanistic studies, chem. methodologies and reagents for the synthesis of isocyanates from carboxylic acids, the conversion of isocyanates to amines and amine derivs., and their applications in the synthesis of bioactive natural products and their congeners.
- 5(a) Guidi, M.; Seeberger, P. H.; Gilmore, K. How to approach flow chemistry. Chem. Soc. Rev. 2020, 49, 8910– 8932, DOI: 10.1039/C9CS00832BGoogle Scholar5ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit1Ciu7bP&md5=b6f511c0d703decef620fcec7e74901bHow to approach flow chemistryGuidi, Mara; Seeberger, Peter H.; Gilmore, KerryChemical Society Reviews (2020), 49 (24), 8910-8932CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. Flow chem. is a widely explored technol. whose intrinsic features both facilitate and provide reproducible access to a broad range of chem. processes that are otherwise inefficient or problematic. At its core, a flow chem. module is a stable set of conditions - traditionally thought of as an externally applied means of activation/control (e.g. heat or light) - through which reagents are passed. In an attempt to simplify the teaching and dissemination of this field, we envisioned that the key advantages of the technique, such as reproducibility and the correlation between reaction time and position within the reactor, allow for the redefinition of a flow module to a more synthetically relevant one based on the overall induced effect. We suggest a rethinking of the approach to flow modules, distributing them in two subclasses: transformers and generators, which can be described resp. as a set of conditions for either performing a specific transformation or for generating a reactive intermediate. The chem. achieved by transformers and generators is (ideally) independent of the substrate introduced, meaning that they must be robust to small adjustments necessary for the adaptation to different starting materials and reagents while ensuring the same chem. outcome. These redefined modules can be used for single-step reactions or in multistep processes, where modules can be connected to each other in reconfigurable combinations to create chem. assembly systems (CAS) targeting compds. and libraries sharing structural cores. With this tutorial review, we provide a guide to the overall approach to flow chem., discussing the key parameters for the design of transformers and generators as well as the development of chem. assembly systems.(b) Baumann, M.; Moody, T. S.; Smyth, M.; Wharry, S. A Perspective on Continuous Flow Chemistry in the Pharmaceutical Industry. Org. Process Res. Dev. 2020, 24, 1802– 1813, DOI: 10.1021/acs.oprd.9b00524Google Scholar5bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmtVGrtw%253D%253D&md5=01603875a35243e7974384146b6c35ccA Perspective on Continuous Flow Chemistry in the Pharmaceutical IndustryBaumann, Marcus; Moody, Thomas S.; Smyth, Megan; Wharry, ScottOrganic Process Research & Development (2020), 24 (10), 1802-1813CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A review. Continuous flow manuf. is an innovative technol. platform, which is gaining momentum within the pharmaceutical industry. The key advantages of continuous flow include faster and safer reactions, which can be more environmentally friendly, smaller footprint, better quality product, and critically, the ability to perform chem. that is difficult or impossible to do in batch mode. Globally, significant efforts have been made to develop the manufg. flexibility and robustness of processes used to produce chems. in a continuous way, yet despite these scientific developments, a major challenge for industry is the established application of flow technol. to com. relevant examples. The identification of opportunities to apply flow solns. to current processes is also crit. to the success of this new technol. for pharmaceutical and fine chem. companies. This review highlights industrial hurdles and the importance of education and showcases recent (2018-2019) and relevant industrial examples where utilization of flow technol. has been successfully performed.(c) Hartman, R. L. Flow chemistry remains an opportunity for chemists and chemical engineers. Curr. Opin. Chem. Eng. 2020, 29, 42– 50, DOI: 10.1016/j.coche.2020.05.002Google ScholarThere is no corresponding record for this reference.(d) Gutmann, B.; Kappe, C. O. Forbidden Chemistries - Paths to a Sustainable Future Engaging Continuous Processing. J. Flow Chem. 2017, 7, 65– 71, DOI: 10.1556/1846.2017.00009Google Scholar5dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXntFygu7s%253D&md5=7201d1e45af8d37f35141317fd3b5e72Forbidden chemistries - paths to a sustainable future engaging continuous processingGutmann, Bernhard; Kappe, C. OliverJournal of Flow Chemistry (2017), 7 (3-4), 65-71CODEN: JFCOBJ; ISSN:2062-249X. (Akademiai Kiado)Optimizing current chem. processes alone does not yield the improvements required in the fine chem. and pharmaceutical industries. At least partially, a switch from batch to continuous manufg. is needed. Cost-, time-, and atom-efficient routes frequently demand the application of high temps., pressures, and concns., and/or the use of highly reactive reagents. These chemistries often cannot be employed in conventional reactors. Costly and long alternative synthetic routes are chosen instead. The application of continuous-flow microreactors allows to access "harsh" or "hazardous" reaction conditions and, furthermore, enables entirely new transformations.(e) Gutmann, B.; Cantillo, D.; Kappe, C. O. Continuous-Flow Technology - A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients. Angew. Chem., Int. Ed. 2015, 54, 6688– 6729, DOI: 10.1002/anie.201409318Google Scholar5ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXosVGnt7k%253D&md5=49251387f0f3378dff4e710afe9fbca8Continuous-Flow Technology-A Tool for the Safe Manufacturing of Active Pharmaceutical IngredientsGutmann, Bernhard; Cantillo, David; Kappe, C. OliverAngewandte Chemie, International Edition (2015), 54 (23), 6688-6728CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. In the past few years, continuous-flow reactors with channel dimensions in the micro- or millimeter region have found widespread application in org. synthesis. The characteristic properties of these reactors are their exceptionally fast heat and mass transfer. In microstructured devices of this type, virtually instantaneous mixing can be achieved for all but the fastest reactions. Similarly, the accumulation of heat, formation of hot spots, and dangers of thermal runaways can be prevented. As a result of the small reactor vols., the overall safety of the process is significantly improved, even when harsh reaction conditions are used. Thus, microreactor technol. offers a unique way to perform ultrafast, exothermic reactions, and allows the execution of reactions which proceed via highly unstable or even explosive intermediates. This Review discusses recent literature examples of continuous-flow org. synthesis where hazardous reactions or extreme process windows have been employed, with a focus on applications of relevance to the prepn. of pharmaceuticals.(f) Jensen, K. F. Flow chemistry - Microreaction technology comes of age. AIChE J. 2017, 63, 858– 869, DOI: 10.1002/aic.15642Google Scholar5fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFGmsbY%253D&md5=fcf4074821a2b517418e32c370bb99c6Flow chemistry-Microreaction technology comes of ageJensen, Klavs F.AIChE Journal (2017), 63 (3), 858-869CODEN: AICEAC; ISSN:0001-1541. (John Wiley & Sons, Inc.)Over the past two decades, microreaction technol. has matured from early devices and concepts to encompass a wide range of com. equipment and applications. This evolution has been aided by the confluence of microreactor development and adoption of continuous flow technol. in org. chem. This Perspective summarizes the current state-of-the art with focus on enabling technologies for reaction and sepn. equipment. Automation and optimization are highlighted as promising applications of microreactor technol. The move towards continuous processing in pharmaceutical manufg. underscores increasing industrial interest in the technol. As an example, end-to-end fabrication of pharmaceuticals in a compact reconfigurable system illustrates the development of on-demand manufg. units based on microreactors. The final section provides an outlook for the technol., including implementation challenges and integration with computational tools. AIChE J, 2017.(g) Ley, S. V.; Chen, Y.; Robinson, A.; Otter, B.; Godineau, E.; Battilocchio, C. A Comment on Continuous Flow Technologies within the Agrochemical Industry. Org. Process Res. Dev. 2021, 25, 713– 720, DOI: 10.1021/acs.oprd.0c00534Google Scholar5ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXlvVejtrs%253D&md5=b6e0a7e1146e341c1ef0226a9473c161A Comment on Continuous Flow Technologies within the Agrochemical IndustryLey, Steven V.; Chen, Yiding; Robinson, Alan; Otter, Benjamin; Godineau, Edouard; Battilocchio, ClaudioOrganic Process Research & Development (2021), 25 (4), 713-720CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A review. The agrochem. sector operates on a large scale within a highly complex environment. Cost-effective prodn. on an increasing scale in a sustainable fashion imposes massive constraints on the industry. Here we offer a perspective on flow chem., with literature highlights showing how the application of this technol. can impact chem. processes (esp. at the early stages of R&D) for agrochems., with clear benefits in comparison with a traditional batch vessel, be it safety, quality, or throughput. The value of flow chem. for the business is clear, and the no. of examples reported in the literature will undoubtably continue to increase in the agrochem. industry.(h) Britton, J.; Raston, C. L. Multi-step continuous-flow synthesis. Chem. Soc. Rev. 2017, 46, 1250– 1271, DOI: 10.1039/C6CS00830EGoogle Scholar5hhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1yjtr0%253D&md5=abcfc0e54556e7cd18445305ec6994fdMulti-step continuous-flow synthesisBritton, Joshua; Raston, Colin L.Chemical Society Reviews (2017), 46 (5), 1250-1271CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. This review article focused on multi-step continuous-flow methodol., which had applications in synthesis of active pharmaceutical ingredients, natural products, and commodity chems. This review described the advancements while highlighted the rapid progress, benefits, and diversification of this expanding field.
- 6(a) Sahoo, H. R.; Kralj, J. G.; Jensen, K. F. Multistep Continuous-Flow Microchemical Synthesis Involving Multiple Reactions and Separations. Angew. Chem., Int. Ed. 2007, 46, 5704– 5708, DOI: 10.1002/anie.200701434Google Scholar6ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXosFOktL4%253D&md5=79030b1d9633d3d520aeed7dcc0b99d4Multistep continuous-flow microchemical synthesis involving multiple reactions and separationsSahoo, Hemantkumar R.; Kralji, Jason G.; Jensen, Klavs F.Angewandte Chemie, International Edition (2007), 46 (30), 5704-5708CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)All for one and one for all: A continuous-flow, multistep microchem. synthesis of carbamates starting from aq. azide and benzoyl chloride by using the Curtius rearrangement reaction is described. The procedure involves three reaction steps and two sepn. steps (one gas-liq. and one liq.-liq.). Formation of a microreactor network for parallel synthesis of analogous compds. is also demonstrated.(b) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.; Smith, C. D. Azide monoliths as convenient flow reactors for efficient Curtius rearrangement reactions. Org. Biomol. Chem. 2008, 6, 1587– 1593, DOI: 10.1039/b801634hGoogle Scholar6bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXkvFCqt7w%253D&md5=ffa199ac6f143c3eafa8297f6f520c52Azide monoliths as convenient flow reactors for efficient Curtius rearrangement reactionsBaumann, Marcus; Baxendale, Ian R.; Ley, Steven V.; Nikbin, Nikzad; Smith, Christopher D.Organic & Biomolecular Chemistry (2008), 6 (9), 1587-1593CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)The prepn. and use of an azide-contg. monolithic reactor is described for use in a flow chem. device and in particular for conducting Curtius rearrangement reactions via acid chloride inputs.(c) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.; Smith, C. D.; Tierney, J. P. A modular flow reactor for performing Curtius rearrangements as a continuous flow process. Org. Biomol. Chem. 2008, 6, 1577– 1586, DOI: 10.1039/b801631nGoogle Scholar6chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXkvFCqt74%253D&md5=1ead8804556a33d9ee2ed0c25628cef1A modular flow reactor for performing Curtius rearrangements as a continuous flow processBaumann, Marcus; Baxendale, Ian R.; Ley, Steven V.; Nikbin, Nikzad; Smith, Christopher D.; Tierney, Jason P.Organic & Biomolecular Chemistry (2008), 6 (9), 1577-1586CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)The use of a mesofluidic flow reactor is described for performing Curtius rearrangement reactions of carboxylic acids in the presence of diphenylphosphoryl azide and trapping of the intermediate isocyanates with various nucleophiles.(d) Phung Hai, T. A.; De Backer, L. J. S.; Cosford, N. D. P.; Burkart, M. D. Preparation of Mono- and Diisocyanates in Flow from Renewable Carboxylic Acids. Org. Process Res. Dev. 2020, 24, 2342– 2346, DOI: 10.1021/acs.oprd.0c00167Google Scholar6dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtVCntLrJ&md5=07862b8898e9d44cfc1c257befea10f6Preparation of Mono- and Diisocyanates in Flow from Renewable Carboxylic AcidsPhung Hai, Thien An; De Backer, Laurent J. S.; Cosford, Nicholas D. P.; Burkart, Michael D.Organic Process Research & Development (2020), 24 (10), 2342-2346CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Diisocyanates used in polyurethanes are commonly prepd. by phosgenation of petroleum-sourced diamines. This involves highly toxic phosgene and produces corrosive HCl, limiting synthetic applications. In our search for a renewable source for diisocyanates, we have developed a practical methodol. for the prodn. of isocyanates from algae-biomass-derived fatty acids or other renewable sources. This technique utilizes flow chem. to prep. and convert high-energy intermediates, thus mitigating safety concerns. By the use of continuous flow, acyl azides are prepd. from hydrazides and subsequently heated to undergo Curtius rearrangement, affording isocyanates in one scalable process. The method is efficient, safe, and sustainable, offers an opportunity to prep. isocyanates and diisocyanates from renewable feedstocks, and is amenable to distributed manufg. processes.
- 7(a) Huard, K.; Bagley, S. W.; Menhaji-Klotz, E.; Preville, C.; Southers, J. A., Jr; Smith, A. C.; Edmonds, D. J.; Lucas, J. C.; Dunn, M. F.; Allanson, N. M.; Blaney, E. L.; Garcia-Irizarry, C. N.; Kohrt, J. T.; Griffith, D. A.; Dow, R. L. Synthesis of spiropiperidine lactam acetyl-CoA carboxylase inhibitors. J. Org. Chem. 2012, 77, 10050– 10057, DOI: 10.1021/jo3014808Google Scholar7ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1Wqs73M&md5=33bd1e75961503acf0c7734592b1da39Synthesis of Spiropiperidine Lactam Acetyl-CoA Carboxylase InhibitorsHuard, Kim; Bagley, Scott W.; Menhaji-Klotz, Elnaz; Preville, Cathy; Southers, James A.; Smith, Aaron C.; Edmonds, David J.; Lucas, John C.; Dunn, Matthew F.; Allanson, Nigel M.; Blaney, Emma L.; Garcia-Irizarry, Carmen N.; Kohrt, Jeffrey T.; Griffith, David A.; Dow, Robert L.Journal of Organic Chemistry (2012), 77 (22), 10050-10057CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Spiro(piperidine)pyrazolopyridinones I (R = 1H-indazole-5-carbonyl) and II were prepd. as acetyl-CoA carboxylase inhibitors for potential use as antidiabetic agents for type II diabetes mellitus using regioselective alkylation, Curtius rearrangement, and Parham-type cyclizations as key steps. Attempts to form the spiro(piperidine)pyrazolopyridinone core by cyclization of an unsatd. piperidinemethylpyrazolecarboxamide, by addn. of an iodopyrazolecarboxamide to a spiroaziridinepiperidine, or by reaction of a carboxylpyrazoleacetic acid anhydride with a piperidinone imine were unsuccessful (no data). Et 3-amino-4-pyrazolecarboxylate was converted in five steps to (iodomethyl)pyrazole III using a regioselective pyrazole tert-butylation; alkylation of Et 1-Boc-4-piperidinecarboxylate with III using LiHMDS at 0° followed by ester hydrolysis yielded IV (R = HO2C). Curtius rearrangement of IV (R1 = HO2C) either in soln. with product isolation or using a flow reactor yielded IV (R1 = NCO); lithium-halogen exchange of IV (R1 = NCO) with sec-butyllithium or tert-butyllithium and intramol. cyclocondensation (a Parham-type cyclization) yielded I (R = Boc), which was deprotected and acylated to yield I (R = 1H-indazole-5-carbonyl). An analogous route provided efficient access to II.(b) Guetzoyan, L.; Ingham, R. J.; Nikbin, N.; Rossignol, J.; Wolling, M.; Baumert, M.; Burgess-Brown, N. A.; Strain-Damerell, C. M.; Shrestha, L.; Brennan, P. E.; Fedorov, O.; Knapp, S.; Ley, S. V. Machine-assisted synthesis of modulators of the histone reader BRD9 using flow methods of chemistry and frontal affinity chromatography. MedChemComm 2014, 5, 540– 546, DOI: 10.1039/C4MD00007BGoogle Scholar7bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXkvF2isbY%253D&md5=68282087a31282867a31cabf4a0fd30bMachine-assisted synthesis of modulators of the histone reader BRD9 using flow methods of chemistry and frontal affinity chromatographyGuetzoyan, Lucie; Ingham, Richard J.; Nikbin, Nikzad; Rossignol, Julien; Wolling, Michael; Baumert, Mark; Burgess-Brown, Nicola A.; Strain-Damerell, Claire M.; Shrestha, Leela; Brennan, Paul E.; Fedorov, Oleg; Knapp, Stefan; Ley, Steven V.MedChemComm (2014), 5 (4), 540-546CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)A combination of conventional org. synthesis, remotely monitored flow synthesis and bioassay platforms, were used for the evaluation of novel inhibitors targeting bromodomains outside the well-studied bromodomain and extra terminal (BET) family, here exemplified by activity measurements on the bromodomain of BRD9 protein, a component of some tissue-specific SWi/SNF chromatin remodelling complexes. The Frontal Affinity Chromatog. combined with Mass Spectrometry (FAC-MS) method proved to be reliable and results correlated well with an independent thermal shift assay.(c) Filipponi, P.; Ostacolo, C.; Novellino, E.; Pellicciari, R.; Gioiello, A. Continuous Flow Synthesis of Thieno[2,3-c]isoquinolin-5(4H)-one Scaffold: A Valuable Source of PARP-1 Inhibitors. Org. Process Res. Dev. 2014, 18, 1345– 1353, DOI: 10.1021/op500074hGoogle Scholar7chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXotFOiu7w%253D&md5=db285a9ce8324f97e0cefce0b6d6ba52Continuous Flow Synthesis of Thieno[2,3-c]isoquinolin-5(4H)-one Scaffold: A Valuable Source of PARP-1 InhibitorsFilipponi, Paolo; Ostacolo, Carmine; Novellino, Ettore; Pellicciari, Roberto; Gioiello, AntimoOrganic Process Research & Development (2014), 18 (11), 1345-1353CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)An efficient multistep method for the continuous flow synthesis of thieno[2,3-c]isoquinolin-5(4H)-one-A (TIQ-A), an important pharmacol. tool and building block for PARP-1 inhibitors, has been developed. The synthesis involves a Suzuki coupling reaction to generate 3-phenylthiophene-2-carboxylic acid which is transformed into the corresponding acyl azide and readily cyclized by a thermal Curtius rearrangement. A statistical design of expts. (DoE) was employed as a valuable support for decision-making of further expts. enabling the development of a robust and reliable protocol for large-scale prepn. As a result, the reactions are facile, safe, and easy to scale-up. The large-scale applicability of this improved flow method was tested by conducting the reactions on multigram scale to produce the desired product in high yield and quality for biopharmacol. appraisals.
- 8Marsini, M. A.; Buono, F. G.; Lorenz, J. C.; Yang, B.-S.; Reeves, J. T.; Sidhu, K.; Sarvestani, M.; Tan, Z.; Zhang, Y.; Li, N.; Lee, H.; Brazzillo, J.; Nummy, L. J.; Chung, J. C.; Luvaga, I. K.; Narayanan, B. A.; Wei, X.; Song, J. J.; Roschangar, F.; Yee, N. K.; Senanayake, C. H. Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement. Green Chem. 2017, 19, 1454– 1461, DOI: 10.1039/C6GC03123DGoogle Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFChtA%253D%253D&md5=b4b60207bf8d3fec6e9ad83a49b5178bDevelopment of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangementMarsini, Maurice A.; Buono, Frederic G.; Lorenz, Jon C.; Yang, Bing-Shiou; Reeves, Jonathan T.; Sidhu, Kanwar; Sarvestani, Max; Tan, Zhulin; Zhang, Yongda; Li, Ning; Lee, Heewon; Brazzillo, Jason; Nummy, Laurence J.; Chung, J. C.; Luvaga, Irungu K.; Narayanan, Bikshandarkoil A.; Wei, Xudong; Song, Jinhua J.; Roschangar, Frank; Yee, Nathan K.; Senanayake, Chris H.Green Chemistry (2017), 19 (6), 1454-1461CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)A convergent, robust, and concise synthesis of a developmental CCR1 antagonist, pyrazole deriv. I, is described using continuous flow technol. In the first approach, following an expeditious SNAr sequence for cyclopropane introduction, a safe, continuous flow Curtius rearrangement was developed for the synthesis of a p-methoxybenzyl (PMB) carbamate. Based on kinetic studies, a highly efficient and green process comprising three chem. transformations (azide formation, rearrangement, and isocyanate trapping) was developed with a relatively short residence time and high material throughput (0.8 kg h-1, complete E-factor = ∼9) and was successfully executed on 40 kg scale. Moreover, mechanistic studies enabled the execution of a semi-continuous, tandem Curtius rearrangement and acid-isocyanate coupling to directly afford the final drug candidate in a single, protecting group-free operation. The resulting API synthesis is further detd. to be extremely green (RPG = 166%) relative to the industrial av. for mols. of similar complexity.
- 9(a) Leslie, A.; Moody, T. S.; Smyth, M.; Wharry, S.; Baumann, M. Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives. Beilstein J. Org. Chem. 2021, 17, 379– 384, DOI: 10.3762/bjoc.17.33Google Scholar9ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXktlKgurs%253D&md5=7cdbc063408d5ca4614434a094ea6e8aCoupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivativesLeslie, Alexander; Moody, Thomas S.; Smyth, Megan; Wharry, Scott; Baumann, MarcusBeilstein Journal of Organic Chemistry (2021), 17 (), 379-384CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)A continuous flow process is presented that couples a Curtius rearrangement step with a biocatalytic impurity tagging strategy to produce a series of valuable Cbz-carbamate products. Immobilized CALB was exploited as a robust hydrolase to transform residual benzyl alc. into easily separable benzyl butyrate. The resulting telescoped flow process was effectively applied across a series of acid substrates rendering the desired carbamate structures in high yield and purity. The derivatization of these products via complementary flow-based Michael addn. reactions furthermore demonstrated the creation of β-amino acid species. This strategy thus highlights the applicability of this work towards the creation of important chem. building blocks for the pharmaceutical and speciality chem. industries.(b) Baumann, M.; Leslie, A.; Moody, T. S.; Smyth, M.; Wharry, S. Tandem Continuous Flow Curtius Rearrangement and Subsequent Enzyme-Mediated Impurity Tagging. Org. Process Res. Dev. 2021, 25, 452– 456, DOI: 10.1021/acs.oprd.0c00420Google Scholar9bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit1GitrnO&md5=ef77a9aa41e322ce90c478a13aa5a1ffTandem Continuous Flow Curtius Rearrangement and Subsequent Enzyme-Mediated Impurity TaggingBaumann, Marcus; Leslie, Alexander; Moody, Thomas S.; Smyth, Megan; Wharry, ScottOrganic Process Research & Development (2021), 25 (3), 452-456CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The use of continuous flow as an enabling technol. within the fine chem. and pharmaceutical industries continues to gain momentum. The assocd. safety benefits with flow for handling of hazardous or highly reactive intermediates are often exploited to offer industrially relevant and scalable Curtius rearrangements. However, in many cases the Curtius rearrangement requires excess nucleophile for the reaction to proceed to high conversions. This can complicate work procedures to deliver high-purity products. However, tandem processing and coupling of the Curtius rearrangement with an immobilized enzyme can elegantly facilitate chemoselective tagging of the residual reagent, resulting in a facile purifn. process under continuous flow.
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Substrate 4a was obtained from alkaline hydrolysis of methyl ester 11a, which was kindly provided by Almac Sciences.
There is no corresponding record for this reference. - 11Lima, F.; Sharma, U. K.; Grunenberg, L.; Saha, D.; Johannsen, S.; Sedelmeier, J.; Van der Eycken, E. V.; Ley, S. V. A Lewis Base Catalysis Approach for the Photoredox Activation of Boronic Acids and Esters. Angew. Chem., Int. Ed. 2017, 56, 15136– 15140, DOI: 10.1002/anie.201709690Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslSiu7%252FM&md5=85a5cb726eb152c3c9d919ab3e3d7800A Lewis Base Catalysis Approach for the Photoredox Activation of Boronic Acids and EstersLima, Fabio; Sharma, Upendra K.; Grunenberg, Lars; Saha, Debasmita; Johannsen, Sandra; Sedelmeier, Joerg; Van der Eycken, Erik V.; Ley, Steven V.Angewandte Chemie, International Edition (2017), 56 (47), 15136-15140CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)We report herein the use of a dual catalytic system comprising a Lewis base catalyst such as quinuclidin-3-ol or 4-dimethylaminopyridine and a photoredox catalyst to generate carbon radicals from either boronic acids or esters. This system enabled a wide range of alkyl boronic esters and aryl or alkyl boronic acids to react with electron-deficient olefins via radical addn. to efficiently form C-C coupled products in a redox-neutral fashion. The Lewis base catalyst was shown to form a redox-active complex with either the boronic esters or the trimeric form of the boronic acids (boroxines) in soln.
- 12(a) Wegner, J.; Ceylan, S.; Kirschning, A. Ten key issues in modern flow chemistry. Chem. Commun. 2011, 47, 4583– 4592, DOI: 10.1039/c0cc05060aGoogle Scholar12ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXktF2nsbk%253D&md5=8327ad1e610bb70d64556b6e7568a5d1Ten key issues in modern flow chemistryWegner, Jens; Ceylan, Sascha; Kirschning, AndreasChemical Communications (Cambridge, United Kingdom) (2011), 47 (16), 4583-4592CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review. Ten essentials of synthesis in the flow mode, a new enabling technol. in org. chem., are highlighted as flash-lighted providing an insight into current and future issues and developments in this field.(b) Baumann, M.; Moody, T. S.; Smyth, M.; Wharry, S. Overcoming the Hurdles and Challenges Associated with Developing Continuous Industrial Processes. Eur. J. Org. Chem. 2020, 2020, 7398– 7406, DOI: 10.1002/ejoc.202001278Google Scholar12bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitVymtrjK&md5=6f028f3c8a88bb0c829da8a83a626ae4Overcoming the Hurdles and Challenges Associated with Developing Continuous Industrial ProcessesBaumann, Marcus; Moody, Thomas S.; Smyth, Megan; Wharry, ScottEuropean Journal of Organic Chemistry (2020), 2020 (48), 7398-7406CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Continuous flow chem. is often viewed as a very simple concept on paper, however scientists with significant flow chem. experience will highlight a no. of challenges that need to be overcome. Crit. for the successful development of any flow process is a high level of understanding of potential pitfalls that may be encountered. A collaborative and multi-disciplinary team of chemists and chem. engineers is essential in the development of a process from lab scale through to prodn. This Minireview will identify and highlight relevant risks and their subsequent mitigation strategies to ensure successful flow processing.(c) Pieber, B.; Gilmore, K.; Seeberger, P. H. Integrated Flow Processing - Challenges in Continuous Multistep Synthesis. J. Flow Chem. 2017, 7, 129– 136, DOI: 10.1556/1846.2017.00016Google Scholar12chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXntFygurc%253D&md5=e137736c47bd548090101fed97244e95Integrated flow processing - challenges in continuous multistep synthesisPieber, Bartholomaeus; Gilmore, Kerry; Seeberger, Peter H.Journal of Flow Chemistry (2017), 7 (3-4), 129-136CODEN: JFCOBJ; ISSN:2062-249X. (Akademiai Kiado)The way org. multistep synthesis is performed is changing due to the adoption of flow chem. techniques, which has enabled the development of improved methods to make complex mols. The modular nature of the technique provides not only access to target mols. via linear flow approaches but also for the targeting of structural cores with single systems. This perspective article summarizes the state of the art of continuous multistep synthesis and discusses the main challenges and opportunities in this area.(d) Akwi, F. M.; Watts, P. Continuous flow chemistry: where are we now? Recent applications, challenges and limitations. Chem. Commun. 2018, 54, 13894– 13928, DOI: 10.1039/C8CC07427EGoogle Scholar12dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1Cgt7nJ&md5=752fc8ed94d2ac9bd1c73e9e8d282df3Continuous flow chemistry: where are we now? Recent applications, challenges and limitationsAkwi, Faith M.; Watts, PaulChemical Communications (Cambridge, United Kingdom) (2018), 54 (99), 13894-13928CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review. A general outlook of the changing face of chem. synthesis is provided in this article through recent applications of continuous flow processing in both industry and academia. The benefits, major challenges and limitations assocd. with the use of this mode of processing are also given due attention as an attempt to put into perspective the current position of continuous flow processing, either as an alternative or potential combinatory technol. for batch processing.(e) Gérardy, R.; Emmanuel, N.; Toupy, T.; Kassin, V.-E.; Tshibalonza, N. N.; Schmitz, M.; Monbaliu, J.-C. M. Continuous Flow Organic Chemistry: Successes and Pitfalls at the Interface with Current Societal Challenges. Eur. J. Org. Chem. 2018, 2018, 2301– 2351, DOI: 10.1002/ejoc.201800149Google Scholar12ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVantLvL&md5=7a3a6095c6e2023dd7015b2e2e56e09cContinuous Flow Organic Chemistry: Successes and Pitfalls at the Interface with Current Societal ChallengesGerardy, Romaric; Emmanuel, Noemie; Toupy, Thomas; Kassin, Victor-Emmanuel; Tshibalonza, Nelly Ntumba; Schmitz, Michael; Monbaliu, Jean-Christophe M.European Journal of Organic Chemistry (2018), 2018 (20-21), 2301-2351CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)This review intends to provide the reader with a clear and concise overview of how preparative continuous flow org. chem. could potentially impact on current important societal challenges. These societal challenges include health/well-being and sustainable development. Continuous flow chem. has enabled significant advances for the manufg. of pharmaceuticals, as well as for biomass valorization toward a biosourced chem. industry. Examples related to pharmaceutical prodn. are herein focused on (a) the implementation of flow chem. to reduce the occurrence of drug shortages, (b) continuous flow manufg. of orphan drugs, (c) continuous flow prepn. of active pharmaceuticals listed on the WHO list of essential medicines and (d) perspectives for the manufg. of peptide-based pharmaceuticals. Examples related to sustainable development are focused on the valorization of biosourced platform mols. Besides pos. impacts on societal challenges, this review also illustrates some of the potentially most threatening perspectives of continuous flow technol. within the actual context of terrorism and drug abuse.(f) Nöel, T. A Personal Perspective on the Future of Flow Photochemistry. J. Flow Chem. 2017, 7, 87– 93, DOI: 10.1556/1846.2017.00022Google Scholar12fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXntFygurs%253D&md5=c3832817edce6797a9e8be9e48227592A personal perspective on the future of flow photochemistryNoel, TimothyJournal of Flow Chemistry (2017), 7 (3-4), 87-93CODEN: JFCOBJ; ISSN:2062-249X. (Akademiai Kiado)Photochem. and photoredox catalysis have witnessed a remarkable comeback in the last decade. Flow chem. has been of pivotal importance to alleviate some of the classical obstacles assocd. with photochem. Herein, we analyze some of the most exciting features provided by photo flow chem. as well as future challenges for the field.
- 13Backpressure regulators (100 psi) were purchased from Kinesis (https://kinesis.co.uk/).Google ScholarThere is no corresponding record for this reference.
- 14
Amberlyst A-15 and Amberlyst A-21 resins were purchased from Sigma-Aldrich and used after washing with water and methanol.
There is no corresponding record for this reference. - 15Paryzek, Z.; Koenig, H.; Tabaczka, B. Ammonium Formate/Palladium on Carbon: A Versatile System for Catalytic Hydrogen Transfer Reductions of Carbon-Carbon Double Bonds. Synthesis 2003, 2023– 2026, DOI: 10.1055/s-2003-41024Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnvFSqtLs%253D&md5=fd49fa33a77ee35b4cf661af6b369b89Ammonium formate/palladium on carbon: A versatile system for catalytic hydrogen transfer reductions of carbon-carbon double bondsParyzek, Zdzislaw; Koenig, Hanna; Tabaczka, BartlomiejSynthesis (2003), (13), 2023-2026CODEN: SYNTBF; ISSN:0039-7881. (Georg Thieme Verlag)Various carbon-carbon double bonds in olefins and α,β-unsatd. ketones were effectively reduced to the corresponding alkanes and satd. ketones, using ammonium formate as a hydrogen transfer agent in the presence of Pd/C as catalyst in refluxing methanol.
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This X-ray structure has been deposited as CCDC 2083011 with the Cambridge Crystallographic Data Centre and is freely available from https://www.ccdc.cam.ac.uk/.
There is no corresponding record for this reference. - 17
For selected examples, please see:
(a) Costello, J. P.; Ferreira, E. M. Regioselectivity Influences in Platinum-Catalyzed Intramolecular Alkyne O-H and N-H Additions. Org. Lett. 2019, 21, 9934– 9939, DOI: 10.1021/acs.orglett.9b03557Google Scholar17ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlait7jM&md5=d81bb8bb803bfb5b1b5b81afc9b81df2Regioselectivity Influences in Platinum-Catalyzed Intramolecular Alkyne O-H and N-H AdditionsCostello, Jeff P.; Ferreira, Eric M.Organic Letters (2019), 21 (24), 9934-9939CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)The steric and electronic drivers of regioselectivity in platinum-catalyzed intramol. hydroalkoxylation are elucidated. A branch point is found that divides the process between 5-exo and 6-endo selective processes, and enol ethers can be accessed in good yields for both oxygen heterocycles. The main influence arises from an electronic effect, where the alkyne substituent induces a polarization of the alkyne that leads to preferential heteroatom attack at the more electron-deficient carbon. The electronic effects are studied in other contexts, including hydroacyloxylation and hydroamination, and similar trends in directionality are predominant although not uniformly obsd.(b) Couture, A.; Deniau, E.; Lebrun, S.; Grandclaudon, P.; Carpentier, J.-F. A new route to ene carbamates, precursors to benzoindolizinones through sequential asymmetric hydrogenation and cyclization. J. Chem. Soc., Perkin Trans. 1 1998, 8, 1403– 1408, DOI: 10.1039/a709053fGoogle ScholarThere is no corresponding record for this reference.(c) Fairfax, D.; Stein, M.; Livinghouse, T.; Jensen, M. Scope of the Intramolecular Imidotitanium-Alkyne [2 + 2] Cycloaddition-Azatitanetine Acylation Sequence. An Efficient Procedure for the Synthesis of 2-(2-Keto-1-alkylidene)tetrahydropyrroles and Related Compounds. Organometallics 1997, 16, 1523– 1525, DOI: 10.1021/om961074fGoogle Scholar17chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXitVOlu7o%253D&md5=07ce283aa6995c36eb958882102b1afeScope of the Intramolecular Imidotitanium-Alkyne [2 + 2] Cycloaddition-Azatitanetine Acylation Sequence. An Efficient Procedure for the Synthesis of 2-(2-Keto-1-alkylidene)tetrahydropyrroles and Related CompoundsFairfax, David; Stein, Matthias; Livinghouse, Tom; Jensen, MichaelOrganometallics (1997), 16 (8), 1523-1525CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)Sequential [2 + 2] cycloaddn. of transient imidotitanium complexes to tethered alkynes followed by C-acylation of the resulting azatitanetines with acyl cyanides has been shown to provide a range of functionalized tetrahydropyrroles and related derivs. in good to excellent yields. E.g., treating CpTiCl3 with MeLi, followed by addn. of 1-methylnon-4-ynamine, then EtCOCN, gave 77% I. The selectivity of product formation is correlated to the pattern of alkyne substitution.(d) Lee, H. K.; Kim, J.; Pak, C. S. Reaction of Thioamides with Zinc Enolate: Synthesis of Vinylogous Carbamates. Tetrahedron Lett. 1999, 40, 2173– 2174, DOI: 10.1016/S0040-4039(99)00141-0Google Scholar17dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXhvVSksbc%253D&md5=09ee3a3db0db1aabce09e23a1f4d048aReaction of thioamides with zinc enolate: synthesis of vinylogous carbamatesLee, Hyeon Kyu; Kim, Jia; Pak, Chwang SiekTetrahedron Letters (1999), 40 (11), 2173-2174CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)Eschenmoser sulfur extrusion failed to produce a vinylogous carbamate from N-(tert-Boc)pyrrolidine-2-thione, but treatment of BrZnCH2CO2Me with N-(tert-Boc)pyrrolidine-2-thione afforded good yield of the desired vinylogous carbamate. This thio-Reformatskii reaction appeared to be sensitive to the structure of substrates, i.e. ring size or N-protecting groups.(e) Hazelden, I. R.; Carmona, R. C.; Langer, T.; Pringle, P. G.; Bower, J. F. Pyrrolidines and Piperidines by Ligand-Enabled Aza-Heck Cyclizations and Cascades of N-(Pentafluorobenzoyloxy)carbamates. Angew. Chem., Int. Ed. 2018, 57, 5124– 5128, DOI: 10.1002/anie.201801109Google Scholar17ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXlt1OnsLo%253D&md5=864785e2aeedef76a6d5633d93de510aPyrrolidines and Piperidines by Ligand-Enabled Aza-Heck Cyclizations and Cascades of N-(Pentafluorobenzoyloxy)carbamatesHazelden, Ian R.; Carmona, Rafaela C.; Langer, Thomas; Pringle, Paul G.; Bower, John F.Angewandte Chemie, International Edition (2018), 57 (18), 5124-5128CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Ligand-enabled aza-Heck cyclizations and cascades of N-(pentafluorobenzoyloxy)carbamates are described. These studies encompass the first examples of efficient non-biased 6-exo aza-Heck cyclizations. The methodol. provides direct and flexible access to carbamate protected pyrrolidines and piperidines. - 18(a) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Cyclizations of N-Acyliminium Ions. Chem. Rev. 2004, 104, 1431– 1628, DOI: 10.1021/cr0306182Google Scholar18ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhvFGgs7Y%253D&md5=defafbefd5cff731e65f3980c5f83b95Cyclizations of N-acyliminium ionsMaryanoff, Bruce E.; Zhang, Han-Cheng; Cohen, Judith H.; Turchi, Ignatius J.; Maryanoff, Cynthia A.Chemical Reviews (Washington, DC, United States) (2004), 104 (3), 1431-1628CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Mechanism and stereochem. of N-acyliminium ion reactions were reviewed. Sources of N-acyliminium ions, reactions of benzenoid nucleophiles, substituent effects, reactions of heterocyclic nucleophiles, competition between carbon nucleophiles, formation of five-membered and seven-membered rings, reactions of bicyclic bridgehead iminium ions, reactions of cyclic ions contg. addnl. heteroatoms, reactions of alkenes, allenes and other related species were all discussed. Solid phase reactions were also reviewed. Comparisons with other related synthetic methods were made. A review.(b) Wu, P.; Nielsen, T. E. Scaffold Diversity from N-Acyliminium Ions. Chem. Rev. 2017, 117, 7811– 7856, DOI: 10.1021/acs.chemrev.6b00806Google Scholar18bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnsVegu78%253D&md5=5fd30c43dd5aa9c3ca57c8df96baa121Scaffold Diversity from N-Acyliminium IonsWu, Peng; Nielsen, Thomas E.Chemical Reviews (Washington, DC, United States) (2017), 117 (12), 7811-7856CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. This review provided an overview of cyclization reactions of N-acyliminium ions derived from various precursors for the assembly of structurally diverse scaffolds, ranging from simple bicyclic skeletons to complex polycyclic systems and natural product-like compds. N-Acyliminium ions proved as a powerful reactive species for the formation of carbon-carbon and carbon-heteroatom bonds.
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Subsequent experiments showed that hydrolysis of products 9c–e proceeds slowly in refluxing in MeOH (containing small amounts of HOAc) with ca. 20% conversion over 3 h; longer reaction times led to partial decomposition.
There is no corresponding record for this reference. - 20Omelian, T. V.; Dobrydnev, A. V.; Ostapchuk, E. N.; Volovenko, Y. M. Synthesis of Novel 3a-Substituted Tetrahydro-1H-1λ6-pyrrolo[1,2-b]isothiazole-1,1,3(2H)-triones through the CSIC Reaction. ChemistrySelect 2019, 4, 4933– 4937, DOI: 10.1002/slct.201900650Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXptFKjtLo%253D&md5=99aa1b9a6520b9b9042e77e19db8ce07Synthesis of Novel 3 a-Substituted Tetrahydro-1H-1λ6-pyrrolo[1,2-b]isothiazole-1,1,3(2H)-triones through the CSIC ReactionOmelian, Taras V.; Dobrydnev, Alexey V.; Ostapchuk, Eugeniy N.; Volovenko, Yulian M.ChemistrySelect (2019), 4 (17), 4933-4937CODEN: CHEMUD; ISSN:2365-6549. (Wiley-VCH Verlag GmbH & Co. KGaA)A strategy for the construction of tetrahydro-1H-1λ6-pyrrolo[1,2-b]isothiazole-1,1,3(2H)-triones bearing the substituents at the 5- and/or 3a-positions. To this purpose, a range of 2-substituted and 2,4-disubstituted Me 2-pyrrolidinecarboxylates were sulfonylated with methanesulfonyl chloride and the resulting sulfonamides were subjected to sulfa-Dieckmann condensation through the CSIC (Carbanion mediated Sulfonate (Sulfonamido) Intramol. Cyclization) reaction to give the desired 1λ6-isothiazolidine-1,1,4-triones. All the precursors, as well as target compds., was synthesized in a multigram scale following the general protocols.
- 21Kelleher, F.; Kelly, S.; Watts, J.; McKee, V. Structure-reactivity relationships of l-proline derived spirolactams and α-methyl prolinamide organocatalysts in the asymmetric Michael addition reaction of aldehydes to nitroolefins. Tetrahedron 2010, 66, 3525– 3536, DOI: 10.1016/j.tet.2010.03.002Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXkvFCmur4%253D&md5=f717b3bae9f04cc3cb9197975017d920Structure-reactivity relationships of L-proline derived spirolactams and α-methyl prolinamide organocatalysts in the asymmetric Michael addition reaction of aldehydes to nitroolefinsKelleher, Fintan; Kelly, Sinead; Watts, John; McKee, VickieTetrahedron (2010), 66 (19), 3525-3536CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)Proline derived spirolactams and α-Me prolinamides act as organocatalysts for the asym. conjugate addn. of aldehydes to nitroolefins in excellent yields, with good diastereoselectivity and enantioselectivity. Furthermore, low catalyst loadings (5 mol %) and a low aldehyde molar excess (1.5 M equiv) were achieved.
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Abstract
Scheme 1
Scheme 1. Overview of the Curtius RearrangementScheme 2
Scheme 2. Intended Curtius Rearrangement Application for N-Boc Proline DerivativesScheme 3
Scheme 3. Batch Synthesis of Substrates 4 by Lithiation of N-Boc Proline Methyl Ester 10Scheme 4
Scheme 4. Flow Approach toward Evaluating the Reaction Scope of Interrupted Curtius RearrangementsFigure 1
Figure 1. Reaction scope rendering acyclic products and unsaturated pyrrolidines.
Scheme 5
Scheme 5. Proposed Reaction Mechanism Accounting for Bifurcated PathwayReferences
ARTICLE SECTIONSThis article references 21 other publications.
- 1(a) Curtius, T. Ueber Stickstoffwasserstoffsäure (Azoimid) N3H. Ber. Dtsch. Chem. Ges. 1890, 23, 3023– 3033, DOI: 10.1002/cber.189002302232Google ScholarThere is no corresponding record for this reference.(b) Curtius, T. 20. Hydrazide und Azide organischer Säuren. J. Prakt. Chem. 1894, 50, 275– 294, DOI: 10.1002/prac.18940500125Google Scholar1bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaD28XosFCntQ%253D%253D&md5=6f94ff08c62ee2934f60c7db68874ecaHydrazides and azides of organic acidsCurtius, T.Journal fuer Praktische Chemie (Leipzig) (1894), 50 (2), 275-94CODEN: JPCEAO ISSN:.The author applies the term acid hydrazides to substances of the formula R.CO.NH.NH2, while the derivatives of azoimide are designated by the term acid azides and have the formula R.CO.N3. An account of the experimental researches, of the results of which, the foregoing is a general statement, will be shortly published.
- 2
For selected reports on complementary approaches, please see:
(a) Thomas, M.; Alsarraf, J.; Araji, N.; Tranoy-Opalinski, I.; Renoux, B.; Papot, S. The Lossen rearrangement from free hydroxamic acids. Org. Biomol. Chem. 2019, 17, 5420– 5427, DOI: 10.1039/C9OB00789JGoogle Scholar2ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXptFKht78%253D&md5=82fe98dc11251705e60bea6a39d84a22The Lossen rearrangement from free hydroxamic acidsThomas, Mikael; Alsarraf, Jerome; Araji, Nahla; Tranoy-Opalinski, Isabelle; Renoux, Brigitte; Papot, SebastienOrganic & Biomolecular Chemistry (2019), 17 (22), 5420-5427CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)A review. The Lossen rearrangement, that allows the conversion of hydroxamic acids into isocyanates, was discovered almost 150 years ago. For more than a century, this transformation was supposed to occur exclusively in the presence of stoichiometric amts. of activating reagents devoted to promoting the dehydration of primary hydroxamic acids. Very recently, it was demonstrated that the Lossen rearrangement can take place directly from free hydroxamic acids offering a renewal of interest for such a reaction. This short review summarizes advances in this field by describing successively the metal-assisted, the self-propagative and the promoted self-propagative Lossen rearrangement with a special emphasis on their mechanisms.(b) Wallis, E. S.; Lane, J. F. The Hofmann Reaction. Organic Reactions 2011, 267, DOI: 10.1002/0471264180.or003.07Google ScholarThere is no corresponding record for this reference.(c) Zagulyaeva, A. A.; Banek, C. T.; Yusubov, M. S.; Zhdankin, V. V. Hofmann Rearrangement of Carboxamides Mediated by Hypervalent Iodine Species Generated in Situ from Iodobenzene and Oxone: Reaction Scope and Limitations. Org. Lett. 2010, 12, 4644– 4647, DOI: 10.1021/ol101993qGoogle Scholar2chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFKmtLrN&md5=ec8a03d9b4bd8d8cdd4f74288536a5b9Hofmann Rearrangement of Carboxamides Mediated by Hypervalent Iodine Species Generated in Situ from Iodobenzene and Oxone: Reaction Scope and LimitationsZagulyaeva, Aleksandra A.; Banek, Christopher T.; Yusubov, Mekhman S.; Zhdankin, Viktor V.Organic Letters (2010), 12 (20), 4644-4647CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)Alkylcarboxamides can be converted to the resp. amines by Hofmann rearrangement using hypervalent iodine species generated in situ from PhI and Oxone in aq. acetonitrile. E.g., using hypervalent iodine species generated in situ from PhI and Oxone in aq. acetonitrile, Hofmann rearrangement of PhCH2CONH2 gave 95% PHCH2NH2 (as the HCl salt). On the basis of this reaction, a convenient exptl. procedure for the prepn. of alkylcarbamates using Oxone as the oxidant in the presence of iodobenzene in methanol has been developed. An efficient method for direct conversion of substituted benzamides to the resp. quinone derivs. by treatment with Oxone and iodobenzene in aq. acetonitrile has also been found. E.g., oxidn. of PhCONH2 gave 98% 1,4-benzoquinone.(d) Huang, X.; Seid, M.; Keillor, J. W. A Mild and Efficient Modified Hofmann Rearrangement. J. Org. Chem. 1997, 62, 7495– 7496, DOI: 10.1021/jo9708553Google Scholar2dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmvVamsbo%253D&md5=ace6c263e23fc08a1d814271340900c4A Mild and Efficient Modified Hofmann RearrangementHuang, Xicai; Seid, Mehran; Keillor, Jeffrey W.Journal of Organic Chemistry (1997), 62 (21), 7495-7496CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Amides RCONH2 [R = 4-MeOC6H4, 3,4-(MeO)2C6H3, 4-MeC6H4, Ph, 4-ClC6H4, 4-O2NC6H4, PhCH2, nonyl, pentadecyl, 2,4-(MeO)2C6H3, 4-Me2NC6H4] underwent Hofmann rearrangement on treatment with NBS and DBU in MeOH to give RNHCO2Me in good yields.(e) Wolff, H. The Schmidt Reaction. Organic Reactions 2011, 307– 336, DOI: 10.1002/0471264180.or003.08Google ScholarThere is no corresponding record for this reference.(f) Lang, S.; Murphy, J. A. Azide rearrangements in electron-deficient systems. Chem. Soc. Rev. 2006, 35, 146– 156, DOI: 10.1039/B505080DGoogle Scholar2fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xot1ajtg%253D%253D&md5=54a2aeae02e9d7ef0f8183bc997505c2Azide rearrangements in electron-deficient systemsLang, S.; Murphy, J. A.Chemical Society Reviews (2006), 35 (2), 146-156CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review discusses the rearrangement reactions of org. azides, particularly Schmidt reactions of azides with carboxylic acids, ketones, and ketals and their derivs. to provide lactams and nitrogen heterocycles. - 3(a) Wentrup, C.; Bornemann, H. The Curtius Rearrangement of Acyl Azides Revisited - Formation of Cyanate (R-O-CN). Eur. J. Org. Chem. 2005, 2005, 4521– 4524, DOI: 10.1002/ejoc.200500545Google ScholarThere is no corresponding record for this reference.(b) Eibler, E.; Sauer, J. Ein Beitrag zur Isocyanatbildung bei der Photolyse von Acylaziden. Tetrahedron Lett. 1974, 15, 2569– 2572, DOI: 10.1016/S0040-4039(01)92295-6Google ScholarThere is no corresponding record for this reference.
- 4(a) Ghosh, A. K.; Brindisi, M.; Sarkar, A. The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry. ChemMedChem 2018, 13, 2351– 2373, DOI: 10.1002/cmdc.201800518Google Scholar4ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVygs7zM&md5=da82f908635028b26540cbe25080ee63The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal ChemistryGhosh, Arun K.; Brindisi, Margherita; Sarkar, AnindyaChemMedChem (2018), 13 (22), 2351-2373CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)The Curtius rearrangement is the thermal decompn. of an acyl azide derived from carboxylic acid to produce an isocyanate as the initial product. The isocyanate can undergo further reactions to provide amines and their derivs. Due to its tolerance for a large variety of functional groups and complete retention of stereochem. during rearrangement, the Curtius rearrangement has been used in the synthesis of a wide variety of medicinal agents with amines and amine-derived functional groups such as ureas and urethanes. The current review outlines various applications of the Curtius rearrangement in drug discovery and medicinal chem. In particular, the review highlights some widely used rearrangement methods, syntheses of some key agents for popular drug targets and FDA-approved drugs. In addn., the review highlights applications of the Curtius rearrangement in continuous-flow protocols for the scale-up of active pharmaceutical ingredients.(b) Ghosh, A. K.; Sarkar, A.; Brindisi, M. The Curtius rearrangement: mechanistic insight and recent applications in natural product syntheses. Org. Biomol. Chem. 2018, 16, 2006– 2027, DOI: 10.1039/C8OB00138CGoogle Scholar4bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjtlKguro%253D&md5=242915726420c02b495c466675f713dcThe Curtius rearrangement: mechanistic insight and recent applications in natural product synthesesGhosh, Arun K.; Sarkar, Anindya; Brindisi, MargheritaOrganic & Biomolecular Chemistry (2018), 16 (12), 2006-2027CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)A review. The Curtius rearrangement is a versatile reaction in which a carboxylic acid can be converted to an isocyanate through an acyl azide intermediate under mild conditions. The resulting stable isocyanate can then be readily transformed into a variety of amines and amine derivs. including urethanes and ureas. There have been wide-ranging applications of the Curtius rearrangement in the synthesis of natural products and their derivs. Also, this reaction has been extensively utilized in the synthesis and application of a variety of biomols. In this review, we present mechanistic studies, chem. methodologies and reagents for the synthesis of isocyanates from carboxylic acids, the conversion of isocyanates to amines and amine derivs., and their applications in the synthesis of bioactive natural products and their congeners.
- 5(a) Guidi, M.; Seeberger, P. H.; Gilmore, K. How to approach flow chemistry. Chem. Soc. Rev. 2020, 49, 8910– 8932, DOI: 10.1039/C9CS00832BGoogle Scholar5ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit1Ciu7bP&md5=b6f511c0d703decef620fcec7e74901bHow to approach flow chemistryGuidi, Mara; Seeberger, Peter H.; Gilmore, KerryChemical Society Reviews (2020), 49 (24), 8910-8932CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. Flow chem. is a widely explored technol. whose intrinsic features both facilitate and provide reproducible access to a broad range of chem. processes that are otherwise inefficient or problematic. At its core, a flow chem. module is a stable set of conditions - traditionally thought of as an externally applied means of activation/control (e.g. heat or light) - through which reagents are passed. In an attempt to simplify the teaching and dissemination of this field, we envisioned that the key advantages of the technique, such as reproducibility and the correlation between reaction time and position within the reactor, allow for the redefinition of a flow module to a more synthetically relevant one based on the overall induced effect. We suggest a rethinking of the approach to flow modules, distributing them in two subclasses: transformers and generators, which can be described resp. as a set of conditions for either performing a specific transformation or for generating a reactive intermediate. The chem. achieved by transformers and generators is (ideally) independent of the substrate introduced, meaning that they must be robust to small adjustments necessary for the adaptation to different starting materials and reagents while ensuring the same chem. outcome. These redefined modules can be used for single-step reactions or in multistep processes, where modules can be connected to each other in reconfigurable combinations to create chem. assembly systems (CAS) targeting compds. and libraries sharing structural cores. With this tutorial review, we provide a guide to the overall approach to flow chem., discussing the key parameters for the design of transformers and generators as well as the development of chem. assembly systems.(b) Baumann, M.; Moody, T. S.; Smyth, M.; Wharry, S. A Perspective on Continuous Flow Chemistry in the Pharmaceutical Industry. Org. Process Res. Dev. 2020, 24, 1802– 1813, DOI: 10.1021/acs.oprd.9b00524Google Scholar5bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmtVGrtw%253D%253D&md5=01603875a35243e7974384146b6c35ccA Perspective on Continuous Flow Chemistry in the Pharmaceutical IndustryBaumann, Marcus; Moody, Thomas S.; Smyth, Megan; Wharry, ScottOrganic Process Research & Development (2020), 24 (10), 1802-1813CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A review. Continuous flow manuf. is an innovative technol. platform, which is gaining momentum within the pharmaceutical industry. The key advantages of continuous flow include faster and safer reactions, which can be more environmentally friendly, smaller footprint, better quality product, and critically, the ability to perform chem. that is difficult or impossible to do in batch mode. Globally, significant efforts have been made to develop the manufg. flexibility and robustness of processes used to produce chems. in a continuous way, yet despite these scientific developments, a major challenge for industry is the established application of flow technol. to com. relevant examples. The identification of opportunities to apply flow solns. to current processes is also crit. to the success of this new technol. for pharmaceutical and fine chem. companies. This review highlights industrial hurdles and the importance of education and showcases recent (2018-2019) and relevant industrial examples where utilization of flow technol. has been successfully performed.(c) Hartman, R. L. Flow chemistry remains an opportunity for chemists and chemical engineers. Curr. Opin. Chem. Eng. 2020, 29, 42– 50, DOI: 10.1016/j.coche.2020.05.002Google ScholarThere is no corresponding record for this reference.(d) Gutmann, B.; Kappe, C. O. Forbidden Chemistries - Paths to a Sustainable Future Engaging Continuous Processing. J. Flow Chem. 2017, 7, 65– 71, DOI: 10.1556/1846.2017.00009Google Scholar5dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXntFygu7s%253D&md5=7201d1e45af8d37f35141317fd3b5e72Forbidden chemistries - paths to a sustainable future engaging continuous processingGutmann, Bernhard; Kappe, C. OliverJournal of Flow Chemistry (2017), 7 (3-4), 65-71CODEN: JFCOBJ; ISSN:2062-249X. (Akademiai Kiado)Optimizing current chem. processes alone does not yield the improvements required in the fine chem. and pharmaceutical industries. At least partially, a switch from batch to continuous manufg. is needed. Cost-, time-, and atom-efficient routes frequently demand the application of high temps., pressures, and concns., and/or the use of highly reactive reagents. These chemistries often cannot be employed in conventional reactors. Costly and long alternative synthetic routes are chosen instead. The application of continuous-flow microreactors allows to access "harsh" or "hazardous" reaction conditions and, furthermore, enables entirely new transformations.(e) Gutmann, B.; Cantillo, D.; Kappe, C. O. Continuous-Flow Technology - A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients. Angew. Chem., Int. Ed. 2015, 54, 6688– 6729, DOI: 10.1002/anie.201409318Google Scholar5ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXosVGnt7k%253D&md5=49251387f0f3378dff4e710afe9fbca8Continuous-Flow Technology-A Tool for the Safe Manufacturing of Active Pharmaceutical IngredientsGutmann, Bernhard; Cantillo, David; Kappe, C. OliverAngewandte Chemie, International Edition (2015), 54 (23), 6688-6728CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. In the past few years, continuous-flow reactors with channel dimensions in the micro- or millimeter region have found widespread application in org. synthesis. The characteristic properties of these reactors are their exceptionally fast heat and mass transfer. In microstructured devices of this type, virtually instantaneous mixing can be achieved for all but the fastest reactions. Similarly, the accumulation of heat, formation of hot spots, and dangers of thermal runaways can be prevented. As a result of the small reactor vols., the overall safety of the process is significantly improved, even when harsh reaction conditions are used. Thus, microreactor technol. offers a unique way to perform ultrafast, exothermic reactions, and allows the execution of reactions which proceed via highly unstable or even explosive intermediates. This Review discusses recent literature examples of continuous-flow org. synthesis where hazardous reactions or extreme process windows have been employed, with a focus on applications of relevance to the prepn. of pharmaceuticals.(f) Jensen, K. F. Flow chemistry - Microreaction technology comes of age. AIChE J. 2017, 63, 858– 869, DOI: 10.1002/aic.15642Google Scholar5fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFGmsbY%253D&md5=fcf4074821a2b517418e32c370bb99c6Flow chemistry-Microreaction technology comes of ageJensen, Klavs F.AIChE Journal (2017), 63 (3), 858-869CODEN: AICEAC; ISSN:0001-1541. (John Wiley & Sons, Inc.)Over the past two decades, microreaction technol. has matured from early devices and concepts to encompass a wide range of com. equipment and applications. This evolution has been aided by the confluence of microreactor development and adoption of continuous flow technol. in org. chem. This Perspective summarizes the current state-of-the art with focus on enabling technologies for reaction and sepn. equipment. Automation and optimization are highlighted as promising applications of microreactor technol. The move towards continuous processing in pharmaceutical manufg. underscores increasing industrial interest in the technol. As an example, end-to-end fabrication of pharmaceuticals in a compact reconfigurable system illustrates the development of on-demand manufg. units based on microreactors. The final section provides an outlook for the technol., including implementation challenges and integration with computational tools. AIChE J, 2017.(g) Ley, S. V.; Chen, Y.; Robinson, A.; Otter, B.; Godineau, E.; Battilocchio, C. A Comment on Continuous Flow Technologies within the Agrochemical Industry. Org. Process Res. Dev. 2021, 25, 713– 720, DOI: 10.1021/acs.oprd.0c00534Google Scholar5ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXlvVejtrs%253D&md5=b6e0a7e1146e341c1ef0226a9473c161A Comment on Continuous Flow Technologies within the Agrochemical IndustryLey, Steven V.; Chen, Yiding; Robinson, Alan; Otter, Benjamin; Godineau, Edouard; Battilocchio, ClaudioOrganic Process Research & Development (2021), 25 (4), 713-720CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A review. The agrochem. sector operates on a large scale within a highly complex environment. Cost-effective prodn. on an increasing scale in a sustainable fashion imposes massive constraints on the industry. Here we offer a perspective on flow chem., with literature highlights showing how the application of this technol. can impact chem. processes (esp. at the early stages of R&D) for agrochems., with clear benefits in comparison with a traditional batch vessel, be it safety, quality, or throughput. The value of flow chem. for the business is clear, and the no. of examples reported in the literature will undoubtably continue to increase in the agrochem. industry.(h) Britton, J.; Raston, C. L. Multi-step continuous-flow synthesis. Chem. Soc. Rev. 2017, 46, 1250– 1271, DOI: 10.1039/C6CS00830EGoogle Scholar5hhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1yjtr0%253D&md5=abcfc0e54556e7cd18445305ec6994fdMulti-step continuous-flow synthesisBritton, Joshua; Raston, Colin L.Chemical Society Reviews (2017), 46 (5), 1250-1271CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. This review article focused on multi-step continuous-flow methodol., which had applications in synthesis of active pharmaceutical ingredients, natural products, and commodity chems. This review described the advancements while highlighted the rapid progress, benefits, and diversification of this expanding field.
- 6(a) Sahoo, H. R.; Kralj, J. G.; Jensen, K. F. Multistep Continuous-Flow Microchemical Synthesis Involving Multiple Reactions and Separations. Angew. Chem., Int. Ed. 2007, 46, 5704– 5708, DOI: 10.1002/anie.200701434Google Scholar6ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXosFOktL4%253D&md5=79030b1d9633d3d520aeed7dcc0b99d4Multistep continuous-flow microchemical synthesis involving multiple reactions and separationsSahoo, Hemantkumar R.; Kralji, Jason G.; Jensen, Klavs F.Angewandte Chemie, International Edition (2007), 46 (30), 5704-5708CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)All for one and one for all: A continuous-flow, multistep microchem. synthesis of carbamates starting from aq. azide and benzoyl chloride by using the Curtius rearrangement reaction is described. The procedure involves three reaction steps and two sepn. steps (one gas-liq. and one liq.-liq.). Formation of a microreactor network for parallel synthesis of analogous compds. is also demonstrated.(b) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.; Smith, C. D. Azide monoliths as convenient flow reactors for efficient Curtius rearrangement reactions. Org. Biomol. Chem. 2008, 6, 1587– 1593, DOI: 10.1039/b801634hGoogle Scholar6bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXkvFCqt7w%253D&md5=ffa199ac6f143c3eafa8297f6f520c52Azide monoliths as convenient flow reactors for efficient Curtius rearrangement reactionsBaumann, Marcus; Baxendale, Ian R.; Ley, Steven V.; Nikbin, Nikzad; Smith, Christopher D.Organic & Biomolecular Chemistry (2008), 6 (9), 1587-1593CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)The prepn. and use of an azide-contg. monolithic reactor is described for use in a flow chem. device and in particular for conducting Curtius rearrangement reactions via acid chloride inputs.(c) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.; Smith, C. D.; Tierney, J. P. A modular flow reactor for performing Curtius rearrangements as a continuous flow process. Org. Biomol. Chem. 2008, 6, 1577– 1586, DOI: 10.1039/b801631nGoogle Scholar6chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXkvFCqt74%253D&md5=1ead8804556a33d9ee2ed0c25628cef1A modular flow reactor for performing Curtius rearrangements as a continuous flow processBaumann, Marcus; Baxendale, Ian R.; Ley, Steven V.; Nikbin, Nikzad; Smith, Christopher D.; Tierney, Jason P.Organic & Biomolecular Chemistry (2008), 6 (9), 1577-1586CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)The use of a mesofluidic flow reactor is described for performing Curtius rearrangement reactions of carboxylic acids in the presence of diphenylphosphoryl azide and trapping of the intermediate isocyanates with various nucleophiles.(d) Phung Hai, T. A.; De Backer, L. J. S.; Cosford, N. D. P.; Burkart, M. D. Preparation of Mono- and Diisocyanates in Flow from Renewable Carboxylic Acids. Org. Process Res. Dev. 2020, 24, 2342– 2346, DOI: 10.1021/acs.oprd.0c00167Google Scholar6dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtVCntLrJ&md5=07862b8898e9d44cfc1c257befea10f6Preparation of Mono- and Diisocyanates in Flow from Renewable Carboxylic AcidsPhung Hai, Thien An; De Backer, Laurent J. S.; Cosford, Nicholas D. P.; Burkart, Michael D.Organic Process Research & Development (2020), 24 (10), 2342-2346CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Diisocyanates used in polyurethanes are commonly prepd. by phosgenation of petroleum-sourced diamines. This involves highly toxic phosgene and produces corrosive HCl, limiting synthetic applications. In our search for a renewable source for diisocyanates, we have developed a practical methodol. for the prodn. of isocyanates from algae-biomass-derived fatty acids or other renewable sources. This technique utilizes flow chem. to prep. and convert high-energy intermediates, thus mitigating safety concerns. By the use of continuous flow, acyl azides are prepd. from hydrazides and subsequently heated to undergo Curtius rearrangement, affording isocyanates in one scalable process. The method is efficient, safe, and sustainable, offers an opportunity to prep. isocyanates and diisocyanates from renewable feedstocks, and is amenable to distributed manufg. processes.
- 7(a) Huard, K.; Bagley, S. W.; Menhaji-Klotz, E.; Preville, C.; Southers, J. A., Jr; Smith, A. C.; Edmonds, D. J.; Lucas, J. C.; Dunn, M. F.; Allanson, N. M.; Blaney, E. L.; Garcia-Irizarry, C. N.; Kohrt, J. T.; Griffith, D. A.; Dow, R. L. Synthesis of spiropiperidine lactam acetyl-CoA carboxylase inhibitors. J. Org. Chem. 2012, 77, 10050– 10057, DOI: 10.1021/jo3014808Google Scholar7ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1Wqs73M&md5=33bd1e75961503acf0c7734592b1da39Synthesis of Spiropiperidine Lactam Acetyl-CoA Carboxylase InhibitorsHuard, Kim; Bagley, Scott W.; Menhaji-Klotz, Elnaz; Preville, Cathy; Southers, James A.; Smith, Aaron C.; Edmonds, David J.; Lucas, John C.; Dunn, Matthew F.; Allanson, Nigel M.; Blaney, Emma L.; Garcia-Irizarry, Carmen N.; Kohrt, Jeffrey T.; Griffith, David A.; Dow, Robert L.Journal of Organic Chemistry (2012), 77 (22), 10050-10057CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Spiro(piperidine)pyrazolopyridinones I (R = 1H-indazole-5-carbonyl) and II were prepd. as acetyl-CoA carboxylase inhibitors for potential use as antidiabetic agents for type II diabetes mellitus using regioselective alkylation, Curtius rearrangement, and Parham-type cyclizations as key steps. Attempts to form the spiro(piperidine)pyrazolopyridinone core by cyclization of an unsatd. piperidinemethylpyrazolecarboxamide, by addn. of an iodopyrazolecarboxamide to a spiroaziridinepiperidine, or by reaction of a carboxylpyrazoleacetic acid anhydride with a piperidinone imine were unsuccessful (no data). Et 3-amino-4-pyrazolecarboxylate was converted in five steps to (iodomethyl)pyrazole III using a regioselective pyrazole tert-butylation; alkylation of Et 1-Boc-4-piperidinecarboxylate with III using LiHMDS at 0° followed by ester hydrolysis yielded IV (R = HO2C). Curtius rearrangement of IV (R1 = HO2C) either in soln. with product isolation or using a flow reactor yielded IV (R1 = NCO); lithium-halogen exchange of IV (R1 = NCO) with sec-butyllithium or tert-butyllithium and intramol. cyclocondensation (a Parham-type cyclization) yielded I (R = Boc), which was deprotected and acylated to yield I (R = 1H-indazole-5-carbonyl). An analogous route provided efficient access to II.(b) Guetzoyan, L.; Ingham, R. J.; Nikbin, N.; Rossignol, J.; Wolling, M.; Baumert, M.; Burgess-Brown, N. A.; Strain-Damerell, C. M.; Shrestha, L.; Brennan, P. E.; Fedorov, O.; Knapp, S.; Ley, S. V. Machine-assisted synthesis of modulators of the histone reader BRD9 using flow methods of chemistry and frontal affinity chromatography. MedChemComm 2014, 5, 540– 546, DOI: 10.1039/C4MD00007BGoogle Scholar7bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXkvF2isbY%253D&md5=68282087a31282867a31cabf4a0fd30bMachine-assisted synthesis of modulators of the histone reader BRD9 using flow methods of chemistry and frontal affinity chromatographyGuetzoyan, Lucie; Ingham, Richard J.; Nikbin, Nikzad; Rossignol, Julien; Wolling, Michael; Baumert, Mark; Burgess-Brown, Nicola A.; Strain-Damerell, Claire M.; Shrestha, Leela; Brennan, Paul E.; Fedorov, Oleg; Knapp, Stefan; Ley, Steven V.MedChemComm (2014), 5 (4), 540-546CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)A combination of conventional org. synthesis, remotely monitored flow synthesis and bioassay platforms, were used for the evaluation of novel inhibitors targeting bromodomains outside the well-studied bromodomain and extra terminal (BET) family, here exemplified by activity measurements on the bromodomain of BRD9 protein, a component of some tissue-specific SWi/SNF chromatin remodelling complexes. The Frontal Affinity Chromatog. combined with Mass Spectrometry (FAC-MS) method proved to be reliable and results correlated well with an independent thermal shift assay.(c) Filipponi, P.; Ostacolo, C.; Novellino, E.; Pellicciari, R.; Gioiello, A. Continuous Flow Synthesis of Thieno[2,3-c]isoquinolin-5(4H)-one Scaffold: A Valuable Source of PARP-1 Inhibitors. Org. Process Res. Dev. 2014, 18, 1345– 1353, DOI: 10.1021/op500074hGoogle Scholar7chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXotFOiu7w%253D&md5=db285a9ce8324f97e0cefce0b6d6ba52Continuous Flow Synthesis of Thieno[2,3-c]isoquinolin-5(4H)-one Scaffold: A Valuable Source of PARP-1 InhibitorsFilipponi, Paolo; Ostacolo, Carmine; Novellino, Ettore; Pellicciari, Roberto; Gioiello, AntimoOrganic Process Research & Development (2014), 18 (11), 1345-1353CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)An efficient multistep method for the continuous flow synthesis of thieno[2,3-c]isoquinolin-5(4H)-one-A (TIQ-A), an important pharmacol. tool and building block for PARP-1 inhibitors, has been developed. The synthesis involves a Suzuki coupling reaction to generate 3-phenylthiophene-2-carboxylic acid which is transformed into the corresponding acyl azide and readily cyclized by a thermal Curtius rearrangement. A statistical design of expts. (DoE) was employed as a valuable support for decision-making of further expts. enabling the development of a robust and reliable protocol for large-scale prepn. As a result, the reactions are facile, safe, and easy to scale-up. The large-scale applicability of this improved flow method was tested by conducting the reactions on multigram scale to produce the desired product in high yield and quality for biopharmacol. appraisals.
- 8Marsini, M. A.; Buono, F. G.; Lorenz, J. C.; Yang, B.-S.; Reeves, J. T.; Sidhu, K.; Sarvestani, M.; Tan, Z.; Zhang, Y.; Li, N.; Lee, H.; Brazzillo, J.; Nummy, L. J.; Chung, J. C.; Luvaga, I. K.; Narayanan, B. A.; Wei, X.; Song, J. J.; Roschangar, F.; Yee, N. K.; Senanayake, C. H. Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement. Green Chem. 2017, 19, 1454– 1461, DOI: 10.1039/C6GC03123DGoogle Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFChtA%253D%253D&md5=b4b60207bf8d3fec6e9ad83a49b5178bDevelopment of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangementMarsini, Maurice A.; Buono, Frederic G.; Lorenz, Jon C.; Yang, Bing-Shiou; Reeves, Jonathan T.; Sidhu, Kanwar; Sarvestani, Max; Tan, Zhulin; Zhang, Yongda; Li, Ning; Lee, Heewon; Brazzillo, Jason; Nummy, Laurence J.; Chung, J. C.; Luvaga, Irungu K.; Narayanan, Bikshandarkoil A.; Wei, Xudong; Song, Jinhua J.; Roschangar, Frank; Yee, Nathan K.; Senanayake, Chris H.Green Chemistry (2017), 19 (6), 1454-1461CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)A convergent, robust, and concise synthesis of a developmental CCR1 antagonist, pyrazole deriv. I, is described using continuous flow technol. In the first approach, following an expeditious SNAr sequence for cyclopropane introduction, a safe, continuous flow Curtius rearrangement was developed for the synthesis of a p-methoxybenzyl (PMB) carbamate. Based on kinetic studies, a highly efficient and green process comprising three chem. transformations (azide formation, rearrangement, and isocyanate trapping) was developed with a relatively short residence time and high material throughput (0.8 kg h-1, complete E-factor = ∼9) and was successfully executed on 40 kg scale. Moreover, mechanistic studies enabled the execution of a semi-continuous, tandem Curtius rearrangement and acid-isocyanate coupling to directly afford the final drug candidate in a single, protecting group-free operation. The resulting API synthesis is further detd. to be extremely green (RPG = 166%) relative to the industrial av. for mols. of similar complexity.
- 9(a) Leslie, A.; Moody, T. S.; Smyth, M.; Wharry, S.; Baumann, M. Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives. Beilstein J. Org. Chem. 2021, 17, 379– 384, DOI: 10.3762/bjoc.17.33Google Scholar9ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXktlKgurs%253D&md5=7cdbc063408d5ca4614434a094ea6e8aCoupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivativesLeslie, Alexander; Moody, Thomas S.; Smyth, Megan; Wharry, Scott; Baumann, MarcusBeilstein Journal of Organic Chemistry (2021), 17 (), 379-384CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)A continuous flow process is presented that couples a Curtius rearrangement step with a biocatalytic impurity tagging strategy to produce a series of valuable Cbz-carbamate products. Immobilized CALB was exploited as a robust hydrolase to transform residual benzyl alc. into easily separable benzyl butyrate. The resulting telescoped flow process was effectively applied across a series of acid substrates rendering the desired carbamate structures in high yield and purity. The derivatization of these products via complementary flow-based Michael addn. reactions furthermore demonstrated the creation of β-amino acid species. This strategy thus highlights the applicability of this work towards the creation of important chem. building blocks for the pharmaceutical and speciality chem. industries.(b) Baumann, M.; Leslie, A.; Moody, T. S.; Smyth, M.; Wharry, S. Tandem Continuous Flow Curtius Rearrangement and Subsequent Enzyme-Mediated Impurity Tagging. Org. Process Res. Dev. 2021, 25, 452– 456, DOI: 10.1021/acs.oprd.0c00420Google Scholar9bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit1GitrnO&md5=ef77a9aa41e322ce90c478a13aa5a1ffTandem Continuous Flow Curtius Rearrangement and Subsequent Enzyme-Mediated Impurity TaggingBaumann, Marcus; Leslie, Alexander; Moody, Thomas S.; Smyth, Megan; Wharry, ScottOrganic Process Research & Development (2021), 25 (3), 452-456CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The use of continuous flow as an enabling technol. within the fine chem. and pharmaceutical industries continues to gain momentum. The assocd. safety benefits with flow for handling of hazardous or highly reactive intermediates are often exploited to offer industrially relevant and scalable Curtius rearrangements. However, in many cases the Curtius rearrangement requires excess nucleophile for the reaction to proceed to high conversions. This can complicate work procedures to deliver high-purity products. However, tandem processing and coupling of the Curtius rearrangement with an immobilized enzyme can elegantly facilitate chemoselective tagging of the residual reagent, resulting in a facile purifn. process under continuous flow.
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Substrate 4a was obtained from alkaline hydrolysis of methyl ester 11a, which was kindly provided by Almac Sciences.
There is no corresponding record for this reference. - 11Lima, F.; Sharma, U. K.; Grunenberg, L.; Saha, D.; Johannsen, S.; Sedelmeier, J.; Van der Eycken, E. V.; Ley, S. V. A Lewis Base Catalysis Approach for the Photoredox Activation of Boronic Acids and Esters. Angew. Chem., Int. Ed. 2017, 56, 15136– 15140, DOI: 10.1002/anie.201709690Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslSiu7%252FM&md5=85a5cb726eb152c3c9d919ab3e3d7800A Lewis Base Catalysis Approach for the Photoredox Activation of Boronic Acids and EstersLima, Fabio; Sharma, Upendra K.; Grunenberg, Lars; Saha, Debasmita; Johannsen, Sandra; Sedelmeier, Joerg; Van der Eycken, Erik V.; Ley, Steven V.Angewandte Chemie, International Edition (2017), 56 (47), 15136-15140CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)We report herein the use of a dual catalytic system comprising a Lewis base catalyst such as quinuclidin-3-ol or 4-dimethylaminopyridine and a photoredox catalyst to generate carbon radicals from either boronic acids or esters. This system enabled a wide range of alkyl boronic esters and aryl or alkyl boronic acids to react with electron-deficient olefins via radical addn. to efficiently form C-C coupled products in a redox-neutral fashion. The Lewis base catalyst was shown to form a redox-active complex with either the boronic esters or the trimeric form of the boronic acids (boroxines) in soln.
- 12(a) Wegner, J.; Ceylan, S.; Kirschning, A. Ten key issues in modern flow chemistry. Chem. Commun. 2011, 47, 4583– 4592, DOI: 10.1039/c0cc05060aGoogle Scholar12ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXktF2nsbk%253D&md5=8327ad1e610bb70d64556b6e7568a5d1Ten key issues in modern flow chemistryWegner, Jens; Ceylan, Sascha; Kirschning, AndreasChemical Communications (Cambridge, United Kingdom) (2011), 47 (16), 4583-4592CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review. Ten essentials of synthesis in the flow mode, a new enabling technol. in org. chem., are highlighted as flash-lighted providing an insight into current and future issues and developments in this field.(b) Baumann, M.; Moody, T. S.; Smyth, M.; Wharry, S. Overcoming the Hurdles and Challenges Associated with Developing Continuous Industrial Processes. Eur. J. Org. Chem. 2020, 2020, 7398– 7406, DOI: 10.1002/ejoc.202001278Google Scholar12bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitVymtrjK&md5=6f028f3c8a88bb0c829da8a83a626ae4Overcoming the Hurdles and Challenges Associated with Developing Continuous Industrial ProcessesBaumann, Marcus; Moody, Thomas S.; Smyth, Megan; Wharry, ScottEuropean Journal of Organic Chemistry (2020), 2020 (48), 7398-7406CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Continuous flow chem. is often viewed as a very simple concept on paper, however scientists with significant flow chem. experience will highlight a no. of challenges that need to be overcome. Crit. for the successful development of any flow process is a high level of understanding of potential pitfalls that may be encountered. A collaborative and multi-disciplinary team of chemists and chem. engineers is essential in the development of a process from lab scale through to prodn. This Minireview will identify and highlight relevant risks and their subsequent mitigation strategies to ensure successful flow processing.(c) Pieber, B.; Gilmore, K.; Seeberger, P. H. Integrated Flow Processing - Challenges in Continuous Multistep Synthesis. J. Flow Chem. 2017, 7, 129– 136, DOI: 10.1556/1846.2017.00016Google Scholar12chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXntFygurc%253D&md5=e137736c47bd548090101fed97244e95Integrated flow processing - challenges in continuous multistep synthesisPieber, Bartholomaeus; Gilmore, Kerry; Seeberger, Peter H.Journal of Flow Chemistry (2017), 7 (3-4), 129-136CODEN: JFCOBJ; ISSN:2062-249X. (Akademiai Kiado)The way org. multistep synthesis is performed is changing due to the adoption of flow chem. techniques, which has enabled the development of improved methods to make complex mols. The modular nature of the technique provides not only access to target mols. via linear flow approaches but also for the targeting of structural cores with single systems. This perspective article summarizes the state of the art of continuous multistep synthesis and discusses the main challenges and opportunities in this area.(d) Akwi, F. M.; Watts, P. Continuous flow chemistry: where are we now? Recent applications, challenges and limitations. Chem. Commun. 2018, 54, 13894– 13928, DOI: 10.1039/C8CC07427EGoogle Scholar12dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1Cgt7nJ&md5=752fc8ed94d2ac9bd1c73e9e8d282df3Continuous flow chemistry: where are we now? Recent applications, challenges and limitationsAkwi, Faith M.; Watts, PaulChemical Communications (Cambridge, United Kingdom) (2018), 54 (99), 13894-13928CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review. A general outlook of the changing face of chem. synthesis is provided in this article through recent applications of continuous flow processing in both industry and academia. The benefits, major challenges and limitations assocd. with the use of this mode of processing are also given due attention as an attempt to put into perspective the current position of continuous flow processing, either as an alternative or potential combinatory technol. for batch processing.(e) Gérardy, R.; Emmanuel, N.; Toupy, T.; Kassin, V.-E.; Tshibalonza, N. N.; Schmitz, M.; Monbaliu, J.-C. M. Continuous Flow Organic Chemistry: Successes and Pitfalls at the Interface with Current Societal Challenges. Eur. J. Org. Chem. 2018, 2018, 2301– 2351, DOI: 10.1002/ejoc.201800149Google Scholar12ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVantLvL&md5=7a3a6095c6e2023dd7015b2e2e56e09cContinuous Flow Organic Chemistry: Successes and Pitfalls at the Interface with Current Societal ChallengesGerardy, Romaric; Emmanuel, Noemie; Toupy, Thomas; Kassin, Victor-Emmanuel; Tshibalonza, Nelly Ntumba; Schmitz, Michael; Monbaliu, Jean-Christophe M.European Journal of Organic Chemistry (2018), 2018 (20-21), 2301-2351CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)This review intends to provide the reader with a clear and concise overview of how preparative continuous flow org. chem. could potentially impact on current important societal challenges. These societal challenges include health/well-being and sustainable development. Continuous flow chem. has enabled significant advances for the manufg. of pharmaceuticals, as well as for biomass valorization toward a biosourced chem. industry. Examples related to pharmaceutical prodn. are herein focused on (a) the implementation of flow chem. to reduce the occurrence of drug shortages, (b) continuous flow manufg. of orphan drugs, (c) continuous flow prepn. of active pharmaceuticals listed on the WHO list of essential medicines and (d) perspectives for the manufg. of peptide-based pharmaceuticals. Examples related to sustainable development are focused on the valorization of biosourced platform mols. Besides pos. impacts on societal challenges, this review also illustrates some of the potentially most threatening perspectives of continuous flow technol. within the actual context of terrorism and drug abuse.(f) Nöel, T. A Personal Perspective on the Future of Flow Photochemistry. J. Flow Chem. 2017, 7, 87– 93, DOI: 10.1556/1846.2017.00022Google Scholar12fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXntFygurs%253D&md5=c3832817edce6797a9e8be9e48227592A personal perspective on the future of flow photochemistryNoel, TimothyJournal of Flow Chemistry (2017), 7 (3-4), 87-93CODEN: JFCOBJ; ISSN:2062-249X. (Akademiai Kiado)Photochem. and photoredox catalysis have witnessed a remarkable comeback in the last decade. Flow chem. has been of pivotal importance to alleviate some of the classical obstacles assocd. with photochem. Herein, we analyze some of the most exciting features provided by photo flow chem. as well as future challenges for the field.
- 13Backpressure regulators (100 psi) were purchased from Kinesis (https://kinesis.co.uk/).Google ScholarThere is no corresponding record for this reference.
- 14
Amberlyst A-15 and Amberlyst A-21 resins were purchased from Sigma-Aldrich and used after washing with water and methanol.
There is no corresponding record for this reference. - 15Paryzek, Z.; Koenig, H.; Tabaczka, B. Ammonium Formate/Palladium on Carbon: A Versatile System for Catalytic Hydrogen Transfer Reductions of Carbon-Carbon Double Bonds. Synthesis 2003, 2023– 2026, DOI: 10.1055/s-2003-41024Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnvFSqtLs%253D&md5=fd49fa33a77ee35b4cf661af6b369b89Ammonium formate/palladium on carbon: A versatile system for catalytic hydrogen transfer reductions of carbon-carbon double bondsParyzek, Zdzislaw; Koenig, Hanna; Tabaczka, BartlomiejSynthesis (2003), (13), 2023-2026CODEN: SYNTBF; ISSN:0039-7881. (Georg Thieme Verlag)Various carbon-carbon double bonds in olefins and α,β-unsatd. ketones were effectively reduced to the corresponding alkanes and satd. ketones, using ammonium formate as a hydrogen transfer agent in the presence of Pd/C as catalyst in refluxing methanol.
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This X-ray structure has been deposited as CCDC 2083011 with the Cambridge Crystallographic Data Centre and is freely available from https://www.ccdc.cam.ac.uk/.
There is no corresponding record for this reference. - 17
For selected examples, please see:
(a) Costello, J. P.; Ferreira, E. M. Regioselectivity Influences in Platinum-Catalyzed Intramolecular Alkyne O-H and N-H Additions. Org. Lett. 2019, 21, 9934– 9939, DOI: 10.1021/acs.orglett.9b03557Google Scholar17ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlait7jM&md5=d81bb8bb803bfb5b1b5b81afc9b81df2Regioselectivity Influences in Platinum-Catalyzed Intramolecular Alkyne O-H and N-H AdditionsCostello, Jeff P.; Ferreira, Eric M.Organic Letters (2019), 21 (24), 9934-9939CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)The steric and electronic drivers of regioselectivity in platinum-catalyzed intramol. hydroalkoxylation are elucidated. A branch point is found that divides the process between 5-exo and 6-endo selective processes, and enol ethers can be accessed in good yields for both oxygen heterocycles. The main influence arises from an electronic effect, where the alkyne substituent induces a polarization of the alkyne that leads to preferential heteroatom attack at the more electron-deficient carbon. The electronic effects are studied in other contexts, including hydroacyloxylation and hydroamination, and similar trends in directionality are predominant although not uniformly obsd.(b) Couture, A.; Deniau, E.; Lebrun, S.; Grandclaudon, P.; Carpentier, J.-F. A new route to ene carbamates, precursors to benzoindolizinones through sequential asymmetric hydrogenation and cyclization. J. Chem. Soc., Perkin Trans. 1 1998, 8, 1403– 1408, DOI: 10.1039/a709053fGoogle ScholarThere is no corresponding record for this reference.(c) Fairfax, D.; Stein, M.; Livinghouse, T.; Jensen, M. Scope of the Intramolecular Imidotitanium-Alkyne [2 + 2] Cycloaddition-Azatitanetine Acylation Sequence. An Efficient Procedure for the Synthesis of 2-(2-Keto-1-alkylidene)tetrahydropyrroles and Related Compounds. Organometallics 1997, 16, 1523– 1525, DOI: 10.1021/om961074fGoogle Scholar17chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXitVOlu7o%253D&md5=07ce283aa6995c36eb958882102b1afeScope of the Intramolecular Imidotitanium-Alkyne [2 + 2] Cycloaddition-Azatitanetine Acylation Sequence. An Efficient Procedure for the Synthesis of 2-(2-Keto-1-alkylidene)tetrahydropyrroles and Related CompoundsFairfax, David; Stein, Matthias; Livinghouse, Tom; Jensen, MichaelOrganometallics (1997), 16 (8), 1523-1525CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)Sequential [2 + 2] cycloaddn. of transient imidotitanium complexes to tethered alkynes followed by C-acylation of the resulting azatitanetines with acyl cyanides has been shown to provide a range of functionalized tetrahydropyrroles and related derivs. in good to excellent yields. E.g., treating CpTiCl3 with MeLi, followed by addn. of 1-methylnon-4-ynamine, then EtCOCN, gave 77% I. The selectivity of product formation is correlated to the pattern of alkyne substitution.(d) Lee, H. K.; Kim, J.; Pak, C. S. Reaction of Thioamides with Zinc Enolate: Synthesis of Vinylogous Carbamates. Tetrahedron Lett. 1999, 40, 2173– 2174, DOI: 10.1016/S0040-4039(99)00141-0Google Scholar17dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXhvVSksbc%253D&md5=09ee3a3db0db1aabce09e23a1f4d048aReaction of thioamides with zinc enolate: synthesis of vinylogous carbamatesLee, Hyeon Kyu; Kim, Jia; Pak, Chwang SiekTetrahedron Letters (1999), 40 (11), 2173-2174CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)Eschenmoser sulfur extrusion failed to produce a vinylogous carbamate from N-(tert-Boc)pyrrolidine-2-thione, but treatment of BrZnCH2CO2Me with N-(tert-Boc)pyrrolidine-2-thione afforded good yield of the desired vinylogous carbamate. This thio-Reformatskii reaction appeared to be sensitive to the structure of substrates, i.e. ring size or N-protecting groups.(e) Hazelden, I. R.; Carmona, R. C.; Langer, T.; Pringle, P. G.; Bower, J. F. Pyrrolidines and Piperidines by Ligand-Enabled Aza-Heck Cyclizations and Cascades of N-(Pentafluorobenzoyloxy)carbamates. Angew. Chem., Int. Ed. 2018, 57, 5124– 5128, DOI: 10.1002/anie.201801109Google Scholar17ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXlt1OnsLo%253D&md5=864785e2aeedef76a6d5633d93de510aPyrrolidines and Piperidines by Ligand-Enabled Aza-Heck Cyclizations and Cascades of N-(Pentafluorobenzoyloxy)carbamatesHazelden, Ian R.; Carmona, Rafaela C.; Langer, Thomas; Pringle, Paul G.; Bower, John F.Angewandte Chemie, International Edition (2018), 57 (18), 5124-5128CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Ligand-enabled aza-Heck cyclizations and cascades of N-(pentafluorobenzoyloxy)carbamates are described. These studies encompass the first examples of efficient non-biased 6-exo aza-Heck cyclizations. The methodol. provides direct and flexible access to carbamate protected pyrrolidines and piperidines. - 18(a) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Cyclizations of N-Acyliminium Ions. Chem. Rev. 2004, 104, 1431– 1628, DOI: 10.1021/cr0306182Google Scholar18ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhvFGgs7Y%253D&md5=defafbefd5cff731e65f3980c5f83b95Cyclizations of N-acyliminium ionsMaryanoff, Bruce E.; Zhang, Han-Cheng; Cohen, Judith H.; Turchi, Ignatius J.; Maryanoff, Cynthia A.Chemical Reviews (Washington, DC, United States) (2004), 104 (3), 1431-1628CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Mechanism and stereochem. of N-acyliminium ion reactions were reviewed. Sources of N-acyliminium ions, reactions of benzenoid nucleophiles, substituent effects, reactions of heterocyclic nucleophiles, competition between carbon nucleophiles, formation of five-membered and seven-membered rings, reactions of bicyclic bridgehead iminium ions, reactions of cyclic ions contg. addnl. heteroatoms, reactions of alkenes, allenes and other related species were all discussed. Solid phase reactions were also reviewed. Comparisons with other related synthetic methods were made. A review.(b) Wu, P.; Nielsen, T. E. Scaffold Diversity from N-Acyliminium Ions. Chem. Rev. 2017, 117, 7811– 7856, DOI: 10.1021/acs.chemrev.6b00806Google Scholar18bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnsVegu78%253D&md5=5fd30c43dd5aa9c3ca57c8df96baa121Scaffold Diversity from N-Acyliminium IonsWu, Peng; Nielsen, Thomas E.Chemical Reviews (Washington, DC, United States) (2017), 117 (12), 7811-7856CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. This review provided an overview of cyclization reactions of N-acyliminium ions derived from various precursors for the assembly of structurally diverse scaffolds, ranging from simple bicyclic skeletons to complex polycyclic systems and natural product-like compds. N-Acyliminium ions proved as a powerful reactive species for the formation of carbon-carbon and carbon-heteroatom bonds.
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Subsequent experiments showed that hydrolysis of products 9c–e proceeds slowly in refluxing in MeOH (containing small amounts of HOAc) with ca. 20% conversion over 3 h; longer reaction times led to partial decomposition.
There is no corresponding record for this reference. - 20Omelian, T. V.; Dobrydnev, A. V.; Ostapchuk, E. N.; Volovenko, Y. M. Synthesis of Novel 3a-Substituted Tetrahydro-1H-1λ6-pyrrolo[1,2-b]isothiazole-1,1,3(2H)-triones through the CSIC Reaction. ChemistrySelect 2019, 4, 4933– 4937, DOI: 10.1002/slct.201900650Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXptFKjtLo%253D&md5=99aa1b9a6520b9b9042e77e19db8ce07Synthesis of Novel 3 a-Substituted Tetrahydro-1H-1λ6-pyrrolo[1,2-b]isothiazole-1,1,3(2H)-triones through the CSIC ReactionOmelian, Taras V.; Dobrydnev, Alexey V.; Ostapchuk, Eugeniy N.; Volovenko, Yulian M.ChemistrySelect (2019), 4 (17), 4933-4937CODEN: CHEMUD; ISSN:2365-6549. (Wiley-VCH Verlag GmbH & Co. KGaA)A strategy for the construction of tetrahydro-1H-1λ6-pyrrolo[1,2-b]isothiazole-1,1,3(2H)-triones bearing the substituents at the 5- and/or 3a-positions. To this purpose, a range of 2-substituted and 2,4-disubstituted Me 2-pyrrolidinecarboxylates were sulfonylated with methanesulfonyl chloride and the resulting sulfonamides were subjected to sulfa-Dieckmann condensation through the CSIC (Carbanion mediated Sulfonate (Sulfonamido) Intramol. Cyclization) reaction to give the desired 1λ6-isothiazolidine-1,1,4-triones. All the precursors, as well as target compds., was synthesized in a multigram scale following the general protocols.
- 21Kelleher, F.; Kelly, S.; Watts, J.; McKee, V. Structure-reactivity relationships of l-proline derived spirolactams and α-methyl prolinamide organocatalysts in the asymmetric Michael addition reaction of aldehydes to nitroolefins. Tetrahedron 2010, 66, 3525– 3536, DOI: 10.1016/j.tet.2010.03.002Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXkvFCmur4%253D&md5=f717b3bae9f04cc3cb9197975017d920Structure-reactivity relationships of L-proline derived spirolactams and α-methyl prolinamide organocatalysts in the asymmetric Michael addition reaction of aldehydes to nitroolefinsKelleher, Fintan; Kelly, Sinead; Watts, John; McKee, VickieTetrahedron (2010), 66 (19), 3525-3536CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)Proline derived spirolactams and α-Me prolinamides act as organocatalysts for the asym. conjugate addn. of aldehydes to nitroolefins in excellent yields, with good diastereoselectivity and enantioselectivity. Furthermore, low catalyst loadings (5 mol %) and a low aldehyde molar excess (1.5 M equiv) were achieved.
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