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Direct Synthesis of Amides from Carboxylic Acids and Amines Using B(OCH₂CF₃)₃

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Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon St, London, WC1H 0AJ, U.K.

*E-mail: [email protected]. Fax: +(44)-(0)20-7679-7463. Phone: +(44)-(0)20-7679-2467.

Cite this: J. Org. Chem. 2013, 78, 9, 4512–4523

Publication Date (Web):April 16, 2013

https://doi.org/10.1021/jo400509n

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Abstract

B(OCH₂CF₃)₃, prepared from readily available B₂O₃ and 2,2,2-trifluoroethanol, is as an effective reagent for the direct amidation of a variety of carboxylic acids with a broad range of amines. In most cases, the amide products can be purified by a simple filtration procedure using commercially available resins, with no need for aqueous workup or chromatography. The amidation of N-protected amino acids with both primary and secondary amines proceeds effectively, with very low levels of racemization. B(OCH₂CF₃)₃ can also be used for the formylation of a range of amines in good to excellent yield, via transamidation of dimethylformamide.

Introduction

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The amide bond is widely prevalent in both naturally occurring and synthetic compounds. It is increasingly important in pharmaceutical chemistry, being present in 25% of available drugs, with amidation reactions being among the most commonly used reactions in medicinal chemistry. There is considerable interest in the development of new approaches to direct amidation, (1, 2) and organizations such as the ACS Green Chemistry Institute Pharmaceutical Roundtable have indicated that amide bond formation is one of the most important reactions used in industry for which better reagents are required. (3) Although there are a large range of reagents and strategies for amide bond formation available, (4) few can really be considered ideal. Currently there is a focus on the development of novel, atom-economical, benign methods for amidation, and there have been many recent developments in this field. An important consideration here is the ease with which the reagent or catalyst can be separated from the resulting product. Direct thermal amide formation from amines and carboxylic acids has been reported using toluene as the reaction solvent (5) or using radiofrequency heating under neat conditions, (6) and this reagent-free approach is practical in many cases, but the substrate scope is quite limited. Alternatively, a number of metal-based catalytic systems have also been reported, with recent examples including the use of Ti(OⁱPr)₄, (7) Cp₂ZrCl₂, (5) and ZrCl₄ (5, 8) under strictly anhydrous dehydrating conditions. Boron mediated amidation reactions have attracted considerable attention, (9-12) and boronic acids have been shown to be effective catalysts for direct amide formation from carboxylic acids and amines. (9) In general, boronic acid catalyzed amidation reactions require the removal of water from the reaction either by a dehydrating agent such as molecular sieves or by azeotropic reflux. The reactions also typically require relatively dilute reaction conditions. Stoichiometric boron reagents for amidation often require anhydrous conditions and/or an excess of either the acid or the amine, however. (10-12) While many of these boron-mediated processes are promising, to date the substrate scope is limited to relatively activated systems.

We have recently reported that simple borate esters are effective reagents for the direct synthesis of amides from carboxylic acids or primary amides. (13) Although commercially available B(OMe)₃ was useful for amidation in some cases, the 2,2,2-trifluoroethanol-derived ester B(OCH₂CF₃)₃ gave consistently higher conversions and was applicable to a much wider range of substrates. The use of B(OCH₂CF₃)₃ as an amidation reagent is operationally simple, as the reaction can be carried out open to the air with equimolar quantities of acid and amine in a solvent in which most amines and acids are readily soluble (MeCN). In all of the examples examined, the thermal background yield of amide was found to be low in comparison to that obtained in the presence of the borate ester.

Herein, we report a method for the large-scale preparation of B(OCH₂CF₃)₃ from readily available B₂O₃ and a full study of the scope and limitations of B(OCH₂CF₃)₃ as a direct amidation reagent. We also describe its application to the formylation of amines by transamidation of DMF. Importantly, a solid phase purification procedure has been developed that enables the amide products to be obtained without aqueous workup or chromatography.

Results and Discussion

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Preparation of the B(OCH₂CF₃)₃ Reagent

In our initial work, we prepared B(OCH₂CF₃)₃ by reaction of 2,2,2-trifluoroethanol with BBr₃ at low temperature (Scheme 1). This gave B(OCH₂CF₃)₃ in excellent yield after purification by distillation. However, BBr₃ is somewhat expensive and can be difficult to handle because of the fact that it readily hydrolyzes on contact with moisture. We therefore sought an alternative method for preparing the amidation reagent. The synthesis of B(OCH₂CF₃)₃ has been previously reported from boric acid (14) and from B₂O₃. (15) We found the latter procedure to be particularly straightforward on multigram scale. Simply heating a suspension of B₂O₃ in 2,2,2-trifluoroethanol for 24 h, followed by distillation, gave the borate ester in 33–48% yield on 25–50 g scale, and up to 28% of the trifluoroethanol could be recovered and recycled. Although this procedure is lower yielding in comparison to our original approach, B₂O₃ is considerably cheaper than BBr₃ and the reaction is not particularly moisture-sensitive. The B(OCH₂CF₃)₃ reagent can be stored at room temperature under inert atmosphere for at least four months without any observable deterioration.

Scheme 1. Synthesis of B(OCH₂CF₃)₃ from (a) BBr₃ and (b) B₂O₃

Development of a Solid Phase Workup Procedure and Evaluation of Other Borates

In order to explore different workup procedures and reagents, the amidation of phenylacetic acid with benzylamine was selected as a test reaction (Table 1). After the amidation reaction, the reaction mixture contains the amide product, borate-ester derived byproducts, and potentially some unreacted amine and/or carboxylic acid. In our preliminary report, the amidation reactions were purified by acid and base washes to remove these impurities. (13) Under our original conditions (2 equiv of borate, 15 h, 80 °C), the amide was obtained in 91% yield (entry 1). The reaction time could be reduced from 15 to 5 h with only a small decrease in yield (entry 2). We explored an alternative solid phase workup for the amidation reactions involving treatment of the crude reaction mixture with three commercially available resins (Amberlyst acidic, basic and Amberlite boron scavenger resins), followed by MgSO₄, and then filtration/evaporation (Figure 1). This provided the amide product in a comparable yield and purity to the aqueous workup (entry 3). This procedure is more convenient for general use and could potentially be used to enable automation of the reaction.

Table 1. Comparison of Boron Reagents and Workup Procedures

entry	reagent	time [h]	yield [%]a
1	B(OCH₂CF₃)₃	15	91b
2	B(OCH₂CF₃)₃	5	88b
3	B(OCH₂CF₃)₃	5	87c
4	B(OMe)₃	5	69c
5	B(OMe)₃	15	92b
6	B₂O₃	5	15b
7	1	5	72c
8	1	15	81c
9	none	15	18b

Isolated yield.

Aqueous workup procedure.

Solid phase workup procedure.

Figure 1. Solid phase workup of amidation reactions.

We subsequently compared different boron reagents under these conditions. Trimethyl borate was effective for amidation (entries 4 and 5), but a longer reaction time was required in order to obtain a good yield. B₂O₃ itself showed low reactivity in the amidation reaction with only 15% yield after a 5 h reaction time (entry 6). Commercially available trimethoxyboroxine 1 is reported to be a stronger Lewis acid than both B(OMe)₃ and B(OCH₂CF₃)₃ but did not offer any significant advantage in the amidation reaction (entry 7). (14) Interestingly, the reaction with 1 did not lead to comparable conversions even after a 15 h reaction time (entry 8). This may be due to the fact that 1 can more readily form oligomeric species such as B₂O₃ upon heating, and such species are much less active in the amidation reaction. It should be noted that the thermal reaction in the absence of any reagent gave only an 18% yield of the amide. In our preliminary communicaton (13) we determined the thermal reaction yield for the 15 other amidation reactions studied to be <9%. This clearly demonstrates the importance of the borate ester in mediating the amidation reaction.

Scope of the Amidation Reactions

The full scope of the amidation reactions was explored with a wide range of amines and carboxylic acids. To evaluate the amine scope, the preparation of phenylactetamides (Figure 2, 2a–2x) from phenylacetic acid was explored using our standard reaction conditions (2 equiv of B(OCH₂CF₃)₃, MeCN, 80 °C). Primary amines including benzylamines (2a–2d), simple aliphatic amines (2e) and even functionalized examples (2f–2h) could be coupled in good yield. A range of cyclic secondary amines also underwent amidation efficiently, including several medicinally relevant examples (2i–2m). The hydrochloride salt of dimethylamine underwent amidation in good yield when two or more equivalents of the hydrochloride salt were employed (2n) in combination with 2 equiv of Hünig’s base. The acyclic secondary amine dibenzylamine showed poor reactivity, however (2o), and a significant quantity of the secondary N-benzyl amide 2a was obtained, indicating that partial cleavage of one of the benzyl units had occurred. Less nucleophilic systems such as anilines (2p–2u) and tert-butylamine (2v) could also be coupled, but higher reaction temperatures were needed in some cases in order to obtain reasonable yields. Extremely unreactive systems such as 2-pyridylamine (2u) gave only very low yields of the coupling product and adamantylamine (2w) and 2-mercaptoaniline (2x) did not undergo amidation at all.

Figure 2. Scope of phenylacetamide synthesis with different amines. All reactions were carried out at 80 °C for 5 h, and the solid phase workup procedure was used unless otherwise stated. (a) Aqueous workup procedure; (b) 80 °C for 15 h; (c) 100 °C for 15 h in a sealed tube; (d) purified by column chromatography; (e) from 1 equiv of Me₂NH·HCl, 1 equiv of DIPEA; (f) from 2 equiv of Me₂NH·HCl, 2 equiv of DIPEA; (g) from 3 equiv of Me₂NH·HCl, 3 equiv of DIPEA; (h) 6% of 2a was also isolated; (i) 100 °C for 24 h in a sealed tube.

The preparation of N-benzylamides (Figure 3, 3a–3v) was explored using our standard conditions in order to evaluate the carboxylic acid scope. A range of N-benzyl-2-arylacetamides (2a, 3a–3i) were obtained in very good yield including α-substituted (3b) and heteroaromatic acids (3h). A simple aliphatic acid (3j) and N-Boc sarcosine (3k) also underwent amidation effectively. Carboxylic acids with conjugated alkyne (3l) and alkene groups (3m–3o) could be coupled efficiently, but more hindered examples required a higher reaction temperature (3n). More hindered aliphatic systems including trifluoroacetic acid (3p) and pivalic acid (3q) could also be coupled effectively by using a higher reaction temperature. Benzoic acids (3r–3v) were also relatively unreactive and required higher reaction temperatures in order for reasonable conversions to be obtained.

Figure 3. Scope of N-benzylamide synthesis using different carboxylic acids. All reactions were carried out at 80 °C for 5 h, and the solid phase workup procedure was used unless otherwise stated. (a) Aqueous workup procedure; (b) 80 °C for 15 h; (c) 100 °C for 15 h in a sealed tube.

The coupling of a selection of other combinations of acids and amines (Figure 4, 4a–4g) was explored, and yields were generally consistent with our observations of the relative reactivity of amines/acids outlined above. Thus, aliphatic amine/acid combinations (4a–4d) generally gave reasonable yields of the amide, even with fairly volatile components (4a, 4b). Less reactive picolinic acid underwent amidation in relatively good yield with glycine methyl ester (4e). The reaction of a fairly nucleophilic aniline with an unsaturated acid also proceeded in good yield (4f). Pleasingly, we were also able to prepare paracetamol (4g) in moderate yield by coupling acetic acid with 4-hydroxyaniline. Interestingly, monoamidation of a dicarboxylic acid could also be achieved in 53% yield (4h). In the majority of cases, the amides 2–4 could be purified by the solid phase workup procedure, with the exception of amides containing strongly basic (2i, 2j, 2t, 2u, 4e) or acidic (4h) groups, which generally required chromatographic purification.

Figure 4. Further scope of the amidation reaction. All reactions were carried out at 80 °C for 15 h and purified by solid phase workup unless otherwise stated. (a) Aqueous workup procedure; (b) 80 °C for 5 h; (c) purified by column chromatography.

Lactam formation could also be achieved effectively (Figure 5, 5a–5c). The background reaction for formation of six- (5a) and seven-membered (5b) lactams from simple thermal condensation was low in comparison to that observed in the presence of B(OCH₂CF₃)₃. Lactamization of Boc-l-ornithine (5c) proceeded in 84% yield.

Figure 5. Lactamization reactions. All reactions were carried out at 80 °C for 5 h unless otherwise stated and purified by solid phase workup. (a) Yield without B(OCH₂CF₃)₃; (b) 100 °C for 5 h in a sealed tube; (c) 80 °C for 15 h; (d) [α]_D²⁵ −9.5 (c 1.22, MeOH) [lit. (16) [α]_D²⁰ −10.6 (c 1.22, MeOH)].

To evaluate the amidation reaction on larger scales, both a secondary (4c) and a tertiary amide (2k) were prepared using gram quantities of material (Scheme 2). Although in both cases a slight reduction in yield was observed, more than 1 g of each amide could be synthesized in less than 15 mL of MeCN. In each case, the product was purified using the solid phase workup, without the need for aqueous workup or column chromatography. For comparison, the same reaction to give 1 g of 4c using a boronic acid catalyst would require ca. 70 mL of solvent. (9i)

Scheme 2. Gram Scale Amidation Reactions

Coupling of Acids with an Adjacent Chiral Center

The amidation of carboxylic acids bearing a chiral center at the α-position is of high importance, and the coupling of α-amino acids is of particular significance. While there are many methods for achieving such couplings, the fact that B(OCH₂CF₃)₃-mediated amidation reactions can be easily purified by a solid phase workup might offer greater convenience. The successful amidation of amino acids using boronic acid catalysts or other boron-based amidation reagents has not been reported to date. We therefore wished to explore the application of B(OCH₂CF₃)₃ to the coupling of a selection of amino acids bearing commonly used nitrogen protecting groups to determine whether the corresponding amides could be obtained without racemization (Figure 6).

The coupling of a range of protected amino acids with benzylamine proceeded in good yield (6a–6e) including both Boc (6a–6d) and Cbz (6e) protected examples. In most cases no significant racemization was observed (6a, 6b, 6d). Where small levels of racemization were observed, this could be reduced significantly by decreasing the reaction time, albeit at the expense of product yield (6b, 6c). The synthesis of prolinamide 6d is notable, as derivatives of this compound have been used as organocatalysts in a variety of reactions. (17) Dipeptides (6f, 6g) could also be obtained in moderate yield, by coupling of two suitably protected amino acids with no observable formation of diastereomeric products. Dipeptides 6f and 6g have previously been synthesized via carbodiimide coupling, (18-21) but purification by aqueous workup, recrystallization or chromatography was required.

Pleasingly, amino acids could also be coupled with cyclic secondary amines (6h–6l) in reasonable yield, and these couplings also proceeded with relatively low levels of racemization. The synthesis of amides 6h–6j has been reported using a range of different coupling reagents, (22-30) but the enantiomeric purity of the products was not directly determined in any of these cases. The preparation of benzamides 6k and 6l has never been previously reported. The preparation of N-benzylamide 6m was achieved in excellent yield with negligible racemization. The coupling of amino acids with acyclic secondary amines was unsuccessful (6n, 6o).

The above reactions serve to illustrate the scope of the B(OCH₂CF₃)₃ reagent for the coupling of acids bearing adjacent chiral centers. Commonly used nitrogen protecting groups (Boc, Cbz) are tolerated under the reaction conditions, and very little racemization is observed in many cases despite the high temperatures employed. Where racemization does occur, it can be reduced significantly by shortening the reaction time. Notably, the coupling of amino acids with secondary amines using conventional coupling reagents is often a considerable challenge, and an aqueous work up and/or chromatographic purification is generally required. Our method therefore offers a potentially valuable approach to tertiary amino acid amides, as it furnishes pure products in reasonable yield with high enantiopurity, following a simple solid phase workup.

Figure 6. Coupling of acids containing adjacent chiral centers. All reactions were carried out at 80 °C for 15 h unless otherwise stated and purified by solid phase workup. (a) 80 °C for 8 h; (b) 100 °C for 24 h in a sealed tube; (c) er measured after conversion to the N-benzoyl amide derivative; (d) 100 °C for 8 h in a sealed tube; (e) 80 °C for 5 h.

Transamidation of DMF using B(OCH₂CF₃)₃

In our preliminary communication, we reported the transamidation of a limited selection of primary amides using B(OCH₂CF₃)₃. Since this report, a number of alternative catalysts and reagents for transamidation reactions have been reported including hydroxylamine hydrochloride, (31) Cp₂ZrCl₂, (32) Cu(OAc)₂, (33) PhI(OAc)₂, (34) boric acid, (35) CeO₂ (36) and l-proline. (37) In many cases these reagents are cheap and readily available, and the reactions have a wide substrate scope. On this basis, it therefore seemed that the potential application of B(OCH₂CF₃)₃ as a reagent for transamidation of primary amides is somewhat limited. However, during our initial solvent screen for the direct amidation of carboxylic acids, we observed that B(OCH₂CF₃)₃ was highly effective for the transamidation of DMF. With this in mind, we opted to investigate the scope of this reaction. Recent literature methods for the N-formylation of amines include HCONH₂/NaOMe, (38) HCONH₂/NH₂OH·HCl, (31) HCONH₂/Cp₂ZrCl₂, (32) HCO₂H in the presence of protic ionic liquids, (39) and HCO₂H/HCO₂Na. (40) All of these methods require high temperatures, anhydrous conditions and purification by column chromatography. The direct transamidation of DMF has recently been achieved with boric acid, (35) PhI(OAc)₂, (34)l-proline, (37) and imidazole, (41) but at high temperatures, (34, 35) with extended reaction times, (34, 35, 41) and/or with purification by column chromatography. (41) We therefore anticipated that B(OCH₂CF₃)₃-mediated transamidation of DMF may provide a useful formylation method, especially if the products could be readily purified by solid phase workup.

The formylation of benzylamine was used as a model for optimization (Table 2). First, we confirmed that the background reaction, observed when the amine was heated in DMF at 100 °C in the absence of B(OCH₂CF₃)₃, was negligible (entry 1). In neat DMF with 2 equiv of B(OCH₂CF₃)₃, a 41% yield of formamide was obtained (entry 2). Surprisingly, the reaction was more effective with small quantities of DMF in acetonitrile as solvent (entries 3–9). Although reasonable yields were obtained with as little as 1 equiv of DMF (entry 3), the use of 10 equiv was found to be optimal (entry 8). The reaction temperature could be lowered to 80 °C without a detrimental effect on yield, and the pure formamide could be obtained in good yield after solid phase workup and evaporation (entry 10). Formylation of benzylamine could also be achieved with similar efficiency using formamide (88% yield) and N-methylformamide (94%). However, DMF is considerably cheaper and easier to separate from the formamide product than these alternative formyl donors.

Table 2. Formylation Optimizationa

entry	DMF [equiv]	yield [%]b
1	neatc	11
2	neatd	41
3	1	60
4	2	62
5	3	66
6	4	72
7	5	74
8	10	98
9	15	92
10e	10	95

Product isolated by solid phase workup followed by column chromatography unless otherwise stated.

Isolated yield.

DMF (0.5 M) as solvent, no B(OCH₂CF₃)₃.

DMF (0.5 M) as solvent.

80 °C, solid phase workup followed by evaporation of DMF, no column chromatography required.

The scope of this reaction was evaluated on a range of amines (Table 3). Aromatic and aliphatic amines underwent formylation in moderate to excellent yield (7a–7f). Amines with α-substituents such as α-methylbenzylamine gave the corresponding formamide in excellent yield (7d). The volatile N-butylformamide (7g) could be obtained in good yield as calculated by ¹H NMR, but a significant loss of the product was observed during isolation. Less nucleophilic systems such as aniline and related derivatives (7h, 7i) were formylated in relatively low yield. Secondary amines (7i, 7j) could also be formylated, although higher temperatures were required to obtain better yields.

Table 3. Formylation of Amines with DMF

^{Table a}

Isolated yield.

^{Table b}

Yield measured using mesitylene as an internal standard.

^{Table c}

100 °C for 5 h in a sealed tube.

Conclusion

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A convenient synthesis of B(OCH₂CF₃)₃ from readily available bulk chemicals has been reported, and the full scope of its application in direct amidation reactions has been explored. A wide range of acids and amines containing varying functionalities can be successfully used in B(OCH₂CF₃)₃-mediated amidation reactions, and the pure amide products can be isolated following an operationally simple solid phase workup procedure using commercially available resins, avoiding the need for aqueous workup or chromatographic purification. The amidation of a series of N-protected amino acids with both primary and secondary amines has been successfully demonstrated, and the products were obtained with high enantiopurity. The formylation of a series of primary and secondary amines via transamidation of DMF was also successfully achieved.

Experimental Section

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General Methods

All solvents and chemicals were used as supplied unless otherwise indicated. Reactions in MeCN at 100 °C were performed in a sealed (screw cap) carousel tube. All resins were washed with CH₂Cl₂ and dried under a vacuum prior to use. Column chromatography was carried out using silica gel, and analytical thin layer chromatography was carried out using aluminum-backed silica plates. Components were visualized using combinations of UV (254 nm) and potassium permanganate. [α]_D values are given in 10^–1 deg cm² g^–1, concentration (c) in g per 100 mL. ¹H NMR spectra were recorded at 300, 400, 500, or 600 MHz in the stated solvent using residual protic solvent CDCl₃ (δ = 7.26 ppm, s), DMSO (δ = 2.56 ppm, qn) or MeOD (δ = 4.87, s and 3.31, quintet) as the internal standard. Chemical shifts are quoted in ppm using the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; qn, quintet; m, multiplet; br, broad or a combination of these. The coupling constants (J) are measured in Hertz. ¹³C NMR spectra were recorded at 75, 100, 125, or 150 MHz in the stated solvent using the central reference of CDCl₃ (δ = 77.0 ppm, t), DMSO (δ = 39.52 ppm, septet) or MeOD (δ = 49.15 ppm, septet) as the internal standard. Chemical shifts are reported to the nearest 0.1 ppm. Mass spectrometry data were collected on either TOF or magnetic sector analyzers. The ionization method is reported in the experimental data. The data for amides 2a, 2d, 2e, 2g, 2h, 3j, 3l, 3o, 3q, 3r, 4a, 4b, 4d, 4f and 6b was reported in our preliminary communication. (13)

Tris-(2,2,2-trifluoroethyl) borate (13)

25 g Scale

A suspension of B₂O₃ (25.6 g, 0.37 mol) in 2,2,2-trifluoroethanol (53 mL, 0.73 mol) was stirred at 80 °C for 8 h. The reaction mixture was then filtered to remove excess boric anhydride. The filtrate was purified by distillation to give B(OCH₂CF₃)₃ as a clear liquid (36.0 g, 117 mmol, 48%).

50 g Scale (With CF₃CH₂OH Recovery)

A suspension of B₂O₃ (48.1 g, 0.69 mol) in 2,2,2-trifluoroethanol (100 mL, 1.37 mol) was stirred at 80 °C for 24 h. The reaction mixture was then filtered to remove excess boric anhydride. The filtrate was purified by distillation to give B(OCH₂CF₃)₃ as a clear liquid (46.3 g, 150 mmol, 33%). 2,2,2-Trifluoroethanol (38.4 g, 28%) was recovered during the distillation: bp 122–125 °C (760 Torr) [lit. (13) 120–123 °C (760 Torr)]; ν_max (film/cm^–1) 3165 (C–H), 1441 (C–F), 1376 (B–O), 1156 (C–O); δ_H (300 MHz, CDCl₃) 4.24 (q, J 8.3 6H); δ_C (75 MHz, CDCl₃) 61.8 (q, J 36.5), 123.2 (q, J 276); δ_F (282 MHz, CDCl₃) −77.06; Found (CI) [M + H]⁺ 309.0334 C₆H₇O₃F₉B, requires 309.0344.

General Procedure for Amidation of Carboxylic acids

All reactions were performed on a 1 mmol scale. B(OCH₂CF₃)₃ (2.0 mmol, 2 equiv) was added to a solution of acid (1.0 mmol, 1 equiv) and amine (1.0 mmol, 1 equiv) in MeCN (2 mL, 0.5 M). The reaction mixture was stirred at the indicated temperature (80 °C, or 100 °C in a sealed tube) for the indicated time (5–24 h).

Solid Phase Workup

After the indicated time, the reaction mixture was diluted with CH₂Cl₂ or EtOAc (3 mL) and water (0.5 mL). Amberlyst A-26(OH) (150 mg), Amberlyst 15 (150 mg) and Amberlite IRA743 (150 mg) were added to the reaction mixture, and it was stirred for 30 min. MgSO₄ was added to the reaction mixture, which was then filtered, the solids were washed three times with CH₂Cl₂ or EtOAc, and the filtrate was concentrated in vacuo to yield the amide product.

For amides 2i, 2j, 2t, 2u and 4e, Amberlyst 15 was not used. In these cases, the product was separated from any excess amine by column chromatography.

Aqueous Workup Procedure

After the reaction was complete, the solvent was removed under reduced pressure. The residue was redissolved in CH₂Cl₂ (15 mL) and washed with aqueous solutions of NaHCO₃ (15 mL, 1 M) and HCl (15 mL, 1 M), dried over MgSO₄, filtered and concentrated under reduced pressure to give the amide product.

General Procedure for the Formylation of Amines with DMF

All reactions were performed on a 1 mmol scale. B(OCH₂CF₃)₃ (2.0 mmol, 2 equiv) was added to a solution of amine (1.0 mmol, 1 equiv) and DMF (10.0 mmol, 10 equiv) in MeCN (2 mL, 0.5 M). The reaction mixture was stirred at 80 °C for 5 h. After 5 h, the reaction mixture was diluted with CH₂Cl₂ or EtOAc (3 mL) and water (0.5 mL). Amberlyst 15 (150 mg) and Amberlite IRA743 (150 mg) were added to the reaction mixture, and it was stirred for 30 min. The reaction mixture was dried over MgSO₄ and then filtered, the solids were washed three times with CH₂Cl₂ or EtOAc, and the filtrate was diluted with toluene (10 mL) and then concentrated in vacuo repeatedly (5 times) to yield the clean product.

N-(2-Methoxybenzyl)-2-phenylacetamide (2b)

Yellow solid (256 mg, 99%): mp 94–95 °C (CH₂Cl₂); ν_max (solid/cm^–1) 3284 (N–H), 3066, 3030, 2939, 2837 (C–H), 1646 (C═O); δ_H (600 MHz, CDCl₃) 3.58 (s, 2H), 3.66 (s, 3H), 4.39 (d, J 5.8, 2H), 6.01 (br s, 1H), 6.80 (d, J 8.1, 1H), 6.87 (td, J 7.4, 0.9, 1H), 7.17 (dd, J 7.4, 1.6, 1H), 7.22–7.25 (m, 3H), 7.27–7.30 (m, 1H), 7.33–7.36 (m, 2H); δ_C (150 MHz, CDCl₃) 40.0, 44.0, 55.1, 110.2, 120.7, 126.1, 127.4, 128.9, 129.0, 129.6, 129.7, 135.1, 157.6, 170.7; Found (EI) [M]⁺ 255.1251 C₁₆H₁₇O₂N, requires 255.1254.

N-(4-Methoxybenzyl)-2-phenylacetamide (2c) (42)

Yellow solid (252 mg, 99%): mp 139–141 °C (CH₂Cl₂) [lit. (42) 138–139 °C]; ν_max (solid/cm^–1) 3235 (N–H), 3063, 3032, 2969, 2936 (C–H), 1623 (C═O); δ_H (600 MHz, CDCl₃) 3.62 (s, 2H), 3.78 (s, 3H), 4.34 (d, J 5.8, 2H), 5.60 (br s, 1H), 6.81–6.83 (m, 2H), 7.09–7.12 (m, 2H), 7.25–7.26 (m, 1H), 7.26–7.30 (m, 2H), 7.32–7.36 (m, 2H); δ_C (150 MHz, CDCl₃) 43.2, 44.0, 55.4, 114.1, 127.5, 129.0, 129.2, 129.6, 130.3, 134.9, 159.1, 170.9; Found (EI) [M]⁺ 255.1257 C₁₆H₁₇O₂N, requires 255.1254.

N-(2-(1H-Indol-3-yl)ethyl)-2-phenylacetamide (2f) (43)

Yellow solid (158 mg, 57%): mp 145–146 °C (CH₂Cl₂) [lit. (43) 151–153 °C]; ν_max (solid/cm^–1) 3391 (N–H), 3249 (N–H), 3062, 3033, 2920, 2850 (C–H), 1634 (C═O); δ_H (500 MHz, CDCl₃) 2.90 (t, J 6.7, 2H), 3.50–3.56 (m, 4H), 5.44 (br s, 1H), 6.77 (s, 1H), 7.08–7.15 (m, 3H), 7.18–7.22 (m, 1H), 7.23–7.28 (m, 1H), 7.26–7.30 (m, 2H), 7.35 (d, J 8.1, 1H), 7.54 (d, J 7.8, 1H), 8.00 (br s, 1H); δ_C (125 MHz, CDCl₃) 25.1, 39.8, 44.0, 111.3, 112.8, 118.7, 119.6, 122.0, 122.3, 127.3, 129.0 (2C), 129.5, 135.0, 136.4, 171.0; Found (ES) [M + Na]⁺ 301.1305 C₁₈H₁₈ON₂Na, requires 301.1317.

N-Methyl-N′-phenylacetylpiperazine (2i) (44)

Purified by column chromatography (Et₂O:MeOH:NEt₃ 89:10:1). Yellow oil (170 mg, 96%): ν_max (film/cm^–1) 3029, 2940, 2853, 2795 (C–H), 1627 (C═O); δ_H (500 MHz, CDCl₃) 2.20 (t, J 5.1, 2H), 2.25 (s, 3H), 2.34 (t, J 5.1, 2H), 3.45 (t, J 5.1, 2H), 3.66 (t, J 5.1, 2H), 3.72 (s, 2H), 7.21–7.25 (m, 3H), 7.29–7.33 (m, 2H); δ_C (125 MHz, CDCl₃) 41.0, 41.7, 46.0 (2C), 54.7, 55.0, 126.9, 128.7, 128.8, 135.1, 169.5.

N-Phenyl-N′-phenylacetylpiperazine (2j)

Purified by column chromatography (Et₂O). Brown solid (209 mg, 76%): mp 91–93 °C (CH₂Cl₂); ν_max (solid/cm^–1) 2919, 2827 (C–H), 1632 (C═O); δ_H (600 MHz, CDCl₃) 2.95–2.98 (m, 2H), 3.10–3.13 (m, 2H), 3.56–3.59 (m, 2H), 3.78–3.82 (m, 4H), 6.87–6.93 (m, 3H), 7.25–7.31 (m, 5H), 7.33–7.37 (m, 2H); δ_C (150 MHz, CDCl₃) 41.2, 41.8, 46.1, 49.3, 49.6, 116.7, 120.6, 127.1, 128.8, 129.0, 129.4, 135.2, 151.0, 169.6; Found (ES) [M + H]⁺ 281.1656 C₁₈H₂₁ON₂, requires 281.1654.

N-Phenylacetylmorpholine (2k) (45)

White solid (182 mg, 89%): mp 65–67 °C (CH₂Cl₂) [lit. (45) 62–64 °C]; ν_max (solid/cm^–1) 3064, 3033, 2961, 2917, 2893, 2851 (C–H), 1640 (C═O); δ_H (400 MHz, CDCl₃) 3.40–3.44 (m, 2H), 3.44–3.48 (m, 2H), 3.63 (s, 4H), 3.72 (s, 2H), 7.21–7.27 (m, 3H), 7.29–7.34 (m, 2H); δ_C (100 MHz, CDCl₃) 40.8, 42.1, 46.5, 66.4, 66.8, 126.9, 128.5, 128.8, 134.8, 169.6.

2-Phenyl-1-(pyrrolidin-1-yl)ethanone (2l)

Clear oil (185 mg, 97%): ν_max (film/cm^–1) 3061, 3030, 2971, 2874 (C–H), 1623 (C═O); δ_H (500 MHz, CDCl₃) 1.80 (quintet, J 6.7, 2H), 1.88 (quintet, J 6.7, 2H), 3.39 (t, J 6.7, 2H), 3.46 (t, J 6.7, 2H), 3.63 (s, 2H), 7.19–7.23 (m, 1H), 7.24–7.31 (m, 4H); δ_C (125 MHz, CDCl₃) 24.4, 26.2, 42.3, 46.0, 47.0, 126.7, 128.6, 129.0, 135.0, 169.6; Found (ES+) [M + H]⁺ 190.1226 C₁₂H₁₆ON, requires 190.1232.

N-Phenylacetylthiomorpholine (2m) (46)

Yellow solid (194 mg, 89%): mp 73–74 °C (CH₂Cl₂) [lit. (46) 73–75 °C]; ν_max (solid/cm^–1) 3024, 2960, 2911 (C–H), 1639 (C═O); δ_H (400 MHz, CDCl₃) 2.26–2.30 (m, 2H), 2.52–2.59 (m, 2H), 3.65–3.70 (m, 2H), 3.72 (s, 2H), 3.85–3.90 (m, 2H), 7.20–7.26 (m, 3H), 7.29–7.34 (m, 2H); δ_C (100 MHz, CDCl₃) 27.2, 27.4, 41.3, 44.4, 48.8, 126.9, 128.5, 128.9, 134.8, 169.4.

N,N-Dimethyl-2-phenylacetamide (2n) (47)

White solid (134 mg, 82 mg): mp 37–39 °C (CH₂Cl₂) [lit. (47) 38–40 °C]; ν_max (solid/cm^–1) 3062, 3029, 2931 (C–H), 1634 (C═O); δ_H (600 MHz, CDCl₃) 2.91 (s, 3H), 2.93 (s, 3H), 3.66 (s, 2H), 7.17–7.23 (m, 3H), 7.25–7.28 (m, 2H); δ_C (150 MHz, CDCl₃) 35.7, 37.8, 41.1, 126.8, 128.7, 128.9, 135.2, 171.1.

N,N-Dibenzyl-2-phenylacetamide (2o) (48)

Purified by column chromatography (Et₂O:PE 3:1). Colorless oil (37 mg, 12%): ν_max (film/cm^–1) 3062, 3029, 2925 (C–H), 1639 (C═O); δ_H (500 MHz, CDCl₃, 35 °C) 3.83 (s, 2H), 4.47 (s, 2H), 4.66 (s, 2H), 7.11–7.17 (m, 2H), 7.19–7.25 (m, 2H), 7.25–7.42 (m, 12H); δ_C (125 MHz, CDCl₃, 35 °C) 41.0, 48.3, 50.3, 126.5, 126.9, 127.4, 127.6, 128.3, 128.5, 128.7, 128.8, 128.9, 135.0, 136.5, 137.3, 171.6.

N,2-Diphenylacetamide (2p) (49)

Off white solid (125 mg, 60%): mp 116–118 °C (CH₂Cl₂) [lit. (49) 116–117 °C]; ν_max (solid/cm^–1) 3254 (N–H), 3135, 3061, 3025 (C–H), 1655 (C═O); δ_H (600 MHz, CDCl₃) 3.69 (s, 2H), 7.09 (t, J 7.4, 1H), 7.27 (t, J 7.8, 2H), 7.33–7.34 (m, 3H), 7.36–7.39 (m, 2H), 7.45 (d, J 8.0, 2H), 7.61 (br s, 1H); δ_C (150 MHz, CDCl₃) 44.8, 120.1, 124.6, 127.7, 129.1, 129.3, 129.6, 134.7, 137.9, 169.6.

N-(2-Methoxyphenyl)-2-phenylacetamide (2q) (50)

Yellow solid (143 mg, 61%): mp 82–83 °C (CH₂Cl₂) [lit. (50) 80–81 °C]; ν_max (solid/cm^–1) 3284 (N–H), 3028, 3011, 2959, 2939, 2918, 2837 (C–H), 1648 (C═O), δ_H (500 MHz, CDCl₃) 3.72 (s, 3H), 3.76 (s, 2H), 6.80 (dd, J 8.1, 1.1, 1H), 6.93 (td, J 7.8, 1.1, 1H), 7.01 (td, J 7.8, 1.5, 1H), 7.31–7.37 (m, 3H), 7.37–7.42 (m, 2H), 7.79 (br s, 1H), 8.35 (dd, J 8.0, 1.4, 1H); δ_C (125 MHz, CDCl₃) 45.3, 55.7, 110.0, 119.6, 121.2, 123.8, 127.5, 127.7, 129.1, 129.7, 134.7, 147.9, 168.9.

2-Phenyl-N-p-tolylacetamide (2r) (49)

White solid (105 mg, 53%): mp 132–133 °C (CH₂Cl₂) [lit. (49) 131–132 °C]; ν_max (solid/cm^–1) 3289 (N–H), 3063, 3031, 2922 (C–H), 1650 (C═O); δ_H (500 MHz, CDCl₃) 2.29 (s, 3H), 3.73 (s, 2H), 7.01 (br s, 1H), 7.08 (d, J 8.4, 2H), 7.28 (d, J 8.4, 2H), 7.31–7.36 (m, 3H), 7.38–7.42 (m, 2H); δ_C (125 MHz, CDCl₃) 23.6, 47.4, 122.9, 130.2, 131.8, 132.2, 133.3, 136.8, 137.5, 138.0, 172.1.

N-(4-Methoxyphenyl)-2-phenylacetamide (2s) (49)

White solid (164 mg, 68%): mp 122–123 °C (CH₂Cl₂) [lit. (49) 124–125 °C]; ν_max (solid/cm^–1) 3315 (N–H), 3084, 3026, 3009, 2943 (C–H), 1650 (C═O); δ_H (500 MHz, CDCl₃) 3.73 (s, 2H), 3.77 (s, 3H), 6.80–6.83 (m, 2H), 6.97 (br s, 1H), 7.29–7.36 (m, 5H), 7.38–7.42 (m, 2H); δ_C (125 MHz, CDCl₃) 44.8, 55.5, 114.1, 121.9, 127.7, 129.3, 129.6, 130.7, 134.6, 156.6, 169.0.

N-(Pyridin-3-yl)-2-phenylacetamide (2t)

Purified by column chromatography (4% MeOH in EtOAc). White solid (114 mg, 53%): mp 107–108 °C (CH₂Cl₂); ν_max (solid/cm^–1) 3170 (N–H), 3032, 2971 (C–H), 1686 (C═O); δ_H (500 MHz, CDCl₃) 3.68 (s, 2H), 7.20 (dd, J 8.3, 4.7, 1H), 7.23–7.33 (m, 5H), 8.06–8.10 (m, 1H), 8.27 (dd, J 4.7, 1.2, 1H), 8.57 (d, J 2.4, 1H), 9.05 (br s, 1H); δ_C (125 MHz, CDCl₃) 44.3, 123.9, 127.5, 127.6, 129.0, 129.3, 134.4, 135.4, 141.3, 144.9, 170.4; Found (EI) [M]⁺ 212.0947 C₁₃H₁₂ON₂, requires 212.0944.

N-(Pyridin-2-yl)-2-phenylacetamide (2u) (49)

Purified by column chromatography (EtOAc:PE 3:1, 10% NEt₃). White solid (25 mg, 12%): mp 121–122 °C (CH₂Cl₂) [lit. (49) 122–124 °C]; ν_max (solid/cm^–1) 3230 (N–H), 3046, 2959, 2921 (C–H), 1656 (C═O); δ_H (500 MHz, CDCl₃) 3.74 (s, 2H), 6.98–7.03 (m, 1H), 7.27–7.33 (m, 3H), 7.33–7.38 (m, 2H), 7.66–7.71 (m, 1H), 8.19–8.27 (m, 2H), 8.52 (br s, 1H); δ_C (125 MHz, CDCl₃) 45.1, 114.1, 120.0, 127.8, 129.3, 129.6, 134.0, 138.5, 147.7, 151.3, 169.6; Found (ES) [M + H]⁺ 213.1035 C₁₃H₁₃ON₂, requires 213.1028.

N-tert-Butyl-2-phenylacetamide (2v) (51)

White solid (116 mg, 60%): mp 104–106 °C (CH₂Cl₂) [lit. (51) 103 °C]; ν_max (solid/cm^–1) 3303 (N–H), 3063, 2962, 2872 (C–H), 1638 (C═O); δ_H (600 MHz, CDCl₃) 1.28 (s, 9H), 3.48 (s, 2H), 5.17 (br s, 1H), 7.24 (d, J 7.2, 2H), 7.26–7.30 (m, 1H), 7.35 (t, J 7.4, 2H); δ_C (150 MHz, CDCl₃) 28.8, 45.0, 51.4, 127.3, 129.1, 129.4, 135.6, 170.4.

N-Benzyl-2-(naphthalen-2-yl)acetamide (3a) (52)

Yellow solid (225 mg, 81%): mp 168–169 °C (CH₂Cl₂) [lit. (52) 170–174 °C]; ν_max (solid/cm^–1) 3225 (N–H), 3053, 3030, 2976, 2936 (C–H), 1628 (C═O); δ_H (500 MHz, CDCl₃) 3.79 (s, 2H), 4.41 (d, J 5.8, 2H), 5.81 (br s, 1H), 7.18 (d, J 7.0, 2H), 7.21–7.30 (m, 3H), 7.39 (dd, J 8.3, 1.7, 1H), 7.46–7.52 (m, 2H), 7.72 (br s, 1H), 7.78–7.82 (m, 1H), 7.82–7.85 (m, 2H); δ_C (125 MHz, CDCl₃) 43.7, 44.1, 126.2, 126.5, 127.4, 127.5, 127.6, 127.7, 127.8, 128.4, 128.7, 129.0, 132.3, 132.6, 133.6, 138.2, 170.8.

N-Benzyl-2,2-diphenylacetamide (3b) (53)

Yellow solid (247 mg, 81%): mp 127–128 °C (CH₂Cl₂) [lit. (53) 126–128 °C]; ν_max (solid/cm^–1) 3311 (N–H), 3060, 3030, 2930 (C–H), 1634 (C═O); δ_H (500 MHz, CDCl₃) 4.48 (d, J 5.7, 2H), 4.96 (s, 1H), 5.94 (br s, 1H), 7.19–7.22 (m, 2H), 7.24–7.30 (m, 8H), 7.30–7.35 (m, 5H); δ_C (125 MHz, CDCl₃) 43.9, 59.3, 127.4, 127.6, 127.7, 128.8, 128.9, 129.0, 138.2, 139.4, 171.8.

N-Benzyl-2-(4-methoxyphenyl)acetamide (3c) (54)

Yellow solid (232 mg, 90%): mp 134–135 °C (CH₂Cl₂) [lit. (54) 136 °C]; ν_max (solid/cm^–1) 3286 (N–H), 3082, 3063, 3033, 2968, 2838 (C–H), 1635 (C═O); δ_H (600 MHz, CDCl₃) 3.57 (s, 2H), 3.79 (s, 3H), 4.40 (d, J 5.8, 2H), 5.75 (br s, 1H), 6.86–6.89 (m, 2H), 7.16–7.19 (m, 4H), 7.23–7.26 (m, 1H), 7.28–7.31 (m, 2H); δ_C (150 MHz, CDCl₃) 43.0, 43.7, 55.4, 114.6, 126.8, 127.5, 127.6, 128.8, 130.7, 138.3, 159.0, 171.5.

N-Benzyl-2-(2-bromophenyl)acetamide (3d) (55)

Yellow solid (276 mg, 90%): mp 143–144 °C (CH₂Cl₂) [lit. (55) 144–145 °C]; ν_max (solid/cm^–1) 3272 (N–H), 3055, 3030, 2920, 2871 (C–H), 1642 (C═O); δ_H (600 MHz, CDCl₃) 3.77 (s, 2H), 4.44 (d, J 5.7, 2H), 5.75 (br s, 1H), 7.16 (td, J 7.7, 1.7, 1H), 7.21–7.27 (m, 3H), 7.30 (app t, J 7.6, 3H), 7.37 (dd, J 7.5, 1.6, 1H), 7.58 (dd, J 8.0, 1.0, 1H); δ_C (150 MHz, CDCl₃) 43.8, 44.2, 125.0, 127.6, 127.7, 128.2, 128.8, 129.4, 131.9, 133.3, 134.8, 138.1, 169.5.

N-Benzyl-2-(4-bromophenyl)acetamide (3e)

Yellow solid (289 mg, 94%): mp 165–166 °C (CH₂Cl₂); ν_max (solid/cm^–1) 3280 (N–H), 3056, 3026, 2917, 2872 (C–H), 1642 (C═O); δ_H (600 MHz, CDCl₃) 3.55 (s, 2H), 4.41 (d, J 5.6, 2H), 5.72 (br s, 1H), 7.15 (d, J 8.4, 2H), 7.19 (d, J 7.0, 2H), 7.25–7.28 (m, 1H), 7.29–7.33 (m, 2H), 7.45–7.48 (m, 2H); δ_C (150 MHz, CDCl₃) 43.2, 43.8, 121.6, 127.7, 127.8, 128.9, 131.2, 132.2, 133.8, 138.0, 170.2; Found (EI) [M]⁺ 303.0256 C₁₅H₁₄ONBr, requires 303.0253.

N-Benzyl-2-(3,4-dimethoxyphenyl)acetamide (3f)

Brown solid (235 mg, 81%): mp 100–101 °C (CH₂Cl₂) [lit. (56) 98–100 °C]; ν_max (solid/cm^–1) 3297 (N–H), 3065, 3033, 3000, 2936, 2835 (C–H), 1634 (C═O); δ_H (600 MHz, CDCl₃) 3.58 (s, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 4.41 (d, J 5.6, 2H), 5.74 (br s, 1H), 6.76–6.80 (m, 2H), 6.83 (d, J 8.0, 1H), 7.18 (d, J 7.0, 2H), 7.23–7.26 (m, 1H), 7.28–7.31 (m, 2H); δ_C (150 MHz, CDCl₃) 43.6, 43.7, 55.98, 56.02, 111.6, 112.4, 121.8, 127.2, 127.58, 127.61, 128.8, 138.3, 148.4, 149.4, 171.3; Found (EI) [M]⁺ 285.1353 C₁₇H₁₉O₃N, requires 285.1359.

N-Benzyl-2-(4-chlorophenyl)acetamide (3g) (57)

Yellow solid (244 mg, 93%): mp 157–158 °C (CH₂Cl₂) [lit. (57) 151–153 °C]; ν_max (solid/cm^–1) 3277 (N–H), 3056, 3027, 2918, 2874 (C–H), 1642 (C═O), 690 (C–Cl); δ_H (600 MHz, CDCl₃) 3.56 (s, 2H), 4.41 (d, J 5.8, 2H), 5.76 (br s, 1H), 7.18–7.22 (m, 4H), 7.24–7.28 (m, 1H), 7.29–7.32 (m, 4H); δ_C (150 MHz, CDCl₃) 43.1, 43.8, 127.69, 127.74, 128.9, 129.2, 130.9, 133.3, 133.5, 138.1, 170.4.

N-Benzyl-2-(thiophen-3-yl)acetamide (3h)

Yellow solid (212 mg, 91%): mp 96–98 °C (CH₂Cl₂); ν_max (solid/cm^–1) 3279 (N–H), 3086, 3062, 3032, 2925 (C–H), 1635 (C═O); δ_H (600 MHz, CDCl₃) 3.65 (s, 2H), 4.42 (d, J 5.8, 2H), 5.85 (br s, 1H), 7.01 (d, J 4.8, 1H), 7.14–7.15 (m, 1H), 7.19 (d, J 7.5, 2H), 7.23–7.34 (m, 4H); δ_C (150 MHz, CDCl₃) 38.3, 43.7, 123.7, 127.0, 127.61, 127.62, 128.6, 128.8, 134.8, 138.2, 170.5; Found (ES) [M + H]⁺ 232.0789 C₁₃H₁₄ONS, requires 232.0796.

N-Benzyl-2-(4-phenoxyphenyl)acetamide (3i)

Yellow solid (298 mg, 95%): mp 125–126 °C (CH₂Cl₂); ν_max (solid/cm^–1) 3285 (N–H), 3085, 3064, 3033, 2921 (C–H), 1636 (C═O); δ_H (600 MHz, CDCl₃) 3.60 (s, 2H), 4.43 (d, J 5.9, 2H), 5.71 (br s, 1H), 6.96–7.01 (m, 4H), 7.10–7.13 (m, 1H), 7.18–7.21 (m, 2H), 7.21–7.24 (m, 2H), 7.25–7.28 (m, 1H), 7.29–7.36 (m, 4H); δ_C (150 MHz, CDCl₃) 43.2, 43.8, 119.2, 119.3, 123.6, 127.6, 127.7, 128.8, 129.5, 129.9, 130.9, 138.2, 156.8, 157.0, 171.0; Found (EI) [M]⁺ 317.1416 C₂₁H₁₉O₂N, requires 317.1410.

Boc-Sarcosine-benzamide (3k) (58)

Yellow solid (265 mg, 95%): mp 82–84 °C (CH₂Cl₂) [lit. (58) 83–85 °C]; ν_max (solid/cm^–1) 3310 (N–H), 3067, 2978, 2931 (C–H), 1664 (C═O), 1685 (C═O); δ_H (400 MHz, CDCl₃, 58 °C) 1.40 (s, 9H), 2.90 (s, 3H), 3.83 (s, 2H), 4.41 (d, J 5.9, 2H), 6.52 (br s, 1H), 7.19–7.24 (m, 3H), 7.25–7.31 (m, 2H); δ_C (100 MHz, CDCl₃, 58 °C) 28.2, 35.7, 43.3, 53.4, 80.6, 127.3, 127.5, 128.6, 138.2, 155.9, 169.1; Found (EI) [M]⁺ 278.1629 C₁₅H₂₂O₃N₂, requires 278.1625.

(E)-N-Benzyl-3-(thiophen-3-yl)acrylamide (3m)

Yellow solid (217 mg, 88%): mp 107–110 °C (CH₂Cl₂); ν_max (solid/cm^–1) 3275 (N–H), 3029, 2971 (C–H), 1739 (C═O); δ_H (600 MHz, CDCl₃) 4.55 (d, J 5.7, 2H), 6.05 (br s, 1H), 6.26 (d, J 15.5, 1H), 7.22–7.24 (m, 1H), 7.26–7.36 (m, 6H), 7.42 (d, J 2.1, 1H), 7.65 (d, J 15.5, 1H); δ_C (150 MHz, CDCl₃) 44.0, 120.2, 125.1, 126.9, 127.4, 127.7, 128.0, 128.9, 135.2, 137.8, 138.3, 166.1; Found (ES+) [M + H]⁺ 244.0800 C₁₄H₁₄NOS, requires 244.0796.

(E)-N-Benzyl-2-methyl-3-phenylacrylamide (3n)

White solid (229 mg, 90%): mp 120–121 °C (CH₂Cl₂); ν_max (solid/cm^–1) 3332 (N–H), 3079, 3059, 2921, 2852 (C–H), 1531 (C═O); δ_H (600 MHz, CDCl₃) 2.11 (s, 3H), 4.56 (d, J 5.7, 2H), 6.69 (br s, 1H), 7.27–7.40 (m, 11H); δ_C (150 MHz, CDCl₃) 14.5, 44.2, 127.7, 127.98, 128.04, 128.5, 128.9, 129.5, 131.9, 134.3, 136.2, 138.5, 169.6; Found (ES) [M + H]⁺ 252.1394 C₁₇H₁₈ON, requires 252.1388.

N-Benzyl-2,2,2-trifluoroacetamide (3p) (59)

Yellow solid (183 mg, 89%): mp 72–74 °C (CH₂Cl₂) [lit. (59) 70–71 °C]; ν_max (solid/cm^–1) 3300 (N–H), 3110, 3035, 2923 (C–H), 1702 (C═O); δ_H (500 MHz, CDCl₃) 4.54 (d, J 5.8, 2H), 6.52 (br s, 1H), 7.28–7.32 (m, 2H), 7.32–7.41 (m, 3H); δ_C (125 MHz, CDCl₃) 43.9, 116.0 (q, J 285.4), 128.0, 128.2, 129.0, 136.1, 157.5 (q, J 36.9); δ_F (282 MHz, CDCl₃) −76.2.

N-Benzyl-4-methoxybenzamide (3s) (60)

Yellow solid (172 mg, 71%): mp 129–130 °C (CH₂Cl₂) [lit. (60) 129–130 °C]; ν_max (solid/cm^–1) 3256 (N–H), 3058, 2957, 2930, 2834 (C–H), 1631 (C═O); δ_H (500 MHz, CDCl₃) 3.85 (s, 3H), 4.64 (d, J 5.7, 2H), 6.28 (br s, 1H), 6.90–6.94 (m, 2H), 7.28–7.32 (m, 1H), 7.36 (m, 4H), 7.74–7.77 (m, 2H); δ_C (125 MHz, CDCl₃) 44.1, 55.5, 113.8, 126.7, 127.6, 128.0, 128.8, 128.9, 138.5, 162.3, 167.0.

N-Benzyl-4-(trifluoromethyl)benzamide (3t) (61)

Yellow solid (212 mg, 76%): mp 168–170 °C (CH₂Cl₂) [lit. (61) 149–151 °C]; ν_max (solid/cm^–1) 3326 (N–H), 3091, 3071, 3036 (C–H), 1643 (C═O); δ_H (600 MHz, CDCl₃) 4.65 (d, J 5.6, 2H), 6.53 (br s, 1H), 7.29–7.33 (m, 1H), 7.33–7.38 (m, 4H), 7.68 (d, J 8.2, 2H), 7.89 (d, J 8.2, 2H); δ_C (150 MHz, CDCl₃) 44.5, 123.7 (q, J 272.5), 125.8 (q, J 3.8), 127.6, 128.0, 128.1, 129.0, 133.4 (q, J 32.7), 137.7, 137.8, 166.2; δ_F (282 MHz, CDCl₃) −63.4.

N,2-Dibenzylbenzamide (3u)

Yellow solid (184 mg, 61%): mp 119–120 °C (CH₂Cl₂); ν_max (solid/cm^–1) 3296 (N–H), 3057, 3025, 3008, 2921, 2873 (C–H), 1633 (C═O), δ_H (600 MHz, CDCl₃) 4.22 (s, 2H), 4.49 (d, J 5.6, 2H), 5.86 (br s, 1H), 7.13 (d, J 7.1, 2H), 7.16–7.19 (m, 3H), 7.21–7.25 (m, 4H), 7.26–7.32 (m, 3H), 7.33–7.37 (m, 1H), 7.39–7.42 (m, 1H); δ_C (150 MHz, CDCl₃) 39.0, 44.1, 126.2, 126.5, 127.3, 127.7, 128.0, 128.6, 128.9, 129.0, 130.3, 131.3, 136.5, 137.9, 139.0, 140.9, 169.9; Found (ES) [M + H]⁺ 302.1532 C₂₁H₂₀ON, requires 302.1545.

N-Benzyl-4-iodobenzamide (3v) (62)

White solid (124 mg, 37%): mp 167–168 °C (CH₂Cl₂) [lit. (62) 166–167 °C]; ν_max (solid/cm^–1) 3311 (N–H), 3083, 3060, 3028 (C–H), 1640 (C═O); δ_H (600 MHz, DMSO) 4.47 (d, J 6.0, 2H), 7.22–7.26 (m, 1H), 7.29–7.35 (m, 4H), 7.66–7.69 (m, 2H), 7.84–7.88 (m, 2H), 9.10 (br t, J 6.0, 1H); δ_C (150 MHz, DMSO) 42.7, 98.9, 126.8, 127.3, 128.3, 129.3, 133.8, 137.2, 139.5, 165.6; Found (EI) [M + H]⁺ 337.9962 C₁₄H₁₃ONI, requires 337.9958.

N-Butyl-2-p-tolylacetamide (4c) (63)

White solid (188 mg, 92%): mp 82–83 °C (CH₂Cl₂) [lit. (63) 73–74 °C]; ν_max (solid/cm^–1) 3301 (N–H), 2959, 2931, 2866 (C–H), 1649 (C═O); δ_H (500 MHz, CDCl₃) 0.86 (t, J 7.3, 3H), 1.24 (sextet, J 7.3, 2H), 1.39 (quintet, J 7.3, 2H), 2.34 (s, 3H), 3.18 (dt, J 7.3, 6.0, 2H), 3.52 (s, 2H), 5.43 (br s, 1H), 7.11–7.17 (m, 4H); δ_C (125 MHz, CDCl₃) 13.8, 20.0, 21.2, 31.6, 39.5, 43.6, 129.5, 129.8, 132.0, 137.1, 171.2; Found (EI) [M]⁺ 205.1464 C₁₃H₁₉ON, requires 205.1461.

Methyl 2-(picolinamido)acetate (4e) (64)

Purified by column chromatography (PE:EtOAc 1:1). White solid (132 mg, 72%): mp 82–84 °C (CH₂Cl₂) [lit. (64) 81–82 °C]; ν_max (film/cm^–1) 3375 (N–H), 3059, 2954, 2852 (C–H), 1746 (C═O), 1668 (C═O); δ_H (600 MHz, CDCl₃) 3.74 (s, 3H), 4.23 (d, J 5.7, 2H), 7.38–7.42 (m, 1H), 7.80 (t, J 7.6, 1H), 8.13 (d, J 7.6, 1H), 8.49 (br s, 1H), 8.53 (br d, J 4.5); δ_C (150 MHz, CDCl₃) 41.3, 52.5, 122.4, 126.6, 137.4, 148.4, 149.3, 164.7, 170.3.

N-(4-Hydroxyphenyl)acetamide (4g) (65)

White solid (97 mg, 69%): mp 169–170 °C (CH₂Cl₂) [lit. (65) 167–168 °C]; ν_max (solid/cm^–1) 3242 (N–H/O–H), 1632 (C═O); δ_H (600 MHz, MeOD) 2.07 (s, 3H), 6.71–6.74 (m, 2H), 7.28–7.32 (m, 2H); δ_C (150 MHz, MeOD) 23.5, 116.2, 123.4, 131.7, 155.4, 171.4.

2-(4-(2-(Benzylamino)-2-oxoethyl)phenyl)acetic acid (4h)

B(OCH₂CF₃)₃ (621.8 mg, 2.02 mmol, 2 equiv) was added to a solution of phenylene diacetic acid (192 mg, 0.99 mmol, 1 equiv) and benzylamine (0.11 mL, 1.01 mmol, 1 equiv) in MeCN (2 mL, 0.5 M). The reaction mixture was stirred at 80 °C for 5 h. After 5 h the solvent was removed in vacuo, and the residue was diluted in Et₂O (20 mL), washed with NaHCO₃ (20 mL, 1 M), and extracted with Et₂O (3 × 20 mL). The aqueous layer was acidifed with HCl (1 M) and extracted with CH₂Cl₂ (3 × 20 mL). The organic layer was dried over MgSO₄ and concentrated in vacuo to yield the product as a white solid (146 mg, 0.52 mmol, 52%): mp 163–166 °C (CH₂Cl₂); ν_max (solid/cm^–1) 3284 (N–H/O–H), 3030, 3060 (C–H), 1699 (C═O), 1632 (C═O); δ_H (600 MHz, DMSO-d₆) 3.45 (s, 2H), 3.53 (s, 2H), 4.26 (d, J 6.0, 2H), 7.16–7.19 (m, 2H), 7.20–7.25 (m, 5H), 7.29–7.32 (m, 2H), 8.55 (br t, J 5.6, 1H), 12.31 (br s, 1H); δ_C (150 MHz, DMSO-d₆) 40.3, 42.0, 42,2, 126.8, 127.3, 128.3, 128.9, 129.3, 133.1, 134.7, 139.5, 170.2, 172.8; Found (EI) [M + H]⁺ 284.1279 C₁₇H₁₈O₃N, requires 284.1287.

Piperidin-2-one (5a) (66)

Colorless oil (95 mg, 99%): ν_max (film/cm^–1) 3245 (N–H), 2945, 2870 (C–H), 1637 (C═O); δ_H (500 MHz, CDCl₃) 1.69–1.82 (m, 4H), 2.30 (t, J 6.5, 2H), 3.26–3.32 (m, 2H), 7.03 (br s, 1H); δ_C (125 MHz, CDCl₃) 20.8, 22.2, 31.5, 42.1, 172.9.

Azepan-2-one (5b) (57)

White solid (100 mg, 86%): mp 67–68 °C (CH₂Cl₂) [lit. (57) 66–68 °C]; ν_max (solid/cm^–1) 3202 (N–H), 2927, 2855 (C–H), 1648 (C═O); δ_H (500 MHz, CDCl₃) 1.60–1.71 (m, 4H), 1.72–1.78 (m, 2H), 2.42–2.47 (m, 2H), 3.17–3.22 (m, 2H), 6.42 (br s, 1H); δ_C (125 MHz, CDCl₃) 23.3, 29.8, 30.6, 36.8, 42.8, 179.5; Found (EI) [M]⁺ 113.0828 C₆H₁₁ON, requires 113.0835.

(S)-tert-Butyl 2-oxopiperidin-3-ylcarbamate (5c) (16)

White solid (180 mg, 84%): mp 100–101 °C (CH₂Cl₂) [lit. (16) 101–103 °C]; [α]_D²⁵ −9.5 (c 1.22, MeOH) [lit. (16) [α]_D²⁰ −10.6 (c 1.22, MeOH)]; ν_max (solid/cm^–1) 3264 (N–H), 2968 (C–H), 1715 (C═O), 1652 (C═O); δ_H (400 MHz, CDCl₃, 58 °C) 1.45 (s, 9H), 1.54–1.67 (m, 1H), 1.82–1.93 (m, 2H), 2.41–2.50 (m, 1H), 3.27–3.33 (m, 2H), 4.01 (dt, J 11.3, 5.6, 1H), 5.45 (br s, 1H), 6.33 (br s, 1H); δ_C (100 MHz, CDCl₃, 58 °C) 21.1, 27.9, 28.3, 41.7, 51.6, 79.5, 155.8, 171.6.

Boc-l-Methionine-benzamide (6a) (67)

Yellow solid (266 mg, 79%): mp 98–100 °C (CH₂Cl₂); [α]_D²⁵–9.1 (c 1.1, CH₂Cl₂) [lit. (67) [α]_D²⁴ −9.2 (c 1.1, CH₂Cl₂)]; ν_max (solid/cm^–1) 3335 (N–H), 3314 (N–H), 3061, 3027, 2968, 2936 (C–H), 1679 (C═O), 1655 (C═O); δ_H (400 MHz, CDCl₃, 58 °C) 1.41 (s, 9H), 1.88–1.97 (m, 1H), 2.05 (s, 3H), 2.06–2.15 (m, 1H), 2.46–2.59 (m, 2H), 4.28 (app q, J 7.1, 1H), 4.36 (dd, J 14.8, 5.8, 1H), 4.43 (dd, J 14.8, 5.9, 1H), 5.42 (br d, J 8.1, 1H), 7.19–7.25 (m, 3H), 7.26–7.30 (m, 2H), 6.86 (br s, 1H); δ_C (100 MHz, CDCl₃, 58 °C) 15.2, 28.3, 30.4, 32.0, 43.4, 54.1, 80.1, 127.3, 127.5, 128.5, 138.2, 155.7, 171.6; Found (ES) [M + Na]⁺ 361.1567 C₁₇H₂₆O₃N₂SNa, requires 361.1562; HPLC (hexane/i-PrOH 92:8, 0.5 mL/min, Chiralcel Daicel OD) t_R (D) = 9.28 min (<1%), t_R (L) = 12.48 min (>99%).

Boc-l-Phenylalanine-benzamide (6c) (68)

Yellow solid (287 mg, 81%): mp 128–129 °C (CH₂Cl₂) [lit. (68) 128 °C]; [α]_D²⁵ +5.2 (c 1.1, CH₂Cl₂) [lit. (67) [α]_D²² +4.9 (c 0.20, CH₂Cl₂)]; ν_max (solid/cm^–1) 3343 (N–H), 3312 (N–H), 3024, 2927 (C–H), 1678 (C═O), 1659 (C═O); δ_H (400 MHz, CDCl₃, 58 °C) 1.43 (s, 9H), 3.09 (dd, J 13.8, 7.2, 1H), 3.13 (dd, J 13.8, 6.7, 1H), 4.32–4.40 (m, 3H), 5.00 (br s, 1H), 6.03 (br s, 1H), 7.12–7.16 (m, 2H), 7.20–7.25 (m, 3H), 7.25–7.32 (m, 5H); δ_C (100 MHz, CDCl₃, 58 °C) 28.2, 38.6, 43.5, 56.4, 80.2, 126.8, 127.4, 127.6, 128.5, 128.6, 129.3, 136.8, 137.8, 155.3, 171.0; HPLC (hexane/i-PrOH 90:10, 0.5 mL/min, Chiralcel Daicel OD) t_R (D) = 10.62 min (<1%), t_R (L) = 13.24 min (>99%).

Boc-l-Proline-benzamide (6d) (69)

Yellow solid (186 mg, 61%): mp 124–125 °C (CH₂Cl₂) [lit. (69) 125–126 °C]; [α]_D²⁵ −77.0 (c 1.0, CH₂Cl₂) [lit. (66) [α]_D²⁴ −76.2 (c 1.0, CH₂Cl₂)]; ν_max (solid/cm^–1) 3303 (N–H), 2978, 2933, 2909, 2874 (C–H), 1682 (C═O), 1653 (C═O); δ_H (400 MHz, CDCl₃, 58 °C) 1.40 (s, 9H), 1.78–2.07 (m, 3H), 2.25 (br s, 1H), 3.37–3.42 (m, 2H), 4.24–4.30 (m, 1H), 4.37 (dd, J 14.8, 5.6, 1H), 4.46 (dd, J 14.8, 5.7, 1H), 6.82 (br s, 1H), 7.18–7.30 (m, 5H); δ_C (100 MHz, CDCl₃, 58 °C) 24.1, 28.3 (2C), 43.3, 47.0, 60.6, 80.3, 127.2, 127.5, 128.5, 138.5, 155.2, 172.1; HPLC (hexane/i-PrOH 90:10, 0.5 mL/min, Chiralcel Daicel OD) t_R (D) = 13.08 min (1%), t_R (L) = 15.79 min (99%).

Cbz-l-Alanine-benzamide (6e) (22)

Yellow solid (245 mg, 78%): mp 138–139 °C (CH₂Cl₂) [lit. (22) 140–141 °C]; [α]_D²⁵ −8.0 (c 1.02, CHCl₃) [lit. (22) [α]_D²²–8.1 (c 1.3, CHCl₃)]; ν_max (solid/cm^–1) 3286 (N–H), 3059, 3035, 2975, 2930 (C–H), 1682 (C═O), 1641 (C═O); δ_H (500 MHz, CDCl₃) 1.37 (d, J 6.9, 3H), 4.28–4.32 (m, 1H), 4.34 (dd, J 15.0, 5.7, 1H), 4.41 (dd, J 15.0, 5.6, 1H), 4.98 (d, J 12.1, 1H), 5.01 (d, J 12.1, 1H), 5.68 (br d, J 6.5, 1H), 6.88 (br s, 1H), 7.18–7.35 (m, 10H); δ_C (125 MHz, CDCl₃) 18.9, 43.5, 50.7, 67.0, 127.5, 127.7, 128.1, 128.3, 128.6, 128.7, 136.2, 138.1, 156.1, 172.5; HPLC (hexane/i-PrOH 90:10, 0.5 mL/min, Chiralcel Daicel AD) t_R (L) = 5.13 min (95%), t_R (D) = 7.88 min (5%).

Boc-l-Ala-d-Phe-OMe (6f)

Yellow solid (136 mg, 42%): mp 93–95 °C (CH₂Cl₂); [α]_D²⁵ −58.9 (c 0.99, CHCl₃); ν_max (solid/cm^–1) 3283 (N–H), 3254 (N–H), 3134, 3060, 3024 (C–H), 1655 (C═O), 1599 (C═O), 1544 (C═O); δ_H (600 MHz, CDCl₃) 1.27 (d, J 7.1, 3H), 1.42 (s, 9H), 3.06 (dd, J 13.8, 6.3, 1H), 3.13 (dd, J 13.8, 5.7, 1H), 3.70 (s, 3H), 4.18 (br t, J 7.1, 1H), 4.85 (m, 1H), 5.04 (br d, J 5.5, 1H), 6.70 (br s, 1H), 7.10 (d, J 7.1, 2H), 7.20–7.24 (m, 1H), 7.25–7.29 (m, 2H); δ_C (150 MHz, CDCl₃) 18.6, 28.4, 38.0, 50.0, 52.5, 53.2, 80.2, 127.2, 128.7, 129.4, 135.9, 155.5, 171.9, 172.4; Found (ES) [M + Na]⁺ 373.1720 C₁₈H₂₆O₅N₂Na, requires 373.1739.

Boc-l-Ala-l-Phe-OMe (6g) (70)

Yellow solid (208 mg, 64%): mp 82–84 °C (CH₂Cl₂) [lit. (70) 85–86 °C]; [α]_D²⁵ +23.2 (c 1.01, CHCl₃) [lit. (71) [α]_D +23.0 (c 0.61, CHCl₃)]; ν_max (solid/cm^–1) 3285 (N–H), 3061, 3030, 2926 (C–H), 1636 (C═O), 1547 (C═O); δ_H (400 MHz, CDCl₃, 58 °C) 1.27 (d, J 7.0, 3H), 1.41 (s, 9H), 3.04 (dd, J 13.9, 6.6, 1H), 3.12 (dd, J 13.9, 6.1, 1H), 3.64 (s, 3H), 4.13 (quintet, J 7.0, 1H), 4.81 (dt, J 7.6, 6.3, 1H), 5.16 (br d, J 7.6, 1H), 6.71 (br d, J 7.3, 1H), 7.08–7.12 (m, 2H), 7.15–7.26 (m, 3H); δ_C (100 MHz, CDCl₃, 58 °C) 18.1, 28.2, 38.0, 50.4, 51.9, 53.3, 79.9, 126.9, 128.4, 129.2, 136.0, 155.3, 171.7, 172.4.

Boc-l-Alanine pyrrolidine amide (6h) (22)

Colorless oil (135 mg, 59%): [α]_D²⁵–6.4 (c 1.1, CHCl₃) [lit. (22) [α]_D²⁴ −6.8 (c 1.1, CHCl₃)]; ν_max (film/cm^–1) 3300 (N–H), 2976, 2936, 2879 (C–H), 1705 (C═O), 1636 (C═O); δ_H (400 MHz, CDCl₃) 1.24 (d, J 6.8, 3H), 1.36 (s, 9H), 1.76–1.84 (m, 2H), 1.91 (app qn, J 6.8, 2H), 3.31–3.39 (m, 2H), 3.41–3.49 (m, 1H), 3.51–3.58 (m, 1H), 4.37 (app qn, J 6.8, 1H), 5.50 (br d, J 7.8, 1H); δ_C (100 MHz, CDCl₃) 18.6, 24.1, 26.0, 28.3, 45.9, 46.2, 47.8, 79.3, 155.1, 171.2; Found (EI) [M + H]⁺ 243.1713 C₁₂H₂₃O₃N₂, requires 243.1709; HPLC measured after conversion to the benzoyl derivative 6k (hexane/i-PrOH 90:10, 0.5 mL/min, Chiralcel Daicel OD) t_R (D) = 15.79 min (<1%), t_R (L) = 23.58 min (>99%).

Boc-l-Alanine thiomorpholine amide (6i)

Yellow solid (113 mg, 41%): mp 65–68 °C (CH₂Cl₂); [α]_D²⁵ −3.8 (c 1.03, CHCl₃); ν_max (solid/cm^–1) 3317 (N–H), 2980, 2927 (C–H), 1699 (C═O), 1638 (C═O); δ_H (400 MHz, CDCl₃) 1.29 (d, J 6.8, 3H), 1.43 (s, 9H), 2.53–2.61 (m, 2H), 2.63–2.76 (m, 2H), 3.65–3.75 (m, 2H), 3.80–3.89 (m, 1H), 3.99–4.08 (m, 1H), 4.59 (app qn, J 7.2, 1H), 5.52 (br d, J 8.0, 1H); δ_C (100 MHz, CDCl₃) 19.3, 27.3, 27.9, 28.4, 44.8, 46.1, 48.1, 79.6, 155.0, 171.3; Found (EI) [M]⁺ 274.1352 C₁₂H₂₂O₃N₂S, requires 274.1346; HPLC measured after conversion to the benzoyl derivative 6l (hexane/i-PrOH 90:10, 0.5 mL/min, Chiralcel Daicel OD) t_R (D) = 22.20 min (8%), t_R (L) = 31.86 min (92%).

Boc-l-Phenylalanine pyrrolidine amide (6j) (22)

Colorless oil (115 mg, 37%): [α]_D²⁵ +37.2 (c 1.0, CHCl₃) [lit. (22) [α]_D²⁰ +37.5 (c 1.0, CHCl₃)]; ν_max (film/cm^–1) 3432 (N–H), 2979, 2880 (C–H), 1702 (C═O), 1631 (C═O); δ_H (400 MHz, CDCl₃) 1.40 (s, 9H), 1.47–1.77 (m, 4H), 2.52–2.59 (m, 1H), 2.90–3.01 (m, 2H), 3.25–3.46 (m, 3H), 4.53–4.61 (m, 1H), 5.49 (br d, J 8.6, 1H), 7.16–7.28 (m, 5H); δ_C (100 MHz, CDCl₃) 24.0, 25.7, 28.3, 40.2, 45.7, 46.2, 53.6, 79.5, 126.8, 128.3, 129.4, 136.6, 155.1, 170.0; HPLC (hexane/i-PrOH 90:10, 0.5 mL/min, Chiralcel Daicel OD) t_R (D) = 10.09 min (4%), t_R (L) = 13.21 (96%).

Benz-l-Alanine-pyrrolidine amide (6k)

White solid (118 mg, 49%): mp 89–91 °C (PE/EtOAc); ν_max (solid/cm^–1) 3301 (N–H), 3061, 2975, 2877 (C–H), 1724 (C═O), 1629 (C═O); δ_H (400 MHz, CDCl₃) 1.42(d, J 6.8, 3H), 1.81–1.89 (m, 2H), 1.96 (quintet, J 6.7, 2H), 3.39–3.54 (m, 3H), 3.65 (dt, J 10.1, 6.7, 1H), 4.90 (quintet, J 7.0, 1H), 7.34–7.40 (m, 2H), 7.41–7.47 (m, 2H), 7.77–7.81 (m, 2H); δ_C (100 MHz, CDCl₃) 18.3, 24.1, 26.0, 46.1, 46.4, 47.3, 127.1, 128.4, 131.5, 134.1, 166.4, 171.0; Found (ES) [M – H]⁺ 245.1290 C₁₄H₁₇N₂O₂, requires 245.1291; HPLC (hexane/i-PrOH 90:10, 0.5 mL/min, Chiralcel Daicel OD) t_R (D) = 17.08 min (2%), t_R (L) = 28.56 min (98%).

Benz-l-Alanine-thiomorpholine amide (6l)

White solid (120 mg, 45%): mp 137–138 °C (PE/EtOAc); ν_max (solid/cm^–1) 3310 (N–H), 3059, 2981, 2918 (C–H), 1631 (C═O); δ_H (400 MHz, CDCl₃) 1.42 (d, J 6.8, 3H), 2.52–2.77 (m, 4H), 3.69–3.80 (m, 2H), 3.89 (ddd, J 2.8, 6.6, 14.0, 1H), 4.04 (ddd, J 2.8, 6.6, 13.3, 1H), 5.07 (quintet, J 7.0, 1H), 7.37–7.51 (m, 4H), 7.78–7.83 (m, 2H); δ_C (100 MHz, CDCl₃)19.1, 27.4, 27.9, 44.9, 45.6, 48.2, 127.1, 128.5, 131.6, 134.0, 166.4, 171.1; Found (ES) [M – H]⁺ 277.1011 C₁₄H₁₇N₂O₂S, requires 277.1011; HPLC (hexane/i-PrOH 90:10, 0.5 mL/min, Chiralcel Daicel OD) t_R (D) = 24.26 min (4%), t_R (L) = 34.28 min (96%).

(S)-N-Benzyl-2-(4-isobutylphenyl)propanamide (6m) (9i)

Yellow solid (294 mg, 98%): mp 77–78 °C (CH₂Cl₂); [α]_D²⁵ +7.2 (c 0.88, CH₂Cl₂) [lit. (9i) [α]_D²⁰ +7.1 (c 0.88, CH₂Cl₂)]; ν_max (solid/cm^–1) 3304 (N–H), 2949, 2866 (C–H), 1638 (C═O); δ_H (600 MHz, CDCl₃) 0.90 (d, J 6.6, 6H), 1.55 (d, J 7.2, 3H), 1.85 (app nonet, J 6.8, 1H), 2.45 (d, J 7.0, 2H), 3.58 (q, J 7.2, 1H), 4.37 (dd, J 15.1, 5.7, 1H), 4.41 (dd, J 15.1, 5.8, 1H), 5.66 (br s, 1H), 7.10–7.14 (m, 4H), 7.19–7.29 (m, 5H); δ_C (150 MHz, CDCl₃) 18.6, 22.5, 30.3, 43.5, 45.1, 46.6, 127.3, 127.41, 127.43, 128.6, 129.6, 138.7, 138.8, 140.6, 174.7; HPLC (hexane/i-PrOH 100:0, 0.5 mL/min, Chiralcel Daicel AD) t_R (S) = 5.01 min (>99%), t_R (R) = 7.41 min (<1%).

N-Benzylformamide (7a) (72)

Mixture of rotamers (1:0.16). Data for major rotamer reported. White solid (139 mg, 98%): mp 63–64 °C (CH₂Cl₂) [lit. (72) 60–62 °C]; ν_max (solid/cm^–1) 3269 (N–H), 3089, 3056, 2925, 2886 (C–H), 1637 (C═O); δ_H (500 MHz, CDCl₃) 4.41 (d, J 6.0, 2H), 6.41 (br s, 1H), 7.20–7.28 (m, 3H) 7.29–7.37 (m, 2H), 8.17 (s, 1H); δ_C (125 MHz, CDCl₃) 42.3, 127.8, 127.9, 128.9, 137.6, 161.1.

N-Phenethylformamide (7b) (35)

Mixture of rotamers (1:0.22). Data for major rotamer reported. Colorless oil (152 mg, 99%): ν_max (film/cm^–1) 3273 (N–H), 3061, 3028, 2934, 2866 (C–H), 1656 (C═O); δ_H (400 MHz, CDCl₃, 58 °C) 2.84 (t, J 7.1, 2H), 3.55 (app q, J 6.7, 2H), 5.96 (br s, 1H), 7.14–7.26 (m, 3H), 7.27–7.34 (m, 2H), 8.09 (s, 1H); δ_C (100 MHz, CDCl₃, 58 °C) 35.5, 39.2, 126.5, 128.59, 128.63, 138.6, 161.1.

N-(4-Methoxybenzyl)formamide (7c) (73)

Mixture of rotamers (1:0.17). Data for major rotamer reported. Yellow solid (101 mg, 61%): mp 81–83 °C (CH₂Cl₂) [lit. (73) 79–80 °C]; ν_max (solid/cm^–1) 3283 (N–H), 3010, 2933, 2891 (C–H), 1642 (C═O); δ_H (600 MHz, CDCl₃) 3.77 (s, 3H), 4.37 (d, J 5.9, 2H), 6.11 (br s, 1H), 6.83–6.86 (m, 2H), 7.17–7.20 (m, 2H), 8.18 (s, 1H); δ_C (150 MHz, CDCl₃) 41.7, 55.4, 114.2, 129.2, 129.9, 159.1, 161.3.

(R)-N-(1-Phenylethyl)formamide (7d) (74)

Mixture of rotamers (1:0.19). Data for major rotamer reported. Pale yellow oil (129 mg, 85%): [α]_D²⁵ +160.9 (c 0.52, CHCl₃) [lit. (74) [α]_D²⁰ +161.4 (c 0.50, CHCl₃)]; ν_max (film/cm^–1) 3270 (N–H), 3032, 2977, 2931, 2829 (C–H), 1653 (C═O); δ_H (500 MHz, CDCl₃) 1.45 (d, J 6.9, 3H), 5.13 (app quintet, J 7.2, 1H), 6.71 (br s, 1H), 7.21–7.35 (m, 5H), 8.04 (s, 1H); δ_C (125 MHz, CDCl₃) 22.0, 47.7, 126.2, 127.4, 128.7, 143.0, 160.7; Found (EI) [M]⁺ 149.0833 C₉H₁₁ON, requires 149.0835.

N-(Cyclohexylmethyl)formamide (7e)

Mixture of rotamers (1:0.25). Data for major rotamer reported. Colorless oil (135 mg, 96%): ν_max (film/cm^–1) 3280 (N–H), 3060, 2922, 2851 (C–H), 1657 (C═O); δ_H (600 MHz, CDCl₃) 0.77–0.88 (m, 2H), 1.00–1.18 (m, 3H), 1.34–1.42 (m, 1H), 1.53–1.68 (m, 5H) 3.01 (t, J 6.6, 2H), 6.71 (br s, 1H), 8.06 (s, 1H); δ_C (150 MHz, CDCl₃) 25.8, 26.4, 30.8, 37.8, 44.4, 161.8; Found (EI) [M + H]⁺ 142.1227 C₈H₁₆NO, requires 142.1226.

N-Cyclohexylformamide (7f) (35)

Mixture of rotamers (1:0.30). Data for major rotamer reported. Brown oil (95 mg, 78%): ν_max (film/cm^–1) 3268 (N–H), 3050, 2929, 2854 (C–H), 1652 (C═O); δ_H (500 MHz, CDCl₃) 1.09–1.39 (m, 5H), 1.53–1.63 (m, 1H), 1.64–1.76 (m, 2H), 1.82–1.95 (m, 2H), 3.78–3.86 (m, 1H), 5.78 (br s, 1H), 8.07 (s, 1H); δ_C (125 MHz, CDCl₃) 24.8, 25.5, 33.1, 47.1, 160.5.

N-Butylformamide (7g)

Mixture of rotamers (1:0.23). Data for major rotamer reported. Yellow oil (31 mg, 30%): ν_max (film/cm^–1) 3280 (N–H), 3058, 2959, 2933, 2868 (C–H), 1655 (C═O); δ_H (500 MHz, CDCl₃) 0.90 (t, J 7.2, 3H), 1.33 (sext, J 7.2, 2H), 1.48 (quintet, J 7.2, 2H), 3.26 (q, J 6.7, 2H), 5.95 (br s, 1H), 8.12 (s, 1H); δ_C (125 MHz, CDCl₃) 13.7, 20.0, 31.5, 37.9, 161.5; Found (EI) [M]⁺ 101.0827 C₅H₁₁ON, requires 101.0835.

N-Phenylformamide (7h) (75)

Mixture of rotamers (1:0.93). Data for major rotamer reported. Yellow oil (25 mg, 21%): ν_max (film/cm^–1) 3273 (N–H), 3066, 2923, 2854 (C–H), 1682 (C═O); δ_H (600 MHz, CDCl₃) 7.08–7.11 (m, 1H), 7.19 (t, J 7.5, 1H), 7.31–7.38 (m, 2H), 7.53–7.56 (m, 1H), 8.41 (br s, 1H), 8.71 (d, J 11.3, 1H); δ_C (150 MHz, CDCl₃) 118.9, 125.4, 129.9, 136.8, 162.8.

1-Indolinecarbaldehyde (7i) (76)

Mixture of rotamers (1:0.22). Data for major rotamer reported. Brown solid (55 mg, 38%): mp 56–58 °C (CH₂Cl₂) [lit. (76) 58–61 °C]; ν_max (solid/cm^–1) 3053, 2960, 2921, 2854 (C–H), 1656 (C═O); δ_H (600 MHz, CDCl₃) 3.14 (2H, t, J 8.6), 4.05 (2H, app td, J 8.5, 0.9), 7.04 (1H, td, J 7.2, 1.5), 7.14–7.22 (2H, m), 7.24 (1H, d, J 7.2) 8.92 (1H, s); δ_C (150 MHz, CDCl₃) 27.3, 44.8, 109.5, 124.4, 126.2, 127.7, 132.1, 141.2, 157.7.

3,4-Dihydro-2(1H)-isoquinolinecarbaldehyde (7j) (77)

Mixture of rotamers (1:0.60). Data for major rotamer reported. Pale yellow oil (119 mg, 71%): ν_max (film/cm^–1) 3056, 3026, 2929, 2886 (C–H), 1646 (C═O); δ_H (500 MHz, CDCl₃) 2.87 (t, J 5.9, 2H), 3.60 (t, J 5.9, 2H), 4.65 (s, 2H), 7.05–7.19 (m, 4H), 8.16 (s, 1H); δ_C (125 MHz, CDCl₃) 29.8, 42.4, 43.3, 126.70, 126.71, 126.8, 129.0, 131.8, 133.7, 161.8.

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Corresponding Author
- Tom D. Sheppard - Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon St, London, WC1H 0AJ, U.K.; Email: [email protected]
Authors
- Rachel M. Lanigan - Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon St, London, WC1H 0AJ, U.K.
- Pavel Starkov - Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon St, London, WC1H 0AJ, U.K.
Notes
The authors declare no competing financial interest.

Acknowledgment

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We would like to thank the EPSRC (Advanced Research Fellowship EP/E052789/1 to T.D.S. and Ph.D. studentship to P.S.) and University College London (Impact Studentship to R.M.L.) for supporting this work. We would also like to acknowledge GlaxoSmithKline for providing samples of some of the carboxylic acids and amines used in this research.

References

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Angewandte Chemie, International Edition (2010), 49 (38), 6840-6843, S6840/1-S6840/39CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
DFT calcns. predict water elimination from a tetrahedral intermediate to be the rate detg. step in the title reaction. This transformation is calcd. to be highly stereoselective, yielding cis amides as the kinetic products. The superior activity of ortho-halophenyl boronic acids results from the Lewis basic character of halogen atoms.
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(i) Gernigon, N.; Al-Zoubi, R. M.; Hall, D. G. J. Org. Chem. 2012, 77, 8386– 8400
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Tris(dialkylamino)boranes. New reagents for the synthesis of enamines and amides
Nelson, P.; Pelter, Andrew
Journal of the Chemical Society (1965), (Sept.), 5142-4CODEN: JCSOA9; ISSN:0368-1769.
PhCH2CO2H (1.17 g.) in 10 cc. C6H6 treated 40 hrs. at room temp. with 1.90 g. tris(pyrrolidinyl)borane (I) yielded 1.40 g. N-phenylacetylpyrrolidine, b18 190-2°. A similar run with 0.33 mole equiv. I during 48 hrs. gave 33% pyrrolidide. Similarly were converted to the corresponding pyrrolidides (using 1 mole I) the following acids (reaction time in hrs., conditions, and % yield of pyrrolidide given): PhCH2O, 1, 24, refluxing C6H6, 78; tert-BuCO2H, 1,20, refluxing C6H6, 62; AmCO2H, 1, 48, room temp. 78. Ac2CH2 (1.01 g.) in 5 cc. dry CHCl3 with 2.2 g. I in 5 cc. dry CHCl3 yielded 70% pyrrolidinylenamine (II). Similarly were prepd. the pyrrolidinylenamine of tert-BuCOCH2Ac in 67% yield, and the dimethylenamine of Ac2CH2 in 75% yield. Iso-Bu2CO (1.85 g.), 3.17 g. I, 1.39 g. pyrrolidine, p-MeC6H4SO3H, and 5 cc. C6H6 refluxed 0.5 hr. yielded 2.1 g. pyrrolidinenamine, b10 96-100°. AcPh (2.28 g.), 4.48 g. I, 1.45 g. pyrrolidine, 5 mg. p-MeC6H4SO3H, and 10 cc. C6H6 refluxed 0.5 hr. yielded 2.24 g. unstable pyrrolidinenamine, b0.001 82-90°. In the same manner were prepd. the pyrrolidinenamines of cholestanone during 45 min. in 70% yield and of cyclohexanone during 3 hrs. in 85% yield.
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Convenient method of amidation of carboxylic acids using boron trifluoride etherate
Tani, Junichi; Oine, Toyonari; Inoue, Ichizo
Synthesis (1975), (11), 714-15CODEN: SYNTBF; ISSN:0039-7881.
Refluxing RC6H4CO2H(R = H, p-NH2, o-NH2, m-Cl, p-NO2), BuCO2H, or PhCH:CHCO2H with HNR1R2 [R1 = PhCH2, Bu, Ph, CH2CH2NEt2; R2 = H; NR1R2 = N(CH2)5] in the presence of BF3.OEt2 in C6H6 or MePh contg. a strong base, e.g., Et3N or 1,8-diazabicyclo[5.4.0]undec-7-ene, gave 28-100% of the resp. carboxamide.
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A new synthesis of amides and macrocyclic lactams
Collum, David B.; Chen, Shen-Chu; Ganem, Bruce
Journal of Organic Chemistry (1978), 43 (22), 4393-4CODEN: JOCEAH; ISSN:0022-3263.
Treatment of catecholborane [I; R = H (II)] with nonanoic acid gave I [R = Me(CH2)7CO], which was treated with HNR1R2 [R1 = H, R2 = PhCH2, Bu, CH2CO2Et; R1 = Me, R2 = PhCH2; NR1R2 = pyrrolidino, morpholine] to give 63-92% Me(CH2)7CONR1R2. Alternatively, amides were prepd. by treating a 1:1 mixt. of acid and amine with II. Treatment of H2N(CH2)nCO2H (n = 3, 5-7, 11, 12, 14) with II in pyridine gave the monomer III and dimer IV in varying proportions depending on ring size.
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Borate esters as convenient reagents for direct amidation of carboxylic acids and transamidation of primary amides
Starkov, Pavel; Sheppard, Tom D.
Organic & Biomolecular Chemistry (2011), 9 (5), 1320-1323CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
Simple borates serve as effective promoters for amide bond formation with a variety of carboxylic acids and amines. With tri-Me or tris(2,2,2-trifluoroethyl) borate, amides are obtained in good to excellent yield and high purity after a simple work-up procedure. Tris(2,2,2-trifluoroethyl) borate can also be used for the straightforward conversion of primary amides to secondary amides via transamidation.
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(BO) bands in the IR spectra of deuterioalkoxyboranes and haloalkoxyboranes
Meller, Anton; Wojnowska, Maria
(1969), 100 (5), 1489-93CODEN: MOCHAP ISSN:.
The ir absorption spectra (625-2000 cm-1) of B(OR)3 (I) were recorded [R = C2D5, CD(CD3)2, CH2CF3, CH(CF3)2, CClMeCF3, and cCl(CClF2)2] and are compared with spectra of I (R = Et and iso-Pr) (W. J. Lehmann et al., 1969). In the spectra of the fully deuterated derivs., the splitting (∼50 cm-1) of the 10BO3-11BO3 asym. stretching vibrational frequencies was greater than in the nondeuterated derivs. due to greater low frequency shifts in the 11BO3 band. Anal. of the relative displacements in the chem. shifts indicate coupling of the (BO) stretching and CH deformation modes.
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Held, Ingmar; Larionov, Evgeny; Bozler, Christian; Wagner, Felicia; Zipse, Hendrik
Synthesis (2009), (13), 2267-2277CODEN: SYNTBF; ISSN:0039-7881. (Georg Thieme Verlag)
A series of 3-alkyl-4-guanidinylpyridines with variable alkylation pattern have been synthesized and characterized with respect to their catalytic potential in acylation reactions of alcs. The ability of the substitution pattern to stabilize acylpyridinium cations, which act as crit. intermediates in the catalytic cycle of pyridine-catalyzed acylation reactions, has been assessed at the MP2(FC)/6-31+G(2d,p)//B98/6-31G(d) level of theory and inclusion of solvent effects in chloroform using the PCM continuum solvation model. The most active 4-guanidinylpyridines are among those having the most electron-rich pyridine ring. The influence of the type and concn. of the auxiliary base on the catalytic activity has also been studied. While the change from triethylamine to N,N-diisopropylethylamine as the auxiliary base does not lead to a systematic increase or decrease in the catalytic rates, the complete absence of auxiliary base leads to a 27-fold redn. in reaction rate.
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Chiral Lewis Base Catalyzed Highly Enantioselective Reduction of N-Alkyl β-Enamino Esters with Trichlorosilane and Water
Wu, Xinjun; Li, Yang; Wang, Chao; Zhou, Li; Lu, Xiaoxia; Sun, Jian
Chemistry - A European Journal (2011), 17 (10), 2846-2848, S2846/1-S2846/66CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
In the presence of chiral proline-derived Lewis base catalyst I, the supposedly moisture-unfriendly redn. system with trichlorosilane was found to be highly efficient and enantioselective when using water as an additive. For the first time, this method enables the redn. of a broad range of N-alkyl β-enamino esters II (R1 = Ph, 4-Me-C6H4, 3-Cl-C6H4, Bn, etc.; R2 = Et, Me, tBu, Bn, cyclohexyl; R3 = Bn, allyl, nPr, tBu) to give N-alkyl β-amino esters in good to high yields and with excellent enantioselectivities.
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Design, synthesis and primary activity of thiomorpholine derivatives as DPP-IV inhibitors
Han, Bei; Liu, Jing Long; Huan, Yi; Li, Peng; Wu, Qi; Lin, Zi Yun; Shen, Zhu Fang; Yin, Da Li; Huang, Hai Hong
Chinese Chemical Letters (2012), 23 (3), 297-300CODEN: CCLEE7; ISSN:1001-8417. (Elsevier B.V.)
Thirteen thiomorpholine-bearing compds. were designed and synthesized as dipeptidyl peptidase IV (DPP-IV) inhibitors, with natural and non-natural L-amino acids as the starting materials. Their structures were characterized by 1H NMR, 13C NMR and HR-MS. The target compds. were screened for the DPP-IV inhibition, and a preliminary SAR result was obtained. Particularly, compds. I (R = i-Pr, i-Bu, t-Bu) with good DPP-IV inhibition in vitro were further evaluated through a mouse oral glucose tolerance test (OGTT). The preliminary result showed the potential value for further studies on those thiomorpholine-bearing compds. as DPP-IV inhibitors.
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Transamidation of primary amides with amines using hydroxylamine hydrochloride as an inorganic catalyst
Allen, C. Liana; Atkinson, Benjamin N.; Williams, Jonathan M. J.
Angewandte Chemie, International Edition (2012), 51 (6), 1383-1386, S1383/1-S1383/33CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A novel transamidation of primary carboxamides with primary or secondary amines to give secondary or tertiary amides is described. Catalyzed with hydroxylamine hydrochloride, a series of amides were obtained using this strategy in good to excellent yields.
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Transamidation of primary amides with amines catalyzed by zirconocene dichloride
Atkinson, Benjamin N.; Chhatwal, A. Rosie; Lomax, Helen V.; Walton, James W.; Williams, Jonathan M. J.
Chemical Communications (Cambridge, United Kingdom) (2012), 48 (95), 11626-11628CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
Zirconocene dichloride has been shown to be an effective catalyst for the transamidation of primary amides with amines in cyclohexane at 80° in 5-24 h. For favorable substrates, the reaction can be performed at temps. as low as 30°.
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Efficient Copper(II)-Catalyzed Transamidation of Nonactivated Primary Carboxamides and Ureas with Amines
Zhang, Min; Imm, Sebastian; Baehn, Sebastian; Neubert, Lorenz; Neumann, Helfried; Beller, Matthias
Angewandte Chemie, International Edition (2012), 51 (16), 3905-3909, S3905/1-S3905/24CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A copper(II) catalyzed transamidation process using nonactivated primary carboxamides and ureas with amines is presented. For this technique, the Cu(OAc)2 is fairly inexpensive and convenient to use without special precautions. Fortunately, a wide range of amides, ureas, chiral amines can be synthesized from primary carboxamides and amines in good to excellent yields. By extension this protocol can be applied to the synthesis of amides, peptide, polyamides and heterocycles.
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Hypervalent iodine catalyzed trans-amidation of carboxamides with amines
Vanjari, Rajeshwer; Kumar Allam, Bharat; Nand Singh, Krishna
RSC Advances (2013), 3 (6), 1691-1694CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
This protocol describes the catalytic use of diacetoxyiodobenzene (DIB) for the efficient trans-amidation of carboxamides with amines under mild reaction conditions. The synthesis of the target compds. was achieved using formamide, acetamide, benzeneacetamide, benzamide, nicotinamide and 1H-isoindole-1,3(2H)-dione (phthalimide) as starting materials in a reaction with benzenamine, piperidine. morpholine, cyclohexanamine, 1-hexanamine, cyclopropanamine, 2-phenylethylamine, 2-pyridinamine, etc. The title compds. thus formed included 2-hexyl-1H-isoindole-1,3(2H)-dione [cyclic imide (hexyl)phthalimide], N-(benzyl)formamide, 1-Piperidinecarboxaldehyde (1-formylpiperidine) and 4-morpholinecarboxaldehyde (formylmorpholine), N-(phenylmethyl)-3-pyridinecarboxamide.
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Boric Acid: A Highly Efficient Catalyst for Transamidation of Carboxamides with Amines
Nguyen, Thanh Binh; Sorres, Jonathan; Tran, Minh Quan; Ermolenko, Ludmila; Al-Mourabit, Ali
Organic Letters (2012), 14 (12), 3202-3205CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
A novel method of transamidation of carboxamides with amines using catalytic amts. of readily available boric acid under solvent-free conditions has been developed. The scope of the methodol. has been demonstrated with (i) primary, secondary, and tertiary amides and phthalimide and (ii) aliph., arom., cyclic, acyclic, primary, and secondary amines.
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Transamidation of amides with amines under solvent-free conditions using a CeO2 catalyst
Tamura, Masazumi; Tonomura, Takuya; Shimizu, Ken-ichi; Satsuma, Atsushi
Green Chemistry (2012), 14 (3), 717-724CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
Among various metal oxides, cerium oxide (CeO2) shows highest catalytic activity for transamidation of picolinamide with n-octylamine. CeO2 acts as a reusable and effective heterogeneous catalyst for transamidation under solvent-free conditions. Transamidation of a variety of amides and amines produced the corresponding N-alkyl amides in high yields. Characterization of the acid-base properties and kinetic studies suggest that the cooperation of the weak Lewis acid sites and adjacent strong base sites play important roles in the transamidation reaction.
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Reactivity of unsubstituted and alkyl-substituted thiomorpholines. Part 3. Joint action of elementary sulfur and gaseous ammonia on ketones. Part 93
Asinger, Friedrich; Saus, Alfons; Hartig, Juergen; Rasche, Peter; Wilms, Elmar
Monatshefte fuer Chemie (1979), 110 (4), 767-89CODEN: MOCMB7; ISSN:0026-9247.
Cyclizing ClCH2CH2SCH2CH2NH2 with KOH gave 49% thiomorpholine. Thiomorpholine and 2-methyl-3-ethylthiomorpholine were acylated by acyl chlorides, dicarboxylic acid chlorides, anhydrides, sulfonic acid chlorides, isocyanates, diisocyanates and isothiocyanates, and N-alkylated by alkyl halides. E.g., thiomorpholines I and II [ R1 = R2 = H, R1 = Me, R2 = Et; R3 = R4CO, R4SO2, CONHR4, C(S)NHR4 (R4 = e.g., C3-18 alkyl, PhCH2, 2-O2NC6H4, CNCH2, allyl, butenyl, crotonyl), X = COX1CO, CONHX2NHCO, X1 = arylylene, oxalyl, adipoyl, terephthaloyl, X2 = phenylene derivs.] (∼100 compds.) were prepd.
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Chemistry - A European Journal (2010), 16 (23), 6820-6827, S6820/1-S6820/26CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
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An exptl. simple and inexpensive catalyst system was developed for the amidation of aryl halides by using 0.2-10 mol % of CuI, 5-20 mol % of a 1,2-diamine ligand, and K3PO4, K2CO3, or Cs2CO3 as base. Catalyst systems based on N,N'-dimethylethylenediamine or trans-N,N'-dimethyl-1,2-cyclohexanediamine were found to be the most active even though several other 1,2-diamine ligands could be used in the easiest cases. Aryl iodides, bromides, and in some cases even aryl chlorides can be efficiently amidated. A variety of functional groups are tolerated in the reaction, including many that are not compatible with Pd-catalyzed amidation or amination methodol.
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Woon, Esther C. Y.; Demetriades, Marina; Bagg, Eleanor A. L.; Aik, WeiShen; Krylova, Svetlana M.; Ma, Jerome H. Y.; Chan, MunChiang; Walport, Louise J.; Wegman, David W.; Dack, Kevin N.; McDonough, Michael A.; Krylov, Sergey N.; Schofield, Christopher J.
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2-Oxoglutarate-dependent nucleic acid demethylases are of biol. interest because of their roles in nucleic acid repair and modification. Although some of these enzymes are linked to physiol., their regulatory roles are unclear. Hence, there is a desire to develop selective inhibitors for them; we report studies on AlkB, which reveal it as being amenable to selective inhibition by small mols. Dynamic combinatorial chem. linked to mass spectrometric analyses (DCMS) led to the identification of lead compds., one of which was analyzed by crystallog. Subsequent structure-guided studies led to the identification of inhibitors of improved potency, some of which were shown to be selective over two other 2OG oxygenases. The work further validates the use of the DCMS method and will help to enable the development of inhibitors of nucleic acid modifying 2OG oxygenases both for use as functional probes and, in the longer term, for potential therapeutic use.
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Applied Catalysis, A: General (2010), 377 (1-2), 64-69CODEN: ACAGE4; ISSN:0926-860X. (Elsevier B.V.)
Treatment of aq. formic acid (85%) with structurally diverse amines in the presence of a catalytic amt. of sulfonic acid supported on hydroxyapatite-encapsulated-γ-Fe2O3 [[email protected]γ-Fe2O3] (0.9 mol.%) as a heterogeneous, reusable and highly efficient catalyst gave the corresponding formamides in good to excellent yields at room temp. The magnetically catalytic system was recovered by-passing time consuming filtration operation by using an external magnet device. In addn. to facility, this methodol., it also enhances product purity and promises economic as well as environmental benefits.
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Journal of the American Chemical Society (2010), 132 (9), 2870-2871CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
We report a fundamentally unique approach to the catalytic kinetic resoln. of amine derivs. based on formamide and thioformamide substrates. Readily accessible histidine-contg. peptides mediate the kinetic resolns. with as little as 5 mol % catalyst. Selectivity factors (krel) as high as 43.7 were obsd. under simple reaction conditions utilizing Boc2O as the reagent at room temp. Mechanistic expts. were conducted that established a higher level of reactivity for thioformamide substrates than for their formamide analogs. The products of these asym. reactions were shown to be readily converted to desirable building blocks such as N-Boc-amines and the parent chiral formamide compds.
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Abstract
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Scheme 1
Scheme 1. Synthesis of B(OCH₂CF₃)₃ from (a) BBr₃ and (b) B₂O₃
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Figure 1
Figure 1. Solid phase workup of amidation reactions.
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Figure 2
Figure 2. Scope of phenylacetamide synthesis with different amines. All reactions were carried out at 80 °C for 5 h, and the solid phase workup procedure was used unless otherwise stated. (a) Aqueous workup procedure; (b) 80 °C for 15 h; (c) 100 °C for 15 h in a sealed tube; (d) purified by column chromatography; (e) from 1 equiv of Me₂NH·HCl, 1 equiv of DIPEA; (f) from 2 equiv of Me₂NH·HCl, 2 equiv of DIPEA; (g) from 3 equiv of Me₂NH·HCl, 3 equiv of DIPEA; (h) 6% of 2a was also isolated; (i) 100 °C for 24 h in a sealed tube.
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Figure 3
Figure 3. Scope of N-benzylamide synthesis using different carboxylic acids. All reactions were carried out at 80 °C for 5 h, and the solid phase workup procedure was used unless otherwise stated. (a) Aqueous workup procedure; (b) 80 °C for 15 h; (c) 100 °C for 15 h in a sealed tube.
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Figure 4
Figure 4. Further scope of the amidation reaction. All reactions were carried out at 80 °C for 15 h and purified by solid phase workup unless otherwise stated. (a) Aqueous workup procedure; (b) 80 °C for 5 h; (c) purified by column chromatography.
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Figure 5
Figure 5. Lactamization reactions. All reactions were carried out at 80 °C for 5 h unless otherwise stated and purified by solid phase workup. (a) Yield without B(OCH₂CF₃)₃; (b) 100 °C for 5 h in a sealed tube; (c) 80 °C for 15 h; (d) [α]_D²⁵ −9.5 (c 1.22, MeOH) [lit. (16) [α]_D²⁰ −10.6 (c 1.22, MeOH)].
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Scheme 2
Scheme 2. Gram Scale Amidation Reactions
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Figure 6
Figure 6. Coupling of acids containing adjacent chiral centers. All reactions were carried out at 80 °C for 15 h unless otherwise stated and purified by solid phase workup. (a) 80 °C for 8 h; (b) 100 °C for 24 h in a sealed tube; (c) er measured after conversion to the N-benzoyl amide derivative; (d) 100 °C for 8 h in a sealed tube; (e) 80 °C for 5 h.
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  A review with 24 refs. discusses the general types of reactions used in processes for the prepn. of drug candidates from the process chem. R&D departments of GlaxoSmithKline, AstraZeneca and Pfizer in order to evaluate potential gaps in chem. technologies for the prepn. of pharmaceuticals. The presence and incorporation of asymmetry in drug candidates, the substitution patterns of arom. and heteroarom. starting materials, and the use of protecting groups and of acylation, alkylation, arylation, oxidn., redn., carbon-carbon bond-forming, and substitution reactions in processes for the prepn. of drug candidates are discussed.
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  (b) Amarnath, L.; Andrews, I.; Bandichhor, R.; Bhattacharya, A.; Dunn, P.; Hayler, J.; Hinkley, W.; Holub, N.; Hughes, D.; Humphreys, L.; Kaptein, B.; Krishnen, H.; Lorenz, K.; Mathew, S.; Nagaraju, G.; Rammeloo, T.; Richardson, P.; Wang, L.; Wells, A.; White, T. Org. Process Res. Dev. 2012, 16, 535– 544
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3. 3
  Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.; Leazer, J. L., Jr.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411– 420
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  Key green chemistry research areas-a perspective from pharmaceutical manufacturers
  Constable, David J. C.; Dunn, Peter J.; Hayler, John D.; Humphrey, Guy R.; Leazer, Johnnie L., Jr.; Linderman, Russell J.; Lorenz, Kurt; Manley, Julie; Pearlman, Bruce A.; Wells, Andrew; Zaks, Aleksey; Zhang, Tony Y.
  Green Chemistry (2007), 9 (5), 411-420CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
  A review. In 2005, the ACS Green Chem. Institute (GCI) and the global pharmaceutical corporations developed the ACS GCI Pharmaceutical Roundtable to encourage the integration of green chem. and green engineering into the pharmaceutical industry. The Roundtable has developed a list of key research areas. The purpose of this perspective is to summarize how that list was agreed, provide an assessment of the current state of the art in those areas, and to highlight areas for future improvement.
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4. 4
  For recent reviews, see:
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  Amide bond formation and peptide coupling
  Montalbetti, Christian A. G. N.; Falque, Virginie
  Tetrahedron (2005), 61 (46), 10827-10852CODEN: TETRAB; ISSN:0040-4020. (Elsevier B.V.)
  A review. Methods and strategies for the amide bond formation and peptide coupling in solns. and on solid phase are discussed and summarized.
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  Amide bond formation: beyond the myth of coupling reagents
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  This crit. review is focussed on the most recently developed coupling reagents with particular attention paid to the pros and cons of the plethora of "acronym" based reagents. Amide bond formation is a fundamentally important reaction in org. synthesis, and is typically mediated by one of a myriad of so-called coupling reagents. It aims to demystify the process allowing the chemist to make a sensible and educated choice when carrying out an amide coupling reaction (179 refs.).
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  Pattabiraman, Vijaya R.; Bode, Jeffrey W.
  Nature (London, United Kingdom) (2011), 480 (7378), 471-479CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  A review. Recent advances in amide-bond-forming reactions were reviewed and summarized, highlighting the successful implementation of new synthetic methodologies and the limitations that need to be overcome to efficiently make the next generation of conventional small-mol. pharmaceuticals, therapeutic peptides, and natural and non-natural proteins.
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5. 5
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  Houlding, T. K.; Tchabanenko, K.; Rahman, Md. T.; Rebrov, E. V. Org. Biomol. Chem. 2013, DOI: 10.1039/C2OB26930A
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  Lundberg, H.; Tinnis, F.; Adolfsson, H. Synlett 2012, 23, 2201– 2204
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  Lundberg, H.; Tinnis, F.; Adolfsson, H. Chem.—Eur. J. 2012, 18, 3822– 3826
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  Direct Amide Coupling of Non-activated Carboxylic Acids and Amines Catalyzed by Zirconium(IV) Chloride
  Lundberg, Helena; Tinnis, Fredrik; Adolfsson, Hans
  Chemistry - A European Journal (2012), 18 (13), 3822-3826, S3822/1-S3822/16CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A novel, mild, versatile, effective and environmentally benign protocol for direct amidation by using catalytic amts. of inexpensive zirconium(IV) chloride is presented herein. This simple and high-yielding method tolerates a wide range of functionalities, including acid labile groups, and is suitable for the amidation of both simple and more complex starting materials, such as indomethacin. The method conserves the enantiomeric purity of the starting materials and is suitable for larger scale synthesis, which indicates its usability in research labs., as well as in industrial applications.
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9. 9
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  The thermal and boron-catalyzed direct amide formation reactions: mechanistically understudied yet important processes
  Charville, Hayley; Jackson, David; Hodges, George; Whiting, Andrew
  Chemical Communications (Cambridge, United Kingdom) (2010), 46 (11), 1813-1823CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  A review. Despite the amide formation reaction being one of the key cornerstone reactions in org. chem., the direct amide formation is both little used and little explored. Acceptance of the feasibility and general applicability of the reaction depends upon the ability of researchers to bring it into the mainstream by development of: (1) an understanding of the mechanism of the reaction; and (2) the design of catalysts which promote the reaction on a wide range of substrates and under ambient conditions. From the earliest report of the direct amide formation in the 19th century, there have been relatively few reports of mechanistic studies, though it is clear that there is not a simple relationship between ease of direct amide formation and the pKa of the carboxylic acid and amine, or whether salt ammonium carboxylate formation is important. Consequently, direct amide formation has historically been run under higher temp. conditions. However, more recently, stoichiometric and catalytic boron compds. have been developed that considerably reduce the reaction temps. under which direct amide formation will proceed. Limited attempts at mechanistic studies point to the formation of acyloxyborate or boronate species acting essentially as mixed anhydrides, though the exact order of these systems remains to be categorically detd.
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  3,4,5-Trifluorobenzeneboronic Acid as an Extremely Active Amidation Catalyst
  Ishihara, Kazuaki; Ohara, Suguru; Yamamoto, Hisashi
  Journal of Organic Chemistry (1996), 61 (13), 4196-4197CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Arylboronic acids possessing electron-withdrawing groups, 3,4,5-trifluorobenzeneboronic acid and 3,5-bis(trifluoromethyl)benzeneboronic acid, work as highly efficient catalysts in amidation between carboxylic acids and amines. The catalytic amidation of optically active aliph. α-hydroxycarboxylic acids with benzylamine proceeded with no measurable loss (<2%) of enantiomeric purity under a reflux condition in toluene. Although most amino acids are barely sol. in nonaq. solvents, their lactams can be prepd. by the present technique under heterogeneous conditions. Esterification was relatively slow, since nucleophilicity of alcs. was lower than that of amines. Nevertheless, the esterification proceeded smoothly if heavy alcs. such as 1-butanol were used.
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  Direct and waste-free amidations and cycloadditions by organocatalytic activation of carboxylic acids at room temperature
  Al-Zoubi, Raed M.; Marion, Olivier; Hall, Dennis G.
  Angewandte Chemie, International Edition (2008), 47 (15), 2876-2879CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Ortho-iodo- and ortho-bromophenylboronic acids are used as exceptional organocatalysts in atom-economical amidations between free carboxylic acids and amines, including functionalized ones, and can also provide LUMO-lowering activation in [4 + 2] cycloaddns. of α,β-unsatd. carboxylic acids.
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  Mechanistic Insights into Direct Amide Bond Formation Catalyzed by Boronic Acids: Halogens as Lewis Bases
  Marcelli, Tommaso
  Angewandte Chemie, International Edition (2010), 49 (38), 6840-6843, S6840/1-S6840/39CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  DFT calcns. predict water elimination from a tetrahedral intermediate to be the rate detg. step in the title reaction. This transformation is calcd. to be highly stereoselective, yielding cis amides as the kinetic products. The superior activity of ortho-halophenyl boronic acids results from the Lewis basic character of halogen atoms.
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  Tris(dialkylamino)boranes. New reagents for the synthesis of enamines and amides
  Nelson, P.; Pelter, Andrew
  Journal of the Chemical Society (1965), (Sept.), 5142-4CODEN: JCSOA9; ISSN:0368-1769.
  PhCH2CO2H (1.17 g.) in 10 cc. C6H6 treated 40 hrs. at room temp. with 1.90 g. tris(pyrrolidinyl)borane (I) yielded 1.40 g. N-phenylacetylpyrrolidine, b18 190-2°. A similar run with 0.33 mole equiv. I during 48 hrs. gave 33% pyrrolidide. Similarly were converted to the corresponding pyrrolidides (using 1 mole I) the following acids (reaction time in hrs., conditions, and % yield of pyrrolidide given): PhCH2O, 1, 24, refluxing C6H6, 78; tert-BuCO2H, 1,20, refluxing C6H6, 62; AmCO2H, 1, 48, room temp. 78. Ac2CH2 (1.01 g.) in 5 cc. dry CHCl3 with 2.2 g. I in 5 cc. dry CHCl3 yielded 70% pyrrolidinylenamine (II). Similarly were prepd. the pyrrolidinylenamine of tert-BuCOCH2Ac in 67% yield, and the dimethylenamine of Ac2CH2 in 75% yield. Iso-Bu2CO (1.85 g.), 3.17 g. I, 1.39 g. pyrrolidine, p-MeC6H4SO3H, and 5 cc. C6H6 refluxed 0.5 hr. yielded 2.1 g. pyrrolidinenamine, b10 96-100°. AcPh (2.28 g.), 4.48 g. I, 1.45 g. pyrrolidine, 5 mg. p-MeC6H4SO3H, and 10 cc. C6H6 refluxed 0.5 hr. yielded 2.24 g. unstable pyrrolidinenamine, b0.001 82-90°. In the same manner were prepd. the pyrrolidinenamines of cholestanone during 45 min. in 70% yield and of cyclohexanone during 3 hrs. in 85% yield.
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  Convenient method of amidation of carboxylic acids using boron trifluoride etherate
  Tani, Junichi; Oine, Toyonari; Inoue, Ichizo
  Synthesis (1975), (11), 714-15CODEN: SYNTBF; ISSN:0039-7881.
  Refluxing RC6H4CO2H(R = H, p-NH2, o-NH2, m-Cl, p-NO2), BuCO2H, or PhCH:CHCO2H with HNR1R2 [R1 = PhCH2, Bu, Ph, CH2CH2NEt2; R2 = H; NR1R2 = N(CH2)5] in the presence of BF3.OEt2 in C6H6 or MePh contg. a strong base, e.g., Et3N or 1,8-diazabicyclo[5.4.0]undec-7-ene, gave 28-100% of the resp. carboxamide.
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  Treatment of catecholborane [I; R = H (II)] with nonanoic acid gave I [R = Me(CH2)7CO], which was treated with HNR1R2 [R1 = H, R2 = PhCH2, Bu, CH2CO2Et; R1 = Me, R2 = PhCH2; NR1R2 = pyrrolidino, morpholine] to give 63-92% Me(CH2)7CONR1R2. Alternatively, amides were prepd. by treating a 1:1 mixt. of acid and amine with II. Treatment of H2N(CH2)nCO2H (n = 3, 5-7, 11, 12, 14) with II in pyridine gave the monomer III and dimer IV in varying proportions depending on ring size.
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  Borate esters as convenient reagents for direct amidation of carboxylic acids and transamidation of primary amides
  Starkov, Pavel; Sheppard, Tom D.
  Organic & Biomolecular Chemistry (2011), 9 (5), 1320-1323CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  Simple borates serve as effective promoters for amide bond formation with a variety of carboxylic acids and amines. With tri-Me or tris(2,2,2-trifluoroethyl) borate, amides are obtained in good to excellent yield and high purity after a simple work-up procedure. Tris(2,2,2-trifluoroethyl) borate can also be used for the straightforward conversion of primary amides to secondary amides via transamidation.
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  Meller, Anton; Wojnowska, Maria
  (1969), 100 (5), 1489-93CODEN: MOCHAP ISSN:.
  The ir absorption spectra (625-2000 cm-1) of B(OR)3 (I) were recorded [R = C2D5, CD(CD3)2, CH2CF3, CH(CF3)2, CClMeCF3, and cCl(CClF2)2] and are compared with spectra of I (R = Et and iso-Pr) (W. J. Lehmann et al., 1969). In the spectra of the fully deuterated derivs., the splitting (∼50 cm-1) of the 10BO3-11BO3 asym. stretching vibrational frequencies was greater than in the nondeuterated derivs. due to greater low frequency shifts in the 11BO3 band. Anal. of the relative displacements in the chem. shifts indicate coupling of the (BO) stretching and CH deformation modes.
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  The catalytic potential of 4-guanidinylpyridines in acylation reactions
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  A series of 3-alkyl-4-guanidinylpyridines with variable alkylation pattern have been synthesized and characterized with respect to their catalytic potential in acylation reactions of alcs. The ability of the substitution pattern to stabilize acylpyridinium cations, which act as crit. intermediates in the catalytic cycle of pyridine-catalyzed acylation reactions, has been assessed at the MP2(FC)/6-31+G(2d,p)//B98/6-31G(d) level of theory and inclusion of solvent effects in chloroform using the PCM continuum solvation model. The most active 4-guanidinylpyridines are among those having the most electron-rich pyridine ring. The influence of the type and concn. of the auxiliary base on the catalytic activity has also been studied. While the change from triethylamine to N,N-diisopropylethylamine as the auxiliary base does not lead to a systematic increase or decrease in the catalytic rates, the complete absence of auxiliary base leads to a 27-fold redn. in reaction rate.
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  Chiral Lewis Base Catalyzed Highly Enantioselective Reduction of N-Alkyl β-Enamino Esters with Trichlorosilane and Water
  Wu, Xinjun; Li, Yang; Wang, Chao; Zhou, Li; Lu, Xiaoxia; Sun, Jian
  Chemistry - A European Journal (2011), 17 (10), 2846-2848, S2846/1-S2846/66CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  In the presence of chiral proline-derived Lewis base catalyst I, the supposedly moisture-unfriendly redn. system with trichlorosilane was found to be highly efficient and enantioselective when using water as an additive. For the first time, this method enables the redn. of a broad range of N-alkyl β-enamino esters II (R1 = Ph, 4-Me-C6H4, 3-Cl-C6H4, Bn, etc.; R2 = Et, Me, tBu, Bn, cyclohexyl; R3 = Bn, allyl, nPr, tBu) to give N-alkyl β-amino esters in good to high yields and with excellent enantioselectivities.
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  A novel transamidation of primary carboxamides with primary or secondary amines to give secondary or tertiary amides is described. Catalyzed with hydroxylamine hydrochloride, a series of amides were obtained using this strategy in good to excellent yields.
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  Zirconocene dichloride has been shown to be an effective catalyst for the transamidation of primary amides with amines in cyclohexane at 80° in 5-24 h. For favorable substrates, the reaction can be performed at temps. as low as 30°.
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  Efficient Copper(II)-Catalyzed Transamidation of Nonactivated Primary Carboxamides and Ureas with Amines
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  Angewandte Chemie, International Edition (2012), 51 (16), 3905-3909, S3905/1-S3905/24CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A copper(II) catalyzed transamidation process using nonactivated primary carboxamides and ureas with amines is presented. For this technique, the Cu(OAc)2 is fairly inexpensive and convenient to use without special precautions. Fortunately, a wide range of amides, ureas, chiral amines can be synthesized from primary carboxamides and amines in good to excellent yields. By extension this protocol can be applied to the synthesis of amides, peptide, polyamides and heterocycles.
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  RSC Advances (2013), 3 (6), 1691-1694CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
  This protocol describes the catalytic use of diacetoxyiodobenzene (DIB) for the efficient trans-amidation of carboxamides with amines under mild reaction conditions. The synthesis of the target compds. was achieved using formamide, acetamide, benzeneacetamide, benzamide, nicotinamide and 1H-isoindole-1,3(2H)-dione (phthalimide) as starting materials in a reaction with benzenamine, piperidine. morpholine, cyclohexanamine, 1-hexanamine, cyclopropanamine, 2-phenylethylamine, 2-pyridinamine, etc. The title compds. thus formed included 2-hexyl-1H-isoindole-1,3(2H)-dione [cyclic imide (hexyl)phthalimide], N-(benzyl)formamide, 1-Piperidinecarboxaldehyde (1-formylpiperidine) and 4-morpholinecarboxaldehyde (formylmorpholine), N-(phenylmethyl)-3-pyridinecarboxamide.
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  Boric Acid: A Highly Efficient Catalyst for Transamidation of Carboxamides with Amines
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  A novel method of transamidation of carboxamides with amines using catalytic amts. of readily available boric acid under solvent-free conditions has been developed. The scope of the methodol. has been demonstrated with (i) primary, secondary, and tertiary amides and phthalimide and (ii) aliph., arom., cyclic, acyclic, primary, and secondary amines.
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  Among various metal oxides, cerium oxide (CeO2) shows highest catalytic activity for transamidation of picolinamide with n-octylamine. CeO2 acts as a reusable and effective heterogeneous catalyst for transamidation under solvent-free conditions. Transamidation of a variety of amides and amines produced the corresponding N-alkyl amides in high yields. Characterization of the acid-base properties and kinetic studies suggest that the cooperation of the weak Lewis acid sites and adjacent strong base sites play important roles in the transamidation reaction.
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  Cyclizing ClCH2CH2SCH2CH2NH2 with KOH gave 49% thiomorpholine. Thiomorpholine and 2-methyl-3-ethylthiomorpholine were acylated by acyl chlorides, dicarboxylic acid chlorides, anhydrides, sulfonic acid chlorides, isocyanates, diisocyanates and isothiocyanates, and N-alkylated by alkyl halides. E.g., thiomorpholines I and II [ R1 = R2 = H, R1 = Me, R2 = Et; R3 = R4CO, R4SO2, CONHR4, C(S)NHR4 (R4 = e.g., C3-18 alkyl, PhCH2, 2-O2NC6H4, CNCH2, allyl, butenyl, crotonyl), X = COX1CO, CONHX2NHCO, X1 = arylylene, oxalyl, adipoyl, terephthaloyl, X2 = phenylene derivs.] (∼100 compds.) were prepd.
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  RCHR1C(:NOH)Cl (R, R1 = Ph, halophenyl, tolyl, alkoxyphenyl) were converted to the resp. RCHR1CONR2R3 (R2 = alkyl, H; R3 = alkyl, PhCH2, Ph; NR2R3 = piperidino, morpholino, 4-methyl-1-piperazinyl). Ph2CHC(:NOH)Cl reacted with Me2NH, and the Ph2CHC(:NOH)NMe2 obtained was hydrolyzed to Ph2CHCONMe2, useful as a herbicide (no data).
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  Hajipour, Abdol Reza; Ghasemi, Majid
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  The synthesis of amides 2 from the corresponding arom. acids and aliph. amines in the presence of catalytic amt. of p-toluenesulfonic acid has been reported. The reactions are accelerated with microwave irradn. under solvent-free conditions to afford a high yielding synthesis of amides.
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  Amide Synthesis from Alcohols and Amines Catalyzed by Ruthenium N-Heterocyclic Carbene Complexes
  Dam, Johan Hygum; Osztrovszky, Gyorgyi; Nordstroem, Lars Ulrik; Madsen, Robert
  Chemistry - A European Journal (2010), 16 (23), 6820-6827, S6820/1-S6820/26CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The direct synthesis of amides from alcs. and amines is described with the simultaneous liberation of dihydrogen. The reaction does not require any stoichiometric additives or hydrogen acceptors and is catalyzed by ruthenium N-heterocyclic carbene complexes. Three different catalyst systems are presented that all employ 1,3-diisopropylimidazol-2-ylidene (IiPr) as the carbene ligand. In addn., potassium tert-butoxide and a tricycloalkylphosphine are required for the amidation to proceed. In the first system, the active catalyst is generated in situ from [RuCl2(cod)] (cod = 1,5-cyclooctadiene), 1,3-diisopropylimidazolium chloride, tricyclopentylphosphonium tetrafluoroborate, and base. The second system uses the complex [RuCl2(IiPr)(p-cymene)] together with tricyclohexylphosphine and base, whereas the third system employs the Hoveyda-Grubbs 1st-generation metathesis catalyst together with 1,3-diisopropylimidazolium chloride and base. A range of different primary alcs. and amines have been coupled in the presence of the three catalyst systems to afford the corresponding amides in moderate to excellent yields. The best results are obtained with sterically unhindered alcs. and amines. The three catalyst systems do not show any significant differences in reactivity, which indicates that the same catalytically active species is operating. The reaction is believed to proceed by initial dehydrogenation of the primary alc. to the aldehyde that stays coordinated to ruthenium and is not released into the reaction mixt. Addn. of the amine forms the hemiaminal that undergoes dehydrogenation to the amide. A catalytic cycle is proposed with the {(IiPr)RuII} species as the catalytically active components.
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  A General and Efficient Copper Catalyst for the Amidation of Aryl Halides
  Klapars, Artis; Huang, Xiaohua; Buchwald, Stephen L.
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  An exptl. simple and inexpensive catalyst system was developed for the amidation of aryl halides by using 0.2-10 mol % of CuI, 5-20 mol % of a 1,2-diamine ligand, and K3PO4, K2CO3, or Cs2CO3 as base. Catalyst systems based on N,N'-dimethylethylenediamine or trans-N,N'-dimethyl-1,2-cyclohexanediamine were found to be the most active even though several other 1,2-diamine ligands could be used in the easiest cases. Aryl iodides, bromides, and in some cases even aryl chlorides can be efficiently amidated. A variety of functional groups are tolerated in the reaction, including many that are not compatible with Pd-catalyzed amidation or amination methodol.
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  Woon, E. C. Y.; Demetriades, M.; Bagg, E. A. L.; Aik, W.; Krylova, S. M.; Ma, J. H. Y.; Chan, M.; Walport, L. J.; Wegman, D. W.; Dack, K. N.; McDonough, M. A.; Krylov, S. N.; Schofield, C. J. J. Med. Chem. 2012, 55, 2173– 2184
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  Dynamic Combinatorial Mass Spectrometry Leads to Inhibitors of a 2-Oxoglutarate-Dependent Nucleic Acid Demethylase
  Woon, Esther C. Y.; Demetriades, Marina; Bagg, Eleanor A. L.; Aik, WeiShen; Krylova, Svetlana M.; Ma, Jerome H. Y.; Chan, MunChiang; Walport, Louise J.; Wegman, David W.; Dack, Kevin N.; McDonough, Michael A.; Krylov, Sergey N.; Schofield, Christopher J.
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  2-Oxoglutarate-dependent nucleic acid demethylases are of biol. interest because of their roles in nucleic acid repair and modification. Although some of these enzymes are linked to physiol., their regulatory roles are unclear. Hence, there is a desire to develop selective inhibitors for them; we report studies on AlkB, which reveal it as being amenable to selective inhibition by small mols. Dynamic combinatorial chem. linked to mass spectrometric analyses (DCMS) led to the identification of lead compds., one of which was analyzed by crystallog. Subsequent structure-guided studies led to the identification of inhibitors of improved potency, some of which were shown to be selective over two other 2OG oxygenases. The work further validates the use of the DCMS method and will help to enable the development of inhibitors of nucleic acid modifying 2OG oxygenases both for use as functional probes and, in the longer term, for potential therapeutic use.
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  Several polyols, which are easily available from sugars through biochem. conversion or hydrogenolytic cleavage, are directly converted into carboxylic acids and amides. This efficient dehydrogenative coupling process, catalyzed by a rhodium(I) diolefin amido complex, is an attractive approach for the prodn. of org. fine chems. from renewable resources. This method tolerates the presence of several hydroxy groups and can be extended to the direct synthesis of lactams from the corresponding amino alcs. under mild conditions.
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Direct Synthesis of Amides from Carboxylic Acids and Amines Using B(OCH2CF3)3

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Abstract

Introduction

Results and Discussion

Preparation of the B(OCH2CF3)3 Reagent

Scheme 1

Development of a Solid Phase Workup Procedure and Evaluation of Other Borates

Figure 1

Scope of the Amidation Reactions

Figure 2

Figure 3

Figure 4

Figure 5

Scheme 2

Coupling of Acids with an Adjacent Chiral Center

Figure 6

Transamidation of DMF using B(OCH2CF3)3

Conclusion

Experimental Section

General Methods

Tris-(2,2,2-trifluoroethyl) borate (13)

25 g Scale

50 g Scale (With CF3CH2OH Recovery)

General Procedure for Amidation of Carboxylic acids

Solid Phase Workup

Aqueous Workup Procedure

General Procedure for the Formylation of Amines with DMF

N-(2-Methoxybenzyl)-2-phenylacetamide (2b)

N-(4-Methoxybenzyl)-2-phenylacetamide (2c) (42)

N-(2-(1H-Indol-3-yl)ethyl)-2-phenylacetamide (2f) (43)

N-Methyl-N′-phenylacetylpiperazine (2i) (44)

N-Phenyl-N′-phenylacetylpiperazine (2j)

N-Phenylacetylmorpholine (2k) (45)

2-Phenyl-1-(pyrrolidin-1-yl)ethanone (2l)

N-Phenylacetylthiomorpholine (2m) (46)

N,N-Dimethyl-2-phenylacetamide (2n) (47)

N,N-Dibenzyl-2-phenylacetamide (2o) (48)

N,2-Diphenylacetamide (2p) (49)

N-(2-Methoxyphenyl)-2-phenylacetamide (2q) (50)

2-Phenyl-N-p-tolylacetamide (2r) (49)

N-(4-Methoxyphenyl)-2-phenylacetamide (2s) (49)

N-(Pyridin-3-yl)-2-phenylacetamide (2t)

N-(Pyridin-2-yl)-2-phenylacetamide (2u) (49)

N-tert-Butyl-2-phenylacetamide (2v) (51)

N-Benzyl-2-(naphthalen-2-yl)acetamide (3a) (52)

N-Benzyl-2,2-diphenylacetamide (3b) (53)

N-Benzyl-2-(4-methoxyphenyl)acetamide (3c) (54)

N-Benzyl-2-(2-bromophenyl)acetamide (3d) (55)

N-Benzyl-2-(4-bromophenyl)acetamide (3e)

N-Benzyl-2-(3,4-dimethoxyphenyl)acetamide (3f)

N-Benzyl-2-(4-chlorophenyl)acetamide (3g) (57)

N-Benzyl-2-(thiophen-3-yl)acetamide (3h)

N-Benzyl-2-(4-phenoxyphenyl)acetamide (3i)

Boc-Sarcosine-benzamide (3k) (58)

(E)-N-Benzyl-3-(thiophen-3-yl)acrylamide (3m)

(E)-N-Benzyl-2-methyl-3-phenylacrylamide (3n)

N-Benzyl-2,2,2-trifluoroacetamide (3p) (59)

N-Benzyl-4-methoxybenzamide (3s) (60)

N-Benzyl-4-(trifluoromethyl)benzamide (3t) (61)

N,2-Dibenzylbenzamide (3u)

N-Benzyl-4-iodobenzamide (3v) (62)

N-Butyl-2-p-tolylacetamide (4c) (63)

Methyl 2-(picolinamido)acetate (4e) (64)

N-(4-Hydroxyphenyl)acetamide (4g) (65)

2-(4-(2-(Benzylamino)-2-oxoethyl)phenyl)acetic acid (4h)

Piperidin-2-one (5a) (66)

Azepan-2-one (5b) (57)

(S)-tert-Butyl 2-oxopiperidin-3-ylcarbamate (5c) (16)

Boc-l-Methionine-benzamide (6a) (67)

Boc-l-Phenylalanine-benzamide (6c) (68)

Boc-l-Proline-benzamide (6d) (69)

Cbz-l-Alanine-benzamide (6e) (22)

Boc-l-Ala-d-Phe-OMe (6f)

Boc-l-Ala-l-Phe-OMe (6g) (70)

Boc-l-Alanine pyrrolidine amide (6h) (22)

Boc-l-Alanine thiomorpholine amide (6i)

Direct Synthesis of Amides from Carboxylic Acids and Amines Using B(OCH₂CF₃)₃

Preparation of the B(OCH₂CF₃)₃ Reagent

Transamidation of DMF using B(OCH₂CF₃)₃

50 g Scale (With CF₃CH₂OH Recovery)