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PyFluor: A Low-Cost, Stable, and Selective Deoxyfluorination Reagent
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† Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
‡ Department of Imaging Research, Merck Research Laboratories, West Point, Pennsylvania 19486, United States
*E-mail: [email protected]
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Cite this: J. Am. Chem. Soc. 2015, 137, 30, 9571–9574
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https://doi.org/10.1021/jacs.5b06307
Published July 15, 2015

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Abstract

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We report an inexpensive, thermally stable deoxyfluorination reagent that fluorinates a broad range of alcohols without substantial formation of elimination side products. This combination of selectivity, safety, and economic viability enables deoxyfluorination on preparatory scale. We employ the [18F]-labeled reagent in the first example of a no-carrier-added deoxy-radiofluorination.

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Organofluorine compounds are featured prominently throughout industry owing to the unique properties that fluorine substitution confers on organic molecules. (1, 2) Notably, in the context of drug design, the introduction of carbon–fluorine bonds can dramatically improve the metabolic stability, solubility, and activity of pharmaceutical candidates. (3) Deoxyfluorination of alcohols is one of the most attractive methods for installing aliphatic C–F bonds due to the abundance and accessibility of alcohol-containing precursors. (4-7) In this technique, a deoxyfluorination reagent generates both an activated leaving group and a nucleophilic fluoride source that react in situ to afford product (Figure 1). Although this transformation may also be achieved through multistep sequences, (8) a one-pot deoxyfluorination often proceeds under milder conditions with broader functional group tolerance.

Figure 1

Figure 1. (a) The popular deoxyfluorination reagent DAST frequently affords elimination side products and displays poor thermal stability. (b) PyFluor is a stable and affordable alternative that demonstrates high selectivity against elimination, thus enabling rapid and facile purification.

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Introduced in the 1970s, diethylaminosulfur trifluoride (DAST) remains the most popular deoxyfluorination reagent due to its availability and general scope. DAST readily fluorinates alcohols and will also convert ketones and aldehydes to geminal difluorides. (5b, 5c) However, the reagent’s cost and propensity for violent decomposition render it unsuitable for process chemistry. (9) Furthermore, DAST reactions feature limited functional group tolerance and afford elimination side products that complicate purification (Figure 1A). Much effort has been dedicated toward developing thermally stable variants such as Deoxo-Fluor, XtalFluor, and Fluolead, (5d-5f) but these options are more expensive and offer only marginal improvements in chemoselectivity. The recently disclosed PhenoFluor exhibits remarkable versatility in the late-stage fluorination of complex natural products, but its high cost and poor shelf stability hinder widespread adoption. (6b) In addition, the inaccessibility of no-carrier-added 18F variants of all of these reagents has precluded adaptation of this powerful transformation to radiolabeling procedures.

Our goal was to identify an inexpensive, operationally convenient, stable, and chemoselective deoxyfluorination reagent that would also be amenable to deoxy-radiofluorination. In this paper, we report a new reagent, 2-pyridinesulfonyl fluoride (PyFluor), which satisfies these criteria (Figure 1B). Previously, our laboratory developed catalytic hydrofluorinations wherein nucleophilic fluoride was generated via esterification of benzoyl fluoride with a sacrificial alcohol. (10) We speculated that increasing the electron-withdrawing nature of the acyl fluoride might instead lead to substitution of the newly formed ester, resulting in a formal deoxyfluorination. The utility of preformed sulfonate esters in multistep fluorination and radiofluorination reactions led us to the investigation of sulfonyl fluorides. Although Vorbrüggen has reported the use of perfluorobutanesulfonyl fluoride (PBSF), (7b) this reagent has failed to gain traction because it produces copious quantities of elimination side products that can render recrystallization or chromatographic separation impossible. (11) Furthermore, in the presence of amines and heterocycles, PBSF liberates gaseous perfluorobutane that can lead to dangerous pressure spikes, making this reagent no more attractive than DAST from a safety perspective. (12) Notwithstanding, we hypothesized that a stable, general, and selective deoxyfluorination using an arylsulfonyl fluoride could be identified based on early literature highlighting their stability toward reduction, hydrolysis, and thermolysis. (13)

We evaluated a broad range of sulfonyl fluorides in the fluorination of alcohol 1 (Table 1; see Supporting Information (SI)). In combination with the amidine base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), PBSF furnished product 2 in 57% yield with 10% elimination side product, a selectivity of 6:1 that is consistent with previous reports (entry 3). (14) We were pleased to find that most electron-deficient aryl- and heteroaryl-sulfonyl fluorides outperformed PBSF in terms of both yield and selectivity. Notably, 2-pyridinesulfonyl fluoride afforded 2 in 79% yield with greater than 20:1 selectivity (entry 7). By comparison, commercially available DAST and Deoxo-Fluor are markedly less selective, providing 13–19% elimination (entries 1, 2). (14, 15) Previous reports have suggested that 2-pyridinesulfonate esters can act as nucleophile-assisted leaving groups in substitution reactions; however the success of both 3- and 4-pyridine-sulfonyl fluorides indicates that pyridine serves primarily as an inductive electron-withdrawing group (entries 8, 9). (16) Consistent with this proposal, incorporation of electron-withdrawing substituents on the pyridine does not attenuate reactivity and may lead to modest improvements in yield (entry 10); however, we chose to pursue our studies with 2-pyridinesulfonyl fluoride (hereafter referred to as PyFluor), as we felt it represented the best combination of cost (vide infra) and efficiency.

Table 1. Sulfonyl Fluorides as Deoxyfluorination Reagents
Table a

Yield of 2 determined by GC using 1-fluoro-naphthalene as an internal standard; average of two runs.

Table b

Ratio of 2 to combined elimination side products as determined by GC.

Table c

1.8 equiv in CH2Cl2, 0 °C; ref 15.

Table d

1.2 equiv in CH2Cl2, −78 °C; ref 14.

In our investigation of reaction conditions, we found that strong amidine and guanidine bases such as DBU and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) are uniquely effective. Optimal conditions employ just 1.1 equiv of PyFluor with 2 equiv of base. Interestingly, the reaction is not highly solvent dependent; toluene and cyclic ethers perform best, but reasonable yields are obtained in DMSO and acetonitrile. It is also noteworthy that this method does not require exclusion of air or moisture. Over the course of a typical reaction, the sulfonate ester forms quantitatively in minutes and is then gradually converted to product within 48 h (see SI for optimization and reaction profile). The only side product detected by LC-MS is cation 3, which arises from nucleophilic attack by DBU on the sulfonate ester intermediate and accounts for the mass balance.

DBU and MTBD are known to behave as both Brønsted bases or nucleophilic acyl transfer catalysts. (17) When PyFluor is mixed with DBU, complex 4 is observed by LC-MS, but it forms several orders of magnitude slower than the sulfonate ester under standard reaction conditions. Moreover, 4 is incompetent for deoxyfluorination of alcohol 1. Taken together, these data suggest that DBU and MTBD function principally as Brønsted bases. We propose that deoxyfluorination proceeds by base-assisted addition of the substrate alcohol to the sulfonyl fluoride. The protonated base then stabilizes the developing fluoride ion leaving group. This proposal is in line with observations by Sharpless that the S–F bond in sulfonyl fluorides must be activated by a protic species in order to be labile. (18) Sulfonyl transfer produces the reactive amidine hydrogen fluoride, which mediates fluorination of the sulfonate ester intermediate.

With optimal conditions in hand, we proceeded to delineate the reagent’s substrate scope (Table 2). PyFluor serves as a general deoxyfluorination reagent for both primary (5) and secondary alcohols (2). Complex biomolecules including carbohydrates (6, 7), steroids (8), and amino acids (9) can be fluorinated in high yield. PyFluor also tolerates a broad range of basic functionality including phthalimides (10), heterocycles (11, 21), and protected and even unprotected amines and anilines (9, 12–15). Furthermore, difluorination can be achieved in good yield (16). Most reactions proceed at room temperature, although cyclic or sterically encumbered substrates may require moderate heating. Additionally, the diastereoselectivity observed with 8, 9, and 14 indicates that fluorination occurs with inversion and without epimerization. (19) These results compare favorably to those obtained using commercially available reagents and highlight the potential of the method for late-stage diversification of natural products and drug-like molecules. (20)

Table 2. Scope of the Deoxyfluorination with PyFluor
Table a

Isolated yield of fluorinated product; average of two runs. Experiments conducted on 0.1–1 mmol scale.

Table b

Heated at 50 °C.

Table c

2.1 equiv of PyFluor, 3.5 equiv of base.

A number of examples of PyFluor’s chemoselectivity are also of note: Primary and secondary alcohols can be fluorinated in the presence of tertiary alcohols (17). Substrates possessing carbonyls do not undergo competing gem-difluorination or form acyl fluorides as with DAST and its derivatives. (5) Homobenzylic alcohols (20, 21), which are highly susceptible to elimination with DAST, perform well under the standard conditions, although some elimination is observed (8–10%). Unhindered benzylic alcohols (22, 23) also deliver fluorinated product, albeit in only moderate yield due to competitive nucleophilic attack by the base on the sulfonate intermediate. In contrast, β-hydroxy carbonyl compounds bearing acidic α protons (24) afford exclusively elimination, exposing a limit of the reagent’s chemoselectivity. Aside from these exceptions, most substrates do not generate elimination side products. This results in trivial purifications; the crude reaction mixture can simply be flushed through a short silica column to remove the ionic side products. As a demonstration of scalability, alcohol 1 can be fluorinated on 5 g scale with no diminution in yield (79%).

The positive attributes of PyFluor extend beyond its reactivity and selectivity profile. PyFluor can be synthesized on multigram scale via the oxidation of 2-mercaptopyridine and halide exchange with potassium bifluoride (Figure 2). This unoptimized procedure consumes only $180 of materials per mol of reagent produced, which suggests that PyFluor could be manufactured at a price competitive to that of DAST ($443 per mol, Oakwood). (21) Yet unlike DAST, PyFluor is remarkably stable. The reagent is a low-melting solid (mp 23–26 °C) that can be handled and stored on the benchtop for over 30 days with no detectable decomposition. Furthermore, the sulfonyl fluoride does not hydrolyze in aqueous emulsion and is even stable on silica gel. DAST, however, must be refrigerated and will react violently with trace moisture. Almost all reported deoxyfluorination reagents exhibit exothermic thermal decomposition; for example, differential scanning calorimetry (DSC) indicates that DAST decomposes explosively at 155 °C with an exotherm of 63 kcal/mol. (9b) In contrast, PyFluor does not undergo exothermic decomposition in the range 0–350 °C (see SI for DSC data). Taken as a whole, PyFluor demonstrates a substantially better safety profile than other low-cost deoxyfluorination reagents.

Figure 2

Figure 2. Multigram synthesis of PyFluor.

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Deoxyfluorination with PyFluor is also translatable to 18F radiolabeling (Figure 3). Substitution of alkyl sulfonates with [18F]KF/K222 forms the basis for the majority of radiotracer syntheses in PET imaging applications. (22) Nevertheless, this methodology fails in the presence of numerous biologically relevant functional groups, requires high temperatures to induce reasonable rates (>100 °C), and often leads to elimination products that are challenging to separate from the radiolabeled target. A 18F-variant of a deoxyfluorination remains an attractive but elusive alternative approach to aliphatic C–18F bond formation. Thus far, all reported deoxy-radiofluorinations require a 19F carrier in the form of an unlabeled reagent in order to generate enough activated electrophile to react with the nanomolar quantities of 18F available under labeling conditions. (23) Furthermore, deoxyfluorination reagents featuring multiple reactive fluorine equivalents (such as DAST) cannot be made isotopically pure, again due to low 18F concentration. Overall, these methods produce radiolabeled products with low specific activity (i.e., a high concentration of stable isotope). In preliminary studies, we found that reaction of 2-pyridinesulfonyl chloride with [18F]KF/K222 at 80 °C for 5 minutes afforded [18F]PyFluor in 88% radiochemical conversion (RCC). (24) Using this reagent, we were able to achieve deoxy-radiofluorination under comparatively mild conditions, delivering [18F]6 in 15% RCC after 20 min at 80 °C. This exciting proof of concept represents the first example of a no-carrier-added deoxy-radiofluorination. By performing both the reagent synthesis and deoxy-radiofluorination in a single pot, the unreacted 2-pyridinesulfonyl chloride enables stoichiometric formation of the sulfonate intermediate, thus obviating the need for carrier addition. Moreover, [18F]6 is inaccessible via conventional radiofluorination methods owing to the instability of the tosylate precursor. (25) This labeling protocol could be particularly useful with substrates for which the sulfonate ester cannot be isolated.

Figure 3

Figure 3. Radiosynthesis of [18F]PyFluor and its application to deoxy-radiofluorination.

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In conclusion, we have developed a low-cost deoxyfluorination reagent that exhibits high chemical and thermal stability. In addition to tolerating a wide range of functionality, PyFluor is highly selective against elimination, allowing for straightforward purifications. Although this method requires longer reaction times and basic conditions, we expect that it will complement existing methods in laboratory screening. Furthermore, we envision that PyFluor will enable preparatory fluorination of alcohols on previously unattainable scale. Finally, we have demonstrated the first example of a no-carrier-added deoxy-radiofluorination with [18F]PyFluor. Our efforts are ongoing to optimize this procedure and interrogate its scope for PET imaging applications.

Supporting Information

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Experimental procedures, additional reaction optimization, and spectroscopic data for all new compounds. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.5b06307.

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Author Information

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  • Corresponding Author
    • Abigail G. Doyle - Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States;  Email: [email protected]
  • Authors
    • Matthew K. Nielsen - Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
    • Christian R. Ugaz - Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
    • Wenping Li - Department of Imaging Research, Merck Research Laboratories, West Point, Pennsylvania 19486, United States
  • Notes
    The authors declare no competing financial interest.

Acknowledgment

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We thank Dr. Thomas J. A. Graham (University of Pennsylvania) for helpful discussions and assistance with DSC measurements and R. Frederick Lambert (Harvard School of Dental Medicine) for experimental assistance. We acknowledge Dr. Eric Hostetler (Merck & Co., Inc., West Point, PA) for furnishing access to radiosynthesis facilities. Financial support was provided by the NSF (CAREER-1148750) and BMS (Innovation Award).

References

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    Umemoto, Teruo; Singh, Rajendra P.; Xu, Yong; Saito, Norimichi
    Journal of the American Chemical Society (2010), 132 (51), 18199-18205CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Versatile, safe, shelf-stable, and easy-to-handle fluorinating agents are strongly desired in both academic and industrial arenas, since fluorinated compds. have attracted considerable interest in many areas, such as drug discovery, due to the unique effects of fluorine atoms when incorporated into mols. This article describes the synthesis, properties, and reactivity of many substituted and thermally stable phenylsulfur trifluorides, in particular, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead, I), as a cryst. solid having surprisingly high stability on contact with water and superior utility as a deoxofluorinating agent compared to current reagents, such as DAST and its analogs. The roles of substituents on I in thermal and hydrolytic stability, fluorination reactivity, and the high-yield fluorination mechanism it undergoes have been clarified. In addn. to fluorinations of alcs., aldehydes, and enolizable ketones, I smoothly converts non-enolizable carbonyls to CF2 groups, and carboxylic groups to CF3 groups, in high yields. I also converts C(=S) and CH3SC(=S)O groups to CF2 and CF3O groups, resp., in high yields. In addn., I effects highly stereoselective deoxofluoro-arylsulfinylation of diols and amino alcs. to give fluoroalkyl arylsulfinates and arylsulfinamides, with complete inversion of configuration at fluorine and the simultaneous, selective formation of one conformational isomer at the sulfoxide sulfur atom. Considering the unique and diverse properties, relative safety, and ease of handling of I in addn. to its convenient synthesis, it is expected to find considerable use as a novel fluorinating agent in both academic and industrial arenas.
  6. 6

    Azolium fluorides – DFI:

    (a) Hayashi, H.; Sonoda, H.; Fukumura, K.; Nagata, T. Chem. Commun. 2002, 1618 DOI: 10.1039/b204471d
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    PhenoFluor:

    (b) Sladojevich, F.; Arlow, S. I.; Tang, P.; Ritter, T. J. Am. Chem. Soc. 2013, 135, 2470 DOI: 10.1021/ja3125405
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    6b
    Late-Stage Deoxyfluorination of Alcohols with PhenoFluor
    Sladojevich, Filippo; Arlow, Sophie I.; Tang, Pingping; Ritter, Tobias
    Journal of the American Chemical Society (2013), 135 (7), 2470-2473CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    An operationally simple protocol for the selective deoxyfluorination of structurally complex alcs. is presented. Several fluorinated derivs. of natural products and pharmaceuticals have been prepd. to showcase the potential of the method for late-stage diversification and its functional group compatibility. For example, testosterone reacted with PhenoFluor to give 17-epi-17-fluoro-17-deoxytestosterone in 88% yield. A series of simple guidelines for predicting the selectivity in substrates with multiple alcs. is given.
  7. 7

    Sulfonyl fluorides – p-Toluenesulfonyl fluoride:

    (a) Shimizu, M.; Nakahara, Y.; Yoshioka, H. Tetrahedron Lett. 1985, 26, 4207 DOI: 10.1016/S0040-4039(00)98993-7
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    Perfluorobutanesulfonyl fluoride:

    (b) Bennua-Skalmowski, B.; Vorbrüggen, H. Tetrahedron Lett. 1995, 36, 2611 DOI: 10.1016/0040-4039(95)00355-G
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    7b
    A facile conversion of primary or secondary alcohols with n-perfluorobutanesulfonyl fluoride/1,8-diazabicyclo[5.4.0]undec-7-ene into their corresponding fluorides
    Bennua-Skalmowski, B.; Vorbrueggen, H.
    Tetrahedron Letters (1995), 36 (15), 2611-14CODEN: TELEAY; ISSN:0040-4039. (Elsevier)
    The combination of n-perfluorobutanesulfonyl fluoride with 1,8-diazabicyclo[5.4.0]undec-7-ene efficiently converts steroidal primary and secondary alcs. in unpolar solvents into their corresponding fluorides. Thus, the reaction with 5α-cholestan-3β-ol gave 61% 3α-fluoro-5α-cholestane.
  8. 8

    Substitution of halides – with AgF:

    (a) Moissan, H. Ann. Chim. Phys. 1890, 19, 266
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    With KF:

    (b) Hoffmann, F. W. J. Am. Chem. Soc. 1948, 70, 2596 DOI: 10.1021/ja01187a505
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    With KF/18-crown-6:

    (c) Liotta, C. L.; Harris, H. P. J. Am. Chem. Soc. 1974, 96, 2250 DOI: 10.1021/ja00814a044
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    Substitution of sulfonate esters – with KF:

    (d) Edgell, W. F.; Parts, L. J. Am. Chem. Soc. 1955, 77, 4899 DOI: 10.1021/ja01623a065
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    With TBAF:

    (e) Henbest, H. B.; Jackson, W. R. J. Chem. Soc. 1962, 954 DOI: 10.1039/jr9620000954
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  9. 9

    DAST solutions may detonate explosively at temperatures as low as 108 °C; see:

    (a) Messina, P. A.; Mange, K. C.; Middleton, W. J. J. Fluorine Chem. 1989, 42, 137 DOI: 10.1016/S0022-1139(00)83974-3
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    9a
    Aminosulfur trifluorides: relative thermal stability
    Messina, Patricia A.; Mange, Kevin C.; Middleton, W. J.
    Journal of Fluorine Chemistry (1989), 42 (1), 137-43CODEN: JFLCAR; ISSN:0022-1139.
    The fluorinating reagent DAST (diethylaminosulfur trifluoride) has the potential to decomp. violently when heated and presents a hazard if not properly handled. This investigation has shown that the decompn. occurs in two steps. First, a non-energetic disproportionation occurs to give sulfur tetrafluoride and bis(diethylamino)sulfur difluoride. The less stable difluoride thus formed then undergoes a vigorous exothermic decompn. (detonation). The relative stabilities of DAST and several of its analogs were detd. by DTA. Morpholinosulfur trifluoride (morpho-DAST) was the most stable of the aminosulfur trifluorides examd., and its use in place of the less stable DAST is recommended for fluorinations of alcs.
    (b) L’Heureux, A.; Beaulieu, F.; Bennett, C.; Bill, D. R.; Clayton, S.; LaFlamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier, M. J. Org. Chem. 2010, 75, 3401 DOI: 10.1021/jo100504x
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    9b
    Aminodifluorosulfinium Salts: Selective Fluorination Reagents with Enhanced Thermal Stability and Ease of Handling
    L'Heureux, Alexandre; Beaulieu, Francis; Bennett, Christopher; Bill, David R.; Clayton, Simon; La Flamme, Francois; Mirmehrabi, Mahmoud; Tadayon, Sam; Tovell, David; Couturier, Michel
    Journal of Organic Chemistry (2010), 75 (10), 3401-3411CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Diethylaminodifluorosulfinium tetrafluoroborate (XtalFluor-E) and morpholinodifluorosulfinium tetrafluoroborate (XtalFluor-M) are cryst. fluorinating agents that are more easily handled and significantly more stable than Deoxo-Fluor, DAST, and their analogs. These reagents can be prepd. in a safer and more cost-efficient manner by avoiding the laborious and hazardous distn. of dialkylaminosulfur trifluorides. Unlike DAST, Deoxo-Fluor, and Fluolead, XtalFluor reagents do not generate highly corrosive free-HF and therefore can be used in std. borosilicate vessels. When used in conjunction with promoters such as Et3N·3HF, Et3N·2HF, or DBU, XtalFluor reagents effectively convert alcs. to alkyl fluorides and carbonyls to gem-difluorides. These reagents are typically more selective than DAST and Deoxo-Fluor and exhibit superior performance by providing significantly less elimination side products.
  10. 10
    (a) Kalow, J. A.; Doyle, A. G. J. Am. Chem. Soc. 2010, 132, 3268 DOI: 10.1021/ja100161d
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    10a
    Enantioselective ring opening of epoxides by fluoride anion promoted by a cooperative dual-catalyst system
    Kalow, Julia A.; Doyle, Abigail G.
    Journal of the American Chemical Society (2010), 132 (10), 3268-3269CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    An enantioselective method for the synthesis of β-fluoroalcs. by catalytic nucleophilic fluorination of epoxides is described. Mild reaction conditions and high selectivity are made possible by the use of benzoyl fluoride as a sol., latent source of fluoride anion. A chiral amine and chiral Lewis acid serve as cooperative catalysts for desymmetrizations of five- through eight-membered cyclic epoxides, affording products in up to 95% ee. The cocatalytic protocol is also effective for kinetic resolns. of racemic terminal epoxides, which proceed with krel values as high as 300.
    (b) Kalow, J. A.; Schmitt, D. E.; Doyle, A. G. J. Org. Chem. 2012, 77, 4177 DOI: 10.1021/jo300433a
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    10b
    Synthesis of β-Fluoroamines by Lewis Base Catalyzed Hydrofluorination of Aziridines
    Kalow, Julia A.; Schmitt, Dana E.; Doyle, Abigail G.
    Journal of Organic Chemistry (2012), 77 (8), 4177-4183CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Lewis base catalysis promotes the in situ generation of amine-HF reagents from benzoyl fluoride and a non-nucleophilic alc. E.g., in presence of 1,5-diazabicyclo[4.3.0]non-5-ene, PhCOF, and HFIP, hydrofluorination of aziridine deriv. (I) gave 92% trans-II. The hydrofluorination of aziridines to provide β-fluoroamines using this latent HF source is described. This protocol displays a broad scope with respect to aziridine substitution and N-protecting groups. Examples of regio- and diastereoselective ring opening to access medicinally relevant β-fluoroamine building blocks are presented.
  11. 11
    Egli, M.; Pallan, P. S.; Allerson, C. R.; Prakash, T. P.; Berdeja, A.; Yu, J.; Lee, S.; Watt, A.; Gaus, H.; Bhat, B.; Swayze, E. E.; Seth, P. P. J. Am. Chem. Soc. 2011, 133, 16642 DOI: 10.1021/ja207086x
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  12. 12
    Bennua-Skalmowski, B.; Klar, U.; Vorbrüggen, H. Synthesis 2008, 2008, 1175 DOI: 10.1055/s-2008-1067007
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  13. 13
    Steinkopf, W. J. Prakt. Chem. 1927, 117, 1 DOI: 10.1002/prac.19271170101
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    13
    Aromatic sulfofluorides
    Steinkopf, Wilhelm; Buchheim, Kurt; Beythien, Kurt; Dudek, Hermann; Eisold, Johannes; Gall, Johannes; Jaeger, Paul; Reumuth, Horst; Semenoff, Alexis; Wemme, Artur
    Journal fuer Praktische Chemie (Leipzig) (1927), 117 (), 1-82CODEN: JPCEAO; ISSN:0021-8383.
    C6H6 (55 g.) added to 225 g. FSO3H at 16-20° during 6 hrs. and then stirred at the same temp. for 9 hrs. gives 62% of benzenesulfofluoride, (I), b14 90-1°, b. 203-4° d420 1.3286, nD18 1.49316; it also results from PhSO2Cl and FSO2H after 24 hrs. at room temp. I (2 g.), shaken with 8 cc, concd. NH4OH 15 min., gives 71% PhSO2NH2; 4 g. I with 8 g. liquid NH2 overnight at room temp. gives 92%. I does not react with PhNH2, after several hrs.' heating at 180-5°. I does not react with EtOH, even after standing several days; on addn. of alkali at temps. not over 15°, 10 g. I gives 9 g. PhSO2Et; 2 g. I and 3 g. PhNHNH2 after 1 day give 0.8 g. PhSO2NHNHPh, m. 154-5°. I (5 g.) and 5 g. AlCl3, in 20 g. CS2, warmed to 50°, give 5 g. PhSO2Cl. I (5 g.), 20 g, C6H6 and 5 g. AlCl3, warmed to 50-5°, give 40% sulfobenzide. Reduction of 10 g. I with excess of Zn gives only 2 g. PhSH. Nitration of I with fuming HNO3 and concd. H2SO4 gives the m-nitro deriv., deep yellow, m. 48°; reduction with Sn in concd. HCl gives the m-amino deriv., m. 29-30°, b. 297-9° (partial decompn.); HCl salt, m. 165-7°. The SnCl4 salt, diazotized in the usual manner, gives benzene-1-sulfofluoride-3-diazonium chloride stannichloride, rose, decomps. 155-6°; the salt couples with β-C10H7OH to give a fiery red dye. The HCl salt, upon being diazotized, gives the light yellow diazoamino-benzene-3,3'-disulfofluoride, m. 175-6° (decompn.). Through the diazo reaction there is obtained m-iodobenzenesulfofluoride, b13-14 137°; with Cl (cooling) there results 1-phenyliodochloride-3-sulfofluoride, yellow, m. 98-9° which is rather stable. m-Cyanobenzenesulfofluoride, m. 69-70° (30-40% yield). m-C6H4(SO2Cl)2 (15 g.) and 80 g. FSO3H, heated 19 hrs. at 90-100°, give 3 g. m-benzenedisulfofluoride, m. 38-9°. PhMe (300 g.) and 1200 g. FSO3H, 12 hrs. at 20-23°, give 89% of a mixt, of o- and p-MeC6H4SO2F, contg. approx. 40% of the o-deriv. Fractional distn. or crystn. gives 23% of the pure p-deriv. (II), m. 43-4°, b16 112.5°, b22, 121.5°, b35 133.8°, b64 144.9°, b67 151°, b132 169.5. The p-deriv. also results from p-MeC6H4SO2Cl and FSO2H. II or the mixt. does not react with boiling H2O during 8 hrs.; with 25% H2SO4 the o-compd. is hydrolyzed less readily than the p-compd. With Me2NH II gives p-toluenesulfondimethylamide, m. 86-7°. 2-Nitro deriv. of II, pale yellow, m. 48-9° (84% yield); 20 hrs.' treatment with liquid NH3 gives the sulfamide, m. 144-5°. Reduction with Sn and concd. HCl gives 83% of 2-aminotoluene-4-sulfofluoride, m. 96-7°; Ac deriv., m. 188.5-9.5°. Toluene-4-sulfofluoride-2-azo-β-naphthol, bright red, m. 217°. Oxidation of II with Cro3 in AcOH gives 32% of 4-sulfofluoridebenzoic acid, m. 270°; NH4 salt; acid chloride, m. 53-3.5°; Et ester, m. 49-9.5°; amide, m. 187-7.5°. 3-ClO2SC6H4CO2H and FSO2H give 58% of 3-sulfofluoridebenzoic acid, m. 154-5°; NH4 salt, m. 130-2°; chloride, m. 108-10°; anhydride, m. 120-2° by heating the acid with Ac2O in C6H4Me2 9 hrs.; amide, m. 109-10° (methylamide, m. 145-7°); Et ester, b. 126.5-8.5° (methylamide, b. 192-4° (high vacuum)); Pr ester, b. 118-20 (high vacuum) (benzylamide, m. 60-1°); anilide, m. 157-8°. Nitration of a mixt. contg. 71% o-MeC6H4SO2F gives 4-nitrotoluene-2-sulfofluoride (III), m. 57-8°; with AlCl3 this gives 4,2-O2N(SO2F)C6H8Me; III does not give ClSO3H during 20 hrs. at room temp. Reduction of III gives the 4-amino deriv., light yellow, m. 62° (45% yield); Ac deriv., m. 120-1°. Through the diazo reaction there results a-toluenesulfofluoride, b65.5 133.9°, b83 146.2°; heated 3 hrs. with FSO2H at 130-40°, there results 48% of toluene-2,4-disulfofluoride, m. 87-8°. p-C6H4Me2 and FSO3H 20 hrs. at 25° give 85% 1,4-dimethylbenzene-2-sulfofluoride, b21 124-5°, m. 24.5°; 6-nitro deriv., m. 74-4.5° (76% yield); AlCl3 in CS2 gives the chloride, m. 61°. m-C6H4Me2 gives 1,3-dimethylbenzene-4-sulfofluoride (IV), b14 149-50°, b. 239-40°; 6-nitro deriv., m. 109-10° (80.6% yield); 6-amino deriv., m. 55-6° (HCl salt, decomps. 191-6°). Heating IV with FSO3H at 100° for 5 hrs. gives 69.6% of 1,3-dimethylbenzene-2,4-disulfofluoride, m. 116-7°. Mesitylenesulfofluoride, m. 73-3.5°, b12 125°; nitro deriv., m. 58-9°. Mesitylenedisulfochloride, from the sulfofluoride and ClSO3H, m. 121.5-2.5°; disulfamide, m. 240-1°. Pseudocumenesulfofluoride, b12 123-6°, b20 137-9°; nitro deriv., b14 163-(6°. 1,3-Dimethyl-5-terl.-butylbenzenesulfofluoride, m. 115-6°; dinitro deriv. m. 127-8°, whose chloride m. 139.5-40.5°. α-Naphthalenesulfofluoride (V), m. 56°, from 250 g. C10H8 in 600 g. H2SO4 and 400 g. FSO3H (65 g. yield); also from C10H7SO3Na and FSO3H. β-Naphthalenesulfofluoride (VI), m. 87-8°. C10H8. (25 g.) and 100 g. FSO3H, 6 hrs. at 70-80°, gives a disulfofluoride, m. 125°, which yields a disulfochloride, m. 118°. V, allowed to stand 24 hrs. with FSO3H, either at room temp. or at 100° gives a mixt., from which Et2O or PhMe exts. naphthalene-1,5-disulfofluoride, m. 203°; the disulfamide does not m. 340°. V, gradually added to ClSO3H, gives naphthalene-1-sulfofluoride-5-sulfochloride, m. 174°; the Et2O soln., satd. with NH3, gives the 5-sulfamide, m. 252-3°. VI (1 part), gradually added to 2.4 parts ClSO3H, gives naphthalene-2-sulfofluoride-6-sulfochloride, m. 114-6°; 6-sulfamide, m. 208°. Tetralin (180 g.) and 730 g. FSO3H, 12 hrs. at 15-20°, give 12-16% of 1-tetralinsulfofluoride, m. 75-7°; nitro deriv., m. 108-9° (methylamide, m. 169-71°); with AlCl3 in CS2 there results an addn. comp. of the fluoride and chloride, C20H20O8N2FClS2, m. 87-8°; amino deriv., decomps. 226-7° (HCl salt, m. 83-4°); cyano deriv., m. 113-6°. PhOH (25 g.) in 30-40 g. CS2, added to 100 g. FSO3H at room temp., gives 27 g. p-phenolsulfofluoride (VII), m. 77°; this also results from p-HOC6H4SO3Na and FSO3H; with NH4 in Et2O it gives the NH4 salt, sinters 120 30°, m. 200-3°; after standing 0.5 yr., there is formed a small amt. of phenyl-p-sulfonylide, m. 276-7°, also formed when an aq. soln. of the salt stands several days. VII and liquid NH3, 3 days at room temp., give di-p-phenolsulfonamide, (p-HOC4H4SO2)2NH, m. 154-5°. VII and 33% EtOH-MeNH2, give p-phenolsulfonmethylamide, m. 81-2°; the dimethylamide, m. 95-6°. VII and PhNH2, heated 1 hr. on the H2O bath, give the PhNH2 salt of p-phenolsulfanilide, m. 112-3°. VII, AlCl3 and C6H6 give p-hydroxydiphenylsulfone, m. 131°. PhOH gives p,p'-dihydroxydiphenylsulfone. Nitration of VII or the action of o-O2NC6H4OH and FSO2H gives the 2-nitro deriv., m. 66-7°; 2-amino deriv., m. 131° (HCl salt, m. 203-5° (decompn.); formyl deriv., m. 241-2°). Heating 25 g. VII and 100 g. FSO3H 3 hrs. at 100° gives 30% of 2,4-phenoldisulfofluoride, m. 120-1°; NH4 salt, m. 184-5°, decomps. 188°. 6-Nitro deriv., m. 98.5-9.5° (68% yield); 6-amino deriv., m. 119-20°. Phenol-2,4-disulfanilide, m. 203-4°; FeCl3 gives a ruby-red color. Phenol-2-sulfochloride-4-sulfofluoride, m. 75-6° p-sulfamide, m. 175-5.5°; 2-sulfotoluide, m. 147-8°. Phenol-2,4-disulfamide, m. 239-40°. p-HOC6H4Me and FSO3H in CS2 at 20° give 36% of 4-hydroxy-1-methylbenzene-3-sulfofluoride, b20 13.5-6°, m. 58-9° (NH4 salt); excess liquid NH3 gives the 3-sulfamide, m. 151-2°. Warming with dil. HNO3 gives 4,3,5-HO((O2N)2C6H2Me, m. 85°; with HNO3 and H2SO4 at -10° there results 85% of the 6-nitre deriv., m. 87-8°; 6-amino deriv., analyzed as the HCl salt. 4,3-HO(KO3S)C6H2Me (20 g.) and 85 g. FSO3H, heated 2 hrs. at 80-90°, gives 8.9 g. of the K salt, brownish white, of 4-hydroxy-1-methylbenzene-3-sulfofluoride-5-sulfonic acid, crystg. with 2.5 mols. H2O, m. 120-1°; NH4 salt, decomps. 265°. 5-Bromo-p-cresol-3-sulfofluoride, m. 75°; NH4 salt, m. 193-6°; 3-sulfodiethylamide, m. 162-3°. 2,6-Diiodophenyl-4-sulfofluoride. m. 132°; NH4 salt, m. 208-10°. o-Cresol-sulfofluoride, m. 56-7° (8% yield); NH4 salt; nitro deriv., light yellow, m. 60-0.5°. m-Cresol-sulfofluoride, b11 169-70°, m. 49-50.5°; di-m-cresolsulfonamide m. 154-6°. p-Anisolesulfofluoride, b60 175°, m. 13° (22% yield); 2-nitro deriv.. m. 78.5°; 2-amino deriv., m. 66° ((HCl salt, m. 202°). p-Phenetolesulfofluoride, m. 38° 2-nitro deriv., m. 73°. 2-Naphthol-3,6-disulfochloride, m. 112-3°; PhNH3 gives the 6(or 3)-sulfanilide, m. 138-9°. 2-Naphthol-3,6-disulfofluoride (VIII), m. 108-9.5°; NH4 salt, yellow. In the prepn. from β-C10H7OH, there is also formed the 2-naphtholsulfonate of VIII, m. 265° (decompn.). VIII heated with FSO3H 16 hrs. at 115-30°, gives 2-naphthol-3,6,8-trisulfofluoride, (IX), m. 153-9°. VIII and 33% Me2N soln. give 2-naphthol-3,6-disulfontetratmethyldiamide, m. 159-60.5°. 2-Naphthol-6,8-disulfofluoride, m. 175-6°, from G-salt and FSO3H; NH4 salt, does not m. 240°. R salt gives IX. 2-Hydroxy-5-sulfofluoridebenzoic acid, m. 183° (36% yield); NH4 salt decomps. 190°; Ac deriv., m. 149°; Me ether, m. 107-8°.
  14. 14
    Yin, J.; Zarkowsky, D. S.; Thomas, D. W.; Zhao, M. M.; Huffman, M. A. Org. Lett. 2004, 6, 1465 DOI: 10.1021/ol049672a
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    14
    Direct and convenient conversion of alcohols to fluorides
    Yin, Jingjun; Zarkowsky, Devin S.; Thomas, David W.; Zhao, Matthew M.; Huffman, Mark A.
    Organic Letters (2004), 6 (9), 1465-1468CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
    Directly mixing primary, secondary, and tertiary alcs. with nC4F9SO2F-NR3(HF)3-NR3 resulted in formation of fluorides, e.g., I, in high yields. The readily available reagents were easy to handle, and the mild, almost neutral, reaction conditions allowed for excellent functional group compatibility. A NR3(HF)3/NR3 ratio of ≤1:2 gave the highest reactivity.
  15. 15
    Kim, K.-Y.; Kim, B. C.; Lee, H. B.; Shin, H. J. Org. Chem. 2008, 73, 8106 DOI: 10.1021/jo8015659
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    (a) Hanessian, S.; Kagotani, M.; Komaglou, K. Heterocycles 1989, 28, 1115 DOI: 10.3987/COM-88-S134
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    (b) Lepore, S. D.; Mondal, D.; Li, S. Y.; Bhunia, A. K. Angew. Chem., Int. Ed. 2008, 47, 7511 DOI: 10.1002/anie.200802472
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    Taylor, J. E.; Bull, S. D.; Williams, J. M. J. Chem. Soc. Rev. 2012, 41, 2109 DOI: 10.1039/c2cs15288f
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    Amidines, isothioureas, and guanidines as nucleophilic catalysts
    Taylor, James E.; Bull, Steven D.; Williams, Jonathan M. J.
    Chemical Society Reviews (2012), 41 (6), 2109-2121CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. Over the last ten years there was a huge increase in development and applications of organocatalysis in which the catalyst acts as a nucleophile. Amidines and guanidines are often only thought of as strong org. bases however, a no. of small mols. contg. basic functional groups have been shown to act as efficient nucleophilic catalysts. This tutorial review highlights the use of amidine, guanidine, and related isothiourea catalysts in org. synthesis, as well as the evidence for the nucleophilic nature of these catalysts. The most common application of these catalysts to date has been in acyl transfer reactions, although the application of these catalysts towards other reactions is an increasing area of interest. In this respect, amidine and guanidine derived catalysts have been shown to be effective in catalyzing aldol reactions, Morita-Baylis-Hillman reactions, conjugate addns., carbonylations, methylations, silylations, and brominations.
  18. 18
    Dong, J.; Krasnova, L.; Finn, M. G.; Sharpless, B. K. Angew. Chem., Int. Ed. 2014, 53, 9430 DOI: 10.1002/anie.201309399
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    18
    Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry
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  • Abstract

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    Figure 1

    Figure 1. (a) The popular deoxyfluorination reagent DAST frequently affords elimination side products and displays poor thermal stability. (b) PyFluor is a stable and affordable alternative that demonstrates high selectivity against elimination, thus enabling rapid and facile purification.

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    Figure 2

    Figure 2. Multigram synthesis of PyFluor.

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    Figure 3

    Figure 3. Radiosynthesis of [18F]PyFluor and its application to deoxy-radiofluorination.

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  • References

    This article references 25 other publications.

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      A historic review. As expected from the fluorine position on the periodic table of elements, it possesses some extreme properties, in particular, ultimate electronegativity and oxidn. potential. Therefore,elemental fluorine can not be prepd. by chem. reaction, and its isolation in 1886 by Henri Moissan required scientific ingenuity and great personal courage. His historic effort earned him a Noble Prize (1906), and the developed electrolysis method is still in use for industrial prodn. of fluorine gas. However, further development of fluorine chem. was extremely sluggish, pursued by a handful of experts capable of handling the violent gas using specially designed lab. equipment. Industrial-scale prodn. of fluorochems. dates back to late 1930s. Currently, there are about 200 pharmaceuticals containingfluorine, including the 40 new compds. discussed in this review. One may agree that the contribution of the past decade indicates a significant 20% increase in the no. of fluorinated drugs on the market.
      (b) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T. J. Med. Chem. 2014, 57, 2832 DOI: 10.1021/jm401375q
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      Data-Mining for Sulfur and Fluorine: An Evaluation of Pharmaceuticals To Reveal Opportunities for Drug Design and Discovery
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      A review. Among carbon, hydrogen, oxygen, and nitrogen, sulfur and fluorine are both leading constituents of the pharmaceuticals that comprise our medicinal history. In efforts to stimulate the minds of both the general public and expert scientist, statistics were collected from the trends assocd. with therapeutics spanning 12 disease categories (a total of 1969 drugs) from our new graphical montage compilation: disease focused pharmaceuticals posters. Each poster is a vibrant display of a collection of pharmaceuticals (including structural image, Food and Drug Administration (FDA) approval date, international nonproprietary name (INN), initial market name, and a color-coded subclass of function) organized chronol. and classified according to an assocn. with a particular clin. indication. Specifically, the evolution and structural diversity of sulfur and the popular integration of fluorine into drugs introduced over the past 50 years are evaluated. The presented qual. conclusions in this article aim to promote innovative insights into drug development.
      (c) Jeschke, P. ChemBioChem 2004, 5, 570 DOI: 10.1002/cbic.200300833
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      The unique role of fluorine in the design of active ingredients for modern crop protection
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      A review. The task of inventing and developing active ingredients with useful biol. activities requires a search for novel chem. substructures. This process may trigger the discovery of whole classes of chems. of potential com. interest. Similar biol. effects can often be achieved by completely different compds. However, compds. within a given structural family may exhibit quite different biol. activities depending on their interactions with different intracellular proteins like enzymes or receptors. By varying the functional groups and structural elements of a lead compd., its interaction with the active site of the target protein, as well as its physicochem., pharmacokinetic, and dynamic properties can be improved. In this context, the introduction of fluorine into active ingredients has become an important concept in the quest for a modern crop protection product with optimal efficacy, environmental safety, user friendliness, and economic viability. Fluorinated org. compds. represent an important and growing family of com. agrochems. A no. of recently developed agrochem. candidates represent novel classes of chem. compds. with new modes of action; several of these compds. contain new fluorinated substituents. However, the complex structure-activity relationships assocd. with biol.-active mols. mean that the introduction of fluorine can lead to either an increase or a decrease in the efficacy of a compd., depending on its changed mode of action, physicochem. properties, target interaction, or metabolic susceptibility and transformation. Therefore, it is still difficult to predict the sites in a mol. at which fluorine substitution will result in optimal desired effects.
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      A review. It has become evident that fluorinated compds. have a remarkable record in medicinal chem. and will play a continuing role in providing lead compds. for therapeutic applications. This tutorial review provides a sampling of renowned fluorinated drugs and their mode of action with a discussion clarifying the role and impact of fluorine substitution on drug potency.
    4. 4

      Fluoroalkylamine (FAR) reagents – Yarovenko’s reagent:

      (a) Yarovenko, N. N.; Raksha, M. A.; Shemanina, V. N.; Vasileva, A. S. J. Gen. Chem. USSR 1957, 27, 2246
      4a
      New methods of preparation of fluorinated carboxylic acids and esters of difluoromethyl alcohol
      Yarovenko, N. N.; Raksha, M. A.; Shemanina, V. N.; Vasil'eva, A. S.
      Zhurnal Obshchei Khimii (1957), 27 (), 2246-50CODEN: ZOKHA4; ISSN:0044-460X.
      To 44 g. Et2NH in a steel autoclave was added with liquid air cooling 40 g. CF2:CF2, the mixt. warmed to room temp. 16 hrs. (max. pressure 18 atm.), and treated with ice yielding 49% CF2HCONEt2 (I), b60 97°, n20D 1.4155, d20 1.1180; if the original mixt. is carefully distd. there may be obtained the intermediate product, CHF2CF2CEt2, b15 31°, which may be obtained in up to 80.5% yields. I (151 g.) and 40 g. NaOH in 400 ml. H2O gave after evapn. 92% CHF2CO2Na, a solid, which distd. from H2SO4 gave 99% CHF2CO2H (II), b. 134°, d20 1.530, n20D 1.3419. The Na salt treated with PBr3 and heated to 150° gave a distillate of 40% CHF2COBr, b. 48°, n20D 1.3820, d20 1.8862. II (58 g.) in 58 ml. H2O was treated with 65 g. HgO, kept 0.5 hr., filtered, and concd. in vacuo yielding 91% (CHF2CO2)2Hg, m. 185°, decomp. 210°. This (19.5 g.) and 30 g. iodine heated in small portions to 125° gave a distillate of 35% CHF2I, b. 22°, and 61.6% CHF2CO2CHF2, b. 64°, n20D 1.300, d20 1.5038; the latter was also prepd. from CHF2I and the Hg salt above in a sealed ampul overnight in 93% yield. Passage of dry CF2:CFCl at 0° into Et2NH and hydrolysis of the resulting mixt. with H2O gave CHClFCONEt2 which heated with concd. H2SO4, distd. (b. 140-65°), and treated with H2SO4 gave 59.5% CHFClCO2H, b. 162-4°, n20D 1.4100.

      Ishikawa’s reagent:

      (b) Takaoka, A.; Iwakiri, H.; Ishikawa, N. Bull. Chem. Soc. Jpn. 1979, 52, 3377 DOI: 10.1246/bcsj.52.3377
      4b
      Perfluoropropene-dialkylamine reaction products as fluorinating agents
      Takaoka, Akio; Iwakiri, Hiroshi; Ishikawa, Nobuo
      Bulletin of the Chemical Society of Japan (1979), 52 (11), 3377-80CODEN: BCSJA8; ISSN:0009-2673.
      The reaction products of perfluoropropene with dialkylamines, mixts. of α,α-difluoroalkylamine and α-fluoro enamine, were useful fluorinating agents for alcs. and carboxylic acids. These reagents were superior to the adduct of ClFC:CF2 with Et2NH, the so-called Yarovenko reagent, for their easier prepn. and higher stability.
    5. 5

      Sulfur (IV) reagents – Sulfur tetrafluoride:

      (a) Hasek, W. R.; Smith, W. C.; Engelhardt, V. A. J. Am. Chem. Soc. 1960, 82, 543 DOI: 10.1021/ja01488a012
      There is no corresponding record for this reference.

      DAST:

      (b) Middleton, W. J. J. Org. Chem. 1975, 40, 574 DOI: 10.1021/jo00893a007
      5b
      New fluorinating reagents. Dialkylaminosulfur fluorides
      Middleton, William J.
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      Trifluorides R2NSF3 (I; R = Me, Et, Me2CH; or R2N = pyrrolidino) were prepd. by the reaction of R2NSiMe3 with SF4 in FCCl3 at -78°; I reacted with R21NSiMe3 to give R2NSF2NR21 (II; R, R1 = Me, Et; or R12 = piperidino). I and II were used to fluorinate alcs., aldehydes, or ketones. E.g., I (R = Et) reacted with Me2CHCH2OH in diglyme at -50 to -78° to give 49% Me2CHCH2F and 21% Me3CF. EtCHO with I (R = Et) in FCCl3 at 25° gave 80% EtCHF2. Among ∼23 other compds. fluorinated were: cyclooctanol, BzH, 1-naphthaldehyde, and menthol.
      (c) Markovskij, L. N.; Pashinnik, V. E.; Kirsanov, A. V. Synthesis 1973, 1973, 787 DOI: 10.1055/s-1973-22302
      There is no corresponding record for this reference.

      Deoxo-Fluor:

      (d) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng, H. J. Org. Chem. 1999, 64, 7048 DOI: 10.1021/jo990566+
      5d
      Bis(2-methoxyethyl)aminosulfur trifluoride: A new broad-spectrum deoxofluorinating agent with enhanced thermal stability
      Lal, Gauri S.; Pez, Guido P.; Pesaresi, Reno J.; Prozonic, Frank M.; Cheng, Hansong
      Journal of Organic Chemistry (1999), 64 (19), 7048-7054CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      Bis(2-methoxyethyl)aminosulfur trifluoride (I), (CH3OCH2CH2)2NSF3 (Deoxo-Fluor reagent), is a new deoxofluorinating agent that is much more thermally stable than DAST, (C2H5)2NSF3, and its congeners. I is effective for the conversion of alcs. to alkyl fluorides, aldehydes/ketones to the corresponding gem-difluorides, and carboxylic acids to trifluoromethyl derivs. with, in some cases, superior performance compared to DAST. The enhanced stability is rationalized on the basis of conformational rigidity imposed by a coordination of the alkoxy groups with the electron-deficient sulfur atom of the trifluoride.

      XtalFluor:

      (e) Beaulieu, F.; Beauregard, L.-P.; Courchesne, G.; Couturier, M.; LaFlamme, F.; L’Heureux, A. Org. Lett. 2009, 11, 5050 DOI: 10.1021/ol902039q
      5e
      Aminodifluorosulfinium Tetrafluoroborate Salts as Stable and Crystalline Deoxofluorinating Reagents
      Beaulieu, Francis; Beauregard, Louis-Philippe; Courchesne, Gabriel; Couturier, Michel; LaFlamme, Francois; L'Heureux, Alexandre
      Organic Letters (2009), 11 (21), 5050-5053CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
      Aminodifluorosulfinium tetrafluoroborate salts were found to act as efficient deoxofluorinating reagents when promoted by an exogenous fluoride source and, in most cases, exhibited greater selectivity by providing less elimination byproduct as compared to DAST and Deoxo-Fluor. Aminodifluorosulfinium tetrafluoroborates are easy handled cryst. salts that show enhanced thermal stability over dialkylaminosulfur trifluorides, are storage-stable, and unlike DAST and Deoxo-Fluor do not react violently with water.

      Fluolead:

      (f) Umemoto, T.; Singh, R. P.; Xu, Y.; Saito, N. J. Am. Chem. Soc. 2010, 132, 18199 DOI: 10.1021/ja106343h
      5f
      Discovery of 4-tert-Butyl-2,6-dimethylphenylsulfur Trifluoride as a Deoxofluorinating Agent with High Thermal Stability as Well as Unusual Resistance to Aqueous Hydrolysis, and Its Diverse Fluorination Capabilities Including Deoxofluoro-Arylsulfinylation with High Stereoselectivity
      Umemoto, Teruo; Singh, Rajendra P.; Xu, Yong; Saito, Norimichi
      Journal of the American Chemical Society (2010), 132 (51), 18199-18205CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Versatile, safe, shelf-stable, and easy-to-handle fluorinating agents are strongly desired in both academic and industrial arenas, since fluorinated compds. have attracted considerable interest in many areas, such as drug discovery, due to the unique effects of fluorine atoms when incorporated into mols. This article describes the synthesis, properties, and reactivity of many substituted and thermally stable phenylsulfur trifluorides, in particular, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead, I), as a cryst. solid having surprisingly high stability on contact with water and superior utility as a deoxofluorinating agent compared to current reagents, such as DAST and its analogs. The roles of substituents on I in thermal and hydrolytic stability, fluorination reactivity, and the high-yield fluorination mechanism it undergoes have been clarified. In addn. to fluorinations of alcs., aldehydes, and enolizable ketones, I smoothly converts non-enolizable carbonyls to CF2 groups, and carboxylic groups to CF3 groups, in high yields. I also converts C(=S) and CH3SC(=S)O groups to CF2 and CF3O groups, resp., in high yields. In addn., I effects highly stereoselective deoxofluoro-arylsulfinylation of diols and amino alcs. to give fluoroalkyl arylsulfinates and arylsulfinamides, with complete inversion of configuration at fluorine and the simultaneous, selective formation of one conformational isomer at the sulfoxide sulfur atom. Considering the unique and diverse properties, relative safety, and ease of handling of I in addn. to its convenient synthesis, it is expected to find considerable use as a novel fluorinating agent in both academic and industrial arenas.
    6. 6

      Azolium fluorides – DFI:

      (a) Hayashi, H.; Sonoda, H.; Fukumura, K.; Nagata, T. Chem. Commun. 2002, 1618 DOI: 10.1039/b204471d
      There is no corresponding record for this reference.

      PhenoFluor:

      (b) Sladojevich, F.; Arlow, S. I.; Tang, P.; Ritter, T. J. Am. Chem. Soc. 2013, 135, 2470 DOI: 10.1021/ja3125405
      6b
      Late-Stage Deoxyfluorination of Alcohols with PhenoFluor
      Sladojevich, Filippo; Arlow, Sophie I.; Tang, Pingping; Ritter, Tobias
      Journal of the American Chemical Society (2013), 135 (7), 2470-2473CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      An operationally simple protocol for the selective deoxyfluorination of structurally complex alcs. is presented. Several fluorinated derivs. of natural products and pharmaceuticals have been prepd. to showcase the potential of the method for late-stage diversification and its functional group compatibility. For example, testosterone reacted with PhenoFluor to give 17-epi-17-fluoro-17-deoxytestosterone in 88% yield. A series of simple guidelines for predicting the selectivity in substrates with multiple alcs. is given.
    7. 7

      Sulfonyl fluorides – p-Toluenesulfonyl fluoride:

      (a) Shimizu, M.; Nakahara, Y.; Yoshioka, H. Tetrahedron Lett. 1985, 26, 4207 DOI: 10.1016/S0040-4039(00)98993-7
      There is no corresponding record for this reference.

      Perfluorobutanesulfonyl fluoride:

      (b) Bennua-Skalmowski, B.; Vorbrüggen, H. Tetrahedron Lett. 1995, 36, 2611 DOI: 10.1016/0040-4039(95)00355-G
      7b
      A facile conversion of primary or secondary alcohols with n-perfluorobutanesulfonyl fluoride/1,8-diazabicyclo[5.4.0]undec-7-ene into their corresponding fluorides
      Bennua-Skalmowski, B.; Vorbrueggen, H.
      Tetrahedron Letters (1995), 36 (15), 2611-14CODEN: TELEAY; ISSN:0040-4039. (Elsevier)
      The combination of n-perfluorobutanesulfonyl fluoride with 1,8-diazabicyclo[5.4.0]undec-7-ene efficiently converts steroidal primary and secondary alcs. in unpolar solvents into their corresponding fluorides. Thus, the reaction with 5α-cholestan-3β-ol gave 61% 3α-fluoro-5α-cholestane.
    8. 8

      Substitution of halides – with AgF:

      (a) Moissan, H. Ann. Chim. Phys. 1890, 19, 266
      There is no corresponding record for this reference.

      With KF:

      (b) Hoffmann, F. W. J. Am. Chem. Soc. 1948, 70, 2596 DOI: 10.1021/ja01187a505
      There is no corresponding record for this reference.

      With KF/18-crown-6:

      (c) Liotta, C. L.; Harris, H. P. J. Am. Chem. Soc. 1974, 96, 2250 DOI: 10.1021/ja00814a044
      There is no corresponding record for this reference.

      Substitution of sulfonate esters – with KF:

      (d) Edgell, W. F.; Parts, L. J. Am. Chem. Soc. 1955, 77, 4899 DOI: 10.1021/ja01623a065
      There is no corresponding record for this reference.

      With TBAF:

      (e) Henbest, H. B.; Jackson, W. R. J. Chem. Soc. 1962, 954 DOI: 10.1039/jr9620000954
      There is no corresponding record for this reference.
    9. 9

      DAST solutions may detonate explosively at temperatures as low as 108 °C; see:

      (a) Messina, P. A.; Mange, K. C.; Middleton, W. J. J. Fluorine Chem. 1989, 42, 137 DOI: 10.1016/S0022-1139(00)83974-3
      9a
      Aminosulfur trifluorides: relative thermal stability
      Messina, Patricia A.; Mange, Kevin C.; Middleton, W. J.
      Journal of Fluorine Chemistry (1989), 42 (1), 137-43CODEN: JFLCAR; ISSN:0022-1139.
      The fluorinating reagent DAST (diethylaminosulfur trifluoride) has the potential to decomp. violently when heated and presents a hazard if not properly handled. This investigation has shown that the decompn. occurs in two steps. First, a non-energetic disproportionation occurs to give sulfur tetrafluoride and bis(diethylamino)sulfur difluoride. The less stable difluoride thus formed then undergoes a vigorous exothermic decompn. (detonation). The relative stabilities of DAST and several of its analogs were detd. by DTA. Morpholinosulfur trifluoride (morpho-DAST) was the most stable of the aminosulfur trifluorides examd., and its use in place of the less stable DAST is recommended for fluorinations of alcs.
      (b) L’Heureux, A.; Beaulieu, F.; Bennett, C.; Bill, D. R.; Clayton, S.; LaFlamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier, M. J. Org. Chem. 2010, 75, 3401 DOI: 10.1021/jo100504x
      9b
      Aminodifluorosulfinium Salts: Selective Fluorination Reagents with Enhanced Thermal Stability and Ease of Handling
      L'Heureux, Alexandre; Beaulieu, Francis; Bennett, Christopher; Bill, David R.; Clayton, Simon; La Flamme, Francois; Mirmehrabi, Mahmoud; Tadayon, Sam; Tovell, David; Couturier, Michel
      Journal of Organic Chemistry (2010), 75 (10), 3401-3411CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      Diethylaminodifluorosulfinium tetrafluoroborate (XtalFluor-E) and morpholinodifluorosulfinium tetrafluoroborate (XtalFluor-M) are cryst. fluorinating agents that are more easily handled and significantly more stable than Deoxo-Fluor, DAST, and their analogs. These reagents can be prepd. in a safer and more cost-efficient manner by avoiding the laborious and hazardous distn. of dialkylaminosulfur trifluorides. Unlike DAST, Deoxo-Fluor, and Fluolead, XtalFluor reagents do not generate highly corrosive free-HF and therefore can be used in std. borosilicate vessels. When used in conjunction with promoters such as Et3N·3HF, Et3N·2HF, or DBU, XtalFluor reagents effectively convert alcs. to alkyl fluorides and carbonyls to gem-difluorides. These reagents are typically more selective than DAST and Deoxo-Fluor and exhibit superior performance by providing significantly less elimination side products.
    10. 10
      (a) Kalow, J. A.; Doyle, A. G. J. Am. Chem. Soc. 2010, 132, 3268 DOI: 10.1021/ja100161d
      10a
      Enantioselective ring opening of epoxides by fluoride anion promoted by a cooperative dual-catalyst system
      Kalow, Julia A.; Doyle, Abigail G.
      Journal of the American Chemical Society (2010), 132 (10), 3268-3269CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      An enantioselective method for the synthesis of β-fluoroalcs. by catalytic nucleophilic fluorination of epoxides is described. Mild reaction conditions and high selectivity are made possible by the use of benzoyl fluoride as a sol., latent source of fluoride anion. A chiral amine and chiral Lewis acid serve as cooperative catalysts for desymmetrizations of five- through eight-membered cyclic epoxides, affording products in up to 95% ee. The cocatalytic protocol is also effective for kinetic resolns. of racemic terminal epoxides, which proceed with krel values as high as 300.
      (b) Kalow, J. A.; Schmitt, D. E.; Doyle, A. G. J. Org. Chem. 2012, 77, 4177 DOI: 10.1021/jo300433a
      10b
      Synthesis of β-Fluoroamines by Lewis Base Catalyzed Hydrofluorination of Aziridines
      Kalow, Julia A.; Schmitt, Dana E.; Doyle, Abigail G.
      Journal of Organic Chemistry (2012), 77 (8), 4177-4183CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      Lewis base catalysis promotes the in situ generation of amine-HF reagents from benzoyl fluoride and a non-nucleophilic alc. E.g., in presence of 1,5-diazabicyclo[4.3.0]non-5-ene, PhCOF, and HFIP, hydrofluorination of aziridine deriv. (I) gave 92% trans-II. The hydrofluorination of aziridines to provide β-fluoroamines using this latent HF source is described. This protocol displays a broad scope with respect to aziridine substitution and N-protecting groups. Examples of regio- and diastereoselective ring opening to access medicinally relevant β-fluoroamine building blocks are presented.
    11. 11
      Egli, M.; Pallan, P. S.; Allerson, C. R.; Prakash, T. P.; Berdeja, A.; Yu, J.; Lee, S.; Watt, A.; Gaus, H.; Bhat, B.; Swayze, E. E.; Seth, P. P. J. Am. Chem. Soc. 2011, 133, 16642 DOI: 10.1021/ja207086x
      There is no corresponding record for this reference.
    12. 12
      Bennua-Skalmowski, B.; Klar, U.; Vorbrüggen, H. Synthesis 2008, 2008, 1175 DOI: 10.1055/s-2008-1067007
      There is no corresponding record for this reference.
    13. 13
      Steinkopf, W. J. Prakt. Chem. 1927, 117, 1 DOI: 10.1002/prac.19271170101
      13
      Aromatic sulfofluorides
      Steinkopf, Wilhelm; Buchheim, Kurt; Beythien, Kurt; Dudek, Hermann; Eisold, Johannes; Gall, Johannes; Jaeger, Paul; Reumuth, Horst; Semenoff, Alexis; Wemme, Artur
      Journal fuer Praktische Chemie (Leipzig) (1927), 117 (), 1-82CODEN: JPCEAO; ISSN:0021-8383.
      C6H6 (55 g.) added to 225 g. FSO3H at 16-20° during 6 hrs. and then stirred at the same temp. for 9 hrs. gives 62% of benzenesulfofluoride, (I), b14 90-1°, b. 203-4° d420 1.3286, nD18 1.49316; it also results from PhSO2Cl and FSO2H after 24 hrs. at room temp. I (2 g.), shaken with 8 cc, concd. NH4OH 15 min., gives 71% PhSO2NH2; 4 g. I with 8 g. liquid NH2 overnight at room temp. gives 92%. I does not react with PhNH2, after several hrs.' heating at 180-5°. I does not react with EtOH, even after standing several days; on addn. of alkali at temps. not over 15°, 10 g. I gives 9 g. PhSO2Et; 2 g. I and 3 g. PhNHNH2 after 1 day give 0.8 g. PhSO2NHNHPh, m. 154-5°. I (5 g.) and 5 g. AlCl3, in 20 g. CS2, warmed to 50°, give 5 g. PhSO2Cl. I (5 g.), 20 g, C6H6 and 5 g. AlCl3, warmed to 50-5°, give 40% sulfobenzide. Reduction of 10 g. I with excess of Zn gives only 2 g. PhSH. Nitration of I with fuming HNO3 and concd. H2SO4 gives the m-nitro deriv., deep yellow, m. 48°; reduction with Sn in concd. HCl gives the m-amino deriv., m. 29-30°, b. 297-9° (partial decompn.); HCl salt, m. 165-7°. The SnCl4 salt, diazotized in the usual manner, gives benzene-1-sulfofluoride-3-diazonium chloride stannichloride, rose, decomps. 155-6°; the salt couples with β-C10H7OH to give a fiery red dye. The HCl salt, upon being diazotized, gives the light yellow diazoamino-benzene-3,3'-disulfofluoride, m. 175-6° (decompn.). Through the diazo reaction there is obtained m-iodobenzenesulfofluoride, b13-14 137°; with Cl (cooling) there results 1-phenyliodochloride-3-sulfofluoride, yellow, m. 98-9° which is rather stable. m-Cyanobenzenesulfofluoride, m. 69-70° (30-40% yield). m-C6H4(SO2Cl)2 (15 g.) and 80 g. FSO3H, heated 19 hrs. at 90-100°, give 3 g. m-benzenedisulfofluoride, m. 38-9°. PhMe (300 g.) and 1200 g. FSO3H, 12 hrs. at 20-23°, give 89% of a mixt, of o- and p-MeC6H4SO2F, contg. approx. 40% of the o-deriv. Fractional distn. or crystn. gives 23% of the pure p-deriv. (II), m. 43-4°, b16 112.5°, b22, 121.5°, b35 133.8°, b64 144.9°, b67 151°, b132 169.5. The p-deriv. also results from p-MeC6H4SO2Cl and FSO2H. II or the mixt. does not react with boiling H2O during 8 hrs.; with 25% H2SO4 the o-compd. is hydrolyzed less readily than the p-compd. With Me2NH II gives p-toluenesulfondimethylamide, m. 86-7°. 2-Nitro deriv. of II, pale yellow, m. 48-9° (84% yield); 20 hrs.' treatment with liquid NH3 gives the sulfamide, m. 144-5°. Reduction with Sn and concd. HCl gives 83% of 2-aminotoluene-4-sulfofluoride, m. 96-7°; Ac deriv., m. 188.5-9.5°. Toluene-4-sulfofluoride-2-azo-β-naphthol, bright red, m. 217°. Oxidation of II with Cro3 in AcOH gives 32% of 4-sulfofluoridebenzoic acid, m. 270°; NH4 salt; acid chloride, m. 53-3.5°; Et ester, m. 49-9.5°; amide, m. 187-7.5°. 3-ClO2SC6H4CO2H and FSO2H give 58% of 3-sulfofluoridebenzoic acid, m. 154-5°; NH4 salt, m. 130-2°; chloride, m. 108-10°; anhydride, m. 120-2° by heating the acid with Ac2O in C6H4Me2 9 hrs.; amide, m. 109-10° (methylamide, m. 145-7°); Et ester, b. 126.5-8.5° (methylamide, b. 192-4° (high vacuum)); Pr ester, b. 118-20 (high vacuum) (benzylamide, m. 60-1°); anilide, m. 157-8°. Nitration of a mixt. contg. 71% o-MeC6H4SO2F gives 4-nitrotoluene-2-sulfofluoride (III), m. 57-8°; with AlCl3 this gives 4,2-O2N(SO2F)C6H8Me; III does not give ClSO3H during 20 hrs. at room temp. Reduction of III gives the 4-amino deriv., light yellow, m. 62° (45% yield); Ac deriv., m. 120-1°. Through the diazo reaction there results a-toluenesulfofluoride, b65.5 133.9°, b83 146.2°; heated 3 hrs. with FSO2H at 130-40°, there results 48% of toluene-2,4-disulfofluoride, m. 87-8°. p-C6H4Me2 and FSO3H 20 hrs. at 25° give 85% 1,4-dimethylbenzene-2-sulfofluoride, b21 124-5°, m. 24.5°; 6-nitro deriv., m. 74-4.5° (76% yield); AlCl3 in CS2 gives the chloride, m. 61°. m-C6H4Me2 gives 1,3-dimethylbenzene-4-sulfofluoride (IV), b14 149-50°, b. 239-40°; 6-nitro deriv., m. 109-10° (80.6% yield); 6-amino deriv., m. 55-6° (HCl salt, decomps. 191-6°). Heating IV with FSO3H at 100° for 5 hrs. gives 69.6% of 1,3-dimethylbenzene-2,4-disulfofluoride, m. 116-7°. Mesitylenesulfofluoride, m. 73-3.5°, b12 125°; nitro deriv., m. 58-9°. Mesitylenedisulfochloride, from the sulfofluoride and ClSO3H, m. 121.5-2.5°; disulfamide, m. 240-1°. Pseudocumenesulfofluoride, b12 123-6°, b20 137-9°; nitro deriv., b14 163-(6°. 1,3-Dimethyl-5-terl.-butylbenzenesulfofluoride, m. 115-6°; dinitro deriv. m. 127-8°, whose chloride m. 139.5-40.5°. α-Naphthalenesulfofluoride (V), m. 56°, from 250 g. C10H8 in 600 g. H2SO4 and 400 g. FSO3H (65 g. yield); also from C10H7SO3Na and FSO3H. β-Naphthalenesulfofluoride (VI), m. 87-8°. C10H8. (25 g.) and 100 g. FSO3H, 6 hrs. at 70-80°, gives a disulfofluoride, m. 125°, which yields a disulfochloride, m. 118°. V, allowed to stand 24 hrs. with FSO3H, either at room temp. or at 100° gives a mixt., from which Et2O or PhMe exts. naphthalene-1,5-disulfofluoride, m. 203°; the disulfamide does not m. 340°. V, gradually added to ClSO3H, gives naphthalene-1-sulfofluoride-5-sulfochloride, m. 174°; the Et2O soln., satd. with NH3, gives the 5-sulfamide, m. 252-3°. VI (1 part), gradually added to 2.4 parts ClSO3H, gives naphthalene-2-sulfofluoride-6-sulfochloride, m. 114-6°; 6-sulfamide, m. 208°. Tetralin (180 g.) and 730 g. FSO3H, 12 hrs. at 15-20°, give 12-16% of 1-tetralinsulfofluoride, m. 75-7°; nitro deriv., m. 108-9° (methylamide, m. 169-71°); with AlCl3 in CS2 there results an addn. comp. of the fluoride and chloride, C20H20O8N2FClS2, m. 87-8°; amino deriv., decomps. 226-7° (HCl salt, m. 83-4°); cyano deriv., m. 113-6°. PhOH (25 g.) in 30-40 g. CS2, added to 100 g. FSO3H at room temp., gives 27 g. p-phenolsulfofluoride (VII), m. 77°; this also results from p-HOC6H4SO3Na and FSO3H; with NH4 in Et2O it gives the NH4 salt, sinters 120 30°, m. 200-3°; after standing 0.5 yr., there is formed a small amt. of phenyl-p-sulfonylide, m. 276-7°, also formed when an aq. soln. of the salt stands several days. VII and liquid NH3, 3 days at room temp., give di-p-phenolsulfonamide, (p-HOC4H4SO2)2NH, m. 154-5°. VII and 33% EtOH-MeNH2, give p-phenolsulfonmethylamide, m. 81-2°; the dimethylamide, m. 95-6°. VII and PhNH2, heated 1 hr. on the H2O bath, give the PhNH2 salt of p-phenolsulfanilide, m. 112-3°. VII, AlCl3 and C6H6 give p-hydroxydiphenylsulfone, m. 131°. PhOH gives p,p'-dihydroxydiphenylsulfone. Nitration of VII or the action of o-O2NC6H4OH and FSO2H gives the 2-nitro deriv., m. 66-7°; 2-amino deriv., m. 131° (HCl salt, m. 203-5° (decompn.); formyl deriv., m. 241-2°). Heating 25 g. VII and 100 g. FSO3H 3 hrs. at 100° gives 30% of 2,4-phenoldisulfofluoride, m. 120-1°; NH4 salt, m. 184-5°, decomps. 188°. 6-Nitro deriv., m. 98.5-9.5° (68% yield); 6-amino deriv., m. 119-20°. Phenol-2,4-disulfanilide, m. 203-4°; FeCl3 gives a ruby-red color. Phenol-2-sulfochloride-4-sulfofluoride, m. 75-6° p-sulfamide, m. 175-5.5°; 2-sulfotoluide, m. 147-8°. Phenol-2,4-disulfamide, m. 239-40°. p-HOC6H4Me and FSO3H in CS2 at 20° give 36% of 4-hydroxy-1-methylbenzene-3-sulfofluoride, b20 13.5-6°, m. 58-9° (NH4 salt); excess liquid NH3 gives the 3-sulfamide, m. 151-2°. Warming with dil. HNO3 gives 4,3,5-HO((O2N)2C6H2Me, m. 85°; with HNO3 and H2SO4 at -10° there results 85% of the 6-nitre deriv., m. 87-8°; 6-amino deriv., analyzed as the HCl salt. 4,3-HO(KO3S)C6H2Me (20 g.) and 85 g. FSO3H, heated 2 hrs. at 80-90°, gives 8.9 g. of the K salt, brownish white, of 4-hydroxy-1-methylbenzene-3-sulfofluoride-5-sulfonic acid, crystg. with 2.5 mols. H2O, m. 120-1°; NH4 salt, decomps. 265°. 5-Bromo-p-cresol-3-sulfofluoride, m. 75°; NH4 salt, m. 193-6°; 3-sulfodiethylamide, m. 162-3°. 2,6-Diiodophenyl-4-sulfofluoride. m. 132°; NH4 salt, m. 208-10°. o-Cresol-sulfofluoride, m. 56-7° (8% yield); NH4 salt; nitro deriv., light yellow, m. 60-0.5°. m-Cresol-sulfofluoride, b11 169-70°, m. 49-50.5°; di-m-cresolsulfonamide m. 154-6°. p-Anisolesulfofluoride, b60 175°, m. 13° (22% yield); 2-nitro deriv.. m. 78.5°; 2-amino deriv., m. 66° ((HCl salt, m. 202°). p-Phenetolesulfofluoride, m. 38° 2-nitro deriv., m. 73°. 2-Naphthol-3,6-disulfochloride, m. 112-3°; PhNH3 gives the 6(or 3)-sulfanilide, m. 138-9°. 2-Naphthol-3,6-disulfofluoride (VIII), m. 108-9.5°; NH4 salt, yellow. In the prepn. from β-C10H7OH, there is also formed the 2-naphtholsulfonate of VIII, m. 265° (decompn.). VIII heated with FSO3H 16 hrs. at 115-30°, gives 2-naphthol-3,6,8-trisulfofluoride, (IX), m. 153-9°. VIII and 33% Me2N soln. give 2-naphthol-3,6-disulfontetratmethyldiamide, m. 159-60.5°. 2-Naphthol-6,8-disulfofluoride, m. 175-6°, from G-salt and FSO3H; NH4 salt, does not m. 240°. R salt gives IX. 2-Hydroxy-5-sulfofluoridebenzoic acid, m. 183° (36% yield); NH4 salt decomps. 190°; Ac deriv., m. 149°; Me ether, m. 107-8°.
    14. 14
      Yin, J.; Zarkowsky, D. S.; Thomas, D. W.; Zhao, M. M.; Huffman, M. A. Org. Lett. 2004, 6, 1465 DOI: 10.1021/ol049672a
      14
      Direct and convenient conversion of alcohols to fluorides
      Yin, Jingjun; Zarkowsky, Devin S.; Thomas, David W.; Zhao, Matthew M.; Huffman, Mark A.
      Organic Letters (2004), 6 (9), 1465-1468CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
      Directly mixing primary, secondary, and tertiary alcs. with nC4F9SO2F-NR3(HF)3-NR3 resulted in formation of fluorides, e.g., I, in high yields. The readily available reagents were easy to handle, and the mild, almost neutral, reaction conditions allowed for excellent functional group compatibility. A NR3(HF)3/NR3 ratio of ≤1:2 gave the highest reactivity.
    15. 15
      Kim, K.-Y.; Kim, B. C.; Lee, H. B.; Shin, H. J. Org. Chem. 2008, 73, 8106 DOI: 10.1021/jo8015659
      There is no corresponding record for this reference.
    16. 16
      (a) Hanessian, S.; Kagotani, M.; Komaglou, K. Heterocycles 1989, 28, 1115 DOI: 10.3987/COM-88-S134
      There is no corresponding record for this reference.
      (b) Lepore, S. D.; Mondal, D.; Li, S. Y.; Bhunia, A. K. Angew. Chem., Int. Ed. 2008, 47, 7511 DOI: 10.1002/anie.200802472
      There is no corresponding record for this reference.
      (c) Ortega, N.; Feher-Voelger, A.; Brovetto, M.; Padrón, J. I.; Martín, V. S.; Martín, T. Adv. Synth. Catal. 2011, 353, 963 DOI: 10.1002/adsc.201000740
      There is no corresponding record for this reference.
    17. 17
      Taylor, J. E.; Bull, S. D.; Williams, J. M. J. Chem. Soc. Rev. 2012, 41, 2109 DOI: 10.1039/c2cs15288f
      17
      Amidines, isothioureas, and guanidines as nucleophilic catalysts
      Taylor, James E.; Bull, Steven D.; Williams, Jonathan M. J.
      Chemical Society Reviews (2012), 41 (6), 2109-2121CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Over the last ten years there was a huge increase in development and applications of organocatalysis in which the catalyst acts as a nucleophile. Amidines and guanidines are often only thought of as strong org. bases however, a no. of small mols. contg. basic functional groups have been shown to act as efficient nucleophilic catalysts. This tutorial review highlights the use of amidine, guanidine, and related isothiourea catalysts in org. synthesis, as well as the evidence for the nucleophilic nature of these catalysts. The most common application of these catalysts to date has been in acyl transfer reactions, although the application of these catalysts towards other reactions is an increasing area of interest. In this respect, amidine and guanidine derived catalysts have been shown to be effective in catalyzing aldol reactions, Morita-Baylis-Hillman reactions, conjugate addns., carbonylations, methylations, silylations, and brominations.
    18. 18
      Dong, J.; Krasnova, L.; Finn, M. G.; Sharpless, B. K. Angew. Chem., Int. Ed. 2014, 53, 9430 DOI: 10.1002/anie.201309399
      18
      Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry
      Dong, Jiajia; Krasnova, Larissa; Finn, M. G.; Sharpless, K. Barry
      Angewandte Chemie, International Edition (2014), 53 (36), 9430-9448CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Aryl sulfonyl chlorides (e.g. Ts-Cl) are beloved of org. chemists as the most commonly used SVI electrophiles, and the parent sulfuryl chloride, O2SVICl2, also was relied on to create sulfates and sulfamides. However, the desired halide substitution event is often defeated by destruction of the sulfur electrophile because the SVI-Cl bond is exceedingly sensitive to reductive collapse yielding SIV species and Cl-. Fortunately, the use of sulfur(VI) fluorides (e.g., R-SO2-F and SO2F2) leaves only the substitution pathway open. As with most of click chem., many essential features of sulfur(VI) fluoride reactivity were discovered long ago in Germany. Surprisingly, this extraordinary work faded from view rather abruptly in the mid-20th century. Here the authors seek to revive it, along with John Hyatt's unnoticed 1979 full paper exposition on CH2=CH-SO2-F, the most perfect Michael acceptor ever found. To this history the authors add several new observations, including that the otherwise very stable gas SO2F2 has excellent reactivity under the right circumstances. Also proton or silicon centers can activate the exchange of S-F bonds for S-O bonds to make functional products, and the sulfate connector is surprisingly stable toward hydrolysis. Applications of this controllable ligation chem. to small mols., polymers, and biomols. are discussed.
    19. 19

      Deoxyfluorination of enantioenriched alcohol 1 afforded inverted product 2 with 94% enantiospecificity; see SI for details.

      There is no corresponding record for this reference.
    20. 20

      As another comparison of PyFluor to commercially available deoxyfluorination reagents, DAST affords product 8 in 47% yield with 44% elimination side product whereas PhenoFluor generates 8 in 84% yield with 11% elimination (ref 6b).

      Bird, T. G. C.; Fredericks, P. M.; Jones, E. R. H.; Meakins, G. D. J. Chem. Soc., Chem. Commun. 1979, 65 DOI: 10.1039/c39790000065
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    21. 21

      PyFluor will be commercially available from Sigma-Aldrich.

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    22. 22
      Ametamey, S. M.; Honer, M.; Schubiger, P. A. Chem. Rev. 2008, 108, 1501 DOI: 10.1021/cr0782426
      22
      Molecular Imaging with PET
      Ametamey, Simon M.; Honer, Michael; Schubiger, Pius August
      Chemical Reviews (Washington, DC, United States) (2008), 108 (5), 1501-1516CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review.
    23. 23
      (a) Straatmann, M. G.; Welch, M. J. J. Nucl. Med. 1977, 18, 151
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      (b) Jelinski, M.; Hamacher, K.; Coenen, H. H. J. Labelled Compd. Radiopharm. 2001, 44, S151 DOI: 10.1002/jlcr.2580440153
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    24. 24
      (a) Matesic, L.; Wyatt, N. A.; Fraser, B. H.; Roberts, M. P.; Pham, T. Q.; Greguric, I. J. Org. Chem. 2013, 78, 11262 DOI: 10.1021/jo401759z
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      (b) Inkster, J. A. H.; Liu, K.; Ait-Mohand, S.; Schaffer, P.; Guérin, B.; Ruth, T. J.; Storr, T. Chem. - Eur. J. 2012, 18, 11079 DOI: 10.1002/chem.201103450
      24b
      Sulfonyl fluoride-based prosthetic compounds as potential 18F labeling agents
      Inkster, James A. H.; Liu, Kate; Ait-Mohand, Samia; Schaffer, Paul; Guerin, Brigitte; Ruth, Thomas J.; Storr, Tim
      Chemistry - A European Journal (2012), 18 (35), 11079-11087, S11079/1-S11079/9CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Nucleophilic incorporation of [18F]F- under aq. conditions holds several advantages in radiopharmaceutical development, esp. with the advent of complex biol. pharmacophores. Sulfonyl fluorides can be prepd. in water at room temp., yet they have not been assayed as a potential means to 18F-labeled biomarkers for PET chem. We developed a general route to prep. bifunctional 4-formyl-, 3-formyl-, 4-maleimido- and 4-oxylalkynl-arylsulfonyl [18F]fluorides from their sulfonyl chloride analogs in 1:1 mixts. of acetonitrile, THF, or tBuOH and Cs[18F]F/Cs2CO3(aq.) in a reaction time of 15 min at room temp. With the exception of 4-N-maleimide-benzenesulfonyl fluoride, pyridine could be used to simplify radiotracer purifn. by selectively degrading the precursor without significantly affecting obsd. yields. The addn. of pyridine at the start of [18F]fluorination (1:1:0.8 tBuOH/Cs2CO3(aq.)/pyridine) did not neg. affect yields of 3-formyl-2,4,6-trimethylbenzenesulfonyl [18F]fluoride and dramatically improved the yields of 4-(prop-2-ynyloxy)benzenesulfonyl [18F]fluoride. The N-arylsulfonyl-4-dimethylaminopyridinium deriv. of the latter (I) can be prepd. and incorporates 18F efficiently in solns. of 100 % aq. Cs2CO3 (10 mg mL-1). As proof-of-principle, [18F]3-formyl-2,4,6-trimethylbenzenesulfonyl [18F]fluoride was synthesized in a preparative fashion [88(±8) % decay cor. (n = 6) from start-of-synthesis] and used to radioactively label an oxyamino-modified bombesin(6-14) analog [35(±6) % decay cor. (n = 4) from start-of-synthesis]. Total prepn. time was 105-109 min from start-of-synthesis. Although the 18F-peptide exhibited evidence of proteolytic defluorination and modification, our study is the first step in developing an aq., room temp. 18F labeling strategy.
    25. 25
      Eby, R.; Schuerch, C. Carbohydr. Res. 1974, 34, 79 DOI: 10.1016/S0008-6215(00)80372-9
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