Direct Synthesis of Acyl Fluorides from Carboxylic ... - ACS Publications

Letter Cite This: Org. Lett. 2017, 19, 5740-5743

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Direct Synthesis of Acyl Fluorides from Carboxylic Acids with the Bench-Stable Solid Reagent (Me4N)SCF3 Thomas Scattolin, Kristina Deckers, and Franziska Schoenebeck* Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany S Supporting Information *

ABSTRACT: A convenient, highly efficient, and selective transformation of aliphatic and aromatic carboxylic acids to acyl fluorides is reported. In contrast to established approaches that require toxic or volatile additives and base and reaction control (i.e., cooling, slow addition), this protocol allows for a straightforward access to various R-COF entities upon direct reaction with the bench-stable, solid reagent (Me4N)SCF3 at room temperature. The method is base- and additive-free, compatible with late-stage synthetic applications, high functional group tolerance, and facile target compound purification via filtration. cyl fluorides are attractive derivatives of carboxylic acids that allow straightforward access to a range of high-value products upon subjection to nucleophiles. Amides (peptides),1 esters,2 or thioesters2 can be efficiently generated from these precursors,3 which are reactive toward a wide range of nucleophiles of varying steric and electronic nature.4 In this context, acyl fluorides have been shown to have improved stability and reactivity features over the commonly employed acyl chlorides.5 While the latter are highly reactive and unstable intermediates, the corresponding fluorides are easily isolable, stable to column chromatography on silica gel, and react less violently. They are comparable in electrophilicity to activated esters but do not suffer from steric constraints. Consequently, acyl fluorides allow for couplings with, for example, more sterically demanding amines or more richly functionalized variants with less byproduct formation compared to acyl chlorides, anhydrides, or activated alternatives.6 Surprisingly, although acyl fluorides’ effects of imparting greater robustness while retaining optimal reactivity patterns are well-documented, acyl chlorides still appear to prevail in synthesis. This might be a consequence of the lack of safe, selective, and straightforward access to acyl fluorides. The few synthetic methods that have been developed to date (Figure 1) involve the use of hazardous and toxic liquid cyanuric fluoride7 or HF/DCC,8 which have limited functional group tolerance. Other methods require specialized reagents, such as DAST, Deoxo-fluor, or XTalFluor, which are all derivatives of sulfur tetrafluoride1,9 and suffer from instability and/or side reactions.3 Alternatively, uronium-based fluorinating agents (e.g., TFFH, BTFFH)10 have also received attention, as they show good conversions while avoiding undesired side reactions. However, urea-based organic byproducts are generated in these transformations, which can be difficult to remove via the common purification approaches. By contrast, this report describes a direct, highly efficient, and byproduct-free synthesis of acyl fluorides from carboxylic acids using the bench-stable solid (Me4N)SCF3. Whereas the easily accessible (Me4N)SCF3 salt has found widespread use as a “SCF3” source in metal-catalyzed trifluoromethylthiolation

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© 2017 American Chemical Society

Figure 1. Common synthetic approaches for the preparation of acyl fluorides.

reactions in recent years,11,12 our group has recently untapped its potential as a fluorinated surrogate of thiophosgene. We demonstrated that subjection of the (Me4N)SCF3 salt to alcohols and primary or secondary amines leads to the direct and highly selective transformation of these compounds to the corresponding monothiocarbonates, isothiocyanates, or thiocarbamoyl fluorides,13 which, in turn, can be manipulated further to highvalue products, such as trifluoromethylamines.13a A special reactivity feature was that there was a distinct selectivity for the “heteroatom-H”, leaving otherwise formally more nucleophilic sites lacking the “H” (such as tertiary amines or deprotonated alcohols) completely untouched. As such, these transformations were characterized by high functional group tolerance and significant late-stage synthetic potential, and we therefore set out to explore its wider synthetic utility. Received: August 14, 2017 Published: October 12, 2017 5740

DOI: 10.1021/acs.orglett.7b02516 Org. Lett. 2017, 19, 5740−5743

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Organic Letters

(10, 17), and amide (15) substituents as well as heterocycles (6, 12, 13, 16) were fully tolerated, showcasing the synthetic potential of this methodology. We also observed that substrates that bear additional reactive functionality, such as primary or secondary amines, can be polyfunctionalized at multiple sites. For example, both the amine and acid moieties could be functionalized in a single step, as showcased with products 17 and 18. Starting from 4-amino-2methoxybenzoic acid, the primary amine moiety was transformed into an isothiocyanate in the case of 17, and from 4(methylamino)benzoic acid, the methylamino group transformed into a thiocarbamoyl fluoride in 18 with concomitant formation of the acid fluoride. The (Me4N)SCF3 reagent is therefore reactive with not only formally basic and acidic groups but also if these functionalities are coexisting in the same molecule or pot. To further study the potential of our methodology in late-stage functionalization, we next investigated molecules of higher complexity and examined key fragments and analogues of pharmaceuticals.14−16 Also in these cases, the corresponding acid fluorides were rapidly generated in high overall yield and with complete selectivity, leaving formally more nucleophilic sites as potential alternative reactive centers completely untouched (see 19−21, Figure 2, top). Moreover, for vitamin B7, we could show

Herein, we report our studies with carboxylic acids. Our investigations commenced with subjection of the solid (Me4N)SCF3 reagent to 1-adamantanecarboxylic acid at room temperature in DCM. Our NMR spectroscopic monitoring of the reaction progress indicated that full consumption of the acid took place in 10 min, and a new fluorinated organic compound was formed. Subsequent isolation revealed that the corresponding acid fluoride had been formed, which could be isolated in 89% yield. The salt (Me4N)HF2 also formed as a byproduct in the reaction. However, this salt could be easily precipitated at the end of the reaction by the addition of low polarity solvents, such as pentane or hexane, which leaves the acid fluoride as the sole product in the organic phase. This allows final purification via simple filtration over a small pad of silica, which now removes the (Me4N)HF2 salt byproduct and delivers the pure filtrate containing the acid fluoride product. We subsequently set out to explore the generality and latestage synthetic potential of this transformation. Our results are summarized in Scheme 1. A wide range of aliphatic and aromatic Scheme 1. Scope of the Synthesis of Acyl Fluoride R-COFa

Figure 2. Synthesis of pharmaceutical analogues (top), application to amide bond formation (middle), and application to variously protected amino acid fluoride19 synthesis (bottom).

that after initial transformation to the acid fluoride in situ, further addition of 1-adamantanamine to the same pot (without purification) gave rise to the sterically demanding adamantylated amide 22 in 84% yield (Figure 2, bottom). Thus, pharmaceutically relevant and structurally more demanding acyl fluorides can also readily be synthesized with this new method and further manipulated via one-pot, purification-free synthetic strategies to challenging amides. In light of the significance of amide bond formation,17 we next assessed the feasibility to generate acyl fluorides from the corresponding N-protected amino acids. Whereas the synthesis of N-protected amino acid chlorides (Fmoc, Boc, and Cbz) for peptide coupling is associated with numerous challenges,

a

Conditions: carboxylic acid (0.2 mmol), (Me4N)SCF3 (39 mg, 0.22 mmol), DCM (1.5 mL). bPurified by chromatography on silica gel. c Conversion determined by quantitative 19F NMR against CFCl3. d Reaction time was 3 h. eReaction performed in MeCN. f2.2 equiv of (Me4N)SCF3 was used.

carboxylic acids were efficiently transformed to the corresponding R-COF products in good to excellent isolated yields of 69− 98% (see Scheme 1). The methodology allowed us to access ortho-, meta-, and para-(poly)-substituted aryl-COF species. Aliphatic acids bearing bulky substituents were also readily converted. Halogen (2, 4, 6, 12, 13), cyano (3), nitro (5), ether 5741

DOI: 10.1021/acs.orglett.7b02516 Org. Lett. 2017, 19, 5740−5743

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Organic Letters

second molecule of acid to B. The latter is subsequently transformed to the acyl fluoride under release of the gaseous carbonyl sulfide (COS) and regeneration of 1 equiv of acid, which can re-engage in another cycle. In line with this, our ReactIR and NMR spectroscopic analyses of the reaction of 1adamantanecarboxylic acid with (Me4N)SCF3 after 3 min reaction time indicated that intermediate B was dominant. To also examine the larger-scale applicability of the transformation, we investigated the reaction of 1-adamantanecarboxylic acid with (Me4N)SCF3 in DCM at 5 mmol scale (ca. 900 mg of acid). Following a single portion addition of the (Me4N)SCF3 salt to a solution of the acid in DCM at room temperature, full conversion to the acid fluoride species was reached within 30 min. We also monitored the temperature of the reaction medium to gain insight on the exothermicity and safety of the transformation. Despite the relatively short reaction time, the temperature increased only by 2.5 °C over the course the reaction (see Supporting Information), suggesting that the methodology is safe to use at larger scale, and no special precautions for excess heat removal need to be implemented (see Figure 3, top). In summary, we have developed a straightforward, rapid, and operationally simple method for the direct conversion of carboxylic acids into acyl fluorides. The bench-stable solid (Me4N)SCF3 serves as the fluorine source and can be added in a single portion to the dissolved acid at room temperature without additional reaction control, even at larger scale (demonstrated for ∼1 g), because virtually no excess heat is generated. All byproducts can be precipitated with low polarity solvents, allowing straightforward purification of the acyl fluoride by simple filtration through a pad of silica and concentration of the filtrate in vacuo. The method is characterized by generality, featuring high functional group tolerance and applicability in latestage synthetic transformations, as showcased for a number of pharmaceutically relevant molecules.

particularly the formation of Leuchs’ anhydride, amino acid fluorides have proven to overcome several of these challenges.18 However, the current methodological repertoire to synthesize Nprotected amino acid fluorides mainly relies on the toxic and hazardous cyanuric fluoride and careful reaction control (e.g., low temperature for Boc and Cbz and inert atmosphere).18 Our method allows for the mild and rapid conversion of the carboxylic acid functionality of Boc-, Fmoc-, and Cbz-Nprotected amino acids to the corresponding acyl fluoride in almost quantitative yields in 5 min at room temperature without the formation of byproduct (see Figure 2, bottom). To gain insight into the mechanism, we monitored the reactions of three electronically different carboxylic acids with (Me4N)SCF3 using in situ FTIR spectroscopy (ReactIR; see Figure 3, top). In all cases, we observed immediate trans-

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02516. Experimental procedures, characterization data, 1H and 13 C NMR spectra of the new compounds (PDF)

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Figure 3. ReactIR experiments21 (top) and proposed mechanism for the transformation (bottom).

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

formations upon mixing, with an exponential decay of starting materials and evolution of products. The reaction speed was in accord with the nucleophilicity of the corresponding carboxylate; that is, the most nucleophilic converts most rapidly to the acid fluoride. The lower the pKa of the acid, the slower the transformation. However, as showcased for 1-adamantanecarboxylic acid in Figure 3, while the starting material (characteristic signal 1697 cm−1) is rapidly consumed, the corresponding RCOF product (1824 cm−1) is generated at a significantly slower rate (see also Supporting Information for additional information, including 3D-ReactIR profile). This behavior would be consistent with a stepwise mechanism that proceeds via intermediates prior to generation of the acyl fluoride. Consequently, we propose the mechanism illustrated in Figure 3. Following concerted activation of the (Me4N)SCF3 by the carboxylic acid,20 the activated intermediate A likely reacts with a

ORCID

Franziska Schoenebeck: 0000-0003-0047-0929 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the RWTH Aachen University and the MIWF NRW. REFERENCES

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DOI: 10.1021/acs.orglett.7b02516 Org. Lett. 2017, 19, 5740−5743

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DOI: 10.1021/acs.orglett.7b02516 Org. Lett. 2017, 19, 5740−5743