Direct Access to Acyl Fluorides from Carboxylic Acids Using a

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Direct Access to Acyl Fluorides from Carboxylic Acids Using a Phosphine/Fluoride Deoxyfluorination Reagent System Socrates B. Munoz,† Huong Dang,† Xanath Ispizua-Rodriguez,† Thomas Mathew, and G. K. Surya Prakash* Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California 90089-1661, United States

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S Supporting Information *

ABSTRACT: A fast and simple method for deoxyfluorination of carboxylic acids is presented. The protocol employs commodity chemicals (PPh3, NBS, fluoride), affording products in excellent yields under mild conditions. Acyloxyphosphonium ion, the key reaction intermediate, was identified by NMR spectroscopic methods. Brønsted acidic conditions are essential for efficient C−F bond formation. The protocol displays scalability, high functional group tolerance, chemoselectivity, and easy purification of products. Deoxyfluorination of active pharmaceutical ingredients was established.

wing to the special role that organofluorine compounds play in life and materials sciences,1 incorporation of fluorine through synthetic protocols that enjoy practicality, operational simplicity, wide functional group compatibility and ease of access of reagents, is a highly desirable goal. Acyl fluorides are versatile intermediates in organic synthesis, owing to their superior stability and distinct reactivity, when compared to other acyl halides. In this context, acyl fluorides have been successfully employed in many challenging amidation and esterification reactions2 (i.e., with electrondeficient or sterically encumbered nucleophiles), and they are ideal intermediates for both solution- and solid-phase peptide synthesis.3 Furthermore, acyl fluorides stand as convenient precursors of anhydrous fluoride ion and have been employed in SNAr fluorination chemistry with great success.4 On the other hand, transition-metal-catalyzed, nondecarbonylative, and decarbonylative transformations of acyl fluorides have also been developed.5 In this fashion, their utilization as electrophiles has enabled access to ketones,5a−c aldehydes,5d,e hydrocarbons,5d trifluoromethylarenes,5f and more recently, biaryls5g (Scheme 1 paths A−F). The known approaches for the preparation of acyl fluorides directly from carboxylic acids date back to the pioneering work

by Olah using cyanuric fluoride6 or SeF4/pyridine complex.7 Alternative α-fluoroamine reagents (Ishikawa’s and Petrov’s reagent, TFFH) were employed in few cases.8 Other deoxyfluorination protocols rely on the use of sulfur-based reagents such as DAST,9 Deoxo-Fluor,10 XtalFluor-E,11 etc. (Scheme 2). However, application of many of these reagents

Scheme 1. Synthetic Utility of Acyl Fluorides

remains limited due to toxicity, environmental pollution, thermal instability, and/or drastic reaction conditions. Olah’s reagent (HF−pyridine) in combination with DCC12 has also been used with low functional group compatibility. A sulfur(VI) fluoride exchange (SuFEx) reaction employing benzene-1,3-disulfonyl fluoride was disclosed as part of an amidation protocol.13 Very recently, Schoenebeck and coworkers14 delineated a protocol employing Me4NSCF3 as an

O

Scheme 2. Prior Art for Acyl Fluoride Synthesis and Current Work

Received: January 16, 2019

© XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.9b00197 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of the Reaction Conditionsa

alternative sulfur-based reagent. However, this reagent is not commercially available and must be prepared from S8, TMSCF3, and expensive anhydrous Me4NF. Considering that acyl fluorides are inexpensive sources of anhydrous fluoride, including expensive Me4NF4 (Scheme 1, path c), utilization of Me4NF-derived Me4NSCF3 in the synthesis of RCOF derivatives requires further justification. Thus, practical, safe, and operationally simple methods that enable access to a wide variety of acyl fluorides are still sought. Due to our longstanding interest in organofluorine chemistry,15 we set out to develop a convenient and inexpensive protocol for direct deoxyfluorination of carboxylic acids. Herein, we report a method that employs readily available commodity chemicals and offers practical utility and operational simplicity to provide the corresponding acyl fluorides. Recognizing the rich chemistry of phosphorus reagents16 and (acyl)oxyphosphonium ions I in peptide coupling,17 Mitsunobu,18 and Appel19 reactions, we surmised that such intermediates could be easily transformed into acyl fluorides under suitable conditions. To the best of our knowledge, such a transformation (Scheme 3, eq 1) and the related Appel-type

entry

solvent

PPh3 (equiv)

NBS (equiv)

fluoride (equiv)

yieldb (%)

1 2 3 4 5 6 7 8c 9 10c 11c,d 12c,d 13d,e

DCM DCM DCM DCM DCM DCM DCM MeCN MeCN MeCN MeCN MeCN MeCN

3 3 3 2 2 2 2 2 2 2 2 2 2

3 3 3 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1

Et3N-3HF (6) Me4NF (3) Et3N-3HF (3) Et3N-3HF (2) KF (2) CsF (2) KHF2 (2) KF (2) CsF (2) KHF2 (2) KF (2) KHF2 (2) KHF2 (2)

99 27 99 99 0 0 0 28 0 trace 47 60 98

a

To a suspension of benzoic acid 1a (0.25 mmol, 1 equiv) and PPh3 in DCM was added solid N-bromosuccinimide (NBS) at 0 °C. After the mixture was stirred for 15 min at room temperature, fluoride source was added and stirring was continued for 2 h. bAs determined by 19F NMR spectroscopy; cReaction time: 17 h; dTrifluoroacetic acid (TFA, 2 equiv) was added along with fluoride; eReaction time: 24 h. See the Supporting Information for full details.

Scheme 3. Working Hypothesis and Related Transformations

quantitative yield (Table 1, entry 13). However, due to its fast reaction rate and ease of addition, Et3N−3HF was used in subsequent studies.20c In the optimal protocol, NBS (2.1 equiv) is added to a suspension of carboxylic acid 1 and PPh3 (2 equiv) in DCM at 0 °C under air. After the activation step is complete (15 min), Et3N−3HF is added.20b In this manner, the corresponding acyl fluorides are formed in nearly quantitative yields within a few hours, and in most cases, they are conveniently isolated without relying on column chromatography by simply passing through a short plug of SiO2. Application of this system to the deoxyfluorination of various carboxylic acids illustrates its synthetic scope (Scheme 4). Benzoic acids bearing electron-neutral, electron-donating (−OMe, −Et, −NMe2), as well as electron-withdrawing functionalities (−I, −Br, −F, −Ac) are converted to the corresponding acyl fluorides in good to excellent yields (2a−i). The present protocol is compatible with unsaturated functionalities, as evidenced by the successful preparation of vinyl substituted acyl fluoride 2d, and cinnamoyl fluorides (2n,o).21d In these cases, no HF addition across the double bond was observed. Halo-substituted benzoic acids (−Br and −F) afford the corresponding products in good yields (2g and 2i, respectively).21c Substitution at the ortho-position of benzoic acid 1f is tolerated, providing the corresponding product 2f in 83% yield. Another attractive feature of this method is its scalability: preparation of 4-methoxybenzoyl fluoride 2c, a reagent employed as anhydrous fluoride source for SNAr fluorinations,4 was performed on a 10 mmol scale and obtained in 70% yield after SiO2 filtration of the reaction mixture.21a Thus, Et3N− 3HF, an acidic and atom-economic fluoride source, could be efficiently utilized for the preparation of an anhydrous fluoride surrogate.

fluorination using halophosphonium ions (Scheme 3, eq 2) has not been reported thus far. This is probably due to the preferred formation of the strong P−F bond, in contrast to other P−X bonds (X = Cl, Br, I). Our experience in superacid-catalyzed transformations and superelectrophilic activation20a led us to hypothesize that under Brønsted acidic conditions, intermediate I could be further protonated to enable the desired C−F bond formation. To interrogate this hypothesis, benzoic acid 1a was selected as a model substrate, and a variety of fluoride sources in combination with PPh3/NBS were screened for a direct deoxyfluorination reaction (Table 1). After activation of 1a by NBS/PPh3 (3 equiv each) in DCM and using an excess of Et3N−3HF, the desired product, benzoyl fluoride 2a, was obtained in almost quantitative yield after 2 h (Table 1, entry 1). Utilization of basic Me4NF (3 equiv) afforded 2a in only 27% yield while generating large amounts of Ph3PF2 (19F NMR = δ −39.5), thus corroborating our initial hypothesis (Table 1, entry 2). Subsequent attempts have shown that by using a 2:2.1:2 molar ratio of PPh3/NBS/ Et3N−3HF, 2a could be formed in close to quantitative yield. Use of other fluoride sources such as KF, CsF, and KHF2 in DCM was unsuccessful, probably due to solubility issues (Table 1, entries 5−7). Using MeCN as solvent led only to marginal improvements, and large amounts of Ph3PF2 were detected in these cases also (Table 1, entries 8−10). As expected, it was found that, under acidic conditions (TFA, 2 equiv), KF and KHF2 could afford the desired product while completely inhibiting the formation of Ph3PF2 (Table 1, entries 11−13). In this fashion, after 24 h, KHF2 also provided 2a in B

DOI: 10.1021/acs.orglett.9b00197 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 4. Direct Deoxyfluorination of Carboxylic Acidsa

Heteroaromatic substrates such as picolinic, nicotinic, and isonicotinic acids were all successfully employed in a tandem deoxyfluorination/amidation sequence using sterically demanding 1-adamantanamine (Ad-NH2) (Scheme 5). All Scheme 5. Tandem Deoxyfluorination/Amidation Sequence*

* Isolated yields shown; average of two runs. aYield of acyl fluoride 3a′−c′ as determined by 19F NMR. See the Supporting Information for full details.

three isomers underwent the desired transformation, affording the corresponding pyridine carboxamides (3a−c) in up to 91% yield, after adding a mixture of Ad-NH2 and Et3N to the formed acyl fluorides (3a′−c′).21a This procedure eliminates the need for isolation of the acyl fluorides and represents a significant advantage over previous synthetic routes.22 Moreover, by employing optimal conditions17c for amidation via acyloxyphosphonium intermediates, 3a was obtained in only 26% yield,21a demonstrating the utility of this tandem one-pot deoxyfluorination/amidation protocol using sterically encumbered amines. To gain a mechanistic understanding of this transformation, a series of 31P and 19F NMR studies were conducted. Addition of NBS to a solution of PPh3 in DCM at 0 °C, led to the formation of a species with 31P signal at δ 31.5, assigned to bromophosphonium ion A. When NBS was added to a mixture of PPh3 and 1a, a new signal corresponding to acyloxyphosphonium ion I appeared at δ 45.2. These species quickly disappeared upon adding Et3N−3HF, and appearance of 2a (δ 17.4) along with small amount of Ph3PF2 (δ −39.3 t, J = 659.6 Hz) was observed in the 19F NMR spectrum. Furthermore, independently prepared Ph3PF2 was found to be a chemically incompetent species to promote the transformation under the reaction conditions (DCM, rt).21a,e These observations are in full agreement with previous literature reports.17 On the basis of these observations, the following mechanistic pathway is proposed (Scheme 6).

a Method A conditions: 1 (0.5 mmol, 1 equiv), PPh3 (2 equiv), DCM (5 mL), N-bromosuccinimide (NBS, 2.1 equiv), 0 °C to rt,15 min. Then Et3N−3HF (2 equiv) rt, 2 h. bMethod B conditions: using polymer-bound phosphine reagent in place of PPh3. Isolated yields, average of two runs. Yields in parentheses determined by 19F NMR spectroscopy, using internal standard. See the Supporting Information for full experimental details.

Next, aliphatic carboxylic acids were tested. In this case, phenylacetic acid, phenylbutyric acid, and 1-adamantanecarboxylic acid were all amenable to the reaction conditions, affording the corresponding products in good isolated yields (2j−l). Notably, the present protocol exhibited excellent chemoselectivity toward −COOH moiety, as demonstrated by the preparation of 4-hydroxybenzoyl fluoride 2p in 50% isolated yield. To further illustrate the synthetic scope of this method, a series of active pharmaceutical ingredients (APIs) bearing the −COOH functionality was subjected to the reaction conditions. Gratifyingly, complex structures bearing double bonds, sulfonamide, indole, keto, nitrile, and thiazole functionalities all afforded the corresponding acyl fluoride analogues in high isolated yields (Scheme 4, bottom section). In pursuit of easier purification of products, we substituted PPh3 with the commercially available, polymer-bound phosphine reagent. The acyl fluoride 2h was obtained in comparable yield (95% by 19F NMR, 72% isolated yield), following purification much easier than before. Similarly, amino acid fluoride bearing the acid-stable Fmoc- protecting group Fmoc-Phe-F 2q was prepared in 50% isolated yield (97% by 19F NMR). As mentioned above, purification of products is easily achieved by simply filtering off the resin, followed by a simple workup procedure21a,b (Scheme 4, method B).

Scheme 6. Mechanistic Hypothesis

Oxidation of PPh3 by NBS generates a bromophosphonium ion A, which reacts with RCOOH derivatives 1, affording acyloxyphosphonium intermediate I. Under acidic conditions, I could be protonated, followed by fluoride attack at the C− acyl moiety, giving rise to RCOF products and Ph3PO. In the case of basic fluoride sources, generation of RCOF is minor C

DOI: 10.1021/acs.orglett.9b00197 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters and fluoride attack at the P-center of I, affording Ph3PF2, seems to be the dominant pathway. In conclusion, a practical and convenient protocol for a direct deoxyfluorination of carboxylic acids, using a phosphorus-based reagent system, in combination with Et3N−3HF as fluoride ion source was developed. This protocol employs inexpensive commodity chemicals and enables facile access to a wide array of substituted acyl fluorides possessing various functional groups. The greater significance of this method is further emphasized by its scalability (demonstrated by the fast and successful preparation of 2c, a common source of anhydrous fluoride) and applicability to a tandem deoxyfluorination/amidation sequence. Utilization of this protocol for the deoxyfluorination of several active pharmaceutical ingredients bearing −COOH as substrates was also successfully established. Application of this approach to deoxyfluorination of alcohols will be reported elsewhere.

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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.9b00197. Experimental procedures as well as NMR spectra and characterization data (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Thomas Mathew: 0000-0002-2896-1917 G. K. Surya Prakash: 0000-0002-6350-8325 Author Contributions †

S.B.M., H.D., and X.I.-R. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support by the Loker Hydrocarbon Research Institute is gratefully acknowledged. REFERENCES

(1) (a) Hiyama, T. In Organofluorine Compounds: Chemistry and Applications; Springer-Verlag: Berlin, 2000. (b) Bégué, J.-P.; BonnetDelpon, D. In Bioorganic and Medicinal Chemistry of Fluorine; WileyVCH: Weinheim, 2008. (c) Catalán, S.; Munoz, S. B.; Fustero, S. Chimia 2014, 68, 382. (2) (a) Schindler, C. S.; Forster, P. M.; Carreira, E. M. Org. Lett. 2010, 12, 4102. (b) Due-Hansen, M. E.; Pandey, S. K.; Christiansen, E.; Andersen, R.; Hansen, S. V. F.; Ulven, T. Org. Biomol. Chem. 2016, 14, 430. (3) (a) Carpino, L. A.; Sadat-Aalaee, D.; Chao, H. G.; DeSelms, R. H. J. Am. Chem. Soc. 1990, 112, 9651. (b) Carpino, L. A.; Beyermann, M.; Wenschuh, H.; Bienert, M. Acc. Chem. Res. 1996, 29, 268. (c) Prabhu, G.; Narendra, N.; Basavaprabhu, V.; Panduranga, V.; Sureshbabu, V. V. RSC Adv. 2015, 5, 48331 and references cited therein . (4) (a) Ryan, S. J.; Schimler, S. D.; Bland, D. C.; Sanford, M. S. Org. Lett. 2015, 17, 1866. (b) Cismesia, M. A.; Ryan, S. J.; Bland, D. C.; Sanford, M. S. J. Org. Chem. 2017, 82, 5020. For related work on deoxyfluorination of phenols, see: (c) Neumann, C. N.; Hooker, J. D

DOI: 10.1021/acs.orglett.9b00197 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters (21) (a) See the Supporting Information for full details. (b) Polymer-bound phosphine was used only for easy purification; in all these cases, PPh3 also affords the corresponding products. (c) Compound 2i exhibits instability toward silica gel, preventing its isolation. (d) Isolated yields of these products were low due to their high volatility. (e) For deoxyfluorination of alcohols using Ph3PF2 under drastic conditions, see: Kobayashi, Y.; Akashi, C. Chem. Pharm. Bull. 1968, 16, 1009. (22) (a) Danilenko, G. I.; Mokhort, N. A.; Trinus, F. P. Pharm. Chem. J. 1976, 10, 1036. (b) Morimoto, H.; Fujiwara, R.; Shimizu, Y.; Morisaki, K.; Ohshima, T. Org. Lett. 2014, 16, 2018.

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DOI: 10.1021/acs.orglett.9b00197 Org. Lett. XXXX, XXX, XXX−XXX