Gram-Scale Preparation of Acyl Fluorides and Their Reactions with Hindered Nucleophiles

Abstract

A series of acyl fluorides was synthesized at 100 mmol scale using phase-transfer-catalyzed halogen exchange between acyl chlorides and aqueous bifluoride solution. The convenient procedure consists of vigorous stirring of the biphasic mixture at room temperature, followed by extraction and distillation. Isolated acyl fluorides (usually 7–20 g) display excellent purity and can be transformed into sterically hindered amides and esters when treated with lithium amide bases and alkoxides under mild conditions.

Key words

acyl fluorides - phase-transfer catalysis - directed ortho-metalation - amides - esters

Publication History

Received: 10 September 2021

Accepted after revision: 20 September 2021

Accepted Manuscript online:
20 September 2021

Article published online:
16 November 2021

• References


For recent reviews on application of acyl fluorides, see:
• 1a Prabhu G, Narendra N, Panduranga BV, Sureshbabu VV. RSC Adv. 2015; 5: 48331
• 1b Blanchard N, Bizet V. Angew. Chem. Int. Ed. 2019; 58: 6814
• 1c Ogiwara Y, Sakai N. Angew. Chem. Int. Ed. 2020; 59: 574
• 1d Sakurai Y, Ogiwara Y, Sakai N. J. Synth. Org. Chem., Jpn. 2020; 78: 585
• 2 One of the very first preparations of benzoyl fluoride was described, see: Borodin A. Justus Liebigs Ann. Chem. 1863; 126: 58
• 3 Zhang Y, Rovis T. Org. Lett. 2004; 6: 1877
• 4a Schindler CS, Forster PM, Carreira EM. Org. Lett. 2010; 12: 4102
• 4b Due-Hansen ME, Pandey SK, Christiansen E, Andersen R, Hansen SV. F, Ulven T. Org. Biomol. Chem. 2016; 14: 430
• 4c Smedley CJ, Barrow AS, Spiteri C, Giel M.-C, Sharma P, Moses JE. Chem. Eur. J. 2017; 23: 9990
• 5 Umezawa T, Seino T, Matsuda F. Org. Lett. 2012; 14: 4206

For selected examples of application of acyl fluorides in metal-catalyzed transformations, see:
• 6a Malapit CA, Bour JR, Laursen SR, Sanford MS. J. Am. Chem. Soc. 2019; 141: 17322
• 6b Wang J, Hoerrner ME, Watson MP, Weix DJ. Angew. Chem. Int. Ed. 2020; 59: 13484
• 6c Keaveney ST, Schoenebeck F. Angew. Chem. Int. Ed. 2018; 57: 4073
• 6d Ogiwara Y, Sakurai Y, Hattori H, Sakai N. Org. Lett. 2018; 20: 4204
• 6e Fu L, Chen Q, Wang Z, Nishihara Y. Org. Lett. 2020; 22: 2350
• 7 For a review of methods of preparation of acyl fluorides, see: Gonay M, Batisse C, Paquin J.-F. Synthesis 2021; 53: 653
• 8 Oláh G, Kuhn S, Beke S. Chem. Ber. 1956; 89: 862
• 9 Ishikawa N, Kitazume T, Yamazaki T, Mochida Y, Tatsuno T. Chem. Lett. 1981; 761
• 10 Tordeux M, Wakselman C. Synth. Commun. 1982; 12: 513
• 11 Tullock CW, Coffman DD. J. Org. Chem. 1960; 25: 2016
• 12 Clark JH, Hyde AJ, Smith DK. J. Chem. Soc., Chem. Commun. 1986; 791

Interesting alternative to the inorganic fluorides is the application of HF or its pyridine complex; however, both are considered highly corrosive species:
• 13a Olah GA, Kuhn SJ. J. Org. Chem. 1961; 26: 237
• 13b Olah GA, Welch JT, Vankar YD, Nojima M, Kerekes I, Olah JA. J. Org. Chem. 1979; 44: 3872
• 14 Scattolin T, Deckers K, Schoenebeck F. Org. Lett. 2017; 19: 5740
• 15 Munoz SB, Dang H, Ispizua-Rodriguez X, Mathew T, Prakash GK. S. Org. Lett. 2019; 21: 1659
• 16 Song H.-X, Tian Z.-Y, Xiao J.-C, Zhang C.-P. Chem. Eur. J. 2020; 26: 16261
• 17 Gonay M, Batisse C, Paquin J.-F. J. Org. Chem. 2020; 85: 10253
• 18 Le B, Wu h, Hu X, Zhou X, Guo Y, Chen Q.-Y, Liu C. Tetrahedron 2020; 61: 152624
• 19 Wang X, Wang F, Huang F, Ni C, Hu J. Org. Lett. 2021; 23: 1764
• 20 Liang Y, Zhao Z, Taya A, Shibata N. Org. Lett. 2021; 23: 847
• 21 Caron S. Org. Process Res. Dev. 2020; 24: 470
• 22 Talko A, Barbasiewicz M. ACS Sustainable Chem. Eng. 2018; 6: 6693
• 23a Zheng Q, Dong J, Sharpless KB. J. Org. Chem. 2016; 81: 11360
• 23b Dong J, Krasnova L, Finn MG, Sharpless KB. Angew. Chem. Int. Ed. 2014; 53: 9430
• 24 For a recent review of the PTC methodology, see: Mąkosza M, Fedoryński M. Catalysts 2020; 10: 1436
• 25 Starks CM. J. Am. Chem. Soc. 1971; 93: 195
• 26 Supposedly the postulated catalyst-assisted migration of the bifluoride anions to the organic phase delivers them in a more reactive form with reduced hydrogen-bond solvation. Compare: Liang S, Hammond GB, Xu B. Chem. Eur. J. 2017; 23: 17850
• 27 See the experimental section and Supporting Information for details.
• 28 Lipophilic catalyst counterions (e.g., iodides) are known to display ‘poisoning effect’ in two-phase catalytic systems. Such ion pairs (e.g., NBu₄ ⁺I^–) are stable because their anions are poorly hydrated with water and thus do not enter the aqueous phase to enable anion exchange.
• 29 Talko A, Antoniak D, Barbasiewicz M. Synthesis 2019; 51: 2278
• 30 Clayden J, Foricher YJ. Y, Lam HK. Eur. J. Org. Chem. 2002; 3558
• 31 In a paper published in 1949, the amide was prepared in 55% yield from amine and benzoyl chloride heated at reflux in anhydrous benzene for 75 h, see: Leonard NJ, Nommensen EW. J. Am. Chem. Soc. 1949; 71: 2808
• 32 For an unsuccessful attempt at the preparation of the amide from benzoyl fluoride by extended heating with amine, see ref. 4b.
• 33 The observed difference between reactivity of benzoyl fluoride and chloride opens a general question about relative electrophilicities of the substrates. In a control experiment, when an equimolar mixture of aroyl fluoride and chloride was treated with 1 equivalent of LDA, both substrates were consumed in comparable amounts. Therefore higher yields of amides obtained with acyl fluorides likely arise from more selective attack at the carbonyl group, without competitive ortho-metalation (probably for steric reasons).
• 34 For an example of the use of TMSCl in acyl substitution, see: Zhang J.-Q, Han L.-B. Org. Lett. 2020; 22: 4633
• 35a Li G, Szostak M. Nat. Commun. 2018; 9: 4165
• 35b Li G, Ji C.-L, Hong X, Szostak M. J. Am. Chem. Soc. 2019; 141: 11161
• 36 For guidelines for the preparation of amides via acyl substitution, see: Rahman MM, Li G, Szostak M. J. Org. Chem. 2019; 84: 12091
• 37 Reaction of LiTMP with enolizable hydrocinnamoyl fluoride (2h) led to a complex mixture, according to NMR analysis.

For the preparation and properties of extremely hindered tertiary amines, see:
• 38a Banert K, Hagedorn M, Heck M, Hertel R, Ihle A, Müller I, Pester T, Shoker T, Rablen PR. J. Org. Chem. 2020; 85: 13630
• 38b Banert K, Heck M, Ihle A, Shoker T, Wörle M, Boese AD. Chem. Eur. J. 2021; 27: 3700
• 39 Mesgar M, Nguyen-Le J, Daugulis O. J. Am. Chem. Soc. 2018; 140: 13703
• 40 Low yield of N-(4-chlorobenzoyl)-2,2,6,6-tetramethylpiperidine (3l, 5%) was accompanied by formation of polar oligomeric product. We suppose that presence of a chlorine atom increases the acidity of protons in the aromatic ring, thus favoring ortho-metalation over carbonyl substitution. Similar observations were reported by Hawkins for LDA/B(OMe)₃ borylation of substituted neopentyl benzoates, see ref. 44.
• 41 1-Adamantanecarbonyl fluoride (2e) failed to react with LiTMP, even when the reaction mixture was warmed to room temperature.
• 42 Interestingly, related di(1-adamantyl)phosphine easily reacts with benzoyl chloride even in neutral form at room temperature, see: Gowrisankar S, Federsel C, Neumann H, Ziebart C, Jackstell R, Spannenberg A, Beller M. ChemSusChem 2013; 6: 85
• 43 Upton CJ, Beak P. J. Org. Chem. 1975; 40: 1094
• 44 Caron S, Hawkins JM. J. Org. Chem. 1998; 63: 2054
• 45 Kristensen J, Lysén M, Vedsø P, Begtrup M. Org. Lett. 2001; 3: 1435
• 46 tert-BuOLi is commercially available as a 1 M THF solution, whereas other lithium alkoxides and phenoxides were generated from the corresponding alcohols and phenols with n-BuLi in THF (ice-water bath).
• 47 Shelkov R, Nahmany M, Melman A. J. Org. Chem. 2002; 67: 8975
• 48 Ohshima T, Iwasaki T, Maegawa Y, Yoshiyama A, Mashima K. J. Am. Chem. Soc. 2008; 130: 2944
• 49 Cohen O, Sasson R, Rozen S. J. Fluorine Chem. 2006; 127: 433
• 50 Wagner R, Wiedel B, Günther W, Görls H, Anders E. Eur. J. Org. Chem. 1999; 2383
• 51 Groß S, Laabs S, Scherrmann A, Sudau A, Zhang N, Nubbemeyer U. J. Prakt. Chem. 2000; 342: 711
• 52 L’Heureux A, Beaulieu F, Bennett C, Bill DR, Clayton S, LaFlamme F, Mirmehrabi M, Tadayon S, Tovell D, Couturier M. J. Org. Chem. 2010; 75: 3401
• 53 Ogiwara Y, Sakino D, Sakurai Y, Sakai N. Eur. J. Org. Chem. 2017; 4324
• 54 Heescher C, Schollmeyer D, Nubbemeyer U. Eur. J. Org. Chem. 2013; 4399
• 55 Bappert E, Müller P, Fu GC. Chem. Commun. 2006; 2604
• 56 Ueda T, Konishi H, Manabe K. Org. Lett. 2013; 15: 5370
• 57 Vlasov VM. J. Gen. Chem. USSR 1967; 37: 156
• 58 Tao C, Liu F, Zhu Y, Liu W, Cao Z. Org. Biomol. Chem. 2013; 11: 3349
• 59 Chen J, Xia Y, Lee S. Org. Lett. 2020; 22: 3504
• 60 Wang W, Zhao X.-M, Wang J.-L, Geng X, Gong J.-F, Hao X.-Q, Song M.-P. Tetrahedron Lett. 2014; 55: 3192
• 61 Lambert KM, Bobbitt JM, Eldirany SA, Kissane LE, Sheridan RK, Stempel ZD, Sternberg FH, Bailey WF. Chem. Eur. J. 2016; 22: 5156
• 62 Pandey G, Koley S, Talukdar R, Sahani PK. Org. Lett. 2018; 20: 5861
• 63 Talukdar R. New J. Chem. 2020; 44: 5303
• 64 Barton DH. R, Ferreira JA. Tetrahedron 1996; 52: 9347
• 65 Evans V, Mahon MF, Webster RL. Tetrahedron 2014; 70: 7593
• 66 Meng G, Szostak M. Org. Biomol. Chem. 2016; 14: 5690
• 67 Yamada K, Hayakawa N, Fujita H, Kitamura M, Kunishima M. Eur. J. Org. Chem. 2016; 4093
• 68 Kissling RM, Gagné MR. Org. Lett. 2000; 2: 4209
• 69 La MT, Kim H.-K. Tetrahedron 2018; 74: 3748
• 70 Lu L, Shi R, Liu L, Yan J, Lu F, Lei A. Chem. Eur. J. 2016; 22: 14484
• 71 Villo P, Dalla-Santa O, Szabó Z, Lundberg H. J. Org. Chem. 2020; 85: 6959
• 72 Iskryk M, Barysevich M, Ošeka M, Adamson J, Kananovich D. Synthesis 2019; 51: 1935