Difluoromethylation of carboxylic acids via the addition of difluorinated phosphorus ylide to acyl chlorides

Article abstract of DOI:10.1021/acs.orglett.7b02601

A one-step protocol for the difluoromethylation of carboxylic acids is described. The reaction involves the interaction of intermediate acyl chlorides with in situ generated difluorinated phosphorus ylide Ph₃P=CF₂. Aromatic acids can be selectively transformed within one step either to bis-difluoromethylated alcohols or to difluorinated ketones depending on the particular reaction conditions. For bulky α-branched carboxylic acids, only ketones are produced.

Full text of DOI:10.1021/acs.orglett.7b02601

Letter
pubs.acs.org/OrgLett
Difluoromethylation of Carboxylic Acids via the Addition of
Difluorinated Phosphorus Ylide to Acyl Chlorides
Alexey L. Trifonov,†,‡ Vitalij V. Levin,† Marina I. Struchkova,† and Alexander D. Dilman*,†
†N. D. Zelinsky Institute of Organic Chemistry, Leninsky prosp. 47, 119991 Moscow, Russian Federation
‡D. Mendeleev University of Chemical Technology of Russia, Higher Chemical College, Miusskaya sq. 9, 125047 Moscow, Russian
Federation
S
* Supporting Information
ABSTRACT: A one-step protocol for the difluoromethylation of
carboxylic acids is described. The reaction involves the interaction of
intermediate acyl chlorides with in situ generated difluorinated
phosphorus ylide Ph3PCF2. Aromatic acids can be selectively
transformed within one step either to bis-difluoromethylated alcohols
or to difluorinated ketones depending on the particular reaction
conditions. For bulky α-branched carboxylic acids, only ketones are
produced.
ucleophilic fluoroalkylation reactions have emerged as a
powerful tool for the direct introduction of fluorinated
on reaction conditions. Given the increasing number of
biologically active substances bearing the difluoromethyl11
and a polyfluorinated isopropyl group,12 compounds 3 and 4
would likely be interesting for medicinal chemistry and related
fields.13 It should also be pointed out that known methods
toward alcohols 3 are rare.14
N
fragments by their addition to common functional groups.1 In
response to the needs of medicinal chemistry over the past 20
years,2 major effort was devoted to the synthesis of CF3-
substituted compounds.3,4 In recent times, the difluoromethyl
group has attracted significant attention, primarily, because of
its unique stereoelectronic properties and ability to serve as a
lipophilic hydrogen bond donor.5 Concerning synthetic aspects,
despite the seemingly little difference between CF3 and CF2H
groups, methods for their introduction frequently require
completely different conditions.6,7
Ylide 1 can be generated by different protocols,8−10 among
which a combination of (bromodifluoromethyl)trimethylsilane
(Me3SiCF2Br),15 triphenylphosphine, and DMPU (1,3-
dimethylpropyleneurea) constitutes the mildest conditions8b
(Scheme 2). When 4-methoxybenzoyl chloride was treated with
1 equiv of in situ generated ylide in acetonitrile at room
temperature, a mixture of mono- and diphosphonium salts 5
and 6 was obtained according to 19F NMR spectroscopy. The
predominant formation of double-addition salt 6 suggests the
higher reactivity of primary product 5 compared to starting acyl
Recently, we described a general approach for the
introduction of the CF2H-group based on the application of
difluorinated phosphorus ylide 18 (Scheme 1). This unstable
Scheme 1. Difluoromethylation Using Phosphorus Ylide 1
Scheme 2. Reaction of 4-Methoxybenzoyl Chloride
species9 can be trapped with various electrophiles,8,10 whereas
the CF2H-group is formed upon facile hydrolysis of the C−P
bond. Aldehydes and ketones proved to be good electrophiles
for the coupling with ylide 1 furnishing CF2H-substituted
alcohols.8 Herein we report the application of this concept to
nucleophilic difluoromethylation of acyl chlorides 2 affording
either mono- or double-addition products 3 and 4 depending
Received: August 22, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02601
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Synthesis of Alcohols 3
a
Isolated yield.
chloride. Use of 2.5 equiv of the silane/phosphine system,
which is equal to 1.25 equiv of the ylide required for the double
addition, led to the formation of salt 6 as a single product.
Though acyl chlorides can be used as isolated reagents, we
decided to generate them from carboxylic acids by treatment
with oxalyl chloride in the presence of catalytic amounts of
DMF. The obtained acyl chlorides were subjected to
difluoromethylation in the same flask without purification
(Table 1). The intermediate diphosphonium salts 6 were
dephosphorylated and desilylated by the addition of pyridine
and water followed by brief heating at 80 °C. The
dephosphorylation likely proceeds through the hydroxide
attack at the positively charged phosphorus followed by
protonation of the polarized C−P bond. Using this protocol,
aromatic and heteroaromatic substrates provided alcohols 3 in
high yields based on carboxylic acids. Cyano and nitro groups,
as well as methyl ester, remained unaffected (entries 3−5).
Aliphatic and α,β-unsaturated substrates gave reduced yields of
products (entries 13 and 14).
When the typical procedure was applied to bulky acyl
chlorides (for example, from 1-adamantanecarboxylic acid), the
corresponding monoaddition salt 5 did not undergo further
reaction of the ylide even under forcing conditions (Scheme 3).
It was also found that diphosphonium salts 6 derived from
aromatic acyl chlorides can be converted back to mono-
phosphonium salts 5 when heated at 100 °C. Another specific
example was noted for phenyl acetic acid chloride. Thus, under
typical conditions, phosphonium salt 7 was formed, likely
Scheme 3. Generation of Monophoshopnium Salts
resulting from the addition to intermediate ketene. Proto-
dephosphorilation of salts 5 and 7 with pyridine/water afforded
corresponding difluoroketones. Using these procedures (meth-
od A, conventional conditions; method B, heating of the double
addition intermediate), a series of carboxylic acids were
converted to α,α-difluorinated ketones 4 in good yields within
one experimental step (Table 2).
The standard conditions were applied to phthalic anhydride
(Scheme 4). In this case, the reaction required a longer time
than in the case with acyl chlorides and, after hydrolysis,
furnished lactone 9, presumably, through the intermediacy of
ring-opened diphosphonium salt 8.
In summary, a method for the one-step conversion of
carboxylic acids to valuable compounds based on difluorinated
phosphorus ylide is described. Aromatic acids can be converted
B
DOI: 10.1021/acs.orglett.7b02601
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Synthesis of Difluorinated Ketones 4
ACKNOWLEDGMENTS
■
This work was supported by the Russian Science Foundation
(Project 17-13-01041). We are grateful to Mr. Artem Zemtsov
(N. D. Zelinsky Institute of organic chemistry) for experimental
assistance.
REFERENCES
■
(1) For general reviews, see: (a) Prakash, G. K. S.; Zhang, Z. In
Modern Synthesis Processes and Reactivity of Fluorinated Compounds;
Groult, H.; Leroux, F. R., Tressaud, A., Eds.; Elsevier: 2017; pp 289−
337. (b) Barata-Vallejo, S.; Torviso, M. R.; Lantano, B.; Bonesi, S. M.;
Postigo, A. J. Fluorine Chem. 2014, 161, 134−141. (c) Prakash, G. K.
S.; Hu, J. Acc. Chem. Res. 2007, 40, 921−930. (d) Wang, H.; Vicic, D.
A. Synlett 2013, 24, 1887−1898.
(2) (a) Wang, J.; Sanchez-Rosello,
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev.
́
M.; Acena, J. L.; del Pozo, C.;
̃
2014, 114, 2432−2506. (b) Muller, K.; Faeh, C.; Diederich, F. Science
̈
2007, 317, 1881−1886. (c) Hagmann, W. K. J. Med. Chem. 2008, 51,
4359−4369.
(3) For nucleophilic trifluoromethylation, see: (a) Prakash, G. K. S.;
Yudin, A. K. Chem. Rev. 1997, 97, 757−786. (b) Liu, X.; Xu, C.; Wang,
M.; Liu, Q. Chem. Rev. 2015, 115, 683−730. (c) Dilman, A. D.; Levin,
V. V. Eur. J. Org. Chem. 2011, 2011, 831−841. (d) Liu, T.; Shen, Q.
Eur. J. Org. Chem. 2012, 2012, 6679−6687. (e) Medebielle, M.;
Dolbier, W. R., Jr J. Fluorine Chem. 2008, 129, 930−942.
(f) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111,
4475−4521.
a
Conditions for the difluoromethylation step: (Method A) MeCN, rt,
b
5 h; (Method B) MeCN, rt, 5 h, then DMF, 100 °C, 1.5 h. Isolated
yield.
(4) For electrophilic and radical trifluoromethylation, see:
(a) Charpentier, J.; Fruh, N.; Togni, A. Chem. Rev. 2015, 115, 650−
̈
682. (b) Chu, L.; Qing, F.-L. Acc. Chem. Res. 2014, 47, 1513−1522.
(c) Koike, T.; Akita, M. Acc. Chem. Res. 2016, 49, 1937−1945.
(d) Koike, T.; Akita, M. Top. Catal. 2014, 57, 967−974. (e) Chatterjee,
T.; Iqbal, N.; You, Y.; Cho, E. J. Acc. Chem. Res. 2016, 49, 2284−2294.
(f) Alonso, C.; de Marigorta, E. M.; Rubiales, G.; Palacios, F. Chem.
Scheme 4. Difluoromethylation of Phthalic Anhydride
́
Rev. 2015, 115, 1847−1935. (g) Mace, Y.; Magnier, E. Eur. J. Org.
Chem. 2012, 2012, 2479−2494. (h) Zhang, C. Org. Biomol. Chem.
2014, 12, 6580−6589.
(5) (a) Zafrani, Y.; Yeffet, D.; Sod-Moriah, G.; Berliner, A.; Amir, D.;
Marciano, D.; Gershonov, E.; Saphier, S. J. Med. Chem. 2017, 60, 797−
804. (b) Sessler, C. D.; Rahm, M.; Becker, S.; Goldberg, J. M.; Wang,
F.; Lippard, S. J. J. Am. Chem. Soc. 2017, 139, 9325−9332. (c) Erickson,
J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60, 1626−1631.
(d) Huchet, Q. A.; Kuhn, B.; Wagner, B. r.; Fischer, H.; Kansy, M.;
either to bis(difluoromethyl)-substituted alcohols or to
difluorinated ketones depending on reaction conditions. At
the same time, the reaction of bulky acids stops at the
monoaddition step leading to ketones as single products.
Zimmerli, D.; Carreira, E. M.; Muller, K. J. Fluorine Chem. 2013, 152,
̈
119−128.
(6) For reviews, see: (a) Hu, J.; Zhang, W.; Wang, F. Chem. Commun.
2009, 7465−7478. (b) Lu, Y.; Liu, C.; Chen, Q.-Y. Curr. Org. Chem.
2015, 19, 1638−1650. (c) Dilman, A. D. In Modern Synthesis Processes
and Reactivity of Fluorinated Compounds; Groult, H., Leroux, F. R.,
Tressaud, A., Eds.; Elsevier: Amsterdam, 2017; pp 181−199. (d) Rong,
J.; Ni, C.; Hu, J. Asian J. Org. Chem. 2017, 6, 139−152.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02601.
(7) For selected examples of reactions using CF2H-based reagents,
see: (a) Zhao, Y.; Huang, W.; Zheng, J.; Hu, J. Org. Lett. 2011, 13,
5342−5345. (b) Deng, Z.; Lin, J.-H.; Cai, J.; Xiao, J.-C. Org. Lett. 2016,
18, 3206−3209. (c) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012,
134, 5524−5527. (d) Prakash, G. K. S.; Ganesh, S. K.; Jones, J.-P.;
Kulkarni, A.; Masood, K.; Swabeck, J. K.; Olah, G. A. Angew. Chem.,
Int. Ed. 2012, 51, 12090−12094. (e) Matheis, C.; Jouvin, K.; Goossen,
L. J. Org. Lett. 2014, 16, 5984−5987. (f) Xu, L.; Vicic, D. A. J. Am.
Chem. Soc. 2016, 138, 2536−2539. (g) Feng, Z.; Min, Q.-Q.; Fu, X.-P.;
An, L.; Zhang, X. Nat. Chem. 2017, 9, 918−923. (h) Gu, Y.; Leng, X.;
Shen, Q. Nat. Commun. 2014, 5, 5405.
(8) (a) Levin, V. V.; Trifonov, A. L.; Zemtsov, A. A.; Struchkova, M.
I.; Arkhipov, D. E.; Dilman, A. D. Org. Lett. 2014, 16, 6256−6259.
(b) Trifonov, A. L.; Zemtsov, A. A.; Levin, V. V.; Struchkova, M. I.;
Dilman, A. D. Org. Lett. 2016, 18, 3458−3461. (c) Wang, F.; Li, L.; Ni,
C.; Hu, J. Beilstein J. Org. Chem. 2014, 10, 344−351.
Experimental procedures, compound characterization
data, copies of NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: adil25@mail.ru.
ORCID
Alexander D. Dilman: 0000-0001-8048-7223
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.7b02601
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) Burton, D. J.; Yang, Z.-Y.; Qiu, W. Chem. Rev. 1996, 96, 1641−
1716.
(10) (a) Zheng, J.; Cai, J.; Lin, J.-H.; Guo, Y.; Xiao, J.-C. Chem.
Commun. 2013, 49, 7513−7515. (b) Li, Q.; Lin, J.-H.; Deng, Z.-Y.;
Zheng, J.; Cai, J.; Xiao, J.-C. J. Fluorine Chem. 2014, 163, 38−41.
(c) Krishnamoorthy, S.; Kothandaraman, J.; Saldana, J.; Prakash, G. K.
S. Eur. J. Org. Chem. 2016, 2016, 4965−4969.
(11) (a) Thompson, S.; McMahon, S. A.; Naismith, J. H.; O’Hagan,
D. Bioorg. Chem. 2016, 64, 37−41. (b) Camerino, E.; Wong, D. M.;
Tong, F.; Korber, F.; Gross, A. D.; Islam, R.; Viayna, E.; Mutunga, J.
̈
M.; Li, J.; Totrov, M. M.; Bloomquist, J. R.; Carlier, P. R. Bioorg. Med.
Chem. Lett. 2015, 25, 4405−4411. (c) Giornal, F.; Pazenok, S.;
Rodefeld, L.; Lui, N.; Vors, J.-P.; Leroux, F. R. J. Fluorine Chem. 2013,
152, 2−11.
(12) (a) SciFinder search identified more than 900 patents since
2012 involving compounds with a perfluorinated isopropyl group,
which are mainly related to the development of agrochemicals. (b)
For an example of approved agrochemical Flubendiamide, bearing an i-
C3F7-group, see: Tohnishi, M.; Nakao, H.; Furuya, T.; Seo, A.;
Kodama, H.; Tsubata, K.; Fujioka, S.; Kodama, H.; Hirooka, T.;
Nishimatsu, T. J. Pestic. Sci. 2005, 30, 354−360.
(13) α,α-Difluorinated ketones have already found applications in
drug discovery; see: (a) Han, C.; Salyer, A. E.; Kim, E. H.; Jiang, X.;
Jarrard, R. E.; Powers, M. S.; Kirchhoff, A. M.; Salvador, T. K.; Chester,
J. A.; Hockerman, G. H.; Colby, D. A. J. Med. Chem. 2013, 56, 2456−
2465. (b) Gelb, M. H.; Svaren, J. P.; Abeles, R. H. Biochemistry 1985,
24, 1813−1817.
(14) In the literature, there is only one example for the synthesis of
alcohols 3 by nucleophilic addition to tetrafluoroacetone; see Moreau,
P.; Naji, N.; Commeyras, A. J. Fluorine Chem. 1985, 30, 315−328.
(15) (a) Kosobokov, M. D.; Dilman, A. D.; Levin, V. V.; Struchkova,
M. I. J. Org. Chem. 2012, 77, 5850−5855. (b) Li, L.; Wang, F.; Ni, C.;
Hu, J. Angew. Chem., Int. Ed. 2013, 52, 12390−12394. (c) For the first
report on the use of Me3SiCF2Br as a source of difluorocarbene, see:
Wang, F.; Zhang, W.; Zhu, J.; Li, H.; Huang, K.-W.; Hu, J. Chem.
Commun. 2011, 47, 2411−2413.
D
DOI: 10.1021/acs.orglett.7b02601
Org. Lett. XXXX, XXX, XXX−XXX