A new method for aromatic difluoromethylation: Copper-catalyzed cross-coupling and decarboxylation sequence from aryl iodides

Article abstract of DOI:10.1021/ol202289z

A new methodology for aromatic difluoromethylation is described. Aryl iodides reacted with α-silyldifluoroacetates upon treatment with copper catalyst in DMSO or DME to give the corresponding aryldifluoroacetates in moderate to good yields. The subsequent hydrolysis of aryldifluoroacetates and KF-promoted decarboxylation afforded a variety of difluoromethyl aromatics.

Full text of DOI:10.1021/ol202289z

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5560–5563
A New Method for Aromatic
Difluoromethylation: Copper-Catalyzed
Cross-Coupling and Decarboxylation
Sequence from Aryl Iodides
Kenichi Fujikawa,† Yasutaka Fujioka,† Akira Kobayashi,‡ and Hideki Amii*,†,‡
Department of Chemistry, Graduate School of Science, Kobe University, Kobe 657-8501,
Japan and Department of Chemistry and Chemical Biology, Graduate School of
Engineering, Gunma University, Kiryu, Gunma 376-8515 Japan
amii@chem-bio.gunma-u.ac.jp
Received August 24, 2011
ABSTRACT
A new methodology for aromatic difluoromethylation is described. Aryl iodides reacted with R-silyldifluoroacetates upon treatment with copper
catalyst in DMSO or DME to give the corresponding aryldifluoroacetates in moderate to good yields. The subsequent hydrolysis of aryl-
difluoroacetates and KF-promoted decarboxylation afforded a variety of difluoromethyl aromatics.
Fluorinated organic compounds play a key role in the
remarkable progress of medicinal, agricultural, and mate-
rial sciences.1 Difluoromethylene compounds have been
considerable synthetic targets because of their wide
utility.2,3 Among them, difluoromethylated aromatic com-
pounds (ArÀCF2H) have received a great deal of attention
in the design and development of bioactive agents.4,5 For
instance, certain difluoromethylated aromatics show poten-
tial inhibitory activities against VanX (a zinc-dependent
D-Ala-D-Ala dipeptidase)6 and CETP (cholesteryl ester
transfer protein).7 Although fluorination of aromatic al-
dehydes (ArÀCHO) by the use of a nucleophilic fluorinat-
ing agent such as SF4, DAST, and its derivatives is an
orthodox method to construct ArÀCF2H skeletons,8,9 an
alternative approaches for selective introduction of CF2H
groups into aromatic compounds have been a topic of
considerable interest.
Fluoroalkyl cross-coupling is one of the most versatile
methods to produce fluoromethylated aromatics. Copper-
mediated cross-coupling reactions for aromatic trifluoro-
methylation have been widely investigated.10À14 Recently,
† Kobe University.
‡ Gunma University.
(1) (a) Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine
Chemistry: Principles and Commercial Applications; Plenum Press: New
York, 2000. (b) Hiyama, T.; Kanie, K.; Kusumoto, T.; Morizawa, Y.; Shimizu,
M. Organofluorine Compounds: Chemistry and Application; Springer-
Verlag: Berlin, 2000. (c) Kirsch, P. Modern Fluoroorganic Chemistry;
Wiley-VCH: Weinheim, 2004. (d) Chambers, R. D. Fluorine in Organic
Chemistry; Blackwell: Oxford, 2004. (e) Uneyama, K. Organofluorine
(7) Hope, H. R.; Heuvelman, D.; Duffin, K.; Smith, C.; Zablocki, J.;
Schilling, R.; Hegde, S.; Lee, L.; Witherbee, B.; Baganoff, M.; Bruce, C.;
Tall, A. R.; Krul, E.; Glenn, K.; Connolly, D. T. J. Lipid Res. 2000, 41,
1604–1614.
(8) A review: Singh, R. P.; Shreeve, J. M. Synthesis 2002, 2561–2578.
(9) (a) Hanson, S. R.; Whalen, L. J.; Wong, C. H. Bioorg. Med. Chem.
2006, 14, 8386–8395. (b) Dolbier, W. R.; Xie, P.; Zhang, R.; Xu, W.;
Chang, Y.; Abboud, K. A. J. Org. Chem. 2008, 73, 2469–2472.
(10) Clark, J. H.; Wails, D.; Bastock, T. W. Aromatic Fluorination;
CRC Press: Boca Raton, FL, 1996.
(11) (a) Grushin, V. V.; Marshall, W. J. Acc. Chem. Res. 2010, 43,
160–171. (b) Lundgren, R. J.; Stradiotto, M. Angew. Chem., Int. Ed.
2010, 49, 9322–9324. (c) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature
2011, 473, 470–477. (d) Roy, S.; Gregg, B. T.; Gribble, G. W.; Le, V. D.;
Roy, S. Tetrahedron 2011, 67, 2161–2195.
ꢀ
ꢀ
Chemistry; Blackwell: Oxford, 2006. (f) Begue, J.-P.: Bonnet-Delpon, D.
Bioorganic and Medicinal Chemistry of Fluorine; John Wiley & Sons, Inc.:
Hoboken, NJ, 2008.
(2) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619–8683.
(3) Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465–7478.
(4) Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60, 1626–
1631.
(5) Matsuo, M.; Tsuji, K.; Ogino, T.; Konishi, N. Eur. Pat. Appl.
554829, 1993.
ꢀ
ꢀ
(6) Araoz, R.; Anhalt, E.; Rene, L.; Badet-Denisot, M.-A.; Courvalin,
P.; Badet, B. Biochemistry 2000, 39, 15971–15979.
r
10.1021/ol202289z
Published on Web 09/28/2011
2011 American Chemical Society

we demonstrated that a small amount of CuIÀphenan-
14a
throline complex engenders the cross-coupling reactions of
Table 1. Cross-Coupling of Aryl Iodides 1 with R-Silyldifluoro-
acetate 5a (Stoichiometric in Copper)
aryl/heteroaryl iodides with CF3SiEt3
and fluoral
derivatives14b to deliver trifluoromethylated arenes. Tri-
fluoromethyl copper intermediates (CF3CuL) contribute
to these transformations (both stoichimetric and catalytic
in copper). Compared with the chemistry of trifluoro-
methylation, that of difluoromethylation has been much
less studied. The use of difluoromethyl copper (HCF2Cu)
is anticipated to yield difluoromethylated aromatic com-
pounds (ArÀCF2H). There have been few reports on the
reactions of HCF2Cu species with electrophiles such as
allylic, propargylic, alkynyl, and benzyl halides.15,16 How-
ever, to the best of our knowledge, the cross-coupling of
HCF2Cu with aromatic halides has never been accom-
plished due to the lack of thermal stability of HCF2Cu
species. Herein, we describe a new reaction sequence
leading to an efficient synthesis of difluoromethylated
aromatic compounds 2 from aryl iodides 1 via 2-aryl-
2,2-difluoroacetates 3 (Scheme 1).
entry
Ar
solvent
yield/%a,b
1
4-NC-C6H4 (1a)
4-NC-C6H4 (1a)
4-NC-C6H4 (1a)
4-NC-C6H4 (1a)
3-NC-C6H4 (1b)
2-NC-C6H4 (1c)
4-O2N-C6H4 (1d)
4-EtO2C-C6H4 (1e)
3,4-Cl2-C6H3 (1f)
4-Br-C6H4 (1g)
4-Ph-C6H4 (1h)
Ph (1i)
DMF
8
2
CH3CN
DME
12
3
72
4
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
88 (71)
85 (69)
57 (44)
41 (29)
81 (73)
84 (73)
76 (54)
78 (68)
75c (40)
78 (72)
88 (87)
5
6
7
8
9
10
11
12
13
14
4-EtO-C6H4 (1j)
2-quinolyl (1k)
Scheme 1
a NMR yields, which were calculated by 19F NMR integration of
products 3 relative to the 2,2,2-trifluoroethanol internal standard. b The
values in parentheses indicate the isolated yields of 3. c Determined by
GC analysis using biphenyl as an internal standard.
wide repertoire of aromatic iodides 1 bearing electron-
withdrawing or -donating substituents underwent cross-
coupling reactions to provide the corresponding gem-
difluoroesters 3 in high yields (entries 4À14). En passant,
aryldifluoroacetates 3 have been used for several appli-
cations.18 To date, the reductive cross-coupling reactions
of bromo- or iododifluoroacetates with aryl harides by
the use of copper bronze are one of the most reliable
methods to prepare 2-aryl-2,2-difluoroacetates 3.19À22 In
these transformations, 2 equiv of copper are required to
generate CuÀCF2CO2R intermediates,19b which partici-
pate in cross-coupling with aryl halides. Compared to the
Initially, Cu-promoted cross-coupling reactions of
aryl iodides 1 with R-silyldifluoroacetates (5)17 were
examined. A mixture of 4-iodobenzonitrile (1a) and ethyl
2-(trimethylsilyl)-2,2-difluoroacetate (5a) in DMF was
heated at 60 °C for 15 h in the presence of CuI (1.0 equiv)
and KF (1.2 equiv) to afford aryldifluoroacetate 3a in only
8% NMR yield (Table 1, entry 1). After the survey of
reaction media (entries 2À4), DMSO was found to be
an effective solvent for the Cu-mediated transforma-
tion (entry 4).
(13) (a) Xiao, J.-C.; Ye, C.; Shreeve, J. M. Org. Lett. 2005, 7, 1963–
1965. (b) Dubinina, G. G.; Furutachi, H.; Vicic, D. A. J. Am. Chem. Soc.
2008, 130, 8600–8601. (c) Dubinina, G. G.; Ogikubo, J.; Vicic, D. A.
Organometallics 2008, 27, 6233–6235. (c) Kieltsch, I.; Dubinina, G. G.;
Hamacher, C.; Kaiser, A.; Torres-Nieto, J.; Hutchison, J. M.; Klein, A.;
Budnikova, Y.; Vicic, D. A. J. Fluorine Chem. 2010, 131, 1108–1112. (d)
Chu, L.; Qing, F.-L. Org. Lett. 2010, 12, 5060–5063. (e) Zhang, C.-P.;
Wang, Z.-L.; Chen, Q.-Y.; Zhang, C.-T.; Gu, Y.-C.; Xiao, J.-C. Angew.
Chem., Int. Ed. 2011, 50, 1896–1900. (f) Knauber, T.; Arikan, F.;
Other examples of the selective formation of 2-aryl-2,
2-difluoroacetates 3 are given in Table 1 (entries 5À14).
Upon treatment with a stoichiometric amount of CuI, a
€
Roschenthaler, G.-V.; Gooben, L. J. Chem.;Eur. J. 2011, 17, 2689–
2697. (g) Senecal, T. D.; Parsons, A. T.; Buchwald, S. L. J. Org. Chem.
2011, 76, 1174–1176. (h) Morimoto, H.; Tsubogo, T.; Litvinas, N. D.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2011, 50, 3793–3798. (i) Xu, J.;
Luo, D.-F.; Xiao, B.; Liu, Z.-J.; Gong, T.-J.; Fu, Y.; Liu, L. Chem.
Commun. 2011, 47, 4300–4302. (j) Liu, T.-F.; Shen, Q.-L. Org. Lett.
2011, 13, 2342–2345. (k) Popov, I.; Lindeman, S.; Daugulis, O. J. Am.
Chem. Soc. 2011, 133, 9286–9289. (l) Weng, Z. Q.; Lee, R.; Jia, W. G.;
Yuan, Y. F.; Wang, W. F.; Feng, X.; Huang, K.-W. Organometallics
2011, 30, 3229–3232. (m) Li, Y. M.; Chen, T.; Wang, H. F.; Zhang, R.;
Jin, K.; Wang, X. N.; Duan, C. Y. Synlett 2011, 1713–1716. (n) Kawai,
H.; Furukawa, T.; Nomura, Y.; Tokunaga, E.; Shibata, N. Org. Lett.
2011, 13, 3596–3599.
(12) (a) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006, 128,
4632–4641. (b) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006,
128, 12644–12645. (c) Ball, N. D.; Kampf, J. W.; Sanford, M. S. J. Am.
Chem. Soc. 2010, 132, 2878–2879. (d) Wang, X.; Truesdale, L.; Yu, J.-Q.
J. Am. Chem. Soc. 2010, 132, 3648–3649. (e) Ye, Y.; Ball, N. D.; Kampf,
J. W.; Sanford, M. S. J. Am. Chem. Soc. 2010, 132, 14682–14687. (f) Cho,
E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.; Buchwald,
S. L. Science 2010, 328, 1679–1681. (g) Kino, T.; Nagase, Y.; Ohtsuka,
Y.; Yamamoto, K.; Uraguchi, D.; Tokuhisa, K.; Yamakawa, T. J.
Fluorine Chem. 2010, 131, 98–105. (h) Ball, N. D.; Gary, J. B.; Ye, Y.;
Sanford, M. S. J. Am. Chem. Soc. 2011, 133, 7577–7584. (i) Loy, R. N.;
Sanford, M. S. Org. Lett. 2011, 13, 2548–2551. (j) Samant, B. S.;
Kabalka, G. W. Chem. Commun. 2011, 47, 7236–7238. (k) Mu, X.;
Chen, S. J.; Zhen, X. L.; Liu, G. S. Chem.;Eur. J. 2011, 17, 6039–6042.
(14) (a) Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009, 1909–
1911. (b) Kondo, H.; Oishi, M.; Fujikawa, K.; Amii, H. Adv. Synth.
Catal. 2011, 353, 1247–1252.
Org. Lett., Vol. 13, No. 20, 2011
5561

previously available methods, our transmetalation meth-
odology has several advantages: (i) the cross-coupling
participants 5 (2-silyl-2,2-difluoroacetates) are stable
and readily available directly from trifluoroacetates or
chlorodifluoroacetates;17,23 (ii) with a high level of func-
tional group tolerance, the reactions proceeded smoothly
under mild conditions; and (iii) fine-tuning of the reaction
conditions rendered a reaction catalytic in copper possible
(Scheme 2).24,25
When a mixture of 1a, Me3SiÀCF2CO2Et (5a), and KF
in DMSO was heated at 60 °C for 15 h in the presence of a
catalytic amount of CuI (0.2 equiv to 1a) under an argon
atmosphere, the cross-coupling reaction proceeded to give
ester 3a in 38% NMR yield. To improve the chemical
yields of cross-coupling using a small amount of CuI, various
screening experiments were undertaken. After systematical
optimization, the use of 2-(triethylsilyl)-2,2-difluoroacetates
(TES-CF2CO2Et, 5b) instead of 5a as a coupling partner
and DME as a solvent was shown to be effective for the
selective formation of aryldifluoroacetate 3 in moderate
yields at a 20 mol % catalyst loading (Scheme 2).
Scheme 2
Next, we explored decarboxylation of 2-aryl-2,2-difluo-
roacetic acids 4, which were readily obtained by alkaline
hydrolysis of esters 3. Upon heating a DMF solution of
aryl-2,2-difluoroacetic acid 4a at 170 °C (without any
catalyst), decarboxylation took place to give difluoro-
methyl arene 2a in 19% yield (Table 2, entry 1). Interest-
ingly, a significant change was observed when the reaction
was conducted in the presence of NaF to provide the
decarboxylation product 2a in 60% yield (entry 2). Heat-
ing of a DMF solution of 4a with KF26 (2 equiv to 4a) led
to formation of difluoromethyl arene 2a in 93% yield
(entry 4). The use of metal fluorides such as NaF, KF,
and CsF was found to be effective for decarboxylation of
4a (entries 2À7). In contrast, addition of KBr instead of
KF gave a poor result for decarboxylation (entry 7).
Table 2. Additive Effect on Decarboxylation of 4a
a Determined by 19F NMR (CF3CH2OH was used as internal
standard).
entry
additive (amount)
time/h
yield/%a
1
2
3
4
5
6
7
none
1
1
1
1
2
1
1
19
60
64
87
93
95
17
(15) (a) Burton, D. J.; Hartgraves, G. A.; Hsu, J. Tetrahedron Lett.
1990, 31, 3699–3702. (b) Burton, D. J.; Hartgraves, G. A. J. Fluorine
Chem. 2007, 128, 1198–1215.
(16) Eujen, R.; Hoge, B.; Brauer, D. J. J. Organomet. Chem. 1996,
519, 7–20.
NaF (1 equiv)
KF (1 equiv)
KF (2 equiv)
KF (2 equiv)
CsF (1 equiv)
KBr (1 equiv)
(17) (a) Uneyama, K.; Mizutani, G.; Maeda, K.; Kato, T. J. Org.
Chem. 1999, 64, 6717–6723. (b) Amii, H.; Kobayashi, T.; Uneyama, K.
Synthesis 2000, 2001–2003. (c) Clavel, P.; Biran, C.; Bordeau, M.;
ꢀ
Roques, N.; Trevin, S. Tetrahedron Lett. 2000, 41, 8763–8767.
a Determined by 19F NMR analysis (CF3CH2OH was used as
internal standard).
(18) (a) Sato, K.; Nishimoto, T.; Tamoto, K.; Omote, M.; Ando, A.;
Kumadaki, I. Heterocycles 2002, 56, 403–412. (b) Kreutter, K. D.; Lu,
T.; Lee, L.; Giardino, E. C.; Patel, S.; Huang, H.; Xu, G.; Fitzgerald, M.;
Haertlein, B. J.; Mohan, V.; Crysler, C.; Eisennagel, S.; Dasgupta, M.;
McMillan, M.; Spurlino, J. C.; Huebert, N. D.; Maryanoff, B. E.;
Tomczuk, B. E.; Damiano, B. P.; Player, M. R. Bioorg. Med. Chem.
Lett. 2008, 18, 2865–2870. (c) Wang, X.-J.; Zhang, F.; Liu, J.-T.
Tetrahedron 2008, 64, 1731–1735.
Hydrolysis of 3 with aqueous K2CO3 followed by dec-
arboxylation of 4 gave difluoromethyl arenes 2. Without
(19) (a) Taguchi, T.; Kitagawa, O.; Morikawa, T.; Nishiwaki, T.;
Uehara, H.; Endo, H.; Kobayashi, Y. Tetrahedron Lett. 1986, 27, 6103–
6106. (b) Kitagawa, O.; Taguchi, T.; Kobayashi, Y. Chem. Lett. 1989,
18, 389–392.
(20) (a) Sato, K.; Kawata, R.; Ama, F.; Omote, M.; Ando, A.;
Kumadaki, I. Chem. Pharm. Bull. 1999, 47, 1013–1016. (b) Sato, K.;
Omote, M.; Ando, A.; Kumadaki, I. J. Fluorine Chem. 2004, 125, 509–
515.
(22) (a) Zhu, J.; Zhang, W.; Zhang, L.; Liu, J.; Zheng, J.; Hu, J.
J. Org. Chem. 2010, 75, 5505–5512. (b) Zhu, J. M.; Wang, F.; Huang,
W. Z.; Zhao, Y. C.; Ye, W. C.; Hu, J. Synlett 2011, 899–902.
(23) R-Silyldifluoroacetates 5 were readily prepared in good yields by
Mg-promoted reductive transformation of ethyl chlorodifluoroacetate
in the presence of Me3SiCl or Et3SiCl.
(24) Pd-catalyzed cross-coupling of aryl bromides with enol ethers of
difluoroketones: (a) Guo, Y.; Shreeve, J. M. Chem. Commun. 2007,
3583–3585. (b) Guo, Y.; Twamley, B.; Shreeve, J. M. Org. Biomol. Chem.
2009, 7, 1716–1722.
(21) Ashwood, M. S.; Cottrell, I. F.; Cowden, C. J.; Wallace, D. J.;
Davies, A. J.; Kennedy, D. J.; Dolling, U. H. Tetrahedron Lett. 2002, 43,
9271–9273.
5562
Org. Lett., Vol. 13, No. 20, 2011

via a hydrolysisÀdecarboxylation sequence. Representa-
tive results are summarized in Table 3. Under the opti-
mized reaction conditions, KF-promoted decarboxylation
worked well for various aryldifluoroacetic acids4. Difluor-
oesters 3aÀf endowed with electron-withdrawing groups
on the aryl rings underwent KF-catalyzed decarboxylation
smoothly to provide the desired difluoromethyl arene 2 in
good yields (entries 1À6). The decarboxylation reactions
of 3g and 3h possessing Br or phenyl groups required the
utilization of CsF under the harsh conditions (at 200 °C,
in NMP) (entries 7 and 8). In contrast, decarboxylation
of 3j bearing an electron-donating substituent such as an
ethoxy group on the aryl ring did not occur at 200 °C
even in the presence of CsF (entry 9). Furthermore,
heteroarene 3k partook in the KF-catalyzed decarboxy-
lation to afford difluoromethylated quinoline 2k in high
yield (entry 10).
Table 3. Synthesis of Difluoromethylated Aromatics 2
In conclusion, we have developed a convenient route to
difluoromethyl arenes from aryl iodides. In the first cross-
coupling reactions, R-silyldifluoroacetates 5 served as a
donor of the difluoromethylene component to aromatics.
For the subsequent decarboxylation step, KF was found to
be a good promoter. The stepwise conversion of the iodo
moieties in 1 to CF2H groups was successfully accom-
plished.27 Thereby, the design of the reaction sequences
enables the development of various practical transforma-
tions, with potential biological and chemical utility.
Acknowledgment. The financial support from the Min-
istry of Education, Culture, Sports, Science and Technol-
ogy of Japan, the Naito Foundation, and Foundation
Nagase Science Technology Development is gratefully
acknowledged. We thank Prof. Masahiko Hayashi (Kobe
University) and Prof. Hiroshi Sano (Gunma University)
for their useful suggestions. Also, we acknowledge Prof.
Atsunori Mori (Kobe University) for supporting HRMS
analyses. We are grateful to Central Glass Co., Ltd. for a
gift of ethyl chlorodifluoroacetate.
a In each reaction, KF (5 equiv) was used unless noted. b Isolated
yields (from esters 3). c These reactions were carried out by the use of CsF
(5 equiv) instead of KF. d The decarboxylation reaction did not occur.
Supporting Information Available. Details of experi-
mental procedures and characterization data (1H, 13C,
and 19F NMR; IR; and mass spectrometry) for all new
compounds. This material is available free of charge via
Internet at http://pubs.acs.org.
isolation of the intermediate carboxylic acid 4a, difluor-
oester 3a was converted cleanly to 2a in 84% overall yield
(26) (a) Nesmeyanov, A. N.; Pecherskaya, K. A.; Uretskaya, G. Y.
Izv. Akad. Nauk SSSR, Ser. Khim. 1948, 240–245. (b) Kim, Y. S.
J. Korean Chem. 1963, 7, 189–196. (c) Battais, A.; Boutevin, B.;
Pietrasanta, Y. J. Fluorine Chem. 1979, 14, 467–484.
(27) Synthesis of fluoromethyl arenes (ArCH2F) via reductive desul-
fonylation of [fluoro(phenylsulfonyl)methyl]arenes using Na(Hg): Ni,
C.; Zhang, L.; Hu, J. J. Org. Chem. 2008, 73, 5699–5713.
(25) Catalytic introduction of fluoroacetate moieties to aryl rings: (a)
Murakami, S.; Ishi, H.; Tajima, T.; Fuchigami, T. Tetrahedron 2006, 62,
3761. (b) Guo, C.; Yue, X.; Qing, F.-L. Synthesis 2010, 1837–1844. (c)
Araki, K.; Inoue, M. Jpn. Kokai Tokkyo Koho JP 2010116363 A
20100527, 2010. (d) Ohtsuka, Y.; Yamakawa, T. Tetrahedron 2011, 67,
2323–2331.
Org. Lett., Vol. 13, No. 20, 2011
5563