S-, N-, and Se-difluoromethylation using sodium chlorodifluoroacetate

Article abstract of DOI:10.1021/ol402370f

A simple protocol for the difluoromethylation of thiols is reported using chlorodifluoroacetate as the difluoromethylating agent. This cheap reagent undergoes smooth decarboxylation at 95 C to afford difluorocarbene, which can be trapped with a variety of aromatic and heteroaromatic thiols. The reaction is also effective for the difluoromethylation of heterocyclic nitrogen compounds and phenylselenol.

Full text of DOI:10.1021/ol402370f

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
S‑, N‑, and Se-Difluoromethylation Using
Sodium Chlorodifluoroacetate
Vaibhav P. Mehta and Michael F. Greaney*
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, U.K.
Michael.Greaney@manchester.ac.uk
Received August 18, 2013
ABSTRACT
A simple protocol for the difluoromethylation of thiols is reported using chlorodifluoroacetate as the difluoromethylating agent. This cheap
reagent undergoes smooth decarboxylation at 95 °C to afford difluorocarbene, which can be trapped with a variety of aromatic and heteroaromatic
thiols. The reaction is also effective for the difluoromethylation of heterocyclic nitrogen compounds and phenylselenol.
Selective fluorination is an important method for control-
ling molecular function and properties. Biological activities
such as potency, log D, and metabolic stability can fre-
quently be modulated through the selective incorporation of
fluorine-containing groups,1 creating great demand for
mild, selective, and cost-effective fluorination strategies.2
Impressive progress in reaction development has been made
in recent years, particularly in the areas of tri- and difluoro-
methylation.3 The cost, however, of many fluorinating and
per-fluorinating agents is recognized as a major barrier to
translating these reactions to industrial processes.4 There is
a clear requirement for cheaper reagents to accomplish
selective per-fluoromethylation in the context of process
chemistry. Our interest in decarboxylative CꢀC bond
formation5 stimulated us to examine fluoroacetate deriva-
tives in this regard. Trifluoroacetic acid and its salts are bulk
chemicals that can be sourced at low cost and have demon-
strated utility in selective trifluoromethylations.6 We were
interested in the related compound sodium chlorodifluor-
oacetate (SCDA), 1. Costing ca. 15% of the commonly used
TMSCF3 reagent, and available in bulk as a crystalline
solid, it has great potential as a cheap, atom economical di-
and trifluoromethylation reagent.The ability of SCDA to
act as a difluorocarbene precursor was first noted by
Haszeldine, who demonstrated difluorocarbene generation
and trapping with alkenes by thermal decarboxylation
(Scheme 1).7 Subsequent work from Chen8 and Burton9
showed that decarboxylation in the presence of fluoride and
(1) (a) Fluorine in Medicinal Chemistry and Chemical Biology, Ojima,
I., Ed.; Wiley: New York, 2009. (b) Hagmann, W. K. J. Med. Chem. 2008,
51, 4359. (c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Chem. Soc. Rev. 2008, 37, 320.
(2) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem., Int. Ed.
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D.-B.; Duan, J.-X.; Chen, Q.-Y. Chem. Commun. 1992, 807.
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Jin, Z.; Hammond, G. B.; Xu, B. Aldrichimica Acta 2012, 45, 67.
(4) For a cost comparison of common trifluoromethylating agents,
see: McReynolds, K. A.; Lewis, R. S.; Ackerman, L. K. G.; Dubinina,
G. G.; Brennessel, W. W.; Vicic, D. A. J. Fluorine Chem. 2010, 131, 1108.
(5) (a) Seo, S.; Slater, M.; Greaney, M. F. Org. Lett. 2012, 14, 2650.
(b) Zhang, F.; Greaney, M. F. Org. Lett. 2010, 12, 4745. (c) Zhang, F.;
Greaney, M. F. Angew. Chem., Int. Ed. 2010, 49, 2768.
(6) (a) Matsui, K.; Tobita, E.; Ando, M.; Kondo, K. Chem. Lett.
1981, 1719. (b) Carr, G. E.; Chambers, R. D.; Holmes, T. F.; Parker,
D. G. J. Chem. Soc., Perkin Trans. 1 1988, 921. (c) Quiclet-Sire, B.;
Saicic, R. N.; Zard, S. Tetrahedron Lett. 1996, 37, 9057. (d) Flachsmann,
F.; Schellhaas, K.; Moya, C. E.; Jacobs, R. S.; Fenical, W. Bioorg. Med.
Chem. 2010, 18, 8324. (d) Schareina, T.; Wu, X.-F.; Zapf, A.; Cotte, A.;
Gotta, M.; Beller, M. Top. Catal. 2012, 55, 426.
(9) MacNeil, J. G., Jr.; Burton, D. J. J. Fluorine Chem. 1991, 55, 225.
(10) Recent examples of sodium and methyl chlorodifluoroacetate
di- and trifluoromethylation: (a) Mulder, J. A.; Frutos, R. P.; Patel,
N. D.; Qu, B.; Sun, X.; Tampone, T. G.; Gao, J.; Sarvestani, M.;
Eriksson, M. C.; Haddad, N.; Shen, S.; Song, J. J.; Senanayake, C. H.
Org. Process Res. Dev. 2013, 17, 940. (b) Sperry, J. B.; Farr, R. M.;
Levent, M.; Ghosh, M.; Hoagland, S. M.; Varsolona, R. J.; Sutherland,
K. Org. Process Res. Dev. 2012, 16, 1854. (c) Sperry, J. B.; Sutherland, K.
Org. Process Res. Dev. 2011, 15, 721. (d) Johnson, P. S.; Underwood,
T. J.; Wheeler, S. Tetrahedron Lett. 2011, 52, 3226. (e) Kmentova, I.;
Sutherland, H. S.; Palmer, B. D.; Blaser, A.; Franzblau, S. G.; Wan, B.;
Wang, Y.; Ma, Z.; Denny, W. A.; Thompson, A. M. J. Med. Chem. 2010,
53, 8421. (f) Ando, M.; Wada, T.; Sato, N. Org. Lett. 2006, 8, 3805. (g)
Ho, J. Z.; Elmore, C. S.; Wallace, M. A.; Yao, D.; Braun, M. P.; Dean,
D. C.; Melillo, D. G.; Chen, C.-Y. Helv. Chim. Acta 2005, 88, 1040.
r
10.1021/ol402370f
XXXX American Chemical Society

Cu salts generated CuCF3 species, which could be harnessed
in C- and O-trifluoromethylations.4,10 In contrast to TFA,
which requires temperatures in excess of 150 °C and a metal
catalyst to decarboxylate, SCDA is reported to undergo loss
of CO2 at lower temperatures and in the absence of metals.
lack of commercial availability and expense, the require-
ment for strongly basic reaction conditions, and/or poor
atom economy mean there is still scope for developing an
inexpensive, mild, and atom economical S-difluoromethy-
lation method.
Table 1. Optimization Study for Difluoromethylation of Thiol 2aa
Scheme 1. Decarboxylative Trifluoromethylation
SDCA
yieldb
(%)
entry
base
solvent
(equiv)
1
K2CO3
K2CO3
K2CO3
Na2CO3
LiOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NMP
DMSO
solventsc
DMF
DMF
DMF
1
1.5
2
2
2
2
2
2
2
2
2
2
2
2
2
2
50
2
78
3
>99(93)
92
4
5
94
6
Cs2CO3
KF
97
7
<5
We were interested in exploring the potential of SCDA for
S-difluoromethylation, an application that has thus far been
restricted to isolated reports in the patent literature.11 The
SCHF2 group is valued in medicinal and agrochemistry for
its lipophilic and H-bonding characteristics,12,13 and is clas-
sically installed with chlorodifluoromethane gas,14 an ozone-
depleting reagent that is subject to environmental regula-
tion. Alternative reagents for S-difluoromethylation have
recently been introduced, such as BrF2CPO(OEt)2,15 FSO2-
CF2CO2TMS,16 PhCOCF2Cl,17 ArSONRCF2H,18 Ar2-
8
NaHCO3
NEt3
<2
9
<1
10
11
12
13
14d
15e
16
DBU
42
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
no base
>95
60
<2
75(62)
<1
n.d.f
a Reaction conditions: In an oven-dried 25 mL screw capped reaction
vial containing a stir bar were added base (0.75 mmol, 1.50 equiv) and 1
(1.00 mmol, 2.00 equiv), and the vial was evacuated and filled with argon
(3 times). Then solvent (3 mL) was added followed by 2a (0.50 mmol,
1.00 equiv) under argon. The vial was tightly sealed and stirred for 8 h.
b 19F NMR yield (value in parentheses indicates isolated yield). c 1,4-
Dioxane, DCE, MeCN, and THF failed to give the desired conversion.
d Reaction temperature 65 °C. e Room temperature. f n.d. = no desired
product observed in 19F NMR spectra.
ꢀ 19
Zn(SO2CF2H)2/tBuOOH,20 CHF2OTf,21
SCHF2þBF4
,
TMSCHF2,22 and CHF3/KOH,23 but limitations such as
(11) (a) Schrimpf, M. R.; Mortell, K. H.; Nersesian, D. L.; Lee,
C.-H.; Clapham, B. U.S. Patent 20090253670, 2009, Chem. Abstr. 2009,
151, 425356. (b) Fugitt, R. B.; Luckenbaugh, R. W. European Patent
50827, 1981, Chem. Abstr. 1982, 97, 109990.
(12) Manteau, B.; Pazenok, S.; Vors, J.-P.; Leroux, F. R. J. Fluorine
Chem. 2010, 131, 140.
(13) For related methods for S-trifluoromethylation, see: (a) Tran,
L. D.; Popov, I.; Daugulis, O. J. Am. Chem. Soc. 2012, 134, 18237. (b)
Zhang, C.-P.; Vicic, D. A. J. Am. Chem. Soc. 2012, 134, 183. (c)
Teverovskiy, G.; Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed.
2011, 50, 7312. (d) Chen, C.; Xie, Y.; Chu, L.; Wang, R.-W.; Zhang, X.;
Qing, F.-L. Angew. Chem., Int. Ed. 2012, 51, 2492.
(14) (a) Hine, J.; Rosscup, R. J.; Duffey, D. C. J. Am. Chem. Soc.
1960, 82, 6120. (b) Shen, T. Y.; Lucas, S.; Sarett, L. H. Tetrahedron Lett.
1961, 2, 43. (c) Langlois, B. R. J. Fluorine Chem. 1988, 41, 247.
(15) Zafrani, Y.; Sod-Moriah, G.; Segall, Y. Tetrahedron 2009, 65,
5278.
(16) Xu, W.; Abboud, K. A.; Ghiviriga, I.; Dolbier, W. R., Jr.; Rapp,
M.; Wnuk, S. F. Org. Lett. 2006, 8, 5449.
(17) Wang, F.; Zhang, L.; Zheng, J.; Hu, J. J. Fluorine Chem. 2011,
132, 521.
(18) (a) Zhang, W.; Wang, F.; Hu, J. Org. Lett. 2009, 11, 2109. (b)
Prakash, G. K. S.; Zhang, Z.; Wang, F.; Ni, C.; Olah, G. A. J. Fluorine
Chem. 2011, 132, 792.
(19) Prakash, G. K. S.; Weber, C.; Chacko, S.; Olah, G. A. Org. Lett.
2007, 9, 1863.
We began our investigations with p-methoxythiophenol,
2a, and were pleased to observe successful difluoromethy-
lation in the presence of 1 equiv of SCDA and K2CO3 at
95 °C (Table 1, entry 1). Raising the equivalents of SCDA
enhanced the reaction, with 2 equiv providing a 93%
isolated yield of 3a (entry 3). The reaction was equally
effective for Na2CO3, LiOH, and Cs2CO3 (entries 4ꢀ6),
but the weaker bases NEt3 and NaHCO3 gave little if any
decarboxylation (entries 8 and 9). A polar solvent such as
DMF, NMP (entry 11) or DMSO (entry 12) was needed in the
reaction, with alternative solvents being completely ineffective
(entry 13). Reducing the reaction temperature maintained
efficiency (62%) at 65 °C (entry 14), but lower temperatures
shut the reaction down (entry 15). Finally, in the absence of
base no difluoromethylated product could be isolated.
(20) Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter, R. D.;
Dixon, D. D.; Collins, M. R.; Blackmond, D. G.; Baran, P. S. J. Am.
Chem. Soc. 2012, 134, 1494.
(21) Fier, P. S.; Hartwig, J. F. Angew. Chem., Int. Ed. 2013, 52, 2092.
(22) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 5524.
(23) Thomoson, C. S.; Dolbier, W. R., Jr. J. Org. Chem. 2013, 78,
8904.
With an optimized protocol in hand, we assayed the reac-
tion against a number of substituted thiophenols (Scheme 2).
Yields of difluoromethylated products were good to excellent
for a range of substitution patterns, being largely independent
B
Org. Lett., Vol. XX, No. XX, XXXX

of the electronic character of the aromatic ring (3aꢀ3r).Steric
hindrance in terms of ortho-substitution was also tolerated,
with o-MeO, Me, CO2Me, Cl, and CF3 groups all undergoing
smooth conversion. Surprisingly, the carboxylic acid group
was tolerated in the reaction, with compound 3j being formed
in 64% yield from the acid substrate.
Scheme 3. Difluoromethylation of Heteroaromatic Thiolsa
Scheme 2. Difluoromethylation of Thiophenolsa
a Reactions were carried out on a 1.00 mmol scale. Isolated yields
(values in parentheses indicates 19F NMR yield).
a Reactions were carried out on a 1.00 mmol scale. Isolated yields (values
b
in parentheses indicates 19F NMR yield). Minor amounts of an uni-
dentified difluoromethylated compound were isolated as a side product.
Double difluoromethylation was also possible, with 1,2-
and 1,3-dithiophenols affording the adducts 3s and 3t in
reasonable yield. The method was not successful for alkyl
thiols, which gave intractable mixtures. The difluoro-
methylation of 4-methoxythiophenol was scaled up to
10 mmol, affording an 86% yield of 3a. A small amount
of disulfide was isolated from this reaction, suggesting that
disulfides do not undergo reaction with SCDA.
Scheme 4. Difluoromethylation of Theophyllinea
We next expanded the protocol to nitrogenous heteroaro-
matic thiols, of the type more commonly found in medicinal
and agrochemistry discovery programs (Scheme 3). These
ambident nucleophiles can react on sulfur or nitrogen to
produce dearomatized products. Difluoromethylation of
1-substituted 5-sulfanyltetrazoles gave clean N-difluoro-
methylation under the reaction conditions (δf (CHF2) =
ꢀ102.95), forming thiones 5a and 5b in high yield (structure
5b confirmed by X-ray crystallography). Yagupol’skii
has studied the difluoromethylation of these, and related
azolemercaptan compounds, with gaseous chlorodifluoro-
methane/KOH and identified S-difluoromethylation as the
kinetic product at low temperature, with formation of the
more stable N-difluoromethylated species observed at higher
temperature (100ꢀ120 °C).24
a Reaction was carried out on 1.00 mmol scale. Isolated yield.
in high yield (X-ray).25 Azole compounds gave mixtures
of N- and S-difluoromethylation in excellent overall
yield,18a indicating smaller differences in stability be-
tween the two products (5h/5h0 and 5i/5i0). This product
ratio was temperature dependent; difluoromethylation of
For azinemercaptans, the SCHF2 products were pre-
ferred for 2-thiopyridines and pyrimidines (5c, 5d, 5f, and5g),
but 4-thiopyridine gave the thione 5e as a single product
(25) CCDC 956096, 953257, 956095, and 948730 contains the crystal-
lographic data for 5b, 5e, 5j, and 7a0. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
(24) Petko, K. I.; Yagupol’skii, L. M. Zh. Org. Khim. 2004, 40, 627.
(b) Petko, K. I.; Yagupol’skii, L. M. J. Fluorine. Chem. 2001, 108, 211.
Org. Lett., Vol. XX, No. XX, XXXX
C

SCDA (Scheme 5). This compound has recently been shown
by Hu to undergo deprotonation and subsequent CꢀC
bond formation, making it a versatile fluorinated synthon
for further functionalization.26
Scheme 5. Difluoromethylation of Phenylselenola
In conclusion, we have developed a simple and cost-
effective protocol for the difluoromethylation of aro-
matic and heteroaromatic thiols using inexpensive so-
dium chlorodifluoroacetate. The cost-effectiveness of the
transformation is matched by the simplicity of the reac-
tion conditions; K2CO3 at 95 °C is sufficient to decarbox-
ylate SCDA in the absence of any transition metal
catalyst systems, and the difluorocarbene generated ef-
fectively captures a variety of S, N, and Se nucleophiles in
generally high yield.
a Reaction was carried out on 1.00 mmol scale. Isolated yield.
2-mercaptobenzothiazole 4h at the higher temperature of
120 °C altered the ratio from 2:1 in favor of SCHF2
(95 °C) to 1:1. 2-Mercaptobenzoxazole 4j was somewhat
anomalous as a substrate, affording the expected NCHF2
compound 5j in 46% isolated yield (confirmed by X-ray),
along with minor amounts of impure difluoromethylated
material that did not correspond to the SCHF2 com-
pound (see Supporting Information).
The N-difluoromethylation reaction pathway could be
extended to theophylline, 6, a non-sulfur-containing sub-
strate,10f with difluoromethylation being observed at both
imidazole nitrogen centers in high overall yield (7a:7a0 =
1:2). An X-ray structure of the major regioisomer charac-
terized it as the 9-NCHF2 regioisomer (Scheme 4).
Acknowledgment. We thank the EPSRC for funding
(postdoctoral fellowship to V.P.M., Leadership Fellow-
ship to M.F.G.). Dr. James Raftery and Dr. Thomas Storr
(University of Manchester) are thanked for X-ray crystal-
lography. Mr. Gareth Smith (University of Manchester) is
thanked for mass spectrometry.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds
is available in the Supporting Information. This material
is available free of charge via the Internet at http://pubs.
acs.org.
Finally, we were able to synthesize (difluoromethyl)-
(phenyl)selane (9) from phenylselenol in 65% yield using
(26) Hu, M.; Wang, F.; Zhao, Y.; He, Z.; Zhang, W.; Hu, J.
J. Fluorine Chem. 2012, 135, 45.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX