Reactions of difluorocarbene with organozinc reagents

Article abstract of DOI:10.1021/ol400122k

Reactions of difluorocarbene with benzyl and alkylzinc halides leading to fluorinated organozinc species have been described. The generated α-difluorinated organozinc reagents are reasonably stable in solution and can be quenched with external electrophiles (iodine, bromine, proton), affording compounds containing the CF₂ fragment.

Full text of DOI:10.1021/ol400122k

ORGANIC
LETTERS
2013
Vol. 15, No. 4
917–919
Reactions of Difluorocarbene with
Organozinc Reagents
Vitalij V. Levin, Artem A. Zemtsov, Marina I. Struchkova, and Alexander D. Dilman*
N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47,
Russian Federation
adil25@mail.ru
Received January 15, 2013
ABSTRACT
Reactions of difluorocarbene with benzyl and alkylzinc halides leading to fluorinated organozinc species have been described. The generated
R-difluorinated organozinc reagents are reasonably stable in solution and can be quenched with external electrophiles (iodine, bromine, proton),
affording compounds containing the CF2 fragment.
Due to increasing importance of fluorine-containing
organic compounds for the development of new pharma-
ceuticals and agrochemicals,1 synthetic methods aimed at
the introduction of fluorinated fragments into organic
molecules have witnessed exponential growth over the last
5 years.2 While various methods for the introduction of the
CF3 group have been documented,2,3 approaches for the
synthesis of compounds bearing the CF2 fragment are
notably less abundant.4À7 In general, the latter compounds
can be prepared using a deoxofluorination reaction (path a),
which is frequently performed using hazardous sulfur
reagents,8 or from halodifluoroacetic esters and similar
CF2-containing building blocks (path b), which may re-
quire a long synthetic sequence.9 Herein we propose a new
efficient approach for assembling CF2-containing prod-
ucts from three independent components;nucleophile,
difluorocarbene, and electrophile (path c) (Scheme 1).
(1) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
€
Soc. Rev. 2008, 37, 320–330. (b) Muller, K.; Faeh, C.; Diederich, F.
Science 2007, 317, 1881–1886. (c) Fluorine in Medicinal Chemistry and
Chemical Biology; Ojima, I., Ed.; Blackwell: Oxford, U.K., 2009.
(2) For recent reviews, see: (a) Studer, A. Angew. Chem., Int. Ed.
2012, 51, 8950–8958. (b) Liu, T.; Shen, Q. Eur. J. Org. Chem. 2012, 6679–
6687. (c) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470–477.
(d) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475–
4521. (e) Dilman, A. D.; Levin, V. V. Eur. J. Org. Chem. 2011, 831–841.
(f) Landelle, G.; Bergeron, M.; Turcotte-Savard, M.-O.; Paquin, J.-F.
Chem. Soc. Rev. 2011, 40, 2867–2908. (g) Shibata, N.; Matsnev, A.;
Cahard, D. Beilstein J. Org. Chem. 2010, 6, 65.
Scheme 1. Approaches toward Compounds with a CF2
Fragment
(3) (a) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975–996.
(b) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757–786.
(4) For an overview of methods toward CF2-containing compounds,
see: Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619–8683.
(5) For a discussion on challenges in preparation of compounds with
RCF2I and RCF2Br fragments, see: Zhao, Y.; Gao, B.; Hu, J. J. Am.
Chem. Soc. 2012, 134, 5790–5793.
(6) For recent methods providing compounds with a CHF2 group,
see: (a) 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, 1494–1497. (b) Fier, P. S.; Hartwig, J. F. J. Am.
Chem. Soc. 2012, 134, 5524–5527. (c) 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. (d) Shen, X.; Zhang, W.;
Ni, C.; Gu, Y.; Hu, J. J. Am. Chem. Soc. 2012, 134, 16999–17002. (e) Wu,
J.; Cao, S.; Liu, N.; Shen, L.; Yu, J.; Zhang, J.; Li, H.; Qian, X. Org.
Biomol. Chem. 2010, 8, 2386–2391. (f) Fujikawa, K.; Fujioka, Y.;
Kobayashi, A.; Amii, H. Org. Lett. 2011, 13, 5560–5563. (g) Liu, G.;
Wang, X.; Lu, X.; Xu, X.-H.; Tokunaga, E.; Shibata, N. ChemistryOpen
2012, 1, 227–231.
(7) For a review on difluorocyclopropanation, see: Dolbier, W. R.;
Battiste, M. A. Chem. Rev. 2003, 103, 1071–1098.
(8) (a) Hudlicky, M. Org. React. 1988, 35, 513–637. (b) Singh, R. P.;
Shreeve, J. M. Synthesis 2002, 2561–2578. (c) Singh, R. P.; Meshri, D. T.;
Shreeve, J. M. In Advances in Organic Synthesis: Modern Organofluorine
Chemistry;Synthetic Aspects; Atta-Ur-Rahman, Laali, K. K., Eds.;
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r
10.1021/ol400122k
2013 American Chemical Society
Published on Web 01/31/2013

Difluorocarbene is intrinsically electrophilic10 and, there-
fore, is capable of interacting with nucleophiles, affording a
new nucleophilic species 1 (Scheme 2). While reactions of
nucleophiles with difluorocarbene have been known, in all
previously reported examples, species 1 were considered as
short-lived intermediates undergoing rapid trapping by an
electrophile from the reaction medium (proton or halogen).
In particular, this scenario is realized in difluoromethyla-
tion of alcohols, thiols, amines, and CH acids,6g,10a,11 bro-
modifluoromethylation of alkynes and malonates,12 bro-
modifluoromethylation of P and S nucleophiles,13 and,
likely, in iododifluoromethylation of lithium enolates.14 In
this work, we demonstrate that reasonably stable reagents
1 can be generated and quenched by subsequent addition
of a desired electrophile.
Benzylzinc bromide (2a), which can be obtained in
different solvents, was selected as a starting nucleophile.
Among various sources of difluorocarbene,17 we preferred
to use (bromodifluoromethyl)trimethylsilane (3)18 since,
supposedly, it can generate difluorocarbene at low tem-
peratures under mildly basic conditions.19 Additionally,
silane 3 can be readily prepared in large quantities.18b
The reaction of 1.5 mmol of benzylzinc bromide with the
silane was performed at À25 °C using sodium acetate as a
Lewis base, and the resulting solution was treated with
iodine to produce compound 5a (Table 1). Rewardingly,
the reaction worked well in various solvents, with the best
result being obtained in MeCN. Increasing the amount of
silane and sodium acetate consistently gave decreased pro-
duct yields, which may be associated with some transforma-
tions of fluorinated zinc species. Addition of LiCl did not
have a beneficial effect20 (entry 8). Finally, the use of 1.2 equiv
of reagents for the generation of difluorocarbene was opti-
mal, affording product 5a in 85% isolated yield21 (entry 4).
Scheme 2. Addition of Organometallics to Difluorocarbene
Table 1. Reaction of Benzylzinc Bromide
Analogous nonfluorinated homologation of organome-
tallics (i.e., insertion of CH2) has been described.15 In the
case of CF2 insertion, the presence of fluorine renders this
process challenging. Indeed, the stability of organometallic
species 1 is a key issue determining the success of this
approach. The stability of reagent 1 is believed to depend
on the nature of the metal. For lithium or magnesium, the
carbonÀmetal bond is strongly polarized, whereas the
metalÀfluorine bond is quite strong, thereby leading to facile
decomposition of 1.16 We surmised that zinc would present a
compromise necessary for noticeable lifetime of species 1.
no. silane 3 (equiv) NaOAc (equiv) solvent timea (h) yieldb (%)
1
1.33
1.33
1.33
1.2
1.33
1.33
1.33
1.2
DMF
6
6
71
2
MeCN
MeCN
MeCN
glyme
THF
58
3
18
18
18
18
18
18
79 (74c)
95 (85c)
82
4
5
1.2
1.2
6
1.2
1.2
78
7
8d
1.1
1.1
MeCN
MeCN
81 (76c)
53
(10) (a) Brahms, D. L. S.; Dailey, W. P. Chem. Rev. 1996, 96, 1585–
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2009, 131, 2128–2130.
1.1
1.1
a For the formation of 4a. b Determined by NMR spectroscopy of
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Y.; Hammond, G. B. Synthesis 2006, 803–806. (c) Everett, T. S.;
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49, 3819–3822.
(15) For a review, see: Marek, I. Tetrahedron 2002, 58, 9463–9475.
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crude material using PhCF3 as internal standard. c Isolated yield. d LiCl
(1 equiv) was added upon the preparation of 2a.
The formationofreagent 4awas supportedby19F NMR
data, which demonstrates the presence of two species due
tothe Schlenkequilibrium (À96.8andÀ95.4ppm ina ratio
of 5:1, respectively). The reagent 4a in acetonitrile solution
slowly decomposes at room temperature (ca. 75% of the
reagent decomposed after 2 h).22 However, addition of
2 equiv of dimethylformamide increases its stability (ca. 30%
of decomposition after 2 h at room temperature). Addition
(18) (a) Yudin, A. K.; Prakash, G. K. S.; Deffieux, D.; Bradley, M.;
Bau, R.; Olah, G. A. J. Am. Chem. Soc. 1997, 119, 1572–1581. (b)
Kosobokov, M. D.; Dilman, A. D.; Levin, V. V.; Struchkova, M. I.
J. Org. Chem. 2012, 77, 5850–5855.
(19) It has previously been reported that Me3SiCF2Br can generate
difluorocarbene even in the presence of chloride ion, though at elevated
temperatures, see ref 17i.
(20) Lithium chloride may affect the reactivity of organozinc species.
See: Metzger, A.;Schade, M. A.;Knochel, P. Org. Lett. 2008, 10, 1107–1110.
(21) The decrease in the yield upon isolation compared to NMR yield
is associated with the volatility of 5a.
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Org. Lett., Vol. 15, No. 4, 2013

Under the optimized conditions, a variety of organozinc
reagents 2 were reacted with silane 3 followed by iodina-
tion (Table 2). Benzylzinc halides worked well in this
process, furnishing products of difluoroiodomethylation
in good yields (entries 1À11). The reaction tolerates halogen,
cyano, ester, and boryl groups on the aromatic ring. Impor-
tantly, secondary benzylzinc reagents successfully provided
final products (entries 10 and 11). The yields with aliphatic
organozinc reagents were variable (entries 12À15). However,
no products were produced starting from arylzinc halides,
presumably, owing to the instability of fluorinated organozinc
reagents ArCF2ZnX under the reaction conditions.
Table 2. Difluoroiodomethylation of Organozinc Reagents
Scheme 3. Bromination and Protonation of Reagent 4h
Besides iodination, fluorinated organozinc reagents can
be brominated and protonated, thereby allowing forma-
tion of CF2Br and CHF2 groups, respectively (Scheme 3).
Thus, the interaction of reagent 4h with bromine pro-
ceeded rapidly, leading to product 6. To effect protona-
tion, addition of 2 equivofDMF alongwithaceticacidwas
found to be important to achieve a high yield of product 7.
It should be pointed out that overall transformation of 2h
to 7 corresponds to difluoromethylation of the starting
organozinc reagent.
In summary, we have proposed a new approach for
the synthesis of compounds containing the CF2 fragment.
The key point of the described methodology is the inser-
tion of difluorocarbene into a carbonÀzinc bond followed
by treatment of newly formed fluorinated organozinc
species with an external electrophile. Our further stud-
ies will be directed toward extending the scope of this
process by variation of organometallic and electro-
philic components.
a Isolated yield based on organozinc halide. b 1.4 equiv of Me3-
SiCF2Br and NaOAc was used. c Time for the CF2 insertion step was
21 h. d DMF (2 equiv) was added before the CF2 insertion step.
Acknowledgment. This paper is dedicated to Professor
Sema Ioffe on the occasion of his 75th birthday. This work
was supported by the Ministry of Science (Project MD)
and the Russian Academy of Sciences.
of 5 equiv of dimethylformamide allows even moderate
heating (ca. 25% of decomposition after 2 h at 40 °C).
Supporting Information Available. Experimental pro-
cedures, compound characterization data, and copies of
NMR spectra for all compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(22) It should be noted that iodination of reagent 4a was carried out
at room temperature. The success of iodination can be explained either
by formation of zinc salt upon iodination, which can influence the
Schlenk equilibrium of 4a, or by more significant deceleration of
decomposition relative to iodination upon decrease of concentration
of 4a. Furthermore, the iodination likely starts at À25 °C, and a longer
period at room temperature was applied to achieve complete conversion.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
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