Difluorophenylsulfanylmethyl radical and difluoromethylene diradical synthons: gem-difluoromethylene building block

Article abstract of DOI:10.1021/jo0489768

Bromodifluorophenylsulfanylmethane has been demonstrated to be a highly versatile gem-difluoromethylene (CF₂) building block via the reaction of difluorophenylsulfanylmethyl radical with olefins. gem-Difluoroalkenes and products containing a mi

Full text of DOI:10.1021/jo0489768

potent antitumor agents,5 broad spectrum antibiotics,6
inhibitors of HIV-1 reverse transcriptase,7 and potent
inhibitors of various proteolytic enzymes.8 Limited ex-
amples have been reported on the introduction of the
gem-difluoromethylene moiety.3 Radical,9 carbene,10 and
ionic11 reactions involving gem-difluorinated carbon spe-
cies have been utilized. New and convenient methods for
the synthesis of gem-difluoromethylene compounds, in-
volving readily available sources of gem-difluorinated
compounds, are still highly desirable.
As part of our ongoing effort in the synthesis of new
fluorinated compounds with potential biological and
synthetic applications, we wish to report the novel use
of bromodifluorophenylsulfanylmethane 1 as a CF2 “build-
ing block” via the carbon-carbon bond formation between
the previously unknown difluorophenysulfanylmethyl
radical 2 and olefins.3 It is anticipated that the presence
of the phenylsulfanyl group will exert a stabilizing effect
on the radical and will provide a functional group in the
adducts for further chemical manipulation.
Diflu or op h en ylsu lfa n ylm eth yl Ra d ica l a n d
Diflu or om eth ylen e Dir a d ica l Syn th on s:
gem -Diflu or om eth ylen e Bu ild in g Block
Vichai Reutrakul,* Thanchanok Thongpaisanwong,
Patoomratana Tuchinda, Chutima Kuhakarn, and
Manat Pohmakotr*
Department of Chemistry, Faculty of Science,
Mahidol University, Rama 6 Road,
Bangkok 10400, Thailand
scvrt@mahidol.ac.th; scmpk@mahidol.ac.th
Received J une 17, 2004
Abstr a ct: Bromodifluorophenylsulfanylmethane has been
demonstrated to be a highly versatile gem-difluoromethylene
(CF2) building block via the reaction of difluorophenylsul-
fanylmethyl radical with olefins. gem-Difluoroalkenes and
products containing a midchain CF2 group and with ma-
nipulatable functionality can be readily synthesized. The
first example of a gem-difluoromethylene radical synthon is
also reported.
Compound 1 was readily synthesized by the reaction
of sodium phenylthiolate with dibromodifluoromethane.12
After considerable experimentation on various reagents
for the generation13 of the radical 2, it was found that
the three procedures are complementary to each other;
The ability of the fluorine atom to enhance biological
and therapeutic activity has led to widespread interest
in the selective introduction of either one or two fluorine
atoms into organic molecules. Organofluorine chemistry
is receiving remarkable interest due to the enormous
utility of organofluorine compounds in several fields such
as medicinal, biological, agricultural, and analytical
chemistry.1 The replacement of hydrogen atoms by
fluorine atoms in biological molecules causes a relatively
small steric perturbation but leads to major changes in
lipophilicity and polarity factors.2 Of particular interest
is the introduction of a gem-difluoromethylene moiety
into organic molecules.3 It has been reported that the CF2
group has a steric profile similar to that of the CH2 group,
but since it has both a very different polarity and
reactivity, it can be regarded as an isopolar and isosteric
replacement for oxygen.1g,4 Certain molecules incorporat-
ing a difluoromethylene unit have been shown to act as
(5) (a) Yamazaki, T.; Haga, J .; Kitasume, T. Bioorg. Med. Chem.
Lett. 1991, 1, 271-276. (b) Fernandez, R.; Castillon, S. Tetrahedron
1999, 55, 8497-8508 and references cited.
(6) Bravo, P.; Crucianelli, M.; Ono, T.; Zanda, M. J . Fluorine Chem.
1999, 97, 27-49 and references cited.
(7) Burkholder, C. R.; Dolbier, W. R., J r.; Medebielle, M. J . Fluorine
Chem. 2000, 102, 369-376.
(8) Balnaves, A. S.; Gelbrich, T.; Hursthouse, M. B.; Light, M. E.;
Palmer, M. J .; Percy, J . M. J . Chem. Soc., Perkin Trans. 1 1999, 2525-
2535 and references cited.
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Buttle, L. A.; Motherwell, W. B. Tetrahedron Lett. 1994, 35, 3995-
3998 and references cited therein. (c) Uneyama, K.; Yanagiguchi, T.;
Asai, H. Tetrahedron Lett. 1997, 38, 7763-7764. (d) Amii, H.; Kondo,
S.; Uneyama, K. Chem. Commun. 1998, 1845-1846. (e) Nguyen, B.
V.; Yang, Z. Y.; Burton, D. J . J . Org. Chem. 1998, 63, 2887-2891. (f)
Itoh, T.; Sakabe, K.; Kudo, K.; Ohara, H.; Takagi, Y.; Kihara, H.;
Zagatti, P.; Renou, M. J . Org. Chem. 1999, 64, 252-265 and references
cited therein. (g) Osipov, S. N.; Burger, K. Tetrahedron Lett. 2000, 41,
5659-5662. (h) Peng, S.; Qing, F. L. J . Fluorine Chem. 2000, 103, 135-
137. (i) Hapiot, P.; Medebielle, M. J . Fluorine Chem. 2001, 107, 285-
300 and references cited therein. (j) Wang, Y.; Zhu, S. Synthesis 2002,
1813-1818. (k) Peng, W.; Zhu, S. Tetrahedron 2003, 59, 4395-4404.
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Fujita, M. Tetrahedron 2004, 60, 4031-4035.
* Corresponding authors. Phone: +66-2-201-5142. Fax: +66-2-644-
5126.
(10) (a) Brahms, D. L. S.; Dailey, W. P. Chem. Rev. 1996, 96, 1585-
1632. (b) Xu, W.; Chen, Q. Y. Org. Biomol. Chem. 2003, 1, 1151-1156
and references cited.
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Biochemical Targets; J ohn Wiley & Sons Ltd.: Chichester and New
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Bioorganic Chemistry; American Chemical Society: Washington, DC,
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10.1021/jo0489768 CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/26/2004
J . Org. Chem. 2004, 69, 6913-6915
6913

TABLE 1. Resu lts of Tr a p p in g th e Ra d ica l 2 w ith Olefin s
olefins 3
% yield of 4, 5 or 6
entry
R1
R2
method Aa
method Ba
method Ca
46
50
37
1
2
3
4
5
6
7
8
Ph
CN
H
4a
4b
4c
4d
4e
4e
6
6
6
4f
4g
53
59
47
34
62
57b
71b
64b
72b
8
46
53
39
49
Me
Me
CO2CH2CHdCH2
SO2Ph
CH2SnBu3
CH2SnBu3
CH2SO2Ph
CH2SOPh
CH2SnBu3
3,4-(MeO)2C6H3CH2
(CH2)9OH
H
12
CO2Me
CO2Me
47 and 12 of 5
12 and 12 of 5
40bof 5
70b
60b
70b
12
32bof 5
67b
56b
61b
12
H
H
H
H
H
9
10
11
8
10
8
a
Methods: (A) 1.5 equiv of SmI2/THF/i-PrOH, 0 °C 20 min and then rt, 2 h; (B) 1.0 equiv of AIBN/2.0 equiv of n-Bu3SnH/benzene/
b
reflux, 10 h; C 1.2 equiv of Et3B/1.5 equiv of n-Bu3SnH/O2/CH2Cl2, rt, overnight. Without i-PrOH (method A) and without n-Bu3SnH
(methods B and C) (see text).
SCHEME 1
SCHEME 3
SCHEME 2
7a , which prevents the elimination of the tri-n-butyltin
radical. In entry 6, when methods B and C were employed
without n-Bu3SnH, only product 5 was isolated in moder-
ate yield in both cases (40 and 32%, respectively),
indicating fast elimination of tri-n-butyltin radical in the
absence of chelation. In the reactions in entries 7-9,
compound 6 was isolated in high yield in the absence of
hydrogen radical sources. Under the same reaction
conditions but with hydrogen radical sources, compound
6 was still the only product isolated but in a much lower
yield (31-38%). These results suggested that the elimi-
nation process of radical 7b was fast compared with its
ability to undergo hydrogen radical abstraction.
Nonactivated olefins, entries 10 and 11, gave low yields
of the products 4f and 4g. These results suggest the
nucleophilic character of the radical 2.9b
The synthetic utility of the reactions described in
Scheme 1 for the synthesis of gem-difluoromethylene
compounds is further demonstrated by the transforma-
tions of selected adducts 4 to gem-difluoroalkenes and
more complex gem-difluoromethylene compounds 13
(Scheme 3).
i.e., method A (SmI2/THF), method B (n-Bu3SnH/AIBN/
benzene), and method C (Et3B/n-Bu3SnH/O2) gave mod-
erate to high yields of the adducts 4 depending on the
olefinic substrates 3 (Scheme 1). The results are sum-
marized in Table 1.
Electrophilic olefins, entries 1-6, gave moderate to
good yields of adducts 4a -e. In entry 5, product 4e
together with a small yield (12%) of compound 5, arising
from the elimination of tri-n-butyltin radical (Scheme 2),
was isolated when methods B and C were employed.
These results can be explained by the competitive rate
of tri-n-butyltin radical elimination versus the hydrogen
radical abstraction from n-Bu3SnH of the stabilized
radical 7a . The formation of product 4e only, in entries
5 and 6 when method A with or without the hydrogen
radical source was employed, can be explained by the
chelation of Sm(III) ion (7c) with the stabilized radical
The sulfoxides 8a -e could be prepared in high yields
(75 to 92%) by oxidation of 4a ,c,d ,f,g, respectively, with
1.1 equiv of m-CPBA. Vacuum pyrolysis gave the corre-
sponding gem-difluoroalkenes14 9a -e in high yields (68-
81%) (Table 2). The reaction of the sulfone 10, readily
prepared by oxidation of 4a with 2.1 equiv of m-CPBA
in 83% yield, with 5.0 equiv of SmI2/THF/HMPA followed
(13) (a) Zard, S. Z. Radical Reactions in Organic Synthesis; Oxford
University Press: Oxford, 2003. (b) Renaud, P.; Gerster, M. Angew.
Chem., Int. Ed. 1998, 37, 2562-2579. (c) Bar, G.; Parsons, A. F. Chem.
Soc. Rev. 2003, 32, 251-263. (d) Kagan, H. B. Tetrahedron 2003, 59,
10351-10372. (e) Sibi, M. P.; Aasmul, M.; Hasegawa, H.; Subramanian,
T. Org. Lett. 2003, 5, 2883-2886 and references cited therein.
(14) For a leading reference on gem-difluoroolefin synthesis, see:
Ichikawa, J . J . Fluorine Chem. 2000, 105, 257-263.
6914 J . Org. Chem., Vol. 69, No. 20, 2004

TABLE 2. Syn th esis of gem -Diflu or oa lk en es 9
difluorophenylsulfanylmethyl radical 2 and as the syn-
thetic equivalent of a gem-difluoromethylene diradical 14
synthon.
adduct 4
sulfoxide 8, %
gem-difluoroalkene 9, %
4a
4c
4d
4f
8a , 92
8b, 79
8c, 77
8d , 75
8e, 81
9a , 81
9b, 71
9c, 68
9d , 80
9e, 62
4g
by the trapping of the radical 11 with olefins 12 gave
the gem-difluoroalkanes 13a -d in moderate to good
yields. These reactions provide a novel method for the
synthesis of products containing a midchain CF2 moiety
and with a functional group for further chemical ma-
nipulation.15
In conclusion, our preliminary results clearly demon-
strate, for the first time, the synthetic potential of
bromodifluorophenylsulfanylmethane 1 as a gem-difluoro
methylene (CF2) building block through the reaction of
Ack n ow led gm en t. We thank the Higher Education
Development Project: Postgraduate Education and
Research Program in Chemistry (PERCH) for financial
support. The awards of the Royal Golden J ubilee Ph.D.
Scholarship to T.T. and a Senior Research Scholar to
V.R. by the Thailand Research Fund are also gratefully
acknowledged.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal details and 1H/13CNMR spectral data for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) (a) Patel, S. T.; Percy, J . M.; Wilkes, R. D. J . org. Chem. 1996,
61, 166-173. (b) Itoh, T.; Kudo, K.; Tanaka, N.; Sakabe, K.; Takagi,
Y.; Kihara, H. Tetrahedron Lett. 2000, 41, 4591-4595.
J O0489768
J . Org. Chem, Vol. 69, No. 20, 2004 6915