Difluoromethyl 2-pyridyl sulfone: A new gem-difluoroolefination reagent for aldehydes and ketones

Article abstract of DOI:10.1021/ol100090r

Chemical equation presented Difluoromethyl 2-pyridyl sulfone, a previously unknown compound, was found to act as a novel and efficient gem-difluoroolefination reagent for both aldehydes and ketones. It was found that the fluorinated sulfinate intermediate in the reaction is relatively stable, which can be observed by ¹⁹F NMR and trapped with CH ₃l.

Full text of DOI:10.1021/ol100090r

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1444-1447
Difluoromethyl 2-Pyridyl Sulfone: A New
gem-Difluoroolefination Reagent for
Aldehydes and Ketones
Yanchuan Zhao, Weizhou Huang, Lingui Zhu, and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai 200032, China
jinbohu@sioc.ac.cn
Received January 14, 2010
ABSTRACT
Difluoromethyl 2-pyridyl sulfone, a previously unknown compound, was found to act as a novel and efficient gem-difluoroolefination reagent
for both aldehydes and ketones. It was found that the fluorinated sulfinate intermediate in the reaction is relatively stable, which can be
observed by 19F NMR and trapped with CH3I.
Incorporation of fluorine atom(s) or fluorinated moieties into
an organic molecule often results in profound changes of
physical, chemical, and biological properties of the target
molecule.1 For instance, unlike other nonfluorinated alkenes,
gem-difluoroalkene (gem-difluoroolefin) functionality is highly
electrophilic and the fluorine atom(s) can be replaced by
nucleophiles through an addition-elimination mechanism,2,3
which enables gem-difluoroalkenes to act as valuable inter-
mediates for the synthesis of other important molecules, such
as 2-fluorinated indoles,3a monofluoroalkenes,3b esters, and
carboxylic acids.3c Moreover, gem-difluorovinyl functionality
is known to act as a bioisostere for carbonyl group,4 and it
is critical to many biologically active molecules such as
mechanism-based enzyme inhibitors.1,5 Owing to their
important applications, various approaches have been de-
veloped for the preparation of gem-difluoroalkenes, among
which the gem-difluoroolefination reaction with aldehydes
or ketones is one of the most straightforward methods.1,2 In
(1) (a) Be´gue´, J-. P.; Bonnet-Delpon, D. Bioorganic and Medicinal
Chemistry of Fluorine; Wiley-VCH: Weinheim, 2008. (b) Kirsch, P. Modern
Fluoroorganic Chemistry: Synthesis, ReactiVity, Applications; Wiley-VCH:
Weinheim, 2004. (c) Organofluorine Compounds: Chemistry and Applica-
tions; Hiyama, T., Ed.; Springer: New York, 2000.
(3) (a) Ichikawa, J.; Wada, W.; Okauchi, T.; Minami, T. J. Chem. Soc.,
Chem Commun. 1997, 1537. (b) Hayashi, S.; Nakai, T.; Ichikawa, N.;
Burton, D. J.; Naae, D. G.; Kesling, H. S. Chem. Lett. 1979, 983. (c)
Hayashi, S.; Nakai, T.; Ichikawa, N. Chem. Lett. 1980, 651. (d) Yokota,
M.; Fujita, D.; Ichikawa, J. Org. Lett. 2007, 9, 4639. (e) Ichikawa, J.; Yokota,
M.; Kudo, T.; Umezaki, S. Angew. Chem., Int. Ed. 2008, 47, 4870.
(4) Motherwell, W. B.; Tozer, M. J.; Ross, B. C. J. Chem. Soc.,
Chem.Commun. 1989, 1437.
(2) (a) Uneyama, K. Organofluorine Chemistry; Blackwell: Oxford,
2006. (b) Welch, J. T.; Eswarakrishnan, S. Fluorine in Biological Chemistry;
Wiley: New York, 1991. (c) Organofluorine Chemistry: Fluorinated Alkenes
and ReactiVe Intermediates; Chambers, R. D., Ed.; Springer: New York,
1997. (d) Ichikawa, J. In Current Fluoroorganic Chemistry; Soloshonok,
V. A., Mikami, K., Yamazaki, T., Welch, J. T., Honek, J. F., Eds.; ACS
Symposium Series 949; American Chemical Society: Washington, DC,
2007. (e) Ichikawa, J. In Fluorine-Containing Synthons; Soloshonok, V. A.,
Ed.; ACS Symposium Series 911; American Chemical Society: Washington,
(5) (a) McDonald, I. A.; Lacoste, J. M.; Bey, P.; Palfreyman, M. G.;
Zreika, M. J. Med. Chem. 1985, 28, 186. (b) Altenburger, J. M.; Lassalle,
G. Y.; Matrougui, M.; Galtier, D.; Jetha, J. C.; Bocskei, Z.; Berry, C. N.;
Lunven, C.; Lorrain, J.; Herault, J. P.; Schaeffer, P.; O’Connor, S. E.;
Herbert, J. M. Biorg. Med. Chem. 2004, 12, 1713. (c) Weintraub, P. M.;
Holland, A. K.; Gates, C. A.; Moore, W. R.; Resvick, R. J.; Bey, P.; Peet,
DC, 2005
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N. P. Biorg. Med. Chem. 2003, 11, 427.
10.1021/ol100090r  2010 American Chemical Society
Published on Web 03/08/2010

Wittig-type reactions developed by Silverstein and Burton,
difluoromethylene ylide generated from the reaction of PPh3
and CF2ClCOONa or CF2Br2 successfully difluoromethyl-
With these considerations in mind, we attempted the
reaction between 312 and anisaldehyde (7a) using t-BuOK
as a base (Scheme 2). Therefore, into an equimolar mixture
enates aldehydes and activated ketones.6 For unactivated
7a-c
ketones, reagents such as HMPT/CF2Br2
or (CF3)2Hg/
NaI/PPh37d are needed. Horner-Wadsworth-Emmons-type
and Horner-Wittig-type gem-difluoroolefination reactions
provide more general routes suitable for both aldehydes and
ketones.8 Alternatively, in classical Julia reaction, difluo-
romethyl phenyl sulfone is empolyed to achieve a three-step
synthesis of gem-difluoroalkenes via a reduction-desulfonation
protocol.9 In these gem-difluoroolefination reactions, how-
ever, low-boiling or toxic reagents, strictly anhydrous reac-
tion conditions, and/or mutistep procedures are often needed.
Herein, we report a concise and efficient method for gem-
difluoroolefination of both aldehydes and ketones via a
Julia-Kocienski protocol.
Scheme 2
.
Difluoromethylenation of Anisaldehyde with
2-PySO2CF2H (3)
of sulfone 3 and aldehyde 7a in DMF at -50 °C was slowly
added a DMF solution of t-BuOK (2 equiv). The reaction
mixture was subsequently warmed to -40 °C over a period
of 15 min and then quenched with 3 N HCl. After routine
workup and purification, we were able to isolate 1-(2,2-
difluorovinyl)-4-methoxybenzene (8a) in 76% yield (Scheme
2). It became apparent that a Julia-Kocienski-type olefina-
tion13 occurred under the present reaction conditions. After
a quick optimization of the reactant ratio (3/7a/t-BuOK )
1.0:1.2:1.8), the product yield of 8a was increased to 86%
(Table 1, entry 1). It should be noted that, to the best of our
knowledge, this is the first example of Julia-Kocienski-type
one-step gem-difluoroolefination reaction.
Previously, we were interested in investigating the
unique synthetic applications of fluorinated sulfones10 and
sulfoximines.11
Difluoromethyl
phenyl
sulfone
(PhSO2CF2H, 1) was found to be a robust nucleophilic
difluoromethylation reagent (via its deprotonated form
PhSO2CF2-), thanks to the excellent modulating ability
of the phenylsulfonyl group on both the stability and
nucleophilicity of the PhSO2CF2- anion species (Scheme
1).10 Recently, we found that when one oxygen atom in
Scheme 1
.
Difluoromethyl Sulfones and Sulfoximines (Ts )
p-Toluenesulfonyl Group)
With the optimized reaction condition (reactant molar ratio
3/7/t-BuOK ) 1.0:1.2:1.8), we examined the generality and
substrate scope of this new gem-difluoroolefination reaction
between 3 and carbonyl compounds 7. As shown in Table
1, various aldehydes and ketones were treated with 3,
smoothly giving the corresponding gem-difluoroalkenes in
good to excellent yields. This method tolerates various
substituents on carbonyl compounds (entries 1-6, 9, 10, and
14-16), which is superior to Wittig-type gem-difluoroole-
fination reactions.6,7 It was found that aldehydes with
electron-donating groups gave slightly higher yield than those
with electron-withdrawing groups (entries 1-6). For the
enolizable aldehyde 7h (entry 8), lower yield was observed
even when LiHMDS was used as a base to suppress the
undesired aldol reaction. The reaction was also amenable to
both aliphatic and aromatic ketones, leading to the formation
of structurally diverse gem-difluoroalkenes 8k-p (entries
11-16). It was reported that difluoroalkenes 8i and 8o were
previously prepared from 7i and 7o in low yields (e41%)
by using toxic (CF3)2Hg reagent,7d but in our cases with
reagent 3, products 8i and 8o were obtained in 62% and 80%
yield, respectively (entries 9 and 15). Furthermore, our
method gave product 8p, an intermediate for the synthesis
of thrombin inhibitor SSR182289A, in 84% yield, which is
also superior to the previously reported results (with 61%
yield through a Wittig-type reaction using excess CF2Br2 and
HMPT).5b It should be noted that reagent 3 is a stable and
crystalline solid12 and the organic byproduct of the reaction
is pyridin-2-ol (water-soluble), both factors making the
current difluoroolefination reaction easy to handle.
compound 1 was replaced by the NTs group (Ts )
p-toluenesulfonyl), the chemical reactivity of the resulting
compound N-tolyl-S-difluoromethyl-S-phenylsulfoximine
2 is significantly different from 1. While compound 1 is
a nucleophilic difluoromethylation agent, compound 2
behaves as an “electrophilic” difluoromethylation reagent
through a difluorocarbene mechanism.11a Intrigued by
these results, we envisioned that as another analogous
compound of 1, difluoromethyl 2-pyridyl sulfone (2-
PySO2CF2H, 312) may possess other interesting reactivities
that are different from those of 1 and 2. Furthermore, it
would also be interesting to compare the reactivity of 3
with those of other difluoromethyl heteroaryl sulfones such
as 1,3-benzothiazol-2-yl difluoromethyl sulfone (4), 1-phen-
yl-1H-tetrazol-5-yl difluoromethyl sulfone (5), and 1-tert-
butyl-1H-tetrazol-5-yl difluoromethyl sulfone (6).
(6) (a) Fuqua, S. A.; Duncan, W. G.; Silverstein, R. M. Tetrahedron
Lett. 1964, 1461. (b) Herkes, F. E.; Burton, D. J. J. Org. Chem. 1967, 32,
1311. (c) Naae, D. G.; Burton, D. J. J. Fluorine Chem 1971, 1, 123. (d)
Burton, D. J.; Wheaton, G. A. J. Org. Chem. 1983, 48, 917.
Org. Lett., Vol. 12, No. 7, 2010
1445

Table 1. gem-Difluoroolefination of Carbonyl Compouds with
Reagent 3
Scheme 3. Synthesis of 10
Considering that in nonfluorinated Julia-Kocienski ole-
fination reactions, 2-pyridyl sulfones generally give lower
yield of olefins than other heteroaryl sulfones such as 1,3-
benzothiazol-2-yl (BT), 1-phenyl-1H-tetrazol-5-yl (PT), and
1-tert-butyl-1H-tetrazol-5-yl (TBT) sulfones,13 we prepared
other three difluoromethyl heteroaryl sulfones 4-612 and
investigated their reactivities in difluoroolefination reactions.
As shown in Table 2, we were surprised to find that under
Table 2. gem-Difluoroolefination with Different Sulfones
a Isolated yield. b Determined by 19F NMR spectroscopy.
a For all cases, the molar ratio of reactants was 3/7/t-BuOK ) 1.0:1.2:1.8.
b Isolated yield. c LiHMDS was used as a base. d Low yield is partially due
to the high volatility of the product. e THF was added as a cosolvent due
to the poor solubility of these substrates in DMF at low temperature.
similar reaction conditions (as those for Table 1), sulfones
4-6 showed lower reactivity in the difluoroolefination
reaction with 2-naphthaldehyde 7g. The reaction with
BTSO2CF2H (4) gave product 8g in 42% yield, while both
PTSO2CF2H (5) and TBTSO2CF2H (6) did not show
significant reactivity with aldehyde 7g. However, the reaction
with reagent 3 provided alkene 8g in 92% isolated yield.
The sharp contrast between the reactivities of nonfluorinated
heteroaryl sulfones13 and difluoromethyl sulfones 3-6 in
Julia-Kocienski olefination was striking and never re-
ported.14 We speculate that the high reactivity of sulfone 3
(compared with other sulfones 4-6) may be due to the fact
To further demonstrate the synthetic potency of our
method with reagent 3, we applied it in the synthesis of
21,21-difluoro-3-hydroxy-20-methylpregna-5,20-diene (10),
a potential inhibitor of steroid C17(20)-lyase.5c Compound 10
was previously prepared from pregnenolone acetate using
(difluoromethyl)diphenylphospine oxide in low yield
(20%).5c We found that by using 3/LiHMDS/THF/HMPA
system, 10 could be produced in 57% yield directly from
unprotected pregnenolone 9 (with recycling of 30% unreacted
9) (Scheme 3).
-
that 2-PySO2CF2 anion possesses the best nucleophilicity
1446
Org. Lett., Vol. 12, No. 7, 2010

(among four HetSO2CF2- anions; Het ) 2-Py, BT, PT, and
TBT) toward carbonyl compounds.15
The reaction mechanism of the current difluoroolefina-
tionwith 3 is proposed in Scheme 4, following the generally
enhanced, and the sulfinate salt 14 readily decomposes to
the desired gem-difluoroalkene product 8, sulfur dioxide, and
2-pyridone 15a (or pyridin-2-ol 15b). This mechanism is
supported by our experimental observations: (a) species 13
2
was observed by 19F NMR [-127.9 ppm (dd, JF-F ) 230
Hz, 3JF-H ) 12 Hz), 1F; -129.0 ppm (dd, 2JF-F ) 230 Hz,
3JF-H ) 15 Hz), 1F; relative to CFCl3], (b) when we
quenched the reaction mixture (from 3 and aldehyde 7a) with
CH3I, methylated compound 16 was isolated in 83% yield
via difluorinated sulfinate intermediate 13a (Scheme 5).
Scheme 4. Proposed Reaction Mechanism
Scheme 5. Trapping the Sulfinate Salt with Iodomethane
accepted mechanism of the Julia-Kocienski reaction.13 First,
sulfone 3 and carbonyl compound 7 condense under basic
condition to afford the adduct 11, which rearranges to a
relatively stable sulfinate salt 13. When protonated at
pyridine, the leaving ability of the 2-pyridyloxyl group is
In conclusion, difluoromethyl 2-pyridyl sulfone 3, a
previously unknown compound that can be readily prepared
from 2-mercaptopyridine,12 was found to be a novel and
efficient gem-difluoroolefination reagent for preparing gem-
difluoroalkenes from both aldehydes and ketones. Our
experimental data suggest that the intermediate sulfinate salt
is relatively stable under basic conditions and decomposes
after protonolysis. The remarkable feature of the present new
difluoroolefination method is its practical simplicity and
broad scope of applicability, which promises it to find many
applications in organic synthesis. The unusual reactivity
difference of sulfones 3-6 (as shown in Table 2) provides
some insights into both fluorinated sulfone chemistry and
Julia-Kocienski reaction. Further exploration of this chem-
istry is currently underway in our laboratory.
(7) (a) Naae, D. G.; Burton, D. J. Synth. Commun. 1973, 3, 197. (b)
Serafinowski, P. J.; Barnes, C. L. Tetrahedron 1996, 52, 7929. (c)
Serafinowski, P. J.; Brown, C. A. Tetrahedron 2000, 56, 333. (d) Nowak,
I.; Robins, J. M. Org. Lett. 2005, 7, 721.
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1982, 23, 2323. (b) Edwards, M. L.; Stemerick, D. M.; Jarvi, E. T.;
Matthews, D. P.; McCarthy, J. R. Tetrahedron Lett. 1990, 31, 5571. (c)
Piettre, S. R.; Cabanas, L. Tetrahedron Lett. 1996, 37, 5881.
(9) (a) Sabol, J. S.; McCarthy, J. R. Tetrahedron Lett. 1992, 33, 3101.
(b) Prakash, G. K. S.; Wang, Y.; Hu, J. B.; Olah, G. A. J. Fluorine Chem.
2006, 127, 1361.
(10) (a) Hu, J. J. Fluorine Chem. 2009, 130, 1130. (b) Prakash, G. K. S.;
Hu, J. Acc. Chem. Res. 2007, 40, 921. (c) Hu, J.; Zhang, W.; Wang, F.
Chem. Commun. 2009, 7465.
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(12) Similar to PhSO2CF2H, difluoromethyl sulfone compounds 3-6
can be readily prepared by difluoromethylation of the corresponding thiols,
followed by simple oxidation (see the Supporting Information). Compounds
3, 5, and 6 were previously unkown, and the chemical reactivities of
compounds 3-6 have never been reported.
(13) See reviews of Julia-Kocienski olefination: (a) Aissa, C. Eur. J.
Org. Chem. 2009, 1831. (b) Blakemore, P. R. J. Chem. Soc., Perkin Trans.
1 2002, 2565.
Acknowledgment. This work was supported by the
National Natural Science Foundation of China (20502029,
20772144, 20825209, 20832008) and the Chinese Academy
of Sciences (Hundreds-Talent Program and Knowledge
Innovation Program) for financial support.
(14) The R-monofluoro sulfones (such as BT- and TBT-based sulfones)
have been successfully used in Julia-Kocienski olefination, and the
efficiency of the monofluoroolefination was similar to non-fluorinated
systems. See selected examples: (a) Ghosh, A. K.; Zajc, B. J. Org. Chem.
2009, 74, 8531. (b) Ghosh, A. K.; Zajc, B. Org. Lett. 2006, 8, 1553. (c)
Pfund, E.; Lebargy, C.; Rouden, J.; Lequeux, T. J. Org. Chem. 2009, 72,
7871. (d) Alonso, D. A.; Fuensanta, M.; Gomez-Bengoa, E.; Najera, C.
AdV. Synth. Catal. 2008, 350, 1823.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(15) For discussion on the stability and nucleophilicity of fluorinated
carbanions, see: (a) Ni, C.; Zhang, L.; Hu, J. J. Org. Chem. 2008, 73,
5699. (b) Ni, C.; Li, Y.; Hu, J. J. Org. Chem. 2006, 71, 6829. (c)
Reference 10a,b.
OL100090R
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