N-tosyl-S-difluoromethyl-S-phenylsulfoximine: A new difluoromethylation reagent for S-, N-, and C-nucleophiles

Article abstract of DOI:10.1021/ol900567c

The first α-difluoromethyl sulfoximine compound, 2, was successfully prepared by using the copper(ll)-catalyzed nitrene transfer reaction. Compound 2 was found to be a novel and efficient difluoromethylation reagent for transferring the CF₂H gr

Full text of DOI:10.1021/ol900567c

ORGANIC
LETTERS
2009
Vol. 11, No. 10
2109-2112
N-Tosyl-S-difluoromethyl-S-phenylsulfoximine:
A New Difluoromethylation Reagent for
S-, N-, and C-Nucleophiles
Wei Zhang, Fei Wang, 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@mail.sioc.ac.cn
Received March 18, 2009
ABSTRACT
The first r-difluoromethyl sulfoximine compound, 2, was successfully prepared by using the copper(II)-catalyzed nitrene transfer reaction.
Compound 2 was found to be a novel and efficient difluoromethylation reagent for transferring the CF2H group to S-, N-, and C-nucleophiles.
Deuterium-labeling experiments suggest that a difluorocarbene mechanism is involved in the current difluoromethylation reactions.
Selective incorporation of fluorine atom(s) or fluoroalkyl
group(s) (such as CF3, CF2H, and CH2F) into organic
molecules has become a trend in the life-sciences-related
applications.1 Many studies showed that the fluorine atom(s)
or fluoroalkyl group(s) can bring about many beneficial
effects in a biologically active molecule, such as the
enhancement of metabolic stability, lipophilicity, and bio-
availability or an increase of binding affinity, as well as an
improvement of membrane permeability through changing
the basicity of the drug molecule.2 Among the fluoroalkyl
groups, the difluoromethyl (CF2H) group is of particular
interest, given the fact that the CF2H moiety is known to be
isosteric and isopolar to a carbinol (CH2OH) unit and also,
as a lipophilic group, can act as a hydrogen donor through
hydrogen bonding.3 Despite the increasing importance of the
CF2H group in medicinal chemistry and drug discovery, and
in contrast to trifluoromethylations, mild and efficient dif-
luoromethylation methods are relatively sparse.4-6 Compared
with both nucleophilic and free radical difluoromethyla-
tions,4,5 electrophilic difluoromethylation is more challenging
regarding the efficiency and generality.6 Both S-(difluorom-
ethyl)diarylsulfonium salt6a and a hypervalent idodine(III)-
(3) (a) Li, Y.; Hu, J. Angew. Chem., Int. Ed. 2006, 44, 5882. (b) Prakash,
G. K. S.; Weber, C.; Chacko, S.; Olah, G. A. Org. Lett. 2007, 9, 1863. (c)
Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60, 1626.
(4) For selected examples of nucleophilic difluoromethylation methods,
see: (a) Beier, P.; Alexandrova, A. V.; Zibinsky, M.; Prakash, G. K. S.
Tetrahedron 2008, 64, 10977. (b) Ni, C.; Liu, J.; Zhang, L.; Hu, J. Angew.
Chem., Int. Ed. 2007, 46, 786. (c) Li, Y.; Hu, J. Angew. Chem., Int. Ed.
2007, 46, 2489. (d) Ni, C.; Hu, J. Tetrahedron Lett. 2005, 46, 8273. (e)
Prakash, G. K. S.; Wang, Y.; Olah, G. A. J. Fluorine Chem. 2005, 126,
1361. (f) Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. Org. Lett. 2004,
6, 4315. (g) Yudin, A. K.; Prakash, G. K. S.; Deffieux, D.; Bradley, M.;
Bau, R.; Olah, G. A. J. Am. Chem. Soc. 1997, 119, 1572. (h) Hagiwara, T.;
(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.
Fuchikami, T. Synlett 1995, 717
.
(2) (a) Mu¨ller, K.; Faeh, C.; Diederich, F. Science 317, 1881. (b)
Hagmann, W. K. J. Med. Chem. 2008, 51, 4359. (c) Bo¨hm, H.-J.; Banner,
D.; Bendels, S.; Kansy, M.; Kuhn, B.; Mu¨ller, K.; Obst-Sander, U.; Stahl,
M. ChemBioChem 2004, 5, 637. (d) Kirk, K. L. Org. Process Res. DeV.
2008, 12, 305. (e) Prakash, G. K. S.; Chacko, S. Curr. Opin. Drug DiscoVery
DeV. 2008, 11, 793.
(5) For selected examples of radical difluoromethylation methods, see:
(a) Cao, P.; Duan, J.-X.; Chen, Q.-Y. J. Chem. Soc., Chem. Commun. 1994,
737. (b) Li, Y.; Liu, J.; Zhang, L.; Zhu, L.; Hu, J. J. Org. Chem. 2007, 72,
5824. (c) Li, Y.; Li, H.; Hu, J. Tetrahedron 2009, 65, 478. (d) Reutrakul,
V.; Thongpaisanwong, T.; Tuchinda, P.; Kuhakarn, C.; Pohmakotr, M. J.
Org. Chem. 2004, 69, 6913
.
10.1021/ol900567c CCC: $40.75
Published on Web 04/15/2009
 2009 American Chemical Society

CF2SO2Ph compound6b have been reported as direct CF2H+-
and PhSO2CF2 -transferring reagents, but the scope of their
N-tosyl-S-difluoromethyl-S-phenylsulfoximine (2) (Scheme
1). Sulfoximines have been widely used in organic synthesis,
but the fluorinated sulfoximines still remain a relatively
poorly studied class of compounds.11 Recently, fluorinated
Johnson reagent was developed by Shibata and co-wor-
kers for the electrophilic trifluoromethylation of carbon
nucleophiles.12a To the best of our knowledge, however,
although both S-trifluoromethyl and S-monofluoromethyl
sulfoximes have been known,12 the S-difluoromethyl sul-
foximines (such as 2) have never been reported. Herein, we
disclose the preparation of N-tosyl-S-difluoromethyl-S-phe-
nylsulfoximine (2) and the use of 2 as a novel “CF2H+”
equivalent in difluoromethylation of S-, N-, and C-nucleo-
philes.
Our initial preparation of S-difluoromethyl sulfoximine by
oxidative iminination12b,d of difluoromethyl phenyl sulfoxide
(3) using hydrazoic acid (generated in situ from NaN3 and
concentrated sulfuric acid or oleum) was not successful. After
a careful survey of different methods, we synthesized the
first S-difluoromethyl sulfoximine compound 2 in 60% yield
by the treatment of 3 with 1.3 equiv of PhIdNTs (4) in the
presence of 10 mol % of copper(II) triflate (Scheme 2).
+
applicability was shown to be limited. There are more reports
on the difluorocarbene-based difluoromethylations using
reagents such as CHClF2, CF2Br2, FSO2CF2COOH, difluo-
rodiazirine, chlorodifluoromethyl ketones and sulfones, among
others.6c-g However, the fact that a large excess of a
difluorocarbene precursor is generally required in the reac-
tions makes it highly desirable to develop more efficient
difluoromethylation methods.
Previously, we were extensively involved in nucleophilic
fluoroalkylations using a series of fluorinated organosulfur
reagents.7 In particular, difluoromethyl phenyl sulfone
(PhSO2CF2H, 1) was found to be a versatile 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).3a,4b,7 PhSO2CF2H
Scheme 1
.
Synthetic Applications of Difluoromethylated
Sulfone 1 and Sulfoximine 2
Scheme 2. Preparation of Sulfoximine 2 from Sulfoxide 3
Compound 2 is a colorless crystalline solid, and its X-ray
single crystal structure was characterized by us (see Sup-
porting Information).
With compound 2 in hand, we were able to explore its
reactivity with a series of nucelophiles in detail. Arylthiolates
(ArSNa), derived from a facile deprotonation of arylthiols 5
with NaH, were found to readily react with 1.2 equiv of 2 at
60 °C. As shown in Table 1, the difluoromethylation of
thiophenol (5a) gave difluoromethy phenyl sulfide 6a in
excellent yield (94%, entry 1), while other arylthiols 5b-f
were difluoromethylated by reagent 2 in satisfactory yields
(61-78%, entries 2-6). Even the aliphatic thiol 5g was also
successfully difluoromethylated (entry 7). Interestingly, both
S- and N-difluoromethylated products 6ha and 6hb were
obtained in the reaction with benzo[d]thiazole-2-thiol (5h)
(entry 8). Furthermore, heteroarylthiol 5i was also difluo-
romethylated in 57% yield (entry 9). It is noteworthy that,
has been successfully used in the organic synthesis as a
difluoromethyl anion equivalent (CF2H-),3a,4b,f,7 a selec-
8
-
tive difluoromethylene dianion equivalent (-CF2 ), and
a difluoromethylidene equivalent (dCF2).9 Furthermore,
PhSO2CF2H can also be indirectly used in free radical
difluoromethylation through
a simple conversion to
PhSO2CF2I (a CF2H• equivalent).5b,c Despite these “chemical
chameleon” behaviors of PhSO2CF2H reagent (Scheme 1),
the use of PhSO2CF2H in efficient electrophilic difluorom-
ethylation (as a CF2H+ equivalent) remains a challenging
task.10 We envisioned that this problem may be solved by
using a potentially chiral analogue of PhSO2CF2H, that is,
(6) For selected examples of electrophilic difluoromethylation methods,
see: (a) Prakash, G. K. S.; Weber, C.; Chacko, S.; Olah, G. A. Org. Lett.
2007, 9, 1863. (b) Zhang, W.; Zhu, J.; Hu, J. Tetrahedron Lett. 2008, 49,
5006. (c) Zheng, J.; Li, Y.; Zhang, L.; Hu, J.; Meuzelaar, G. J.; Federsel,
H.-J. Chem. Commun. 2007, 5149. (d) Zhang, L.; Zheng, J.; Hu, J. J. Org.
Chem. 2006, 71, 9845. (e) Langlois, B. R. J. Fluorine Chem. 1988, 41,
247. (f) Chen, Q.-Y.; Wu, S.-W. J. Org. Chem. 1989, 54, 3023. (g) Iseki,
K.; Asada, D.; Takahashi, M.; Nagai, T.; Kobayashi, T. Tetrahedron
Asymmetry 1996, 7, 1205.
(10) Previously, PhSO2CF2H has been recognized as a poor electrophilic
difluoromethylation agent (via difluorocarbene mechanism), see: (a) Hine,
J.; Porter, J. J. J. Am. Chem. Soc. 1960, 82, 6178. (b) See ref 6c.
(11) See reviews: (a) Reggelin, M.; Zur, C. Synthesis 2000, 1. (b)
Okamura, H.; Bolm, C. Chem. Lett. 2004, 33, 482. (c) Harmata, M.
Chemtracts-Org. Chem. 2003, 16, 660.
(7) For an account, see: Prakash, G. K. S.; Hu, J. Acc. Chem. Res. 2007,
40, 921.
(12) (a) Noritake, S.; Shibata, N.; Nakamura, S.; Toru, T.; Shiro, M.
Eur. J. Org. Chem. 2008, 3465. (b) Kondratendo, N. V.; Radchenko, O. A.;
Yagupol’skii, L. M. Zh. Org. Khim. 1984, 2250. (c) Magnier, E.;
Wakselman, C. Synthesis 2003, 565. (d) Boys, M. L.; Collington, E. W.;
Finch, H.; Swanson, S.; Whitehead, J. F. Tetrahedron Lett. 1988, 29, 3365.
(e) Adachi, K.; Ishikara, S. JP 20030388769, 2003.
(8) Prakash, G. K. S.; Hu, J.; Mathew, T.; Olah, G. A. Angew. Chem.,
Int. Ed. 2003, 42, 5216.
(9) Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. Angew. Chem.,
Int. Ed. 2003, 43, 5203.
2110
Org. Lett., Vol. 11, No. 10, 2009

Table 1. Difluoromethylation of S-Nucleophiles with 2
Table 2. Difluoromethylation of N-Nucleophiles with 2
b
a Isolated yield. Determined by 19F NMR spectroscopy using PhCF3
as internal standard. c NaH was not used.
without an additional base, sodium 4,6-dimethylpyrimidine-
2-thiolate (5j) was also smoothly difluoromethylated by
reagent 2 in 71% yield (entry 10).
Next, we examined the scope of the N-difluoromethylation
reaction with reagent 2. The results are summarized in Table
2. By using similar conditions as for Table 1, a wide range
of imidazole derivatives were readily difluoromethylated in
moderate to good yields (entries 1-4, 6, 9). It was found
that phenyltetrazole (7e) and benzotriazole (7g) could be
difluoromethylated with reagent 2 (entries 5 and 7). When
7h was subjected to the difluoromethylation with 2, product
8h was obtained in low yield (entry 8).
Thereafter, we applied the reagent 2 in the difluorom-
ethylation of phenylacetylene derivatives (Table 3). It showed
that lithium acetylides derived from 9a-9e smoothly reacted
with reagent 2 to give the desired C-difluoromethylated
products 10a-10e in moderate to good yields (Table 3).
Electrophilic difluoromethylation of acetylene derivatives was
generally difficult, and our current methodology with reagent
2 represents a good alternative to the previously known
Freon-based approaches.13
b
a Isolated yield. Determined by 19F NMR spectroscopy using PhCF3
as internal standard.
formed in 80% overall yield with a ratio 6a:6a′ ) 1:6 (eq
1). It should be mentioned that in this reaction, although
unreacted 2 was recovered, no deuterium-labeled derivative
of 2 [PhSO(NTS)CF2D] was oberved, which suggests there
was no H/D exchange occurring with reagent 2 under the
reaction conditions. In the presence of NaOD in D2O-DMF
at 60 °C, no H/D exchange was observed with reagent 2 in
a period of 14 h (eq 2). We also noticed that product 6a was
unable to undergo H/D exchange either in the presence of
PhSNa/D2O/DMF or in the presence of preprepared
N-phenylsulfinyl-p-toluenesulfonamide anion 1114 and D2O/
DMF (eq 3). These experimental results rule out the
possibility of the involvement of an SN2 or free radical
To gain some insights into the current S-, N-, and
C-difluoromethylations with reagent 2, we carried out several
deuterium-labeling experiments (Scheme 3). When sodium
phenylthiolate (5a′) was treated with 2 in D2O-DMF at 60
°C for 14 h, both PhSCF2H (6a) and PhSCF2D (6a′) were
(13) (a) Konno, T.; Kitazume, T. Chem. Commun. 1996, 19, 2227. (b)
Xiao, L.; Kitazume, T. Tetrahedron Asymmetry 1997, 8, 3597.
(14) Johnson, C. R.; Katekar, G. F. J. Am. Chem. Soc. 1970, 92, 5753.
Org. Lett., Vol. 11, No. 10, 2009
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Table 3. Difluoromethylation of C-Nucleophiles with 2
Scheme 4. Proposed Reaction Mechanism
a Determined by 19F NMR spectroscopy using PhCF3 as an internal
standard and calculated on the basis of the amount of reagent 2 used.
In summary, we have successfully prepared the first
R-difluoromethyl sulfoximine compound, 2, by using the
copper(II)-catalyzed nitrene transfer reaction. Compound 2
was found to be a novel and efficient difluoromethylation
reagent for transferring CF2H group to S-, N-, and C-
nucleophiles. Our deuterium-labeling experiments suggest
that a difluorocarbene mechanism was involved in the current
difluoromethylation reactions with reagent 2. Not only do
our results present a novel and practically useful synthetic
method for many potential applications; the remarkably
different reactivity patterns between reagent 2 (as an elec-
trophilic fluoroalkylation reagent) and the previously well-
known PhSO2CF2H (1, as an nucleophilic fluoroalkylation
reagent) also provides important insights into the unique
chemical reactivities of fluorinated sulfones and sulfoximines.
Further exploration of fluorinated sulfoximine chemistry is
currently underway in our laboratory.
Scheme 3. Deuterium-Labelling Experiments
a Determined by 19F NMR spectroscopy.
mechanism as a major pathway in the current electrophilic
difluoromethylation with 2 and suggest that the difluorom-
ethylation of S-, N-, and C-electrophiles proceeded via a
difluorocarbene mechanism (as shown in Scheme 4). The
nucleophiles (such as S-, N-, and C-anions) can act as a base
to deprotonate 2, which generates difluorocarbene species
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. Mr. Yanchuan
Zhao is thanked for his helpful input in the mechanistic
aspect.
-
and anion 11 in a fast process. The expected PhSO(NTs)CF2
anion (12) is likely to be a highly unstable species, since
both the deuteriation of 12 by D2O (eqs 1 and 2) and
electrophilic quenching of 12 by benzaldehyde were not
successful. Nucleophiles (Nu-) react with difluorocarbene
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and X-ray crystal-
lographic information files. This material is available free
of charge via the Internet at http://pubs.acs.org.
-
intermediate to generate NuCF2 , and the latter could be
protonated by 2 or NuH to give difluoromethylated products
NuCF2H. In the presence of D2O, a deuteriated product
(NuCF2D) can be produced (Scheme 4).
OL900567C
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Org. Lett., Vol. 11, No. 10, 2009