Catalyst-free alkylation of sulfinic acids with sulfonamides via sp 3 C-N bond cleavage at room temperature

Article abstract of DOI:10.1021/ol900788r

An unprecedented catalyst-free alkylation of sulfinic acids with sulfonamides has been developed via sp³ C-N bond cleavage at room temperature. In the absence of external catalysts and additives, a wide variety of N-benzylic and N-allylic sulfonamides couple with sulfinic acids to give structurally diversified sulfones in moderate to excellent yields. Furthermore, the reaction of N-(2-acyl)allylic sulfonamides with sulfinic acids provides a convenient access to trisubstituted allyl sulfones with exclusive Z selectivity.

Full text of DOI:10.1021/ol900788r

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2543-2545
Catalyst-Free Alkylation of Sulfinic
Acids with Sulfonamides via sp3 C-N
Bond Cleavage at Room Temperature
Cong-Rong Liu, Man-Bo Li, Dao-Juan Cheng, Cui-Feng Yang, and Shi-Kai Tian*
Department of Chemistry, UniVersity of Science and Technology of China,
Hefei, Anhui 230026, China
tiansk@ustc.edu.cn
Received April 10, 2009
ABSTRACT
An unprecedented catalyst-free alkylation of sulfinic acids with sulfonamides has been developed via sp3 C-N bond cleavage at room temperature.
In the absence of external catalysts and additives, a wide variety of N-benzylic and N-allylic sulfonamides couple with sulfinic acids to give
structurally diversified sulfones in moderate to excellent yields. Furthermore, the reaction of N-(2-acyl)allylic sulfonamides with sulfinic acids
provides a convenient access to trisubstituted allyl sulfones with exclusive Z selectivity.
Although sp3 C-N bond cleavage can be realized by metals
such as Pd, Rh, Ru, and Na, strong bases such as t-BuLi
and t-BuOK, and some other reagents such as
CCl3CH2OCOCl, DDQ, and PhSeH under various reaction
conditions, amines and amine derivatives have rarely been
applied to the alkylation of protic nucleophiles.1 In 1983,
Kunakova and co-workers disclosed a palladium-catalyzed
coupling reaction of sulfinic acids with allylic amines via
sp3 C-N bond cleavage at 100 °C.2 This reaction can provide
a direct access to sulfones that can serve as versatile building
blocks for organic synthesis owing to the useful reactivity
of R-sulfonyl carbanions.3 More than 10 years later, Na-
gakura and co-workers found that palladium could catalyze
the removal of the allyl group from N-allyl-N-pentylaniline
with p-toluenesulfinic acid at room temperature.4 This
method, however, has not been extended to the alkylation
of sulfinic acids with nonallylic amines and amine deriva-
tives.
When the nitrogen atoms of benzylic (or allylic) primary
amines are attached to appropriate electron-withdrawing groups
(EWGs), either Brønsted5 or Lewis acids6,7 are able to facilitate
the amino groups to serve as leaving groups toward a range
of nucleophiles. In the course of exploring new reactions
with a combination of acids,7,8 we found, however, that the
sulfonyl-activated amines (sulfonamides) could couple with
(4) Honda, M.; Morita, H.; Nagakura, I. J. Org. Chem. 1997, 62, 8932–
8936.
(5) (a) Chung, K. H.; Kim, J. N.; Ryu, E. K. Tetrahedron Lett. 1994,
35, 2913–2914. (b) Seong, M. R.; Lee, H. J.; Kim, J. N. Tetrahedron Lett.
1998, 39, 6219–6222. (c) Lee, H. J.; Seong, M. R.; Kim, J. N. Tetrahedron
Lett. 1998, 39, 6223–6226.
(1) For reviews, see: (a) Greene, T. W.; Wuts, P. G. M. ProtectiVe
Groups in Organic Synthesis, 3rd ed.; Wiley: New York, 1999. (b) Escoubet,
S.; Gastaldi, S.; Bertrand, M. Eur. J. Org. Chem. 2005, 3855–3873.
(2) Kunakova, R. V.; Gaisin, R. L.; Sirazova, M. M.; Dzhemilev, U. M.
IzV. Akad. Nauk SSSR Ser. Khim 1983, 32, 157–160. Kunakova, R. V.;
Gaisin, R. L.; Sirazova, M. M.; Dzhemilev, U. M. Bull. Acad. Sci. USSR
DiV. Chem. Sci. (Engl. Transl.) 1983, 32, 157–160.
(6) (a) Esquivias, J.; Go´mez-Arraya´s, R.; Carretero, J. C. Angew. Chem.,
Int. Ed. 2006, 45, 629–633. (b) Alonso, I.; Esquivias, J.; Go´mez-Arraya´s,
R.; Carretero, J. C. J. Org. Chem. 2008, 73, 6401–6404
(7) Liu, C.-R.; Li, M.-B.; Yang, C.-F.; Tian, S.-K. Chem.-Eur. J. 2009,
15, 793–797
.
.
(8) (a) Liu, C.-R.; Li, M.-B.; Yang, C.-F.; Tian, S.-K. Chem. Commun.
2008, 1249–1251. (b) Yang, B.-L.; Tian, S.-K. Eur. J. Org. Chem. 2007,
464, 6–4650. (c) Song, Q.-Y.; Yang, B.-L.; Tian, S.-K. J. Org. Chem. 2007,
(3) For reviews, see: (a) Simpkins, N. S. Sulfones in Organic Synthesis;
Pergamon Press: New York, 1993. (b) Blackmore, P. R. J. Chem. Soc.,
Perkin Trans. 1 2002, 2563–2585.
72, 5407–5410
.
10.1021/ol900788r CCC: $40.75
Published on Web 05/18/2009
 2009 American Chemical Society

sulfinic acids via sp3 C-N bond cleavage in the absence of
external catalysts and additives at room temperature. This
finding is totally out of our expectation because the acidity
of a sulfinic acid is much weaker relative to that of a sulfonic
acid,9 which nevertheless failed to catalyze the sp3 C-N
bond cleavage for the alkylation of acetyl acetone with
N-tosyl benzhydrylamine.7 In addition, sulfinic acids and their
salts are not powerful nucleophiles, and a simple alkylation
reaction of sulfinate anions is not trivial and often requires
readjusting the reaction conditions.10 Herein, we describe
this unprecedented catalyst-free alkylation of sulfinic acids
with sulfonamides, which adds a new and direct entry to
the synthesis of structurally diversified sulfones.
room temperature to give the corresponding sulfones in good
to excellent yields (Table 2, entries 1-15). Notably, no
Table 2. Catalyst-Free Alkylation of Sulfinic Acids with
Sulfonamidesa
As demonstrated by the alkylation of benzenesulfinic acid
with 4-methoxybenzylamine derivatives in chloroform at room
temperature, the activating group (EWG) attached to the
nitrogen atom played a vital role for the benzylic sp3 C-N bond
cleavage to take place in the absence of external catalysts and
additives (Table 1, entries 1-5). To our delight, sulfone 2a was
Table 1. Survey of EWGs and Solventsa
entry
1, EWG
1a, Ts
1ab, p-Ns
1ac, PO(OPh)2
1ad, COPh
1ae, Cbz
1a, Ts
1a, Ts
1a, Ts
1a, Ts
1a, Ts
solvent
time/h
yield/%b
1
2
3
4
5
6
7
8
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
(ClCH2)2
toluene
MeCN
THF
14
24
24
24
24
16
24
24
24
24
24
24
67
55
13
30
0
58
36
13
54
0
a Reaction conditions: sulfonamide (0.50 mmol), sulfinic acid (0.60 mmol),
CHCl3 (0.50 mL), rt. b Isolated yield. c MeCN was used as the solvent to
dissolve methanesulfinic acid.
isomerization was observed in the reaction of benzylic prop-
argylic amine derivative 1i with benzenesulfinic acid, which
proceeded cleanly to give sulfone 2i as a single product in 96%
yield (Table 2, entry 9). Furthermore, the displacement of the
sulfonamido group of allylic amine derivative 1k by benzene-
sulfinic acid took place only at the original allylic position,
presumably to maintain a maximum degree of conjugation
(Table 2, entry 11).11 Nevertheless, no reaction took place with
simple sulfonamides such as N-tosyl benzylamine (1m) and
N-tosyl allylamine (1n) (Table 2, entries 16 and 17).
The cross-coupling reaction of optically active sulfonamide
(R)-1b (95% ee) with 0.50 equiv of benzenesulfinic acid
proceeded at room temperature for 10 h to give sulfone 2b
(Table 2, entry 2) in nearly racemic form (3% ee), and at the
same time the optical purity of recovered sulfonamide (R)-1b
decreased from 95% to 66%. Furthermore, the formation of
sulfone 2b was found to be irreversible based on the fact that
no reaction took place between sulfone 2b and p-toluenesulfinic
acid at room temperature for 24 h.12 These results suggest that
carbocation 3 is generated from sulfonamide 1 via a sulfinic
acid-promoted sp3 C-N bond cleavage (Scheme 1). The
resulting sulfinate anion acts as an S-nucleophile to couple with
carbocation 3 to give sulfone 2 (Scheme 1, path a).
9
10
11
12
1a, Ts
1a, Ts
EtOAc
MeNO2
0
7
a Reaction conditions: amine derivative (0.50 mmol), benzenesulfinic acid
(0.60 mmol), solvent (0.50 mL), rt. b Isolated yield. PMP ) p-methoxyphenyl.
p-Ns ) p-nitrobenzenesulfonyl.
obtained in 67% yield when using the tosyl group, a strong
electron-withdrawing group that can be introduced conveniently
from inexpensive p-toluenesulfonyl chloride (Table 1, entry 1).
Nevertheless, the use of another common organic solvent instead
of chloroform just led to a lower yield or even no desired sulfone
product at all (Table 1, entries 6-12).
A broad range of tosyl-activated benzylic and allylic primary
amines coupled with aromatic and aliphatic sulfinic acids at
(9) For example, the pKa value of TfOH is 0.3 in DMSO, and that of
PhSO2H is 7.1. See: Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463.
(10) For a review, see: (a) Solladie, G. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991,
Vol. 6, pp 133-170. For examples, see: (b) Wu, J.-P.; Emeigh, J.; Su, X.-
P. Org. Lett. 2005, 7, 1223–1225. (c) Crandall, J. K.; Pradat, C. J. Org.
Chem. 1985, 50, 1327–1329.
(11) No SN2′ product was detected by 1H NMR analysis of the reaction
mixture.
However, a sulfinic acid can also act as an O-nucleophile
toward a “harder” carbon electrophile relative to N-benzylic and
1
(12) Determined by H NMR analysis of the reaction mixture.
2544
Org. Lett., Vol. 11, No. 12, 2009

Scheme 1
.
Proposed Reaction Pathways
Table 3. Catalyst-Free Alkylation of Benzenesulfinic Acid with
N-(2-Acetyl)allylic Sulfonamidesa
entry
1q-1y, R
1q, Ph
product
time/h
yield/%b
1
2
3
4
5
6
7
8
9
2q
2r
2s
6
6
6
24
5
6
24
6
24
73
61
80
51
58
70
51
58
49
N-allylic sulfonamides (Scheme 1, path b).13 While no reaction
took place between acyclic N-alkyl sulfonamides and sulfinic
acids, N-cyclohexyl sulfonamide 1o coupled smoothly with
benzenesulfinic acid at room temperature, and the resulting
product was identified as sulfinate 4a rather than expected
sulfone 2p (Scheme 2), which could alternatively be synthesized
1r, PMP
1s, 4-MeC6H4
1t, 4-ClC6H4
1u, 4-O2NC6H4
1v, 2-MeC6H4
1w, 2-furyl
2t
2u
2v
2w
2x
2y
1x, (E)-PhCH)CH
1y, 1-hexyl
a Reaction conditions: sulfonamide (0.50 mmol), benzenesulfinic acid (0.60
mmol), CHCl3 (0.50 mL), rt. b Isolated yield.
Scheme 2. Synthesis of Sulfinate 4a and Sulfone 2p
formation A, which is energetically favored relative to
reactive conformation B by relieving the allylic 1,2-strain
(Figure 1).5c,15c
by catalytic hydrogenation of allylic sulfone 2l, previously
prepared from alcohol 1l and benzenesulfinic acid (Table 2,
entry 12).
Figure 1. Reactive Conformations A and B.
Furthermore, a third reaction pathway was observed in the
reaction of sulfinic acids with N-allylic sulfonamides bearing
activated terminal CdC double bonds.14 As shown in Table 3,
a range of N-(2-acetyl)allylic sulfonamides coupled with ben-
zenesulfinic acid to give the corresponding trisubstituted allyl
sulfones with exclusive Z selectivity.15,16 Obviously, such an
SN2′-type process is allowed to take place by the activation
of a terminal CdC double bond with the acetyl group, and
tentatively, the Z selectivity originates from reactive con-
In summary, we have developed a catalyst-free alkylation
reaction of sulfinic acids with sulfonamides via sp3 C-N bond
cleavage at room temperature. In the absence of external
catalysts and additives, a wide variety of N-benzylic and
N-allylic sulfonamides couple with sulfinic acids to give
structurally diversified sulfones in moderate to excellent yields.
Furthermore, the reaction of N-(2-acyl)allylic sulfonamides with
sulfinic acids provides a convenient access to trisubstituted allyl
sulfones with exclusive Z selectivity.
(13) For examples on the ambident nucleophilicity of sulfinate anions
toward carbon electrophiles, see: (a) Reference 10b. (b) Cacchi, S.; Fabrizi,
G.; Goggiamani, A.; Parisi, L. M. Synlett 2003, 361–364. (c) Watanabe,
S.; Kurosawa, H. Organometallics 1998, 17, 479–482.
Acknowledgment. We are grateful for the financial support
from the National Natural Science Foundation of China
(20732006 and 20672105) and the Chinese Academy of
Sciences.
(14) For reviews on the preparation and application of such highly
functionalized sulfonamides, see: (a) Masson, G.; Housseman, C.; Zhu, J.
Angew. Chem., Int. Ed. 2007, 46, 4614–4628. (b) Declerck, V.; Martinez,
J.; Lamaty, F. Chem. ReV. 2009, 109, 1–48.
(15) For the stereoselective synthesis of trisubstituted allyl sulfones, see:
(a) Kabalka, G. W.; Venkataiah, B.; Dong, G. Tetrahedron Lett. 2003, 44,
4673–4675. (b) Chandrasekhar, S.; Saritha, B.; Jagadeshwer, V.; Narsih-
mulu, C.; Vijay, D.; Sarma, G. D.; Jagadeesh, B. Tetrahedron Lett. 2006,
47, 2981–2984. (c) Reddy, L. R.; Hu, B.; Prashad, M.; Prasad, K. Angew.
Supporting Information Available: Experimental proce-
1
dures, characterization data, and copies of H and 13C NMR
spectra for the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
Chem., Int. Ed. 2009, 48, 172–174
.
(16) The stereochemistry of new products 2v, 2w, and 2y was assigned
by 2D NOESY analysis, and the stereochemistry of new product 2s was
assigned by analogy. For details, see the Supporting Information
.
OL900788R
Org. Lett., Vol. 11, No. 12, 2009
2545