Expedient synthesis of sulfinamides from sulfonyl chlorides

Article abstract of DOI:10.1021/jo062296i

Sulfinamides were synthesized from sulfonyl chlorides using a procedure involving in situ reduction of sulfonyl chlorides. The reaction is broad in scope and easy to perform.

Full text of DOI:10.1021/jo062296i

SCHEME 1
Expedient Synthesis of Sulfinamides from
Sulfonyl Chlorides
Michael Harmata,* Pinguan Zheng, Chaofeng Huang,
Maria G. Gomes, Weijiang Ying, Kanok-On Ranyanil,
Gayatri Balan, and Nathan L. Calkins
oxidation with tert-butyl hypochlorite and subsequent treatment
with an alkene or alkyne in the presence of a Lewis acid.
(Scheme 1).10 The requisite sulfinamide was prepared from a
sulfinyl chloride in high yield. While sulfinyl chlorides are not
exceptionally difficult to make, they are sensitive to hydrolysis
and require preparation using noxious reagents such as thionyl
chloride. We thought that a procedure to quickly access
sulfinamides would be useful in exploring both sulfinamide
chemistry and derivatives such as sulfonimidoyl chlorides. A
number of years ago Sharpless11 reported the synthesis of
sulfinate esters from sulfonyl chlorides by a one-pot reductive
esterification reaction using phosphites as the reducing agent.
Attempts to prepare sulfinamides by the Sharpless group were
not successful. We thought, however, that modification of the
synthesis of sulfinate esters introduced by Toru,12 which used
triarylphosphines as the reductant, would be suitable for the
synthesis of such compounds. This note reports the realization
of that idea.
Department of Chemistry, UniVersity of MissourisColumbia,
Columbia, Missouri 65211
HarmataM@Missouri.edu
ReceiVed NoVember 6, 2006
Sulfinamides were synthesized from sulfonyl chlorides using
a procedure involving in situ reduction of sulfonyl chlorides.
The reaction is broad in scope and easy to perform.
We began our studies by simply using Toru’s procedure for
sulfinate ester formation.11 The results are summarized in Table
1. When a CH2Cl2 solution of triphenylphosphine was added
to the mixture of TsCl, TEA (10 equiv), and BzNH2 in CH2Cl2
at 0 °C, only sulfonamide 6 and PPh3 were detected by NMR
analysis of the crude mixture (entry 1). However, a small change
in the addition sequence offered an encouraging result. When
PPh3 and benzylamine in CH2Cl2 were added to a mixture of
triethylamine and tosyl chloride, the desired sulfinamide was
isolated in 62% yield (entry 2). Only a 14% yield of sulfinamide,
accompanied by 40% sulfonamide, was isolated when the
reaction was performed by addition of PPh3 to TsCl in CH2Cl2
over 1 h followed by addition of a mixture of BzNH2 and TEA
(entry 3). The low yield of sulfinamide was due to over-
reduction of the sulfonyl chloride and presumably dispropor-
tionation. The yield was improved slightly (entry 4, sulfinamide
66%; sulfonamide 13%) by adding a CH2Cl2 solution of PPh3,
TEA (2 equiv), and BzNH2 to the TsCl in CH2Cl2. We also
examined temperature and solvent effects in this reaction. A
slightly lower yield was obtained at 25 °C (entry 5). A
significant amount of sulfonamide was isolated at -20 °C (entry
6). A poor yield of sulfinamide was realized when the reactions
were carried out in acetonitrile, THF, and EtOAc (entries 7-9).
In short, the best reaction conditions were found to be addition
of benzylamine and triphenylphosphine (1 equiv) to a CH2Cl2
solution of TEA (2.0 equiv) at 0 °C.
Sulfinamides, especially chiral sulfinamides, play vital roles
in modern asymmetric chemistry.1 Furthermore, sulfinamides
can also act as N-sulfinyl protecting group for ease of removal
under mild conditions.2 Even though there are various proce-
dures reported for the preparation of sulfinamides from sulfinic
acids,3 sulfinates,4 sulfinyl chlorides,5 disulfides,6 and homolytic
substitution at the sulfur atom,7 these reactions often require
two or more synthetic steps. A one-step process would be useful
and increase the exploration of sulfinamide chemistry.
Sulfinamides are useful compounds and can be transformed
to a number of other important functional groups.8 For example,
they can be converted to sulfonimidoyl chlorides, whose
chemistry is both interesting and useful.9 We reported that
benzothiazines can be prepared from N-aryl sulfinamides by
(1) (a) Ellman, J. A. Pure Appl. Chem. 2003, 75, 39. (b) Senanayake, C.
H.; Krishnamurthy, D.; Lu, Z.-H.; Han, Z.; Gallor, I. Aldrichim. Acta 2005,
38, 93.
(2) (a) Tang, T. P.; Volkman, S. K.; Ellman, J. A. J. Org. Chem. 2001,
66, 8772. (b) Hannam, J.; Harrison, T.; Heath, F.; Madin, A.; Merchant, K.
Synlett 2006, 833. (c) Kells, K. W.; Chong, J. M. Org. Lett. 2003, 5, 4215.
(3) Furukawa, M.; Okawara, T. Synthesis 1976, 339.
(4) (a) Billard, T.; Greiner, A.; Langlois, B. R. Tetrahedron 1999, 55,
7243. (b) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D.
L.; Zhang, H. J. Org. Chem. 1999, 64, 1403. (c) Davis, F. A.; Reddy, R.
E.; Szewczyk, J. M.; Reddy, G. V.; Portonovo, P. S.; Zhang, H.; Fanelli,
D.; Reddy, R. T.; Zhou, P.; Carroll, P. J. J. Org. Chem. 1997, 62, 2555. (d)
Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003.
(5) Uchino, M.; Sekiya, M. Chem. Pharm. Bull. 1980, 28, 126.
(6) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. A.; Ellman, J. A. J. Am.
Chem. Soc. 1998, 120, 8011.
Next, we studied the effects of substituent changes on the
phosphine (Table 2). A 50% excess of PPh3 slightly decreased
(7) Coulomb, J.; Certal, V.; Fensterbank, L.; Lacoˆte, E.; Malacria, M.
Angew. Chem., Int. Ed. 2006, 45, 633.
(8) Tillet, J. G. Sulfinamides. In The Chemistry of Sulphinic Acids, Esters
and their DeriVatiVes; Patai, S., Ed.; Wiley: Chicheter, 1990; pp 603-22.
(9) For examples, see: (a) Reggelin, M.; Junker, B. Chem. Eur. J. 2001,
7, 1232. (b) Furusho, Y.; Okada, Y.; Takata, T. Bull. Soc. Chem. Jpn. 2000,
73, 2827. (c) Roy, A. K. J. Am. Chem. Soc. 1993, 115, 2598. (d) Kim, Y.
H.; Yoon, D. C. Synth. Commun. 1989, 19, 1569. (e) Johnson, C. R.; Bis,
K. G.; Cantillo, J. H.; Meanwell, N. A.; Reinhard, M. F. D.; Zeller, J. R.;
Vonk, G. P. J. Org. Chem. 1983, 48, 1.
(10) (a) Harmata, M.; Schlemper, E. O. Tetrahedron Lett. 1987, 28, 5997.
(b) Harmata, M.; Claassen, R. J., II; Barnes, C. L. J. Org. Chem. 1991, 56,
5059. (c) Harmata, M.; Kahraman, M. J. Org. Chem. 1998, 63, 6845. (d)
Harmata, M.; Kahraman, M.; Jones, D. E.; Pavri, N.; Weatherwax, S. E.
Tetrahedron 1998, 54, 9995.
(11) Klunder, J. M.; Sharpless, K. B. J. Org. Chem. 1987, 52, 2598.
(12) Wantanabe, Y.; Mase, N.; Tateyama, M.; Toru, T. Tetrahedron
Asymmetry 1999, 10, 737.
10.1021/jo062296i CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/23/2006
J. Org. Chem. 2007, 72, 683-685
683

TABLE 3. Preparation of a Series of Sulfinamides
entrya ArSO2Cl 7
R1R2NH 8
n-PrNH2
c-pentyl-NH2
c-hexyl-NH2
c-hexyl-NH2
c-heptyl-NH2
c-C12H23-NH2
t-BuNH2
pyrolidine
Et2NH
i-Pr2NH
(allyl)2NH
9 (%)
9a:62
10 (%)
FIGURE 1. Benzothiazine formation from a sulfinamide.
1
2
3
4
5
6
7b
8
9
Ph
Ph
Tol
Ph
Tol
Ph
9b:59
9c:65
9d:70
9e:48
9f:47
9g:92
9h:15
9i:59
9j:88
9k:73
9l:77
10b:13
10c:12
TABLE 1. Optimization of Solvent and Temperature
10e:19
10f:10
Ph
Tol
Tol
Ph
10h:28
10i:37
10
11
12
13
14
15
16
17
Ph
Ph
Tol
Tol
Ph
3,4-OMe-BzNH2
(R)1-phenyl ethyl amine 9m:39 1.0:1.0c
TEA
(x equiv)
solvent,f T
sulfinamide 5
sulfonamide 6
PhCH2CH2NH2
PhCH2CH2NH2
propargyl
9n:44
9o:53
9p:32
10n:6
entry
(oC)
(%)
(%)
Ph
Tol
10p:15
1a
2c
3d
4e
5e
6e
7e
8e
9e
10
10
10
2.0
2.0
2.0
2.0
2.0
2.0
DCM, 0
DCM, 0
DCM, 0
DCM, 0
DCM, 25
DCM, -20
ACN, 0
0
62
14
66
60
53
26
49
49
b
0
40
13
8
21
40
30
32
(-)-sulfoximine
9q:44 (53d)
1.2:1.0c
9r:38
18
19
20
21
22
23
24
25b
Ph
aniline
10r:8
Tol
Tol
Tol
Tol
Ph
o-Br-aniline
p-nitroaniline
p-Cl-o-Me aniline
p-t-Bu-aniline
p-anisidine
9s:35 (53d)
e
9t:35 (59d)
9u:22
10u:35
THF, 0
EtOAc, 0
9v:8
Ph
Tol
TMS-aniline
2,6-di-i-Pr-aniline
9w:41f
a Method A: To the mixture of TsCl (1.0 eq), BzNH2 (1.0 eq), and TEA
(10.0 eq) in CH2Cl2 solution was added PPh3 in CH2Cl2 solution over a 1
h period at 0 °C. b Only sulfonamide and PPh3 were detected by NMR
analysis of the crude product. c Method B: To the mixture of TsCl (1.0
equiv) and TEA (10.0 equiv) in CH2Cl2 solution was added PPh3 (1.0 equiv)
and BzNH2 (1.0 equiv) in CH2Cl2 solution over a 1 h period at 0 °C.
d Method C: To the mixture of TsCl (1.0 equiv) in CH2Cl2 solution was
added PPh3 (1.0 equiv) in CH2Cl2 solution over a 1 h period at 0 °C,
followed by addition of the mixture of BzNH2 and TEA in CH2Cl2 solution
over a 1 h period at 0 °C. e Method D: To TsCl (1.0 equiv) in CH2Cl2
solution at 0 °C was added a mixture of BzNH2 (1.0 equiv), TEA (2.0
equiv), and PPh3 (1.0 equiv) in CH2Cl2 solution over a 1 h period. f DCM:
dichloromethane. ACN: acetonitrile.
a In all cases, the reactions were carried out using method C except where
noted. b Reactions were carried out using method D. c Diastereomeric ratios
were determined by 1H NMR analysis of the crude mixture. d Yields were
corrected for the recovered starting material. e A complicated mixture was
isolated from the reaction mixture. f Desilylated product was isolated in
41% yield.
BzNH2, suggesting that the substrate amine should remain the
limiting reagent in the reaction (entry 3). Electron-rich phos-
phines (trifuryl phosphine, tri-n-butyl phosphine) or an electron-
poor phosphine (tri-p-trifluoromethyl phosphine) did not produce
any of the desired sulfinamide. Interestingly, tri-o-tolyl phos-
phine gave an acceptable yield of the desired product. All things
considered, triphenylphosphine is the reductant of choice and
only 1 equiv was used in the subsequent studies.
TABLE 2. Optimization of Phosphine
We applied the first-generation reaction conditions (method
B) together with the second-generation reaction conditions
(method D) to perform further studies of this reductive amination
reaction. Results are summarized in Table 3. With cyclic,
primary amines, the yield of the sulfinamide increased slightly
when the ring size changed from 5 to 6 membered (entries 2-4).
For larger ring systems, the yield was only about 50% (entries
5-6). Perhaps not surprisingly, the sterically hindered amines
(t-BuNH2 and i-Pr2NH) gave excellent yields (entries 7 and 10).
We conclude that their reaction with sulfonyl chloride is slow
but quite rapid with the corresponding sulfinyl chloride or other
active sulfinylating agent formed in the reaction mixture. A
chiral amine (entry 13) and chiral sulfoximine (entry 17)
afforded reasonable yields of sulfinyl derivatives, but no
diastereoselection was found.13 It is not immediately clear why
pyrollidine (entry 8) and propargylamine (entry 16) reacted so
poorly, but for the former, a considerable amount of sulfonamide
BzNH2
(y equiv)
sulfinamide 5
sulfonamide 6
entrya
PR3(z equiv)
(%)
(%)
1
2
3
4
5
6
7
1.0
1.0
1.5
1.0
1.0
1.0
1.0
Ph (1.0)
Ph (1.5)
Ph (1.0)
2-furyl (1.0)
p-CF3-Ph (1.0)
o-tolyl (1.0)
n-Bu (1.0)
66
68
55
0
0
60
0
13
4
32
b
b
10
b
a These experiments were carried out using Method D. b Only sulfona-
mide and PPh3 were detected by NMR analysis of the crude product.
the amount of sulfonamide obtained in the reaction but did little
to improve the yield of the sulfinamide (entry 2). The yield of
sulfonamide increased to 32% with the use of 1.5 equiv of
(13) An enantioselective version of the reaction is conceivable, see:
Nakamura, S.; Tateyama, M.; Sugimoto, H.; Nakagawa, M.; Watanabe, Y.;
Shibata, N.; Toru, T. Chirality 2005, 17, 85 and references therein.
684 J. Org. Chem., Vol. 72, No. 2, 2007

TABLE 4. Reactions with Different Sulfonyl Chlorides
scope of the process is reasonably broad and may expand further
with continued investigation. Further application of this reaction
in sulfonimidoyl chloride and benzothiazine chemistry is
currently underway.
Experimental Section
entrya
Ar SO2Cl 11
sulfinamide 12
sulfonamide 13
General Method B for the Preparation of Sulfinamide. To a
solution of p-toluenesulfonyl chloride (190 mg, 1 mmol) and
triethylamine (1.4 mL, 10 mmol) in CH2Cl2 (3.0 mL) solution at
0 °C was added a solution of triphenylphosphine (262 mg, 1 mmol)
and benzylic amine (109 µL, 1 mmol) in CH2Cl2 (3.0 mL) solution
using a syringe pump over a period of 1 h. After addition, TLC
showed all of the sulfonyl chloride was consumed. The reaction
mixture was concentrated by rotary evaporation. Crude mixture was
purified by column chromatography (20% EtOAc) to give the
desired sulfinamide 5 (152 mg, 62%).
General Method D for the Preparation of Sulfinamide. To a
solution of p-toluenesulfonyl chloride (190 mg, 1 mmol) in CH2-
Cl2 (3.0 mL) solution at 0 °C was added a mixture of triph-
enylphosphine (262 mg, 1 mmol), benzylic amine (109 µL,
1 mmol), and triethylamine (278.7 µL, 2.0 mmol) in CH2Cl2
(3.0 mL) solution using a syringe pump over a period of 1 h. After
addition, TLC showed all of the sulfonyl chloride was consumed.
The reaction mixture was concentrated by rotary evaporation and
purified by flash chromatography on silica.
N-Benzyl-p-toluenesulfinamide (5). According to the general
procedure, 5 was obtained by column chromatography (hexane/
EtOAc ) 5:1) as a white solid (62%, method B; 66%, method D).
1H NMR and 13C NMR matched literature values.15 1H NMR (250
MHz, CDCl3): δ 7.64-7.68 (m, 2H), 7.27-7.34 (m, 7H), 4.22-
4.28 (m, 2H), 3.91 (dd, J ) 14.6, 8.5 Hz, 1H), 2.42 (s, 3H). 13C
NMR (62.5 MHz, CDCl3): δ 141.2, 140.8, 137.8, 129.5, 128.5,
128.2, 127.5, 125.9, 44.2, 21.2.
1
2
3
4
5
6
7
8b
p-CF3-Ph
o-NO2-Ph
2-Naph
o-F-Ph
o-Cl-Ph
o-Br-Ph
i-Pr
12a:25
12b:55
12c:70
12d:63
12e:80
12f:46
12g:3.1
12h:47
13a:26
13b:21
13c:11
13d:9
13e:12
13f:20
13g:4.7
0
CF3
a In all cases, reactions were carried out using method D. b Method E:
A solution of CF3SO2Cl in CH2Cl2 solution and a mixture of TEA, BzNH2,
and PPh3 were added at the same rate to a 25 mL round-bottom flask
at 0 °C.
was isolated. The triple bond in propargylamine may be reactive
under the reaction conditions.
With acceptable results using aliphatic amines in hand, we
turned our attention to less nucleophilic amines, namely,
anilines. With aniline itself, only a 38% yield of sulfinamide
along with 8% of the corresponding sulfonamide was isolated
(entry 18). Adding an electron-withdrawing nitro group to the
aromatic ring gave a complicated mixture, perhaps due to
reaction between the nitro group and triphenylphosphine (entry
20).14 o-Bromoaniline and p-chloro-o-methylaniline gave results
similar to that of aniline (entries 19 and 21). Furthermore, neither
an increase in the electron density on the phenyl ring (entries
22-23) nor an increase in the steric bulk on or near the
aniline nitrogen gave acceptable yields of sulfinamides (entries
24 and 25).
We also carried out reactions with different sulfonyl chlorides.
The results are shown in Table 4. Strongly electrophilic
arylsulfonyl chlorides (entries 1 and 2) gave significant amounts
of sulfonamides. Of the o-haloarylsulfonyl chlorides examined,
the chloro compound seems to have an appropriate balance
between steric and electronic effects to afford high yields of
sulfinamide relative to the corresponding fluoro and bromo
species (entries 4-6). While 2-propanesulfonyl chloride afforded
a poor yield of sulfinamide (entry 7), triflyl chloride gave a
respectable yield of sulfinamide (entry 8).
N-Benzyl-p-toluenesulfonamide (6). 6 was obtained as a white
1
solid (13%, method D). H NMR matched literature values.16 1H
NMR (250 MHz, CDCl3): δ 7.76 (d, J ) 7.5 Hz, 2H), 7.18-7.33
(m, 7H), 4.78 (t, J ) 6.0 Hz, 1H), 4.12 (d, J ) 6.2 Hz, 2H),
2.44 (s, 3H).
Acknowledgment. We gratefully acknowledge financial
support from the NIH (1R01-AI59000-01A1). We thank Dr.
Charles L. Barnes for X-ray data.
Supporting Information Available: Experimental procedures
as well as characterization and copies of proton and carbon spectra
for all previously unreported compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
In conclusion, we developed a simple and effective method-
ology to synthesize sulfinamides from sulfonyl chlorides. The
JO062296I
(15) Garc´ıa-Ruano, J.; Alonso, R.; Zarzuelo, M. M.; Noheda, P.
Tetrahedron: Asymmetry 1995, 6, 1133.
(14) Though one might not expect such a reaction at low temperatures,
see: Masaki, M.; Fukui, K.; Kita, J. Bull. Soc. Chem. Jpn. 1977, 50, 2013.
(16) Xiao, X.; Wang, H.; Huang, Z.; Yang, J.; Bian, X.; Qin, Y. Org.
Lett. 2006, 8, 139.
J. Org. Chem, Vol. 72, No. 2, 2007 685