Mild and general method for the synthesis of sulfonamides

Article abstract of DOI:10.1055/s-2007-1000850

Reaction of methyl sulfinates with lithium amides followed by 3-chloroperoxybenzoic acid oxidation of the resulting sulfinamides provides primary, secondary, and tertiary alkane-, arene-and heteroarenesulfonamides in high yields. This constitutes a mild and facile experimental protocol that avoids the use of hazardous, unstable, or volatile reagents and does not affect the configurational stability of the amines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-1000850

FEATURE ARTICLE
311
Mild and General Method for the Synthesis of Sulfonamides
M
ild and
G
eneral Meth
s
od for the
é
Synthesis of Sul
L
f
onamides uis García Ruano,*a Alejandro Parra,a Francisco Yuste,*b Virginia M. Mastranzob
a
b
Mexico
E-mail: yustef@servidor.unam.mx
Received 21 November 2007
palladium11 have also recently been used to provide ac-
cess to sulfonamides. Although all these methods have
proved to be of great utility for the generation of specific
substrate classes, there remains a need for straightforward
Abstract: Reaction of methyl sulfinates with lithium amides fol-
lowed by 3-chloroperoxybenzoic acid oxidation of the resulting sul-
finamides provides primary, secondary, and tertiary alkane-, arene-
and heteroarenesulfonamides in high yields. This constitutes a mild
and facile experimental protocol that avoids the use of hazardous, routes to sulfonamides, in which the nature of the groups
unstable, or volatile reagents and does not affect the configurational
stability of the amines
on both the nitrogen and sulfur portions of the sulfon-
amide can be widely varied.
Key words: sulfonamides, oxidation, sulfinamides, methyl sulfi-
Given that most of the problems associated with the syn-
nates, chemoselectivity
thesis of sulfonamides are related to the use of sulfonic
acid derivatives as intermediates, we reasoned that other
easily available sulfur derivatives exhibiting a reactivity
Sulfonamides1 are a very important class of compounds,
similar to, but a stability greater than, sulfonyl chlorides
in part, because of their pronounced antibacterial activity
(especially a lower sensitivity to water), might be good al-
(sulfa drugs), a therapeutic area where they have been in
ternative precursors of sulfonamides. Since nucleophilic
use for more than seventy years.2 In addition, sulfona-
substitution at sulfur should be quite sensitive to steric
mides are frequently used as diuretics, hypoglycemic
hindrance, sulfur tricoordinated species should be more
agents, antihypertensive agents, antiviral agents, anti-in-
reactive than their tetracoordinated counterparts, thus sug-
flammatory agents, and as protease inhibitors.3 They are
gesting the use of the very stable ester derivatives of trico-
also often used as protecting groups for both oxygen and
ordinated sulfur acids as sulfonamide progenitors. Thus,
nitrogen functionalities,4 and recently they have been uti-
the conversion of methyl sulfinates into sulfinamides and
lized as a new type of linker for solid phase organic syn-
the subsequent oxidation thereof to sulfonamides
thesis.5 The vast majority of sulfonamides are prepared by
(Scheme 1) might be a general synthesis of sulfonamides
the reaction of ammonia, a primary amine, or a secondary
that does not suffer the drawbacks of the widely used sul-
amine with a sulfonyl chloride in the presence of a base.6
fonyl chloride route. As a bonus, this method would not
There are several important problems, however, associat-
require the use of hazardous reagents or complex experi-
ed with this method which restrict its scope. One of these
mental procedures in any step. In this paper we report the
is related to side reactions provoked by the base or the lib-
advantages of preparing sulfonamides from methyl sulfi-
erated chloride ion acting as a nucleophile. More impor-
nates according to the procedure depicted in Scheme 1.
tant problems, however, concern the harsh conditions
frequently required to synthesize the sulfonyl chlorides,
O
S
O
S
O
S
LiNR2R3
THF
MCPBA
CH2Cl2
and the difficulty in handling and storing these often lach-
rymatory and water-sensitive agents once they have been
obtained. As a consequence, considerable effort has re-
cently been devoted to the development of milder routes
to sulfonyl chlorides,7 several of which are based on the
use of sulfur dioxide as an electrophilic sulfur source.8
Other methodology, based on the use of leaving groups
other than chloride,9 does not avoid all the drawbacks of
the sulfonyl chlorides because special methods are often
required to prepare such sulfonylating species. In addi-
tion, syntheses based on sulfonylation of aromatics using
dialkylaminosulfonyl chloride catalyzed by indium(III)
triflate10 or N-arylation of sulfonamides catalyzed by
R1
NR2R3
R1
NR2R3
R1
OMe
O
R1 = alkyl, aryl
R2, R3 = H, alkyl, aryl
Scheme 1
With regard to the availability of methyl sulfinates, the
large number of commercially available disulfides12,13 and
the broad scope of the Brownbridge’s method14 of con-
verting them into sulfinates with N-bromosuccinimide un-
der mild conditions, provides efficient access to almost
any conceivable alkane- or arenesulfinate. We have im-
proved the original experimental procedure14 by treating
the crude reaction mixture with sodium bisulfite (to re-
duce excess NBS) prior to washing with hydrogen carbon-
ate. The crude methyl sulfinates shown in Tables 1 and 2,
SYNTHESIS 2008, No. 2, pp 0311–0319
x
x
.
x
x
.2
0
0
8
Advanced online publication: 18.12.2008
DOI: 10.1055/s-2007-1000850; Art ID: Z26707SS
© Georg Thieme Verlag Stuttgart · New York

312
J. L. García Ruano et al.
FEATURE ARTICLE
were obtained in nearly quantitative yields, and of suffi- methyl sulfinates and sulfonyl chlorides is not greatly
cient purity, in most cases, to be used without purification different and supported our assumption that the tricoordi-
in the next step.
nated character of the sulfinate is able to compensate for
the higher lability of chloride as a leaving group. The rel-
ative reactivity of both compounds with water, which can
be used as a criterion of stability, was established by
studying the reaction of water (0.7 equiv) with a mixture
of methyl benzenesulfinate (10 equiv) and 4-toluenesulfo-
nyl chloride (1 equiv). The formation of 0.7 equivalents of
4-toluenesulfonic acid was observed after 30 minutes,
whereas benzenesulfinic acid was not detected.15 This re-
sult indicates that, in contrast to the results obtained with
We then investigated the relative reactivity of methyl sul-
finates and sulfonyl chlorides in reactions with nitrogen-
and oxygen-based nucleophilic reagents. The competitive
reaction of methyl benzenesulfinate and 4-toluenesulfo-
nyl chloride with both lithium diethylamide and diethyl-
amine (Table 1, Methods A and B) provided in each case
a 1:2 mixture of the benzenesulfinamide and the 4-tolu-
enesulfonamide, which indicated that the reactivity of
Biographical Sketches
José Luis García Ruano JSPS in 2006. He was ap- centered on the chemistry of
earned his Ph.D. from the pointed full Professor in Or- sulfoxides and related com-
Universidad Complutense ganic
(Madrid, 1973). He has held Universidad Autónoma de tions
Chemistry
at pounds and their applica-
in asymmetric
appointments as a visiting Madrid in 1982 and has synthesis. In these fields, he
Professor at the Florida served as Vice-President of has published approximate-
State (1992) and Emory the Spanish Royal Society ly 300 papers and super-
(2003) Universities and re- of Chemistry for four years. vised thirty-five Ph.D.
ceived a fellowship with the His research interests are theses.
Alejandro Parra was born oratory of Prof. Andrew the supervision of Prof. José
in 1980 in Toledo, Spain. Myers at Harvard Universi- Luis García Ruano. His re-
He obtained a B.Sc. degree ty (USA) working on the search concerns asymmetric
in chemistry at the Univer- chemistry of tetracyclines. synthesis with sulfur com-
sidad Autónoma of Madrid He is now pursuing his pounds.
(Spain) in 2004. In 2006 he Ph.D. at the Universidad
spent four months in the lab- Autónoma de Madrid under
Francisco Yuste was born working with Fernando research interests include
in 1947 in México City. He Walls on synthesis of natu- organic sulfur chemistry
studied chemistry at the ral products. Since 1990, he and asymmetric synthesis
Universidad Nacional Au- has been a full Professor in using sulfoxides.
tónoma de México where he the Instituto de Química of
obtained his Ph.D. in 1982 this University. His current
Virginia M. Mastranzo she obtained her Ph.D. in of Francisco Yuste at the In-
was born in Tlaxcala, Méxi- 2005 working with Cecilia stituto de Química of the
co. She studied chemistry at Anaya. Since 2005 she has Universidad Nacional Au-
Benemérita
Universidad worked as a postdoctoral re- tónoma de México.
Autónoma de Puebla, where search associate in the group
Synthesis 2008, No. 2, 311–319 © Thieme Stuttgart · New York

FEATURE ARTICLE
Mild and General Method for the Synthesis of Sulfonamides
313
nitrogen-based nucleophiles, the reactivity of methyl ben- Table 2 Synthesis of Secondary and Tertiary Sulfonamides
zenesulfinate toward water is much lower (i.e., its stability
MCPBA
(1.5 equiv)
O
S
O
S
O
S
LiNR2R3
R2
R3
R2
R3
is much higher16) than that of 4-toluenesulfonyl chloride.
R1
R1
N
R1
OMe
N
THF, –78 °C
CH2Cl2
5 min
After confirming that methyl sulfinates possessed accept-
able reactivity with nitrogen-based nucleophiles, we in-
vestigated the reaction sequence shown in Scheme 1. We
first studied the reaction of methyl benzenesulfinate with
various amine-based nucleophiles under different condi-
tions in order to optimize the synthesis of benzenesulfin-
amides. The reaction with equimolecular amounts of
primary or secondary lithium amides (aliphatic or aromat-
ic), at –78 °C, provided sulfinamides in few minutes
(Table 1, Method A), in good yields, and of sufficient pu-
rity to be used without purification in the oxidation step.17
Benzenesulfinamides were also obtained, in moderate
yields, by heating mixtures of methyl benzenesulfinate
with three equivalents of primary or secondary alkyl-
amine at reflux temperature (no solvent; Table 1, Method
B) for several hours; the excess amine can be easily recov-
ered.18 Volatile amines require the use of sealed tube con-
ditions. Thus, for the synthesis of sulfonamides from such
amines, Method A has clear cut advantages.
O
1a–k
2a–aa
3a–aa
Entry R1
NR2R3
Prod. Yield (%)
Step 1 Step 2
1
2
3
4
5
6
7
8
9
Ph
NHCy
3a
3b
3c
3d
3e
3f
72
84
80
79
80
86
82
80
79
98
73
84
83
82
93
31
98
–
89
82
79
95
74
75
90
83
89
93
81
87
76
84
64
–
Ph
NHCH2CH=CH2
NHPh
Ph
Ph
NEt2
Ph
pyrrolidin-1-yl
morpholin-4-yl
NHCH2CH=CH2
NEt2
Ph
4-MeC6H4
4-MeC6H4
4-MeOC6H4
3g
3h
3i
NHt-Bu
10 4-MeOC6H4
NEt2
3j
Table 1 Synthesis of Benzenesulfinamides from Methyl Benzene-
sulfinate and Lithium Amides or Amines
11 4-EtO2CC6H4 NHPh
12 4-EtO2CC6H4 NEt2
3k
3l
A: LiNR1R2, THF, –78 °C
O
S
O
S
R1
R2
or
N
OMe
B: NHR1R2, no solvent, reflux
13 4-ClC6H4
14 4-ClC6H4
NHCH2CH=CH2
NEt2
3m
3n
3o
3p
3p
3q
3q
3r
3s
1a
2c,d,f
Entry NR1R2
Method Amine Product Conversiona
15 4-(TIPSO)C6H4 NEt2
(equiv)
(%)
60
79
66
30
67
98
16 2-pyridyl
17a 2-pyridyl
18 2-pyridyl
19a 2-pyridyl
20 2-thienyl
21 n-Pr
NHCy
1
2
3
4
5
6
NEt2
NEt2
NEt2
NEt2
NEt2
A
A
A
B
B
B
1.1
2d
2d
2d
2d
2d
2f
NHCy
–
1.2
morpholin-4-yl
morpholin-4-yl
NHBn
–
1.5
65
73
71
51
72
55
75
79
75
78
0
81
81
82
77
76
83
85
92
80
90
–
1.5
3.0
NH(CH2)2Ph
pyrrolidin-1-yl
NHPh
morpholin-4-yl
3.0
22 n-Pr
3t
a Measured by 1H NMR.
23 i-Pr
3u
3v
3w
3x
3y
3z
24 i-Bu
morpholin-4-yl
NHCH2CH=CH2
morpholin-4-yl
(R)-NHCHMePh
(S)-NHCHMeEt
With these results in hand, the reaction sequence shown in
Scheme 1 was used to prepare most, but not all, of the sec-
ondary and tertiary arenesulfonamides and alkanesulfon-
amides shown in Table 2. In three instances, Method B
gave better product yields in the first step of the sequence
(entries 17, 19, and 30). The so obtained sulfinamides
were usually oxidized without purification with 3-chlo-
roperoxybenzoic acid, providing secondary and tertiary
sulfonamides 3a–aa in very good overall yield. This pro-
tocol was successful for the reaction of primary or second-
ary lithium amides with benzenesulfinates (Table 2,
entries 1–6) as well as for arene derivatives bearing elec-
25 t-Bu
26 t-Bu
27b Ph
28b Ph
29 Ph
(S)-NHCH(Bn)CO2Me 3aa
30a,b Ph
(S)-NHCH(Bn)CO2Me 3aa 98c
88
a Method B was used in these cases.
b Epimerization was not observed in these cases.
tron-donating (entries 7–10 and 15) or electron-withdraw- c The excess amino acid was recovered in 83% yield.
Synthesis 2008, No. 2, 311–319 © Thieme Stuttgart · New York

314
J. L. García Ruano et al.
FEATURE ARTICLE
ing groups (entries 11 and 12). The presence of a was effected satisfactorily under similar conditions (entry
carboxylic acid ester group in the molecule did not inter- 19). We have attempted to effect both steps of Scheme 1
fere in the overall process (methyl sulfinates are much without isolating the intermediate sulfinamide. This one-
more reactive). Chloro derivatives 3m and 3n, which are pot procedure gave good results for the preparation of the
potential precursors of more complex compounds by 3d (83% yield), but when it was applied to other cases the
cross-coupling reactions, are also easily obtained (entries results were less satisfactory.21
13 and 14). The reaction of pyridine-2-sulfinates with lith-
We have also applied our procedure to the preparation of
ium amides afforded the corresponding sulfinamides in
primary sulfonamides. Davis demonstrated that the reac-
very low yield (entries 16 and 18); Method B gave much
tion of lithium amide with methyl sulfinates provided only
better results in these cases (entries 17 and 19). The reac-
moderate yields of sulfinamides, but these were improved
tion of methyl alkanesulfinates was analogously efficient
when lithium hexamethyldisilazanide was used as the lith-
with both primary and secondary lithium amides (entries
ium amide equivalent.
21–26). It is noteworthy that the highly hindered 2-meth-
Following the Davis procedure22 we have prepared sever-
ylpropane-2-sulfinamides were also obtained in satisfac-
al sulfinamides, which were then oxidized with 3-chlorop-
tory yields under the lithium amide conditions (entries 25
eroxybenzoic acid (1.5 equiv) at room temperature. The
and 26).
method was successfully used in the synthesis of alkane or
We have also studied the formation of sulfinamides de-
arenesulfonamides (Table 3).
rived from enantiomerically pure amines to determine the
Another consequence of the process is that enantiomeri-
configurational stability of the products under the reaction
cally pure sulfonamides can be obtained via reaction of ra-
cemic amines with an enantiomerically pure sulfinate. We
illustrate one example of this possibility using ( )-
norephedrine (6) and (–)-menthyl 4-toluenesulfinate as
the starting materials (Scheme 2). The putative dianion
derived from ( )-norephedrine (6) and butyllithium react-
ed with (–)-menthyl 4-toluenesulfinate to give the two
conditions. For this purpose, we studied the sulfination of
(R)-1-phenylethylamine and (S)-1-methylpropylamine
(entries 27 and 28). As expected, both reacted via the cor-
responding lithium amides affording sulfinamides with-
out appreciable racemization. This result prompted us to
extend the procedure to the synthesis of sulfonamides de-
rived from amino acids, because they are known to en-
hance both the pharmacological potency and the
selectivity of sulfonamides derived from certain amines.19
Table 3 Synthesis of Primary Sulfonamides
The reaction of methyl benzenesulfinate with phenylala-
MCPBA
(1.5 equiv)
O
S
O
S
O
S
LHMDS
R1
nine methyl ester using Method A (lithium amide) afford-
ed a complex mixture (entry 29). However, to our delight,
the use of Method B [a-amino ester (3 equiv), reflux] pro-
vided the sulfinamide in good yield, neither affecting the
ester group nor the configurational integrity of the chiral
center (entry 30).
R1
R1
OMe
NH2
NH2
THF, –78 °C
CH2Cl2
5 min
O
1a–k
4a–d
5a–d
Entry
R1
Product
Yield (%)
Step 1
Step 2
86
The oxidation of the sulfinamides with 3-chloroperoxy-
benzoic acid resulted in satisfactory sulfonamide yields in
most cases. Arene- and alkanesulfinamides (even the
bulky tert-butyl derivatives, entries 25 and 26) are easily
oxidized and the presence of a double bond does not inter-
fere with the oxidation step (entries 2, 7, 13, and 25). The
oxidation of 2p failed in our hands20 (entries 16 and 17),
which is not easy to explain given that the oxidation of 2q
1
Ph
5a
5b
5c
5d
78
81
86
–
2
4-MeC6H4
i-Pr
85
3
75
4a
t-Bu
84
a Commercial 2-methylpropane-2-sulfinamide was used.
Me
Ph
Me
O
Ph
O
O
MCPBA
CH2Cl2
S
Tol
N
H
S
Tol
Tol
N
H
OH
H
H
OH
H
H
Me
H2N
(1R,2R)-8
(–)-menthyl
4-toluenesulfinate
31%
Ph
(SS,1R,2R)-7
[α]D –9.0 (c 1.0, MeOH)
H
OH
H
n-BuLi (2 equiv)
Me
Ph
O
Me
Ph
H
O
O
6
MCPBA
CH2Cl2
S
N
H
S
OH
H
H
Tol
N
OH
H
H
(SS,1S,2S)-7
(1S,2S)-8 26%
[α]D +8.7 (c 1.0, MeOH)
(Lit.23 [α]D +9.3 (c 1.0, MeOH)
Scheme 2
Synthesis 2008, No. 2, 311–319 © Thieme Stuttgart · New York

FEATURE ARTICLE
Mild and General Method for the Synthesis of Sulfonamides
N-Allylbenzenesulfinamide (2b)
315
possible diastereomeric sulfinamides (SS,1R,2R)-7 and
(SS,1S,2S)-7 exclusively. These readily chromatographi-
cally separable sulfinamides were independently oxidized
to the corresponding enantiomerically pure sulfonamides
(1R,2R)-8 and (1S,2S)-8, one of which was correlated
with the previously reported (1S,2S)-isomer.23 Thus, not
only can enantiomerically pure sulfonamides be produced
in this manner, but the process also tolerates the presence
of a free hydroxy moiety.
Following Method A, 2b was directly obtained pure by removal of
the excess amine under vacuum; yellow oil; yield: 84%.
1H NMR (300 MHz, CDCl3): d = 7.69–7.64 (m, 2 H), 7.47–7.42 (m,
3 H), 5.84–5.73 (m, 1 H), 5.18 (d, J = 14.8 Hz, 1 H), 5.05 (d, J = 5.3
Hz, 1 H), 4.47 (br s, 1 H), 3.67–3.61 (m, 1 H), 3.41–3.33 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 143.9, 134.5, 130.7, 128.7, 125.9,
117.2, 43.5.
N-tert-Butyl-4-methoxybenzenesulfinamide (2i)
Following Method A, 2i was directly obtained pure by removal of
the excess amine under vacuum; orange oil; yield: 79%.
1H NMR (300 MHz, CDCl3): d = 7.58 and 6.96 (AA¢BB¢ system
J = 8.9 Hz, 4 H), 3.82 (s, 3 H), 1.38 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 161.5, 127.2, 114.8, 114.0, 55.4,
54.0, 31.1.
In conclusion, we have found that methyl sulfinates have
a similar reactivity towards nitrogen-based nucleophiles
as sulfonyl chlorides whereas their stability in air is much
higher (reactivity towards water much lower). These spe-
cial features have allowed us to develop a new and effi-
cient method to obtain sulfonamides by the reaction of
methyl sulfinates with lithium amides, and subsequent ox-
idation with 3-chloroperoxybenzoic acid. The experimen-
tal method is very simple, uses less aggressive reagents
and milder conditions than most methods used to date, and
the overall yield for the two-step sequence is usually bet-
ter than those of the procedures so far reported. It is the
first method of general scope that does not use sulfonyl
chlorides in any of the steps involved in the synthesis, thus
avoiding all the drawbacks that have been reported for
these reagents. As an additional advantage, methyl sulfi-
nates have a higher compatibility with different functional
groups present in the amine moiety than sulfonyl chlo-
rides. Lastly, it has been shown that enantiomerically pure
alkanesulfinates can be used as resolving agents for race-
mic amines.
MS (FAB): m/z (%) = 228 ([M + 1], 100), 219 (20), 201 (42), 195
(71).
HRMS: m/z [M + 1] calcd for C11H17NO2S: 228.1058; found:
228.1064.
N,N-Diethyl-4-methoxybenzenesulfinamide (2j)
Following Method A, 2j was directly obtained pure by removal of
the excess amine under vacuum; colorless oil; yield: 98%.
1H NMR (300 MHz, CDCl3): d = 7.57 and 6.99 (AA¢BB¢ system, 4
H), 3.86 (s, 3 H), 3.12 (qd, J = 7.2 and 1.8 Hz, 4 H), 1.12 (t, J = 7.2
Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 161.5, 135.6, 127.8, 114.1, 55.4,
41.7, 14.4.
Ethyl 4-(N-Phenylsulfinamoyl)benzoate (2k)
Following Method A, 2k was obtained pure by precipitation in hex-
ane; white solid; yield: 73%; mp 124–125 °C.
1H and 13C NMR spectra were acquired at 300 MHz and 75 MHz,
respectively, (unless otherwise indicated) relative to CDCl3 (d =
7.26 and 77.0). Melting points were determined in open capillary
tubes. All reactions were carried out in anhydrous solvents and un-
der argon. THF and Et2O were distilled from Na/benzophenone un-
der argon. Flash column chromatography was performed using
silica gel Merck-60 (230–400 mesh). All disulfides are commercial-
ly available except 1o and 1r, which were synthesized from the cor-
responding thiols by atmospheric oxidation.13 Compounds 2a,24
2c,25 2d,26 2e,27 2f,28 2g,29 2h,30 2u,31,32 2x,33 2y/2y¢,34 2aa/2aa¢,35
3a,36 3b,37 3c,38 3d,7,39 3e,40 3f,41 3g,9g 3h,42 3i,9j 3j,43 3k,44 3l,7 3m,45
3n,7,39 3q,46 3r,47 3v,48 3x,49 3y,50 and 3z51 have been previously
described in the literature. The procedure used for synthesizing sul-
finamides 4a–d has been previously reported by Davis,22 and the
primary sulfonamides 5a–d are commercially available.
1H NMR (300 MHz, CDCl3): d = 8.17 and 7.86 (AA¢BB¢ system
J = 8.0 Hz, 4 H), 7.30 (t, J = 7.4 Hz, 2 H), 7.12 (d, J = 7.7 Hz, 3 H),
6.62 (br s, 1 H), 4.44 (q, J = 6.9 Hz, 2 H), 1.45 (t, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 165.5, 148.9, 140.2, 133.1, 130.1,
129.5, 125.7, 123.9, 119.2, 61.5, 14.2.
MS (FAB): m/z (%) = 289 ([M + 1], 10), 283 (100), 239 (77).
HRMS: m/z [M + 1] calcd for C15H15NO3S: 289.0773; found:
289.0770.
Ethyl 4-(N,N-Diethylsulfinamoyl)benzoate (2l)
Following Method A, 2l was directly obtained pure by removal of
the excess amine under vacuum; yellow oil; yield: 84%.
1H NMR (300 MHz, CDCl3): d = 8.11 and 7.70 (AA¢BB¢ system
J = 7.1 Hz, 4 H), 4.36 (q, J = 3.8 Hz, 2 H), 3.10 (q, J = 7.4 Hz, 4 H),
1.38 (t, J = 3.9 Hz, 3 H), (q, J = 7.3 Hz, 6 H).
Secondary and Tertiary Sulfinamides 2a–aa (Table 2); General
Procedure
MS (FAB): m/z (%) = 270 ([M + 1], 75), 239 (58), 195 (100).
Method A: To a stirred soln of the methyl sulfinate 1 (1 mmol) in
THF (4 mL) at r.t. under argon, a soln of the lithium amide of the
primary or secondary amine [prepared from amine (1.2 equiv) in
THF (4 mL) and n-BuLi (1.2 equiv) at –78 °C] was added via can-
nula. The reaction was monitored by TLC. Upon completion (1–1.5
h), aq 0.1 M Na2HPO4 (5 mL) was added and the mixture was ex-
tracted with CH2Cl2 (3 × 20 mL). The combined organic phases
were dried (MgSO4) and concentrated under vacuum. The residue
was ready to use in the next step without purification.
HRMS: m/z [M + 1] calcd for C13H19NO3S: 270.1164; found:
270.1165.
N-Allyl-4-chlorobenzenesulfinamide (2m)
Following Method A, 2m was directly obtained pure by removal of
the excess amine under vacuum; yellow oil; yield: 83%.
1H NMR (300 MHz, CDCl3): d = 7.52 and 7.32 (AA¢BB¢ system
J = 8.7 Hz, 4 H), 5.76–5.63 (m, 1 H), 5.20 (br s, 1 H), 5.06 (d,
J = 14.0 Hz, 1 H), 4.96 (d, J = 8.9 Hz, 1 H), 3.57–3.48 (m, 1 H),
3.29–3.20 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 142.2, 136.5, 134.2, 128.5, 127.2,
116.7, 42.8.
Method B: A mixture of the methyl sulfinate (1 mmol) and amine (3
mmol) was heated to reflux for 4 h. The volatiles were evaporated
under vacuum and the residue was chromatographed to produce the
corresponding sulfinamide 2.
Synthesis 2008, No. 2, 311–319 © Thieme Stuttgart · New York

316
J. L. García Ruano et al.
FEATURE ARTICLE
MS (FAB): m/z (%) = 216 ([M + 1], 100), 199 (16), 195 (26), 182
1-(Propylsulfinyl)pyrrolidine (2t)
(10).
Following Method A, 2t was obtained as a very unstable colorless
oil; yield: 51%.
HRMS: m/z [M + 1] calcd for C9H10ClNOS: 216.0249; found:
216.0256.
1H NMR (300 MHz, CDCl3): d = 3.48–3.38 (m, 2 H), 3.20–3.10 (m,
2 H), 2.71 (t, J = 7.5 Hz, 2 H), 1.89–1.84 (m, 4 H), 1.76–1.58 (m, 2
H), 1.04 (t, J = 7.5 Hz, 3 H).
4-Chloro-N,N-diethylbenzenesulfinamide (2n)
Following Method A, 2n was directly obtained pure by removal of
the excess amine under vacuum; colorless oil; yield: 82%.
4-(Isobutylsulfinyl)morpholine (2v)
Following Method A, 2v was purified by flash chromatography
(hexane–EtOAc, 3:1) to give a colorless oil; yield: 55%.
1H NMR (300 MHz, CDCl3): d = 3.78 (m, 4 H), 3.16 (m, 4 H), 2.71
(dd, J = 13.2, 6.9 Hz, 1 H), 2.61 (dd, J = 13.2, 6.9 Hz, 1 H), 2.03 (m,
1 H), 1.06 (d, J = 6.6 Hz, 6 H).
1H NMR (200 MHz, CDCl3): d = 7.60 and 7.47 (AA¢BB¢ system, 4
H), 3.13 (q, J = 7.2 Hz, 4 H), 1.12 (t, J = 7.0 Hz, 6 H).
13C NMR (50 MHz, CDCl3): d = 142.9, 136.8, 128.9, 127.8, 42.0,
14.3.
N,N-Diethyl-4-(triisopropylsilyloxy)benzenesulfinamide (2o)
Following Method A, 2o was directly obtained pure by removal of
the excess amine under vacuum; colorless oil; yield: 93%.
1H NMR (300 MHz, CDCl3): d = 7.51 and 6.97 (AA¢BB¢ system, 4
H), 3.21–3.02 (m, 4 H), 1.32–1.20 (m, 3 H), 1.12–1.07 (m, 24 H).
13C NMR (75 MHz, CDCl3): d = 158.3, 135.9, 127.8, 120.2, 41.8,
17.8, 14.4, 12.6.
13C NMR (75 MHz, CDCl3): d = 66.8, 60.7, 45.8, 24.5, 22.5, 22.1.
N-Allyl-2-methylpropane-2-sulfinamide (2w)
Obtained using Ellman methodology54 with S-tert-butyl 2-methyl-
propane-2-sulfinothioate as the electrophile instead of methyl sulfi-
nate following the same experimental procedure for Method A. The
product was purified by flash chromatography (hexane–EtOAc,
2:1); colorless oil; yield: 75%.
1H NMR (300 MHz, CDCl3): d = 5.95–5.82 (m, 1 H), 5.26 (dd,
J = 16.0, 1.5 Hz, 1 H), 5.17 (dd, J = 8.8, 1.3 Hz, 1 H), 3.89 (br s, 1
H), 3.82–3.78 (m, 2 H), 1.40 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 134.5, 117.0, 59.9, 47.1, 24.3.
N-Cyclohexylpyridine-2-sulfinamide (2p)
Following Method B using with cyclohexylamine (3 equiv), 2p was
obtained pure by precipitation in acetone; white solid; yield: 98%;
mp 145–147 °C.
1H NMR (300 MHz, CD3OD): d = 7.60–7.57 (m, 2 H), 7.39–7.30
(m, 2 H), 2.98–290 (m, 1 H), 1.92–1.89 (m, 2 H), 1.78–1.74 (m, 2
H), 1.65–1.59 (m, 1 H), 1.34–1.11 (m, 5 H).
13C NMR (75 MHz, CD3OD): d = 130.6, 129.5 (2C), 125.2 (2C),
51.4, 31.9, 25.9, 25.4.
(SS/RS)-N-[(S)-sec-Butyl]benzenesulfinamide (2z/2z¢)
Following Method A gave a mixture of diastereomeric sulfin-
amides;55 pure product was directly obtained by removal of the ex-
cess amine under vacuum; colorless oil; yield: 78%.
1H NMR (300 MHz, CDCl3): d (major diastereomer) = 7.60–7.56
(m, 2 H), 7.37–7.31 (m, 3 H), 4.24 (d, J = 7.6 Hz, 1 H), 3.27–3.11
(m, 1 H), 1.53–1.32 (m, 2 H), 1.01 (d, J = 6.6 Hz, 3 H), 0.84 (t,
J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d (major diastereomer) = 145.1, 130.1,
128.1, 125.4, 51.9, 30.8, 21.9, 9.9.
1H NMR (300 MHz, CDCl3): d (minor diastereomer) = 7.60–7.56
(m, 2 H), 7.37–7.31 (m, 3 H), 4.36 (d, J = 7.6 Hz, 1 H), 3.27–3.11
(m, 1 H), 1.30–1.22 (m, 2 H), 1.15 (d, J = 6.4 Hz, 3 H), 0.69 (t,
J = 7.4 Hz, 3 H).
4-(2-Pyridylsulfinyl)morpholine (2q)
Following Method B using morpholine (3 equiv), chromatography
of the residue (hexane–EtOAc, 1:2) gave 2q as a colorless oil; yield:
65%.
1H NMR (200 MHz, CDCl3): d = 8.76–8.70 (m, 1 H), 8.05–7.90 (m,
2 H), 7.48–7.38 (m, 1 H), 3.83–3.63 (m, 4 H), 3.35–2.83 (m, 4 H).
13C NMR (50 MHz, CDCl3): d = 162.0, 150.1, 137.5, 125.2, 121.5,
66.7, 45.8.
N-Benzylthiophene-2-sulfinamide (2r)
Following Method A, 2r was obtained pure by precipitation in hex-
13C NMR (75 MHz, CDCl3): d (minor diastereomer) = 144.7, 130.1,
128.2, 125.5, 50.7, 30.5, 21.9, 9.7.
ane; white solid; yield: 73%; mp 76–77 °C.
MS (FAB): m/z (%) = 198 ([M + 1], 100), 195 (35), 168 (12), 154
(11).
1H NMR (300 MHz, CDCl3): d = 8.73 (d, J = 4.7 Hz, 1 H), 8.04 (d,
J = 7.0 Hz, 1 H), 7.92 (t, J = 7.7 Hz, 1 H), 7.42 (t, J = 4.7 Hz, 1 H),
7.28 (s, 4 H), 4.80 (br s, 1 H), 4.26 (dd, J = 4.7, 2.1 Hz, 1 H), 3.92
(dd, J = 4.7, 2.1 Hz, 1 H).
HRMS: m/z [M + 1] calcd for C10H15NOS: 198.0952; found:
198.0994.
13C NMR (75 MHz, CDCl3): d = 162.9, 150.1, 137.6, 128.5, 128.3,
127.6, 125.2, 121.4, 44.8.
(1R,2R)-2-[(Ss)-4-Methylphenylsulfinylamino]-1-phenylpro-
pan-1-ol [(SS,1R,2R)-7]
Following Method A, in this case (–)-menthyl 4-toluenesulfinate,
( )-norephedrine (6), and n-BuLi (2.2 equiv) were used. A mixture
of diastereomeric sulfinamides was obtained, and was purified by
flash chromatography (hexane–EtOAc, 4:1); colorless oil; yield:
33%.
N-Phenethylpropane-1-sulfinamide (2s)
Following Method A, 2s was purified by flash chromatography
(hexane–EtOAc, 2:1) to give a colorless oil; yield: 71%.
1H NMR (300 MHz, CDCl3): d = 7.36–7.31 (m, 2 H), 7.27–7.22 (m,
3 H), 4.26 (dd, J = 4.7, 2.1 Hz, 1 H), 3.40 (q, J = 5.3 Hz, 2 H), 2.91
(t, J = 7.0 Hz, 2 H), 2.71 (t, J = 7.2 Hz, 2 H), 1.68 (q, J = 6.4 Hz, 2
H), 1.04 (t, J = 5.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 138.4, 128.8, 128.5, 126.5, 57.2,
44.2, 37.0, 16.8, 13.2.
[a]D20 –21.0 (c 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.56 (d, J = 8.2 Hz, 2 H), 7.37–
7.32 (m, 7 H), 5.26 (d, J = 8.5 Hz, 1 H), 4.62 (dd, J = 5.1, 2.4 Hz, 1
H), 3.39 (d, J = 9.8 Hz, 1 H), 3.48–3.41 (m, 1 H), 2.45 (s, 3 H), 0.94
(d, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 141.4, 139.9, 139.0, 129.6, 128.0,
127.4, 127.0, 126.2, 74.8, 55.3, 21.3, 18.2.
Synthesis 2008, No. 2, 311–319 © Thieme Stuttgart · New York

FEATURE ARTICLE
Mild and General Method for the Synthesis of Sulfonamides
317
(1S,2S)-2-[(SS)-4-Methylphenylsulfinylamino]-1-phenylpro-
pan-1-ol [(SS,1S,2S)-7]
Following Method A, in this case (–)-menthyl 4-toluenesulfinate,
( )-norephedrine (6), and n-BuLi (2.2 equiv) were used. The prod-
uct was purified by flash chromatography (hexane–EtOAc, 4:1);
white solid; yield: 37%; mp 95–97 °C.
[a]D20 +46.0 (c 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.58 (d, J = 8.2 Hz, 2 H), 7.32–
7.26 (m, 7 H), 4.87 (m, 1 H), 4.58 (d, J = 9.3 Hz, 1 H), 4.32 (br s, 1
H), 3.30–3.74 (m, 1 H), 2.43 (s, 3 H), 1.10 (d, J = 6.8 Hz, 3 H).
1H NMR (300 MHz, CDCl3): d = 7.42 (br s, 1 H), 7.25–7.17 (m, 4
H), 7.06–7.01 (m, 1 H), 3.22 (sext., J = 6.8 Hz, 1 H), 1.29 (d, J = 6.8
Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 137.3, 129.4, 124.5, 119.9, 55.3,
16.3.
MS (FAB): m/z (%) = 199 (M, 100), 195 (78), 166 (12), 158 (13).
HRMS: m/z [M] calcd for C9H13NO2S: 199.0667; found: 199.0668.
N-Allyl-2-methylpropane-2-sulfonamide (3w)
Obtained pure without additional purification; colorless oil; yield:
85%.
1H NMR (300 MHz, CDCl3): d = 5.95–5.83 (m, 1 H), 5.27 (dd,
J = 15.7, 1.5 Hz, 1 H), 5.18 (dd, J = 8.9, 1.3 Hz, 1 H), 3.80 (t, J = 6.1
Hz, 2 H), 1.40 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 134.5, 117.0, 59.9, 47.1, 24.3.
MS (EI): m/z (%) = 177 (M+, 15), 167 (46), 137 (58), 65 (44).
HRMS (EI): m/z [M]+ calcd for C7H15NO2S: 177.0790; found:
13C NMR (75 MHz, CDCl3): d = 141.5, 141.3, 140.4, 129.5, 128.0,
127.2, 126.4, 125.6, 76.3, 57.2, 21.3, 16.5.
Sulfonamides 3a–aa (Table 2) and 5a–d (Table 3); General Pro-
cedure
To a soln of the sulfinamide 2a–aa (or 4a–d) in CH2Cl2 (6 mL),
commercial MCPBA (1.5 equiv) was added in 1 portion at r.t. When
the reaction was complete (5 min), 40% sodium bisulfite (5 mL)
was added and the mixture was stirred for 5 min. The soln was ex-
tracted with CH2Cl2 (3 × 20 mL), the organic phase was washed
with sat. NaHCO3 (2 × 40 mL), dried (Na2SO4), and concentrated.
The corresponding sulfonamide was obtained pure in most cases;
when not, it was purified by column chromatography.
177.0763.
Methyl (S)-3-Phenyl-2-(phenylsulfonylamino)propanoate (3aa)
Obtained pure without additional purification; yellow oil; yield:
88%; 99% ee [HPLC (Chiralpak AD column, hexane–i-PrOH, 95:5,
flow rate: 1.0mL/min): tR = 22.1 (S), 26.6 min (R)].
N,N-Diethyl-4-(triisopropylsiloxy)benzenesulfonamide (3o)
Purified by flash chromatography (hexane–EtOAc, 10:1); white
solid; yield: 64%; mp 49–50 °C.
1H NMR (300 MHz, CDCl3): d = 7.68 and 6.93 (AA¢BB¢ system, 4
H), 3.22 (q, J = 7.2 Hz, 4 H), 1.33–1.21 (m, 3 H), 1.18–1.05 (m, 24
[a]D20 –5.0 (c 0.2, acetone).
1H NMR (300 MHz, CDCl3): d = 7.75 (d, J = 1.9 Hz, 2 H), 7.54–
7.52 (m, 1 H), 7.47–7.42 (m, 1 H), 7.26–7.22 (m, 4 H), 7.07–7.04
(m, 2 H), 5.06 (d, J = 9.2 Hz, 1 H), 4.22 (dd, J = 9.3, 5.6 Hz, 1 H),
3.48 (s, 3 H), 3.04 (d, J = 5.6 Hz, 2 H).
H).
13C NMR (75 MHz, CDCl3): d = 171.1, 139.5, 134.8, 132.7, 129.3,
128.9, 128.6, 127.3, 127.1, 56.6, 52.4, 39.3.
13C NMR (75 MHz, CDCl3): d = 159.7, 132.5, 129.0, 120.1, 41.8,
17.8, 14.0, 12.6.
MS (EI): m/z (%) = 385 (M+, 35), 342 (100), 314 (48), 286 (70), 272
(24), 206 (17), 150 (16), 136 (39).
HRMS (FAB): m/z [M + H]+ calcd for C19H35NO3SSi: 386.2185;
Acknowledgment
We thank the Spanish Government for financial support (Grant
CTQ2006-06741). A.P. thanks the Ministerio de Educación y Cien-
cia for predoctoral fellowships. We also thank Dr. J. M. Muchowski
for reviewing the manuscript.
found: 386.2187.
N-Phenethylpropane-1-sulfonamide (3s)
Obtained pure without additional purification; white solid; yield:
82%; mp 49–50 °C.
1H NMR (300 MHz, CDCl3): d = 7.27–7.12 (m, 5 H), 4.25 (br s, 1
H), 3.30 (q, J = 6.8 Hz, 2 H), 2.29 (t, J = 5.13 Hz, 4 H), 1.71–1.59
(m, 2 H), 0.91 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 137.9, 128.8, 128.6, 126.8, 54.3,
44.4, 36.6, 17.2, 12.8.
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Synthesis 2008, No. 2, 311–319 © Thieme Stuttgart · New York

318
J. L. García Ruano et al.
FEATURE ARTICLE
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