Fast and efficient synthesis of sulfinamides by the oxidation of sulfenamides using potassium fluoride and m-chloroperoxybenzoic acid

Article abstract of DOI:10.1080/00397911.2010.543748

A procedure for the synthesis of N-alkyl-, N-cycloalkyl-, N,N-dialkyl-, and N-arylarenesulfinamides from the corresponding sulfenamides using KF/m-chloroperoxybenzoic acid (CPBA) in CH₃CN-H₂O is described. High efficiency (fast react

Full text of DOI:10.1080/00397911.2010.543748

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Fast and Efficient Synthesis of
Sulfinamides by the Oxidation of
Sulfenamides Using Potassium Fluoride
and m-Chloroperoxybenzoic Acid
Mrityunjoy Datta a & Alan J. Buglass a
a Department of Chemistry, Korea Advanced Institute of Science and
Technology, Daejeon, Republic of Korea
Accepted author version posted online: 17 Nov 2011.Published
online: 27 Feb 2012.
To cite this article: Mrityunjoy Datta & Alan J. Buglass (2012) Fast and Efficient Synthesis of
Sulfinamides by the Oxidation of Sulfenamides Using Potassium Fluoride and m-Chloroperoxybenzoic
Acid, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 42:12, 1760-1769, DOI: 10.1080/00397911.2010.543748
To link to this article: http://dx.doi.org/10.1080/00397911.2010.543748
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Synthetic Communications1, 42: 1760–1769, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.543748
FAST AND EFFICIENT SYNTHESIS OF SULFINAMIDES
BY THE OXIDATION OF SULFENAMIDES USING
POTASSIUM FLUORIDE AND
m-CHLOROPEROXYBENZOIC ACID
Mrityunjoy Datta and Alan J. Buglass
Department of Chemistry, Korea Advanced Institute of Science and
Technology, Daejeon, Republic of Korea
GRAPHICAL ABSTRACT
Abstract A procedure for the synthesis of N-alkyl-, N-cycloalkyl-, N,N-dialkyl-, and
N-arylarenesulfinamides from the corresponding sulfenamides using KF/m–chloroperoxy-
benzoic acid (CPBA) in CH3CN-H2O is described. High efficiency (fast reactions, ease
of manipulation, and good yields) and absence of overoxidation are the major advantageous
features of this protocol.
Keywords KF=m-CPBA; oxidation; sulfenamides; sulfinamides
INTRODUCTION
The chiral sulfinyl group [R-S(O)-] is an important functional group for the con-
trol of numerous asymmetric synthesis because it effectively transfers chirality to a
wide range of centers.[1] Sulfinamides[2] are useful sulfinyl chiral auxiliaries for syn-
thesis of amines,[3] aziridines,[4] sulfoximines and related species,[5] benzothiazines,[6]
olefins, and ketones.[7] Sulfinamides[2b,c] play pivotal roles in modern asymmetric
synthesis as key precursors of chiral molecules and also as organocatalysts in the
enantioselective reduction of ketimines.[8] In particular, cyclic sulfinamides[9] are used
as synthetic intermediates[10] and have elicited interest in medicinal chemistry.[11]
They have also been used in materials science as imaging agents.[12] Moreover, in view
of the growing use of sulfonamides[13] as antibacterial agents, hypoglycemic agents,
antiviral agents, anti-inflammatory agents, and protease inhibitors[14] we were inter-
ested in the synthesis of sulfinamides as these can serve as precursors of corresponding
sulfonamides.
Received October 11, 2010.
Address correspondence to Alan J. Buglass, Department of Chemistry, Korea Advanced Institute
of Science and Technology, Daejeon 305-701, Republic of Korea. E-mail: alan_buglass@yahoo.com
1760

SULFINAMIDE TO SULFENAMIDES OXIDATION
1761
There are various procedures reported for the preparation of sulfinamides from
sulfinic acids,[15] sulfinates,[16] sulfinyl chlorides,[17] thiosulfinates,[18] N-sulfinyla-
mines,[19] oxathiazolidine oxide,[20] sulfoximines,[21] benzothiazines[22] and homolytic
substitution at the sulfur atom.[23] These reactions often require two or more syn-
thetic steps. Additionally, sulfinamides can be obtained from sulfonyl chlorides[24]
but sulfonamides are also produced as by-products, thus presenting a serious draw-
back. Also, the harsh conditions frequently required for synthesis of the sulfonyl
chlorides and the difficulty in handling and storing these often lachrymatory and
water-sensitive agents give cause for concern. Very recently, sulfinamides were
synthesized from methyl sulfinates[13] with lithium amide, but the method required
strict control of the very low temperature (ꢀ78 ꢁC).
There are several reports on the synthesis of sulfinamides via the oxidation of sul-
fenamides, although each one is rather limited in scope.[25] Sagramora et al.[25a] used
(þ)-monopercamphoric acid, whereas Davis et al.[25b] and Harpp and Back[25c] used
chloroperoxybenzonic acid(m-CPBA) in chlorinated hydrocarbon solvents to produce
N-alkylidenearenesulfinamides and N-(alkylsulfinyl)phthalimides, respectively. More-
over, m-CPBA has been used to oxidize sulfenamides to sulfonamides, rather than
sulfinamides, using a sulfenamide– m-CPBA molar ratio of 13.5:30.[25d] Additionally,
there is a report on the N-chlorosuccinimide oxidation of N,N-dialkylalkanesulfena-
mides to the corresponding sulfinamides, in dichloromethane solvent.[25e]
In view of the available methods, our aim was to devise a one-step nonstereo-
selective synthesis of sulfinamides by oxidation of sulfenamides, using m-CPBA or
other oxidizing agents. A one-step process would be useful and would increase the
exploration of sulfinamide chemistry.
RESULTS AND DISCUSSION
Initially, we used 1 equivalent of m-CPBA, which led to the formation of
sulfinamide, along with corresponding sulfonamide, within a few minutes, even at
ꢀ20 ꢁC. However, we could not control the formation of sulfonamide. Moreover,
partial solubility of m-CPBA in dichloromethane and the separation of by-product
m-chlorobenzoic acid was also a serious problem. Other oxidizing agents also gave
a mixture of sulfinamide and sulfonamide in every case.
The KF=m-CPBA reagent, sometimes known as Camps’s reagent, was first
described by Camps et al.[26] and used in the Baeyer–Villiger oxidation of substituted
benzaldehydes to formates and in the epoxidation of alkenes. It was originally used
as a solid-phase reagent (i.e., as a slurry in dichloromethane), in a substrate–KF–m-
CPBA ratio of 0.4:2:1, but the stability of the m-CPBA ꢂ KF complex was demon-
strated to be greater in homogeneous solution.[27]
Recently, KF=m-CPBA system has been used in the preparation of 1-phenyl-
sulfonylindolyl methyl sulfoxides[28] and also for the oxidation of thioglycosides to
glycosyl sulfoxides[29] without any overoxidation. Previously, the KF=m-CPBA sys-
tem had been successfully employed for the preparation of glycal epoxides,[30] the
conversion of epoxy ketones into epoxy esters,[31] and the oxidative conversion of
fluorodimethylsilyl groups to hydroxyl groups,[32] the so-called Tamao-Kumada[33]
reaction. Also, it has been observed that azides can be converted to nitro compounds
and sulfides can be oxidized to sulfones using HOF ꢂ CH3CN.[34]

1762
M. DATTA AND A. J. BUGLASS
Agnihotri and Misra suggested[29] that KF=m-CPBA in CH3CN-H2O may
produce KOF ꢂ CH3CN, whose conjugate acid was demonstrated earlier as a most
powerful oxygen-transfer agent[34] and it is noteworthy that the CH3CN-H2O (5:1)
solvent system was found to be most effective in producing better yields than other
commonly used solvents, such as dichloromethane, tetrahydrofuran (THF), or
CH3CN.
On the basis of these observations, we decided to explore the KF=m-CPBA
system in acetonitrile–water for the general oxidation of sulfenamides (prepared
by standard methods[35]) to sulfinamides, in the molar ratio substrate–KF–m-CPBA
of 0.5:1:1, supposing that the highly electrophilic nature of oxygen atom of
KOF ꢂ CH3CN could be used for oxidation of sulfenamides to sulfinamides without
overoxidation to sulfonamides.
The results of oxidation of N-alkyl-, N-cycloalkyl-, N,N-dialkyl-, and N-arylar-
enesulfenamides employing KF=m-CPBA in CH3CN-H2O at 0 ꢁC (Scheme 1) are
presented in Table 1. It can be seen that all 18 substrates were transformed rapidly
to the corresponding sulfinamides at 0 ꢁC in good yields. Indeed, under these con-
ditions, the lowest recorded yield was 82% and the slowest oxidation took 20 min.
The rate of oxidation appears to be dependent on both the electronic nature of
the aromatic substituents and steric hindrance caused by ortho substituents on both
S-aryl and N-aryl rings of N-arylarenesulfenamides. By contrast, the nature of the
alkyl groups in N-alkylarenesulfenamides seems to have little influence on either
the reaction rate or yield.
The most rapid oxidation occurs when para electron donors (tBu, Me, MeO)
are present in either or both of the aromatic rings of N-arylarenesulfenamides
(Table 1 entries 8, 9, and 15) and also when present in the S-aryl group (entries 6,
7,10, and 11). Conversely, para electron-withdrawing groups (Cl, NO2) in the S-aryl
group appear to promote slower oxidation (entries 1–3 and 18). Slowest oxidation is
claimed for N-arylarenesulfenamides with two ortho methyl groups in the N-aryl ring
(entries 2 and 4), probably because of steric hindrance.
These observations are in accord with the suggestion that KF=m-CPBA in
acetonitrile water behaves like or generates KOF ꢂ CH3CN,[29] whereupon oxygen
is transferred to sulfur via nucleophilic attack of a sulfenamide sulfur lone pair of
electrons on the highly electrophilic oxygen of HOF, produced by salt hydrolysis
of KOF. The presence of ortho and=or para electron donors in the sulfenamide S-
aryl ring increases the electron density at sulfur, thereby increasing the reactivity,
whereas the presence of electron acceptors in this ring has the opposite effect.
In the solid state, the N-C(aryl) bond in N-arylalkanesulfinamides is much
´
˚
shorter (1.408 A for N-pheny-tert-butanesulfinamidel) than N-C(alkyl) bonds of
´
˚
N-alkylalkanesulfinamides (1.470–1.530 A), a result of significant interaction of the
Scheme 1. Synthesis of arenesulfinamides.

SULFINAMIDE TO SULFENAMIDES OXIDATION
1763
Table 1. Synthesis of sulfinamides with KF=m-CPBA in CH3CN-H2O (5:1) at 0 ꢁC
Time
(min)a
Yield
(%)b
Entry
1
Substrate
Product
12
95
90
2
3
4
5
15
15
20
10
84
88
87
6
7
8
8
8
7
90
83
91
9
5
8
94
88
10
(Continued )

1764
M. DATTA AND A. J. BUGLASS
Table 1. Continued
Time
(min)a
Yield
(%)b
Entry
11
Substrate
Product
8
10
10
10
7
86
85
84
87
88
82
90
82
12
13
14
15
16
17
18
10
10
12
aTime to completion of reaction, as determined by TLC (silica gel, dichloromethane–hexane [1:1]).
bYields refer to chromatographically isolated pure products, which were identified by their spectral char-
acteristics (IR, 1H NMR, 13C NMR, EIMS) and microanalysis (1a–4a) or by comparison of melting point
and spectral data with literature data (5a–18a).
nitrogen lone pair with the N-aryl p–system.[36] Such interaction lowers the electron
density at sulfur. However, the aforementioned interaction is weakened if there is a
para electron donor in the N-aryl ring, as indicated by a rather longer N-C(aryl)
[37]
It is reasonable
´
˚
bond (1.423 A) in N-(4-methoxyphenyl)-tert-butanesulfinamide.
to suppose that this argument can be applied to the corresponding sulfenamides, thus
explaining why those with a powerful N-aryl electron donor in the para position
(Table I; entries 9 and 15) are among the most reactive.

SULFINAMIDE TO SULFENAMIDES OXIDATION
1765
CONCLUSION
In conclusion, we have synthesized several sulfinamides from the correspond-
ing sulfenamides using KF=m-CPBA in CH3CN-H2O. High reaction rates, manipu-
lative simplicity, generality, lack of serious hazards, and absence of overoxidation
are the main advantages of this method. We hope this to be a method of choice
for nonstereoselective preparation of sulfinamides, particularly for high-throughput
chemistry.
EXPERIMENTAL
Reagents and chemicals were purchased from commercial sources and used as
received. Chromatographic separations were carried out using Sigma-Aldrich silica
gel (230–400 mesh). Analytical thin-layer chromatographym (TLC) was performed
on Sigma-Aldrich silica-gel TLC plates with ultraviolet indicator. The melting points
reported were measured with a Reichert hot-stage apparatus and are uncorrected.
Infrared (IR) spectra were recorded on a Perkin-Elmer 1600 series Fourier transform
1
(FT)–IR spectrometer. H NMR and 13C NMR spectra were recorded at room
temperature on a Bruker ARX-400 spectrometer at 400 MHZ and 100 MHZ respect-
ively and are reported in parts per million (ppm, d) from tetramethylsilane (TMS: d
0.0 ppm).
General Procedure for the Synthesis of Sulfinamides from
Sulfenamides
Typical experimental procedure for 1a: 70% m-CPBA (660 mg, 3.84 mmol) was
added to a solution of KF (223 mg, 3.84 mmol) in CH3CN-H2O (20 mL, v=v 5:1), and
the reaction mixture was stirred at 0 ꢁC for 30 min. To this ice-cooled reaction mix-
ture, N-(4-methylphenyl)-4-nitrobenzenesulfenamide (500 mg, 1.92 mmol, entry 1)
was added in aliquots and stirred for 12 min. After completion of the reaction
(TLC-monitored), it was then poured into saturated aqueous NaHCO3 solution
and extracted with ethyl acetate (3 ꢃ 30 mL). The organic extracts were combined,
dried over MgSO4, and concentrated under reduced pressure. The residue was puri-
fied by column chromatography (CH2Cl2– hexane, 1:4) to afford N-(4-methylphe-
nyl)-4-nitrobenzenesulfinamide (1a) as a yellow powder (503 mg, 95%). Other
sulfinamides were prepared in an analogous manner.
Spectroscopic and Other Data for 1a–18a
N-(4-Methylphenyl)-4-nitrobenzenesulfinamide (1a). Mp 150–151 ꢁC;
FTIR (KBr) nmax (cmꢀ1) 3030, 1530, 1511, 1476, 1432, 1346, 1097, 1069, 1014, 936,
1
856. H NMR (400 MHz, CDCl3) d 8.34 (dd, J ¼ 7.0, 1.6 Hz, 2H), 7.96–7.93 (m,
2H) 7.06 (d, J ¼ 8.2 Hz, 2H), 6.95 (d, J ¼ 8.3 Hz, 2H), 6.11 (bs, 1H), 2.27 (s, 3H).
13C NMR (100 MHz, CDCl3) d 151.23, 149.70, 136.50, 134.75, 130.11, 127.17,
124.10, 120.85, 20.77. EIMS m=z (%) 276 (Mþ., 16), 107 (40), 106 (Mþ.– ArSO,
100). Anal. calcd. for C13H12N2O3S: C, 56.52; H, 4.34; N, 10.15. Found: C, 56.55;
H, 4.31; N, 10.13.

1766
M. DATTA AND A. J. BUGLASS
N-(2,4,6-Trimethylphenyl)-4-nitrobenzenesulfinamide (2a). Mp 140 ꢁC;
FTIR (KBr) nmax (cmꢀ1) 3320, 3037, 2918, 1605, 1531, 1482, 349, 1144, 1095, 1069,
1013, 854. 1H NMR (400 MHz, CDCl3) d 8.39 (dd, J ¼ 7.0, 1.7 Hz, 2H), 8.09
(dd, J ¼ 6.9, 1.7 Hz, 2H), 6.91 (s, 2H), 5.57 (bs, 1H), 2.37 (s, 6H), 2.27 (s, 3H).
13C NMR (100 MHz, CDCl3) d 152.65, 149.73, 136.54, 133.87, 133.51, 129.68,
126.78, 124.08, 20.72, 19.03. EIMS m=z (%) 304 (Mþ., 55), 170 (Mþ.– ArNH, 12),
134 (Mþ.– ArSO, 100), 119 (11), 91 (50). Anal. calcd. for C15H16N2O3S: C, 59.21;
H, 5.26; N, 9.21. Found: C, 59.23; H, 5.20; N, 9.25.
N-(4-Methylphenyl)-2,4-dinitrobenzenesulfinamide (3a). Mp 134 ꢁC;
FTIR (KBr) nmax (cmꢀ1) 3106, 3079, 2359, 1669, 1605, 1541, 1511, 1345, 1083,
1
106, 1016, 858. H NMR (400 MHz, CDCl3) d 8.96 (d, J ¼ 2.1 Hz, 1H), 8.57 (dd,
J ¼ 8.5, 2.1 Hz, 1H), 8.42 (d, J ¼ 8.5 Hz, 1H), 7.01 (d, J ¼ 8.2 Hz, 2H), 6.88 (d,
J ¼ 8.2 Hz, 2H), 5.95 (bs, 1H), 2.24 (s, 3H). 13C NMR (100 MHz, CDCl3) d
149.65, 147.60, 146.29, 136.03, 135.58, 130.08, 129.48, 128.0, 121.87, 120.57, 20.82.
EIMS m=z (%) 322 (MHþ, 12), 321 (Mþ., 72), 240 (12), 216 (9), 106 (Mþ.– ArSO,
100). Anal. calcd. for C13H11N3O5S: C, 48.56; H, 3.43; N, 13.08. Found: C, 48.58;
H, 3.44; N, 13.05.
N-(2,4,6-Trimethylphenyl)-2,4-dinitrobenzenesulfinamide
(4a). Mp
133 ꢁC; FTIR (KBr) nmax (cmꢀ1) 3035, 2367, 1597, 1541, 1479, 1347, 1105, 927,
1
910, 833, 816. H NMR (400 MHz, CDCl3) d 8.96 (d, J ¼ 2.2 Hz, 1H), 8.64 (dd,
J ¼ 8.5, 2.2 Hz, 1H), 8.49 (d, J ¼ 8.5 Hz, 1H), 6.84 (s, 2H), 5.68 (s, 1H), 2.23 (s,
3H), 2.21 (s, 6H). 13C NMR (100 MHz, CDCl3) d 149.64, 149.04, 146.20, 136.97,
134.87, 131.76, 129.82, 128.53, 128.04, 120.36, 20.80, 18.88. EIMS m=z (%) 349
(Mþ., 22), 215 (Mþ.– ArNH, 10), 134 (Mþ.– ArSO, 100). Anal. calcd. for C15H15
N3O5S: C, 51.58; H, 4.30; N, 12.03. Found: C, 51.55; H, 4.33; N, 12.01.
Compounds 5a–18a. Compounds 5a–18a have been reported previously, and
each was identified by comparison of actual and literature melting points and=or
spectral data, as follows. 5a (mp 90 ꢁC; lit.[24] 88–89 ꢁC), 6a (colorless oil[38]), 7a
(mp 52–54 ꢁC; lit.[39] 50–52 ꢁC), 8a (mp 76–77 ꢁC; lit.[39] 77–79 ꢁC), 9a (mp 126 ꢁC;
lit.[24] 128 ꢁC), 10a (colorless oil[13]), 11a (orange oil[13]), 12a (colorless oil[40]), 13a
(mp 76–78 ꢁC; lit.[13] 75–76 ꢁC), 14a (colorless liquid24), 15a (mp 106–108 ꢁC; lit.[24]
105–106 ꢁC), 16a (mp 88–90 ꢁC; lit.[24] 88–89 ꢁC), 17a (mp 114 ꢁC; lit.[24] 116–
118 ꢁC), and 18a (colorless oil[13]).
ACKNOWLEDGMENT
Financial support from Korea Advanced Institute of Science and Technology
(KAIST) is gratefully acknowledged.
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