Efficient synthesis of N-acylarenesulfenamides by acylation of arenesulfenamides

Article abstract of DOI:10.1016/S0040-4020(02)01554-5

Acylation of arenesulfenamides proceeds efficiently by using either perfluorocarboxylic anhydrides or acid chlorides in the presence of pyridine as a base at low temperatures to give N-acylarenesulfenamides. Some N-alkylcarbonyl derivatives exist with imidic acid tautomers in an aprotic solvent.

Full text of DOI:10.1016/S0040-4020(02)01554-5

Tetrahedron 59 (2003) 303–309
Efficient synthesis of N-acylarenesulfenamides
by acylation of arenesulfenamides
a
a,b
Ming Bao,a Masao Shimizu,a Shigeru Shimada and Masato Tanaka
,
*
aNational Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central 5, 1-1-1 Higashi, Tsukuba,
Ibaraki 305-8565, Japan
bChemical Resources Laboratory, Tokyo Institute of Technology, 4259 Nagatsuda, Midori-ku, Yokohama 226-8503, Japan
Received 3 September 2002; accepted 25 November 2002
Abstract—Acylation of arenesulfenamides proceeds efficiently by using either perfluorocarboxylic anhydrides or acid chlorides in the
presence of pyridine as a base at low temperatures to give N-acylarenesulfenamides. Some N-alkylcarbonyl derivatives exist with imidic acid
tautomers in an aprotic solvent. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
N-Acylarenesulfenamides are not only versatile intermedi-
ates in the synthesis of a variety of sulfur compounds,1 but
also important compounds in view of their biological
activities. For example, N-benzoyl-4-chlorobenzenesulfen-
amide has been claimed to be potentially useful as a plant
growth regulator.2 N-Acylarenesulfenamides are usually
synthesized by the reaction of sulfenyl chlorides with
amides,3 although it was described in a previous review that
the sulfenamides resemble amines rather than amides and
that their acetyl and benzoyl derivatives easily formed by
conventional methods.4 Generation of sulfenyl chloride,
however, requires chlorination of disulfides or thiols with
hazardous, poisonous and corrosive chlorine gas, the use of
which does not meet the recent requirement in contempo-
rary organic synthesis for reagents of little or no risk.5 To
the best of our knowledge, only two examples of acylation
of arenesulfenamides for alternative synthesis of N-acylar-
enesulfenamides have been reported; treatment of arene-
sulfenamides at room temperature with acetic anhydride
(coupled with anhydrous sodium acetate) for a long reaction
time forms N-acetylarenesulfenamides, but the yield is not
satisfactory.6 The use of acid chlorides does not appear to
afford desired N-acylarenesulfenamide.7 Could other
acylating reagents be used to achieve acylation of
arenesulfenamides? Is it really impossible to prepare
N-acylarenesulfenamides with acid chlorides? This paper
will answer these questions.
Attempted acylation of 2-methoxycarbonylbenzenesulfen-
amide (1a) using carboxylic acid in combination with 1,3-
dicyclohexylcarbodiimide8 or N-acylimidazole,9 both
known as excellent reagents for acylation of amines, failed
to afford desired products and the starting material 1a was
recovered. The use of (CH3CH2CO)2O or (PhCO)2O did not
work either. However, when (CF3CO)2O was used as a
strong acylation reagent in the presence of pyridine at room
temperature, the acylation did proceed to give N-trifluoro-
acetyl-2-methoxycarbonylbenzenesulfenamide (2a) in 46%
yield (Scheme 1, Eq. (1)). Lowering the reaction tempera-
ture to 08C increased the yield of 2a to 73%.
A similar attempt to use benzoyl chloride in place of
(CF3CO)2O in the acylation reaction of 1a at room
temperature failed to provide desired N-benzoyl-2-
methoxycarbonylbenzenesulfenamide (2h). The product
obtained in practice was a disulfenylamine (3; 56%), the
formation of which is, as described in the literatures,7 due
presumably to the rapid reaction of intermediary N-benzoyl-
2-methoxycarbonylbenenesulfenamide hydrochloride with
1a.2c However, the foregoing experiments with (CF3CO)2O
suggests that the reaction temperature plays an important
role to determine the reaction course. Indeed, the reaction of
1a with benzoyl chloride, when effected at 08C, worked
much better to form the desired product 2h in 78% yield
along with only 20% of 3. At 2208C formation of the latter
was totally suppressed to furnish 2h in 96% yield (Scheme
1, Eq. (2)).
Both of these new acylation procedures have proved to be
applicable to a wide range of arenesulfenamides. The results
obtained under the standard conditions (0.5 mmol of
Keywords: acylation; sulfenamides; amides; acid chlorides; imidic acids.
*
Corresponding author. Tel.: +81-298-61-4575; fax: +81-298-61-4487;
e-mail: m.shimizu@aist.go.jp
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01554-5

304
M. Bao et al. / Tetrahedron 59 (2003) 303–309
Scheme 1. Acylation reaction of 1a with trifluoroacetic anhydride and benzoyl chloride.
arenesulfenamide 1, 0.6 mmol of perfluorocarboxylic anhy-
dride or acid chloride and 1.5 equiv. of pyridine in 6 mL
CH2Cl2 at 08C or 2208C for 30 min) are summarized in
Table 1. When 2-bromobenzenesulfenamide (1b) was
employed in the acylation with (CF3CO)2O, N-trifluoro-
acetyl-2-bromobenzenesulfenamide (2b) was obtained in
80% yield (entry 2). Several other arenesulfenamides, such
as 4-nitrobenzenesulfenamide (1c), 4-methylbenzenesulfen-
amide (1d), and benzenesulfenamide (1e), also underwent
the acylation with (CF3CO)2O, and N-trifluoroacetyl-4-
nitrobenzenesulfenamide (2c), N-trifluoroacetyl-4-methyl-
benzenesulfenamide (2d), and N-trifluoroacetylbenzenesul-
fenamide (2e) were obtained in 82, 63 and 78% yields,
respectively (entries 3–5). When the acylation of 1e with
(CF3CO)2O was carried out at lower temperature such as
2208C, 2e was obtained in almost the same yield as the
acylation was performed at 08C (entry 6). This result
indicated that acylation of 1 with (CF3CO)2O did not need
proceeding at lower than 08C to afford 2 in good yields.
(CF3CF2CO)2O used as acylating reagent instead of
(CF3CO)2O also worked efficiently in the reaction of 1a
and 1c, and N-pentafluoropropionyl-2-methoxycarbonyl-
benzenesulfenamide (2f) and N-pentafluoropropionyl-4-
nitrobenzenesulfenamide (2g) were obtained in good yields
(90 and 85%, respectively, entries 7 and 8).
The acylations of 1c–f with benzoyl chloride at 2208C
furnished N-benzoylarenesulfenamides (2h–l) also in good
yields (entries 9–13). Especially, N-benzoyl-4-chloroben-
zenesulfenamide (2l), which was claimed to be a plant
growth regulator,2 was synthesized in 85% yield (entry 13).
It is interesting that some of parent arenesulfenamides, in
particular those that do not have a strongly electron-
withdrawing substituent on the aromatic ring, are thermally
rather unstable. Thus, 1b, 1d, and 1e deteriorate over a few
hours at room temperature to generate disulfenylamines.
However, the corresponding N-acylarenesulfenamides 2b,
2d, 2e, 2j, and 2k are stable crystalline materials, which
retain the structural integrity even after several months at
room temperature.
When acetyl chloride was used in acylation of 1a, an
acetylated product was obtained, and X-ray crystal structure
determination of the product clearly shows that the structure
is N-acetyl-2-methoxycarbonylbenzenesulfenamide (4a)
(Fig. 1).10 However, the 1H NMR spectrum of 4a in
CDCl3 at room temperature showed mixtures of amide (4a)
and imidic acid (5a) forms, which could be deduced from
the tautomerism in N-(acetylaminothio)phthalimide
reported in the literature.11 The ratio of 4a to 5a increased
with the addition of protic solvent, CD3OD, to the solution
of 4a in CDCl3. Only the amide structure was finally
Table 1. Acylation of arenesulfenamides with perfluorocarboxylic
anhydrides or acid chlorides
Entry
1
R1
Acylating reagent Temperature
(8C)
2
Yielda
(%)
1
observed when the H NMR spectrum of 4a was measured
in CD3OD.
1
2
3
4
5
6
7
8
1a 2-CO2Me (CF3CO)2O
0
0
0
0
0
2a
2b
2c
2d
2e
73
80
82
63
78
76
90
85
96
81
67
69
85
1b 2-Br
1c 4-NO2
1d 4-Me
(CF3CO)2O
(CF3CO)2O
(CF3CO)2O
(CF3CO)2O
(CF3CO)2O
The structures of two tautomers, 4 and 5, in CDCl3 were
assigned from the following data. When 4a was treated with
iodomethane in the presence of sodium hydride, N-
methylated product 6a was only obtained, which was
1e
1e
H
H
220 2e
1a 2-CO2Me (CF3CF2CO)2O
1c 4-NO2 (CF3CF2CO)2O
1a 2-CO2Me PhCOCl
0
0
2f
2g
1
assigned by N-methyl peaks in H and 13C NMR spectra
9
220 2h
220 2i
220 2j
220 2k
220 2l
(Scheme 2, Eq. (3)). Preparation of methyl N-sulfenylacet-
imidate (8) was succeeded by the reaction of sulfenyl
chloride (7) with methyl acetimidate hydrochloride in the
10
11
12
13
1c 4-NO2
1d 4-Me
PhCOCl
PhCOCl
PhCOCl
PhCOCl
1e
1f 4-Cl
H
1
presence of triethylamine (Scheme 2, Eq. (4)). H NMR
spectra of 6 and 8 in CDCl3 showed that the absorption of
a
Isolated yield.

M. Bao et al. / Tetrahedron 59 (2003) 303–309
305
Figure 1. Crystal structure of 4a.
Table 2. Acylation of 1 with aliphatic acid chlorides
Entry
1
R1
R2
Me
Me
Me
Me
Me
Et
i-Pr
PhCH2
Yielda (%)
Products in CDCl3
Ratiob of 4 to 5
1
2
3
4
5
6
7
8
1a
1d
1e
1f
1g
1a
1a
1a
2-CO2Me
4-Me
H
4-Cl
2-NO2
2-CO2Me
2-CO2Me
2-CO2Me
94
65
72
82
78
98
85
74
4a, 5a
4b, 5b
4c, 5c
4d, 5d
4e, 5e
4f, 5f
43:57
45:55
39:61
37:63
57:43
50:50
71:29
74:26
4g, 5g
4h, 5h
a
Isolated yield.
Calculated with 1H NMR spectra.
b
methyl groups of an acetyl group and an imidate group
appeared at around dH 2.3 and 2.2, respectively; methyl
groups in acetyl groups appeared in downer field than those
in imidate groups. According to these observations, the
ratios of 4 to 5 in CDCl3 were determined (Table 2).
reagents to achieve the acylation of arenesulfenamide at
08C. Acid chlorides also can be used as efficient acylating
reagent, but the reaction temperature plays a key role; at
room temperature undesired disulfenylamines are formed,
whereas at a low reaction temperature such as 2208C the
desired N-acylarenesulfenamides are obtained in high
yields. These methods offer convenient and safe routes to
synthesize N-acylarenesulfenamides. N-Alkylcarbonyl-
arenesulfenamides tautomerized to the imidic acid isomer
in an aprotic solvent. Further investigations towards
mechanism of tautomerization are currently underway.
3. Conclusion
In summary, perfluorocarboxylic anhydrides are efficient
4. Experimental
4.1. General
Melting points were determined on a Mettler FP90
1
microscopic plate and are uncorrected. H and 13C NMR
spectra were obtained with a JEOL LA-500 spectrometer,
and chemical shifts are reported in parts per million relative
to internal tetramethylsilane and CDCl3 (77 ppm), respec-
tively. IR spectra were recorded on a JASCO FTIR-5300
spectrophotometer. Sulfenamides 1 were prepared by the
method described in a previous paper.5a
Scheme 2. Synthesis of N-methyl-N-sulfenylacetamides 6 and methyl
N-sulfenylacetimidate 8.

306
M. Bao et al. / Tetrahedron 59 (2003) 303–309
4.2. General procedure for the acylation of
arenesulfenamides with perfluorocarboxylic anhydrides
zenesulfenamide (2f). Colorless crystal with mp 117–
1188C (from CH2Cl2–hexane); 1H NMR (500 MHz,
CDCl3) d 3.96 (3H, s), 7.14 (1H, dd, J¼8.2, 0.6 Hz), 7.26
(1H, ddd, J¼8.0, 7.3, 0.6 Hz), 7.53 (1H, ddd, J¼8.2, 7.3,
1.5 Hz), 7.55 (1H, br s), 8.04 (1H, dd, J¼8.0, 1.5 Hz); 13C
NMR (125 MHz, CDCl3) d 52.8, 107.1 (tq, JCF¼266.8,
39.3 Hz, CF2), 117.7 (qt, JCF¼285.4, 34.0 Hz, CF3), 121.5,
124.5, 125.5, 131.8, 133.6, 142.4, 159.8 (t, JCF¼26.8 Hz,
CvO), 167.4; IR (KBr) 3252, 1707, 1443, 1319, 1213,
1148, 1032, 747 cm21; HRMS calcd for C11H8F5NO3S:
329.0145. Found 329.0094.
To a mixture of 1 (0.5 mmol) and pyridine (0.75 mmol,
59.3 mg) in CH2Cl2 (6 mL) at 08C was added perfluoro-
carboxylic anhydride (0.6 mmol). The mixture was stirred
for 30 min and then the solvent was removed under a
reduced pressure. The crude product was purified with silica
gel column chromatography (eluent: CH2Cl2).
4.2.1. N-Trifluoroacetyl-2-methoxycarbonylbenzenesul-
fenamide (2a). Colorless crystal with mp 127–1288C (from
CH2Cl2–hexane); 1H NMR (500 MHz, CDCl3) d 3.96 (3H,
s), 7.17 (1H, dd, J¼8.6, 0.6 Hz), 7.27 (1H, td, J¼7.6,
0.6 Hz), 7.50 (1H, br s), 7.54 (1H, ddd, J¼8.6, 7.6, 1.2 Hz),
8.04 (1H, dd, J¼7.6, 1.2 Hz); 13C NMR (125 MHz, CDCl3)
d 52.8, 115.7 (q, JCF¼287.4 Hz, CF3), 121.5, 124.5, 125.5,
131.3, 133.6, 142.4, 159.2 (q, JCF¼37.0 Hz, CvO), 167.4;
IR (KBr) 3223, 3090, 2959, 1713, 1696, 1468, 1441, 1319,
1206, 1163, 747 cm21; HRMS calcd for C10H8F3NO3S:
279.0177. Found 279.0141.
4.2.7. N-Pentafluoropropionyl-4-nitrobenzenesulfen-
amide (2g). Colorless crystal with mp 88–898C (from
CH2Cl2–hexane); 1H NMR (500 MHz, CDCl3) d 7.34 (2H,
dt, J¼9.2, 2.5 Hz), 7.67 (1H, br s), 8.24 (2H, dt, J¼9.2,
2.5 Hz); 13C NMR (125 MHz, CDCl3) d 107.0 (tq,
JCF¼266.8, 40.3 Hz, CF2), 117.5 (qt, JCF¼285.4, 34.0 Hz,
CF3), 124.4, 124.6, 144.7, 146.8, 159.8 (t, JCF¼26.8 Hz,
CvO); IR (KBr) 3260, 1721, 1512, 1451, 1346, 1208, 1181,
1157, 1030, 855 cm21; HRMS calcd for C9H5F5N2O3S:
315.9941. Found 315.9930.
4.2.2. N-Trifluoroacetyl-2-bromobenzenesulfenamide
(2b). Colorless crystal with mp 89–908C (from CH2Cl2–
hexane); 1H NMR (500 MHz, CDCl3) d 7.13–7.16 (2H, m),
7.33 (1H, ddd, J¼8.6, 7.3, 1.2 Hz), 7.54 (1H, dd, J¼8.6,
1.2 Hz), 7.56 (1H, br s); 13C NMR (125 MHz, CDCl3) d
115.5 (q, JCF¼288.4 Hz, CF3), 119.9, 126.3, 128.3, 128.8,
133.2, 136.1, 159.0 (q, JCF¼38.1 Hz, CvO); IR (KBr)
4.3. General procedure for the acylation of arene-
sulfenamides with acid chlorides
To a mixture of 1a (0.5 mmol, 91.5 mg) and pyridine
(0.75 mmol, 59.3 mg) in CH2Cl2 (6 mL) at 2208C was
added acid chloride (0.6 mmol). The mixture was stirred for
30 min and then the solvent was removed under a reduced
pressure. The crude product was purified with silica gel
3225, 1723, 1468, 1447, 1211, 1167, 1150, 741 cm21
;
HRMS calcd for C8H5BrF3NOS: 298.9227, 300.9207.
Found 298.9210, 300.9216.
column
chromatography
(eluent:
CH2Cl2/ethyl
acetate¼10:1 or 20:1).
4.2.3. N-Trifluoroacetyl-4-nitrobenzenesulfenamide (2c).
Colorless crystal with mp 111–1138C (from CH2Cl2–
hexane); 1H NMR (500 MHz, CDCl3) d 7.34 (2H, dt, J¼9.2,
2.5 Hz), 7.74 (1H, br s), 8.22 (2H, dt, J¼9.2, 2.5 Hz); 13C
NMR (125 MHz, CDCl3) d 115.4 (q, JCF¼288.4 Hz, CF3),
124.4, 124.6, 144.8, 146.8, 159.0 (q, JCF¼39.1 Hz, CvO);
IR (KBr) 3274, 1726, 1580, 1522, 1458, 1341, 1211, 1169,
1132 cm21; HRMS calcd for C8H5F3N2O3S: 265.9973.
Found 265.9953.
4.3.1. N-Benzoyl-2-methoxycarbonylbenzenesulfen-
amide (2h). Colorless crystal with mp 156–1588C (from
ethyl acetate–hexane); 1H NMR (500 MHz, CDCl3) d 3.92
(3H, s), 7.16 (1H, t, J¼7.6 Hz), 7.30 (1H, d, J¼7.9 Hz),
7.41–7.45 (3H, m), 7.54 (1H, d, J¼7.9 Hz), 7.56 (1H, br s),
7.91 (2H, d, J¼7.7 Hz), 7.99 (1H, d, J¼7.7 Hz); 13C NMR
(125 MHz, CDCl3) d 52.4, 122.1, 124.2, 124.6, 127.7,
128.8, 131.1, 132.4, 133.1, 144.9, 167.1, 169.0; IR (KBr)
3264, 3063, 2951, 1701, 1663, 1453, 1433, 1312, 1256,
1105, 745, 693 cm21; Anal. calcd for C15H13NO3S: C,
62.70; H, 4.56; N, 4.87. Found: C, 62.68; H, 4.27; N, 4.76.
4.2.4. N-Trifluoroacetyl-4-methylbenzenesulfenamide
(2d). Colorless crystal with mp 84–868C (from CH2Cl2–
1
hexane); H NMR (500 MHz, CDCl3) d 2.36 (3H, s), 7.18
(2H, d, J¼8.0 Hz), 7.43 (2H, d, J¼8.0 Hz), 7.53 (1H, br s);
4.3.2. N-Benzoyl-4-nitrobenzenesulfenamide (2i). Color-
less crystal with mp 157–1588C (from ethyl acetate–
hexane, lit.,3a 157–1588C); H NMR (500 MHz, CDCl3) d
13C NMR (125 MHz, CDCl3)
d
21.3, 115.6 (q,
1
JCF¼287.4 Hz, CF3), 130.2, 130.9, 131.9, 140.1, 159.1 (q,
JCF¼38.1 Hz, CvO); IR (KBr) 3289, 3239, 2926, 1725,
1468, 1321, 1163, 804 cm21; HRMS calcd for C9H8F3NOS:
235.0279. Found 235.0291.
7.26 (2H, dt, J¼9.1, 2.4 Hz), 7.48 (2H, ddd, J¼8.2, 7.6,
1.5 Hz), 7.61 (1H, tt, J¼7.6, 1.2 Hz), 7.73 (1H, br s), 7.90
(2H, dd, J¼8.2, 1.2 Hz), 8.10 (2H, dt, J¼9.1, 2.4 Hz); 13C
NMR (125 MHz, CDCl3) d 122.8, 124.2, 127.8, 129.0,
132.3, 133.1, 145.9, 148.3, 168.7; IR (KBr) 3191, 1659,
4.2.5. N-Trifluoroacetylbenzenesulfenamide (2e). Color-
1
less crystal with mp 70–728C (from CH2Cl2–hexane). H
1580, 1512, 1339, 1269, 837, 694 cm21
.
NMR (500 MHz, CDCl3) d 7.32–7.39 (3H, m), 7.43–7.46
(2H, m), 7.53 (1H, br s); 13C NMR (125 MHz, CDCl3) d
115.6 (q, JCF¼287.4 Hz, CF3), 129.0, 129.1, 129.5, 135.5,
159.1 (q, JCF¼37.1 Hz, CvO); IR (KBr) 3245, 1717, 1441,
1321, 1186, 740, 689 cm21; HRMS calcd for C8H6F3NOS:
221.0122. Found 221.0145.
4.3.3. N-Benzoyl-2-methylbenzenesulfenamide (2j). Col-
orless crystal with mp 131.5–1338C (from ethyl acetate–
1
hexane, lit.,3b 123–1248C); H NMR (500 MHz, CDCl3) d
2.29 (3H, s), 7.08 (2H, d, J¼7.3 Hz), 7.28 (2H, d,
J¼7.6 Hz), 7.39 (2H, t, J¼7.6 Hz), 7.51 (1H, t,
J¼7.6 Hz), 7.69 (1H, br s), 7.82 (2H, d, J¼7.3 Hz); 13C
NMR (125 MHz, CDCl3) d 21.1, 127.3, 127.6, 128.7, 129.8,
4.2.6. N-Pentafluoropropionyl-2-methoxycarbonylben-

M. Bao et al. / Tetrahedron 59 (2003) 303–309
307
132.3, 133.4, 135.0, 137.5, 169.2; IR (KBr) 3302, 1667,
1495, 1418, 1263, 806, 691, 639, 502 cm21
CDCl3) d 2.21 (3H, s), 6.76 (1H, b rs), and aromatic protons.
Compound 5a: 1H NMR (500 MHz, CDCl3) d 2.16 (3H, s),
and aromatic protons.
.
4.3.4. N-Benzoylbenzenesulfenamide (2k). Colorless crys-
tal with mp 116.5–1178C (from ethyl acetate–hexane; lit.,1a
122–1248C); 1H NMR (500 MHz, CDCl3) d 7.14–7.17
(1H, m), 7.23–7.26 (4H, m), 7.34–7.37 (2H, m), 7.48–7.51
(1H, m), 7.84 (2H, d, J¼7.3 Hz), 7.89 (1H, br s); 13C NMR
(125 MHz, CDCl3) d 125.4, 126.7, 127.7, 128.6, 128.9,
132.3, 133.1, 138.6, 169.3; IR (KBr) 3285, 1665, 1420,
4.3.9. N-Acetyl-4-chlorobenzenesulfenamide (4d). Color-
less crystal with mp 115–1178C (from CH2Cl2–hexane); 1H
NMR (500 MHz, CD3OD) d 2.14 (3H, s), 7.20 (2H, dt,
J¼8.6, 2.1 Hz), 7.31 (2H, dt, J¼8.6, 2.1 Hz); 13C NMR
(125 MHz, CD3OD) d 22.8, 127.1, 130.1, 133.2, 139.3,
175.4; IR (KBr) 3241, 1671, 1453, 1248, 1092, 1011,
814 cm21; Anal. calcd for C8H8ClNOS: C, 47.64; H, 4.00;
N, 6.95. Found: C, 47.80; H, 3.71; N, 6.90.
1262, 741, 691 cm21
.
4.3.5. N-Benzoyl-4-chlorobenzenesulfenamide (2l). Col-
orless crystal with mp 143–1438C (from CH2Cl2–hexane,
Mixture of 4d and 5d. Compound 4d: 1H NMR (500 MHz,
CDCl3) d 2.20 (3H, s), 6.63 (1H, br s), 7.14 (2H, d,
J¼8.4 Hz), 7.34 (2H, d, J¼8.4 Hz). Compound 5d: 1H
NMR (500 MHz, CDCl3) d 2.18 (3H, s), 7.02 (1H, br s),
7.20 (2H, d, J¼8.4 Hz), 7.27 (2H, d, J¼8.4 Hz).
1
lit.,3b 143–144); H NMR (500 MHz, CDCl3) d 7.25 (4H,
s), 7.45 (2H, dd, J¼8.0, 7.5 Hz), 7.56 (1H, tt, J¼7.5,
1.2 Hz), 7.60 (1H, br s), 7.85 (2H, d, J¼8.0 Hz); 13C NMR
(125 MHz, CDCl3) d 127.3, 127.6, 128.8, 129.2, 132.6,
132.9, 133.1, 137.0, 169.0; IR (KBr) 3291, 1669, 1451,
1420, 1263, 1096, 816, 691 cm21
.
4.3.10. N-Acetyl-2-nitrobenzenesulfenamide (4e). Yellow
crystal with mp 175–176.58C (from ethyl acetate, lit.,13
179–1808C); 1H NMR (500 MHz, CD3OD) d 2.15 (3H, s),
7.29 (1H, t, J¼8.3 Hz), 7.36 (1H, d, J¼8.3 Hz), 7.62 (1H, t,
J¼8.3 Hz), 8.22 (1H, d, J¼8.3 Hz); 13C NMR (125 MHz,
CD3OD) d 23.0, 125.0, 126.8, 126.8, 135.6, 142.4, 144.2,
175.6; IR (KBr) 3221, 1667, 1505, 1435, 1339, 1248, 1107,
4.3.6. N-Acetyl-2-methoxycarbonylbenzenesulfenamide
(4a). Colorless crystal with mp 129–1308C (from ethyl
acetate–hexane); 1H NMR (500 MHz, CD3OD) d 2.21 (3H,
s), 3.91 (3H, s), 7.22 (1H, td, J¼7.6, 1.0 Hz), 7.28 (1H, dd,
J¼8.3, 1.0 Hz), 7.54 (1H, ddd, J¼8.3, 7.6, 1.2 Hz), 8.02
(1H, dd, J¼7.6, 1.2 Hz); 13C NMR (125 MHz, CD3OD) d
23.0, 52.8, 123.1, 125.3, 125.5, 132.1, 134.2, 146.5, 168.3,
175.8; IR (KBr) 3264, 2957, 1703, 1667, 1439, 1314, 1290,
1242, 1148, 747 cm21; Anal. calcd for C10H11NO3S: C,
53.32; H, 4.92; N, 6.22. Found: C, 53.44; H, 4.65; N, 6.11.
735 cm21
.
1
Mixture of 4e and 5e. Compound 4e: H NMR (500 MHz,
CDCl3) d 2.32 (3H, s), 6.69 (1H, br s), 7.32–7.37 (m, 1H),
7.63 (1H, t, J¼7.6 Hz), 8.31 (1H, d, J¼7.6 Hz). Compound
5e: 1H NMR (500 MHz, CDCl3) d 2.18 (3H, s), 6.39 (1H, br
s), 7.41 (1H, t, J¼7.6 Hz), 7.55 (1H, d, J¼7.6 Hz), 7.73 (1H,
t, J¼7.6 Hz), 8.37 (1H, d, J¼7.6 Hz).
1
Mixture of 4a and 5a. Compound 4a: H NMR (500 MHz,
CDCl3) d 2.28 (3H, s), 3.93 (3H, s), 6.75 (1H, br s), 7.19
(1H, t, J¼7.3 Hz), 7.24–7.28 (1H, m), 7.49 (1H, t,
J¼7.7 Hz), 8.01 (1H, d, J¼7.7 Hz). Compound 5a: 1H
NMR (500 MHz, CDCl3) d 2.16 (3H, s), 3.96 (3H, s), 6.39
(1H, br s), 7.24–7.28 (1H, m), 7.41 (1H, d, J¼8.3 Hz), 7.58
(1H, t, J¼8.3 Hz), 8.07 (1H, d, J¼7.4 Hz).
4.3.11. N-Propionyl-2-methoxycarbonylbenzenesulfen-
amide (4f). Colorless crystal with mp 138–1398C (from
ethyl acetate–hexane); 1H NMR (500 MHz, CD3OD) d 1.21
(3H, t, J¼7.6 Hz), 2.50 (2H, q, J¼7.7 Hz), 3.90 (3H, s), 7.21
(1H, td, J¼7.8, 1.2 Hz), 7.26 (1H, d, J¼7.8 Hz), 7.53 (1H,
td, J¼7.8, 1.5 Hz), 8.01 (1H, dd, J¼7.8, 1.2 Hz); 13C NMR
(125 MHz, CD3OD) d 10.2, 30.4, 52.8, 123.0, 125.3, 125.5,
132.1, 134.1, 146.7, 168.3, 179.4; IR (KBr) 3239, 2986,
2949, 2882, 1705, 1676, 1439, 1300, 1277, 1258, 1190,
756 cm21; Anal. calcd for C11H13NO3S: C, 55.21; H, 5.48;
N, 5.85. Found: C, 55.42; H, 5.23; N, 5.77.
4.3.7. N-Acetyl-4-methylbenzenesulfenamide (4b). Color-
less crystal with mp 105.5–106.58C (from ethyl acetate–
hexane, lit.,1b 102–1058C); 1H NMR (500 MHz, CD3OD) d
2.20 (3H, s), 2.20 (3H, s), 7.04 (2H, d, J¼8.5 Hz), 7.07 (2H,
d, J¼8.5 Hz); 13C NMR (125 MHz, CD3OD) d 21.0, 22.8,
127.1, 130.7, 136.7, 138.1, 175.5; IR (KBr) 3712, 1680,
1458, 1246, 802, 590 cm21
.
1
Mixture of 4f and 5f. Compound 4f: H NMR (500 MHz,
Mixture of 4b and 5b. Compound 4b: 1H NMR (500 MHz,
CDCl3) d 2.22 (3H, s), 2.34 (3H, s), 6.49 (1H, br s), 7.12–
CDCl3) d 1.09 (3H, t, J¼7.3 Hz), 2.50 (2H, q, J¼7.3 Hz),
3.93 (3H, s), 6.75 (1H, br s), 7.18 (1H, t, J¼7.0 Hz), 7.22–
7.26 (1H, m), 7.47 (1H, d, J¼7.3 Hz), 8.00 (1H, d,
1
7.14 (2H, m), 7.18 (2H, d, J¼7.9 Hz). Compound 5b: H
1
NMR (500 MHz, CDCl3) d 2.15 (3H, s), 2.32 (3H, s), 6.78
(1H, br s), 7.12–7.14 (2H, m), 7.26 (2H, d, J¼8.2 Hz).
J¼7.3 Hz). Compound 5f: H NMR (500 MHz, CDCl3) d
1.27 (3H, t, J¼7.3 Hz), 2.50 (2H, q, J¼7.3 Hz), 3.96 (3H, s),
6.37 (1H, br s), 7.22–7.26 (1H, m), 7.40 (1H, d, J¼7.9 Hz),
7.57 (1H, t, J¼7.6 Hz), 8.06 (1H, d, J¼7.6 Hz).
4.3.8. N-Acetylbenzenesulfenamide (4c). Colorless crystal
with mp 103.5–104.58C (from ethyl acetate–hexane, lit.,12
1
102.5–1048C); H NMR (500 MHz, CD3OD) d 2.09 (3H,
4.3.12. N-Isobutyryl-2-methoxycarbonylbenzenesulfen-
amide (4g). Colorless crystal with mp 148–1498C (from
ethyl acetate–hexane). 1H NMR (500 MHz, CD3OD) d 1.24
(6H, d, J¼7.0 Hz), 2.76 (1H, sept, J¼7.0 Hz), 3.92 (3H, s),
7.21 (1H, t, J¼7.3 Hz), 7.25 (1H, d, J¼8.2 Hz), 7.52 (1H, ddd,
J¼8.2, 7.3, 1.2 Hz), 8.02 (1H, dd, J¼8.0, 1.2 Hz); 13C NMR
(125 MHz, CD3OD) d 19.9, 36.7, 52.7, 122.7, 125.0, 125.3,
s), 7.07 (1H, t, J¼7.3 Hz), 7.11 (2H, dd, J¼7.3, 1.2 Hz),
7.20 (2H, t, J¼7.3 Hz); 13C NMR (125 MHz, CD3OD) d
22.8, 125.6, 127.5, 130.0, 140.3, 175.5; IR (KBr) 3243,
1672, 1454, 1246, 741, 594 cm21
.
1
Mixture of 4c and 5c. Compound 4c: H NMR (500 MHz,

308
M. Bao et al. / Tetrahedron 59 (2003) 303–309
132.0, 133.9, 146.4, 168.1, 182.2; IR (KBr):3210, 1701, 1674,
1435, 1101, 750 cm21;Anal. calcdforC12H15NO3S:C,56.90;
H, 5.97; N, 5.53. Found: C, 57.07; H, 5.85; N, 5.40.
4.5. Synthesis of methyl N-sulfenylacetimidate 8
To a solution of 2-nitrobenzenesulfenyl chloride (7,
189.5 mg, 1.0 mmol) in acetonitrile (20 mL) was added
methyl acetimidate hydrochloride (131.5 mg, 1.2 mmol)
and triethylamine (303 mg, 3.0 mmol) at room temperature.
The mixture was stirred for 2 h and the solvent was removed
under a reduced pressure. The crude product was purified
with silica gel column chromatography (eluent: CH2Cl2/
hexane¼2:1).
1
Mixture of 4g and 5g. Compound 4g: H NMR (500 MHz,
CDCl3) d 1.28 (6H, d, J¼7.0 Hz), 2.67 (1H, sept,
J¼7.0 Hz), 3.92 (3H, s), 6.74 (1H, br s), 8.00 (1H, d,
1
J¼7.6 Hz), and aromatic protons. Compound 5g: H NMR
(500 MHz, CDCl3) d 1.08 (6H, d, J¼6.1 Hz), 3.18 (1H, brs),
3.96 (3H, s), 6.23 (1H, br s), 8.06 (1H, d, J¼7.6 Hz), and
aromatic protons.
4.5.1. Methyl N-(2-nitrobenzenesulfenyl)acetimidate (8).
Yield 48%; yellow crystal with mp 103–103.58C (from
hexane); H NMR (500 MHz, CDCl3) d 2.24 (3H, s), 3.87
(3H, s), 7.26 (1H, ddd, J¼8.5, 7.0, 1.2 Hz), 7.66 (1H, ddd,
J¼8.5, 7.0, 1.2 Hz), 8.32 (2H, dt, J¼8.5, 1.2 Hz); 13C NMR
(125 MHz, CDCl3) d 18.5, 53.6, 124.1, 125.4, 125.5, 133.9,
141.7, 142.0, 163.2; IR (KBr) 1644, 1591, 1499, 1273,
1042, 893, 733 cm21; Anal. calcd for C9H10N2O3S: C,
47.78; H, 4.45; N, 12.38. Found: C, 48.00; H, 4.22; N, 12.09.
4.3.13. N-Phenylacetyl-2-methoxycarbonylbenzenesulfen-
amide (4h). Colorless crystal with mp 144.5–1458C (from
ethyl acetate–hexane). 1H NMR (500 MHz, CD3OD) d 3.76
(2H, s), 3.89 (3H, s), 7.02 (1H, dd, J¼8.2, 0.9 Hz), 7.01–
7.03 (1H, m), 7.28–7.39 (6H, m), 7.97 (1H, dd, J¼7.9,
1.2 Hz); 13C NMR (125 MHz, CD3OD) d 44.3, 52.8, 123.0,
125.2, 125.5, 128.3, 129.7, 130.3, 132.1, 134.0, 136.2,
146.5, 168.3, 176.4; IR (KBr): 3196, 1703, 1661, 1435,
1107, 741 cm21; Anal. calcd for C16H15NO3S: C, 63.77; H,
5.02; N, 4.65. Found: C, 63.95; H, 4.92; N, 4.56.
1
Mixture of 4h and 5h. Compound 4h: 1H NMR (500 MHz,
CDCl3) d 3.83 (2H, s), 3.90 (3H, s), 6.53 (1H, br s), 7.97
(1H, d, J¼7.9 Hz), and aromatic protons. Compound 5h: 1H
NMR (500 MHz, CDCl3) d 3.85 (2H, s), 3.98 (3H, s), 6.34
(1H, br s), 8.05 (1H, d, J¼7.3 Hz), and aromatic protons.
References
1. (a) Miura, Y.; Katsura, Y.; Kinoshita, M. Bull. Chem. Soc. Jpn
1978, 51, 3004–3007. (b) Harpp, D. N.; Mullins, D. F.;
Steliou, K.; Triassi, I. J. Org. Chem. 1979, 44, 4196–4197. (c)
Koval’, I. V.; Oleinik, T. G.; Kremlev, M. M. Zh. Org. Khim.
1980, 16, 633–636, J. Org. Chem. USSR (Engl. Transl.) 1980,
16, 553; Chem. Abstr. 1980, 93, 71232h. (d) Miura, Y.;
Shibata, Y.; Kinoshita, M. Bull. Chem. Soc. Jpn 1986, 59,
3291–3292.
4.4. General procedure for the methylation of 4
To a solution of 4 (0.7 mmol) in THF (20 mL) was added
sodium hydride (1.5 mmol) at 08C. Iodomethane (1.5 mmol,
213 mg) in THF (5 mL) was added to the solution. The
mixture was stirred for 2 h and was quenched with water.
Products were extracted with dichloromethane, and the
organic layer was washed with water and dried over
magnesium sulfate. The solvent was removed under a
reduced pressure, and the crude product was purified with
silica gel column chromatography (eluent: CH2Cl2/
acetone/methanol¼100:5:1).
2. (a) Pel’kis, N. P.; Karabanov, Y. V.; Borisenko, V. P.;
Levchenko, E. S. Fiziol. Akt. Veshch. 1984, 16, 47–49, Chem.
Abstr. 1985, 103, 18314k. (b) Craine, L.; Raban, M. Chem.
Rev. 1989, 89, 689–712.
3. For references on synthesis of N-acylarenesulfenamides with
sulfenyl chlorides, see: (a) Goerdeler, J.; Doerk, K. Chem. Ber.
1962, 95, 389–393. (b) Dubinina, T. N.; Levchenko, E. S.;
Zabolotnaya, T. G. Zh. Org. Khim. 1982, 18, 162–168, J. Org.
Chem. USSR (Engl. Transl.) 1982, 18, 143–148; Chem. Abstr.
1982, 96, 162244s. (c) See: Ref. 1.
4.4.1. N-Acetyl-N-methyl-2-methoxycarbonylbenzene-
sulfenamide (6a). Yield 48%; colorless crystal with mp
4. Kharasch, N.; Potempa, S. J.; Wehrmeister, H. L. Chem. Rev.
1946, 39, 269–332.
1
106–1078C (from hexane); H NMR (500 MHz, CDCl3) d
2.29 (3H, s), 3.29 (3H, s), 3.96 (3H, s), 7.07 (1H, dd, J¼8.2,
0.9 Hz), 7.27 (1H, ddd, J¼7.9, 7.3, 0.9 Hz), 7.58 (1H, ddd,
J¼8.2, 7.3, 1.5 Hz), 8.10 (1H, dd, J¼7.9, 1.5 Hz); 13C NMR
(125 MHz, CDCl3) d 21.5, 38.9, 52.5, 121.1, 123.9, 125.0,
131.7, 133.7, 144.5, 167.0, 176.8; IR (KBr) 1705, 1669,
1279, 745 cm21; Anal. calcd for C11H13NO3S: C, 55.21; H,
5.48; N, 5.85. Found: C, 55.22; H, 5.38; N, 5.85.
5. Recently, we have synthesized many arenesulfenamides with a
chlorine-free procedure: (a) Shimizu, M.; Kikumoto, H.;
Konakahara, T.; Gama, Y.; Shibuya, I. Heterocycles 1999, 51,
3005–3012. (b) Shimizu, M.; Takagi, T.; Shibakami, M.;
Gama, Y.; Shibuya, I. Heterocycles 2000, 53, 2803–2808. (c)
Shimizu, M.; Sugano, Y.; Konakahara, T.; Gama, Y.; Shibuya,
I. Tetrahedron 2002, 58, 3779–3783.
¨
6. (a) Zincke, Th.; Rose, H. Ann. 1914, 406, 103–126. (b) Carr,
E. L.; Smith, Jr. G. E. P.; Alliger, G. J. Org. Chem. 1949, 14,
921–934.
4.4.2. N-Acetyl-N-methyl-2-nitrobenzenesulfenamide
(6b). Yield 74%; yellow crystal with mp 117.5–118.58C
(from ethyl acetate–hexane); 1H NMR (500 MHz, CDCl3) d
2.31 (3H, s), 3.31 (3H, s), 7.19 (1H, d, J¼8.2 Hz), 7.42 (1H,
t, J¼8.2 Hz), 7.72 (1H, td, J¼8.2, 1.2 Hz), 8.39 (1H, dd,
J¼8.2, 1.2 Hz); 13C NMR (125 MHz, CDCl3) d 21.6, 38.8,
122.7, 126.1, 126.5, 135.1, 140.5, 142.6, 176.2; IR (KBr)
1678, 1510, 1337, 1304, 1102, 968, 920, 737 cm21; Anal.
calcd for C9H10N2O3S: C, 47.78; H, 4.45; N, 12.38. Found:
C, 47.84; H, 4.19; N, 12.30.
7. (a) Ignatov, V. A.; Akchurina, R. A.; Volkov, I. V.; Pirogov,
P. A. Zh. Obshch. Khim. 1977, 47, 1096–1103, J. Gen. Chem.
USSR (Engl. Transl.) 1977, 47, 1004–1010. (b) See: Refs. 2(b)
and 6(b).
8. (a) Bonner, W. A.; McNamee, P. I. J. Org. Chem. 1961, 26,
2554–2555. (b) Guo, J.; Wu, J.; Siuzdak, G.; Finn, M. G.
Angew. Chem., Int. Ed. Engl. 1999, 38, 1755–1758. (c)

M. Bao et al. / Tetrahedron 59 (2003) 303–309
309
˚
Johnson, II., D. C.; Widlanski, T. S. Tetrahedron Lett. 2001,
42, 3677–3679.
distances (A) and angles (8) are shown as follows: S(1)–N(1)
1.695(1), S(1)–C(1) 1.784(1), O(3)–C(9) 1.226(1), N(1)–
C(9) 1.360(2), N(1)–S(1)–C(1) 101.00(5), S(1)–N(1)–C(9)
122.00(8), O(3)–C(9)–N(1) 122.0(1), N(1)–C(9)–C(10)
115.43(10). Atomic coordinates, other bond lengths, and
other angles and the other important parameters have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication, CCDC No. 186164. Copies of this
information can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: þ44-
1233-336033 or e-mail: deposit@ccdc.cam.ac.uk).
9. (a) Iwataki, I. Bull. Chem. Soc. Jpn 1972, 45, 3572–3579. (b)
Kamijo, T.; Yamamoto, R.; Harada, H.; Iizuka, K. Chem.
Pharm. Bull. 1982, 30, 4242–4244. (c) Calmes, M.; Daunis,
J.; Jacquier, R.; Verducci, J. Tetrahedron 1987, 43,
2285–2292. (d) Suwinski, J.; Walczak, K. Pol. J. Chem.
1994, 68, 675–681, Chem. Abstr. 1994, 121, 255714v. (e)
Myers, T. G.; Thummel, K. E.; Kalhorn, T. F.; Nelson, S. D.
J. Med. Chem. 1994, 37, 860–867.
10. X-Ray crystallographic analysis was carried out on a Rigaku
AFC7R diffractometer using a rotating anode with graphite
11. Bryce, M. R.; Taylor, P. C. J. Chem. Soc., Perkin Trans. 1
1990, 3225–3235.
ˇˇ
12. Gordon, E. M.; Pluscec, J. J. Org. Chem. 1979, 44,
1218–1221.
˚
monochromated Mo Ka radiation (l¼0.7107 A). Crystal data
for 4a: C10H11NO3S, M¼225.26, monoclinic, space group
˚
P21/a, a¼8.791(2), b¼8.188(2), c¼14.896(1) A, a¼908,
3
˚
b¼92.122(8)8, g¼908, V¼1071.5(2) A , T¼173.2 K, Z¼4,
13. Sayo, H.; Mori, K.; Michida, T. Chem. Pharm. Bull. 1979, 27,
351–356.
Dc¼1.396 g cm23, m¼0.288 mm21, goodness of fit¼1.433,
R1 [I.2s(I)]¼0.0283, wR2¼0.1045 (all data). Selected bond