Regioselective alkylation of thiazolylsulfonamides: Direct and efficient synthesis of 3-alkylthiazolidene derivatives

Article abstract of DOI:10.1080/00397910500186730

Various N-3-alkylated thiazolidenesulfonamide derivatives were efficiently prepared by the direct endo-selective alkylation of thiazolylsulfonamides. The effects of different bases and solvents were investigated, and the NaH-THF combination was found to b

Full text of DOI:10.1080/00397910500186730

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Regioselective Alkylation of
Thiazolylsulfonamides: Direct
and Efficient Synthesis of
3‐Alkylthiazolidene Derivatives
Naoyuki Masuda a , Osamu Yamamoto a , Masahiro
Fujii a , Tetsuro Ohgami a , Ayako Moritomo a , Toru
Kontani a , Shunji Kageyama a & Mitsuaki Ohta a
a Institute for Drug Discovery Research, Astellas
Pharma Inc., Miyukigaoka, Tsukubu‐shi, Ibaraki,
Japan
Published online: 18 Aug 2006.
To cite this article: Naoyuki Masuda , Osamu Yamamoto , Masahiro Fujii , Tetsuro
Ohgami , Ayako Moritomo , Toru Kontani , Shunji Kageyama & Mitsuaki Ohta (2005)
Regioselective Alkylation of Thiazolylsulfonamides: Direct and Efficient Synthesis of
3‐Alkylthiazolidene Derivatives, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 35:17, 2305-2316
To link to this article: http://dx.doi.org/10.1080/00397910500186730
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Synthetic Communicationsw, 35: 2305–2316, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500186730
Regioselective Alkylation of
Thiazolylsulfonamides: Direct and Efficient
Synthesis of 3-Alkylthiazolidene Derivatives
Naoyuki Masuda, Osamu Yamamoto, Masahiro Fujii,
Tetsuro Ohgami, Ayako Moritomo, Toru Kontani,
Shunji Kageyama, and Mitsuaki Ohta
Institute for Drug Discovery Research, Astellas Pharma Inc.,
Miyukigaoka, Tsukubu-shi, Ibaraki, Japan
Abstract: Various N-3-alkylated thiazolidenesulfonamide derivatives were efficiently
prepared by the direct endo-selective alkylation of thiazolylsulfonamides. The effects
of different bases and solvents were investigated, and the NaH–THF combination was
found to be the most effective at conferring high yields and endo-selectivity.
Keywords: Alkylation, alkyl halide, regioselective, sulfonamide
Thiazolylbenzenesulfonamide analogues show great potential as novel
anti–human immunodeficiency virus (HIV) agents.[1] The pharmacological
profiles of these chemicals are critically dependent on the nature of the substi-
tuents on the thiazole and phenyl rings: an endo-alkylated compound (1a)
shows more potent antiretroviral activity than an exo-alkylated compound
(1b) (Fig. 1). However, further exploration of their structure–activity relation-
ship requires the identification of a convenient approach to N-3-alkylated
thiazolidene synthesis.
Received in Japan February 28, 2005
Address correspondence to Naoyuki Masuda, Institute for Drug Discovery
Research Astellas Pharma Inc., 21, Miyukigaoka, Tsukubu-shi, Ibaraki, 305–8585,
Japan. E-mail: masuda.naoyuki@yamanouchi.co.jp
2305

2306
N. Masuda et al.
Figure 1. Structure of thiazolylsulfonamide derivatives.
The synthesis of N-3-alkylated thiazolidenesulfonamides has been
reported through the cyclization of a-bromoketones and N-alkyl-N0-
benzenesulfonylthioureas or by ring opening on 5,6-dihydroimidazo[2,1-b]
[1,3]thiazoles.[2,3] However, the starting materials for these reactions need
to be prepared in many steps. Although several methods have been suggested
for achieving this objective (for example, through the sulfonylation of N-3-
alkylated aminothiazoles), the yields are low and it is difficult to synthesize
a variety of substituents.[4] Kaye and colleagues reported the N-3 alkylation
of 2-acetamidothiazole using LiNH2 as a base;[5] however, the reaction was
limited to the amide and the yield was low. These difficulties prompted us
to explore a direct synthesis to obtain the desired endo-alkylated thiazolidene-
sulfonamides in good yield in the presence of various substituents. Here we
describe the efficient endo-selective alkylation of thiazoles, which allows
the direct introduction of various alkyl groups at the 3-position of thiazoles
(Scheme 1).
Initially, the effects of several bases and solvents on the selectivity of N-3
methylation were investigated (Table 1). The alkylated positions of the
products were confirmed by their nuclear magnetic resonance (NMR)
spectra. Nuclear Overhauser effects (NOE) between the alkyl proton substi-
tuted on the nitrogen and either the 4-methyl or aromatic proton were
observed in the endo- or exo-adduct, respectively (Fig. 2). When trimethylsi-
lyldiazomethane was used as a methylating agent, alkylation proceeded non-
selectively (Run 1). In the absence of a base, alkylation with iodomethane did
not occur (Run 2). Using Hu¨nig’s base, which has been reported to be effective
for the endo-alkylation of 2-aminopyridines,[6] the reaction proceeded to give
the endo-adduct with moderate selectivity in low yield (Run 3).
To improve the selectivity and yield, further investigation of the bases
was carried out using THF as a solvent. The use of K2CO3, Cs2CO3, and
NaOH gave improved yields (Runs 4–6). Alkylation with strong bases,
Scheme 1.

Regioselective Alkylation of Thiazolylsulfonamides
2307
Table 1. The effect of bases and solvents on methylation
Selectivitya
endo (1a) exo (1b)
Alkylating
agents
Yieldb
(%)
Run
Base
None
Solvent
MeOH
THF
1
2
TMSCHN2
MeI
MeI
59
—
41
—
19
20
22
18
5
30
N.R.c
23
None
3
DIPEAd
K2CO3
Cs2CO3
NaOH
t-BuOK
NaHMDSe
NaH
THF
THF
81
80
4
MeI
MeI
70
71
5
THF
THF
78
82
6
MeI
MeI
79
45
7
THF
THF
95
95
8
MeI
MeI
5
50
92
9
THF
.98
97
,2
3
10
11
12
NaH
NaH
MeI
MeI
DMF
1,4-dioxane
DMSO
63
38
97
97
3
NaH
MeI
3
39
aThe endo and exo selectivity were determined by high-performance liquid chrom-
atography (HPLC) area (%).
bIsolated yield of endo-adduct 1a.
cN.R.: no reaction.
dDIPEA: N,N-diisopropylethylamine.
eNaHMDS: sodium hexamethyldisilazide.
such as t-BuOK and NaHMDS, proceeded with high selectivity, but the yields
were low and by-products were observed (Runs 7 and 8). It should be noted
that the use of NaH significantly enhanced both the endo-selectivity and the
yield (Run 9). Although solvent effects on the regioselectivity of alkylation
were not apparent, the use of DMF, DMSO, and 1,4-dioxane decreased
the product yields and the starting materials persisted (Runs 10–12). The
regioselectivity of methylation was found to be dependent on the strength
Figure 2. Key NOE correlations of endo- and exo-adducts.

2308
N. Masuda et al.
of the base used. These results suggest that the alkylation position might be
kinetically controlled and the derived anion might be favored to afford
endo-products because of steric repulsion of the benzenesulfonyl group. For
regioselective N-3-alkylation, the optimal combination was found to be
NaH–THF.
We next explored the scope and limitations of various alkylating agents
and thiazoles using the NaH–THF combination (Table 2). In the case of
bulky alkylating agents, such as iodoethane, benzylbromide, ethyl bromoace-
tate, and 1,3-dioxorane-2-ylethylbromide, endo-adducts were obtained in
moderate yields with high selectivity (Runs 1–4). The alkylation proceeded
efficiently without decomposition with ester or acetal substituents (Runs 3
and 4). The effects of substituents on the thiazole and phenyl rings were
also investigated (Runs 5–12). The position and the electronic nature of
the substituent (R3) on the phenyl ring had little effect on the selectivity of
the alkylation; however, the selectivity was highly dependent on the nature
of the substituent (R1) at the 4-position of the thiazole ring. The introduction
of electron-withdrawing substituents at the 4-position led to a decrease in
endo-selectivity (Runs 6 and 7). These results suggested that the decrease of
endo-selectivity was due to reducing the nucleophilicity or increasing the
steric bulkiness of the ring nitrogen through electron-withdrawing substitu-
ents. When alkylating amido- and ureido-thiazole, endo-methyl compounds
were obtained in high yields (Runs 13 and 14). These results demonstrate
that NaH–THF is effective for the synthesis of various N-3-alkylated thiazo-
lidene derivatives.
In conclusion, direct regioselective alkylation of thiazolylsulfonamides at
the N-3 position was achieved using NaH–THF. We also explored the scope
and limitations of this reaction and revealed the effects of thiazole and phenyl-
ring substituents. This method allows the convenient and efficient preparation
of various N-3-alkylated thiazolidene derivatives. In addition, it enables the
detailed exploration of thiazolidene analogues as a novel class of anti-HIV
agents.
GENERAL PROCEDURE
Melting points were determined on a Yanaco micromelting apparatus or Bu¨chi
melting-point apparatus B-545 and are uncorrected. Proton magnetic
resonance (1H NMR) spectra were obtained in CDCl3 or dimethylsulfoxide-
d6 (DMSO-d6) using a JEOL JNM-EX400, JNM-GX500, or JNM-A500
spectrometer. Chemical shifts are recorded in parts per million (d),
downfield relative to tetramethylsilane as the internal standard. Mass
spectra (MS) were recorded on a JEOL JMS-DX300 or a Hitachi M-80
mass spectrometer. Elemental analysis was carried out on Yanaco MT-3 or
MT-5 CHN analyzer and a Yokogawa IC7000S ion chromatoanalyzer.
Chromatographic separations were performed using a silica-gel column

Table 2. The effect of substituents on the regioselective alkylation
Selectivitya
Yieldb
(%)
Run
L
R1
R2
R3
R4-X
endo
exo
1
2
3
4
SO2
Me
Me
Me
Me
t-Bu
t-Bu
t-Bu
t-Bu
3-NO2
3-NO2
3-NO2
3-NO2
EtI
85 (3a)
85 (4a)
15 (3b)
15 (4b)
,2 (5b)
,2 (6b)
70
75
92
75
SO2
SO2
SO2
BnBr
EtOCOCH2Br
.98 (5a)
.98 (6a)
5
6
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
CO
H
i-Pr
3-NO2
3-NO2
3-NO2
H
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
.98 (7a)
63 (8a)
27 (9a)
,2 (7b)
37 (8b)
73 (9b)
76
43
19
95
62
50
76
90
71
60c
CO2Me
CF3
Me
i-Pr
7
i-Pr
8
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
.98 (10a)
82 (11a)
95 (12a)
83 (13a)
95 (14a)
81 (15a)
86 (16a)
,2 (10b)
18 (11b)
5 (12b)
9
Me
2-NO2
4-NO2
3-OMe
3-Cl
10
11
12
13
14
Me
Me
17 (13b)
5 (14b)
Me
Me
3-NO2
3-NO2
19 (15b)
14 (16b)
CONH
Me
aSee footnotes to Table 1.
bIsolated yield of endo-adducts 3a–16a.
cAnilino-nitrogen was also alkylated.

2310
N. Masuda et al.
(Merck Kieselgel 60). HPLC was performed using Hitachi Degasser
L-7610 under these conditions: column: Wakosil-II 5C18 AR, dimensions:
4.6 ꢀ 30 mm, mobile phase: 5 mM of trifluoroacetic acid (TFA) in
methanol/5 mM TFA in H2O ¼ 10 : 90, flow late: 4.0 mL/min, temperature:
358C, detection: UV at 254 nm. The following known 2-aminothiazoles
were prepared as described in the literature.[4,7,8] The exo-adducts 5b, 7b,
8b, and 11b–14b were not isolated and the structure were assumed by
HPLC data.
General Procedure for the Sulfonylation of 2-Aminothaizoles
Sulfonylchloride (12 mmol) was added to a solution of 2-aminothiazole
(10 mmol) in pyridine (50 ml) and the solution was stirred at room temperature
for 12 h. The reaction mixture was poured into water and extracted with ethyl
acetate. The organic layer was washed with saturated aqueous sodium
hydrogen carbonate solution, 1 M of hydrochloric acid, and brine, and dried
over anhydrous sodium sulfate. The solvent was removed under reduced
pressure. The residue was purified by silica-gel column chromatography
(ethyl acetate–hexane) to give target N-thiazolylbenzensulfonamide.
N-(5-tert-Butyl-4-methyl-1,3-thiazol-2-yl)-3-nitrobenzenesulfonamide
(2): 69% yield; mp 212–2138C (ethyl acetate–hexane). 1H NMR (CDCl3) d:
1.30 (9H, s), 2.16 (3H, s), 7.86 (1H, t, J ¼ 8.3 Hz), 8.21 (1H, dd, J ¼ 2.0,
8.3 Hz), 8.42 (1H, ddd, J ¼ 1.8, 2.0, 8.3 Hz), 8.46 (1H, t, J ¼ 1.8 Hz), 12.58
(1H, br s). FAB-MS m/z: 356 (Mþ þ1). Anal. calcd. for C14H17N3O4S2: C,
47.31; H, 4.82; N, 11.82; S, 18.04. Found: C, 47.06; H, 4.84; N, 11.80; S,
17.84.
N-(5-Isopropyl-1,3-thiazol-2-yl)-3-nitrobenzenesulfonamide:
51%
yield; mp 162–1638C (toluene). 1H NMR (DMSO-d6) d: 1.19 (6H, d,
J ¼ 6.8 Hz), 2.94 (1H, heptet, J ¼ 6.8 Hz),7.05 (1H, s), 7.86 (1H, dd,
J ¼ 7.8, 8.3 Hz), 8.23 (1H, br d, J ¼ 7.8 Hz), 8.42 (1H, ddd, J ¼ 1.5, 1.9,
8.3 Hz), 8.47 (1H, dd, J ¼ 1.5, 1.9 Hz), 12.71 (1H, br s). FAB-MS m/z: 328
(Mþ þ1). Anal. calcd. for C12H13N3O4S2: C, 44.02; H, 4.00; N, 12.84; S,
19.59. Found: C, 43.96; H, 3.93; N, 12.78; S, 19.63.
Methyl 5-isopropyl-2-f[(3-nitrophenyl)sulfonyl]aminog-1,3-thiazole-
4-carboxylate: 75% yield; mp 131–1328C (ethyl acetate–hexane). 1H
NMR (CDCl3) d: 1.30 (6H, d, J ¼ 7.0 Hz), 3.95 (1H, heptet, J ¼ 7.0 Hz),
3.93 (3H, s), 7.69 (1H, dt, J ¼ 7.7, 8.3 Hz), 8.27 (1H, ddd, J ¼ 1.1, 1.8,
7.7 Hz), 8.38 (1H, ddd, J ¼ 1.1, 2.4, 8.3 Hz), 8.77 (1H, t, J ¼ 1.8 Hz). FAB-
MS m/z: 386 (Mþ þ1). Anal. calcd. for C14H15N3O6S2: C, 43.63; H, 3.92;
N, 10.90; S, 16.64. Found: C, 43.50; H, 4.00; N, 10.75; S, 16.44.
N-(5-Isopropyl-4-trifluoromethyl-1,3-thiazol-2-yl)-3-nitrobenzene-
1
sulfonamide: 78% yield; mp 257–2598C (ethyl acetate–hexane). H NMR
(CDCl3) d: 1.14 (6H, d, J ¼ 6.0 Hz), 3.24 (1H, m), 7.71 (1H, dt, J ¼ 1.1,
7.1 Hz), 8.13 (1H, dd, J ¼ 1.1, 7.1 Hz), 8.26 (1H, dd, J ¼ 1.1, 7.1 Hz), 8.49

Regioselective Alkylation of Thiazolylsulfonamides
2311
(1H, d, J ¼ 1.8 Hz). FAB-MS m/z: 393 (Mþ 21). Anal. calcd. for
C13H12F3N3O4S2: C, 39.49; H, 3.06; N, 10.63; S, 16.22; F, 14.42. Found: C,
39.52; H, 3.01; N, 10.74; S, 16.21; F, 14.19.
N-(5-tert-Butyl-4-methyl-1,3-thiazol-2-yl)benzenesulfonamide: 61%
1
yield; mp 224–2258C (ethyl acetate–hexane). H NMR (DMSO-d6) d: 1.28
(9H, s), 2.14 (3H, s), 7.54 (3H, m), 7.78 (2H, m), 12.32 (1H, br s). FAB-
MS m/z: 311 (Mþ þ1). Anal. calcd. for C14H18N2O2S2: C, 54.17; H, 5.84;
N, 9.02; S, 20.66. Found: C, 54.05; H, 5.94; N, 8.95; S, 20.52.
N-(5-tert-Butyl-4-methyl-1,3-thiazol-2-yl)-2-nitrobenzenesulfonamide:
1
79% yield; H NMR (DMSO-d6) d: 1.30 (9H, s), 2.18 (3H, s), 7.80 (2H, m),
7.87 (1H, m), 8.03 (1H, m), 12.65 (1H, br s). FAB-MS m/z: 356 (Mþ þ1).
Anal. calcd. for C14H17N3O4S2: C, 47.31; H, 4.82; N, 11.82; S, 18.04.
Found: C, 47.51; H, 4.67; N, 12.00; S, 17.83.
N-(5-tert-Butyl-4-methyl-1,3-thiazol-2-yl)-4-nitrobenzenesulfonamide:
1
85% yield; mp 206–2078C (ethyl acetate–hexane). H NMR (DMSO-d6) d:
1.30 (9H, s), 2.16 (3H, s), 8.03 (2H, d, J ¼ 8.8 Hz), 8.36 (2H, d, J ¼ 8.8Hz),
12.58 (1H, br s). FAB-MS m/z: 356 (Mþ þ1). Anal. calcd. for
.
C14H17N3O4S2 0.2H2O: C, 46.83; H, 4.88; N, 11.70; S, 17.86. Found: C,
46.87; H, 4.85; N, 11.71; S, 17.76.
N-(5-tert-Butyl-4-methyl-1,3-thiazol-2-yl)-3-chlorobenzenesulfonamide:
99% yield; mp 182–1838C (acetonitrile). 1H NMR (DMSO-d6) d: 1.29 (9H, s),
2.16 (3H, s), 7.58 (1H, t, J ¼ 7.8 Hz), 7.67 (1H, br d, J ¼ 7.8Hz), 7.74 (1H, br
s), 7.75 (1H, br d, J ¼ 7.8 Hz), 12.46 (1H, br s). FAB-MS m/z: 345 (Mþ þ1).
Anal. calcd. for C14H17ClN2O2S2: C, 48.76; H, 4.97; N, 8.12; S, 18.60; Cl,
10.28. Found: C, 48.53; H, 4.87; N, 8.09; S, 18.88; Cl, 10.33.
N-(5-tert-Butyl-4-methyl-1,3-thiazol-2-yl)-3-methoxybenzenesulfona-
1
mide: 61% yield; mp 205–2078C (ethyl acetate). H NMR (DMSO-d6) d:
1.29 (9H, s), 1.98 (3H, s), 3.80 (3H, s), 7.14 (1H, dd, J ¼ 2.5, 8.3 Hz), 7.26
(1H, t, J ¼ 2.5 Hz), 7.36 (1H, br d, J ¼ 7.8 Hz), 7.45 (1H, t, J ¼ 7.8 Hz),
12.34 (1H, br s). FAB-MS m/z: 341 (Mþ þ1). Anal. calcd. for
C15H2/N2O3S2: C, 52.92; H, 5.92; N, 8.23; S, 18.84. Found: C, 53.11; H,
5.93, N; 8.15, S; 18.87.
N-(5-tert-Butyl-4-methyl-1,3-thiazol-2-yl)-3-nitrobenzamide: prepared
with 3-nitrobenzoyl chloride in the same manner. 81% yield; mp 173–1758C
(ethyl acetate–hexane). 1H NMR (CDCl3) d: 1.46 (9H, s), 2.43 (3H, s), 7.74
(1H, m), 8.45 (3H, m), 9.03 (1H, br s). FAB-MS m/z: 320 (Mþ þ1). Anal.
calcd. for C15H17N3O3S: C, 56.41; H, 5.37; N, 13.16; S, 10.04. Found: C,
56.27; H, 5.07; N, 13.28; S, 9.96.
N-(5-tert-butyl-4-methyl-1,3-thiazol-2-yl)-N0-(3-nitrophenyl)urea: pre-
pared with 3-nitrobenzoyl isocyanate in the same manner. 98% yield;
1
mp 203–2058C (ethyl acetate–hexane). H NMR (CDCl3) d: 1.36 (9H, s),
2.28 (3H, s), 7.55 (1H, t, J ¼ 8.3 Hz), 7.81 (2H, m), 8.61 (1H, t, J¼
2.0 Hz), 9.43 (1H, br s). FAB-MS m/z: 335 (Mþ þ1). Anal. calcd. for
C15H18N4O3S: C, 53.88; H, 5.43; N, 16.75; S, 9.59. Found: C, 53.80; H,
5.38; N, 16.68; S, 9.50.

2312
N. Masuda et al.
General Procedure for the Alkylation of
N-Thiazolylbenzensulfonamide
To a solution of N-thiazolylbenzensulfonamide (5.0 mmol) in tetrahydrofuran
(15 ml) was added sodium hydride (60% dispersion in mineral oil: 6.0 mmol)
and iodomethane (15 mmol) under ice-bath cooling. The solution was warmed
to room temperature and stirred for 3 h. The reaction mixture was poured into
ice water and extracted with ethyl acetate. The organic layer was washed with
brine and then dried over anhydrous sodium sulfate. The solvent was removed
under reduced pressure and the residue was purified by silica-gel column
chromatography (ethyl acetate–hexane) to give the target 3-alkylated thiazo-
lidene derivatives.
N-(5-tert-Butyl-3,4-dimethyl-1,3-thiazol-2(3H)-ylidene)-3-nitrobenze-
1
nesulfonamide (1a): mp 143–1458C. H NMR (DMSO-d6) d: 1.32 (9H, s),
2.12 (3H), 3.60 (3H, s), 7.84 (1H, dd, J ¼ 7.9, 8.3 Hz), 8.26 (1H, br d,
J ¼ 7.9 Hz), 8.41 (1H, dd, J ¼ 2.5, 8.3 Hz), 8.49 (1H, t, J ¼ 2.5 Hz). FAB-
MS m/z: 370 (Mþ þ1). Anal. calcd. for C15H19N3O4S2: C, 48.76; H, 5.18;
N, 11.37; S, 17.36. Found: C, 48.69; H, 5.25; N, 11.31; S, 17.37.
N-(5-tert-Butyl-4-methyl-1,3-thiazol-2-yl)-N-methyl-3-nitrobenzene-
1
sulfonamide (1b): mp 91–928C. H NMR (DMSO-d6) d: 1.36 (9H, s), 2.26
(3H), 3.30 (3H, s), 7.72 (1H, t, J ¼ 7.8 Hz), 8.25 (1H, br d, J ¼ 7.8 Hz),
8.48 (1H, t, J ¼ 1.9 Hz), 8.57 (1H, ddd, J ¼ 0.9, 1.9, 8.3 Hz). FAB-MS m/z:
370 (Mþ þ1). Anal. calcd. for C15H19N3O4S2: C, 48.76; H, 5.18; N, 11.37;
S, 17.36. Found: C, 48.87; H, 5.28; N, 11.27; S, 17.30.
N-(5-tert-Butyl-3-ethyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-3-nitro-
benzenesulfonamide (3a): mp 139–1418C (diethyl ether–hexane). 1H
NMR (DMSO-d6) d: 1.12 (3H, t, J ¼ 6.8 Hz), 1.32 (9H, s), 2.31 (3H, s),
3.96 (2H, q, J ¼ 6.8 Hz), 7.85 (1H, t, J ¼ 8.3 Hz), 8.25 (1H, ddd, J ¼ 1.0,
1.9, 8.3 Hz), 8.42 (1H, dd, J ¼ 1.0, 1.9, 8.3 Hz), 8.48 (1H, t, J ¼ 1.9 Hz).
FAB-MS m/z: 384 (Mþ þ1). Anal. calcd. for C16H21N3O4S2: C,
50.11; H, 5.52; N, 10.96; S, 16.72. Found: C, 50.06; H, 5.49; N, 11.02; S,
16.81.
N-(5-tert-Butyl-4-methyl-1,3-thiazol-2-yl)-N-ethyl-3-nitrobenzenesul-
fonamide (3b): mp 105–1078C (diethyl ether). 1H NMR (CDCl3) d: 1.26 (3H,
t, J ¼ 7.0 Hz), 1.41 (9H, s), 2.34 (3H, s), 3.83 (2H, d, J ¼ 7.0 Hz), 7.72 (1H, t,
J ¼ 8.2 Hz), 8.17 (1H, ddd, J ¼ 0.9, 1.6, 7.7 Hz), 8.44 (1H, ddd, J ¼ 0.9, 2.2,
8.2 Hz), 8.72 (1H, t, J ¼ 1.8 Hz). FAB-MS m/z: 384 (Mþ þ1). Anal. calcd. for
C16H21N3O4S2: C, 50.11; H, 5.52; N, 10.96; S, 16.72. Found: C, 50.17; H,
5.55; N, 10.96; S, 16.71.
N-(3-Benzyl-5-tert-butyl-4-methyl-1,3-thiazol-2(3H)-ylidene)-3-nitro-
benzenesulfonamide (4a): mp 213–2148C. 1H NMR (CDCl3) d: 1.37 (9H, s),
2.20 (3H, s), 5.21 (2H, s), 6.96 (4H, m), 7.22 (2H, m), 7.58 (1H, t, J ¼ 7.8 Hz),
8.15 (2H, m), 8.30 (1H, ddd, J ¼ 1.0, 2.5, 8.3 Hz), 8.68 (1H, t, J ¼ 2.0 Hz).
FAB-MS m/z: 446 (Mþ þ1). Anal. calcd. for C21H23N3O4S2: C, 56.61; H,
5.20; N, 9.43; S, 14.39. Found: C, 56.56; H, 5.25; N, 9.45; S, 14.50.

Regioselective Alkylation of Thiazolylsulfonamides
2313
N-Benzyl-N-(5-tert-butyl-4-methyl-1,3-thiazol-2-yl)-3-nitrobenzene-
1
sulfonamide (4b): mp 142–1438C. H NMR (CDCl3) d: 1.37 (9H, s), 2.33
(3H, s), 5.02 (2H, s), 7.24 (4H, m), 7.35 (2H, m), 7.64 (1H, t, J ¼ 7.8 Hz),
8.04 (1H, m), 8.38 (1H, ddd, J ¼ 1.0, 2.5, 8.3 Hz), 8.58 (1H, t, J ¼ 2.0 Hz).
FAB-MS m/z: 446 (Mþ þ1). Anal. calcd. for C21H23N3O4S2: C, 56.61; H,
5.20; N, 9.43; S, 14.39. Found: C, 56.65; H, 5.19; N, 9.39; S, 14.28.
Ethyl [5-tert-butyl-4-methyl-2-f[(3-nitrophenyl)sulfonyl]iminog-1,3-
1
thiazol-3(2H)-yl]acetate (5a): mp 104–1058C (ethyl acetate–hexane). H
NMR (CDCl3) d: 1.24 (3H, t, J ¼ 7.0 Hz), 1.37 (9H, s), 2.21 (3H, s), 4.17
(2H, q, J ¼ 7.0 Hz), 4.71 (2H, s), 7.64 (1H, t, J ¼ 7.9 Hz), 8.28 (2H, m),
7.73 (1H, t, J ¼ 1.8 Hz). FAB-MS m/z: 442 (Mþ þ1). Anal. calcd. for
C18H23N3O6S2: C, 48.97; H, 5.25; N, 9.52; S, 14.53. Found: C, 48.99; H,
5.20; N, 9.47; S, 14.49.
N-[5-tert-Butyl-3-[2-(1,3-dioxolan-2-yl)ethyl]-4-methyl-1,3-thiazol-
2(3H)-ylidene]-3-nitrobenzenesulfonamide (6a): mp 212–2148C (ethyl
acetate–hexane). H NMR (DMSO-d6) d: 1.32 (9H, s), 1.85 (2H, m), 2.29
1
(3H, s), 3.71 (2H, m), 3.84 (2H, m), 4.00 (2H, m), 4.81 (1H, t, J ¼ 4.4 Hz),
7.85 (1H, t, J ¼ 7.8 Hz), 8.25 (1H, m), 8.41 (1H, br d, J ¼ 2.4, 8.3 Hz),
8.49 (1H, t, J ¼ 2.0 Hz). FAB-MS m/z: 456 (Mþ þ1). Anal. calcd. for
C19H25N3O6S2: C, 50.09; H, 5.53; N, 9.22; S, 14.08. Found: C, 50.00; H,
5.64; N, 9.02; S, 13.98.
N-(5-tert-Butyl-4-methyl-1,3-thiazol-2-yl)-N-[2-(1,3-dioxolan-2-yl)-
ethyl]-3-nitrobenzenesulfonamide (6b): mp 185–1878C (ethyl acetate–
hexane). H NMR (DMSO-d6) d: 1.38 (9H, s), 1.86 (2H, m), 2.29 (3H, s),
1
3.74 (2H, m), 3.85 (4H, m), 4.82 (1H, t, J ¼ 4.9 Hz), 7.95 (1H, t, J ¼ 8.3 Hz),
8.26 (1H, br d, J ¼ 7.8 Hz), 8.49 (1H, t, 2.0 Hz), 8.56 (1H, dd, J ¼ 1.5,
8.3 Hz). FAB-MS m/z: 456 (Mþ þ1). Anal. calcd. for C19H25N3O6S2: C,
50.09; H, 5.53; N, 9.22; S, 14.08. Found: C, 49.95; H, 5.60; N, 8.99; S, 13.85.
N-(5-Isopropyl-3-methyl-1,3-thiazol-2(3H)-ylidene)-3-nitrobenzene-
1
sulfonamide (7a): mp 150–1518C (isopropanol). H NMR (DMSO-d6) d:
1.19 (6H, d, J ¼ 6.9 Hz), 2.95 (1H, heptet, J ¼ 6.9 Hz), 3.45 (3H, s), 7.22
(1H, s), 7.86 (1H, d, J ¼ 7.8, 8.3 Hz), 8.26 (1H, br d, J ¼ 7.8 Hz), 8.43 (1H,
ddd, J ¼ 1.0, 1.9, 8.3 Hz), 8.49 (1H, t, J ¼ 1.9 Hz). FAB-MS m/z: 342
(Mþ þ1). Anal. calcd. for C13H15N3O4S2: C, 45.73; H, 4.43; N, 12.31; S,
18.78. Found: C, 45.66; H, 4.31; N, 12.30; S, 18.89.
Methyl 5-Isopropyl-3-methyl-2-f[(3-nitrophenyl)sulfonyl]iminog-2,3-
dihydro-1,3-thiazole-4-carboxylate (8a): mp 120–1218C (ethyl acetate–
1
hexane). H NMR (CDCl3) d: 1.29 (6H, d, J ¼ 6.8 Hz), 3.67 (3H, s), 3.68
(1H, heptet, J ¼ 6.8 Hz), 3.93 (3H, s), 7.88 (1H, br t, J ¼ 8.2 Hz), 8.29 (1H,
br d, J ¼ 7.7 Hz), 8.37 (1H, dd, J ¼ 2.0, 8.2 Hz), 8.79 (1H, t, J ¼ 2.0 Hz).
FAB-MS m/z: 400 (Mþ þ1). Anal. calcd. for C15H17N3O6S2: C, 45.10; H,
4.29; N, 10.52; S, 16.06. Found: C, 44.93; H, 4.10; N, 10.62; S, 16.09.
Methyl 5-tert-butyl-2-fmethyl[(3-nitrophenyl)sulfonyl]aminog-1,3-
thiazole-4-carboxylate (8b): mp 121–1238C (ethyl acetate–hexane). 1H
NMR (CDCl3) d: 1.36 (6H, d, J ¼ 6.9 Hz), 3.48 (3H, s), 3.89 (3H, s), 4.07

2314
N. Masuda et al.
(1H, heptet, J ¼ 6.9 Hz), 7.75 (1H, t, J ¼ 8.1 Hz), 8.14 (1H, m), 8.48 (1H, ddd,
J ¼ 1.0, 2.0, 8.1 Hz), 8.69 (1H, t, J ¼ 2.0 Hz). FAB-MS m/z: 400 (Mþ þ1).
Anal. calcd. for C15H17N3O6S2: C, 45.10; H, 4.29; N, 10.52; S, 16.06.
Found: C, 44.98; H, 4.14; N, 10.43; S, 15.94.
N-(5-Isopropyl-3-methyl-4-trifluoromethyl-1,3-thiazol-2(3H)-2-
ylidene)-3-nitrobenzenesulfonamide (9a): mp 127–1288C (ethyl acetate–
1
hexane). H NMR (CDCl3) d: 1.31 (6H, d, J ¼ 7.0 Hz), 3.53 (1H, m), 3.58
(3H, br s), 7.70 (1H, t, J ¼ 7.8 Hz), 8.30 (1H, dt, J ¼ 2.0, 7.8 Hz), 8.39 (1H,
m), 8.79 (1H, t, J ¼ 2.0 Hz). FAB-MS m/z: 410 (Mþ þ1). Anal. calcd. for
C14H14F3N3O4S2: C, 41.07; H, 3.45; N, 10.26; S, 15.66; F, 13.92. Found: C,
41.02; H, 3.37; N, 10.23; S, 15.64; F, 13.83.
N-[5-tert-Butyl-4-(trifluoromethyl)-1,3-thiazol-2-yl]-N-methyl-3-
1
nitrobenzenesulfonamide (9b): mp 119–1208C (ethyl acetate–hexane). H
NMR (CDCl3) d: 1.36 (6H, d, J ¼ 6.9 Hz), 3.44 (3H, s), 3.51 (1H, heptet,
J ¼ 6.9 Hz), 7.78 (1H, t, J ¼ 7.8 Hz), 8.14 (1H, m), 8.50 (1H, ddd, J ¼ 1.0,
2.4, 8.3 Hz), 8.67 (1H, t, J ¼ 2.4 Hz). FAB-MS m/z: 410 (Mþ þ1). Anal.
calcd. for C14H14F3N3O4S2: C, 41.07; H, 3.45; N, 10.26; S, 15.66; F, 13.92.
Found: C, 41.03; H, 3.39; N, 10.21; S, 15.72; F, 13.88.
N-(5-tert-Butyl-3,4-dimethyl-1,3-thiazol-2(3H)-ylidene)benzenesulfo-
namide (10a): mp 188–1898C (ethyl acetate–hexane). 1H NMR (DMSO-d6)
d: 1.31 (9H, s), 2.26 (3H, s), 3.40 (3H, s), 7.54 (3H, m), 7.82 (2H, m). FAB-MS
m/z: 325 (Mþ þ1). Anal. calcd. for C14H18N2O2S2: C, 54.17; H, 5.84; N,
9.02; S, 20.66. Found: C, 54.00; H, 5.94; N, 8.95; S, 20.53.
N-(5-tert-Butyl-3,4-dimethyl-1,3-thiazol-2(3H)-ylidene)-2-nitrobenze-
nesulfonamide (11a): mp 138–1398C. 1H NMR (CDCl3) d: 1.36 (9H, s), 2.28
(3H, s), 3.45 (3H, s), 7.61 (3H, m), 8.25 (1H, m). FAB-MS m/z: 370 (Mþ þ1).
Anal. calcd. for C15H19N3O4S2: C, 48.76; H, 5.18; N, 11.37; S, 17.36. Found:
C, 48.76; H, 4.99; N, 11.38; S, 17.69.
N-(5-tert-Butyl-3,4-dimethyl-1,3-thiazol-2(3H)-ylidene)-4-nitrobenze-
nesulfonamide (12a): mp 184–1858C (ethyl acetate–hexane). 1H NMR
(CDCl3) d: 1.37 (9H, s), 2.27 (3H, s), 3.46 (3H, s), 8.15 (2H, dt, J ¼ 2.4,
8.8 Hz), 8.29 (2H, dt, J ¼ 2.4, 8.8 Hz). FAB-MS m/z: 370 (Mþ þ1). Anal.
calcd. for C15H19N3O4S2: C, 48.76; H, 5.18; N, 11.37; S, 17.36. Found: C,
48.70; H, 4.98; N, 11.51; S, 17.43.
N-(5-tert-Butyl-3,4-dimethyl-1,3-thiazol-2(3H)-ylidene)-3-methoxy-
benzenesulfonamide (13a): mp 192–1938C (diethyl ether). 1H NMR
(DMSO-d6) d: 1.31 (9H, s), 2.27 (3H, s), 3.40 (3H, s), 3.81 (3H, s), 7.14
(1H, ddd, J ¼ 1.0, 2.5, 7.8 Hz), 7.29 (1H, t, J ¼ 2.5 Hz), 7.39 (1H, br d,
J ¼ 7.8 Hz), 7.44 (1H, t, J ¼ 7.8 Hz). FAB-MS m/z: 355 (Mþ þ1). Anal.
calcd. for C16H22N2O3S2: C, 54.21; H, 6.26; N, 7.90; S, 18.09. Found: C,
54.31; H, 6.25; N, 7.86; S, 18.17.
N-(5-tert-Butyl-3,4-dimethyl-1,3-thiazol-2(3H)-ylidene)-3-chloroben-
zenesulfonamide (14a): mp 138–1398C (chloroform). 1H NMR (DMSO-d6)
d: 1.31 (9H, s), 2.28 (3H, s), 3.42 (3H, s), 7.57 (1H, dd, J ¼ 7.8, 8.3 Hz), 7.66
(1H, ddd, J ¼ 1.0, 2.0, 8.3 Hz), 7.79 (1H, br s), 7.80 (1H, br d, J ¼ 7.8 Hz).

Regioselective Alkylation of Thiazolylsulfonamides
2315
FAB-MS m/z: 359 (Mþ þ1). Anal. calcd. for C15H19ClN2O2S2Cl: C, 50.20;
H, 5.34; N, 7.81; S, 17.87; Cl, 9.88. Found: C, 50.01; H, 5.26; N, 7.76; S,
18.00; Cl, 10.04.
N-(5-tert-Butyl-3,4-dimethyl-1,3-thiazol-2(3H)-ylidene)-3-nitroben-
zamide (15a): mp 212–2138C (chloroform). 1H NMR (CDCl3) d: 1.44
(9H, s), 2.43 (3H, s), 3.84 (3H, s), 7.60 (1H, t, J ¼ 7.3 Hz), 8.31 (1H, ddd,
J ¼ 1.4, 2.0, 7.3 Hz), 8.61 (1H, dt, J ¼ 1.4, 7.3 Hz), 9.46 (1H, t,
J ¼ 2.0 Hz). FAB-MS m/z: 334 (Mþ þ1). Anal. calcd. for C14H24N2O2S:
C, 57.64; H, 5.74; N, 12.60; S, 9.62. Found: C, 57.41; H, 5.64; N, 12.45; S,
9.61.
N0-(5-tert-Butyl-3,4-dimethyl-1,3-thiazol-2(3H)-ylidene)-N-methyl-N-
(3-nitrophenyl)urea (16a): mp 136–1378C (chloroform). 1H NMR (CDCl3)
d: 1.37 (9H, s), 2.29 (3H, s), 3.45 (3H, s), 3.53 (3H, s), 7.45 (1H, t, J ¼ 8.3 Hz),
7.74 (1H, br d, J ¼ 8.3 Hz), 7.94 (1H, dd, J ¼ 1.9, 8.3 Hz), 8.39 (1H, t,
J ¼ 1.9 Hz). FAB-MS m/z: 363 (Mþ þ1). Anal. calcd. for C17H22N4O3S:
C, 56.33; H, 6.12; N, 15.46; S, 8.85. Found: C, 56.17; H, 6.02; N, 15.36; S,
8.86.
ACKNOWLEDGMENT
We acknowledge helpful discussion with Susumu Igarashi. We also thank
members of the Division of Analytical Research for performing instrumental
analysis.
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