Convenient one-pot two-step synthesis of 1,3-thiazoles via organocatalyzed epoxidation of nitroolefins

Article abstract of DOI:10.1055/s-0031-1291139

A convenient novel one-pot two-step strategy and its substrate scope for the synthesis of 1,3-thiazole heterocycles via organocatalytic epoxidation of nitroolefins with the TBHP/DBU system, and subsequent reaction of α-nitroepoxides with thioamides is reported. Georg Thieme Verlag KG · Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1291139

PRACTICAL SYNTHETIC PROCEDURES
▌3441
pCraoctincavl seynnthieeticnptroOcednurees-Pot Two-Step Synthesis of 1,3-Thiazoles via Organocatalyzed
Epoxidation of Nitroolefins
One-Pot Synthesis of 1,3-Thiazoles
Shengwei Wei, Katharina M. Weiß, Svetlana B. Tsogoeva*
Department of Chemistry and Pharmacy, Institute of Organic Chemistry 1,
University of Erlangen-Nuremberg, Henkestraße 42, 91054 Erlangen, Germany
Fax +49(9131)8526865; E-mail: tsogoeva@chemie.uni-erlangen.de
PSP
Received: 20.03.2012; Accepted: 22.03.2012
No237
Abstract: A convenient novel one-pot two-step strategy and its substrate scope for the synthesis of 1,3-thiazole heterocycles via organo-
catalytic epoxidation of nitroolefins with the TBHP/DBU system, and subsequent reaction of α-nitroepoxides with thioamides is reported.
Key words: thiazole, epoxidation, DBU, one-pot reaction, organocatalysis
S
NH2
O
N
NO2
NO2
TBHP
R2
DBU (5 mol%)
3
S
r.t.
r.t.
R1
R1
R2
R1
1
2
4
not isolated
Scheme 1 One-pot two-step process for the synthesis of 1,3-thiazoles
Thiazole heterocycles are of prominent importance be- methods in modern synthetic chemistry due to the reduc-
cause of their potential as versatile building blocks for tion of time, costs, materials, and waste generation.11
pharmaceuticals and natural products.1–4 It is obvious, fur-
Very recently, we disclosed a facile approach to thiazole
thermore, that compounds with the thiazole ring have po-
derivatives:12 one-pot two-step synthesis, which involves
tential biological activity.5,6
an organocatalytic epoxidation of nitroolefins with
The most salient method to synthesize thiazoles is the TBPH/DBU (t-BuOOH/1,8-diazabicyclo[5.4.0]undec-7-
Hantzsch thiazole synthesis where α-haloketones are re- ene) system, followed by reaction with different thiobenz-
acted with thioamides.7 One of the less explored methods amides at room temperature (Scheme 1).
is to prepare thiazoles from the corresponding epoxides
Herein we report the examined substrate scope (20 exam-
ples) in our one-pot two-step process using the optimized
(e.g., 2-chlorooxiranes, α-nitroepoxides) and thioamides
or thioureas.8 For the synthesis of epoxides diverse ap-
reaction conditions, as well as propose a plausible reac-
proaches to catalytic epoxidations have been developed in
tion mechanism for 1,3-thiazole formation starting from
α-nitroepoxides.
recent years.9 Newman first reported the thiazole synthe-
sis from the corresponding α-nitroepoxides (generated
Concerning our idea to develop a one-pot procedure to-
wards thiazole synthesis, we first studied the epoxidation
of β-methyl-β-nitrostyrene (1). The known strategy for
epoxidation of α,β-unsaturated δ-lactones and other
enones using anhydrous TBHP as an oxidant and DBU as
a base (at 120 mol% loading) at 0 °C13 was recently ex-
tended to the epoxidation of the more challenging ni-
troolefins as substrates.12 In order to develop a catalytic
epoxidation of β-methyl-β-nitrostyrene (1), we used
merely catalytic amounts of DBU in combination with
TBHP as oxidant. After an optimization series, it was
found that DBU could be used in only 5 mol% loading in
n-hexane at room temperature to generate high conver-
sions of the corresponding α-nitroepoxide 2 after one hour
reaction time. Epoxide 2 can be used directly without any
from nitroolefins with H2O2/NaOH system).8a,b In contin-
uation of our research on organocatalytic epoxidation re-
actions,10 we decided to develop an organocatalytic
epoxidation of nitroolefins with an intention to further ap-
ply the corresponding products, α-nitroepoxides, without
workup and purification for the synthesis of 1,3-thiazoles.
Notably, one-pot processes, in which chemical transfor-
mations are carried out without intermediate isolation and
purification steps, are very attractive and sustainable
SYNTHESIS 2012, 44, 3441–3446
Advanced online publication: 04.07.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1291139; Art ID: SS-2012-Z0278-PSP
© Georg Thieme Verlag Stuttgart · New York

3442
S. Wei et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 1 Scope of Substrates (continued)
workup procedures for the synthesis of the thiazole het-
erocycles 4 simply by adding the corresponding thio-
benzamide 3 to the reaction mixture. After some
investigations, the optimal conditions for the second step
of this one-pot procedure proved to be 2.0 equivalents of
thiobenzamide with 10 mol% TFA (trifluoroacetic acid)
as additive. The corresponding thiazole products were iso-
lated after stirring for 24 hours at room temperature.
step 1:
TBHP (1.0 equiv)
N
DBU (5 mol%)
hexane, 1 h, r.t.
NO2
S
S
R1
R2
step 2:
R1
(1.0 equiv)
NH2
(2.0 equiv)
TFA (0.1 equiv)
hexane, 24 h, r.t.
R2
We examined the scope of the one-pot process for differ-
ent aromatic nitroalkenes as well as for different thiobenz-
amides using the optimized reaction conditions. All
reactions investigated could be performed in 22–70%
yield, applying DBU at only 5 mol% loading. Higher
yields (65–70%) were obtained using β-methyl-β-nitro-
styrene and thiobenzamides with R2 = H, electron-with-
drawing, or neutral substituents (Table 1, entries 1–3).
Entry R1
R2
Product
Yield
(%)b
N
N
6a 4-Cl
4-t-Bu
48
52
40
S
S
Cl
t-Bu
Table 1 Scope of Substrates
4f
step 1:
TBHP (1.0 equiv)
N
DBU (5 mol%)
NO2
7a 4-Br
H
hexane, 1 h, r.t.
Br
S
S
R1
R2
step 2:
R1
4g
(1.0 equiv)
NH2
N
(2.0 equiv)
TFA (0.1 equiv)
hexane, 24 h, r.t.
R2
S
8a 2-OMe 4-Cl
Cl
OMe
Entry R1
R2
Product
Yield
(%)b
4h
N
N
N
N
N
N
N
9a 4-Br
10a 4-Cl
11a 4-Cl
4-OMe
51
40
22
S
S
S
1
H
H
70
Br
OMe
S
S
S
S
4i
4a
4b
4-Cl
Cl
Cl
2
3
4
H
H
4-Cl
65
65
Cl
4j
4-OMe
Cl
OMe
4-t-Bu
t-Bu
OMe
4k
4c
N
12a 4-OMe
H
H
30
31
S
H
4-OMe
41
50
MeO
4l
4d
N
N
5a 4-Cl
H
S
13a 2-OMe
S
Cl
OMe
4e
4m
Synthesis 2012, 44, 3441–3446
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
One-Pot Synthesis of 1,3-Thiazoles
3443
Table 1 Scope of Substrates (continued)
Furthermore, the yields decreased from 65–70% to 30–
35% when phenyl moiety in β-methyl-β-nitrostyrene was
replaced by naphthyl group and used in the reactions with
the same thiobenzamides, where R2 = H, electron-with-
drawing, or neutral substituents (entries 17–19 vs entries
1–3). Interestingly, the reaction conditions using TFA (0.1
equiv) and MeOH (100 equiv) as additive’s combination
were found to be better suitable (with respect to observed
yields) for aromatic nitroolefines with R1 = electron-with-
drawing and/or -donating groups (entries 5–16).
step 1:
TBHP (1.0 equiv)
DBU (5 mol%)
hexane, 1 h, r.t.
N
NO2
S
S
R1
R2
step 2:
R1
(1.0 equiv)
NH2
(2.0 equiv)
TFA (0.1 equiv)
hexane, 24 h, r.t.
R2
On the basis of related literature known reactions,15 a pro-
posed mechanism for the thiazole formation could be de-
scribed as follows (Scheme 2). The thiobenzamide attacks
the epoxide at the less hindered carbon atom, followed by
ring closure acompanied with release of nitrous acid that
presumably decomposes to NO2 and NO (formation of
brown volatiles/gas was observed during the reaction). Fi-
nally, aromatization to the thiazole heterocycle occurs un-
der release of water.
Entry R1
R2
Product
Yield
(%)b
N
14a 4-OMe 4-t-Bu
33
24
S
MeO
t-Bu
4n
N
Ph
S
15a 2-OMe 4-t-Bu
t-Bu
S
O
OMe
S
NH2
O
NO2
Ph
Ph
NH2
4o
Ph
H+
NO2
N
Ph
16a 4-Br
4-t-Bu
41
35
Ph
N
S
Ph
Br
t-Bu
S
S
S
NH
N
– H2O
4p
– HNO2
OH
NO2
Ph
Ph
OH
Ph
H
N
3,4-
17a
Scheme 2 Plausible mechanism for 1,3-thiazole formation using α-
S
H
(CH)4
nitroepoxides as key starting compounds
4q
4r
4s
4t
In conclusion, the developed one-pot process provides a
useful route for the formation of 1,3-thiazoles from easily
accessible aromatic nitroolefins. The application of DBU
as a readily available organocatalyst for the epoxidation of
nitroolefins with TBHP, followed by the reaction with
thiobenzamides, and the very mild conditions used for
both transformations, make this process a simple and con-
venient approach to obtain a broad range of 1,3-derived
thiazoles in 22–70% yields.
N
N
N
3,4-
18a
S
S
S
4-Cl
30
32
(CH)4
Cl
3,4-
19a
4-t-Bu
(CH)4
t-Bu
Chemicals were used as received from common commercial sourc-
es. All solvents were distilled before use. n-Hexane (HPLC grade)
was obtained from Fisher Scientific and used as received. Petro-
leum ether (PE) used refers to the fraction boiling at 40–60 °C.
NMR spectra were recorded on Jeol (300 and 400) or Bruker
Avance (300 or 400) spectrometer. NMR spectra were referenced to
the residual solvent signal (1H: CDCl3, 7.24 ppm; 13C: CDCl3, 77.0
ppm) and recorded at ambient probe temperature. IR spectra were
recorded as thin films on a Varian IR-660 spectrometer. FAB mass
spectra were measured with a Micromass ZabSpec and EI mass
spectra were recorded with a Finnigan MAT 95 XP spectrometer.
Gas chromatography was conducted on a Thermo instrument Trace
GC Ultra with a 7 m TR5 column. Thin-layer chromatography was
carried out on ALUGRAM® SIL G/UV254 (Macherey-Nagel) and
visualized by UV. Flash column chromatography was performed
using silica gel 60 M (Macherey-Nagel).
3,4-
20a
4-OMe
33
(CH)4
OMe
a MeOH (100 equiv) was added as a second additive.
b Isolated yield after column chromatography.
Notably, the presence of OMe group at the aromatic ni-
troolefin or at the thiobenzamide gave lower yields of the
corresponding thiazoles (entries 4, 8, 11–15, 20 vs entries
1–3).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3441–3446

3444
S. Wei et al.
PRACTICAL SYNTHETIC PROCEDURES
MS (EI): m/z (%) = 285 (100, M+), 182 (75).
One-Pot Two-Step Synthesis of Thiazoles; General Procedure
A round-bottomed flask was charged with trans-β-methyl-β-nitro-
styrene 1 (0.028 g, 0.170 mmol), DBU (1.3 μL, 0.008 mmol), and
n-hexane (0.56 mL). Then, TBHP (34.1 μL, 0.170 mmol) was added
in one portion. The reaction mixture was stirred at r.t. for 1 h. Then,
thiobenzamide (0.047 g, 0.340 mmol) and TFA (1.3 μL, 0.017
mmol) were added, and the mixture was stirred for 24 h at r.t. The
crude product was extracted with Et2O (3 × 3 mL), the solvent evap-
orated, and the residue purified by column chromatography (SiO2,
PE–EtOAc, 97:3) to yield the desired product.
HRMS (EI): m/z calcd for C16H12ClNS: 285.0379; found: 285.0389.
2-[4-(tert-Butyl)phenyl]-5-(4-chlorophenyl)-4-methylthiazole
(4f)
Yield: 28 mg (48%); white solid; mp 95 °C.
1H NMR (300 MHz, CDCl3): δ = 7.83 (d, J = 9.0 Hz, 2 H), 7.45–
7.39 (m, 6 H), 2.52 (s, 3 H), 1.33 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 165.0, 152.9, 148.5, 133.2, 130.4,
130.3, 129.9, 128.4, 125.6, 125.4, 34.4, 30.7, 15.9.
4-Methyl-2,5-diphenylthiazole (4a)14
Yield: 30 mg (70%); white solid; mp 56 °C.
MS (EI): m/z = 341 (100%, M+).
HRMS (EI): m/z calcd for C20H20ClNS: 341.1005; found: 341.0993.
1H NMR (400 MHz, CDCl3): δ = 7.94 (m, 2 H), 7.49–7.32 (m, 8 H),
2.55 (s, 3 H).
Anal. Calcd for C20H20ClNS: C, 70.26; H, 5.90; N, 4.10; S, 9.38.
Found: C, 69.67; H, 6.35; N, 4.05; S, 9.39.
13C NMR (100 MHz, CDCl3): δ = 165.0, 148.8, 133.7, 132.2, 129.8,
129.1, 128.9, 128.7, 127.7, 126.3, 16.4.
MS (FAB): m/z = 252 (100%, M + H+).
5-(4-Bromophenyl)-4-methyl-2-phenylthiazole (4g)
Yield: 29 mg (52%); white solid; mp 110 °C.
1H NMR (300 MHz, CDCl3): δ = 7.92–7.90 (m, 2 H), 7.54 (d, J =
9.0 Hz, 2 H), 7.43–7.24 (m, 5 H), 2.52 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 164.9, 161.8, 148.7, 133.0, 131.4,
130.7, 130.2, 129.5, 128.5, 125.8, 15.9.
2-(4-Chlorophenyl)-4-methyl-5-phenylthiazole (4b)14
Yield: 32 mg (65%); white solid; mp 114 °C.
IR (film): 2922, 2360, 1653, 1600, 1572, 1534 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.88–7.84 (m, 2 H), 7.48–7.35 (m,
MS (EI): m/z = 329 (100%, M+).
7 H), 2.54 (s, 3 H).
HRMS (EI): m/z calcd for C16H12BrNS: 328.9782; found: 328.9797.
13C NMR (75 MHz, CDCl3): δ = 163.6, 149.0, 135.7, 132.6, 132.2,
131.9, 129.1, 129.1, 128.7, 127.9, 127.4, 16.3.
MS (EI): m/z = 285 (100%, M+).
Anal. Calcd for C16H12BrNS: C, 58.19; H, 3.66; N, 4.24; S, 9.71.
Found: C, 57.82; H, 4.22; N, 4.10; S, 10.07.
HRMS (EI): m/z calcd for C16H12ClNS: 285.0379; found: 285.0372.
2-(4-Chlorophenyl)-5-(2-methoxyphenyl)-4-methylthiazole(4h)
Yield: 16 mg (40%); white solid; mp 121 °C.
Anal. Calcd for C16H12ClNS: C, 67.24; H, 4.23; N, 4.90; S, 11.22.
Found: C, 66.78; H, 4.55; N, 4.67; S, 12.41.
IR (film): 3002, 2958, 2919, 2831, 1581, 1537 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.85 (d, J = 8.4 Hz, 2 H), 7.39–
7.31 (m, 4 H), 7.04–6.97 (m, 2 H), 3.84 (s, 3 H), 2.40 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 164.0, 156.5, 150.4, 135.0, 132.0;
131.5, 129.4, 128.6, 127.5, 127.0, 120.1, 120.0, 110.7, 55.1, 15.9.
2-[4-(tert-Butyl)phenyl]-4-methyl-5-phenylthiazole (4c)
Yield: 34 mg (65%); white solid; mp 109 °C.
IR (film): 3058, 2961, 2868, 1773, 1736, cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.86 (d, J = 8.4 Hz, 2 H), 7.50–
MS (EI): m/z = 315 (100%, M+).
7.39 (m, 6 H), 7.36–7.31 (m, 1 H), 2.55 (s, 3 H), 1.34 (s, 9 H).
HRMS (EI): m/z calcd for C17H14ClNOS: 315.0485; found:
315.0467.
13C NMR (100 MHz, CDCl3): δ = 165.3, 153.3, 148.7, 132.4, 131.8,
131.1, 129.2, 128.7, 127.7, 126.1, 125.9, 34.8, 31.1, 16.3.
MS (EI): m/z (%) = 307 (85, M+), 292 (100, M – CH3).
5-(4-Bromophenyl)-2-(4-methoxyphenyl)-4-methylthiazole (4i)
Yield: 31 mg (51%); white solid; mp 123 °C.
HRMS (EI): m/z calcd for C20H21NS: 307.1395; found: 307.1408.
1H NMR (300 MHz, CDCl3): δ = 7.84 (d, J = 9.0 Hz, 2 H), 7.54 (d,
J = 9.0 Hz, 2 H), 7.32 (d, J = 9.0 Hz, 2 H), 6.93 (d, J = 9.0 Hz, 2 H),
3.84 (s, 3 H), 2.50 (s, 3 H).
Anal. Calcd for C20H21NS: C, 78.13; H, 6.88; N, 4.56; S, 10.43.
Found: C, 78.32; H, 6.98; N, 4.55; S, 10.20.
13C NMR (75 MHz, CDCl3): δ = 164.9, 160.6, 148.4, 131.4, 130.8,
130.1, 129.4, 127.3, 126.0, 121.3, 113.8, 55.0, 15.9.
MS (EI): m/z = 358 (100%, M+).
2-(4-Methoxyphenyl)-4-methyl-5-phenylthiazole (4d)
Yield: 19 mg (41%); white solid; mp 63 °C.
IR (film): 3001, 2960, 2931, 2853, 1604, 1574, 1559, 1515 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 9.2 Hz, 2 H), 7.48–
7.24 (m, 5 H), 6.94 (d, J = 9.2 Hz, 1 H), 3.84 (s, 3 H), 2.53 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 165.0, 161.0, 148.4, 132.4, 131.2,
129.1, 128.7, 127.7, 127.6, 126.7, 114.2, 55.4, 16.4.
MS (EI): m/z = 281 (100%, M+).
HRMS (EI): m/z calcd for C17H14ONBrS: 358.9979; found:
358.9993.
Anal. Calcd for C17H14ONBrS: C, 56.67; H, 3.92; N, 3.89; S, 8.90.
Found: C, 56.32; H, 3.92; N, 3.87; S, 9.00.
2,5-Bis(4-chlorophenyl)-4-methylthiazole (4j)
Yield: 22 mg (40%); white solid; mp 172 °C.
HRMS (EI): m/z calcd for C17H15NOS: 281.0874; found: 281.0874.
1H NMR (300 MHz, CDCl3): δ = 7.84 (d, J = 9.0 Hz, 2 H), 7.40–
7.37 (m, 6 H), 2.51 (s, 3 H).
Anal. Calcd for C17H15NOS: C, 72.57; H, 5.37; N, 4.98; S, 11.40.
Found: C, 72.50; H, 5.72; N, 5.29; S, 11.25.
13C NMR (75 MHz, CDCl3): δ = 164.1, 149.5, 136.0, 134.1, 132.2,
131.4, 130.6, 130.5, 129.1, 127.6, 16.5.
MS (EI): m/z (%) = 320 (20, M+), 321 (80), 319 (100).
5-(4-Chlorophenyl)-4-methyl-2-phenylthiazole (4e)14
Yield: 25 mg (50%); white solid; mp 90 °C.
1H NMR (300 MHz, CDCl3): δ = 7.92–7.90 (m, 2 H), 7.43–7.39 (m,
7 H), 2.52 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 164.9, 148.7, 133.3, 133.0, 130.4,
HRMS (EI): m/z calcd for C16H11Cl2NS: 318.9989; found:
318.9931.
130.2, 129.9, 129.5, 125.9, 15.9.
Synthesis 2012, 44, 3441–3446
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
One-Pot Synthesis of 1,3-Thiazoles
3445
Anal. Calcd for C16H11Cl2NS: C, 60.01; H, 3.46; N, 4.37; S, 10.01.
Found: C, 59.51; H, 3.27; N, 4.34; S, 10.27.
HRMS (EI): m/z calcd for C20H20BrNS: 385.04998; found:
385.0500.
5-(4-Chlorophenyl)-2-(4-methoxyphenyl)-4-methylthiazole (4k)
Yield: 12 mg (22%); white solid; mp 120 °C.
4-Methyl-5-(naphthalen-2-yl)-2-phenylthiazole (4q)
Yield: 18 mg (35%); white solid; mp 130 °C.
1H NMR (300 MHz, CDCl3): δ = 8.31(d, J = 9.0 Hz, 1 H), 7.98 (d,
J = 9.0 Hz, 1 H), 7.86 (d, J = 9.0 Hz, 2 H), 6.97–6.91 (dd, J = 9.0,
15 Hz, 4 H), 3.84 (s, 3 H), 2.50 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 164.8, 162.0, 160.7, 160.6, 148.3,
133.1, 131.5, 129.4, 129.1, 128.3, 127.1, 125.0, 114.1, 113.5, 55.0,
15.9.
1H NMR (300 MHz, CDCl3): δ = 7.93–7.85 (m, 6 H), 7.61 (d, J =
3.0 Hz, 2 H), 7.53–7.49 (m, 4 H), 2.62 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.8, 148.6, 133.2, 132.8, 132.1,
131.9, 129.4, 129.1, 128.4, 127.9, 127.6, 127.5, 127.3, 126.6, 126.2,
126.0, 125.9, 16.1.
MS (EI): m/z = 301 (100%, M + H+).
MS (EI): m/z = 315 (100%, M+).
HRMS (EI): m/z calcd for C20H15NS: 301.0915; found: 301.0925.
HRMS (EI): m/z calcd for C17H14ClNOS: 315.04846; found:
315.0485.
2-(4-Chlorophenyl)-4-methyl-5-(naphthalen-2-yl)thiazole (4r)
Yield: 17 mg (30%); white solid; mp 160 °C.
1H NMR (300 MHz, CDCl3): δ = 7.90–7.87 (m, 6 H), 7.59–7.51 (m,
3 H), 7.41 (d, J = 6.0 Hz, 2 H), 2.61 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 163.4, 148.8, 135.3, 134.7, 132.8,
132.2, 132.1, 131.7, 128.9, 128.7, 128.0, 127.7, 127.6, 127.3, 127.0,
126.5, 126.3, 126.1, 16.0.
5-(4-Methoxyphenyl)-4-methyl-2-phenylthiazole (4l)
Yield: 11 mg (30%); white solid; mp 70 °C.
1H NMR (300 MHz, CDCl3): δ = 7.93 (d, J = 6.0 Hz, 2 H), 7.42–
7.38 (m, 4 H), 6.97 (d, J = 3.0 Hz, 2 H), 3.84 (s, 3 H), 2.52 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 164.0, 156.5, 150.4, 133.4, 131.5,
129.4, 129.1, 128.3, 127.1, 125.0, 120.0, 110.7, 55.1, 15.9.
MS (EI): m/z = 281 (100%, M+).
MS (EI): m/z = 335 (100%, M+).
2-(4-tert-Butylphenyl)-4-methyl-5-(naphthalen-2-yl)thiazole
(4s)
5-(2-Methoxyphenyl)-4-methyl-2-phenylthiazole (4m)
Yield: 11 mg (31%); white solid; mp 69 °C.
Yield: 19 mg (32%); white solid; mp 137 °C.
1H NMR (300 MHz, CDCl3): δ = 7.87–7.61 (m, 6 H), 7.60 (d, J =
6.0 Hz, 1 H), 7.57–7.49 (m, 3 H), 7.47 (d, J = 12.0 Hz, 1 H), 2.62
(s, 3 H), 1.34 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 165.0, 152.7, 148.5, 140.9, 132.8,
132.0, 131.3, 130.5, 129.3, 127.9, 127.6, 127.5, 127.2, 126.6, 126.2,
125.9, 125.6, 125.4, 34.4, 30.7, 16.1.
1H NMR (300 MHz, CDCl3): δ = 7.93 (d, J = 6.0 Hz, 2 H), 7.41–
7.33 (m, 4 H), 7.04–6.99 (m, 2 H), 3.84 (s, 3 H), 2.41 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 165.5, 156.5, 150.2, 133.4, 131.5,
129.3, 129.1 128.3, 127.1, 125.8, 120.2, 120.0, 110.7, 55.1, 15.9.
MS (EI): m/z = 281 (100%, M+).
MS (EI): m/z = 357 (100%, M+).
2-(4-tert-Butylphenyl)-5-(4-methoxyphenyl)-4-methylthiazole
(4n)
Yield: 14 mg (33%); white solid, mp 80 °C.
2-(4-Methoxyphenyl)-4-methyl-5-(naphthalen-2-yl)thiazole (4t)
Yield: 18 mg (33%); white solid; mp 119 °C.
1H NMR (300 MHz, CDCl3): δ = 8.51–8.46 (m, 6 H), 8.20–8.10 (m,
3 H), 7.57–7.53 (m, 2 H), 4.46 (s, 3 H), 3.21 (s, 3 H).
1H NMR (300 MHz, CDCl3): δ = 7.86 (d, J = 6.0 Hz, 2 H), 7.43 (d,
J = 6.0 Hz, 2 H), 7.35 (d, J = 6.0 Hz, 2 H), 7.03 (m, 2 H), 3.84 (s, 3
H), 2.40 (s, 3 H), 1.33 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 165.6, 156.5, 152.4, 150.3, 131.5,
130.8, 129.2, 126.6, 125.6, 120.4, 120.0, 110.7, 55.1, 34.4, 30.7,
16.0.
13C NMR (100 MHz, CDCl3): δ = 135.0, 133.0, 132.0, 131.9, 131.0,
129.3, 128.7, 127.9, 127.5, 127.3, 127.2, 126.6, 126.3, 126.2, 126.1,
125.9, 113.8, 54.9.
MS (EI): m/z = 337 (100%, M+).
MS (EI): m/z (%) = 331 (80, M+), 298(100).
HRMS (EI): m/z calcd for C21H23NOS: 337.1488; found: 337.1500.
Acknowledgment
2-(4-tert-Butylphenyl)-5-(2-methoxyphenyl)-4-methylthiazole
(4o)
The authors gratefully acknowledge generous financial support
from the Deutsche Forschungsgemeinschaft and the BMBF (DLR,
Project MDA 08/010).
Yield: 10 mg (24%); white solid; mp 93 °C.
1H NMR (300 MHz, CDCl3): δ = 7.43 (d, J = 6.0 Hz, 2 H), 7.41 (d,
J = 3.0 Hz, 2 H), 7.35 (d, J = 3.0 Hz, 2 H), 7.03 (m, 2 H), 3.84 (s, 3
H), 2.41 (s, 3 H), 1.33 (s, 9 H).
References
13C NMR (75 MHz, CDCl3): δ = 165.6, 156.5, 152.4, 150.0, 131.5,
130.8, 129.2, 126.6, 125.6, 125.3, 120.4, 120.0, 110.7, 55.1, 34.4,
30.8, 15.9.
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1H NMR (300 MHz, CDCl3): δ = 7.85 (d, J = 3.0 Hz, 2 H), 7.82 (d,
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3441–3446

3446
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Synthesis 2012, 44, 3441–3446
© Georg Thieme Verlag Stuttgart · New York