Novel one-pot three-step reaction using supported reagents system: synthesis of 2-aminothiazoles

Article abstract of DOI:10.1016/j.tet.2007.09.017

One-pot tandem three-step reaction has been developed by using supported reagents system. The synthesis of 2-aminothiazoles was selected for confirming the effectiveness of the method using supported reagents system. One-pot three-step reaction effectivel

Full text of DOI:10.1016/j.tet.2007.09.017

Tetrahedron 63 (2007) 11933–11937
Novel one-pot three-step reaction using supported reagents
system: synthesis of 2-aminothiazoles
a
a
b
Tadashi Aoyama,a, Sumiko Murata, Toshio Takido and Mitsuo Kodomari
*
aDepartment of Materials and Applied Chemistry, College of Science and Technology, Nihon University,
1-8-14 Kanda Surugadai, Chiyoda-ku, Tokyo 101-8308, Japan
bDepartment of Applied Chemistry, Shibaura Institute of Technology, Toyosu, Koto-ku, Tokyo 135-8548, Japan
Received 28 August 2007; revised 6 September 2007; accepted 7 September 2007
Available online 12 September 2007
Abstract—One-pot tandem three-step reaction has been developed by using supported reagents system. The synthesis of 2-aminothiazoles
was selected for confirming the effectiveness of the method using supported reagents system. One-pot three-step reaction effectively pro-
ceeded, and the yield of the products is higher than that in step-wise process.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Traditional process
One-pot synthesis, which can carry out multi-step reactions
A
+
X
B
or multiple reactions in one-pot, is very attractive in organic
synthesis. In traditional process, the reaction and the isolation
of products have to be carried out more than once to synthe-
size the target compounds. One-pot process, however, can
provide the target compounds in not only a single operation
and with low cost but also in high total yield. Much effort
has been devoted to the development of one-pot reaction pro-
cesses. One-pot synthesis using inorganic solid-supported
reagents is unique because, if three kinds of inorganic
solid-supported reagents are used in one-pot, three different
reaction stages are able to existseparatelyin the samevessel.1
Thus, synthesis of a compound which is prepared step-wise
in homogeneous solution could be possible in one-pot if
each step in the multi-step reaction can be achieved using in-
organic solid-supported reagents (Scheme 1). We have dem-
onstrated the possibility of two-step reactions in one-pot by
using a couple of supported reagents, e.g., ZnCl2/SiO2–
K2CO3/Al2O3,2 CuBr2/Al2O3–KSCN/SiO2,3 KSCN/SiO2–
RNH3OAc/Al2O3,4,5 CuBr2/Al2O3–Na2CO3/Al2O3,1 and
Na2CO3/SiO2–PPA/SiO2.6,7 If these reagents are not sup-
ported on inorganic solids, these reagents react with each
other rapidly in solution. Therefore, two-step reaction in
one-pot is impossible. In these reports, we realized the possi-
bility of one-pot three-step reaction.1 One-pot three-step
reaction, however, could not proceed in excellent yield.
Thus, our efforts were devoted to the development of one-
pot three-step reaction which affords products in excellent
yields. One-pot three-step reaction using inorganic supported
B
C
+
+
Y
Z
C
D
A
Y
X
B
One-pot process
A
C
D
Z
Supported reagent
=
S
D
S = X, Y, Z
Scheme 1. One-pot multi-step synthesis using supported reagents system.
reagents has not been reported. Similar reaction using
polymer supported reagents, however, has been reported by
Parlow.8 The desired product was prepared as showed in
Scheme 2. But this method could not be extended to the an-
alog synthesis. In this paper, we describe one-pot three-step
reactions which constitute a novel method for organic
OH
O
O
(a)
55%
(b)
Br
Ph
Ph
(c)
98%
Ph
O
78%
48%
Cl
N
O
CF3
Ph
N
Scheme 2. (a) Poly(4-vinylpyridinium dichromate) in cyclohexane at 60 ꢀC
for 12 h. (b) Perbromide on AmberlystÒ A-26 in cyclohexane at 65 ꢀC for
12 h. (c) AmberliteÒ IRA-900(4-chloro-1-methyl-5-(trifluoromethyl)-1H-
pyrazol-3-ol) in cyclohexane at 65 ꢀC for 12 h.
* Corresponding author. Tel./fax: +81 3 3259 0818; e-mail: aoyama@chem.
cst.nihon-u.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.017

11934
T. Aoyama et al. / Tetrahedron 63 (2007) 11933–11937
O
O
Table 1. Preparation of 2-benzylamino-4-methyl-5-phenylthiazoles
N
S
NHR2
O
O
N
R1
R1
Na2CO3/SiO2-KSCN/SiO2-BnNH3OAc/Al2O3
Toluene, 80 °C, 6 h
Br
n
NHB
1
4
Br
Bn
S
4a
Bn
1a
R2NH3OAc/Al2O3
Na2CO3/SiO2
O
Entry Na2CO3/SiO2 KSCN/SiO2 BnNH3OAc/Al2O3 Yielda (%)
O
R1
R1
(mmol)
(mmol)
(mmol)
Br
SCN
3
1
2
3
4
5
3.00
2.25
1.50
2.25
2.25
5.00
5.00
5.00
5.00
5.00
6.00
6.00
6.00
6.00
6.00
54
74
50
44
55
2
KSCN/SiO2
Scheme 3.
a
Isolated yield.
synthesis. The synthesis of 2-aminothiazoles was selected for
confirming the effectiveness of one-pot three-step reaction
(Scheme 3). Thiazoles are very useful compounds in medi-
cinal, drug, and agricultural chemistry. For example, amino-
thiazole ring system is a useful structural element
in medicinal chemistry and has found broad application in
drug development for the treatment of allergies,9 hyperten-
sion,10 inflammation,11 bacterial infection,12 and HIV.13
In order to determine the optimum conditions for the syn-
thesis of 2-aminothiazoles in high yields, molar ratios of re-
agents were investigated (Table 1). Steps of thiocyanation
and cyclization–amination reactions have been optimized
in our previous report.14 In the synthesis of 4a, when
2.25 mmol of Na2CO3/SiO2 was used against 1 mmol of
1a, 4a was afforded in 74% yield. The use of reduced
amount of Na2CO3/SiO2 led to a decrease of a yield of
4a. When a reaction time was prolonged 4a was given in
low yield. When alumina was used as support instead of sil-
ica gel, the yield of 4a was 40%. This result is due to the
adsorption of products onto alumina. Thus, we decided to
use 2.25 mmol of Na2CO3/SiO2, 5.00 mmol of KSCN/
SiO2, and 6.00 mmol of RNH3OAc/Al2O3 against 1 mmol
of 3-alkyl-3-bromopentane-2,4-diones (1) for subsequent
reactions.
2. Results and discussion
A mixture of 3-benzyl-3-bromopentane-2,4-dione (1a:
1 mmol), Na2CO3/SiO2 (3 mmol), KSCN/SiO2 (5 mmol),
and BnNH3OAc/Al2O3 (6 mmol) in toluene was stirred at
80 ꢀC for 6 h to give 2-benzylamino-5-benzyl-4-methylthi-
azole (4a) in 54% yield (Scheme 4). We carried out the three
reactions, respectively, using inorganic supported reagents
in order to confirm the effectiveness of one-pot reaction.
Deacetylation reaction of 2-bromo-1,3-diketones with
Na2CO3/SiO2 gave a-bromo ketone (2a) in 91% yield.
Then the product was converted to a-thiocyanato ketone
(3a) quantitatively by treating with KSCN/SiO2. Cycliza-
tion–amination of 3a with BnNH3OAc/Al2O3 gave very
low yield of corresponding thiazole (15%). In our previous
report,14 we found that the amination process successfully
proceeds in the presence of a large excess of ammonium
salt (RNH3OAc). In one-pot process, a-thiocyanato ketone,
generated from a-bromo ketone and KSCN/SiO2, reacts im-
mediately with RNH3OAc/Al2O3 because large excess of
RNH3OAc to a-thiocyanato ketone is always present. There-
fore, the yield in one-pot three-step synthesis is higher than
that in step-wise process. We also carried out the reaction of
2a with KSCN/SiO2–BnNH3OAc/Al2O3; 4a was afforded in
62% yield. The total yield of 4a from 1a using KSCN/SiO2–
BnNH3OAc/Al2O3 pathway was comparable to the yield in
one-pot three-step synthesis.
A series of compounds 1 (b–j) were allowed to react under
the optimized conditions (Table 2). When benzylic group
in starting diketones has methyl group and chlorine at
para-position, the yields of products were comparable to
the yield of 4a (entries 3 and 4). Diketones having ester
group did not undergo hydrolysis by Na2CO3/SiO2. There-
fore, desired product 4f was obtained in good yield. When
a diketone which has bromine at the end of alkyl chain
instead of ester group was used, desired product (4g) and
by-product (4g0) were obtained in 23% and 42% yields,
respectively (entry 6). This reaction was carried out with
various amounts of KSCN/SiO2 in order to synthesize selec-
tively 4g or 4g0, but selective synthesis could not be
achieved. For instance, the use of a small amount of
KSCN/SiO2 caused a low yield, and a rate of 4g did not in-
crease. The yield of the thiazoles decreased with the increase
of the length of alkyl substituents at a-position in the starting
O
O
O
O
KSCN/SiO2
Bn
Na2CO3/SiO2
91%
Bn
99%
SCN
3a
Br
Bn
Br
1a
2a
N
NHBn
S
4a
Bn
Scheme 4.

T. Aoyama et al. / Tetrahedron 63 (2007) 11933–11937
11935
Table 2. Preparation of 4 from various 2-bromo-1,3-diketonesa
3. Experimental
O
O
N
NHBn
3.1. General
Toluene
80 °C, 6 h
Br
R1
R1
S
Melting points were determined on Yanako Micro melting
point apparatus or were uncorrected. Elemental analysis
was performed on a Yanako CHN corder MT-5. NMR spec-
tra were recorded on a JEOL JNM-GX400 spectrometer.
Tetramethylsilane (d¼0) was used as an internal standard
Entry
R1
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
C6H5–
C6H5(CH2)2–
4-CH3C6H4CH2–
4-ClC6H4CH2–
CH3CH2OCO(CH2)3–
Br(CH2)5–
n-C8H17
n-C10H21
n-C20H41
4b
4c
4d
4e
4f
4g
4h
4i
60
49
75
64
1
for H NMR. Mass analysis was performed on an Agilent
76
G1969 LC/MDS TOF. IR spectra were recorded on a Thermo
Electron Nicolet 380 spectrometer.
23 (42)c
48
33
–
–
–
4j
N.D.
3.1.1. Preparation of Na2CO3/SiO2. Silica gel [Wakogel C-
200 (Wako Pure Chemical Ind. LTD.), 16.82 g] was added to
a solution of sodium carbonate (30 mmol, 3.18 g) in distilled
water, and the mixture was stirred at room temperature for
0.5 h. The water was removed by rotary evaporator under re-
duced pressure below 60 ꢀC, and the resulting reagent was
dried in vacuo (10 mmHg) at room temperature for 5 h.
a
All reactions were carried out using
1 (1 mmol), Na2CO3/SiO2
(2.25 mmol), KSCN/SiO2 (5 mmol), and NH4OAc/Al2O3 (6 mmol).
Isolated yield.
b
c
The figure in parentheses indicates the yield of 4g0 [R1¼NCS(CH2)5–].
diketones. The diketone which has octyl group at a-position
gave the desired product in 48% yield, whereas the one
having decyl group afforded the desired product in 33%
yield. When the diketone having icosyl group was used, no
thiazole was yielded and a small amount of thiocyanate
was detected (3j) (entries 7–9).
3.1.2. Preparation of KSCN/SiO2. Silica gel [Wakogel C-
200 (Wako Pure Chemical Ind. LTD.), 25.70 g] was added
to a solution of potassium thiocyanate (250 mmol, 24.3 g)
in distilled water, and the mixture was stirred at room tem-
perature for 0.5 h. The water was removed by rotary evapo-
rator under reduced pressure, and the resulting reagent was
dried in vacuo (10 mmHg) at 150 ꢀC for 2 h.
A variety of alumina supported alkyl ammonium salts were
used for the reaction with 1a (Table 3). Each of alkyl amines
afforded the corresponding thiazole in moderate yields. The
successful use of allylamine and ethanolamine indicates that
this procedure is unaffected by the presence of a functional
group such as a C–C double bond and a hydroxy group in
an amine (entries 6 and 7).
3.1.3. Preparation of NH4OAc/Al2O3. Alumina (ICN Bio-
medical N-Super 1, 9.23 g) was added to a solution of
ammonium acetate (10 mmol, 0.77 g) in methanol, and the
mixture was stirred at room temperature for 0.5 h. The meth-
anol was removed by rotary evaporator under reduced pres-
sure, and the resulting reagent was dried in vacuo
(10 mmHg) at room temperature for 2 h.
In conclusion, we demonstrated a possibility of one-pot
three-step reaction using inorganic supported reagents sys-
tem. Notable advantages are as follows: this one-pot method
provides highly efficient synthesis of 2-aminothiazoles than
that of step-wise method, and all of three reagents were un-
eventfully removed from crude products by simple filtration.
Moreover, this method is applicable for many analogs. Other
one-pot multi-step chemical transformations using this con-
cept are now under investigations.
3.2. Typical procedure for the preparation
of 2-aminothiazoles
A mixture of 3-alkyl-3-bromopentane-2,4-diones (1 mmol),
Na2CO3/SiO2 (2.25 mmol), KSCN/SiO2 (5 mmol), and
RNH3OAc/Al2O3 (6 mmol) was stirred in toluene (15 mL)
at 80 ꢀC for 6 h, and then the used supported reagents
were removed by filtration. The filtrate was evaporated to
leave crude product, which was purified by column chroma-
tography.
Table 3. Preparation of 4 using various alumina supported alkyl ammonium
salta
O
O
3.2.1. 2-Benzylamino-5-benzyl-4-methylthiazole (4a). Mp
134 ꢀC (hexane/ethyl acetate). Anal. Calcd for C18H18N2S:
C, 73.43; H, 6.16; N, 9.51. Found: C, 73.34; H, 6.19; N,
9.21. HRMS (TOF-CI) calcd for C18H19N2S (MH+):
295.1269. Found: 295.1268. IR (neat): 3151, 3064, 3025,
N
S
NHR2
Toluene
80 °C, 6 h
Br
Bn
Bn
1a
4k-q
Entry
R2
Product
Yieldb (%)
2919, 1572, 1452, 1292, 763, 697 cmꢁ1
.
1H NMR
1
2
3
4
5
6
7
n-C4H9–
iso-C4H9–
4k
4l
50
65
51
43
54
43
38
(400 MHz, DMSO): d 2.08 (3H, s), 3.84 (2H, s), 4.34 (2H,
d, J¼5.8 Hz), 7.15–7.32 (10H, m), 7.73 (1H, t, J¼5.8 Hz).
n-C10H21
cyclo-C6H11
C6H5(CH2)2–
–
4m
4n
4o
4p
4q
–
3.2.2. 2-Benzylamino-4-methyl-5-phenylthiazole (4b).
Mp 153–154 ꢀC (hexane/ethyl acetate). Anal. Calcd for
C17H16N2S: C, 72.82; H, 5.75; N, 9.99. Found: C, 72.64;
H, 5.46; N, 9.86. HRMS (TOF-CI) calcd for C17H17N2S
(MH+): 281.1112. Found: 281.1112. IR (neat): 3198, 3060,
CH2]CH–CH2–
HO(CH2)2–
a
All reactions were carried out using 1a (1 mmol), Na2CO3/SiO2
(2.25 mmol), KSCN/SiO2 (5 mmol), and NH4OAc/Al2O3 (6 mmol).
Isolated yield.
b
3026, 2934, 1589, 1465, 1355, 1301, 761, 702 cmꢁ1
.

11936
T. Aoyama et al. / Tetrahedron 63 (2007) 11933–11937
1
1H NMR (400 MHz, CDCl3): d 2.27 (3H, s), 4.48 (2H, s),
6.28 (1H, s), 7.21–7.40 (10H, m).
719, 696 cmꢁ1. H NMR (400 MHz, CDCl3): d 0.88 (3H,
t, J¼6.8 Hz), 1.26–1.30 (10H, m), 1.50 (2H, quint,
J¼7.3 Hz), 2.08 (3H, s), 2.53 (2H, t, J¼7.3 Hz), 4.41 (2H,
s), 5.87 (1H, s), 7.26–7.37 (5H, m).
3.2.3. 2-Benzylamino-4-methyl-5-phenethylthiazole (4c).
Mp 99–100 ꢀC (hexane/ethyl acetate). HRMS (TOF-CI)
calcd for C19H21N2S (MH+): 309.1425. Found: 309.1434.
IR (neat): 3200, 3065, 3025, 2896, 1593, 1494, 1452,
3.2.10. 2-Benzylamino-5-decyl-4-methylthiazole (4i). Mp
70 ꢀC (hexane/ethyl acetate). Anal. Calcd for C21H32N2S:
C, 73.20; H, 9.36; N, 8.13. Found: C, 72.99; H, 9.58; N,
8.10. HRMS (TOF-CI) calcd for C21H33N2S (MH+):
345.2364. Found: 345.2368. IR (neat): 3205, 3104, 3068,
1
1299, 744, 697 cmꢁ1. H NMR (400 MHz, CDCl3): d 1.97
(3H, s), 2.78–2.88 (4H, m), 4.41 (2H, s), 5.48 (1H, s),
7.13–7.36 (10H, m).
2917, 1594, 1466, 1454, 1300, 720, 695 cmꢁ1. H NMR
1
3.2.4. 2-Benzylamino-4-methyl-5-(4-methylbenzyl)thi-
azole (4d). Mp 157–158 ꢀC (hexane/ethyl acetate). Anal.
Calcd for C19H20N2S: C, 73.99; H, 6.54; N, 9.08. Found:
C, 73.90; H, 6.67; N, 8.99. HRMS (TOF-CI) calcd for
C19H21N2S (MH+): 309.1425. Found: 309.1426. IR (neat):
3151, 3062, 3029, 2917, 1571, 1512, 1451, 1293, 718,
(400 MHz, CDCl3): d 0.88 (3H, t, J¼6.8 Hz), 1.26–1.30
(14H, m), 1.51 (2H, quint, J¼7.3 Hz), 2.11 (3H, s), 2.54
(2H, t, J¼7.3 Hz), 4.42 (2H, s), 5.54 (1H, s), 7.27–7.38
(5H, m).
3.2.11. 5-Benzyl-2-butylamino-4-methylthiazole (4k). Mp
108–109 ꢀC (hexane/ethyl acetate). Anal. Calcd for
C11H12N2S: C, 64.67; H, 5.92; N, 13.71. Found: C, 64.43;
H, 5.70; N, 13.48. HRMS (TOF-CI) calcd for C11H13N2S
(MH+): 205.0799. Found: 205.0792. IR (neat): 3413, 3270,
1
696 cmꢁ1. H NMR (400 MHz, CDCl3): d 2.18 (3H, s),
2.31 (3H, s), 3.86 (2H, s), 4.38 (2H, s), 5.50 (1H, s), 7.05–
7.11 (4H, m), 7.26–7.36 (5H, m).
3.2.5. 2-Benzylamino-5-(4-chlorobenzyl)-4-methylthi-
azole (4e). Mp 151–152 ꢀC (hexane/ethyl acetate). HRMS
(TOF-CI) calcd for C18H18ClN2S (MH+): 329.0879. Found:
329.0884. IR (neat): 3150, 3061, 3023, 2915, 1572, 1489,
3062, 1629, 1523, 1494, 1330, 698 cmꢁ1 1H NMR
.
(400 MHz, CDCl3): d 2.19 (3H, s), 3.90 (2H, s), 4.88 (2H,
s), 7.17–7.31 (5H, m).
1
1466, 1295, 729, 697 cmꢁ1. H NMR (400 MHz, CDCl3):
3.2.12. 5-Benzyl-2-isobutylamino-4-methylthiazole (4l).
Mp 108 ꢀC (hexane/ethyl acetate). Anal. Calcd for
C15H20N2S: C, 69.19; H, 7.74; N, 10.76. Found: C, 69.31;
H, 7.71; N, 10.68. HRMS (TOF-CI) calcd for C15H21N2S
(MH+): 261.1425. Found: 261.1426. IR (neat): 3205, 3106,
d 2.16 (3H, s), 3.86 (2H, s), 4.39 (2H, s), 5.59 (1H, s), 7.10
(2H, d, J¼8.3 Hz), 7.25 (2H, d, J¼8.0 Hz), 7.27–7.34
(5H, m).
1
3.2.6. 2-Benzylamino-5-(4-ethoxy-4-oxobutyl)-4-methyl-
thiazole (4f). HRMS (TOF-CI) calcd for C17H23N2O2S
(MH+): 319.1480. Found: 319.1486. IR (neat): 3326, 3030,
2948, 1592, 1470, 1453, 1330, 759, 697 cmꢁ1. H NMR
(400 MHz, CDCl3): d 0.94 (6H, d, J¼6.8 Hz), 1.81–1.94
(1H, m), 2.19 (3H, s), 2.97 (2H, d, J¼6.8 Hz), 3.91 (2H,
s), 5.33 (1H, s), 7.18–7.32 (5H, m).
1
2979, 172, 1548, 1479, 1453, 1300, 701 cmꢁ1. H NMR
(400 MHz, CDCl3): d 1.24 (3H, t, J¼7.2 Hz), 1.83 (2H,
quint, J¼7.4 Hz), 2.05 (3H, s), 2.30 (2H, t, J¼7.4 Hz),
2.59(2H, t, J¼7.4 Hz), 4.11 (2H, q, J¼7.2 Hz), 4.40 (2H,
s), 6.32 (1H, s), 7.25–7.34 (5H, m).
3.2.13. 5-Benzyl-2-decylamino-4-methylthiazole (4m).
Mp 62–63 ꢀC (hexane/ethyl acetate). HRMS (TOF-CI) calcd
for C21H33N2S (MH+): 345.2364. Found: 345.2364. IR
(neat): 3153, 3088, 2921, 1565, 1470, 1454, 1297, 761,
3.2.7. 2-Benzylamino-5-(5-bromopentyl)-4-methylthi-
azole (4g). HRMS (TOF-CI) calcd for C16H22BrN2S
(MH+): 353.0687. Found: 353.0692. IR (neat): 3204, 2932,
699 cmꢁ1 1H NMR (400 MHz, CDCl3): d 0.88 (3H, t,
.
J¼7.0 Hz), 1.25–1.35 (14H, m), 1.58 (2H, quint,
J¼7.0 Hz), 2.19 (3H, s), 3.14 (2H, t, J¼7.0 Hz), 3.91 (2H,
s), 5.08 (1H, s), 7.18–7.31 (5H, m).
1
2153, 1699, 1590, 1454, 1358, 1275, 731, 701 cmꢁ1. H
NMR (400 MHz, CDCl3): d 1.43–1.57 (4H, m), 1.86 (2H,
quint, J¼6.9 Hz), 2.08 (3H, s), 2.56 (2H, t, J¼7.3 Hz),
3.39 (2H, t, J¼6.9 Hz), 4.41 (2H, s), 5.93 (1H, br s), 7.27–
7.37 (5H, m).
3.2.14. 5-Benzyl-2-cyclohexylamino-4-methylthiazole
(4n). HRMS (TOF-CI) calcd for C16H21N2S (MH+):
273.1425. Found: 273.1433. IR (neat): 3183, 3064, 2953,
1552, 1452, 1301, 762, 697 cmꢁ1 1H NMR (400 MHz,
.
3.2.8. 2-Benzylamino-4-methyl-5-(5-thiocyanatopen-
tyl)thiazole (4g0). Mp 87–88 ꢀC (hexane/ethyl acetate).
Anal. Calcd for C17H21N3S2: C, 61.59; H, 6.39; N, 12.68.
Found: C, 61.41; H, 6.18; N, 12.46. HRMS (TOF-CI) calcd
for C17H22N3S2 (MH+): 332.1255. Found: 332.1252. IR
(neat): 3198, 3096, 3028, 2917, 2149, 1594, 1466, 1455,
CDCl3): d 1.45–1.53 (2H, m), 1.54–1.63 (2H, m), 1.63–
1.72 (2H, m), 1.94–2.03 (2H, m), 2.19 (3H, s), 3.69–3.75
(1H, m), 3.92 (2H, s), 4.91 (1H, s), 7.19–7.32 (5H, m).
3.2.15. 5-Benzyl-2-phenethylamino-4-methylthiazole
(4o). Mp 139 ꢀC (hexane/ethyl acetate). Anal. Calcd for
C19H20N2S: C, 73.99; H, 6.54; N, 9.08. Found: C, 73.99;
H, 6.32; N, 9.17. HRMS (TOF-CI) calcd for C19H21N2S
(MH+): 309.1425. Found: 309.1424. IR (neat): 3096, 3082,
1304, 753, 698 cmꢁ1
.
1H NMR (400 MHz, CDCl3):
d 1.44–1.61 (4H, m), 1.83 (2H, quint, J¼7.3 Hz), 2.10
(3H, s), 2.58 (2H, t, J¼7.3 Hz), 2.92 (2H, t, J¼7.3 Hz),
4.42 (2H, s), 5.75 (1H, s), 7.27–7.37 (5H, m).
3060, 1590, 1492, 746, 695 cmꢁ1 1H NMR (400 MHz,
.
CDCl3): d 2.19 (3H, s), 2.90 (2H, t, J¼6.8 Hz), 3.44 (2H,
3.2.9. 2-Benzylamino-4-methyl-5-octylthiazole (4h). Mp
63–64 ꢀC (hexane/ethyl acetate). HRMS (TOF-CI) calcd
for C19H29N2S (MH+): 317.2051. Found: 317.2048. IR
(neat): 3204, 3103, 3028, 2915, 1593, 1465, 1454, 1301,
t, J¼6.8 Hz), 3.91 (2H, s), 5.01 (1H, s), 7.18–7.31 (10H, m).
3.2.16. 2-Allylamino-5-benzyl-4-methylthiazole (4p). Mp
111–112 ꢀC (hexane/ethyl acetate). Anal. Calcd for

T. Aoyama et al. / Tetrahedron 63 (2007) 11933–11937
11937
2. Kodomari, M.; Nawa, S.; Miyoshi, T. J. Chem. Soc., Chem.
Commun. 1995, 1895.
3. Suzuki, Y.; Kodomari, M. Chem. Lett. 1998, 1091.
4. Kodomari, M.; Aoyama, T.; Suzuki, Y. Tetrahedron Lett. 2002,
43, 1717.
5. Aoyama, T.; Murata, S.; Nagata, S.; Takido, T.; Kodomari, M.
Tetrahedron Lett. 2005, 46, 4875.
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7. Aoyama, T.; Okada, K.; Nakajima, H.; Matsumoto, T.; Takido,
T.; Kodomari, M. Synlett 2007, 387.
C14H16N2S: C, 68.81; H, 6.60; N, 11.46. Found: C, 68.82; H,
6.58; N, 11.41. HRMS (TOF-CI) calcd for C14H17N2S
(MH+): 245.1112. Found: 245.1110. IR (neat): 3194, 3085,
3062, 2906, 1581, 1469, 1455, 1342, 972, 918, 700 cmꢁ1
.
1H NMR (400 MHz, CDCl3): d 2.19 (3H, s), 3.81 (2H, d,
J¼5.6 Hz), 3.91 (2H, s), 5.16 (1H, dd, J¼10.5, 1.5 Hz),
5.27 (1H, dd, J¼17.1, 1.5 Hz), 5.59 (1H, s), 5.84–5.93
(1H, m), 7.18–7.31 (5H, m).
3.2.17. 2-(2-Hydroxyethyl)amino-5-benzyl-4-methylthi-
azole (4q). HRMS (TOF-CI) calcd for C13H17N2OS (MH+):
249.1061. Found: 249.1070. IR (neat): 3187, 3061, 3028,
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26, 1158.
1
2923, 1656, 1494, 1454, 1273, 1075, 701 cmꢁ1. H NMR
10. Patt, W. C.; Hamilton, H. W.; Taylor, M. D.; Ryan, M. J.;
Taylor, D. J. J.; Connoly, C. J. C.; Doherty, A. M.; Klutchko,
S. R.; Sircar, I.; Steinbaugh, B. A.; Batly, B. L.; Painchaud,
C. A.; Rapundalo, S. T.; Michniewicz, B. M.; Olson, S. C. J.
J. Med. Chem. 1992, 35, 2562.
(400 MHz, DMSO): d 2.10 (3H, s), 3.24 (2H, q, J¼5.6 Hz),
3.53 (2H, t, J¼5.6 Hz), 3.85 (2H, s), 4.80 (1H, s), 7.16–7.20
(3H, m), 7.26–7.29 (2H, m), 7.28 (1H, t, J¼5.6 Hz).
11. Haviv, F.; Ratajczyk, J. D.; DeNet, R. W.; Kerdesky, F. A.;
Walters, R. L.; Schmidt, S. P.; Holms, J. H.; Young, P. R.;
Carter, G. W. J. Med. Chem. 1988, 31, 1719.
12. Tsuji, K.; Ishikawa, H. Bioorg. Med. Chem. Lett. 1994, 4, 1601.
13. Bell, F. W.; Cantrell, A. S.; Hoberg, M.; Jaskunas, S. R.;
Johansson, N. G.; Jordon, C. L.; Kinnick, M. D.; Lind, P.;
Morin, J. M., Jr.; Noreen, R.; Oberg, B.; Palkowitz, J. A.;
Parrish, C. A.; Pranc, J.; Zhang, H.; Zhou, X.-X. J. Med.
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Acknowledgements
This research was partially supported by the Ministry of
Education, Science, Sports, and Culture, Grant-in-Aid for
Young Scientists (B), 18710066, 2006.
References and notes
1. Aoyama, T.; Takido, T.; Kodomari, M. Tetrahedron Lett. 2004,
45, 1873.
14. Aoyama, T.; Murata, S.; Arai, I.; Araki, N.; Takido, T.; Suzuki,
Y.; Kodomari, M. Tetrahedron 2006, 62, 3201.