One pot synthesis using supported reagents system KSCN/SiO 2-RNH3OAc/Al2O3: Synthesis of 2-aminothiazoles and N-allylthioureas

Article abstract of DOI:10.1016/j.tet.2006.01.075

A simple and efficient method has been developed for the synthesis of 2-aminothiazoles and N-allylthioureas from commercially available materials in one pot by using a supported reagents system, KSCN/SiO₂-RNH ₃OAc/Al₂O₃, in which α-halo ketone reacts first KSCN/SiO₂ and the product, α-thiocyanatoketone, reacts with RNH₃OAc/Al₂O₃ to give the final product, 2-aminothiazoles, in good yield and allyl bromide reacts with KSCN/SiO ₂ and the product, allyl isothiocyanate, reacts with RNH ₃OAc/Al₂O₃ to give N-allylthiourea.

Full text of DOI:10.1016/j.tet.2006.01.075

Tetrahedron 62 (2006) 3201–3213
One pot synthesis using supported reagents system
KSCN/SiO2–RNH3OAc/Al2O3: synthesis of 2-aminothiazoles
and N-allylthioureas
a
a
a
a
Tadashi Aoyama,a, Sumiko Murata, Izumi Arai, Natsumi Araki, Toshio Takido,
*
Yoshitada Suzukib and Mitsuo Kodomarib
aDepartment of Materials and Applied Chemistry, College of Science and Technology, Nihon University,
Kanda Surugadai, Chiyoda-ku, Tokyo 101-8308, Japan
bDepartment of Applied Chemistry, Shibaura Institute of Technology, Shibaura, Minato-ku, Tokyo 108-8548, Japan
Received 24 November 2005; revised 20 January 2006; accepted 20 January 2006
Available online 13 February 2006
Abstract—A simple and efficient method has been developed for the synthesis of 2-aminothiazoles and N-allylthioureas from commercially
available materials in one pot by using a supported reagents system, KSCN/SiO2–RNH3OAc/Al2O3, in which a-halo ketone reacts first
KSCN/SiO2 and the product, a-thiocyanatoketone, reacts with RNH3OAc/Al2O3 to give the final product, 2-aminothiazoles, in good yield
and allyl bromide reacts with KSCN/SiO2 and the product, allyl isothiocyanate, reacts with RNH3OAc/Al2O3 to give N-allylthiourea.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
by the reaction of a-thiocyanatoketones with aromatic or
aliphatic amine hydrochloride.8 a-Thiocyanatoketones are
prepared from the reaction of a-halo ketones with
potassium thiocyanate. There are many procedures for
the synthesis of symmetrical and unsymmetrical thiour-
eas.9–14 The most common method is the condensation of
primary or secondary amines with isothiocyanates.6,15
N-Allylthioureas are prepared from the reaction of
allylisothiocyanate with amines. Allylic isothiocyanates
are easily prepared from the reaction of potassium
thiocyanate and allylic halides.16 Thus, both 2-aminothia-
zoles and allylthioureas could be able to synthesize by
using a same reaction process, thiocyanation and amination
process (Scheme 1).
Thiazoles and thioureas are very useful compounds in
medicinal, drug and agricultural chemistry. For example,
the aminothiazole ring system is a useful structural element
in medicinal chemistry and has found broad application in
drug development for the treatment of allergies,1 hyperten-
sion,2 inflammation,3 bacterial infection4 and HIV.5
Symmetrical and unsymmetrical thioureas are an important
class of compounds in agricultural and medicinal chem-
istry6 and are also used as building blocks for the synthesis
of both five and six membered heterocycles.7 2-Ami-
nothiazoles are usually synthesized either by the conden-
sation of a-halo ketones with monosubstituted thioureas or
Scheme 1. Stepwise synthesis of aminothiazole and allylthiourea.
Keywords: Thiazoles; Thioureas; One pot process.
*
Corresponding author. Tel./fax: C81 3 3259 0818; e-mail: aoyama@chem.cst.nihon-u.ac.jp
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.075

3202
T. Aoyama et al. / Tetrahedron 62 (2006) 3201–3213
Scheme 2. One-pot synthesis of thiazoles and thioureas using supported reagents.
One-pot synthesis, which can carry out multi-step reactions or
multiple reactions in one pot, is very attractive in organic
synthesis. In traditional process, the reaction and the isolation
of productshaveto be carried out more than once to synthesize
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 process. One-
pot synthesis using polymer or inorganic solid supported
reagents is unique. Three different reaction stages are able to
exist separately in the same vessel when three kinds of
inorganic solid supported reagents are used.17 Thus, synthesis
of a compound, which is prepared stepwise in homogeneous
solution could be possible in one-pot if each step in the multi-
step reaction can be achieved using inorganic solid supported
reagents. We have demonstrated the possibility of multi-step
reactions in one-pot by using a couple of supported reagents,
Next, various inorganic solids were tested to decide the most
effective inorganic support for NH4OAc. The results
obtained were summarized in Table 2. Neutral alumina
was the most effective inorganic support for NH4OAc. The
other inorganic solids tested gave a moderate yield of 3a.
When using magnesium oxide (MgO) as a support, 3a was
formed in a very low yield, and 2a was obtained as a main
product in 72% yield. Thus, we decided to use neutral
alumina as a support for NH4OAc.
The optimum amount of NH4OAc loaded on Al2O3 was
investigated (Table 3). When the loading ratio of
Table 1. Preparation of 3a using KSCN/SiO2–NH4OAc/Al2O3
for example, ZnCl2/SiO2–K2CO3/Al2O3,18a CuBr2/Al2O3–
18c,d
KSCN/SiO2,18b KSCN/SiO2–RNH3OAc/Al2O3
CuBr2/
Al2O3–Na2CO3/Al2O3 and Na2CO3/SiO2–PPA/SiO2.18e
We described recently the highly efficient method for the
one-pot synthesis of 2-aminothiazoles and N-allylthioureas
from a-halo ketones and allylic halides by using a supported
reagents system, silica gel-supported potassium thiocyanate
(KSCN/SiO2)-alumina-supported ammonium acetates
(RNH3OAc/Al2O3). In this paper, we report on the one-pot
synthesis using the supported reagents system, KSCN/SiO2–
RNH3OAc/Al2O3, in detail (Scheme 2).
17
Entry
KSCN/SiO2
(mmol)
NH4OAc/Al2O3 Yield (%)a
(mmol)
1
2
3
4
1
2
3
5
2
2
6
6
44
46
75
83
a Isolated yield.
Table 2. Preparation of 3a using various inorganic supported NH4OAc
Support
SSA (m2/g)a
pH
Yield (%)b
2. Results and discussion
Neutral alumina
Acidic alumina
Basic alumina
Silica gel
MS-5A
Magnesium oxide
200
200
200
450
400
70
7.5
4.5
10.0
5.5–7.0
11.0
11.1
83
72
58
47
2.1. Determination of the optimum conditions
67 (24)c
17 (72)c
First, we optimized molar ratios of the reagents by using the
reaction of phenacyl bromide (1a) as a model reaction
(Table 1). A mixture of 1a (1 mmol), KSCN/SiO2 (1 mmol)
and NH4OAc/Al2O3 (2 mmol) in benzene was stirred at
80 8C for 6 h to gave the desired product 3a in 44% yield
along with large amount of 1a (entry 1). Although twice
amount of KSCN/SiO2 was used under the same reaction
conditions, the yield of 3a did not increase. a-Thiocyanato-
ketone (2a) was formed as a main product (entry 2). The use
of large amount of NH4OAc/SiO2 (6 mmol) gave 3a in 75%
yield along with acetic acid phenacyl ester, which
was formed from the reaction of 1a with NH4OAc/Al2O3
(entry 3). When 5 mmol of KSCN/SiO2 and 6 mmol of
NH4OAc/Al2O3 was used against 1 mmol of 1a, 3a was
obtained in 83% yield (entry 4).
a Specific surface area.
b Isolated yield.
c Yield 2a.
Table 3. Effect of loading ratio NH4OAc/Al2O3
Entry
Loading ratio (mmol/g)
Yield of 3a (%)a
1
2
3
4
5
0.5
1.0
2.0
4.0
6.0
32
83
45 (46)b
34 (60)b
40 (63)b
a Isolated yield.
b Yield of 2a.

T. Aoyama et al. / Tetrahedron 62 (2006) 3201–3213
Table 5. One-pot synthesis of 2-aminothiazolesa
3203
NH4OAc/Al2O3 was over 2.0 mmol/g, the yield of 3a
was low and 2a was formed. In these cases NH4OAc/
Al2O3 worked as well as NH4OAc. The reaction using
NH4OAc/Al2O3 with a loading of 0.5 mmol/g also gave
3a in low yield but 2a was not detected. In this case, the
reaction proceeded completely but 3a was strongly
adsorbed on the surface of alumina. When a mixture of
3a (1 mmol) and alumina (12 g) was stirred in benzene
for 6 h, trace amount of 3a was in solution. When 3a
adsorbed on alumina was extracted with ethyl acetate, 3a
was recovered in 93% yield. NH4OAc/Al2O3 with a
loading of 1.0 mmol/g was the most effective for the
reaction and was used in the subsequent reactions.
Entry
X
R1
R2
Product Yield
(%)b
1
2
3
4
5
6
7
8
Cl
Br
Br
Br
Cl
Cl
Br
Br
C6H5
C6H5
4-Me–C6H4
4-Cl–C6H4
CH3
CH3
C6H5
4-Cl–C6H4
H
3a
3b
3c
3d
3e
3f
80
87
90
92
83
58
46
74
C6H5
C6H5
C6H5
H
CH3
CH3
CH3
3g
3h
Previously, we have reported that silica gel is effective
support for KSCN and KSCN/SiO2 is a useful reagent
for transformation of alkyl halides to alkyl
thiocyanates.19
a All reactions were carried out using 1 (1 mmol), KSCN/SiO2 (5 mmol)
and NH4OAc/Al2O3 (6 mmol).
b Isolated yield.
was obtained in 80% yield (Table 1, entry 4 vs Table 5,
entry 1). The halo ketones in which, halogen is attached to
the primary carbon and the benzylic carbon, afforded the
corresponding 2-aminothiazoles in high yield (entries 1–5).
On the other hand, in the reactions with the halo ketones
having a halogen attached on the secondary carbon, the
yields were low (entries 6–8). 2-Bromopropiophenone (1g)
gave bis[2-(4-phenyl-5-methyl)thiazoyl] amine (8g) as a
main product in 54% yield and expected 3g in 46% yield
(Scheme 3). Compound 8g was resulted from the reaction of
2g with 3g.
This supported reagents system, KSCN/SiO2–NH4OAc/
Al2O3, worked well for the thiocyanation and the
amination in one pot, whereas in the case of the reaction
using the unsupported reagents system or using the
reagents system in which one reagent is supported on
inorganic solid and the other is unsupported, the yields of
products were lower than that in the reaction using the
supported reagents system. 3a was also synthesized by
using stepwise reaction process, thiocyanation and
amination process, and the total yield of 3a was lower
than that from the reaction using KSCN/SiO2–NH4OAc/
Al2O3. The reaction of 1a with KSCN/SiO2 in benzene
proceeded at 80 8C to give 2a in quantitatively after
1.5 h. The reaction of 2a with NH4OAc/Al2O3 also
occurred in benzene under similar conditions and
afforded 3a in 54% yield after 6 h. When the reaction
using 0.1 mmol of 2a and 6 mmol of NH4OAc/Al2O3
was carried out under the similar conditions, 3a was
formed in 78% yield. This result suggests that the
amination process successfully proceeds in the presence
of a large excess of NH4OAc. In one-pot process, 2a
formed from the reaction of 1a and KSCN/SiO2 reacts
immediately with NH4OAc/Al2O3, in which a large
excess of NH4OAc to 2a is always present. Therefore
the yield in one-pot synthesis is higher than that in
stepwise process (see Table 4).
Scheme 3. Formation of 8g from 1g.
The reaction of various combinations of a-halo ketones and
alkylammonium acetate were carried out. The results were
shown in Table 6. The reaction of a-bromo propiophenone
with various alkylammonium acetates gave the correspon-
ding 2-alkylaminothiazoles in good to excellent yields. The
yields of the products were not affected by the length of
alkyl chain attached on an amine. When alicyclic
ammonium acetate was used the yields were increased.
The successful use of ethanolamine, 2-hydroxypropylamine
and allylamine indicates that this procedure is unaffected by
the presence of a functional group such as a C–C double
bond and a hydroxyl group in an amine part. The reaction of
3-chloro-2-butanone with 2-hydroxyethylamino acetate and
2-hydroxypropylamino acetate gave unexpected com-
pounds, 4,5-dimethyl-3-(2-hydroxyethyl)-1,3-thiazole-
2(3H)-imine (30ao) and 4,5-dimethyl-3-(2-hydroxypropyl)-
1,3-thiazole-2(3H)-imine (30ap), along with desired 3ao and
3ap (entries 33 and 34). We examined whether 30 was
formed from isomerization reaction of 3. When 3ao was
stirred in benzene in the presence of KSCN/SiO2 and
RNH3OAc/Al2O3 at 80 8C for 6 h, isomerization reaction
Table 4. Reaction of 1a with various reagents systemsa
Reagents system
Yield of 3a (%)b
KSCN–NH4OAc
14
31
32
83
KSCN–NH4OAc/SiO2
KSCN/SiO2–NH4OAc
KSCN/SiO2–NH4OAc/Al2O3
a All reactions were carried out using 1a (1 mmol), KSCN/(SiO2) (5 mmol)
and NH4OAc/(Al2O3) (6 mmol).
b Isolated yield.
2.2. Preparation of 2-aminothiazoles
As shown in Table 5, various a-halo ketones react with
KSCN/SiO2 and NH4OAc/Al2O3 in one pot to afford the
desired 2-aminothiazoles in moderate to high yields. When
phenacyl chloride was used instead of phenacyl bromide, 3a

3204
T. Aoyama et al. / Tetrahedron 62 (2006) 3201–3213
Table 6. One-pot synthesis of 2-alkylamino thiazoles from haloketones and various alkylammonium acetatesa
Entry
X
R1
R2
R3
Product
Yield (%)b
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Cl
Cl
Cl
Cl
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
n-C4H9
iso-C4H9
sec-C4H9
C10H21
cyclo-C5H9
cyclo-C6H11
CH2C6H5
C2H4C6H5
CH2CHCH2
C2H4OH
CH2CH(OH)CH3
n-C4H9
iso-C4H9
sec-C4H9
C10H21
cyclo-C5H9
cyclo-C6H11
CH2C6H5
C2H4C6H5
CH2CHCH2
C2H4OH
CH2CH(OH)CH3
CH2C6H5
CH2CHCH2
C2H4OH
CH2CH(OH)CH3
CH2C6H5
CH2CHCH2
C2H4OH
CH2CH(OH)CH3
CH2C6H5
CH2CHCH2
C2H4OH
CH2CH(OH)CH3
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
85
83
88
87
92
88
79
83
99
60
99
65
80
69
60
97
95
88
86
94
62
96
80
73
45
54
82
72
39
53
46
55
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
3v
3w
3x
3y
3z
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ao
3ap
CH3
CH3
CH3
C6H5
C6H5
C6H5
C6H5
CH3
CH3
CH3
CH3
17 (7)c
17 (4)d
a All reactions were carried out using 1 (1 mmol), KSCN/SiO2 (5 mmol) and R3NH3OAc/Al2O3 (6 mmol).
b Isolated yield.
c Yield of 4,5-dimethyl-3-(2-hydroxyethyl)-1,3-thiazole-2(3H)-imine (30ao).
d Yield of 4,5-dimethyl-3-(2-hydroxypropyl)-1,3-thiazole-2(3H)-imine (30ap).
was not observed. Considerable mechanism was proposed
in Scheme 4. The reaction between an intermediate,
a-thiocyanatoketones, and RNH3OAc/Al2O3 proceeds
through two pathways. When the reaction proceeds with
path A, only 2-aminated thiazoles are formed. If nucleo-
philic attack of an amine to the thiocyanato group occurs
faster than cyclization of a-thiocyanatoketones (path B), an
intermediate (9) are produced. In principle, both nitrogen
atoms can attack the carbonyl carbon. It is known that the
sp2 nitrogen atom is a better base and nucleophile than the
sp3 nitrogen atom.20 The ring closure provably occurs in a
fast step, therefore 2-aminothiazoles are mainly produced in
many cases.
pyrrolidino thiazole (3aq) in 89% yield. All of the sec-
alicyclic ammonium acetate afforded the corresponding
N,N-disubstituted-2-aminothiazoles in good yields. The
reaction of 1b with 2-hydroxy-N-methylethylamine salt
gave 3at in moderate yield. Dibutyl ammonium and di-iso-
butyl ammonium acetate are soluble in benzene, thus, in the
case of these amines an ammonium trifluoroacetate were
used. 3au and 3av were also obtained in good yields from
1b.
Kurz et al. have reported the synthesis of the
aminothiazole derivatives from the reaction of a-thio-
cyanato malonic acid derivatives and hydroxylamines
(Scheme 5).22 We carried out the synthesis of similar
compounds from a-bromo-a-methyl malonic acid
diethyl ester by using a couple of supported reagents
KSCN/SiO2 and NH4OAc/Al2O3. However, the
expected compounds were not observed, and a small
amount of thiocyanated compounds were detected.
a-Bromo-a-methyl malonic acid diethyl ester did not
react with KSCN/SiO2 under similar conditions. There-
fore our method could not be applicable for the halo
Schantl et al. have reported one-pot synthesis of 2-ami-
nothiazoles in methanol.21 However, the synthesis of N,N-
disubstituted-2-aminothioureas by this method is sluggish
and the yields are low. In contrast, our procedure gave N,N-
disubstituted-2-aminothioureas in high yields. The results
were summarized in Table 7. For instance the reaction of
2-bromo-2-phenyl benzophenone (1b) with KSCN/SiO2 and
alumina supported pyrrolidino acetate gave 4,5-diphenyl-2-

T. Aoyama et al. / Tetrahedron 62 (2006) 3201–3213
3205
Scheme 5. Reaction of thiocyanato malonic acid derivatives and
hydroxylamines.
ketone containing a halogen attached on the tertiary
carbon.
2.3. Preparation of N-allylthioureas
The synthesis of N-allylthioureas using KSCN/SiO2–
NH4OAc/Al2O3 system was also tried. In order to
determine the optimum conditions for the synthesis of
N-allylthioureas in fast and efficient way, molar ratios
of the supported reagents and the reaction time were
investigated (see Table 8). The reaction of cinnamyl
bromide with KSCN/SiO2 (5 mmol) and BnNH3OAc/
Al2O3 (6 mmol) in benzene at 80 8C for 3 h gave 7a in
68% yield along with
a
a small amount of diben-
zylthiourea as byproduct (entry 1). This diben-
zylthiourea is presumed to result from the
transamination of 7a with benzylamine, which released
from benzyl ammonium acetate. Transamination of
N-benzoyl-N0-alkylthioureas with amines has been
reported.23 When 3 mmol of BnNH3OAc/Al2O3 was
used for the reaction, 7a was yielded without
dibenzylthiourea, and the reaction intermediate 5a was
observed in the reaction mixture (entry 2). When the
reaction time was prolonged to 6 h, the yield of 7a
increased to 78% (entry 3). Using 1.5 mmol of
BnNH3OAc/Al2O3, the yield of 7a decreased (entry
4). Thus, we decided to use 5 mmol of KSCN/SiO2
and 3 mmol of BnNH3OAc/Al2O3 against 1 mmol of
allylic bromide for subsequent reactions.
Scheme 4. Reaction path of 2-aminothiazoles.
Table 7. Preparation of 2-dialkylamino-4,5-diphenylthiazolesa
Product
Yield (%)b
89
94
84
Table 8. Preparation of 7a using KSCN/SiO2–BnNH3OAc/Al2O3
Entry
KSCN/SiO2
(mmol)
BnNH3OAc/Al2O3
(mmol)
Time
(h)
Yield
(%)a
65
1
2
3
4
5
5
5
5
6
3
3
1.5
3
3
6
6
68
68
78
67
72c
a Isolated yield.
Various combination of ammonium acetates and allylic
bromides were used for the synthesis of N-allylthioureas. The
results were summarized in Table 9. Various allylic bromides
reacted with KSCN/SiO2 and BnNH3OAc/Al2O3 in one pot
to afford the corresponding thioureas (entries 1–3). The
reaction of crotyl bromide and of 1-bromo-3-methyl-2-
butene gave the desired products 7c and 7d in excellent
67c
a All reactions were carried out using 1b (1 mmol), KSCN/SiO2 (5 mmol)
and R1R2NH2OAc/Al2O3 (6 mmol).
b Isolated yield.
c Using a salt of trifluoroacetic acid.

3206
T. Aoyama et al. / Tetrahedron 62 (2006) 3201–3213
Table 9. One-pot synthesis of N-allylthioureas from allylic bromides and various alkylammonium acetatesa
Entry
R1
R2
R3
Product
Yield (%)b
1
2
3
4
5
6
7
8
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
CH2C6H5
CH2C6H5
CH2C6H5
n-C4H9
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
59
92
94
74
65
51
60
50
70
51
89
82
88
88
92
90
89
79
73
62
71
82
85
92
CH3
CH3
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
iso-C4H9
sec-C4H9
CH2CHCH2
cyclo-C5H9
cyclo-C6H11
C2H4C6H5
n-C4H9
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
iso-C4H9
sec-C4H9
CH2CHCH2
cyclo-C5H9
cyclo-C6H11
C2H4C6H5
n-C4H9
iso-C4H9
7t
sec-C4H9
CH2CHCH2
cyclo-C5H9
cyclo-C6H11
C2H4C6H5
7u
7v
7w
7x
7y
a All reaction were carried out using 4 (1 mmol), KSCN/SiO2 (5 mmol) and R3NH3OAc/Al2O3 (3 mmol).
b Isolated yield.
yields, respectively. Cinnamyl bromide and 1-bromo-2-
methyl-2-butene were also converted into the corresponding
N-allylthioureas in good yields under the same conditions.
Allyl bromide was the most inactive among the allylic
bromides used for the transformations. When cinnamyl
chloride was used instead of cinnamyl bromide for the
reaction, the yield of 7a was lower than that of cinnamyl
bromide. The reactions of allylic bromides and a series of
alkylammonium acetate gave the corresponding thioureas,
however, tert-butylammonium acetate did not give the
desired thiourea. The yields of N-allylthioureas depended
on the allylic bromides used. For instance, cinnamyl bromide
gave the products in moderate yields, whereas, 2-bromo-3-
methyl-2-butene gave the product in good to excellent yields.
The yields seem to depend on the rate of the rearrangement
from the thiocyanate into the isothiocyanate. A mixture of
allylic bromides and KSCN/SiO2 was stirred in benzene at
80 8C for 6 h, and then the ratio of the thiocyanate to the
RNH4OAc/Al2O3. It is particularly noteworthy that this
method does not need to handle of the isolation of
reaction intermediate and this method may be applicable
to laboratory scale and combinatorial synthesis of
2-aminothiazoles and N-allylthioureas.
3. Experimental
3.1. General
Melting points were determined on a Yanako Micro melting
point apparatus or on a Bu¨chi 535 or were uncorrected.
Elemental analysis were performed on a Yanako CHN
corder MT-5. NMR spectra were recorded on a JEOL JNM-
GX400 or on a JEOL JNM-LA300 spectrometer. Tetra-
methylsilane (dZ0) was used as an internal standard for 1H
NMR. Mass analysis were performed on an Agilent G1969
LC/MDS TOF. IR spectra were recorded on a HORIBA FT-
710 or on a Thermo Electron Nicolet 380 spectrometer.
1
isothiocyanate in the solution was measured by H NMR.
The correlation, however, between the yield and the rate of
the rearrangement was not observed. Further investigation is
now in progress. Although Bergmann et al.24 has reported
that cinnamyl thiocyanate isomerizes without allyl
rearrangement and cinnamyl isothiocyanate is formed
instead of the anticipated a-phenyl isothiocyanate, in our
reaction process cinnamyl thiocyanate rearranged into
a-phenyl isothiocyanate, resulting thioureas (7e–7k) were
1-phenylallyl type compound.
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, 24.30 g) in
distilled water, and the mixture was stirred at room
temperature for 0.5 h. The water was removed by rotary
evaporator under reduced pressure, and the resulting reagent
was dried in vacuo (10 mmHg) at 150 8C for 2 h.
Preparation of NH4OAc/Al2O3. Alumina (ICN Biomedical
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 methanol was
In conclusion, various a-halo ketones and allylic
bromides were converted into 2-aminothiazoles and
N-allylthioureas in the presence of KSCN/SiO2–

T. Aoyama et al. / Tetrahedron 62 (2006) 3201–3213
3207
removed by rotary evaporator under reduced pressure, and
the resulting reagent was dried in vacuo (10 mmHg) at room
temperature for 2 h.
(3H, s), 4.95 (2H, s), 7.27–7.32 (1H, m), 7.37–7.42 (2H, m),
7.55–7.57 (2H, m).
3.2.8. Bis[2-(4-phenyl-5-methyl)thiazoyl] amine (8g).
Yellow solid. Mp 128–129 8C (hexane/ethyl acetate). HR-
MS (TOF-CI) Calcd for C20H18N3S2 (MHC): 364.0942.
Found: 364.0945. IR (neat): 3199, 3055, 2932, 2857, 1587,
3.2. Typical procedure for the preparation of
2-aminothiazoles
1
1533, 1445, 1311, 770, 697 cmK1. H NMR (400 MHz,
A mixture of a-halo ketones (1 mmol), KSCN/SiO2
(5 mmol, 1 g) and RNH3OAc/Al2O3 (6 mmol, 6 g) was
stirred in benzene (10 mL) at 80 8C 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 chromatography.
DMSO): d 2.45 (6H, s), 7.32–7.36 (2H, m), 7.44–7.48 (4H,
m), 7.68–7.70 (4H, m), 12.04 (1H, s).
3.2.9. 2-Amino-4-(p-chlorophenyl)-5-methylthiazole
(3h). Yellow needles. Mp 144–145 8C (hexane/ethyl
acetate). HR-MS (TOF-CI) Calcd for C10H10ClN2S
(MHC): 225.0253. Found: 225.0258. IR (KBr): 3437,
3.2.1. 2-Amino-4-phenylthiazole (3a). Yellow needles. Mp
150–151 8C (hexane/ethyl acetate) (lit.25 150 8C). HR-MS
(TOF-CI) Calcd for C9H9N2S (MHC): 177.0486. Found:
177.0494. IR (KBr): 3436, 3115, 1598, 1518, 1342,
1
3261, 3107, 1624, 1541, 1487, 1335, 1092, 835 cmK1. H
NMR (300 MHz, CDCl3): d 2.95 (3H, s), 5.22 (2H, s), 7.35
(2H, d, JZ8.4 Hz), 7.49 (2H, d, JZ8.4 Hz).
1
716 cmK1. H NMR (300 MHz, CDCl3): d 5.33 (2H, s),
3.2.10. 2-Butylamino-5-methyl-4-phenylthiazole (3i).
Brown oil. HR-MS (TOF-CI) Calcd for C14H19N2S
(MHC): 247.1268. Found: 247.1274. IR (neat): 3203,
6.71 (1H, s), 7.25–7.31 (1H, m), 7.35–7.40 (2H, m), 7.74–
7.78 (2H, m).
1
3100, 2957, 2930, 1585, 1332, 773, 670 cmK1. H NMR
3.2.2. 2-Amino-4,5-diphenylthiazole (3b). White solid.
Mp 189–190 8C (hexane/ethyl acetate). HR-MS (TOF-CI)
Calcd for C15H13N2S (MHC): 253.0799. Found: 253.0805.
IR (KBr): 3423, 3273, 3060, 1631, 1543, 1529, 1336, 764,
(400 MHz, CDCl3): d 0.95 (3H, t, JZ7.3 Hz), 1.41 (2H,
sext, JZ7.3 Hz), 1.63 (2H, quint, JZ7.3 Hz), 2.40 (3H, s),
3.22 (2H, t, JZ7.3 Hz), 5.47 (1H, s), 7.25–7.31 (1H, m),
7.36–7.40 (2H, m), 7.55–7.58 (2H, m).
1
696 cmK1. H NMR (300 MHz, CDCl3): d 5.25 (2H, s),
7.23–7.28 (8H, m), 7.44–7.47 (2H, m).
3.2.11. 2-iso-Butylamino-5-methyl-4-phenylthiazole (3j).
White crystals. Mp 123–124 8C (hexane/ethyl acetate).
Anal. Calcd for C14H18N2S: C, 68.25; H, 7.36; N, 11.37.
Found: C, 68.24; H, 7.40; N, 11.49. HR-MS (TOF-CI) Calcd
for C14H19N2S (MHC): 247.1268. Found: 247.1275. IR
(neat): 3199, 3106, 2951, 2865, 1590, 1464, 1432, 1330,
774, 696 cmK1. 1H NMR (400 MHz, CDCl3): d 0.96 (6H, d,
JZ6.8 Hz), 1.85–1.97 (1H, m), 2.40 (3H, s), 3.02 (2H, t, JZ
6.3 Hz), 5.30 (1H, s), 7.26–7.30 (1H, m), 7.37–7.40 (2H, m),
7.56–7.58 (2H, m).
3.2.3. 2-Amino-4-(p-methylphenyl)-5-phenylthiazole
(3c). Yellow solid. Mp 181–182 8C (hexane/ethyl acetate).
HR-MS (TOF-CI) Calcd for C16H15N2S (MHC): 267.0955.
Found: 267.0961. IR (KBr): 3433, 3255, 3059, 1622, 1525,
1504, 1331, 829, 760, 692 cmK1 1H NMR (300 MHz,
.
DMSO): d 2.27 (3H, s), 7.06 (2H, d, JZ8.3 Hz), 7.19 (2H,
s), 7.20–7.32 (7H, m).
3.2.4. 2-Amino-4-(p-chlorophenyl)-5-phenylthiazole
(3d). Yellow powder. Mp 188–189 8C (hexane/ethyl
acetate). HR-MS (TOF-CI) Calcd for C15H12ClN2S
(MHC): 287.0409. Found: 287.0408. IR (KBr): 3429,
3.2.12. 2-sec-Butylamino-5-methyl-4-phenylthiazole
(3k). Brown oil. HR-MS (TOF-CI) Calcd for C14H19N2S
(MHC): 247.1268. Found: 247.1261. IR (neat): 3199, 3081,
3251, 3076, 1618, 1525, 1493, 1331, 841, 762, 694 cmK1
.
1
2966, 2930, 2874, 1626, 1449, 1334, 770, 699 cmK1. H
1H NMR (300 MHz, CDCl3): d 5.24 (2H, s), 7.19–7.28 (7H,
m), 7.37–7.41 (2H, m).
NMR (400 MHz, CDCl3): d 0.96 (3H, t, JZ7.3 Hz), 1.23
(3H, d, JZ6.3 Hz), 1.55–1.66 (2H, m), 2.38 (3H, s), 3.30–
3.39 (1H, m), 5.76 (1H, s), 7.26–7.30 (1H, m), 7.35–7.39
(2H, m), 7.55–7.57 (2H, m).
3.2.5. 2-Amino-4-methylthiazole (3e). Yellow oil. HR-MS
(TOF-CI) Calcd for C4H7N2S (MHC): 115.0329. Found:
115.0336. IR (neat): 3444, 3290, 1620, 1545, 1520, 1442,
1331, 787 cmK1. 1H NMR (300 MHz, CDCl3): d 2.13 (3H,
s), 5.61 (2H, s), 5.96 (1H, s).
3.2.13. 2-Decylamino-5-methyl-4-phenylthiazole (3l).
Brown oil. HR-MS (TOF-CI) Calcd for C20H31N2S
(MHC): 331.2207. Found: 331.2212. IR (neat): 3205,
3101, 3058, 2925, 2854, 1587, 1466, 1333, 773, 698 cmK1
.
1H NMR (400 MHz, CDCl3): d 0.88 (3H, t, JZ7.1 Hz),
1.24–1.33 (14H, m), 1.53–1.60 (2H, m), 2.38 (3H, s), 3.14
(2H, t, JZ7.1 Hz), 5.82 (1H, s), 7.26–7.30 (1H, m), 7.35–
7.40 (2H, m), 7.54–7.57 (2H, m).
3.2.6. 2-Amino-4,5-dimethylthiazole (3f). Yellow solid.
Mp 83–84 8C (hexane/ethyl acetate). HR-MS (TOF-CI)
Calcd for C5H9N2S (MHC): 129.0486. Found: 129.0485. IR
(KBr): 3423, 3296, 1612, 1520, 1317, 877 cmK1. 1H NMR
(300 MHz, CDCl3): d 2.10 (3H, s), 2.17 (3H, s), 4.92 (2H, s).
3.2.14. 2-cyclo-Pentylamino-5-methyl-4-phenylthiazole
(3m). Yellow solid. Mp 99–100 8C (hexane/ethyl acetate).
HR-MS (TOF-CI) Calcd for C15H19N2S (MHC): 259.1268.
Found: 259.1271. IR (neat): 3184, 3056, 2953, 2868, 1622,
3.2.7. 2-Amino-5-methyl-4-phenylthiazole (3g). Brown
crystals. Mp 115–116 8C (hexane/ethyl acetate). HR-MS
(TOF-CI) Calcd for C10H11N2S (MHC): 191.0642. Found:
191.0635. IR (KBr): 3419, 3276, 3080, 1635, 1597, 1537,
1333, 773, 700 cmK1. 1H NMR (300 MHz, CDCl3): d 2.39
1
1447, 1353, 769, 698 cmK1. H NMR (400 MHz, CDCl3):
d 1.46–1.70 (6H, m), 1.96–2.04 (2H, m), 2.39 (3H, s),

3208
T. Aoyama et al. / Tetrahedron 62 (2006) 3201–3213
3.71–3.76 (1H, m), 5.68 (1H, s), 7.25–7.28 (1H, m),
7.35–7.39 (2H, m), 7.55–7.57 (2H, m).
3.2.21. 2-Butylamino-4,5-diphenylthiazole (3t). White
crystals. Mp 117–118 8C (hexane/ethyl acetate) (lit.27
117–118 8C). HR-MS (TOF-CI) Calcd for C19H21N2S
(MHC): 309.1425. Found: 309.1428. IR (KBr): 3203,
3.2.15. 2-cyclo-Hexylamino-5-methyl-4-phenylthiazole
(3n). Yellow crystals. Mp 97–99 8C (hexane/ethyl acetate).
Anal. Calcd for C16H20N2S: C, 70.55; H, 7.40; N, 10.28.
Found: C, 70.71; H, 7.29; N, 10.49. HR-MS (TOF-CI) Calcd
for C16H21N2S (MHC): 273.1425. Found: 273.1433. IR
(neat): 3171, 3079, 2925, 2851, 1577, 1447, 1333, 770,
1
3097, 2983, 2954, 1585, 1436, 1334, 756, 694 cmK1. H
NMR (300 MHz, DMSO): d 0.90 (3H, t, JZ7.2 Hz), 1.36
(2H, s, JZ7.2 Hz), 1.56 (2H, q, JZ7.2 Hz), 3.24 (2H, q, JZ
6.8 Hz), 7.18–7.30 (8H, m), 7.37–7.40 (2H, m), 7.72 (1H, t,
JZ5.3 Hz).
1
694 cmK1. H NMR (400 MHz, CDCl3): d 1.18–1.44 (5H,
m), 1.60–1.62 (1H, m), 1.73–1.78 (2H, m), 2.07–2.11 (2H,
m), 2.40 (3H, s), 3.23–3.32 (1H, m), 4.92 (1H, d, JZ
7.3 Hz), 7.26–7.30 (1H, m), 7.36–7.40 (2H, m), 7.56–7.59
(2H, m).
3.2.22. 2-(iso-Butylamino)-4,5-diphenylthiazole (3u).
White powder. Mp 115 8C (hexane/ethyl acetate). Anal.
Calcd for C19H20N2S: C, 73.99; H, 6.54; N, 9.08. Found: C,
74.00; H, 6.41; N, 9.14. HR-MS (TOF-CI) Calcd for
C19H21N2S (MHC): 309.1425. Found: 309.1429. IR (KBr):
3199, 3093, 2960, 2866, 1570, 1462, 1427, 1335, 758,
698 cmK1. 1H NMR (300 MHz, DMSO): d 0.92 (6H, d, JZ
6.6 Hz), 1.89 (1H, m), 3.07 (2H, t, JZ5.7 Hz), 7.17–7.30
(8H, m), 7.36–7.40 (2H, m), 7.78 (1H, t, JZ5.7 Hz).
3.2.16. 2-Benzylamino-5-methyl-4-phenylthiazole (3o).
White solid. Mp 152–153 8C (hexane/ethyl acetate) (lit.26
151–153 8C). HR-MS (TOF-CI) Calcd for C17H17N2S
(MHC): 281.1112. Found: 281.1107. IR (KBr): 3186,
1600, 1576, 1452, 1331, 777, 696 cmK1 1H NMR
.
(300 MHz, CDCl3): d 2.35 (3H, s), 4.33 (2H, s), 6.42 (1H,
s), 7.22–7.36 (8H, m), 7.53–7.57 (2H, m).
3.2.23. 2-(sec-Butylamino)-4,5-diphenylthiazole (3v).
White powder. Mp 93–94 8C (hexane/ethyl acetate). Anal.
Calcd for C19H20N2S: C, 73.99; H, 6.54; N, 9.08. Found: C,
74.12; H, 6.43; N, 9.17. HR-MS (TOF-CI) Calcd for
C19H21N2S (MHC): 309.1425. Found: 309.1434. IR (KBr):
3157, 3080, 2968, 2927, 2879, 1618, 1442, 1335, 756,
688 cmK1. 1H NMR (300 MHz, DMSO): d 0.92 (3H, t, JZ
7.3 Hz), 1.19 (3H, d, JZ6.4 Hz), 1.45–1.66 (2H, m), 3.58–
3.71 (1H, m), 7.20–7.31 (8H, m), 7.39–7.42 (2H, m), 7.63
(1H, d, JZ7.7 Hz).
3.2.17. 2-(2-Phenylethylamino)-5-methyl-4-phenylthia-
zole (3p). White crystals. Mp 118–119 8C (hexane/ethyl
acetate). HR-MS (TOF-CI) Calcd for C18H19N2S (MHC):
295.1268. Found: 295.1278. IR (neat): 3186, 3085, 1581,
1493, 1433, 772, 691 cmK1. 1H NMR (400 MHz, CDCl3): d
2.41 (3H, s), 2.95 (2H, t, JZ7.1 Hz), 3.51 (2H, dt, JZ7.1,
5.9 Hz), 5.10 (1H, s), 7.22–7.34 (6H, m), 7.37–7.41 (2H, m),
7.56–7.59 (2H, m).
3.2.24. 2-Decylamino-4,5-diphenylthiazole (3w). White
solid. Mp 57 8C (hexane/ethyl acetate). Anal. Calcd for
C25H32N2S: C, 76.48; H, 8.22; N, 7.14. Found: C, 76.58; H,
8.22; N, 7.17. HR-MS (TOF-CI) Calcd for C25H33N2S
(MHC): 393.2364. Found: 393.2368. IR (KBr): 3192, 3080,
3.2.18. 2-Allylamino-5-methyl-4-phenylthiazole (3q).
Crystals. Mp 102–103 8C (hexane/ethyl acetate). Anal.
Calcd for C13H14N2S: C, 67.79; H, 6.13; N, 12.16. Found:
C, 67.69; H, 6.05; N, 12.18. HR-MS (TOF-CI) Calcd for
C13H15N2S (MHC): 231.0955. Found: 231.0957. IR (KBr):
3194, 1645, 1589, 1421, 1331, 966, 914, 773, 703 cmK1. 1H
NMR (300 MHz, CDCl3): d 2.38 (3H, s), 3.76 (2H, d, JZ
4.4 Hz), 5.12–5.17 (1H, m), 5.22–5.29 (1H, m), 5.78–5.91
(1H, m), 6.05 (1H, s), 7.25–7.31 (1H, m), 7.38 (2H, t, JZ
7.5 Hz), 7.56 (2H, d, JZ7.5 Hz).
1
3060, 2918, 2850, 1581, 1433, 1338, 758, 694 cmK1. H
NMR (300 MHz, DMSO): d 0.83 (3H, t, JZ7.0 Hz), 1.23–
1.30 (14H, m), 1.57 (2H, quint, JZ6.8 Hz), 3.22 (2H, q, JZ
6.8 Hz), 7.17–7.31 (8H, m), 7.35–7.39 (2H, m), 7.71 (1H, t,
JZ5.5 Hz).
3.2.25. 2-cyclo-Pentylamino-4,5-diphenylthiazole (3x).
White powder. Mp 144 8C (hexane/ethyl acetate). Anal.
Calcd for C20H20N2S: C, 74.96; H, 6.29; N, 8.74. Found: C,
75.07; H, 6.32; N, 8.80. HR-MS (TOF-CI) Calcd for
C20H21N2S (MHC): 321.1425. Found: 321.1430. IR (KBr):
3.2.19.
2-(2-Hydroxyethylamino)-5-methyl-4-phe-
nylthiazole (3r). Brown oil. HR-MS (TOF-CI) Calcd for
C12H15N2OS (MHC): 235.0905. Found: 235.0908. IR
(neat): 3277, 3082, 2917, 2859, 1564, 1539, 1490, 1441,
1330, 1070, 773, 699 cmK1. 1H NMR (400 MHz, DMSO): d
2.32 (3H, s), 3.28 (2H, q, JZ5.9 Hz), 3.55 (2H, t, JZ
5.9 Hz), 4.79 (1H, s), 7.26–7.30 (1H, m), 7.36–7.41 (3H, m),
7.55–7.58 (2H, m).
3192, 3080, 2947, 2868, 1562, 1441, 1338, 756, 696 cmK1
.
1H NMR (300 MHz, DMSO): d 1.51–1.61 (4H, m), 1.63–
1.67 (2H, m), 1.89–1.94 (2H, m), 3.94 (1H, m), 7.17–7.30
(8H, m), 7.36–7.40 (2H, m), 7.76 (1H, d, JZ6.5 Hz).
3.2.26. 2-cyclo-Hexylamino-4,5-diphenylthiazole (3y).
White powder. Mp 154 8C (hexane/ethyl acetate). HR-MS
(TOF-CI) Calcd for C21H23N2S (MHC): 335.1581. Found:
335.1581. IR (KBr): 3205, 3078, 2929, 2856, 1558, 1439,
1338, 756, 694 cmK1. 1H NMR (300 MHz, DMSO): d 1.14–
1.36 (5H, m), 1.54–1.57 (1H, m), 1.69 (2H, m), 1.96–1.99
(2H, m), 3.48 (1H, m), 7.16–7.29 (8H, m), 7.35–7.38 (2H,
m), 7.67 (1H, d, JZ7.5 Hz).
3.2.20. 2-(2-Hydroxypropylamino)-5-methyl-4-phe-
nylthiazole (3s). White powder. Mp 92–93 8C (hexane/
ethyl acetate). Anal. Calcd for C13H16N2OS: C, 62.87; H,
6.49; N, 11.28. Found: C, 62.67; H, 6.47; N, 11.26. HR-MS
(TOF-CI) Calcd for C13H17N2OS (MHC): 249.1061.
Found: 249.1059. IR (KBr): 3345, 3319, 3205, 1600,
1560, 1443, 1134, 1078, 771, 700 cmK1 1H NMR
.
(300 MHz, CDCl3): d 1.07 (3H, d, JZ6.2 Hz), 2.31 (3H,
s), 3.15 (2H, t, JZ5.7 Hz), 3.75–3.87 (1H, m), 4.82 (1H, d,
JZ4.6 Hz), 7.27 (1H, t, JZ7.3 Hz), 7.35–7.41 (3H, m),
7.55 (2H, d, JZ7.2 Hz).
3.2.27. 2-Benzylamino-4,5-diphenylthiazole (3z). White
powder. Mp 142 8C (hexane/ethyl acetate). Anal. Calcd for

T. Aoyama et al. / Tetrahedron 62 (2006) 3201–3213
3209
1
C22H18N2S: C, 77.16; H, 5.30; N, 8.18. Found: C, 77.18; H,
5.11; N, 8.21. HR-MS (TOF-CI) Calcd for C22H19N2S
(MHC): 343.1268. Found: 343.1271. IR (KBr): 3199, 3099,
2947, 2918, 1562, 1541, 1067 cmK1. H NMR (400 MHz,
DMSO): d 2.01 (3H, s), 3.18 (2H, q, JZ5.6 Hz), 3.44 (2H, t,
JZ5.6 Hz), 4.69 (1H, s), 6.05 (1H, s), 7.33 (1H, t, JZ
5.6 Hz).
2972, 2887, 1581, 1448, 760, 694 cmK1 1H NMR
.
(300 MHz, DMSO): d 4.49 (2H, d, JZ5.8 Hz), 7.12–7.41
(15H, m), 8.26 (1H, t, JZ5.8 Hz).
3.2.35. 2-(2-Hydroxypropylamino)-4-methylthiazole
(3ah). Yellow solid. Mp 71 8C (hexane/ethyl acetate). HR-
MS (TOF-CI) Calcd for C7H13N2OS (MHC): 173.0748.
Found: 173.0748. IR (KBr): 3240, 1558, 1543, 1442, 1321,
1146, 1066, 690 cmK1. 1H NMR (300 MHz, DMSO): d 1.04
(3H, d, JZ6.2 Hz), 2.06 (3H, s), 3.10 (2H, t, JZ5.7 Hz),
3.71–3.82 (1H, m), 4.77 (1H, d, JZ4.7 Hz), 6.09 (1H, s),
7.38 (1H, t, JZ5.7 Hz).
3.2.28. 4,5-Diphenyl-2-(2phenethylamino)thiazole (3aa).
White powder. Mp 137–138 8C (hexane/ethyl acetate). HR-
MS (TOF-CI) Calcd for C23H21N2S (MHC): 357.1425.
Found: 357.1427. IR (KBr): 3195, 3086, 1583, 1495, 1335,
758, 696 cmK1. 1H NMR (300 MHz, DMSO): d 2.91 (2H, t,
JZ7.3 Hz), 3.49 (2H, q, JZ6.8 Hz), 7.17–7.33 (13H, m),
7.39–7.42 (2H, m), 7.85 (1H, t, JZ5.5 Hz).
3.2.36. 2-Benzylamino-4-phenylthiazole (3ai). Yellow
solid. Mp 98–99 8C (hexane/ethyl acetate). HR-MS (TOF-
CI) Calcd for C16H15N2S (MHC): 267.0955. Found:
267.0956. IR (KBr): 3234, 2972, 1591, 1481, 1448, 1334,
3.2.29. 2-Allylamino-4,5-diphenylthiazole (3ab). White
powder. Mp 131–132 8C (hexane/ethyl acetate). HR-MS
(TOF-CI) Calcd for C18H17N2S (MHC): 293.1112. Found:
293.1122. IR (KBr): 3188, 3078, 2972, 2925, 1581, 1439,
1
712 cmK1. H NMR (300 MHz, CDCl3): d 4.45 (2H, s),
1425, 1338, 1309, 964, 910, 760, 698 cmK1
.
1H NMR
6.35 (1H, s), 6.66 (1H, s), 7.22–7.35 (8H, m), 7.77–7.80
(2H, m).
(300 MHz, DMSO): d 3.91 (2H, t, JZ5.5 Hz), 5.13 (1H, dd,
JZ10.3, 1.5 Hz), 5.27 (1H, dd, JZ17.0, 1.5 Hz), 5.86–5.99
(1H, m), 7.18–7.31 (8H, m), 7.36–7.39 (2H, m), 7.88 (1H, t,
JZ5.5 Hz).
3.2.37. 2-Allylamino-4-phenylthiazole (3aj). Yellow crys-
tals. Mp 73 8C (hexane/ethyl acetate). HR-MS (TOF-CI)
Calcd for C12H13N2S (MHC): 217.0799. Found: 217.0797.
IR (KBr): 3192, 1601, 1585, 1483, 1442, 1423, 926, 702,
3.2.30. 4,5-Diphenyl-2-(2-hydroxyethylamino)thiazole
(3ac). White solid. Mp 91 8C (hexane/ethyl acetate). HR-
MS (TOF-CI) Calcd for C17H17N2OS (MHC): 297.1061.
Found: 297.1057. IR (KBr): 3311, 3199, 3107, 3016, 2924,
1
671 cmK1. H NMR (300 MHz, CDCl3): d 3.86 (2H, m),
5.14–5.19 (1H, m), 5.25–5.32 (1H, m), 5.82–5.94 (1H, m),
6.26 (1H, s), 6.68 (1H, s), 7.24–7.30 (1H, m), 7.34–7.39
(2H, m), 7.56–7.80 (2H, m).
1572, 1444, 1336, 1068, 756, 694 cmK1 1H NMR
.
(300 MHz, DMSO): d 3.36 (2H, q, JZ5.7 Hz), 3.60 (2H,
q, JZ5.7 Hz), 4.83 (1H, t, JZ5.4 Hz), 7.18–7.32 (8H, m),
7.37–7.41 (2H, m), 7.77 (1H, t, JZ5.7 Hz).
3.2.38. 2-(2-Hydroxyethylamino)-4-phenylthiazole (3ak).
Brown oil. HR-MS (TOF-CI) Calcd for C11H13N2OS
(MHC): 221.0748. Found: 221.0749. IR (neat): 3282,
1
3.2.31. 4,5-Diphenyl-2-(2-hydroxypropylamino)thiazole
(3ad). White powder. Mp 111–112 8C (hexane/ethyl
acetate). Anal. Calcd for C18H18N2OS: C, 69.65; H, 5.84;
N, 9.02. Found: C, 69.71; H, 5.72; N, 9.02. HR-MS (TOF-
CI) Calcd for C18H19N2OS (MHC): 311.1218. Found:
311.1215. IR (KBr): 3357, 3209, 3082, 2972, 1558, 1442,
3116, 1556, 1051, 773, 706 cmK1. H NMR (400 MHz,
DMSO): d 3.35 (2H, q, JZ5.6 Hz), 3.58 (2H, q, JZ5.6 Hz),
4.78 (1H, t, JZ5.6 Hz), 7.02 (1H, s), 7.23–7.26 (1H, m),
7.33–7.37 (2H, m), 7.64 (1H, t, JZ5.6 Hz), 7.79–7.81 (2H,
m).
1
1336, 1124, 1072, 758, 696 cmK1. H NMR (300 MHz,
3.2.39. 2-(2-Hydroxypropylamino)-4-phenylthiazole
(3al). Yellow powder. Mp 104–105 8C (hexane/ethyl
acetate). Anal. Calcd for C12H14N2OS: C, 61.51; H, 6.02;
N, 11.96. Found: C, 61.57; H, 5.94; N, 11.93. HR-MS (TOF-
CI) Calcd for C12H15N2OS (MHC): 235.0905. Found:
235.0905. IR (KBr): 3359, 3113, 1560, 1483, 1340, 1119,
943, 704 cmK1. 1H NMR (300 MHz, DMSO): d 1.11 (3H, d,
JZ6.2 Hz), 3.24 (2H, t, JZ5.6 Hz), 3.81–3.93 (1H, m),
4.85 (1H, d, JZ4.6 Hz), 7.03 (1H, s), 7.26 (1H, t, JZ
7.2 Hz), 7.37 (2H, t, JZ7.2 Hz), 7.65 (3H, t, JZ5.6 Hz),
7.82 (2H, d, JZ7.2 Hz).
DMSO): d 1.11 (3H, d, JZ6.2 Hz), 3.21 (2H, t, JZ5.7 Hz),
3.85 (1H, m), 4.83 (1H, d, JZ4.8 Hz), 7.16–7.31 (8H, m),
7.35–7.39 (2H, m), 7.74 (1H, t, JZ5.7 Hz).
3.2.32. 2-Benzylamino-4-methylthiazole28 (3ae). White
solid. Mp 95–96 8C (hexane/ethyl acetate). HR-MS (TOF-
CI) Calcd for C11H13N2S (MHC): 205.0799. Found:
205.0802. IR (KBr): 3201, 1589, 1468, 1450, 1360, 980,
1
731, 692 cmK1. H NMR (300 MHz, CDCl3): d 2.16 (3H,
s), 4.44 (2H, s), 6.02 (1H, s), 6.39 (1H, s), 7.25–7.38 (5H,
m).
3.2.40. 2-Benzylamino-4,5-dimethylthiazole28 (3am).
Brown powder. Mp 114–115 8C (hexane/ethyl acetate).
HR-MS (TOF-CI) Calcd for C12H15N2S (MHC): 219.0955.
Found: 219.0958. IR (KBr): 3199, 1593, 1468, 1454, 1354,
3.2.33. 2-Allylamino-4-methylthiazole (3af). Brown oil.
HR-MS (TOF-CI) Calcd for C7H11N2S (MHC): 155.0642.
Found: 155.0649. IR (neat): 3205, 1583, 1547, 1427, 1417,
1
1
922, 688 cmK1. H NMR (300 MHz, DMSO): d 2.05 (3H,
712 cmK1. H NMR (300 MHz, DMSO): d 1.97 (3H, s),
s), 3.83 (2H, d, JZ5.0 Hz), 5.07–5.12 (1H, m), 5.18–5.25
(1H, m), 5.82–5.94 (1H, m), 6.14 (1H, s), 7.58 (1H, m).
2.08 (3H, s), 4.35 (2H, d, JZ5.5 Hz), 7.18–7.39 (5H, m),
7.68 (1H, t, JZ5.5 Hz).
3.2.34. 2-(2-Hydroxyethylamino)-4-methylthiazole (3ag).
Brown oil. HR-MS (TOF-CI) Calcd for C6H11N2OS
(MHC): 159.0592. Found: 159.0590. IR (neat): 3280,
3.2.41. 2-Allylamino-4,5-dimethylthiazole (3an). Brown
needles. Mp 69 8C (hexane/ethyl acetate). HR-MS (TOF-
CI) Calcd for C8H13N2S (MHC): 169.0799. Found:

3210
T. Aoyama et al. / Tetrahedron 62 (2006) 3201–3213
1
169.0797. IR (KBr): 3203, 3103, 1593, 1427, 1344, 1306,
1228, 966, 912, 704 cmK1. 1H NMR (300 MHz, CDCl3): d
2.11 (3H, s), 2.18 (3H, s), 3.83 (2H, d, JZ5.3 Hz), 5.15–
5.20 (1H, m), 5.26–5.33 (1H, m), 5.60 (1H, s), 5.84–5.98
(1H, m).
1444, 1336, 1120, 762, 702 cmK1. H NMR (300 MHz,
DMSO): d 3.41 (4H, t, JZ4.8 Hz), 3.72 (4H, t, JZ4.8 Hz),
7.22–7.30 (8H, m), 7.39–7.42 (2H, m).
3.2.49. 4,5-Diphenyl-2-(N-methyl-2-hydroxyethylami-
no)thiazole (3at). White powder. Mp 69 8C (hexane/ethyl
acetate). HR-MS (TOF-CI) Calcd for C18H19N2OS (MHC):
311.1218. Found: 311.1215. IR (KBr): 3367, 2924, 2862,
3.2.42. 2-(2-Hydroxyethylamino)-4,5-dimethylthiazole
(3ao). Brown oil. HR-MS (TOF-CI) Calcd for
C7H13N2OS (MHC): 173.0748. Found: 173.0747. IR
1599, 1552, 1415, 1333, 754, 696 cmK1 1H NMR
.
(neat): 3270, 2923, 2854, 1542, 1058, 822 cmK1
.
1H
(300 MHz, DMSO): d 3.10 (3H, s), 3.53 (2H, t, JZ
5.7 Hz), 3.67 (2H, q, JZ5.7 Hz), 4.86 (1H, t, JZ5.7 Hz),
7.19–7.31 (8H, m), 7.39–7.42 (2H, m).
NMR (400 MHz, DMSO): d 1.96 (3H, s), 2.08 (3H, s),
3.19 (2H, q, JZ5.9 Hz), 3.48 (2H, t, JZ5.9 Hz), 4.74–4.92
(1H, m), 7.12 (1H, t, JZ5.1 Hz).
3.2.50. 2-(N,N-Dibutylamino)-4,5-diphenylthiazole
(3au). Yellow oil. HR-MS (TOF-CI) Calcd for C23H29N2S
(MHC): 365.2051. Found: 365.2051. IR (KBr): 1600, 1545,
3.2.43. 4,5-Dimethyl-3-(2-hydroxyethyl)-1,3-thiazole-
2(3H)-imine (30ao). White solid. Mp 176–177 8C (hexane/
ethyl acetate). HR-MS (TOF-CI) Calcd for C7H13N2OS
(MHC): 173.0748. Found: 173.0742. IR (neat): 3170, 3092,
2961, 2925, 2878, 1655, 1502, 1444, 1402, 1057 cmK1. 1H
NMR (400 MHz, DMSO): d 1.94 (3H, s), 2.04 (3H, s), 3.58
(2H, q, JZ5.8 Hz), 3.88 (2H, t, JZ5.8 Hz), 4.85 (1H, t, JZ
5.8 Hz), 11.81 (1H, s).
1
1495, 1444, 1336, 756, 696 cmK1. H NMR (300 MHz,
DMSO): d 0.98 (6H, t, JZ7.4 Hz), 1.39 (4H, m), 1.69 (4H,
m), 3.45 (4H, t, JZ7.4 Hz), 7.15–7.30 (8H, m), 7.51–7.55
(2H, m).
3.2.51. 2-(N,N-Di-iso-butylamino)-4,5-diphenylthiazole
(3av). Yellow oil. HR-MS (TOF-CI) Calcd for C23H29N2S
(MHC): 365.2051. Found: 365.2056. IR (KBr): 1601, 1541,
3.2.44. 2-(2-Hydroxypropylamino)-4,5-dimethylthiazole
(3ap). Brown oil. HR-MS (TOF-CI) Calcd for C8H15N2OS
(MHC): 187.0905. Found: 187.0897. IR (neat): 3250, 2961,
2923, 2857, 1562, 1454, 1410, 1375, 1085 cmK1. 1H NMR
(400 MHz, DMSO): d 1.03 (3H, d, JZ6.6 Hz), 1.96 (3H, s),
2.07 (3H, s), 3.00–3.11 (2H, m), 3.70–3.78 (1H, m), 4.77
(1H, s), 7.13 (1H, t, JZ5.4 Hz)
1
1495, 1442, 1336, 756, 696 cmK1. H NMR (300 MHz,
DMSO): d 0.96 (12H, d, JZ6.6 Hz), 2.24 (2H, m), 3.34 (4H,
d, JZ7.5 Hz), 7.25–7.37 (8H, m), 7.40–7.47 (2H, m).
3.3. Typical procedure for the preparation
of N-allylthioureas
3.2.45. 4,5-Dimethyl-3-(2-hydroxypropyl)-1,3-thiazole-
2(3H)-imine (30ap). White powder. Mp 160–161 8C
(hexane/ethyl acetate). Anal. Calcd for C8H14N2OS: C,
51.58; H, 7.58; N, 15.04. Found: C, 51.49; H, 7.62; N, 14.98.
HR-MS (TOF-CI) Calcd for C8H15N2OS (MHC): 187.0905.
Found: 187.0897. IR (neat): 3374, 3103, 2962, 2947, 2926,
A mixture of allyl bromides (1 mmol), KSCN/SiO2
(5 mmol, 1 g) and RNH3OAc/Al2O3 (3 mmol, 3 g) was
stirred in benzene (10 mL) at 80 8C 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 chromatography.
1
2892, 1660, 1493, 1438, 1401, 1369, 1134, 936 cmK1. H
NMR (400 MHz, DMSO): d 1.05 (3H, d, JZ6.3 Hz), 1.94
(3H, s), 2.03 (3H, s), 3.55 (1H, dd, JZ13.5, 8.2 Hz), 3.89
(1H, dd, JZ13.5, 4.0 Hz), 4.00–4.06 (1H, m), 4.79 (1H, d,
JZ5.1 Hz), 11.79 (1H, s).
3.3.1. 1-Benzyl-3-(1-phenylallyl)-thiourea (7a). White
powder. Mp 80–81 8C (hexane/ethyl acetate). Anal. Calcd
for C17H18N2S: C, 72.30; H, 6.42; N, 9.92. Found: C, 72.21;
H, 6.53; N, 10.10. HR-MS (TOF-CI) Calcd for C17H19N2S
(MHC): 283.1268. Found: 283.1273. IR (neat): 3266,
1
3.2.46. 4,5-Diphenyl-2-pyrrolidinothiazole (3aq). Yellow
solid. Mp 116–117 8C (hexane/ethyl acetate). HR-MS
(TOF-CI) Calcd for C19H19N2S (MHC): 307.1268. Found:
307.1277. IR (KBr): 2914, 2852, 1599, 1560, 1495, 1331,
1549 cmK1. H NMR (300 MHz, CDCl3): d 4.55 (2H, s),
5.06–5.18 (2H, m), 5.54 (1H, s), 5.83–5.93 (1H, m), 6.30
(1H, s), 6.40 (1H, s), 7.08–7.26 (10H, m).
1
762, 700 cmK1. H NMR (300 MHz, DMSO): d 1.94–2.00
3.3.2. 1-Allyl-3-benzyl thiourea (7b). White solid. Mp
93 8C (hexane/ethyl acetate). Anal. Calcd for C11H14N2S: C,
64.04; H, 6.84; N, 13.58. Found: C, 64.10; H, 6.94; N, 13.83.
HR-MS (TOF-CI) Calcd for C11H15N2S (MHC): 207.0955.
(4H, m), 3.39 (4H, t, JZ6.5 Hz), 7.17–7.30 (8H, m), 7.39–
7.42 (2H, m).
1
3.2.47. 4,5-Diphenyl-2-piperidinothiazole (3ar). Yellow
crystals. Mp 152–153 8C (hexane/ethyl acetate) (lit.27 152–
153 8C). HR-MS (TOF-CI) Calcd for C20H21N2S (MHC):
321.1425. Found: 321.1432. IR (KBr): 2933, 2852, 1600,
Found: 207.0962. IR (neat): 3237, 1558 cmK1. H NMR
(400 MHz, CDCl3): d 4.03 (2H, s), 4.65 (2H, s), 5.14–5.19
(2H, m), 5.76–5.86 (1H, m), 6.19 (1H, s), 6.37 (1H, s), 7.27–
7.37 (5H, m).
1541, 1495, 1444, 1329, 761, 698 cmK1 1H NMR
.
(300 MHz, DMSO): d 1.61 (6H, m), 3.45 (4H, m), 7.20–
7.33 (8H, m), 7.36–7.41 (2H, m).
3.3.3. 1-Benzyl-3-(1-methylallyl)-thiourea (7c). White
solid. Mp 68–69 8C (hexane/ethyl acetate). Anal. Calcd
for C12H16N2S: C, 65.41; H, 7.32; N, 12.71. Found: C,
65.44; H, 7.44; N, 12.70. HR-MS (TOF-CI) Calcd for
C12H17N2S (MHC): 221.1112. Found: 221.1108. IR (neat):
3221, 1558 cmK1. 1H NMR (300 MHz, CDCl3): d 1.20 (3H,
d, JZ6.8 Hz), 4.42 (1H, s), 4.62 (2H, s), 5.02–5.10 (2H, m),
3.2.48. 4,5-Diphenyl-2-morpholinothiazole (3as). White
crystals. Mp 116–117 8C (hexane/ethyl acetate). HR-MS
(TOF-CI) Calcd for C19H19N2OS (MHC): 323.1218.
Found: 323.1226. IR (KBr): 2960, 2845, 1599, 1572,

T. Aoyama et al. / Tetrahedron 62 (2006) 3201–3213
3211
5.67–5.78 (1H, m), 6.08 (1H, s), 6.29 (1H, s), 7.23–7.30
(5H, m).
4.31 (1H, s), 5.25–5.33 (2H, m), 5.58 (1H, s), 5.88 (1H, s),
5.98–6.07 (1H, m), 6.12 (1H, s), 7.30–7.40 (5H, m).
3.3.4. 1-Benzyl-3-(1,1-dimethylallyl)-thiourea (7d).
White crystals. Mp 58–59 8C (hexane/ethyl acetate). Anal.
Calcd for C13H18N2S: C, 66.62; H, 7.74; N, 11.95. Found:
C, 66.76; H, 7.85; N, 12.04. HR-MS (TOF-CI) Calcd for
C13H19N2S (MHC): 235.1268. Found: 235.1268. IR (KBr):
3267, 1545 cmK1. 1H NMR (300 MHz, CDCl3): d 1.35 (6H,
s), 4.77 (2H, d, JZ5.1 Hz), 5.13–5.22 (2H, m), 5.94 (1H, dd,
JZ17.9, 10.6 Hz), 6.26 (1H, s), 6.29 (1H, s), 7.22–7.29
(5H, m).
3.3.10. 1-cyclo-Hexyl-3-(1-phenylallyl)-thiourea (7j).
White powder. Mp 136–137 8C (hexane/ethyl acetate).
Anal. Calcd for C16H22N2S: C, 70.03; H, 8.08; N, 10.21.
Found: C, 69.78; H, 8.19; N, 10.28. HR-MS (TOF-CI) Calcd
for C16H23N2S (MHC): 275.1581. Found: 275.1578. IR
1
(neat): 3250, 1541 cmK1. H NMR (400 MHz, CDCl3): d
1.01–1.18 (3H, m), 1.27–1.40 (2H, m), 1.54–1.63 (3H, m),
1.84–1.87 (1H, m), 1.97–1.99 (1H, m), 4.03 (1H, s), 5.25–
5.32 (2H, m), 5.42 (1H, s), 5.77 (1H, s), 5.96–6.04 (1H, m),
6.25 (1H, s), 7.28–7.39 (5H, m).
3.3.5. 1-Butyl-3-(1-phenylallyl)-thiourea (7e). White
powder. Mp 77–78 8C (hexane/ethyl acetate). Anal. Calcd
for C14H20N2S: C, 67.70; H, 8.12; N, 11.28. Found: C,
67.60; H, 8.28; N, 11.26. HR-MS (TOF-CI) Calcd for
C14H21N2S (MHC): 249.1425. Found: 249.1425. IR (neat):
3264, 1545 cmK1. 1H NMR (400 MHz, CDCl3): d 0.87 (3H,
t, JZ7.3 Hz), 1.25 (2H, sext, JZ7.3 Hz), 1.47 (2H, quint,
JZ7.3 Hz), 3.44 (2H, s), 5.24–5.31 (2H, m), 5.49 (1H, s),
5.88 (1H, s), 5.97–6.05 (1H, m), 6.30 (1H, s), 7.28–7.39
(5H, m).
3.3.11. 1-Phenetyl-3-(1-phenylallyl)-thiourea (7k).
Yellow oil. HR-MS (TOF-CI) Calcd for C18H21N2S
(MHC): 297.1425. Found: 297.1429. IR (neat): 3260,
1545 cmK1 1H NMR (400 MHz, CDCl3): d 2.70–2.82
.
(2H, m), 3.69 (2H, s), 5.07–5.14 (2H, m), 5.45 (1H, s), 5.82–
5.90 (1H, m), 6.13 (1H, s), 6.59 (1H, s), 7.07 (2H, d, JZ
6.8 Hz), 7.15–7.29 (8H, m).
3.3.12. 1-Butyl-3-(1-methylallyl)-thiourea (7l). Yellow
oil. HR-MS (TOF-CI) Calcd for C9H19N2S (MHC):
3.3.6. 1-iso-Butyl-3-(1-phenylallyl)-thiourea (7f). White
powder. Mp 92–93 8C (hexane/ethyl acetate). Anal. Calcd
for C14H20N2S: C, 67.70; H, 8.12; N, 11.28. Found: C,
67.40; H, 8.21; N, 11.49. HR-MS (TOF-CI) Calcd for
C14H21N2S (MHC): 249.1425. Found: 249.1421. IR (neat):
187.1268. Found: 187.1276. IR (neat): 3263, 1549 cmK1
.
1H NMR (400 MHz, CDCl3): d 0.94 (3H, t, JZ7.5 Hz), 1.32
(3H, d, JZ6.8 Hz), 1.37 (2H, sext, JZ7.5 Hz), 1.58 (2H,
quint, JZ7.5 Hz), 3.48 (2H, s), 4.55 (1H, s), 5.15–5.27 (2H,
m), 5.81–5.89 (1H, m), 6.15 (2H, s).
1
3266, 1552 cmK1. H NMR (400 MHz, CDCl3): d 0.81–
0.84 (6H, m), 1.73–1.86 (1H, m), 3.29 (2H, s), 5.25–5.32
(2H, m), 5.42 (1H, s), 5.89 (1H, s), 5.97–6.05 (1H, m), 6.34
(1H, s), 7.29–7.39 (5H, m).
3.3.13. 1-iso-Butyl-3-(1-methylallyl)-thiourea (7m). Col-
orless oil. HR-MS (TOF-CI) Calcd for C9H19N2S (MHC):
187.1268. Found: 187.1269. IR (neat): 3264, 1549 cmK1
.
1H NMR (400 MHz, CDCl3): d 0.94 (6H, d, JZ6.8 Hz),
1.31 (3H, d, JZ6.8 Hz), 1.90 (1H, m), 3.31 (2H, s), 4.66
(1H, s), 5.13–5.25 (2H, m), 5.81–5.90 (1H, m), 6.55 (2H, s).
3.3.7. 1-sec-Butyl-3-(1-phenylallyl)-thiourea (7g). White
powder. Mp 112–113 8C (hexane/ethyl acetate). Anal.
Calcd for C14H20N2S: C, 67.70; H, 8.12; N, 11.28. Found:
C, 67.72; H, 8.27; N, 11.16. HR-MS (TOF-CI) Calcd for
C14H21N2S (MHC): 249.1425. Found: 249.1430. IR (neat):
3.3.14. 1-sec-Butyl-3-(1-methylallyl)-thiourea (7n).
White powder. Mp 72–73 8C (hexane/ethyl acetate). Anal.
Calcd for C9H18N2S: C, 58.02; H, 9.74; N, 15.04. Found: C,
57.99; H, 10.04; N, 14.92. HR-MS (TOF-CI) Calcd for
C9H19N2S (MHC): 187.1268. Found: 187.1262. IR (neat):
3266, 1536 cmK1 1H NMR (400 MHz, CDCl3): d 0.72
.
(1.5H, t, JZ7.4 Hz), 0.90 (1.5H, t, JZ7.4 Hz), 1.06 (1.5H,
d, JZ6.3 Hz), 1.15 (1.5H, d, JZ6.3 Hz), 1.36–1.43 (1H,
m), 1.44–1.57 (1H, m), 4.18 (1H, s), 5.24–5.34 (2H, m),
5.38 (1H, s), 5.59 (1H, s), 5.96–6.06 (1H, m), 6.20 (1H, s),
7.30–7.40 (5H, m).
1
3236, 1553 cmK1. H NMR (400 MHz, CDCl3): d 0.90–
0.96 (3H, m), 1.17–1.20 (3H, m), 1.32 (3H, d, JZ6.6 Hz),
1.50–1.62 (2H, m), 4.21 (1H, s), 4.42 (1H, s), 5.18–5.28
(2H, m), 5.80–5.89 (2H, m), 6.07 (1H, s).
3.3.8. 1-Allyl-3-(1-phenylallyl)-thiourea (7h). White pow-
der. Mp 56–57 8C (hexane/ethyl acetate). Anal. Calcd for
C13H16N2S: C, 67.20; H, 6.94; N, 12.06. Found: C, 67.35;
H, 6.91; N, 11.95. HR-MS (TOF-CI) Calcd for C13H17N2S
(MHC): 233.1112. Found: 233.1113. IR (neat): 3251,
3.3.15. 1-Allyl-3-(1-methylallyl)-thiourea (7o). Yellow
oil. HR-MS (TOF-CI) Calcd for C8H15N2S (MHC):
171.0955. Found: 171.0960. IR (neat): 3261, 1549 cmK1
.
1H NMR (400 MHz, CDCl3): d 1.32 (3H, d, JZ6.8 Hz),
4.13 (2H, s), 4.52 (1H, s), 5.17–5.27 (4H, m), 5.80–5.93
(2H, m), 6.09 (2H, s).
1
1540 cmK1. H NMR (400 MHz, CDCl3): d 4.09 (2H, s),
5.09–5.14 (2H, m), 5.24–5.31 (2H, m), 5.61 (1H, s), 5.76–
5.85 (1H, m), 5.96–6.05 (1H, m), 6.09 (1H, s), 6.40 (1H, s),
7.29–7.38 (5H, m).
3.3.16. 1-cyclo-Pentyl-3-(1-methylallyl)-thiourea (7p).
White powder. Mp 72–73 8C (hexane/ethyl acetate). Anal.
Calcd for C10H18N2S: C, 60.56; H, 9.15; N, 14.12. Found:
C, 60.33; H, 9.18; N, 14.32. HR-MS (TOF-CI) Calcd for
C10H19N2S (MHC): 199.1268. Found: 199.1264. IR (neat):
3240, 1549 cmK1. 1H NMR (400 MHz, CDCl3): d 1.32 (3H,
d, JZ6.6 Hz), 1.45–1.52 (2H, m), 1.59–1.72 (4H, m), 2.00–
2.05 (2H, m), 4.34 (1H, s), 4.60 (1H, s), 5.16–5.26 (2H, m),
5.82–5.90 (1H, m), 5.99 (1H, s), 6.13 (1H, s).
3.3.9. 1-cyclo-Pentyl-3-(1-phenylallyl)-thiourea (7i).
White powder. Mp 137–138 8C (hexane/ethyl acetate).
Anal. Calcd for C15H20N2S: C, 69.19; H, 7.74; N, 10.76.
Found: C, 69.12; H, 7.89; N, 10.99. HR-MS (TOF-CI) Calcd
for C15H21N2S (MHC): 261.1425. Found: 261.1430. IR
1
(neat): 3263, 1539 cmK1. H NMR (400 MHz, CDCl3): d
1.31–1.47 (2H, m), 1.54–1.63 (4H, m), 1.89–2.04 (2H, m),

3212
T. Aoyama et al. / Tetrahedron 62 (2006) 3201–3213
3.3.17. 1-cyclo-Hexyl-3-(1-methylallyl)-thiourea (7q).
White powder. Mp 107–108 8C (hexane/ethyl acetate).
Anal. Calcd for C11H20N2S: C, 62.22; H, 9.49; N, 13.19.
Found: C, 62.10; H, 9.77; N, 13.35. HR-MS (TOF-CI) Calcd
for C11H21N2S (MHC): 213.1425. Found: 213.1423. IR
for C11H21N2S (MHC): 213.1425. Found: 213.1429. IR
1
(KBr): 3246, 1513 cmK1. H NMR (400 MHz, CDCl3): d
1.41 (6H, s), 1.44–1.49 (2H, m), 1.56–1.67 (4H, m), 1.97–
2.05 (2H, m), 4.56–4.64 (1H, m), 5.29–5.36 (2H, m), 6.04
(1H, dd, JZ17.7, 10.6 Hz), 6.12 (1H, s), 6.36 (1H, s).
1
(neat): 3240, 1552 cmK1. H NMR (400 MHz, CDCl3): d
1.15–1.24 (3H, m), 1.32 (3H, d, JZ6.8 Hz), 1.34–1.43 (2H,
m), 1.59–1.71 (3H, m), 1.99–2.04 (2H, m), 4.03 (1H, s),
4.40 (1H, s), 5.18–5.28 (2H, m), 5.79–5.88 (1H, m), 5.86
(1H, s), 5.95 (1H, s).
3.3.24. 1-cyclo-Hexyl-3-(1,1-dimethylallyl)-thiourea (7x).
White solid. Mp 97–99 8C (hexane/ethyl acetate). Anal.
Calcd for C12H22N2S: C, 63.67; H, 9.80; N, 12.37. Found:
C, 63.39; H, 10.11; N, 12.21. HR-MS (TOF-CI) Calcd for
C12H23N2S (MHC): 227.1581. Found: 227.1575. IR (KBr):
3.3.18. 1-(1-Methylallyl)-3-phenetyl thiourea (7r). White
powder. Mp 54–55 8C (hexane/ethyl acetate). Anal. Calcd
for C13H18N2S: C, 66.62; H, 7.74; N, 11.95. Found: C,
66.60; H, 7.87; N, 11.74. HR-MS (TOF-CI) Calcd for
C13H19N2S (MHC): 235.1268. Found: 235.1275. IR (neat):
3224, 1550 cmK1. 1H NMR (400 MHz, CDCl3): d 1.24 (3H,
d, JZ6.8 Hz), 2.88–2.92 (2H, m), 3.81 (2H, s), 4.20 (1H, s),
4.98–5.04 (2H, m), 5.64–5.72 (1H, m), 5.92 (1H, s), 6.09
(1H, s), 7.19–7.25 (3H, m), 7.28–7.33 (2H, m).
1
3220, 1540 cmK1. H NMR (400 MHz, CDCl3): d 1.14–
1.28 (2H, m), 1.36–1.47 (2H, m), 1.40 (6H, s), 1.54–1.65
(4H, m), 1.98–2.02 (2H, m), 4.18–4.27 (1H, m), 5.29–5.36
(2H, m), 6.02 (1H, dd, JZ17.7, 10.6 Hz), 6.02 (1H, s), 6.04
(1H, s).
3.3.25. 1-(1,1-Dimethylallyl)-3-phenetyl thiourea (7y).
White needles. Mp 70–71 8C (hexane/ethyl acetate). Anal.
Calcd for C14H20N2S: C, 67.70; H, 8.12; N, 11.28. Found:
C, 67.52; H, 8.34; N, 11.35. HR-MS (TOF-CI) Calcd for
C14H21N2S (MHC): 249.1425. Found: 249.1417. IR (neat):
3254, 1551 cmK1. 1H NMR (400 MHz, CDCl3): d 1.24 (6H,
s), 2.91 (2H, t, JZ6.6 Hz), 3.91 (2H, dt, JZ6.6, 5.4 Hz),
4.90–4.98 (2H, m), 5.76 (1H, dd, JZ17.7, 10.6 Hz), 5.93
(1H, s), 6.22 (1H, s), 7.20–7.25 (3H, m), 7.29–7.33 (2H, m).
3.3.19. 1-Butyl-3-(1,1-dimethylallyl)-thiourea (7s).
Yellow oil. HR-MS (TOF-CI) Calcd for C10H21N2S
(MHC): 201.1425. Found: 201.1425. IR (neat): 3258,
1
1545 cmK1. H NMR (400 MHz, CDCl3): d 0.93 (3H, t,
JZ7.5 Hz), 1.34 (2H, sext, JZ7.5 Hz), 1.40 (6H, s), 1.54
(2H, quint, JZ7.5 Hz), 3.56–3.61 (2H, m), 5.29–5.36 (2H,
m), 6.02 (1H, s), 6.02 (1H, dd, JZ17.6, 10.7 Hz), 6.14
(1H, s).
3.3.20. 1-(1,1-Dimethylallyl)-3-iso-butylthiourea (7t).
White solid. Mp 48–49 8C (hexane/ethyl acetate). Anal.
Calcd for C10H20N2S: C, 59.95; H, 10.06; N, 13.98. Found:
C, 59.94; H, 10.31; N, 13.89. HR-MS (TOF-CI) Calcd for
C10H21N2S (MHC): 201.1425. Found: 201.1418. IR (neat):
3234, 1533 cmK1. 1H NMR (400 MHz, CDCl3): d 0.92 (6H,
d, JZ6.7 Hz), 1.41 (6H, s), 1.89 (1H, m), 3.43 (1H, d, JZ
6.7 Hz), 3.44 (1H, d, JZ6.7 Hz), 5.31–5.38 (2H, m), 6.04
(1H, dd, JZ17.7, 10.6 Hz), 6.09 (1H, s), 6.14 (1H, s).
References and notes
1. Hargrave, K. D.; Hess, F. K.; Oliver, J. T. J. Med. Chem. 1983,
26, 1158.
2. 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.
3.3.21. 1-sec-Butyl-3-(1,1-dimethylallyl)-thiourea (7u).
Colorless oil. HR-MS (TOF-CI) Calcd for C10H21N2S
(MHC): 201.1425. Found: 201.1428. IR (neat): 3258,
3. 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.
1
1542 cmK1. H NMR (400 MHz, CDCl3): d 0.91 (3H, t,
4. Tsuji, K.; Ishikawa, H. Bioorg. Med. Chem. Lett. 1994, 4,
1601.
JZ7.3 Hz), 1.17 (3H, d, JZ6.6 Hz), 1.40 (3H, s), 1.40 (3H,
s), 1.53 (2H, quint, JZ7.3 Hz), 4.31–4.42 (1H, m), 5.29–
5.37 (2H, m), 5.91 (1H, s), 6.03 (1H, dd, JZ17.7, 10.6 Hz),
6.04 (1H, s).
5. 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. Chem.
1995, 38, 4929.
3.3.22. 1-Allyl-3-(1,1-dimethylallyl)-thiourea (7v). White
solid. Mp 55–57 8C (hexane/ethyl acetate). Anal. Calcd for
C9H16N2S: C, 58.65; H, 8.75; N, 15.20. Found: C, 58.59; H,
8.99; N, 15.11. HR-MS (TOF-CI) Calcd for C9H17N2S
(MHC): 185.1112. Found: 185.1118. IR (neat): 3246,
6. (a) Bloom, J. D.; Dushin, R. G.; Curran, K. J.; Donahue, C. F.;
Norton, E. B.; Terefenko, E.; Jones, T. R.; Ross, A. A.; Feld,
B.; Lang, S. A.; DiGrandi, M. J. Bioorg. Med. Chem. Lett.
2004, 14, 3401. (b) Lee, J.; Kim, S. Y.; Lee, J.; Kang, M.; Kil,
M.-J.; Choi, H.-K.; Jin, M.-K.; Wang, Y.; Toth, A.; Pearce,
L. V.; Lundberg, D. J.; Tran, R.; Blumberg, P. M. Bioorg. Med.
Chem. 2004, 12, 3411.
1
1545 cmK1. H NMR (400 MHz, CDCl3): d 1.43 (6H, s),
4.24–4.27 (2H, m), 5.14–5.21 (2H, m), 5.29–5.37 (2H, m),
5.83–5.93 (1H, m), 6.03 (1H, dd, JZ17.6, 10.7 Hz), 6.10
(1H, s), 6.33 (1H, s).
7. St. Laurent, D. R.; Gao, Q.; Wu, D.; Serrano-Wu, M. H.
Tetrahedron Lett. 2004, 45, 1907.
3.3.23. 1-cyclo-Pentyl-3-(1,1-dimethylallyl)-thiourea
(7w). White solid. Mp 66–67 8C (hexane/ethyl acetate).
Anal. Calcd for C11H20N2S: C, 62.22; H, 9.49; N, 13.19.
Found: C, 62.24; H, 9.86; N, 13.03. HR-MS (TOF-CI) Calcd
8. (a) Baily, N.; Dean, A. W.; Judd, D. B.; Middlemiss, D.;
Storer, R.; Watson, S. P. Bioorg. Med. Chem. Lett. 1996, 6,
1409. (b) Kearnery, P. C.; Fernandez, M. J. Org. Chem.
1998, 63, 196. (c) Rudolp, J. Tetrahedron 2000, 56, 3161.

T. Aoyama et al. / Tetrahedron 62 (2006) 3201–3213
3213
(d) Schantl, J. G.; Lagoja, I. M. Synth. Commun. 1998, 28,
1451.
ˇ
9. Ciszewski, L.; Xu, D.; Repic, O.; Blacklock, T. J. Tetrahedron
Lett. 2004, 45, 8091.
1091. (c) Kodomari, M.; Aoyama, T.; Suzuki, Y. Tetrahedron
Lett. 2002, 43, 1717. (d) Aoyama, T.; Murata, S.; Nagata, S.;
Takido, T.; Kodomari, M. Tetrahedron Lett. 2005, 46, 4875.
(e) Aoyama, T.; Takido, T.; Kodomari, M. Synlett 2005, 2739.
19. (a) Kodomari, M.; Kuzuoka, T.; Yoshitomi, S. Synthesis 1983,
141. (b) Ando, T.; Clark, J. H.; Cork, D. G.; Fujita, M.;
Kimura, T. J. Org. Chem. 1987, 52, 681.
10. Ballini, R.; Bosica, G.; Fiorini, D.; Maggi, R.; Righi, P.;
Sartori, G.; Sartorio, R. Tetrahedron Lett. 2002, 43, 8445.
11. Katritzky, A. R.; Ledoux, P.; Witek, R. M.; Nair, S. K. J. Org.
Chem. 2004, 69, 2976.
20. (a) Forlani, L.; De Maria, P. J. Chem. Soc., Perkin Trans. 2
1982, 535. (b) Forlani, L.; De Maria, P.; Fini, A. J. Chem. Soc.,
Perkin Trans. 2 1980, 1156.
12. Mohanta, P. K.; Dhar, S.; Samal, S. K.; Ila, H.; Junjappa, H.
Tetrahedron 2000, 56, 629.
13. Boas, U.; Gertz, H.; Christensen, J. B.; Heegaard, P. M. H.
Tetrahedron Lett. 2004, 45, 269.
14. Sharma, S. Synthesis 1978, 803.
21. Schantl, J. S.; Lagoja, I. M. Synth. Commun. 1998, 28, 1451.
22. Kurz, T.; Geffken, D. Heterocycl. Commun. 1999, 5, 325.
´ ´ ´
23. Marquez, H.; Perez, E. R.; Plutın, A. M.; Morales, M.; Loupy,
15. (a) Chakrabarty, M.; Ghosh, N.; Harigaya, Y. Tetrahedron
Lett. 2004, 45, 4955. (b) Zhang, W.; Chen, C. H.-T.;
Nagashima, T. Tetrahedron Lett. 2003, 44, 2065.
16. Li, Q.; Yin, D.; Gu, X. Huaxue Tongbao 1993, 10, 41.
17. (a) Aoyama, T.; Takido, T.; Kdomari, M. Tetrahedron Lett.
2004, 45, 1873. (b) Parlow, J. J. Tetrahedron Lett. 1995, 36,
1395.
A. Tetrahedron Lett. 2000, 41, 1753.
24. Bergmann, E. J. Chem. Soc. 1935, 1361.
25. Khanna, M. S.; Garg, C. P.; Kapoor, R. P. Indian J. Chem.,
Sect. B 1993, 32, 364.
26. Schantl, J. G.; Lagoja, I. M. Synth. Commun. 1998, 28, 1451.
27. Yamanaka, H.; Konno, S.; Amano, M.; Sagi, M. Yakugaku
Zasshi 1990, 110, 105.
18. (a) Kodomari, M.; Nawa, S.; Miyoshi, T. Chem. Commun.
1995, 1895. (b) Suzuki, Y.; Kodomari, M. Chem. Lett. 1998,
28. Boga, C.; Forlani, L.; Silvestroni, C.; Corradi, A. B.;
Sgarabotto, P. J. Chem. Soc., Perkin Trans. 1 1999, 1363.