Novel isothiocyanate transposition in 2-alkyliminothiazoles: a simple solution for regiochemical problem

Article abstract of DOI:10.1016/j.tetlet.2007.02.084

Novel alkyl/aryl transposition in the reaction of 2-iminothiazoles with alkyl/aryl isothiocyanates was found out, and the reaction was very easy to handle and gave good to excellent chemical yields. Moreover, transposition reaction provided a simple but excellent solution for regiochemical problems in 2-iminothiazole synthesis.

Full text of DOI:10.1016/j.tetlet.2007.02.084

Tetrahedron Letters 48 (2007) 3089–3092
Novel isothiocyanate transposition in 2-alkyliminothiazoles:
a simple solution for regiochemical problem
Dongyun Shin,* Jihoon Lee, Kee Dal Nam and Hoh-Gyu Hahn*
Life Sciences Research Division, Korea Institute of Science and Technology (KIST), 39-1 Hawolgok-dong,
Seongbuk-gu, Seoul 136-791, Republic of Korea
Received 25 January 2007; revised 14 February 2007; accepted 16 February 2007
Available online 22 February 2007
Abstract—Novel alkyl/aryl transposition in the reaction of 2-iminothiazoles with alkyl/aryl isothiocyanates was found out, and the
reaction was very easy to handle and gave good to excellent chemical yields. Moreover, transposition reaction provided a simple but
excellent solution for regiochemical problems in 2-iminothiazole synthesis.
Ó 2007 Elsevier Ltd. All rights reserved.
2-Aminothiazole (1) and its isoform, 2-iminothiazole
(2), are important classes of 5-membered heterocyclic
compounds because of their wide utilities1 (Fig. 1). They
are not only seen as building blocks in natural products,
but are also considered to be extraordinarily useful
scaffolds, especially in combinatorial and medicinal
chemistry.2,3 Their inherent low toxicities and good
pharmacokinetic profile for drug development make
them one of the privileged structures in the realm of
medicinal chemistry. With these reasons, there have
been lots of reports on efficient and diversified syntheses
of their derivatives and applications to specific drug tar-
gets.3 In spite of a thorough investigation on the syn-
thetic methods and applications of 2-aminothiazole,4,5
less attention has been devoted to the chemistry of 2-
iminothiazole, an isoform of N,N-dialkyl-2-aminothiaz-
ole.6 2-Iminothiazole also can be easily synthesized from
a-halocarbonyls and N,N0-dialkylthiourea, and has an
additional advantage over 2-aminothiazole that there
are four derivatizable positions in it. Recently, we
reported solution- and solid-phase syntheses of 2-akyl
and aryl iminothiazoles from 4-chloroacetoanilides and
dialkylthioureas, which were utilized in the establish-
ment of diverse/focused chemical library of high qual-
ity.7 But when unsymmetrical N,N0-dialkylthioureas
were used, regiochemistry of the products was predeter-
mined depending on the size of the substituents: a large
group positioned at the imino nitrogen, which is general
regiochemical trend in the type of reaction (Fig. 2).
In the course of studies on the functionalization of
2-iminothiazoles, we have found that the alkyl group
attached at the imine nitrogen is substituted with that of
alkyl isothiocyanate in mild conditions (Fig. 3). Herein,
we disclose an unprecedent finding of alkyl/aryl transpo-
sition between 2-alkyliminothiazoline and alkyl/aryl iso-
thiocyanate by rearrangement, more importantly, which
gave an excellent solution for regiochemical problems in
2-iminothiazole formation.
R1
2-Iminothiazole 3 was prepared by condensation of 3-
chloro-2-butanone and N,N0-cyclohexylmethylthiourea.
With this, the reaction condition of this transposition
R1
R2
S
N
S
N
R4
R3
N
N
H
R2
R3
2-Iminothiazole (2)
2-Aminothiazole (1)
Figure 1. Structures of 2-aminothiazole and 2-iminothiazole.
Me
Me
X
S
Me
Me
S
N
+
N
Me
N
N
Keywords: 2-Iminothiazole; Isothiocyanate; Transposition; Regio-
O
H
H
Bulkier group
chemistry.
Me
*
Corresponding authors. Tel.: +82 2 958 5143/5139; fax: +82 2 958
5189; e-mail addresses: dyshin21@kist.re.kr; hghahn@kist.re.kr
Figure 2. Regiochemical trend in the formation of 2-iminothiazole.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.084

3090
D. Shin et al. / Tetrahedron Letters 48 (2007) 3089–3092
R1
R2
products could be obtained just in moderate yields. Ele-
vated amounts of alkyl isothiocyanates (5 equiv) and
prolonged reaction times were needed for better chemi-
cal yields. However, the reaction did not complete. The
above results imply that the reactivity of isothiocyanate
transposition is very sensitive to the electronic properties
of the substituents of isothiocyanate, and reverse trans-
position is possible. And phenyl isothiocyanate also
worked in this transposition reaction (entry 9).
S
N
R1
R2
N R5
S
N
R4
N
+ R5
N C S
R3
R3
+
R4 N C S
Figure 3. Novel isothiocyanate transposition of iminothiazole.
was carefully selected considering the reactivity of iso-
thiocyanate and the reaction rate. After screening of sol-
vents and temperature, toluene as a solvent showed
optimal reaction rates and yields.8 Therefore, all reac-
tions were carried out under the condition of stirring
in toluene for 16 h at 105 °C. Lower reaction tempera-
ture diminished the reaction rates. The transposition
results are summarized in Table 1. As shown in entries
1–4, the substituted benzyl isothiocyanates afforded the
rearranged products in almost quantitative yields
regardless of the substituents on the phenyl ring. It
seems that a mild electron-withdrawing effect of benzyl
group makes the substituted benzyl isothiocyanates
more reactive and prevents the transpositioned products
from reverse transposition. But in case of alkyl isothio-
cyanate (entries 5–8) in which alkyl groups are consid-
ered to have electron donating effect, the desired
Scheme 1 illustrates the possible mechanism of this reac-
tion. At first, imine nitrogen activated by nitrogen in the
thiazole attacks the isothiocyanate, which generated for-
mally thiazolinium ion 6. Then, nitrogen is added to this
thiazolinium ion, followed by rearrangement to release
substituted product and cyclohexylisothiocyanate.
½7 ! 8 ! 5aꢀ
One of the major limitations in the generation of N,N0-
dialkyliminothiazole scaffold-based chemical libraries
for medicinal chemistry is that the regiochemistry of
the two alkyl groups is predetermined depending on
the steric and electronic properties. As mentioned
above, when unsymmetrical N,N0-dialkylthioureas are
Table 1. Isothiocyanate transposition
S
R
S
N
Toluene
N
+
R
N
C
S
+
N
C S
N
N
105 oC
16 hrs
4
5
3
Entry
1
4
R
Amount (equiv)
3
5, Yielda (%)
5a, 90
4a
2
3
4
4b
4c
4d
3
3
3
5b, 95
5c, 93
5d, 92
Me
F
Cl
5
6
7
4e
4f
5
3
5
5e, 64
5f, 44
5g, 47b
Me
Cl
4g
Me
Me
8
9
4h
4i
4j
5
3
3
5h, 51
5i, 57
5j, 99
O
10
O
a Isolated yields.
b The products were inseparable from starting material through normal SiO2 TLC or column chromatography, and the yields were calculated by 1H
NMR ratio of starting material and products in the mixtures.

D. Shin et al. / Tetrahedron Letters 48 (2007) 3089–3092
3091
tuted benzyl isothiocyanates could be obtained in nearly
quantitative yields and the product was very stable, but
it took longer reaction times in order to complete the
reaction (reaction time; 32 h).
Me
Me
S
N
+
N
N=C=S
3
4a
In conclusion, we found novel isothiocyanate transposi-
tion of N,N0-dialkyl-2-imino-1,3-thiazole. In this reac-
tion, both alkyl and aryl isothiocyanates showed good
reactivities. The main advantages of this reaction are
that it is very easy to handle and deliver good chemical
yields. Moreover, transposition reaction provided a sim-
ple but excellent solution for regiochemical problem in
2-iminothiazole synthesis from unsymmetrical N,N0-
dialkylthioureas. The works on detailed scopes and lim-
itations of this reaction including 2-iminothiazoles with
various alkyl/aryl substituents are ongoing, and fruitful
results will be reported in the near future.
Me
Me
S
Me
S
N
N
N
N
S
N+
S-
Me
N
7
6
NCS
Me
Me
S
N
Me
Me
S
N
N-
N+
Typical procedure. To a solution of iminothiazole 3
(110 mg, 0.491 mmol) in anhydrous toluene (2.5 mL)
was added benzyl isothiocyanate 4a (0.199 mL,
1.47 mmol). After stirring at 105 °C for 16 h, the reac-
tion mixture was cooled and the solvent was evaporated
in vacuo. The residues were purified by SiO2 column
chromatography to afford desired product 5a (103 mg,
8
5a
Scheme 1. Possible transposition mechanism.
used in this ring formation reaction, bulky alkyl groups
take their positions at the imine nitrogen. So, we envi-
sioned that this problem could be solved by applying
our new transposition reaction. As a model substrate,
we prepared N,N0-dicyclohexyl iminothiazoline 9 from
symmetric bulky N,N0-dialkylthiourea and haloketone.
Under the established reaction condition, transposition
reactions were carried out with less bulkier alkyl isothio-
cyanates. As summarized in Table 2, the desired substi-
tuted iminothiazoles 10 with reverse regiochemistry were
obtained in good to excellent yields, which showed the
same reaction trend as the previous data. The substi-
1
90%). Yellowish solid, mp = 76.5 °C H NMR: d 7.35–
7.27 (m, 4H), 7.22–7.17 (m, 1H), 4.15 (s, 2H), 3.21 (s,
3H), 2.03 (s, 3H), 2.02 (s, 3H) 13C NMR: d 159.08,
141.845, 130.76, 128.76, 128.02, 126.95, 101.33, 57.84,
31.45, 12.63, 11.92; IR (KBr, cmꢁ1): 1646.9, 1578.7,
1424.2, 1365.3, 1351.7, 727.0. Mass (FAB+): m/z 233
[M+H]+; HRMS calculated for C13H17N2S: 233.1112.
Found: C13H17N2S: 233.1119 [M+H]+.
Acknowledgements
The authors wish to thank the Korea Institute of Science
and Technology for financial support of this work.
Table 2. Synthesis of reverse regiochemical product by isothiocyanate
transposition
S
S
N
R
N
Supplementary data
N
toluene
N
+
R N C S
105 oC, 32 hrs
4
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.02.084.
9
10
Amount (equiv) 9, Yielda (%)
Entry
4
R
References and notes
1
2
3
4
4a
4b
4c
4d
5
5
5
5
10a, 60
10b, 89
10c, 99
10d, 99
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F
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4e
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5
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10j, 87
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a Isolated yields.

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