Intermolecular alkyl/aryl exchange of 2-iminothiazoles with isothiocyanates and isocyanates: Scopes and limitations

Article abstract of DOI:10.1016/j.tet.2010.05.015

2-Iminothiazole an isoform of 2-aminothiazole, is a scaffold of synthetic and medicinal significance. We have reported an efficient method by which alkyl group of 2-alkyliminothiazoles is changed into other alkyl groups by isothiocyanates. In this article, a detailed mechanistic aspect, and the scopes and limitations were disclosed. All the reactions were carried out in toluene at 105 °C without any additive. The reaction is a reversible process and the equilibrium is determined by the reactivity of both reactants, in which the more electron-withdrawing alkyl or aryl groups at the 2-imino group or isothiocyanate showed higher reactivities. With this simple method, we effectively altered the alkyl group attached on the imine nitrogen. A synthetic problem in 2-iminothiazole chemistry, synthesis of amino acid-derived 2-iminothiazole was solved in a very simple manner. Using suitably designed 2-iminothiazole substrate, the electrophilic reactivity of various isothiocyanates could be empirically compared by this exchange reaction. Moreover, successful exchange reaction using isocyanates instead of isothiocyanates broadened the utility of this reaction.

Full text of DOI:10.1016/j.tet.2010.05.015

Tetrahedron 66 (2010) 5707e5713
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Intermolecular alkyl/aryl exchange of 2-iminothiazoles with isothiocyanates
and isocyanates: scopes and limitations
*
Dongyun Shin , Jihoon Lee, Hoh-Gyu Hahn
Life/Health Division, Korea Institute of Science and Technology, 39-1 Hawolgok-dong, Seongbuk-gu, Seoul 136-791, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Iminothiazole, an isoform of 2-aminothiazole, is a scaffold of synthetic and medicinal significance. We
have reported an efficient method by which alkyl group of 2-alkyliminothiazoles is changed into other
alkyl groups by isothiocyanates. In this article, a detailed mechanistic aspect, and the scopes and limi-
tations were disclosed. All the reactions were carried out in toluene at 105 ꢀC without any additive. The
reaction is a reversible process and the equilibrium is determined by the reactivity of both reactants, in
which the more electron-withdrawing alkyl or aryl groups at the 2-imino group or isothiocyanate
showed higher reactivities. With this simple method, we effectively altered the alkyl group attached on
the imine nitrogen. A synthetic problem in 2-iminothiazole chemistry, synthesis of amino acid-derived
2-iminothiazole was solved in a very simple manner. Using suitably designed 2-iminothiazole substrate,
the electrophilic reactivity of various isothiocyanates could be empirically compared by this exchange
reaction. Moreover, successful exchange reaction using isocyanates instead of isothiocyanates broadened
the utility of this reaction.
Received 19 March 2010
Received in revised form 3 May 2010
Accepted 4 May 2010
Available online 10 May 2010
Keywords:
Synthesis
Medicinal
Iminothiazole
Thiazole
Isothiocyanate
Isocyanate
Ó 2010 Published by Elsevier Ltd.
1. Introduction
Five-membered heterocycles are not only found in numerous
natural products, but also are widely used as valuable scaffolds in
medicinal chemistry and combinatorial chemistry.1 Among them, 2-
iminothiazole (1), isoform of 2-aminothiazole, is considered to be the
privileged structures for the drug discovery due to its inherent low
toxicities and good pharmacokinetic profiles, and their chemical di-
versity in substituents makes them very frequently utilized as a core
scaffold in the construction of chemical library as well (Fig. 1).2,3
2-Iminothiazole is generally prepared by the single step reaction
Figure 1. Structure of 2-iminothiazole.
thermal condition (Fig. 2).6 Herein, we would present the scope and
limitation of our novel finding on this exchange. With this new
exchange reaction, a synthetic problem in 2-iminothiazole chem-
istry, synthesis of amino acid-derived 2-iminothiazole was solved
in simple manner. Successful exchange reaction using isocyanates
instead of isothiocyanate is also addressed.
of thioureas and
a-halocarbonyls, where thioureas should be di-
substituted at both of the nitrogens. Unless substituents at the two
nitrogen are identical, there are two possible regiomers. The general
tendency of regiochemistry in the synthesis of 2-iminothiazole is that
the smaller substituent positions at the 3-nitrogen and the bulkier
one at the 2-imino nitrogen under neutral conditions, though acidity
of reaction solvent can lead to the regiomeric mixtures.4,5
Recently, novel finding of the aryl/alkyl exchange reaction be-
tween 2-iminothiazole and isothiocyanate was reported by us,
which describes that alkyl or aryl group at the 2-imino nitrogen of
2-iminothiazole is exchanged with R2 in the isothiocyanate under
* Corresponding author. Tel.: þ82 958 5143; fax: þ82 958 5189; e-mail address:
dyshin21@kist.re.kr (D. Shin).
Figure 2. Intermolecular alkyl/aryl exchange of 2-Iminothiazoles with Isothiocyanates.
0040-4020/$ e see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.05.015

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D. Shin et al. / Tetrahedron 66 (2010) 5707e5713
2. Results and discussion
resulting benzyl 2-iminothiazole 5, less reactive toward the first
addition step of cyclohexylisothiocyanate in this exchange (5/Int-
3). While we presented the stepwise process for the four-mem-
bered intermediate Int-3 from Int-2, direct [2þ2]-cycloaddition
mechanism is also possible. C-5 substituted product 6 was gener-
ated by the introduction of additional benzylisothiocyanate (3a).
Cyclohexylisothiocyanate was detected in reaction mixture by
GCeMS. It is obvious that this exchange reaction is highly affected
by the reactivity of alkylisothicyanate and the rearrangement pro-
cess is faster than C-5 alkylation of thiazole (vide infra).
2.1. Initial observation of novel exchange reaction
Initially, we focused our efforts on the expansion of our 2-imi-
nothiazole chemistry to functionalize the 5-position in 2-imino-
thiazole. We assumed that the 5-position in 2-iminothiazole might
be chemically activated due to its characteristics of an enamine.
Therefore, we envisioned that 5-position could be alkylated by
electrophiles with suitable reactivities. With structural features in
mind, testing material, 2-cyclohexylimino-3,4-dimethylthizoline
(2), was readily prepared by the condensation of 1-chloroacetone
and 2-N-cyclohexyl-3-N0-methylthiourea, which was subjected to
thiocarbamoylation with benzylisothiocyanate (3a) in toluene at
105 ꢀC. Through this experiment, we could isolate one major and
two minor products, along with a small amount of substrate. By 1H
NMR spectrum analysis and other spectra data, their structures
were able to be characterized, as shown in Scheme 1. One minor
compound proved to be the expected 2-iminothiazole 4, which was
the electrophilically substituted one at 5-carbon in 2-iminothiazole
by one molecule of isothiocyanate. However, the major product was
the completely unexpected 2-benzyliminothiazole 5, in which the
cyclohexyl group was substituted with the benzyl group, which is
originated from benzylisothiocyanate (3a). Another minor product
was 2-benzyliminothiazole 6, which underwent additional elec-
trophilic substitution at C-5 after a substitution of cyclohexyl with
benzyl at 2-imino position. From those results, in accordance with
our expectation, 5-carbon of 2-iminothiazole showed moderate
reactivity toward isothiocyanate to afford 5-substituted 2-imino-
thiazole (2/4). More importantly, a new alkyl exchange reaction
between 2-alkyliminothiazole and alkylisothiocyanate (3/5) was
found, where the 2-nitrogen of 2-iminothiazole exhibited un-
foreseen nucleophilicity toward the isothiocyanate electrophile.
2.3. Reaction scopes and limitations
In previous communication,6 we revealed our initial results on
this chemistry, which include optimization of reaction conditions
(solvents, temperature, and reaction time) and brief reaction ten-
dency using 2-cyclohexy-4,5-dimethyl-3-N-methyliminothiazole,
where the 5-position is substituted with methyl group in order to
block 5-acylation occurring in the reaction with alkylisothiocya-
nate. Toluene as a solvent, 13 h as reaction time, and 105 ꢀC as
reaction temperature was selected as an optimal condition.
In order to broaden the utility of this method, we devised more
complex substrates, such as 4-phenyl-5-methyl iminothiazole 7,
4-methoxycarbonylmethyl-5-phenyl iminothiazole 8, and 4-phe-
nyl-5-phenyl iminothiazole 9, which are C-4 and C5-derivatized
thiazoles instead of methyl group. The substrates can be simply
prepared by the established method in high yield. The exchange
reaction was carried out with two different isothiocyanates 3a and
3b. As depicted in Table 1, all chemical yields were good to excellent
though the reaction time was slightly longer than before. (entries
1e6). The 2-iminothiazole 8 possessing methoxycarbonylmethyl at
C-4, which has mild electron-withdrawing effect, was less reactive
than other substrates 7 and 9. Though any significant side reactions
Scheme 1. The reaction of alkyliminothiazoles with Benzylisothiocyanate.
2.2. Possible mechanism of isothiocyanate transposition
were not observed in the reaction of 8, a small portion of starting
material was not completely consumed (entries 2 and 5).
A possible mechanism is illustrated in Scheme 2. Path A, leading
to only C-5 substituted compound 4, proceeded through direct al-
kylation (Int-1) of enamine by isothiocyanate, followed by re-aro-
matization-type isomerization. In Path B, all the steps from
substrate 2 to compound 5 are thought to be reversible, and the
force driving the process to completion is the difference of relative
reactivity of two imino nitrogens (2 and 5), and alkylisothiocya-
nates (3a) and cyclohexylisothiocyanate. Larger electron-with-
drawing effect of benzyl group than cyclohexyl, makes
benzylisothiocyanate (3a) more reactive (2/Int-2), and the
It was expected that the relative reactivities of alkyl/aryl iso-
thiocyanates could be revealed by the chemical yields of this
reaction (Table 2). For this purpose, two model substrates, 2-(2,4-
dimethoxy)phenyliminothiazole 13 and 2-phenyliminothiazole 14
were prepared. Based on the previous results, substrate 13 was
expected to have higher reactivity to this exchange than substrate
14 due to its electron-rich characteristic of phenyl group. Entries
1e4 presents the chemical yields of exchange reaction of four
benzyl and substituted benzylisothiocyanates. Among them, p-
Fluorobenzylisothiocyanate showed the highest reactivity (87%),

D. Shin et al. / Tetrahedron 66 (2010) 5707e5713
5709
Scheme 2. A plausible mechanism.
Table 1
Alkyl exchange of diversified 2-cyclohexyliminothiazoles with benzylisothiocyanate
and ethyl isothiocyanatoacetate
Table 2
Comparison of relative reactivities of various isothiocyanates by chemical yields
Entrya
Thiazole
R
Product
Yieldb (%)
1
2
3
7
8
9
Benzyl (3a)
10a
11a
12a
92
65
98
4
5
6
7
8
9
EtO2CCH2 (3b)
10b
11b
12b
92
73
99
Entrya
Substrate
3 (R0)
Product
Yieldb (%)
a
In all reactions, 3 equiv of isothiocyanates 3 were used, and the reactions were
1
2
3
4
5
6
7
8
9
13
13
13
13
13
13
13
13
14
3a (C6H5CH2)
15a
15c
15d
15e
15f
15g
15h
15i
67
35
87
75
10
55
23
90
NRc
conducted for 13 h.
3c (p-MeeC6H4CH2)
3d (p-FeC6H4CH2)
3e (o-CleC6H4CH2)
3f (Methyl)
3g (ClCH2CH2)
3h (Isopropyl)
3i (4-EteC6H4)
3i (4-EteC6H4)
b
Purified yields after silica gel chromatography.
and the order of yields was p-chlorobenzylisothiocyanate (75%),
benzylisothiocyanate (65%) p-methylbenzylisothiocyanate (35%).
And, in accordance with our assumption, the 4-ethyl-
phenylisothiocyanate (3h), which is considered to have its re-
activity between the 2,4-dimethoxyphenylisothiocyanate 13 and
phenylisothiocyanate 14, showed great reactivity differences to-
ward two 2-iminothiazole substrates. (90% in 13, 0% in 14, re-
spectively) In the case of 2-(2,4-dimethoxy)phenyliminothiazole
15i
a
In all reactions, 3 equiv of isothiocyanates 3 were used, and the reactions were
conducted for 20 h.
b
Purified yields after silica gel chromatography.
No reaction.
c

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D. Shin et al. / Tetrahedron 66 (2010) 5707e5713
13, the isolated yield was 90%, while any isolable product was not
obtained for 2-phenyliminothiazole 14 (Table 2, entries 7 and 8).
Alkylisothiocyanates 3feh revealed low reactivity toward this ex-
change reaction. Those results imply that this reaction can give an
empirical comparison of the relative reactivity of isothiocyanates
using suitable 2-iminothiazole substrate. This result further sup-
ports that the electronic effect is very important in this reaction.
Next, we turned our attention toward applying our novel
method in solving some synthetic problems in thiourea prepara-
tion in 2-iminothiazole chemistry. Since amino acids are common
precursor or building block in medicinal chemistry, amino acid-
derived thiourea, therefore, can be used as a useful reagent for
2-iminothiazole synthesis.
were carried out under the same conditions as above. In accordance
with our expectation, all reactions were successful with good to
excellent yields, as summarized in Table 3. The reaction tendency
shows that smaller (3j) and more electropositive (3l) iso-
thiocyanate give higher yields. And also, all the products of this
exchange reaction using chiral amino acid-derived isothiocyanates
were optically active.
2.4. Exchange reaction using isocyanate
Isocyanates are common alternatives for isothiocyanates in me-
dicinal chemistry. Both species usually show similar reactivity toward
nucleophiles. Therefore, we envisioned that isocyanates would par-
ticipate in this exchange reaction. We carried out reactions with
several isocyanates under the same conditions as the isothiocyanate
reaction (Table 4). As shown in entries 1e4, alkyl exchanges of
2-cyclohexyliminothiazole with alkylisocyanates 19 were successful,
and desired products were obtained in high yields without any side
reactions. It is noteworthy that chloroethylimino compound 15g was
gained from 2-chloroethylisocyanate (20g) in much higher yield
(88%) than from the chloroethylisothicyanate. However, the reaction
with phenyl isocyanate delivered only indefinable products (entry 5).
The amino acid-derived 2-iminothizole is expected to be obtained
by the reaction of a-haloketone with amino acid-derived thiourea;
however, as illustrated in Scheme 3, when amine reacts with amino
acid-derived isothiocyanate for the synthesis of thiourea, the reaction
doesn’t stop at thiourea 17, but proceeds to cyclization to the 2-thi-
oxoimidazolidin-4-one20.7 It isnoteasytopreparethevariousamino
acid-derived thioureas, and as a consequence, amino acid-derived 2-
iminothiazole cannot be readily synthesized. Our new exchange
method can provide a solution for this problem.
Scheme 3. Reaction of amine and amino acid-derived isothiocyanate with amine.
As shown in Table 1, entries 4e6, ethyl 2-isothiocyanatoacetate
derived from glycine exhibited an excellent reactivity toward this
exchange reaction. This result can easily be explainable because
methoxycarbonylmethyl group has an electron-withdrawing effect
on the isothiocyanate moiety. With commercially available amino
acid-derived isothiocyanate 3j, 3k, and 3l, the exchange reactions
3. Conclusion
We found a new reactivity-driven isothiocyanate exchange of
2-iminothiazole. Through our experiments, the reaction tendency
that electronic effect of substrates and alkylisothiocyanates is the
most significant factor in this reaction, and reaction scopes were
Table 3
Application of alkyl exchange to the reactions with isothiocyanates derived from amino acids
Entrya
3
Reaction time
Product
Yieldb (%)
1
2
3
3j
3k
3l
20 h
20 h
20 h
15j
15k
15l
70
66
88
a
In all reactions, 3 equiv of isothiocyanates 3 were used.
Purification yield after silica gel chromatography.
b

D. Shin et al. / Tetrahedron 66 (2010) 5707e5713
5711
designated time in the text). After stirring at 105 ꢀC for 13 h (or the
designated time in the text), the reaction mixture was cooled and
the solvent was evaporated in vacuo. The residues were purified by
SiO2 column chromatography to afford a desired product.
Table 4
Alkyl exchange reaction of 2-iminothiazole with alkylisocyanates
4.3.1. N-(3,5-Dimethyl-4-phenylthiazol-2(3H)-ylidene)(phenyl)
methanamine (10a). Yield: 92%, yellowish oil; 1H NMR (300 MHz,
DMSO-d6):
d 7.52e7.46 (m, 5H), 7.41e7.36 (m, 2H), 7.33e7.28 (m,
Entrya
20
R
Product
Yieldb (%)
3H), 4.47 (s, 2H), 3.22 (s, 3H), 2.04 (s, 3H); 13C NMR (75 MHz,
1
2
3
4
5
20a
20b
20e
20g
20o
C6H5CH2
15a
15b
15e
15g
NR
83
99
88
95
d
CDCl3):
d 160.7, 141.0, 135.5, 131.0, 130.3, 129.1, 129.0, 128.6, 128.0,
EtO2CCH2
o-CleC6H4CH2
2-chloroethyl
Phenyl
126.9, 106.5, 58.1, 33.6, 13.1; IR (KBr, cmꢁ1): 2920, 1598, 1497, 1367,
1293, 1120, 701. Mass (FABþ): m/z 295 [MþH]þ; HRMS calculated
for C18H19N2S: 295.1269; found:C18H19N2S:295.1262 [MþH]þ.
a
In all reactions, 3 equiv of isocyanates 20 were used, and the reaction time was
13 h.
b
4.3.2. Ethyl 2-(2-(benzylimino)-2,3-dihydro-3,5-dimethylthiazol-4-
Purified yields after silica gel chromatography.
yl)acetate (11a). Yield: 65%, yellowish oil; 1H NMR (300 MHz,
disclosed. And also, we were able to establish reaction mechanism,
in which all the exchange processes are thought to be reversible.
Synthetic problem in 2-iminothiazole chemistry, synthesis of amino
acid-derived 2-iminothiazole, was solved by using this exchange
reaction, where it was unnecessary to prepare the amino acid-de-
rived thioureas. We showed an empirical method of comparing the
relative reactivities of isothiocyanates. Moreover, successful
exchange reaction using isocyanates broadened the utility of this
reaction. Our current efforts are ongoing to apply this method to
solid-phase synthesis of more diversified 2-iminothiazoles.
DMSO-d6):
d 7.45e7.43 (m, 2H), 7.37e7.32 (m, 2H), 7.28e7.25 (m,
1H), 4.37 (s, 2H), 3.76 (s, 3H), 3.49 (s, 2H), 3.38 (s, 3H), 2.13 (s, 3H);
13C NMR (75 MHz, CDCl3):
d 169.6, 160.2, 140.9, 128.5, 127.9, 126.8,
126.7, 107.3, 57.9, 52.8, 31.8, 31.6, 12.6; IR (KBr, cmꢁ1): 2922, 1740,
1611, 1433, 1337, 1170, 721. Mass (FABþ): m/z 305 [MþH]þ.
4.3.3. N-(3-Methyl-4,5-diphenylthiazol-2(3H)-ylidene)(phenyl)meth-
anamine (12a). Yield: 98%, yellowish oil; 1H NMR (300 MHz, DMSO-
d6):
7.38e7.35 (m, 2H), 7.32e7.30 (m, 1H), 7.19e7.15 (m, 3H), 7.09e7.06
(m, 2H), 4.55 (s, 2H), 3.27 (s, 3H); 13C NMR (75 MHz, CDCl3):
159.2,
d 7.58e7.56 (m, 2H), 7.51e7.48 (m, 3H), 7.45e7.41 (m, 2H),
d
4. Experimental section
4.1. General
141.1, 135.8, 133.0, 131.8, 130.7, 129.6, 129.5, 128.6, 128.0, 128.0, 126.9,
126.8, 110.9, 58.4, 33.1; IR (KBr, cmꢁ1) 3430, 2905, 1623, 1418, 1360,
726. Mass (FABþ): m/z 357 [MþH]þ; HRMS calculated for C23H21N2S:
357.1425; found:C23H21N2S: 357.1427 [MþH]þ.
All Isothiocyanates and isocyanates reaction with 2-alkyl/aryl
iminothiazoles was performed a following reaction procedure. The
equivalent of Isothiocyanates and isocyanates and the reaction time
are presented in the text or tables.
4.3.4. Ethyl 2-(3,5-dimethyl-4-phenylthiazol-2(3H)-ylideneamino)
acetate (10b). Yield: 92%, yellowish oil; 1H NMR (300 MHz, DMSO-
d6):
d
7.47e7.39 (m, 3H), 7.23e7.20 (m, 2H), 4.21 (q, J¼6.9 Hz, 2H),
3.97 (s, 2H), 3.10 (s, 3H), 1.95 (s, 3H), 1.27 (t, J¼6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3):
d 171.6, 162.6, 135.6, 130.8, 130.2, 129.1, 120.0,
4.2. General information
106.5, 61.0, 55.9, 33.4, 14.5, 13.0; IR (KBr, cmꢁ1): 2915, 1750, 1634,
1603, 1330, 1183. Mass (FABþ): m/z 291 [MþH]þ; HRMS calculated
for C15H19N2O2S: 291.1167; found: C15H19N2O2S: 291.1162 [MþH]þ.
All reactions were carried out using oven-dried glassware, and
all solvents and commercially available chemicals were used
without additional purification. For thin-layer chromatography
4.3.5. Ethyl 2-(2-(ethoxycarbomethylimino)-2,3-dihydro-3,5-dime-
(TLC) analysis, Merck precoated TLC plate (silica gel 60 GF245
,
thylthiazol-4-yl)acetate (11b). Yield: 73%, yellowish oil; 1H NMR
0.25 mm) were used. For flash column chromatography, Merck
Kieselgel 60 (70e230 mesh) was used. Yields refer to purified and
spectroscopically pure compounds. All melting points were mea-
sured in open capillaries and are uncorrected. Infrared (IR) spectra
were recorded on a Fourier Transform Infrared Spectrometer and
(300 MHz, DMSO-d6):
d
4.13 (q, J¼7.2 Hz, 2H), 3.84 (s, 2H), 3.64 (s,
3H), 3.38 (s, 2H), 3.23 (s, 3H), 2.02 (s, 3H), 1.20 (t, J¼7.2 Hz, 3H); 13C
NMR (75 MHz, CDCl3):
d 171.6, 169.4, 162.0, 126.8, 107.3, 61.0, 55.8,
52.8, 31.6, 31.6, 14.5, 12.5; IR (KBr, cmꢁ1): 2980, 1749, 1733, 1606,
1416, 1260, 1181. Mass (FABþ): m/z 300 [MþH]þ.
were reported as wavenumbers (n
, cmꢁ1). Nuclear magnetic reso-
nance (1H NMR and 13C NMR) spectra were measured on 300 MHz
spectrometer operating 300 MHz for 1H nuclei and 75 MHz for 13C,
using DMSO-d6 or CDCl3 as solvents, and their spectra were
4.3.6. Ethyl 2-(3-methyl-4,5-diphenylthiazol-2(3H)-ylideneamino)
acetate (12b). Yield: 99%, yellowish oil; 1H NMR (300 MHz, DMSO-
d6):
d 7.44e7.41 (m, 3H), 7.29e7.26 (m, 2H), 7.15e7.08 (m, 3H),
reported in parts per million relative to DMSO (
7.24) for 1H NMR and relative to the central DMSO-d6
CDCl3 (
77.23) resonance for 13C NMR. 1H NMR data is reported as
chemical shift, relative integral, multiplicity (s, singlet; d, doublet;
dd, doublet of doublets; dq, doublet of quartets; t, triplet; m,
multiplet; br s, broad singlet), and coupling constants (J) in 1H NMR
are in hertz.
d
2.50) or CHCl3
(d
7.01e7.6.98 (m, 2H), 4.27 (q, J¼6.9 Hz, 2H), 4.09 (s, 2H), 3.19 (s, 3H),
(d
39.51) or
1.33 (t, J¼6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 171.5, 161.5,
d
135.8, 132.6, 131.5, 130.6, 129.6, 129.4, 128.6, 128.0, 126.9, 111.2, 61.1,
56.0, 33.1, 14.6; IR (KBr, cmꢁ1): 2815, 1747, 1615, 1594, 1417, 1361,
1174. Mass (FABþ): m/z 353 [MþH]þ; HRMS calculated for
C20H21N2O2S: 353.1324; found: C20H21N2O2S: 353.1315 [MþH]þ.
4.3.7. Phenyl-N-(3,4,5-trimethylthiazol-2(3H)-ylidene)methanamine
4.3. General procedure
(15a). Yield: 67% from 13; 83% from 19, yellowish solid, mp:
76e77 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
7.35e7.27 (m, 4H),
7.22e7.17 (m, 1H), 4.15 (s, 2H), 3.21 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H);
13C NMR (75 MHz, DMSO-d6):
159.1,141.8,130.8,128.8,128.0,126.9,
To a solution of iminothiazole (1 equiv) in anhydrous toluene
(0.3 M) was added isothiocyanate or isocyanate (3 equiv or the
d

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D. Shin et al. / Tetrahedron 66 (2010) 5707e5713
101.3, 57.8, 31.5, 12.6, 11.9; IR (KBr, cmꢁ1): 2922, 1646, 1578, 1424,
1365,1351, 727. Mass (FABþ): m/z 233 [MþH]þ; HRMS calculated for
C13H17N2S: 233.1112; found: C13H17N2S: 233.1119 [MþH]þ.
111.4, 53.7, 35.9, 21.7, 12.3, 11.9; IR (KBr, cmꢁ1): 2842, 1597, 1374,
1154, 719. Mass (FABþ): m/z 185 [MþH]þ; HRMS calculated for
C9H17N2S: 185.1112; found: C9H17N2S: 185.1111 [MþH]þ.
4.3.15. 4-Ethyl-N-(3,4,5-trimethylthiazol-2(3H)-ylidene)benzen-
amine (15i). Yield: 90%, yellowish solid, mp: 82e83 ꢀC; 1H NMR
4.3.8. Ethyl
2-(3,4,5-trimethylthiazol-2(3H)-ylideneamino)acetate
(15b). Yield: 99%, yellowish solid, mp: 44e45 ꢀC; 1H NMR
(300 MHz, DMSO-d6):
d
7.09 (d, J¼8.4 Hz, 2H), 6.83 (d, J¼8.4 Hz,
(300 MHz, CDCl3):
d
4.16 (q, J¼7.2 Hz, 2H), 3.88 (s, 2H), 3.27 (s, 3H),
2H), 3.29 (s, 3H), 2.51 (q, J¼7.5 Hz, 2H), 2.04 (s, 3H), 2.00 (s, 3H),
2.01 (s, 3H), 1.96 (s, 3H), 1.24 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz,
1.18e1.13 (t, J¼7.5 Hz, 3H); 13C NMR (75 MHz, DMSO-d6):
d 158.4,
CDCl3): d 171.7, 162.9, 130.0, 103.2, 61.0, 55.6, 31.5, 14.5, 12.4, 11.9; IR
150.1, 138.0, 130.4, 129.2, 121.7, 101.7, 31.9, 28.3, 13.5, 12.35, 12.0; IR
(KBr, cmꢁ1): 1961, 1591, 1504, 1333, 838. Mass (FABþ): m/z 247
[MþH]þ; HRMS calculated for C14H19N2S: 247.1269; found:
C14H19N2S: 247.1272 [MþH]þ.
(KBr, cmꢁ1): 1917, 1750, 1605, 1403, 1193, 1030. Mass (FABþ): m/z
229 [MþH]þ; HRMS calculated for C10H17N2O2S: 229.1011; found:
C10H17N2O2S:229.1006 [MþH]þ.
4.3.16. Methyl 2-(3,4,5-trimethylthiazol-2(3H)-ylideneamino)prop-
4.3.9. p-Tolyl-N-(3,4,5-trimethylthiazol-2(3H)-ylidene)methanamine
anoate (15j). Yield: 70%, yellowish oil; 1H NMR (300 MHz, CDCl3):
(15c). Yield: 35%, yellowish solid, mp: 80e81 ꢀC; 1H NMR
d
3.75e3.68 (m, 1H), 3.68 (s, 3H), 3.28 (s, 3H), 2.02 (d, J¼0.9 Hz, 3H),
(300 MHz, DMSO-d6):
d
7.21e7.18 (d, J¼8.1 Hz, 2H), 7.10e7.07 (d,
1.96 (d, J¼0.9 Hz, 3H), 1.45 (d, J¼6.6 Hz, 3H); 13C NMR (75 MHz,
J¼8.1 Hz, 2H), 4.11 (s, 2H), 3.02 (s, 3H), 2.26 (s, 3H), 2.02 (s, 3H), 2.00
(s, 3H); 13C NMR (75 MHz, DMSO-d6):
d
159.2, 138.6, 135.9, 130.8,
CDCl3): d 174.8, 161.3, 129.6, 102.6, 62.4, 52.2, 31.6, 19.5, 12.4, 11.8; IR
(KBr, cmꢁ1): 2947, 1742, 1588, 1324, 1136. Mass (FABþ): m/z 229
[MþH]þ; HRMS calculated for C10H17N2O2S: 229.1011; found:
C10H17N2O2S: 229.1015 [MþH]þ.
129.3, 128.0, 101.7, 57.4, 21.40, 12.6, 11.9; IR (KBr, cmꢁ1): 2919, 1607,
1418,1359, 797. Mass (FABþ): m/z 247 [MþH]þ; HRMS calculated for
C14H19N2S: 247.1269; found: C14H19N2S: 247.1272 [MþH]þ.
4.3.17. Methyl
methylpentanoate (15k). Yield: 66%, yellowish oil; 1H NMR
(300 MHz, CDCl3): 3.67 (s, 3H), 3.65e3.60 (m, 1H), 3.27 (s, 3H),
2.02 (s, 3H), 1.96 (s, 3H), 1.78e1.66 (m, 3H), 0.88 (dd, J¼21.9, 6.0 Hz,
2-(3,4,5-trimethylthiazol-2(3H)-ylideneamino)-4-
4.3.10. 4-Fluorophenyl-N-(3,4,5-trimethylthiazol-2(3H)-ylidene)
methanamine (15d). Yield: 87%, yellowish solid, mp: 90e91 ꢀC; 1H
d
NMR (300 MHz, DMSO-d6):
4.12 (s, 2H), 3.20 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H); 13C NMR (75 MHz,
DMSO-d6):
d 7.38e7.33 (m, 2H), 7.10e7.07 (m, 2H),
6H); 13C NMR (75 MHz, CDCl3):
d 174.7, 161.2, 129.5, 102.4, 65.9,
d
160.9 (d, J¼239 Hz), 137.2 (d, J¼3 Hz), 130.1, 129.97 (d,
52.0, 43.4, 31.6, 25.1, 23.4, 22.2,12.4,11.8; IR (KBr, cmꢁ1): 2953,1745,
1600, 1349, 1143. Mass (FABþ): m/z 271 [MþH]þ; HRMS calculated
for C13H23N2O2S: 271.1480; found: C13H23N2O2S: 271.1487 [MþH]þ.
J¼8 Hz), 114.7 (d, J¼21 Hz), 100.4, 56.1, 30.7, 11.9, 11.15; IR (KBr,
cmꢁ1): 2920, 1598, 1507, 1408, 1222, 857. Mass (FABþ): m/z 251
[MþH]þ; HRMS calculated for C13H16N2SF: 251.1018; found:
C13H16N2SF: 251.1016 [MþH]þ.
4.3.18. Methyl
phenylpropanoate (15l). Yield: 88%; 1H NMR (300 MHz, DMSO-d6):
7.29e7.21 (m, 5H), 3.66e3.60 (m, 1H), 3.53 (s, 3H), 3.11 (s, 3H),
3.11e3.04 (m, 1H), 2.92e2.85 (m, 1H), 1.96 (s, 3H), 1.95 (s, 3H); 13C
2-(3,4,5-trimethylthiazol-2(3H)-ylideneamino)-3-
4.3.11. 2-Chlorophenyl-N-(3,4,5-trimethylthiazol-2(3H)-ylidene)
d
methanamine (15e). Yield: 75% from 13; 88% from 19, yellowish
solid, mp: 88e89 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
7.61e7.58 (m,
1H), 7.42e7.39 (m, 1H), 7.34e7.32 (m, 2H), 4.18 (s, 1H), 3.26 (s, 3H),
2.04e2.03 (d, 1.5, 6H); 13C NMR (75 MHz, DMSO-d6):
159.8, 138.9,
NMR (75 MHz, CDCl3): d 173.1,160.7,139.0,130.7,129.9, 128.8, 126.9,
101.7, 69.4, 52.2, 40.4, 31.5, 12.4, 11.9; IR (KBr, cmꢁ1): 2922, 1745,
1589, 1416, 1207, 704. Mass (FABþ): m/z 305 [MþH]þ; HRMS cal-
culated for: C16H21N2O2S: 305.1324; found: C16H21N2O2S: 305.1329
[MþH]þ.
d
132.8, 130.9, 129.8, 129.5, 128.7, 127.7, 101.7, 55.2, 31.5, 12.58, 11.9; IR
(KBr, cmꢁ1): 2922, 1602, 1417, 1351, 1050, 747. Mass (FABþ): m/z 267
[MþH]þ; HRMS calculated for C13H16N2SCl: 267.0723; found:
C13H16N2SCl: 267.0715 [MþH]þ.
Acknowledgements
4.3.12. N-(3,4,5-Trimethylthiazol-2(3H)-ylidene)methanamine
This work is supported by Korea Institute of Science and Tech-
nology (KIST).
(15f). Yield: 10%, yellowish oil; 1H NMR (300 MHz, DMSO-d6):
d
3.11 (s, 3H), 2.08 (s, 3H), 2.01 (s, 3H), 1.98 (s, 3H); 13C NMR
(75 MHz, DMSO-d6):
d 167.5, 135.0, 111.8, 34.4, 33.6, 12.1, 11.8; IR
Supplementary data
(KBr, cmꢁ1): 2981, 2833, 1617, 1404. Mass (FABþ): m/z 157 [MþH]þ;
HRMS calculated for C7H13N2S: 157.0799; found: C7H13N2S:
157.0796 [MþH]þ.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.05.015. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
4.3.13. 2-Chloro-N-(3,4,5-trimethylthiazol-2(3H)-ylidene)ethan-
amine (15g). Yield: 55% from 13; 95% from 19, yellowish solid, mp:
100e102 ꢀC; 1H NMR (300 MHz, CDCl3):
d
3.72 (t, J¼6.9 Hz, 2H),
References and notes
3.75e3.70 (2H, J¼6.9 Hz, 2H), 3.45e3.41 (s, 3H), 2.06 (s, 3H), 2.00 (s,
3H); 13C NMR (75 MHz, CDCl3):
d 161.8, 130.0, 103.7, 56.0, 44.5, 31.8,
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