Intramolecular nucleophilic substitution at an sp2 carbon: synthesis of substituted thiazoles and imidazole-2-thiones

Article abstract of DOI:10.1016/j.tetlet.2008.12.118

The nucleophilic substitution reactions of vinylic bromides with intramolecular thioamide or thiourea moieties proceed to give a series of substituted thiazoles and imidazole-2-thiones.

Full text of DOI:10.1016/j.tetlet.2008.12.118

Tetrahedron Letters 50 (2009) 3161–3163
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Intramolecular nucleophilic substitution at an sp2 carbon: synthesis
of substituted thiazoles and imidazole-2-thiones
Shu-Su Shen, Mao-Yi Lei, Yun-Xuan Wong, Mun-Ling Tong, Priscilla Lu-Yi Teo,
*
Shunsuke Chiba, Koichi Narasaka
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
The nucleophilic substitution reactions of vinylic bromides with intramolecular thioamide or thiourea
moieties proceed to give a series of substituted thiazoles and imidazole-2-thiones.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 15 December 2008
Revised 19 December 2008
Accepted 19 December 2008
Available online 11 January 2009
Keywords:
Intramolecular nucleophilic substitution
Vinylic substitution
Thiazoles
Imidazole-2-thiones
Concerted nucleophilic substitution reactions at sp3 atoms are
commonly encountered in mechanistic and synthetic organic
chemistry. Although such a substitution reaction at a vinylic sp2
carbon of unactivated vinyl halides rarely occurs, some examples
were reported recently. For examples, 2-bromoallylamines were
cyclized to aziridines by base treatment, and the stereospecificity
of the cyclization reaction suggested that amino group approached
from the backside of the C–Br bond.1 Ochiai et al. published the
intermolecular vinylic substitution reactions of vinyl iodonium
salts,2 in which the products were formed with inversion of the
stereochemistry.
We have also reported nucleophilic substitution reactions of
unactivated vinylic halides.3 That is, various haloalkenes bearing
intramolecular alcohol, sulfonamide, active methine, and thiol
moieties at the suitable position gave the corresponding five-mem-
bered ring compounds by treatment with base.3a We were partic-
ularly interested in the substitution with a thiol moiety, and it was
recently found that unique four-membered ring compounds, 2-
alkylidenethietanes could be prepared by the cyclization of S-acet-
yl 3-bromo-3-alkenethiols (Scheme 1).3b
compounds with thioamide and the Gabriel synthesis,6 in which
the -(acylamino)ketones react with P4S10 or Lawesson’s reagent.
It was supposed that this intramolecular nucleophilic substitution
reaction would provide another unique method to prepare 2,5-
disubstituted thiazoles by an intramolecular cyclization of N-2-
bromoalk-2-enylthioamides (Scheme 2).
When N-(2-bromo-prop-2-enyl)benzothioamide (1a) was trea-
ted with potassium carbonate in N,N-dimethylformamide (DMF)
at 80 °C, 5-methyl-2-phenylthiazole (2a) was obtained in 79% yield
(Scheme 3), which suggested that five-membered ring closure (S-
attack) was preferred over three-membered ring formation (N-
attack).
As the above substitution reaction proceeded smoothly, gener-
ality of the cyclization of various N-(2-bromoprop-2-enyl)thioam-
ides 1 was investigated under the same reaction conditions, and
the results are summarized in Table 1.7 The cyclization was found
a
O
1.5 mol equiv. K2CO3
S
S
Me
Ph
10 mol equiv. MeOH
These findings had prompted us to examine the synthesis of
2,5-disubstituted thiazoles by the cyclization of N-2-bromoalk-2-
enylthioamides. There have been some synthetic approaches4 of
2,5-disubstitued thiazoles, mainly by condensation reactions, such
Br
Ph
Br
DMI (degassed)
120 ºC, 1.5 h
as Hantzsch synthesis5 via the cyclocondensation of
a-halocarbonyl
S
Ph
93%
* Corresponding author. Tel.: +65 6316 8900; fax: +65 6791 1961.
E-mail address: narasaka@ntu.edu.sg (K. Narasaka).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.118

3162
S.-S. Shen et al. / Tetrahedron Letters 50 (2009) 3161–3163
1g (entry 7, 35% yield) gave the products in low yields due to the
R2 R2
R2 R2
R2 R2
instability of the starting materials even though CsF was utilized
as a base instead of K2CO3. Take entry 7, for example, 1,2-diph-
enyldisulfide that was isolated as a by-product, which suggested
the elimination of benzenethiol from 1g. Generally, the initially
formed 4,5-dihydrothiazoles 3 were isomerized to five-substituted
thiazole. Only in the reaction of a thioamide having a terminal
disubstituted vinyl moiety, N-(2-bromo-3-methylbut-2-enyl)ben-
zothioamide (1h) (entry 8), dihydrothiazole 3h (59% yield) was
obtained as a major product with 15% yield of thiazole 2h. When
N-4-aryloxy-2-bromobutenylthioamide 1i was treated with
K2CO3 (entry 9), 5-vinylthiazole 2j was obtained with the elimina-
tion of 4-bromophenol. Bicyclic thiazole 2j was successfully pre-
pared from 1j in 75% yield (entry 10).
Thus, thiazoles bearing a variety of substituents such as ali-
phatic, aromatic, heterocyclic, or alkenyl groups were prepared
from N-2-bromoalk-2-enylthioamides. We then turned our atten-
tion to the cyclization of N-2-bromoalk-2-enylthioureas. When
N-2-bromoalk-2-enyl-N0-phenylthiourea 1k was treated with
K2CO3, 2-aminothiazole 2k and 1,5-disubstituted imidazole-2-thi-
one 4k were isolated in 14% and 41% yields, respectively (Scheme
4). This result demonstrated the competition reactions between S-
and N-nucleophiles.
base
H
N
R1
R1
R1
N
R1
N
Br
Br
Br
S
S
S
1
N
S
N
S
R1
R2
R2
R2
R2
3
2
Scheme 2.
N
S
H
N
1.5 mol equiv. K2CO3
DMF, 80 ºC
Ph
Ph
Br
Me
S
1a
2a 79%
Scheme 3.
to proceed smoothly in most cases, affording the corresponding
2,5-disubstituted thiazoles in good yields (entries 1–5). Notably,
acetylenic thioamide 1f (entry 6, 23% yield) and dithiocarbamate
Imidazole-2-thiones and its derivatives have received atten-
tions because of their bioactivities and application for pharmaceu-
tical synthesis. The Marckward method8 has long been known as a
general synthetic tool, which has been modified into a one-pot
fashion9 in 1997. They could be also prepared by the condensa-
tion10 between thioureas and 3-hydroxy-2-butanones in boiling
1-hexanol. Although many synthetic methods11 have been re-
ported on the formation, here, we described the first intramolecu-
lar vinylic substitution to approach them.
To control the chemoselectivity of the cyclization of thiourea
derivatives, we prepared two types of N,N0-trisubstituted thioureas
1l and 1m. As shown in Scheme 5, when the terminal nitrogen has
two substituents such as 1l, azirine 5 was obtained although the
yield was not good (Scheme 5a). It was noted that 1,3,4-trisubsti-
Table 1
Synthesis of substituted thiazoles 2a
Entry
Thioamides 1
Thiazoles 2 (yield%)b
H
H
N
H
N
R1
R1
Br
S
Me
S
1
2
3
1a: R1 = Ph
1b: R1
1c: R1 = n-C10H21
2a (79)
2b (83)
2c (68)
=
Ph
4
1d: R1
=
=
2d (76)
S
5
6
7
1e: R1
1f: R1
2e (74)
2f (23)
2g (35)c
H
N
S
O
N
2k 14%
4k 41%
=
Ph
Ph
Me
Me
H
N
H
N
1.5 mol equiv. K2CO3
DMF, 80 ºC
+
1g: R1 = SPh
Ph
Br
H
N
S
N
S
1k
Ph
S
Me
Me
8
Me
Me
N
2h (15)
H
Ph
N
Ph
Br
N
S
Scheme 4.
Ph
1h
Me
Me
S
3h (59)
Br
Me
N
N
N
Ph
Me
O
9
H
N
S
S
Me
N
5 28%
H
N
1.5 mol equiv. K2CO3
DMI, 120 ºC
Cl
Br
Ph
2i (70)e
Br
1id
Cl
S
Me
S
N
2l trace
N
H
N
1l
N
Ph
S
Me
Ph
10
(a)
Ph
S
S
2j (75)f
Br
1j
Me
Me
a
Me
Me
Reaction conditions unless otherwise noted: treatment of
(1.5 mol equiv) in DMF at 80 °C.
Isolated yield.
1
with K2CO3
1.5 mol equiv. K2CO3
DMF, 80 ºC
N
H
4m 78%
S
b
c
d
e
f
N
N
Br
Ph
N
Ph
Me
CsF (1.5 mol equiv) was used instead if K2CO3.
S
A single stereoisomer was used. Stereochemistry (E or Z) was not determined.
4-Bromophenol was detected from the crude mixtures.
K2CO3 (3.0 mol equiv) was used.
1m
(b)
Scheme 5.

S.-S. Shen et al. / Tetrahedron Letters 50 (2009) 3161–3163
3163
Table 2
5. (a) Bailey, N.; Dean, A. W.; Judd, D. B.; Middlemiss, D.; Storer, R.; Watson, S. P.
Bioorg. Med. Chem. Lett. 1996, 6, 1409; (b) Aitken, K. M.; Aitken, R. A.
Tetrahedron 2008, 64, 4384.
6. (a) Caballero, A.; Lloveras, V.; Curiel, D.; Tárraga, A.; Espinosa, A.; García, R.;
Vidal-Gancedo, J.; Rovira, C.; Wurst, K.; Molina, P.; Veciana, P. Inorg. Chem.
2007, 46, 825; (b) Thomsen, I.; Pedersen, U.; Rasmussen, P. B.; Yde, B.;
Andersen, T. P.; Lawesson, S. O. Chem. Lett. 1983, 809.
7. Typical procedure for 2-(furan-2-yl)-5-methylthiazole (2e): To a solution of N-(2-
bromoprop-2-enyl)furan-2-carbothioamide (1e) (100 mg, 0.41 mmol) in DMF
(20 mL) was added K2CO3 (84 mg, 0.61 mmol), and the mixture was stirred at
80 °C for 17 h. After the completion of the reaction, the mixture was quenched
with a pH 9 ammonium buffer solution, and extracted with diethyl ether
(10 mL ꢀ 3), the combined extracts were washed by brine and dried over
MgSO4. The solvent was removed in vacuo, and the resulting crude was purified
by PTLC (silica gel; ethyl acetate/hexane = 1/4) to afford the pure product 2-
(furan-2-yl)-5-methylthiazole (2e) in 74% yield. Yellow solid; mp 65–66 °C; 1H
NMR (300 MHz, CDCl3) d 7.43–7.46 (2H, m, overlapped), 6.90 (1H, d, J = 3.4 Hz),
6.50 (1H, dd, J = 1.8, 3.4 Hz), 2.49 (3H, s); 13C NMR (75 MHz, CDCl3) d 156.7,
Synthesis of imidazole-2-thiones 4
R1
N
R1
H
S
1.5 mol equiv. K2CO3
DMF, 80 ºC
N
N
N
Me
Br
S
R2
1m-r
4
R2
Entry
Thioureas
R1
R2
Imidazole-2-thiones 4 (yield%)a
1
2
3
4
5
6
1m
1n
1o
1p
1q
1r
i-C3H7
i-C3H7
i-C3H7
Ph
H
4m (78)
4n (77)
4o (81)
4p (87)
4q (91)
4r (65)
NO2
MeO
H
MeO
H
Ph
149.1, 143.2, 141.2, 133.2, 112.1, 108.0, 11.9; IR (NaCl)
m 3117, 2922, 1526,
1499, 1437, 1225, 1134, 1022, 883, 737 cmꢁ1; HRMS (ESI) calcd for C8H7NOS
(M+H+) 166.0327, found: 166.0326.
PhCH2
a
Isolated yield.
8. (a) Wohl, A.; Marckwald, W. Chem. Ber. 1889, 22, 568; (b) Marckwald, W. Chem.
Ber. 1892, 25, 2354.
9. Matsuda, K.; Yanagisawa, I.; Isomura, Y.; Mase, T.; Shibanuma, T. Synth.
Commun. 1997, 27, 3565.
10. Norbert, K.; Thomas, K. Synthesis 1993, 561.
tuted imidazole-2-thione 4m could be prepared selectively in good
yield from N,N0-trisubstituted thiourea 1m whose inner nitrogen
has two substituents (Scheme 5b).12,13
Several 1-(2-bromoprop-2-enyl)thioureas 1m–r have been
evaluated under the same reaction conditions as shown in Table
2. Various 1,3,4-trisubstituted imidazole-2-thiones 4 were pre-
pared in good yields.
In summary, by the nucleophilic substitution reaction of vinyl
bromide with intramolecular thioamide moieties, substituted thia-
zoles and imidazole-2-thiones could be successfully synthesized.
This vinylic substitution method would provide unique synthetic
routes for a variety of heterocycles.
11. (a) Heath, H.; Lawson, A.; Rimington, C. J. Chem. Soc. 1951, 2217; (b) Bullerwell,
R. A. F.; Lawson, A. J. Chem. Soc. 1951, 3030; (c) Avalos, M.; Babiano, R.; Cintas,
P.; Jimenez, J. L.; Palacios, J. C.; Silvero, G.; Valencia, C. Tetrahedron 1999, 55,
4377.
12. Typical procedure for 1-isopropyl-4-methyl-3-phenyl-1H-imidazole-2(3H)-thione
(4m): To a solution of 1-(2-bromoprop-2-enyl)-1-isopropyl-3-phenylthiourea
(1m) (100 mg, 0.31 mmol) in DMF (20 mL), was added K2CO3 (66 mg,
0.48 mmol), and the mixture was stirred at 80 °C for 2 h. After the
completion of the reaction, the mixture was quenched with
a pH 9
ammonium buffer solution, and extracted with ethyl acetate (10 mL ꢀ 3), the
combined extracts were washed by brine and dried over MgSO4. The solvent
was removed in vacuo, and the resulting crude was purified by PTLC (silica gel;
ethyl acetate/hexane = 1/2) to afford the pure product 4m in 78% yield. Faint
yellow crystals; mp 185–186 °C; 1H NMR (300 MHz, CDCl3) d 7.41–7.50 (3H,
m), 7.28–7.32 (2H, m), 6.59 (1H, s), 5.17 (1H, septet, J = 6.8 Hz), 1.93 (3H, s),
1.38 (6H, d, J = 6.8 Hz); 13C NMR (75 MHz, CDCl3) d 162.2, 136.5, 129.4(2),
Acknowledgment
129.0, 128.5(2), 126.5, 110.1, 48.5, 21.8(2), 11.0; IR (NaCl)
m 2976, 1518, 1499,
1408, 1344 cmꢁ1; HRMS (ESI) calcd for C13H16N2S (M+H+): 233.1112, found:
233.1112.
We acknowledge the Nanyang Technological University for
funding of this research.
13. The structure of 4m was secured by X-ray crystallographic analysis as shown
below
References and notes
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X-ray of 4m
.
CCDC-706193 contains the supplementary crystallographic data for compound
4m. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic Data Center, 12 Union
Road, Cambridge, CB21 EZ, UK; fax: (+44)1223-336-033; or deposit@cdc.
cam.ac.uk).