The cyclopropyliminium rearrangement of cyclopropylthiazoles

Article abstract of DOI:10.1016/j.mencom.2013.01.007

2-Cyclopropylthiazole hydrobromides undergo iminocyclopropane-pyrroline rearrangement in a melt to give the corresponding fused heterocycles, viz. 6,7-dihydro-5H-pyrrolo[2,1-b]thiazol-4-ium bromides. 2-Alkyl- and 2-aryl-4-cyclopropylthiazoles transform into analogous fused heterocycles as hydroiodides and noticeably longer.

Full text of DOI:10.1016/j.mencom.2013.01.007

Mendeleev
Communications
Mendeleev Commun., 2013, 23, 22–23
The cyclopropyliminium rearrangement of cyclopropylthiazoles
Yury V. Tomilov,* Rinat F. Salikov, Dmitry N. Platonov, Dmitry L. Lipilin and Aleksandr E. Frumkin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 6390; e-mail: tom@ioc.ac.ru
DOI: 10.1016/j.mencom.2013.01.007
2-Cyclopropylthiazole hydrobromides undergo iminocyclopropane-pyrroline rearrangement in a melt to give the corresponding fused
heterocycles, viz. 6,7-dihydro-5H-pyrrolo[2,1-b]thiazol-4-ium bromides. 2-Alkyl- and 2-aryl-4-cyclopropylthiazoles transform into
analogous fused heterocycles as hydroiodides and noticeably longer.
We have previously shown1 that 2-cyclopropylbenzazoles demon-
strate similar reactivity of a cyclopropyl moiety as cyclopropyl-
ketimines2–4 and cyclopropanethiomethylimidates5 and can
undergo rearrangement into condensed 2,3-dihydro-1H-benzopyr-
roloazoles under acid nucleophilic catalysis conditions. Similar
reaction was observed for the isoquinoline derivative.6 Reactivity
of these azoles increases in the series of cyclopropyl-substituted
benzimidazole, benzothiazole and benzoxazole, and the reaction
even involves oxazole ring opening in the case of benzoxazole.1
To study the method that we suggest for synthesizing condensed
azoles, it was important to determine whether the absence of a
stabilizing benzene ring in the substrate is critical in the
rearrangement of 2-cyclopropylthiazoles. Of some interest is
also the possibility of rearrangement of 4-cyclopropylthiazoles
that do not contain a cyclopropyliminium moiety in explicit
form. However, only one example of a similar rearrangement of
2-amino-4-cyclopropylthiazinium bromide on melting (~200°C)
into 3-amino-6,7-dihydro-5H-pyrrolo[1,2-c]thiazolium bromide
was reported so far.7 Formation of the same fused heterocyclic
system was also observed in the reaction of 2-bromo-1-cyclo-
propylethanone with 2-cyano-3-hetarylprop-2-enethioamides in
DMF at 20°C.8 The mechanism of this process is not clear, but
formationandisomerisationofintermediate4-cyclopropylthiazoles
seems unlikely as the reaction conditions are very mild.
Aside from higher reactivity, the main specific feature of the
rearrangement of 2-cyclopropylbenzothiazole in comparison with
that of 2-cyclopropylbenzimidazole is that its rearrangement pro-
duct is a salt-like compound which cannot be easily deprotonated.
This feature allows this moiety to be efficiently used as a building
block to create pharmacologically active compounds, since the
positively charged thiazolium fragment should favour a better
solubility in water. In some publications,9,10 the possibility of using
thiazolium salts as prodrugs for malaria treatment was demonstrated.
The thiazolyl moiety in these compounds is activated inside the
organism to form the active moiety of the drug. Note that com-
pounds with a dihydropyrrolothiazole moiety have not been studied
for bioactivity because of their limited availability. The method we
propose has a number of advantages over the methods described
before.11
R1
R1
O
H2N
S
N
N
MeOH
reflux
or
R2
R2
+
S
S
Hal
1a–c
2a–d
3a,b
4a–c
Ketone
Thioamide
Product Yield (%)
1a R1 = Me, Hal = Cl
1b R1 = Ph, Hal = Cl
2a R2 = c-C3H5
2a R2 = c-C3H5
3a
3b
4a
4b
83
90
67
95
62
1c R1 = c-C3H5, Hal = Br 2b R2 = Me
1c R1 = c-C3H5, Hal = Br 2c R2 = Ph
1c R1 = c-C3H5, Hal = Br 2d R2 = pyridin-4-yl 4c
Scheme 1
In this case, complete conversion of the starting cyclopropyl-
thiazoles is observed in 30 min.
The rearrangement of 4-cyclopropylthiazolium hydrobromides
4a,b that are isomeric to compounds 3a,b occurs extremely
slowly at 150°C in comparison with that of 2-cyclopropyl-
thiazoles, which may be due to the absence of a cyclopropyl-
iminium moiety in explicit form. Still, we attempted to enhance
the reactivity of compounds 4a,b and performed a rearrange-
ment of their hydroiodides since hydroiodides rearrange much
†
Synthesis of cyclopropylthiazoles. A solution of halo ketone 1a–c
(27 mmol) and thioamide (27 mmol) in 100 ml of methanol was heated to
reflux for 2 h for bromo ketones or 10 h for chloro ketones. The solvent
was removed in vacuo, the residue was treated with 100 ml of saturated
NaHCO3 solution and extracted with chloroform (3×70 ml). The combined
organic layer was dried over anhydrous MgSO4 and evaporated in vacuo
to give the crude product, which was additionally purified by flash column
chromatography.
2-Cyclopropyl-4-phenylthiazole 3b. IR (CHCl3, n/cm−1): 3112, 3064,
3024, 3004, 1688, 1652, 1600. 1H NMR (200 MHz, CDCl3) d: 1.10–1.20
(m, 4H, CH2CH2), 2.38 (m, 1H, CH), 7.22 (s, 1H, H5), 7.36 and 7.90 (2m,
3+2H, Ph). 13C NMR (50 MHz, CDCl3) d: 11.1 (CH2CH2), 14.7 (CH),
110.3 (C5), 126.3 and 128.7 (o- and m-CH), 127.9 (p-CH), 133.8 (i-C),
154.8 (C4), 173.5 (C2). EI MS, m/z: 201 (82) [M]+, 200 (66) [M–H]+, 175
(32), 134 (100). Found (%): C, 71.69; H, 5.48; N, 6.90. Calc. for C12H11NS
(%): C, 71.60; H, 5.51; N, 6.96.
4-Cyclopropyl-2-(pyridin-4-yl)thiazole 4c. IR (CHCl3, n/cm−1): 3406,
3085, 3033, 3009, 1597, 1518, 1410. 1H NMR (300 MHz, CDCl3) d: 0.99
(m, 4H, CH2CH2), 2.10 (m, 1H, CH), 6.95 (s, 1H, H5), 7.77 (d, 2H, H3',
H5', J 6 Hz), 8.68 (d, 2H, H2', H6', J 6 Hz). 13C NMR (75 MHz, CDCl3)
d: 8.4 (CH2CH2), 12.3 (CH), 112.7 (C5), 120.2 (C3', C5' ), 140.7 (C4' ),
150.3 (C2', C6' ), 161.0 and 164.1 (C2 and C4). EI MS, m/z: 202 (100)
[M]+, 201 (78) [M–H]+, 122 (34), 97 (85). Found (%): C, 65.22; H, 5.51;
N, 13.91. Calc. for C11H10N2S (%): C, 65.32; H, 4.98; N, 13.85.
For characteristics of compounds 3a,15 4a12 and 4b, see Online Sup-
plementary Materials.
In order to study the cyclopropyliminium rearrangement in
thiazole series, we used the Hantzsch reaction to synthesize a set
of cyclopropylthiazoles† from a-halo ketones 1a–c and thio-
amides 2a–d to give both 2-cyclopropylthiazoles 3a,b and 4-cyclo-
propyl-substituted thiazoles 4a–c12 (Scheme 1).
Similarly to the reaction of 2-cyclopropylbenzothiazole,1
2-cyclopropylthiazole hydrobromides 3a,b undergo rearrangement
in a melt to afford 6,7-dihydro-5H-pyrrolo[2,1-b]thiazol-4-ium
bromides 5a,b in 69 and 85% yields, respectively (Scheme 2).‡
© 2013 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2013, 23, 22–23
H
N
Br–
R
H
R
R
N
S
R
I–
N
N
150°C
30 min
150°C
2–4 h
Br–
I–
S
S
S
a R = Me
b R = Ph
3a,b·\HBr
5a (69%)
5b (85%)
4a,b·HI
6a (58%)
6b (68%)
a R = Me
b R = Ph
Scheme 2
Scheme 3
more readily than the corresponding hydrobromides.1 In fact,
hydroiodides 4a,b on heating at 150°C§ for a longer time (2–4 h)
undergo isomerization with opening of the cyclopropane ring, by
analogy with the cyclopropyliminium rearrangement, to produce
the corresponding thiazolium iodides 6a,b in 58 and 68% yields,
respectively (Scheme 3).
Heating of dihydroiodide 4c at 150°C for 2 h leads to complete
conversion of the starting cyclopropylthiazole, but a hardly iden-
tifiable mixture of compounds is formed. The low selectivity of
this reaction is probably owing to the rather high nucleophilicity
of the pyridine ring resulting in intermoleculer alkylation or
dehydrohalogenation of the intermediate to give oligomeric pro-
ducts in both cases.
tetrazolium hydrohalides), 2-cyclopropylthiazolium hydrobromides
3a,b and 4-cyclopropylthiazolium hydroiodides 4a,b can undergo
a rearrangement via a mechanism similar to that of cyclopropyl-
iminium rearrangement to form the corresponding dihydropyrrolo-
thiazolium salts 5a,b and 6a,b. The rearrangement of 4-cyclo-
propylthiazoles occurs, despite the formal lack of a cyclopropyl-
iminium moiety, but under more drastic conditions (hydroiodides
and longer heating at 150°C are required).
H
N
H
R
R
N
X
X
S
S
8
7
The observed difference in the reactivity of 2- and 4-cyclo-
propylthiazoles results from the large difference in the transition
state energies when the cyclopropane ring is opened by a halide
ion. The small ring opening stage is highly endothermal (largely
due to violation of the thiazole ring aromaticity during this process),
hence, owing to Hammond’s postulate, the energies and structures
of the transition states in the rearrangement of 2- and 4-cyclo-
propylthiazoles would be similar to the energies and structures
of corresponding intermediates 7 and 8. Obviously, intermediate
7 should be more stable than zwitter-ionic intermediate 8.
Using known techniques, we also synthesized 5-cyclopropyl-
tetrazole13 and 5-methyl-3-cyclopropyl-1,2,4-oxadiazole.14 How-
ever, their hydrobromides underwent full conversion at 100–150°C
to yield complex mixture of products.
This work was supported by the Presidium of the Russian
Academy of Sciences (Program for Basic Research ‘Elaboration
of Methods for the Synthesis of Chemical Substances and Creation
of New Materials’) and the Division of Chemistry and Materials
Science of the Russian Academy of Sciences (Program for Basic
Research ‘Medical Chemistry’).
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2013.01.007.
References
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Thus, similarly to 2-cyclopropylbenzimidazolium and benzo-
thiazolium hydrohalides (unlike cyclopropyloxadiazolium and
‡
General procedure for the rearrangement of 2-cyclopropylthiazoles
3a,b. Hydrobromic acid (1.1 equiv., 48% in water) was added to a solution
of 2-cyclopropylthiazole 3a or 3b in methanol, the reaction mixture was
stirred for 10 min and the solvent was removed in vacuo. The residue was
heated at 150°C for 30 min to give the crude thiazolium bromide 5a or 5b.
The products obtained were purified by recrystallization from propan-2-ol.
3-Methyl-6,7-dihydro-5H-pyrrolo[2,1-b]thiazol-4-ium bromide 5a:16
mp 197–200°C. IR (KBr, n/cm−1): 3040, 2968, 2884, 1576, 1428. 1H NMR
(200 MHz, DMSO-d6) d: 2.45 (s, 3H, Me), 2.69 (m, 2H, H2C6), 3.50 (t, 2H,
H2C7, J 7.5 Hz), 4.46 (t, 2H, H2C5, J 7.6 Hz), 7.81 (s, 1H, H2). 13C NMR
(50 MHz, DMSO-d6) d: 12.1 (Me), 25.1 (C6), 30.5 (C7), 51.0 (C5) 122.5
(C2), 139.5 (C3), 175.1 (C7a). EI MS, m/z: 140 (53) [M–Br]+, 139 (100)
[M–H]+, 113 (69). Found (%): C, 38.13; H, 4.63; N, 6.29. Calc. for
C7H10BrNS (%): C, 38.19; H, 4.58; N, 6.36.
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For characteristics of compound 5b,17 see Online Supplementary Materials.
General procedure for the rearrangement of 4-cyclopropylthiazoles
§
4a–c. Hydroiodic acid (1.1 equiv. for 4a and 4b or 2.1 equiv. for 4c,
57% in water) was added to a solution of 4-cyclopropylthiazoles 4a–c in
methanol, the reaction mixture was stirred for 10 min and the solvent was
removed in vacuo. The residue was heated at 150°C for 2–4 h to give the
crude thiazolium iodides 6a or 6b. The products were purified by recrys-
tallization from either propan-2-ol (6a) or ethanol (6b). Rearrangement
of 4c gives a hardly identifiable mixture of products.
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3-Methyl-6,7-dihydro-5H-pyrrolo[1,2-c]thiazol-4-ium iodide 6a: heating
for 2 h, mp 192–194°C. IR (KBr, n/cm–1): 3039, 2885, 1575, 1427. 1H NMR
(200 MHz, DMSO-d6) d: 2.64 (m, 2H, H2C6), 2.88 (s, 3H, Me), 3.06 (t,
2H, H2C7, J 7.3 Hz), 4.36 (t, 2H, H2C5, J 7.4Hz), 7.69 (s, 1H, H1). 13C NMR
(50 MHz, DMSO-d6) d: 15.0 (Me), 24.7 (C6), 27.1 (C7), 49.9 (C5), 112.8
(C1), 151.3 (C7a), 165.4 (C3). EI MS, m/z: 267 (12) [M]+, 140 (65) [M–I]+,
128 (100), 113 (100). Found (%): C, 31.49; H, 3.90; N, 5.20. Calc. for
C7H10INS (%): C, 31.47; H, 3.77; N, 5.24.
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Received: 19th October 2012; Com. 12/3999
For characteristics of compound 6b, see Online Supplementary Materials.
– 23 –