The unprecedented ring transformation from thiazoline-spiro-thiophene to thieno[2,3-b]pyrazine involved in the reaction of 2-thiocarbamoyl thiazolium salts with dimethyl acetylenedicarboxylate

Article abstract of DOI:10.1039/b712098b

Reaction of 2-thiocarbamoyl thiazolium salts with dimethyl acetylenedicarboxylate proceeded via a tandem [3 + 2] cycloaddition and a unprecedented ring transformation to produce functionalized thieno[2,3-b] pyrazine derivatives in good to excellent yields

Full text of DOI:10.1039/b712098b

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The unprecedented ring transformation from thiazoline-spiro-thiophene
to thieno[2,3-b]pyrazine involved in the reaction of 2-thiocarbamoyl
thiazolium salts with dimethyl acetylenedicarboxylate{
Yang Guang Ma and Ying Cheng*
Received (in Cambridge, UK) 7th August 2007, Accepted 20th September 2007
First published as an Advance Article on the web 5th October 2007
DOI: 10.1039/b712098b
imidazolinium salts 2 reacted with dimethyl acetylenedicarboxylate
(DMAD) to produce respectively, cycloadduct benzimidazoline-
spiro-thiophenes 3 or imidazolidine-spiro-thiophenes 4,8a,b whereas
the same reaction between 2-arylthiocarbamoyl imidazolium salts
5 and DMAD afforded imidazoline substituted olefins 7 via
cycloaddition followed by fragmentation of the thiophene ring
(Scheme 1).8d In order to gain a full understanding of the chemistry
of 2-thiocarbamoyl iminium inner salts and to further explore their
synthetic applications, we undertook the current study of the
reaction of 2-thiocarbamoyl thiazolium inner salts with DMAD.
Interestingly, the reaction proceeded through a tandem [3 + 2]
cycloaddition and an unprecedented ring transformation reaction
to produce novel thieno[2,3-b]pyrazine derivatives in good to
excellent yields.
Reaction of 2-thiocarbamoyl thiazolium salts with dimethyl
acetylenedicarboxylate proceeded via tandem [3 2]
a
+
cycloaddition and a unprecedented ring transformation to
produce functionalized thieno[2,3-b]pyrazine derivatives in
good to excellent yields.
Ring transformation reactions constitute a research area of
particular interest both synthetically and theoretically. For
decades, ring transformations have become important and
fascinating strategies for the construction of cyclic and, especially,
heterocyclic compounds which are not easily accessible by other
methods.1 Some ring transformations, for example, have been
successfully used in the total synthesis of natural products and
bioactive compounds.2 In addition to their synthetic values, ring
transformations usually, if not always, proceed through intriguing
reaction mechanisms, which largely enrich the theory of organic
reactions. Most of the ring transformation reactions were induced
by some reagents such as acids,3a,b bases,3c nucleophiles3d or
oxidants3e that proceed intermolecularly or intramolecularly,
whereas a few transformations took place simply through thermal
In this work, 2-arylthiocarbamoyl thiazolium inner salts 8 were
prepared in 64–95% yield from the reaction of aryl isothiocyanates
with thiazole carbenes, which were generated in situ from the
thiazolium salts with sodium hydride. We started our investigation
by examining the reaction between N-ethyl-2-(p-nitrophenyl)thio-
carbamoyl thiazolium salt 8a and DMAD. When treated with one
equivalent of DMAD in dichloromethane at ambient temperature,
the zwitterion 8a was transformed into thieno[2,3-b]pyrazine 9a in
48% yield (based on 8a). Having realized the formation of adduct
9a from reactants in a 1 : 2 ratio, the reaction was optimized under
various conditions employing 2.5 equivalents of DMAD (Table 1).
As summarized in Table 1, the reaction proceeded very rapidly and
efficiently. In most cases, for example, the conversion of 8a into 9a,
which was monitored by TLC, was completed within 30 min. The
highest chemical yield (97%) was obtained when the reaction was
performed in dichloromethane at 0 uC (entry 2). High reaction
ring rearrangements.4 The transformation of
a spirocyclic
compound to a fused one generally proceeds via a sigmatropic
shift of the chemical bond from the spiro atom to its adjacent
atom.5 Ring expansion transformation of a spiro heterocycle
involving an exocyclic atom is very rare.6
Nucleophilic N-heterocyclic carbenes including benzimidazole,
imidazoline, imidazole, triazole and thiazole carbenes are known
to react with isothiocyanates to form stable zwitterions, 2-thio-
carbamoyl benzimidazolium,7a -imidazolinium,7b,c -imidazolium,7d
-triazolium5a and -thiazolium inner salts,7e,f respectively. Very
recently, we found that the inner salts derived from imidazole-type
carbenes are unique ambident bis-dipolar compounds.8 Depending
on the nature of the dipolarophiles, these ambident zwitterions can
act as either C+–C–S2 or C+–C–N2dipolar species toward
electron-deficient alkynes, alkenes and ketenes to produce [3 + 2]
cycloadducts, spiro-thiophene or spiro-pyrrole derivatives.8a–c We
have also shown that the structure of N-heterocyclic carbenes also
played an intriguing part in regulating the outcomes of the
reactions. For example, 2-arylthiocarbamoyl benzimidazolium 1 or
Chemistry Department, Beijing Normal University, Beijing, 100875,
China. E-mail: ycheng2@bnu.edu.cn; Fax: +86-10-58802075;
Tel: +86-10-58805558
{ Electronic supplementary information (ESI) available: Experimental
procedures for the preparation of dipoles 8 and products 9, full
characterization for 8 and 9, and NMR spectra of all products 9. See
DOI: 10.1039/b712098b
Scheme 1 Reaction of 2-thiocarbamoyl benzimidazolium, -imidazoli-
nium, -imidazolium salts with DMAD.
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80–85% were obtained (entries 3–5). The nature of the aryl group
Table 1 The reaction of N-ethyl-2-(p-nitrophenyl)thiocarbamoyl
thiazolium salt 8a with DMAD under different conditions
on the thiocarbamoyl function exhibited only marginal effect on
the reaction, as all reactions produced the products 9f–9p in 72–
82% yields (entries 6–16).
The structures of all products were elucidated on the basis of
spectroscopic data and microanalysis. The NMR spectra, mass
spectral data and elemental analysis indicated that the product 9
was the adduct of one dipole 8 and two DMAD molecules.
Since spectroscopic data did not allow full verification of the
structure, X-ray diffraction analysis indicated unambiguously that
the compound 9b was (E)-1-butyl-2-methyl-3-(1,2-dimethoxy-
carbonylvinylthio)-4-(p-nitrophenyl)-1,4-dihydrothieno[2,3-b]pyra-
zine-6,7-dicarboxylate (see Fig. 1 in ESI{).9
The formation of fused thieno[2,3-b]pyrazine ring product from
the 2-thiocarbamoyl thiazolium salt with DMAD is very
intriguing. Although the di(methoxycarbonyl)-substituted thio-
phene substructure was conceivable based on the [3 + 2]
cycloaddition between the C+–C–S2 dipolar specie of 8 and
DMAD followed by aromatization, the construction of fully
substituted 1,4-dihydro-1,4-pyrazine was not expected. A plausible
mechanism is proposed in Scheme 2. Acting as a C+–C–S2dipolar
component, zwitterion 8 undergoes 1,3-dipolar cycloaddition
reaction with DMAD to form thiazole-spiro-thiophene intermedi-
ate 10. Selective S–C bond cleavage of 10 probably gives a
zwitterion 11 that undergoes an aromatizative electrocyclization
reaction to form the fused ring intermediate 12. Isomerization of
12 followed by S-nucleophilic addition to DMAD affords product
9 (Scheme 2). The rearrangement of thiazole-spiro-thiophene to
thieno[2,3-b]pyrazine proceeded via a unique ring transformation
process, in which the thiazole ring was expended to the exo-cyclic
nitrogen atom with its sulfur atom being contracted out of the ring
system.
Entry
Reaction conditionsa
Yield of 9ab (%)
1
2
3
4
5
6
7
8
9
a
CH2Cl2, 225 uC, 2.5 h
CH2Cl2, 0 uC, 30 min
CH2Cl2, rt, 30 min
CH2Cl2, reflux, 10 min
ClCH2CH2Cl, 0 uC, 30 min
THF, 0 uC, 30 min
C6H6, 0 uC, 40 min
CH3COCH3, 0 uC, 30 min
CH3CN, 0 uC, 30 min
87
97
89
84
95
94
72
84
87
b
The ratio between reactants 8a and DMAD was 1 : 2.5. Isolated
yield.
temperature led to a slight decrease of chemical yield, while at
lower temperature the conversion became slightly slow. Other
solvents such as 1,2-dichloroethane, THF, benzene, acetone and
acetonitrile were proved to be good media for the reaction giving
product 9a in yields of 72–95% (entries 5–8).
The scope of the reaction was then studied under optimal
conditions by using dipoles 8 that bear different substituents. As
evidenced by the results summarized in Table 2, the reaction
showed tolerance for the substituent on the zwitterion reactants 8.
All reactions underwent completion in 30 min to afford products 9
in good to excellent yields. The N-ethyl (R = Et) and N-butyl (R =
n-Bu) substituted reactants 8a and 8b gave an almost quantitative
yield of 9a and 9b, respectively (entries 1 and 2, Table 2). When the
N-substituent on the thiazolium was replaced by a benzyl (CH2Ph)
or a substituted benzyl group, chemical yields in the range of
The different reaction outcomes of thiazolium
8 from
benzimidazolium 1 and imidazolinium 2 and from imidazolium
inner salts 5 (Scheme 1) deserve comment. All ambident dipoles
derived from the reaction between N-heterocyclic carbenes such as
benzimidazole, imidazoline, imidazole and thiazole carbene and
Table 2 The reaction of 2-arylthiocarbamoyl thiazolium inner salts 8
with 2.5 equivalents of DMAD in CH2Cl2 at 0 uC
Entry
8
R
X
9
Yield (%)
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
Et
n-Bu
Bn
p-MeBn
p-BrBn
Bn
Bn
Bn
Bn
Bn
p-MeBn
p-MeBn
p-BrBn
p-BrBn
p-BrBn
p-BrBn
p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
H
p-Me
p-F
m-NO2
p-CF3
p-F
p-CF3
p-Me
p-F
m-NO2
p-CF3
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
97
95
82
85
80
75
72
77
77
82
72
81
76
82
82
82
9
10
11
12
13
14
15
16
Scheme 2 The proposed mechanism for the formation of thieno[2,3-
b]pyrazine 9.
5088 | Chem. Commun., 2007, 5087–5089
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aryl isothiocyanates act as the highly reactive C+–C–S2 dipolar
species toward DMAD to produce [3 + 2] spiro-thiophene
cycloadducts. The stability and reactivity of the resulting spiro-
thiophene cycloadducts, however, are strongly dependent on
the structures of the heterocyclic N-carbenes. Apparently,
the benzimidazoline-spiro-thiophenes and imidazolidine-spiro-
thiophenes are stable at the ambident temperature. The imidazo-
line-spiro-thiophene and thiazoline-spiro-thiophene analogues, on
the contrary, are not isolable products under the reaction
conditions. Interestingly, imidazoline-spiro-thiophene and thiazo-
line-spiro-thiophene intermediates follow dramatically different
ring transformation pathways. For example, imidazoline-spiro-
thiophenes undergo selectively thiophene ring fragmentation
reaction via a cheletropic elimination to give imidazoline-
substituted olefins (Scheme 1).8a,b,d In sharp contrast, however,
thiazoline-spiro-thiophenes selectively expand the thiazole ring to
yield thieno[2,3-b]pyrazines via the electrocyclization reaction. It
seems that the cleavage of C–S bond rather than that of a C–N
bond occurs.
Notes and references
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The thieno[2,3-b]pyrazine ring system has been found in natural
products such as urothion and its derivatives,10 and in some
synthetic compounds with biological activities.11 For example,
thieno[2,3-b]pyrazine-2,3-diones are useful in treating central
nervous system ailments,11c and benzothieno[2,3-b]pyrazine is
active against both Gram positive and negative bacteria and
fungi.11a The known methods for the construction of the
thieno[2,3-b]pyrazine skeleton are all based on the annulation of
a functionalized pyrazine10d,12 or a thiophene derivative.13 No ring
transformation methodology has been reported so far in the
construction of a thieno[2,3-b]pyrazine ring system. To the best of
our knowledge, this is the first report of the preparation of
thieno[2,3-b]pyrazine derivatives using a ring transformation
method starting from neither a pyrazine nor a thiophene
compound.
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9 Crystal data for 9b: C27H29N3O10S2, M = 619.65, T = 113 K,
monoclinic, space group P21/n, a = 15.1455(12), b = 12.530(1), c =
3
23
˚
˚
15.4095(12) A, b = 92.180(5)u, V = 2922(4) A , Z = 4, Dc = 1.408 g cm
absorption coefficient 0.243 mm21, reflections collected/unique 36155/
6953 (Rint = 0.0527), final R indices [I . 2s(I)]: R1 = 0.0496, wR2
,
=
In conclusion, we have shown that the interaction of
2-thiocarbamoyl thiazolium inner salts with DMAD proceeded
via a tandem [3 + 2] cycloaddition/ring-expansion process to
produce thieno[2,3-b]pyrazine derivatives in good to excellent
yields. A unique ring transformation reaction from thiazoline-
spiro-thiophene to thieno[2,3-b]pyrazine was unveiled. The easy
availability of 2-thiocarbamoyl thiazolium salts and their high
efficiency in the reaction with DMAD render this reaction a
powerful and unique ring-transformation methodology for the
construction of polyfunctional thieno[2,3-b]pyrazine derivatives
that are not readily accessible by other methods. This work
revealed that the N-heterocyclic carbene-derived ambident 1,3-
dipoles are remarkable intermediates not only in synthesis of spiro
heterocycles but also fused heterocyclic compounds.
0.1100. CCDC 656512. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b712098b.
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This work was supported by the National Natural Science
Foundation of China for Distinguished Young Scholars (No.
20525207) and National Natural Science Foundation of China
(20672013).
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 5087–5089 | 5089