Rhodium(II)-catalyzed transannulation of 1-sulfonyl-1,2,3-triazoles with 2H-azirines: A new method to dihydropyrazines

Article abstract of DOI:10.1016/j.tetlet.2014.12.032

An efficient rhodium(II)-catalyzed transannulation method of 1-sulfonyl-1,2,3-triazoles with 2H-azirines has been utilized for the synthesis of phenyl-substituted dihydropyrazines. The dihydropyrazine products can be further converted to pyrazines under b

Full text of DOI:10.1016/j.tetlet.2014.12.032

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rhodium(II)-catalyzed transannulation of 1-sulfonyl-1,2,3-triazoles
with 2H-azirines: a new method to dihydropyrazines
Haixin Ding a,b, Sanguo Hong a, Ning Zhang a,
⇑
a Department of Chemistry, Nanchang University, Nanchang, Jiangxi 330031, China
b Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi 330013, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient rhodium(II)-catalyzed transannulation method of 1-sulfonyl-1,2,3-triazoles with 2H-azirines
has been utilized for the synthesis of phenyl-substituted dihydropyrazines. The dihydropyrazine prod-
ucts can be further converted to pyrazines under basic conditions in excellent yield.
Ó 2014 Published by Elsevier Ltd.
Received 4 November 2014
Revised 3 December 2014
Accepted 8 December 2014
Available online xxxx
Keywords:
Transannulation
1-Sulfonyl-1,2,3-trizaole
Dihydropyrazine
2H-Azirine
Rhodium
Table 1
Dihydropyrazines and pyrazines are important structural motifs
found in natural products and bioactive molecules.1 For instance,
phenyl-substituted dihydropyrazines are known as neuropeptide
Y (NPY) antagonist and possess DNA strand-breaking activity.2
Currently, only a few synthetic approaches are available for the
synthesis of dihydropyrazines and pyrazines from different sub-
strates. The Staedel–Rugheimer’s pyrazine synthesis via the self-
condensation of amino ketones,3 Taylor’s dihydropyrazine and pyr-
Optimization of the transannulation reaction of triazole 1a and 2H-azirine 2aa
Yieldb (%)
azine synthesis from
a
-hydroxyketones and diamines,4 and Lee’s
Entry
Catalyst (mol %)
Solvent
Temp (°C)
dihydropyrazine synthesis from reduction of pyridinium salts5
have been reported. However, these methods are still limited by
the availability of the starting materials and the diversity of the
products.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Rh2(OAc)4 (2.5)
Rh2(TFA)4 (2.5)
Rh2(Oct)4 (2.5)
Rh2(esp)4 (2.5)
Cu(OTf)2 (5.0)
Cu(TFA)2 (5.0)
Rh2(esp)4 (5.0)
Rh2(OAc)4 (5.0)
Rh2(OAc)4 (5.0)
Rh2(OAc)4 (5.0)
Rh2(OAc)4 (5.0)
Rh2(OAc)4 (5.0)
Rh2(OAc)4 (5.0)
Rh2(OAc)4 (5.0)
Rh2(OAc)4 (5.0)
Rh2(OAc)4 (5.0)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCE
DMF
CH3CN
THF
Dioxane
Toluene
Toluene
Toluene
110
110
110
110
110
110
110
110
Reflux
Reflux
Reflux
Reflux
Reflux
90
49
Trace
26
53
NRc
NRc
57
In heterocycle chemistry, transition-metal catalysis is an effi-
cient method in promoting the formation of heterocycles with a
wide range of functionalities, thereby making the synthesis appli-
cable to complex molecules. In recent years, it has been elucidated
that N-sulfonyl-1,2,3-trizaoles could react with transition metals,
75
27
NPd
NPd
NRc
NRc
63
especially rhodium(II), to generate
a-imino metal carbene com-
plexes, which would further react with a variety of nucleophiles
to form the corresponding aza-heterocycles including pyrrole,6
imidazole,7 indole,8 oxazoline, and N-fused hetetocycles.9 Inspired
by these results, we conceived that the substituted dihydropyra-
zines could be constructed via the rhodium(II)-catalyzed transann-
ulation of N-sulfonyl-1,2,3-triazoles with 2H-azirines, which are
70
60
28
NRc
a
The reaction was carried out with triazole 1a (0.20 mmol) and 2H-azirine 2a
(0.26 mmol) in 2 mL of solvent under N2 atmosphere for 10 h.
b
Isolated yield.
NR: no reaction.
NP: no product.
c
d
⇑
Corresponding author. Tel.: +86 791 83779427; fax: +86 791 83969514.
E-mail address: nzhang.ncu@163.com (N. Zhang).
http://dx.doi.org/10.1016/j.tetlet.2014.12.032
0040-4039/Ó 2014 Published by Elsevier Ltd.
Please cite this article in press as: Ding, H.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.12.032

2
H. Ding et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Scheme 1. Rh-catalyzed synthesis of dihydropyrazines (3a–3o) and electronic effects of triazoles and 2H-azirines.
highly strained three-membered heterocyclic compounds that
have been exploited as useful precursors for reactive intermediates
such as vinyl nitrenes and nitrile ylides.10 Under rhodium(II)-cata-
lyzed conditions, dihydropyrazine heterocycle may be generated
with Rh2(OAc)4 as the catalyst significantly improved to 75% yield
compared to that with Rh2(esp)4 (entries 7–8). But further incre-
ment of the amount of Rh2(OAc)4 to 10 mol % resulted in no
improvement of yield.
by nucleophilic addition of 2H-azirines to
a
-imino rhodium
With 5 mol % Rh2(OAc)4 as the best catalyst, other reaction
parameters such as solvent and reaction temperature were sys-
tematically investigated to optimize the reaction conditions. To
elucidate the solvent effect, the reaction was performed in a series
of organic solvents under refluxing conditions (entries 9–13). It
was observed that no reaction happened in THF, acetonitrile, and
dioxane. Though dichloroethane (DCE) afforded the desired prod-
uct 3a, the yield was as low as 27%. In contrast, the reaction in
DMF led to an alternative reaction path and resulted in the forma-
tion of an unidentified product. These results suggested that the
nonpolar organic solvent favored the formation of the dihydropyr-
azine product. Finally, the reaction temperature was lowered to
determine whether the reaction could be conducted under milder
conditions (entries 14–16). It was observed that when the temper-
ature dropped, the reaction rate and yield of 3a decreased accord-
ingly. When the reaction temperature was below 70 °C, the
reaction could not happen.
carbene intermediates. In this paper, we report the synthesis of a
series of phenyl-substituted dihydropyrazines from the N-sulfo-
nyl-1,2,3-triazoles and 2H-azirines in the presence of rhodium(II)
catalyst. The treatment of the dihydropyrazines with potassium
hydroxide at 140 °C provides efficient access to the corresponding
pyrazines.
In the preliminary experiment, 4-phenyl-1-tosyl-1,2,3-triazole
(1a) prepared from phenylacetylene and tosylazide in the presence
of CuTC11 was treated with 2,3-diphenyl-2H-azirine 2a12 with
2.5 mol % of Rh2(OAc)4 in refluxing toluene. 2,3,5-Triphenyl-1-
tosyl-1,2-dihydropyrazine (3a) was isolated in 49% yield (Table 1,
entry 1). On the basis of this promising result, a series of Rh(II)
catalysts were tested for their catalytic activities under the same
conditions. While Rh2(TFA)4 and Rh2(Oct)4 resulted in much lower
yields of the product (entries 2–3), Rh2(esp)4 afforded 3a in
comparable yield (53%, entry 4). In addition, Cu(II) catalysts were
also tested for this reaction. But both Cu(OTf)2 and Cu(TFA)2
(5.0 mol %) showed no catalytic effect on the formation of 3a
(entries 5–6). In the next step, the amounts of Rh2(OAc)4 and
Rh2(esp)4 catalysts were increased to 5.0 mol %, and the reaction
With the optimized reaction conditions in hand, a variety of
triazole substrates 1a–l were examined to reveal the scope of this
method (Scheme 1). First, the electronic effect of substituents on
the phenylsulfonyl moiety was investigated. The reactions with
Please cite this article in press as: Ding, H.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.12.032

H. Ding et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
substituent’s electronic effect of the phenyl ring. While the triazole
substrate having a butyl substituent afforded 3k in moderate yield,
the one with a cyclopropyl substituent only gave a trace amount of
product 3i (<5%) under the same conditions.
The substituent’s electronic effect on the 2H-azirine substrates
was also investigated. When the 2H-azirine substrates having p-
Me and p-OMe groups on the phenyl ring reacted with triazole
3a, the corresponding products (3m and 3o) were obtained in good
yields. However, when an electronic-withdrawing group, p-Cl, was
introduced to 2H-azirine, the efficiency of reaction was obviously
affected. These results indicated that the Rh(II)-catalyzed trans-
annulation was also significantly subjected to electronic effect of
the 2H-azirine substrate.
Though the phenyl-substituted dihydropyrazine products
obtained were characterized by 1H and 13C NMR and high resolu-
tion mass spectrometry, we believed that the X-ray crystallogra-
phy data was necessary to confirm the structures of the target
molecules due to the lack of spectra data of structurally similar
molecules. The crystal of product 3a was obtained by recrystalliza-
tion from hexane/dichloromethane. As shown in Figure 1, the
structure of 3a was determined by X-ray crystallography was well
in agreement with that proposed from NMR data.
Figure 1. X-ray structures of 3a.
To further extend the application of this reaction, we attempted
to convert the dihydropyrazine products to the corresponding
pyrazine derivatives. 2,3,5-Triphenyl-1-tosyl-1,2-dihydropyrazine
(3a) was treated with potassium hydroxide in DMF at 140 °C for
4 h. The reaction afforded the desired 2,3,5-triphenylpyrazine
(4a) in 92% yield (Scheme 2).
Scheme 2. Synthesis of substituted pyrazine 4a.
A plausible mechanism for the formation of dihydropyrazine 3
from 1-sulfonyl-1,2,3-triazole 1 and 2H-azirine 2 is shown in
Scheme 3. First, a reversible tautomerization of N-tosyltriazole 1
triazole substrates having electron-donating substituents on the
phenylsulfonyl moiety afforded the corresponding dihydropyr-
azine products in good yields (3a–b, 3d). In contrast, the triazole
substrate having an electron-withdrawing p-NO2 substituent on
the phenylsulfonyl moiety only gave the desired product in much
lower yield (33%). It was also noticed that the reaction with a
methylsulfonyl group on triazole substrate (3e) worked as well
as the one with a toluenesulfonyl group (3a).
In the following research, we studied the effect of the substitu-
ents at triazole C-4 position. A series of substrates with different
types of substituents were tested. When a phenyl group with a
para electron-withdrawing substituent including p-Cl, p-COCH3,
and p-COOEt was introduced to the triazole ring, the reaction affor-
ded the corresponding dihydropyrazine products (3g–i) in high
yield (>80%). However, when a phenyl group with a para elec-
tron-donating substituent such as p-CH3 and p-OMe was attached
to the triazole, the yield of the corresponding product (3f and 3j)
was significantly lower (<50%). These results indicated that the
Rh(II)-catalyzed transannulation had strong dependence on the
gives
alyst generates
a
-diazo imine A.13 The following reaction of A with Rh(II) cat-
a-imino Rh(II) carbenoid B together with the
release of one molecule of nitrogen gas. Nucleophilic addition of
2 to the Rh(II) carbene B affords the zwitterionic intermediate C
which is in equilibrium with its tautomer D. Then, concerted
release of the Rh(II) cation and cyclization at the azacarbenium
position on intermediate D affords the bicyclic intermediate E with
the regeneration of Rh(II) catalyst. Finally, the highly strained E
quickly rearranges to dihydropyrazine 3 via an intramolecular
hydrogen transfer mechanism.
In summary, we reported a novel and efficient method for the
synthesis of a diversity of substituted dihydropyrazines via the
transannulation of a-imino Rh(II) carbenes generated in situ from
1-sulfonyl-1,2,3-trizaoles with 2H-azirines. The experimental
results indicated that the Rh(II)-catalyzed transannulation for the
synthesis of dihydropyrazines is dependent on the electronic
effects of both the triazole and 2H-azirine substrates. Furthermore,
treatment of the dihydropyrazines under basic conditions fur-
nished clean conversion to the corresponding pyrazines.
Acknowledgments
This work was supported by the National Natural Science Foun-
dation of China (No. 21261017), the Natural Science Foundation of
Jiangxi Province (Nos. 20133ACB20001 and 20114BAB203006),
and the Project of the Science Funds of Jiangxi Education Office
(No. GJJ11012).
Supplementary data
Supplementary data associated (experimental procedures and
spectral data for all new compounds) with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.12.
032.
Scheme 3. Proposed mechanism for the transannulation of N-tosyltriazoles with
2H-azirines.
Please cite this article in press as: Ding, H.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.12.032

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13652–13655; (f) Parr, B. T.; Green, S. A.; Davies, H. M. L. J. Am. Chem. Soc.
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