Switchable Synthesis of Pyrroles and Pyrazines via Rh(II)-Catalyzed Reaction of 1,2,3-Triazoles with Isoxazoles: Experimental and DFT Evidence for the 1,4-Diazahexatriene Intermediate

Article abstract of DOI:10.1021/acs.joc.6b02389

4-Aminopyrrole-3-carboxylates and pyrazine-2-carboxylates were synthesized from 5-alkoxyisoxazoles and 1-sulfonyl-1,2,3-triazoles by tuning the Rh(II) catalyst and the reaction conditions. The reaction in chloroform at 100 °C under Rh₂(OAc)₄ catalysis provides 4-aminopyrrole-3-carboxylates in good yields. The use of Rh₂(Piv)₄ in refluxing toluene results in the formation of 1,2-dihydropyrazine-2-carboxylates as the main products, which can be converted by a one-pot procedure to pyrazine-2-carboxylates by heating with catalytic amounts of TsOH. According to the NMR and DFT investigations of the reaction mechanism, pyrroles and dihydropyrazines are formed, respectively, via 1,5- and 1,6-cyclization of common (5Z)-1,4-diazahexa-1,3,5-triene intermediates. The influence of the nature of the catalyst on the product distribution is rationalized in terms of the Rh-catalyzed isomerization of a pyrrolin-2-ylium-3-aminide zwitterion, the primary product of 1,4-diazahexatriene 1,5-cyclization.

Full text of DOI:10.1021/acs.joc.6b02389

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Article
Switchable synthesis of pyrroles and pyrazines via Rh(II)-
catalyzed reaction of 1,2,3-triazoles with isoxazoles: experimental
and DFT evidence for the 1,4-diazahexatriene intermediate
Nikolai V. Rostovskii, Julia O. Ruvinskaya, Mikhail Sergeevich Novikov,
Alexander F. Khlebnikov, Ilia A. Smetanin, and Anastasiya V. Agafonova
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02389 • Publication Date (Web): 06 Dec 2016
Downloaded from http://pubs.acs.org on December 7, 2016
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Switchable Synthesis of Pyrroles and Pyrazines via Rh(II)ꢀCatalyzed Reaction
of 1,2,3ꢀTriazoles with Isoxazoles: Experimental and DFT Evidence for the
1,4ꢀDiazahexatriene Intermediate
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Nikolai V. Rostovskii, Julia O. Ruvinskaya, Mikhail S. Novikov,* Alexander F. Khlebnikov, Ilia
A. Smetanin, Anastasiya V. Agafonova
St. Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya nab., St. Petersburg,
199034 Russia
Corresponding Author
*Eꢀmail: m.novikov@spbu.ru
Graphical abstract
ABSTRACT: 4ꢀAminopyrroleꢀ3ꢀcarboxylates and pyrazineꢀ2ꢀcarboxylates were synthesized
from 5ꢀalkoxyisoxazoles and 1ꢀsulfonylꢀ1,2,3ꢀtriazoles by tuning the Rh(II) catalyst and the
reaction conditions. The reaction in chloroform at 100 °C under Rh2(OAc)4 catalysis provides 4ꢀ
aminopyrroleꢀ3ꢀcarboxylates in good yields. The use of Rh2(Piv)4 in refluxing toluene results in
the formation of 1,2ꢀdihydropyrazineꢀ2ꢀcarboxylates as the main products which can be
converted by a oneꢀpot procedure to pyrazineꢀ2ꢀcarboxylates by heating with catalytic amounts
of TsOH. According to the NMR and DFT investigations of the reaction mechanism pyrroles and
dihydropyrazines are formed respectively via 1,5ꢀ and 1,6ꢀcyclization of common (5Z)ꢀ1,4ꢀ
diazahexaꢀ1,3,5ꢀtriene intermediates. The influence of the nature of the catalyst on the product
distribution is rationalized in terms of the Rhꢀcatalyzed isomerization of
pyrroliniosulfonylamide zwitterion, the primary product of 1,4ꢀdiazahexatriene 1,5ꢀcyclization.
a
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Introduction
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Conjugated azapolyenes have found wide application in the synthesis of various nitrogen
heterocycles, most of which belong to sixꢀmembered systems.1 In recent years electronꢀpoor
azapolyenes have attracted increasing attention due to the discovery of a wide range of new
effective and selective reactions leading to the formation of not only sixꢀ and fiveꢀ, but even
fourꢀmembered systems. Furthermore, the synthetic sequence “azapolyene formation –
cyclization” can provide a convenient tool for transferring of synthetically important functional
groups from readily available lowꢀmolecular starting compounds to the target heterocycle.
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Scheme 1. Nꢀ and N,Oꢀheteropolyenes in the synthesis of 4−6ꢀmembered heterocycles
N
N
1,4-
N
1,6-
1,6-
1,5-
O
N
RhLn
N
N
N
1a
1c
1b
or
N
O
O
N
N
N
N
1e
1d
1,6-
1f
1,6-
O
1,6-
O
N
N
N
N
[9]
Previous work
N
SO2R1
R2
NHSO2R1
N
N
O
Ar
N
4
N
Rh(II)
H
5
2
R2 = ArCO, CO2Me
N
SO2R1
This work
N
N
O
MeO
N
4
Rh(II)
conditions 1
3
N
SO2R1
N
N
MeO2C
N
4
Rh(II)
conditions 2
N
6
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Depending on the substituents, azapolyenes at ambient temperature can be both stable
compounds and reactive intermediates which rapidly and selectively undergo 1,4ꢀ, 1,5ꢀ or 1,6ꢀ
cyclizations to form fourꢀ2, fiveꢀ2a,c,3 and sixꢀmembered Nꢀ4 and N,Oꢀheterocycles.5 The most
convenient method for the preparation of the starting azapolyenes is the reaction of rhodium
carbenoids with isoxazoles or 2Hꢀazirines (Scheme 1). 2ꢀAzabutaꢀ1,3ꢀdienes 1a, 2ꢀazahexaꢀ
1,3,5ꢀtrienes 1b, 3ꢀazahexaꢀ1,3,5ꢀtrienes 1c, 1ꢀoxaꢀ4ꢀazahexaꢀ1,3,5ꢀtrienes 1d, and 1ꢀoxaꢀ5ꢀ
azahexaꢀ1,3,5ꢀtrienes 1e, which are convenient precursors of 2,3ꢀdihydroazetes, indoles,
pyridines, 2Нꢀ1,4ꢀoxazines, and 2Нꢀ1,3ꢀoxazines were synthesized by the reaction of azirines
with carbenoids generated from αꢀdiazo carbonyl compounds (Scheme 1).2,4b,5a−d The synthesis
of pyrazine derivatives from αꢀdiazo oxime ethers and 2Hꢀazirines, involving transient formation
of 1,4ꢀdiazaꢀ1,3,5ꢀhexatriene 1f, was also recently reported.6 According to recent researches
isoxazoles proved to be a much more convenient starting material than azirines for the
generation of 2ꢀazabutaꢀ1,3ꢀdienes2b,c,5b and 3ꢀazahexaꢀ1,3,5ꢀtrienes.4f A lot of simple and
effective methods for the introduction of various substituents in all positions of the isoxazole
ring are known.7 This, together with the usability and simplicity in storage, makes isoxazoles one
of the most attractive building blocks for the incorporation of the C=C−N moiety into an
azapolyene system. Within our ongoing project on the application of alkoxyisoxazoles for the
synthesis of highly functionalized heterocycles, we have set the goal to employ the azapolyene
methodology for the preparation of N,Nꢀheterocyclic compounds, specifically, pyrazine
derivatives 6, by 5ꢀalkoxyisoxazole−αꢀimino carbenoid coupling. Rhodium αꢀimino carbenoids
(or rhodium azavinyl carbenes) were generated from the corresponding 1ꢀsulfonylꢀ1,2,3ꢀtriazoles
4 under Rh(II)ꢀcatalysis.8 While our research was underway, Lei, Li et al. reported the formation
of 3ꢀaminopyrroles 5 from alkylꢀ/arylꢀsubstituted isoxazoles and Nꢀsulfonylꢀ1,2,3ꢀtriazoles under
Rh(II) catalysis.9 Meanwhile we found that the use of readily available alkoxyisoxazoles in these
reactions provides the capability of the application of αꢀimino carbenoids in the synthesis of not
only fiveꢀ, but also sixꢀmembered heterocycles. Virtually at the same time it has been established
that the Rh(II)ꢀcatalyzed reaction of 2Hꢀazirines with Nꢀsulfonylꢀ1,2,3ꢀtriazoles also leads to
pyrrole and pyrazine derivatives.10−13 However, the factors controlling the formation of these
products are still not clear. Thus, Ryu et al. reported the Rh(II)ꢀcatalyzed reaction of azirineꢀ2ꢀ
carboxylates with Nꢀsulfonylꢀ1,2,3ꢀtriazoles, leading to pyrazines through the intermediate
formation of 1,2ꢀdihydropyrazines,10 while Wang et al. reported the Rh(II)ꢀcatalyzed reaction of
azirineꢀ2ꢀcarboxylates with Nꢀsulfonylꢀ1,2,3ꢀtriazoles leading exclusively to 3ꢀaminopyrroles.11
Furthermore, Zhao et al. observed the formation of both 3ꢀaminopyrroles and 1,2ꢀ
dihydropyrazines.12 These experimental findings require explanation which can be found with
the help of a detailed study of the reaction mechanism.
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Herein we report the switchable synthesis of 4ꢀaminopyrroleꢀ3ꢀcarboxylates and pyrazineꢀ
2ꢀcarboxylates from 5ꢀalkoxyisoxazoles and Nꢀsulfonylꢀ1,2,3ꢀtriazoles, achieved simply by
changing the Rh(II) catalyst and the reaction conditions. The synthesis is supplemented by a
theoretical and an experimental study of the reaction mechanism, which allowed effective
reaction control. The obtained results were also employed to rationalize the mechanistic features
of the published reactions of azirines with 1,2,3ꢀtriazoles.
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Results and Discussion
Reactions of NꢀSulfonylꢀ1,2,3ꢀtriazoles with 5ꢀAlkoxyisoxazoles. In contrast to the
aboveꢀmentioned reaction9 of alkylꢀ/arylꢀsubstituted isoxazoles, treatment of 5ꢀmethoxyꢀ3ꢀ
phenylisoxazole 3a (1.0 equiv) with 4ꢀphenylꢀ1ꢀtosylꢀ1Hꢀ1,2,3ꢀtriazole 4a (2.5 equiv) under
Rh2(Piv)4 catalysis gave two products, 3ꢀaminopyrrole 5a and 1,2ꢀdihydropyrazine 6a, in nearly
equal amounts and a good overall yield (Table 1, entry 1). This result induced us to carry out
additional optimization experiments in order to improve the reaction selectivity. It was found
that such a bulky catalyst as Rh2(esp)2 provides the same selectivity as Rh2(Piv)4, but the use of
Rh(II) catalysts with less bulky ligands, such as Rh2(OAc)4 or Rh2(Oct)4, increases both the
reaction time and the yield of pyrrole 5a (entries 2, 3). With another rhodium carboxylate,
Rh2(tfa)4, only traces of the products were obtained (entry 4). We also found that carrying out the
reaction in dilute solutions promotes formation of 1,2ꢀdihydropyrazine 6a (entries 5, 6), clearly
indicating that the formation of pyrrole 5a involves intermolecular processes. The Rh2(Piv)4
catalyst in refluxing toluene proved to be the conditions of choice for the synthesis of 6a (entry
7), whereas the reaction in chloroform led mostly to pyrrole 5a (entry 11). It was found that the
decomposition of the triazole occurs much more rapidly in toluene or TFT than in chloroform.
Next, it was observed that addition of the triazole in smaller portions also affects the 5a/6a ratio,
providing 1,2ꢀdihydropyrazine 6a in 67% yield (entry 8). The decrease of the reaction
temperature disfavors dihydropyrazine formation (entry 9) but promotes pyrrole formation (entry
12). A decrease in catalyst loading (2.5 mol %) slightly affects the reaction course in toluene
(entry 10) but rises the pyrrole share in chloroform (entry 13). Thus, the maximal yields of
pyrroles 5 can be achieved by use of 2.5 mol % Rh2(OAc)4 in chloroform at 100 °С (sealed tube)
(Method A). The best conditions for the synthesis of dihydropyrazines 6 are the addition of a 2–3
fold excess of the triazole in 0.5 equiv portions in each 0.5–1ꢀmin steps to a refluxing solution
of isoxazole and Rh2(Piv)4 (Method B).
Table 1. Optimization of Reaction Conditions for Synthesis of 5a and 6aa
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catalyst,
mol %
ratio 5a : 6ab
yield of 5a
yield of 6a
entry
conditions
(%)c
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64
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ꢀ
(%)c
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ꢀ
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Rh2(Piv)4, 5.0
Rh2(OAc)4, 5.0
Rh2(Oct)4, 5.0
Rh2(tfa)4, 5.0
Rh2(Piv)4, 5.0
Rh2(Piv)4, 5.0
Rh2(Piv)4, 5.0
Rh2(Piv)4, 5.0
Rh2(Piv)4, 5.0
Rh2(Piv)4, 2.5
Rh2(OAc)4, 5.0
Rh2(OAc)4, 5.0
Rh2(OAc)4, 2.5
1.1: 1
2.9 : 1
2.3 : 1
ꢀ
1 : 1.3
1 : 1.8
1 : 2.3
1 : 2.9
1 : 1.7
1 : 3.0
3.5 : 1
4.0 : 1
5.5 : 1
TFT (0.5 mL), 102 °C
TFT (0.5 mL), 102 °C
TFT (0.5 mL), 102 °C
TFT (0.5 mL), 102 °C
TFT (1 mL), 102 °C
TFT (3 mL), 102 °C
toluene (3 mL), 110 °C
toluene (3 mL), 110 °C
toluene (3 mL), 90 °C
toluene (3 mL), 110 °C
CHCl3 (0.5 mL), 100 °C
CHCl3 (0.5 mL), 85 °C
CHCl3 (0.5 mL), 100 °C
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8d
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10d
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aReaction conditions: 3a (0.29 mmol), 4a (2.5 equiv for entries 1–10, 1.5 equiv for entries 11–13); TFT = α,α,αꢀ
trifluorotoluene, Oct = octanoate, Piv = pivalate, tfa = trifluoroacetate, esp = α,α,α’,α’ꢀtetramethylꢀ1,3ꢀ
benzenedipropanoate. bRatios were determined by 1H NMR spectroscopy. c1H NMR yields using 1ꢀ
methylnaphthalene as an internal standard. d0.72 mmol of 4a was added in 5 equal portions.
With the optimized reaction conditions in hand, we next turned attention to the scope of
the reaction for the synthesis of both 3ꢀaminopyrroles and 1,2ꢀdihydropyrazines (Table 2).
Generally, 3ꢀaminopyrroles 5 can be obtained in good yields from differently substituted
alkoxyisoxazoles and 1ꢀsulfonylꢀ1,2,3ꢀtriazoles by the method A. Only in the case of strong
electronꢀwithdrawing substituents in the phenyl ring, such as pꢀNO2, pꢀCN, or oꢀF (entries 8, 9,
15), the yields of pyrroles 5 are noticeably lower due to the formation of significant amounts of
corresponding dihydropyrazines 6. In contrast, electronꢀdonating substituents strongly facilitate
the formation of 3ꢀaminopyrroles, and no dihydropyrazines were detected in the reaction
mixtures obtained under the conditions of the method A (entries 4, 5). The reaction also could be
applied to the synthesis of pyrroles with carboxamide (entry 16) and benzoyl substituents (entry
17), although the yields of the products in these cases are lower. Unfortunately, we could not
obtain the desired products from 4ꢀbutylꢀ1ꢀtosylꢀ1,2,3ꢀtriazole 1f because of the enhanced
tendency of the intermediate carbenoid to undergo 1,2ꢀHꢀshift.12
Table 2. Synthesis of Pyrroles and Dihydropyrazines from Isoxazoles 3 and 1ꢀsulfonylꢀ
1,2,3ꢀtriazoles 4 a,b
R1/R2
R3/ R4
entry
yield of 5 and 6 (%)
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76 (5a), 15 (6a)
81 (5b), 6 c (6b)
77 (5c), 7 c (6c)
87 (5d), 0 c (6d)
75 (5e), 0 (6e)
66 (5f), 26 (6f)
61 (5g), 25 (6g)
17 (5h), 30 (6h)
29 (5i), 62 (6i)
65 (5j), 23 (6j)
55 (5k), 5 c (6k)
78 (5l), 8 c (6l)
55 (5m), 0 (6m)
60 (5n), 18 c (6n)
43 (5o), 33 (6o)
28 (5p), 0 c (6p)
45 (5q), 7 (6q)
Ph/MeO (3a)
Ph/Ts (4a)
Ph/Ts (4a)
Ph/Ts (4a)
Ph/Ts (4a)
4ꢀMeC6H4/MeO (3b)
2,4ꢀ(Me)2C6H3/MeO (3c)
4ꢀMeOC6H4/MeO (3d)
3,4ꢀ(O(CH2)2O)C6H3/MeO (3e) Ph/Ts (4a)
4ꢀBrC6H4/MeO (3f)
4ꢀClC6H4/MeO (3g)
4ꢀNCC6H4/MeO (3h)
4ꢀO2NC6H4/MeO (3i)
Ph/tBuO (3j)
Me/MeO (3k)
Ph/MeO (3a)
Ph/MeO (3a)
Ph/MeO (3a)
Ph/Ts (4a)
Ph/Ts (4a)
Ph/Ts (4a)
Ph/Ts (4a)
Ph/Ts (4a)
Ph/Ts (4a)
Ph/Ms (4b)
4ꢀMeOC6H4/Ts (4c)
4ꢀClC6H4/Ts (4d)
2ꢀFC6H4/Ts (4e)
Ph/Ts (4a)
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Ph/MeO (3a)
Ph/pyrrolidinꢀ1ꢀyl (3l)
Ph/Ph (3m)
Ph/Ts (4a)
aReaction conditions: 3 (0.29 mmol), 4 (1.5 equiv), Rh2(OAc)4 (0.025 equiv), CHCl3 (0.5 mL) in sealed
tube. bIsolated yield. c1H NMR yields using 1ꢀmethylnaphthalene as an internal standard.
Optimization experiments showed that the method B results in preferred formation of
dihydropyrazines (Table 1, entry 10). Even though these compounds proved to be rather
unstable, they can be prepared in an analytically pure form. Thus, dihydropyrazines 6a,l were
obtained in toluene under reflux in the presence of 2.5 mol % Rh2(Piv)4 in reasonable yields
(Scheme 2).
Scheme 2. Synthesis of 1,2ꢀdihydropyrazines
The compounds 6a,l decompose on storage to form the corresponding pyrazines 7, along
with several unidentified products. Assuming that this reaction could be used for preparing the
target pyrazineꢀ2ꢀcarboxylates we took effort to optimize the reaction conditions. For
transformation of dihydropyrazines 6 to pyrazines 7, several conditions were examined: reflux in
toluene in the presence of (a) Et3N, (b) pꢀtoluenesulfonic acid (TsOH), or (c)
azobisisobutyronitrile and (d) reflux in oꢀxylene without any additive. All these conditions were
found to be suitable for the transformation (20% Et3N, 130 °C, 10 h; oꢀxylene, 144 °C, 5 h), but
we chose TsOH in refluxing toluene, which allows smooth conversion of dihydropyrazines 6 to
pyrazines 7 within 3 h. We assume that the acid may facilitate elimination of toluenesulfinic acid
through protonation of the carbonyl oxygen. Oneꢀpot protocol for the preparation of pyrazines
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from isoxazoles and triazoles without isolation of dihydropyrazines was found to be more
effective. Thus, isoxazole 3a (1 equiv) was reacted with triazole 4a (2.5 equiv) in the presence of
Rh2(Piv)4 (2.5 mol %) in toluene under reflux (method B). The resulting mixture, without
isolation of dihydropyrazine 6a, was further treated with TsOH (0.2 equiv) and refluxed for an
additional 3 h to give pyrazine 7a in 63% yield (Table 3, entry 1). To test the generality of the
protocol, other isoxazoles (except for isoxazoles bearing strong electronꢀdonating groups) and
triazoles were examined under the oneꢀpot conditions. Expectedly, pyrazines having electronꢀ
withdrawing substituents were obtained in good yields (entries 3–5, 8–10). It was encouraging
that under the given conditions pyrazines can be prepared in acceptable yields from isoxazoles
which produce only traces of dihydropyrazines under the conditions of the method A (entries 2,
7, 11). The reaction also proceeds smoothly also with isoxazole 3j containing the bulky tertꢀ
butoxy group to form the corresponding pyrazine in 72% yield (entry 6).
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Table 3. OneꢀPot Synthesis of Pyrazines from Isoxazoles and 1ꢀSulfonylꢀ1,2,3ꢀtriazolesa,b
entry
1
2
3
4
5
6
7
8
R1/R2
Ph/MeO
4ꢀMeC6H4/MeO
4ꢀBrC6H4/MeO
4ꢀClC6H4/MeO
4ꢀO2NC6H4/MeO
Ph/tBuO
Me/MeO
Ph/MeO
Ph/MeO
4ꢀClC6H4/MeO
Ph/Ph
R3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4ꢀClC6H4
2ꢀFC6H4
4ꢀClC6H4
Ph
yield of 7 (%)
63 (7a)
44 (7b)
70 (7c)
72 (7d)
77 (7e)
72c (7f)d
32c (7g)
61 (7h)
75 (7i)
3
4
3a
3b
3f
3g
3i
4a
4a
4a
4a
4a
4a
4a
4d
4e
4d
4a
3j
3k
3a
3a
3g
3m
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11
71 (7j)
25 (7k)
a Reaction conditions: 3 (0.29 mmol), 4 (2.5 equiv), Rh2(Piv)4 (0.025 equiv), TsOH (0.2 equiv), toluene (3 mL). b
Isolated yield. c Et3N (2 equiv) was used instead of TsOH. d 2,6ꢀDiphenylpyrazine (7l) in 53% yield was obtained
under reflux in oꢀxylene without any additive on the 2nd stage.
Experimental exploration of the reaction mechanism. One can find in the literature
three different mechanisms for the formation of dihydropyrazines B from 1ꢀsulfonylꢀ1,2,3ꢀ
triazoles and azirines A under Rh(II) catalysis (Scheme 3).10−13 In all cases the reaction is
supposed to occur via metalꢀbounded ylide D. Zhang and coauthors suggested that
dihydropyrazine B is formed from ylide D via 1,5ꢀcyclization followed by aziridine ring
opening.13 However, this hypothesis contradicts the experimental data for 3ꢀarylꢀ2Hꢀazirineꢀ2ꢀ
carboxylates obtained by Lee and coauthors who, in turn, suggested two other possibilities for
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the transformation of D into B: a) oneꢀstep transformation or b) ring opening to 1,4ꢀ
diazahexatriene G followed by 1,6ꢀcyclization.10 The formation of intermediate G was not
excluded by Wang, Lei and Tang as well.11 However, relying on the effect of C2ꢀsubstituents in
the azirine on the B/C ratio, they preferred intermediate F as a precursor of dihydropyrazine B.
All authors concur on the intermediate formation of metalꢀbounded ylide D on the route both to
dihydropyrazine B and pyrrole C. One of the two suggested mechanisms for the formation of
pyrrole C involves the generation of a 1Нꢀazirine intermediate, its recyclization to 3Нꢀpyrrole J
followed by isomerization to pyrrole C.12 The alternative version inclines to the formation of a
3Нꢀpyrrole intermediate J via the transformation of ylide D to zwitterꢀion I.11 Diazatriene G was
not considered as an intermediate on the route to pyrrole C from ylide D, but the formation of G
was postulated for rationale of the formation of pyrrole C from isoxazolium ylide L, generated
from isoxazole K and 1ꢀsulfonylꢀ1,2,3ꢀtriazole.9
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Scheme 3. Published mechanistic schemes
None of the aboveꢀmentioned mechanisms can explain why the reaction outcome
depends on temperature and on the change of the starting material from azirine to isoxazole. The
structure of the common precursor (if any) of pyrrole and dihydropyrazine and mechanistic
differences in the transformations of azirinium and isoxazolium ylides to final products are the
key issues remaining unclear.
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To gain insight into the mechanism of the formation of 3ꢀaminopyrroles and 1,2ꢀ
dihydropyrazines, several additional experiments were performed (Table 4). Firstly, isoxazole 3a
and azirine 8 were reacted with triazole 4a under the conditions of methods A and B. Under
conditions A (Rh2(OAc)4/CHCl3/100 °C) isoxazole 3a and azirine 8 did not display considerable
difference in products yields (Table 4, entries 1, 2). In contrast, under conditions B
(Rh2(Piv)4/toluene/110 °C) azirine 8 gave 3ꢀaminopyrrole 5a substantially while from isoxazole
3a dihydropyrazine 6a was obtained as a major product (Table 4, entries 3, 4). Thus, a key point
for successful synthesis of dihydropyrazines/pyrazines is the use of 5ꢀalkoxyisoxazoles but not
corresponding azirineꢀ2ꢀcarboxylates.
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An additive of TsOH in the reaction of isoxazole 3a with triazole 4a led to a significant
increase of pyrrole/dihydropyrazine ratio and somewhat decreased overall yield of products
(Table 4, entry 5). It is interesting that water did not have any effect on the ratio and yields of
aminopyrrole 5a and 1,2ꢀdihydropyrazine 6a (Table 4, entry 6).
Table 4. Reactions of Triazole 4a with Isoxazole 3a and Azirine 8 under Rh(II) catalysis
entry starting
compounds
3a + 4a
conditionsa
(additive)
A
A
B
B
5a : 6a ratiob overall yieldc,
%
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6
3.6 : 1
4.1 : 1
1 : 3
93
90
91
90
72
94
8 + 4a
3a + 4a
8 + 4a
3a + 4a
3a + 4a
1.4 : 1
B (0.05 equiv TsOH) 1.1 : 1
B (1 equiv H2O) 1 : 3
a Conditions A: 4a (1.5 equiv), Rh2(OAc)4 (0.025 equiv), CHCl3, 100 °C, 2 h;
conditions B: 4a (2.5 equiv), Rh2(Piv)4 (0.025 equiv), toluene, 110 °C, 3 min;
b The ratios were determined by 1H NMR spectroscopy.
c The yields were determined by 1H NMR spectroscopy using 1ꢀmethylnaphthalene as an
internal standard.
To find out what is the possible intermediate on the way to isomeric products 5 and 6, we
have analyzed the reaction mixture obtained by the method B at the early stage of the reaction
(addition of 1 equiv of triazole 4a to isoxazole 3a, heating for 30 s followed by fast cooling). To
1
our delight, according to H NMR, along with aminopyrrole 5a and dihydropyrazine 6a, a
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significant amount of another compound was present in the reaction mixture (Figure 1, record 1).
The positions of signals of this intermediate in the 1H NMR spectrum (8.89, 5.48 and 3.59 ppm)
and cross peaks in the 2D 1Hꢀ13C HSQC spectrum (1H 8.89 ppm – 13C 165.2 ppm, 1H 5.48 ppm –
13C 96.3 ppm) (Fig. Sꢀ1, Supporting Information) allowed unequivocal identification of (5Z)ꢀ1,4ꢀ
diazaꢀ1,3,5ꢀtriene Zꢀ9a (Scheme 4). The chemical shift of the C6 atom less than 100 ppm in the
13C NMR spectrum is characteristic of the 3ꢀaminocinnamate moiety with Z configuration of the
C=C bond.2b,5b The diazatriene Zꢀ9a/pyrrole 5a/dihydropyrazine 6a ratio in the reaction mixture
after 30 s was 3.7 : 1 : 2.4 (Figure 1, record 1). Unfortunately, all attempts to isolate this
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1
compound by chromatography failed due to its instability. Meanwhile, H NMR monitoring of
the reaction mixture has proved to be helpful for study of the transformations of intermediate Zꢀ
9a. When kept in toluene for 24 h at room temperature, intermediate Zꢀ9a gradually transformed
mainly into pyrrole 5a (CH3O shift is 3.42 ppm) with partial decomposition (Figure 1, record 2).
While under reflux in toluene for 5 min about three quarters of diazatriene Zꢀ9a converted into
dihydropyrazine 6a (CH3O shift is 3.66 ppm) and only one quarter, into pyrrole 5a (Figure 1,
record 3). These results provide unequivocal evidence showing that both 3ꢀaminopyrrole 5a and
1,2ꢀdihydropyrazine 6a are formed from the same precursor, (5Z)ꢀ1,4ꢀdiazaꢀ1,3,5ꢀtriene Zꢀ9a
(Scheme 4).
Scheme 4. Formation of 1,4ꢀDiazatriene Intermediates 9a in the Reactions of Triazole 4a
with Isoxazole 3a and Azirine 8
1
Figure 1. H NMR Monitoring (CDCl3) of the Transformation of Intermediate Zꢀ9a in the
reaction of Triazole 4a and Isoxazole 3a
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The reaction of triazole 4a with azirine 8 (Scheme 4) under the same conditions and
stopped by cooling after 30 s gave the same three products, Zꢀ9a,5a, and 6a (Fig. Sꢀ2,
1
Supporting Information), but, according to H NMR, their ratio (1 : 6 : 2) differed markedly
from that observed in the reaction of isoxazole 3a (Figure 1, record 1). The dramatic effect of
substrate nature on the reaction progress and product distribution can be rationalized in terms of
a change in the key intermediate: from diazatriene Zꢀ9a in isoxazole reaction to diazatriene Eꢀ9a
in azirine reaction (Scheme 4). Isoxazole 3a reacts with αꢀimino carbenoid to form diazatriene Zꢀ
9a exclusively, while the reaction of azirine 8 can yield both isomers: Eꢀ9a and Zꢀ9a. The
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stereoselectivity of the latter reaction is defined by the selectivity of ring opening in the metalꢀ
bounded azirinium ylide (Scheme 3) or the metalꢀfree azirinium ylide formed after elimination
D
5
6
7
8
of the catalyst. It is known that related azirinium ylides with the same substitution pattern of the
ring, generated from azirines and diazo carbonyl compounds, provide a mixture of isomeric
azadienes across С=С bond with the E/Z ratio ca. 2 : 1.2b,5c Thereby, there is every reason to
believe that an isoxazolium ylide undergoes ringꢀopening into diazatriene Zꢀ9a exclusively,
while an azirinium ylide provides both the Eꢀ9a and Zꢀ9a diazatrienes with a significant
prevalence of the former isomer (Scheme 4). The absence of isomer Eꢀ9a in the reaction mixture,
resulted from azirine 8, can be explained by its higher reactivity in comparison with Zꢀ9a toward
isomerization to pyrrole 5a. To validate these hypotheses, we performed quantumꢀchemical
calculations of the transformation pathways of diazatriene species to compounds 5 and 6.
Theoretical calculations. DFT calculations were used to compare the two competitive
routes of cyclization of isomeric diazatrienes and to clarify the reasons for the high sensitivity of
the reaction outcome to temperature and reаgent concentrations. The pathways for the
transformations of model diazatrienes Zꢀ9b (Z configuration of the C=C bond) and Eꢀ9b (E
configuration of the C=C bond) generated from 1ꢀmesylꢀ4ꢀphenylꢀ1,2,3ꢀtriazole (4b) and
isoxazole 3a or azirine 8 were studied using Gaussian 09 programs package at B3LYP 6ꢀ
31+G(d,p) theory level. To take into account the influence of the solvent, the PCM solvation
model for toluene was employed (Scheme 5, Figure 2). In the Fig. 2 for clarity only the
transformations with the lowest barriers are presented.
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The calculations reveal that dihydropyrazine 6l is formed directly via 1,6ꢀcyclization of
diazatriene Zꢀ9b (TS1) (Fig. 2, blue line). The alternative twoꢀstep pathway involving the
formation of 2Hꢀ1,3ꢀoxazine 17 and Copeꢀrearrangement does not occur due to the absence of
pericyclic transition state on the second stage: the rearrangement of oxazine 17 to
dihydropyrazine 6l occurs via TS1 as well. Nevertheless, 1,3ꢀoxazine 17 is really generated in
this reaction and exists in equilibrium with diazatriene Zꢀ9b. The transition state energies for 1,5ꢀ
cyclization of Zꢀ9b and Eꢀ9b (TS2 and TS4) are significantly lower than those for 1,6ꢀ
cyclizations (TS1 and TS3). The barriers for alternative 1,5ꢀcyclizations of these intermediates
through transition states TS6 and TS7 are significantly higher (Fig. Sꢀ3, Supporting
Information). It is important, that unlike 1,6ꢀcyclizations, the formation of a 5ꢀmembered ring is
a reversible process in all cases under the used reaction conditions. Diazatriene Zꢀ9b cyclizes to
zwitterion cisꢀ10b that exists in rapid equilibrium with aziridine cisꢀ11b. With isomeric
diazatriene Eꢀ9b, 1,5ꢀcyclization and aziridine ring closure occur in one step to give aziridine
transꢀ11b which is 4.3 kcal·molꢀ1 less stable than initial Eꢀ9b. The search for the unimolecular
isomerization pathways of zwitterion cisꢀ10b to final pyrrole 5l did not reveal any with the
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energy profile lying below than that for the competitive 1,6ꢀcyclization of Zꢀ9b to
dihydropyrazine 6l (TS1). The following unimolecular transformations as initial steps were
5
6
calculated (Scheme 5): C
→
C [1,2]ꢀHꢀshift to 3ꢀiminopyrroline 14 (TS9, route a), C
→O 1,4ꢀ
prototropic shift to 3Hꢀpyrrole 15 (TS10, route b), and C
→
N 1,2ꢀprototropic shift to 3Hꢀpyrrole
7
8
16 (TS11, route c) (Fig. Sꢀ3, Supporting Information). Pyrrole 5l most probably results from
lowꢀbarrier intramolecular 1,5ꢀHꢀshifts in 3Hꢀpyrrole 13b which, in turn, could be formed in an
unimolecular fashion only from aziridine transꢀ11b (TS12), the 1,5ꢀcyclization product of
diazatriene Eꢀ9b (Fig. 2, red line). According to the calculations, the transformation of transꢀ11b
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to 3Hꢀpyrrole 12b occurs via C
(TS12). The alternative isomerization pathways of aziridine transꢀ11b via C
shift (TS13) and C N 1,3ꢀprototropic shift (TS14) have much higher barriers (Figure Sꢀ3,
Supporting Information). The unimolecular isomerization of isoxazoleꢀderived diazatriene Zꢀ9b
into pyrrole 5l via cisꢀ11b or zwitterion cisꢀ10b (similar to isomerization transꢀ11b 12b) is not
→
O 1,5ꢀprototropic shift coupled with aziridine ring opening
→
O 1,4ꢀprototropic
→
→
feasible due to the trans arrangement of H3 and sulfonylamide moiety in these species. At the
same time, the experiments showed that the isomerization of diazatriene Zꢀ9a to pyrrole 5a
occurs in the reaction mixture even at room temperature (Figure 1, records 1, 2), while the
increasing temperature favors 1,6ꢀcyclization. These facts, as well as the pronounced effect of
the nature of the rhodium catalyst and dilution of the reaction mixture on the 5/6 ratio (Table 1)
are the arguments for a) intermolecular character of isomerization of zwitterion cisꢀ10b to
pyrrole 13b and b) participation of the rhodium catalyst in this process. We assumed that
dirhodium tetracarboxylate catalyzes the prototropic shift in zwitterion cisꢀ10b via the
intermediate formation of cisꢀ10b·RhLn complex. The latter further undergoes intermolecular
prototropic shift to pyrrole 13b, most likely under the promotion of the basic diazatriene Zꢀ9b.
The sulfonylamide moiety in zwitterion cisꢀ10b is shielded by the cisꢀmethoxycarbonyl group,
which should result in a significant depression of the Nꢀcomplexation ability. On the other hand,
the less sterically hindered zwitterion transꢀ10b (not shown in Scheme 5), which does not exist
in a free state (Fig. 2), could be trapped by dirhodium tetracarboxylate as a complexation agent.
Moreover, Rh2(OAc)4 with less bulky carboxylate ligands must be much more active
complexation agent than Rh2(Piv)4 and Rh2(esp)2. According to the quantumꢀchemical
calculations (DFT B3LYP/6ꢀ31G(d)/Stuttgart RSC 1997 ECP), zwitterion transꢀ10b which has
no local minimum on the PPE gave N
−
Rhꢀcomplexes transꢀ10b·Rh2(RCO2)4 (Fig. Sꢀ4,
Rh bond in cisꢀ10b·Rh2(Piv)4 in
Supporting Information). The significant lengthening of the N
−
comparison with cisꢀ10b·Rh2(OAc)4 reflects the lower stability of the former, and therefore, its
lower concentration in the solution. Evidence for the aboveꢀmentioned destabilizing effect of the
cisꢀoriented CO2Me group in complexes cisꢀ10b·Rh2(Piv)4 and cisꢀ10b·Rh2(OAc)4 comes from
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the fact that they have higher energies than transꢀ10b·Rh2(Piv)4 and transꢀ10b·Rh2(OAc)4: 16.9
and 8.9 kcal/mol, respectively. Thus, the highest concentration of a zwitterion complex active
toward intermolecular isomerization into pyrrole 5 has to be expected in a Rh2(OAc)4ꢀcatalyzed
reaction of azirineꢀ2ꢀcarboxylates, while the lowest, in a Rh2(Piv)4ꢀcatalyzed reaction of 5ꢀ
alkoxyisoxazoles. Besides, these facts provide a good rationale for observed low stability of
diazatriene Eꢀ9a in the “azirine reaction” in comparison with diazatriene Zꢀ9a stability in the
“isoxazole reaction”.
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Scheme 5. Possible Pathways for the Formation of Pyrrole 5l and Dihydropyrazine 6l from
Diazatrienes Zꢀ9b and Eꢀ9b
Figure 2. Energy Profiles (Zeroꢀpoint Exclusive Energies, B3LYP/6ꢀ31+G(d,p), kcal⋅
molꢀ1,
373K, toluene) for Unimolecular Transformations of Diazatrienes Zꢀ9b and Eꢀ9b
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The significant effect of aryl substituents on the 5/6 ratio (Table 2) can be explained in the
context of their cationꢀstabilizing ability in complexes cisꢀ10·RhLn. Electronꢀwithdrawing aryl
substituents adjacent to the cationic center destabilize the zwitterion, and the dihydropyrazine
percentage increases (Table 2). In contrast, electronꢀdonating aryl substituents at the same
positions stabilize the zwitterion, which reveals itself in the observed full absence of
dihydropyrazine.
Addition of an acid in the reaction mixture can facilitate the isomerization of intermediate
cisꢀ10b·RhLn complex to 3Hꢀpyrroles 13b, a precursor of 1Hꢀpyrrole 5l, via Nꢀprotonation/Cꢀ
deprotonation, resulting in increase of the 5/6 ratio. Such effect was indeed observed in the
reaction of isoxazole 3a with triazole 4a when catalytic amounts of TsOH were added (Table 4,
entry 5).
Thus, the following features become apparent upon analysis of the calculation results and
experimental data: a) both stereoisomeric diazatrienes undergo relatively slow but irreversible
1,6ꢀcyclization to the dihydropyrazine, while 1,5ꢀcyclization occurs rapidly and reversibly; b)
azirineꢀderived Eꢀdiazatriene undergoes 1,5ꢀcyclization with a lower barrier than isoxazoleꢀ
derived Zꢀdiazatriene; c) there is no one single unimolecular step competitive with 1,6ꢀ
cyclization on the way from the primary 1,5ꢀcyclization products of Zꢀdiazatrienes to pyrroles 5;
and d) the formation of pyrrole 5 in both azirine and isoxazole reactions is controlled by the
ability of the azirinopyrrole intermediate to produce via aziridine ring opening the zwitterion
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intermediate or/and its rhodium complex. Taking into account these data the mechanistic scheme
for the catalytic reaction of isoxazoles 3a k with triazoles 4a e (Scheme 6) involves the
−
−
5
6
7
8
formation of diazatriene Zꢀ9 that exists in equilibrium with zwitterion cisꢀ10 and azirinopyrrole
cisꢀ11. At elevated temperatures and in more dilute solutions, the diazatriene preferably
undergoes irreversible 1,6ꢀcyclization to dihydropyrazine 6. And, conversely, a decrease in
temperature and an increase in concentration of reactants accelerates the competitive reaction of
zwitterion cisꢀ10 with the catalyst to form a rhodium complex. The latter irreversibly isomerizes
to 3Нꢀpyrrole 13 which further undergoes two 1,5ꢀHꢀshifts to give pyrrole 5.
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Scheme 6. Reaction mechanism
Conclusion
In conclusion, 4ꢀaminopyrroleꢀ3ꢀcarboxylates and pyrazineꢀ2ꢀcarboxylates were synthesized by
a Rh(II)ꢀcatalyzed reaction of 1ꢀsulfonylꢀ1,2,3ꢀtriazoles with stable and readily available 5ꢀ
alkoxyisoxazoles. The reasonable yields of each product were achieved by tuning the Rh(II)
catalyst and the reaction conditions. The reaction in chloroform at 100 °C in the presence of
Rh2(OAc)4 as a catalyst is most suitable for the synthesis of 4ꢀaminopyrroleꢀ3ꢀcarboxylates. The
use of Rh2(Piv)4 in refluxing toluene results in the formation of 1,2ꢀdihydropyrazineꢀ2ꢀ
carboxylates as the main products which were transformed to pyrazineꢀ2ꢀcarboxylates in a oneꢀ
pot procedure by heating with catalytic amounts of TsOH. The NMR data and DFT calculations
revealed that both products, pyrrole and dihydropyrazine, are formed via 1,4ꢀdiazahexaꢀ1,3,5ꢀ
triene intermediate having C=C bond with Z configuration. The Eꢀdiazatriene isomer generated
from the azirineꢀ2ꢀcarboxylate isomeric to the 5ꢀalkoxyisoxazole produces predominantly the
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corresponding 4ꢀaminopyrroleꢀ3ꢀcarboxylate, which makes the azirineꢀtype substrates poorer
candidates for the preparation of pyrazineꢀ2ꢀcarboxylate derivatives. The influence of the nature
of the rhodium catalyst on the product distribution is rationalized in terms of the Rhꢀcatalyzed
isomerization of the pyrroliniosulfonamide zwitterion, the primary product of 1,4ꢀ
diazahexatriene 1,5ꢀcyclization.
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EXPERIMENTAL SECTION
General methods. Melting points were determined on a melting point apparatus and are
1
uncorrected. The H NMR spectra were recorded at 400 MHz. The 13C NMR spectra were
recorded at 100 MHz. Chemical shifts (δ) are reported in ppm downfield from tetramethylsilane
in solvents indicated below. Highꢀresolution mass spectra were recorded on an HRMSꢀESIꢀ
QTOF instrument, electrospray ionization, positive mode. Thinꢀlayer chromatography (TLC)
was conducted on aluminum sheets precoated with SiO2 ALUGRAM SIL G/UV254. Column
chromatography was performed on silica gel 60 M (0.04–0.063 mm). All solvents were distilled
and dried prior to use. Toluene was distilled and stored over sodium metal. Chloroform was
washed with concentrated H2SO4, water, then distilled from P2O5 and stored refrigerated in the
dark over anhydrous K2CO3. The catalysts Rh2(Oct)4,14 Rh2(Piv)4 and Rh2(esp)2 were
prepared by the reported procedures and gave satisfactory elemental analyses. Isoxazoles 3a–h,2b
3l,17 3m,18 1,2,3ꢀtriazoles 4a c,f,19 and azirine 820 were prepared by the reported procedures.
−
General procedure for the preparation of 5ꢀmethoxyisoxazoles 3i,k.2b To a stirred
suspension/solution of isoxazolone (1 equiv) in dry Et2O (50 mL) a solution of diazomethane (2
equiv) in Et2O, prepared from NꢀnitrosoꢀNꢀmethylurea and KOH, was added dropwise at 0 °С.
The resulting mixture was stirred at rt for 2 h and then concentrated in vacuo. The residue was
purified by column chromatography on silica gel (eluent petroleum ether–EtOAc 3:1).
5ꢀMethoxyꢀ3ꢀ(4ꢀnitrophenyl)isoxazole (3i). Compound 3i was obtained from 3ꢀ(4ꢀ
nitrophenyl)isoxazolꢀ5(4H)ꢀone 19 and a solution of diazomethane as a colorless solid (1.71 g,
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yield 74%); mp 122–124 °С (Et2O/hexane); Rf = 0.42 (hexane/EtOAc 2:1); H NMR (CDCl3) δ
8.35–8.29 (m, 2Н), 7.98–7.92 (m, 2Н), 5.63 (s, 1H), 4.11 (s, 3H); 13С NMR (CDCl3) δ 175.0,
162.3, 148.7, 135.6, 127.3, 124.1, 75.8, 59.0; HRMS−ESI [M + Na]+ calcd for С10Н8N2O4Na+
243.0376; found 243.0381.
5ꢀMethoxyꢀ3ꢀmethylisoxazole (3k).21 Compound 3k was obtained from 3ꢀmethylisoxazolꢀ
5(4H)ꢀone21 and a solution of diazomethane as a colorless smelly oil (350 mg, yield 56%); Rf =
1
13
0.41 (hexane/EtOAc 2:1); H NMR (CDCl3) δ 5.07 (s, 1H), 3.96 (s, 3H), 2.21 (s, 3H) С NMR
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+
(CDCl3) δ 174.1, 162.2, 77.7, 58.5, 12.3; HRMSꢀESI [M + H]+ calcd for C5H8NO2 114.0550;
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found 114.0550.
5ꢀ(tertꢀButoxy)ꢀ3ꢀphenylisoxazole (3j).22 A mixture of 5ꢀchloroꢀ3ꢀphenylisoxazole22 (500
mg, 2.8 mmol), potassium tertꢀbutoxide (374 mg, 3.34 mmol) in dry tetrahydrofuran (7 mL) was
refluxed for 1 h. The precipitate of potassium chloride was filtered off and the filtrate was
concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent
petroleum ether–Et2O 3:1) to give compound 3j as a colorless oil (549 mg, yield 91%). Rf = 0.61
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(hexane/EtOAc 2:1); H NMR (CDCl3) δ 7.81–7.76 (m, 2H), 7.50–7.42 (m, 3H), 5.68 (s, 1H),
1.56 (s, 9H); 13С NMR (CDCl3) δ 172.0, 163.9, 129.85, 129.84, 128.8, 126.4, 84.9, 82.4, 28.3;
HRMS−ESI [M + Na]+ calcd for C13H15O2NNa+ 240.0995; found 240.0999.
General procedure for the preparation of 1ꢀsulfonylꢀ1,2,3ꢀtriazoles 4d,e.19 To a
stirred solution of terminal alkyne (1.1 equiv), sulfonyl azide (1 equiv), and 2ꢀaminophenol (0.05
equiv) in MeCN was added Cu(OAc)2·H2O (0.1 equiv) at room temperature. After sulfonyl azide
was consumed (0.5–3 h, monitored by TLC) the solvent was removed in vacuo. The residue was
purified by column chromatography on silica gel (eluent petroleum ether–EtOAc 3:1).
4ꢀ(4ꢀChlorophenyl)ꢀ1ꢀ(4ꢀmethylphenylsulfonyl)ꢀ1Hꢀ1,2,3ꢀtriazole (4d).23 White solid
(1.26 g, yield 59%); Rf = 0.56 (hexane/EtOAc 2:1); 1H NMR (CDCl3) δ 8.33 (s, 1H), 8.05 (d, J =
8.5 Hz, 2H), 7.79 (d, J = 8.5 Hz, 2H), 7.45–7.40 (m, 4H), 2.48 (s, 3H).
4ꢀ(2ꢀFluorophenyl)ꢀ1ꢀ(4ꢀmethylphenylsulfonyl)ꢀ1Hꢀ1,2,3ꢀtriazole (4e). White solid (550
mg, yield 70%); mp 132–134 °С; Rf = 0.56 (hexane/EtOAc 2:1); 1H NMR (CDCl3) δ 8.50 (d, J =
3.4 Hz, 1H), 8.28 (td, J = 7.6, 1.8 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H),
7.40–7.33 (m, 1H), 7.27 (td, J = 7.6, 1.2 Hz, 1H), 7.18 (ddd, J = 11.0, 8.3, 1.1 Hz, 1H), 2.47 (s,
3H) ; 13С NMR (CDCl3) δ 159.4 (d, J = 249 Hz), 147.3, 140.86 (d, J = 2.2 Hz), 133.1, 130.5,
130.3 (d, J = 8.7 Hz), 128.7, 128.07 (d, J = 3.0 Hz), 124.68 (d, J = 3.5 Hz), 121.93 (d, J = 13.7
Hz), 117.06 (d, J = 12.6 Hz), 115.8 (d, J = 21.4 Hz), 21.8; HRMS−ESI [M + H]+ calcd for
С15Н13FN3O2S+ 318.0707; found 318.0706.
Rhꢀcatalyzed reactions of isoxazoles 3a−m with 1ꢀsulfonylꢀ1,2,3ꢀtriazoles 4a−e.
Method A. Isoxazole 3 (0.29 mmol, 1 equiv), triazole 4 (0.32 mmol, 1.1 equiv),
Rh2(OAc)4 (3.2 mg, 0.025 equiv), and CHCl3 (0.5 mL) were placed to a screw cap glass tube and
heated at 100 °C (oil bath temperature) under stirring for 1–6 h until full consumption of
isoxazole was detected (control by TLC, hexane–Et2O 3:1), if necessary, an additional amount of
triazole was added (total amount see below). The solvent was removed in vacuo and the residue
was purified by column chromatography on silica gel (eluent petroleum ether–EtOAc 3:1 unless
otherwise stated) to give the desired products.
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Method B. Isoxazole 3 (0.29 mmol, 1 equiv), Rh2(Piv)4 (4.4 mg, 0.025 equiv), and toluene
(3.0 mL) were placed to a roundꢀbottom flask under an ambient atmosphere and rapidly heated
to reflux (oil bath temperature 130 °C) under stirring. Then triazole 4 as a solid was added in 0.5
equiv portions (total amount see below) until full consumption of isoxazole was detected (control
by TLC, hexane–Et2O 3:1). Each subsequent portion of triazole was added after the nitrogen
evolution has stopped (about 0.5–1 min). The solvent was removed in vacuo and the residue was
purified by column chromatography on silica gel (eluent petroleum ether–Et2O 3:1 unless
otherwise stated) to give the desired products. For the synthesis of pyrazines 7 the above reaction
mixture before chromatographic purification was treated with pꢀtoluenesulfonic acid (10 mg, 0.2
equiv) and refluxed for 3 h.
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Methyl 4ꢀ(4ꢀmethylbenzenesulfonamido)ꢀ2,5ꢀdiphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate
(5a).
Obtained from isoxazole 3a and triazole 4a (1.5 equiv, 128 mg, 0.43 mmol) according to the
method A as a white solid (98 mg, yield 76%); mp 166−168 °C; Rf = 0.53 (hexane/EtOAc 1:1);
1H NMR (acetoneꢀd6) δ 10.77 (br s, 1H), 7.87 (d, J = 7.3 Hz, 2H), 7.76 (s, 1H), 7.56−7.51 (m,
2H), 7.45 (d, J = 8.1 Hz, 2H), 7.42−7.31 (m, 5H), 7.25 (t, J = 7.3 Hz, 1H), 7.19 (d, J = 8.1 Hz,
2H), 3.37 (s, 3H), 2.34 (s, 3H); 13C NMR (acetoneꢀd6) δ 165.1, 143.9, 137.9, 136.3, 132.7, 132.2,
130.3, 130.1, 129.8, 128.93, 128.90, 128.6, 128.4, 127.9, 127.8, 118.7, 110.8, 50.8, 21.4;
HRMS−ESI [M + H]+ calcd for C25H23O4N2S+ 447.1373; found 447.1390.
Methyl
2ꢀ(4ꢀmethylphenyl)ꢀ4ꢀ(4ꢀmethylbenzenesulfonamido)ꢀ5ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀ
carboxylate (5b). Obtained from isoxazole 3b and triazole 4a (1.2 equiv, 102 mg, 0.34 mmol)
according to the method A as a white solid (108 mg, yield 81%); mp 174−176 °C; Rf = 0.55
(hexane/EtOAc 1:1); 1H NMR (DMSOꢀd6) δ 11.62 (s, 1H), 9.03 (s, 1H), 7.66−7.61 (m, 2H), 7.38
(d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 7.27 (t, J = 7.4 Hz, 2H), 7.24−7.18 (m, 3H), 7.10
(d, J = 8.2 Hz, 2H), 3.32 (s, 3H), 2.34 (s, 3H), 2.27 (s, 3H); 13C NMR (DMSOꢀd6) δ 164.0, 142.0,
137.9, 137.2, 134.5, 130.7, 129.8, 128.84, 128.79, 128.6, 128.4, 127.8, 127.0, 126.6, 126.5,
115.9, 111.0, 50.3, 20.85, 20.81; HRMS−ESI [M + Na]+ calcd for C26H24N2NaO4S+ 483.1349;
found 483.1342.
Methyl 2ꢀ(2,4ꢀdimethylphenyl)ꢀ4ꢀ(4ꢀmethylbenzenesulfonamido)ꢀ5ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀ
carboxylate (5c). Obtained from isoxazole 3c and triazole 4a (1.4 equiv, 119 mg, 0.40 mmol)
according to the method A as a white solid (104 mg, yield 76%); mp 186−188 °C; Rf = 0.59
(hexane/EtOAc 1:1); 1H NMR (DMSOꢀd6) δ 11.67 (s, 1H), 8.80 (s, 1H), 7.76−7.71 (m, 2H), 7.33
(d, J = 8.2 Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.20 (t, J = 7.3 Hz, 1H), 7.14 (d, J = 8.2 Hz, 2H),
7.08 (d, J = 7.5 Hz, 2H), 7.02 (d, J = 7.9 Hz, 1H), 3.16 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H), 2.09 (s,
3H); 13C NMR (DMSOꢀd6) δ 163.3, 142.2, 137.5, 137.3, 137.1, 135.0, 130.9, 130.4, 130.1,
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129.3, 128.83, 128.78, 127.9, 126.8, 126.56, 126.49, 125.6, 115.3, 111.1, 50.0, 20.86, 20.76,
19.5; HRMS−ESI [M + Na]+ calcd for C27H26O4N2NaS+ 497.1505; found 497.1510.
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Methyl
2ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀ(4ꢀmethylbenzenesulfonamido)ꢀ5ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀ
carboxylate (5d). Obtained from isoxazole 3d and triazole 4a (1.3 equiv, 111 mg, 0.37 mmol)
according to the method A as a white solid (118 mg, yield 86%); mp 163−165 °C; Rf = 0.44
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(hexane/EtOAc 1:1); H NMR (DMSOꢀd6) δ 11.58 (s, 1H), 8.98 (s, 1H), 7.65 (d, J = 7.5 Hz,
2H), 7.44 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.27 (t, J = 8.4 Hz, 2H), 7.21 (t, J = 7.2
Hz, 1H), 7.11 (d, J = 8.1 Hz, 2H), 6.97 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H), 3.32 (s, 3H), 2.28 (s,
3H); 13C NMR (DMSOꢀd6) δ 164.0, 159.0, 142.0, 137.9, 134.6, 130.7, 130.3, 129.6, 128.8,
127.8, 127.0, 126.5 (2C), 123.8, 115.8, 113.2, 110.6, 55.2, 50.2, 20.9; HRMS−ESI [M + H]+
calcd for C26H25O5N2S+ 477.1479; found 477.1492.
Methyl
2ꢀ(2,3ꢀdihydrobenzo[b][1,4]ꢀdioxinꢀ6ꢀyl)ꢀ4ꢀ(4ꢀmethylbenzenesulfonamido)ꢀ5ꢀ
phenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (5e). Obtained from isoxazole 3e and triazole 4a (1.2 equiv,
102 mg, 0.34 mmol) according to the method A (filtration and washing with CHCl3 instead of
column chromatography) as a white solid (108 mg, yield 74%); mp 232−234 °C; Rf = 0.36
(hexane/EtOAc 1:1); 1H NMR (DMSOꢀd6) δ 11.55 (s, 1H), 8.98 (s, 1H), 7.66−7.61 (m, 2H), 7.31
(d, J = 8.2 Hz, 2H), 7.27 (t, J = 7.3 Hz, 2H), 7.20 (t, J = 7.3 Hz, 1H), 7.10 (d, J = 8.0 Hz, 2H),
7.03 (d, J = 2.1 Hz, 1H), 6.96 (dd, J = 8.4, 2.1 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.27 (s, 4H),
3.32 (s, 3H), 2.28 (s, 3H); 13C NMR (DMSOꢀd6) δ 164.0, 143.3, 142.6, 142.0, 137.9, 134.1,
130.6, 129.6, 128.9, 127.8, 127.0, 126.6, 126.5, 124.5, 122.2, 117.6, 116.4, 115.8, 110.8, 64.2,
64.1, 50.3, 20.9; HRMS−ESI [M + Na]+ calcd for C27H24N2NaO6S+ 527.1247; found 527.1248.
Methyl
2ꢀ(4ꢀbromophenyl)ꢀ4ꢀ(4ꢀmethylbenzenesulfonamido)ꢀ5ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀ
(5f) and methyl 3ꢀ(4ꢀbromophenyl)ꢀ1ꢀ(4ꢀmethylphenylsulfonyl)ꢀ5ꢀphenylꢀ1,2ꢀ
carboxylate
dihydropyrazineꢀ2ꢀcarboxylate (6f). Obtained from isoxazole 3f and triazole 4a (1.2 equiv, 102
mg, 0.34 mmol) according to the method A. Compound 5f. White solid (99 mg, yield 65%); mp
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115−118 °C; Rf = 0.58 (hexane/EtOAc 1:1); H NMR (DMSOꢀd6) δ 11.76 (s, 1H), 9.07 (s, 1H),
7.63 (d, J = 7.3 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.1 Hz,
2H), 7.28 (d, J = 7.3 Hz, 2H), 7.23 (t, J = 7.3 Hz, 1H), 7.10 (d, J = 8.1 Hz, 2H), 3.34 (s, 3H),
2.27 (s, 3H); 13C NMR (DMSOꢀd6) δ 163.8, 142.0, 137.8, 133.0, 130.9, 130.7, 130.52, 130.48,
130.46, 128.8, 127.9, 127.1, 126.8, 126.5, 121.1, 116.1, 111.6, 50.4, 20.8; HRMS−ESI [M + H]+
calcd for C25H22O4N279BrS+ 525.0478; found 525.0496. Compound 6f. Unstable yellow oil (39
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mg, yield 26%); H NMR (CDCl3) δ 7.83−7.75 (m, 4H), 7.62−7.55 (m, 4H), 7.41 (t, J = 7.2 Hz,
2H), 7.34 (t, J = 7.2 Hz, 1H), 7.12 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 1.3 Hz, 1H), 6.03 (d, J = 1.3
Hz, 1H), 3.65 (s, 3H), 2.34 (s, 3H).
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Methyl
2ꢀ(4ꢀchlorophenyl)ꢀ4ꢀ(4ꢀmethylbenzenesulfonamido)ꢀ5ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀ
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carboxylate (5g) and methyl 3ꢀ(4ꢀchlorophenyl)ꢀ1ꢀ(4ꢀmethylphenylsulfonyl)ꢀ5ꢀphenylꢀ1,2ꢀ
dihydropyrazineꢀ2ꢀcarboxylate (6g). Obtained from isoxazole 3g and triazole 4a (1.1 equiv, 94
mg, 0.31 mmol) according to the method A. Compound 5g. White solid (85 mg, yield 61%); mp
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8
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189−191 °C; Rf = 0.61 (hexane/EtOAc 1:1); H NMR (DMSOꢀd6) δ 11.76 (s, 1H), 9.07 (s, 1H),
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7.67−7.62 (m, 2H), 7.52 and 7.47 (ABꢀq, J = 8.7 Hz, 4H), 7.32 (d, J = 8.2 Hz, 2H), 7.29 (t, J =
7.6 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 7.10 (d, J = 8.2 Hz, 2H), 3.33 (s, 3H), 2.27 (s, 3H); 13C
NMR (DMSOꢀd6) δ 163.8, 142.0, 137.9, 133.0, 132.5, 130.7, 130.47, 130.45, 130.2, 128.9,
127.9, 127.8, 127.1, 126.8, 126.5, 116.1, 111.6, 50.4, 20.8; HRMS−ESI [M + H]+ calcd for
C25H22O4N235ClS+ 481.0983; found 481.0995. Compound 6g. Unstable yellow oil (35 mg, yield
25%); 1H NMR (CDCl3) δ 7.88 (d, J = 8.6 Hz, 2H), 7.81−7.76 (m, 2H), 7.57 (d, J = 8.2 Hz, 2H),
7.46−7.38 (m, 4H), 7.34 (t, J = 7.2 Hz, 1H), 7.12 (d, J = 8.2 Hz, 2H), 7.08 (d, J = 1.0 Hz, 1H),
6.05 (s, 1H), 3.65 (s, 3H), 2.33 (s, 3H).
Methyl
2ꢀ(4ꢀcyanophenyl)ꢀ4ꢀ(4ꢀmethylbenzenesulfonamido)ꢀ5ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀ
(5h) and methyl 3ꢀ(4ꢀcyanophenyl)ꢀ1ꢀ(4ꢀmethylphenylsulfonyl)ꢀ5ꢀphenylꢀ1,2ꢀ
carboxylate
dihydropyrazineꢀ2ꢀcarboxylate (6h). Obtained from isoxazole 3h and triazole 4a (1.6 equiv, 138
mg, 0.46 mmol) according to the method A. Column chromatography (petroleum ether−EtOAc
6:1−3:1). Compound 5h. White solid (23 mg, yield 17%); mp 157−159 °C; Rf = 0.55
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(hexane/EtOAc 1:1); H NMR (DMSOꢀd6) δ 11.96 (s, 1H), 9.16 (s, 1H), 7.87 (d, J = 8.4 Hz,
2H), 7.70 (d, J = 8.4 Hz, 2H), 7.66−7.61 (m, 2H), 7.34−7.22 (m, 5H), 7.09 (d, J = 8.1 Hz, 2H),
3.37 (s, 3H), 2.27 (s, 3H); 13C NMR (DMSOꢀd6) δ 163.8, 142.1, 137.8, 135.7, 132.0, 131.7,
131.5, 130.2, 129.5, 128.9, 127.9, 127.2, 127.1, 126.5, 118.8, 116.5, 112.8, 109.9, 50.6, 20.8;
HRMS−ESI [M + Na]+ calcd for C26H21O4N3NaS+ 494.1145; found 494.1168. Compound 6h
.
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Yellow solid (41 mg, yield 30%); mp 121−123 °C; Rf = 0.40 (hexane/EtOAc 2:1); H NMR
(CDCl3) δ 8.06 (d, J = 8.3 Hz, 2H), 7.80−7.73 (m, 4H), 7.61 (d, J = 8.2 Hz, 2H), 7.43 (t, J = 7.3
Hz, 2H), 7.36 (t, J = 7.3 Hz, 1H), 7.15 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 1.2 Hz, 1H), 6.08 (d, J =
1.2 Hz, 1H), 3.65 (s, 3H), 2.35 (s, 3H); 13C NMR (CDCl3) δ 166.6, 145.2, 145.0, 139.4, 135.4,
135.1, 135.0, 132.3, 129.8, 128.6, 128.2, 128.0, 126.5, 124.8, 118.3, 113.9, 111.0, 53.3, 52.5,
21.5; HRMS−ESI [M + Na]+ calcd for C26H21O4N3NaS+ 494.1145; found 494.1166.
Methyl
4ꢀ(4ꢀmethylbenzenesulfonamido)ꢀ2ꢀ(4ꢀnitrophenyl)ꢀ5ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀ
and methyl 1ꢀ(4ꢀmethylphenylsulfonyl)ꢀ3ꢀ(4ꢀnitrophenyl)ꢀ5ꢀphenylꢀ1,2ꢀ
carboxylate
(5i)
dihydropyrazineꢀ2ꢀcarboxylate (6i). Obtained from isoxazole 3i and triazole 4a (1.5 equiv, 128
mg, 0.43 mmol) according to the method A. Compound 5i. Yellow solid (40 mg, yield 28%); mp
1
186−188 °C; Rf = 0.50 (hexane/EtOAc 1:1); H NMR (DMSOꢀd6) δ 12.00 (s, 1H), 9.21 (s, 1H),
8.25 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 7.65−7.60 (m, 2H), 7.34−7.22 (m, 5H), 7.09
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(d, J = 8.1 Hz, 2H), 3.39 (s, 3H), 2.27 (s, 3H); 13C NMR (DMSOꢀd6) δ 163.7, 146.3, 142.1,
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137.8, 137.6, 131.9, 131.4, 130.1, 129.6, 128.9, 127.9, 127.3, 127.1, 126.5, 123.0, 116.7, 113.4,
+
50.7, 20.8; HRMS−ESI [M + Na]+ calcd for C25H21N3NaO6S 514.1043; found 514.1050.
Compound 6i. Orange solid (88 mg, yield 62%); mp 136−138 °C; Rf = 0.45 (hexane/EtOAc 2:1);
1H NMR (CDCl3) δ 8.31 (d, J = 8.7 Hz, 2H), 8.13 (d, J = 8.7 Hz, 2H), 7.79 (d, J = 7.4 Hz, 2H),
7.63 (d, J = 8.1 Hz, 2H), 7.44 (t, J = 7.4 Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.20−7.12 (m, 3H),
6.13 (s, 1H), 3.66 (s, 3H), 2.35 (s, 3H); 13C NMR (CDCl3) δ 166.6, 148.8, 145.1, 144.8, 141.0,
135.4, 135.1, 134.9, 129.9, 128.6, 128.4, 128.2, 126.5, 124.8, 123.7, 111.2, 53.3, 52.6, 21.5;
HRMS−ESI [M + Na]+ calcd for C25H21N3NaO6S + 514.1043; found 514.1046.
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tertꢀButyl 4ꢀ(4ꢀmethylbenzenesulfonamido)ꢀ2,5ꢀdiphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate
(5j)
and tertꢀbutyl 1ꢀ(4ꢀmethylphenylsulfonyl)ꢀ3,5ꢀdiphenylꢀ1,2ꢀdihydropyrazineꢀ2ꢀcarboxylate (6j).
Obtained from isoxazole 3j and triazole 4a (1.5 equiv, 128 mg, 0.43 mmol) according to the
method A. Compound 5j. White solid (92 mg, yield 65%); mp 200−201 °C (dec.); Rf = 0.65
(hexane/EtOAc 1:1); 1H NMR (CDCl3) δ 8.30 (br s, 1H), 7.71 (d, J = 7.5 Hz, 2H), 7.57 (s, 1H),
7.51 (d, J = 8.1 Hz, 2H), 7.44−7.34 (m, 7H), 7.28 (t, J = 7.2 Hz, 1H), 7.11 (d, J = 7.5 Hz, 2H),
2.36 (s, 3H), 1.22 (s, 9H); 13C NMR (CDCl3) δ 163.8, 143.0, 136.0, 135.2, 132.0, 131.0, 129.3,
128.9, 128.5, 128.4, 128.0, 127.7, 127.5, 127.4, 126.4, 118.8, 109.8, 80.8, 27.9, 21.4;
HRMS−ESI [M + Na]+ calcd for C28H28N2NaO4S+ 511.1662; found 511.1670. Compound 6j
.
Unstable yellow oil (32 mg, yield 23%); 1H NMR (CDCl3) δ 7.97−7.92 (m, 2H), 7.78 (d, J = 7.4
Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.49−7.37 (m, 5H), 7.33 (t, J = 7.4 Hz, 1H), 7.10 (d, J = 8.1
Hz, 2H), 7.04 (s, 1H), 5.97 (s, 1H), 2.32 (s, 3H), 1.30 (s, 9H); HRMS−ESI [M + Na]+ calcd for
C28H28N2NaO4S+ 511.1662; found 511.1669.
Methyl
2ꢀmethylꢀ4ꢀ(4ꢀmethylbenzenesulfonamido)ꢀ5ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate
(5k). Obtained from isoxazole 1k and triazole 4a (1.2 equiv, 102 mg, 0.34 mmol) according to
the method A as a white solid (61 mg, yield 55%); mp 194−196 °C; Rf = 0.41 (hexane/EtOAc
1:1); 1H NMR (DMSOꢀd6) δ 11.47 (s, 1H), 8.77 (s, 1H), 7.65−7.59 (m, 2H), 7.31 (d, J = 8.2 Hz,
2H), 7.27 (t, J = 7.4 Hz, 2H), 7.18 (t, J = 7.4 Hz, 1H), 7.13 (d, J = 8.1 Hz, 2H), 3.31 (s, 3H), 2.36
(s, 3H), 2.29 (s, 3H); 13C NMR (DMSOꢀd6) δ 164.1, 141.9, 138.0, 134.1, 131.1, 128.7, 127.9,
127.5, 126.6, 126.24, 126.15, 114.9, 109.5, 49.9, 20.8, 12.9; HRMS−ESI [M + Na]+ calcd for
C20H20O4N2NaS+ 407.1036; found 407.1046.
Methyl 4ꢀ(methanesulfonamido)ꢀ2,5ꢀdiphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (5l). Obtained
from isoxazole 3a and triazole 4b (1.2 equiv, 76 mg, 0.34 mmol) according to the method A as a
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white solid (83 mg, yield 77%); mp 179−181 °C; Rf = 0.44 (hexane/EtOAc 1:1); H NMR
(DMSOꢀd6) δ 11.83 (s, 1H), 8.81 (s, 1H), 7.87−7.82 (m, 2H), 7.58−7.53 (m, 2H), 7.47−7.36 (m,
5H), 7.30 (t, J = 7.3 Hz, 1H), 3.64 (s, 3H), 2.61 (s, 3H); 13C NMR (DMSOꢀd6) δ 164.4, 135.0,
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131.6, 130.7, 129.9, 129.1, 128.2, 127.9, 127.8, 127.2, 127.1, 116.4, 111.0, 50.7, 40.4;
HRMS−ESI [M + H]+ calcd for C19H19O4N2S+ 371.1060; found 371.1071.
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Methyl
5ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀ(4ꢀmethylbenzenesulfonamido)ꢀ2ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀ
carboxylate (5m). Obtained from isoxazole 3a and triazole 4c (1.3 equiv, 125 mg, 0.38 mmol)
according to the method A as a white solid (76 mg, yield 55%); mp 187−190 °C; Rf = 0.48
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(hexane/EtOAc 1:1); H NMR (DMSOꢀd6) δ 11.58 (s, 1H), 8.98 (s, 1H), 7.56 (d, J = 8.8 Hz,
2H), 7.51−7.46 (m, 2H), 7.40 (t, J = 7.3 Hz, 2H), 7.37−7.30 (m, 3H), 7.10 (d, J = 8.1 Hz, 2H),
6.84 (d, J = 8.8 Hz, 2H), 3.78 (s, 3H), 3.32 (s, 3H), 2.28 (s, 3H); 13C NMR (DMSOꢀd6) δ 164.0,
158.3, 141.9, 138.1, 133.9, 131.5, 130.2, 128.9, 128.8, 128.4, 127.8, 127.6, 126.5, 123.2, 115.1,
113.3, 111.1, 55.0, 50.3, 20.8; HRMS−ESI [M + Na]+ calcd for C26H24N2NaO5S+ 499.1298;
found 499.1299.
Methyl
5ꢀ(4ꢀchlorophenyl)ꢀ4ꢀ(4ꢀmethylbenzenesulfonamido)ꢀ2ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀ
carboxylate (5n). Obtained from isoxazole 3a and triazole 4d (1.2 equiv, 114 mg, 0.34 mmol)
according to the method A as a white solid (84 mg, yield 60%); mp 156−157 °C; Rf = 0.57
1
(hexane/EtOAc 1:1); H NMR (DMSOꢀd6) δ 11.78 (s, 1H), 9.10 (s, 1H), 7.63 (d, J = 8.6 Hz,
2H), 7.53−7.48 (m, 2H), 7.42 (t, J = 7.3 Hz, 2H), 7.36 (t, J = 7.3 Hz, 1H), 7.34−7.29 (m, 4H),
7.10 (d, J = 8.1 Hz, 2H), 3.37 (s, 3H), 2.29 (s, 3H); 13C NMR (DMSOꢀd6) δ 163.9, 142.2, 137.9,
134.8, 131.4, 131.3, 129.4, 128.9, 128.8, 128.7, 128.6, 127.9, 127.8 (2C+2C), 126.5, 116.5,
111.5, 50.4, 20.9; HRMS−ESI [M + Na]+ calcd for C25H2135ClN2NaO4S+ 503.0803; found
503.0802.
Methyl
5ꢀ(2ꢀfluorophenyl)ꢀ4ꢀ(4ꢀmethylbenzenesulfonamido)ꢀ2ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀ
(5o) and methyl 5ꢀ(2ꢀfluorophenyl)ꢀ1ꢀ(4ꢀmethylphenylsulfonyl)ꢀ3ꢀphenylꢀ1,2ꢀ
carboxylate
dihydropyrazineꢀ2ꢀcarboxylate (6o). Obtained from isoxazole 3a and triazole 4e (1.3 equiv, 118
mg, 0.37 mmol) according to the method A. Compound 5o. White solid (58 mg, yield 43%); mp
1
89−92 °C; Rf = 0.60 (hexane/EtOAc 1:1); H NMR (DMSOꢀd6) δ 11.80 (s, 1H), 8.99 (s, 1H),
7.51−7.45 (m, 3H), 7.41 (t, J = 7.4 Hz, 2H), 7.38−7.31 (m, 2H), 7.27 (d, J = 8.0 Hz, 2H),
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7.17−7.10 (m, 2H), 7.08 (d, J = 8.0 Hz, 2H), 3.41 (s, 3H), 2.29 (s, 3H); C NMR (DMSOꢀd6) δ
164.0, 159.1 (d, J = 248 Hz), 142.0, 137.5, 134.5, 131.34 (d, J = 2.5 Hz), 131.30, 129.41 (d, J =
5.1 Hz), 128.8, 128.6, 127.9, 127.8, 126.3, 124.6, 123.78 (d, J = 2.8 Hz), 118.60 (d, J = 14.6 Hz),
117.5, 115.38 (d, J = 21.8 Hz), 110.5, 50.4, 20.9; HRMS−ESI [M + Na]+ calcd for
C25H21FN2NaO4S+ 487.1098; found 487.1093. Compound 6o (mixture with pyrazine 7i).
Unstable yellow oil (44 mg, yield 33%); 1H NMR (CDCl3) δ 8.02−7.92 (m, 3H), 7.63 (d, J = 8.3
Hz, 2H), 7.40 (s, 1H), 7.22−7.08 (m, 4H), 6.15 (s, 1H), 3.65 (s, 3H), 2.32 (s, 3H).
Nꢀ[2,5ꢀDiphenylꢀ4ꢀ(pyrrolydineꢀ1ꢀcarbonyl)ꢀ1Hꢀpyrrolꢀ3ꢀyl]ꢀ4ꢀmethylbenzenesulfonꢀ
amide (5p).Obtained from isoxazole 3l and triazole 4a (2.2 equiv, 188 mg, 0.63 mmol) according
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to the method A. Column chromatography (petroleum ether−EtOAc 2:1). White solid (39 mg,
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yield 28%); mp 127−128 °C; Rf = 0.45 (EtOAc); H NMR (DMSOꢀd6) δ 11.35 (s, 1H), 9.25 (s,
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1H), 7.61−7.54 (m, 2H), 7.46 (d, J = 7.4 Hz, 2H), 7.42−7.32 (m, 2H), 7.30−7.16 (m, 4H), 7.05
(d, J = 7.4 Hz, 2H), 3.17 (br s, 2H), 2.76 (br s, 2H), 2.25 (s, 3H), 1.57 (br s, 2H), 1.41 (br s, 2H);
13C NMR (DMSOꢀd6) δ 164.1, 141.8, 138.2, 131.8, 130.7, 130.1, 128.7, 128.5, 127.7, 127.3,
126.9 (2C), 126.4, 126.3, 125.7, 118.8, 114.4, 46.6, 44.9, 25.0, 23.8, 20.8; HRMS−ESI [M +
Na]+ calcd for C28H27O3N3NaS+ 508.1665; found 508.1677.
Nꢀ(4ꢀBenzoylꢀ2,5ꢀdiphenylꢀ1Hꢀpyrrolꢀ3ꢀyl)ꢀ4ꢀmethylbenzenesulfonamide (5q)9 and (3,5ꢀ
diphenylꢀ1ꢀtosylꢀ1,2ꢀdihydropyrazinꢀ2ꢀyl) (phenyl)methanone (6q). Obtained from isoxazole 3m
and triazole 4a (2.2 equiv, 188 mg, 0.63 mmol) according to the method A. Compound 5q. White
solid (64 mg, yield 45%); mp 118−120 °C; Rf = 0.57 (hexane/EtOAc 1:1); 1H NMR (DMSOꢀd6)
δ 11.71 (s, 1H), 9.17 (s, 1H), 7.69−7.63 (m, 2H), 7.46−7.40 (m, 2H), 7.36 (t, J = 7.4 Hz, 1H),
7.28 (t, J = 7.4 Hz, 2H), 7.25−7.10 (m, 10H), 6.79 (d, J = 8.0 Hz, 2H), 2.03 (s, 3H); 13C NMR
(DMSOꢀd6) δ 191.3, 141.8, 137.8, 136.8, 133.3, 131.7, 131.2, 130.5, 130.3, 129.5, 128.7, 128.3,
127.9, 127.8, 127.4, 127.2, 127.1, 126.7, 126.5, 120.3, 116.1, 20.7; HRMS−ESI [M + H]+ calcd
for C30H25O3N2S+ 493.1580; found 493.1594. Compound 6q. White solid (10 mg, yield 7%); mp
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124−126 °C; Rf = 0.50 (hexane/EtOAc 2:1); H NMR (CDCl3) δ 8.23 (d, J = 7.2 Hz, 2H),
7.72−7.63 (m, 5H), 7.55 (t, J = 7.7 Hz, 2H), 7.48−7.33 (m, 8H), 6.95 (d, J = 8.1 Hz, 2H), 6.75 (d,
J = 0.9 Hz, 1H), 6.62 (d, J = 0.9 Hz, 1H), 2.29 (s, 3H); 13C NMR (CDCl3) δ 193.7, 151.3, 144.7,
140.3, 136.2, 135.2, 134.5, 134.2, 133.7, 130.9, 129.4, 129.2, 128.7, 128.44 (2C), 128.39, 127.4,
126.4, 125.4, 107.9, 56.6, 21.5; HRMS−ESI [M + H]+ calcd for C30H25O3N2S+ 493.1580; found
493.1595.
Methyl 1ꢀ(4ꢀmethylbenzenesulfonyl)ꢀ3,5ꢀdiphenylꢀ1,2ꢀdihydropyrazineꢀ2ꢀcarboxylate (6a).
Obtained from isoxazole 3a and triazole 4a (2.0 equiv, 174 mg, 0.58 mmol) according to the
method B. Column chromatography (petroleum ether−Et2O 10:1). Yellow oil (82 mg, yield
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63%); Rf = 0.45 (hexane/EtOAc 2:1); H NMR (CDCl3) δ 7.97−7.92 (m, 2H), 7.83−7.79 (m,
2H), 7.57 (d, J = 8.3 Hz, 2H), 7.51−7.38 (m, 5H), 7.34 (t, J = 7.4 Hz, 1H), 7.11−7.05 (m, 3H),
6.12 (s, 1H), 3.66 (s, 3H), 2.31 (s, 3H); 13C NMR (CDCl3) δ 167.0, 147.4, 144.6, 135.6, 135.5
(3C), 130.8, 129.7, 128.49, 128.47, 128.0, 127.7, 126.4, 124.9, 109.8, 53.1, 52.8, 21.5;
HRMS−ESI [M + H]+ calcd for C25H23O4N2S+ 447.1373; found 447.1373.
Methyl 1ꢀ(methanesulfonyl)ꢀ3,5ꢀdiphenylꢀ1,2ꢀdihydropyrazineꢀ2ꢀcarboxylate (6l). Obtained
from isoxazole 3a and triazole 4b (2.5 equiv, 162 mg, 0.73 mmol) according to the method B as
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a yellow oil (57 mg, yield 53%); Rf = 0.44 (hexane/EtOAc 2:1); H NMR (CDCl3) δ 8.18−8.11
(m, 2H), 7.86 (d, J = 7.5 Hz, 2H), 7.56−7.51 (m, 3H), 7.44 (t, J = 7.5 Hz, 2H), 7.36 (t, J = 7.2
Hz, 1H), 6.98 (s, 1H), 6.16 (s, 1H), 3.69 (s, 3H), 3.16 (s, 3H); 13C NMR (CDCl3) δ 167.8, 147.6,
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135.6, 135.5, 134.2, 131.1, 128.8, 128.6, 128.0, 127.8, 124.9, 110.1, 53.3, 52.5, 41.4;
HRMS−ESI [M + Na]+ calcd for C19H18N2NaO4S+ 393.0879; found 393.0870.
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Methyl 3,5ꢀdiphenylpyrazineꢀ2ꢀcarboxylate (7a). Obtained from isoxazole 3a and triazole
4a (2.0 equiv, 174 mg, 0.58 mmol) according to the method B as a white solid (53 mg, yield
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63%); mp 98−100 °C; Rf = 0.44 (hexane/EtOAc 2:1); H NMR (CDCl3) δ 9.04 (s, 1H),
8.21−8.16 (m, 2H), 7.77−7.73 (m, 2H), 7.59−7.50 (m, 6H), 3.89 (s, 3H); 13C NMR (CDCl3) δ
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166.8, 153.0, 152.7, 141.7, 138.4, 137.4, 135.4, 130.7, 129.6, 129.1, 128.7, 128.4, 127.4, 52.8;
+
HRMS−ESI [M + Na]+ calcd for C18H14N2NaO2 313.0947; found 313.0952.
Methyl 3ꢀ(4ꢀmethylphenyl)ꢀ5ꢀphenylpyrazineꢀ2ꢀcarboxylate (7b). Obtained from isoxazole 3b
and triazole 4a (2.5 equiv, 218 mg, 0.73 mmol) according to the method B as a white solid (39
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mg, yield 44%); mp 85−87 °C; Rf = 0.45 (hexane/EtOAc 2:1); H NMR (CDCl3) δ 9.01 (s, 1H),
8.21−8.15 (m, 2H), 7.66 (d, J = 7.9 Hz, 2H), 7.59−7.51 (m, 3H), 7.33 (d, J = 7.9 Hz, 2H), 3.91
(s, 3H), 2.46 (s, 3H); 13C NMR (CDCl3) δ 167.0, 152.9, 152.6, 141.5, 139.8, 138.1, 135.5, 134.5,
+
130.6, 129.2, 129.1, 128.7, 127.4, 52.8, 21.4; HRMS−ESI [M + H]+ calcd for C19H17N2O2
305.1285; found 305.1287.
Methyl 3ꢀ(4ꢀbromophenyl)ꢀ5ꢀphenylpyrazineꢀ2ꢀcarboxylate
(7c). Obtained from
isoxazole 3f and triazole 4a (2.5 equiv, 218 mg, 0.73 mmol) according to the method B as a
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white solid (75 mg, yield 70%); mp 168−169 °C; Rf = 0.43 (hexane/EtOAc 2:1); H NMR
(CDCl3) δ 9.05 (s, 1H), 8.20−8.13 (m, 2H), 7.66 and 7.61 (ABꢀq, J = 8.6 Hz, 4H), 7.59−7.53 (m,
3H), 3.91 (s, 3H); 13C NMR (CDCl3) δ 166.5, 152.8, 152.1, 141.2, 138.8, 136.4, 135.1, 131.6,
+
130.9, 130.4, 129.2, 127.4, 124.3, 53.0; HRMS−ESI [M + Na]+ calcd for C18H1379BrN2NaO2
391.0053; found 391.0054.
Methyl 3ꢀ(4ꢀchlorophenyl)ꢀ5ꢀphenylpyrazineꢀ2ꢀcarboxylate
(7d). Obtained from
isoxazole 3g and triazole 4a (2.5 equiv, 218 mg, 0.73 mmol) according to the method B as a
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white solid (68 mg, yield 72%); mp 154−155 °C; Rf = 0.42 (hexane/EtOAc 2:1); H NMR
(CDCl3) δ 9.05 (s, 1H), 8.19−8.14 (m, 2H), 7.68 (d, J = 8.6 Hz, 2H), 7.60−7.53 (m, 3H), 7.50 (d,
J = 8.6 Hz, 2H), 3.91 (s, 3H); 13C NMR (CDCl3) δ 166.5, 152.8, 152.0, 141.3, 138.7, 136.0,
135.9, 135.1, 130.8, 130.1, 129.1, 128.7, 127.4, 53.0; HRMS−ESI [M + Na]+ calcd for
+
C18H1335ClN2NaO2 347.0558; found 347.0573.
Methyl 3ꢀ(4ꢀnitrophenyl)ꢀ5ꢀphenylpyrazineꢀ2ꢀcarboxylate (7e). Obtained from isoxazole 3i
and triazole 4a (2.5 equiv, 218 mg, 0.73 mmol) according to the method B. Column
chromatography (CHCl3). White solid (75 mg, yield 77%); mp 211−212 °C; Rf = 0.30
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(hexane/EtOAc 2:1); H NMR (CDCl3) δ 9.14 (s, 1H), 8.39 (d, J = 8.8 Hz, 2H), 8.21−8.15 (m,
2H), 7.89 (d, J = 8.8 Hz, 2H), 7.62−7.56 (m, 3H), 3.93 (s, 3H); 13C NMR (CDCl3) δ 165.9,
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HRMS−ESI [M + Na]+ calcd for C18H13N3NaO4 358.0798; found 358.0808.
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tertꢀButyl 3,5ꢀdiphenylpyrazineꢀ2ꢀcarboxylate (7f). Obtained from isoxazole 3j and triazole
4a (3 equiv, 260 mg, 0.87 mmol) according to the method B. After the decomposition of the last
triazole portion, the reaction mixture was transferred to a screw cap glass tube and heated at 90
°C (oil bath temperature) with Et3N (50 mg, 0.5 mmol) as additive for 5 h. Further workup
according to the method B gave compound 7f as a white solid (69 mg, yield 72%); mp 109−111
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°C; Rf = 0.57 (hexane/EtOAc 2:1); H NMR (CDCl3) δ 9.03 (s, 1H), 8.19−8.13 (m, 2H),
7.78−7.73 (m, 2H), 7.58−7.49 (m, 6H), 1.43 (s, 9H); 13C NMR (CDCl3) δ 165.6, 152.4, 152.1,
143.7, 138.5, 137.9, 135.6, 130.4, 129.3, 129.0, 128.9, 128.3, 127.3, 83.2, 27.6; HRMS−ESI [M
+
+ Na]+ calcd for C21H20N2NaO2 355.1417; found 355.1421.
Methyl 3ꢀmethylꢀ5ꢀphenylpyrazineꢀ2ꢀcarboxylate (7g). Obtained from isoxazole 3k and
triazole 4a (2.5 equiv, 218 mg, 0.73 mmol) according to the method B. After the decomposition
of the last triazole portion, the reaction mixture was transferred to a screw cap glass tube and
heated at 90 °C (oil bath temperature) with Et3N (50 mg, 0.5 mmol) as additive for 5 h. Further
workup according to the method B gave compound 7g as a white solid (21 mg, yield 32%); mp
1
64−66 °C; Rf = 0.36 (hexane/EtOAc 2:1); H NMR (CDCl3) δ 8.96 (s, 1H), 8.15−8.09 (m, 2H),
7.60−7.51 (m, 3H), 4.05 (s, 3H), 2.96 (s, 3H); 13C NMR (CDCl3) δ 165.7, 155.1, 153.5, 140.0,
+
138.3, 135.5, 130.7, 129.1, 127.4, 52.9, 23.6; HRMS−ESI [M + Na]+ calcd for C13H12N2NaO2
251.0791; found 251.0791.
Methyl 5ꢀ(4ꢀchlorophenyl)ꢀ3ꢀphenylpyrazineꢀ2ꢀcarboxylate (7h). Obtained from isoxazole
3a and triazole 4d (2 equiv, 194 mg, 0.58 mmol) according to the method B as a white solid (58
1
mg, yield 61%); mp 111−113 °C; Rf = 0.43 (hexane/EtOAc 2:1); H NMR (CDCl3) δ 9.01 (s,
1H), 8.13 (d, J = 8.6 Hz, 2H), 7.76−7.70 (m, 2H), 7.56−7.50 (m, 5H), 3.88 (s, 3H); 13C NMR
(CDCl3) δ 166.7, 153.0, 151.5, 141.9, 138.1, 137.2, 137.1, 133.8, 129.7, 129.4, 128.7, 128.6,
+
128.5, 52.9; HRMS−ESI [M + Na]+ calcd for C18H1335ClN2NaO2 347.0558; found 347.0564.
Methyl 5ꢀ(2ꢀfluorophenyl)ꢀ3ꢀphenylpyrazineꢀ2ꢀcarboxylate (7i). Obtained from isoxazole
3a and triazole 4e (2.5 equiv, 228 mg, 0.72 mmol) according to the method B as a white solid
(67 mg, yield 75%); mp 101−103 °C; Rf = 0.52 (hexane/EtOAc 2:1); 1H NMR (CDCl3) δ 9.14 (d,
J = 2.5 Hz, 1H), 8.21 (td, J = 7.8, 1.8 Hz, 1H), 7.77−7.71 (m, 2H), 7.57−7.47 (m, 4H), 7.34 (td, J
= 7.8, 1.0 Hz, 1H), 7.25 (ddd, J = 11.3, 8.4, 0.8 Hz, 1H), 3.90 (s, 3H); 13C NMR (CDCl3) δ
166.7, 160.9 (d, J = 252 Hz), 153.0, 149.36 (d, J = 3.4 Hz), 142.0, 141.9, 137.2, 132.24 (d, J =
8.7 Hz), 131.26 (d, J = 2.5 Hz), 129.7, 128.7, 128.5, 124.91 (d, J = 3.5 Hz), 123.51 (d, J = 12.0
Hz), 116.47 (d, J = 22.7 Hz), 52.9; HRMS−ESI [M + Na]+ calcd for C18H13FN2NaO2+ 331.0853;
found 331.0863.
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Methyl 3,5ꢀdi(4ꢀchlorophenyl)pyrazineꢀ2ꢀcarboxylate (7j). Obtained from isoxazole 3g and
triazole 4d (2.5 equiv, 243 mg, 0.73 mmol) according to the method B as a white solid (74 mg,
1
yield 71%); mp 158−160 °C; Rf = 0.44 (hexane/EtOAc 2:1); H NMR (CDCl3) δ 9.01 (s, 1H),
8.11 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.6 Hz, 3H), 7.49 (d, J = 8.5 Hz,
2H), 3.91 (s, 3H); 13C NMR (CDCl3) δ 166.4, 152.0, 151.6, 141.6, 138.4, 137.2, 136.1, 135.6,
9
+
133.5, 130.1, 129.4, 128.7, 128.6, 53.0; HRMS−ESI [M + Na]+ calcd for C18H1235Cl2N2NaO2
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381.0168; found 381.0176.
(3,5ꢀDiphenylpyrazinꢀ2ꢀyl)(phenyl)methanone (7k). Obtained from isoxazole 3m and
triazole 4a (3 equiv, 260 mg, 0.87 mmol) according to the method B as a white solid (24 mg,
1
yield 25%); mp 137−139 °C; Rf = 0.57 (hexane/EtOAc 2:1); H NMR (CDCl3) δ 9.07 (s, 1H),
8.26−8.20 (m, 2H), 7.95 (d, J = 7.2 Hz, 2H), 7.78−7.71 (m, 2H), 7.65−7.53 (m, 4H), 7.49 (t, J =
7.7 Hz, 2H), 7.44−7.36 (m, 3H); 13C NMR (CDCl3) δ 194.3, 152.6, 152.1, 148.4, 138.0, 136.9,
135.9, 135.7, 133.8, 130.5, 130.4, 129.6, 129.16, 129.14, 128.63, 128.60, 127.3; HRMS−ESI [M
+ H]+ calcd for C23H17N2O+ 337.1346; found 337.1335.
2,6ꢀDiphenylpyrazine (7l).24 Obtained from isoxazole 3j and triazole 4a (3 equiv, 260 mg,
0.87 mmol) according to the method B. After the decomposition of the last portion of triazole the
solvent was removed in vacuo and the residue was dissolved in oꢀxylene (3.0 mL) and refluxed
for 2 h. Further workup according to the method B gave compound 7l as a white solid (35 mg,
yield 53 %); mp 84–86 °C (lit.24 84–86 °C); Rf = 0.47 (hexane/EtOAc 2:1); H NMR (CDCl3) δ
9.00 (s, 2H), 8.22–8.16 (m, 4H), 7.61–7.49 (m, 6H); 13C NMR (CDCl3) δ 151.6, 139.9, 136.5,
129.9, 129.0, 127.0; HRMS−ESI [M + H]+ calcd for C16H13N2 233.1073; found 233.1073.
1
+
Methyl 3ꢀ(4ꢀnitrophenyl)ꢀ3ꢀoxopropanoate (18).25 The procedure of Clark et al.26 was
modified. To a rapidly stirred solution of diisopropylamine (16.3 mL, 116 mmol) in dry
tetrahydrofuran (60 ml) under argon at –80 °C was added nꢀbutyllithium (2.5 M in hexane, 47
mL), followed after 10 min by methyl acetate (9.3 mL, 116 mmol). The mixture was maintained
below –80 °C for 5 min, after which time a solution of methyl 4ꢀnitrobenzoate (10.2 g, 56.3
mmol) in dry tetrahydrofuran (50 mL) was introduced via syringe. The mixture was stirred at –
80 °C until no starting 4ꢀnitrobenzoate was observed by TLC (about 10–15 min), then quenched
with 20% hydrochloric acid (60 mL) and extracted with ether (600 mL). The organic layer was
washed intensively with 5% NaHCO3 (300 mL), water (300 mL) and brine (300 mL), dried and
concentrated in vacuo, affording the product as a pale yellow solid (11.4 g, yield 91%); mp 103–
105 °C (lit.25 110 °C). Rf = 0.51 (hexane/EtOAc 2:1); 1H NMR (CDCl3) δ [keto form] 8.39–8.34
(m, 2Н), 8.17–8.11 (m, 2Н), 4.08 (s, 2H), 3.79 (s, 3H); [enol form] 12.51 (s, 1H), 8.33–8.27 (m,
2Н), 8.00–7.93 (m, 2Н), 5.80 (s, 1H), 3.86 (s, 3H).
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3ꢀ(4ꢀNitrophenyl)isoxazolꢀ5(4H)ꢀone (19).26 Methyl 3ꢀ(4ꢀnitrophenyl)ꢀ3ꢀoxopropanoate
18 (3.0 g, 13.5 mmol) and H2NOH·HCl (2.8 g, 40.3 mmol) were refluxed in water (15 mL) for 5
min. Then ethanol (18 mL) was added to the reaction mixture and refluxing continued for 30
min. The mixture was cooled and filtered off to give isoxazolone 19 as a yellow solid (2.5 g,
89%); mp 143–146 °C (lit.26 145–148 °C).
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ASSOCIATED CONTENT
Supporting Information
Figures Sꢀ1, Sꢀ2 with NMR spectra of reaction mixtures, Sꢀ3 with energy profiles for the
transformations of diazatrienes 9b, 1H and 13C NMR spectra for all new compounds,
computation details with energies of the reactants, transition states, their Cartesian coordinates,
and tube representation of the calculated molecules. This material is available free of charge via
the Internet at http://pubs.acs.org.
ACKNOWLEDGEMENTS
We gratefully acknowledge the financial support of the Russian Foundation for Basic Research
(Grant No. 16ꢀ03ꢀ00596, 16ꢀ33ꢀ60130, and 16ꢀ33ꢀ00651) and St. Petersburg State University
(Grant No. 12.38.239.2014 and 12.38.217.2015). This research used resources of ‘Magnetic
Resonance Research Centre’, ‘Chemical Analysis and Materials Research Centre’, ‘Computing
Centre’ and ‘Chemistry Educational Centre’ of the Research Park of St. Petersburg State
University.
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