Pseudopericyclic Dearomative 1,6-Cyclization of 1-(2-Pyridyl)-2-azabuta-1,3-dienes: Synthesis and Ring–Chain Valence Equilibria of 4H-Pyrido[1,2-a]pyrazines

Article abstract of DOI:10.1002/ejoc.202000210

The 1,6-electrocyclization of 1-(2-pyridyl)-2-azabuta-1,3-dienes obtained by Rh^II-catalyzed reaction of pyridotriazoles with 2H-azirines affords stable non-aromatic 4H-pyrido[1,2-a]pyrazines despite the fact that the reaction proceeds with irreversible dearomatization of the pyridine aromatic system. This pseudopericyclic cyclization occurs when the 2-azabutadiene contains H, alkyl, or Ph at the C4 atom and an electron-withdrawing substituent at the C1 atom. A number of stable 4H-pyrido[1,2-a]pyrazines as well as 1H-pyrazino[1,2-a]quinoline and 4H-benzo[4,5]oxazolo[3,2-a]pyrazine derivatives were synthesized. Whereas 4-alkyl-substituted pyridopyrazines are stable at room temperature, 4-phenyl-substituted pyridopyrazines exist in ring–chain valence equilibrium with 1-(2-pyridyl)-2-azabutadienes. Thermodynamic stability of the 4H-pyrido[1,2-a]pyrazine decreases with increasing size of the substituent at the C6 atom.

Full text of DOI:10.1002/ejoc.202000210

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Dearomative Electrocyclization
Pseudopericyclic Dearomative 1,6-Cyclization of 1-(2-Pyridyl)-
2-azabuta-1,3-dienes: Synthesis and Ring–Chain Valence
Equilibria of 4H-Pyrido[1,2-a]pyrazines
Ilya P. Filippov,[a] Mikhail S. Novikov,[a] Alexander F. Khlebnikov,[a] and
Nikolai V. Rostovskii*[a]
Abstract: The 1,6-electrocyclization of 1-(2-pyridyl)-2-azabuta- pyrido[1,2-a]pyrazines as well as 1H-pyrazino[1,2-a]quinoline
1,3-dienes obtained by RhII-catalyzed reaction of pyridotriazoles and 4H-benzo[4,5]oxazolo[3,2-a]pyrazine derivatives were syn-
with 2H-azirines affords stable non-aromatic 4H-pyrido[1,2-a]- thesized. Whereas 4-alkyl-substituted pyridopyrazines are stable
pyrazines despite the fact that the reaction proceeds with irre- at room temperature, 4-phenyl-substituted pyridopyrazines ex-
versible dearomatization of the pyridine aromatic system. This ist in ring–chain valence equilibrium with 1-(2-pyridyl)-2-aza-
pseudopericyclic cyclization occurs when the 2-azabutadiene butadienes. Thermodynamic stability of the 4H-pyrido[1,2-a]-
contains H, alkyl, or Ph at the C4 atom and an electron-with- pyrazine decreases with increasing size of the substituent at the
drawing substituent at the C1 atom. A number of stable 4H- C6 atom.
Introduction
The aza-1,6-electrocyclization is a powerful and atom-economic
approach to the formation of N-heterocyclic compounds such
as pyridines, quinolines, and isoquinolines, including natural
products and medicines.[1] Thus, the 1,6-electrocyclization of 1-
aza-,[2] 2-aza-,[3] and 3-azahexa-1,3,5-trienes[4] leads to the for-
mation of 1,2-, 2,3-, and 3,4-dihydropyridines (Scheme 1, reac-
tions 1–3). Such cyclization easily occurs when none of the dou-
ble bonds of the azatriene fragment are included in the aro-
matic cycle.[2a–2e,3a,3b,4a–4d,5] When one of the double bonds of
starting azatriene is a part of an aromatic system, 1,6-electro-
cyclization can occur reversibly (if aromatization of the primary
dihydropyridine product is impossible)[6] or irreversibly (if aro-
matization of the primary dihydropyridine intermediate into
pyridine is plausible).[2f–2j,3c–3f,4e]
The examples of the 1,6-electrocyclization of diazahexa-
1,3,5-trienes are much rarer.[7] The 1,6-electrocyclization of diaz-
ahexa-1,3,5-trienes occurs when the C=N-termini of the diaza-
hexatriene is a part of an imine or oxime group, and does not
occur when the C=N-termini is included in an aromatic system.
In particular, in recent studies it has been shown on many ex-
amples that the 1,6-cyclization of 1,4-diazatrienes leads to 1,2-
dihydropyrazines[8] (Scheme 1, reaction 4) which in some cases
undergo aromatization to give pyrazines.[8c–8h] Similarly, the
[a] I. P. Filippov, Prof. Dr. M. S. Novikov, Prof. Dr. A. F. Khlebnikov,
Dr. N. V. Rostovskii
St. Petersburg State University, Institute of Chemistry,
7/9 Universitetskaya nab., St. Petersburg 199034, Russia
E-mail: n.rostovskiy@spbu.ru
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202000210.
Scheme 1. 1,6-Electrocyclizations of aza- and diazahexa-1,3,5-trienes.
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1,6-cyclizations of 1,3-diazatrienes[9] and 1,5-diazatrienes[10] (re-
actions 5 and 6) afford dihydropyrimidines. Conversely, several
1-(2-pyridyl)-2-azabuta-1,3-dienes are known,[11] but the dearo-
mative cyclization of these compounds involving a pyridine ring
was not mentioned anywhere in the literature. Thus, no thermo-
dynamically favorable 1,6-electrocyclizations of aza- and diaza-
hexatrienes accompanied by dearomatization[12] and formation
of a stable non-aromatic product were published till now.
In this work, we were able to demonstrate that such proc-
esses indeed exist. We studied 1,6-electrocyclizations of 1-(2-
pyridyl)-2-azabuta-1,3-dienes as representatives of 1,4-diaza-
hexatrienes with the C=N bond incorporated in aromatic pyr-
idine system. It was found that these cyclizations could afford
stable 4H-pyrido[1,2-a]pyrazines despite the fact that the reac-
tion proceeded with irreversible dearomatization of the pyrid-
ine aromatic system (Scheme 1, reaction 7). The factors affect-
ing stability of the diazatriene and pyridopyrazine forms were
identified, and a number of stable 4H-pyrido[1,2-a]pyrazines
were isolated. These findings significantly expand the scope of
the 1,6-electrocyclization in organic synthesis.
Scheme 2. The reaction of pyridotriazole 1a with azirine 2a.
ene (Z,E)-3a, pyridopyrazine 5a, azadiene (Z,Z)-3a, and dihydro-
azete 4 in a 10.8:3:1:2.5 ratio. Heating at higher temperature
(70 °C) for 36 h resulted in an equilibrium mixture of azadiene
(Z,E)-3a, pyridopyrazine 5a, and azadiene (Z,Z)-3a in a 1:4.4:6.5
ratio. This reaction mixture was subjected to chromatographic
separation. However, both isolated products, pyridopyrazine 5a
and azadiene (Z,Z)-3a, were rapidly interconverted.
Encouraged by the formation of pyridopyrazine 5a, we stud-
ied the influence of various substituents in pyridotriazoles 1
and azirines 2 on the reaction outcome (Scheme 3). The main
goal was to find out which substituents shifted the equilibrium
3%5 toward pyridopyrazine 5. The results obtained are sum-
marized in Table 1.
Results and Discussion
In previous works, we have developed the convenient method
for the synthesis of 2-azabutadienes via the reactions of 2H-
azirines with RhII carbenoids derived from diazo compounds.[13]
In order to synthesize 1-(2-pyridyl)-2-azabuta-1,3-dienes for our
study, we exploited a similar approach in which pyridotri-
azoles[14] were used as precursors of carbenoids. The advantage
of this approach is that it permits to prepare the desired 1-(2-
pyridyl)-2-azabuta-1,3-dienes with a different substitution pat-
tern in one synthetic operation. In our initial experiment, we
performed the reaction of pyridotriazole 1a with 2,3-diphenyl-
azirine 2a at 110 °C in the presence of Rh2(OAc)4 (2 mol-%)
(Scheme 2). The products of the reaction were 1-(2-pyridyl)-2-
azabutadiene (Z,E)-3a and 2,3-dihydroazete 4, the product of
4π-electrocyclization[13c,13e,13g,13h] of (Z,E)-3a (the first stereode-
scriptor refers to the configuration of the C=N bond, the second
one to the C=C bond). These products were separated by rapid
column chromatography, but all attempts to record NMR spec-
tra of analytically pure samples of these compounds failed be-
cause of their rather fast interconversion in solution at room
temperature. In order to determine the configurations of the
Scheme 3. The reactions of pyridotriazoles 1 with azirines 2.
The variation of substituents in azirines 2 showed that 2-
double bonds in (Z,E)-3a, we used X-ray diffraction analysis of methyl-substituted azirine 2b gave pyridopyrazines 5b–d as a
the crystals obtained from the mixture of (Z,E)-3a and 4 by slow major product (Table 1, entries 2–4). These reactions provided
evaporation of their Et2O solution (Scheme 2). Pure samples of the equilibrium mixtures of 4-methyl-2-azabutadienes 3b–d
compound (Z,E)-3a were obtained as yellow crystals using col- and 4-methylpyridopyrazines 5b–d. However, the latter were
umn chromatography followed by slow crystallization.
stable in pure form at room temperature and did not isomerize
to azadienes 3b–d in solid state and solution. Pyridopyrazines
5b–d were characterized by the data of NMR spectroscopy and
HRMS. The structure of pyridopyrazine 5d was confirmed by
X-ray diffraction analysis (Figure 1).
It was found that the solution of a mixture of azadiene (Z,E)-
3a and dihydroazete 4 gradually turned orange upon keeping
at room temperature in CDCl3. A detailed analysis of the reac-
1
tion mixture by H NMR (two doublets of doublets at 6.75 and
6.86 ppm) and TLC (red-orange spot) led us to the conclusion
The optimization of the reaction conditions for the prepara-
about the presence of pyrido[1,2-a]pyrazine 5a in the solution tion of pyridopyrazine 5c [Rh2(OAc)4, Rh2(Piv)4, and Rh2(esp)2;
(Scheme 2). An attempt to increase the content of pyridopyr- toluene and 1,2-dichloroethane; 110 and 140 °C] did not allow
azine 5a by keeping the above solution at room temperature to increase the yield of the product. In contrast, a noticeable
for long period (14 days) led to an equilibrium mixture of azadi- decrease in yield was observed when using an excess of pyrido-
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Table 1. The results of the reactions of pyridotriazoles 1 with azirines 2.[a]
Entry
Pyridotriazole
X
R1
Azirine
R2
R3
R4
Yield of 3 [%]
Yield of 5 [%]
1
2
3
4
5
6
7
8
1a
1a
1b
1c
1b
1b
1d
1e
1b
1a
1f
Br
Br
Cl
MeO
Cl
Cl
H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CN
CO2Me
CO2Me
CO2Me
Ph
2a
2b
2b
2b
2c
2d
2b
2b
2e
2f
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
CH2CO2Me
H
Me
Me
H
H
H
H
H
H
H
H
Me
H
H
H
77 [(Z,E)-3a]
17 (3b)[b]
15 (3c)[c]
18 (3d)[d]
63 (3e)[e]
–
–
60 (5b)
60 (5c)
39 (5d)
15 (5e)
65 (5f)
31 (5g)
– (5h)
trace
–
Ph
4-NO2C6H4
Ph
Ph
Ph
Ph
Ph
Ph
–
H
– (3h)
77 (3i)
9
Cl
Br
H
Me
CO2Me
Ph
10
11[g]
12
89 (3j)[f]
26 (3k)
61 [(E)-3l][h]
2a
2g
–
–
1b
Cl
CO2Me
(E)-CH=CHCO2Me
[a] Isolated yields. [b] A 1:1 mixture of (Z)- and (E)-isomers. [c] A 5:1 mixture of (Z)- and (E)-isomers. [d] A 2:1 mixture of (Z)- and (E)-isomers. [e] A 1.6:1 mixture
of (Z)- and (E)-isomers. [f] A 1: 1.6 mixture of (Z)- and (E)-isomers. [g] Rh2(esp)2 (1 mol-%) was used as a catalyst at 140 °C. [h] Dimethyl 2-(6-chloropyridin-2-
yl)-6-phenyl-1,2-dihydropyridine-2,3-dicarboxylate 6 (yield 17 %) was isolated as a by-product.
long-term reaction at such high temperature resulted in the
formation of by-products. A slow dropwise addition of pyrido-
triazole 1d as well as the use of microwave irradiation did not
increase the yield of pyridopyrazine 5g. In view of recent publi-
cations,[14a,14f,14h–14j] we also tested copper(II) compounds
[Cu(acac)2, Cu(tfacac)2, and Cu(OTf)2] as catalysts. However, they
were inactive, and pyridopyrazine 5g in these reactions was not
detected at all. Another C7-unsubstituted pyridotriazole 1e
gave complex mixture of unstable products (Table 1, entry 8).
The introduction of two methyl groups at the C4 position of
2-azadiene (3i) only led to traces of the corresponding pyrido-
pyrazine (Table 1, entry 9).
Finally, some reactions led to azadienes 3 which did not
cyclize to pyrido[1,2-a]pyrazines 5 even under heating (Table 1,
entries 10,11). These azadienes contain ester or phenyl substitu-
ents at the C1 and C4 positions of the azabutadiene fragment
(R1 and R3). Under harsh conditions (o-xylene, 165 °C) azadiene
(E)-3j slowly isomerized across the C=C bond to azadiene (Z)-
3j, and no traces of the desired cyclization product were de-
tected. 1-Phenyl-substituted 2-azadiene 3k was obtained in low
yield, which was due to an extremely low reactivity of pyridotri-
azole 1f. This led to a low conversion of the starting compounds
and the formation of unidentifiable by-products under long-
term heating. For azadiene 3l, the 6π-electrocyclization of the
2-azahexa-1,3,5-triene fragment to the 2,3-dihydropyridine de-
rivative followed by tautomerization to 1,2-dihydropyridine 6
was more preferable than cyclization onto the pyridine ring
(Table 1, entry 12).
Figure 1. X-ray structure of 4H-pyrido[1,2-a]pyrazine 5d.
triazole 1b or 1 mol-% of Rh2(OAc)4 probably due to signifi-
cantly increased reaction time.
The change of methyl to CH2CO2Me substituent at the C4
position of the 2-azabutadiene decreased the yield of pyrido-
pyrazine (5e) (Table 1, entry 5). Like pyridopyrazines 5b–d, com-
pound 5e was stable at room temperature.
An attempt to synthesize pyrido[1,2-a]pyrazine 5m with
benzoyl substituent at the C1 atom failed due to 2-azadiene
3m underwent 1,6-cyclization onto the C=O bond to give 2H-
1,4-oxazine 7 more readily than 1,6-cyclization onto the pyrid-
ine C=N bond (Scheme 4).
We also performed the reaction of pyridotriazole 1b with 3-
(4-nitrophenyl)azirine 2d. The product, pyrido[1,2-a]pyrazine 5f,
turned out to be quite stable and it was obtained in good yield
(Table 1, entry 6).
In the reaction of azirine 2b with pyridotriazole 1d having
the unsubstituted C7 position, the only product was pyrido-
[1,2-a]pyrazine 5g (Table 1, entry 7), the corresponding 2-azadi-
ene was not observed in the reaction mixture. The low yield of
the product 5g is related to the low reactivity of pyridotriazole
1d. For example, pyridotriazole 1d and azirine 2b were not fully
We also studied the reactions of azirine 2b with triazoloquin-
oline 1h and diazo compound 1i bearing benzoxazole substitu-
ent (Scheme 5). The reaction of triazoloquinoline 1h gave pyr-
azinoquinoline 5n in 50 % yield. The moderate yield in this case
was due to low conversion of triazoloquinoline 1h. The reaction
consumed even in 4 h at 140 °C in toluene in the presence of of diazo compound 1i with azirine 2b, to our delight, afforded
2 mol-% of Rh2(esp)2 or 5 mol-% of Rh2(OAc)4. Naturally, the benzo[4,5]oxazolo[3,2-a]pyrazine derivative 5o. Unlike triazolo-
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position of pyridopyrazines 5 can be replaced by an alkoxy
group that was demonstrated for 6-chloro-substituted pyrido-
pyrazine 5c. When treated with KOH in methanol solution, this
compound quantitatively transformed to 6-methoxy-substi-
tuted pyridopyrazine 5d. The reduction of pyridopyrazine 5c by
ammonium formate in the presence of Pd/C led to the removal
of chlorine and formation of C6-unsubstituted pyridopyrazine
5h. This reaction proved to be of particular interest to us in the
light of unsuccessful experiments on the synthesis of pyridopyr-
azine 5h directly from azirine 2b and pyridotriazole 1e (Table 1,
entry 8). Unexpectedly, C6-unsubstituted pyridopyrazine 5h
turned out to be quite stable: it did not undergo ring opening
into the corresponding pyridylazadiene even when heated.
Scheme 4. The reaction of 3-benzoylpyridotriazole 1g with azirine 2b.
quinoline 1h, diazo compound 1i was quite active, but its reac-
tion was accompanied by the formation of some quantities of
by-products which decreased the yield of product 5o. In both
reactions, the formation of the corresponding azadienes was
not observed.
Scheme 6. Modification of the C6 position of 6-chloropyridopyrazine 5c.
The results obtained show that the nature of the C6-substitu-
ent in pyridopyrazines 5 is one of critical factors affecting the
equilibrium 3%5. The question arises whether this substituent
affects only the equilibrium position or the cyclization rate as
well. Another issue to be clarified is whether the isomerization
of azadienes 3 around the C=N bond (N-inversion) affects the
yield of pyridopyrazines 5. To shed some light on these prob-
Scheme 5. Synthesis of 1H-pyrazino[1,2-a]quinoline 5n and 4H-benzo[4,5]ox-
azolo[3,2-a]pyrazine 5o.
Since pyrido[1,2-a]pyrazines are known only either in fully lems, the DFT calculations (wB97XD/cc-pvtz, PCM for toluene,
hydrogenated[15] or 4-oxo-substituted form,[16] it was of interest 383K) of activation barriers for 1,6-electrocyclization and N-in-
to explore some chemical properties of novel 4H-pyrido[1,2-a]- version of azadienes E,Z- and E,E-3c,h were performed (Figure 2,
pyrazines 5 obtained (Scheme 6). The halogen atom at the C6 blue lines correspond to R = Cl (c), red lines to R = H (h)).
Figure 2. Energy diagram for 1,6-electrocyclization and E/Z isomerization of azadienes E,Z- and E,E-3c,h (wB97XD/cc-pvtz, PCM for toluene, 383K).
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An analysis of the structures of the transition states for the 5c, the distance between the H4 and Cl atoms is just 0.244 nm
1,6-electrocyclizations (TSH1, TSH2, TSCl1, and TSCl2) revealed (Figure 3, compound 5c).
that these transformations are pseudopericyclic reactions.[17,18]
As can be seen in Table 1 and Scheme 2, the position of the
The fact that the π-orbital of the pyridine C=N bond is not
involved in bonding follows from the small deviation of the
dihedral angle ∠C4–N5–C6–C7 from 180°. The dihedral angle
values for all the transition states are in the range of 164.4–
175.7° (Figure 3, TSH1 and TSH2).
equilibrium 3%5 is also affected by the nature of the substitu-
ent at C4 of the pyridopyrazine (5a). The introduction of a
phenyl substituent at the C4 position shifts the equilibrium to-
ward azadiene 3a and increases the rate of the isomerization,
which occurs even at room temperature (Scheme 2). All this can
be rationalized in terms of the energetically favorable conjuga-
tion of the aromatic substituent with the π-system of the azadi-
ene. Probably for the same reason, pyridopyrazines 5 were not
observed in some other reactions (Table 1, entries 10–12).
In order to clarify the reasons for the thermodynamic stabil-
ity of 4-methyl-substituted pyridopyrazines 5 relative to the cor-
responding azadienes 3, we used the data of X-ray diffraction
for compounds (Z,E)-3a and 5d and the quantum chemical cal-
culations. According to these data, there is a weak conjugation
of unsaturated fragments in 2-azadienes 3. For example, the
values of the dihedral angle ∠C1–N2–C3–C4 (Figure 3, com-
pound E,Z-3c) in the calculated optimized geometries of iso-
mers 3c,h are in the range of 39.2–58.8°. According to X-ray
diffraction analysis, the same angle in azadiene (Z,E)-3a is 61.1°.
In contrast, all pyridopyrazines 5 contain nearly flat conjugated
8-amino-1-azaoctatetraene system (Figure 1 and Figure 3, com-
pound 5c) with the C1- and C3-substituents being in the effec-
tive conjugation with the pyridopyrazine π-system. Thus, the
extended conjugated system of non-aromatic pyridopyrazine 5
is more beneficial than weakly conjugated 2-azadiene 3 con-
taining an aromatic pyridine substituent.
Figure 3. The calculated structures of TSH1, TSH2, E,Z-3c, and 5c.
According to the calculations (Figure 2), the activation barri-
ers for the cyclizations of E,E-3c and E,E-3h to the correspond-
ing pyridopyrazines (TSCl1 and TSH1) are close in value (21.9
and 23.4 kcal/mol). Both these barriers are lower than that for
the cyclizations of E,Z-3c and E,Z-3h (27.4 and 27.2 kcal/mol).
The configuration of the C=C bond in compounds 3, thus, has
greater effect on the cyclization to 5 than the nature of a sub-
stituent in the α-position of the pyridine ring. The activation
barriers for N-inversions in azadienes 3c (TSCl3 and TSCl4) and
3h (TSH3 and TSH4) are lower than the barriers for their cycliza-
tion to 5 by 4.9–12.3 kcal/mol (Figure 2). From this it follows
that the equilibrium between the N-invertomers, E,E%Z,E and
E,Z%Z,Z, is rapidly attained already at room temperature, and,
therefore, these isomerizations should not affect the formation
of pyridopyrazines 5.
Due to the extended conjugated system, compounds 5 are
colored. Their color varies from yellow (for 5o) to purple (for 5f).
We recorded the absorption spectra of compounds 5, which are
presented in Figure 4. For pyridopyrazines obtained, the inten-
sive absorption band lies in the visible region: for most com-
pounds long wave maximum is in the range of 464–488 nm.
The exceptions are pyridopyrazine 5f (λmax = 530 nm) contain-
ing a nitro group in aryl substituent and benzoxazolopyrazine
5o (λmax = 401 nm). The maximum extinction coefficients
The relative energies of chlorinated pyridopyrazine 5c and
four isomers of 3c are close to each other (Figure 2). Compound
5c and the most stable azadienes, Z,Z-3c and Z,E-3c, thus, can
be in equilibrium at elevated temperatures. Such equilibrium
was indeed observed experimentally (Table 1, entry 3). In con-
trast, non-chlorinated pyridopyrazine 5h is much more stable
than azadienes 3h. This fact, along with rather high barriers for
the ring opening of pyridopyrazine 5h (33.9 and 36.0 kcal/mol),
makes the 1,6-cyclizations of azadienes E,Z- and E,E-3h into 5h
irreversible. The destabilization of the cyclic form and a de-
crease in the barrier for the ring opening, caused by the intro-
duction of a chlorine atom in the α-position of the pyridine
ring, can be explained by the steric repulsion between the H4
atom and the chlorine atom. According to the calculation for
Figure 4. Absorption spectra of compounds 5b–h,n,o.
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14.08 (s, 1H). 13C NMR (100 MHz, CDCl3) δ (both forms): 48.1, 53.2,
53.5, 95.7, 106.4, 108.6, 114.0, 116.5, 125.2, 128.3, 128.4, 128.9, 129.1,
133.0, 135.8, 136.7, 138.9, 139.6, 152.7, 155.9, 160.4, 161.8, 163.7,
197.0. HRMS (ESI): calcd. for C14H13NNaO2+, [M + Na]+: 250.0838,
found 250.0836.
(ε = 11300–12800 mol–1 cm–1) were observed for pyridopyr-
azine 5d bearing an electron-donating methoxy group, as well
as for compounds 5n,o, possessing additional fused benzene
ring.
General Procedure for the Synthesis of Pyridotriazoles 1a–e,g–
i: To a dichloromethane (DCM) solution (10 mL) of the correspond-
ing (2-pyridyl)acetate (1 equiv.) and TsN3 (1.1 equiv.) a solution of
1,8-diazabicyclo[5.4.0]undec-7-ene (1.1 equiv.) in DCM (5 mL) was
added dropwise at 0 °C. The mixture was stirred at room tempera-
ture until consumption of the (2-pyridyl)acetate, and the reaction
mixture was poured into saturated NH4Cl solution. The water layer
was extracted with DCM, combined organic layers were washed
with water, brine and dried with Na2SO4. The DCM was evaporated
in vacuo, and the residue was purified by column chromatography
on silica gel.
Conclusion
1-(2-Pyridyl)-2-azabuta-1,3-dienes were synthesized by RhII-cat-
alyzed reaction of pyridotriazoles with 2H-azirines, and their
pseudopericyclic 1,6-cyclization involving dearomatization of a
pyridine ring was studied. The 2-azadienes containing H, alkyl,
or Ph at the C4 atom and an electron-withdrawing substituent
at the C1 atom were able to undergo 1,6-electrocyclization to
4H-pyrido[1,2-a]pyrazine derivatives. A number of stable 4H-
pyrido[1,2-a]pyrazines mainly containing methyl group at the
C4 atom were synthesized. Whereas 4-alkyl-substituted pyrido-
pyrazines are stable at room temperature, 4-phenyl-substituted
pyridopyrazines exist in ring–chain valence equilibrium with the
corresponding 2-azadienes. Thermodynamic stability of the
4H-pyrido[1,2-a]pyrazine decreases with increasing the steric
volume of a substituent at the C6 atom. The 1,6-cyclization was
also expanded to the synthesis of 1H-pyrazino[1,2-a]quinoline
and 4H-benzo[4,5]oxazolo[3,2-a]pyrazine derivatives. The 2-aza-
dienes containing phenyl or ester groups at both the C1 and
the C4 positions did not cyclize to the pyridopyrazines.
Methyl
7-Bromo-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate
(1a):[14k] Compound 1a (322 mg, yield 34 %) was obtained accord-
ing to the general procedure. Colorless solid, m.p. 149–150 °C (de-
comp.). 1H NMR (400 MHz, CDCl3) δ: 4.06 (s, 3H), 7.41 (br s, 1H), 7.47
(t, J = 8.0 Hz, 1H), 8.31 (br s, 1H).
Methyl
7-Chloro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate
(1b):[14b] Compound 1b (624 mg, yield 85 %) was obtained accord-
ing to the general procedure. Beige solid, m.p. 143–145 °C (lit.[14c]
147 °C). 1H NMR (400 MHz, CDCl3) δ: 4.05 (s, 3H), 7.23 (br s, 1H),
7.55 (t, J = 8.0 Hz, 1H), 8.27 (br s, 1H).
Methyl 7-Methoxy-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate
(1c): Compound 1c (127 mg, yield 80 %) was obtained according
1
to the general procedure. Colorless solid, 138–139 °C (decomp.). H
Experimental Section
General Information
NMR (400 MHz, CDCl3, 233K) δ: 4.03 (s, 3H), 4.26 (s, 3H), 6.48 (d, J =
7.5 Hz, 1H), 7.61 (t, J = 8.1 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H). 13C NMR
(100 MHz, CDCl3, 233K) δ = 52.3, 57.3, 92.9, 110.1, 128.7, 131.9,
136.2, 149.3, 161.8. HRMS (ESI): calcd. for C9H9N3NaO3+, [M + Na]+:
230.0536, found 230.0543.
Melting points were determined on a melting point apparatus
SMP30. 1H (400 MHz) and 13C (100 MHz) NMR spectra were re-
corded on a Bruker AVANCE 400 spectrometer in CDCl3. Chemical
shifts (δ) are reported in parts per million downfield from tetra-
methylsilane. Electrospray ionization (ESI) mass spectra were re-
corded on a Bruker MaXis mass spectrometer. UV/Vis spectra were
recorded on a Shimadzu UV-1800 spectrometer in 1,2-dichloroeth-
ane (DCE). Single crystal X-ray data for (Z,E)-3a and 5d were col-
lected by means of a SuperNova, Single source at offset/far, Hy-
Pix3000 diffractometer at 100 K using monochromated Cu-Kα radia-
tion. Thin-layer chromatography (TLC) was conducted on aluminum
sheets precoated with SiO2 ALUGRAM SIL G/UV254. Column chro-
matography was performed on Macherey-Nagel silica gel 60 M
(0.04–0.063 mm). Toluene was distilled and stored over sodium
metal. 1,2-Dichloroethane and dichloromethane were washed with
concentrated H2SO4 and water, distilled from P2O5, and stored over
anhydrous K2CO3. Pyridotriazole 1f was prepared by the reported
procedure.[14b] Azirines 2a,[19] 2b,[20] 2c,[21] 2d,[22] 2e,[23] 2f,[24] and
2g[25] were prepared by the reported procedures.
[1,2,3]Triazolo[1,5-a]pyridine-3-carbonitrile (1d):[27] Compound
1d (1.42 g, yield 94 %) was obtained according to the general pro-
cedure. Colorless solid, m.p. 143–145 °C (lit.[27] 146 °C). 1H NMR
(400 MHz, CDCl3) δ: 7.28 (td, J = 6.9, 1.1 Hz, 1H), 7.67 (ddd, J = 8.9,
6.9, 1.0 Hz, 1H), 7.96 (dt, J = 8.9, 1.1 Hz, 1H), 8.91 (dt, J = 6.9, 1.0 Hz,
1H).
Methyl [1,2,3]Triazolo[1,5-a]pyridine-3-carboxylate (1e):[14k]
Compound 1e (1.01 g, yield 80 %) was obtained according to the
general procedure. Colorless solid, m.p. 139–141 °C (lit.[14c] 140–
141 °C). H NMR (400 MHz, CDCl3) δ: 4.05 (s, 3H), 7.18 (td, J = 6.9,
1.2 Hz, 1H), 7.57 (ddd, J = 8.9, 6.9, 0.9 Hz, 1H), 8.29 (dt, J = 8.9,
1.2 Hz, 1H), 8.85 (dt, J = 6.9, 0.9 Hz, 1H).
1
(7-Methoxy-[1,2,3]triazolo[1,5-a]pyridin-3-yl)(phenyl)methan-
one (1g): Compound 1g (784 mg, yield 84 %) was obtained accord-
ing to the general procedure. Colorless solid, m.p. 135–137 °C (de-
comp.). 1H NMR (400 MHz, CDCl3) δ: 4.24 (s, 3H), 6.51 (d, J = 7.6 Hz,
1H), 7.54–7.58 (m, 2H), 7.61–7.67 (m, 2H), 8.17–8.19 (m, 2H), 8.41 (s,
2H). 13C NMR (100 MHz, CDCl3/[D6]DMSO, 233K) δ = 57.1, 93.7,
111.1, 128.1, 130.0, 132.6, 132.8, 136.3, 136.8, 136.9, 149.2, 186.4.
HRMS (ESI): calcd. for C14H11N3NaO2+, [M + Na]+: 276.0743, found
276.0753.
CCDC 1844058 [for (Z,E)-3a], and 1980147 (for 5d) contain the sup-
plementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre.
2-(6-Methoxypyridin-2-yl)-1-phenylethanone: This compound
(0.90 g, yield 40 %) was obtained according to the literature proce-
dure.[26] Yellow oil. H NMR (400 MHz, CDCl3) δ: [keto form] 3.88 (s, Ethyl [1,2,3]Triazolo[1,5-a]quinoline-3-carboxylate (1h): Com-
1
3H), 4.39 (s, 2H), 6.62 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H),
pound 1h (185 mg, yield 47 %) was obtained according to the gen-
7.38–7.44 (m, 2H), 7.48 (t, J = 7.6 Hz, 2H), 8.11–8.13 (m, 2H); [enol eral procedure. Pale-yellow solid, m.p. 168–169 °C. 1H NMR
form] 4.05 (s, 3H), 6.09 (s, 1H), 6.55 (d, J = 8.2 Hz, 1H), 6.72 (d, J = (400 MHz, CDCl3) δ: 1.53 (t, J = 7.1 Hz, 3H), 4.57 (q, J = 7.1 Hz, 2H),
7.5 Hz, 1H), 7.51–7.53 (m, 1H), 7.55–7.59 (m, 3H), 7.83–7.85 (m, 2H),
7.71 (t, J = 7.6 Hz, 1H), 7.82 (d, J = 9.3 Hz, 1H), 7.86 (t, J = 7.9 Hz,
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1H), 7.95 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 9.3 Hz, 1H), 8.89 (d, J = (5a), 126.6 (5a), 126.65, 126.69 (5a), 128.1, 128.2, 128.27, 128.33,
8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 14.4, 61.2, 115.5, 116.5,
128.65 (5a), 128.74 (5a), 128.8 (5a), 129.2 (5a), 129.4, 130.4, 131.6
123.9, 127.7, 128.6, 130.2, 130.8, 131.3, 131.5, 133.5, 161.5. HRMS (5a), 134.8 (5a), 136.0, 136.9 (5a), 137.5 (5a), 137.7, 139.0, 140.4 (5a),
(ESI): calcd. for C13H11N3NaO2+, [M + Na]+: 264.0743, found
264.0747.
141.5, 146.3, 153.6, 160.4, 163.9, 165.7 (5a). HRMS (ESI): calcd. for
C22H1779BrN2NaO2+, [M + Na]+: 443.0366, found 443.0360.
Methyl 2-(Benzo[d]oxazol-2-yl)-2-diazoacetate (1i):[28] Com-
pound 1i (160 mg, yield 88 %) was obtained according to the gen-
eral procedure. Yellow solid, m.p. 126–127 °C (lit.[28] 127–128 °C). 1H
NMR (400 MHz, CDCl3) δ: 3.99 (s, 3H), 7.28–7.36 (m, 2H), 7.54–7.56
(m, 1H), 7.68–7.70 (m, 1H).
Methyl 2-(6-Bromopyridin-2-yl)-2-[(1-phenylprop-1-en-1-yl)-
imino]acetate (3b) and Methyl 6-Bromo-4-methyl-3-phenyl-4H-
pyrido[1,2-a]pyrazine-1-carboxylate (5b): Azadiene 3b (5 mg,
yield 17 %) and pyridopyrazine 5b (17 mg, yield 60 %) were ob-
tained according to the general procedure from pyridotriazole 1a
(24 mg, 0.09 mmol) and azirine 2b (16 mg, 0.08 mmol) [110 °C,
30 min, Rh2(OAc)4 (2 mol-%, 0.7 mg), eluent for chromatography
EtOAc/hexane, 1:6].
General Procedure for the Reaction of Pyridotriazoles 1 with
Azirines 2: 2H-azirine 2 (1 equiv.), pyridotriazole 1 or diazo com-
pound 1i (0.6–1.5 equiv.), rhodium carboxylate (1–5 mol-% on
azirine), and dry toluene (0.5 mL) were placed into a screw-cap glass
tube and heated at 110 °C or 140 °C (oil bath temperature) whilst
stirring until gas evolution had ceased. The solvent was evaporated
in vacuo, and the residue was purified by column chromatography
on silica gel.
Compound 3b: (mixture of Z and E isomers in 1:1 ratio). Unstable
yellow oil which is rapidly transformed to 5b. 1H NMR (400 MHz,
CDCl3) δ: 1.71 (d, J = 7.1 Hz, 3H, Z), 1.79 (d, J = 7.2 Hz, 3H, E), 3.73
(s, 3H, Z), 3.82 (s, 3H, E), 5.44 (q, J = 7.2 Hz, 1H, E), 5.52 (q, J = 7.1 Hz,
1H, Z), 7.30–7.34 (m, 3H), 7.38–7.45 (m, 7H), 7.54 (d, J = 7.8 Hz, 1H),
7.62 (t, J = 7.7 Hz, 2H), 7.70 (t, J = 7.8 Hz, 1H), 8.10 (d, J = 7.6 Hz,
1H, E), 8.26 (d, J = 7.0 Hz, 1H, Z).
(Z)-Methyl 2-(6-Bromopyridin-2-yl)-2-{[(E)-1,2-diphenylvinyl]-
imino}acetate [(Z,E)-3a] and (2RS,3SR)-Methyl 2-(6-Bromopyr-
idin-2-yl)-3,4-diphenyl-2,3-dihydroazete-2-carboxylate (4): Aza-
diene (Z,E)-3a (230 mg, yield 77 %) and dihydroazete 4 (27 mg,
yield 9 %) were obtained according to the general procedure from
pyridotriazole 1a (200 mg, 0.78 mmol) and azirine 2a (137 mg,
0.7 mmol) [110 °C, 1 min, Rh2(OAc)4 (2 mol-%, 6.2 mg), eluent for
chromatography EtOAc/hexane, 1:5]. Just after isolation both com-
pounds were identified by TLC as pure but due to rapid interconver-
tion in solution their NMR spectra contained signals of both com-
pounds. Pure (Z,E)-3a in crystal form was obtained by slow evapora-
tion of the Et2O solution of (Z,E)-3a and 4 mixture.
Compound (Z,E)-3a: Orange solid, m.p. 106–109 °C. 1H NMR
(400 MHz, CDCl3) δ: 3.87 (s, 3H), 6.25 (s, 1H), 7.07–7.08 (m, 2H), 7.16–
7.17 (m, 2H), 7.33–7.35 (m, 4H), 7.40–7.42 (m, 2H), 7.58 (d, J = 7.9 Hz,
1H), 7.66 (t, J = 7.9 Hz, 1H), 8.14 (d, J = 7.6 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ = 52.1, 115.6, 120.9, 126.9, 128.1, 128.5, 128.5,
129.3, 129.5, 130.0, 135.5, 135.7, 138.8, 141.3, 149.6, 154.0, 157.1,
164.7. HRMS (ESI): calcd. for C22H1879BrN2O2+, [M + H]+: 421.0547,
found 421.0545.
Compound 5b: Red solid, m.p. 97–98 °C. 1H NMR (400 MHz, CDCl3)
δ: 1.22 (d, J = 6.8 Hz, 3H), 3.91 (s, 3H), 6.32 (q, J = 6.7 Hz, 1H), 6.67
(d, J = 6.9 Hz, 1H), 6.85 (dd, J = 9.3, 7.0 Hz, 1H), 7.38 (t, J = 7.2 Hz,
1H), 7.44 (t, J = 7.4 Hz, 2H), 7.92 (d, J = 7.4 Hz, 2H), 8.45 (d, J =
9.3 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 13.0, 51.4, 52.2, 111.0,
117.7, 120.3, 125.2, 126.0, 128.8, 129.1, 132.2, 135.8, 139.0, 140.4,
166.1. HRMS (ESI): calcd. for C17H1679BrN2O2+, [M + H]+: 359.0390,
found 359.0402. λmax (DCE, ε): 390 (7400), 470 (5800).
Methyl 2-(6-Chloropyridin-2-yl)-2-[(1-phenylprop-1-en-1-yl)-
imino]acetate (3c) and Methyl 6-Chloro-4-methyl-3-phenyl-4H-
pyrido[1,2-a]pyrazine-1-carboxylate (5c): Azadiene 3c (13 mg,
yield 15 %) and pyridopyrazine 5c (52 mg, yield 60 %) were ob-
tained according to the general procedure from pyridotriazole 1b
(55 mg, 0.25 mmol) and azirine 2b (33 mg, 0.25 mmol) [110 °C,
30 min, Rh2(OAc)4 (2 mol-%, 2.2 mg), eluent for chromatography
EtOAc/hexane, 1:6].
Compound 3c: (mixture of Z and E isomers in 5:1 ratio). Unstable
yellow oil which is rapidly transformed to 5c. 1H NMR (400 MHz,
CDCl3) δ: 1.72 (d, J = 7.1 Hz, 15H, Z), 1.79 (d, J = 7.2 Hz, 3H, E), 3.74
(s, 15H, Z), 3.83 (s, 3H, E), 5.44 (q, J = 7.2 Hz, 1H, E), 5.52 (q, J =
7.1 Hz, 5H, Z), 7.29–7.34 (m, 13H), 7.38–7.41 (m, 16H), 7.44–7.48 (m,
7H), 7.73 (t, J = 7.8 Hz, 1H, E), 7.81 (t, J = 7.8 Hz, 5H, Z), 8.07 (d, J =
7.7 Hz, 1H, E), 8.24 (d, J = 7.1 Hz, 5H, Z).
1
Compound 4: Pale-yellow oil. H NMR (400 MHz, CDCl3) δ (identi-
fied signals): 3.28 (s, 3H), 5.77 (s, 1H), 7.80 (d, J = 7.2 Hz, 2H). 13C
NMR (100 MHz, CDCl3) δ (identified signals): 56.9, 121.5, 126.8,
128.7, 128.9, 132.3, 188.6.
(Z)-Methyl 2-(6-Bromopyridin-2-yl)-2-{[(Z)-1,2-diphenylvinyl]-
imino}acetate [(Z,Z)-3a] and Methyl 6-Bromo-3,4-diphenyl-4H-
pyrido[1,2-a]pyrazine-1-carboxylate (5a): Azadiene (Z,Z)-3a
(35 mg, yield 35 %) and pyridopyrazine 5a (52 mg, yield 52 %) were
obtained by heating solution of azadiene (Z,E)-3a (100 mg) in CDCl3
(0.5 mL) in a sealed tube at 70 °C for 36 h followed by rapid column
chromatography (eluent EtOAc/hexane, 1:4).
Compound 5c: Red solid, m.p. 121–123 °C. 1H NMR (400 MHz,
CDCl3) δ: 1.23 (d, J = 6.8 Hz, 3H), 3.90 (s, 3H), 6.31 (q, J = 6.7 Hz,
1H), 6.47 (dd, J = 7.0, 1.1 Hz, 1H), 6.94 (dd, J = 9.4, 7.0 Hz, 1H), 7.36
(m, 1H), 7.43 (m, 2H), 7.91 (m, 2H), 8.40 (dd, J = 9.4, 0.9 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ: 13.1, 48.9, 51.3, 110.6, 113.0, 119.6, 125.9,
128.7, 129.0, 132.0, 134.9, 135.7, 138.5, 140.1, 166.2. HRMS (ESI):
calcd. for C17H1635ClN2O2+, [M + H]+: 315.0895, found 315.0910. λmax
(DCE, ε): 327 (5200), 472 (4300).
Compound (Z,Z)-3a: Orange solid. This compound is rapidly trans-
formed to 5a. 1H NMR (400 MHz, CDCl3) δ: 3.48 (s, 3H), 6.43 (s, 1H),
7.19 (t, J = 7.3 Hz, 1H), 7.29–7.31 (m, 2H), 7.36–7.41 (m, 5H), 7.49 (d,
J = 7.0 Hz, 2H), 7.63 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 8.33
(d, J = 7.6 Hz, 1H).
Methyl 2-(6-Methoxypyridin-2-yl)-2-[(1-phenylprop-1-en-1-yl)-
imino]acetate (3d) and Methyl 6-Methoxy-4-methyl-3-phenyl-
4H-pyrido[1,2-a]pyrazine-1-carboxylate (5d): Azadiene 3d
(17 mg, yield 18 %) and pyridopyrazine 5d (37 mg, yield 39 %) were
obtained according to the general procedure from pyridotriazole
1c (63 mg, 0.3 mmol) and azirine 2b (40 mg, 0.3 mmol) [110 °C,
30 min, Rh2(OAc)4 (2 mol-%, 2.7 mg), eluent for chromatography
EtOAc/hexane, 1:4]. Pyridopyrazine 5d was also obtained in 98 %
yield by stirring pyridopyrazine 5c in saturated solution of potas-
Compound 5a: Red solid. This compound is rapidly transformed to
1
(Z,Z)-3a. H NMR (400 MHz, CDCl3) δ: 3.86 (s, 3H), 6.75 (dd, J = 6.9,
1.0 Hz, 1H), 6.86 (dd, J = 9.4, 6.9 Hz, 1H), 7.16–7.18 (m, 2H), 7.22–
7.27 (m, 3H), 7.36 (s, 1H), 7.39–7.42 (m, 1H), 7.46 (t, J = 7.4 Hz, 2H),
8.00 (d, J = 7.3 Hz, 2H), 8.41 (d, J = 9.3 Hz, 1H).
Mixture of (Z,Z)-3a and 5a: 13C NMR (100 MHz, CDCl3) δ: 51.4 (5a),
51.8, 57.0 (5a), 113.3 (5a), 115.0, 117.5 (5a), 120.6, 125.3 (5a), 126.5
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sium hydroxide (4 equiv.) in methanol at room temperature for 24 h %, 5.5 mg), eluent for chromatography EtOAc/PhH, 1:10]. Red oil.
followed by chromatographic purification on silica gel.
1H NMR (400 MHz, CDCl3) δ: 1.33 (d, J = 6.7 Hz, 3H), 5.39 (q, J =
6.7 Hz, 1H), 6.38 (dt, J = 7.0, 4.0 Hz, 1H), 7.09 (d, J = 3.6 Hz, 2H),
7.13 (d, J = 6.8 Hz, 1H), 7.35–7.43 (m, 3H), 7.81–7.85 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ: 15.8, 55.0, 91.5, 112.7, 118.7, 120.6, 125.4,
128.7, 129.0, 133.6, 135.0, 135.1, 137.8, 139.9. HRMS (ESI): calcd. for
C16H14N3+, [M + H]+: 248.1183, found 248.1179. λmax (DCE, ε): 400
(7900), 474 (7000).
Compound 3d: (mixture of Z and E isomers in 1.9:1 ratio). Unstable
yellow oil which is rapidly transformed to 5d. 1H NMR (400 MHz,
CDCl3) δ: 1.72 (d, J = 7.1 Hz, 5.7H, Z), 1.79 (d, J = 7.2 Hz, 3H, E), 3.73
(s, 3.7H, Z), 3.81 (s, 3H, E), 3.91 (s, 3H, E), 3.92 (s, 5.7H, Z), 5.42 (q,
J = 7.2 Hz, 1H, E), 5.52 (q, J = 7.0 Hz, 1.9H, Z), 6.82 (d, J = 8.1 Hz,
1H, E), 6.89 (d, J = 8.2 Hz, 1.9H, Z), 7.31–7.46 (m, 16H), 7.63–7.67 (m,
1H, E), 7.71–7.77 (m, 3H), 7.93 (d, J = 7.3 Hz, 1H, Z).
Methyl 4-Methyl-3-phenyl-4H-pyrido[1,2-a]pyrazine-1-carb-
oxylate (5h): A solution of pyridopyrazine 5c (12 mg, 0.04 mmol)
in methanol (0.5 mL) was added to the mixture of ammonia formate
(25 mg, 10 equiv.) and Pd/C (1.2 mg, 10 mass. % on 5c) and heated
at 90 °C for 1 h in a screw-cap glass tube. Methanol was evaporated
in vacuo, and the product was purified by column chromatography
on silica gel to give pyridopyrazine 5h (11 mg, yield 93 %). Red oil.
1H NMR (400 MHz, CDCl3) δ: 1.30 (d, J = 6.8 Hz, 3H), 3.91 (s, 3H),
5.39 (q, J = 6.7 Hz, 1H), 6.48 (t, J = 6.3 Hz, 1H), 7.16–7.20 (m, 2H),
7.35 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.89 (d, J = 7.5 Hz,
2H), 8.49 (d, J = 9.3 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 15.2, 51.2,
55.7, 107.8, 113.4, 121.1, 125.5, 128.6 (2C), 133.6, 134.8, 135.9, 136.0,
139.1, 166.4. HRMS (ESI): calcd. for C17H17N2O2, [M + H]+: 281.1285,
found 281.1292. λmax (DCE, ε): 327 (9400), 466 (7800).
1
Compound 5d: Orange solid, m.p. 175–177 °C. H NMR (400 MHz,
CDCl3) δ: 1.20 (d, J = 6.7 Hz, 3H), 3.89 (s, 3H), 3.96 (s, 3H), 5.78 (dd,
J = 7.5, 0.9 Hz, 1H), 6.23 (q, J = 6.7 Hz, 1H), 7.11 (dd, J = 9.3, 7.5 Hz,
1H), 7.29–7.34 (m, 1H), 7.37–7.42 (m, 2H), 7.88–7.91 (m, 2H), 8.09
(dd, J = 9.3, 0.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 13.7, 44.3,
51.1, 56.7, 89.6, 108.0, 112.4, 125.6, 128.3, 128.5, 134.6, 136.3, 137.3,
139.8, 154.6, 166.5. HRMS (ESI) [M + H]+: calcd. for C18H19N2O3
,
+
311.1391, found 311.1398. λmax (DCE, ε): 369 (10300), 476 (12800).
Methyl 4-{[1-(6-Chloropyridin-2-yl)-2-methoxy-2-oxoethyl-
idene]amino}but-3-enoate (3e) and Methyl 6-Chloro-4-(2-meth-
oxy-2-oxoethyl)-3-phenyl-4H-pyrido[1,2-a]pyrazine-1-carboxyl-
ate (5e): Azadiene 3e (114 mg, yield 63 %) and pyridopyrazine 5e
(28 mg, yield 15 %) were obtained according to the general proce-
dure from pyridotriazole 1b (116 mg, 0.55 mmol) and azirine 2c
(89 mg, 0.5 mmol) [110 °C, 15 min, Rh2(OAc)4 (2 mol-%, 4.4 mg),
eluent for chromatography EtOAc/hexane, 1:5].
Methyl 2-(6-Chloropyridin-2-yl)-2-[(2-methyl-1-phenylprop-1-
en-1-yl)imino]acetate (3i): Azadiene 3i (26 mg, yield 77 %) was
obtained according to the general procedure from pyridotriazole
1b (26 mg, 0.12 mmol) and azirine 2e (15 mg, 0.1 mmol) [140 °C,
5 min, Rh2(OAc)4 (2 mol-%, 0.9 mg), eluent for chromatography
EtOAc/hexane, 1:15]. Yellow oil. 1H NMR (400 MHz, CDCl3) δ: 1.78 (s,
3H), 2.04 (s, 3H), 3.46 (s, 3H), 7.24–7.27 (m, 2H), 7.29–7.31 (m, 1H),
7.33–7.37 (m, 3H), 7.72 (t, J = 7.8 Hz, 1H), 8.15 (d, J = 7.7 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ = 20.2, 21.5, 51.6, 119.6, 125.5, 127.4,
127.8, 129.3, 130.3, 137.1, 138.8, 141.3, 150.6, 154.7 (2C), 165.4.
HRMS (ESI): calcd. for C18H1835ClN2O2, [M + H]+: 329.1052, found
329.1059.
Compound 3e: (mixture of Z and E isomers in 1:1.6 ratio). Unstable
orange oil which is rapidly transformed to 5e. 1H NMR (400 MHz,
CDCl3) δ: 3.16–3.20 (m, 5.2H), 3.71–3.73 (m, 11H), 3.92 (s, 5H, E), 5.41
(t, J = 7.7 Hz, 1.6H, E), 5.68 (t, J = 7.1 Hz, 1H, Z), 7.32–7.48 (m, 16H),
7.74 (t, J = 7.8 Hz, 1.6H, E), 7.82 (t, J = 7.8 Hz, 1H, Z), 8.07 (d, J =
7.7 Hz, 1.6H, E), 8.21 (d, J = 7.7 Hz, 1H, Z). 13C NMR (100 MHz, CDCl3)
δ = 32.8 (Z), 33.7 (E), 51.8 (Z), 51.9 (E), 52.0 (E), 52.1 (Z), 104.6 (Z),
106.9 (E), 120.3 (Z), 120.4 (E), 125.9 (E), 126.2 (E), 126.7 (Z), 128.3 (2C,
Z), 128.4 (E), 128.5 (Z), 128.7 (E), 134.7 (E), 136.0 (Z), 139.1 (E), 139.3
(Z), 148.2 (Z), 150.8 (E), 151.0 (Z), 151.5 (E), 152.7 (Z), 153.4 (E), 157.2
(E), 160.5 (Z), 164.3 (Z), 164.5 (E), 171.8 (E), 171.9 (Z).
Compound 5e: Red solid, m.p. 132–134 °C. 1H NMR (400 MHz,
CDCl3) δ: 2.33 (dd, J = 15.6, 4.0 Hz, 1H), 2.83 (dd, J = 15.6, 9.7 Hz,
1H), 3.60 (s, 3H), 3.93 (s, 3H), 6.55 (dd, J = 6.9, 1.1 Hz, 1H), 6.73 (dd,
J = 9.7, 4.0 Hz, 1H), 6.99 (dd, J = 9.4, 7.0 Hz, 1H), 7.37–7.42 (m, 1H),
7.46 (t, J = 7.4 Hz, 2H), 7.94–7.99 (m, 2H), 8.39–8.44 (m, 1H). 13C
NMR (100 MHz, CDCl3) δ: 29.8, 48.8, 51.5, 52.0, 112.5, 113.1, 119.6,
126.3, 128.6, 129.3, 131.6, 134.9, 135.2, 135.8, 139.4, 165.7, 169.9.
HRMS (ESI): calcd. for C19H1835ClN2O4, [M + H]+: 373.0950, found
373.0939. λmax (DCE, ε): 464 (7000).
(E)-Methyl 3-{[1-(6-Bromopyridin-2-yl)-2-methoxy-2-oxoethyl-
idene]amino}-3-phenylacrylate [(E)-3j] and (Z)-Methyl 3-{[1-(6-
Bromopyridin-2-yl)-2-methoxy-2-oxoethylidene]amino}-3-
phenylacrylate [(Z)-3j]: Azadiene (E)-3j (46 mg, yield 33 %) and
unseparated mixture of (E)-3j and (Z)-3j in 1:1.6 ratio (79 mg, yield
56 %) were obtained according to the general procedure from pyr-
idotriazole 1a (116 mg, 0.46 mmol) and azirine 2f (61 mg,
0.35 mmol) [140 °C, 1 min, Rh2(OAc)4 (5 mol-%, 7.7 mg), eluent for
chromatography EtOAc/hexane, 1:4].
Compound (E)-3j: Yellow solid, m.p. 116–119 °C. 1H NMR (400 MHz,
CDCl3) δ: 3.64 (s, 3H), 3.96 (s, 3H), 5.46 (s, 1H), 7.40–7.43 (m, 3H),
7.53–7.55 (m, 2H), 7.60 (d, J = 7.9 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H),
8.06–8.08 (m, 1H). 13C NMR (100 MHz, CDCl3) δ: 51.3, 52.3, 102.1,
121.2, 127.9, 128.6, 129.6, 130.6, 134.0, 138.9, 141.5, 152.9, 156.3,
163.0, 163.2, 165.9.
Compound (Z)-3j: [not separated from (E)-3j]. Yellow oil. 1H NMR
(400 MHz, CDCl3) δ: 3.69 (s, 3H), 3.81 (s, 3H), 5.71 (s, 1H), 7.40–7.42
(m, 3H), 7.56–7.58 (m, 2H), 7.61–7.63 (m, 1H), 7.72 (t, J = 7.8 Hz, 1H),
8.22 (d, J = 7.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 51.3, 52.3,
97.6, 121.9, 126.6, 128.7, 130.4, 134.7, 139.0, 141.4, 152.9, 158.0,
160.1, 162.7, 163.0, 166.0. HRMS (ESI) of the mixture of (E)-3j and
(Z)-3j: calcd. for C18H1579BrN2NaO4+, [M + Na]+: 425.0108, found
425.0111.
Methyl 6-Chloro-3-(4-nitrophenyl)-4H-pyrido[1,2-a]pyrazine-1-
carboxylate (5f): Pyridopyrazine 5f (56 mg, yield 65 %) was ob-
tained according to the general procedure from pyridotriazole 1b
(43 mg, 0.2 mmol) and azirine 2d (40 mg, 0.25 mmol) [110 °C, 5 min,
Rh2(OAc)4 (1 mol-%, 0.9 mg), eluent for chromatography EtOAc/
hexane, 1:4]. Purple solid, m.p. 156–158 °C. 1H NMR (400 MHz,
CDCl3) δ: 3.89 (s, 3H), 4.84 (s, 2H), 6.65 (d, J = 7.0 Hz, 1H), 7.10 (dd,
J = 9.2, 7.2 Hz, 1H), 8.02 (d, J = 8.7 Hz, 2H), 8.23 (d, J = 8.7 Hz, 2H),
8.31 (d, J = 9.3 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ = 44.2, 51.4,
113.7, 114.2, 119.2, 124.0, 126.5, 129.2, 133.4, 135.0, 141.7, 142.6,
147.1, 165.5. HRMS (ESI): calcd. for C16H1335ClN3O4+, [M + H]+:
346.0590, found 346.0598. λmax (DCE, ε): 275 (9200), 530 (5000).
4-Methyl-3-phenyl-4H-pyrido[1,2-a]pyrazine-1-carbonitrile
1,2-Diphenyl-N-[phenyl(pyridin-2-yl)methylene]ethenamine
(5g): Pyridopyrazine 5g (17 mg, yield 31 %) was obtained according (3k): Azadiene 3k (47 mg, yield 26 %) was obtained according to
to the general procedure from pyridotriazole 1d (44 mg, 0.38 mmol)
and azirine 2b (33 mg, 0.25 mmol) [140 °C, 3 h, Rh2(OAc)4 (5 mol-
the general procedure from pyridotriazole 1f (150 mg, 0.77 mmol)
and azirine 2a (114 mg, 0.6 mmol) [140 °C, 3 h, Rh2(esp)2 (1 mol-%,
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4.5 mg), eluent for chromatography EtOAc/hexane, 1:6]. Unstable solid, m.p. 168–169 °C. 1H NMR (400 MHz, CDCl3) δ: 1.59 (d, J =
1
yellow oil. H NMR (400 MHz, CDCl3) δ = 6.20 (s, 1H), 7.12–7.28 (m,
7H), 7.40–7.54 (m, 9H), 7.87–7.95 (m, 2H), 8.41 (s, 1H). 13C NMR
(100 MHz, CDCl3) δ = 112.0, 123.0, 124.6, 125.9, 126.1, 127.5, 128.1,
6.8 Hz, 3H), 3.26 (s, 3H), 5.66 (q, J = 6.8 Hz, 1H), 6.53 (d, J = 8.0 Hz,
1H), 7.30–7.33 (m, 3H), 7.45–7.53 (m, 5H), 7.58 (t, J = 7.8 Hz, 1H),
7.65 (d, J = 7.2 Hz, 1H), 8.01–8.04 (m, 2H). 13C NMR (100 MHz, CDCl3)
128.1, 128.2, 128.3, 128.4, 128.9, 131.0, 132.9, 135.0, 137.0, 137.2, δ: 15.0, 52.4, 67.0, 108.5, 114.0, 126.6, 126.7, 127.7, 128.6, 128.7,
147.8, 148.5. HRMS (ESI): calcd. for C26H21N2+, [M + H]+: 361.1700,
found 361.1714.
130.0, 130.3, 134.9, 135.1, 138.5, 142.2, 151.8, 153.2, 162.5. HRMS
(ESI): calcd. for C23H21N2O2+, [M + H]+: 357.1598, found 357.1605.
(2E,4E)-Methyl 5-{[1-(6-Chloropyridin-2-yl)-2-methoxy-2-
oxoethylidene]amino}-5-phenylpenta-2,4-dienoate [(E)-3l] and
Dimethyl 6′-Chloro-6-phenyl-1,2-dihydro-[2,2′-bipyridine]-2,3-
dicarboxylate (6): Azatriene (E)-3l (47 mg, yield 61 %) and dihydro-
pyridine 6 (13 mg, yield 17 %) were obtained according to the gen-
eral procedure from pyridotriazole 1b (42 mg, 0.2 mmol) and azirine
2g (40 mg, 0.2 mmol) [110 °C, 1 min, Rh2(OAc)4 (2 mol-%, 1.8 mg),
eluent for chromatography EtOAc/hexane, 1:5].
Acknowledgments
We gratefully acknowledge the financial support of the Russian
Science Foundation (№ 19-73-10090). We especially thank
Galina L. Starova and Olesya V. Khoroshilova for performing the
X-ray diffraction studies. This research used resources of the
Magnetic Resonance Research Centre, Chemical Analysis and
Compound (E)-3l: Yellow oil. 1H NMR (400 MHz, CDCl3) δ: 3.73 (s, Materials Research Centre, Centre for X-ray Diffraction Studies,
3H), 3.87 (s, 3H), 5.98 (dd, J = 16.5, 13.6 Hz, 2H), 6.00 (d, J = 15.4 Hz,
1H), 7.42–7.49 (m, 7H), 7.76 (t, J = 7.8 Hz, 1H), 8.07 (d, J = 7.8 Hz,
1H). 13C NMR (100 MHz, CDCl3) δ: 51.4, 52.3, 112.3, 120.7, 121.5,
126.7, 128.5, 129.1, 129.4, 134.2, 139.2, 141.1, 151.0, 152.8, 156.8,
157.2, 164.0, 167.4. HRMS (ESI): calcd. for C20H1835ClN2O4+, [M + H]+:
385.0950, found 385.0966.
Computing Centre, and Chemistry Educational Centre of the
Research Park of St. Petersburg State University.
Keywords: Nitrogen heterocycles · Fused-ring systems ·
Rhodium · Strained molecules · Electrocyclic reactions
1
Compound 6: Yellow oil. H NMR (400 MHz, CDCl3) δ: 3.76 (s, 3H),
3.84 (s, 3H), 5.44 (dd, J = 6.7, 1.8 Hz, 1H), 5.93 (s, 1H), 7.24 (dd, J =
7.8, 0.5 Hz, 1H), 7.42–7.46 (m, 4H), 7.55 (d, J = 6.7 Hz, 1H), 7.62 (t,
J = 7.8 Hz, 1H), 7.70–7.74 (m, 2H). 13C NMR (100 MHz, CDCl3) δ:
51.6, 53.3, 67.7, 95.2, 110.6, 121.1, 123.3, 127.0, 128.9, 130.4, 135.0,
137.8, 138.7, 149.4, 150.0, 162.2, 166.3, 172.9. HRMS (ESI): calcd. for
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20H1835ClN2O4+, [M + H]+: 385.0950, found 385.0969.
Ethyl 1-Methyl-2-phenyl-1H-pyrazino[1,2-a]quinoline-4-carb-
oxylate (5n): Pyrazinoquinoline 5n (77 mg, yield 50 %) was ob-
tained according to the general procedure from triazoloquinoline
1h (125 mg, 0.5 mmol) and azirine 2b (60 mg, 0.45 mmol) [140 °C,
3 h, Rh2(esp)2 (1 mol-%, 3.4 mg), eluent for chromatography EtOAc/
1
hexane, 1:4]. Red solid, m.p. 78–80 °C. H NMR (400 MHz, CDCl3) δ:
1.30 (d, J = 6.7 Hz, 3H), 1.49 (t, J = 7.1 Hz, 3H), 4.35–4.50 (m, 2H),
6.20 (q, J = 6.7 Hz, 1H), 7.22 (t, J = 7.4 Hz, 1H), 7.30 (d, J = 9.8 Hz,
1H), 7.40–7.52 (m, 5H), 7.64 (d, J = 8.6 Hz, 1H), 8.03 (d, J = 7.4 Hz,
2H), 8.46 (d, J = 9.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 12.8, 14.6,
45.9, 60.0, 111.7, 112.2, 120.9, 123.3, 125.5, 125.9, 128.4, 128.6, 129.1,
130.3, 131.8, 136.1, 136.8, 137.4, 140.7, 166.3. HRMS (ESI): calcd. for
C22H21N2O2+, [M + H]+: 345.1598, found 345.1603. λmax (DCE, ε): 291
(12800), 487 (12000).
Methyl 4-Methyl-3-phenyl-4H-benzo[4,5]oxazolo[3,2-a]pyr-
azine-1-carboxylate (5o): Oxazolopyrazine 5o (60 mg, yield 47 %)
was obtained according to the general procedure from diazo com-
pound 1i (96 mg, 0.44 mmol) and azirine 2b (53 mg, 0.4 mmol)
[110 °C, 5 min, Rh2(OAc)4 (2 mol-%, 3.5 mg), eluent for chromatogra-
phy EtOAc/hexane, 1:2]. Yellow solid, m.p. 97–100 °C. 1H NMR
(400 MHz, CDCl3) δ: 1.49 (d, J = 6.6 Hz, 3H), 3.96 (s, 3H), 5.91 (q, J =
6.5 Hz, 1H), 7.19–7.25 (m, 2H), 7.29–7.33 (m, 1H), 7.37–7.48 (m, 4H),
7.96 (d, J = 7.3 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ = 16.1, 50.2,
51.3, 95.1, 108.1, 111.3, 123.8, 124.9, 126.0, 128.6, 129.0, 129.2, 135.5,
140.3, 147.7, 154.0, 164.7. HRMS (ESI): calcd. for C19H17N2O3+, [M +
H]+: 321.1234, found 321.1246. λmax (DCE, ε): 310 (9300), 401
(11300).
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Received: February 16, 2020
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© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
doi.org/10.1002/ejoc.202000210
EurJOC
European Journal of Organic Chemistry
Dearomative Electrocyclization
I. P. Filippov,
M. S. Novikov,
A. F. Khlebnikov,
N. V. Rostovskii* ............................... 1–11
Pseudopericyclic Dearomative 1,6-
Cyclization of 1-(2-Pyridyl)-2-aza-
buta-1,3-dienes:
Synthesis
and
Ring–Chain Valence Equilibria of 4H-
Pyrido[1,2-a]pyrazines
The 1,6-electrocyclization of 1-(2-pyrid- non-aromatic 4H-pyrido[1,2-a]pyrazines
yl)-2-azabuta-1,3-dienes, obtained by despite the fact that the reaction pro-
RhII-catalyzed reaction of pyridotri- ceeds with irreversible dearomatization
azoles with 2H-azirines, affords stable of the pyridine aromatic system.
doi.org/10.1002/ejoc.202000210
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
11
© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim