Synthesis of 3-(1,2-dioxoethyl)- and 2,3-dicarbonyl-containing pyrroles

Article abstract of DOI:10.1016/j.tet.2015.02.030

The transition metal-catalyzed reaction of 2H-azirines with 1,2,4-tricarbonyl compounds leads to 3-(1,2-dioxoethyl)- and 2,3-dicarbonyl-pyrrole derivatives, useful building blocks for the preparation of 3-heterocyclyl pyrroles and pyrroles fused with heterocycles. The influence of catalysts and the reaction conditions on the yields of pyrroles and the regioselectivity of the reaction were studied. Experimental and theoretical results suggest that the reaction proceeds via the formation of an intermediate azirine-metal complex and subsequent nucleophilic N-C³ bond cleavage.

Full text of DOI:10.1016/j.tet.2015.02.030

Accepted Manuscript
Synthesis of 3-(1,2-dioxoethyl)- and 2,3-dicarbonyl-containing pyrroles
Alexey V. Galenko, Alexander F. . Khlebnikov, Mikhail S. Novikov, Margarita S.
Avdontceva
PII:
S0040-4020(15)00165-9
10.1016/j.tet.2015.02.030
TET 26419
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 December 2014
Revised Date: 26 January 2015
Accepted Date: 6 February 2015
Please cite this article as: Galenko AV, . Khlebnikov AF, Novikov MS, Avdontceva MS, Synthesis
of 3-(1,2-dioxoethyl)- and 2,3-dicarbonyl-containing pyrroles, Tetrahedron (2015), doi: 10.1016/
j.tet.2015.02.030.
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ACCEPTED MANUSCRIPT
Graphical abstract
1

ACCEPTED MANUSCRIPT
Synthesis of 3-(1,2-dioxoethyl)- and 2,3-dicarbonyl-containing pyrroles
a
a ∗
a
b
Alexey V. Galenko, Alexander F . Khlebnikov, Mikhail S. Novikov, Margarita S. Avdontceva
a
Institute of Chemistry, Saint-Petersburg State University,
Universitetskii pr. 26, 198504 St.-Petersburg, Russia;
b
Institute of Earth Sciences, Saint Petersburg State University,
Universitetskaya nab. 7-9, 199034, St.-Petersburg, Russia.
ABSTRACT:
The transition metal-catalyzed reaction of 2H-azirines with 1,2,4-tricarbonyl compounds leads to 3-
1,2-dioxoethyl)- and 2,3-dicarbonyl-pyrrole derivatives, useful building blocks for the preparation
(
of 3-heterocyclyl pyrroles and pyrroles fused with heterocycles. The influence of catalysts and the
reaction conditions on the yields of pyrroles and the regioselectivity of the reaction were studied.
Experimental and theoretical results suggest that the reaction proceeds via the formation of an
intermediate azirine-metal complex and subsequent nucleophilic N-C3 bond cleavage.
Keywords: pyrrole, azirine, cyclocondensation, metal catalysis
1
. Introduction
Pyrroles and their fused derivatives are widely present in natural compounds, medicine and
1
,2
materials. Consequently, the development of methods for the synthesis of such compounds is a
very active area of research. Although a lot of preparative methods for the synthesis of pyrroles
2
have been developed it is still a great challenge to find simple ways to functionalized pyrroles from
cheap and available starting materials. An attractive goal would be pyrroles 1,2 containing carbonyl
functions which allow them to be used as synthetic blocks for the preparation a variety of 3-
heterocyclyl pyrroles 3 and pyrroles fused with heterocycles 4 by reactions with bis-nucleophiles
(Scheme 1). The approach to compounds 1,2, which seems straightforward enough, consists of
3
using the reaction of 2H-azirines 5, readily available by numerous reliable syntheses, with C-
3
,4
nucleophiles 6 (Scheme 1). According to this scheme cyclocondensation of azirines across the
C2-C3 or C3-C4 bond of a 1,2,4-tricarbonylcompound would produce 2,3-dicarbonylpyrrole or 3-
(1,2-dioxoethyl)pyrrole derivatives, respectively.
∗
Corresponding author. Tel.: +7 812 4286733; fax: +7 812 4286939; e-mail address:
a.khlebnikov@spbu.ru (A.F. Khlebnikov).
2

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Scheme 1. Retrosynthetic scheme for compounds 3,4.
2
. Results and discussion
Reaction of tricarbonyl compounds with azirines has so far not been studied to the best of our
knowledge. Therefore, before starting an experimental search for the reaction conditions for the
preparation of 1,2 by reaction of azirines with compounds 6, the literature on the reactions of
azirines with mono- and dicarbonyl compounds, leading to pyrroles, was analyzed. This revealed
that there is no general procedure for the formation of the pyrrole ring by this route. Additionally,
quantum-chemical calculations for the model reaction of 3-phenyl-2H-azirine 7a with acetylacetone
8
, which is often used for the preparation of pyrroles, were performed to reveal possible ways to
control the reaction.
4
a,d,e,j
4a,d
Enolates, generated from alkyl ketones
and nitriles
by treatment with NaH in DMSO or
4
f
from aldehydes by treatment with KH in THF, react with non-activated azirines (e.g. 3-phenyl-, 2-
alkyl-3-phenyl- and 2,2-dialkyl-3-phenyl-2H-azirines) to give 1H- and 2H-pyrrole derivatives. Na-
enolates of acetylacetates react in boiling THF with 1-alkyl-2H-azirinylphosphine oxides and -
phosphonates to give 1H-pyrrole-2-phosphine oxides and -phosphonates, whereas Na-enolates of
4
o
alkyl malonates react with the same azirines already at room temperature. Tri- or tetra-substituted
pyrroles were synthesized by the reaction of vinyl azides with 1,3-dicarbonyl compounds in toluene
at 100 °C. The author assumed this proceeds via the reaction of transient 2H-azirine with enols of
4
l,n
1
,3-dicarbonyl compounds. However, in many cases 1,3-dicarbonyl substrates do not react with
non-activated azirines without a catalyst or the reaction proceeds only at high temperatures giving
3

ACCEPTED MANUSCRIPT
low yields of the targeted pyrroles. In order to force the mentioned reaction, catalysis by
4
c
4m,q
4k
Ni(acac) , Cu(acac)
or VO(OSiPh3)3 was therefore used.
2
2
The plausible mechanism that has been proposed for reactions of intermediate azirines derived from
corresponding azides with enolizable ketones, involves the attack of the nucleophilic carbon of the
4
l,n
enol on the C=N double bond of azirine (Scheme 2).
4
l,n
Scheme 2. Plausible mechanism for the reaction of 3-phenyl-2H-azirine 7a with acetylacetone 8.
Calculations of the energy profile for the reaction of 3-phenyl-2H-azirine 7a with the enol of
acetylacetone 9 were performed at the DFT B3LYP/6-31G(d) level to evaluate the possibility of this
mechanism (Figure 1).
Fig. 1. Energy profiles of the reaction of 3-phenyl-2H-azirine 7a with the enol of acetylacetone 9.
-1
Relative free energies [kcal⋅mol , 298K, toluene (PCM)] computed at the DFT B3LYP/6-31G(d)
level.
4

ACCEPTED MANUSCRIPT
According to the calculations there is indeed a transition state A involving simultaneous transfer of
the enol hydrogen to the azirine nitrogen and formation of C-C bond between C3 of 9 and C3 of 7a,
leading to intermediate B. The latter can undergo inversion of nitrogen to give invertomer C that
further can transform to conformer D. This in turn can form aminoketone E via simultaneous
transfer of the hydrogen from C-3 to the nitrogen and aziridine ring opening. Cyclization of the
aminoketone E and consecutive dehydration will give pyrrole 11. The calculated barrier for
-1
formation of B (transition state A, 41.5 kcal⋅mol ) is, however, too high for the reaction to proceed,
even at 100 °C. Bearing in mind that the reaction of acetylacetone 8 with 1-phenylvinylazide 10,
which according to the authors’ assumption proceeds via intermediate azirine 7a, gave 85% of
4
l
pyrrole 11 (toluene, 100 °C, 24 h), we decided to carry out the reaction of azirine 7a with
acetylacetone 8 under the same conditions. Unexpectedly it was found that only ca. 3% of pyrrole
1
1 was formed after heating an equimolar solution of azirine 7a with acetylacetone 8 in toluene at
00 °C for 12 h. This means that the reaction of acetylacetone 8 with 1-phenylvinylazide 10 most
1
probably does not proceed via intermediate formation of azirine 7a, since the latter is in fact
unreactive under the conditions used.
Taking into account the lower nucleophilicity of the enols of tricarbonyl compounds 6 compared to
the enol of acetylacetone 9 it was not surprising that enol 12a did not react with azirine 7a under
reflux in toluene (Table 1, entry 1). There are some possibilities to force the reaction to proceed:
enhance the nucleophilicity of the 1,3-dicarbonyl compound or the electrophilicity of the azirine. To
fit the first possibility we reacted azirine 7a with the anion generated from ethyl 2,4-dioxo-4-
phenylbutanoate 12a and NaH in DMSO or THF at room temperature under the conditions used for
4
a,d,e,f,j
reactions of azirines with enolizable ketones and aldehydes.
It was revealed, however, that the
reaction of 7a did not proceed at all and the starting compounds remained unchanged, whereas
when heated the azirine decomposed completely without formation of any pyrrole derivatives
(Table 1, entries 2-3).
To evaluate the second possibility of forcing the reaction to proceed, acid catalysis was theoretically
+
tested at first. According to calculations the reaction of protonated azirine 7a-H with the enol of
acetylacetone 9 should proceed much easier than non-protonated azirine (Figure 2). In this case the
+
formation of the C-C bond between C-3 of 9 and C-3 of 7a-H , leading to intermediate G, proceeds
via the relatively low free energy barrier (transition state F). Intermediate G can undergo the low
barrier cyclization by attack of the aziridine nitrogen on the carbon of the protonated carbonyl
group, giving the bicyclic intermediate H. Ring opening of the aziridine will then lead to protonated
5

ACCEPTED MANUSCRIPT
+
pyrrole I, which then will give the final product 11 by losing H O . Therefore, the reaction of
3
azirine 7a and acetylacetone 8 proceeds much easier under acid catalysis.
+
Fig. 2. Energy profiles of the reaction of protonated 3-phenyl-2H-azirine 7a-H with the enol of
-1
acetylacetone 9. Relative free energies [kcal⋅mol , 298K, toluene (PCM)] computed at the DFT
B3LYP/6-31G(d) level.
5
6
Unfortunately, it is known that organic and inorganic acids react irreversibly with azirines due to
the ring opening. It is therefore not surprisingly that the addition of a catalytic amount of
TsOH*H O or maleic acid to the reaction of azirine 7a and acetylacetone 8 did not lead to an
2
improved yield of the pyrrole 11 and only tarring of the reaction mixture occurred.
Faced with the inability to perform the reaction under acidic or basic conditions we turned to
transition metal catalysis, since the formation of a coordination bond between the azirine nitrogen
and metal should increase the electrophilicity of the azirine. Unlike the reaction of azirines with
acids, however, it may be reversible, as some transition metals are complexed to azirines with
7
-9
retention of the azirine ring.
6

ACCEPTED MANUSCRIPT
Table 1
Optimization of the reaction conditions for the condensation of azirine 7a with compound 12a (1:1)
a
d
En
try
Reaction conditions
Catalyst or
additive
Yield of products, % Conversion
of 7a, %
1
3a
14a
b
1
2
3
4
5
6
7
8
9
MePh, reflux, 6 h
DMSO, 25 °C, 8 h
THF, reflux, 8 h
NaH
NaH
0
0
0
0
0
0
0
0
0
0
b
b
NaH
100
100
100
100
100
100
100
100
100
100
88
100
100
100
100
100
100
100
100
90
b
THF, reflux, 8 h
NaH, Cu(acac)2
e
e, f
MePh, reflux, 1 h
MePh, reflux, 0.5 h
MePh, 50 °C, 10 h
THF, 50 °C, 48 h
EtOH, 50 °C, 48 h
TEA, 50 °C, 2.5 h
MeCN, 50 °C, 24 h
MeCN, 60 °C, 18 h
MeCN, 70 °C, 7 h
DMF, 50 °C, 16 h
Cu(acac)2
Cu(OAc) ·H O
32
35
33
50
25
0
47
49
28
28
25
0
2
2
c
Cu(OAc) ·H O
Cu(OAc) ·H O
2
2
2
2
Cu(OAc) ·H O
2
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
Cu(OAc) ·H O
2 2
Cu(OAc) ·H O
Cu(OAc) ·H O
58
60
45
34
38
37
28
12
46
40
36
35
19
32
38
28
16
39
32
21
15
37
44
52
36
28
62
63
53
0
2
2
2
2
e
e
Cu(OAc) ·H O
Cu(OAc) ·H O
2
2
2
2
CHCl , 50 °C, 10 h
Cu(OAc) ·H O
2 2
3
CCl , 50 °C, 24 h
Cu(OAc) ·H O
2 2
4
PhH, 50 °C, 15 h
DMSO, 50 °C, 48 h
Cu(OAc) ·H O
2 2
Cu(OAc) ·H O
2 2
MeNO , 60 °C, 4 h
Cu(OAc) ·H O
2 2
2
DCE, 50 °C, 9 h
DCE, 60 °C, 6 h
DCE, 50 °C, 6 h
DCE, 70 °C, 48 h
DCE, 50 °C, 20 h
DCE, 70 °C, 6 h
DCE, 70 °C, 65 h
DCE, 70 °C, 65 h
DCE, 70 °C, 65 h
DCE, 70 °C, 65 h
DCE, 60 °C, 1 h
DCE, 60 °C, 26 h
DCE, 60 °C, 26 h
Cu(OAc) ·H O
2 2
Cu(OAc) ·H O
Cu(OAc) ·H O
2
2
e
e
e
e
2
2
CuI
70
100
98
100
0
Co(OAc) ·4H O 35
2
2
Co(OAc) ·4H O 31
2
2
NiCl ·6H O
29
0
2
2
FeCl ·6H O
3
2
KMnO4
(VO)SO ·nH O
0
0
0
0
0
0
4
2
Tb(NO ) ·5H O
YCl3
(ZrO)Cl ·8H O
0
0
0
0
100
100
0
2
3
2
0
0
2
2
a
5
1
1
mol %.
equivalent.
0 mol %.
b
с
d
e
f
1
Yield according to H NMR analysis of reaction mixture with 2-methylnaphthalene as internal standard.
Preparative yield after column chromatography.
Additionally 1-(2-methyl-4-phenyl-1H-pyrrol-3-yl)ethanone 15 (4%) was isolated.
7

ACCEPTED MANUSCRIPT
Unexpectedly the reaction of azirine 7a with compound 12a for 20 h, under conditions
found for the reaction of azirines with 1,3-dicarbonyl compounds (1.2 mol % Ni(acac) , acetone, rt,
2
4
c
2
-3 h), gave only traces of compounds 13a,14a. When Cu(acac) was tried as a catalyst in boiling
2
4
m,q
toluene,
the target products 13a,14a were isolated in 79% overall yield (Table 1, entry 5).
Additionally, 1-(2-methyl-4-phenyl-1H-pyrrol-3-yl)ethanone 15 (4%), derived from the reaction of
azirine 7a with Cu(acac) , was isolated as byproduct. It is worth mentioning here that the addition
2
of Cu(acac) to a mixture of azirine 7a with enolate generated from ethyl 2,4-dioxo-4-
2
phenylbutanoate 12a and NaH gave no pyrroles 13a, 14a and led only to rapid decomposition of the
azirine (Table 1, entry 4).
1
13
The structures of compounds 13a, 14a were verified by H and C NMR, IR spectroscopy,
and mass-spectrometry and were confirmed by X-ray analysis (Fig. 3).
Fig. 3. Molecular structures of compounds 13a, 14a.
Encouraged with the preliminary results we tested different catalysts and reaction conditions
to improve the yields of the pyrroles and to find out the possibilities of controlling the
regioselectivity of the reaction (Table 1). First of all, copper(II) salts instead of Cu(acac) , to avoid
2
the formation of byproduct 15, were tested on the assumption that trione 12a can promote
dissolution of the salts in organic solvents by forming complexes similar to Cu(acac) . Surprisingly,
2
it was found that Cu(OAc) dissolved in 1,2-dichloroethane (DCE) in the presence of only azirine
2
7
a to give a turquoise colored solution. It means that most probably just the formation of the azirine
copper complex facilitates the reaction with trione 12a. It was found the Cu(II) but not Cu(I) salts
are more preferable for the preparation of pyrroles 13a, 14a (Table 1, entries 20–23). Longer
heating in toluene at a lower temperature with a higher percentage of the catalyst gave more tarry
reaction mixture with reversed regioselectivity and lower yield of the products (Table 1, entries
6
,7). Use of MeCN as solvent at 60 °C gave increasing relative yields of pyrrole 13a (13a 60%, 14a
8%; Table 1, entry 12) comparing with DCE (13a 36%, 14a 52%; Table 1, entry 21). In other
3
polar solvents (THF, EtOH, DMF, DMSO, MeNO ) overall yields were lower than in MeCN. In
2
order to increase the percentage of pyrrole 14a Co(OAc) can be used as catalyst (13a 31%, 14a
2
8

ACCEPTED MANUSCRIPT
6
3%; Table 1, entry 25). Use of NiCl also provides preferably pyrrole 14a, but its overall yield
2
becomes slightly lower (Table 1, entry 26). Other tested salts showed poor results. Thus, we found
catalysts and reaction conditions to give pyrroles 13a, 14a in high overall yield. Although we could
not achieve complete regioselectivity of the reaction, we have found a reasonable preparation of
pyrroles 13a,14a, since they can be easily isolated by chromatographic separation.
Further, the scope of the reaction for the preparation of pyrroles 13, 14 and reaction
regioselectivity, depending on the substituents both in azirine 7 and carbonyl component 12, were
explored. For this study heating at 60 °C in 1,2-dichloroethane with copper(II) acetate as a catalyst
was used due to the high overall yield of the products and short reaction time, found in the
preliminary tests (Table 1, entry 21). The results are listed in Table 2. The structures of compounds
1
13
1
3, 14 were verified by H and C NMR, IR spectroscopy, and mass-spectrometry and for
compounds 13d, 14f were also confirmed by X-ray analysis (Fig. 4).
Fig. 4. Molecular structures of compounds 13d, 14f.
Electron-donor and weak electron-withdrawing substituents in the 4-aryl ring of 4-aryl-2,4-
dioxobutanoates only slightly influence the product yield and distribution of pyrroles (Table 2,
entries 1-3). Introduction of a strong electron-withdrawing NO -substituent at this position could
2
increase the percentage of the corresponding pyrrole 14, but in these cases the reaction became
much slower, probably due to a lowering of the nucleophilicity of enol 12 (Table 2, entries 4,5).
This resulted in the complete decomposition of the azirine in the reaction of compound 12d, and
tarring of the reaction of compound 12e, which led to the necessity of 3 recrystallizations of pyrrole
1
3d to obtain the pure compound in low yield. A 4-tert-butyl-group in the 2,4-dioxobutanoate 12f,
unexpectedly, had a little influence on the regioselectivity (Table 2, entry 6).
9

ACCEPTED MANUSCRIPT
Table 2
Yields of analytically pure pyrroles 13 and 14 prepared by the condensation of azirines 7 with
compounds 12 at 60 °C in 1,2-dichloroethane with copper(II) acetate (5 mol %.) as a catalyst
Entry Azirine 7
Compound 12
Time, h Yield, %
1
2
3
4
R
R
R
R
X
13
14
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
a
a
a
a
a
a
a
a
a
a
a
a
a
b
b
b
b
b
c
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
H
a
b
c
Ph
4-MeOC H4 EtO
EtO
O
6
(a) 35
(b) 24
(c) 30
(a) 36
(b) 39
(c) 46
H
H
O
O
7
6
4-BrC H4
MeO
EtO
EtO
EtO
Ph
10
42
11
12
8
6
a
a
H
H
d
e
4-NO C H
O
O
0
0
2
6
4
4
3-NO C H
(d) 11
(d) 33
2
6
b
b
H
H
f
t-Bu
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
(e) 20
(e) 30
(f) 42
(f) 69
a
c
g
g
h
h
i
(f) 0
a
d,e
c
H
H
Ph
O
HN
5
7
(f) 0
a, c
EtO
EtO
Ph
(a) 0
(a) 0
(a) 25
(a) 89
(f) 29
(a) 26
a
d,e
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
H
H
HN
4-ClC H N
9
7
a, c
c
(f) 0
6
4
a, c
c
H
H
j
EtO
Ph
4-MeOC H N
MeS
O
7
(a) 0
6
4
a
a
k
a
b
f
40
24
20
24
35
24
70
70
0
0
Ph
Ph
Ph
Ph
Ph
EtO
(g) 18
(h) 22
(i) 10
(j) 40
(g) 15
4-MeOC H4 EtO
O
(h) 19
(i) 10
(j) 26
(k) 42
(l) 68
(m) 65
(n) 56
(o) 26
(p) 33
(q) 22
(r) 49
(s) 49
6
t-Bu
Me
Ph
EtO
MeO
Ph
O
O
l
a
g
a
b
m
a
b
c
O
O
(k) 0
e
e
EtO C
Ph
EtO
(l) 28
2
c
c
EtO C
EtO C
2
4-MeOC H4 EtO
6
O
O
(m) 26
(n) 27
(o) 28
(p) 27
(q) 28
(r) 19
(s) 21
e
3-BrC H4
MeO
EtO
100
55
55
2
6
d
d
d
e
EtO C
EtO C
2
Ph
O
O
4-MeOC H4 EtO
2
6
e
EtO C
3-BrC H4
MeO
MeO
MeO
EtO
O
O
60
2
6
2-BrC H
H
H
H
m
l
3-BrC H4
7.5
2.5
6
6
4
4
4
6
e
e
2-BrC H
2-BrC H
6
Me
t-Bu
O
O
a
b
2
a
f
1
(t) 0
(t) 7
6
No the pyrrole product according to H NMR analysis of the reaction mixture.
Yield of crude product (ca. 90% purity).
Recovery of compound 12 after chromatographic purification was 62-68%.
equivalents of azirine 7 was used.
Reaction temperature was 75 °C.
b
c
d
e
3
No pyrrole 13f was detected in the case of the reaction of 1,4-diphenylbutane-1,2,4-trione 12g and
this is most probably due to the higher reactivity of the 2-keto group in 1,2-diketones relatively to 2-
ketoesters (Table 2, entry 7). Enamines 13h-j reacted slower than enoles, giving regioselectively
pyrroles 14a,f, but a lot of the azirine was wasted on side reactions (Table 2, entries 9–12). To
1
0

ACCEPTED MANUSCRIPT
improve the yields of pyrroles 14a,f an excess of azirine can be used (Table 2, entries 8, 10).
Methylsulfanyl-substituted compound 12k did not react with azirine 7a (Table 2, entry 13).
2
,3-Diphenyl-2H-azirine 7b reacted much slower than azirine 7a (Table 2, entries 14–18),
and pyrroles 13 were formed in a slightly larger amount than isomers 14 (Table 2, entries 14,15). At
the same time an exchange of the tert-butyl-group in position 4 of 2,4-dioxobutanoate with a
methyl-group led to a considerable increase in the 13:14 ratio (Table 2, entries 16,17). 1,4-
Diphenylbutane-1,2,4-trione 12g again reacted regioselectively to give only pyrrole 14k (Table 2,
entry 18).
3
-Substituted-2H-azirine-2-carboxylates 7c,d were much less reactive than azirines 7a,b and
a higher temperature was needed for reaction completion. The reactions of ethyl 3-phenyl-2H-
azirine-2-carboxylate 7c gave excellent overall yields of the pyrroles in a ratio of more than 2:1 in
favor of isomer 14. (Table 2, entries 19–21). The overall yields of pyrroles from azirine 7d were
less than from azirine 7c, apparently due to less thermal stability of the former. It is noteworthy that
the increase of steric bulk of the substituent in the 3-position of the azirine led to a higher
regioselectivity of the condensation in favor of pyrroles 14. This occured both on the exchange of
the 3-Me-group with 3-Ph (azirines 7d → 7e) and on the exchange of the 3-Ph-group with 3-(2-
BrC H ) (azirines 7a → 7c).
6
4
Further, the influence on the reaction outcome of some additives that can coordinate with
copper was tested. It was found that addition of 10 mol. % of L-proline practically has no effect on
the pyrrole ratio, but decreases their overall yields and time of conversion of azirine, as well led to
formation of a lot of by-products. Probably, L-proline acts like triethylamine (Table 1, entry 10) and
acids (vide supra) by transforming the azirine to by-products. Addition of 10 mol. % of 1,10-
phenanthroline diminished the rate of reaction by ca. 10 times, but practically had no influence on
the regioselectivity and overall yields of the pyrroles, most probably due to the deactivation of the
catalyst.
According to the structures of products 13, 14, the pyrrole ring is formed via cleavage of the
3
N-C bond of the azirine ring. Albeit azirine reactions catalyzed by transition metals often proceed
2
4q, 3d,e, 10
3
3d,e, 4c, 11
via cleavage of the N-C bond,
there are also examples of N-C bond cleavage.
The
probable pathway for the formation of pyrroles 13, 14, based on the results of the study, is outlined
in Scheme 3. Complexes of azirines with Cu(II) are unknown, but structures of complexes of
7
8
9
azirines with Pd, Rh and Re were determined by X-ray analysis. We assume that the copper
complex of type 16, which has a higher electrophilicity than the starting azirine, reacts with the
enol-form (or enamine or metal-enolate) of butane-1,2,4-trione 12, giving intermediate 17/18, that
under further attack of the aziridine nitrogen on C-4 or C-2 of 17/18 is transformed into
intermediate 19 or 20. Intermediates 19 or 20 give pyrroles 13, 14 via aziridine ring opening and
1
1

ACCEPTED MANUSCRIPT
elimination of H X. The attack of the aziridine nitrogen proceeds easily on the quasi protonated
2
+
C=OH group (cf. Fig.2), and therefore the position of the equilibrium 17ꢀ18, which depends on
different factors, such as electronic character and steric bulk of substituents and metal, solvent
polarity etc., determines the selectivity of the reaction. The scheme is in accord with the selectivity
of the reaction of azirines with enamines 12 (Table 2, entries 9–12). In this case the equilibrium
1
7ꢀ18 has to be completely shifted to the 17 side, providing the selective formation of pyrroles 14.
Scheme 3. Plausible mechanism for the metal-catalyzed reaction of 2H-azirines with butane-1,2,4-
trione derivatives.
At the end of our study we prepared 3-heterylpyrrole 23 and fused pyrrole 24 from the
synthesized compounds 13a, 14a (Scheme 4) using the published procedure for the analogous
1
2
compound. 3,4-Substituted maleimides of type 23 are of particular interest due to their biological
1
3
activity.
Scheme 4. Synthesis of 3-heterylpyrrole 23 and fused pyrrole 24.
1
2

ACCEPTED MANUSCRIPT
3
. Conclusions
The metal-catalyzed reaction of azirines with butane-1,2,4-triones leads to 3-(1,2-
dioxoethyl)pyrroles 13 and 2,3-dicarbonylpyrroles 14, which are useful building blocks for the
preparation of 3-heterocyclyl pyrroles and pyrroles fused with heterocycles. Carrying out the
Cu(II)-catalyzed reaction of 3-phenyl-2H-azirine with ethyl 2,4-dioxo-4-phenylbutanoate in MeCN
increases the relative yield of 3-(1,2-dioxoethyl)pyrrole derivative 13 in comparing with non-polar
toluene or DCE. To increase the relative yield of the 2,3-dicarbonylpyrrole derivative 14 the Co(II)-
catalyzed reaction can be used. The Cu(II)-catalyzed reactions of azirines with enamines of butane-
1
,2,4-triones are completely regioselective and give only 2,3-dicarbonylpyrrole derivatives 14. The
increase of steric bulk of the substituent in 3-position of azirine leads to higher regioselectivity of
the condensation with butane-1,2,4-triones in favor of pyrroles 14. 3-Substituted-2H-azirine-2-
carboxylates are much less reactive than azirines without an alkoxycabonyl-group in position 2, and
higher temperatures are needed for the reaction to complete. Overall yields of reactions of butane-
1
,2,4-triones with ethyl 3-phenyl-2H-azirine-2-carboxylate 7c are excellent, with yields of pyrroles
1
4 more than two times higher than isomers 13. Experimental and theoretical results implied that
the reactions proceed via the formation of an intermediate azirine-metal complex.
4
4
. Experimental section
.1. General methods
1
Melting points were determined on a capillary melting point apparatus Stuart® SMP30. H (300
13
MHz, 400 MHz) and C (75 MHz, 100 MHz) NMR spectra were determined in CDCl with Bruker
3
DPX 300 and Bruker AVANCE III 400. Chemical shifts (δ) are reported in parts per million
1
downfield from tetramethylsilane (TMS δ = 0.00); H NMR spectra were calibrated according to
the residual peak of CDCl (7.26 ppm) or DMSO-d (2.50 ppm). Mass spectra were recorded on a
3
6
Bruker maXis HRMS-ESI-QTOF, electrospray ionization, positive mode. IR-spectra were recorded
on a Bruker FT-IR spectrometer Tensor 27 for tablets in KBr, only characteristic absorption is
indicated. Single crystal X-ray data were collected using an Agilent Technologies Supernova Atlas
and an Agilent Technologies Excalibur Eos diffractometers. The crystals were kept at 100 K during
data collection. The structures have been solved by the direct methods and refined by means of the
1
4
15
SHELXL–97 program incorporated in the OLEX2 program package. The carbon-bound H atoms
were placed in calculated positions and were included in the refinement in the ‘riding’ model
approximation, with U (H) set to 1.2U (C) and C–H 0.97 Å for the CH groups and U (H) set to
iso
eq
2
iso
1
.5U (N) and C–H 0.96 Å for the CH groups. Empirical absorption correction was applied in
eq 3
1
6
CrysAlisPro program complex using spherical harmonics, implemented in SCALE3 ABSPACK
1
3

ACCEPTED MANUSCRIPT
scaling algorithm. The crystallographic data for all samples and refinement parameters are given in
Table 1 of The Supporting Information. Supplementary crystallographic data for this paper have
been deposited at Cambridge Crystallographic Data Centre (CCDC 1033500–1033503) and can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.
Acetonitrile, 1,2-dichloroethane, carbon tetrachloride and chloroform were distilled
successively over phosphorous pentoxide and calcined potassium carbonate under argon
atmosphere. Tetrahydrofuran and toluene were distilled from sodium benzophenone-ketyl.
Methanol and ethanol were dried with magnesium/CCl . Triethylamine was distilled from
4
potassium hydroxide. N,N-Dimethylformamide was purchased from Fluka, nitromethane and
dimethylsulphoxide were purchased from “VEKTON” and were used without purification. Thin-
layer chromatography (TLC) was conducted on aluminium sheets with 0.2 mm silica gel
(fluorescent indicator, Macherey-Nagel).
1
7
18
19
20
The azirines were synthesized by known literature procedures: 7a,e, 7b, 7c, 7d. Ethyl
2
1
22
5
,5-dimethyl-2,4-dioxohexanoate 12f, enamines 12h,j, 2-(methylsulfanyl)-1,4-diphenylbut-2-
2
3
24
ene-1,4-dione 12k and butanetriones 12g,i were prepared by the reported methods. The other
2
5
compounds 12 were obtained using modified procedure A.
4
.1.1. General procedure A. A solution of the ketone (20.0 mmol) and diethyloxalate (20.0 mmol)
in ethyl or methyl alcohol (in amount enough to provide clear solution) was added dropwise to a
M solution of sodium alcoholate in alcohol (5 ml, 20.0 mmol) under vigorous stirring and cooling
4
with ice bath. The reaction mixture was stirred overnight at room temperature. The solid formed
was filtered off, thoroughly washed with alcohol (5 mL), Et O (2×20 mL), and dried in vacuo.
2
Sodium enolate of 12 obtained was then suspended in an ice-cold mixture of water (25 mL) and
alcohol (5 mL), and acidified with H SO to give the corresponding 2,4-dioxobutanoic acid ether,
2
4
that was filtered off, washed with water, dried and recrystallized from an appropriate solvent.
4
.2. Synthesis of pyrroles 13a-d,g-j,l-s and 14 a-d, f-s
4
.2.1. General procedure B for the reaction conditions screening. Compound 12a (0.25 mmol) was
dissolved in an appropriate solvent (1 mL) in a thick-wall tube (5 mL) with screw cap, an
appropriate catalyst (5-10% mol) or additives (see Table 1 for details) as well as 2-
methylnaphthalene as internal standard were added and the suspension obtained was stirred at room
temperature under an argon atmosphere for 30 minutes. A solution of 2H-azirine 7a (0.25 mmol) in
1
mL of the same solvent was then added in one portion and stirring was continued at a temperature
of 50–115 °C for the period indicated (Table 1). The solvent was removed on a rotary evaporator
and the crude reaction mixture obtained was passed through silica (5.0 g) eluting with a
1
4

ACCEPTED MANUSCRIPT
benzene/ethyl acetate mixture (50 mL, 4/1). Solvents were evaporated and the mixture obtained was
1
analyzed by H NMR. In some particular cases the products were isolated by column
chromatography (silica, eluent benzene/ethyl acetate 50/1 → 4/1).
4
.2.2. General procedure C for the preparation of pyrroles 13a-d,g-j,l-s and 14a-d, f-s. Compound
2a-m (1.0 mmol) was dissolved in DCE (5 mL) in a thick-wall tube (15 mL) with screw cap,
1
copper(II) acetate monohydrate (10.0 mg, 0.05 mmol, 5% mol) was added, and the suspension
obtained was stirred at 50 °C under argon atmosphere for 15 minutes. A solution of 2H-azirine 7a-e
(1.0 mmol) in DCE (1 mL) was then added in one portion and stirring was continued at 60–75 °C
for 6–100 h (Table 2). The solvent was removed on a rotary evaporator and the reaction mixture
was separated by column chromatography on silica using benzene/ethyl acetate or hexane/acetone
mixtures as eluents. Isolated pyrroles were then recrystallized from an appropriate solvent.
4
.2.3. Ethyl 2-(2,4-diphenyl-1H-pyrrol-3-yl)-2-oxoacetate (13a). Compound 13a (36.0 mg, 45%)
was obtained from 3-phenyl-2H-azirine 7a (30.0 mg, 0.25 mmol) and ethyl 2,4-dioxo-4-
phenylbutanoate 12a (55 mg, 0.25 mmol) according to procedure B, using MeCN as a solvent and
copper(II) acetate monohydrate (2.5 mg, 12.5 ꢀmol, 5% mol) as catalyst at 70 °C for 7 h. A
benzene/ethyl acetate mixture (12/1 → 4/1) was used as eluent for column chromatography. Pale
1
yellow solid, mp 134.5–136.0 °C (hexane/chloroform). Н NMR (CDCl ): 8.67 (br. s., 1 H), 7.57–
3
7
.53 (m, 2 H), 7.46–7.40 (m, 5 H), 7.36 (t, J = 7.3 Hz, 2 H), 7.32–7.27 (m, 1 H), 6.86 (d, J = 2.5
1
3
Hz, 1 H), 3.64 (q, J = 7.2 Hz, 2H), 1.00 (t, J = 7.2 Hz, 3H). С NMR (CDCl ): δ 183.5, 164.2,
3
1
40.4, 134.4, 131.2, 129.10, 129.08, 129.0, 128.6, 128.5, 128.1, 127.0, 118.1, 115.7, 61.7, 13.5.
+
-1
ESI/HRMS (m/z): 320.1281 calcd for C Н NO [M+H] , found 320.1282. IR (KBr, cm ): ν 3252,
2
0
17
3
1
705, 1649. CCDC 1033501.
4
.2.4. Ethyl 3-benzoyl-4-phenylpyrrole-2-carboxylate (14a). Compound 14a (36.0 mg, 63%) was
obtained from 3-phenyl-2H-azirine 7a (30.0 mg, 0.25 mmol) and ethyl 2,4-dioxo-4-phenylbutanoate
2a (55 mg, 0.25 mmol) according to procedure B, using DCE as a solvent and cobalt(II) acetate
1
tetrahydrate (3.1 mg, 12.5 ꢀmol, 5% mol) as catalyst at 70 °C for 6 h. A benzene/ethyl acetate
mixture (12/1 → 4/1) was used as eluent for column chromatography. Light beige crystals, mp
1
1
15.5–118.0 °C (hexane/chloroform). Н NMR (CDCl ): 9.63 (br. s, 1H), 7.92–7.87 (m, 2H), 7.52
3
(tt, J = 7.4, 1.3 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.33–7.29 (m, 2H), 7.25–7.21 (m, 2H), 7.19–7.14
13
(
m, 2H), 4.06 (q, J = 7.2 Hz, 2H), 0.89 (t, J = 7.2 Hz, 3H). С NMR (CDCl ): δ 194.9, 160.5,
3
1
38.5, 133.4, 133.1, 129.5, 128.6, 128.3, 127.5, 126.9, 126.7, 126.5, 121.6, 120.5, 60.8, 13.5.
+
-1
ESI/HRMS (m/z): 320.1281 calcd for C Н NO [M+H] , found 320.1289. IR (KBr, cm ): ν 3283,
2
0
17
3
1
691, 1641. CCDC 1033500.
1
5

ACCEPTED MANUSCRIPT
Compound 14a was also obtained in higher preparative yield (142 mg, 89%) from 3-phenyl-2H-
azirine 7a (176.0 mg, 1.50 mmol) and ethyl 2-imino-4-oxo-4-phenylbutanoate 12h (110 mg, 0.5
mmol) according to procedure C, using DCE as a solvent and copper(II) acetate monohydrate (5.0
mg, 25.0 ꢀmol, 5% mol) as catalyst at 75 °C for 9 h.
4
.2.5. Ethyl 2-(2-(4-methoxyphenyl)-4-phenyl-1H-pyrrol-3-yl)-2-oxoacetate (13b) and ethyl 3-(4-
methoxybenzoyl)-4-phenyl-1H-pyrrole-2-carboxylate (14b).Compounds 13b (84.0 mg, 24%) and
1
4b (135.0 mg, 39%) were obtained from 3-phenyl-2H-azirine 7a (117.0 mg, 1.0 mmol) and ethyl
-(4-methoxyphenyl)-2,4-dioxobutanoate 12b (250.0 mg, 1.0 mmol) according to the procedure C,
4
using DCE as a solvent and copper(II) acetate monohydrate (10.0 mg, 50.0 ꢀmol, 5% mol) as
catalyst at 60 °C for 7 h. A benzene/ethyl acetate mixture (12/1 → 4/1) was used as eluent for
column chromatography.
1
Compound 13b.Yellow crystals, mp 150.0–152.0 °C (hexane/chloroform). Н NMR (CDCl ): 8.76
3
(br. s, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.42–7.38 (m, 2H), 7.37–7.32 (m, 2H), 7.27–7.31 (m, 1H),
6
.93 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 2.5 Hz, 1H), 3.83 (s, 3H), 3.64 (q, J = 7.2 Hz, 2H), 1.00 (t, J
1
3
=
7.2 Hz, 3H). С NMR (CDCl ): δ 183.4, 164.4, 160.3, 140.6, 134.5, 130.5, 129.1, 128.5, 128.1,
3
1
26.9, 123.6, 117.7, 115.4, 113.9, 61.6, 55.3, 13.5. ESI/HRMS (m/z): 350.1387 calcd for
+
-1
C Н NO [M+H] , found 350.1383. IR (KBr, cm ): ν 3292, 1722, 1646.
21
19
4
1
Compound 14b. Colorless crystals, mp 122.6–124.7 °C (hexane/chloroform). Н NMR (CDCl ):
3
9
7
3
1
.53 (br. s, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 7.3 Hz, 2H), 7.22 (t, J = 7.3 Hz, 2H), 7.19 -
.09 (m, 2H), 6.86 (d, J = 8.6 Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 0.96 (t, J = 7.1 Hz,
1
3
H). С NMR (CDCl ): δ 193.5, 163.6, 160.5, 133.5, 131.9, 131.7, 128.6, 127.4, 126.8, 126.7,
3
26.6, 121.3, 120.4, 113.6, 60.8, 55.4, 13.7. ESI/HRMS (m/z): 350.1387 calcd for C Н NO
4
2
1
19
+
-1
[
M+H] , found 350.1389. IR (KBr, cm ): ν 3249, 1707, 1640.
4
.2.6. Methyl 2-(2-(4-bromophenyl)-4-phenyl-1H-pyrrol-3-yl)-2-oxoacetate (13c) and methyl 3-(4-
bromobenzoyl)-4-phenyl-1H-pyrrole-2-carboxylate (14c). Compounds 13c (116.0 mg, 30%) and
1
4c (175.0 mg, 46%) were obtained from 3-phenyl-2H-azirine 7a (117.0 mg, 1.0 mmol) and methyl
-(4-bromophenyl)-2,4-dioxobutanoate 12c (285.0 mg, 1.0 mmol) according to procedure C, using
4
DCE as a solvent and copper(II) acetate monohydrate (10.0 mg, 50.0 ꢀmol, 5% mol) as catalyst at
0 °C for 10 h. A benzene/ethyl acetate mixture (25/1 → 10/1) was used as eluent for column
chromatography.
Compound 13c. Bright yellow solid, mp 164.5–166.2 °C (hexane/chloroform). Н NMR (CDCl ):
6
1
3
8
.78 (br. s, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 7.40–7.34 (m, 4H), 7.34–7.28
1
3
(
m, 1H), 6.85 (d, J = 2.5 Hz, 1H), 3.24 (s, 3H). С NMR (CDCl ): δ 183.0, 164.4, 138.9, 134.0,
3
1
6

ACCEPTED MANUSCRIPT
1
31.7, 130.6, 130.0, 129.1, 128.9, 128.3, 127.2, 123.4, 118.1, 116.0, 52.1. ESI/HRMS (m/z):
+
-1
3
84.0230 calcd for C Н BrNO [M+H] , found 384.0227. IR (KBr, cm ): ν 3238, 1736, 1629.
1
9
14
3
1
Compound 14c. Colorless solid, mp 165.4–166.3 °C (hexane/chloroform). Н NMR (CDCl ): 9.46
3
1
3
(
br. s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.29–7.14 (m, 6H), 3.63 (s, 3H). С
NMR (CDCl ): δ 193.8, 160.6, 137.0, 133.1, 131.7, 130.9, 128.7, 128.5, 127.4, 127.0, 126.9, 126.2,
3
+
1
21.3, 120.6, 51.8. ESI/HRMS (m/z): 384.0230 calcd for C Н BrNO [M+H] , found 384.0234.
1
9
14
3
-1
IR (KBr, cm ): ν 3231, 1726, 1642.
4
.2.7. Ethyl 2-((3-nitrophenyl)-4-phenyl-1H-pyrrol-3-yl)-2-oxoacetate (13d) and ethyl 3-(3-
nitrobenzoyl)-4-phenyl-1H-pyrrole-2-carboxylate (14d). Compounds 13d (40.0 mg, 11%) 14d
(
120.0 mg, 33%) were obtained from 3-phenyl-2H-azirine 7a (120.0 mg, 1.03 mmol) and ethyl 4-
3-nitrophenyl)-2,4-dioxobutanoate 12e (265.0 mg, 1.0 mmol) according to procedure C, using
(
DCE as a solvent and copper(II) acetate monohydrate (10.0 mg, 50.0 ꢀmol, 5% mol) as catalyst at
0 °C for 11 h. A benzene/ethyl acetate mixture (50/1 → 12/1) was used as eluent for column
6
chromatography. Further, compound 13d was recrystallized twice from hexane/ethyl acetate and
subsequently from light petroleum/dichloromethane.
1
Compound 13d. Bright yellow crystals, mp 193.0–194.3 °C (light petroleum/dichloromethane). Н
NMR (CDCl ): 8.92 (br. s, 1H), 8.45 (t, J = 1.7 Hz, 1H), 8.24 (dd, J = 8.2, 1.2 Hz, 1H), 8.01 (d, J =
3
8
.0 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.43–7.28 (m, 5H), 6.93 (d, J = 2.5 Hz, 1H), 3.67 (q, J = 7.2
1
3
Hz, 3H), 1.02 (t, J = 7.2 Hz, 3H). С NMR (CDCl ): δ 183.5, 163.7, 148.1, 136.5, 135.5, 133.8,
3
1
32.7, 129.4, 129.3, 129.1, 128.39, 128.37, 123.6, 123.5, 118.4, 117.0, 61.9, 13.5. ESI/HRMS
+
-1
(
m/z): 365.1132 calcd for C Н N O [M+H] , found 365.1135. IR (KBr, cm ): ν 3258, 1723,
20 16 2 5
1
657. CCDC 1033502.
1
Compound 14d. Yellow crystals, mp 143.9–145.8 °C (petrol ether/dichloroethane). Н NMR
CDCl ): 9.55 (br. s, 1H), 8.64 (t, J = 1.8 Hz, 1H), 8.35 (ddd, J = 8.0, 2.3, 1.1 Hz, 1H), 8.22 (dt, J =
(
3
8
7
1
.0, 1.4 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.32–7.13 (m, 6H), 4.12 (d, J = 7.1 Hz, 2H), 1.00 (t, J =
1
3
.1 Hz, 3H). С NMR (CDCl ): δ 192.3, 159.9, 148.3, 139.7, 134.8, 133.0, 129.6, 128.7, 127.7,
3
27.30, 127.27, 127.1, 125.1, 124.3, 121.8, 120.8, 61.1, 13.8. ESI/HRMS (m/z): 365.1132 calcd for
+
-1
C Н N O [M+H] , found 365.1137. IR (KBr, cm ): ν 3256, 1696, 1672, 1350.
20
16
2
5
4
.2.8. (4-Phenyl-1H-pyrrole-2,3-diyl)bis(phenylmethanone) (14f). Compound 14f (149.0 mg, 42%)
was obtained as the single identified product from ethyl 3-phenyl-2H-azirine 7a (117.0 mg, 1.0
mmol) and 1,4-diphenylbutane-1,2,4-trione 12g (252.0 mg, 1.0 mmol) according to procedure C,
using DCE as a solvent and copper(II) acetate monohydrate (10.0 mg, 50.0 ꢀmol, 5% mol) as
catalyst at 60 °C for 8 h. A benzene/ethyl acetate mixture (50/1 → 12/1) was used as eluent for
1
7

ACCEPTED MANUSCRIPT
1
column chromatography. Brown crystals, mp 143.5–145.5 °C (petrol ether/dichloromethane). Н
NMR (CDCl ): 9.72 (br. s, 1H), 7.45–7.38 (m, 4H), 7.37–7.31 (m, 4H), 7.29–7.19 (m, 4H), 7.18–
3
13
7
.12 (m, 4H). С NMR (CDCl ): δ 194.1, 186.8, 139.2, 138.6, 133.3, 132.6, 131.9, 131.0, 129.1,
3
1
28.6, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 126.9, 122.4. ESI/HRMS (m/z): 352.1332 calcd for
+
-1
C Н NO [M+H] , found 352.1335. IR (KBr, cm ): ν 3273, 1657, 1628. CCDC 1033503.
24
17
2
Compound 14f was also obtained in higher preparative yield (121 mg, 69%) from 3-phenyl-2H-
azirine 7a (176.0 mg, 1.50 mmol) and ethyl 1,4-diphenylbutane-1,2,4-trione 12g (126 mg, 0.5
mmol) according to procedure C, using DCE as a solvent and copper(II) acetate monohydrate (5.0
mg, 25.0 ꢀmol, 5% mol) as catalyst at 75 °C for 5 h.
4
.2.9. Ethyl 2-oxo-2-(2,4,5-triphenyl-1H-pyrrol-3-yl)acetate (13g) and ethyl 3-benzoyl-4,5-
diphenyl-1H-pyrrole-2-carboxylate (14g). Compounds 13g (52.0 mg, 18%) and 14g (44.0 mg,
1
5%) were obtained from 2,3-diphenyl-2H-azirine 7b (145.0 mg, 0.75 mmol) and ethyl 2,4-dioxo-
-phenylbutanoate 12a (165.0 mg, 0.75 mmol) according to procedure C, using DCE as a solvent
4
and copper(II) acetate monohydrate (8.0 mg, 40.2 ꢀmol, 5% mol) as catalyst at 60 °C for 24 h. A
benzene/ethyl acetate mixture (50/1 → 12/1) was used as eluent for column chromatography.
1
Compound 13g. Yellow solid, mp 166.7–167.6 °C (petrol ether/dichloroethane). Н NMR (CDCl ):
3
9
7
1
1
3
.62 (br. s, 1H), 7.93–7.85 (m, 2H), 7.52–7.47 (m, 1H), 7.38 (t, J = 7.6 Hz, 2H), 7.34–7.27 (m, 5H),
1
3
.20–7.13 (m, 5H), 4.01 (q, J = 7.1 Hz, 2H), 0.85 (t, J = 7.1 Hz, 3H). С NMR (CDCl ): δ 183.5,
3
64.2, 139.5, 133.9, 131.3, 131.1, 130.9, 129.9, 129.09, 129.06, 128.7, 128.6, 128.1, 127.4, 127.3,
+
27.2, 124.4, 118.1, 61.5, 13.6. ESI/HRMS (m/z): 396.1594 calcd for C Н NO [M+H] , found
2
6
21
3
-1
96.1595. IR (KBr, cm ): ν 3346, 1718, 1657.
1
Compound 14g. Colorless crystals, mp 202.2–204.1 °C (petrol ether/dichloroethane). Н NMR
(CDCl ): 9.62 (br. s, 1H), 7.93–7.85 (m, 2H), 7.52–7.47 (m, 1H), 7.38 (t, J = 7.6 Hz, 2H), 7.34–7.27
3
1
3
(
m, 5H), 7.20–7.13 (m, 5H), 4.01 (q, J = 7.1 Hz, 2H), 0.85 (t, J = 7.1 Hz, 3H). С NMR (CDCl ): δ
3
1
1
94.2, 160.7, 138.6, 133.6, 133.3, 132.9, 131.0, 130.0, 129.5, 129.3, 128.7, 128.3, 128.2, 128.1,
+
27.9, 126.9, 123.8, 120.2, 60.9, 13.5. ESI/HRMS (m/z): 396.1594 calcd for C Н NO [M+H] ,
2
6
21
3
-1
found 396.1603. IR (KBr, cm ): ν 3297, 1677.
4
.2.10. Ethyl 2-(2-(4-methoxyphenyl)-2-oxo-4,5-diphenyl-1H-pyrrol-3-yl)acetate (13h) and. ethyl 3-
(4-methoxybenzoyl)-4,5-diphenyl-1H-pyrrole-2-carboxylate (14h). Compounds 13h (71.0 mg, 22%)
and 14h (60.0 mg, 19%) were obtained from 2,3-diphenyl-2H-azirine 7b (145.0 mg, 0.75 mmol)
and ethyl 4-(4-methoxyphenyl)-2,4-dioxobutanoate 12b (188.0 mg, 0.75 mmol) according to
procedure C, using DCE as a solvent and copper(II) acetate monohydrate (8.0 mg, 40.2 ꢀmol, 5%
1
8

ACCEPTED MANUSCRIPT
mol) as catalyst at 60 °C for 20 h. A benzene/ethyl acetate mixture (25/1) was used as eluent for
column chromatography.
1
Compound 13h. Bright yellow crystals, > 128.0 °C (dec., petrol ether/diethyl ether). Н NMR
(
CDCl ): 8.69 (br. s, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.33–7.27 (m, 5H), 7.26–7.17 (m, 5H), 6.96 (d,
3
1
3
J = 8.8 Hz, 2H), 3.85 (s, 3H), 3.59 (q, J = 7.2 Hz, 2H), 1.02 (t, J = 7.2 Hz, 3H). С NMR (CDCl ):
3
δ 183.5, 164.4, 160.4, 139.7, 134.0, 131.4, 131.0, 130.5, 129.5, 128.6, 128.0, 127.3, 127.2, 127.1,
1
24.2, 123.5, 117.7, 114.0, 61.5, 55.4, 13.6. ESI/HRMS (m/z): 426.1700 calcd for C Н NO
2
7
23
4
+
-1
[
M+H] , found 426.1705. IR (KBr, cm ): ν 3444, 1733, 1630.
1
Compound 14h. Pale yellow solid, mp 179.4–180.4 °C (petrol ether/diethyl ether). Н NMR
(
CDCl ): 9.52 (br. s, 1H), 7.85 (d, J = 8.7 Hz, 2H), 7.33–7.27 (m, 5H), 7.19–7.12 (m, 5H), 6.85 (d,
3
1
3
J = 8.7 Hz, 2H), 4.05 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 0.93 (t, J = 7.1 Hz, 3H). С NMR (CDCl ):
3
δ 192.8, 163.5, 160.7, 133.5, 131.83, 131.81, 131.1, 130.0, 129.7, 128.7, 128.3, 128.1, 127.9, 126.9,
+
1
23.6, 119.9, 113.5, 60.8, 55.4, 13.7. ESI/HRMS (m/z): 426.1700 calcd for C Н NO [M+H] ,
2
7
23
4
-1
found 426.1710. IR (KBr, cm ): ν 3262, 1678, 1648, 1600.
4
.2.11. Ethyl 2-(2-(tert-butyl)-2-oxo-4,5-diphenyl-1H-pyrrol-3-yl)acetate (13i) and ethyl 4,5-
diphenyl-3-pivaloyl-1H-pyrrole-2-carboxylate (14i). Compound 13i (79.0 mg, 14%) and 14i (63.0
mg, 11%) were obtained from 2,3-diphenyl-2H-azirine 7b (300.0 mg, 1.55 mmol) and ethyl 5,5-
dimethyl-2,4-dioxohexanoate 12f (300.0 mg, 1.50 mmol) according to procedure C, using DCE as a
solvent and copper(II) acetate monohydrate (10.0 mg, 50.0 ꢀmol, 3.3% mol) as catalyst at 60 °C for
3
0 h. A benzene/ethyl acetate mixture (50/1 → 10/1) was used as eluent for column
chromatography.
Compound 13i. Bright yellow crystals, mp 195.0–197.0 °C (petrol ether/diethyl ether). Н NMR
1
(
CDCl ): δ 8.53 (br. s, 1H), 7.31–7.17 (m, 8H), 7.11 (d, J = 6.7 Hz, 2H), 3.51 (q, J = 7.1 Hz, 2H),
3
1
3
1
.54 (s, 9H), 1.05 (t, J = 7.1 Hz, 3H). С NMR (CDCl ): δ 184.9, 164.9, 148.6, 134.1, 131.6,
3
1
31.2, 128.7, 128.0, 127.13, 127.12, 127.0, 126.0, 124.9, 116.9, 61.4, 33.5, 28.5, 13.6. ESI/HRMS
+
-1
(
m/z): 376.1907 calcd for C Н NO [M+H] , found 376.1909. IR (KBr, cm ): ν 3296, 2964,
24 25 3
1
728, 1641.
1
Compound 14i. Colorless crystals, mp 206.6–207.8 °C (petrol ether/dichloromethane). Н NMR
CDCl ): δ 9.18 (br. s, 1H), 7.30–7.23 (m, 8H), 7.22–7.18 (m, 2H), 4.32 (q, J = 7.2 Hz, 2H), 1.34 (t,
(
3
1
3
J = 7.2 Hz, 3H), 0.90 (s, 9H). С NMR (CDCl ): δ 121.0, 160.5, 134.4, 133.0, 131.0, 130.9, 130.4,
3
1
28.7, 128.5, 128.1, 127.8, 127.2, 121.7, 118.3, 61.0, 45.1, 27.0, 14.4. ESI/HRMS (m/z): 376.1907
+
-1
calcd for C Н NO [M+H] , found 376.1906. IR (KBr, cm ): ν 3300, 2976, 1678.
2
4
25
3
1
9

ACCEPTED MANUSCRIPT
4
.2.12. Methyl 2-(4,5-diphenyl-2-methyl-1H-pyrrol-3-yl)-2-oxoacetate (13j) and methyl 3-acetyl-
4
,5-diphenyl-1H-pyrrole-2-carboxylate (14j). Compounds 13j (123.0 mg, 40%) 14j (82.0 mg, 26%)
and were obtained from 2,3-diphenyl-2H-azirine 7b (193.0 mg, 1.0 mmol) and methyl 2,4-
dioxopentanoate 12l (143.0 mg, 1.0 mmol) according to procedure C, using DCE as a solvent and
copper(II) acetate monohydrate (10.0 mg, 50.0 ꢀmol, 5% mol) as catalyst at 60 °C for 35 h. A
benzene/ethyl acetate mixture (10/1 → 5/1) was used as eluent for column chromatography.
1
Compound 13j. Yellow crystals, mp 187.1–189.0 °C (hexane-dichloromethane). Н NMR (CDCl ):
3
1
3
δ 9.40 (br. s, 1H), 7.32–7.23 (m, 8H), 7.23–7.18 (m, 2H), 3.86 (s, 3H), 2.30 (s, 3H). С NMR
(
CDCl ): δ 201.2, 160.9, 133.4. 133.2, 132.4, 130.8, 130.1, 128.7, 128.5, 128.2, 127.8, 127.3, 122.4,
3
+
1
18.2, 52.0, 32.5. ESI/HRMS (m/z): 320.1281 calcd for C Н NO [M+H] , found 320.1287. IR
2
0
17
3
-1
(
KBr, cm ): ν 3231, 1740, 1624, 1602.
1
Compound 14j. Colorless crystals, mp 161.8–163.5 °C (hexane-dichloromethane). Н NMR
(
CDCl ): δ 8.78 (br. s, 1H), 7.33–7.16 (m, 3H), 7.25–7.15 (m, 5H), 7.14–7.09 (m, 2H), 3.18 (s, 3H),
3
1
3
2
.64 (s, 3H). С NMR (CDCl ): δ 184.0, 165.3, 139.5, 134.0, 131.4, 130.9, 128.6, 128.2, 127.9,
3
1
27.2, 127.1, 126.9, 123.0, 117.6, 51.7, 14.1. ESI/HRMS (m/z): 320.1281 calcd for C Н NO
3
2
0
17
+
-1
[
M+H] , found 320.1285. IR (KBr, cm ): ν 3287, 1707, 1687.
4
.2.13. (4,5-Diphenyl-1H-pyrrole-2,3-diyl)bis(phenylmethanone) (14k). Compound 14k (133.0 mg,
4
2%) was obtained from 2,3-diphenyl-2H-azirine 7b (145.0 mg, 0.75 mmol) and 1,4-
diphenylbutane-1,2,4-trione 12g (189.0 mg, 0.75 mmol) according to procedure C, using DCE as a
solvent and copper(II) acetate monohydrate (8.0 mg, 40.2 ꢀmol, 5% mol) as catalyst at 60 °C for 24
h A benzene/ethyl acetate mixture (50/1 → 25/1) was used as eluent for column chromatography.
1
Pale yeillow solid, mp 227.0–229.5 °C (petrol ether/chloroform). Н NMR (CDCl ): 9.94 (br. s,
3
1
3
1
1
1
H), 7.45–7.28 (m, 11H), 7.24–7.16 (m, 5H), 7.16–7.08 (m, 4H). С NMR (CDCl ): δ 193.5,
3
86.7, 139.3, 138.9, 135.1, 133.2, 132.4, 131.9, 131.0, 130.6, 130.5, 129.8, 129.0, 128.7, 128.4,
+
28.2, 128.0, 128.0, 127.8, 127.2, 125.5. ESI/HRMS (m/z): 428.1645 calcd for C Н NO [M+H] ,
3
0
21
2
-1
found 428.1653. IR (KBr, cm ): ν 3305, 1660, 1607.
4
.2.14. Ethyl 2-(2-ethoxycarbonyl-3,5-diphenyl-1H-pyrrol-4-yl)-2-oxoacetate (13l) and diethyl 3-
benzoyl-4-phenyl-1H-pyrrole-2,5-dicarboxylate (14l). Compound 13l (111.0 mg, 28%) and 14l
265.0 mg, 68%) were obtained from ethyl 3-phenyl-2H-azirine-2-carboxylate 7c (190.0 mg, 1.0
(
mmol) and ethyl 4-phenyl-2,4-dioxobutanoate 12a (220.0 mg, 1.0 mmol) according to procedure C,
using DCE as a solvent and copper(II) acetate monohydrate (10.0 mg, 50.0 ꢀmol, 5% mol) as
catalyst at 75 °C for 70 h. A benzene/ethyl acetate mixture (50/1 → 20/1) was used as eluent for
column chromatography.
2
0

ACCEPTED MANUSCRIPT
1
Compound 13l. Colorless crystals, mp 138.4–139.7 °C (hexane/benzene). Н NMR (CDCl ): 9.76
3
(br. s, 1H), 7.62 (dd, J = 6.3, 2.8 Hz, 2H), 7.49–7.42 (m, 3H), 7.40–7.33 (m, 5H), 4.09 (q, J = 7.2
1
3
Hz, 2H), 3.59 (q, J = 7.2 Hz, 2H), 1.06 (t, J = 7.2 Hz, 3H), 1.02 (t, J = 7.2 Hz, 3H). С NMR
(
CDCl ): δ 183.4, 163.6, 161.0, 141.3, 133.6, 132.6, 130.7, 130.2, 129.6, 129.2, 128.5, 127.8, 127.3,
3
+
1
20.1, 119.0, 61.7, 60.9, 13.8, 13.6. ESI/HRMS (m/z): 392.1492 calcd for C Н NO [M+H] ,
2
3
21
5
-1
found 392.1498. IR (KBr, cm ): ν 3267, 1730, 1656.
Compound 14l. Colorless crystals, mp 150.1–152.1 °C (hexane/benzene). Н NMR (CDCl ): 10.02
1
3
(br. s, 1H), 7.78 (d, J = 7.3 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.7 Hz, 2H), 7.31–7.26
(m, 2H), 7.25–7.19 (m, 3H), 4.25 (q, J = 7.1 Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H), 1.19 (t, J = 7.1 Hz,
1
3
3
1
3
H), 0.92 (t, J = 7.1 Hz, 3H). С NMR (CDCl ): δ 192.7, 160.1, 159.6, 138.2, 133.1, 132.0, 131.2,
3
30.1, 129.4, 128.8, 128.3, 127.7, 127.5, 122.7, 122.1, 61.4, 61.2, 14.0, 13.5. ESI/HRMS (m/z):
+
-1
92.1492 calcd for C Н NO [M+H] , found 392.1494. IR (KBr, cm ): ν 3278, 1712, 1673.
2
3
21
5
4
.2.15. Ethyl 2-(2-ethoxycarbonyl-5-(4-methoxyphenyl)-3-phenyl-1H-pyrrol-4-yl)-2-oxoacetate
3-(4-methoxybenzoyl)-4-phenyl-1H-pyrrole-2,5-dicarboxylate (14m).
Compounds 13m (109.0 mg, 26%) and 14m (280.0 mg, 65%) were obtained from ethyl 3-phenyl-
H-azirine-2-carboxylate 7c (190.0 mg, 1.0 mmol) and ethyl 4-(4-methoxyphenyl)-2,4-
(13m) and diethyl
2
dioxobutanoate 12b (250.0 mg, 1.0 mmol) according to procedure C, using DCE as a solvent and
copper(II) acetate monohydrate (10.0 mg, 50.0 ꢀmol, 5% mol) as catalyst at 75 °C for 70 h. A
benzene/ethyl acetate mixture (25/1 → 10/1) was used as eluent for column chromatography.
1
Compound 13m. Pale yellow crystals, mp 138.3–140.7 °C (hexane/benzene). Н NMR (CDCl ):
3
9
7
3
1
.53 (br. s, 1H), 7.59 (d, J = 8.7 Hz, 2H), 7.39–7.33 (m, 5H), 6.97 (d, J = 8.7 Hz, 2H), 4.11 (q, J =
.1 Hz, 2H), 3.85 (s, 3H), 3.59 (q, J = 7.2 Hz, 2H), 1.08 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.2 Hz,
1
3
H). С NMR (CDCl ): δ 183.4, 163.7, 161.0, 160.8, 141.4, 133.6, 132.7, 130.7, 130.6, 127.7,
3
27.3, 122.5, 119.7, 118.6, 114.0, 61.7, 60.8, 55.4, 13.8, 13.6. ESI/HRMS (m/z): 422.1598 calcd for
+
-1
C Н NO [M+H] , found 422.1604. IR (KBr, cm ): ν 3283, 1724, 1666.
24
23
6
1
Compound 14m. Colorless crystals, mp 144.1–145.6 °C (hexane/benzene). Н NMR (CDCl ): 9.92
3
(br. s, 1H), 7.75 (d, J = 8.9 Hz, 2H), 7.31–7.27 (m, 2H), 7.25–7.19 (m, 3H), 6.83 (d, J = 8.9 Hz,
2
H), 4.25 (q, J = 7.1 Hz, 2H), 4.13 (q, J = 7.10 Hz, 2H), 3.83 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H), 0.99
1
3
(
t, J = 7.10 Hz, 3H). С NMR (CDCl ): δ 191.3, 163.6, 160.1, 159.6, 132.1, 131.7, 131.4, 131.0,
3
1
4
30.1, 129.2, 127.6, 127.5, 122.4, 121.9, 113.5, 61.4, 61.2, 55.4, 14.0, 13.7. ESI/HRMS (m/z):
+
-1
22.1598 calcd for C Н NO [M+H] , found 422.1604. IR (KBr, cm ): ν 3278, 1714, 1596.
2
4
23
6
4
.2.16. Methyl 2-(5-(3-bromophenyl)-2-ethoxycarbonyl-3-phenyl-1H-pyrrol-4-yl)-2-oxoacetate
(13n). Compound 13n (123.0 mg, 27%) and 14n (255.0 mg, 56%) were obtained from ethyl 3-
2
1

ACCEPTED MANUSCRIPT
phenyl-2H-azirine-2-carboxylate 7c (190.0 mg, 1.0 mmol) and methyl 4-(3-bromophenyl)-2,4-
dioxobutanoate 12m (285.0 mg, 1.0 mmol) according to procedure C, using DCE as a solvent and
copper(II) acetate monohydrate (10.0 mg, 50.0 ꢀmol, 5% mol) as catalyst at 75 °C for 100 h. A
benzene/ethyl acetate mixture (20/1 → 10/1) was used as eluent for column chromatography.
1
Compound 13n. Colorless solid, mp 124.5–126.3 °C (hexane/dichloromethane). Н NMR (CDCl ):
3
9
.82 (br. s, 1H), 7.79 (t, J = 1.9 Hz, 1H), 7.58 (dt, J = 8.0, 1.9 Hz, 2H), 7.40–7.30 (m, 6H), 4.10 (q,
1
3
J = 7.1 Hz, 2H), 3.23 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H). С NMR (CDCl ): δ 182.9, 163.8, 161.0,
3
1
39.5, 133.6, 132.6, 132.3, 132.1, 132.0, 130.7, 130.0, 128.1, 127.9, 127.4, 122.5, 120.4, 119.2,
+
6
1.1, 52.1, 13.8. ESI/HRMS (m/z): 456.0441 calcd for C Н BrNO [M+H] , found 456.0446. IR
2
2
18
5
-1
(
KBr, cm ): ν 3265, 1750, 1660.
1
Compound 14n. Colorless crystals, mp 112.6–114.6 °C (hexane/dichloromethane). Н NMR
(
CDCl ): 10.01 (br. s, 1H), 7.86 (t, J = 1.8 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.60–7.56 (m, 1H),
3
1
3
7
.27–7.18 (m, 6H), 4.26 (q, J = 7.1 Hz, 2H), 3.70 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H). С NMR
(
CDCl ): δ 191.2, 159.9, 159.7, 139.5, 136.0, 132.2, 131.7, 131.1, 130.0, 129.9, 128.4, 127.9, 127.8,
3
1
27.6, 122.6, 122.5, 122.1, 61.3, 52.3, 14.0. ESI/HRMS (m/z): 456.0441 calcd for C Н BrNO
22 18 5
+
-1
[
M+H] , found 456.0447. IR (KBr, cm ): ν 3268, 1722, 1676.
4
.2.17. Ethyl 2-(2-ethoxycarbonyl-3-methyl-5-phenyl-1H-pyrrol-4-yl)-2-oxoacetate (13o) and
Diethyl 3-benzoyl-4-methyl-1H-pyrrole-2,5-dicarboxylate (14o). Compounds 13o (92.0 mg, 28%)
and 14o (86.0 mg, 26%) were obtained from ethyl 3-methyl-2H-azirine-2-carboxylate 7d (130.0
mg, 1.02 mmol) and ethyl 4-phenyl-2,4-dioxobutanoate 12a (220.0 mg, 1.0 mmol) according to
procedure C, using DCE as a solvent and copper(II) acetate monohydrate (10.0 mg, 50.0 ꢀmol, 5%
mol) as catalyst at 60 °C for 55 h. A hexane/acetone mixture (10/1) was used as eluent for column
chromatography.
1
Compound 13o. Colorless crystals, mp 153.0–155.1 °C (hexane/dichloromethane). Н NMR
(
CDCl ): 9.42 (br. s, 1H), 7.47–7.39 (m, 5H), 4.31 (q, J = 7.1 Hz, 2H), 3.67 (q, J = 7.2 Hz, 2H),
3
1
3
2
1
.61 (s, 3H), 1.36 (t, J = 7.10 Hz, 3H), 1.02 (t, J = 7.2 Hz, 3H). С NMR (CDCl ): δ 183.7, 164.0,
3
61.7, 142.5, 131.6, 130.6, 129.6, 129.1, 128.7, 120.8, 118.7, 61.7, 60.9, 14.4, 13.5, 11.7.
+
-1
ESI/HRMS (m/z): 330.1336 calcd for C Н NO [M+H] , found 330.1343. IR (KBr, cm ): ν 3241,
1
8
19
5
1
741, 1677, 1648.
Compound 14o. Light beige crystals, mp 146.6–148.5 °C (petrol ether/diethyl ether). Н NMR
CDCl ): 9.76 (br. s, 1H), 7.82 (d, J = 7.3 Hz, 2H), 7.56 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H),
1
(
3
4
7
.39 (q, J = 7.2 Hz, 2H), 4.02 (q, J = 7.2 Hz, 2H), 2.28 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H), 0.87 (t, J =
1
3
.2 Hz, 3H). С NMR (CDCl ): δ 193.3, 160.6, 159.6, 138.5, 133.2, 129.4, 128.5, 128.4, 127.6,
3
2
2

ACCEPTED MANUSCRIPT
1
22.8, 122.7, 61.3, 61.1, 14.4, 13.4, 10.7. ESI/HRMS (m/z): 330.1336 calcd for C Н NO
18 19 5
+
-1
[
M+H] , found 330.1344. IR (KBr, cm ): ν 3284, 1713, 1656.
4
.2.18. Ethyl 2-(5-(4-methoxyphenyl)-2-ethoxycarbonyl-3-methyl-1H-pyrrol-4-yl)-2-oxoacetate
(
13p) and diethyl 3-(4-methoxybenzoyl)-4-methyl-1H-pyrrole-2,5-dicarboxylate (14p). Compounds
3p (97.0 mg, 27%) and 14p (119.0 mg, 33%) were obtained from ethyl 3-methyl-2H-azirine-2-
carboxylate 7d (130.0 mg, 1.02 mmol) and ethyl 4-(4-methoxyphenyl)-2,4-dioxobutanoate 12b
250.0 mg, 1.0 mmol) according to procedure C, using DCE as a solvent and copper(II) acetate
monohydrate (10.0 mg, 50.0 ꢀmol, 5% mol) as catalyst at 60°C for 55 h. A hexane/acetone mixture
10/1) was used as eluent for column chromatography.
Compound 13p. Colorless crystals, mp 159.7–161.2 °C (petrol ether/diethyl ether). Н NMR
CDCl ): 9.24 (br. s, 1H), 7.34 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.6 Hz, 2H), 4.32 (q, J = 7.1 Hz,
1
(
(
1
(
3
2
3
1
H), 3.84 (s, 3H), 3.75 (q, J = 7.2 Hz, 2H), 2.60 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.2 Hz,
1
3
H). С NMR (CDCl ): δ 183.8, 164.2, 161.7, 160.8, 142.5, 131.6, 130.5, 122.9, 120.5, 118.5,
3
+
14.1, 61.7, 60.8, 55.4, 14.4, 13.6, 11.7. ESI/HRMS (m/z): 360.1442 calcd for C Н NO [M+H] ,
1
9
21
6
-1
found 360.1448. IR (KBr, cm ): ν 3272, 1736, 1680, 1649.
1
Compound 14p. Colorless crystals, mp 133.1–134.8 °C. Н NMR (CDCl ): 9.72 (br. s, 1H), 7.80 (d,
3
J = 8.7 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 4.07 (q, J = 7.2 Hz, 2H), 3.86 (s,
1
3
3
1
1
3
H), 2.25 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.2 Hz, 3H). С NMR (CDCl ): δ 191.9,
3
63.8, 160.7, 159.7, 131.8, 131.5, 129.1, 127.3, 122.6, 122.4, 113.7, 61.2, 61.0, 55.5, 14.4, 13.6,
+
-1
0.7. ESI/HRMS (m/z): 360.1442 calcd for C Н NO [M+H] , found 360.1449. IR (KBr, cm ): ν
1
9
21
6
270, 1704, 1649, 1599.
4
.2.19. Methyl 2-(5-(4-bromophenyl)-2-ethoxycarbonyl-3-methyl-1H-pyrrol-4-yl)-2-oxoacetate
(13q) 5-ethyl 2-methyl 3-(4-bromobenzoyl)-4-methyl-1H-pyrrole-2,5-dicarboxylate (14q).
Compound 13q (110.0 mg, 28%) and 14q (87.0 mg, 22%) were obtained from ethyl 3-methyl-2H-
azirine-2-carboxylate 7d (130.0 mg, 1.02 mmol) and methyl 4-(4-bromophenyl)-2,4-dioxobutanoate
1
2c (285.0 mg, 1.0 mmol) according to procedure C, using DCE as a solvent and copper(II) acetate
monohydrate (10.0 mg, 50.0 ꢀmol, 5% mol) as catalyst at 75 °C for 60 h. A benzene/ethyl acetate
mixture (20/1 → 10/1) was used as eluent for column chromatography.
1
Compound 13q. Colorless crystals, mp 149.9–151.7 °C (hexane/ethyl acetate). Н NMR (CDCl ):
3
9
3
1
.64 (br. s, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.38 (s,
1
3
H), 2.58 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). С NMR (CDCl ): δ 183.1, 164.2, 161.7, 141.2, 131.8,
3
31.5, 130.7, 129.4, 124.1, 121.1, 118.9, 61.1, 52.2, 14.4, 11.6. ESI/HRMS (m/z): 394.0285 calcd
+
-1
for C Н BrNO [M+H] , found 394.0289. IR (KBr, cm ): ν 3263, 1745, 1677, 1657.
1
7
16
5
2
3

ACCEPTED MANUSCRIPT
1
Compound 14q. Light yellow crystals, mp 139.6–140.1 °C (hexane/ethyl acetate). Н NMR
(
CDCl ): 9.77 (br. s, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 4.40 (q, J = 7.1 Hz,
3
1
3
2
1
3
1
H), 3.60 (s, 3H), 2.24 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). С NMR (CDCl ): δ 192.2, 160.5, 159.8,
3
37.1, 131.8, 130.8, 128.5, 128.4, 127.4, 122.9, 122.4, 61.2, 52.1, 14.4, 10.8. ESI/HRMS (m/z):
+
-1
94.0285 calcd for C Н BrNO [M+H] , found 394.0291. IR (KBr, cm ): ν 3251, 1729, 1702,
1
7
16
5
666.
4
.2.20. Methyl 2-(2-(3-bromophenyl)-4-(2-bromophenyl)-1H-pyrrol-3-yl)-2-oxoacetate (13r) and
methyl 3-(3-bromobenzoyl)-4-(2-bromophenyl)-1H-pyrrole-2-carboxylate (14r). Compounds 13r
(
66.0 mg, 19%) and 14r (175.0 mg, 49%) were obtained from 3-(2-bromophenyl)-2H-azirine 7e
147.0 mg, 0.75 mmol) and methyl 4-(3-bromophenyl)-2,4-dioxobutanoate 12m (214.0 mg, 0.75
(
mmol) according to procedure C, using DCE as a solvent and copper(II) acetate monohydrate (7.5
mg, 37.5 ꢀmol, 5% mol) as catalyst at 60 °C for 7.5 h. A benzene/ethyl acetate mixture (100/1 →
1
0/1) was used as eluent for column chromatography.
1
Compound 13r. Light yellow crystals, mp 168.2–170.1 °C (hexane/chloroform). Н NMR (CDCl ):
3
8
.74 (br. s, 1H), 7.72 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 7.8 Hz,
1
3
1
H), 7.28–7.34 (m, 3H), 7.15–7.23 (m, 1H), 6.86 (d, J = 2.4 Hz, 1H), 3.30 (s, 3H). С NMR
(
CDCl ): δ 182.2, 164.2, 137.7, 135.0, 133.1, 132.6, 132.3, 132.1, 131.8, 130.1, 129.0, 127.8, 127.0,
3
1
26.9, 124.8, 122.5, 119.2, 116.9, 52.0. ESI/HRMS (m/z): 463.9314 calcd for C Н Br NO
19 13 2 3
+
-1
[
M+H] , found 463.9318. IR (KBr, cm ): ν 3294, 1726, 1654.
1
Compound 14r. Light brown glassy solid, mp 65.0–75.0 °C. Н NMR (CDCl ): 9.55 (br. s, 1H),
3
7
0
1
1
.93 (t, J = 1.7 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.56 (dd, J = 7.8, 0.9 Hz, 1H), 7.51 (dd, J = 7.8,
1
3
.9 Hz, 1H), 7.25–7.14 (m, 4H), 7.04 (td, J = 7.6, 1.8 Hz, 1H), 3.64 (s, 3H). С NMR (CDCl ): δ
3
91.8, 160.6, 139.9, 135.7, 133.9, 132.8, 132.3, 132.2, 129.7, 129.0, 128.1, 127.2, 127.0, 125.8,
+
23.8, 122.6, 122.4, 121.1, 51.9. ESI/HRMS (m/z): 463.9314 calcd for C Н Br NO [M+H] ,
1
9
13
2
3
-1
found 463.9323. IR (KBr, cm ): ν 3285, 1709, 1659.
4
.2.21. Methyl 2-(4-(2-bromophenyl)-2-methyl-1H-pyrrol-3-yl)-2-oxoacetate (13s) and methyl 3-
acetyl-4-(2-bromophenyl)-1H-pyrrole-2-carboxylate (14s). Compounds 13s (67.0 mg, 21%) and
4s (156.0 mg, 49%) were obtained from 3-(2-bromophenyl)-2H-azirine 7e (196.0 mg, 1.0 mmol)
1
and methyl 2,4-dioxopentanoate 12l (143.0 mg, 1.0 mmol) according to procedure C, using DCE as
a solvent and copper(II) acetate monohydrate (10.0 mg, 50.0 ꢀmol, 5% mol) as catalyst at 60 °C for
6
h. A hexane/acetone mixture (5/1) was used as eluent for column chromatography.
Compound 13s. Light beige crystals, mp 131.0–132.7 °C (hexane/dichloromethane). Н NMR
CDCl ): δ 8.72 (br. s, 1H), 7.64–7.59 (m, 1H), 7.32–7.24 (m, 2H), 7.16 (ddd, J = 2.2, 6.9, 7.9 Hz,
1
(
3
2
4

ACCEPTED MANUSCRIPT
1
3
1
H), 6.62 (d, J = 2.3 Hz, 1H), 3.28 (s, 3H), 2.60 (s, 3H). С NMR (CDCl ): δ 182.9, 165.1, 139.3,
3
1
35.4, 132.5, 128.7, 126.8, 125.4, 124.9, 117.1, 115.8, 52.8, 14.1. ESI/HRMS (m/z): 322.0073
+
-1
calcd for C Н BrNO [M+H] , found 322.0074. IR (KBr, cm ): ν 3282, 1745, 1720, 1646.
1
4
12
3
1
Compound 14s. Colorless solid, mp 159.6–161.2 °C (hexane/chloroform). Н NMR (CDCl ): δ 9.41
3
(br. s, 1H), 7.64–7.59 (m, 1H), 7.33–7.27 (m, 2H), 7.21–7.13 (m, 1H), 6.94 (d, J = 3.0 Hz, 1H),
1
3
3
1
.89 (s, 3H), 2.41 (s, 3H). С NMR (CDCl ): δ 199.4, 160.6, 134.7, 132.7, 132.1, 130.2, 129.0,
3
27.2, 125.2, 124.1, 121.8, 119.8, 52.0, 31.6. ESI/HRMS (m/z): 322.0073 calcd for C Н BrNO
3
1
4
12
+
-1
[
M+H] , found 322.0077. IR (KBr, cm ): ν 3188, 1714, 1671.
4
.3. Synthesis of 3-heterylpyrrole 23 and fused pyrrole 24
.3.1. 4-(Naphthalen-1-yl)-2',4'-diphenyl-1H,1'H-[3,3'-bipyrrole]-2,5-dione (23). Compound 23
4
1
2a
was synthesized according to published procedure. A solution of potassium tert-butoxide (115
mg, 0.90 mmol) in THF (5 mL) was added dropwise to a solution of ethyl 2-oxo-2-(2,4-diphenyl-
1
H-pyrrol-3-yl)acetate (13a) (144 mg, 0.45 mmol) and 2-(naphthalene-1-yl)acetamide (56 mg, 0.3
mmol) in THF (10 mL) at 0 ~ -5 °C The reaction was stirred at 0 °C for 0.5 h and then at room
temperature overnight. The mixture was cooled down to 0°C and quenched with saturated aqueous
NH Cl (8 ml). Water was added to provide full dissolution of the precipitate formed and the mixture
4
was extracted with dichloromethane (2×10 ml). The combined organic extracts were washed with
water (10 ml), brine and dried over Na SO . Volatiles were removed in vacuo and the residue was
2
4
subjected to column chromatography on silica with 0.2% methyl alcohol in dichloromethane as
eluent to provide the maleimide 23 (34 mg, 26%) that was recrystallized from chloroform/hexane to
1
give deep red crystals, mp 298.8–299.2 °C. Н NMR (DMSO-d ): 11.55 (br. s, 1H), 11.21 (br. s,
6
1
3
1
1
1
H), 7.84–7.68 (m, 2H), 7.44–6.90 (m, 15H), 6.68 (s, 1H). С NMR (DMSO-d ): δ 171.8, 171.5,
6
39.4, 139.1, 135.4, 132.7, 132.4, 130.0, 128.9, 128.5, 128.2, 127.8, 127.6, 127.1, 126.7, 126.5,
26.3, 125.6, 125.33, 125.26, 124.6, 117.9, 106.7. ESI/HRMS (m/z): 441.1598 calcd for
+
C Н N O [M+H] , found 441.1610.
30
20
2
2
4
.3.2. 3,4-Diphenyl-1H-pyrrolo[2,3-d]pyridazin-7(6H)-one (24). Compound 24 was obtained
1
2c
analogously to the published procedure. A solution of the ethyl 3-benzoyl-4-phenylpyrrole-2-
carboxylate (14a) (96 mg, 0.30 mmol), hydrazine hydrate (50 mg, 1.0 mmol) and a drop of
hydrochloric acid in EtOH (2 mL) was refluxed for 48 h. The precipitate formed after cooling the
reaction mixture was filtered off, washed with cold EtOH and dried in vacuo to give the title
1
compound 24 (69 mg, 80%) as colourless crystals, dec. ≥ 363 °C. Н NMR (DMSO-d ): 12.97 (br. s,
6
1
H), 12.64 (s, 1H), 7.57 (s, 1H), 7.23–7.16 (m, 1H), 7.16–7.10 (m, 2H), 7.10–7.02 (m, 3H), 6.99 (t,
1
3
J = 7.5 Hz, 2H), 6.87 (d, J = 7.3 Hz, 2H). С NMR (DMSO-d ): δ 154.6, 144.0, 136.1, 133.6,
6
2
5

ACCEPTED MANUSCRIPT
1
29.3, 128.6, 127.8, 127.6, 127.4, 127.3, 126.8, 125.9, 120.3, 119.6. ESI/HRMS (m/z): 288.1131
+
calcd for C Н N O [M+H] , found 288.1137.
1
8
13
3
4
.4. Calculation details
All calculations were carried out at the DFT B3LYP/6-31G(d) level
2
6-28
by using the
2
9
Gaussian 09 suite of quantum chemical programs at Resource center ‘Computer center of Saint
Petersburg State University’. Geometry optimizations of intermediates, transition states, reactants,
and products in toluene were performed using PCM model. Intrinsic reaction coordinates were
calculated to authenticate all transition states.
Acknowledgments
We gratefully acknowledge the financial support of the Russian Foundation for Basic
Research (Grant No. 14-03-00187) and Saint Petersburg State University (Grant No.
1
2.50.1565.2013, 12.38.239.2014, 12.38.217.2015). This research used resources of the resource
center ‘Computer Center’, ‘Research resource center for Magnetic Resonance’, ‘Center for
Chemical Analysis and Material Research’, and ‘Research resource Center for X-ray Diffraction
Studies’ of Saint Petersburg State University.
Supplementary data
1
13
Crystallographic data, H and C NMR spectra for all new compounds. Computational
details: energies of molecules, transition states and their Cartesian coordinates of atoms.
Supplementary data related to this article can be found online at http://dx.doi.org/.....
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