Ambivalent role of metal chlorides in ring opening reactions of 2H-azirines: Synthesis of imidazoles, pyrroles and pyrrolinones

Article abstract of DOI:10.1016/j.tet.2012.06.069

2H-Azirines were found to react with imines, enaminones and enaminoesters in the presence of metal salts. Imidazoles, pyrroles and new pyrrolinones derivatives are isolated in good overall yields. The role of metal salts was investigated as they can act as Lewis acids or electron donors. Mechanisms are proposed suggesting that imidazoles arise from addition of azirine to imines via radical or ionic mechanism; pyrroles and pyrrolinones are obtained from azirines with enamino derivatives when the salt acts as a Lewis acid. In the latter case the properties of the metallic compound influence the reaction regioselectivity.

Full text of DOI:10.1016/j.tet.2012.06.069

Tetrahedron 68 (2012) 7441e7449
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Ambivalent role of metal chlorides in ring opening reactions of 2H-azirines:
synthesis of imidazoles, pyrroles and pyrrolinones
*
Sergio Auricchio , Ada M. Truscello, Mirvana Lauria, Stefano V. Meille
Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
2H-Azirines were found to react with imines, enaminones and enaminoesters in the presence of metal
salts. Imidazoles, pyrroles and new pyrrolinones derivatives are isolated in good overall yields. The role of
metal salts was investigated as they can act as Lewis acids or electron donors. Mechanisms are proposed
suggesting that imidazoles arise from addition of azirine to imines via radical or ionic mechanism;
pyrroles and pyrrolinones are obtained from azirines with enamino derivatives when the salt acts as
a Lewis acid. In the latter case the properties of the metallic compound influence the reaction
regioselectivity.
Received 20 March 2012
Received in revised form 25 May 2012
Accepted 18 June 2012
Available online 23 June 2012
Keywords:
Azirines
Lewis acids
Imines
Ó 2012 Elsevier Ltd. All rights reserved.
Imidazoles
Pyrroles
1. Introduction
In the past years we have been involved in the study of cleavage
reactions of heterocyclic rings under mild conditions and we found
2H-Azirines are the smallest unsaturated nitrogen-containing
heterocyclic rings. Due to their high reactivity they have been the
object of extensive studies for various synthetic purposes and
several general reviews have appeared.1 The strain of the three-
membered ring, the polarization of the C]N bond and the basic-
ity of the nitrogen atom make 2H-azirines particularly attractive in
organic synthesis as they are able to react with nucleophilic and
electrophilic reagents and also with dienophiles or dipolarophiles
in cycloadditions. The cleavage of an azirine ring gives reactive
intermediates that can lead to various nitrogen-containing het-
erocycles. Since cleavage of each of the three bonds is possible
different synthons such as vinylnitrenes, iminocarbenes and nitrile
ylides can be obtained. Regioselective single CeN bond cleavage
can be achieved by thermolysis of 2H-azirines and involves highly
reactive vinylnitrenes; this cleavage can be activated by Lewis acids
or by transition metal compounds.2 Thermolysis of CeC bond of
2H-azirines is the less common event,3 but it can be selectively
achieved upon irradiation1,4 and results in reaction through the
formation of nitrile ylides. Cleavage of C]N bond can be obtained
after initial nucleophilic attack on the polarized double bond and
subsequent cleavage of the ring. Lewis acid or transition metal
compound activation of this fission is reported.5
in particular that FeCl2 was very efficient in the azirine ring cleav-
age. Reactions give different products according to the substituent
at 2-position of the ring: 2-benzoyl azirines are reduced to enam-
inones (Scheme 1, a), 2-carboxymethyl azirines are reduced to
enaminoesters (Scheme 1, b) and reaction leads also to pyrroles6
while azirines not substituted at the 2-position give pyridazines
and imidazoles7 (Scheme 1, c).
Ph
a
R
NH2
R = COPh
R
Ph
Ph
R
Ph
R = COOMe
+
FeCl2
+
Ph
N
R
b
NH2
Ph
R
N
H
R = H
N
+
Ph
Ph
Me
c
N
Ph
N
N
Scheme 1. Previous work.
For all these reactions we proposed radical intermediates
formed by single electron transfer from iron dichloride to the
azirine in the early stages of reaction.
* Corresponding author. Tel.: þ39 02 23993036; fax: þ39 02 23993080; e-mail
address: sergio.auricchio@polimi.it (S. Auricchio).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.069

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S. Auricchio et al. / Tetrahedron 68 (2012) 7441e7449
Recently, it was reported that the amination of aromatic CeH
Our investigation was extended to other azirines performing
reactions in the presence of 2 equiv of FeCl3. In all cases the main
product involves the C]N bond cleavage (Table 2).
bonds can be achieved via ring opening of 2H-azirines induced by
FeCl2;8 this reaction shows again that iron dichloride can be an
efficient promoter in azirine chemistry. The authors, surprisingly,
ruled out a radical pathway for the ring opening and proposed
a mechanism via cleavage of the CeN single bond of azirine and
formation of a vinylnitrene intermediate. It was suggested that
FeCl2 acts only as a Lewis acid although other Lewis acids as AlCl3 or
FeCl3 were completely ineffective.
We found that FeCl2 is able to promote reactions of azirines with
imines, enaminoesters and enaminones acting both as single
electron donor and Lewis acid. Radical and ionic pathways allow
different azirine ring cleavages and therefore lead to different
products. Use of other metal salts leads to the selective obtainment
of products and clarifies the two different routes. Specifically, re-
actions of azirines with imines promoted by FeCl2 lead to imidaz-
oles, reactions of azirines with enaminoesters lead to pyrroles and
surprisingly to pyrrolinones while reactions with enaminones lead
to pyrroles and iminopyrroles.
Table 2
a,b
Reactions of azirines 1aed and imines 2a,b with FeCl3
Entry
Azirine 1
Imine 2
Yield (%)
N
Ph
Ph
Ph
N
PhCH]NPh
2a
N
Ph
1
N
1a
3a (42)
4-Me-C6H4
H4
Ph
4-Me-C6
PhCH]NPh
2a
N
Ph
2
3
N
1b
3b (38)
N
-F-C H
4
6
4
H4
Ph
4-F-C6
Ph
PhCH]NPh
2a
N
Ph
N
2. Results
1c
3c (43)
In the presence of FeCl2, 3-phenyl-2H-azirine (1a) reacts with
imine 2a giving imidazoles 3a and 4a (Scheme 2). The two imid-
azoles arise from two different azirine bond cleavages. The struc-
ture of imidazole 3a, corresponding to C]N cleavage, was assigned
on the basis of literature data.9a The structure of imidazole 4a,
corresponding to CeN cleavage, was also assigned on the basis of
literature data9b and further confirmed by comparison with data
from a sample prepared by an unambiguous synthetic procedure.9c
N
Ph
Ph
PhCH]NMe
2b
N
Me
4
N
1a
3d (29)
MeOOC
N
COOMe
1d
Ph
PhCH]NPh
2a
Ph
Ph
3e (65)
Ph
5
N
N
Ph
Ph
MCln
N
Ph
N
+
+
N Ph
N
Ph
Ph
a
Ph
N
Ph
Yields are given after purification by column chromatography.
Imidazoles arising from single bond CeN cleavage were not isolated except for
N
Ph
b
reaction of 1a with 2a.
2a
1a
3a
4a
In previous literature, intermolecular reactions of azirine and
imines were reported to proceed only via photochemical activation
giving imidazoles corresponding to the CeC bond cleavage10
whereas intramolecular reactions of iminoazirines lead to pyr-
azoles and involve CeN cleavage.2k We now found that use of Fe(III)
chloride allows reaction of azirine with imines via cleavage of C]N
bond.
The different behaviour of iron(II) and (III) chlorides in the
cleavage of azirine ring was also studied in reactions between
azirines and enaminoesters. With enaminoester 5a in the presence
of FeCl2 and FeCl3, 3-phenyl-2H-azirine (1a) gives pyrroles 6a and
6b in different ratios (Scheme 3) together with dimerization
products7 (Scheme 1).
Scheme 2. Reaction of azirine 1a and imine 2a.
Since, in principle, iron dichloride can act as Lewis acid or as
one-electron donor, the reaction of azirine 1a and imine 2a was also
performed in the presence of other Lewis acids as AlCl3 or FeCl3, in
different amounts. Imidazoles 3a and 4a are obtained in different
ratios as reported in Table 1. Azirine dimerization products are also
always present in variable amounts.
The best overall yields are obtained when iron(III) chloride is
used (Table 1, entries 6 and 7). All salts induce mainly the C]N
bond cleavage but iron(II) leads to the lowest 3a/4a ratio (Table 1,
entries 1 and 2) while aluminium and zinc salts induce only C]N
cleavage (Table 1, entries 3 and 4). The amount of iron(III) strongly
influences yields and ratios 3a/4a: 2 equiv are required to obtain
good overall yields and higher ratio 3a/4a (entries 5e7). A classical
Lewis acid, BF3$Et2O, did not give imidazoles even in traces.
Ph
COOEt
+
COOEt
Me
Me
+
Ph
OEt
FeCln
N
O
NH2
Me
Ph
N
H
N
H
Table 1
Reactions of azirines 1a with imine 2a with various promotersa
5a
6b
1a
6a
Entry Promoter Equiv MCln Yield (%) of 3a Yield (%) of 4a Ratio 3a/4a
Scheme 3. Reaction of azirine 1a and enaminoester 5a.
1
2
3
4
5
6
7
FeCl2
FeCl2(aq)
AlCl3
ZnCl2
FeCl3
FeCl3
FeCl3
1
1
1
1
0.5
1
2
13
22
15
18
21
42
65
11
21
d
d
15
12
9
1.2
1.0
Again two different cleavages may take place and pyrroles 6a
and 6b, corresponding, respectively, to the C]N and the CeN bond
cleavages, were formed. Both structures were assigned on the basis
of literature data.11,12 Yields of pyrroles 6a and 6b are reported in
Table 3.
1.4
3.5
7.2
a
Yields are given by HPLC analysis using internal standard.

S. Auricchio et al. / Tetrahedron 68 (2012) 7441e7449
7443
Table 3
Reactions of azirine 1a with enaminoester 5aa
Entry
Promoter
Yield (%) of 6a
Yield (%) of 6b
Ratio 6a/6b
1
2
FeCl2
FeCl3
4
18
17
1
0.24
18
a
Dimerization products, coming from the reaction of azirine 1a were also found
as by products in variable low yields.
Investigations were extended to more stable 2-substituted
azirine 1d. Yields increase significantly but only one cleavage oc-
curred and the unexpected pyrrolinones 7 were isolated. Reactions
of 2H-azirine 1d with enaminoesters 5a and 5b, carried out in the
presence of various salts give pyrroles 6c,d and pyrrolinones 7a,b in
very high overall yields (Scheme 4). Both products result from the
C]N cleavage and addition to the double bond of the enaminoester
with different regioselectivity. 3-Ylidene-pyrrolin-2-one de-
rivatives 7 are new molecules,13 never isolated before in reactions
of azirines. As their benzo-condensed analogues, namely methyl-
eneoxindoles, have pharmaceutical relevance,14 it appeared im-
portant to try to obtain also these products in good yield. The use of
different promoters leads to different ratios of products 7/6 as
reported in Table 4.
Fig. 1. A view of the molecular structure of 7b (thermal ellipsoids drawn at 40%
probability level) determined by X-ray diffraction.
performed at different temperatures as reported in Table 5. Both
the yields and the regioselectivity increase with increasing tem-
perature (entry 4).
COOMe
Ph
R
Ph
MeOOC
COOEt
Ph
NH2
N
1d
+
Table 5
R
MeOOC
O
Reactions of azirine 1d with enaminoester 5a in the presence of FeCl3 in acetonitrile
N
H
N
H
MCln
OEt
Entry Temp (ꢀC) Yield (%) of 6c Yield (%) of 7a Overall yield (%) Ratio 7a/6c
+
6c,d
1
2
3
4
rt
12
24
25
25
14
44
48
55
26
68
73
80
1.2
1.8
1.9
2.2
7a,b
R
40
60
80
c: R = Me
d: R = Ph
a: R = Me
b: R = Ph
NH2
O
a: R = Me
b: R = Ph
5a, b
Scheme 4. Reaction of azirine 1d and enaminoesters 5.
No significant change in yields of products 6c and 7a was found
modifying the concentration of azirine 1d.
The last investigated reaction involves azirine 1d with enami-
nones 8aec in the presence of FeCl3 and AlCl3 giving pyrroles in
good overall yields.(Scheme 5, Table 6).
Table 4
Reactions of azirine 1d with enaminoesters 5a,b
Entry
5
Promoter Solvent Yield of products by C]N cleavage (%)
a
1
2
3
4
5
6
5a
5a
5a
5a
FeCl2
FeCl3
AlCl3
ZnCl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
6c (25)
6c (25)
6c (11)
6c (32)
6d (26)
6c (Traces)
7a (35)
7a (55)
7a (72)
7a (23)
7b (68)
7a (Traces)
HN
O
Ph
Ph
MeOOC
COOMe
Ph
R2
R1
R2
R1
N
1d
5b AlCl3
5a AlCl3
+
N
H
MeOOC
N
H
a
Side products, coming from reaction of azirine 1d (Scheme 1, b) were also found
MCln
R2
9a
+
as in low and variable yields.
10a-d
R1
Ph
The structure of pyrrole 6c was assigned on the basis of litera-
ture data,15 while the structures 7a,b were determined by standard
analytic methods. In particular the molecular structure of 7b was
unambiguously determined through X-ray single crystal analysis16
(Fig. 1). The stereochemistry of the exocyclic double bond is un-
ambiguously assigned and an intramolecular H-bond between
aminic hydrogen and the carbonyl oxygen is apparent.
The overall yields and the regioselectivity of the addition of the
azirine 1d to the carbonecarbon double bond of enaminoester 5a
is affected by the metal salt used: the best yields and higher se-
lectivity are obtained when AlCl3 is used (Table 4: entries 1e4),
while we found a reverse selectivity when ZnCl2 is used (Table 4:
entry 4).
+
NH2
O
MeOOC
Ph
N
H
8a-c
11
Scheme 5. Reaction of azirine 1d and enaminones 8.
The synthesis of pyrroles 9, 10 and 11 from reaction of azirine 1d
with enaminones occurs, as observed for the reaction with enam-
inoesters in the presence of non-reducing Lewis acids, only with
the C]N bond cleavage in the azirine ring.
When R1 and R2 are phenyl groups (Table 6, entries 1 and 2)
three products are formed: 9a, 10a and 11. Iminopyrrole 9a was
isolated, together with pyrrole 10a, despite the acidic condition of
reaction and work up. Pyrrole 10a can actually arise from a different
attack on the carbonecarbon double bond of enaminone or from
hydrolysis of 9a. 4H-Pyrrole 11 arises from decarbonylation of
Enaminoester 5b (R¼Ph) gives also both pyrrole 6d and pyrro-
linone 7b in very good overall yields (Table 4, entry 5) but with less
selectivity than derivative 5a (R¼Me). Reactions were also

7444
S. Auricchio et al. / Tetrahedron 68 (2012) 7441e7449
Table 6
but in some cases, when the conformational restrictions, steric
Reactions of 1d with enaminones 8aec in acetonitrile
hindrance, polar effects or stabilizing groups (e.g., benzylic) are
present, attack at nitrogen18 is possible. Addition of alkyl radicals
to imines has been studied in the presence of ZnEt2 and both
addition at the carbon atom and at the nitrogen atom of the C]N
bond was observed.19 In Scheme 6, route b, the radical attack to
the nitrogen atom is justified both by the benzylic stabilization in
structure 17 and by subsequent cyclization to intermediate 18
with electron transfer to the neighbouring metal.
Entry
8
MCln Yield (%)
of pyrroles
Overall
yield (%)
1
2
3
4
5
8a R1¼R2¼Ph
8b R1¼R2¼Me
FeCl3 11 (18)
AlCl3 9a (51)
FeCl3
9a (37)
10a (22) 11 (Traces) 73
10b (57)
10a (42)
97
57
65
8c R1¼Me; R2¼Ph FeCl3 10c (45) 10d (11) 11 (9)
AlCl3 10c (57) 10d (4)
11 (Traces) 61
When reactions of azirines with imines are performed with
non-reducing Lewis acids as AlCl3 or ZnCl2, only the imidazole
isomer 3 is formed (Table 1, entry 3) and, as found for FeCl2, only
route a of Scheme 6 is viable. When FeCl3 is used, imidazole 3 is
indeed the main product, especially if Fe(III) is used in large
amount. Traces of Fe(II) are unavoidably present but become less
influent as amounts of iron(III) increase as shown by the different
3a/4a ratios obtained (Table 1, entries 5e7).
The same reactivity was discovered when azirine 1a reacts with
enaminoesters in the presence of iron(II) and iron(III). Two pyrroles
are formed (Scheme 3) consistently again with two possible dif-
ferent ring cleavages. When FeCl2 is used route b of Scheme 6 is
possible and the main product comes by single bond CeN cleavage
(Table 3, entry 1, ratio 6a/6b¼0.24); at variance, with FeCl3, the
main product arises by double bond C]N cleavage (Table 3, entry 2,
ratio 6a/6b¼18).
pyrrole 10a. Aluminium trichloride (entry 2) induces more selec-
tivity, favours the formation of pyrrole 9a and minimizes the for-
mation of 11.
When R1 and R2 are methyl groups (Table 6, entry 3) the reaction
leads only to pyrrole 10b. In this case the imino derivative of 10b
was not isolated as it probably hydrolyses easily.
When R1 and R2 are different groups (Table 6, entries 4 and 5),
addition of azirine to carbonecarbon double bond of enaminones
takes place with different regioselectivity and pyrroles 10c and 10d
are obtained together with pyrrole 11.
3. Discussion
We found that FeCl2 promotes reactions of azirines with imines
leading to two different isomers: imidazoles 3 and 4 (Table 1, en-
tries 1 and 2) corresponding to two different ring cleavages. Iron(II)
can play different roles acting both as Lewis acid and as single
electron donor.
We suggest that FeCl2 really exhibits both roles in the mecha-
nism that leads to formation of 3 and 4 by two different pathways
after an initial N-donor complexation to give intermediate 12a as
outlined in Scheme 6. Azirine complexes with various metals are
reported in the literature.1f,2k,17
When a more stable azirine as 1d is used, overall yields increase
(Table 4, entries 1e5). In this case FeCl3 and AlCl3 proved to be very
efficient agents in promoting C]N cleavage. We propose that the
mechanism that leads to the formation of pyrroles and pyrrolinones
from azirine 1d (Schemes 4 and 5, Tables 4e6), promoted by metal
salts is, in this case, exclusively ionic and radical addition does not
play any role. Indeed the properties of zinc chloride and aluminium
chloride offer little scope for rationalisation based on redox pathways
+
Ar
Ar
Ar
C
Ar
C+
-H2
R
N
NH
N
N
R
Ar
+
N
NH
N
R
R
+ NH
a
Fe(II)
Ph
C
-FeCl2
Fe(II)
N
Ph
Fe(II)
Ph
Ph
14
3
13
15
Fe(II)
b
12a
Ar
.
CH2
Ar
Ar
R
-H2
Ar
HN
N
+
N
N
N
N
R
N
HN
-FeCl2
R
R
Ph
Fe(III)
CH
Ph
Ph
.
Fe(II)
Fe(III)
Ph
17
18
16a
4
Scheme 6. Proposed mechanism for reaction of azirines with imines.
When iron(II) acts as a Lewis acid (route a) imidazole 3 is
formed through attack of imine to intermediate 13 and formation
of intermediates 14 and 15. When Fe(II) acts as one-electron donor
(route b) isomeric imidazole 4 is formed. In the proposed mech-
anism (route b), the radical addition of intermediate 16a occurs at
the iminic nitrogen and leads to 17 that, after cyclization to in-
termediate 18, can afford imidazole 4 by loss of hydrogen and
hydrolysis. We have already proposed in previous work7 that
radical intermediates like 16a play a key role in azirines’ di-
merizations and in reactions of azirines with alkenes. Usually,
radical addition to C]N iminic bond occurs at the carbon atom,
(Table 4, entries 3e5). On the contrary, when Fe(II) is used, formation
of radical intermediate 16b (Scheme 7) is possible. This intermediate
obtained by the initial electron transfer, however, evolves to enami-
noester 19 rather than reacting with another molecule.
Products arising from reduction of azirine 1d are always present
in the crude,6 and only the use of non-reducing Lewis acids as
promoters increases yields (Table 4, entries 2e5) avoiding the for-
mation of reduction and dimerization side products.
Surprisingly pyrrolinones and iminopyrroles are obtained be-
side pyrroles through the same C]N cleavage. Both products arise
from attack of azirine to enaminoesters or enaminones double

S. Auricchio et al. / Tetrahedron 68 (2012) 7441e7449
7445
equilibrium from enaminic form 5 or 8 (Scheme 8, route a) to iminic
form 50 or 80 (Scheme 8, route b) as reported in literature.21 The
proposed mechanism explains also the results obtained in the re-
action of azirine 1d with different substituted enaminoesters 5a
and 5b. When R¼Ph (5b), intermediates formed via route b are
more stabilized and therefore the 6d/7b ratio (Table 5, entry 5,
ratio¼0.38) is greater than the corresponding 6c/7a ratio obtained
from 5a (R¼Me) (Table 5, entry 3, ratio¼0.15).
.
Ar
COOMe
Fe(III)/H2O
CH
Ar
O
Ar
O
OMe
N
NH
OMe
NH2
19
Fe(III)
Fe(II)
16b
12b
Scheme 7. Reduction of azirine 1d.
bonds with different regioselectivity, the product ratio depending
upon the specific salt used and the temperature.
4. Conclusion
In order to explain these results we suggest that the azirine
complex 12b undergoes nucleophilic attack by the enaminic double
bond (Scheme 8), to give intermediates 20 or 21, which can afford
the different products 22 or 23 depending upon the different
intramolecular linkage with nitrogen (route a) or oxygen (route b).
The role of azirine metal complexes as key intermediates is in
agreement with the non-occurrence of the reaction when per-
formed in DMF, a solvent able to give coordination highly com-
petitive with respect to azirines (Table 4, entry 6).
The different intermediates of the two routes can account for
the different regioselectivity induced by metals. Oxophilic metals
such as iron(III) and especially aluminium favour the formation of
intermediates 23 and 24 that then afford pyrrolinones 7 and imi-
nopyrrole 9a (Table 4, entries 2,3 and 5; route b); pyrrole 10 can
arise from hydrolysis of 9a. The azophilic metal zinc favours the
formation of intermediates 22 and 25 that afford pyrroles as for
instance 6 (Table 4, entry 4; route a).20
These results clarify the role of some metal salts in reactions of
azirines with imines, enaminoesters and enaminones. The use of
FeCl3 allows the synthesis of imidazoles by cleavage of the azirine
C]N bond, never achieved before with other methods. Up to now,
reactions of azirines with enaminoesters or enaminones were
known not to occur or to occur with low yields.15 In the present
investigation we found that azirines such as methyl 3-aryl-2H-
azirine-3-carboxylate, and electron-poor enaminocarbonyl com-
pounds react under these conditions. In particular, the synthesis of
nitrogen heterocycles from azirines and enaminoesters or enami-
nones without loss of nitrogen atoms giving, respectively, pyrroli-
nones or iminopyrroles can be achieved. Although in fact pyrroles
can be obtained from reaction of azirines, or even from vinyl azides
with 1,3-dicarbonyl compounds, it was by no mean obvious that
pyrrolinones and iminopyrroles can be synthesized by these
reactions.5a,22
The dual role of FeCl2 in reactions of azirines with imines ex-
plains the variety of obtained products. The formation of azirine
complexes followed by the attack of two tautomeric forms of
Selectivity 7/6 increases as temperature increases (Table 5, en-
tries 1e4). This is in agreement with the shift of tautomeric
R2
R2
Ph
R2
O
O
C+
R2
Ph
R1
R1
Ph
O
C+
-NH3
R3
C+
N
O
Ph
[MCln]-
R3
H2N
N
[MCln]-
22
H2N
NH
R1
N
H
R3
R2
-
N
H
R3
R1
[MCln]
MCl
25
a
O
20
6c,d; 10a-d
-R2CONH2
- MCln
Ph
NH2
R1
5; 8
R3
Ph
R1
R3
N
H
N
+
11
[MCln]
R1
R1
R1
12b
Ph
H2N
O
Ph
NH
OH
R3
O
R3
N
N
H
R2
H
b
R2
5'; 8'
10
7a,b
R1
R1
H2O
R2 = OEt
-NH3
- MCln
-EtOH
R1
HN
HO
HN
C+
HO
Ph
Ph
R2
R1
R2
C+
R3
Ph
R3
R2 = Me,Ph
HN
R2
Ph
HN
C+
N
N
[MCln]-
[MCln]-
R3
O
[MCln]-
- MCln -H2O
N
H
N
H
R3
R2
21
9a
23
24
Scheme 8. Proposed mechanism for the reactions with enaminones.

7446
S. Auricchio et al. / Tetrahedron 68 (2012) 7441e7449
enaminoesters or enaminones explains the different reactivity and
leads to the formation of pyrrolinones and pyrroles.
5.3.1. Reaction of 3-phenyl-2H-azirine (1a) and N-benzylideneaniline
(2a) with Fe(III). Column chromatography on silica gel (n-hexane/
ethyl acetate) gives 1,2,4-triphenyl-1H-imidazole (4a; 66 mg, 5%)
and 1,2,5-triphenyl-1H-imidazole (3a; 535 mg, 42%).
Synthesis of nitrogen heterocycles has always been a challeng-
ing goal and the use of azirines as building blocks for the prepa-
ration of pyrroles or imidazoles has always stimulated and still is of
great interest.23 Although reactions of azirines in the presence of
metal complexes or Lewis acids have been studied profusely,2,5
often by use of expensive metal complexes, we found that the
use of common, inexpensive and readily available iron and alu-
minium salts in azirines reactions has not been sufficiently
exploited and makes novel syntheses possible. The azirine ring has
again proven a very useful precursor of other compounds of the
nitrogen heterocyclic class.
Compound 4a: Rf (30% ethyl acetate/n-hexane) 0.42; 1H NMR
(250 MHz, CDCl3, 25 ꢀC):
d
7.20e7.34 (m, 6H), 7.35e7.52 (m, 8H),
7.84e7.96 (m, 2H); 13C NMR (62.9 MHz, CDCl3, 25 ꢀC):
d
118.5, 125.0,
125.8, 127.0, 128.2, 128.4, 128.6, 128.8, 129.4, 130.1, 133.7, 138.4,
141.6, 146.9.
Compound 3a: Rf (30% ethyl acetate/n-hexane) 0.19; 1H NMR
(250 MHz, CDCl3, 25 ꢀC):
d
7.02e7.15 (m, 4H), 7.17e7.42 (m, 12H);
13C NMR (62.9 MHz, CDCl3, 25 ꢀC):
d
127.4, 127.9, 128.1, 128.2,
128.48, 128.53, 128.8, 129.4, 129.7, 130.4, 135.1; 137.1, 147.9.
5. Experimental section
5.3.2. Reaction of 3-(p-tolyl)-2H-azirine (1b) and N-benzylidenani-
line (2a) with Fe(III). Column chromatography on silica gel (n-
hexane/ethyl acetate) gave imine 2a (73 mg, 9%), 2,5-di-p-tolyl-
pyrazine26 (85 mg, 15%); Rf (20% ethyl acetate/n-hexane) 0.56 and
1,2-diphenyl-5-(4-methylphenyl)imidazole27 (3b; 510 mg, 38%); Rf
(20% ethyl acetate/n-hexane) 0.11.
5.1. General experimental section
NMR spectra were determined with TMS as internal standard, on
a Bruker 250 MHz or on a 400 MHz instrument. MS spectra were
performed on a Finnigan TSQ 70 instrument. GCeMS analyses were
performed on a Agilent 6890 gas-chromatograph equipped with
5.3.3. Reaction of 3-(4-fluorophenyl)-2H-azirine (1c) and N-benzy-
lideneaniline (2a) with Fe(III). Column chromatography on silica gel
(n-hexane/ethyl acetate) gave 1,2-diphenyl-5-(4-fluorophenyl)im-
idazole (3c; 580 mg, 43%).
a
5973 mass-detector, using
a
HP5MS column (30 mꢁ0.25
mmꢁ0.25 m); the following temperature program was employed:
m
40 ꢀC (10)//2 ꢀC/min//45 ꢀC (10)//10 ꢀC/min//200 ꢀC (10)//20 ꢀC/min//
280 ꢀC (100). IR spectra were registered with a Perkin Elmer 257 in-
strument or with a Nicolet Nexus FTIR spectrometer. Chromato-
graphic separations were performed using Merck Kieselgel 60 silica
gel. Melting points were determined with a Buchi 535 instrument and
are uncorrected. HPLC analyses were performed on Varian 9010
equipped with a diode array detector. Azirines 1aec were prepared by
thermal reaction of the corresponding azides.24 Azirine 1d was pre-
pared from the corresponding isoxazole.6 Imines 2a,b and enami-
noester 5a were purchased from Aldrich. Enaminoester 5b and
enaminones 8aec were prepared from the corresponding ketoester
and diketones according to standard literature procedures.25
Compound 3c: white solid (MeOH), mp 238e240 ꢀC. Rf (50%
ethyl acetate/n-hexane) 0.35; FTIR (ATR) 1492, 1222, 1159 cmꢂ1; 1H
NMR (250 MHz, CDCl3, 25 ꢀC):
d
6.84e7.16 (m, 6H), 7.16e7.48 (m,
115.3 (d, J¼21.1 Hz);
13
9H); C NMR (100.6 MHz, CDCl3, 25 ꢀC):
d
126.0 (d, J¼3.0 Hz), 128.1, 128.16, 128.21, 128.3, 128.6, 128.8, 129.4,
130.3 (d, J¼8.3 Hz), 130.6, 134.1, 137.1, 148.1, 162.1 (d, J¼247.7 Hz);
MS: m/z 314 Mþ, (100). Elemental analysis for C21H15FN2: calcd. C
80.24, H 4.81, F 6.04, N 8.91; found C 80.44, H 4.83, F 6.01, N 8.86.
5.3.4. Reaction of 3-phenyl-2H-azirine (1a) and N-benzylideneme-
thylamine (2b) with Fe(III). Column chromatography on silica gel
(n-hexane/ethyl acetate) gave 2,5-diphenyl-pirazine28 (27 mg, 5%)
[Rf (30% ethyl acetate/n-hexane) 0.47] and 1-methyl-2,5-diphenyl-
1H-imidazole29 (3d; 290 mg, 29%) [Rf (30% ethyl acetate/n-hexane)
0.10].
5.2. General procedure for the reaction of 3-phenyl-2H-
azirine (1a) and N-benzylideneaniline (2a) with different
promoters
To a solution of azirine 1a (504 mg, 4.30 mmol) in CH3CN
(43 mL), kept under stirring and under nitrogen, imine 2a (780 mg,
4.30 mmol) and the different promoters were added. After total
conversion of azirine 1a (from 2 to 6 h except for reaction with
ZnCl2, which required 48 h) the crude was evaporated, washed
with aq HCl 4 M or aq NaHCO3 (when AlCl3 or ZnCl2 were used as
promoters), extracted with CH2Cl2 and analysed by HPLC. Promoter,
corresponding amount and yields are given in Table 1. Imidazoles
1,2,4-triphenyl-1H-imidazole9b (4a) and 1,2,5-triphenyl-1H-imi-
dazole9a (3a) were then purified by column chromatography on
silica gel (n-hexane/ethyl acetate).
5.3.5. Reaction of azirine 1d and N-benzylidenaniline (2a) with
Fe(III). Column chromatography on silica gel (n-hexane/ethyl ace-
tate) gave unconverted azirine 1d (110 mg, 15%) [Rf (50% ethyl ac-
etate/n-hexane) 0.53] and methyl 1,2,5-triphenyl-1H-imidazole-4-
carboxylate (3e; 990 mg, 65%).
Compound 3e: solid (ethyl acetate), mp 209e210 ꢀC; Rf (50%
ethyl acetate/n-hexane) 0.24; FTIR (ATR) 1717, 1213, 1145 cmꢂ1; 1H
NMR (250 MHz, CDCl3, 25 ꢀC):
d
3.86 (s, 3H), 6.94e7.03 (m, 2H),
7.15e7.35 (m, 11H), 7.35e7.44 (m, 2H); 13C NMR (62.9 MHz, CDCl3,
25 ꢀC):
51.7, 127.7, 128.1, 128.2, 128.65, 128.71, 128.8, 128.9, 129.18,
d
129.24, 129.5, 129.6, 130.8, 136.2, 140.4, 147.5, 163.6 ppm. EIMS: m/z
355 (26), 354 (Mþ, 100), 323 (36), 322 (25), 295 (45), 180 (81), 165
(25). Elemental analysis for C23H18N2O2: calcd. C 77.95, H 5.12, N
7.90; found C 78.26, H 5.13, N 7.87.
5.3. General procedure for the reaction of azirine 1aed with
imines 2a,b with iron trichloride
To a solution of azirines 1aed (4.30 mmol) in CH3CN (43 mL),
kept under stirring and under nitrogen, imine 2a or 2b (4.30 mmol)
and FeCl3 (1.39 g, 8.6 mmol) were added and reaction kept at room
temperature. After total conversion of azirines 1aec (from 2 to
24 h) or conversion of imine for reaction of 1d (48 h), solvent is
evaporated and 40 mL of HCl 4 M were added to the crude. The
mixture was extracted with CH2Cl2, washed with aq NaHCO3 2%,
concentrated and dried over Na2SO4. The crude was purified by
column chromatography on silica gel (n-hexane/ethyl acetate) to
afford the corresponding imidazoles 3aee.
5.4. General procedure for the reaction of azirine 1a with
ethyl 3-aminocrotonate (5a) with different promoters
To a solution of azirine 1a in anhydrous CH3CN, enaminoester 5a
and FeCl2 or FeCl3 were added. The mixture was stirred under N2
atmosphere at room temperature. After 2e3 h dichloromethane
and a solution of aq HCl 0.1 M were added to the reaction mixture.
The organic layer was washed with aq NaHCO3 5%, with H2O, dried
and concentrated.

S. Auricchio et al. / Tetrahedron 68 (2012) 7441e7449
7447
5.4.1. Reaction of 3-phenyl-2H-azirine (1a) with ethyl 3-
1448, 1263 cmꢂ1
;
1H NMR (250 MHz, CDCl3, 25 ꢀC):
d
0.86 (t,
aminocrotonate (5a) and iron dichloride. To a solution of azirine
1a (433 mg, 3.70 mmol) in anhydrous CH3CN (37 mL), enami-
noester 5a (1.926 g, 14.91 mmol) and FeCl2 (491 mg, 3.87 mmol)
were added. After 3 h and work up, the crude was purified by
column chromatography (n-hexane/ethyl acetate from 95:5 to 1:1)
to give ethyl 2-methyl-5-phenyl-pyrrole-3-carboxylate12 (6b;
142 mg, 17%) [Rf (50% ethyl acetate/n-hexane) 0.49] and ethyl 2-
methyl-4-phenyl-pyrrole-3-carboxylate11 (6a; 37 mg, 4%) [Rf (50%
ethyl acetate/n-hexane) 0.27].
J¼7.0 Hz, 3H), 3.67 (s, 3H), 3.96 (q, J¼7.0 Hz, 2H), 7.30e7.70 (m,
13
10H), 9.30 (br s, 1H) ppm; C NMR (62.9 MHz, CDCl3, 25 ꢀC):
d
13.5, 51.6, 60.0, 114.9, 119.2, 127.2 (two overlapped signals), 128.3,
128.9, 129.0, 129.9, 131.1, 133.5, 134.3, 139.0, 161.4, 164.5 ppm.
EIMS: m/z 350 (21), 349 (Mþ, 100), 317 (44), 304 (22), 289 (28),
272 (86), 271 (38), 245 (21), 216 (40), 189 (41). Elemental analysis
for C21H19NO4: calcd. C 72.19, H 5.48, N 4.01; found C 72.22, H
5.50, N 3.99.
Compound 7b: yellow solid (EtOH), mp 259e260 ꢀC; Rf (ethyl
acetate) 0.29; IR (KBr) 3431, 1712, 1639, 1551, 1486, 1282 cmꢂ1 1H
;
5.4.2. Reaction of 3-phenyl-2H-azirine (1a) with ethyl 3-
aminocrotonate (5a) and iron trichloride. To a solution of 1a
(406 mg, 3.47 mmol) in anhydrous CH3CN (35 mL), enaminoester
5a (1.789 g, 13.85 mmol) and FeCl3 (563 mg, 3.47 mmol) were
added. After 2 h and work up, the crude was purified by column
chromatography (n-hexane/ethyl acetate from 95:5 to 1:1) to give
ethyl 2-methyl-5-phenylpyrrole-3-carboxylate (6b; 9 mg, 1%) and
ethyl 2-methyl-4-phenylpyrrole-3-carboxylate (6a; 144 mg, 18%).
NMR (250 MHz, CDCl3, 25 ꢀC):
6.80e7.20 (m, 10H), 7.94 (br s, 1H), 10.74 (br s, 1H) ppm; 1H NMR
(250 MHz, DMSO-d6, 25 ꢀC):
3.46 (s, 3H), 6.70e7.20 (m, 10H), 8.71
(br s, 1H), 10.21 (s, 1H), 10.76 (br s, 1H) ppm; 13C NMR (62.9 MHz,
DMSO-d6, 25 ꢀC):
50.6, 101.1, 114.3, 125.6, 126.1, 127.1, 128.0, 128.4,
129.2, 130.0, 133.3, 133.9, 160.3, 165.7, 166.9 ppm; EIMS: m/z 321
(23), 320 (Mþ, 100), 287 (37), 232 (26), 231 (22). Elemental analysis
for C19H16N2O3: calcd. C, 71.24, H 5.03, N 8.74; found: C 71.23, H
5.05, N 8.71.
d 3.62 (s, 3H), 5.78 (br s, 1H),
d
d
5.5. General procedure for the reaction of azirine 1d with
ethyl 3-aminocrotonate 5a with different promoters
5.6.1. Crystal data and structure refinement for 7b. Crystals of 7b
suitable for single crystal X-ray diffraction were obtained by slow
evaporation of an ethyl alcohol solution. Data were collected on
To a solution of 2-carbomethoxy-phenylazirine 1d (400 mg,
2.28 mmol) in appropriate anhydrous solvent (23 mL), ethyl 3-
aminocrotonate 5a (890 mg, 6.89 mmol) and the promoter
(2.28 mmol) were added. The mixture was stirred under N2 at-
mosphere at 80 ꢀC (or lower temperatures as specified in Table 5).
After 3 h dichloromethane and a solution of aq HCl 0.1 M were
added to the reaction mixture. The organic layer was washed with
aq NaHCO3 5%, with H2O and dried upon Na2SO4. By concentration,
a yellow solid precipitated and the solid was filtered to give 7a.
The residue was purified by column chromatography on silica gel
(from n-hexane/ethyl acetate 8:2 to ethyl acetate/methanol 1:1)
to give 4-ethyl 2-methyl 5-methyl-3-phenyl-1H-pyrrole-2,4-
dicarboxylate15 6c [Rf (50% ethyl acetate/n-hexane) 0.46] and (Z)-
methyl 4-(1-aminoethylidene)-5-oxo-3-phenyl-4,5-dihydro-1H-
pyrrole-2-carboxylate 7a. Yields are reported in Tables 4 and 5.
Compound 7a: yellow solid (EtOH), mp 254e255 ꢀC; Rf (ethyl
a Bruker P4 diffractometer at room temperature, using graphite
ꢀ
monochromated Cu-K
a
radiation (
l
¼1.54178 A) and
u/2q scans. No
absorption correction was deemed necessary. C19H16O3N2,
Mr¼320.34, monoclinic, space group C2/c (no. 15), a¼23.6370(13),
3
ꢀ
ꢀ
b¼9.9330(5), c¼17.3870(13) A,
b
¼127.350(6)ꢀ, V¼3245.1(3) A ,
Z¼8, Dc¼1.311 Mg mꢂ3
,
m
¼0.734 mmꢂ1, F(000)¼1344; 3328 re-
flections (2735 unique, Rint¼0.0248). The final refinement, for 231
refined parameters converged to wR(F2)¼0.1584 (R¼0.0612) for
2735 unique reflections and to wR(F2)¼0.1517 (R¼0.0551) for 2372
unique reflections with I>2s(I), with a final goodness of fit of 1.059.
The structure was solved by direct methods and refined by full-
matrix least squares using the SHEXTL v2011.4-1 suite of pro-
grams.16 Non-hydrogen atoms were treated anisotropically. Stan-
ꢀ
dard distances of 0.96 and 0.93 A were used, respectively, for
aliphatic and aromatic CeHs, whereas hydrogen atoms bound to
nitrogen atoms were located by Fourier methods and refined.
Crystallographic data for 7b have been deposited with the Cam-
bridge Crystallographic Data Centre. Copies of the data can be
obtained, free of charge, on application to The Director, CCDC
871184, Union Road, Cambridge CB2 1EZ, UK. Fax: þ44 1223 336033
or email: deposit@ccdc.cam.ac.uk.
acetate) 0.13; IR (KBr) 3322, 1676, 1616, 1418, 1296, 1167 cmꢂ1
NMR (400 MHz, DMSO-d6, 25 ꢀC):
1.56 (s, 3H), 3.43 (s, 3H),
7.15e7.25 (m, 2H), 7.27e7.40 (m, 3H), 8.54 (br s, 1H), 9.88 (s, 1H),
10.62 (br s, 1H) ppm; 13C NMR (62.9 MHz, DMSO-d6, 25 ꢀC):
19.6,
;
1H
d
d
50.5, 101.7, 113.3, 126.9, 127.5, 128.9, 129.6, 136.0, 160.4, 165.8 ppm;
EIMS: m/z 259 (21), 258 (Mþ, 100), 225 (40), 169 (24). Elemental
analysis for C14H14N2O3: calcd. C 65.11, H 5.46, N 10.85; found C
65.36, H 5.44, N 10.81.
5.7. General procedure for the reaction of azirine 1d with
enaminones 8aec
5.6. Reaction of azirine 1d with ethyl 3-amino-3-
phenylacrylate (5b)
To a solution of azirine 1d in anhydrous CH3CN, enaminone 8
and FeCl3 or AlCl3 were added. The mixture was stirred under N2
atmosphere at 80 ꢀC. After 30e90 min dichloromethane and a so-
lution of aq HCl 0.1 M were added to the reaction mixture. The
organic layer was washed with aq NaHCO3 5%, with H2O, dried and
concentrated. The yields are given in Table 6.
To a solution of 2-carbomethoxy-phenylazirine (1d; 400 mg,
2.28 mmol) in anhydrous acetonitrile (23 mL), enaminoester 5b
(1.36 g, 7.11 mmol) and AlCl3 (310 mg, 2.32 mmol) were added. The
mixture was stirred under N2 atmosphere at 80 ꢀC. After 6 h water
and CH2Cl2 were added and the mixture washed with aq NaHCO3 10%
and then with water. The organic layer was separated and dried upon
Na2SO4. By concentration a yellow solid precipitated and the solid
was filtered to give 7b. The residue was purified by column chro-
matography (n-hexane/ethyl acetate and ethyl acetate/methanol) to
give 4-ethyl 2-methyl 3,5-diphenyl-1H-pyrrole-2,4-dicarboxylate
(6d; 210 mg, 26%), and (Z)-methyl 4-(amino(phenyl)methylene)-5-
oxo-3-phenyl-4,5-dihydro-1H-pyrrole-2-carboxylate (7b) that was
combined with the precipitate (500 mg, 68%).
5.7.1. Reaction of azirine 1d with 3-amino-1,3-diphenylprop-2-en-1-
one (8a). To a solution of azirine 1d (455 mg, 2.60 mmol) in anhy-
drous CH3CN (23 mL), enaminone 8a (697 mg, 3.12 mmol) and FeCl3
or AlCl3 (3.12 mmol)wereadded. After 90 minand work up, thecrude
was purified by column chromatography (n-hexane/ethyl acetate
from 95:5 to 2:8), to give methyl 3,5-diphenyl-1H-pyrrole-2-
carboxylate (11)15 [Rf (50% ethyl acetate/n-hexane) 0.57], methyl
4-benzoyl-3,5-diphenyl-1H-pyrrole-2-carboxylate (10a) and methyl
4-(imino(phenyl)methyl)-3,5-diphenyl-1H-pyrrole-2-carboxylate
(9a). The yields are given in Table 6.
Compound 6d: white solid (ethyl acetate), mp 161e162 ꢀC; Rf
(50% ethyl acetate/n-hexane) 0.47; IR (KBr) 3445, 3297, 1719, 1675,

7448
S. Auricchio et al. / Tetrahedron 68 (2012) 7441e7449
Compound 10a: pale yellow crystals (EtOH), mp 168e169 ꢀC; Rf
Supplementary data
(50% ethyl acetate/n-hexane) 0.46; IR (KBr) 3280, 1696, 1651, 1447,
1258 cmꢂ1
;
1H NMR (250 MHz, CDCl3, 25 ꢀC):
d
3.68 (s, 3H),
7.05e7.75 (m, 15H), 9.75 (br s, 1H) ppm; 13C NMR (62.9 MHz, CDCl3,
25 ꢀC):
51.6, 118.7, 123.2, 127.2, 127.3, 127.8, 128.0, 128.6 (two
1H and 13C NMR spectra for compounds 3a, 3c, 3e, 4a, 7a, 6d, 7b,
10a, 9a, 10c and 10d. Supplementary data related to this article can
be found online at http://dx.doi.org/10.1016/j.tet.2012.06.069.
d
overlapped signals), 129.7, 130.2, 130.4, 132.5, 132.9, 133.1, 136.9,
138.1, 161.7, 193.8 ppm. EIMS: m/z 381 (Mþ, 86), 349 (27), 273 (20),
272 (100), 216 (21), 189 (31), 174 (21). Elemental analysis for
C25H19NO3: calcd. C 78.72, H 5.02, N 3.67; found: C 78.93, H 5.04, N
3.69.
References and notes
1. (a) Padwa, A. Adv. Heterocycl. Chem. 2010, 99, 1e31; (b) Padwa, A. In Compre-
hensive Heterocyclic Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V.
, Taylor, R. J. K., Eds.; Elsevier: Oxford, UK, 2008; Vol. 1; Chapter 1, pp 1e104; (c)
Palacios, F.; Ochoa de Retana, A. M.; Martinez de Marigorta, E.; de los Santos, J.
M. J. Org. Prep. Proc. Int. 2002, 34, 219e269; (d) Palacios, F.; Ochoa de Retana, A.
M.; Martinez de Marigorta, E.; de los Santos, J. M. Eur. J. Org. Chem. 2001,
2401e2414; (e) Gilchrist, T. L. Aldrichimica Acta 2001, 51e55; (f) Heimgartner, H.
Angew. Chem., Int. Ed. Engl. 1991, 30, 238e264; (g) Padwa, A.; Woolhouse, A. D.
In Comprehensive Heterocyclic Chemistry I; Katritzky, A. R., Rees, C. W., Lwowski,
W., Eds.; Pergamon: Oxford, UK, 1984; Vol. 7; Chapter 5, pp 47e93; (h) Nair, V.
In The Chemistry of Heterocyclic Compounds; Hassner, A., Ed.; Wiley: New York,
NY, 1983; Vol. 42; Chapter 2, part 1, pp 215e332.
2. (a) Alper, H.; Prickett, J. E.; Wollowitz, S. J. Am. Chem. Soc. 1977, 99, 4330e4333;
(b) Bader, H.; Hansen, H.-J. Helv. Chim. Acta 1978, 61, 286e304; (c) Candito, D. A.;
Lautens, M. Org. Lett. 2010, 12, 3312e3315; (d) Stevens, K. L.; Jung, D. K.; Alberti,
M. J.; Badiang, J. G.; Peckham, G. E.; Veal, J. M.; Cheung, M.; Harris, P. A.;
Chamberlain, S. D.; Peel, M. R. Org. Lett. 2005, 7, 4753e4756; (e) Izumi, T.; Alper,
H. Organometallics 1982, 1, 322e325; (f) Alper, H.; Perera, C. P.; Ahmed, F. R. J. Am.
Chem. Soc. 1981, 103, 1289e1291; (g) Isomura, K.; Uto, K.; Taniguchi, H. J. Chem.
Soc., Chem. Commun. 1977, 664e665; (h) Padwa, A.; Stengel, T. Tetrahedron Lett.
2004, 45, 5991e5993; (i) Nitta, M.; Kobayashi, T. J. Chem. Soc., Perkin Trans. 11985,
1401e1406; (j) Alper, H.; Prickett, J. E. Inorg. Chem. 1977, 16, 67e71; (k) Faria dos
Santos Filho, P.; Schuchardt, U. J. Organomet. Chem. 1984, 263, 385e393.
3. (a) Dietliker, K.; Heimgartner, H. Helv. Chim. Acta 1983, 66, 262e295; (b) De-
moulin, A.; Gorissen, H.; Hesbain-Frisque, A.-M.; Ghosez, L. J. Am. Chem. Soc.
1975, 97, 4409e4410.
Compound 9a: pale yellow crystals (EtOH), mp 180e181 ꢀC; Rf
(50% ethyl acetate/n-hexane) 0.33; IR (KBr) 3267, 1695, 1676, 1446,
1292, 1271 cmꢂ1
;
1H NMR (250 MHz, DMSO-d6, 25 ꢀC):
d
3.64 (s,
3H), 7.05e7.65 (m, 15H), 10.39 (s, 1H),12.31 (br s,1H) ppm; 13C NMR
(62.9 MHz, CDCl3, 25 ꢀC):
51.5, 118.7, 123.4, 127.2 (two overlapped
d
signals), 127.5, 127.9, 128.0, 128.3, 128.7, 130.0 (two overlapped
signals), 130.4, 131.9, 133.1, 134.0, 138.7, 161.7, 173.2 ppm; EIMS: m/z
380 (Mþ, 34), 379 (64), 347 (100), 242 (29), 173 (24), 159 (42), 158
(41), 146 (20). Elemental analysis for C25H20N2O2: calcd. C 78.93, H
5.30, N 7.36; found: C 78.11, H 5.32, N 7.30.
5.7.2. Reaction of azirine 1d with 4-amino-pent-3-en-2-one (8b). To
a solution of azirine 1d (424 mg, 2.42 mmol) in anhydrous CH3CN
(24 mL), enaminone 8b (285 mg, 2.88 mmol) and FeCl3 (467 mg,
2.88 mmol) were added. After 90 min and work up, the crude was
recrystallized from EtOH to give methyl 4-acetyl-5-methyl-3-
phenyl-1H-pyrrole-2-carboxylate15 (10b; 354 mg, 57%).
4. Hansen, H. J.; Heimgartner, H. In 1,3-Dipolar Cycloaddition; Padwa, A., Ed.;
Wiley: New York, NY, 1984; Vol. 1, pp 177e290.
5.7.3. Reaction of azirine 1d with 3-amino-1-phenyl-but-2-en-1-one
(8c) and aluminium trichloride. To a solution of azirine 1d (422 mg,
2.41 mmol) in anhydrous CH3CN (22 mL), enaminone 8c (470 mg,
2.92 mmol) and AlCl3 (385 mg, 2.89 mmol) were added. After
30 min and work up, the crude was purified by column chroma-
tography (n-hexane/ethyl acetate from 9:1 to 2:8) to give 11 in
traces, methyl 4-acetyl-3,5-diphenyl-1H-pyrrole-2-carboxylate
(10c; 33 mg, 4%) and methyl 4-benzoyl-5-methyl-3-phenyl-1H-
pyrrole-2-carboxylate (10d; 442 mg, 57%).
5. (a) Faria dos Santos Filho, P.; Schuchardt, U. Angew. Chem., Int. Ed. Engl. 1977, 16,
647e648; (b) Alper, H.; Prickett, J. E. Tetrahedron Lett. 1976, 17, 2589e2590; (c)
Inada, A.; Heimgartner, H.; Schmid, H. Tetrahedron Lett. 1979, 20, 2983e2986;
(d) Inada, A.; Heimgartner, H. Helv. Chim. Acta 1982, 65, 1489e1498; (e) Arn-
hold, F.; Chaloupka, S.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 1995, 78,
899e909.
6. Auricchio, S.; Bini, A.; Pastormerlo, E.; Truscello, A. M. Tetrahedron 1997, 53,
10911e10920.
7. Auricchio, S.; Grassi, S.; Malpezzi, L.; Sarzi Sartori, A.; Truscello, A. M. Eur. J. Org.
Chem. 2001, 1183e1187.
Compound 10c: white solid (EtOAc), mp 134e135 ꢀC; Rf (50%
ethyl acetate/n-hexane) 0.44; IR (KBr) 3273, 1698, 1669, 1447, 1258,
8. Jana, S.; Clements, M. D.; Sharp, B. K.; Zheng, N. Org. Lett. 2010, 12, 3736e3739.
9. (a) Bellina, F.; Cauteruccio, S.; Mannina, L.; Rossi, R.; Viel, S. Eur. J. Org. Chem.
2006, 693e703; (b) Adib, M.; Ansari, S.; Feizi, S.; Damavandi, J. A.; Mirzaei, P.
Synlett 2009, 3263e3266; (c) Coskun, N.; Asutay, O.; Summengen, D. Chim. Acta
Turcica 1996, 24, 165e167.
1217 cmꢂ1; 1H NMR (250 MHz, CDCl3, 25 ꢀC):
d
1.90 (s, 3H), 3.64 (s,
3H); 7.30e7.62 (m, 10H); 9.47 (br s, 1H) ppm. 13C NMR (62.9 MHz,
CDCl3, 25 ꢀC):
31.3, 51.6, 118.9, 124.9, 127.7, 127.8, 128.6, 128.9,
10. (a) Muller, F.; Mattay, J. Chem. Ber. 1993, 126, 543e549; (b) Muller, F.; Mattay, J.
d
Angew. Chem., Int. Ed. Engl. 1991, 30, 1336e1337.
129.2, 130.0, 131.1, 132.3, 134.1, 137.5, 161.3, 197.4 ppm; EIMS: m/z
319 (Mþ, 38), 304 (22), 272 (100), 189 (22), 113 (21). Elemental
analysis for C20H17NO3: calcd. C 75.22, H 5.37, N 4.39; found: C
75.50, H 5.39, N 4.41.
11. Alberola, A.; Gonzalez Ortega, A.; Sadaba, M. L.; Sanudo, C. Tetrahedron 1999, 55,
6555e6566 (for compound 6a).
12. Petruso, S.; Caronna, S.; Sferlazzo, M.; Sprio, V. J. Heterocycl. Chem. 1990, 27,
1277e1280 (for compound 6b).
13. As far as we know, the formation of pyrrolinones in low and variable yields was
reported only in one paper: Farnum, D. G.; Mehta, G.; Moore, G. G. I.; Siegal, F. P.
Tetrahedron Lett. 1974, 15, 2549e2552.
Compound 10d: white solid (EtOAc), mp 179e180 ꢀC; Rf (50%
ethyl acetate/n-hexane) 0.37; IR (KBr) 3287, 1695, 1672, 1636, 1447,
ꢁ
14. Cantagrel, G.; de Carne-Carnavalet, B.; Meyer, C.; Cossy, J. Org. Lett. 2009, 11,
1277 cmꢂ1; 1H NMR (250 MHz, CDCl3, 25 ꢀC):
d
2.45 (s, 3H), 3.72 (s,
3H), 6.95e7.35 (m, 8H), 7.48e7.58 (m, 2H), 9.74 (br s, 1H) ppm; 13C
NMR (62.9 MHz, CDCl3, 25 ꢀC):
13.1, 51.5, 116.8, 123.1, 126.9, 127.1,
4262e4265 and references cited therein.
15. Law, K. W.; Lai, T.-F.; Sammes, M. P.; Katritzky, A. R.; Mak, T. C. W. J. Chem. Soc.,
Perkin Trans. 1 1984, 111e118.
d
16. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112e121.
127.7, 129.4, 130.6, 131.8, 132.7, 133.4, 137.5, 138.8, 161.9, 193.8 ppm;
EIMS: m/z 319 (Mþ, 50), 318 (50), 287 (23), 286 (100), 210 (73), 127
(33). Elemental analysis for C20H17NO3: calcd. C 75.22, H 5.37, N
4.39; found: C 75.53, H 5.41, N 4.37.
17. (a) Roedel, J. N.; Wurzenberger, X.; Lorenz, I.-P. Inorg. Chem. Commun. 2008, 11,
829e831; (b) Hassner, A.; Bunnell, C. A.; Haltiwanger, K. J. Org. Chem. 1978, 43,
57e61.
18. (a) Marco-Contelles, J.; Balme, G.; Bouyssi, D.; Destabel, C.; Henriet-Bernard, C.
D.; Grimaldi, J.; Hatem, J. M. J. Org. Chem. 1997, 62, 1202e1209; (b) Ryu, I.;
Matsu, K.; Minakata, S.; Komatsu, M. J. Am. Chem. Soc. 1998, 120, 5838e5839; (c)
McClure, C. K.; Kiessling, A. J.; Link, J. S. Tetrahedron 1998, 54, 7121e7126; (d)
Calestani, G.; Leardini, R.; McNab, H.; Nanni, D.; Zanardi, G. J. Chem. Soc., Perkin
Trans. 1 1998, 1813e1824; (e) Bowman, W. R.; Bridge, C. F.; Brookes, P. Tetra-
hedron Lett. 2000, 41, 8989e8994.
5.7.4. Reaction of azirine 1d with 3-amino-1-phenyl-but-2-en-1-one
(8c) and iron trichloride. To a solution of azirine 1d (417 mg,
2.38 mmol) in anhydrous CH3CN (22 mL), enaminone 8c (477 mg,
2.96 mmol) and FeCl3 (464 mg, 2.86 mmol) were added. After 1 h and
work up, the crude was purified by column chromatography (n-
hexane/ethyl acetate from 9:1 to 2:8) to give methyl 3,5-diphenyl-
1H-pyrrole-2-carboxylate (11; 57 mg, 9%), methyl 4-acetyl-
3,5-diphenyl-1H-pyrrole-2-carboxylate(10d; 86 mg, 11%) and
19. Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. Synlett 1999, 1148e1150.
20. Velezheva, V. S.; Solokov, A. I.; Kornienko, A. G.; Lyssenko, K. A.; Neliubina, Y. V.;
Godovikov, I. A.; Peregudov, A. S.; Mironov, A. F. Tetrahedron Lett. 2008, 49,
7106e7109.
21. Ahlbrecht, H. Tetrahedron Lett. 1968, 9, 4421e4424.
22. (a) Ng, E. P. J.; Wang, Y.-F.; Hui, BW.-Q.; Lapointe, G.; Chiba, S. Tetrahedron 2011,
67, 7728e7737; (b) Chiba, S.; Wang, Y.-F.; Lapointe, G.; Narasaka, K. Org. Lett.
2008, 10, 313e316; (c) Wang, Y.-F.; Toh, K. K.; Chiba, S.; Narasaka, K. Org. Lett.
2008, 10, 5019e5022.
methyl
4-benzoyl-5-methyl-3-phenyl-1H-pyrrole-2-carboxylate
(10c;342 mg, 45%).

S. Auricchio et al. / Tetrahedron 68 (2012) 7441e7449
7449
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9472e9477; (b) Jiang, Y.; Chan, W. C.; Park, C.-M. J. Am. Chem. Soc. 2012, 134,
4104e4107.
24. Hortmann, A. G.; Robertson, D. A.; Gillard, B. K. J. Org. Chem. 1972, 37,
322e324.
8c: Holtzclaw, H. F., Jr.; Collman, J. P.; Alire, R. M. J. Am. Chem. Soc. 1958, 80,
1100e1103.
26. Alper, H.; Laplante, M. Tetrahedron 1978, 34, 625e626.
27. Katritzky, A. R.; Zhu, L.; Lang, H.; Denisko, O.; Wang, Z. Tetrahedron 1995, 51,
13271e13276.
25. (a) For compound 5b: Zhou, Y.-G.; Tang, W.; Wang, W.-B.; Li, W.; Zang, X. J. Am.
Chem. Soc. 2002, 124, 4952e4953; (b) For compound 8b: Baraldi, P. G.; Simoni,
D.; Manfredini, S. Synthesis 1983, 902e903; (c) For compound 8a: Bredereck,
H.; Gompper, R.; Morlock, G. Chem. Ber. 1957, 90, 942e952; (d) For compound
28. Chaignaud, M.; Gillaizeau, I.; Ouhamou, N.; Coudert, G. Tetrahedron 2008, 64,
8059e8066.
29. Baranoff, E.; Fantacci, S.; De Angelis, F.; Zhang, X.; Scopelliti, R.; Graetzel, M.;
Nazeeruddin, M. K. Inorg. Chem. 2011, 50, 451e462.