FeCl3-Catalyzed Formal [3+2] Cyclodimerization of 4-Carbonyl-1,2-diaza-1,3-dienes

Article abstract of DOI:10.1002/ejoc.202101046

Substituted 1-aminopyrroles are easily accessible by iron-catalyzed cascade reaction of 1,2-diaza-1,3-dienes. Mechanistically, a formal [3+2] cyclodimerization is hypothesized to proceed through a [4+2] cyclodimerization of 4-substitued 1,2-diaza-1,3-dienes followed by intramolecular ring closure to fused diaziridin-pyrrolines which is successively opened to undergo a ring contraction process and consequently generate the desired pyrrole moiety. The presence of activated hydrogen in the terminal position of the azo-enic moiety is crucial for the synthesis of pyrroles.

Full text of DOI:10.1002/ejoc.202101046

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: FeCl3-catalyzed formal [3 + 2] cyclodimerization of 4-
carbonyl-1,2-diaza-1,3-dienes
Authors: Giacomo Mari, Matteo Corrieri, Lucia De Crescentini,
Gianfranco Favi, Stefania Santeusanio, and Fabio Mantellini
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1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202101046
FULL PAPER
FeCl -catalyzed formal [3 + 2] cyclodimerization of 4-carbonyl-1,2-
3
diaza-1,3-dienes
[
a]
[a]
[a]
[a]
[a]
Giacomo Mari,* Matteo Corrieri, Lucia De Crescentini, Gianfranco Favi, Stefania Santeusanio,
[
a]
and Fabio Mantellini*
[
a]
Dr. G. Mari, Dr. M. Corrieri, Dr. L. De Crescentini, Prof. Dr.G. Favi, Dr S. Santeusanio, Prof. Dr. F. Mantellini
Department of Biomolecular Sciences, Section of Chemistry and Pharmaceutical Technologies,
University of Urbino “Carlo Bo”
Via I Maggetti 24, 61029 Urbino (PU), Italy
https://www.uniurb.it/persone/fabio-mantellini
https://www.uniurb.it/persone/giacomo-marii
E-mail: fabio.mantellini@uniurb.it
Twitter: @HUniurb
Supporting information for this article is given via a link at the end of the document.
Abstract: Substituted 1-aminopyrroles are easily accessible by
means of iron-catalyzed cascade reaction that requires as starting
materials the solely 1,2-diaza-1,3-dienes. Mechanistically, the formal
industrial chemistry put the pyrroles into the center of attention
of a vast audience of chemists and the development of
innovative synthetic methods devoted to their preparation is a
[
19]
[
3 + 2] cyclodimerization is hypothesized to proceed through a [4 +
] cyclodimerization of 4-substitued 1,2-diaza-1,3-dienes followed by
very active field of the heterocyclic researches.
2
intramolecular ring closure to fused diaziridin-pyrrolines whose
successive opening results in a ring contraction process with
consequent generation of the pyrrole moiety. The presence of
activated hydrogen in the terminal position of the azo-enic moiety is
crucial for the success of the synthesis.
Introduction
Pyrroles are one of the most relevant heterocyclic scaffolds that
play a prominent role in different branches of chemistry such as
[
1]
biochemistry, medicinal chemistry and drug discovery, or
industrial chemistry where they represent useful building blocks
[2]
[3]
[4]
in the preparation of polymers,
dyes,
agrochemicals,
[
5]
corrosion inhibitors, and other widespread chemical products.
Few examples are sufficient to fully understand the importance
and the strategic role of these simple aromatic nitrogen
heterocycles in several biological processes: they are a key
structural motif in porphyrins that are the core of chlorophyll,
heme, vitamin B12, or bile pigments like bilirubin and biliverdin,
as well as they are present in several natural derivatives such as
Figure 1. Some representative examples of pyrrole-containing drugs.
However, despite these numerous efforts, the synthetic
approaches dedicated to the preparation of fully substituted
symmetrical pyrroles remain represented only by sporadic
[
6]
[7]
[8]
[9]
[10]
[20]
sceptrin, prodigiosin, lamellarin, ryanodine, halitulin.
examples.
In the design of an innovative synthetic
The pyrrole core is also common in natural derivatives of marine
origin so much that the definition “marinopyrroles” has been
coined. Some of these compounds exhibit strong activity against
methodology, a primary target to be achieved consists in the
development of simple and efficient procedures able to quickly
assemble the desired structure. These aspects are correlated to
the concept of the “step economy”, concerning the development
of processes that require the least number of manipulations. The
reduction to the fewest number of synthetic steps can translate
into both economic and environmental benefits. Avoiding the
isolation and the purification of the reaction intermediates, the
advantages obtained concern both a saving of time and labor as
[11]
[12]
methicillin-resistant bacteria,
and anticancer activity.
In
addition to the natural products, several pyrroles of synthetic
origin display interesting biological activities, as evidenced by
the considerable number of pyrrole-derived drugs. Some
examples include Atorvastatine, one of the top-selling branded
[
13]
drugs employed as antihyperlipidemic, Sunitinib, used for the
[14]
[21]
treatment of some cancers,
Pyrvinium, an efficient
well as a lower waste of materials such as silica and solvents.
[
15]
anthelmintic agent with promising anticancer activity, Tolmetin, Furthermore, procedures that require simple work-up are
[
16]
an important non-steroidal anti-inflammatory drug,
just to
amenable to automation and/or easily adapted to an eventual
[
22]
mention a few of the most representative (Figure 1). Then, the
scale-up. Over the years, the 1,2-diaza-1,3-butadienes (DDs),
also called azoalkenes, have proven to be versatile and
multifaceted starting materials for the construction of several
[
17]
high abundance in natural products,
applications,
the several therapeutic
[
18]
the high request from different areas of the
1
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European Journal of Organic Chemistry
10.1002/ejoc.202101046
FULL PAPER
[23]
heterocyclic frameworks by reactions with nucleophilic agents.
Results and Discussion
In particular, DDs are excellent precursors of pyrroles, and
several synthetic pathways with different partners such as
Our research activities started with the investigation on the
behavior of 4-substituted-DDs employing the 1-tert-butyl 3,4-
dimethyl 1,2-diaza-1,3-diene-1,4-dicarboxylate 1a as model
(Table 1). Initially, according to the procedure reported by Lu
[
24]
[25]
[26]
enamines, -dicarbonyl compounds, -ketosulphones, α-
[
27]
[28]
[29]
oxophosphoranes, activated nitriles, aldehydes, silyl enol
[
30]
[31]
ethers,
butadienes
Danishefsky’s dienes,
or 1,3-bis(silyloxy)-1,3-
[
32]
[33]
[34]
have been developed. DDs can also react with
and Zhou,
or by Suryavanshi, the DD 1a was treated with
themselves providing tetrahydropyridazines, as reported in two
quite recently published papers. In the first one, Lu and Zhou
described an elegant catalyst-free self [4 + 2] cycloaddition of in
potassium carbonate in dichloromethane (DCM). Unfortunately,
even refluxing the reaction, the desired tetrahydropyridazine 2
was not formed (Table 1, entry 1) and only a little amount of a
degradation product as the corresponding -oxo-hydrazone was
isolated. Since the basic treatment did not provide results, 1a
was successively refluxed in THF, but also in this case, only a
[
33]
situ-generated azoalkenes,
while in his interesting work,
[
35]
Suryavanshi reported a [4 + 2] cyclodimerization of in situ-
[
34]
generated DDs followed by a C−N bond cleavage (Figure 2a).
Both reactions use -halohydrazones as starting reagents which, little amount of degradation products were formed (Table 1,
by basic treatment, generate the corresponding 4-unsubstituted
DDs. These latter compounds are characterized by poor stability
and aptitude to give side reactions. Usually 4-unsubstituted DDs
cannot be stored even at low temperatures and for this reason
they are generated in situ. On the contrary, the alkoxy- or the
amino-4-carbonyl DDs do not manifest in the time the tendency
to give the formation of by-products, usually they require a
simple and lean work-up and, last but not least, their chemical
behavior is often different from the one exhibited by the 4-
unsubstituted DDs. So, motivated by these considerations, we
tried to adapt to the 4-substituted DDs the methodologies
entry 2). On the other hand, it is well known that Lewis acids are
[36]
able to catalyze the Diels-Alder reactions,
so as further
attempt, to a solution of 1a in dichloromethane at room
temperature a catalytic amount (10%) of copper dichloride was
added (Table 1, entry 3).
[
a]
Table 1. Reaction conditions optimization.
[
33]
previously reported by Lu and Zhou,
in an attempt to
synthesize the corresponding new alkoxy- or amino-4-carbonyl
substituted pyridazines. With our great surprise and pleasure,
we observed that, in this case, only the formation of fully
substituted symmetrical pyrroles occurred through an
unexpected formal [3 + 2] cyclodimerization (Figure 2b). Herein,
we report full details of this synthesis.
Yield
Catalyst
(%)
Time
(h)
Entry
Solvent
Temperature
Catalyst
3a
[
b]
(%)
[
c],[d]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
CH
2
Cl
2
reflux
reflux
r.t.
K
-
2
CO
3
100
-
48.0
48.0
72.0
72.0
72.0
72.0
72.0
72.0
72.0
72.0
72.0
72.0
72.0
72.0
72.0
72.0
72.0
72.0
72.0
24.0
72.0
72.0
24.0
0
THF
0
[
[
[
[
[
[
[
e]
f]
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
2
2
2
2
2
2
2
2
2
2
CuCl
CuSO
Cu(OTf)
2
10
32
0
r.t.
4
10
e]
e]
e]
e]
e]
r.t.
2
10
36
18
14
5
r.t.
Bi(OTf)
3
10
r.t.
Yb(OTf)
3
10
r.t.
ZnBr
TiCl
SmCl
2
10
r.t.
3
10
14
17
41
24
43
7
[
[
[
[
[
[
[
[
[
[
e]
0
1
2
3
4
5
6
7
8
9
0
1
2
3
r.t.
3
10
e]
r.t.
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
3
3
3
3
3
3
3
3
3
3
3
3
10
e]
r.t.
6H
2
O
10
e]
reflux
r.t.
10
e]
CHCl
CHCl
3
3
10
e]
reflux
r.t.
10
28
e],[g]
e],[g]
e]
CH
CH
3
CN
CN
10
trace
trace
50
3
reflux
r.t.
10
THF
THF
THF
THF
THF
THF
10
e]
reflux
reflux
reflux
reflux
reflux
10
71
20
63
[
[
e]
e]
5.0
2.5
5.0+5.0
69
48
[
h]
FeCl
3
95
[
a]
Unless otherwise stated, the reactions were conducted on 0.5 mmol of DD
[
b]
[c]
1a in 5.0 mL of solvent.
Isolated yields of 3a.
0.46 mmol of 1a were
[
d]
[34] [e]
recovered unreacted.
0.027 mmol of -oxo-hydrazone were isolated.
[
f]
DD 1a was not fully converted. The reaction does not occur and a only little
[
34]. [g]
amount of oxo-hydrazone was obtained.
TLC analysis reveals a
Figure 2. Different regioselectivities in the cyclodimerization of 4-
unsubstituted-DDs or alkoxy-/amino-4-carbonyl DDs.
[
h]
complicated reaction profile where only traces of 3a were detected. To a first
2
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European Journal of Organic Chemistry
10.1002/ejoc.202101046
FULL PAPER
[
39]
amount of 5% of FeCl
3
at the beginning of the reaction, a second portion (5%)
(see Scheme 1d). In particular, the two doublets at 3.51 and
3.99 ppm ascribable to the protons on C4 and C5 and the signal
at 83.3 ppm attributable to the C6 of the diazenyl-
was added after 6.0 h and then the reaction was further refluxed for 18.0 h.
[33]
In this case, the reaction partially proceeded and its profile was
tetrahydropyridazine are diagnostic for the proposed structure.
quite complicated as revealed by
a TLC analysis. By
chromatography, it was possible to recover only two products:
Table 2. Substrate scope of the synthesis of pyrroles 3aq by employing
[
35]
[a],[b]
the first was detected as the -oxo-hydrazone
while the
exclusively 4-substituted DDs 1aq.
second one, with our great surprise and pleasure, was identified
as the 1-aminopyrrole 3a. The expected tetrahydropyridazine 2
instead was not isolated. This result has encouraged us to
continue our researches and several Lewis acids such as
CuSO
anhydrous FeCl
12). Using CuSO
4
, Cu(OTf)
2
, Bi(OTf)
, FeCl 6H
, no formation of pyrrole 3a occurred. The
3
, Yb(OTf)
3 2 3 3
, ZnBr , TiCl , SmCl ,
3
3
2
O were tested (Table 1, entries
4
4
other tested catalysts manifested inhomogeneous performances
by providing yields of 3a between 5 and 41%. It is noteworthy
that the best result was furnished by anhydrous FeCl , while the
3
reaction conducted employing its analogous hexahydrate form
produced the desired 3a with a significantly lower yield (41% vs
24%, Table 1 entries 11,12). In the literature there are several
examples of effective syntheses of pyrroles or related five
[
37]
membered azacycles based on iron catalysis.
This is due to
the several inherent advantages of these catalysts such as low
and stable cost, excellent functional group tolerance, and
[
38]
relative low toxicity.
Subsequently, different solvents were
tried both at room temperature as well as under reflux (Table 1,
entries 1319). The tests carried out have shown that the
reaction in THF under reflux furnished the best results in terms
of yield, although the DD 1a was not fully converted after 72
hours (Table 1, entry 19). Increasing the catalyst up to 20%, the
DD 1a was fully consumed, but a loss in yield of pyrrole 3a was
observed (Table 1 entry 20). The decrease of the amount of
[
a]
Reaction conditions: 1 (1.0 mmol), FeCl
3
(0.05 mmol), THF, 10.0 mL, reflux
3
FeCl to 5% did not cause a significant loss in yield of 3a (69%),
6
.0 h, then to the crude other FeCl (0.05 mmol) was added and the reaction
3
which however occurred by further lowering the quantity of the
catalyst to 2.5% (Table 1 entries 21, 22). Also in these two latter
cases, we noticed as also after 72.0 h, an amount of the starting
DD 1a was recovered unreacted. So, we tried two successive
additions: to the initial aliquot of catalyst (5%), a further amount
[
b]
[c]
was further refluxed for 18.024.0 h.
obtained starting from 8.0 mmol of 1b.
Isolated yields.
3b (1.202 g) was
In order to obtain information on the mechanistic details, some
experiments were conducted (Scheme 1). Obviously, 4,4-
disubstituted DDs, lacking hydrogen, are not able to supply the
final pyrroles 3, as evidenced in the case of the DDs 1r,s
(
5%) was added after 6 hours from the beginning of the reaction.
To our satisfaction, in this case, the DD 1a was completely
converted in 24.0 h and the desired pyrrole 3a was isolated in
[
40]
(
Scheme 1a). The same behavior was noted using the cyclic
95% yield (Table 1, entry 23). The efficiency and validity of these
[
41]
DD 1t,
a stable compound that can be easily handled and
optimized conditions have been verified employing several DDs
[
42]
1
stored for a long time (Scheme 1b).
Also the isolated 3,4-unsubstituted-tetrahydropyridazine 2b
obtained from the N'-(2-chloro-1-
phenylethylidene)benzohydrazide 4a according to the Zhou’s
procedure is not able to supply the corresponding pyrrole both
by acid or basic treatments (Scheme 1c, and Table S2
Supporting Information). On the contrary, the treatment under
the optimized conditions of the isolated tetrahydropyridazine 3,4-
dicarboxylate 2a furnished the corresponding 1-aminopyrrole 3p
in 87% yield (Scheme 1d). The set of collected data clearly
indicates that the presence of activated hydrogens originally
located in position four of the azo-ene system of the starting
DDs 1 is determinant for the success of the reaction. Based on
these evidences, a plausible mechanism can involve an initial [4
with different N-protective groups such as esters 1am (R = Me,
1
Et, tBut), or amides 1nq (R = NH
2
, NHPh), bearing in 3-
position of the azo-ene system alkyl groups of different length
2
(
R = Me, Et, n-Pr), and functionalized in 4-position with esters
ag,i,j,lq and amides 1h,k, (see Table S1, Supporting
1
Information) to tentatively synthesize the corresponding
functionalized pyrroles 3aq. The adaptability to scale-up and
synthetic utility of this method was highlighted conducing a
gram-scale synthesis of 3b that was obtained without loss of
yield (85%, Table 2). As described in Table 2, the yields are
generally good with the exception of the pyrroles 3f and 3g (41%
and 29%, respectively). Analyzing the set of the collected data, it
is possible to notice how the yields decrease, also in a sensitive
way, with the increase of the steric hindrance of the substituents.
It is noteworthy that in the reaction of DD 1p it was possible to
[
43]
+
2] cycloaddition in which one DD acts as a diene and a second
one as a dienophile: this aza-Diels-Alder reaction produces the
diazenyl-tetrahydropyridazine-3,4-dicarboxylates 2 accordingly
to what previously observed by Lu and Zhou
Suryavanshi (Scheme 2).
isolate by flash chromatography
a little amount of the
corresponding 1,4,5,6-tetrahydropyridazine 2a that was quickly
[
33]
1
13
or by
characterized by means of the H- and C-NMR spectroscopy
[
34]
In this case, the role of the Lewis
3
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European Journal of Organic Chemistry
10.1002/ejoc.202101046
FULL PAPER
[
48]
acid is crucial, as confirmed by the lack of reactions in the
resulting in ring contraction and generation of the pyrrole D.
[44]
absence of catalyst (Table 1, entry 2).
The azo group
The final tautomeric process determines the formation of the
combined with the presence of electron withdrawing groups
such as esters and amides, makes the DDs electron deficient
dienes.
products 3.
[
22]
Scheme 2. Plausible reaction mechanism.
Scheme 1. Control experiments.
The structure of pyrroles 3 was confirmed by NMR comparison
with the spectroscopic data of the same compounds obtained by
[49]
means of different procedures, as well as by the hydrolysis of
the amide BOC (5a, Scheme 3a), or by NN bond cleavage (6a,
[
50]
Scheme 3b).
Scheme 3. Synthetic transformations of 3.
It is known as the catalytic activity of Lewis acid affects the
dienes in the inverse electron demand Diels−Alder reaction
[
45]
(
IEDDA reaction) favoring the cycloaddition.
Similarly to the
behavior observed by Suryavanshi the C−N bond cleavage is
probably due to a regioselective nucleophilic attack to the acyl
carbonyl group of the diazenyl-tetrahydropyridazine 2 which
triggers the nitrogen elimination with consequent formation of an
unstable carbanion that is readily protonated to produce the
[
34]
intermediate A.
In the reaction medium probably the FeCl
3
degrades making necessary the addition of a second portion of
[46]
the catalyst during the course of the reaction.
An alternative
way for the formation of A that involves a radical mechanism, as
observed by Stephanidou-Stephanatou on similar systems, can
be excluded since the reaction was not suppressed if TEMPO
(
2,2,6,6-tetramethylpiperidin-1-oxyl), as radical-trapping reagent,
[
47]
was added (Scheme 1e).
The successive spontaneous
oxidation leads to the 1,4-dihydropyridazine intermediate B. The
elimination of H(4), activated by the ester function, triggers the
internal aza-Michael-addition of the N(2) onto the C(6),
producing the diaziridin-pyrrolinic intermediate C. The keto-
enolic tautomerism causes the opening of the diaziridine nucleus,
4
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European Journal of Organic Chemistry
10.1002/ejoc.202101046
FULL PAPER
These evidences further corroborates the occurred ring
contraction and excludes unequivocally the possible six-
membered structure for derivatives 3. An example of the
The dimethyl 1-((tert-butoxycarbonyl)amino)-2,5-dimethyl-1H-pyrrole-3,4-
dicarboxylate 3a (0.3 mmol) was dissolved in 15.0 mL of methanol and
then 0.15 mL of HCl 37 % was added. The reaction was refluxed for 2 h
(controlling reaction progress by TLC). The reaction mixture was then
synthetic utility of the products
3 is represented by the
neutralized by addition of Na CO , anhydrified with Na SO . Successively,
2
3
2
4
construction of an unprecedented bicyclic-fused derivative such
as the pyrrolo[1,2-d][1,3,4]oxadiazine 7a. The treatment of
pyrrole 3b with CAN in a mixture of acetonitrile/water induces
the solution was filtered, and the crude was concentrated under reduced
pressure. Product 5a was isolated by chromatography on silica gel
column using cyclohexane/ethyl acetate mixtures as eluent and purified
by crystallization from ethyl acetate.
[
51]
the selective oxidation of the methyl groups.
The reaction
proceeds through the preliminary formation of the alcohol that in
turn gives a nucleophilic attack onto the carbammate function
producing the oxadiazine nucleus. The other methyl, instead, is
oxidized to formyl group (Scheme 3c).
[
50]
General procedure for the synthesis of 1H-pyrrole 6a.
To
butoxycarbonyl)amino)-2,5-dimethyl-1H-pyrrole-3,4-dicarboxylate 3a (0.5
mmol) in MeCN (10.0 mL), the DD 2l (1.0 mmol) and K CO (1.5 mmol)
a
magnetically
stirred
solution
of
dimethyl
1-((tert-
2
3
were added and the reaction mixture was refluxed for 1 hour, until the
TLC analysis revealed the disappearance of the starting reagent 3 and
Conclusion
2 3
the formation of 1H-pyrrole 6a. After the filtration of K CO , the solvent
In summary, we have developed an unusual and practical FeCl
3
-
was removed in vacuo; the so-formed product 6a was purified by silica
gel column chromatography using cyclohexane/ethyl acetate mixtures as
eluent and then was crystallized from ethyl acetate/petroleum ether.
catalyzed formal [3 + 2] cyclodimerization of 4-substituted DDs
for the preparation of fully substituted symmetric 1-
aminopyrroles. The key steps of this sequence involved a “ring-
General procedure for the synthesis of diethyl 7-formyl-2-oxo-2,4-
closure-ring-opening” process that determines
a
cycle
dihydro-1H-pyrrolo[1,2-d][1,3,4]oxadiazine-5,6-dicarboxylate
starting from pyrrole 3a.
7a
contraction. The ring closure is triggered by the loss of the
activated proton, originally located in the terminal position of the
azo-ene system of the 4-amino- or 4-alkoxy-carbonyl-DDs. As
demonstrated, the replacement of the in situ generated 4-
unsubstituted DDs with the 4-substituted-ones is crucial for the
success of the whole sequence that leads to the pyrrole
formation. This strategy makes simplicity its main strength, and it
was demonstrated to efficiently proceed since it can be easily
scaled up.
The dimethyl 1-((tert-butoxycarbonyl)amino)-2,5-dimethyl-1H-pyrrole-3,4-
dicarboxylate 3a (0.3 mmol) was dissolved in 9.0 mL of a mixture of
acetonitrile/water (8:1 v/v) and then cerium(IV) ammonium nitrate was
added (2.4 mmol). The reaction was refluxed for 5 h (controlling reaction
progress by TLC). The reaction mixture was cooled to r.t., concentrated
under vacuum, washed with H
acetate (2 × 20 mL). The combined organic layers were washed with H
2 × 10 mL), brine (10 mL), and dried over NaSO . The solvent was
2
O (20 mL) and extracted with ethyl
2
O
(
4
removed under reduced pressure and the residue was subjected to
chromatography on a short silica column (cyclohexane-ethyl acetate).
Experimental Section
General procedure for the synthesis of 1,4,5,6-tetrahydropyridazine
Acknowledgements
2a and 1-aminopyrroles 3aq.
[
41]
To
tetrahydrofuran (10.0 mL), FeCl
was refluxed. After 6.0 h a second aliquot of FeCl
a
solution of 1,2-diaza-1,3-dienes 1aq (1.0 mmol)
(0.05mmol) was added and the mixture
(0.05 mmol) was
in
The authors thank Dr. Giada Maraia for her precious advices
and Dr. Anna Maria Gioacchini who competently performed the
mass spectra.
3
3
added to the solution that was refluxed for other 18.024.0 h until the
complete disappearance of the starting 1,2-diaza-1,3-dienes 1aq (TLC
monitoring). Then, the solvent was removed in vacuo; the so-formed 1-
aminopyrroles 3aq were purified by silica gel column chromatography
using cyclohexane/ethyl acetate mixtures as eluent and then were
crystallized from ethyl acetate/petroleum ether. In the case of the
reaction of 1,2-diaza-1,3-diene 1p it was possible to isolate the
corresponding diazenyl-1,4,5,6-tetrahydropyridazine 2a by stopping the
Keywords: Cyclization • Domino reactions • Michael addition •
Pyrroles • Ring contraction.
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European Journal of Organic Chemistry
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[
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4
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6
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European Journal of Organic Chemistry
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FULL PAPER
[44] Recently it was demonstrated as the aza-Diels−Alder reaction of
nonactivated dienes and imines was catalyzed through the action of the
+
-
ionpaired Lewis acid catalyst [FeCl
2
] [FeCl
4
]
generated by the in situ
+
-
disproportionation of FeCl
3
. The uniquely high reactivity of [FeCl
2
] [FeCl4] was
+
attributed to both the highly Lewis acidic[FeCl
2
]
and thermodynamically stable
-
FeCl
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[
1
7
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European Journal of Organic Chemistry
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Entry for the Table of Contents
The 1,2-diaza-1,3-diene’s cyclodimerization that provides symmetrically fully substituted 1-amino pyrroles through an unusual formal
3+2] reaction is investigated. The study has demonstrated as the presence of electron withdrawing groups onto the terminal carbon
[
atom of the azo-ene system is crucial for the success of the reaction. The synthesis occurs with complete regioselectivity and
requires a very easy work-up procedure.
8
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