A convenient one-pot synthesis of polysubstituted pyrroles from N-protected succinimides

Article abstract of DOI:10.1016/j.tetlet.2014.03.021

The dienamine products formed by the reaction between polysubstituted succinimides and the Petasis reagent were subjected to isomerization under mild acidic conditions to give polysubstituted pyrroles in excellent yields (85-95%). The scope and limitations of this methodology are explored.

Full text of DOI:10.1016/j.tetlet.2014.03.021

Tetrahedron Letters 55 (2014) 2523–2526
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A convenient one-pot synthesis of polysubstituted pyrroles from
N-protected succinimides
b
c
Marwan Kobeissi a, , Ogaritte Yazbeck , Yamama Chreim
⇑
a Laboratoire de Synthèse Organique, équipe de Physiotoxicité Environnementale, Lebanese University, Faculty of Sciences, Department of Chemistry, Section V, Lebanon
b Laboratoire de Synthèse Organique, Lebanese University, Faculty of Sciences, Department of Chemistry, Section I, Hadath, Lebanon
c Laboratoire de Synthèse Organique, Lebanese University, Faculty of Sciences, Department of Chemistry, Section V, Lebanon
a r t i c l e i n f o
a b s t r a c t
Article history:
The dienamine products formed by the reaction between polysubstituted succinimides and the Petasis
reagent were subjected to isomerization under mild acidic conditions to give polysubstituted pyrroles
in excellent yields (85–95%). The scope and limitations of this methodology are explored.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 30 December 2013
Revised 15 February 2014
Accepted 5 March 2014
Available online 14 March 2014
Keywords:
Dienamines
Petasis reagent
Methylenation
Succinimides
Polysubstituted pyrroles
Pyrrole is one of the most significant heterocyclic structural
scaffolds, which is present in a large number of biologically active
molecules1,2 with a wide range of applications in medicinal chem-
istry.3 Besides their pharmacological activity, pyrrole derivatives
play a crucial role in materials science.4 The traditional methods
for their synthesis rely on the cyclization of amines with ketones
or diketones, as described by Knorr and Paal in the 1880s.5,6 Since
then, many publications have appeared on this reaction, but still,
this method is under active investigation because of its simplicity.
A number of methods and catalysts have been reported, for exam-
ple supercritical carbon dioxide,7 silver-salts promoted three-com-
ponent reactions,8 manganese(III)-catalyzed [3+2] annulation,9
rhodium(III)-catalyzed bond functionalization,10 palladium-in-
duced three-component reactions,11 gold(I)-catalyzed amino-Cla-
isen rearrangement,12 and zinc chloride.13 Some of these
reported methods involve the use of expensive reagents, hazardous
solvents, long reaction times, and tedious work-up procedures.
Therefore, it is desirable to develop more efficient and practical
methods for the synthesis of pyrrole derivatives.
3 of succinimides, the authors managed to perform a selective
methylenation on the least hindered carbonyl.
We were intrigued by the elegant monomethylenation of five-
membered cyclic anhydrides and thioanhydrides described by
Schauble15 and co-workers using the Petasis reagent (dimethyltit-
anocene), and tried to demonstrate further the versatility of this
methodology by applying it to the synthesis of polysubstituted
symmetrical and unsymmetrical pyrroles.
We reasoned that if the dimethylenation of succinimides could
be accomplished, the resulting dienamines would be isomerized
completely under mild acidic conditions to give the corresponding
pyrroles (Scheme 1).
The formation of N-substituted cyclic imides has been studied
comprehensively and various procedures have been developed
and implemented. Most transformations to such ring structures in-
volve a three-step synthesis: (1) reaction of a cyclic anhydride with
a primary amine, (2) conversion of the intermediate monoamide
into an activated ester with N,N0-disuccinimidyl oxalate,16 acetic
anhydride17–19 or thionyl chloride,20 and (3) thermal and chemical
dehydration to the corresponding cyclic imides. Succinimides 1k–l
were prepared using this classical methodology. In this work, we
used polyphosphoric acid (PPA) as a suitable and convenient re-
agent to prepare N-substituted cyclic imides 1b–j from succinic
acid,21 in excellent yields and purities. Succinimides 1m–r were
prepared in good yields, by the method described by Seres22
et al. with 3-substituted succinimide derivatives.
Grubbs and co-workers reported the dimethylenation of succin-
imides derivatives, using the Tebbe reagent.14 Remarkably in this
Letter, by increasing the bulkiness of the substituent at position
⇑
Corresponding author. Tel.: +961 (70)222005; fax: +961 (7)761173.
E-mail addresses: marwan.kobeissi@liu.edu.lb (M. Kobeissi), ogaritte.yazbek@
liu.edu.lb (O. Yazbeck), ychreim@ul.edu.lb (Y. Chreim).
http://dx.doi.org/10.1016/j.tetlet.2014.03.021
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2524
M. Kobeissi et al. / Tetrahedron Letters 55 (2014) 2523–2526
R1
R1
R1
R2
R2
R2
Cp2Ti(CH3)2
3.5 to 4 eq.
TsOH
O
O
THF, r.t.
N
N
N
THF, 65 o
C
R
R
R
1a-r
2a-r
3a-r
Yield = 85-95%
Scheme 1. Synthesis of pyrroles from succinimides using dimethyltitanocene.
R1
R2
R1
O
O
R2
N
Me
Me
R
1
Toluene or THF
Ti
+
Ti CH2
Ti
O
N
60-65 °C
- CH4
R
2
Scheme 2. Dimethylenation of succinimides using dimethyltitanocene.
Dimethyltitanocene [Cp2Ti(CH3)2] (Petasis reagent) is easily
prepared starting from dichlorotitanocene and a methylating agent
such as MeLi23 or a Grignard reagent.24 It is non-pyrophoric and is
relatively stable to air and water. This reagent has shown high effi-
ciency in the methylenation of carbonyl derivatives. As would be
expected from the nucleophilic nature of the titanocene methyli-
dene intermediate, Petasis methylenation of amides proceeds more
slowly than the methylenation of other carbonyl groups.25 Further-
more, the resulting dimethylenated compounds are often difficult
to purify. Consequently, they are generated in situ in all our exper-
iments (Scheme 2).
Table 1
Conversion of symmetrical N-substituted succinimides 1a–m (R1 = R2 = H) into
pyrroles
Entry
1
Starting material
Product
Time (h)
22
Yielda (%)
85
O
N
N
O
3a
1a
O
N
N
2
3
4
5
6
18
20
20
15
20
88
86
91
94
90
O
3b
1b
Thermolysis of dimethyltitanocene23 in the presence of succin-
imides 1a–r (Scheme 1) resulted in the desired dimethylenated
products 2a–r. Dienamines 2 were not isolated, but were treated
in situ in the presence of a catalytic amount of p-toluenesulfonic
acid26 (PTSA) to afford pyrroles 3a–r in very good yields (Tables
1 and 2). The first methylenation is observed to be faster than
the second. Thus, by using dimethyltitanocene as the limiting re-
agent, a mixture of isomeric 6 and 7 can be separated preparatively
(R1 – R2) (Scheme 3). Products of monomethylenation 4 and 5 are
of high synthetic potential and are subject to further investigation
in our laboratory.
O
N
N
O
3c
1c
O
N
Cl
N
O
Cl
3d
1d
1e
1f
O
N
O
N
NO2
NO2
NO2
NO2
NO2
NO2
3e
A typical procedure for dimethylenation27 involves reaction of
20 mmol of dimethyltitanocene with 5 mmol of succinimide 1 in
THF at 65 °C for 15–22 h under argon, followed by the addition
of a catalytic amount of PTSA. Under such conditions, pyrroles 3
are obtained in isolated yields of 85–95%. When the amount of
dimethyltitanocene was decreased to 12.5 mmol (10–18 h), only
compounds 6 and 7 were obtained in more than 90% yields.
We initially investigated the influence of the substituent on the
nitrogen atom in our succinimides. The results obtained are sum-
marized in Table 1.
As shown in Table 1, N-alkyl succinimides (entries 1, 11 and 12)
were less reactive than N-aryl succinimides (entries 2–10) toward
the Petasis reagent. This is probably due to the deactivation of the
lone pair of the nitrogen by delocalization through the phenyl ring.
As predicted, electron-withdrawing groups on the phenyl ring (en-
tries 4, 5, 7–9 and 10) gave better yields than those substituted
with electron-donating groups (entries 3 and 6). A trifluoromethyl
group at the meta postion (entry 7) gave a better yield than that on
the ortho position (entry 8). The outcome of this reaction can be
better ascribed to steric factors than to electronic effects. Highly
O
N
O
N
3f
O
N
O
N
7
8
16
21
95
86
CF3
CF3
3g
1g
O
N
O
N
NO2
NO2
F3C
3h
F3C
1h
O
N
O
N
O
NO2
NO2
NO2
NO2
9
19
20
85
90
O
CH3
CH3
3i
1i
O
N
O
N
10
O2N
3j
O2N
1j

M. Kobeissi et al. / Tetrahedron Letters 55 (2014) 2523–2526
2525
Table 1 (continued)
1) 1.5 eq. Cp2Ti(Me)2, 65 oC, 15 h
O
O
N
2) 2 eq. Cp2Ti(CH2Ph)2, 65 oC, 15 h
3) HCl 6 M, heat, 2 h
Entry
Starting material
Product
Time (h)
22
Yielda (%)
86
N
H
O
OMe
O
N
O
Yield = 90%
1m
8
N
11
Scheme 4. The one-pot synthesis of unsymmetrical pyrrole 8.
3k
1k
1l
O
N
O
N
12
13
22
15
87
96
Me
Me
CH3
SiMe3
SiMe3
CH3
Ti
Ti
Ti
Ti
Ti
3l
O
N
N
CO2Me
Petasis reagent
analogues of the Petasis reagent
CO2Me
O
3m
1m
Figure 1. The Petasis reagent and known analogues.
a
Yields calculated after purification by column chromatography. Structures were
confirmed by 1H NMR as well as elemental analyses.
reaction conditions, thus extending the scope of the methodology
used.
Next, we investigated the dimethylenation of cyclic five-
membered unsymmetrical succinimides (Table 2) with dimethyl-
titanocene using 2,5-dioxo-3-phenyl-pyrrolidine-1-carboxylic acid
methyl ester (1p), as a model compound. Reaction of 6 mmol of
succinimide 1p and 15 mmol of dimethyltitanocene in THF, fol-
lowed by the addition of a catalytic amount of PTSA afforded a
mixture of isomeric 5-methyl-2-oxo-3-phenyl-2,3-dihydropyr-
role-1-carboxylic acid methyl ester (6 and 7) (R1 = H; R2 = Ph)
and pyrrole 3p in 90% and 4% isolated yields, respectively. When
dimethyltitanocene (15 mmol) was preheated at 65 °C for one hour
before the addition of succinimide 1p (6 mmol), compounds 6, 7
and 3p were obtained in 65% and 25% respective isolated yields.
However, when the reagent was preheated for longer, its methyle-
nating ability was greatly diminished. Reaction of 24 mmol of dim-
ethyltitanocene and 6 mmol of succinimide 1p for 20 h (without
preheating the reagent) resulted in only pyrrole 3p in 93% yield
after isomerization. Quantitative conversion of dienamines 2 into
the respective pyrroles 3 was observed upon standing for one hour
in THF containing a catalytic amount of p-toluenesulfonic acid.
Isomerization was also noted for NMR samples of these dienam-
ines after two hours in CDC13.
To further exploit the synthetic potential of this methodology
for the preparation of pyrroles with different substituents at posi-
tions 2 and 5, a one-pot successive methylenation–benzylidena-
tion–deprotection was attempted on succinimide 1m. Thus, the
reaction of 1m with 1.5 equiv of dimethyltitatocene, followed by
its reaction with 2 equiv of dibenzyltitanocene [Cp2Ti(CH2Ph)2]
and deprotection in acidic medium, afforded pyrrole 828 in 90%
yield (Scheme 4). This result is promising and the scope of the se-
quence is now under investigation in our laboratory.
Table 2
Conversion of unsymmetrical N-substituted succinimides 1n–r (R1 – R2) into pyrroles
Entry
Starting material
Product
Time (h)
Yielda (%)
O
O
O
N
N
1
16
94
CO2Me
3n
CO2Me
1n
2
20
90
O
N
N
CO2Me
1o
CO2Me
3o
O
N
CO2Me
1p
O
O
O
N
3
4
5
20
22
22
93
93
92
CO2Me
3p
O
N
N
CO2Me
CO2Me
1q
3q
CF3
CF3
O
N
N
CO2Me
1r
CO2Me
3r
a
Yields calculated after purification by column chromatography. Structures were
confirmed by 1H NMR as well as elemental analyses.
In summary, we have developed a novel, facile methodology for
the one-step synthesis of polysubstituted pyrroles in high purity
and yield. However, application to other N-aryl and N-heteroaryl
compounds has to be confirmed. The salient features of the
synthetic methodology are: (1) the flexibility to synthesize pyr-
roles with various substituents at the 2- and 5-positions by the
successive use of different Petasis reagents29 (Fig. 1); (2) a wide
selection of substituents that can be accessed from commercially
activated succinimide 1m (entry 13) proved to be a very good
starting material in this reaction and gave the best yield of product.
Further stabilization of the negative charge on the oxygen atom
would be the reason behind this observation. Furthermore, as
shown in entry 12, retention of the absolute configuration of the
asymmetric carbon is observed under our conditions. Finally, we
were pleased to see that many functional groups survived the mild
R1
R1
R1
R2
R1
R2
R1
R2
R2
R2
Cp2Ti(CH3)2
1.5 to 2.5 eq.
TsOH
+
O
+
O
O
O
O
O
N
N
N
N
N
THF, r.t.
THF, 65 o
C
R
R
R
R
R
1
4
5
6
7
1a-m R1 = R2 = H
1n-r R1 ≠ R2
Scheme 3. Monomethylenation of succinimides using dimethyltitanocene.

2526
M. Kobeissi et al. / Tetrahedron Letters 55 (2014) 2523–2526
15. Kates, M. J.; Schauble, J. H. J. Org. Chem. 1994, 59, 494–496.
available succinic acids and amines; and (3) the use of mild reac-
tion conditions. Further modifications of this methodology and
applications to biologically important compounds are currently
under investigation.
16. Kometani, T.; Fitz, T.; Watt, D. S. Tetrahedron Lett. 1986, 27, 919.
17. Stiz, D. S.; Souza, M. M.; Golin, V.; Neto, R. A. S.; Corrêa, R.; Nunes, R. J.; Yunes,
R. A.; Cechinel-Filho, V. Pharmazie 2000, 55, 12.
18. Wanner, M. J.; Koomen, G.-J. Tetrahedron 1991, 47, 8431.
19. Akula, M. R.; Kabalka, G. W. Synth. Commun. 1998, 28, 2063.
20. Caulfield, W. L.; Gibson, S.; Rae, D. R. J. Chem. Soc., Perkin Trans. 1 1996, 545.
21. Mederski, W. W. K. R.; Baumgarth, M.; Germann, M.; Kux, D.; Weitzel, T.
Tetrahedron Lett. 2003, 44, 2133–2136.
Acknowledgments
22. Seres, J.; Daréczi, I.; Vzirkonyi, J.; Horvath, G.; Szilégyi, L.; Radvanyi, B. U.S.
Patent 4,353,734, 1982; Chem. Abstr. 1970, 72, 43221b.
23. Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392–6394.
24. Payack, J. F.; Hughes, D. L.; Cai, D.; Cottrell, I. F.; Verhoeven, T. R. D. Org. Synth.
2002, 79, 19.
We are grateful for financial support from the Lebanese Univer-
sity and the CNRSL (Centre National de la Recherche Scientifique
Libanaise).
25. Petasis, N. A.; Lu, S. P. Tetrahedron Lett. 1995, 36, 2393–2396.
26. Acid-catalyzed isomerization of dienol thioethers and dienol ethers obtained
by reaction of the corresponding cyclic five-membered thioanhydrides and
anhydrides with stabilized phosphorus ylides have been observed. See: (a)
Flitach, W.; Schwiezer, J.; Strunk, U. Liebigs Ann. Chem. 1975, 1967; (b) Babidge,
P. J.; Massy-Westropp, R. A. Aust. J. Chem. 1977, 30, 1629.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
03.021.
27. Representative experimental procedure: 2,5-Dimethyl-1-phenyl-1H-pyrrole (3b):
Dichlorotitanocene [Cp2Ti(Cl)2] (4 mmol with respect to the corresponding
succinimide) was introduced in a Schlenk tube and distilled Et2O (5 mL) was
added under Argon via a syringe. A solution of CH3MgCl in THF [8.25 mmol
with respect to Cp2Ti(Cl)2] was added and the mixture stirred for 1 h at ꢀ10 °C
while slowly warming to 0 °C, affording an orange solution of the Petasis
reagent. The solvent was then removed under vaccum and distilled THF (8 mL)
was added. Succinimide 1b (1 mmol) in distilled THF (2 mL) was introduced to
the mixture via a syringe and the solution was heated at 65 °C for 18 h.
0.05 mmol PTSA (5%) in distilled THF (1 mL) was added and the solution was
allowed to stirr at rt for 1 h. The mixture was then diluted with petroleum
ether (100–150 mL) and allowed to stand until precipitation was complete.
Filtration and removal of the solvent in vacuo left a residue which was purified
by flash column chromatography on Et3N pre-treated silica gel using
petroleum ether/EtOAc (10:1 to 5:1) as eluent to afford pure pyrrole 3b.
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Yield = 88%. Colorless solid; mp 51–53 °C; IR (KBr) m
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