Oligopyrrole synthesis by 1,3-dipolar cycloaddition of azomethine ylides with bissulfonyl ethylenes

Article abstract of DOI:10.1002/anie.200703258

(Chemical Equation Presented) One by one or two by two: In a general approach to the iterative construction of oligopyrroles, the cycloaddition of azomethine ylides derived from pyrrolyl α-iminoesters with 1,2-bis(phenylsulfonyl)-ethylene is followed by the elimination of the sulfonyl groups in situ under basic conditions. This strategy is amenable to the introduction of one or two pyrrole units in each iterative cycle.

Full text of DOI:10.1002/anie.200703258

Angewandte
Chemie
DOI: 10.1002/anie.200703258
Heterocycle Synthesis
Oligopyrrole Synthesis by 1,3-Dipolar Cycloaddition of Azomethine
Ylides with Bissulfonyl Ethylenes**
Ana López-PØrez, Rocío Robles-Machín, Javier Adrio, and Juan Carlos Carretero*
The pyrrole core is a structural motif of particular interest in
synthetic and medicinal chemistry, as it is present in a large
number of natural products[1] and biologically active com-
pounds.[2] Furthermore, cyclic[3] and linear p-conjugated
oligo- and polypyrrolic systems are of growing relevance in
materials science, supramolecular chemistry, and nanotech-
nology. For example, they have found application in anion
binding,[4] cation coordination,[5] conducting polymers,[6]
liquid crystals,[7] and nonlinear optics.[8]
catalyzed 1,3-dipolar cycloaddition of commercially available
1,2-bis(phenylsulfonyl)ethylene[24] with a-iminoesters, fol-
lowed by in situ aromatization of the bissulfone adduct
through the double elimination of the sulfone moieties under
basic conditions (Scheme 1).[25] Straightforward conversion of
the ester substituent on the pyrrole into a new a-iminoester
This wide array of interesting properties has inspired the
development of a plethora of procedures for the preparation
of differently substituted pyrroles.[9] Methods of synthesis
range from the classical Knorr,[10] Paal–Knorr,[11] and
Hantzsch[12] strategies to 1,3-dipolar cycloaddition procedures
with activated alkynes and alkenes,[13] the dehydrogenation of
pyrrolidines,[14] transition-metal-catalyzed coupling,[15] and
multicomponent protocols.[16] On the other hand, methods
for the construction of a,a’-linked oligopyrroles remain
limited. Of particular interest are the Vilsmeier condensa-
tion,[17] the Paal–Knorr cyclization,[18] the oxidative coupling
of a-unsubstituted pyrroles,[19] Ullmann coupling,[20] and other
metal-mediated coupling reactions.[21] However, there is room
for improvement in oligopyrrole synthesis, especially in
reducing the number of steps in the preparation of the
coupling partners and increasing the functional group toler-
ance and structural scope of the current procedures.
The metal-catalyzed 1,3-dipolar cycloaddition of azome-
thine ylides with electron-poor alkenes is one of the most
convergent and most practical approaches to the synthesis of
pyrrolidines substituted with electron-withdrawing groups, in
particular with carbonyl-based substituents and nitro
groups.[22] Given the excellent ability of sulfones to act as
both electron-withdrawing groups and leaving groups,[23] we
envisaged that 5-substituted pyrrole-2-carboxylic esters could
be prepared readily in a one-pot procedure by the metal-
Scheme 1. Strategy for the synthesis of pyrroles.
moiety could lead to an iterative approach to the synthesis of
a,a’-oligopyrroles and related structures. Herein, we describe
the structural versatility of this novel strategy and its efficient
application to the synthesis of a,a’-linked bipyrroles, terpyr-
roles, quaterpyrroles, and pentapyrroles.
On the basis of our recent results on the Cu-catalyzed
asymmetric 1,3-dipolar cycloaddition of simple phenyl vinyl
sulfone,[26] we chose to study as a model reaction the
cycloaddition between N-benzylidene glycine methyl ester
and trans-1,2-bis(phenylsulfonyl)ethylene (1) in THF under
the catalysis of [Cu(CH3CN)4]PF6 (3 mol%) with the ligand
PPh3 (3 mol%) in the presence of the base Et3N (18 mol%).
We were pleased to find that a clean reaction occurred at
room temperature, with complete disappearance of the
dipolarophile in 5 h, to provide
a single bissulfonyl
adduct.[27] Interestingly, it was not necessary to isolated this
adduct: The addition of DBU[28] to the crude reaction mixture
promoted the rapid elimination of the sulfonyl groups with
formation of the expected pyrrole 3, which was isolated in
90% yield (Table 1, entry 1). cis-1,2-Bis(phenylsulfonyl)-
ethylene (2) was also tested as a dipolarophile under the
same reaction conditions (Table 1, entry 2). However, this
alkene proved to be much less reactive than the trans isomer,
and the final pyrrole 3 was obtained in only 27% yield after a
cycloaddition reaction time of 5 h.
[*] A. López-PØrez, R. Robles-Machín, Dr. J. Adrio,
Prof. Dr. J. C. Carretero
Departamento de Química Orgµnica
Facultad de Ciencias, Universidad Autónoma de Madrid
Cantoblanco 28049 Madrid (Spain)
Fax: (+34)914-973-966
This procedure for the synthesis of pyrrole-2-carboxylic
esters by 1,3-dipolar cycloaddition with the bissulfone 1
displays high tolerance with regard to the substitution of the
a-iminoester precursor (Table 1). When a-iminoesters with
aromatic (Table 1, entries 1, 3, and 4), a,b-unsaturated
(entry 5), and aliphatic substituents (entries 6 and 7) were
used, the corresponding pyrroles were obtained in good yields
(72–93%). Azomethine ylides with furyl (Table 1, entry 8),
thienyl (entry 9), and pyrrolyl substituents (entries 10–13)
deserve particular attention, as they are of interest for the
preparation of oligopyrroles and related structures. Those
E-mail: juancarlos.carretero@uam.es
[**] This research was supported by the Ministerio de Educación y
Ciencia (MEC, project CTQ2006-01121) and the Consejería de
Educación de la Comunidad de Madrid, Universidad Autónoma de
Madrid (UAM/CAM CCG06-UAM/PPQ-0557). A.L.P. thanks the
CAM for a predoctoral fellowship. J.A. and R.R. thank the MEC for a
Ramón y Cajal contract and a predoctoral fellowship, respectively.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 9261 –9264
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9261
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Communications
Table 1: One-pot synthesis of 2,5-disubstituted pyrroles.
and submitted immediately to 1,3-dipolar cycloaddition with
the bissulfone 1 under the standard reaction conditions,
followed by DBU-promoted desulfonylation in situ. The
resulting terpyrroles 21 and 22 and the related compound 20
were obtained after chromatographic purification in good
yields of 61–69% (from aldehydes 17–19). This modular
approach to the introduction of the pyrrole units allows the
selective construction of orthogonally protected terpyrroles,
such as 22, as well as mixed heterocyclic systems, such as the
thienylbipyrrole 20. Furthermore, these terpyrroles could be
used as building blocks in the preparation of highly valuable
substituted polypyrroles and expanded porphyrins.[3]
To accelerate the construction process for the synthesis of
higher order oligoheterocycles, we next explored whether the
1,3-dipolar cycloaddition could be used to generate two
pyrrole rings in a one-pot procedure from a bis(a-iminoester)
as a precursor to bisazomethine ylide. This (1+2) and
(1+2+2) approach from N-benzylpyrrole-2,5-dicarbaldehyde
(23) and thiophene-2,5-dicarbaldehyde (24) is illustrated in
Scheme 3.
Entry
Bissulfone
R
Product
Yield [%][a]
1
2
3
4
5
6
7
8
9
10
11
12
13
1
2
1
1
1
1
1
1
1
1
1
1
1
Ph
Ph
3
3
4
5
6
7
8
9
10
–
90
27
72
93
88
80
86
72
97
–
4-(MeO)C6H4
3-FC6H4
CH CH Ph
tBu
cyclohexyl
2-furyl
2-thienyl
2-pyrrolyl
N-Boc-2-pyrrolyl
N-Bn-2-pyrrolyl
N-Tos-2-pyrrolyl
=
ꢀ
11
12
13
67
78
61
[a] Yield of the pure product after silica-gel chromatography. Bn=benzyl,
The pyrrole dialdehyde 23[30] was condensed with excess
glycine methyl ester, and the resulting crude bisimine 25 was
treated immediately with excess bissulfone 1 under the usual
conditions of Cu catalysis, followed by DBU. The expected
symmetrical terpyrrole 27 was obtained as the main product
in 53% yield from 23 along with a minor amount of the
bipyrrole aldehyde (11%) that results from monocycloaddi-
tion with hydrolysis of the second imine unit. The terpyrrole
diester was converted efficiently into the N-protected terpyr-
role dialdehyde 29 in the three steps developed for the
iterative (2+1) strategy (N benzylation followed by reduction
Boc=tert-butoxycarbonyl,
Tos =p-toluenesulfonyl.
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene,
examined underwent the desired reaction to provide the
corresponding a,a’-linked bisheterocycles in good yields (61–
92%), except for the substrate with the unprotected pyrrole
substituent (Table 1, entry 10).[29]
The resulting bipyrroles and related structures serve in
turn as substrates for a sequence of reactions in which a
further pyrrole ring is constructed to give terpyrroles and
analogues (Scheme 2). First, the free NH group of the
bipyrroles 12 and 13 and the thienylpyrrole 10 was benzylated
under standard conditions (BnBr, NaH, DMF) to provide the
protected pyrroles 14, 15, and 16. The resulting bipyrrole (and
thienylpyrrole) esters were converted in high yield in a
straightforward reduction (LiAlH4)/oxidation (MnO2) proce-
dure into the corresponding aldehydes 17, 18, and 19, which
were condensed with glycine methyl ester to give the key
bipyrrole a-iminoesters. These a-iminoesters were isolated
Scheme 2. Synthesis of the terpyrroles 21 and 22 and the thienylbipyr-
role 20: a) BnBr, NaH, DMF, room temperature, 12 h; b) LiAlH4, THF,
08C, 3 h; c) MnO2, acetone, room temperature, 14 h; d) glycine methyl
ester hydrochloride, Et3N, MgSO4, CH2Cl2, room temperature, 15 h;
e) 1, [Cu(CH3CN)4]PF6, PPh3, Et3N, THF, room temperature, 5 h; then
DBU, room temperature, 30 min. DMF=N,N-dimethylformamide.
Scheme 3. Synthesis of the pentaheterocycles 31 and 32: a) glycine
methyl ester hydrochloride, Et3N, EtOH, SiO2, ultrasound, room
temperature, 2 h; b) 1, [Cu(CH3CN)4]PF6, PPh3, Et3N, CH2Cl2, 4-Š
molecular sieves, room temperature, 5 h; then DBU, room temper-
ature, 30 min; c) BnBr, NaH, DMF, room temperature, 12 h; d) LiAlH4,
THF, 08C, 3 h; e) MnO2, acetone, room temperature, 14 h.
9262 www.angewandte.org
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Angewandte
Chemie
of the ester groups and alcohol oxidation with MnO2). The
terpyrrole dialdehyde 29 was then used as a substrate for the
simultaneous construction of two pyrrole rings via the
corresponding bis(a-iminoester) to provide the pentapyrrole
31 as the main product in 47% yield from 29. The
quaterpyrrole aldehyde that results from monocycloaddition
was also isolated as a minor product (12%). As a demon-
stration of the generality of this novel method for the
synthesis of a,a’-linked oligopyrroles, the trisheterocycle 28
(47%) and pentaheterocycle 32 (44% yield[31] from the
dialdehyde 30) were obtained by the same reaction sequence
from the thiophene dialdehyde 24.
Finally, to complement these syntheses of oligopyrroles
with an odd number of pyrrole units, we applied a similar
(2+2) construction strategy to the synthesis of oligopyrroles
with an even number of pyrrole units, such as quaterpyrroles
(Scheme 4). Vilsmeier formylation (POCl3, DMF)[32] of the
Keywords: azomethine ylides · cycloaddition · oligopyrroles ·
pyrroles · vinyl sulfones
.
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Scheme 4. Synthesis of the quaterpyrrole 35: a) POCl3, DMF, 08C!RT,
12 h; b) glycine methyl ester hydrochloride, Et3N, EtOH, SiO2, ultra-
sound, room temperature, 2 h; c) 1, [Cu(CH3CN)4]PF6, PPh3, Et3N,
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previously prepared bipyrrole aldehyde 18 provided the
symmetrical bipyrrole dialdehyde 33 (76% yield), a suitable
substrate for the construction of two further pyrrole rings.
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azomethine ylides derived from a-iminoesters, followed by
DBU-promoted elimination of the sulfonyl groups in situ,
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Received: July 20, 2007
Published online: October 23, 2007
Angew. Chem. Int. Ed. 2007, 46, 9261 –9264
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 9263
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Communications
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for the elimination of the sulfonyl groups provided the pyrrole
product in lower yields.
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[29] The very lowreactivity of the imine that has a free pyrrole
moiety could be ascribed to competitive coordination of the
pyrrole nitrogen atom with the copper catalyst.
[30] C. E. Loader, H. J. Anderson, Synthesis 1978, 295 – 297.
[31] The quaterpyrrole that results from a single 1,3-dipolar cyclo-
addition and hydrolysis of the second imine unit was also
isolated as a minor product in 14% yield; see the Supporting
Information for details.
[32] T. Zielinski, J. Jurczak, Tetrahedron 2005, 61, 4081 – 4089.
[33] In the synthesis of the quaterpyrrole 35, the best result was
obtained by prior purification of the sulfonyl adduct by flash
chromatography then DBU-promoted aromatization (51%
overall yield from the dialdehyde 33). A minor amount of the
terpyrrole (7%) that results from monocycloaddition was also
isolated; see the Supporting Information for details.
9264 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 9261 –9264
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