Straightforward acid-catalyzed synthesis of pyrrolyldipyrromethenes

Article abstract of DOI:10.1002/anie.201202850

Three for one: Pyrrolyldipyrromethenes having different functional groups were efficiently synthesized from POCl₃-promoted condensations between 5-chloro-2-formylpyrrole or isoindole derivatives and suitable pyrrole or indole fragments through a novel nucleophilic aromatic substitution of the initially formed protonated azafulvene rings. Copyright

Full text of DOI:10.1002/anie.201202850

Angewandte
Chemie
DOI: 10.1002/anie.201202850
Synthetic Methods
Straightforward Acid-Catalyzed Synthesis of Pyrrolyl-
dipyrromethenes**
Changjiang Yu, Lijuan Jiao,* Xujun Tan, Jun Wang, Yajun Xu, Yangchun Wu, Gaosheng Yang,
Zhaoyun Wang, and Erhong Hao*
Conjugated oligopyrroles are the core component of many
natural products including porphyrins, expanded porphyrins,
streptorubin B, tambjamines, and prodigiosins (Figure 1).
They have found wide applications in organic synthesis,
medicinal chemistry, material science, supramolecular
chemistry, and nanotechnology[1] as anion binding and
cation coordination reagents,[1b,2] and photosensitizers,[1f] as
well as key synthetic precursors for the construction of
conducting polymers,[3] liquid crystals,[4] and nonlinear optical
devices.[5] Among these, pyrrolyldipyrromethenes, wherein
each of the pyrrole units is either covalently linked at the 2,2’-
positions or through a methylene bridge, serves as the core
structure of prodigiosins and analogues and have received
special attention because of the wide range of interesting
biological activities associated with these structures.[6–8]
Currently, only limited methods are available for the
construction of 2,2’-linked oligopyrroles, including the Vils-
meier condensation,[9] Paal–Knorr cyclization,[10] oxidative
coupling of a-unsubstituted pyrroles,[11] Ullmann coupling,[12]
and other metal-mediated coupling reactions.[13] Among
these, few strategies are applicable for the construction of
pyrrolyldipyrromethenes in which the key synthetic step is
also the construction of the 2,2’-bipyrrole unit, that is, the
direct covalent bond between the pyrrole unit A and azaful-
vene unit B (Figure 1). The available synthetic methods[1c,14–18]
for pyrrolyldipyrromethenes, although elegant, involve multi-
ple steps, often require the use of expensive catalysts, and
suffer from limited diversity of bipyrrole units. Such diversity
is desirable for studying the structure–activity relationships of
these pyrrole alkaloids. For example, the derivation of the C-
ring alkyl substituents of prodigiosin or undecylprodiginine to
produce Obatoclax and PNU-156804 (Figure 1) has improved
the therapeutic potential of their natural analogues.[19,20]
Herein we report a straightforward POCl3-promoted
synthesis of pyrrolyldipyrromethenes in good yields from
the condensation of 5-halogenated-2-formylpyrrole deriva-
tives or analogues thereof (isoindoles) with suitable pyrrole
(or indole) fragments through a novel nucleophilic aromatic
substitution (SNAr) of the protonated azafulvene rings. Our
synthesis features the use of a common acid catalyst to
generate the target pyrrolyldipyrromethenes within two steps,
and is also diversity oriented.
Initially, the reaction was performed by condensing 5-
chloro-2-formylisoindole (2a) with excess amounts of pyrrole
in the presence of POCl3 in dichloromethane at room
temperature under argon (Scheme 1), and the desired pyrro-
ledipyrromethene 1a was smoothly generated as the major
product in 61% yield. Subsequently, our synthetic strategy
was extended to the condensation of 2a with a set of alkyl-
substituted pyrroles, from which the corresponding pyrrolyl-
dipyrromethenes 1b–d were obtained in 57–75% yields upon
isolation. Among these, the use of 3-acetyl-2,4-dimethyl
pyrrole, possessing an electron-withdrawing acetyl group,
for the reaction led to the lowest yield (1d).
By contrast, 5-chloro-2-formylpyrrole (2b) and 5-bromo-
2-formyl-3-methoxylpyrrole (2c) slowly condensed with pyr-
roles under the above reaction conditions. By replacing
dichloromethane with 1,2-dichloroethane under refluxing
conditions, we were still able to obtain the desired pyrrolyl-
dipyrromethenes 1e–h in 41–48% yields upon isolation.
To demonstrate the versatility of our one-pot synthesis of
pyrrolyldipyrromethenes 1 and to introduce functionality
onto the methene bridge in the pyrroledipyrromethene
chromophore, we used 5-chloro-2-acetylisoindole (2d), an
Figure 1. Naturally occurring pyrrolyldipyrromethenes (prodigiosin and
undecylprodiginine) and their corresponding synthetic analogues
(Obatoclax and PNU-156804).
[*] C. Yu, Prof. Dr. L. Jiao, X. Tan, J. Wang, Y. Xu, Y. Wu, Prof. Dr. G. Yang,
Z. Wang, Prof. Dr. E. Hao
Laboratory of Functional Molecular Solids, Ministry of Education
Anhui Laboratory of Molecule-Based Materials
School of Chemistry and Materials Science
Anhui Normal University, Wuhu, 241000 (China)
E-mail: jiao421@mail.ahnu.edu.cn
haoehong@mail.ahnu.edu.cn
[**] This work is supported by the National Nature Science Foundation
of China (Grants 20802002, 20902004 and 21072005), Anhui
Province (Grants 090416221 and KJ2009A130), and the Ministry of
Education of China (Grant 20093424120001).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202850.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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Scheme 2. Proposed mechanism for the formation of pyrrolyldipyrro-
methenes under POCl3-promoted condensation conditions.
ated azafulvene unit in this in situ generated A could
participate in an unexpected SNAr reaction with a suitable
a-unsubstituted pyrrole to form the pyrroledipyrromethene
B. Therefore, the isolation of this intermediate A would
provide opportunities for the construction of unsymmetrical
pyrrolyldipyrromethenes in a two-step fashion.
To test our hypothesis, 9-chlorodipyrromethene (4a) was
prepared in 79% yield, using a modified literature proce-
dure,[23] from the acid-catalyzed condensation of equal
equivalents of 5-chloro-2-acetylisoindole (2d) with 3-ethyl-
2,4-dimethylpyrrole, and was applied for the subsequent
condensation with pyrrole (Scheme 3). The pyrroledipyrro-
methene 3a was smoothly generated in 90% yield upon
isolation.
Scheme 1. POCl3-promoted one-pot syntheses of pyrrolyldipyrrome-
thenes 1a–k. Reaction conditions for 1a–d and 1i–k: dichloromethane,
room temperature, 2 h. Reaction conditions for 1e–f and 1g–h: 1,2-
dichloroethane, refluxing, 7–8 h.
isoindole ketone, for the condensation. Interestingly, a high
reactivity was observed for 2d as compared to that of 2a: the
condensation can be performed at room temperature, and the
desired pyrrolyldipyrromethenes 1i–k were obtained in 72–
79% yields upon isolation.
This interesting one-pot formation of pyrrolyldipyrrome-
thenes prompted us to study the possible mechanism for this
reaction. The acid-catalyzed condensation of a 2-formylpyr-
role with an a-unsubstituted pyrrole is known to form
dipyrromethenes in a salt form[21] before subsequent work-
up with base. Since their initial synthesis, by Hans Fischer in
1934, dipyrromethenes as dipyrrinato ligands have been
widely studied and continually attract interest because of
their synthetic utility as porphyrin precursors and their rich
photophysical properties.[22] In our case, the acid-catalyzed
condensation of 5-halo-2-formylpyrroles (or isoindoles) with
an a-unsubstituted pyrrole generated the 9-halodipyrrome-
thene A in salt form (Scheme 2). Subsequently, the proton-
Scheme 3. Syntheses of 9-chlorodipyrromethenes 4a–d and pyrrolyldi-
pyrromethenes 3a–g.
2
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As shown in Scheme 3, condensation of the 9-chlorodi-
pyrromethenes 4b–d with pyrrole and various substituted
pyrroles at room temperature efficiently generated the
corresponding pyrrolyldipyrromethenes 3b–e in 76–90%
yields upon isolation. Interestingly, indole derivatives also
showed good reactivities in this reaction and gave 3 f and 3g
in 76 and 51% yields, respectively.
Most natural prodigiosin analogues have a B-ring 3-
methoxy group in their structure, and it is closely associated
with their many biological activities. To further study the
versatility of our synthetic method and to investigate its
possible applicability for the preparation of certain natural
prodigiosin analogues, the pyrrolyldipyrromethene 5 was
synthesized in 41% yield from the reaction of pyrrole with
dipyrromethene 6, which was generated from the reaction of
5-bromo-2-formyl-3-methoxylpyrrole (2c) with 2,4-dimethyl-
3-ethylpyrrole by adopting a modified literature procedure[23]
(Scheme 4).
Figure 3. X-Ray structure of 3d. Selected torsional angle [8]: N1-C4-C5-
N2, À3.2. C grey, N blue, O red. For details of the X-ray analysis
results, including the CCDC number, see the Supporting Informa-
tion.[25]
hydrogen atoms of prodiginine 1g·HCl are oriented towards
the chloride counterion to form hydrogen-bonding interac-
tions, and the NH···Cl distances are almost equal.
Beyond these hydrogen-bonding interactions, the chloride
ion is hydrogen bonded to a methylene chloride molecule in
the crystal lattice. The compound was crystallized from
methylene chloride and in the absence of any other hydro-
gen-bonding partner, thus 1g·HCl forms a dimer of two
molecules in the asymmetric unit held together by a network
of intermolecular hydrogen bonds to methylene chloride
molecule in the crystal lattice. It bridges two such chlorides
and helps the formation of a dimer structure in the lattice.
Such a CH–Cl interaction is similar to those OH–Cl
interactions reported in the literature.[24]
We have developed a new synthetic strategy for the facile
preparation of a series of pyrrolyldipyrromethenes, and it
features the usage of POCl3 as promoter to generate the
desired pyrrolyldipyrromethenes in good to excellent yields
within two steps and is diversity oriented. Our methodology
may provide an efficient way for the facile synthesis of 2,2’-
bipyrroles and oligopyrroles. Additional investigations of
their anticancer efficiency, their synthetic applications in
building macrocyles, and the photophysical properties of their
metal complexes are underway.
Scheme 4. Syntheses of the B-ring methoxy pyrrolyldipyrromethene 5.
The single-crystal X-ray structures of 1g and 3d are shown
in Figures 2 and 3, respectively. The pyrroledipyrromethene
framework of these two compounds are extremely flat with
only the methyl, methoxy, and acetyl groups lying out of the
plane of these pyrrolyldipyrromethene cores. In both cases,
the azafulvene ring is clearly identifiable as the B ring and the
three nitrogen atoms of the rings are all oriented in the same
direction on the same side of the chormophore. All three NH
Received: April 13, 2012
Published online: && &&, &&&&
Keywords: aromatic substitution · dyes/pigments ·
.
homogeneous catalysis · nitrogen heterocycles ·
synthetic methods
Figure 2. X-Ray structure of the 1g·HCl dimer. Selected bond lengths
[ꢀ]: N1H–Cl1 2.30, N2H–Cl1 2.36, N3H–Cl1 2.33, N4H–Cl2 2.33,
N5H–Cl2 2.38, N6H–Cl2 2.35. Selected torsional angles [8]: N1-C5-C7-
N2 2.3, N2-C10-C13-N3 1.5, N4-C23-C25-N5 0.8, N5-C28-C31-N6 2.5.
C grey, N blue, O red, Cl green. For details of the X-ray analysis results,
including the CCDC number, see the Supporting Information.[25]
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4
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Synthetic Methods
C. Yu, L. Jiao,* X. Tan, J. Wang, Y. Xu,
Y. Wu, G. Yang, Z. Wang,
E. Hao*
&&&& — &&&&
Straightforward Acid-Catalyzed Synthesis
of Pyrrolyldipyrromethenes
Three for one: Pyrrolyldipyrromethenes
having different functional groups were
efficiently synthesized from POCl3-pro-
moted condensations between 5-chloro-
2-formylpyrrole or isoindole derivatives
and suitable pyrrole or indole fragments
through a novel nucleophilic aromatic
substitution of the initially formed pro-
tonated azafulvene rings.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!