Lewis acid-catalyzed one-pot, three-component route to chiral 3,3′-bipyrroles

Article abstract of DOI:10.1021/ol800115p

(Chemical Equation Presented) 3,3′-Bipyrroles 3 could be synthesized using a double Michael addition reaction involving diaroyl acetylene 1 and the appropriate 1,3-dicarbonyls 2 using ammonium acetate as a nitrogen source. The axial chirality of bipyrrole was anticipated from the X-ray crystal structure and DFT calculations and confirmed by separating the racemates on a chiral column and subsequent CD spectra of the enantiomers. The absolute configuration of the enantiomers was achieved by theoretical CD spectra calculation using the ZINDO method.

Full text of DOI:10.1021/ol800115p

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1373-1376
Lewis Acid-Catalyzed One-Pot,
Three-Component Route to Chiral
3,3′-Bipyrroles
Sumit Dey,† Churala Pal,† Debkumar Nandi,† Venkatachalam Sesha Giri,†
|
|
Marek Zaidlewicz,‡ Marek Krzeminski,‡ Lidia Smentek,§, B. Andes Hess, Jr.,
Jacek Gawronski, Marcin Kwit, N. Jagadeesh Babu,# Ashwini Nangia,# and
Parasuraman Jaisankar*,†
Department of Chemistry, Indian Institute of Chemical Biology (Unit of C.S.I.R),
JadaVpur, Calcutta 700 032, India, Faculty of Chemistry and Institute of Physics,
Nicolaus Copernicus UniVersity, 87-100 Torun´, Poland, Department of Chemistry,
Vanderbilt UniVersity, NashVille, Tennessee 37235, Department of Chemistry,
Adam Mickiewicz UniVersity, 60-780 Poznan´, Poland, and School of Chemistry,
UniVersity of Hyderabad, Hyderabad 500 046, India
jaisankar@iicb.res.in
Received January 18, 2008
ABSTRACT
3,3′-Bipyrroles 3 could be synthesized using a double Michael addition reaction involving diaroyl acetylene 1 and the appropriate 1,3-dicarbonyls
2 using ammonium acetate as a nitrogen source. The axial chirality of bipyrrole was anticipated from the X-ray crystal structure and DFT
calculations and confirmed by separating the racemates on a chiral column and subsequent CD spectra of the enantiomers. The absolute
configuration of the enantiomers was achieved by theoretical CD spectra calculation using the ZINDO method.
Bipyrroles not only are key subunits in important natural
products but also are known for their conducting properties.
Polypyrroles are one of the most extensively studied1 con-
ducting polymers, since they possess numerous attractive
features that are important to material science such as good
redox properties, environmental stability, and high electrical
conductivity. They have found applications as supercapaci-
tors, electrochemical sensors, antistatic coatings, and drug
delivery systems.2 Bipyrroles are found as natural products
belonging to the prodigiosin family,3 and they are also known
to exhibit a broad range of activity against bacteria, protozoa,
and pathogenic fungi. They are capable of inducing apoptosis
in many different human cancer cell lines with few side
effects.4
A few halogenated bipyrroles have also been isolated from
the blubber of marine mammals.5 The commonly encoun-
† Indian Institute of Chemical Biology.
‡ Faculty of Chemistry, Nicolaus Copernicus University.
§ Institute of Physics, Nicolaus Copernicus University.
| Vanderbilt University.
(2) (a) Scrosati, B. Applications of ElectroactiVe Polymers; Chapman &
Hall: London, 1993. (b) Rodriguez, J.; Grande, H. J.; Otero, T. F. In
Handbook of Organic ConductiVe Molecules and Polymers; Nalwa, H. S.,
Eds.; John Wiley & Sons: New York, 1997; p 415.
(3) Rapoport, H.; Holden, K. G. J. Am. Chem. Soc. 1962, 84, 635.
(4) (a) Yamamoto, C.; Takemoto, H.; Kuno, H.; Yamamoto, D.; Tsubura,
A.; Kamata, K.; Hirata, H.; Yamamoto, A.; Kano, H.; Seki, T.; Inoue, K.
Hepatology 1999, 30, 894. (b) Montaner, B.; Pe´rez-Toma´s, R. Life Sci.
2001, 68, 2025.
Adam Mickiewicz University.
# University of Hyderabad.
(1) (a) Simonet, J.; Berthelot, J. R. Prog. Solid State Chem. 1991, 21, 1.
(b) Wise, D. L.; Winek, G. E.; Trantolo, D. J.; Cooper, T. M.; Gresser, J.
D. In Electrical and Optical Polymer Systems; Marcel Dekker Inc.: New
York, 1998, Vol. 17.
10.1021/ol800115p CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/13/2008

tered bipyrroles possess mainly the 2,2′-bipyrrole basic
moiety. Hinz et al.6 have synthesized 2,2′-bipyrrole using
pyrolysis of 2-azido-5-(2-pyrrolyl)penta-2,4-dienoic esters.
Apart from 2,2′-bipyrrole, Zaitsev et al.7 have also prepared
2,3′-analogues of bipyrrole through the intermediacy of
O-vinyloxime pyrroles. The first notable observation was
made during the synthesis of CC-1065, a potent antitumor
and antibiotic wherein 3,3′-bipyrrole was the building block.8
The importance of the bipyrrole came to the fore recently
when Wasserman et al.9 synthesized the natural product
isochrysohermidin, earlier isolated from Mercurialis leio-
carpa in the d,l and meso form using singlet oxygen
oxidation of the 3,3′-bipyrrole scaffold as the key step.
Gleiter et al.10 have reported palladium mediated synthesis
of 3,3′-bipyrroles. Che et al.11 have also synthesized highly
luminescent functionalized bipyrroles. The synthesis by
Peters et al.12 of crown-ether functionalized bipyrroles having
the property of conducting ions undoubtedly encouraged the
organic chemist to explore this area of bipyrroles.
Table 1. Synthesis of Chiral 3,3′-Bipyrroles 3a-k
entry
Ar
R
product time (min) yield (%)
a
b
c
d
e
f
g
h
i
C6H5
C6H5
C6H5
4-Me-C6H4
4-Me-C6H4
4-Br-C6H4
4-Br-C6H4
4-Cl-C6H4
4-Cl-C6H4
OEt
OMe
Me
OEt
OMe
OEt
OMe
OEt
OMe
3a
3b
3c
3d
3e
3f
3g
3h
3i
45
30
25
40
35
50
30
25
30
35
50
76
72
64
70
73
61
65
62
66
64
67
j
k
3-Cl-4-Me-C6H3 OEt
3-Cl-4-Me-C6H3 OMe
3j
3k
InCl3, ZnCl2, and FeCl3 all of which promoted the reaction.
In(OTf)3 and InCl3 in catalytic quantities (20 mol %) pro-
vided the best result in comparison to other Lewis acids
investigated (see the Supporting Information). In the absence
of the metal salts the desired product was not formed in good
yield.
The reaction has also been studied using different solvents
at 80-90 °C using InCl3 as a catalyst. Among the solvents
used only isopropyl alcohol (IPA) and methanol gave the
desired product in reasonable yields with isopropyl alcohol
(IPA) providing a better yield (see the Supporting Informa-
tion). It is pertinent to mention here that when the same
reaction was performed with a catalytic amount of saturated
anhydrous HCl in IPA the reaction failed to proceed even
after 4 h of refluxing.
In our endeavor to synthesize some key nitrogen hetero-
cycles, it was envisaged that dissymmetrical bipyrroles could
be synthesized through a multicomponent synthetic approach
involving double Michael addition followed by cyclization.
In this reaction, diaroyl acetylene 1a-e, â-keto esters 2a,b,
and ammonium acetate in the presence of a Lewis acid cata-
lyst (Scheme 1) resulted in 3,3′-bipyrroles 3a,b,d-k in good
Scheme 1. One-Pot Synthesis of 3,3′-Bipyrroles 3a-k
In order to investigate the mechanistic pathway leading
to the product during the reaction of dibenzoyl acetylene (1a)
and ethyl acetoacetate (2a) in the presence of InCl3 in IPA
at 80-90 °C, the intermediate 4a formed was isolated and
characterized. It was possible to isolate 4 when the above
reaction was stopped before completion. This intermediate
4 results from the Lewis acid assisted Michael addition of
â-keto carbonyl 2 with diaroyl acetylene 1, followed by
ammonia addition and subsequent cyclization with loss of
water.13 4 then undergoes Michael addition with another
molecule of â-keto carbonyls 2 followed by a similar reaction
sequence resulting in 3,3′-bipyrroles 3 (Scheme 2).
Scheme 2. Proposed Mechanism for Formation of
3,3′-Bipyrroles 3a-k
yield (Table 1). Also, reaction of 1a and acetyl acetone (2c)
gave the expected bipyrrole 3c, but reactions involving di-
aroyl acetylene 1b-e and acetyl acetone (2c) gave an insep-
arable mixture of products. The reaction has been studied to
obtain optimum conditions necessary for the product for-
mation. Thus, the reaction was performed in the pres-
ence of various Lewis acids in isopropyl alcohol (IPA) at
80-90 °C. The Lewis acid catalysts used include In(OTf)3,
(5) (a) Vetter, W.; Alder, L.; Palavinskas, R. Rapid Commun. Mass
Spectrom. 1999, 13, 2118. (b) Tittlemier, S. A.; Simon, M.; Jarman, W.
M.; Elliott, J. E.; Norstrom, R. EnViron. Sci. Technol. 1999, 33, 26.
(6) Hinz, W.; Jones, R. A.; Patel, S. U.; Karatza, M.-H. Tetrahedron
1986, 42, 3753.
(7) Zaitsev, A. B.; Schmidt, E. Y.; Mikhaleva, A. M.; Afonin, A. V.;
Ushakov, I. A. Chem. Heterocycl. Compd. (N. Y.) 2005, 41, 722.
The bipyrroles were expected to show atropisomerism, and
as anticipated the X-ray crystal structure (Figure 1) of 3a
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Org. Lett., Vol. 10, No. 7, 2008

Figure 1. ORTEP diagram of 3,3′-bipyrrole 3a (without hydrogen
atoms for clarity).
Figure 3. Chiral HPLC profile of 3c.
revealed that the two-pyrrole rings are disposed with a
C3-C4-C18-C17 torsion angle of 82.72 and a C5-C4-
C18-C19 torsion angle of 87.90, which confirms that they
are not in the same plane. This is further corroborated by
the DFT calculations of 3c. It was found (see the Supporting
Information) that there are potentially ten diastereomeric
conformers of 3c. All reasonable transition structures linking
these ten diastereomers were located computationally, and
the recently generalized Winstein-Holness equation14 was
used to compute the activation energy for the racemization
of 3c (26.7 kcal/mol). This prompted us to attempt the
resolution of 3a. To date only three chiral bipyrroles, one
with a 1,1′-attachment15 and two with a 2,2′-linkage,16,17 have
been reported. Atropisomerism has also been observed in a
poly-â-pyrrole.18
The absolute configuration of the two enantiomers of 3a
follows from the theoretical CD spectra calculation using
The racemic bipyrroles 3a (Figure 2) and 3c (Figure 3)
were indeed separated by HPLC on a chiral OD-H column,
Figure 4. CD spectra of the two enantiomers of 3a.
the ZINDO method. The calculations were performed for
both the X-ray determined structure (not optimized) and the
(8) (a) Magnus, P.; Or, Y.-S. J. Chem. Soc., Chem. Commun. 1983, 26.
(b) Magnus, P.; Gallagher, T.; Schultz, J.; Or, Y.-S.; Ananthanarayan, T.
P. J. Am. Chem. Soc. 1987, 109, 2706. (c) Carter, P.; Fitzjohn, S.; Halazy,
S.; Magnus, P. J. Am. Chem. Soc. 1987, 109, 2711. (d) Hanka, L. J.; Dietz,
A.; Gerpheide, S. A.; Kuentzel, S. L.; Martin, D. G. J. Antibiot. 1978, 31,
1211. (e) Hurley, L. H.; Needham-VanDevanter, D. R. Acc. Chem. Res.
1986, 19, 230.
(9) Wasserman, H. H.; Rotello, V. M.; Frechette, R.; DeSimone, R. W.;
Yoo, J. U.; Baldino, C. M. Tetrahedron 1997, 53, 8731 and references cited
therein.
(10) Gleiter, R.; Ritter, J. Tetrahedron 1996, 52, 10383.
(11) Che, C.-M.; Wan, C.-W.; Lin, W.-Z.; Yu, W.-Y.; Zhou, Z.-Y.; Lai,
W.-Y.; Lee, S.-T. Chem. Commun. 2001, 721.
Figure 2. Chiral HPLC profile of 3a.
(12) Peters, M.; Hallensleben, M. L.; van Hooren, M. J. Mater. Chem.
1999, 9, 1465.
(13) Barton, D. H. R.; Motherwell, W. B.; Zard, S. Z. Tetrahedron Lett.
1984, 25, 3707.
(14) Baldwin, J. E.; Raghavan, A. S.; Hess, B. A., Jr.; Smentek, L. J.
Am. Chem. Soc. 2006, 128, 14854.
and the CD spectra of the separated enantiomers confirm
this (Figure 4). (+)-3a and (-)-3a represent the enantiomers
with retention times of 11.328 and 18.015 min, respectively.
Org. Lett., Vol. 10, No. 7, 2008
1375

In summary, 3,3′-bipyrroles 3 could be synthesized using
a very simple and efficient double Michael addition reaction.
Reaction of a diaroyl acetylene 1 and the appropriate 1,3-
dicarbonyl 2 with ammonium acetate as the nitrogen source
results in pyrrole 4 which undergoes another Michael addi-
tion and nitrogen insertion for the bipyrrole formation. The
atropisomers were separated on a chiral column and char-
acterized. This work has necessitated further studies involv-
ing the application of the bipyrroles as chiral ligands and
also screening of the compounds in vitro for anticancer activ-
ity. The importance of the electrochemical sensing property
of the bipyrroles requires studies in this direction also.
Acknowledgment. Financial support from the Depart-
ment of Science and Technology (DST), New Delhi, Govern-
ment of India and Ministry for Scientific Research and
Higher Education (MNII), Warsaw, Poland (Grant INT/POL/
P-06/05) under “Indo-Polish Programme of Cooperation in
Science and Technology” is gratefully acknowledged. The
authors S.D., C.P., and D.N. thankfully acknowledge the
UGC and CSIR, New Delhi India, respectively, for the
financial support in the form of a research fellowship. Thanks
are also due to Dr. P. K. Das of the Indian Association for
the Cultivation of Science, Calcutta, India for CD spectra
and Mr. S. Samaddar, IICB for IR analyses.
Figure 5. Comparison of experimental CD spectrum (in mdeg) of
(+)-3a and ZINDO calculated CD spectra (Rvel) of 3a with assumed
M-helicity of the 3,3′-bipyrrole unit.
PM3 optimized structure. The structures differ in the mag-
nitude of the 3,3′-bipyrrole dihedral angle (see the Supporting
Information). However, the calculated CD spectra for the
two structures with assumed M-helicity are qualitatively
similar. Moreover, the experimental CD spectrum for
(+)-3a agrees well with the calculated CD spectra (Figure
5). Therefore the absolute configurations of (+)-3a and
(-)-3a are found to be R and S, respectively (Figure 6).
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds,
X-ray crystal structure coordinates and files in CIF format,
DFT calculation data and theoretical CD spectra studies, and
HPLC profiles of 3a and 3c. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL800115P
(15) Chang, C.; Adams, R. J. Am. Chem. Soc. 1931, 53, 2353.
(16) Webb, J. L. A. J. Org. Chem. 1953, 18, 1423.
(17) Skowronek, P.; Lightner, D. A. Monatsh. Chem. 2003, 134, 889.
(18) Magnus, P.; Danikiewicz, W.; Kadoh, T.; Huffman, J. C.; Folting,
K. J. Am. Chem. Soc. 1990, 112, 2684.
Figure 6. Absolute configuration of the two enantiomers of 3a.
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Org. Lett., Vol. 10, No. 7, 2008