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
1374
Org. Lett., Vol. 10, No. 7, 2008