2
828
other α-position (entry 6), no oxidation takes place. If the EWG is at a β-position and opposite to the
4
formyl group (entries 7 and 8), moderate yields of ∆ -pyrrolin-2-one can be isolated; when the two
3
4
EWGs are adjacent (entry 9), no oxidation is detected. The structural assignments as ∆ and ∆ have
7
,8,12
4
been made in correlation with previous works on the subject,
showing H-3 of the ∆ form to be at
3
3
higher field than H-5 of the ∆ form. The ∆ structure was confirmed by the equivalence of the two H-5s
entries 1 to 5) and the ∆ by unambiguous NMR structure assignment of a parent compound. These
4
13
(
mild conditions allow the reaction to be carried out with pyrroles bearing a wide variety of substituents,
thus making it particularly interesting for the synthesis of bile pigments, which often bear alkyl, propionic
acid or vinyl side-chains, the latter being easily generated from the protected 2-hydroxyethyl group (as
1
4
in entry 4).
Only one example of α-free dipyrromethane oxidation with H O , giving a moderate yield (45%) of
2
2
8
the 4,5-dihydrodipyrrin-1-one (4), has been reported. Dipyrromethanes behave similarly to monopyr-
roles. Table 2 shows the results for α-formyldipyrromethanes (3), which are oxidized with concomitant
loss of the formyl group; if the second α-position is free, low yields of products are obtained (entry
1
0), while with a larger excess of H O the α-free pyrrole ring (B) is also oxidized (39%, not shown).
2
2
0
With α-formyldipyrromethanes bearing an EWG at the α -position, only 4,5-dihydrodipyrrin-1-ones are
obtained in good yields, the NMR exhibiting a new sp carbon (C-4) bearing a proton (entries 11 to 17).
3
This is of special interest for bile pigment synthesis, as 4,5-dihydrodipyrrinones can only be prepared
through reduction by sodium amalgam or sodium dithionite of their dipyrrinones formed by condensation
of pyrrolin-2-ones with α-formylpyrroles, often in variable yields and with side-product formation.1b
4,5-Dihydrodipyrrinones are also smoothly dehydrogenated in excellent yields to the corresponding
dipyrrinones (5) with 10% Pd–C in mesitylene at reflux. As mentioned above, the vinyl side-chain, often
present in bile pigments, can be easily generated from the protected 2-hydroxyethyl group (as in entries
1
4
1
5 and 16).
In summary, a variety of substituted α-formylpyrroles and -dipyrromethanes have been oxidized
by H O under very mild conditions, giving good to excellent yields of pyrrolin-2-ones and 4,5-
2
2
dihydrodipyrrin-1-ones, thus showing a substantial improvement over most of the other methods describ-
ed in the literature. This represents the first report of H O oxidation of α-formyldipyrromethanes. The
2
2
compatibility of the reaction conditions with diverse functional groups present in bile pigments further
demonstrates its usefulness for preparative purposes. Indeed, this oxidation provides an alternative route
for bile pigment synthesis and especially, should lead to improved yields for the preparation of urobilins
1
4,15
and coprobilins.
Acknowledgements
We thank the NIH (NIDDK) for financial support through a MERIT award.
References
1
2
. Falk, H. In The Chemistry of Linear Oligopyrroles and Bile Pigments; Springer–Verlag: New-York, 1989; pp. 20–39,
55–399, 369–372.
. Katritzky, A. R.; Rees, C. W. In Comprehensive Heterocyclic Chemistry: the Structure, Reactions, Synthesis, and Uses of
Heterocyclic Compounds; Pergamon: Oxford, 1984; Vol. 4, pp. 246–254. Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.
In Comprehensive Heterocyclic Chemistry: a Review of the Literature 1982–1995: the Structure, Reactions, Synthesis, and
Uses of Heterocyclic Compounds; Pergamon: New York, 1996; Vol. 2, pp. 69–70.
3
3
. Jones, R. A.; Bean, G. P. In The Chemistry of Pyrroles; Academic Press: London, 1977; pp. 209–225.
Pichon-Santander, Clotilde
