pyrrole6a,7b,9,10 in multistep processes. An approach to 3,4-
disubstituted pyrrole-2,5-dicarboxylates consists in de novo
ring construction applying reductive ring contraction of 1,2-
diazines prepared in azadiene Diels-Alder reactions,1 trans-
formation of 1H-pyrrolo-3,4-dialkyl-5-methyl-2-carboxylates
derived from 3-substituted 2,4-pentanediones,11 or using the
Paal-Knorr reaction of anilines with 2,5-dihydroxyhexa-2,4-
dienedioic acid diethyl ester.7a The last procedure is limited
to only N-substituted pyrrole-2,5-dicarboxylates. All of the
mentioned methods lead to designed pyrrole-2,5-dicarboxy-
late derivatives in long, multistep syntheses.
In 1999, Periasamy reported a simple procedure for
preparation of some N-substituted 2,5-diarylpyrroles from
aromatic ketimines12 via titanium(IV) enamines, but the
method is limited only to ketimines generated from aryl-
methyl ketones.
In our research, we focused on the oxidative coupling of
titanium(IV) enolates derived from 2-azidocarboxylic esters.
Titanium(IV) enolates were obtained in accordance with the
method described by Matsumura.13 The titanium(IV) enolates
of 2-azidoesters 2 are very unstable and undergo an intensive
nitrogen extrusion14 even below -80 °C to give intermediate
titanium(IV) complexes of 2-iminoesters 3. The nonisolable
complexes 3 undergo smooth transformation into 3,4-
disubstituted 1-H-pyrrole-2,5-dicarboxylates 4 (Table 1).
pyrrole-2,5-dicarboxylate derivatives 4 is a three-step process.
The first fast step consists in the transformation of 2-azi-
doester 1 to the appropriate 2-iminoester 3. Then the
intermediate 3 can be indicated in a gas chromatogram as
2-ketoester 5 owing to a hydrolytic workup of the sample
isolated from the reaction mixture.
The second slow step is an oxidative coupling of the
2-iminoester 3 followed by very rapid heterocyclization.
Concentration of the final product, 1-H-pyrrole-2,5-dicar-
boxylate derivative 4, increases, while the quantity of the
appropriate 2-iminoester 3 is gradually decreased (see the
Supporting Information).
The total time needed for a complete conversion depends
on the chemical structure of the starting 2-azidoester. Ethyl
2-azidopropionate 1a is fully transformed into pyrrole-2,5-
dicarboxylate 4a in 2 h, but the similar reaction of ethyl
2-azidopalmitate 1f needs 24 h and gives a mixture of
pyrrole-2,5-dicarboxylate 4f and ethyl 2-ketohexadecanoate
5f.
Similarly, L-menthyl 2-azidopropionate 6 can be trans-
formed into pyrrole-2,5-dicarboxylate 7 within 12 h, but the
reaction mixture includes also L-menthyl pyruvate 8 as a
byproduct. A bulky ester group has no influence on conver-
sion of 2-azidocarboxylate into 2-iminoester but makes the
oxidative dimerization slower (Scheme 1).
Table 1. Yields, Conditions, and Reaction Time for
Transformations of Ethyl 2-Azidocarboxylates 1a-f
Scheme 1. Conversion of L-Menthyl 2-Azidopropanoate 6 to
Pyrrole-2,5-dicarboxylate 7 and L-Menthyl Pyruvate 8
entry
R
reaction timea (h)
yield (%) of 4
An analysis of the results makes an assumption that the
oxidative coupling of 2-azidocarboxylates strongly depends
on the substituents at the C-3 carbon atom. A reaction of
ethyl 2-azidoisovalerate 9 having a tertiary carbon atom C-3,
with titanium(IV) chloride and DIEA, can be the confirma-
tion of this hypothesis. GC-MS spectra of the reaction
mixture show that the process stopped after formation of
2-iminoester 10 and there are no traces of the oxidative
coupling products (Scheme 2) including the open-chain
intermediate 11. This experiment proved that the oxidative
a
b
c
d
e
f
H
CH3
C2H5
C3H7
C5H11
1.5
2.5
4.0
5.0
6.4
24
83
76
68
75
55
29
C13H27
a After addition of DIEA.
Monitoring of the reaction with gas chromatography leads
to the conclusion that the conversion of 2-azidoesters 1 into
(8) (a) Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213–7256. (b)
Tsutomu, F.; Yukie, H.; Masatomo, I. Heterocycles 2009, 77 (2), 1105–
(10) Barker, P.; Gendler, P.; Rappoport, H. J. Org. Chem. 1978, 43,
4849–4853.
1122
(9) Matsuki, S.; Mizuno, A.; Annoura, H.; Tatsuoka, T. J. Heterocycl.
Chem. 1997, 34, 87
.
(11) Baciocchi, E.; Muraglia, E.; Sleiter, G. J. Org. Chem. 1992, 57
(8), 2486–2490, references therein.
.
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