Synthesis of 2,3,5-substituted pyrrole derivatives

Article abstract of DOI:10.1016/S0040-4039(02)00810-9

2,3,5-Substituted pyrrole derivatives are prepared by treatment of 2,3-dihydrofuran derivatives with trifluoroacetic acid. These in turn are obtained by Michael addition of carbon nucleophiles of the β-dicarbonyl type to N-(4-toluenesulfonyl)-N-(tert-buty

Full text of DOI:10.1016/S0040-4039(02)00810-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4491–4493
Synthesis of 2,3,5-substituted pyrrole derivatives
Paula M. T. Ferreira,* Hernaˆni L. S. Maia and Lu´ıs S. Monteiro
Department of Chemistry, University of Minho, Gualtar, P-4700-320 Braga, Portugal
Received 4 April 2002; accepted 25 April 2002
Abstract—2,3,5-Substituted pyrrole derivatives are prepared by treatment of 2,3-dihydrofuran derivatives with trifluoroacetic acid.
These in turn are obtained by Michael addition of carbon nucleophiles of the b-dicarbonyl type to N-(4-toluenesulfonyl)-N-(tert-
butyloxycarbonyl)-dehydroalanine methyl ester. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
(tert-butyloxycarbonyl)-dehydroalanine methyl ester
[Tos-DAla(N-Boc)-OMe].5 These additional products
behaved differently according to the structure of the
nucleophile. Thus, the products of the addition of diethyl
malonate and cyclohexane-1,3-dione, namely, Tos-
Pyrrole derivatives represent a class of compounds of
great importance in heterocyclic chemistry. These com-
pounds can have intrinsic biological activity and also
constitute the structural feature of many biologically
active compounds. The synthetic approaches to pyrrole
derivativesaremostlymultistepandlowyielding.1–4 Thus,
development of new synthetic methods still remains an
attractive goal.
Ala[N-Boc,b-bis(ethoxycarbonyl)-methyl]-OMe
and
Tos-Ala[N-Boc,b-(2,6-dioxocyclohexyl)]-OMe are sta-
ble. However, those of the addition of nucleophiles having
at least one alkyl group bonded to one of the carbonyl
groups, viz. pentane-2,4-dione and methyl acetocetate,
gave cyclic amino acids of the furan type, i.e. 2-(tert-butyl-
oxycarbonylamino)-2-methoxycarbonyl-4-(1-oxoethyl)-
5-methyl-2,3-dihydrofuran (2a)5 and 2-(tert-butyloxy-
carbonylamino) - 2,4 - bis(methoxycarbonyl) - 5 - methyl-
2,3-dihydrofuran (2b).5 We believe that these compounds
result from rearrangement of the detosylated b-substi-
tuted alanine derivative via enolisation with attack of
2. Results and discussion
We have reported the synthesis of b-substituted alanine
derivatives by Michael addition of carbon nucleophiles
of the b-dicarbonyl type to N-(4-toluenesulfonyl)-N-
Scheme 1.
Keywords: dehydroalanine; dihydrofuran; pyrrole; dehydroproline.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00810-9

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P. M. T. Ferreira et al. / Tetrahedron Letters 43 (2002) 4491–4493
Table 1. Yields obtained in the synthesis of 2,3-dihydrofurans (2a–e) and 2,3,5-substituted pyrrole derivatives (3a–e)
Entry
NuH
Compound no.
Yield (%)a
Compound no.
Yield (%)a
1
2
3
4
5
Pentane-2,4-dione (a)
Methyl acetoacetate (b)
Benzoyl acetone (c)
Benzyloxycarbonyl acetone (d)
Isobutylcarbonyl acetone (e)
2a5
2b5
2c
2d
2e
88
86
80
78
82
3a
3b
3c
3d
3e
92
90
77
79
88
a Crude yield of pure material.
the enolic oxygen atom at the amino acid a-carbon
atom (Scheme 1, Table 1). Initially the reactions
were carried out using an excess of K2CO3 as base;
however, it was found that the use of 1 equiv. of
Cs2CO3 leads to less complex reaction mixtures and,
thus, higher yields of dihydrofuran derivatives. This
method was successfully extended to other b-carbonyl
nucleophiles, namely benzoyl acetone (c), benzyloxycar-
bonyl acetone (d) and isobutylcarbonyl acetone (e) to
give new 2,3-dihydrofuran derivatives in good yields.
acetonitrile (0.1 mol dm−3), Cs2CO3 (1 equiv.) was
added at room temperature with rapid stirring, fol-
lowed by benzyloxycarbonyl acetone (1 equiv.), The
reaction was monitored by TLC and when no starting
material was detected, the solution was filtered and the
solvent evaporated at reduced pressure to give 2d (78%)
as an oil, lH (300 MHz; CDCl3; Me4Si) 1.44 (9H, s,
CH3 Boc), 2.27 (3H, s, CH3), 3.20 (2H, q, J=15.9 Hz,
CH2), 3.84 (3H, s, CH3 OMe), 5.16 (2H, s, CH2), 5.89
(1H, s, aNH), 7.36–7.61 (5H, m, ArH); lC (75.4 MHz;
CDCl3) 28.02, 39.75, 53.42, 67.07, 81.34, 91.15, 100.60,
127.99, 128.30, 128.44, 128.54, 129.75, 136.18, 153.23,
164.65, 166.99, 168.74.
The above 2,3-dihydrofurans showed to be excellent
starting materials for the synthesis of the corresponding
pyrrole derivatives, by treatment at room temperature
with 10% trifluoroacetic acid (TFA) in dichloromethane
(Scheme 2, Table 1). This reaction seems to proceed via
cleavage of the Boc group with ring opening and subse-
quent attack of the nitrogen atom of the amine function
on the enolic carbon atom.
3.2. Preparation of the 2,3,5-substituted pyrrole
derivative 3d
To a solution of 2d (1 mmol) in dichloromethane (0.1
mol dm−3), TFA (10%) was added at room temperature
with rapid stirring. The reaction was monitored by
TLC and when no starting material was detected, 30
cm3 of dichloromethane were added and the solution
was washed with NaHCO3 1 mol dm−3 and saturated
brine (3×10 cm3 each) and dried over MgSO4. Removal
of the solvent at reduced pressure afforded 3d (79%),
mp 129.5–130.5°C (from diethyl ether/n-hexane),
(found: C, 65.92; H, 5.51; N, 5.15. Calcd for
C15H15NO4: C, 65.93; H, 5.53; N, 5.13%); lH (300
MHz; CDCl3; Me4Si) 2.58 (3H, s, CH3), 3.86 (3H, s,
CH3 OMe), 5.29 (2H, s, CH2), 7.28 (1H, d, J=2.7 Hz,
CH), 7.33–7.44 (5H, m, ArH), 9.21 (1H, s, aNH); lC
(75.4 MHz; CDCl3) 13.51, 51.69, 65.58, 113.83, 117.40,
120.43, 128.01, 128.51, 129.76, 136.45, 139.72, 161.29,
164.31.
The pyrrole derivatives described above are dehydro-
prolines, which may have intrinsic biological activity,
making them suitable for the synthesis of modified
peptides to which they would certainly impose high
conformational constraints. Thus, we believe this
method to be excellent for the synthesis of furanic
amino acids and dehydroprolines derivatives.
3. General experimental procedure (example)
3.1. Preparation of the 2,3-dihydrofuran derivative 2d
To a solution of Tos-DAla(N-Boc)-OMe (1 mmol) in
Scheme 2.

P. M. T. Ferreira et al. / Tetrahedron Letters 43 (2002) 4491–4493
615–628.
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Acknowledgements
2. Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1999,
2849–2866.
We wish to thank the Fundac¸a˜o para a Cieˆncia e a
Tecnologia for financial support (project POCTI/1999/
QUI/32689).
3. Lagu, B.; Pan, M.; Wachter, M. P. Tetrahedron Lett. 2001,
42, 6027–6030.
4. Attanasi, O.; Fillipone, P.; Perrulli, F. R.; Santensanio, S.
Tetrahedron 2001, 57, 1387–1394.
5. Ferreira, P. M. T.; Maia, H. L. S.; Monteiro, L. S.;
Sacramento, J. J. Chem. Soc., Perkin Trans. 1 2001, 3167–
3174.
References
1. Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1998,