An effective new synthesis of 4-aminopyrrole-2-carboxylates

Article abstract of DOI:10.1021/ol0262690

(Matrix presented) A series of 4-amino-1H-pyrrole-2-carboxylic acid benzyl esters has been synthesized in 61-84% yields on treatment of N-PhF-4-oxoproline benzyl ester and its 3-alkyl-substituted derivatives with different primary and secondary amines and

Full text of DOI:10.1021/ol0262690

ORGANIC
LETTERS
2002
Vol. 4, No. 15
2601-2603
An Effective New Synthesis of
4-Aminopyrrole-2-carboxylates†
Fe´lix-Antoine Marcotte and William D. Lubell*
De´partement de chimie, UniVersite´ de Montre´al, C.P. 6128, Succursale Centre-Ville,
Montre´al, Que´bec, Canada H3C 3J7
lubell@chimie.umontreal.ca
Received May 30, 2002
ABSTRACT
A series of 4-amino-1H-pyrrole-2-carboxylic acid benzyl esters has been synthesized in 61−84% yields on treatment of N-PhF-4-oxoproline
benzyl ester and its 3-alkyl-substituted derivatives with different primary and secondary amines and a catalytic amount of TsOH in THF.
4-Hydroxy-1H-pyrrole-2-carboxylic acid benzyl esters were prepared in 59 and 70% yields by treatment of N-PhF-4-oxoproline benzyl esters
with ammonium hydroxide in THF.
As constituents of cytotoxic drugs, such as netropsin and
distamycin, 4-aminopyrrole-2-carboxylates have served as
principle components for constructing a diverse series of
DNA-binding ligands exhibiting antibiotic, antiviral, and
oncolytic properties.1 The related 3-aminopyrroles have also
exhibited anticonvulsant activity by blocking sodium ion
channels.2 Effective methodology for synthesizing 3- and
4-aminopyrroles is thus essential for furthering their applica-
tion in medicinal and biological chemistry. Drawbacks
inherent in previous routes for their preparation have,
however, limited the molecular diversity produced by existing
aminopyrrole synthesis methods.2,3
The most commonly used method for the synthesis of
4-aminopyrrole-2-carboxylates involves Friedel-Crafts acyl-
ation of N-methylpyrrole with trichloroacetyl chloride fol-
lowed by nitration and subsequent reduction of the nitro
group.1f This route has furnished N-methyl-4-aminopyrrole-
2-carboxylate in suitably protected form for oligomer
synthesis.1e,f However, the harsh reaction conditions for
installing the amine and carboxylate limits greatly the
introduction of diverse functional groups. Alternative meth-
ods for aminopyrrole synthesis have recently been reviewed2
and do not provide easy access for adding functionality to
the 1- and 3-positions as well as onto the 4-amino substituent.
We have developed effective syntheses of enantiopure
pyrrolidine-2-carboxylates from 4-hydroxyproline as an
inexpensive chiral educt.4 In particular, alkylation and
triflation of enolates of 4-oxo-N-(PhF)prolinates 2 and 4 have
† Dedicated to the memory of Professor Henry Rapoport, deceased March
7, 2002.
(1) (a) Wang, C. C. C.; Dervan P. B. J. Am. Chem. Soc. 2001, 123,
8657. (b) Woods, C. R.; Ishii, T.; Bair, K. W.; Boger, D. L. J. Am. Chem.
Soc. 2002, 124, 2148. (c) Wellenzohn, B.; Wolfgang, F.; Winger, R. H.;
Hallbrucker, A.; Mayer, E.; Liedl, K. R. J. Am. Chem. Soc. 2001, 123,
5044, and refs 1-33 therein. (d) Sharma, S. K.; Tandon M.; Lown, J. W.
J. Org. Chem. 2001, 66, 1030. (e) Wurtz, N. R.; Turner, J. M.; Baird, E.
E.; Dervan, P. B. Org. Lett. 2001, 3 (8), 1201. (f) Baird, E. E.; Dervan, P.
B. J. Am. Chem. Soc. 1996, 118, 6141. (g) Dyatkina, N. B.; Roberts, C. D.;
Keicher, J. D.; Dai, Y.; Nadherny, J. P.; Zhang, W.; Schmitz, I.;
Kongpachith, A.; Fung, K.; Nokikov, A. A.; Lou, L.; Velligan, M.; Khorlin,
A. A.; Chen, M. S. J. Med. Chem. 2002, 45, 805.
(3) (a) Sauve´, G.; Mansour, T. S. Heterocycles 1988, 27, 315. (b)
Nishiwaki, N.; Nakanishi, M.; Hida, T.; Miwa, Y.; Tamura, M.; Hori, K.;
Tohda, Y.; Ariga, M. J. Org. Chem. 2001, 66, 7535. (c) Selic, L.; Stanovnik,
B. HelV. Chim. Acta 1998, 81, 1634. (d) Ferreira, V. F.; de Souza, M. C.;
Cunha, A. C.; Pereira, L. O.; Ferreira, L. G. Org. Prep. Proc. 2001, 33,
411.
(4) (a) Sharma, R.; Lubell, W. D. J. Org. Chem. 1996, 61, 202. (b)
Rondeau, D.; Gill, P.; Chan, M.; Curry, K.; Lubell, W. D. Bioorg. Med.
Chem. Lett. 2000, 10, 771. (c) Gill, P.; Lubell, W. D. J. Org. Chem. 1995,
60, 2658.
(2) Unverferth, K.; Engel, J.; Ho¨fgen, N.; Rostock, A.; Gu¨nther, R.;
Lankau, H.-J.; Menzer, M.; Rolfs, A.; Liebscher, J.; Mu¨ller, B.; Hofmann,
H.-J. J. Med. Chem. 1998, 41, 63.
10.1021/ol0262690 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/25/2002

provided effective means for introducing substituents at the
proline 3- and 4-positions (PhF ) 9-(9-phenylfluorenyl)).4,5
Enolization and alkylation of N-PhF protected 4-oxoproline
2 is complementary to the alkylation of enamines derived
from the corresponding N-acyl 4-oxoprolines.6 We now
report that reaction with pyrrolidine and p-toluenesulfonic
acid in benzene at reflux did not produce the respective
enamine. Instead, benzyl 4-pyrrolidino-1H-pyrrole-2-car-
boxylate 1a was isolated in 62% yield after purification by
chromatography (Scheme 1). The formation of 1a provided
Table 1. Synthesis of 4-Aminopyrrole 1
Scheme 1
a novel entry into the 4-aminopyrrole system and was clearly
demonstrated by a dramatic transformation of the aromatic
region of the 1H NMR spectrum in which the signals for the
PhF protons were lost and new pyrrole protons at 6.4 and
6.5 ppm were detected.7 Heating the reaction to 50 °C in
THF increased the yield of 1a and diminished the reaction
time. TsOH (10 mol %) catalyzed the generation of 1a.
Excess amine (400 mol %) was necessary for reaction
completion.
The influence of a 3-position substituent was examined
by similarly treating 3-methyl- and 3-allyl-4-oxoprolines 4a
and 4b with pyrrolidine, which produced respectively 3-alkyl
pyrroles 1n and 1o in 73% and 61% yields. No double bond
migration was observed during the synthesis of 3-allylated
analogue 1o.
Best conditions were employed with a variety of amines
and 2 to provide a series of pyrroles 1 in 61-84% (Table
1).7 The sterically hindered diisopropylamine failed to yield
4-aminopyrrole after 12 h and aside for some loss of the
PhF group, 2 was recovered. Treatment of 2 with amines
bearing remote amine and carboxylate functionality was well
tolerated (entries d, j-m).
a Reaction performed in MeCN at room temperature.
1i was obtained, and 4-allylamino-1H-pyrrole 1i was isolated
in 75% yield after chromatography.
Attempts to synthesize 4-aminopyrrole 1p by reacting 2
and TsOH in THF with aqueous ammonium hydroxide, and
in THF and in dioxane with ammonia, all provided 4-hy-
droxypyrrole 2-benzyl ester 5 (Scheme 2). Similarly, treat-
Scheme 2
Allylamine reacted by two different oxidation pathways
undergoing either loss of phenylfluorene to give 1H-pyrrole
1 or hydrogen to provide the N-(PhF)pyrrole counterpart 3.
N-(PhF)Pyrrole 3i could be minimized by using acetonitrile
as solvent. For example, allylamine reacted with proline 2
in THF at 50 °C to give a 1:1 ratio of N-(PhF)pyrrole 3i and
1H-pyrrole 1i. In acetonitrile at 50 °C, this ratio was reduced
to 1:2.5; at room temperature, after 8 h, a 1:4 ratio of 3i and
ment of 3-methyl-4-oxoproline 4a with TsOH and ammo-
nium hydroxide in THF furnished the corresponding 3-methyl-
4-hydroxypyrrole 6 in 59% yield. 4-Aminopyrrole-2-
carboxylate 1p could be isolated in 75% yield after
deprotection of allylaminopyrrole 1i (Scheme 3).
(5) For related methods see (a) Blanco, M.-J.; Paleo, R. P.; Penide, C.;
Sardina, F. J. J. Org. Chem. 1999, 64, 8786. (b) Koskinen, A. M. P.;
Schwerdtfeger, J.; Edmonds, M. Tetrahedron Lett. 1997, 38, 5399.
(6) (a) Holladay, M. W.; Lin, C. W.; May, C. S.; Garvey, D. S.; Witte,
D. G.; Miller, T. R.; Wolfram, C. A. W.; Nadzan, A. M. J. Med. Chem.
1991, 34, 4, 457. (b) Baldwin, J. E.; Rudolph, M.; Tetrahedron Lett. 1994,
35, 6163. (c) Baldwin, J. E.; Bamford, S.; Fryer, A. M.; Rudolph, M. P.
W., Wood, M. E. Tetrahedron 1997, 53, 5233.
When the importance of the 2-carboxylate substituent was
explored using N-(PhF)pyrrolidin-3-one, the corresponding
2602
Org. Lett., Vol. 4, No. 15, 2002

Scheme 3
Scheme 4
loses the aromatic phenylfluorenyl anion9 to form an azadiene
intermediate that aromatizes to pyrrole 1 (Scheme 4).
A series of 4-amino-1H-pyrrole-2-carboxylic acid benzyl
esters have been synthesized in 61-84% yields on treatment
of N-PhF-4-oxoproline benzyl esters 2 and 4 with different
primary and secondary amines and a catalytic amount of
TsOH in THF. 4-Hydroxy-1H-pyrrole-2-carboxylic acid
benzyl esters 5 and 6 were respectively prepared in 70 and
59% yields by treatment of 2 and 4a with ammonium
hydroxide in THF. In light of their importance as components
of drugs, polymers, and materials, this new synthesis of
pyrrole analogues should provide a practical means for
making novel libraries of these valuable compounds.
3-aminopyrrole was not isolated from the reaction with
pyrrolidine and TsOH in THF at 50 °C. Instead, enamine
formation was identified by the presence of vinylic protons
at δ 6.51 (m, J ) 7.6 Hz, 1H) and 5.90 (d, J ) 15.9 Hz,
1
1H) ppm in the crude H NMR spectrum.
A plausible mechanism for the formation of 4-amino-
pyrrole 2-carboxylate may thus involve condensation of the
amine with the ketone to form an imminium ion. Tautomer-
ization toward the 3-position provides an enamine,8 which
(7) A stirred solution of benzyl N-PhF-4-oxo-prolinate (2, 300 mg, 0.653
mmol) in 30 mL of THF was treated with pyrrolidine (185 mg, 2.61 mmol)
followed by TsOH (12 mg, 0.07 mmol), heated to 50 °C, stirred 4 h, and
treated with a solution of saturated aqueous NH4Cl followed by 30 mL of
EtOAc. The layers were separated, and the aqueous layer was extracted
with EtOAc (30 mL × 2). The organic layers were combined, washed with
brine, dried (MgSO4), and concentrated to a residue that was purified by
column chromatography on silica gel using 10% ethyl acetate in hexanes
as eluant. Evaporation of the collected fractions yielded pyrrole 1a (139
Acknowledgment. This research was supported in part
by the NSERC of Canada and the FCAR of Que´bec. F.-
A.M. thanks NSERC for a postgraduate scholarship.
1
mg, 0.514 mmol, 79%) as a green solid: mp 105-107 °C. H NMR (400
Supporting Information Available: Experimental details
for the preparation of aminopyrroles 1a-p and hydroxy-
pyrroles 5 and 6 and full characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
MHz, CDCl3) δ 8.91 (s, 1H), 7.44-7.34 (m, 5H), 6.47 (s, 1H), 6.35 (s,
1H), 5.30 (s, 2H), 3.09 (t, J ) 6.2 Hz, 4H), 1.96 (t, J ) 3.1 Hz, 4H). 13C
NMR (125 MHz, CDCl3) δ 160.6, 140.1, 136.7, 129.0, 128.6, 128.5, 121.0,
107.2, 103.4, 66.3, 51.1, 25.2. HRMS: calcd for C16H18N2O2: 270.1371;
found: 270.1368. Anal. Calcd for C16H18N2O2: C, 71.09; H, 6.71; N, 10.36.
Found: C, 70.79; H, 6.77; N, 10.17.
OL0262690
(8) Enolization of N-alkylpyrrolidin-3-one occurs predominantly away
from the nitrogen-bearing carbon: Garst, M. E.; Bonfiglio, J. N.; Grudoski,
D. A.; Marks, J. J. Org. Chem. 1980, 45, 2307.
(9) Lubell, W. D.; Rapoport, H. J. Am. Chem. Soc. 1987, 109, 236.
Org. Lett., Vol. 4, No. 15, 2002
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