2-vinylpyrroles and pyrrolo[3,2-d]pyrimidines from direct addition of aldehydes to 4-amino-pyrrole-2-carboxylate derivatives

Article abstract of DOI:10.1021/ol702994g

A new methodology for the direct preparation of 2-vinylpyrroles is presented. Treatment of 4-amino-pyrrole-2-carboxylates 5a-c and 6a-d with aliphatic aldehydes and TFA furnished 2-vinylpyrroles 2a-k in 9-87% yields. Under similar conditions ureidopyrroles 5a-c reacted with aryl aldehydes to provide pyrrolo[3,2-d]pyrimidines 1a-d in 28-63% yields.

Full text of DOI:10.1021/ol702994g

ORGANIC
LETTERS
2008
Vol. 10, No. 5
849-852
2-Vinylpyrroles and
Pyrrolo[3,2-d]pyrimidines from Direct
Addition of Aldehydes to
4-Amino-pyrrole-2-carboxylate
Derivatives
Gil Fridkin 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
william.lubell@umontreal.ca
Received December 12, 2007
ABSTRACT
A new methodology for the direct preparation of 2-vinylpyrroles is presented. Treatment of 4-amino-pyrrole-2-carboxylates 5a
aliphatic aldehydes and TFA furnished 2-vinylpyrroles 2a k in 9 87% yields. Under similar conditions ureidopyrroles 5a c reacted with aryl
aldehydes to provide pyrrolo[3,2-d]pyrimidines 1a d in 28 63% yields.
−c and 6a−d with
−
−
−
−
−
2-Vinylpyrroles are valuable for the synthesis of natural
products such as porphyrins and chlorophylls, as well as
photo- and electroconducting materials.1 They are usually
prepared from C-formyl and C-acetylpyrroles by way of
condensations onto malonates, esters, ketones, and alkyli-
denephosphoranes.2 C-Vinypyrroles have also been synthe-
sized from electrophilic substitution of pyrroles using
acetylenes and electron-deficient alkenes.2 In light of the
propensity of pyrroles to form dipyrromethenes in reactions
with aldehydes,1-3 N-methylpyrroles have only been con-
verted to vinylpyrroles by way of reactions with ketones
onto osmium4 and lithium5 complexes. To the best of our
knowledge, no method for the preparation of 2-vinylpyrrole
from direct addition of aldehydes onto the pyrrole ring exists
in the literature.
Pyrrolo[3,2-d]pyrimidines exhibit biological activity as
receptor ligands,6 and enzyme inhibitors.7 Such deazapurine
derivatives have typically been prepared by pyrrole annu-
lation on properly substituted pyrimidines.8 Recently, we
have presented effective solution- and solid-phase methodol-
(4) Hodges, L. M.; Spera, M. L.; Moody, M. W.; Harman, W. D. J. Am.
Chem. Soc. 1996, 118, 7117.
(5) Andersen, K. E.; Braestrup, C.; Grøenwald, F. C.; Jøergensen, S.
A.; Nielsen, E. B.; Sonnewald, U.; Søerensen, P. O.; Suzdak, P. D.; Knutsen,
L. J. S. J. Med. Chem. 1993, 36, 1716.
(1) Trofimov, B. A.; Sobenina, L. N; Demenev, A. P.; Mikhaleva, A. I.
Chem. ReV. 2004, 104, 2481 and references within.
(2) Sobenina, L. N.; Demenev, A. P.; Mikhaleva, A. I.; Trofimov, B. A.
Russ. Chem. ReV. 2002, 71, 563 and references within.
(3) Garabatos-Perera, J. R.; Rotstein, B. H.; Thompson, A. J. Org. Chem.
2007, 72, 7382.
(6) Grahner, B.; Winiwarter, S.; Lanzner, W.; Muller, C. E. J. Med. Chem.
1994, 37, 1526.
(7) Evans, G. B.; Furneaux, R. H.; Gainsford, G. J.; Hanson, J. C.; Kicska,
G. A.; Sauve, A. A.; Schramm, V. L.; Tyler, P. C. J. Med. Chem. 2003,
46, 155.
(8) Amarnath, V.; Mdhav, R. Synthesis 1974, 837.
10.1021/ol702994g CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/31/2008

ogy for pyrrolopyrimidine synthesis starting from 4-amino-
pyrrole-2-carboxylates.9-11
tion, we have now explored the intramolecular Pictet-
Spengler reaction of 4-ureidopyrrole 2-carboxylates and
obtained pyrrolopyrimidines using aryl aldehydes. Employing
aliphatic aldehydes in these conditions has also led to a new
route to C-vinylpyrroles.
N,N′-Dibenzylureidopyrrole 5a was selected as the model
substrate and prepared by our reported method9 featuring
acylation of benzyl 4-(benzylamino)-1H-pyrrole-2-carboxy-
late (4)20 with benzyl isocyanate (Scheme 1). Ureidopyrrole
In the context of our program on the synthesis and
screening of libraries of pyrrolo[3,2-d]pyrimidines, we have
now explored a variation of the Pictet-Spengler12 reaction
featuring condensation of ureidopyrroles with aldehydes to
introduce diversity at the C4 position (Table 1). The Pictet-
Table 1. Pyrrolopyrimidines from Heating Ureidopyrroles and
Aromatic Aldehydes with Trifluoroacetic Acid
Scheme 1. Synthesis of Ureidopyrroles 5a-c
product
R4
isolated yield %
1a
1b
1c
1d
Ph
p-MePh
p-MeOPh
p-NO2Ph
55
63
53
28a
a 1000 mol % R4CHO, 300 mol % TFA, toluene, 110 °C, 1.5 h.
Spengler reaction refers typically to the condensation of an
aminoalkyl indole (i.e., tryptamine or tryptophan derivative)
with an aldehyde or ketone to furnish â-carboline.13 Ami-
noalkyl aromatic systems possessing relatively electron-rich
aromatic rings (i.e., L-DOPA,13,14 tyramine,13 alkylamino-
imidazoles,15 and thiophenes16) have also served as substrates;
however, few aminoalkyl pyrroles have been examined in
Pictet-Spengler reactions. To the best of our knowledge,
only three reports use primary aminoalkyl N-substituted
pyrrole substrates in Pictet-Spengler reactions.17-19 Ureas
have been rarely used in Pictet-Spengler reactions relative
to their aminoalkyl counterparts.14,16 In such cases, electron-
rich aryl derivatives (i.e., tryptophan, L-DOPA, thiophene,
and furan analogues) served as the C-nucleophiles in
intramolecular reactions in which only one urea nitrogen was
incorporated into the heterocycle.14,16
5a was treated with different aldehydes under various
conditions, including the common Pictet-Spengler reaction
conditions of neutral and acidic media in hot toluene in a
Dean-Stark apparatus,13 as well as heating at reflux in the
presence of TFA (up to 10% v/v) in alternative solvents
(THF, acetonitrile, and DCM). However, in all cases, the
desired products were obtained only in trace amounts as
ascertained from LC/MS analyses, which gave mostly
unreacted staring material. Pyrrolopyrimidines were obtained
in better yield using solvent-free conditions. For example,
heating ureidopyrrole 5a (100 mol %) in benzaldehyde (1000
mol %) with TFA (300 mol %) at 140 °C for 1.5 h gave
55% yield of pyrrolopyrimidine 1a after chromatography on
silica gel (Table 1).
Electron-rich aromatic aldehydes, p-tolualdehyde and
p-anisaldehyde, reacted with 5a under similar conditions to
give pyrrolopyrimidines 1b and 1c in 63% and 53% yields,
respectively (Table 1). The electron-defficient aryl aldehyde,
p-nitrobenzaldehyde, reacted with ureidopyrrole 5a to give
pyrrolopyrimidine 1d in only 28% yield. This reaction
required heating in toluene at reflux due to inability to use
p-nitrobenzaldehyde, a solid at rt, under standard conditions
in neat aldehyde at 140 °C. The lower yield of 1d may thus
stem from using lower temperature and concentration, rather
than electronic effects.
The use of a pyrrole-urea combination has, to the best
of our knowledge, no precedent in Pictet-Spengler chem-
istry. With the interest in preserving the pyrrole NH and
2-position carboxylate for potential hydrogen bonding in
molecular recognition events, and for subsequent diversifica-
(9) Marcotte, F.-A.; Rombouts, F. J. R.; Lubell, W. D. J. Org. Chem.
2003, 68, 6984.
(10) Rombouts, F. J. R.; Fridkin, G.; Lubell, W. D. J. Comb. Chem.
2005, 7, 589.
(11) Fridkin, G.; Lubell, W. D. J. Comb. Chem. 2005, 7, 977.
(12) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030.
(13) Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797.
(14) Lee, S. C.; Park, S. B. J. Comb. Chem. 2006, 8, 50.
(15) De la Figuera, N.; Fiol, S.; Ferna´ndez, J.-C.; Forns, P.; Ferna´ndez-
Forner, D.; Albericio, F. Synlett 2006, 12, 1903.
(16) Diness, F.; Beyer, J.; Meldal, M. Chem. Eur. J. 2006, 12, 8056.
(17) Rousseau, J. F.; Dodd, R. H. J. Org. Chem. 1998, 63, 2731.
(18) Raiman, M. V.; Pukin, A. V.; Tyvorskii, V. I.; De Kimpe, N.;
Kulinkovich, O. G. Tetrahedron 2003, 59, 5265.
The scope of the reaction was next examined using
isobutyraldehyde and ureidopyrrole 5a. Considering high
(19) Xiang, J. B.; Zheng, L. Y.; Chen, F.; Dang, Q.; Bai, X. Org. Lett.
2007, 9, 765.
(20) Marcotte, F.-A.; Lubell, W. D. Org. Lett. 2002, 4, 2601.
Org. Lett., Vol. 10, No. 5, 2008
850

To widen this new entrance to vinylpyrroles, other ureido-
pyrroles and aliphatic aldehydes were examined. N-Benzyl
N′-R-methylbenzylureidopyrrole 5b was prepared from acy-
lation of aminopyrrole 4 with R-methylbenzyl isocyanate in
96% yield, and N-benzylureidopyrrole 5c was made in 80%
yield by treating 4 in dioxane/water with potassium cyanate
and AcOH. From the same conditions with isobutyraldehyde,
ureidopyrroles 5b and 5c yielded 2-vinylpyrroles 2e and 2g
in 57% and 35% yields, respectively, after chromatography.
Ureidopyrroles 5a and 5b reacted similarly with propional-
dehyde and isovaleraldehyde to provide 2-vinylpyrroles 2a,
2c, 2d, and 2f in 51-74% yields (Figure 1). The trans-olefin
isomer was indicated in all cases by the large vinylic proton
J coupling constant value (16.2-16.9 Hz). Ureidopyrrole 5a
failed to react with pivalaldehyde and acetone.
Crystals of vinylpyrrole 2e were grown from EtOAc in
hexanes and examined by X-ray diffraction (Figure 2). Other
Figure 2. X-ray crystal structure of 2-vinylpyrrole, 2e.
than 1,1,2,2-tetra(2-pyrrolyl)ethene,23 to the best of our
knowledge, the crystal structure of 2e represents the first
example of a pyrrole ring connected to a double bond. The
olefin bond length (1.33 Å) was in agreement with the typical
ethylene bond length (1.32 Å)24 and in conjugation with the
pyrrole as ascertained from their connecting bond length
(1.45 Å) which corresponded with bond lengths in butadiene
and biphenyl (1.48 Å).24
Considering the mechanism, two routes to vinylpyrrole
appeared possible (Figure 3). In accord with the Pictet-
Spengler mechanism,13 initial condensation of the aldehyde
onto the urea nitrogen would yield acyl imminium ion that
is attacked by pyrrole with subsequent aromatization to form
the pyrrolo[3,2-d]pyrimidine. Subsequently, â-elimination of
the urea could provide the C-vinyl ureidopyrrole. Pyrrolo-
pyrimidines from aryl aldehydes may be stable, because they
cannot undergo â-elimination to C-vinylpyrrole. A second
mechanism would involve attack of pyrrole directly onto the
aldehyde to furnish an alcohol intermediate that eliminates
water to afford C-vinylpyrrole (Figure 3).
Figure 1. Isolated yields of 2-vinylpyrroles from microwave
heating of 4-amino-pyrrole-2-carboxylates and aldehydes. Yields
in parentheses are based on recovered starting material.
temperatures important for ring annulation, the lower-boiling
aliphatic aldehyde and 5a were heated in a sealed tube using
microwave irradiation. Microwave heating of 5a and iso-
butyraldehyde (0.02 M) at 140 °C for 2.5 h followed by
chromatography on silica gel gave a major product in 67%
yield with 14% yield of recovered starting material, which
was recycled. Although the product’s molecular ion cor-
responded to a C4 alkyl pyrrolopyrimidine,22 examination
of its 1H- and 13C NMR spectra revealed a structural isomer.
The methyl groups of the isopropyl moiety appeared as
singlets rather than doublets, no isopropyl CH proton was
observed, and a new vinyl proton and urea NH proton were
observed, indicating that no cyclization occurred and
2-vinylpyrrole 2b was formed (Figure 1).
To examine the Pictet-Spengler mechanism and the
necessity for the urea nitrogen, benzyl 4-[N-(Cbz)-N-ben-
(21) Sharma, R.; Lubell, W. D. J. Org. Chem. 1996, 61, 202.
(22) Blankenship, J.W.; Lubell, W.D. Synthesis of pyrrolo[3,2-d]-
pyrimidines for application as â-sheet mimics. In Peptides 2004: Proceed-
ings 3rd International and 28th European Peptide Symposium; Prague,
Czech Republic, September 5-10, 2004; Flegel, M., Fridkin, M., Gilon,
C., Slaninova, J., Eds.; Kenes International: Israel, 2005; p 746.
(23) Khoury, R.G.; Jaquinod, L.; Smith, K.M. Chem. Commun. 1997,
1057.
(24) Smith, M.B.; March, J. AdVanced Organic Chemistry, 5th ed.;
Wiley-Interscience: New York, 2001; Chapter 1, p 20.
Org. Lett., Vol. 10, No. 5, 2008
851

benzoyl and benzenesulphonyl chloride, and reacted with
isobutyraldehyde to give 2-vinylpyrroles 2i and 2j in 17%
and 9% yields, respectively, with recovered starting material
(54% and 80% for 6b and 6c). 4-Morpholinopyrrole20 6d
reacted qauntitatively with isobutyraldehyde to give 2-vinyl-
pyrrole 2k in 87% isolated yield. Multiple products were
respectively obtained from reactions of pyrrole and benzyl
4-hydroxy-pyrrole-2-carboxylate with isobutyraldehyde under
the same conditions. Vinylpyrrole yield correlated with the
electron density of the aminopyrroles. Yields were typically
>50% and comparable with alternative methods for making
vinylpyrroles that usually require multiple steps.
2-Vinylpyrroles and pyrolo[3,2-d]pyrimidines were syn-
thesized from acid-induced condensations of 4-ureido-pyr-
role-2-carboxylates with aliphatic and aryl aldehydes, respec-
tively. Mechanistic study revealed that C-vinylpyrrole arose
from pyrrole reacting as a C-nucleophile onto the aliphatic
aldehyde and indicated that other aminopyrrole analogues
react to give vinylpyrrole under the reaction conditions. Con-
sidering the utility of C-vinylpyrroles and the biological activ-
ity of pyrrolo[3,2-d]pyrimidines, the scope of these reactions
is under further investigation.
Acknowledgment. This research was supported by the
Natural Sciences and Engineering Research Council of
Canada (NSERC), the Fonds Que´becois de la recherche sur
la nature et les technologies (FQRNT), and the Canadian
Institutes of Health Research (CIP-79848). G.F. thanks
MCETC/FRSQ/CIHR Strategic training program in Cancer
Experimental Therapeutics for a postdoctoral fellowship. We
thank Dr. John W. Blankenship (U. Montre´al) for helpful
disccussions, Mr. Wajih Ben-Tahar (U. Montre´al) and Ms.
Quynh Vy Nguyen (U. Montre´al) for help in preparing
starting materials, and Mrs. Francine Be´langer-Garie´py (U.
Montre´al) for X-ray crystal structure determination.
Figure 3. Possible mechanisms for vinylpyrrole formation
zylamino]pyrrole-2-carboxylate 6a was synthesized in 67%
yield by acylation of aminopyrrole 4 with benzylchlorofor-
mate, and then reacted with isobutyraldehyde under the same
conditions as used with ureidopyrroles 5a-c. After chro-
matography on silica gel, C-vinylpyrrole 2h was isolated in
50% yield, and carbamatopyrrole 6a was recovered in 30%
yield and recycled. Although the Pictet-Spengler-like mech-
anism may not be totally excluded for ureas 5, it is impossible
for carbamate 6a; thus, vinylpyrrole synthesis was extended
to pyrroles bearing other ring substituents. Benzamido- and
benzenesulphonamidopyrroles 6b and 6c were prepared
respectively in 67% and 65% yields by acylation of 4 with
Supporting Information Available: General experimen-
1
tal methods, copies of H NMR and 13C NMR spectra of
compounds 1, 2, 5 and 6, and X-ray structure data of
compound 2e. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL702994G
852
Org. Lett., Vol. 10, No. 5, 2008