One-step synthesis of 3,5-disubstituted-2-pyridylpyrroles from the condensation of 1,3-diones and 2-(aminomethyl)pyridine

Article abstract of DOI:10.1021/ol017147v

Equation Presented 3,5-Disubstituted-and 3,4,5-trisubstituted-2-(2-pyridyl)pyrroles may be synthesized efficiently from the novel condensation of 2-(aminomethyl)-pyridine and 1,3-diones. The cyclization reaction was found to proceed through the intermedia

Full text of DOI:10.1021/ol017147v

ORGANIC
LETTERS
2002
Vol. 4, No. 3
435-437
One-Step Synthesis of
3,5-Disubstituted-2-pyridylpyrroles from
the Condensation of 1,3-Diones and
2-(Aminomethyl)pyridine
Jamie J. Klappa, Autumn E. Rich, and Kristopher McNeill*
Department of Chemistry, UniVersity of Minnesota, 207 Pleasant Street SE,
Minneapolis, Minnesota 55455
mcneill@chem.umn.edu
Received November 29, 2001
ABSTRACT
3,5-Disubstituted- and 3,4,5-trisubstituted-2-(2-pyridyl)pyrroles may be synthesized efficiently from the novel condensation of 2-(aminomethyl)-
pyridine and 1,3-diones. The cyclization reaction was found to proceed through the intermediacy of a (2-pyridyl)methylimine. A marked dependence
of the regioselectivity in the reaction of unsymmetrical diones on the presence of additional aminomethylpyridine suggests that two pathways
to the product pyrroles are available.
2-(2-Pyridyl)pyrroles are a potentially useful class of com-
pounds. In separate studies, they have been shown to be
antioxidants,1 P38 kinase inhibitors,2 and prolyl-4-hydroxy-
lase inhibitors.3 Because of their structural similarity to other
R-diimine ligands such as 2,2′-bipyridine, there has also been
significant interest in the metal-binding properties of 2-(2-
pyridyl)pyrroles.4-8 There are many synthetic routes to these
compounds; however, most of them entail many steps and
low yields are normally obtained.9-16 Through our attempts
to prepare bis-N-(pyridylmethyl)-1,3-diimines as ligands for
transition metal complexation, we have discovered a novel
route to pyridylpyrroles involving 2-(aminomethylpyridine)
1 and 1,3-diones.
Heating a xylene solution of 1, 2, 0.1 equiv p-CH3C6H4-
SO3H, and molecular sieves at 170 °C for 8 h resulted in
conversion to 3,5-dimethyl-2-(2-pyridyl)pyrrole 12 (Scheme
1, Table 1). The reaction was found to be tolerant of a range
of R groups with different steric demands, including phenyl,
trifluoromethyl, and tert-butyl groups (Table 1). Unfortu-
nately, our attempts to perform the reaction of 2-aryl-1,3-
dialdehydes resulted in only small amounts of the desired
products. The reaction appears to proceed through the
(1) Lehuede, J.; Fauconneau, B.; Barrier, L.; Ourakow, M.; Piriou, A.;
Vierfond, J.-M. Eur. J. Med. Chem. 1999, 34, 991-996.
(2) de Laszlo, S. E.; Visco, D.; Agarwal, L.; Chang, L.; Chin, J.; Croft,
G.; Forsyth, A.; Fletcher, D.; Frantz, B.; Hacker, C.; Hanlon, W.; Harper,
C.; Kostura, M.; Li, B.; Luell, S.; MacCoss, M.; Mantlo, N.; O’Neill, E.
A.; Orevillo, C.; Pang, M.; Parsons, J.; Rolando, A.; Sahly, Y.; Sidler, K.;
Widmer, W. R.; O’Keefe, S. J. Bioorg. Med. Chem. Lett. 1998, 8, 2689-
2694.
(3) Dowell, R. I.; Hales, N. J.; Tucker, H. Eur. J. Med. Chem. 1993, 28,
513-516.
(4) Wu, F.; Chamchoumis, C. M.; Thummel, R. P. Inorg. Chem. 2000,
39, 584-590.
(5) Chiswell, B. Inorg. Chim. Acta 1972, 6, 629-634.
(6) Jena, S.; Rath, N.; Dash, K. C. Indian J. Chem., Sect. A: Inorg.,
Bio-inorg., Phys., Theor. Anal. Chem. 1999, 38A, 350-354.
(7) Perry, C. L.; Weber, J. H. J. Inorg. Nucl. Chem. 1971, 33, 1031-
1039.
(8) Liu, S. F.; Wu, Q.; Schmider, H. L.; Aziz, H.; Hu, N. X.; Popovic,
Z.; Wang, S. J. Am. Chem. Soc. 2000, 122, 3671-3678.
(9) Petrova, O. V.; Mikhaleva, A. I.; Sobenina, L. N.; Shmidt, E. Y.;
Kositsina, E. I. Russ. J. Org. Chem. 1997, 33, 11007-1009.
(10) Firl, J. Chem. Ber. 1968, 101, 218-225.
(11) Seki, K.; Ohkura, K.; Terashima, M.; Kanaoka, Y. Heterocycles
1984, 22, 2347-2350.
(12) Savoia, D.; Concialini, V.; Roffia, S.; Tarsi, L. J. Org. Chem. 1991,
56, 1822-1827.
(13) Bean, G. P. In Pyrroles: Part 1; Jones, R. A., Ed.; John Wiley &
Sons: New York, 1990; Vol. 48, pp 105-294.
(14) Emmert, B.; Brandl, F. Chem. Ber. 1927, 60, 2211-2216.
(15) Wibaut, J. P.; Dingemanse, E. Recl. TraV. Chim. 1923, 42, 1033-
1049.
(16) Wibaut, J. P. Recl. TraV. Chim. 1926, 45, 657-670.
10.1021/ol017147v CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/11/2002

Scheme 1
Scheme 2. Proposed Involvement of the Enamine Tautomer 23
in the Cyclization Reaction
intermediacy of a â-iminoketone, which usually forms readily
under ambient conditions. For example, when mixed at room
temperature, 1 and 2 gave 4-(2-pyridylmethyl)imino-2-
pentanone (22) within 10 min as determined by GCMS
(Scheme 2).
The cyclization is thought to occur by nucleophilic attack
on the ketone carbonyl by the carbon atom R to the pyridine.
It is proposed that the nucleophilicity of the (2-pyridyl)methyl
carbon arises from the enamine tautomer, 23. This hypothesis
is bolstered by the fact that 4-(aminomethyl)pyridine, which
can also tautomerize to an enamine structure, participates in
this reaction to give 24, whereas 3-(aminomethyl)pyridine
and benzylamine, which are unable to form enamines, do
not participate in the reaction under the same conditions
(Scheme 3). This mechanistic proposal is closely related to
Scheme 3
Table 1. Products Obtained from the Condensation of
2-(Aminomethyl)pyridine (1) and Various 1,3-Diones
that put forth for the formation of pyrroles from the reaction
of 1,3-diones with 2-aminoesters.13,17,18 Under the same
conditions, the reaction of 1 with unsymmetrically substituted
1,3-diones displays little regioselectivity, although this can
be greatly improved by isolation of the intermediate â-imi-
noketone. The regioselectivity under the one-pot conditions
is low although the initial imine formation is usually very
selective. For diones 8, 10, and 11, the intermediate â-imi-
noketone regioisomers are formed in ratios of 85:15, 99.2:
0.8, and 94:6, respectively. After heating at 170 °C, the
products, 18, 20, and 21, are found in 83:17, 45:55, and 76:
25 ratios, respectively. There are notable exceptions to this
general rule. For example, when substrate 9, which contains
tert-butyl and trifluoromethyl substituents, is treated with 1
only one intermediate imine, resulting from reaction at the
CF3-substituted ketone, and one product, 19, are observed.
Also, the reaction of 4-(aminomethyl)pyridine with substrate
10 is very regioselective, resulting in the formation of the
4-pyridyl analogues of 20a and 20b in a 94:6 ratio.
The loss of the regioselectivity with increased heating
suggests that the pyrrole formation is under thermodynamic
control at 170 °C. However, the situation is somewhat more
(17) Mataka, S.; Takahashi, K.; Tsuda, Y.; Tashiro, M. Synthesis 1982,
2, 157-159.
(18) Paine, J. B., III; Dolphin, D. J. Org. Chem. 1985, 50, 5598-5604.
a Isolated as a mixture of regioisomers.
436
Org. Lett., Vol. 4, No. 3, 2002

complicated. If the reaction were truly under thermodynamic
control, then submitting one of the regioisomeric products
to the reaction conditions should produce a mixture of both
regioisomers. When 20a is heated to 170 °C in the presence
of tosic acid and 1, no interconversion with 20b is observed.
Further evidence against thermodynamic control of the
reaction comes from the dependence of the regioisomeric
ratio on the amount of 2-(aminomethyl)pyridine, 1, present.
When 25a, isolated and purified by vacuum distillation, is
heated with a catalytic amount of tosic acid, primarily one
product regioisomer, 20a, is formed. Performing the same
reaction with increased amounts of 1 leads to increased
production of the opposite regioisomer, 20b (Table 2).
Scheme 4. Proposed Mechanism for Formation of 20a and 20b
Table 2. Effect of Added 1 on the Regioselectivity of the
Conversion of â-Iminoketone 25a to 20a and 20b
regioisomeric ratio
entry
equiv of 1
20a
20b
1
2
3
4
5
0.0
90
85
79
76
64
10
15
21
24
36
0.25
0.52
0.76
1.0
20b via the second pathway is therefore catalytic in 1.
Presumably there is an analogous set of pathways leading
from 25b to 20a and 20b (the dashed arrows in Scheme 4),
but these are believed to be much less important and are not
needed to explain the results obtained. From a practical
synthetic standpoint, these results indicate that the regio-
selectivity of the reaction with unsymmetrical diones can
be greatly enhanced by isolation of the intermediate â-imi-
noketone and performing the cyclization in the absence of
1.
The role that 1 performs in facilitating the formation of
both regioisomers of the product is not fulfilled by close
structural mimics. Because pyridine and benzylamine contain
the same functional groups in isolation that 2-(aminomethyl)-
pyridine has in concert, the cyclization of 25a to pyrrole
products was performed in the presence of these compounds.
When 25a is heated in the presence of pyridine as well as
the tosic acid catalyst and molecular sieves, conversion to
20a is observed. When 25a is heated similarly with benzyl-
amine, imine metathesis is observed, in which the 2-(ami-
nomethyl)pyridine group is replaced by benzylamine.
These results lead to a mechanistic proposal that contains
two pathways for the formation of products from the
â-iminoketone intermediate, 25a (Scheme 4). The first
pathway involves nucleophilic attack of the ketone carbonyl
by the aminomethyl carbon, as described above. This
pathway would lead to only one regioisomeric product, 20a.
The second pathway involves the condensation of a second
equivalent of 1 with 25a to form â-diimine, 26. Intermediate
26 is capable of cyclizing two ways, leading to both
regioisomeric products. The conversion of 25a to 20a and
Acknowledgment. We thank Prof. George O’Doherty
(University of Minnesota) for helpful discussions. We would
also like to thank Dr. Letitia Yao for extensive help with
the NMR experiments and Mr. Keith Jensen for help in
preparing 14. This work was supported by the University of
Minnesota.
Supporting Information Available: Detailed descrip-
tions of experimental procedures and spectroscopic and
analytical data are available for compounds 6, 12-25a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL017147V
Org. Lett., Vol. 4, No. 3, 2002
437