N-propargylic β-enaminones: Common intermediates for the synthesis of polysubstituted pyrroles and pyridines

Article abstract of DOI:10.1021/ol800518j

N-Propargylic β-enaminones have been used as common intermediates for the synthesis of polysubstituted pyrroles and pyridines. Best results have been obtained using DMSO as solvent. In the presence of Cs₂CO₃ N-propargylic β-enaminone

Full text of DOI:10.1021/ol800518j

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2629-2632
N-Propargylic ꢀ-Enaminones: Common
Intermediates for the Synthesis of
Polysubstituted Pyrroles and Pyridines
Sandro Cacchi,* Giancarlo Fabrizi,* and Eleonora Filisti
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente AttiVe,
UniVersita` degli Studi “La Sapienza”, P.le A. Moro 5, 00185, Rome, Italy
sandro.cacchi@uniroma1.it
Received January 11, 2008
ABSTRACT
N-Propargylic ꢀ-enaminones have been used as common intermediates for the synthesis of polysubstituted pyrroles and pyridines. Best
results have been obtained using DMSO as solvent. In the presence of Cs2CO3 N-propargylic ꢀ-enaminones are cyclized to pyrroles in good
to high yields, whereas omitting bases and using CuBr leads to the selective formation of pyridines.
Due to the presence of the ambident nucleophilic character
of the enamine moiety and the ambident electrophilic
character of the enone moiety, ꢀ-enaminones are useful
synthetic intermediates1 and their utilization in organic
synthesis is a subject of great current interest. A variety of
intra-2 and intermolecular3 reactions have been performed
taking advantage of their electronic properties. Transition
metal-promoted4 and -catalyzed5 processes have also been
described. Because of our general interest in the alkyne-based
synthesis of heterocycles,6 we decided to tether a carbon-
carbon triple bond to the enaminone framework and to
(4) (a) Osuka, A.; Mori, Y.; Suzuki, H. Chem. Lett. 1982, 2031. (b)
Yang, S. C.; Wang; Huey, M.; Kuo, C. S.; Chen, L. C. Heterocycles 1991,
32, 2399. (c) Gravestock, D.; Dovey, M. C. Synthesis 2003, 523. (d)
Gravestock, D.; Dovey, M. C. Synthesis 2003, 1470.
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104, 2433.
(5) For some selected Pd-catalyzed reactions, see: (a) Iida, H.; Yuasa,
Y.; Kibayashi, C. J. Org. Chem. 1980, 45, 2938. (b) Kasahara, A.; Izumi,
T.; Murakami, S.; Yanai, H.; Takatori, M. Bull. Chem. Soc. Jpn. 1986, 59,
927. (c) Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Synthesis
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1993, 34, 8365. (e) Koerber-Ple´, K.; Massiot, G. Synlett 1994, 759. (f) Chen,
L.-C.; Yang, S.-C.; Wang, H.-M. Synthesis 1995, 385. (g) Chen, L.-C.;
Yang, S.-C.; Wang, H.-M. Synthesis 1995, 385. (h) Latham, E. J.; Stanfoth,
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Y. J. Org. Chem. 2003, 68, 6011. (n) Sorensen, U. S.; Pombo-Villar, E.
(2) For some recent references, see: (a) Tietcheu, C.; Garcia, C.; Gardette,
D.; Dugat, D.; Gramain, J.-C. J. Heterocycl. Chem. 2002, 39, 965. (b) White,
J. D.; Ihle, D. C. Org. Lett. 2006, 8, 1081. (c) Bellur, E.; Langer, P.
Tetrahedron Lett. 2006, 47, 2151. (d) Cruz, M. C.; Jime´nez, F.; Delgado,
F.; Tamariz, J. Synlett 2006, 749. (e) Ursic, U.; Bevk, D.; Pirc, S.; Pezdirc,
L.; Stanovnik, B.; Svete, J. Synthesis 2006, 2376. (f) Davis, F. A.; Xu, H.;
Zhang, J. J. Org. Chem. 2007, 72, 2046. (g) Yan, S.; Wu, H.; Wu, N.;
Jiang, Y. Synlett 2007, 2699.
(3) For some recent references, see: (a) Vohra, R. K.; Bruneau, C.;
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Tamura, M.; Ariga, M. Synlett 2006, 1437. (d) Pesˇkova´, M.; Simu`nek, P.;
Bertolasi, V.; Macha´e`ek, V.; Lye`ka, A. Organometallics 2006, 25, 2025.
(e) Tu, S.; Jiang, B.; Jia, R.-H.; Zhang, J.-Y.; Zhang, Y.; Chang-Sheng
Yao, C.-S.; Shi, F. Org. Biomol. Chem. 2006, 4, 3664. (f) Huang, J.; Liang,
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Chem. 2007, 9, 1144. (h) Cheng, X.-M.; Liu, X.-M. J. Comb. Chem. 2007,
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Dommisse, R. A.; Lemie`re, G. L. F.; Kosˇmrlj, J.; Ma´tyus, P. Tetrahedron
2004, 60, 2283. For Cu-catalyzed reactions, see: (p) Yan, S.; Wu, H.; Wu,
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10.1021/ol800518j CCC: $40.75
Published on Web 05/29/2008
2008 American Chemical Society

investigate the potential of the resultant alkyne-containing
derivatives as precursors of heterocycles.
Herein we report that N-propargylic ꢀ-enaminones 1 are
useful common intermediates for the synthesis of polysub-
stituted pyrroles 2 and pyridines 3 (Scheme 1).
Table 1. Synthesis of NH Free Polysubstituted Pyrroles 2a
Scheme 1
N-Propargylic ꢀ-enaminones 1 were readily prepared via
Sonogashira cross-coupling of terminal alkynes with acyl
chlorides,7 followed by the conjugate addition of propargy-
lamine with the resultant R,ꢀ-enones and further Sonogashira
cross-coupling of the propargyl derivative 4 with aryl halides
(Scheme 2). N-Propargylic ꢀ-enaminones 1 and 4 have
Scheme 2
a Unless otherwise stated, reactions were carried out under argon on a
0.2 mmol scale using 2 equiv of Cs2CO3 in 3 mL of anhydrous DMSO at
room temperature for 10-120 min. b Yields are given for isolated products.
c Carried out on a 0.3 mmol scale using the same amount of solvent. d At
60 °C.
the basis of previous studies on base-catalyzed cyclizations
of alkynes containing proximate nucleophiles,8 it is likely
that this carbocyclization proceeds through the following
basic steps: (a) a 5-exo-dig cyclization involving an intramo-
lecular nucleophilic attack of the CR terminus of the anion
generated in situ from 1 on the closer acetylenic carbon (one
of the orbitals of the acetylenic system allows for a nearly
planar mode of approach of the nucleophile; Figure 1a),9
always been isolated as single isomers. The Z stereochemistry
of 1k (R1 ) n-C5H11; R2 ) Ph; R3 ) p-Me-C6H4) and 4a
(R1 ) Ph; R2 ) Me; R3 ) H) has been assigned by NOESY
experiments which showed also the presence of an intramo-
lecular hydrogen bond (N-H···O). That of the other N-
propargylic ꢀ-enaminones has been assigned on the basis of
these data.
We started our study by examining the conversion of 1a
(R1) Ph; R2 ) Me; R3 ) p-MeO-C6H4) into the correspond-
ing NH free pyrrole derivative 2a. After an initial screen of
bases, solvents, and reaction temperatures, we found that the
use of 2 equiv of Cs2CO3 in anhydrous DMSO at room
temperature produced 2a after 2 h in 75% yield.
Using these conditions, we next explored the scope and
generality of the process. Our preparative results are sum-
marized in Table 1. Pyrrole products containing a variety of
neutral, electron-donating, and electron-withdrawing sub-
stituents were usually isolated in good to high yields. On
Figure 1. Suggested ring-closure pathways for the cyclization of
1: (a) base-catalyzed 5-exo-dig cyclization; (b) transition metal-
catalyzed 6-endo-dig cyclization (M ) transition metal).
(b) a protonation step to afford a five-membered ring
methylidene intermediate, and (c) an isomerization to the
pyrrole product 2.10 We then decided to investigate the role
of transition-metal catalysis in the cyclization step. In
particular, the working hypothesis was that under neutral
conditions and with a transition metal coordinating the C-C
(6) (a) Arcadi, A.; Cacchi, S.; Cascia, L.; Fabrizi, G.; Marinelli, F. Org.
Lett. 2001, 3, 2501. (b) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Zappia,
G. Org. Lett. 2001, 3, 2539. (c) Arcadi, A.; Cacchi, S.; Di Giuseppe, S.;
Fabrizi, G.; Marinelli, F. Org. Lett. 2002, 4, 2409. (d) Ambrogio, I.; Cacchi,
S.; Fabrizi, G. Org. Lett. 2006, 8, 2083.
(7) Karpov, A. S.; Muller, T. J. J. Org. Lett. 2003, 5, 3451.
2630
Org. Lett., Vol. 10, No. 13, 2008

triple bond, stereoelectronic requirements might influence the
cyclization process so as to favor the 6-endo-dig cyclization
as shown in Figure 1b. Indeed, coordination of the C-C
triple bond to the transition metal would decrease its bond
order and introduce strain on the transition state leading to
the 5-exo-dig cyclization product.9
The cyclization of 1a was investigated as the model system
and copper was selected as the transition metal catalyst.
Representative optimization experiments are summarized in
Table 2.
16 vs 14). Using 1,2-cyclohexandiamine led to the recovery
of 1a in 77% yield at 60 °C (Table 2, entry 10) while
increasing the reaction temperature to 80 °C formed 3b in
40% yield along with other unidentified products (Table 2,
entry 11). Even performing the reaction under a balloon of
oxygen or adding 1,4-benzoquinone did not afford satisfac-
tory results (Table 2, entries 12 and 13). Increasing the
amount of recrystallized CuBr to 0.4 equiv led to isolation
of 3b in a satisfactory 69% in 0.5 h (Table 2, entry 14).
With 0.4 equiv of nonrecrystallized CuBr, 3b was isolated
only in 54% yield (Table 2, entry 15). As expected, no
reaction was observed omitting copper salts (Table 2, entry
17). On the basis of these studies, we decided to use 0.4
equiv of CuBr in DMSO at 60 °C omitting ligands and
additives when the procedure was extended to include other
N-propargylic ꢀ-enaminones. Our preparative results are
summarized in Table 3.
Table 2. Copper, Ligands, Solvents, and Temperature in the
Cyclization of 1a to 3ba
Table 3. Synthesis of Polysubstituted Pyridines 3a
a Unless otherwise stated, reactions were carried out under argon on a
0.2-0.25 mmol scale using 0.4 equiv of recrystallized CuBr in 3 mL of
anhydrous DMSO at 60 °C for 0.5-5 h. b Yields are given for isolated
products. c At 80 °C.
a Unless otherwise stated, reactions were carried out under argon on a
0.25 mmol scale using 0.1 equiv of copper salt in 3 mL of solvent at 60
°C. b Yields are given for isolated products. c At 80 °C. d 0.2 equiv of CuBr.
e Recrystallized CuBr. f 1a was recovered in 77% yield. g Under an oxygen
atmosphere (balloon). h 1a was recovered in 36% yield. i 0.4 equiv of CuBr.
l 1a was recovered in 70% yield.
By analogy with other Cu-catalyzed cyclizations of acety-
lenic compounds,13 a likely mechanism for the formation of
the pyridine ring from 1 involves (Scheme 3) the coordination
of the alkyne moiety with copper to give A, followed by a
(8) For some selected references, see: (a) Shin, K.; Ogasawara, K. Synlett
1996, 922. (b) Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997,
62, 6507. (c) Antonio, A.; Cacchi, S.; Fabrizi, G.; Manna, F.; Pace, P. Synlett
1998, 446. (d) Rodriguez, A. L.; Koradin, C.; Dohle, W.; Knochel, P. Angew.
Chem., Int. Ed. 2000, 39, 2488. (e) Dai, W.-M.; Sun, L.-P.; Guo, D.-S.
Tetrahedron Lett. 2002, 42, 7699. (f) Koradin, C.; Dohle, W.; Rodriguez,
A. L.; Schmid, B.; Knochel, P. Tetrahedron 2003, 59, 1571. (g) Suzuki,
N.; Yasaki, S.; Yasuhara, A.; Sakamoto, T. Chem. Pharm. Bull. 2003, 51,
1170. (h) Wattreson, S. H.; Dhar, T. G. M.; Ballentine, S. K.; Shen, Z.;
Barrish, J. C.; Cheney, D.; Fleener, C. A.; Rouoleau, K. A.; Townsend, R.;
Hollenbaugh, D. L.; Iwanowicz, E. J. Bioorg. Med. Chem. Lett. 2003, 13,
1273. (i) Sun, L.-P.; Huang, X.-H.; Dai, W.-M. Tetrahedron 2004, 60,
10983.
Pleasingly, subjecting 1a to several commercially available
copper salts under neutral conditions afforded selectively the
6-endo-dig product 3b, whose formation includes even an
oxidation step. However, low to moderate yields were
obtained (Table 2, entries 1-6).11 Utilization of recrystallized
CuBr12 led to a faster reaction rate and a slightly higher yield
(Table 2, entry 7 vs 4). Adding ligands such as PPh3, (()-
1,1′-binaphthalene-2,2′-diol [(()-BINOL], and 1,10-phenant-
roline did not affect a remarkable change to the reaction
outcome compared with the same reactions carried out in
the absence of ligands (Table 2, entries 8 and 9 vs 7; entry
(9) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 738. (b)
Baldwin, J. E.; Thomas, R. C.; Kruse, L. I.; Silberman, L. J. Org. Chem.
1977, 42, 3846.
Org. Lett., Vol. 10, No. 13, 2008
2631

pyridines, tolerates a variety of useful functional groups and
requires only inexpensive reagents such as Cs2CO3 (pyrroles)
and CuBr (pyridines).
Scheme 3
Acknowledgment. Work carried out in the framework of
FIRB 2003 supported by the Ministero dell’Universita` e della
Ricerca Scientifica e Tecnologica and by the University “La
Sapienza.
Supporting Information Available: A complete descrip-
tion of experimental details and product characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL800518J
6-endo-dig cyclization via the intramolecular nucleophilic
attack of the carbon R to the carbonyl group to the activated
C-C triple bond. Substitution of the C-H bond for the
C-Cu bond of the resultant vinylic-copper intermediate B
affords C with concomitant regeneration of CuBr. Subse-
quently, an oxidation step converts C into the pyridine
derivative 3. We have not investigated the details of this
oxidation reaction and further studies would be required to
clear this point up.
In conclusion, an efficient approach providing pyrroles and
pyridines in good to high yields from readily available
N-propargylic ꢀ-enaminones has been developed. The new
method, which can be particularly useful for the preparation
of libraries of three independently substituted pyrroles and
(10) Since N-propargylic ꢀ-enaminones contain traces of Pd, palladium
catalysis might be involved in the cyclization step. However, this hypothesis
seems to be flawed by the observation that the same reaction rate was
observed when 1l was treated with Cs2CO3 in DMSO at rt with and without
PdCl2.
(11) A similar result was obtained with PdCl2 as precatalyst. For
example, 3b was isolated in 29% yield upon treatment of 1l with PdCl2 in
MeCN for 24 h at 80 °C. No evidence of pyrrole formation was attained.
(12) Dieter, R. K.; Silks, L. A.; Fishpaugh, J. A.; Kastner, M. E. J. Am.
Chem. Soc. 1985, 107, 4679.
(13) (a) Messina, F.; Botta, M.; Corelli, F.; Villani, C. Tetrahedron:
Asymmetry 2000, 11, 1681. (b) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson,
J.; Yu, S.; Cook, J. M. J. Org. Chem. 2001, 66, 4525. (c) Hiroya, K.; Itoh,
S.; Ozawa, M.; Kanamori, Y.; Sakamoto, T. Tetrahedron Lett. 2002, 43,
1277. (d) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843. (e)
Hiroya, K.; Itoha, S.; Sakamoto, T. Tetrahedron 2005, 61, 10958.
(14) See also Macomber, D. W.; Rausch, M. D. J. Am. Chem. Soc. 1983,
105, 5325.
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Org. Lett., Vol. 10, No. 13, 2008