Palladium-catalyzed coupling of vinylogous amides with aryl halides: Applications to the synthesis of heterocycles

Article abstract of DOI:10.1021/ol000031z

Described herein is the first example of the palladium-catalyzed coupling of vinylogous amides with aryl bromides and chlorides. The scope of this reaction with respect to the aryl component is investigated. Additionally, a tandem reaction sequence in which the above coupling is followed by an intramolecular Heck reaction is presented. These reactions can be applied to high-yielding, one-pot syntheses of nitrogen-containing heterocycles.

Full text of DOI:10.1021/ol000031z

ORGANIC
LETTERS
2000
Vol. 2, No. 8
1109-1112
Palladium-Catalyzed Coupling of
Vinylogous Amides with Aryl Halides:
Applications to the Synthesis of
Heterocycles
Scott D. Edmondson,* Anthony Mastracchio, and Emma R. Parmee
Department of Medicinal Chemistry, Merck Research Laboratories,
Rahway, New Jersey 07065
scott_edmondson@merck.com
Received February 14, 2000
ABSTRACT
Described herein is the first example of the palladium-catalyzed coupling of vinylogous amides with aryl bromides and chlorides. The scope
of this reaction with respect to the aryl component is investigated. Additionally, a tandem reaction sequence in which the above coupling is
followed by an intramolecular Heck reaction is presented. These reactions can be applied to high-yielding, one-pot syntheses of nitrogen-
containing heterocycles.
The palladium-catalyzed C-N bond formation using aryl
halides has been an area of intense research in recent
literature.1 Elegant work by the groups of Buchwald and
Hartwig has detailed the palladium-catalyzed formation of
nitrogen-aryl bonds using primary and secondary amines,
hydrazines, anilines, imines, and nitrogen-containing het-
erocycles.1,2 To date, the coupling of less nucleophilic
nitrogen sources has received comparably little attention,
being restricted to a few examples of simple carbamates,
lactams, sulfoximines, and the intramolecular coupling of
amides and carbamates.2d,3
(enaminones). Current methods for the formation of these
moieties vary depending on the electronic state of the starting
aniline derivative. Moreover, moderate yields using these
methods are often obtained.4 We sought a mild, universal,
and high-yielding process for the synthesis of these versatile
synthetic intermediates that did not rely upon aniline deriva-
tives as starting materials. A palladium-catalyzed coupling
of primary vinylogous amides to aryl halides would not only
constitute an extension of known methodology in the field
but also provide a novel entry to N-aryl enaminones. We
were pleased to discover that this process proved to be an
efficient and widely applicable synthesis of N-aryl enami-
nones (Table 1).5
Over the course of our search for novel therapeutics, we
needed convenient access to N-aryl vinylogous amides
(1) For recent reviews, see: (a) Hartwig, J. F. Angew. Chem., Int. Ed.
1998, 37, 2046. (b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S.
L. Acc. Chem. Res. 1998, 31, 805. (c) Yang, B. H.; Buchwald, S. L. J.
Organomet. Chem. 1999, 576, 125.
(2) (a) Mann, G.; Hartwig, J. F.; Driver, M. S.; Fernandez-Rivas, C. J.
Am. Chem. Soc. 1998, 120, 827. (b) Hamann, B. C.; Hartwig, J. F. J. Am.
Chem. Soc. 1998, 120, 7369. (c) Old, D. W.; Wolfe, J. P.; Buchwald, S. L.
J. Am. Chem. Soc. 1998, 120, 9722. (d) Hartwig, J. F.; Kawatsure, M.;
Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem.
1999, 64, 5575. (e) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65,
1144. (f) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L.
J. Org. Chem. 2000, 65, 1158.
(3) (a) Yang, B. Y.; Buchwald, S. L. Org. Lett. 1999, 1, 35. (b)
Shakespeare, W. C. Tetrahedron Lett. 1999, 40, 2035. (c) Bolm, C.;
Hildebrand, J. P. J. Org. Chem. 2000, 65, 169.
(4) (a) Jirkovsky, I. Can. J. Chem. 1974, 52, 55. (b) Greenhill, J. V.
Chem. Soc. ReV. 1977, 6, 277. (c) Tamura, Y.; Chen, L. C.; Fujita, M.;
Kiyokawa, H.; Kita, Y. Chem. Ind. (London) 1979, 668. (d) Chen, L. C.;
Yang, S. C.; Wang, H. M. Synthesis 1995, 385.
(5) A related palladium-catalyzed transformation has been reported in
moderate yield using a titanium isocyanate complex. The scope and exact
mechanism of this process, however, is unclear. See: Mori, M.; Uozumi,
Y.; Shibasaki, M. Heterocycles 1992, 33, 819.
10.1021/ol000031z CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/23/2000

In the case of para- and meta-substituted bromides,
2-substituted enaminones such as 5 were sometimes encoun-
tered as side products. Since no 2-aryl derivatives of 1 itself
were detected, these products presumably arise from a Heck
reaction which occurs after initial C-N bond formation. Up
to 15% of enaminones 5f and 5h could be isolated when
Table 1. Palladium-Catalyzed Coupling of 1 with Aryl Halides
more than 1.5 equiv of the bromides was used for extended
reaction times (>24 h). Fortunately, this side reaction can
usually be suppressed using shorter reaction times and less
of the bromide coupling partner. Because of the facility of
the Heck reaction with highly reactive bromide 2a, only a
moderate yield of 3a could be attained. The problem could
be circumvented, however, with the use of 1.1 equiv of
chloride 2j, which afforded product 3a in a much improved
92% yield. Not surprisingly, this side reaction was not
encountered with aryl chlorides or with sterically crowded
substrates such as 2-substituted enaminones (vide infra) and
ortho-substituted aryl bromides.
The coupling reaction typically affords high yields of the
desired N-aryl enaminones regardless of substitution pattern
or electronic state of the aryl halide. As expected on the basis
of literature precedent, ligand 4 induces the coupling of aryl
chlorides as efficiently as aryl bromides.2f A direct com-
parison of aryl bromides with chlorides reveals that higher
yields are often obtained with chlorides in the case of
enaminone 1. Heterocycles 2o and 2p also undergo efficient
coupling with 1 under the described reaction conditions.10
Although the presence of a carbamate (2e) did not affect
the reaction, some epimerization of phenylalanine derivative
3e was observed.11
To examine the sensitivity of this coupling reaction to
steric effects, we sought a sterically demanding 2-substituted
enaminone. Since 1,3-cyclohexanedione affords good yields
of C-alkylation products with reactive electrophiles such as
benzyl bromide,12 we decided to investigate the 2-benzyl
derivative. The corresponding enaminone 7 was easily
synthesized in 86% yield by treatment of â-diketone 6 with
ammonium acetate under Dean-Stark conditions (Scheme
1).13
In order to investigate the conditions for this process, the
reaction of commercially available enaminone 1 with 4-bro-
mobenzonitrile (2b) was initially studied (entry 2, Table 1).6
A quick survey of reaction conditions revealed that moderate
yields (20-50%) of 3b could be obtained by heating 1 and
2b in DME with cesium carbonate, ligand 4 (10 mol %),7
and a palladium source such as Pd2(dba)3 (5 mol %).
Although substitution of ligand 4 with 2-(dicyclohexylphos-
phino)biphenyl was tolerated, other ligands proved to be
inferior.8 While we discovered that THF could replace DME
as solvent, toluene could not be used due to the insolubility
of the enaminone. Optimal yields (60-70%) were obtained
when an excess of bromide 2b (1.5 equiv relative to
enaminone 1) was used. The use of equivalent amounts of
bromide and enaminone resulted in slightly diminished yields
of products.9
Scheme 1
(6) All reactions were performed using Radley’s Carousel Reaction
Station (see http//radleys.co.uk). All products were characterized by 1H and
13C NMR and LC-MS.
(7) Recently made commercially available by Strem Chemical Co.
(8) With some electron deficient aryl bromides, DPPF could be used as
the ligand, but the reaction was slower and less efficient than with 4. The
replacement of 4 with other ligands such as PPh3, BINAP, P(t-Bu)3, or
1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldicyclohexylphosphine was
not well tolerated and produced little or no product under the above
conditions after 48 h. Pd(OAc)2 could be used as a Pd source in the reaction
while Pd(PPh3)4 was ineffective as a catalyst.
Enaminone 7 was then coupled to halides 2a-o using the
optimized conditions (Table 2). The additional steric demand
(9) Control experiments in which the optimized conditions were applied
to the reaction of 1 with 2b in the absence of either palladium or ligand 4
failed to produce 3b. Reactions in Tables 1 and 2 were not optimized with
respect to reaction times.
1110
Org. Lett., Vol. 2, No. 8, 2000

Another application of this methodology lies with the
synthesis of 2,3-disubstituted indoles (Scheme 3).4d,16 We
Table 2. Palladium-Catalyzed Coupling of 7 with Aryl Halides
Scheme 3
hoped to take advantage of this palladium-catalyzed reaction
by combining C-N bond formation with an intramolecular
Heck reaction to achieve a one-pot indole synthesis. Indeed,
we were encouraged by the facility with which side products
5 were produced from the corresponding intermolecular Heck
reactions from Table 1 above. Consequently, exposure of
1,2-dibromobenzene (11) to the standard coupling conditions
for 24 h afforded a 1.4:1 mixture of addition product 12 and
indole 13 (Scheme 3).17 After some experimentation,18 we
of the benzyl group is apparent by the decrease in reaction
rates of aryl halides with 8 relative to unsubstituted enami-
none 1. Although the rates were slower, the coupling yields
of enaminone 7 with aryl bromides were almost uniformly
superior to those of enaminone 1, most likely due to the
absence of the aforementioned side reaction. Aryl chlorides
on the other hand appear to be more sensitive to the
additional steric crowding and thus typically require longer
reaction times and afford products in slightly diminished
yields.14
In addition to the formation of N-aryl enaminones, the
above reaction can be applied in a tandem fashion to form
heterocycles. For example, quinoline 10 can be synthesized
in a single step from bromoaldehyde 9 in quantitative yield
under these reaction conditions (Scheme 2). By comparison,
(10) It should be noted that the deprotected version of 2p (without the
Boc) did not undergo a coupling reaction with 1.
(11) Chiral HPLC failed to separate enantiomers, so deprotection of 3e
(TFA/CH2Cl2) followed by Mosher amide analysis of the resulting amine
indicated 33% ee of product.
(12) Rajamannar, T.; Palani, N.; Balasubramanian, K. K. Synth. Commun.
1993, 23, 3095.
(13) For a convenient, high-yielding method for the synthesis of primary
vinylogous amides, see: Baraldi, P. G.; Simoni, D.; Manfredini, S. Synthesis
1983, 902.
(14) As before, a 33% ee was observed in 8e by chiral HPLC (ChiralPak
AS column, 1:3 alcohol/hexanes). Also, no coupling was observed with
the deprotected version of 2o.
(15) Tominaga, Y.; Okuda, H.; Kohra, S.; Mazume, H. J. Hetereocycl.
Chem. 1991, 28, 1245.
Scheme 2
(16) For other examples of palladium-catalyzed formation of indoles,
see: (a) Iida, H.; Yuasa, Y.; Kibayashi, C. J. Org. Chem. 1980, 45, 2938.
(b) Hegedus, L. S.; Mulhern, T. A.; Mori, A. J. Org. Chem. 1985, 50, 4282.
(c) Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Synthesis 1990,
215. (d) Koerber-Ple, K.; Massiot, G. Synlett 1994, 759. (e) Akermark, B.;
Oslob, J. D.; Heuschert, U. Tetrahedron Lett. 1995, 36, 1325. (f) Chen, C.
Y.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. J.
Org. Chem. 1997, 62, 2676.
(17) Suzuki, H.; Thiruvikraman, S. V.; Osuka, A. Synthesis 1984, 616.
(18) Extended reaction times, higher reaction temperatures (refluxing
DME), and an increase in the starting amounts of cesium carbonate and/or
ligand 4 failed to induce complete conversion of 12 to 13.
the reported synthesis of 10 was accomplished in four steps
and 18% overall yield.15
Org. Lett., Vol. 2, No. 8, 2000
1111

discovered that addition of a second portion of palladium
catalyst and ligand 4 to the reaction mixture after 12 h
induced conversion of enaminone 1 to indole 13 in 61%
yield. Interestingly, exposure of enaminone 7 to the same
conditions produced cyclized product 16.19 Although the
precise mechanism of this transformation is uncertain,
intermediate 14 was isolated as the major product when the
second portion of catalyst and ligand was omitted. Most
likely 14 gives way to Heck cyclization product 15 which
then leads to 16 in high yield (84%) after acyl migration.
In conclusion, the first application of Hartwig-Buchwald
couplings to the synthesis of N-aryl enaminones has been
accomplished in high yields under palladium catalysis with
commercially available ligand 4. The reaction is widely
applicable to a variety of electron rich, electron poor, and
neutral aromatic bromides or chlorides as well as heterocyclic
halides. Excellent yields were obtained regardless of the
substitution pattern on the aromatic halide. Additionally, the
first tandem Hartwig-Buchwald-Heck cyclization has been
reported and applied to the synthesis of 2,3-disubstituted
indole derivatives. This extension of the current methodology
should be a valuable addition to natural product total
synthesis as well as the synthesis of molecules of medicinal
interest. Moreover, these coupling reactions should also be
amenable to applications involving solid-phase synthesis.20
Further investigations into the scope of these reactions and
their application to heterocycle synthesis are currently
underway.21
Acknowledgment. We gratefully acknowledge Drs.
Steven L. Colletti and Jean-Francois Marcoux and Mr.
Richard Berger for helpful discussions.
Supporting Information Available: Full experimental
1
details and H/13C NMR spectroscopic data for heretofore
unreported compounds 3, 5, 7, 8, 12, and 16. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL000031Z
(20) For examples of Hartwig-Buchwald couplings on solid phase,
see: (a) Ward, Y. D.; Farina, V. Tetrahedron Lett. 1996, 37, 6993. (b)
Willoughby, C. A.; Chapman, K. T. Tetrahedron Lett. 1996, 37, 7181. For
a lead reference involving solid-phase indole synthesis, see: Zhang, H. C.;
Ye, H.; Moretto, A. F.; Brumfield, K. K.; Maryanoff, B. E. Org. Lett. 2000,
2, 89.
(21) Representative procedure: Pd2(dba)3 (23 mg, 0.025 mmol) was
added to a mixture of bromide 2d (128 mg, 0.75 mmol), enaminone 1 (70
mg, 0.5 mmol), ligand 4 (20 mg, 0.05 mmol), and Cs2CO3 (260 mg, 0.8
mmol) in 5 mL of THF. Next, the mixture was stirred at 80 °C under
nitrogen until TLC showed complete reaction (24 h). The reaction mixture
was then diluted with 120 mL of EtOAc, washed with saturated NH4Cl
(20 mL) and brine (20 mL), dried over Mg2SO4, filtered, and concentrated.
The crude orange oil was then purified by preparative TLC (SiO2, 80%
EtOAc/hexanes) to afford 3d (88 mg, 77%) as a waxy yellow solid.
(19) For 16: IR (CDCl3) 3068, 3026, 2954, 2910, 2839, 1703, 1617,
1
1494, 1458 cm-1; H NMR (500 MHz, CDCl3) δ 8.54 (d, J ) 7.9 Hz, 1
H), 7.40 (d, J ) 7.9 Hz, 1 H), 7.34-7.22 (m, 7 H), 4.06 (s, 2 H), 2.94 (t,
J ) 6.3 Hz, 2 H), 2.81 (t, J ) 6.3 Hz, 2 H), 2.11 (quin, J ) 6.3 Hz, 2 H);
13C NMR (500 MHz, CDCl3) δ 169.5, 140.0, 135.0, 134.7, 130.6, 128.8
(2C), 128.5 (2C), 126.5, 124.5, 124.1, 118.6, 116.7, 115.6, 34.7, 30.2, 22.2,
21.5; LC-MS (m/z) 276.19 (M++1). Not surprisingly 16 is inert to NaBH4
reduction.
1112
Org. Lett., Vol. 2, No. 8, 2000