A novel palladium-catalyzed synthesis of 1,2-dihydroquinoxalines and 3,4-dihydroquinoxalinones.

Article abstract of DOI:10.1021/ol025640g

Reactions of enamines, derived from 2-nitroanilines and alpha-substituted aldehydes, with carbon monoxide (6 atm) in the presence of a catalytic amount of bis(dibenzylideneacetone)palladium(0) (Pd(dba)(2)) and 1,3-bis(diphenylphosphino)propane (dppp) affo

Full text of DOI:10.1021/ol025640g

ORGANIC
LETTERS
2002
Vol. 4, No. 8
1339-1342
A Novel Palladium-Catalyzed Synthesis
of 1,2-Dihydroquinoxalines and
3,4-Dihydroquinoxalinones
,†
Bjo1rn C. G. So1derberg,* Jeffery M. Wallace,† and Joaqu´ın Tamariz‡
Department of Chemistry, West Virginia UniVersity,
Morgantown, West Virginia 26506-6045, and Department of Organic Chemistry,
I.P.N. Prol. Carpio y Plan de Ayala, 11340 Me´xico, D.F., Mexico
bjorn.soderberg@mail.wVu.edu
Received January 29, 2002
ABSTRACT
Reactions of enamines, derived from 2-nitroanilines and r-substituted aldehydes, with carbon monoxide (6 atm) in the presence of a catalytic
amount of bis(dibenzylideneacetone)palladium(0) (Pd(dba)2) and 1,3-bis(diphenylphosphino)propane (dppp) afford readily separated mixtures
of 1,2-dihydroquinoxalines and 3,4-dihydroquinoxalinones. Addition of a catalytic amount of 1,10-phenanthroline to the reaction mixture
substantially improved the yield of products.
A variety of nitrogen-containing heterocyclic compounds
have been prepared by transition metal-catalyzed reductive
N-heteroannulation of ortho-substituted nitrobenzenes in the
presence of carbon monoxide. Examples of heterocycles
obtained in this fashion include indoles,1 2(1H)-indazoles,1f,2
quinolines,1f 4(1H)-quinolones,3 quinazolines,4 4(3H)-quinazoli-
nones,5 pyrrolines,6 benzimidazoles,1g,7 2(1H)-benzimid-
azolones,7 benzotriazoles,8 2,1-benzoisoxazole,1f benzo[c]-
cinnoline,9 1,4-dihydro-(2H)-3,1-benzoxazine-2-ones,10 and
2(1H)-benzoxazolone.11 Palladium complexes have predomi-
nantly been used as the catalyst for reductive N-hetero-
annulations, but a number of other transition metals, such
as iron, manganese, cobalt, ruthenium, platinum, selenium,
and rhodium, have successfully been employed.
Reductive N-heteroannulations of 2-nitro-N-(arylmethyl-
ene)benzenamines have previously been reported by Cenini
et al. to afford 2-arylbenzimidazoles.1g,7a For example,
reaction of 2-nitro-N-(phenylmethylene)benzeneamine (1)
with carbon monoxide (50 atm, 220 °C), in the presence of
a catalytic amount of triruthenium dodecacarbonyl, gave
2-phenylbenzimidazole (2) in 86% yield (Scheme 1). A
palladium-based catalyst system has been developed, by the
† West Virginia University.
‡ Escuela Nacional de Ciencias Biolo´gicas.
(1) (a) So¨derberg, B. C.; Chisnell, A. C.; O’Neil, S. N.; Shriver, J. A. J.
Org. Chem. 1999, 64, 9731. (b) So¨derberg, B. C.; Rector, S. R.; O’Neil, S.
N. Tetrahedron Lett. 1999, 40, 3675. (c) Ragaini, F.; Sportiello, P.; Cenini,
S. J. Organomet. Chem. 1999, 577, 283. (d) Nishiyama, Y.; Maema, R.;
Ohno, K.; Hirose, M.; Sonoda, N. Tewtrahedron Lett. 1999, 40, 5717. (e)
So¨derberg, B. C.; Shriver, J. A. J. Org. Chem. 1997, 62, 5838. (f) Akazome,
M.; Kondo, T.; Watanabe, Y. J. Org. Chem. 1994, 59, 3375. (g) Tolari, S.;
Cenini, S.; Crotti, C.; Gianella, E. J. Mol. Catal. 1994, 87, 203. (h) Tolari,
S.; Cenini, S.; Crotti, C.; Gianella, E. J. Mol. Catal. 1994, 87, 2811. (i)
Crotti, C.; Cenini, S.; Todeschini, R.; Tollari, S. J. Chem. Soc., Faraday
Trans. 1991, 2811-20. (j) Crotti, C.; Cenini, S.; Rindone, B.; Tollari, S.;
Demartin, F. J. Chem. Soc., Chem. Commun. 1986, 784.
(2) Akazome, N.; Kondo, T.; Watanabe, Y. J. Chem. Soc., Chem.
Commun. 1991, 1466.
(6) Watanabe, Y.; Yamamoto, J.; Akazome, M.; Kondo, T.; Mitsudo,
T.-a. J. Org. Chem. 1995, 60, 8328.
(7) (a) Crotti, C.; Cenini, S.; Ragaini, F.; Porta, F.; Tollari, S. J. Mol.
Catal. 1992, 72, 283. (b) Watanabe, Y.; Suzuki, N.; Tsuji, Y. Bull. Chem.
Soc. Jpn. 1982, 55, 2445.
(3) (a) Annunziata, R.; Cenini, S.; Palmisano, G.; Tollari, S. Synth.
Commun. 1996, 26, 495. (b) Tollari, S.; Cenini, S.; Ragaini, F.; Cassar, L.
J. Chem. Soc., Chem. Commun. 1994, 1741.
(4) Akazome, M.; Yamamoto, J.; Kondo, T.; Watanabe, Y. J. Organomet.
Chem. 1995,494, 229.
(8) Pizzotti, M.; Cenini, S.; Psaro, R.; Constanzi, S. J. Mol. Catal. 1990,
63, 299.
(9) Kmiecik, J. E. J. Org. Chem. 1965, 30, 2014.
(10) Cenini, S.; Console, S.; Crotti, C.; Tollari, S. J. Organomet. Chem.
1993, 451, 157.
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310.
(11) Braunstein, P.; Kervennal, J.; Richert, J. L. Angew. Chem, Int. Ed.
Engl. 1985, 24, 768.
10.1021/ol025640g CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/15/2002

can be invoked.13 For example, benzimidazole 2 has been
prepared by reductive annulation of 1 with triethyl phosphite
although in substantially lower yield compared to the metal-
catalyzed reactions.14 To the best of our knowledge, annu-
lation of enamines to give dihydroquinoxaline derivatives
is a novel reaction which does not have a counterpart in more
classical nitrene type chemistry.
Scheme 1
Probably the most widely used method for the preparation
of quinoxaline derivatives is the Hinsberg condensation of
1,2-diaminobenzenes with 1,2-dicarbonyl compounds.15
A
same group, for the transformation of in situ formed imines
to benzimidazoles.1g In addition, potassium tetracarbonyl-
hydridoferrate (KHFe(CO)4) has been reported to mediate
the transformation of 1 to 2 in low isolated yield.12
disadvantage of this type reaction is the formation of isomeric
products using unsymmetrically substituted reactants. In our
case, the cyclization is inherently regioselective and may be
a viable alternative to the Hinsberg condensation reaction.
A selection of additional enamines was examined, and the
results thereof are summarized in Table 1.16 For all reactions
in the table, unless otherwise stated, a 0.7-1.2 M solution
of the enamine in DMF was reacted with carbon monoxide
(6 atm, 70 °C) in the presence of Pd(dba)2 (6 mol %), dppp
(6 mol %), and 1,10-phenanthroline (12 mol %). Although
acetonitrile worked well as the solvent in our initial reaction
using 3a, DMF was found to be a superior solvent for the
functionalized enamines. For example, no product was
obtained from 3c, using the conditions shown in Scheme 2.
Addition of phenanthrolines, or related chelating nitrogen
donor ligands, has been shown to accelerate a number of
reductive N-heteroannulation and carbonylation reactions of
nitroaromatic compounds.10 This was also the case in some
but not all of our reactions. For example, reaction of the
methoxy-substituted enamine 3b in the presence of 1,10-
phenanthroline gave 57% of 4b and 40% of 5b (entry 2). In
sharp contrast, reaction in the absence of 1,10-phenanthroline
gave a 7% total yield of 4b + 5b (entry 1). As seen in Table
1, aromatic rings having electron-donating and moderately
electron-withdrawing substituents readily undergo the an-
nulation reaction. Enamines substituted with a strong electron-
withdrawing substituent on the benzene ring apparently do
not participate in the annulation reaction. For example, the
enamine derived from 2,4-dinitrobenzenamine and 2-methyl-
propanal was completely consumed under standard reaction
conditions; however, no major product was identified.
Heteroaromatic enamines can also be used as substrates
for the palladium-catalyzed annulation reaction. For example,
reaction of the pyridine-derived enamine 3i gave the expected
products 4i and 5i, albeit in somewhat lower yield compared
In a systematic effort to expand our milder palladium-
catalyzed methodology1e to the synthesis of benzimidazoles
and other heterocycles containing two or more nitrogen
atoms, we turned our attention to reactions of imines. 2-Nitro-
N-(4-nitrophenylmethylene)benzenamine, formed by con-
densation between 2-nitrobenzenamine and 4-nitrobenz-
aldehyde, was reacted with carbon monoxide (4 atm, 70 °C)
in the presence of a catalytic amount of palladium diacetate
and triphenylphosphine. Somewhat to our disappointment,
no benzimidazole was produced under the reaction condi-
tions; only recovered imine and hydrolysis products thereof
were isolated. We have previously noted that some substi-
tuted 2-nitrostyrenes do not undergo annulation to form
indoles under the above conditions but could be cyclized
using a catalytic amount of Pd(dba)2, dppp, and 1,10-
phenanthroline in DMF under 6 atm of carbon monoxide at
temperatures between 70 and 120 °C. However, the latter
conditions also failed to produce the expected benzimidazole.
Enamines were next examined as potential substrates for
reductive annulation. Reaction of enamine 3a, formed by
condensation of 2-nitrobenzenamine with 2-methylpropanal
in the presence of molecular sieves, with carbon monoxide
(4 atm, 70 °C) in the presence of Pd(dba)2 and dppp in
acetonitrile produced a mixture of 1,2-dihydroquinoxaline
4a and 3,4-dihydroquinoxalinone 5a (Scheme 2). The
products were readily separated by column chromatography
on silica gel.
Metal-catalyzed N-heteroannulations in many cases closely
resemble reactions wherein a nitrene or nitrenoid intermediate
Scheme 2
(12) Watanabe, Y.; Takatsuki, K.; Shim, S. C.; Mitsudo, T.-a.; Takegami,
Y. Bull. Chem. Soc. Jpn. 1978, 51, 3397.
(13) For a review, see: So¨derberg, B. C. G. Curr. Org. Chem. 2000, 4,
727.
(14) Cadogan, J. I. G.; Marshall, R.; Smith, D. M.; Todd, M. J. J. Chem.
Soc. C 1970, 2441.
(15) (a) Grivas, S.; Tian, W.; Andersson, R. J. Chem. Res., Synop. 1992,
328. (b) Loriga, M.; Nuvole, A.; Paglietti, G. J. Chem. Res. 1989, 202. (c)
Porter, A. E. A. In ComprehensiVe Heterocyclic Chemistry; Katritsky, A.
R., Rees, C. W., Eds.; Pergamon Press: 1984; Vol. 3, p 179.
(16) Typical experimental procedure: To an ACE-Glass pressure tube
were added 3b (107 mg, 0.48 mmol), Pd(dba)2 (18 mg, 0.031 mmol), dppp
(13 mg, 0.032 mmol), 1,10-phenanthroline (10 mg, 0.055 mmol), and DMF
(5 mL). A pressure head was attached; the reaction mixture was pressurized
to 6 atm of carbon monoxide and heated at 70 °C for 4 h. A slow change
in color from deep purple to brown was observed. Extractive workup with
dichloromethane and brine followed by flash chromatography (98:2,
hexanes:ethyl acetate) gave 57% of 4b and 40% of 5b.
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Org. Lett., Vol. 4, No. 8, 2002

The overall yield of products was low; however, interestingly,
a fully aromatic quinoxaline (4h) was obtained. The annu-
lation reaction is apparently restricted to enamines that can
be isolated and, at least partially, purified. Attempted
palladium-catalyzed cyclization of enamines formed in situ
from aldehydes and anilines was unsuccessful. An additional
restriction is the unfavorable imine-enamine equilibrium
observed using R-unsubstituted aldehydes and the complete
lack of reaction between ketones and 2-nitroanilines.
Adventitious water in the solvent, or in the carbon
monoxide, was initially considered a possible source of the
3,4-dihydroquinoxalinone oxygen. However, reaction of
enamine 3a in a 1:1 DMF-water mixture gave only 1,2-
dihydroquinoxaline 4a in 37% isolated yield in addition to
a small amount of starting material. No trace of 3,4-
dihydroquinoxalinone 5a was observed. Oxidation of the 1,2-
dihydroquinoxaline to the 3,4-dihydroquinoxalinone was not
observed under standard reaction conditions. For example,
1,2-dihydroquinoxaline 4e was recovered unchanged from
the reaction mixture. The reverse reaction, i.e., reduction of
3,4-dihydroquinoxalinone to 1,2-dihydroquinoxaline, was
also disproved under the same conditions. These results
suggest that the 3,4-dihydroquinoxalinone oxygen is derived
from the nitro group.
Table 1. Synthesis of 1,2-Dihydroquinoxalines and
3,4-Dihydroquinoxalinones
The mechanism of the annulation reaction is presently
unclear; however, a few possible sequences of events are
outlined in Schemes 3 and 4. Transition metal catalyzed
Scheme 3
deoxygenation of organic nitro compounds has been pro-
posed to proceed via the formation of nitrene, or nitrenoid,
intermediates. Carbon monoxide is crucial for the reaction
Scheme 4
a Isolated yield of enamine from the corresponding 2-nitroaniline and
aldehyde. b Isolated yield of pure 1,2-dihydroquinoxaline or 3,4-dihydro-
quinoxalinone. c In the absence of 1,10-phenanthroline. d Isolated as a 1:1
cis:trans mixture.
to aniline derived enamines (entry 9). A spirocyclic 1,2-
dihydroquinoxaline and 3,4-dihydroquinoxalinone were ob-
tained upon reaction of a cyclohexane-substituted enamine
(entry 7). Finally, substrates having only one â-substituent
on the enamine moiety underwent the cyclization (entry 8).
Org. Lett., Vol. 4, No. 8, 2002
1341

to proceed, functioning as a reducing agent to give a putative
metal-bound nitrene and carbon dioxide. Metal-bound ni-
trenes have been reported; for example, a ruthenium-bound
nitrene derived from 2-nitrosobiphenyl has been isolated and
characterized by X-ray crystallography.17 Decomposition of
this complex gave carbazole, the expected nitrene insertion
product.
A formal, intramolecular, [2 + 2] cycloaddition between
the intermediately formed palladium-bound nitrene 6 and the
alkene would furnish the bicyclic compound 7. Sequential
â-hydride elimination, at least formally, to give 8 followed
by reductive elimination would produce the 1,2-dihydro-
quinoxaline and regenerate the active palladium(0) catalyst.
The regioselectivity of the cycloaddition parallels the selec-
tivity observed for intramolecular ketene-alkene cyclo-
additions of terminally disubstituted alkenes. A related
mechanism has been suggested for thermal decompositions
of arylamino-substituted Fischer carbene complexes forming
quinolines.18
The formation of 3,4-dihydroquinoxalinones presents, to
our knowledge, an unknown reaction path. It is plausible
that, prior to complete deoxygenation to give the palladium-
bound nitrene 7, insertion of the alkene into the inter-
mediately formed metallacyclopropane 9 (a metal-bound
nitrosarene)19 occurs (Scheme 4). Two different metalla-
cyclopentane insertion products having a bond between the
oxygen and the vinylic CH carbon of the enamine can be
envisioned (10-11). Complex 11 appears to be the more
likely candidate since a simple â-hydride elimination-
reductive elimination sequence would furnish a 3,4-dihy-
droquinoxalinone. Intramolecular insertions of alkenes into
metal-bound nitrosarenes, the first step in Scheme 4, have
been proposed.20
In summary, we have developed a novel palladium-
catalyzed N-heteroannulation of enamines, formed by con-
densation of 2-nitrobenzenamines with aldehydes, to afford
readily separated 1,2-dihydroquinoxalines and 3,4-dihydro-
quinoxalinones. The annulation reaction is inherently regio-
selective. An in-depth study of the scope, limitation, and
mechanism of this reaction is underway in our laboratories.
Acknowledgment. Support has been provided by a grant
from the National Institutes of Health (Grant R15 GM51030).
J.T. is grateful to OAS (F54111), CONACYT (250099), and
COFAA-IPN (9711220214) for financial support during his
sabbatical leave in the USA (1997-1998). Copy editing by
Diana G. Duran is gratefully acknowledged.
Supporting Information Available: Synthetic procedures
and full characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL025640G
(19) For X-ray structures of related ruthenium complexes, see: (a) Skoog,
S. J.; Gladfelter, W. L. J. Am. Chem. Soc. 1997, 119, 11049. (b) Skoog, S.
J.; Campbell, J. P.; Gladfelter, W. L. Organometallics 1994, 13, 4137.
(20) Ragaini, F.; Cenini, S.; Tollari, S.; Tummollilo, G.; Beltrami, R.
Organometallics 1999, 18, 928.
(17) Crotti, C.; Cenini, S.; Bassoli, A, Rindone, B.; Demartin, F. J. Mol.
Catal. 1991, 70, 175.
(18) So¨derberg, B. C.; Helton, E. S.; Austin, L. R.; Odens, H. H. J. Org.
Chem. 1993, 58, 5589.
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Org. Lett., Vol. 4, No. 8, 2002