A new synthesis of naphthyridinones and quinolinones: Palladium-catalyzed amidation of o-carbonyl-substituted aryl halides

Article abstract of DOI:10.1021/ol049165t

(Equation Presented) An alternative to the Friedlander condensation for the synthesis of naphthyridinones and quinolinones has been discovered. Palladium-catalyzed amidation of halo aromatics substituted in the ortho position by a carbonyl functional group or its equivalent with primary or secondary amides leads to the formation of substituted naphthyridinones and quinolinones.

Full text of DOI:10.1021/ol049165t

ORGANIC
LETTERS
2004
Vol. 6, No. 14
2433-2435
A New Synthesis of Naphthyridinones
and Quinolinones: Palladium-Catalyzed
Amidation of o-Carbonyl-Substituted
Aryl Halides
Peter J. Manley* and Mark T. Bilodeau
Department of Medicinal Chemistry, Merck & Co., Inc., P.O. Box 4,
West Point, PennsylVania 19486
peter_manley@merck.com
Received May 7, 2004
ABSTRACT
An alternative to the Friedlander condensation for the synthesis of naphthyridinones and quinolinones has been discovered. Palladium-
catalyzed amidation of halo aromatics substituted in the ortho position by a carbonyl functional group or its equivalent with primary or
secondary amides leads to the formation of substituted naphthyridinones and quinolinones.
In an ongoing medicinal chemistry program we required the
synthesis of 3-arylnaphthyridinones and 3-arylquinolinones
as key intermediates. The literature reports a number of
synthetic routes to these compounds,1 and among these the
Friedlander condensation of amino aldehydes, ketones, and
esters with enolizable acids and esters stands out as the most
general method. The Friedlander condensation with enoliz-
able ketones to form naphthyridines and quinolines is often
performed as a single step in a single pot. However, the
condensation with enolizable acids and esters to form
naphthyridinones and quinolinones often requires two sepa-
rate reactions to achieve the requisite bond constructions.
As an alternative, we envisioned using a cascade sequence
wherein a palladium-catalyzed cross-coupling reaction be-
tween 2-halonicotinaldehyde and 2-phenylacetamide would
provide an intermediate which would then cyclize and
dehydrate to give the desired naphthyridinone product. While
the coupling of amides, sulfonamides, carbamates, and ureas
with aryl halides has been well documented,3-5 the presence
A number of the intermediates that we required either had
not been synthesized using this methodology or gave poor
yields. For example, 3-phenyl-1,8-naphthyridin-2(1H)-one
can be synthesized in 6% yield by the Friedlander condensa-
tion of 2-aminonicotinaldehyde and 2-phenylacetic acid with
catalytic piperidine in ethanol at reflux for 5 days (eq 1).2
(1) (a) Jones, G. In ComprehensiVe Heterocyclic Chemistry; Boulton,
A. J., McKillop, A., Eds.; Pergamon Press: Oxford, 1984; Vol. 2, 2.08, pp
395-510. (b) Lowe, P. A. In ComprehensiVe Heterocyclic Chemistry;
Boulton, A. J., McKillop, A., Eds.; Pergamon Press: Oxford, 1984; Vol.
2, 2.11, pp 581-627.
(2) Hawes, E. M.; Wibberley, D. G. J. Chem. Soc. C 1966, 315-321.
(3) (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043-
6048 and references therein. (b)Yin, J.; Buchwald, S. L. Org. Lett. 2000,
2, 1101-1104.
10.1021/ol049165t CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/11/2004

of enolizable carbonyl functionality, especially ketones, has
been complicated by a competing R-arylation reaction.6 To
minimize this side reaction, we utilized the relatively mildly
basic coupling conditions of Buchwald.3 When 2-bromo-
nicotinaldehyde and 2-phenylacetamide were combined in
the presence of Cs2CO3, Pd2(dba)3, and xantphos7 in anhy-
drous toluene at 100 °C, product 1, the result of amide
coupling and cyclodehydration, was obtained in 91% after
only 1 h (eq 2). In a control experiment under identical
conditions where palladium and ligand were absent, a very
small amount of aldol condensation product was observed
and none of the desired amide or naphthyridinone products
were produced.
Table 2. Tandem Pd(0)-Catalyzed Amidation/Aldol
Condensation of o-Keto, Carboxy, and Cyano Aryl Halides with
2-Phenylacetamide
entry
R1
R2
R3
yield (%)a
1
2
3
4
5
H
H
H
Ph
H
COMe
COPh
CO2Me
CO2Me
CN
Me
Ph
OH
OH
NH2
65
55
33b
74b
52b
Given the simplicity and potential for diversity in this
cascade reaction sequence, we began to investigate its scope
and limitations for the synthesis of substituted naphthyridi-
nones and quinolinones. Table 1 demonstrates the scope of
a Isolated yields of compounds which were characterized by H NMR,
13C NMR, and HRMS. b After initial cross-coupling, the reaction mixture
was heated to reflux.
1
reaction (Table 2). The enolizable methyl ketone 2-bromo-
acetophenone gave the desired 4-methyl-substituted quino-
linone (entry 1) without producing any R-arylation products.
2-Bromobenzophenone gave the 4-phenyl-substituted quino-
linone (entry 2) in good yield. Coupling of methyl 2-bro-
mobenzoate or methyl 2-bromo-5-phenylbenzoate (entries 3
and 4) with 2-phenylacetamide gave the 4-hydroxyquinoli-
none derivatives. 2-Bromobenzonitrile (entry 5) coupled with
2-phenylacetamide to give the 4-aminoquinolinone derivative
in moderate yield. For ester and nitrile substrates (entries
3-5), after the initial cross-coupling reaction was complete
(as determined by LC/MS) overnight heating of the reaction
was required to affect the cyclization step.
Table 1. Tandem Pd(0)-Catalyzed Amidation/Aldol
Condensation of o-Formyl Aryl Halides with 2-Phenylacetamide
Next, we turned our attention to the amide coupling partner
(Table 3). Primary aryl and heterocyclic acetamides worked
well (entries 1-3) with the exception of 2-pyridylacetamide
which failed to couple using our standard conditions.
Employing the procedure of Buchwald8 for the use of
catalytic CuI and N,N′-dimethylethylenediamine to couple
amides with aryl halides at 150 °C in a sealed tube, we were
able to synthesize 3-pyridin-2-ylquinolin-2(1H)-one in 62%
isolated yield (entry 4). The secondary amide N-methyl-2-
phenylacetamide participated in the palladium-catalyzed
reaction in good yield (entry 5); however, this seemed to be
the limiting case. Neither the more sterically demanding
N-isopropyl-2-phenylacetamide nor the N-arylamide N-phen-
yl-2-phenylacetamide was coupled with 2-bromobenzalde-
hyde using our standard conditions. Other palladium-derived
catalyst systems known to couple sterically demanding cyclic
carbamates5 were investigated without success. The coupling
of N-phenyl-2-phenylacetamide with 2-bromobenzaldehyde
to form 1,3-diphenylquinolin-2(1H)-one was achieved using
the copper methodology described above albeit in low yield
(entry 6). N-Isopropyl-2-phenylacetamide failed to couple
under every set of conditions that were investigated.
1
a Isolated yields of compounds which were characterized by H NMR,
13C NMR, and HRMS.
the aryl halide partner. While both bromides and chlorides
are effective in this reaction (entry 1), chlorides required
longer reaction times than bromides (6 h versus 2 h). In
addition to 1,8-naphthyridinones (e.g., 1), 1,5- and 1,7-
naphthyridinones (entries 2 and 3, respectively) could also
be synthesized using this methodology. Even an electron-
rich aryl bromide, as in entry 4, participated in this reaction,
albeit in moderate yield.
The reaction was not limited to o-halo aldehydes. Other
carbonyl or equivalent substituents were successful in this
(4) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. N.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575-5580.
(5) Ghosh, A.; Sieser, J. E.; Riou, M.; Cai, W.; Rivera-Ruiz, L. Org.
Lett. 2003, 5, 2207-2210 and references therein.
(6) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360-1370 and references therein.
In an effort to further the scope of this reaction, primary
and secondary alkyl amides were subjected to the standard
(8) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421-7428 and references therein.
(7) 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene.
2434
Org. Lett., Vol. 6, No. 14, 2004

Table 3. Tandem Pd(0)-Catalyzed Amidation/Aldol
Condensation of 2-Bromobenzaldehyde with Acetamides
Figure 1. Compounds 4 and 5.
addition of excess NaO-t-Bu in t-BuOH to give the desired
quinolinone (entry 7). N-Methylpropionamide could be
coupled with 2-bromobenzaldehyde in moderate isolated
yield (68%) but failed to cyclize under the reaction condi-
tions. Using the method discovered above this substrate did
cyclize by the addition of NaO-t-Bu in t-BuOH to give the
desired quinolinone (entry 8) in low yield. Alkyl amides
containing a strong electron-withdrawing substituent, such
as ethyl 3-amino-3-oxopropanoate and 2-cyanoacetamide,
also failed in this reaction.
In summary, we have developed an alternative strategy
for the synthesis of 3-aryl naphthyridinones and quinolinones
using a palladium-catalyzed cross-coupling reaction between
enolizable primary and secondary amides and o-carbonyl
substituted aryl halides. It has the advantage of being a
convergent one-pot cascade sequence rather than one which
often requires multiple steps. Another attractive feature of
this methodology is the broader availability of o-carbonyl-
containing aryl halides versus their amino or nitro counter-
parts.
a Method A: Pd2(dba)3/xantphos; Method B: CuI, N,N′-dimethylethyl-
enediamine. b Isolated yields of compounds which were characterized by
1H NMR, 13C NMR, and HRMS. c 1,4-Dioxane added as cosolvent. d NaO-
t-Bu in t-BuOH added to facilitate cyclization step.
Acknowledgment. We thank Dr. Art Coddington, Dr.
Charles W. Ross, Dr. Harri Ramjit, and Joan S. Murphy for
mass spectral analysis.
reaction conditions. Both propionamide and 2-cyclopropyl-
acetamide coupled with 2-bromobenzaldehyde to give the
amides 4 and 5 (Figure 1) in excellent isolated yields but
failed to cyclize under the reaction conditions. After isolation,
attempts to cyclize 4 or 5 under a number of acidic or basic
conditions failed to give the desired quinolinone products.
This proved true for nearly every example that was studied.
Two exceptions to this general trend were identified.
2-Methoxyacetamide could be cyclized after coupling by the
Supporting Information Available: Experimental details
and physical characterization data for quinolinones and
naphthyridinones (Scheme 1, Tables 1-3, and Figure 1). This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL049165T
Org. Lett., Vol. 6, No. 14, 2004
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