Palladium-catalyzed carboxamidation reaction and aldol condensation reaction cascade: A facile approach to ring-fused isoquinolinones

Article abstract of DOI:10.1021/ol802067y

(Chemical Equation Presented) Palladium-catalyzed carboxamidation reaction and aldol condensation reaction cascade are very useful for the synthesis of various ABC ring substituted fused isoquinolinones.

Full text of DOI:10.1021/ol802067y

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4987-4990
Palladium-Catalyzed Carboxamidation
Reaction and Aldol Condensation
Reaction Cascade: A Facile Approach to
Ring-Fused Isoquinolinones
Gagan Chouhan and Howard Alper*
Centre for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of
Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
howard.alper@uottawa.ca
Received September 3, 2008
ABSTRACT
Palladium-catalyzed carboxamidation reaction and aldol condensation reaction cascade are very useful for the synthesis of various ABC ring
substituted fused isoquinolinones.
The isoquinolinone moiety is an important class of heterocyclic
compounds from both synthetic and biological points of view.
It is well-known that many compounds possessing this subunit
display biological activities of medicinal interest.1 Ring-fused
isoquinolinone heterocyclic compounds are also valuable as
synthetic precursors for the large and diverse family of
biologically important alkaloids such as 22-hydroxyacuminatine
and rosettacins.2,3 There are very few synthetic methods found
in the literature for ring-fused isoquinolinones based on the
use of homophthalic anhydride,4a an oxidative radical
cyclization process,4b or photochemical reactions.4c These
methods, however, typically provide low to moderate product
yields. Very recently, a one-pot domino N-amidoacylation/
aldol-type condensation reaction has also been reported for
the synthesis of ring-fused isoquinolinones.4d
Transition-metal-catalyzed reactions are widely used for
the synthesis of various heterocyclic ring systems.5 Among
these, palladium-catalyzed carbonylative-cyclization is a
valuable synthetic tool for the formation of a wide variety
of oxygen and nitrogen containing heterocyclics.6 In the
course of our studies on the palladium-catalyzed synthesis
of heterocyclic compounds, we have recently reported new
methods for the preparation of benzoxazinones,7 quinazoli-
nones,8 and medium-ring tricyclic lactams.9 Herein, we now
(1) Ukita, T.; Nakamura, Y.; Kubo, A.; Yamamoto, Y.; Moritani, Y.;
Saruta, K.; Higashijoma, T.; Kotera, J.; Takagi, M.; Kikkawa, K.; Omori,
K. J. Med. Chem. 2001, 44, 2204.
(2) (a) Rao, A. K.; Gadre, J. N.; Pendkar, S. Indian J. Chem. 1997, 36,
410. (b) Babjak, M.; Kanazawa, A.; Anderson, R. J.; Green, A. E. Org.
Biomol. Chem. 2006, 4, 407
.
(3) (a) Marchand, C.; Antony, S.; Kohn, K. W.; Cushman, M.;
Ioanoviciu, A.; Staker, B. L.; Burgin, A. B.; Stewart, L.; Pommier, Y. Mol.
Cancer Ther. 2006, 5, 287. (b) Lin, L. Z.; Cordell, G. A. Phytochemistry
1989, 28, 1295. (c) Fox, B. M.; Xiao, X.; Antony, S.; Kohlhagen, G.;
Pommier, Y.; Staker, B. L.; Stewart, L.; Cushman, M. J. Med. Chem. 2003,
46, 3275. (d) Cheng, K.; Rahier, N. J.; Eisenhauer, B. M.; Gao, R.; Thomas,
(4) (a) Coppola, G. M. J. Heterocycl. Chem. 1981, 18, 767. (b) Osornio,
Y. M.; Miranda, L. D.; Cruz-Almanza, R.; Muchowski, J. M. Tetrahedron
Lett. 2004, 45, 2855. (c) Senthivelan, A.; Thirumalai, D.; Ramakrishna,
V. T. Tetrahedron 2005, 61, 4213. (d) Pin, F.; Comesse, S.; Sanselme, M.;
Da¨ıch, A. J. Org. Chem. 2008, 73, 1975.
(5) Hegedus, L. S. Transition Metals in the Synthesis of Complex
Organic Molecules; University Science Book: Sausalito, CA, 1999.
S. J.; Hecht, S. M. J. Am. Chem. Soc. 2005, 127, 838
.
10.1021/ol802067y CCC: $40.75
Published on Web 10/11/2008
2008 American Chemical Society

report a new palladium-catalyzed carboxamidation reaction
and aldol condensation reaction cascade of active methylene
compouds 1, lactams 2, and CO for rapid access to a variety
of ring-fused isoquinolinones (Figure 1).10,11
Table 1. Optimization of the Reaction Conditions for the
Reaction of Ethyl 2-(2-Iodophenyl)acetate with 2-Pyrrolidonea
entry
base
solvent
T (°C)
3ab (%)
4b (%)
1
2
3
4
5
tBuOK
TEA
K2CO3
K2CO3
K2CO3
CH3CN
THF
CH3CN
THF
110
80
110
80
60c
trace
38d, e
68e
95e
THF
50
24f
40
a Reaction conditions: ethyl 2-(2-iodophenyl)acetate 1a (1 mmol),
Figure 1. Strategy for the synthesis of ring-fused isoquinolinones.
2-pyrrolidone 2a (1.1 mmol), Pd(OAc)2 (0.03 mmol), triphenylphosphine
b
1
(0.135 mmol), base (3 equiv), solvent (5 mL). Determined by H NMR
and GC. c Using 300 psi CO pressure. d 61% 1a was left unreacted. e Using
200 psi CO pressure. f Using 100 psi CO pressure, 36% 1a was left
unreacted.
Initially, we examined the noted strategy by reacting ethyl
2-(2-iodophenyl)acetate 1a (1 mmol) as an active methylene
compound with the five-membered ring lactam 2-pyrrolidone
2a (1.1 mmol) at 300 psi of carbon monoxide in the presence
of Pd(OAc)2 (0.03 mmol), triphenylphosphine (PPh3) (0.135
mmol), and KOtBu (3 equiv) in acetonitrile at 110 °C for 24 h.
The reaction with KOtBu afforded 60% yield of the desired
fused isoquinolinone (3a) with several byproducts (Table 1,
entry 1).12 Thus, a series of bases and solvents were screened
at various temperatures to optimize the reaction conditions.
When the organic base triethylamine was used with THF at 80
°C, 38% carboxamidation product (4) was obtained, while 61%
of starting material was left unreacted. It was found that the
use of K2CO3 as the base and THF as the solvent at 80 °C
provides the desired product in 95% yield (Table 1, entry 4).We
have also studied other reaction parameters such as lower
pressure of carbon monoxide or lower temperature, which
resulted in incomplete consumption of starting materials with
undesired carboxamidation product 4 (Table 1, entries 5).
Having optimized the reaction conditions, the scope of this
cascade reaction was further explored by treating different
active methylene compounds with a variety of lactams. The
results are summarized in Table 2.
The reaction of ethyl 2-(2-iodophenyl)acetate (1a) with
five-membered ring lactams 2-pyrrolidone (2a) and ethyl
pyroglutamate (2b)13 gave the corresponding ring-fused
isoquinolinone 3a and 3b in excellent yield (Table 2, entries
1 and 2). Even the reaction with six- and seven-membered
ring lactams 2-piperidone (2c) and caprolactam (2d) also
provided good yields of fused isoquinolinones (3c and 3d)
(Table 2, entries 3 and 4).
The Pd-catalyzed carboxamidation reaction and aldol
condensation reaction cascade could be extended to the
electron-rich substrate ethyl 2-(2-iodo-4,5-dimethoxypheny-
l)acetate (1b) and to ethyl 3,4-methylenedioxy-6-iodophe-
nylacetate (1c). It was noteworthy that, under the optimized
reaction conditions, the expected fused isoquinolinone (3e)
was not observed upon reacting the electron-rich substrate
1b with lactam 2-pyrrolidone (2a), and only the carboxa-
midation product was obtained.
A beneficial effect of using the stronger base Cs2CO3 on
this reaction was observed,14 and the desired fused isoquino-
linone product (3e) was isolated in 90% yield (Table 2, entry
5). Furthermore, reaction of substrate 1b with ethyl pyro-
glutamate (2b) also provided isoquinolinone 3f in good yield
(Table 2, entry 6); however, the yield was moderate using
the lactam 2-piperidone (2c) (Table 2, entry 7).
The reaction also occurred with the ethyl 3,4-methylene-
dioxy-6-iodophenylacetate (1c) affording 90% and 95%
yields of the desired isoquinolinone products, 3h and 3i,
respectively, upon reaction with the lactams 2a and 2b (Table
2, entries 8 and 9).
(6) (a) Negishi, E., Ed. Handbook of Organopalladium Chemistry for
Organic Synthesis; John Wiley and Sons: New York, 2002; Vol. 2. (b)
Tsuji, J. Palladium Reagents and Catalysts: InnoVations in Organic
Synthesis; John Wiley and Sons: New York, 1995. (c) Tsuji, J. Palladium
Reagents and Catalysts: New PerspectiVes for the 21st Century; John Wiley
and Sons: New York, 2003. (d) Tsuji, J., Ed. Palladium in Organic
Synthesis; Springer: Berlin, 2005. (e) Heck, R. F. Palladium Reagents in
Organic Synthesis; Academic Press: New York, 1985. (f) Li, J. J.; Gribble,
G. W. Palladium in Heterocyclic Chemistry; Pergamon: New York, 2000
(7) Larksarp, C.; Alper, H. Org. Lett. 1999, 1, 1619
(8) Zheng, Z.; Alper, H. Org. Lett. 2008, 10, 829
(9) Lu, S.-M.; ALper, H. J. Am. Chem. Soc. 2008, 130, 6451
.
.
.
.
(10) For use of aldol condensation in cascade reactions, see: (a) Cho,
C. S.; Lim, D. K.; Zhang, J. Q.; Kim, T.-J.; Shim, S. C. Tetrahedron Lett.
2004, 45, 5623. (b) Kim, Y. H.; Lee, H.; Kim, Y. J.; Kim, B. J.; Heo, J.-N.
J. Org. Chem. 2008, 73, 495. (c) Manley, P. J.; Bilodeau, M. T. Org. Lett.
Apart from ethyl 2-iodophenylacetate, 2-iodophenylacetoni-
triles (1d-f) and 2-iodobenzyl phenyl sulfone (1g) were also
examined for this Pd-catalyzed carboxamidation reaction and
aldol condensation reaction cascade, and the results are listed
2004, 6, 2433
.
(11) For palladium-catalyzed carboxamidation reaction with lactams, see:
(a) Mori, M; Hiromi, K; Masaya, K.; Ban, Y. Heterocycles 1985, 23, 2803.
(b) Mori, M.; Kimura, M.; Uozuni, Y.; Ban, Y. Tetrahedron Lett. 1985,
26, 5947. (c) Karimi, F.; Kihlberg, T.; Långstro¨m, B. J. Chem. Soc., Perkin
Trans. 1 2001, 1528. (d) For aminocarbonylation, see: Schnyder, A.;
(13) Silverman, R. B.; Lavy, M. A. J. Org. Chem. 1980, 45, 815.
(14) For reviews on the “cesium effect”, see: (a) Ostrowicki, A.; Vogtle,
F. In Topics in Current Chemistry; Weber, E., Vogtle, F., Eds.; Springer:
Berlin, Heidelberg, 1992; Vol. 161, p 37. (b) Galli, C. Org. Prep. Proced.
Int. 1992, 24, 287. (c) Blum, Z. Acta Chem. Scand. 1989, 43, 248.
Indolese, A. F. J. Org. Chem. 2002, 67, 594
(12) (a) Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron Lett. 2001,
42, 7983. (b) Chon, C.-y.; Dromer, P. G. J. Org. Chem. 2005, 70, 6964.
.
4988
Org. Lett., Vol. 10, No. 21, 2008

in Table 2. 2-Iodophenylacetonitrile (1d) was effectively
converted to isoquinolinones 3j and 3k under optimized cascade
reaction conditions with the 2-pyrrolidone (2a) and ethyl
pyroglutamate (2b) (Table 2, entries 10 and 11), respectively,
whereas reaction with the six-membered ring lactam 2-piperi-
done (2c) provided the corresponding isoquinolinone (3l) in
85% yield. Electron-rich 2-iodophenylacetonitriles (1e and 1f)
required the use of a strong base Cs2CO3 to convert them to
the corresponding fused isoquinolinones (3m-o) in 63-80%
yields (Table 2, entries 13-15).
Table 2. Palladium-Catalyzed Carboxamidation Reaction and
Aldol Condensation Reaction Cascade of Active Methylene
Compounds 1 with Lactams 2a
The reaction was also successfully extended to 2-iodobenzyl
phenyl sulfone (1g) which on treatment with lactams 2a and
2b affords 3p and 3q in 90% and 85% yield, respectively
(Table2, entries 16 and 17).
A possible reaction mechanism for the formation of fused
isoquinolinones 3 is depicted in Figure 2. Oxidative addition
Figure 2. Proposed reaction mechanism.
of 1 to the in situ generated palladium(0) species15 leads to
a palladium complex 4. Carbon monoxide insertion into the
aryl carbon-palladium bond of 4 affords 5 and nucleophilic
attack of the lactam on a aroylpalladium complex gives
intermediate 6 which undergoes reductive elimination af-
fording carboxamide 7 with regeneration of palladium(0).
The intramolecular condensation of the lactam carbonyl
group with benzylic anion 8 (generated by treatment with
base) gives intermediate 9 which on dehydration ultimately
afford the ring-fused isoquinolinone 3.
In summary, we have developed an efficient and simple
synthetic method for the synthesis of biologically and medici-
nally important ring-fused isoquinolinones by utilizing a pal-
ladium-catalyzed carboxamidation reaction and aldol conden-
sation reaction cascade protocol. The products of this cascade
reaction can be transferred to other functionality and hence
provides further scope for molecular manipulation. Moreover,
the method gives easy access to a variety of ABC ring
substituted fused isoquinolinones and thus could be very useful
to generate a diverse array of ring-fused substituted isoquino-
linones for assessing their pharmaceutical and medicinal
a Reaction conditions: 1 (1 mmol), 2a (1.1 mmol), Pd(OAc)2 (0.03
mmol), triphenylphosphine (0.135 mmol), base (3 equiv), THF (5 mL), 80
°C, 24 h. b Isolated yield. c Recrystallization yield.
(15) Macrind, R.; Ferguson, G.; Arsenault, G.; McAless, A. J.; Stephen-
son, D. K. J. Chem. Res., Synop. 1984, 360.
Org. Lett., Vol. 10, No. 21, 2008
4989

research activities. We are presently exploring the applicability
of this cascade protocol to the synthesis of related biologically
important heterocycles.
Supporting Information Available: Experimental pro-
cedures, characterization data for all new compounds, and
1
copies of H NMR and 13C NMR spectra for substrates
1a-c,e-g and products 3a-q.This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada for financial
support of this research.
OL802067Y
4990
Org. Lett., Vol. 10, No. 21, 2008