Synthesis of ring-fused oxazolo- and pyrazoloisoquinolinones by a one-pot Pd-catalyzed carboxamidation and aldol-type condensation cascade process

Article abstract of DOI:10.1021/jo9010574

(Chemical Equation Presented) A three-component cascade process is described for the synthesis of ring-fused oxazolo- and pyrazoloisoquinolinones by a one-pot carboxamidation/aldol-type condensation reaction. The cascade process involves Pd-catalyzed carboxamidation of an aryl halide/active methylene compound with oxazolidinone or pyrazolidinone, and subsequent intramolecular base-catalyzed cyclization/dehydration through an aldol-type condensation process, to give ring-fused oxazolo- and pyrazoloisoquinolinones. This methodology provides an easy one-step approach to these important classesof nitrogen-containing heterocycles and can tolerate a wide array of functional groups, including ester, nitrile, methoxy, and halide.

Full text of DOI:10.1021/jo9010574

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Synthesis of Ring-Fused Oxazolo- and Pyrazoloisoquinolinones by a
One-Pot Pd-Catalyzed Carboxamidation and Aldol-Type Condensation
Cascade Process
Gagan Chouhan and Howard Alper*
Centre for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie
Curie, Ottawa, Ontario K1N 6N5, Canada
howard.alper@uottawa.ca
Received May 24, 2009
A three-component cascade process is described for the synthesis of ring-fused oxazolo- and pyrazolo-
isoquinolinones by a one-pot carboxamidation/aldol-type condensation reaction. The cascade process
involves Pd-catalyzed carboxamidation of an aryl halide/active methylene compound with oxazolidinone
or pyrazolidinone, and subsequent intramolecular base-catalyzed cyclization/dehydration through an
aldol-type condensation process, to give ring-fused oxazolo- and pyrazoloisoquinolinones. This metho-
dology provides an easy one-step approach to these important classes of nitrogen-containing heterocycles
and can tolerate a wide array of functional groups, including ester, nitrile, methoxy, and halide.
Introduction
natural products.1 Among these, derivatives of isoquino-
linone comprise an important class of heterocycles often
encountered in alkaloids and other pharmacologically im-
portant compounds.2 Ring-fused oxazoloisoquinolinones
exhibiting diverse biological properties such as anti-inflam-
matory and analgesic activities have been described.3 In
addition, the pyrazoloisoquinolinone fragment found in
natural products such as antibiotics of type APHEs1-4,
produced by the actinomycete Strepto verticilliam griseo
carnim, exhibited remarkable cytotoxic activity against sev-
eral tumor cell lines of different origin.4 In spite of the
occurrence of these heterocycles in a significant number of
Nitrogen-containing heterocycles constitute a widespread
structural motif in many biologically active molecules and
*To whom correspondence should be addressed. Fax: (þ01)613-562-
5871.
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istry, 2nd ed.; Pergamon Press: New York, 2000. (b) Joule, J. A.; Mills, K.
Heterocyclic Chemistry, 4th ed.; Blackwell: Oxford, UK, 2000. (c) Katritzky,
A. R.; Rees, C. W.; Scriven, E. F. Comprehensive Heterocyclic Chemistry;
Elsevier Science Ltd.: Oxford, UK, 1996. (d) Deiters, A.; Martin, S. F. Chem. Rev.
2004, 104, 2199.
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J. Chem. 1997, 36, 410. (c) Babjak, M.; Kanazawa, A.; Anderson, R. J.;
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DOI: 10.1021/jo9010574
r
Published on Web 07/17/2009
J. Org. Chem. 2009, 74, 6181–6189 6181
2009 American Chemical Society

Chouhan and Alper
JOCArticle
SCHEME 1
SCHEME 2
medicinal agents active toward a variety of diseases, there are
very few synthetic methods described in the literature for the
preparation of ring-fused oxazoloisoquinolinones. One
approach is based on the condensation reaction of homo-
phthalic anhydrides and homophthalic acids with cyclic
imino ether and 2-amino ethanol, respectively.3,5 These
methods, however, typically provide moderate to low pro-
duct yields (Scheme 1). Furthermore, to our knowledge, the
synthesis of pyrazoloisoquinolinones has not yet been re-
ported. Thus, we believe that the development of a facile
approach to the synthesis of substituted ring-fused oxazolo-
and pyrazoloisoquinolinone is a very worthwhile goal.
Classical organic synthesis usually involves the stepwise
formation of individual bonds in the construction of
a targeted molecule. However, the development of new
methods for the simultaneous formation for example of both
C-C and C-N (O) bonds in a single step is quite advanta-
geous, since it allows the rapid buildup of molecular com-
plexity from relatively simple starting materials.6
heterocycles, are a valuable synthetic tool for achieving
this goal.9-12
In the context of our interest in the application of Pd-
catalyzed cascade processes for the synthesis of heterocyclic
compounds, we have recently described some new methods for
the preparation of isoindolinones,13 2-carboxyindoles,14 and
substituted indocyclic enol lactones.15 Specifically, we reported
a novel cascade process for the synthesis of ring-fused sub-
stituted isoquinolinones using a three-component carboxa-
midation/aldol-type condensation cascade sequence from the
corresponding aryl iodide/active methylene compound, car-
bon monoxide, and lactam in 60-95% yields (Scheme 2).16
In an effort to further diversify this cascade process, we
evaluated the use of oxazolodinone and pyrazolidinone for
the synthesis of the ring-fused oxazolo- and pyrazoloiso
quinolinones (Scheme 3). This methodology provides high
structural diversity in all three rings of the isoquinolinone
skeleton.
Transition metal-catalyzed reactions,8 especially palladium-
catalyzed carbonylative cyclization reactions for the forma-
tion of a wide variety of oxygen- and nitrogen-containing
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S.; Heitzer, H. Justus Liebigs Ann. Chem. 1978, 283.
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Kilner, C.; Dumronchai, N.; Kongkathip, B.; Kongkathip, N.; Ploysuk, C.;
Sridharan, V. Angew. Chem., Int. Ed. 2005, 44, 7570. (c) Grigg, R.; Sridharan,
V. J. Organomet. Chem. 1999, 576, 65. (d) Tietze, L. F. Chem. Rev. 1996, 96,
115. (e) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev. 1996, 96, 195.
(f) Grigg, R.; Inman, M.; Kilner, C.; Koppen, I.; Marchbank, J.; Selby, P. J.;
Sridharan, V. Tetrahedron 2007, 63, 6152. (g) Salcedo, A.; Neuville, L.;
Rondot, C.; Retailleau, P.; Zhu, J. Org. Lett. 2008, 10, 857. (h) Thansandote,
P.; Raemy, M.; Rudolph, A.; Lautens, M. Org. Lett. 2007, 9, 5255. (i) Pinto,
A.; Neuville, L.; Retailleau, P.; Zhu, J. Org. Lett. 2006, 8, 4927. (j) Yanada,
R.; Obika, S.; Inokuma, T.; Yanada, K.; Yamashita, M.; Ohta, S.;
Takemoto, Y. J. Org. Chem. 2005, 70, 6972. (k) Abbiati, G.; Arcadi, A.;
Canevari, V.; Capezzuto, L.; Rossi, E. J. Org. Chem. 2005, 70, 6454. (l) Cuny,
G.; Bois-Choussy, M.; Zhu, J. Angew. Chem., Int. Ed. 2003, 42, 4774.
(m) Rossi, E.; Arcadi, A.; Abbiati, G.; Attanasi, O. A.; De Crescentini, L.
Angew. Chem., Int. Ed. 2002, 41, 1400. (n) Poli, G.; Giambastiani, G.;
Heumann, A. Tetrahedron 2000, 56, 5959.
Results and Discussion
Synthesis of Ring-Fused Substituted Oxazoloisoquino-
linones. In our initial study in this area,16 we found the
optimized reaction conditions for this type of cascade pro-
cess. Thus, the present reaction was first attempted by using
1 mmol of ethyl 2-(2-iodophenyl)acetate 1a as the active
methylene compound with the oxazolidinone 2a (1.1 equiv)
(7) (a) Von Seebach, M.; Grigg, R.; De Meijere, A. Eur. J. Org. Chem.
2002, 19, 3268. (b) Bedford, R. B.; Betham, M. J. Org. Chem. 2006, 71, 9403.
(c) Fayol, A.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 4203.
(8) Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic
Molecules; University Science Book: Sausalito, CA, 1999.
(11) For recent examples of the palladium-catalyzed cascade process see:
(a) Tadd, A. C.; Matsuno, A.; Fielding, M. R.; Willis, M. C. Org. Lett. 2009,
11, 583. (b) Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2008, 73, 7175.
(c) Grigg, R.; Sridharan, V.; Shah, M.; Mutton, S.; Kilner, C.; MacPherson,
D.; Milner, P. J. Org. Chem. 2008, 73, 8352.
(12) For palladium-catalyzed carbonylation reactions see: (a) Abbiati,
G.; Arcadi, A.; Canevari, V.; Capezzuto, L.; Rossi, E. J. Org. Chem. 2005, 70,
6454. (b) Dai, G.; Larock, R. C. J. Org. Chem. 2002, 67, 7042. (c) Gabriele,
B.; Mancuso, R.; Salerno, G.; Lupinacci, E.; Ruffolo, G.; Costa, M. J. Org.
Chem. 2008, 73, 4971. (d) Haddad, N.; Tan, J.; Farina, V. J. Org. Chem. 2006,
71, 5031. (e) Hu, Y.; Zhang, Y.; Yang, Z.; Fathi, R. J. Org. Chem. 2002, 67,
2365. (f) Kadnikov, D. V.; Larock, R. C. J. Org. Chem. 2004, 69, 6772.
(g) Nieman, J. A.; Ennis, M. D. J. Org. Chem. 2001, 66, 2175. (h) Siamaki, A.
R.; Black, D. A.; Arndtsen, B. A. J. Org. Chem. 2008, 73, 1135. (i) Xiao,
W.-J.; Alper, H. J. Org. Chem. 1999, 64, 9646.
(9) For palladium-catalyzed reactions in organic synthesis see: (a) Hand-
book of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.;
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) Palladium in
Organic Synthesis; Tsuji, J., Ed.; Springer: Berlin, Germany, 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.
(10) For palladium-catalyzed heterocycles synthesis see: (a) Colquhoun,
H. M.; Thompson, D. J.; Twigg, M. V. Carbonylation: Direct Synthesis of
Carbonyl Compounds; Plenum Press: New York, 1991. (b) Minatti, A.; Muniz, K.
Chem. Soc. Rev. 2007, 36, 1142. (c) Takacs, E.; Varga, C.; Skoda-Foeldes, R.;
Kollar, L. Tetrahedron Lett. 2007, 48, 2453. (d) Karimi, F.; Langstroem, B.
J. Chem. Soc., Perkin Trans. 1 2002, 2111. (e) Morera, E.; Ortar, G. Tetrahedron
Lett. 1998, 39, 2835. (f) Mori, M.; Chiba, K.; Ohta, N.; Ban, Y. Heterocycles
1979, 13, 329. (g) Perry, R. J.; Turner, S. R. J. Org. Chem. 1991, 56, 6573.
(13) Cao, H.; McNamee, L.; Alper, H. Org .Lett. 2008, 10, 5281.
(14) Vieira, T. O.; Meaney, L. A.; Shi, Y.-L.; Alper, H. Org. Lett. 2008,
10, 4899.
(15) Li, Y.; Yu, Z.; Alper, H. Org. Lett. 2007, 9, 1647.
(16) Chouhan, G.; Alper, H. Org. Lett. 2008, 10, 4987.
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SCHEME 3
SCHEME 4
SCHEME 5
with the active methylene compound 1a. In this reaction no
decarboxylation was observed, and the desired ring-fused
substituted oxazoloisoquinolinone 5a was obtained in 41%
isolated yield (Scheme 6).
Since the formation of the desired ring-fused oxazoloiso-
quinolinone seemed to be dependent on the substitution of
the oxazolidinone ring, we prepared various substituted
oxazolodinones with a substituent located R to nitrogen
and R to oxygen atoms to react under similar conditions.
The synthesis of various alkyl-substituted oxazolidinones
was accomplished by reaction of the corresponding amino
alcohols (6c-e) with triphosgene in the presence of the base,
TEA, as shown in Scheme 7.
SCHEME 6
We next investigated the reaction of ethyl 2-(2-
iodophenyl)acetate 1a, with (R)-4-methyloxazolidin-2-one
2c in the presence of 3 mol % of Pd(OAc)2 and 13.5 mol %
of PPh3 with 3 equiv of Cs2CO3 in THF (6 mL) at 80 °C for
24 h with 200 psi of CO. No acyclic product was detected and
the ratio of the desired oxazolidinone 5b to the undesired
decarboxylated product 4b was 86:14 (determind by GC and
1H NMR analysis, Scheme 8).
SCHEME 7
Since the conversion of the active methylene compound 1a
to the desired ring-fused oxazolo-isoquinolinone was higher
with (R)-4-methyloxazolidin-2-one 2c, we decided to further
optimize the reaction conditions by varying the nature and
amount of the catalyst, reaction time, and CO pressure. The
results are summarized in Table 1.
After some experimentation, we found that the cascade
reaction could best be carried out by employing 1.5 mol % of
Pd(OAc)2 at 100 psi CO pressure for a reaction time of 4 h
(Table 1, entry 3). The selectivity for the desired product 5b
decreased when the time was further reduced to 2 h (Table 1,
entry 4). 1,3-Bis(diphenylphosphino)propane is a useful
bidentate ligand for this transformation (Table 1, entry 5).
The most active palladium catalyst for this cascade reaction
is PdCl2(PPh3)2, which afforded nearly complete conversion
to the desired product 5b (Table 1, entry 6). The reaction is
sensitive to the nature of base, solvent, and the catalyst
(Table 1, entries 7 and 8). Replacement of Cs2CO3 with
K2CO3 gave poor conversion, while the use of different
in the presence of 3 mol % of Pd(OAc)2, 13.5 mol % of PPh3,
and 3.0 equiv of K2CO3 as a base in 6 mL of THF at 80 °C for
24 h under 200 psi of carbon monoxide. None of the expected
cyclic product was formed, but we isolated two products
from the reaction mixture, carboxamidated 3a and decar-
boxylated 4a in 42% and 20% yields, respectively
(Scheme 4).
We then considered modifications to the reaction condi-
tions, one of which involved change of the base from
potassium carbonate to cesium carbonate. The use of
Cs2CO3 afforded only the decarboxylated product 4a in
40% isolated yield (Scheme 5).
Noting the importance of the base in this reaction, we
decided to react an oxazolidinone containing a substituent R
to the nitrogen atom, (S)-4-isopropyl-2-oxazolidinone 2b
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SCHEME 8
TABLE 1. Optimization of the Carboxamidation/Aldol-Type Condensation Cascade Reaction of Ethyl 2-(2-Iodophenyl)acetate 1a with (R)-4-
Methyloxazolidin-2-one 2ca
entry
catalyst /phosphine (mol %)
CO (PSI)
base
solvent
time, h
ratiob 1a/3b/4b/5b
1
2
3
4
5
6
7
8
9
Pd(OAc)2 (3)/PPh3 (12)
Pd(OAc)2 (1.5)/PPh3 (6)
Pd(OAc)2 (1.5) /PPh3 (6)
Pd(OAc)2 (1.5) /PPh3 (6)
Pd(OAc)2 (1.5) /dppp (3)
PdCl2(PPh3)2(1.5)/PPh3 (1.5)
PdCl2(PPh3)2 (1.5)/PPh3 (1.5)
PdCl2(PPh3)2 (1.5)/PPh3 (1.5)
PdCl2(o-tol)2 (1.5)/P(o-tol)3(1.5)
PdCl2(dppf)2 (1.5)/dppf (1.5)
Pd2(dba)3 (1.5)/ PPh3 (4)
Pd(PPh)4 (1.5)
200
200
100
100
100
100
100
100
100
100
100
100
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
THF
THF
THF
THF
THF
THF
CH3CN
THF
THF
THF
THF
THF
15
7
4
2
7
-/-/14/86
-/-/14/86
-/-/15/85
-/13/14/73
-/-/14/86
-/-/9/91
14/39/18/29
-/45/40/15
4/-/20/76
-/-/18/82
-/-/19/81
-/-/15/85
4
24
24
4
4
4
10
11
12
4
aReaction conditions: ethyl 2-(2-iodophenyl)acetate 1a (1 mmol), (R)-4-methyl-oxazolidin-2-one 2c (1.1 mmol), base (3 equiv), solvent (6 mL). bRatio
determined by 1H NMR and by GC.
TABLE 2. Synthesis of Ring-Fused Oxazoloisoquinolinones by Car-
boxamidation/Aldol-Type Condensation Cascade of Ethyl 2-(2-
Iodophenyl)acetate 1a with Oxazolidinones 2b-ea
palladium catalysts and phosphine ligands such as PdCl2(o-
tol)2/P(o-tol)3, PdCl2(dppf)2/dppf, and Pd2(dba)3/PPh3 pro-
vided reduced product ratios (Table 1, entries 9, 10, 11, and
12). Using the optimized reaction conditions we investigated
the reaction of various substituted oxazolidinones with ethyl
2-(2-iodophenyl)acetate. The results are summarized in Ta-
ble 2.
The reaction of ethyl 2-(2-iodophenyl)acetate 1a with (R)-
4-methyloxazolidin-2-one 2c and 5-methyloxazolidin-2-one
2d gave the desired products 5b and 5c in 65% and 61%
yields, respectively. Similarly, good product yields were
obtained with (R)-4-ethyl-oxazolidin-2-one 2e (Table 2, pro-
ducts 5d).
We also examined the reactivity of ethyl 2-(2-iodophenyl)-
acetate bearing an electron-donating methoxy group.
When ethyl 2-(2-iodo-4,5-dimethoxyphenyl)acetate 1b was
subjected to the cascade reaction under the optimized
reaction conditions with (R)-4-methyloxazolidin-2-one
2c, none of the desired product was formed, instead only
the carboxamidated product 3c was isolated in 61% yield
(Scheme 9).
In an effort to obtain the desired product, we extended
the reaction time and temperature (24 h, 110 °C) and also
employed the strong base KOtBu. However, neither of
these conditions provided ring-fused isoquinolinones and
multiple products were detected on TLC because of the
instability of oxazolidinones at higher temperatures and in
the presence of a strong base. We also studied the reaction
aReaction conditions: ethyl 2-(2-iodophenyl)acetate 1a (1 mmol),
oxazolidinone 2b-e (1.1 mmol), PdCl2(PPh3)2 (1.5 mol %), PPh3 (1.5
mol %), Cs2CO3 (3 equiv), CO (100 psi), THF (6 mL), 80 °C, 4 h .
of 3,4-methylenedioxy-6-iodophenylethyl acetate 1c with
(R)-4-methyloxazolidin-2-one 2c, which afforded 5e in
43% isolated yield (Scheme 9). It is noteworthy that when
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JOCArticle
SCHEME 9
TABLE 3. Synthesis of Ring-Fused Pyrazoloisoqunolinones by Carboxamidation/Aldol-Type Condensation Cascade of Ethyl 2-(2-Iodophenyl)acetates
1a-c with Pyrazolidinones 7a-ca
aReaction conditions: 1a-c (1 mmol), 7a-c (1.1 mmol), PdCl2(PPh3)2 (1.5 mol %), PPh3 (1.5 mol %), Cs2CO3 (3 equiv), CO (100 psi), THF (6 mL),
80 °C, 4 h.
the reaction was carried out with 4-ethyloxazolidin-2-one 2e,
no cyclization was observed and only the carboxamidated
product 3d was isolated in 72% yield (Scheme 9).
the latter (1 mmol) was reacted with 1-phenylpyrazolid-
inone (1.1 mmol), carbon monoxide (100 psi), PdCl2(PPh3)2
(0.015 mmol), PPh3 (0.015 mmol), and Cs2CO3(3 equiv) in
dry THF (6 mL) at 80 °C for 4 h, the desired product 8a was
obtained in 76% isolated yield (Table 3).
A variety of ethyl 2-(2-iodophenyl)acetates 1a-c were
reacted with different pyrazolidinones 7a-c under the opti-
mized reaction conditions, and the results are listed in
Table 3. The cacade reaction of 1a with 4-methyl-1-phenyl-
pyrazolidin-3-one 7b and 1-methylpyrazolidinone 7c pro-
vided the corresponding ring-fused pyrazoloisoquinolinones
in 70% and 78% isolated yields, respectively. We have also
Synthesis of Ring-Fused Substituted Pyrazoloisoquno-
linones. In an effort to expand the scope of this cascade
reaction, we investigated the reaction of various pyrazolid-
inones with different active methylene compounds to pre-
pare ring-fused substituted pyrazoloisoquinolinones.
Reaction of Pyrazolidinones with Ethyl 2-(2-Iodophenyl)-
acetates. In seeking access to ring-fused pyrazoloisoquino-
linones, 1-phenylpyrazolidinone 7a seemed an excellent cas-
cade reactant with ethyl 2-(2-iodophenyl)acetate 1a. When
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TABLE 4. Synthesis of Ring-Fused Pyrazoloisoqunolinone by Carboxamidation/Aldol-Type Condensation of 2-Iodophenyl Acetonitriles 9a,b with
Pyrazolidinones 7a-ca
aReaction conditions: 9a,b (1 mmol), 7a-c (1.1 mmol), PdCl2(PPh3)2 (1.5 mol %), PPh3 (1.5 mol %), Cs2CO3 (3 equiv), CO (100 psi), THF (6 mL),
80 °C, 4 h.
SCHEME 10
studied the reaction of ethyl 2-(2-iodophenylethyl)acetate
bearing electron-donating groups (1b and 1c) with various
pyrazolidinones 7a-c. The cascade reaction of electron-rich
substrates (1b and 1c) with pyrazolidionones 7a-c afforded
the corresponding ring-fused pyrazoloisoquinolinones 8d-i
in 60-72% isolated yield.
reaction (Scheme 10). Thus, 2-iodophenyl acids were
reduced to their corresponding alcohols (12a-d) by using
BH3 THF.17 Alcohols 12a-d were then treated with
3
PPh3 Br2 in DCM to form the corresponding benzyl bro-
3
mides 13a-d and the latter were subjected to reaction with
NaSO2Ph in DMF at 80 °C for 2 h to give 2-iodobenzyl
sulfones 14a-d in 83-89% yields.
Reaction of Pyrazolodinone with 2-Iodophenyl Acetoni-
triles. We also extended the reaction to active methylene
compound bearing a nitrile group. When 2-iodophenyl
acetonitrile 9a was subjected to reaction with 1-phenyl
pyrazolidinone 7a under the usual conditions, the desired
product was obtained in 75% isolated yield (Table 4).
The cascade reaction of 2-iodophenyl acetonitrile 9a with
4-methyl-1-phenylpyrazolidin-3-one 7b and 1-methylpyra-
zolidinone 7c provided the products in excellent yield
(84% and 75%, respectively). The electron-rich (2-iodo-4,
5-dimethoxyphenyl)acetonitrile 9b upon reacting with
1-phenylpyrazolidionone 7a and 4-methyl-1-phenylpyrazo-
lidin-3-one 7b afforded corresponding ring-fused pyrazo-
loisoquinolinones in 72% and 61% yields, respectively.
Reaction of Pyrazolidinones with 2-Iodobenzyl Phenyl Sul-
fones. Various 2-iodobenzyl phenyl sulfones were prepared
from the corresponding 2-iodophenyl acids in three steps in
order to explore their reactivity for this type of cascade
After preparation of the desired 2-iodobenzyl sulfones
they were reacted with various pyrazolidinones 7a-c to form
the corresponding ring-fused pyrazoloisoquinolinones. The
first substrate we tested was 2-iodobenzyl sulfone 14a, which
reacted with 1-phenyl pyrazolidinone 7a to form pyrazoloi-
soquinolinone 15a in 60% isolated yield (Table 5). On the
other hand, reaction of 14a with 4-methyl-1-phenylpyrazo-
lidin-3-one 7b and 1-methylpyrazolidinone 7c provided pyra-
zoloisoquinolinones 15b and 15c in 58% and 41% isola-
ted yield, respectively. We also examined the reactivity of
2-iodobenzyl sulfone bearing an electron-withdrawing
bromo- and chloro-substituent. The electron-withdrawing
groups had little influence on the product yields as the
pyrazoloisoquinolinones 15d-i were obtained in 40-68%
(17) Yoon, N. M.; Pak, C. S.; Brown Herbert, C.; Krishnamurthy, S.;
Stocky, T. P. J. Org. Chem. 1973, 38, 2786.
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Chouhan and Alper
JOCArticle
TABLE 5. Synthesis of Ring-Fused Pyrazoloisoqunolinone by Carboxamidation/Aldol-Type Condensation of 2-Iodobenzyl Sulfones 14a-d with
Pyrazolidinones 7a-ca
aReaction conditions: 14a-d (1 mmol), 7a-c (1.1 mmol), PdCl2(PPh3)2 (1.5 mol %), PPh3 (1.5 mol %), Cs2CO3 (3 equiv), CO (100 psi), THF (6 mL),
80 °C, 4 h.
yields. However, the presence of an electron-donating methyl
group afforded pyrazoloisoquinolinones 15j-l in somewhat
higher yields (68-70%).
transformation works well by employing Pd2(dba)3 as the Pd-
catalyst (3 mol % Pd), [HPtBu3][BF4] as the ligand (12 mol %),
and Cs2CO3 (3 equiv) as the base at 200 psi of CO pressure in
toluene at 110 °C for 24 h to form pyrazoloisoquinolinone 8a
in 66% yield from 1-phenylpyrazolodinone (Table 6, entry 7).
Several 2-bromobenzyl sulfones were also used as
substrates for the reaction. Treatment of 2-bromobenzyl
sulfone 18 with 1-phenylpyrazolidinone 7a provides the
corresponding ring-fused pyrazoloisoquinolinone 15a in
43% yield (Scheme 11). Similarly, 2-benzenesulfonyl-
methyl-1-bromonaphthalene 21, which was prepared from
1-bromo-2-methylnaphthalene 19 in two steps, on reaction
with 1-phenylpyrazolidinone 7a and 4-methyl-1-phenylpyr-
azolidin-3-one 7b afforded the corresponding ring-fused
pyrazoloisoquinolinones 22a and 22b in 43% and 50%
isolated yield, respectively (Scheme 12).
Ring-Fused Pyrazoloisoquinolinones from 2-Bromo-Substi-
tuted Active Methylene Compounds. The cascade reaction
sequence was next applied to 2-bromo-substituted active
methylene compounds. Ethyl 2-(2-bomophenyl)acetate 16
was reacted with 1-phenylpyrazolidinone 7a under the opti-
mized reaction conditions; however, none of the desired
product was obtained (Table 6, entry1). Increasing the reac-
tion temperature or CO pressure or using toluene as a solvent
also were unsuccessful (Table 6, entry 2), as was the use of
bidentate phosphene ligands such as Xantphos and dppp
with Pd2(dba)3 (Table 6, entries 3 and 4). The electron-rich
phosphine PCy3 afforded 8a in 5% yield (Table 6, entry 5).
After some experimentation, wefound that this type of cascade
J. Org. Chem. Vol. 74, No. 16, 2009 6187

Chouhan and Alper
JOCArticle
TABLE 6. Synthesis of Ring-Fused Pyrazoloisoquinolinone by Carboxamidation/Aldol-Type Condensation of Ethyl 2-(2-Bromophenyl)acetate 16 with
Pyrazolidinones 7aa
entry
Pd- catalyst (mol %)
ligand (mol %)
solvent
psi of CO
temp, °C
time, h
yield,a %
1
2
3
4
5
6
7
8
PdCl2(PPh3)2 (1.5)
PdCl2(PPh3)2 (1.5)
Pd2(dba)3 (3)
Pd2(dba)3 (3)
Pd2(dba)3 (3)
Pd2(dba)3 (3)
Pd2(dba)3 (3)
Pd2(dba)3 (3)
PPh3 (1.5)
PPh3 (1.5)
Xantphos (6)
dppp (6)
[HPCy3][BF4] (12)
[HPtBu3][BF4](12)
[HPtBu3][BF4](12)
[HPtBu3][BF4](12)
THF
100
200
200
200
200
200
200
100
80
110
110
110
80
80
110
110
24
24
24
24
24
24
24
24
0
0
0
0
5
14
66
30
toluene
toluene
toluene
toluene
toluene
toluene
toluene
aDetermine by 1H NMR of crude.
SCHEME 11
SCHEME 12
Conclusion
In conclusion, we have developed a new route to ring-
fused substituted oxazolo- and pyrazoloisoquinolinones via
a three-component cascade process through one-pot carbox-
amidation/aldol-type condensation reaction sequences. A
range of ring-fused oxazoloisoquinolinones and pyrazolo-
isoquinolinones were obtained from a variety of active
methylene compounds. The products of these cascade reac-
tions contain different functional groups that can be further
functionalized and hence this methodology enables further
molecular manipulation of these interesting nitrogen-con-
taining heterocycles. Moreover, the strategy gives easy access
to a variety of ring-substituted fused oxazolo- and pyrazo-
loisoquinolinones and thus could find wide applicability in
pharmaceutical and medicinal research programs.
Mechanism
A possible reaction mechanism for the formation of ring-
fused oxazolo- and pyrazoloisoquinolinones is outlined in
Figure 1. Oxidative addition of aryl halide/active methylene
compound to the in situ generated palladium(0) species18
leads to a palladium complex 23. Insertion of carbon mon-
oxide into the aryl carbon-palladium bond of 23 affords
24 and nucleophilic attack of the oxazolidinone or pyra-
zolidinone on an arylpalladium complex may give intermedi-
ate 25. The latter can undergo reductive elimination affor-
ding carboxamide 26 with regeneration of palladium(0).
The intramolecular condensation of the carbonyl group with
benzylic anion 27 (generated by treatment with base) af-
forded intermediate 28, which on dehydration gave the ring-
fused oxazolo- and pyrazoloisoquinolinones.
Experiment Section
General Procedure for the Palladium-Catalyzed Carboxyami-
dation/Aldol-Type Condensation Reaction of Aryl Halide/Active
Methylene Compounds with Oxazolidinones and Pyrazolid-
inones. A glass liner containing a mixture of aryl halide active
methylene compounds 1a-c, 9a,b, and 14a-d (1 mmol),
oxazolidinones 2b-e or pyrazolidinones 7a-c (1.1 mmol),
catalyst PdCl2(PPh3)2 (0.015 mmol), ligand PPh3 (0.015 mmol),
base Cs2CO3 (3 mmol), and THF (6 mL) was placed in a 45 mL
autoclave equipped with a magnetic stirring bar. The autoclave
was flushed three times with carbon monoxide and pressurized
to 100 psi and heated at 80 °C for 4 h. The autoclave was
removed from the oil bath and cooled to room temperature prior
to the release of excess carbon monoxide. The reaction mixture
was then filtered through a medium frit glass filter, rinsing with a
minimal amount of reaction solvent, concentrated by rotary
evaporation to yield the crude products; the latter was then
(18) Macrind, R.; Ferguson, G.; Arsenault, G.; McAless, A. J.;
Stephenson, D. K. J. Chem. Res., Synop. 1984, 360.
6188 J. Org. Chem. Vol. 74, No. 16, 2009

Chouhan and Alper
JOCArticle
FIGURE 1. Proposed reaction mechanism for the formation of ring-fused oxazolo- and pyrazoloisoquinolinones.
purified by flash chromatography on silica gel with a mixture of
ethyl acetate/hexanes as the eluant to afford 5a-e, 8a-i, 10a-e,
and 15a-l (products 10a-e were recrystallized from acetone-
dichloromethane).
carbon monoxide. The reaction mixture was then filtered
through a medium frit glass filter, rinsing with a minimal
amount of reaction solvent, concentrated by rotary evaporation
to yield the crude products, which were purified by flash
chromatography on silica gel with a mixture of ethyl acetate/
hexanes as the eluant to afford 8a, 15a, and 22a,b.
General Procedure for the Palladium-Catalyzed Carboxyami-
dation/Aldol-Type Condensation Reaction of 2-Bromo-Substi-
tuted Active Methylene Compounds with Pyrazolidinones. A
glass liner containing a mixture of aryl bromide/active methy-
lene compounds 16, 18, and 21 (1 mmol), pyrazolidinones 7a,
b (1.1 mmol), catalyst Pd2(dba)3 (3 mol % Pd), ligand
[HPtBu3][BF4] (12 mol %), base Cs2CO3 (3 mmol), and toluene
(6 mL) was placed in a 45 mL autoclave equipped with a
magnetic stirring bar. The autoclave was flushed three times
with carbon monoxide, pressurized to 200 psi, and heated at
110 °C for 24 h. The autoclave was removed from the oil bath
and cooled to room temperature prior to the release of excess
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada for financial
support of this research.
Supporting Information Available: Experimental proce-
dures, characterization data for all new compounds, and copies
of 1H NMR and 13C NMR spectra for substrates and products.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 74, No. 16, 2009 6189