Palladium-catalyzed carbonylation-decarboxylation of diethyl(2-iodoaryl) malonates with imidoyl chlorides: An efficient route to substituted isoquinolin-1(2H)-ones

Article abstract of DOI:10.1021/ol801991m

(Chemical Equation Presented) A wide variety of substituted isoquinolin-1(2H)-ones were synthesized in reasonable to good yields by the palladium-catalyzed cyclization of diethyl(2-iodoaryl)malonates with imidoyl chlorides and carbon monoxide in tetrahydrofuran. A palladium-catalyzed carbonylation-decarboxylation process may be involved in the one-step synthesis of the isoquinolin-1(2H)-ones.

Full text of DOI:10.1021/ol801991m

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4903-4906
Palladium-Catalyzed
Carbonylation-Decarboxylation of
Diethyl(2-iodoaryl)malonates with
Imidoyl Chlorides: An Efficient Route to
Substituted Isoquinolin-1(2H)-ones
Zhaoyan Zheng 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 August 26, 2008
ABSTRACT
A wide variety of substituted isoquinolin-1(2H)-ones were synthesized in reasonable to good yields by the palladium-catalyzed cyclization of
diethyl(2-iodoaryl)malonates with imidoyl chlorides and carbon monoxide in tetrahydrofuran. A palladium-catalyzed carbonylation-decarboxylation
process may be involved in the one-step synthesis of the isoquinolin-1(2H)-ones.
Isoquinolin-1(2H)-one derivatives are an important class
of heterocyclic compounds with substantial biological
activities1 that can be found in naturally occurring products
and synthetic pharmaceuticals such as thalifoline,2 doria-
nine,3 narciclasine,4 pancratistain,5 and lycoricidine.5 In
addition, isoquinolin-1(2H)-ones are versatile building
blocks for the total synthesis of natural alkaloids.6 There
are a number of approaches to the synthesis of isoquino-
lin-1(2H)-ones reported in the literature including the
rearrangement of 2-(2-benzofuranyl)-benzonitriles,7 base-
promoted condensation reaction of 2-(bromomethyl)-
benzonitrile,8 transformation of isocoumarins or 3-hy-
droxyphthalides,9 double metalation of arylbenzamides,10
the cyclization of 2-chlorobenzonitriles with ꢀ-ke-
toesters,11 intramolecular Diels-Alder reactions,12 Wittig
reaction,13 as well as photochemical reactions,14 etc.
Recently, several examples of transition metal-catalyzed
routes to isoquinolin-1(2H)-ones have appeared in the
literature.3,15
Although some of the methods are effective for the
synthesis of isoquinolones, these usually afford the 2- or
(6) (a) Coelho, F.; Veronese, D.; Lopes, E. C. S.; Rossi, R. C.
Tetrahedron Lett. 2003, 44, 5731. (b) Heaney, H.; Shuhaibar, K. F. Synlett
1995, 47.
(7) Gutillaumel, J.; Boccara, N.; Demersemann, P.; Royer, R. J. Chem.
Soc., Chem. Commun. 1998, 1604.
(8) Jagtap, P. G.; Baloglu, E.; Southan, G.; Williams, W.; Roy, A.;
Nivorozhkin, A.; Landrau, N.; Desisto, K.; Salzman, A. L.; Szabo, C. Org.
Lett. 2005, 7, 1753.
(1) (a) Jayaraman, M.; Fox, B. M.; Hollingshead, M.; Kohlhagen, G.;
Pommier, Y.; Cushman, M. J. Med. Chem. 2000, 43, 3688. (b) Zhang, H.;
Zembower, D.; Chen, Z. Bioorg. Med. Chem. Lett. 1997, 7, 2687. (c) Bernan,
V. S.; Montenegro, D. A.; Korshalla, J. D.; Maiese, W. M.; Steinberg, D. A.;
Greenstein, M. J. Antibiot. 1994, 47, 1417.
(9) Otha, S.; Kimoto, S. Tetrahedron Lett. 1975, 16, 2279.
(10) (a) Fisher, L. E.; Muchowski, J. M.; Clark, R. D. J. Org. Chem.
1992, 57, 2700. (b) Davis, S. E.; Church, A. C.; Griffith, C. L.; Beam,
C. F. Synth. Commun. 1997, 27, 2961.
(2) Chern, M. S.; Li, W. R. Tetrahedron Lett. 2004, 45, 8323.
(3) Glushkov, V. A.; Shklyaev, Y. V. Chem. Heterocycl. Compd. 2001,
37, 663.
(11) Snow, R. J.; Butz, T.; Hammach, A.; Kapadia, S.; Morwick, T. M.;
Prokopowicz, A. S.; Takahashi, H.; Tan, J. D.; Tschantza, M. A.; Wang,
X. J. Tetrahedron Lett. 2002, 43, 7553.
(4) Gonzalez, D.; Martinot, T.; Hudlickly, T. Tetrahedron Lett. 1999,
40, 3077.
(12) Gutierrz, A. J.; Shea, K. J.; Svoboda, J. J. J. Org. Chem. 1989, 54,
4335.
(5) Thompson, R. C.; Kallmerten, J. J. Org. Chem. 1990, 55, 6076.
10.1021/ol801991m CCC: $40.75
Published on Web 10/09/2008
2008 American Chemical Society

3-substituted target compounds. The introduction of polysub-
stituents in the isoquinolone ring often requires multistep
reactions.
yield of 3a increased to 34% (Table 1, entry 2). An
As part of our continuing effort to attain the efficient
preparation of different carbonyl-containing heterocycles by
palladium-catalyzed cyclocarbonylation, we have synthesized
thiochroman-4-ones,16 lactones,17 2(5H)-furanones,18 1,3-
oxazin-4-ones,19 1,3-benzothiazin-2-ones,20 quinazolin-4(3H)-
ones,21 and different ring-sized lactams.22
Table 1. Optimization of the Reaction of
Diethyl(2-iodoaryl)malonate with N-(Phenyl)benzimidoyl
Chloridea
Encouraged by these results, we decided to explore the
application of Pd-catalyzed carbonylation to the construction
of the isoquinolin-1(2H)-one skeleton. Initial studies focused
on the Pd-catalyzed cyclocarbonylation of ethyl(2-iodophe-
nyl)acetate and N-(phenyl)benzimidoyl chloride using 3 mol
% of Pd(OAc)2, 13.5 mol % of PPh3 as the catalyst, and 3
equiv of Et3N in 8 mL of THF at 400 psi of pressure of
carbon monoxide at 120 °C for 24 h. However, the substrates
failed to produce any of the desired isoquinolin-1(2H)-one
(Scheme 1).
catalyst
system
yield
entry
base
Et3N
Et3N
Et3N
Et3N
Et3N
time(h) CO (psi) (%)b
1
2
3
4
5
6
7
8
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/dppb
Pd(OAc)2/dppp
Pd(OAc)2/dppf
24
48
48
48
48
48
48
48
48
48
48
48
48
48
400
400
400
400
400
400
400
400
400
400
400
200
400
400
21
34
trace
trace
trace
33
Pd(OAc)2/(m-tolyl)3P Et3N
Pd(OAc)2/Bu3P
Et3N
Et3N
K2CO3
Cs2CO3
i-Pr2NEt
i-Pr2NEt
NDc
47
41
44
53
31
40
48
Pd(OAc)2/TDMPP
Pd(OAc)2/TDMPP
Pd(OAc)2/TDMPP
Pd(OAc)2/TDMPP
Pd(OAc)2/TDMPP
9
10
11
12
13
14
Scheme 1. Carbonylation of N-(Phenyl)benzimidoyl Chloride
with Ethyl(2-iodophenyl)acetate or Diethyl(2-iodophenyl)malonate
PdCl2(PPh3)/TDMPP i-Pr2NEt
Pd2(dba)3/ TDMPP i-Pr2NEt
a Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), Pd cat. (0.03
mmol), phosphine ligand (0.135 or 0.07 mmol), base (3.0 mmol), CO 200
or 400 psi, 120 °C, THF (8.0 mL). b Isolated yield. c Not determined: a
complex mixture of unidentified compounds was obtained.
interesting feature of this reaction is that the formation of
the isoquinolin-1(2H)-one is accompanied by CO insertion
and an ethyl carboxylate group leaving in a single operational
step.
Optimization of the reaction was effected using different
conditions, and the results are summarized in Table 1. Entries
2-8 indicated that the choice of phosphine ligand was
important for this transformation. When bidentate phosphine
ligands were employed (Table 1, entries 3-5), only trace
amounts of the desired isoquinolin-1(2H)-ones were detected,
while N-phenylbenzamide was obtained as a major product
in good yields. Use of the tri-m-tolylphosphine ((m-tolyl)3P)
as ligand afforded 3a in only 33% yield (Table 1, entry 6),
while the trialkylphosphine and tributylphosphine gave a
complex mixture of products (Table 1, entry 7). Performing
the same reaction using the tri(2,6-dimethoxyphenyl)phos-
phine (TDMPP) as the ligand increased the yield of 3a to
47% (Table 1, entry 8).
The yield of isoquinolin-1(2H)-one 3a was also dependent
on the nature of the base. The presence of inorganic bases,
such as K2CO3 and Cs2CO3, gave 3a in 41% and 44% yield,
respectively (Table 1, entries 9 and 10). The more hindered
amine base N,N-diisopropylethylamine (i-Pr2NEt) afforded
3a in 53% yield with a small amount of N-phenylbenzamide
The same reaction using diethyl(2-iodophenyl)malonate
instead of ethyl(2-iodophenyl)acetate did produce 2,3,4-
trisubstituted isoquinolone 3a in 21% yield with some
recovered starting material and N-phenylbenzamide as a
byproduct (Scheme 1). The starting materials were consumed
completely by extending the reaction time to 48 h, and the
(13) Epsztajin, J.; Grzelak, R.; Jozwiak, A. Synthesis 1996, 1212.
(14) (a) Guastavino, J. F.; Barolo, S. M.; Rossi, R. A. Eur. J. Org. Chem.
2006, 3898. (b) Griesbeck, A. G.; Hirt, J.; Kramer, W.; Dallakian, P.
Tetrahedron 1998, 54, 3169. (c) Weidner-Wells, M. A.; Oda, K.; Mazzochi,
P. H. Tetrahedron 1997, 53, 3475.
(15) (a) Cherry, K.; Duchene, A.; Thibonnet, J.; Parrain, L.; Abarbri,
M. Synthesis 2005, 2349. (b) He, Z.; Yudin, A. K. Org. Lett. 2006, 8, 5892.
(c) Kajita, Y.; Matsubara, S.; Kurahashi, T. J. Am. Chem. Soc. 2008, 130,
6058. (d) Hudlicky, T.; Olivo, H. F. J. Am. Chem. Soc. 1992, 114, 9694.
(e) Grigg, R.; Sridharan, V.; Xu, L. H. J. Chem. Soc., Chem. Commun.
1995, 1903. (f) Miura, T.; Yamauchi, M.; Murakami, M. Org. Lett. 2008,
10, 3085.
(16) Xiao, W. J.; Alper, H. J. Org. Chem. 1999, 64, 9646.
(17) (a) Cao, H.; Xiao, W. J.; Alper, H. AdV. Synth. Catal. 2006, 348,
1807. (b) Li, Y.; Alper, H. Org. Lett. 2006, 8, 5199. (c) El Ali, B.; Okuro,
K.; Vasapollo, G.; Alper, H. J. Am. Chem. Soc. 1996, 118, 4264.
(18) Yu, W. Y.; Alper, H. J. Org. Chem. 1997, 62, 5684.
(19) Larksarp, C.; Alper, H. J. Org. Chem. 1999, 64, 9194.
(20) Rescourio, G.; Alper, H. J. Org. Chem. 2008, 73, 1612.
(21) (a) Larksarp, C.; Alper, H. J. Org. Chem. 2000, 65, 2773. (b) Zheng,
Z. Y.; Alper, H. Org. Lett. 2008, 10, 829.
(22) (a) Lu, S. M.; Alper, H. J. Am. Chem. Soc. 2008, 130, 6451. (b)
Lu, S. M.; Alper, H. Chem.-Eur. J. 2007, 13, 5908. (c) Lu, S. M.; Alper,
H. J. Am. Chem. Soc. 2005, 127, 14776.
4904
Org. Lett., Vol. 10, No. 21, 2008

Table 2. One-Step Synthesis of Substituted Isoquinolones from
Diethyl(2-iodophenyl)malonates 1 and Imidoyl Chlorides 2a
Scheme 2
. Proposed Mechanism for the Pd-Catalyzed
Carbonylation Reaction of 1 and 2
Reducing the pressure of carbon monoxide from 400 to 200
psi resulted in the recovery of some starting material and a
lower yield for 3a (Table 1, entry 12).
On the basis of the above results, reactions were effected
using the catalytic system comprised of Pd(OAC)2 and
TDMPP, in i-Pr2NEt as the base and CO (400 psi) at 120
°C in THF for 48 h.
The scope of the present synthetic method was extended
to a variety of ethyl(2-iodoaryl)malonates and different
imidoyl chlorides. The results are summarized in Table 2.
Reaction of 1a with an imidoyl chloride containing a
4-methoxyl or 4-methyl phenyl group at nitrogen or carbon
gave the corresponding 2,3,4-trisubstituted isoquinolin-1(2H)-
ones 3b-e in 48-63% yields (Table 2, entries 2-5). The
reaction tolerates both the electron-donating and -withdraw-
ing substituents. Concerning the latter, the use of imidoyl
chlorides having a 4-chlorophenyl group afforded 3f and 3g
in 50% and 42% yields, respectively (Table 2, entries 6 and
7). The yield of 3h was only 33% when the imidoyl chloride
bearing two 4-chlorophenyl groups was subjected to the
normal reaction conditions. An imidoyl chloride bearing an
alkyl substituent gave better product yields. Treatment of
1a with the imidoyl chloride having a t-butyl or isopropyl
group afforded the expected products, 3i and 3j, in 64% and
65% yields (Table 2, entries 9 and 10). The diethyl(2-
iodophenyl)malonate derivative having electron-donating
dimethoxy substituents 1b reacted with 2a to form the
corresponding product 3k in 65% yield (Table 2, entry 11).
In a similar manner, 1b underwent carbonylation with 2i
affording 3l in 70% yield (Table 2, entry 12).
a Diethyl(2-iodophenyl)malonate 1 (1.0 mmol), imidoyl chloride 2 (1.0
mmol), Pd(OAc)2 (0.03 mmol), TDMPP (0.135 mmol), i-Pr2NEt (3.0 mmol),
CO 400 psi, THF (8.0 mL), 120 °C, 48 h. b Ioslated yield.
A possible reaction mechanism for the formation of
isoquinolin-1(2H)-ones 3 is outlined in Scheme 2. It is
conceivable that an imidoyl chloride reacts with diethyl(2-
iodoaryl)malonate in the presence of a base to generate
intermediate 4. Oxidative addition of 4 to the in situ
as a byproduct (Table 1, entry 11). While Pd2(dba)3 or
PdCl2(PPh)3 can be used to catalyze the reaction (Table 1,
entries 13 and 14), neither are as effective as Pd(OAc)2.
Org. Lett., Vol. 10, No. 21, 2008
4905

generated palladium(0) species23 can lead to the arylpalla-
dium complex 5. Insertion of carbon monoxide into the aryl
carbon-palladium bond of 5 would afford the aroylpalladium
iodide complex 6, and the imine nitrogen then attacks the
acylpalladium to form a seven-membered palladacyclic
ammonium salt 7.24 Reductive elimination of 7 may lead to
the isoquinolone salt 8 and regenerate the palladium(0)
species. The salt 8 subsequently undergoes base-induced
decarboalkoxylation to afford isoquinolin-1(2H)-one 3.
In conclusion, we have developed a novel and effective
approach for the one-step synthesis of polysubstituted
isoquinolin-1(2H)-ones. The reaction is compatible with a
variety of functional groups and affords the heterocycles in
quite good yields. In addition, the present methodology
demonstrates the viability of the Pd-catalyzed cyclocarbonyla-
tion-decarboxylation pathway.
Acknowledgment. We are grateful to the Natural
Sciences and Engineering Research Council of Canada
(NSERC) for support of this research.
Supporting Information Available: Experimental pro-
1
cedures, characterization data, and copies of H and 13C
NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(23) MaCrindle, R.; Ferguson, G.; Arsenault, G. J.; McAlees, A. J.;
Stephenson, D. K. J. Chem. Res., Synop. 1984, 360.
(24) Roesch, K. R.; Zhang, H. M.; Larock, R. C. J. Org. Chem. 2001,
66, 8042.
OL801991M
4906
Org. Lett., Vol. 10, No. 21, 2008