A ligand-free Pd-catalyzed cascade reaction: An access to the highly diverse isoquinolin-1(2 H)-one derivatives via isocyanide and Ugi-MCR synthesized amide precursors

Article abstract of DOI:10.1021/ol301131s

A novel ligand-free palladium-catalyzed cascade reaction for the synthesis of highly diverse isoquinolin-1(2H)-one derivatives from isocyanide and amide precursors synthesized by Ugi-MCR has been developed. A broad variety of acids, amines, and isocyanide

Full text of DOI:10.1021/ol301131s

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Ligand-Free Pd-Catalyzed Cascade
Reaction: An Access to the Highly Diverse
Isoquinolin-1(2H)-one Derivatives via
Isocyanide and Ugi-MCR Synthesized
Amide Precursors
Vikas Tyagi,† Shahnawaz Khan,† Archana Giri,† Harsh M. Gauniyal,‡ B. Sridhar,§ and
Prem M. S. Chauhan*,†
Medicinal and Process Chemistry Division, Sophisticated Analytical Instrument
Facility, CSIR-Central Drug Research Institute, Lucknow, 226 001, India, and
Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology,
Hyderabad, 500 607, India
Premsc58@hotmail.com; prem_chauhan_2000@yahoo.com
Received May 3, 2012
ABSTRACT
A novel ligand-free palladium-catalyzed cascade reaction for the synthesis of highly diverse isoquinolin-1(2H)-one derivatives from isocyanide
and amide precursors synthesized by Ugi-MCR has been developed. A broad variety of acids, amines, and isocyanides were used as starting
materials for Ugi-MCR leading to various amide precursors, which in turn provided entry into diverse isoquinolin-1(2H)-one derivatives. The
reaction proceeds through tandem isocyanide insertion with intramolecular cyclization followed by a MazurciewitczÀGanesan type sequence to
provide isoquinoline-1(2H)-one derivatives in moderate to good yields.
Isoquinolin-1(2H)-one is a frequently encountered struc-
tural subunit of numerous biologically active natural
products such as narciclasine 1, lycoricidine 2, 7-deoxy-
pancratistatin 3x, dorianine 4, ruprechstyril 5, and thalifo-
line 6 depicted in Figure 1.1 Isoquinolin-1(2H)-one deriv-
atives have received significant attention owing to their
antihypertensive and anticancer activities.2 These are also
known to inhibit enzymes such as topoisomerase I, Lck kinase,
Rho-kinase, and JNK.3
However, there are several methods accessible for the
preparation of isoquinolin-1(2H)-one derivatives,4 but
most of them suffer from a poor precursor scope with
fewer points of diversity.
† Medicinal and Process Chemistry Division, CSIR-Central Drug Re-
search Institute.
‡ Sophisticated Analytical Instrument Facility, CSIR-Central Drug Re-
search Institute.
(3) (a) Van, H. T. M; Khadka, D. B.; Yang, S. H.; Le, T. N.; Cho,
S. H.; Zhao, C.; Lee, I.-S.; Kwonb, Y.; Lee, K.-T.; Kim, Y.-C.; Cho,
W.-J. Bioorg. Med. Chem. 2011, 19, 5311. (b) Snow, R. J.; Cardozo,
M. G.; Morwick, T. M.; Busacca, C. A.; Dong, Y.; Echner, R. J.; Jakes,
S.; Kapadia, S.; Lukas, S.; Moss, N.; Panzenbeck, M.; Peet, G. W.;
Peterson, J. D.; Prokopowicz, A. P.; Sellati, R.; Tschantz, M. A. J. Med.
Chem. 2002, 45, 3394. (c) Bosanac, T.; Hickey, E. R; Ginn, J.; Kashem,
M.; Kerr, S.; Kugler, S.; Li, X.; Olague, A.; Schlyer, S.; Young, E. R. R.
Bioorg. Med. Chem. Lett. 2010, 20, 3746. (d) Asano, Y.; Kitamura, S.;
Ohra, T.; Itoh, F.; Kajino, M.; Tamura, T.; Kaneko, M.; Ikeda, S.;
Igata, H.; Kawamoto, T.; Sogabe, S.; Matsumoto, S.; Tanaka, T.;
Yamaguchi, M.; Kimura, H.; Fukumoto, S. Bioorg. Med. Chem. 2008,
16, 4699.
§ CSIR-Indian Institute of Chemical Technology.
(1) (a) Rigby, J. H.; Maharoof, U. S. M.; Mateo, M. E. J. Am. Chem.
Soc. 2000, 122, 6624. (b) Hudlicky, T.; Rinner, U.; Gonzalez, D.; Akgun,
H.; Schilling, S.; Siengalewicz, P.; Martinot, T. A.; Pettit, G. R. J. Org.
Chem. 2002, 67, 8726. (d) Glushkov, V. A.; Shklyaev, Y. V. Chem.
Heterocycl. Compd. 2001, 37, 663. (e) Pettit, G. R.; Meng, Y. H.; Herald,
D. L.; Graham, K. A. N.; Pettit, R. K.; Doubek, D. L. J. Nat. Prod. 2003,
66, 1065. (f) Krane, B. D.; Shamma, M. J. Nat. Prod. 1982, 45, 377.
(2) (a) Saeed, A.; Ashraf, Z. Pharm. Chem. J. 2008, 42, 277. (b) Cho,
W-J; Park, M-J; Chuang, B-H; Lee, C.-O. Bioorg. Med. Chem. Lett.
1998, 8, 41.
r
10.1021/ol301131s
XXXX American Chemical Society

In the recent past, isocyanides have emerged as powerful
building blocks in the construction of medicinally impor-
tant molecules and natural products.8 Isocyanides have an
isoelectronic relationship with carbon monoxide,9 which
enables their inclusion into the organic molecules in transi-
tion metal catalyzed protocols.10 The use of isocyanides in
transition metal catalyzed reactions in place of CO has
considerable advantages, such as simple handling, an extra
diversity point, and possibilities for further elaboration
using convertible isocyanide.11
Recently, transition metal catalyzed reactions with the
insertion of isocyanide for the synthesis of biologically
important heterocycles12 have been reported, e.g. Pd-cat-
alyzed multicomponent synthesis of oxazoline and
benzoxazole,13 Pd-catalyzed synthesis of 4-aminophthala-
zin-1(2H)-one,14 and synthesis of quinazolino[3,2-a]-
quinazolines via a palladium-catalyzed three-component
reaction.15
As part of our program to develop new strategies for the
diversity oriented synthesis of biologically important
heterocycles,16 we have developed and reported herein
the synthesis of highly diverse isoquinoline derivatives
via a ligand-free Pd-catalyzed coupling cascade with the
insertion of isocyanide into amide precursors obtained by
Ugi-MCR under microwave conditions. To the best of our
knowledge, it is the first report on the cascade reaction that
involves isocyanide insertion with intramolecular cycliza-
tion followed by a Mazurciewitcz-Ganesan type procedure
under ligand-free Pd-catalyzed conditions.
Figure 1. Biologically active natural products containing iso-
quinolin-1(2H)-one scaffold.
The broad range of biological activities exhibited by the
isoquinolin-1(2H)-one derivatives make them an attractive
and challenging synthetic target, and a concise synthetic
methodology involving commercially available and cheap
starting materials is still required for their viable synthesis.
In this context, transition metal catalyzed synthesis of
substituted isoquinolin-1(2H)-one derivatives has received
noteworthy attention.5 Thus, Yang and co-workers have
reported the synthesis of isoquinolin-1(2H)-one deriva-
tives via isocyanide based Ugi-MCR followed by a Heck
reaction.6 Furthermore, Fu and co-workers developed a
copper catalyzed approach for the synthesisofisoquinolin-
1(2H)-one derivatives.7
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Scheme 1. General Strategy for the Synthesis of Isoquinolin-
1(2H)-one
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Survey of the Reaction Conditions for Pd-Catalyzed
Coupling Reactiona
Scheme 2. Three Possible Structures in Pd-Catalyzed Coupling
Conditions
temp
yieldb
(%)
entry
catalyst
base
solvent
(°C)
1
À
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
DMF
150
150
150
150
150
150
150
150
150
150
150
120
150
0c
2
PdCl2
DMF
trace
12
3
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DMF
4
DMF
DMF
89
61
5
6
K3PO4
DMF
49
7
KOtBu
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
31
8
DMF
40
9
DMSO
Toluene
CH3CN
DMF
72
10
11
12
13
13
19
35
39d
DMF
a Reaction conditions: substrate 10a (1 mmol), tert-butyl isocyanide
(1.2 mmol), catalyst (10 mol %), base (2 mmol), solvent (2 mL) under
nitrogen atmosphere, reaction temperature (150 οC), reaction time (20 min).
b Isolated yield. c No addition of catalyst. d Loading of catalyst (5 mol %).
Scheme 3. Proposed Mechanism of the Reaction
Figure 2. ORTEP diagram of compound 13e.
As shown in Scheme 1, various acids, amines, and
isocyanides can be used for Ugi 4-CR to prepare the
corresponding amide precursors,17 which were used as
starting materials for the ligand-free palladium-catalyzed
cascade reaction involving insertion and intramolecular
cylization of an isocyanide. Further, as depicted in Scheme 2,
there can be three probable products A, B, and C of
the same molecular weight under Pd-catalyzed conditions.
1H NMR, 13C NMR, and X-ray crystallograhpy data of
compound13e (Figure2) confirmedthattheproducts have
the general structure C.
In the initial phase of the investigation, amide precursor
10a was used as a substrate for the optimization of the
palladium-catalyzed insertion and cyclization reaction of
isocyanides. The reaction was carried out using different
catalysts, ligands, bases, solvents, and temperature
(Table 1). The reaction failed to proceed when palladium
was excluded (Table 1, entry 1). Among the three catalysts
(PdCl2, Pd(PPh)3, and Pd(OAc)2) used, Pd(OAc)2 was
found to be the best and furnished the product 13a in
89% yield in DMF as a solvent at 150 °C (Table 1, entry 4).
On the other hand PdCl2 and Pd(PPh)3 resulted in poor
yields of 13a (Table 1, entries 2 and 3). With Pd(OAc)2 as a
(17) Bonnaterre, F.; Choussy, M.; Zhu, J. Org. Lett. 2006, 8, 4351.
Org. Lett., Vol. XX, No. XX, XXXX
C

yield of 13a (Table 1, entry 12). Also, various bases were
screened in DMF at 150 °C, using Pd(OAc)2 as a
catalyst, and Cs2CO3 was found to be the most effective
base (Table 1, entry 4). Using Pd(OAc)2 as the catalyst
and Cs2CO3 as the base in DMSO resulted in a slightly
lower yield (Table 1, entry 9), while using toluene and
CH3CN under the same conditions provided 13a in
only poor yields (Table1, entries 10 and 11). The
efficiency of transformation was affected when the
catalyst loading was decreased from 10 to 5 mol %
(Table 1, entry 13). The reaction proceeded to comple-
tion within 20 min under MW conditions at 150 °C,
while in the absence of MW irradiation it took 4À5 h to
reach completion (disappearance of amide precursour
on TLC). With this standard protocol in hand, we
extended it to the synthesis of various substituted
isoquinolin-1(2H)-ones (13aÀ13o) via different Ugi-
MCR synthesized amide precursors in moderate to
good yields (Figure 3). Of the various isocyanides
tested, only tert-butyl isocyanide was found to effec-
tively undergo insertion and cyclization and, hence,
was the only isocyanide used.13À15
A plausible mechanism for the synthesis of an isoquino-
lin-1(2H)-one of type 13 is depicted in Scheme 3. Thus,
oxidative insertion of Pd to the amide precursor 10 leads to
the intermediate 14 which on insertion of tert-butyl iso-
cyanide leads to Pd(II) species 15. Intermediate 15 via
intramolecular cyclization followed by subsequent reduc-
tive elimination provides species 16. Intermediate 16 then
undergos a Mazurciewitcz-Ganesan type18 procedure with
de-tert-butylation to afford 13.
In summary, we have developed an efficient method for
the synthesis of highly diverse isoquinolin-1(2H)-one deri-
vatives via isocyanide-based ligand-free Pd-catalyzed reac-
tions. The strategy allows synthesis of biologically
important molecules in a straightforward and atom-eco-
nomical fashion. Additionally, a range of acids, amines,
and isocyanides has been used in the reaction protocol,
which offers an opportunity for the synthesis of highly
diverse isoquinoline derivatives for combinatorial and
medicinal chemistry.
Acknowledgment. V.T. and S.K. are thankful to the
University Grant Commission, New Delhi, for financial
support in the form of SRF. The authors also acknowledge
SAIF-CDRI for providing spectral and analytical data.
The CDRI Communication Number is 8253.
Figure 3. Synthesis of substituted isoquinolin-1(2H)-one via a Pd-
catalyzed coupling reaction of amide 10 and isocyanide 12. Condi-
tions: Pd(OAc)2 (10 mol %), Cs2CO3 (2 mmol), DMF (2 mL),
MW, 150 οC, reaction time 20 min. Yields refer to isolated products.
Supporting Information Available. Experimental pro-
cedure, characterization data of all the compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
catalyst and DMF as solvent, lowering of the reaction
temperature to 120 °C resulted in a significantly lower
(18) (a) Mazurkiewicz, R. Monatsh. Chem. 1989, 120, 973. (b) Snider,
B.; Zeng, H. Heterocycles 2003, 61, 173. (c) Wang, H.; Ganesan, A. J.
Org. Chem. 1998, 63, 2432.
The authors declare no competing financial interest.
D
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