Synthesis of highly substituted isoquinolone derivatives by nickel-catalyzed annulation of 2-halobenzamides with alkynes

Article abstract of DOI:10.1021/ol101371c

(Equation Presented). An efficient method for the synthesis of substituted 1(2H)-isoquinolone derivatives via nickel-catalyzed annulation of substituted 2-halobenzamides with alkynes is described. This protocol is successfully applied to the total synthes

Full text of DOI:10.1021/ol101371c

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3518-3521
Synthesis of Highly Substituted
Isoquinolone Derivatives by
Nickel-Catalyzed Annulation of
2-Halobenzamides with Alkynes
Chuan-Che Liu, Kanniyappan Parthasarathy, and Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu 30013, Taiwan
chcheng@mx.nthu.edu.tw
Received June 14, 2010
ABSTRACT
An efficient method for the synthesis of substituted 1(2H)-isoquinolone derivatives via nickel-catalyzed annulation of substituted 2-halobenzamides
with alkynes is described. This protocol is successfully applied to the total synthesis of oxyavicine with excellent yield.
Highly substituted isoquinolones are versatile building
blocks for many naturally occurring products1a-f and have
attracted much attention due to their unique biological
activities.1g-i Several approaches are available for the
synthesis of isoquinolone derivatives such as base-promoted
condensation of 2-(bromomethyl)benzonitriles,2a transforma-
tion of isocoumarins or 3-hydroxyphthalides,2b double meta-
lation of arylbenzamides,2c,d and the cyclization of 2-chlo-
robenzonitriles with ꢀ-keto esters.2e In addition to these
classical methods, efficient methods for the synthesis of
various heterocyclic compounds catalyzed by metal com-
plexes have been demonstrated recently.3 A few examples
of palladium-,4a-i copper-,4j,k and rhodium-catalyzed syn-
thesis of isoquinolone derivatives were reported.4l An
intermolecular nickel-catalyzed decarbonylation reaction of
N-arylphthalimides with alkynes to form substituted isoqui-
nolones was shown by Matsubara and Kurahashi in 2008.5
At about the same time, Murakami et al. reported a nickel-
(2) (a) 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. (b) Otha, S.; Kimoto, S. Tetrahedron Lett. 1975, 16,
2279. (c) Fisher, L. E.; Muchowski, J. M.; Clark, R. D. J. Org. Chem.
1992, 57, 2700. (d) Davis, S. E.; Church, A. C.; Griffith, C. L.; Beam,
C. F. Synth. Commun. 1997, 27, 2961. (e) 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. (f)
Gutierrez, A. J.; Shea, K. J.; Svoboda, J. J. J. Org. Chem. 1989, 54, 4335.
(3) (a) Varela, J. A.; Saa, C. Chem. ReV. 2003, 103, 3787. (b) Nakamura,
I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127. (c) Alonso, F.; Beletskaya,
I. P.; Yus, M. Chem. ReV. 2004, 104, 3079. (d) Cacchi, S.; Fabrizi, G.
Chem. ReV. 2005, 105, 2873.
(4) (a) Hudlicky, T.; Olivo, H. F. J. Am. Chem. Soc. 1992, 114, 9694.
(b) Grigg, R.; Sridharan, V.; Xu, L.-H. J. Chem. Soc., Chem. Commun.
1995, 1903. (c) Mahanty, J. S.; De, M.; Kundu, N. G. J. Chem. Soc., Perkin
Trans. 1 1997, 2577. (d) Sashida, H.; Kawamukai, A. Synthesis 1999, 1145.
(e) Xiang, Z.; Luo, T.; Lu, K.; Cui, J.; Shi, X.; Fathi, R.; Chen, J.; Yang,
Z. Org. Lett. 2004, 6, 3155. (f) Cherry, K.; Duchene, A.; Thibonnet, J.;
Parrain, J.-L.; Abarbri, Synthesis 2005, 2349. (g) Batchu, V. R.; Barange,
D. K.; Kumar, D.; Sreekanth, B. R.; Vyas, K.; Reddy, E. A.; Pal, M. Chem.
Commun. 2007, 1966. (h) Zheng, Z.; Alper, H. Org. Lett. 2008, 10, 4903.
(i) Thansandote, P.; Hulcoop, D. G.; Langer, M.; Lautens, M. J. Org. Chem.
2009, 74, 1673. (j) Wang, F.; Liu, H.; Fu, H.; Jiang, Y.; Zhao, Y. Org.
Lett. 2009, 11, 2469. (k) Lu, J.; Gong, X.; Yang, H.; Fu, H. Chem. Commun.
2010, 4172. (l) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc.
2010, 132, 6908.
(1) (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. (c) Lewis, J. R. Nat. Prod. Rep. 1994, 11, 329. (d) Gonza´lez,
M. C.; Zafra-Polo, C.; Bla´zquez, A.; Serrano, A.; Cortes, D. J. Nat. Prod.
1997, 60, 108. (e) Zhang, Z.; Li, S.; Zhang, S.; Liang, C.; Gorenstein, D.;
Beasley, R. S. Planta Med. 2004, 70, 1216. (f) Glushkov, V. A.; Shklyaev,
Y. V. Chem. Heterocycl. Compd. 2001, 37, 663. (g) Nagarajan, M.; Morrell,
A.; Fort, B. C.; Meckley, M. R.; Antony, S.; Kohlhagen, G.; Pommier, Y.;
Cushman, M. J. Med. Chem. 2004, 47, 5651. (h) Ruchelman, A. L.;
Houghton, P. J.; Zhou, N.; Liu, A.; Liu, L. F.; LaVoie, E. J. J. Med. Chem.
2005, 48, 792. (i) Cappelli, A.; Mohr, G. P.; Giuliani, G.; Galeazzi, S.;
Anzini, M.; Mennuni, L.; Ferrari, F.; Makovec, F.; Kleinrath, E. M.; Langer,
T.; Valoti, M.; Giorgi, G.; Vomero, S. J. Med. Chem. 2006, 49, 6451.
(5) Kajita, Y.; Matsubara, S.; Kurahashi, T. J. Am. Chem. Soc. 2008,
130, 6058.
10.1021/ol101371c  2010 American Chemical Society
Published on Web 07/07/2010

Table 1. Results of the Reaction of 2-Halobenzamides with Alkynesa
a Unless otherwise mentioned, all reactions were carried out with 2-halobenzamide 1 (1.00 mmol), alkyne 2a (1.50 mmol), Ni(dppe)Br2 (5 mol %), Zn
(3.00 mmol), Et3N (2.00 mmol), and CH3CN (3.0 mL) at 80 °C for 16 h under N2. b Isolated yields. c Reaction was carried out for 36 h.
catalyzed synthesis of functionalized isoquinolones via
denitrogenative addition of triazinones with alkynes.6 Very
recently, we observed a nickel-catalyzed reaction of 2-ha-
lobenzaldimines with alkynes to give isoquinolinium salts,
which were easily converted to isoquinolones.7g However,
the nickel catalysts used were generally air- and moisture-
sensitive and must be stored under an inert atmosphere at
low temperature to prevent their decomposition.
Our continued interest in the nickel-catalyzed cyclization
reactions7a-c and synthesis of heterocyclic compounds7d-h
Org. Lett., Vol. 12, No. 15, 2010
3519

prompted us to explore the possibility of using air-stable
nickel complexes as catalysts for the reaction of substituted
2-halobenzamides with alkynes. Herein, we wish to report a
very efficient method for the synthesis of highly substituted
isoquinolones. Moreover, the method can be used for the
synthesis of isoquinolinone alkaloid natural products.
of 1,4-dimethoxy-2-butyne (2c) and acetylene gas (2d) with
1a gave isoquinolones 3k and 3l in 92 and 70% yield,
respectively (entries 12 and 13). To understand the regiose-
lectivity of the present reaction, unsymmetrical alkynes 2e-h
were investigated. Thus, 1-phenyl-1-butyne (2e) and phe-
nylpropiolate 2f underwent cyclization successfully with 1a
to give regioisomeric products 3m and 3m′ in 65 and 13%
yield and 3n and 3n′ in 82 and 8% yield, respectively (entries
14 and 15). In contrast, N-methyl o-iodobenzamide (1e)
reacted with 2e, affording regioisomer 3o exclusively in 72%
yield (entry 16). The regiochemistry of these isoquinolone
isomers was confirmed by NOE experiments. Similarly,
4-phenyl-3-butyn-2-one (2h) also reacted with 1a in a highly
regioselective manner, providing isoquinolone derivative 3p
exclusively in 74% yield (entry 17). Encouraged by the above
results, terminal alkynes were tested for the present cycliza-
tion reaction. Thus, phenylacetylene 2i reacted well with 1a
to give regioisomeric products 3q and 3q′ in 67 and 16%
yield, respectively (entry 18). However, the reaction of
2-iodobenzamide 1f with 2g gave a single regioisomeric
product 3r in 81% yield (entry 19).
The reaction of N-p-tolyl-2-iodobenzamide 1a with di-
phenyl acetylene 2a in the presence of [Ni(dppe)Br2], Zn,
and Et3N in acetonitrile at 80 °C for 16 h gave isoquinolone
3a in 92% isolated yield (Table 1, entry 1). Product 3a was
1
thoroughly characterized by its H and 13C NMR and mass
spectral analysis.
This nickel-catalyzed annulation reaction depends greatly
on the reaction conditions. To understand the nature of this
reaction and to find the optimized reaction conditions, the
effect of solvent, base, and nickel complexes was examined.
First, the reaction of 1a and 2a in acetonitrile in the presence
of Et3N but without Zn metal powder or nickel complex was
carried out at 80 °C for 16 h; no 3a was observed in both
cases. Under similar reaction conditions, nickel com-
plexes with monodentate phosphine ligands, including
[Ni(PPh3)2Br2] and [Ni(PPh3)2Cl2], showed some catalytic
activity for the reaction, giving 3a in only 12 and 18% yield,
respectively. The use of bidendate nickel complexes greatly
improves the product yield. Among the complexes examined,
[Ni(dppe)Br2] was most effective for the cyclization of 1a
with 2a, furnishing 3a in 92% yield. Other bidendate
nickel(II) systems tested, including [Ni(Phen)Cl2], [Ni(Phen)-
Br2], [Ni(Bipy)Br2], [Ni(dppe)Cl2], [Ni(dppf)Cl2], [Ni(dppp)-
Br2], and [Ni(dppb)Br2], were also active, giving 3a in 45,
62, 41, 26, 35, 57, and 53% yield, respectively. The catalytic
reaction did not proceed in the absence of a base. Various
bases were used for the catalytic reaction. Among them, Et3N
gave the highest product yield of 92%. Other bases are less
effective, giving 3a in lower yields. The choice of solvents
is also vital to the catalytic reaction. The best solvent is
acetonitrile, in which 3a was obtained in 92% yield. THF is
also effective, giving 3a in 53% yield. Other solvents such
as DCE, DMF, and toluene were less effective for the
catalytic reaction (see Supporting Information for details).
The significance of this nickel-catalyzed annulation reaction
is demonstrated by its application to the total synthesis of
isoquinolinone alkaloid natural products. The synthesis of
oxyavicine using this methodology is shown in Scheme 1. Thus,
Scheme 1. Application of Total Synthesis of Oxyavicine
Under the same reaction conditions, 2-chloro-substituted
benzamide (1a-Cl) also reacted well with 2a to give 3a in
71% yield, albeit a much longer reaction time of 36 h (entry
2) was required. In addition to 1a, various N-substituted
2-iodobenzamides (N-propyl, 1b; N-benzyl, 1c; N-allyl, 1d;
N-methyl, 1e) were tested for the reaction with 2a, affording
the corresponding N-substituted isoquinolones, 3b-e, in
77-80% yield (entries 3-6). Interestingly, the nonsubstituted
2-iodobenzamide 1f also reacted efficiently with 2a to afford
isoquinolone derivative 3f in 75% yield (entry 7). In a similar
fashion, o-bromobenzamides 1g-i having 4-chloro, 5-meth-
oxy, and 4,5-dimethoxy substituents on the aryl ring under-
went cyclization with diphenyl acetylene 2a smoothly to give
the corresponding isoquinolones 3g-i in moderate to good
yields (entries 8-10). The present catalytic reaction was also
successfully extended to aliphatic alkynes 2b-d. Thus, 1a
reacted with oct-4-yne (2b) to give isoquinolone derivative
3j in 63% yield (entry 11). In a similar manner, the reaction
the reaction of benzamide 1j with alkyne 2j in the presence of
[Ni(dppe)Br2], Zn, and Et3N in acetonitrile at 80 °C for 16 h
provided isoquinolone derivative 3s in 83% yield in a highly
regioselective manner. No other regioisomer of 3s was detected
in this catalytic reaction. The regiochemistry of product 3s was
confirmed by NOE experiments. We then converted this
isoquinolone intermediate to the corresponding aldehyde deriva-
tive 4a in 95% yield by Swern oxidation.8 After a successful
acid-catalyzed ring-closing and dehydration reaction, we ob-
tained oxyavicine (5a) in 97% yield. The procedure in Scheme
1 appears to be the most efficient method for the synthesis of
oxyavicine, affording a total of 76% yield starting from 1j and
2j. Both 1j and 2j can be prepared in essentially quantitative
yield from amidation of the corresponding acid of 1j and the
Sonogashira reaction of commercially available 5-bromo-
benzo[d][1,3]dioxole and 3-butyn-1-ol, respectively.7g,9 It is
3520
Org. Lett., Vol. 12, No. 15, 2010

interesting to note that this natural product has exhibited
analgesic and anti-inflammatory effects in the biological
evaluation.10 There are many isoquinolinone alkaloids exist-
ing in nature with a similar core structure as oxyavicine. As
a result, the methodology shown in Scheme 1 should be very
useful for the synthesis of these alkaloids.
of B and C affords the final isoquinolinone 3a and the
regeneration of the Ni(0) catalyst for the next catalytic cycle.
There are two possible pathways for the insertion of a
coordinated alkyne into nickelacycle A. We propose that a
carbon-carbon triple bond can insert into the carbon-nickel
bond or the nitrogen-nickel linkage in A depending on the
nature of the alkynes.7d,g
In conclusion, we have demonstrated an easy and conve-
nient nickel-catalyzed annulation of substituted 2-haloben-
zamides with alkynes to give the corresponding isoquinoli-
none in good yields. The present protocol is successfully
applied to the total synthesis of oxyavicine with excellent
yield. Further applications of this methodology in natural
product synthesis are in progress.
On the basis of the known metal-catalyzed cyclization
reactions and synthesis of heterocyclic compounds,5-7
a
possible reaction mechanism is proposed to account for the
present nickel-catalyzed reaction (Scheme 2). The reaction
Scheme 2
.
Proposed Mechanism for the Cyclization Reaction of
2-Halobenzamides with Alkynes
Acknowledgment. We thank the National Science Council
of the Republic of China (NSC-96-2113-M-007-020-MY3)
for support of this research.
Supporting Information Available: General experimental
procedure and characterization details. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL101371C
(6) Miura, T.; Yamauchi, M.; Murakami, M. Org. Lett. 2008, 10, 3085.
(7) (a) Rayabarapu, D. K.; Sambaiah, T.; Cheng, C.-H. Angew. Chem.,
Int. Ed. 2001, 40, 1286. (b) Rayabarapu, D. K.; Cheng, C.-H. Chem.sEur.
J. 2003, 9, 3164. (c) Rayabarapu, D. K.; Shukla, P.; Cheng, C.-H. Org.
Lett. 2003, 5, 4903. (d) Korivi, R. P.; Cheng, C.-H. Org. Lett. 2005, 7,
5179. (e) Korivi, R. P.; Cheng, C.-H. J. Org. Chem. 2006, 71, 7079. (f)
Yeh, C.-H.; Korivi, R. P.; Cheng, C.-H. Angew. Chem., Int. Ed. 2008, 47,
4892. (g) Korivi, R. P.; Wu, Y.-C.; Cheng, C.-H. Chem.sEur. J. 2009, 15,
10727. (h) Parthasarathy, K.; Cheng, C.-H. J. Org. Chem. 2009, 74, 9357,
and references therein.
(8) Burke, S. D.; Danheiser, R. L. Oxidizing and Reducing Agents;
Wiley: New York, 2000; p 154.
likely starts with the reduction of Ni(II) to Ni(0) by zinc
powder. The oxidative addition of 2-iodobenzamide 1a to
Ni(0) in the presence of Et3N leads to the formation of a
five-membered ring nickelacycle A. Coordinative insertion
of alkyne into the nickelacycle to give seven-membered ring
nickelacycle intermediates B and C. Reductive elimination
(9) (a) Rene, B.; Helene, G.; Michele, B.-C. J. Chem. Soc., Perkin Trans.
1 1982, 5, 1149. (b) Luo, Y.; Mei, Y.; Zhang, J.; Lu, W.; Tang, J.
Tetrahedron 2006, 62, 9131.
(10) (a) Arthur, H. R.; Hui, W. H.; Ng, Y. L. J. Chem. Soc. 1959, 4007.
(b) Wang, S.-Q.; Wang, G.-Q.; Huang, B.-K.; Zhang, Q.-Y.; Qin, L.-P.
Chem. Nat. Compd. 2007, 43, 100. (c) Hu, J.; Zhang, W.-D.; Liu, R.-H.;
Zhang, C.; Shen, Y.-H.; Li, H.-L.; Liang, M.-J.; Xu, X.-K. Chem.
BiodiVersity 2006, 3, 990.
Org. Lett., Vol. 12, No. 15, 2010
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