Copper(II)chloride-mediated cyclization reaction of N-alkoxy- orthoalkynylbenzamides

Article abstract of DOI:10.1021/ol1029035

A regioselective intramolecular cyclization/halogenation reaction of N-alkoxy-o-alkynylbenzamides with CuCl₂/NCS was developed. The corresponding 3-(chloromethylene)isobenzofuran-1-ones were exclusively obtained via 5-exo-dig cyclization in moderate to excellent yields within 0.5-1 h. This approach has been successfully used to synthesize a biaryl compound by the Suzuki-Miyaura reaction.

Full text of DOI:10.1021/ol1029035

ORGANIC
LETTERS
2011
Vol. 13, No. 3
518-521
Copper(II)Chloride-Mediated Cyclization
Reaction of N-Alkoxy-ortho-
alkynylbenzamides
Manita Jithunsa, Masafumi Ueda, and Okiko Miyata*
Kobe Pharmaceutical UniVersity, Motoyamakita, Higashinada, Kobe,
Hyogo 658-8558, Japan
miyata@kobepharma-u.ac.jp
Received December 1, 2010
ABSTRACT
A regioselective intramolecular cyclization/halogenation reaction of N-alkoxy-o-alkynylbenzamides with CuCl2/NCS was developed. The
corresponding 3-(chloromethylene)isobenzofuran-1-ones were exclusively obtained via 5-exo-dig cyclization in moderate to excellent yields
within 0.5-1 h. This approach has been successfully used to synthesize a biaryl compound by the Suzuki-Miyaura reaction.
Isobenzofuran-1-ones and isocoumarins are key components
among several lactone natural products containing important
biological activities1 such as antifungal,2 antimicrobial,3 and
acting as reactive intermediates4 for target molecules.
Consequently, numerous straightforward synthetic methods
have been developed.5-12
Among these methods, the typical strategy for the synthesis
of isobenzofuran-1-one is a transition metal,10 organic base-
catalyzed,11 or halogen-mediated12 cyclization of alkynes
(6) For the synthesis of lactones from the oxidation of diols, see: (a)
Sternberg, V. I.; Perkins, R. J. J. Org. Chem. 1963, 28, 323. (b) Fetizon,
M.; Golfier, M.; Louis, J.-M. Tetrahedron 1975, 31, 171.
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Roy, S.; Neuenswander, B.; Hill, D.; Larock, R. C. J. Comb. Chem. 2009,
11, 1128. (b) Nagarajan, A.; Balasubramanian, T. R. Indian J. Chem. 1987,
26B, 917. (c) Nagarajan, A.; Balasubramanian, T. R. Indian J. Chem. 1988,
27B, 380. (d) Liang, Y.; Xie, Y.-X.; Li, J.-H. Synthesis 2007, 400. (e)
Peuchmaur, M.; Lisowski, V.; Gandreuil, C.; Maillard, L. T.; Martinez, J.;
Hernandez, J.-F. J. Org. Chem. 2009, 74, 4158.
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D. T.; Gloer, J. B. J. Nat. Prod. 2006, 69, 113.
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1972, 2732. (b) Gutsche, C. D.; Jason, E. F.; Coffey, R. S.; Johnson, H. E.
J. Am. Chem. Soc. 1958, 80, 5756. (c) Ziegert, R. E.; Torang, J.; Knepper,
K.; Brase, S. J. Comb. Chem. 2005, 7, 147.
(9) For the synthesis of lactones via intramolecular Diel-Alder reactions,
see: (a) Klemm, L. H.; Gopinath, K. W. J. Heterocycl. Chem. 1965, 2,
225. (b) Klemm, L. H.; Lee, L. H.; Gopinath, K. W.; Klopfenstein, C. E.
J. Org. Chem. 1966, 31, 2376. (c) Klemm, L. H.; Gopinath, K. W.
Tetrahedron Lett. 1963, 4, 1243. (d) Klemm, L. H.; Gopinath, K. W.; Lee,
D. H.; Kelly, F. W.; Trod, E.; Mcquire, T. M. Tetrahedron 1966, 22, 1797.
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J. Chem. Soc., Chem. Commun. 1993, 86. (d) Inack-Ngi, S.; Rahmani, R.;
Commeiras, L.; Chouraqui, G.; Thibonnet, J.; Duchene, A.; Abarbri, M.
AdV. Synth. Catal. 2009, 351, 779. (e) Doroh, B.; Sulikowski, G. A. Org.
Lett. 2006, 8, 903. (f) Noriyuki, H. H.; Osaki, T.; Nakano, M.; Mori, H.;
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Osaki, T.; Mori, H.; Katsumura, S. Angew. Chem., Int. Ed. 2002, 41, 1023.
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9017. (b) Loughlin, W. A.; Jenkins, I. D.; Henderson, L. C.; Campitelli,
M. R.; Healy, P. C. J. Org. Chem. 2008, 73, 3435. (c) Zhang, H.; Zhang,
S.; Liu, L.; Luo, G.; Duan, W.; Wang, W. J. Org. Chem. 2010, 75, 368. (d)
Hauser, F. M.; Gauuan, P. J. F. Org. Lett. 1999, 1, 671. (e) Fujimoto, T.;
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Schlessinger, R. H.; Ponticello, I. S. J. Chem. Soc., Chem. Commun. 1969,
1013
.
10.1021/ol1029035  2011 American Chemical Society
Published on Web 12/28/2010

possessing a nucleophile. However, the synthesis often
suffers from a lack of regioselectivity due to competitive
cyclization through the 5-exo or 6-endo mode. Larock has
succeeded in the synthesis of 4-iodoisocoumarins and 3-io-
domethylisobenzofuranones by the regioselective electro-
philic cyclization;13 however, this selectivity was highly
dependent on the bulkiness of the substituent. Thus, the
development of a practical method for the synthesis of
isobenzofuranones is highly desirable.
Table 1. Optimized Conditions in the Cyclization of
N-Alkoxy-o-alkynylbenzamide 1aa
Although intramolecular annulation of carboxylic acids,14
esters15 and amides16 to a variety of alkenes and alkynes
for the synthesis of heterocycles have been reported, nothing
is known about the cyclization of the Weinreb amide onto
an alkyne. Therefore, we are interested in the potential of
the Weinreb amide for the reaction with an alkyne moiety.
In general, a carbonyl group of Weinreb amides is more
electrophilic than that of regular amides.17 However, there
are few reports on a property of oxygen on carbonyl group
in Weinreb amides. We anticipated that the enhancement of
nucleophilicity of the carbonyl oxygen atom by an electron
donation of the methoxy group (the alpha effect)18 would
lead to the chemoselective nucleophilic attack of the carbonyl
oxygen over the other heteroatoms. Furthermore, it is thought
that the coordination ability and partial C-N double bond
character would influence the regioselectivity of cyclization.
As a part of our program directed toward seeking the novel
synthetic methodology of the substrate bearing N-O bond,19
we report herein the CuCl2-mediated chlorocyclization of
N-alkoxy-o-alkynyl-benzamide for the selective synthesis of
3-(chloromethylene)isobenzofuran-1-ones.
Cu salt
(equiv)
additive
(equiv)
entry
solvent
t (h) yieldb (%)
2a 3a
1
2
3
4
5
6
7
8
CuCl2 (2.5)
CuCl2 (2.5) NCS (2) MeCN
none
none
MeCN
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
57
90
7
-
-
41
-
-
-
-
-
-
8
NCS (2) MeCN
NCS (2) MeCN
NCS (1) MeCN
NCS (2) MeCN
NCS (2) MeCN
NCS (2) MeCN
NCS (2) toluene
CuCl (2.5)
CuCl2 (2)
CuCl2 (2)
CuCl2 (1)
CuCl2 (0.5)
CuCl2 (2.5)
CuCl2 (2.5)
CuCl2 (2.5)
CuCl2 (2.5)
CuCl2 (2.5)
CuCl2 (2.5)
24
64
83
61
36
38
57
30
34
36
80
9
17
10
11
12
13
14e
NCS (2) 1,4-dioxane 16
NCS (2) DCEc
NCS (2) DMA
NCS (2) DMFd
NCS (2) MeCN
0.5
18
3
26
12
31
-
0.5
a Conditions: 1a (0.2 mmol), solvent (0.05 M) under Ar atmosphere.
b Isolated yield. c Reaction was carried out at 90 °C. d Reaction was carried
out at 130 °C. e The reaction was carried out with 1 g of 1a.
only the E-isomer product 2a was obtained. Using only NCS
predominantly generated the six-membered-ring product 3a
in moderate yield (entry 3). These results indicated that CuCl2
plays a pivotal role in a selective formation of five-
membered-rings and the chlorocyclization was activated by
NCS. It is also possible to use Cu(I)chloride as a chloride
source; however, the efficiency to this reaction was low
(entry 4). Reducing the amount of reagents led to a decrease
in the chemical yields of 2a (entries 5-8). Efficiency and
selectivity of this reaction were strongly influenced by the
reaction solvent. The use of nonpolar solvents and polar
aprotic solvents except for MeCN afforded 2a and/or 3a in
moderate yields (entries 9-13). Additionally, this reaction
can be applied to a gram scale synthesis; thus, the chloro-
cyclization of 1a (1 g) afforded 2a in 80% yield (entry 14).
To confirm the priority of the Weinreb amide, other
carbonyl derivatives as shown in Scheme 1 were tested.
Chlorocyclization of primary, secondary and tertiary amides
1b-d produced the mixture of products 2a and 3a in low to
moderate yields. In contrast, exclusive formation of isocou-
marin 3a was observed when methyl ester 1e was subjected
to the cyclization reaction.7d These results indicate a neces-
sary component of the Weinreb amide for the selective 5-exo-
dig cyclization. We anticipate that CuCl2/NCS cyclization
will provide direct access to the compounds isobenzofuran-
1-one and isocoumarin by delivering 1a and 1e as a substrate,
respectively.
We found that chlorobenzylidene isobenzofuran-1-one 2a
was exclusively obtained in 57% via regioselective cycliza-
tion, when N-methoxy-o-alkynylbenzamide 1a was treated
with 2.5 equivalents of CuCl2 in MeCN at reflux for 0.5 h
(Table 1, entry 1). Various additives and solvents have been
screened to optimize the reaction conditions. The cyclization
proceeded successfully in the presence of 2 equivalents of
NCS to produce 2a in 90% yield (entry 2). Interestingly,
(11) (a) Uchiyama, M.; Ozawa, H.; Takuma, K.; Matsumoto, Y.;
Yonehara, M.; Hiroya, K.; Sakamoto, T. Org. Lett. 2006, 8, 5517. (b)
Kanazawa, C.; Terada, M. Tetrahedron Lett. 2007, 48, 933. (c) Terada,
M.; Kanazawa, C.; Yamanaka, M. Heterocycles 2007, 74, 819. (d) Biagetti,
M.; Bellina, F.; Carpita, A.; Viel, S.; Mannina, L.; Rossi, R. Eur. J. Org.
Chem. 2002, 1063. (e) Ogliaruso, M. A.; Wolfe, J. F. In Synthesis of lactones
and lactams; Patai, S., Rappoport, Z., Eds.; John Wiley & Sons Ltd.:
England, 2003; p 3.
(12) (a) Biagetti, M.; Bellina, F.; Carpita, A.; Stabile, P.; Rossi, R.
Tetrahedron 2002, 58, 5023. (b) Bellina, F.; Biagetti, M.; Carpita, A.; Rossi,
R. Tetrahedron 2001, 57, 2857. (c) Sofia, M. J.; Katzenellenbogen, J. A.
J. Med. Chem. 1986, 29, 230.
(13) Yao, T.; Larock, R. C. J. Org. Chem. 2003, 68, 5936.
(14) (a) Sashida, H.; Kawamukai, A. Synthesis 1999, 1145. (b) Larock,
R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298. (c) Izumi, T.;
Morishita, N. J. Heterocyl.Chem. 1994, 31, 145. (d) Korte, D. E.; Hegedus,
L. S.; Wirth, R. K. J. Org. Chem. 1977, 42, 1329.
(15) (a) Woon, E. C. Y.; Dhami, A.; Mahon, M. F.; Threadgill, M. D.
Tetrahedron 2006, 62, 4829. (b) Hellal, M.; Bourguignon, J.-J.; Bihel, F. J.-
J. Tetrahedron Lett. 2008, 49, 62.
(16) (a) Bian, M.; Yao, W.; Ding, H.; Ma, C. J. Org. Chem. 2010, 75,
269. (b) Sakamoto, T.; An-naka, M.; Kondo, Y.; Yamanaka, H. Chem.
Pharm. Bull. 1986, 34, 2754.
(17) Balasubramaniam, S.; Aidhen, I. S. Synthesis 2008, 23, 3707.
(18) Klopman, G. Tetrahedron 1970, 26, 4549.
(19) (a) Ueda, M.; Kawai, S.; Hayashi, M.; Naito, T.; Miyata, O. J.
Org. Chem. 2010, 75, 914. (b) Ueda, M.; Sato, A.; Ikeda, Y.; Miyoshi, T.;
Naito, T.; Miyata, O. Org. Lett. 2010, 12, 2594.
With the optimal conditions in hand, we then explored
the scope of substrates (Table 2). The reaction of various
Org. Lett., Vol. 13, No. 3, 2011
519

with a silyloxymethyl group underwent chlorolactonization
and then desilylation to yield the allylic alcohol 2l in 64%
yield (entry 7).
Scheme 1.
Cyclization of Substrates 1 with Substituents on R1
We next investigated the substitution variation of the
benzamide moiety (Scheme 2). Particularly noteworthy is
Scheme 2
.
CuCl2-Mediated Cyclization of Substituted
N-Alkoxy-o-alkynylbenzamides
acetylenic substrates with CuCl2/NCS displayed broad
substrate capability and the reaction was tolerable toward a
range of substituents on the acetylenic unit carrying a cyclic
moiety or an acyclic moiety. An excellent chemical yield
was observed in the reaction of TMS-substituted alkyne
1h (entry 3), albeit a relatively lower yield was given by
1i with t-butyl group (entry 4). Substrates bearing aliphatic
substituents also worked well (entries 5-6). Alkyne 1l
Table 2. CuCl2-Mediated Chlorocyclization of
N-Methoxy-o-alkynylbenzamide: the Effect of Substituents on
Acetylenesa
the tolerance of halogen groups. The manipulation of the
benzamide bearing a halogen substituent such as a fluoro or
chloro atom para or meta to the carbonyl group produced
2m-p in very good yields (Scheme 2). Conversely, the
substrate bearing an ortho-fluoro group to the carbonyl group
afforded 2q in lower yield. 1r with an additional alkyne gave
2r as a sole product without suppression of the desired
reaction.
Alternatively, systems bearing electron-deficient or electron-
rich substituents performed well (2s-u). Surprisingly, the
cyclization worked well to give 2v in 96% yield when the
substrate contained a methoxy group ortho to the alkyne.
Moreover, the naphthyl substrate was also demonstrated,
affording 2w in 64% yield.
Although the precise mechanism of this reaction could not
be fully elucidated, a possible reaction pathway is shown in
Scheme 3. The activation of an alkyne moiety of 1 by CuCl2
is followed by the nucleophilic addition of the carbonyl
oxygen to form an intermediate B via 5-exo-dig cyclization.
The Cu(II) species are oxidized by another equivalent of
a Conditions: 1f-l (0.2 mmol), CuCl2 (2.5 equiv), NCS (2.0 equiv),
MeCN (0.05 M) under Ar atmosphere. b Isolated yield.
520
Org. Lett., Vol. 13, No. 3, 2011

Scheme 3
.
Plausible Reaction Pathway
Scheme 4. Suzuki-Miyaura Coupling of 2a
isobenzofuran-1-one derivatives. This work should open new
perspectives in the chemistry of isobenzofuran-1-one and
represents a useful tool for other reaction designs.
CuCl2 to generate Cu(III) species C.20 After chlorination at
the copper atom by NCS, reductive elimination affords D.
Finally, the work up process transforms the intermediate D
to the product 2.
The utilization of our products is challenging and provides
a broad insight into chlorosubstitued iso-benzofuran-1-one.
The Suzuki-Miyaura coupling of 2a with p-methoxyphe-
nylboronic acid yielded the biaryl product 4a in 62%
(Scheme 4).
Acknowledgment. We thank the partial support by Grants-
in-Aid from the Ministry of Education, Culture, Sports,
Science and Technology of Japan, and the Science Research
Promotion Fund of the Japan Private School Promotion
Foundation. M.U. is grateful for the Research Foundation
for Pharmaceutical Science.
In conclusion, we have developed a simple and rapid
CuCl2-mediated cyclization reaction of N-alkoxy-o-alkyl-
benzamides with a broad range of substitution and function-
alization patterns for the synthesis of 3-(chloromethylene)-
Supporting Information Available: Experimental details,
1
characterization data, and copies of H NMR, 13C NMR
spectra of all new compounds (compounds 1-4). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) (a) King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc.
2009, 131, 5044. (b) Wu, H.; Hynes, J., Jr. Org. Lett. 2010, 12, 1192.
OL1029035
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