CuBr-catalyzed coupling of N-tosylhydrazones and terminal alkynes: Synthesis of benzofurans and indoles

Article abstract of DOI:10.1021/ol103009n

A new method for the synthesis of benzofurans or indoles via ligand-free CuBr-catalyzed coupling/cyclization of terminal alkynes with N-tosylhydrazones derived from o-hydroxy-or o-aminobenzaldehydes has been developed. A wide range of functional groups we

Full text of DOI:10.1021/ol103009n

ORGANIC
LETTERS
2011
Vol. 13, No. 5
968–971
CuBr-Catalyzed Coupling of
N-Tosylhydrazones and Terminal Alkynes:
Synthesis of Benzofurans and Indoles
Lei Zhou, Yi Shi, Qing Xiao, Yizhou Liu, Fei Ye, Yan Zhang, and Jianbo Wang*
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of
Chemistry, Peking University, Beijing 100871, China
wangjb@pku.edu.cn
Received December 12, 2010
ABSTRACT
A new method for the synthesis of benzofurans or indoles via ligand-free CuBr-catalyzed coupling/cyclization of terminal alkynes with N-tosyl-
hydrazones derived from o-hydroxy- or o-aminobenzaldehydes has been developed. A wide range of functional groups were found that are able to
tolerate the reaction conditions.
Benzofuran and indole moieties are common structural
units in natural products and exhibit interesting biological
activities and potential pharmaceutical applications.1 Among
the methods to construct such structures, Pd-based cross-
coupling reactions of o-iodophenols or o-iodoaniline with
terminal alkynes with copper iodide as a cocatalyst
(Sonagashira coupling), followed by 5-endodig cyclization,
have been studied extensively in recent years.2,3 However,
a major drawback of this process for large-scale synthesis
is the use of two metal catalysts, making recovery of the
expensive palladium difficult.
sequences have emerged for the synthesis of furans
and indoles.4 For example, Venkataraman and co-workers
have recently reported a protocol for the synthesis of benzo-
furans from o-iodophenols and terminal alkynes catalyzed
by a well-defined [Cu(phen)(Ph3P)2]NO3 catalyst.4b The
synthesis of 2-substituted indoles was developed by Ma
(2) For reviews on Pd/Cu-catalyzed coupling and cyclization reac-
tions, see: (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127.
(b) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285. (c) Zeni, G.;
Larock, R. C. Chem. Rev. 2006, 106, 4644. (d) Cacchi, S.; Fabrizi, G.
Chem. Rev. 2005, 105, 2873. (e) Humphrey, G. R.; Kuethe, J. T. Chem.
Rev. 2006, 106, 2875. (f) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180.
(3) For recent examples, see: (a) Kundu, N. G.; Pal, M.; Mahanty, J. S.;
Dasgupta, S. K. J. Chem. Soc., Chem. Commun. 1992, 41. (b) Kundu, N. G.;
Pal, M.; Mahanty, J. S.; De, M. J. Chem. Soc., Perkin Trans. 1 1997, 2815.
(c) Khan, M. W.; Alam, M. J.; Rashid, M. A.; Chowdhury, R. Bioorg. Med.
Chem. 2005, 13, 4796. (d) Sakai, H.; Tsutsumi, K.; Morimoto, T.; Kakiuchi,
K. Adv. Synth. Catal. 2008, 350, 2498. (e) Zhang, H.-C.; Ye, H.; Moretto,
A. F.; Brumfield, K. K.; Maryanoff, B. E. Org. Lett. 2000, 2, 89.
(f) Djakovitch, L.; Rollet, P. Adv. Synth. Catal. 2004, 346, 1782. (g) Leogane,
O.; Lebel, H. Angew. Chem., Int. Ed. 2008, 47, 350. (h) Pal, M.; Subramanian,
V.; Yeleswarapu, K. R. Tetrahedron Lett. 2003, 44, 8221. (i) Kabalka, G. W.;
Wang, L.; Pagni, R. M. Tetrahedron 2001, 57, 8017. (j) McLaughlin, M.;
Palucki, M.; Davies, I. W. Org. Lett. 2006, 8, 3307. (k) Palimkar, S. S.;
Kumar, P. H.; Lahoti, R. J.; Srinivasan, K. V. Tetrahedron 2006, 62, 5109.
(l) Pal, M.; Subramanian, V.; Batchu, V. R.; Dager, I. Synlett 2004, 11, 1965.
(m) Bochicchio, A.; Chiummiento, L.; Funicello, M.; Lopardo, M. T.;
Lupattelli, P. Tetrahedron Lett. 2010, 51, 2824.
Compared to noble-metal catalysts, copper-based methods
have obvious economic attractiveness. Recently, several highly
efficient copper-based Sonogashira coupling/cyclization
(1) For selected reviews, see: (a) Cagniant, P.; Cagniant, D. Adv.
Heterocycl. Chem. 1975, 18, 343. (b) Donnelly, D. M. X.; Meegan, M. J.
In Comprehensive Heterocyclic Chemistry, Vol. 4; Katritzky, A. R., Rees,
C. W., Eds.; Pergamon Press: Oxford, 1984; pp 657-712. (c) Keay, B. A.;
Dibble, P. W. In Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, U.K.,
1996; Vol. 2, p 395. (d) Gribble, G. W. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon
Press: Oxford, U.K., 1996; Vol. 2, p 207. (e) Kawasaki, T.; Higuchi, K.
Nat. Prod. Rep. 2007, 24, 843.
r
10.1021/ol103009n
Published on Web 01/26/2011
2011 American Chemical Society

and co-workers using a CuI/L-proline system.4f We noted,
however, in these cases ligands were essential for the success
of the reactions. Considering the importance of benzofurans
and indoles, it is highly desirable to develop alternative and
novel methods for the synthesis of these structures.
Scheme 1. Cu-Catalyzed Coupling of N-Tosylhydrazone and
Terminal Alkyne
In the past few years, N-tosylhydrazones have been proven
as a new type of coupling partner for Pd-catalyzed cross-
coupling reactions.5 Moreover, palladium-based three-
component coupling of N-tosylhydrazone, aryl bromide,
and terminal alkyne with copper iodide as a cocatalyst has
been reported by our group.6 More recently, we have
developed a method for the synthesis of substituted allenes
via Cu(I)-catalyzed coupling of N-tosylhydrazones with
terminal alkynes.7 In this case, a bisoxazoline ligand was
crucial for efficient allene formation. The mechanism for
the allene formation is proposed as shown in Scheme 1. Cu
carbene intermediate A is formed through dediazotization
of the in situ generated diazo substrate. Subsequently, the
alkynyl group of the Cu carbene A goes through a migratory
insertion into the carbenic carbon to form intermediate B,
which is followed by protonation to afford the allene product.
We haveconceived that ifa suitableintramolecularnucleo-
phile is introduced, the initially formed allene or inter-
mediate B may undergo a cyclization to afford benzofuran
orindole if the nucleophile isa hydroxyor anamino group,
as shown by the transformation from B to D to E.8 Herein
we wish to report a method for the synthesis of benzo-
furans and indoles from N-tosylhydrazones derived
from o-hydroxy- or o-aminobenzaldehydes and terminal
alkynes based on a ligand-free CuBr-catalyzed coupling-
allenylation-cyclization sequence.
Table 1. Optimization of Reaction Conditionsa
Initially, the reaction conditions were optimized starting
from N-tosylhydrazone 1a and phenylacetylene (2a) in 1,
4-dioxane at 100 °C with various copper catalysts, as sum-
marized in Table 1. It was observed that CuBr gave the best
result (Table 1, entries 1-5). Cu(OAc)2 and CuBr2 were
also effective, albeit affording the products with slightly
entry
catalyst
base
solvent
yield%b
1
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
MeCN
DMF
74
82
63
69
68
58
55
0
2
CuBr
3
CuCl
4
CuOTf
Cu(MeCN)4PF6
Cu(OAc)2
CuBr2
FeCl2
5
(4) (a) Okuro, K.; Furuune, M.; Enna, M.; Miura, M.; Nomura, M.
J. Org. Chem. 1993, 58 (16), 4716. (b) Bates, C. G.; Saejueng, P.;
Murphy, J. M.; Venkataraman, D. Org. Lett. 2002, 4, 4727. (c) Saejueng,
P.; Bates, C. G.; Venkataraman, D. Synthesis 2005, 1706. (d) Li, J. H.; Li,
J. L.; Wang, D. P.; Pi, S. F.; Xie, Y. X.; Zhang, M. B.; Hu, X. C. J. Org.
Chem. 2007, 72, 2053. (e) Li, J.-H.; Li, J.-L.; Wang, D.-P.; Pi, S.-F.; Xie,
Y.-X.; Zhang, M.-B.; Hu, X.-C. J. Org. Chem. 2007, 72, 2053. (f) Liu, F.;
Ma, D. J. Org. Chem. 2007, 72, 4844. (g) Wu, M.; Mao, J.; Guo, J.; Ji, S.
Eur. J. Org. Chem. 2008, 4050. (h) Jaseer, E. A.; Prasad, D. J. C.; Sekar,
G. Tetrahedron 2010, 66, 2077.
6
7
8
9
AgOTf
AuCl3
none
trace
7
10
11
12
13
14
15
16
17
18
19c
0
CuBr
CuBr
90
77
70
10
48
51
11
45
ꢀ
(5) (a) Barluenga, J.; Moriel, P.; Valdes, C.; Aznar, F. Angew. Chem.,
ꢀ
CuBr
DCE
Int. Ed. 2007, 46, 5587. (b) Barluenga, J.; Tomas-Gamasa, M.; Moriel,
CuBr
toluene
MeCN
ꢀ
P.; Aznar, F.; Valdes, C. Chem.-Eur. J. 2008, 14, 4792. (c) Barluenga, J.;
ꢀ
Escribano, M.; Moriel, P.; Aznar, F.; Valdes, C. Chem.-Eur. J. 2009, 15,
CuBr
CuBr
tBuOK
MeCN
3291. (d) Zhao, X.; Jing, J.; Lu, K.; Zhang, Y.; Wang, J. Chem. Commun.
2010, 1724. (e) Xiao, Q.; Ma, J.; Yang, Y.; Zhang, Y.; Wang, J. Org. Lett.
2009, 11, 4732.
CuBr
NaOMe
Cs2CO3
MeCN
CuBr
MeCN
(6) Zhou, L.; Ye, F.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2010,
132, 13591.
(7) Xiao, Q.; Xia, Y.; Li, H.; Zhang, Y.; Wang, J. Angew. Chem., Int.
Ed. 2011, 50, online, DOI: 10.1002/anie.201005741.
(8) For examples of ring-closing reaction of allenes, see: (a) Mukai,
C.; Yamashita, H.; Kitagaki, S. Org. Lett. 2001, 3, 3385. (b) Mukai, C.;
Ohta, M.; Yamashita, H.; Kitagaki, S. J. Org. Chem. 2004, 69, 6867.
(c) Ohno, H.; Hamaguchi, H.; Ohata, M.; Kosaka, S.; Tanaka, T. J. Am.
Chem. Soc. 2004, 126, 8744. (d) Yu, X.; Seo, S.-Y.; Marks, T. J. J. Am.
Chem. Soc. 2007, 129, 7244. (e) Kitagaki, S.; Kawamura, T.; Shibata, D.;
Mukai, C. Tetrahedron 2008, 64, 11086. (f) Inuki, S.; Yoshimitsu, Y.;
Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2009, 11, 4478.
a All the reactions were carried out in sealed tubes using 0.4 mmol of
tosylhydrazone 1a, 0.5 mmol of phenylacetylene, 10 mol % of catalyst,
and 3 equiv of base in the solvent at 100 °C for 4 h. b Yields were deter-
mined by GC using dodecane as internal standard. c The reaction was
carried out at 80 °C.
diminished yields (entries 6 and 7). Other catalysts such
as FeCl2, AgOTf, and AuCl3 were found to be essentially
Org. Lett., Vol. 13, No. 5, 2011
969

Table 2. Reaction of N-Tosylhydrazone 1a with Various
Terminal Alkynes Catalyzed by CuBra,8
Table 3. CuBr-Catalyzed Reaction of N-Tosylhydrazone with
1-Alkynesa,8
a Reaction conditions: N-tosylhydrazone 1 (0.4 mmol), 1-alkyne 2
(0.5 mmol), CuBr (10 mol %), Cs2CO3 (1.2 mmol), MeCN (5 mL), 100 °C,
4 h. b Isolated yield.
(entries 12-14), whereas nonpolar solvent toluene was
found to be unfavorable (entry 15). Then, a series of bases
t
such as K2CO3, BuOLi, and NaOMe were examined;
a Reaction conditions: N-tosylhydrazone 1a (0.4 mmol), alkyne 2
(0.5 mmol), CuBr (10 mol %), Cs2CO3 (1.2 mmol), MeCN (5 mL), 100 °C,
4 h. b Isolated yield. c 31% yield of alkyne was recovered.
however, they were all less efficient compared with Cs2CO3
(entries 16-18). Finally, we found that the yield of 3a
decreased sharply when the reaction was carried out at
lower temperature (entry 19).
Having optimized the reaction conditions, we then explored
the scope and limitation of the present CuBr-catalyzed
tandem coupling-allenylation-cyclization method with a
variety of terminal alkynes and N-tosylhydrazones.9 As
shown in Table 2, various functional groups including the
ineffective in this reactions (entries 8-10). A control ex-
periment showed that no product could be detected in the
absence of a copper catalyst (entry 11).
Further inspection of the reaction conditions revealed
that this reaction proceeded more efficiently in polar solvents
such as MeCN, DMF, and 1,2-dichloroethane (DCE)
970
Org. Lett., Vol. 13, No. 5, 2011

aryl, alkyl, naphthyl, and heterocycle present in alkynes 2
were tolerant of the reaction conditions. The reaction
was found to be not significantly affected by the substitu-
ents on the aromatic ring of the terminal alkyne; both
electron-rich (entries 2-3 and 6-7) and electron-deficient
aryl substituted alkynes (entries 4 and 5) were effective.
Treatment of 3-thienylacetylene with N-tosylhydrazone 1a
furnished the benzofuran 3h in a yield of 91% (entry 8).
Naphthyl and alkyl alkynes were also suitable for the
reactions, albeit generating the corresponding products
with moderately high yields (entries 7 and 9-10). We were
pleased to find that the alkyne bearing a hydroxyl group
reacted with N-tosylhydrazone 1a under the optimized
conditions to afford the desired benzofuran in 64% yield
without the need of functional group protection (entry11).
To further expand the scope of the reaction, various sub-
stituted salicyl N-tosylhydrazones were employed as sub-
strates to react with phenylacetylene. As shown in Table 3,
hydrazones with a methoxy group at the meta- or para-
position were both effective, affording the corresponding
benzofurans 3l and 3m in yields of 79% and 72% respectively
(entries 1 and 2). In another case, coupling of phenylace-
tylene with hydrazone bearing a naphthyl group (1d) led to
the product 3n in 53% yield (entry 3). It is noteworthy that
a bromo substituent could survive in the reaction of 1e and
phenylacetylene (entry 4). Further examination of the scope
of N-tosylhydrazone showed that the strong electron-
withdrawing group on the aromatic ring hampered the
formation of benzofurans. When N-tosylhydrazone 1f was
employed, the reaction with phenylacetylene yielded the
benzofuran 3p in only 48% (entry 5). Next, we checked the
possibility of assembling 2-substituted indoles by our
process and were pleased to observe that reaction of
N-tosylhydrazone 1g with phenylacetylene, 3-thienylace-
tylene, and 4-phenyl-1-butyne delivered the corresponding
indole 3q-s in yields of 74%, 72%, and 41% respectively
(entries 6-8). As an additional example, it was found that
using Ac protected N-tosylhydrazone 1h also afforded the
desired product in 38% yield (entry 9).
In summary, we have developed a new method for the
synthesis of benzofuran and indole via CuBr-catalyzed
coupling/allenylation/cyclization of terminal alkynes with
N-tosylhydrazone derivatives. This method is based on
salicyl N-tosylhydrazones, which are easily available from
the coressponding aldehydes. A wide range of functional
groups were found that are able to tolerate the reaction
conditions. Moreover, this reaction uses inexpensive CuBr
as a catalyst and is ligand-free, thus offering significant
economic advantages over the many previous methods.
Further application of this method is currently under
investigation in our laboratory, and the results will be
reported in due course.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (Grant Nos. 20902005,
20832002, 210722009, 20821062), 973 Program (No. 2009-
CB825300), GSK R&D China and China Postdoctoral
Science Foundation is gratefully acknowledged.
(9) General procedure CuBr-catalyzed reaction of N-tosylhydrazone
and alkyne: CuBr (5.8 mg, 10 mol%), Cs2CO3 (1.2 mmol, 390 mg), and
N-tosylhydrazone 1a-h (0.4 mmol) were suspended in MeCN (5 mL) in a
10 mL Schlenk tube under nitrogen. Then terminal alkynes 2 (0.5 mmol)
were added. The resulting solution was stirred at 100 °C for 4 h. After
cooling to room temperature, the resulting mixture was filtered through a
short path of silica gel, eluting with hexane and CH2Cl2. The volatile
compounds were removed in vacuo, and the residue was purified by
column chromatography (SiO2, hexane).
Supporting Information Available. Procedures for syn-
thesis and characterization of products (1H and 13C NMR
data). This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 5, 2011
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