Synthesis of 3-alkyl-or 3-allenyl-2-amidobenzofurans via electrophilic cyclization of o-anisole-substituted ynamides with carbocations

Article abstract of DOI:10.1021/ol303474a

A facile carbocation-induced electrophilic cyclization reaction has been developed for the synthesis of 3-alkyl-or 3-allenyl-2-amidobenzofurans from o-anisole-substituted ynamides and diarylmethanol or 1,1-diarylprop-2-yn-1-ol.

Full text of DOI:10.1021/ol303474a

ORGANIC
LETTERS
2013
Vol. 15, No. 2
422–425
Synthesis of 3‑Alkyl- or 3‑Allenyl-2-
amidobenzofurans via Electrophilic
Cyclization of o‑Anisole-Substituted
Ynamides with Carbocations
Yulong Kong,† Kezhi Jiang,† Jian Cao,* Lingzi Fu, Lian Yu, Guoqiao Lai, Yuming Cui,
Ziqiang Hu, and Guanhai Wang
Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of
Education, Hangzhou Normal University, Wenyi Road 222, Hangzhou 310012,
People’s Republic of China
caojianhznu@yahoo.cn
Received December 19, 2012
ABSTRACT
A facile carbocation-induced electrophilic cyclization reaction has been developed for the synthesis of 3-alkyl- or 3-allenyl-2-amidobenzofurans
from o-anisole-substituted ynamides and diarylmethanol or 1,1-diarylprop-2-yn-1-ol.
Since new and more efficient methods for accessing
ynamides were established,1 ynamides have emerged as
important synthons in modern organic synthesis.2 A vari-
ety of important functional groups and cyclic systems such
as enamides,3 amidines,4 indoles,5 and pyridines6 were suc-
cessfully synthesized from ynamides. Benzofurans are the
fundamental motif found in various natural products and
the key structural units for pharmaceutical compounds.7
As a special class of functionalized benzofurans, 2-amido-
benzofurans are of considerable interest8À11 and many
methods have been established for their synthesis, such as
† These authors contributed equally.
(1) (a) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.;
Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc.
2003, 125, 2368. (b) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz,
K. C. M.; Vera, E. L. Org. Lett. 2004, 6, 1151. (c) Zhang, X.; Zhang, Y.;
Huang, J.; Hsung, R. P.; Kurtz, K. C. M.; Oppenheimer, J.; Petersen,
M. E.; Sagamanova, I. K.; Shen, L.; Tracey, M. R. J. Org. Chem. 2006,
71, 4170. (d) Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G. Angew.
Chem., In. Ed. 2009, 48, 4381. (e) Coste, A.; Couty, F.; Evano, G. Org.
Lett. 2009, 11, 4454. (f) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem.
Soc. 2008, 130, 833. (g) Jia, W.; Jiao, N. Org. Lett. 2010, 12, 2000. (h)
Jouvin, K.; Couty, F.; Evano, G. Org. Lett. 2010, 12, 3272. (i) Sueda, T.;
Oshima, A.; Teno, N. Org. Lett. 2011, 13, 3996. (j) Laouiti, A.; Rammah,
M. M.; Rammah, M. B.; Marrot, J.; Couty, F.; Evano, G. Org. Lett.
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756. (l) Laouiti, A.; Jouvin, K.; Bourdreux, F.; Rammah, M. M.;
Rammah, M. B.; Evano, G. Synthesis 2012, 44, 1491.
(2) (a) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.;
Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064. (b) Evano, G.;
Coste, A.; Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840. (c) Evano,
G.; Jouvin, K.; Coste, A. Synthesis 2013, 45, 17.
(3) (a) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P.; Coverdale, H.;
Frederick, M. O.; Shen, L.; Zificsak, C. A. Org. Lett. 2003, 5, 1547.
(b) Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R. P.; Kurtz, K. C. M.;
Oppenheimer, J.; Petersen, M. E.; Sagamanova, I. K.; Shen, L.; Tracey,
M. R. J. Org. Chem. 2006, 71, 4170. (c) Cao, J.; Kong, Y.; Deng, Y.; Lai,
G.; Cui, Y.; Hu, Z.; Wang, G. Org. Biomol. Chem. 2012, 10, 9556.
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(4) (a) Kramer, S.; Dooleweerdt, K.; Lindhardt, A. T.; Rottlander,
M.; Skrydstrup, T. Org. Lett. 2009, 11, 4208. (b) Shindoh, N.; Takemoto,
Y.; Takasu, K. Chem.;Eur. J. 2009, 15, 7026.
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(c) Zhang, Y.; Hsung, R. P.; Zhang, X.; Huang, J.; Slater, B. W.; Davis,
A. Org. Lett. 2005, 7, 1047. (d) Yao, P.-Y.; Zhang, Y.; Hsung, R. P.;
Zhao, K. Org. Lett. 2008, 10, 4275. (e) Witulski, B.; Alayrac, C.;
Tevzadze-Saeftel, L. Angew. Chem., Int. Ed. 2003, 42, 4257. (f) Kramer,
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S.; Dooleweerdt, K.; Lindhardt, A. T.; Rottlander, M.; Skrydstrup, T.
Org. Lett. 2009, 11, 4208. (g) Cao, J.; Xu, Y.; Kong, Y.; Cui, Y.; Hu, Z.;
Wang, G.; Deng, Y.; Lai, G. Org. Lett. 2012, 14, 38.
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2007, 129, 10096. (b) Garcia, P.; Moulin, S.; Miclo, Y.; Leboeuf, D.;
Gandon, V.; Aubert, C.; Malacria, M. Chem.;Eur. J. 2009, 15, 2129.
(c) Tanaka, R.; Yuza, A.; Watai, Y.; Suzuki, D.; Takayama, Y.; Sato, F.;
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George, P.; Sevrin, M.; Ricci, G.; Malacria, M.; Aubert, C.; Gandon, V.
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r
10.1021/ol303474a
Published on Web 01/09/2013
2013 American Chemical Society

Beckmann rearrangement of aryl benzofuranyl oximes,9
Curtius rearrangement of benzofuran-2-carboxylic acid,10
and nitration/reduction/N-acylation of 2-trimethylstannyl
benzofurans.11 Recently, Hsung and co-workers developed
an elegant synthesis of 2-amidobenzofurans from O-anisyl
ynamides via a Rh(I)-catalyzed demethylationÀcyclization
reaction,12 and the Skrydstrup group reported a Pd-cata-
lyzed, one-pot, two-step synthesis of 2-amidobenzofurans
from ynamides and o-iodophenol.13 However, these meth-
ods could only afford 3-unsubstituted 2-amidobenzofurans.
Electrophilic cyclization chemistry developed by Larock
and co-workers provided access to various heterocyclic
compounds including benzofurans.14 Many electrophilic
reagents (I, Br, PhSe, PhS, etc.) could induce the electrophilic
cyclization of a carbonÀcarbon triple bond (Scheme 1a).
To the best of our knowledge, carbocation-induced
electrophilic cyclization of alkynes is still unreported.
Considering that ynamides are more electron-rich than
ordinary alkynes because of the donating ability of the
nitrogen lone pair toward the alkynyl motif, we anticipate
that ynamides would undergo electrophilic cyclization
reactions with carbocations to form a CÀC and CÀO
bond (Scheme 1, b). Herein, we wish to report the novel
synthesis of 3-substituted 2-amidobenzofurans via elec-
trophilic cyclization of o-anisole-substituted ynamides
with carbocations.
Initial studies focused on the reaction of O-anisyl
ynamide 1a with diphenylmethanol 2a. ZnCl2 was first
chosen as the Lewis acid to generate the carbocation with
diphenylmethanol in CH2Cl2. Fortunately, the expected
2-amidobenzofuran 3a was obtained in 37% yield.
Subsequent screening of Lewis acids showed that ZnBr2
gave a better result than ZnCl2 or ZnI2 did (Table 1, entries
1À3), while other Lewis acids such as AlCl3, FeCl3, and
BF3 OEt2 were not effective (entries 4À6). Solvents were
3
also important. Other common solvents such as toluene or
THF did not give any expected product 3a (entries 7À8). It
should be noted thatwhena catalyticamount of ZnBr2 was
used, theyield wasreduced dramatically (entry9). Thus the
following reaction conditions were chosen as optimum for
all subsequent reactions: 0.5 mmol of 1, 1.0 mmol of 2, and
1.0 mmol of ZnBr2 in CH2Cl2 were stirred at rt under N2.
Table 1. Optimization of the Reaction Conditionsa
Lewis
acid
time
(h)
yield of
entry
solvent
3a (%)
1
2
3
4
5
6
7
8
9b
ZnCl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
4
37
72
66
0
Scheme 1
ZnBr2
ZnI2
3
3
AlCl3
FeCl3
14
14
1
0
BF3 OEt2
trace
0
3
ZnBr2
ZnBr2
ZnBr2
1
12
12
NR
7
CH2Cl2
a Unless specified otherwise, the reaction was carried out using 1a
(0.5 mmol), 2a (1.0 mmol), and a Lewis acid (1.0 mmol) in solvent (4 mL)
at rt under N2. b 0.05 mmol of ZnBr2 was added.
Under the optimized conditions, the scope of this car-
bocation-induced electrophilic cyclization reaction was
further investigated. The reaction was successful for var-
ious O-anisyl ynamides (Table 2, entries 1À5). It should be
noted that when the amido group in 1 was replaced by an
aryl or alkyl group, the corresponding 3-alkylbenzofuran
was not detected. Substituted diarylmethanol, 1-arylprop-
2-en-1-ol, and 1-arylprop-2-yn-1-ol worked well to
afford the corresponding 3-alkyl, allyl, and propargyl
2-amidobenzofuran respectively (Table 2, entries 6À9),
while simple phenylmethanol could not undergo this elec-
trophilic cyclization reaction.
(8) (a) Makovetskii, V. P.; Dzvinchuk, I. B.; Yaremko, V. V.; Svishchuk,
A. A. Ukr. Khim. Zh. 1979, 45, 652. (b) King, T. J.; Newall, C. E. J. Chem.
Soc. 1965, 974.
(9) Demerseman, P.; Guillaumel, J.; Cheutin, A.; Royer, R. Bull. Soc.
Chim. Fr. 1970, 2253.
€
(10) Carrer, A.; Florent, J.; Auvrouin, E.; Rousselle, P.; Bertounesque,
E. J. Org. Chem. 2011, 76, 2502.
(11) Einhorn, J. F.; Demerseman, P.; Royer, R. Synthesis 1984, 978.
(12) Oppenheimer, J.; Johnson, W. L.; Tracey, M. R.; Hsung, R. P.;
Yao, P.-Y.; Liu, R.; Zhao, K. Org. Lett. 2007, 9, 2361.
(13) Dooleweerdt, K.; Ruhland, T.; Skrydstrup, T. Org. Lett. 2009,
11, 221.
Interestingly, 3-allenyl-2-amidobenzofurans 5were formed
when 1,1-diarylprop-2-yn-1-ols 4were used as the precursors
of carbocations, and the corresponding 3-propargyl-2-
amidobenzofurans were not found. As shown in Table 3,
the reaction was successful for various O-anisyl ynamides
(entries1À4). The R3 and R4 groups of 4can be a substituted
(14) For electrophilic cyclization chemistry, see: (a) Yue, D.; Yao,
T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292. (b) Cho, C.-H.;
Neuenswander, B.; Lushington, G.; Larock, R. C. J. Comb. Chem.
2008, 10, 941. (c) Manarin, F.; Roehrs, J. A.; Mozzaquatro Gay, R.;
~
Brandao, R.; Menezes, P. H.; Nogueira, C. W.; Zeni, G. J. Org. Chem.
2009, 74, 2153. (d) Yao, T.; Yue, D.; Larock, R. C. J. Org. Chem. 2005,
70, 9985. (e) Mehta, S.; Waldo, J. P.; Larock, R. C. J. Org. Chem. 2009,
74, 1141. (f) Mehta, S.; Larock, R. C. J. Org. Chem. 2010, 75, 1652.
Org. Lett., Vol. 15, No. 2, 2013
423

Table 2. Synthesis of 3-Alkyl-2-amidobenzofurans 3a
Table 3. Synthesis of 3-Allenyl-2-amidobenzofurans 5a
a The reaction was carried out using 1 (0.5 mmol), 2 (1.0 mmol), and
ZnBr2 (1.0 mmol) in CH2Cl2 (4 mL) at rt under N2.
a The reaction was carried out using 1 (0.5 mmol), 4 (1.0 mmol), and
ZnBr2 (1.0 mmol) in CH2Cl2 (4 mL) at rt under N2.
424
Org. Lett., Vol. 15, No. 2, 2013

while the byproduct MeBr was obviously observed by
GC-MS analysis of the gas composition of the reac-
tion (see the Supporting Information for details). On the
basis of the above experimental observations, a possible
mechanism is given in Scheme 2. Initially, carbocation A
would be formed from alcohol 2 with ZnBr2. Electrophilic
addition of the in situ generated carbocation with O-anisyl
ynamide 1 gives the intermediate B.16 Subsequent cycliza-
tion occurred to afford O-methyl benzofuran C, which is
demethylated by a bromide anion to produce 2-amidoben-
zofuran3. In the caseof alcohol 4, propargylic carbocation/
allenylic carbocation D formed from 4 and ZnBr2 reacts
with ynamide 1 to afford 3-allenyl-2-amidobenzofuran 5
selectively probably because of the steric hindrance of the
two aryl groups.
Scheme 2
In conclusion, we have described a novel carbocation-
induced electrophilic cyclization reaction of o-anisole-
substituted ynamides. 3-Alkyl, allyl, and propargyl 2-ami-
dobenzofuran were provided respectively from various
disubstituted alcohols. By utilization of 1,1-diarylprop-2-
yn-1-ol, 3-allenyl-2-amidobenzofurans were afforded in high
yield. Further investigation for the construction of other
heterocyclic and carbocyclic systems via this carbocation-
induced electrophilic cyclization reaction is ongoing in our
laboratory.
phenyl group with either an electron-donating or -with-
drawing group (entries 6À7), while R5 can be an aryl or
alkyl group (entries 4, 5, 8). Thus this reaction provided
access to benzofuran-substituted allenes which are impor-
tant synthons in modern organic synthesis.15
Acknowledgment. We are grateful to the National Natural
Science Foundation of China (Project No. 21102029) for
financial support.
The ESI-TOF MS analysis of the reaction mixture of 1b
and 2a showed the existence of a diphenylmethyl cation,
(15) (a) Krause, N.; Winter, C. Chem. Rev. 2011, 111, 1994. (b)
Aubert, C.; Fensterbank, L.; Garcia, P.; Malacria, M.; Simonneau, A.
Chem. Rev. 2011, 111, 1954. (c) Yu, S.; Ma, S. Angew. Chem., Int. Ed.
2012, 51, 3074.
(16) For the generation of keteniminium ions from ynamides, see:
(a) Zhang, Y.; Hsung, R. P.; Zhang, X.; Huang, J.; Slater, B. W.; Davis,
A. Org. Lett. 2005, 7, 1047. (b) Mulder, J. A.; Hsung, R. P.; Frederick,
M. O.; Tracey, M. R.; Zificsak, C. A. Org. Lett. 2002, 4, 1383.
Supporting Information Available. Spectroscopic data
for all new compounds. Detailed experimental proce-
dures. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 2, 2013
425