Regioselective synthesis of indenols via nickel-catalyzed carbocyclization reaction

Article abstract of DOI:10.1021/jo0346508

2-Halophenyl ketones 1a-e (1a, o-IC₆H₄COCH ₃) undergo carbocyclization with alkyl propiolates (2a, CH ₃(CH₂)₄C≡CCO₂CH₃; 2b, TMSC≡CCO₂Et 2c, CH₃C≡CCO ₂CH₃; 2d, CH₃OCH₂C≡CCO ₂CH₃; 2e, CH₃(CH₂) ₃C≡CCO₂CH₃; 2f, PhC≡CCO ₂CH₃; and 2g, (CH₃)₃C≡CCO ₂CH₃) in the presence of Ni(dppe)Br₂ and zinc powder in acetonitrile at 80 °C to afford the corresponding indenol derivatives 3a-m with remarkable regioselectivity in good to excellent yields. The nickel-catalyzed carbocyclization reaction was successfully extended to other simple disubstituted alkynes. Thus, the reaction of2-halophenyl ketones 1a - e with disubstituted alkynes (2h, PhC≡CPh; 2i, CH₃C ₆H₄C≡CC₆H₄-CH₃; 2j, CH₃CH₂C≡CCH₂CH₃; 2k, PhC≡CCH₃; 21, TMSC≡CCH₃; and 2m, PhC≡C(CH₂)₃CH₃) proceeded smoothly to afford the corresponding indenols 4a-t in good to excellent yields. For unsymmetrical alkynes 2k-m, the carbocyclization gave two regioisomers with regioselectivities ranging from 1:2 to 1:12 depending on the substituents on the alkyne and on the aromatic ring of halophenyl ketone. A possible mechanism for this nickel-catalyzed carbocyclization reaction is also proposed.

Full text of DOI:10.1021/jo0346508

Regioselective Syn th esis of In d en ols via Nick el-Ca ta lyzed
Ca r bocycliza tion Rea ction
Dinesh Kumar Rayabarapu, Chun-Hui Yang, and Chien-Hong Cheng*
Department of Chemistry, Tsing Hua University, Hsinchu, Taiwan 300, ROC
chcheng@mx.nthu.edu.tw
Received May 15, 2003
2-Halophenyl ketones 1a -e (1a , o-IC6H4COCH3) undergo carbocyclization with alkyl propiolates
(2a , CH3(CH2)4CtCCO2CH3; 2b, TMSCtCCO2Et 2c, CH3CtCCO2CH3; 2d , CH3OCH2CtCCO2CH3;
2e, CH3(CH2)3CtCCO2CH3; 2f, PhCtCCO2CH3; and 2g, (CH3)3CtCCO2CH3) in the presence of
Ni(dppe)Br2 and zinc powder in acetonitrile at 80 °C to afford the corresponding indenol derivatives
3a -m with remarkable regioselectivity in good to excellent yields. The nickel-catalyzed carbo-
cyclization reaction was successfully extended to other simple disubstituted alkynes. Thus, the
reaction of2-halophenylketones 1a-e with disubstituted alkynes (2h ,PhCtCPh;2i,CH3C6H4CtCC6H4-
CH3; 2j, CH3CH2CtCCH2CH3; 2k , PhCtCCH3; 2l, TMSCtCCH3; and 2m , PhCtC(CH2)3CH3)
proceeded smoothly to afford the corresponding indenols 4a -t in good to excellent yields. For
unsymmetrical alkynes 2k -m , the carbocyclization gave two regioisomers with regioselectivities
ranging from 1:2 to 1:12 depending on the substituents on the alkyne and on the aromatic ring of
halophenyl ketone. A possible mechanism for this nickel-catalyzed carbocyclization reaction is also
proposed.
In tr od u ction
ladium-catalyzed carbocyclization of o-bromophenyl ke-
tones with disubstituted alkynes to give indenols.5 Our
continuous interest in nickel chemistry10-13 led us to
investigate the catalytic activity of nickel complexes for
carbocyclization reactions. In a preliminary communica-
tion, we reported that nickel complexes effectively cata-
lyzed the cyclization of o-iodophenyl ketones with propi-
The indenol moiety is an important and central struc-
tural unit present in various biologically active com-
pounds. Some indenol derivatives have shown analgesic
and myorelaxation activity,1 and others are used as
valuable intermediates for the synthesis of indenyl
chrysanthemates that possess insecticidal properties.2
Despite the high utility of indenols, only very few
synthetic routes are available in the literature.3-5 Re-
cently, transition-metal-catalyzed carbocyclization proved
to be a very powerful synthetic tool for the construction
of carbocycles with various ring sizes.6-9 Vicente and co-
workers reported stoichiometric and catalytic synthesis
of indenols from mono- and disubstituted alkynes and
organomercuric compounds in the presence of palladium
complexes,4 whereas Yamamoto et al. described a pal-
(6) For recent reviews on metal-catalyzed carbocyclization, see: (a)
Grotjahn, D. B. In Comprehensive Organomatallic Chemistry II;
Hegedus, L. S., Ed.; Pergamon/Elsevier Science: Kidlington, 1995; Vol.
12, pp 703, 741. (b) Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996,
96, 49. (c) Ojima, I.; Tzamarioudaki, M.; Li, Z. R.; Donovan, J . Chem.
Rev. 1996, 96, 635. (d) Fruhauf, H. W. Chem. Rev. 1997, 97, 523.
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Organometallics 1989, 8, 2550. (b) Larock, R. C.; Doty M. J .; Cachi, S.
C. J . Org. Chem. 1993, 58, 4579. (c) Padwa, A.; Krumpe, K. E.; Gareau,
Y.; Chiacchio, U. J . Org. Chem. 1991, 56, 2523.
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(b) Catellani, M.; Chiusoli, G. P.; Fagnola, M. F.; Salari, G. Tetrehedron
Lett. 1994, 35, 5923. (c) Larock, R. C.; Doty, M. J .; Han, X. J . Org.
Chem. 1999, 64, 8770 and references therein. (d) Liao, H.-Y.; Cheng,
C.-H. J . Org. Chem. 1995, 60, 3711.
(9) (a) (a) Larock, R. C.; Tian, Q.; Pletnev, A. A.J . Am. Chem. Soc.
1999, 121, 3238. (b) Larock, R. C.; Yum, E. K. J . Am. Chem. Soc. 1991,
113, 6689. (c) Larock, R. C.; Zennerr, J . M. J . Org. Chem. 1995, 60,
482. (d) Larock, R. C.; Yum, E. K.; Doty, M. J .; Sham, K. K. C. J . Org.
Chem. 1995, 60, 3270.
(10) (a) Rayabarapu, D. K.; Chiou, C.-F.; Cheng, C.-H. Org. Lett.
2002, 4, 1679. (b) Rayabarapu, D. K.; Cheng, C.-H. J . Am. Chem. Soc.
2002, 124, 5630.
(11) Rayabarapu, D. K.; Sambaiah, T.; Cheng, C.-H. Angew. Chem.,
Int. Ed. Engl. 2001, 40, 1286.
(12) (a) Shanmugasundaram, M.; Wu, M.-S.; Cheng, C.-H. Org. Lett.
2001, 3, 4233. (b) Majumdar, K. K.; Cheng, C.-H. Org. Lett. 2000, 2,
2295.
(13) (a) Huang, D.-J .; Rayabarapu, D. K.; Li, L.-P.; Sambaiah, T.;
Cheng, C.-H., Chem. Eur. J . 2000, 6, 3706. (b) Hsiao, T.-Y.; Santhosh,
K. C.; Liou, K.-F.; Cheng, C.-H. J . Am. Chem. Soc. 1998, 120, 12232.
(c) Sambaiah, T.; Huang, D.-J .; Cheng, C.-H. J . Chem. Soc., Perkin.
Trans. 1 2000, 195. (d) Sambaiah, T.; Li, L.-P.; Huang, D.-J .; Lin, C.-
H.; Rayabarapu, D. K.; Cheng, C.-H. J . Org. Chem. 1999, 64, 3663.
(1) (a) Kurakay Co. Ltd. J pn. Kokai Tokkyo Koho J P 81, 113, 740
(C1.C07C69/017), 7 Sept 1981; Chem. Abstr. 1982, 96, 68724b. (b)
Kurakay Co., Ltd. J pn. Kokai Tokkyo Koho J P 82 04,945 (C1. C07C69/
013), 11 J an 1982; Chem. Abstr. 1982, 96, 199935u.
(2) Samula, K.; Cichy, B. Acta Pol. Pharm. 1985, 42, 256; Chem.
Abstr. 1986, 105, 171931v.
(3) Other methods of indenol synthesis, see: (a) Liebeskind, L. S.;
Gasdaska, J . R.; MaCallum, J . S.; Tremont, S. J . J . Org. Chem. 1989,
54, 669. (b) Cambie, R. C.; Metzler, M. R.; Rutledge, P. S.; Woodgate,
P. D. J . Organomet. Chem. 1990, 381, C26. (c) Cambie, R. C.; Metzler,
M. R.; Rutledge, P. S.; Woodgate, P. D. J . Organomet. Chem. 1990,
398, C22. (d) Robinson, N. P.; Main, L.; Nicholson, B. K. J . Organomet.
Chem. 1989, 364, C37.
(4) (a) Vicente, J .; Abad J .-A.; Gil-Rubio, J . J . Organomet. Chem.
1992, 436, C9. (b) Vicente, J .; Abad J . A.; Rubio, J . G. Organometallics
1996, 15, 3509. (c) Vicente, J .; Abad, J . A.; Lopez-Pelaez, B.; Martinez-
Pivente, E. Organometallics 2002, 21, 58.
(5) (a) Quan, L. G.; Gevorgyan V.; Yamamoto, Y. J . Am. Chem. Soc.
1999, 121, 3545. (b) Quan, L. G.; Gevorgyan V.; Yamamoto, Y. J . Am.
Chem. Soc. 1999, 121, 9485. (c) Gevorgyan, V.; Quan L. G.; Yamamoto,
Y. Tetrahedron Lett. 1999, 40, 4089.
10.1021/jo0346508 CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/31/2003
6726
J . Org. Chem. 2003, 68, 6726-6731

Synthesis of Indenols via Ni-Catalyzed Carbocyclization Reaction
TABLE 1. Effect of Ca ta lyst a n d Solven t on th e
Ca r bocycliza tion of 1c w ith 2a a
SCHEME 1
entry
catalyst
solvent
yieldb (%)
1
2c
3d
4
5
6
7
8
9
10
11
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
DMF
0
0
0
Ni(dppe)Br2
Zn
Ni (PPh3)2Br2/Zn
Ni(dppm)Br2/Zn
Ni(dppe)Br2/Zn
Ni(dppb)Br2/Zn
Ni(bipy)Br2/Zn
Ni(dppb)Br2/Zn
Ni(dppe)Br2/Zn
Ni(dppe) Br2/Zn
26
57
86
21
trace
0
19
51
THF
a
Unless stated otherwise, all reactions were carried out using
o-iodophenyl ketone (1c) (0.50 mmol), methyl 2-octynoate (2a ) (1.5
equiv), Ni catalyst (5 mol %), and Zn (2.75 equiv) in solvent (3.0
b
mL) at 80 °C under N2 for 13 h. Yields of 3g were determined
by 1H NMR using mesitylene as an internal standard. c No Zn
d
powder was used in the reaction. No Ni catalyst was used in the
reaction.
propiolates 2b-e (2b, TMSCtCCO2Et; 2c, CH3CtCCO2-
CH3; 2d , CH3OCH2CtCCO2CH3; 2e, CH3(CH2)3CtCCO2-
CH3) in the presence of Ni(dppe)Br2 and Zn in acetonitrile
at 80 °C to provide the corresponding indenols 3b-e in
86, 74, 68, and 87% yields, respectively (Scheme 1, Table
2, entries 2, 3, 7, and 8). A small amount of homotrim-
erization product ([2 + 2 + 2]) of propiolate was observed
in the case of methyl 2-butynoate (2c). Similarly, 1a
underwent cyclization with 2f, PhCtCCO2CH3, smoothly
to afford the desired carbocycle 3f in 52% isolated yield.
In all reactions using substituted propiolates as the
alkyne substrates, only one regioisomer was detected in
the carbocyclization product. The regiochemistry of these
products suggests that the catalytic cyclization reaction
follows a Michael-type addition pattern and is governed
purely by the electronic properties rather than the steric
factor of substrate 2.
In a similar fashion, o-bromophenyl ketone (1b) un-
derwent cyclization with propiolates 2a -c smoothly to
give the corresponding indenols 3a -c, albeit in lower
yields (Table 2, entries 4-6). The present carbocyclization
can be extended to substituted o-iodophenyl ketones.
Thus, treatment of 1c bearing a methoxy group on the
aromatic ring with propiolates 2a and 2c provided the
corresponding substituted indenols 3g and 3h in 75 and
70% yields, respectively (Table 2, entries 10, 11), while
the reaction of 1c with propiolate 2g (CH3)3CCtCCO2-
CH3) bearing a sterically bulky tert-butyl group proceeded
readily affording the desired indenol 3i but in slightly
lower yield (entry 12). In addition to 1a -c, 1-(2-iodophen-
yl)-1-pentanone (1d ) underwent carbocyclization with
various propiolates 2a -c,f efficiently to give the desired
indenols 3j-m in 85, 82, 88, and 48% yields, respectively
(entries 13-16). Again, the carbocyclization reactions
(entries 10-16) are completely regioselective giving only
the Michael-type addition product.
olates to give 2,3-disubstituted indenols in moderate to
excellent yields with remarkably high regioselectivity.14
Herein, we report the details of these studies and the
results of the extension of this methodology to simple
disubstituted alkynes.
Resu lts a n d Discu ssion
Treatment of 2-iodoacetophenone 1a (0.50 mmol) with
methyl 2-octynoate 2a (1.5 equiv) in the presence of Ni-
(dppe)Br2 (dppe: bis(diphenylphosphino)ethane) (5 mol
%) and zinc metal powder (2.75 equiv) in acetonitrile (3.0
mL) at 80 °C for 13 h gave the corresponding 2,3-
disubstituted indenol 3a in 87% isolated yield. The
structure of 3a that is derived from one molecule of 1a
and 2a was confirmed by its 1H NMR, 13C NMR, and
mass data. The reaction is highly regioselective, affording
only a single regioisomer. The regiochemical assignment
of the propiolate moiety was carefully established on the
basis of the NOE experiments.14
To understand the nature of this nickel-catalyzed
carbocyclization, the effect of solvent and nickel com-
plexes used in the reaction of 1c with 2a was investi-
gated. The results are summarized in Table 1. As shown
in entries 1-3, in the absence of either nickel catalyst
or zinc powder, no cyclization product 3g was observed
(Table 1, entries 1-3). Several nickel complexes, Ni-
(PPh3)2Br2, Ni(dppm)Br2, Ni(dppe)Br2, Ni(bipy)Br2, and
Ni(dppb)Br2, were also tested for the catalytic activity
in acetonitrile. Among these complexes examined, Ni-
(dppe)Br2 is most active catalyst for the cyclization of 1c
with 2a furnishing 3g in 86% yield (entry 6), while other
nickel complexes gave 3g in 21-57% yields (entries 4-8).
The choice of solvent for the present catalytic reaction
has a profound effect on the yield of product 3g. Of the
solvents screened (acetonitrile, THF, toluene, and DMF),
only acetonitrile afforded a high yield of product 3g (entry
6). DMF and THF gave low to moderate yields (entries
10 and 11), while toluene was totally inactive (entry 9).
This nickel-catalyzed carbocyclization was successfully
extended to other substituted propiolates, and the results
are demonstrated in Table 2. Thus, 1a reacts with
The regiochemistry of products 3a -m was assigned on
the basis of the NOE experiments. As an example, the
results of NOE experiments of compound 3g are shown
in Figure 1. Selective irradiation of methyl protons at δ
1.62 led to the enhancement of the signals at δ 3.37 for
the hydroxy proton by 0.97% and at δ 7.37 for the
aromatic proton Hb by 0.83%, respectively, whereas
irradiation of the aromatic proton Ha at δ 6.90 resulted
in the enhancement of the signals at δ 3.80 for the
methoxy protons by 1.39% and at δ 2.84 for methylene
(14) Rayabarapu, D. K.; Cheng, C.-H. Chem. Commun. 2002, 942.
J . Org. Chem, Vol. 68, No. 17, 2003 6727

Rayabarapu et al.
TABLE 2. Resu lts of Nick el-Ca ta lyzed Ca r bocycliza tion of o-Ha lok eton e (1) w ith P r op iola tes (2)a
a
Unless stated otherwise, all reactions were carried out using o-halophenyl ketone (0.50 mmol), propiolate (1.50 equiv), Ni(dppe)Br2
b
(5.0 mol %), and Zn (2.75 equiv) in CH3CN (3.0 mL) at 80 °C under N2 (1 atm) for 13 h. Isolated yields; yields in the parentheses were
determined by 1H NMR using mesitylene as an internal standard.
powder in acetonitrile at 80 °C to give the correponding
indenol products. The results are summarized in Table
3. Treatment of diphenylacetylene (2h ) with 2-iodo-
acetophenone (1a ) and 2-iodo-3-methoxyphenyl ketones
(1c-e) in the presence of Ni(dppe)Br2 and zinc metal
powder afforded the desired indenols 4a -d in 87, 82, 80,
and 86% isolated yields, respectively (Table 3, entries 1,
3-5). Similarly, the reaction of 2i, CH3C6H4CtCC6H4-
CH3 with 1a and 1c-e provided the corresponding
indenol products 4e-h in 31, 54, 55, and 60% yields,
respectively (entries 6-9). The carbocylization reaction
also works with dialkylacetylenes. Accordingly, the reac-
tion of 2j, CH3CH2CtCCH2CH3 with 1a , 1c-e afforded
4i-l in 78, 54, 45, and 82% yields, respectively (entries
F IGURE 1.
10, 12-14). For the carbocyclization of simple unsym-
metrical alkynes, two regioisomers were formed as
anticipated due to the lack of strong electronic control
as observed for substituted propiolates (vide supra). Thus,
the reaction of 1a with PhCtCCH3 (2k ) afforded two
regioisomers 4m and 4m ′ in 70 and 23% yields, respec-
protons by 2.52%. These NOE results strongly support
the proposed structure of product 3g shown in Figure 1.
Simple disubstituted alkynes also react with o-halophen-
yl ketones in the presence of Ni(dppe)Br2 and zinc metal
6728 J . Org. Chem., Vol. 68, No. 17, 2003

Synthesis of Indenols via Ni-Catalyzed Carbocyclization Reaction
TABLE 3. Resu lts of Nick el-Ca ta lyzed Ca r bocycliza tion of 2-Ha lop h en yl Keton es 1 w ith Alk yn es 2a
a
Unless stated otherwise, all reactions were carried out using o-halophenyl ketone (0.50 mmol), alkyne (1.50 equiv), Ni(dppe)Br2 (5.0
b
mol %), and Zn (2.75 equiv) in CH3CN (3.0 mL) at 80 °C under N2 (1 atm) for 13 h. Isolated yields; yields in parentheses were determined
by 1H NMR using mesitylene as an internal standard. c Contains an inseparable mixture of two isomers.
J . Org. Chem, Vol. 68, No. 17, 2003 6729

Rayabarapu et al.
substrates shows that in most cases the major products
are the regioisomers (4m ,p -t) in which the alkyne
carbon bearing a less electron-donating group is con-
nected to the keto group of 1 and the alkyne carbon with
a more electron-donating substituent is attached to the
ortho carbon of aryl ketone moiety. The electron-donating
ability of the substituents in 2k -m are CH3 > Ph in
PhCtCCH3 (2k ); TMS > CH3 in TMSCtCCH3 (2l); and
CH3(CH2)3 > Ph in PhCtC(CH2)3CH3) (2m ). These
unsymmetrical disubstituted alkynes 2k -m do not have
a strong electron-withdrawing group like the ester func-
tionality in propiolates, but the Michael-type addition
pattern still dominates the product distribution and the
trend of regiochemistry is similar to that of propiolate
products. The regiochemistry for the carbocyclization of
1c with 2k is an exception (Table 3, entry 17). While the
exact reason is not known, the electron-donating ability
of methoxy group in 1c is likely responsible for the
observed reverse regioselectivity.
It is interesting to compare the difference between the
current nickel-catalyzed carbocyclization and the pal-
ladium-catalyzed reaction reported previously.5 The
present nickel catalyst is very effective for o-iodophenyl
ketones, while the palladium system prefers o-bromophe-
nyl ketones to the corresponding iodo substrates. Second,
the nickel catalyst system generally requires shorter
reaction time i.e., ca. 13 h at 80 °C for the completion of
reaction, whereas the reaction catalyzed by the palladium
system was carried out at 100 °C and requires much
longer reaction time. The low reducing power of KOAc/
DMF in palladium system relative to zinc metal in the
nickel system possibly accounts at least in part for the
long reaction time and higher temperature in the pal-
ladium-catalyzed reaction. Third, the nickel-catalyzed
carabocyclization appears to give slightly better yields
and regioselectivity when compared to the palladium-
catalyzed reactions. For example, the nickel system
afforded 4a in 87% yield while the palladium system
produced the same product in 63% yield. Similarly the
nickel system furnished 4m /4m ′ in 70% and 23% yields
respectively, whereas the palladium gave 4m and 4m ′
in 48% and 20% yields. Fourth, the Ni(dppe)Br2/Zn
system is very effective for the cyclization of o-halophenyl
ketones with propiolates, but the cyclization by palladium
complexes has not been explored previously.
F IGURE 2.
tively (Table 3, entry 15). The regiochemistry of these
two isomers 4m and 4m ′ was carefully assigned based
on the NOE experiments. For 4m , selective irradiation
of methyl protons at δ 1.47 led to the enhancement of
the signals at δ 7.41 aromatic protons by 5.51% and at δ
7.52 by 3.71%, respectively, whereas irradiation of the
methyl protons at δ 2.09 attached to the double bond
caused enhancement of the aromatic proton signals at δ
7.31 by 7.5% and at δ 7.52 by 6.27%. No NOE was
detected between the two methyl groups at δ 1.47 and δ
2.09. These NOE results strongly support the proposed
structure 4m shown in Figure 2.
For 4m ′, the selective irradiation of methyl protons at
δ 1.57 led to enhancement of the aromatic proton signal
at δ 7.48 by 3.51% and methyl proton signal at δ1.99 by
4.92%, respectively, whereas irradiation of the methyl
proton signal attached to the double bond at δ 1.99
resulted in enhancement of the signals at δ 7.45 by 8.71%
and at δ 1.57 by 7.12%. The strong NOE effect between
the two methyl groups at δ 1.57 and δ 1.99 clearly
support the proposed structure 4m ′ shown in Figure 2.
It is interesting to mention that the major product 4m
has the phenyl group next to the hydroxy moiety.
Treatment of 1c with 2k afforded two regioisomers 4n
and 4n ′ in 60 and 31% yields, respectively. Surprisingly,
the observed regiochemistry for 4n and 4n ′ is opposite
to that observed for 4m and 4m ′ (Table 3, entry 17). In
the present case, the major isomer 4n has two methyl
groups adjacent to each other, whereas the major isomer
4m has methyl group adjacent to phenyl group.
The nickel catalyst is also effective for the cyclization
of 2-bromoacetophenone (1b) with alkynes 2h -j (see
entries 2, 11, and 16), but the yields are comparably lower
than those from the corresponding iodo derivatives. Both
1a and 1b gave similar regioselectivity (the same major
product 4m ) when reacted with unsymmetrical alkyne
2k (entries 15 and 16).
The reaction of unsymmetrical acetylene 2l, TMSCt
CCH3, with 1a and 1c afforded two regioisomers 4p /4p ′
and 4q/4q′ in 47/6% and 62/5% yields, respectively
(entries 19 and 20). The regiochemistry of these isomers
was carefully assigned based on the NOE experiments.
Both the major isomers 4p and 4q have the TMS group
away from hydroxy and methyl groups. In a similar
fashion, the reaction of 1a with acetylene 2m , PhCt
C(CH2)3CH3), afforded two regioisomers 4r and 4r ′ in 80%
and 10% yields, respectively (Table 3, entry 21). Alkyne
2m also reacts with other iodophenyl ketones 1c and 1e
to furnish the corresponding regioisomers 4s/4s’ and 4t/
4t′ in 75/18% and 57/24% yields, respectively.
On the basis of the above observations and the known
organometallic chemistry of nickel, a catalytic cycle is
proposed as shown in Scheme 2. Reduction of Ni(II) to
Ni(0) by zinc metal powder15 is likely the first step and
initiates the catalytic cycle. Oxidative addition of aryl
iodide to nickel(0) species to yield nickel(II) intermediate
5. Regioselective insertion of alkyne (wherever applicable)
into the nickel-aryl bond generates a seven-membered
oxa-nickallocycle 7.16 Intramolecular nucleophilic addi-
tion of nickel-carbon bond of 7 to the carbonyl carbon
leads to a nickel alkoxide intermediate 8. Subsequent
transmetalation with zinc halide furnishes zinc alkoxide
9 and a Ni(II) species. Reduction of the latter by zinc
(15) (a) Kende, A. S.; Liebeskindand, L. S.; Braitsen, D. M. Tetra-
hedron Lett. 1975, 3375. (b) Zembayashi, M.; Tamao, K.; Yoshida, J .;
Kumada, M. Tetrahedron Lett. 1977, 4089.
(16) For nickel oxametallacycles, see: (a) Kimura, M.; Matsuo, S.;
Shibata, K.; Tamaru, Y. Angew. Chem., Int. Ed. 1999, 38, 3386. (b)
Sato, Y.; Takanashi, T.; Mori, M. Organometallics 1999, 18, 4891.
A careful examination of the regiochemistry for the
carbocyclization using unsymmetrical alkynes 2k -m as
6730 J . Org. Chem., Vol. 68, No. 17, 2003

Synthesis of Indenols via Ni-Catalyzed Carbocyclization Reaction
SCHEME 2. P r op osed Mech a n ism for th e Nick el-Ca ta lyzed Ca r bocycliza tion
metal regenerates the Ni(0) active catalyst. Zinc alkoxide
9 upon protonation is converted to the final product 3
and Zn(OH)X.
broad range of alkynes under relatively mild reaction
conditions.
Exp er im en ta l Section
The observation that a bidentate phosphine ligand
enhances the catalytic activity of nickel complex for
carbocyclization supports the presence of catalytic inter-
mediates 6 and 7 with cis structures.17 The cis arrange-
ment enhances the catalytic activity by promoting an
intramolecular nucleophilic addition in 7 to give carbo-
cyclization product 8. For nickel catalyst with monoden-
tate triphenylphosphine as ligand, the oxidative addition
of aryl halide to Ni(0) gives trans-NiL2(Ar)X because of
steric repulsion of the two phosphine ligands. The trans
structure remains even after insertion of an alkyne into
this Ni-Ar bond. Such a structure is unfavorable for
further carbocyclization.
All reactions were conducted under nitrogen on a dual-
manifold Schlenk line by using purified deoxygenated solvents
and standard inert-atmosphere techniques, unless otherwise
stated. Reagents and chemical were used as purchased without
further purification. Substituted 2-iodophenyl ketones were
prepared following literature procedures.18 The nickel catalysts
19a
Ni(PPh3)2X2 and Ni(dppe)Br219b were synthesized according
to reported procedures.
Gen er a l P r oced u r e for th e Cycliza tion of Ha loa r yl
Keton es 1 w ith Alk ylp r op iola tes 2. A round-bottom side-
arm flask (25 mL) containing o-iodoaryl ketone 1 (0.50 mmol),
Ni(dppe)Br2 (5.0 mol %), and zinc powder (2.75 equiv) was
evacuated and purged with nitrogen gas three times. Freshly
distilled CH3CN (3.0 mL) was added followed by addition of
propiolate 2 (1.5 equiv). The reaction mixture was heated with
stirring at 80 °C for 13 h, cooled and diluted with dichlo-
romethane, and stirred in the air for 15 min. The mixture was
filtered through a Celite and silica gel pad and washed with
dichloromethane several times. The filtrate was concentrated,
and the residue was purified on a silica gel column using
hexanes-ethyl acetate as eluent to afford the desired cycliza-
tion products 3.
Con clu sion
In conclusion, we have demonstrated that a nickel-
bidentate ligand system effectively catalyzes the carbo-
cyclization of o-halophenyl ketones with propiolates to
afford indenol derivatives in moderate to excellent yields
with remarkably high regioselectivity. This nickel-
catalyzed carbocyclization reaction is successfully ex-
tended to simple disubstituted alkynes furnishing highly
substituted indenols in moderate to good yields. The
present bidentate nickel catalyst system is active for a
Ack n ow led gm en t. We thank the National Science
Council of Republic of China (NSC 91-2113-M-007-053)
for support of this research.
Su p p or tin g In for m a tion Ava ila ble: NOE experimental
data for compounds 3a and 4n ,n ′,p ,q, the spectral data for
all compounds, 1H NMR spectra for compounds 3a ,b,e,g,i,k
and 4a ,b,e,j,l,m ,p ,p ′, and 13C NMR spectra of compounds 3a
and 4a ,i. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Similar kind of catalytic activity for nickel-bidentate ligand
system was observed for the arylation of aldehydes, see ref 12b.
(18) Hellwinkel, D.; Siegbert, S. Chem. Ber. 1987, 120, 1151.
(19) (a) Colquhoun, H. M.; Thompson, D. J .; Twigg, M. V. Carbo-
nylation; Plenum Press: New York, 1991. (b) Colquhoun, H. M.; Holton,
J .; Thompson, D. J .; Twigg, M. V. New Pathways for Organic Synthesis-
Practical Applications of Transition Metals; Plenum Press: New York,
1988.
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