Ruthenium-catalyzed cyclization of 2-alkyl-1-ethynylbenzenes via a 1,5-hydrogen shift of ruthenium-vinylidene intermediates

Article abstract of DOI:10.1021/jo062573l

(Chemical Equation Presented) Catalytic cyclization of 2-alkyl-1- ethynylbenzene derivatives was implemented by TpRuPPh₃(CH ₃CN)₂PF₆ (10 mol %) in hot toluene (105 °C, 36-100 h) to form 1-substituted-1H-indene and 1-indanone products; such cyclizations proceeded more efficiently for substrates bearing electron-rich benzenes. We propose that the cyclization mechanism involves a 1,5-hydrogen shift of initial metal-vinylidene intermediate.

Full text of DOI:10.1021/jo062573l

Ruthenium-Catalyzed Cyclization of 2-Alkyl-1-ethynylbenzenes via a
1,5-Hydrogen Shift of Ruthenium-Vinylidene Intermediates
Arjan Odedra, Swarup Datta, and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua UniVersity, Hsinchu, Taiwan, 30043, Republic of China
rsliu@mx.nthu.edu.tw
ReceiVed December 15, 2006
Catalytic cyclization of 2-alkyl-1-ethynylbenzene derivatives was implemented by TpRuPPh3(CH3CN)2PF6
(10 mol %) in hot toluene (105 °C, 36-100 h) to form 1-substituted-1H-indene and 1-indanone products;
such cyclizations proceeded more efficiently for substrates bearing electron-rich benzenes. We propose
that the cyclization mechanism involves a 1,5-hydrogen shift of initial metal-vinylidene intermediate.
SCHEME 1
Electrocyclization of polyenes across a benzene group occurs
less readily than for an alkene group because the former leads
to dearomatization of a benzene group.1 For instance, 6-π-
electrocyclization of cis-1,3,5-trienes normally occurs at 60-
100 °C2 whereas the same cyclization of 1,2-divinylbenzenes
requires severe conditions1 (300-350 °C). Although a 1,5-
hydrogen shift is well documented for cis-1,3-dienes,3,4 this
process remains virtually unknown for cis-3-en-1-ynes before
our report that TpRuPPh3(CH3CN)2PF6 (Tp ) tris(1-pyrazoly)-
borate) was an active catalyst for this cyclization to yield
cyclopentadiene derivatives.5 The mechanism of this cyclization
is confirmed to involve a 1,5-sigmatropic hydrogen shift of
ruthenium vinylidene intermediate A according to deuterium
labeling studies, as depicted in Scheme 1 (eq 1). This unique
(1) Lamberts, J. J. M.; Laarhoven, W. H. J. Org. Chem. 1984, 49, 100.
(2) Okamura, W. H.; Delera, A. R. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, UK, 1991; Vol.
5, Part 6.2, p 699.
(3) (a) Robin, M. J.; Guo, Z. O.; Samano, M. C.; Wnuk, S. F. J. Am.
Chem. Soc. 1999, 121, 1425. (b) Okamura, W. H.; Aurrecoechea, J. M.;
Gibbs, R. A.; Norman, A. W. J. Org. Chem. 1989, 54, 4072. (c)
Chandraratna, R. A. S.; Bayerque, A. L.; Okamura, W. A. J. Am. Chem.
Soc. 1983, 105, 3588.
deuterium distribution of cyclopentadiene product d3-2 derived
from 3-en-1-yne d3-1 cannot be rationalized according to a
reaction mechanism of the Murai-type.6 The success of this
ruthenium-catalyzed cyclization actually mimics thermal cy-
clization of cis-1,2,4-hexatriene, which occurs at 90 °C (eq 2)
close to the conditions (100 °C, toluene, 8-10 h) of ruthenium
catalysis.
(4) (a) Alabugin, I. V.; Manoharan, M.; Breiner, B.; Lewis, F. D. J. Am.
Chem. Soc. 2003, 125, 9329. (b) Kless, A.; Nendel, M.; Willsey, S.; Houk,
K. N. J. Am. Chem. Soc. 1999, 121, 4524. (c) Loncharich, R. J.; Houk, K.
N. J. Am. Chem. Soc. 1988, 110, 2089. (d) Hess, B. A., Jr.; Baldwin, J. E.
J. Org. Chem. 2002, 67, 6025. (e) Replogle, K. S.; Carpenter, B. K. J. Am.
Chem. Soc. 1984, 106, 5751.
(5) For the communication of this paper, see: Datta, S.; Odedra, A.;
Liu, R.-S. J. Am. Chem. Soc. 2005, 127, 11606. The content of that work
will not be repeatedly reported in this full account.
1H-Indene is an important building block for complex
bioactive molecules.7 To enhance the synthetic utility, in this
full account, we sought to achieve catalytic cyclization of
2-alkyl-1-ethynylbenzene derivatives to form 1H-indene prod-
ucts as depicted in eq 3. This cyclization appears to be more
(6) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826.
10.1021/jo062573l CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/03/2007
J. Org. Chem. 2007, 72, 3289-3292
3289

Odedra et al.
TABLE 1. Ruthenium-Catalyzed Cyclization of
2-Alkyl-1-ethynylbenzenes
SCHEME 2
SCHEME 3a,b
entry
1
benzenea
time, h
36
product (yields)b
X ) H, Y ) OMe
R ) Ph (11)
X ) OMe, Y ) H
R ) Ph (12)
X ) H, Y ) F
R ) Ph (13)
X ) F, Y ) H
R ) Ph (14)
X, Y ) -OCH2O-
R ) Ph (15)
X ) Y ) H
R ) n-C5H11 (16)
X ) H, Y ) OMe
R ) n-C5H11 (17)
X, Y ) -OCH2O-
R ) n-C5H11 (18)
X ) Y ) OMe
R ) n-C3H7 (19)
20A (85%)
21A (75%)
22A (55%)
23A (66%)
24 (A/B ) 3.1, 85%)
25A (38%)
26A (63%)
27A (87%)
28A (61%)
2
3
4
5
6
7
8
9
36
48
40
32
100
36
30
30
a Toluene, 105 °C, 10% catalyst, [substrate] ) 0.15 M. b Products were
given after separation from a silica column.
a Toluene, 105 °C, 10% catalyst, [substrate] ) 0.02 M. b Products were
given after separation from a silica column.
challenging because the intermediate A in the preceding
mechanism involves an electrocyclization across a benzene
group, which will retard a 1,5-sigmatropic shift (eq 3).8,9
Thermal cyclization of 2-alkyl-1-allenylbenzenes actually pro-
ceeds at 185 °C (eq 4),9 at which terminal alkynes are prone to
oligomerization in the presence of TpRuPPh3(CH3CN)2PF6.10
One approach to facilitate this ruthenium-catalyzed cyclization
is to place electron-donating groups X, Y at the benzene group
to stabilize transition state geometry C′ (Scheme 2). We envisage
that the pentadienyl fragment of this transition state should have
positive character because of its conjugation with the [Rud
CH2]+ fragment.
As shown in Scheme 3, we first examined cyclization of
ethynylbenzene 3 with TpRuPPh3(CH3CN)2PF6 catalyst (10 mol
%) in hot toluene (105 °C, 48 h), giving products in a messy
mixture, from which the desired indene derivative 7 was only
isolated in 11% yield. The low yield of indene 7 over a
protracted period reflects the difficulty of a 1,5-hydrogen shift;
we observed a serious polymerization in this case. We thought
that the PF6 salt was likely hydrolyzed by residual water to form
a phosphate species during prolonged heating of the reaction
solution.11 The use of SbF6 salt greatly enhanced the cyclization
efficiency, presumably via stabilization of the catalyst; this salt
led to a 64% yield of indene 7. The SbF6 salt also effected
cyclization of ethynylbenzenes 4-5 bearing a trifluoromethyl
and a methoxy group, respectively; the cyclized indenes 8 and
9 were obtained in respective yields of 46% and 69%. Benzene
derivative 6 bearing an o-methoxy is very suitable for this
cyclization to give the corresponding indene 10 in 81% yield.
To study the scope of this catalytic cyclization, we prepared
various 2-alkyl-1-ethynylbenzenes 11-19 via variation of the
X, Y, and R substituents of substrates; the results are depicted
in Table 1. The resulting indene products 20-28 were exclu-
sively obtained in 1-substituted-1H-indene regioisomer except
species 24 containing a 3-phenyl isomer 24B. Relative to the
preceding ethynylbenzene 3, the phenyl C(4) and C(5) methoxy
groups of substrates 11 and 12 worked as an activating group,
and increased the cyclized yields of indene products 21A and
22A in 85% and 75%, respectively. In contrast, benzene
substrates 13 and 14 bearing a fluoro substituent at the same
carbon showed no enhancement of the cyclization efficiency.
Benzene derivative 15 bearing a methylenedioxy group was
cyclized efficiently to give the desired indene 24 as a mixture
of two regioisomer isomers. We further examined this cycliza-
tion on benzene species 16-19 bearing an n-pentyl or n-propyl
group. For species 16, completion of the cyclization required a
prolonged period (100 h) in hot toluene (105 °C); the yield was
only 38%. With an activating methoxy group at the phenyl C(4)
and C(5) carbons, the cyclization efficiency of benzene sub-
strates 17-19 was significantly improved, and the corresponding
indene products 26A-28A were obtained in 61-87% yields.
(7) For selected examples, see: (a) Xi, Z.; Guo, R.; Mito, S.; Yan, H.;
Kanno, K.-i.; Nakajima, K.; Takahashi, T. J. Org. Chem. 2003, 68, 1252.
(b) O’Brien, X. M.; Parker, J. A.; Lessard, P. A.; Sinskey, A. J. Appl.
Microbiol. Biotechnol. 2002, 59, 389.
(8) For example, the 1,5-hydrogen shift proceeds rapidly for cyclopen-
tadiene framework at ambient temperatures, but it becomes very difficult
in an indene structure. See the following review: Spangler C. W. Chem.
ReV. 1976, 76, 187.
(9) Heimgartner, H.; Zsindely, J.; Hansen, H.-J.; Schmid, H. HelV. Chim.
Acta 1973, 56, 305.
(10) Examples for generation of catalytic vinylidene intermediates using
TpRuPPh3(CH3CN)2PF6, see selected examples: (a) Lian, J.-J.; Odedra,
A. Wu, C.-J.; Liu, R.-S. J. Am. Chem. Soc. 2005, 127, 4186. (b) Madhushaw,
R. J.; Lo, C.-Y.; Su, M. D.; Shen, H.-C.; Pal, S.; Shaikh, I. R.; Liu, R.-S.
J. Am. Chem. Soc. 2004, 126, 15560. (c) Shen, H.-C.; Pal, S.; Lian J.-J.;
Liu, R.-S. J. Am. Chem. Soc. 2003, 125, 15762. (d) Datta, S.; Chang, C.-
L.; Yeh, K.-L.; Liu, R.-S. J. Am. Chem. Soc. 2003, 125, 9294.
-
(11) For BF4-, PF6-, and SbF6 anions, these salts may undergo
dissociation at elevated temperatures, MFn+1- f MFn + F-. In this catalytic
system, BF4-and PF6- are more prone to this dissociation than SbF6-, and
residual water will cause hydrolysis of the resulting BF3 and PF5 species
to form borate and phosphate. See: (a) Krossing, I.; Raabe, I. Chem. Eur.
J. 2004, 10, 5017. (b) Krossing, I.; Raabe, I. Angew. Chem., Int. Ed. 2004,
43, 2066.
3290 J. Org. Chem., Vol. 72, No. 9, 2007

Ru-Catalyzed Cyclization of 2-Alkyl-1-ethynylbenzenes
TABLE 2. Ruthenium-Catalyzed Cyclization of Siloxy-Containing
3-En-1-ynes and Ethynylbenzenes
SCHEME 4
SCHEME 5
species, which was a preceding intermediate for metal vinylidene
intermediates.12 For compound 37 bearing a deuterated benzyl
group, its resulting indene 46A has full deuterium content each
at the C(1) and C(2) carbons, respectively. In entry (2), we did
not obtain indanone 46B from ruthenium-catalyzed isomeriza-
tion of indene 46A, likely due to the kinetic isotopic effect.13
Scheme 5 shows a plausible mechanism to rationalize
deuterium-labeling experiments as well as the results in Tables
1 and 2. The distribution of cyclized product d2-46A has a
distinct deuterium distribution from those of d2-2 because of
different structural frameworks. The deuterium labeling experi-
ment in Scheme 4 (entry 1) indicates the involvement of
ruthenium-vinylidene species C, which undergoes a 1,5-
hydrogen shift to give ruthenium-containing 1,3,5-hexatriene
D. A subsequent 6-π-electrocyclization2 of species D is expected
to generate ruthenium-containing cyclohexadiene E, which
undergoes reductive elimination to produce the observed
1-substituted-1H-indene 46A rather than their 3-substituted-
indene isomers. This proposed mechanism rationalizes not only
the preceding deuterium-labeling experiments but also the
observed indene regioselectivity depicted in Table 1.
a 105 °C, toluene, 10% catalyst, [substrate] ) 0.02 M. b Products were
given after separation from a silica column.
The scope of our previous ruthenium-catalyzed cyclization
of cis-en-1-ynes is restricted to unfunctionalized substrates.5
Table 2 manifests the synthetic values of this new cyclization,
which provides cyclopentenones, 1H-1-indanones, or 1H-1-
indenols from cis-en-1-ynes 29-33 and 2-alkyl-1-ethynylben-
zenes 34-37 bearing a siloxy group. In these reactions, a dilute
solution of substrate (0.02 M) was used to reduce polymerization
of alkyne substrates. The cyclization of 3-en-1-ynes 29-33 was
completed in short periods (20 h) in hot toluene (105 °C), and
gave cyclopentenone derivatives 38-42 in reasonable yields
(58-65%, entries 1-5). In the absence of a methoxy group,
cyclization efficiency of ethynylbenzene 34 was low over a 48-h
period to give its cyclized 1-indanone 43B in 38% yield. For
electron-rich benzenes 35-37, their phenyl methoxy groups
facilitate the cyclization, and gave 1-indanones 44B and 45A
and 1-siloxyindenes 46A and 46B with better yields (entries
7-9). The results in entry 10 suggest that 1-indanone 46B seems
to arise from 1-siloxyindene 46A catalyzed by TpRuPPh3(CH3-
CN)2SbF6. In a separate experiment, we confirmed that treatment
of 1-siloxyindene 46A with this ruthenium catalyst (10 mol %)
in hot toluene (105 °C, 24 h) produced 1-indanone 46B in 53%
yield in addition to unreacted indene 46A(35%), whereas
1-siloxyindene 46A remained unreacted if it was heated alone
in toluene (105 °C, 24 h).
According to this proposed mechanism, the presence of an
electron-donating group at the phenyl X and Y of substrates is
expected to enhance the cyclization efficiency because of their
stabilization effect on transition state structure C′ during the
hydrogen shift. This speculation is consistent with our observa-
tion that methoxy derivatives 11, 12, 15, and 17-19 are much
more efficient in the cyclization than their unsubstituted benzene
analogues 3 and 16, and a similar trend was observed in Table
We performed deuterium-labeling experiments to characterize
the mechanism of cyclization. As depicted in Scheme 4,
ethynylbenzene 37 bearing an alkynyl deuterium produced its
cyclized 1H-indene 46A with deuterium content 65% at its
indenyl C(3) carbon (entry 1), indicative of a 1,2-hydrogen
shift.12 The loss of deuterium contents in this case is caused by
the exchange of residual water with alkynylmetal hydride
(13) We propose that the ruthenium-catalyzed transformation of 1-siloxy-
1H-indenes into 1-indanones presumably proceeds via a sequential 1,2-
hydride shift of intermediate. The discussion of this mechanism is provided
in the Supporting Information.
(12) Bustelo, E.; Carbo, J. J.; Lledos, A.; Mereiter, K.; Puerta, M. C.;
Valerga, P. J. Am. Chem. Soc. 2003, 125, 3311.
J. Org. Chem, Vol. 72, No. 9, 2007 3291

Odedra et al.
SCHEME 6
reduced pressure and residue was subjected to column to afford 47
(1.61 g, 6.5 mmol) in 65% yield.
(b) Synthesis of ((2-Benzylphenyl)ethynyl)trimethylsilane (48).
To a dry toluene (20 mL) solution of Pd(PhCN)2Cl2 (36 mg, 0.11
mmol) and CuI (21 mg, 0.11 mmol) was added P(t-Bu)3 (44 mg
0.22 mmol), HN(i-Pr)2 (0.47 g, 4.69 mmol), bromo compound 47
(0.89 g, 3.61 mmol), and trimethylsilyl acetylene (0.42 g, 4.33
mmol), and this mixture was stirred at room temperature for 10 h.
The reaction mixture was diluted with hexane (40 mL), filtered
through a small silica pad, concentrated, and purified by flash
chromatography, to yield the desired product 48 (0.81 g, 85%) as
a colorless oil.
2. The formation of cyclopentenones from 5-siloxy-3-en-1-ynes
29-33 is not surprising because a 1,5-sigmatropic shift occurs
rapidly on a cyclopentadiene framework3,4 at ambient temper-
atures as depicted in Scheme 6. This shift should be very
difficult for indene structure at 100 °C but we observed a
transformation of 1-siloxy-1H-indene 46A into 1-indanone 46B
catalyzed by TpRuPPh3(CH3CN)2SbF6 (vide infra). We tenta-
tively proposed that this isomerization is caused by a sequential
1,2-hydride shift of carbocationic intermediate H,14 and the
speculated mechanism is provided in the Supporting Informa-
tion.
In summary, we report from this investigation the feasibility
of a through-benzene 1,5-hydrogen shift activated by a cationic
ruthenium-vinylidene intermediate. This new key step allows
catalytic cyclization of 2-alkyl-1-ethynylbenzene derivatives to
form 1-substituted-1H-indene products. This proposed mecha-
nism rationalizes not only key deuterium-labeling experiments
but also the observed indene regioselectivity. The synthetic value
of this new cyclization is manifested by its efficient synthesis
of cyclopentenones, 1H-1-indanones, and 1H-1-indenols. Further
use of this new method to construct the complex carbocyclic
framework is under current investigation.
(c) Synthesis of 1-Benzyl-2-ethynylbenzene (3). To a methanol/
dichloromethane solution (20 mL, 2:1, v/v) of 48 (0.81 g, 3.06
mmol) was added K2CO3 (0.507 g, 3.67 mmol), and resulting
mixture was stirred at 25 °C for 2 h. The mixture was quenched
with water, and the organic layer was extracted with ether (3 × 20
mL), washed with saturated NaCl solution, dried over MgSO4, and
concentrated under reduced pressure. The residues were chromato-
graphed on a silica column to afford pure 3 (0.54 g, 2.81 mmol) in
92% yields. IR (neat, cm-1): 2952 (s), 2103 (w), 1599 (s). 1H NMR
(600 MHz, CDCl3): δ 7.55 (d, 1 H, J ) 7.8 Hz), 7.33-7.16 (m,
8 H), 4.23 (s, 2 H), 3.29 (s, 1 H). 13C NMR (150 MHz, CDCl3):
δ 143.6, 140.4, 132.8, 129.3, 128.9, 128.3, 126.0, 121.7, 82.5, 81.1,
39.9. HRMS calcd for C15H12 192.0939, found 192.0939.
(2) Representative Procedures for Catalytic Reaction: (A)
Ruthenium-Catalyzed Synthesis of Indene 7. To a toluene
solution (0.15 M) of ethynyl benzene 3 (100 mg, 0.52 mmol) was
added TpRuPPh3(CH3CN)2SbF6 (46 mg, 0.052 mmol), and the
mixture was heated at 105 °C for 36 h. The reaction mixture was
passed through a short silica pad with hexane as eluent to remove
catalyst. The solvent was removed under reduced pressure and the
residue was chromatographed on a silica column to afford indene
7 (62 mg, 32 mmol, 62%) as a colorless oil. IR (neat, cm-1): 3068
Experimental Section
(1) Representative Procedure for Preparation of 2-Alkyl-1-
Ethynylbenzenes: (A) Synthesis of 1-Benzyl-2-ethynylbenzene
(3).
1
(s), 2885 (w), 1610 (s). H NMR (600 MHz, CD2Cl2): δ 7.38 (d,
1 H, J ) 7.2 Hz), 7.26-7.19 (m, 3 H), 7.13-7.08 (m, 2 H), 6.90
(s, 1 H), 6.58 (s, 1 H), 4.61 (s, 1 H). 13C NMR (150 MHz, CD2-
Cl2): 148.7, 144.5, 140.1, 139.9, 131.9, 129.1, 128.1, 127.2, 125.6,
124.2, 121.6, 56.9. HRMS calcd for C15H12 192.0939, found
192.0939.
(B) Ruthenium-Catalyzed Cycloisomerization of Siloxy-Con-
tanining 3-En-1-ynes: Synthesis of Cyclopentenone 38. To a
toluene solution (0.02 M) of enyne 29 (100 mg, 0.40 mmol) was
added TpRuPPh3(CH3CN)2SbF6 (36 mg, 0.04 mmol), and the
mixture was heated at 105 °C for 20 h. The solution was passed
through a short silica column (ether) to remove catalyst. Solvent
was removed under reduced pressure and column chromatography
on silica gel (hexane:EtOAc, 10:1) afforded pure cyclopentenone
38 (34 mg, 0.25 mmol, 63%). IR (neat, cm-1): 2930 (w), 2850
(a) Synthesis of 1-Benzyl-2-bromobenzene (47). In a pressure
tube, 2-bromobenzyl alcohol (1.87 g, 10.0 mmol) and FeCl3 (10
mol %, 0.05 mmol) were dissolved in benzene (20 mL). After being
stirred for 12 h at 100 °C the reaction mixture was passed though
short silica pad with ether as eluent. Solvent was removed under
1
(w), 1695 (s), 1645 (m). H NMR (400 MHz, CDCl3): δ 2.46-
2.40 (m, 2 H), 2.31 (t, 2 H, J ) 4.4 Hz), 2.29-2.25 (m, 2 H),
2.08-2.03 (m, 2 H), 1.69-1.63 (m, 2 H), 1.61-1.56 (m, 2 H). 13
C
NMR (100 MHz, CDCl3): δ 209.0, 173.6, 138.6, 34.4, 30.0, 28.5,
22.0, 21.6, 19.9. HRMS calcd for C9H12O 136.0888, found
136.0890.
(14) Sames et al. recently reported a unique Lewis acid-catalyzed
hydroalkylation of electron-deficient alkenes,15 indicating the feasibility of
a through-space 1,5-hydride shift. We cannot exclude this mechanism
because our experimental results in this work are also compatible with a
through-space 1,5-hydride shift. We prefer the classical 1,5-hydrogen shift
because it was reported for 2-alkyl-1-allenylbenzenes at 185 °C.9
Acknowledgment. The authors wish to thank National
Science Council, Taiwan, for support of this work.
Supporting Information Available: Mechanistic discussion of
the isomerization between species 46A and 46B,14 experimental
procedures for the synthesis of 2-alkyl-1-ethynylbenzene substrates,
NMR spectra, and spectral data for compounds 4-46B. This material
is available free of charge via the Internet at http://pubs.acs.org.
(15) Pastine, S. J.; McQuaid, K. V.; Sames, D. J. Am. Chem. Soc. 2005,
127, 12180.
JO062573L
3292 J. Org. Chem., Vol. 72, No. 9, 2007