Catalytic cyclization of o-alkynylbenzaldehyde acetals and thioacetals. Unprecedented activation of the platinum catalyst by olefins. Scope and mechanism of the reaction

Article abstract of DOI:10.1021/ja044603c

A general protocol for the synthesis of functionalized indenes from o-alkynylbenzaldehyde acetals and thioacetals has been elaborated. Acetals uniformly give cyclization products having the alkyl group from the starting acetylene migrated to the α-position, whereas the cyclization of the corresponding thioacetals proceeds without alkyl migration. Optimization of the catalytic system for the cyclization of o-alkynylbenzaldehyde acetals revealed an unknown activation effect: PtCl₂ was found to be a better catalyst for the cyclization of acetals in the presence of olefins than without. A similar catalytic system (PtCl₂/ benzoquinone) has been found to be appropriate for the cyclization of cyclic acetals, whereas the optimal catalyst for the reaction of thioacetals is PdI₂. NMR monitoring of two reactions, acetal 3a + Pd(CH₃CN)-Cl₂ in CD₃CN and thioacetal 5j + PdI₂ in CD₂Cl₂, revealed that in both reactions similar cationic species are formed at the early stage of the transformation. Computational data (B3LYP/SDD level of theory) suggest that the difference in the reaction pathways for acetals and thioacetals can be rationalized by taking into account the relative stabilities of the corresponding vinylpalladium intermediates (22 vs 20 and 19 vs 21), which suggests a reversible thermodynamically controlled alkyl migration in the intermediate vinylcationic species.

Full text of DOI:10.1021/ja044603c

Published on Web 11/04/2004
Catalytic Cyclization of o-Alkynylbenzaldehyde Acetals and
Thioacetals. Unprecedented Activation of the Platinum
Catalyst by Olefins. Scope and Mechanism of the Reaction
Itaru Nakamura, Gan B. Bajracharya, Huanyou Wu, Kengo Oishi, Yuya Mizushima,
Ilya D. Gridnev,* and Yoshinori Yamamoto*
Contribution from the Department of Chemistry, Graduate School of Science,
Tohoku UniVersity, Sendai 980-8578, Japan
Received September 6, 2004; E-mail: yoshi@yamamoto1.chem.tohoku.ac.jp
Abstract: A general protocol for the synthesis of functionalized indenes from o-alkynylbenzaldehyde acetals
and thioacetals has been elaborated. Acetals uniformly give cyclization products having the alkyl group
from the starting acetylene migrated to the R-position, whereas the cyclization of the corresponding
thioacetals proceeds without alkyl migration. Optimization of the catalytic system for the cyclization of
o-alkynylbenzaldehyde acetals revealed an unknown activation effect: PtCl2 was found to be a better catalyst
for the cyclization of acetals in the presence of olefins than without. A similar catalytic system (PtCl2/
benzoquinone) has been found to be appropriate for the cyclization of cyclic acetals, whereas the optimal
catalyst for the reaction of thioacetals is PdI2. NMR monitoring of two reactions, acetal 3a + Pd(CH3CN)-
Cl2 in CD3CN and thioacetal 5j + PdI2 in CD2Cl2, revealed that in both reactions similar cationic species
are formed at the early stage of the transformation. Computational data (B3LYP/SDD level of theory) suggest
that the difference in the reaction pathways for acetals and thioacetals can be rationalized by taking into
account the relative stabilities of the corresponding vinylpalladium intermediates (22 vs 20 and 19 vs 21),
which suggests a reversible thermodynamically controlled alkyl migration in the intermediate vinylcationic
species.
Introduction
The nature of the reaction product is considered to be defined
by the properties of the resulting vinylpalladium intermediates
and the nucleophiles present in the reaction mixture. The product
can be formed directly via reductive elimination from the
initially formed vinylpalladium intermediates, or the vinylpal-
ladium intermediates can rearrange into further intermediate
species, insert CO, or interact with other substrates present in
the reaction mixture prior to the reductive elimination regenerat-
ing the catalyst.
Intramolecular palladium-catalyzed cyclization of alkynes is
a useful tool for the synthesis of five-membered carbo- and
heterocycles.1 The heterocyclic products include unsaturated
lactones,2 furans,3 pyrroles, and indoles,4 whereas the carbocy-
clizations of this type provide a convenient approach to highly
functionalized cyclopentanes5 (Scheme 1). These reactions are
usually thought to proceed via the initial formation of pal-
ladium-alkyne π-complexes, which undergo nucleophilic attack
of G (C, N, O nucleophiles).1
Despite the large amount of synthetic studies for this type of
the catalytic cycle, experimental evidence supporting the
structure of the reactive intermediates is still lacking. Although
several palladium-alkyne π-complexes of either Pd0 or PdII
have been characterized,6 we are unaware of any experimental
studies of the mechanism of the Pd-catalyzed cyclizations of
alkynes.
(1) Recent review: Takacs, J. M.; Vayalakkada, S.; Jiang, X. Science of
Synthesis; Thieme: Stuttgart, Germany, 2003; Vol. 1, pp 265-318.
(2) (a) Lambert, C.; Utimoto, K.; Nozaki, H. Tetrahedron Lett. 1984, 25, 5323.
(b) Mandai, T.; Ohta, K.; Baba, N.; Kawada, M.; Tsuji, J. Synlett 1992,
671. (c) Tsuda, T.; Ohashi, Y.; Nagahama, N.; Sumiya, R.; Saegusa, T. J.
Org. Chem. 1988, 53, 2650. (d) Arcadi, A.; Burini, A.; Cacchi, S.;
Delmastro, M.; Marinelli, F.; Pietroni, B. R. J. Org. Chem. 1992, 57, 976.
(3) (a) Wakabayashi, Y.; Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki, H.
Tetrahedron 1985, 41, 3655. (b) Schabbert, S.; Schaumann, E. Eur. J. Org.
Chem. 1998, 1873. (c) Gabriele, B.; Salerno, G.; De Pascali, F.; Costa,
M.; Chiusoli, G. P. J. Organomet. Chem. 2000, 593, 409. (d) Gabriele, B.;
Salerno, G.; De Pascali, F.; Sciano, G. T.; Costa, M.; Chiusoli, G. P.
Tetrahedron Lett. 1997, 38, 6877. (e) Gabriele, B.; Salerno, G.; De Pascali,
F.; Costa, M.; Chiusoli, G. P. J. Org. Chem. 1999, 64, 7693. (f) Monteiro,
N.; Balme, G. Synlett 1998, 746. (g) Cacchi, S.; Fabrizi, G.; Moro, L. Synlett
1998, 741. (h) Arcadi, A.; Cacchi, S.; Larock, R. C.; Marinelli, F.
Tetrahedron Lett. 1993, 34, 2813. (i) Cacchi, S.; Fabrizi, G.; Moro, L. J.
Org. Chem. 1997, 62, 5327.
Recently we have reported a palladium-catalyzed intramo-
lecular carbalkoxylation reaction accompanied by an unprec-
edented 1,2-alkyl migration (eq 1).7 It should be noted that such
(4) (a) Iritani, K.; Matsubara, S.; Utimoto, K. Tetrahedron Lett. 1988, 29, 1799.
(b) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1992, 33, 3915.
(c) Luo, F.-T.; Wang, R.-T. Tetrahedron Lett. 1992, 33, 6835. (d) Cacchi,
S.; Fabrizi, G.; Pace, P. J. Org. Chem. 1998, 63, 1001. (e) Cacchi, S. J.
Organomet. Chem. 1999, 576, 42. (f) Kamijo, S.; Yamamoto Y. J. Org.
Chem. 2003, 68, 4764.
9
10.1021/ja044603c CCC: $27.50 © 2004 American Chemical Society
J. AM. CHEM. SOC. 2004, 126, 15423-15430
15423

A R T I C L E S
Scheme 1
Nakamura et al.
Table 1. Effect of the Olefin on the Reaction of 1aa
type of alkyl migration is a quite rare phenomenon in transition-
metal-catalyzed reactions. The only other alkyl migration
example we are aware of occurs during the rhodium-catalyzed
decomposition of some R-diazo esters.8
Here we report the scope of the catalytic carbocyclization
with respect to the substrates and reagent structures, nature of
the catalyst, and reaction conditions together with the mecha-
nistic details revealed by NMR interception of intermediates
and state-of-the-art DFT calculations.
entry
olefin
isolated yield, %
1
2
3
4
5
6
7
8
â-pinene
93
93
90
75
69
67
40
24
â-pineneb
â-pinenec
1,5-cyclooctadiene
2,3-dihydrofuran
cyclohexene
methylenecyclohexane
benzoquinone
maleic anhydride
R-pinene
9
12
11
9
10
11
12
13
Results and Discussion
2-ethyl-1-butene
1-octene
none
decomposition
no reaction
Scope of the Reaction and Modification of the Catalyst.
We have found that the catalytic carbocyclization can be carried
out for a wide range of the substrates, but in many cases
modification of the catalyst is required. Thus, although the
initially reported catalyst (PdCl2(CH3CN)2) gave acceptable
results with substrates 1a (R1 ) n-Pr, R2 ) Me), 1b (R1 )
n-Hex, R2 ) Me), 1j (R1 ) n-Pr, R2 ) Et), and 1k (R1 ) n-Pr,
R2 ) Bu), the yields were only moderate to low when applied
to the substrates 1c-i (Table 2, eq 1). Moreover, our attempts
to extend the scope of the reaction to the substrates containing
a bulkier acetal group (1l and 1m), various substituents on the
benzene rings (1n-r), or cyclic acetals (3a-g) using the same
catalyst system gave unsatisfactory results.
a The reaction of 1a (0.4 mmol) was carried out in the presence of 10
mol % of PtCl2 and 40 mol % of the olefin in acetonitrile at 30 °C. b 7 mol
% of PtCl2 and 28 mol % of â-pinene were used. c 7 mol % of PtCl2 and
14 mol % of â-pinene were used.
not proceed at all or was very sluggish. However, quite
unexpectedly it was discovered that the PtCl2-catalyzed reaction
of substrate 1g afforded the desired carbocyclization product
2g in 76% yield after 4 h at room temperature, compared to
only 23% yield (and longer reaction times) with PdCl2(CH3-
CN)2 (eq 2).
In our search for a better catalyst, we have tried several
palladium and platinum compounds (PdCl2, PdI2, PtCl2, PtBr2,
PtI2, and PtCl4). Despite these changes, the reaction either did
(5) (a) Monteiro, N.; Gore, J.; Balme, G. Tetrahedron 1992, 48, 10103. (b)
Monteiro, N.; Balme, G.; Gore, J. Synlett 1992, 227. (c) Monteiro, N.;
Gore, J.; Van Hemelryck, B.; Balme, G. Synlett 1994, 447. (d) Tsukada,
N.; Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1997, 36, 2477. (e) Marat,
X.; Monteiro, N.; Balme, G. Synlett 1997, 845.
(6) (a) Uson, R.; Fornies, J.; Tomas, M.; Menjon, B.; Welch A. J. J. Organomet.
Chem. 1986, 304, C24. (b) Pan, Y.; Mague, J. T.; Fink, M. J. Organome-
tallics 1992, 11, 3495. (c) Krause, J.; Bonrath, W.; Poerschke, K.-R.
Organometallics 1992, 11, 1158. (d) Fornies, J.; Gomez-Saso, M. A.;
Lalinde, E.; Martinez, F.; Moreno, M. T. Organometallics 1992, 11, 2873.
(e) Berenguer, J. R.; Fornies, J.; Lalinde, E.; Martinez, F. Organometallics
1996, 15, 4537. (f) Schager, F.; Bonrath, W.; Poerschke, K.-R.; Kessler,
M.; Kruger, C.; Seevogel, K. Organometallics 1997, 16, 4276.
(7) Nakamura, I.; Bajracharya, G. B.; Mizushima, Y.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2002, 41, 4328.
(8) (a) Ye, T.; McKervey, M. A. Tetrahedron 1992, 48, 8007. (b) Baudouy,
R.; Gore, J.; Ruest, L. Tetrahedron 1987, 43, 1099. (c) Baird, M. S.;
Hussain, H. H. Tetrahedron 1987, 43, 215. (d) Nagao, K.; Chiba, M.; Kim,
S. W. Synthesis 1983, 197.
Since the main structural feature distinguishing 1g from all
other substrates probed under the same conditions is the terminal
olefin functionality, we argue that PtCl2 might be activated in
the presence of olefins. Indeed, as detailed in Table 1, a number
of olefins are capable of promoting the catalytic carbocyclization
of 1a (eq 3). Moreover, when â-pinene was used as the
9
15424 J. AM. CHEM. SOC. VOL. 126, NO. 47, 2004

Synthesis of Functionalized Indenes from Acetals
A R T I C L E S
gave the corresponding tricyclic compound 4a in 55% yield
(entry 1). The reaction of 3a using â-pinene instead of
benzoquinone afforded 4a in 29% yield. The tricyclic com-
pounds 4b-g were obtained from the corresponding cyclic
acetals 3b-g in good to acceptable yields (entries 2-7). Since
cyclic acetals are generally more stable than acyclic acetals,
the reaction of 3 would require much longer reaction times and
more drastic conditions.
activating agent, the yield of the product was significantly higher
compared to our original reaction conditions (PdCl2(CH3CN)2,
entries 1-3). The reaction of 1a in the presence of catalytic
amounts of PdCl2(CH3CN)2 and â-pinene proceeded sluggishly,
affording 2a in 16% yield.
We have found that olefins activate platinum chloride as a
catalyst in the carbocyclization of alkynylacetals. The origin of
this effect is not clear, and we are not aware of other examples
of such activation in the literature. A possible explanation could
be formation of PtCl2(CH3CN)2 and replacement of the aceto-
nitrile ligands with the olefin. However, we have failed to find
Encouraged by these results, we have carried out the
carbocyclizations of the substrates 1a-r with the newly
designed and optimized catalytic conditions (eq 4, Table 2).
The reaction of the substrates 1a-d, which had an alkyl group
at the alkynyl moiety, gave the products 2a-d in good to
excellent yields (entries 1-4). Various functional groups, such
as bromo, ester, siloxy, alkenyl, phenyl, and nitro, were tolerated
in this reaction (entries 5-8, 16). The substrate 1i bearing a
terminal alkynyl group was converted to the product 2i in 81%
yield (entry 9). Not only the substrates bearing di-normal-alkyl
acetal group (1j and 1k) but also 1l and 1m, which had a bulkier
acetal group, reacted very smoothly (entries 10-13). The
reaction of 1n-p with an electron-withdrawing group on the
aromatic ring proceeded in a similar manner, while the reaction
of 1q and 1r, which had a methoxy group on the benzene ring,
was sluggish (entries 14-18).
1
any indication of such coordination in the H, 13C, and 195Pt
NMR spectra of the samples containing either PtCl2 and
â-pinene or PtCl2(CH3CN)2 and â-pinene in CD3CN. Besides,
the carbocyclization of 1a in the presence of PtCl2(CH3CN)2
occurred only very slowly. Addition of â-pinene accelerated
the reaction but far beyond the rate range obtained by the use
of the PtCl2/â-pinene system. Since PtCl2 is very insoluble in
acetonitrile (it can be dissolved by prolonged heating, yielding
PtCl2(CH3CN)2), heterogeneous catalysis cannot be excluded.
To expand the synthetic scope of the catalytic carbocycliza-
tion, we carried out the reaction with the structurally similar
thioacetals. Although PdCl2(CH3CN)2 was not an appropriate
catalyst, yielding complicated reaction mixtures after prolonged
heating, when the PtCl2/â-pinene system was applied to 5a in
acetonitrile a 55% yield of a new cyclization product (6a)
resulted. The new cyclization product is isomeric to the one in
the acetal case. Further variation of the catalyst showed that
A similar catalytic system (PtCl2/benzoquinone) was found
to be effective for the carbocyclization of the cyclic acetals 3
(eq 5, Table 3). The reaction of the cyclic acetal 3a in the
presence of 20 mol % of PtCl2 and 50 mol % of benzoquinone
Table 2. Catalytic Carbocyclization of Acyclic Acetals of o-Alkynylbenzaldehydes 1a
isolated yield, %
-pinenea
PtCl2/â PdCl2(CH3CN)2
b
entry
1
R1
R2
R3
2
1
2
1a
1b
1c
1d
1e
n-Pr
n-Hex
cyclohexyl
Me
Me
Me
Me
Me
Me
H
H
H
H
H
2a
2b
2c
2d
2e
93
96
87
62
85
75
65
52
11
45
3c,d
4c,d
5
(CH2)3OCOAr
(Ar ) p-BrC6H4)
6
1f
(CH2)3OTBS
Me
Me
Me
Me
Et
n-Bu
i-Pr
Bn
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
4-CF3
5-CF3
5-NO2
4-OMe
5-OMe
2f
76
81
92
81
85
91
89
69
76
87
65
12
trace
30
23
40
25
87
80
42
25
57
7
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
(CH2)3CHdCH2
Ph
H
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
8d
9
10
11
12d,e
13d,e
14
15
16f
17
18
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
52
29
no reaction
no reaction
a The reaction of 1 (0.4 mmol) was carried out in the presence of 7 mol % of PtCl2 and 28 mol % of â-pinene in acetonitrile (1.6 mL) at 30 °C. b The
reaction of 1 (0.5 mmol) was carried out in the presence of 10 mol % of PdCl2(CH3CN)2 in acetonitrile (2 mL) at 30 °C. c The reaction was carried out at
60 °C. d 14 mol % of PtCl2 and 56 mol % of â-pinene were used. e For 2 days. f For 20 h.
9
J. AM. CHEM. SOC. VOL. 126, NO. 47, 2004 15425

A R T I C L E S
Nakamura et al.
Table 3. Platinum-Catalyzed Carbocyclization of Cyclic Acetals of
o-Alkynylbenzaldehydes 3a
entry
3
n
R1
4
isolated yield,%
1
2
3
4
3a
3b
3c
3d
3e
3f
1
1
1
1
2
2
2
n-Pr
4a
4b
4c
4d
4e
4f
55
50
55
38
53
43
44
n-Bu
n-Hex
Ph
n-Pr
n-Bu
n-Hex
5b
6b
7b
3g
4g
a The reaction of 3 (0.5 mmol) was carried out in the presence of 20
mol % of PtCl2 and 50 mol % of benzoquinone in acetonitrile at 100 °C.
b 10 mol % of PtCl2 and 40 mol % of benzoquinone were used.
Figure 1. ORTEP drawing of 6l.
Table 4. Palladium-Catalyzed Carbocyclization of o-Alkynyl-
benzaldehyde Thioacetals 5a
in the carbocyclization of acetals and thioacetals. Minor
intermediate species with similar NMR spectra have been
observed in all reactions. Hence, our choice of the particular
reactions for the detailed NMR and computational studies has
been motivated rather by technical convenience than by the
performance of the catalytic system. Thus, although the catalytic
system PtCl2/â-pinene provided the best synthetic results, we
have failed so far to determine the nature of the active catalytic
species (vide infra), so we leave this question open for further
studies. On the other hand, when the carbocyclization of 1a in
the presence of PdCl2(CH3CN)2 was monitored in CD3CN, clean
formation of a single intermediate was observed (vide supra),
making this reaction an attractive goal for mechanistic studies.
Furthermore, the reaction of the thioacetal 5a catalyzed by PdI2
in CD2Cl2 was also quite clean, and the intermediacy of the
observed minor species was beyond any reasonable doubt. We
therefore have chosen these two reactions catalyzed by the same
metal for the comparative mechanistic study trying to reveal
the origin of the difference in the structures of the final products.
entry
5
R1
R2
6
isolated yield, %a
1
2
3
4
5
5a
5b
5c
5d
5e
5f
5g
5h
5i
n-Pr
n-Bu
Et
Et
Et
Et
Et
Et
Et
Et
Ph
Me
Ph
Ph
6a
6b
6c
6d
6e
6f
6g
6h
6i
95
95
97
80
97
95
98
92
34
93
70
85
n-Hex
Me
Ph
6b
7b
8b
9
p-MeC6H4
p-MeOC6H4
p-CF3C6H4
H
10
11
12
5j
5k
5l
n-Pr
n-Pr
Ph
6j
6k
6l
a The reaction of 5 (0.5 mmol) was carried out in the presence of 5 mol
% of PdI2 in CH2Cl2 at 30 °C. b At 60 °C.
The 1H spectrum taken immediately after addition of substrate
1a to a suspension of PdCl2(CH3CN)2 in CD3CN at room
temperature showed the presence of a species with a charac-
teristic low-field-shifted set of signals in the aromatic region
(e.g., Figure 2). The concentration of this new species was
1-3% from the total sample concentration (substrate + product
+ intermediate). This concentration was found to be ap-
proximately constant during the whole transformation. After all
the substrate had been consumed, the signals of the new species
disappeared from the NMR spectra. We conclude on the basis
of these observations that the observed low-concentration species
is an intermediate in the catalytic interconversion of 1a to 2a.
Its low concentration might be regulated by the relative rates
of its formation and decay (stationary kinetics); however, the
restricted solubility of the Pd complex might also be responsible
for the impossibility to acquire high concentrations of the
intermediate even if the reaction mixture was kept for a long
time at low temperatures.
this transformation can be carried out most effectively using 5
mol % of PdI2 in dichloromethane (eq 6). The results of the
reaction of the o-alkynylbenzaldehyde thioacetals 5 are sum-
marized in Table 4. The reaction of 5a-d, which had an alkyl
group at the alkynyl moiety, afforded 6a-d in 95, 95, 97, and
80% yields, respectively (entries 1-4). The reaction of the
dimethyl acetal of arylalkynylbenzaldehydes (5e-h), in which
the aromatic ring was substituted by an electron-withdrawing
group or electron-donating group at the para-position, proceeded
very smoothly (entries 5-8). The reaction of 5i having a
terminal alkynyl group proceeded sluggishly, producing 6i in
34% yield (entry 9). Dimethyl thioacetal 5j and diphenyl
thioacetals 5k and 5l were converted to 6j-l in good to excellent
yields (entries 10-12). The structures of 6 were explicitly
confirmed by spectral data, and the structure of 6l was
unambiguously confirmed by the X-ray crystallographic analysis
of 6l (Figure 1).
The minor second isomer of the reaction intermediate is
clearly seen in the 1H NMR spectrum (Figure 2, see asterisks);
the ratio of the isomers is 5:1 at 298 K. Dynamic effects
NMR Search for the Reaction Intermediates. Several
catalytic systems have been studied in the search for the
appropriate conditions for the characterization of intermediates
9
15426 J. AM. CHEM. SOC. VOL. 126, NO. 47, 2004

Synthesis of Functionalized Indenes from Acetals
A R T I C L E S
Figure 2. Section plot of the 1H NMR spectrum (600 MHz, 298 K, CD3CN)
of the reaction mixture prepared by adding 10 mg of 1a to a suspension of
8 mg of PdCl2(CH3CN)2 in 0.75 mL of CD3CN. The assignment of protons
1
was made from the H-1H COSY spectrum. The signals of minor isomer
are marked with asterisks.
Figure 3. Section plot (signals of the propyl group) of the 13C NMR
spectrum (150 MHz, 298 K, CD3CN) of the same reaction mixture as in
Figure 2; the signals of the low-concentrated intermediate are marked with
asterisk.
Figure 4. Molecular structures and optimized geometries (B3LYP/SDD)
of the coordination complexes 7, 8, and 9a,b.
observed upon variation of the temperature suggest that these
two isomers are interconverting reversibly in solution.
In the 13C NMR spectrum, some signals of the observed
intermediate were reliably detected by 2D C-H correlation
experiments. For example, Figure 3 demonstrates the absence
of any other species in the reaction mixture. Noteworthy was
the extremely high chemical shift of the CH(OMe)2 carbon (δ
) 168.2) in the intermediate. The chemical shifts of the four
CH carbons of the aromatic cycle were not remarkable (δ )
128.8, 125.9, 127.8, 130.5).
mode of the initial coordination of PdCl2 corresponds to the
structure 9b, which is approximately 5 kcal/mol more favorable
than 8 or 9a and 10 kcal/mol more stable than 7. This finding
illuminates the importance of the chelating coordination of
palladium in the catalytic cyclizations of functionalized alkynes,
which has often been suggested as a driving force of such
reactions.4f,9
To check if either of the coordination complexes can be
associated with the observed intermediate, we have computed
the 1H and 13C NMR chemical shifts (GIAO) for 7, 8, and 9a,b
and compared them with the experimentally observed values
(Table 5). The most characteristic chemical shifts of the
observed intermediate are δ(1H) and δ(13C) of the CH unit of
the acetal group (9.62 and 168.2 respectively), and δ(1H) of
the aromatic proton at the ortho-position to the acetal group
(9.26). As can be seen from Table 5, the computed chemical
shifts of compounds 7, 8, and 9a,b are quite different from those
of the experimentally observed intermediate species. In par-
ticular, the experimental chemical shifts are significantly more
strongly low-field-shifted, hinting at the more cationic character
of the observed intermediate. This conclusion prompted us to
look for intermediates with more clearly defined cationic centers,
such as 10a,b (Figure 5).
Addition of the thioacetal 5j to a suspension of PdI2 in CD2Cl2
at ambient temperature resulted in the formation of a low-
concentration species with the characteristic low-field signals
1
in the H NMR spectrum (singlet at δ ) 10.54 and doublet at
δ ) 9.66) quite similar to those of the intermediate in the
catalytic cyclization of 1a.
Computational Studies
Computational Assignment of the NMR-Detected Inter-
mediates. Since the low concentration of the detected transient
species precluded the unambiguous assignment of their struc-
tures solely by NMR, we approached this problem computa-
tionally using the available NMR data as a reference.
It is a generally accepted assumption that the Pd-catalyzed
cyclizations begin from the coordination of Pd to the nucleo-
philic center (or centers) of the substrate. We therefore looked
for the possible structures of such complexes. Figure 4 shows
the optimized structures of four intermediates (7, 8, and 9a,b)
corresponding to the initial coordination stage (Me-substituted
compound 1d has been used for the calculations).
The computed chemical shifts for the structures 10a and 10b
(Table 5) are in a reasonable accordance with the experimentally
observed intermediate species, reproducing well the significant
low-field shifts of the protons and carbon atom in the close
The relative energies of the coordination complexes 7, 8, and
9a,b are shown in Table 5. The least energetically demanding
(9) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto Y. J. Am. Chem. Soc.
2002, 124, 764.
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A R T I C L E S
Nakamura et al.
Table 5. Computed Relative Energies,a NMR Chemical Shifts (GIAO) of the Intermediates 7-10, and Experimental NMR Chemical Shifts
for the Transient Species Observed in the Reaction of 1a with PdCl2(CH3CN)2
compound
experimental
7
8
9a
9b
10a
10b
major
minor
relative energy, kcal/mol
δ(1H) acetal C-H
30.3
6.03
113.7
8.77
26.1
6.18
128.8
8.92
25.5
7.58
119.6
8.06
21.0
4.75
123.2
7.28
48.4
46.5
10.19
168.6
8.83
10.86
146.2
8.69
9.62
168.2
9.26
9.92
-
9.18
b
δ(13C) acetal C-H
δ(1H) o-H of Ar group
a The geometries were optimized at the B3LYP/SDD level of theory; all relative energies are referred to 1a + PdCl2(CH3CN)2. b Not detected.
If, on the other hand, not only the oxygen atoms in the
compound 10a were replaced with sulfur atoms, but simulta-
neously both chlorines were replaced with iodine atoms (yielding
a sulfur-PdI2 analogue 14), the optimization would predict
compound 11 (Scheme 2). Apparently, the larger size and
polarizability of the iodine compared to chlorine prevents the
occurrence of the irreversible exchange reaction similar to that
leading to the formation of 13.
Thus, the combined NMR data and computational results
suggest that both the carbocyclization of acetals accompanied
by 1,2-alkyl migration catalyzed by PdCl2(CH3CN)2 and the
carbocyclization of thioacetals proceeding without rearrange-
ment have common early intermediates (cationic species 10 and
Figure 5. Molecular structures and optimized geometries (B3LYP/SDD)
of the cationic complexes 10a,b.
11). Hence, the origin of the different structures of the reaction
products must be searched at the later stages of the reaction.
Computation of the Later Intermediates: Vinylpalladium
Species. Apparently, the next transformation of the cationic
species 10 (or 11) is the electrophilic attack by the cationic
center on the triple bond, formally yielding a vinyl cation, which
is further stabilized via the vinylpalladium intermediate. Facile
alkyl migrations are a well-known feature of vinyl cations.10
We argue, therefore, that the alkyl migration accompanying the
carbocyclization of acetals can occur at this stage of the reaction
(Scheme 3). If this is the case, the formation of different
vinylpalladium species 19 (from thioacetals) or 20 (from acetals)
can be explained by selective trapping of equilibrating vinyl
cations 16 and 18 or 15 and 17, respectively (Scheme 3). To
support this assumption, we optimized geometries of four
vinylpalladium species 19-22 (Figure 7). As can be seen from
Figure 7, the relative stabilities of vinylpalladium species 19-
22 are different for the two reactions: the vinylpalladium
intermediate 19 is 13.4 kcal/mol more stable than 21, which
could form by trapping of the rearranged vinyl cation 18
(Scheme 3). On the other hand, in the acetal case, the
vinylpalladium species 20, originating from the rearranged vinyl
cation 17, is 6.8 kcal/mol more stable than 22 produced directly
from 15. These data are in accord with the experimental outcome
of both reactions.
Figure 6. Structure of cationic intermediate 11 optimized at the B3LYP/
SDD level of theory.
vicinity of the carbocationic center. We consider that this is a
sufficient reason to suggest that two isomers of the intercon-
verting intermediates detected in the NMR spectra of the reaction
mixture have the corresponding structures.
Similarly, the low-field chemical shifts for the H(acetal) and
H(ortho) protons of the transient species observed in the course
of the reaction of thioacetal 5a catalyzed by PdI2 were in
accordance with cationic intermediate of type 11 (Figure 6).
Thus, we conclude that generation of cationic intermediates
10 or 11 is an essential condition for the occurrence of the
carbocyclization of o-alkynylbenzaldehyde acetals and thioac-
etals. This conclusion helps to explain the difference in outcomes
for the various catalytic systems. Thus, the cyclization of acetals
is catalyzed by the chloride derivatives of Pd or Pt, whereas
the cyclization of thioacetals requires palladium iodide as a
catalyst. If the oxygen atoms in the optimized structure of the
cationic intermediate 10a were replaced with sulfur atoms and
the resulting structure (12) was then used as an input for the
computations, compound 13 containing the covalent C-Cl bond
was obtained after the optimization (Scheme 2). This result can
be explained by stronger binding of Pd with sulfur (Pd-S bond
is stronger than the Pd-O bond), making the intermediate
cationic structure collapse into 13, thus stopping the catalytic
cycle.
Thus, the mechanistic study of the Pd-catalyzed carbocy-
clizations of alkynylacetals and thioacetals suggests that both
reactions proceed via cationic intermediates formed at the early
stage of the reaction from the Pd coordination complexes, in
which the triple bond and the acetal (or thioacetal) group are
both bonded to the metal. Ring closure of the cationic
intermediates leads to cyclic vinyl cations, which are further
stabilized via the vinylpalladium intermediates. The particular
structure of the products can be regulated by the relative
(10) For recent references, see: (a) Gronheid, R.; Lodder, G.; Ochiai, M.; Sueda,
T.; Okuyama, T. J. Am. Chem. Soc. 2001, 123, 8760. (b) Gronheid, R.;
Lodder, G.; Okuyama, T. J. Org. Chem. 2002, 67, 693.
9
15428 J. AM. CHEM. SOC. VOL. 126, NO. 47, 2004

Synthesis of Functionalized Indenes from Acetals
A R T I C L E S
Scheme 2
Scheme 3
thermodynamic stabilities of the vinylpalladium intermediates
formed from rearranged and non-rearranged cyclic vinyl cations.
formation of a real carbocationic center and palladate anion in
the course of the cyclizations reactions studied in this work.
Although the possibility of such charge separation in the Pd(II)-
catalyzed reactions was suggested quite early,11 we are unaware
of any published data supporting this possibility. Further
synthetic applications of Pd-catalyzed reactions involving the
carbocationic centers are being actively investigated in our
laboratory.
Conclusions
The synthetic results presented in this study demonstrate a
general strategy for building polycyclic molecules via transition-
metal-catalyzed cyclizations of ortho-functionalized phenyl-
acetylenes. A representative series of substrates has been
transformed into the corresponding functionalized indenes via
mild catalytic conditions. Moreover, using either acetals or
thioacetals as substrates allowed us to obtain selectively indenes
with alkyl substituents in different position. This observation
should find use in constructing various indenyl building blocks
for organic synthesis.
Mechanistic results obtained in the NMR and computational
studies confirm some long-existing assumptions but also bring
up previously unknown aspects of the mechanisms of Pd-
catalyzed reactions. Thus, we have demonstrated the importance
of the chelate coordination of palladium involving both the triple
bond and the acetal group for the occurrence of the reaction.
Furthermore, our NMR and computational data put forward the
Experimental Section
General Procedure of Carbocyclization of Acyclic Acetals 1. To
PtCl2 (7.4 mg, 0.028 mmol) and â-pinene (17 µL, 0.112 mmol) in 1.6
mL of acetonitrile was added the o-alkynylbenzaldehyde dialkyl acetal
1 (0.5 mmol) in 1 mL of acetonitrile under an Ar atmosphere in a
pressure vial. After being heated at 30 °C for 15 h, the reaction mixture
was filtered through a short silica gel column using ethyl acetate as an
eluent. Separation by silica gel column chromatography using hexane/
EtOAc (30/1) as an eluent afforded the products 2.
General Procedure of Carbocyclization of Cyclic Acetals 3. To
a mixture of PtCl2 (26.6 mg, 0.1 mmol), 1,4-benzoquinone (27.0 mg,
(11) Trost, B. M.; Tanoury, G. J. J. Am. Chem. Soc. 1988, 110, 1636.
9
J. AM. CHEM. SOC. VOL. 126, NO. 47, 2004 15429

A R T I C L E S
Nakamura et al.
reaction mixture was filtered through a short silica gel column using
ethyl acetate as an eluent. Separation by silica gel column chromatog-
raphy using hexane/EtOAc (100/1) as an eluent afforded the products
6.
Computational Details. Geometries of all stationary points were
optimized using analytical energy gradients of self-consistent-field12
and density functional theory (DFT).13 The latter utilized Becke’s three-
parameter exchange-correlation functional14 including the nonlocal
gradient corrections described by Lee, Yang, and Parr (LYP),15 as
implemented in the Gaussian 98 program package.16 All geometry
optimizations were performed using the SDD basis set.17
NMR chemical shifts were computed with the gauge-invariant atomic
orbital (GIAO) approach17 in conjunction with the B3LYP func-
tional.15,16 The absolute shifts (σ) of tetramethylsilane (TMS) were used
to compute the relative chemical shifts δ† ) σreference - σcompound
.
Supporting Information Available: Characterization data of
the products 2, 4, and 6 and Cartesian coordinates for the
intermediates 7-11 and 19-22. This material is available free
of charge via the Internet at http://pubs.acs.org.
JA044603C
(12) Pulay, P. In Modern Theoretical Chemistry; Schaefer, H. F., Ed.; Plenum:
New York, 1977; Vol. 4, p 153.
(13) Parr, R. G.; Yang, W. Density Functional Theory of Atoms and Molecules;
Oxford University Press: New York, 1989.
(14) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(15) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785.
(16) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann,
R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin,
K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi,
R.; Mennucci, B.; Pomelli, C., Adamo, C.; Clifford, S.; Ochterski, J.;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz,
J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng,
C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-
Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, Revision A.6;
Gaussian, Inc.: Pittsburgh, PA, 1998.
Figure 7. Molecular structures, optimized geometries (B3LYP/SDD), and
relative energies of the vinylpalladium intermediates 19-22.
0.25 mmol), and o-alkynylbenzaldehyde cyclic acetal 3 (0.5 mmol)was
added 2 mL of acetonitrile under an Ar atmosphere in a pressure vial.
After being heated at 100 °C for 1-7 days, the reaction mixture was
filtered through a short alumina column to remove catalyst from the
reaction mixture by using ethyl acetate as an eluent. The mixture was
then purified by silica gel column chromatography using a hexane/
ethyl acetate mixture as an eluent to afford the products 4.
(17) (a) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213. (b)
Dunning, T. H., Jr.; Hay, P. J. In Modern Theoretical Chemistry; Schaefer,
H. F., III, Ed.; Plenum Press: New York, 1977; Vol. 4. (c) Dolg, M. In
Modern Methods and Algorithms of Quantum Chemistry; Grotendorst, J.,
Ed.; John von Neumann Institute for Computing, Ju¨lich, 2000; Vol. 1, pp
479-508.
General Procedure of Carbocyclization of Thioacetals 5. To PdI2
(9.0 mg, 0.025 mmol) in 1 mL of CH2Cl2 was added the o-
alkynylbenzaldehyde dialkyl thioacetal 5 (0.5 mmol) under an Ar
atmosphere in a pressure vial. After being heated at 30 °C for 2 h, the
(18) Wolinski, K.; Hinton, J. F.; Pulay, P. J. Am. Chem. Soc. 1990, 112, 8251.
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15430 J. AM. CHEM. SOC. VOL. 126, NO. 47, 2004