Table 2: Pd-catalyzed 5-exo-dig carbocyclization of 1.
Further optimizations revealed that the employment of the
Pd(OAc)2 catalyst in combination with Ph3P ligand enabled
the exclusive 5-exo-dig carbocyclization of 1a, producing 2a
in 20% yield, as a single regio-[6] and stereoisomer (Table 1,
entry 5), albeit with unexpected E-geometry of the double
bond! Employment of BINAP resulted in a slight improve-
ment of the reaction yield (Table 1, entry 6). Use of 1,1’-
bis(diphenylphosphino)ferrocene (dppf) led to further
improvement of the reaction yield (Table 1, entry 7). Switch-
ing to electron-rich 1,1’-bis(diisopropylphosphino)ferrocene
(d-i-prpf) resulted in the dramatic improvement of the
reaction outcome (Table 1, entry 8).[5] Finally, employment
of 6 mol% d-i-prpf allowed us to obtain 2a in 95% yield
(Table 1, entry 9).
Next, the scope of this Pd-catalyzed cyclization was
examined (Table 2). We found that this reaction was efficient
for a wide range of alkynyl ketones 1, providing the
alkylidene indanones 2a–l as single E isomers in good to
excellent yields (Table 2). Various functional groups, such as F
(Table 2, entries 4, 9), OMe (Table 2, entries 3, 7, 14), Cl
(Table 2, entry 6), and CN (Table 2, entry 7) were perfectly
tolerated under the reaction conditions. Cyclization of
pyridine derivatives of o-alkynyl ketones occurred unevent-
fully as well, producing 2k (Table 2, entry 11) and 2l (Table 2,
entry 12) in 86% and 52% yield, respectively. Notably, the
Pd-catalyzed cyclization of o-alkynyl aryl ketones possessing
aryl substituents a to the carbonyl group (R1 = Ar) resulted in
formation of isomeric indenone structures 2m (Table 2,
entry 13) and 2n (Table 2, entry 14) in good yields. The
cyclization of a substrate possessing a fluorine substituent
ortho to the carbonyl function was effective as well, providing
indanone 2o in 75% yield (Table 2, entry 15).
Naturally, we were intrigued by the unexpected
E-geometry of the double bond in the product 2. Different
potential reaction pathways could account for the formation
of E-alkylidene indanone 2 from 1 in this Pd-catalyzed
cyclization reaction (Scheme 2). The first scenario (path A)
features a well-known p-philic activation of the triple bond in
1 with PdII catalyst (3)[2a,7] and subsequent intramolecular
5-exo-dig carbocyclization of the enol tautomer 4 to produce
trans-addition intermediate 5. Protiodepalladation of the
latter furnishes E-alkylidene indanone 2 directly. Alterna-
tively, the reaction may occur by the initial coordination of
the palladium catalyst to the carbonyl group in alkynyl ketone
1 to form 6, which upon deprotonation would produce a Pd
enolate species 7 (path B). The subsequent coordination of Pd
in 7 to the triple bond would form the alkyne-coordinated Pd
enolate 8. This species, upon intramolecular carbopalladation
of the triple bond, would lead to a vinylpalladium species 9.
The subsequent E–Z isomerization of the double bond[8]
would furnish isomeric vinylpalladium intermediate 5, which
upon protiodepalladation would produce E isomer 2.
Entry
1
Product
Yield
[%][a]
Entry
9
Product
Yield
[%][a]
92
98
93
98
93
69
76
71
98
86
86
52
73
81
75
2
3
4
5
6
7
8
10
11
12
13
14
15
[a] Yield of isolated product. See the Supporting Information for details.
these reaction conditions was observed.[10] This observation,
together with the shown earlier low efficiency of Pd(OAc)2
[9f]
alone to catalyzed this transformation, did not support the
possibility of the electrophilic path A for this transformation.
To further shed light on the possible reaction mechanism
of the Pd-catalyzed cyclization of o-alkynyl ketones, density
functional theory (DFT) calculations of the possible reaction
pathways A and B were performed (Scheme 3).[11] Accord-
ingly, pathway A was ruled out owing to the high free energy
(49.3 kcalmolÀ1) of the corresponding transition state from 4
to 5.[12] In contrast, pathway B, having the lower energy profile
and consisting of two major steps with nearly equivalent
energy barriers (TS-1 and TS-2), was found to be the most
probable pathway for this transformation.[12] Thus, reaction
starts with the formation of a complex 6 upon slightly
endothermic coordination of compound 1 with the palladium
catalyst. The subsequent intramolecular deprotonation of the
To verify the possibility of the electrophilic mechanism for
this transformation (Scheme 2, path A), the carbocyclization
of alkynyl ketone 1a was tested in the presence of several
p-philic metal salts, including AuCl, AuCl3, PtCl2, electro-
philic [Ph3PAuOTf], and Cu(OTf)2,[9] known to mediate
cyclizations by p-philic activation of the alkyne moiety.
However, no formation of the desired product 2a under
Angew. Chem. Int. Ed. 2011, 50, 2342 –2345
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2343