Ruthenium-catalyzed regioselective 1,3-methylene transfer by cleavage of two adjacent σ-carbon-carbon bonds: An easy and selective synthesis of highly subsituted benzenes

Article abstract of DOI:10.1021/ja0504901

We report a new ruthenium-catalyzed 6-endo-dig cyclization of 6,6-cycloalkylidenyl-3,5-dien-1-ynes, which produces highly substituted benzenes with considerable structural reorganization. In this process, we observe a regioselective 1,3-methylene migratio

Full text of DOI:10.1021/ja0504901

Published on Web 03/04/2005
Ruthenium-Catalyzed Regioselective 1,3-Methylene Transfer by Cleavage of
Two Adjacent σ-Carbon-Carbon Bonds: An Easy and Selective Synthesis of
Highly Subsituted Benzenes
Jian-Jou Lian, Arjan Odedra, Chang-Jung Wu, and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua UniVersity, Hsinchu, Taiwan, ROC
Received January 25, 2005; E-mail: rsliu@mx.nthu.edu.tw
Scheme 1 a
Metal-catalyzed cleavage of a σ-carbon-carbon bond is an
interesting and useful method in organic reactions.1 Reported
examples of such reactions focus exclusively on the activation of
strained2 or functionalized carbon-carbon bonds.3 Although there
has been significant advancement in the metal-catalyzed activation
of carbon-carbon double and triple bonds,4,5 catalytic cleavage of
a
* means C ) 13% 13C. [Ru] ) TpRuPPh3(CH3CN)PF6.
Scheme 2
a σ-carbon-carbon bond of the aliphatic type (Scheme 1, eq 1)
has attained less progress.2a,3a One perspective method involves the
use of electrophilic metals to activate functionalized alkynes and
generates carbocations or carbene species to facilitate the cleavage
of adjacent carbon-carbon bonds.6,7 This approach is applicable
to reactions of the metathesis type7 and 1,2-alkyl shift.8c,8d In this
study, we report a ruthenium-catalyzed 1,3-regioselective methylene
transfer in the cycloisomerization of 3,5-dien-1-ynes, which involves
cleavage of two σ-carbon-carbon bonds of the aliphatic type (eq
2).
Cyclization of 3,5-dien-1-ynes to benzene derivatives has been
implemented by metal complexes via formation of metal-vi-
nylidene intermediates.8 We sought to apply this method to the
synthesis of highly substituted benzenes,9 which is an important
subject in catalytic reactions.10 As shown in Scheme 2, heating 6,6-
ficiently for cyclopentylidenyl derivatives 9 and 12 than their
disubstituted 3,5-dien-1-yne 1 in hot toluene (100 °C, 10 h) with
cyclohexylidenyl analogues 10 and 11. In the cyclization of 3,5-
dien-1-ynes 13 and 14 (entries 5-6), the resulting benzenes 21-
22 have the methyl group located at the phenyl C(3)-carbon
according to the proton-NOE spectra.11 This observation is con-
sistent with our observed 1,3-methylene transfer in the 13C-labeling
experiment (Scheme 2, eq 3). The value of this cyclization is
reflected by the selective 1,2-shift of the cycloalkylidene alkyl
groups, and the examples are manifested by 3,5-dien-1-ynes 15-
17 (entries 7-9). According to proton-NOE effects,11 the resulting
products 23-25 show no shift for the phenyl substituent, a 1,2-
shift for the uncleaved benzyl group, and a 1,3-shift for the methyl
(or methylene) group. This structural rearrangement is amazing
because the phenyl and its cleaved methyl group are in the remote
meta position. The synthetic value of this cyclization is evident
from its reaction generality shown in Table 1, which provides an
easy and selective synthesis of highly substituted benzenes10 as
represented by compound 25 bearing six unequivalent phenyl
substituents.
We prepared deuterated dienyne d-7 to understand better this
novel 1,3-methylene transfer. The results shown in Scheme 3 (eq
1, entry 1, Z ) H) confirm that the C(1)X2(X ) 0.94 D) fragment
of the cyclopentylidene group is cleaved. The corresponding
cyclized product d-8 has a fused cyclopentyl ring with the CH2
and the CX2 (X ) 0.91 D) units respectively linking to the phenyl
C(5) and C(4) carbons, whereas the CHY2 methyl (Y ) 0.90 D) is
located at the C(3) carbon without loss of deuterium content. This
structural arrangement is identical to those of benzenes 23-25. One
of the methyl protons of species d-8 (entry 2) arises mainly from
the alkynyl deuterium d-7. A similar phenomenon is also observed
8c,9
10% TpRuPPh3(CH3CN)2PF6
catalyst gave 6-propyl-1,2,3,4-
tetrahydronaphthalene 2 in 42% yield. Under similar conditions,
the cyclopropylidenyl and cyclobutylidenyl derivatives 3 and 4
preferably gave benzene products 5 and 6, resulting from a
regioselective 1,2-alkyl shift, in yields of 23% and 68% respectively.
In such cyclizations, we observed a 1,2-shift of the alkynyl proton
of species d-4, indicative of a vinylidene intermediate.8 To our
astonishment, the catalytic transformation on the cyclopentylidene
analogue 7 gave tricyclic benzene 8 in 87% yield; this product
contained an unexpected methyl group. The structure of benzene 8
was determined by the proton-NOE effect.11 This transformation
involves not only a regioselective 1,2-alkyl shift, but also a transfer
of the methylene group. We prepared a 13C-labeled sample 7, in
which the C(5) carbon (8 atom 13C %) migrated only to the C(6)H
carbon of benzene 8 (eq 3). This information suggests that formation
of benzene 8 arises from the 6-endo-dig cyclization12 of dienyne
7, with one methylene group of the cyclopentylidene ring 1,3-
migrating to the C(2)-alkyne carbon. Such a 1,3-methylene transfer
involves cleavage of two adjacent σ-carbon-carbon bonds. The
yields of benzene 8 are highly dependent on the solvents: benzene
(57%, 80 °C, 7 h), DMF (71%, 100 °C, 6 h), DMSO (87%, 100
°C, 6 h), 1,4-dioxane (65%, 100 °C, 4 h), dichloroethane (61%, 80
°C, 8 h).
We prepared various 6,6-cycloalkylidenyl-3,5-dien-1-ynes 9-17
to examine the generality of this cyclization using the same catalyst
(10 mol %). The reactions worked well for 3,5-dien-1-ynes 9-12
(entries 1-4), and gave substituted benzenes 18, 8, and 19-20 in
63-93% yields. The cyclization evidently proceeded more ef-
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10.1021/ja0504901 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Ruthenium-Catalyzed Regioselective Methylene Transfer
Reaction
highly substituted benzenes with atom economy. In this structural
reorganization, we observe a regioselective 1,3-methylene migration
via extrusion from a cycloalkylidenyl ring, in addition to a
regiocontrolled 1,2-alkyl migration.
Acknowledgment. We thank the National Science Council,
Taiwan, for supporting this work.
Supporting Information Available: NMR spectra, spectral data
of compounds 1-25, I-15, and I-23, NMR spectra of 2H- and 13C-labeled
1
d-7 and d-8, and H NOE of 8, 21, 23, 24, and 25. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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a 10 mol % catalyst, [substrate] )1.0 M, 100 °C, toluene. b 1.5 h. c 4.0
h. d 8.0 h. e Yields were reported by separation from a silica column.
Scheme 3
(3) These functionalized molecules include benzonitrile,a acylnitrile,b aldehyde,
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9294 and references therein.
Scheme 4
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(9) Cyclization of 2′,2′-disubstituted (o-ethynyl)styrenes by TpRuPPh3(CH3-
CN)2PF6 followed 5-endo-dig mode and gave 2-alkenyl indenes exclu-
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6-endo-dig mode leads to dearomatization of the reaction intermediate.
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for the alkynyl iodide species I-15 (eq 2), which transfers its iodide
to the benzyl methylene group of product I-23.
Shown in Scheme 4 is our proposed mechanism, in which the
initial step involves formation of a ruthenium-vinylidene species
A8 via 1,2-shifts of hydrogen and iodo groups.8b 6-endo-dig
Electrocyclization12 of species A gives cyclohexadienyl cation B.
We envisage that cationic charge of species B resides mainly on
the Ru-C carbon8c,13 and induces a selective 1,2-alkyl shift to give
cationic intermediate C. This species is stabilized by a cationic
pentadienyl resonance. Attack of the ruthenium center of species
C at the remote benzyl CH2 carbon induces 1,2-phenyl shift, and
gives cyclobutylruthenium species D; the driving force for this
transformation is the formation of an extra Ru-C bond. For species
D, the 1,5-sigmatropic alkyl shift14 (via suprafacial retention) leads
to intermediate E, and ultimately gives the observed products 23
and 24. We do not exclude the possibility that species B can be
directly transformed into species D through a “push-pull” mech-
anism, as shown by structure B′. In this pathway, the ruthenium
attacks at the benzyl carbon simultaneously when the Ru-C
carbocation induces a 1,2-shift of the other benzyl group. The
proposed mechanism15,16 rationalizes the observed alkynyl 2H and
iodide shifts of starting 3,5-die-1-nynes d-7 and I-16 (Scheme 3).
In summary, we report a new ruthenium-catalyzed 6-endo-dig
cyclization of 6,6-cycloalkylidenyl-3,5-dien-1-ynes17 that produces
(11) The 1H-NOE spectra of benzene derivatives 8, 21, 23, 24, and 25 are
provided in Supporting Information.
(12) Cyclization of 3,5-dien-1-ynes to benzene products by this catalyst can
be achieved by the 5-endo-dig pathway, but the C(5)-carbon of starting
3,5-dien-1-yne shows a 1,2-shift. Our 13C(5)-labeling experiment in
Scheme 2 (eq 3) is characteristic of 6-endo-dig cyclization. See ref 8c.
(13) The cationic charge in structure B should reside mainly on the Ru-C
carbon because the TpRu fragment is an electron-rich center, which
stabilizes the adjacent carbocation more efficiently.
(14) (a) Hess, B. A., Jr.; Schadd, L. J.; Pancir, J. J. Am. Chem. Soc. 1985,
107, 149. (b) Bernardt, F.; Robb, M. A.; Schlegel, H. B.; Tonachini, G.
J. Am. Chem. Soc. 1984, 106, 1198..
(15) The behavior of 3,5-dien-1-yne 1 is distinct from its cycloalkylidene
analogues. We envisage that its elongation product 2 (Scheme 2, eq 1)
arises from the C-H activation of either the methyl or the CH2CH3 group
by ruthenium via intermediate B. Such C-H activations are unlikely to
occur for cycloalkylidene analogues because of their restricted ring
conformations. The mechanism will be characterized in future studies.
(16) Benzene products 5 and 6 (Scheme 2, eq 2) are proposed to arise from an
intermediate such as species C (Scheme 4) which will not undergo ring
contraction to yield an intermediate like D.
(17) This 1,3-methylene reaction is not applicable to common internal alkynes
except for iodoalkynes.
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