Metal-catalyzed cycloisomerization of enyne functionalities via a 1,3-alkylidene migration

Article abstract of DOI:10.1021/ja062515h

We report a new metal-catalyzed 6-endo-dig cyclization of cis-4,6-dien-1-yn-3-ols, which produces substituted benzene and naphthalene derivatives with structural reorganization. In this process, we observe a 1,3-alkylidene migration via cleavage of the olefin double bond of the starting substrates. The ease and reliability of this cyclization are manifested by its compatibility with a wide array of diverse substrates and several π-alkyne activators, including PtCl₂, Zn(OTf)₂, AuCl, and AuCl₃. Copyright

Full text of DOI:10.1021/ja062515h

Published on Web 07/06/2006
Metal-Catalyzed Cycloisomerization of Enyne Functionalities via a
1,3-Alkylidene Migration
Ming-Yuan Lin, Arindam Das, and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua UniVersity, Hsinchu 30043, Taiwan, Republic of China
Received April 27, 2006; E-mail: rsliu@mx.nthu.edu.tw
Scheme 1
Metal-catalyzed cycloisomerization of enynes often leads to
skeletal rearrangement because “nonclassical” cations participate
as reaction intermediates.1 Among literature reports, migration of
a 1,2- and 1,3-alkylidene fragment is very interesting in mechanistic
and synthetic aspects (eqs 1 and 2 in Scheme 1).2a,3 In such
processes, the olefin double bond of the enyne substrate is cleaved
and migrated to the alkyne carbon (eqs 1-3 in Scheme 1). Reports
of a 1,3-alkylidene migration are limited strictly to formation of
metathesis-type product II;3 little is known for other processes.3e
Echavarren recently proposed a 1,3-alkylidene migration in the
+
cycloisomerization of 1,6-enynes using AuPPh3 catalyst as
depicted in eq 3.3e,4 Unfortunately, this cyclization is only extensible
to only two instances, IV and V (yields > 50%, eq 3), whereas
most 1,6-enynes are catalyzed by this gold catalyst to give 1,3-
diene II, cyclopropane derivative III, and other byproducts.3e,4,5
Here we report a new metal-catalyzed cycloisomerization of cis-
Scheme 2
4,6-dien-1-yn-3-ols, for which the 1,3-alkylidene migration is
unambiguously established by both 13C-labeling experiments and
product structures. This new cycloisomerization is applicable to a
wide range of substrates.
As shown in Scheme 2, treatment of cis-4,6-dien-1-yn-3-ol 1
with PtCl2 (5 mol %) in hot toluene (80 °C, 30 min) produced
styrene derivative 2 in 92% isolated yield. The ease and reliability
with this catalytic reaction are manifested by the high efficiencies
of other catalysts at optimum conditions: Zn(OTf)2/MS 4 Å (10
mol %, 78% 2) and AuCl/MS 4 Å (5 mol %, 81% 2). In the absence
of MS 4 Å, AuCl alone (5 mol %) gave tertiary alcohol 3 (CH2-
Cl2, 20 °C) in 75% yield in addition to species 2 (6%). AuCl3 was
equally active in catalytic activity at 20 °C (entry 6). The structures
1
of compounds 2 and 3 were identified by H NOE effect, which
reveals that the vinyl and tertiary alcohols of compounds 2 and 3
are located at the C(2) rather than the expected C(4) carbon, clearly
indicative of a 1,3-isopropylidene migration.6
AuCl3/MS 4 Å gave desired 25 in low yield (25%) at 60 °C in
DCE. In the presence of MS 4 Å, Zn(OTf)2 and AuCl gave product
25 in respective yields of 81 and 70% (see Table S-1 in Supporting
Information). Accordingly, Zn(OTf)2/MS 4 Å was selected as the
catalyst because of its best cyclization efficiency. Cyclization of
these alcohols with Zn(OTf)2 in hot toluene (90 °C, 3 h) yielded
We prepared various cis-4,6-dien-1-yn-3-ols 4-17 to generalize
this catalytic cyclization, and all these substrates gave a single
product efficiently, except alcohol 17. For alcohols 4-10, PtCl2
was used as the catalyst because of its better chemoselectivity and
cyclization efficiency. Entries 1-3 provide additional examples for
cyclization of cis-4,6-dien-1-yn-3-ols 4-6, which afforded styrene
1
naphthalene derivatives 26-30 in 81-86% yields. We used H
NOE effects to elucidate the structures of 27, 28, and 30,6 which
reveal that their alkenyl substituents are located at the C(2) carbon
rather than the original C(4) carbon, consistent with a 1,3-shift.
The cyclization of alcohol 17 bearing a disubstituted alkene,
however, gave expected naphthalene 31 in low yield (33%).
We prepared 13C-enriched samples C(6)-1 and C(3)-1 with 10%
13C content at the C(6) and C(3) carbons of alcohol 1, respectively
(see Supporting Information). Treatment of C(6)-1 with PtCl2
produced styrene C(4)-2 with the 13C content at the C(4) carbon
according to 13C-1H HMQC and HMBC spectra. Similarly, alcohol
C(3)-1 gave product C(1)-2 with the 13C content at the C(1) carbon.
1
derivatives 18-20 in 78-82% yields. H NOE effects confirmed
the structures of compounds 19 and 20. This cyclization works
efficiently with alcohols 7 and 8 via alternation of their alkenyl
substituents, giving desired styrene derivatives 21-22 in 86-87%
yields. This catalytic reaction is extensible to acyclic substrates 9
and 10, producing species 23 and 24 in 86 and 75% yields,
respectively. The value of this catalytic reaction is again demon-
strated by its applicability to 2-alkenylbenzylic alcohols 11-16.
We examined the catalytic cyclization of alcohol 11 with PtCl2,
AuCl, AuCl3, and Zn(OTf)2; PtCl2/MS 4 Å gave isopropylidene
product 25 in 64% yield in addition to a byproduct (6%), whereas
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10.1021/ja062515h CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
catalyst.8-10 The key factor to accelerate the 1,3-isopropylidene shift
is the formation of an allylic cation D, which causes the cleavage
of the C(4) isopropyl σ-carbon bond of species C. Further cleavage
of the cyclopropane ring of species D via dissociation of PtCl2
regenerates cyclohexadienyl alcohol intermediate E, which in the
presence of PtCl2 gives tertiary benzylic cation F and ultimately
leads to observed products 2 and 3. In the case of benzylic alcohol
substrate 11, we envisage that the nonclassical carbocation C′ forms
a stable benzylic cation I, and ultimately afforded observed
naphthalene 25 through formation of intermediate E′.
Table 1. Metal-Catalyzed Cyclization of Various
4,6-Dien-1-yn-3-ols
In summary, we report the metal-catalyzed cycloisomerization
of cis-4,6-dien-1-yn-3-ols with an unusual skeletal rearrangement;
this catalytic reaction is applicable to a wide range of substrates.
Its 1,3-migration pathway is clearly established by suitable experi-
mental evidences. Application of this new catalysis of a complex
molecule is under current investigation.
Acknowledgment. The authors thank to the National Science
Council, Taiwan, for supporting this work.
Supporting Information Available: Table for cyclization of
alcohol 11 using various catalysts, formation of product H from internal
alkyne analogues using the PtCl2 catalyst, experimental procedure, NMR
spectra (including HMQC, HMBC, and 13C-labeling experiments), and
spectra data of compounds 1-31. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
Scheme 3
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process,2b respectively, for cycloisomerization of 1,5-enynes and 6,6-
disubstituted 3,5-dien-1-ynes using TpRuPPh3(CH3CN)2PF6 to generate
initial ruthenium-vinylidene intermediates. The mechanism and reaction
pattern of the two cyclizations are completely different from those observed
for this new cyclization. See: (a) Madhushaw, R.; Lo, C.-Y.; Hwang,
C.-W.; Su, M.-D.; Shen, H.-C.; Pal, S.; Shaikh, I. R.; Liu, R.-S. J. Am.
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Scheme 4
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lyst: (a) Trost, B. M.; Yanai, M.; Hoogstein, K. J. Am. Chem. Soc. 1993,
115, 5294. (b) Chatani, N.; Kataoka, K.; Murai, S.; Furukawa, N.; Seki,
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(4) In this AuPPh3+-based catalysis,3e the cycloisomerization proceeds at room
temperatures; however, the chemoselectivity heavily depends on alternation
of the alkenyl substituents, the connecting atom X.3e
(5) Diene products IV and V were also produced from Rh(1)-catalyzed
cycloisomerization of 1,6-enynes via initial formation of rhodium-
vinylidene intermediates; however, there is no skeletal rearrangement
2
according to the H-labeling experiments. See: Kim, H.; Lee, C. J. Am.
These labeling results reconfirm the occurrence of a 1,3-isopropy-
lidene shift for alcohol 1.
Chem. Soc. 2005, 127, 10180.
(6) Treatment of alcohol 1 with TfOH (10 mol %) in toluene (23 °C, 10
min) produced two new products distinct from 2 and 3, and this
information indicates that the catalytic activity of Zn(OTf)2 is not caused
by TfOH. See Scheme S2 in the Supporting Information.
(7) (a) Winstein, S.; Shtavsky, M.; Norton, C.; Woodward, R. B. J. Am. Chem.
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(9) Our preliminary results reveal that product H was produced in 65% yield
from an internal alkyne analogue S3 (see Scheme S1 in Supporting
Information).
The lack of byproducts, such as species II and III (Scheme 1),
leads us to believe that this new cycloisomerization proceeds
through an unprecedented mechanistic pathway. The low cyclization
efficiency of alcohol 17 suggests the participation of a tertiary
carbocationic intermediate generated from other alcohols 4-16. As
shown in Scheme 4, the mechanism involves an initial 6-endo-dig
cyclization of Pt(II)-π-alkyne A to give species B, which forms a
nonclassical carbocation C via a through-space overlap of the
tertiary cation with the electron-rich Pt-CdCH double bond.7,8a
The participation of platinum carbenoid G, proposed by Echavarren
in the gold example,3e is not evident here, but cyclohexenone H
was obtained for an internal alkyne analogue using the PtCl2
(10) In the PtCl2 catalysis, the methoxy derivative of alcohol 1 in hot toluene
(80 °C, 30 min) gave naphthalene product 2 in 76% yield; this information
suggests that propargyl OPtCl2- is not involved in the reaction mechanism.
JA062515H
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