A gold-catalyzed unique cycloisomerization of 1,5-enynes: Efficient formation of 1-carboxycyclohexa-1,4-dienes and carboxyarenes

Article abstract of DOI:10.1021/ja066220f

A novel Au-catalyzed migratory cycloisomerization strategy is advanced. Implementation of this strategy led to the development of a unique Au-catalyzed 1,5-enyne cycloisomerizatioin involving carboxy migration and Au-mediated C-C single bond formation. 1-

Full text of DOI:10.1021/ja066220f

Published on Web 10/13/2006
A Gold-Catalyzed Unique Cycloisomerization of 1,5-Enynes: Efficient
Formation of 1-Carboxycyclohexa-1,4-dienes and Carboxyarenes
Shaozhong Wang and Liming Zhang*
Department of Chemistry/216, UniVersity of NeVada, Reno, 1664 North Virginia Street, Reno, NeVada 89557
Received August 27, 2006; E-mail: lzhang@chem.unr.edu
Table 1. AuIII-Catalyzed Cycloisomerization of 1,5-Enynes
Transition metal-catalyzed enyne cycloisomerization is one of
the most important strategies for forming functionalized cyclic
structures.1 Lately, Au catalysis2 has elicited new excitement in
this active research area, and novel modes of enyne cycloisomer-
ization have been revealed. Among a range of applicable enyne
substrates, 1,5-enynes are one of the most studied and have been
efficiently converted into cyclic products such as bicyclo[3.1.0]-
hexenes,3 cyclohexadienes,4 methylenecyclopentenes,5 and hetero-
bicycloalkenes.6 These reactions are often proposed to proceed with
initial formation of a cyclopropyl gold carbenoid.7
Recently we showed that the alkenylgold intermediates generated
in situ from propargylic esters were significantly nucleophilic and
participated efficiently in intramolecular C-C bond formation
reactions.8 We reason this C-C bond formation reaction can be
generally applied to other alkyne substrates as well, and a unique
cycloisomerization strategy is envisioned. As shown in Scheme 1,
Scheme 1. General Design of Au-Catalyzed Cycloisomerization
Au activation of the C-C triple bond can result in a migration of
the nucleophilic X group, providing the carbon cation generated is
sufficiently stabilized. Subsequent nucleophilic attack9 by the
alkenylgold will then lead to cyclized products.
Our effort in implementing this novel strategy10 led to the
development of an efficient synthesis of 1-carboxycyclohexa-1,4-
dienes and carboxyarenes from 5,1-enyn-4-yl carboxylates. Sig-
nificantly, this novel Au-catalyzed cycloisomerization of 1,5-enynes
does not likely undergo the often-invoked initial formation of
cyclopropyl gold carbenoid. Herein we disclose the results of this
study.
a Enynes 4 were conveniently prepared by reacting enones with propar-
gylaluminate followed by acetylation or methylcarbonation. b Due to the
difficulty of purification, the cyclohexadiene product was dehydrogenated
using DDQ to afford the corresponding biaryl acetate.
On the outset, we chose 1,5-enyne 1 as the substrate, with acetoxy
as the migrating group (Scheme 2), with two considerations in
Scheme 2. Initial AuIII-Catalyzed Reaction of 1,5-Enyne Acetate 1
40 °C, 1 h], and 1-acetoxycyclohexa-1,4-diene 212 was isolated in
82% yield. Other solvents, such as CH3CN, toluene, and ClCH2-
CH2Cl, were suitable as well but with diminished efficiency. The
likely mechanism of this reaction is proposed in accordance with
the general strategy (Scheme 2).
The initial scope study of this reaction with substrates derived
from arylidene-substituted cyclic ketones is shown in Table 1.13
Enynes 4 with different ring sizes were generally tolerated, as both
five- and seven-membered substrates reacted smoothly, yielding
cyclohexa-1,4-diene 5a and aromatized product 5b14 in good yields
(entries 1 and 2). Besides phenyl group, various other aryl groups,
including electron-rich (entry 5), electron-poor (entry 4), and
sterically demanding ones (entries 3 and 6), were compatible with
this reaction, and generally good yields of the corresponding
cyclohexadienes were isolated (entries 4 and 6). In the cases of
p-methoxyphenyl and o-tolyl groups (entries 3 and 5), the reaction
mind: (1) the phenyl group can provide further stabilization to the
carbon cation, permitting an efficient migration of the acetoxy
group, and (2) the cyclohexane ring can provide conformation
control to the allylic cation. Gratifyingly, this reaction did proceed
in high efficiency under carefully optimized reaction conditions
[i.e., 5 mol % of dichloro(pyridine-2-carboxylato)gold (3),11 THF,
9
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C O M M U N I C A T I O N S
mixtures were subsequently treated with DDQ to yield biaryls 5c
and 5e for ease of purification. Interestingly, the aryl group,
important for the stabilization of the intermediate allylic cation,
can be placed on the other side of the allyl moiety. Hence, enyne
4g derived from R-tetralone cyclized efficiently, affording func-
tionalized tetrahydrophenathrene 5g in 86% yield in only 15 min.
Besides acetoxy group, methoxycarboxy group can be the migrating
entity as well, giving rise to cyclohexadienyl carbonate 5h in fairly
good yield (entry 8). A remarkable observation from Table 1 is
the substantial variation of the reaction conditions from entry to
entry. While dichloro(pyridine-2-carboxylato)gold (3) is the catalyst/
precatalyst of choice, the reaction temperature and solvent were
optimized, as no single set of conditions worked well for all the
substrates. Noteworthy are the conditions used for the difficult
substrates 4d and 4f. The slow reaction of these substrates always
led to catalyst decomposition and incomplete reaction, and increas-
ing the catalyst loading did not noticeably improve the conversion.
However, the catalyst system appeared to be substantially stabilized
by the addition of KAuCl4.15 The addition of CaO16 further
improved the reaction yields.
provides an efficient formation of phenolic acetates with much
flexibility in aromatic substitution pattern.
Further expanding the scope of this chemistry to substrates
derived from enals was unsuccessful with Au catalysts. However,
PtCl2 provided an encouraging alternative. As shown in eq 4, enyne
12, derived from trans-cinnamaldehyde, was converted into cyclo-
hexadiene 13 in 60% yield. Notably, 20 mol % of PtCl2 was needed,
and the reaction was run under air, as nitrogen protection led to
significant retardation and inferior yield. The role of oxygen in this
reaction is to be further studied.18
In summary, we have developed a unique Au-catalyzed 1,5-enyne
cycloisomerizatioin involving carboxy group migration and Au-
mediated C-C single bond formation. 1-Carboxycyclohexa-1,4-
dienes and carboxyarenes can be prepared with good efficiency
and with flexible substitution patterns. Further study in applying
the novel Au-catalyzed migratory cycloisomerization strategy to
other substrates is underway.
To expand the scope of this remarkable reaction, we examined
substrates derived from linear aryl-substituted enones (eq 1). While
Acknowledgment. This work is supported by the University
of Nevada, Reno and ACS PRF (no. 43905-G1).
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
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Synlett 1998, 1-16. (c) Lloyd-Jones, G. C. Org. Biomol. Chem. 2003, 1,
215-236.
enyne 6a was converted into cyclohexadiene 7a in only 38% yield
with 48% 6a remaining due to catalyst decomposition, replacing
its methyl group with a bulky isopropyl group (i.e., enyne 6b)
resulted in faster reaction and 71% yield. Further increasing the
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Int. Ed. 2000, 39, 4237-4239. (b) Hashmi, A. S. K. Gold Bull. 2003, 36,
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t
steric size by using a Bu group (i.e., enyne 6c) substantially
enhanced the desired reactivity, and 7c was isolated in excellent
yield. This reactivity trend of enynes 6 can be rationalized with
conformational analysis of the proposed allylic cation intermediates
A and B: bulky R groups prefer conformer B in order to minimize
steric interactions, leading to facile 6-endo cyclization, while R )
Me likely leads to a predominance of conformer A, resulting in
slow reaction and unsatisfactory conversion. This rationale is also
in accordance with the observation that the enyne derived from
trans-cinnamaldehyde (i.e., compound 12, R ) H) did not yield
the cyclohexadiene product under the same reaction conditions.
The existence of an aryl group in the substrates, however, is not
a necessity. We envisioned that the role of the aryl group to stabilize
the allylic cation can be readily fulfilled by other electron-donating
groups. For example, treatment of enyne 8 with a phenoxy
substituent at the C-C double bond led to efficient formation of
aromatized acetate 9,17 with the expected facile elimination of
phenol (eq 2). Moreover, linear enyne 10, with methoxycarboxy
(4) (a) Sun, J.; Conley, M. P.; Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc.
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(6) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2005, 127, 6962-6963.
(7) For pioneering work in 1,6-enyne cycloisomerization involving cyclopropyl
gold carbenoid, see: Nieto-Oberhuber, C.; Munoz, M. P.; Bunuel, E.;
Nevado, C.; Cardenas, D. J.; Echavarren, A. M. Angew. Chem., Int. Ed.
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(9) Alternatively, an electrophilic reaction of the cation with the C-C double
bond, followed by facile elimination of Au, is possible. For a similarly
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Chem., Int. Ed. 2006, 45, 4473-4475.
(10) After our submission, a study employing a similar strategy appeared,
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(11) AuI complexes, such as Au(PPh3)SbF6, did not catalyze this reaction.
(12) The structure of 2 was deduced from extensive NMR studies. The
cyclohexa-1,4-diene motif is supported by the characteristic long-range
coupling between H-3 and H-6 (J ) 7.5 Hz).
(13) Substrates with internal C-C triple bonds did not yield desired products.
(14) Due to the partial aromatization upon column purification of the
corresponding cyclohexadiene product and for the ease of purification,
the reaction mixture was treated with DDQ subsequently to yield arene
5b.
(15) KAuCl4 itself does not catalyst the reaction. Its role is likely to scavenge
the pyridine-2-carboxylate upon the decomposition of catalyst 3.
(16) CaO was intended to trap the acid generated upon catalyst decomposition.
(17) The structure of 9 was confirmed by independent preparation of it from
commercially available 5,6,7,8-tetrahydro-2-naphthol.
(18) (PhIO)n has been used together with PtCl2 previously, and Pt(IV) was
suggested as the likely catalytic species, see: Prasad, B. A. B.; Yoshimoto,
F. K.; Sarpong, R. J. Am. Chem. Soc. 2005, 127, 12468-12469.
as the stabilizing group, also underwent similar tandem cycloisom-
erization and aromatization, affording aryl acetate 11 in good yield
upon ready elimination of methanol and CO2 (eq 3). This approach
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