Olefination of α,α′-divinyl ketones through catalytic Meyer-Schuster rearrangement

Article abstract of DOI:10.1021/jo101497f

The direct olefination of 1,4-dien-3-ones remains a synthetic challenge. A two-step protocol, employing acetylide addition followed by catalytic Meyer-Schuster rearrangement has been developed for the olefination of 1,4-pentadien-3-ones to afford [3]dendr

Full text of DOI:10.1021/jo101497f

pubs.acs.org/joc
Olefination of r,r0-Divinyl Ketones through Catalytic Meyer-Schuster
Rearrangement
Curtis J. Rieder, Karl J. Winberg, and F. G. West*
Department of Chemistry, University of Alberta, E3-43 Gunning-Lemieux Chemistry Centre,
Edmonton AB T6G 2G2, Canada
frederick.west@ualberta.ca
Received July 29, 2010
The direct olefination of 1,4-dien-3-ones remains a synthetic challenge. A two-step protocol,
employing acetylide addition followed by catalytic Meyer-Schuster rearrangement has been
developed for the olefination of 1,4-pentadien-3-ones to afford [3]dendralenes. Many of the traditional
methods for the Meyer-Schuster rearrangement of alkynyl carbinols are not suitable with these highly
unsaturated substrates because of their acid sensitivity. Unexpected reactivity during attempted rearrange-
ment, including Nazarov-type electrocyclizations, is presented, along with conditions to promote the
Meyer-Schuster rearrangement of ethoxyacetylene adducts using catalytic VO(acac)2.
Introduction
Our interest in the reaction arose from efforts to develop a
“vinylogous Nazarov reaction” (Scheme 1).3 One of the early
challenges encountered in this study centered around forma-
tion of the requisite cross-conjugated trienes ([3]dendralenes) 1.4
The most direct method would appear to be a Wittig or
Horner-Wadsworth-Emmons-type olefination of the cross-
conjugated dienones 4 used in the traditional Nazarov
electrocyclization. However, a combination of steric hindrance
and electronic deactivation precludes use of such a direct
olefination process.
[3]Dendralenes and their higher order counterparts can be
prepared through dibromoolefination/cross-coupling proto-
cols using various aldehydes.4e-g Unfortunately, in our
hands, this approach suffered poor yields and limited substrate
scope in generating the carbonyl-substituted [3]dendralenes we
Recently, there has been a resurgence in interest in the
Meyer-Schuster rearrangement,1 a process in which pro-
pargyl alcohols are converted into R,β-unsaturated carbonyl
compounds through a formal 1,3-oxygen transposition.2
Increased focus on this venerable reaction may be attributed
to its potential use as part of a two-step olefination process
through combination with a prior alkynyl anion addition to
an aldehyde or ketone acceptor. An important feature of this
transformation is its applicability to hindered ketones that
are unreactive under traditional olefination conditions.
Moreover, the atom-economy of the overall process is
attractive.
(1) (a) Lopez, S. S.; Engel, D. A.; Dudley, G. B. Synlett 2007, 949–953.
ꢀ
(b) Marion, N.; Carlqvist, P.; Gealageas, R.; de Fremont, P.; Maseras, F.;
Nolan, S. P. Chem.;Eur. J. 2007, 13, 6437–6451. (c) Lee, S. I.; Baek, J. Y.;
Sim, S. H.; Chung, Y. K. Synthesis 2007, 2107–2114. (d) Engel, D. A.; Lopez,
S. S.; Dudley, G. B. Tetrahedron 2008, 64, 6988–6996. (e) Trost, B. M.;
Livingston, R. C. J. Am. Chem. Soc. 2008, 130, 11970–11978. (f) Engel, D. A.;
Dudley, G. B. Org. Biomol. Chem. 2009, 7, 4149–4158. (g) Cadierno, V.;
Frandos, J.; Gimeno, J. Tetrahedron Lett. 2009, 50, 4773–4776.
(2) (a) Meyer, K. H.; Schuster, K. Chem. Ber. 1922, 55, 819–823.
(b) Vartanyan, S. A.; Babanyan, S. O. Russ. Chem. Rev. 1967, 36, 670–686.
(c) Swaminat, S.; Narayana, K. V. Chem. Rev. 1971, 71, 429–438. (d) Cadierno,
V.; Crochet, P.; Garcia-Garrido, S. E.; Gimeno, J. Dalton Trans. 2010, 39, 4015–
4031.
(3) Rieder, C. J.; Winberg, K. J.; West, F. G. J. Am. Chem. Soc. 2009, 131,
7504–7505.
(4) Reviews on [3]dendralenes: (a) Hopf, H. Angew. Chem., Int. Ed. 1984,
23, 947–960. (b) Gholami, M.; Tykwinski, R. R. Chem. Rev. 2006, 106, 4997–
5027. For recent synthetic approaches, see: (c) Fielder, S.; Rowan, D. D.;
Sherburn, M. S. Angew. Chem., Int. Ed. 2000, 39, 4331–433. (d) Chin, C. S.;
Lee, H.; Park, H.; Kim, M. Organometallics 2002, 21, 3889–3896. (e) Park, S.;
Lee, D. Synthesis 2007, 2313–2316. (f) Bradford, T. A.; Payne, A. D.; Willis,
A. C.; Paddon-Row, M. N.; Sherburn, M. S. Org. Lett. 2007, 9, 4861–4864.
(g) Miller, N. A.; Willis, A. C.; Paddon-Row, M. N.; Sherburn, M. S. Angew.
Chem., Int. Ed. 2007, 46, 937–940.
50 J. Org. Chem. 2011, 76, 50–56
Published on Web 11/24/2010
DOI: 10.1021/jo101497f
r
2010 American Chemical Society

Rieder et al.
JOCArticle
SCHEME 1. Vinylogous Nazarov Reaction
SCHEME 2. Acetylide Addition and Silica-Mediated Cyclization
to our surprise, during attempted purification on silica gel,
3a underwent Meyer-Schuster rearrangement to trienoate
1a in excellent yield, presumably via catalysis by the mildly
acidic silica. In fact, pretreatment of this sorbent with Et3N
cosolvent effectively inhibited the rearrangement. Unfortu-
nately, this convenient transformation did not prove to be
general, with most other adducts 3 found to be unreactive
during chromatography or extended stirring over silica gel.
Given the lack of generality for the silica-mediated rear-
rangement, we turned our attention to other methods to
effect Meyer-Schuster rearrangement of dienone-acetylide
adducts. Propargyl alcohol 3b, obtained in near-quantitative
yield from dibenzylidene-3-pentanone 4b and ethoxyacety-
lene, was inert to silica gel and was chosen as a model substrate to
optimize the Meyer-Schuster rearrangement. Our initial focus
was on the use of gold(III) chloride in light of the promising
results in Dudley’s early report (Table 1, entries 1-3). Indeed,
treatment of 3b under gold(III) catalysis gave the desired
trienoate; however, the reaction was capricious and fre-
quently furnished significant quantities of cycloisomerized
byproducts such as 2b or 5b.
As a result of the high degree of variability of reactivity
observed with gold(III) chloride, other promoters were ex-
amined to effect the Meyer-Schuster rearrangement. Aque-
ous HCl (entry 4) and other π-acids,8 such as gold(I), silver,
and platinum salts (entries 5-7), were explored and met with
minimal success. Gallium(III) chloride and hexachloropla-
tinic acid, due to their extreme hygroscopicity, gave rise to
significant quantities of hydration product 8b (entries 8 and 9).
While the use of TiCl4 as an acid promoter in the Meyer-
Schuster rearrangement worked exceptionally well in select
cases (Scheme 3), the results did not generalize to all sub-
strates. With 3b, TiCl4 not only provided the requisite triene
but also effected vinylogous Nazarov ring closure to give 2b
(entry 10). Metal oxides gave variable yields of the desired
trienoate 1b (entries 12-14), with the greatest reproducibly
obtained using the cost-effective VO(acac)2.
sought. A variety of other multistep sequences and rearrange-
ments were also attempted to generate the cross-conjugated
trienes we desired but were met with minimal success. During
these investigations, we became aware of a report of olefina-
tions through a two-step sequence employing acetylide addi-
tions to hindered ketones followed by their subsequent Meyer-
Schuster rearrangement under gold(III) catalysis.5 Of particu-
lar interest was an example employing verbenone, a hin-
dered, unsaturated ketone. This suggested an alternative
approach to the desired dendralenes from dienones 4 via this
two-step sequence. Here we describe the results of this study,
including an efficient olefination strategy to afford sensitive
[3]dendralenes substituted with ester groups on the central
alkene and a variety of unexpected premature cyclization pro-
cesses encountered during attempted Meyer-Schuster rearran-
gement of the initial alkyne adducts. To the best of our
knowledge, these are the first successful examples making
use of R,R0-divinyl propargylic alcohols in the Meyer-
Schuster rearrangement.6
Results and Discussion
Prior to the present work, we had observed very few successful
examples of 1,2-addition of organometallic reagents to 1,4-
pentadien-3-ones, mainly involving allylmagnesium halides.7
Success in these cases was attributed to prior complexation of
Mg2þ to the carbonyl oxygen and addition with allylic inversion
through a six-centered transition state. However, lithium acet-
ylides were expected to be highly effective nucleophiles7b to
afford the corresponding propargyl bis(allylic) alcohols.
Facile addition by acetylides would result from the minimal
steric demand of these cyclindrically symmetric anions.
In the event, initial efforts focused on the highly reactive
lithium salt of ethoxyacetylene and dicyclopentenyl ketone
4a (Scheme 2). Acetylide addition proceeded without inci-
dent to furnish propargyl alcohol 3a in high yield. However,
Exposure of 3b to AuCl3 at elevated temperature imme-
diately gave rise to significant amounts of 5b. Prolonged
exposure led to the formation of 6b at the expense of 5b. This
appears to likely be the result of simple acid-mediated iso-
merization9 to the more thermodynamically stable endocyclic
olefin. Finally, treatment of 3b with TsOH (entry 11) gave
(5) Engel, D. A.; Dudley, G. B. Org. Lett. 2006, 8, 4027–4029.
(6) Some previous attempted Meyer-Schuster reactions employing
R-vinyl propargylic alcohols were not successful, possibly due to the acces-
sibility of other competing acid-mediated processes: Yoshimatsu, M.; Naito,
M.; Kawahigashi, M.; Shimizu, H.; Kataoka, T. J. Org. Chem. 1995, 60,
4798–4802.
(7) (a) Bender, J. A.; Winberg, K. J.; West, F. G. Unpublished results.
(b) Magnesium acetylides were also examined and found to give mixtures of
1,2- and 1,4-addition products.
€
(8) (a) Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410–
3449. (b) Lee, S. I.; Chatani, N. Chem. Commun 2008, 371–384. (c) Yamamoto,
Y.; Gridnev, I. D.; Patil, N. T.; Jin, T. Chem. Cþommun 2009, 5075–5087.
(9) For evidence of AuCl3 acting as an H source, see: Wabnitz, T. B.;
Yu, J.-Q.; Spencer, J. B. Chem.;Eur. J. 2004, 10, 484–493.
J. Org. Chem. Vol. 76, No. 1, 2011 51

Rieder et al.
JOCArticle
TABLE 1. Catalyst Screening
% yielda
entry
catalyst
loading (mol %)
solvent
T (°C)
time (h)
1b
2b
5b
6b
7b
8b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
AuCl3/EtOH
AuCl3
AuCl3
1 M HCl
AuClPPh3
AuClPPh3/AgSbF6
PtCl4
10% H2PtCl6
GaCl3
TiCl4
5/1000
2
2
1000
5
5/5
5
40
100
10
5
5
5
CH2Cl2
THF
THF
CH2Cl2
THF
THF
THF
THF
THF
CH2Cl2
PhMe
PhMe
PhMe
PhMe
rt
50
rt
rt
rt
rt
rt
rt
rt
-78
rt
80
80
80
2 min
2 min
10
90
63
16
48
62
70
10
50
10
70
9
20
8
24b
20
33
60
2 min
2
2
2
3
2
2
2
2
30
28
36
42
46
42
TsOH
62
TiO(acac)2
VO(Oi-Pr)3
VO(acac)2
18
56
84
5
5
aYields for entries 1-4 are based on ratios measured in crude NMR spectra of the product mixtures. Yields for entries 5-14 are for isolated products
after chromatographic purification. bReaction proceeded to only 20% conversion, even after 24 h.
SCHEME 3. TiCl4-Catalyzed Meyer-Schuster Reaction
TABLE 2. Additive Effects in AuCl3-Catalyzed Reactions
alkynylcyclopentene 7b, formally the result of sequential
dehydration/Nazarov cyclization. This result is particularly
interesting, as it indicates that electrocyclization can proceed
faster than Meyer-Schuster rearrangement under dehydra-
tive conditions and suggests a possible mechanistic scheme to
explain the formation of various cyclized byproduct (vide infra).
The effect of various additives on the gold-catalyzed process
was evaluated (Table 2). Addition of electron-rich carbonyl
compounds or silver salts was of little benefit, giving complex
mixtures of products. On the other hand, exogenous water
was found to enhance the rate of conversion to enoate. This
observation is in accord with Dudley’s proposed mechanism,1d
in which added alcohol was found to be beneficial by means of
apparent formation an intermediate ketene acetal. Oddly,
the use of EtOH as a cosolvent in CH2Cl2 gave predomi-
nately 6b. The reason for the discrepancy in the effect of
ethanol and water additives remains obscure.
In contrast to the results of added water, inclusion of
molecular sieves resulted in none of the desired trienoate 1b,
instead providing cyclized alkyne 7b in high yield. Notably,
exposure of 7b to the normal reaction conditions resulted in
hydration of the alkyne and alkene isomerization to yield 6b
as the only isolable product. This outcome implicates 7b as a
possible intermediate in the undesired pathway to 2b, 5b, and
6b. If the premature cyclization products result from dehy-
dration of 3b, then acid scavengers would be expected to
additive
None
AgBF4
AgSbF6
EtOAc
cyclohexanone
EtOH
H2O
loading
time
% yielda
2 min to 2 h
30 min
30 min
30 min
30 min
30 min
5 min
24 h
24 h
5 min
variable
intractable
intractable
intractable
intractable
1: 9b
70
53
51
93c
15 mol %
10 mol %
10 equiv
10 equiv
10 equiv
1 equiv
i-Pr2NEt
2,6-lutidine
˚
4 A MS
10 mol %
10 mol %
aIsolated yield after purification. bRatio refers to 1b:6b measured via
integration of the 1H NMR spectrum of the crude reaction mixture.
Nearly identical results were obtained with CH2Cl2 as the solvent.
cRefers to the isolated yield of 7b.
€
suppress this pathway. Indeed, the addition of Hunig’s base
or 2,6-lutidine quelled the byproduct formation, but at the
cost of significantly increased reaction times.
Given the results above, we propose a dehydrative mech-
anism for the formation of cycloisomerized byproduct
(Scheme 4). Protonation of the teriary alcohol of 3b and
subsequent loss of water would afford the corresponding
pentadienyl cation 9b. Conrotatory ring closure and elim-
ination would furnish 7b.10 Hydration of the resulting alkyne
would provide 5b, which could then isomerize to 6b. The
formation of varying amounts of the trienoate under these
52 J. Org. Chem. Vol. 76, No. 1, 2011

Rieder et al.
JOCArticle
SCHEME 4. Proposed Dehydrative Mechanism
SCHEME 5. Proposed Catalytic Cycle of Gold-Catalyzed
Meyer-Schuster Rearrangement
conditions is presumed to result from hydration of the
initially formed the cation 9b at the oxygenated terminus
and subsequent tautomerization to 1b.
Suppression of cycloisomerization upon the addition of
base suggests that successful gold-mediated Meyer-Schuster
rearrangement would avoid dehydration as the initial step,
thereby avoiding the reactive pentadienyl cation 9b. Activa-
tion of the alkyne by gold(III) could allow for intramolecular
nucleophilic attack by the free alcohol to afford a gold-
substituted oxetene intermediate (Scheme 5) or attack by
water in those cases employing added water.11 Opening of
the oxetene would yield a gold trienoate which, following
protonolysis, would afford the observed trienoate.
Despite the observation of occasional higher yields with
gold(III) catalysis, the capricious nature of those reactions
with these highly conjugated substrates compelled us to
focus on VO(acac)2 as the catalyst of choice for the conver-
sion of divinyl propargyl alcohols to trienoates. Following
optimization, it was found that aromatic hydrocarbon sol-
vents gave the cleanest reactions while elevated temperatures
permitted short reaction times (Table 3). Unfortunately, no
effective E/Z selectivity was obtained when adducts of un-
symmetrically substituted dienones were used. This was not
surprising given the similarity in vinyl group substitution.
One limitation of the VO(acac)2-catalyzed protocol is its
lack of applicability to the adducts of other acetylides apart
from ethoxyacetylene. In these cases, the starting propargyl
alcohols underwent decomposition with no evidence for the
formation of carbonyl-containing compounds.12 Therefore,
the gold-catalyzed Meyer-Schuster reaction was also at-
tempted on acetylide adducts of dienone 4b (Scheme 6).5
With these propargyl alcohols, no Meyer-Schuster products
were observed, but cycloisomerization did occur. Exclusive
formation of the dehydrative cyclization product in good to
excellent yield was possible when the reaction was carried out
in the presence of molecular sieves, giving the corresponding
methylene cyclopentenes. A trans relationship between the
neighboring phenyl substituents was seen in all of these
products, confirmed by X-ray diffraction analysis in the case
of 10b. This stereochemical outcome provides support for a
Nazarov-type conrotatory cyclization pathway. Akai’s mod-
ified conditions13 were also attempted, also giving rise to the
methylenecyclopentenes described.
Finally, one other example of unanticipated reactivity was
observed under gold catalysis with a propargyl alcohol
derived from a different dienone (Scheme 7). Treatment of 4e
under the conditions previously described afforded cyclo-
pentanedione 13e as the major product, along with lesser
(10) The exocyclic elimination over the expected Saytzeff elimination has
also been observed in the tandem Nazarov cyclization/Michael addition of
arenes to dienones with bulky β-substituents: Rieder, C. J.; Fradette, R. J.;
West, F. G. Chem Commun. 2008, 1572–1574.
(11) In the absence of added water, an intermolecular hydroxylation
seems unlikely since trienoate is formed under stringently anhydrous condi-
tions. Additionally, the trienoate is the sole product observed in the crude 1H
NMR with no evidence of hydration product 8.
(12) While the attempted rearrangement of alkynes bearing nonethoxy
groups was unsuccessful, it should be noted that the ester provides a
convenient functional group for further modification via conversion to the
corresponding Weinreb amide and treatment with Grignard reagent. See ref
3 for details.
(13) Egi, M.; Yamaguchi, Y.; Fujiwara, N.; Akai, S. Org. Lett. 2008, 10,
1867–1870.
J. Org. Chem. Vol. 76, No. 1, 2011 53

Rieder et al.
SCHEME 7. Unexpected Gold-Catalyzed Cyclization of 4e
JOCArticle
TABLE 3. Meyer-Schuster Homologation of Dienones
% yieldb
dienonea
R1
R2
R3
R4
3
1
4a
4b
4c
4d
4e
4f
4g
4h
4i
(CH2)3
Ph
i-Pr
(CH2)3
Me
Me
Me
Me
(CH2)4
Me
H
Me
99
99
98
92
93
96
97
99
99
98
61
84
76
81c
80c
78
75
82
70
79
Me
Me
Me
Ph
i-Pr
H
Ph
(CH2)4
(CH2)4
Me
Ph
4-ClPh
4-MeO Ph
H
Me
H
Me
Me
Me
Ph
4-ClPh
4-MeO Ph
4j
Me
aDienones 4a-g, alcohols 3a-g, and trienes 1a-g are previously
described in the Supporting Information for ref 3. bAll yields indicate
isolated product following purification. cUnsymmetrical dienones 4d
and 4e furnished mixtures of geometrical isomers: 1d (inseparable 1:1 E/Z
mixture) and 1e (separable 7:3 E/Z mixture).
On the other hand, catalytic gold(III) chloride appears to
effect Brønsted-acid mediated dehydration. The resulting
pentadienyl cation then undergoes rapid cyclization, gener-
ating alkylidene cyclopentenes. The additionof an aminebase
prevents the initial dehydration sequence, allowing for alkyne
activation by the gold catalyst and generating R,β-unsaturated
esters via a possible oxetene intermediate.
SCHEME 6. Gold-Catalyzed Dehydrative Cyclization of
Propargyl Alcohols
Experimental Section
Reactions were carried out in flame-dried glassware under a
positive argon atmosphere unless otherwise stated. Transfer of
anhydrous solvents and reagents was accomplished with
oven-dried syringes or cannulas. Solvents were distilled before
use: methylene chloride from calcium hydride; tetrahydrofuran,
diethyl ether, and benzene from sodium/benzophenone ketyl;
toluene from sodium metal. Thin-layer chromatography was
performed on glass plates precoated with 0.25 mm Kieselgel 60
F254. Flash chromatography columns were packed with 230-
400 mesh silica gel. Proton nuclear magnetic resonance spectra
(1H NMR) were recorded at 300, 400, or 500 MHz, and coupling
constants (J) are reported in hertz (Hz). Carbon nuclear magnetic
resonance spectra (13C NMR) were recorded at 100 or 125 MHz.
amounts of desired trienoate 1e.14 This surprising product is
believed to arise from gold activation of the alkyne, followed
by formal 5-endo ring closure to give a fused bicyclic inter-
mediate with a bridgehead carbocation. Oxygen-assisted 1,2-
shift followed by gold protonolysis and enol ether hydrolysis
would then afford the observed product 13e. Unique ob-
servation of this cyclization with 4e may be the result of
unusual conformation preferences, but explanation for the
occurrence of this unexpected result requires further study.
n
Typical Procedure for Acetylide Addition15. BuLi (860 μL,
3.1 M, 2.7 mmol) was added to a stirred solution of ethyl ethynyl
ether (475 μL, 2.7 mmol) in THF (4.0 mL) at -78 °C. After 30 min,
the reaction was allowed to warm to 0 °C and held there for 2 h. The
mixture was cooled to -78 °C and dibenzylidene-3-pentanone
4b (710 mg, 2.7 mmol) in THF (6.0 mL) was added dropwise by
cannula forming awhite precipitate. After 30 min, the reactionwas
allowed to warm to 0 °C, which redissolved the precipitate. The
reaction was quenched with H2O (5 mL), and the layers were
separated. The aqueous phase was neutralized with 1 M HCl
(aq) and was extracted with Et2O (3 ꢀ 5 mL). The combined
organic layers were washed with H2O (5 mL) and brine (5 mL),
dried over MgSO4, filtered, and concentrated. Flash chroma-
tography (50 g silica, 20:1 hexanes/EtOAc) gave 901 mg (100%)
of the desired alcohol 3b as a viscous orange oil.
Summary
Because of the sensitivity of R,R0-divinylpropargyl alco-
hols, even under mildly acidic conditions, many of the methods
previously reported fail to promote their Meyer-Schuster
rearrangement to the corresponding [3]dendralenes, generating
a host of byproducts. The use of metal oxides allows for the 1,3-
transposition of the alcohol regioselectively across the alkyne
functionality, generating cross-conjugated trienoates as a result.
(14) Product 13e was formed as a single diastereomer, but the relative
stereochemistry could not be conclusively assigned based on 2D TROESY
data.
(15) References for previously reported dienones 4a-h and preparative
procedures for 4i,j are found in the Supporting Information.
54 J. Org. Chem. Vol. 76, No. 1, 2011

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3-Ethoxyethynyl-1,5-diphenyl-1,4-pentadien-3-ol (3h): yellow
oil; H NMR (500 MHz, CDCl3) δ 7.41-7.44 (m, 4H), 7.29-
(20 mL). The mixture was concentrated and purified through
flash chromatography (20:1 hexanes/EtOAc; 5 g silica) to
provide 49 mg (82%) of the trienyl ester 1h as a viscous yellow
oil: 1H NMR (500 MHz, CDCl3) δ 8.24 (dd, 1H, J = 16.5, 1.0 Hz),
7.56-7.59 (m, 2H), 7.51-7.53 (m, 2H), 7.29-7.42 (m, 6H), 7.06
(br s, 2H), 7.02 (d, 1H, J = 16.5 Hz), 6.03 (s, 1H), 4.25 (q, 2H,
J = 7.1 Hz), 1.35 (t, 3H, J = 7.1 Hz); 13C NMR (125 MHz,
CDCl3) δ 166.7, 151.3, 136.7, 136.5, 136.3, 135.2, 128.8, 128.7,
128.7, 128.6, 127.3, 127.2, 127.1, 125.2, 115.5, 60.0, 14.4; IR
(film) ν 3059, 3026, 2980, 2936, 1702, 1631, 1616, 1580, 1570,
1497, 1448, 1150 cm-1; HRMS (EI) m/z calcd for C21H20O2
(Mþ) 304.1463, found 304.1460 (10%). Anal. Calcd for C21H20O2:
C, 82.68; H, 6.62. Found: C, 83.06; H, 6.87.
1
7.33 (m, 4H), 7.22-7.27 (m, 2H), 6.89 (d, 2H, J = 15.7 Hz),
6.32 (d, 2H, J = 15.7 Hz), 4.21 (q, 2H, J = 7.1 Hz), 1.44 (t, 3H,
J = 7.1 Hz); 13C NMR (125 MHz, CDCl3) δ 136.5, 132.6, 129.1,
128.6, 127.8, 126.8, 96.3, 75.0, 71.3, 38.9, 14.5; IR (film) ν 3457
(br), 3062, 3030, 2981, 2937, 2903, 2253, 1956, 1890, 1630, 1599,
1584, 1495, 1451 1372 cm-1. Anal. Calcd for C21H20O2: C,
82.68; H, 6.62. Found: C, 82.92; H, 6.81.
3-Ethoxyethynyl-1,5-bis(4-chlorophenyl)-2,4-dimethyl-1,4-
pentandien-3-ol (3i): yellow oil; H NMR (500 MHz, CDCl3)
1
δ 7.32 (br d, 4H, J = 8.7 Hz), 7.24 (br d, 4H, J = 8.7 Hz), 7.01
(br s, 2H), 4.19 (q, 2H, J = 7.1 Hz), 2.27 (s, 1H), 1.84 (d, 6H, J =
1.3 Hz), 1.43 (t, 3H, J = 7.1 Hz); 13C NMR (125 MHz, CDCl3)
δ 139.4, 136.3, 132.2, 130.3, 128.3, 125.1, 96.2, 78.3, 74.9, 39.5,
14.5, 13.9; IR (film) νmax 3434 (br), 2982, 2921, 2850, 2262, 1652
(w), 1592 (w), 1490, 1442, 1401 cm-1; HRMS (EI) m/z calcd for
C23H22O2Cl2 (Mþ) 400.0997, found 400.0993 (25%), 402.0968
(17%). Anal. Calcd for C23H22O2Cl2: C, 68.83; H, 5.53. Found:
C, 68.82; H, 5.57.
Ethyl 5-(4-chlorophenyl)-3-(1-methyl-2-(4-chlorophenyl)vinyl)-
4-methyl-2,4-pentadienoate (1i): colorless oil; 1H NMR (500 MHz,
CDCl3) δ 7.32-7.38 (m, 6H), 7.22-7.26 (m, 2H), 6.90 (br s, 1H),
6.24 (q, 1H, J = 1.5 Hz), 6.01 (s, 1H), 4.20 (q, 2H, J = 7.1 Hz), 2.13
(d, 3H, J = 1.5 Hz), 2.10 (d, 3H, J = 1.2 Hz), 1.29 (t, 3H, J =
7.1 Hz); 13C NMR (125 MHz, CDCl3) δ 166.7, 161.4, 137.0, 136.2,
136.1, 134.1, 133.4, 132.6, 130.9, 130.5, 128.7, 128.6, 127.5, 116.2,
60.3, 19.3, 15.7, 14.6; IR (film) ν 2980, 1716, 1589, 1489 cm-1
;
3-Ethoxyethynyl-1,5-bis(4-methoxyphenyl)-2,4-dimethyl-1,4-
pentandien-3-ol (3j). Yellow oil; IR (film) νmax 3478 (br), 3031,
HRMS (EI) m/z calcd for C23H22O2Cl2 (Mþ) 400.0997, found
400.1005 (98%), 402.0980 (67%). Anal. Calcd for C23H22O2Cl2: C,
68.83; H, 5.53. Found: C, 68.69; H, 5.49.
2955, 2913, 2835, 2260, 1607, 1574 (w), 1510, 1465, 1442 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.28 (d, 4H, J = 8.6 Hz), 7.01
(br s, 2H), 6.90 (d, 4H, J = 8.6 Hz), 4.18 (q, 2H, J = 7.1 Hz), 3.38
(s, 6H), 2.29 (s, 1H), 1.87 (d, 6H, J = 1.3 Hz), 1.43 (t, 3H, J =
7.1 Hz); 13C NMR (125 MHz, CDCl3) δ 158.2, 137.3, 130.5, 130.3,
125.4, 113.6, 95.9, 78.6, 74.7, 55.3, 40.0, 14.5, 14.0; HRMS (EI) m/z
calc’d for C25H28O4 (Mþ) 392.1988; found 392.1990 (13%). Anal.
Calcd for C25H28O4 C, 76.50; H, 7.19. Found C, 76.35; H, 6.80.
2,4-Dimethyl-1,5-diphenyl-3-phenylethynyl-1,4-pentadien-3-
ol (3k): white solid; mp 95-96 °C (uncorr); 1H NMR (400 MHz,
CDCl3) δ 7.53-7.57 (m, 2H), 7.36-7.41 (m, 11H), 7.26-7.31
(m, 2H), 7.22 (q, 2H, J = 1.3 Hz), 2.54 (s, 1H), 2.00 (d, 6H, J =
1.3 Hz); 13C NMR (100 MHz, CDCl3) δ 137.8, 137.7, 131.8,
129.1, 128.6, 128.4, 128.2, 126.9, 126.7, 122.6, 89.9, 87.6, 78.8,
13.9; IR (film) ν 3445 (br), 3081, 3056, 3023, 2981, 2953, 2917,
2225, 1599, 1499, 1443 cm-1; HRMS (EI) m/z calc’d for
C27H24O (Mþ) 364.1827, found 364.1828 (37%). Anal. Calcd
for C27H24O: C, 88.97; H, 6.64. Found: C, 88.88; H, 6.63.
2-Methyl-3-(1-methyl-2-phenylvinyl)-1-phenylnon-1-en-4-yn-
3-ol (3l): colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.32-7.45
(m, 8H), 7.21-7.26 (m, 2H), 7.10 (br s, 2H), 2.35 (t, 2H, J =
6.9 Hz), 2.22 (d, 1H, J = 1.4 Hz), 1.88 (d, 6H, J = 1.3 Hz),
1.54-1.62 (m, 2H), 1.43-1.53 (m, 2H), 0.95 (t, 3H, J = 7.2 Hz);
13C NMR (100 MHz, CDCl3) δ 138.2, 137.8, 129.6, 129.0, 128.4,
128.1, 126.5, 126.3, 88.5, 81.0, 78.4, 30.7, 22.0, 18.6, 13.8, 13.6;
IR (film) ν 3456 (br), 3081, 3056, 3023, 2957, 2931, 2872, 2861,
2232, 1622, 1492, 1445 cm-1; HRMS (EI) m/z calcd for C25H28O
(Mþ) 344.2140, found 344.2135 (2.5%), 326.2040 [M - H2O]þ
(100%). Anal. Calcd for C25H28O: C, 87.16; H, 8.19. Found: C,
87.21; H, 8.01.
2,4-Dimethyl-1,5-diphenyl-3-(trimethylsilyl)ethynyl-1,4-pen-
tadien-3-ol (3m): Colorless oil; 1H NMR (400 MHz, CDCl3)
δ 7.32 - 7.39 (m, 8H), 7.22 - 7.27 (m, 2H), 7.11 (br s, 2H), 1.89
(d, 6H, J = 1.2 Hz), 0.24 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 137.6, 137.4, 129.0, 128.0, 126.6, 126.5, 105.9, 92.5, 78.4, 13.6,
-0.27; IR (film) ν 3549, 3446 (br) 3082, 3057, 3024, 2959, 2919,
2860, 2163, 1600, 1494, 1444, 1381, 1251 cm-1; HRMS (EI) m/z
calcd for C24H28SiO (Mþ) 360.1910, found 360.1898 (10%),
342.1799 [M - H2O]þ (33%). Anal. Calcd for C24H28SiO: C,
79.95; H, 7.83. Found: C, 79.92; H, 7.89.
Typical Procedure for VO(acac)2 Rearrangements. Vanadium
oxyacetylacetonate (2 mg, 8 μmol) was added to a stirred solu-
tion of dibenzylidene-2-(ethoxyethynyl)-2-propanol 3b (60 mg,
0.20 mmol) in toluene (2 mL). The reaction was then brought to
80 °C over 1 h and held there for 1 h. The reaction mixture was
cooled and filtered through a silica gel plug with diethyl ether
Ethyl 5-(4-methoxyphenyl)-3-(1-methyl-2-(4-methoxyphenyl)-
vinyl)-4-methyl-2,4-pentadienoate (1j): colorless oil; 1H NMR
(500 MHz, CDCl3) δ 7.34-7.38 (m, 2H), 7.26-7.30 (m, 2H),
6.91-6.96 (m, 5H), 623 (br s, 1H), 5.96 (s, 1H), 4.18 (q, 2H, J =
7.2 Hz), 3.85 (s, 3H), 3.85 (s, 3H), 2.14 (d, 3H, J = 1.4 Hz), 2.12
(d, 3H, J = 1.1 Hz), 1.28 (t, 3H, J = 7.2 Hz); 13C NMR (125 MHz,
CDCl3) δ 167.1, 162.7, 159.1, 158.5, 135.1, 134.8, 131.2, 130.7,
130.4, 130.3, 128.0, 115.1, 113.92, 113.90, 60.2, 55.5, 19.3, 15.8,
14.6; IR (film) ν 2978, 2954, 2836, 1715, 1606, 1586, 1511,
1464 cm-1; HRMS (EI) m/z calcd for C25H28O4 (Mþ) 392.1988,
found 392.1994 (100%). Anal. Calcd for C25H28O4: C, 76.50; H,
7.19. Found: C, 76.10; H, 7.23.
Typical Procedure for Gold-Catalyzed Reactions. AuCl3 (1.3 mg,
˚
4 μmol) and 4 A MS (10 mg) were added to a 3 dram vial equipped
with a septum. The vial was alternately evacuated and flushed with
argon. THF (4.0 mL) was then added and allowed to stand for
15 min. A solution of dibenzylidene-3-(2-phenylethynyl)-3-pentanol
3i (20 mg, 0.055 mmol) in THF (1 mL) was added via cannula. After
5 min, the reaction mixture was filtered through silica gel (2 g) with
Et2O (25 mL). The filtrate was concentrated and purified by flash
chromatography (10 g silica, 20:1 hexanes/EtOAc) to give 19 mg
(98%) of dienyne 10b as a crystalline white solid (mp = 109-
110 °C).
1-Methyl-3-methylene-4,5-trans-diphenyl-1-cyclopentene-1-
acetic acid, ethyl ester (5b): yellow oil; 1H NMR (400 MHz,
CDCl3) δ 7.32-7.08 (m, 10H), 4.93 (d, 1H, J = 2.1 Hz), 4.55
(m, 1H), 4.20 (q, 2H, J = 7.1 Hz), 3.75 (m, 1H), 3.68 (m, 1H),
3.39 (d, 1H, JAB = 15.8 Hz), 3.36 (d, 1H, JAB = 15.8 Hz), 1.70
(s, 3H), 1.30 (t, 3H, J = 7.1 Hz); 13C NMR (125 MHz, CDCl3)
δ 170.9, 157.5, 147.5, 145.6, 143.9, 132.3, 128.6, 128.5, 127.6,
127.6, 126.6, 126.2, 102.2, 64.45, 60.8, 58.4, 31.4, 14.2, 13.9; IR
(film) ν 3082, 30631, 3027, 2980, 2930, 1736, 1627, 1601, 1492,
1452, 1171 cm-1; HRMS (EI) m/z calcd for C23H24O2 (Mþ)
332.1776, found 332.1778 (100%). Anal. Calcd for C23H24O: C,
83.10; H, 7.28. Found: C, 82.77; H, 7.46.
2-Ethoxyethynyl-1-methyl-3-methylene-4,5-trans-diphenyl-1-
cyclopentene (7b): yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.20-
7.33 (m, 6H), 7.07-7.14 (m, 4H), 5.22 (d, 1H, J = 2.4 Hz), 4.60
(d, 1H, J = 1.4 Hz), 4.27 (q, 2H, J = 7.1 Hz), 3.81 (m, 1H), 3.74
(m, 1H), 1.81 (d, 3H, J = 1.3 Hz), 1.50 (t, 3H, J = 7.1 Hz); 13
C
NMR (100 MHz, CDCl3) δ 159.8, 145.1, 143.8, 128.9, 128.7, 128.1,
127.9, 126.9, 126.5, 103.9, 75.4, 64.4, 58.7, 33.3, 15.5, 14.7; IR (film)
ν 3083, 3061, 3027, 2982, 2927, 2852, 2256, 1634, 1601, 1492,
1452 cm-1; HRMS (EI) m/z calcd for C23H22O (Mþ) 314.1670,
J. Org. Chem. Vol. 76, No. 1, 2011 55

Rieder et al.
JOCArticle
found 314.1669 (40%). Anal. Calcd for C23H22O: C, 87.86; H, 7.05.
Found: C, 87.97; H, 7.27.
1-Methyl-3-methylene-4,5-trans-diphenyl-2-phenylethynyl-1-
cyclopentene (10b): white solid; mp 109-110 °C (uncorr); H
NMR (400 MHz, CDCl3) δ 7.54-7.56 (m, 2H), 7.28-7.38 (m, 7H),
7.21-7.25 (m, 2H), 7.09-7.15 (m, 4H), 5.36 (dq, 1H, J = 2.5,
0.5 Hz), 4.70 (dq, 1H, J = 2.0, 0.5 Hz), 3.87 (m, 1H), 3.80
(m, 1H), 1.92 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 155.4,
154.9, 144.5, 143.0, 131.7, 131.5, 128.7, 128.6, 128.5, 128.3, 128.3,
128.3, 128.3, 128.2, 128.0, 127.8, 127.7, 126.8, 126.4, 124.1, 123.3,
104.7, 95.3, 82.8, 64.6, 58.5, 15.6; IR (film) ν 3081, 3060, 3027, 2969,
2929, 2905, 2206, 1600, 1491, 1452 cm-1; HRMS (EI) m/z calcd for
C27H22 (Mþ) 346.1721, found 346.1716 (45%). Anal. Calcd for
C27H22: C, 93.60; H, 6.40. Found: C, 93.41; H, 6.41.
2149, 1636, 1600, 1494, 1452, 1261 cm-1; HRMS (EI) m/z calcd for
C24H26Si (Mþ) 342.1804, found 342.1803 (78%). Anal. Calcd for
C24H26Si: C, 84.15; H, 7.75. Found: C, 84.30; H, 7.80.
1
4-Isopropenylhexahydro-1,3-indandione (13e): colorless oil;
1H NMR (500 MHz, CDCl3) δ 5.94 (m, 1H), 5.82 (m, 1H),
3.75 (m, 1H), 3.39 (dd, 1H, J = 15.6, 2.2 Hz), 2.92 (dd, 1H, J =
15.6, 1.4 Hz), 2.56 (m, 1H), 2.10 (m, 1H), 1.96 (dd, 3H, J = 1.5,
0.9 Hz), 1.64 (m, 2H), 1.58 (m, 2H), 1.24 (m, 1H), 1.11 (m, 1H);
13C NMR (125 MHz, CDCl3) δ 206.4, 203.8, 140.3, 126.0, 60.0,
58.2, 41.6, 34.2, 22.2, 21.3, 20.7, 18.6; IR (film) ν 2932, 2858,
1780, 1664, 1448 cm-1; HRMS (EI) m/z calcd for C12H16O2
(Mþ) 192.1150, found 192.1151.
Hydration of 3b with GaCl3. GaCl3 (5 mg, 28 μmol) was added
to a 5 mL round-bottom flask and alternatively evacuated and
flushed with argon. (N.B. During weighing and transfer, the
white/gray solid GaCl3 begins to smoke, and portions melt into
a black liquid.) To this was added THF (1 mL) and the mixture
cooled to -40 °C. To this was added 3b (9.5 mg, 29 μmol) in THF
(1 mL) and the mixture immediately brought toroom temperature.
After 1 h, the reaction was treated with saturated aqueous
NaHCO3 (1 mL) and extracted with Et2O (3 ꢀ 3 mL). The com-
bined organic phases were dried over MgSO4, concentrated, and
purified with PTLC (10:1 hexanes/EtOAc) to give 1b (2.7 mg,
28%) and 8b (4.4 mg, 46%):
Ethyl 3-hydroxy-4-methyl-3-(1-methyl-2-phenylvinyl)-5-phe-
nyl-4-pentenoate (8b): colorless oil; 1H NMR (500 MHz, CDCl3)
δ 7.20-7.36 (m, 10H), 6.70 (s, 2H), 4.75 (s, 1H), 4.21 (q, 2H, J =
7.1 Hz), 3.02 (s, 2H), 1.84 (d, 6H, J = 1.3 Hz), 1.27 (t, 3H, J =
7.1 Hz); 13C NMR (100 MHz, CDCl3) δ 173.2, 139.5, 137.9,
129.0, 128.2, 128.1, 126.4, 125.7, 79.5, 61.1, 41.4, 14.1; IR (film) ν
3470 (br), 3057, 3023, 2958, 2927, 2857, 1719, 1599, 1492, 1445,
1370, 1195, 1162 cm-1; HRMS (EI) m/z calcd for C23H24O2
[M - H2O]þ 331.1776, found 331.1779 (100%).
2,4-Dimethyl-1,5-diphenyl-3-phenylethynyl-1,3-cyclopenta-
diene (endo-10b). Upon standing in the presence of trace acid or
chromatography on untreated silica gel, 10b underwent double-
bond isomerization into the ring to give varying mixtures of 10b
and the corresponding alkynylcyclopentadiene endo-10b: yellow
1
oil; H NMR (400 MHz, CDCl3) δ 7.07-7.56 (m, 15H), 4.45
(q, 1H, J = 1.9 Hz), 2.30 (d, 3H, J = 1.9 Hz), 2.02 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ 154.0, 142.1, 138.3, 137.1, 136.3,
131.5, 128.6, 128.4, 128.3, 128.3, 128.2, 128.0, 126.5, 126.0, 125.3,
123.6, 94.5, 84.4, 63.0, 14.4, 13.5; IR (film) ν 3080, 3060, 3027, 2967,
2928, 2871, 2192, 1599, 1491, 1451 cm-1; HRMS (EI) m/z calcd for
C27H22 (Mþ) 346.1721, found 346.1719; Anal. Calcd for C27H22:
C, 93.60; H, 6.40. Found: C, 93.96; H, 6.55.
1-Methyl-3-methylene-4,5-trans-diphenyl-2-(1-hexynyl)-1-cy-
clopentene (11b): colorless oil; 1H NMR (400 MHz, CDCl3)
δ 7.05-7.33 (m, 10H), 5.25 (dq, 1H, J = 2.5, 0.7 Hz), 4.26
(dq, 1H, J = 2.0, 0.7 Hz), 3.81 (m, 1H), 3.74 (m, 1H), 2.50 (t, 2H,
J = 7.0 Hz), 1.83 (d, 3H, J = 1.5 Hz), 1.48-1.69 (m, 4H), 0.98
(t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 156.3, 153.3,
145.0, 143.5, 128.9, 128.7, 128.5, 128.4, 128.2, 127.9, 126.9, 126.7,
126.6, 104.4, 96.7, 74.0, 64.6, 58.7, 31.3, 22.2, 19.5, 15.6, 13.9; IR
(film) ν 3085, 3061, 3029, 2959, 2932, 2872, 2215, 1681, 1601,
1495, 1452 cm-1; HRMS (EI) m/z calcd for C25H26 (Mþ)
326.2035, found 326.2032 (15%). Anal. Calcd for C25H26: C,
91.97; H, 8.03. Found C, 91.80; H, 8.16.
Acknowledgment. We thank the National Science and
Engineering Research Council of Canada (NSERC) and the
Canadian Institute for Health Research (CIHR) for their
support of this work as well as the province of Alberta for the
Queen Elizabeth II Graduate Scholarship to C.J.R. We
thank Dr. Robert McDonald for the X-ray crystallographic
analysis of 10b.
1-Methyl-3-methylene-4,5-trans-diphenyl-2-(trimethylsilyl)-
ethynyl-1-cyclopentene (12b). Compound 12b partially isomerizes to
its corresponding endo-isomer during the necessary time frame of
13C NMR spectral acquisition: white solid; H NMR (500 MHz,
1
CDCl3) δ 7.20-7.32 (m, 6H), 7.10-7.12 (m, 2H), 7.05-7.08
(m, 2H), 5.27 (dq, 1H, J = 2.5, 0.6 Hz), 4.66 (dq, 1H, J = 2.1,
0.6 Hz), 3.82 (m, 1H), 3.75 (m, 1H), 1.886 (app dt, 3H, J = 1.6,
0.6 Hz), 0.26 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.7, 155.3,
144.4, 142.9, 128.7, 128.5, 127.8, 127.7, 126.8, 126.4, 104.7, 100.6,
64.5, 58.5, 15.6, 0.2; IR (film) ν 3083, 3061, 3027, 2961, 2926, 2854,
Supporting Information Available: Experimental procedures
for 4i,j; 1H and 13C NMR spectra for 1h-j, 3i-m, 4i,j, 5b, 7b, 8b,
10b, endo-10b, 11b, 12b, and 13e; and ORTEP structure and X-ray
data for 10b. This material is available free of charge via the Internet
at http://pubs.acs.org.
56 J. Org. Chem. Vol. 76, No. 1, 2011