Cycloaromatization protocol for synthesis of polysubstituted phenol derivatives: Method development and mechanistic studies

Article abstract of DOI:10.1021/jo3010952

The scope of the cycloaromatization of propargylic ethers was explored using operationally simple air- and moisture-insensitive conditions. Highly substituted phenol derivatives were obtained in high yields. Mechanistic experiments indicate that the reaction occurs by an electrocyclization followed by 1,3-proton transfer.

Full text of DOI:10.1021/jo3010952

Note
pubs.acs.org/joc
Cycloaromatization Protocol for Synthesis of Polysubstituted Phenol
Derivatives: Method Development and Mechanistic Studies
William T. Spencer III and Alison J. Frontier*
Department of Chemistry, University of Rochester, Rochester, New York 14627, United States
S
* Supporting Information
ABSTRACT: The scope of the cycloaromatization of
propargylic ethers was explored using operationally simple
air- and moisture-insensitive conditions. Highly substituted
phenol derivatives were obtained in high yields. Mechanistic
experiments indicate that the reaction occurs by an electro-
cyclization followed by 1,3-proton transfer.
We were impressed by the high yield and operational
simplicity of the reaction, which could be run in wet solvent
under air and gave 4a in high purity after workup without
chromatography. A variety of propargylic ethers were prepared
to test the scope of the reaction (Scheme 2). We expected that
ecause of their pervasive presence in naturally occurring
Bcompounds, drugs, and materials, new protocols for the
synthesis of substituted phenols are of value, especially if they
can be conducted inexpensively and conveniently. Procedures
that deliver the aromatic system in one step from an acyclic
precursor are valuable components of the toolbox because they
can allow access to substitution patterns that cannot be
installed directly through conventional aromatic substitution or
cross-coupling chemistry. In this note, we report an efficient
method for the preparation of functionalized phenol derivatives.
We recently reported our synthetic efforts toward the
synthesis of the cytostatic natural product ( )-rocaglamide,1
in which the key step was an oxidation-initiated Nazarov
cyclization2 of a benzofuryl allene intermediate. During these
studies, we found that treatment of propargylic ether 1a with a
substoichiometric amount of Triton B in DMSO was the most
effective way to isomerize 1a to terminal allene 2 (Scheme 1).
Oxidation-initiated Nazarov cyclization with dimethyldioxirane
(DMDO) produced des-phenyl rocaglamide intermediate 3. It
was interesting to find that when 1a was treated with Triton B
in DMSO at 80 °C overnight, the product isolated was 4a (90%
yield), instead of the expected alkoxyallene 2.
Scheme 2. Synthesis of Propargylic Ethers
Scheme 1. Cyclization Reactions of Propargylic Ether 1a
substrates of type 1, bearing an alkoxyl substituent, would
facilitate the initial allene isomerization and polarize electro-
cyclization of the resulting dienyl allene. As such, we treated
aldehydes 5a, 5b, and 5d−h with an alkynylmetal to form
intermediate propargylic alcohols, which were O-alkylated to
give propargylic ethers 1a−h.
Subjection of propargylic ethers 1a−h to the cyclo-
aromatization conditions (Triton B, DMSO, 80 °C) provided
benzenoid products 4a−h (Scheme 3).
Alkenes (4g and 4h), benzene rings (4a−c and 4f), and
heteroaromatic rings (4a and 4e) were all viable π-components
Received: June 21, 2012
Published: August 14, 2012
© 2012 American Chemical Society
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Note
Scheme 3. Cycloaromatization of Propargylic Ethers
Scheme 4. Isomerization−Electrocyclization−Isomerization
of Propargyl Dienes
intermediate π-systems,4a,b,d,e,5b,c with no coherent study of the
entire reaction sequence. This prompted us to conduct a
systematic examination of the three-step cycloaromatization
sequence that converts propargyl dienes I into phenol
derivatives V (R1 = OR).
In one cycloaromatization experiment of 1h using identical
conditions as shown in Scheme 3, we isolated a methyl-
enecyclohexadiene intermediate of type IV instead of the
expected product 4h. This supports electrocyclization of a
dienyl allene of type III, which must then undergo subsequent
isomerization to form the aromatic product V.
Two isomerization mechanisms are possible: [1,7]-hydride
shift or proton transfer. In most reports of related cyclo-
aromatizations, a mechanism for isomerization is not proposed.
However, Burton4a and Zhou4d have shown through
deuterium-labeling experiments that proton transfer from the
solvent is at least partially responsible for isomerization. We
were interested in extending these studies in the context of our
system.
Experiments with base provide insight into the isomerization
mechanism: when allene 2 is heated in DMSO at 80 °C in the
absence of Triton B, we observed a mixture of starting allene 2,
cycloaromatized product 4a, and some decomposition. A
proton transfer mechanism is consistent with the experimental
observation that base improves isomerization efficiency and
suggests that a [1,7]-hydride shift is not the primary
mechanistic pathway.
To examine whether the isomerization is intramolecular
([1,3]-proton transfer) or intermolecular (involving solvent),
we subjected deuterium-labeled substrate 1i to the reaction
conditions (Scheme 5). We observed a mixture of 35% α-
toluyl-nondeuterated product (4i) and 65% -deuterated (4i′)
product, indicating that some proton transfer from the solvent
must occur.8
To determine whether deuterium incorporation in the
product is the result of intra- or intermolecular deuterium
transfer between molecules of type IV, we performed a
deuterium-labeling crossover experiment (Scheme 6).
We subjected a 1:1 mixture of 1c/1i to the reaction
conditions and did not observe crossover product 4c′, which is
consistent with a [1,3]-intramolecular proton transfer mecha-
nism.9 The ratio of 4i to 4i′ was the same as that obtained in
the original labeling experiment (Scheme 5).
a
Temperature of 95 °C required; 80 °C produced only allene
intermediate.
in the cycloaromatization. In multiple cases (4b, 4c, 4e, and
4g), the crude products were obtained pure and in quantitative
yields. However, naphthalene-containing propargylic ether 1d
cyclized less efficiently, yielding phenanthrene product 4d in
47% yield. Cyclization of propargylic ether 1f, in which both
non-allene π-components are benzene rings, proceeded in a
modest 57% yield and required heating (95 °C) to achieve
complete conversion to 4f. Cyclization of propargylic ether 1h
(R4 = Ph) produced a low yield of 4h (16%). In this reaction,
we observed incomplete conversion of the propargylic ether to
the allenol ether, sluggish cyclization, and decomposition.
Another substrate with a terminal alkyne substituent (R4 = n-
Bu) gave a similar result: incomplete alkyne-allene isomer-
ization and inefficient electrocyclization, resulting in a low yield.
Cycloaromatizations of both propargyl dienes of type I3 and
conjugated propargyl dienes of type II4 have been reported.
With respect to the specific case of dienyl propargylic ethers (I;
R1 = OR), the only examples we found involved highly reactive
π-systems bearing multiple heteroatoms.3 These cycloaromati-
zation reactions have been postulated to begin with base-
catalyzed or -promoted isomerization of I or II to dienyl allene
III,5 which undergoes electrocyclization to form methylenecy-
clohexadiene intermediate IV,6,7 which finally isomerizes to
aromatic system V (Scheme 4). In many of the reported
examples, the three-step sequence converting I/II to V occurs
in situ, without isolation or even observation of intermediates
III and IV. Support for the proposed mechanism in Scheme 4 is
limited to data from individual experiments across different
If the basic conditions employed in the cycloisomerization of
deuterated substrate 1i were altered, different product ratios
were observed. When sodium methoxide powder in DMSO was
used rather than Triton B (40% in methanol) in DMSO, nearly
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Note
If the electrocyclization rate is unchanged, isolation of the
uncyclized product suggests that the isomerization following
electrocyclization is less favorable under these reaction
conditions. Furthermore, the 1:1 ratio of 4i/4i′ indicates a
decrease in intramolecular proton transfer relative to that
observed using Triton B (∼2:1 ratio; see Scheme 5). One
possible explanation is that, at low methanol concentrations,
the methanol−carbanion complex in the intramolecular 1,3-
proton transfer mechanism proposed by Cram is less likely to
form.9 This would result in a decrease in the rate of
intramolecular 1,3-proton transfer relative to intermolecular
proton transfer and may allow the simple isomerization
pathway that produces 6 to become competitive. The
heightened basicity of the medium may also favor the
conversion of 1i to 6.11
Scheme 5. Deuterium-Labeling Experiment
It seems plausible that biaryl product 6 may be formed from
intermediate allene of type III (Scheme 4) through a series of
base-catalyzed double-bond transpositions. Since reducing the
alcohol content in the alcohol/DMSO solvent systems is
known to dramatically increase the rates of alkoxide-catalyzed
isomerizations and other reactions that involve deprotona-
tion,11 it is not surprising that this alternate pathway competes
with cycloaromatization under these conditions.
Scheme 6. Double-Labeling Crossover Experiment
In conclusion, we have demonstrated a simple method for
the base-catalyzed cycloaromatization of propargylic ethers and
provided mechanistic evidence that the reaction proceeds
through the electrocyclization of an allenyl diene followed by a
combination of intra- and intermolecular proton transfer. The
reaction is not air- and moisture-sensitive, tolerates a range of
alkenyl and aromatic π-components, and proceeds in good to
excellent yields, making it an appealing option for the synthesis
of phenol derivatives.
EXPERIMENTAL SECTION
■
General Experimental Methods. Reactions were carried out in
oven- or flame-dried glassware under argon with magnetic stirring
unless otherwise specified. Dry solvents were obtained from a solvent
purification system or distilled over calcium hydride prior to use.
Reagents were used as received unless otherwise specified. n-Butyl
lithium was titrated periodically with diphenylacetic acid. Thin layer
chromatography was visualized with p-anisaldehyde/heat, potassium
permanganate/heat, vanillin/heat, or a UV lamp. H NMR and 13C
1
NMR spectroscopy were performed at ambient temperature. 2-
Bromocyclohex-1-enecarbaldehyde,12 phenylboronic acid-d5,13 and
4,6-dimethoxy-2-(4-methoxyphenyl)benzofuran-3-carbaldehyde
(5a)1b were prepared according to literature procedures.
General Procedure for the Synthesis of Aldehydes 5b and
5d−i. To an argon-sparged solution of the corresponding bromide
(400 mg, 2.13 mmol), boronic acid derivative (519 mg, 4.26 mmol),
and cesium carbonate (2.08 g, 6.39 mmol) in dry THF (21 mL) was
added tetrakis(triphenylphosphine)palladium(0) (492 mg, 0.426
mmol). After an additional 2 min sparging, the mixture was stirred
at 60 °C for 16 h at which time it was diluted with water (100 mL) and
extracted with dichloromethane (3 × 150 mL). The combined
organics were washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The resulting residue was flash
chromatographed on silica gel to afford the product aldehyde.
3,4,5,6-Tetrahydro-[1,1′-biphenyl]-2-carbaldehyde (5b). Com-
pound 5b was obtained from 2-bromocyclohex-1-enecarbaldehyde
and phenylboronic acid following the general procedure. Silica gel
purification eluting with 99:1−9:1 hexanes/EtOAc afforded aldehyde
5b (360 mg, 92%) as a clear oil: 1H NMR (400 MHz, CDCl3) δ 9.54
(s, 1H), 7.50−7.36 (m, 3H), 7.33−7.25 (m, 2H), 2.61−2.58 (m, 2H),
2.43−2.39 (m, 2H), 1.94−1.67 (m, 4H); 13C NMR (101 MHz,
CDCl3) δ 193.5, 159.3, 139.4, 135.7, 128.6, 128.2, 128.1, 33.9, 22.4,
22.3, 21.4 (lit.14 1H NMR, 13C NMR).
a 1:1 mixture of cycloaromatization products 4i and 4i′ (73%
combined yield) was obtained, along with 27% of unexpected
biaryl product 6 (Scheme 7). Finally, when 1i was treated with
sodium methoxide in neat methanol,10 no reaction was
observed.
Scheme 7. Competing Isomerization
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Note
2-(Naphthalen-1-yl)cyclohex-1-enecarbaldehyde (5d). Com-
pound 5d was obtained from 2-bromocyclohex-1-enecarbaldehyde
and 1-naphthylboronic acid following the general procedure. Silica gel
purification eluting with 99:1−9:1 hexanes/EtOAc afforded aldehyde
(0.10 mL, 0.77 mmol) was added slowly. The mixture was stirred to
room temperature over 16 h, then diluted with saturated aqueous
ammonium chloride (70 mL) and a 5% w/w aqueous solution of
lithium chloride (80 mL). The resulting aqueous mixture was extracted
with ethyl acetate (3 × 150 mL), and the combined organics were
washed with a 5% w/w aqueous solution of lithium chloride (4 × 50
mL) and brine, dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The resulting yellow residue was purified by
flash chromatography on silica gel (95:5−7:3 hexanes/ethyl acetate) to
afford the product propargylic ether.
4,6-Dimethoxy-3-(1-((4-methoxybenzyl)oxy)prop-2-yn-1-yl)-2-(4-
methoxyphenyl)benzofuran (1a). Compound 1a was obtained from
compound 5a following the general procedure, using para-
methoxybenzyl chloride as the alkylating agent. Silica gel purification
eluting with 99:1−9:1 hexanes/EtOAc afforded propargylic ether 1a
(125 mg, 36% over 2 steps): 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J
= 8.9 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 6.83
(d, J = 8.6 Hz, 2H), 6.63 (d, J = 1.9 Hz, 1H), 6.30 (d, J = 1.9 Hz, 1H),
6.02 (d, J = 2.4 Hz, 1H), 4.69 (d, J = 11.5 Hz, 1H), 4.60 (d, J = 11.5
Hz, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 2.37
(d, J = 2.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 159.8, 159.2,
158.9, 155.4, 154.3, 152.5, 130.1, 129.7, 128.3, 123.1, 113.6, 113.5,
111.9, 111.7, 94.6, 87.9, 81.5, 73.6, 69.8, 61.6, 55.8, 55.4, 55.3; HRMS
(ESI+, TOF) m/z calcd for C28H26O6Na [M + Na+] 481.1627, found
481.1631.
1
5d (845 mg, 84%): H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H),
7.90−7.79 (m, 2H), 7.76−7.65 (m, 1H), 7.57−7.38 (m, 3H), 7.38−
7.28 (m, 1H), 2.64−2.55 (m, 1H), 2.46−2.36 (m, 2H), 1.89−1.72 (m,
4H); 13C NMR (125 MHz, CDCl3) δ 193.5, 158.6, 137.5, 137.1,
133.5, 131.4, 128.5, 128.2, 126.7, 126.2, 125.8, 125.1, 125.1, 34.7, 30.9,
22.5, 22.0, 21.7; HRMS (ESI+, TOF) m/z calcd for C17H17O [M + H]
237.1279, found 237.1269.
2-(Thiophen-3-yl)cyclohex-1-enecarbaldehyde (5e). Compound
5e was obtained from 2-bromocyclohex-1-enecarbaldehyde and 3-
thienylboronic acid following the general procedure. Silica gel
purification eluting with 99:1−9:1 hexanes/EtOAc afforded aldehyde
5e (575 mg, 70%): 1H NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 7.37
(dd, J = 5.0, 3.0 Hz, 1H), 7.20 (dd, J = 3.0, 1.2 Hz, 1H), 7.07 (dd, J =
5.0, 1.2 Hz, 1H), 2.62−2.49 (m, 2H), 2.42−2.28 (m, 2H), 1.86−1.64
(m, 4H); 13C NMR (101 MHz, CDCl3) δ 193.5, 153.5, 139.7, 136.5,
128.0, 126.0, 125.1, 33.3, 22.6, 22.5, 21.4; HRMS (EI+, sector
instrument) m/z calcd for C11H12OS [M] 192.0609, found 192.0616.
[1,1′-Biphenyl]-2-carbaldehyde (5f). Compound 5f was obtained
from 2-bromobenzaldehyde and phenylboronic acid following the
general procedure. Silica gel purification eluting with 99:1−9:1
1
hexanes/EtOAc afforded aldehyde 5f (1.36 g, 92%): H NMR (400
MHz, CDCl3) δ 10.00 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.65 (dt, J =
7.8, 1.3 Hz, 1H), 7.56−7.33 (m, 7H); 13C NMR (101 MHz, CDCl3) δ
192.3, 145.9, 137.7, 133.7, 133.5, 130.8, 130.1, 128.4, 128.1, 127.8,
127.5 (lit.15 1H NMR, 13C NMR).
6-(1-Methoxyprop-2-yn-1-yl)-2,3,4,5-tetrahydro-1,1′-biphenyl
(1b). Compound 1b was obtained from compound 5b following the
general procedure, using iodomethane as the alkylating agent. Silica gel
purification eluting with 99:1−9:1 hexanes/EtOAc afforded prop-
argylic ether 1b (184 mg, 52% over 2 steps) along with recovered
2-(Prop-1-en-2-yl)benzaldehyde (5g). Compound 5g was obtained
from 2-bromobenzaldehyde and 4,4,5,5-tetramethyl-2-(prop-1-en-2-
yl)-1,3,2-dioxaborolane following the general procedure, using
potassium phosphate as the base. Silica gel purification eluting with
1
propargylic alcohol (48 mg, 14%): H NMR (400 MHz, CDCl3) δ
7.35−7.29 (m, 2H), 7.28−7.22 (m, 1H), 7.19−7.14 (m, 2H), 4.46 (d, J
= 2.1 Hz, 1H), 3.19 (s, 3H), 2.45 (d, J = 2.1 Hz, 1H), 2.42−2.18 (m,
4H), 1.78−1.69 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 142.4,
138.5, 130. 5, 128.2, 128.1, 126.9, 82.1, 73.7, 71.2, 55.8, 32.5, 23.3,
23.0, 22.5; HRMS (ESI+, TOF) m/z calcd for C16H19O [M + H+]
227.1436, found 227.1436.
1
99:1−96:4 hexanes/EtOAc afforded aldehyde 5g (657 mg, 84%): H
NMR (400 MHz, CDCl3) δ 10.25 (s, 1H), 8.00−7.89 (m, 1H), 7.64−
7.52 (m, 1H), 7.50−7.32 (m, 4H), 5.48 (s, 1H), 4.96 (s, 1H), 2.22 (s,
3H) (lit.16 1H NMR).
2-Vinylcyclohex-1-enecarbaldehyde (5h). Compound 5h was
obtained from 2-bromocyclohex-1-enecarbaldehyde and 4,4,5,5-
tetramethyl-2-vinyl-1,3,2-dioxaborolane following the general proce-
dure, using potassium phosphate as the base. Silica gel purification
eluting with 99:1−8:2 hexanes/EtOAc afforded aldehyde 5h (30 mg,
6-(1-(Benzyloxy)prop-2-yn-1-yl)-2,3,4,5-tetrahydro-1,1′-biphenyl
(1c). Compound 1c was obtained from compound 5b following the
general procedure, using benzyl bromide as the alkylating agent. Silica
gel purification eluting with 99:1−9:1 hexanes/EtOAc afforded
1
propargylic ether 1c (240 mg, 73% over 2 steps): H NMR (400
1
MHz, CDCl3) δ 7.37−7.19 (m, 8H), 7.18−7.08 (m, 2H), 4.69 (d, J =
2.2 Hz, 1H), 4.47 (d, J = 11.6 Hz, 1H), 4.33 (d, J = 11.6 Hz, 1H), 2.48
(d, J = 2.2 Hz, 1H), 2.46−2.19 (m, 4H), 1.84−1.68 (m, 4H); 13C
NMR (126 MHz, CDCl3) δ 142.4, 138.4, 137.9, 130.7, 128.5, 128.3,
128.3, 128.1, 127.6, 126.9, 82.4, 74.0, 70.0, 69.0, 32.6, 23.6, 23.1, 22.6;
HRMS (ESI+, TOF) m/z calcd for C22H22ONa [M + Na+] 325.1568,
found 325.1568.
83%): H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 7.29 (dd, J =
17.2, 11.1 Hz, 1H), 5.51 (d, J = 17.2 Hz, 1H), 5.40 (d, J = 11.1 Hz,
1H), 2.40 (t, J = 6.1 Hz, 2H), 2.28 (t, J = 6.1 Hz, 2H), 1.71−1.53 (m,
4H); 13C NMR (101 MHz, CDCl3) δ 190.8, 151.9, 135.6, 131.7,
119.1, 27.0, 22.8, 21.7, 21.4; HRMS (EI+, sector instrument) m/z
calcd for C9H12O [M] 136.0888, found 136.0880.
3,4,5,6-Tetrahydro-[1,1′-biphenyl]-2-carbaldehyde-d5 (5i). Com-
pound 5i was obtained from 2-bromocyclohex-1-enecarbaldehyde and
phenylboronic acid-d5 following the general procedure. Silica gel
purification eluting with 99:1−9:1 hexanes/EtOAc afforded aldehyde
5i (184 mg, 61%).
General Procedure for the Synthesis of Propargylic Ethers
1a−i. To a solution of aldehyde (250 mg, 0.8 mmol) in
tetrahydrofuran (8 mL) was added ethynylmagnesium bromide17
(0.5 M in tetrahydrofuran, 1.8 mL, 0.88 mmol) at −78 °C. After
addition, the cooling bath was removed and the reaction solution was
stirred at room temperature for 16 h. The solution was quenched with
saturated aqueous ammonium chloride (50 mL) and partially
concentrated in vacuo to remove tetrahydrofuran. Distilled water
(150 mL) was added, then the mixture was extracted with
dichloromethane (3 × 150 mL). The combined organic layers were
washed with brine (100 mL), dried over anhydrous MgSO4, filtered,
and concentrated in vacuo. The resulting residue was purified by flash
chromatography on silica gel to afford the product propargylic alcohol.
To a solution of propargylic alcohol (218 mg, 0.64 mmol) in dry
N,N-dimethylformamide (5.4 mL) at 0 °C was added sodium hydride
(60% dispersion in mineral oil, 31 mg, 0.77 mmol) in one portion. The
deep red suspension was stirred for 45 min, after which an alkyl halide
1-(2-(1-Methoxyprop-2-yn-1-yl)cyclohex-1-en-1-yl)naphthalene
(1d). Compound 1d was obtained from compound 5d following the
general procedure, using iodomethane as the alkylating agent. Silica gel
purification eluting with 98:2−92:8 hexanes/EtOAc afforded prop-
argylic ether 1d (532 mg, 56% over 2 steps) as a 1:1 mixture of
1
atropisomers: H NMR (400 MHz, CDCl3) δ 7.92−7.81 (m, 4H),
7.78 (d, J = 8.3 Hz, 2H), 7.53−7.38 (m, 6H), 7.25 (d, J = 8.3 Hz, 2H),
4.19 (s, 2H), 3.16 (s, 3H), 3.00 (s, 3H), 2.63−2.19 (m, 10H), 1.99−
1.75 (m, 8H); 13C NMR (101 MHz, CDCl3) δ 140.2, 139.9, 137.0,
136.5, 133.8, 133.7, 132.6, 132.1, 131.3, 130.9, 128.3, 128.3, 127.2,
126.1, 126.0, 125.9, 125.8, 125.7, 125.6, 125.4, 125.0, 82.2, 81.7, 73.7,
73.3, 71.6, 71.2, 56.2, 55.83, 32.9, 32.7, 23.2, 23.1, 23.1, 23.0, 22.7;
HRMS (ESI+, TOF) m/z calcd for C20H21O [M + H+] 277.1592,
found 277.1589.
3-(2-(1-Methoxyprop-2-yn-1-yl)cyclohex-1-en-1-yl)thiophene
(1e). Compound 1e was obtained from compound 5e following the
general procedure, using iodomethane as the alkylating agent. Silica gel
purification eluting with 98:2−92:8 hexanes/EtOAc afforded prop-
1
argylic ether 1e (191 mg, 70% over 2 steps): H NMR (400 MHz,
CDCl3) δ 7.27 (dd, J = 4.9, 2.9 Hz, 1H), 7.09 (d, J = 2.9 Hz, 1H), 6.99
(d, J = 4.9 Hz, 1H), 4.67 (d, J = 2.0 Hz, 1H), 3.25 (s, 3H), 2.48 (d, J =
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Note
2.0 Hz, 1H), 2.42−2.16 (m, 4H), 1.81−1.62 (m, 4H); 13C NMR (101
MHz, CDCl3) δ 142.2, 133.1, 131.5, 127.9, 125.1, 122.0, 82.0, 74.0,
71.3, 55.8, 32.1, 23.7, 22.9, 22.3; HRMS (ESI+, TOF) m/z calcd for
C14H16OSNa [M + Na+] 255.0820, found 255.0822.
10-Methoxy-9-methyl-1,2,3,4-tetrahydrophenanthrene (4b).
Compound 4b was obtained from compound 1b following the
general procedure (45 mg, >99%): H NMR (400 MHz, CDCl3) δ
8.00−7.91 (m, 2H), 7.53−7.38 (m, 2H), 3.77 (s, 3H), 3.11 (t, J = 6.2
Hz, 2H), 2.89 (t, J = 6.2 Hz, 2H), 2.59 (s, 3H), 2.00−1.82 (m, 5H);
13C NMR (126 MHz, CDCl3) δ 154.36, 132.27, 131.54, 130.35,
129.93, 124.95, 124.46, 124.26, 123.14, 121.77, 60.48, 25.91, 24.54,
23.03, 22.66, 11.34; HRMS (ESI+, TOF) m/z calcd for C16H19O [M +
H+] 227.1436, found 227.1432.
10-(Benzyloxy)-9-methyl-1,2,3,4-tetrahydrophenanthrene (4c).
Compound 4c was obtained from compound 1c following the general
procedure (30 mg, >99%): 1H NMR (400 MHz, CDCl3) δ 8.04−7.92
(m, 2H), 7.59−7.30 (m, 7H), 4.86 (s, 2H), 3.18−3.06 (m, 2H), 3.02−
2.86 (m, 2H), 2.63 (s, 3H), 2.01−1.79 (m, 4H); 13C NMR (101 MHz,
CDCl3) δ 153.1, 137.7, 132.3, 131.6, 130.5, 130.1, 128.6, 128.0, 127.8,
125.0, 124.6, 124.4, 123.2, 122.2, 74.7, 26.0, 24.9, 23.0, 22.7, 11.7;
HRMS (ESI+, TOF) m/z calcd for C22H23O [M + H+] 303.1749,
found 303.1746.
5-Methoxy-6-methyl-1,2,3,4-tetrahydrobenzo[c]phenanthrene
(4d). Compound 4d was obtained from compound 1d following the
general procedure. Silica gel purification eluting with 99:1−98:2
hexanes/EtOAc afforded compound 4d (20 mg, 47%): 1H NMR (500
MHz, CDCl3) δ 8.73−8.68 (m, 1H), 7.93−7.78 (m, 2H), 7.71 (d, J =
9.0 Hz, 1H), 7.56−7.51 (m, 2H), 3.81 (s, 3H), 3.53 (t, J = 5.9 Hz,
2H), 3.06 (t, J = 6.8 Hz, 2H), 2.67 (s, 3H), 2.03−1.94 (m, 2H), 1.80−
1.72 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 155.0, 135.1, 133.0,
131.4, 130.9, 130.8, 128.4, 128.2, 127.9, 126.3, 125.2, 124.6, 123.1,
122.9, 60.4, 34.0, 24.6, 24.1, 22.4, 12.1; HRMS (ESI+, TOF) m/z calcd
for C20H21O [M + H+] 277.1592, found 277.1589.
1
2-(1-Methoxyprop-2-yn-1-yl)-1,1′-biphenyl (1f). Compound 1f
was obtained from compound 5f following the general procedure,
using iodomethane as the alkylating agent. Silica gel purification
eluting with 99:1−97:3 hexanes/EtOAc afforded propargylic ether 1f
(180 mg, 23% over 2 steps): 1H NMR (400 MHz, CDCl3) δ 7.87 (dd,
J = 7.6, 1.4 Hz, 1H), 7.50−7.35 (m, 7H), 7.30 (dd, J = 7.6, 1.4 Hz,
1H), 4.98 (d, J = 2.1 Hz, 1H), 3.36 (s, 3H), 2.62 (d, J = 2.1 Hz, 1H);
13C NMR (101 MHz, CDCl3) δ 141.5, 140.3, 136.0, 130.1, 129.4,
128.5, 128.2, 128.1, 128.0, 127.4, 82.2, 75.5, 70.0, 56.2; HRMS (ESI+,
TOF) m/z calcd for C16H14ONa [M + Na+] 245.0942, found
245.0932.
1-(1-Methoxyprop-2-yn-1-yl)-2-(prop-1-en-2-yl)benzene (1g).
Compound 1g was obtained from compound 5g following the general
procedure, using iodomethane as the alkylating agent. Silica gel
purification eluting with 99:1−97:3 hexanes/EtOAc afforded prop-
1
argylic ether 1g (309 mg, 37% over 2 steps): H NMR (400 MHz,
CDCl3) δ 7.78 (dd, J = 7.2, 1.8 Hz, 1H), 7.47−7.28 (m, 2H), 7.20 (dd,
J = 7.2, 1.8 Hz, 1H), 5.34−5.25 (m, 2H), 4.99 (s, 1H), 3.46 (s, 3H),
2.63 (d, J = 2.1, 1H), 2.15−2.08 (m, 3H); 13C NMR (101 MHz,
CDCl3) δ 144.0, 143.2, 135.2, 128.4, 127.8, 127.5, 116.0, 82.4, 75.3,
69.9, 56.2, 25.4; HRMS (EI+, sector instrument) m/z calcd for
C13H14O [M − H+] 185.09665, found 185.09758.
1-(1-Methoxyprop-2-yn-1-yl)-2-(prop-1-en-2-yl)benzene (1h).
Compound 1h was obtained from compound 5h following the
general procedure, using iodomethane as the alkylating agent. Silica gel
purification eluting with 99:1−8:1 hexanes/EtOAc afforded prop-
5-Methoxy-4-methyl-6,7,8,9-tetrahydronaphtho[2,1-b]thiophene
1
(4e). Compound 4e was obtained from compound 1e following the
argylic ether 1h (225 mg, 36% over 2 steps): H NMR (400 MHz,
1
general procedure (30 mg, >99%): H NMR (400 MHz, CDCl3) δ
CDCl3) δ 7.47−7.41 (m, 2H), 7.33−7.27 (s, 3H), 6.88 (dd, J = 17.3,
10.9 Hz, 1H), 5.28 (d, J = 17.3 Hz, 1H), 5.11 (d, J = 10.9 Hz, 1H),
3.44 (s, 3H), 2.51−2.19 (m, 4H), 1.73−1.59 (m, 4H); 13C NMR (101
MHz, CDCl3) δ 133.6, 133.4, 132.9, 131.8, 128.3, 128.2, 122.8, 113.6,
87.0, 86.0, 70.0, 56.0, 25.7, 25.3, 22.5, 22.4; HRMS (ESI+, TOF) m/z
calcd for C18H20O [M+] 252.1509, found 252.1506.
7.43−7.30 (m, 2H), 3.78 (s, 1H), 3.07−2.95 (m, 2H), 2.92−2.79 (m,
2H), 2.50 (s, 3H), 1.97−1.80 (m, 4H); 13C NMR (101 MHz, CDCl3)
δ 153.5, 138.6, 134.9, 130.2, 127.6, 124.6, 121.9, 120.8, 60.4, 27.1, 23.9,
22.9, 22.8, 14.1; HRMS (EI+, sector instrument) m/z calcd for
C14H16OS [M+] 232.09219, found 232.09274.
9-Methoxy-10-methylphenanthrene (4f). Compound 4f was
obtained from compound 1f following the general procedure. Silica
gel purification eluting with 99:1−9:1 hexanes/EtOAc afforded
1-(1-Methoxyprop-2-yn-1-yl)-2-(prop-1-en-2-yl)benzene-d5 (1i).
Compound 1i was obtained from compound 5i following the general
procedure, using iodomethane as the alkylating agent. Silica gel
purification eluting with 99:1−8:1 hexanes/EtOAc afforded prop-
1
compound 6f (16 mg, 57%): H NMR (400 MHz, CDCl3) δ 8.70−
1
8.64 (m, 2H), 8.21−8.16 (m, 1H), 8.06−8.02 (m, 1H), 7.66−7.58 (m,
4H), 3.94 (s, 3H), 2.68 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
151.5, 132.9, 130.8, 128.2, 127.8, 126.8, 126.7, 126.2, 125.3, 124.6,
122.8, 122.8, 122.6, 121.9, 61.4, 11.8; HRMS (ESI+, TOF) m/z calcd
for C16H15O [M+] 223.1123, found 223.1120.
argylic ether 1i (123 mg, 56% over 2 steps): H NMR (400 MHz,
CDCl3) δ 4.48 (d, J = 2.1 Hz, 1H), 3.20 (s, 3H), 2.46 (d, J = 2.2 Hz,
1H), 2.44−2.19 (m, 4H), 1.81−1.68 (m, 4H); 13C NMR (126 MHz,
CDCl3) δ 142.2, 138.5, 130.5, 127.9, 127.8, 127.7, 127.6, 127.5, 127.5,
82.1, 73.8, 71.2, 55.8, 32.5, 23.3, 23.1, 22.5; HRMS (ESI+, TOF) m/z
calcd for C16H14D5O [M + H+] 232.1750, found 232.1754.
General Cycloaromatization Procedure. To a solution of
propargylic ether (44 mg, 0.13 mmol) in DMSO (0.31 mL) was added
a 40% w/w solution of benzyltrimethylammonium hydroxide in
methanol (Triton B, 0.03 mL, 0.06125 mmol) in one portion. Upon
addition of the base, the reaction turned a deep red color. The mixture
was stirred at 80 °C over 16 h, then diluted with saturated aqueous
ammonium chloride (40 mL) and water (20 mL). The resulting
aqueous mixture was extracted with ethyl acetate (3 × 50 mL), and the
combined organics were washed with brine and dried over anhydrous
MgSO4, filtered, and concentrated in vacuo to provide the benzenoid
product which was either pure in crude form or purified by flash
chromatography on silica gel.
1-Methoxy-2,4-dimethylnaphthalene (4g). Compound 4g was
obtained from compound 1g following the general procedure (31 mg,
>99%): 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.0 Hz, 1H), 7.94
(d, J = 7.6 Hz, 1H), 7.59−7.43 (m, 2H), 7.16 (s, 1H), 3.91 (s, 3H),
2.63 (s, 3H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 151.9,
132.4, 129.9, 129.8, 128.1, 125.5, 125.4, 125.0, 124.4, 122.2, 61.2, 57.8,
18.9, 15.7; HRMS (EI+, sector instrument) m/z calcd for C13H14O
[M+] 186.10447, found 186.10508.
6-Benzyl-5-methoxy-1,2,3,4-tetrahydronaphthalene (4h). Com-
pound 4h was obtained from compound 1h following the general
procedure. Purification was performed using preparative thin layer
chromatography eluting with 97:3 hexanes/EtOAc three times to
1
afford compound 4h (5 mg, 16%): H NMR (400 MHz, CDCl3) δ
7.30−7.13 (m, 5H), 6.85 (d, J = 7.8 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H),
3.98 (s, 2H), 3.64 (s, 3H), 2.80−2.64 (m, 4H), 1.81−1.68 (m, 4H);
13C NMR (101 MHz, CDCl3) δ 156.2, 141.4, 137.1, 130.7, 130.6,
128.9, 128.3, 127.7, 125.8, 124.9, 60.1, 35.6, 29.3, 23.7, 22.9, 22.9;
HRMS (EI+, sector instrument) m/z calcd for C18H20O [M+]
252.15142, found 252.15107.
Simple Deuterium-Labeling Experiment of 1i. To a solution of
propargylic ether 1i (30 mg, 0.13 mmol) in DMSO (0.30 mL) was
added a 40% w/w solution of benzyltrimethylammonium hydroxide in
methanol (Triton B, 0.03 mL, 0.06 mmol) in one portion. Upon
addition of the base, the reaction turned a deep red color. The mixture
3,7,9-Trimethoxy-6-((4-methoxybenzyl)oxy)-5-methylnaphtho-
[1,2-b]benzofuran (4a). Compound 4a was obtained from compound
1
1a following the general procedure (36 mg, 90%): H NMR (400
MHz, CDCl3) δ 8.28 (d, J = 9.0 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H),
7.28 (d, J = 1.9 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 6.94 (d, J = 8.5 Hz,
2H), 6.84 (d, J = 1.9 Hz, 1H), 6.43 (d, J = 1.9 Hz, 1H), 5.02 (s, 2H),
3.96 (s, 3H), 3.90 (s, 3H), 3.84 (s, 3H), 3.69 (s, 3H), 2.55 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 159.9, 159.1, 157.8, 157.8, 154.9, 151.2,
148.8, 133.1, 130.5, 128.9, 122.6, 119.6, 116.7, 114.1, 113.7, 112.5,
107.3, 104.2, 94.5, 88.5, 76.1, 55.8, 55.7, 55.3, 11.7; HRMS (ESI+,
TOF) m/z calcd for C28H27O6 [M + H+] 459.1808, found 459.1810.
7734
dx.doi.org/10.1021/jo3010952 | J. Org. Chem. 2012, 77, 7730−7736

The Journal of Organic Chemistry
Note
was stirred at 80 °C over 16 h then diluted with saturated aqueous
ammonium chloride (40 mL) and water (20 mL). The resulting
aqueous mixture was extracted with ethyl acetate (3 × 50 mL), and the
combined organics were washed with brine and dried over anhydrous
MgSO4, filtered, and concentrated in vacuo to provide a 4:6 mixture of
pure 4i/4i′, the ratio of which was determined by quantitative 13C
129.6, 129.2, 128.9, 128.7, 127.8, 127.5, 127.3, 126.8, 126.0, 80.7, 56.4,
30.9, 10.4; HRMS (EI+, sector instrument) m/z calcd for C16H13D5O
[M+] 231.16716, found 231.16640.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
NMR (28 mg, 93%): H NMR (400 MHz, CDCl3) δ 3.80 (s, 3H),
Copies of 1H and 13C NMR spectra of new compounds and X-
ray crystallographic views for compounds 4a and 6. This
material is available free of charge via the Internet at http://
pubs.acs.org.
3.13 (t, J = 5.9 Hz, 1H), 2.93 (t, J = 5.9 Hz, 1H), 2.62 (4i, s, ∼0.81H),
2.60 (4i′, t, J = 1.9 Hz, ∼1.56H), 2.01−1.84 (m, 4H); 13C NMR (126
MHz, CDCl3) δ 154.4, 154.3, 132.2, 131.5, 130.3, 129.9, 124.6, 124.4,
124.2, 124.1, 124.0, 123.9, 123.8, 123.7, 123.6, 122.9, 122.7, 122.5,
121.7, 121.7, 60.5, 25.9, 24.5, 23.0, 22.7, 11.3 (4i, s, 0.35C), 11.1 (4i′,
t, J = 18.9 Hz, 0.65C); HRMS (EI+, sector instrument) m/z calcd for
C16H14D4O [M+] 230.16088, found 230.16119 (4i, 36.2% base);
C16H13D5O [M+] 231.16716, found 231.16812 (4i′, 61.5% base).
Deuterium-Labeling Crossover Experiment of 1c and 1i. To
a solution of propargylic ether 1c (39 mg, 0.13 mmol) and propargylic
ether 1i (30 mg, 0.13 mmol) in DMSO (0.6 mL) was added a 40% w/
w solution of benzyltrimethylammonium hydroxide in methanol
(Triton B, 0.06 mL, 0.13 mmol) in one portion. Upon addition of the
base, the reaction turned a deep red color. The mixture was stirred at
80 °C over 16 h, then diluted with saturated aqueous ammonium
chloride (60 mL) and water (30 mL). The resulting aqueous mixture
was extracted with ethyl acetate (3 × 70 mL), and the combined
organics were washed with brine and dried over anhydrous MgSO4,
filtered, and concentrated in vacuo to provide a ∼5:2:3 mixture of 4c/
4i/4i′. The ratio of 4i/4i′ was determined by quantitative 13C NMR
AUTHOR INFORMATION
Corresponding Author
*E-mail: frontier@chem.rochester.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Professor Joseph P. Dinnocenzo (University
of Rochester) for helpful discussions. We are also grateful to
Dr. Furong Sun (University of Illinois at UrbanaChampaign)
and Dr. A. Bergmann (SUNY Buffalo) for carrying out high-
resolution mass spectrometry, and Dr. W. Brennessel for
solving the X-ray structures of 4a and 6. This work was funded
by the NIH (NIGMS R01GM079364).
1
(69 mg, >99%): H NMR (400 MHz, CDCl3) δ 8.04−7.92 (4c, m,
2H), 7.59−7.30 (4c, m, 7H), 4.86 (4c, s, 2H), 3.77 (4i + 4i′, s, 3H),
3.18−3.07 (4c + 4i + 4i′, m, 4H), 2.99−2.86 (4c + 4i + 4i′, m, 4H),
2.63 (4c, s, 3H), 2.61−2.54 (4i + 4i′, m, 3H), 2.00−1.80 (4c + 4i +
4i′, m, 8H); 13C NMR (126 MHz, CDCl3) δ 154.4 (4i/4i′), 153.1
(4c), 137.7 (4c), 132.3 (4c), 132.2 (4i/4i′), 131.6 (4c), 131.5 (4i/
4i′), 130.49 (4c), 130.3 (4i/4i′), 130.1 (4c), 129.9 (4i/4i′), 128.6
(4c), 128.0 (4c), 127.8 (4c), 125.0 (4c), 124.5 (4i/4i′), 124.3 (4i/
4i′), 123.2 (4c), 122.2 (4c), 121.7 (4i/4i′), 74.7 (4c), 60.5 (4i/4i′),
26.0 (4c), 25.9 (4i/4i′), 24.9 (4c), 24.5 (4i/4i′), 23.0 (4i/4i′), 23.0
(4c), 22.7 (4c), 22.7 (4i/4i′), 11.7 (4c), 11.3 (4i, s, 0.35C), 11.1 (4i′,
t, J = 18.9 Hz, 0.65C).
REFERENCES
■
(1) (a) Malona, J. A.; Cariou, K.; Frontier, A. J. J. Am. Chem. Soc.
2009, 131, 7560−7561. (b) Malona, J. A.; Cariou, K. C.; Spencer, W.
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H. J. Am. Chem. Soc. 1982, 104, 6115−6117. (f) Miller, B.; Baghdadchi,
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Chem. 1989, 54, 4028−4033. (h) Porter, N. A.; Hogenkamp, D. J.;
Khouri, F. F. J. Am. Chem. Soc. 1990, 112, 2402−2407.
(i) Andemichael, Y. W.; Wang, K. K. J. Org. Chem. 1992, 57, 796−
798. (j) Ezcurra, J. E.; Pham, C.; Moore, H. W. J. Org. Chem. 1992, 57,
4787−4789. (k) Wang, K. K.; Zhang, Q.; Liao, J. Tetrahedron Lett.
1996, 37, 4087−4090.
Deuterium-Labeling Experiment of 1i Using Sodium
Methoxide without Added Methanol. To a solution of propargylic
ether 1i (50 mg, 0.22 mmol) in DMSO (0.54 mL) was added sodium
methoxide powder (6.0 mg, 0.11 mmol) in one portion. The mixture
was stirred at 80 °C over 16 h then diluted with saturated aqueous
ammonium chloride (40 mL) and water (20 mL). The resulting
aqueous mixture was extracted with ethyl acetate (3 × 50 mL), and the
combined organics were washed with brine and dried over anhydrous
MgSO4, filtered, and concentrated in vacuo to provide a 36:37:27
1
mixture of 4i/4i′/6 (50 mg, 99%): H NMR (400 MHz, CDCl3) δ
7.56 (7, dd, J = 7.8 Hz, 1.3 Hz, 0.37H), 7.43 (7, t, J = 7.1 Hz, 0.8 Hz,
0.37H), 7.33 (7, td, J = 7.6, 1.3 Hz, 0.37H), 7.22 (7, dd, J = 7.6, 0.8 Hz,
0.37H), 4.22 (7, dd, J = 7.6, 5.4 Hz, 0.37H), 3.80 (4i + 4i′, s, 3H), 3.17
(7, s, 1H), 3.13 (4i + 4i′, t, J = 5.9 Hz, 1H), 2.93 (4i + 4i′, t, J = 5.9
Hz, 1H), 2.62 (4i, s, ∼1.25H), 2.60 (4i′, t, J = 1.9 Hz, ∼1.33H), 2.01−
1.84 (4i + 4i′, m, 4H), 1.80−1.60 (7, m, 1.13H), 0.82 (7, t, J = 7.4 Hz,
1.11H); 13C NMR (126 MHz, CDCl3) δ 154.4 (4i/4i′), 154.3 (4i/
4i′), 142.0 (7), 141.0 (7), 139.9 (7), 132.2 (4i/4i′), 131.5 (4i/4i′),
130.3 (4i/4i′), 129.9 (4i/4i′), 129.6 (7), 129.2 (7), 128.9 (7), 128.7
(7), 127.8 (7), 127.5 (7), 127.3 (7), 126.8 (7), 126.0 (7), 124.6 (4i/
4i′), 124.4 (4i/4i′), 124.2 (4i/4i′), 124.1 (4i/4i′), 124.0 (4i/4i′),
123.9 (4i/4i′), 123.8 (4i/4i′), 123.7 (4i/4i′), 123.6 (4i/4i′), 122.9
(4i/4i′), 122.7 (4i/4i′), 122.5 (4i/4i′), 121.7 (4i/4i′), 121.7 (4i/4i′),
80.7 (7), 60.5 (4i/4i′), 56.4 (7), 30.9 (7), 25.9 (4i/4i′), 24.5 (4i/4i′),
23.0 (4i/4i′), 22.7 (4i/4i′), 11.3 (4i, s, 0.49C), 11.1 (4i′, t, J = 18.9
Hz, 0.51C), 10.4 (7).
(7) For electrocyclizations of ene-diallenes, see: (a) Bowes, C. M.;
Montecalvo, D. F.; Sondheimer, F. Tetrahedron Lett. 1973, 3181−
3184. (b) Braverman, S.; Segev, D. J. Am. Chem. Soc. 1974, 96, 1245−
1247. (c) Braverman, S.; Duar, Y.; Segev, D. Tetrahedron Lett. 1976,
3181−3184. (d) Braverman, S.; Duar, Y. Tetrahedron Lett. 1978,
1493−1496. (e) Braverman, S.; Duar, Y. J. Am. Chem. Soc. 1990, 112,
2-(1-Methoxypropyl)-1,1′-biphenyl-d5 (6): 1H NMR (400 MHz,
CDCl3) δ 7.56 (dd, J = 7.8 Hz, 1.3 Hz, 1H), 7.43 (t, J = 7.1 Hz, 0.8 Hz,
1H), 7.33 (td, J = 7.6, 1.3 Hz, 1H), 7.22 (dd, J = 7.6, 0.8 Hz, 1H), 4.22
(dd, J = 7.6, 5.4 Hz, 1H), 3.17 (s, 3H), 1.80−1.60 (m, 2H), 0.82 (t, J =
7.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 142.0, 141.0, 139.9,
7735
dx.doi.org/10.1021/jo3010952 | J. Org. Chem. 2012, 77, 7730−7736

The Journal of Organic Chemistry
Note
5830−5837. (f) Tanaka, K.; Takamoto, N.; Tezuka, Y.; Kato, M.;
Toda, F. Tetrahedron 2001, 57, 3761−3767. (g) Generation of ene-
diallene by cyclobutene ring opening: Ezcurra, J. E.; Moore, H. W.
Tetrahedron Lett. 1993, 34, 6177−6180. (h) Taing, M.; Moore, H. W.
J. Org. Chem. 1996, 61, 329−340. (i) Generation of ene-diallene by
[2,3]-sigmatropic rearrangement of sulfenates: Kitagaki, S.; Ohdachi,
K.; Katoh, K.; Mukai, C. Org. Lett. 2006, 8, 95−98. (j) Hakuba, H.;
Kitagaki, S.; Mukai, C. Tetrahedron 2007, 63, 12639−12645.
(8) This result is in good agreement with that of Burton’s in a similar
system (see ref 4a).
(9) Intramolecular proton transfer proceeding through a hydrogen-
bonded conjugate acid−carbanion complex: (a) Cram, D. J.; Uyeda, R.
T. J. Am. Chem. Soc. 1962, 84, 4358−4359. (b) Cram, D. J.; Willey, F.;
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