Isoaromatization of 4-alkylidene-3-oxo-1-cyclohexene-1-carboxylates. Convenient synthesis of methyl 4-alkyl-3-hydroxybenzoates

Full text of DOI:10.1021/jo9522724

4806
J . Org. Chem. 1996, 61, 4806-4809
Sch em e 1a
Isoa r om a tiza tion of 4-Alk ylid en e-3-oxo-1-
cycloh exen e-1-ca r boxyla tes. Con ven ien t
Syn th esis of Meth yl
4-Alk yl-3-h yd r oxyben zoa tes†
Erin Campbell, J ohn J . Martin, J on Bordner,‡ and
Edward F. Kleinman*
Pfizer Central Research, Eastern Point Road, Groton,
Connecticut 06340
a
Key: (a) PhCHO, TsOH, PhCH3, ∆; (b) DBU, PhCH3.
Received December 28, 1995
Sch em e 2
In tr od u ction
While the isoaromatization of 6-alkylidene-2-cyclo-
hexen-1-ones 1 to 2-alkylphenols 2 has been observed in
several systems,1a-f this transformation, formally a double
tautomerization, has rarely been exploited for the syn-
thesis of phenols with defined substitution patterns (eq
1).2 In connection with our interest in the antiasthmatic
aldehydes,6c the Claisen rearrangement,7a-c and o-alk-
enylation with 1-alkynes,8 which could suffer from poor
regiocontrol in the case of unsymmetrical phenols and
be incompatible with sensitive functionality, especially
in cases employing organometallic intermediates.
Resu lts a n d Discu ssion
Initial model studies focused on the preparation of
methyl 4-benzylidene-3-oxo-1-cyclohexene-1-carboxylate
(5a ,b) and its subsequent isoaromatization to methyl
3-hydroxy-4-(phenylmethyl)benzoate (6) (Scheme 1). Acid-
catalyzed aldol condensation of methyl 3-oxo-1-cyclohex-
ene-1-carboxylate (4), prepared on a large scale by
oxidation of methyl 1-cyclohexene-1-carboxylate,9 with
benzaldehyde under Dean-Stark conditions in refluxing
toluene afforded the E-dienone 5a in 62% yield after
chromatography. None of the Z-dienone 5b was isolated,
nor any products arising from aldol condensation at the
γ-position of the enone, nor phenol 6. The regiochemistry
of this acid-catalyzed aldol condensation paralleled that
of the kinetic enolate aldol condensation of 3-alkoxy-2-
cyclohexen-1-ones, which also occur at the R′-position.10
Dienone 5a , while stable to acidic and neutral media and
to a solution of triethylamine, even at elevated temper-
ature, underwent smooth conversion to phenol 6 by
treatment with DBU at rt. Two- and one-proton singlets,
diagnostic of the dibenzylic methylene and hydroxyl
protons of 6, were observed at δ 4.01 and 5.37 ppm,
respectively. That base strength was crucial to the
isoaromatization reaction suggests that the rate-limiting
step is deprotonation of 5a to produce enolate 7a , which
then rearranges to 6 (Scheme 2). To demonstrate the
convenience of this method for the synthesis of 6, the
sequence was repeated without isolation of 5a by simply
treating the crude aldol mixture with DBU at rt (eq 2).
By this “one-pot” procedure, phenol 6 was obtained in
47% overall yield.
LTD4 antagonist ICI-204,219 (3),3 a general synthesis of
the central 4-alkyl-3-hydroxybenzoate core unit was
sought which would allow rapid variation of the alkyl
substituent. We wish to report a convenient synthesis
of methyl 4-alkyl-3-hydroxybenzoates that employs an
isoaromatization reaction of the type depicted in eq 1 as
a key step. This strategy complements methods of
o-phenol alkylation, such as alkylation via o-lithiated
species4 and o-quinone methides,5 phenylboronic acid-6ab
and dichlorophenylborane-mediated condensations with
† Dedicated to Clayton H. Heathcock on the occasion of his 60th
birthday.
‡ To whom correspondence should be addressed concerning the X-ray
structures of dienones 5a and 5b.
(1) (a) Morris, I. G.; Pinder, A. R. J . Chem Soc. 1963, 1841. (b)
Kobayashi, T.; Kumazawa. S.; Kato, T.; Kitahara, Y. Chem. Lett. 1975,
301. (c) Kaiser, R.; Lamparsky, D.; Schudel, P. J . Agric. Food Chem.
1975, 23, 943. (d) Aizenshtat, Z.; Hausmann, M.; Pickholtz, Y.; Tal,
D.; Blum, J . J . Org. Chem. 1977, 42, 2386. (e) Wiberg, K. B.; Matturro,
M. G.; Okarma, P. J .; J ason, M. E.; Dailey, W. P.; Burgmaier, G. J .,
Bailey, W. F.; Warner, P. Tetrahedron 1986, 42, 1895. (f) Birch, A. J .;
Quartey, J . A. K.; Smith, H. J . Chem. Soc. 1952, 1768.
(2) Reference 1d describes the synthesis of 2,6-dialkyl-, 2,3,6-
trialkyl-, and 2,4,6-trialkylphenols by high-temperature, transition
metal-catalyzed isoaromatization of the corresponding 2,6-dialkyl-
idenecyclohexanones. All subsituents in the 2- and 6-positions are
identical. The reaction was shown to proceed via 6-alkylidine-2-
cyclohexen-1-one intermediates.
(3) Matassa, V. G.; Maduskuie, T. P., J r.; Shapiro, H. S.; Hesp, B.;
Snyder, D. W.; Aharony, D.; Krell, R. D.; Keith, R. A. J . Med. Chem.
1990, 33, 1781.
(4) See: Morey, J .; Costa, A.; Deya, P. M.; Suner, G.; Saa, J . M. J .
Org. Chem. 1990, 55, 3902 and references cited therein.
(5) See: Katritzky, A. R.; Zhang, Z.; Lan, X.; Lang, H. J . Org. Chem.
1994, 59, 1900 and references cited therein.
Kinetic enolate aldol condensation was next investi-
gated for the preparation of dienones 5a ,b , since the
(6) (a) Nagata, W.; Okada, K.; Aoki, T. Synthesis 1979, 365. (b) Lau,
C. K.; Williams, H. W. R.; Tardiff, S.; Dufresne, C.; Scheigetz, J .;
Belanger, P. C. Can. J . Chem. 1989, 67, 1384. (c) Lau, C. K.; Mintz,
M.; Bernstein, M. A.; Dufresne, C. Tetrahedron Lett. 1993, 34, 5527.
(7) (a) Goering, H. L.; J acobsen, R. R. J . Am. Chem. Soc. 1958, 80,
3277. (b) Harwood, L. M. J . Chem. Soc., Chem. Commun. 1983, 530.
(c) Robertson, D. W.; Lacefield, W. B.; Bloomquist, W.; Pfeifer, W.;
Simon, R. L.; Cohen, M. L. J . Med. Chem. 1992, 35, 310.
S0022-3263(95)02272-9 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 14, 1996 4807
Ta ble 1.a Syn th esis of Meth yl 4-Alk yl-3-h yd r oxyben zoa tes
by Sequ en tia l Kin etic En ola te Ald ol Con d en sa tion ,
Deh yd r a tion , a n d Isoa r om a tiza tion
Sch em e 3a
a
Key: (a) (i) LHMDS, THF, -78 °C; (ii) PhCHO; (b) MeO2C-
NSO2N(Et)3, PhH, ∆.
a
form
form
Reaction conditions: (a) (i) LHMDS, THF, -78 °C; (ii) RCHO;
(b) MeO2CNSO2N(Et)3, PhH, ∆; (c) DBU, PhCH3.
F igu r e 1. Key dihedral angles from the X-ray structures of
dienones 5a and 5b.
X-ray structure of 5b represents the first example of a
(Z)-6-alkylidene-2-cyclohexen-1-one.13
With the structures of 5a and 5b secure, their relative
rate of rearrangement to phenol 6 was studied qualita-
tively by NMR. Interestingly, in an experiment in which
a 50:50 mixture of 5a and 5b in CDCl3 was treated with
1.5 equiv of DBU, it was found that at a time point (30
min) where all of 5a had reacted, half of 5b remained.
On the basis of our mechanism, which postulates that
deprotonation of 5a ,b is the rate-determining step for the
base-catalyzed isoaromatization to 6 (see Scheme 2), the
slower rate of reaction for the more strained dienone 5b
can be explained by the fact that the distorted C(3)-C(4)
dihedral angle reduces π-overlap of the corresponding
enolate 7b relative to that of 7a , rendering 5b less acidic
than 5a and, hence, less reactive. The strain in enolate
7b could be further compounded by the steric effect of
the cation (BH+).
thermodynamically controlled, acid-catalyzed condensa-
tion proved to be less reliable in the case of less reactive
and more volatile aldehydes. Addition of the lithium
enolate of 4 to benzaldehyde gave a mixture of diaster-
eomeric aldols 8a ,b predominating, as expected,10 in the
threo diastereomer 8a (Scheme 3). Several methods to
effect dehydration of aldols 8a ,b to 5a ,b were investi-
gated, such as Ac2O/pyridine, TFAA/TEA, and TFAA/
DBU, but only complex mixtures containing unreacted
aldols, acylated intermediates, dienones 5a ,b, and phenol
6 were obtained. Treatment of 8a with Burgess reagent11
in refluxing benzene, however, led smoothly to a mixture
of dienones 5a and 5b, respectively, from which the more
strained 5b was isolated for the first time by flash
chromatography. Structural assignments of 5a and 5b
were initially based on NMR, where a 0.9 ppm downfield
chemical shift was observed for the deshielded styryl
proton of 5a relative to that of 5b, and were ultimately
confirmed by X-ray crystallography.12 Key dihedral
angles obtained from the X-ray structures of 5a and 5b
are shown in Figure 1, where it should be noted that 5b
crystallized in two distinct forms (forms A and B)
differing mainly in the dihedral angle about the styrene
single bond (C(4′)-C(5′)). The additional strain inherent
in the Z-isomer 5b, due to the steric interaction between
the phenyl group and the ketone carbonyl, was evident
in the large dihedral angle about the C(3)-C(4) bond,
35° and 37° for forms A and B, respectively. This
compared to 7°, or close to planarity, for the correspond-
ing dihedral angle of the E-isomer 5a . We believe the
The kinetic enolate aldol condensation-dehydration-
isoaromatization sequence was next repeated without
purification of aldol and dienone intermediates in order
to demonstrate its utility for the synthesis of 4-alkyl-3-
hydroxybenzoates. Using benzaldehyde as the aldehyde
component and a 10% excess of the enolate of 4, phenol
6 was obtained in 75% overall yield after final purifica-
tion (Table 1). The sequence was then applied success-
fully to four aromatic and two aliphatic aldehyde sub-
strates, affording the corresponding phenols 9-14 in
yields ranging from 35 to 73%. Pyridine (9), nitro (11),
and ester (12) functionalities were compatible with the
(8) Yamaguchi, M.; Hayashi, A.; Hirama, M. J . Am. Chem. Soc.
1995, 117, 1151.
(9) Lange, G. L.; Otulakowski, J . A. J . Org. Chem. 1982, 47, 5093.
(10) Torii, S.; Inokuchi, T.; Ogawa, H. Bull. Chem. Soc. J pn. 1979,
52, 1233.
(11) Burgess, E. M.; Penton, H. R., J r.; Taylor, E. A. J . Org. Chem.
1973, 38, 26.
(12) The author has deposited atomic coordinates for these struc-
tures with the Cambridge Crystallographic Data Centre. The coordi-
nates can be obtained, on request, from Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(13) A computer-assisted substructure search of the Cambridge
Structural Data Base was performed.

4808 J . Org. Chem., Vol. 61, No. 14, 1996
Notes
mL (625 mg, 5.90 mmol) of benzaldehyde, 20 mL of toluene, and
20 mg of p-TsOH acid was placed in a flask fitted with a soxhlet
extractor containing 3 Å molecular sieves in the thimble. The
mixture was heated to reflux for 7 h. The solvent was evapo-
rated, and the residue was diluted with 100 mL of EtOAc,
washed with saturated NaHCO3 solution (2 × 75 mL), dried
(MgSO4), and evaporated to give 1.71 g of an orange oil.
Purification by flash chromatography (100 g of silica gel) using
a 20% EtOAc-hexane eluant afforded 889 mg (62%) of 5a as a
yellow oil. Crystallization from hexane gave 460 mg of a bright
yellow solid: mp 93-94 °C: 1H NMR (CDCl3) δ 2.61 (2 H, dt, J
) 2, 7 Hz), 3.04 (2 H, dt, J ) 2, 7 Hz), 3.83 (3 H, s), 6.94 (1 H,
s), 7.23-7.45 (5 H, m), 7.65 (1 H, s); MS m/z 242 (M+), 241 (base),
181, 115. Suitable crystals for X-ray analysis were grown by
slow evaporation from MeOH. Anal. Calcd for C15H14O3: C,
74.36; H, 5.82. Found: C, 74.01; H, 5.91.
reaction conditions. Lower yields in the case of 10 and
13 were due to incomplete aldol condensation, while high
aqueous solubility during workup was responsible for a
diminished yield of the pyridyl derivative 9 (see the
Experimental Section).
Con clu sion
Kinetic enolate aldol condensation of enone 4 with
aliphatic and aromatic aldehydes, followed by sequential
dehydration and base-catalyzed isoaromatization, was
found to be a reliable method for the synthesis of methyl
4-alkyl-3-hydroxybenzoates, which may be elaborated to
produce analogs of the LTD4 antagonist ICI-204,219. This
strategy should be applicable to other enones capable of
kinetic deprotonation at the R′-position, thus providing
access to 2-alkylphenols with various substitution pat-
terns. It may be used as an alternative to other methods
of o-phenol alkylation, especially in cases that involve
sensitive functionality. With certain aldehyde sub-
strates, acid-catalyzed aldol condensation with in situ
dehydration may be employed, which shortens the overall
sequence by one step.
(Z)-Met h yl 4-Ben zylid en e-3-oxo-1-cycloh exen e-1-ca r -
boxyla te (5b). Isola tion of Dia ster eom er s 8a a n d 8b.
A
50 mL, three-necked flask equipped with a low-temperature
thermometer, N2 inlet, and septum was charged with 1.95 mL
(1.95 mmol) of a 1 M THF solution of LHMDS and 15 mL of
THF. The mixture was cooled to -78 °C, and a solution of 300
mg (1.95 mmol) of enone 4 in 2 mL of THF was added dropwise
via syringe at such a rate that the exotherm did not exceed -65
C. The resulting yellow mixture was allowed to stir for an
additional 10 min at -78 °C, and 0.178 mL (185 mg, 1.77 mmol)
of benzaldehyde was added dropwise. After being stirred for
an additional 1 h at -78 °C, the mixture was quenched by the
addition of 6 mL of saturated aqueous NH4Cl solution and then
allowed to warm to rt. The THF was removed by partial
evaporation, and the residue was partitioned between 100 mL
of EtOAc and water, respectively. The organic layer was
separated, dried (MgSO4), and evaporated to 580 mg of a yellow
oil, which was purified by flash chromatography (50 g of silica
gel, 15 mL fractions) using a 20-40% EtOAc-hexane eluant.
Fractions 21-24 were combined and concentrated to give 4 mg
of the erythro diastereomer 8b as a yellow oil: 1H NMR (CDCl3)
δ 1.73-2.75 (5 H, m), 2.50 (1 H, d, J ) 5 Hz), 3.80 (3 H, s), 4.54
(1 H, br t), 6.75 (1 H, d, J ) 2 Hz), 7.24-7.38 (5 H, m). Fractions
27-32 were combined and concentrated to give 136 mg of the
threo diastereomer 8a as a light yellow oil: 1H NMR (CDCl3) δ
1.43-1.65 (2 H, m), 2.27-2.68 (3 H, m), 3.80 (3 H, s), 4.37 (1 H,
d, J ) 2 Hz), 4.83 (1 H, dd, J ) 2, 7 Hz), 6.75 (1 H, d, J ) 2 Hz),
7.23-7.39 (5 H, m). The mixed fractions were combined and
concentrated to give 295 mg of a mixture 8a and 8b; total yield
) 94%.
A mixture of 135 mg (0.519 mmol) of 8a , 185 mg (0.779 mmol)
of Burgess reagent, and 7 mL of benzene was heated to reflux
for 3 h. The mixture was evaporated, and the residue was
diluted with 50 mL of EtOAc, washed with saturated aqueous
NaHCO3 (2 × 40 mL), dried (MgSO4), and evaporated to 108
mg of a yellow oil, which was separated by flash chromatography
(10 g of silica gel, 15 mL fractions) using a toluene eluant.
Fractions 42-47 were combined and concentrated to a yellow
semisolid, which was triturated in hexane to give 15 mg of
dienone 5b as a yellow solid: 1H NMR (CDCl3) δ 2.65-2.84 (4
H, m), 3.82 (3 H, s), 6.72 (1 H, s), 6.80 (1 H, s), 7.21-7.32 (3 H,
m), 7.42-7.48 (2 H, m). Suitable crystals for X-ray analysis were
grown by slow evaporation from EtOAc.
Meth yl 3-Hydr oxy-4-(ph en ylm eth yl)ben zoate (6). Meth od
A: Isoa r om a tiza tion of Dien on e 5a . A solution of 300 mg
(1.24 mmol) of 5a in 5 mL of toluene was treated dropwise with
188 mg (0.185 mL, 1.24 mmol) of DBU, and the resulting mixture
was stirred for 3 h at rt. The solvent was evaporated, and the
residue was dissolved in 35 mL of EtOAc, washed with aqueous
1 N HCl solution (2 × 50 mL), dried (MgSO4), and evaporated
to 333 mg of a light yellow solid, which was triturated in hexane
to give 265 mg (88%) of 6 as a white solid, mp 133-135 °C (see
method C below for spectral and analytical data).
Meth od B: Acid -Ca ta lyzed Ald ol Con d en sa tion /Isoa r o-
m a tiza tion . A mixture of 0.500 g (3.24 mmol) of enone 4, 0.300
mL (313 mg, 2.95 mmol) of benzaldehyde, 20 mL of toluene, and
15 mg of p-TsOH was heated to reflux in a flask fitted with a
soxhlet extractor containing 3 Å molecular sieves in the thimble.
After 5 h, TLC analysis indicated that the reaction was 75%
complete, so an additional 15 mg of p-TsOH was added and
reflux was continued for an additional 2 h. The mixture was
allowed to cool to rt and then treated dropwise with 0.49 mL
Exp er im en ta l Section
1H NMR spectra were determined with a 300 MHz spectrom-
eter. Mass spectra (MS) were measured using the electron
impact method on a GC/MS instrument. Elemental analyses
were performed by the Schwarzkopf Microanalytical Laboratory.
Melting points are uncorrected and were obtained on open
capillaries. All reactions involving oxygen- or moisture-sensitive
compounds were performed under a dry N2 atmosphere. THF
was distilled from Na/benzophenone prior to use. Starting
aldehydes were purchased commercially and purified by recrys-
tallization or distillation prior to use. Lithium bis(trimethylsil-
yl)amide solution (1 M THF) and Burgess reagent ([(methoxy-
carbonyl)sulfamoyl]trimethylammonium hydroxide) were pur-
chased from Aldrich. All other starting materials and reagents
were obtained from commercial suppliers and used without
purification.
Flash chromatography was performed using silica gel Woelm
(32-63 µm) or Baker silica gel (40 µm). Analytical thin-layer
chromatography (TLC) was performed with Merck Kiesselgel 60
F254 using ultraviolet light for visualization.
Meth yl 3-Oxo-1-cycloh exen e-1-ca r boxyla te (4). Follow-
ing the procedure of Lange and Otulakowski,9 in a 3-L, three-
necked flask equipped with a mechanical stirrer was placed a
mixture of 400 mL of acetic anhydride and 800 mL of acetic acid.
After the mixture was cooled to 0 °C in an ice bath, 160 g (1.60
mol) of CrO3 was added in portions to the stirring mixture, and
when the addition was complete the mixture was allowed to
warm to rt. Meanwhile, a solution of 75.0 g (0.535 mol) of methyl
1-cyclohexene-1-carboxylate in 275 mL of benzene was prepared
in 3-L, three-necked flask equipped with a mechanical stirrer,
addition funnel, and thermometer. This ice-chilled solution was
treated with the oxidizing solution dropwise at such a rate that
the exotherm did not exceed 15 °C. When the addition was
complete, the mixture was allowed to stir for an additional 0.5
h at rt, chilled to 0 °C, and adjusted to pH 9 by the careful
addition of 50% aqueous KOH solution (ca. 2 L) while the
temperature was maintained below 15 °C. The mixture was
diluted with a mixture of 250 mL of benzene and 1 L of ether,
and the organic layer was separated. The aqueous layer was
extracted with ether (2 × 500 mL), and the combined organic
layers were washed with saturated aqueous NaHCO3 solution
(1 L) and brine (1 L), dried (MgSO4), and evaporated to 56 g of
a yellow oil. The oil was combined with 82 g of additional
material prepared identically from 115 g of methyl 1-cyclohex-
ene-1-carboxylate and distilled using a Vigreux column to
provide 82.2 g (39%) of 4 as a light yellow oil: bp 70-72 °C/0.15
Torr (lit.9 bp 95-100 °C/1.6 Torr).
(E)-Met h yl 4-Ben zylid en e-3-oxo-1-cycloh exen e-1-ca r -
boxyla te (5a ). A mixture of 1.00 g (6.49 mmol) of enone 4, 0.600

Notes
J . Org. Chem., Vol. 61, No. 14, 1996 4809
(499 mg, 3.25 mmol) of DBU. After being stirred for 2 h at rt,
the dark brown mixture was evaporated, dissolved in 100 mL
of EtOAc, washed with aqueous 1 N HCl solution (1 × 75 mL)
and saturated aqueous NaHCO3 solution (1 × 75 mL), dried
(MgSO4), and evaporated to 927 mg of a yellow oil. Purification
by flash chromatography (100 g of silica gel) using a 25%
EtOAc-hexane eluant gave 339 mg (47%) of phenol 6 as a yellow
solid.
aqueous 1 N HCl wash was replaced by a water wash, and
additional crude product was obtained by backwashing the
combined aqueous layers with CHCl3, as described above. From
the reaction of the original 560 mg of dienone, 378 mg of crude
9 was obtained as a yellow solid after workup, which was
purified by flash chromatography and then triturated in ether
to afford 255 mg of 9 as light yellow solid, mp 196-197 °C. A
second crop (45 mg) was obtained by similar purification of the
evaporated mother liquor combined with the material (263 mg)
derived from the reaction of the 202 mg of recovered crude
dienone (from the aqueous layers), mp 193-194 °C: 1H NMR
(DMSO-d6) δ 3.81 (3 H, s), 3.95 (2 H, s), 7.21 (2 H, d, J ) 6 Hz),
7.24 (1 H, d, J ) 8 Hz), 7.38 (1 H, dd, J ) 2, 8 Hz), 7.45 (1 H, d,
J ) 2 Hz), 8.44 (2 H, d, J ) 6 Hz), 10.02 (1 H, s); MS m/z 243
(M+, base), 212, 184. Anal. Calcd for C14H13NO3: C, 69.12; H,
5.39 N, 5.76. Found: C, 68.96; H, 5.34; N, 5.53.
Meth od C: Kin etic En ola te Ald ol Con d en sa tion /Deh y-
d r a tion /Isoa r om a tiza tion . A 100 mL, three-necked flask
equipped with a low-temperature thermometer, N2 inlet, and
septum was charged with 3.24 mL (3.24 mmol) of a 1 M THF
solution of LHMDS and 30 mL of THF. The mixture was cooled
to -78 °C, and a solution of 500 mg (3.24 mmol) of enone 4 in 5
mL of THF was added dropwise via syringe at such a rate that
the exotherm did not exceed -65 °C. The resulting yellow
mixture was allowed to stir for an additional 15 min at -78 °C,
and a solution of 0.299 mL (312 mg, 2.95 mmol) of benzaldehyde
in 5 mL of THF was added dropwise at such a rate that the
exotherm did not exceed -65 °C. After being stirred for 1 h at
-78 °C, the mixture was quenched by the addition of 10 mL of
saturated aqueous NH4Cl solution and was then allowed to
warm to rt. The THF was removed by partial evaporation, and
the residue was partitioned between 50 mL of EtOAc and water,
respectively. The organic layer was separated, combined with
two 50 mL EtOAc washes of the aqueous layer, dried (MgSO4),
and evaporated to give 835 mg (>100%) of aldols 5a ,b as a yellow
oil.
To a solution of aldols 5a ,b above (2.95 mmol) in 60 mL of
benzene was added 1.05 g (4.42 mmol) of Burgess reagent, and
the resulting mixture was heated to reflux for 2 h. After being
cooled to rt, the solvent was evaporated and the residue was
concentrated and partitioned between 100 mL of EtOAc and
saturated aqueous NaHCO3 solution, respectively. The aqueous
layer was removed, and the organic layer was washed with
additional saturated aqueous NaHCO3 solution (1 × 50 mL) and
brine (1 × 50 mL), dried (MgSO4), and evaporated to give 823
mg (>100%) of a mixture of dienones 5a and 5b (ratio ) 15:1,
NMR).
Meth yl 3-h ydr oxy-4-[(4-m eth oxyph en yl)m eth yl]ben zoate
(10): 40% yield; chromatography solvent, 20% EtOAc-hexane.
The chromatographed product (374 mg) was triturated in hexane
(320 mg), mp 107-109 °C. The analytical sample was prepared
by recrystallization from benzene, mp 122.5-123.5 °C: 1H NMR
(CDCl3) δ 3.75 (3 H, s), 3.87 (3 H, s), 3.96 (2 H, s), 5.29 (1 H, s),
6.81 (2 H, d, J ) 8 Hz), 7.09-7.14 (3 H, m), 7.49 (1 H, s), 7.51
(1 H, d, J ) 8 Hz); MS m/z 272 (M+), 108 (base). Anal. Calcd
for C16H16O4: C, 70.58; H, 5.92. Found: C, 70.35; H, 5.88.
Met h yl 3-h yd r oxy-4-[(4-n it r op h en yl)m et h yl]b en zoa t e
(11): 73% yield; chromatography solvent, 25% EtOAc-hexane.
The chromatographed product (650 mg) was triturated in ether
(448 mg), mp 158.5-159.5 °C. A second crop (168 mg) was
obtained by trituration of the concentrated mother liquor in
hexane, mp 155-157 °C: 1H NMR (CDCl3) δ 3.88 (3 H, s), 4.01
(2 H, s), 5.48 (1 H, s), 7.14 (1 H, d, J ) 8 Hz), 7.35 (2 H, d, J )
8 Hz), 7.54 (1 H, s), 7.55 (1 H, d, J ) 8 Hz), 8.11 (2 H, d, J ) 8
Hz); MS m/z 287 (M+, base), 270, 256, 240, 228, 207, 181, 152.
Anal. Calcd for C15H13NO5: C, 62.72; H, 4.56; N, 4.88. Found:
C, 62.57; H, 4.99; N, 4.80.
Meth yl 3-h yd r oxy-4-[[4-(m eth oxyca r bon yl)p h en yl]m e-
th yl]ben zoa te (12): 69% yield; chromatography solvent, 30%
EtOAc-hexane. The chromatographed product (640 mg) was
triturated in hexane (613 mg), mp 161-162 °C: 1H NMR (CDCl3)
δ 3.87 (6 H, s), 4.05 (2 H, s), 5.53 (1 H, s), 7.12 (1 H, d, J ) 8
Hz), 7.38 (2 H, d, J ) 8 Hz), 7.50 (1 H, s), 7.52 (1 H, d, J ) 8
Hz), 7.93 (2 H, d, J ) 8 Hz); MS m/z 300 (M+), 269, 241 (base).
Anal. Calcd for C17H16O5: C, 67.99; H, 5.37. Found: C, 67.94;
H, 5.35.
A solution of dienones 5a ,b above (2.95 mmol) in 15 mL of
benzene was treated dropwise with 0.661 mL (672 mg, 4.42
mmol) of DBU, and the mixture was stirred for 1.5 h at rt. The
mixture was diluted with 50 mL of EtOAc, washed with aqueous
1 N HCl solution (2 × 25 mL) and brine (1 × 25 mL), dried
(MgSO4), and evaporated to 715 mg of a yellow solid. Purifica-
tion by flash chromatography (50 g of silica gel) using a 20%
EtOAc-hexane eluant gave 592 mg of a white solid, mp 115-
120 °C, which was triturated in ice-cold hexane to afford 535
mg (75%) of 6 as white colorless crystals, mp 131-132 °C: 1H
NMR (CDCl3) δ 3.88 (3 H, s), 4.01 (2 H, s), 5.37 (1 H, s), 7.11-
7.55 (8 H, m); MS m/z 242 (M+), 211, 183 (base), 165. Anal.
Calcd for C15H14O3: C,74.36; H, 5.82. Found: C, 74.06; H, 5.80.
Rela tive Ra te of Isoa r om a tiza tion of Dien on es 5a a n d
5b. In a NMR tube was placed a solution of 20 mg (0.083 mmol)
of a 50:50 mixture of dienones 5a and 5b in 1 mL of CDCl3. The
mixture was treated with 19 µL (19 mg, 0.13 mmol) of DBU at
Meth yl 4-bu tyl-3-h yd r oxyben zoa te (13): 35% yield; chro-
matography solvent, 20% EtOAc-hexane. The chromato-
graphed product (260 mg) was triturated in hexane (196 mg),
mp 80-81 °C. A second crop (37 mg) was obtained by rechro-
matography of the evaporated mother liquor and impure frac-
tions followed by trituration in ice-cold hexane, mp 81-82 °C:
1H NMR (CDCl3) δ 0.91 (3 H, t, J ) 7 Hz), 1.22-1.39 (2 H, m),
1.47-1.62 (2 H, m), 2.64 (2 H, t, J ) 7 Hz), 3.87 (3 H, s), 6.58 (1
H, s), 7.14 (1 H, d, J ) 8 Hz), 7.49 (1 H, dd, J ) 1, 8 Hz), 7.61
(1 H, d, J ) 1 Hz); MS m/z 208 (M+), 165 (base). Anal. Calcd
for C12H16O3: C, 69.21; H, 7.74. Found: C, 68.97; H, 7.58.
1
rt, and the progress of the reaction was monitored by H NMR
by observing the disappearance of the signals for the corre-
sponding vinyl protons (nonaromatic; 5a , δ 6.94, 7.65; 5b, δ 6.72,
6.80). After 30 min, the consumption of 5a was complete, while
that of 5b was 50%.
Gen er a l P r ep a r a tion of Meth yl 4-Alk yl-3-h yd r oxyben -
zoa tes 9-14. Method C was followed, substituting the ap-
propriate aldehyde for benzaldehyde. All reactions were run
starting with 500 mg of enone 4. Yields of 9-14 were based on
final purification by flash chromatography in the indicated
eluant followed by trituration in the indicated solvent. The yield
of 14 was based on purification by flash chromatography only.
All reactions were monitored by TLC. A modification of the
workup procedure of compound 9 is noted.
Meth yl 3-h yd r oxy-4-(cycloh exylm eth yl)ben zoa te (14):
72% yield; chromatography solvent, 10% ether-toluene. Tritu-
ration of the chromatographed product (524 mg), mp 142-144
°C, in hexane provided the analytical sample (308 mg), mp 148-
149 °C: 1H NMR (CDCl3) δ 0.81-1.65 (11 H, m), 2.51 (2 H, d, J
) 7 Hz), 3.87 (3 H, s), 5.02 (1 H, s), 7.10 (1 H, d, J ) 8 Hz), 7.46
(1 H, s), 7.50 (1 H, d, J ) 8 Hz); MS m/z 248 (M+), 166 (base).
Anal. Calcd for C15H20O3: C, 72.55; H, 8.12. Found: C, 72.26;
H, 8.48.
Meth yl 3-h ydr oxy-4-[(4-pyr idyl)m eth yl]ben zoate (9): 39%
yield; chromatography solvent, 5% MeOH-CHCl3. In the
Burgess reagent-mediated elimination reaction, which gave 560
mg of crude dienone, an additional 202 mg of crude dienone was
obtained by extraction of the combined aqueous layers with
CHCl3 (4 × 100 mL), drying (MgSO4), and evaporation. This
material and the original 560 mg of crude dienone were subjected
to the isoaromatization reaction separately. During workup, the
Ack n ow led gm en t. We would like to thank Profes-
sors E. J . Corey and S. V. Ley and Drs. Katherine E.
Brighty, J otham W. Coe, Beryl W. Dominy, Robert W.
Dugger, and Robert A. Volkmann for helpful discussions
and comments.
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