Wittig-Horner-Emmons reactions of triethyl 3-methyl-phosphonocrotonate with 3-formylchroniones en route to benzophenone-based retinoid candidates

Article abstract of DOI:10.3987/com-06-10955

Wittig-Horner-Emmons (WHE) reaction conditions were used in conjunction with other reactions to prepare benzophenone-based retinoid candidates. The chromone nucleus was reacted with triethyl 3-methyl-phosphonocrotonate to afford benzophenones following a known rearrangement of a reaction intermediate. Confirmations of the structure of rearranged products are provided in the form of the X-ray crystal structures and speculation regarding the mechanism for the rearrangements is included. The method provides a facile route to substituted benzophenone-based candidate ligands for retinoic acid receptors (RARs) or for a wide variety of other applications.

Full text of DOI:10.3987/com-06-10955

HETEROCYCLES, Vol. 71, No. 3, 2007
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HETEROCYCLES, Vol. 71, No. 3, 2007, pp. 557 - 567. © The Japan Institute of Heterocyclic Chemistry
Received, 22nd November, 2006, Accepted, 22nd January, 2007, Published online, 23rd January, 2007. COM-06-10955
WITTIG-HORNER-EMMONS REACTIONS OF TRIETHYL 3-METHYL-
PHOSPHONOCROTONATE WITH 3-FORMYLCHROMONES EN
ROUTE TO BENZOPHENONE-BASED RETINOID CANDIDATES
Weilin Sun,1,* Shyam Desai,1,* Huri Piao,2 Patrick Carroll,3 and Daniel J. Canney1,**
1Department of Pharmaceutical Sciences, School of Pharmacy, Temple University,
3307 N. Broad Street, Philadelphia, PA 19140, USA, 2Yanbian University Medical
College, 121 Juzi St., Yanji City, P. R. China, 3Department of Chemistry,
University of Pennsylvania, 34th Street, Philadelphia, PA 19104, USA
* These authors have contributed equally to this paper.
**To whom all correspondence should be addressed.
email: daniel.canney@temple.edu, phone: (001) 215-707-6924.
Abstract- Wittig-Horner-Emmons (WHE) reaction conditions were used in
conjunction with other reactions to prepare benzophenone-based retinoid
candidates.
The chromone nucleus was reacted with triethyl 3-methyl-
phosphonocrotonate to afford benzophenones following a known rearrangement of
a reaction intermediate. Confirmations of the structure of rearranged products are
provided in the form of the X-ray crystal structures and speculation regarding the
mechanism for the rearrangements is included. The method provides a facile route
to substituted benzophenone-based candidate ligands for retinoic acid receptors
(RARs) or for a wide variety of other applications.
INTRODUCTION
Our interest in the design and synthesis of ligands for retinoic acid receptors led to the synthesis of the
benzophenone-based compounds reported herein. Vitamin A (retinol) and its biologically active analogs,
collectively called retinoids, play a critical role in the development and homeostasis of vertebrate
tissues.1,2 All-trans retinoic acid (ATRA) and 9-cis retinoic acid (9-cis RA) (Figure 1) are endogenous
ligands for retinoic acid receptors (RARs) and retinoid X receptors (RXRs). A variety of structurally
diverse compounds have been developed that also bind to these receptors with high affinity (Figure 1).3-5

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HETEROCYCLES, Vol. 71, No. 3, 2007
Figure 1. Structures of ATRA, 9-cis RA, SR 11294 (RAR ligand) and BMS 230749 (RXR ligand).
R
O
COOH
COOH
OH
9- cis-retinoic acid
(9-cis RA)
SR 11294 R = Phenyl
COOH
all-trans-retinoic acid (ATRA)
BMS 230749
The aim of the present work is the preparation of novel RAR and/or RXR candidate ligands using the
commercially available 3-formylchromones. The product of Wittig reactions between this chromone-
aldehyde and commercially available phosphoranes might be expected to be chromones with poly-
olefinic side chains (Scheme 1; EP-1 and EP-2, EP-3).6, 7 However, Wittig-Horner-Emmons (WHE)
reactions involving triethyl 3-methylphosphonocrotonate and a series of 3-formylchromones resulted in
the isolation of benzophenone-based compounds.8 Similar rearrangements of the chromone nucleus have
been reported in the literature. We herein report the use of the WHE reaction to synthesize
benzophenone-based compounds following this predictable and reproducible rearrangement.9, 10
Scheme 1. Expected Products (EP) of Wittig and W-H-E Reactions.
O
O
O
R1
R2
CHO
R1
R2
COOEt
R1
R2
COOR
(a)
O
O
EP-1
O
(b), (c), (d)
1
R = H
R = CH3
EP-2
(e)
EP-3
Conditions: a) triethyl 3-methylphosphonocrotonate, n-BuLi, HMPA, -78oC, 1 h to rt 24 h; b) LAH; c) MnO2 , 0oC; d) methyl
(triphenylphosphoranyl)acetate hydrobromide, n-BuLi, -78oC; e) LiOH, MeOH/THF/H2O.
The structures of rearranged products are confirmed via X-ray crystal data. A mechanism for the
rearrangement of the WHE reaction intermediate to the corresponding benzophenone is proposed. The
facile synthetic routes reported herein are used to prepare RAR or RXR candidate ligands. The route has
general applicability in the synthesis of a variety of substituted benzophenones (e.g., BMS 230749).11
RESULTS AND DISCUSSION
The product of a WHE reaction between 3-formylchromone (1) and triethyl 3-methyl-4-
phosphonocrotonate might be predicted to be the diene (EP-1; see Scheme 1).12, 13 This compound could
be further elaborated as shown to provide expected chromone EP-3 in acceptable yield (Scheme 1).
Hence, EP-1 was reduced to the alcohol with LAH and then oxidized to the corresponding aldehyde
(MnO2). The aldehyde was reacted with methyl (triphenylphosphoranyl)acetate hydrobromide under
1
standard Wittig conditions to provide a methyl ester (EP-2; Scheme 1). However, H NMR data of the

HETEROCYCLES, Vol. 71, No. 3, 2007
559
actual product (4; See Scheme 2) shows an exchangeable proton peak (CD3OD) located at 11.8 ppm. In
addition, DEPT 13C NMR spectra show seven peaks for carbons with no protons attached consistent with
compound (4) (EP-2 would contain six such carbon peaks; Figure 2).
Figure 2. DEPT 13C NMR of Compound (4).
Taken together, the data described above suggest that a rearrangement had occurred and a benzophenone
intermediate (2) was obtained (see Scheme 2). Compound (2) then underwent reduction (LAH),
oxidation (MnO2), and a Wittig reaction to provide ester (4) in good yield. The target, (E)-3-(5-(2-
hydroxybenzoyl)-2-methylphenyl)acrylic acid (5), was isolated in acceptable yield following basic
hydrolysis.
Scheme 2. Synthesis of Compound (5).
O
COOH
O
OCH3
O
O
O
O
CHO
(a)
COOEt
(b)
CHO
(c)
(d)
(e)
O
OH
OH
OH
OH
1
3
2
4
5
Conditions: a) triethyl 3-methyl-4-phosphonocrotonate, n-BuLi, HMPA, -78oC; b) LAH; c) MnO2, five portions over 2 h, 0
oC; d) (methoxycarbonylmethyl) triphenylphosphonium bromide, n-BuLi, -78 oC; e) LiOH, MeOH/THF/H2O, 2 h.
All spectroscopic data for (5) was consistent with the presence of the benzophenone system. In addition,
the crystal structure shown in Figure 3 clearly demonstrates the formation of the benzophenone product.
Hence, the initial WHE reaction provides the triene intermediate (I-1; Scheme 3) which undergoes
cyclization to the more stable aromatic structure compound (2) (Scheme 3). Once the benzophenone
nucleus is formed, it undergoes the reactions shown in Scheme 2 to provide the target acid (5).

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Figure 3. ORTEP representation of crystal structure of compound (5) with 30% probability thermal
ellipsoids.
O4
C16
O1
C5
O3
O2
C7
C15
C14
C10
C11
C9
C4
C3
C6
C1
C8
C13
C17
C12
C2
To test the general applicability of this approach several chromones were used to prepare novel retinoid
candidate ligands using the same synthetic route. In order to introduce aliphatic substituents into the
lipophilic region of retinoid ligands, alkyl substituted chromones were used. For example, 6-isopropyl-3-
formylchromone was reacted with triethyl 3-methyl-4-phosphonocrotonate under similar WHE reaction
1
13
conditions as shown in Scheme 4. As seen with compound (5) above, H and C DEPT NMR data for
the product of this reaction suggested a hydroxyl group was present.
Scheme 3. Proposed mechanism for the rearrangement/cyclization to form key intermediates 2, 6, 9.
O
O
O
O
R1
R2
R1
R2
R1
R2
COOEt
R1
R2
CHO
(a)
O
O
O
O
H
COOEt
COOEt
1
I-2
I-1
I-3
O
OH
O
R1
R2
R1
R2
COOEt
2 = R1 = R2 = H
6 = R1 =CH(CH3)2, R2 = H
9 = R1 = R2 = (CH3)2-CH-CH2-CH2-CH-(CH3)2
OH
COOEt
I-4
Conditions: a) triethyl 3-methyl-4-phosphonocrotonate, n-BuLi, HMPA, -78oC, 1 h to rt 24 h.
Hence, cyclization of the intermediate triene (I-1) and ring opening of the chromone nucleus provides
benzophenone (6) (Scheme 4) which is consistent with all spectroscopic data for the compound.
Hydrolysis of the ester provides the target acid as a potential RAR candidate ligand.

HETEROCYCLES, Vol. 71, No. 3, 2007
561
Scheme 4. WHE reaction of 6-isopropyl-3-formylchromone with triethyl 3-methyl-4-phosphonocrotonate.
OH
O
O
COOEt
CHO
(a)
O
6
Conditions: a) triethyl 3-methyl-4-phosphonocrotonate, n-BuLi, HMPA, -78oC, 1 h to rt 24 h.
Lastly, 6,6,9,9-tetramethyl-4-oxo-6,7,8,9-tetrahydro-4H-benzo[g]chromene-3-carbaldehyde (8 below)
was reacted with triethyl 3-methyl-4-phosphonocrotonate under WHE reaction conditions. In this case,
the key starting intermediate (7) was prepared using known published procedures.14-17
Scheme 5. Synthesis of Compound (10).
O
O
O
OH
CHO
(b)
COOH
COOEt
(c)
(a)
CH3
O
OH
OH
7
10
8
9
O
Conditions: a) POCl3, DMF; b) triethyl 3-methyl-4-phosphonocrotonate, n-BuLi, HMPA, -78oC, 1 h to rt 24 h; c) LiOH,
MeOH/THF/H2O, 2 h.
In the first reaction in the sequence, 2,5-dimethyl-2,5-hexanediol and concentrated HCl were stirred
vigorously at rt for 3 - 4 h to afford 2,5-dichloro-2,5-dimethylhexane in good yield (90%).14 Phenol and
2,5-dichloro-2,5-dimethylhexane were then reacted under Friedel Craft reaction conditions to provide
intermediate which was acetylated using AlCl3 in dried CH2Cl2 to yield (7).15,16 Compound (7) was
converted to the chromone aldehyde (8) using freshly distilled phosphorus oxy-chloride (POCl3) in
anhydrous DMF at rt. Compound (8) (6,6,9,9-tetramethyl-4-oxo-6,7,8,9-tetrahydro-4H-
benzo[g]chromene-3-carbaldehyde) was used in the synthesis of the target benzophenone (10) as shown
in Scheme 5.
6,6,9,9-Tetramethyl-4-oxo-6,7,8,9-tetrahydro-4H-benzo[g]chromene-3-carbaldehyde (8) was reacted with
the commercially available triethyl 3-methyl-4-phosphonocrotonate in the presence of n-BuLi in dried
THF to give compound (9) following the previously observed rearrangement. The target ligand (10) was
obtained following basic hydrolysis.
1
As anticipated, the product of this reaction had an exchangeable proton at 11.5 ppm in the H NMR
spectrum. In addition, IR spectra showed carbonyl and carboxylate bands expected of benzophenone-

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containing compounds possessing a carboxylic acid. These data suggest that the rearrangement had
occurred as previously observed for the ligands reported above. The structure of (10) was confirmed via
X-ray crystal analysis as shown in Figure 4.
Figure 4. ORTEP representation of crystal structure of compound (10) with 30% probability thermal
ellipsoids.
O4
O1
O2
C7
C14
C9
C5
C10
C4
C3
C8
O3
C6
C1
C22
C11
C13
C19
C2
C16
C23
C12
C15
C18
C21
C17
C20
CONCLUSION
Rearrangements of chromones under similar reaction conditions have been reported in the literature. The
data provided herein provides further evidence for this useful, yet unanticipated synthetic route to
substituted benzophenones. The reaction of 3-formylchromone with phosphoranes under WHE reaction
conditions is a generally applicable route to substituted benzophenones. These cyclization reactions
proceed at low temperatures, under mild conditions and provide facile routes to a variety of substituted
benzophenones.
EXPERIMENTAL
General. Reactions were carried out in oven-dried glassware under a nitrogen atmosphere and were
magnetically stirred and monitored by thin-layer chromatography (TLC) with Analtech 250 micron pre-
coated silica gel plates. Tetrahydrofuran (THF) were freshly distilled from sodium/benzophenone under
nitrogen and dichloromethane (CH2Cl2) distilled from calcium hydride. Except as otherwise indicated, all
reagents were purchased and used without purification. Flash column chromatography was performed
using silica gel 60 (particle size 230-400 mesh) supplied by Aldrich. Yields refer to chromatographically
pure compounds. Melting points were obtained on a Thomas-Hoover apparatus and are not corrected.
1
Nuclear magnetic resonance spectra were recorded on a Bruker Avance 400 at 400MHz for H NMR
(some on a GE at 500 MHz) and 100MHz for 13C NMR. Chemical shifts were reported relative to
solvents or an internal standard (TMS). Low- and high- resolution mass spectrometry data were recorded
by the Department of Chemistry, Drexel University using a VG70-SE high resolution magnetic sector
instrument operating at 7 KV acceleration voltages. Samples are dissolved in a matrix of nitrobenzoyl
alcohol (NBA) doped with NaBr and bombarded with a 35 KV Cs ion beam (LSI, API, EPI-MS).

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Elemental analyses were performed by Atlantic Micro lab Inc, Norcross, GA. X-ray crystallographic
analysis was performed at Department of Chemistry, University of Pennsylvania.
Ethyl 5-(2-hydroxybenzoly)-2-methylbenzoate (2)
To a solution of triethyl 3-methyl-4-phosphonocrotonate (1.3 mL, 5.4 mmol) in dry THF (15 mL) was
added n-butyllithium (2M in heptane, 4.5 mL, 9 mmol) and HMPA (0.16 mL, 0.9 mmol). The mixture
was cooled to -78oC, stirred under N2 for 30 min and 3-formylchromone (0.85 g, 4.9 mmol) in dry THF (5
mL) was added dropwise. The resulting mixture was stirred at -78oC for 1 h and allowed to warm to rt
and stirred for 24 h. The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL) and
extracted with EtOAc (50 mL × 3). The organic layer was washed with brine, dried over MgSO4,
condensed and purified by flash chromatography (silica gel; 10:1 to 3:1, hexane/EtOAc) to afford
compound (2) (0.82 g; yield: 56%) as colorless oil: 1H NMR (500 MHz, CDCl3): δ 11.9 (s, 1 H), 8.16 (s,
1 H), 7.62 (d, J = 7.9 Hz, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.44 (t, J = 7.9 Hz, 1 H), 7.30 (d, J = 7.9 Hz, 1
H), 6.99 (d, J = 8.4 Hz, 1 H), 6.81 (t, J = 7.6 Hz, 1 H), 4.27-4.33 (q, J = 7.1 Hz, 2 H), 2.62 (s, 3 H), 1.31
13
(t, J = 7.1 Hz, 3 H). C NMR (100 MHz, CDCl3): δ 200.8, 167.1, 163.6, 144.9, 136.9, 135.9, 133.7,
132.6, 132.2, 131.9, 130.6, 119.4, 119.2, 118.9, 61.6, 22.3, 14.7.
5-(2-Hydroxybenzoly)-2-methylbenzaldehyde (3)
To a solution of ester (2) (0.82 g, 2.7 mmol) in dry THF (25 mL) was added LAH powder (0.5 g, 12.9
mmol) with stirring at rt. The reaction mixture was treated in order with H2O (10 mL), 10% NaOH (10
mL) and H2O (10 mL), condensed under reduced pressure and the remaining residue was extracted with
EtOAc (50 mL × 2). The EtOAc layer was washed with brine, dried over MgSO4, condensed and purified
by flash chromatography (silica gel; 1:1, hexane/EtOAc) to afford colorless oil. To a solution of the oil
(0.45 g, 1.7 mmol) in dry CH2Cl2 (25 mL) was added MnO2 (in five portions; 1.5 g, 17 mmol) and 0.5 g
of molecular sieve (4 Å) powder. The mixture was chilled in an ice bath and stirred for 2 h. Another 1.5 g
of MnO2 was added in five portions over 2 h. After stirring for 30 min, the resulting mixture was filtered
through Celite 450 and washed with CH2Cl2. The collected CH2Cl2 solution was condensed and purified
by flash chromatography (silica gel; 1:1, hexane/EtOAc) to afford compound (3) (0.22 g, 40% for two
steps) as a yellow solid: 1H NMR (500 MHz, CDCl3): δ 11.8 (s, 1 H), 10.3 (s, 1 H), 8.13 (s, 1 H), 7.82 (d,
J = 7.5 Hz, 1 H), 7.53-7.57 (m, 2 H), 7.44 (d, J = 8.0 Hz, 1 H), 7.10 (d, J = 8.0 Hz, 1 H), 6.91 (t, J = 7.5
Hz, 1 H), 2.79 (s, 3 H).
(E)-Methyl 3-(5-(2-hydroxybenzoyl)-2-methylphenyl)acrylate (4)
To a solution of (methoxycarbonylmethyl) triphenylphosphonium bromide (0.37 g, 0.8 mmol) in dry THF

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(20 mL) was added n-butyllithium (2M in heptane, 0.4 mL, 0.8 mmol) and HMPA (0.05 mL). The
mixture was cooled to -78oC and stirred under N2 for 30 min, followed by the dropwise addition of the
aldehyde (3) (0.16 g, 0.6 mmol) in dry THF (5 mL). The resulting mixture was stirred at -78oC for 1 h and
allowed to warm to rt. After 24 h, the reaction mixture was quenched with saturated aqueous NH4Cl (20
mL) and extracted with EtOAc (30 mL × 3). The organic layer washed with brine, dried over MgSO4,
condensed and purified by flash chromatography (silica gel; 10:1 to 3:1, hexane/EtOAc) to afford
compound (4) (0.1 g; yield: 51%) as a white solid: 1H NMR (400 MHz, CDCl3): δ 11.9 (s, 1 H), 7.92 (d, J
= 15.9 Hz, 1 H), 7.77 (s, 1 H), 7.48-7.52 (t, J = 7.8 Hz, 2 H), 7.42-7.46 (t, J = 8.6 Hz, 1 H), 7.27 (d, J =
7.9 Hz, 1 H), 7.00 (d, J = 8.4 Hz, 1 H), 6.79-6.83 (t, J = 8.2 Hz, 1 H), 6.32 (d, J = 15.9 Hz, 1 H), 3.74 (s, 1
H), 2.45 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ 200.7, 167.0, 163.2, 141.8, 141.3, 136.4, 136.2, 133.7,
133.2, 130.8, 130.4, 127.3, 120.6, 119.1, 118.7, 118.5, 51.8, 19.9. NOE.
(E)-3-(5-(2-Hydroxybenzoyl)-2-methylphenyl)acrylic acid (5)
To a solution of the methyl ester (4) (20 mg, 0.06 mmol) in MeOH/THF/H2O (6 mL; 1:1:1) was added
LiOH (15 mg) and the mixture was stirred at rt for 2 h. The reaction was acidified to pH 1.5 by dropwise
addition of 5 N HCl. The mixture was condensed and purified by chromatography (silica gel; 5:5:1,
EtOAc/CH2Cl2/MeOH) to afford acid (5) as a pale yellow solid in quantitative yield: 1H NMR (400 MHz,
CD3OD): δ 7.90 (d, J = 15.9 Hz, 1 H), 7.78 (s, 1 H), 7.49-7.53 (m, 2 H), 7.46 (t, J = 8.3 Hz, 1 H), 7.29 (d,
J = 7.9 Hz, 1 H), 6.99 (d, J = 8.4 Hz, 1 H), 6.84 (t, J = 8.1 Hz, 1 H), 6.31 (d, J = 15.9 Hz, 1 H), 2.45 (s, 3
H). 13C NMR (100 MHz, CD3OD): δ 202.7, 171.1, 164.3, 143.7, 143.1, 138.2, 137.9, 135.7, 135.1, 132.6,
132.1, 129.1, 123.4, 121.0, 120.8, 119.6, 21.5. LC-MS (API-ESI): 297.3 (M-1), 298.4 (M+).
Ethyl 5-(2-hydroxy-5-isopropylbenzoyl)-2-methylbenzoate (6)
A solution of triethyl 3-methyl-phosphonocrotonate (0.14 mL, 0.5 mmol) in dried THF (15 mL) was
cooled in an ice bath, stirred and treated with n-butyllithium (2 M in heptane, 0.5 mL, 1.0 mmol). The
reaction mixture was stirred at 0oC for 30 min and a solution of 3-formylisopropylchromone (0.1 g, 0.46
mmol) in dried THF (5 mL) added dropwise. The resulting mixture was stirred for 2 h at 0oC and allowed
to warm to rt. After two days at rt the mixture was quenched with saturated aqueous NH4Cl and extracted
with EtOAc (20 mL × 3). The combined organic layer was washed with brine, dried over MgSO4,
condensed and purified by flash chromatography (silica gel; 10:1, hexane/EtOAc) to afford compound (6)
(60 mg; yield: 40%) as a yellow oil: 1H NMR (400 MHz, CDCl3): δ 11.8 (s, 1 H), 8.27 (d, J = 1.9 Hz, 1
H), 7.74-7.76 (dd, J = 1.9, 7.9 Hz, 1 H), 7.40 (m, 3 H, H2, H4 and H5), 7.02 (d, J = 7.2 Hz, 1 H), 4.35 (q, J
= 7.1 Hz, 2 H), 2.84 (m, 1 H), 2.70 (s, 3 H), 1.40 (t, J = 7.1 Hz, 3 H), 1.19 (d, J = 6.9 Hz, 6 H); 13C NMR:
δ 200.5, 167.0, 161.7, 144.9, 139.5, 136.0, 135.4, 132.6, 132.3, 132.1, 131.2, 130.8, 119.0, 118.6, 61.5,

HETEROCYCLES, Vol. 71, No. 3, 2007
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33.6, 24.3, 22.2, 14.7. (400 MHz, Pyridine-d5): δ 13.33 (s, 1 H), 9.71 (d, J = 1.9 Hz, 1 H), 9.09-9.11 (dd,
J = 1.9, 7.9 Hz, 1 H), 8.75 (d, J = 2.3 Hz, 1 H, H2), 8.53-8.56 (dd, J = 2.3, 8.5 Hz, H4), 8.47 (d, J = 7.9 Hz,
1 H), 8.34 (d, J = 8.2 Hz, 1 H, H5), 5.40-5.46 (m, 2 H), 3.93 (m, 1 H), 3.78 (s, 3 H), 2.29-2.35 (m, 9 H).
MS m/z (CI): 326 (M+); (FAB): 327 (M+H); HR-MS (FAB): 327.1593 (Calcd for C20H23O4 327.1596);
Anal. [C20H22O4] C, H. Found: C, 73.46; H, 7.00.
1-(3-Hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone (7)
To 2,5-dimethyl-2,5-hexanediol (2 g, 2.67 mmol) was added concentrated HCl (20mL) with vigorous
stirring at rt for 3 - 4 h. Chloroform (CHCl3; 25 mL) was added to the solution and the two layers were
separated. The aqueous layer was extracted with CHCl3 (2 x 25 mL), the organic layers were combined,
dried over MgSO4 and condensed under reduced pressure. This was purified by flash chromatography
(silica gel; 10:1, hexane/EtOAc) to afford a tan amorphous solid of 2,5-dichloro-2,5-dimethylhexane
1
(1.90g, yield: 90%). H NMR (500 MHz, CDCl3): δ 2.0 (s, 4H), 1.6 (s, 12H). To a solution of the 2,5-
dichloro-2,5-dimethylhexane (1g, 5.46 mmol) and phenol (0.616g, 6.55 mmol) was added AlCl3 (1.09g,
8.19mmol) in small portions and the mixture stirred at rt for 12 h. The reaction was quenched by
dropwise addition of water and extracted with EtOAc (3 x 30mL). The combined organic layers were
washed with brine, dried over MgSO4, condensed under reduced pressure and purified by flash
chromatography (silica gel; 11:1, hexane/EtOAc) to afford 5,5,8,8-tetramethyl-5,6,7,8-
1
tetrahydronaphthalen-2-ol (0.82g; yield: 82%): H NMR (400 MHz, CDCl3): δ 7.16 (d, J = 8.50 Hz, 1H,
Ar), 6.75 (d, J = 2.76 Hz, 1H, Ar), 6.62 (dd, J = 2.77, 8.49 Hz, 1H, Ar), 4.65 (s, 1H), 1.65 (m, 4H), 1.24
(d, J = 2.58 Hz, 12H). A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ol (0.48g, 2.35
mmol) in dried CH2Cl2 was added slowly to AlCl3 (0.313g, 2.35 mmol). To this mixture CH3COCl
(0.22g, 2.82mmol) was added dropwise and the reaction refluxed for 8-12h. Water was added and the
layers separated. The aqueous phase was extracted with EtOAc (3 x 25mL) and the combined organic
layers were dried over MgSO4, reduced under pressure and purified by flash chromatography (silica gel;
10:1, hexane/EtOAc) to afford (7) (0.3g; yield: 51%): 1H NMR (500 MHz, CDCl3): δ 7.4 9 (d, 1H), 6.98
(d, 1H), 2.4 (s, 3H), 1.8 (s, 4H), 1.4 (s, 12H).
6,6,9,9-Tetramethyl-4-oxo-6,7,8,9-tetrahydro-4H-benzo[g]chromene-3-carbaldehyde (8)
To a solution of (7) (0.3g, 1.217 mmol) in anhydrous DMF (15 mL), freshly distilled POCl3 (0.933g,
6.085 mmol) was added dropwise. The mixture was refluxed overnight and monitored by TLC. Solvent
was removed under vacuum and ice cold water was added. The aqueous phase was extracted with
CH2Cl2 (3 x 25 mL), and the organic layers combined, washed with brine, dried over MgSO4, reduced
under pressure and purified by flash chromatography (silica gel; 12:1 to 7:1, hexane/EtOAc) to afford

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HETEROCYCLES, Vol. 71, No. 3, 2007
compound (8) (0.2g; yield: 57%): 1H NMR (500 MHz, CDCl3): δ 10.4 (s, 1H), 8.5 (s, 1H), 8.23 (s, 1H),
7.45 (s, 1H), 1.75 (s, 4H), 1.36 (s, 12H).
Ethyl 5-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carbonyl)-2-
methylbenzoate (9)
To a solution of triethyl 3-methyl-phosphonocrotonate (0.465 g, 1.76 mmol) in dry THF (20 mL) was
added dropwise n-butyllithium (2M in heptane, 1.76 mL, 3.52 mmol) and the mixture cooled to -78oC and
stirred under N2 for 30 min. A solution of aldehyde (8) (0.5g, 1.76 mmol) in dry THF (5 mL) was added
dropwise to the mixture. The reaction was stirred at -78oC for 1-2 h and allowed to warm to rt and stirred
over 24 h. The reaction was quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc
(3 x 30 mL). The organic layers were washed with brine, dried over MgSO4, condensed and purified by
flash chromatography (silica gel; 15:1 to 7:1, hexane/EtOAc) to afford compound (9) (0.2g; yield: 28%)
1
as a yellowish solid: H NMR (400 MHz, CDCl3): δ 11.57 (s, 1H), 8.27 (d, J = 1.94, 1H), 7.76 (dd, J =
1.94, 7.87, 1H), 7.54 (s, 1H), 7.41 (d, J = 7.95, 1H) 7.0 (s, 1H), 4.37 (q, 2H), 2.72 (s, 3H), 1.68 (m, 4H),
1.37 (t, 3H), 1.31 (s, 6H), 1.20 (s, 6H).
5-(3-Hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carbonyl)-2-methylbenzioc acid
(10)
To a solution of the ethyl ester (9) (0.12g, 0.3041 mmol) in MeOH/THF/H2O (6 mL; 1:1:1) was added
LiOH (14mg, 0.6082 mmol) and the mixture stirred at rt for 2-6 h. The reaction was acidified to pH 1.5 –
2.0 by dropwise addition of 5 N HCl and extracted with EtOAc (2 x 25 mL). The combined organic
layers was dried over MgSO4, condensed under reduced pressure and purified by flash chromatography
(silica gel; 10:1: 0.1, hexane/ EtOAc/ HCOOH) to afford acid (10) as a yellow solid in quantitative yield
1
(0.1g, yield: 89%). H NMR (400 MHz, CDCl3): δ 11.5 (s, 1H), 8.43 (d, J = 1.9 Hz, 1H), 7.83 (dd, J =
1.93, 7.88 Hz, 1H), 7.53 (s, 1H), 7.45 (d, J = 7.96 Hz, 1H), 7.01 (s, 1H), 2.77 (s, 3H), 1.68 (m, 4H), 1.31
13
(s, 6H), 1.20 (s, 6H). C NMR (100 MHz, CDCl3): δ 199.55, 172.24, 160.60, 155.98, 145.98, 136.40,
133.57, 132.66, 132.06, 128.58, 117.66, 115.85, 35.22, 34.05, 32.08, 22.59. Anal. [C23H26O4] C, H.
Found: C, 75.09; H, 7.34.
ACKNOWLEDGEMENT
We gratefully acknowledge the Dean’s office, School of Pharmacy, Temple University and Wyeth
Research for financial support. We thank the Department of Chemistry, Temple University for use of the
NMR Facility and Dr. Debrosse, Director of the NMR Facility for his help with NMR interpretation. We
also thank Dr. Franklin A. Davis for his helpful remarks in the preparation of this material.

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