Synthesis of benzyl substituted naphthalenes from benzylidene tetralones

Article abstract of DOI:10.1016/j.tetlet.2011.11.065

A convenient and efficient synthesis of novel highly substituted dimethoxybenzylnaphthalenes, which are precursors to several dihydroxynaphthoic acids, is described. The approach involves the use of aldol chemistry to provide a number of benzylidene tetra

Full text of DOI:10.1016/j.tetlet.2011.11.065

Tetrahedron Letters 53 (2012) 373–376
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Tetrahedron Letters
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Synthesis of benzyl substituted naphthalenes from benzylidene tetralones
Lorraine M. Deck a, , Quintino Mgani a, , Andrea Martinez a, Alice Martinic a, Lisa J. Whalen a,
⇑
David L. Vander Jagt b, Robert E. Royer b
a Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM 87131, USA
b Department of Biochemistry and Molecular Biology, University of New Mexico, School of Medicine, Albuquerque, NM 87131, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and efficient synthesis of novel highly substituted dimethoxybenzylnaphthalenes, which
are precursors to several dihydroxynaphthoic acids, is described. The approach involves the use of aldol
chemistry to provide a number of benzylidene tetralones, which are converted to the target naphthalenes
in three steps, with good to excellent yields. Grignard reaction of intermediate benzyl tetralones provided
1-substituted benzyl naphthalenes. The reported synthesis is flexible and scalable and provides access to
naphthalenes having a variety of substitution patterns. These benzyl substituted naphthalenes are being
converted to naphthoic acids and the bioactivities of these compounds are currently being investigated.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 1 August 2011
Revised 11 November 2011
Accepted 14 November 2011
Available online 25 November 2011
Keywords:
Benzylidene tetralone
Benzylnaphthalene
Benzyltetralone
One area of our research focuses on the synthesis of highly
substituted naphthoic acids as therapeutics for breast, prostate,
and pancreatic cancers. 7-Benzyl-2,3-dihydroxy-6-methyl-4-pro-
pyl-1-naphthoic acid, compound1, has been shownto inhibitlactate
dehydrogenase A (LDHA) reducing ATP levels and importantly
inducing significant oxidative stress and cell death in cancer cells (
Fig. 1).1 Compound 1 also inhibits tumorigenesis in human lym-
phoma and pancreatic cancer xenograft models and along with an-
other inhibitor induces lymphoma regression. The structure of
compound 1 is modeled on the structure of the natural product gos-
sypol, compound 2, which occurs in cottonseed (Fig. 1). Gossypol
itself exhibits multiple biological properties including spermicidal,2
antiparasitic,3–6 anticancer7–10 and antiviral.11–14 Multiple bioactiv-
ities of gossypol have stimulated wide interest in the development
of gossypol derivatives to explore structure–activity relationships
(SARs).15–20 Unfortunately gossypol is toxic, due to the aldehyde
groups, and derivatives which do not have an aldehyde functional
group retain or show enhanced biological activity. However, these
derivatives are not selective inhibitors.14 Dihydroxynaphthoic acids,
which can be viewed as analogs of gossypol, are selective non-toxic
inhibitors of LDHA. Our interest lies in synthesizing several analogs
of compound 1 that could be tested for the inhibition of LDHA with
the hope of developing more potent inhibitors.
efficient, and convenient synthetic scheme to synthesize benzyl
substituted dimethoxynaphthalenes from benzylidene tetralones.
The synthetic schemes were designed to provide a number of 7-ben-
zyl substituted dihydroxynaphthoic acids that could be synthesized
from the benzylnaphthalenes. The benzylidene tetralones were syn-
thesized from the known tetralones compounds 10a21 and 10o18
and the new tetralone, compound 10m. Tetralones 10a and 10o
were synthesized using procedures described in the literature18,21
except cyclization of known 4-(3,4-dimethoxyphenyl)butanoic acid
to form 10a was performed using polyphosphoric ester rather than
polyphosphoric acid. Polyphosphoric ester produced better yields
and purer product.
Compound 10m was synthesized using a procedure previously
described by our group18 as shown in Scheme 1. Bromination of
1-ethyl-2,3-dimethoxybenzene (4) at 0 °C using bromine, via an
electrophilic aromatic substitution mechanism, afforded com-
pound 5 in a 90% yield.22,23 In some preparations small amounts
of another regioisomer 1-bromo-4-ethyl-2,3-dimethoxybenzene
were formed. To avoid the formation of both isomers an alternate
efficient and highly regioselective silica gel catalyzed synthesis
using N-bromosuccinimide produced the desired regioisomer in a
97% yield24 and avoided the use of corrosive bromine. Since both
isomers display a pair of doublets in the aromatic area of the proton
NMR spectra, HMQC and HMBC experiments confirmed that the
bromine was ortho to the ethyl group in compound 5. Additionally,
confirmation of formation of the correct regioisomer came from
comparison with data from the literature.17,18
The precursors needed for the synthesis of various analogs of
compound 1 are benzyl substituted dimethoxynaphthalenes, simi-
lar structurally to compound 3 (Fig. 1). In order to explore SARs of
various benzyl substituted naphthoic acids we developed a short,
The synthesis of compound 7 features the incorporation of the
carbon atoms for the second ring of the naphthalene system in
one step by the reaction of the Grignard reagent formed from com-
pound 5 with ethyl 3-methyl-4-oxo-2-butenoate (6) in an 89%
⇑
Corresponding author. Tel.: +1 505 277 5438.
E-mail address: ldeck@unm.edu (L.M. Deck).
Present address: University of Dar Es Salaam, Africa.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.065

374
L. M. Deck et al. / Tetrahedron Letters 53 (2012) 373–376
H
O
COOH
R3
C
OH
HO
HO
CH2Ph
H3CO
H3CO
CH2PhX
R2
HO
HO
2
CH2CH2CH3
R1
7-Benzyl-2,3-dihydroxy-6-methyl-
Benzyldimethoxynaphthalenes (3)
Gossypol (2)
4-propylnaphthoic acid (1)
Figure 1.
H3CO
H3CO
H3CO
COOEt
H3CO
(b) Mg
H3CO
H3CO
H3CO
H3CO
COOH
(a) Br2
COOH
H3CO
(d) H2
H3CO
Br
CH2CH3
(c) KOH
CO2Et
OH
CH2CH3
OH
CH3CH2
CH3CH2
CH3CH2
OHC
4
7
9
5
8
6
(e) PPE
O
H3CO
H3CO
CH3CH2
10
Scheme 1. Synthesis of tetralone: Reagents and conditions: (a) Br2 (1 equiv), CH2Cl2, 0 °C to rt, 2 h or NBS (1.1 equiv), silica gel, CCl4, rt, 12 h, 90%; (b) Mg (1.5 equiv),
CH3CH2Br (0.1 equiv), I2, THF, reflux, 1.0 h then 6 (1.2 equiv), 0 °C to rt, 12 h, then H2O/HCl, 89%; (c) KOH (4 equiv), EtOH, H2O, reflux, 8.0 h, then HCl/ice, 90%; (d) H2, 10% Pd/C,
HOAc, 60 psi, 60 °C, 8h, 75%; (e) PPE, CH2Cl2, reflux, 5 h, then H2O, 88%.
O
O
O
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
(b) H2
EtOAc
H3CO
H3CO
(a) R3CHO
(c) NaBH4
(d) HCl
R3
R3
R3
R2
R2
R2
R2
R1
R1
11a-11u
R1
12a-12u
R1
10a, 10m, 10o
13a-13u
H3CO
(e) Pd/C, triglyme
(f) H2,
MeOH
a: R1, R2 = H; R3 = C6H5
b: R1, R2 = H; R3 = 4-CH3C6H4
c: R1, R2 = H; R3 = 2-CH3C6H4
d: R1, R2 = H; R3 = 4-CF3C6H4
e: R1, R2 = H; R3 = 2-CF3C6H4
f: R1, R2 = H; R3 = 3-CH3C6H4
R3
R2
H3CO
H3CO
H3CO
R1
15
14a-14f, 14h, 14j-14u
g: R1, R2 = H; R3 = 4-BrC6H4
h: R1, R2 = H; R3 = 4-(CH3)2CHC6H4
i: R1, R2 = H; R3 = 2-BrC6H4
j: R1,R2 = H; R3 = 1-C10 H7
k: R1, R2 = H; R3 = 2-C10H7
l: R1, R2 = H; R3 = 4-FC6H4
m: R1 = CH2CH3, R2 = CH3; R3 = C6H5
n: R1 = CH2CH3, R2 = CH3; R3 = 4-CH3C6H4
o: R1 = CH2CH2CH3, R2 = CH3; R3 = 3-CH3C6H4
p: R1 = CH2CH2CH3, R2 = CH3; R3 = 4-(CH3)2CHC6H4
q: R1 = CH2CH2CH3, R2 = CH3; R3 = 4-CH3CH2C6H4
r: R1 = CH2CH2CH3, R2 = CH3; R3 = 3-CH3OC6H4
s: R1= CH2CH2CH3, R2 = CH3; R3 = 4-CH3C6H4
t: R1 = CH2CH2CH3, R2 = CH3; R3 = 4-CF3C6H4
u: R1 = CH2CH2CH3, R2 = CH3; R3 =C6H5
Scheme 2. Synthesis of benzyl naphthalenes: Reagents and conditions: (a) R3CHO (1.1 equiv), 5% KOH/EtOH, rt, 24–36 h, then H2O, 80–95%; (b) H2, 10% Pd/C, EtOAc, 30 psi, rt,
1 h, 83–100%; (c) NaBH4 (2 equiv), EtOH, reflux, 2 h then; (d) 6 M HCl, reflux, 2 h, 85–95%; (e) 10% Pd/C, triglyme, reflux, 5 h, filter then H2O, 90–95%; (f) 11g, H2, 10% Pd/C,
CH3OH, 30 psi, rt, 2 h, 60%.
yield.17,18 Since the precursor, compound 6, is not readily available,
it was prepared by Wadsworth–Emmons reaction of pyruvic alde-
hyde dimethyl acetal with triethylphosphonoacetate in tetrahy-
drofuran or dimethylformamide followed by hydrolysis.25–27 The
E/Z ratio of the product is different for the Wadsworth–Emmons
reaction in the two solvents but hydrolysis in acid affords 96% of
trans (E) stereospecifically. The E/Z ratio of compound 6 did not
affect the progress of the subsequent reactions in the synthesis.
The stereochemical assignment of the aldehyde, compound 6, is
based upon proton NMR analysis.25,26 The Grignard reagent is
added slowly to a cold solution of ethyl 3-methyl-4-oxo-2-buteno-
ate (6) to ensure attack at the more reactive aldehyde carbonyl car-
bon to give an 89% yield of predominately the E ester. To confirm
the diastereoselectivity of the reaction and the structure of the
product a NOE spectrum (300 MHz) was taken. Irradiation of the
methyl group in compound 7 resulted in no enhancement of the
resonance of the alkene hydrogen and enhancement of the hydro-
gen on the alcohol carbon, which verifies that the ester has E
stereochemistry. Pure ester was isolated by chromatography but
reduction of the crude mixture or the pure compound using
hydrogen in acetic acid was unsuccessful and afforded a complex
mixture. Therefore the crude ester, compound 7, was saponified

L. M. Deck et al. / Tetrahedron Letters 53 (2012) 373–376
375
R2
R2
a: R1 = C6H5; R2 = CH2CH3
b: R1 = C6H5; R2 = CH3
c: R1 = 3-CH3C6H4; R2 = CH2CH3
(a) R2MgBr
H3CO
H3CO
(c) Pd/C, triglyme H3CO
12a, 12f
R1
R1
(b) HCl or
MgSO4
H3CO
16a-16c
17a-17c
Scheme 3. Synthesis of 1-substituted benzylnaphthalenes: Reagents and conditions: (a) R2MgBr (1.5 equiv), THF, reflux, 2.0 h, then HCl/H2O, 75% then; (b) 6 M HCl reflux 2 h
or MgSO4, toluene, reflux, 2 h, 80%; (c) 10% Pd/C, triglyme, reflux, 4 h, filter then H2O, 80%.
using potassium hydroxide in ethanol/water and acidified to give a
90% yield of carboxylic acid, 8, as an oil that solidified. Trituration
and recrystallization from ethyl acetate/hexane afforded com-
pound 8 as a white crystalline solid and was determined to be
the E isomer by a NOE experiment. The infrared spectrum con-
firmed the presence of the allylic alcohol group, the carboxyl group
and the alkene.
Hydrogenation and hydrogenolysis of the crude or pure acid, 8,
was accomplished using hydrogen in concentrated acetic acid at
60 psi (Parr hydrogenator) and 60 °C in the presence of 10% palla-
dium on charcoal to afford the saturated acid, compound 9, in a
75% yield. Cyclization with polyphosphoric ester in a Friedel–Crafts
type of reaction gave an 88% yield of tetralone 10. The cyclization
reaction gives higher yields and purer product with polyphospho-
ric ester than with other reagents such as polyphosphoric acid, sul-
furic acid or methanesulfonic acid.
Conversion of tetralones 10a, 10m and 10o to benzylnaphtha-
lenes, compounds 14a–14f, 14h and 14j–14u is shown in Scheme
2. Benzylidene tetralones, compounds 11a–11u, were readily
formed from tetralones 10a, 10m and 10o by aldol condensation
of the appropriate aldehyde in ethanolic potassium hydroxide
solution in 80–95% yields.28–36 The proton NMR spectra of com-
pounds 11a–11u display a downfield shift of the vinyl proton
due to the diamagnetic anisotropy effect of the carbonyl group,
which indicates that the benzylidene compounds are the E iso-
mers.37 The 2-bromo compound, 11i, and the 2-trifluoromethyl
compound, 11e, gave the same type of unexpected result as
observed by Yee et al. for the monomethoxy compound (2-(2-bro-
mobenzylidene)-6-methoxy-1-tetralone) in the proton NMR
(300 MHz) spectrum.38 They observed a singlet at 2.9 ppm corre-
sponding to the four CH2 protons of 3,4-dihydronaphthalene in-
stead of two distinct multiplets at 2.5 and 3.0 ppm. Compound
11i has one multiplet at 2.9 ppm and compound 11e has a singlet
at 2.9 ppm for the four CH2 protons of the 3,4-dihydronaphthalene
ring system. In all other compounds except for compound 11c, the
four CH2 protons of the 3,4-dihydronaphthalene are two distinct
multiplets at 2.5 and 3.0 ppm. Compound 11c has two distinct
multiplets but at 2.96 and 2.87 ppm. This unexpected degeneracy
occurred with ortho substituted compounds and did not occur with
meta or para substituted benzyl compounds.
in the infrared and 13C NMR spectra. Furthermore the loss of a chi-
ral center in compounds 12a–12u by the formation of a double
bond in compounds 13a–13u resulted in well-resolved peaks in
the alkyl proton area of the NMR spectrum.
Aromatization of alkenes, 13a–13u, to compounds 14a–14u
using dichlorodicyano-benzoquinone (DDQ) in refluxing benzene
did not give the desired results possibly due to the oxidation of
the benzylic methylene carbon. To circumvent this difficulty an
alternate aromatization using palladium on carbon in triglyme
proved successful and the naphthalene compounds, 14a–14f,
14h, and 14j–14u were obtained in 90–95% yields. It was observed
that under these conditions compounds 13g and 13i, which have a
bromobenzyl substituent, underwent dehalogenation, which was
facilitated by the high reflux temperature and the palladium cata-
lyst. As expected, compound 13l did not undergo dehalogenation.
An attractive route to the formation of 1-substituted benzyl-
naphthalenes is reaction of compounds 12a and 12f with a
Grignard reagent followed by dehydration and oxidation as shown
in Scheme 3. Introduction of a group ortho to the benzyl group was
easily accomplished by reaction of compounds 12a and 12f with
methylmagnesium bromide and ethylmagnesium bromide. The
resulting tertiary alcohols were readily dehydrated using dilute
hydrochloric acid or refluxing with magnesium sulfate in toluene
to form alkenes 16a–16c in an 80% yield.21 Aromatization occurred
upon refluxing 16a–16c in triglyme containing 10% palladium on
charcoal to afford compounds 17a–17c in an 80% yield.
In conclusion, a short and convenient synthetic scheme was
developed to afford several benzylsubstituted naphthalenes that
are being converted to naphthoic acids. Bioactivities of these com-
pounds are currently being investigated
Acknowledgments
This research was supported in part by grants HL68598 and
GM060201 from the National Institutes of Health. High resolution
mass spectra (HRMS) were obtained at the UNM Mass Spectrome-
try Facility, Albuquerque, New Mexico.
Supplementary data
Supplementary data (1H, 13C NMR spectroscopic and HRMS
data) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.11.065.
Compounds 11a–11u were hydrogenated using 10% palladium
on charcoal in ethyl acetate for 1 h at 30 psi (Parr hydrogenator) to
afford benzyl substituted tetralones, compounds 12a–12u, in 80–
95% yield.39–41 Hydrogenation in ethyl acetate using palladium on
charcoal for 2 h and/or hydrogenation for 1 h using palladium on
calcium carbonate resulted in loss of the double bond and bromine
in compounds 11g and 11i to give compound 12a. When compound
11g was hydrogenated for 2 h in methanol using palladium on char-
coal loss of the double bond, bromine, and the carbonyl oxygen re-
sulted, affording compound 15 in a 60% yield.38,39 The proton NMR
exhibited an upfield shift of the aromatic hydrogen due to the loss
of the carbonyl group. The loss of the carbonyl group was also veri-
fied by 13C NMR and infrared spectroscopy.
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