Convenient, tandem and one-reaction vessel synthesis of mixed dialkylated 2-naphthols from 2-tetralone

Article abstract of DOI:10.1139/v03-064

A convenient acid-catalyzed method for the synthesis of 1-alkyl-2-alkoxynaphthalenes by one-reaction vessel mixed alkylation of 2-tetralone, using aryl or alkyl aldehydes and alcohols followed by aromatization, is described.

Full text of DOI:10.1139/v03-064

293
Convenient, tandem and one-reaction vessel
synthesis of mixed dialkylated 2-naphthols from
2-tetralone
Amitabh Jha and Jonathan R. Dimmock
Abstract: A convenient acid-catalyzed method for the synthesis of 1-alkyl-2-alkoxynaphthalenes by one-reaction vessel
mixed alkylation of 2-tetralone, using aryl or alkyl aldehydes and alcohols followed by aromatization, is described.
Key words: ethers, aromatization, rearrangement, alkylation, 2-alkoxynaphthalenes.
Résumé : On décrit une méthode pratique de synthèse acidocatalysée des 1-alkyl-2-alkoxynaphtalènes impliquant une
réaction monotope d’alkylation mixte de la 2-tétralone à l’aide d’alcools et d’aldéhydes aliphatiques ou aromatiques
suivie d’une aromatisation.
Mots clés : éthers, aromatisation, réarrangement, alkylation, 2-alkoxynaphtalènes.
Jha and Dimmock 296
Introduction
2-naphthol (8). Some of these reactions yield side products
(5, 8, 9, 11).
A variety of methods are known for the synthesis of 2-
alkoxy-1-arylmethylnaphthalenes (1, R = aryl), including the
reduction of 1-(2-alkoxynaphthyl) aryl ketones (1) or the re-
duction of 1-(2-alkoxynaphthyl) aryl carbinols (2), Pd(II)-
catalyzed C—C bond formation among 2-alkoxy-1-halon-
aphthalenes and substituted toluenes (3), and other proce-
dures that are cumbersome (4, 5). The C-1 alkylation and
etherfication of 2-naphthol using dialkyl sulfates leading to
2-alkoxy-1-alkylnaphthalenes (1, R = H, R′ = CH3; R = CH3,
R′ = C2H5) is known (6). This procedure has at least two
limitations: (i) the synthesis of the corresponding mixed
dialkyl derivatives is not possible; and (ii) the unavailability
of dialkyl sulfates limits the wider utility of this procedure.
Another compound belonging to this class, namely 1-butyl-
2-methoxynaphthlene (1, R = n-C3H7, R′ = CH3), was made
by a very lengthy and unwieldy procedure (7).
2-Alkoxy-1-arylmethylnaphthalenes (1, R = aryl, R′=
alkyl) may also be obtained by the etherification of the cor-
responding 1-arylmethyl-2-naphthols (1, R = aryl, R′ = H),
for which a number of methods are known. These include a
Fries-type rearrangement of 2-benzyloxynaphthalene (8), a
base-catalyzed reaction between benzyl chloride or benzyl
alcohol and 2-naphthol (9–12), as well as Zn-catalyzed
transfer of a benzyl group from various benzyl aryl ethers to
Recently this research group reported a novel synthetic
route to this class of compounds, which involved two simple
reaction steps (13). 1-Arylmethylene-2-tetralones (A, R =
aryl) (14) were converted to 2-alkoxy-1-arylmethylnaphth-
alenes (1, R = aryl, R′ = alkyl) under anhydrous acidic con-
ditions in common alcohols and the yields were generally
satisfactory (13). As the synthesis of 1-arylmethylene-2-
tetralones (A, R = aryl) can be carried out under anhydrous
acidic conditions (13–15) and the subsequent reactions
yielding the title compounds were also carried out under an-
hydrous acidic conditions (13), we thought that it should be
possible to carry out these two reactions in the same pot,
without isolating the corresponding intermediate 1-aryl-
methylene-2-tetralones (A, R = aryl). It was also realized
that the success of this three-component reaction would de-
pend on the sequence of occurrence of the two competing
reactions, viz. condensation of the aldehyde group with the
active methylene of 2-tetralone and the vinyl ether formation
between the alcohol and the enolic form of 2-tetralone based
on the reaction mechanism described previously (13) (and
later in this paper). This could easily be verified by perform-
ing the reactions.
The formation of 2-alkoxy-1-alkylnaphthalenes 1a–1i
(Fig. 1) from a mixture of 2-tetralone, aryl or alkyl alde-
hydes, and an absolute alcohol under anhydrous acidic con-
ditions (Scheme 1) is reported herein.
Received 18 November 2002. Published on the NRC
Research Press Web site at http://canjchem.nrc.ca on
2 May 2003.
Experimental section
A. Jha1,2 and J.R. Dimmock. College of Pharmacy and
Nutrition, University of Saskatchewan, Saskatoon,
SK S7N 5C9 Canada.
General
2-Tetralone and the substituted aldehydes were obtained
from Aldrich Chemical Co. Column chromatography
purifications were undertaken using silica gel (60–230 mesh)
obtained from Aldrich Chemical Co. Hydrogen chloride gas
was freshly generated in the laboratory by the action of con-
1Corresponding author (e-mail: amitabh.jha@acadiau.ca).
2Present address: Department of Chemistry, Acadia University,
Wolfville, NS B4P 2R6, Canada.
Can. J. Chem. 81: 293–296 (2003)
doi: 10.1139/V03-064
© 2003 NRC Canada

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Can. J. Chem. Vol. 81, 2003
Fig. 1. Chemical structures of compounds 1a–1i.
Scheme 1.
CDCl3) δ: 0.95 (3H, t, J = 7.4 Hz, CH2CH3), 1.44–1.54
(2H, m, CH2), 1.73–1.82 (2H, m, CH2), 4.11 (2H, t, J =
6.4 Hz, OCH2), 4.50 (2H, s, Ar-CH2-Ar′), 7.10–7.22 (5H, m,
Ar′-Hs), 7.30–7.34 (2H, m, H-3, 6), 7.38–7.42 (1H, m, H-7),
7.76–7.80 (2H, m, H-4, 5), 7.93 (1H, d, J = 8.5 Hz, H-8).
HR-MS calcd. for C21H22O: 290.1670; found: 290.1677. EI-
MS (70 eV) m/z (% int.): 290 (100), 234 (89), 215 (36), 202
(30), 156 (29), 128 (24), 91 (47).
centrated sulfuric acid on the mixture of sodium chloride in
concentrated hydrochloric acid in an appropriate apparatus.
1H NMR spectra were recorded on a Bruker AMX 300
NMR spectrometer at 300 MHz and HR-MS spectra were
obtained on VG-Analytical (Manchester, U.K.) VG-70 SEQ
spectrometer. Melting points were recorded on an electro-
thermal apparatus and are uncorrected.
2-Methoxy-1-(4-nitrophenylmethyl)naphthalene (1d)
Syntheses of 2-alkoxy-1-alkylnaphthalenes (1a–1i)
White solid (yield: 87%). Rf = 0.41 (10% EtOAc – hex-
1
ane), mp 103–105°C (Lit. value (3) 106–108°C). H NMR
General procedure
data was found to be identical to that of the literature report
(3). HR-MS calcd. for C18H15NO3: 293.1052; found:
293.1058. EI-MS (70 eV) m/z (% int.): 293 (100), 278 (6),
262 (7), 231 (18), 215 (29), 202 (28), 171 (24), 141 (21),
128 (12), 101 (9).
A mixture of 2-tetralone (3 mmol) and an appropriate al-
dehyde (3 mmol) in absolute alcohol (10 mL) was cooled by
an ice bath to 0–5°C. Under anhydrous conditions, freshly
generated dry hydrogen chloride gas was passed briskly
through the solution for 20 min. The reaction mixture was
stirred at room temperature for 24 h. Thin layer chromatog-
raphy using precoated fluorescent silica gel and a developing
solvent of hexane:chloroform (1:4) showed the formation of
a faster moving product. The reaction mixture was evapo-
rated to dryness under vacuum. Products (1a–1c, 1e, 1f, 1h,
1i) were purified using a silica gel (230–400 mesh) column
with hexane as the eluent. Compounds 1d and 1g were ob-
tained as solid powders from the reaction and were quite
pure after filtration as viewed on TLC.
1-(4-Chlorophenylmethyl)-2-methoxynaphthalene (1e)
White crystalline solid (yield: 92%). Rf = 0.49 (10%
EtOAc – hexane), mp 51 to 52°C. 1H NMR (300 MHz,
CDCl3) δ: 3.94 (3H, s, OCH3), 4.44 (2H, s, Ar-CH2-Ar′),
7.10 (2H, d, J = 8.6 Hz, H-2′, 6′), 7.16 (2H, d, J = 8.6 Hz, H-
3′, 5′), 7.32–7.36 (2H, m, H-3, 6), 7.39–7.47 (1H, m, H-7),
7.79–7.87 (3H, m, H-4, 5, 8). HR-MS calcd. for C18H15ClO:
282.0811; found: 282.0820. EI-MS (70 eV) m/z (% int.): 282
(100), 267 (13), 251 (20), 231 (26), 215 (49), 202 (31), 171
(29), 141 (20), 125 (18), 115 (14), 101 (17).
2-Methoxy-1-phenylmethylnaphthalene (1a)
White crystalline solid (yield: 76%). Rf = 0.59 (10%
EtOAc – hexane), mp 91 to 92°C (Lit. value (1) 81 to 82°C.
1H NMR (300 MHz, CDCl3) δ: 3.95 (3H, s, -OCH3), 4.50
(2H, s, Ar-CH2-Ar′), 7.10–7.22 (5H, m, Ar′-Hs), 7.30–7.36
(2H, m, H-3, 6), 7.38–7.42 (1H, m, H-7), 7.79–7.82 (2H, m,
H-4, 5), 7.91 (1H, d, J = 8.6 Hz, H-8). HR-MS calcd. for
C18H16O: 248.1201; found: 248.1196. EI-MS (70 eV) m/z
(% int.): 248 (100), 233 (16), 215 (39), 202 (24), 171 (21),
141 (17), 91 (14).
2-Methoxy-1-(4-methylphenylmethyl)naphthalene (1f)
White crystalline solid (yield: 84%). Rf = 0.47 (10%
EtOAc – hexane), mp 58 to 59°C. 1H NMR (300 MHz,
CDCl3) δ: 2.27 (3H, s, Ar-CH3), 3.95 (3H, s, OCH3), 4.46
(2H, s, Ar-CH2-Ar′), 7.02 (2H, d, J = 8.0 Hz, H-2′, 6′), 7.09
(2H, d, J = 8.2 Hz, H-3′, 5′) 7.30–7.37 (2H, m, H-3, 6),
7.38–7.43 (1H, m, H-7), 7.78–7.82 (2H, m, H-4, 5), 7.93
(1H, d, J = 8.6, H-8). HR-MS calcd. for C19H18O: 262.1357;
found: 262.1363. EI-MS (70 eV) m/z (% int.): 262 (100),
247 (25), 231 (34), 215 (34), 202 (19), 189 (8), 171 (15),
158 (10), 141 (14), 115 (13), 105 (16).
2-Ethoxy-1-phenylmethylnaphthalene (1b)
White crystalline solid (yield: 71%). Rf = 0.67 (10%
EtOAc – hexane), mp 74–76°C. 1H NMR (300 MHz,
CDCl3) δ: 1.40 (3H, t, J = 7.0 Hz, CH3), 4.17 (2H, q, J =
7.0 Hz, OCH2), 4.49 (2H, s, Ar-CH2-Ar′), 7.10–7.21 (5H, m,
Ar′-Hs), 7.29–7.34 (2H, m, H-3, 6), 7.38–7.41 (1H, m, H-7),
7.75–7.80 (2H, m, H-4, 5), 7.92 (1H, d, J = 8.4 Hz, H-8).
HR-MS calcd. for C19H18O: 262.1357; found: 262.1354. EI-
MS (70 eV) m/z (% int.): 262 (100), 233 (44), 215 (34), 156
(19), 128 (21), 91 (31).
1-(4-Carbomethoxyphenylmethyl)-2-methoxynaphthalene
(1g)
White solid (yield: 90%). Rf = 0.28 (10% EtOAc – hex-
1
ane), mp 88 to 89°C. H NMR (300 MHz, CDCl3) δ: 3.86
(3H, s, CO2CH3), 3.94 (3H, s, OCH3), 4.52 (2H, s, Ar-CH2-
Ar′), 7.21–7.25 (2H, d, J = 8.5 Hz, H-2′, 6′), 7.32–7.44
(3H, m, H-3′, 5′, 6), 7.78–7.89 (5H, m, Ar-Hs). HR-MS
calcd. for C20H18O: 306.1256; found: 306.1266. EI-MS
(70 eV) m/z (% int.): 306 (100), 291 (4), 275 (14), 231 (15),
215 (27), 202 (14), 171 (13), 141 (12), 101 (7), 83 (27).
2-Butoxy-1-phenylmethylnaphthalene (1c)
White crystalline solid (yield: 76%). Rf = 0.78 (10%
EtOAc – hexane), mp 30–32°C. 1H NMR (300 MHz,
© 2003 NRC Canada

Jha and Dimmock
295
Scheme 2.
oxy-1-propylnapthalene
1h
and
1-heptyl-2-
2-Methoxy-1-propylnaphthalene (1h)
methoxynapthalene 1i in 30 and 78% yield, respectively.
The likely mechanism of formation of these compounds
seems similar to what was proposed in our previous paper
(13) except that 1-arylidene-2-tetralone (A, R = Ar) or 1-
alkylidene-2-tetralone (A, R = alkyl) are intermediates here.
The formation of the enol ether B and subsequent rearrange-
Light brown viscous oil (yield: 30%). Rf = 0.61 (10%
EtOAc – hexane). H NMR (300 MHz, CDCl3) δ: 1.02 (3H,
1
t, J = 7.3 Hz, CH2CH3), 1.63–1.70 (2H, m, CH2CH2CH3),
3.07 (2H, t, J = 7.9 Hz, ArCH2), 3.95 (3H, s, OCH3), 7.25–
7.37 (2H, m, H-3, 6), 7.44–7.51 (1H, m, H-7), 7.70–7.81
(2H, m, H-4, 5), 7.97 (1H, d, J = 8.6, H-8). 13C NMR
(75 MHz, CDCl3) δ: 14.70, 23.57, 27.20, 56.82, 113.75,
123.31, 123.64, 124.46, 126.26, 127.55, 128.70, 129.48,
133.28, 154.55. HR-MS calcd. for C14H16O: 200.1201;
found: 200.1208. EI-MS (70 eV) m/z (% int.): 200 (44), 183
(26), 171 (100), 157 (96), 141 (66), 128 (56), 115 (24).
ment to
C makes use of the extended conjugation
(Scheme 2). Formation of an α,β-unsaturated species from
the corresponding active methylene compound and alde-
hyde is very common in anhydrous acidic conditions (14,
15). Enol ethers are also easily formed under similar condi-
tions especially when the ketone has an α-hydrogen atom
(16), while hydronaphthalenes are quite amenable to
aromatization (13, 17). Aromatization reactions usually re-
quire catalysts and harsh conditions (17), though highly fac-
ile aromatizations in different structural moieties are known
(18). It was demonstrated by isotopic labeling studies in our
previous work (13) that the rearrangement of protons does
not take place by the less likely concerted 1,5-sigmatropic
type rearrangement (for which a cisoid conformation is a
prerequisite (19)) but follows the more favorable dissocia-
tion mechanism.
Based on these results, it can also be concluded that the
condensation of the aldehyde group with the active methy-
lene of 2-tetralone leading to the formation of A was favored
over the formation of vinyl ether D as the highly predomi-
nant (or exclusive) intermediate. No efforts were made to
detect the formation of D in the reaction mixture.
1-Heptyl-2-methoxynaphthalene (1i)
Colorless viscous oil (yield: 78%). Rf = 0.65 (10%
1
EtOAc – hexane). H NMR (300 MHz, CDCl3) δ: 0.93 (3H,
t,
J
=
6.8 Hz, CH2CH3), 1.30–1.53 (8H, m,
ArCH2CH2(CH2)4CH3), 1.63–1.69 (2H, m, ArCH2CH2CH2),
3.11 (2H, t, J = 7.7 Hz, ArCH2), 3.96 (3H, s, OCH3), 7.29
(1H, d, J = 9.0 Hz, H-3), 7.33–7.39 (1H, m, H-6), 7.47–7.52
(1H, m, H-7), 7.73 (1H, d, J = 9.0 Hz, H-4), 7.81 (1H, d, J =
8.1, H-5), 8.0 (1H, d, J = 8.5, H-8). HR-MS calcd. for
C18H24O: 256.1827; found: 256.1825. EI-MS (70 eV)
m/z (% int.): 256 (51), 171 (100), 141 (31), 115 (7).
Results and discussion
It was found that when dry hydrogen gas was passed
through a solution of 2-tetralone and benzaldehyde in abso-
lute methanol for 20 min, and the reaction stirred at room
temperature for 24 h, the TLC showed the formation of a
faster moving spot. This product upon workup was charac-
terized as 2-methoxy-1-phenylmethylnaphthalene (1a) in
good yield.
The initial reactions in the present study were carried out
in methyl alcohol (1a, 1d–1g), but to confirm the generality
of this procedure, one reaction in each of ethyl alcohol and
n-butyl alcohol were also carried out under similar condi-
tions. These attempts with 2-tetralone and benzaldehyde suc-
cessfully yielded the compounds 1b and 1c. In the case of
the reaction of 2-tetralone with 4-carboxybenzaldehyde in
methanol, the obtained product (1g) had the carbomethoxy
group as expected. We also found that this reaction worked
for aliphatic aldehydes also and using propionaldehyde and
heptaldehyde in methanol, we were able to make 2-meth-
Conclusions
In conclusion, we have devised an exceptionally simple
method to perform efficient and selective mixed C- and O-
alkylation leading to 2-alkoxy-1-alkylnaphthalenes from 2-
tetralone using an aldehyde and an alcohol under anhydrous
acidic conditions. This transformation could be of impor-
tance to synthetic and combinatorial chemists. We are work-
ing towards widening the scope of this procedure.
Acknowledgement
Purdue Neuroscience Company, U.S.A., supported this
work.
© 2003 NRC Canada

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Can. J. Chem. Vol. 81, 2003
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