A new route towards the synthesis of substituted naphthalenes via Friedel-Crafts acylation

Article abstract of DOI:10.1016/S0040-4039(00)00145-3

A novel approach towards the synthesis of substituted naphthalene derivatives is achieved by a treatment of the 4-aryl-4-hydroxy-3-p- toluenesulfonylbutanal ethylene acetals (6a-e) with a catalytic amount of p- toluene sulfonic acid. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00145-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2207–2210
A new route towards the synthesis of substituted naphthalenes via
Friedel–Crafts acylation
Chai-Lin Kao, Shu Y. Yen and Ji-Wang Chern ∗
School of Pharmacy, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei (100), Taiwan,
Republic of China
Received 15 September 1999; accepted 18 January 2000
Abstract
A novel approach towards the synthesis of substituted naphthalene derivatives is achieved by a treatment of the
4-aryl-4-hydroxy-3-p-toluenesulfonylbutanal ethylene acetals (6a–e) with a catalytic amount of p-toluene sulfonic
acid. © 2000 Elsevier Science Ltd. All rights reserved.
Substituted naphthalene derivatives constitute a class of biologically important substances and have
recently attracted attention.1 Compound 1 was found to be a potent protein tyrosine kinase inhibitor.2
Compound 23 was reported to be an HIV integrase inhibitor and compound 34 is a phosphodiesterase type
V inhibitor. Hydroxylated naphthalene derivatives are of special interest since they have demonstrated
potential biological activity in several aspects, and an efficient and versatile approach for their synthesis
is needed.
A perusal of the literature has revealed that there are several approaches towards the synthesis of
substituted naphthalenes.5 Herein, we report an alternative approach for polyhydroxylated naphthalene
derivatives by treatment of 4-aryl-4-hydroxy-3-p-toluenesulfonylbutanal ethylene acetals (6) with acid.
This was reported by Kotake et al.6 that a series of 4-substituted 4-hydroxy-3-p-toluenesulfonylbutanal
ethylene acetals have been utilized in synthesizing 2-substituted furans via a transacetalization mechan-
ism. Most examples involved treatment of 4-alkyl-substituted materials with a catalytic amount of p-
toluenesulfonic acid to provide the 2-alkylfuran. There was only one example with a 4-phenyl group.
∗
Corresponding author. Tel: 886-2-2393-9462; fax: 886-2-2393-4221; e-mail: chern@jwc.mc.ntu.edu.tw (J.-W. Chern)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00145-3
tetl 16425

2208
However, it afforded only 2-phenylfuran (7b) in 58% yield without any other product.7 We reasoned that
compounds 6 might react by an alternative pathway, a Friedel–Crafts acylation followed by aromatization
and elimination of one molecule of water and ethylene glycol to provide the substituted naphthalene
8. Competitive ring closure of 6, either through the intramolecular Friedel–Crafts reaction to form the
naphthalene skeleton 8, or through intramolecular transacetalization to form the furan ring 7, is possible.
For the preparation of polyhydroxynaphthalene derivatives, we assumed that an electron-donating group
on the 4-aryl ring of 6 would favor the formation of the naphthalene derivatives 8 (Scheme 1).
Scheme 1.
To examine this hypothesis, compound 6a, prepared by treating 3-p-toluenesulfonylpropanal ethylene
acetal (4)6 with 4-benzyloxy-3-methoxybenzaldehyde (5a) in the presence of LDA in THF at −78°C,
was refluxed in benzene with a catalytic amount of p-toluene sulfonic acid. As expected, the naphthalene
derivative (8a) was isolated as the sole product instead of 7a. Confirmation of the structure of 8a was
achieved by X-ray crystallographic analysis of 9,7 which was obtained in 46% yield by treatment of
8a with Raney nickel (Scheme 2). Encouraged by this exciting result, we re-examined the ring closure
reaction of 6b under Kotake’s conditions.8 Surprisingly, 2-phenylfuran (7b) was isolated in only 22%
yield. In addition, 8b was obtained in 57% yield as the major product. This lends support to our
assumption that there is competition between the formation of the 2-substituted furan and substituted
hydroxylated naphthalene, and that an electron-donating group on the 4-phenyl substituent of 6 facilitates
formation of substituted polyhydroxynaphthalene derivatives.
Scheme 2.
To study the positional effect of the alkoxy groups on the ring closure, compounds 6c–e, obtained by
treatment of 4 with a variety of alkoxy-substituted benzaldehydes, were subjected to ring closure in the
same manner.9 The results are summarized in Table 1 and demonstrate that compounds 6 with an alkoxy
group at the meta-position of the 4-phenyl group, provide moderate to excellent yields of 8 (entries 1,
3–5).
Attempts to perform this ring closure with compounds 6 having an electron-withdrawing group, such
as trifluoromethyl and nitro, at either the para- or meta-position, failed. These reactions gave complex
mixtures and difficult to separate products. To our surprise, no obvious transacetalization products, 2-
substituted furans 7, were observed in these reactions. This is probably due to the instability of these
compounds under the reaction conditions. These results confirm our assumption that an electron-donating

2209
Table 1
Ring closure of compound 6
group on the benzene ring, especially at the meta-position of 6, plays an important role in promoting
the Friedel–Crafts cyclization. Thus, the ring closure of 6a is facilitated by participation of the lone
pair electrons of the oxygen atom of the meta-methoxy group, consistent with common electrophilic
substitution reactions, via the oxocarbenium ion generated by protonation-ring opening of the acetal
(Scheme 3).
Scheme 3.
To explore the generality of this reaction, it was reasoned that treatment of 14 with a catalytic amount
of p-toluenesulfonic acid should provide 15. The reaction of compound 11a with 5a in the presence of
magnesium in THF failed to give compound 13a, presumably because the ethylene acetal is not stable
enough to survive these conditions.10 Interestingly, when compound 11b was used, 12b and 13b were
formed in 57 and 38% yields, respectively. Compound 12b was probably formed by air oxidation of
13b. Compound 12b was obtained in 75% yield by direct oxidation of 13b with MnO2. Compound
12b was treated with benzyl bromide in the presence of magnesium in THF to provide 14b, which was
subsequently subjected to ring closure under acidic conditions to afford 15 in 41% yield (Scheme 4).
In summary, this investigation provides a new approach for the synthesis of various substituted poly-
hydroxynaphthalene derivatives starting from 4-substituted phenyl-4-hydroxybutanal ethylene acetals in
acidic conditions. Compounds with an electron-donating group at the meta-position of the 4-phenyl ring
of 6 facilitate this reaction.
Acknowledgements
This investigation was supported by a research grant from the National Science Council (NSC 88-
2314-B-002-009) of the Republic of China on Taiwan. S.-Y. Yen is a summer student from the College
of Chemical Engineering, The University of Michigan, Ann Arbor, Michigan, USA.

2210
Scheme 4.
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