A synthesis of trifluoromethyl-substituted naphthalenes

Article abstract of DOI:10.1016/S0040-4039(00)01254-5

Alkyl and aryl Grignard reagents add to 1-(3,4-dihydro-2H-5-pyranyl)-2,2,2-trifluoro-1-ethanone by 1,4-addition, but benzyl Grignard reagents react in good yield by 1,2-addition. Dehydration of the resulting alcohols affords intermediate dienes, which readily undergo cyclisation to give substituted trifluoromethyl-naphthalenes. Addition to other trifluoromethylketones permits access to a range of novel fluorinated naphthalenes and benzenes. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01254-5

Tetrahedron Letters 41 (2000) 7383±7386
A synthesis of tri¯uoromethyl-substituted naphthalenes
John M. Mellor,a,* Afaf H. El-Sagheera and Ezz El-Din M. Salemb
aDepartment of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
bDepartment of Chemistry, Faculty of Science, Suez Canal University, Ismailia, Egypt
Received 9 June 2000; revised 14 July 2000; accepted 20 July 2000
Abstract
Alkyl and aryl Grignard reagents add to 1-(3,4-dihydro-2H-5-pyranyl)-2,2,2-tri¯uoro-1-ethanone by 1,4-
addition, but benzyl Grignard reagents react in good yield by 1,2-addition. Dehydration of the resulting
alcohols a€ords intermediate dienes, which readily undergo cyclisation to give substituted tri¯uoromethyl-
naphthalenes. Addition to other tri¯uoromethylketones permits access to a range of novel ¯uorinated
naphthalenes and benzenes. # 2000 Published by Elsevier Science Ltd.
Keywords: additions; Grignard reagents; naphthalenes; tri¯uoromethylketones.
Acyclic ¯uorinated building blocks1 have been used widely in the synthesis of ¯uorinated
heterocyclic compounds. Introduction of tri¯uoromethyl side chain substituents into aromatic
carbocycles via a building block approach permitting construction of the ring with incorporation
of the tri¯uoromethyl substituent is little developed. The possibility that the [3+3] benzannulation
procedures, recently developed by Junjappa et al.2 and reviewed by Katritzky et al.,3 might be
used to give ¯uorinated naphthalenes, is attractive. In this methodology an unsaturated ketone is
reacted with a benzyl organometallic reagent to a€ord a 1,2-adduct, which on dehydration
a€ords aromatic products. In order that this procedure might be applied to tri¯uoromethyl-
ketones, thus giving tri¯uoromethyl substituted aromatic compounds, it is essential that the
benzyl organometallic reagent undergo 1,2-addition with, for example, a b-alkoxy-a,b-unsatu-
rated ketone, rather than the possible 1,4-addition (see Scheme 1).
In the case of additions of Grignard reagents to unsaturated ketones, not having b-alkoxy- or
other heteroatom substitutions, it has been recognised4 that a charge control preferentially leads
to 1,2-addition, but, in contrast, an orbital control leads preferentially to 1,4-addition. Allyl
Grignards uniformly react5 preferentially by 1,2-addition, but examples are known6 of
preferential 1,4-addition of benzyl Grignard reagents and in many examples7 alkyl, aryl and
benzyl Grignard reagents give mixtures of products. Examples have been reported by
Gustafsson,8 where benzyl magnesium halides preferentially react by 1,2- or 1,4-depending upon
the nature of the halide. In the case of b-alkoxy-a,b-unsaturated methyl ketones9 reaction with
* Corresponding author. E-mail: jmm4@soton.ac.uk
0040-4039/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01254-5

7384
Scheme 1.
phenyl magnesium bromide gives both 1,2- and 1,4-adducts. Cases having both a b-alkoxy-sub-
stituent and tri¯uoromethyl-substitution have been little examined. With the b-alkoxy-a,b-
unsaturated tri¯uoromethyl ketone (1)10 aryl magnesium bromides undergo 1,4-addition. We
establish in this paper that, in contrast to alkyl and aryl Grignard reagents, which preferentially
undergo 1,4-addition, reaction with benzyl Grignard reagents occurs by 1,2-addition, thus
enabling us to synthesise a range of substituted tri¯uoromethylnaphthalenes.
The required acyclic and cyclic b-alkoxy-a,b-unsaturated tri¯uoromethyl ketones (1±3)11 are
readily available and a b-amino analogue 4,12 prepared from proline, has recently been described.
Reactions of both the acyclic ketone 1 and the cyclic ketone 2 with phenyl magnesium
bromide and alkyl magnesium bromides give mainly products of 1,4-addition; e.g. phenyl mag-
nesium bromide and octyl magnesium bromide give by 1,4-addition with the ketone 2 cis-products
in 79 and 67% yields, respectively. Similarly, ketone 1 reacts10 with phenyl magnesium bromide
via 1,4-addition, but not 1,2-addition. In sharp contrast we ®nd that benzyl magnesium bromides
give 1,2-adducts with the cyclic ketone 2 in satisfactory yields13 (see Table 1). The structures of
the 1,2-adducts are established by observation of the signal of the vinylic proton at about ꢀ 6.5
1
ppm and the OH absorption at 3450 cm . A structural con®rmation was obtained14 by a single
crystal X-ray analysis of the adduct 9, prepared from ketone 2. Similarly, benzyl magnesium
halides preferentially undergo 1,2-addition to the acyclic ketone 1, the cyclic ketone 3 and the
pyrrole analogue 4 a€ording the alcohols (5, 6, 11 and 12). The spectroscopic data obtained for
all the alcohols (5±12) reported in Table 1 are in good agreement with data obtained for the
alcohol 9. These additions establish that a route to tri¯uoromethylnaphthalenes can be based on

7385
Table 1
a preferred 1,2-addition of benzyl Grignards to cyclic a,b-unsaturated tri¯uoromethyl ketones,
having b-heteroatom substituents. Allyl magnesium bromide also adds to the ketones 1 and 2 by
1,2-addition, giving the alcohols 13 and 14 and crotyl magnesium bromide and cinnamyl mag-
nesium bromide add to the ketones 1 and 2 by 1,2-addition.
An e€ective procedure for dehydration a€ording naphthalenes was established using
p-toluenesulphonic acid in toluene as the catalyst. Under mild conditions dehydration of adduct 7
gave the dienes 15 in 84% yield. Under more vigorous conditions the adduct 7 gave the naph-
thalene 16 in 82% yield. Under similar conditions the dienes 15 gave the naphthalene 16. Adducts
from the cyclic ketones 2 and 3 gave the alcohols (17±20) in good yield (see Table 1). Similarly,
dehydration of alcohol 12 gave the naphthalene 21 having an amide side-chain in 63% yield. The
procedure is also e€ective with adducts derived from the acyclic ketone 1. Dehydration of the
adducts 5 and 6 a€orded the known 2-tri¯uoromethylnaphthalene15 22 and 2-methyl-6-tri-
¯uoromethylnaphthalene 23, respectively. Reaction of the adduct 14 under similar conditions,
but for a longer period, gave the tosylate 24.
The major signi®cance of these results is the development of a regiospeci®c route to 2-tri-
¯uoromethyl benzenes and naphthalenes. 3,6-Disubstituted 2-tri¯uoromethyl-naphthalenes have
not been prepared prior to our work. The interest in the side-chain alcohols is enhanced by their
possible transformation to other substituents, thus o€ering a wider range of aromatic end-groups.
The point is illustrated by oxidation using Jones' reagent of the alcohols 16 and 20 to the naph-
thyl-propionic and acetic acids 25 (90%) and 26 (85%), respectively. 3-Substituted-2-tri-
¯uoromethylnaphthalenes have already been prepared16 in a study of candidate drugs to be used
against diabetes. Our access to a series of tri¯uoromethyl-substituted naphthalenes carrying
additional alcohol, acid and amine end-groups promises much scope for structural elaboration.
Acknowledgements
We thank the Egyptian Government for a studentship (A.H.El-S.) and EPSRC for X-ray
facilities.

7386
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