Lewis acid-catalysed reaction of (cyclo)alkenes with oxiranes

Article abstract of DOI:10.1016/S0040-4039(99)02253-4

The Lewis acid-catalysed reaction of (cyclo)alkenes with oxiranes can give homologous aldehydes, unsaturated alcohols, and fused furans. Many of these materials are of interest to the fragrance industry. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02253-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1483–1486
Lewis acid-catalysed reaction of (cyclo)alkenes with oxiranes
David Munro ∗ and Chris Newman
Quest International, Ashford, Kent TN24 0LT, UK
Received 3 November 1999; accepted 3 December 1999
Abstract
The Lewis acid-catalysed reaction of (cyclo)alkenes with oxiranes can give homologous aldehydes, unsaturated
alcohols, and fused furans. Many of these materials are of interest to the fragrance industry. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: alcohol; aldehyde; alkene; flavour and fragrance; furan; oxirane.
Woody-amber odour is greatly appreciated in the fragrance industry, but is frequently associated with
molecules which are relatively expensive to produce. Two such materials are Hydroxyambran® (2) and
Lignoxan® (3). The literature syntheses of these molecules1,2 utilise cyclododecanone (1) as starting
material (Scheme 1).
Scheme 1. Reagents: (i) BrCH(CH3)CO2Et, Zn; (ii) LiAlH4; (iii) Raney Ni, H2, EtOH; (iv) allyl bromide, NaOH (aq.), phase
transfer; (v) Al(OPri)3; (vi) H+, toluene, reflux
In principle, it appeared that (2) could be obtained via a Friedel–Crafts type reaction of cyclododecene
(4) with propylene oxide. The desired overall process is indicated in Scheme 2, where the intermediate
carbonium ion collapses to give a mixture of isomeric 2-(cyclododecenyl)propan-1-ols (6). Catalytic
hydrogenation would then give Hydroxyambran® (2).
However, unlike the well-known Friedel–Crafts reaction of aromatic systems, the use of alkenes as
substrates is known to have problems as a reliable synthetic method.3 No relevant prior art was found in
the Lewis acid-catalysed reaction of (cyclo)alkenes with oxiranes.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02253-4
tetl 16181

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Scheme 2.
The AlCl3-catalysed reaction of cyclododecene (4) with propylene oxide in dichloromethane at −30°C
was found to give three major products (Scheme 3). These were the aldehyde (7) obtained in 25%
yield, the furan (3) (as an unresolved mixture of diastereomers) isolated in 18% yield, and the isomeric
unsaturated alcohols, containing mainly 1-(2-cyclododecenyl)propan-1-ol (8), which was isolated as a
mixture of E:Z-isomers, (ratio 82:11.5).
Scheme 3.
The aldehyde (7) was readily reduced to give the target molecule (2). This procedure, therefore, allow-
ed access to both desirable woody-amber materials (2) and (3), together with (8), a useful material for
related areas of investigation. In this reaction, it appears that two isomeric carbonium ion intermediates
(5) and (9) are initially formed (Scheme 4). Intermediate (9) can ring close to give the tetrahydrofuran
(2), or can lose a proton to give the unsaturated alcohol (8). Intermediate (5) undergoes rearrangement
by hydrogen shift to give the aldehyde (7).
Scheme 4.

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A substituted oxirane is necessary in order to obtain an aldehyde as the final product of reaction path
2. The use of ethylene oxide offers no stabilisation of the intermediate corresponding to (10). Also, if
1-alkylcycloalkenes (11: R=alkyl) are used, the carbonium ion will not migrate out of the ring (Scheme
5).
Scheme 5.
These considerations apart, the reaction has been shown to be general for (optionally substituted)
cycloalkenes (11: R=H, n=1, 3, 7), and alkyl-substituted oxiranes. Introduction of further unsaturation
into the cycloalkene substrates gave products derived from domino-type reactions, and will be reported
separately.4 The utilisation of open-chain alkenes in this reaction also gives valuable products. For
example, 5-(sec-butyl)-2-(3,5-dimethyl-3-cyclohexenyl)-5-methyl-1,3-dioxane (14) is an intense amber
material with woody, floral overtones. It is produced5 by Quest International under the trade name
Karanal®. The intermediate diol (13) has been obtained by hydroformylation of 3-methylpent-2-ene to
give 2,3-dimethylpentan-1-al (12) (as an unresolved mixture of diastereomers), followed by the Tollens
reaction (Scheme 6).
Scheme 6.
The dehydration–rearrangement [step (i)] and the hydroformylation [step (ii)] both require dedicated
facilities, a problem which can be circumvented by the present methodology. When 2-butene and
propylene oxide are reacted at −30°C using AlCl3 as catalyst, 2,3-dimethylpentan-1-al (12) is obtained
in 33% isolated yield (Scheme 7).
Further applications of this reaction6 to materials of fragrance interest have been carried out. While
this work was in progress, a further synthesis of molecule (2) was reported,7 via radical-initiated addition
of propionic acid derivatives to cyclododecene (4), followed by high pressure hydrogenation.

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Scheme 7.
1. Experimental
AlCl3-Catalysed reaction of cyclododecene with propylene oxide:AlCl3 (180 g:1.35 mol) was suspen-
ded in CH2Cl2 (1 litre), and cooled to −30°C. A mixture of cyclododecene (200 g:1.2 mol) and propylene
oxide (100 g:1.72 mol) was added dropwise with stirring under N2, maintaining this temperature with
external cooling. After complete addition (1 h), the reaction mixture was immediately quenched by
addition to a stirred mixture of ice (2 litres) and Et2O (2 litres). The organic layer was separated,
washed, and dried over MgSO4. The solvent was removed in vacuo, and the residue chromatographed
(silica:hexane) to give recovered cyclododecene (19.6 g). Further elution, using (hexane 90%:Et2O 10%)
as eluent gave a colourless oil (61.3 g:25.2%), identified as 2-cyclododecylpropan-1-al (7), which could
be reduced by various procedures (NaBH4 or H2, 5% Pd/C) to give material (2), spectroscopic properties
identical to an authentic sample. Continued elution gave a colourless oil (44.6 g:18.3%), identified as
2-methyltetradecahydrocyclododeca[b]furan (3), whose spectroscopic characteristics were identical to a
commercial sample of (3) (Lignoxan®, ex Wacker).
The solvent polarity was increased (hexane 50%:Et2O 50%). Following elution of two poorly-defined
multicomponent mixtures [(2.3 g)+(8.7 g)], a further discrete major product was isolated as a colourless
oil (64.8 g:26.6%). This material was identified as 1-(2-cyclododecenyl)propan-2-ol (8). 13C NMR
(CDCl3): δ 135.7 (CH_CH), 132.2 (CH_CH), 67.7 (CH(CH3)OH), 46.0 (CH2CH(CH3)OH), 41.9
(CHCH2CH(CH3)OH), 34.0 (CH2), 32.4 (CH2), 26.5 (CH2), 26.1 (CH2), 26.1 (CH2), 25.7(CH2), 24.7
(CH2), 23.6 (CH2), 23.4 (CH2), 22.8 (CH3).
References
1. Hafner,W.; Gebauer, H.; Markel, E.; Regiert, M. US Patent 4,948,780 (August, 1990).
2. Consortium fur Elektrochemische Industrie GmbH, US Patent 4,496,748 (January, 1985).
3. Vukicevic, R.; Konstantinovic, S.; Joksovic, L.; Ponticelli, G.; Mihailovic, M. Lj. Chem.Lett. 1995, 275.
4. Munro, D.; Sell, C. S. World Patent WO 9921847 (May, 1999).
5. Newman, C. P.; Rossiter, K. European Patent EP 276,998 (January, 1987).
6. Munro, D.; Sell, C. S.; World Patent WO 9921817 (May, 1999).
7. Ebel, K.; Pinkos, R. World Patent WO 9857914 (December, 1998).