Odorants

Details Odorants Odorants

2000-10-05

2001-09-04

Shippen, Michael (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C512S018000, C568S445000

Reexamination Certificate

active

06284929

ABSTRACT:

The invention relates to novel odorants derived from campholenic aldehyde. In particular these are compounds of the general formula
in which R
1
to R
7
are, independently, H, methyl or ethyl, R
8
+R
9
together form methylene (—CH
2
—) (i.e., forming a cyclopropane ring at the 3′, 4′ position of the cyclopentane ring) or a single bond (thus resulting in a double bond between 3′ and 4′ positions), or R
1
+R
2
together form —(CH
2
)
n
—, with n being 3 or 4′, or R
3
+R
5
or R
5
+R
7
together form methylene or a single bond; and the presence of at least one cyclopropane ring in the molecule is compulsory and the side chain can be saturated or contains one double bond in position &agr;,&bgr; or &bgr;,&ggr;.
The novel compounds I may be obtained by a process comprising
a) mono- or dicyclopropanating a compound of formulae
or
b) reducing a compound of formulae
in a manner known per se, and, if desired, hydrogenating any double bond present in the compound I thereby obtained.
Possible routes to these novel compounds I starting from campholenic aldehyde and passing through the compounds II-IV are outlined in reaction schemes 1 and 2 hereafter.
The scheme 2 also shows a preferred route to the intermediate compound IV.
For the sake of clarity these two schemes do not include the optional alcohol protection and deprotection steps which can, preferably, be effected before and after cyclopropanation (steps e) and f) respectively).
As shown in these schemes, the route from the known intermediates makes use of known chemical transformations. These are:
a) aldol condensation, effecting elongation of the side chain, e.g. by reacting campholenic aldehyde with the reactant R
2
CH
2
C(O)R
1
under basic conditions, e.g. using any organic or inorganic base,
b) Wittig-Horner alkenation of aldehydes and ketones using phosphoranes or phosphonates, e.g. triethylphosphonoacetate,
c) reduction of carboxylic esters to alcohols, e.g. using hydrides, e.g. LiAlH
4
in ether solvents,
d) reduction of carbonyl groups to saturated and unsaturated alcohols, e.g. using hydrides, e.g. borohydrides, e.g. NaBH
4
in alkanols,
e) cyclopropanation of C═C double bonds via methylene transfer, e.g. according to Simmon-Smith, e.g. using CH
2
X
2
, X being I or Br, and a metal (e.g. zinc-copper or zinc-silver) couple or diethylzinc or trialkyl aluminium etc., optionally in the presence of an activator such as acetyl bromide, TiCl
4
or ultrasound,
f) cyclopropanation by formation of and reductive dehalogenation of 1,1-dihalocyclopropanes, e.g. with CHX
3
(X═Cl,Br) and a base, conveniently under phase transfer conditions, or with an alkali metal salt or an alkyl ester of trichloroacetic acid and at elevated temperatures, followed by a reduction using, e.g. an alkali metal e.g. in THF or in ethanol, etc. Steps e) and f) lead to mono- and dicyclopropanated products depending on the reaction conditions and the relative reactivity of the C═C double bonds of IIa,
g) cyclopropanation of C═C double bonds of &agr;,&bgr;-enones using ylides, e.g. using dimethylsulfonium or dimethyloxosulfonium methylide with or without solvent (e.g. THF, CH
2
Cl
2
, DMS, etc.),
h) deconjugation or deconjugative alkylation of &agr;,&bgr;,-enones, e.g. by providing first basic conditions, then reacting with R
3
X (X═Cl, Br, I) or H
+
, or, in the case of deconjugation, using an acid, or metal based catalysts,
i) conjugated addition of organometallics to &agr;,&bgr;-enones, leading to &bgr;-substituted carbonyl compounds, e.g. by the couple MeMgBr/CuI, conveniently in an ether as solvent,
j) reduction of &agr;,&bgr;- or &bgr;,&ggr;-enones to saturated alcohols, e.g. by catalytic hydrogenation, such as H
2
/Pt, using any inert organic solvent,
k) protection of the aldehyde function, e.g. as a dioxolane, before cyclopropanation,
l) deprotection of the aldehyde function following cyclopropanation, e.g. using a strong acid, such as HCl/SiO
2
,
m) protection and deprotection of the alcohol function, preferably in steps e) and f), e.g. as esters, ethers, silyl ethers, etc., see Protective Groups in Organic Synthesis, T. Greene, P. G. M. Wuts, John Wiley & Sons, Inc. New York, 1991.
As pointed out above, these transformations as exemplified in the experimental part are known and their principles described in detail, e.g. in Comprehensive Organic Synthesis, Ed. Trost B. M., Fleming I., Pergamon Press, Oxford, England 1991 (for a-h) and in Protective Groups in Organic Synthesis, Greene T., Wuts P. G. M., John Wiley & Sons Inc., New York, 1991 (for the protection/deprotection steps): namely in
a) vol 2, p 133 seq.
b) vol 1, p 755 seq.
c) vol 8, p 242 seq.
d) vol 8, p 1 seq.
e) vol 4, p 951 seq.
f) vol 4, p 999 seq.
g) vol 4, p 987
h) vol 3, p 21 seq.
i) vol 4, p 69 seq.
j) vol 8, p 523 seq.
k) p 175 seq.
l) p 175 seq.
m) p 10 seq.
Campholenic aldehyde is a most important starting material for the synthesis of synthetic odorants exhibiting the odor profile of sandalwood oil (see, e.g. U.S. Pat. Nos. 4,052,341, 4,6967,66).
No campholenic aldehyde derived cyclopentylbutanols or pentanols bearing a cyclopropane ring have however been published up to now.
Adding one or two such cyclopropane rings on campholenic aldehyde derivatives modifies in particular the odor and substantivity (i.e. persistence of the odor) of the new derivatives. The new alcohols of the general formula I exhibit various woody odor aspects; most of them exert a sandalwood odor, but some are also just woody/amber-like.
Among the novel compounds, [1-methyl-2-(1,2,2-trimethyl-bicyclo-[3.1.0]hex-3-ylmethyl)cyclopropyl]methanol has the most natural, the strongest and most persistent sandalwood odor, superior to any existing synthetic (commercial) raw materials exhibiting sandalwood odor. All four stereoisomers of this compound contribute to its overall natural creamy, flowery, woody odor, but one of the (3″R)-diastereomers was found to constitute the main odor vector, approximatively 34 times more powerful than the second strongest among the synthesized stereoisomers.
The new cyclopropanated carbonyl compounds 1, 3, 4 as well as the new derivatives of the general formula IIb (with R
4
=Me) exhibit also useful olfactory properties, their odor belonging also ta the amber/woody/ sandalwood family of odors.
The present invention thus comprises also the compounds I, IIb, 3, 4 and their use as odorants, and a process to prepare compounds I.
The olfactory properties of the novel compounds harmonize with a multitude of natural or synthetic products widely used in compositions, in particular for generating middle and bottom notes, since the novel compounds are endowed with very good tenacity.
The compounds I harmonize particularly well with all floral notes, in particular with rose, iris, jasmine, ylang-ylang and narcissus notes. They also harmonize with balsamic or resinous dry-out notes such as styrax, incense, and benzoin, and woody notes, such as oak moss or tree moss, patchouli and vetiver.
They thus provide most distinguished mixtures with a multitude of natural and synthetic raw materials.
Examples are:
natural products, such as, for example, tree moss absolute, basil oil, tropical fruit oils (such as bergamot oil, mandarine oil, etc.), mastix absolute, myrtle oil, palmarosa oil, patchouli oil, petitgrain oil, wormwood oil, lavender oil, rose oil, jasmin oil or ylang-ylang oil etc.;
alcohols, such as farnesol, geraniol, linalool, nerol, phenylethyl alcohol, rhodinol, cinnamic alcohol, cis-3-hexenol, menthol, (x-terpineol etc.;
aldehydes, such as citral, &agr;-hexyl cinnamaldehyde, hydroxycitronellal, Lilial, (p-tert-butyl-&agr;-methyl-dihydrocinnamaldehyde), methyl-nonylacetaldehyde, phenylacetaldehyde, anisaldehyde, vanillin etc.;
ketones, such as allylionone, &agr;-ionone, &bgr;-ionone, isoraldein (isomethyl-&agr;-ionone), verbenone, nootkatone, geranylacetone etc.;
esters, such as allyl phenoxyacetate, benzyl salicylate, cinnamyl propionate, citronellyl acetate, decyl acetate,

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