Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-28
2003-05-06
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C436S903000, C534S558000, C548S966000, C548S967000, C548S968000, C548S969000, C585S377000, C585S378000
Reexamination Certificate
active
06559323
ABSTRACT:
The present invention relates to a process for the preparation of oxiranes from aldehydes or ketones, of aziridines from imines, or of cyclopropanes from alkenes.
It is known from WO95/11230 to prepare oxiranes, aziridines and cyclopropanes by reacting a diazo compound with an aldehyde, ketone, imine or alkene as appropriate in the presence of both a sulphide and either an organometallic or an inorganic reagent to form a sulphur ylide. As diazo compounds are difficult to handle due to their toxicity and explosive nature it would be advantageous to generate the diazo compounds in situ for this process thereby minimising the handling of these hazardous materials.
Thus, according to one aspect of the present invention there is provided a process for the preparation of an oxirane, aziridine or cyclopropane of formula (I), wherein X is oxygen, NR
4
or CHR
5
; R
1
is hydrogen, alkyl, aryl, heteroaromatic, heterocyclic or cycloalkyl; R
2
is hydrogen, alkyl, aryl, heteroaromatic, CO
2
R
8
, CHR
14
NHR
13
, heterocyclic or cycloalkyl; or R
1
and R
2
join together to form a cycloalkyl ring; R
3
and R
10
are, independently, hydrogen, alkyl, aryl, heteroaromatic, CO
2
R
8
, R
8
3
Sn, CONR
8
R
9
, trialkylsilyl or triarylsilyl; R
4
is an electron withdrawing group; R
5
is alkyl, cycloalkyl, aryl, heteroaromatic, SO
2
R
8
, SO
3
R
8
, COR
8
, CO
2
R
8
, CONR
8
R
9
, PO(R
8
)
2
, PO(OR
8
)
2
or CN; R
8
and R
9
are independently alkyl or aryl; and R
13
and R
14
are independently hydrogen, alkyl or aryl; the process comprising the steps of:
(a) degrading a compound of formula (II), (IIa), (IIb) or (IIc), wherein R
3
and R
10
are as defined above; Y is a cation; depending on the nature of Y, r is 1 or 2; and L is a suitable leaving group, to form a diazo compound of formula (III) wherein R
3
and R
10
are as defined above;
(b) reacting the compound of formula (III) with a suitable transition metal catalyst
(c) reacting the product of step (b) with a sulphide of formula SR
6
R
7
, wherein R
6
and R
7
are independently alkyl, aryl or heteroaromatic, or R
6
and R
7
join together to form an optionally substituted ring which optionally includes an additional heteroatom; and
(d) reacting the product of step (c) with a compound of formula (IV) wherein R
1
and R
2
are as defined above.
When the compound of formula (IV) is an alkene (that is, when X in the compound of formula (IV) is CHR
5
) it is an electron deficient alkene.
When the process of the present invention is used to prepare an oxirane (that is, a compound of formula (I) wherein X is O, it is necessary to balance the reactivity of the compound of formula (IV) against the reactivity of the product of step (c).
It is preferred that the compounds of formula (II) are degraded thermally (see, for example, Synth. Comm. 1978, 8(8) 569 or Bull. Soc. Chim. Belg. 1977, 86, 739); that the compounds of formula (IIa) are degraded by contacting the compounds with, for example, lead tetraacetate or manganese dioxide (see, for example, the procedure of Holton in J. Org. Chem. 1995, 60, 4725 and references cited therein); that the compounds of formula (IIb) are degraded thermally or by the action of light (hv) (see, for example, the procedure of Doyle in Tett. Lett. 1989, 30, 3049 and references cited therein); and that the compounds of formula (IIc) are degraded by thermal oxidation (see, for example, the procedure of Horner in Chem. Ber. 1961, 94, 279).
The process of the present invention can be carried out in the presence of a solvent. Suitable solvents include nitrites (such as acetonitrile), chlorinated solvents (such as CH
2
Cl
2
or CHCl
3
), aromatic solvents (such as benzene, toluene and o-, m- or p-xylene), aliphatic alcohols (such as methanol, ethanol or tert-butanol), chain or cyclic ethers (such as diethyl ether, tert-butyl methyl ether, diisopropyl ether, glymes (for example monoglyme, diglyme or triglyme) or tetrahydrofuran), aliphatic or alicyclic hydrocarbons (such as n-hexane or cyclohexane), N,N-dimethylformamide, sulpholane, dimethylsulphoxide or N-methylpyrrolidone.
Alternatively, the process can be carried out in a mixture of miscible solvents (such as a mixture of water and acetonitrile), or different reagents may be added in different solvents.
Phase transfer reagents can be used during the process of the present invention (for example when the process of the invention is carried out in a solvent and the reaction mixture is not homogenous). Suitable phase transfer reagents include ammonium salts (such as benzyltriethylammonium chloride) or crown ethers.
It is preferred that the process of the present invention is carried out at a temperature in the range −30 to 100° C., especially in the range 20 to 70° C., such as at about 50° C.
In preferred embodiments of the first aspect of the present invention, the compound of formula (II), (IIa), (IIb) or (IIc) is decomposed in the presence of the transition metal catalyst, the sulphide and the substrate compound of formula (IV).
According to a second aspect of the present invention, there is provided a process for the generation of diazo compounds, wherein a compound of formula II is thermally decomposed in the presence of an aprotic solvent and a phase transfer catalyst, but in the absence of free base.
In the process of the second aspect of the present invention, the aprotic solvent may comprise a nitrile (such as acetonitrile); a chlorinated solvent (such as CH
2
Cl
2
or CHCl
3
); an aromatic solvent (such as benzene, toluene and o-, m- or p-xylene); a chain or cyclic ether (such as diethyl ether, tert-butyl methyl ether, diisopropyl ether, a glyme (for example monoglyme, diglyme or triglyme) or tetrahydrofuran); an aliphatic or alicyclic hydrocarbon (such as n-hexane or cyclohexane); N,N-dimethylformamide; sulpholane; dimethylsulphoxide or N-methylpyrrolidone. Acetonitrile is particularly preferred. Most preferably, the process according to the second aspect is carried out under anhydrous conditions, ie in the substantial absence of water. Preferred phase transfer catalysts include quaternary ammonium salts, particularly trialkylbenzyl and tetraalkyl ammonium halides, especially chlorides, and most preferably those wherein each alkyl is independently a C
1-16
alkyl group. When the compound of formula II is a quaternary ammonium salt, the compound of formula II also serves as phase transfer catalyst. Most advantageously, the compound of formula II is substantially insoluble in the aprotic solvent, and is employed as a suspension. It is particularly preferred that the compound of formula II is a sodium salt. The thermal decomposition is often effected at a temperature of from 0 to 70° C., preferably from about 15 to about 50° C.
The compounds of formula (I) may have one, two or three chiral ring-carbon atoms and the process of the first aspect of the present invention is capable of forming all structural isomers of the compounds of formula (I). When one or more of R
1
, R
2
, R
3
, R
4
or R
5
is chiral it can affect the stereochemical nature of the compound of formula (I) produced by the process of the present invention.
The term alkyl whenever it is used refers to straight or branched alkyl chains preferably containing from 1 to 10, especially from 1 to 6, for example from 1 to 4, carbon atoms. Alkyl is, for example, methyl, ethyl, n-propyl, n-butyl or tert-butyl. All alkyl groups are optionally substituted. Preferred substituents are one or more of aryl (such as phenyl), aryloxy (such as phenoxy), heteroaromatic, heterocyclic (such as reduced forms of oxazole), cycloalkyl (such as cyclopropyl), C
1-6
alkoxy (such as methoxy or ethoxy), C
1-6
thioalkyl (such as methylthio), halogen (to form, for example, CCl
3
, CF
3
or CH
2
CF
3
), C
1-6
haloalkoxy (such as OCF
3
), cyano, hydroxy or CO
2
(C
1-6
)alkyl. In addition the alkyl groups of R
5
may terminate with an aldehyde (C(H)═O) group or be interrupted with a carbonyl (C═O) group.
Halogen is fluorine, chlorine, bromine or iodine.
Alkoxy and haloalkoxy groups are straight or branched chains,
Aggarwal Varinder Kumar
Studley John Richard
Avecia Limited
Pillsbury & Winthrop LLP
Trinh Ba K.
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