Organic compounds -- part of the class 532-570 series – Organic compounds – Heavy metal containing
Reexamination Certificate
2001-05-03
2003-08-26
Nazario-Gonzalez, Porfirio (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heavy metal containing
C556S144000, C556S466000, C556S478000, C585S665000
Reexamination Certificate
active
06610871
ABSTRACT:
This invention relates to selective synthesis and catalysts therefor.
According to the invention an allylic compound is reacted with an organozinc compound Zn(R
6
)
2
to eliminate a group (the leaving group) from the allylic compound and to add a group from the organozinc compound to it in the presence of a copper salt catalyst and a chiral organic ligand for the copper. Preferably the ligand is a primary or secondary amine in which the nitrogen atom is directly linked to the chiral centre. The allylic compound is suitably of formula
where X is the leaving group for example a chlorine atom and in which A is hydrogen or an alkyl or aryl group, preferably having 1-20 carbon atoms. If substitution occurs at the carbon atom marked * a chiral centre may be formed. This process is known as Sn2′ substitution; an alternative substitution at the carbon atom marked † may occur in which case there may be no chiral centre, this process is known as Sn2 substitution.
The reactions are shown as follows:
where R
6
is a group from the organozinc compound. Surprisingly, in this process the former reaction is generally favoured and is influenced by the leaving group, ligands and solvents as shown below, tetrahydofuran being a particularly favourable solvent. The process is normally chemoselective for Sn2′ substitution and/or stereoselective.
In a preferred form of the invention the reaction is as shown below:
R
1
-R
6
are alkyl, alkenyl, alkynyl, aryl, aralkyl or heterocyclyl groups optionally substituted by for example halogen, alkoxy, aryloxy, acyloxy, nitro, amide, acetamide, carboxylate, cyano, acetal, sulphide, sulphonate, sulfone, sulfoxide, phosphite, phosphonate, phosphine groups, each preferably having at most 20 and preferably less than 10 carbon atoms, or R
1
to R
5
may be H, R
7
is an aryl for example a phenyl or ferrocenyl or substituted aryl or ferrocenyl group of which the substituents may be for example 1-aminobenzyl, 1-amino-2-naphthylmethyl, 1-amino-(4-tert-butylphenyl)methyl, trimethylsilyl, phosphite, phosphine, alkyl, alkoxy, thiophosphonate, amino and/or halogen (eg Cl or Br) atoms and R
8
is an alkyl or aryl, preferably a methyl, ethyl, propyl, tert-butyl, phenyl or naphthyl for example 2-naphthyl group which may be substituted for example by nitro, alkoxy, alkyl and/or haloalkyl group. X is halogen, OR
9
, OCOR
9
, OCO
2
R
9
, OSO
2
R
9
, OCS
2
R
9
CH(OR
10
)
2
, OPO(OR
9
)
2
, SOR
9
, or SO
2
R
9
where R
9
and R
10
are optionally substituted C
1
-C
10
alkyl or aryl, of which the substituents may be halogen, nitro, methoxy, trifluoromethoxy, methyl, ethyl, tert butyl or sulphonate groups e.g. methyl, ethyl, trifluoromethyl, phenyl, tosyl, p-bromophenyl, p-nitrophenyl, p-methoxyphenyl, or R7 and R8 may together form a 5 or 6 membered carbocyclic or heterocyclic ring providing that a carbon atom to which the nitrogen is attached is chiral. for example R7 and R8 together may be 1-indane, bornylamine or 2-cyclohexylamine. Y is halogen, carboxylate for example, acetate, acetoacetate, cyanide, or thiocyanate and Z is an ether or thioether for example dimethylsulfide, tetrahydrofuran or diethylether. Preferably R
1
-R
2
and R
3
and one of R
4
or R
5
are H and the other one of R
4
or R
5
is aryl, for example phenyl, 4-chlorophenyl or 4-trifluoromethyl phenyl or is a trialkyl (e.g. tri-isopropyl) silyl oxymethyl groups R
6
is alkyl, tri-alkyl (e.g. trimethyl) silyl methyl, phenyl or 2,2-dimethylbut-3-enyl. R
7
is ferrocenyl, R
8
is naphthyl, X is chloride, Y is chloride or bromide and Z is dimethylsulfide. R
5
is preferably phenyl and R
6
is preferably neopentyl. The substituents of R
7
preferably have at most 10 carbon atoms in total and those of R
8
preferably at most 8 carbon atoms in total. Alkanes, cyclo alkanes and/or aromatic solvents for example toluene may be present.
Preferred solvents are ethers for example diethylether, 1,4-dioxane, tertbutylmethylether and especially tetrahydrofuran. Preferred temperatures are −120° C. to 25° C. more preferably −100° C. to 20° C. and especially −90° C. to −50° C.
Preferred concentrations of catalyst are 0.1 atom % to 20 atom %, especially 0.5 atom % to 5 atom % expressed as copper atoms based on moles of the allylic compound.
The ratio of copper atoms to the amine ligand molecules is suitably 1:10 to 2:1.
Compounds for formula
in which A is a ferrocenyl or substituted ferrocenyl group and B is a group R
8
other than a methyl or phenyl group are believed to be novel. The groups A and B should be different in order to obtain stereospecificity. B is preferably a 2-naphthyl group.
REFERENCES:
Enders, “Enantioselective synthesis of 1-ferrocenylalkylamines via 1,2-addition of organolithium compounds to ferrocenecarboxaldehyde-SAMP-hydrazone”, SYNLETT, No. 2, Feb. 1996, pp. 126-128.*
Glorian, “Enantioselective synthesis of (R)-and (S)-ferrocenylalkylamines. Reduction of enantiopure ferrocenylimines obtained from valinol and phenylgycinol”, TETRAHEDRON:ASYMMETRY. vol. 8, No. 3, Feb. 6, 1997, pp. 355-358.*
Enders:, “Enantioselective synthesis of 1-ferrocenylalkylamines via 1,2-addition of organolithium compounds to ferrocenecarboxaldehyde-SAMP-hydrazone” SYNLETT, No. 2, Feb. 1996, pp. 126-128, XP002122255.
Glorian:, “Enantioselective synthesis of -and (S)-ferrocenylalkylamines. Reduction of enantiopure ferrocenylimines obtained from valinol and Ihenylgylcinol”, TETRAHEDRON: ASYMMETRY., vol. 8, No. 3, Feb. 6, 1997, pp. 355-358, XP002122256, p. 356, last paragragh, p. 357, scheme 3.
Van Klaveren:, “Chiral arenethiolatocopper (I) catalyzed substitution reactions of acyclic allylic substrates with Grignard reagents”, TETRAHEDRON LETTERS, vol. 36, No. 17, Apr. 24, 1995, pp. 3059-3062, XP002122257, p. 3060, scheme 2; p. 3061, table I.
Dubner:, “Copper (I)-catalyzed enantioselective substitution of allyl chlorides with diorganozinc compounds”, ANGEWANDTE CHEMIE INTERNATIONAL EDITION., vol. 38, No. 2, Feb 1m 1999, pp. 379-381, XP002122258.
Gaudemar: “Preparation D'Esters y-Ethyleniques par allylation du reactif de reformatsky en presence de sels de cuivre”, TETRAHEDRON LETTERS, vol. 24, No. 27, pp. 2749-2752, 1983.
Fujii, et al: “Sn2′ Selective Alkylation of Allylic Chlorides and Mesylates with RZnX Regagents Generated from Grignards Reagents, Zinc Chloride, Lithium Chloride, and Ce(II)-Salts”, TETRAHEDRONS LETTERS, vol. 34, No. 26, pp. 4227-4230, 1993.
Duebner Frank
Knochel Paul
Avecia Limited
Nazario-Gonzalez Porfirio
Pillsbury & Winthrop LLP
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