Process of synthesizing binaphthyl derivatives

Details Process of synthesizing binaphthyl derivatives Process of synthesizing binaphthyl derivatives

1995-05-18

2001-12-25

Dawson, Robert (Department: 1712)

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

Organic compounds

Phosphorus containing

C560S100000, C568S808000

Reexamination Certificate

active

06333435

ABSTRACT:

BACKGROUND OF THE INVENTION
2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) has become an important chiral ligand for catalytic asymmetric induction. Its wide application has been somewhat limited due to the scarce supply. The present invention relates to a simple and inexpensive process for the synthesis of BINAP derivatives in which the naphthyl groups are substituted, avoiding the necessity of multistep syntheses and minimizing the formation of secondary products.
SUMMARY OF THE INVENTION
A process of synthesizing a compound of formula 1 is disclosed
wherein each R′ is independently selected from the group consisting of: C
1-4
alkyl, hydroxyl, C
1-4
alkoxyl, C
1-4
acyl, carboxyl, C
1-4
alkoxycarbonyl, —OP and —COOP wherein P is a protecting group,
comprising reacting a compound of the formula 2:
wherein R is selected from the group consisting of triflate, mesylate and tosylate, and R′ is as defined above,
with diphenylphosphine in the presence of an amine base and a nickel catalyst to produce a compound of formula 1.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the following terms and definitions apply.
The abbreviation “Ph” refers to phenyl. Diphenylphosphine is abbreviated Ph
2
PH.
BINAP stands for the compound 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl which has the structural formula 1:
BINAP derivatives as used herein refers to BINAP with substituent groups attached to the naphthyl portions of the molecule. The substituent groups can be selected from the group consisting of: C
1-4
alkyl, hydroxyl, C
1-4
alkoxyl, C
1-4
acyl, carboxyl, C
1-4
alkoxycarbonyl, —OP and —COOP wherein P is a protecting group.
Preferred BINAP derivatives include the following:
Such preferred BINAP derivatives are included in pure form as well as mixtures of isomers.
Alkyl refers to hydrocarbon radicals having 1-4 carbon atoms, which can be straight or branched for the C
3
and C
4
members of the group.
C
1-4
acyl refers to the group: C
1-4
alkyl—C(O)—.
Carboxyl refers to the group: —COOH.
C
1-4
alkoxycarbonyl refers to the group: C
1-4
alkyl-O—C(O)—.
In —OP and in —COOP, P represents a protecting group for hydroxyl and carboxyl. These protecting groups are readily removable, i.e., they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule. Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with fluoride ion, treatment with a transition metal catalyst and a nucleophile, and catalytic hydrogenation.
Examples of suitable hydroxyl protecting groups are: t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and allyloxycarbonyl. Preferred hydroxyl protecting groups are trimethylsilyl and triethylsilyl.
Examples of suitable carboxyl protecting groups are: benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethylsilyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyl and t-butyl. A preferred carboxyl protecting group is p-nitrobenzyl.
Many other suitable hydroxyl and carboxyl protecting groups are known in the art. See, e.g., T. W. Greene,
Protective Groups in Organic Synthesis,
John Wiley & Sons, Inc., (2nd ed. 1991) (Chapters 2 and 5).
Triflate (OTf) refers to the leaving group trifluoromethane sulfonate.
Mesylate (OMs) refers to the leaving group methanesulfonate.
Tosylate (OTs) refers to the leaving group toluenesulfonate.
The catalyst which is included herein is a nickel catalyst. Such catalysts are selected from the group consisting of: NiCl
2
.bis(diphenyl)phosphinyl C
1-4
alkanes, NiBr
2
, NiCl
2
, NiCl
2
-bis(diphenyl)phosphinyl ferrocene, abbreviated NiCl
2
/dppf; NiCl
2
-bis(triphenylphosphine), abbreviated NiCl
2
/(Ph
3
P)
2
; Ni-tetrakis(triphenylphosphine), abbreviated Ni(Ph
3
P)
4
; Ni-tetrakis(triphenylphosphite), abbreviated Ni[(PhO)
3
]
4
and Ni-dicarbonyl bis(triphenyl)phosphine, abbreviated Ni(CO)
2
(Ph
3
P)
2
.
The preferred catalysts for use herein are the NiCl
2
.bis(diphenyl)phosphinyl C
1-4
alkanes. In particular, the C
2-3
alkanes are preferred. Hence, the preferred catalysts are NiCl
2
.bis(diphenyl)phosphinylethane, which is abbreviated “NiCl
2
dppe”, and NiCl
2
.bis(diphenyl)phosphinylpropane, which is abbreviated “NiCl
2
dppp”. The most preferred catalyst for use in the process described herein is NiCl
2
dppe.
In one embodiment of the invention, an R(+) isomer of the compound of formula 1 is provided. An R (+) isomer of a compound of formula 2:
wherein R and R′ are as previously defined,
is reacted with diphenylphosphine in the presence of an amine base and a nickel catalyst to produce the R (+) isomer of a compound of formula 1.
In another embodiment of the invention, the S (−) isomer of a compound of the formula 2: wherein R and R′ are as previously defined, is reacted with diphenylphosphine in the presence of an amine base and a nickel catalyst to produce the S (−) isomer of a compound of formula 1.
One more preferred process which is described herein directly converts the R (+) chiral ditriflate of 1,1′-bi-2-naphthol to R (+) chiral BINAP 1. Likewise, another preferred process directly coverts the S(−) chiral ditriflate of 1,1′-bi-2-naphthol to the (S)-chiral BINAP 1. Essentially no racemization occurs in these preferred embodiments.
Diphenylphosphine is added in a suitable solvent at a temperature which is effective for allowing the formation of BINAP 1 in the presence of an amine-containing base and the nickel catalyst. Since diphenylphosphine is a good ligand for nickel, the amount of diphenylphosphine present in the reaction medium can significantly effect the reaction rate, slowing the reaction if the amount of diphenylphosphine is too great. When the diphenylphosphine is added stepwise during the reaction, the reaction can be completed in about 2 days. The coupling reaction slows down at later stages, possibly due to product and impurity poisoning. The reaction is typically completed in 3~4 days if all the diphenylphosphine is added at once.
Suitable solvents include those which do not substantially oxidize the diphenylphosphine at the appropriate temperature, while maintaining the desired solubility. Polar solvents are preferred. Illustrative of these solvents are dimethylformamide (DMF), acetonitrile and N-methylpyrrolidinone. The most preferred solvent is DMF.
The amine base and amount of base included in the reaction influence the reaction selectivity and reaction rate. Amine bases as used herein include the following: diazabicyclo(2.2.2)octane (DABCO), triethylamine (Et
3
N), diisopropylethylamine, tri n-propylamine, and tri n-butylamine. The preferred amine bases are DABCO and Et
3
N. The most preferred base is DABCO.
The reaction is typically run at a temperature which allows the reaction to proceed without producing undesirable quantities of side products. The temperature range is from about 80 to about 120° C., with about 100° C. being preferred. The temperature, time and base which are preferred are dependent upon the starting bis naphthol derivative which is used. When a bis naphthol ditriflate is used as the starting material, the reaction proceeds well using DMF as the solvent and DABCO as the base at a temperature of about 100° C. Generally, the isolated product is crystalline, which is contaminated in minor amounts with a mono-oxide of the formula:
The exclusion of oxygen from the reaction tends to minimize the formation of this side product.
In a particularly preferred embodiment of the invention, the known compound 6-methylnaphthol is reacted to form 6,6′-bismethyl-1,1′-binaphthol (±). The racemic mixture of

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