JPH0499786A - Chiral ferrocene derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is 1-6C alkyl; R<2> and R<3> are H, 1-6C alkyl or together with bonded N form a 4-6C heterocyclic group; R<4> and R<5> are H, 2-6C alkyl or aryl; when R<1> to R<3> are methyl, R<4> and R<5> are not phenyl at the same time). EXAMPLE:(S)-N,N-dimethyl-1-[(R)-2-((R)-phenylhydroxymethyl)- ferrocenyl]ethylamine. USE:Catalyst for asymmetric synthesis. PREPARATION:A ferrocene iodide of formula II is lithiated with n-butyllithium and the lithiated product is made to react with a ketone or aldehyde of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to chiral ferrocene derivatives, and more particularly to chiral ferrocene derivatives useful as catalysts for asymmetric synthesis.

[Conventional technology]

In the asymmetric synthesis method, which is one of the methods for producing optically active substances, a catalyst for asymmetric synthesis is often used. Well-known catalysts include compounds derived from natural products such as ephedrine and prolinol derivatives.

However, these compounds derived from natural products often have substrate specificity, and have a high enantioselectivity.
There are substrates that do not. Therefore, some reactions are either inapplicable or inefficient.

Therefore, attempts have been made to improve catalysts for asymmetric synthesis derived from natural products in order to reduce such substrate specificity and improve properties such as reaction efficiency. However, it is often not easy to change the substituents on these asymmetric carbon atoms, and it has often been impossible to obtain catalysts for asymmetric synthesis having desired properties.

[Problem to be solved by the invention]

Therefore, an object of the present invention is to provide a novel catalyst for asymmetric synthesis that can replace the above-mentioned compounds derived from natural products.

A further object of the present invention is to provide a catalyst for asymmetric synthesis in which substituents on asymmetric carbon atoms can be changed relatively easily.

[Means to solve the problem]

The present invention relates to a chiral ferrocene derivative represented by the following symbol [I].

(In the formula, R1 represents a lower alkyl group having 1 to 6 carbon atoms,
R2 and R3 are the same or different and represent a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms; R4 and R5 are the same or different, hydrogen, carbon number 2
~6 lower alkyl group or aryl group. Tatashi,
When Rl, R2 and R3 are methyl groups, R
4 and R5 are not phenyl groups at the same time. ) The present invention will be explained in detail below.

Number of carbon atoms in R', R'' and R3 of one shipman CI'J is 1 to 6
Examples of the lower alkyl group include methyl, ethyl, n-propyl, 1so-propyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, and the like. In particular, R1 is preferably methyl or 1so-propyl, and R2 and R3 are methyl, ethyl or 1so-propyl.
So-propyl is preferred.

Examples of the heterocycle formed by R2 and R3 together with the nitrogen atom to which they are bonded include pyrrolidyl and piperidyl, with piperidyl being particularly preferred.

Examples of the lower alkyl group having 2 to 6 carbon atoms represented by R4 and R5 include ethyl, n-propyl, 1so-propyl, n-butyl, tert-butyl, n-pentyl,
Mention may be made of n-hexyl and the like. Particularly preferred are 1so-propyl and tert-butyl. Examples of the aryl group represented by R4 and R5 include a phenyl group, a 2,6-simethoxyphenyl group, and a 4-methoxyphenyl group.

Table 1 shows R1-R3 of specific examples of the compounds of the present invention.

Table 1 Me Methyl, 1so-Pr: Isoprobyl, Pb Phenyl No. 5, R2, N in R1 column is R2, R3
The method for producing the compound of the present invention is explained below.The compound of the present invention is produced by reacting the iodide of ferrocene represented by the general formula [■] with n-butyllithium to lithiate it, and then reacting the lithiated product with n-butyllithium. General formula CI[]R'CR'
It can be obtained by reacting with a ketone (or aldehyde) shown in

The organolithium compound used for the lithiation is n
-In addition to butyllithium, 5ec-butyllithium, t-
Examples include butyllithium, methyllithium and phenyllithium. The amount of these organic lithium compounds used is 01 to 20 equivalents relative to ferrocene iodide [II],
The amount is preferably 0.7 to 1.5 equivalents. Further, these organolithium compounds are preferably used as a 5-30% solution in hexane or ether. Furthermore, the lithiation reaction can be carried out using a solvent (for example, ethers such as ethyl ether and tetrahydrofuran; hydrocarbons such as pentane, hexane, and heptane; aromatic hydrocarbons such as benzene, toluene, xylene, and dichlorobenzene; or one kind or a mixture of two or more kinds of solvents)
It is appropriate to carry out the reaction under the following conditions in the presence of

Reaction temperature: 30° to 50°C, preferably 110° to
30°C Reaction time = 0.1 to 5 hours Reaction pressure Normal pressure to increased pressure, preferably 1 to 3 atmospheres Atmosphere: under nitrogen or argon Next, the reaction between the lithiated product and the ketone (or aldehyde) [■] This is preferably carried out by adding an ether solution of a ketone (or aldehyde) [■] to the reaction system. The amount of ketone (or aldehyde) [■] used is 01 to 2.
It is appropriate to set the amount to 0 equivalents, preferably 07 to 1.5 equivalents.

This reaction is preferably carried out under the following conditions.

Reaction temperature: 40 to 706C, preferably -20 to 406C Reaction time: 1 to 3 hours Reaction pressure: Normal pressure to pressurized, preferably 1 to 3 atmospheres Atmosphere: Under nitrogen or argon At the end of the reaction, phosphoric acid is added to the reaction system. After stopping the reaction by adding an aqueous solution, the aqueous layer is made alkaline and then extracted with ether, and the desired product, the compound of general formula CI), can be fractionated by column chromatography.

Among the raw material compounds for the above reaction, the ketone (or aldehyde) of general formula (I[I) is commercially available.

Moreover, the compound of -Funenin [II) is synthesized as follows.

General formula [IV] (J, Am, Ch
emSac, Vol. 92, 5389 (1970)) is reacted with methyl iodide to form a quaternary ammonium salt, and then reacted with a primary or secondary amine derivative or ammonia.
Appropriately R2 and R3 are ferrocene derivatives other than methyl [■
] can be synthesized [G, Gokel et al., Angew,
Chem, Int, Ed, Engl, 9, 64 (1970).

[■]

[■] Reaction to form quaternary ammonium salt Mel: 0.5-40 equivalents Solvent: Ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile and benzonitrile Temperature: 30 to 80°C, preferably -10 to 40°C Time = 0.1 to 5 hours Normal pressure to pressurized, preferably 1 to 3 atmospheres Atmosphere: Isolation under nitrogen or argon: If the product is crystallized, by filtration, otherwise ethyl ether or hexane is added to precipitate crystals, and then filtered.

Reaction with amine or ammonia HNR2R3: 1 to 30 equivalents Solvent Nitriles such as niacetonitrile and benzonitrile, ethers such as ethyl ether and tetrahydrofuran Temperature: 0° to 100°C, preferably 10° to 90°C Time = 0.5 to 100 hours pressure Pressure from normal pressure, preferably 1 to 3 atm atmosphere: Isolation under nitrogen or argon: Recrystallization or column chromatography The ferrocene derivative of the general formula [■] is purified by Tetrahedr.
On.

26.5453 (1970), haloferrocene derivatives of general formula CIr) can be synthesized according to the following scheme.

Separately from the above method, a haloferrocene derivative represented by the general formula [■] is produced by lithiation of the ferrocene derivative represented by the general formula [~I] with an organic lithiated material, and then reacting with a halosaponizing agent. I can do something.

The organolithium compound used for the lithiation is n
Examples include -butyllithium, 5ec-butyllithium, t-butyllithium, methyllithium, and funyllithium. The amount of these organic lithium compounds to be used is suitably 01 to 20 equivalents, preferably 0.7 to 1.5 equivalents, relative to the ferrocene derivative [■]. Further, these organolithium compounds are preferably used as a 5 to 30% solution in hexane or ether. Furthermore, the lithiation reaction can be carried out using a solvent (e.g. ethyl ether,
In the presence of ethers such as tetrahydrofuran, hydrocarbons such as pentane, hexane, heptane; aromatic hydrocarbons such as hensen, toluene, xylene, and chlorobenzene; or a mixed solvent of one or more of these solvents), It is appropriate to carry out the test under the following conditions.

Reaction temperature: 30° to 50°C, preferably 10 to 30°C
C. Reaction time: 0.1 to 5 hours Reaction window Pressure from normal pressure to 1 to 3 atmospheres, preferably 1 to 3 atmospheres Atmosphere: nitrogen or argon Note that the lithiation reaction is carried out by a known method (Ugi et al. J, Am.

Chem, Sac, vol. 92, 5389 (197
0)) can also be performed.

Next, the lithium compound can be halogenated using, for example, iodine, bromine, chlorine, N-iodosuccinimide, N-bromosuccinimide, or N-chlorosuccinimide as a halogenating agent. These halogenating agents can be added to the reaction system as they are or as a solution dissolved in a solvent.

As the solvent, those exemplified as the lithio substitute solvent can be used, and as the halogenation reaction solvent, those exemplified as the lithio substitute solvent can also be used. The amount of halogenating agent used is the ferrocene derivative [V] used for lithiation.
0.1 to 2.0 equivalents, preferably 0.7 to 1.
It is appropriate to use 5 equivalents.

The halogenation reaction is preferably carried out under the following conditions.

Reaction temperature: 120° to 0°C, preferably 100° to
-308C Reaction time 20.1 to 10 hours Reaction window Pressure from normal pressure to pressurized, preferably 1 to 3 atm Atmosphere: under nitrogen or argon The progress of halogenation can be judged by thin layer chromatography. . At the end of the reaction, water is added to the reaction system to stop the reaction, followed by extraction with ether, and the desired product can be fractionated by column chromatography.

Furthermore, R2 among the haloferrocene derivatives of -Funenin (III)
Compounds in which R3 and R3 are methyl groups can be prepared by converting R2 and R3 to methyl by appropriately selecting the -class and secondary amines by the above-mentioned quaternary ammonium saltation with methyl iodide and then reaction with primary or secondary amines. can be converted into compounds other than groups (1. Ugi et al., J. Org.
Chem, vol. 37, 3052 (1972); T.
Hayashi et al., Bull, Chem, Soc.
, Jpn.

53, 1138 (1980); G, Gokel
et al., Angew, Chem, , Int., E.
d, Engl. 9.64 (1970)).

〔Usefulness〕

The optically active ferrocene derivative of the present invention can be an effective ligand for Lewis acid metals, and can be used in asymmetric introduction reactions using Lewis acid metals such as zinc, aluminum, titanium, cerium, and nickel. In this method, a catalyst exhibiting high enantioselectivity can be provided.

According to the present invention, chiral ferrocene derivatives having various substituents can be provided, and these derivatives can be applied to various asymmetric synthesis reactions. Furthermore, the optically active ferrocene derivative of the present invention can also be used to provide polymers useful as catalysts for heterogeneous asymmetric synthesis, gels for optical resolution of polymers, etc.
F., S., Arimot.

et al., J. Am., Chem, Soc,, vol. 77, 6.
295 (1955); G, F. Hayes et al., F! olymer, l vol. 8, 1286 (19
77)).

Reference Example 1 Under an argon atmosphere, (-)-(S)-N,N-dimethyl-1-
Ferrocenylethylamine 270g (I 0.5 m
mof) and dissolved in ether 25-. After cooling with water, cyclohexane solution of secondary butyl lithium 12.4
i (0.94 M, 11.7 mmoA) was added dropwise. The reaction was allowed to proceed for 1 hour under water cooling. After cooling in a dry ice-acetone bath, 3. OOg (11,7 mmoj
') dissolved in 25 Wl of tetrahydrofuran was added dropwise. After reacting for 1 hour under cooling, water was added to stop the reaction. The aqueous layer was made alkaline and extracted with ether. The organic layer was dried with anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by alumina column chromatography, and the result was (+)-(S)-N N-
3.30 g (manufacturing yield: 82%) of dimethyl-1-C(R)-2-iodoferrocenyl]ethylamine was obtained.

Further, it was recrystallized from acetonitrile.

C(1]o = +9.35° (c 1.42.
EtOH) Melting point 78-79°C 90MHz 'HNMR (CDCf s) δ1.47
(d, J=6.3Hz, 3H), 2.13
(s, 6H), 3.60 (Q, J7.5Hz,
IH), 4.10(s, 5H), 4.
11-4.3Hm, 2H).

4.38-4.53 (m, IH) IR (KBr) 3100, 2970.2940.280
2.2760.1370.1185.1102.108
5.1000.918.820an-'Reference Example 2 Under an argon atmosphere, the (S)-N,N-dimethyl-1-[ obtained in Reference Example 1 was placed in a glass normal pressure reactor equipped with a stirrer.
(R)-2-iodoferrocenyl]ethylamine 2.9
Add 4 g (7.66 mmof) of acetone 15-
It was dissolved in Methyl iodide 2.1++/(
34 mmof) was added and reacted for 10 minutes. Add ethyl ether 80- to form a precipitate, and filter it.
402 g (7.66 mmof) of quaternary ammonium salt was obtained.

Subsequently, the obtained quaternary ammonium salt was dissolved in 100 rnl of acetonitrile and then dissolved in 20 ml of piperidine.
1 (200 mmof) was added and stirred at 30°C for 48 hours. Ethyl ether was added and the mixture was washed with water. The ethyl ether solution was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was recrystallized using ethyl alcohol to obtain 3.08 g (manufacturing yield: 95%) of (S)-1-((R)-2-iodoferrocenyl-1-piperidinoethane.

[(1] o +21.9° (c O,844
ELOH) Melting point 67-68°C 90MHz 'HNMR (CDCA 3) δ1.16
~1.75 (m, 6)1), 1.50 (d
, J=6.3flz, 3H).

2.36 (t, J=5.1Hz, 4H),
3.70 (q, J=6.6Hz, LH)4
．． 10 (s, 5H), 4.11-4.28
(m, 2H), 4.35-4.49 (m I
H) IR(KBr) 3100.2998.2950.2
860.2805.2760.1377.1108.1
002.917.820an-'Reference Example 3 Isopropylamine 17rd (
(S)-N-isopropyl-1-(
(R-2-iodo'ferrocenyl]ethylamine2.
83 g (manufacturing yield 93%) was obtained.

90MHz 'HNMR (CDCf3) δ1.01
(d, J-3Hz, 3H), 1.08
(dl, 52 (d, J=6.3Hz,
3H), 2.703.76 (q, 6.6 to
)1z, LH), 4.124.28(m,
2H), 4.36-4.48 (mIR(neat)
3100.2960.2865.1000. 93
8.820 an J=3H2,3H) ~3.08 -1 IH) (s, 5H) 4.15 ~ IH) 1370.1165.1109, Example 1 Under argon atmosphere, glass normal pressure with stirrer (S)-N N-dimethyl-1- obtained in Reference Example 1 was added to the reaction apparatus.
[(R)-2-iodoferrocenyl]ethylamine2.
70 g (7.06 mmof) were added and dissolved in ethyl ether 15i. After cooling with water, a hexane solution of n-butyllithium 5.0 m/(1,56 M, 7.8 mmoA
) was added dropwise. After reacting for 5 minutes under water cooling, a solution of 0.94 g (8.8 mmof) of henzaldehyde in ethyl ether 15- was added. The reaction was allowed to proceed for 1 hour at room temperature. 8
% phosphoric acid aqueous solution was added to stop the reaction, and the mixture was stirred for 4 hours. After washing the acidic liquid with ethyl ether, a concentrated alkaline aqueous solution was added to make the acidic liquid strongly alkaline. The mixture was extracted with ethyl ether and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by alumina column chromatography to give (S)-N.

1.80 g (manufacturing yield: 70%) of N-dimethyl=1-[(R)-2-((R)-phenylhydroxymethyl)ferrocenyl]ethylamine was obtained.

3.38-3.58 (m, IH), 3.80
~4.40 (t3H).

4.03 (s, 5H), 5.93 (s
, IH).

7.12~7.46 (m, 3H), 7.46~
7.69 (m, 28).

7.92 (br s, LH)rR(neat
) 3102.3049.2998.2955.28
49.2800.1605.1450.1369.12
70.1180.1105.1042.1019.10
00.938.819.770.738.700an-
'Examples 2 to 6 The same operations as in Example 1 were repeated except that the raw materials shown in Table 2 were used as the ferrocene compound and the carbonyl compound to obtain the products shown in Table 2.

[α].

+ 121.6 ° (c 1.04. EtO
H) Oil 90MHz 'HNMR (CDCn a) δ1.35
(d, J=6.6Hz, 3H), 2.
21 (s, 6) 1) Product of Example 2 90M1(z'l(NMR (CDCI 3) δ1.
33 (d, J=6.9Hz, 3H), 2.19
(s, 6H) 3.84 (s, 3H), 4.0
1~4.15 (m, 4H) 4.03 (s, 5H
), 6.94 (s IH), 6.95.7.0
8.7.507.65 (AB pattern, J=9H
z, 4H) IR (KBr) 3095.2980.
2825.1610.1460.1240.1167.
1102.1068.1035.999.930.82
0 cm Product of Example 3 90M1 (z'HNMR (CDCf s) δ1.35
(d, J-6,6)1z, 38), 2.20
(s, 8H) 3.63-4.00 (m, 2H),
3.82 (s, 6) () 3.97 (s, 5H)
, 4.02~4.20 (m, IH) 4.30 (
q, J=6.9Hz, LH), 6.58 (s,
LH) 6.68 (d, J: 3.3Hz, 2) 1
)7.23 (dd, J:6.9Hz, 8.4Hz
, 1) I) IR (KBr) 3450.3100.
2998.2950.2848.2800°1595.
1475.1245.1180.1100.1072.
1004.920.808.730an-' Product of Example 4 90MHz 'HNMR (CDCI23) δ0.37
(d, j-6,6)1z, 3)1),
0.831, 26 (d, J-6,6t+z, 6
H), 1.45], 60-1. ．． 97 (m,
HL), 2.12 (δ2.30 to 2.68
(m, LH), 3.78-34, 09
(s 5t() 4.11~4..27(m7.
69 (br s, 18) IR (KBr)
3420, 3100.2998.1460, 12
50, 1108, 1015, 20 cm Product of Example 5 90 MHz 'HNMR (at CDC) δ 0.29-1
．． 40 (m, 6H), 1.24 (δ2.25
(t, J・5.7Hz, 4H), 3,823.8
9-4. O1, ([0, IH), 4.03-44.2
0-4.30 (m, LH), 4.40 (Q6,
98~7.45 (m, 8f(), 7.50~78
．． 72 (br s, IH) IR (KBr) 3460.3100.3070°2
840, 1600.1444.1248, (d, J (d, J 6H) 95 (m 3H) 6.3Hz 6.6Hz ], H) 3H) 3H) 2960. 1004. 2898.2800. 941.828. 6.3Hz 311) 5H) (m, IH) 6.9tlz IH) (m, 2H) 3050. 1104. 2998. 1068. 2950°1036, 1002.820.762.753.703an-'Product of Example 6 90MHz 'HNMR(CDCj's) δ0.70
(d, J=6.6Hz, 3H), 1.09 (
d, J: 3H2, 3H).

1.16 (d, J: 3Hz, 3H), 2.68
~3.10 (m, IH).

3.20-3.58 (m, LH), 3.66 (
q, J4.2Hx, LH).

3.95-4.19 (m, LH), 4.13 (
s, 5H).

7.06~7.43 (m, 8H), 7.45~7
．． 68 (m, 2H)IR(neat) 3450.
3100.3020.2950.2850.1600.
1480.1225.1178.1105.1050.
1030.1002.820.759.705an-' Example 7 (S)-N,N-dimethyl-1-ferrocenylisobutylamine (known compound) in a glass atmospheric pressure reactor equipped with a stirrer under an argon atmosphere 1899g (5,58m
mof) was added and dissolved in 15 Tl of ethyl ether. After cooling with water, 3.9 m of n-butyllithium hexane solution
/ (1,63M, 6.35 mmof) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Under water cooling, no benzaldehyde
．． 69 g (6.48 mmon) of a solution in ethyl ether 10- were added. The reaction was allowed to proceed at room temperature for 3 hours. After the reaction was stopped by adding an 8% aqueous phosphoric acid solution, the mixture was stirred for 2 hours.

After washing the acidic liquid with ethyl ether, the acidic liquid was made strongly alkaline by adding a concentrated aqueous alkali solution, and then extracted with ethyl ether and dried over anhydrous sodium sulfate.

After distilling off the solvent, the residue was purified by alumina column chromatography to obtain (S)-N,N-dimethyl-1
-[(R)-2-((R)-phenylhydroxymethyl)ferrocenylisobutylamine was obtained in an amount of 0.94 g (manufacturing yield: 43%).

[α].

+ 142.4 ° (c O, 644EtOH)
Oil 90MHz 'HNMR (CDCf 3) δ1.25
(d, J=6.6Hz, 3H), 1.
46 (d, J・6.6Hz, 3H)2.4
5 (s, 6H), 2.46-2.80
(m, IH), 3.45-3.62 (m,
LH), 3.82-4.29 (m, 3H)
, 4.01 (s, 5H) 5.87 (S
, IH), 7.17-7.48 (m,
3H), 7.48-7.69 ([[l, 2H)
, 7.75 (br s, 18)IR(n
eat) 3100.3040. 2960.294
0.2880.2800°1600.1446.138
2.1363.1262.1197.1181.110
4.1078.1041.1018.1000.942
．． 840.816.740.700an-

Claims (1)

[Claims] A chiral ferrocene derivative represented by the following general formula [I]. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] (In the formula, R^1 represents a lower alkyl group having 1 to 6 carbon atoms, and R^2 and R^3 are the same or different and represent a hydrogen atom, a carbon Shows a lower alkyl group of numbers 1 to 6, or R^2 and R^3
forms a heterocycle having 4 to 6 carbon atoms with the nitrogen atom to which they are bonded, and R^4 and R^5 are the same or different and represent hydrogen, a lower alkyl group or aryl group having 2 to 6 carbon atoms; . However, when R^1, R^2 and R^3 are methyl groups, R^4 and R^5 are not phenyl groups at the same time. )