CS203074B2 - Method for the asymmetric reduction of prochiral or racemic substrates - Google Patents

Abstract

1460781 Reduction SNAMPROGETTI SpA 9 April 1974 [13 April 1973] 15781/74 Headings C2C and C2P The invention comprises a process for converting by hydrogen transfer a prochiral or racemic starting material to an optically active product, which process comprises reacting the starting material with an alane selected from (a) optically active aminoalanes having the two following general formulae and and (b) optically active polyiminoalanes having in their molecule a group having the general formula wherein X is a hydrogen, chlorine or bromine atom or a group of the formula -NR<SP>3</SP> 2 or -OR<SP>3</SP>, n is an integer having a value greater than 4, each of R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP>, which can be the same or different, is an alkyl, aryl, alkaryl, aralkyl or cycloalkyl radical, or R<SP>1</SP> and R<SP>2</SP> together represent a divalent alkylene radical and with the nitrogen atom to which they are attached form a hetero ring; with the proviso that in the alane at least one radical attached to the nitrogen atom(s) contains at least one asymmetric centre, and with the proviso that in the polyiminoalane there is for each aluminium atom, at least one direct Al-N bond and in the polyiminoalane there is at least one Al-H bond. Examples describe the preparation of α- methyl benzyl alcohol; but-2-yl-n-butylamine; 3 - methyl - 1 - phenyl - 1 - phosphacyclopent- 3-ene and 1,2-dimethyl-n-butylamine.

Description

The invention relates to a method of asymmetric reduction of prochiral or racemic substrates to obtain optically active products.

The synthesis of optically active compounds, such as alcohols, amines with a high degree of steric purity, is one of the most important technical and economic problems.

Recently, research has focused on obtaining natural products by partial or complete synthesis, with the greatest interest in direct synthesis of optically active compounds without the need for resolutions of optical antipodes.

To date, the purest asymmetric products have been obtained by enzymatic or microbiological reactions, but some of the problems associated with such reactions, for example, in production continuity, show the advantages of chemical syntheses for example in 35% reduction of prochiral substrates such as ketones, imines or racemic substrates. such as epoxides or trialkylphosphine oxides, in obtaining the corresponding optically active alcohols and amines using optically active metal hydride complexes.

Hitherto known, direct or indirect and imetacetic reductions of said substrates with hydrides of elements belonging to group 3 of the periodic system were only reactions of hydrogen transfer from aluminum or lithium hydride in the presence of optically active alcohols. Such reactions generally take place to form the corresponding metal alkoxy hydrides, at low optical induction values, and with a significant reduction in the choice of reaction conditions due to the poor solubility of the reactants.

The highest optical yields reported are in the range of from about 45 to about 50%, the optical yield being derived from the ratio &quot; i ⁰⁰ (a) max.

It has now been found and proposed that asymmetric hydrogen transfer reactions from optically active aluminum hydrides can be carried out at very high optical induction values by replacing optically active aluminum alkoxy hydrides containing an asymmetric alkoxy group with optically active aminoalanes or polyiminoalanes.

The invention thus relates to a process for the asymmetric reduction of prochiral or racemic substrates, for example ketones, imines, N-substituted imines or racemic alkylene dioxides and trialkyl phosphine oxides, characterized in that the reduction is carried out by optical means. active aminoalanes or polyiminolaria groups formed by compounds of the general formulas

HAINR1R2,

HA1 (NR1R2) 2, (HA1NR) n in which

R, R 1 and R 2 denote an alkyl, aryl or cycloalkyl radical containing from 1 to 10 carbon atoms, n being a number from 4 to 10 containing at least one direct A-N bond and an Al-H · bond to an aluminum atom, the third substituent bonded to an aluminum atom may be halogen, hydrogen or a group

R /

—N, r, or —OR, where

R is as defined above, and in which the asymmetric centers are a primary or secondary amine group containing at least one optically active alkyl radical of 1 to 10 carbon atoms, the reaction being carried out at a temperature of from -100 to + 50 ° C.

By using said derivatives in the asymmetric hydrogenation of prochiral ketones, imines, N-substituted imines, oximes or racemic alkylene oxides and trialkylphosphine oxides, corresponding optically active reduced compounds with very high optical induction values are obtained. The values obtained optical yields are around 85 ^l% Solubility of said compounds in different solvents allows their use at low temperatures, as reducing agents under conditions where A1H3 and L1AIH4 or other hydrides not provide good results.

Amino- and iminolanes were prepared from optically active primary or secondary imines and from AlH3. D or L1AIH4 according to the following equations:

> -Al-N * o 4

AlH ^£ D + R ^ ^ M.

LtAlH ^ R ^{R NC} > HCl ---) RR ^A N ~ AH +

- t ^Z

AlH ₃ D + · R NH — R RN-A1 H ^£ D + H +

AlJXD <RR * NN --->& RN-AIHX * (X = Cl, Br) RR * N ~ AIH ~ NRR + ΰ ~ 2Η ^ rx * ~ ^2N Z

FACE + 2H

A1H-D ⁺ 2YR * NN>

[D = Lewis base: (CH 3) 3 N, (C 2 H 5) s N etc.].

The amine may be, for example, bornylamine, sec-butylamine, phenethylamine, methylamine and another primary amine containing a subjectively active substance or a secondary amine containing at least one optically active substituent, such as N-methyl phenethylamine , pipecoline, desoxyephedrine, O-tetrazine ephedrine, wherein the other substituent may be chiral or achiral.

Some of the amines prepared as described above are listed below:

г *

I Al —H *

Al-H

prochiral reduction

The reaction scheme of the substrates is shown below:

H ₂ O h ₂ o + X = NR (H)

Rrr = p + O (Al-H *) *

Al-H

W ^C v

R * ^X OH + 1/3 Al (OH).

□

R OH \ * /

C + 1/3 Al (OHL \ h. ³ /

NHR (H) A + 1/3 Al (OH)

RH ³

H ₂ O

------->

H ₉ 0

R RR P * + 1/3 Al

= optically active dialkylaminoalan or polyiminoalan.

After completion of the reaction, the asymmetric amine is regenerated almost completely, without a measurable indication of racemization. This highlights the possibility of transferring hydrogen from an asymmetric carbon atom when the amine corresponds to the general formula

The advantage of using said aminoalanes lies in the possibility of a larger temperature range and a large number of different solvents, obtaining much higher optical yields compared to other metal hydride based systems hitherto used in asymmetric hydrogenation and almost complete recovery of the optical inducing agent.

He did

0.215 mol. of acetophenone, dissolved in 100 ml of ethyl ether, was slowly added dropwise to a solution of 0.11 mol. With N-methylphenylaminoalan in 600 mL of ether, cooled to 0 ° C. After 4 hours, the solution was hydrolyzed with ice water and the pH was kept at pH 4 with hydrochloric acid. The organic phase was then separated: the aqueous phase was extracted with three portions of 100 ml of ether. The combined extracts were evaporated to a small volume. The residual oil was treated with semicarbazide, hydrochloric acid, and sodium acetate in an aqueous-ethanolic solution for 0.25 hr at 60 ° C.

Diluting with a small amount of water and cooling to 0 ° C separated unreacted acetophenone as semicarbazone, which was filtered off. The clear solution was extracted four times with 100 mL of ether. The combined extracts were dried over sodium sulfate and the solvent was evaporated. The residue was distilled under vacuum.

The procedure described above gave 23.6 g of phenylmethylcarbinol (90% yield). ²³ = -5.5 °, optical yield = 12.5%.

From the mother liquor, 19.1 g of N-methylphenethylamino was recovered by alkalinization, ether extraction and reaction with hydrogen chloride gas. HCl, 93% yield,

[Α] D = -29.9 ° (EtOH, c = 5), (Et = ethyl).

Aminchlorhydrát used in the synthesis dialkylaminoalanu possesses a [ «] 5 ₄₆ ²³ Abs = -30.0 ° (EtOH, c = 5).

Example 2

Under the same conditions as in Example 1, acetophenone and N-methylphenethylaminoalan (2: 1) in ethyl ether were reacted at -73 ° C. The corresponding carbinol obtained in a yield of 57.5% showed a [?] Dabs ²³ = -37.2 °.

The optical yield was 85%.

Example 3

Using the same reaction conditions as in Example 1, acetophenone and N-methylphenethylamine (2: 1) were reacted at 0 ° C in toluene. The corresponding carbinol, obtained in a yield of 88%, showed a [α] Dabs of ²³ = -12.04 ° and an optical yield = 27.4%.

Example 4

Using the same conditions as in Example 1, acetophenone and N-methylphenethylamine (2: 1) were reacted at -70 ° C in toluene. The corresponding carbinol, obtained in 63.5% yield, exhibited a value of [ajoabs]. ²⁵ = -32.6 °;

the optical yield was 74%.

Example 5

At -70 ° C, 11.4 g of N (n-butyl) imino-2-butanone was added to a solution of 16.3 g of N-methylphenethylaminoalan in ethyl ether. After completion of the reaction, the reaction mixture was hydrolyzed with ice-cold sodium hydroxide. The ether fraction was separated and the aqueous phase extracted three times with ether. The combined ether extracts were dried over sodium sulfate and evaporated under reduced pressure. From the residual oil sec-butylamine was obtained by fractionation at 1599.8 Pa, in a yield of 40-45%;

[alDabs. ²⁵ = +2.9; optical yield = 18%. ж

Example 6

Under the same conditions as in Example 1, acetophenone and (+) pipecolinoalan (2: 1) were reacted at -70 ° C in tetrahydrofuran. The corresponding carbinol, obtained in a yield of 60%, showed a [α] ²³ = -9.8 °; optical yield = 22.5%.

Example 7

Under the same conditions as in the example, acetophenone and poly [(phenethyl) iminoalan were reacted at 0 ° C in ethyl ether The corresponding carbinol, obtained in 80% yield, showed a [αDabs ²³ = + 4.42 °;

optical yield = 14.4%.

Example 8

A solution of 0.31 mol of N-methylphenethylaminoalan was added at 25 ° C to the benzene solution of 3-imidazol-1-phenyl-l-4-phosphol and -3-cyclopentene-1-oxide (I).

CH ₃ (I)

After the addition was complete, the reaction mixture was left at ambient temperature for three hours with stirring and then hydrolyzed with ice and sodium hydroxide. The benzene phase was extracted, dried over potassium hydroxide and evaporated under reduced pressure. N-methylphenethylamino (boiling point 48 ° C, yield 70-75%, optical purity 98%) was recovered by distillation at 13.33 Pa.

Another fraction consisted of 3-methyl-1-phenyl-1-phospha-3-cyclopentene [II].

(II)

- Yield = 55 - 60 ^; ° / o;

[.alpha.] D @ 25 = + 6.78 DEG.

The maximum specific rotation of this phosphine is unknown.

Example 9

13.2 g (0.115 mol) of 1-butylmethylketoxime was slowly added over 1 hour and thirty minutes to a solution of 20.8 g (0.13 mol) of N-nieibylphenethylaminoalan in 250 ml of ether at 0 ° C.

The solution was refluxed for 3 hours and then hydrolysed with ice. After adjusting the pH of the solution to completely basic, the solution was extracted with ether (3 x 100 mL). The combined and dried extracts over solid potassium hydroxide were evaporated. The residue was distilled under pressure

1999,5 Pa. The various fractions were analyzed by GLC chromatography. This procedure afforded isobutylmethylamine in a yield of 50% and a [αDabs * ⁵ = -0.63 ° (scientific print indicates —10.7 °); the optical yield was 5.9%.

N-Methylphenethylamine was isolated as the chlorohydrate from the distillation residue in a yield of 90 ^% .

The optical purity of the recovered amine was 98% based on the original value.

All rotational optical force measurements were performed on pure and not diluted samples.

Claims (1)

A method of asymmetric reduction of prochiral or racemic substrates, for example ketones, imines, N-substituted imines or racemic alkylene oxides and trialkylphosphine oxides, characterized in that the reduction is carried out by optically active aminelanes or polyiminolanes from the group consisting of compounds of the formulas HA1NR1R2, HA1 (NRiR ₂₎ 2, (HÁlNR) n in which R, R 1 and R ²¹ denote an alkyl, aryl or cycloalkyl radical containing 1 to 10 carbon atoms, n being a number 4 to 10, containing at least one direct Al-N bond and an Al-H bond to an aluminum atom, the third substituent bonded at an aluminum atom, is halogen, hydrogen or optionally -OR where R is as defined above, and in which the asymmetric center is primary or secondary. an amine group containing at least one optically active alkyl radical of 1 to 10 carbon atoms, the reaction being carried out at a temperature of from -100 to +50 ° C.