Method for the synthesis of unsymmetrical tertiary amines

Abstract

Disclosed is a new method for the synthesis of unsymmetrical tertiary amines using alcohol and an imine, and to new tertiary amines.

Claims

1. A method of preparation of unsymmetrical tertiary amines comprising using an alcohol and an imine as reactants, wherein the alcohol is a primary or secondary alcohol of formula (C)
R.sub.4OH  (C) wherein R.sub.4 represents a C.sub.2 to C.sub.10 alkyl, or a C.sub.3 to C.sub.10 cycloalkyl, and wherein the imine is an imine of formula (D) ##STR00199## wherein R.sub.1 and R.sub.2 represent a hydrogen, aryl, allyl, C.sub.1 to C.sub.10 alkyl, or C.sub.3 to C.sub.10 cycloalkyl, R.sub.3 represents an aryl, allyl, C.sub.1 to C.sub.10 alkyl, C.sub.3 to C.sub.10 cycloalkyl, a C.sub.1 to C.sub.10 carbonyl derivative, or a C.sub.3 to C.sub.10 formate, wherein the tertiary amines are of formula (E) ##STR00200## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined above, wherein the tertiary amines carry three different substituents, said method comprising a step of alkylation of an alcohol of formula (C)
R.sub.4OH  (C) on an imine of formula (D) ##STR00201## to obtain the compound of formula (E) wherein the step of alkylation is catalyzed by an iron(0) complex.

2. The method according to claim 1, wherein the iron(0) complex is chosen from the following formulas: ##STR00202## wherein Ts=tosyl ##STR00203## TMS=trimethylsilyl ##STR00204## TBDMS=tert-butyldimethylsilyl ##STR00205## TIPS=triisopropylsilyl ##STR00206## or the following formula (B): ##STR00207## in which TBDMS=tert-butyldimethylsilyl ##STR00208## Ts=tosyl ##STR00209##

3. The method according to claim 1, wherein the step of alkylation is catalyzed either by the complex of formula (B) formed prior to the preparation of tertiary amines, ##STR00210## in which TBDMS=tert-butyldimethylsilyl ##STR00211## Ts=tosyl ##STR00212## or by the catalyst formed in situ during said preparation of tertiary amines by adding trimethylamine oxide to the complex of formula (A) ##STR00213##

4. The method according to claim 1, wherein the step of alkylation is performed in an organic solvent, or in ethanol, or ethylene glycol, or in a mixture of solvents, or in a mixture of solvents composed of THF and of ethanol or of ethylene glycol.

5. The method according to claim 1, wherein the primary alcohol of formula (C), is also used as solvent for the step of alkylation.

6. The method according to claim 1, wherein the primary alcohol of formula (C), is also used as solvent for the step of alkylation, in a number of equivalents higher than 10 equivalents.

7. The method according to claim 1, wherein the imine of formula (D) is either formed prior to the preparation of the tertiary amines, or is formed in situ during said preparation of tertiary amines by a method comprising contacting an aldehyde or ketone of formula (F) ##STR00214## wherein R.sub.1, R.sub.2 represents a hydrogen, aryl, allyl, C.sub.1 to C.sub.10 alkyl, or C.sub.3 to C.sub.10 cycloalkyl, and an amine of formula (G)
R.sub.3—NH.sub.2  (G) wherein R.sub.3 represents an aryl, allyl, C.sub.1 to C.sub.10 alkyl, C.sub.3 to C.sub.10 cycloalkyl, a C.sub.1 to C.sub.10 carbonyl derivative or a C.sub.3 to C.sub.10 formate.

8. The method according to claim 1, wherein the step of alkylation is performed in the presence of a catalyst of formula (B) ##STR00215## to obtain the compound of formula (E) as defined above, or comprising a first step of preparing of the catalyst comprising a step of adding trimethylamine oxide on the complex of formula (A) ##STR00216## and a second step of alkylation of an alcohol of formula (C)
R.sub.4OH  (C) wherein R.sub.4 represents a C.sub.2 to C.sub.10 alkyl, or a C.sub.3 to C.sub.10 cycloalkyl, on an imine of formula (D) ##STR00217## wherein R.sub.1 and R.sub.2 represent a hydrogen, aryl, allyl, C.sub.1 to C.sub.10 alkyl or a C.sub.3 to C.sub.10 cycloalkyl, R.sub.3 represents an aryl, allyl, C.sub.1 to C.sub.10 alkyl, C.sub.3 to C.sub.10 cycloalkyl, a C.sub.1 to C.sub.10 carbonyl derivative, or a C.sub.3 to C.sub.10 formate, in the presence of a catalyst of formula (B) prepared during the preceding step and as defined above, to obtain the compound of formula (E) ##STR00218## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined above, or comprising a first step of preparing imines of formula (D) ##STR00219## wherein R.sub.1 and R.sub.2 represent a hydrogen, aryl, allyl, C.sub.1 to C.sub.10 alkyl, or cycloalkyl C.sub.3 to C.sub.10, R.sub.3 represents an aryl, allyl, C.sub.1 to C.sub.10 alkyl, C.sub.3 to C.sub.10 cycloalkyl, a C.sub.1 to C.sub.10 carbonyl derivative, or a C.sub.3 to C.sub.10 formate, comprising a step of contacting with an aldehyde or a ketone of formula (F) ##STR00220## wherein R.sub.1 and R.sub.2 are as defined above, and an amine of formula (G)
R.sub.3—NH.sub.2  (G) wherein R.sub.3 is as defined above, to obtain the imine of formula (D) as defined above; and a second step of alkylation of an alcohol of formula (C)
R.sub.4OH  (C) wherein R.sub.4 represents a C.sub.2 to C.sub.10 alkyl, or a C.sub.3 to C.sub.10 cycloalkyl, on an imine of formula (D) prepared in the preceding step and as defined above, in the presence of a catalyst of formula (B) ##STR00221## to obtain the compound of formula (E) ##STR00222## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined above, or comprising a prior step of preparing of imines of formula (D) ##STR00223## wherein R.sub.1 and R.sub.2 represent a hydrogen, aryl, allyl, C.sub.1 to C.sub.10 alkyl, or C.sub.3 to C.sub.10 cycloalkyl, R.sub.3 represents an aryl, allyl, C.sub.1 to C.sub.10 alkyl, C.sub.3 to C.sub.10 cycloalkyl, a C.sub.1 to C.sub.10 carbonyl derivative, or a C.sub.3 to C.sub.10 formate, comprising a step of contacting an aldehyde or ketone of formula (F) ##STR00224## wherein R.sub.1 and R.sub.2 are as defined above, and an amine of formula (G)
R.sub.3—NH.sub.2  (G) wherein R.sub.3 is as defined above, to obtain the imine of formula (D) as defined above; a prior step of preparing the catalyst comprising a step of adding trimethylamine oxide to the complex of formula (A): ##STR00225## said two prior steps may occur in any order, and a step of alkylation of an alcohol of formula (C)
R.sub.4OH  (C) wherein R.sub.4 represents a C.sub.2 to C.sub.10 alkyl, or a C.sub.3 to C.sub.10 cycloalkyl, on an imine of formula (D) prepared in the previous step ##STR00226## wherein R.sub.1, R.sub.2 and R.sub.3 are as defined above, in the presence of catalyst of formula (B) prepared in the preceding step and as above, to obtain the compound of formula (E) ##STR00227## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined above.

9. The tertiary amines having one of the following formulae: ##STR00228## ##STR00229## ##STR00230## ##STR00231## ##STR00232## ##STR00233## ##STR00234## ##STR00235##

Description

EXAMPLES

Example 1 Study of the Catalyst

(1) TABLE-US-00001 TABLE 1 Tests with different iron catalysts Ratio GC (starting/ Catalyst. Additive reduction/alkylation) Yield [%] A Me.sub.3NO 0/0/100 97 B — 0/0/100 99

Example 2 Study of the Solvent

(2) TABLE-US-00002 TABLE 2 Tests with different solvents Temperature Ratio GC(starting/reduction/ Solvent [° C.] alkylation/dialkylation) DCE/EtOH  80 18/72/10/0 (svt/3 eq) THF/EtOH  80 27/65/8/0 (svt/3 eq) THF/EtOH (1/1)  80 15/1/79/5 THF/EtOH (1/1) 110 23/5/72/0 CPME/EtOH (1/2) 110 73/18/9/0

Example 3: Study of the Alcohol

(3) TABLE-US-00003 TABLE 3 Study of several alcohols as alkylating agents Ratio GC(starting/reduction/ Yield Catalyst Alcool alkylation/dialkylation) [%] B ethylene glycol 0/0/100/0 18 B ethanol 0/0/100/0 99

Example 4: Aromatic Imines

(4) TABLE-US-00004 TABLE 4 Exemplification with various aromatic aldehydes, substituted in the para position Ratio GC (starting/reduction/ Alkylation Product Catalyst akylation/dialkylation) yield [%] 0 A/Me.sub.3NO B 16/23/48/13 5/20/74/1 28 68 A/Me.sub.3NO B 0/0/100/0 0/0/88/12 88 55 A/Me.sub.3NO B 0/0/100/0 0/0/100/0 97 99 A/Me.sub.3NO B B à 130° C. 35/25/40/0 45/37/18/0 6/39/55/0 33 15 50 A/Me.sub.3NO B 3/50/35/12 8/13/75/4 26 68 A/Me.sub.3NO B 48/33/19/0 0/0/86/14 12 74 A/Me.sub.3NO B 34/19/43/4 0/0/84/16 54 85 A/Me.sub.3NO B — 0/29/41/30 — 38 B 36/39/25/0 20

(5) TABLE-US-00005 TABLE 5 Exemplification with various aromatic aldehydes Ratio GC (starting/reduction/ Alkylation Product Catalyst akylation/dialkylation) yield [%] 0 A/Me.sub.3NO B — 19/3/78/0 — 70 A/Me.sub.3NO B — — 70 72 A/Me.sub.3NO B 0/0/83/17 0/0/72/28 49 55 A/Me.sub.3NO B 0/0/92/8 0/0/90/10 78 70 A/Me.sub.3NO B — 5/0/90/5 — 78 A/Me.sub.3NO B — 0/31/29/40 — 21 B 0/0/15/85 10

Example 5: Allylated Imines

(6) TABLE-US-00006 TABLE 6 Exemplification with various conjugated aldehydes Ratio GC (starting/reduction/ Alkylation Product Catalyst akylation/dialkylation) yield [%] A/Me.sub.3NO B — — 67 A/Me.sub.3NO B — 48 30

Example 6: Alkylated Imines

(7) TABLE-US-00007 TABLE 7 Exemplification with various aliphatic aldehydes 0 Ratio GC (starting/reduction/ Alkylation Product Catalyst akylation/dialkylation) yield [%] A/Me.sub.3NO B — 0/0/78/22 52 54 A/Me.sub.3NO B — 0/40/17/43 — 14

Example 7: Aromatic Imines

(8) TABLE-US-00008 TABLE 8 Exemplification with various aromatic amines Ratio GC (starting/reduction/ Alkylation Product akylation/dialkylation) yield [%] 0/58/42/0 30 0/10/90/0 88 45/37/18/0 12 0/34/36/30 18

(9) TABLE-US-00009 TABLE 9 Exemplification with various aliphatic amines Ratio GC (starting/reduction/ Alkylation Product akylation/dialkylation) yield [%] 0/0/100/0 85 0/0/100/0 85 0 0/0/67/33 51 0/0/100/0 75 0/0/100/0 47 39/9/52/0 18

Example 8: Allylated Imines

(10) TABLE-US-00010 TABLE 10 Exemplification with various substituted aromatic amines Ratio GC (starting/reduction/ Alkylation Product Catalyst akylation/dialkylation) yield [%] A/Me.sub.3NO B — 0/0/100/0 — 57 A/Me.sub.3NO B — 0/0/100/0 — 85 A/Me.sub.3NO B — Incomplete conversion — 38 A/Me.sub.3NO B — 0/0/100/0 — 88 A/Me.sub.3NO B — 0/0/100/0 — 72 0 A/Me.sub.3NO B — 0/0/100/0 — 55 A/Me.sub.3NO B — 0/8/92/0 — 76 B 0/0/100/0 15

(11) TABLE-US-00011 TABLE 11 Exemplification with various allylic or aliphatic amines Ratio GC (starting/reduction/ Alkylation Product Catalyst akylation/dialkylation) yield [%] B 0/0/100/0 22

Example 9 Other Imines

(12) TABLE-US-00012 TABLE 12 Exemplification with various imines Ratio GC (starting/reduction/ Alkylation Product Catalyst akylation/dialkylation) yield [%] A B — 23/42/35/0 — 30 A B — 0/4/96/0 — 78 A B — 0/47/35/18 — 35 A B — 0/0/90/10 ou 0/0/83/17 — 71 0 A B — 0/27/73/0 (or starting 27) — 53 A B — 0/0/100/0 — 29 B 0/0/87/13 80 Cond A: [Fe] (5 mol %), Me.sub.3NO (5 mol %), EtOH 110° C. Cond B: [Fe][MeCN] (5 mol %), EtOH 110° C.

Example 10: Intermolecular Version

(13) TABLE-US-00013 TABLE 13 Optimization of the intermolecular version on the model substrates Ratio GC (starting/ Catalyst Additive Temperature [° C.] reduction/akylation/dialkylation) Yield [%] B — 110 0/0/68/32 65

(14) TABLE-US-00014 TABLE 4 Exemplification of the intermolecular version of the reaction Ratio GC (starting/reduction/ Alkylation Product akylation/dialkylation) yield [%] 18/0/34/48/ ou 0/18/34/48 10 48/0/34/19 26 0/0/54/46 35 51/0/29/20 19
Alkylation Reactions of Imines (Conditions A)

(15) In the glove box, catalyst A (0.05 eq.), trimethylamine oxide (0.05 eq.), previously distilled and degassed ethanol (0.05 M) were introduced into a tube equipped with a magnetic stirrer. The reaction mixture was stirred at room temperature for 30 minutes. The substrate (50 mg, 1 eq.) was then added, the tube was sealed with a Teflon plug and removed from the glovebox. Thereafter, the reaction tube is immersed in a bath preheated to 110° C. and stirred for 24 hours. After returning to ambient temperature, the reaction is stopped by adding methanol (1 ml) and sodium hydroxide (1 ml, 1 M). The organic phases are extracted with 3×5 ml of diethyl ether, washed with a saturated solution of sodium chloride (5 ml), then dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel column (12 g SiO.sub.2 already treated with 5% triethylamine, cyclohexane/ethyl acetate, 95/5) to obtain the desired alkyl amine.

(16) Alkylation Reactions of Imines (Conditions B)

(17) In a catalyst tube (10 ml), equipped with a magnetic stirrer, the substrate (50 mg, 1 eq.), the catalyst B (0.05 eq.) and ethanol previously distilled and degassed (0.05 M) are introduced. The tube was placed under argon and then sealed with a Teflon stopper. Thereafter, the reaction tube is immersed in a bath preheated to 110° C. and stirred for 24 hours. After returning to ambient temperature, the reaction is stopped by adding methanol (1 ml) and sodium hydroxide (1 ml, 1 M). The organic phases were extracted with 3×5 ml of diethyl ether, washed with a saturated solution of sodium chloride (5 ml), then dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel column (12 g SiO.sub.2 already treated with 5% triethylamine, cyclohexane/ethyl acetate, 95/5) to obtain the desired alkyl amine.