Organic Syntheses, Vol. 76, 23
[1,2-Ethanediamine, N,N'-dimethyl-1,2-diphenyl-, [R-(R,R)]- and [S-(R,R)-]]
Submitted by Alex Alexakis, Isabelle Aujard, Tonis Kanger, and Pierre Mangeney
1.
Checked by Nabi Magomedov and David J. Hart.
1. Procedure
A.
N-Methylbenzimine. Under a
well-ventilated hood, a
250-mL Erlenmeyer flask is equipped with a magnetic stirrer and charged with an aqueous solution
(40% w/w, 100 mL) of methylamine. Freshly distilled
benzaldehyde (26.5 g, 0.25 mol) is added to the stirred solution of
methylamine at room temperature. A mildly exothermic reaction occurs resulting in a milky white emulsion. The Erlenmeyer flask is stoppered and the mixture is stirred overnight (15 hr). The milky emulsion is transferred to a
separatory funnel,
diethyl ether (200 mL) is added, and the organic phase is separated and dried over
potassium carbonate (K2CO3). The solids are removed by filtration, washed with
ether (50 mL), and the combined filtrate and washings are concentrated on a
rotary evaporator. The residue is distilled through a
10-cm Vigreux column using a
water aspirator to give
28.3 g (
95%) of imine as a water white liquid (bp
99-100°C/25 mm) (Note
1).
B.
meso- and dl-N,N'-Dimethyl-1,2-diphenylethylenediamine. A
flame-dried, three-necked, round-bottomed flask (500 mL) is equipped with a mechanical or magnetic stirrer, a thermometer, water condenser connected to a nitrogen inlet, and a septum, and then charged with
zinc (Zn) powder (13.1 g, 0.2 mol) and
anhydrous acetonitrile (50 mL) under an atmosphere of
nitrogen (Note
2). The
zinc powder is activated by the addition of
1,2-dibromoethane (1.5 mL, 3.5 g, 0.02 mol) via syringe followed by warming the mixture at reflux for 1 min and then allowing the mixture to cool to room temperature. A small amount of
chlorotrimethylsilane (Me3SiCl) is added via syringe, whereupon evolution of
ethylene gas is observed (Note
3). The mixture is stirred for 45 min, and then
N-methylbenzimine (23.8 g, 0.2 mol) is added in one portion via syringe, followed by
anhydrous acetonitrile (100 mL). The septum is replaced with an
addition funnel (100 mL), and
chlorotrimethylsilane (Note 4) (32.5 g, 38 mL, 0.3 mol) is slowly added (30 min) at a rate that maintains the internal temperature below 30°C. The reaction mixture is stirred for 2 hr and then cooled to 0°C with an
ice bath. The vigorously stirred mixture is hydrolyzed by
cautiously adding, via the addition funnel, a solution prepared by mixing concentrated
aqueous ammonium hydroxide (60 mL) with saturated aqueous ammonium chloride (140 mL). The excess
zinc is removed by filtration at 1 atm, washed with
ether (200 mL), and the residual
zinc is covered with water (Note
5). The organic layer is separated, and the aqueous phase is extracted with
diethyl ether (1 × 200 mL) and
dichloromethane (2 × 200 mL) (Note
6). The combined organic phases are dried over anhydrous K
2CO
3. The salts are removed by filtration, washed with
diethyl ether (50 mL), and the solvent is removed on a rotary evaporator to afford
24.3 g of a semi-solid residue that is used directly in the next reaction (Note
7) and (Note
8).
C. Isomerization of the diamine: dl-N,N'-Dimethyl-1,2-diphenylethylene-diamine. A solution of the crude
diamine (24.3 g) in
anhydrous tetrahydrofuran (THF) (200 mL) is placed in a
three-necked, round-bottomed flask equipped with a mechanical or magnetic stirrer, a thermometer, an addition funnel, and a water condenser fitted with a nitrogen inlet. The addition funnel is removed, and small pieces of freshly cut
lithium wire (1.8 g, 0.26 mol) are added in one portion (Note
9).
Isoprene (10.2 g, 15 mL, 0.15 mol) is slowly added from the addition funnel while the solution is stirred vigorously. An exothermic reaction occurs, and the internal temperature is maintained below 40°C with the aid of a
water bath. The
lithium pieces become brilliant and the solution turns dark red. The course of the reaction is carefully monitored by TLC (Note
10) until the meso-diamine is isomerized into the dl-isomer. This takes approximately 1-2 hr. The reaction mixture is then cooled to 0°C, and the excess
lithium metal is removed by gravity filtration through a funnel containing a plug of glass wool. The excess
lithium is stored under oil. The filtrate is cooled in an ice bath and hydrolyzed by slow addition of aqueous
2.5 N hydrochloric acid (HCl, 200 mL). The layers are separated, and the aqueous phase is extracted with
ether (Et2O, 2 × 100 mL). The organic layer is discarded, and the aqueous layer is made basic with aqueous
35% (w/w) sodium hydroxide (50 mL). The aqueous solution is extracted with
Et2O (2 × 200 mL). The
ether extracts are dried over K
2CO
3, the solids are removed by filtration, and the solvent is removed using a rotatory evaporator to give
23.4 g (
95%) of crude dl-diamine as a brown oil (Note
11). Pure dl-diamine is isolated as follows. A
1-L, round-bottomed flask, equipped with a magnetic stirrer and a water condenser, is charged with the above crude diamine,
racemic dl-tartaric acid (14.4 g, 0.096 mol) (Note
12) and absolute
ethanol (700 mL). The heterogeneous mixture is brought to reflux at which point the precipitate is mainly dissolved. After 10 min at reflux, the mixture is left at room temperature for 2-4 hr. The resulting precipitate is collected by suction filtration and rinsed with
ethanol (50 mL). The collected salt is added to a mixture of
aqueous 35% (w/w) sodium hydroxide (60 mL), demineralized water (200 mL) and
Et2O (200 mL). The mixture is stirred for 30 min, the phases are separated and the aqueous layer is extracted with
Et2O (2 × 200 mL). The combined organic phases are dried over K
2CO
3, the salts are removed by filtration and the solvent is removed on a rotatory evaporator to give
12.2 g (
51%) of pure dl-diamine as a colorless oil (Note
13).
D. Resolution of the dl-diamine:
(R,R)-(+)-N,N'-Dimethyl-1,2-diphenylethylenediamine and (S,S)-(−)-N,N'-Dimethyl-1,2-diphenylethylenediamine. A
1-L, round-bottomed flask, equipped with a magnetic stirring bar and a water condenser, is charged with pure
dl-diamine (12 g, 0.05 mol),
natural L-(+)-tartaric acid (7.1 g, 0.05 mol) (Note
14) and
absolute ethanol (350 mL). The heterogeneous mixture is brought to reflux and the precipitate dissolves completely (Note
15). After 30 min the solution is allowed to cool to room temperature and stand overnight (17 hr). The precipitate is collected by filtration and washed with
ethanol (2 × 50 mL). The salt is added to a mixture of aqueous
35% (w/w) NaOH (30 mL), demineralized water (100 mL) and
Et2O (100 mL). The solution is stirred for 30 min, and the phases are separated. The aqueous layer is extracted with
Et2O (2 × 100 mL), and the combined extracts are dried over K
2CO
3. The solids are removed by filtration, and the solvent is removed on a
rotary evaporator to give
5.5 g (
90%) of crude (R,R)-diamine as a white powder, mp
49-50°C (Note
16). The mother liquor is concentrated under reduced pressure, and the residue is stirred with a mixture of
aqueous 35% (w/w) NaOH (30 mL), demineralized water (100 mL) and
Et2O (100 mL). The solution is stirred for 30 min, and the phases are separated. The aqueous layer is extracted with
Et2O (2 × 100 mL), and the combined extracts are dried over K
2CO
3. The solids are removed by filtration, and the solvent is removed on a rotary evaporator to give
6.15 g (
101%) of crude (S,S)-diamine as an oil that solidifies upon drying under reduced pressure, mp
45-48°C (Note
17).
2. Notes
1. Spectral data for the imine follow:
1H NMR (CDCl
3) δ: 3.5 (d, 3 H, J = 1.7), 7.4 (m, 3 H), 7.7 (m, 2 H), 8.2 (q, 1 H, J = 1.7);
13C NMR (CDCl
3) δ: 48.1, 127.9, 128.5, 130.5, 136.4, 162.3.
2.
Zinc powder (325 mesh) was purchased from Aldrich Chemical Company, Inc., or Prolabo.
Anhydrous acetonitrile was purchased directly from Aldrich Chemical Company, Inc., and used without purification.
3. Activation of
zinc is not always needed. For
zinc purchased from Prolabo, the submitters report that the coupling reaction proceeds directly. The checkers note that gas evolution begins upon addition of the
1,2-dibromoethane and increases upon addition of the
chlorotrimethylsilane.
4. Commercial
chlorotrimethylsilane (Janssen Chimica or Aldrich Chemical Company, Inc.) is used without any purification.
5. The excess
zinc is highly reactive and when dry could be exothermically oxidized by air.
6. The meso-diamine is less soluble in Et
2O than the dl-diamine. Therefore,
dichloromethane is used to extract both isomers completely.
7. This crude diamine is a 50/50 mixture of meso- and dl-isomers. The mixture also contains
2-5% of N-methylbenzylamine and small amounts of other unidentified contaminants.
8.
1H NMR analysis of the mixture (CDCl
3) shows the following distinct signals due to the meso-isomer δ: 2.09 (s, 6 H), 3.62 (s, 2 H); the dl-isomer δ: 2.25 (s, 6 H), 3.53 (s, 2 H); and N-methylbenzylamine δ: 2.45 (s, 3 H), 3.75 (s, 2 H).
9. The submitters indicate that the isomerization rate is faster when
lithium containing
0.5-1.0% sodium is used.
10. An aliquot of approximately 0.5 mL is withdrawn from the reaction using a
Pasteur pipette and mixed with an equal volume of
aqueous saturated ammonium chloride (NH4Cl). Approximately
0.5 mL of ethyl acetate is added followed by brief mixing and withdrawal of the upper organic layer via pipette. TLC analysis of this sample is performed over
silica gel using
diethyl ether-triethylamine (95:5) as the eluant with a UV lamp for visualization. The R
f values of the dl-diamine and meso-diamine are 0.8 and 0.6, respectively. Close monitoring of the reaction is important as reduction of the diamine to afford
N-methylbenzylamine (R
f = 0.35) can occur. The reaction can also be monitored by
1H NMR analysis of the aforementioned aliquot after drying and concentration under reduced pressure.
11. This material is a mixture of dl-diamine:meso-diamine:
N-methylbenzylamine (approximately 82.6:4.4:13.0) as shown by
1H NMR (see (Note
8)).
12. Any commercial source of
dl-tartaric acid works well. The ratio of
tartaric acid to diamine is 1:1. The checkers found that if isomerization of the meso-diamine is incomplete, this purification procedure provides a mixture of meso- and dl-diamines.
13. Spectral data for the dl-diamine follow:
1H NMR (CDCl
3) δ: 1.95 (b s, 2 H), 2.25 (s, 6 H), 3.53 (s, 2 H), 7.05 (m, 4 H), 7.15 (m, 6 H);
13C NMR (CDCl
3) δ: 34.7, 71.4, 127.0, 128.0, 128.1, 141.2.
15. The shape of the precipitate becomes lighter and finer until total dissolution. Total dissolution is achieved only with absolute
ethanol. With
95% grade ethanol the fine precipitate does not dissolve completely, but the resolution proceeds equally well.
16. The crude (R,R)-diamine has
[α]D +19.2 (CHCl
3,
c 0.01) and an enantiomeric excess of >99%. Recrystallization of a 1.0-g sample from
pentane at 0°C gave
0.66-0.72 g of (R,R)-diamine with mp
50-51°C; [α]D +20.0 (CHCl
3,
c 0.01) and an enantiomeric excess of >99%. The enantiomeric excess was measured as follows:
2 Into a dry NMR tube under
nitrogen is placed a solution of the
(r.htm,R)-diamine (32 mg, 0.13 mol) in
0.8 mL of dry deuterochloroform (CDCl3). To this solution are added dry
N,N-diethylaniline (80 μL) and a solution of freshly distilled
phosphorus trichloride (PCl3, 50 μL of a 3.2 M solution in
dry CDCl3, 0.16 mmol). The solution is shaken vigorously.
31P NMR analysis indicates the formation of a "P-Cl" species at δ 176.2. Enantiomerically pure
l-menthol (25 mg, 0.16 mmol) is dissolved in 0.8 mL of dry CDCl3, and the resulting solution is added to the NMR tube under
nitrogen. The tube is shaken, and
31P NMR analysis indicates the formation of only one "P-OR" species at δ 143.5. The diastereomeric "P-OR" species derived from the (S,S)-diamine appears at δ 141.2. If the sample is contaminated with meso-diamine, the signal for the corresponding "P-OR" species appears at δ 138.9. Depending on the quality of reagents, some additional peaks may appear in the spectrum, but they do not interfere with the measurement of % ee.
17. The crude (S,S)-diamine has
[α]D −17.1 (CHCl
3,
c 0.01) and an enantiomeric excess of approximately 96% using the method described above. Recrystallization of a 1.0-g sample from
pentane at 0°C gave
0.71 g of (S,S)-diamine with mp
49.5-50.5°C,
[α]D −19.7 (CHCl
3,
c 0.01) and an enantiomeric excess of >99% using the method described above. A second recrystallization of this material gave
0.5 g of material with little change in physical properties: mp
50-50.5°C,
[α]D −20.0 (CHCl
3,
c 0.01).
Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
There are a few reports on the synthesis of
N,N'-dimethyl-1,2-diphenylethylenediamine by pinacol couplings
3,4,5,6,7,8 or by N-methylation of the primary diamine.
9,10 Pinacol type couplings of imines have been reported for the synthesis of other C
2 symmetrical N-substituted or unsubstituted 1,2-diarylethylenediamines using various reducing metals in different solvents.
11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30 However, the present synthesis of
N,N'-dimethyl-1,2-diphenylethylenediamine is the most suitable for large scale preparation. There are no expensive or hazardous starting materials, and the procedure does not require tedious filtrations or chromatographic separation of diastereomers.
N,N'-Dimethyl-1,2-diphenylethylenediamine and related chiral diamines are not only useful chiral auxiliaries in asymmetric synthesis, but they have also found applications as analytical reagents. They allow the resolution and the determination of enantiomeric composition of aldehydes by formation of diastereomeric aminals.
31,32,33,34 Combined with PCl
3, they allow determination of the enantiomeric composition of alcohols, biphenols, thiols and amines.
35,36 The diamine described here is used most extensively.
Formation of aminals (the
nitrogen equivalent of acetals) is a very easy process and occurs without any catalyst and at room temperature. The chiral imidazolidine ring thus formed is a powerful stereodifferentiating group, acting either by steric effects or through chelation control. Aminals also serve as efficient protective groups of aldehyde functionality, allowing the easy recovery of this functionality without epimerization, even in the α-position. Several applications of this concept are summarized in Scheme 1.
37,38,39,40,41,42,43,44,45,46,47,48,49,50,51
The present method, with additional examples, was recently published.
52,53
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
(R,R)-N,N'-Dimethyl-1,2-diphenylethylene-1,2-diamine: 1,2-Ethanediamine, N,N'-dimethyl-1,2-diphenyl-, [R-(R,R)]- (12); (118628-68-5)
(S,S)-N,N'-Dimethyl-1,2-diphenylethylene-1,2-diamine: 1,2-Ethanediamine, N,N'-dimethyl-1,2-diphenyl-, [S-(R,R)]- (10); (70749-06-3)
N-Methylbenzimine: Methylamine, N-benzylidene- (8); Methanamine, N-(phenylmethylene)- (9); (622-29-7)
Methylamine (8); Methanamine (9): (74-89-5)
Benzaldehyde (8,9); (100-52-7)
meso-N,N'-Dimethyl-1,2-diphenylethylenediamine: 1,2-Ethanediamine, N',N'-dimethyl-1,2-diphenyl-, (R,S)- (9); (60509-62-8)
meso-N,N'-Dimethyl-1,2-diphenylethylenediamine: 1,2-Ethanediamine, N,N'-dimethyl-1,2-diphenyl-, (R,S)- (9); (60508-97-6)
Zinc (8,9); (7440-66-6)
Acetonitrile: TOXIC: (8,9); (75-05-8)
1,2-Dibromoethane: Ethane, 1,2-dibromo- (8,9); (106-93-4)
Chlorotrimethylsilane: Silane, chlorotrimethyl- (8,9); (75-77-4)
Ethylene (8); Ethene (9); (74-85-1)
Lithium (8,9); (7439-93-2)
Isoprene (8); 1,3-Butadiene, 2-methyl- (9); (78-79-5)
DL-Tartaric acid: Tartaric acid, DL- (8); Butanedioic acid, 2,3-dihydroxy-, (R,R)-(±)- (9); (133-37-9)
L-Tartaric acid: Tartaric acid, L- (8); Butanedioic acid, 2,3-dihydroxy-, [R-(R,R)]- (9); (87-69-4)
N-Methylbenzylamine: Aldrich: See: Benzylmethylamine: Benzylamine, N-methyl- (8); Benzenemethanamine, N-methyl- (9); (103-67-3)
N,N-Diethylaniline: Aniline, N,N-diethyl- (8); Benzeneamine, N,N-diethyl- (9); (91-66-7)
Phosphorus trichloride (8,9); (7719-12-2)
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