Organic Syntheses, Vol. 76, 133
Checked by Sam Derrer and Andrew B. Holmes.
1. Procedure
A.
2-(3,4-Dimethoxyphenyl)-N,N-dimethylacetamidine. An
oven-dried, 250-mL, single-necked, round-bottomed flask containing a 3-cm magnetic stirring bar is charged with
7.96 g (0.045 mol) of (3,4-dimethoxyphenyl)acetonitrile (Note
1) and
4.95 g (0.050 mol) of copper(I) chloride (Note
2), fitted with a septum, flushed with
argon, and maintained under a static pressure of
argon using a
gas bubbler. Using a
20-mL gas-tight syringe,
45 mL (0.067 mol) of a 1.5 M ethanolic solution of dimethylamine (Note
3) is added successively in three 15-mL portions at room temperature with vigorous stirring. The heterogeneous pale brown mixture is then heated at 70°C for 24 hr, during which time it becomes brown-red. The mixture is cooled to room temperature and poured with vigorous stirring into a
250-mL Erlenmeyer flask containing
70 mL of aqueous 30% sodium hydroxide and
100 mL of diethyl ether (Note
4); the mixture was stirred vigorously for 3 min. The organic layer is separated, and the aqueous layer is extracted with three
75-mL portions of diethyl ether (Note
5). The combined organic extracts are dried over
sodium sulfate and filtered through a
sintered glass funnel layered with 2 cm of Celite. The solid residue is washed with
diethyl ether (20 mL). The combined filtrate and washings are concentrated by rotary evaporation followed by drying under reduced pressure (0.1 mm) for 1.5 hr to provide
9.1-9.4 g (
93-96% yield) of a dark brown oil (Note
6),(Note
7). The compound is stored under
argon at −18°C until used in step B.
2. Notes
2.
Copper(I) chloride was obtained as a light green powder from Aldrich Chemical Company, Inc. (ref. Aldrich 21,294-6). The submitters obtained material with the same catalog number as sticks, which were carefully ground immediately before use.
3. The 1.5 M solution of
dimethylamine in
ethanol was prepared as follows:
Aqueous 40% dimethylamine is heated at 65°C under a flow of
argon. The gas is passed through
potassium hydroxide pellets and blown across a known quantity
(100 mL) of absolute ethanol (analytical grade used without purification), then cooled to 0°C in an
ice bath, with continuous stirring, for 3 hr. The ethanolic solution is weighed and diluted to 150 mL with absolute alcohol. The ethanolic
dimethylamine solution (ca. 1.5 M) is carefully capped and kept under an inert atmosphere at −18°C. The concentration may be measured by pouring a
1-mL aliquot of the ethanolic dimethylamine solution into
aqueous 1 N hydrogen chloride. Water and
ethanol are removed by rotary evaporation, and the residue is dried over
potassium hydroxide pellets under vacuum (0.3 mbar, 2.5 mm) for one night. The weight of residue allows the exact concentration of the ethanolic
dimethylamine solution to be measured.
With other less volatile amines (see Table I), the mixture of Cu(I)Cl, nitrile, and amine is simply refluxed in
ethanol. In such a case, 1.1 equiv only of amine can be used.
4.
Reagent grade diethyl ether may be used without further purification.
5. The phases were separated with difficulty because of the presence of copper salts. Some product adheres to the flask and separatory funnel.
6. The submitters carried out the drying at 0.3 mbar (2.5 mm) (1 hr) and reported
98% yield. Under these conditions the checkers observed residual
ethanol (δ 1.13, t, 3 H J = 7; 3.58, q, 2 H, J = 7) in the
1H NMR spectrum of the product. Most of the
ethanol was removed after drying for the longer time at higher vacuum.
7. The product exhibits the following spectral properties : IR (film) ν cm
−1: 3380 (ν
N-H), 1590 (ν
C=N);
1H NMR (300 MHz, CDCl
3) δ: 2.96 (s, 6 H, N-CH
3), 3.59 (s, 2 H), 3.84 (s, 3 H, 4-OCH
3), 3.87 (s, 3 H, 3-OCH
3), 5.50 (br s, 1 H, NH), 6.78-6.87 (m, 3 H);
13C NMR (75 MHz, CDCl
3) δ: 37.8 (2 × CH
3), 40.9 (CH
2), 55.7 (2 × CH
3), 111.2 (CH), 112.3 (CH), 121.6 (CH), 127.8 (Cq), 147.9 (Cq), 148.9 (Cq), 167.2 (Cq); Mass (EI) m/z 222 (M
+•, 75%), 207 (50%), 177 (45%), 152 (50%), 151 (50%), 71 (100%). HRMS Calcd. for C
12H
18N
2O
2: 222.136826. Found: 222.136823. The level of
ethanol contamination still remaining was evident from the elemental analysis: Calcd. for C
12H
18N
2O
2: C, 64.8; H, 8.2; N, 12.6. Found: C, 63.75; H, 8.2; N, 12.0 %.
9.
Sodium borohydride was obtained from Aldrich Chemical Company, Inc. and used without further purification.
10. The product exhibits the following spectral properties, in agreement with literature data:
3 IR (film) ν cm
−1: 2810 (ν
N-Me), 2750 (ν
N-Me);
1H NMR (300 MHz, CDCl
3) δ: 2.28 (s, 6 H, N-CH
3), 2.46-2.58 (m, 2 H, Ar-CH
2), 2.70-2.82 (m, 2 H, N-CH
2), 3.85 (s, 3 H, 4-OCH
3), 3.89 (s, 3 H, 3-OCH
3), 6.72-6.82 (m, 3 H);
13C NMR (75 MHz, CDCl
3) δ: 34.0 (CH
2), 45.5 (2 × CH
3), 55.8 (CH
3), 55.9 (CH
3), 61.7 (CH
2), 111.3 (CH), 111.9 (CH), 120.5 (CH), 133.0 (Cq), 147.3 (Cq), 148.8 (Cq); Mass (EI) m/z 209 (M
+•, 6%), 151 (8%), 58 (100%). HRMS. Calcd. for C
12H
19NO
2: 209.1417. Found: 209.1419. The checkers could not obtain satisfactory elemental analyses. The freshly prepared sample was >95% pure as shown by NMR. Further distillation (through a 5''-Vigreux column or Kugelrohr apparatus) afforded material, bp
96-98°C/0.1 mm, of >98% purity [Hewlett-Packard 5890 series II GC, capillary column SGE 25QC3BP5-0.5, 5%
phenylpolysiloxane, temperature gradient 100°C (1 min), 20°C/min, 250°C (5 min)] with 85% mass recovery. After 3 months storage the purity of material dropped to ca. 90%. The hydrochloride has mp
195-196°C (submitters reported
197°C) (from
ethanol/
diethyl ether) (lit.,
3 196-197°C).
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academic Press; Washington, DC, 1995.
3. Discussion
The procedure described above illustrates a general, two-step method for the preparation of secondary or tertiary amines. It can be considered as a reductive N-alkylation of a nitrile or an N-monoalkylation of a primary or secondary amine. The first step in the procedure involves direct addition of an aliphatic amine to a nitrile promoted by a stoichiometric amount of
cuprous chloride, as fully described recently.
4 This method may be used with a large variety of nitriles and primary or secondary aliphatic amines. The nitrile itself may be used as solvent (
acetonitrile, benzonitrile). In the case of a primary amine, substrate stoichiometry must be adapted to obtain selectively either the N-monosubstituted amidine [1 eq amine, 1.2 eq Cu(I)Cl in
acetonitrile] or the N,N-disubstituted amidine [4 eq amine, 1 eq Cu(I)Cl, 1 eq
acetonitrile in alcohol or DMSO].
4
As summarized in Table I, this strategy is applicable to the synthesis of many secondary or tertiary amines. It must, however, be noted that some arylamines are not sufficiently nucleophilic to be used in this synthesis. For example, anilines do not react under these conditions, although
2-aminopyridine does. The functionality in some amines is incompatible with
copper; thus those amines that chelate with
copper do not react with nitriles.
Compared with these methods, the reductive N-alkylation of nitriles is much more efficient and practical. The starting materials and reagents are cheaper, and only two steps are involved that proceed in a higher overall yield. Reductive N-alkylation affords, without any chromatographic separation, a product of high purity.
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