Org. Synth. 1973, 53, 56
DOI: 10.15227/orgsyn.053.0056
DIRECTED LITHIATION OF AROMATIC COMPOUNDS: (2-DIMETHYLAMINO-5-METHYLPHENYL)DIPHENYLCARBINOL
[Benzenemethanol, 2-(dimethylamino)-5-methyl-α,α-diphenyl-]
Submitted by J. V. Hay and T. M. Harris
1.
Checked by Robert A. Auerbach and Herbert O. House.
1. Procedure
A dry, 500-ml., two-necked flask containing 6.75 g. (0.0500 mole) of N,N-dimethyl-p-toluidine (Note 1) and 175 ml. of anhydrous hexane (Note 2) is fitted with a Teflon-coated magnetic stirring bar, a pressure-equalizing dropping funnel capped with a rubber septum, and a nitrogen inlet tube. The reaction vessel is flushed with nitrogen, and a static nitrogen atmosphere is maintained within the apparatus for the remainder of the reaction sequence. A solution of 8.8 g. (0.076 mole of N,N,N',N'-tetramethylethylenediamine (Note 3) in 40 ml. of anhydrous hexane is added to the dropping funnel, followed by a hexane solution containing 0.076 mole of n-butyllithium (Note 4). The resulting solution, which becomes warm as the organolithium-diamine complex forms, is allowed to stand for 15 minutes, then added to the reaction mixture, dropwise and with stirring over 15–20 minutes. The resulting bright yellow, turbid reaction mixture is stirred at room temperature for 4 hours longer before a solution of 13.8 g. (0.0758 mole) of benzophenone (Note 5) in 40 ml. of anhydrous diethyl ether is added to the reaction mixture, dropwise and with stirring over 20 minutes. The resulting, deep-green solution is stirred for an additional 20 minutes, then poured into a vigorously stirred solution of 12 g. (0.20 mole) of acetic acid in 30 ml. of ether (Note 6). After the reaction solution has been successively extracted with 50 ml. of water and four 50-ml. portions of 5% hydrochloric acid, the aqueous extracts are combined (Note 7) and made basic with aqueous 10% sodium hydroxide. The alkaline mixture is heated to boiling and maintained at this temperature until the escaping vapor is no longer basic to moistened pHydrion paper (Note 8). The mixture is then cooled, and the white solid product which separates is collected on a Büchner funnel and washed with three 20-ml. portions of water. The crude product (m.p. 142–168°) is recrystallized from 250 ml. of 3 : 1 (v/v) hexane-ethyl acetate, giving 6.6–8.2 g. of the amino alcohol product as colorless prisms, m.p. 168–171°. Concentration of the mother liquors gives an additional 0.8–1.2 g. of product, m.p. 167–169°, for a total yield of 7.8–9.0 g. (49–57%). Although the product is sufficiently pure for most purposes, a second recrystallization from hexane-ethyl acetate raises the melting point to 169.5–172° (Note 9).
2. Notes
1.
Commercial
N,N-dimethyl-p-toluidine, obtained from Aldrich Chemical Company, Inc., was used without purification.
2.
An
A.C.S. grade of hexane, obtained from Fisher Scientific Company, was used without further purification.
3.
N,N,N',N'-Tetramethylethylenediamine, purchased from Aldrich Chemical Company, Inc., was distilled from
calcium hydride immediately before use; b.p.
120–122°.
4.
Hexane solutions of n-butyllithium, purchased from either Alfa Inorganics, Inc., or Foote Mineral Company, were standardized by the titration procedure of Watson and Eastham.
2 A detailed procedure for this titration is provided in
Org. Synth., Coll. Vol. 6, 121 (1988).
5.
Benzophenone, purchased from Fisher Scientific Company, was used without purification.
6.
Reversal of this hydrolysis procedure, the addition of
acetic acid to the reaction mixture, had an adverse effect on the yield of product.
7.
Some of the aqueous extracts may contain small amounts of suspended particulate matter.
8.
This simple steam distillation removes the unchanged
N,N-dimethyl-p-toluidine present in the crude product.
9.
The purified product has the following spectral properties: IR (CCl
4) 3050 cm.
−1 (associated OH); UV (95% C
2H
5OH) max (ε) 251 (905), 258 (823), 264 (720), and 275 nm (432); NMR (CDCl
3), δ 2.19 (s, 3H, C-C
H3), 2.38 [s, 6H, N(C
H3)
2] 6.55 (s, 1H, O
H), and 7.00–7.50 (m, 13H, aromatic C
H);
m/e (rel. int.), 317(
M+, 100), 240(84), 225(28), 224(91), 222(43), 150(25), 134(41), 120(32), 105(41), 91(51), and 77(42).
3. Discussion
This procedure is an adaptation of one described by Hauser and co-workers.
3 The product has also been prepared from
2-bromo-N,N-dimethyl-p-toluidine by halogen-metal interchange with
n-butyllithium followed by condensation with
benzophenone,
3 a procedure less convenient than that presently described.
Tertiary amines such as
N,N,N',N'-
tetramethylethylenediamine (TMEDA) and
1,4-diazabicyclo[2.2.2]octane (DABCO) strongly catalyze metallations by alkyllithium reagents. Uncatalyzed lithiation of
toluene is very poor,
4 whereas a yield of 90% has been obtained when TMEDA is employed as a catalyst.
5It is noteworthy that metallation of
N,N-dimethyl-p-toluidine takes place at a position
ortho to the dimethylamino group rather than on or
ortho to the aryl methyl group. Apparently, coordination of
lithium by the amino group plays a dominant role in directing metallation even in the presence of TMEDA. Other cases have been reported in which the site of metallation is altered by addition of TMEDA.
6,7
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
hydrochloric acid (7647-01-0)
acetic acid (64-19-7)
ethyl acetate (141-78-6)
ether,
diethyl ether (60-29-7)
sodium hydroxide (1310-73-2)
nitrogen (7727-37-9)
toluene (108-88-3)
Benzophenone (119-61-9)
Benzenemethanol (100-51-6)
lithium (7439-93-2)
n-butyllithium (109-72-8)
hexane (110-54-3)
calcium hydride (7789-78-8)
1,4-diazabicyclo[2.2.2]octane (280-57-9)
(2-Dimethylamino-5-methylphenyl)diphenylcarbinol (23667-05-2)
tetramethylethylenediamine (20485-44-3)
N,N,N',N'-tetramethylethylenediamine (110-18-9)
N,N-dimethyl-p-toluidine (99-97-8)
2-bromo-N,N-dimethyl-p-toluidine
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