C-C linkage by replacement of hydroxyl by carbon 957These ring-closures often occur in excellent yield; they are included in the
book cited above.
6973General experimental details are as follows.
69713It is usual first to mix the
carbonyl component with the amine, which is presented as, e.g., hydrochloride
or acetate. An appropriate hydrogen ion concentration must be maintained.
For the preparation of aminoalkyl compounds that are liable to hydrolysis it
is recommended that the water produced be removed by a drying agent or
by azeotropic distillation. Dioxan is a suitable solvent, but it is often recom-
mended that acetic acid be added to it. Ketones react better in alcohol with
paraformaldehyde. Copper chloride or iron chloride is said to be a useful
addition in reactions of acetylenes. Reactions of amines, phenols, and furans,
even under mild conditions, may be accompanied by multiple condensation
or resinification. 4-Hydroxybenzylamine is reported
706to be obtained in 92%
yield when ammonia is led into a mixture of phenol and formaldehyde.
Two detailed examples must suffice.
3-(Dimethylamino)propiophenone hydrochloride:^715 Acetophenone (60 g, 58.5 ml, 0.5mole),
dimethylammonium chloride (52.7 g, 0.65 mole), and paraformaldehyde (19.8 g, 0.66 mole)
are placed in a round-bottomed flask (capacity 500 ml). A mixture of concentrated hydro-
chloric acid (t/1.19; 1 ml) and 95% ethanol (80 ml) is added and the whole is boiled under
reflux for 2 h. If the yellowish solution produced is turbid it is filtered through a heated filter
and, whilst still hot, diluted with acetone (400 ml). The solution is allowed to cool slowly to
room temperature and placed in a refrigerator overnight. The crystals formed are filtered
off, washed with acetone (25 ml), and dried for 2.5 h at 40-50°; this crude product is obtained
in 68-72% yield (72-77 g) and melts at 138-141°. It is somewhat hygroscopic and if dried
for a further 4 h melts at 152-153°. It can be recrystallized by dissolution in 95% ethanol
(85-90 ml) and slow addition of acetone (450 ml); recovery is then about 90%, the m.p.
being 155-156°.
2,4,6-Tris[(dimethylamino)methyl]phenol:^716 A mixture of phenol (94 g, 1 mole) with
25 % aqueous dimethylamine solution (720 g, 4 moles) is cooled to 20° in a three-necked
flask (capacity 21) fitted with a stirrer, thermometer, and dropping funnel. 30 % Aqueous
formaldehyde solution (350 g) is dropped in with stirring, at a rate such that the temperature
remains at 25-30° (about 0.5 h). Stirring is then continued for a further hour at that temper-
ature, after which the dropping funnel is replaced by a reflux condenser and the mixture is
heated, still with stirring, for 2 h on a water-bath. Sodium chloride (200 g) is then added
to the hot solution, and heating and stirring are continued for about 20 min. The organic
layer is separated from the hot solution, transferred to a Claisen flask (capacity 500 ml), and
distilled in a vacuum, the fraction boiling at 130-150c/l-2mm (228 g, 86%) being collected.
Its pale red color can be removed by a second distillation (b.p. 13O-135°/l mm).
In some cases, e.g., if water is to be excluded, it is advisable to use the very
reactive O,N- or iV,iV-acetals.
717This method makes it possible to use car-
bonyl compounds that do not otherwise undergo the Mannich reaction. (For
examples of the reaction with JV,iV-acetals see page 973.)
RH + NR/
2 CHR"NR/
2 > CHRR"NR' 2 + NHR' 2RH + R/OCHR"NR/ 2 > CHRR"NR' 2 + R'OHRH + HOCH 2 NR/COCH 3 > CH 2 RNR/COCH 3 + H 2 O(^715) C. E. Maxwell, Org. Syn., 23,30 (1943).
(^716) G. F. Grillot and W. T. Gormley, Jr., /. Amer. Chem. Soc, 67, 1968 (1945); H. A.
Bruson and C. W. McMullen, /. Amer. Chem. Soc, 63, 270 (1941).
(^717) H. Bohme, H. J. Bohn, E. Kohler, and J. Roehr, Ann. Chem., 664, 130 (1963).