Narcissus and Daffodil

318 V.N. Bulavka and O.N. Tolkachev
of 53% (±)-1 and 31% (±)-4. The total yield of (±)-1 according to this scheme was
7.5%, which exceeded by 3.5 times the results published in the work of Kametani
et al. (1969a,b). Taking into account that isovanilline (18) is usually obtained from
veratric aldehyde (38) in 61% yield (100% conversion) (Brossi et al., 1967), in this
scheme Szewczyk et al. (1988, 1995) used all commercially available compounds.
The synthesis seems to be simple in realisation on a preparative scale, but its basic
deficiency is the use of the inflammable LiAlH4 .
Galanthamine synthesis developed by the Russian group
A comparative analysis of the known approaches to galanthamine synthesis has
revealed the best route to the production of the key compound containing the
carbonyl moiety as the formamido group, shown in Figure 12.11. The failing of
the majority of known methods is the low yields obtained. The present authors
have used the following strategy in a large-scale approach to its synthesis: the
use of cheap and commercially available materials, a minimum number of steps,
and the use of synthones with unsubstituted hydroxy groups. We have proposed
the synthesis of (±)-1 from 4-hydroxyphenethylamine (17), or its O-alkyl derivatives,
and 2-bromo-5-hydroxy-4-methoxy-benzaldehyde (39) (Bulavka, 1993;
Bulavka et al., 1990, 1991, 1993, 1994a,b,c, 1999; Bulavka and Tolkachev, 1995)
(Figure 12.12).
The known methods of parent compound production were modified. Thus,
4-hydroxy- and 4-alkoxyphenethylamines (86, R = H, Me, Et, Pr, PhCH 2 ) were
obtained from the corresponding 4-substituted benzaldehydes (84) via substituted
2′-nitrostyrenes (85) through zinc dust reduction in diluted hydrochloric acid or
in a mixture of hydrochloric and acetic acids. The method was optimised to produce
the expected 4-hydroxy- and 4-alkoxyphenethylamines in 80–98% yields in
one operation (Bulavka et al., 1993, 1994a,c), higher yields than in earlier published
methods. Primary amines 86 afforded formamides 87 (90–95%) with formic
acid. 87 (R = Me) was reduced to N-methylated amine 91 with NaBH 4 – acetic acid
(74%) and alternatively with zinc dust and sulphuric acid in tetrahydrofouran
(67%) (Bulavka, 1993; Bulavka et al., 1994c). The alternative method of N-methyl-
4-methoxyphenethylamine and N-methyl-4-hydroxyphenethylamine production
starting from 4-methoxyacetophenone (88) via N-methyl-4-methoxyphenylthioacetamide
(89) was also studied. The Willgerodt-Kindler reaction of 88 and
MeNH 2 (160–170 °C in ampoules) gave a complex mixture of products, from
which 89 (10.4%) was isolated together with the by-product N-methyl-4-methoxyphenylacetamide
(21.9%). The method was modified as follows: interaction of
4-methoxyacetophenone (88) with methylamine in the presence of dehydrating
agents gave the expected Schiff base 90 in 77% yield, which was then transformed
to desired thioamide 89 in 21.5% yield. The reaction of 88 with methylamine
hydrochloride and sulphur in dimethylformamide (100 °C, sodium acetate, or 60–
70 °C, 4-toluenesulfonic acid – Et 3 N) gave 89 in 57–58% yields. The reaction of 88
with MeNHCHO and sulphur (170–180 °C) afforded the expected 89 in 30–35%
yield. Subsequent reduction of 89 with zinc dust and hydrochloric acid afforded
N-methyl-4-methoxyphenethylamine (91) (91%), which was demethylated with
hydrochloric acid at 170 °C to N-methyl-4-hydroxyphenethylamine (92) (98%)
(Bulavka, 1993; Bulavka et al., 1999).