August 1998
SYNLETT
875
Isomerization of meso Diamines into their C Symmetrical d,l Isomers
2
Alexandre Alexakis*, Isabelle Aujard, Pierre Mangeney
Department of Organic Chemistry, Université P. et M. Curie, T44-45, case 183, 4 place Jussieu, Paris 75005, France
Fax (int.) 33 1 44 27 75 67; e-mail alexakis@moka.ccr.jussieu.fr
Received 7 May 1998
Abstract : An efficient isomerization method is disclosed which allows
We therefore formed the bis lithium amide of the meso diamine 2a’,
with 2 equiv. n-BuLi, in THF, and we added a catalytic amount (10%) of
naphthalene/Li, in order to be under the same experimental conditions
stated in Scheme 2. After 1h at room temperature, all the meso diamine
was isomerized into the d,l one 2a, in quantitative yield. It should be
pointed out that the bis-amide is required ; the corresponding aminal of
formaldehyde does not isomerize, even with one full equiv. of
naphthalene/Li.
the obtention of the useful d,l isomers of C symmetrical diamines,
2
starting from their meso isomer.
In the preceding article, we described an efficient and practical method
for the synthesis of C symmetrical diamines through reductive coupling
2
of imines by the combination Zn/TMSCl. Despite the formation of a 1/1
ratio of the d,l and meso diastereomers, we used this technique for the
synthesis of large amounts of d,l N,N'-dimethyl-1,2-diphenylethane-1,2-
diamine. Thus, we accumulated a large amount of meso diamine and
investigated ways to isomerize it into the useful d,l isomers.
To improve the isomerization and to avoid the large volumes of solvent
generated by 1.6 M commercial n-BuLi solutions, we used another way
3
4
to form the bis amide. According to Gaudemar and Reetz, lithium
amides may be formed with 1 atom equivalent of Li and 0.5 equivalent
5
of an electron acceptor such as styrene or even isoprene, which also
acts as proton acceptor. Accordingly, our optimized procedure is the
following one:
Scheme 3
Several solvents were also tried, but THF was the best one in our hands.
It should be pointed out that the reduction product 3 is also formed in
slight amounts. However, its amount increases as the reaction time is
prolonged, and after 12h only 3 is obtained. If Li is replaced by Na, the
isomerization process is much faster and only the reduction product was
produced. It is probable that the radical anion postulated in Scheme 2, or
the dianion formed by further reduction, is slowly protonated by the
solvent. Therefore, the isomerization reaction should be carefully
monitored to avoid larger amounts of reduction product.
Scheme 1
Despite our efforts using anionic (by analogy to the isomerization of
1,2-diphenylethanediol), cationic, radical or photochemical ways, we
1
could not observe any significant amount of isomerization. However,
during our attempts to disclose new coupling methods, we observed that
naphthalene/Li or naphthalene/Na gave rise to exclusively the d,l isomer
(see Scheme 1), albeit in very low yield, due to the large formation of
reduction product. In addition, the reaction was not complete. This
result may be explained by Smith's hypothesis of a reversible formation
An interesting question is which driving force is responsible for the
reaction to occur. To address this point, we submitted anoptically pure
sample of diamine 2 to the standard isomerization conditions. After 1h,
a small amount of reduction product appeared (<5%) and the starting
diamine was recovered in, still, 50% ee. This result means that the rate
of isomerization of the d,l diamine is much slower than that of the meso
one, thus allowing the accumulation of the d,l isomer in the reaction
mixture.
2
of the bis-amide from the radical anion (see Scheme 2).
The isomerization reaction may be conveniently performed directly on
the crude mixture(d,l/meso 1/1) obtained from the coupling reaction
described in the preceding article. Thus, the combination of these two
reactions allows a very efficient synthesis of the useful d,l diamines. A
generalization of this process to other diamines is shown in the Table,
according to the following Scheme :
Scheme 2
Scheme 4