Kinetic resolution of heterocyclic amines
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
1255
takes place to give a tetrahedral intermediate whose poꢀ
larity is higher than that of the initial molecule, i.e., acylaꢀ
tion occurs with charge separation. In more polar solꢀ
vents, it proceeds via relatively loose transition states in
which the steric requirements are less stringent, which
results in leveling out of the acylation rates of the enanꢀ
tiomers.
tion and in the reaction with the acylammonium salt),
each being characterized by its own diastereodifferenꢀ
tiation pattern.
Our studies showed that the efficiency of kinetic resoꢀ
lution of compound 1a can be somewhat increased comꢀ
pared to that observed under conditions employed previꢀ
1
ꢁ21ꢀ
ously
by using Nꢀmethylmorpholine for chloride ꢀ
The influence of the structure and properties of the
tertiary amine on the diastereoselectivity of acylation of
amine 1a with chlorides ꢀ and ꢂ is most pronounced when
the reaction is carried out in benzene (see Table 1). The
highest diastereoselectivity was found in the presence of
aliphatic amines, Nꢀmethylmorpholine (in the case of
and Et N for chloride ꢂ and with benzene as the solvent.
3
Experimental
1H NMR spectra were recorded on a Bruker DRXꢀ400 inꢀ
strument (400 МHz) in CDCl3 with tetramethylsilane as
the internal standard. HPLC analysis was carried out on a
acylation with chloride ꢀ) and Et N (in the case of ꢂ). In
3
the presence of tertiary amine, the process is appreciably
complicated, because several competing reactions can
occur simultaneously in both the formation of the acylꢀ
ammonium salt and HCl elimination. These processes
involve, to a certain extent, both the molecules of the
auxiliary base and secondary amine enantiomers. Thereꢀ
fore, elucidation of the fine mechanisms determining the
predominant formation of one amide diastereomer reꢀ
quires further investigations. However, the fact that the
de values of the products obtained in different solvents in
the presence of aliphatic tertiary amines differ substanꢀ
tially from those for the products obtained without terꢀ
tiary amines suggests that the reaction involves the interꢀ
mediate formation of salt A and, to a lesser extent, salt B.
The role of the tertiary amine is mainly reduced to the
abstraction of HCl from the acylammonium salt.
4
ꢀUV Milikhrom chromatograph using a 80×2 mm column,
Silasorb 600, and UV detection at 230 nm. The rate of elution
was 200 µL min– ; a hexane—Pr OH mixture (120 : 1) was used
as the mobile phase to analyze the diastereomeric composition
of 5a2b, τR = 7.4 (5a), 5.5 min (5b) and a hexane—Pr OH mixꢀ
ture (15 : 1) was used to analyze the diastereomeric composition
of 6a2b, τR = 3.6 (6a), 5.7 min (6b).
1
i
i
Chlorides ꢀ and ꢂ obtained from the corresponding acids
and (COCl) in dry benzene were used in the acylation without
additional purification. According to H NMR data, freshly
prepared chlorides ꢀ and ꢂ contained 97 to 100% of the major
compound.
2
1
Prior to use, benzene was purified and dehydrated by refluxꢀ
ing and distillation over metallic Na; CH Cl2 was washed with
concentrated H SO4 and water and distilled over anhydrous
CaCl ; MeCN was purified and dehydrated by two distillations
over P O5 with subsequent distillation over K CO . Tertiary
2
2
2
2
2
3
amines, Et N, Py and Nꢀmethylmorpholine, were refluxed and
3
In the presence of DMAP, the diastereoselectivity of
acylation is markedly lower (5a, de 20%; 6b, de 14%) than
that observed in reactions in benzene in the presence of
other bases. Apparently, this is due to the fact that DMAP
is a hypernucleophile and forms stable salt B much faster
than other amines.
distilled over KOH; commercial DPEA and DMAP (Lancaster)
were used as received. (± )ꢀ3ꢀMethylꢀ2,3ꢀdihydroꢀ4Hꢀ1,4ꢀ
17
benzoxazine was prepared by a known procedure.
Kinetic resolution of racemic amine 1a (general procedure±.
A solution of chloride ꢀ or ꢂ (0.1 mmol) in 1 mL of the appropriꢀ
ate solvent was added to a solution of amine 1a (0.030 g,
0
.2 mmol) and tertiary amine (0.1 mmol) (or without it) in 1 mL
In a more polar solvent, CH Cl , the content of amide
2
2
of the same solvent. The reaction mixture was kept in a thermoꢀ
stat at 20 °C for 24 h and passed through a silica gel layer. The
filtrate (0.2 mL) was diluted with 0.5 mL of CH Cl , 0.2 mL of
6
b (de 11.6%) is also lower with DMAP than with other
bases. In MeCN, the reaction of chloride ꢂ with amine 1a
gives numerous byꢀproducts, and the diastereomeric comꢀ
position could not be determined by HPLC.
2
2
the resulting solution was diluted with 0.5 mL of the correꢀ
sponding mobile phase, and the solution was analyzed by HPLC.
The predominant formation of amide 5a in CH Cl
2
2
and MeCN in the presence of DMAP (de 77.6% and
de 70.2%, respectively), compared to the reactions in the
presence of other bases in the same solvents, was unexꢀ
pected.
Generally, the results of the study on the influence of
various factors on the diastereoselectivity of the kinetic
resolution of racemic amine 1a under the action of
This work was financially supported by the Russian
Foundation for Basic Research (Projects No. 03ꢀ03ꢀ33091
and No. 04ꢀ03ꢀ32344) and President of the Russian Fedꢀ
eration (Program for the Support of Leading Scientific
Schools, NSh 1766.2003.3).
References
(
S)ꢀnaproxen and Nꢀtosylꢀ(S)ꢀproline chlorides indicate
that the stereochemical outcome depends not only on the
structure of the acylating agent but also on the solvent and
the auxiliary base.
1
2
. H. B. Kagan and J. C. Fiaud, Top. Stereochem., 1988, 18, 249.
. E. L. Eliel and S. H. Wilen, Stereochemistry of Organic comꢀ
pounds, J. Wiley and Sons, Inc., New York, 1994, 1267 pp.
This dependence is probably due to the involvement
of several acylation mechanisms (both in direct substituꢀ
3. J. M. Keith, J. F. Larrow, and E. N. Jacobsen, Adv. Synth.
Cat., 2001, ꢀꢂꢀ, 5.
Krasnov
