N-tosyl-(S)-prolyl chloride in kinetic resolution of racemic heterocyclic amines

Article abstract of DOI:10.1007/s10593-014-1432-4

The kinetic resolution of racemic heterocyclic amines via acylation with N-tosyl-(S)-prolyl chloride was systematically investigated. It was established that racemic mixtures of aromatic amines could be resolved with high efficiency, while the acylation of 2- and 3-methylpiperidines occurred with low diastereoselectivity. A method for the preparation of enantiomerically pure (3R)-7,8-difluoro-3-methyl-3,4-dihydro-2H-[1,4]benzoxazine was developed.

Full text of DOI:10.1007/s10593-014-1432-4

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Chemistry of Heterocyclic Compounds, Vol. 49, No. 12, March, 2014 (Russian Original Vol. 49, No. 12, December, 2013)
N-TOSYL-(S)-PROLYL CHLORIDE IN KINETIC
RESOLUTION OF RACEMIC HETEROCYCLIC AMINES
1
1
1
1
*
D. A. Gruzdev , S. A. Vakarov , G. L. Levit , and V. P. Krasnov
The kinetic resolution of racemic heterocyclic amines via acylation with N-tosyl-(S)-prolyl chloride was
systematically investigated. It was established that racemic mixtures of aromatic amines could be
resolved with high efficiency, while the acylation of 2- and 3-methylpiperidines occurred with low
diastereoselectivity. A method for the preparation of enantiomerically pure (3R)-7,8-difluoro-3-methyl-
3,4-dihydro-2H-[1,4]benzoxazine was developed.
Keywords: amines, (3R)-7,8-difluoro-3-methyl-3,4-dihydro-2H-[1,4]benzoxazine, N-tosyl-(S)-proline,
acylation, diastereoisomers, kinetic resolution, stereoselectivity.
Chiral amines are valuable precursors and structural fragments of biologically active compounds, chiral
ligands, derivatizing reagents, etc. The synthesis of enantiomerically pure amines and their derivatives is among
the most important tasks of modern organic synthesis. Among such targets of interest are chiral heterocyclic
amines: derivatives of tetrahydroquinoline [1], dihydrobenzoxazine [2], and indoline [3].
Kinetic resolution (KR) of racemates is one of the methods for isolating individual enantiomers of
amines [4]. Acylative KR processes present a significant interest [5, 6]. The methods for enantioselective
acylation of amines using enzymes [7, 8], synthetic acyl transfer catalysts [9-11], and chiral acylating reagents
[12, 13] have been extensively studied.
In recent years we have developed a method for the preparation of enantiomerically pure amines by KR
of racemic amines with N-protected amino acyl chlorides [14-17] and 2-arylpropionyl chlorides [18-20]. This
type of KR provided enantiomers of heterocyclic amines with higher than 99% optical purity.
Proline derivatives have been widely used as chiral resolving agents for alcohols [21-24] and amines
[25, 26]. We have previously demonstrated the application of N-tosyl-(S)-prolyl chloride as an effective reagent
for KR of heterocyclic amines 1a-c [14].
The current work was aimed at systematic investigation of KR methods for racemic heterocyclic amines
1a-g and their structural analogs 1h,i, using acylation with N-tosyl-(S)-prolyl chloride.
The acylation of racemic amines 1a-i was performed for 6 h at a 2:1 molar ratio of the amine and acyl
chloride with a 0.1 M initial amine concentration in toluene or dichloromethane, and at various temperatures
(Table 1). Each experiment was carried out in 2-4 parallel runs.
_______
*To whom correspondence should be addressed, e-mail: gruzdev-da@ios.uran.ru.
1I. Ya. Postovskii Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 22
S. Kovalevskoi St. / 20 Akademicheskaya St., Yekaterinburg 620990, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1936-1950, December, 2013.
Original article submitted October 1, 2013.
0009-3122/14/4912-1795©2014 Springer Science+Business Media New York
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O
Ts
N
NH
Alk
Solvent
6 h
NH
·HCl
N
Cl
+
+
N
Alk
Alk
O
Ts
(R,S)-3a–i
(S)-1a–i
(major)
rac-1a–i
2
(major)
(0.5 equiv.)
F
NH
Me
NH
Me
NH
Me
F
NH
Me
O
O
1a
1b
1c
1d
F
NH
Me
NH
NH
NH
NH
S
O
Me
Me
Bu-t
Me
1e
1f
1g
1h
1i
TABLE 1. The KR Results for Amines 1a-i with Acyl Chloride 2*
(R,S)-amide,
de, %*2
(S)-amine, Conversion (C),
Amine
Solvent
T, °С
Selectivity factor (s)
ee, %*2
%
PhMe
CH2Cl2
PhMe
CH2Cl2
PhMe
CH2Cl2
PhMe
CH2Cl2
PhMe
CH2Cl2
PhMe
PhMe
CH2Cl2
PhMe
CH2Cl2
PhMe
PhMe
PhMe
CH2Cl2
PhMe
PhMe
CH2Cl2
PhMe
CH2Cl2
CH2Cl2
PhMe
+20
+20
-20
3a 84.6
3a 68.0
3a 90.2
3a 65.5
3b 70.4
3b 21.9
3b 78.1
3b 13.2
3c 39.4
3c 31.8
3c 47.0
3d 76.7
3d 82.7
3d 89.1
3d 81.9
3e 56.0
3e 61.9
3f 89.4
3f 33.8
3f 93.5
3g 48.2
3g 44.6
3h 18.0
3h 37.3
3h 46.5
3i 8.6
1a 75.0
1a 56.2
1a 75.9
1a 56.5
1b 58.8
1b 17.8
1b 50.6
1b 9.3
1c 37.8
1c 29.8
1c 44.9
1d 59.0
1d 66.8
1d 43.9
1d 58.1
1e 40.5
1e 43.7
1f 35.9
1f 24.0
1f 10.6
1g 26.7
1g 24.8
1h 17.6
1h 35.1
1h 44.5
1i 5.5
47
45
46
47
46
45
39
41
49
48
48
44
45
33
42
42
41
29
42
10
36
36
49
48
49
39
50
28
9.1
44
7.9
10
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1d
1d
1d
1d
1e
1e
1f
-20
+20
+20
-20
1.9
13
-20
1.4
3.3
2.5
4.4
14
21
27
18
5.2
6.5
25
2.5
32
3.7
3.3
1.7
3.0
4.2
1.2
1.1
+20
+20
-20
+20
+20
-20
-20
+20
-20
+20
+20
-20
+20
+20
+20
+20
-20
1f
1f
1g
1g
1h
1h
1h
1i
+20
+20
CH2Cl2
3i 4.3
1i 4.3
1i
_______
*The average values from 2-4 parallel runs.
*2According to HPLC data (see Experimental).
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Fig. 1. The structures of (R,S)-amides а) 3b and b) 3d with atoms represented by thermal vibration ellipsoids of
50% probability.
The diastereomeric excess (de) of the obtained amides 3a-i was determined by HPLC, as well as by
NMR spectroscopy. Most of the amide NMR signals at room temperature were broadened and overlapped. The
NMR signals of amides 3a-h became sharper in DMSO-d6 at 100°C, which allowed to determine the
diastereomer ratio of acylation products.
The enantiomeric excess (ee) of unreacted amines 1a-i was determined by chiral HPLC, where amines
1c,h,i were derivatized with benzoyl chloride prior to the analysis. The formulas published by Kagan and Fiaud
[4] were used to calculate the conversion of the starting racemate C = [eeamine / (eeamine + deamide)] × 100% and the
selectivity factor s = ln[(1 - C) × (1 - eeamine)] / ln[(1 - C) × (1 + eeamine)], which represented the ratio of reaction rates
for the fast and slow reacting enantiomers (Table 1). Acylation of amines 1a-i with acyl chloride 2 in all the
cases led to the predominant formation of (R,S)-amides, while unreacted amines were enriched in the
(S)-enantiomers according to chiral HPLC. The absolute configuration of the chiral centers in (R,S)-amides
3b,d,e, as well as in amide (S,S)-3g were confirmed by X-ray structural analysis, starting from the known
configuration of the acyl fragment (Fig. 1, 2).
The data in Table 1 indicate that for racemic amines 1a,b,f, KR was more efficient in toluene than in
dichloromethane. The difluoro-substituted benzoxazine 1d was acylated with an equal diastereoselectivity both
in toluene and in dichloromethane. A decrease of reaction temperature enhanced the selectivity in all the cases,
but slightly lowered the conversion of the starting racemic amine.
Fig. 2. The structures of amides а) (R,S)-3e and b) (S,S)-3g with atoms represented by thermal vibration
ellipsoids of 50% probability.
The acylation of 3,4-dihydro-2H-[1,4]benzoxazines 1a,d and 3,4-dihydro-2H-[1,4]benzothiazine 1f was
more diastereoselective than the acylation of 1,2,3,4-tetrahydroquinolines 1b,e and indoline 1c. The KR of
racemic 3-methyl-3,4-dihydro-2H-[1,4]benzothiazine 1f in toluene at +20°C was as selective as the KR of its
oxygen-containing analog 1a, but proceeded with a lower conversion (in toluene de (R,S)-3f 89.4%, C 29%,
s 25). The KR of racemic amine 1f at +50°C provided amide 3f in a higher yield (de (R,S)-3f 89.4%, C 35%,
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s 29). A further increase of the reaction temperature to +80°C improved the racemate conversion, but at the
same time the selectivity was much lower (de (R,S)-3f 53.8%, C 47%, s 5.2).
The low conversion and the moderate stereoselectivity in the case of 3-tert-butyl- substituted
dihydrobenzoxazine 1g (toluene, +20°C: de (R,S)-3g 48.2%, C 36%, s 3.7) is likely to be caused by the steric
hindrance due to the bulky tert-butyl substituent.
The presence of fluorine atoms in the aromatic fragments of amines 1d,e decreased the acylation
stereoselectivity compared to non-fluorinated analogs 1a,b. For fluorinated amine 1d, the KR in toluene at
+20°C had the selectivity factor s equal to 14 (de (R,S)-3d 76.7%), while its non-fluorinated analog 1a was
acylated with a higher selectivity (s 28, de (R,S)-3a 84.6%). Tetrahydroquinolines 1b and 1e also gave different
stereochemical results (at +20°C the s was 10 and 5.2, respectively).
Aromatic interactions are known to play a major role in stereoselective acylation processes [21, 27-30].
The stereoselectivity of the acylation of heterocyclic aromatic amines 1a-g with acyl chloride 2 apparently
could be explained by a combination of steric hindrances due to the amide bond formation, in particular those
created by the substituents at the amine stereocenter, and the –-interactions between the aromatic ring of
amine and the protective group of acylating agent (Fig. 3).
Fig. 3. The proposed stereodifferentiation mechanism during the acylation of amines 1a,g with acyl chloride 2.
The preferred direction of approach between the reagent molecules may be explained by -stacking
interactions of the electron-rich aromatic amine (due to the (+M)-effect of alkoxy and amino groups) and the
electron-deficient aromatic protective group of the acylating reagent (due to the (-M)-effect of sulfamide group).
There may be a different degree of steric hindrance in (S)- and (R)-enantiomers due to the chlorocarbonyl group
and the substituent at position 3 of 3,4-dihydrobenzoxazine during the approach of amine molecule to a
molecule of reagent 2, if the aromatic rings have a parallel arrangement.
Apparently the interaction of reagents 1a and 2 created a lesser steric hindrance for the (R)-amine–(S)-
acyl chloride pair (Fig. 3, the pair (R)-1a–2); the methyl substituent of (S)-amine hindered the reaction (Fig. 3,
the pair (S)-1a–2). The bulky tert-butyl substituent in the case of amine 1g apparently caused the significant
steric hindrance for both pairs (S)-1g–2 and (R)-1g–2 (Fig. 3).
The lower diastereoselectivity of acylation of tetrahydroquinolines 1b,e compared to benzoxazine 1a
may be due to the lower electron density (-) at the aryl ring in compounds 1b,e, along with the greater
conformational flexibility of the heterocycle. The moderate acylation stereoselectivity observed with
2-methylindoline (1c) may be caused by smaller ring size and higher rigidity of the ring in the amine molecule.
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