A new approach to the enantioseparation of Betti bases

Article abstract of DOI:10.1055/s-2007-967941

An improved method for enantioseparation of racemic 1-(α-aminobenzyl) -2-naphthols has been developed by the reaction in situ of Betti base product mixtures with L-(+)-tartaric acid taken in a 1:1 ratio. The products of this reaction are (-)-1-(α-aminobenzyl)-2-naphthol tartrate, the acetal of benzaldehyde and tartaric acid as well as (+)-1,3-diaryl-2,3-dihydro-1H- naphth[1,2-e][1,3]oxazine, which can be easily separated by crystallization. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-967941

4
88
LETTER
A New Approach to the Enantioseparation of Betti Bases
a
a
b
b
a
E
V
nantioseparation
lo f Bett
a
i
Bases dimir A. Alfonsov,* Kirill E. Metlushka, Charles E. McKenna, Boris A. Kashemirov, Olga N. Kataeva,
a
a
a
Viktor F. Zheltukhin, Dilyara N. Sadkova, Alexey B. Dobrynin
a
A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of the Russian Academy of Sciences, 8 Arbuzov St.,
Kazan 420088, Russian Federation
Fax +7(8432)732253; E-mail: alfonsov@iopc.knc.ru
b
Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA
Received 9 November 2006
OH
Abstract: An improved method for enantioseparation of racemic 1-
+
NH3
+
CHO
(
a-aminobenzyl)-2-naphthols has been developed by the reaction in
situ of Betti base product mixtures with L-(+)-tartaric acid taken in
a 1:1 ratio. The products of this reaction are (–)-1-(a-aminobenzyl)-
2
-naphthol tartrate, the acetal of benzaldehyde and tartaric acid as
well as (+)-1,3-diaryl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine,
which can be easily separated by crystallization.
N
C
H
–
H2O
OH
Key words: enantioseparation,
1-(a-aminobenzyl)-2-naphthols,
1
,3-diaryl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine, tartaric acid
A
Chiral 1-(a-aminobenzyl)-2-naphthols are available from
the condensation of b-naphthol with benzaldehydes and
ammonia or amines. These compounds are very attrac-
tive for chemists who work on asymmetric syntheses and
are seeking enantiopure chiral inductors or chiral precur-
sors. 1-(a-Aminobenzyl)-2-naphthols, known as Betti
bases, are suitable for such purposes owing to their ease of Scheme 1 Classical synthesis of the original 1-(a-aminobenzyl)-2-
synthesis, the ready availability of precursors, and poten- naphthol (only one member from each pair of enantiomers B and C is
tial for enantiomeric separation. For many years, this class
H
H
N
N
1
–3
O
O
B
C
1
shown).
of compounds remained little exploited, but during the
last decade, owing to increasing emphasis on enantiopure Recently, Hu and co-workers described kinetic resolution
drug synthesis, they have attracted growing interest.4
,5
of racemic Betti bases by L-(+)-tartaric acid in acetone.9
This method provides enantiomeric products in good
chemical and optical yields. However, in this case it is
necessary to begin the synthesis with free racemic Betti
base. This entails synthesis, separation and purification of
the Betti base, which is not very stable.
Classical synthesis of the original 1-(a-aminobenzyl)-2-
naphthol, i.e. Betti base, involves several steps. The first
and most important one is the three-component condensa-
tion of b-naphthol, benzaldehyde and ammonia in alco-
1,2
holic solution at room temperature during several days
3
,6
with formation of imine A, shown later to be in solution In this paper we report the successful separation of the
equilibrium with two diastereomeric trans- and cis-ox- Betti base condensation products 1 into enantiomers by
azine structures (B and C), formed by tautomeric N,O- reaction with tartaric acid in one pot. One equivalent of
proton transfer (Scheme 1).
tartaric acid reacts with one equivalent of the Betti con-
densation products 1, resulting in formation of 0.5 equiv-
alents of 2,3-O-benzylidene tartaric acid (tartaric acid
acetal) and 0.5 equivalents of free Betti base.
7
Optically active Betti bases were obtained by Betti him-
self in 1906, a separation procedure being published by
Cardellicchio and co-workers much later. The procedure
8
primarily involves hydrolysis of condensation products 1 We anticipated that tartaric acid (0.5 equiv) would react
(
B ' A ' C) in hydrochloric acid to give hydrochloride with the Betti base stereoselectively, giving 0.5 equiva-
salts. The unstable free base can be isolated by treatment lents of a Betti base tartrate containing the chiral carbon
with alkali, and separated via formation of diastereomeric atom in one configuration, the other enantiomer being left
tartrates which can be fractionally crystallized. Each step unreacted and crystallizable as an oxazine.
entails losses of chemical and optical purity, the oxazine
final yield being about 60%.
Our supposition was confirmed. The interaction of the pri-
mary Betti condensation product 1 with L-(+)-tartaric acid
upon heating in a mixture of dry dichloromethane and ab-
SYNLETT 2007, No. 3, pp 0488–0490
Advanced online publication: 07.02.2007
DOI: 10.1055/s-2007-967941; Art ID: G33506ST
1
5.
0
2.
2
0
0
7
solute methanol resulted in the crystalline (R,R)-tartrate of
10
(
S)-1-(a-aminobenzyl)-2-naphthol (2, 85%, Scheme 2 ).
After filtration, the mother liquor yielded enantiopure
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Enantioseparation of Betti Bases
489
HO
HOOC
OH
The structure of acetal 3 was established by IR spectros-
HO
OH
H
copy, as well as by comparison of its physical constants
NH3·
COOH
12
with literature data.
(±)-1
1/2
OOC
COOH
OH
An important advantage of this approach is that the very
stable Betti base derivatives – salt 2 and oxazine 1 – are
obtained directly. These reaction products can be conve-
niently stored unchanged for a long period, and whenever
desired, transformed into enantiopure free base.
2
+
Ph
H
H H
N
1/2
HOOC
1/2
In summary, we have demonstrated a new, efficient one-
pot method to isolate enantiomeric precursors of 1-(a-
aminobenzyl)-2-naphthol (Betti base), which can be used
as a chiral inductor or initial reagent in stereoselective
organic synthesis.
+
O
COOH
3
(R)-(–)-1
Scheme 2
Crystal data for (R)-(–)-1: C H NO, M = 337.40, colorless crystal
2
4
19
oxazine (R)-(–)-1 (60%) and 2,3-O-benzylidene tartaric 0.65 × 0.10 × 0.10 mm, monoclinic, space group P2 , Z = 2,
1
a = 13.242(1), b = 5.477(1), c = 13.289(1) Å, b = 115.98(3)°,
acid (3).
3
–3
–1
V = 866.4(2) Å , r = 1.293 g cm , m = 0.78 cm , l = 0.71073 Å,
calc
The molecular structure of 2 was established by single
T = 293 K, Nonius Kappa CCD diffractometer, 13204 reflections
–
1
crystal X-ray diffraction. One of the protons of the tartaric collected (±h, ±k, ±l), [(sinq)/l] = 0.60 Å , 3129 independent
acid is transferred to the Betti base nitrogen atom. A large (Rint = 0.041) and 2525 observed reflections [I 2s(I)], 238 refined
parameters, R1 = 0.036, wR2 = 0.076, max. residual electron den-
number of hydrogen bond donors and acceptors result in
a complex three-dimensional hydrogen-bonded network.
–
3
sity 0.11 (–0.17) e Å , flack = 0.10(15). CCDC 628868.
Crystal data for 2: C H NO·C H O , M = 399.39, colorless crystal
1
7
16
4
5
6
As the reaction involved enantiopure (R,R)-tartaric acid,
the absolute configuration of the amine counterion was
unambiguously determined by X-ray single crystal dif-
0
.5 × 0.3 × 0.05 mm, monoclinic, space group P21, Z = 2,
a = 7.512(1), b = 7.990(3), c = 15.793(6) Å, b = 98.88(2)°,
3
–3
–1
V = 936.5(5) Å , r = 1.729 g cm , m = 1.25 cm , l = 0.71073 Å,
calc
fraction as S. Crystals of 2 were homogeneous: melting T = 293 K, Nonius CAD-4 diffractometer, 2205 reflections
2
0
–1
point 185–187 °C, [a]D +45.0 (c 1.0, DMSO).
collected (±h, ±k, ±l), [(sinq)/l] = 0.50 Å , 2045 independent
(
R = 0.022) and 1824 observed reflections [I 3s(I)], 273 refined
int
It should be noted that the salt 2 does not contain a water
molecule in its crystal lattice, in contrast to the structure
obtained by Hu and co-workers.
parameters, R1 = 0.047, wR2 = 0.119, max. residual electron den-
–3
sity 0.29 (–0.28) e Å , flack = –0.6(16). CCDC 628867.
9
The IR spectrum of salt 2 had bands at 1700, 1710 (C=O),
Acknowledgment
+
–1
2
100–2700 (N H) and 3264, 3458, 3487 (OH) cm . The
1
This work was supported by the Civilian Research and Develop-
ment Foundation (grant no. RUC2-2638-KA-05) and the Russian
Foundation for Basic Research (grant no. 03-03-33082).
H NMR spectrum in DMSO-d had a singlet [CHN (1 H),
6
d = 6.24 ppm], a slightly broadened singlet [CHO (2 H)
d = 4.11 ppm], a multiplet [CH (11 H) d = 7.26–7.99
ar
ppm], and an averaged broad signal for the mobile protons
(
3 HN and 3 HO, d = 6.47–7.25 ppm).
References and Notes
The free Betti base [(S)-(+)-1-(a-aminobenzyl)-2-naph-
(1) Betti, M. Gazz. Chim. Ital. 1900, 30, II-310.
(2) Betti, M. Org. Synth., Coll. Vol. I; Wiley: New York, 1941,
381.
8
thol] obtained from salt 2 using a standard procedure had
2
0
[
a] +56.0 (c 4.4, benzene), which corresponds to the
8,9
D
(3) Smith, H. E.; Cooper, N. E. J. Org. Chem. 1970, 35, 2212.
literature data for an enantiopure sample.
(
4) Review on the synthesis and transformation of 1-(a-amino-
benzyl)-2-naphthol derivatives: Szatmári, I.; Fülöp, F. Curr.
Org. Synth. 2004, 1, 155.
The oxazine (R)-(–)-1 isolated from the mother liquor
after separation of 2 had values in agreement with the
1
1
(5) (a) Cardellicchio, C.; Ciccarella, G.; Naso, F.; Perna, F.;
Tortorella, P. Tetrahedron 1999, 55, 14685. (b)Palmieri,G.
Tetrahedron: Asymmetry 2000, 11, 3361. (c) Gong, Y.;
Kato, K. Tetrahedron: Asymmetry 2001, 12, 2121.
literature. In CDCl solution (R)-(–)-1 exists as a mix-
3
ture of B ' A ' C, resonances from all three forms being
1
present in the H NMR spectrum. The X-ray data showed
that the more thermodynamically stable trans-form B
crystallizes.
(
d) Saidi, M. R.; Azizi, N.; Naimi-Jamal, M. R. Tetrahedron
Lett. 2001, 42, 8111. (e) Cimareli, C.; Mazzanti, A.;
Palmieri, G.; Volpini, E. J. Org. Chem. 2001, 66, 4759.
An interesting feature of this crystal structure is the
absence of intermolecular hydrogen bonds with the NH
oxazine group. This feature is additionally confirmed by
(
f) Liu, D.-X.; Zhang, L.-C.; Wang, Q.; Da C, S.; Xin, Z.-Q.;
Wang, R.; Choi, M. C. K.; Chan, A. S. C. Org. Lett. 2001, 3,
733. (g) Wang, Y.; Li, X.; Ding, K. Tetrahedron:
2
–
1
the narrow IR band at 3319 cm in the IR spectrum of
Asymmetry 2002, 13, 1291. (h) Lu, J.; Xu, X.; Wang, C.; He,
J.; Hu, Y.; Hu, H. Tetrahedron Lett. 2002, 43, 8367.
(
R)-(–)-1, characteristic of a free NH group.
(
2
i) Zhang, Y.; Zhang, L.; Guo, Z.; Zhu, L. J. Coord. Chem.
002, 55, 1393. (j) Li, K.; Zhou, Z.; Wang, L.; Zhou, Q.;
Tang, C. Main Group Met. Chem. 2002, 25, 663. (k) Saidi,
Synlett 2007, No. 3, 488–490 © Thieme Stuttgart · New York

4
90
V. A. Alfonsov et al.
LETTER
crystalline sediments being periodically filtered off. The
M. R.; Azizi, N. Tetrahedron: Asymmetry 2003, 14, 389.
(
l) Ji, J.-X.; Qiu, L.-Q.; Yip, C. W.; Chan, A. S. C. J. Org.
crystals so obtained were washed with a boiling mixture of
CH Cl and benzene (1:1), filtered and dried in vacuo. Yield:
Chem. 2003, 68, 1589. (m) Xu, X.; Lu, J.; Dong, Y.; Li, R.;
Ge, Z.; Hu, Y. Tetrahedron: Asymmetry 2004, 15, 475.
2
2
0.75 g (85.4%) of (S)-(+)-1-(a-aminobenzyl)-2-naphthol
tartrate (2). The mother liquor was evaporated in vacuo
under dried argon, leaving a brown residue which was
extracted by hot EtOAc (2 × 7 mL). The insoluble residue
was isolated and recrystallized from a (4:1) mixture of
benzene–diisopropyl ether. Yield: 0.45 g (61%) of (R)-(–)-
1,3-diphenyl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine
(n) Dong, Y.; Sun, J.; Wang, X.; Xu, X.; Cao, L.; Hu, Y.
Tetrahedron: Asymmetry 2004, 15, 1667. (o) Szatmári, I.;
Martinek, T. A.; Lázár, L.; Koch, A.; Kleinpeter, E.;
Neuvonen, K.; Fülöp, F. J. Org. Chem. 2004, 69, 3645.
(
2
J. Heterocycl. Chem. 2004, 41, 367. (r) Wang, X.; Dong,
Y.; Sun, J.; Xu, X.; Li, R.; Hu, Y. J. Org. Chem. 2005, 70,
1
p) Xu, X.; Lu, J.; Li, R.; Ge, Z.; Dong, Y.; Hu, Y. Synlett
004, 122. (q) Szatmári, I.; Hetényi, A.; Lázár, L.; Fülöp, F.
2
0
[(R)-(–)-1], mp 162–163 °C; [a] –170 (c 1.0, CHCl3)
D
1
1
20
{lit. mp 163–164 °C; [a]D +169 (c 1.0, CHCl ) for S-(+)-
3
1
897. (s) Dahmen, S.; Lormann, M. Org. Lett. 2005, 7,
597. (t) Ji, J.-X.; Wu, J.; Au-Yeung, T. T.-L.; Yip, C.-W.;
1}. H NMR (CDCl ) d (tautomer A) = 6.48 (s, CH–N), 8.64
3
4
(s, CH =N) ppm; d (tautomer C) = 5.68 (s, CHN), 5.73 (s,
CHO) ppm; d (tautomer C) = 5.86 (s, CHN), 5.99 (s, CHO)
ppm; d (tautomers A + B + C) = 7.23–7.92 (m, CHarom) ppm.
Tautomeric mixture (%): A (27.5), B (63.2), C (9.3). From
the EtOAc extract a solvent was removed in vacuo under dry
argon. Yield: 0.25 g (48%) of crystalline residue 2,3-O-
benzylidene tartaric acid (3), mp 127–128 °C. IR (KBr): n =
Haynes, R. K.; Chan, A. S. C. J. Org. Chem. 2005, 70, 1093.
(
6) Szatmári, I.; Martinek, T. A.; Lázár, L.; Fülöp, F.
Tetrahedron 2003, 59, 2877.
(
(
7) Betti, M. Gazz. Chim. Ital. 1906, 36, II-392.
8) Cardellicchio, C.; Ciccarella, G.; Naso, F.; Schingaro, E.;
Scordari, F. Tetrahedron: Asymmetry 1998, 9, 3667.
9) Dong, Y.; Li, R.; Lu, J.; Xu, X.; Wang, X.; Hu, Y. J. Org.
Chem. 2005, 70, 8617.
–
1
12
(
1728 (C=O) cm (lit. mp 128.5–129.5 °C). From 2
8
following a published procedure (S)-(+)-1-(a-amino-
2
0
(
10) Separation Procedure of 1 Using l-(+)-Tartaric Acid.
benzyl)-2-naphthol was obtained; mp 136–137; [a] +56.0
D
8
20
To 1.48 g (4.4 mmol) of 1 dissolved in 15 mL of dry CH Cl
at 35–40 °C was added a solution of 0.66 g (4.4 mmol) L-(+)-
tartaric acid, 7 mL of abs. MeOH and 3 mL of CH Cl . The
(c 4.4, benzene) {lit. mp 136–137 °C; [a] +56.0 (c 4.4,
2
2
D
benzene)}.
(11) Betti, M. Gazz. Chim. Ital. 1907, 37, I-63.
(12) Roush, W. R.; Banfi, L. J. Am. Chem. Soc. 1988, 110, 3979.
2
2
mixture was refluxed for 2 h, then kept at r.t. during 3 d, the
Synlett 2007, No. 3, 488–490 © Thieme Stuttgart · New York