Improved procedures for the synthesis of (S)-2-[N-(N'-benzyl- prolyl)amino]benzophenone (BPB) and Ni(II) complexes of Schiff's bases derived from BPB and amino acids

Article abstract of DOI:10.1016/S0957-4166(98)00449-2

(S)-N-Benzylproline (BP) was obtained by the reaction of (S)-proline and benzylchloride in high chemical yield (89%). (S)-2-[N-(N'- Benzylprolyl)amino]benzophenone (BPB) was synthesized in amounts greater than 100 g by the SOCl₂ promoted condensation of BP with 2-aminobenzophenone (yield 82%). Ni(II) complexes of Schiff's bases derived from BPB and amino acids were prepared by an improved procedure involving the use of KOH as a base and MeOH as solvent (yield 90-91%).

Full text of DOI:10.1016/S0957-4166(98)00449-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 4249–4252
Improved procedures for the synthesis of (S)-2-[N-(N0-benzyl-
prolyl)amino]benzophenone (BPB) and Ni(II) complexes of
Schiff’s bases derived from BPB and amino acids
Yuri N. Belokon’,a,∗ Vitali I. Tararov,a Viktor I. Maleev,a Tatiana F. Savel’eva a and
Michael G. Ryzhov b
aA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 117813, Vavilov 28, Moscow,
Russia
bRussian Scientific Center (Applied Chemistry), Petersburg, Dobrolubov 14, Russia
Received 22 October 1998; accepted 2 November 1998
Abstract
(S)-N-Benzylproline (BP) was obtained by the reaction of (S)-proline and benzylchloride in high chemical yield
(89%). (S)-2-[N-(N0-Benzylprolyl)amino]benzophenone (BPB) was synthesized in amounts greater than 100 g by
the SOCl2 promoted condensation of BP with 2-aminobenzophenone (yield 82%). Ni(II) complexes of Schiff’s
bases derived from BPB and amino acids were prepared by an improved procedure involving the use of KOH as a
base and MeOH as solvent (yield 90–91%). © 1998 Elsevier Science Ltd. All rights reserved.
For the last 10 years, our group has been developing a new method of stoichiometric asymme-
tric synthesis of non-proteinogenic amino acids based on use of the chiral auxiliary (S)-2-[N-(N0-
benzylprolyl)amino]benzophenone (BPB) and alkylation of Ni(II) complexes of Schiff’s bases, derived
from BPB and amino acids.1 The method has some advantages, including the simplicity of operation,
ambient temperatures of the reaction media, very high concentrations of the reagents, and the use of
cheap bases (NaOH, KOH, MeONa, NaH). Other attractive features of the synthetic protocol are high
rates of the alkylation reactions and facile recovery of the amino acids and the chiral auxiliary, which
are convenient for the synthesis of enantiomerically enriched C-11 labelled amino acids with a short life
period, employed for PET diagnostics.2
Unfortunately, the procedure for BPB synthesis reported by us earlier3 is inconvenient for large scale
applications. In this paper, we report a modified procedure for the synthesis of both BPB and Ni(II)
Schiff’s base complexes1a,b derived from BPB and amino acids. The synthetic protocol allows the
preparation of the auxiliary and the complexes in bulk quantities (greater than 1 kg).
∗
Corresponding author. E-mail: yubel@ineos.ac.ru
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00449-2

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The modification of the previous synthesis included a new procedure for (S)-proline N-alkylation,
which greatly improved the yields of the mono-alkylation product, N-benzylproline (BP), and the
condensation of BP with 2-aminobenzophenone promoted by SOCl2 at low temperatures (Scheme 1).
Further improvement of the preparation of the Ni(II) complexes (Scheme 1) was achieved by the
substitution of MeONa by KOH in the synthetic protocol. The enantiomeric purity of BPB (>99%),
prepared in this way and included in the corresponding Ni-complexes, was checked by the GLC
enantiomeric analysis of the amino acids (>99%) recovered from the pure diastereoisomers1 obtained
after alkylation of either gly-Ni-BPB or ala-Ni-BPB. The diastereoisomeric complexes were purified
by chromatography, as described in our previous publications.1 Their diastereoisomeric purity (before
decomposition and recovery of the amino acids) was checked by NMR.
Scheme 1.
1. Experimental
The optical rotations were recorded on a Perkin–Elmer M241 polarimeter. Melting points are uncor-
rected. The solvents were used as purchased, without purification.
1.1. Synthesis of (S)-N-benzylproline (BP)
A solution of 173 g (1.17 mol) of (S)-proline and 254 g (4.5 mol) of KOH in 1 litre of i-PrOH was
prepared with stirring at 40°C. As soon as the solution became transparent, slow addition of freshly
distilled BnCl (208 g, 1.8 mol) was commenced under stirring at the same temperature. The dropwise
addition took 3 h to complete, and the stirring was continued for another 6 h at the same temperature.
The reaction mixture was neutralized with concentrated aqueous HCl (about 188 ml) until pH 5–6
(indicator paper), then was added to the reaction mixture CHCl3 (400 ml) with stirring. The mixture
was left overnight, then filtered and the precipitate was washed with CHCl3. The CHCl3 solutions were
combined and evaporated, the residue was treated with acetone and the precipitate of crude BP filtered
and additionally washed with acetone. Some BP was also recovered from the acetone washings. The

Y. N. Belokon’ et al. / Tetrahedron: Asymmetry 9 (1998) 4249–4252
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crude material was dried in air and then over P2O5 in vacuo to give 273 g (89%) of BP {m.p. 174–175°C,
20
20
[α]D −25.8 (c=1 in abs. EtOH); lit.4: m.p. 164°C, [α]D −28.4 (c=1 in abs. EtOH)}, which was used
further without any purification.
1.2. Synthesis of (S)-2-[N-(N0-benzylprolyl)amino]benzophenone (BPB)
To a solution of BP (78 g, 0.4 mol) in CH2Cl2 (400 ml) was added freshly distilled SOCl2 (35.5 g, 0.5
mol), with stirring, at −20°C or −30°C within a period of 10 min. The stirring was continued at −10°C
until the reaction mixture became almost transparent. Then a solution of 2-aminobenzophenone (50 g,
0.25 mol) in CH2Cl2 (200 ml) was added to the reaction mixture at −30°C with stirring. The stirring was
continued at the ambient temperature for another 10 h and then a solution of Na2CO3 (80 g, 0.76 mol) in
water (300 ml) was added to the reaction mixture with stirring at 0°C. The organic layer was separated,
the aqueous layer extracted several times with CH2Cl2 (2×75 ml) and the organic solutions were
combined and evaporated. The residue was crystallized from EtOH (150 ml). The crystalline product was
filtered, the filtrate evaporated and the residue crystallized from EtOH. The combined crystalline product
was dried over P2O5 in vacuo to give 79.4 g (81% calculated on the initial 2-aminobenzophenone) of
BPB (m.p. 101–102°C, [α]D −134, c=1 in MeOH, lit.3 m.p. 101–102°C, [α]D −134.5, c=0.5 in
MeOH). Additional amounts of the hydrochloride of BPB were recovered from the mother liquor by
the addition of concentrated aqueous HCl until pH 1 (indicator paper) and evaporation to dryness. The
insoluble BPB·HCl was purified by washing the residue with acetone. The procedure could be scaled up
to 1–2 kg of BPB production.
20
25
1.3. Syntheses of Gly-Ni-BPB and Ala-Ni-BPB
A solution of KOH (78.4 g, 1.4 mol) in MeOH (300 ml) was poured into a mechanically stirred mixture
of BPB (76.8 g, 0.2 mol), Ni(NO3)2·6H2O (116.3 g, 0.4 mol), glycine (75 g, 1 mol) or alanine (36 g, 0.4
mol) in MeOH (700 ml) under inert gas at 40–50°C. The resulting mixture was stirred at 55–65°C for
1 h in the case of Gly-Ni-BPB and 2 h in the case of Ala-Ni-BPB (a prolonged heating of the reaction
mixture might result in a partial racemization of the BPB moiety) and then neutralized with AcOH (80
ml, 1.4 mol) and diluted with water to 3 litre volume. After 6 h the separated crystalline solid was filtered
and washed twice with water. The complexes were sufficiently pure for further use without additional
purification. In the case of the preparation of Ala-Ni-BPB, the employment of enantiomerically pure
(S)- or racemic (R,S)-alanine had no influence on the final diastereomeric purity (>90%) of the isolated
(S)-Ala-Ni-BPB. The complex could be further used for the synthesis of α-methyl-α-amino acids, as
described previously.1a
The same procedure was shown to be valid for the syntheses, starting with BPB·HCl. In this form the
chiral auxiliary was usually isolated after the alkylation procedures.1 An additional equivalent amount of
KOH should be used to neutralize the HCl evolving in the case of Ni-complex synthesis.
Gly-Ni-BPB. Average yield 91 g (91%). [α]D25 +2006, [α]57825 +2284 (c=0.1 in MeOH), lit.:3 [α]578
+2136.
25
25
(S)-Ala-Ni-BPB (de >90%). Average yield 93 g (91%). [α]D +2643, [α]578 +2967 (c=0.036 in
MeOH).

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Acknowledgements
This work was supported by the EU through INCO-Copernicus grant IC-15-CT96-0722.
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