Efficient resolution of (±)-1-(9-anthryl)ethylamine

Article abstract of DOI:10.1081/SCC-120014769

Conditions for efficient resolution of (±)-1-(9-anthryl)ethylamine ((±)-1) by fractional crystallization of its salts with (S)-(+)-mandelic acid (2) are reported. When crystallization was performed by fast addition of chloroform solution of an equivalent

Full text of DOI:10.1081/SCC-120014769

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EFFICIENT RESOLUTION OF (±)-1-(9-
ANTHRYL)ETHYLAMINE
a
a
b
Marin Roje , Zdenko Hameršak & Vitomir Šunjić
a
“
Ruder Bošković” Institute , P.O. Box 180, Bijenička c. 54, Zagreb, HR-10001, Croatia
Ruder Bošković” Institute , P.O. Box 180, Bijenička c. 54, Zagreb, HR-10001, Croatia
b
“
Published online: 22 May 2009.
To cite this article: Marin Roje , Zdenko Hameršak & Vitomir Šunjić (2002) EFFICIENT RESOLUTION OF (±)-1-(9-
ANTHRYL)ETHYLAMINE, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 32:22, 3413-3417, DOI: 10.1081/SCC-120014769
To link to this article: http://dx.doi.org/10.1081/SCC-120014769
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 22, pp. 3413–3417, 2002
EFFICIENT RESOLUTION OF
(
1)-1-(9-ANTHRYL)ETHYLAMINE
2
ˇ
*
ˇ
ak, and Vitomir Sunjic
´
Marin Roje, Zdenko Hamers
‘
‘Ruder Boskovic’’ Institute, P.O. Box 180,
ˇ
ka c. 54, HR-10001 Zagreb, Croatia
´
Bijenic
ˇ
ABSTRACT
Conditions for efficient resolution of (ꢀ)-1-(9-anthryl)ethyl-
amine ((ꢀ)-1) by fractional crystallization of its salts with
(
S)-(þ)-mandelic acid (2) are reported. When crystallization
was performed by fast addition of chloroform solution of an
equivalent of (ꢀ)-1 to the hot chloroform solution of (þ)-2,
crystals of mandelate of (þ)-1-(9-anthryl)ethylamine ((R,S)-3)
are collected in 56% yield. (R)-(þ)-1 (98.6% e.e.) is isolated
by extraction from bicarbonate solution of mandelate salt.
Ulterior collection of four crops afforded (R,S)-3 with
7
1.5% cumulative yield and >98% e.e. of (þ)-1 in a any
single crop. With only 0.5 equivalents of (þ)-2 crystallization
afforded (R,S)-3 in 47.4% yield and (þ)-1 with 98.1% e.e.
*
Corresponding author. Fax: (00385)-1-4680195; E-mail: sunjic@rudjer.irb.hr
3
413
DOI: 10.1081/SCC-120014769
Copyright & 2002 by Marcel Dekker, Inc.
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ˇ
ROJE, HAMERSAK, AND SUNJIC
ˇ
´
3
414
Enantiomerically pure 1-arylethylamines emerge as important chiral
[
1,2]
auxiliaries in stoichiometric and catalytic asymmetric reactions,
and for
enantiorecognition. Whereas both enantiomers of phenylethylamine are
[3]
[
4]
nowadays biotechnologically produced in multiton quantities, and
[
have found application on an industrial scale, enantiomerically pure
-(1-naphthyl)ethylamine still represents an expensive laboratory reagent.
5]
[
6]
1
A number of 1-arylethylamines are nowadays available in the enantiomeri-
cally pure form following ‘‘family approach’’ to the resolution of their
[7]
racemates. Neither racemic nor enantiomerically pure 1-(9-anthryl)ethyl-
amine (1) is commercially available, however. Its use as chiral auxiliary is
described in a few papers, where the authors have reported resolution of
racemate to (À)-1 via (À)-mandelic acid salt. This enantiomer was obtained
in a very low (8%) yield (>99% e.e.) only after repeated crystallizations of
[
8,9]
its mandelate salt from ethanol.
been assigned on the bases of the NMR spectra of its camphanic acid
Absolute (R) configuration of (þ)-1 has
[10]
amide,
and calculated CD spectra of its s-triazine derivative.
We have recently attempted resolution of racemic 1, via enantio-
and more recently confirmed by the analysis of the experimental
[
9b]
[
11]
selective acetylation (kinetic resolution) by lipases in organic solvents.
Best results (E>200) were obtained only at low conversions (<30%) with
Candida antarctica A lipase, which were also difficult to reproduce on a
larger scale. Prompted by this result, and inefficient resolutions reported
[
8,9]
previously,
1
we have focused our attention on resolution of the racemic
by crystallisation, Sch. 1.
On screening, chloroform turned out as the solvent of choice, while
[
8]
formerly used ethanol proved inconvenient. We also observed that the
traditional crystallisation procedure, mixing of equimolar quantities of the
solid racemate and optically pure acid in the selected solvent and then
heating, inevitably led to partial crystallisation of optically impure
(
R,S)-3. Examination of the solubility of the samples of pure diastereomeric
salts revealed very low (0.9 mg/mL) solubility of (S)-(þ)-mandelate salt of
(
þ)-1 ((R,S)-3) in chloroform, and surprisingly, complete miscibility of the
oily mandelate of (À)-enantiomer ((S,S)-3), with this solvent. We also
Scheme 1.

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(
1)-1-(9-ANTHRYL)ETHYLAMINE
3415
2
observed that solubility of (þ)-mandelic acid ((S)-(þ)-2) rises from
ꢁ ꢁ
5 mg/mL at 20 C to 45 mg/mL at 60 C. Having these data at hand, we
1
completed fractional crystallisation by fast addition of the saturated sol-
ution of (ꢀ)-1 in chloroform to hot, saturated solution of (þ)-2 in the
same solvent. On slow crystallisation (R,S)-3 was obtained in 56% yield,
and (R)-(þ)-1 was isolated with 98.6% e.e. On repeated partial evaporation
and crystallisation additional crops of (R,S)-3 were collected; 71.5% overall
yield was achieved and the isolate (þ)-1 regularly exhibited >98% e.e.
In view of the large difference in solubility of the two diastereomeric
salts, in the set of experiments an attempt was made to ‘‘titrate’’ racemic
amine by less than equimolar quantity of acid (þ)-2, expecting selective
recovery of (R)-(þ)-1 in the less soluble salt (R,S)-3. Quite promising results
were obtained; e.g., with 0.5 mol equivalent of (þ)-1 47.8% yield and 98.1%
e.e. of the salt (R,S)-3, obtained in two crops. This yield is ca 10% lower
than obtained at the same concentration of (ꢀ)-3 with equimolar quantity of
acid (þ)-2, while the e.e. is only slightly lower.
Finally, it is interesting that using various ratios of (ꢀ)-1/(þ)-2 a much
higher quantity of (R,S)-3 salt remained in solution then expected from its
very low solubility, indicating certain ‘‘salting in’’ effect of the second dia-
stereomeric salt.
In conclusion, efficient resoluton of (ꢀ)-1 is completed in two different
modes, by crystallization of its salt with (þ)-mandellic acid in chloroform,
which substantially improve former results and is amenable to the large-
scale preparation of (þ)-1 with high enantiomeric purity.
EXPERIMENTAL
A typical experimental procedure of the resolution of (ꢀ)-1 is as
ꢁ
follows: to the hot, ca 60 C, solution of (þ)-2 (880 mg, 5.8 mmol) in
CHCl (30 mL) amine (ꢀ)-1 (1280 mg, 5.8 mmol) in CHCl (5.0 mL) was
3
3
added in one shot. This solution was seeded, while hot, with crystals of
mandelate salt (R,S)-3, then slowly cooled to room temperature and kept
ꢁ
at 5 C overnight. Precipitate was collected on filter and washed with cold
CHCl (2 Â 5.0 mL), to obtain diastereomeric salt (R,S)-3, colourless to
3
ꢁ
25
slightly yellow crystals (610 mg, 56%), m.p. 193–194 C, ½ꢀŠ þ 9.0
D
(
6
c ¼ 1.0, EtOH). Anal. calcd. for C H NO (373.46): C 77.19%, H
2
4
23
3
.21%, N 3.75%. Found: C 77.42%, H 6.46%, N 3.91%.
This salt was suspended in CH Cl (20 mL) and satd. aqueous
2
2
NaHCO solution was added dropwise to the stirred suspension. Stirring
3
was continued for 45 min at r.t., and the resulting mixture extracted with
CH Cl (3 Â 15 mL). Organic extracts were dried, filtered and evaporated
2
2

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ˇ ˇ
´
ROJE, HAMERSAK, AND SUNJIC
3
416
affording pure (R)-(þ)-1 (355 mg, quantitative) pale yellow crystals, m.p.
ꢁ
1
10–113 C, e.e. 98.6% [ꢀ] þ 18.0 (c ¼ 1.0, CHCl ).
D
3
The HPLC conditions for enantioseparation of (ꢀ)-1 were as follows:
Chiralcel OD-R column (250 Â 4.6 mm), MeCN/0.5 M NaClO pH 2.5
4
(
HClO ) (7 : 3) as mobile phase, flow 0.5 mL/min, UV detector at 254nm.
4
Note: The solubility of mandelic acid in CHCl3 was determined
gravimetrically, the solubility of the diastereomeric salt (R,S)-3 was
determined spectrophotometrically at 366 nm, both for samples from satd.
thermostated solutions.
ACKNOWLEDGMENT
This work was supported by the Ministry of Science and Technology,
Republic of Croatia, grant No. 980701.
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(
1)-1-(9-ANTHRYL)ETHYLAMINE
3417
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, V. Tetrahedron:
1
Received in the Netherlands November 11, 2001

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