Self-disproportionation of enantiomers of non-racemic chiral amine derivatives through achiral chromatography

Article abstract of DOI:10.1016/j.tet.2012.03.054

Efficient self-disproportionation of enantiomers of several non-racemic chiral amines was achieved through conversion to N-acetamides and subsequent MPLC using an achiral column. The MPLC of these non-racemic N-acetamide derivatives gave the chart having a clear boundary between two fractions. Thus, in the less polar fraction, remarkable enantiomer enrichment was observed (>99%ee), while the ee of more polar fraction was considerably reduced. The magnitude of the enantiomer enrichments and depletions strongly depended on substituent on the amino group.

Full text of DOI:10.1016/j.tet.2012.03.054

Tetrahedron 68 (2012) 4013e4017
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Self-disproportionation of enantiomers of non-racemic chiral amine derivatives
through achiral chromatography
Tsuyoshi Nakamura a, Kaori Tateishi a, Shiori Tsukagoshi a, Saori Hashimoto a, Shotaro Watanabe b,
,
d
c
a,
*
Vadim A. Soloshonok c , Jose Luis Acena , Osamu Kitagawa
ꢀ
~
a Department of Applied Chemistry, Shibaura Institute of Technology, 3-7-5 Toyosu, Kohto-ku, Tokyo 135-8548, Japan
b TAIHO Pharmaceutical Co., Ltd., 200-22, Motohara, Kamikawa-machi, Kodama-gun, Saitama 367-0241, Japan
c Department of Organic Chemistry I, University of Basque Country, San Sebastian 20018, Spain
d IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 March 2012
Received in revised form 16 March 2012
Accepted 18 March 2012
Available online 23 March 2012
Efficient self-disproportionation of enantiomers of several non-racemic chiral amines was achieved
through conversion to N-acetamides and subsequent MPLC using an achiral column. The MPLC of these
non-racemic N-acetamide derivatives gave the chart having a clear boundary between two fractions.
Thus, in the less polar fraction, remarkable enantiomer enrichment was observed (>99%ee), while the ee
of more polar fraction was considerably reduced. The magnitude of the enantiomer enrichments and
depletions strongly depended on substituent on the amino group.
Keywords:
Enantiomers
Ó 2012 Elsevier Ltd. All rights reserved.
Enrichment
Self-disproportionation
Chromatography
Phenylethylamines
1. Introduction
conditions of achiral chromatography is of very general nature
and should be expected for any structural type of chiral com-
Since the fundamental work by Kagan1 and Noyori2 it is well
known that in a solution, enantiomerically enriched compounds
usually aggregate to form either homo- or heterochiral higher order
species.3 Such species, for instance dimers, have different chemical
and physical properties as compared to monomers, giving rise to
various non-linear phenomena.3c This behavior is particularly im-
portant in the area of asymmetric catalysis and has received com-
prehensive experimental and theoretical treatment.4 On the other
hand, the effect of the formation of such high order species on
behavior of enantiomerically enriched compounds under condition
of achiral chromatography is still largely overlooked and virtually
unstudied.5,6 Similarly to the non-linear effects in asymmetric ca-
talysis, for instance, homo- or heterochiral dimers and the corre-
sponding monomers, have different chromatographic behavior and
thus can be separated under totally achiral conditions.6,7 This
process is one of the manifestations of Self-Disproportionation of
Enantiomers (SDE)8 and usually results in separation of racemic
form from the excess enantiomer. Literature results5,6 as well
as theoretical treatment7 clearly suggest that SDE under the
pounds. However, as mentioned above, this effect remains un-
derappreciated and has never received a systematic study. As
pointed out by many authors6 there are at least two issues of
greater importance to be addressed: first, unawareness of the SDE
can result in mistaken determination of enantiomeric purity if
a sample was chromatographically treated; and second, there is
clearly unexplored potential of the SDE via achiral chromatography
as a new optical purification technique.
In this paper, we report our results on studying the SDE in
a series of amides derived from several chiral amines via achiral
MPLC. Namely, we found that MPLC of N-acetyl derivatives of var-
ious chiral amines gave the chart having a clear boundary, and in
the less polar fraction, remarkable enantiomer enrichment was
observed (>99%ee). Furthermore, the magnitude of the SDE was
clarified to strongly depend on substituent on the amino group.
2. Results and discussion
First we studied the chromatographic behavior of 1-
phenylethylamine (PEA) derivatives. The choice of this substrate
was based on several considerations. PEA is structurally very sim-
ple, and if a significant magnitude of the SDE is found, this would
* Corresponding author. E-mail address: kitagawa@shibaura-it.ac.jp (O. Kitagawa).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.054

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T. Nakamura et al. / Tetrahedron 68 (2012) 4013e4017
serve as warning because PEA is used as a classical compound to be
prepared in the development of asymmetric synthesis of chiral
amines. In addition, PEA and its derivatives are the most studied
and used chiral auxiliaries, and thus its chemical, physicochemical,
and chirooptical properties have been studied for about a century.9
Therefore, it could hardly be expected that application of regular
silica gel for purification of its enantiomerically enriched forms can
present any surprise to organic chemists.
possible prospective or this research area for the development of
new optical purification method, we would like to emphasize that
the isolated 24 mg of enantiomerically pure (S)-1a in fact consti-
tutes about 66% of the theoretical yield with which the excess (S)-
enantiomer can possibly be separated from the racemic form. One
should also note that purification procedure was remarkably easy
and time-efficient taking less than 2 h of chromatography pro-
cedure time-span.
To achieve efficient SDE of PEA, we performed a detailed survey
of substituents on the amino group. 1-Phenylethylamine de-
rivatives 1aei (w70%ee, w50 mg) having various N-substituents
were prepared, and the MPLC using an achiral column (packed
The choice of an eluent is important for the present SDE. When
n-hexane and 2-propanol instead of n-hexane and ethyl acetate
were used as eluent in MPLC of 1a, no SDE was observed.
Our next goal was to study possible effect of the initial enan-
tiomeric purity of amide 1a on magnitude of the SDE and the ap-
plicability, as well efficiency, of this optical purification procedure
for compounds of various enantiomeric purities. To this end we
investigated chromatographic behavior of three samples of 1a of
60%ee, 49%ee, 30%ee. The results obtained (Fig. 2), clearly show that
the initial enantiomeric purity of the samples has virtually no effect
on their chromatographic behavior and the efficiency of this
method in preparation of enantiomerically pure amide 1a. In all
cases studied separation of racemic and enantiomerically pure
peaks were observed appearing in the same order and at about
the same retention times. One may conclude that these prelimi-
nary results suggest rather high degree of generality of SDE via
achiral chromatography as optical purification procedure, in terms
of %ee of a given sample. In our opinion, it is quite a significant
feature rendering this method potentially superior to the conven-
tional approach via recrystallization, in particular, for preparation
of enantiomerically pure samples starting from compounds of
low %ee.
10
m
m of silica gel, 20ꢀ250 mm) was subsequently performed
(Table 1). Mixtures of n-hexane and ethyl acetate were used as el-
uents, and the polarity of each eluent was adjusted in order to show
similar retention times (ca. 1 h) for all compounds 1aei.
Table 1
MPLC separation of various non-racemic phenethylamine derivatives 1aei
less polar
MPLC using
achiral SiO2 column
NHR
Me
fraction
+
Ph
eluent: hexane/AcOEt
more polar
fraction
1 (~ 70%ee)
Entry
1 (mg,a %eeb)
R
Less polar
More polar
fraction mg,c %eeb
fraction mg,c %eeb
1
2
3
4
5
6
7
8
9
1a (51, 71)
1b (50, 69)
1c (51, 71)
1d (48, 70)
1e (57, 72)
1f (51, 74)
1g (50, 70)
1h (50, 70)
1i (50, 68)
CH3CO
HCO
24, >99
21, >99
17, >99
20, >99
6, 93
21, 28
24, 40
31, 55
28, 55
33, 65
36, 70
41, 65
36, 62
39, 67
C2H5CO
n-C4H9CO
c-C6H11CO
CF3CO
PhCO
9, 93
7, >99
11, 97
7, 73
more polar
fraction
less polar
fraction
> 99%ee
(22 mg)
COOMe
Ts
26%ee
(28 mg)
NHAc
CH3
a
Injection weight.
The ee was determined by HPLC analysis using a chiral column.
Recovery weight.
b
c
1a (51mg, 60%ee)
Among 1aei, MPLC of acetamide 1a showed the best SDE (Fig. 1
and Table 1). That is, the MPLC chart of 1a (71%ee, 51 mg) shows
two distinct peaks and looks like a regular chart observed for
a mixture of two chemically different compounds (Fig.1). Indeed, in
this case the enantiomerically pure and racemic forms of com-
pound 1a do behave as two different compounds giving maxima
with different retention times. The eluted product was collected in
two fractions across the boundary point. Analysis of enantiomeric
purity (chiral HPLC) of these fractions showed that less polar frac-
tion (24 mg) contained enantiomerically pure (S)-1a (>99%ee)
while the second fraction (21 mg) was of only 28%ee. Considering
40 (min)
50
60
70
80
retention time
more polar
less polar
fraction
> 99%ee
(16 mg)
fraction
26%ee
(32 mg)
NHAc
CH3
1a (50mg, 49%ee)
40
(min)
50
60
70
80
retention time
less polar fraction
>99%ee (24 mg)
more polar
fraction
12.5%ee
(39 mg)
less polar
fraction
> 99%ee
(11 mg)
more polar fraction
28%ee (21 mg)
NHAc
Me
NHAc
CH3
1a (51 mg, 71%ee)
1a (50mg, 30%ee)
(min)
40
50
60
50 (min)
70
70
60
80
(retention time)
retention time
Fig. 1. MPLC chart of 1a (71%ee, eluent: hexane/EtOAc¼5/4).
Fig. 2. MPLC chart of 1a (60%ee, 49%ee, and 30%ee, eluent: hexane/AcOEt¼1).

T. Nakamura et al. / Tetrahedron 68 (2012) 4013e4017
4015
Table 2
Similar efficient SDE was also observed in MPLC of formamide
MPLC separation of various non-racemic N-acetyl chiral amines 2ae5a
1b. MPLC chart of 1b (69%ee, 50 mg) showed a clear boundary, and
the ee of 1b in the less polar fraction and more polar fraction were
>99%ee (21 mg) and 40%ee (24 mg), respectively (Table 1, entry 2,
see Supplementary data). Although the efficiency slightly reduced
in comparison with 1a and 1b, under similar conditions, non-
racemic propanamide 1c (71%ee) and pentanamide 1d (70%ee)
were also separated to less polar fractions involving almost opti-
cally pure forms and more polar fraction involving lower ee of
substrates (entries 3 and 4, see Supplementary data).
The magnitude of the SDE strongly depends on the substituent
on the amino group (Table 1). In MPLC of cyclohexane carboxamide
1e, trifluoroacetamide 1f, benzamide 1g, and methyl carbamate 1h,
the boundary of the peak for the separation is unclear (1h: Fig. 3,
1eeg: see Supplementary data), and the recovery yields and optical
purities (93e99%ee) of 1eeh obtained from each less polar frac-
tions significantly decreased in comparison with those (>99%ee) of
1aed (entries 5e8). With tosyl amide 1i, SDE was hardly observed
(entry 9). Based on the data obtained, it seems reasonable to con-
clude that a linear aliphatic acyl group on the nitrogen atom is most
favorable for intermolecular interaction.
less polar
MPLC using
achiral SiO2 column
NHAc
R'
fraction
R
+
eluent: hexane/AcOEt
more polar
fraction
(~ 70%ee)
2a-5a
Entry
1
2ae5a
Less polar fractionb More polar fractionb
NHAc
Me
29 mg
23 mg
42%ee
>99%ee
Me
2a (53 mg, 70%ee) a
NHAc
Me
2
28 mg
>99%ee
24 mg
35%ee
MeO
3a (54 mg, 71%ee) a
Me
NHAc
less polar fraction
more polar fraction
97%ee (11 mg)
62%ee (36 mg)
O
3
4
24 mg
>99%ee
18 mg
22%ee
MeO NH
Me
4a (50 mg, 67%ee) a
COOEt
1h (50 mg, 70%ee)
17 mg
>99%ee
32 mg
52%ee
NHAc
5a (50 mg, 69%ee) a
(min)
50
70
60
aInjection weight and the ee are described.
retention time
b
Recovery weight and ee of each fractions are described.
Fig. 3. MPLC chart of 1h (70%ee, eluent: hexane/EtOAc¼14).
under chromatographic conditions the racemic form of 1a is locked
in high order aggregates (dimers, oligomers) while excess enan-
tiomer 1a is present mostly in monomeric less polar form.
The present SDE was also applied to other chiral amine de-
rivatives. Three readily available N-acetyl derivatives bearing
p-methyl 2a, p-methoxy 3a groups as well as
b-(naphthyl)ethyl
3. Conclusion
amine derived amide 4a were investigated. The chromatographic
data obtained are presented in Table 2 (entries 1e3). In all of these
three cases clear separation of peaks was observed (see
Supplementary data) and the first, less polar fraction furnished
enantiomerically pure (R)-2a, (R)-3a, and (R)-4a, respectively. Also,
the recovery of the excess enantiomer was in the range of practi-
cally useful method. These data strongly suggest that substituent
on the phenyl ring of the N-acetyl amide 1a is of much less im-
portance for the magnitude of the SDE and may be of quite general
nature.
Although the boundary for the separation was slightly unclear
and the magnitude reduced, the SDE was also observed in N-acetyl
derivative of an amino acid. Non-racemic N-acetyl phenylalanine
ethyl ester 5a (69%ee, 50 mg) was separated to >99%ee (17 mg) and
52%ee (32 mg) of 5a through the MPLC (entry 4).
We found that SDE via MPLC of N-acetyl derivatives of various
chiral amines has a noticeable magnitude and is of rather general
nature. These results suggest that application of achiral chroma-
tography for chemical purification of this type of compounds
should be handled with caution as it may influence their enantio-
meric composition. Of particular importance is that MPLC can be
used for practical separation of racemic form from excess enan-
tiomer and thus provide an alternative and reliable method for
preparation of enantiomerically pure compounds. The elucidation
of the mechanism for efficient SDE of chiral amines using N-acetyl
derivatives is currently in progress.
4. Experimental
In all substrates 1aeh and 2ae5a, which brought about SDE, less
polar fraction led to increase in the ee and more polar fraction
resulted in the decrease in the ee.
4.1. General techniques
While the detailed mode of intramolecular interactions of the
compounds is unclear at the present time, a tentative rational for
racemic fraction being more polar can be derived from X-ray data of
the amide 1a.10 Thus, both racemic 1a and enantiomerically pure
(S)-1a form infinite hydrogen bonding between NeH/O atoms.
The difference however is that (S)-1a forms isotactic and racemic 1a
syndiotactic chains. The latter arrangement is less organized and
easier to form in solution phase. Therefore, one may assume that
Melting points were uncorrected. 1H and 13C NMR spectra were
recorded on a 300 MHz spectrometer. In 1H and 13C NMR spectra,
chemical shifts were expressed in
(7.26 ppm) and CDCl3 (77.0 ppm), respectively. Mass spectra were
recorded by electron impact or chemical ionization. Column chro-
matography was performed on silica gel (75e150 mm). Medium-
pressure liquid chromatography (MPLC) was performed on
d (ppm) downfield from CHCl3
a 25ꢀ4 cm i. d. prepacked column (silica gel, 10
mm) with a UV

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T. Nakamura et al. / Tetrahedron 68 (2012) 4013e4017
detector. High-performance liquid chromatography (HPLC) was
performed on a 25ꢀ0.4 cm i. d. chiral column with a UV detector.
(0.067 mL, 0.5 mmol) in accordance with the procedure for the
synthesis of 1a. Purification of the residue by column chroma-
tography (hexane/AcOEt¼1) gave 1e (102 mg, 88%). 1H NMR of 1e
coincided with that of literature.15 Subsequently, 1e (57 mg, 72%
ee) was separated to less polar fraction (6 mg, 93%ee) and more
polar fraction (33 mg, 65%ee) by MPLC (hexane/AcOEt¼8). The ee
of 1e was determined by HPLC analysis using a CHIRALPACK AD
column [25 cmꢀ0.46 cm i.d.; 5% i-PrOH in hexane; flow rate,
1.0 mL/min; (S)-1e (major); tR¼16.0 min, (R)-1e (minor);
tR¼11.3 min].
4.2. Synthesis and chromatographic properties of various
chiral amides (all amides 1aeh and 2ae5a are known
compounds)
4.2.1. (S)-N-(1-Phenylethyl)acetamide (1a). (S)-1-Phenylethylamine
and (R)-phenylethylamine were mixed in a ratio of 85/15. To the
mixture (242 mg, 2.0 mmol) in THF (6.0 mL) were added Et3N
(0.42 mL, 3.0 mmol) and acetyl chloride (0.14 mL, 2.0 mmol) at 0 ꢁC.
After being stirred for 15 min at rt, the mixture was poured into
NH4Cl aq and extracted with AcOEt. The AcOEt extracts were washed
with brine, dried over MgSO4, and evaporated to dryness. Purifica-
tion of the residue by column chromatography (hexane/AcOEt¼1)
gave 1a (319 mg, 98%). 1H NMR of 1a coincided with that of litera-
ture.11 Subsequently, 1a (51 mg, 71%ee) was separated to less polar
fraction (24 mg, >99%ee) and more polar fraction (21 mg, 28%ee) by
MPLC (hexane/AcOEt¼5/4). The ee of 1a was determined by HPLC
analysis using a CHIRALPACK AD column [25 cmꢀ0.46 cm i.d.; 5% i-
PrOH in hexane; flow rate, 1.5 mL/min; (S)-1a (major); tR¼11.1 min,
(R)-1a (minor); tR¼9.0 min].
4.2.6. (S)-N-(1-Phenylethyl)trifluoroacetamide
(1f). Compounds
(S)-1f and (R)-1f (commercially available) were mixed in a ratio of
85/15. Subsequently, 1f (51 mg, 74%ee) was separated to less polar
fraction (9 mg, 93%ee) and more polar fraction (36 mg, 70%ee) by
MPLC (hexane/AcOEt¼50). The ee of 1f was determined by HPLC
analysis using a CHIRALPACK AD column [25 cmꢀ0.46 cm i.d.; 10%
i-PrOH in hexane; flow rate, 1.0 mL/min; (S)-1f (major);
tR¼14.5 min, (R)-1f (minor); tR¼12.5 min].
4.2.7. (S)-N-(1-Phenylethyl)benzamide (1g). Compound 1g was
prepared from 1-phenylethylamine (121 mg, 1.0 mmol, S/R¼85/15)
and benzoyl chloride (0.12 mL, 1.0 mmol) in accordance with the
procedure for the synthesis of 1a. Purification of the residue by
column chromatography (hexane/AcOEt¼4) gave 1g (221 mg, 98%).
1H NMR of 1g coincided with that of literature.16 Subsequently, 1g
(50 mg, 70%ee) was separated to less polar fraction (7 mg, >99%ee)
and more polar fraction (41 mg, 65%ee) by MPLC (hexane/
AcOEt¼21/2). The ee of 1g was determined by HPLC analysis using
a CHIRALPACK OD-3 column [25 cmꢀ0.46 cm i.d.; 5% i-PrOH in
hexane; flow rate, 1.5 mL/min; (S)-1g (major); tR¼23.6 min, (R)-1g
(minor); tR¼15.4 min].
4.2.2. (S)-N-(1-Phenylethyl)formamide(1b). To the 1-phenyletylamine
(242 mg, 2.0 mmol, S/R¼85/15) in toluene (5.0 mL) were added hexane
solution of Me3Al (1.4 mL,1.5 mmol) and subsequently methyl formate
(0.097 mL, 2.4 mmol) at 0 ꢁC. After being stirred for 1.5 h at rt, the
mixture was poured into 2 N HCl and extracted with AcOEt. The AcOEt
extracts were washed with brine, dried over MgSO4, and evaporated to
dryness. Purification of the residue by column chromatography (hex-
ane/AcOEt¼1) gave 1b (244 mg, 82%). 1H NMR of 1b coincided with
that of literature.12 Subsequently, 1b (50 mg, 69%ee) was separated to
less polar fraction (21 mg, >99%ee) and more polar fraction (24 mg, 40%
ee) by MPLC (hexane/AcOEt¼7/5). The ee of 1b was determined by
HPLC analysis using a CHIRALPACK OD-3 column [25 cmꢀ0.46 cm i.d.;
5% i-PrOH in hexane; flow rate, 1.5 mL/min; (S)-1b (major);
tR¼19.9 min, (R)-1b (minor); tR¼15.2 min].
4.2.8. (S)-Methyl (1-phenylethyl)carbamate (1h). Compound 1h
was prepared from 1-phenylethylamine (61 mg, 0.5 mmol, S/R¼85/
15) and methyl chloroformate (0.057 mL, 0.6 mmol) in accordance
with the procedure for the synthesis of 1a. Purification of the res-
idue by column chromatography (hexane/AcOEt¼3) gave 1h
(72 mg, 80%). 1H NMR of 1h coincided with that of literature.17
Subsequently, 1h (50 mg, 70%ee) was separated to less polar frac-
tion (11 mg, 97%ee) and more polar fraction (36 mg, 62%ee) by
MPLC (hexane/AcOEt¼14). The ee of 1h was determined by HPLC
analysis using a CHIRALPACK AD column [25 cmꢀ0.46 cm i.d.; 3% i-
PrOH in hexane; flow rate, 1.0 mL/min; (S)-1h (major); tR¼13.1 min,
(R)-1h (minor); tR¼11.8 min].
4.2.3. (S)-N-(1-Phenylethyl)propamide (1c). Compound 1c was
prepared from 1-phenylethylamine (242 mg, 2.0 mmol, S/R¼85/15)
and propionyl chloride (0.175 mL, 2.0 mmol) in accordance with the
procedure for the synthesis of 1a. Purification of the residue by col-
umn chromatography (hexane/AcOEt¼1) gave 1c (308 mg, 87%). 1H
NMRof1ccoincided withthatofliterature.13 Subsequently,1c(51 mg,
71%ee) was separated to less polar fraction (17 mg, >99%ee) and more
polar fraction (31 mg, 55%ee) by MPLC (hexane/AcOEt¼7/2). The ee of
1c was determined by HPLC analysis using a CHIRALPACK AD column
[25 cmꢀ0.46 cm i.d.; 5% i-PrOH in hexane; flow rate,1.5 mL/min; (S)-
1c (major); tR¼10.3 min, (R)-1c (minor); tR¼8.1 min].
4.2.9. (S)-(1-Phenylethyl)-4-methylbenzenesulfonamide
(1i). Compound 1i was prepared from 1-phenylethylamine
(200 mg, 1.65 mmol, S/R¼85/15) and p-toluenesulfonyl chloride
(312 mg, 1.65 mmol) in accordance with the procedure for the
synthesis of 1a. Purification of the residue by column chroma-
tography (hexane/AcOEt¼5) gave 1i (454 mg, quant.). 1H NMR of
1i coincided with that of literature.18 Subsequently, 1i (50 mg, 68%
ee) was separated to less polar fraction (7 mg, 73%ee) and more
polar fraction (39 mg, 67%ee) by MPLC (hexane/AcOEt¼13). The ee
of 1i was determined by HPLC analysis using a CHIRALPACK AS
column [25 cmꢀ0.46 cm i.d.; 10% i-PrOH in hexane; flow rate,
1.5 mL/min; (S)-1i (major); tR¼15.0 min, (R)-1i (minor);
tR¼12.0 min].
4.2.4. (S)-N-(1-Phenylethyl)pentamide (1d). Compound 1d was
prepared from 1-phenylethylamine (121 mg, 1.0 mmol, S/R¼85/15)
and methyl pentanoate (0.12 mL, 0.9 mmol) in accordance with the
procedure for the synthesis of 1b. Purification of the residue by
column chromatography (hexane/AcOEt¼3) gave 1d (174 mg, 85%).
1H NMR of 1d coincided with that of literature.14 Subsequently, 1d
(48 mg, 70%ee) was separated to less polar fraction (20 mg, >99%
ee) and more polar fraction (28 mg, 55%ee) by MPLC (hexane/
AcOEt¼11/2). The ee of 1d was determined by HPLC analysis using
a CHIRALPACK AD column [25 cmꢀ0.46 cm i.d.; 5% i-PrOH in hex-
ane; flow rate, 1.0 mL/min; (S)-1d (major); tR¼7.2 min, (R)-1d
(minor); tR¼5.4 min].
4.2.10. (R)-N-(1-(4-Tolyl)ethyl)acetamide (2a). Compound 2a was
prepared from 1-(4-tolyl)ethylamine (260 mg, 1.92 mmol, R/S¼85/
15) and acetyl chloride (0.14 mL, 1.92 mmol) in accordance with the
procedure for the synthesis of 1a. Purification of the residue by
column chromatography (hexane/AcOEt¼1/2) gave 2 (212 mg,
62%). 1H NMR of 2a coincided with that of literature.11
4. 2. 5. (S)-N-(1-Phenylethyl)cyclohexanecarboxamide
(1e). Compound 1e was prepared from 1-phenylethylamine
(61 mg, 0.5 mmol, S/R¼85/15) and cyclohexylcarbonyl chloride

T. Nakamura et al. / Tetrahedron 68 (2012) 4013e4017
4017
Subsequently, 2a (53 mg, 70%ee) was separated to less polar frac-
tion (29 mg, >99%ee) and more polar fraction (23 mg, 42%ee) by
MPLC (hexane/AcOEt¼1). The ee of 2a was determined by HPLC
analysis using a CHIRALPACK AD column [25 cmꢀ0.46 cm i.d.; 5% i-
PrOH in hexane; flow rate, 1.5 mL/min; (R)-2a (major); tR¼8.1 min,
(S)-2a (minor); tR¼10.7 min].
10% i-PrOH in hexane; flow rate, 1.0 mL/min; (R)-5a (major);
tR¼9.2 min, (S)-5a (minor); tR¼11.0 min].
Supplementary data
Copies of 1H and 13C NMR spectra and MPLC charts of all com-
pounds 1aei and 2ae5a. Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/
j.tet.2012.03.054.
4.2.11. (R)-N-(1-(4-Methoxyphenyl)ethyl)acetamide (3a). Compound
3a was prepared from 1-(4-methoxyphenyl)ethylamine (200 mg,
1.32 mmol, R/S¼85/15) and acetyl chloride (0.094 mL, 1.32 mmol) in
accordance with the procedure for the synthesis of 3a. Purification of
the residue by column chromatography (hexane/AcOEt¼1/2) gave
3a (224 mg, 88%). 1H NMR of 3a coincided with that of literature.11
Subsequently, 3a (54 mg, 71%ee) was separated to less polar frac-
tion (85 mg, >99%ee) and more polar fraction (92 mg, 35%ee) by
MPLC (hexane/AcOEt¼17/16). The ee of 3 was determined by HPLC
analysis using a CHIRALPACK AD column [25 cmꢀ0.46 cm i.d.; 5%
i-PrOH in hexane; flow rate, 1.5 mL/min; (R)-3a (major);
tR¼12.8 min, (S)-3a (minor); tR¼17.1 min].
References and notes
1. Puchot, C.; Samuel, O.; Dunach, E.; Zhao, S.; Agami, C.; Kagan, H. B. J. Am. Chem.
Soc. 1986, 108, 2353.
2. Kitamura, M.; Suga, S.; Oka, H.; Noyori, R. J. Am. Chem. Soc. 1998, 120, 9800.
3. (a) Williams, T.; Pitcher, R. G.; Bommer, P.; Gutzwiller, J.; Uskokovic, M. J. Am.
Chem. Soc. 1969, 91, 1871; (b) Dobashi, A.; Saito, N.; Motoyama, Y.; Hara, S. J. Am.
Chem. Soc. 1986, 108, 307; (c) Baciocchi, R.; Juza, M.; Classen, J.; Mazzotti, M.;
ꢀ
Morbidelli, M. Helv. Chim. Acta 2004, 87, 1917; (d) Klika, K. D.; Budovska, M.;
ꢀ
Kutschy, P. J. Fluorine Chem. 2010, 131, 46; (e) Klika, K. D.; Budovska, M.; Kutschy,
P. Tetrahedron: Asymmetry 2010, 21, 647.
4. Blackmond, D. G. Tetrahedron: Asymmetry 2010, 21, 1630.
4.2.12. (R)-N-(1-(Naphthalene-1-yl)ethyl)acetamide (4a). Compound
4a was prepared from 1-(naphthalene-1-yl)ethylamine (50 mg,
0.29 mmol, R/S¼85/15) and acetyl chloride (0.021 mL, 0.29 mmol) in
accordance with the procedure for the synthesis of 1a. Purification of
the residue by column chromatography (hexane/AcOEt¼1) gave 4a
(50 mg, 81%). 1H NMR of 4a coincided with that of literature.11
Subsequently, 4a (50 mg, 67%ee) was separated to less polar frac-
tion (24 mg, >99%ee) and more polar fraction (18 mg, 22%ee) by
MPLC (hexane/AcOEt¼3/2). The ee of 4a was determined by HPLC
analysis using a CHIRALPACK As column [25 cmꢀ0.46 cm i.d.; 10% i-
PrOH in hexane; flow rate, 1.5 mL/min; (R)-4a (major); tR¼12.6 min,
(S)-4a (minor); tR¼10.3 min].
5. For literature reports on SDE via achiral chromatography prior 2006, see re-
view: Soloshonok, V. A.; Berbasov, D. O. Chim. Oggi/Chem. Today 2006, 24, 44.
6. Typical examples of SDE through achiral chromatography: (a) Cundy, K. C.;
Crooks, P. A. J. Chromatogr. 1983, 281, 17; (b) Charles, R.; Gil-Av, E. J. Chromatogr.
1984, 298, 516; (c) Dobashi, A.; Motoyama, Y.; Kinoshita, K.; Hara, S.; Fukasaku,
N. Anal. Chem. 1987, 59, 2209; (d) Matusch, R.; Coors, C. Angew. Chem., Int. Ed.
Engl. 1989, 101, 624; (e) Carman, R. M.; Klika, K. D. Aust. J. Chem. 1991, 44, 895; (f)
Diter, P.; Taudien, S.; Samuel, O.; Kagan, H. B. J. Org. Chem. 1994, 59, 370; (g)
Takahata, H. Yuki Gosei Kagaku Kyokaishi 1996, 54, 708; (h) Kosugi, H.; Abe, M.;
Hatsuda, R.; Uda, H.; Kato, M. Chem. Commun. 1997, 1857; (i) Tanaka, K.; Osuga,
H.; Suzuki, H.; Shogase, Y.; Kitahara, Y. J. Chem. Soc., Perkin Trans. 1 1998, 935; (j)
Stephani, R.; Cesare, V. J. J. Chromatogr., A 1998, 813, 79; (k) Ernholt, B. V.;
Thomsen, I. B.; Lohse, A.; Plesner, I. W.; Jensen, K. B.; Hazell, R. G.; Liang, X.;
Jacobsen, A.; Bols, M. Chem.dEur. J. 2000, 6, 278; (l) Suchy, M.; Kutschy, P.;
Monde, K.; Goto, H.; Harada, N.; Takasugi, M.; Dzurilla, M.; Balentova, E. J. Org.
Chem. 2001, 66, 3940; (m) Soloshonok, V. A. Angew. Chem., Int. Ed. 2006, 45,
766; (n) Takahashi, M.; Tanabe, H. ,; Nakamura, T.; Kuribara, H.; Yamazaki, T.;
Kitagawa, O. Tetrahedron 2010, 66, 288; (o) Ogawa, S.; Nishimine, T.; Tokunaga,
E.; Nakamura, S.; Shibata, N. J. Fluorine Chem. 2010, 131, 521.
4.2.13. (R)-N-Acetyl phenylalanine ethyl ester (5a). (R)-Phenylala-
nine and (R)-phenylethylamine were mixed in a ratio of 85/15. To
the mixture (200 mg, 1.21 mmol) in EtOH (6 mL) was added concd-
H2SO4 (0.065 mL). After heating for 28 h at 80 ꢁC, the mixture was
poured into saturated NaHCO3 aq and extracted with AcOEt. The
AcOEt extracts were washed with brine, dried over Na2SO4, and
evaporated to dryness. To the residue were added Et3N (0.20 mL,
1.49 mmol) and acetyl chloride (0.07 mL, 1.0 mmol). After being
stirred for 10 min at rt, the mixture was poured into NH4Cl and
extracted with AcOEt. The AcOEt extracts were washed with brine,
dried over MgSO4, and evaporated to dryness. Purification of the
residue by column chromatography (hexane/AcOEt¼1/2) gave 5a
(195 mg, 84%). 1H NMR of 5a coincided with that of literature.19
Subsequently, 5a (50 mg, 69%ee) was separated to less polar frac-
tion (17 mg, >99%ee) and more polar fraction (32 mg, 52%ee) by
MPLC (hexane/AcOEt¼2/1). The ee of 5 was determined by HPLC
analysis using a CHIRALPACK OD-3 column [25 cmꢀ0.46 cm i.d.;
7. Trapp, O.; Schurig, V. Tetrahedron: Asymmetry 2010, 21, 1334.
8. (a) Soloshonok, V. A.; Berbasov, D. O. J. Fluorine Chem. 2006, 127, 597; (b) Ueki,
H.; Yasumoto, M.; Soloshonok, V. A. Tetrahedron: Asymmetry 2010, 21, 1396; (c)
Soloshonok, V. A.; Ueki, H.; Yasumoto, M.; Mekala, S.; Hirschi, J. S.; Singleton, D.
A. J. Am. Chem. Soc. 2007, 129, 12112.
ꢀ
9. (a) Juaristi, E.; Escalante, J.; Leon-Romo, J. L.; Reyes, A. Tetrahedron: Asymmetry
ꢀ
1998, 9, 715; (b) Juaristi, E.; Leon-Romo, J. L.; Reyes, A.; Escalante, J. Tetrahedron:
Asymmetry 1999, 10, 2441.
10. Druot, S.; Petit, M. N.; Petit, S.; Coquerel, G.; Chanh, N. B. Mol. Cryst. Liq. Cryst.
1996, 275, 271.
11. Li, G.; Antilla, J. C. Org. Lett. 2009, 11, 1075.
12. Hill, D. R.; Hsiao, C.-N.; Kurukulasuriya, R.; Wittenberger, S. J. Org. Lett. 2002, 4, 111.
13. Claire, R.; David, B. J. Org. Chem. 2011, 76, 6636.
14. Demyanovich, V.; Shishkina, I. N. Khim. Geterotsikl. Soedin. 1996, 944.
15. Funasaka, S.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2008, 81, 148.
16. Kanta De, C.; Klauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2009, 131, 17060.
17. Leathen, M. L.; Peterson, E. A. Tetrahedron Lett. 2010, 51, 2888.
18. Soeta, T.; Nagai, K.; Fujihara, H.; Kuriyama, M.; Tomioka, K. J. Org. Chem. 2003,
68, 9723.
19. Amere, M.; Lasne, M.-C.; Rouden, J. Org. Lett. 2007, 9, 2621.