Fast DKR of amines using isopropyl 2-methoxyacetate as acyl donor

Article abstract of DOI:10.1002/ejoc.200700568

The dynamic kinetic resolution (DKR) of various primary amine substrates was performed using a modified version of the Baeckvall system. A single equivalent of isopropyl 2-methoxyacetate was used as acyl donor in combination with p-MeO Shvo complex as the racemization catalyst and Novozym 435 as the acylation catalyst. A reaction temperature of 100°C was employed to ensure a high racemization rate. Adding 2,4-dimethyl-3-pentanol (DMP) as hydrogen donor at a concentration of 0.5 M successfully suppressed side product formation. Under these modified DKR conditions, complete conversion was observed for most substrates within 26 h showing both high ee values and good chemoselectivity, whereas the original system required a reaction time of 72 h. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700568

FULL PAPER
DOI: 10.1002/ejoc.200700568
Fast DKR of Amines Using Isopropyl 2-Methoxyacetate as Acyl Donor
Martijn A. J. Veld,[a] Karl Hult,[b] Anja R. A. Palmans,*[a] and E. W. Meijer*[a]
Keywords: Dynamic kinetic resolution (DKR) / Amines / Enzyme catalysis / Asymmetric synthesis / Ruthenium
The dynamic kinetic resolution (DKR) of various primary
amine substrates was performed using a modified version of
the Bäckvall system. A single equivalent of isopropyl 2-meth-
at a concentration of 0.5 M successfully suppressed side prod-
uct formation. Under these modified DKR conditions, com-
plete conversion was observed for most substrates within
oxyacetate was used as acyl donor in combination with p- 26 h showing both high ee values and good chemoselectivity,
MeO Shvo complex as the racemization catalyst and Novo-
zym 435 as the acylation catalyst. A reaction temperature of
100 °C was employed to ensure a high racemization rate.
Adding 2,4-dimethyl-3-pentanol (DMP) as hydrogen donor
whereas the original system required a reaction time of 72 h.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
and ruthenium-based[6,7] organometal complexes have been
developed. A very attractive system for the DKR of both
aliphatic and benzylic amines was introduced by Bäckvall.[6]
They used the p-anisyl-modified Shvo catalyst 3 for the ra-
cemization step and Novozym 435, Candida antarctica Li-
pase B immobilized on a macro-porous polyacrylic resin,
for the catalyst in the kinetic resolution step. Despite the
good chemo- and enantioselectivity, this system requires a
large excess (7-fold) of acyl donor and relatively long (72 h)
reaction times. Given the exciting results, optimisation of
this process is of great interest. In a successful DKR system,
the asymmetric transformation and the racemization step
should have similar rate constants.[8] Improvement of this
system should focus both on an increase in the racemization
and the acylation rate while keeping high selectivity. Here
we like to show an improvement of the Bäckvall system for
Introduction
The preparation of enantiomerically pure organic com-
pounds is a major challenge in organic chemistry. The dy-
namic kinetic resolution (DKR) of racemic starting materi-
als is a particularly attractive method since it allows the
synthesis of an optically pure product in theoretically 100%
yield from racemic starting material. This immediately
shows its advantage over normal, enzyme based, kinetic res-
olutions having a maximum yield of only 50%. Notably, the
DKR of secondary alcohols is applied on industrial scale
nowadays because of its immense importance in the field of
fine chemistry.[1]
The DKR of amines has been a challenging topic in or-
ganic chemistry during the past 10 years. Racemization of
amines generally requires relatively harsh reaction condi-
tions and suffers from the formation of side products. Dur-
ing racemization the amine substrate is catalytically oxid-
ized to give a non-chiral imine intermediate, which is sub-
sequently reduced. However, the imine intermediate can re-
act with the amine substrate to generate an aminal that
readily looses ammonia, making these side-reactions
irreversible.
Initial DKR systems for benzylic amines relied on Pd/C-
catalyzed racemization with the disadvantage of moderate
selectivity and long reaction times.[2] Over the past years,
new racemization methods for amines based on Pd-nano-
particles,[3] alkylsulfanyl radical chemistry[4] and iridium-[5]
[a] Laboratory of Macromolecular and Organic Chemistry, Techni-
sche Universiteit Eindhoven,
P. O. Box 513, 5600 MB Eindhoven, The Netherlands
E-mail: E.W.Meijer@tue.nl
A.Palmans@tue.nl
[b] Department of Biotechnology, Royal Institute of Technology
10691 Stockholm, Sweden
Scheme 1. DKR of amine substrates 1a–h (DMP: 2,4-dimethyl-3-
pentanol, added as hydrogen donor).
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
5416
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5416–5421

Fast DKR of Amines
the DKR of various amines, both in terms of reaction time or the same amount of isopropyl butyrate as acyl donor
(26 h) and the required amount of acyl donor (1.1 equiv.), was performed and both reactions were followed in time by
while preserving good selectivity and high ee values chiral GC analysis (see electronic supporting information).
(Scheme 1).
All DKR experiments were performed under reduced pres-
sure to remove the isopropyl alcohol from the reaction mix-
ture. The latter can be oxidized to acetone by the racemiza-
tion catalyst and subsequent reaction with the amine sub-
strates followed by reduction results in the undesirable for-
mation of secondary isopropylamines. The use of 4 as acyl
donor results in a complete acylation of (R)-1-phenylethan-
amine within 2 h. For this reason, the racemization of the
residual amine substrate is more effective, resulting in a
faster overall DKR process. However, at 100 °C spontane-
Results and Discussion
As a start we reproduced the results of Bäckvall et al.
(Table 1, entry 1)[6] for the racemization of 1-phenylethan-
amine (1a) with catalyst 3 and investigated if higher racemi-
zation rates could be obtained by altering the reaction con-
ditions. We compared the racemization rates at a reaction
temperature of 90 and 100 °C at identical catalyst and sub-
strate loading (Table 1, entries 2 and 3). Although krac in-
deed increased (to 0.062 h–1), the selectivity towards the
substrate was slightly lower (92% after 24 h) compared to
the original system (entry 1). At longer reaction times, a
further decrease in selectivity was found (86% after 46 h).
Reducing the amount of racemization catalyst gave no sig-
nificant improvement in the selectivity (94% after 24 h, en-
try 4) and the krac dropped to 0.029 h–1.
Table 2. Results for the DKR of amine substrates 1a–h (0.50 mmol
amine groups) using p-MeO Shvo catalyst (3) (26.5 mg,
0.02 mmol), isopropyl 2-methoxyactate (4) (68 µL, 1.0 equiv.), No-
vozym 435 (20 mg), Na2CO3 (20.0 mg, 0.20 mmol) in toluene
(8 mL) containing 0.5  DMP at 100 °C and 750 mbar for 26 h.
After 24 h an additional amount of 4 (7 µL, 0.1 equiv.) was added
to complete the reaction.
Table 1. Overview of racemization rates and selectivities for op-
tically pure 1-phenylethanamine (96% ee) using 3 as racemization
catalyst. Racemization of optically pure 1-phenylethanamine
(0.50 mmol, 96% ee) in toluene (2 mL) using varying amounts of
racemization catalyst 3 and reaction temperatures.
Entry 3 [mmol]
T [°C]
krac [h–1
]
Selectivity[a] [%]/time [h]
1[b]
2
3
0.02
0.02
0.02
0.01
0.01
90
90
100
100
100
0.025
0.020
0.062
0.029
0.022
95/24
92/20
92/24, 86/47
94/24, 74/47
99/24, 98/47
4
5[c]
[a] Selectivity based on GC measurements vs. internal standard.
[b] Data calculated from literature.[6] [c] 2,4-Dimethyl-3-pentanol
(0.50 ) was added as hydrogen donor.
To increase the selectivity towards the substrate, we
added 0.50  2,4-dimethyl-3-pentanol (DMP) as hydrogen
donor to more effectively reduce the imine intermediate.
DMP was selected since it has been established that this
alcohol is not accepted as a substrate by Novozym 435 due
to its steric bulkiness.[9] The addition of DMP resulted in a
major improvement in selectivity (99% after 24 h) and a
small decrease of krac to 0.022 h–1 (entries 4 and 5). To have
a sufficiently high racemization rate and good selectivity in
the DKR experiments, a catalyst loading of 0.04 mmol of 3
per mmol of amine substrate was selected in combination
with a temperature of 100 °C and the addition of 0.5 
DMP.
To increase the acylation rate during DKR, we evaluated
the effect of changing the acyl donor from isopropyl acetate
into isopropyl 2-methoxyacetate (4). Alkyl 2-methoxyace-
tates emerged as very effective acyl donors for the enzy-
matic acylation of amine substrates. In lipase-catalyzed ki-
netic resolution of 1-phenylethanamine rate increases up to
200 times have been observed by using methyl 2-meth-
oxyacetate instead of methyl butyrate as acyl donor.[10] The
[a] Isolated yields with greater than 95% purity according to 1H
NMR. [b] The ee value of purified 2-methoxyacetamide was deter-
mined by chiral GC unless otherwise noted. [c] Total reaction time
42.5 h. instead of 26 h. [d] The ee value was determined by chiral
GC on hydrolyzed 2-methoxyacetamide after Ac2O derivatization.
[e] Purity over 90% according to 1H NMR. [f] ee determined by
DKR of rac-1-phenylethanamine (1a) using 1.25 equiv. of 4 chiral HPLC on hydrolyzed methoxyacetamide.
Eur. J. Org. Chem. 2007, 5416–5421
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5417

M. A. J. Veld, K. Hult, A. R. A. Palmans, E. W. Meijer
FULL PAPER
ous acylation of the amine substrate by 4 was observed,
resulting in a lower ee of the desired reaction product. To
limit this chemical background reaction, a single equivalent
of acyl donor was used in all further experiments. In case
of isopropyl butyrate as acyl donor, the complete initial
acylation of all (R)-1-phenylethanamine was not observed
and the ee of the residual amine substrate stays relatively
low, indicating similar acylation and racemization rates.
Further optimization showed that a DMP concentration
of 0.5  in combination with a substrate concentration of
62.5 µ and the addition of 1 equiv. of acyl donor were
found to give highest selectivity for the DKR process of 1-
phenylethanamine. These reaction conditions were sub-
sequently used for the DKR of seven other (di)amine sub-
strates (see Table 2).
Experimental Section
General: Column chromatography was performed over flash silica
gel (40–63 µm; purchased from Grace Division). 1H-NMR and
13C-NMR spectra were recorded at 400, 300 or 200 MHz and at
100, 75 or 50 MHz respectively. Peaks are notated as singlet (s),
doublet (d), triplet (t), quartet (q), quintet (qui.) or heptet (h),
broadened peaks are notated as (br.). Chemical shifts are reported
in ppm and are with respect to TMS (δ = 0 ppm) or the solvent
peak (CDCl3, δ = 77.16Ϯ0.32 ppm). Chiral GC analysis was per-
formed on a Shimadzu GC-17A equipped with a FID, an AOC-
20i autosampler and a CP-Chiralcel-Dex-CB column (25 m, i.d.
0.25 mm) using helium as carrier gas. Unless otherwise stated, the
following settings were used: Tinj = 250 °C, Tdet = 300 °C. The sepa-
ration of the 2-methoxyacetamides was optimized using the race-
mic compounds, which were prepared as described below. Chiral
HPLC measurements were performed by Syncom B.V. (Groningen,
the Netherlands) using an Agilent 1100 HPLC system (G1322A
degasser, G1311A Quatpump, G1313A Autosampler) equipped
After 23.5 h a small sample of the reaction mixture was
1
analyzed by H NMR spectroscopy. Complete conversion
of the amine groups was observed in all cases except for with a Daicel Crownpak CR(-) 150ϫ4 mm column and using
aqueous HClO4 (pH =1) as eluent. A G3115 DAD-detector at a
wavelength of 208 (+/–4) nm was used for detection.
substrate 1e (conversion 63%). To complete the reaction,
another 0.1 equiv. of 4 was added and the reaction was con-
tinued for 2 more hours. All crude products were obtained
Formamide, 1,3,5-tri-tert-butylbenzene, 1,3-diacetylbenzene, 1,4-
in quantitative yield and 1H NMR analysis revealed a diacetylbenzene, 1-(1-naphthyl)ethylamine, 1-p-tolylethylamine, 2-
octylamine, were purchased from Sigma–Aldrich. 4,4Ј-Dimeth-
oxybenzil, 2-(4-methoxyphenyl)acetic acid, formic acid, isopropyl
acetate, 2-methoxyacetic acid, 4-bromo-α-phenethylamine and 1-
aminoindan were obtained from Acros. rac-1-Phenylethanamine
was purchased from Merck, (R)-1-phenylethanamine and (S)-1-
phenylethanamine were obtained from Jansen Chimica. Novozym
435 was obtained from Novozymes. Tetracarbonylruthenium was
purchased from Strem. All used solvents were purchased from
Biosolve (The Netherlands).
chemoselectivity of Ͼ 90% for all substrates investigated.
The isolated yields of the pure products, however, are 10–
20% lower than those reported by Bäckvall for the corre-
sponding acetamide, which is mainly due to separation
problems during column chromatography. Chiral GC or
HPLC analysis of the isolated products showed ee values
which were directly comparable to those reported for the
original amine DKR system. Formation of meso-bis(me-
thoxyacetamides) was observed for both substrates 1g and
1h. In case of substrate 1h, an excellent ee value of 99%
and a low amount of the meso product were observed after
hydrolysis as determined by chiral HPLC analysis. The re-
sults described here show that chiral primary amides can be
rac-1-Phenylethanamine, (R)-1-phenylethanamine, (S)-1-phenyl-
ethanamine and 2-octylamine were distilled over KOH and stored
over 4 Å molecular sieves under an Argon atmosphere. Toluene was
stored over 4 Å molecular sieves. Na2CO3 was dried under vacuum
for 3 h at 300 °C and kept in a well closed vial afterwards. All
obtained within 26 h and with high ee, and that this im- other chemicals were used as received. The prepared racemization
catalyst (3) was weighed out in the air and put under an Argon
atmosphere afterwards. Novozym 435 was used as received.
proved method is also applicable to produce primary di-
amides with high ee values.
General Methods for Racemization and DKR Experiments
All glassware for the racemization and DKR experiments was dried
for at least 2 h at 120 °C.
Conclusions
Racemization Experiments and DKR Optimization Experiments:
The use of a single equivalent of isopropyl 2-methoxyace-
tate (4) as acyl donor combined with the addition of 0.5 
DMP as hydrogen donor and a reaction temperature of
100 °C results in a reaction time of less than 26 h for the
DKR of various amine substrates. Complete conversions
A
stock solution containing 1-phenylethanamine (606 mg,
5.00 mmol) and 1,3,5-tri-tert-butylbenzene (internal standard)
(123 mg, 0.50 mmol) in dry toluene (10 mL) was prepared. Racemi-
zation catalyst (3) (26.5 mg, 0.020 mmol) and dry Na2CO3 (20 mg)
were weighed into a dry Schlenk tube. The Schlenk tube was evacu-
and high selectivities were observed for most substrates and ated and backfilled with Argon 3 times. Toluene (6.4 mL), 2,4-di-
methyl-3-pentanol (560 µL) and stock solution (1.0 mL) were
added by syringe. The Schlenk tube was evacuated to 200 mbar
and backfilled with argon 3 times and heated to the desired tem-
perature. Small samples (0.05 mL) were withdrawn from the reac-
tion mixture at regular time intervals, filtered over a piece of cotton
in a pipette and diluted with DCM (ca. 1.5 mL). The underivatized
samples were directly analyzed by means of GC-FID. To determine
the ee of the substrate, acetic anhydride (2–3 drops) was added to
the sample and all volatiles were evaporated under reduced pressure
after which the residue was redissolved and measured again on GC-
FID.
the obtained ee values are directly comparable to those de-
scribed for the original system, although isolated yields are
somewhat lower due to isolation problems. Additionally,
the first successful DKR of phenylene bis(ethanamine) sub-
strates 1g and 1h was shown. Especially the DKR of 1h
showed excellent enantioselectivity for the enzymatic acyl-
ation step resulting in high ee values and limited amounts
of meso product. In future research, those two substrates
will be combined with a diacyl donor under DKR condi-
tions with the intended formation of chiral polyamides.
5418
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5416–5421

Fast DKR of Amines
For the optimization of the DKR of 1-phenylethanamine, Novo- a piece of cotton and normal silica gel (ca. 2 cm). The vial was
zym 435 (20 mg) was weighed into the Schlenk tube together with
the racemization catalyst (26.5 mg, 0.020 mmol) and Na2CO3
(20 mg) and acyl donor (typically 1 mol-equiv.) was added by sy-
ringe after the addition of the stock solution. GC-FID Tempera-
ture Program: 105 °C | 9 min Ǟ 180 °C, 40 °C/min | 10 min.
rinsed with DCM (2ϫ5 mL) and the solvent was removed under
reduced pressure. The racemic methoxy acetamides were isolated
in sufficient purity (Ͼ 90%) according to 1H NMR and directly
used without further purification to optimize the GC-FID tem-
perature programs.
For the racemization experiments, selectivity was defined as the
residual substrate area divided by the initial substrate area (data
normalized to internal standard area). For the DKR experiments,
the amount of substrate conversion was determined with respect to
the initial substrate area (data normalized to internal standard
area) and the selectivity was defined as follows:
(R)-2-Methoxy-N-(1-phenylethyl)acetamide (2a): Compound 2a was
synthesized from 1-phenylethanamine (61.0 mg, 0.50 mmol) follow-
ing the general procedure described above. After column
chromatography (pentane/EtOAc, 1:4), 2a was isolated as a white
solid (66 mg, 68%, 98% ee). 1H NMR (400 MHz, CDCl3): δ =
7.54–7.06 (m, 4 H, ArH), 6.88–6.60 (br. s, 1 H, -NH), 5.18 (dq, J
= 13.9, J = 6.9 Hz, 1 H, -CHCH3), 3.91 (d, J = 15.0 Hz, 1 H,
Hα -CH2OCH3), 3.88 (d, J = 15.0 Hz, 1 H, Hβ -CH2OCH3), 3.40
Aproduct
S =
Aproduct + Σ Aside poducts
(s, 3 H, -CH2OCH3), 1.52 (d, J = 6.9 Hz, 3 H, -CHCH3) ppm. 13
C
Dynamic Kinetic Resolution (DKR) Experiments. General Pro-
cedure: Novozym 435 (20.0 mg), Na2CO3 (20.0 mg, 0.20 mmol), ra-
cemization catalyst (26.5 mg, 0.020 mmol) were weighed into a dry
Schlenk tube. The Schlenk tube was evacuated and backfilled with
Argon 3 times. The amine substrates (0.50 mmol amine groups)
were weighed into a sample vial and put under an Argon atmo-
sphere. Toluene (7.4 mL in total) was added portion wise to this
vial and the amine was transferred quantitively into the Schlenk
tube after which 2,4-dimethyl-3-pentanol (560 µL, 4.0 mmol) and
isopropyl methoxyacetate (4) (68 µL, 0.50 mmol, 1 equiv.) were
added. The Schlenk tube was evacuated to a pressure of 200 mbar
and backfilled with Argon to atmospheric pressure 3 times. After
this procedure, the reaction vessels were immediately heated to
100 °C at a pressure of 750 mbar under an Argon atmosphere. Af-
ter 23.5 h reaction time, a sample (0.10 mL) was withdrawn, filtered
over a piece of cotton in a pipette, diluted with CDCl3 and ana-
lyzed by 1H NMR to check the conversion. 24 h after the start
of the reaction more isopropyl methoxyacetate (7 µL, 0.050 mmol,
0.1 equiv.) was added and stirring was continued at 100 °C and
750 mbar for 2 h. After cooling to room temp., the reaction mixture
was filtered over a paper filter and the Schlenk tube was rinsed
with DCM (3ϫ20 mL) after which all volatiles were removed in
vacuo. The residue was co-evaporated with toluene (2ϫ5 mL), af-
ter which the crude product was purified by column chromatog-
raphy over silica gel to give the 2-methoxyacetamide. For tR values
see Table 3.
NMR (100 MHz, CDCl3): δ = 168.6, 143.1, 128.8, 127.5, 126.2,
72.07, 59.2, 48.1, 22.0 ppm. GC-FID temperature program: 105 °C
| 9 min Ǟ 180 °C, 40 °C/min | 10 min. tR(S): 14.43 min, tR(R):
14.58 min. C11H15NO2 (193.24): calcd. C 68.3, H 7.82, N 7.25;
found C 67.96, H 7.89, N 7.05.
(R)-N-(1-p-Tolylethyl)-2-methoxyacetamide (2b): Compound 2b
was synthesized from 1-p-tolylethanamine (67.0 mg, 0.50 mmol)
following the general procedure described above. After column
chromatography (pentane/EtOAc, 1:1), 2b was isolated as a white
solid (75 mg, 73%, 99% ee). 1H NMR (400 MHz, CDCl3): δ = 7.22
(d, J = 8.1 Hz, 2 H, ArH), 7.14 (d, J = 8.1 Hz, 2 H, ArH), (br. d,
J = 5.8 Hz, 1 H, -NH), 5.15 (dq, J = 7.5, J = 7.0 Hz, 1 H,
-CHCH3), 3.89 (d, J = 15.0 Hz, 1 H, Hα -CH2OCH3), 3.86 (d, J =
15.0 Hz, 1 H, Hβ -CH2OCH3), 3.38 (s, 3 H, -CH2OCH3), 2.33 (s,
3 H, ArCH3), 1.50 (d, J = 6.9 Hz, 3 H, -CHCH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 168.5, 140.1, 137.1, 129.4, 126.1, 72.0, 59.1,
47.8, 21.9, 21.1 ppm. GC-FID temperature program: 120 °C | 5 min
Ǟ 180 °C, 10 °C/min | 5 min. tR(S): 14.71 min, tR(R): 14.92 min.
C12H17NO2 (207.27): calcd. C 69.54, H 8.27, N 6.76; found C
68.95, H 8.02, N 6.55.
(R)-N-[1-(4-Bromophenyl)ethyl]-2-methoxyacetamide (2c): Com-
pound 2c was synthesized from 1-(4-bromophenyl)ethanamine
(100.0 mg, 0.50 mmol) following the general procedure described
above. After column chromatography (pentane/EtOAc, 1:4), 2c was
isolated as a white solid (81 mg, 59%, 97% ee). 1H NMR
(400 MHz, CDCl3): δ = 7.46 (d, J = 8.5 Hz, 2 H, ArH), 7.20 (d, J
= 8.3 Hz, 2 H, ArH), 6.73 (br. d, J = 6.4 Hz, 1 H, -NH), 5.12 (dq,
J = 8.2, J = 7.0 Hz, 1 H, -CHCH3), 3.90 (d, J = 15.0 Hz, 1 H, Hα
-CH2OCH3), 3.87 (d, J = 15.0 Hz, 1 H, Hβ -CH2OCH3), 3.41 (s, 3
H, -CH2OCH3), 1.49 (d, J = 7.0 Hz, 3 H, -CHCH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 168.7, 142.3, 131.9, 128.0, 121.3,
72.0, 59.25, 47.65, 21.89 ppm. GC-FID temperature program:
110 °C | 5 min Ǟ 200 °C, 5 °C/min | 20 min. tR(S): 24.61 min,
tR(R): 24.80 min. C11H14BrNO2 (272.14): calcd. C 48.55, H 5.19,
N 5.15; found C 48.59, H 5.09, N 5.13.
Table 3. Overview of retention times for compounds in DKR and
racemization experiments.
Compound
tR [min]
(R)-1-Phenylethanamine
(S)-1-Phenylethanamine
1,3,5-Tri-tert-butylbenzene
8.08
8.29
11.88
13.51
13.68
14.70
14.87
15.61
16.14
(S)-N-(1-Phenylethyl)-2-acetamide
(R)-N-(1-Phenylethyl)-2-acetamide
(S)-N-(1-Phenylethyl)-2-methoxyacetamide
(R)-N-(1-Phenylethyl)-2-methoxyacetamide
(S)-N-(1-Phenylethyl)-2-butyramide
(R)-N-(1-Phenylethyl)-2-butyramide
(R)-N-(2,3-Dihydro-1H-inden-1-yl)-2-methoxyacetamide (2d): Com-
pound 2d was synthesized from 1-aminoindan (66.7 mg,
0.50 mmol) following the general procedure described above. After
column chromatography (pentane/EtOAc, 1:4), 2d was isolated as
an off-white solid (82 mg, 80%, 96% ee). 1H NMR (400 MHz,
CDCl3): δ = 7.34–7.14 (m, 4 H, ArH), 6.76 (br. d, J = 6.8 Hz, 1
H, -NH), 5.53 (q, J = 7.8 Hz, 1 H, -CHCH2CH2), 3.94 (s, 2 H,
-CH2OCH3), 3.39 (s, 3 H, -CH2OCH3), 3.04-2.93 (m, 1 H, Hα
-CHCH2CH2), 2.93–2.81 (m, 1 H, Hβ -CHCH2CH2), 2.68–2.52 (m,
1 H, Hα CHCH2CH2), 1.90–1.76 (m, 1 H, Hβ -CHCH2CH2) ppm.
13C NMR (100 MHz, CDCl3): δ = 169.4, 143.5, 143.0, 128.1, 126.9,
124.9, 124.1, 72.1, 59.2, 54.0, 34.1, 30.3 ppm. GC-FID temperature
General Procedure for the Synthesis of rac-2-Methoxyacetamides
2a–g: 0.10 mmol of the desired amine was put in a dry 5 mL vial
equiped with a stirring bar and flushed with Argon. A solution of
DIPEA (0.15 mmol/mL) in dry dichloromethane (1.0 mL) was
added to the vial, followed by the addition of in-situ prepared
methoxy acetylchloride (15) (200 µL, 0.51 mmol/mL, 1 equiv.). The
vial was flushed with Argon and stirred overnight at room tempera-
ture. The contents of the vial were filtered over a pipette containing
Eur. J. Org. Chem. 2007, 5416–5421
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5419

M. A. J. Veld, K. Hult, A. R. A. Palmans, E. W. Meijer
FULL PAPER
program: 130 °C | 5 min Ǟ 160 °C, 2 °C/min Ǟ 190 °C, 1 °C/min | (1R,1ЈR)-N,NЈ-(1,4-Phenylene)bis(ethane-1,1Ј-diyl)bis(2-methoxy-
10 min. tR(S): 29.00 min, tR(R): 29.34 min. C12H15NO2 (205.25): acetamide) (2h): Compound 2h was synthesized from 1,1Ј-(1,4-
calcd. C 70.22, H 7.37, N 6.82; found C 69.56, H 7.31, N 6.77.
phenylene)bis(ethanamine) (1h) (41.0 mg, 0.25 mmol) following the
general procedure described above. After column chromatography
(pentane/EtOAc, 1:4), 2h was isolated as a off-white solid (42 mg,
55%, 99% ee, ratio chiral/meso = 1:0.09). 1H NMR (400 MHz,
CDCl3): δ = 7.30 (s, 4 H, ArH), 6.74 (br. d, 2 H, -NH), 5.15 (dq,
J = 13.9, J = 7.0 Hz, 2 H, -CHCH3), 3.90 (d, J = 15.0 Hz, 2 H,
Hα -CH2OCH3), 3.89 (d, J = 15.0 Hz, 2 H, Hβ -CH2OCH3), 3.40
(R)-2-Methoxy-N-[1-(naphthalen-1-yl)ethyl]acetamide (2e): Com-
pound 2e was synthesized from 1-(1-naphthyl)ethanamine
(85.6 mg, 0.50 mmol) following the general procedure described
above. After 23.5 h, incomplete conversion of the substrate was ob-
served, for this reason the reaction mixture was stirred for a total
time of 42.5 h. After column chromatography (pentane/EtOAc,
1:4), 2e was isolated as a white solid (69 mg, 57%, 99% ee). 1H
NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 8.5 Hz, 1 H, ArH), 7.86
(dd, J = 8.4, 1.1 Hz, 1 H, ArH), 7.79 (d, J = 8.1 Hz, 1 H, ArH),
7.57–7.42 (m, 4 H, ArH), 6.78 (br. d, J = 7.8 Hz, 1 H, -NH), (dq,
J = 15.5, J = 6.8 Hz, 1 H, -CHCH3), 3.93 (d, J = 15.2 Hz, 1 H,
Hα -CH2OCH3), 3.87 (d, J = 15.2 Hz, 1 H, Hβ CH2OCH3), 3.31
(s, 3 H, -CH2OCH3), 1.68 (d, J = 6.8 Hz, 3 H, -CHCH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 168.5, 138.2, 134.0, 131.2, 128.9,
128.5, 126.6, 125.9, 125.3, 123.5, 122.7, 72.0, 59.1, 44.0, 21.1 ppm.
GC-FID analysis of compound 2e was not directly possible, this
compound was hydrolyzed as described below for compounds 2g
and 2h. The ee was determined by means of GC-FID after derivati-
zation with acetic anhydride. GC-FID temperature program for N-
[1-(naphthalen-2-yl)ethyl]acetamide: 140 °C | 1 min Ǟ 200 °C 1 °C/
min | 10 min. tR(S): 45.26 min, tR(R): 45.86 min. C15H17NO2
(243.3): calcd. C 74.05, H 7.04, N 5.76; found C 73.71, H 6.93, N
5.77.
(s, 6 H, -CH2OCH3), 1.50 (d, J = 6.9 Hz, 6 H, -CHCH3) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 186.6, 142.3, 126.6, 72.1, 59.2, 47.9,
21.9 ppm. GC-FID analysis of compound 2g was not possible, this
compound was hydrolyzed as described below and the ee was deter-
mined by means of chiral HPLC using the method described above.
Racemic 1h was used as reference for the determination of the ee,
tR(R,R): 46.57 min, tR(meso): 76.34 min, tR(S,S): 93.46 min, ratio
chiral/meso = 1:0.09, ee(chiral): 99%. Elemental analysis is not
available for this compound.
Determination of ee Values for 2e, 2g, and 2h: No direct chiral GC
analysis of compounds 2e, 2g, 2h and was possible. These methoxy
acetamides were hydrolyzed and the ee was determined by means of
chiral HPLC (2g–h) or by GC-FID after derivatization with Ac2O.
General Hydrolysis Procedure for the Hydrolysis of 2-Methoxyacet-
mides 2a–g: Compound 2g or 2h (typically 40 mg, 0.13 mmol) was
put in a 25 mL flask and aqueous HCL was added (5 mL, 3 ).
The resulting solution was refluxed under an Argon atmosphere
for a period of 4 h. After cooling to room temp., the reaction mix-
ture was diluted with water (5 mL) and extracted with Et2O
(2ϫ5 mL). The pH of the aqueous layer was adjusted to Ͼ10 by
careful addition of concentrated NaOH (4 ), followed by extrac-
tion with Et2O (3ϫ15 mL). The combined organic layers were
washed with 4  NaOH (5 mL) and dried with Na2SO4. After re-
moval of the solvent under reduced pressure, the free amines were
obtained as a yellow colored liquid in typically 50% yield. 1H
NMR showed a purity of at least 80% for hydrolyzed 2g and at
least 90% for hydrolyzed 2h.
(R)-2-Methoxy-N-(octan-2-yl)acetamide (2f): Compound 2f was
synthesized from 2-octylamine (64.6 mg, 0.50 mmol) following the
general procedure described above. After column chromatography
(pentane/EtOAc, 1:1), 2f was isolated as a white solid (66 mg, 66%,
94% ee). KMnO4 staining followed by gentle heating was required
1
for analysis of the TLC plates. H NMR (400 MHz, CDCl3): δ =
6.29 (br. d, J = 6.8 Hz, 1 H, -NH), 4.08–3.95 (m, 1 H, -CHCH3),
3.87 (s, 2 H, -CH2OCH3), 3.41 (s, 3 H, -CH2OCH3), 1.50–1.40 (m,
2 H, -CHCH2CH2-) 1.37–1.20 (m, 6 H, CHCH2CH2CH2-), 1.15 (d,
J = 6.6 Hz, 3 H, -CHCH3), 0.88 (t, J = 6.8 Hz, 3 H, -CH2CH3)
ppm. 13C NMR (100 MHz, CDCl3): δ = 168.7, 72.1, 59.2, 44.7,
37.0, 31.8, 29.2, 26.0, 22.7, 21.0, 14.1 ppm. GC-FID temperature
program: 150 °C | 5 min Ǟ 180 °C, 10 °C/min. tR(S): 6.88 min,
tR(R): 6.99 min. C11H23NO2 (201.31): calcd. C 65.63, H 11.52, N
6.96; found C 65.62, H 11.55, N 6.91.
In a reference experiment in which 2a was hydrolyzed and derivat-
ized with Ac2O under identical conditions, no significant amount
of racemization was observed (97.4% ee after hydrolysis vs. 98.3%
before).
Derivatization of Hydrolyzed 2e: Ac2O (+/– 10 mg) was added to
1 mL of the Et2O extract containing hydrolyzed 2e. All volatiles
were evaporated under reduced pressure for 30 min at 50 °C. The
obtained crude white solid was directly used for chiral GC analysis
to determine the ee values.
(1R,1ЈR)-N,NЈ-(1,3-Phenylene)bis(ethane-1,1Ј-diyl)bis(2-methoxy-
acetamide) (2g): Compound 2g was synthesized from 1,1Ј-(1,3-
phenylene)bis(ethanamine) (1g) (41.0 mg, 0.25 mmol) following the
general procedure described above. After column chromatography
(pentane/EtOAc, 1:4), 2g was isolated as a light yellow solid
(53 mg, 70%, 86% ee, ratio chiral/meso = 1:0.21). According to
1H NMR residues of the racemization catalyst were still present,
resulting in a purity of approximately 90 mol-%. 1H NMR
(400 MHz, CDCl3 ): δ = 7.20–7.36 (m, 4 H, ArH), 6.80–6.70 (br.
s, 2 H, -NH), 5.18 (dq, J = 14.4, J = 7.1 Hz, 2 H, -CHCH3), 3.91
(d, J = 15.0 Hz, 2 H, Hα -CH2OCH3), 3.88 (d, J = 15.0 Hz, 2 H,
Hβ -CH2OCH3), 3.41 (s, 6 H, -CH2OCH3), (d, J = 6.9 Hz, 6 H,
-CHCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.6, 143.5,
129.2, 125.2, 124.3, 72.0, 59.2, 48.1, 22.0 ppm. GC-FID analysis of
compound 2g was not possible, this compound was hydrolyzed as
described below and the ee was determined by means of chiral
HPLC using the method described above. Racemic 1g was used as
reference for the determination of the ee, tR(R,R): 45.17 min,
tR(meso): 63.13 min, tR(S,S): 71.74 min, ratio chiral/meso = 1:0.21,
ee(chiral): 86%. C16H24N2O4 (308.37): calcd. C 62.32, H 7.84, N
9.08; found C 62.43, H 7.21, N 7.16.
Supporting Information (see also the footnote on the first page of
this article): Procedures for the preparation of starting materials,
analytical data, comparison between the use of isopropyl butyrate
and isopropyl 2-methoxyacetate as acyl donor in the DKR of 1-
phenylethanamine and the optimisation of the DKR of 1-phenyl-
ethanamine.
Acknowledgments
The authors would like to thank Dr. Jef Vekemans, Bart van As
and Jeroen van Buijtenen from the TU/e for stimulating dis-
cussions. Marloes Verbruggen is acknowledged for her help with
the diamine synthesis. The Council for the Chemical Sciences of
the Netherlands Organization for Scientific Research (CW-NWO)
is acknowledged for financial support to A. P. and M. V.
5420
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5416–5421

Fast DKR of Amines
[4] S. Gastaldi, S. Escoubet, N. Vanthuyne, G. Gil, M. P. Bertrand,
Org. Lett. 2007, 9, 837–839.
[5] M. Stirling, J. Blacker, M. I. Page, Tetrahedron Lett. 2007, 48,
1247–1250.
[1] a) P. M. Dinh, J. A. Howarth, A. R. Hudnott, J. M. J. Williams,
W. Harris, Tetrahedron Lett. 1996, 37, 7623–7626; b) J. H.
Choi, Y. K. Choi, Y. H. Kim, E. S. Park, E. J. Kim, M.-J. Kim,
J. Park, J. Org. Chem. 2004, 69, 1972–1977; c) G. K. M. Verzijl,
Q. B. Broxterman Process for the preparation of enantiomer-
ically enriched esters and alcohols. WO2005014509, 20040706,
2005; d) B. A. Persson, A. L. E. Larsson, M. Le Ray, J. E.
Bäckvall, J. Am. Chem. Soc. 1999, 121, 1645–1650; e) B. Mar-
tin-Matute, M. Edin, K. Bogar, J. E. Bäckvall, Angew. Chem.
Int. Ed. 2004, 43, 6535–6539; f) J. H. Choi, Y. H. Kim, S. H.
Nam, S. T. Shin, M. J. Kim, J. Park, Angew. Chem. Int. Ed.
2002, 41, 2373–2376.
[6] J. Paetzold, J.-E. Bäckvall, J. Am. Chem. Soc. 2005, 127, 17620–
17621.
[7] O. Pàmies, A. H. Ell, J. S. M. Samec, N. Hermanns, J. E.
Bäckvall, Tetrahedron Lett. 2002, 43, 4699–4702.
[8] M. Kitamura, M. Tokunaga, R. Noyori, Tetrahedron 1993, 49,
1853–1860.
[9] H. M. Jung, J. H. Koh, M. J. Kim, J. Park, Org. Lett. 2000, 2,
409–411.
[10] M. Cammenberg, K. Hult, S. Park, ChemBioChem 2006, 7,
1745–1749.
[2] a) Y. K. Choi, M. J. Kim, Y. Ahn, M. J. Kim, Org. Lett. 2001,
3, 4099–4101; b) A. Parvulescu, D. De Vros, P. Jacobs, Chem.
Commun. 2005, 5307–5309; c) M. T. Reetz, K. Schimossek,
Chimia 1996, 50, 668–669.
Received: June 20, 2007
Published Online: September 4, 2007
[3] M. J. Kim, W. H. Kim, K. Han, Y. K. Choi, J. Park, Org. Lett.
2007, 9, 1157–1159.
Eur. J. Org. Chem. 2007, 5416–5421
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5421