Dynamic double kinetic resolution of amines and alcohols under the cocatalysis of Raney nickel/Candida antarctica lipase B: From concept to application

Article abstract of DOI:10.1002/ejoc.201400042

Herein, we have established a dynamic double kinetic resolution (DDKR) strategy under the co-catalysis of Raney nickel and Candida antarctica lipase B (CAL-B) for the one-pot simultaneous resolution of primary amines and secondary alcohols (or esters). The DDKR strategy was successfully applied to the resolution of a series of racemic amines and secondary alcohols (or esters) as well as mexiletine, an important antiarrhythmic agent. The catalysts could be recycled and reused several times with the same high activity. Scale-up experiments were also successful. As a more atom-economical and efficient process than traditional simple kinetic resolutions, the DDKR strategy can be widely used to prepare optically pure amines and alcohols.

Full text of DOI:10.1002/ejoc.201400042

FULL PAPER
DOI: 10.1002/ejoc.201400042
Dynamic Double Kinetic Resolution of Amines and Alcohols under the
Cocatalysis of Raney Nickel/Candida antarctica Lipase B: From Concept to
Application
Bo Xia,[a] Guilin Cheng,[a] Xianfu Lin,[a] and Qi Wu*[a]
Keywords: Kinetic resolution / Chirality / Enzymes / Nickel / Amines / Alcohols
Herein, we have established a dynamic double kinetic reso- tant antiarrhythmic agent. The catalysts could be recycled
lution (DDKR) strategy under the co-catalysis of Raney nickel
and Candida antarctica lipase B (CAL-B) for the one-pot si-
multaneous resolution of primary amines and secondary
alcohols (or esters). The DDKR strategy was successfully ap-
plied to the resolution of a series of racemic amines and sec-
ondary alcohols (or esters) as well as mexiletine, an impor-
and reused several times with the same high activity. Scale-
up experiments were also successful. As a more atom-eco-
nomical and efficient process than traditional simple kinetic
resolutions, the DDKR strategy can be widely used to prepare
optically pure amines and alcohols.
carded. Taking into account that the resolution of a single
racemic nucleophile is often the only goal of an enzymatic
resolution of an alcohol or amine, it is a challenging job to
achieve the simultaneous resolution of an alcohol and an
amine in a one-pot process. One possible strategy in the
resolution of a racemic amine is to use a racemic ester that
has a stereogenic center at the leaving alcohol moiety as the
acyl donor. Thus, both the nucleophilic process between the
active serine site of the lipase and the carbonyl carbon of
the acyl donor to give an acyl–enzyme complex and the
nucleophilic process with the amine to give an acyl–enzyme
complex can provide chiral output, namely, the leaving chi-
ral alcohol and the final chiral amide, respectively (see
Scheme 1).
The advantages of this strategy are obvious. First, the
chiral alcohol (or ester) and amine (or amide) can be ob-
tained with high enantiomeric excess (ee) values in only one
step. Furthermore, it is a more atom-economical process
than two traditional simple kinetic resolutions of an amine
and alcohol, because there is no leaving achiral alcohol
group of the activated ester to discard. When this strategy
is combined with a metal-catalyzed racemization to provide
a DKR-like process, that is, a dynamic double kinetic reso-
lution (DDKR), there should be high expectations for the
application potential. In a DDKR process, a mixture of
highly optically pure components (amides, esters, and
alcohols) can be easily separated by simple column
chromatography because of their very different polarities.
However, this DDKR process is much less documented
than the simple KR and DKR reactions, and only some
examples of procedures of two resolutions of a single KR
process have been reported. For example, the use of
Introduction
Optically active amines and alcohols are useful building
blocks for many chiral pharmaceuticals, agrochemicals, and
natural products.[1] Lipase-catalyzed kinetic resolution
(KR) and dynamic kinetic resolution (DKR) are widely
used for the preparation of optically active amines and
alcohols.[2] The first examples of the chemoenzymatic DKR
of 1-phenylethylamine[3] and 1-phenylethanol[4] were re-
ported by Reetz and Williams, respectively, in 1996. Since
then, the DKR of racemates by utilizing lipases and a race-
mizing transition-metal catalyst has been proven to be par-
ticularly effective, as pioneered by Bäckvall,[5] Kim[6] and
other researchers.[7] This promising route can overcome the
limitations of KR such as conversions that do not exceed
50% for the preparation of optically pure compounds from
racemic mixtures, and it does not involve the isolation of
the undesired enantiomer. To shift the equilibrium of the
reaction towards the product, activated esters such as vinyl
acetate, trihalogenated esters, and thioesters are routinely
employed, and an excess amount of the ester is needed.
Usually, a single nucleophile such as an alcohol or amine
undergoes a transesterification or an aminolysis to form an
acyl–enzyme complex and obtain the useful ester or amide
products along with the recovered unreacted alcohol or
amine with high ee values. The leaving achiral alcohol of
the activated ester exists as useless byproduct to be dis-
[a] Department of Chemistry, Zhejiang University,
Hangzhou, P. R. China
E-mail: llc123@zju.edu.cn
http://mypage.zju.edu.cn/en/0003155
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201400042.
Eur. J. Org. Chem. 2014, 2917–2923
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2917

B. Xia, G. Cheng, X. Lin, Q. Wu
FULL PAPER
Scheme 1. Dynamic double kinetic resolution of amines and alcohols.
alcohols and an amine,[8] a thiol[9] or a diol[10] as nucleo-
philes has been attempted, although the enantiomeric ex-
cess values are sometimes lower than those of the corre-
Results and Discussion
We first investigated the simultaneous resolution of two
sponding single resolutions as a result of a mismatched pair alcohol nucleophiles, one of which part of the racemic acyl
of substrates. In the case of the KR of amines and alcohols donor, and used the reaction between 1-phenylethyl prop-
in one pot, which was reported by Gotor and co-workers,[8a] ionate (2e) and 2-octanol (1d) as the model. The ee values
the limitation of the 50% conversion led to modest enantio- of both the leaving alcohol and the product ester were excel-
meric excess values of the recovered acyl donor and amines lent (up to 99%ee), but the conversion was low (just 10%,
(most ee values were in the range of 21–70%). In the last see Table S2, Entry 1). Six different combinations of esters
decade, the DDKR strategy has never been demonstrated and alcohols were investigated, and the results are shown
with regard to the simultaneous resolution of an alcohol in Table S2. No improvements to the conversions were ob-
and amine in a one-pot process.
served by changing the structures of two alcohol nucleo-
Herein, we establish the Raney nickel/Candida antarctica philes, although the resolutions showed high stereoselecti-
lipase B (CAL-B) catalyzed DDKR strategy for the simul- vity.
taneous resolution of primary amines and secondary
After comparing the effect of the acyl donor structure
alcohols in one pot (see Scheme 1). This highly efficient on the enzymatic co-resolution, 1-phenylethyl 2-meth-
DDKR process provided a series of chiral amides and oxyacetate (2a) was selected as the acyl donor. Much better
alcohols (esters) in good yields with high ee values. We fur- results were obtained when the methoxyacetyl ester was
ther demonstrated the successful application of DDKR to used as the acyl group (see Table 1). The highest conversion
the resolution of mexiletine, an important antiarrhythmic reached up to 42%, and high ee values were achieved (see
agent. The catalysts CAL-B and Raney nickel can be recy- Table 1, Entry 3).
cled and reused four times with the same activity. Scale-up
experiments were then done with satisfactory results.
As stated in the introduction, our goal is to develop a
process for dynamic double kinetic resolution. However, it
Table 1. Double kinetic resolution of secondary alcohols.[a,b,c]
Entry
R1
% ee (R)-2b–2d % ee (S)-1b–1d % Conversion[d]
% ee (S)-2a
% ee (R)-1a
% Conversion[e]
1
2
3
4-MeOC6H4
4-BrC6H4
n-C6H13
35
87
87
31
25
26
20
37
43
35
70
93
89
95
32
39
42
36[f]
[a] Reagents and conditions: alcohol (0.1 mmol), ester (0.1 mmol), toluene (2 mL), CAL-B (5 mg), 70 °C, 48 h. [b] All of the ee values
were determined by chiral GC analysis. [c] The conversions were determined by chiral GC analysis, which used n-dodecane as the internal
standard assay. [d] Conversions based on racemic alcohols 1b–1d. [e] Conversions based on racemic ester 2a. [f] The ee value was deter-
mined by its acetate.
2918
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2917–2923

Dynamic Double Kinetic Resolution of Amines and Alcohols
is impossible to achieve in the co-resolution of two alcohol acyl donors afforded low yields of corresponding amides
nucleophiles, because both the resolved alcohol substrate (67 and 68%, respectively) and unsatisfying enantio-
and the leaving chiral alcohol moiety can be racemized un- selectivities of the leaving alcohols (73 and 77%ee, respec-
der the metal catalysis. On these occasions, only the alcohol tively; (see Table 3, Entries 1 and 3). When the propionyl
substrate could be resolved, whereas the leaving alcohol was group was employed as the acyl donor, excellent results with
still racemic.
regard to both the enantioselectivity and conversion were
To display the advantages of a DDKR, we focused on obtained (see Table 3, Entry 2). As a result, the propionyl
the simultaneous co-resolution of primary amines and sec- group was selected as the acyl donor. Finally, to optimize
ondary alcohol nucleophiles. Palladium, ruthenium, and the DDKR further, we investigated different molar ratios
iridium complexes are commonly used as racemization cat- of amine to ester. To gain an optimized yield and ee value,
alysts for the DKRs of primary amines.[11,5b] Initially, we we adopted the amine/ester molar ratio of 1:1.9.
screened Pd-C, Pd-BaSO4, Pd-Al2O3, and Raney nickel as
With the optimized reaction conditions in hand, we in-
racemization catalysts (see Table 2). We found that when Pd vestigated the scope of substrates of this new DDKR pro-
was used as catalyst, the ee values (92–98%) and yields (76– cess. We examined a series of compounds that contained
95%) of the amide were high, however, 1-phenylethanol and aromatic and aliphatic groups. Most of these compounds
its ester were preferentially converted into ethylbenzene in could be resolved with excellent enantiomeric excess values
the presence of CAL-B and hydrogen. Other aromatic and in excellent yields (see Table 4). We found that the aro-
alcohols also suffered from this problem, as in accordance matic ester that contained an electron-withdrawing group
with Mäki-Arvela’s report.[12] When Raney nickel was used (see Table 4, Entry 3) showed decreased selectivity and a
as the racemization catalyst, this problem was avoided, and lower conversion. When aliphatic amines were treated with
excellent yields and ee values were obtained.
aromatic esters (see Table 4, Entries 1, 2, and 7), the
In addition, the acyl group was found to have a signifi- DDKRs showed better performance. In the resolution of
cant influence on the results of the DDKR process. Herein, aromatic amines (see Table 4, Entries 5 and 6), the selectiv-
three acyl groups, which include methoxyacetyl, acetyl, and ity of the amides was excellent, whereas the yields of the
propionyl, were selected and employed in the DDKR of 2- amide and leaving alcohol were usually lower than those
aminoheptane and the ester of 1-phenylethanol (see that resulted from the resolution of aliphatic amines (see
Table 3). Among them, both the methoxyacetyl and acetyl Table 4, Entries 5 vs. 2 or 7 and 6 vs. 4 or 8). This could
Table 2. Selection of racemization catalyst in DDKR of 2-aminoheptane.[a,b]
Entry
Catalyst
(R)-3a
(R)-1a
(S)-2e
% Conversion
% ee
% Yield
% ee
% Yield[c]
% ee
[d]
[d]
[d]
[d]
[d]
[d]
1
2
3
4
Pd-C
93
98
92
93
76
95
–
–
–
–
–
–
–
–
[d]
[d]
[d]
Pd-BaSO4
Pd-Al2O3
Raney Ni
–
–
[d]
[d]
[d]
83
–
–
93[e]
93
47[e]
85
51[e]
[a] Reagents and conditions: amine (0.1 mmol), ester (0.19 mmol), toluene (2 mL), CAL-B (5 mg), Raney nickel (5 mg), 70 °C, 48 h. [b] All
of the ee values were determined by chiral GC analysis. [c] Theoretical amount is 0.19 mmol. [d] 1-Phenylethanol and its ester were
preferentially converted into ethylbenzene. [e] Isolated yields and conversions after column chromatography.
Table 3. Selection of acyl donors in DDKR of 2-aminoheptane.[a,b]
Entry
R
(R)-3a,3e,3f
% Yield[d]
(R)-1a
(S)-2a,2e,2i
% Conversion[d]
% ee
% ee
% Yield[c,d]
% ee
1
2
3
CH2OCH3 (2a)
Et (2e)
Me (2i)
98
93
99
67
93
68
73
93
77
31
47
42
60
85
87
30
51
34
[a] Reagents and conditions: amine (0.1 mmol), ester (0.19 mmol), toluene (2 mL), CAL-B (5 mg), Raney nickel (5 mg), 70 °C, 48 h. [b] All
of the ee values were determined by chiral GC analysis. [c] Theoretical amount is 0.19 mmol. [d] Isolated yields and conversions after
column chromatography.
Eur. J. Org. Chem. 2014, 2917–2923
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2919

B. Xia, G. Cheng, X. Lin, Q. Wu
FULL PAPER
Table 4. Dynamic kinetic resolution of primary amines.[a,b]
Entry
R1
R2
(R)-3a–3c
(R)-1a–1d
%Yield[c,d]
(S)-2e–2h
% ee
%Yield[c]
% ee
% ee
% Conversion[c]
1
2
3
4
5
6
7
8
n-C5H11
n-C5H11
n-C5H11
n-C5H11
Ph
Ph
n-C6H13
n-C6H13
Ph
93
95
53
97
99
99
93
87
93
91
71
90
85
76
92
77
93
97
47
47
37
43
44
35
46
39
85
79
59
81
75
51
75
63
51
47
39
43
45
38
47
42
4-MeOC6H4
4-BrC6H4
n-C6H13
4-MeOC6H4
n-C6H13
4-MeOC6H4
n-C6H13
99
93[e]
95
92[e]
90
91[e]
[a] Reagents and condition: amine (0.1 mmol), ester (0.19 mmol), toluene (2 mL), CAL-B (5 mg), Raney nickel (5 mg), 70 °C, 48 h. [b] All
of the ee values were determined by chiral GC analysis. [c] Isolated yields and conversions after column chromatography. [d] Theoretical
amount is 0.19 mmol. [e] The ee values were determined by using the acetate.
result from the differences between the racemizing abilities when 1-phenylethyl propionate was used, the resolution
of aliphatic and aromatic amines.
proceeded much faster than with 1-(4-methoxyphenyl)ethyl
After obtaining these results, we were also interested in propionate. Therefore, we employed 1-phenylethyl propion-
applications of this DDKR method. Mexiletine is an im- ate as the co-resolution substrate for the DDKR of mexilet-
portant antiarrhythmic agent. The (R)-mexiletine enantio- ine. By using the DDKR process, the optically pure amide
mer is more potent than its (S) counterpart towards experi- of mexiletine was obtained in high yield (see Table 5, En-
mental arrhythmias and in binding studies of cardiac so- try 1). During this same process, 1-phenylethyl propionate
dium channels.[13] It was considered risky when mexiletine and 1-phenylethanol, which are valuable building blocks of
was used in its racemic form for the treatment of ventricular chiral pharmaceuticals, agrochemicals, and natural prod-
tachyarrhythmia.[14] Our group has reported the dynamic ucts, were also obtained with high ee value and in high
kinetic resolution of mexiletine as well the synthesis of its yields. Because of their completely different polarities, the
chiral polymer prodrugs.[15] In continuation of this effort, mixture of the three optical products (the amide, ester, and
we decided to apply DDKR to the preparation of chiral alcohol) were easily separated by simple column
mexiletine.
chromatography. All of this made the DDKR of mexiletine
In our initial investigation, we used 1-phenylethyl prop- more efficient and atomic economical than the traditional
ionate and 1-(4-methoxyphenyl)ethyl propionate, respec- DKR process.
tively, as the co-resolution substrates (see Table 5, Entries 1
As an application to an important drug, an 18 mg reac-
and 2). We found that both 1-phenylethyl propionate and tion scale did not provide a sufficient amount of the op-
1-(4-methoxyphenyl)ethyl propionate gave good results, but tically pure compound. Therefore, we increased the scale of
Table 5. Dynamic double kinetic resolution of mexiletine.[a]
Entry
R
(R)-3d
(R)-1a,1b
(S)-2e,2
% Conversion[c]
% ee[b]
% Yield[c]
% ee[d]
% Yield[c]
% ee[d]
1
Ph
98
95
98
97
93
85
87
84
91
93
95
93
46
47
47
45
91
83
92
87
46
54
52
48
2
4-MeOC6H4
Ph
Ph
3[e]
4[f]
[a] Reagents and conditions mexiletine (0.1 mmol), ester (0.19 mmol), toluene (2 mL), CAL-B (5 mg), Raney nickel (5 mg), 70 °C, 48 h.
[b] The ee values of the mexiletine amide (3d) were determined by chiral HPLC analysis. [c] Isolated yields and conversions after column
chromatography. [d] All the ee values of the alcohols and esters were determined by GC analysis. [e] The first scale-up was from 18 mg
(0.1 mmol) to 180 mg (1.0 mmol) of mexiletine. [f] The second scale-up was from 180 mg to 1.8 g (10 mmol) of mexiletine.
2920
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2917–2923

Dynamic Double Kinetic Resolution of Amines and Alcohols
200 °C, 5 °Cmin–1, n-dodecane as internal standard). All the
the DDKR of mexiletine. First, we increased the scale of
the DDKR reaction tenfold (from 18 to 180 mg of mexilet-
ine; see Table 5, Entry 3), and then we increased the reac-
tion scale another tenfold from 180 mg to 1.8 g (see Table 5,
Entry 4). Each increase provided good results. The catalysts
had the capability to be reused, which was another impor-
tant feature of this DDKR strategy. In our case, the cata-
lytic activity and selectivity of both the enzyme and Raney
nickel were still well maintained after being reused four
times (see Figure 1).
1
known products were characterized by comparing the H and 13C
NMR spectroscopic data with those reported in the literature. The
absolute stereochemistry of the amines, alcohols, amides, and esters
were determined by comparison with literature values. Toluene
(99%) was purchased from Sinopharm Chemical Reagent Co. Ltd
(China). All alcohols and amines were purchased from Sigma–Ald-
rich. (R,S)-Mexiletine hydrochloride was purchased from Jiangsu
Jintan Yabang Pharmaceutical Co. Ltd (China). Lipase B from
Candida antarctica (CAL-B, EC 3.1.1.3, Ն10,000 Ug–1) was pur-
chased from Sigma and immobilized on an acrylic resin. Pd-BaSO4,
Pd-C, Pd-Al2O3, and Raney nickel (W-2) were purchased from
Aladdin (China). 1-Phenylethyl acetate (2i) and N-(heptan-2-yl)
acetamide (3f) were purchased from Aladdin (China).
Procedure for Double Kinetic Resolution of Alcohols: CAL-B (5 mg)
was added to a solution of the alcohol (0.1 mmol) and ester
(0.1 mmol) in toluene (2 mL), and the mixture was stirred at 70 °C
for 48 h. The reaction mixture was then analyzed by chiral GC.
Procedure for Dynamic Double Kinetic Resolution of Amines: CAL-
B (5 mg) was added to a solution of the amine (0.1 mmol), ester
(0.19 mmol), and Raney nickel (5 mg) in toluene (2 mL), and the
resulting mixture was stirred at 70 °C for 48 h under hydrogen
(0.1 MPa). After chiral GC analysis indicated that the reaction was
complete, the mixture was filtered to remove the catalysts. The cata-
lysts were washed with DCM (3ϫ 5 mL), and the combined or-
ganic phases were concentrated in vacuo. The alcohol, ester, and
amide were separated by the column chromatography (petroleum
ether/EtOAc) to obtain the yields and conversions. The structures
of the isolated (R) products (i.e., amides 3a–3c) and (S) products
(i.e., esters 2e–2h) were confirmed by 1H and 13C NMR spectro-
scopic analysis. The structures of the (R) products (i.e., alcohols
1a–1d) were confirmed by comparison with the standards, which
were purchased from Sigma–Aldrich.
Figure 1. Enantiomeric excess values (A) and yields (B) after the
CAL-B/Raney nickel catalysis system was recycled one, two, three,
and four times.
(R)-N-(Heptan-2-yl)propionamide [(R)-3a]: 1H NMR (400 MHz,
CDCl3): δ = 5.18 (br. s, 1 H), 3.94–3.87 (m, 1 H), 2.14–2.08 (q, J
= 24 Hz, 2 H), 1.34–1.31 (m, 2 H), 1.23–1.20 (m, 5 H), 1.11–1.04
(m, 7 H), 082–0.79 (m, 3 H) ppm. 13C NMR (400 MHz, CDCl3):
δ = 173.1, 45.1, 36.9, 31.6, 29.9, 25.6, 22.5, 21.0, 14.0, 10.0 ppm.
(R)-N-(1-Phenylethyl)propionamide [(R)-3b]: 1H NMR (400 MHz,
CDCl3): δ = 7.27–7.19 (m, 5 H), 5.08–5.05 (m, 1 H), 2.15–2.13 (m,
2 H), 1.42–1.41 (d, J = 4 Hz, 3 H), 1.10–1.06 (t, J = 16 Hz, 3
H) ppm. 13C NMR (400 MHz, CDCl3): δ = 172.8, 143.3, 128.6,
127.3, 126.1, 48.6, 29.8, 21.7, 9.8 ppm.
(R)-N-(Octan-2-yl)propionamide [(R)-3c]: 1H NMR (400 MHz,
CDCl3): δ = 5.91–5.71 (br. s, 1 H), 4.09–3.93 (m, 1 H), 2.23–2.15
(m, 2 H), 1.47–1.08 (m, 16 H), 0.88–0.85 (m, 3 H) ppm. 13C NMR
(400 MHz, CDCl3): δ = 173.1, 45.1, 36.9, 31.6, 29.9, 25.6, 22.5,
21.0, 14.0, 10.0 ppm.
(S)-1-Phenylethyl Propionate [(S)-2e]: 1H NMR (400 MHz,
CDCl3): δ = 7.28–7.18 (m, 5 H), 5.85–5.80 (q, J = 20 Hz, 1 H),
3.31–3.25 (m, 2 H), 1.47–1.45 (d, J = 8 Hz, 3 H), 1.08–1.04 (t, J =
16 Hz, 3 H) ppm. 13C NMR (400 MHz, CDCl3): δ = 172.6, 140.8,
127.4, 126.7, 125.0, 71.0, 26.8, 21.2, 8.0 ppm.
Conclusions
In summary, a highly efficient dynamic double kinetic
resolution strategy under the co-catalysis of Raney nickel/
Candida antarctica lipase B was successfully established.
Applications of this DDKR strategy to the efficient resolu-
tion of a series of racemic amines and secondary alcohols
(or esters) as well as mexiletine, an important antiarrhyth-
mic agent, were achieved in good yields and with high ee
values. The isolation of each optically pure product was
easily achieved by simple column chromatography. The cat-
alysts CAL-B and Raney nickel can be recycled and reused
four times with the same conversions and ee values. Our
scale-up experiments were also successful. As a more atom-
economical and efficient process than traditional simple ki-
netic resolutions, the DDKR strategy can be widely used to
prepare optically pure amines and alcohols.
(S)-1-(4-Methoxyphenyl)ethyl Propionate [(S)-2f]: 1H NMR
(400 MHz, CDCl3): δ = 7.21–7.19 (d, J = 12 Hz, 2 H), 6.80–6.78
(dd, J = 8 Hz, 2 H), 5.78–5.77 (m, 1 H), 3.70 (s, 3 H), 2.25–2.22
(m, 2 H), 1.44–1.42 (d, J = 8 Hz, 3 H), 1.05–1.01 (t, J = 16 Hz, 3
H) ppm. 13C NMR (400 MHz, CDCl3): δ = 173.7, 159.2, 133.9,
127.5, 113.8, 71.7, 55.2, 27.9, 22.0, 9.0 ppm.
Experimental Section
1
General Methods: The H and 13C NMR spectroscopic data were
recorded with a Bruker AMX-400 MHz spectrometer, and TMS
was used as the internal standard. Chiral HPLC was performed
with an AD-H column [250ϫ4.6 mm, mobile phase: n-hexane/eth-
anol (99:1), flow: 0.5 mLmin–1] and a UV detector (220 or 254 nm).
Chiral GC was performed with a CP-chirasil-DEX CB 25ϫ 0.25 (S)-1-(4-Bromophenyl)ethyl Propionate [(S)-2g]: 1H NMR
(Agilent) column (from 110 to 140 °C, 2 °Cmin–1, from 140 to
(400 MHz, CDCl3): δ = 7.39–7.37 (d, J = 8 Hz, 2 H), 7.15–7.13 (d,
Eur. J. Org. Chem. 2014, 2917–2923
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2921

B. Xia, G. Cheng, X. Lin, Q. Wu
FULL PAPER
J = 8 Hz, 2 H), 5.76–5.74 (m, 1 H), 2.29–2.25 (m, 2 H), 1.43–1.41
trated in vacuo. The residue was dissolved in ethyl acetate, and the
(d, J = 8 Hz, 3 H), 1.07–1.03 (t, J = 16 Hz, 3 H) ppm. 13C NMR solution was washed with water. The organic phase was separated,
(400 MHz, CDCl3): δ = 173.6, 140.9, 131.6, 127.8, 131.6, 71.4, 27.8,
22.1, 9.0 ppm.
and the aqueous phase was extracted with EtOAc (3ϫ 20 mL). The
combined organic phases were washed with 1 m hydrochloric acid
(2ϫ 20 mL) and then saturated sodium hydrogen carbonate (2ϫ
20 mL). Then, the organic phase was dried with MgSO4 and con-
centrated in vacuo. The crude product was purified by chromatog-
raphy on a silica gel column (EtOAc/petroleum ether).
(S)-Octan-2-yl Propionate [(S)-2h]: 1H NMR (400 MHz, CDCl3): δ
= 4.92–4.89 (m, 1 H), 2.31–2.26 (m, 2 H), 1.27–1.11 (m, 16 H),
0.88–0.87 (m, 3 H) ppm. 13C NMR (400 MHz, CDCl3): δ = 174.1,
70.7, 35.9, 31.7, 29.0, 27.9, 25.3, 22.5, 19.9, 13.9, 9.1 ppm.
1-Phenylethyl 2-Methoxyacetate (2a): The product was isolated by
column chromatography (petroleum ether EtOAc, 5:1) to give 2a
in 76% yield. 1H NMR (400 MHz, CDCl3): δ = 7.39–7.32 (m, 5
H), 6.03–6.02 (m, 1 H), 4.11–4.02 (m, 2 H), 3.46 (s, 3 H), 1.61–1.59
(d, J = 8 Hz, 3 H) ppm. 13C NMR (400 MHz, CDCl3): δ = 169.5,
141.1, 128.5, 128.0, 126.1, 72.9, 70.0, 59.3, 22.1 ppm.
Application of DDKR to the Resolution of Mexiletine: CAL-B
(5 mg) was added to a solution of mexiletine (18 mg), 1-phenylethyl
propionate (33.8 mg), and Raney nickel (5 mg) in toluene (2 mL).
The mixture was then stirred at 70 °C for 48 h under hydrogen
(0.1 MPa). After chiral GC analysis indicated that the reaction was
complete, the mixture was filtered to remove the catalysts. The cata-
lysts were then washed with DCM (3ϫ 5 mL), and the combined
organic phases were concentrated in vacuo. The alcohol, ester, and
amide were separated by the column chromatography (petroleum
ether/EtOAc, from 5:1 to 3:1 and then EtOAc). The structure of the
isolated (R) product (i.e., amide of mexiletine 3d) was confirmed by
1H and 13C NMR spectroscopic analysis. The structures of the (S)
product [i.e., 1-phenylethyl propionate (2e)], and (R) product [i.e.,
1-phenylethanol (1a)] were compared with the standards, which
were confirmed in the DDKR of the amines.
1-(4-Methoxyphenyl)ethyl 2-Methoxyacetate (2b): The product was
isolated by column chromatography (petroleum ether/EtOAc, 5:1)
to give 2b in 82% yield. 1H NMR (400 MHz, CDCl3): δ = 7.33–
7.31 (d, J = 8 Hz, 2 H), 6.91–6.89 (d, J = 8 Hz, 2 H), 6.0–5.98 (m,
1 H), 4.08–3.98 (m, 2 H), 3.81 (s, 3 H), 3.49 (s, 3 H), 1.59–1.57 (d,
J = 8 Hz, 3 H) ppm. 13C NMR (400 MHz, CDCl3): δ = 169.9,
159.4, 133.1, 127.7, 113.8, 72.6, 70.0, 59.3, 55.2, 21.8 ppm.
1-(4-Bromophenyl)ethyl 2-Methoxyacetate (2c): The product was
isolated by column chromatography (petroleum ether/EtOAc, 5:1)
to give 2c in 80% yield. 1H NMR (400 MHz, CDCl3): δ = 7.41–
7.39 (d, J = 8 Hz, 2 H), 7.19–7.15 (d, J = 8 Hz, 2 H), 5.88–5.83
(m, 1 H), 4.01–3.91 (m, 2 H), 3.35 (s, 3 H), 1.48–1.46 (d, J = 8 Hz,
3 H) ppm. 13C NMR (400 MHz, CDCl3): δ = 169.4, 140.1, 131.7,
127.9, 121.9, 72.1, 69.9, 59.3, 22.0 ppm.
1
(R)-Amide of Mexiletine (R)-3d: H NMR (400 MHz, CDCl3): δ =
7.01–6.90 (m, 3 H), 6.02 (br. s, 1 H), 4.37 (br. s, 1 H), 3.79–3.71
(m, 2 H), 2.41–2.05 (m, 8 H), 1.41–1.40 (d, J = 4 Hz, 3 H), 1.20 (s,
3 H) ppm. 13C NMR (400 MHz, CDCl3): δ = 173.2, 154.8, 130.7,
129.0, 124.1, 73.9, 45.3, 29.9, 17.8, 16.1, 9.9 ppm.
Scale-Up Procedure for DDKR of Mexiletine: First scale-up: CAL-
B (20 mg) was added to a solution of mexiletine (0.18 g), 1-phenyl-
ethyl propionate (0.34 g), and Raney nickel (20 mg) in toluene
(2 mL). The mixture was then stirred at 70 °C for 48 h under hydro-
gen (0.1 MPa). After chiral GC analysis indicated that the reaction
was complete, the mixture was handled as above in the procedure
of the DDKR of mexiletine. The structures of the isolated products
were compared with the standards, which were confirmed in the
DDKR of mexiletine. Second scale-up: CAL-B (80 mg) was added
to a solution of mexiletine (1.8 g), 1-phenylethyl propionate (3.4 g),
and Raney nickel (80 mg) in toluene (2 mL). The mixture was then
stirred at 70 °C for 48 h under hydrogen (0.1 MPa). After chiral
GC analysis indicated that the reaction was complete, the mixture
was handled as above in the procedure of the DDKR of mexiletine.
The structures of the isolated products were compared with the
standards, which were confirmed in the DDKR of mexiletine.
Octan-2-yl 2-Methoxyacetate (2d): The product was isolated by
column chromatography (petroleum ether/EtOAc, 5:1) to give 2d
in 87% yield. 1H NMR (400 MHz, CDCl3): δ = 5.04–4.99 (m, 1
H), 4.0 (s, 3 H), 3.45 (s, 3 H), 1.64–1.23 (m, 13 H), 0.90–0.86 (m,
3 H) ppm. 13C NMR (400 MHz, CDCl3): δ = 169.9, 71.8, 70.0,
59.2, 35.8, 31.6, 29.0, 25.3, 22.5, 19.9, 14.0 ppm.
N-(Heptan-2-yl)-2-methoxyacetamide (3e): The product was iso-
lated by column chromatography (petroleum ether/EtOAc, 2:1) to
1
give 3e in 90% yield. H NMR (400 MHz, CDCl3): δ = 4.97–4.92
(m, 1 H), 3.93 (s, 2 H), 3.38 (s, 3 H), 1.57–1.16 (m, 13 H), 0.82–
0.79 (t, J = 12 Hz, 3 H) ppm. 13C NMR (400 MHz, CDCl3): δ =
169.9, 71.8, 70.0, 59.2, 35.8, 31.6, 29.0, 25.3, 22.5, 19.9, 14.0 ppm.
General Procedure for Synthesis of rac-(2e–2h) and rac-(3a–3d):
Propionic anhydride (0.12 mol) was added dropwise to a solution
of the alcohol or amine (0.01 mol), 4-(dimethylamino)pyridine (10
wt.-%), and triethylamine (0.02 mol) in DCM (10 mL). The mix-
ture was then stirred at room temperature. After TLC indicated
that no substrate remained, the reaction mixture was washed with
1.0 m hydrochloric acid (2ϫ 20 mL) and saturated hydrogen carb-
onate (2ϫ 20 mL). The organic phase was dried with MgSO4 and
concentrated in vacuo. The crude product was purified by
chromatography on a silica gel column (EtOAc/petroleum ether).
Recycling the Catalysts for the DDKR of Mexiletine: CAL-B
(20 mg) was added to a solution of mexiletine (0.18 g), 1-phenyl-
ethyl propionate (0.34 g), and Raney nickel (20 mg) in toluene
(2 mL). The mixture was then stirred at 70 °C for 48 h under hydro-
gen (0.1 MPa). After chiral GC analysis indicated that the reaction
was complete, the mixture was filtered. The catalysts were washed
with DCM (4ϫ 5 mL). The filtrate was handled according to the
general procedure for the DDKR of mexiletine, and the catalysts
were carefully collected and dried in vacuo. These catalysts were
reused according to the procedure for the DDKR of mexiletine.
The structures of the isolated products were compared with the
standards, which were confirmed in the DDKR of mexiletine.
1-Phenylethyl Propionate (2e): The product was isolated by column
chromatography (petroleum ether/EtOAc, 5:1) to give 2e in 92%
1
yield. H NMR (400 MHz, CDCl3): δ = 7.28–7.18 (m, 5 H), 5.85–
5.80 (q, J = 20 Hz, 1 H), 3.31–3.25 (m, 2 H), 1.47–1.45 (d, J =
8 Hz, 3 H), 1.08–1.04 (t, J = 16 Hz, 3 H) ppm. 13C NMR
(400 MHz, CDCl3): δ = 172.6, 140.8, 127.4, 126.7, 125.0, 71.0, 26.8,
21.2, 8.0 ppm.
General Procedure for the Synthesis of rac-(2a–2d), and rac-3e:
Methoxyacetyl chloride (0.015 mol) was added dropwise to a solu-
tion of the alcohol or amine (0.01 mol) in pyridine (10 mL). The
resulting mixture was stirred at room temperature. After TLC indi-
1-(4-Methoxyphenyl)ethyl Propionate (2f): The product was isolated
by column chromatography (petroleum ether/EtOAc, 5:1) to give
1
cated that no substrate remained, the reaction mixture was concen- 2f in 87% yield. H NMR (400 MHz, CDCl3): δ = 7.21–7.19 (d, J
2922
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2917–2923

Dynamic Double Kinetic Resolution of Amines and Alcohols
= 12 Hz, 2 H), 6.80–6.78 (dd, J = 8 Hz, 2 H), 5.78–5.77 (m, 1 H),
3.70 (s, 3 H), 2.25–2.22 (m, 2 H), 1.44–1.42 (d, J = 8 Hz, 3 H), [1] a) T. C. Nugent, D. E. Negru, M. EI-Shazly, D. Hu, A. Sadiq,
1.05–1.01 (t, J = 16 Hz, 3 H) ppm. 13C NMR (400 MHz, CDCl3):
δ = 173.7, 159.2, 133.9, 127.5, 113.8, 71.7, 55.2, 27.9, 22.0, 9.0 ppm.
A. Bibi, M. N. Umar, Adv. Synth. Catal. 2011, 353, 2085–2092;
b) T. C. Nugent, M. EI-Shazly, Adv. Synth. Catal. 2010, 352,
753–819.
[2] a) M. Hoehn, U. T. Bornscheuer, ChemCatChem 2009, 1, 42–
51; b) A. O. Magnusson, M. Takwa, A. Hamberg, K. Hult,
Angew. Chem. 2005, 117, 4658; Angew. Chem. Int. Ed. 2005,
44, 4582–4585; c) Y. Sato, Y. Kayaki, T. Ikariya, Chem. Com-
mun. 2012, 48, 3635–3637; d) B. Chen, H. F. Yin, Z. S. Wang,
J. Y. Liu, J. H. Xu, Chem. Commun. 2010, 46, 2754–2756; e)
G. L. Cheng, B. Xia, Q. Wu, X. F. Lin, RSC Adv. 2013, 3,
9820–9828; f) P. Hoyos, V. Pace, A. R. Alcántara, Adv. Synth.
Catal. 2012, 354, 2585–2611; g) A. Bartoszewicz, N. Ahlsten,
B. M. Matute, Chem. Eur. J. 2013, 19, 7274–7302; h) Q. Wu, P.
Soni, M. T. Reetz, J. Am. Chem. Soc. 2013, 135, 1872–1881.
[3] M. T. Reetz, K. Schimossek, Chimia 1996, 50, 668–669.
[4] P. M. Dinh, J. A. Howarth, A. R. Hudnott, J. M. J. Williams,
W. Harris, Tetrahedron Lett. 1996, 37, 7623–7626.
[5] a) J. Paetzold, J. E. Bäckvall, J. Am. Chem. Soc. 2005, 127,
17620–17621; b) O. Pàmies, J. E. Bäckvall, Chem. Rev. 2003,
103, 3247–3261; c) K. Engström, M. Vallin, P. O. Syrén, K.
Hult, J. E. Bäckvall, Org. Biomol. Chem. 2011, 9, 81–82.
[6] a) S. B. Ko, B. Baburaj, M. J. Kim, J. Park, J. Org. Chem. 2007,
72, 6860–6864; b) Y. Kim, J. Park, M. J. Kim, ChemCatChem
2011, 3, 271–277; c) Y. Kim, J. Park, M. J. Kim, Tetrahedron
Lett. 2010, 51, 5581–5584.
[7] a) A. Parvulescu, D. D. Vos, P. Jacobs, Chem. Commun. 2005,
3, 5307–5309; b) A. N. Parvulescu, P. A. Jacobs, D. E. De Vos,
Adv. Synth. Catal. 2008, 350, 113–121; c) F. Poulhes, N. Van-
thuyne, M. P. Bertrand, S. Gastaldi, G. Gil, J. Org. Chem. 2011,
76, 7281–7286; d) L. E. Blidi, N. Vanthuyne, D. Siri, S. Gas-
taldi, M. P. Bertrand, G. Gil, Org. Biomol. Chem. 2010, 8,
4165–4168; e) A. Parvulescu, J. Janssens, J. Vanderleyden, D. E.
De Vos, Top. Catal. 2010, 53, 931–941; f) V. Gotor-Fernandez,
V. Gotor, Curr. Opin. Drug Discov. Devel. 2009, 12, 784–797.
[8] a) E. Garcia-Urdiales, F. Rebolledo, V. Gotor, Tetrahedron:
Asymmetry 2000, 11, 1459–1463; b) V. M. Sánchez, F. Rebol-
ledo, V. Gotor, J. Org. Chem. 1999, 64, 1464–1470.
1-(4-Bromophenyl)ethyl Propionate (2g): The product was isolated
by column chromatography (petroleum ether ether/EtOAc, 5:1) to
1
give 2g in 90% yield. H NMR (400 MHz, CDCl3): δ = 7.39–7.37
(d, J = 8 Hz, 2 H), 7.15–7.13 (d, J = 8 Hz, 2 H), 5.76–5.74 (m, 1
H), 2.29–2.25 (m, 2 H), 1.43–1.41 (d, J = 8 Hz, 3 H), 1.07–1.03 (t,
J = 16 Hz, 3 H) ppm. 13C NMR (400 MHz, CDCl3): δ = 173.6,
140.9, 131.6, 127.8, 131.6, 71.4, 27.8, 22.1, 9.0 ppm.
Octan-2-yl Propionate (2h): The product was isolated by column
chromatography (petroleum ether/EtOAc, 5:1) to give 2h in 85%
1
yield. H NMR (400 MHz, CDCl3): δ = 4.92–4.89 (m, 1 H), 2.31–
2.26 (m, 2 H), 1.27–1.11 (m, 16 H), 0.88–0.87 (m, 3 H) ppm. 13C
NMR (400 MHz, CDCl3): δ = 174.1, 70.7, 35.9, 31.7, 29.0, 27.9,
25.3, 22.5, 19.9, 13.9, 9.1 ppm.
N-(Heptan-2-yl)propionamide (3a): The product was isolated by col-
umn chromatography (petroleum ether/EtOAc, 2:1) to give 3a in
74% yield. 1H NMR (400 MHz, CDCl3): δ = 5.18 (br. s, 1 H),
3.94–3.87 (m, 1 H), 2.14–2.08 (q, J = 24 Hz, 2 H), 1.34–1.31 (m, 2
H), 1.23–1.20 (m, 5 H), 1.11–1.04 (m, 7 H), 0.82–0.79 (m, 3
H) ppm. 13C NMR (400 MHz, CDCl3): δ = 173.1, 45.1, 36.9, 31.6,
29.9, 25.6, 22.5, 21.0, 14.0, 10.0 ppm.
N-(1-Phenylethyl)propionamide (3b): The product was isolated by
column chromatography (petroleum ether/EtOAc, 2:1) to give 3b
in 78% yield. 1H NMR (400 MHz, CDCl3): δ = 7.27–7.19 (m, 5
H), 5.08–5.05 (m, 1 H), 2.15–2.13 (m, 2 H), 1.42–1.41 (d, J = 4 Hz,
3 H), 1.10–1.06 (t, J = 16 Hz, 3 H) ppm. 13C NMR (400 MHz,
CDCl3): δ = 172.8, 143.3, 128.6, 127.3, 126.1, 48.6, 29.8, 21.7,
9.8 ppm.
N-(Octan-2-yl)propionamide (3c): The product was isolated by col-
umn chromatography (petroleum ether/EtOAc, 2:1) to give 3c in
82% yield. 1H NMR (400 MHz, CDCl3): δ = 5.91–5.71 (br. s, 1
H), 4.09–3.93 (m, 1 H), 2.23–2.15 (m, 2 H), 1.47–1.08 (m, 16 H),
[9] N. Öhrner, C. Orrenius, A. Mattson, T. Norin, K. Hult, En-
zyme Microb. Technol. 1996, 19, 328–331.
[10] G. L. Lin, S. H. Liu, S. J. Chen, F. C. Wu, H. L. Sun, Tetrahe-
dron Lett. 1993, 34, 6057–6058.
0.88–0.85 (m, 3 H) ppm. 13C NMR (400 MHz, CDCl3): δ = 173.1, [11] a) S. I. Murahashi, N. Yoshimura, T. Tsumiyama, T. Kojima,
J. Am. Chem. Soc. 1983, 105, 5002–5011; b) K. Engström, M.
Shakeri, J. E. Bäckvall, Eur. J. Org. Chem. 2011, 1827–1830; c)
Y. K. Choi, Y. Kim, K. Han, J. Park, M. J. Kim, J. Org. Chem.
2009, 74, 9543–9545; d) G. Xu, X. T. Dai, S. M. Fu, J. P. Wu,
L. R. Yang, Tetrahedron Lett. 2014, 55, 397–402; e) B. G. Vaz,
C. D. F. Milagre, M. N. Eberlin, H. M. S. Milagre, Org. Biomol.
Chem. 2013, 11, 6695–6698; f) A. J. Blacker, M. J. Stirling,
M. I. Page, Org. Process Res. Dev. 2007, 11, 642–648; g) J. De-
ska, C. D. P. Ochoa, J. E. Bäckvall, Eur. J. Org. Chem. 2010,
999–1015.
45.1, 36.9, 31.6, 29.9, 25.6, 22.5, 21.0, 14.0, 10.0 ppm.
Amide of Mexiletine 3d: The product was isolated by column
chromatography (petroleum ether/EtOAc, 2:1) to give 3d in 89%
1
yield. H NMR (400 MHz, CDCl3): δ = 7.01–6.90 (m, 3 H), 6.02
(br. s, 1 H), 4.37 (br. s, 1 H), 3.79–3.71 (m, 2 H), 2.41–2.05 (m, 8
H), 1.41–1.40 (d, J = 4 Hz, 3 H), 1.20 (s, 3 H) ppm. 13C NMR
(400 MHz, CDCl3): δ = 173.2, 154.8, 130.7, 129.0, 124.1, 73.9, 45.3,
29.9, 17.8, 16.1, 9.9 ppm.
[12] P. Mäki-Arvela, S. Sahin, K. Eränen, D. Y. Murzin, Res. Chem.
Intermed. 2010, 36, 245–252.
[13] a) J. Turgeon, A. C. G. Uprichard, P. M. Belanger, D. W. G.
Harron, O. Grech-Belanger, J. Pharm. Pharmacol. 1991, 43,
630–635; b) R. J. Hill, H. J. Duff, R. S. Sheldon, Mol. Pharma-
col. 1988, 34, 659–663.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, GC and HPLC data of DDKR process
of alcohols, amines, and mexiletine as well as NMR spectra.
[14] Y. Wang, S. J. Gao, W. H. Ye, H. S. Yoon, Y. Y. Yang, Nat.
Mater. 2006, 5, 791–796.
Acknowledgments
[15] X. Q. Qian, Z. Y. Jiang, Q. Wu, X. F. Lin, J. Polym. Sci., Part
A: Polym. Chem. 2013, 51, 2049–2057.
The financial support from the National Natural Science Founda-
tion of China (NSFC) (grant numbers 21072172 and 21272208) is
gratefully acknowledged.
Received: January 10, 2014
Published Online: March 18, 2014
Eur. J. Org. Chem. 2014, 2917–2923
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2923