First chemoenzymatic synthesis of organoselenium amines and amides

Article abstract of DOI:10.1016/j.tetasy.2008.04.026

A series of organoselenium amines have been synthesized and submitted to the enzymatic kinetic resolution by acetylation mediated by CAL-B (Novozym 435) to give the corresponding chiral amides in an enantiomerically pure form. After evaluating the appropriate lipase, solvent, temperature, and lipase/substrate ratio in the kinetic resolution, the chiral organoselenium amides were obtained with enantiomeric excess of up to 99%.

Full text of DOI:10.1016/j.tetasy.2008.04.026

Tetrahedron: Asymmetry 19 (2008) 1175–1181
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: http://www.elsevier.com/locate/tetasy
First chemoenzymatic synthesis of organoselenium amines and amides
*
Leandro H. Andrade , Alexandre V. Silva
Institute of Chemistry, University of São Paulo, Av. Prof. Lineu Prestes, 748, CEP 05508-900, São Paulo, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of organoselenium amines have been synthesized and submitted to the enzymatic kinetic reso-
lution by acetylation mediated by CAL-B (Novozym 435) to give the corresponding chiral amides in an
enantiomerically pure form. After evaluating the appropriate lipase, solvent, temperature, and lipase/sub-
strate ratio in the kinetic resolution, the chiral organoselenium amides were obtained with enantiomeric
excess of up to 99%.
Received 21 January 2008
Accepted 2 April 2008
Available online 26 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
matic kinetic resolution (EKR) of the racemic organoselenium
amines by their acetylation mediated by lipases to yield the corre-
In recent years chiral organoselenium compounds have been
prepared by several methods ranging from selenocyclization to
biocatalysis.1–9 The constant interest in this area can be devoted
to the wide application of selenium to organic synthesis and bio-
logical chemistry. For example, we mention that compounds
containing a selenium atom have important antioxidant and anti-
inflammatory activities.10,11 Besides those biological applications,
this class of compounds has been intensively applied as ligands
for asymmetric catalysis, such as asymmetric hydrosilylation of
ketones and imines, enantioselective addition of diorganozinc
reagents to aldehydes, enantioselective conjugate addition of orga-
nometallic reagents to enones, and palladium-catalyzed asymmet-
ric allylic alkylation.12–14 Among the chiral selenium compounds
found as ligands, we observe that amino selenides and disele-
nides,15,16 selenium-oxazolidines,17 chiral selenium-imine,18,19
and, more recently, chiral b-organoselenium amides20,21 have been
demonstrated to be excellent catalysts. Notwithstanding the in-
tense activity in the field of organoselenium chemistry over the
last three decades, to our knowledge, no synthetic studies employ-
ing biocatalysis to prepare organoselenium amines have been pub-
lished to date. As part of our current interest in biocatalytic
reactions applied to the selenium chemistry, we decided to devel-
op a chemoenzymatic methodology to synthesize chiral organo-
selenium amines and amides without the use of organolithium or
organomagnesium reagents. Herein we report the incorporation of
the selenium atom to aromatic ketones by the use of reactions of
potassium selenocyanate and diazonium salts to yield seleno-
cyanate acetophenones. These ketones were alkylated with alkyl
halides to result in organoselenium acetophenones which were
converted into their corresponding racemic organoselenium
amines by reductive amination. Finally, we carried out the enzy-
sponding chiral organoselenium amines and amides in an enantio-
merically pure form.
2. Results and discussion
2.1. Synthesis of the organoselenium amines
The methodology of choice for the synthesis of organoselenium
amines 6a–c was the reductive amination of organoselenium
ketones. In this way, in order to avoid organolithium or organo-
magnesium compounds for the insertion of a selenium atom in
the acetophenones5,22,23 an easy synthetic methodology was devel-
oped by using the reaction of KSeCN and diazonium salts (Scheme
1). The first step was the preparation of diazonium salts 2a–c from
ortho-, meta-, and para-aminoacetophenones followed by the addi-
tion of KSeCN to produce the corresponding selenocyanate aceto-
phenones 3a–c (yields, 28–65%) as described in Scheme 1. As
KSeCN has low stability in acid conditions, needed for the diazoti-
zation reaction, and under light exposure, elemental selenium was
formed during the reaction affecting the final yield.24,25
The next step was the alkylation of the selenium atom in the
ketones 3a–c using NaBH4 and ethyl bromide to give ortho-,
meta-, and para-ethylselenium acetophenones (63–78% yield). An
interesting feature of this methodology is the facility to prepare
several organoselenium ketones by simply changing the alkylating
agent. After the alkylation step, we carried out the reductive
amination of the organoselenium ketones 5a–c to afford the (RS)-
organoselenium amines 6a–c (39–73% yield). The protocol chosen
involved the use of ammonia, titanium(IV) isopropoxide, and
ketones 5a–c to give a titanium(IV) complex,26 followed by the
addition of NaBH4. The reducing agent (NaBH4), under these condi-
tions, can also reduce the unreacted ketone 5a–c, consequently,
decreasing the yield of desired amines 6a–c.
* Corresponding author. Tel.: +55 11 3091 2287; fax: +55 11 3815 5579.
E-mail address: leandroh@iq.usp.br (L. H. Andrade).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.04.026

1176
L. H. Andrade, A. V. Silva / Tetrahedron: Asymmetry 19 (2008) 1175–1181
O
O
O
NaBH4
1) HCl/H2O
2) NaNO2
KSeCN
pH 4
Methanol/ 0°C
-Cl+N2
NCSe
H2N
2a: para-N2+Cl-
2b: meta-N2+Cl-
2c: ortho-N2+Cl-
1a: para-NH2
1b: meta-NH2
1c: ortho-NH2
3a: para-SeCN (65%)
3b: meta-SeCN (28%)
3c: ortho-SeCN (60%)
NH2
O
O
1) NH3 in ethanol
EtBr
Methanol/ 0°C
EtSe
2) Ti(IV)
(isopropoxide)
3) NaBH4
H3BNa+ -Se
EtSe
4a: para-Se- +NaBH3
4b: meta-Se- +NaBH3
4c: ortho-Se- +NaBH3
5a: para-SeEt (63%)
(RS)-6a: para-SeEt (73%)
(RS)-6b: meta-SeEt (39%)
(RS)-6c: ortho-SeEt (63%)
5b: meta-SeEt (78%)
5c: ortho-SeEt (65%)
Scheme 1. Synthesis of organoselenium amines 6a–c.
2.2. Kinetic resolution of organoselenium amines catalyzed by
lipases
arctica, Novozyme 435). This lipase catalyzed the preferential acet-
ylation of the (R)-enantiomer of the racemic organoselenium
amine 6a to give the organoselenium amide (R)-7a in 96% enantio-
meric excess. The remaining lipases did not give satisfactory
results. For example, when the reaction was performed by lipase
Amano M, the amide 7a was obtained in 69% of conversion (C) with
very low enantioselectivity (E) (Table 1, entry 11). On the other
hand, the lipase of Pseudomonas sp. conducted the preferential
acetylation of the (R)-organoselenium amine 6a with 65% ee in
low conversion (Table 1, entry 14).
Having in hands the organoselenium amines 6a–c, we have
chosen (RS)-1-[4-(ethylselanyl)phenyl]ethanamine 6a as a model
substrate for the study of kinetic resolution. In this study, we have
screened for appropriate lipases, solvent, temperature, and lipase/
substrate ratio. Initially, we carried out a screening test using 14
lipases for kinetic resolution of (RS)-organoselenium amine 6a
with ethyl acetate as an acyl donor and toluene as a solvent at
40 °C (Table 1).
In order to achieve higher enantioselectivity for the process, we
decided to evaluate the kinetic resolution of 6a with CAL-B in
different solvents (Table 2, hexane, toluene, ethyl acetate, and
According to the screening test, the lipase which exhibited the
highest enantioselectivity was CAL-B (lipase B from Candida ant-
Table 1
Screening of lipases for the kinetic resolution of (RS)-6aa
NH2
NHAc
NH2
Lipase
+
EtOAc
+
Toluene
EtSe
EtSe
EtSe
(RS)-6a
(S)-6a
(R)-7a
Entry
Lipase
Product (R)-amide eeb (%)
Substrate (S)-amine eec (%)
Conv.d
Ee
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Porcine pancreatic
Candida cylindracia
Amano AK
Candida rugosa
Lipozyme IM
Amano PS-C II
Amano A (Aldrich)
Lipolase 100T
CAL-B
Amano PS-DI
Amano M
Amano PS
Amano G
Pseudomonas sp.
21
8
1
1
1
1
1
1
1
3
52
2
5
11
4
16
8
2
3
9
35
3
2
1
2
1
1
4
2
2
82
4
25
16
11
62
29
31
96
59
4
9
1
3
1
69
3
5
1
2
4
5
35
59
65
2
a
Reaction conditions: Selenium amine (0.2 mmol); lipase (20 mg); ethyl acetate (0.8 mmols); toluene (1 mL); 40 °C; 48 h.
Ee determinated by HPLC (OD column).
b
c
Ee determinated by HPLC after derivatization of the amine using acetic anhydride.
d
e
Conversion: c = ees/(ees + eep).27
E = {ln[eeP(1 ꢀ eeS)]/(eeP + eeS)}/{ln[eeP(1 + eeS)]/(eeP + eeS)}.27

L. H. Andrade, A. V. Silva / Tetrahedron: Asymmetry 19 (2008) 1175–1181
1177
Table 2
of (RS)-1-[4-(ethylselanyl)phenyl]ethanamine 6a using hexane
and toluene as solvents (Table 2, entries 5–18).
Initially, we evaluated the influence of the temperature (Table
2, entries 2 and 4–10). The reactions were carried out at 30, 40,
50, and 60 °C. The best results were obtained at 30 °C for both sol-
vents (Table 2, entries 9 and 10). According to this study, it was ob-
Evaluation of the enzymatic kinetic resolution of (RS)-6a under different reaction
conditionsa
Entry Solvent
Temperature
Product (R)-
amide eeb (%) amine eec (%)
Substrate (S)- Conv.d Ee
(°C)
1
Ethyl
ether
Toluene
Ethyl
40
78
7
8
8.7
served that the increase of temperature yielded
a higher
2
3
40
40
96
29
52
50
35
63
82
2.8
conversion accomplished with the decrease of enantioselectivity.
For example, when the kinetic resolution was performed using
hexane at 30 °C, the E was 131 (Table 2, entry 9), however, at
60 °C the E dropped to 10 (Table 2, entry 7). In toluene, the enanti-
oselectivity observed at 30 °C was 79 (Table 2, entry 10) but, at
60 °C, this E value dropped to 15 (Table 2, entry 8). These results
showed that the best conditions were obtained at 30 °C for both
solvents (hexane and toluene).
A study to choose the appropriated amount of CAL-B was car-
ried out at 30 °C using hexane and toluene as solvents. The reaction
was performed using 20, 40, 60, 80, and 100 mg of CAL-B to
0.2 mmol of (RS)-organoselenium amine 6a (Table 2, entries 9–18).
As it can be seen in Table 2, entries 9–18, the increase of the
amount of CAL-B did not improve the conversion of the kinetic res-
olution. However, the enantiomeric purity of the amides formed
was poorly affected, especially when hexane was used as a solvent.
For the reactions in hexane, the highest conversion was obtained
using 40 mg of CAL-B (Table 2, c = 29, entry 11) but the highest
enantioselectivities were observed using 60 mg and 100 mg of
CAL-B (Table 2, E > 200, entries 13 and 17). According to these re-
sults, we can conclude that the best amount of CAL-B was 60 mg
from 0.2 mmol of (RS)-organoselenium amine 6a. After the best
conditions for EKR for compound 6a were established, this meth-
odology has been employed on the organoselenium amine deriva-
tives 6b and 6c. The results of EKR for these organoselenium
amines are shown in Table 3.
acetate
Hexane
Hexane
Toluene
Hexane
Toluene
Hexane
Toluene
Hexanef
Toluenef
Hexaneg
Tolueneg
Hexaneh
Tolueneh
Hexanei
Toluenei
4
5
6
7
8
40
50
50
60
60
30
30
30
30
30
30
30
30
30
30
97
94
94
76
77
98
97
98
95
99
98
98
98
99
97
58
91
77
28
70
29
20
40
33
22
46
32
33
25
12
37
49
45
27
48
23
17
29
26
18
32
25
25
20
11
118
102
75
10
15
131
79
146
53
>200
156
135
136
>200
73
9
10
11
12
13
14
15
16
17
18
a
Reaction conditions: Selenium amine (0.2 mmol); CAL-B (20 mg); ethyl acetate
(0.8 mmols); hexane or toluene (1 mL); temperature (°C); 48 h.
b
Ee determinated by HPLC (OD column).
Ee determinated by HPLC after derivatization of the amine using acetic
c
anhydride.
d
Conversion: c = ees/(ees + eep).27
e
E = {ln[eeP(1 ꢀ eeS)]/(eeP + eeS)}/{ln[eeP(1 + eeS)]/(eeP + eeS)}.27
f
CAL-B (40 mg).
CAL-B (60 mg).
CAL-B (80 mg).
CAL-B (100 mg).
g
h
i
diethyl ether; entries 1–4). As we can see in Table 2, the lipase CAL-
B showed the highest enantioselectivity in hexane (E = 118), in
spite of the low solubility of the compound 6a in this solvent.
When toluene was used as solvent, the enantioselectivity was also
good (E = 82) and no problems with solubility were observed.
However, when the reactions were performed with diethyl ether
and ethyl acetate as solvent, a significant decrease in the enanti-
oselectivity was observed (Table 2, E = 8.7 and E = 2.8; entries 1
and 3, respectively).
As we can see in Table 3, the kinetic resolution of organo-
selenium amines 6b and 6c mediated by CAL-B, ethyl acetate as
an acyl donor, and hexane as a solvent afforded the organo-
selenium amides 7b and 7c with 99% and 98% enantiomeric
excesses, respectively (Table 3, entries 1 and 3). The low conver-
sion for the kinetic resolution of 6c can be attributed to the known
selenium–nitrogen interaction (Se–N).28 Due to this interaction,
the nucleophilicity of the amine group decreases and, con-
sequently, a low conversion was observed. The same interaction
cannot occur when the selenium atom is at the para or meta
position in the aromatic ring.
Based on these results, we decided to evaluate the effect of dif-
ferent temperature and enzyme amount on the kinetic resolution
Table 3
Enzymatic kinetic resolution of (RS)-6b–c mediated by CAL-Ba
NHAc
NH2
NH2
CAL-B
+
+
EtOAc
EtSe
(RS)-6b-c
EtSe
EtSe
(R)-7b meta-SeEt
(R)-7c ortho-SeEt
(S)-6b-c
Entry
Selenium amine/solvent
Product (R)-amide eeb (%)
Substrate (S)-amine eec (%)
Conv.d
Ee
1
2
3
4
6b: meta-SeEt/hexane
6b: meta-SeEt/toluene
6c: ortho-SeEt/hexane
6c: ortho-SeEt/toluene
99
96
98
82
38
16
8
28
14
8
>200
57
107
10
7
8
a
Reaction conditions: Selenium amine (0.2 mmol); CAL-B (60 mg); ethyl acetate (0.8 mmols); hexane or toluene (1 mL); temperature (30 °C); 48 h.
Ee determinated by HPLC (OD column).
b
c
Ee determinated by HPLC after derivatization of the amine using acetic anhydride.
d
e
Conversion: c = ees/(ees + eep).27
E = {ln[eeP(1 ꢀ eeS)]/(eeP + eeS)}/{ln[eeP(1 + eeS)]/(eeP + eeS)}.27

1178
L. H. Andrade, A. V. Silva / Tetrahedron: Asymmetry 19 (2008) 1175–1181
NHAc
*
NHAc
*
1) n-BuLi / THF, 0°C
2) H2O
EtSe
(R)- or (S)-7a-c
(R)- or (S)-N-(1-phenylethyl)acetamide 8
Scheme 2. Chemical reaction performed to transform organoselenium amides 7a–c into (R)-and (S)-N-(1-phenylethyl)acetamide 8.
2.3. Determination of the enantiomeric excesses and absolute
configuration for 6a–c and 7a–c
a carrier gas (100 kPa). The GC chiral column used was a Chirasil-
Dex CB b-cyclodextrin (25 m ꢁ 0.25 mm) for determination of the
enantiomeric excesses. Low Resolution Mass Spectra (LRMS) were
recorded on a Shimadzu GCMS P5050A (70 eV) spectrometer. HPLC
analyses were performed in a Shimadzu SPD-10AV instrument
with a UV–vis detector. The HPLC chiral column used was a Chiral-
cel OD-H (0.46 cm ꢁ 25 cm) for determination of the enantiomeric
excesses. Optical rotations were determined on a JASCO DIP-378
polarimeter. Infrared spectra were recorded on a Perkin–Elmer
1750-FT-IR spectrometer. NMR spectra were recorded on Bruker
DPX 500, DPX 300 or DPX 200 instrument. For 1H (instrument
operating at 500.13 MHz, 300 MHz, or 200 MHz) d values are refer-
enced to (CH3)4Si (0 ppm) and for 13C (instrument operating at
125.77 MHz, 75.5 MHz, or 50 MHz) d values are referenced to
CDCl3 (77.0 ppm). Chemical shifts are given in ppm and coupling
constants are given in Hertz (s = singlet, d = doublet, dd = double
doublet, t = triplet, quart. = quartet, m = multiplet). High resolution
mass spectra (HRMS) analyses were performed in a LCMS-Bruker
Daltonik Microtof with ESI ionization.
The enantiomeric excesses of organoselenium amines 6a, 6b,
and 6c were calculated from the chiral HPLC chromatograms after
derivatization with acetic anhydride (see Section 4.7). The enantio-
meric excesses of selenium amides 7a, 7b, and 7c were also calcu-
lated from the chiral HPLC chromatograms. The absolute
configuration of the amides were attributed by chiral GC chro-
matographic comparison with authentic samples of (R)- and (S)-
N-(1-phenylethyl)acetamide 8 after removing the organoselenium
group from organoselenium amides 7a–c by n-butyllithium in THF
as shown in Scheme 2.
It was supposed that the lithium–selenium exchange reaction
did not affect the stereogenic center of the compounds 7a, 7b,
and 7c. To support this assumption, (R)-N-(1-phenylethyl)acetam-
ide 8 (ee >99%) was also reacted with n-butyllithium in THF using
the same methodology described above, and an identical enantio-
meric excess (ee >99%) was observed at the end of the process. The
results obtained showed that the stereochemical preference of
CAL-B for the acylation of the organoselenium amines is in accor-
dance with Kazlauska’s rule.29
4.2. Synthesis of 1-((selenocyanate)phenyl)ethanones 3a–c
The procedure was adopted from that reported by Kirmse
et al.25 To an Erlenmeyer flask, aminoacetophenones 1a–c
(3.51 g, 26 mmol) and an aqueous HCl solution (50 mL, 2 M) were
added. The solution was cooled to 0 °C and a water solution of
NaNO2 (24 mmol, 12 mL, 2 M) was added dropwise. At 0 °C,
sodium acetate (8 g, 60 mmol) was added, followed by the addition
of acetate buffer solution until pH 4.3. The inorganic salt KSeCN
(5 g, 35 mmol) was then added under vigorous agitation and the
solution was kept at 0 °C for 1 h. Sodium acetate was added until
pH 5.5. The resulting solution was extracted with CH2Cl2
(3 ꢁ 30 mL). The combined organic phases were dried over MgSO4.
The solvent was removed in vacuum and the residue purified by
silica gel column chromatography, using a mixture of hexane and
ethyl acetate (8:2) as solvent. The solvent was removed to give
the selenocyanate acetophenones 3a–c.
3. Conclusion
In order to develop a chemoenzymatic methodology to synthe-
size chiral organoselenium amines/amides without the use of
organolithium or organomagnesium reagents, we have shown that
the selenium atom can be incorporated onto an aromatic ketone by
using the reaction of potassium selenocyanate and diazonium salts
to obtain the selenocyanate acetophenones 3a–c. These ketones
were alkylated with ethyl bromide to give the organoselenium
acetophenones 5a–c which were converted into their correspond-
ing racemic organoselenium amines 6a–c by reductive amination
in good yields. At the end of the process, we employed the kinetic
resolution of these racemic organoselenium amines by their acetyl-
ation mediated by lipases to give the corresponding chiral amides/
amines in an enantiomerically pure form (up to 99% ee). The
stereochemistry of the resolved organoselenium amines and their
acetates is in accordance with Kazlauska’s rule.
4.2.1. 1-((4-Selenocyanate)phenyl)ethanone 3a
Yield: 65%. IR (KBr) cmꢀ1: 3434, 3342, 2964, 2920, 2151, 1685,
1586, 1394, 1360, 1266, 1185, 960, 816, 587, 520, 464. 1H NMR
(200 MHz, CDCl3) d: 7.99–7.95 (d, J = 8.3 Hz, 2H), 7.73–7.68 (d,
J = 8.8 Hz, 2H), 2.62 (s, 3H). 13C NMR (50 MHz) d: 196.99, 137.73,
132.88, 129.40, 128.55, 100.62, 26.84. LRMS [EI], m/z (relative
abundance): 225 (M+, 50), 210 (100), 208 (71), 182 (47), 180
(23), 76 (31), 63 (19), 43 (82). HRMS [ESI(+)], calcd for [C9H7NOSe+
Na]+: 247.9591, found 247.9586.
4. Experimental
4.1. General methods
Lipase B from C. antarctica, Novozym 435, was a gift from Novo-
zymes A/S. Solvents were purified by standard procedures. All
other reagents are commercially available and were used without
further purification. Thin-layer chromatography (TLC) was per-
formed using precoated plates (Aluminum foil, Silica Gel 60 F254
Merck, 0.25 mm). Silica gel (0.035–0.070 mm, Acros) was used
for column chromatography. GC analyses were performed in a Shi-
madzu GC-17A instrument with a FID detector, using hydrogen as
4.2.2. 1-((3-Selenocyanate)phenyl)ethanone 3b
Yield: 28%. IR (KBr) cmꢀ1: 3430, 3332, 2151, 1675, 1563, 1414,
1359, 1256, 959, 900, 799, 684, 592, 523. 1H NMR (300 MHz,
CDCl3) d: 8.20 (s, 1H), 8.01–7.98 (d, J = 7.8 Hz, 1H), 7.87–7.84 (m,
1H), 7.57–7.52 (t, J = 7.8 Hz, 1H), 2.63 (s, 3H). 13C NMR (75 MHz)
d: 196.36, 138.79, 136.81, 132.16, 130.71, 129.53, 122.89, 100.87,

L. H. Andrade, A. V. Silva / Tetrahedron: Asymmetry 19 (2008) 1175–1181
1179
26.63. LRMS [EI], m/z (relative abundance): 225 (M+, 36), 210 (87),
182 (35), 156 (11), 76 (25), 63 (14), 43 (100). HRMS [ESI(+)], calcd
for [C9H7NOSe+Na]+: 247.9591, found 247.9587.
found 229.0124; (M+Na)+; calcd for [C10H12OSe+Na]: 250.9951,
found 250.9952.
4.4. Synthesis of (RS)-1-((ethylselanyl)phenyl)ethanamines
4.2.3. 1-((2-Selenocyanate)phenyl)ethanone 3c
6a–c
Yield: 60%. IR (KBr) cmꢀ1: 3439, 3072, 2994, 2144, 1645, 1582,
1555, 1430, 1363, 1300, 1280, 1265, 1026, 962, 703, 603, 481. 1H
NMR (500 MHz, CDCl3) d: 8.11–8.08 (m, 2H), 7.65–7.61 (m 1H),
7.53–7.50 (t, J = 7.5 Hz, 1H), 2.70 (s, 3H). 13C NMR (125 MHz) d:
199.90, 134.75, 132.74, 132.13, 131.56, 130.68, 127.71, 106.77,
25.75. LRMS [EI], m/z (relative abundance): 225 (M+, 37), 210
(53), 208 (26), 182 (18), 180 (8), 43 (100). HRMS [ESI(+)], calcd
for [C9H7NOSe+Na]+: 247.9591, found 247.9584.
The procedure was carried out in a way similar to that re-
ported by Bhattacharyya et al.26 To a two-necked round-bot-
tomed flask, ethylselenium acetophenones 5a–c (228 mg,
1 mmol), titanium(IV) isopropoxide (0.6 mL, 2 mmol), and a solu-
tion of NH3 in ethanol (5 mmol, 2.5 mL, 2 M) under N2 were
added. The solution was stirred at room temperature for 12 h.
After this period, NaBH4 (57 mg, 1.5 mmol) was added and the
resulting solution was stirred for an additional 12 h. Finally, the
reaction was quenched with aqueous ammonia solution (2.5 mL,
2 M) and the resulting mixture was filtered off under vacuum.
The remaining solid was washed with ethyl acetate (2 ꢁ 3 mL).
The phases were separated and the aqueous phase was extracted
with ethyl acetate (3 ꢁ 3 mL). The organic phases were combined
and then extracted with an aqueous HCl solution (3 ꢁ 3 mL, 1 M).
Saturated aqueous NaOH solution was added to the resulting acid
aqueous phase until pH 10 and it was then extracted with ethyl
acetate (4 ꢁ 5 mL). The combined organic phases were washed
once with brine (3 mL) and dried over MgSO4. The solvent was
removed in vacuum to give the (RS)-organoselenium amines in
a pure form. These compounds were employed directly in the
enzymatic kinetic resolution.
4.3. Synthesis of 1-((ethylselanyl)phenyl)ethanones 5a–c
To a two-necked round-bottomed flask, selenocyanate aceto-
phenones 3a–c (225 mg, 1 mmol) and methanol (5 mL) under N2
were added. The solution was cooled to 0 °C and ethyl bromide
(300 lL, 4 mmol) was added, followed by the slow addition of
NaBH4 (42 mg, 1.1 mmol). The solution was stirred for 2 h at
0 °C. The solvent was removed in vacuum and the residue was
diluted in ethyl acetate (3 mL) followed by the addition of satu-
rated aqueous solution of NH4Cl (3 mL). After phase separation,
the aqueous phase was extracted with ethyl acetate (2 ꢁ 3 mL).
The combined organic phases were dried over MgSO4. The solvent
was removed in vacuum and the residue purified by silica gel
column chromatography, using a mixture of hexane and ethyl
acetate (8:2) as solvent. The solvent was removed to give the
ethylselenium acetophenones 5a–c.
4.4.1. (RS)-1-(4-(Ethylselanyl)phenyl)ethanamine 6a
Yield: 73%. IR (KBr) cmꢀ1: 3359, 3286, 3070, 2961, 2923, 2866,
1591, 1492, 1447, 1372, 1230, 1014, 822, 770, 541. 1H NMR
(200 MHz, CDCl3) d: 7.47–7.43 (d, J = 8.3 Hz, 2 H), 7.26–7.22 (d,
J = 8.3 Hz, 2H), 4.13–4.04 (quart., J = 6.5 Hz, 1H), 2.95–2.84 (quart.,
J = 7.5 Hz, 2H), 1.81 (s, 2H), 1.46–1.39 (t, J = 7.0 Hz, 3H), 1.39–1.35
(d, J = 6.6 Hz, 3H). 13C NMR (50 MHz) d: 146.52, 133.22, 128.42,
126.67, 51.15, 25.74, 21.66, 15.72. LRMS [EI], m/z (relative abun-
dance): 229 (M+, 27), 214 (100), 185 (39), 120 (20), 104 (21), 78
(33), 42 (42). HRMS [ESI(+)], calcd for [C10H15NSeꢀNH2]+:
213.0182, found 213.0174.
4.3.1. 1-(4-(Ethylselanyl)phenyl)ethanone 5a
Yield: 63%. IR (KBr) cmꢀ1: 3438, 2966, 2929, 2870, 1677, 1586,
1393, 1357, 1269, 1234, 1182, 1083, 858, 812, 605, 588, 458. 1H
NMR (200 MHz, CDCl3) d: 7.84–7.80 (d, J = 8.3 Hz, 2 H), 7.50–7.45
(d, J = 8.8 Hz, 2H), 3.07–2.95 (quart., J = 7.5 Hz, 2H), 2.57 (s, 3H),
1.52–1.45 (t, J = 7.5 Hz, 3H). 13C NMR (50 MHz) d: 196.72, 138.19,
134.15, 129.57, 128.03, 25.77, 19.79, 14.45. LRMS [EI], m/z (relative
abundance): 228 (M+, 84), 213 (100), 209 (18), 185 (44), 181 (26),
156 (17), 105 (18), 91 (11), 77 (22), 63 (12), 43 (86). HRMS [ESI(+)],
calcd for [C10H12OSe+H]+: 229.0131, found 229.0131; (M+Na)+; for
[C10H12OSe+Na]: 250.9951, found 250.9946.
4.4.2. (RS)-1-(3-(Ethylselanyl)phenyl)ethanamine 6b
Yield: 38%. IR (KBr) cmꢀ1: 3358, 3285, 3052, 2961, 2923, 2866,
1589, 1570, 1448, 1372, 1231, 887, 786, 700, 445. 1H NMR
(300 MHz, CDCl3) d: 7.47 (s, 1H), 7.36–7.33 (m, 1H), 7.22–7.19
(m, 2H), 4.11–4.05 (quart., J = 6.6 Hz, 1H), 2.98–2.89 (quart.,
J = 7.5 Hz, 2H), 2.03 (s, 2H), 1.46–1.41 (t, J = 7.5 Hz, 3H), 1.39–
1.37 (t, J = 6.9 Hz, 3H). 13C NMR (75 MHz) d: 148.32, 130.72,
130.49, 129.77, 129.09, 124.15, 51.15, 25.49, 21.23, 15.48. LRMS
[EI], m/z (relative abundance): 229 (M+, 43), 214 (100), 185 (43),
120 (12), 104 (19), 78 (28), 44 (84). HRMS [ESI(+)], calcd for
[C10H15NSeꢀNH2]+: 213.0182, found 213.0167; calcd for
[C10H15NSe+H]+: 230.0448, found 230.0441.
4.3.2. 1-(3-(Ethylselanyl)phenyl)ethanone 5b
Yield: 78%. IR (KBr) cmꢀ1: 3526, 3354, 3057, 2962, 2923, 2867,
1686, 1568, 1413, 1355, 1254, 962, 908, 788, 687, 588, 467. 1H
NMR (200 MHz, CDCl3) d: 8.06 (s, 1H), 7.82–7.78 (m, 1H), 7.69–
7.64 (m, 1H), 7.39–7.32 (t, J = 7.7 Hz, 1H), 3.03–2.92 (quart.,
J = 7.5 Hz, 2H), 2.60 (s, 3H), 1.49–1.41 (t, J = 7.5 Hz, 3H). 13C NMR
(50 Hz) d: 197.63, 137.63, 136.68, 131.79, 131.27 129.01, 126.51,
26.60, 21.41, 15.34. LRMS [EI], m/z (relative abundance): 228 (M+,
63), 213 (34), 185 (42), 156 (15), 117 (7), 105 (12), 91 (7), 77
(17), 51 (9), 43 (100). HRMS [ESI(+)], calcd for [C10H12OSe+H]+:
229.0131, found 229.0123; (M+Na)+; for [C10H12OSe+Na]:
250.9951, found 250.9952.
4.4.3. (RS)-1-(2-(Ethylselanyl)phenyl)ethanamine 6c
Yield: 63%. IR (KBr) cmꢀ1: 3357, 3287, 3055, 2962, 2923, 2866,
1660, 1585, 1447, 1371, 1230, 1032, 755, 663, 598, 549, 462. 1H
NMR (300 MHz, CDCl3) d: 7.51–7.44 (m, 2H), 7.29–7.23 (m, 1H),
7.18–7.12 (m, 1H), 4.63–4.56 (quart., J = 6.6 Hz, 1H), 2.95–2.87
(quart., J = 5.7 Hz, 2H), 2.21 (s, 2H), 1.46–1.41 (t, J = 7.5 Hz, 3H),
1.40–1.38 (d, J = 7.2 Hz, 3H). 13C NMR (75 MHz) d: 148.02,
132.38, 129.84, 127.42, 127.29, 125.28, 48.86, 24.34, 21.46, 15.20.
LRMS [EI], m/z (relative abundance): 229 (M+, 22), 214 (12), 200
(52), 183 (55), 157 (6), 119 (46), 104 (85), 91 (29), 77 (42), 51
(24), 44 (100). HRMS [ESI(+)], calcd for [C10H15NSeꢀNH2]+:
213.0182, found 213.0170; calcd for [C10H15NSe+H]+: 230.0448,
found 230.0441.
4.3.3. 1-(2-(Ethylselanyl)phenyl)ethanone 5c
Yield: 65%. IR (KBr) cmꢀ1: 2960, 2923, 2850, 1665, 1585, 1455,
1431, 1359, 1251, 1038, 956, 753, 599, 468. 1H NMR (300 MHz,
CDCl3) d: 7.93–7.90 (dd, J = 7.5Hz, J = 1.5 Hz, 1H), 7.51–7.48 (m,
1H), 7.44–7.38 (m, 1H), 7.27–7.22 (m, 1H), 2.90–2.82 (quart.,
J = 7.5 Hz, 2H), 2.63 (s, 3H), 1.50–1.45 (t, J = 7.5 Hz, 3H). 13C NMR
(75 MHz) d: 198.80, 138.24, 135.36, 132.30, 131.78, 128.26,
124.23, 27.52, 18.49, 13.65. LRMS [EI], m/z (relative abundance):
228 (M+, 19), 199 (100), 182 (5), 157 (9), 91 (40), 77 (17), 51
(10), 43 (62). HRMS [ESI(+)], calcd for [C10H12OSe+H]+: 229.0131,

1180
L. H. Andrade, A. V. Silva / Tetrahedron: Asymmetry 19 (2008) 1175–1181
4.5. Synthesis of N-(1-((ethylselanyl)phenyl)ethyl)acetamides
7a–c
A saturated aqueous NaOH solution was added to the combined
aqueous solution until pH 10. The resulting solution was extracted
with CH2Cl2 (3 ꢁ 2 mL). The organic phases were combined and
washed with brine (3 mL), dried over MgSO4. The solvent was
removed in vacuum and the residue, containing the organo-
selenium amines 6a–c, was acetylated with acetic anhydride for
further HPLC analysis (see Section 4.5).
To
a Schlenck-flask, organoselenium amines 6a–c (50 mg,
0.22 mmol), CH2Cl2 (1 mL), acetic anhydride (62 lL, 0.66 mmol),
and triethylamine (62 lL, 0.44 mmol) were added. The resulting
solution was stirred for 1 h at 50 °C. After this period, the reaction
mixture was diluted with CH2Cl2 (5 mL) and the resulting solution
was then washed with an aqueous HCl solution (2 ꢁ 2 mL, 1 M).
The organic phase was washed with brine (2 mL), dried over
MgSO4, and the solvent was removed in vacuum to give organose-
lenium amides 7a–c.
4.6.2. Small scale reaction
To a Schlenk-flask, hexane (2.5 mL), ethyl acetate (195 lL,
2.5 mmol), CAL-B, Novozym 435, (150 mg) and the appropriate
organoselenium amines 6a–c (115 mg, 0.5 mmol) was added. The
reaction mixture was stirred on a rotary shaker (30 °C, 160 rpm)
for 48 h. After this time, the enzyme was filtered off and washed
with CH2Cl2 (10 mL). The organic phase was extracted with an
aqueous HCl solution (3 ꢁ 5 mL, 1 M), washed with brine (5 mL)
and dried over MgSO4. The solvent was removed in vacuum and
the residue purified by silica gel column chromatography, using
ethyl acetate as a solvent. The solvent was removed to give the
organoselenium amides 7a–c, which were readily analyzed by
HPLC (see Section 4.7).
A saturated aqueous NaOH solution was added to the combined
aqueous solution until pH 10. The resulting solution was extracted
with CH2Cl2 (3 ꢁ 5 mL). The organic phases were combined and
washed with brine (5 mL), dried over MgSO4. The solvent was
removed in vacuum to give the organoselenium amines 6a–c.
The enantiomeric purities of the compounds 6a–c were measured
by HPLC analysis (see Section 4.7) after derivatization with acetic
anydride (see Section 4.5).
4.5.1. (RS)-N-(1-(4-(Ethylselanyl)phenyl)ethyl)acetamide 7a
Yield: 97%. IR (KBr) cmꢀ1: 3314, 3075, 2971, 2927, 2867, 2822,
1646, 1545, 1374, 1137, 816, 724, 535. 1H NMR (300 MHz, CDCl3)
d: 7.46–7.44 (d, J = 8.1 Hz, 2H), 7.22–7.20 (d, J = 8.1 Hz, 2H), 5.98
(s, 1H), 5.11–5.06 (quart., J = 7.2 Hz, 1H), 2.94–2.87 (quart.,
J = 7.0 Hz, 2H), 2.01 (s, 3 H), 1.49–1.46 (d, J = 7.0 Hz, 3H), 1.45–
1.40 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz) d: 169.38, 141.70,
132.84, 129.25, 126.91, 48.60, 23.31, 21.62, 21.43, 15.51. LRMS
[EI], m/z (relative abundance): 271 (M+, 61), 253 (39), 214 (99),
181 (18), 156 (14), 120 (45), 104 (33), 78 (26), 43 (100). HRMS
[ESI(+)], calcd for [C12H17NOSe+H]+: 272.0554, found 272.0556.
4.5.2. (RS)-N-(1-(3-(Ethylselanyl)phenyl)ethyl)acetamide 7b
Yield: 92%. IR (KBr) cmꢀ1: 3284, 3064, 2975, 2926, 2867, 1712,
1651, 1549, 1374, 1232, 885, 786, 701, 620, 450. 1H NMR
(300 MHz, CDCl3) d: 7.43–7.35 (m, 2H), 7.27–7.16 (m, 2H), 6.01
(s, 1H), 5.13–5.04 (quart., J = 7.2 Hz, 1H), 2.97–2.89 (quart.,
J = 7.5 Hz, 2H), 2.00 (s, 3H), 1.49–1.46 (d, J = 7.2 Hz, 3H), 1.46–
1.41 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz) d: 169.46, 143.91,
131.18, 130.87, 130.10, 129.27, 124.64, 48.75, 23.32, 21.72, 21.33,
15.44. LRMS [EI], m/z (relative abundance): 271 (M+, 100), 256
(12), 228 (21), 214 (94), 200 (27), 183 (24), 120 (67), 104 (36),
77 (26), 43 (92). HRMS [ESI(+)], calcd for [C12H17NOSe+H]+:
272.0554, found 272.0551.
4.6.2.1. 1-((Ethylselanyl)phenyl)ethanamines 6a–c.
26
(S)-6a: Yield = 57%, ½aꢂD ¼ ꢀ5:0 (c 0.5, ethyl acetate), ee = 22%;
26
(S)-6b: Yield = 62%, ½aꢂD ¼ ꢀ5:8 (c 2.24, ethyl acetate), ee = 34%;
26
(S)-6c: Yield = 51%, ½aꢂD ¼ ꢀ2:5 (c 3.49, ethyl acetate), ee = 8%.
4.6.2.2. N-(1-(4-(Ethylselanyl)phenyl)ethyl)acetamides 7a–c.
24
(R)-7a: Yield = 19%, ½aꢂD ¼ þ102:8 (c 0.59, ethyl acetate),
ee = 99%;
4.5.3. (RS)-N-(1-(2-(Ethylselanyl)phenyl)ethyl)acetamide 7c
Yield: 90%. IR (KBr) cmꢀ1: 3432, 3272, 3079, 2965, 2923, 2856,
1646, 1558, 1443, 1373, 1305, 1033, 752, 512, 458. 1H NMR
(300 MHz, CDCl3) d: 7.53–7.51 (dd, J = 4.5 Hz, J = 0.6 Hz, 1H), 7.33–
7.31 (dd, J = 4.5 Hz, J = 0.6 Hz, 1H), 7.27–7.23 (m, 1H), 7.19–7.16
(m, 1H), 6.36 (s, 1H), 5.49–5.44 (quart., J = 4.2 Hz, 1H), 2.95–2.93
(quart., J = 4.2 Hz, 2H), 2.02 (s, 3H), 1.50–1.48 (d, J = 4.2 Hz, 3H),
1.44–1.40 (t, J = 4.2 Hz, 3H). 13C NMR (75 MHz) d: 169.38, 144.68,
134.09, 130.22, 127.91, 127.54, 126.05, 49.68, 29.71, 22.13, 21.85,
15.29. LRMS [EI], m/z (relative abundance): 271 (M+, 3), 228 (12),
183 (18), 162 (100), 120 (29), 104 (15), 77 (12), 43 (28). HRMS
[ESI(+)], calcd for [C12H17NOSe+H]+: 272.0554, found 272.0552.
24
(R)-7b: Yield = 30%, ½aꢂD ¼ þ88:7 (c 0.21, ethyl acetate),
ee = 98%;
24
(R)-7c: Yield = 08%, ½aꢂD ¼ þ21:8 (c 0.50, ethyl acetate),
ee = 99%.
4.7. HPLC analysis for determination of the enantiomeric
excess (ee)
The enantiomeric purities of the organoselenium amides 7a–c
were measured by HPLC analysis. The analysis was carried out on
Chiralcel OD-H column and the peaks were detected by a UV detec-
tor at 254 nm. Eluent: hexane/isopropanol (95:05), flow rate:
1.0 mL/min. Retention times for:
4.6. Enzymatic kinetic resolution of (RS)-1-((ethylselanyl)-
phenyl)ethanamines 6a–c
(RS)-N-(1-(4-(Ethylselanyl)phenyl)ethyl)acetamide
[(R)-7a = 20.44 min; (S)-7a = 24.93 min].
(RS)-N-(1-(3-(Ethylselanyl)phenyl)ethyl)acetamide
[(R)-7b = 19.19 min; (S)-7b = 28.29 min].
(RS)-N-(1-(2-(Ethylselanyl)phenyl)ethyl)acetamide
[(R)-7c = 16.92 min; (S)-7c = 44.46 min].
7a:
7b:
7c:
4.6.1. Screening reactions
To a Schlenk-flask, solvent (1 mL, see Table 2), ethyl acetate
(78 lL, 0.8 mmol), lipase (amount indicated in Table 2), and the
appropriated organoselenium amines 6a–c (46 mg, 0.2 mmol)
were added. The reaction mixture was stirred on a rotary shaker
(temperature indicated in Table 2, 160 rpm) for 48 h. After this per-
iod, the enzyme was filtered off and washed with CH2Cl2 (5 mL).
The organic phase was extracted with an aqueous HCl solution
(3 ꢁ 2 mL, 1 M), washed with brine (3 mL), and dried over MgSO4.
The solvent was removed in vacuum and the residue, containing
the organoselenium amides 7a–c, was readily analyzed by HPLC
(see Section 4.6).
4.8. GC analysis for determination of the enantiomeric excess of
N-(1-phenylethyl)acetamide 8
The enantiomeric excess of (RS)-N-(1-phenylethyl)acetamide 8
and the products of the reactions shown in Section 4.9 were ana-
lyzed by GC/FID in a chiral capilary column (Chirasil-Dex CB-Var-

L. H. Andrade, A. V. Silva / Tetrahedron: Asymmetry 19 (2008) 1175–1181
1181
5. Comasseto, J. V.; Andrade, L. H.; Omori, A. T.; Assis, L. F.; Porto, A. L. M.
Tetrahedron: Asymmetry 2007, 18, 1048–1053.
6. Clososki, G. C.; Costa, C. E.; Missio, L. J.; Cass, Q. B.; Comasseto, J. V. Synth.
Commun. 2004, 34, 817–828.
7. Da Costa, C. E.; Closoki, G. C.; Comasseto, J. V.; Barchesi, H. B.; Zanotto, S. P.;
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8. Braga, A. L.; Schneider, P. H.; Paixão, M. W.; Deobald, A. M.; Peppe, C.; Bottega,
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ian). GC conditions: Injector 220 °C; detector: 220 °C; pressure:
100 kPa. Column temperature: 70 °C, 3 °C/min up to 180 °C.
Retention times for (RS)-N-(1-phenylethyl)acetamide 8: [(R)-
8 = 25.06 min, (S)-8 = 24.21 min].
4.9. Determination of the absolute configurations of the
organoselenium amines 6a–c and amides 7a–c
The absolute configurations of the organoselenium amides 7a–c
were assigned by chromatographic comparison with standard
samples of (R)- and (S)-8 after removing the organoselenium group
from 7a–c with n-butyllithium according to the procedure above.
To a two-necked round-bottomed flask, the chiral organosele-
nium amides 7a–c (68 mg, 0.25 mmol), THF (10 mL), and n-butyl-
lithium (3.3 mmol) at 0 °C were added, under N2. The solution
was stirred at 0 °C for 2 h and, finally, the reaction was quenched
with brine (10 mL). The organic layer was separated and the aque-
ous phase was extracted with ethyl ether (4 ꢁ 3 mL). The com-
bined organic phases were washed once with brine (3 mL) and
dried over MgSO4. The solvent was removed in vacuum and the
product was readily analyzed by chiral GC and compared with
authentic samples of (R)- and (S)-N-(1-phenylethyl)acetamide 8
(see Section 4.8).
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