Efficient dual catalytic enantioselective diethylzinc addition to the exocyclic C{double bond, long}N double bond of some 1,2,4-N-triazinylarylimines using polymer-supported chiral β-amino alcohols derived from norephedrine

Article abstract of DOI:10.1016/j.tet.2007.04.041

Chiral N,N-dialkylnorephedrines and their corresponding copolymers were evaluated as chiral ligands for the enantioselective diethylzinc addition to the exocyclic C{double bond, long}N double bond of some 4-arylideneamino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones 2a-f. The use of a dual catalytic system (amino alcohol/halosilane) in the titled asymmetric reaction was examined. The enantioselective ethylation reaction has been successfully carried out in the heterogeneous system even at low temperature. The corresponding 4-(1-arylpropyl)amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones 4a-f were obtained in high yields with high enantioselectivities using chiral polymers (up to 91% ee), which are almost the same as those obtained from homogeneous analogues (up to 92% ee). The diethylzinc reagent neither opened the 1,2,4-triazinyl heterocyclic ring nor attacked the carbonyl or the thione groups of the 1,2,4-triazinyl heterocyclic ring and the addition reaction took place exclusively at the exocyclic electrophilic carbon atom yielding the C-ethylated products 4a-f. Reductive cleavage of the 1,2,4-triazinyl heterocyclic ring led smoothly to the corresponding primary aromatic amines 11a-f without significant loss of enantiomeric purity. A?suggestion about the possible transition state for the addition reaction is also presented.

Full text of DOI:10.1016/j.tet.2007.04.041

Tetrahedron 63 (2007) 5490–5500
Efficient dual catalytic enantioselective diethylzinc addition
to the exocyclic C]N double bond of some 1,2,4-N-
triazinylarylimines using polymer-supported chiral
b-amino alcohols derived from norephedrine
,y
*
Ashraf A. El-Shehawy
Department of Chemistry, Faculty of Education, Kafr El-Sheikh University, Kafr El-Sheikh, PO Box 33516, Egypt
Received 19 January 2007; revised 26 March 2007; accepted 12 April 2007
Available online 19 April 2007
Abstract—Chiral N,N-dialkylnorephedrines and their corresponding copolymers were evaluated as chiral ligands for the enantioselective
diethylzinc addition to the exocyclic C]N double bond of some 4-arylideneamino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones 2a–f.
The use of a dual catalytic system (amino alcohol/halosilane) in the titled asymmetric reaction was examined. The enantioselective ethylation
reaction has been successfully carried out in the heterogeneous system even at low temperature. The corresponding 4-(1-arylpropyl)amino-3-
mercapto-6-methyl-4H-1,2,4-triazin-5-ones 4a–f were obtained in high yields with high enantioselectivities using chiral polymers (up to 91%
ee), which are almost the same as those obtained from homogeneous analogues (up to 92% ee). The diethylzinc reagent neither opened the
1,2,4-triazinyl heterocyclic ring nor attacked the carbonyl or the thione groups of the 1,2,4-triazinyl heterocyclic ring and the addition reaction
took place exclusively at the exocyclic electrophilic carbon atom yielding the C-ethylated products 4a–f. Reductive cleavage of the 1,2,4-tri-
azinyl heterocyclic ring led smoothly to the corresponding primary aromatic amines 11a–f without significant loss of enantiomeric purity.
A suggestion about the possible transition state for the addition reaction is also presented.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis of optically active amines. We have previously re-
ported on the enantioselective allylation of various prochiral
imines using various chiral ligands including chiral amino
alcohols and their corresponding copolymers affording
the corresponding optically active homoallylic amines in
quantitative yields with enantioselectivities up to 96% ee.4
Diastereoselective allylation of chiral imines derived from
(S)-valine activated by Lewis acids, which afforded the cor-
responding optically active secondary homoallylic amines in
excellent yields with perfect diastereoselectivities has been
also developed by us.5
Since homogeneous reagents and catalysts have been found
to be more efficient in asymmetric synthesis than their het-
erogeneous counterparts, the immobilization of homoge-
neous reagents and catalysts is of great interest.1 The use
of polymer-bound chiral ligands offers the advantages of
solid phase organic synthesis; their easy separation from
the reaction mixture and the easy reuse are major advantages
of polymer-supported chiral reagents over homogenous
chiral reagents.2
The synthetic usefulness of enantiomerically pure amines
has stimulated great interest in developing methods for the
asymmetric preparation of such molecules.3 The asymmetric
addition of organometallic reagents to the C]N double
bonds is amongst the most important reactions for the
The enantioselective addition of diorganozinc reagents to
imines, as a route to optically active amines, has recently re-
ceived much attention, due to the good tolerance of various
functionalities with respect to organolithiums and Grignard
reagents.6 As a result of the poor electrophilic character of
imines, several quite effective methods based on the cata-
lytic enantioselective dialkylzinc addition to imines have
been recently developed.7
Keywords: Polymeric reagents and catalysts; Chiral polymers; 1,2,4-Tri-
azines; Arylimines; Dual catalytic; Enantioselective ethylation; Lewis
acids.
The addition of nucleophiles such as Grignard reagents and
alkylithiums to the exocyclic C]N double bond of 4-aryl-
ideneamino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones 2,
prepared from the reaction of 1 with the corresponding alde-
hyde,8 in the existence of C]O and C]N groups of the tri-
azine heterocyclic ring had been difficult and the obtained
* Tel.: +20 10 1576679; fax: +20 47 3223415; e-mail: elshehawy2@yahoo.
com
Present address: Polymeric and Organic Materials Department, Graduate
y
School of Science and Engineering, Tokyo Institute of Technology,
H-127, 2-12-1, O-okayama, Meguro-ku, Tokyo, 152-8552, Japan.
Tel.: +81 3 5734 2131; fax: +81 3 5734 2887.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.041

A. A. El-Shehawy / Tetrahedron 63 (2007) 5490–5500
5491
Table 1. Enantioselective diethylzinc addition to benzaldimine 2a in the
presence of chiral ligands (1S,2R)-3a–da
results proved that this heterocyclic ring was particularly
sensitive towards such reagents.9 However, we have recently
reported on the successful chemoselective addition of vari-
ous allylmetal reagents in homogeneous and heterogeneous
systems to the exocyclic C]N double bond of some aldimi-
nomercaptotriazinones 2, in the presence of Lewis acids as
activators, without any possibility for attacking the 1,2,4-tri-
azine nucleus.10 We have further recently reported on the
first evaluation of 4-arylideneamino-3-mercapto-6-methyl-
4H-1,2,4-triazin-5-ones 2, activated by halosilanes as Lewis
acids, in the diethylzinc addition reaction, using chiral b-
amino alcohols (1S,2R)-N-alkyl-N-benzylnorephedrines
3a–d as homogeneous chiral ligands.11 The enantioselective
diethylzinc addition to the exocyclic C]N double bond of
arylimines 2 proceeded smoothly affording the correspond-
ing optically active secondary amines with high yields and
with enantiomeric excesses up to 92% ee.
Entry
Chiral ligand
R
Yieldb (%)
eec,d (%)
1
2
3
3a
3b
3c
3d
3b
H
Me
Et
n-Bu
Me
14
55
41
33
69
57
79
76
70
82
4
5a
a
All reactions were performed in the presence of a stoichiometric amount
of chiral ligand 3 at room temperature for 48 h except for run 5, which was
performed for 5 days.
Isolated yields after flash chromatography (pentane/ethyl acetate: 3:7).
Determined by HPLC analysis using a Chiralcel OD-H column.
The absolute configuration was assigned as the S-isomer based on the
absolute configuration of the primary amine obtained after reductive
cleavage of the 1,2,4-triazinyl heterocyclic ring and comparing its HPLC
retention time with the literature value.11,12
b
c
d
nitrogen atom was found to be the most effective for the
enantioselective diethylzinc addition to benzaldimine 2a
(55% yield, 79% ee, entry 2, Table 1). The chiral amino al-
cohol 3c possessing ethyl group on its nitrogen resulted in
a slightly diminished 76% ee (entry 3). Further increase in
the bulkiness of the R group by replacement of the methyl
of 3b with n-butyl group of 3d led to significant decreases
Thus, we wish here to extend this study to the enantioselec-
tive addition of diethylzinc to such arylimines using chiral b-
amino alcohols derived from norephedrine supported on
polystyrene in comparison with the results that are obtained
from the corresponding low-molecular-weight counterparts.
A suggestion about the possible transition state for the addi-
tion reaction is also presented.
Me
N
HS
N
Ph
HS
N
N
O
(1S, 2R)-3a: R = H
(1S, 2R)-3b: R = Me
(1S, 2R)-3c: R = Et
(1S, 2R)-3d: R = n-Bu
N
N
H
N
N
OH
Me
H2N
Me
Ar
Ph
R
O
1
2
3
2. Results and discussion
in each of the chemical and optical yields (33% yield,
70% ee, entry 4), probably because the catalytic activity de-
creases due to steric hindrance on the nitrogen atom. It is
worth mentioning that when the diethylzinc addition reac-
tion to benzaldimine 2a was performed for 5 days, in the
presence of chiral ligand 3b that showed the best result,
the addition reaction did not go to completion and the
product 4a was obtained in only 69% yield, whilst slightly
higher enantioselectivity was observed (82% ee, entry 5,
Table 1).
In order to design a highly enantioselective polymeric chiral
ligand, it is necessary to consider the related monomeric
chiral ligands that would afford a highly enantioselective re-
action. We have recently investigated the enantioselective
diethylzinc addition to various N-triazinylarylimines using
chiral b-amino alcohols derived from norephedrine as chiral
ligands.11 We first investigated the asymmetric ethylation
reaction of 4-benzylideneamino-3-mercapto-6-methyl-4H-
1,2,4-triazin-5-one 2a as a standard substrate with diethyl-
zinc (3 equiv) in the presence of an equimolar amount of
chiral amino alcohols (1S,2R)-3a–d as chiral ligands in tol-
uene at room temperature (Scheme 1). The obtained results
are summarized in Table 1.
The addition of silylating agents acting as Lewis acids in the
dialkylzinc addition reaction to imines has been reported to
enhance the reaction rate through activation of the arylimine
substrates, while leaving asymmetric induction untouched.13
ꢀ
Pericas and co-workers have successfully applied an
interesting approach for the use of a dual catalytic system
consisting of a chiral amino alcohol, to control the enantio-
selectivity of the addition process, and a bulky silylating
agent, to further activate the imine substrate.13b,c We have re-
cently investigated analogous dual amino alcohol/halosilane
mediation for the diethylzinc addition reaction to benzaldi-
mine 2a using chiral ligand 3b in conjunction with a stoichio-
metric amount of different silylating reagents.11 Among
various silylating reagents as well as various reaction condi-
tions examined, the highest level of catalytic activity was ob-
served by adding a stoichiometric amount of silylating agent
i-Pr3SiCl (TIPSCl; 95% yield, 84% ee, entry 2, Table 2,
Scheme 2).11
HS
N
HS
H
N
N
N
H
N
Chiral ligand 3a-d
N
N
Me
Ph
Me
Ph
(S) N
Et2Zn, toluene, rt., 48 h
H
O
2a
O
4a
Scheme 1.
The results in Table 1 showed that N,N-disubstituted chiral
ligands (1S,2R)-3b–d showed relatively higher reactivity
and stereoselectivity than N-monosubstituted chiral ligand
3a. Among chiral ligands examined, (1S,2R)-N-benzylephe-
drine 3b that possesses benzyl and methyl substituents on its

5492
A. A. El-Shehawy / Tetrahedron 63 (2007) 5490–5500
Table 2. Enantioselective diethylzinc addition to imine 2a activated by
3a–d/TIPSCla
chiral b-amino alcohols as pendant groups in the above-
mentioned enantioselective ethylation reaction. There are
two main methods to obtain the polymer-supported chiral
amino alcohol ligands, namely a chemical modification
method and a copolymerization method. However, our
previous research on asymmetric reactions using polymer-
supported chiral amino alcohols showed that the chemical
modification method always resulted in decreased enantio-
selectivities.4b,d,14 We have thus decided to employ the
copolymerization method, which is the polymerization of
a chiral monomer with styrene and a crosslinking agent, to
obtain the polymer-supported chiral ligand. For this purpose,
the chiral monomers N-alkyl-N-vinylbenzylnorephedrines
5a–e were prepared and subjected to polymerization with
styrene and divinylbenzene (DVB) as a crosslinker under
the conditions of suspension polymerization in aqueous
media4d,15 to afford the corresponding polymer-supported
chiral amino b-alcohols 6–10 in good yields (Scheme 3).
Entry
Chiral ligand
R
Yieldb (%)
eec,d (%)
1
2
3
3a
3b
3c
3d
—
H
Me
Et
n-Bu
—
48
95
91
93
92
59
84
77
73
—
4
5e
a
Unless otherwise specified, all reactions were carried out in the presence
of a stoichiometric amount of chiral ligand 3 and TIPSCl at ꢀ20 ꢁC for
24 h.
Isolated yields after flash chromatography (pentane/ethyl acetate: 3:7).
Determined by HPLC analysis using a Chiralcel OD-H column.
The absolute configuration was assigned as the S-isomer based on the ab-
solute configuration of the primary amine obtained after reductive cleav-
age of the 1,2,4-triazinyl heterocyclic ring and comparing its HPLC
retention time with the literature value.11,12
b
c
d
e
The reaction was performed in the absence of any chiral ligands.
HS
H
HS
N
N
O
N
O
(1) 3a-d / toluene
(2) Et2Zn, 0 °C, 0.5 h
N
N
Loading of the chiral amino alcohol residues and the degree
of crosslinking were easily controlled by the polymerization
method. From chiral amino alcohol (1S,2R)-5b, several
polymers 7a–h, having various crosslinking and loading
degrees, were prepared (Table 3). The loading degree of
the chiral amino alcohol residues was easily estimated
from the elemental analysis of the nitrogen atom.
H
N
N
Me
(S)
Ph
N
H
Me
Ph
(3) TIPSCl (1 equiv) / -20 °C, 24 h
2a
4a
Scheme 2.
In an extension to the above-mentioned study and under the
same reaction conditions that are displayed in Scheme 2, the
chiral ligands 3a, c, d were tested further in the enantioselec-
tive ethylation of benzaldimine 2a in the presence of a stoi-
chiometric amount of TIPSCl as Lewis acid catalyst (Table
2). As expected, in all cases, the reaction rate was also
greatly enhanced and the addition product (S)-4a was ob-
tained in excellent yields within 24 h of reaction time. Inter-
estingly, the order of catalytic activity of chiral ligands 3a–d
was in complete accordance with that observed for the same
reaction in the absence of TIPSCl (see Tables 1 and 2). More
interestingly, on performing the above-mentioned reaction
with diethylzinc but without using any chiral ligands, the
addition product 4a was obtained in 92% chemical yield as
a racemic mixture (entry 5, Table 2). The above-mentioned
set of experiments seem to strongly confirm that in the dual
catalytic system under investigation, turnover is primarily
controlled by the silylating agent, while, as expected, enan-
tioselectivity mainly depends on the presence of the chiral
amino alcohol ligand.
The synthesized chiral polymers 6–10 were examined as
chiral ligands in the enantioselective diethylzinc addition
Table 3. Synthesis of polymer-supported chiral b-amino alcohols 6–10
Entry Chiral
monomer
Chiral
polymer
Molar
Yield Loading of
chiral amino
alcohol residues
ratiosa (%)
(mmol/g)b (DF)c
1
2
3
4
5
6
7
8
(1S,2R)-5a (1S,2R)-6
(1S,2R)-5b (1S,2R)-7a
(1S,2R)-5b (1S,2R)-7b 1:8:1
(1S,2R)-5b (1S,2R)-7c 1:6:3
(1S,2R)-5b (1S,2R)-7d 1:5:4
(1S,2R)-5b (1S,2R)-7e
(1S,2R)-5b (1S,2R)-7f
(1S,2R)-5b (1S,2R)-7g
1:7:2
1:7:2
91
89
93
90
94
91
90
95
87
90
89
93
0.764 (0.10)
0.771 (0.10)
0.750 (0.10)
0.821 (0.10)
0.735 (0.10)
1.292 (0.20)
1.863 (0.30)
2.127 (0.40)
2.449 (0.50)
0.792 (0.10)
0.721 (0.10)
0.807 (0.10)
2:6:2
3:5:2
4:4:2
9
(1S,2R)-5b (1S,2R)-7h 5:3:2
10
11
12
(1S,2R)-5c
(1S,2R)-5d (1S,2R)-9
(1R,2S)-5e (1R,2S)-10
(1S,2R)-8
1:7:2
1:7:2
1:7:2
a
Molar ratio of copolymerization: chiral monomer:styrene:DVB.
Determined by elemental analysis.
Degree of functionalization.
b
c
The above-mentioned interesting results encouraged us to
explore further the use of chiral polymers possessing similar
Me
N
Ph
Me
N
Ph
Suspension Polymerization
AIBN
*
*
*
*
OH
OH
+
+
R
Benzene-THF-H2O, 0 °C, 1h
then 75 °C, 30 h
R
5a-e
(1S, 2R)-5a: R = H
(1S, 2R)-5b: R = Me
(1S, 2R)-5c: R = Et
(1S, 2R)-5d: R = n-Bu
(1R, 2S)-5e: R = Me
6-10
(1S, 2R)-6: R = H
(1S, 2R)-7: R = Me
(1S, 2R)-8: R = Et
(1S, 2R)-9: R = n-Bu
(1R, 2S)-10: R = Me
Scheme 3. Preparation of polymer-supported chiral b-alcohols 6–10.

A. A. El-Shehawy / Tetrahedron 63 (2007) 5490–5500
5493
reaction to benzaldimine 2a (Scheme 4). From our survey on
the effect of solvent in the enantioselective addition of di-
alkylzinc reagents to imines using the same family of poly-
mer-supported N,N-disubstituted norephedrines as chiral
ligands, we have found that hexane as well as toluene affords
the addition products with higher ee values.15b,16 Moreover,
the nonpolar solvent toluene was found to maximize the rate
difference between the catalyzed and noncatalyzed reac-
tion.12d,17 Based on the above-mentioned findings, toluene
was used as a reaction medium.
substituents on the nitrogen atom of their pendant groups af-
forded the addition product 4a with much higher enantio-
selectivities than did the chiral polymers possessing the
hydrogen atom (6) and n-butyl (9) substituents. Thus,
polymer-supported chiral ligand 7a afforded the addition
product (S)-4a with the highest chemical yield and enantio-
selectivity (92%, 82% ee, respectively; entry 2, Table 4). It
is noteworthy that chiral polymer 9 having n-butyl group
on the nitrogen atom of its pendant group afforded the addi-
tion product (S)-4a in a much decreased eevalue (48% ee, en-
try 4, Table 4) when compared to the result that was obtained
from the corresponding monomeric chiral ligand 3d (73% ee,
entry 4, Table 2). This result suggests that the bulky butyl
group on the nitrogen atom decreases the catalytic activity
when the chiral moiety is directly connected to the polymer
support. Surprisingly, the obtained results clearly showed
that the order of catalytic activity of chiral polymers 6, 7a,
8 and 9 in the diethylzinc addition reaction to benzaldimine
2a (Table 4) is similar to that of the same family of the corre-
sponding monomericchiral ligands 3a–d(seeTables1and2).
HS
N
N
HS
H
(1) Chiral polymers 6 - 10 / toluene
(2) Et2Zn, 0 °C, 0.5 h
N
N
H
N
N
N
Me
Ph
∗
Me
Ph
N
H
(3) TIPSCl (1 equiv)
O
2a
O
4a
Scheme 4. Enantioselective diethylzinc addition to benzaldimine 2a using
chiral polymers 6–10.
In the first series of experiments, the copolymers 6, 7a, 8 and
9 (molar ratio of copolymerization; chiral monomer:styrene:
DVB¼1:7:2) were examined as chiral ligands in the enantio-
selective ethylation of benzaldimine 2a. In the presence of
chiral ligands 6–9 and a stoichiometric amount of TIPSCl,
benzaldimine 2a reacted with diethylzinc (3 molar equiv),
in toluene at ꢀ10 ꢁC to afford the corresponding optically
active secondary amine 4a (Scheme 4, Table 4).
In order to improve the chemical yield and enantioselectiv-
ity, we have thus tried to optimize the reaction conditions of
the enantioselective ethylation of benzaldimine 2a using chi-
ral polymer (1S,2R)-7a, which had been shown to give the
best results (entry 2, Table 4).
To clarify the effect of reaction temperature, the enantio-
selective ethylation reaction of benzaldimine 2a was exam-
ined, in the presence of a stoichiometric amount of TIPSCl
as a catalyst, at different temperatures using chiral polymer
(1S,2R)-7a (Table 4). The enantioselective ethylation reac-
tion of benzaldimine 2a using chiral polymer 7a was found
to be temperature-dependant as expected and in the best
case, the ethylated product (S)-4a was obtained with the
highest enantiomeric excess (82% ee) and with chemical
yield of 92% at ꢀ10 ꢁC (entry 2, Table 4). At ꢀ20 ꢁC,
only a slight increase in the enantiomeric excess was ob-
served but there was a considerable decrease in the chemical
yield even on performing the reaction for 3 days (entry 7,
Table 4). At both room temperature and 0 ꢁC, the enantio-
selectivities and the chemical yields of the addition product
(S)-4a were markedly decreased (entries 5 and 6, Table 4).
However, considering the accepted mechanism of the amino
alcohol mediated addition of diethylzinc to aldehydes18 and
imines,13a–c which involves as a first step the formation of a
very stable ethylzinc alkoxide chelate from diethylzinc and
the amino alcohol, the free amino alcohol ligand should
never coexist with the trialkylsilyl halide. In this way, both
activation modes could be, in principle, compatible. As it
has been mentioned previously,13a–c success in this dual
(amino alcohol/Lewis acid) activation would critically de-
pend on the absence of temporary coexistence of free amino
alcohol and silylating agent, which would lead to deactiva-
tion of the chiral ligand as well as on the stability towards
Lewis acids of the initially formed ethylzinc alkoxide che-
late. To ensure maximum adherence to these conditions,
the experimental protocol mentioned here (Scheme 4)
should be followed and the reaction temperature should be
low as much as possible.
In spite of the heterogeneous reaction, the diethylzinc addi-
tion reaction to benzaldimine 2a using chiral polymers 6–9
smoothly occurred even at low temperature to afford the de-
sired secondary amine (S)-4a in moderate to high yields
(Table 4). The diethylzinc addition reaction to benzaldimine
2a using chiral polymers possessed methyl (7a) and ethyl (8)
Table 4. Enantioselective diethylzinc addition to benzaldimine 2a activated
by chiral polymers 6–10/TIPSCla
Entry Chiral polymer Temp (ꢁC)
Addition product 4a
Yieldb (%) eec (%) Config.d
1
2
3
4
(1S,2R)-6
ꢀ10
ꢀ10
ꢀ10
ꢀ10
rt
44 (48)e
92 (95)e
82 (91)e
64 (93)e
41
55
71
82
75
65
93
85
81
74
93
55 (59)e
82 (84)e
73 (77)e
48 (73)e
61
73
84
78
75
63
81
77
72
61
82
S
(1S,2R)-7a
(1S,2R)-8
(1S,2R)-9
S
S
S
S
S
S
S
S
S
S
S
S
S
R
5
(1S,2R)-7a
(1S,2R)-7a
(1S,2R)-7a
(1S,2R)-7b
(1S,2R)-7c
(1S,2R)-7d
(1S,2R)-7e
(1S,2R)-7f
(1S,2R)-7g
(1S,2R)-7h
(1R,2S)-10
6
0
7a
8
ꢀ20
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
9
10
11
12
13
14
15
a
All reactions were carried out in toluene in the presence of a stoichiometric
amount of TIPSCl for 48 h except for run 5, which was performed for
3 days.
Isolated yields after flash chromatography (pentane/ethyl acetate: 3:7).
Determined by HPLC analysis using a Chiralcel OD-H column.
The absolute configuration was assigned based on the absolute configura-
tion of the primary amine obtained after reductive cleavage of the 1,2,4-
triazinyl heterocyclic ring and comparing its HPLC retention time with
the literature value.11,12
b
c
d
e
The effect of the molar ratio of DVB as a crosslinking
reagent on the enantioselective ethylation reaction of
Yields and % enantioselectivities in parentheses were obtained from the
corresponding low-molecular-weight reagents in solution system.11

5494
A. A. El-Shehawy / Tetrahedron 63 (2007) 5490–5500
Table 5. Effect of the amount of polymeric ligand (1S,2R)-7aa
benzaldimine 2a was next examined using the copolymer-
ized chiral ligands (1S,2R)-7a–d possessing different ratios
of DVB under the above optimal reaction conditions men-
tioned in Table 4 (entry 2) and the obtained results are also
shown in Table 4 (entries 2, 8–10). The ee of the resulting
secondary amine (S)-4a was as high as 82% when (1S,2R)-
7a having 2 molar equiv. of DVB was utilized as a chiral li-
gand (entry 2, Table 4). Interestingly, the enantioselectivity
of the addition product 4a obtained from the use of 7b hav-
ing 1 molar equiv. of DVB was very close to that observed
with the use of 7c having 3 molar equiv. of DVB (78 and
75% ee, entries 8 and 9, respectively, Table 4). Significant
decreases in each of the chemical yields and enantioselectiv-
ities of the addition product 4a were observed with chiral
polymer 7d (65% yield and 63% ee), which had a higher ra-
tio of crosslinking (4 molar equiv.; entry 10, Table 4).
Entry
7a (equiv)
Yieldb (%)
eec,d (%)
1
2
3
4
5
0.4
0.6
0.8
1.0
2.0
63
71
81
92
75
62
69
77
82
83
a
All reactions were performed for 48 h at ꢀ10 ꢁC in the presence of equi-
molar amount of TIPSCl.
b
c
d
Isolated yields after flash chromatography (pentane/ethyl acetate: 3:7).
Determined by HPLC analysis using a Chiralcel OD-H column.
The absolute configuration was assigned as the S-isomer based on the ab-
solute configuration of the primary amine obtained after reductive cleav-
age of the 1,2,4-triazinyl heterocyclic ring and comparing its HPLC
retention time with the literature value.11,12
The use of a lesser amount of chiral polymer 7a (0.4–
0.8 mol %; entries 1–3, Table 5) resulted in the decreased
yields and enantioselectivities of the addition product (S)-
4a. No considerable change in the enantioselectivity of the
addition product (S)-4a could be observed on using more
than 1 equiv of chiral polymer 7a but a considerable de-
crease in the chemical yield was observed (entry 5, Table
5). It is noticeable that these characteristics were identical
to those observed on examining the same effect using the
corresponding chiral ligand N-benzyl-N-methylnorephe-
drine 3b (at ꢀ20 ꢁC) in the same reaction under similar re-
action conditions.11 As expected, the above-mentioned set
of results strongly confirms that the enantioselectivity of
the addition product 4a mainly depends on the amount of
the chiral amino alcohol ligand.
The effect of the loading degree of the chiral amino alcohol
residue in chiral polymer 7 was also examined. The use of
chiral polymers (1S,2R)-7e–h (DF¼0.2–0.5, entries 11–14,
Table 4) having higher loading ratios of the chiral amino
alcohol residues than chiral polymer 7a (DF¼0.1, entry 2,
Table 4) for the enantioselective diethylzinc addition to
benzaldimine 2a was found to have a significant effect on
the enantioselective ethylation reaction. With the use of chi-
ral polymer 7e (DF¼0.2), no significant change in each of
the chemical yield and enantioselectivity of the addition
product 4a was observed (entry 11, Table 4), whilst signifi-
cant decreases in the chemical yields and enantioselectiv-
ities were observed with increasing the loading ratio of
chiral amino alcohol residue (entries 12–14, Table 4). The
use of chiral polymer 7h (DF¼0.5) afforded the addition
product in a much decreased enantioselectivity (61%; entry
14, Table 4), a result probably explained in terms of a higher
degree of polymer loading of ephedrine in (1S,2R)-7h than
in other chiral polymers. A high degree of polymer loading
may give rise to active site interactions, which interfere with
the formation of an appropriate transition state.
In order to evaluate the generality of the above-mentioned
asymmetric reaction, the optimal procedure for the diethyl-
zinc addition reaction to the benzaldehyde derived imine 2a
using polymeric chiral ligand 7a was thereafter examined for
other N-arylimines having various substituents bonded to the
phenyl group at different positions. The results of the di-
ethylzinc addition reactions that are displayed in Scheme 5
are summarized in Table 6.
In asymmetric synthesis it is important that both enantio-
mers of a given compound can be prepared. Thus, polymer-
supported chiral ligand (1R,2S)-10 was prepared from its
correspondingchiral monomer(1R,2S)-5e. The enantioselec-
tive ethylation of benzaldimine 2a using the polymeric chiral
ligand (1R,2S)-10 worked as well as chiral polymer (1R,2S)-
7a that was prepared from chiral monomer (1S,2R)-5b and
led smoothly to the desired secondary chiral amine 4a with
almost the same chemical yield and enantioselectivity, but
with reversed stereoselectivity (entry 15, Table 4).
In the presence of stoichiometric amounts of polymeric chi-
ral ligand 7a and TIPSCl, the diethylzinc addition reaction to
various N-arylimines containing ortho- and para-substitu-
ents on the phenyl group proceeded smoothly to afford the
desired chiral amines (S)-4a–f with chemical yields up to
93% and good to high enantioselectivities (62–87%). Table
6 shows that varying the substituents on the phenyl group of
arylimine 2 exhibited a dramatic influence on the reaction.
Generally, imines bearing an ortho-substituted phenyl group
would provide lower enantioselectivities than their ana-
logues containing a phenyl group with para-substituents.
For example, the diethylzinc addition reaction to imine 2c,
having a p-methylphenyl group, afforded the addition prod-
uct 4c with a relatively higher enantioselectivity of 84% ee
(entry 3) than that of 75% ee (entry 2) given by its analogue
2b, which possessed an ortho-methylphenyl group. Similar
results were also observed with imines 2d and 2e having
ortho-methoxyphenyl and para-methoxyphenyl groups
(entries 4 and 5, Table 6), respectively. Arylimine 2f bearing
a 2,4,6-trimethylphenyl group provided the addition product
4f with a lower chemical yield of 71% and enantioselectivity
of 62%. This result might be explained on the basis of the
The amount of the chiral polymeric ligand 7a used in the re-
action was then further examined (Table 5). With the other
reaction conditions fixed (reaction time¼48 h, reaction
temperature¼ꢀ10 ꢁC, solvent¼toluene, and an equivalent
amount of TIPSCl), the amount of chiral polymer 7a was
varied in the range of 0.4–2.0 equiv compared with the
benzaldimine 2a. As can be seen from the results shown in
Table 5, the enantiomeric excess increased with increasing
the amount of chiral polymer 7a.
The chemical yield and enantioselectivity of the addition
product (S)-4a was maximized with equivalent amounts of
polymer 7a as the chiral ligand and substrate 2a (entry 4).

A. A. El-Shehawy / Tetrahedron 63 (2007) 5490–5500
5495
HS
N
O
HS
N
2,4a: C6H5
N
O
(1) Chiral ligand 7a
(2) Et2Zn, 0 °C, 0.5 h
N
H
N
H
b: 2-CH3-C6H4
N
N
Ar
c: 4-CH3-C6H4
(S)
Me
N
H
Me
Ar
(3) TIPSCl (1 equiv) / -10 °C, 48 h
d: 2-CH3O-C6H4
e: 4-CH3O-C6H4
f: 2,4,6-Tri-CH3-C6H4
4
2
Scheme 5. Diethylzinc addition to arylimines 2a–f using 7a as chiral ligand.
Table 6. Diethylzinc addition to arylimines 2a–f mediated by (1S,2R)-7a/
simple filtration and were easily recovered quantitatively
during the workup in a typical experiment. The recovered
polymeric chiral ligand could be reused in further experi-
ments and showed unchanged reactivity and enantioselectiv-
ity in the same reaction. In entry 7 (Table 6), recycled chiral
polymeric ligand, which had been used in entry 5, recovered
by filtration and washed with acid and base, was examined.
As a result, (S)-4a was obtained with almost the same ee
(86% ee) and chemical yield (91%) as that in entry 5 (87%
ee and 93% yield, Table 6).
TIPSCla
Entry Imine Ar
Adduct Yieldb
product (%)
eec,d (%)
1
2
3
4
2a
2b
2c
2d
2e
2f
Ph
4a
4b
4c
4d
4e
92 (90)e 82 (84)e
89 (88)e 75 (79)e
91 (93)e 84 (87)e
93 (92)e 77 (82)e
93 (95)e 87 (88)e (91)f
71 (78)e 62 (72)e
2-CH3–C6H4
4-CH3–C6H4
2-CH3O–C6H4
4-CH3O–C6H4
2,4,6-Tri-CH3–C6H4 4f
4-CH3O–C6H4 4e
5
6
7g
2e
91
86
a
All reactions were carried out at ꢀ10 ꢁC (molar ratio: imine 7a/TIPSCl/
Et2Zn: 1:1:3).
It is noteworthy that under the above-mentioned reaction
conditions, when 4-amino-3-mercapto-6-methyl-4H-1,2,4-
triazin-5-one 1 was allowed to react with diethylzinc, in
the presence of equimolar amounts of chiral ligand 3b or
its polymeric analogue 7a and in the presence of TIPSCl,
the starting material was recovered almost unchanged.
This result indicates that the diethylzinc reagent neither
opened the hetero-ring in the arylimine derivatives 2 nor at-
tacked the carbonyl or the thione group of the 1,2,4-triazinyl
heterocyclic ring. Therefore, under all the aforementioned
reaction conditions, the addition of diethylzinc to arylimines
2a–f took place exclusively at the exocyclic electrophilic
carbon atom yielding the C-ethylated products 4a–f as
evidenced by their microanalytical and spectral data.11
b
c
d
Isolated yields after flash chromatography (pentane/ethyl acetate: 3:7).
Determined by HPLC analysis using a Chiralcel OD-H column.
The absolute configuration was assigned as the S-isomer based on the ab-
solute configuration of the primary amine obtained after reductive cleav-
age of the 1,2,4-triazinyl heterocyclic ring and comparing its HPLC
retention time with the literature value.11,12
e
f
Values in parentheses are for the results obtained from the corresponding
low-molecular-weight counterparts.11
Value in parenthesis obtained after crystallization from petroleum ether/
ethanol (1:9).
Recovered polymer was used.
g
steric hindrance imposed by the di-ortho-substituted ben-
zene ring (entry 6, Table 6).
It should be noted that all the addition products 4a–h
obtained are solids and thus their optical purity could be
enhanced by crystallization. For example, the enantiomeric
purity of 4e (87%, entry 5, Table 6) could be upgraded to
91% by a simple crystallization from petroleum ether/etha-
nol (entry 5, Table 6).
The removal of the 1,2,4-triazinyl heterocyclic ring via
reductive cleavage was uneventful and furnished the corre-
sponding free optically active 1-arylpropylamines 11a–f
without significant racemization and in nearly quantitative
yields in addition to the expected known 3-mercapto-
6-methyl-4H-1,2,4-triazine-5-one 128 (Scheme 6). The
absolute configurations of the major isomer of the addition
products 4a–f were assigned based on the absolute configu-
rations of products 11a–f and comparison of the HPLC re-
tention times with the literature values.12 The ee values of
the 1-arylpropylamines 11a–f were determined by HPLC
analysis after derivation of the amine to the corresponding
acetamide derivatives by a reported method12d and compar-
ison with the literature values.12 The obtained ee values were
found to be in very good agreement with the enantiomeric
excess of the starting secondary amine 4a–f.
Interestingly, the order of catalytic activity obtained using
the polymeric chiral ligand 7a was found to be also in com-
plete accordance with that of the corresponding monomeric
chiral ligand 3b, under similar reaction conditions, as shown
from the values in parentheses in Table 6. More interestingly,
the enantioselectivity of the addition product 4a obtained
from the diethylzinc addition reaction to benzaldimine 2a
using monomeric chiral ligand (1S,2R)-3b and its corre-
sponding polymer-supported analogue (1S,2R)-7a is seen
to be high.
Although the mechanistic details for the asymmetric process
are currently unclear, the observed results might be rational-
ized assuming that the addition takes place through the
depicted transition state 13. However, sulfur is more
One of the advantages of a polymeric chiral ligand is its
easier separation from the reaction mixture. The chiral poly-
mers were easily separated from the reaction mixture by
HS
N
HS
N
N
H
N
H
NH2
(1) Zn/HCl, EtOH, 55-60 °C, 24h
(2) 15% NaOH
N
HN
+
Me
Me
Ar
N
H
Ar
O
O
(S)-11a-f
12
(S)-4a-f
Scheme 6. Preparation of chiral amines 11a–f via reductive cleavage of the 1,2,4-triazinyl heterocyclic ring.

5496
A. A. El-Shehawy / Tetrahedron 63 (2007) 5490–5500
nucleophilic than oxygen and proved particularly to be
stronger than oxygen in complexation with Zn atom.19
Therefore, the mercapto group (SH) should be more nucleo-
philic than the carbonyl group (C]O) and consequently S–
Zn interaction may be stronger than that of the O–Zn. The
steric hindrance brought about by each of the substituents
on the nitrogen atom of chiral ligands 3 as well as by the tri-
azine heterocyclic ring forces ZnB to be in the position
shown, determining in this way the stereochemistry at
ZnA. Coordination of the ligand to Zn atoms (N–ZnA and
O–ZnB), coordination of the imine nitrogen to ZnA as well
as the extra coordination between the mercapto group
(SH) with zinc (S–ZnB) would lead to the formation of bicy-
clic transition state like that as shown in structure 13. The
transfer of one of the ethyl groups of ZnB to the imine carbon
would give the addition products with the observed stereo-
chemistry.
diethylzinc addition reaction to arylimines to be easy, effi-
cient, and high yield reaction. Reductive cleavage of the
1,2,4-triazinyl heterocyclic ring from the addition products
4a–f afforded the corresponding optically active primary
amines 11 without significant loss of optical purity. Due to
the simplicity of the process and the good availability of
the imine precursors, we believe that a broad applicability
of the reported catalytic reaction can be anticipated. The ex-
tension of this methodology to other organozinc reagents and
other kinds of branched polymers to achieve higher stereo-
selectivity is in progress and will be reported in due course.
4. Experimental
4.1. General
All reactions were performed under dry nitrogen atmo-
sphere. Toluene was freshly distilled from CaH2 under nitro-
gen prior to use. Diethylzinc in hexane was purchased from
Aldrich Co. Chiral ligands N-alkyl-N-benzylnorephedrines
3a–d15b,16b,20 and 5a–d,15a,b,16a,21 were readily prepared ac-
cording to the respective literature procedures. The required
4-arylideneamino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-
ones 2a–f were prepared by the reaction of 4-amino-
3-mercapto-6-methyl-4H-1,2,4-triazine-5-one 1 with the
corresponding aldehyde in refluxing methanol according to
the literature.8 Deactivated silica gel plates (Merck 5554,
60F254) were obtained by eluting TLC plates with 5% Et3N
in pentane and drying before applying the sample and the
spots were detected with UV model UVGL-58. It turned out
to be crucial to deactivate the silica gel with Et3N before pu-
rifying the products by flash chromatography in order to get
good yields, presumably due to decomposition on the other-
Me
Ph
O
Et
N
N
N
R
N
Me
Ph
A
N
O
S
B
R'
R'
Et
R'
13
Proposed transition state for the diethylzinc
addition reaction to arylimines 2a-f
As shown in structure 13, the product with the S absolute
configuration should be given by ligands (1S,2R)-3a–d or
their correspondingpolymeric analogues (1S,2R)-6–9, which
was consistent with our experimental results. The transition
state 13 also clearly explained that the presence of ortho-
substituents on the phenyl group bonded to the imine carbon
would disfavour the formation of the well-ordered bicyclic
transition state than that formed by imine bearing para-
substituted phenyl groups, leading to a decrease in the
enantioselectivity, which has been observed experimentally
(compare entry 1 with entries 2, 4 and 6, Table 6). Therefore,
arylimines with a para-substituent afforded higher enantio-
selectivities than their structural analogues bearing an ortho-
substituted phenyl group. Moreover, as shown in structure
13, for steric reasons, it appears advantageous to have a small
alkyl (R) group on the nitrogen atom of the monomeric chi-
ral ligands 3 or their corresponding copolymers 6–9 in order
to get high selectivities, and this assumption was also borne
out experimentally (entries 1–4 in each of Tables 1, 2 and 4).
1
wise slightly acidic silica. H NMR and 13C NMR spectra
were recorded on a JEOL GSX-400 (400/100.4 MHz) spec-
trophotometer in CDCl3; chemical shifts are relative to TMS
as internal reference. High resolution mass spectra were re-
corded on a JEOL JMS-SX120A. IR spectra were recorded
on Perkin Elmer 1760 FTIR spectrophotometer instrument.
Optical rotations were measured using a Perkin-Elmer 341
Polarimeter in a 10 cm cell with the solvent indicated. High
performance liquid chromatography (HPLC) analyses were
carried out on a chiral column (Chiralcel OD-H column,
Daicel, 25 cm, 30 ꢁC), with a 254 nm UV detector and a
flow rate of 1.0 mL/min. Loading of the polymers is ex-
pressed in millimoles of functional groups per gram of the
dry resin (mmol/g) or as degree of functionalization (DF).
For example, DF¼0.10 if 10% of the styrene units are
functionalized.
3. Conclusion
4.2. General procedure for the enantioselective
diethylzinc addition to benzaldimine 2a using
chiral ligands 3a–d in the presence of TIPSCl
Enantioselective diethylzinc addition to the exocyclic C]N
double bond of easily accessible arylimines derived from 3-
aminotriazine using chiral b-amino alcohols derived from
norephedrine and their corresponding copolymers as chiral
ligands in the presence of TIPSCl as activator have been dem-
onstrated. The enantioselectivities of the addition products
obtained from the use of copolymerized chiral ligands (up
to 91% ee) were comparable and have similar tendency
with those obtained from the use of the corresponding mono-
meric chiral ligands (up to 92% ee). The activation of aryl-
imines with silylating reagents renders (or leads to) the
Benzaldimine 2a (73.9 mg, 0.3 mmol) and chiral ligand
3 (0.3 mmol) were dissolved in dry toluene (2.0 mL), at room
temperature, and the reaction mixture was cooled to 0 ꢁC. To
this mixture, 0.9 mL (0.9 mmol) of 1.0 M Et2Zn in hexane
was added dropwise. After stirring at 0 ꢁC for 30 min, the re-
action mixture was cooled to ꢀ20 ꢁC and TIPSCl (64 mL,
0.3 mmol) was added. Stirring was continued for 24 h at
that temperature and the reaction mixture was then quenched

A. A. El-Shehawy / Tetrahedron 63 (2007) 5490–5500
5497
with saturated aqueous NH4Cl (2 mL). The aqueous phase
4.4. General procedure for the enantioselective
ethylation of arylimines using copolymerized chiral
ligands in the presence of TIPSCl as a Lewis acid
was extracted with CH2Cl2 (3ꢂ15 mL), and the combined
organic layers were dried over MgSO4. After removal of the
solvents, the residue was purified by flash chromatography
on silica gel (deactivated silica gel, pentane/ethyl acetate:
95:5 to 30:70) to afford 4-(1-phenylpropyl)amino-3-mercap-
to-6-methyl-4H-1,2,4-triazin-5-one (4a) as a white solid.
The product was analyzed by HPLC on a Chiralcel OD-H
column. The yields and enantiomeric compositions of the
secondary amine 4a obtained with arylimine 2a are shown
in Table 2. The absolute configuration of the addition prod-
uct 4a was determined to be S-isomer based on the absolute
configuration of the corresponding (S)-1-phenylpropyl-
amine obtained after reductive cleavage of the 1,2,4-tri-
azinyl heterocyclic ring and correlated to that described in
the literature 11,12 (see the hydrolysis part).
To an ice cold suspension of chiral polymer (0.2 mmol,
based on the content of the nitrogen atom by elemental anal-
ysis of chiral polymer) in dry toluene (3 mL) were added the
appropriate imine (0.2 mmol) and Et2Zn (0.6 mmol, 1 M
hexane solution, 6.0 mL). The reaction mixture was cooled
to ꢀ10 ꢁC and TIPSCl (42 mL, 0.2 mmol) was added. Stir-
ring was continued for 24 h at that temperature and the reac-
tion mixture was then quenched by adding hydrochloric acid
(1 M, 5 mL). The polymer was removed by filtration and
washed thoroughly with dichloromethane. The filtrate was
extracted with CH2Cl2 (3ꢂ10 mL) and the combined ex-
tracts were dried over anhydrous sodium sulfate and the sol-
vent was evaporated under reduced pressure. The residue
was purified by flash chromatography on silica gel (deacti-
vated silica gel, pentane/ethyl acetate: 95:5 to 30:70) to
afford the corresponding optically active secondary amine
4-(1-arylpropyl)amino-3-mercapto-6-methyl-4H-1,2,4-tri-
azin-5-one (4). The yields and enantiomeric excesses of the
secondary amines obtained with arylimines 2a–f are shown
in Tables 4–6. The enantiomeric excesses for the addition
products 4a–f were determined by HPLC analysis using
a chiral stationary-phase column (Daicel Chiralcel OD-H,
254 nm UV detector, 30 ꢁC). The absolute configuration of
the major isomer of the secondary amine 4 was assigned
based on the absolute configuration of the secondary amine
1-arylpropylamine obtained after the reductive cleavage of
the 1,2,4-triazinyl heterocyclic ring and correlated with
that described in literature.11,12 The structure of the addition
products 4a–f was confirmed by microanalytical and spec-
tral data.11
4.3. Preparation of polymer-supported chiral ligands
(1S,2R)-6, 7a, 8 and 9
4.3.1. Typical procedure for the synthesis of chiral poly-
mer 7a. To a water solution (25 mL) of poly(vinyl alcohol)
(0.1 g) were added (1S,2R)-5b (R¼Me) (0.56 g, 2 mmol),
styrene (1.64 g, 1.6 mL, 14 mmol), divinylbenzene (DVB,
0.52 g, 0.57 mL, 4 mmol), a0,a0-azobisisobutyronitrile
(AIBN, 0.065 g, 4 mmol), benzene (6 mL) and tetrahydrofu-
ran (6 mL). After 1 h of stirringat 0 ꢁC tohomogenizethepar-
ticle size, the temperaturewas raised to 75 ꢁC and the reaction
mixture was stirred vigorously for 30 h at the same tempera-
ture. The resultingpolymerbeadswerefiltered off andwashed
successively with water, MeOH, THF/MeOH, THF and
MeOH (50 mL each), followed by drying in vacuo at 40 ꢁC
for 5 h to afford the corresponding chiral polymer (1S,2R)-
7a. Elemental analysis of (1S,2R)-7a [Found (%) C, 89.85;
H, 7.80; N, 1.08] indicated that the content of chiral amino
alcohol in (1S,2R)-7a corresponding to 0.771 mmol/1.0 g of
polymer.
4.4.1. 4-(1-Phenylpropyl)amino-3-mercapto-6-methyl-
4H-1,2,4-triazin-5-one 4a. White solid, mp 117–118 ꢁC;
[a]2D5 ꢀ57.4 (c 1.03, CH2Cl2); HPLC conditions: 9%
i-PrOH in hexane, retention times, 20.18 min (minor, R-
isomer) and 27.26 min (major, S-isomer); Anal. Calcd for
C13H16N4OS: C, 56.50; H, 5.84; N, 20.27; S, 11.60. Found:
C, 56.51; H, 5.79; N, 20.30; S, 11.58; IR (cmꢀ1) 3277 (NH),
In a similar manner, copolymerization using (1S,2R)-5a,
(1S,2R)-5c and (1S,2R)-5d afforded the corresponding chiral
polymers (1S,2R)-6, (1S,2R)-8 and (1S,2R)-9, respectively.
Elemental analysis of 6: Found (%) C, 89.88; H, 7.79; N,
1.07. Content of chiral amino alcohol: 0.764 mmol/1.0 g
of polymer; 8: Found (%) C, 89.61; H, 7.95; N, 1.11. Content
of chiral amino alcohol: 0.792 mmol/1.0 g of chiral poly-
mer: 9: Found (%) C, 89.63; H, 8.13; N, 1.01. Content of chi-
ral amino alcohol: 0.721 mmol/1.0 g of chiral polymer.
1
1707 (C]O), 1205 (C]S); H NMR (400 MHz, CDCl3)
d (ppm) 0.89 (3H, t, J¼7.5 Hz, CH3CH2), 1.75–1.88 (1H,
m, CH2CH3), 1.96–2.08 (1H, m, CH2CH3), 2.38 (3H, s,
CH3–C6), 3.42 (1H, m, NHN), 4.04–4.16 (1H, m, CHNH),
7.33–7.68 (5H, m, HAr), 12.17 (1H, br s, SH); 13C NMR
(100 MHz, CDCl3) d (ppm) 11.63 (CH3CH2), 17.92 (CH3–
C6), 31.25 (CH2CH3), 56.36 (CHNH), 128.39 (CAr),
129.33 (CAr), 130.26 (CAr), 137.30 (CAr), 149.31 (C6),
165.40 (C5), 170.11 (C3); MS (EI) (m/z, relative intensity)
276 (M+, 6), 249 (44), 248 (14), 232 (8), 157 (14), 146
(71), 142 (6), 134 (33), 130 (17), 119 (23).
4.3.2. Synthesis of chiral polymers (1S,2R)-7b–h. Chiral
polymers (1S,2R)-7b–h were synthesized in a similar man-
ner for the preparation of (1S,2R)-7a except for the use of
various ratios of the chiral monomer 5b, styrene and DVB
that are indicated in Table 3. Elemental analysis of the nitro-
gen atom in the resulting polymers indicated the loading ra-
tios of chiral amino alcohols corresponding to the values that
are shown in Table 3.
4.4.2. 4-[1-(20-Methylphenyl)propyl]amino-3-mercapto-
6-methyl-4H-1,2,4-triazin-5-one 4b. White solid, mp
152–153 ꢁC; [a]D25 ꢀ96.8 (c 0.98, CHCl3); HPLC condi-
tions: 12% i-PrOH in hexane, retention times, 14.62 min
(minor, R-isomer) and 22.97 min (major, S-isomer); Anal.
Calcd for C14H18N4OS: C, 57.91; H, 6.25; N, 19.29; S,
11.04. Found: C, 60.02; H, 6.24; N, 19.31; S, 11.09; IR
4.3.3. Synthesis of chiral polymer (1R,2S)-10. Chiral poly-
mer (1R,2S)-10 was synthesized in a similar manner for the
preparation of (1S,2R)-7a except for the use of chiral mono-
mer (1R,2S)-5e. Elemental analysis of (1R,2S)-10: Found
(%) C, 89.82; H, 7.85; N, 1.10. Content of nitrogen atom:
0.807 mmol/1.0 g of polymer.
1
(cmꢀ1) 3270 (NH), 1701 (C]O), 1207 (C]S); H NMR
(400 MHz, CDCl3) d (ppm) 0.79 (3H, t, J¼7.4 Hz,

5498
A. A. El-Shehawy / Tetrahedron 63 (2007) 5490–5500
CH3CH2), 1.78–1.90 (1H, m, CH2CH3), 1.96–2.09 (1H, m,
CH2CH3), 2.32 (3H, s, Ar–CH3), 2.56 (3H, s, CH3–C6),
3.28 (1H, br s, NHC), 3.99–4.08 (1H, m, CHNH), 6.78–
6.98 (2H, m, HAr), 7.09–7.44 (2H, m, HAr), 12.29 (1H,
br s, SH); 13C NMR (100 MHz, CDCl3) d (ppm) 10.66
(CH3CH2), 16.69 (CH3–C6), 21.49 (Ar–CH3), 31.93
(CH2CH3), 57.36 (CHNH), 120.93 (CAr), 126.71 (CAr),
127.85 (CAr), 133.29 (CAr), 152.31 (C6), 165.92 (C5),
169.67 (C3); MS (EI) (m/z, relative intensity) 290 (M+, 9),
262 (33), 246 (6.5), 218 (8), 158 (11), 146 (56), 134 (14),
131 (38), 119 (13), 109 (29), 105 (14), 91 (6).
(400 MHz, CDCl3) d (ppm) 0.87 (3H, t, J¼7.5 Hz,
CH3CH2), 1.75–1.92 (1H, m, CH2CH3), 1.98–2.11 (1H, m,
CH2CH3), 2.42 (3H, s, CH3–C6), 3.34 (1H, br s, NHC),
3.82 (3H, s, OCH3), 4.09–4.17 (1H, m, CHNH), 6.93
(2H, d, J¼8.7, HAr), 7.26 (2H, d, J¼8.7, HAr), 11.87
(1H, br s, SH); 13C NMR (100 MHz, CDCl3) d (ppm)
11.7 (CH3CH2), 17.87 (CH3–C6), 31.3 (CH2CH3), 55.59
(OCH3), 56.44 (CHNH), 115.87 (CAr), 126.67 (CAr),
134.72 (CAr), 146.43 (CAr), 152.52 (C6), 164.55 (C5),
171.09 (C3); MS (EI) (m/z, relative intensity) 306 (M+,
18), 279 (22), 262 (6), 234 (4), 157 (24), 150 (21), 146
(64), 130 (16), 119 (9), 105 (7).
4.4.3. 4-[1-(40-Methylphenyl)propyl]amino-3-mercapto-
6-methyl-4H-1,2,4-triazin-5-one 4c. White solid, mp
182–183 ꢁC; [a]D25 ꢀ78.1 (c 1.28, CH2Cl2); HPLC condi-
tions: 15% i-PrOH in hexane, retention times, 21.55 min
(minor, R-isomer) and 27.82 min (major, S-isomer); Anal.
Calcd for C14H18N4OS: C, 57.91; H, 6.25; N, 19.29; S,
11.04. Found: C, 57.87; H, 6.30; N, 19.23; S, 11.12; IR
4.4.6. 4-[1-(20,40,60-Tri-methylphenyl)propyl]amino-3-
mercapto-6-methyl-4H-1,2,4-triazin-5-one 4f. White
solid, mp 198–199 ꢁC; [a]D25 ꢀ46.6 (c 0.98, CH2Cl2);
HPLC conditions: 15% i-PrOH in hexane, retention times,
12.82 min (minor, R-isomer) and 19.42 min (major, S-iso-
mer); Anal. Calcd for C16H22N4OS: C, 60.35; H, 6.96; N,
17.59; S, 10.07. Found: C, 60.31; H, 6.99; N, 17.58; S,
10.11; IR (cmꢀ1) 3283 (NH), 1704 (C]O), 1205 (C]S); 1H
NMR (400 MHz, CDCl3) d (ppm) 0.91 (3H, t, J¼7.7 Hz,
CH3CH2), 1.72 (3H, s, Ar–CH3), 1.84–1.96 (1H, m,
CH2CH3), 2.01–2.11 (1H, m, CH2CH3), 2.21 (6H, s, Ar–
CH3), 2.31 (3H, s, Ar–CH3), 2.40 (3H, s, CH3–C6), 3.39 (1H,
br s, NHC), 4.16–4.31 (1H, m, CHNH), 6.72 (1H, s, HAr),
6.89 (1H, s, HAr), 7.31 (1H, s, HAr), 11.57 (1H, br s, SH);
13C NMR (100 MHz, CDCl3) d (ppm) 11.18 (CH3CH2),
17.12 (CH3–C6), 19.98 (Ar–CH3), 20.55 (Ar–CH3), 21.95
(Ar–CH3), 31.8 (CH2CH3), 53.44 (CHNH), 128.31 (CAr),
131.67 (CAr), 136.19 (CAr), 139.52 (CAr), 152.18 (C6),
165.49 (C5), 169.78 (C3); MS (EI) (m/z, relative intensity)
318 (M+, 13), 290 (21), 274 (4), 246 (7), 175 (32), 162
(29), 158 (23), 146 (61), 131 (33), 118 (17), 105 (8), 91 (12).
1
(cmꢀ1) 3280 (NH), 1703 (C]O), 1208 (C]S); H NMR
(400 MHz, CDCl3) d (ppm) 0.86 (3H, t, J¼7.6 Hz,
CH3CH2), 1.74–1.87 (1H, m, CH2CH3), 1.97–2.13 (1H, m,
CH2CH3), 2.35 (3H, s, Ar–CH3), 2.44 (3H, s, CH3–C6),
3.42 (1H, br s, NHC), 4.06–4.16 (1H, m, CHNH), 7.07
(2H, d, J¼8.3, HAr), 7.18 (2H, d, J¼8.3, HAr), 11.57 (1H,
br s, SH); 13C NMR (100 MHz, CDCl3) d (ppm) 10.95
(CH3CH2), 16.92 (CH3–C6), 21.64 (Ar–CH3), 32.2
(CH2CH3), 54.65 (CHNH), 125.88 (CAr), 128.84 (CAr),
136.38 (CAr), 140.69 (CAr), 150.43 (C6), 166.76 (C5),
170.18 (C3); MS (EI) (m/z, relative intensity) 290 (M+,
11), 263 (27), 246 (9.5), 218 (4), 158 (9), 146 (52), 134
(18), 130 (25), 119 (21), 105 (9), 91 (19).
4.4.4. 4-[1-(20-Methoxyphenyl)propyl]amino-3-mer-
capto-6-methyl-4H-1,2,4-triazin-5-one 4d. White solid, mp
129–131 ꢁC; [a]D25 ꢀ94.5 (c 0.77, CHCl3); HPLC conditions:
15% i-PrOH in hexane, retention times, 10.41 min (minor, R-
isomer) and 18.16 min (major, S-isomer); Anal. Calcd for
C14H18N4O2S: C, 54.88; H, 5.92; N, 18.29; S, 10.47. Found:
C, 54.79; H, 5.97; N, 18.36; S, 10.38; IR (cmꢀ1) 3285 (NH),
4.5. General procedure for the reductive cleavage
of the 1,2,4-triazinyl heterocyclic ring
To a stirred solution of 4-(1-arylpropyl)amino-3-mercapto-
6-methyl-4H-1,2,4-triazin-5-one 4 (3 mmol) in ethanol
(15 mL), concd HCl (5 mL) and Zn (0.2 g) were added
and the reaction mixture was heated under reflux at 55–
60 ꢁC for 24 h (TLC-control). The solvent was evaporated
and 1.5 M aqueous HCl (15 mL) was added. The reaction
mixture was then extracted with diethyl ether (3ꢂ10 mL).
The aqueous layer was basified with 15% aqueous NaOH
and extracted with ethyl acetate (3ꢂ15 mL). The combined
organic layers were dried over MgSO4 and the solvent was
removed in vacuo. Purification by flash chromatography (de-
activated silica gel, pentane/ether: 95:5 to 80:20) afforded
the pure 1-arylpropylamine. All the physical and spectro-
scopic data for compounds 11a–f were in complete agree-
ment with the reported data.12 The absolute configurations
of the major isomer of addition products 4a–f were assigned
based on the absolute configuration of 11a–f and comparison
of the HPLC retention times with the literature values.11,12
The ee values of the (S)-1-arylpropylamines 11a–f were de-
termined by HPLC analysis after their derivation to the cor-
responding acetamide derivatives by reported method12d by
treatment with acetic anhydride and triethylamine and com-
parison with the literature value.12 The ee values determined
by HPLC were found to be in very good agreement with the
enantioselectivities of the starting secondary amines 4a–f.
1
1795 (C]O), 1209 (C]S); H NMR (400 MHz, CDCl3)
d (ppm) 0.76 (3H, t, J¼7.4 Hz, CH3CH2), 1.74–1.89 (1H,
m, CH2CH3), 1.96–2.05 (1H, m, CH2CH3), 2.37 (3H, s,
CH3–C6), 3.28 (1H, br s, NHC), 3.83 (3H, s, OCH3), 4.38–
4.52 (1H, m, CHNH), 6.98 (1H, d, J¼8.0 Hz, HAr), 7.09
(1H, t, J¼7.6 Hz, HAr), 7.35 (1H, t, J¼7.6 Hz, HAr), 7.59
(1H, d, J¼7.6, HAr), 8.08 (1H, dd, J¼1.94, 1.77, HAr), 12.44
(1H, br s, SH); 13C NMR (100 MHz, CDCl3) d (ppm) 10.93
(CH3CH2), 17.49 (CH3–C6), 32.29 (CH2CH3), 53.49
(OCH3), 57.62 (CHNH), 121.73 (CAr), 127.52 (CAr), 128.21
(CAr), 131.89 (CAr), 151.09 (C6), 165.87 (C5), 170.19 (C3);
MS (EI) (m/z, relative intensity) 306 (M+, 14), 278 (19), 262
(11), 234 (5), 157 (13), 146 (76), 150 (26), 131 (28), 118
(17), 105 (13), 91 (37), 91 (11).
4.4.5. 4-[1-(40-Methoxyphenyl)propyl]amino-3-mer-
capto-6-methyl-4H-1,2,4-triazin-5-one 4e. White solid, mp
144–145 ꢁC; [a]D25 ꢀ34.6 (c 2.39, CH2Cl2); HPLC condi-
tions: 15% i-PrOH in hexane, retention times, 9.32 min (mi-
nor, R-isomer) and 15.52 min (major, S-isomer); Anal. Calcd
for C14H18N4O2S: C, 54.88; H, 5.92; N, 18.29; S, 10.47.
Found: C, 55.01; H, 5.89; N, 18.33; S, 10.45; IR (cmꢀ1
3285 (NH), 1695 (C]O), 1210 (C]S); 1H NMR
)

A. A. El-Shehawy / Tetrahedron 63 (2007) 5490–5500
5499
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M. I.; Collado, M.; Escorihuela, J.; Garcıa-Verdugo, E.;
Vicent, M. J.; Martens, J. Ind. Eng. Chem. Res. 2003, 42,
5977; (g) Liu, P. N.; Gu, P. M.; Wang, F.; Tu, Y. Q. Org. Lett.
2004, 6, 169.
The aqueous layer was acidified again with dilute HCl
and the solid obtained was filtered off and crystallized
from ethanol to afford 12. In all cases, the product was
identified as the expected known 3-mercapto-6-methyl-4H-
1,2,4-triazin-5-one 12.8 All physical and analytical data
of compound 12 were found to be identical with those
reported.8
3. (a) Denmark, S. E.; Nicaise, O. J.-C. Chem. Commun. 1996,
999; (b) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry
1997, 8, 1895; (c) Federsel, H.-J.; Collins, A. N.; Sheldrake,
G. N.; Crosby, J. Chirality Industry II; John Wiley and
Sons: Chichester, UK, 1997; p 225; (d) Bloch, R. Chem. Rev.
1998, 98, 1407; (e) Denamrk, S. E.; Nizaise, O. J.-C.
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4.6. Typical procedure for the recovery of chiral
polymer 7a
The used polymer 7a (2.0 g) recovered from the quenched
mixture by filtration, was stirred in a mixture of THF
(15 mL), 6 M aqueous HCl (2 mL) and water (5 mL) and
then after being filtered off it was stirred again for 4 h in a
mixture of THF (15 mL) and 2 M aqueous sodium hydrox-
ide (5 mL). The polymer 7a was then filtered off and washed
successively with 50 mL portions of water, methanol, THF,
aqueous THF, THF and methanol. After being dried at 40 ꢁC
in vacuo for 5 h, it was recycled and used for the enantio-
selective ethylation reaction (recovery: 1.84 g).
ˆ ꢁ
(g) Cote, A.; Charete, A. B. J. Org. Chem. 2005, 70, 10864;
(h) Chelucci, G. Tetrahedron: Asymmetry 2005, 16, 2353.
4. (a) Itsuno, S.; Watanabe, K.; Ito, K.; El-Shehawy, A. A.;
Sarhan, A. A. Angew. Chem., Int. Ed. 1997, 36, 109; (b)
El-Shehawy, A. A.; Abdelaal, M. Y.; Watanabe, K.; Ito, K.;
Itsuno, S. Tetrahedron: Asymmetry 1997, 8, 1731; (c) Itsuno,
S.; Watanabe, K.; Matsumoto, T.; Kuroda, S.; Yokoi, A.;
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Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.04.041.
6. (a) Pinho, P.; Anderson, P. G. Tetrahedron 2001, 57, 1615; (b)
Zhang, X.; Gong, L.; Mi, A.; Cui, X.; Jiang, Y.; Choi, M. C. K.;
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