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-one derivatives

Article abstract of DOI:10.1016/j.tetasy.2006.10.013

4-Arylideneamino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones 2a-f have been evaluated as substrates in the enantioselective diethylzinc addition reaction in the presence of (1S,2R)-N-alkyl-N-benzylnorephedrines 3a-d as chiral ligands. The utility of using a dual catalytic system (amino alcohol/halosilane) for the diethylzinc addition reaction has been also examined. The addition products 4-(1-arylpropyl)amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones 4a-f were obtained in high yields and with enantiomeric excesses of up to 92%. The treatment of arylimines 2a-f with a diethylzinc reagent did not affect the hetero-ring opening although the C{double bond, long}N double bond of the lateral chain did undergo an addition reaction to yield the C-ethylated products 4a-f. The reductive cleavage of the 1,2,4-triazinyl heterocyclic ring from addition products 4a-f led smoothly to the corresponding free primary amines 5a-f without a significant loss of enantiomeric purity.

Full text of DOI:10.1016/j.tetasy.2006.10.013

Tetrahedron: Asymmetry 17 (2006) 2617–2624
Enantioselective diethylzinc addition to the exocyclic
C@N double bond of some 4-arylideneamino-3-mercapto-
6-methyl-4H-1,2,4-triazin-5-one derivatives
Ashraf A. El-Shehawy*
Department of Chemistry, Faculty of Education, Kafr El-Sheikh, Kafr El-Sheikh University, PO Box 33516, Egypt
Received 14 July 2006; revised 22 September 2006; accepted 2 October 2006
Abstract—4-Arylideneamino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones 2a–f have been evaluated as substrates in the enantioselective
diethylzinc addition reaction in the presence of (1S,2R)-N-alkyl-N-benzylnorephedrines 3a–d as chiral ligands. The utility of using a dual
catalytic system (amino alcohol/halosilane) for the diethylzinc addition reaction has been also examined. The addition products 4-(1-
arylpropyl)amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones 4a–f were obtained in high yields and with enantiomeric excesses of
up to 92%. The treatment of arylimines 2a–f with a diethylzinc reagent did not affect the hetero-ring opening although the C@N double
bond of the lateral chain did undergo an addition reaction to yield the C-ethylated products 4a–f. The reductive cleavage of the 1,2,4-
triazinyl heterocyclic ring from addition products 4a–f led smoothly to the corresponding free primary amines 5a–f without a significant
loss of enantiomeric purity.
ꢀ 2006 Published by Elsevier Ltd.
1. Introduction
The addition of Grignard reagents and alkylithiums to the
exocyclic C@N double bond of 4-arylideneamino-3-mer-
capto-6-methyl-4H-1,2,4-triazin-5-ones 2 in the presence
of C@O and C@N groups of the triazine heterocyclic ring
had been reported to be difficult. The results obtained par-
ticularly proved that this heterocyclic ring was very sensi-
tive towards such reagents.6 It is worth mentioning that
we have recently reported on the successful addition of var-
ious allylmetal reagents to the exocyclic C@N double bond
of some aldiminomercaptotriazinones, in the presence of
Lewis acids as activators, without any possibility for
attacking the 1,2,4-triazine nucleus.7 These promising
results prompted us to further explore the dialkylzinc addi-
tion to such arylimines 2. To the best of our knowledge,
the evaluation of such arylimines as substrates in the di-
alkylzinc addition reaction has not been reported so far.
Herein we report the first evaluation of 4-arylideneamino-
3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones 2 as substrates
in the diethylzinc addition reaction, using chiral b-amino
alcohols 3a–d as chiral ligands and halosilanes as activators
(Fig. 1). The reductive cleavage of the 1,2,4-triazinyl group
from the addition products was also investigated, which
afforded the corresponding free amines, without the
loss of enantiomeric purity. A suggestion about the possi-
ble transition state for the addition reaction is also
presented.
The important synthetic uses of chiral amines has stimu-
lated a great interest in developing methods for the asym-
metric preparation of such molecules.1 The development
of efficient methods for preparing chiral amines has
received much attention. We have recently reported on
an efficient method for the enantioselective addition of
chirally modified allylboron reagents to various prochiral
imines with the resulting homoallylic amines being ob-
tained in high yields with enantioselectivities up to 96%.2
We have also reported on the diastereoselective allylation
of chiral imines derived from (S)-valine, which afforded
enantiomerically pure secondary amines in excellent yields
with perfect diastereoselectivities.3
Enantioselective dialkylzinc addition to imines is an effi-
cient approach to chiral amines and has recently received
much attention.4 Dialkylzinc addition to imines has been
extensively studied. As a result of the poor electrophilic
character of imines, several quite effective methods based
on the catalytic enantioselective addition of dialkylzinc
reagents to activated imines have been developed.5
*
Tel./fax: +20 47 3223415; e-mail: elshehawy2@yahoo.com
0957-4166/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2006.10.013

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A. A. El-Shehawy / Tetrahedron: Asymmetry 17 (2006) 2617–2624
Me
N
HS
N
Ph
HS
N
(1S,2R)-3a: R = H
(1S,2R)-3b: R = Me
(1S,2R)-3c: R = Et
(1S,2R)-3d: R = n-Bu
N
O
N
N
H
N
N
OH
H2N
Me
Me
Ar
Ph
R
O
1
3
2
Figure 1.
2. Results and discussion
Chiral amino alcohol 3c possessing an ethyl group on its
nitrogen resulted in a slightly reduced stereochemical out-
come of 76% ee (run 3). A further increase in the bulkiness
of the R group by the replacement of the methyl 3b with
n-butyl group 3d led to a significant decrease in each of
the chemical yield and enantiomeric excess (run 4) proba-
bly because the catalytic activity decreases by steric hin-
drance on the nitrogen atom. It is noteworthy to mention
that when the diethylzinc addition reaction to benzaldimine
2a using chiral ligand 3b was performed for 5 days, the
reaction was not complete and addition product 4a was
obtained only in a 69% chemical yield after work-up,
together with some unreacted starting imine 2a. However,
a slightly higher enantioselectivity was obtained (82% ee,
run 5). Interestingly, the above-mentioned chiral ligands
3a–d exhibited similar behaviour for both applications in
terms of catalytic activity and enantioselectivity when they
were employed in the enantioselective addition of diethyl-
zinc to N,N-diphenylphosphinoyl imines.8b,c,11 This might
represent a solid evidence in favour of a close similarity
of the transition states for these processes.
Chiral ligands (1S,2R)-N-alkyl-N-benzylorephedrines
3a–d (Fig. 1) selected for the present study were readily
synthesized using the reported method by the reaction of
N-(alkyl)norephedrine
or
ephedrine
hydrochloride
(2 mmol) with benzyl chloride (2 mmol) in the presence
of potassium carbonate (4 mmol) in refluxing ethanol for
7 h.8 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-tri-
azine-5-one 1 with the corresponding aldehyde in refluxing
methanol, according to the literature.9
Our initial efforts focused on examining the efficiency of the
chiral ligands (1S,2R)-3a–d bearing different alkyl groups
on their nitrogen atoms in terms of chemical yields and
enantioselectivities, in the diethylzinc addition reaction to
benzaldimine 2a as a standard substrate. The non-polar
solvent toluene, which was found to maximize the rate dif-
ference between the catalyzed and noncatalyzed reaction,10
was chosen as a reaction medium. The asymmetric ethyl-
ation of benzaldimine 2a with diethylzinc (3 equiv), in the
presence of (1S,2R)-3a–d (1 equiv) as chiral ligands, in tol-
uene at room temperature was first examined (Scheme 1).
The summarized results are shown in Table 1.
In an attempt to enhance the reaction rate, while leaving
the asymmetric induction untouched, silylating agents act-
ing as Lewis acids in the dialkylzinc addition reaction to
imines have been successfully used to activate the arylimine
substrates.12 Pericas et al. have recently successfully
`
As can be seen in Table 1, the size of the substituents
bonded to the nitrogen atom of chiral ligands (1S,2R)-
3a–d led to an obvious effect on each of the chemical yields
and enantiomeric excesses. In general, N,N-disubstituted
chiral ligands 3b–d showed relatively higher reactivities
and stereoselectivities than does the N-monosubstituted
chiral ligand 3a. In the diethylzinc reaction using
(1S,2R)-2-benzylamino-1-phenylpropan-1-ol 3a, as the chi-
ral ligand, which is a secondary amine, the addition prod-
uct 4a was obtained in a poor chemical yield (14%) with a
moderate ee value of 57% (Table 1, run 1). Among the chi-
ral ligands examined, (1S,2R)-N-benzylephedrine 3b was
found to be the most effective for the diethylzinc addition
reaction to benzaldimine 2a under the above-mentioned
reaction conditions affording addition product 4a with an
ee of 79% in moderate chemical yield (55%, run 2).
applied an interesting approach for the use of a dual cata-
Table 1. Enantioselective addition of diethylzinc to benzaldimine 2a in the
presence of chiral ligands 3a–da
Run
Ligand
Yieldb (%)
eec (%)
1
2
3
4
5a
3a
3b
3c
3d
3b
14
55
41
33
69
57
79
76
70
82
a All reactions were carried out in the presence of a stoichiometric amount
of chiral ligand 3 at room temperature for 48 h except run 5 which was
performed for 5 days.
b Isolated yields after flash chromatography (pentane/ethyl acetate: 3/7).
c Determined by HPLC analysis on a Chiralcel OD-H column.
HS
N
N
HS
N
N
H
N
Chiral ligands 3a-d
H
N
Me
Ph
N
Et2Zn, toluene, rt., 48 h
*
Ph
Me
N
H
O
O
2a
4a
Scheme 1. Diethylzinc addition to benzaldimine 2a in the presence of chiral ligands 3a–d.

A. A. El-Shehawy / Tetrahedron: Asymmetry 17 (2006) 2617–2624
2619
HS
H
N
O
HS
N
N
O
(i) Chiral ligand 3b
(ii) Et2Zn, 0 oC, 0.5 h
N
N
H
N
N
Ph
*
Me
N
H
Me
Ph
(iii) R'3SiCl (1 equiv) / −20 oC, 24 h
4a
2a
Scheme 2. Diethylzinc addition to benzaldimine 2a in the presence of ligand 3b and halosilanes.
lytic system consisting of a chiral amino alcohol, to control
the enantioselectivity of the addition process, and a bulky
silylating agent, to further activate the imine substrate.12b,c
Stimulated by these reports, an analogous dual amino
alcohol/halosilane mediation was investigated for the
diethylzinc addition to benzaldimine 2a using chiral ligand
3b that showed the highest level of enantioselectivity. In the
primary stage of this study, chiral ligand 3b was tested in
conjunction with a stoichiometric amount of different
silylating agents in the diethylzinc addition to benzaldimine
2a (Scheme 2, Table 2), to determine optimal reaction
conditions.
effect of decreasing the amount of chiral ligand 3b in the
same transformation. In the presence of TIPSCl (1 equiv)
which provided the most promising result, several addition
reactions of diethylzinc (3 equiv) to benzaldimine 2a were
set up with different amounts of ligand 3b (0.75, 0.50 and
0.25 equiv; Table 2, runs 5–7, respectively), under identical
reaction conditions as for the stoichiometric process. On
decreasing the amount of chiral ligand 3b (runs 5–7), chem-
ical conversions were found to be very similar to those ob-
served in the stoichiometric reaction (run 4) within the
same reaction time. However, the enantioselectivities
obtained when decreasing the amounts of ligand 3b are
very promising. Only a small loss in enantioselectivity
was observed when going from a full equivalent of chiral
ligand 3b (84% ee, run 4) to 0.75 equiv (81% ee, run 5)
and to 0.5 equiv (77% ee, run 6). A moderate value of
65% ee resulted from decreasing the amount of ligand 3b
from a stoichiometric amount to 0.25 equiv (run 7) is also
very promising. Interestingly, in the presence of TIPSCl
(1 equiv) and in the absence of any chiral ligand, the
diethylzinc addition reaction to benzaldimine 2a afforded
the addition product 4a in a 92% chemical yield as an
almost racemic mixture (run 8).
As clearly seen in Table 2, the use of silylating agents
greatly enhanced the diethylzinc addition reaction rate
and excellent yields of the addition product 4a were ob-
tained only after 24 h of reaction time. Among the various
i
Lewis acids tested, the silylating agent Pr3SiCl (TIPSCl)
was found to give the best results (95% yield, 84% ee; run
4). Interestingly, silylating agents containing the bulkiest
silyl groups still provoked a substantial rate increase,
while the observed enantioselectivity remained high.
Prompted by the previously mentioned results obtained
from the use of TIPSCl in the diethylzinc addition reaction
to benzaldimine 2a (Table 2, run 4), we explored further the
The previously mentioned set of experiments seemed to
strongly confirm that in the dual catalytic system under
investigation, the yield is primarily controlled by the silyl-
ating agent, while, as expected, enantioselectivity mainly
depends on the amount of the chiral amino alcohol ligand.
Table 2. Enantioselective diethylzinc addition to benzaldimine 2a acti-
vated by 3b/R03SiCla
In order to evaluate the generality of the titled asymmetric
reaction, the optimal procedure for the diethylzinc addition
reaction to the benzaldehyde derived imine 2a (Table 2, run
4) was thereafter examined for N-arylimines having various
substituents bonded to the phenyl group at different posi-
tions. The results of the diethylzinc addition reactions that
are displayed in Scheme 3 are summarized in Table 3.
Run
3b (equiv)
Additives
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1.00
1.00
1.00
1.00
0.75
0.50
0.25
—
Me3SiCl
Ph3SiCl
tBuPh2SiCl
iPr3SiCl
iPr3SiCl
iPr3SiCl
iPr3SiCl
iPr3SiCl
89
93
97
95
93
95
94
92
54
78
73
84
81
77
65
—
In the presence of stoichiometric amounts of chiral ligand
3b and TIPSCl, the diethylzinc addition reaction to various
N-arylimines containing ortho- and para-substituents on
the phenyl group proceeded smoothly to afford the corre-
sponding chiral amines 4a–f with chemical yields up to
a All reactions were performed for 24 h at ꢀ20 ꢁC.
b Refers to the isolated yield after flash chromatography (pentane/ethyl
acetate: 3/7).
c Determined by HPLC analysis on a Chiralcel OD-H column.
HS
H
N
O
HS
2,4 a. C6H5
b. 2-CH3-C6H4
N
O
(i) Chiral ligand 3b
(ii) Et2Zn, 0 oC, 0.5 h
N
N
H
N
N
c. 4-CH3-C6H4
Ar
(S)
Me
N
H
Me
Ar
N
(iii) TIPSCl (1 equiv) / −20 oC, 24 h
d. 2-CH3O-C6H4
e. 4-CH3O-C6H4
f. 2,4,6-Tri-CH3-C6H4
4
2
Scheme 3. Diethylzinc addition reaction to arylimines 2a–f in the presence of TIPSCl.

2620
A. A. El-Shehawy / Tetrahedron: Asymmetry 17 (2006) 2617–2624
Table 3. Enantioselective ethylation to arylimines 2a–f mediated by 3b/
a typical experiment. The recovered ligand could be used
in further experiments without a significant loss of chiral
induction.
TIPSCla
Run Ar
Imine Adduct Yieldb (%) eec,d (%)
1
2
3
4
5
6
Ph
2a
2b
2c
2d
2e
4a
4b
4c
4d
4e
4f
90
88
93
92
95
78
84
79
87
82
88 (92)e
72
It is worthwhile to note 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 diethyl-
zinc, in the presence of equimolar amounts of ligand 3b and
TIPSCl, the starting material was recovered almost
unchanged. This result indicates that the diethylzinc
reagent neither opened the hetero-ring in the 1,2,4-triazine
derivative 2a nor attacked the carbonyl or the thione group
of the 1,2,4-triazine 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-ethyl-
ated products 4a–f as evidenced by the microanalytical and
spectral data.
2-CH3–C6H4
4-CH3–C6H4
2-CH3O–C6H4
4-CH3O–C6H4
2,4,6-Tri-CH3–C6H4 2f
a All reactions were carried out at ꢀ20 ꢁC (Molar ratio: Imine/3b/TMSiCl/
Et2Zn = 1:1:1:3).
b Refers to the isolated yields after flash chromatography (pentane/ethyl
acetate: 3/7).
c Determined by HPLC analysis using a Chiralcel OD-H column.
d The absolute configuration was assigned to be S based on the specific
rotation of the amine resulted after reductive cleavage and comparison
with the literature (see Section 4).
e Crystallized from hexane/ethanol (1/9).
Additional studies demonstrated that the process can be
extended to asymmetric primary amine synthesis through
deprotection of the N-triazinyl group. The removal of the
1,2,4-triazinyl heterocyclic ring via reductive cleavage was
uneventful and furnished the corresponding free (S)-1-
aryl-1-propylamines 5a–f without racemization and in
nearly quantitative yields in addition to the expected 4-ami-
no-3-mercapto-6-methyl-4H-1,2,4-triazine-5-one 69 (Scheme
4). The absolute configurations of the major isomer of the
addition products 4a–f were assigned to be (S)-isomer
based on the absolute configuration of products 5a–f
obtained after the reductive cleavage of the 1,2,4-triazinyl
heterocyclic ring from the addition products 4a–f and a
comparison of the retention times on HPLC with the liter-
ature values.10b,13 The ee values of the (S)-1-aryl-1-propyl-
amines 5a–f were determined by HPLC analysis after
derivation of the amine to the corresponding acetamide
derivatives 7a–f by a reported method10b by the treatment
of 5a–f with acetic anhydride and triethylamine and
comparison with the literature value.13 The ee values were
found to be in very good agreement with the enantiomeric
excesses of the starting secondary amines 4a–f.
95% and good to high enantioselectivities (72–88%). It
should be noted in Table 3, which 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 analogues containing
a phenyl group with para-substituents. For example, the
diethylzinc addition reaction to imine 2c, having a p-meth-
ylphenyl group, afforded addition product 4c with a rela-
tively higher enantioselectivity of 87% ee (run 3) than
that of 79% ee (run 2) given by its analogue 2b, which pos-
sessed an ortho-methylphenyl group. Similar results were
also observed with imines 2d and 2e having ortho-methoxy-
phenyl and para-methoxyphenyl groups (Table 3, runs 4
and 5), respectively. Arylimine 2f, bearing a 2,4,6-tri-meth-
ylphenyl group, provided the addition product 4f with a
lower yield of 78% and enantioselectivity of 72%, which
may be due to the steric hindrance imposed by the di-
ortho-substituted benzene ring (run 6).
It should be noted that all addition products 4a–f obtained
are solids and thus their enantiomeric excess could be
enhanced by crystallization. For example, the enantiomeric
purity of 4e (88%, run 4) could be upgraded to 92% by a
simple crystallization from hexane/ethanol (Table 3, run 5).
Although the mechanistic details for the asymmetric
process are currently unclear, the observed results might
be rationalized by assuming that the addition takes place
through the transition states depicted in Figure 2. How-
ever, sulfur is more nucleophilic than oxygen and proved
particularly to be stronger than oxygen in complexation
with a Zn atom.14 Therefore, the mercapto group (SH)
It is worth noting that, although a stoichiometric amount
of amino alcohol as chiral ligand was used, more than
90% of it could be easily recovered during the work-up in
HS
N
HS
N
N
H
N
(i) Zn/HCl, EtOH, 55-60 oC, 24 h
H
NH2
N
HN
+
Me
Me
Ar
N
H
Ar
(ii) 15% NaOH
O
O
(S)-5a-f
6
(S)-4a-f
H
Ac2O, Et3N
Toluene, rt.
Ar
NHCOCH3
(S)-7a-f
Scheme 4. Preparation of chiral amines 5a–f via reductive cleavage of the triazinyl group.

A. A. El-Shehawy / Tetrahedron: Asymmetry 17 (2006) 2617–2624
2621
up to 92%. The removal of the 1,2,4-triazinyl heterocyclic
ring via reductive cleavage was uneventful and furnished
the corresponding free (S)-1-aryl-1-propylamines 5a–f
without racemization and in nearly quantitative yields.
Due to the simplicity of the process and the ready availabil-
ity of imine precursor 2, we believe that a broad applicabil-
ity of the reported catalytic reaction can be anticipated.
Further work in this area is still needed. Efforts along this
line including the use of other organozinc reagents to
achieve higher stereoselectivities are currently under way
and the results will be reported in due course.
Me
Me
S
Ph
Ph
O
O
Et
Et
N
N
N
N
N
N
R
N
N
Me
Ph
Me
Ph
R
A
A
N
N
O
O
S
B
B
R''
R''
Ar
Et
Et
R''
B
A
Figure 2. Proposed transition state for the diethylzinc addition reaction to
arylimines 2a–f.
4. Experimental
would be more nucleophilic than the carbonyl group
(C@O) and consequently the S–Zn interaction may be
stronger than that of O–Zn. The steric hindrance brought
about by each of the substituents on the nitrogen atom
of ligand 3, as well as by the triazine heterocyclic ring
forces ZnB to be in the position shown, thus determining
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 a bicyclic transition state such as the one
shown in Figure 2. The transfer of one of the ethyl groups
of ZnB to the imine carbon would give the addition
products with the observed stereochemistry.
All reactions were performed under a nitrogen atmosphere.
Melting points were measured on an electrothermal digital
melting point apparatus and are uncorrected. All commer-
cially available reagents and solvents were employed as
supplied, except for toluene, which was freshly distilled
under nitrogen prior to use. Diethylzinc reagent was
purchased from Aldrich Co. Flash chromatography was
performed on deactivated silica gel (Matrix 60A, 37–
70 lm) and the spots were detected with UV model
UVGL-58. Optical rotations were measured with a Per-
kin–Elmer 341 Polarimeter in a 10 cm cell with the solvent
indicated. HPLC analyses were carried out on a chiral
column (Chiralcel OD-H column, 25 cm, 30 ꢁC), with a
1
254 nm UV detector and a flow rate of 1.0 mL/min. H
and 13C NMR spectra were recorded on a JEOL GSX-
400 (400/100.4 MHz) spectrophotometer in CDCl3; chemi-
cal shifts are relative to TMS as internal reference. Mass
spectra were recorded on a JEOL JMS-SX120A. IR spectra
were recorded on Perkin–Elmer 1760 FTIR spectrophoto-
meter instrument.
As shown in structure A, products with an (S)-absolute
configuration should be given by ligands 3a–d, which was
consistent with our experimental results. The transition
state B clearly explained that the presence of ortho-substit-
uents 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
(Table 3, compare entry 1 with entries 2, 4 and 6). There-
fore, arylimines with a para-substituent afforded higher
enantioselectivities than their structural analogues bearing
an ortho-substituted phenyl group. Moreover, as shown
in structure A, for steric reasons, it appears advantageous
to have a small alkyl (R) group on the nitrogen atom of
the ligand 3 in order to get high selectivities, and this
assumption was also borne out experimentally (Table 1,
runs 1–4).
4.1. Enantioselective addition of diethylzinc to arylimines 2
in the presence of chiral ligands 3
4.1.1. In the absence of Lewis acids. Typical experimental
procedure. Benzaldimine 2a (73.9 mg, 0.3 mmol) and
amino alcohol 3b (76.6 mg, 0.3 mmol) were dissolved in
dry toluene (2.0 mL) under nitrogen and the mixture was
stirred for 10 min at room temperature. The solution was
cooled to 0 ꢁC and diethylzinc (0.9 mL, 1.0 M solution in
hexane, 0.9 mmol) was added dropwise. The reaction mix-
ture was stirred at 0 ꢁC for a further 30 min. The reaction
mixture was allowed to rise slowly to room temperature
and stirred for a further 48 h at that temperature and then
quenched with saturated aqueous NH4Cl (15 mL). The
reaction mixture was extracted with CH2Cl2 (3 · 15 mL)
and the combined organic extracts were dried over MgSO4.
The solvents were evaporated and the residue purified by
flash chromatography on silica gel (deactivated silica gel,
pentane/ethyl acetate: 95:5–30:70) to afford 45.6 mg (55%
yield) of 4a. The resultant solid was analyzed by HPLC
on a Chiralcel OD-H column. The obtained yields and
ee’s with the use of other ligands are given in Table 1.
3. Conclusion
In conclusion, we have demonstrated the first application
of diethylzinc addition reaction to the exocyclic C@N dou-
ble bond of 4-arylideneamino-3-mercapto-6-methyl-4H-
1,2,4-triazin-5-ones 2a–f as substrates in the presence of
b-amino alcohols 3a–d as chiral ligands and chloro trialkyl-
silanes as activators. The activation of arylimines with sily-
lating reagent renders the alkylation to be an easy, efficient,
and high yielding reaction. In the presence of 3b/TIPSCl,
the addition reaction took place smoothly affording the
addition products in high yields with enantioselectivities
4.1.2. In the presence of Lewis acids. Typical experimental
procedure. Arylimine 2e (82.8 mg, 0.3 mmol) and ligand
3b (76.6 mg, 0.3 mmol) were dissolved in dry toluene

2622
A. A. El-Shehawy / Tetrahedron: Asymmetry 17 (2006) 2617–2624
(2.0 mL) under nitrogen, at room temperature, and the
reaction mixture was cooled to 0 ꢁC. To this mixture,
0.9 mL (0.9 mmol) of 1 M Et2Zn in hexane was added
dropwise. After stirring at 0 ꢁC for 30 min, the reaction
mixture was cooled to ꢀ20 ꢁC and TIPSCl (64 lL,
0.3 mmol) was added. Stirring was continued for 24 h at
that temperature and the reaction mixture then quenched
with saturated aqueous NH4Cl. The aqueous phase was
extracted with CH2Cl2 (3 · 15 mL), and the combined
organic layers dried over MgSO4. After removal of the sol-
vents, the residue was purified by flash chromatography on
silica gel (deactivated silica gel, pentane/ethyl acetate: 95:5–
30:70) to afford 4-[1-(40-methoxyphenyl)propyl]amino-3-
mercapto-6-methyl-4H-1,2,4-triazin-5-one 4e in 95% yield
(87.3 mg) as a white solid and in 88% ee. The enantiomeric
purity of 4e could be upgraded to 92% by simple crystal-
lization from hexane/ethanol (1:9). The product was ana-
lyzed by HPLC on a Chiralcel OD-H column. The yields
and enantiomeric compositions of the secondary amines
obtained with arylimines 2a–f are shown in Tables 2 and 3.
4.1.5.
4-[1-(40-Methylphenyl)propyl]amino-3-mercapto-6-
methyl-4H-1,2,4-triazin-5-one 4c. White solid, mp 182–
25
183 ꢁC; ½aꢁD ¼ ꢀ78:1 (c 1.28, CH2Cl2); HPLC conditions:
i
15% PrOH in hexane, retention times, 21.55 min (minor,
R-isomer) and 27.82 min (major, S-isomer); IR (cmꢀ1
)
3280 (NH), 1703 (C@O), 1208 (C@S); 1H NMR
(400 MHz, CDCl3): d (ppm) 0.86 (t, 3H, J = 7.6 Hz,
CH3CH2), 1.74–1.87 (m, 1H, CH2CH3), 1.97–2.13 (m,
1H, CH2CH3), 2.35 (s, 3H, Ar–CH3), 2.44 (s, 3H, CH3–
C6), 3.42 (br s, 1H, NHC), 4.06–4.16 (m, 1H, CHNH),
7.07 (d, J = 8.3 Hz, 2H, HAr), 7.18 (d, J = 8.3, 2H, HAr),
11.57 (br s, 1H, 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 (Ar), 128.84 (Ar),
136.38 (Ar), 140.69 (Ar), 150.43 (C6), 166.76 (C5), 170.18
(C3); MS (EI) m/z (rel. intensity) 290 (M+, 11%), 263
(27), 246 (9.5), 218 (4), 158 (9), 146 (52), 134 (18), 130
(25), 119 (21), 105 (9) and 91 (19). 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.
4.1.6. 4-[1-(20-Methoxyphenyl)propyl]amino-3-mercapto-6-
4.1.3. 4-(1-Phenylpropyl)amino-3-mercapto-6-methyl-4H-
1,2,4-triazin-5-one 4a. White solid, mp 117–118 ꢁC;
methyl-4H-1,2,4-triazin-5-one 4d. White solid, 129–
25
131 ꢁC; ½aꢁD ¼ ꢀ94:5 (c 0.77, CHCl3); HPLC conditions:
25
½aꢁD ¼ ꢀ57:4 (c 1.03, CH2Cl2); HPLC conditions: 9%
i
15% PrOH in hexane, retention times, 10.41 min (minor,
iPrOH in hexane, retention times, 20.18 min (minor, R-iso-
mer) and 27.26 min (major, S-isomer); IR (cmꢀ1) 3277
(NH), 1707 (C@O), 1205 (C@S); 1H NMR (400 MHz,
CDCl3): d (ppm) 0.89 (t, 3H, J = 7.5 Hz, CH3CH2), 1.75–
1.88 (m, 1H, CH2CH3), 1.96–2.08 (m, 1H, CH2CH3),
2.38 (s, 3H, CH3–C6), 3.42 (m, 1H, NHN), 4.04–4.16 (m,
1H, CHNH), 7.33–7.68 (m, 5H, HAr), 12.17 (br s, 1H,
SH); 13C NMR (100 MHz, CDCl3): d (ppm) 11.63
(CH3CH2), 17.92 (CH3–C6), 31.25 (CH2CH3), 56.36
(CHNH), 128.39 (Ar), 129.33 (Ar), 130.26 (Ar), 137.30
(Ar), 149.31 (C6), 165.40 (C5), 170.11 (C3); MS (EI) m/z
(rel. intensity) 276 (M+, 6%), 249 (44), 248 (14), 232 (8),
157 (14), 146 (71), 142 (6), 134 (33), 130 (17) and 119
(23). 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.
R-isomer) and 18.16 min (major, S-isomer); IR (cmꢀ1
)
3285 (NH), 1795 (C@O), 1209 (C@S); 1H NMR
(400 MHz, CDCl3): d (ppm) 0.76 (t, 3H, J = 7.4 Hz,
CH3CH2), 1.74–1.89 (m, 1H, CH2CH3), 1.96–2.05 (m,
1H, CH2CH3), 2.37 (s, 3H, CH3–C6), 3.28 (br s, 1H,
NHC), 3.83 (s, 3H, OCH3), 4.38–4.52 (m, 1H, CHNH),
6.98 (d, 1H, J = 8.0 Hz, HAr), 7.09 (t, 1H, J = 7.6 Hz,
HAr), 7.35 (t, 1H, J = 7.6 Hz, HAr), 7.59 (d, 1H,
J = 7.6 Hz, HAr), 8.08 (dd, J = 1.94, 1.77 Hz, 1H, HAr),
12.44 (br s, 1H, 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 (Ar), 127.52 (Ar),
128.21 (Ar), 131.89 (Ar), 151.09 (C6), 165.87 (C5), 170.19
(C3); MS (EI) m/z (rel. intensity) 306 (M+, 14%), 278
(19), 262 (11), 234 (5), 157 (13), 146 (76), 150 (26), 131
(28), 118 (17), 105 (13), 91 (37) and 91 (11). 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.
4.1.4.
4-[1-(20-Methylphenyl)propyl]amino-3-mercapto-6-
methyl-4H-1,2,4-triazin-5-one 4b. White solid, mp 152–
25
153 ꢁC; ½aꢁD ¼ ꢀ96:8 (c 0.98, CHCl3); HPLC conditions:
4.1.7. 4-[1-(40-Methoxyphenyl)propyl]amino-3-mercapto-6-
i
12% PrOH in hexane, retention times, 14.62 min (minor,
methyl-4H-1,2,4-triazin-5-one 4e. White solid, 144–
25
R-isomer) and 22.97 min (major, S-isomer); IR (cmꢀ1
)
145 ꢁC; ½aꢁD ¼ ꢀ34:6 (c 2.39, CH2Cl2); HPLC conditions:
3270 (NH), 1701 (C@O), 1207 (C@S); 1H NMR
(400 MHz, CDCl3): d (ppm) 0.79 (t, 3H, J = 7.4 Hz,
CH3CH2), 1.78–1.90 (m, 1H, CH2CH3), 1.96–2.09 (m,
1H, CH2CH3), 2.32 (s, 3H, Ar–CH3), 2.56 (s, 3H, CH3–
C6), 3.28 (br s, 1H, NHC), 3.99–4.08 (m, 1H, CHNH),
6.78–6.98 (m, 2H, HAr), 7.09–7.44 (m, 2H, HAr), 12.29
(br s, 1H, 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 (Ar), 126.71 (Ar),
127.85 (Ar), 133.29 (Ar), 152.31 (C6), 165.92 (C5), 169.67
(C3); MS (EI) m/z (rel. 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) and 91 (6). 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.
15% PrOH in hexane, retention times, 9.32 min (minor,
i
R-isomer) and 15.52 min (major, S-isomer); IR (cmꢀ1
)
3285 (NH), 1695 (C@O), 1210 (C@S); 1H NMR
(400 MHz, CDCl3): d (ppm) 0.87 (t, 3H, J = 7.5 Hz,
CH3CH2), 1.75–1.92 (m, 1H, CH2CH3), 1.98–2.11 (m,
1H, CH2CH3), 2.42 (s, 3H, CH3–C6), 3.34 (br s, 1H,
NHC), 3.82 (s, 3H, OCH3), 4.09–4.17 (m, 1H, CHNH),
6.93 (d, J = 8.7 Hz, 2H, HAr), 7.26 (d, J = 8.7 Hz, 2H,
HAr), 11.87 (br s, 1H, 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 (Ar), 126.67 (Ar),
134.72 (Ar), 146.43 (Ar), 152.52 (C6), 164.55 (C5), 171.09
(C3); MS (EI) m/z (rel. intensity) 306 (M+, 18%), 279
(22), 262 (6), 234 (4), 157 (24), 150 (21), 146 (64), 130
(16), 119 (9) and 105 (7). Anal. Calcd for C14H18N4O2S:

A. A. El-Shehawy / Tetrahedron: Asymmetry 17 (2006) 2617–2624
2623
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.
one. Melting and mixed melting point determinations gave
no depression.9
4.1.8. 4-[1-(20,40,60-Tri-methylphenyl)propyl]amino-3-mer-
Acknowledgement
capto-6-methyl-4H-1,2,4-triazin-5-one 4f. White solid,
25
198–199 ꢁC; ½aꢁD ¼ ꢀ46:6 (c 0.98, CH2Cl2); HPLC condi-
The author would like to thanks Professor Shinichi Itsuno
(Department of Materials Science, Toyohashi University of
Technology, Japan) for his valuable discussion during this
work.
i
tions: 15% PrOH in hexane, retention times, 12.82 min
(minor, R-isomer) and 19.42 min (major, S-isomer); IR
1
(cmꢀ1) 3283 (NH), 1704 (C@O), 1205 (C@S); H NMR
(400 MHz, CDCl3): d (ppm) 0.91 (t, 3H, J = 7.7 Hz,
CH3CH2), 1.72 (s, 3H, Ar–CH3), 1.84–1.96 (m, 1H,
CH2CH3), 2.01–2.11 (m, 1H, CH2CH3), 2.21 (s, 6H, Ar–
CH3), 2.31 (s, 3H, Ar–CH3), 2.40 (s, 3H, CH3–C6), 3.39
(br s, 1H, NHC), 4.16–4.31 (m, 1H, CHNH), 6.72 (s, 1H,
Ar–H), 6.89 (s, 1H, HAr), 7.31 (s, 1H, HAr), 11.57 (br s,
1H, 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 (Ar), 131.67 (Ar), 136.19 (Ar), 139.52 (Ar), 152.18
(C6), 165.49 (C5), 169.78 (C3); MS (EI) m/z (rel. intensity)
318 (M+, 13%), 290 (21), 274 (4), 246 (7), 175 (32), 162
(29), 158 (23), 146 (61), 131 (33), 118 (17), 105 (8) and 91
(12). 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.
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