Novel O,N,N,O-tetradentate ligand from tartaric acid

Article abstract of DOI:10.1016/j.tet.2013.05.049

A new class of highly stable O,N,N,O-tetradentate bioxazoline ligands were synthesized from l-tartaric acid. Exploration of those ligands in Pd-catalyzed asymmetric allylic alkylation yielded alkylated product up to 96% ee. Necessity of additional chelation to obtain high enantioselectivity was also demonstrated. Structural modifications of this ligand might result in identification of a novel privileged chiral ligand from an inexpensive chiral pool.

Full text of DOI:10.1016/j.tet.2013.05.049

Accepted Manuscript
Novel O,N,N,O-tetradentate ligand from tartaric acid
Kaluvu Balaraman, Ravichandran Vasanthan, Venkitasamy Kesavan
PII:
S0040-4020(13)00784-9
10.1016/j.tet.2013.05.049
TET 24387
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 March 2013
Revised Date: 9 May 2013
Accepted Date: 13 May 2013
Please cite this article as: Balaraman K, Vasanthan R, Kesavan V, Novel O,N,N,O-tetradentate ligand
from tartaric acid, Tetrahedron (2013), doi: 10.1016/j.tet.2013.05.049.
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Novel O,N,N,O-tetradentate ligand from
tartaric acid
Leave this area blank for abstract info.
Kaluvu Balaramana , Ravichandran Vasanthana and Venkitasamy Kesavana,
a Chemical Biology Laboratory, Bhupat and Jyothi Mehta School of Biosciences Building, Indian Institute of
Technology Madras, Chennai 600 036, India

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Tetrahedron
journal homepage: www.elsevier.com
Novel O,N,N,O-tetradentate ligand from tartaric acid
Kaluvu Balaramana , Ravichandran Vasanthana and Venkitasamy Kesavana,
a Chemical Biology Laboratory, Bhupat and Jyothi Mehta School of Biosciences Building, Indian Institute of Technology Madras, Chennai 600 036, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new class of highly stable O,N,N,O-tetradentate bioxazoline ligands were synthesized from L-
tartaric acid. Exploration of those ligands in Pd-catalyzed asymmetric allylic alkylation yielded
alkylated product up to 96% ee. Necessity of additional chelation to obtain high
enantioselectivity was also demonstrated. Structural modifications of this ligand might result in
identification of a novel privileged chiral ligand from an inexpensive chiral pool.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Bioxazoline
Tetradentate ligand
Tartaric acid
Allylic alkylation
Enantioselective
enantioselectivities up to 93%.6c Whereas bioxazolines 3 which
1. Introduction
form similar coordination did not show such promising
Enantioselective synthesis of physiologically active
pharmacophores/natural products is a need of the decade.1
Asymmetric catalysis is emerging as the method of choice to
synthesize enantiomerically pure pharmacophores/natural
products.2 Organic chemists play a pivotal role in the design and
the synthesis of novel chiral ligands to facilitate metal mediated
asymmetric transformations.3 It is desirable if a chiral ligand can
be synthesized from an inexpensive chiral pool like tartaric acid4
or natural amino acids.5
enantioselectivity. In our continuing efforts in synthesizing novel
ligands from chiral pool, we wish to report here a novel
O,N,N,O-tetradentate ligand from tartaric acid and its application
in asymmetric allylic alkylation (AAA).
Tartaric acid derived diamine 2 could be exploited to
synthesize novel chiral ligands by combining with acids which
have additional chelation moieties (Figure 2). Lee et al.7
synthesized and demonstrated the usefulness of P,N,N,P-ligand 4
in asymmetric allylic alkylation and asymmetric transfer
hydrogenation of aromatic ketones. To the best of our knowledge
there is no report in the literature to synthesize O,N,N,O-
tertradentate bioxazoline ligand 5 from diamine 2. Since the
coordinating atoms in tetradentate bioxazoline 5a are similar to
salen ligands, which would accommodate various metals, thus
may provide opportunities to evaluate its efficiency in various
asymmetric transformations. Since it has the potential to become
a privileged ligand such as salen from an inexpensive chiral pool,
we dedicated our efforts in synthesizing ligand 5a and
demonstrated its efficiency in catalyzing asymmetric allylic
alkylation.8
Figure 1. Bioxazoline from tartaric acid.
In our lab, we developed novel bioxazolines by fusing tartaric
acid derived diamine 2 with optically active acids e.g. Naproxen
(Figure 1). It was demonstrated that although ligand 1 forms only
5-membered chelate with metal, it catalyzed Henry reaction,6a
alkyne addition to imines,6b enantioselective fluorination and
allylic alkylation with very good
efficiency and
———
Corresponding author. Tel.: +91 44 2257 4124; fax: +91 44 2257 4102; e-mail: vkesavan@iitm.ac.in

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Tetrahedron
Scheme 1. Attempts to synthesize O,N,N,O-tetradentate ligand
Initial efforts were made to synthesize O,N,N,O-tetradentate
ligand 5a by reacting 2-methoxy benzoylchloride (6) with
diamine 2 to afford diamide 7 in 97% yield. Our attempts to
deprotect benzyl groups were not successful (H2-Pd/C at 1 atm as
well as high pressure, BCl3, and HI, FeCl3), and only very little
conversion into diol 9 was observed under these reaction
conditions (Scheme 1). By employing a modified synthetic
pathway, diol 9 was synthesized efficiently by reacting diamine 8
with 2-methoxy benzoylchloride (6). However due to presence of
electron releasing o-methoxy group, cyclization of diol 9 into
corresponding bioxazoline 10a did not materialize. Since o-
methoxy group hindered our efforts in synthesizing our target
ligand 5a, we altered the strategy to achieve our goal.
Figure 2. Tetradentate ligands derived from tataric acid
2. Results and discussion
2.1 Synthesis of tetradentate bioxazoline ligands
Bioxazoline 3a was synthesized as reported earlier with the
focus of synthesizing tetradentate ligand 5a. We hoped that
presence of electron withdrawing oxazoline ring might facilitate
the substitution of fluorine atom in 3a by methoxide anion.
Accordingly, bioxazoline 3a was treated with sodium methoxide
in tetrahydrofuran (THF) to afford bioxazoline 10a, but the
deprotection of methyl group under acidic conditions resulted in
the ring opening of oxazoline. Since our goal is to incorporate -
OH chelation we changed the anion counterpart by using sodium
salt of benzylalcohol and made bioxazoline 10b, which was
subsequently deprotected to afford O,N,N,O-tetradentate
bioxazoline 5a in good yield (Scheme 2). Apart from standard
characterization techniques, structure of ligand 5a was solved by
X-ray crystallography also (CCDC No: 825879) (Figure 3).9
BnO
O
OBn
O
HO
O
OH
O
O
O
COCl
2/Et3N
CH2Cl2
NH HN
N
N
NH HN
F
MsCl, Et3N
H2-Pd/C
0-25 oC
3h, 97%
F
F
F
F
F
F
THF
0-25 oC, 88%
CH3OH
25 oC, 91%
CF3
CF3
F3C
CF3
F3C
CF3
F3C
13
12
11
O
O
O
N
O
O
O
BnOH, NaH
THF, 25 oC
N
N
N
H2-Pd/C
CH3OH
25 oC, 88 & 92%
N
N
87 & 85%
F
F
OBn
R
BnO
OH
HO
R
R
R
R = H (3a)
R = CF3 (13)
R
R
R = H (5a)
R = H (10b)
R = CF3 (5b)
R = CF3 (14)
Scheme 2. Synthesis of novel O,N,NO-tetradentate ligand 5a
2.2. Evaluation of Bioxazoline and Salen Ligands on
Asymmetric Allylic Alkylation
Enantioselective formation of carbon-carbon and carbon-
hetero atom bonds can be achieved by using palladium catalyzed
asymmetric allylic substitution reactions. Bis(oxazoline)s, P,N-
ligands and P,N,N,P-ligands have been extensively used for
above said purposes. Nevertheless there is always room for
improvement in case of substrate selectivity especially for
Figure 3. ORTEP drawing of the molecular structure of ligand 5a
unsymmetrical
allylic
acetates.10
Since bisphosphine-
To evaluate the efficiency of ligand 5a as a chiral ligand in
Pd-catalyzed allylic substitutions, the traditional reaction
between rac-(E)-1,3-diphenyl-2-propen-1-yl acetate (15a) and
dimethyl malonate (16a) was examined. Dimethyl malonate
(16a) was treated with allylic substrate 15a in the presence of
bis(oxazoline) 4 was explored well with AAA, first we decided
to evaluate the potential of tetradentate-bioxazoline 5a in
catalyzing AAA. Moreover, there is no literature precedence of
using O,N,N,O-tetradentate ligands in allylic substitution
reactions and to the best of our knowledge this is first time
O,N,N,O-tetradentate bioxazoline ligands are being explored.
[(η3-C3H5)PdCl]2 (5 mol %) and ligand 5a (10 mol %) at 25 C
o
and the results are summarized in Table 1. As seen from table 1,
ligand 5a exhibited modest increase in efficiency in catalyzing
allylic substitution reaction with 81% ee in 79% yield (Table 1,
entry 1). It is prudent to compare the catalytic efficiency of newly

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developed O,N,N,O-ligand 5a with similar chelating ligands i.e
salen.11 Hence we synthesized various salen ligands (18 & 19)
(Figure 4) as reported earlier and gauged their ability in
catalyzing AAA (Table 1, entries 2-5). The best performing salen
ligands 18a and 19a in other asymmetric transformations failed
to induce very good asymmetric induction (Table 1, entries 2 &
4). Poor enantioselectivity (22 & 36% ee) was observed using
salen ligands 18a and 19a under the identical reaction conditions.
Since tetradentate ligand 5a does not contain any bulky
substituents as in salen ligands 18a and 19a, it is necessary to
screen salen ligands with no steric substituents. To simulate the
similar steric environment of ligand 5a, salen ligands 18b and
19b were evaluated for their efficiency in the formation of 17a.
Both salen ligands 18b and 19b neither catalyzed the reaction
efficiently nor improved the asymmetric induction in AAA. Only
low yields and moderate enantioselectivities were obtained using
ligand 18b and 19b (Table 1, entries 3 & 5).
catalyzed AAA using ion-paired ligand.12 Although we
observed the similar effects it is necessary to prove the need of
free –OH, hence we screened ligand 10a where the phenolic –OH
protected with methyl which showed only 38% enantioselectivity
(Table 1, entry 8). This experiment clearly showed the
importance of additional chelation to enhance the reactivity as
well as enantioselectivity. Thus we have identified a novel
O,N,N,O-tetradentate ligand 5a for asymmetric allylic alkylation
reaction.
In case of Salen-complexes it is proven that presence of
trifluoromethyl group at the ortho position increases the
enantioselectivity considerably for asymmetric epoxidation.13 In
an attempt to optimize the structure of tetradentate ligand 5a, we
accomplished the synthesis of ligand 5b by choosing the
respective benzoic acid derivative. Screening of ligand 5b in
allylic substitution afforded the product 17a in moderate yield
and enantioselectivity (Table 1, entry 9). Presence of CF3- group
at ortho position did not bring in the desired effect.
Table 1. Catalytic efficiency of tetradentate Bioxazoline
ligands over bidentate Bioxazoline and Salen ligands in Pd-
catalyzed asymmetric allylic alkylation (AAA) reaction.[a]
2.3. Effect of Solvents and Additives on AAA
Table 2. Solvent and additive effect on enantioselectivity.a
Entry
Ligand
5a
18a
18b
19a
19b
3a
3b
10a
5b
T [days]
Yield [%][b]
ee [%][c]
81 (R)
22 (R)
28 (R)
36 (S)
40 (S)
49 (R)
64 (R)
38 (R)
53 (R)
Entry Solvent
Base
t [days] Yield [%]b
ee [%]c
82
81
48
54
56
nd
64
nd
71
84
77
92
1
2
3
4
5
6
7
8
9
3
3
3
2
2
6
6
3
3
79
69
34
92
28
52
80
73
57
1
2
Dichloroethane
Chloroform
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
LiOAc
NaOAc
AgOAc
3
3
3
3
3
4
4
3
3
3
3
4
70
48
51
49
57
traces
88
traces
53
83
3
THF
4
5
Diethylether
TBME
6
Dioxane
7
8
Acetonitrile
Toluene
Reaction conditions: ligand (10 mol %), [(η3-C3H5)PdCl]2 (5 mol %), 15a
a
9
Benzene
(0.2 mmol), CH2(COOMe)2 (0.6 mmol), BSA (0.6 mmol) in 1 mL of
10
11
12
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane at 25 oC.
78
70
b Isolated yield.
c Determined by chiralpak AD-H column.
a
Reaction conditions: 5a (10 mol%), [(η3-C3H5)PdCl]2 (5 mol%), 15a (0.2
It is clear from these results that in case of AAA performance
of our ligand 5a is superior to salen ligands. It is necessary to
prove the importance of additional chelation i.e phenoxy groups
beyond reasonable doubt. Evaluating bioxazlines 3a, 3b and 10a
in allylic substation will give a clear indication about the need of
additional chelation. Under the reaction conditions neither
bioxazolines 3a nor 3b performed better than tetradentate ligand
5a in inducing enantioselectivity (Table 1, entries 6 & 7). Only
moderate enantioselectivity was obtained when bidentate
bioxazolines 3a and 3b were used. These experiments indicate
the need of additional chelation moiety in these types of
bioxazolines to effect Pd-catalyzed allylic substitution. The
substantially improved enantioselectivity obtained support that
our ligand 5a is better than the parent ligand 3 in which reaction
took 6 days to complete (Table 1, entries 6 & 7).
mmol), CH2(COOMe)2 (0.6 mmol), BSA (0.6 mmol) in 1 mL of solvent at 25
oC.
b Isolated yield.
c Determined by chiralpak AD-H column.
To improve the enantioselectivity further the role of solvents
was investigated by performing the reaction in various solvents
using the [Pd(η-C3H5)Cl]2/5a in the presence of BSA and KOAc.
It was observed that the choice of the solvent affected both the
yield and the enantioselectivity. Among the chlorinated solvents
dichloromethane was found to be most suitable solvent in
mediating the reaction in the presence of KOAc to afford allylic
alkylation product 17a in 79% yield and with 81% ee (Table 1,
entry 1). Neither dichloroethane nor chloroform as the reaction
medium affected the yield or enantioselectivity favourably (Table
2, entries 1-2). Ethereal solvents such as THF, diethylether and
tert-butyl methyl ether (TBME) failed to play an optimal role in
terms of both yield (49-57%) and enantioselectivity (48-56%)
(Table 2, entries 3-5). Only trace amount of product was formed
when dioxane was used as the solvent (Table 2, entry 6) even
after extending the reaction duration for 4 days. In acetonitrile,
allylic substitution proceeded smoothly and came to completion
in 4 days. Although the product isolated had 88% yield, only a
moderate asymmetric induction was observed (64% ee) (Table 2,
entry 7). No betterment of yield or enantioselectivity was noticed
when toluene or benzene was used as reaction medium (Table 2,
Figure 4. Structures of salen ligands
entries
8 & 9). With these findings, we concluded that
dichloromethane is the most suitable solvent for ligand 5a in
catalyzing allylic substitution. Hence identification of a befitting
base was carried out in dichloromethane (Table 2, entries 10-12).
Recently Ooi and his co-workers found enhanced
enantioselectivity and yield by phenolic –OH in case of Pd-

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4
Tetrahedron
Among the bases screened AgOAc was found as the most apt
Although the allylic alkylation using symmetrical substrates
was explored well in the literature, alkylation of unsymmetrical
allylic substrates is less explored.14 Especially the substrate
bearing two different terminal groups such as phenyl and methyl
20 showed only 43% ee using chiral ferrocenyl phosphine-
thioether ligands reported by Chan et al.14e All other reports
including the well explored bis(oxazoline)14g ligands catalyzed
allylic substitution with poor enantioselectivity. Hence we chose
substrate 20 as a model substrate to explore the potentiality of
our catalytic system for unsymmetrical allylic acetates. In this
case we observed predominant nucleophilic attack at the least
hindered carbon with extended conjugation to afford 21 with
76% enantioselectivity (Scheme 3). To the best of our knowledge
there is no literature precedence to achieve this level of
enantioselectivity while using 20 as a substrate for AAA. This
promising result indicates that this tetradentate ligand might be
the ideal choice to effect allylic substitution reaction in case of
unsymmetrical allylic acetates, which is under investigation in
our lab.
base in conjunction with N,O-bis(trimethylsilyl)acetamide.
Allylic substitution product 17a was obtained in 70% yield and
very good enantioselectivity (92% ee).
2.4. Substrate Scope of AAA
With this optimized reaction conditions, the scope of catalytic
asymmetric allylic alkylation (AAA) was demonstrated by the
treatment of various allylic acetates with several carbon
nucleophiles in the presence of 10 mol % of the ligand 5a and 5
mol % of Pd in dichloromethane at room temperature. Aromatic
allylic acetates with electron withdrawing substituents such as F,
Cl and Br underwent allylic alkylation smoothly with very good
enantioselectivity (87-96% ee, Table 3, entries 1-5). Whereas
electron releasing groups in the aromatic ring such as -CH3, and -
OMe as well as napthyl-allylic acetates provided the
corresponding alkylated product with enantiomeric excess in the
range of 69-84% (Table 3, entries 6, 7 and 8). The above
discussed reactions were carried out using dimethyl malonate as a
nucleophile.
3. Conclusion
Table 3. Alkylation of racemic allylic acetates in the
optimized reaction conditions. Structural effects on the
enantioselectivity.a
In conclusion we developed a novel tetradentate bioxazoline
from tartaric acid and it was utilized successfully for AAA. Easy
synthesis of this ligand paves the way to optimize its structure to
increase its application in various mechanistically different
asymmetric transformations. We are confident that structural
optimization of tetradentate ligand 5a might lead to the
development of a novel privileged ligand for asymmetric
catalysis.
Entry
1
2
3
4
5
6
7
8
9
10
11
R1
4-FC6H4
Product
17b
17c
17d
17e
17f
17g
17h
17i
R2
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
COMe
CN
Yield [%]b
79
ee [%]
93
3-ClC6H4
4-ClC6H4
3-BrC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
2-Napthyl
4-ClC6H4
4-ClC6H4
4-ClC6H4
81
87
79
83
79
78
86
84
87
77
90
93
96
87
84
69
79
70
82
78
4. Experimental section
4.1 General Information
Tetrahydrofuran (THF) was distilled prior to use under argon
atmosphere over sodium benzophenone ketyl radical.
Triethylamine (Et3N) and diisopropylethylamine (DIPEA) were
distillated under normal pressure and stored over potassium
hydroxide. Dichloromethane (DCM) was stirred with calcium
hydride and distilled before use. Petroleum ether (PE) and ethyl
acetate (EA) were purified prior to use by distillation. The ligand
precursor (2S,3S)-1,4-bis(benzyloxy)butane-2,3-diamine (2),15
(2S,3S)-2,3-diaminobutane-1,4-diol (8),16 Bioxazoline ligands
(3)4a-4d and SALEN ligands (18 & 19)17 were prepared according
to the published procedures. All other chemicals were purchased
from Aldrich and used as received without further purification.
17j
17k
17l
a
Reaction conditions: 5a (10 mol%), [(η3-C3H5)PdCl]2 (5 mol%), 15 (0.2
mmol), 16 (0.6 mmol), BSA (0.6 mmol) in 1 mL of CH2Cl2 at 25 oC.
b Isolated yield.
Apart from the scope of various allylic acetates in asymmetric
alkylation we also found the reactivity and selectivity using
various carbon nucleophiles for AAA reaction under our
optimized reaction conditions. Since the reactivity of 4-ClC6H4
(15d) was very fast in the previous experiments we chose 15d as
allylic substrate for the evaluation of various carbon nucleophiles
such as diethyl malonate (16b), acetyl acetone (16c) and
malononitrile (16d) in AAA. Under the identical reaction
conditions treatment of 15d with diethyl malonate (16b) afforded
the corresponding alkylated product 17j in very good yield with
moderate enatioselectivity (70% ee, Table 3, entry 9). Allylic
alkylation using acetyl acetone (16c) or malononitrile (16d)
instead of using malonate ester was also found suitable
nucleophiles for our catalytic system yielded the corresponding
alkylated product (17k and 17l) in very good yields and with
good enantiomeric excess (78-82% ee, Table 3, entries 10 and
11).
1H, 13C NMR and DEPT-135 data were recorded with a
Bruker AVANCE AV500 (500 MHz and 125.7 MHz)
spectrometer with tetramethylsilane (TMS) as an internal
1
standard. All H NMR spectra were reported in delta (δ) units,
parts per million (ppm) downfield from the internal standard.
Coupling constants were reported in Hertz (Hz). High resolution
mass spectra (HRMS) were measured under the condition of
electro spray ionization (ESI) accurate masses were reported for
the molecular ion ([M]+ and [M+1]+). IR spectra were recorded
on PERKIN ELMER FT-IR instrument. Optical rotations were
measured on a RUDOLPH AUTOPOL II, Automatic Polari-
meter with a sodium lamp and are reported as follows: [α]λT °C (c
= g/100 mL, solvent). Column chromatography was carried out
using 230-400 mesh silica gel (Merck) in PE and EA. Thin layer
chromatography (TLC) was performed on commercially
available pre-coated aluminium-backed plates (0.25 mm silica
gel with fluorescent indicator UV254). Visualization was
accomplished with UV light and phosphomolybdic acid stain,
followed by heating.
Scheme 3. AAA of unsymmetrical allylic acetate

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5
4.2 Experimental procedure for the preparation of
tetradentate bioxazoline 5a and 5b:
135.6, 130.1 (d, J = 3.7 Hz), 128.4, 127.9 (d, J = 2.5 Hz), 124.3
(d, J = 3.7 Hz), 123.2, 123.1 (d, J = 11.3 Hz), 121.1, 118.9 (m),
73.5, 68.5, 50.9 ppm; FTIR (KBr): 3285, 3087, 2923, 1650,
1641, 1557, 1466, 1455, 1324, 1161, 1023, 919, 750 cm-1; ESI-
4.2.1. (4S,4'S)-2,2'-bis(2-(benzyloxy)phenyl)-4,4',5,5'-tetrahydro-
4,4'-bioxazole (10b). To a solution of benzyl alcohol (1.5 mL, 15
mmol) and NaH (638 mg (60%), 20 mmol) in 25 mL of dry THF
was added (4S,4'S)-2,2'-bis(2-fluorophenyl)-4,4',5,5'-tetrahydro-
4,4'-bioxazole (3a) (1.64 g, 5 mmol) at room temperature. The
resultant mixture was stirred at rt for 12h. After completion, the
reaction was quenched with water and it was extracted with
EtOAc and washed with water dried over Na2SO4 and
concentrated under reduced pressure to afford crude compound.
The purification of the crude compound by column
chromatography over silica gel using 1:1 EtOAc-hexane to yield
the pure title compound 10b (2.19 g, 87%) as a colorless solid;
MS (m/z): 725 (M+H)+; HRMS (ESI) calcd. for [C34H29N2O6F8]+
25
requires 681.2000, found 681.1991; [α]D
-45.80 (c 1.00,
CHCl3).
4.2.4. N,N'-((2S,3S)-1,4-dihydroxybutane-2,3-diyl)bis(2-fluoro-3-
(trifluoromethyl)benzamide) (12). To a solution of compound 11
(2.72 g, 4 mmol) in methanol (20 mL) were added 10% Pd/C (0.5
g) under H2 atmosphere. The reaction mixture was stirred for 12
hours at 25 °C. The catalyst was removed by filtration over
Celite, and the filtrate was concentrated under reduced pressure
to remove all volatile materials. The white solid residue was
purified by flash column chromatography using CH2Cl2 and
CH3OH to give 12 with the yield of 91% (1.82 g) as a colorless
solid; mp: 183-184 °C; Rf = 0.3 (CH2Cl2/CH3OH, 19:1); 1H NMR
(500 MHz, DMSO-d6): δ = 8.23 (d, J = 8.0 Hz, 2H, NH), 7.90 (q,
J = 6.5 Hz, 4H, ArH), 7.48 (t, J = 7.5 Hz, 2H, ArH), 4.83 (t, J =
6.0 Hz, 2H, OH), 4.36-4.30 (m, 2H, CH), 3.59-3.56 (m, 4H, CH2)
ppm; 13C NMR (125.7 MHz, DMSO-d6): δ = 163.3, 156.4 (d, J =
257.6 Hz), 135.1, 129.4 (d, J = 5.0 Hz ), 126.5 (m), 125.3 (d, J =
3.7 Hz), 124.0, 121.8, 119.6, 117.6 (m), 61.1, 52.4 ppm; FTIR
(KBr): 3281, 3084, 2930, 2888, 1642, 1546, 1465, 1317, 1239,
1154, 1136, 1081, 1019, 832 cm-1; ESI-MS (m/z): 725 (M+H)+;
HRMS (ESI) calcd. for [C20H17N2O4F8]+ requires 501.1061,
found 501.1047; [α]D 25 +3.60 (c 0.50, CHCl3 : CH3OH (1:1)).
1
mp: 125-127 °C; Rf = 0.4 (PE/EtOAc, 1:1); H NMR (500 MHz,
CDCl3): δ = 7.70 (dd, J = 7.5, 1.5 Hz, 2H, ArH), 7.47 (d, J = 7.5
Hz, 4H, ArH), 7.40-7.33 (m, 6H, ArH), 7.30-7.27 (m, 2H, ArH),
7.00-7.95 (m, 4H, ArH), 5.17 (s, 4H, CH2-Ph), 4.88 (dd, J = 7.5,
7.5 Hz, 2H, CH), 4.36-4.30 (m, 4H, CH2-OBn) ppm; 13C NMR
(125.7 MHz, CDCl3): δ = 164.5, 157.4, 136.8, 132.3, 131.2,
128.4, 127.7, 126.9, 120.7,117.8, 113.6, 70.6, 68.9, 68.3 ppm;
FTIR (KBr): 3364, 3067, 2932, 2884, 1736, 1644, 1531, 1452,
1300, 1229, 1103, 1049, 755 cm-1; ESI-MS (m/z): 505 (M+H)+;
HRMS (ESI) calcd. for [C32H29N2O4]+ requires 505.2127, found
505.2132; [α]D 25 -36.60 (c 1.00, CHCl3).
4.2.2.
2,2'-((4S,4'S)-4,4',5,5'-tetrahydro-4,4'-bioxazole-2,2'-
diyl)diphenol (5a). To a solution of compound 10b (1.51 g, 3
mmol) in methanol (20 mL) were added 10% Pd/C (0.7 g) under
H2 atmosphere. The reaction mixture was stirred for 8 hours at 25
°C. The catalyst was removed by filtration over Celite, and the
filtrate was concentrated under reduced pressure to remove all
volatile materials. The white solid residue was purified by flash
column chromatography using EtOAc and hexanes to give 5a
with the yield of 88% (855 mg) as a colorless solid; mp: 155 °C;
Rf = 0.5 (PE/EtOAc, 4:1); 1H NMR (500 MHz, CDCl3): δ = 11.74
(s, 2H, OH), 7.64 (dd, J = 7.9, 1.7 Hz, 2H, ArH), 7.35 (dt, J =
7.3, 1.7 Hz, 2H, ArH), 6.95 (dd, J = 8.3, 1.1 Hz 2H, ArH), 6.85
(dt, J = 7.6, 1.1 Hz, 2H, ArH), 4.81-4.76 (m, 2H, CH), 4.47-4.43
(m, 2H, CH2), 4.39-4.35 (m, 2H, CH2) ppm; 13C NMR (125.7
MHz, CDCl3): δ = 167.1, 159.8, 133.7, 128.3, 118.7, 116.7,
110.0, 68.2, 67.5 ppm; FTIR (Neat): 3020, 2950, 2930, 2868,
1650, 1541, 1390, 1264, 1210, 1099, 1030, 851, 697 cm-1; ESI-
4.2.5.
(4S,4'S)-2,2'-bis(2-fluoro-3-(trifluoromethyl)phenyl)-
4,4',5,5'-tetrahydro-4,4'-bioxazole (13). To a solution of 12 (1.5
g, 3 mmol) in 20 mL of dry THF was added dry Et3N (2.8 mL, 20
mmol) and MsCl (0.7 mL, 9 mmol) at 0 oC. After stirring at room
temperature for 2 days, the volatiles were removed under vacuum
to give a yellow solid. The residue was then extracted with DCM
and washed with brine and it was dried over anhydrous Na2SO4,
filtered and concentrated in vacuo. Crude product was purified by
column chromatography (1:1 hexane and EtOAc) yielded title
compound in 88% (1.2 g) yield as a colorless solid, mp: 80-81
1
°C; Rf = 0.4 (PE/EtOAc, 1:1); H NMR (500 MHz, CDCl3): δ =
8.03 (dt, J = 7.3, 1.1 Hz, 2H, ArH), 7.72 (dt, J = 7.3, 1.1 Hz, 2H,
ArH), 7.28 (t, J = 7.2 Hz, 2H, ArH), 4.86-4.82 (m, 2H, CH),
4.53-4.47 (m, 4H, CH2) ppm; 13C NMR (125.7 MHz, CDCl3): δ =
161.2 (d, J = 3.7 Hz), 158.3 (d, J = 267.7 Hz), 134.8, 129.9 (t, J =
5.0 Hz), 125.4, 123.7 (d, J = 2.5 Hz), 123.2, 121.1, 119.7 (d, J =
12.57 Hz), 119.4 (m), 117.4 (d, J = 11.3 Hz), 69.1, 69.0 ppm;
FTIR (KBr): 2902, 1638, 1612, 1462, 1375, 1314, 1210, 1144,
1079, 971, 748 cm-1; ESI-MS (m/z): 725 (M+H)+; HRMS (ESI)
calcd. for [C20H13N2O2F8]+ requires 465.0849, found 465.0865;
[α]D 25 -38.00 (c 0.50, CHCl3).
MS (m/z): 725 (M+H)+; HRMS (ESI) calcd. for [C18H17N2O4]+
25
requires 325.1188, found 325.1179; [α]D
+40.58 (c 1.00,
CH2Cl2).
4.2.3.
N,N'-((2S,3S)-1,4-bis(benzyloxy)butane-2,3-diyl)bis(2-
fluoro-3-(trifluoromethyl)benzamide) (11). To a stirred solution
of diamine 2 (1.5 g, 5 mmol) and Et3N (1.71 mL, 10 mmol) in
anhydrous CH2Cl2 (50 mL) was added 2-fluoro-3- 4.2.6.(4S,4'S)-2,2'-bis(2-(benzyloxy)-3-(trifluoromethyl)phenyl)-
(trifluoromethyl)benzoyl chloride (2.265 g, 10 mmol) at 0 °C 4,4',5,5'-tetrahydro-4,4'-bioxazole (14). Prepared according to the
under argon atmosphere. The solution was further stirred for 6 h procedure outlined for 10b by using 13 (928 mg, 2 mmol), benzyl
at room temperature. Completion of the reaction was ascertained alcohol (0.62 mL, 6 mmol) and NaH (255 mg (60%), 8 mmol) in
by TLC and quenched by addition of water and diluted with 20 mL of dry THF yielded the title compound 14 as a colorless
CH2Cl2. The organic phase was washed successively with 2% solid (1.08 g, 85%), mp: 102-103 °C; Rf = 0.6 (PE/EtOAc, 1:1); 1H
aqueous HCl solution, saturated NaHCO3, and brine solution and NMR (500 MHz, CDCl3): δ = 7.90 (dd, J = 8.0, 1.5 Hz, 2H, ArH),
dried over anhydrous Na2SO4. After evaporation of the solvent, 7.69 (dd, J = 8.0, 1.5 Hz, 2H, ArH), 7.45-7.43 (m, 4H, ArH), 7.37-
the residue was purified by column chromatography (20% EtOAc 7.30 (m, 6H, ArH), 7.12 (t, J = 8.0 Hz, 2H, ArH), 5.01-4.89 (m,
in hexanes on silica gel) yielded title compound 11 with 97% (3.3 4H, CH2), 4.68-4.64 (m, 2H, CH), 4.50-4.47 (m, 2H, CH2), 4.39-
g) as a colorless solid; mp: 147-148 °C; Rf = 0.4 (PE/EtOAc, 4.35 (m, 2H, CH2) ppm; 13C NMR (125.7 MHz, CDCl3): δ =
1
4:1); H NMR (500 MHz, CDCl3): δ = 8.09 (t, J = 8.0 Hz, 2H, 136.6, 135.3, 130.0 (q, J = 5.0 Hz), 128.3, 128.0, 127.9, 125.7,
ArH), 7.70 (t, J = 8.0 Hz, 2H, ArH), 7.44 (t, J = 8.0 Hz, 2H, 125.4, 124.3, 123.5, 123.4, 122.1, 69.3, 69.0 ppm; FTIR (KBr):
ArH), 7.34-7.26 (m, 12H, ArH and NH), 4.73-4.72 (m, 2H, CH), 3060, 3029, 2950, 2920, 2858, 1392, 1264, 1210, 1099, 1040, 859,
4.50 (s, 4H, CH2-Ph), 3.70-3.62 (m, 4H, CH2) ppm; 13C NMR 697 cm-1; ESI-MS (m/z): 505 (M+H)+; HRMS (ESI) calcd. for
(125.7 MHz, CDCl3): δ = 162.2, 156.5 (d, J = 258.9 Hz), 137.2,

ACCEPTED MANUSCRIPT
6
Tetrahedron
25
[C34H27N2O4F6]+ requires 641.1875, found 641.1878; [α]D
-
127.5, 127.1, 126.3, 57.6, 52.6, 52.4, 49.2 ppm; FTIR (KBr):
68.40 (c 0.50, CHCl3).
3654, 3473, 3028, 2952, 1953, 1739, 1599, 1494, 1452, 1435,
1027, 967, 766, 699 cm-1.
4.2.7.
6,6'-((4S,4'S)-4,4',5,5'-tetrahydro-4,4'-bioxazole-2,2'-
diyl)bis(2-(trifluoromethyl)phenol) (5b). Prepared according to
the procedure outlined for 5a by using 14 (960 mg, 1.5 mmol) in
methanol (15 mL) were added 10% Pd/C (400 mg) under H2
atmosphere yielded the title compound 5b as a colorless solid
(634 mg, 92%); mp: 178 °C; Rf = 0.3 (PE/EtOAc, 4:1); 1H NMR
(500 MHz, CDCl3): δ = 12.57 (s, 2H, OH), 7.81 (dd, J = 7.8, 1.4
Hz, 2H, ArH), 7.62 (dt, J = 7.6, 1.0 Hz, 2H, ArH), 6.90 (t, J = 7.7
Hz, 2H, ArH), 4.78-4.74 (m, 2H, CH), 4.55-4.47 (m, 4H, CH2)
ppm; 13C NMR (125.7 MHz, CDCl3): δ = 166.8, 157.9, 132.1,
131.0 (q, J = 5.0 Hz), 124.4, 122.3, 118.0, 111.2, 68.7, 67.5 ppm;
FTIR (KBr): 3029, 2966, 2931, 2858, 1643, 1541, 1392, 1264,
1210, 1099, 1030, 851, 697 cm-1; ESI-MS (m/z): 725 (M+H)+;
HRMS (ESI) calcd. for [C20H15N2O6F6]+ requires 461.0936,
found 461.0925; [α]D 25 +49.20 (c 1.00, CHCl3).
4.3.3. (E)-dimethyl 2-(1,3-bis(4-fluorophenyl)allyl)malonate.
(17b). Prepared according to the general procedure using (E)-1,3-
bis(4-fluorophenyl)-2-propen-1-yl acetate (57 mg, 0.198 mmol)
and dimethyl malonate (0.07 mL, 0.594 mmol), while the
reaction time was 4 days. The desired product was obtained as
colorless oil (56 mg, 79% yield); The ee was determined by
HPLC
with
a
Chiralpak
AD-H
column
(90:10
hexanes:isopropanol, 0.8 mL/min, 254 nm); major enantiomer tr
1
= 11.6 min, minor enantiomer tr = 18.0 min; 93% ee; H NMR
(500 MHz): δ 7.29-7.23 (m, 4H, ArH), 7.03-6.94 (m, 4H, ArH),
6.41 (d, J = 15.6 Hz, 1H, ═CH), 6.21 (dd, J = 15.5, 8.5 Hz, 1H,
═CH), 4.26-4.22 (m, 1H, CH), 3.88 (d, J = 11.0 Hz, 1H, CH)
3.70 (s, 3H, CH3), 3.53 (s, 3H, CH3) ppm; 13C NMR (125.7 MHz,
CDCl3): δ 168.0, 167.3, 163.0 (d, J = 64.1 Hz), 161.1 (d, J = 64.1
Hz), 135.8 (d, J = 3.7 Hz), 132.8 (d, J = 3.7 Hz), 130.8, 129.4 (d,
J = 8.7 Hz), 128.5, 127.8 (d, J = 7.5 Hz), 115.6 (d, J = 21.3 Hz),
115.4 (d, J = 21.3 Hz), 57.6, 52.6, 52.5, 48.2 ppm; FTIR (KBr):
3643, 3005, 2956, 1746, 1755, 1601, 1509, 1436, 1338, 1159,
1025, 971, 847 cm-1; ESI-MS (m/z): 383 (M+Na)+; HRMS (ESI)
calcd. for [C20H18O4F2Na]+ requires 383.1071, found 383.1074.
4.2.8.
(4S,4'S)-2,2'-bis(2-methoxyphenyl)-4,4',5,5'-tetrahydro-
4,4'-bioxazole. (10a). To a stirred solution of 3a (656 mg, 2
mmol) in 10 mL of dry THF was added sodium methoxide (162
mg, 3 mmol) at room temperature. The resultant mixture was
stirred at rt for 8h. After completion, the reaction was quenched
with water and it was extracted with EtOAc and washed with
water dried over Na2SO4 and concentrated under reduced
pressure to afford crude compound. The purification of the crude
compound by column chromatography over silica gel using 1:1
EtOAc-hexane to yield the pure title compound 10a (598 mg,
85%) as a colorless solid; mp: 156 °C; Rf = 0.2 (PE/EtOAc, 1:1);
1H NMR (500 MHz, CDCl3): δ = 7.69 (dd, J = 8.0, 2.0 Hz, 2H,
ArH), 7.62 (dt, J = 2.0, 8.0 Hz, 2H, ArH), 6.96 (t, J = 8.0 Hz 2H,
ArH), 4.90-4.85 (m, 2H, CH), 4.42-4.33 (m, 4H, CH2), 3.83 (s,
6H, OCH3) ppm; 13C NMR (125.7 MHz, CDCl3): δ = 164.3,
158.4, 132.4, 131.2, 120.2, 117.1, 111.6, 69.1, 68.3, 55.9, 29.7
ppm; FTIR (KBr): 2978, 2864, 1650, 1570, 1392, 1265, 1217,
1099, 1030, 858 cm-1; [α]D 25 -57.32 (c 1.00, CH2Cl2).
4.3.4. (E)-dimethyl 2-(1,3-bis(3-chlorophenyl)allyl)malonate.
(17c). Prepared according to the general procedure using (E)-1,3-
bis(3-chlorophenyl)-2-propen-1-yl acetate (63 mg, 0.198 mmol)
and dimethyl malonate (0.07 mL, 0.594 mmol), while the
reaction time was 4 days. The desired product was obtained as
colorless oil (63 mg, 81% yield); The ee was determined by
HPLC
with
a
Chiralpak
AD-H
column
(90:10
hexanes:isopropanol, 0.8 mL/min, 254 nm); major enantiomer tr
= 7.4 min, minor enantiomer tr = 9.5 min; 90% ee; 1H NMR (500
MHz): δ 7.33-7.29 (m, 2H, ArH), 7.28-7.27 (m, 1H, ArH), 7.25-
7.18 (m, 5H, ArH), 6.44 (d, J = 15.5 Hz, 1H, ═CH), 6.32 (dd, J =
15.5, 9.0 Hz, 1H, ═CH), 4.26 (dd, J = 11.0, 9.0 Hz, 1H, CH),
3.94 (d, J = 10.5 Hz, 1H, CH), 3.73 (s, 3H, CH3), 3.58 (s, 3H,
CH3) ppm; 13C NMR (500 MHz, CDCl3): δ 167.9, 167.5, 141.9,
138.4, 134.6, 134.5, 131.2, 130.1, 129.8, 128.1, 127.7, 126.3,
126.1, 124.7, 57.2, 52.8, 52.6, 48.7 ppm; FTIR (KBr): 3668,
3470, 2950, 2920, 1917, 1739, 1596, 1489, 1452, 1435, 1027,
955, 766 cm-1.
4.3 The catalytic asymmetric allylic alkylation reaction:
4.3.1. General procedure. To a stirring solution of [Pd(η3-
C3H5)Cl]2 (1.8 mg, 0.005 mmol) in CH2Cl2 was added ligand 5a
(6.4 mg, 0.02 mmol) under inert atmosphere. After 2 hours, rac-
(E)-1,3-diphenyl-2-propen-1-yl acetate (15a) (50 mg, 0.198
mmol) was added and the solution was stirred for 30 min. N,O-
Bis( trimethylsilyl)acetamide (0.145 ml, 0.594 mmol), dimethyl
malonate (0.09 ml, 0.594 mmol) and AgOAc (0.007 mmol) were
then added at 25 °C and solution was stirred further till the
reaction is completed. The solvent was evaporated in vacuo and
column chromatography on silica gel (hexane–EtOAc 4 : 1) of
the residue yielded the pure product 17a of 70%.
4.3.5. (E)-dimethyl 2-(1,3-bis(4-chlorophenyl)allyl)malonate.
(17d). Prepared according to the general procedure using (E)-1,3-
bis(4-chlorophenyl)-2-propen-1-yl acetate (63 mg, 0.198 mmol)
and dimethyl malonate (0.07 mL, 0.594 mmol), while the
reaction time was 4 days. The desired product was obtained as
colorless oil (67 mg, 87% yield); The ee was determined by
HPLC
with
a
Chiralpak
AD-H
column
(90:10
hexanes:isopropanol, 0.8 mL/min, 254 nm); major enantiomer tr
= 15.6 min, minor enantiomer tr = 24.6 min; 93% ee; 1H NMR
(500 MHz): δ 7.30-7.27 (m, 2H, ArH), 7.25-7.20 (m, 6H, ArH),
6.39 (d, J = 16.0 Hz, 1H, ═CH), 6.25 (dd, J = 16.0, 9.0 Hz, 1H,
═CH), 4.23 (dd, J = 11.0, 9.0 Hz, 1H, CH), 3.89 (d, J = 10.5 Hz,
1H, CH), 3.70 (s, 3H, CH3), 3.54 (s, 3H, CH3) ppm; 13C NMR
(500 MHz, CDCl3): δ 167.9, 167.5, 138.5, 135.0, 133.4, 133.1,
131.0, 129.3, 129.2, 128.9, 128.7, 127.6, 57.3, 52.7, 52.6, 48.4
ppm; FTIR (KBr): 3665, 3462, 2953, 1899, 1754, 1594, 1488,
1159, 1013, 827 cm-1.
4.3.2. (E)-dimethyl 2-(1,3-diphenylallyl)malonate. (17a).
Prepared according to the general procedure using (E)-1,3-
diphenyl-2-propen-1-yl acetate (50 mg, 0.198 mmol) and
dimethyl malonate (0.07 mL, 0.594 mmol), while the reaction
time was 4 days. The desired product was obtained as colorless
oil (44 mg, 70% yield); The ee was determined by HPLC with a
Chiralpak AD-H column (90:10 hexanes:isopropanol, 0.8
mL/min, 254 nm); major enantiomer tr = 17.1 min, minor
enantiomer tr = 22.7 min; 92% ee. Configuration assignment:
The absolute stereochemistry was assigned as (R) by comparison
1
of the retention times in HPLC reported in the literature13f, 18 ; H
4.3.6. (E)-dimethyl 2-(1,3-bis(3-bromophenyl)allyl)malonate.
(17e). Prepared according to the general procedure using (E)-1,3-
bis(3-bromophenyl)-2-propen-1-yl acetate (81 mg, 0.198 mmol)
and dimethyl malonate (0.07 mL, 0.594 mmol), while the
reaction time was 4 days. The desired product was obtained as
colorless oil (75 mg, 79% yield); The ee was determined by
NMR (500 MHz): δ 7.35-7.21 (m, 10H, ArH), 6.50 (d, J = 15.7
Hz, 1H, ═CH), 6.35 (dd, J = 15.7, 8.1 Hz, 1H, ═CH), 4.29 (dd, J
= 10.7, 8.5 Hz, 1H, CH), 3.98 (d, J = 10.8 Hz, 1H, CH), 3.73 (s,
3H, CH3), 3.54 (s, 3H, CH3) ppm; 13C NMR (500 MHz, CDCl3):
δ 168.2, 167.7, 140.1, 136.8, 131.8, 129.1, 128.7, 128.4, 127.8,

ACCEPTED MANUSCRIPT
7
HPLC
with
a
Chiralpak
AD-H
column
(90:10
HRMS (ESI) calcd. for [C22H24O6Na]+ requires 407.1471, found
407.1466.
hexanes:isopropanol, 0.8 mL/min, 254 nm); major enantiomer tr
= 7.4 min, minor enantiomer tr = 9.5 min; 96% ee; 1H NMR (500
MHz): δ 7.49-7.45 (m, 2H, ArH), 7.41-7.35 (m, 2H, ArH), 7.25-
7.20 (m, 3H, ArH), 7.18-7.15 (m, 1H, ArH), 6.42 (d, J = 16.0 Hz,
1H, ═CH), 6.31 (dd, J = 15.5, 8.5 Hz, 1H, ═CH), 4.24 (dd, J =
10.5, 8.5 Hz, 1H, CH), 3.93 (d, J = 10.5 Hz, 1H, CH), 3.74 (s,
3H, CH3), 3.59 (s, 3H, CH3) ppm; 13C NMR (500 MHz, CDCl3):
δ 167.8, 167.4, 142.2, 138.7, 131.1, 131.0, 130.7, 130.5, 130.4,
130.1, 129.9, 129.2, 126.5, 125.2, 122.8, 122.7, 57.2, 52.8, 52.6,
48.6 ppm; FTIR (KBr): 3486, 3455, 3028, 2956, 1953, 1759,
1610, 1434, 1072, 967, 826, 766 cm-1.
4.3.10. (E)-dimethyl 2-(1,3-di(naphthalen-2-yl)allyl)malonate.
(17i). Prepared according to the general procedure using (E)-1,3-
bis(naphthalene-2-yl)-2-propen-1-yl acetate (69 mg, 0.198 mmol)
and dimethyl malonate (0.07 mL, 0.594 mmol), while the
reaction time was 4 days. The desired product was obtained as
colorless oil (72 mg, 86% yield); Enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (90:10
hexanes:isopropanol, 0.8 mL/min, 254 nm); major enantiomer tr
1
= 20.5 min, minor enantiomer tr = 27.4 min; 79% ee; H NMR
(500 MHz): δ 7.86-7.75 (m, 7H, ArH), 7.70 (S, 1H, ArH), 7.57-
7.55 (m, 1H, ArH), 7.52-7.43 (m, 5H, ArH), 6.71 (d, J = 15.5 Hz,
1H, ═CH), 6.57 (dd, J = 15.5, 8.5 Hz, 1H, ═CH), 4.56-4.52 (m,
1H, CH), 4.16 (d, J = 10.5 Hz, 1H, CH), 3.76 (s, 3H, CH3), 3.52
(s, 3H, CH3) ppm; 13C NMR (125.7 MHz, CDCl3): δ 168.2,
167.8, 137.6, 134.2, 133.6, 133.5, 132.9, 132.6, 132.2, 129.3,
128.5, 128.1, 127.9, 127.8, 127.7, 127.6, 126.5, 126.3, 126.2,
126.1, 126.1, 125.8, 123.5, 57.6, 53.4, 52.6, 49.3 ppm; FTIR
(KBr): 3454, 3049, 2951, 1743, 1723, 1432, 1317, 1261, 1157,
1025, 979, 970, 820, 749 cm-1.
4.3.7. (E)-dimethyl 2-(1,3-bis(4-bromophenyl)allyl)malonate.
(17f). Prepared according to the general procedure using (E)-1,3-
bis(3-bromophenyl)-2-propen-1-yl acetate (81 mg, 0.198 mmol)
and dimethyl malonate (0.07 mL, 0.594 mmol), while the
reaction time was 4 days. The desired product was obtained as
colorless oil (79 mg, 83% yield); The ee was determined by
HPLC
with
a
Chiralpak
AD-H
column
(90:10
hexanes:isopropanol, 0.8 mL/min, 254 nm); major enantiomer tr
1
= 16.4 min, minor enantiomer tr = 24.4 min; 87% ee; H NMR
(500 MHz): δ 7.48-7.45 (m, 2H, ArH), 7.43-7.40 (m, 2H, ArH),
7.20-7.17 (m, 4H, ArH), 6.41 (d, J = 15.5 Hz, 1H, ═CH), 6.29
(dd, J = 16.0, 8.5 Hz, 1H, ═CH), 4.24 (dd, J = 11.0, 8.5 Hz, 1H,
CH), 3.91 (d, J = 10.5 Hz, 1H, CH), 3.72 (s, 3H, CH3), 3.57 (s,
3H, CH3) ppm; 13C NMR (500 MHz, CDCl3): δ 167.9, 167.5,
138.9, 135.5, 131.9, 131.6, 131.1, 129.6, 129.2, 127.9, 121.5,
121.2, 57.2, 52.7, 52.6, 48.4 ppm; FTIR (KBr): 3462, 3026,
2952, 1738, 1487, 1434, 1312, 1254, 1160, 1072, 968, 824 cm-1.
4.3.11. (E)-diethyl 2-(1,3-bis(4-chlorophenyl)allyl)malonate.
(17j). Prepared according to the general procedure using (E)-1,3-
bis(4-chlorophenyl)-2-propen-1-yl acetate (63 mg, 0.198 mmol)
and diethyl malonate (0.09 mL, 0.594 mmol), while the reaction
time was 4 days. The desired product was obtained as colorless
oil (70 mg, 84% yield); The ee was determined by HPLC with a
Chiralpak AD-H column (90:10 hexanes:isopropanol, 0.8
mL/min, 254 nm); major enantiomer tr = 14.3 min, minor
enantiomer tr = 22.8 min; 70% ee; 1H NMR (500 MHz): δ 7.30-
7.21 (m, 8H, ArH), 6.40 (dd, J = 15.7, 0.4 Hz, 1H, ═CH), 6.28
(dd, J = 15.75, 8.5 Hz, 1H, ═CH), 4.25-4.15 (m, 3H, CH2 and
CH), 4.00 (m, 2H, CH2), 3.86 (d, J = 10.7 Hz, 1H, CH), 1.2 (t, J
= 7.1 Hz 3H, CH3), 1.05 (t, J = 7.1 Hz 3H, CH3) ppm; 13C NMR
(125.7 MHz, CDCl3): δ 167.5, 167.1, 138.7, 135.1, 133.3, 133.0,
130.9, 129.5, 129.4, 128.8, 128.7, 127.5, 61.7, 61.5, 57.5, 48.4,
14.1, 13.8 ppm; FTIR (KBr): 3462, 2982, 1751, 1733, 1491,
1369, 1305, 1253, 1174, 1093, 1032, 969, 829 cm-1.
4.3.8.
(E)-dimethyl 2-(1,3-dip-tolylallyl)malonate.
(17g).
Prepared according to the general procedure using (E)-1,3-bis(4-
methylphenyl)-2-propen-1-yl acetate (55 mg, 0.198 mmol) and
dimethyl malonate (0.07 mL, 0.594 mmol), while the reaction
time was 4 days. The desired product was obtained as colorless
oil (55 mg, 79% yield); The ee was determined by HPLC with a
Chiralpak AD-H column (90:10 hexanes:isopropanol, 0.8
mL/min, 254 nm); major enantiomer tr = 24.6 min, minor
1
enantiomer tr = 35.1 min; 84% ee; H NMR (500 MHz): δ 7.23-
7.18 (m, 4H, ArH), 7.14-7.08 (m, 4H, ArH), 6.50 (d, J = 15.5 Hz,
1H, ═CH), 6.27 (dd, J = 16.0, 8.5 Hz, 1H, ═CH), 4.23 (dd, J =
11.0, 8.5 Hz, 1H, CH), 3.94 (d, J = 11.0 Hz, 1H, CH), 3.71 (s,
3H, CH3), 3.55 (s, 3H, CH3), 2.33 (s, 6H, CH3) ppm; 13C NMR
(500 MHz, CDCl3): δ 168.3, 167.8, 137.3, 137.2, 136.6, 134.1,
131.4, 129.3, 129.1, 128.2, 127.7, 126.2, 57.7, 52.5, 52.4, 48.8,
21.1, 21.0 ppm; FTIR (KBr): 3463, 3024, 2952, 1759, 1513,
1434, 1312, 1256, 1159, 1021, 968, 818, 781 cm-1.
4.3.12.
(E)-3-(1,3-bis(4-chlorophenyl)allyl)pentane-2,4-dione.
(17k). Prepared according to the general procedure using (E)-1,3-
bis(4-chlorophenyl)-2-propen-1-yl acetate (63 mg, 0.198 mmol)
and acetyl acetone (0.06 mL, 0.594 mmol), while the reaction
time was 4 days. The desired product was obtained as colorless
oil (62 mg, 87% yield); The ee was determined by HPLC with a
Chiralpak AD-H column (90:10 hexanes:isopropanol, 0.8
mL/min, 254 nm); major enantiomer tr = 32.0 min, minor
enantiomer tr = 22.5 min; 82% ee; 1H NMR (500 MHz): δ 7.31-
7.28 (m, 2H, ArH), 7.25-7.22 (m, 2H, ArH), 7.20-7.16 (m, 4H,
ArH), 6.35 (d, J = 16.0 Hz, 1H, ═CH), 6.11 (dd, J = 16.0, 8.2 Hz,
1H, ═CH), 4.34-4.26 (m, 2H, 2CH), 2.23 (s, 3H, CH3), 1.94 (s,
3H, CH3) ppm; 13C NMR (500 MHz, CDCl3): δ 202.3, 202.1,
138.4, 134.8, 133.6, 133.2, 130.9, 129.3, 129.3, 129.2, 128.7,
127.6, 74.4, 48.2, 29.9, 29.6 ppm; FTIR (KBr): 3402, 2978,
2320, 2138, 1641, 1465, 1381, 1301, 1161, 1128, 950, 815 cm-1.
4.3.9. (E)-dimethyl 2-(1,3-bis(4-methoxyphenyl)allyl)malonate.
(17h). Prepared according to the general procedure using (E)-1,3-
bis(4-methoxylphenyl)-2-propen-1-yl acetate (61 mg, 0.198
mmol) and dimethyl malonate (0.07 mL, 0.594 mmol), while the
reaction time was 4 days. The desired product was obtained as
colorless oil (59 mg, 78% yield); The ee was determined by
HPLC
with
a
Chiralpak
AD-H
column
(90:10
hexanes:isopropanol, 0.8 mL/min, 254 nm); major enantiomer tr
1
= 19.9 min, minor enantiomer tr = 32.5 min; 69% ee; H NMR
4.3.13. (E)-2-(1,3-bis(4-chlorophenyl)allyl)malononitrile. (17l).
Prepared according to the general procedure using (E)-1,3-bis(4-
chlorophenyl)-2-propen-1-yl acetate (63 mg, 0.198 mmol) and
malononitrile (0.04 mL, 0.594 mmol), while the reaction time
was 4 days. The desired product was obtained as colorless oil (49
mg, 77% yield); The ee was determined by HPLC with a
Chiralpak AD-H column (90:10 hexanes:isopropanol, 0.8
mL/min, 254 nm); major enantiomer tr = 15.2 min, minor
enantiomer tr = 16.3 min; 78% ee; 1H NMR (500 MHz): δ 7.44-
7.41 (m, 2H, ArH), 7.35-7.30 (m, 6H, ArH), 6.65 (d, J = 15.8 Hz,
(500 MHz): δ 7.24-7.19 (m, 4H, ArH), 6.85-6.78 (m, 4H, ArH),
6.38 (d, J = 15.5 Hz, 1H, ═CH), 6.16 (dd, J = 15.5, 8.5 Hz, 1H,
═CH), 4.19 (dd, J = 10.5, 8.5 Hz, 1H, CH), 3.88 (d, J = 11.0 Hz,
1H, CH), 3.78 (s, 3H, CH3), 3.77 (s, 3H, CH3), 3.69 (s, 3H, CH3),
3.52 (s, 3H, CH3) ppm; 13C NMR (500 MHz, CDCl3): δ 168.3,
167.9, 159.1, 158.5, 132.4, 130.9, 129.7, 128.8, 127.5, 127.1,
114.0, 113.8, 57.9, 55.3, 55.2, 52.5, 52.4, 48.4 ppm; FTIR (KBr):
3491, 2954, 2837, 1755, 1738, 1608, 1512, 1463, 1302, 1250,
1176, 1033, 968, 832, 813 cm-1; ESI-MS (m/z): 407 (M+Na)+;

ACCEPTED MANUSCRIPT
8
Tetrahedron
Lett 2006, 8, 3097-3100; (g) Pellissier, H. Tetrahedron 2008, 64,
1H, ═CH), 6.39 (dd, J = 15.8, 7.5 Hz, 1H, ═CH), 4.11-4.07 (m,
2H, 2CH) ppm; 13C NMR (125.7 MHz, CDCl3): δ 135.2, 135.0,
134.7, 134.6, 133.7, 130.0, 129.1, 129.0, 128.0, 123.9, 111.4,
111.3, 49.1, 30.1 ppm; FTIR (KBr): 3443, 2907, 2256, 1902,
1728, 1594, 1492, 1413, 1249, 1093, 1014, 969, 826 cm-1; ESI-
MS (m/z): 349 (M+Na)+; HRMS (ESI) calcd. for
[C18H12Cl2N2Na]+ requires 349.0276, found 349.0274.
10279-10317; (h) Teller, H.; Fluegge, S.; Goddard, R.; Fuerstner,
A. Angew. Chem., Int. Ed. 2010, 49, 1949-1953; (i) Hong, K.;
Morken, J. P. J. Org. Chem. 2011, 76, 9102-9108; (j) Drusan, M.;
Loelsberg, W.; Skvorcova, A.; Schmalz, H.-G.; Sebesta, R. Eur. J.
Org. Chem. 2012, 2012, 6285-6290; (k) McInturff, E. L.;
Yamaguchi, E.; Krische, M. J. J. Am. Chem. Soc. 2012, 134,
20628-20631; (l) Naeemi, Q.; Dindaroglu, M.; Kranz, D. P.;
Velder, J.; Schmalz, H.-G. Eur. J. Org. Chem. 2012, 2012, 1179-
1185; (m) Teller, H.; Corbet, M.; Mantilli, L.; Gopakumar, G.;
Goddard, R.; Thiel, W.; Fuerstner, A. J. Am. Chem. Soc. 2012,
134, 15331-15342.
4.3.14. (E)-dimethyl 2-(4-phenylbut-3-en-2-yl)malonate. (21).
Prepared according to the general procedure using (E)-4-
phenylbut-3-en-2-yl acetate (37 mg, 0.198 mmol) and dimethyl
malonote (0.09 mL, 0.594 mmol), while the reaction time was 4
days. The desired product was obtained as colorless oil (45 mg,
88% yield); The ee was determined by HPLC with a Chiralcel
OD-H column (90:10 hexanes:isopropanol, 0.8 mL/min, 254
nm); major enantiomer tr = 23.0 min, minor enantiomer tr = 20.8
5. (a) Johnson, J. S.; Evans, D. A. Acc. Chem. Res 2000, 33, 325-
335; (b) Rhyoo, H. Y.; Yoon, Y.-A.; Park, H.-J.; Chung, Y. K.
Tetrahedron: Lett 2001, 42, 5045-5048; (c) Desimoni, G.; Faita,
G.; Quadrelli, P. Chem. Rev 2003, 103, 3119-3154; (d) Desimoni,
G.; Faita, G.; Jørgensen, K. A. Chem. Rev 2006, 106, 3561-3651;
(e) Hargaden, G. i. C.; Guiry, P. J. Chem. Rev 2009, 109, 2505-
2550; (f) Ahlford, K.; Adolfsson, H. Catal. Communs 2011, 12,
1118-1121; (g) Dungan, V. J.; Wong, S. M.; Barry, S. M.;
Rutledge, P. J. Tetrahedron 2012, 68, 3231-3236.
1
min; 76% ee; H NMR (500 MHz): δ 7.34-7.19 (m, 5H, ArH),
6.45 (d, J = 15.5, 1H, ═CH), 6.12 (dd, J = 16.0, 8.5 Hz, 1H,
═CH), 3.75 (s, 3H, CH3), 3.67 (s, 3H, CH3), 3.40 (d, J = 9.0, 1H,
CH), 3.16-3.09 (m, 1H, CH), 1.19 (d, J = 6.5, 3H, CH3) ppm;
FTIR (KBr): 3463, 2954, 1754, 1738, 1435, 1246, 1158, 1022,
968, 748, 694 cm-1.
6. (a) Balaraman, K.; Vasanthan, R.; Kesavan, V. Synthesis 2012, 44,
2455-2462; (b) Balaraman, K.; Vasanthan, R.; Kesavan, V.
Tetrahedron:
Lett
2013,
http://dx.doi.org/10.1016/j.tetlet.2013.04.108; (c) Balaraman, K.;
Kesavan, V. Unpublished results.
7. (a) Lee, S.-g.; Lim, C. W.; Song, C. E.; Kim, K. M.; Jun, C. H. J.
Org. Chem 1999, 64, 4445-4451; (b) Lee, S.-g.; Jung, H. R.; Kim,
K. M.; Song, C. E.; Cho, C. E. Bull. Korean Chem. Soc 2003, 24,
1407-1409
Acknowledgments
This work was supported by the Department of Science &
Technology, Government of India, New Delhi (Grant No.
SR/S1/OC-60/2006). We thank sophisticated analytical
instruments facility (SAIF) and Department of Chemistry, IIT
Madras for the analytical data. KB thanks the University Grants
Commission, New Delhi for the research fellowship.
8. (a) Trost, B. M.; Van Vranken, D. L. Angew. Chem., Int. Ed 1992,
31, 228-230; (b) von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed
1993, 32, 566-568; (c) Sprinz, J.; Helmchen, G. Tetrahedron: Lett
1993, 34, 1769-1772; (d) Dawson, G. J.; Frost, C. G.; Williams, J.
M. J.; Coote, S. J. Tetrahedron: Lett 1993, 34, 3149-3150; (e)
Brown, J. M.; Hulmes, D. I.; Guiry, P. J. Tetrahedron 1994, 50,
4493-4506; (f) Trost, B. M.; Van Vranken, D. L. Chem. Rev 1996,
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4479-4483.
Supplementary data
Supplementary data related to this article can be found at
http://dx.doi.org.
9. Crystallographic data for the structure reported in this paper have
been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC 825879. Copies of the
data can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: +44-(0)1223-
336033; e-mail: deposit@ccdc.cam.ac.uk).
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(d) Clarke, E. F.; McGarrigle, E. M.; Gilheany, D. G. ARKIVOC
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Supporting Information
Novel O,N,N,O-tetradentate ligand from tartaric acid
Kaluvu Balaraman, Ravichandran Vasanthan and Venkitasamy Kesavan*
1

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Copies of 1H NMR and 13C NMR spectra
1H NMR of 10b
13C NMR of 10b
2

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1H NMR of 5a
13C NMR of 5a
3

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1H NMR of 11
13C NMR of 11
4

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1H NMR of 12
13C NMR of 12
5

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1H NMR of 13
13C NMR of 13
6

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1H NMR of 14
13C NMR of 14
7

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1H NMR of 5b
13C NMR of 5b
8

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1H NMR of 10a
13C NMR of 10a
9

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Copies of HPLC chromatograms
Racemic of 17a
Table:2, Entry:12
10

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Racemic of 17b
Table:3, Entry:1
11

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Racemic of 17c
Table:3, Entry:2
12

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Racemic of 17d
Table:3, Entry:3
13

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Racemic of 17e
Table:3, Entry:4
14

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Racemic of 17f
Table:3, Entry:5
15

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Racemic of 17g
Table:3, Entry:6
16

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Racemic of 17h
Table:3, Entry:7
17

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Racemic of 17i
Table:3, Entry:8
18

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Racemic of 17j
Table:3, Entry:9
19