Application of tartarate derived bidentate bioxazolines in enantioselective addition of terminal alkynes to imines

Article abstract of DOI:10.1016/j.tetlet.2013.04.108

A series of highly efficient and inexpensive bioxazoline ligands were easily synthesized from tartaric acid and further explored for enantioselective addition of terminal alkynes to imines in combination with copper(II) salts. This is the first ever repor

Full text of DOI:10.1016/j.tetlet.2013.04.108

Tetrahedron Letters 54 (2013) 3613–3616
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Application of tartarate derived bidentate bioxazolines in enantioselective
addition of terminal alkynes to imines
⇑
Kaluvu Balaraman, Ravichandran Vasanthan, Venkitasamy Kesavan
Chemical Biology Laboratory, Bhupat and Jyothi Mehta School of Biosciences Building, Indian Institute of Technology Madras, Chennai 600 036, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of highly efficient and inexpensive bioxazoline ligands were easily synthesized from tartaric acid
and further explored for enantioselective addition of terminal alkynes to imines in combination with cop-
per(II) salts. This is the first ever report showing application of bidentate bioxazoline ligands in the syn-
thesis of propargylamines with good enantioselectivity.
Received 15 March 2013
Revised 22 April 2013
Accepted 25 April 2013
Available online 3 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Propargylamine
Alkyne addition
Bioxazoline
Tartaric acid
Enantioselective
Chiral propargylamines are one of the most important synthetic
building blocks for the preparation of nitrogen heterocycles,1 nat-
ural products,2 and biologically active molecules.3 Addition of me-
tal acetylide to imine is the convenient and powerful method for
the preparation of propargylamines and their derivatives.4
Enantioselective synthesis of propargylamines was achieved by
Li and co-workers5 using 1,3-bis(oxazolin-2-yl)pyridine ligands
(pybox, 1)6 (Fig. 1) and copper salts led to the development of a
three-component reaction of aldehyde, amine, and alkyne. Apart
from pybox ligands, several catalysts were reported for the synthe-
sis of chiral propargylamines.7 Application of bidentate bis(oxazo-
line) ligands (2), which are privileged ligands to induce good
enantioselectivity in propargylamine synthesis was not successful
(<5% ee).5,8 Similarly ligand 4 which is derived from tartaric acid
and amenable to modification was completely overlooked by the
research community because of its inability to promote mechanis-
O
O
O
O
O
O
Ph
Ph
O
O
N
N
N
N
N
N
N
R
R
N
N
Ph
Ph
4a
Ph
Ph
R = Ph (
R = 2-FC6H4 (4b)
)
R
R
2
3
1
Figure 1. Structure of various bis(oxazoline) ligands.
R1
O
O
COOH
BnO
H2N
OBn
NH2
R2
HOOC
HO
COOH
OH
R1
R1
N
N
R2
R2
7
5
6
Scheme 1. Retrosynthesis of bidentate bioxazoline.
⇑
Corresponding author. Tel.: +91 44 2257 4124; fax: +91 44 2257 4102.
E-mail address: vkesavan@iitm.ac.in (V. Kesavan).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.108

3614
K. Balaraman et al. / Tetrahedron Letters 54 (2013) 3613–3616
O
O
O
O
O
O
N
N
N
N
N
N
OCH3
(S,S)-Nap-(S,S)-Box (
H3CO
OCH3
H3CO
OCH3
H3CO
5a
)
(R,R)-Nap-(S,S)-Box (5b)
(S,S)-Nap-(R,R)-Box (5c)
O
O
O
O
O
O
N
N
N
N
N
N
OCH3
H3CO
4c
2-Naph-(S,S)-Box (
)
5e
)
(S,S)-Ibu-(S,S)-Box (
(R,R)-Nap-(R,R)-Box (5d)
Figure 2. Structure of tartarate derived bioxazoline ligands.
tically different asymmetric transformations with good
enantioselectivity.9
4-methoxyaniline (12a), and phenylacetylene (9a) under similar
reaction conditions. Propargylamine 10a with 22% enantioselectiv-
ity in low yield (30%) was obtained (Scheme 3). Apart from low
yield, very low enantioselectivity was also observed when com-
pared with the addition of alkyne to imine 8a (Scheme 2). Use of
cyclic amines such as piperidine and pyrrolidine instead of anilines
led to the formation of 1,3-diynes (Scheme 3).12 These two demer-
its forced us to optimize reaction conditions by using the pre-
formed imine 8a.
Other Cu(I) and Cu(II) pre-catalysts such as Cu(OTf), CuCl, CuBr,
Cu(PF6)(CH3CN)4, Cu(OTf)2, Cu(ClO4)2ꢀ6H2O, and Cu(OAc)2ꢀH2O
were investigated in this reaction in order to choose a suitable me-
tal partner (Table 1). Except Cu(OAc)2ꢀH2O, every other copper salts
catalyzed the formation of propargylamine 10a in moderate to
good yields. Among them Cu(ClO4)2ꢀ6H2O fared better in inducing
enantioselectivity (43%) at ambient temperature (Table 1 entry 8).
Further attempts to enhance enantioselectivity by reducing the
temperature to 0 °C were not fruitful. Even after 2 days, no forma-
tion of propargylamine 10a was observed (Table 1, entry 9).
5 mol % of Cu(ClO4)2ꢀ6H2O with 10 mol % of 5a at ambient tem-
perature furnished the target product 10a with better enantiose-
lectivity (81% yield, 52% ee) (Table 1, entry 10). After
identification of Cu(ClO4)2ꢀ6H2O as a suitable metal partner and
25 °C as an optimal reaction temperature we went ahead to choose
the appropriate reaction medium (Table 2).
Under the same reaction conditions optimized previously, a
profound solvent effect on the yield and the enantioselectivity
was observed. No product was isolated when the reaction was car-
ried out in acetonitrile, acetone, and dimethoxyethane (DME)
(Table 2, entries 4, 6, and 9). Reaction in dichloroethane, diethyl
ether, and tetrahydrofuran (THF) contrived only a trace amount
of propargylamine 10a in TLC visualization and hence no attempts
were made to isolate the product (Table 2, entries 3, 8, and 10). Up
to 70% yield was obtained with toluene, tert-butyl methyl ether
(TBME), and dimethylformamide (DMF) as a reaction medium
but very poor enantioselectivity was observed (up to 17%) in these
cases (Table 2, entries 5, 7, and 11). Excellent conversion (up to
87%) was observed only in chlorinated solvents such as
dichloromethane and chloroform. Enantioselectivity observed
in chloroform was better (52%) (Table 2, entry 1) than of
enantioselectivity in dichloromethane (29%) (Table 2, entry 2).
Thus chloroform was identified as the most suitable reaction med-
ium for the enantioselective synthesis of propargylamines using li-
gand 5a.
In our lab we re-designed tartaric acid derived bioxazoline
ligand (4) by introducing another stereogenic center as shown in
ligand 5 near the coordination sphere (Scheme 1). This modifica-
tion mitigated the poor chirality transfer of ligand 4, in asymmetric
transformations.
The application of newly developed bioxazoline ligands 5
(Fig. 2) in asymmetric catalysis was successfully demonstrated in
copper catalyzed enantioselective Henry reaction and good
enantioselectivities with
a broad range of substrates were
achieved.10 We applied the same ligand to achieve asymmetric
allylic alkylation (AAA) with >95% ee.11 Since the amino acid de-
rived bidentate bis(oxazolines) 2 and 3 are inefficient in catalyzing
enantioselective synthesis of propargylamines, we decided to ex-
plore the efficiency of tartaric acid derived bidentate bioxazoline
5 for the same synthesis. Only unnatural and highly expensive ami-
no acid (tert-leucine, phenylglycine) derived pybox ligands 1 are
responsible for very good enantioselectivity to synthesize propar-
gylamines, whereas our catalytic system was prepared using inex-
pensive and naturally available tartaric acid. This makes tartarate
derived bidentate bioxazoline 5 as an alternative in terms of price
and availability to achieve enantioselective synthesis of chiral
propargylamines.
An initial exploration of enantioselective propargylamine syn-
thesis was carried out using ligand 5a which was identified as a
suitable ligand for the asymmetric Henry reaction. The reaction
of phenylacetylene (9a) and imine 8a was performed in chloroform
(CHCl3) at 25 °C using 5 mol % CuI and 10 mol % of 5a. The desired
product 10a was obtained with 35% yield and 31% enantiomeric
excess after 72 h (Scheme 2).
This superiority of ligand 5a over bis(oxazoline) ligands 2 & 3
encouraged us to optimize the reaction conditions further to in-
crease enantioselectivity of the product.
In an attempt to enhance the efficiency of the reaction, we car-
ried out the reaction in one pot manner using benzaldehyde (11a),
PMP
PMP
HN
Ph
N
5a
/CuI
Ph
+
Ph
CHCl3, rt
8a
9a
Ph
35% yield, 31% ee
10a
Scheme 2. Copper catalyzed enantioselective addition of alkyne to imine.

K. Balaraman et al. / Tetrahedron Letters 54 (2013) 3613–3616
3615
MeO
NH2
N
H
/CuI
PMP
12a
HN
Ph
5a /CuI
5a
Ph
Ph
Ph
Ph CHO +
4 Å MS, CHCl3, rt
13
CHCl3, rt
Ph
9a
11a
98% yield
30% yield, 22% ee
10a
Scheme 3. One-pot enantioselective propargylamine reaction.
Table 1
Optimization studies of enantioselective propargylamine reactiona
Table 3
Evaluation of box ligands in asymmetric propargylamine reactiona
PMP
HN
Ph
PMP
PMP
PMP
N
N
5a
/Cu salt
HN
Ph
L
Ph
-Cu(ClO4)2.6H2O
CHCl3, 25 oC
+
Ph
+
Ph
CHCl3
Ph
8a
Ph
eed (%)
9a
8a
10a
9a
Ph
10a
Entry
Cu salt
Time (h)
L/M
T (°C)
Yieldc (%)
Entry
Ligand
Time (d)
Yieldb (%)
ee (%)
1
2
3
4
5
6
7
8
CuCl
CuBr
CuI
24
24
24
24
24
48
24
24
48
36
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
2:1
25
25
25
25
25
25
25
25
0
65
72
35
81
47
—
87
89
—
20
26
31
27
7
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
4a
4b
4c
2
2
2
2
3
2
2
3
81
65
75
72
78
71
68
68
52 (R)
29 (R)
24 (S)
27 (S)
27 (R)
0
Cu(OTf)
Cu(PF6)(CH3CN)4
Cu(OAc)2ꢀH2O
Cu(OTf)2
Cu(ClO4)2ꢀ6H2O
Cu(ClO4)2ꢀ6H2O
Cu(ClO4)2ꢀ6H2O
—
27
43
—
0
0
9
10b
25
81
52
a
Ratio of ligand, Cu(ClO4)2ꢀ6H2O, 8a, and 9a was 0.1:0.05:1:1.5 in 3 mL of CHCl3.
a
b
Reactions were performed on a 1 mmol scale: Cu salt (5 mol %) and ligand 5a
Isolated yield.
(5 mol %) were stirred in CHCl3 (3 mL) under Ar at 25 °C. After a stirring period of
3 h, imine 8a (1 equiv) and 9a (1.5 equiv) were added.
b
5 mol % of Cu salt and 10 mol % of ligand were used.
Isolated yields after chromatography.
Absolute configurations of the product 10a were assigned as R by the reported
c
when compared to the other diastereomers (5b–5d) (Table 3, en-
tries 2–4) including ligand 5e (Table 3, entry 5). Also, the absolute
configuration of the product was identified as R configuration. This
is in accordance with our previous results that the absolute config-
uration was dictated by the chirality of oxazoline backbone, and
not of the chirality possessed by chiral appendage.
To prove the essentiality of additional chiral appendage, we also
carried out the transformation using control ligands 4a, 4b, and 4c.
All these ligands failed to induce the enantioselectivity (Table 3,
entries, 6–8). This proves unequivocally that chiral appendage is
essential for asymmetric induction to synthesize chiral propargyl-
amines. This result is no different from our earlier observation for
the Henry reaction.10
d
HPLC retention times in the literature.
After optimizing the reaction conditions systematically, we pro-
ceeded to optimize the ligand structure in order to identify the
matched pair of diastereomeric ligand to achieve the higher
enantioselectivity possible. All four different diastereomeric li-
gands (5a–5d) ( Fig. 2) were obtained using respective starting
materials and were evaluated in the enantioselective synthesis of
propargylamine 10a. From these results we came to know that
only ligand 5a induced good asymmetry (52% ee, Table 3, entry 1)
With these optimized conditions in hand, we proceeded to eval-
uate the scope of enantioselective propargylamine formation for
various terminal acetylenes with structurally diverse imines.13
Addition of phenylacetylene (9a) to imine derived from simple aro-
matic substrates such as benzaldehyde and aniline resulted in the
formation of 10b with very good enantioselectivity (80% ee) (Table
4, entry 1), whereas imine 8a formed from p-methoxyaniline
showed only 52% enantioselectivity in the formation of the corre-
sponding propargylamine 10a (Table 4, entry 2). Since, electron
releasing group diminished the enantioselectivity we carried out
the reaction using electron deficient imine 8c with 4,40-dichloro
substitution to the formation of 10c. Unfortunately electron with-
drawing substituents did not induce good enantioselectivity in the
formation of the corresponding propargylamine 10c. Only moder-
ate yield and enantioselectivity were obtained in this case (Table 4,
entry 3). To diversify the scope of substrates further we also made
sulfonyl imine 8d from the corresponding sulfonamide. But there
was no formation of product even after 4 days, when imine 8d
was used as a substrate (Table 4, entry 4).
Table 2
Effect of solvents on enantioselective propargylamine reactiona
PMP
PMP
+
HN
Ph
N
5a
/Cu(ClO4)2.6H2O
Ph
Ph
8a
Solvent, 25 o
C
Ph
9a
10a
Entry
Solvent
Chloroform
Dichloromethane
Dichloroethane
Acetonitrile
Toluene
Acetone
TBME
Diethyl ether
DME
THF
Time (d)
Yieldb (%)
ee (%)
1
2
3
4
5
6
7
8
2
2
4
4
3
4
3
4
4
4
3
81
87
<5
—
68
—
38
<5
—
<5
70
52
29
—
—
17
—
15
—
—
—
4
9
10
11
DMF
a
Various aldehydes were reacted with aniline to prepare struc-
turally diverse imines for the enantioselective addition of phenyl-
Ratio of 5a, Cu(ClO4)2ꢀ6H2O, 8a, and 9a was 0.1:0.05:1:1.5 in 3 mL of solvent.
b
Isolated yield.

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K. Balaraman et al. / Tetrahedron Letters 54 (2013) 3613–3616
Table 4
Enantioselective alkynylation of imines with (S,S)-Nap-(S,S)-Box (5a)a
R2
HN
R1
R2
N
5a
/Cu(ClO4)2.6H2O
CHCl3, 25 oC
+
R3
R1
R3
Product
9
10
8
Entry
R1
R2
R3
Time (d)
Yieldb (%)
ee (%)
1
2
3
4
5
6
7
8
Ph
Ph
4-ClC6H4
Ph
4-PhC6H4
4-OMeC6H4
2-OMeC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2
4
2
4
3
4
4
2
2
2
3
10b
10a
10c
10d
10e
10f
10g
10h
10i
72
81
69
—
76
67
—
81
86
78
77
80
52
66
—
70
10
—
64
60
64
52
4-OMeC6H4
4-ClC6H4
Ts
Ph
Ph
Ph
Ph
Ph
Ph
9
10
11
10j
10k
Ph
SiMe3
a
Ratio of 5a, Cu(ClO4)2ꢀ6H2O, 8, and 9 was 0.1:0.05:1:1.5 in 3 mL of CHCl3.
b
Isolated yields after chromatography.
E. Org. Lett. 2004, 6, 1601–1603; (f) Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc.
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acetylenes. Addition of phenylacetylene to 4-phenyl substituted
imine made from 4-phenylbenzaldehyde and aniline resulted in
the formation of 10e with 76% yield with good enantioselectivity
(70%) (Table 4, entry 5). As observed in the case of anilines electron
releasing substituents at the aldehyde part also diminished the
enantioselectivity when compared with electron withdrawing sub-
stitutions. Imine 8f with p-methoxy substitution on the aldehyde
part yielded 67% of propargylamine 10f with only 10% enantiose-
lectivity (Table 4, entry 6). Similarly imine 8g synthesized using
2-methoxybenzaldehyde and aniline did not react well under our
catalytic system even after 4 days (Table 4, entry 7). Imines 8h–
8j having electron withdrawing groups such as Cl, Br, and NO2 on
the aldehyde part, furnished corresponding propargylamines
10h–10j with almost similar enantioselectivities of 60–64% and
yields 78–86% (Table 4, entries 8, 9, and 10). To extend the sub-
strate scope further, we employed TMS-acetylene 9b instead of
phenylacetylene (9a). The reaction was carried out using imine
8k with TMS-acetylene 9b which yielded 52% enantioselectivity
with 77% yield of 10k (Table 4, entry 11). Thus a broad range of
imines underwent alkyne addition to afford propargylamines in
good yields with moderate to very good enantioselectivity.
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In conclusion, we applied a new class of bidentate bioxazoline
ligands to synthesize optically active propargylamines. Further
optimization of the ligand structure might evolve this bioxazoline
as a viable competitor for pybox in terms of price and availability
of the chiral sources. Currently efforts are dedicated in our lab to
utilize bioxazoline 5a, in various asymmetric transformations.
Acknowledgments
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This work was supported by the Department of Science & Tech-
nology, Government of India, New Delhi (Grant No. SR/S1/OC-60/
2006). KB thanks the University Grants Commission, New Delhi
for the research fellowship.
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11. Unpublished results.
References and notes
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(10a–10k) catalyzed by the Cu(II)–5a complex:
A solution of ligand 5a
(0.05 mmol, 5 mol %) and Cu(ClO4)2ꢀ6H2O (0.1 mmol, 10 mol %) in dry
chloroform (3 mL) was stirred at room temperature for 60 min. Imine
(1 mmol) and an alkyne (1.5 mmol) were added, and the whole mixture was
stirred at 25 °C for 2–4 days. After completion of the reaction (monitoring by
TLC), the mixture was concentrated in vacuo and purified over silica gel by
column chromatography (10–20% EtOAc in hexane) yielding pure
propargylamine (10a–10k).