Enantioselective one-pot three-component synthesis of propargylamines catalyzed by copper(I)-pyridine bis-(oxazoline) complexes

Article abstract of DOI:10.1016/j.tet.2011.05.114

A one-pot three-component coupling of aldehydes and amines in presence of terminal alkynes has been efficiently catalyzed by copper (I) complex of i-Pr-pybox-diPh 2b or s-Bu-pybox-diPh 2c. The process is simple and allows the synthesis of various propargy

Full text of DOI:10.1016/j.tet.2011.05.114

Tetrahedron 68 (2012) 3480e3486
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective one-pot three-component synthesis of propargylamines
catalyzed by copper(I)epyridine bis-(oxazoline) complexes
,
,b,
Alakesh Bisai a b, Vinod K. Singh a
*
a Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208 016, UP, India
b Department of Chemistry, Indian Institute of Science Education and Research Bhopal, ITI (Gas Rahat) Building, Govindpura, Bhopal 462 023, MP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot three-component coupling of aldehydes and amines in presence of terminal alkynes has been
efficiently catalyzed by copper (I) complex of i-Pr-pybox-diPh 2b or s-Bu-pybox-diPh 2c. The process is
simple and allows the synthesis of various propargylamines in good to excellent enantioselectivities (up
to 99% ee) and in higher yields. The nature of the substituents attached to imines plays a vital role on the
enantioselectivities obtained. The presence of gem-diphenyl group at C-5 position and secondary alkyl
substituents at the C-4 chiral center of the oxazoline rings of the chiral ligands was found to be crucial for
Received 11 March 2011
Received in revised form 24 May 2011
Accepted 27 May 2011
Available online 6 June 2011
Keywords:
higher enantioselectivities. A transition state model involving
stereochemical outcome.
p
e
p
stacking is also proposed for the
Propargylamines
Pybox-diPh ligands
Terminal alkynes
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
p-methoxyphenyl amine in the reaction has special significance,
due to its easy removal from the final product via an oxidative
cleavage using suitable oxidant.
Asymmetric catalysis continues to be one of the most efficient
and promising protocols for the synthesis of optically pure organic
molecules. Various approaches have been developed so far, for
synthesis of enantiopure propargylamines, which are further used
in the synthesis of nitrogen-containing chiral building blocks of
various amino acids, aza-sugars, and alkaloids.1,2 Propargylamines
could be synthesized either via diastereoselective reactions,3,4 such
as, the addition of organometallic reagents to the C]N bond of
chiral imines5 or through enantioselective metal catalyzed CeC
bond-forming reactions using enantioenriched ligands.6e9 Enan-
tioselective synthesis of propargylamines includes mainly two
different types of CeC bond-forming reactions; one involving cat-
alytic asymmetric addition of alkynylmetals to an imine and the
other implicates the addition of an alkylmetal to an alkynylimine.10
The former method was disclosed by Li and co-workers,11 which
involves additions to various arylimines in the presence of 10 mol %
Cu(I) complex of pybox ligand 1a (Fig. 1). The reactions were carried
out in organic solvent as well as in aqueous media. Despite higher
enantioselectivities in these reactions, they are limited only to the
reaction between phenylacetylene (ees upto 78e99%) and aromatic
imines. Also, the corresponding enantiopure products could not be
further deprotected to release the free amines. Thus, the use of an
aromatic amine containing electron donating group, such as
Some of the literature known enantioselective processes
include Knochel’s Cu(I)eQuinap12 catalyzed reaction, Hoveyda’s
Zr-(IV) complex in the presence of chiral amino acid-based peptide
ligand,13 Benaglia’s chiral binaphthyl amines based ligands,14 Car-
riera’s atropisomeric P,N ligand (PINAP),15 Jiang’s Zn-acetylide ad-
dition to reactive ketoimines in presence of amino alcohol based
ligands,16 Chong’s alkynylation to N-acylimines with binaphthol
based alkynylboronates,17a and its application to the anticancer
(ꢀ)-N-acetylcolchinol etc.17b Parallel with our report,18 in 2006,
Carreira and co-workers reported coupling of aldehydes, alkynes,
and 4-piperidone hydrochloride hydrate to afford the corre-
sponding propargylamines using Cu(I)ePINAP.19 Some more
enantioselective approaches involving ionic liquid20 as media or
solid supported pybox ligands21 are also present in literature using
Cu(I)epybox complexes.
Several examples of selective transformations of the prop-
argylamine products show the potential synthetic utility of this
method. For instance, an asymmetric alkynylation of
could be diversified to formation of enantioenriched unnatural
-amino acids of great biological importance.22e24 The two carbon
a-imino esters
a
acetylenic moiety present in the product could easily be hydroge-
nated or semi reduced to afford glycine or vinyl glycine derivatives,
respectively.25e27 Recently, Chan and co-workers established the
first example of catalytic asymmetric alkynylation of a-imino ester
by employing Cu(I)eIndabox.26 Herein, we wish to elaborate
* Corresponding author. Tel.: þ91 512 2597291; fax: þ91 512 2597436; e-mail
a complete detail of our previously reported work18 on the
address: vinodks@iitk.ac.in (V.K. Singh).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.114

A. Bisai, V.K. Singh / Tetrahedron 68 (2012) 3480e3486
3481
enantioselective one-pot three-component coupling of aldehydes
and amines in presence of terminal alkynes catalyzed by a copper(I)
complex of pybox-diPh ligands.
as p-methoxyphenyl (PMP) amine also gave high enantioselectivity,
which can be oxidatively removed to get chiral free amines.13,43
At the outset, the three-component coupling reaction was
examined by taking 1:1:1.5 mixtures of benzaldehyde, aniline, and
phenylacetylene at 0e25 ꢁC in chloroform by using 10 mol % of
Cu(I)PF6eligand complexes.18a The i-Pr-box-diPh 3 (Fig. 2) afforded
only racemic product. After 4 days of reaction i-Pr-pybox-diEt 2a
(Fig. 2) gave 56% ee. Also, in this case the reaction was sluggish and
did not go to completion even after 4 days (43% yield). When gem-
diphenylsubstituted ligand i-Pr-pybox-diPh 2b was used, the
product was obtained in 95% yield and 85% ee. This result was
highly promising in contrast to the results obtained from the ligand
i-Pr-pybox 1b and i-Pr-pybox-diEt 2a. This clearly indicates that
diphenyl substitution drastically affect the rate as well as enan-
tioselectivity of the reaction. The three-component coupling re-
action was carried out in different solvents, and it was found that
chloroform gave the best results in terms of yields and enantiose-
lectivity at 0 ꢁC to rt. The enantioselectivity was similar (96% ee) if
10 mol % of (CuOTf)2$PhMe-2b was used as a catalyst. The reactions
were equally good with similar enantioselectivity (94% ee) by using
10 mol % of Cu(II)OTf-2b, but with comparatively slower reaction
rates as compared to Cu(I) complexes.18a
The reaction was extended to different aromatic aldehydes with
aniline as amine source and most of them gave high enantiose-
lectivity (91e98% ee).18a Both, electron rich aldehydes, such as
4-alkylbenzaldehyde and electron poor aldehydes, such as
4-nitrobenzaldehyde afforded products with 94e95% ee. A maxi-
mum of 98% ee was obtained in the case of 2-chlorobenzaldehyde
using aniline and phenylacetylene. In most of the cases chemical
yield was good to excellent. The stereochemistry of the product was
assigned by comparing with the literature reported data by Li and
co-workers.11b The three-component coupling reaction was further
extended in the presence of different aromatic amines. Halogen
substituted aromatic, such as 4-bromoaniline, 3-chloroaniline, and
3-fluoroaniline amines were found to be equally efficient (ees up to
96% with up to 98% yield). Further, when we used p-methoxyphenyl
(PMP) amines, which could be oxidatively removed,43b we could
get up to 90% ee (up to 98% yield) in this reaction when 10 mol % of
the catalyst 2b was used at 0 ꢁC to rt.18a
2. Results and discussion
The enantioselective addition of terminal alkynes28 to imines
provides direct access to chiral propargylamines, which could be
further transformed to many biologicallyactive nitrogen-containing
compounds.1a,29 This is an important CeC bond-forming reaction
that proceeds via CeH bond activation bya metal complex.30 Design,
synthesis, and tuning of a suitable chiral ligand around a metal
center is an important task in asymmetric synthesis.31 Pyridine bis-
(oxazoline) type ligand (pybox, Fig. 1) was first introduced by
Nishiyama for asymmetric hydrosilylation reactions.32 Later on,
these ligands were used for asymmetric dehydrogenative silylation
of ketones,33 chiral recognition of binapthol,34 cyclopropanation
reactions,35 aldol condensation,36 DielseAlder reactions37 etc.
R= Ph, Ph-pybox; 1a
R= i-Pr, i-Pr-pybox; 1b
R= t-Bu, t-Bu-pybox; 1c
O
O
N
N
N
R
R
Fig. 1. First generation pybox ligands.
For last more than a decade our group was also engaged in
designing chiral ligands for enantioselective allylic oxidation of
olefins using a catalytic amount of copper complex of chiral pyri-
dine bis(diphenyloxazoline) ligand. The i-Pr-pybox ligand of the
type 1b (Fig. 1) plays a crucial role in the area of enantioselective
reactions.35a,38,39 Our efforts in this direction led to a slightly
modified version of ligand 1b, i.e., i-Pr-pybox-diph 2b (Fig. 2) to
which we incorporated a gem disubstitution at C-5 position of
oxazoline core. The ligand 2b has successfully been used in the area
of enantioselective cyclopropanation,40a allylic oxidation,40bee
allylation to aldehydes,41 FriedeleCraft reaction of indole and pyr-
role.42 While working on an asymmetric allylic oxidation reaction
using 2b, we envisioned that its copper complex would be quite
stable as a catalyst for the enantioselective propargylation reaction
on imines. We observed that diphenyl group at C-5 of oxazoline
rings of 2b played a crucial role in enhancing the enantioselectiv-
ities in the allylic oxidation of olefins. The lower enantioselectivity
(<45% ee) provided by the i-Pr-pybox ligand 1b by Li co-workers,11a
would never encourage anybody to use ligand 2b (Fig. 2) for the
addition of alkyne to an imine. Based on our intuition, we used
ligand 2b in synthesis of propargylamines and as per our expec-
tation, excellent enantioselectivities were obtained. Further, it was
observed that preformed imine was not needed and the reaction
worked well in one-pot fashion. Above all, N-protected amine, such
We were then interested to screen a variety of gem-disubstitued
Pybox-diPh prepared from naturally occurring
a-amino acids by
our earlier reported procedures.40b,c All the ligands listed in Fig. 3
were applied to these enantioselective reactions and the results
are summarized in Table 1.
R= s-Bu, s-Bu-pybox-diPh; 2c
R= i-Bu, i-Bu-pybox-diPh; 2d
R= Bn, Bn-pybox-diPh; 2e
R= Me, Me-pybox-diPh; 2f
R= Ph, Ph-pybox-diPh; 2g
R= t-Bu, t-Bu-pybox-diPh; 2h
O
O
Ph
Ph
Ph
Ph
N
N
N
R
R
Fig. 3. Second generation pybox used in present study.
Apparently, both the ligands 2b (i-Pr-pybox-diPh) and 2c (s-Bu-
pybox-diPh) are superior to all other ligands in providing enan-
tioselectivities (Table 1, entries 1e8). s-Bu-pybox-diPh 2c (93% ee,
entry 3) is further superior to i-Pr-pybox-diPh 2b (90% ee, entry 2).
Unfortunately, t-Bu-pybox-diPh 2h could hardly provide a maxi-
mum of 86% ee in this reaction (entry 8). As per the observations
obtained in case of ligand 2b and 2c, we assumed, t-Bu-pybox-diPh
2h to provide even higher ee but all in vain. This may be because of
O
O
O
R
R
R
R
R= Et, i-Pr-pybox-diEt; 2a
R= Ph, i-Pr-pybox-diPh; 2b
N
N
N
O
Ph
Ph
Ph
Ph
N
N
extra hindrance created by t-Bu at the b-position of the ligand 2h,
which disturbed the formation of a stable transition state leading
fall in enantioselectivity. Other ligands provided ees in the range of
53e75% (entries 4e7). With these results, we decided to check the
effect of p-methoxyaniline (PMPNH2) in one-pot three-component
i-Pr-box-diPh; 3
Fig. 2. Second generation pybox and box ligands.

3482
A. Bisai, V.K. Singh / Tetrahedron 68 (2012) 3480e3486
Table 1
Table 3
Scope of different pybox on enantioselectivity
Scope of different terminal alkynes on enantioselectivity using Cu(I)-PF6-2b and 2c
NHPMP
10 mol% Cu(I)PF6-L,
10 mol% Cu(I)PF6-2b
or 2c, CHCl3, 0 °C-rt
NHPMP
CHCl3, 0 °C-rt
+
+
PhCHO PMPNH2 Ph
R
PMPNH2
+
p-X-C6H4CHO
R
Ph
R
R
(6)
X
Ph
ee (%)
(4)
Entry
X
R
10 mol % Cu(I)PF6-2b
10 mol % Cu(I)PF6-2c
Entry
Pybox
Time
Yielda (%)
Time
(h)
Yielda
(%)
eeb
(%)
Time
(h)
Yielda
(%)
eeb
(%)
1
2
3
4
5
6
7
8
i-Pr-pybox-diEt-2a
i-Pr-pybox-diPh-2b
s-Bu-pybox-diPh-2c
i-Bu-pybox-diPh-2d
Bn-pybox-diPh-2e
Me-pybox-diPh-2f
Ph-pybox-diPh-2g
t-Bu-pybox-diPh-2h
6 days
16 h
18 h
4 days
5 days
4 days
28 h
46
98
97
56
45
51
96
90
68
90
93
63
64
53
1
2
H
F
C6H5-CH2CH2
C6H5-CH2CH2
n-C4H9
n-C4H9
4-Me-C6H4
4-Me-C6H4
4-n-Pent-C6H4 18
4-n-Pent-C6H4 20
4-Br-C6H4
4-Br-C6H4
4-OMe-C6H4
4-OMe-C6H4
42
62
28
62
18
18
86 (6a)
80 (6b)
67 (6c)
67 (6d)
98 (6e)
94 (6f)
92 (6g)
91 (6h)
93 (6i)
93 (6j)
96 (6k)
98 (6l)
84
82
87
84
93
93
92
93
90
90
93
92
48
72
70
72
17
22
21
22
20
24
23
26
66 (6a)
70 (6b)
71 (6c)
65 (6d)
99 (6e)
88 (6f)
92 (6g)
90 (6h)
94 (6i)
93 (6j)
94 (6k)
97 (6l)
88
89
90
91
94
96
95
97
91
94
94
96
3
4
H
F
75 (S)b
68
5
6
H
F
22 h
7
8
H
F
a
All the reactions were performed under an argon atmosphere and yields were
reported after column chromatography.
9
H
F
H
F
18
20
20
24
b
(R,R)-Ligand was used.
10
11
12
synthesis of propargylamines using both 2b and 2c and the
results are summarized in Table 2. It is clearly depicted that the
synthesis of propargylamine by this one-pot protocol is quite effi-
cient and a maximum of 99% ee was obtained in case of 2,4-
dimethylbenzaldehyde (Table 2, entry 12).
a
Isolated yield after column chromatography.
ee,s were determined using Chiralpak AD-H column (See Experimental section).
b
donating groups, such as 4-methyl and 4-pentylphenylacetylene,
the enantioselectivities were in the range of 92e97% (Table 3, en-
tries 5e8). Terminal alkynes having halogen substitution at para-
position, were also proved to be good substrates yielding enantio-
selectivities in the range of 90e94% (Table 3, entries 9 and 10).
When a terminal alkyne having a strong electron donating group,
such as methoxy group at para-position, was used the enantiose-
lectivities reached to 96% (Table 3, entries 11 and 12). All aromatic
alkynes having electron donating groups or halogen group at the
para-position afforded more than 90% ees (Table 3, entries 5e12). It
has also been observed that in all the cases s-Bu-pybox-diPh 2c was
superior over i-Pr-pybox-diPh 2b in terms of efficiency.
As shown in Table 2, ortho-substituted aromatic aldehydes, such
as 2-chloro and 2,4-dimethylbenzaldehydes provided a maximum
of 99% ee (Table 2, entries 9 and 12), hence, we were interested to
check variation of enantioselectivities using different terminal al-
kynes on these two ortho-substituted benzaldehydes in the pres-
ence of both the chiral metal complexes CuIPF6-2b and CuIPF6-2c.
To our delight, we could get excellent enantioselectivities and
yields using these catalysts under optimized condition (Table 4).
Table 2
Scope of different aldehydes on enantioselectivity using Cu(I)-PF6-2b and 2c
10 mol% Cu(I)PF6-2b or
NHPMP
2c, CHCl3, 0 °C-rta
PMPNH2
Ph
+
ArCHO
+
Ar
Ph
(5)
Entry
10 mol % CuIPF6-2b
10 mol % CuIPF6-2c
Ar
Time (h) Yield (%) eeb (%) Time (h) Yield (%) eeb (%)
1
2
3
4
5
6
7
8
3-MeeC6H4
4-i-PreC6H4
4-CleC6H4
3-FeC6H4
4-FeC6H4
3-BreC6H4
3-CleC6H4
3-Cle4-FeC6H3 16
2-CleC6H4 16
3,5-DiMeeC6H3 16
4-NO2eC6H4 46
2,4-DiMeeC6H3 18
22
22
28
26
24
26
16
99 (5a) 92 (R) 22
87 (5b) 83 (R) 20
91 (5c) 90 (R) 20
90 (5d) 85 (R) 22
95 (5e) 91 (R) 20
96 (5f) 80 (R) 23
92 (5g) 82 (R) 30
90 (5h) 86 (R) 28
98 (5a) 95 (R)
92 (5b) 96 (R)
93 (5c) 95 (R)
97 (5d) 92 (R)
97 (5e) 96 (R)
90 (5f) 87 (R)
97 (5g) 89 (R)
92 (5h) 92 (R)
9
94 (5i)
98 (5j)
97 (S) 24
93 (R) 18
90 (5i)
96 (5j)
97 (S)
96 (R)
10
11
12
90 (5k) 90 (R) 46
97 (5l) 99 (S) 16
89 (5k) 97 (R)
98 (5l) 99 (S)
aRatio of CuIPF6, ligand 2b and/or 2c, aldehyde, PMPNH2, and phenylacetylene was
0.05:0.06:1.0:1.0:1.5.
Table 4
b
Enantiomeric excesses were determined by Chiralpak AD-H column.
Effect of ortho-substitution on the enantioselectivity using Cu(I)-PF6-2b and 2c
CHO
NHPMP
10 mol% Cu(I)PF6-2b or 2c,
CHCl3, 0 °C-rt
S
It was observed that the enantioselectivity increases by changing
i-Pr group to s-Bu in the oxazoline core of the pybox-diPh (Table 2,
entries 1e12). This is may be due to increasing proper steric
+
PMPNH2
+
R
X
X
R
(7)
crowding at b-position of the ligand, makes the transition states
Entry
X
R
10 mol % Cu(I)PF6-2b 10 mol % Cu(I)PF6-2c
even compact and thus facilitates the reaction. In case of aromatic
aldehydes having ortho-substitution, such as 2-chlorobenzaldehye
and 2,4-dimethylbenzaldehyde, the enantioselectivities goes up to
99% with the use of ligand 2b (entries 9 and 12). The chemical yields
in all the cases were good to excellent. Continuing our studies, we
examined the effect of variety of terminal alkynes on enantiose-
lectivity and the results were summarized Table 3.
It is noteworthy that the enantioselectivities were very good to
excellent in all substituted alkynes (Table 3). However, aliphatic
alkynes afforded propargylamines with lower yields and also
reaction was comparatively sluggish with respect to aromatic al-
kynes (Table 3, entries 1e4). With terminal alkynes having electron
Time Yielda
(h) (%)
eeb Time Yielda
(%) (h) (%)
eeb
(%)
1
2
3
4
5
6
7
8
9
2-Cl
C6H5eCH2CH2 48
2,4-DiMe C6H5eCH2CH2 62
61 (7a) 85
92 (7b) 97
67 (7c) 87
97 (7d) 98
94 (7e) 98
91 (7f)
92 (7g) 87
95 (7h) 97
68
70
68
25
22
26
25
22
22
61 (7a) 91
75 (7b) 97
63 (7c) 87
89 (7d) 98
90 (7e) 98
95 (7f) 99
92 (7g) 87
93 (7h) 97
2-Cl
2-Cl
n-C4H9
4-MeeC6H4
48
22
18
2,4-DiMe 4-MeeC6H4
2-Cl
2,4-DiMe 4-OMeeC6H4 22
4-OMeeC6H4 24
98
2-Cl
4-BreC6H4
22
24
2,4-DiMe 4-BreC6H4
95 (7i)
98
96 (7i)
99
a
Isolated yield after column chromatography.
ee,s were determined using Chiralpak AD-H column (See Experimental section).
b

A. Bisai, V.K. Singh / Tetrahedron 68 (2012) 3480e3486
3483
ꢀ
In case of aliphatic aldehyde, we were unable to get optically
active propargylamines 8 under this condition (Scheme 1). The
reaction showed decomposed products, from which neither prop-
argylamine 8 nor propargylalcohol 9a were isolated. Further, we
decided to check propargylation reaction on benzaldehyde in the
presence of Cu(I)-complex of 2b. Unfortunately, we did not observe
formation of propargylalcohol 9b, and benzaldehyde was isolated
quantitatively from the reaction mixture. This is not surprising to
us, as it is reported that Cu-alkynylides do not normally undergo
nucleophilic additions to aldehydes.44,45
distance (w3.5 A) from the aryl ring so as to provide stabilizing
interactions.46 This is possible when the right side phenyl is parallel
and the left side phenyl is orthogonal to the aryl ring. Thus, the
transition state becomes highly organized due to the above three
stabilizing interactions and the copper acetylide attacks the imine
from Si-face to provide propargylamine. The Re-face attack is dis-
favored due to the
left oxazoline ring.
The steric effect also plays an important role in this kind of re-
action, such as in case of s-Bu-pybox-diPh 2c, which afforded ex-
cellent ees than i-Pr-pybox-diPh 2b, the alkyl group on the
b-alkyl group on the chiral carbon atom of the
10 mol% Cu(I)-2b,
0 °C - rt, 5 days
b
-carbon of the oxazoline rings is bulkier in case of 2c than 2b, thus
NHPMP
rigidifying the transition states in greater extent. The same case
may arise when aromatic aldehydes having ortho-substitution
(Table 2, entries 9 and 12; and Table 4) were used in this reaction.
The steric effect of ortho-substituent on the benzaldehyde, also ri-
gidifies the transition state than substitution at other positions. Due
to lack of aromatic rings in the case of aliphatic imines (Scheme 1),
these types of stabilization of transition states is not possible.
Another important feature of our catalytic system is that, aro-
matic alkynes works well than aliphatic alkynes and the isolated
yields in most of the cases were good to excellent. This can be
+
+
PMPNH2
Ph
CHO
(8)
or
Ph
Ph
OH
(9a)
10 mol% Cu(I)-2b,
0 °C - rt, 5 days
HO
Ph
PhCHO
Ph
+
explained by considering a CeH/
p interaction between aromatic
ring of the terminal alkynes with CeH of i-Pr group47 and a
p
/p
Ph
(9b)
interaction between aromatic ring of the terminal alkynes with the
phenyl ring of gem-disubstituted pybox in the transition states (T.S.
10b in Fig. 5). This is quite possible as the distance between two
Scheme 1. Alkynylations on other substrates.
ꢀ
Our results inferred the superiority of i-Pr-pybox-diPh 2b over
i-Pr-pybox-diEt 2a and i-Pr-pybox 1b. Also s-Bu-pybox-diPh 2c is
superior over i-Pr-pybox-diPh 2b in most of the cases in terms of
achieving excellent enantioselectivities. The salient features of our
catalytic system is that; (a) chiral Cu(II)-complex of i-Pr-pybox-diPh
2b gave slightly lower ees than Cu(I)-complexes. (b) It appeared
that only gem-diphenylsubstituted pybox like s-Bu-pybox-diPh 2b
and i-Pr-pybox-diPh 2c is highly efficient to catalyze the reaction.
The ligand 2c gave excellent ees in all the cases than 2b. (c) The in
situ prepared imines from aromatic aldehydes are highly efficient
than their aliphatic counterpart. (d) ortho-Substituted aromatic
aldehydes afforded excellent ees when s-Bu-pybox-diPh 2c or i-Pr-
pybox-diPh 2b was used (Table 4). (e) When aromatic alkyne was
replaced by aliphatic alkyne, the reaction became sluggish and
a significant decrease in enantioselectivities was observed.
aromatic rings is approximately w4.0 A and distance between aryl
group of terminal alkynes and CeH of i-Pr group is approximately
w2.5 A.
ꢀ
~3.5 Å
C-H...π
X
~4.5 Å
~3
.5 Å
O
N
O
H
N
N
N
Cu
H
~4.0 Å
π...π
Y
Si-Face approach
Considering the above facts and on the basis of our earlier ex-
periences on enantioselective allylic oxidation of olefins using such
kind of ligands,41 we proposed that the ‘N’ of an imine prefers to
chelate the Cu-complex in a manner where there are three stabi-
Favored Transition State Assembly
Fig. 5. Proposed favored transition state (T.S.-10b).
lizing
p-interactions; two CeH/p and one p/p as indicated in
Fig. 4 (T.S. 10a in Fig. 4). In this favored model, the aryl group on the
sp2 carbon of the imine could orient itself in a manner that it is
orthogonal to the pyridine ring. Thus, one of the phenyl rings on
each oxazoline unit can attain a conformation to provide a suitable
In an unfavored model (T.S. 10c in Fig. 6), the ‘N’ of the imine can
chelate with the copper complex in a manner where the aryl of the
‘N’ is orthogonal to the pyridine ring causing severe non-bonding
repulsion.
~3.5
Å
X
~4.5 Å
Y
C-H...π
~3.5
Å
O
O
N
O
O
H
N
H
N
N
N
N
N
Cu
N
Cu
H
H
R
Si-Face approach
Y
R
X
Favored Transition State Assembly
Disfavored Transition State
Fig. 4. Proposed favored transition state (T.S.-10a).
Fig. 6. Proposed unfavored transition state (T.S.-10c).

3484
A. Bisai, V.K. Singh / Tetrahedron 68 (2012) 3480e3486
Table 6
3. Synthesis of b,g-alkynyl-a-amino esters
Substrate scopes for one-pot three-component coupling
10 mol% Cu(OTf)2- 2b
or 2c, toluene, 0°C-rt
b
,
g
-Alkynyl
a
-amino acid derivatives 11 are compounds having
O
NHPMP
COOEt
a
a-ethynyl amine substituents and are a special class of non-
+ PMPNH2
COOEt
H
(11)
proteinogenic amino acids. These are gaining rapidly increasing
popularity as they are important tools in protein engineering and
peptide-based drug discovery.48 Thus continuing our studies, we
were interested for one-pot three-component synthesis of optically
R
+
R
Entry
Cu salt-ligand
R
Time
% Yield
ee a,b(%)
1
2
3
4
5
6
7
8
Cu(II)OTf-2b
Cu(II)OTf-2c
Cu(II)OTf-2b
Cu(II)OTf-2c
Cu(II)OTf-2b
Cu(II)OTf-2c
Cu(II)OTf-2b
Cu(II)OTf-2c
Cu(II)OTf-2b
Cu(II)OTf-2c
Cu(II)OTf-2b
Cu(II)OTf-2c
Cu(II)OTf-2b
Cu(II)OTf-2c
C6H5eCH2CH2
C6H5eCH2CH2
n-C4H9
n-C4H9
C6H5
48
20
48
48
12
12
10
10
12
12
16
16
12
12
69 (11a)
79 (11a)
80 (11b)
83 (11b)
90 (11c)
92 (11c)
91 (11d)
97 (11d)
90 (11e)
88 (11e)
92 (11f)
91 (11f)
94 (11g)
88 (11g)
39
46
41
48
39
43
50
52
20
21
38
38
48
56
active unnatural a
-amino acid derivatives.49
At the outset the three-component coupling reaction was
examined by using 1:1:1.5 mixture of ethylglyoxylate, PMPNH2,
and 4-phenyl-1-butyne at 0e25 ꢁC in toluene for 24 h in the
presence of 10 mol % complex of Cu(MeCN)4PF6-2b. The product
11a was obtained in 88% yield and 41% ee (Table 5, entry 2). Among
all other solvents were used, chloroform gave a similar ees but the
reaction was sluggish (entries 2e5). The ees were increased to 46%
when 10 mol % of a complex of Cu(OTf)2-2c in toluene was used
(entry 11). Thus, by changing the ligand from 2b to 2c, the enan-
tioselectivity increases from 39% to 46%, respectively (entries 9 and
C6H5
4-Pent-C6H4
4-Pent-C6H4
4-BreC6H4
4-BreC6H4
4-OMeeC6H4
4-OMeeC6H4
4-MeeC6H4
4-MeeC6H4
9
10
11
12
13
14
ꢀ
a
11). Further addition of 4 A powdered molecular sieves did not help
ees were determined by Chiralpak AD-H column using iso-propanol and hexane
in increasing the ees, rather the reaction requires longer time to go
to completion.
as eluent.
b
The absolute configuration was made by analogy according to the literature
data.
Table 5
Optimization of
b
,
g
-alkynyl-
a
-amino esters synthesis
the enantioselective one-pot three-component synthesis of prop-
argylamines from aromatic aldehydes, aromatic amines, and ter-
minal alkynes. The reaction is completed in few hours. The
procedure is operationally very simple and can furnish a wide va-
riety of propargylamines in good to excellent yields (up to 99%)
with excellent enantioselectivities (up to 99% ee). We have
explained the stereochemical outcome with a proposed transition
state model. The enantioselective one-pot three-component re-
O
H
10 mol%
NHPMP
COOEt
Cu salt-Ligand
Ph
+
PMPNH2
COOEt
(11a)
+
Ph
Entry Cu salt-liganda Solvent
Temp
Toluene rt
Toluene 0 ꢁC to rt 24 h
Time
18 h
% Yield eeb,c (%)
1
2
3
4
5
6
7
8
Cu(I)PF6-2b
Cu(I)PF6-2b
Cu(I)PF6-2b
Cu(I)PF6-2b
Cu(I)PF6-2b
Cu(I)PF6-2b
Cu(I)OTf-2b
Cu(II)OTf-2b
Cu(II)OTf-2b
Cu(II)OTf-2c
Cu(II)OTf-2c
Cu(II)OTf-2c
91
88
82
23
41
15
41
09
44d
35
31
39
45
46
45d
Et2O
CHCl3
MTBE
0
0
ꢁC to rt 24 h
action was also extended to the synthesis of
b
-g-alkynyl-a-amino
ꢁC to rt 03 days 33
acid derivatives. The procedure furnished a variety of
a-amino acid
0 ꢁC to rt 72 h
25
76
76
86
69
81
79
73
derivatives in good to excellent yields (up to 99%) with moderate
enantioselectivities (up to 56% ee). These results open a novel way
to design and synthesize new chiral ligands for enantioselective
reactions.
Toluene rt
Toluene rt
Toluene rt
48 h
16 h
16 h
9
Toluene
0
ꢁC to rt 48 h
12 h
10
11
12
Toluene rt
Toluene 0 ꢁC to rt 20 h
Toluene rt
48 h
5. Experimantal section
5.1. General methods
a
Complex (10 mol %) was used unless stated otherwise.
ees were determined by Chiralpak AD-H column.
The absolute configuration was made by analogy according to the literature
b
c
data.
d
Chemicals were purchased and used without further purifica-
ꢀ
4 A powdered (50 mg) MS were added.
tion. 1H and 13C NMR spectra were recorded on a JEOL JNM-LA400
Having the optimized condition (Table 5, entry 11), we then
explored the substrate scopes using a variety of terminal alkynes. It
was found that, when aliphatic terminal alkynes were used, the
reactions were very slow (Table 6, entries 1e4). A maximum of 48%
ees were obtained when 1-hexyne was used in the presence of
Cu(OTf)2-2c complex (entry 4). However, in case of aromatic al-
kynes the reaction was faster in comparison to aliphatic alkynes
and very good to excellent yields were obtained (entries 5e14).
4-Pentyl substituted aromatic alkynes provided a maximum of 52%
ee (Table 6, entry 8). 4-Bromo phenylacetylene afforded lowest ees
of 20e21% (entries 9 and 10). Electron donating group on terminal
alkynes, such as 4-pentylphenylacetylene the ees were enhanced to
50e52% (entries 7 and 8). In case of 4-methyl phenylacetylene the
ees reached to a maximum of 56% (entry 14).
spectrometer. All chemical shifts are quoted on the
d scale, TMS as
internal standard, and coupling constants are reported in hertz.
Routine monitoring of reactions were performed by TLC, and using
0.2 mm Kieselgel 60 F254 precoated aluminum sheets, commercially
available from Merck. Visualization was done by fluorescence
quenching at 254 nm, by exposure to iodine vapor. All the column
chromatographic separations were done by using silica gel (Acme’s,
60e120 mesh). Petroleum ether used was of boiling range
60e80 ꢁC. Reactions that needed anhydrous conditions were run
under an atmosphere of nitrogen or argon using flame-dried
glassware. The organic extracts were dried over anhydrous so-
dium sulfate. Evaporations of solvents were performed at reduced
pressure. Tetrahydrofuran (THF) was distilled from sodium ben-
zophenone ketyl under nitrogen. Dichloromethane and chloroform
were distilled from CaH2. All the aldehydes, amines, and terminal
alkynes were purchased either from Aldrich or Alfa-Aesar. Melting
points were determined by using Perfit apparatus and are un-
corrected. The enantiomeric excesses were determined by Diacel
Chiralpak AD-H or Chiralcel OD-H column using iso-propanol and
n-hexane as eluents at 25 ꢁC.
4. Conclusion
In summary, chiral Cu(I)-2b and Cu(I)-2c complexes prepared
from Cu(I)PF6 and C2-symmetric i-Pr-pybox-diPh 2b and s-Bu-
pybox-diPh 2c, respectively, were found to be effective catalysts for

A. Bisai, V.K. Singh / Tetrahedron 68 (2012) 3480e3486
3485
5.2. General procedure for the enantioselective three-
component synthesis of propargylamines catalyzed by Cu(I)-
(S,S)-2b and 2c complexes
137.9, 133.1, 129.7, 128.9, 128.6, 127.1, 115.7, 114.5, 85.6, 78.6, 55.5,
48.8, 30.6, 21.8, 18.4, 13.5. Anal. Calcd for C20H22ClNO: C, 73.27; H,
6.76; N, 4.27. Found: C, 73.51; H, 6.82; N, 4.29.
A dry and argon-flushed 10 mL flask equipped with a magnetic
5.2.5. (R)-[1-(2-Chlorophenyl)-3-(4-methylphenyl)-prop-2-ynyl]-(4-
methoxyphenyl) amine (7d) (Table 4, entry 4). Yield 98% ee; isolated
in 97% yield as yellow gel; Rf 0.48 (EtOAc/petroleum ether¼1:9);
stirrer and
a septum was charged with Cu(I)(MeCN)4PF6
(0.01 mmol, 5 mol %) and ligand 2b or 2c (0.012 mmol, 6 mol %).
Anhydrous chloroform (2 mL) was added and the mixture was
stirred at rt for 30 min. After that aldehyde (0.2 mmol) and aromatic
amine (0.2 mmol) were added and stirred for addition 15 min at rt.
The reaction was cooled to 0 ꢁC and terminal alkyne was added
(0.3 mmol) and then the reaction mixture was allowed to warm to
25 ꢁC. After the reaction was completed (monitoring by TLC) it was
concentrated in vacuo and purified by chromatography on silica gel
(2e10% EtOAc in hexane) yielding the pure propargylamines.
[a
]
25 þ100.6 (c 1.0, CHCl3); HPLC conditions: Diacel Chiralpak AD-
D
H (4.6 cm I.D.ꢂ25 cm), 85:15 hexanes/i-PrOH, 1.0 mL/min flow rate,
l
¼254 nm, tR (major)¼16.98 min and tR (minor)¼10.95 min; 1H
NMR (CDCl3, 400 MHz):
d
: 7.79 (dd, J¼7.6, 1.9 Hz, 1H), 7.41 (dd,
J¼7.6, 1.9 Hz, 1H), 7.28 (m, 4H), 7.08 (d, J¼7.8 Hz, 2H), 6.76 (m, 4H),
5.72 (s, 1H), 3.73 (s, 3H), 2.32 (s, 3H). Anal. Calcd for C23H20ClNO: C,
76.34; H, 5.57; N, 3.87. Found: C, 76.51; H, 5.61; N, 3.89.
5.2.6. (R)-[1-(2,4-Dimethylphenyl)-3-(4-methylphenyl)-prop-2-
5.2.1. (R)-[1-Phenyl-3-(4-pentylphenyl)-prop-2-ynyl]-(4-
methoxyphenyl) amine (6g) (Table 3, entry 7). Yield 92% ee; isolated
in 92% yield as yellow gel; Rf 0.52 (EtOAc/petroleum ether¼1:9);
ynyl]-(4-methoxyphenyl) amine (7e) (Table 4, entry 5). Yield 98% ee;
isolated in 94% yield as yellow gel; Rf 0.50 (EtOAc/petroleum
25
ether¼1:9); [
a]
þ131.6 (c 1.0, CHCl3); HPLC conditions: Diacel
D
[
a]
25 þ101.7 (c 1.0, CHCl3); HPLC conditions: Diacel Chiralcel AD-H
Chiralpak AD-H (4.6 cm I.D.ꢂ25 cm), 80:20 hexanes/i-PrOH,
D
(4.6 cm I.D.ꢂ25 cm), 80:20 hexanes/i-PrOH, 1.0 mL/min flow rate,
1.0 mL/min flow rate,
l¼254 nm, tR (major)¼13.03 min and tR
l
¼254 nm, tR (major)¼10.27 min and tR (minor)¼12.31 min; 1H
(minor)¼12.15 min; 1H NMR (CDCl3, 400 MHz):
: 7.79 (d, J¼7.8 Hz,
d
NMR (CDCl3, 400 MHz)
d
: 7.65 (m, 2H), 7.21e7.39 (m, 5H), 7.14 (m,
1H), 7.32 (d, J¼7.8 Hz, 2H), 7.08 (m, 4H), 6.81 (dd, J¼28.8, 8.7 Hz,
4H), 5.47 (s, 1H), 3.76 (s, 3H), 2.45 (s, 3H), 2.35 (s, 3H), 2.34 (s, 3H).
Anal. Calcd for C25H25NO: C, 84.47; H, 7.09; N, 3.94. Found: C, 84.55;
H, 7.12; N, 3.96.
2H), 6.74e6.78 (m, 4H), 5.39 (s, 1H), 3.74 (s, 3H), 2.57 (m, 2H), 1.58
(m, 2H), 1.30 (m, 4H), 0.88 (br s, 3H). Anal. Calcd for C27H29NO: C,
84.55, H, 7.62, N, 3.65. Found: C, 84.63, H 7.65, N, 3.68.
5.2.2. (S)-{1-(2-Chloro-phenyl)-5-phenyl-pent-2-ynyl}-(4-
methoxyphenyl) amine (7a) (Table 4, entry 1). Yield 85% ee; isolated
in 61% yield as yellow gel; Rf 0.54 (EtOAc/petroleum ether¼1:9);
5.2.7. (R)-[1-(2-Chlorophenyl)-3-(4-n-pentylphenyl)-prop-2-ynyl]-
(4-methoxyphenyl)amine (7f) (Table 4, entry 6). Yield 98% ee; iso-
lated in 91% yield as yellow gel; Rf 0.50 (EtOAc/petroleum
25
[
a]
25 þ51.4 (c 1.4, CHCl3); HPLC conditions: Diacel Chiralpak AD-H
ether¼1:9); [
a
]
þ105.3 (c 1.0, CHCl3); HPLC conditions: Diacel
D
D
(4.6 cm I.D.ꢂ25 cm), 95:5 hexanes/i-PrOH, 1.0 mL/min flow rate,
Chiralpak AD-H (4.6 cm I.D.ꢂ25 cm), 85:15 hexanes/i-PrOH,
l
¼254 nm, tR (major)¼21.15 min and tR (minor)¼12.96 min; IR
(thin film): 3392 (br), 3028, 2927, 2856, 1597, 1511, 1445,
1283 cmꢀ1 1H NMR (CDCl3, 400 MHz)
: 7.59e7.61 (m, 1H),
1.0 mL/min flow rate,
l¼254 nm, tR (major)¼26.42 min and tR
(minor)¼15.89 min; 1H NMR (CDCl3, 400 MHz)
: 7.79 (d, J¼7.8 Hz,
d
;
d
1H), 7.40 (d, J¼1.7, 7.6 Hz, 1H), 7.31 (d, J¼8.0 Hz, 2H), 7.27 (m, 2H),
7.09 (d, J¼8.0 Hz, 2H); 6.72 (m, 4H), 5.72 (s, 1H), 3.74 (s, 3H), 3.72 (s,
3H). Anal. Calcd for C23H20ClNO2: C, 73.11; H, 5.33; N, 3.71. Found: C,
73.30; H, 5.36; N, 3.72.
7.36e7.38 (m, 1H), 7.14e7.27 (m, 7H), 6.70 (d, J¼8.8 Hz, 2H), 5.45 (s,
1H), 3.72 (s, 3H), 2.79 (t, J¼7.32 Hz, 2H), 2.51 (t, J¼7.6 Hz, 2H); 13C
(CDCl3, 100 MHz) d: 152.9, 140.5, 137.7, 133.1, 129.7, 129.0, 128.6,
128.5, 128.3, 127.1, 126.2, 115.6, 114.6, 84.6, 79.6, 55.6, 48.7, 34.8,
20.9. Anal. Calcd for C24H22ClNO: C, 76.69; H, 5.90; N, 3.73. Found:
C, 76.93; H, 5.96; N, 3.75.
5.2.8. (R)-[1-(2,4-Dimethylphenyl)-3-(4-methoxyphenyl)-prop-2-
ynyl]-(4-methoxyphenyl)amine (7g) (Table 4, entry 7). Yield 87% ee;
isolated in 92% yield as yellow gel; Rf 0.35 (EtOAc/petroleum
25
5.2.3. (S)-{1-(2,4-Dimethylphenyl)-5-phenyl-pent-2-ynyl}-(4-
methoxyphenyl) amine (7b) (Table 4, entry 2). Yield 97% ee; isolated
in 92% yield as yellow gel; Rf 0.52 (EtOAc/petroleum ether¼1:9);
ether¼1:9); [
a
]
þ116.2 (c 1.0, CHCl3); HPLC conditions: Diacel
D
Chiralpak AD-H (4.6 cm I.D.ꢂ25 cm), 80:20 hexanes/i-PrOH,
1.0 mL/min flow rate,
l
¼254 nm, tR (major)¼20.39 min and tR
[
a]
25 þ69.3 (c 1.1, CHCl3); HPLC conditions: Diacel Chiralpak AD-H
(minor)¼17.09 min; 1H NMR (CDCl3, 400 MHz)
: 7.65 (d, J¼7.6 Hz,
d
D
(4.6 cm I.D.ꢂ25 cm), 95:5 hexanes/i-PrOH, 1.0 mL/min flow rate,
1H), 7.33 (d, J¼8.7 Hz, 2H), 7.05 (m, 2H), 6.79 (d, J¼7.3 Hz, 4H), 6.73
(m, 2H), 5.43 (s, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 2.42 (s, 3H), 2.32 (s,
3H). Anal. Calcd for C25H25NO2: C, 80.83; H, 6.78; N, 3.77. Found: C,
80.99; H, 6.81; N, 3.78.
l
¼254 nm, tR (major)¼15.91 min and tR (minor)¼13.21 min; 1H
NMR (CDCl3, 400 MHz)
d
: 7.96 (d, J¼7.8 Hz, 1H), 7.47 (d, J¼8.3 Hz,
1H), 7.23 (m, 2H), 7.01 (m, 2H), 6.92 (d, J¼8.6 Hz, 2H), 6.75 (d,
J¼8.8 Hz, 2H), 6.62 (d, J¼8.7 Hz, 2H), 5.17 (s, 1H), 3.76 (s, 3H), 2.78 (t,
J¼7.3 Hz, 2H), 2.53 (t, J¼7.3 Hz, 2H), 2.45 (s, 3H), 2.35 (s, 3H). Anal.
Calcd for C26H27NO: C, 84.51; H, 7.37; N, 3.79. Found: C, 84.79; H,
7.39; N, 3.81.
5.2.9. (R)-[1-(2-Chlorophenyl)-3-(4-bromophenyl)-prop-2-ynyl]-(4-
methoxyphenyl)amine (7h) (Table 4, entry 8). Yield 97% ee; isolated
in 95% yield as yellow gel; Rf 0.60 (EtOAc/petroleum ether¼1:9);
[a
]
25 þ91.0 (c 1.0, CHCl3); HPLC conditions: Diacel Chiralpak AD-H
D
5.2.4. (S)-{1-(2-Chloro-phenyl-hept-2-ynyl)}-(4-methoxyphenyl)
amine (7c) (Table 4, entry 3). Yield 87% ee; isolated in 67% yield as
(4.6 cm I.D.ꢂ25 cm), 85:15 hexanes/i-PrOH, 1.0 mL/min flow rate,
l
¼254 nm, tR (major)¼23.46 min and tR (minor)¼12.97 min; 1H
25
yellow gel; Rf 0.60 (EtOAc/petroleum ether¼1:9); [
a
]
þ64.8 (c
NMR (CDCl3, 400 MHz)
d: 7.76 (dd, J¼7.6, 2.0 Hz, 1H), 7.42 (m, 3H),
D
1.2, CHCl3); HPLC conditions: Diacel Chiralpak AD-H (4.6 cm
I.D.ꢂ25 cm), 95:5 hexanes/i-PrOH, 0.5 mL/min flow rate, ¼254 nm,
tR (major)¼11.23 min and tR (minor)¼8.00 min; IR (thin film): 3385,
3061, 2956, 2931, 2865, 1593, 1512, 1466, 1239 cmꢀ1 1H NMR
(CDCl3, 400 MHz)
7.29 (m, 4H), 6.78 (m, 4H), 5.71 (s, 1H), 3.73 (s, 3H). Anal. Calcd for
C22H17BrClNO: C, 61.92; H, 4.02; N, 3.28. Found: C, 62.09; H, 4.05; N,
3.30.
l
;
d
: 7.72 (dd, J¼7.6, 1.96 Hz, 1H), 7.37 (dd, J¼7.4,
5.2.10. (R)-[1-(2,4-Dimethylphenyl)-3-(4-bromophenyl)-prop-2-
ynyl]-(4-methoxyphenyl)amine (7i) (Table 4, entry 9). Yield 99% ee;
1.40 Hz, 1H), 7.19e7.28 (m, 2H), 6.70 (dd, J¼37.7, 12.4 Hz, 4H), 5.48
(s, 1H), 3.71 (s, 3H), 2.18e2.22 (m, 2H), 1.43e1.48 (m, 2H), 1.25e1.38
isolated in 95% yield as yellow gel; Rf 0.58 (EtOAc/petroleum
25
(m, 2H), 0.87 (t, J¼7.3 Hz, 3H); 13C (CDCl3, 100 MHz)
d
: 152.8, 140.5,
ether¼1:9); [
a
]
þ103.7 (c 1.0, CHCl3); HPLC conditions: Diacel
D

3486
A. Bisai, V.K. Singh / Tetrahedron 68 (2012) 3480e3486
18. (a) For a preliminary communication of this work, see; Bisai, A.; Singh, V. K. Org.
Lett. 2006, 8, 2405; (b) For a review, see; Singh, P. K.; Singh, V. K. Pure Appl.
Chem. 2010, 82, 1845.
19. Aschwanden, P.; Stephenson, C. R. J.; Carreira, E. M. Org. Lett. 2006, 8, 2437.
20. Rosa, J. N.; Santos, A. G.; Afonso, C. A. M. J. Mol. Catal. A: Chem. 2004, 214, 161.
21. (a) Weissberg, A.; Halak, B.; Portnoy, M. J. Org. Chem. 2005, 70, 4556; (b) Zeng,
T.; Yang, L.; Hudson, R.; Song, G.; Moores, A. R.; Li, C.-J. Org. Lett. 2011, 13, 442.
22. (a) Chin, J. W.; Cropp, T. A.; Anderson, J. C.; Mukherji, M.; Zhang, Z.; Schultz, P. G.
Science 2003, 301, 964; (b) Wang, L.; Schultz, P. G. Angew. Chem., Int. Ed. 2004, 44,
34; (c) Cropp, T. A.; Schultz, P. G. Trends Genet. 2004, 20, 625.
Chiralpak AD-H (4.6 cm I.D.ꢂ25 cm), 80:20 hexanes/i-PrOH,
1.0 mL/min flow rate,
l
¼254 nm, tR (major)¼15.33 min and tR
(minor)¼13.21 min; 1H NMR (CDCl3, 400 MHz)
: 7.62 (d, J¼7.8 Hz,
d
1H), 7.38 (d, J¼8.5 Hz, 2H), 7.22 (d, J¼8.3 Hz, 2H), 7.04 (m, 2H), 6.76
(dd, J¼32.2, 8.8 Hz,1H); 5.43 (s,1H), 3.73 (s, 3H), 2.41 (s, 3H), 2.32 (s,
3H). Anal. Calcd for C24H22BrNO: C, 68.58; H, 5.28; N, 3.33. Found: C,
68.69; H, 5.27; N, 3.34.
23. (a) Scott, J. W. In Topics in Stereochemistry; Eliel, E. L., Wilen, S. H., Eds.; Wiley:
New York, NY, 1989; Vol. 19, p 209; (b) Kaptain, B.; Boesten, W. H. J.; Broxter-
mann, Q. B.; Peters, P. J. H.; Schoemaker, H. E.; Kamphuis, J. Tetrahedron:
Asymmetry 1993, 4, 1113.
5.3. General experimental procedure for the catalytic
asymmetric alkynylation of a-imino ester
24. (a) Rossen, K. Angew. Chem., Int. Ed. 2001, 40, 4611; (b) Noyori, R.; Ohkuma, T.
Angew. Chem., Int. Ed. 2001, 40, 40; (c) Burk, M. J. Acc. Chem. Res. 2000, 33, 363.
25. (a) Pena, D.; Minnaard, A. J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. Org.
Lett. 2003, 4, 475; (b) Evans, D. A.; Michael, F. E.; Tedrow, J. S.; Campos, K. R.
J. Am. Chem. Soc. 2003, 125, 3534.
The procedure was same as one-pot three-component synthesis
of (R) propargylamines except Cu(II)OTf and ethylglyoxylate were
used instead of Cu(I)PF6 and aromatic aldehydes, respectively.
26. Ji, J.-X.; Xu, J.; Chan, A. S. C. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 11196.
27. Combs, T. L. PCT Int. Appl., 2003, WO 2003/087036; Chem. Abstr. 139, 308017.
28. Kamble, R. K.; Singh, V. K. Tetrahedron Lett. 2003, 44, 5347.
29. Kauffman, G. S.; Harris, G. D.; Dorow, R. L.; Stone, B. R. P.; Parsons, R. L., Jr.; Pesti,
J. A.; Magnus, N. A.; Fortunak, J. M.; Confalone, P. N.; Nugent, W. A. Org. Lett.
2000, 2, 3119.
Acknowledgements
V.K.S. thanks the DST, India for a research grant through J.C. Bose
fellowship. A.B. thanks the CSIR, New Delhi for a Senior Research
Fellowship.
30. Shilov, A. E.; Shul’pin, G. B. Chem. Rev. 1997, 97, 2879.
31. Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, NY, 1994.
32. (a) Nishiyama, H.; Kondo, M.; Nakamura, T.; Itoh, K. Organometallics 1991, 10,
846; (b) Nishiyama, H.; Yamaguchi, S.; Kondo, M.; Itoh, K. J. Org. Chem. 1992, 57,
4306.
Supplementary data
33. Nagashimha, H.; Ueda, T.; Nishiyama, H.; Itoh, K. Chem. Lett. 1993, 347.
34. Nishiyama, H.; Tajima, T.; Takayama, M.; Itoh, K. Tetrahedron: Asymmetry 1993,
4, 1461.
35. (a) Nishiyama, H.; Itoh, Y.; Matsumoto, H.; Park, S.-B.; Itoh, K. J. Am. Chem. Soc.
1994, 116, 2223; (b) Doyle, M. P.; Petersom, C. S.; Zhou, Q.-L.; Nagashimha, H.
Chem. Commun. 1997, 951.
Selected 1H and 13C data of the synthesized compounds. Sup-
plementary data associated with this article can be found in online
version, at doi:10.1016/j.tet.2011.05.114.
36. (a) Evans, D. A.; Murry, J. A.; Kozlowski, M. C. J. Am. Chem. Soc. 1996, 118, 5814;
(b) Evans, D. A.; MacMillan, D. W. C.; Campos, K. R. J. Am. Chem. Soc. 1997, 119,
10859.
References and notes
37. (a) Evans, D. A.; Murry, J. A.; Von Matt, P.; Norcross, R. D.; Miller, S. J. Angew.
Chem., Int. Ed. Engl. 1995, 34, 798; (b) Davies, I. W.; Gerena, L.; Cai, D.; Larsen, R.
D.; Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett. 1997, 38, 1145.
38. Nishiyama, H.; Sakaguchi, H.; Nakamura, T.; Horihata, M.; Kondo, M.; Itoh, K.
Organometallics 1989, 8, 846.
39. For some applications of i-Pr-pybox 1b in enantioselective reactions, see: (a)
Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325; (b) Sammis, G. M.;
Danjo, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 9928; (c) Fischer, C.; Fu, G.
C. J. Am. Chem. Soc. 2005, 127, 4594; (d) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc.
2005, 127, 10482 and references cited therein.
40. (a) DattaGupta, A.; Bhuniya, D.; Singh, V. K. Tetrahedron 1994, 50, 13725;
(b) Ginotra, S.; Singh, V. K. Org. Biomol. Chem. 2006, 4, 4370; (c) Ginotra, S.;
Singh, V. K. Tetrahedron 2006, 62, 3573; (d) Sekar, G.; DattaGupta, A.; Singh, V.
K. J. Org. Chem. 1998, 63, 2961; (e) DattaGupta, A.; Singh, V. K. Tetrahedron Lett.
1996, 37, 2633.
41. (a) Lu, J.; Ji, S.-J.; Teo, Y.-C.; Loh, T.-P. Org. Lett. 2005, 7, 159; (b) Lu, J.; Ji, S.-J.; Loh,
T.-P. Chem. Commun. 2005, 2345; (c) Lu, J.; Hong, M. L.; Ji, S.-J.; Teo, Y. C.; Loh, T.
P. Chem. Commun. 2005, 4217; (d) Lu, J.; Ji, S. J.; Teo, Y.-C.; Loh, T.-P. Tetrahedron
Lett. 2005, 46, 7435.
1. (a) Huffman, M. A.; Yasuda, N.; DeCamp, A. E.; Grabowski, E. J. J. J. Org. Chem.
1995, 60, 1590; (b) Yu, P. H.; Davis, B. A.; Bouton, A. A. J. Med. Chem. 1992, 35,
3705.
2. Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki, T.; VanDuyne, G. D.; Clardy, J. J. Am.
Chem. Soc. 1990, 112, 3715.
€
3. (a) Mecozzi, T.; Petrini, M. J. Org. Chem. 1999, 64, 8970; (b) Franz, D. E.; Fassler,
R.; Carreira, E. M. J. Am. Chem. Soc. 1999, 121, 11245; (c) Carreira, E. M.; Franz, D.
E.; Fassler, R.; Tomooka, C. S. Acc. Chem. Res. 2000, 33, 373; (d) Mahrwald, R.;
Quint, S. Tetrahedron Lett. 2001, 42, 1655; (e) Carriera, E. M. Chimia 2001, 55,
818; (f) Sakai, N.; Hirasawa, M.; Konakahara, T. Tetrahedron Lett. 2003, 44, 4171;
(g) Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. Angew. Chem., Int. Ed. 2003, 42,
4244.
4. (a) Marshall, J. A.; Wolf, M. A. J. Org. Chem. 1996, 61, 3238; (b) Poerwono, H.;
Higashiyama, K.; Takahashi, H. J. Org. Chem. 1998, 63, 2711; (c) Rae, A.; Ker, J.;
Tabor, A. B.; Castro, J.; Parsons, S. Tetrahedron Lett. 1998, 39, 6561.
5. (a) Bloch, R. Chem. Rev. 1998, 98, 1407; (b) Enders, D.; Reinhold, U. Tetrahedron:
Asymmetry 1997, 8, 1895.
6. (a) Mori, Y.; Hayashi, H. Tetrahedron 2000, 58, 1789; (b) Galliford, C. V.; Beenen,
M. A.; Nguyen, S. T.; Scheidt, K. A. Org. Lett. 2003, 5, 3487; (c) Garcia, C. I.;
Tillack, A.; Hartung, C. G.; Beller, M. Tetrahedron Lett. 2003, 44, 3217.
7. (a) Takahashi, T.; Bao, F.; Gao, G.; Ogasawara, M. Org. Lett. 2003, 5, 3479;
(b) Qian, M.; Negishi, E. Org. Process Res. Dev. 2003, 7, 412.
42. (a) Singh, P. K.; Singh, V. K. Org. Lett. 2008, 10, 4121; (b) Singh, P. K.; Singh, V. K.
Org. Lett. 2010, 12, 80.
43. For use of PMPNH2 and their removal under oxidative cleavage, see; (a) Cordova,
ꢁ
A.; Notz, W.; Zhong, G.; Betancort, M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124,
1842; (b) Enders, D.; Grondal, C.; Vrettou, M.; Raabe, G. Angew. Chem., Int. Ed.
2005, 44, 4079; (c) For removal of o-anisidyl group under oxidative condition,
see; Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am. Chem. Soc.
2001, 123, 10409.
8. Tuulmets, A.; Pallin, V.; Tammiku-Taul, J.; Burk, P.; Raie, K. J. Phys. Org. Chem.
2002, 15, 701.
9. (a) Harada, T.; Fujiwara, T.; Iwazaki, K.; Oku, A. Org. Lett. 2000, 2, 1855;
(b) Rosas, N.; Sharma, P.; Alvarez, C.; Gomez, E.; Gutierrez, Y.; Mendez, M.;
Toscano, R. A.; Maldonado, L. A. Tetrahedron Lett. 2003, 44, 8019.
10. Akullian, L. C.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 5971.
11. (a) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638; (b) Wei, C.; Mague, J. T.; Li,
C.-J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5749; (c) For a review, see: Wei, C.; Li,
Z.; Li, C.-J. Synlett 2004, 1472.
44. (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 1806; (b)
Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687.
45. Beckwith, A. L. J.; Zavitas, A. A. J. Am. Chem. Soc. 1986, 108, 8230 and references
cited therein.
46. Fora reviewon the p-stackingeffect in asymmetric synthesis, see: (a) Jones, G. B.;
12. (a) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed.
2003, 42, 5763; (b) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed.
2002, 41, 2535; (c) Koradin, C.; Gommermann, N.; Polborn, K.; Knochel, P. Chem.
Eur. J. 2003, 9, 2997; (d) Gommermann, N.; Knochel, P. Chem. Commun. 2004,
2324; (e) Gommermann, N.; Knochel, P. Chem. Commun. 2005, 4175.
13. Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. Org. Lett. 2003, 5, 3273.
14. (a) Benaglia, M.; Negri, D.; Dell’Anna, G. Tetrahedron Lett. 2004, 45, 8705;
(b) Orlandi, S.; Colombo, F.; Benaglia, M. Synthesis 2005, 1689; (c) Colombo, F.;
Benaglia, M.; Orlandi, S.; Usuelli, F.; Celentano, G. J. Org. Chem. 2006, 71, 2064.
Chapman, B. J. Synthesis 1995, 475; (b) Meyer, E. A.; Castellano, R. K.; Diederich, F.
Angew. Chem., Int. Ed. 2003, 42, 1210.
47. For CH/p interaction between aromatic ring and aliphatic CeH atom, see: (a)
Dreos, R.; Geremia, S.; Nardin, G.; Randaccio, L.; Tauzher, G.; Vuano, S. Inorg.
Chim. Acta 1998, 272, 74; (b) Mandal, D.; Gupta, B. D. Organometallics 2006, 25,
3305.
48. (a) Enzyme Inhibitors as Drugs; Sandler, M., Ed.; The MacMillan Ltd.: London,
1980; (b) Abdulganeeva, S. A.; Erzhanov, K. B. Russ. Chem. Rev. 1991, 60, 676; (c)
Angst, C. Pure Appl. Chem. 1987, 59, 373.
€
15. Knopfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew.
49. (a) Ji, J.-X.; Au-Yeung, T. T.-L.; Wu, J.; Yip, C. W.; Chan, A. S. C. Adv. Synth. Catal.
2004, 346, 42; (b) Shao, Z.; Wang, J.; Ding, K.; Chan, A. S. C. Adv. Synth. Catal.
2007, 349, 2375; (c) Wang, J.; Shao, Z.; Yu, K. D. W. Y.; Chan, A. S. C. Adv. Synth.
Catal. 2009, 351, 1250.
Chem., Int. Ed. 2004, 43, 5971.
16. Jiang, B.; Si, Y.-G. Angew. Chem., Int. Ed. 2004, 43, 216.
17. (a) Wu, T. R.; Chong, J. M. Org. Lett. 2006, 8, 15; (b) Vorogushin, A. V.; Predeus, A.
V.; Wulff, W. D.; Hansen, H. J. J. Org. Chem. 2003, 68, 5826.