Enantioselective one-pot three-component synthesis of propargylamines

Article abstract of DOI:10.1021/ol060793f

A copper(I) complex of i-Pr-pybox-diPh has been found to be an efficient catalyst for an enantioselective one-pot three-component synthesis of propargylamines from aldehydes, amines, and alkynes. The reaction has been applied to a wide variety of aromatic

Full text of DOI:10.1021/ol060793f

ORGANIC
LETTERS
2006
Vol. 8, No. 11
2405-2408
Enantioselective One-Pot
Three-Component Synthesis of
Propargylamines
Alakesh Bisai and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology, Kanpur, India 208 016
Vinodks@iitk.ac.in
Received April 3, 2006
ABSTRACT
A copper(I) complex of i-Pr-pybox-diPh has been found to be an efficient catalyst for an enantioselective one-pot three-component synthesis
of propargylamines from aldehydes, amines, and alkynes. The reaction has been applied to a wide variety of aromatic aldehydes with excellent
yields (up to 99%) and enantiomeric excesses (up to 99% ee). A transition-state model has been proposed to explain the stereochemical
outcome of the reaction.
The enantioselective addition of terminal alkynes to imines
provides direct access to optically active propargylamines,
which are important for the synthesis of many biologically
active nitrogen compounds.1 This is an important C-C bond
formation reaction that proceeds via C-H bond activation
by a metal complex.2 A variety of chiral ligands have been
used in this reaction. High asymmetric induction has been
reported using quinap ligands.3,4 A metal complex of chiral
amino acids,5 chiral alcohols,6 and chiral binaphthylamines7
has also been used in this reaction. Although reasonable
progress has been made in this area, tunable and easily
procured ligands are often desired because of their strong
substrate dependence in most cases. Even small changes in
conformational, steric, and/or electronic properties of the
chiral ligands can often lead to dramatic variation in the
enantioselectivity. The pybox ligand of the type 1a (Figure
1) has marked a place in the area of enantioselective
reactions.8,9
(1) (a) Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki, T.; VanDuyne, G.;
Clardy, J. J. Am. Chem. Soc. 1990, 112, 3715. (b) Huffman, M. A.; Yasuda,
N.; DeCamp, A. E.; Grabowski, E. J. Org. Chem. 1995, 60, 1590. (c)
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.
During our pursuit in this area, we used i-Pr-pybox-diPh
1b for enantioselective cyclopropanation10 and enantiose-
(5) (a) Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. Org. Lett. 2003,
5, 3273. (b) Akullian, L. C.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2003, 42, 5971.
(2) (a) Shilov, A. E.; Shul’pin, G. B. Chem. ReV. 1997, 97, 2879. (b)
Bloch, R. Chem. ReV. 1998, 98, 1407.
(3) (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) Gommer-
mann, N.; Knochel, P. Chem. Commun. 2004, 2324. (e) Gommermann, N.;
Knochel, P. Chem. Commun. 2005, 4175.
(6) Jiang, B.; Si, Y.-G. Angew. Chem., Int. Ed. 2004, 43, 216.
(7) (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.
(8) The pybox ligand 1a was first introduced by Professor Nishiyama.
For reference, see: Nishiyama, H.; Sakaguchi, H.; Nakamura, T.; Horihata,
M.; Kondo, M.; Itoh, K. Organometallics 1989, 8, 846.
(4) Kno¨pfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira,
E. M. Angew. Chem., Int. Ed. 2004, 43, 5971.
10.1021/ol060793f CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/06/2006

Table 1. Solvent Study on Enantioselectivity
Cu
%
ee
entry salt-liganda
solvent temp
time
5 h
4 days
36 h
8 h
19 h
6 h
5 h
yield (%)b,c
Figure 1. C2 symmetric pyridine bis(oxazoline) ligands.
1
2
3
4
5
6
7
8d
9
CuIPF6-1b
CuIPF6-1c
CuIPF6-1b
CuIPF6-1b
CuIPF6-1b
CuIPF6-1b
CuIPF6-1b
CuIPF6-1b
CuIPF6-1b
CuIPF6-1b
CuIPF6-1be
CuIOTf-1b
CuIOTf-1be
toluene rt
toluene rt
hexane rt
95
43
72
99
92
99
99
92
98
80
98
95
94
95
85
85
56
63
90
62
93
95
95
96
96
96
95
96
94
94
lective allylic oxidation of olefins.11 We observed that the
diphenyl group at the 5-carbon of the oxazoline rings played
a crucial role in enhancing the ee in the enantioselective
allylic oxidation of olefins. Looking at the lower enantiose-
lectivity (<45% ee) with the pybox ligand 1a,12 one would
not think of using ligand 1b for the addition of an alkyne to
an imine. Nevertheless, on the basis of our intuition, we used
it in this reaction, and to our delight, the enantioselectivity
was excellent. It was further observed that there was no need
to use preformed imine, and the reaction worked in one-pot
fashion as well. Above all, N-protected amines such as
p-methoxyphenylamine also gave high ee. In this paper, we
wish to report the preliminary results of this reaction.
At the outset, the three-component coupling reaction was
examined by taking a 1:1:1.5 mixture of benzaldehyde,
aniline, and phenylacetylene at 0-25 °C in chloroform for
12 h using 10 mol % of a complex of 1b with Cu-
(MeCN)4PF6. The product was obtained in 98% yield and
96% ee (Table 1, entry 9). This result was highly promising
in contrast to the results obtained from the ligands 1a and
1c, which required 4 days for completion of the reaction with
much lower enantioselectivities of less than 45% and 56%
ee, respectively. This clearly indicated that diphenyl groups
have a drastic effect in enhancing the ee and reducing the
reaction time. The reaction was carried out in different
solvents (Table 1), but chloroform gave the best results. The
enantioselectivity was similar (96% ee) if (CuOTf)2‚PhMe
(Table 1, entry 13) was used as a salt. The reaction was
equally catalyzed with an almost similar enantioselectivity
(94% ee) by using Cu(II) triflate as a salt.
DCE
EtOAc
rt
rt
CH2Cl2 rt
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
rt
rt
16 h
12 h
0-rt
10 °C 43 h
10
11
12
13
14
15
0-rt
0-rt
0-rt
0-rt
0-rt
12 h
12 h
18 h
24 h
72 h
Cu(OTf)2-1b CHCl3
Cu(OTf)2-1be CHCl3
a 10 mol % of the complex was used unless stated otherwise. b ee’s were
determined by a Chiralcel OD-H column using 2-propanol and hexane as
eluent. c The absolute configuration was made by analogy according to the
literature data. d 4 Å MSs were also used. e 5 mol % of the complex was
used.
entry 9) using aniline as an aromatic amine. The chemical
yield was excellent in most of the cases.
Table 2. Effect of Different Aldehydes on Enantioselectivitya
entry
Ar
time (h)
% yieldb,c
ee (%)d
1
2
3
4
5
6
7
8
9
4-i-Pr-Ph
4-NO2-Ph
3-Me-Ph
4-Cl-Ph
3-F-Ph
3-Br-Ph
3,5-diMe-Ph
3-Cl-4-F-Ph
2-Cl-Ph
20
28
12
24
28
26
12
26
12
89
82
91
94
85
92
98
97
93
95 (R)
94 (R)
96 (R)
96 (R)
93 (R)
91 (R)
95 (R)
91 (R)
98 (S)
The reaction was extended to different aldehydes, and most
of them gave high enantioselectivity (Table 2). Both electron-
rich and -poor aldehydes gave 94-95% ee in this one-pot
reaction (Table 2, entries 1 and 2). A maximum of 98% ee
was obtained in the case of 2-chlorobenzaldehyde (Table 2,
(9) For some applications of the pybox ligand 1a in enantioselective
reactions, see: (a) Nishiyama, H.; Itoh, Y.; Matsumoto, H.; Park, S.-B.;
Itoh, K. J. Am. Chem. Soc. 1994, 116, 2223. (b) Johnson, J. S.; Evans, D.
A. Acc. Chem. Res. 2000, 33, 325. (c) Sammis, G. M.; Danjo, H.; Jacobsen,
E. N. J. Am. Chem. Soc. 2004, 126, 9928. (d) Fischer, C.; Fu, G. C. J. Am.
Chem. Soc. 2005, 127, 4594. (e) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc.
2005, 127, 10482.
a All the reactions were done under an argon atmosphere. b Ratio of
CuIPF6, i-Pr-pybox-diPh, aldehyde, aniline, and phenylacetylene was 0.05:
0.06:1:1:1.5. c Isolated yield after column chromatography over silica gel
using 5-10% of EtOAc in hexane. d Enantiomeric excess was determined
by HPLC using Chiralcel OD-H and Chiralpak AD-H columns (see
Supporting Information).
(10) DattaGupta, A.; Bhuniya, D.; Singh, V. K. Tetrahedron 1994, 50,
13725.
(11) (a) Ginotra, S.; Singh, V. K. Tetrahedron 2006, 62, 3573. (b) Sekar,
G.; DattaGupta, A.; Singh, V. K. J. Org. Chem. 1998, 63, 2961. (c)
DattaGupta, A.; Singh, V. K. Tetrahedron Lett. 1996, 37, 2633.
(12) (a) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638. (b) Wei,
C.; Mague, J. T.; Li, C.-J. PNAS 2004, 101, 5749. (c) For a review, see:
Wei, C.; Li, Z.; Li, C.-J. Synlett 2004, 1472.
We, then, extended the three-component coupling reaction
by using different aromatic amines. Halogen-substituted
aromatic amines were found to be equally efficient. For
2406
Org. Lett., Vol. 8, No. 11, 2006

instance, 4-bromoaniline gave 96% ee in the above reaction
(Table 3, entry 3). To our delight, we could get more than
efficient as 99% ee was obtained in the case of 2,4-
dimethylbenzaldehyde (Table 4, entry 14). The reaction
worked very well in the case of aliphatic alkynes (Table 4,
entries 10 and 11).
Further, we examined the effect of a variety of terminal
alkynes on the asymmetric induction in the reaction. It is
noteworthy that the enantioselectivity was excellent in all
the substituted aromatic alkynes (Table 5, entries 2-4).
Table 3. Effect of Different Aromatic Amines on
Enantioselectivity
Table 5. Effect of Different Terminal Alkynes on
Enantioselectivity
entry
Ar
Ph
3-F-Ph
4-Br-Ph
3-Cl-Ph
PMP
R
time (h)
% yielda
ee (%)
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
Ph
12
24
24
24
48
16
98
93
98
93
56
98
96
95
96
95
77
90b
PMP
entry
R
time (h)
% yielda
ee (%)b
a Isolated yield after column chromatography. b 10 mol % of the complex
was used.
1
2
3
4
5
6
Ph
16
18
20
20
42
28
98
98
96
93
86
67
90
93
93
90
84
87
4-Me-Ph
4-MeO-Ph
4-Br-Ph
PhCH2CH2
n-Bu
90% ee in this reaction using p-methoxyphenyl (PMP)
amines, which could be oxidatively removed (Table 3, entry
6).13 Using PMP amines, we carried out the reaction with
different aldehydes and alkynes (Table 4). It is very clear
a Isolated yield after column chromatography. b Enantiomeric excess was
determined by HPLC using a Chiralpak AD-H column.
However, aliphatic alkynes afforded propargylamines
with slightly lower ee’s and the reaction was also slug-
gish in comparison with aromatic alkynes (Table 5, entries
5 and 6).
Table 4. Reactions with p-Methoxyanilinea
The mechanism of this type of reaction has been proposed
previously.3,7c There is enough evidence in the literature that
Cu(I) salt can form a pentacoordinated (distorted trigonal
bipyramid) complex through a Cu(III) intermediate, which
has been detected spectroscopically.11b,14 Our results inferred
the superiority of the i-Pr-pybox-diPh ligand over i-Pr-pybox-
diEt and i-Pr-pybox. On the basis of our earlier experience
on the enantioselective allylic oxidation of olefins using the
same kind of ligands,11 we propose that the ‘N’ of an imine
prefers to chelate the Cu complex in a manner where there
are three stabilizing π-interactions; two C-H‚‚‚π and one
π‚‚‚π as indicated in Figure 2. In this favored model, the
aryl group on the sp2 carbon of the imine could orient itself
in a manner so 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 distance (∼3.5 Å) from
the aryl ring so as to provide stabilizing interactions.15 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 because of the above three
stabilizing interactions, and the copper acetylide attacks the
entry
Ar
R
time (h) % yield ee (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3-Me-Ph
4-i-Pr-Ph
4-Cl-Ph
3-F-Ph
4-F-Ph
3-Br-Ph
3-Cl-Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
22
22
28
26
24
26
16
16
16
48
48
16
16
18
99
87
91
90
95
96
92
90
94
61
67
98
90
97
92 (R)
83 (R)
90 (R)
85 (R)
91 (R)
80 (R)
82 (R)
86 (R)
97 (S)
85 (S)
87 (S)
93 (R)
90 (R)
99 (S)
3-Cl-4-F-Ph Ph
2-Cl-Ph
2-Cl-Ph
2-Cl-Ph
3,5-diMe-Ph Ph
4-NO2-Ph Ph
2,4-diMe-Ph Ph
Ph
PhCH2CH2
n-Bu
a Ratio of CuIPF6, i-Pr-pybox-diPh, aldehyde, p-methoxyaniline, and
phenylacetylene was 0.10:0.12:1.0:1.0:1.5. b Enantiomeric excess was
determined by a Chiralpak AD-H column.
from the table that the synthesis of propargylamine by this
one-pot protocol catalyzed by a Cu(I) complex of 1b is
(14) Beckwith, A. L. J.; Zavitas, A. A. J. Am. Chem. Soc. 1986, 108,
8230 and references therein.
(13) (a) Co´rdova, 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.
(15) For a review on the π-stacking effect in asymmetric synthesis, see:
(a) Jones, G. B.; Chapman, B. J. Synthesis 1995, 475. (b) Meyer, E. A.;
Castellano, R. K.; Diederich, F. Angew. Chem., Int. Ed. 2003, 42, 1210.
Org. Lett., Vol. 8, No. 11, 2006
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found to be an effective catalyst for the enantioselective
three-component synthesis of aromatic alkynylamines from
aldehydes, amines, and alkynes. The reaction is complete in
a few hours. The procedure is operationally very simple and
can furnish a wide variety of propargylamines in good to
excellent yields with excellent enantioselectivities (up to 99%
ee). We have also explained the stereochemical outcome of
these type of reactions by invoking a transition-state model.
These results open a novel way to design and synthesize
new chiral ligands for enantioselective reactions.16,17
Acknowledgment. V.K.S. thanks the Department of
Science and Technology, India, for a research grant. A.B.
thanks the Council of Scientific and Industrial Research, New
Delhi, for a Senior Research Fellowship.
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL060793F
(16) The chiral ligand 1b has also been used for other enantioselective
reactions. For references, see: (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.
Figure 2. Proposed transition-state model.
(17) General Procedure for the enantioselective three-component synthesis
of propargylamines catalyzed by the Cu(I)-(S,S)-1b complex: A solution
of ligand 1b (0.012 mmol, 6 mol %) and CuI(MeCN)4PF6 (0.010 mmol, 5
mol %) in dry chloroform (2 mL) was stirred at room temperature for 30
min. An aldehyde (0.20 mmol) and an aromatic amine (0.20 mmol) were
added, and the whole mixture was stirred for an additional 15 min at the
same temperature. The reaction mixture was cooled to 0 °C, and an alkyne
(0.30 mmol) was added. The reaction mixture was allowed to warm to 20-
25 °C. After completion of the reaction (monitoring by TLC), the mixture
was concentrated in vacuo and purified over silica gel by column
chromatography (2-10% EtOAc in hexane) yielding pure propargylamine.
imine from the si face to provide propargylamine. The re
face attack is retarded because of the â-alkyl group on the
chiral carbon atom of the left oxazoline ring. In an unfavored
model, 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 nonbonding repulsion.
In conclusion, the chiral Cu(I)-1b complex prepared from
CuIPF6 and the C2-symmetric i-Pr-pybox-diPh ligand 1b was
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Org. Lett., Vol. 8, No. 11, 2006