Copper-catalyzed enantioselective three-component synthesis of optically active propargylamines from aldehydes, amines, and aliphatic alkynes

Article abstract of DOI:10.1002/chem.200903550

Enantioselective three-component synthesis of propargylamines from aldehydes, amines, and aliphatic alkynes was catalyzed by a Cu^I complex of 1,3-bis (imidazolin-2-ly)pyridine (pybim). The reaction is applied to a wide variety of aromatic aldeh

Full text of DOI:10.1002/chem.200903550

DOI: 10.1002/chem.200903550
Copper-Catalyzed Enantioselective Three-Component Synthesis of Optically
Active Propargylamines from Aldehydes, Amines, and Aliphatic Alkynes
Shuichi Nakamura,* Mutsuyo Ohara, Yuko Nakamura, Norio Shibata, and
Takeshi Toru[a]
Optically active propargylamines are important synthetic
intermediates for the preparation of various natural prod-
ucts[1] and biologically active compounds.[2] A typical route
to prepare chiral propargylamines is the stereoselective ad-
dition of terminal alkynes to imines.[3] Since the pioneering
work of Li and co-workers on the highly enantioselective
three-component reaction of aldehydes, amines, and alkynes
by using 1,3-bis(oxazolin-2-yl)pyridine ligands (pybox)[4] and
a copper salt to give optically active propargylamines,[5] re-
markable progress has been made in the copper-catalyzed
three-component reaction because of the simplified opera-
tion.[6,7] Although there are many reports on the highly
enantioselective addition of aryl- and silyl-substituted al-
kynes with in situ generated imines, the three-component re-
action with aliphatic terminal alkynes remains unsolved
probably due to the low steric hindrance of alkyl alkynes. To
the best of our knowledge, there exist only a handful of ex-
amples of highly enantioselective three-component reactions
of aldehydes, amines, and aliphatic alkynes with chiral cata-
lysts.[6a,c,f,g] Recently, Singh and Bisai reported the highly
enantioselective synthesis of propargylamines through the
three-component reaction by using bulky pybox–CuI cata-
lysts; however, the reaction with aliphatic alkynes afforded
products with lower enantioselectivity (up to 87% enantio-
meric excess (ee)) than that with aryl-substituted alkynes.[6g]
The best result for this type of reaction with an aliphatic
alkyne was reported by Carreira and co-workers, in which
an enantioselective three-component reaction of 2-methyl-
butanal, dibenzylamine, and 1-hexyne as an aliphatic alkyne
with a chiral pinap–CuI catalyst (pinap=[2-(diphenylphos-
phino)-1-naphthalenyl]-N-(1-phenylethyl)-1-phthalazina-
mine) gave a product with 94% ee.[6c] Therefore, expanding
the scope of catalytic enantioselective three-component re-
actions with respect to both the chiral catalyst and the sub-
strate would be highly desirable. On the other hand, we re-
cently developed chiral bis(imidazoline)–CuII catalysts as
highly tuneable chiral catalysts.[8,9] Herein, our ongoing in-
terest was extended to a highly enantioselective three-com-
ponent reaction of aldehydes, amines, and aliphatic alkynes
by using a chiral bis(imidazoline)–CuI catalyst.
We first examined the reaction of benzaldehyde, p-anisi-
dine, and 4-phenylbutyne as the aliphatic alkyne with CuI
catalysts of chiral bis(imidazoline)s 1a–1h. The results are
shown in Table 1. When the reaction was carried out with
N-tosyl 1,3-bis(imidazolin-2-ly)pyridine (N-Ts-pybim, 1a,
10 mol%)[10] as the ligand, 1a–(CuOTf)2·toluene complex
gave product 3 with moderate enantioselectivity, whereas,
the reaction with N-benzoyl pybim, 1b–(CuOTf)2·toluene
complex afforded 3 in 93% yield with 98% ee (Table 1, en-
tries 1 and 2). After fine-tuning various substituents on the
nitrogen in the imidazolines, the benzoyl group was found
to be the best substituent to obtain a high yield with high
enantioselectivity (Table 1, entries 3–6). On the other hand,
the desired enantioselective addition product was formed in
low enantioselectivity by using the bidentate 1,3-bis(imida-
zolin-2-ly)benzene (Phebim) with (CuOTf)2·toluene in
CH2Cl2 (Table 1, entries 7 and 8). The reaction with the
pybox ligand 2 afforded 3 with good enantioselectivity, but
in low yield (Table 1, entry 9). The reaction with the use of
various copper salts, such as CuCl, CuI, [Cu
and Cu(OTf)2, did not afford good results (Table 1, en-
tries 10–13).
ACHTNUGERTN(NUGN CH3CN)4]PF6,
AHCTUNGTRENNUNG
[a] Prof. S. Nakamura, M. Ohara, Y. Nakamura, Prof. N. Shibata,
Prof. T. Toru
Department of Frontier Materials, Graduate School of Engineering
Nagoya Institute of Technology, Gokiso, Showa-ku
Nagoya 466-8555 (Japan)
Fax : (+81)52-735-5245
E-mail: snakamur@nitech.ac.jp
Optimization experiments, for both amines and solvents,
were carried out to improve both the yield and enantioselec-
tivity of the reaction in the presence of 1b–
(CuOTf)2·toluene complex (Table 2), the reaction with p-
anisidine in CH2Cl2 was very effective for the three-compo-
nent synthesis of propargylamines (Table 2, entry 1).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903550.
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Chem. Eur. J. 2010, 16, 2360 – 2362

COMMUNICATION
Table 1. Enantioselective three-component reaction with various chiral
ligands and copper salts.[a]
with (CuOTf)2·toluene, the results of which are summarized
in Table 3. The reaction of imines derived from benzalde-
hyde and p-anisidine with various aliphatic alkynes afforded
Table 3. Enantioselective three-component reaction of various aldehydes
and alkynes by using 1b–CuI.[a]
Entry Aldehyde (R1) Alkyne (R2)
Product
t
Yield ee
[%] [%]
[h]
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH2CH2Ph
CH2CH2CH3
T
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
12 93
98
95
96
97
96
94
94
96
98
98
94
95
92
89
93
96
92
93
98
95
92
81
2[b]
3[b]
4
36 69
84 73
36 83
60 78
36 58
60 75
60 73
60 65
72 61
96 90
36 82
120 28
84 89
108 86
84 75
84 62
36 84
96 74
84 78
60 84
108 39
Entry
Ligand
Cu salt
(CuOTf)2·toluene
(CuOTf)2·toluene
(CuOTf)2·toluene
(CuOTf)2·toluene
(CuOTf)2·toluene
(CuOTf)2·toluene
(CuOTf)2·toluene
(CuOTf)2·toluene
(CuOTf)2·toluene
Yield [%]
ee [%][b]
E
5
6
7
8
R
1
1a
1b
1c
1d
1e
1 f
1g
1h
2
1b
1b
1b
1b
U
61
93
79
82
38
54
19
71
33
trace
–
84
98
97
95
87
93
22
4
82
–
–
91
90
cyclopropyl
cyclopentyl
cyclohexyl
CH2CH2Br
CH2CH2OH
2[c]
3
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
4
5
6
7
8
9
10
11
12
13
ACHTUNGTRENNUNG
9
ACHTUNGTRENNUNG
10
11
12
13
14
15
16
17
18
19
20
21
22
ACHTUNGTRENNUNG
CACHTNGUTERNNU(G CH3)2OH
ACHTUNGTRENNUNG
Ph
ACHTUNGTRENNUNG
Ph
TMS[c]
G
2-MeOC6H4
2-ClC6H4
3-MeOC6H4
3-ClC6H4
4-MeOC6H4
4-ClC6H4
4-NO2C6H4
1-naphthyl
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CuCl
CuI
[Cu
N
19
53
CuAHCTUNGRT(EUNNNG OTf)2
[a] Reaction conditions: PhCHO (0.25 mmol), p-anisidine (0.3 mmol), 4-
phenylbutyne (0.37 mmol), Cu salt (0.025 mmol), 1 (0.025 mmol) at RT
for 36 h; OTf=trifluoromethanesulfonate, Ts=tosyl, Bz=benzoyl. [b] ee
was determined by HPLC analysis by using chiral columns. [c] Performed
at RT for 12 h.
AHCTNURTGEG(NNNU CH3)2CHCH2
[a] Reaction conditions: aldehyde (0.25 mmol), amine (0.3 mmol), alkyne
(0.37 mmol), (CuOTf)2·toluene (0.025 mmol), and 1 (0.025 mmol) at RT.
[b] Alkyne (3 equiv) was used. [c] TMS=trimethylsilyl.
Table 2. Enantioselective three-component reaction with various amines
in various solvents.[a]
products 3–10 with high enantioselectivity (Table 3, en-
tries 1–8). The reaction with alkynes containing a halogen
and a hydroxy group gave good enantioselectivities (Table 3,
entries 9–11). The reaction with phenylacetylene as an ex-
ample of an aryl alkyne also gave product 14 in high yield
with high enantioselectivity (Table 3, entry 12). Although
the reaction with trimethylsilylacetylene afforded product 15
in low yield, the reaction with 2-methyl-3-butyn-2-ol, which
acts as an acetylide anion equivalent, gave product 13 in
high yield with high enantioselectivity (Table 3, entry 11 vs.
13). The reaction with various aromatic aldehydes also gave
products 16–23 with good enantioselectivity (Table 3, en-
tries 14–21).
Entry
Amine
Solvent
Yield [%]
ee[b] [%]
1
2
3
4
5
6
7
8
9
p-MeOC6H4NH2
C6H5NH2
o-MeOC6H4NH2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
ClCH2CH2Cl
Et2O
toluene
H2O
93
38
trace
trace
10
90
75
9
40
98
93
–
(PhCH2)2NH
–
p-MeOC6H4NH2
p-MeOC6H4NH2
p-MeOC6H4NH2
p-MeOC6H4NH2
p-MeOC6H4NH2
92
98
94
83
90
In conclusion, we have developed an enantioselective
three-component reaction of aldehydes, amines, and aliphat-
ic alkynes catalyzed by C2-symmetric pybim CuI catalysts to
give propargylamines in good yields and with high enantio-
selectivity. This process has many advantages, such as simpli-
fied operation and mild reaction conditions. These results
open a novel way to synthesize optically active propargyl-
amines. The scope, mechanism, and synthetic application of
[a] Reaction conditions: PhCHO (0.25 mmol), amine (0.3 mmol), 4-phe-
nylbutyne (0.37 mmol), (CuOTf)2·toluene (0.025 mmol), and
(0.025 mmol) at RT for 36 h. [b] ee was determined by HPLC analysis by
1
using chiral columns.
With these optimized conditions, a variety of aldehydes
and alkynes were examined by using the combination of 1b
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www.chemeurj.org
2361

S. Nakamura et al.
À
[6] For the enantioselective three-component reaction of aldehydes,
amines, and alkynes, see: a) N. Gommermann, C. Koradin, K. Pol-
born, P. Knochel, Angew. Chem. 2003, 115, 5941–5944; Angew.
Chem. Int. Ed. 2003, 42, 5763–5766; b) N. Gommermann, P. Kno-
chel, Chem. Commun. 2004, 2324–2325; c) T. F. Knçpfel, P. Asch-
wanden, T. Ichikawa, T. Watanabe, E. M. Carreira, Angew. Chem.
2004, 116, 6097–6099; Angew. Chem. Int. Ed. 2004, 43, 5971–5973;
d) N. Gommermann, P. Knochel, Synlett 2005, 2799–2801; e) N.
Gommermann, P. Knochel, Chem. Commun. 2005, 4175–4177; f) J.-
X. Ji, J. Wu, A. S. C. Chan, Proc. Natl. Acad. Sci. USA 2005, 102,
11196–11200; g) A. Bisai, V. K. Singh, Org. Lett. 2006, 8, 2405–
2408; h) Z. Shao, X. Pu, X. Li, B. Fan, A. S. C. Chan, Tetrahedron:
Asymmetry 2009, 20, 225–229; with zinc catalysts, see: L. Zani, T.
Eichhorn, C. Bolm, Chem. Eur. J. 2007, 13, 2587–2600.
[7] For recent examples of catalytic enantioselective additions of al-
kynes to imines, see: a) F. Colombo, M. Benaglia, S. Orlandi, F.
Usuelli, G. Celentano, J. Org. Chem. 2006, 71, 2064–2070; b) M.
Rueping, A. P. Antonchick, C. Brinkmann, Angew. Chem. 2007, 119,
7027–7030; Angew Chem. Int. Ed. 2007, 46, 6903–6906; c) J. Liu, B.
Liu, X. Jia, X. Li, A. S. C. Chan, Tetrahedron: Asymmetry 2007, 18,
396–399; d) B. Liu, L. Huang, J. Liu, Y. Zhong, X. Li, A. S. C.
Chan, Tetrahedron: Asymmetry 2007, 18, 2901–2904; e) R. Dodda,
C.-G. Zhao, Tetrahedron Lett. 2007, 48, 4339–4342; f) G. Blay, L.
Cardona, E. Climent, J. R. Pedro, Angew. Chem. 2008, 120, 5675–
5678; Angew Chem. Int. Ed. 2008, 47, 5593–5596; g) M. Hatano, T.
Asai, K. Ishihara, Tetrahedron Lett. 2008, 49, 379–382; h) M. Irmak,
M. M. K. Boysen, Adv. Synth. Catal. 2008, 350, 403–405.
the enantioselective reaction as well as other C C bond for-
À
mations through C H activation are under investigation.
Experimental Section
General procedure: A solution of ligand 1b (0.025 mmol, 10 mol%) and
(CuOTf)2·toluene (0.025 mmol, 10 mol%) in dry CH2Cl2 (0.6 mL) was
stirred at RT (23–258C) for 1 h. An aldehyde (0.25 mmol), p- anisidine
(0.30 mmol), and an alkyne (0.37 mmol) were added and the whole mix-
ture was stirred at RT. After completion of the reaction, as monitored by
TLC, the mixture was concentrated and purified over silica gel by
column chromatography (hexane/EtOAc 90:10) yielding pure propargyla-
mines.
Acknowledgements
This work was partly supported by the Mitsubishi Chemical Corporation
Fund.
Keywords: alkynylation
·
asymmetric
catalysis
·
enantioselectivity · imidazolines · multicomponent reactions
[8] a) S. Nakamura, K. Hyodo, Y. Nakamura, N. Shibata, T. Toru, Adv.
Synth. Catal. 2008, 350, 1443–1448; for related recent studies from
our group, see: b) N. Hara, S. Nakamura, N. Shibata, T. Toru, Chem.
Eur. J. 2009, 15, 6790–6793; c) S. Nakamura, N. Hara, H. Nakashi-
ma, K. Kubo, N. Shibata, T. Toru, Chem. Eur. J. 2008, 14, 8079–
8081; d) S. Nakamura, H. Nakashima, H. Sugimoto, H. Sano, M.
Hattori, N. Shibata, T. Toru, Chem. Eur. J. 2008, 14, 2145–2152;
e) S. Nakamura, H. Nakashima, A. Yamamura, N. Shibata, T. Toru,
Adv. Synth. Catal. 2008, 350, 1209–1212; f) S. Nakamura, Y. Sakurai,
H. Nakashima, N. Shibata, T. Toru, Synlett 2009, 1639–1642.
[9] For a recent review on bis(imidazoline)ligands, see: H. Liu, D.-M.
Du, Adv. Synth. Catal. 2009, 351, 489–519, and references therein.
[10] For pybim ligands, see: a) S. Bhor, G. Anilkumar, M. K. Tse, M.
Klawonn, C. Dçbler, B. Bitterlich, A. Grotevendt, M. Beller, Org.
Lett. 2005, 7, 3393–3396; b) G. Anilkumar, S. Bhor, M. K. Tse, M.
Klawonn, B. Bitterlich, M. Beller, Tetrahedron: Asymmetry 2005, 16,
3536–3561; c) K. Ma, J. You, Chem. Eur. J. 2007, 13, 1863–1871;
d) S. Enthaler, B. Hagemann, S. Bhor, G. Anilkumar, M. K. Tse, B.
Bitterlich, K. Junge, G. Erre, M. Beller, Adv. Synth. Catal. 2007, 349,
853–860.
[1] a) M. Konishi, H. Ohkuma, T. Tsuno, T. Oki, G. VanDuyne, J.
Clardy, J. Am. Chem. Soc. 1990, 112, 3715–3716; b) B. M. Trost,
C. K. Chung, A. B. Pinkerton, Angew. Chem. 2004, 116, 4427–4429;
Angew. Chem. Int. Ed. 2004, 43, 4327–4329; c) M. H. Davidson,
F. E. McDonald, Org. Lett. 2004, 6, 1601–1603.
[2] a) M. A. Huffman, N. Yasuda, A. E. DeCamp, E. J. J. Grabowski, J.
Org. Chem. 1995, 60, 1590–1594; b) G. S. Kauffman, G. D. Harris,
R. L. Dorow, P. R. Stone, R. L. Parsons, J. Pesti, Jr., N. A. Magnus,
J. M. Fortunak, P. N. Confalone, W. A. Nugent, Org. Lett. 2000, 2,
3119–3121; c) S. N. Osipov, P. Tsouker, L. Hennig, K. Burger, Tetra-
hedron 2004, 60, 271–274.
[3] For reviews, see: a) B. M. Trost, A. H. Weiss, Adv. Synth. Catal.
2009, 351, 963–983; b) L. Zani, C. Bolm, Chem. Commun. 2006,
4263–4275; c) C.-M. Wei, Z.-G. Li, C.-J. Li, Synlett 2004, 1472–
1483; d) P. G. Cozzi, R. Hilgraf, N. Zimmermann, Eur. J. Org. Chem.
2004, 4095–4105.
[4] For a recent review on pybox ligands, see: a) G. Desimoni, G. Faita,
P. Quadrelli, Chem. Rev. 2003, 103, 3119–3154; for the first report
of pybox, see: b) H. Nishiyama, H. Sakaguchi, T. Nakamura, M. Ho-
rihata, M. Kondo, K. Itoh, Organometallics 1989, 8, 846–848.
[5] a) C. Wei, C.-J. Li, J. Am. Chem. Soc. 2002, 124, 5638–5639; b) C.
Wei, J. T. Mague, C.-J. Li, Proc. Natl. Acad. Sci. USA 2004, 101,
5749–5754.
Received: December 26, 2009
Published online: January 27, 2010
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Chem. Eur. J. 2010, 16, 2360 – 2362