Copper-catalyzed enantioselective propargylic amination of propargylic esters with amines: Copper-allenylidene complexes as key intermediates

Article abstract of DOI:10.1021/ja1047494

The scope and limitations of the copper-catalyzed propargylic amination of various propargylic esters with amines are presented, where optically active diphosphines such as Cl-MeO-BIPHEP and BINAP work as good chiral ligands. A variety of secondary amines are available as nucleophiles for this catalytic reaction to give the corresponding propargylic amines with a high enantioselectivity. The results of some stoichiometric and catalytic reactions indicate that the catalytic amination proceeds via copper-allenylidene complexes formed in situ, where the attack of amines to the electrophilic γ-carbon atom in the allenylidene complex is an important step for the stereoselection. Investigation of the relative rate constants for the reaction of several para-substituted propargylic acetates with N-methylanilines reveals that the formation of the copper-allenylidene complexes is involved in the rate-determining step. The result of the density functional theory calculation on a model reaction also supports the proposed reaction pathway involving copper-allenylidene complexes as key intermediates. The catalytic procedure presented here provides a versatile and direct method for the preparation of a variety of chiral propargylic amines.

Full text of DOI:10.1021/ja1047494

Published on Web 07/09/2010
Copper-Catalyzed Enantioselective Propargylic Amination of
Propargylic Esters with Amines: Copper-Allenylidene
Complexes as Key Intermediates
Gaku Hattori,† Ken Sakata,*,‡ Hiroshi Matsuzawa,† Yoshiaki Tanabe,†
Yoshihiro Miyake,† and Yoshiaki Nishibayashi*,†
Institute of Engineering InnoVation, School of Engineering, The UniVersity of Tokyo, Yayoi,
Bunkyo-ku, Tokyo 113-8656, Japan, and Faculty of Pharmaceutical Sciences, Hoshi UniVersity,
Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
Received June 1, 2010; E-mail: ynishiba@sogo.t.u-tokyo.ac.jp; sakata@hoshi.ac.jp
Abstract: The scope and limitations of the copper-catalyzed propargylic amination of various propargylic
esters with amines are presented, where optically active diphosphines such as Cl-MeO-BIPHEP and BINAP
work as good chiral ligands. A variety of secondary amines are available as nucleophiles for this catalytic
reaction to give the corresponding propargylic amines with a high enantioselectivity. The results of some
stoichiometric and catalytic reactions indicate that the catalytic amination proceeds via copper-allenylidene
complexes formed in situ, where the attack of amines to the electrophilic γ-carbon atom in the allenylidene
complex is an important step for the stereoselection. Investigation of the relative rate constants for the
reaction of several para-substituted propargylic acetates with N-methylanilines reveals that the formation
of the copper-allenylidene complexes is involved in the rate-determining step. The result of the density
functional theory calculation on a model reaction also supports the proposed reaction pathway involving
copper-allenylidene complexes as key intermediates. The catalytic procedure presented here provides a
versatile and direct method for the preparation of a variety of chiral propargylic amines.
have already been prepared by the use of the Nicholas reaction.4
However, in this reaction, a stoichiometric amount of Co2(CO)8
is required, and several steps are necessary to obtain the
propargylic-substituted products from propargylic alcohols
via cationic dicobalt hexacarbonyl complexes such as
[(propargyl)Co2(CO)6]+.4,5
Since the ruthenium-catalyzed propargylic substitution reac-
tions of propargylic alcohols with heteroatom-centered nucleo-
philes as well as carbon-centered ones have been reported by
us,6,7 where ruthenium-allenylidene complexes worked as key
intermediates,8–10 a number of catalytic propargylic substitution
reactions have appeared.11 Thus, several Lewis acids as well
as transition-metal complexes were disclosed to work as
Introduction
Transition-metal-catalyzed allylic substitution reactions of
allylic alcohol derivatives with nucleophiles are among the most
reliable methods in organic synthesis. The process is catalyzed
by various transition-metal complexes, and a wide variety of
nucleophiles are available for this reaction to afford the
corresponding allylated products with high chemo- and regi-
oselectivities. An enantioselective version of this process has
also been extensively studied, providing useful methods for the
synthesis of various optically active compounds, including
natural products.1
In sharp contrast, much less attention has been paid to
transition-metal-catalyzed propargylic substitution reactions of
propargylic alcohol derivatives with nucleophiles, although an
acetylenic carbon-carbon triple bond has a high potential for
a wide variety of transformations.2,3 The Nicholas reaction has
been used as an effective tool for propargylic substitution
reactions of propargylic alcohols and their derivatives with a
variety of nucleophiles to give the corresponding propargylic-
substituted products.4 In fact, various kinds of natural products
(2) (a) Brandsma, L. PreparatiVe Acetylene Chemistry, 2nd ed.; Elsevier:
Amsterdam, 1988. (b) Modern Acetylene Chemistry; Stang, P. J.,
Diederich, F., Eds.; VCH: Weinheim, 1995. (c) Acetylene Chemistry;
Diederich, F., Stang, P. J., Tykwinski, R. R., Eds.; VCH: Weinheim,
2005. (d) Brandsma, L. Synthesis of Acetylenes, Allenes and Cumu-
lenes: Methods and Techniques; Elsevier: Amsterdam, 2004.
(3) For recent reviews, see: (a) Tejedor, D.; Lo´pez-Tosco, S.; Cruz-Acosta,
F.; Me´ndez-Abt, G.; Garc´ıa-Tellado, F. Angew. Chem., Int. Ed. 2009,
48, 2090. (b) Anaya de Parrodi, C.; Walsh, P. J. Angew. Chem., Int.
Ed. 2009, 48, 4679.
† The University of Tokyo.
(4) For recent reviews, see: (a) Nicholas, K. M. Acc. Chem. Res. 1987,
20, 207. (b) Caffyn, A. J. M.; Nicholas, K. M. In ComprehensiVe
Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson,
G., Eds.; Pergamon: Oxford, 1995; Vol. 12, p 685. (c) Green, J. R.
Curr. Org. Chem. 2001, 5, 809. (d) Mu¨ller, T. J. J. Eur. J. Org. Chem.
2001, 2021. (e) D´ıaz, D. D.; Betancort, J. M.; Mart´ın, V. S. Synlett
2007, 343.
‡ Hoshi University.
(1) For selected reviews, see: (a) Tsuji, J. Palladium Reagents and
Catalysts; Wiley: New York, 1995; p 290. (b) Trost, B. M.; Van
Vranken, D. L. Chem. ReV. 1996, 96, 395. (c) Trost, B. M.; Lee, C. B.
In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-
VCH: New York, 2000; p 593. (d) Trost, B. M.; Crawley, M. L. Chem.
ReV. 2003, 103, 2921. (e) Nishibayashi, Y.; Uemura, S. In Compre-
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D. M. P., Eds.; Elsevier: Amsterdam, 2007; Vol. 11, p 75. (f) Lu, Z.;
Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258.
(5) Asymmetric versions of the Nicholas reaction have already been
reported: (a) Nicholas, K. M.; Mulvaney, M.; Bayer, M. J. Am. Chem.
Soc. 1980, 102, 2508. (b) Ljungdahl, N.; Pera, N. P.; Andersson,
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9
10592 J. AM. CHEM. SOC. 2010, 132, 10592–10608
10.1021/ja1047494  2010 American Chemical Society

Cu-Catalyzed Enantioselective Amination of Propargylic Esters
A R T I C L E S
effective catalysts to give the corresponding propargylic com-
pounds from propargylic alcohols or their derivatives.11 These
catalytic processes are now becoming a powerful synthetic
method as an alternative to the Nicholas reaction. As an
extension of these studies, their asymmetric versions have also
been disclosed, such as the ruthenium-catalyzed asymmetric
propargylic alkylation of propargylic alcohols with acetone (up
to 82% ee)12 and similar propargylation of aromatic compounds
(up to 95% ee).13,14 Further, we have also disclosed that
ruthenium-catalyzed intramolecular carbon-carbon bond-form-
ing reactions between propargylic alcohols and alkenes gave
the corresponding 1,5-enynes in good to high yields with a high
to excellent enantioselectivity (up to 99% ee),15 while Fu and
Smith have reported nickel-catalyzed enantioselective carbon-
carbon bond-forming reactions at the propargylic position of
propargylic halides.16 These results prompted us to investigate
other transition-metal-catalyzed enantioselective propargylic
substitution reactions with a variety of nucleophiles.
substitution reactions of propargylic esters with various second-
ary amines by using optically active diphosphines such as
BINAP20 and BIPHEP21 as chiral ligands are described in detail,
together with the density functional theory calculation of the
proposed reaction pathway which involves copper-allenylidene
complexes as key intermediates.
Optically active propargylic amines are synthetically versatile
intermediates for the construction of various biologically active
compounds and polyfunctional amino derivatives.22 Recently,
the transition-metal-catalyzed enantioselective addition of ter-
minal alkynes to imines has been developed to produce the
corresponding chiral propargylic amines with a high enantiose-
(9) For recent reviews of transition metal-allenylidene complexes, see:
(a) Bruneau, C.; Dixneuf, P. H. Angew. Chem., Int. Ed. 2006, 45,
2176. (b) Metal Vinylidenes and Allenylidenes in Catalysis: From
ReactiVity to Applications in Synthesis; Bruneau, C., Dixneuf, P. H.,
Eds.; Wiley-VCH: Weinheim, 2008. (c) Cadierno, V.; Gimeno, J.
Chem. ReV. 2009, 109, 3512.
We focused on the copper-catalyzed propargylic amination
of propargylic esters with a variety of amines, where the
corresponding propargylic amines have been produced in good
to high yields.17 In this reaction system, we envisioned that this
propargylic amination may proceed via copper-allenylidene
complexes as key intermediates because only propargylic esters
bearing a terminal acetylene moiety were available as substrates.
In fact, the first successful example of the copper-catalyzed
enantioselective propargylic amination of propargylic acetates
with primary amines was reported by van Maarseveen and co-
workers, where optically active 2,6-bis(oxazolinyl)pyridines
(pybox) worked as good chiral ligands (up to 88% ee).18
Independently, we have found a similar copper-catalyzed
enantioselective reaction,19 and, in the present article, the scope
and limitations of our catalytic enantioselective propargylic
(10) (a) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Milton, M. D.; Hidai,
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Y.; Uemura, S.; Nishibayashi, Y. J. Am. Chem. Soc. 2007, 129, 5175.
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Nishibayashi, Y.; Uemura, S. Curr. Org. Chem. 2006, 10, 135. (b)
Nishibayashi, Y.; Uemura, S. In ComprehensiVe Organometallic
Chemistry III; Crabtree, R. H., Mingos, D. M. P., Eds.; Elsevier:
Amsterdam, 2007; Vol. 11, p 123. (c) Kabalka, G. W.; Yao, M.-L.
Curr. Org. Synth. 2008, 5, 28. (d) Ljungdahl, N.; Kann, N. Angew.
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van Maarseveen, J. H. Eur. J. Org. Chem. 2009, 6263.
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122, 11019. (b) Nishibayashi, Y.; Wakiji, I.; Ishii, Y.; Uemura, S.;
Hidai, M. J. Am. Chem. Soc. 2001, 123, 3393. (c) Nishibayashi, Y.;
Inada, Y.; Hidai, M.; Uemura, S. J. Am. Chem. Soc. 2002, 124, 7900.
(d) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Hidai, M.; Uemura,
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Nishibayashi, Y.; Inada, Y.; Yoshikawa, M.; Hidai, M.; Uemura, S.
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Y.; Hidai, M.; Uemura, S. J. Am. Chem. Soc. 2003, 125, 6060. (h)
Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Hidai, M.; Uemura, S.
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M. D.; Nishibayashi, Y.; Uemura, S. Eur. J. Org. Chem. 2006, 881.
(k) Nishibayashi, Y.; Shinoda, A.; Miyake, Y.; Matsuzawa, H.; Sato,
M. Angew. Chem., Int. Ed. 2006, 45, 4835. (l) Daini, M.; Yoshikawa,
M.; Inada, Y.; Uemura, S.; Sakata, K.; Kanao, K.; Miyake, Y.;
Nishibayashi, Y. Organometallics 2008, 27, 2046. (m) Yamauchi, Y.;
Miyake, Y.; Nishibayashi, Y. Organometallics 2009, 28, 48. (n) Kanao,
K.; Miyake, Y.; Nishibayashi, Y. Organometallics 2010, 29, 2126.
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S. Organometallics 2004, 23, 26. (b) Nishibayashi, Y.; Imajima, H.;
Onodera, G.; Inada, Y.; Hidai, M.; Uemura, S. Organometallics 2004,
23, 5100. (c) Miyake, Y.; Endo, S.; Nomaguchi, Y.; Yuki, M.;
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Endo, S.; Yuki, M.; Tanabe, Y.; Nishibayashi, Y. Organometallics
2008, 27, 6039. (e) Tanabe, Y.; Kanao, K.; Miyake, Y.; Nishibayashi,
Y. Organometallics 2009, 28, 1138.
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Organometallics 2003, 22, 873. (b) Inada, Y.; Nishibayashi, Y.;
Uemura, S. Angew. Chem., Int. Ed. 2005, 44, 7715.
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Ed. 2007, 46, 6488. (b) Matsuzawa, H.; Kanao, K.; Miyake, Y.;
Nishibayashi, Y. Org. Lett. 2007, 9, 5561. (c) Kanao, K.; Matsuzawa,
H.; Miyake, Y.; Nishibayashi, Y. Synthesis 2008, 3869. (d) Kanao,
K.; Miyake, Y.; Nishibayashi, Y. Organometallics 2009, 28, 2920.
(14) For a recent review, see: Catalytic Asymmetric Friedel-Crafts
Alkylations; Bandini, M., Umani-Ronchi, A., Eds.; VCH: Weinheim,
2009.
(15) Fukamizu, K.; Miyake, Y.; Nishibayashi, Y. J. Am. Chem. Soc. 2008,
130, 10498.
(16) Smith, S. W.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 12645.
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1994, 59, 2282. (b) Geri, R.; Polizzi, C.; Lardicci, L.; Caporusso, A. M.
Gazz. Chim. Ital. 1994, 124, 241. (c) Godfrey, J. D., Jr.; Mueller,
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(18) (a) Detz, R. J.; Delville, M. M. E.; Hiemstra, H.; van Maarseveen,
J. H. Angew. Chem., Int. Ed. 2008, 47, 3777. (b) Prof. van Maarseveen
and co-workers achieved the first enantioselective propargylic ami-
nation and presented a part of their result at the PAC Symposium
2007 (March 1, 2007, Utrecht).
(19) A preliminary result of the copper-catalyzed enantioselective prop-
argylic amination has already been reported by our group: Hattori,
G.; Matsuzawa, H.; Miyake, Y.; Nishibayashi, Y. Angew. Chem., Int.
Ed. 2008, 47, 3781.
(8) The result of the density functional theory calculation on the model
reaction also supports the proposed reaction pathway of the ruthenium-
catalyzed propargylic substitution reactions of propargylic alcohols
with nucleophiles, where ruthenium-allenylidene complexes work as
key intermediates: (a) Ammal, S. C.; Yoshikai, N.; Inada, Y.;
Nishibayashi, Y.; Nakamura, E. J. Am. Chem. Soc. 2005, 127, 9428.
(b) Sakata, K.; Miyake, Y.; Nishibayashi, Y. Chem. Asian J. 2009, 4,
81.
(20) (R)-BINAP ) (R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl: Noyori,
R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345.
(21) BIPHEP ) 2,2′-bis(diphenylphosphino)-1,1′-biphenyl: Schmid, R.;
Foricher, J.; Cereghetti, M.; Scho¨nholzer, P. HelV. Chim. Acta 1991,
74, 370.
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J. AM. CHEM. SOC. VOL. 132, NO. 30, 2010 10593

A R T I C L E S
Hattori et al.
Table 1. Investigation of the Effect of Optically Active Phosphine
Ligands on Copper-Catalyzed Propargylic Amination of Propargylic
Acetate (1a) with N-Methylanilinea
Table 2. Investigation of the Effect of Optically Active Biaryl
Diphosphine Ligands on Copper-Catalyzed Propargylic Amination
of Propargylic Acetate (1a) with N-Methylanilinea
run
ligand
time (h)
yield of 2a (%)b
ee of 2a (%)c
run
ligand
time (h)
yield of 2a (%)b
ee of 2a (%)c
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L7
L8
L9
1.5
3
69
78
71
46
0d
78
3
3
1
2
3
4
5
6
7
8
9
L1
1.5 (12)d
18
1.5
12
1.5
1.5
12
24
1.5 (12)d
69 (80)d
62
58
75
67
78 (85)d
18
59
71
75
71
68
L10
L11
L12
L13
L14
L15
L16
L17
18
24
24
18
24
9
4
0d
61
75
86
67
44
10
2
15
61
1
24
91 (88)d
79 (86)d
a All the reactions of 1a (0.20 mmol) with N-methylaniline (0.24
mmol) and N,N-diisopropylethylamine (0.24 mmol) were carried out in
the presence of copper trifluoromethanesulfonate-benzene complex
(0.010 mmol) and ligand (0.020 mmol) in MeOH (2.0 mL) at room
temperature. b Yield of isolated product. c Determined by HPLC
(see Supporting Information for experimental details). d 1-Phenyl--
2-propyn-1-ol was obtained quantitatively.
a All the reactions of 1a (0.20 mmol) with N-methylaniline (0.24
mmol) and N,N-diisopropylethylamine (0.24 mmol) were carried out in
the presence of copper trifluoromethanesulfonate-benzene complex
(0.010 mmol) and ligand (0.020 mmol) in MeOH (2.0 mL) at room
temperature. b Yield of isolated product. c Determined by HPLC (see
Supporting Information for experimental details). d At 0 °C.
lectivity.23 Especially the copper-catalyzed reactions are used
as the most reliable method to obtain chiral propargylic
amines.24 The procedure described in the present article provides
another versatile and direct method for the preparation of chiral
propargylic amines.25
Scheme 1. Enantioselective Propargylic Amination of 1a with
PhNHMe Catalyzed by CuOTf ·1/2C6H6 and (R)-BINAP (L1)
Results and Discussion
Catalytic Propargylic Amination. Treatment of 1-phenyl-2-
propynyl acetate (1a) with N-methylaniline (1.2 equiv) and N,N-
diisopropylethylamine (1.2 equiv) in the presence of catalytic
amounts of copper trifluoromethanesulfonate-benzene complex,
CuOTf·1/2C6H6 (5 mol %), and (R)-BINAP (L1; 6 mol %) in
methanol at room temperature for 1.5 h gave N-methyl-N-(1-
phenyl-2-propynyl)aniline (2a) in 75% yield with 75% ee (S)
(Scheme 1). No formation of other byproducts such as allenylic
(22) (a) Porco, J. A., Jr.; Schoenen, F. J.; Stout, T. J.; Clardy, J.; Schreiber,
S. L. J. Am. Chem. Soc. 1990, 112, 7410. (b) Nicolaou, K. C.; Hwang,
C.-K.; Smith, A. L.; Wendeborn, S. V. J. Am. Chem. Soc. 1990, 112,
7416. (c) Yu, P. H.; Davis, B. A.; Boulton, A. A. J. Med. Chem. 1992,
35, 3705. (d) Jiang, B.; Xu, M. Angew. Chem., Int. Ed. 2004, 43,
2543. (e) Yamamoto, Y.; Hayashi, H.; Saigoku, T.; Nishiyama, H.
J. Am. Chem. Soc. 2005, 127, 10804. (f) Fleming, J. J.; Du Bois, J.
J. Am. Chem. Soc. 2006, 128, 3926.
1
isomers was observed by H NMR. Use of an excess amount
of (R)-BINAP (10 mol %) slightly increased the enantioselec-
tivity of 2a (78% ee). The excess amount of (R)-BINAP is
considered to inhibit the dissociation of (R)-BINAP from the
copper atom of the catalyst. This catalytic reaction proceeded
smoothly even when triethylamine was used in place of N,N-
diisopropylethylamine, but no reaction occurred at all in the
(23) For a recent review, see Zani, L.; Bolm, C. Chem. Commun. 2006,
4263.
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10594 J. AM. CHEM. SOC. VOL. 132, NO. 30, 2010

Cu-Catalyzed Enantioselective Amination of Propargylic Esters
A R T I C L E S
Table 3. Investigation of the Effect of Leaving Groups in
Propargylic Alcohol Derivatives on Copper-Catalyzed Propargylic
Amination of Propargylic Alcohol Derivatives (1a) with
N-Methylanilinea
Table 4. Copper-Catalyzed Enantioselective Propargylic Amination
of Propargylic Acetates (1) with N-Methylanilinea
run
propargylic acetate 1 (R)
time (h)
yield of 2 (%)b
ee of 2 (%)c
1
2
3
4
5
6
7
8
Ph (1a)
12
12
12
12
12
48
48
12
12
12
12
12
12
12
12
12
12
48
88 (2a)
92 (2b)
91 (2c)
92 (2d)
95 (2e)
91 (2f)
88 (2g)
91 (2h)
83 (2i)
72 (2j)
95 (2k)
90 (2l)
94 (2m)
92 (2n)
94 (2o)
95 (2p)
92 (2q)
0
86
81
83
82
82
85
85
77
83
7
86
82
85
85
80
85
30
run
propargylic esters 1 (R)
time (h)
yield of 2a (%)b
ee of 2a (%)c
p-MeC6H4 (1g)
m-MeC6H4 (1h)
o-MeC6H4 (1i)
p-PhC6H4 (1j)
p-ClC6H4 (1k)
p-BrC6H4 (1l)
p-MeOC6H4 (1m)
3,5-Me2C6H3 (1n)
2,6-Me2C6H3 (1o)
1-naphthyl (1p)
2-naphthyl (1q)
2-furyl (1r)
1
2
3
COMe (1a)
COPh (1b)
COC6F5 (1c)
CO2Me (1d)
CO2Me (1d)
H (1e)
1.5
1.5
0.5
0.5
1.5
48
91
91
87
88
71
0e
79
76
25
54
13
4
5d
6
7
COCF3 (1f)
0.5
0f
9
10
11
12
13
14
15
16
17
18
a All the reactions of 1 (0.20 mmol) with N-methylaniline (0.24
mmol) and N,N-diisopropylethylamine (0.24 mmol) were carried out in
the presence of copper trifluoromethanesulfonate-benzene complex
(0.010 mmol) and (R)-Cl-MeO-BIPHEP (0.020 mmol) in MeOH (2.0
mL) at room temperature. b Yield of isolated product. c Determined by
HPLC (see Supporting Information for experimental details). d In the
absence of N,N-diisopropylethylamine. e 1e was recovered in quan-
3-furyl (1s)
2-thienyl (1t)
3-thienyl (1u)
Ph2CdCH (1v)
cyclohexyl (1w)
f
1
titative yield. 1e was obtained in 97% H NMR yield.
a All the reactions of 1 (0.20 mmol) with N-methylaniline (0.24
mmol) and N,N-diisopropylethylamine (0.24 mmol) were carried out in
the presence of copper trifluoromethanesulfonate-benzene complex
(0.010 mmol) and (R)-Cl-MeO-BIPHEP (0.020 mmol) in MeOH (2.0
mL) at 0 °C. b Yield of isolated product. c Determined by HPLC (see
Supporting Information for experimental details).
absence of such base, showing that use of a stoichiometric
amount of tertiary amine is necessary to promote the catalytic
reaction.
We examined this catalytic amination in the presence of a
variety of chiral ligands. Typical results are shown in Table 1.
When optically active diphosphines such as (S,S)-DIOP26 (L2),
(R,R)-QuinoxP*27 (L3), and Trost ligand28 (L4) were used in
place of L1, low enantioselectivities were observed in all cases
(Table 1, runs 2-4). Use of other diphosphines such as (R,R)-
Me-DUPHOS29 (L5) and (S,S)-CHIRAPHOS30 (L6) as chiral
ligands resulted in the formation of the corresponding propar-
gylic alcohol in quantitative yields (Table 1, runs 5 and 6). In
the case of other optically active compounds such as (R)-MeO-
MOP31 (L7), (S)-(S)-ip-FOXAP32 (L8), and (S)-(R,R)-phos-
Table 5. Copper-Catalyzed Enantioselective Propargylic Amination
of Propargylic Acetate (1a) with para-Substituted N-Methylanilinesa
run
R
time (h)
yield of 2 (%)b
ee of 2 (%)c
1
2
3
4
5
CF3
Cl
H
Me
MeO
12
12
12
12
12
72 (2r)
87 (2s)
88 (2a)
94 (2t)
82 (2u)
93
89
86
82
80
(24) For examples, see: (a) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002,
124, 5638. (b) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem.,
Int. Ed. 2002, 41, 2535. (c) Kno¨pfel, T. F.; Aschwanden, P.; Ichikawa,
T.; Watanabe, T.; Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43,
5971. (d) Dube, H.; Gommermann, N.; Knochel, P. Synthesis 2004,
2015. (e) Sakai, N.; Uchida, N.; Konakahara, T. Synlett 2008, 1515.
(25) In related work, we have found the copper-catalyzed diastereo- and
enantioselective sequential reactions of propargylic acetates with (E)-
2,4-pentadienylaniline to give the corresponding 1,2-disubstituted
tetrahydroisoindoles in high yields with high diastereo- and enanti-
oselectivities, where only a single copper salt works as a catalyst to
promote both propargylic amination and intramolecular [4+2] cy-
cloaddition reaction: Hattori, G.; Miyake, Y.; Nishibayashi, Y.
ChemCatChem 2010, 2, 155.
a All the reactions of 1a (0.20 mmol) with N-methylanilines (0.24
mmol) and N,N-diisopropylethylamine (0.24 mmol) were carried out in
the presence of copper trifluoromethanesulfonate-benzene complex
(0.010 mmol) and (R)-Cl-MeO-BIPHEP(0.020 mmol) in MeOH (2.0
mL) at 0 °C. b Yield of isolated product. c Determined by HPLC (see
Supporting Information for experimental details).
phoramidite33 (L9), the enantioselectivities were also low (Table
1, runs 7-9). These results clearly show that (R)-BINAP is the
best ligand for the present enantioselective propargylic amination.
Next, we investigated the propargylic amination in the
presence of a variety of atropisomeric diphosphines based on a
(26) (S,S)-DIOP ) (4S,5S)-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphe-
nylphosphino)butane: Kagan, H. B.; Dang, T.-P. J. Am. Chem. Soc.
1972, 94, 6429.
(27) (R,R)-QuinoxP* ) (R,R)-2,3-bis(tert-butylmethylphosphino)quinoxa-
line: Imamoto, T.; Sugita, K.; Yoshida, K. J. Am. Chem. Soc. 2005,
127, 11934.
(28) Trost ligand ) (1R,2R)-1,2-diaminocyclohexane-N,N-µ-bis-2′-(diphe-
nylphosphinobenzoyl): Trost, B. M.; Machacek, M. R.; Aponick, A.
Acc. Chem. Res. 2006, 39, 747, and references therein.
(32) (S)-(S)-ip-FOXAP ) (S,S)-[2-(4′-isopropyloxazolin-2′-yl)ferrocenyl-
]diphenylphosphine: Miyake, Y.; Nishibayashi, Y.; Uemura, S. Synlett
2008, 1747, and references therein.
(29) (R,R)-Me-DUPHOS ) 1,2-bis-((2R,5R)-2,5-dimethylphospholano)ben-
zene: Burk, M. J. Acc. Chem. Res. 2000, 33, 363, and references
therein.
(33) (S)-(R,R)-Phosphoramidite ) (S)-(+)-(3,5-dioxa-4-phospha-cyclohep-
ta[2,1-a;3,4-a′]dinaphthalen-4-yl)bis[(1R)-1-phenylethyl]amine: (a) de
Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2374–2376. (b) Feringa, B. L.; Pineschi, M.; Arnold,
L. A.; Imbos, R.; de Vries, A. H. M. Angew. Chem., Int. Ed. Engl.
1997, 36, 2620–2623.
(30) (S,S)-CHIRAPHOS ) (2S,3S)-bis(diphenylphosphino)butane: Fryzuk,
M. D.; Bosnich, B. J. Am. Chem. Soc. 1977, 99, 6262.
(31) (R)-MeO-MOP ) (R)-2-(diphenylphophino)-2′-methoxy-1,1′-biphenyl:
Hayashi, T. Acc. Chem. Res. 2000, 33, 354, and references therein.
9
J. AM. CHEM. SOC. VOL. 132, NO. 30, 2010 10595

A R T I C L E S
Hattori et al.
Table 6. Copper-Catalyzed Enantioselective Propargylic Amination of Propargylic Acetates (1) with Trifluoromethyl-N-methylanilinesa
run
propargylic acetate 1 (Ar)
position of CF3 group
time (h)
yield of 2 (%)b
ee of 2 (%)c
1
2
3
4
5
6
7
8
9
10
Ph (1a)
p-CF3
p-CF3
p-CF3
p-CF3
p-CF3
p-CF3
p-CF3
p-CF3
m-CF3
m-CF3
12
48
48
12
12
12
12
12
12
12
72 (2r)
72 (2v)
78 (2w)
85 (2x)
87 (2y)
93 (2z)
91 (2aa)
90 (2ab)
81 (2ac)
91 (2ad)
93
92
93
90
92
98
91
90
89
88
p-ClC6H4 (1k)
p-BrC6H4 (1l)
3-furyl (1s)
3-thienyl (1u)
1-naphthyl (1p)
2-naphthyl (1q)
1-(4-methyl)naphthyl (1x)
Ph (1a)
1-naphthyl (1p)
a All the reactions of 1 (0.20 mmol) with trifluoromethyl-N-methylanilines (0.24 mmol) and N,N-diisopropylethylamine (0.24 mmol) were carried out
in the presence of copper trifluoromethanesulfonate-benzene complex (0.010 mmol) and (R)-Cl-MeO-BIPHEP (0.020 mmol) in MeOH (2.0 mL) at 0
°C. b Yield of isolated product. c Determined by HPLC (see Supporting Information for experimental details).
Scheme 2. Enantioselective Propargylic Amination of 1a Catalyzed
biaryl skeleton similar to L1 as chiral ligands (Table 2). In
contrast to L1, (R)-H8-BINAP34 (L10) was not a suitable ligand
(Table 2, run 2). Use of (R)-SEGPHOS35 (L11), which is known
to be a more effective chiral ligand than L1 in several catalytic
reactions, resulted in only a moderate enantioselectivity (Table
2, run 3). In the case of other atropisomeric diphosphines such
as (R)-DIFLUOPHOS36 (L12), (R)-SYNPHOS37 (L13), CTH-
(R)-P-PHOS38 (L14), and (R)-MeO-BIPHEP39 (L15), the amine
2a was produced in a similar yield with a slightly lower
enantioselectivity (Table 2, runs 4-7). Unfortunately, no
enantioselectivity was observed at all when (R)-Ph-MeO-
BIPHEP40 (L16) was used as a chiral ligand (Table 2, run 8).
In contrast to the case of L15, the presence of a chloro group
in the benzene ring dramatically increased the catalytic activity.
Thus, the propargylic amination in the presence of (R)-Cl-MeO-
BIPHEP41 (L17) proceeded quite smoothly to give 2a in 91%
yield with 79% ee (Table 2, run 9) and even at a lower reaction
temperature such as 0 °C provided 2a in 88% yield with 86%
ee (Table 2, runs 1 and 9). Interestingly, the reaction proceeded
effectively even in the presence of a lower concentration of the
catalyst such as 1 mol % of CuOTf ·1/2C6H6 and 2 mol % of
L17 to give 2a in 81% yield (turnover number (TON) ) 81)
with 83% ee (S), although a longer reaction time was necessary
to complete the conversion (Scheme 2). It is noteworthy that
by a Lower Concentration of CuOTf ·1/2C6H6 and
(R)-Cl-MeO-BIPHEP (L17)
only 1 mol % of the catalyst promoted the propargylic amination
quite smoothly.
The nature of a leaving group in the propargylic ester affected
the enantioselectivity of the propargylic amination (Table 3).
A similar enantioselectivity was observed when propargylic
benzoate (1b) was used as a substrate (Table 3, run 2). Reactions
of other propargylic esters such as pentafluorobenzoate (1c) and
methyl carbonate (1d) proceeded rapidly, but substantially lower
enantioselectivities were achieved in both cases (Table 3, runs
3 and 4). Even in the absence of N,N-diisopropylethylamine,
the reaction of propargylic carbonate (1d) proceeded, but with
a low enantioselectivity (Table 3, run 5). No reaction occurred
at all when propargylic alcohol (1e) was used as a substrate
(Table 3, run 6). Merely the hydrolyzed product, propargylic
alcohol 1e, was obtained (97%) when the reaction of propargylic
trifluoroacetate (1f) was carried out under the same reaction
conditions (Table 3, run 7).
Next, the catalytic amination of various propargylic acetates
(1) with N-methylaniline (1.2 equiv) and N,N-diisopropylethy-
lamine (1.2 equiv) was carried out in the presence of catalytic
amounts of CuOTf ·1/2C6H6 (5 mol %) and (R)-Cl-MeO-BIPHEP
(10 mol %) in methanol at 0 °C (Table 4). The introduction of
a substituent such as a methyl, chloro, bromo, or phenyl group
at the para-, meta-, or ortho-position in the benzene ring of 1
did not much affect the enantioselectivity (Table 4, runs 1-7).
A substantially lower enantioselectivity was observed when a
methoxy group was introduced at the para-position of the
(34) (R)-H8-BINAP ) (R)-2,2′-bis(diphenylphosphino)-5,5′,6,6′,7,7′,8,8′-
octahydro-1,1′-binaphthyl: Zhang, X.; Mashima, K.; Koyano, K.; Sayo,
N.; Kumobayashi, H.; Akutagawa, S.; Takaya, H. Tetrahedron Lett.
1991, 32, 7283.
(35) (R)-SEGPHOS ) (R)-5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzo-
dioxole: Nagasaki, I.; Matsumura, K.; Sayo, N.; Saito, T. Acc. Chem.
Res. 2007, 40, 1385, and references therein.
(36) (R)-DIFLUOROPHOS ) (R)-5,5′-bis(diphenylphosphino)-2,2′,2,2′-
tetrafluoro-5,5′-bi-1,3-benzodioxole: Duprat de Paule, S.; Ratovelo-
manana-Vidal, V.; Geneˆt, J.-P.; Champion, N.; Dellis, P. Angew.
Chem., Int. Ed. 2004, 43, 320.
(37) (R)-SYNPHOS ) (R)-6,6′-bis(diphenylphosphino)-2,2′,3,3′-tetrahydro-
5,5′-bi-1,4-benzodioxin: Duprat de Paule, S.; Jeulin, S.; Ratovelo-
manana-Vidal, V.; Geneˆt, J.-P.; Champion, N.; Dellis, P. Tetrahedron
Lett. 2003, 44, 823.
(38) CTH-(R)-P-PHOS ) (R)-2,2′,6,6′-tetramethoxy-4,4′-bis(diphenylphos-
phino)-3,3′-bipyridine: Pai, C.-C.; Lin, C.-W.; Lin, C.-C.; Chen, C.-
C.; Chan, A. S. C.; Wong, W. T. J. Am. Chem. Soc. 2000, 122, 11513.
(39) (R)-MeO-BIPHEP ) (R)-6,6′-dimethoxy-2,2′-bis(diphenylphosphino)-
1,1′-biphenyl: see ref 21.
(40) (R)-Ph-MeO-BIPHEP ) (R)-3,3′-diphenyl-6,6′-dimethoxy-2,2′-bis-
(diphenylphosphino)-1,1′-biphenyl: Wu, S.; He, M.; Zhang, X. Tet-
rahedron: Asymmetry 2004, 15, 2177.
(41) (R)-Cl-MeO-BIPHEP ) (R)-5,5′-dichloro-6,6′-dimethoxy-2,2′-bis-
(diphenylphosphino)-1,1′-biphenyl: (a) Huddleston, R. R.; Jang, H.-
Y.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 11488. (b) Jang,
H.-Y.; Hughes, F. W.; Gong, H.; Zhang, J.; Brodbelt, J. S.; Krische,
M. J. J. Am. Chem. Soc. 2005, 127, 6174. (c) Rhee, J. U.; Krische,
M. J. J. Am. Chem. Soc. 2006, 128, 10674. (d) Skucas, E.; Kong,
J. R.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 7242.
9
10596 J. AM. CHEM. SOC. VOL. 132, NO. 30, 2010

Cu-Catalyzed Enantioselective Amination of Propargylic Esters
A R T I C L E S
Table 7. Copper-Catalyzed Enantioselective Propargylic Amination of Propargylic Acetates (1) with Aminesa
a All the reactions of 1 (0.20 mmol) with amines (0.24 mmol) and N,N-diisopropylethylamine (0.24 mmol) were carried out in the presence of copper
trifluoromethanesulfonate-benzene complex (0.010 mmol) and (R)-Cl-MeO-BIPHEP (0.020 mmol) in MeOH (2.0 mL) at 0 °C. b Yield of isolated
product. c Determined by HPLC (see Supporting Information for experimental details).
benzene ring of 1 (Table 4, run 8). In sharp contrast to
propargylic acetate bearing a 3,5-dimethylphenyl moiety, the
reaction of propargylic acetate bearing a 2,6-dimethylphenyl
moiety afforded the corresponding propargylic amine in a similar
yield but with quite low enantioselectivity (Table 4, runs 9 and
10). The propargylic amination of propargylic acetates bearing
a naphthyl, furyl, or thienyl moiety proceeded with a high
enantioselectivity (Table 4, runs 11-16). On the other hand,
the reaction of propargylic acetate bearing an alkenyl group at
the propargylic position gave the corresponding propargylic
amine without any formation of byproduct, but only a low
enantioselectivity was observed in the produced amine (Table
4, run 17). No reaction occurred at all under the same reaction
conditions when 1-cyclohexyl-2-propynyl acetate was used as
a substrate (Table 4, run 18). These results indicate that the
presence of an aryl moiety at the propargylic position of 1 is
necessary to promote the catalytic amination with a high
enantioselectivity. The reason for a quite low enantioselectivity
in the reaction of 1o is mentioned in the later section.
The substituent in the benzene ring of N-methylaniline affects
the enantioselectivity of the propargylic amination of 1a (Table
5). Reactions with N-methyl-4-trifluoromethylaniline and N-meth-
yl-4-chloroaniline gave the corresponding propargylic amines
with 93 and 89% ee, respectively (Table 5, runs 1 and 2). In
contrast, reactions with N-methyl-4-methylaniline and N-methyl-
4-methoxyaniline proceeded with a slightly lower enantiose-
lectivity (82 and 80% ee, respectively) (Table 5, runs 4 and 5).
These results show that the presence of an electron-withdrawing
group such as trifluoromethyl in the benzene ring of aniline
increases the enantioselectivity.
The propargylic amination of various propargylic acetates
with N-methyl-trifluoromethylanilines was then carried out
9
J. AM. CHEM. SOC. VOL. 132, NO. 30, 2010 10597

A R T I C L E S
Hattori et al.
Table 8. Copper-Catalyzed Enantioselective Propargylic Amination
of Propargylic Acetate (1) with Dialkylaminesa
Scheme 3. Copper-Catalyzed Enantioselective Propargylic
Amination of 1a with Aniline
Scheme 4. Propargylic Substitution Reaction of 1a with Aniline
Catalyzed by CuI and Optically Active Pyridine-2,6-bisoxazoline
Derivative Reported by van Maarseveen’s Group18
10-12), while a slightly lower enantioselectivity was observed
in the reaction with N-methylaniline bearing a carbonyl moiety
at the methyl part (Table 7, run 13). Use of other acyclic amines
such as N-allylaniline and N-propargylaniline gave the corre-
sponding amines with a high enantioselectivity (Table 7, runs
14 and 15). Cyclic amines such as 1,2,3,4-tetrahydroquinoline
and indoline were also available as nitrogen-centered nucleo-
philes, where a high enantioselectivity was achieved in both
cases (Table 7, runs 16 and 17).
Furthermore, the catalytic amination with secondary dialky-
lamines was investigated under the same reaction conditions
(Table 8). Good enantioselectivity was observed in the reaction
with cyclic dialkylamines such as 1,2,3,4-tetrahydroisoquinoline,
piperidine, and azepane (hexamethyleneimine) (Table 8, runs
1-3), although azocane (heptamethyleneimine) did not work
as an effective nucleophile (Table 8, run 4). This result indicates
that the enantioselectivity of the produced amines depends much
on the ring size of the cyclic dialkylamines. Reactions with
acyclic dialkylamines such as N-cyclohexyl-N-methylamine,
dipropylamine, and diallylamine proceeded smoothly to give
the corresponding amines with high enantioselectivities (Table
8, runs 5-7). It is noteworthy that simple dialkylamines work
as effective nucleophiles for our reaction system.
It is also noteworthy that the reaction with a primary amine such
as aniline proceeded smoothly, but only a moderate enantioselec-
tivity (54% ee) was achieved under the same reaction conditions
(Scheme 3).42 This result is in sharp contrast to the result reported
by van Maarseveen and co-workers, where only aniline derivatives
worked as suitable nucleophiles (Scheme 4).18 Interestingly, van
Maarseveen and co-workers did not achieve a high enantioselec-
tivity when secondary amines were used as nitrogen-centered
nucleophiles.18 Thus, our system described in the present paper
using secondary amines complements van Maarseveen’s system18
for the copper-catalyzed propargylic amination.
a All the reactions of 1 (0.20 mmol) with dialkylamines (0.24 mmol)
and N,N-diisopropylethylamine (0.24 mmol) were carried out in the
presence of copper trifluoromethanesulfonate-benzene complex (0.010
mmol) and (R)-Cl-MeO-BIPHEP (0.020 mmol) in MeOH (2.0 mL) at 0
°C. b Yield of isolated product. c Determined by HPLC (see Supporting
Information for experimental details).
(Table 6). Reactions of propargylic acetates bearing a p-
chlorophenyl, p-bromophenyl, furyl, or thienyl moiety with
N-methyl-4-trifluoromethylaniline gave the corresponding ami-
nated products with high enantioselectivities (90-93% ee)
(Table 6, runs 2-5). The enantioselectivity was substantially
increased when 1-(1-naphthyl)-2-propynyl acetate was used as
a substrate (Table 6, run 6). In contrast, catalytic reactions with
N-methyl-3-trifluoromethylaniline gave the corresponding amines
with a slightly lower enantioselectivity (Table 6, runs 9 and
10).
Next, we investigated the scope and limitations of amines in
the catalytic amination as shown in Table 7. In addition to
N-methylaniline derivatives, the amination proceeded smoothly
with a high enantioselectivity (up to 94% ee) when N-
ethylaniline derivatives were used as nucleophiles (Table 7, runs
1-5). The introduction of a functional group such as a
hydroxymethyl, alkoxycarbonyl, or cyano group at the methyl
moiety in N-methylaniline did not greatly affect the enantiose-
lectivity of the produced amines (Table 7, runs 6-9). Thus,
reactions of various propargylic acetates with N-methylaniline
bearing an alkoxycarbonyl group gave the corresponding
propargylic amines with a high enantioselectivity (Table 7, runs
(42) (a) Reactions of 1a with other anilines such as 4-methylaniline,
4-chloroaniline, and 4-trifluoromethylaniline were investigated under
the same reaction conditions to give the corresponding propargylic
amines in good yields with only a moderate enantioselectivity (45-
55% ee). (b) Unfortunately, no propargylic amination occurred at all
when primary alkylamines such as tert-butylamine and 1-adamanty-
lamine were used as nucleophiles.
9
10598 J. AM. CHEM. SOC. VOL. 132, NO. 30, 2010

Cu-Catalyzed Enantioselective Amination of Propargylic Esters
A R T I C L E S
Scheme 5. Preparation of [Cu(µ-Cl)diphosphine]2 by Reaction of CuCl with Diphosphines
Copper Complexes. In order to obtain some information on
the reaction pathway, the following stoichiometric and catalytic
reactions were investigated. Treatment of CuCl with a stoichio-
metric amount of (R)-Cl-MeO-BIPHEP in dichloromethane at
reflux temperature for 4 h gave the corresponding chloride-
bridged dicopper complex [Cu(µ-Cl){(R)-Cl-MeO-BIPHEP}]2
(3a) in quantitative yield (Scheme 5). The molecular structure
of 3a was unambiguously characterized by X-ray crystal-
lography, and an ORTEP drawing of 3a is shown in Figure 1.
The X-ray study has revealed that 3a is a diamagnetic copper(I)
centrosymmetrical dimer where two copper atoms bridged by
two chlorine atoms are located at a nonbonding distance of
3.1580(5) Å apart. Each copper(I) atom chelated by (R)-Cl-
MeO-BIPHEP exhibits four-coordination with a slightly dis-
torted tetrahedral geometry. The P-Cu-P bite angles (102.6°,
mean) and Cu-P distances (2.25 Å, mean) are quite close to
the reported values found in other dicopper complexes [Cu(µ-
Cl)(diphosphine)]2.43 Similarly, chloride-bridged dicopper com-
plex [Cu(µ-Cl){(R)-BINAP}]2 (3b) was obtained in quantitative
yield from the reaction of CuCl with a stoichiometric amount
of (R)-BINAP under the same reaction conditions (Scheme 5).44
The molecular structure of 3b was also unambiguously char-
acterized by X-ray crystallography, and an ORTEP drawing of
3b is shown in Figure 2.
equiv) in the presence of a catalytic amount of 3a (2.5 mol %)
in methanol at 0 °C for 12 h gave 2a in 84% yield with 85% ee
(S) (Table 9, run 1). The catalytic activity of 3a was almost the
same as that of the complex which might be formed in situ
under the present catalytic reaction conditions using (R)-Cl-
MeO-BIPHEP (Table 9, run 2). This result indicates that the
copper complex bearing one chiral diphosphine ligand works
as a reactive species in the catalytic propargylic amination, even
though twice the amount of (R)-Cl-MeO-BIPHEP was used
relative to the copper complex in many cases. Separately, we
also confirmed that the catalytic activity of 3b was similar to
that of the complex formed in situ using (R)-BINAP (Table 9,
runs 4 and 5).
As described above, we confirmed that the reaction of
propargylic acetates bearing an internal alkyne moiety such as
1,3-diphenyl-2-propynyl acetate under similar conditions did not
proceed at all.19 In addition, we have previously reported many
ruthenium-catalyzed propargylic substitution reactions with a
variety of nucleophiles, where ruthenium-allenylidene com-
plexes from reactions of ruthenium complexes with propargylic
alcohols bearing a terminal alkyne moiety were clarified to work
as key intermediates experimentally and theoretically.6–8 These
results lead us to envisage that copper-catalyzed propargylic
amination may proceed via copper-allenylidene complexes as
key intermediates. At first, we attempted to isolate some reactive
intermediates of the catalytic amination. The reaction of 3b with
a stoichiometric amount of 1a in the presence of N,N-
diisopropylethylamine in methanol gave only a complex mixture,
We then carried out the propargylic amination using the above
isolated chloride-bridged dicopper complexes as catalysts.
Typical results are shown in Table 9. Treatment of 1a with
N-methylaniline (1.2 equiv) and N,N-diisopropylethylamine (1.2
Figure 1. ORTEP drawing of [Cu(µ-Cl){(R)-Cl-MeO-BIPHEP}]2 (3a).
Selected bond distances (Å) and angles (deg) for 3a: Cu-Cl, 2.366; Cu-P,
2.248; Cl-Cu-Cl, 96.3; Cl-Cu-P, 114.6; P-Cu-P, 102.6; Cu-Cl-Cu,
83.7 (mean values).
Figure 2. ORTEP drawing of [Cu(µ-Cl){(R)-BINAP}]2 (3b). Selected bond
distances (Å) and angles (deg) for 3b (values without standard errors in
parentheses are averaged): Cu-Cl, 2.378; Cu-P, 2.260; Cl-Cu-Cl,
98.01(5); Cl-Cu-P, 114.9; P-Cu-P, 100.15(5); Cu-Cl-Cu, 81.26(4).
9
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A R T I C L E S
Hattori et al.
a
Table 9. Catalytic Reactivities of [Cu(µ-Cl)diphosphine]2 and [Cu(µ-CtCtol)diphosphine]2
run
copper catalyst
time (h)
yield of 2a (%)b
ee of 2a (%)c
1
2
3
4
5
6
2.5 mol % [Cu(µ-Cl){(R)-Cl-MeO-BIPHEP}]2 (3a)
5 mol % CuOTf ·1/2C6H6 + 10 mol % (R)-Cl-MeO-BIPHEP
2.5 mol % [Cu(µ-CtCtol){(R)-Cl-MeO-BIPHEP}]2 (4a)
2.5 mol % [Cu(µ-Cl){(R)-BINAP}]2 (3b)
12
12
12
36
12
36
84
88
85
81
80
82
85
86
85
80
85
80
5 mol % CuOTf ·1/2C6H6 + 10 mol % (R)-BINAP
2.5 mol % [Cu(µ-CtCtol){(R)-BINAP}]2 (4b)
a All the reactions of 1a (0.20 mmol) with N-methylaniline (0.24 mmol) and N,N-diisopropylethylamine (0.24 mmol) were carried out in the presence
of copper catalyst in MeOH (2.0 mL) at 0 °C. b Isolated yield of 2a. c Determined by HPLC (see Supporting Information for experimental details).
Scheme 6. Attempts for Preparation of Copper-Allenylidene
Complex
where the corresponding copper-allenylidene complex was not
isolated in a pure form (Scheme 6). In the absence of N,N-
diisopropylethylamine or methanol, no reaction occurred at all.
At present, we have been unsuccessful in isolating any reactive
intermediates, including copper-allenylidene complexes.
Instead of copper-allenylidene complexes, we separately
attempted to isolate copper-acetylide complexes because
copper-allenylidene complexes are expected to be formed via
copper-acetylide complexes from propargylic acetates. Thus,
the reaction of 3a with an excess amount of lithium acetylide
in THF at room temperature for 2 h gave the corresponding
acetylide-bridged dicopper complex [Cu(µ-CtCtol){(R)-Cl-
MeO-BIPHEP}]2 (4a) in 21% isolated yield (Scheme 7). The
molecular structure of 4a was unambiguously characterized by
X-ray crystallography, and an ORTEP drawing of 4a is shown
in Figure 3. An X-ray analysis of 4a has demonstrated that 4a
contains two copper(I) atoms bridged by two acetylide groups
in a µ-η1 bonding mode. Each copper atom chelated by (R)-
Cl-MeO-BIPHEP displays a slightly distorted tetrahedral ge-
ometry. The two copper atoms are separated from one another
at a distance of 2.4199(4) Å, which is close to the reported
values found among the acetylide-bridged complexes [Cu(µ-
CtCR)(diphosphine)]2, the short copper-copper separation of
which having been suggested to be derived from the σ-donor
Figure 3. ORTEP drawing of [Cu(µ-CtCtol){(R)-Cl-MeO-BIPHEP}]2
(4a). Selected bond distances (Å) and angles (deg) for 4a (values without
standard errors in parentheses are averaged): Cu-C, 2.095; Cu-P, 2.271;
C-Cu-C, 109.44(10); C-Cu-P, 111.6; P-Cu-P, 101.16(3); Cu-C-Cu,
70.6.
capabilities of the acetylides.45 A similar acetylide-bridged
dicopper complex, [Cu(µ-CtCtol){(R)-BINAP}]2 (4b), was also
obtained in 25% isolated yield from the reaction of 3b with
lithium acetylide under the same reaction conditions (Scheme
7). The molecular structure of 4b was also confirmed by a
preliminary X-ray crystallographic study.46
Interestingly, the produced acetylide-bridged dicopper com-
plexes also have a catalytic activity to promote the amination.
In fact, the reaction of 1a with N-methylaniline (1.2 equiv) and
N,N-diisopropylethylamine (1.2 equiv) in the presence of a
Scheme 7. Preparation of [Cu(µ-CtCtol)diphospine]2
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Cu-Catalyzed Enantioselective Amination of Propargylic Esters
A R T I C L E S
Figure 5. Linear relationship between the ee value of (R)-Cl-MeO-BIPHEP
and the ee value of 2r obtained for the reaction of 1a with N-methyl-4-
trifluoromethylaniline catalyzed by CuOTf·1/2C6H6 in MeOH at 0 °C.
acetylide complexes generally have a tendency to aggregate into
the corresponding polynuclear complexes.47,48 However, we
consider that a monomeric copper-acetylide complex generated
from polynuclear copper-acetylide complexes works as one
(or more) species to promote the catalytic reaction. In addition,
we plotted the ee value of (R)-Cl-MeO-BIPHEP against the ee
value of the produced propargylic amine 2a in the catalytic
reaction of 1a with N-methylaniline (Figure 5). The result clearly
showed the linear relationship49,50 between the ee value of (R)-
Cl-MeO-BIPHEP and the ee value of the produced propargylic
amine, supporting our proposal that a monomeric complex may
work as one (or more) species to promote the catalytic reaction.
Figure 4. Rate measurement for the propargylic amination of 1a with
N-methylaniline catalyzed by CuOTf ·1/2C6H6 and (R)-Cl-MeO-BIPHEP in
CD3OD at 20 °C: (a) kinetic data obtained for different catalyst concentra-
tions; (b) reaction order with respect to CuOTf·1/2C6H6 and (R)-Cl-MeO-
BIPHEP.
Proposed Reaction Pathway. By considering all the experi-
mental evidence, a reaction pathway for the catalytic amination
is proposed in Scheme 8, where copper-allenylidene51 complex
may be formed as a key intermediate.52 The copper-allenylidene
catalytic amount of 4a (2.5 mol %) in methanol at 0 °C for
12 h gave 2a in 85% yield with 85% ee (S) (Table 9, run 3).
The catalytic activity of 4a is almost the same as that of the
complex prepared in situ from the reaction of CuOTf ·1/2C6H6
with 2 equiv of (R)-Cl-MeO-BIPHEP. Separately, we confirmed
that the catalytic activity of 4b is also similar to that of the
complex prepared in situ from the reaction of CuOTf ·1/2C6H6
with 2 equiv of (R)-BINAP (Table 9, run 6). These results show
that the copper-acetylide complexes bearing a chiral diphos-
phine might work as precursors of the reactive species in the
catalytic propargylic amination.
In order to obtain more information on the reactive intermedi-
ates in the propargylic amination, the rate constants at different
initial concentrations of the catalyst were estimated, and the
reaction order with respect to the catalyst, 0.91 for the copper
complex (an almost first order to copper salt), was obtained by
plotting the log k against log [Cu0] of the catalyst as shown in
Figure 4. As described in the previous paragraph, copper-
(45) (a) D´ıez, J.; Gamasa, M. P.; Gimeno, J.; Aguirre, A.; Garc´ıa-Granda,
S.; Holubova, J.; Falvello, L. R. Organometallics 1999, 18, 662. (b)
Mealli, C.; Godinho, S. S. M. C.; Calhorda, M. J. Organometallics
2001, 20, 1734.
(46) Preliminary crystallographic data for 4b · CH2Cl2: C107H80Cl2Cu2P4,
FW ) 1687.70, monoclinic, space group P21, a ) 13.4997(5), b )
20.7940(6), and c ) 15.3709(5) Å, ꢀ ) 94.0290(10)°, V ) 4304.1(2)
Å3, Z ) 2, dcalcd ) 1.302 g cm-3, µ ) 6.800 cm-1, R1 (wR2) ) 0.0762
(0.1419) for 18 587 unique reflections and 1032 parameters. Heavy
disorder among acetylides and dichloromethane prohibited sufficient
refinement of the structure.
(47) (a) Knotter, D. M.; Spek, A. L.; van Koten, G. J. Chem. Soc., Chem.
Commun. 1989, 1738. (b) D´ıez, J.; Gamasa, M. P.; Gimeno, J.; Aguirre,
A.; Garc´ıa-Granda, S. Organometallics 1991, 10, 380. (c) Baxter,
C. W.; Higgs, T. C.; Bailey, P. J.; Parsons, S.; McLachlan, F.;
McPartlin, M.; Tasker, P. A. Chem.sEur. J. 2006, 12, 6166. (d) Bruce,
M. I.; Zaitseva, N. N.; Skelton, B. W.; Somers, N.; White, A. H. Inorg.
Chim. Acta 2007, 360, 681. (e) Asano, Y.; Ito, H.; Hara, K.; Sawamura,
M. Organometallics 2008, 27, 5984.
(48) (a) Straub, B. F. Chem. Commun. 2007, 3868. (b) Meldal, M.; Tornøe,
C. W. Chem. ReV. 2008, 108, 2952, and references therein.
(49) Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. 1998, 37, 2922, and
references therein.
(43) (a) Baker, R. T.; Calabrese, J. C.; Westcott, S. A. J. Organomet. Chem.
1995, 498, 109. (b) Pinto, P.; Calhorda, M. J.; Fe´lix, V.; Avile´s, T.;
Drew, M. G. B. Monatsh. Chem. 2000, 131, 1253.
(50) (a) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew.
Chem., Int. Ed. 2003, 42, 5763. (b) Lipshutz, B. H.; Noson, K.;
Chrisman, W.; Lower, A. J. Am. Chem. Soc. 2003, 125, 8779. (c)
Harutyunyan, S. R.; Lo´pez, F.; Browne, W. R.; Correa, A.; Pen˜a, D.;
Badorrey, R.; Meetsma, A.; Minnaard, A. J.; Feringa, B. L. J. Am.
Chem. Soc. 2006, 128, 9103.
(44) The complex 3b has already been prepared by the Lipshutz group,
butthecrystallographicstructureof3bhasnotyetbeenmentioned:Lipshutz,
B. H.; Frieman, B.; Birkedal, H. Org. Lett. 2004, 6, 2305.
9
J. AM. CHEM. SOC. VOL. 132, NO. 30, 2010 10601

A R T I C L E S
Hattori et al.
Scheme 8. Proposed Reaction Pathway
complex (D) might be formed by the elimination of an acetyl
moiety from the copper-acetylide complex (C), the protonated
species of B, while B is formed from the copper-π-alkyne
complex (A) between 1 and copper complex bearing (R)-Cl-
MeO-BIPHEP. N,N-Diisopropylethylamine promotes these depro-
tonation and protonation processes from A to the copper-
allenylidene complex D, where the copper-acetylide complex
bearing a cationic γ-carbon (E) exists as a resonance structure
of D. An amine then attacks the copper-allenylidene complex
D to afford the corresponding copper-acetylide complex (F).
Finally, the higher acidity of the proton of conjugated amine in
F promotes a hydrogen atom shift to the R-carbon on the ligand
to give a copper-π-alkyne complex (G). This proposed reaction
pathway is supported by the following kinetic study on the
catalytic reactions. The relative reactivity (the Hammett linear
free-energy relationship)53 of substituted propargylic acetates
(XC6H4CH(OAc)CtCH, X ) p-Me, H, p-Cl) with N-methy-
laniline in the presence of a catalytic amount of the chiral copper
complex was determined from the relative rates of the conver-
Figure 6. Relative reactivity of substituted propargylic acetates (X ) Me, 0;
X ) H, 4; X ) Cl, O) in the reaction with N-methylaniline in the presence of
catalytic amounts of CuOTf ·1/2C6H6 and (R)-Cl-MeO-BIPHEP.
Table 10. Relative Rate Constants for the Copper-Catalyzed
Propargylic Amination of Propargylic Acetate (1) with
N-Methylaniline
(51) No copper-allenylidene complex has yet been isolated until now, but
the first example of a silver-allenylidene complex has recently been
reported: (a) Asay, M.; Donnadieu, B.; Schoeller, W. W.; Bertrand,
G. Angew. Chem., Int. Ed. 2009, 48, 4796. Recently, the first example
of a palladium-allenylidene complex has been reported: (b) Kessler,
F.; Szesni, N.; Po˜hako, K.; Weibert, B.; Fischer, H. Organometallics
2009, 28, 348.
X in propagylic acetate (1)
σ+
(σ)
kX/kH
log(kX/kH)
p-Me
H
-0.31
0
(-0.17)
(0)
4.90
0
0.69
0
(52) Quite recently, we reported the copper-catalyzed enantioselective ring-
opening reactions of ethynyl epoxides with amines, where copper-
allenylidene complexes were proposed to work as key intermediates:
Hattori, G.; Yoshida, A.; Miyake, Y.; Nishibayashi, Y. J. Org. Chem.
2009, 74, 7603.
p-Cl
0.11
(0.23)
0.41
-0.39
sion of propargylic acetates when conversions were low (<10%)
(Figure 6 and Table 10). The rate data correlated well with the
Hammett linear free energy relationship by use of σ and σ+
values. Better correlation (F ) -2.50) was obtained with a σ+
(Figure 7),53 showing that the formation of the propargylic cation
(53) For reviews, see: (a) Exner, O. In Correlation Analysis in Chemisty;
Chapman, N. B., Shorter, J., Eds.; Plenum Press: New York, 1978;
Chapter 10. (b) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991,
91, 165.
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Cu-Catalyzed Enantioselective Amination of Propargylic Esters
A R T I C L E S
Scheme 9. Model Reaction between Propargyl Acetate and N,N-
Dimethylamine Catalyzed by Copper Complex [Cu(PH3)2(MeOH)]+
Theoretical Calculations for Reaction Pathway. To get further
insight into the reaction pathway of the copper-catalyzed
propargylic amination, density functional theory (DFT) calcula-
tions using the B3LYP hybrid functional54 with Gaussian03
program55 (SDD56 for Cu atom and 6-311G** 57 for other
atoms) were carried out for the following model reaction
between propargyl acetate and N,N-dimethylamine in the
presence of a cationic copper complex [Cu(PH3)2(MeOH)]+
(Scheme 9). For simplicity, we adopted the model where the
aryl group at the propargylic position of propargylic acetates is
replaced with a hydrogen atom, ignoring the π-conjugation effect
by the aryl group in intermediate structures.
Figure 7. Hammett linear free-energy relationship between σ+ and
log(kX/kH).
as reactive intermediate may be involved in the rate-determining
step. On the other hand, no correlation was observed with a σ
value when the relative reactivity of propargylic acetate with
substituted N-methylanilines (XC6H4NMe, X ) p-Me, H, p-Cl)
was determined in the presence of a catalytic amount of the
chiral copper complex.
Figure 8. Optimized structures of stationary points for (a) the reaction between [Cu(MeOH)(PH3)2]+ and propargyl acetate bearing methanol I and (b) the
reaction between the copper-allenylidene complex V and N,N-dimethylamine bearing methanol. Bond lengths are in Å.
9
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A R T I C L E S
Hattori et al.
Figure 9. Relative energy diagram (kcal/mol) for the model reaction. Values in parentheses are relative Gibbs free energies at 298.15 K in the gas phase.
Scheme 10. Reaction Pathway for the Reaction via Copper-Allenylidene Complex Assisted by One Methanol Molecule (Path A)
The optimized structures and energy diagram for the reaction
pathway are shown in Figures 8 and 9, respectively (Scheme 10).
The complexation between the copper complex [Cu]+
([Cu(PH3)2(MeOH)]+) and propargyl acetate with a methanol
molecule (I) gives the π-alkyne complex II with a stabilization
(54) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785. (b) Becke,
A. D. J. Chem. Phys. 1993, 98, 5648. (c) Stephens, P. J.; Devlin, F. J.;
Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994, 98, 11623.
(55) Frisch, M. J.; et al. Gaussian 03, revision D.02; Gaussian, Inc.:
Wallingford, CT, 2004.
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Cu-Catalyzed Enantioselective Amination of Propargylic Esters
A R T I C L E S
Figure 10. Optimized structures of stationary points for the reaction between [Cu(MeOH)(PH3)2]+ and propargyl acetate bearing trimethylamine XIX.
Bond lengths are in Å.
energy of 22.3 kcal/mol. The deprotonation of acetylenic hydrogen
in the propargyl acetate with methanol molecule via TSI then gives
the copper-acetylide complex III. In the complex III, the
protonated methanol interacts with both the acetate group and the
R-carbon. The reaction barrier of TSI from the complex II to III
is +23.6 kcal/mol, and the relative energy ∆E of TSI is +1.3 kcal/
mol. The dissociation of acetic acid from III gives the complex
IV via TSII. The acetic acid in IV still interacts weakly with the
γ-carbon. The energy required for the complete dissociation of IV
into acetic acid and the copper-allenylidene complex V is 10.9
kcal/mol, and the ∆E of the state V is +19.6 kcal/mol. Nucleophilic
attack of N,N-dimethylamine at the γ-carbon atom in V then gives
the complex VI without a barrier height. This attack of dimethy-
lamine provides the large stabilization energy (48.8 kcal/mol). In
the following step, the activation barrier from VI to give the
copper-acetylide complex VII via TSIII is 22.8 kcal/mol.
Hydrogen transfer from an acidic proton on the methanol molecule
to the R-carbon in the acetylide ligand via TSIV affords the
π-alkyne complex VIII. Finally, the dissociation of propargyl amine
(IX) from VIII occurs to give the starting copper complex [Cu]+.
The relative Gibbs free energy of the state ([Cu]+ + IX) at 298 K
is lower than that of VIII by 3.5 kcal/mol, so the dissociation into
the product IX is considered to occur smoothly. The relative energy
∆E and the relative free energy ∆G of the product state ([Cu]+ +
IX) are -14.4 and -11.5 kcal/mol, respectively. Thus, the
calculated reaction system as shown in Schemes 9 and 10 is
exothermic as a whole.
As described in Figures 8 and 9, the catalytic reaction proceeds
smoothly via the copper-allenylidene complex V as a key
intermediate (Scheme 10, Path A). In this reaction pathway, one
methanol molecule assists the formation of the copper-acetylide
complexes III and VII, where the reaction barriers are 23.6 kcal/
mol in TSI from II and 22.8 kcal/mol in TSIII from VI,
respectively. Separately, we confirmed that the formation of the
copper-acetylide complexes hardly occurred in the absence of one
assisting methanol molecule,58 indicating that the assistance of one
methanol molecule is one of the most important factors to promote
the propargylic amination. The result of the present theoretical study
is consistent with the experimental result, because no propargylic
amination occurred when dichloromethane was used as a solvent
in place of methanol.
Another important factor to be considered is the role of base,
iPr2NEt or triethylamine, in the present reaction system. We
investigated further the reaction pathway between the copper
complex [Cu]+ and propargyl acetate with trimethylamine
(XIX). The optimized structures and energy diagram for the
reaction are shown in Figures 10 and 11, respectively (Scheme
11, Path C). From the reactant species, [Cu]+ and XIX, the π-
(56) Dolg, M.; Wedig, U.; Stoll, H.; Preuss, H. J. Chem. Phys. 1987, 86,
866.
(57) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio
Molecular Orbital Theory; Wiley: New York, 1986.
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A R T I C L E S
Hattori et al.
Figure 11. Relative energy diagram (kcal/mol) for the model reaction (Path C). Values in parentheses are relative Gibbs free energies at 298.15 K in the
gas phase.
Scheme 11. Reaction Pathway for the Reaction Assisted by
Trimethylamine (Path C)
weakly with the R-carbon, via TSXI. The protonated trimethy-
lamine in XXII transfers from the R-carbon to the oxygen atom
of acetyl group via TSXII. Bond dissociation between the
R-carbon and the oxygen atom then occurs, together with
hydrogen transfer from trimethylamine to an acetyl group,
affording the complex XXIV via TSXIII. Finally, the complete
dissociation of acetic acid with trimethylamine from XXIV gives
the copper-allenylidene complex V.
In the Path C reaction pathway, trimethylamine instead of
methanol in Path A assists the formation of the copper-acetylide
complex. The reaction barrier in TSX from XX to XXI is 10.1
kcal/mol, which is smaller than that in TSI from II to III at
Path A. Therefore, trimethylamine, which is more basic than
methanol, makes the formation of the copper-acetylide complex
easier. Furthermore, dissociation of acetic acid leads to the
formation of the copper-allenylidene complex V in Path C,
where the acetic acid is neutralized with trimethylamine. Thus,
the relative energy of V in Path C (16.3 kcal/mol) is smaller
than that in Path A (19.6 kcal/mol). These results are consistent
with the experimental results and support the proposed reaction
pathway shown in Scheme 8.
(58) (a) Separately, we carried out theoretical calculations of the propargylic
amination in the absence of one methanol molecule. In this case, the
propargylic amination is considered to proceed via copper-vinylidene
complexes as key intermediates (Path B; see Supporting Information
for experimental details). However, the energy barriers of the
propargylic amination via copper-vinylidene complexes (Path B) are
relatively higher than those via copper-acetylide complexes (Path A).
alkyne complex XX is formed. The abstraction of the acetylenic
hydrogen by trimethylamine gives the complex XXI via TSX,
and then XXI is easily transformed into the copper-acetylide
complex XXII, in which the protonated trimethylamine interacts
Thus, Path A is more preferred than Path B. (b) Some copper-catalyzed
transformations of terminal alkynes are considered to proceed via
copper-vinylidene complexes as key intermediates. For example, see:
Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.;
Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210.
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Cu-Catalyzed Enantioselective Amination of Propargylic Esters
A R T I C L E S
Scheme 13. Model of the Transition State of the
Copper-Allenylidene Complex Bearing (R)-BIPHEP
two fragments (INT). As a result, the stabilization by the INT
term in V is much smaller than that in V′, and the bond strength
between the copper and the R-carbon in V is relatively weak.
This result indicates that the copper-allenylidene complex V
should be less stable than the ruthenium-allenylidene complex
V′.
Figure 12.
Optimized molecular structures of [Cu(PH3)2
(MeOH)(dCdCdCH2)]+ (V) and [CpRu(PH3)2(dCdCdCH2)]+ (V′). Bond
lengths (Å) are in italics, and bond orders are in bold.
Origin of Enantioselectivity. As described in the previous
section, we have not yet isolated any copper-allenylidene
complexes, but we proposed a transition state consisting of
copper-allenylidene complex bearing a chiral ligand BIPHEP
to account for the high enantioselective formation of (S)-
propargylic amine (2a) as shown in Scheme 13 and Figure 13.
N-Methylaniline attacks the γ-carbon of the ligand in the
copper-allenylidene complex D′ from the re face,21,60 where
edge-to-face aromatic interaction between the two phenyl groups
is considered to play an important role in achieving the high
enantioselectivity.61,62 Thus, the presence of a CH moiety at
the ortho-position in the benzene ring of propargylic acetate is
necessary to achieve the high enantioselectivity. In fact, no
enantioselectivity was observed at all in the catalytic amination
of propargylic acetate bearing a 2,6-dimethylphenyl moiety (1o)
at the propargylic position, in sharp contrast to the high
enantioselectivity in the catalytic amination of propargylic
acetate bearing a 2-methylphenyl moiety (1i) (Table 4, runs 4
and 10). A similar edge-to-face aromatic interaction between a
phenyl group of the substrate and a phenyl group of the ligand
has been observed in the ruthenium-catalyzed transfer hydro-
genation of carbonyl compounds reported by Noyori and
co-workers.63,64
Scheme 12. Fragment Analysis of the Copper-Allenylidene
Complex (V) and Ruthenium-Allenylidene Complex (V′)
a B3LYP/631LAN level by Nakamura and co-workers.8a
As described in the proposed reaction pathway, the copper-
allenylidene complex V is considered to be a key reactive
intermediate. Next, we compared the molecular structure and
reactivity of V with those of the ruthenium-allenylidene
complex8a [CpRu(PH3)2(dCdCdCH2)]+ (V′; Cp ) η5-C5H5)
because the chemistry of allenylidene complexes is dominated
by a series of ruthenium-allenylidene complexes which are
prepared by simple activation of propargylic alcohols.9 As
shown in Figure 12, the bond distance between the R- and
ꢀ-carbons in V (1.264 Å) is slightly shorter than that in V′ (1.268
Å), while the bond distance between the ꢀ- and γ-carbons in V
(1.326 Å) is slightly longer than that in V′ (1.324 Å). In response
to these bond lengths, the Mayer bond order59 between the R-
and ꢀ-carbons in V (2.294) is larger than that in V′ (1.918),
while the bond order between the ꢀ- and γ-carbons in V (1.667)
is smaller than that in V′ (1.744). These results indicate that, in
V, the weight of the copper-acetylide complex bearing a
cationic γ-carbon (E in Scheme 8) is larger than that of its
resonance structure, the copper-allenylidene complex (D in
Scheme 8).
As described in the previous section, a good enantioselectivity
was observed in the catalytic amination only when atropisomeric
In order to examine the bond strength between the metal and
the R-carbon, fragment analysis of V and V′ was carried out
(Scheme 12). The complexes were separated into two fragments,
and the complexation energies between two fragments ∆E were
divided into the deformation energy associated with the
structural changes (DEF) and the interaction energy between
Figure 13. Model for the transition state of the copper-allenylidene
complex bearing (R)-BIPHEP.
(59) Mayer, I. Chem. Phys. Lett. 1983, 97, 270.
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A R T I C L E S
Hattori et al.
the magnitude of JP-Se in the 77Se isotopomer of the corre-
sponding phosphine-selenide (Table 12).36,66 The result shows
that Cl-MeO-BIPHEP displays an equivalent σ-basicity with
BINAP and SEGPHOS, although MeO-BIPHEP has a slightly
lower σ-basicity. At present, we believe that only the steric
property of Cl-MeO-BIPHEP may control the enantioselectivity
in the propargylic amination.
Table 11. Dihedral Angles of the Biaryl Backbone in the Optimized
a
Structure of [Cu(diphosphine)]+
dihedral angle in
[Cu(diphosphine)]+ (°)
ee of propargylic
amine 2a (%)b
diphosphines
Cl-MeO-BIPHEP
BINAP
MeO-BIPHEP
SEGPHOS
92.9
92.3
94.0
95.1
97.0
79
78
68
59
18
H8-BINAP
a B3LYP-6-31G*(C, H, O, N, P, Cl)/LANL2DZ(Cu). b Detailed
conditions are shown in Table 2.
Conclusion
We have found that copper-catalyzed enantioselective pro-
pargylic amination of propargylic acetates with a variety of
secondary amines gives the corresponding propargylic amines
in high yields with a high to excellent enantioselectivity. The
high enantioselectivity in the catalytic substitution reaction has
been realized by use of atropisomeric diphosphines such as Cl-
MeO-BIPHEP and BINAP as chiral ligands.67 The result of the
density functional theory calculation on the model reaction
supports that the catalytic amination proceeds via a copper-
allenylidene complex, where the attack of amines to the γ-carbon
atom of the allenylidene ligand is a key step, although the
isolation of copper-allenylidene complexes has not been
successful until now. The procedure described in the present
article provides a versatile method for the preparation of
optically active propargylic amines, which are synthetically
versatile intermediates for the construction of various biologi-
cally active compounds and polyfunctional amino derivatives.22
Table 12. 31P-77Se Coupling Constants in Optically Active
Diphosphine-Diselenides
diphosphine
1JP,Se in diselenide (Hz)
ee of propargylic amine 2a (%)a
Cl-MeO-BIPHEP
BINAP
SYNPHOS
MeO-BIPHEP
SEGPHOS
739
79
78
75
68
59
738b
740b
742b
738b
a Detailed conditions are shown in Table 2. b Reported constant.36
diphosphines were used as chiral ligands. Finally, we estimated
the relationship between the ee value of the produced propargylic
amine and the dihedral angle36 of the biaryl backbone in the
copper-diphosphine complex. Due to the lack of information about
the copper-diphosphine complexes, the dihedral angles of the
biaryl backbone in [Cu(diphosphine)]+ were determined by ge-
ometry optimization using B3LYP hybrid density functional
theory.65 Typical results are shown in Table 11. The dihedral angles
of SEGPHOS and H8-BINAP are larger than those of Cl-MeO-
BIPHEP and BINAP, indicating that use of a chiral diphosphine
bearing a smaller dihedral angle of the biaryl backbone has a tendency
to give a higher enantioselectivity in the propargylic amination.
On the other hand, we compared the σ-donor ability of Cl-
MeO-BIPHEP with that of other diphosphines by measuring
Acknowledgment. This work was supported by Grants-in-Aid
for Scientific Research for Young Scientists (S) (No. 19675002)
and for Scientific Research on Priority Areas (No. 18066003) from
the Ministry of Education, Culture, Sports, Science and Technology,
Japan. Some of the calculations were performed at Research Center
for Computational Science, Okazaki, Japan. K.S. is grateful to the
Research Center for Computational Science for generous permission
to use its computing facilities. G.H. is a recipient of the JSPS
Predoctoral Fellowships for Young Scientists and acknowledges
the Global COE Program for Chemistry Innovation. Y.N. thanks
the Asahi Glass Foundation.
(60) The X-ray analysis of a major enantioisomer of 2ae indicates that the
absolute configuration of 2ae is S. The molecular structure of 2ae
was confirmed by X-ray analysis. See Supporting Information for
experimental details.
(61) The result of the calculated model structure of the copper-allenylidene
complex D′ with the collinearity of the Cu-C(R)-C(ꢀ)-C(γ) bond
and the dihedral angle (C(1)(phenyl)-C(γ)-Cu-O(methanol)) of-
90° supports the edge-to-face interaction between the two phenyl
groups, where one of the ortho C-H bonds of the phenyl group in
the allenylidene ligand is tilting toward one of the phenyl groups at
the phosphorous atom in BIPHEP. The phenyl ring centroid-centroid
separation (6.09 Å) of these neighboring two phenyl groups is within
the range of phenyl ring centroid separations observed for the existence
of aromatic-aromatic interactions (3.4-6.5 Å). To obtain more exact
information, we are investigating isolation of the copper-allenylidene
complex.
Supporting Information Available: Experimental and com-
putational details, characterization data, X-ray data, and com-
plete ref 55 (PDF, CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
JA1047494
(65) Ohshima, T.; Miyamoto, Y.; Ipposhi, J.; Nakahara, Y.; Utsunomiya,
M.; Mashima, K. J. Am. Chem. Soc. 2009, 131, 14317.
(66) (a) Allen, D. W.; Taylor, B. F. J. Chem. Soc., Dalton Trans. 1982,
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Andersen, N. G.; Parvez, M.; Keay, B. A. Org. Lett. 2000, 2, 2817.
(d) Sua´rez, A.; Mendez-Rojas, M. A.; Pizzano, A. Organometallics
2002, 21, 4611.
(62) For the edge-to-face aromatic interaction, see: (a) Burley, S. K.; Petsko,
G. A. Science 1985, 229, 23. (b) Burley, S. K.; Petsko, G. A. J. Am.
Chem. Soc. 1986, 108, 7995. (c) Meyer, E. A.; Castellano, R. K.;
Diederich, F. Angew. Chem., Int. Ed. 2003, 42, 1210. (d) Nishio, M.
Tetrahedron 2005, 61, 6923.
(63) Noyori, R.; Yamakawa, M.; Hashiguchi, S. J. Org. Chem. 2001, 66, 7931.
(64) Quite recently, we found that edge-to-face aromatic interaction between
two the phenyl groups in the ruthenium-allenylidene complex plays
a critical role for the ruthenium-catalyzed enantioselective propargylic
substitution reactions: Kanao, K.; Tanabe, Y.; Miyake, Y.; Nishiba-
yashi, Y. Organometallics 2010, 29, 2381.
(67) During the preparation of this manuscript, the copper-catalyzed
enantioselective propargylic alkylation of propargylic acetates with
enamines was reported by using our reaction system, where Cl-MeO-
BIPHEP and BINAP worked as good chiral ligands: Fang, P.; Hou,
X.-L. Org. Lett. 2009, 11, 4612.
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10608 J. AM. CHEM. SOC. VOL. 132, NO. 30, 2010