Copper-catalyzed asymmetric propargylic substitution reactions of propargylic acetates with amines

Article abstract of DOI:10.1002/anie.200800276

(Chemical Equation Presented) Flexing your bipheps: Enantioselective propargylic substitution reactions of propargylic acetates with amines catalyzed by a copper-(R)-Cl-MeO-biphep or -binap complex give the corresponding propargylic amines in excellent yi

Full text of DOI:10.1002/anie.200800276

Angewandte
Chemie
DOI: 10.1002/anie.200800276
Asymmetric Amination
Copper-Catalyzed Asymmetric Propargylic Substitution Reactions of
Propargylic Acetates with Amines**
Gaku Hattori, Hiroshi Matsuzawa, Yoshihiro Miyake, and Yoshiaki Nishibayashi*
Recently, we have reported the ruthenium-catalyzed asym-
metric propargylic alkylation of propargylic alcohols with
acetone to give the corresponding propargylic alkylated
products in good yields with a high enantioselectivity (up to
82% ee).[1] This was the first successful example of enantio-
selective and catalytic propargylic substitution reactions
catalyzed by chiral thiolate-bridged diruthenium complexes.[1]
More recently, as an extension of our study, we found the
asymmetric propargylation of aromatic compounds with
propargylic alcohols catalyzed by the same diruthenium
complexes to give the corresponding propargylated aromatic
compounds with a high enantioselectivity (up to 94% ee).[2]
This method provided a novel approach for the catalytic
asymmetric Friedel–Crafts alkylation of aromatic compounds
by using propargylic alcohols as a new type of electrophile.
However, propargylic substitution reactions with heteroatom-
centered nucleophiles, such as alcohols, amines, thiols, and
diphenylphosphine oxide, did not proceed enantioselectively
in the presence of a catalytic amount of the same chiral
diruthenium complexes. These results prompted us to inves-
tigate other transition-metal-catalyzed asymmetric propar-
gylic substitution reactions with heteroatom-centered nucle-
ophiles.[3]
enantioselective version of the copper-catalyzed propargylic
substitution reactions of propargylic esters with amines that
was originally reported by Murahashi and co-workers.[7] The
first example of the copper-catalyzed asymmetric propargylic
substitution reactions with amines has quite recently been
reported by using optically active 2,6-bis(oxazolinyl)pyridines
(pybox)[8] as chiral ligands, where the corresponding amines
were obtained with up to 88% ee.[9] Herein, we describe a
preliminary result of the copper-catalyzed enantioselective
propargylic substitution reactions of propargylic acetates with
amines by using optically active diphosphines, such as binap[10]
and biphep,[11] as chiral ligands to afford the corresponding
propargylic amines with a high enantioselectivity (up to
89% ee).
Treatment of 1-phenyl-2-propynyl acetate (1a) with N-
methylaniline and N,N-diisopropylethylamine[12] in the pres-
ence of a catalytic amount of copper trifluoromethanesulfo-
nate benzene complex, CuOTf·(benzene)0.5, (5 mol%) and
(R)-Cl-MeO-biphep[13,14] (10 mol%) in methanol[15] at 08C for
12 h gave N-methyl-N-(1-phenyl-2-propynyl)aniline (2a)
quantitatively with 85% ee (Scheme 1). The use of an equal
amount of (R)-Cl-MeO-biphep (5 mol%) to the copper
complex slightly decreased the enantioselectivity of 2a.
When (R)-binap was used in place of (R)-Cl-MeO-biphep
as the chiral diphosphine, the reaction proceeded sluggishly
with a similar enantioselectivity.[16]
Optically active propargylic amines are synthetically
versatile intermediates for the construction of various bio-
logically active compounds and polyfunctional amino deriv-
atives.[4] Recently, the transition-metal-catalyzed enantiose-
lective addition of terminal alkynes to imines has been
developed to produce the corresponding chiral propargylic
amines with a high enantioselectivity,[5] with copper-catalysis
being most reliable.[6] As another synthetic approach to chiral
propargylic amines, we have now envisaged developing an
[*] G. Hattori, Dr. H. Matsuzawa, Dr. Y. Miyake, Prof. Dr. Y. Nishibayashi
Institute of Engineering Innovation
School of Engineering
The University of Tokyo
Yayoi, Bunkyo-ku, Tokyo, 113-8656 (Japan)
Fax: (+81)3-5841-1175
E-mail: ynishiba@sogo.t.u-tokyo.ac.jp
Homepage: http://park.itc.u-tokyo.ac.jp/nishiba/
[**] This work was supported by Grant-in-Aids for Scientific Research for
Young Scientists (S) (No. 19675002) and for Scientific Research on
Priority Areas (No. 18066003) fromthe Ministry of Education,
Culture, Sports, Science and Technology (Japan). G.H. acknowl-
edges the Global COE Programfor Chemistry Innovation. Y.N. also
thanks to the Iketani Science & Technology Foundation and the
Japan Securities Scholarship Foundation. We thank Mr. Yusuke
Shimada for some experiments at the initial stage of this work.
Scheme 1. Reactions of 1-phenyl-2-propynyl acetate (1a) with N-meth-
ylaniline in the presence of a catalytic amount of copper trifluorome-
thanesulfonate benzene complex and (R)-Cl-MeO-biphep or (R)-binap.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or fromthe author.
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Table 2: Copper-catalyzed enantioselective propargylic amination of 1-
phenyl-2-propynyl acetate (1a) with amines.[a]
Next, the catalytic propargylic amination of other prop-
argylic acetates (1) was investigated by using (R)-Cl-MeO-
biphep as a chiral ligand. Typical results are shown in Table 1.
Table 1: Copper-catalyzed enantioselective propargylic amination of
propargylic acetates (1) with N-methylaniline.[a]
Entry
R1, R2
t [h]
Yield of 2 [%][b]
ee of 2 [%][c]
1
2
Ph, Me
12
12
12
12
12
12
12
12
2a, 96
2j, 96
2k, 92
2l, 97
2m, 64
2n, 97
2o, 95
2p, 90
85
89
89
82
80
81
83
53
p-ClC6H4, Me
p-ClC6H4, Me
p-MeC6H4, Me
-(CH2)5-
3[d]
4
Entry
R
t [h]
Yield of 2 [%][b]
ee of 2 [%][c]
5
6
7
8
1
2
3
4
5
6
7
8
9
1a, Ph
12
12
12
24
36
12
12
12
48
2a, 96
2b, 98
2c, 99
2d, 94
2e, 91
2 f, 99
2g, 99
2h, 99
2i, 0
85
81
82
85
85
84
85
83
–
-C6H4(CH2)3-[e]
Ph, Et
1b, p-MeC6H4
1c, p-MeOC6H4
1d, p-ClC6H4
1e, p-BrC6H4
1 f, p-PhC6H4
1g, 1-naphthyl
1h, 2-naphthyl
1i, cyclohexyl
Ph, H
[a] All the reactions of 1a (0.20 mmol) with amines (0.40 mmol) and
N,N-diisopropylethylamine (0.80 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 08C.
[b] Yield of isolated product. [c] Determined by HPLC (see Supporting
Information for experimental details). [d] 1d was used in place of 1a.
[e] 1,2,3,4-Tetrahydroquinoline was used as an amine.
[a] All the reactions of 1 (0.20 mmol) with N-methylaniline (0.40 mmol)
and N,N-diisopropylethylamine (0.80 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 08C. [b] Yield of isolated product. [c] Determined by HPLC
(see Supporting Information for experimental details).
reactions with aniline afforded the highest enantioselectivity
of the products, only a low enantioselectivity was observed in
our case (Table 2, entry 8).
To obtain more information on the enantioselective
propargylic amination, the stereochemistry of the product
2a was determined. Hydrogenation of 2a in the presence of a
catalytic amount of Pd/C under 1 atm of H2 at room temper-
ature for 4 h gave N-methyl-N-(1-phenylpropyl)aniline (3a;
Scheme 2). The absolute configuration was in accord with (S)-
3a obtained by the reported method,[17,18] showing that the
original propargylic amine 2a has an S absolute configura-
tion. In a separate experiment, a low enantioselectivity was
observed in 1a after recovered a short reaction time as shown
in Equation (1). This result means that there is a small
difference in the reactivity between (R)-1a and (S)-1a, the
latter being slightly more reactive. Although the detailed
reaction pathway is not yet clear, we consider that N-
methylaniline might attack the copper acetylide complex,
which has a cationic g-carbon atom, from the re face. The
The introduction of substituents such as methyl, methoxy,
chloro, bromo, and phenyl, at the para-position in the benzene
ring of the propargylic acetate 1a did not appreciably effect
the yield and enantioselectivity of the products (2; Table 1,
entries 1–6). Enantioselectivity of the same level was also
observed in the reactions of 1-naphthyl-2-propynyl acetates
(1g and 1h) with N-methylaniline under the same reaction
conditions (Table 1, entries 7 and 8). After recrystallization,
optically pure propargylic amines were obtained in some
cases. The presence of an aryl group at the propargylic
position of the propargylic acetate was necessary to achieve a
high enantioselectivity, and the reaction of 1-cyclohexyl-2-
propynyl acetate (1i) with N-methylaniline did not proceed at
all under the same reaction conditions (Table 1, entry 9).
Further, the also reaction did not proceed when propargylic
acetate bearing an internal alkyne moiety, such as 1,3-
diphenyl-2-propynyl acetate, was used as a substrate, indicat-
ing that only the propargylic acetates bearing a terminal
alkyne moiety can be employed successfully for this reaction.
A variety of amines are available as nitrogen-centered
nucleophiles. Typical results are shown in Table 2. The
introduction of substituents in the benzene ring of N-
methylaniline slightly affected the enantioselectivity of the
product. In fact, the presence of a chloro moiety at para-
position of the benzene ring slightly increased the enantio-
selectivity, but that of a methyl group at para-position slightly
decreased it (Table 2, entries 1–4). The use of cyclic amines
such as piperidine and 1,2,3,4-tetrahydroquinoline as nucle-
ophiles slightly decreased the enantioselectivity (Table 2,
entries 5 and 6). A similar enantioselectivity was achieved
when N-ethylaniline was used (Table 2, entry 7). In sharp
contrast to the copper–pybox system[9] with which the
Scheme 2. Determination of the absolute configuration of propargylic
amine (2a).
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copper acetylide complex is formed in situ from 1a and the
copper complex bearing (R)-Cl-MeO-biphep.
In summary, we have found the copper-catalyzed enan-
tioselective propargylic substitution reactions of propargylic
acetates with amines to give the corresponding propargylic
amines in excellent yields with a high enantioselectivity (up to
89% ee). Optically active diphosphines such as Cl-MeO-
biphep and binap have been found to function as suitable
chiral ligands. The reaction described may provide a novel
synthetic method for the preparation of chiral propargylic
amines. Further investigation of the reaction mechanism[19]
and for broadening the synthetic application of this asym-
metric propargylic amination is in progress.
[5] For a recent review, see: L. Zani, C. Bolm, Chem. Commun.
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[10] Binap = 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl.
[11] Biphep = 2,2’-bis(diphenylphosphino)-1,1’-biphenyl.
[12] No reaction occurred in the absence of N,N-diisopropylethyl-
amine. When triethylamine was used in place of N,N-diisopro-
Experimental Section
A typical experimental procedure for the reaction of 1-phenyl-2-
propynyl acetate (1a) with N-methylaniline: CuOTf·(benzene)0.5
(2.5 mg,
0.010 mmol)
and
(R)-Cl-MeO-biphep
(13.0 mg,
0.020 mmol) were placed in a 20 mL round-bottomed flask under
N2. Anhydrous methanol (1.0 mL) was added, and then the mixture
was stirred at 608C for 1 h with a magnetic stirrer. Then, 1a (34,8 mg,
0.20 mmol), N-methylaniline (42.8 mg, 0.40 mmol), and diisopropyl-
ethylamine (103.3 mg, 0.80 mmol) in anhydrous methanol (1.0 mL)
were added under N2, and the reaction flask was kept at 08C for 12 h.
The solvent was concentrated under reduced pressure by an aspirator,
and the residue was purified by the column chromatography (SiO2)
with hexane and ethyl acetate (97:3) as eluent to give N-methyl-N-(1-
phenyl-2-propynyl)aniline (2a)[20] as a pale yellow solid (42.5 mg,
0.19 mmol; 96% isolated yield). [a]2D2 = + 10.7 (c 1.42, CHCl3). The
optical purity of 2a was determined by HPLC analysis; DAICEL
Chiralpak AD, hexane/iPrOH = 97/3, flow rate = 1.0 mLminÀ1, l =
254 nm, retention time; 5.64 min (minor) and 7.04 min (major),
85% ee.
pylethylamine as
observed.
a base, a similar enantioselectivity was
[13] (R)-Cl-MeO-biphep = (R)-5,5’-dichloro-6,6’-dimethoxy-2,2’-
bis(diphenylphosphino)-1,1’-biphenyl, is a commercially avail-
able reagent from Strem Chemicals.
[14] a) R. R. Huddleston, H.-Y. Jang, M. J. Krische, J. Am. Chem.
Soc. 2003, 125, 11488; b) H.-Y. Jang, F. W. Hughes, H. Gong, J.
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10674.
[15] The reaction did not proceed smoothly in other solvents such as
EtOH, CH2Cl2, toluene, THF, MeCN, DMF, and 1,4-dioxane.
[16] Although a variety of optically active diphosphines and mono-
phosphines, such as Duphos, chiraphos, diop, and mop, were
investigated as chiral ligands for the propargylic amination,
these did not work effectively. As a result, (R)-Cl-MeO-biphep
was found to be the ligand of choice for the present propargylic
amination. The detailed experimental results will be reported in
due course.
[17] D. Pei, Z. Wang, S. Wei, Y. Zhang, J. Sun, Org. Lett. 2006, 8, 5913.
[18] A. M. Johns, N. Sakai, A. Ridder, J. F. Hartwig, J. Am. Chem.
Soc. 2006, 128, 9306.
[19] The molecular structure of a copper-(R)-Cl-MeO-biphep com-
plex has been determined by X-ray crystallography. The detailed
experimental results will be reported in due course.
Received: January 18, 2008
Published online: April 11, 2008
Keywords: amination · asymmetric catalysis · copper ·
.
nucleophilic substitution · P ligands
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Angew. Chem. Int. Ed. 2008, 47, 3781 –3783
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