Copper-catalyzed enantioselective propargylic amination of nonaromatic propargylic esters with amines

Article abstract of DOI:10.1021/ol200703g

Chemical equations presented. The enantioselective propargylic amination of propargylic pentafluorobenzoates bearing an alkyl group at the propargylic position with amines in the presence of catalytic amounts of a copper complex and an optically active diphosphine such as BINAP has been found to give the corresponding propargylic amines in good yields with high enantioselectivity.

Full text of DOI:10.1021/ol200703g

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2460–2463
Copper-Catalyzed Enantioselective
Propargylic Amination of Nonaromatic
Propargylic Esters with Amines
Akiko Yoshida, Gaku Hattori, Yoshihiro Miyake, and Yoshiaki Nishibayashi*
Institute of Engineering Innovation, School of Engineering, The University of Tokyo,
Yayoi, Bunkyo-ku, Tokyo, 113-8656, Japan
ynishiba@sogo.t.u-tokyo.ac.jp
Received March 16, 2011
ABSTRACT
The enantioselective propargylic amination of propargylic pentafluorobenzoates bearing an alkyl group at the propargylic position with amines in
the presence of catalytic amounts of a copper complex and an optically active diphosphine such as BINAP has been found to give the
corresponding propargylic amines in good yields with high enantioselectivity.
Quite recently we have found copper-catalyzed enantio-
selective propargylic substitution reactions of propargylic
acetates with amines to give the corresponding propargylic
amines with up to 98% ee.1,2 The result of the den-
sity functional theory calculation on a model reaction
indicates that the propargylic amination proceeded via
copperꢀallenylidene3 complexes as key intermediates.1,2
We believe that the methods developed by our group and
Maarseveen’s group4 opened up a new field for transition-
metal-catalyzed enantioselective propargylic substitution
reactions.5ꢀ7 However, unfortunately, only propargylic
acetates bearing an aryl group at the propargylic position
(1) (a) Hattori, G.; Matsuzawa, H.; Miyake, Y.; Nishibayashi, Y.
Angew. Chem., Int. Ed. 2008, 47, 3781. (b) Hattori, G.; Sakata, K.;
Matsuzawa, H.; Tanabe, Y.; Miyake, Y.; Nishibayashi, Y. J. Am. Chem.
Soc. 2010, 132, 10592. (c) Hattori, G.; Yoshida, A.; Miyake, Y.;
Nishibayashi, Y. J. Org. Chem. 2009, 74, 7603. (d) Hattori, G.; Miyake,
Y.; Nishibayashi, Y. ChemCatChem 2010, 2, 155. (e) Yoshida, A.; Ikeda,
M.; Hattori, G.; Miyake, Y.; Nishibayashi, Y. Org. Lett. 2011, 13, 592.
(2) 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; see: Fang, P.; Hou, X.-L. Org. Lett. 2009, 11, 4612.
(3) For recent reviews of transition metalꢀallenylidene 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.
(5) For recent reviews, see: (a) Nishibayashi, Y.; Uemura, S. Curr.
Org. Chem. 2006, 10, 135. (b) Nishibayashi, Y.; Uemura, S. Compre-
hensive Organometallic Chemistry III, Vol. 11; Crabtree, R. H., Mingos,
D. M. P., Eds.; Elsevier: Amsterdam, 2007; p 123. (c) Kabalka, G. W.;
Yao, M.-L. Curr. Org. Synth. 2008, 5, 28. (d) Ljungdahl, N.; Kann, N.
Angew. Chem., Int. Ed. 2009, 48, 642. (e) Miyake, Y.; Uemura, S.;
Nishibayashi, Y. ChemCatChem 2009, 1, 342. (f) Detz, R. J.; Hiemstra,
H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2009, 6263. (g) Emer, E.;
Sinisi, R.; Capdevila, M. G.; Petruzziello, D.; Vincentiis, F. D.; Cozzi,
P. G. Eur. J. Org. Chem. 2011, 647.
(6) (a) Inada, Y.; Nishibayashi, Y.; Uemura, S. Angew. Chem., Int.
Ed. 2005, 44, 7715. (b) Matsuzawa, H.; Miyake, Y.; Nishibayashi, Y.
Angew. Chem., Int. Ed. 2007, 46, 6488. (c) Matsuzawa, H.; Kanao, K.;
Miyake, Y.; Nishibayashi, Y. Org. Lett. 2007, 9, 5561. (d) Kanao, K.;
Matsuzawa, H.; Miyake, Y.; Nishibayashi, Y. Synthesis 2008, 3869. (e)
Kanao, K.; Miyake, Y.; Nishibayashi, Y. Organometallics 2009, 28,
2920. (f) Fukamizu, K.; Miyake, Y.; Nishibayashi, Y. J. Am. Chem. Soc.
2008, 130, 10498. (g) Kanao, K.; Miyake, Y.; Nishibayashi, Y. Organo-
metallics 2010, 29, 2126. (h) Ikeda, M.; Miyake, Y.; Nishibayashi, Y.
Angew. Chem., Int. Ed. 2010, 49, 7289.
(4) (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 amina-
tion and presented a part of their result at the PAC-Symposium 2007
(March 1, 2007, Utrecht).
(7) Motoyama, K.; Ikeda, M.; Miyake, Y.; Nishibayashi, Y. Eur. J.
Org. Chem. 2011, 2239.
r
10.1021/ol200703g
Published on Web 04/07/2011
2011 American Chemical Society

were available as substrates for copper-catalyzed enantio-
selective amination.
MeO-BIPHEP11 as a chiral ligand slightly decreased the
enantioselectivity of 2a (76%ee). Other diphosphines such as
(R)-DTBM-MeO-BIPHEP12 as chiral ligands did not work
as effective ligands toward the propargylic amination.
We have now envisaged that the introduction of other
leaving groups, in place of the acetate group, into the
propargylic ester may promote the propargylic amination
of propargylic esters even bearing an alkyl group at the
propargylic position. In fact, the propargylic amination of
propargylic pentafluorobenzoates with amines proceeded in
the presence of catalytic amounts of a copper complex and a
chiral diphosphine such as BINAP to give the corresponding
propargylic amines in good yields with high enantioselec-
tivity. This is the first successful example of the enantioselec-
tive propargylic substitution reactions of propargylic alcohol
derivatives bearing an alkyl group at the propargylic position
with nucleophiles catalyzed by transition metal catalysts.8,9
Preliminary results are described here.
Table 1. Copper-Catalyzed Enantioselective Propargylic Ami-
nation of Propargylic Pentafluorobenzoates (1) with Anilinesa
aniline
1
yield of
2 (%)b
ee of 2
(%)c
run
n
Ar
R
Scheme 1
1
2
3
4
5
6
7
1 (1a)
1 (1a)
1 (1a)
1 (1a)
1 (1a)
2 (1b)
3 (1c)
Ph
Me
Me
Me
50 (2a)
50 (2b)
57 (2c)
56 (2d)
53 (2e)
47 (2f)
52 (2g)
82
83
81
77
54
83
78
4-ClC6H4
4-MeC6H4
indoline
Ph
Ph
Ph
H
Me
Me
a All reactions of 1 (0.20 mmol) with anilines (0.60 mmol) were
carried out in the presence of CuOTf l/2C6H6 (0.01 mmol), (R)-BINAP
3
i
(0.02 mmol), and Pr2NEt (0.24 mmol) in MeOH (2 mL) at 0 °C.
b Isolated yield of 2. c Determined by HPLC (see the Supporting
Information for experimental details).
a Isolated yield of 2a.
Propargylic amination with various anilines proceeded
smoothly to afford the corresponding propargylic amines
with high enantioselectivity. Typical results are shown in
Table 1. Reactions of 1a with 4-chloro-N-methylaniline
and N,4-dimethylaniline under the same reaction condi-
tions gave the corresponding propargylic amines (2b and
2c) with similarly high enantioselectivity (Table 1, runs 2
and 3). Interestingly, indoline was also available as aniline
derivatives togivetheN-propargylicindoline(2d) (Table 1,
run 4). Unfortunately, only low enantioselectivity was
observed when aniline was used in place of N-methylani-
line (Table 1, run 5). On the other hand, propargylic
amination of propargylic pentafluorobenzoates bearing a
cyclic alkyl group such as cycloheptyl and cyclooctyl
moieties at the propargylic position (1b and 1c) with N-
methylaniline under the same reaction conditions gave the
corresponding propargylic amines (2f and 2g) (Table 1,
runs 6 and 7). These results indicate that a variety of
propargylic pentafluorobenzoates bearing a cyclic alkyl
moiety at the propargylic position are available as sub-
strates toward the propargylic amination.
Treatment of 1-cyclohexyl-2-propynyl pentafluoro-
benzoate (1a) with N-methylaniline (3 equiv) and N,N-
diisopropylethylamine (1.2 equiv) in the presence of catalytic
amounts of copper trifluoromethanesulfonateꢀbenzene
1
complex CuOTf /2(C6H6) (5 mol %) and (R)-BINAP10
3
(10 mol %) in methanol at 0 °C for 96 h gave N-(1-
cyclohexyl-2-propynyl)-N-methylaniline (2a) in 50% yield
with 82% ee (Scheme 1). No propargylic amination occurred
at all when 1-cyclohexyl-2-propynyl acetate was used in place
of 1a. This result indicates that the nature of the ester group
in propargylic esters plays a critical role in promoting the
catalytic amination. This result is in sharp contrast to the pre-
vious result that only a lower enantioselectivity was observed
when 1-phenyl 2-propynyl pentafluorobenzoate was used in
place of 1-phenyl 2-propynyl acetate.1a,b The use of (R)-Cl-
(8) (a) Prof. van Maarseveen and co-workers have already found the
copper-catalyzed enantioselective propargylic amination of propargylic
acetates bearing an alkyl group at the propargylic position by using
pybox derivatives as a chiral ligands. However, the detailed result has
been reported only in a Ph.D. thesis; see: Detz, R. J. Ph.D. thesis,
University of Amsterdam (2009). (b) Prof. van Maarseveen and co-workers
described a comment on the preliminary result in ref 5f.
(11) (R)-Cl-MeO-BIPHEP = (R)-5,50-dichloro-6,60-dimethoxy-2,20-
bis(diphenylphosphino)-1,10-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) Prof. Fu and co-worker found the nickel-catalyzed cross-coupling
reactions between propargylic halides and organozinc reagents, but we
do not include this type of cross-coupling reactions as nucleophilic
substitution reactions of propargylic alcohol derivatives; Smith, S. W.;
Fu, G. C. J. Am. Chem. Soc. 2008, 130, 12645.
(10) BINAP = 2,20-bis(diphenylphosphino)-1,10-binaphthyl: Noyori,
R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345.
(12) BIPHEP = 2,20-Bis(diphenylphosphino)-1,10-biphenyl.
Org. Lett., Vol. 13, No. 9, 2011
2461

Next, we investigated the reaction of propargylic penta-
fluorobenzoates bearing an acyclic alkyl group at the
propargylic position. The reaction of 1-hexyn-3-yl penta-
fluorobenzoate (1d) with N-methylaniline (3 equiv) under
the same reaction conditions gave the N-(1-hexyn-3-yl)-N-
methylaniline (2h) in 50% yield with 89% ee (Scheme 2).
Similar results were observed when substituted N-methyl-
anilines such as 4-chloro-N-methylaniline and N,4-
dimethylaniline were used in place of N-methylaniline to
give the corresponding propargylic amines with 90% and
86% ee (2i and 2j), respectively. Indoline was also available
as aniline derivatives to give the N-propargylic indoline
with 82% ee (2k). It is noteworthy that the presence of a
simple linear alkyl moiety at the propargylic position of
propargylic pentafluorobenzoates affords the high enan-
tioselectivity of the produced propargylic amines.
position of BINAP is considered to play an important role
in achieving high enantioselectivity (Scheme 3). In this reac-
tion system, for the formation of major products (R)-2,
anilines attack the Re-face of copperꢀallenylidene com-
plexes leading to the carbonꢀnitrogen bond formation of
(R)-2 at the propargylic position.18,19
Scheme 3a
Scheme 2
a For clarity, biphenyl group was used in place of binaphthyl moiety
in BINAP.
It is well-known that optically active propargylic amines
are synthetically versatile intermediates for the construc-
tion of various biologically active compounds and poly-
functional amino derivatives. In sharp contrast to the
enantioselective preparation of propargylic amines bear-
ing an aryl group at the propargylic position, the prepara-
tion of optically active propargylic amines bearing an alkyl
group at the propargylic position is quite limited to only a
few examples.20 We believe that the procedure described in
the present article provides a versatile method for the
preparation of chiral propargylic amines bearing a simple
cyclic or acyclic alkyl moiety at the propargylic position.
In summary, we have found the copper-catalyzed enantio-
selective propargylic amination of propargylic esters bearing
an alkyl group at the propargylic position with aniline deri-
vatives to give the corresponding propargylic amines in good
yields with high enantioselectivity (up to 90% ee). The intro-
duction of pentafluorobenzoate as an ester group results in
the propargylic amination of propargylic esters even bearing
an alkyl group at the propargylic position. We believe that
the method described in this paper may provide a novel
synthetic approach to the preparation of optically active
propargylic amines bearing an alkyl moiety at the propargylic
position. Further work is currently in progress to apply this
strategy to other reaction systems and to clarify the scope and
limitations of the present propargylic amination.
a Isolated yield of 2.
After one recrystallization of the protonated products of
2a and 2h with trifluoromethanesulfonic acid and HCl,
respectively, enantiomerically pure ammonium salts 3a and
3h were obtained and their absolute configurations (R) were
determined by X-ray analysis.13 ORTEP drawings of (R)-3a
and (R)-3h are shown in Figures S1 and S2, respectively.13
The information on the stereochemistry of the pro-
pargylic amines indicates that the asymmetric induction
of the propargylic amination catalyzed by the copper com-
plex was achieved in a similar way with that by the edge-to-
face aromatic interaction between the two phenyl groups,
which was proposed in the previous paper.1a,b Thus, an
edge-to-face interaction14ꢀ17 between a CꢀH bond of the
substrate and a phenyl group at the pseudoequatorial
(13) See Supporting Information for experimental details.
(14) 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.
(15) For a recent review, see: Meyer, E. A.; Castellano, R. K.;
Diederich, F. Angew. Chem., Int. Ed. 2003, 42, 1210.
(16) Ribas, J.; Cubero, E.; Luque, F. J.; Orozco, M. J. Org. Chem.
2002, 67, 7057.
(17) Quite recently, we found that edge-to-face aromatic interaction
between the two phenyl groups in the rutheniumꢀallenylidene complex
plays a critical role in the ruthenium-catalyzed enantioselective pro-
pargylic substitution reactions: Kanao, K.; Tanabe, Y.; Miyake, Y.;
Nishibayashi, Y. Organometallics 2010, 29, 2381.
(18) Separately, we confirmed that no effective kinetic resolution
occurred effectively under these reaction conditions. In fact, the catalytic
reaction of 1a with N-methylaniline was carried out only for 24 h; 1a was
recovered in 16% recovery with 32% ee together with 2a in 31% yield
with 84% ee.
(19) The reaction of 1-cyclohexyl-3-phenyl-1-propynyl pentafluoro-
benzoate with N-methylaniline under the same reaction conditions gave
the corresponding propargylic alcohol in 92% NMR yield. This result
indicates that only the use of propargylic esters bearing a terminal alkyne
moiety were available as substrates.
(20) Gommermann, N.; Knochel, P. Tetrahedron 2005, 61, 11418.
2462
Org. Lett., Vol. 13, No. 9, 2011

Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research for Young Scientists
(S) from the Ministry of Education, Culture, Sports,
Science and Technology, Japan (No. 19675002) and Fund-
ing Program for Next Generation World-Leading Re-
searchers (GR025). G.H. acknowledges the Global COE
program for Chemistry Innovation. Y.N. thanks to the
Ube Industries LTD. We also thank the Research Hub for
Advanced Nano Characterization at The University of
Tokyo for X-ray analysis.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 9, 2011
2463