CuBr-catalyzed efficient alkynylation of sp3 C-H bonds adjacent to a nitrogen atom

Article abstract of DOI:10.1021/ja0460763

A simple and effective catalytic method to construct propargylamine was developed by using copper bromide and tert-BuOOH via a combination of sp3 C-H bond and sp C-H bond activations followed by C-C bond formation. Copyright

Full text of DOI:10.1021/ja0460763

Published on Web 09/02/2004
CuBr-Catalyzed Efficient Alkynylation of sp3 C-H Bonds Adjacent to a
Nitrogen Atom
Zhiping Li and Chao-Jun Li*
Department of Chemistry, McGill UniVersity, 801 Sherbrooke Street West, Montreal, Quebec H3A 2K6, Canada
Received July 1, 2004; E-mail: cj.li@mcgill.ca
Scheme 1. Various Methods for Forming Propargylamines
Transition metal-catalyzed C-H bond activation and subsequent
C-C bond formations have attracted much interest in recent years.1
Although many excellent results have been achieved, catalytic
functionlization of sp3 C-H bonds is still a challenge.2 Various
transition metals such as Rh, Ru, Ir, Pd, Au, and Pt have been used
to activate sp3 C-H bonds.3
Direct oxidative functionalization of tertiary amines is of
importance both enzymatically and synthetically.4 Propargylic
amines are of great pharmaceutical interest and are synthetic
intermediates for the synthesis of various nitrogen compounds as
well as carbohydrates.5 There are three main methods to construct
Table 1. Selection of Copper Catalysta
propargylic amines (Scheme 1): Path A stands for stoichiometric
nucleophilic reactions.6 Path B is the transition metal-catalyzed
reactions of alkynes and imines generated from aldehydes and
amines. There are many excellent examples of these two methods.
Recently, we7 and others8 have described the direct addition of a
entry
catalyst
NMR yieldb
terminal alkyne to aldehyde and imines to afford propargyl alcohols
and propargylamines. With Cu(I)-pybox as a chiral catalyst, a highly
enantioselective imine addition in either water or toluene was
developed.9 We also developed the coupling of alkynes with
N-acylimines and N-acyliminium ions by a CuBr catalyst and the
gold or silver-catalyzed coupling reaction of alkyne, aldehyde, and
amine in water.10 Although these are effective methods, they need
a leaving group or imines formed from aldehyde and amine.
Therefore, the direct construction of propargylic amines by the
catalytic coupling of sp3 C-H adjacent to nitrogen with a terminal
alkyne is an attractive method (Path C).11 Herein we report an
effective CuBr-catalyzed oxidative cross-coupling of amine with
alkyne via a direct sp3 C-H bond alkynylation.
To begin our study, various copper salts were examined as
catalysts for the alkynylation of N,N-dimethylaniline (Table 1).
CuBr and CuCl proved to be the best catalysts. CuI and Cu(I)2Se
showed lower catalytic activities. No reaction was observed in the
absence of copper catalyst. To improve the yields, various ratios
of N,N-dimethylaniline and alkynes as well as tert-butyl hydrop-
eroxide were examined. The best yield was obtained when the N,N-
dimethylaniline/alkynes/tert-butyl hydroperoxide ratio wass 2:1:1.
From the NMR spectrum of crude reaction mixture, nearly 1 equiv
of N,N-dimethylaniline remained after the reaction was finished.
When the amount of N,N-dimethylaniline was reduced, however,
the yields also decreased. The yields were markedly decreased when
the amount of tert-butyl hydroperoxide was reduced to 0.5 equiv
and 0.25 equiv. The reaction did not proceed without tert-butyl
hydroperoxide.
1
2
3
4
5
6
7
8
9
CuBr
CuB2
CuCl
CuCl2
CuI
Cu(I)2Se
CuOTf
Cu(OTf)2
no
77
72
75
73
56
61
25
8
0
a 4.0 mmol aniline, 2.0 mmol phenylacetylene, 0.1 mmol copper salt,
and 0.8 mL tBuOOH (5-6 M in decane). b Reported yields were based on
alkynes and determined by NMR using an internal standard.
For aliphatic alkynes, the corresponding product was formed in
lower yields (entry 10). The reactions also tolerated functional
groups such as alcohol and ester (entries 7-9).
When benzyldimethylamine was reacted with phenylacetylene
under the standard conditions, alkynylation of the methyl group
was the main product (Scheme 2). The minor product could not be
isolated. This result, where the alkynylation takes place preferen-
tially at the alkyl rather than the benzyl position, is similar to anodic
methoxylation of the amine.12
Cyclic amines such as tetrahydroisoquinoline can be selectively
converted into the corresponding R-alkynylation compound in 74%
isolated yield (Scheme 3). Interestingly, 1-phenyl-piperidine reacted
with phenylacetylene in the presence of a catalytic amount of CuBr
and 1 equiv of tert-butyl hydroperoxide to give the desired direct
alkynylation product in 12% yield together with a tert-butyloxide
alkynylation compound (12%) (Scheme 4). The 1H NMR spectrum
of the tert-butyloxide alkynylation product showed the expected
AB system, JH -H 2.4 Hz. Chemdraw 3D models indicate that in
the trans-H1, H2 case, the dihedral angle between H1 and H2 is
approximately 74°, while the cis-isomer is 53° (after minimizing
the molecular energy). Compared with similar compounds,13 our
product is most likely the trans-isomer.
Subsequently, various alkynes were reacted with amines. Rep-
resentative examples are shown in Table 2. The reaction of N,N-
dimethylaniline (2 equiv) with phenylacetylene in the presence of
a CuBr catalyst (5 mol %) and tert-butyl hydroperoxide (1.0-1.2
equiv) at 100 °C for 3 h gave N-methyl-N-(3-phenylprop-2-ynyl)-
benzenamine in 74% isolated yield (entry 1). For aromatic alkynes,
the reaction often provided good yields of the desired products.
1
2
9
11810
J. AM. CHEM. SOC. 2004, 126, 11810-11811
10.1021/ja0460763 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Copper-Catalyzed Alkynylation of Aminesa
Subsequently, coupling of the two intermediates resulted in the
desired product and regenerated the copper catalyst.14 Alternatively,
it is possible that tert-butylperoxide products were involved as
intermediates,15 which were further converted into the corresponding
alkynylation amine via CuBr.16
In summary, we report here a simple and effective catalytic
method to form propargylamine by using copper bromide via a
combination of sp3 C-H bond and sp C-H bond activations and
C-C bond formations. Because piperidine derivatives and 1,2,3,4-
tetrahydro-isoquinoline derivatives are important structural features
of natural products and pharmaceuticals, this catalytic reaction will
be an efficient method for the synthesis of such compounds. The
scope, mechanism, and synthetic application of this reaction is under
investigation.
entry
Ar
R
product
yieldb
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
74
82
74
74
60
36
40
58
25
12
73
53
69
4-MeOPh
4-MePh
4-BrPh
4-PhPh
2-Py
HOCH2
EtCOOCH2
CH3OCO
Bu
9
10
11
12
13
3j
3k
3l
4-MePh
2-MePh
4-BrPh
Ph
Ph
Ph
Acknowledgment. We are grateful to the Canada Research
Chair (Tier I) foundation (to C.J.L.), the CFI, NSERC, Merck
Frosst, and McGill University for support of our research.
3m
a 4.0 mmol amine, 2.0 mmol alkyne, 0.1 mmol copper bromide, and 0.4
Supporting Information Available: Representative experimental
procedure and characterization of all new compounds (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
mL tBuOOH (5-6 M in decane). b Isolated yields were based on alkynes.
Scheme 2. Reaction of N,N-Dimethylbenzylamine
Scheme 3. Reaction of Cyclic Benzylamine
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A tentative mechanism for the product formation is proposed in
Scheme 5. Copper catalyzed the formation of an imine-type
intermediate (coordinated to copper) through activation of sp3 C-H
adjacent to nitrogen. Copper also activated the terminal alkyne.
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