Copper-catalyzed coupling of tertiary aliphatic amines with terminal alkynes to propargylamines via C-H activation

Article abstract of DOI:10.1021/jo800279j

(Chemical Equation Presented) We have developed a convenient and efficient method for coupling of tertiary aliphatic amines with terminal alkynes to propargylamines via C-H activation. The protocol uses CuBr as the catalyst, NBS as the free radical initia

Full text of DOI:10.1021/jo800279j

lent examples based on the direct sp3 C-H bond activation
adjacent to a nitrogen atom for the C-C bond formations were
reported.4,5 Very recently, we have also developed an inexpen-
sive and effective CuBr/tBuOOH system for the amidation of
unactivated sp3 C-H bonds adjacent to a nitrogen atom.6
Propargylamines are major skeletons7 or versatile and key
intermediates8 for the synthesis of many biologically active
compounds, such as ꢀ-lactams, oxotremorine analogues, con-
firmationally restricted peptides, isosteres, and natural products
Copper-Catalyzed Coupling of Tertiary Aliphatic
Amines with Terminal Alkynes to
Propargylamines via C-H Activation
Mingyu Niu,† Zhengming Yin,‡ Hua Fu,*,† Yuyang Jiang,†,§
and Yufen Zhao†
Key Laboratory of Bioorganic Phosphorus Chemistry and
Chemical Biology (Ministry of Education), Department of
Chemistry, Tsinghua UniVersity, Beijing 100084, People’s
Republic of China, Department of Chemistry, Key
Laboratory of Chemical Biology and Organic Chemistry
(Henan ProVince), Zhengzhou UniVersity,
Zhengzhou 450052, Peopple’s Republic of China, and Key
Laboratory of Chemical Biology (Guangdong ProVince),
Graduate School of Shenzhen, Tsinghua UniVersity,
Shenzhen 518057, People’s Republic of China
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fuhua@mail.tsinghua.edu.cn
ReceiVed February 3, 2008
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We have developed a convenient and efficient method for
coupling of tertiary aliphatic amines with terminal alkynes
to propargylamines via C-H activation. The protocol uses
CuBr as the catalyst, NBS as the free radical initiator, CH3CN
as the solvent, and the alkynylation was selectively performed
on the methyl of tertiary aliphatic amines at 80 °C. This is
an economical and practical method for the synthesis of
propargylamines.
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2003, 125, 15312. (b) Doye, S. Angew. Chem., Int. Ed. 2001, 40, 3351. (c)
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Direct and selective conversion of carbon-hydrogen bonds
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and long-standing goal in chemistry, and this process has great
potential in synthesis because it avoids the preparation of
functional groups and makes synthetic schemes shorter and more
efficient.1 Recently, great progress has been achieved on the
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attention in industrial and academic research because of their
biological and pharmaceutical properties. Recently, some excel-
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* To whom correspondence should be addressed. Fax: 86-10-62781695.
† Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology
(Ministry of Education).
‡ Key Laboratory of Chemical Biology (Henan Province).
§ Key Laboratory of Chemical Biology (Guangdong Province).
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10.1021/jo800279j CCC: $40.75
Published on Web 04/12/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3961–3963 3961

TABLE 1. Reactions of Phenylacetylene with N,N-Dimethylbenzylamine: Optimization of Conditionsa
entry
cat. (equiv)
CuBr (0.1)
NBS (equiv)
solvent
time
yield (%)b
1
2
3
4
5
6
7
8
9
10
2
2
2
0.1
4
2
2
2
2
DMSO
EtOAc
10
10
10
10
6
6
6
6
6
13
10
15
trace
20
52
50
45
28
35
CuBr (0.1)
CuBr (0.1)
CuBr (0.1)
CuBr (0.1)
CuBr (0.4)
CuCl (0.4)
CuI (0.4)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CuCl2 (0.4)
Cu(O2CCF3)2 (0.4)
2
6
a Reaction condition: under nitrogen atmosphere, N,N-dimethylbenzylamine (1 mmol), phenylacetylene (0.5 mmol), solvent (1 mL), catalyst (0.2 mmol), NBS
(1 mmol). b Isolated yield.
and therapeutics drug molecules,9 so their preparation has
attracted great interest. Three-component one-pot coupling
reactions of aldehydes, alkynes, and amines are prevalent in
the previous methods, and their reaction mechanism is by the
addition of alkynes to in situ generated iminium ions from
aldehydes and secondary amines.10 Although these methods are
effective, they need imines formed by the prefunctionalized
aldehydes and amines. Obviously, the direct C-C bond forma-
tion of terminal alkynes with tertiary amines via C-H activation
is an economical and practical approach. Recently, Li and
workers have developed copper-catalyzed alkynylations of the
tertiary aryl amines in the presence of oxidant tBuOOH.11 As
a complement of the previous methods, we have developed an
inexpensive and practical catalyst/free radical initiator system
to efficiently reach alkynylations of tertiary aliphatic amines
under mild conditions.
Since direct introduction of a substituent at the R-position of
tertiary amines is performed in two stepssR-C-H activation
to produce iminium ion intermediates and subsequent reaction
with nucleophiles12–14we chose N-bromosuccinimide (NBS) as
the oxidant15 or free radical initiator16 to promote iminium
formation of tertiary aliphatic amines. N,N-Dimethylbenzy-
lamine and phenylacetylene were used as the model substrates
to optimize reaction conditions including optimization of the
copper catalysts and solvents at 80 °C under nitrogen atmosphere
as shown in Table 1, and the alkynylation was performed on
one methyl of N,N-dimethylbenzylamine. The effect of solvents
(DMSO, ethyl acetate, CH3CN) was first investigated (entries
1-3) by using 10 mol % CuBr (relative to phenylacetylene) as
the catalyst and 2 equiv of NBS as the free radical initiator,
and CH3CN proved to be the best solvent (entry 3). We
attempted to change the amount of CuBr and NBS (entries 3-6),
and the results showed that use of 40 mol % CuBr and 2 equiv
of NBS relative to phenylacetylene was the best choice (entry
6). Several copper salts, CuBr, CuCl, CuI, CuCl2 and
Cu(O2CCF3)2, were tested in CH3CN (entries 6-10), Cu(I) salts
showed higher catalytic activity than Cu(II) ones, and CuBr was
the most effective catalyst. No alkynylation product was
observed in the absence of copper catalyst or NBS. After the
optimization process for catalysts, solvents, and amount of catalyst
and NBS, the following alkynylation reactions were performed
under our standard conditions: 40 mol % CuBr as the catalyst, 2
equiv of NBS as the free radical initiator (relative to alkynes), and
CH3CN as the solvent at 80 °C under nitrogen atmosphere.
As shown in Table 2, various substrates were examined, and
they provided the corresponding propargylamines in different
yields. For the tertiary aliphatic amines, N,N-dimethylbenzy-
lamine, N,N-dimethyldodecylamine, N,N-dimethylcyclohexy-
lamine, and N-benzyl-N-ethylmethylamine, the stereo effect is
a key factor. For example, N,N-dimethylbenzylamine with less
hindrance gave higher yields, while N,N-dimethylcyclohexy-
lamine with a bulky group (cyclohexyl) provided a lower yield
(entry 11). Several terminal alkynes, phenylacetylene, 4-ethy-
nyltoluene, 4-ethynylanisole, 1-ethynyl-4-nitrobenzene, 1-bromo-
2-ethynylbenzene, 1-ethynylnaphthalene, cyclopropylacetylene,
and 1-octyne, were examined, and aryl alkynes showed higher
reactivity than aliphatic ones. For aryl alkynes, the substrates
containing electron-donating groups gave higher yields. The
alkynylation selectively occurred on the methyl group because
of the stereo effect for tertiary aliphatic amines containing
different alkyl groups, such as compound 1d with one methyl,
one ethyl, and one benzyl. In fact, the palladium-catalyzed
selective C-H activation to C-O bond formation on methyl
of Boc-protected N-methylamines was found by Yu and co-
workers before.17 In addition, the electronic effect of tertiary
amines also affects the activity of alkynylation, and tertiary aryl
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3962 J. Org. Chem. Vol. 73, No. 10, 2008

TABLE 2. Couplings of Tertiary Aliphatic Amines with Terminal
SCHEME 1. Possible Mechanism for Coupling of Tertiary
Aliphatic Amines with Terminal Alkynes to Propargylamines
via C-H Activation
Alkynes to Propargylamines via C-H Activationa
In summary, we have developed a simple and effective
catalyst/free radical initiator system (CuBr/NBS) to promote
alkynylations of tertiary aliphatic amines to propargylamines via
C-H activation at 80 °C, and the alkynylation was selectively
performed on the methyl of tertiary amines. The method is
economical and practical for the synthesis of propargylamines and
a valuable complement to the previous methods.
Experimental Section
General Experimental Procedure for the Synthesis of Pro-
pargylamines. NBS (1.0 mmol) was added to a mixture of CuBr
(0.2 mmol), tertiary aliphatic amine (1.0 mmol), and terminal alkyne
(0.5 mmol) in CH3CN (1.0 mL) under nitrogen atmosphere at room
temperature, and the solution was stirred at 80 °C for 6 h. The
reaction mixture was cooled to room temperature, and 10 mL of
chloroform and 10 mL of Na2CO3 saturated solution were added
to the flask. The separated organic phase was dried over anhydrous
Na2SO4 and concentrated under rotary evaporation, and the residue
was purified by column chromatography on silica gel (eluting with
petroleum ether/ethyl acetate ) 10:1) to provide the target
compound. Two selected examples are shown as follows.
N-Benzyl-N-methyl-[3-(2-bromophenyl)-2-propynyl]amine (3e).
1
Colorless oil, 95 mg, yield 60%. H NMR (300 MHz, CDCl3) δ
7.14-7.59 (m, 9H), 3.70 (s, 2H), 3.57 (s, 2H), 2.45 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ 138.4, 133.5, 132.3, 129.2, 129.1, 128.3,
127.2, 126.9, 125.4, 89.4, 84.2, 59.9, 45.6, 42.0. HRMS m/z calcd
for C17H17NBr [M + H]+ 314.0544, found 314.0549.
N-Dodecyl-N-methyl-[3-(4-methylphenyl)-2-propynyl]amine
(3i). Colorless oil, 71 mg, yield 44%. 1H NMR (300 MHz, CDCl3)
δ 7.32 (d, J ) 8.2 Hz, 2H), 7.10 (d, J ) 8.2 Hz, 2H), 3.53 (s, 2H),
2.46 (t, J ) 7.6 Hz, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 1.47-1.52 (m,
2H), 1.25-1.29 (m, 18H), 0.88 (t, J ) 6.5 Hz, 3H). 13C NMR (75
MHz, CDCl3) δ 137.9, 131.6, 128.9, 120.2, 85.3, 83.7, 56.1, 46.4,
41.9, 31.9, 29.6, 29.3, 27.6, 27.5, 22.7, 21.4, 14.1. HRMS m/z calcd
for C23H38N [M + H]+ 328.3004, found 328.3001.
a Reaction condition: under nitrogen atmosphere, amine (1 mmol),
alkyne (0.5 mmol), CuBr (0.2 mmol), NBS (1 mmol), CH3CN (1 mL).
b Isolated yield.
amines are weak substrates. For example, reaction of N,N-
dimethyl-p-toluidine with phenylacetylene only gave a trace
amount of alkynylation product. Although the present method
is only suitable to alkynylation of tertiary aliphatic amines, it
is a valuable complement for the previous methods.11
Acknowledgment. This work was supported by the National
Natural Science Foundation of China (Grant Nos. 20672065
and 20472042), Programs for New Century Excellent Talents
in University (NCET-05-0062) and Changjiang Scholars and
innovative Research Team in University (PCSIRT) (No. IRT0404)
in China, and the Key Subject Foundation from Beijing
Department of Education (XK100030514).
According to our results and the related literature,11–14
a
possible mechanism for alkynylation of tertiary aliphatic amines
is proposed in Scheme 1. NBS first yields succinimide and
chlorine free radicals (FR), and reaction of alkyne with CuI
unexceptionally formed copper(I) acetylide (A).18 Reaction of
the tertiary aliphatic amine with free radicals FR produces new
free radical B, removal of hydrogen free radical at the R-position
of B gives the iminium ion intermediate whose combination
with copper ion forms C, and nucleophilic attack of A to C
leads to the target product 3.
Supporting Information Available: Synthetic procedures,
characterization data and 1H, 13C NMR spectra of these synthesized
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
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JO800279J
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