Copper/diethyl azodicarboxylate Mediated regioselective alkynylation of unactivated aliphatic tertiary methylamine with terminal alkyne

Article abstract of DOI:10.1021/ol802974b

Mediated by copper/diethyl azodicarboxylate, regioselective alkynylation of unactivated aliphatic tertiary methylamine with terminal alkyne was successfully established. It is not necessary for the tertiary methylamines to be aryl substituted to modulate

Full text of DOI:10.1021/ol802974b

ORGANIC
LETTERS
2009
Vol. 11, No. 4
1027-1029
Copper/Diethyl Azodicarboxylate
Mediated Regioselective Alkynylation of
Unactivated Aliphatic Tertiary
Methylamine with Terminal Alkyne
Xiaoliang Xu and Xiaonian Li*
Institute of Industrial Catalysis, College of Chemical Engineering and Materials
Science, Zhejiang UniVersity of Technology, Hangzhou 310032,
People’s Republic of China
xnli@zjut.edu.cn
Received December 27, 2008
ABSTRACT
Mediated by copper/diethyl azodicarboxylate, regioselective alkynylation of unactivated aliphatic tertiary methylamine with terminal alkyne
was successfully established. It is not necessary for the tertiary methylamines to be aryl substituted to modulate the properties of amines.
The alkynylation reaction described here has the advantage of simple operation, mild reaction conditions, good to excellent yields, and no
need to exclude air and moisture.
Carbon-carbon bond formation reactions are the most
important processes in organic synthesis. Traditional methods
usually employ prefunctionalized substrates. However, due
to the requirement of environmental concerns, the carbon-
carbon bond formation via cross oxidative coupling of two
C-H bonds has attracted great interest in recent years.1 The
starting materials could be used directly in such transforma-
tions without prefunctionalization, and the synthetic proce-
dure could be shorter, simpler, and atom economical. A
number of excellent achievements have been made, and a
variety of substrates with different types of hybridized
carbons could be coupled.1,2
Propargylic amine derivatives have received much atten-
tion over the past decades and found wide application in
medicinal chemistry and synthetic chemistry.3 Traditional
synthetic methods included nucleophilic alkynyl of func-
tionalized amines and transition-metal-catalyzed addition of
alkynes to imines.4 Although these are effective methods,
they require the presence of a leaving group or the use of
imines prepared from the prefunctionalized aldehydes and
(1) For examples: (a) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem.
Soc. 2008, 130, 9254. (b) Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008,
47, 7075. (c) Deng, G.; Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008,
47, 6278. (d) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (e) Hull,
K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904. (f) Chiong,
H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449. (g) Dwight, T. A.; Rue, N. R.;
Charyk, D.; Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137. (h) Rech,
J. C.; Yato, M.; Duckett, D.; Ember, B.; LoGrasso, P. V.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 490. (i) Cai, G.; Fu, Y.; Li, Y.;
Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 7666. (j) Beck, E. M.;
Grimster, N. P.; Hatley, R.; Gaunt, M. J. J. Am. Chem. Soc. 2006, 128,
2528. (k) Takahashi, M.; Masui, K.; Sekiguchi, H.; Kobayashi, N.; Mori,
A.; Funahashi, M.; Tamaoki, N. J. Am. Chem. Soc. 2006, 128, 10930. (l)
Yokota, T.; Tani, M.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc. 2003,
125, 1476. (m) Jia, C.; Lu, W.; Kitamura, T.; Fujiwara, Y. Org. Lett. 1999,
1, 2097. (n) Brown, S. H.; Crabtree, R. H. J. Am. Chem. Soc. 1989, 111,
2935.
(2) (a) Li, Z.; Yu, R.; Li, H. Angew. Chem., Int. Ed. 2008, 47, 7497. (b)
Cheng, D.; Bao, W. J. Org. Chem. 2008, 73, 6881. (c) Cheng, D.; Bao, W.
AdV. Synth. Catal. 2008, 350, 1263. (d) Zhang, Y.; Li, C.-J. Eur. J. Org.
Chem. 2007, 4654. (e) Li, Z.; Cao, L.; Li, C.-J. Angew. Chem., Int. Ed.
2007, 46, 6505. (f) Li, Q.; Wei, Y.; Hao, J.; Zhu, Y.; Wang, L. J. Am.
Chem. Soc. 2007, 129, 5810. (g) Campos, K. R. Chem. Soc. ReV. 2007, 36,
1069. (h) Zhang, Y.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 4242. (i) Zhang,
Y.; Li, C.-J. Angew. Chem., Int. Ed. 2006, 45, 1949. (j) DeBoef, B.; Pastine,
S. J.; Sames, D. J. Am. Chem. Soc. 2004, 126, 6556
.
(3) (a) Sienkiewich, P.; Bielawski, K.; Bielawska, A.; Palka, J. EnViron.
Toxicol. Pharmacol. 2005, 20, 118. (b) Greenhill, J. V.; Lue, P. Prog. Med.
Chem. 1993, 30, 203.
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therein.
10.1021/ol802974b CCC: $40.75
Published on Web 01/21/2009
2009 American Chemical Society

amines. Direct oxidative functionalization of tertiary amines
represents an alternative method for the synthesis of prop-
argylic amine derivatives5 and other nitrogen-containing
compounds.6 Recently, Li reported an efficient method for
the direct synthesis of propargylic amines by copper-
catalyzed coupling of sp3 C-H adjacent to nitrogen with a
terminal alkyne.5b,c However, the reaction required an aryl
or benzyl substituted on the tertiary methylamine nitrogen
so as to induce the coupling. Fu reported a new method for
the cross coupling of aliphatic tertiary amines with terminal
alkynes promoted by copper/NBS; however, the yields were
very low in most cases.5a Herein, we report a novel oxidative
coupling of terminal alkynes with tertiary methylamines
where the nitrogen is substituted only by alkyls. This reaction
is mediated by copper and diethyl azodicarboxylate (DEAD)
and has the advantage of simple operation, mild conditions,
good to excellent yields, and no need to exclude air and
moisture.
Table 1. Synthesis of 3a Under Various Conditionsa
entry
catalyst
solvent
THF
THF
THF
time (h)
yield (%)b
1
2
3
4
5
6
7
8
9
-
6
6
12
16
7
8
7
7
7
0
87c
83
85
81
78
86
77
79
57
CuI
CuBr
CuCl
CuI
CuI
CuI
CuI
CuI
CuI
THF
toluene
CH3CN
1,4-dioxane
CH2Cl2
ClCH2CH2Cl
DMF
10
10
a DEAD (1.1 mmol), N,N-dimethylcyclohexylamine (1 mmol), pheny-
lacetylene (1.5 mmol), copper catalyst (0.05 mmol) in solvent (2 mL).
b Isolated yields. c 2H-DEAD was isolated in 85% yield.
DEAD, as a versatile reagent, has been widely used in
organic synthesis.7 Recently, we reported DEAD promoted
dehydrogenation of tertiary amine and tandem reaction with
sulfonyl azide.8 As far as the mechanism was concerned, it
revealed that a zwitterionic intermediate may be formed in
the reaction.8,9 Accordingly, we envisioned that it is probable
for this intermediate to subsequently react with terminal
alkyne and thus form the alkynylation product. In the
mechanism, when an ethyl is present, the elimination of both
R- and ꢀ-hydrogens of nitrogen was inevitable.8 However,
with a methyl group, the elimination could not happen due
to the absence of a ꢀ-hydrogen. Then, what will happen with
the coexistence of isopropyl and methyl?
catalyst compared with CuBr and CuCl (Table 1, entries
2-4). After prolonging the reaction for several hours, CuBr
and CuCl can also give excellent results. Using CuI as a
catalyst under room temperature, satisfactory yields could
be obtained using several solvents, such as CH3CN, CH2Cl2,
DCE, toluene, and 1,4-dioxane (Table 1, entries 5-9). DMF
gave the desired product in only 57% yield (Table 1, entry
10). The reaction rate varied with different solvents. The
reaction proceeded most rapidly in THF while most slug-
gishly in DMF.
Our study initiated with N,N-dimethylcyclohexylamine and
phenylacetylene as the substrates. In the presence of DEAD
and with copper as a catalyst, it was found that the reaction
between this pair of substrates afforded 3a as a product. This
result indicated that the dehydrogenation under this reaction
system occurred regioselectively at the methyl group,
whereas the R-hydrogen located at the cyclohexyl remained
intact although N,N-dimethylcyclohexylamine has two types
of R-hydrogens adjacent to the nitrogen atom.
The optimization of the reaction conditions for the
formation of 3a was done by screening several solvents and
copper catalysts. No reaction occurred in the absence of
copper catalyst (Table 1, entry 1). CuI proved to be the best
With the optimized conditions (Table 1, entry 2), a variety
of terminal alkynes and aliphatic tertiary methylamines were
examined, and the corresponding alkynylation products were
obtained in good to excellent yields (Table 2). Aromatic
alkynes substituted at the phenyl ring with MeO, Me, CF3,
F, Cl, and n-pentyl were all converted into the corresponding
products efficiently, indicating no remarkable electronic and
position effects of the substituents on the reaction (Table 2,
entries 2-6 and 16). 3-Ethynylpyridine and 3-ethynylth-
iophene were successfully coupled with N,N-dimethylcyclo-
hexylamine and afforded the corresponding propargylic
amines smoothly (Table 2, entries 9 and 10). Benzyl
acetylene also served as a good partner (Table 2, entry 7). It
is noteworthy that 1-hexyne and phenethylacetylene, two
aliphatic alkynes, afforded the desired products in good yields
as well (Table 2, entries 8 and 11). Trimethylsilyl could be
tolerated under the conditions (Table 2, entry 12). Several
types of aliphatic tertiary methylamines can be used in this
study. The dehydrogenation of an R-hydrogen at the isopro-
pyl and analogous group was not observed. Bulky groups,
such as iso-propyl and tert-butyl, have exerted no appreciable
influence on the reaction efficiency. In the case of N,N-
dimethylbenzylamine, the ratio for the alkynylation of methyl
and methylene is ∼63:37 in 82% overall yield (Table 2, entry
19). However, when N,N-dimethylaniline was used as the
substrate, the desired propargylic amine could not be obtained
in spite of the attempts with more reaction conditions, and
(5) (a) Niu, M.; Yin, Z.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem.
2008, 73, 3961. (b) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810.
(c) Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997.
(6) (a) Murahashi, S.-I.; Nakae, T.; Terai, H.; Komiya, N. J. Am. Chem.
Soc. 2008, 130, 11005. (b) Li, Z.; Bohle, S.; Li, C.-J. Proc. Natl. Acad.
Sci. U.S.A. 2006, 103, 8928. (c) Chatani, N.; Asaumi, T.; Yorimitsu, S.;
Ikeda, T.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2001, 123, 10935. (d)
Doye, S. Angew. Chem., Int. Ed. 2001, 40, 3351. (e) Murahashi, S.-I. Pure
Appl. Chem. 1992, 64, 403.
(7) (a) Nair, V.; Biju, A. T.; Mathew, S. C.; Babu, B. P. Chem. Asian
J. 2008, 3, 810. (b) Berlin, J. M.; Fu, G. C. Angew. Chem., Int. Ed. 2008,
47, 7048. (c) Mitsunobu, O.; Eguchi, M. Bull. Chem. Soc. Jpn. 1971, 44,
3427.
(8) Xu, X.; Li, X.; Ma, L.; Ye, N.; Weng, B. J. Am. Chem. Soc. 2008,
130, 14048.
(9) Huisgen R. In The AdVenture Playground of Mechanisms and NoVel
Reaction: Profiles, Pathwanys and Dreams; Seeman, J. I., Eds.; ACS:
Washington DC, 1994; p 62
.
1028
Org. Lett., Vol. 11, No. 4, 2009

Table 2. Synthesis of 3a Promoted by CuI/DEAD
Scheme 1. Proposed Mechanism
entry
R1
R2; R3
yield (%)b
1
Ph (1a)
Me; c-hexyl (2a)
3a; 87
3b; 90
3c; 83
3d; 72
3e; 74
3f; 69
3g; 71
3h; 73
3i; 66
3j; 64
3k; 82
3l; 81
3m; 83
3n; 90
3o; 94
3p; 75
3q; 82
2
4-MeOC6H4 (1b)
4-MeC6H4 (1c)
2-CF3C6H4 (1d)
3-FC6H4 (1e)
3-ClC6H4 (1f)
PhCH2 (1g)
PhCH2CH2 (1h)
3-pyridyl (1i)
3-thienyl (1j)
n-butyl (1k)
Me3Si (1l)
2a
3
2a
4
2a
5
2a
6
2a
7
2a
8
2a
9
2a
10
11
12
13
14
15
16
17
18
19
2a
2a
2a
1a
Me; c-pentyl (2b)
Me; c-heptyl (2c)
c-hexyl; c-hexyl (2d)
1a
1a
4-CH3(CH2)4C6H4 (1m) Me; Pri (2f)
copper alkynylide on C gives the desired product 3 and
liberates the copper catalyst to complete the catalytic cycle.
When the R2 or R3 is a phenyl group, the reaction route
follows path a to form the adduct product E preferably.
1a
1a
1a
Pri; But (2g)
Me; 3′-Me-2-pentyl (2f) 3r; 77
Me; PhCH2 (2e)
3s+3t; 82c
a DEAD (1.1 mmol), aliphatic tertiary methylamine (1 mmol), alkyne
(1.5 mmol), CuI (0.05 mmol), THF (2 mL), 6-12 h (see Supporting
Information). b Isolated yields. c Mixture of isomers.
In conclusion, an efficient CuI/DEAD mediated alkyny-
lation of aliphatic tertiary methylamines with alkynes is
successfully established. The reaction described here is mild,
general, and efficient, thus providing an extremely preferable
way for the alkynylation of aliphatic tertiary methylamine.
only the adduct of DEAD with N,N-dimethylaniline was
isolated in excellent yield.
According to the literature,8,9 a tentative mechanism was
proposed in Scheme 1. First, DEAD and aliphatic tertiary
methylamine 2 undergoes a nucleophilic addition reaction
and forms a 1:1 adduct A, which could be in equilibrium
with B by an intramolecular hydrogen transfer. Then adduct
A cleaves to form an ion pair consisting of imine cation C
and 1H-DEAD D. The nitrogen anion of D further abstracts
a hydrogen from the terminal alkyne with itself being
transformed into 2H-DEAD in the presence of the copper
catalyst, and the terminal alkyne is transformed into copper
alkynylide (path b). A further addition of the in situ generated
Acknowledgment. This work was supported by the grant
from National Natural Science Foundation of China (No.
20872131) and Natural Science Foundation of Zhejiang
Province (Y407250).
Supporting Information Available: Experimental details
and spectroscopic data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
OL802974B
Org. Lett., Vol. 11, No. 4, 2009
1029