Catalyzed imidation of tertiary amines by simple copper salts

Article abstract of DOI:10.1002/ejoc.200900143

Copper salt catalyzed imidation of tertiary amines by using sulfonyl azides as the nitrogen source was achieved with moderate to high yields. Formation of the carbon-nitrogen bond occurred chemoselectively with the use of a simple and inexpensive catalyst

Full text of DOI:10.1002/ejoc.200900143

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900143
Catalyzed Imidation of Tertiary Amines by Simple Copper Salts
Nan Liu,[a] Bo-Yang Tang,[a] Yue Chen,[b] and Ling He*[a]
Keywords: Amines / Sulfur / Imidation / Copper
Copper salt catalyzed imidation of tertiary amines by using
sulfonyl azides as the nitrogen source was achieved with
moderate to high yields. Formation of the carbon–nitrogen
bond occurred chemoselectively with the use of a simple and
inexpensive catalyst under moderate conditions, with a sim-
ple workflow, and with easy preparation of the nitrogen pre-
cursors.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
saturated C–H bonds of tertiary amines catalyzed by simple
copper salts by using sulfonyl azides as the nitrene source
(Scheme 1). The imidation reaction of tertiary amines cata-
lyzed by a simple and inexpensive catalyst with the use of
easily prepared nitrogen precursors is not known.
Introduction
Construction of C–N bonds catalyzed by transition-
metal complexes is a fascinating methodology for pro-
cessing many natural products, biologically active com-
pounds, and many interesting organic molecules.[1] There-
fore, to increase the applications of this methodology, we
studied catalyzed amidation reactions of cyclic ethers.[1l] Al-
though a series of studies on catalyzed inter- or intramolec-
ular amidation reactions by transition-metal complexes
have demonstrated that the method could effectively form
carbon–nitrogen bonds in systems with sp2 C–H bonds of
benzene,[1i,1j] aromatic heterocycles,[1k] and sp3 C–H bonds
of cyclohexane and alkyl aromatics,[1c–1h] the amidation re-
actions of tertiary amines with azide as a nitrogen source
are not reported in the literature.[2–4] We envisioned that
tertiary amine substrates could function in the same way as
cyclic ethers for a new approach to carbon–nitrogen bond
formation. Recently, we found by chance that cuprous chlo-
ride could activate the imidation reaction of tertiary amines
with sulfonyl azides as the nitrene source to give nonamid-
ation products in good yields. Meanwhile, Li and co-
workers reported the synthesis of sulfonyl amidines through
a diethyl azodicarboxylate activated elimination reaction of
both the α- and β-hydrogen atoms of tertiary amines.[3a] In
this paper, we processed the intermolecular imidation of
Scheme 1. Copper salt catalyzed imidation of tertiary amines.
Results and Discussion
We initially investigated the reaction of triethylamine
with 4-methylbenzenesulfonyl azide in the presence of
Cu(OAc)2 in acetonitrile. However, the resulting tosylimi-
doformamide was isolated in 52% yield. This prompted us
to undertake further investigation, and it was finally found
that the reaction of p-toluenesulfonyl azide with triethyl-
amine in CH3CN in the presence of CuCl could afford the
tosylimidoformamide in 88% yield (Table 1, Entry 2). Sub-
sequently, we found TsN=NTs in the control experiment,
and the reaction of N,N-diethyl-N-phenylamine with p-tolu-
enesulfonyl azide in CH3CN in the presence of TsN=NTs
could afford N-ethyl-N-phenyl-NЈ-tosylimidoformamide.
On the basis of the experimental results and combined with
literature findings,[3–7] we speculated that an enamine may
be formed in this system, as in the work by Li.[3a] A tenta-
tive mechanism was proposed as follows (Scheme 2). Firstly,
p-toluenesulfonyl azide is decomposed in the presence of
the copper salt to form the nitrene, and then it couples to
[a] Key Laboratory of Drug Targeting and Drug-Delivery Systems
of the Ministry of Education, Department of Medicinal Chem-
istry, West China School of Pharmacy, Sichuan University,
Chengdu, 610041, China
Fax: +86-28-85502940
E-mail: lhe2001@yahoo.com.cn
[b] Department of Nuclear Medicine, Affiliated Hospital, Luzhou
Medical College,
No. 25 Taiping Street, Luzhou, Sichuan, 646000, China
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2009, 2059–2062
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N. Liu, B.-Y. Tang, Y. Chen, L. He
SHORT COMMUNICATION
give TsN=NTs. Secondly, triethylamine undergoes nucleo-
philic addition to form TsN=NTs and forms an adduct.
Thirdly, the adduct undergoes intramolecular hydrogen
transfer to form an ion pair consisting of an imine cation
and TsNH–TsN–. The nitrogen anion abstracts the β-hydro-
gen of the nitrogen atom of triethylamine to generate the
enamine to form TsNH–NHTs. Finally, the enamine reacts
with p-toluenesulfonyl azide through a 1,3-dipolar cycload-
dition and produces triazoline, which is unstable and re-
leases one molecule of CH2N2 to afford the product N,N-
diethyl-NЈ-tosylimidoformamide.
Table 1. Optimization of reaction conditions.[a]
Scheme 2. Tentative mechanism for the imidation of tertiary
amines with TsN3 as the nitrogen source.
Entry
Catalyst 1
Solvent
Equiv. of
R–N3
Yield
[%][b]
nium(II) porphyrins, rhodium acetate, manganese prophy-
rin, InCl3, Hg(OAc)2, ZnCl2, FeSO4, AgNO3, CoCl2, cop-
per acetate, Cu(OTf)2, Cu(acac)2, Cu(hfac)2, CuI, CuCl,
and CuCl2, have been employed, but only cupric salt was
found to be effective in the intermolecular C-imidation of
tertiary amines. InCl3, ZnCl2, rhodium acetate, manganese
prophyrin, and ruthenium(II) porphyrin catalysts were
found to be poor catalysts for this intermolecular imidation
reaction, and only a trace amount of 3b was found under
similar conditions. In contrast, the similar reactions with Hg
(OAc)2, CoCl2, FeSO4, or AgNO3, respectively, as catalysts
gave 3b in evidently lower yields (Table 1, Entries 9, 12–14).
To examine the versatility of the cupric salt catalyst, a
variety of tertiary amine derivatives were treated with se-
lected sulfonyl azides as the nitrogen source. Table 2 clearly
shows that adipose tertiary amines are more reactive and
give excellent yields (Table 2, Entries 1, 2, 6, 7), and tertiary
amines containing electron-donating groups (Table 2, En-
tries 15, 22) are more reactive and give better yields (66,
70% yield, respectively) of the products. Similarly, tertiary
amine derivatives with electron-withdrawing substituents
(Table 2, Entries 12–14, 16, 19–21, 23) were found to be less
reactive than the corresponding substrates containing elec-
tron-donating groups (Table 2, Entries 15, 22). However, ni-
trogen heterocycles with electron-withdrawing substituents
(Table 2, Entries 27–30) give the corresponding products in
trace amounts. In the same way, the reactivity of substrates
suffering from steric hindrance (ortho substituted, long
chain) was low or only starting materials were recovered
under strictly identical conditions.
1
2
3
4
5
6
7
8
Cu(OAc)2
CuCl
CuCl2
CuBr2
CuI
Cu(acac)2
Cu(CF3SO3)2
Cu(CH3CN)+ClO4
Hg(OAc)2
InCl3
ZnCl2
CoCl2
FeSO4
AgNO3
CuCl
CuCl
CuCl
CuCl
CuCl
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
CH3OH
THF
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
1
2
5
3
3
3
3
52
88
53
66
48
31
5
–
trace
15
trace
trace
22
9
10
11
12
13
14
15
16
17
18
19
20
21
22[c]
23[d]
24[e]
25[f]
20
10
trace
trace
trace
trace
57
63
88
88
68
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
45
80
[a] Unless otherwise noted, all reactions were carried out with a
molar ratio 2b/catalyst 1/benzyltriethylammonium chloride
(TEBA), 1:0.2:0.1 under reflux for 8 h. [b] Yield of isolated prod-
uct. [c] Molar ratio 2b/catalyst, 1:0.3. [d] Molar ratio 2b/catalyst,
1:0.1. [e] Molar ratio 2b/catalyst, 1:0.05. [f] Molar ratio 2b/catalyst,
1:0.3, without TEBA.
To evaluate the catalytic efficiency of various catalysts,
The solvent effect on the C-imidation was also studied.
the reaction of tertiary amines with p-toluenesulfonyl azide Some of solvents were surveyed to ascertain the effect of
as the nitrene source was studied by using different catalysts the reaction medium on the yield. Among these solvents
with acetonitrile as the solvent (molar ratio of substrate/p- studied, acetonitrile and 1,4-dioxane were found to be more
toluenesulfonyl azide, 1:3). The results are summarized in effective for this reaction under reaction conditions similar
Table 1. It is noticeable that several catalysts, namely, ruthe- tot hose used with dichloromethane and toluene.
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Catalyzed Imidation of Tertiary Amines by Simple Copper Salts
Table 2. CuCl-catalyzed imidation of 2a–IV.[a]
[a] All reactions were carried out under reflux for 8 h with a molar ratio 2/R1C6H5SO2N3/CuCl/TEBA, 1:3:0.2:0.1. [b] Yield of isolated
product.
By using compound 2b as the substrate, the effect of tem- (20%), and the corresponding tosylimidoformamide deriva-
perature on the imidation reaction was examined. It was tives were obtained. Several tertiary amine derivatives were
found that the imidation reaction was best performed at employed to demonstrate the imidation universality of
82 °C. When the temperature was decreased to 20 °C, the simple copper salt catalyzed intermolecular reactions
yield of the product decreased to a trace amount.
(Table 2).
The reaction of the effect of azide[8] was carried out by
using several different azides under strictly identical condi-
tions. We noticed that the imidation of sulfonyl azides with
electron-donating groups in the para position have moder-
ate to high yields (88–90%) (Table 3, Entries 1, 2); however,
a sulfonyl azide with an electron-withdrawing substituent in
the para position (Table 3, Entry 3) gave 20% of the corre-
sponding p-nitrophenylsulfonylimidoformamide product;
azides lacking the sulfonyl group (Table 3, Entries 4–7) gave
only trace amounts of products.
Conclusions
In summary, we have developed an efficient procedure for
the direct imidation of tertiary amines catalyzed by simple
copper salts to form the corresponding tosylimidoformam-
ide by using sulfonyl azides as the nitrogen source. The
method was shown to be applicable to a broad range of
tertiary amines (such as tertiary amines with carboxyl and
In this work, the imidation of tertiary amines with hydroxy groups) and has advantages such as the require-
sulfonyl azides as the imidation reagents was conducted in ment for a simple and inexpensive catalyst, moderate condi-
acetonitrile at reflux in the presence of a copper salt catalyst tions, simple workflow, easy preparation of the nitrogen
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N. Liu, B.-Y. Tang, Y. Chen, L. He
SHORT COMMUNICATION
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[a] All reactions were carried out under reflux for 8 h with a molar
ratio 2b/R-N3/CuCl/TEBA, 1:3:0.2:0.1. [b] Yield of isolated prod-
uct.
precursors, moderate to high yields, and chemoselectivity.
The imidation reaction proceeds only at the sp3 carbon
atom of the tertiary amines. We are currently investigating
the scope and applications of this reaction and the pharma-
cological activity of the products.
Supporting Information (see footnote on the first page of this arti-
cle): General procedure for the imidation of tertiary amines; char-
1
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Received: February 12, 2009
Published Online: March 24, 2009
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