An unexpected diethyl azodicarboxylate-promoted dehydrogenation of tertiaryamine and tandem reaction with sulfonyl azide

Article abstract of DOI:10.1021/ja8047514

It is shown here for the first time that diethyl azodicarboxylate promotes dehydrogenation of tertiaryamines to afford enamines, which subsequently take place in tandem reactions with sulfonyl azides to give the N-sulfonyl amidine derivatives. A number of different substituted tertiaryamines and sulfonyl azides can successfully be coupled, and several functionalized groups are tolerated in this system. The reaction described here is mild, general, and efficient, thus providing an extremely preferable method for synthesis of a variety of N-sulfonyl amidine derivatives. Copyright

Full text of DOI:10.1021/ja8047514

Published on Web 10/01/2008
An Unexpected Diethyl Azodicarboxylate-Promoted Dehydrogenation of
Tertiaryamine and Tandem Reaction with Sulfonyl Azide
Xiaoliang Xu,† Xiaonian Li,*,† Lei Ma,† Ning Ye,† and Bojie Weng‡
College of Chemical Engineering and Materials Science and College of Pharmaceutical Science, Zhejiang
UniVersity of Technology, Hangzhou 310032, People’s Republic of China
Received July 2, 2008; E-mail: xnli@zjut.edu.cn
Table 1. DEAD Promoted Synthesis of 3aa
Construction of complex molecules via convenient methods is
highly required due to modern environmental concerns. The
methodology of cross dehydrogenative coupling could be well-fitted
for this criterion.1,2 Thereinto, activation of the hydrogen located
at the R-position of the nitrogen atom represents an efficient
method.2 This may be due to the nitrogen atom not only activating
entry
solvent
time (h)
yield (%)b
the adjacent sp3 C-H bond but also stabilizing the in situ formed
intermediates. However, simultaneous activation or elimination of
both the R and ꢀ hydrogens of a nitrogen atom remains a challenge.3
Amidine derivatives are structurally unique and possess a variety
of interesting chemical properties. Accordingly, they have been
widely used in medicinal and synthetic chemistry.4 Also, substituted
amidines are useful intermediates for the synthesis of a variety of
heterocyclic compounds and metal complexes.5 Traditional syn-
theses of amidines rely basically on the functional group transfor-
mation from such precursors as thioamides, isonitriles, and al-
doximes.6 With the requirement of more efficient synthesis of
sulfonyl amidine derivatives, Chang recently reported tandem
reactions of sulfonyl azides, alkynes, and secondary amines either
intermolecularly or intramolecularly.7 Herein we wish to report a
very simple and efficient synthesis of sulfonyl amidines via a novel
reaction, where diethyl azodicarboxylate8 (DEAD)-activated elimi-
nation of both the R- and ꢀ-hydrogens of tertiary amine afforded
enamine, followed by a tandem 1,3-dipolar addition reaction with
sulfonyl azide (Caution: Azides and diazoalkanes may be hazardous
and/or explosiVe).
1
2
3
4
5
6
7
8
9
CH3CN
DMSO
DMF
hexane
CH3NO2
CH2Cl2
ClCH2CH2Cl
toluene
THF
1,4-dioxane
1,4-dioxane
6
2
4
6
4
4
4
4
4
4
5
32c
11
25
29
21
47
49
56
62
68
76
10
11d
a p-Toluenesulfonyl azide (1 mmol), triethylamine (1 mmol), DEAD
(1 mmol) in solvent (3 mL) under ambient temperature unless otherwise
specified. b Isolated yields. c 2H-DEAD was isolated in 87% yield.
d Reaction temperature: 10-15 °C for 1 h, then ambient temperature for
4 h.
Scheme 1. Proposed Mechanism
With the interest of synthesizing potentially bioactive nitrogen-
containing compounds,9 we have focused on the application of sulfonyl
azides. Recently, we reported the MCRs of sulfonyl azides, terminal
alkynes, and carbodiimides catalyzed by copper.9a As a extension, a
three-component reaction of p-toluenesulfonyl azide, phenylacetylene,
and DEAD catalyzed by CuI in the presence of triethylamine was
further conducted. However, sulfonyl amidine 3a as a major product
was unexpectedly isolated in 15% yield. This prompted us to undertake
further investigation so as to elucidate the source for the formation of
3a, and it was finally found that the reaction of p-toluenesulfonyl azide,
triethylamine, and DEAD in CH3CN could afford 3a in 32% yield
(Table 1, entry 1), indicating that CuI and phenylacetylene did not
participate in the reaction. A literature survey found that DEAD could
form a 1:1 adduct with N,N-dimethyl aniline, which involved reaction
of the R-hydrogen adjacent to the nitrogen atom of N,N-dimethyl
aniline.10 Huisgen later proposed an alternative mechanism where the
key step was a zwitterionic intermediate.11 Combined with the literature
findings12 and aforementioned experimental results, we envisioned it
is probable that enamine may be formed in this system. Correspond-
ingly, a tentative mechanism was proposed in Scheme 1. First,
triethylamine underwent nucleophilic addition to DEAD and forms a
1:1 adduct A, which can be in equilibrium with B by undergoing an
intramolecular hydrogen transfer. The adduct finally cleaves to form
an ion pair consisting of imine cation C and 1H-DEAD D. The nitrogen
anion of D further abstracts the ꢀ-hydrogen of the nitrogen atom of
triethylamine to generate enamine 4 with itself being transformed into
2H-DEAD. Enamine 4 reacts with 1a through 1,3-dipolar addition and
produces triazoline E, which is unstable and releases one molecule of
CH2N2 to afford product 3a. The mechanism was subsequently
supported by successful capture of enamine 4 and CH2N2 using
chalcone and benzoic acid as the respective capturing reagent (see
Supporting Information (SI)).
† College of Chemical Engineering and Materials Science.
‡ College of Pharmaceutical Science.
9
14048 J. AM. CHEM. SOC. 2008, 130, 14048–14049
10.1021/ja8047514 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. DEAD Promoted Synthesis of Sulfonyl Amidinesa
participated in this reaction readily, and the desired products were
obtained smoothly (Table 2, entries 11-12). It is worth mentioning
that diphenylphosphoryl azide and benzyloxycarbonyl azide could
be successfully used in this reaction system (Table 2, entries
23-24). Unfortunately, use of benzoyl azide as the substrate failed.
In the case of N-ethylpiperidine, it was found that the major
product was 3y, which indicated that it was more difficult for the
cyclic hydrogens to be eliminated and the steric effect may account
for the observation (eq 1). The ratio 3y/3z is ∼78:22 in 65% overall
yield. Product 3z may be formed by hydrogen migration ac-
companied by one molecule of nitrogen being released after the
1,3-dipolar addition.
entry
R1
R2; R3; R4
yield (%)b
1
2
4-CH3C6H4 (1a)
2,4,6-(CH3)3C6H2 (1b)
H; Et; Et (2a)
H; Et; Et (2a)
3a; 76
3b; 71
3c; 64
3d; 73
3e; 72
3f; 73
3g; 71
3h; 66
3i; 65
3j; 62
3k; 78
3l; 91
3m;46
3n; 74
3o; 63
3p; 57
3q; 51
3r; 21
3s; 34
3t; 82
3u; 79
3v; 75
3w;42
3x; 15
3
Ph (1c)
H; Et; Et (2a)
4
2-phthanyl (1d)
H; Et; Et (2a)
5
6
2-MeOOCC6H4 (1e)
H; Et; Et (2a)
H; Et; Et (2a)
4-PriC6H4 (1f)
7
4-ClC6H4 (1g)
H; Et; Et (2a)
8
4-CH3OC6H4 (1h)
H; Et; Et (2a)
9
3-NO2C6H4 (1i)
H; Et; Et (2a)
10
11
12
13c
14
15
16
17d
18d
19d
20e
21e
22e
23f
24f
2-thienyl (1j)
4-CH3C6H4CH2 (1k)
CH3(CH2)3 (1l)
1a
1a
1a
1a
1a
1a
1a
1a
1d
H; Et; Et (2a)
H; Et; Et (2a)
H; Et; Et (2a)
H; Me; Me (2b)
Et; Bu; Bu (2c)
Bu; Hexyl; Hexyl (2d)
H; Et; c-Hexyl (2e)
H; Et; Ph (2f)
H; Et; 3-MeC6H4 (2g)
H; Ph; Bn (2h)
H; morpholine (2i)
H; morpholine (2i)
H; morpholine (2i)
H; Et; Et (2a)
In conclusion, an efficient DEAD-promoted dehydrogenation of
tertiary amine to afford enamine and subsequent tandem reaction
with sulfonyl azide are successfully established, notably without
the assistance of metal. The reaction described here is mild, general,
and efficient, thus providing an extremely preferable method for
synthesis of a variety of N-sulfonyl amidine derivatives.
1i
Acknowledgment. This work was supported by the grant from
the Natural Science Foundation of Zhejiang Province (Y407250)
and a starter grant from Zhejiang University of Technology.
(PhO)2PON3
PhCH2OCON3
H; Et; Et (2a)
a Standard conditions: sulfonyl azide (1 mmol), amine (1 mmol),
DEAD (1 mmol), 1,4-dioxane (3 mL), 10-15 °C for 1 h, then room
temperature for 4 h unless otherwise noted. b Isolated yields. c DEAD
(1.5 mmol), 2b (2.2 mmol). d Neat, DEAD (3 mmol), 75 °C, 6 h.
e DEAD (2 mmol), 2e (2 mmol), 75 °C, 2 h. f DEAD (3 mmol), 2a (3
mmol).
Supporting Information Available: Experimental details and
spectroscopic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
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