Highly stereoselective synthesis of cis-β-enaminones mediated by diethyl azodicarboxylate

Article abstract of DOI:10.1039/c2cc16997e

Promoted by diethyl azodicarboxylate, a novel and highly stereoselective synthesis of cis-β-enaminones via oxidative dehydrogenation and hydration of the substituted propargylamines was realized. The possible mechanism was also proposed.

Full text of DOI:10.1039/c2cc16997e

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COMMUNICATION
Highly stereoselective synthesis of cis-b-enaminones mediated
by diethyl azodicarboxylatew
Xiaoliang Xu,*a Ping Du,a Dongping Cheng,b Hong Wanga and Xiaonian Li*a
Received 11th November 2011, Accepted 8th December 2011
DOI: 10.1039/c2cc16997e
Promoted by diethyl azodicarboxylate, a novel and highly stereo-
selective synthesis of cis-b-enaminones via oxidative dehydro-
genation and hydration of the substituted propargylamines was
realized. The possible mechanism was also proposed.
Recently, the reaction of 1.2 equiv. of propargylamine 1a with
equal amount of DEAD and water using wet CH3CN as a
solvent was tried, and it was found that 2,3-dihydrogen-cis-b-
enaminone 2a was unexpectedly isolated in 15% yield. We
note that the stereoselectivity of the addition reaction was
excellent, and the cis-form isomer 2a was formed exclusively.
According to its structural feature and the reported Meyer–
Schuster rearrangement mechanism,8 the possible route for the
formation of 2a might be as follows: initially, DEAD reacted
with propargylamine 1a by nucleophilic attack and then
hydrogen transfer to afford an ion pair consisting of first
generated imine cation A or its subsequently-formed equilibrium
substituted allene cation B and 1H-DEAD C. 1,4-Addition of
the intermediate A or B with one molecule of water could take
place to form the intermediate D, which subsequently underwent
stereoselective enol–keto tautomerization to afford the final
product 2a. The selective formation of cis-isomer 2a could be
explained by the more favorable electrophilic attack of proton
from the direction of less steric hindrance and the effect of
intramolecular hydrogen bonding.2a,5 From the proposed
mechanism, maybe there are two activated reaction intermediates
A and B coexisting, which competed with the attacking
nucleophilic reagent. 1,2-Hydration addition of intermediate
A produced the undesired side product propargyl aldehyde
(Scheme 1).
b-Enaminones have attracted much attention over the past
decades owing to their intrinsic biological properties.1
Moreover, they have been widely used as versatile synthetic
and pharmaceutical intermediates for the preparation of a
variety of heterocyclic derivatives including natural products
and analogues, such as indoles, pyridines and pyrroles.1,2 In
coordination chemistry, some can be used as good chelating
ligands for main group and transition metals.3 The classical
methods2 for the synthesis of such compounds mainly rely on
the condensation of amines with carbonyl compounds, addition
reaction of metal enolates to unsaturated carbon–nitrogen
bonds, and cleavage of heterocycles in addition to some novel
unconventional routes.4 According to their structural features,
cis- and trans-forms of b-enaminones exhibited different
chemical reactivities and electronic characters in synthetic
and coordination chemistry.2 However, upon checking the
literatures, reports about the synthesis of the cis-form were
very rare.2a,5 As far as the cis-form was concerned, there is
no synthetic method reported up to date for the synthesis of
2,3-dihydrogen-cis-b-enaminone derivatives.
Then several elements were surveyed to suppress the 1,2-addition
reaction in order to enhance the 1,4-addition selectively
(Table 1). Lots of solvents such as THF, DMF, DMSO, ether,
Diethyl azodicarboxylate (DEAD) has been widely used in
organic synthesis.6 Mediated by DEAD, a lot of efficient and
excellent chemical transformations such as Mitsunobu reaction,
carbon–nitrogen bond formation, oxidative coupling have
been accomplished. Recent studies in our group have focused
on the usability of diethyl azodicarboxylate on the oxidative
application of tertiary amine.7 Due to the structural diversity
of tertiary amines, different structures and chemical characters of
zwitterionic intermediates initiated by DEAD could be generated.
a Institute of Industrial Catalysis, College of Chemical Engineering
and Materials Science, Zhejiang University of Technology,
Hangzhou 310014, People’s Republic of China.
E-mail: xuxiaoliang@zjut.edu.cn, xnli@zjut.edu.cn;
Fax: +86 571 88320409; Tel: +86 571 88320409
b College of Pharmaceutical Science, Zhejiang University of
Technology, Hangzhou 310014, People’s Republic of China
w Electronic supplementary information (ESI) available: General
procedure for synthesis of compounds 2a–2k, characterization data
for compounds 2a–2k, and 1H and 13C NMR spectra of compounds
2a–2k. See DOI: 10.1039/c2cc16997e
Scheme 1 Proposed mechanism.
c
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Chem. Commun., 2012, 48, 1811–1813 1811

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Table 1 Synthesis of 2a under various conditionsa
Table 2 Synthesis of 2 under optimized conditionsa
Entry Propargylamines 1 R1
NR2
Yieldb (%)
Entry Mol ratio of 1a : H2O : DEAD Solvent (2 mL) Yieldb (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph Piperidyl
4-CH3OC6H4 Piperidyl
55 (2a)
48 (2b)
57 (2c)
55 (2d)
55 (2e)
54 (2f)
1
2
3
4
5
6
7
8
1 : 1.2 : 1.2
1 : 1.2 : 1.2
1 : 1.2 : 1.2
1 : 1.2 : 1.2
1 : 1.2 : 1.2
1 : 1.2 : 1.2
1 : 1.2 : 1.2
1 : 1.2 : 1.2
1 : 1.2 : 1.2
1 : 1.5 : 1.5
1 : 1.2 : 1.5
1 : 2 : 1.2
1 : 1.5 : 1.5
1 : 1.5 : 2
CH3CN
DMF
DMSO
THF
Toluene
CHCl3
CH2Cl2
DCE
—
DCE
—
—
—
—
15
12
15
16
23
28
39
45
39
25
36
32
55
36
4-FC6H4
4-ClC6H4
4-BrC6H4
3-ClC6H4
Ph
Piperidyl
Piperidyl
Piperidyl
Piperidyl
Morpholinyl 38 (2g)
Diethylamine 18 (2h)c
Dibutylamine 35 (2i)d
Ph
Ph
9
9
10
11
12
1j
1k
1l
CH3(CH2)4
3-Thienyl
2-Pyridyl
Piperidyl
Piperidyl
Piperidyl
51 (2j)
41 (2k)
—
10
11
12
13
14
e
a
Propargylamine 1 (1 mmol), DEAD (1.5 mmol), H2O (1.5 mmol) at
0–10 1C under neat conditions for 6 h; please see ESI for details.
Isolated yields. About 10% trans-form isomer was detected. Less
a
b
b
c
d
The reaction was carried out at 0–10 1C for 6 h. Isolated yield
based on 1a.
e
than 5% trans-form was detected. Complex mixture.
CH2Cl2 were examined. It was found that the high polarity
solvents, such as DMF or DMSO, have no positive effect and
lower yield of the desired product was obtained (entries 2–3).
The other solvents for instance THF or toluene observed no
obvious assistance (entries 4–5). Slightly better results came
from the use of a chlorinated hydrocarbon solvent, and for
example, 45% yield of the desired product could be obtained
when DCE was used as the solvent (entries 6–8). Further
screening of the ratio of reactants established the optimal
reaction conditions: 1.5 equiv. of DEAD and H2O under neat
conditions at 0–10 1C for 6 h with 55% yield of 2a (entry 13).
In all cases, the 1,2-addition reaction could not be fully
excluded.
However, using 2-pyridyl substituted propargylamine 1l as
the substrate, no desired product was obtained under the
identical conditions (entry 12).
In conclusion, a highly stereoselective synthesis of 2,3-
dihydrogen-cis-b-enaminones using propargylamines and
DEAD has been successfully established. Further investiga-
tions concerning the scope of enaminones, applications, and
mechanistic details are currently ongoing in our laboratory
and will be published in due course.
The authors are grateful to the National Natural Science
Foundation of China (NSFC-20872131) and National Basic
Research Program of China (973 Program) (No. 2011CB710800).
To explore the substrate scope and limitations of this
reaction, a range of propargylamines were then examined
under the optimized reaction conditions. As shown in
Table 2, in all successful cases except 1h and 1i, the cis
selectivities for the formation of b-enaminones were excellent.
It was found that the electronic property of the substituents on
the aryl ring of propargylamines has little effect on the reaction
(entries 2–6). Electron-donating as well as electron-withdrawing
substituents are well accommodated. It was noteworthy that
pentyl substituted propargylamine 1j, an aliphatic alkyne
substrate, was also subjected to the reaction, and the desired
product 2j was obtained in moderate yield (entry 10). 3-Thienyl
substituted substrate 1k acted as the appropriate candidate
successfully (entry 11). On the other hand, several structural
diversity types of amines, such as piperidyl, morpholinyl,
diethylamine, and dibutylamine substituted substrates, could
also be employed in this reaction. For less steric hindrance
diethylamine substituted propargylamine 1h, about 10% yield
of the trans-form isomer was obtained except for the desired
product 2h, which may further support the proposed mechanism
(entry 8). Compared with the results of entry 8, dibutyl
substituted propargylamine 1i showed good results, which
was in accordance with our previous reports (entry 9).7
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