Synthesis of α-aryl enaminones through reactions of β-aryl enones with benzyl azide

Article abstract of DOI:10.1016/j.tetlet.2012.09.125

Reaction of benzalacetones and dibenzalacetones with benzyl azide promoted by BF₃·OEt₂ afforded Z and E densely substituted acyclic α-aryl enaminones in 21-95% yield. For benzalacetones major Z-isomers were obtained, while E-isomers

Full text of DOI:10.1016/j.tetlet.2012.09.125

Tetrahedron Letters 53 (2012) 6710–6713
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Synthesis of
a-aryl enaminones through reactions of b-aryl enones
with benzyl azide
⇑
Silvio Cunha , Amenson Trindade Gomes
Instituto de Química, Universidade Federal da Bahia, Campus de Ondina, 40170-290 Salvador, BA, Brazil
Instituto Nacional de Ciência e Tecnologia – INCT em Energia e Ambiente, Universidade Federal da Bahia, Campus de Ondina, 40170-290 Salvador, BA, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of benzalacetones and dibenzalacetones with benzyl azide promoted by BF3ÁOEt2 afforded Z and
Received 6 September 2012
Revised 24 September 2012
Accepted 26 September 2012
Available online 3 October 2012
E densely substituted acyclic
a-aryl enaminones in 21–95% yield. For benzalacetones major Z-isomers
were obtained, while E-isomers were the tendency for dibenzalacetones. The synthesis involves domino
1,3-dipolar cycloaddition and 1,2-aryl migration, and is the first metal free practical alternative to the
preparation of acyclic
materials.
a
-aryl enaminones from commercial available or easily prepared starting
Keywords:
Enaminones
Ó 2012 Elsevier Ltd. All rights reserved.
Benzalacetones
1,2-Aryl migration
1,3-Dipolar reaction
Benzylidene acetones
Introduction
a) Aub et al., 20035
H
O
O
N
Ph
The synthesis of enaminones is a theme of ongoing interest1 be-
cause this class of compound is a versatile intermediate in organic
synthesis2 as well as due to their biological activity.3 Among the
available methods for enaminone’s synthesis, the method which
employ the reaction of amines with 1,3-dicarbonyl compounds
has been intensively investigated.1,4 However, in the case of unsym-
metrical 1,3-diketones, mixtures of regioisomeric enaminones are
formed due to the no discrimination of the two electrophilic ketone
moieties. To circumvent this limitation there is no satisfactory solu-
tion yet.
Recently, Aubé and co-workers described their study concern-
ing the acid promoted (TMSOTf, BF3ÁOEt2, and TFA) reaction of alkyl
azides with cyclic enones, wherein enaminones were obtained, but
only one example of enaminone from an acyclic enone was re-
ported, Figure 1.5 In this context, Johnston and co-workers de-
scribed the TfOH-promoted addition of electron-rich azides with
methyl vinyl ketone affording aziridines.6 Complementarily, Casey
N3
Ph
R1
TMSOTf
R1
CH2Cl2
( )n
( )n-1
H
O
O
N
Ph
N3
Ph
TMSOTf
CH2Cl2
b) Johnston et al., 20056
O
O
N3
Ph
TfOH
N
Ph
CH3CN
c) Casey et al., 20037
O
O
O
NaN3 2 equiv
H2SO4
N
R2
+
R2NH2
NO2
et al. showed that cyclic
c,d-unsaturated b-diketones react with
O
hydrazoic acid in the presence of H2SO4 as solvent, affording cyclic
enaminones in good yields.7 This late reaction is an extension of
the reaction of HN3 and a chalcone activated by electron-with-
drawing substituent, which yielded acyclic N-aryl enaminone, as
described many years ago by Donald and Marks. This late protocol
d) Donald and Marks, 19678
O
H
1) HN3
O
N
2) H2SO4
NO2
⇑
Corresponding author.
E-mail address: silviodc@ufba.br (S. Cunha).
Figure 1. Previously described azide-enone route to enaminones.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.125

S. Cunha, A. T. Gomes / Tetrahedron Letters 53 (2012) 6710–6713
6711
H
O
Ph
N
O
O
Ph
N
H
+
2a
3a
81% (7:1)
3b
H
O
Ph
N
O
O
Ph
N
H
+
2b
O
4b
4a
95% (1:3)
H
O
Ph
N
O
Ph
N
H
+
2c
5b
5a
21% (6:1)
1
N3
Ph
Ph
N
O
H
O
N
O
+
H
Cl
2d
Cl
BF3Et2O
CH2Cl2
Cl
6b
6a
Cl
45% (1:2.5)
Cl
Ph
O
H
Ph
O
N
O
N
H
2e
+
7a
7b
50% (1:2)
Ph
O
O
N
H
OMe
MeO
OMe
2f
8
42%
OMe
a-aryl enaminones.
Scheme 1. Synthesis of
represents the first and unique description of synthesis of enami-
none employing a b-aryl enone as precursor.8
through the reactions of acyclic b-aryl enones with benzyl azide,
with emphasis on synthetic and mechanistic implications.
Despite the great contribution of the studies described in
Figure 1, there is no report of acyclic
by the ‘azide-enone’ route. Besides, new one-pot routes to
a
-aryl enaminone synthesis
-aryl
Results and discussion
a
enaminones is desirable because these enaminones are advanced
intermediates in the synthesis of alkaloids,2q and antibacterial
compounds.3a
To explore a direct one-pot route towards acyclic a-aryl enami-
nones from b-aryl enones and benzyl azide 1, this late was reacted
with 2a in CH2Cl2, Scheme 1. After experimentation, the best pro-
portion of enone and benzyl azide was 1:2, using 2 and 3 equiv of
BF3ÁEt2O (H2SO4 and TFA were inefficient).5 1H NMR analyses of the
crude reaction mixture after usual workup revealed that the
isomeric enaminones 3a–3b were obtained in good yield. Chro-
matographic purification afforded enhanced samples of each
isomer.
Our continued fascination for the chemistry of enaminones9
prompted us to rationalize that the introduction of an aryl group
at the beta position of the enone should circumvents the limitation
of the ‘azide-enone’ route to enaminones, due to the potential aryl
neighboring-group participation via a phenonium ion that, in spe-
cific cases, should results in its 1,2-migration,1d,10 as in the condi-
tion described by Aubé and co-workers in the synthesis of densely
substituted acyclic enaminones.5 Thus, we disclosure herein our
Contrary to the previous description of acyclic enone reaction
with benzyl azide,5 no 1,2-H migration was observed in the reaction
results concerning the one-pot synthesis of
a-aryl enaminones
of 2a. Instead of this, all obtained compounds were
a-aryl

6712
S. Cunha, A. T. Gomes / Tetrahedron Letters 53 (2012) 6710–6713
enaminones, which were formed from the planned 1,2-aryl migra-
tion, and the spectral 1H NMR analyses permitted the structural
assignments of each one as well as the aryl shift confirmation. For
instance, for isolated Z isomer 3a the typical deshielding enaminone
N–H (d 10.60 ppm) was observed due to the hydrogen bonding with
the carbonyl group, corroborating the assigned configuration, while
the N–H signal of E isomer 3b appears at d 7.45 ppm. These data are
in accordance with NMR description of reported b-aryl enone iso-
mers whose structures were elucidated by X-ray also.11 The phenyl
regiochemistry could be easily identified due to the disappearing of
Ph
1
N
N
N
N
Ph
N
BF3
N
9
O
O
R2
R2
2a-f
R1
R1
O
N
Ph
Ph
R2
N
N
N
10
R2
original olefinic C–H of the enone moiety and, moreover, the
a
presence of C–Hb 3J coupling with the N–H at beta position. No such
coupling would be observed for the opposite phenyl regiochemist-
ry. Continuing in this line of reasoning and additional comparison of
full spectral data of obtained enaminones 3–8 to analogous Z (and
O
11
- N2
R1
R1
E)
a
-aryl (and b-aryl) enaminones described in the literature11
Ph
H O
Ph
O
supported the structural determination of all enaminones here
synthesized.
R2
N
R2
N
3a-8a
The protocol was applied to enones 2b–c and, as occurred to 2a,
the major Z isomer was formed. However, when p-chlorobenzalac-
etone 2d was submitted to the same reaction condition, the enami-
none moiety could be assigned based on NMR spectra, but no
methyl group was detected in the isolated product. Instead of this,
additional four aromatic hydrogen and four aromatic carbon signal
were observed, and also a vinyl moiety with trans stereochemistry
(3J 15.6 Hz), which suggests methyl group transformation. In this
way, the structures of isomeric enaminones 6a–b were deduced.
Formation of these enaminones from p-chlorobenzalacetone 2d,
where the methyl moiety was functionalized, is in contrast with
the behavior of the closed related benzalacetones 2a–c, Scheme 1.
Apparently, the presence of the electron-withdrawing chlorine at
the aromatic ring in 2d induces a retro Claisen–Schmidt reaction
promoted by the Lewis acid, forming p-chlorobenzaldeyde and ace-
tone, which now react to afford the corresponding dibenzalacetone,
and this late suffer the domino reactions with benzyl azide to yield
enaminones 6a–b. To support the hypothesis that dibenzalacetones
12
+
1,3 H shift
Ph
R1
R1
O
R2
N
H
3b-8b
R1
Scheme 3. Proposed mechanism to the formation of enaminones 3–8.
enaminones is limited to simple a,b-unsaturated ketones as 2a–d,
being tolerated variation at the carbonyl moiety as in 2e–f.
Mechanistically, formation of enaminones can be rationalized as
a domino process initiated by 1,3-dipolar cycloaddition of the ben-
zyl azide 1 and the olefinic moiety of the enones 2a–f, Scheme 3, as
pointed out by Aubé and co-workers.5 In the sequence, the opening
of the unstable dihydro triazole ring 9 occurs, and the nitrogen
extrusion is assisted by the aromatic ring in 10, and then the rearo-
matization step of phenonium ion 11 affords the 1,2-aryl migration
product 12, which thus yield enaminones 3–8 after 1,3H shift.
In conclusion, this study shows that the rational combination of
‘BF3ÁEt2O-induced phenyl migration’1d and ‘BF3ÁEt2O-azide-enone’5
route applied to acyclic b-aryl enones and benzyl azide can be a
are reactive substrates for the synthesis of a-aryl enaminones via
the azide-enone route, and to corroborate the structure of enami-
nones 6a–b, compounds 2e–f were treated with benzyl azide and
enaminones 7a,b–8 could be isolated. For tested dibenzalacetones
2e–f the observed stereochemical preference was to the E enami-
none, being this isomer the major (6b, 7b) or the sole (8) one
detected in the reaction mixture.
To gain further insight into the scope and limitation of the
developed protocol, extension of the reaction condition to com-
pounds depicted in Scheme 2 were investigated. These substrates
were selected as representative structural variations involving
the carbonyl (amide 2h and ester 2i) and the olefin (heterocyclic
practical synthetic route to densely substituted acyclic
a-aryl
enaminones, being an alternative methodology to access this syn-
thetically important class of compound from commercial available
or easily prepared starting materials.
2g and a,b,c,d-unsaturated 2j) moieties. However, these substrates
Acknowledgments
did not afford the corresponding enaminones, being recovered
even after prolonged reaction time for 2g and 2i, or a complex mix-
ture was formed for 2h and 2j (analyzed by spectroscopic and
The authors gratefully acknowledge the financial support of
Conselho Nacional de Desenvolvimento Científico e Tecnológico
(CNPq) and Fundação de Amparo à Pesquisa do Estado da Bahia
(FAPESB). We also thank CNPq for fellowship to A.T.G., and a
research fellowship to S.C., and Professor Mauricio Victor for the
comments.
chromatographic techniques). In this way, the formation of a-aryl
O
O
N
Supplementary data
H
O
2g
O
2h
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.09.125.
O
OCH3
References and notes
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Scheme 2. Compounds which do not afforded enaminones.

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6713
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