Solvent-free Mukaiyama and Mukaiyama-Michael vinylogous reactions of a dioxinone-derived silyl enol ether promoted by Lewis bases

Article abstract of DOI:10.1016/j.tetlet.2010.05.016

The vinylogous aldol-type addition of a dienolsilyl ether, derived from 2,2,6-trimethyl-4H-1,3-dioxin-4-one, showed to occur with complete γ-selectivity by enolate activation promoted by neutral Lewis bases under solvent-free conditions. Moderate to high

Full text of DOI:10.1016/j.tetlet.2010.05.016

Tetrahedron Letters 51 (2010) 3658–3661
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Tetrahedron Letters
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Solvent-free Mukaiyama and Mukaiyama–Michael vinylogous reactions
of a dioxinone-derived silyl enol ether promoted by Lewis bases
a
b
a
a,
Arrigo Scettri a, , Vincenzo De Sio , Rosaria Villano , Patrizia Manzo , Maria Rosaria Acocella
*
*
a Dipartimento di Chimica, Università di Salerno, Via Ponte Don Melillo, 84084 Fisciano (Salerno), Italy
b Istituto di Chimica Biomolecolare del CNR , Traversa La Crucca 3. 07040 Li Punti (Sassari), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 March 2010
Revised 6 May 2010
Accepted 10 May 2010
Available online 13 May 2010
The vinylogous aldol-type addition of a dienolsilyl ether, derived from 2,2,6-trimethyl-4H-1,3-dioxin-4-
one, showed to occur with complete -selectivity by enolate activation promoted by neutral Lewis bases
under solvent-free conditions. Moderate to high yields were obtained with aromatic, hetero-aromatic,
c
and aliphatic aldehydes, as well as activated ketones. Under the same conditions and in the absence of
catalyst, the first Mukaiyama–Michael addition of the masked acetoacetate ester to
hydes took place in satisfactory way.
a,b-unsaturated alde-
Keywords:
Mukaiyama
Ó 2010 Elsevier Ltd. All rights reserved.
Mukaiyama–Michael
Dioxinone
Vinylogous
Aldol reaction
1. Introduction
In fact, the significant formation of products deriving from
-addition was observed in related processes for the vinylogous
a
The vinylogous aldol reaction1 of the masked acetoacetate ester
1 is considered a valuable tool for the generation of a d-hydroxy-b-
ketoester core, which represents the main structural feature of the
important key intermediates 4 in the synthesis of a variety of nat-
ural and unnatural bioactive compounds (Scheme 1).2
From the preparative point of view the typical approach is
based on carbonyl activation (Scheme 2, Path a) usually by chiral
and achiral Lewis acids (LA) such as Ti(IV),3 B(III),4 Eu(III),5 Cu(II),6
Si(IV),7 and Bi(III)8 compounds and complexes.
aldol reaction of dienolates.11
However, previous reports, concerning the aldol-type condensa-
tion of trimethylsilyl enolates (usually silyl ketene acetals) suitably
activated by neutral Lewis bases (such as dimethyl sulfoxide,12
N-oxides,13 N-methyl imidazole,14 and phosphine15) suggested an
investigation on the reactivity of silyloxydiene 1 under conditions
involving enolate activation.
2. Results and discussion
Furthermore, the use of some hydrogen bond donors has re-
cently proven to be successful in the vinylogous Mukaiyama reac-
tion of 1 with aldehydes.9,10
Conversely, in the past years rather comparable attention has
not been paid to the alternative approach, involving enolate activa-
In a preliminary phase, aldehyde 2a (Table 1, Fig. 1) was chosen
as the representative substrate and was submitted to treatment
with 1 in the presence of catalytic amount of a variety of Lewis
bases under solvent-free conditions.
tion, presumably because of a competing
a-addition leading to ald-
It has to be noted that, in the absence of activator the formation
of the protected vinylogous aldol 7a was found to occur in a not
negligible way (Table 1, entry 1). The occurrence of the background
reaction can be reasonably explained taking in mind a previous
report10 pointing out, through an experiment similar to the one
reported in entry 1 (Table 1), that the formation of a TMSO-pro-
tected vinylogous aldol by reaction of 1 with benzaldehyde could
be promoted by benzoic acid, usually present as auto-oxidation
product in not freshly distilled starting material. Therefore acid-free
aldehydes were always used in the following experiments.
The activation by dimethyl sulfoxide (DMSO) gave rather poor
results, resulting in the formation of a mixture of protected and
ols of type 5 and/or 6 (Scheme 2, path b).
Scheme 1. Synthesis of 4 by vinylogous aldol reaction of silyloxydiene 1.
* Corresponding authors.
E-mail address: scettri@unisa.it (A. Scettri).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.016

A. Scettri et al. / Tetrahedron Letters 51 (2010) 3658–3661
3659
Scheme 2. Different activation pathways for vinylogous aldol reaction of dienol silyl ether 1.
Table 2
PyN+–OÀ-catalyzed vinylogous aldol addition of 1 to carbonyl compounds 2
Table 1
Lewis base-catalyzed vinylogous aldol addition of 1 to 2a
Entrya R1
R2
Time (h) 3 yieldb (%) 7 yieldb (%)
1
2
3
4
4-MeC6H4 2a
H
H
H
H
3
3
3
1
3a: 18
3b: —
3c: —
3d: —
7a: 65
7b: 88
7c: 65
7d: 72
Entrya
Lewis base
Time (h)
3a yieldb (%)
7a yieldb (%)
4-MeOC6H4 2b
4-ClC6H4 2c
6-NO2-Piperonal
2d
4-CNC6H4 2e
2-MeOC6H4 2f
5-NO2-2-Furyl 2g
PhCH2CH2 2h
Me 2i
1
2
3
4
5
6c
—
DMSO
DMF
HMPA
PyN+-OÀ
PyN+-OÀ
3
24
2
2
2
—
27
—
—
—
33
17
84
84
87
65
5
6
7
8
9
H
H
H
H
COOEt
COMe
Me
2
2
1
24
1
1
3e: 22
3f: 16
3g: 19
3h: —
3i: —
7e: 50
7f: 64
7g: 56
7h: 50
7i: 48
7j: 56
7k: 40
3
18
a
In all entries 1/1.5/0.1 aldehyde 2a/1/Lewis base ratio was used.
b
All the yields refer to isolated chromatographically pure compound whose
10
11
Me 2j
4-NO2C6H4 2k
3j: —
3k: —
structure was confirmed by conversion into 3a by Carreira procedure.3f
4
In this entry PyN+–OÀ was used in 5 mol % amount.
c
a
In all entries 1/1.5/0.05 aldehyde 2a/1/Lewis base ratio was used.
All the yields refer to isolated chromatographically pure compounds whose
b
structures were assigned by analytical and spectroscopic data. Particularly, the
structure of products 7a, 7b, 7c, 7e, 7f, 7h, and 7i refer to that of isolated chro-
matographically pure compounds which were further confirmed by comparison of
desilylated known aldols3c,9,10,16 3a, 3b, 3c, 3e, 3f, 3h, and 3i obtained through
Carreira’s protocol.3f
free vinylogous aldols (respectively, 7a and 3a) in low overall yield
after prolonged reaction times.
Conversely, very satisfactory results in terms of both efficiency
and
c-selectivity were obtained by using dimethyl formamide
(DMF) (entry 3), hexamethyl phosphoramide (HMPA) (entry 4),
and pyridine N-oxide (PyN+-OÀ) (entry 5) under the conditions de-
picted in Table 1. In fact, the protected vinylogous aldol 7a was
usually isolated in rather good yields and no evidence of formation
Less reactivity was exhibited by aliphatic aldehydes (entry 8)
since the corresponding product 7h could be isolated in moderate
yield after 24 h.
Rather interestingly, the procedure proved to be successful with
activated ketones (entries 9–11) affording rapidly the vinylogous
TMS-derivatives 7i–7k in 40–56% yield.
The presence of a vicinal (Table 2, entries 9 and 10) or remote
electron-withdrawing group (Table 2, entry 11) seemed to be nec-
essary for the efficiency of the reaction: in fact, when a non-acti-
vated ketone (such as acetophenone) was submitted to treatment
with 1 under the conditions used in entry 7, Table 1, the reaction
took place in only 16% yield after 24 h. No improvement was ob-
served by performing the reaction in the presence of higher cata-
lyst loading (20 mol %).
As regard to the mechanistic aspects, the enhancement of the
nucleophilic properties of 1 by pyridine N-oxide (as well as the
other Lewis bases) can be reasonably explained by its coordination
to the silicon atom, resulting in the increase of the electron density
on the silyloxydiene moiety as depicted in A (Scheme 3). Further-
of a product deriving from
It is notable that in the presence of a lower PyN+-OÀ amount
(5 mol %) the -vinylogous addition was again found to be the
a-addition of 1 to 2a could be detected.
c
exclusive process affording in high overall yield the free aldol 3a
(16% yield) and the corresponding TMS-derivative 7a (65% yield).
Furthermore, the use of a solvent seemed to cause a significant
lowering of the efficiency and reaction rate: in fact, when the
experiment of entry 6 was carried out in CH2Cl2 solution 7a was
isolated in 70% yields after 24 h. In view of a possible achievement
of an asymmetric version of the reaction, the wide availability of
procedures leading to chiral mono- and bidentate N-oxides sug-
gested to check the scope of the protocol by using PyN+-OÀ as
the activator (Table 2, Fig. 2). Therefore a broad variety of carbonyl
compounds was submitted to reaction with 1 under the conditions
used in entry 6, Table 1.
As reported in Table 2, entries 1–7, various substituted aromatic
and hetero-aromatic aldehydes revealed a very satisfactory reac-
tivity, resulting in the formation of the protected vinylogous aldols
7a–7g as only or most abundant products, contaminated occasion-
ally by lower amounts of free vinylogous aldols of type 3.
more, shielding of C(
responsible for the observed
ene A is then converted into the alkoxide intermediate B by
a
) atom by silicon ligands can be considered
c
-selectivity. The activated silyloxydi-

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A. Scettri et al. / Tetrahedron Letters 51 (2010) 3658–3661
It has to be noted that 1 has been rarely used in a vinylogous
Mukaiyama–Michael additions and the poor available reports con-
cern the employment of particularly activated Michael acceptors,
such as 2-acyl-naphthoquinones.17
Furthermore, the easy access to polyfunctional compounds of
type 9 can be considered of synthetic value because of the wide
possibility of functional manipulation.
3. Conclusions
In conclusion, the vinylogous aldol-type addition of dienolsily-
lether 1 by enolate activation promoted by neutral Lewis bases
under solvent-free conditions, proved to be a valid alternative to
the classical carbonyl activation by Lewis acids. The procedure
revealed to be successful with various substituted aromatic and
hetero-aromatic aldehydes and ketones.
Scheme 3. Proposed catalytic cycle for PyN+–OÀ-catalyzed vinylogous aldol
reaction of 1.
Moreover, the first vinylogous Mukaiyama–Michael addition of
silyloxydiene 1 to
a,b-unsaturated aldehydes was performed,
proceeding in satisfactory yields and with chemoselectivity in
the absence of any catalyst under solvent-free conditions.
The novelty, the operative simplicity, and the solvent-free
conditions make this procedure synthetically useful and environ-
mental friendly.
Table 3
Addition of silyloxydiene 1 to
a,b-unsaturated aldehydes 8
Acknowledgments
Entrya
R
PyN+-OÀ (mol %)
Time (h)
9 yield (%)b,c
We are grateful to MIUR and University of Salerno for financial
support.
1
2
3
4
5
6
7
C6H5 8a
C6H5 8a
C6H5 8a
4-NO2C6H4 8b
CH3 8c
5
—
—
—
—
—
—
6
23
6
23
23
23
23
9a: 34(36)
9a: 56(26)
9a: 20(9)
9b: 68(nd)
9c: 73(5)
9d: 57(7)
9e: 60(14)
Supplementary data
C2H5 8d
C3H7 8e
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.05.016.
a
In all entries 1/1.5 aldehyde 2a/1 ratio was used.
b
All the yields refer to isolated chromatographically pure compounds whose
structures were assigned by analytical and spectroscopic data.
References and notes
c
Values in parentheses refer to isolated TMSO-protected vinylogous aldols.
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in a very reduced way.

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