On the synthesis of β-keto-1,3-dithianes from conjugated ynones catalyzed by magnesium oxide

Article abstract of DOI:10.1016/j.tetlet.2008.02.030

MgO was used for the first time as a heterogeneous basic catalyst to synthesize β-keto-1,3-dithianes, potentially useful synthetic intermediates, from conjugated ynones and ynoates.

Full text of DOI:10.1016/j.tetlet.2008.02.030

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2454–2456
On the synthesis of b-keto-1,3-dithianes from conjugated
ynones catalyzed by magnesium oxide
a
a
a
a,
*
Chunli Xu , Jonathan K. Bartley , Dan I. Enache , David W. Knight ,
Matthew Lunn b, Martin Lok b, Graham J. Hutchings a,*
a School of Chemistry, Cardiff University, Main College, Park Place, Cardiff, CF10 3AT, UK
b Johnson Matthey Plc., PO Box 1, Belasis Avenue, Billingham, Cleveland, TS23 1LB, UK
Received 14 December 2007; revised 18 January 2008; accepted 7 February 2008
Available online 10 February 2008
Abstract
MgO was used for the first time as a heterogeneous basic catalyst to synthesize b-keto-1,3-dithianes, potentially useful synthetic
intermediates, from conjugated ynones and ynoates.
Ó 2008 Elsevier Ltd. All rights reserved.
b-Keto-1,3-dithianes 2 are highly functionalized three-
O
O
carbon units, which are of much importance as potentially
useful synthetic intermediates.1 For example, the 1,3-dithi-
ane substituent may, if desired, be hydrolyzed to a carbonyl
group and hence provides an attractive and useful strategy
for ketone protection in general. Alternatively, it may be
converted into a methylene group by reductive desulfuri-
zation.2 Alkylation with this three-carbon unit has also
been utilized in several syntheses.3 Procedures reported
for the preparation of b-keto-1,3-dithianes 2 include
a-alkylation of carbonyl compounds with 1,3-dithiane or
its derivatives,2,4 nucleophilic addition of 1,3-dithiane to
epoxides followed by oxidation,3 conjugate reduction of
a-oxo ketene dithio acetals5 and double Michael addition
of 1,3-propanedithiol to a,b-acetylenic ketones 1 (Scheme
1).6 Systems related to the mono-protected 1,3-diones 2
have also been prepared by dithiane alkylation using halo-
acetaldehyde acetals,7 in a reverse sense by b-keto-ester
dianion alkylation using 2-chloro-1,3-dithiane8 and various
exchange reactions.9 However, these syntheses are homo-
geneous and in most cases relatively complicated; certainly,
HS
SH
S
S
R1
R1
R2
R2
1
2
Scheme 1. The generalized conversion of ynones 1 into b-keto-1,3-
dithianes 2.
most of the existing procedures are not especially environ-
mentally friendly.
In recent years, there has been increasing emphasis on
the design and use of environmentally friendly solid acid
and base catalysts to reduce the amount of toxic waste
and by-products arising from chemical processes prompted
by stringent environmental protection laws.10 Hence, reus-
able heterogeneous catalysts will have a distinct advantage
but only if they can match the performance of homo-
geneous catalysts.
To date, there has been only one report regarding the
synthesis of b-keto-1,3-dithianes 2 by Michael additions
induced by a heterogeneous catalyst,11 when solid alumina
was used. This was readily reused; however, a large excess
(7 equiv) was required. There has been no other report of
using a heterogeneous basic catalyst to synthesize b-keto-
1,3-dithianes 2. Magnesium oxide (MgO) is a typical basic
*
Corresponding authors.
E-mail address: knightdw@cf.ac.uk (D. W. Knight).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.030

C. Xu et al. / Tetrahedron Letters 49 (2008) 2454–2456
2455
oxide (Hammett constant H = +26.0)12 and has the lowest
O
O
solubility among the alkaline earth oxides (MgO, BaO,
CaO and SrO) and so can potentially be reused, as it will
not be lost due to leaching into the reaction mixture. Fur-
thermore, MgO is inexpensive and easily obtained so that it
could be applied to large scale manufacture. In view of our
success in using MgO as a basic catalyst in both Knoevena-
gel and especially Michael additions, it appeared that this
catalyst might be useful for triggering the ‘double’ Michael
addition of 1,3-dithianes to propargylic carbonyl systems 1
to give b-keto-1,3-dithianes 2. In this Letter, we report the
successful outcome of using this inexpensive and easily
obtained heterogeneous basic catalyst for this purpose
(Scheme 1).
The catalysts used in this study were obtained by calci-
nation of the precursors (450 °C, static air, 2 h) with a heat-
ing ramp of 10 °C/min (Table 1), except MgO-AD and
MgO-RIB. MgO-AD was the commercially available
MgO from Aldrich. MgO-RIB was obtained by igniting
Mg ribbon in air.
Initial trial reactions to test the various catalysts
involved the addition of the particular MgO sample
(2.5 equiv or 1.0 equiv) in one portion to a stirred solution
of 4-phenyl-3-butyn-2-one 1a (1 mmol) and propane-1,3-
dithiol (1 mmol) in THF (2 ml) cooled in ice-water. The
cooling bath was then removed and the mixture stirred at
ambient temperature and reaction progress followed by
withdrawing samples (about 0.5 ml), which were filtered
and the filtrate divided into two parts. One part was
directly analyzed by GC or GC–MS. The other part was
evaporated and the residue analyzed by 1H NMR and
13C NMR using CDCl3 as solvent. The conversions
observed are summarized in Table 1.
A series of substrates were then tested using MgO-CBC
as the catalyst, as this showed one of the highest surface
areas, clearly a key factor in the activity of this class of cat-
alyst. After the reaction, the solution was filtered through
silica gel to remove the catalyst and the solvent evaporated.
No further purification was usually necessary. The results
(Scheme 2) show that MgO-CBC is a very active catalyst
for the synthesis of b-keto-1,3-dithianes 2. Substrates
1a–g underwent clean additions with propane-1,3-dithiol
by this procedure to give the corresponding b-keto-1,3-
HS
SH
S
S
R1
R1
R2
MgO-CBC
THF, 0~20 ºC
R2
2
1
a) R1 = Me; R2 = Ph [1 h; 98%]
f) R1 = EtO; R2 = H [4 h; 95%]
g) R1 = MeO; R2 = H [2 h; 88%]
h) R1 = EtO; R2 = Me [24 h; 65%]
b) R1 = R2 = Ph [1 h; 90%]
c) R1 = H; R2 =
n-pent [3 h; 98%]
d) R1 = Me; R2 = SiMe3 [1 h; 95%] i) R1 = MeO; R2 = Ph [24 h; 30%]
e) R1 = Me; R2 = H; [1 h; 90%]
Scheme 2. The addition of 1,3-propanedithiol to ynones and ynoates 1
catalyzed by magnesium oxide.
dithianes 2. The experimental procedure is very simple
and the reactions are fast and clean.
Ley and co-workers proposed a mechanism6 for these
double conjugate additions of dithiols to propargylic car-
bonyl systems to generate b-keto-1,3-dithianes 2 when
using sodium methoxide as the trigger, which features
sequential deprotonation at sulfur, Michael addition and
enolate protonation to give both cis- and trans-isomers of
the a,b-unsaturated carbonyl intermediates 3. These are
themselves substrates for a second conjugate addition,
now an intramolecular process, which gives the desired b-
keto-1,3-dithianes 2. However, this second addition com-
petes with the reaction of substrate 3 with another molecule
of ynone to give dimeric side products 4, which are
observed in some cases (Scheme 3).
All five products 2a–e obtained from ynones and ynals
1a–e were essentially free of contamination by either inter-
mediates 3 or ‘dimers’ 4 and only traces of these were vis-
ible in the 1H NMR spectra of products 2f and 2g, derived
from propynoates 1f,g. This is clearly consistent with these
mechanistic proposals, as the propynoates would be
expected to be marginally poorer Michael acceptors rela-
tive to the ynones. The two final substrates, ethyl 2-butyno-
ate 1h and its phenyl homologue 1i, were understandably
significantly less reactive, the alkyne substituent doubtless
hindering the Michael addition steps significantly relative
to propynoates 1f,g (Scheme 2). This, coupled with the gen-
erally lower ester reactivity resulted in the requirement for
much longer reaction times and the inevitable accumula-
tion of by-products; both ‘dimer’ 4 and partly reacted
Table 1
O
S
1,3-Propanedithiol additions to 4-phenyl-3-butyn-2-one 1a in the presence
of various MgO catalysts (1.0 equiv) for 1 h in tetrahydrofuran
HS
SH
1
R1
R2 SH
MgO-CBC
THF, 0~20 ºC
Entry
Precursors
SBET (m2 gÀ1
)
Yield (%)
3
MgO-RIB
MgO-AD
MgO-CAD
MgO-COH
Mg ribbon
10
25
25
65
277
20
0
MgO (Aldrich)
MgO (Aldrich)
Mg(OH)2 (Fluka)
66
98
98
98
98
98
O
S
R2
O
MgO-ROH Mg(OH)2 (Fluka)a
+
2
R1
R2
S
R1
MgO-CBC
MgO-OX
MgO-CC
a
(MgCO3)4Mg(OH)2 (Fluka) 288
Mg[O(CO)2O]
MgCO3 (Acros Organics)
312
229
4
Scheme 3. Double Michael addition prior to final ring closure.
Calcined at 600 °C for 2 h, refluxed in H2O for 3 h, then oven-dried.

2456
C. Xu et al. / Tetrahedron Letters 49 (2008) 2454–2456
alkenoates 3 were easily identified in the product mixtures.
Yields of 60–70% were obtained with ethyl-2-butynoate 1h
as the substrate, but only a 30% yield for methyl phenyl-
propiolate 1i.13 In summary, it is clear that the ynones
are more reactive than the corresponding esters, the yno-
ates in these reactions. Much the same observations were
made when NaOMe was used as the triggering base.6
The activity of MgO is higher or comparable with that
of the previously published homogeneous base catalyst
NaOMe.6 When 4-phenyl-3-butyn-2-one 1a was tested as
the substrate and MgO as the catalyst, 98% yield was
reached in 61 h, while for the homogeneous base catalyst
NaOMe, 24 h was needed to obtain these high yields,
although this time may not have been optimized. Further-
more, as far as the catalyst amount is concerned, the
required quantity of MgO (1.0 equiv) is less than that of
the homogeneous base catalyst NaOMe (2.5 equiv). The
same pattern was observed for ynoate 1f: the reaction rate
was similarly more rapid when MgO was used as catalyst
relative to the homogeneous base catalyst NaOMe.
The effect of the MgO preparation method was further
investigated. When 2.5 equiv of MgO was used, all the
types of MgO, except MgO-RIB and MgO-AD, catalyzed
the test reaction (Table 1) to 98% yield within 1 h. When
1.0 equiv MgO was used, MgO-RIB, MgO-AD and
MgO-CAD were less active than the others. The low activ-
ity of MgO-RIB and MgO-AD may be attributed to the
fact that these two catalysts were not degassed before
testing. MgO-AD was calcined to obtain MgO-CAD. The
conversion increased from 0% to 66% when transferring
MgO-AD to MgO-CAD.
This is the first report of the synthesis of b-keto-1,3-
dithianes 2 by Michael additions through the use of a
heterogeneous basic catalyst. It was proven that the activity
of MgO is higher than the previously published homo-
geneous catalyst NaOMe in some reactions.
Acknowledgements
We thank Johnson Matthey Plc and the EPSRC for
financial support.
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