The regioselective preparation of 1,3-diketones within a micro reactor

Article abstract of DOI:10.1039/b201220k

We demonstrate a simple method for the regioselective preparation of 1,3-diketones within a micro reactor from silyl enol ethers where the products are free from both competing O-acylation and diacylation products.

Full text of DOI:10.1039/b201220k

The regioselective preparation of 1,3-diketones within a micro reactor
a
a
a
b
Charlotte Wiles, Paul Watts, Stephen J. Haswell* and Esteban Pombo-Villar
a
Department of Chemistry, Faculty of Science and the Environment, University of Hull, Cottingham Road,
Hull, UK HU6 7RX. E-mail: s.j.haswell@hull.ac.uk; Fax: 01482 466416; Tel: 01482 465475
Nervous Systems Research, WSJ-386.07.15, Novartis Pharma Ltd, CH4002 Basel, Switzerland
b
Received (in Cambridge, UK) 6th February 2002, Accepted 2nd April 2002
First published as an Advance Article on the web 11th April 2002
We demonstrate a simple method for the regioselective
preparation of 1,3-diketones within a micro reactor from
silyl enol ethers where the products are free from both
competing O-acylation and diacylation products.
Over the past three years, there has been a rapid growth in the
development of micro reaction technology exploiting the
1
technique of electroosmotic flow (EOF). Recent research has
demonstrated that along with multi-component reactions such
2
3
as the Suzuki coupling and the Wittig reaction, multi-step
peptide synthesis can also be performed within a micro
reactor.4
The enolate has been described as the most important
intermediate in C–C bond formation. Its ambident nature
however, allows the formation of bonds at either the carbon or
the oxygen. In the case of acylation, this can result in the
formation of a mixture of O- and C-acylated products which are
Fig. 1 Schematic of the micro reactor used in the synthesis of 1.
2
1
(
Typical flow rates of 0.3–0.4 ml min were observed from
each reservoir). Reaction products were determined by GC-MS
via the comparison of retention times and spectra with those
obtained from synthetically prepared standards.12
5
difficult to separate, often resulting in low yields. A large
amount of work has been undertaken in order to explore and
understand the reaction conditions that promote the re-
gioselective acylation of enolates, these include; the nature of
the counter ion, reaction temperature, solvent, stoichiometry of
reagents, order of reagent addition and type of acylating
reagent.6 Although careful selection of the aforementioned
conditions has been shown to influence the regioselectivity of
A synthetic standard of product 1 was prepared via the
dropwise addition of the enol ether of acetophenone 2 (0.1 g,
.52 mmol) to a stirred solution of anhydrous TBAF (0.014 g,
.05 mmol) and benzoyl fluoride 3 (0.06 g, 0.52 mmol) in
anhydrous THF (10 ml)(Scheme 1). The reaction mixture was
stirred for 1 h, subsequent analysis by GC-MS showed that
0
0
,7
the acylation, the 1,3-diketones produced remain contaminated
1
00% conversion of the silyl enol ether of acetophenone 2 to the
product 1 had been achieved.
with small amounts of O-acylated products.8
,9,10
The procedure
is however, still regarded as being heavily substrate depend-
Having demonstrated that 1 could be prepared from the silyl
enol ether 2, this represented a synthetic target for preparation
within a micro reactor (Fig. 1). Prior to the synthesis, the micro
reactor was primed with anhydrous THF in order to remove any
air or moisture from the channels and micro porous silica frits.
A standard solution of TBAF (40 ml, 0.1 M) in anhydrous THF
was placed in reservoir A, a solution of benzoyl fluoride 3 (40
ml, 1.0 M) in anhydrous THF in reservoir B and the silyl enol
ether of acetophenone 2 (40 ml, 1.0 M) in anhydrous THF was
placed in reservoir C. The reaction products were collected in
anhydrous THF in reservoir D over a period of 20 min. The
reagents were manipulated within the device by the application
of the following applied fields; 333, 455, 333 and 0 V cm
resulting in 100% conversion to 1 (no products of C-acylation 4
or diacylation were observed).
Having successfully demonstrated the O-acylation of acet-
ophenone within a micro reactor, we wished to also demonstrate
that C-acylation was possible.
11
ent.
We recently demonstrated a simple technique for the
regioselective preparation of uncontaminated 1,3-diketones in
high to excellent conversions ( > 95%) via the reaction of silyl
enol ethers with acyl fluorides (1 h) and cyanides (24 h) in the
presence of a catalytic amount of anhydrous TBAF (tetra-
butylammonium fluoride).12 We found that a-substituted
ketones react with both acyl fluorides and cyanides to give
100% C-acylated products compared with non a-substituted
ketones which gave 100% O-acylated products when reacted
with acyl fluorides and C-acylated products when reacted with
acyl cyanides. In this paper we wish to demonstrate the
regioselective acylation of silyl enol ethers within a micro
reactor using catalytic amounts of anhydrous TBAF. We also
report reduced reaction times within a micro reactor in
comparison to traditional batch reactions.
2
1
,
The borosilicate micro reactor used in this work was prepared
using a standard fabrication procedure developed at Hull.13 The
reactions were carried out using a 4 channel micro reactor, as
illustrated in Fig. 1, with approximate channel dimensions of
100 3 50 mm and outer dimensions of 20 3 20 3 25 mm. Micro
porous silica frits were placed within the channels in order to
minimise hydrodynamic effects.14 An in-house LabVIEW™
program was used to set and monitor the voltages applied to
platinum electrodes placed in the reservoirs (power supply was
built by Kingfield electronics).
All micro reactions were carried out under fume extraction in
order to minimise exposure to the reagents used. The micro
reactions were performed over a period of 20 min in order to
ensure a sufficient volume of product was generated for analysis
Scheme 1 Formation of 1 via the silyl enol ether of acetophenone 2.
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034
CHEM. COMMUN., 2002, 1034–1035
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A synthetic standard of dibenzoylmethane 4 was prepared via
the reaction of the silyl enol ether of acetophenone 2 and
benzoyl cyanide 5 (Scheme 2). In order to obtain high
conversion of the enol ether 2 to the product 4, extended
reaction times of 24 h were necessary. This is due to the reduced
reactivity of benzoyl cyanide 5 compared with benzoyl fluoride
3. Under the conditions stated above, 98% conversion with
respect to the enol ether 2 was observed in bulk. Using a micro
reactor, a standard solution of TBAF (40 ml, 0.1 M) in
anhydrous THF was placed in reservoir A, a solution of benzoyl
cyanide 5 (40 ml, 1.0 M) in anhydrous THF in reservoir B and
the silyl enol ether of acetophenone 2 (40 ml, 1.0 M) was placed
in reservoir C. The reaction products were collected in
anhydrous THF in reservoir D over a period of 20 min. The
reagents were manipulated within the device using the follow-
Scheme 4 Preparation of 8 via the silyl enol ether of propiophenone 9.
silyl enol ether 9 was converted to product 8. Using a micro
reactor, a standard solution of TBAF (40 ml, 0.1 M) in
anhydrous THF was placed in reservoir A, a solution of benzoyl
fluoride 3 (40 ml, 1.0 M) in anhydrous THF in reservoir B and
the silyl enol ether of propiophenone 9 (40 ml, 1.0 M) was
placed in reservoir C. The reaction products were collected in
anhydrous THF in reservoir D over a period of 20 min. The
reagents were manipulated within the device using the follow-
2
1
ing applied fields; 416, 318, 476 and 0 V cm , this resulted in
00% conversion of the enol ether 2 to product 4. In order to
1
demonstrate the generality of the technique, the silyl enol ethers
of propiophenone and cyclohexanone were also investigated.
2
1
ing applied fields; 375, 455, 405 and 0 V cm . This resulted in
1
00% conversion of the silyl enol ether of propiophenone 9 to
product 8.
In conclusion, we have developed a simple, room tem-
perature route to the regioselective formation of uncon-
taminated 1,3-diketones or O-acylated products depending
upon the acylating reagents used. In all instances, no competing
diacylation products were observed. The use of ammonium
enolates is also advantageous as it removes the effect of a metal
counter ion along with the observed reactions between aminated
bases and acylating reagents.
Scheme 2 Formation of 4 via the silyl enol ether of acetophenone 2.
In the preparation of b-hydroxyketones from silyl enol ethers
A synthetic standard of 2-benzoylcyclohexanone 6 was
prepared via the reaction of the silyl enol ether of cyclohex-
anone 7 and benzoyl fluoride 3 (Scheme 3). Within 1 h, 100%
conversion with respect to the silyl enol ether 7 was obtained in
bulk. A standard solution of TBAF (40 ml, 0.1 M) in anhydrous
THF was placed in reservoir A, a solution of benzoyl fluoride 3
we previously demonstrated that enhancements in both reaction
1
5
rates and conversion are observed when using micro reactors.
This work therefore re-emphasises the increase in reaction rates.
Typically, the formation of 4 in batch required extended
reaction times of 24 h due to reduced reagent reactivity
however, when transferred to a micro reactor, quantitative
conversions were observed in minutes.
(
40 ml, 1.0 M) in anhydrous THF in reservoir B and the silyl enol
ether of cyclohexanone 7 (40 ml, 1.0 M) was placed in reservoir
C. The reaction products were collected in anhydrous THF in
reservoir D over a period of 20 min. The reagents were
manipulated within the device using the following applied
Notes and references
2
1
fields; 208, 409, 357 and 0 V cm . This resulted in 100%
1
P. D. I. Fletcher, S. J. Haswell and V. N. Paunov, Analyst, 1999, 124,
1273.
2 G. M. Greenway, S. J. Haswell, D. O. Morgan, V. Skelton and P.
Styring, Sens. Actuators, B, 2000, 63, 153.
3 V. Skelton, G. M. Greenway, S. J. Haswell, P. Styring, D. O. Morgan,
B. Warrington and S. Y. F. Wong, Analyst, 2001, 126, 7.
conversion of the silyl enol ether of cyclohexanone 7 to product
6
. The reaction was repeated using benzoyl cyanide (40 ml, 1.0
M) and the following applied fields; 208, 409, 381 and 0 V
2
1
cm , this resulted in 100% conversion of the enol ether of
cyclohexanone 7 to 2-benzoylcyclohexanone 6.
4
P. Watts, C. Wiles, S. J. Haswell, E. Pombo-Villar and P. Styring, J.
Chem. Soc., Chem. Commun., 2001, 990.
5
H. House, R. Auerbach, M. Gall and N. P. Peet, J. Org. Chem., 1972, 38,
5
14.
6
7
8
9
M. W. Rathke and J. Dietch, Tetrahedron Lett., 1971, 2953.
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1
0 H. T. Black, S. M. Arrivo, J. S. Schumm and J. M. Knobeloch, J. Org.
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Scheme 3 Preparation of 2-benzoylcyclohexanone 6 via the silyl enol ether
of cyclohexanone 7.
1
1
1 G. Stork and P. F. Hudrlik, J. Am. Chem. Soc., 1968, 90, 4462.
2 C. Wiles, P. Watts, S. J. Haswell and Esteban Pombo-Villar,
Tetrahedron Lett., 2002, 43, 2945.
We subsequently extended the technique to the preparation of
product 8 within a micro reactor. A synthetic standard of 8 was
prepared via the reaction of the silyl enol ether of propiophe-
none 9 with benzoyl fluoride 3 (Scheme 4). After stirring for 1
h, the reaction mixture was analysed by GC-MS and 99% of the
1
1
3 T. McCreedy, Anal. Chim. Acta, 2001, 427, 39.
4 P. D. Christensen, S. W. P. Johnson, T. McCreedy, V. Skelton and N. G.
Wilson, Anal. Commun., 1998, 35, 341.
15 C. Wiles, P. Watts, S. J. Haswell and Esteban Pombo-Villar, Lab on a
Chip, 2001, 1, 100.
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