The regioselective preparation of 1,3-diketones

Article abstract of DOI:10.1016/S0040-4039(02)00432-X

The regioselectivity of the acylation of Li enolates and silyl enol ethers is reported using acyl halides and acyl cyanides. We illustrate a simple method for the preparation of 1,3-diketones via the silyl enol ether in excellent yields, free from competing O-acylation and diacylation products.

Full text of DOI:10.1016/S0040-4039(02)00432-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2945–2948
The regioselective preparation of 1,3-diketones
Charlotte Wiles,a Paul Watts,a Stephen J. Haswella,* and Esteban Pombo-Villarb
aDepartment of Chemistry, Faculty of Science and the Environment, University of Hull, Cottingham Road, Hull HU6 7RX, UK
bNervous Systems Research, WSJ-386.07.15, Novartis Pharma Ltd., CH4002, Basel, Switzerland
Received 28 November 2001; revised 18 February 2002; accepted 1 March 2002
Abstract—The regioselectivity of the acylation of Li enolates and silyl enol ethers is reported using acyl halides and acyl cyanides.
We illustrate a simple method for the preparation of 1,3-diketones via the silyl enol ether in excellent yields, free from competing
O-acylation and diacylation products. © 2002 Elsevier Science Ltd. All rights reserved.
The enolate has been described as the most important
intermediate in CꢀC 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 undesirable formation of a mixture of
O- and C-acylated products which are difficult to sepa-
rate, often resulting in low yields.1 A large amount of
work has been undertaken in order to explore and
understand the reaction conditions that promote the
regioselective acylation of enolates, these include; the
nature of the counterion, reaction temperature, solvent,
stoichiometry of reagents, order of reagent addition
and type of acylating reagent.2,3 Although careful selec-
tion of the aforementioned conditions has been shown
to influence the regioselectivity of the acylation, the
1,3-diketones produced remain contaminated with
small amounts of O-acylated product.4,5 The procedure
is still therefore regarded as being heavily substrate
dependant.6
acylating reagent and amide base (LDA), previously
observed by Rathke et al.2 Howard and co-workers12
have also demonstrated the C-acylation of Li enolates
(generated using LDA) using acyl cyanides.13,14 Using
this methodology, no competing O-acylation, diacyl-
ation or reactions of the enolate with the cyanide group
were reported.
Although many techniques have demonstrated the for-
mation of CꢀC bonds via the use of Li enolates and
silyl enol ethers, there are few that enable the prepara-
tion of clean O-acylated products. Noyori et al. how-
ever demonstrated the selective O-acylation of silyl enol
ethers using stoichiometric amounts of the expensive
fluoride source, tris(dimethylamino)sulfonium difluoro-
trimethyl silicate (TASF).15 Limat and co-workers, sub-
sequently demonstrated the use of a catalytic amount of
tetrabutylammonium fluoride trihydrate to afford enol
esters in good yields.16
In the late 1960s, Stork et al. demonstrated that an
enolate could be transformed into a silyl enol ether and
then converted back to the enolate.6 The technique
therefore enables the temporary trapping of an enolate
while maintaining the regio- and stereochemical fea-
tures.7,8 Stork described the regeneration of enolates via
the use of methyllithium. However, more recently anhy-
drous fluoride salts9 and reagents such as potassium
ethoxide10 have found use in desilylation reactions.
Beck et al. demonstrated the C-acylation of Li enolates
generated by the treatment of silyl enol ethers with
methyllithium.11 This technique proved advantageous
as it removed the undesirable reaction between the
We report here a simple procedure for the regioselective
acylation of ketones from their respective Li enolates
(prepared using LiHMDS)17 and silyl enol ethers18,19
using a series of acylating reagents. The enolates are
regenerated from the silyl enol ethers using a catalytic
amount of anhydrous TBAF.20 This effectively means
that the enolate formed is ‘naked’ i.e. remains relatively
unaffected by its counterion, in this case the ‘soft’
ammonium ion.7 As Table 1 illustrates, the products
were isolated in good to excellent yields.
As Table 1 illustrates, the acylation of the Li enolate of
acetophenone with acetyl chloride results in the forma-
tion of the O-acetylated product 1.21 O-Acylation 323
was also observed when using the reagent benzoyl
chloride (Table 1), no contamination from competing
Keywords: acylation; silyl enol ethers; enolates; regioselectivity.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00432-X

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C. Wiles et al. / Tetrahedron Letters 43 (2002) 2945–2948
Table 1. Products obtained from the acylation of a series of Li enolates and their respective silyl enol ethers

C. Wiles et al. / Tetrahedron Letters 43 (2002) 2945–2948
2947
C-acylation was observed in either reaction. Subse-
quent reactions of the Li enolate of acetophenone with
acetyl cyanide and benzoyl cyanide however, resulted in
the formation of the C-acylated products, benzoyl ace-
tone 222 and dibenzoylmethane 5,24 respectively. Again
no contamination occurred from competing O-
acylation (1 and 3).23
5. The NMR and mass spectral data obtained from the
silyl enol ethers were in accordance with published data.
(a) Kopka, I.; Rathke, M. W. J. Org. Chem. 1981, 46,
3771; (b) Black, H. T.; Arrivo, S. M.; Schumm, J. S.;
Knobeloch, J. M. J. Org. Chem. 1987, 52, 5425.
6. Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968, 90,
4462.
7. Kuwajima, I.; Nakamura, E. Acc. Chem. Res. 1985, 18,
181.
8. Kuwajima, I.; Nakamura, E.; Hashimoto, K. Org.
Synth. 1982, 61, 122.
9. Nakamura, E.; Murofushi, T.; Shimizu, M.; Kuwajima,
I. J. Am. Chem. Soc. 1976, 98, 2346.
10. Yu, W.; Jin, Z. Tetrahedron Lett. 2001, 42, 369.
11. Beck, A. K.; Hoestra, S. M.; Seebach, D. Tetrahedron
Lett. 1977, 1187.
12. Howard, A. S.; Meerholz, C. A.; Michael, J. P. Tetra-
hedron Lett. 1979, 15, 1339.
13. Renger, B.; Hugel, H.; Wykypiel, W.; Seebach, D.
Chem. Ber. 1978, 111, 2630.
14. Taylor, E. C.; Andrade, J. G.; John, K. C.; McKillop,
A. J. Org. Chem. 1978, 43, 2280.
15. Noyori, R.; Nishida, I.; Sakata, J. J. Am. Chem. Soc.
1983, 105, 1598.
Upon treatment of the silyl enol ether of acetophenone
with acetyl chloride and benzoyl chloride, no reactions
were observed. This phenomenon was also noted by
Olofson et al. whereby the use of chloroformates in
place of fluoroformates impeded the synthesis of enol
carbonates from silyl enol ethers.27 The acyl chlorides
were therefore replaced by their respective acyl fluoride
and again, O-acylation was observed 4. Treatment of
the silyl enol ether of acetophenone with benzoyl cya-
nide resulted in C-acylation and the preparation of
dibenzoylmethane 5.24 As Table 1 illustrates, the
acylation of propiophenone25 (6 and 7) and
cyclohexanone26 (8, 9 and 10) via both the Li enolates
and their respective silyl enol ethers resulted in the
formation of the C-acylated product regardless of the
acylating reagent used.
16. Limat, D.; Schlosser, M. Tetrahedron 1995, 51, 5799.
17. Example of a typical Li enolate procedure: cyclohex-
anone (1.00 g, 10.20 mmol) was added dropwise to a
stirred solution of lithium bis(trimethylsilyl)amide (LiH-
MDS) (10.20 ml, 1.0 M, 10.20 mmol) in THF (100 ml)
over a period of 30 min. The resulting solution was
stirred for a further 15 min prior to the addition of
benzoyl fluoride (1.11 ml, 10.20 mmol) in THF (10 ml).
The reaction mixture was stirred for 15 min and subse-
quently extracted using ethyl acetate (3×50 ml). The
combined organic solvents were dried over magnesium
sulfate and concentrated in vacuo. Purification was
achieved using silica gel chromatography. Elution with
10% ethyl acetate in hexane yielded 2-benzoylcyclohex-
anone (1.44 g, 70%).
18. Example of a typical silyl enol ether preparation: A solu-
tion of cyclohexanone (0.10 g, 1.02 mmol) in anhydrous
THF (10 ml) was added dropwise to a stirred solution
of LiHMDS (1.02 ml, 1.0 M, 1.02 mmol) over a period
of 30 min. The solution was then stirred for a further 15
min prior to the addition of chlorotrimethylsilane (0.13
ml, 1.20 mmol). The reaction mixture was concentrated
in vacuo and the resulting residue dissolved in DCM (50
ml). The inorganics were removed by filtration and the
resulting solution concentrated in vacuo to yield the silyl
enol ether of cyclohexanone (0.16 g, 93%).
The regioselectivity of both the acylations of Li eno-
lates and silyl enol ethers was found to be dependent
upon the type of ketone used i.e. a-substituted ketones
gave C-acylated products and non a-substituted
resulted in O-acylation with acyl halides and C-
acylation with acyl cyanides. In all cases, the products
were found to be 100% C- or O-acylated, no mixtures
were observed. In comparison to the use of acyl halides,
the treatment of a Li enolate with an acyl cyanide
showed an increase in yield. An increase in conversion
was also observed when using the silyl enol ether
approach, compared to the direct acylation of the Li
enolate.
In conclusion, the use of silyl enol ethers is advanta-
geous as it removes the effect of a metal counterion
along with the observed reactions between aminated
bases and acylating reagents. The procedure provides a
simple, room temperature, route to the formation of
uncontaminated 1,3-diketones or O-acylated products
in high yields.
Acknowledgements
19. Example of a typical acylation using a silyl enol ether:
The silyl enol ether of cyclohexanone (0.10 g, 0.59
mmol) was added dropwise to a stirred solution of
anhydrous TBAF (0.015 g, 0.059 mmol) and benzoyl
fluoride (0.06 ml, 0.59 mmol) in anhydrous THF (10
ml). The reaction mixture was extracted into ethyl ace-
tate (3×50 ml) and the combined organic solvents dried
over magnesium sulfate. Purification was achieved using
silica gel chromatography. Elution with 10% ethyl actate
in hexane gave 2-benzoyl cyclohexanone (100% conver-
sion, calculated by GC-MS, with respect to residual silyl
enol ether).
We acknowledge Novartis Pharmaceuticals (C.W. and
P.W.) who financially supported this research.
References
1. House, H.; Auerbach, R. A.; Gall, M.; Peet, N. P. J.
Org. Chem. 1972, 38, 514.
2. Rathke, M. W.; Deitch, J. Tetrahedron Lett. 1971, 2953.
3. Katritzky, A. R.; Pastor, A. J. Org. Chem. 1999, 3679.
4. Tirpak, R. E.; Rathke, M. W. J. Org. Chem. 1982, 47,
5099.

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C. Wiles et al. / Tetrahedron Letters 43 (2002) 2945–2948
20. Anhydrous tetrabutylammonium fluoride was prepared
from TBAF·3H2O, purchased from Aldrich. The
TBAF·3H2O was dried over phosphorous pentoxide
under vacuum (10 mm Hg) for 48 h to afford a gelata-
neous solid. The use of TBAF·3H2O proved unsuccess-
(CH), 133.7 (CH), 134.4 (C) and 134.7 (C); m/z (EI) 225
(M++1, 5%), 224 (20), 105 (100) and 77 (20).
24. Compound 5: lH (400 MHz, CDCl3/TMS) 6.84 (2H, s,
CH2), 7.51 (6H, m, Ar) and 7.98 (4H, m, Ar); lC (100
MHz, CDCl3/TMS) 93.3 (CH2), 127.3 (CH), 128.8 (CH),
132.6 (CH), 135.6 (C) and 185.9 (CO); m/z (EI) 225
(M++1, 25%), 224 (50), 223 (75), 105 (100) and 77 (75).
25. Compound 6: lH (400 MHz, CDCl3/TMS) 1.59 (1H, d,
J 7.0, CH3), 5.28 (3H, q, J 7.0, CH), 7.96 (6H, m, Ar)
and 7.45 (4H, m, Ar); lC (100 MHz, CDCl3/TMS) 14.5
(CH3), 51.1 (CH2), 128.6 (CH), 129.0 (CH), 130.0 (CH),
133.6 (C) and 197.3 (CO); m/z (EI) 239 (M++1, 2%), 238
(10) and 105 (100).
26. Compound 8: lH (400 MHz, CDCl3/TMS) 1.74 (2H, m,
CH2), 1.98 (2H, m, CH2), 2.28 (2H, m, CH2), 2.54 (2H,
m, CH2), 4.38 (1H, m, CH), 7.44 (2H, m, Ar), 7.54 (1H,
m, Ar) and 7.89 (2H, m, Ar); lC (100 MHz, CDCl3/
TMS) 23.2 (CH2), 23.5 (CH2), 27.4 (CH2), 30.1 (CH2),
58.9 (CH), 128.6 (CH), 128.7 (CH), 133.3 (CH), 136.6
(C), 197.7 (CO) and 208.7 (CO); m/z (EI) 203 (M++1,
15%), 202 (30), 201 (28), 105 (100) and 77 (55).
ful as
a catalytic desilylation agent as the added
moisture resulted in the protonation of the enolate, con-
verting it back to the corresponding ketone.
21. Compound 1: lH (400 MHz, CDCl3/TMS) 2.24 (3H, s,
CH3), 4.87 (1H, d, J 2.2, CHH), 5.33 (1H, d, J 2.2,
CHH), 7.29 (2H, m, Ar) and 7.33 (3H, m, Ar); m/z (EI)
163 (M++1, 26%), 162 (65), 161 (100) and 105 (50).
22. Compound 2: lH (400 MHz, CDCl3/TMS) 2.19 (3H, s,
CH3), 6.17 (2H, s, CH2), 7.43 (3H, m, Ar) and 7.86 (2H,
m, Ar); lC (100 MHz, CDCl3/TMS) 25.9 (CH3), 96.8
(CH2), 125.6 (CH), 128.7 (CH), 132.4 (CH), 134.9 (C),
183.4 (CO) and 194.0 (CO); m/z (EI) 163 (M++1, 100%),
162 (30), 161 (35), 105 (45) and 77 (10).
23. Compound 3: lH (400 MHz, CDCl3/TMS) 5.16 (1H, d,
J 2.3, CHH), 5.59 (1H, d, J 2.3, CHH), 7.35 (3H, m,
Ar) and 7.95 (7H, m, Ar); lC (100 MHz, CDCl3/TMS)
102.4 (CH2), 125.0 (CH), 128.7 (CH), 128.8 (CH), 130.2
27. Olofson, R. A.; Cuomo, J. Tetrahedron Lett. 1980, 819.