2152
D. Lim et al.
PRACTICAL SYNTHETIC PROCEDURES
5,5-Dimethyl-1-phenylhexane-1,3-dione (17); Typical Proce-
dure (Table 3, Entry 1)
This reaction was conducted using untreated CH2Cl2, open to the
air.
Finally, we examined the impact of the coupling reaction
on the stereochemical integrity of the starting materials.
As mentioned above, conventional methods for b-dicar-
bonyl synthesis are limited to substrates lacking acidic
functionality. This includes compounds having base
epimerizable stereogenic centers a to a carbonyl group.
To test the effect of our coupling conditions on such com-
pounds, racemic 3 was prepared from racemic 1 and ace-
tophenone. This was analyzed via HPLC using a chiral,
nonracemic stationary phase under conditions that gave
baseline separation of the enantiomers. Subsequent analy-
sis of compound 3 derived from optically pure 1 and ace-
tophenone, and from optically pure 37 and 1-
benzoylbenzotriazole under the same conditions estab-
lished that no racemization had occurred during either of
the synthetic procedures. This demonstrates that our soft
enolization method for 1,3-dicarbonyl synthesis is also
compatible with substrates prone to base induced epimer-
ization under conventional hard enolization conditions.
Acetophenone (2; 0.065 mL, 0.63 mmol) was added dropwise via a
syringe to a stirred suspension of 3,3-dimethyl-1-oxobutylbenzotri-
azole (0.1648 g, 0.76 mmol) and MgBr2·OEt2 (0.4144 g, 1.58
mmol) in CH2Cl2 (10 mL), followed by i-Pr2NEt (0.33 mL, 1.90
mmol). The reaction flask was capped to prevent evaporation. The
stirring was continued for 2.5 h, by which time a solution had
formed, and 10% aq HCl (10 mL) was added. The stirring was con-
tinued for 5 min and the aqueous layer was extracted with CH2Cl2
(3 ´ 5 mL) and the combined organic extracts were dried (MgSO4),
filtered, and evaporated to give a yellow oil. Flash chromatography
over silica gel using 10:90 EtOAc–hexanes gave 17 (0.4168 g,
96%) as a pure, yellow oil. Spectroscopic data were identical to
those reported previously.9
Acknowledgment
D.L. and G.Z. are grateful for Burroughs Wellcome Fellowships
from the Duke University Department of Chemistry. A.E.L. thanks
GlaxoSmithKline for an Undergraduate Summer Research Fel-
lowship. This work was supported, in part, by the ACS Petroleum
Research Fund.
In conclusion, we have developed an efficient direct cou-
pling reaction between ketones and N-acylbenzotriazoles
or O-Pfp esters based on soft enolization that proceeds un-
der extremely mild conditions to generate 1,3-diketones
(Scheme 1). The reaction is conducted using inexpensive
MgBr2·OEt2 in untreated, reagent grade solvent open to
the air, and produces innocuous by-products on workup.
Furthermore, it is compatible with a range of substrates,
including those having base-epimerizable centers adja-
cent to carbonyl groups, as well as those possessing other
base sensitive functionality. Thus, syntheses employing
this carbon–carbon bond-forming method are likely to
benefit in the avoidance of protecting groups. Given the
importance of 1,3-dicarbonyl compounds in general,
along with the operational simplicity and mild nature of
this reaction, we expect that it will meet with wide appli-
cation in synthetic chemistry.
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Unless stated to the contrary, where applicable, the following con-
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Synthesis 2008, No. 13, 2148–2152 © Thieme Stuttgart · New York