phase was concentrated under reduced pressure. The crude product
was purified by flash column chromatography on silica gel by using
ether or ether/petroleum ether as an eluent.
For proving the effect of the electropositive nature of the
ketones, 3′-fluoro-2,2,2-trifluoroacetophenone 2d and 2a are
reacted with 1a. The reaction with 2d in DMF works faster
and in higher yield (95%) with respect to the reactions with 2a
(85%) (entries 1 and 10).
Diethyl 3,3,3-trifluoro-1-oxo-1,2-diphenylpropan-2-yl phos-
phate (4a):7a white solid; H NMR (CDCl3) δ 1.07 (3H, dt, J1 )
1
1.0 Hz, J2 ) 7.1 Hz), 1.20 (3H, dt, J1 ) 1.0, J2 ) 7.1 Hz),
3.61-3.78 (2H, m), 3.93-4.09 (2H, m), 7.15-7.21 (2H, m), 7.32-
7.37 (4H, m), 7.45-7.55 (2H, m), 7.60-7.63 (2H, m); 13C NMR
(CDCl3) δ 15.7 (d, J ) 3.7 Hz), 15.8 (d, J ) 3.8 Hz), 64.2 (d, J )
6.1 Hz), 64.7 (d, J ) 6.1 Hz), 86.3 (d, J ) 28 Hz), 125 (q, J ) 287
Hz), 126.4, 128.0, 128.9, 130.0, 130.3, 132.1(d, J ) 10.4 Hz), 133.0,
134.0, 189.6; 31P NMR (CDCl3) δ -6.38. Anal. Calcd for
C19H20F3O5P: C, 54.81; H, 4.84. Found: C, 54.66; H, 4.75.
Procedure for the Coupling of Aromatic Acyl Phospho-
nates with Cyclohexanone. KCN (20 mol %), 18-crown-6 (20 mol
%), and catalyst (3,5-bistrifluoromethylphenyl)thiourea (25 mol %)
were placed in a round-bottomed flask, and then 2 mL of freshly
dried THF was added via a syringe. One millimole of aromatic
acyl phosphonate and 2 mmol of cyclohexanone were added to the
reaction mixture under an inert atmosphere at ambient temperature.
After completion, the reaction (1 h) mixture was diluted with 15 mL
of ether and worked up as aromatic-aromatic reactions. This procedure
is only valid for the coupling of dimethyl(4-methoxyphenyl)oxomethyl
phosphonate and cyclohexanone.
The coupling of enolizable aldehydes and ketones in acyloin
reactions is always problematic. This is obvious from a few
reactions that utilize aliphatic aldehydes in acyl anion chemistry.
In our initial investigation we chose 1a and commercially
available 1,1,1-trifluorobutan-2-one (2e) as model substrates for
aldehyde/ketone cross-acyloin coupling. To perform the coupling
reaction, 1j and 2e were reacted in various solvents (hexane,
diethylether, DCM, THF, and DMF) at room temperature. The
addition of a phase transfer catalyst such as 18-crown-6,
Bu4NBr, and the application of the TMS + CsF system7a did
not give the coupling reaction. Finally, when 1j in DMF was
treated with 2e in the presence of Cu(OTf)2, the desired product
4k was isolated in 7% yield. Carrying out the same reaction in
DMF and increasing the reaction temperature to 50 °C gave
the product 4k in 41% yield (entry 11).
We tried acetophenone as a substrate without and with
additives (Lewis and Bronsted acids) without success. Next, we
chose cyclohexanone as an acceptor. Our initial attempt to
activate cyclohexanone was executed by using Lewis acid-like
LiClO4 and metal triflates. Lewis acid activation in different
solvents (hexane, THF, DCM, toluene, DMF) did not furnish
the product, only unreacted starting materials were isolated. The
use of thiourea derivative (3,5-bistrifluoromethylphenyl)thiourea
to activate cyclohexanone in dry THF in the presence of 18-
crown-6 as a catalyst at ambient temperature furnished acyloin
4l in 54% yield (entry 12).
Fortunately, we can obtain aliphatic acyl phosphonates with
2a and 2b in tolune in the presence of 18-crown-6 at 80 °C
(entries 13-17). Enolizable phosphonates 1l and 1m each
provided with 2a two nonseparable products that are identified
as accepted trifluoromethyl (data not shown) and difluoromethyl
acyloins 4p and 4q (entries 16 and 17). For the formation of
these compounds, we suggest that during the reaction, 2,2-
difluoroacetophenone (2b) is formed first and then reacted with
acyl anion to form the products 4p and 4q (the proposed
mechanism is depicted in the Supporting Information).
The O-protected acyloins can be easily deproctected to
acyloins according to the procedures described in the literature.7b
In summary, the first catalytic intermolecular aldehyde-ketone
coupling via acyl phosphonate is described. The cyanide ion-
catalyzed formation of acyl anion from acyl phosphonates and
the reaction of this anion with activated ketones furnished
aldehyde-ketone coupling products in 41-95% yields. The
cross-acyloin reaction is dependent on the electropositive nature
of the acceptor molecule and electronegative nature of an acyl
anion. A more detailed study concerning the activation of
ketones for an acyloin reaction is currently under investigation.
(1-p-Methoxybenzoylcyclohexyl)dimethyl phosphate (4l):
1
white solid; H NMR (CDCl3) δ 1.24-1.33 (2H, m), 1.55-1.60
(3H, m), 1.67-1.77 (2H, m), 1.95-2.01 (2H, m), 2.17-2.25 (2H,
m), 3.54 (6H, d, J ) 11.3 Hz), 3.79 (3H, s), 6.84 (2H, d, J ) 9.0
Hz), 8.07 (2H, d, J ) 8.9 Hz); 13C NMR (CDCl3) δ 20.6, 23.9,
33.5, 33.6, 53.3 (d, J ) 5.5 Hz), 54.4, 88.0 (d, J ) 6.9 Hz), 112,4,
126.4, 131.3, 162,0, 196.1; 31P NMR (CDCl3) δ -1.67. Anal. Calcd
for C16H23O6P: C, 56.14; H, 6.77. Found: C, 56.36; H, 6.71.
General Procedure for Aliphatic-Aromatic Acyl Phospho-
nate/Ketone Coupling. KCN (20 mol %) and 18-crown-6 were
(20 mol %) were placed in a round-bottomed flask, and then 5 mL
of dried toluene was added via a syringe. One millimole of aliphatic
acylphoshonate and 2 mmol of 2,2,2-trifluoroacetophenone were
added to the reaction mixture under an inert atmosphere. The
reaction mixture was heated to 80 °C, in which the reaction was
monitored by TLC or NMR (40-50 min). After completion, the
reaction mixture was diluted with 15 mL of ether and water. The
organic phase was separated and the aqueous phase was extracted
with 10 mL of ether three times. The combined organic phase was
extracted with a brine solution, separated, and dried over MgSO4.
The organic phase was concentrated under reduced pressure. The
crude product was purified by flash column chromatography on
silica gel, using ether or ether/petroleum ether as an eluent.
Diethyl 1,1,1-trifluoro-2-(3-fluorophenyl)-4,4-dimethyl-3-oxo-
pentan-2-yl phosphate (4m): yellow oil; 1H NMR (CDCl3) δ 1.10
(9H, s), 1.26-1.32 (6H, m), 4.12-4.19 (4H, m), 7.06-7.10 (1H,
m), 7.19-7.25 (2H, m), 7.29-7.36 (1H, m); 13C NMR (CDCl3) δ
14.8, 14.9, 15.0, 27.9, 45.0, 63.8 (d, J ) 6.0 Hz), 64.0 (d, J ) 6.0
Hz), 113.7 (d, J ) 24.5 Hz), 116.1 (d, J ) 21.3 Hz), 119.6, 122.1,
128.9 (d, J ) 7.9 Hz), 132.5, 162.8 (d, J ) 254 Hz), 203.6; 31P
NMR (CDCl3) δ -7.60. Anal. Calcd for C17H23F4O5P: C, 49.28;
H, 5.60. Found: C, 49.11; H, 5.55.
Acknowledgment. Financial support from the Scientific and
Experimental Section
¨
Technological Research Council of Turkey (TUBITAK), the
¨
Turkish Academy of Science (TUBA), the Turkish State
General Procedure for Aromatic-Aromatic Acyl Phospho-
nate/Ketone Coupling. To a solution of 1 mmol of acyl phospho-
nate in 2 mL of dry DMF were added 1.1 mmol of ketone (2,2,2-
trifluoroacetophenone) and 10 mol % of KCN. The reaction was
monitored by TLC. After the completion of the reaction, the reaction
mixture was diluted by 10 mL of ether and water. The organic
phase was separated and the aqueous phase was extracted with 10
mL of ether three times. The combined organic phase was extracted
with a brine solution, separated, and dried over MgSO4. The organic
Planning Organization, and the Middle East Technical Univer-
sity (METU) are all gratefully acknowledged.
Supporting Information Available: Experimental proce-
dures and characterization data for the compounds. This material
JO8026627
J. Org. Chem. Vol. 74, No. 5, 2009 2199