LETTER
Synthesis of Optically Active (2-Fluoroacyl)benzenes
1807
(
20) General procedures: A: Anhydrous FeCl (4.9 g, 30 mmol)
3H), 3.95 (s, OCH ), 5.63 (ddd, J = 50 Hz, CHF), 7.29, 7.63,
3
3
HF
was suspended in 25 ml of the aromatic compound under
exclusion of air and cooled to 0 C in an ice bath. 30 mmol of
7.67 und 8.03 (2 AA’XX‘, 8H).
(22) Gas chromatographic analysis on Chiraldex G-TA (20 m
capillary, Astec, Wippany/USA).
(23) Inczedy, J. Analytical Application of Complex Equilibria,
Wiley, New York 1976.
(24) Toluene and mesitylene solutions of 1 (X = C H , R = CH )
o
the optically active 2-fluorocarboxylic acid chloride were
added with stirring. Stirring of the reaction mixture was
continued, see Table 1 for reaction times and temperatures.
The reaction mixture was then poured into a solution of 12 g
6
5
3
o
citric acid in 100 ml water at 0 C and extracted with CH Cl .
were analyzed by GC on Chiraldex G-TA using biphenyl as
internal standard.
2
2
The organic phase was washed with water, dried (MgSO ) and
4
distilled. The residue was further purified by column
chromatography (silicagel, petroleum ether/AcOEt).
(25) Hydrolysis was performed by refluxing 10 g of 1 (X =
CH OCOO-C H , R = CH ) in a mixture of 100 ml CH OH
3
6
4
3
3
B: Anhydrous FeCl (4.9 g, 30 mmol) was suspended in 10-15
and 40 ml of 2N HC1 for 32 h. Dilution with CH Cl ,
3
2 2
ml of solvent under exclusion of air. 30 mmol of the optically
active 2-fluorocarboxylic acid chloride were added at the
reaction temperature (see Table 1) with stirring. The aromatic
compound was then added and stirring continued for the given
reaction time. Workup was performed as in A.
extraction with sodium bicarbonate solution, drying (MgSO4)
and evaporation to dryness gave 1 (X = HOCOO-C H , R =
6
4
CH ) which was recrystallized from toluene. Yield of isolated
3
o
22
1
1 45 %, mp. 138 C, [a] = + 1.75 (c = 2.0, CH Cl ), H-NMR
D
2
2
(CDC1 ): d = 1.70 (dd, JHF=25 Hz, JHH= 8 Hz, CH ), 5.74 (dq,
3
3
(
21) 1H NMR (300 MHz, CDCl , TMS) d for compound 1 (R =
CHF), 6.94, 7.56, 7.67, 8.06 (2 AA'XX', 8 H).
3
CH , X = C H ): 0.88 (mc, CH ), 1.20-1.40 (m, 3 CH ), 1.63
(26) Esterification is performed by reaction of 1 (X = HO-C H , R
3
6
13
3
2
6 4
(
mc, CH ), 1.66 (dd, J = 25 Hz, J = 8 Hz, CH ), 2.67 (t, J
= CH ) with 1.2 equiv. acid chloride and 1.2 equiv. pyridine in
2
HF
HH
3
3
=
8 Hz, CH ), 5.70 (dq, J = 50 Hz, JHH = 8 Hz, CHF), 7.60
CH Cl at room temperature overnight. After usual workup
2
HF
2
2
(
1
mc, 4 aromat. H), 1 (R = CH , X = C H ): 0.87 (mc, CH ),
the crude product is purified by column chromatography
(silicagel, CH Cl ). Etherification is performed by refluxing 1
3
12 25
3
.13-1.40 (m, 9 CH ), 1.63 (mc, CH ), 1.66 (dd, J = 25 Hz,
2 2 HF
2
2
JHH = 8 Hz, CH ), 2.67 (t, J = 8 Hz, CH ), 5.70 (dq, J = 50
(X = HO-C H , R = CH ) in acetone/acetonitrile (5: 1) with 1
3
2
HF
6 4 3
Hz, JHH = 8 Hz, CHF), 7.59 (mc, 4 aromat. H), 1 (R = CH , X
– 2 equiv. alkyl bromide and 5 equiv. potassium carbonate for
90 hours. After filtration the crude product is purified by
column chromatography (silicagel, petroleum ether/AcOEt
9:1), .
3
=
c-C H ): 1.2-1.5 (m), 1.63 (mc, CH ), 1.65 (dd, J = 25
12 11 2 HF
Hz, JHH = 8 Hz, CH ), 1.7-2.0 (m), 2.57 (mc, CH), 5.73 (dq,
3
JHF = 50 Hz, JHH = 8 Hz, CHF), 7.62 (mc, 4 aromat. H), 1 (R
=
CH , X = C H ) : 1.70 (dd, J = 23 Hz, JHH = 8 Hz, CH3),
(27) Prepared compounds 1: X = YCOO-C H or ZO-C H with Y
3
6
5
HF
6
4
6
4
2
0
5.73 (dq, JHF = 50 Hz, JHH = 8 Hz, CHF), 7.3-7.5 (mc, 4
= 4-n-C H -C H , (([a] = + 0.89 (c = 3.5, CH Cl )), Y = 4-
6
13
6
4
D
2
2
20
aromat. H), 1 (R = CH , X = 4-CH CHF*CO C H ) : 1.70 and
n-C H -C H (([a] = + 1.4 (c = 2.5, CH Cl )), Y = n-C H
11 23
3
3
2
6
5
7
15
6
4
D
2
2
2
3
23
1.78 (2 dd, JHF = 25 Hz, JHH = 8 Hz, 2 CH ), 5.29 and 5.73 (2
([a]D = + 0.4 (c = 1.0, CH Cl )), Z = n-C H (([a] = – 0.7
1
3
2
2
12 25
D
dq, JHF = 50 Hz, JHH = 8 Hz, 2 CHF), 7.26 (m, 2H), 7.63-7.73
(c = 1.0, CH Cl )). All compounds gave correct H-NMR-
2 2
(
m, 4H), 8.07 (m, 2H), 1 (R = CH , X = 4-CH OCOO-C H ):
spectra.
3
3
6
5
1
.70 (dd, JHF = 25 Hz, JHH = 8 Hz, CH ), 3.93 (s, OCH ), 5.73
3
3
(dq, JHF = 50 Hz, JHH = 8 Hz, CHF), 7.29, 7.63, 7.67, 8.07 (2
AA’XX‘, 8H), 1 (R = CH CH(CH ) , X = 4-CH OCOO-
Article Identifier:
2
3 2
3
C H ): 1.00 and 1.08 (2 d, J = 8 Hz, 2 CH ), 1.57-2.07 (m,
1437-2096,E;1999,0,11,1805,1807,ftx,en;G02699ST.pdf
6
5
3
Synlett 1999, No. 11, 1805–1807 ISSN 0936-5214 © Thieme Stuttgart · New York