An improved method for the addition reactions of 1,3-dichloroacetone with combined organolithium-cerium trichloride reagents

Article abstract of DOI:10.1002/jccs.200300130

Alkyl-, phenyl- and alkynyllithium reagents in combination with anhydrous cerium(III) chloride underwent addition reactions with 1,3-dichloroacetone in a very efficient manner. The addition products are versatile precursors for 2-substituted epichlorohydrins and glycidols. Fluconazole, a potent antifungal agent, was thus synthesized in 67% yield by addition of 1,3-dichloroacetone to 2,4-difluorophenyllithium in the presence of cerium(III) chloride, followed by substitution of the chlorine atoms with 1,2,4-triazole.

Full text of DOI:10.1002/jccs.200300130

Journal of the Chinese Chemical Society, 2003, 50, 927-930
927
An Improved Method for the Addition Reactions of 1,3-Dichloroacetone
with Combined Organolithium-Cerium Trichloride Reagents
Same-Ting Chen (
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan, R.O.C.
) and Jim-Min Fang* (
)
Alkyl-, phenyl- and alkynyllithium reagents in combination with anhydrous cerium(III) chloride under-
went addition reactions with 1,3-dichloroacetone in a very efficient manner. The addition products are versa-
tile precursors for 2-substituted epichlorohydrins and glycidols. Fluconazole, a potent antifungal agent, was
thus synthesized in 67% yield by addition of 1,3-dichloroacetone to 2,4-difluorophenyllithium in the presence
of cerium(III) chloride, followed by substitution of the chlorine atoms with 1,2,4-triazole.
Keywords: 1,3-Dichloroacetone; Organolithium reagents; Cerium(III) chloride; Fluconazole;
Epichlorohydrins; Glycidols.
INTRODUCTION
As 1,3-dichloroacetone (1) is a highly enolizable
1,3-dichloroacetone was then added at -78 °C. The addition
reaction was completed in 10 min to give high yields (84-
96%) of the desired addition products 2a-d. The yields de-
creased by adding organolithium reagents to the mixture of
1,3-dichloroacetone and CeCl3. If the organolithium reagent
(e.g. PhLi) was replaced by Grignard reagent (e.g. PhMgCl),
the yield of addition product also decreased significantly
(e.g. dropping from 96% to 62% in the case of 2a). In the ab-
sence of CeCl3, the addition reactions using either organolith-
ium or Grignard reagents gave inferior yields as shown in the
previous reports.3 For example, our study showed a 96%
yield of 2d from the addition reaction of 1,3-dichloroacetone
with the combined reagents of 2,4-difluorophenyllithium and
CeCl3. However, the yield of 2d dropped to 64% when CeCl3
was absent in the reaction.3c
ketone, its addition reactions with basic organolithium and
organomagnesium reagents may be complicated by side reac-
tions such as deprotonation and reductive dechlorination re-
action.1 On the other hand, organolanthanoid reagents are
known to be more oxophilic and less basic than organolith-
ium and organomagnesium reagents.2 The successful appli-
cation of organolanthanoides, particularly organocerium re-
agents, to carbonyl addition reactions has been extensively
investigated.2 Along this line, we wish to report an improved
procedure by using organolithium reagents together with ce-
rium(III) chloride to achieve the addition reactions with
1,3-dichloroacetone.1a,3 This method thus provided an expe-
dient route to tertiary alcohols 2a-d (equation 1).4
N
N
N
N
OH
OH
OH
O
Cl
Cl
F
N
N
F
RLi/CeCl3, THF
K2CO3, DMF
NH
reflux, 16 h
N
N
Cl
Cl
Cl
Cl
(1)
+
2
(2)
-78 oC, 10 min
R
1
2a R = Ph
F
F
2b R = C4H9
2d
3
2c R =
Ph
2d R = 2,4-F2C6H3
Fluconazole (3), 2-(2,4-difluorophenyl)-l,3-bis(1,2,4-
triazol-l-yl)-2-propanol, is useful in treatment of topical in-
fections in man caused by fungi such as the species of
Candida, Trichophyton, Microsporum, Epidermophyton,
Cryptococcus, Aspergillus, Coccidiodes, Paracoccidiodes,
Histoplasma, and Blastomyces.4 The antifungal activity is
evaluated both in vitro and in vivo. For human use, flucon-
azole can be administered either orally or by injection. Flu-
conazole was introduced under the brand name of Diflucan®
RESULTS AND DISCUSSION
The required anhydrous CeCl3 was prepared by heating
the commercially available CeCl3 heptahydrate at 140 °C in
vacuo for at least 3 h. The organolithium reagent was pre-
mixed with CeCl3 in THF under an atmosphere of argon, and

928 J. Chin. Chem. Soc., Vol. 50, No. 4, 2003
Chen and Fang
by the Pfizer Pharmaceutical Company in 1994. The previous
syntheses of fluconazole had the drawback of low overall
yields (< 35%).4,5 As we had an easy access to the tertiary al-
cohol 2d with 1,3-dichloro substituents, we investigated fur-
ther the substitution reaction with 1,2,4-triazole (equation 2).
After several modifications, we were able to obtain flucon-
azole in 70% yield by heating a mixture of 2d, 1,2,4-triazole
(2.2 equiv) and K2CO3 (2.2 equiv) in DMF solution. This
sample of fluconazole, mp 138.5-140 °C (recrystallization
from EtOAc/hexane) was pure and fully characterized. No
contamination of the isomers derived by substitutions at the
N-4 atoms of 1,2,4-triazoles was found as evidenced by the
NMR analyses.5c
1,3-Dichloro-2-phenyl-2-propanol (2a)1a,3b
A sample of CeCl3·7 H2O (5.58 g, 15 mmol) was dried
at 140 °C in vacuo for at least 3 h, cooled under an argon at-
mosphere, and anhydrous tetrahydrofuran (THF, 75 mL) was
added. The suspension was stirred at room temperature for 4
h, cooled to -78 °C in a dry ice-acetone bath, and a solution of
phenyllithium (10.1 mmol, 5.50 mL of 2 M cyclohexane-
ether solution) was added dropwise over a period of 5 min.
The mixture was stirred at -78 °C for 40 min; a solution of
1,3-dichloroacetone (1.27 g, 10 mmol) in THF (5 mL) was
added rapidly. After which, the mixture was stirred for 10 min
at -78 °C, and quenched by addition of aqueous acetic acid
solution (10%, 1 mL). The mixture was diluted with brine (15
mL), and extracted with ethyl acetate (EtOAc, 3 ´ 20 mL).
The combined extracts were dried (Na2SO4) and filtered. The
filtrate was concentrated by rotary evaporation, and the resi-
due was purified on a silica gel column by elution with
EtOAc/hexane (2:98) to give the title compound (1.96 g, 96%
yield based on 1,3-dichloroacetone). Oil; TLC (EtOAc/hex-
ane (2:98)) Rf = 0.12; IR (neat) 3552, 3034, 2967, 1176, 1071
cm-1; 1H NMR (200 MHz, CDCl3) d 2.91 (1H, s), 3.89 (2H, d,
J = 11.5 Hz), 3.96 (2H, d, J = 11.5 Hz), 7.35-7.51 (5H, m); MS
m/z (rel intensity) 204 (1, M+), 155 (100); HRMS calcd for
C8H835ClO (M+ - CH2C1) 155.0263, found m/z 155.0236.
OH
O
Cl
HO
Cl
HO
O
R
R
R
4a R = Ph
4c R =
5a R = Ph
5c R =
6a R = Ph
Ph
Ph
Epichlorohydrin is often utilized as a cross-linking
agent for polymers. Treatments of the addition products 2a
and 2c with t-BuOK at room temperature in t-BuOH solution
gave 2-substituted epichlorohydrins 4a and 4c in 92% and
90% yields, respectively. The acid-catalyzed hydrolyses of
4a and 4c gave diols 5a and 5c. Compound 5a was in turn
treated with K2CO3 in MeOH to afford glycidol 6a. The func-
tional transformations and applications of 2-substituted epi-
chlorohydrins and glycidols in organic synthesis have been
explored.3b,6
1-Chloro-2-(chloromethyl)-2-hexanol (2b)3b
A suspension of anhydrous CeCl3 (2.47 g, 10 mmol) in
THF (50 mL) was placed in a round-bottomed flask (100 mL)
and stirred at room temperature for 4 h. The suspension was
cooled to -78 °C in a dry ice-acetone bath; a solution of
butyllithium (10 mmol, 6.25 mL of 1.6 M hexane solution)
was added dropwise over a period of 5 min. The mixture was
stirred at -78 °C for 40 min; a solution of 1,3-dichloroacetone
(1.27 g, 10 mmol) in THF (5 mL) was added rapidly. After
which, the mixture was stirred for 10 min at -78 °C, and
quenched by addition of aqueous acetic acid solution (10%, 1
mL). The mixture was worked up as usual to give the title
compound (1.56 g, 84% yield). Oil; TLC (EtOAc/hexane
In summary, we have found an efficient method to carry
out the addition reactions of 1,3-dichloroacetone with alkyl-,
phenyl- and alkynyllithium reagents by the mediation of an
appropriate lanthanoid Lewis acid CeCl3. The versatile uses
of these addition products have been demonstrated by the
synthesis of fluconazole and transformations to epichloro-
hydrins and glycidols.
(1:9)) Rf = 0.25; IR (neat) 3446, 2956, 1028 cm-1; H NMR
1
EXPERIMENTAL
(200 MHz, CDCl3) d 0.89 (3H, t, J = 7.2 Hz), 1.38-1.29 (4H,
m), 1.66-1.57 (2H, m), 2.36 (1H, br s, OH), 3.53 (2H, d, J =
11.2 Hz), 3.62 (2H, d, J = 11.2 Hz); 13C NMR (75 MHz,
CDCl3) d 13.8, 22.9, 24.7, 34.6, 48.3 (2 ´), 73.7; MS m/z (rel
intensity) 167 (1), 135 (100); HRMS calcd for C6Hl235ClO
(M+ - CH2C1) 135.0576; found m/z 135.0582.
Melting points are uncorrected. Tetramethylsilane (d
H
= 0 ppm) and CDCl3 (d = 77.0 ppm for the central line of
C
1
triplet) were used as internal standards in H and 13C NMR
spectra, respectively. Mass spectra were recorded at an ioniz-
ing voltage of 70 or 20 eV. Silica gel 60F sheets were used for
analytical thin-layer chromatography. Column chromatogra-
phy was performed on SiO2 (70-230 mesh); gradients of
EtOAc and hexane were used as eluents. The reagents and
solvents were dried according to standard procedure.
1-Chloro-2-(chloromethyl)-4-phenyl-3-butyn-2-ol (2c)
A solution of phenylacetylene (1.07 g, 10.5 mmol) in
THF (10 mL) was treated with butyllithium (10.8 mmol, 6.75

Reactions of Dichloroacetone with Organocerium Reagents
J. Chin. Chem. Soc., Vol. 50, No. 4, 2003 929
mL of 1.6 M hexane solution) at 0 °C for 30 min. The pre-
pared (phenylethynyl)lithium solution was added dropwise
to a suspension of anhydrous CeCl3 (3.70 g, 15 mmol) in THF
(60 mL) at -78 °C. The mixture was stirred at -78 °C for 40
min; a solution of 1,3-dichloroacetone (1.27 g, 10 mmol) in
THF (5 mL) was added rapidly. After which, the mixture was
stirred for 10 min at -78 °C, and quenched by addition of
aqueous acetic acid solution (10%, 1 mL). The mixture was
worked up as usual to give the title compound (2.06 g, 90%
yield). Oil; TLC (EtOAc/hexane (1:9)) Rf = 0.21; IR (neat)
1.0 g, 4.0 mmol) in DMF (5 mL) was added dropwise. The
mixture was heated at reflux for 16 h and cooled. Water (100
mL) was added, and the mixture was extracted with EtOAc (3
´ 50 mL). The combined organic phase was dried (Na2SO4)
and concentrated in vacuo. The residue was chromato-
graphed on a silica gel column by elution with MeOH/CH2Cl2
(5:95) to give the title compound. Recrystallization from
EtOAc/hexane gave white solids (890 mg, 70% yield), mp
138.5-140 °C (lit.4 mp 138-140 °C).
TLC (MeOH/CH2Cl2 (5:95)) Rf = 0.23; IR (KBr) 3126,
1
1
3439, 3057, 2963, 2233, 1041 cm-1; H NMR (200 MHz,
1618, 1503, 1422, 1278, 1140, 967, 678 cm-1; H NMR
CDCl3) d 3.13 (1H, s), 3.85 (4H, s), 7.29-7.32 (3H, m),
7.42-7.47 (2H, m); MS m/z (rel intensity) 228 (5, M+), 211
(1), 179 (100), 115 (80), 77 (30); HRMS calcd for
C11H1035Cl2O (M+) 228.0109; found m/z 228.0107.
(CDCl3, 300 MHz) d 4.43 (2H, d, J = 14.3 Hz), 4.72 (2H, d, J
= 14.3 Hz), 5.51 (1H, s), 6.68-6.82 (2H, m), 7.34-7.44 (1H,
1
m), 7.81 (2H, s), 8.02 (2H, s); H NMR (acetone-d6, 200
MHz) d 4.65 (2H, d, J = 14.3 Hz), 4.95 (2H, d, J = 14.3 Hz),
6.85-6.90 (2H, m), 7.26-7.37 (1H, m), 7.80 (2H, s), 8.35 (2H,
s); 13C NMR (CDCl3, 75 MHz) d 54.8, 54.9, 75.3, 103.9,
104.3, 104.6, 112.0, 112.3, 130.1, 144.6, 151.9. Anal. Calcd.
for C13H12F2N6O: C, 50.98; H, 3.95; N, 27.44. Found: C,
51.20; H, 4.10; N, 27.07.
1,3-Dichloro-2-(2,4-difluorophenyl)-2-propanol (2d)5a,c
A sample of CeCl3·7 H2O (2.44 g, 6.53 mmol) was dried
at 140 °C in vacuo for at least 3 h, and then cooled under an
argon atmosphere. Anhydrous THF (32.5 mL) was added,
and the suspension was stirred for at least 4 h before use. Un-
der an atmosphere of argon, a solution of 1-bromo-2,4-di-
fluorobenzene (1.21 g, 6.0 mmol) in THF (5 mL) was stirred
at -78 °C, and butyllithium (7.5 mmol, 4.9 mL of 1.6 M solu-
tion in hexane) was added dropwise over a period of 10 min.
After the addition was completed, the dark solution was
stirred for 20 min, and then transferred via a Teflon tube un-
der a pressure of nitrogen to the prepared suspension of ce-
rium trichloride (6.53 mmol) in THF at -78 °C. The mixture
was stirred at -78 °C for 1 h, and a solution of 1,3-dichloro-
acetone (0.61 g, 4.81 mmol) in THF (3 mL) was added in one
portion. After which the mixture was stirred for 15 min, and
quenched by addition of aqueous acetic acid (10%, 1 mL).
The mixture was diluted with brine (15 mL), and extracted
with ethyl acetate (3 ´ 20 mL). The combined extracts were
dried (Na2SO4) and filtered. The filtrate was concentrated by
rotary evaporation, and the residue was purified on a silica
gel column by elution with EtOAc/hexane (3:97) to give the
title compound (1.11 g, 96% yield based on 1,3-dichloro-
acetone). Oil; TLC (EtOAc/hexane (3:97)) Rf = 0.27; IR
(neat) 3580 (br), 1568, 1458, 1340, 1215, 988, 878, 707 cm-1;
1H NMR (CDCl3, 200 MHz) d 3.67-3.77 (1H, OH), 3.96 (2H,
d, J = 11.3 Hz), 4.10 (2H, d, J = 11.3 Hz), 6.79-7.57 (3H, m).
2-Chloromethyl-2-phenyloxirane (4a)3b
A mixture of 1,3-dichloro-2-phenyl-2-propanol (2a,
385 mg, 1.8 mmol) and t-BuOK (430 mg, 3.6 mmol) in
t-BuOH (10 mL) was stirred at room temperature for 30 min.
After removal of solvent under reduced pressure, the residue
was taken up with EtOAc (20 mL) and washed with brine (2 ´
5 mL). The organic phase was dried (Na2SO4), concentrated,
and chromatographed on a silica gel column by elution with
EtOAc/hexane (5:95) to give the title compound (278 mg,
92%). Oil; TLC (EtOAc/hexane 5:95)) Rf = 0.25; IR (neat)
3061, 2992, 1254, 1071 cm-1; 1H NMR (200 MHz, CDCl3) d
2.90 (1H, d, J = 5.2 Hz), 3.18 (1H, d, J = 5.2 Hz), 3.80 (1H, d,
J = 12.0 Hz), 4.07 (1H, d, J = 12.0 Hz), 7.32-7.45 (5H, m); 13C
NMR (50 MHz, CDCl3) d 47.8, 55.1, 59.1, 126.1, 128.0 (2 ´),
128.3 (2 ´), 136.5; MS m/z (rel intensity) 168 (7, M+), 133
(40), 104 (100); HRMS calcd for C9H9ClO (M+) 168.0341;
found m/z 168.0347.
2-Chloromethyl-2-(phenylethynyl)oxirane (4c)
The reaction of 1-chloro-2-(chloromethyl)-4-phenyl-
3-butyn-2-ol (2c, 684 mg, 3 mmol) with t-BuOK (672 mg, 6
mmol) in t-BuOH, by a procedure similar to that for 4a, gave
oxirane 4c (530 mg) in 90% yield. Oil; TLC (EtOAc/hexane
(1:99)) Rf = 0.14; IR (neat) 3058, 2236, 1488 cm-1; 1H NMR
(300 MHz, CDCl3) d 3.03 (1H, d, J = 5.3 Hz), 3.18 (1H, d, J =
5.3 Hz), 3.72 (2H, s), 7.28-7.30 (3H, m), 7.44-7.46 (2H, m);
13C NMR (75 MHz, CDCl3) d 47.2, 50.3, 54.1, 84.3 (2 ´),
121.2, 128.1 (2 ´), 128.8 (2 ´), 131.7; MS m/z (rel intensity)
Fluconazole (3)4
A mixture of 1,2,4-triazole (602 mg, 8.7 mmol) and po-
tassium carbonate (1.2 g, 8.7 mmol) in DMF (25 mL) was
heated at reflux for 1 h under a nitrogen atmosphere. A solu-
tion of 1,3-dichloro-2-(2,4-difluorophenyl)-2-propanol (2d,

930 J. Chin. Chem. Soc., Vol. 50, No. 4, 2003
Chen and Fang
192 (25, M+), 162 (35), 127 (100); HRMS calcd for
J = 5.3 Hz), 3.99 (1H, dd, J = 12.5, 8.6 Hz), 4.10 (1H, dd, J =
12.5, 3.8 Hz), 7.28-7.40 (5H, m); 13C NMR (50 MHz, CDCl3)
d 52.4, 60.4, 63.0, 125.9, 128.0 (2 ´), 128.4 (2 ´), 137.0; MS
m/z (rel intensity) 150 (10, M+), 133 (75), 91 (100); HRMS
calcd for C9H10O2 (M+) 150.0680, found m/z 450.0676.
C11H935ClO (M+) 192.0341; found m/z 192.0331.
3-Chloro-2-phenyl-1,2-propanediol (5a)6c
A solution of 2-chloromethyl-2-phenyloxirane (4a, 204
mg, 1.9 mmol) and concentrated H2SO4 (0.5 mL) in CH3CN
(20 mL)/water (10 mL) was heated at reflux for 2 h. After re-
moval of CH3CN under reduced pressure, the residue was ex-
tracted with EtOAc (2 ´ 10 mL). The organic phase was
washed with saturated aqueous NaHCO3, dried (Na2SO4),
and chromatographed on a silica gel column by elution with
EtOAc/hexane (3:7) to give diol 5a (148 mg, 80%). Oil; TLC
(EtOAc/hexane (3:7)) Rf = 0.12; IR (neat) 3355, 2929, 1444,
1044, 763 cm-1; 1H NMR (200 MHz, CDCl3) d 2.72 (1H, br s),
3.38 (1H, br s), 3.78 (1H, br s), 3.79 (1H, br s), 3.87 (1H, d, J
= 11.4 Hz), 3.95 (1H, d, J = 11.4 Hz), 7.30-7.46 (5H, m); 13C
NMR (50 MHz, CDCl3) d 50.6, 67.7, 76.3, 125.4, 127.9 (2 ´),
128.4 (2 ´), 140.5; MS m/z (rel intensity) 186 (1, M+), 155
(100); HRMS calcd for C9H1135ClO2 (M+) 186.0447, found
m/z 186.0440.
ACKNOWLEDGMENT
We thank the National Science Council for financial
support.
Received December 4, 2002.
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2-Hydroxymethyl-2-phenyloxirane (6a)6c
A mixture of 3-chloro-2-phenyl-1,2-propanediol (5a,
185 mg, 1 mmol) and K2CO3 (1.4 mg) was stirred in MeOH (6
mL) at room temperature for 8 h. The mixture was filtered,
and the filtrate was concentrated under reduced pressure. The
residue was chromatographed on a silica gel column by elu-
tion with EtOAc/hexane (2:8) to give glycidol 6a (130 mg,
90%). Oil; TLC (EtOAc/hexane (2:8)) Rf = 0.18; IR (neat)
1
3389, 3058, 1491, 1440, 1040 cm-1; H NMR (300 MHz,
CDCl3) d 2.20 (1H, br s), 2.82 (1H, d, J = 5.3 Hz), 3.27 (1H, d,