Synthesis of cholesteryl esters of heterocyclic analogs of cinnamic acid and hetaroyloxycinnamic acids by the Wittig reaction

Article abstract of DOI:10.1023/A:1022693427914

The reaction of cholesteryl triphenylphosphonioacetate chloride with heterocyclic aldehydes and hetaroyloxyarenecarbaldehydes in the presence of base gave the corresponding cholesteryl esters of substituted propenoic acids possessing liquid crystal proper

Full text of DOI:10.1023/A:1022693427914

Chemistry of Heterocyclic Compounds, Vol. 38, No. 12, 2002
SYNTHESIS OF CHOLESTERYL ESTERS
OF HETEROCYCLIC ANALOGS OF CINNAMIC
ACID AND HETAROYLOXYCINNAMIC
ACIDS BY THE WITTIG REACTION
V. N. Listvan, V. V. Listvan, and A. N. Shekel'
The reaction of cholesteryl triphenylphosphonioacetate chloride with heterocyclic aldehydes and
hetaroyloxyarenecarbaldehydes in the presence of base gave the corresponding cholesteryl esters of
substituted propenoic acids possessing liquid crystal properties.
Keywords: heterocyclic aldehydes, liquid crystals, cinnamic acid, α,β-unsaturated acids, triethylamine,
phosphonium salts, phosphorylides, cholesteryl esters, acylation, Wittig reaction.
Cholesteryl esters of cinnamic, p-nitrocinnamic, and several other α,β-unsaturated acids are
manufactured for use as liquid crystals. Interest in these compounds is based on their thermodynamically stable
high-temperature mesophase [1]. The presence of double bonds, especially, conjugated bonds, favors the
formation of the cholesteric mesophase [2]. Various workers have sought new and effective compounds in this
class [3-6].
In previous work [7], we showed that cholesteryl triphenylphosphonioacetate chloride (1) is a suitable
synthone for the preparation of cholesteryl esters of α,β-unsaturated acids and may be readily converted to
alkylidenephosphorane 2. In the present work, this salt was used for the preparation of cholesteryl esters of
heterocyclic analogs of cinnamic acid and heteroaroyloxycinnamic acids from the corresponding
heterocarbaldehydes 3a-g and hetaroyloxyarenecarbaldehydes 4a-c. The synthesis of 4a-c will be given below.
The Wittig reaction between alkylidenephosphorane 2 formed from salt 1 by the action of triethylamine and
aldehydes 3 and 4 is carried out under mild conditions at room temperature. Heating is required in only a few
cases to dissolve aldehydes with low solubility.
Lower alcohols – ethanol and 2-propanol are convenient solvents for this reaction. The starting
phosphonium salt is readily soluble in these alcohols, while the resultant cholesteryl esters 5a-g and 6a-c form a
precipitate (see Table 1). The crystallization of these esters usually begins 1-5 min after adding triethylamine to
the solution of salt 1 and aldehyde.
Triethylamine proved a sufficiently strong base for the conversion of triphenylphosphonium salt 1 into
alkylidenephosphorane 2, which then reacts with aldehydes. The reaction proceeds less rapidly when a weaker
→
base – pyridine is used. The reversible equilibrium 1
2 is obviously considerably shifted toward the
←
phosphonium salt by the action of pyridine. However, the reaction may be accomplished also in the presence of
pyridine in the case of sufficiently active aldehydes such as, for example, 5-nitro-2-thiophenecarbaldehyde 3b.
The reactivity of 3b relative even to stable alkylidenephosphoranes is so high that it was recommended for the
__________________________________________________________________________________________
Zhitomir State Pedagogical University, 10008 Zhitomir, Ukraine. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 12, pp. 1678-1681, December, 2002. Original article submitted July 10,
2000, submitted after revision April 24, 2001.
1480
0009-3122/02/3812-1480$27.00©2002 Plenum Publishing Corporation

qualitative determination of this class of compounds [8, 9]. The reaction of aldehyde 3b with salt 1 in the
presence of pyridine is complete after several hours and product 5b separates out as a greenish yellow
precipitate.
Et3N
+
[Ph3P–CH2–COOChol] Cl–
Ph3P=CH–COOChol
– HCl
1
2
O
Me
Me
R–CHO 3a–g / 4a–c
Me
RCH=CHC
–Ph3PO
Me
OChol
5a–g, 6a–c
Me
Chol =
e R =
c R =
b R =
O2N
d R =
5 a R =
Br
S
S
O
N
N
O
g R =
6 a R =
f R =
O
O
O
Ph
O
Cl
N
O
O
b R =
c R =
O
N
O
Me
Aldehydes 4a-c required for the synthesis of esters of hetaroyloxycinnamic acids 6a-c were obtained by
the reaction of furancarboxylic or nicotinic acid chlorides with p-hydroxybenzaldehyde or vanillin in the
presence of triethylamine (4a,b) or pyridine (4c).
O
Het
O
C6H5N
– HCl
HO
CHO
CHO
O
Het–C
+
Cl
R1
R1
4a–c
a, c Het =
, b Het =
a, b R1 = H, c R1= MeO
,
O
N
Esters 5a-g and 6a-c are obtained predominantly as the trans isomers, sometimes with a slight
admixture of the cis isomer. The products are purified to remove the cis isomer by single crystallization. These
esters form a high-temperature mesophase at 140-200°C, while esters 5c and 5d form blue phase.
EXPERIMENTAL
1
The H NMR spectra were obtained on a Varian VXR-300 spectrometer with TMS as the internal
standard. The characteristics of 5a-g and 6a-c are given in Table 1.
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TABLE 1. Characteristics of Cholesteryl Esters Synthesized
Found, %
——————
Com-
pound
Empirical
formula
Yield,
%
Calculated, %
mp, °С
C
H
Hal (S)
C34H49BrO3
13.92
13.64
179-180
74
5a
C34H49NO4S
C34H50O2S
C35H51NO2
C35H51NO2
C39H52ClNO2
C40H54O3
(5.43)
144-145
180-181
155-156
141-142
205-206
137-139
190-191
160-161
150-151
82
67
70
83
75
50
70
66
71
5b
5c
5d
5e
5f
(5.65)
(5.87)
(6.13)
81.50
81.19
9.81
9.93
80.18
9.68
81.19
9.93
6.09
5.90
82.97
82.43
9.22
9.34
5g
6a
6b
6c
C41H54O5
79.04
8.89
78.55
8.68
C42H55NO4
C42H56O6
78.75
79.08
8.61
8.69
76.35
8.43
76.78
8.59
Cholesteryl Esters of 3-Hetarylpropenoic Acids (5a-g) (General Method). Hetarylcarbaldehyde 3a-g
(3 mmol) was added to solution of salt 1 (2.2 g, 3 mmol) in 2-propanol or ethanol (20-30 ml). The mixture was
sometimes slightly heated and an additional amount of solvent was added to improve the solubility of
carbaldehyde. After complete dissolution of aldehyde, triethylamine (0.5 ml, 3.5 mmol) was added and
crystallization of ester 5a-g began after 2-5 min. The reaction mixture was maintained for 2-3 h. The precipitate
was filtered off, washed with solvent, dried, and crystallized (in most cases, from heptane).
4-(2-Furoyloxy)benzaldehyde (4a). 2-Furoyl chloride (13.3 g, 0.102 mol), a strong lacrimator, was
added to solution of 4-hydroxybenzaldehyde (12.2 g, 0.1 mol) in dry dioxane (60 ml). Triethylamine (14.2 ml,
0.103 mol) was added to the stirred solution dropwise with ice water cooling over 45 min. Anhydrous pyridine
may also be used. Triethylammonium chloride separates out as a precipitate. The reaction mixture was stirred
for an additional 15 min and left in a sealed flask at room temperature for several hours. Then, cold water
(50 ml) was added in portions with shaking. Ammonium salt gradually dissolved and product 4a began to
precipitate out. The reaction mixture was maintained for several hours for complete crystallization of the
product, which was then filtered and washed with 1:1 aqueous dioxane and a small amount of ethanol. Yield of
compound 4a 18-19.5 g (85-90%). When the starting reagents were sufficiently pure, aldehyde 4a was obtained
1
as a pure product. When necessary, the crude product was crystallized from ethanol; mp 95°C. H NMR
spectrum (DMSO-d6), δ, ppm: 9.88 (1H, s, CHO); 8.02 (2H, m, 2-, 6-H in C6H4); 7.43 (1H, m, 5-HFur); 7.13 (2H,
m, 3-, 5-H in C6H4); 6.90 (1H, m, 3-HFur); 6.40 (1H, m, 4-HFur). Found, %: C 67.02; H 3.87. C12H8O4.
Calculated, %: C 66.66; H 3.73.
4-Nicotinoyloxybenzaldehyde (4-Formylphenyl-3-pyridinecarboxylate) (4b) was obtained in 68%
yield from 4-hydroxybenzaldehyde and nicotinic acid chloride analogously to aldehyde 4a; mp 93-94°C.
1H NMR spectrum (DMSO-d6), δ, ppm: 10.04 (1H, s, CHO); 9.28 (1H, s, HHet); 8.92 (1H, m, HHet); 8.47 (1H, m,
HHet); 8.03 (2H, m, C6H4); 7.65 (1H, m, HHet); 7.60 (2H, m, C6H4). Found, %: N 6.30. C13H9NO3. Calculated, %:
N 6.16.
4-(2-Furoyloxy)-3-methoxybenzaldehyde (4c). 2-Furoyl chloride (10 ml) in dry ether (20 ml) was
added dropwise over 1 h to stirred solution of vanillin (15.2 g, 0.1 mol) in dry ether (300 ml) and pyridine
(10 ml) cooled with ice water. The reaction mixture was stirred for an additional hour at room temperature and
then maintained at this temperature for several hours. The precipitate consisting of pyridinium chloride and
1482

most of product 4c was filtered off and washed consecutively with ether and several water portions with good
stirring. Pyridinium salt was washed out and virtually pure product 4c remained. After distilling of most of ether
(to a volume of 20-30 ml), an additional small amount of pure product 4c precipitated out of the ethereal filtrate.
When necessary, crude product 4c was crystallized from 2-propanol. Yield of aldehyde 4c 80%; mp 103-104°C.
1H NMR spectrum (CDCl3), δ, ppm: 9.87 (1H, s, CHO); 7.64 (1H, m, C6H3); 7.61 (1H, m, C6H3); 7.44 (1H, m,
HFur); 6.97 (1H, m, C6H3); 6.88 (1H, m, HFur); 6.40 (1H, m, HFur); 3.82 (3H, s, CH3). Found, %: C 62.93; H 4.22.
C13H10O5. Calculated, %: C 63.42; H 4.09.
Cholesteryl Ester of 4-(2-Furoyloxy)cinnamic Acid (6a). Triethylamine (0.5 ml, 3 mmol) was added
to solution of salt 1 (2.2 g, 3 mmol) and aldehyde 4a (0.64 g, 3 mmol) in 2-propanol (30 ml). Product 6a
crystallized out over 2-3 min and was filtered off after 2 h. The product was washed with 2-propanol, dried, and
crystallized from CCl4.
Cholesteryl Ester of 4-Nicotinoyloxycinnamic Acid (6b). Triethylamine (0.5 ml) was added to
solution of salt 1 (3 mmol) and aldehyde 4b (3 mmol) in 2-propanol (25 ml). Product 6b began to crystallize out
immediately and was filtered off after 2 h. The crude product was washed with 2-propanol and recrystallized
1
from heptane. H NMR spectrum (CDCl3), δ, ppm, J (Hz): 9.40 (1H, s, HHet); 8.88 (1H, m, HHet); 7.71 (2H, m,
C6H4); 7.60 (2H, m, C6H4); 7.49 (1H, m, HHet); 6.45 (1H, J = 19.5, =CHCO); 5.42 (1H, m, =CHC6H4); 4.76 (1H,
m, HChol); 2.40-0.69 (44H, m, HChol).
Cholesteryl Ester of 3-Methoxy-4-furoyloxycinnamic Acid (6c). Triethylamine (0.5 ml) was added to
solution of salt 1 (2.2 g, 3 mmol) and aldehyde 4c (0.65 g, 3 mmol) in 2-propanol (30 ml). A precipitate of
product 6c began to form during the first 5 min and was filtered off after 3 h. The crude product was dried and
1
crystallized from heptane. H NMR spectrum (CDCl3), δ, ppm, J (Hz): 7.68 (1H, m, HFur); 7.4 (1H, J = 7.3,
HFur); 7.16 (3H, m, C6H3); 6.60 (1H, m, HFur); 6.44 (1H, J = 19.2, =CHCO); 5.42 (1H, m, =CHC6H3); 4.76 (1H,
m, HChol); 3.86 (3H, s, OCH3); 2.40-0.69 (44H, m, HChol).
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