Preparation of some alkenoic acid derivatives as new plant growth regulators

Article abstract of DOI:10.1007/s11164-013-1315-9

A number of 3-alkoxy-5-substituted-2,4-alkadienoic acids (4a-f) have been synthesized from the reaction of ethyl (E)-3-alkoxy-2-butenoate with different ketones in the presence of KOH in DMSO. Similarly, several (2Z,4E)-5-[4-(benzylthio)phenyl]-3-alkoxyhe

Full text of DOI:10.1007/s11164-013-1315-9

Res Chem Intermed
DOI 10.1007/s11164-013-1315-9
Preparation of some alkenoic acid derivatives as new
plant growth regulators
•
Kayed A. Abu Safieh Ala’a K. Hasan
•
•
Mikdad T. Ayoub Mohammad S. Mubarak
Received: 11 May 2013 / Accepted: 12 June 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract A number of 3-alkoxy-5-substituted-2,4-alkadienoic acids (4a–f) have
been synthesized from the reaction of ethyl (E)-3-alkoxy-2-butenoate with different
ketones in the presence of KOH in DMSO. Similarly, several (2Z,4E)-5-[4-(ben-
zylthio)phenyl]-3-alkoxyhexa-2,4-dienoic acids were prepared via condensation of
ethyl (E)-3-alkoxy-2-butenoate with 4-(benzylthio)acetophenone in the presence of
KOH in DMSO. The structures of all synthesized compounds were confirmed by IR,
1H NMR, 13C NMR, and MS spectra and by elemental analysis.
Keywords 2,4-Alkadienoic acids ꢀ Ethyl (E)-3-alkoxy-2-butenoate ꢀ KOH/DMSO ꢀ
Plant growth regulators
Introduction
Pentadienoic acids (PDAs) and hexanedienoic acids (HDAs) have attracted
considerable interest in recent years due to their relationship with the important
plant hormone abscisic acid (ABA) (1) and the presence of a diene system in their
molecules. In this respect, it is worth mentioning that abscisic acid, which is the most
common 2,4-pentadienoic acid, isolated from the young cotton fruit [1], has been
employed as plant antitranspirant [2]. Some other related compounds have been used
as antioxidants [3] and as effective plant hormones to inhibit rice germination [4, 5].
Other PDA derivatives exhibit a wide spectrum of pharmacological effects and have
several useful industrial applications. Some PDA compounds are used in medicinal
K. A. Abu Safieh (&) ꢀ A. K. Hasan ꢀ M. T. Ayoub
Chemistry Department, Science Faculty, Hashemite University, P.O. Box 330127, Zarqa 13133,
Jordan
e-mail: kayedas@hu.edu.jo
M. S. Mubarak
Department of Chemistry, The University of Jordan, Amman 11942, Jordan
123

K. A. Abu Safieh et al.
chemistry as antidiabetic agents with a high serum glucose-reducing activity [6, 7],
while others are employed as hyperuricemia agents to reduce plasma uric acid levels
[8], useful in the treatment of liver disorder [9], and have retinoid-like biological
activity [10, 11]. Moreover, other derivatives are useful in industry as adhesive
compounds [12, 13], and sunscreens [14]. In addition, some PDAs are used as plant
growth regulators [15].
Alternatively, some derivatives are used as ultraviolet light absorbents in cosmetic
manufacturing and in skin disease therapy [16, 17], while others are important in
chemotherapy for the treatment of inflammations, atherosclerosis, restenosis, and
immune disorders such as arthritis, transplant rejection [18], and antimalarial agents
[19]. Also, other PDAs are used as starting materials for the manufacturing of
penicillin [20]. Furthermore, some of these acids show antitranspirant activity either
as free acids [21] or when applied as sodium or ammonium salts [22]. Nanzyo and
co-workers reported that some PDA derivatives have a growth inhibitory activity on
rice seedings [23], whereas amide derivatives of pentadienoic acid have been used as
antagonists of platelet activating factor [24], antiallergic agents [25], as bactericides
and fungicides [26, 27], to inhibit microbial growth storage in mango pulp [28], and
to prevent the excessive bone resorption associated with osteoporosis [29–31], or as
blood platelet aggregation inhibitors [32].
HDAs, on the other hand, exhibit a wide range of biological activities. It has been
reported that some HDA derivatives have been used as antimicrobial agents [33],
insecticidal [34], while others were used in chemotherapy and showed good
antiproliferative properties [35]. Sorbic acid (2) (Fig. 1) is one of the most common
2,4-hexadienoic acids with interesting biological activities, was first isolated from
unripe berries of Rowan (Sorbus aucuparia), and has been used as a food
preservative [36]. Some sorbic acid derivatives showed a wide range of
antimicrobial activities against spoilage bacteria [36], while others are used in the
food industry as preservatives [37], and as effective antifungal agents [38].
The biological importance of alkenoic acids has stimulated an intensive research
work for the synthesis of many new derivatives [4]. In addition to being present in
various naturally occurring compounds with a wide range of biological and
pharmaceutical activities, these acids have also been shown, in many cases, to serve
as effective synthons in the construction of a wide variety of interesting molecules
[39]. The high cost resulting from a long and difficult synthesis of alkenoic acids as
plant growth regulators [40] prompted researchers to develop new methods for the
CO2H
CO2H
(B)
O
(A)
Fig. 1 Abscisic acid (A) and Sorbic acid (B) structures
123

Preparation of alkenoic acid derivatives
synthesis of these important molecules. The reaction of phosphorous, arsenic, or
tellurium ylides with some aldehydes and ketones afforded the corresponding
alkenoic acids through Wittig-type reactions [41–43]. In addition, synthesis of some
alkenoic acids has been achieved through Stille coupling, Reformatsky, and
Vilsmeier Haak reactions [44, 45]. Similarly, condensation of ethyl (2E)-3-
alkoxybut-2-enoate (3a and 3b) with carbonyl compounds, mainly aldehydes, in
tellurium ylidespresence of several bases, such as sodium hydride [46], lithium
diisopropylamide (LDA) [47], and lithium or sodium amide [48, 49], has been used
to prepare some of these acids. In view of the wide interest in the chemistry of
alkenoic acids, and within the framework of research related to the chemistry of
synthesis of ethyl (2E)-3-alkoxybut-2-enoate (1a and 1b), the synthesis and
characterization of a number of new alkenoic acid derivatives with expected
biological activities are discussed.
Experimental
Materials and equipments
All chemicals used were obtained from commercial sources and were used as
received without further purification. Progress of reactions was monitored by thin
layer chromatography (TLC) using glass plates pre-coated with silica gel (Merck
Kiesegel 60 F254 layer thickness 0.25 mm). Melting points were measured on a
Stuart scientific melting point apparatus in open capillary tubes. Infrared spectra
(IR) were obtained, as potassium bromide (KBr) discs, on Nicolet-MAGNA-IR-560
spectrophotometer; only characteristic peaks are indicated in wave number (cm-1).
1H and 13C NMR spectra were acquired with the aid of a Bruker DPX 300 MHz
spectrometer (Germany) with DMSO-d6 as solvent and TMS as the internal standard.
Peak multiplicities of the signals are abbreviated as follows: s-singlet, d-doublet,
t-triplet, q-quartet, and m-multiplet. Chemical shifts are expressed in d units; J values
1
for H–1H coupling constants are given in Hertz. High resolution mass spectra
(HRMS) were obtained using an electrospray ion trap (ESI) technique by collision-
induced dissociation on a Bruker APEX-4 (7-Tesla) instrument (Bremen, Germany).
The samples were dissolved in acetonitrile, diluted in spray solution (methanol/water
1:1 v/v ?0.1 % formic acid), and infused using a syringe pump with a flow rate of
2 mL min-1. External calibration was conducted using an arginine cluster in a mass
range m/z 175–871. Elemental analyses were performed on a Euro-Vector Euro, C,
H, N, and S elemental analyzer (EA3000); the obtained results agreed with the
calculated percentages to within 0.4 %. Compounds were checked for their purity
by TLC using glass plates, precoated with silica gel 60 GF254, supplied by Fluka.
General procedure for preparation of ethyl (2E)-3-alkoxybut-2-enoate
(3a and 3b)
Compounds 3a and 3b were synthesized and purified according to the general
procedure described by Mubarak and co-workers which involves reacting ethyl
123

K. A. Abu Safieh et al.
acetoacetate (1) (19.5 g, 0.15 mol) with each of trimethyl orthoformates (2a) and
with triethyl orthoformates (2b) (0.15 mol) in methanol (15 mL). Concentrated
hydrochloric acid HCl (0.07 mL) was added, and the mixture was immediately
distilled to give ethyl (2E)-3- methoxyoxybut-2-enoates (3a) and ethyl (2E)-3-
ethoxyoxybut-2-enoates (3b) [50].
Ethyl (2E)-3-methoxybut-2-enoate (3a)
Yield: 21.0 g, 96 %; b.p. = 182–192 °C, (lit. 188–196 °C) [39].
Ethyl (2E)-3-ethoxybut-2-enoate (3b)
Yield: 21.3 g, 91 %; b.p. = 186–195 °C, (lit. 193–196 °C) [39].
General procedure for preparation of 3-alkoxy-5-substituted-2,4-alkadienoic
acids (4a–f)
Compounds 4a–f were synthesized and purified according to the following general
procedure. To a solution of (10.0 mol) of each of ethyl (2E)-3-methoxybut-2-
enoates (3a) and ethyl (2E)-3-ethoxybut-2-enoates (3b) in 5.0 mL of dimethyl
sulphoxide (DMSO) were added 10.0 mmol of the corresponding ketone and 0.56 g
(10.0 mmol) of potassium hydroxide. The mixture was heated for 4–6 h at 100 °C;
completion of the reaction was checked by TLC with dichloromethane, DCM or
(hexane/ethyl acetate) as eluents. After cooling, the mixture was diluted with water
and the by-products were extracted with diethyl ether. The aqueous layer was
acidified with dilute hydrochloric acid and the precipitated product was filtered,
washed with water, and dried to give the desired products. The following
compounds were synthesized according to the afroementioned general procedure.
(2Z)-3-Methoxy-5,5-diphenylpenta-2,4-dienoic acid (4a)
Yield: 1.12 g, 40 %; m.p. 157–159 °C. IR (KBr): 3,444, 2,936, 1,680, 1,608, 1,550,
1
1,183 cm-1. H NMR (DMSO-d6): d 3.23 (s, 3H), 5.13 (s, 1H), 7.34 (m, 11 H),
11.72 (s, 1H) ppm. 13C NMR (DMSO-d6): d 55.5, 94.9, 121.6, 127.8, 128.1, 128.3,
128.8, 129.3, 129.6, 140.6, 142.4, 147.5, 167.7, 168.3 ppm. HRMS m/z: [M ? Na]?
calcd. for C18H16NaO3 303.09994; found: 303.09917. Anal. calcd. for C18H16O3: C,
77.12; H, 5.75. Found: C, 77.44; H, 5.82.
(2Z,4E)-3-Methoxy-5-phenylhexa-2,4-dienoic acid (4b)
Yield: 0.92 g, 42 %; m.p. 166–168 °C. IR (KBr): 3,446, 2,929, 1,685, 1,624, 1,567,
1
1,202 cm-1. H NMR (DMSO-d6): d 2.24 (s, 3H), 3.71 (s, 3H), 5.16 (s, 1H), 7.82
(m, 6H), 11.5 (s, 1H) ppm. 13C NMR (DMSO-d6): d 18.7, 55.8, 94.0, 115.5, 120.7,
128.4, 128.5, 139.9, 142.4, 168.2, 168.3 ppm. HRMS m/z: [M ? Na]? calcd. for
C13H14NaO3 241.08406; found: 241.08367. Anal. calcd. for C13H14O3: C, 71.54; H,
6.47. Found: C, 71.88; H, 6.62.
123

Preparation of alkenoic acid derivatives
(2Z,4E)-3-Methoxy-5-(4-methylphenyl) hexa-2,4-dienoic acid (4c)
Yield: 0.93 g, 41 %; m.p. 158–160 °C. IR (KBr): 3,444, 2,917, 1,671, 1,623, 1,564,
1,175 cm-1. 1H NMR (DMSO-d6): d 2.24 (s, 3H), 2.50 (s, 3H), 3.71 (s, 3H), 5.13 (s,
1 H), 7.19 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.26 (s, 1H), 11.3 (s, 1H)
ppm. 13C NMR (DMSO-d6): d 18.6, 21.1, 55.8, 93.7, 119.9, 126.3, 129.4, 137.9,
140.6, 143.5, 168.2, 168.6 ppm. HRMS m/z: [M ? Na]? calcd. for C14H16NaO3
255.09995; found 255.09917. Anal. calcd. for C14H16O3: C, 72.39; H, 6.94. Found:
C, 72.31; H, 7.20.
(2Z)-3-Ethoxy-5,5-diphenylpenta-2,4-dienoic acid (4d)
Yield: 0.97 g, 33 %; m.p. 159–161 °C. IR (KBr): 3,425, 2,929, 1,668, 1,614, 1,557,
1
1,181 cm-1. H NMR (DMSO-d6): d 0.56 (t, J = 6.8 Hz, 3H), 3.52 (q, J = 6.6,
13.4 Hz, 2H), 5.12 (s, 1H), 7.24 (m, 11 H), 11.68 (s, 1H) ppm. 13C NMR (DMSO-d6):
d 13.5, 3.7, 95.0, 121.6, 127.6, 128.1, 128.2, 128.9, 129.2, 129.5, 141.1, 142.3,
147.7, 166.9, 168.4 ppm. HRMS m/z: [M ? Na]? calcd. for C19H18NaO3
317.11559; found: 317.11482. Anal. calcd. for C19H18O3: C, 77.53; H, 6.16.
Found: C, 77.11; H, 6.17.
(2Z,4E)-3-Ethoxy-5-phenylhexa-2,4-dienoic acid (4e)
Yield: 1.18 g, 51 %; [m.p 144–146 °C. IR (KBr): 3,445, 2,990, 1,668, 1,618, 1,558,
1,191 cm-1. 1H NMR (DMSO-d6): d 1.36 (t, J = 6.8 Hz, 3H), 2.29 (s, 3H), 3.94 (q,
J = 6.7, 13.7 Hz, 2H), 5.17 (s, 1H), 7.68 (m, 6 H). 11.60 (s, 1H) ppm. 13C NMR
(DMSO-d6): d 14.5, 18.6, 64.2, 94.2, 120.8, 126.5, 128.4, 128.8, 143.6, 143.7,
167.6, 168.5 ppm. HRMS m/z: [M ? Na]? calcd. for C14H16NaO3 255.09995;
found: 255.09917. Anal. calcd. for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.42;
H, 7.00.
(2Z,4E)-3-Ethoxy-5-(4-methylphenyl) hexa-2,4-dienoic acid (4f)
Yield:1.0 g, 41 %; [m.p. 160–162 °C. IR (KBr): 3,446, 2,923, 1,681, 1,620, 1,559,
1,198 cm-1. 1H NMR (DMSO-d6): d 1.43 (t, J = 6.3 Hz, 3H), 2.27 (s, 3H), 2.30 (s,
3H), 3.91 (q, J = 6.7, 13.5 Hz 2H), 5.11 (s, 1H), 7.18 (d, J = 7.3 Hz, 2H), 7.38 (d,
J = 7.2 Hz, 2H), 7.31 (s, 1H), 11.55 (s, 1H) ppm. 13C NMR (DMSO-d6): d 14.5,
18.6, 21.0, 64.1, 93.9, 120.0, 126.3, 129.4, 137.8, 140.8, 143.6, 167.8, 168.3 ppm.
HRMS m/z: [M ? Na]? calcd. for C15H18NaO3 269.11560; found: 269.11482.
Anal. calcd. for C15H18O3: C, 73.15; H, 7.37. Found: C, 73.31; H, 7.32.
Synthesis of 4-(benzylthio)acetophenone (7)
Potassium hydroxide (1.50 g, 26.6 mol) was added to a solution of benzyl thiol (6)
(3.13 mL, 26.6 mmol) in 15.0 mL of ethanol. The mixture was heated to reflux until
123

K. A. Abu Safieh et al.
the KOH had completely dissolved and was then cooled to room temperature. A
solution of 4-fluoroacetophenone (5) (3.25 mL, 26.6 mol) in 15.0 mL of ethanol
was then added drop-wise and the mixture was heated to reflux for 7 h; completion
of reaction was checked by TLC (in DCM). When cooled to room temperature, the
precipitate was filtered and washed with water and recrystallized from ethyl acetate
to afford the desired product, 7, as white needles. Yield: 5.8 g, 90 % Yield; m.p.
112–114 °C (lit. 110–112 °C) [52].
General procedure for preparation of (2Z,4E)-5-[4-(benzylthio)-phenyl]-
3-alkoxyhexa-2,4-dienoic acids (8a, b)
To a solution of (5.0 mmol) of each of 3a and 3b in 3.0 mL of dimethyl sulphoxide
(DMSO) were added (5.0 mmol) of 4-(benzylthio)acetophenone (7) and (0.28 g,
5.0 mol) of potassium hydroxide and the mixture was heated for about 6 h at
100 °C; completion of the reaction was checked by TLC. After cooling, the mixture
was diluted with water and the by-products were removed by extraction with diethyl
ether. The aqueous layer was acidified with dilute HCl and the precipitated product
was filtered, washed with water, and dried to give the desired products. The
following compounds were synthesized according to the above mentioned general
procedure.
(2Z,4E)-5-[4-(Benzylthio)phenyl]-3-methoxyhexa-2,4-dienoic acid (8a)
Yield: 1.16 g, 68 %; [m.p. 140–142 °C. IR (KBr): 3,446, 2,924, 1,678, 135, 153,
1,176 cm-1. 1H NMR (DMSO-d6): d 2.22 (s, 3H), 3.71 (s, 3H), 4.27 (s, 2H), 5.14 (s,
1H), 7.39 (m, 10H), 11.3 (s, 1H) ppm. 13C NMR (DMSO-d6): d 18.4, 36.8, 55.8,
94.0, 120.3, 126.9, 127.5, 128.3, 128.8, 129.2, 136.8, 137.8, 140.7, 142.8, 168.2,
168.4 ppm. HRMS m/z: [M ? Na]? calcd. for C20H20NaO3S 363.10308; found
363.10254. Anal. calcd. for C20H20O3S: C, 70.56; H, 5.92; S, 9.42. Found: C, 70.56;
H, 6.06; S, 9.42. 9.72.
(2Z,4E)-5-[4-(benzylthio)phenyl]-3-ethoxyhexa-2,4-dienoic-acid (8b)
Yield 1.15 g, 65 %; m.p. 139–141 °C. IR (KBr): 3,447, 2,985, 1,680, 137,
1
1,562, 1,198 cm-1. H NMR (DMSO-d6): d 1.33 (t, J = 5.7 Hz, 3H), 2.26 (s,
3H), 3.96 (q, J = 6.7, 13.3 Hz, 2H), 4.27 (s, 2H), 5.15 (s, 1H), 7.33 (m, 10H),
11.58 (s, 1H) ppm. 13C NMR (DMSO-d6): d 14.5, 18.4, 36.8, 64.2, 94.2, 120.3,
126.9, 127.5, 128.3, 128.8, 129.2, 136.8, 137.8, 140.9, 142.8, 168.3, 168.4 ppm.
HRMS m/z: [M ? Na]? calcd. for C21H22NaO3S 377.11896, found: 377.11819.
Anal. calcd. for C21H22O3S: C, 71.16; H, 6.26; S, 9.05. Found: C, 71.30; H,
5.97; S, 8.97.
123

Preparation of alkenoic acid derivatives
Results and discussion
Chemistry
Ethyl (2E)-3-alkoxybut-2-enoate (3a and 3b), required in this study were
efficiently synthesized according to a procedure described by Mubarak and
coworkers [50] (equation 1) which involves the reaction of ethyl acetoacetate (1)
and trialkyl orthoformate (2a and 2b), followed by the addition of concentrated
hydrochloric acid. Immediate distillation of the reaction mixture afforded the
desired product as a mixture of E- and Z- isomers with the E- isomer as the major
product, in excellent yields: 96 % for 3a and 91 % for 3b. Syntheses of 3-alkoxy-
5-substituted-2,4-alkadienoic acids (4a–f) were carried out via the route shown in
Scheme 1. Thus, treatment of 3a or 3b with ketones in DMSO and in the presence
of KOH yielded alkadienoic acids with good yields as depicted in Scheme 1,
presumably through 2-oxo-5,6-dihydro-2H-pyrans as intermediate in the reac-
tion; these intermediates were not isolated but they have been previously reported
[39, 51].
R
O
O
CH(OR)3
(2)
HCl, CH3OH
O
O
O
O
(1)
(3)
(1)
Compounds 2 and 3
a
b
R CH3 CH3CH2
Similarly, 4-(benzylthio)acetophenone (7) was synthesized in 90 % yield through
nucleophilic aromatic substitution reaction SNAr, (addition–elimination mecha-
nism) according to a procedure outlined by Mulder et al. [52] as shown from the
reaction of 40-fluoroacetophenone (5) and benzyl thiol (6) in the presence of KOH.
Treatment of 7 with each of 3a and 3b in DMSO and in presence of KOH gave the
desired products; (2Z,4E)-5-[4-(benzylthio)phenyl]-3-alkoxyhexa-2,4-dienoic acids
(8a and 8b) in moderate yields (65–68 %).
O
O
SH
+
S
F
(5)
(7)
(6)
(2)
123

K. A. Abu Safieh et al.
R
O
O
R
-
O
O
H C
OCH CH
2
2
3
KOH/ DMSO
R
R
1
OCH CH
2
3
O
(3)
2
R
R
R
O
O
O
O
- CH3CH2O-
H
H
-
O
R
R
1
1
R
1
-
O
O
O
R
O
R
OCH CH
2 3
R
OCH CH
2
2
2
2
3
R
R
R
O
R
1
O
1
- H+
HCl
R
R
2
2
CO H
CO -
2
2
(4)
Compounds (4a-f)
a
b
c
d
e
f
R1
CH3
CH3
CH3
CH3
R2
R
H3C
H3C
CH3
CH3CH2
Scheme 1 Preparation of compounds 4a–f
123

Preparation of alkenoic acid derivatives
R
O
O
O
O
O
OH
R
(3a and 3b)
1. KOH/DMSO
2. HCl
+
O
S
(8a and 8b)
S
(7)
(3)
The structures of the prepared compounds were confirmed by NMR, mass
spectrometry, IR, and elemental analysis. These data, detailed in ‘‘Experimental’’,
1
are consistent with the suggested structures. The H and 13C NMR spectra of all
prepared compounds are in total agreement with their assigned structures. DEPT
experiments were employed to differentiate secondary and quaternary carbons from
primary and tertiary ones. Additional supports of the proposed structures come from
mass spectral data. From the mass spectra display, the correct molecular ion peaks
for which the measured high resolution (HRMS) data are in good agreement with
the calculated values as suggested by their molecular formulas. In addition, IR
spectra of the synthesized compounds showed absorption bands corresponding to
the different functional groups present.
Acknowledgment We wish to thank the Hashemite University for financial support.
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