Synthesis and Importance of Oxime...
Transcript of Synthesis and Importance of Oxime...
Chapter 4
Synthesis and Importance of Oxime esters
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Section 4.1: Synthesis of zerumbone oxime fatty acid esters
4.1.1 Introduction
The oxime esters are the group of organic compounds synthesized by
condensation of aldoximes or ketoximes with carboxylic acids. The oxime esters
form a small, but significant, group of active molecules explored for the synthesis of
peptides [1] and fragrances [2]. Oxime esters are also studied for DNA cleavage [3-
5], herbicidal [6], and antitumor activities [7]. Oxime esters serves as an important
intermediates and precursor for the synthesis of heterocyclic compounds that possess
many bioactive properties [8]. The quinoline oxime esters are an important class of
organic molecules both in medicinal and synthetic chemistry. The oxime esters
having quinoline skeleton are having many bioactive properties like anti-HIV, anti-
inflammatory, antitumor, antidepressants, herbicidal, and fungicidal activity [9].
Some of the oxime esters are used in the production of food aromas, perfumes and
also used in alcohol, candy industries [10]. In the field of agrochemicals and
medicine, the oxime esters and their derivatives are drawing the attention of the
researchers due to their potential bioactive attributes [11-13]. Oxime esters of
dihydrocumic acid possess excellent antibacterial activity against Gram positive and
Gram negative bacteria [14]. Owing to the importance of oxime esters in perfumery
and medicinal field, we were interested in utilizing the oxime functionality present in
the zerumbone oxime and prepare its esters with range of carboxylic acids. Also,
interested in assaying the bioactivity attributes of synthesized oxime esters and
establish the structure-activity relationship of zerumbone oxime fatty acid esters.
The oxime esters are prepared (Scheme 4.1.1) by condensation of oximes with
acid chlorides in basic condition or by acid anhydrides in the presence of strong acids
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[4, 5, 10, 15]. The substrates that are unstable under strongly acidic or basic condition
are seldom used in these methods. There is also an additional step for the preparation
of acid chlorides from carboxylic acids. The acid chlorides are also unstable and need
to be handled under anhydrous conditions.
NOH
+ R
O
Cl
NO R
OBase
NOH
+ R O
ON
O R
OAcidR
O
Scheme 4.1.1: General methods of synthesis of oxime esters
In the present study, we report the synthesis of zerumbone oxime fatty acid
esters (ZOFA) by a new facile protocol. Molecules were synthesized by reacting
zerumbone oxime with fatty acids using EDCI reagent in high yield [16]. The fatty
acids from C4 to C18 chain lengths were selected for the study. An aromatic acid like
benzoic acid was also included in the study. The ZOFA's were screened for their
antibacterial potential against four foodborne pathogenic bacteria such as Bacillus
cereus, Staphylococcus aureus, Escherichia coli and Yersinia enterocolitica. The
anti-mutagenic study of ZOFA was also carried out on Salmonella typhimurium tester
strains (TA 98 and TA 1538) by Ames test. The bioactivity attributes of ZOFA are
discussed in Chapter 5.
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4.1.2 Experimental
4.1.2.1 Preparation of zerumbone oxime
(1Z,2E,6E,10E)-2,6,9,9-tetramethylcycloundeca-2,6,10-trienone oxime
In a 50 mL RB flask, zerumbone (20 mmol, 4.36 g) was taken with 60 mL
ethanol. To this solution, hydroxylamine hydrochloride (13.9 g, 0.2 mol) and
anhydrous K2CO3 (27.6 g, 0.2 mol) were added slowly. The mixture was stirred at
room temperature until the completion of reaction. The progress of the reaction was
monitored by TLC. After completion of the reaction, the mixture was filtered, and the
residue was washed with ethanol. The filtrate was concentrated under reduced
pressure, and the concentrated mass was taken in DCM (30 mL). The DCM layer was
washed with water (3×30 mL) followed by brine solution (30 mL), and traces of water
were removed by adding anhydrous Na2SO4. The clear solution was concentrated to
get a pure product, which was taken for next step. The spectral characterization data
are presented below.
White solid, yield: 4.21 g (90%), m.p. 172-174 °C; 1H NMR (500 MHz,
DMSO-d6): δ = 10.56 (bs, 1H, N-OH), 6.14 (d, 1H, at C11, J = 16.4 Hz), 5.38 (d, 1H,
at C10, J = 16.6 Hz), 5.28 (bs, 1H, at C3), 5.15 (t, 1H, J = 7.2 Hz, at C7), 2.08- 2.32
(br, 6H, at C4, C5 & C8), 1.78 (s, 3H, at C12), 1.46 (s, 3H, at C13), 1.02-1.18 (broad,
6H, at C14 & C15); 13C NMR (125 MHz, DMSO-d6): δ = 160.23 (C1), 151.87 (C10),
138.70 (C3), 135.33 (C6), 133.44 (C2), 124.20 (C7), 120.83 (C11), 39.47 (C5 & C8),
36.26 (C9), 29.96 (C14), 24.13 (C15), 23.39 (C4), 15.19 (C12), 15.02 (C13): IR (ν
cm-1): 3217.2 (br, -OH), 1636 (-C=N); HRMS(ESI-positive): [M+H]+ for C15H24NO,
found: 234.1761, calculated: 234.1857.
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4.1.2.2 General procedure for synthesis of ZOFA
In a 100 mL two neck RB flask, zerumbone oxime (1 mmol) was taken with
DCM (20 mL). To this solution, carboxylic acid (1 mmol) was added slowly
followed by DMAP (0.2 mmol) and EDCI (2.5 mmol). The reaction mixture was
magnetically stirred under nitrogen atmosphere at room temperature until completion
of the reaction. The progress of the reaction was monitored by TLC by eluting with
the mixture of petroleum ether and EtOAc. After completion of the reaction, 20 mL
water was added to the mixture and stirred for a minute then the organic layer was
separated using a separating funnel. Trace of moisture was removed by adding
anhydrous Na2SO4. The clear organic solution was concentrated to get crude product.
Further to the crude product, 2-3 mL of petroleum ether was added and sonicated in
bath type sonicator. During this process, the pure product separated out as solid,
which was filtered and dried. On the other hand, liquid products were purified by
column chromatography using SiO2 (100-200 mesh size). The pure products were
characterized by NMR, IR, HRMS spectral studies. The physical and spectral data of
zerumbone oxime fatty acid esters (ZOFA) is presented below.
(1Z,2E,6E,10E)-2,6,9,9-tetramethylcycloundeca-2,6,10-trien-1-one-O-butyryl
oxime
NO
O
3a
Pale yellow liquid, yield:104 mg (80%): 1H NMR (500 MHz, CDCl3): δ =
6.24 (d, 1H, J = 16.4 Hz), 5.63 (d, 1H, J = 16.4 Hz), 5.53 (t, 1H, J = 6.53 Hz ), 5.17
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(t, 1H, J = 7.9 Hz), 2.43 (t, 2H, J = 7.4 Hz), 2.39 (t, 1H, J = 7.4 Hz), 2.32 (t, 1H, J =
8.7 Hz), 2.11- 2.55 (m, 3H ), 1.83-1.90 (m, 1H),1.72 (sextet, 2H, J = 7.37 Hz),1.96 (s,
3H), 1.51 (s, 3H ), 1.04-1.17 (broad, 6H, ), 1.00 (s, 3H )13C NMR (125 MHz, CDCl3):
δ = 171.14 , 168.63, 156.19, 143.52, 135.52 , 132.19 , 123.91, 119.59 , 42.29, 39.40
,37.30, 34.62 , 23.67, 18.06,15.05, 14.68, 14.79,13.37: IR (ν cm-1): 1761 (-C=O),
1635 (C=N), 1580 (-N-O); HRMS (ESI-positive): [M+H]+ for C19H29NO2, found:
304.2265, calculated: 304.2276.
(1Z,2E,6E,10E)-2,6,9,9-tetramethylcycloundeca-2,6,10-trien-1-one-O-benzoyl
oxime
NO
O
3b
White solid, Yield: 120 mg (83%). m.p.: 95-97 °C; 1H NMR (500 MHz,
CDCl3): δ = 8.04 (d, 2H, J = 7.3 Hz),7.57, (t, 1H, J = 7.3 Hz), 7.45, (t, 2H, J = 7.6
Hz), 6.35 (d, 1H, J = 16.5 Hz), 5.68 (d, 1H, J = 16.4 Hz), 5.60 (t, 1H, J = 5.79 Hz ),
5.18 (t, 1H, J = 7.6 Hz), 2.09- 2.31 (m, 5H), 2.02( s, 3H), 1.89 (bs, 1H), 1.52 (s, 3H ),
1.03-1.27 (broad, 6H,); 13C NMR (125 MHz, CDCl3): δ = 169.90 , 163.90, 159.64,
156.73, 144.32 , 140.38 ,135.90, 133.00 , 129.55 ,128.45, 124.24, 123.41, 119.86,
42.51, 39.71, 37.70, 24.03,15.14, 15.06; IR (ν cm-1): 1753 (-C=O), 1675 (C=N),
1580 (-N-O); HRMS (ESI-positive): [M+H]+ for C22H28NO2, found: 338.2216,
calculated: 338.2120.
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(1Z,2E,6E,10E)-2,6,9,9-tetramethylcycloundeca-2,6,10-trien-1-one-O-hexanoyl
oxime
NO
O
3c
Pale yellow liquid: Yield: 129 mg (91%); 1H NMR (500 MHz, CDCl3): δ =
6.23 (d, 1H, J = 16.27 Hz), 5.62 (d, 1H, J = 16.49 Hz), 5.52 (t, 1H, J = 5.99 Hz ),
5.16 (t, 1H, J = 7.8 Hz), 2.43 (t, 2H, J = 7.8 Hz), 2.13- 2.31 (m, 4H ), 1.69 (t, 3H, J =
7.3 Hz),1.57(d, 1H, J = 0.9 Hz),1.95 (s, 3H ), 1.51 (s, 3H ),1.31-1.38 (m, 4H ), 1.02-
1.20 (bs, 6H, ), 0.90 (t, 3H, J = 6.6 Hz): 13C NMR (125 MHz, CDCl3): δ = 171.27 ,
168.58, 156.20, 143.48, 135.52 , 132.17 , 123.89 , 119.59 , 42.28, 39.39 ,37.29, 32.71,
30.93, 24.26, 23.66, 23.51, 21.97, 14.80, 14.70,13.54; IR (ν cm-1): 1760 (-C=O), 1636
(C=N), 1580 (-N-O); HRMS (ESI-positive): [M+H]+ for C21H34NO2, found:
332.2580, calculated: 332.2589.
(1Z,2E,6E,10E)-2,6,9,9-tetramethylcycloundeca-2,6,10-trien-1-one-O-octanoyl
oxime
NO
O
3d
Color less liquid: yield: 139 mg (90%): 1H NMR (500 MHz, CDCl3): δ = 6.22
(d, 1H, J = 16.25 Hz), 5.61 (d, 1H, J = 16.38 Hz), 5.51 (t, 1H, J = 5.89 Hz ), 5.15 (t,
1H, J = 7.7 Hz), 2.44 (t, 2H, J = 7.59 Hz), 2.13- 2.33 (m, 4H ), 1.69 (t, 2H, J = 7.15
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Hz),1.26-1.38(m, 10H ),1.95 (s, 3H ), 1.50 (s, 3H ), 1.04-1.20 (bs, 6H, ), 0.87 (t, 3H, J
= 7.2 Hz): 13C NMR (125 MHz, CDCl3): δ = 171.27 , 168.57, 156.18, 143.46, 135.52
, 132.20 , 123.91 , 119.60 , 42.40, 39.40 ,37.29, 32.76, 31.30, 28.75, 28.59, 24.58,
23.67, 22.25, 21.97, 14.79, 14.70,13.70; IR (ν cm-1): 1760 (-C=O), 1635 (C=N), 1580
(-N-O); HRMS (ESI-positive): [M+H]+ for C23H38NO2 found: 360.2944, calculated:
360.2902.
(1Z,2E,6E,10E)-2,6,9,9-tetramethylcycloundeca-2,6,10-trien-1-one-O-decanoyl
oxime
NO
O
3e
Pale Yellow liquid: yield: 140 mg (84%); 1H NMR (500 MHz, CDCl3): δ =
6.24 (d, 1H, J = 16.36 Hz), 5.66 (d, 1H, J = 16.36 Hz), 5.53 (t, 1H, J = 5.7 Hz ),
5.17 (t, 1H, J = 7.7 Hz), 2.42 (t, 2H, J = 7.4 Hz), 2.12- 2.31 (m, 4H ), 1.67 (t, 2H, J =
7.4 Hz),1.22-1.34(m, 13H ),1.98 (s, 3H ), 1.52 (s, 3H ), 1.07-1.22 (bs, 6H, ), 0.88 (t,
3H, J = 6.8 Hz); 13C NMR (125 MHz, CDCl3): δ = 171.29 , 168.58, 156.19, 143.46,
135.53 , 132.20 , 123.91 , 119.60 , 42.30, 39.40 ,37.30, 32.76,31.52, 29.06, 28.93,
28.79, 24.58, 23.67,23.52, 22.31, 21.97, 14.79, 14.70,13.74; IR (ν cm-1): 1761 (-
C=O), 1636 (C=N), 1580 (-N-O); HRMS (ESI-positive): [M+H] + for C25H42NO2
found: 388.3254. calculated: 388.3215.
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(1Z,2E,6E,10E)-2,6,9,9-tetramethylcycloundeca-2,6,10-trien-1-one-O-dodecanoyl
oxime
O
O
N
3f
Pale Yellow liquid: yield: 159 mg (89%); 1H NMR (500 MHz, CDCl3): δ =
6.25 (d, 1H, J = 16.38 Hz), 5.64 (d, 1H, J = 16.38 Hz), 5.54 (t, 1H, J = 5.46 Hz ),
5.18 (t, 1H, J = 7.72 Hz), 2.45 (t, 2H, J = 7.3 Hz), 2.16- 2.35 (m, 4H ), 1.70 (m, 2H
),1.25-1.35(m, 18H ),1.98 (s, 3H ), 1.53 (s, 3H ), 1.09-1.21 (bs, 6H, ), 0.90 (t, 3H, J =
6.7 Hz); 13C NMR (125 MHz, CDCl3): δ = 171.30 , 168.59, 156.19, 143.46, 135.54 ,
132.22 , 123.92 , 119.62 , 42.32, 39.41 ,37.31, 32.78 ,31.57, 29.27, 29.11, 28.98,
28.95, 28.89, 28.81, 24.60, 23.68 ,23.53, 22.34, 14.80, 14.71, 13.75; IR (ν cm-1):
1761 (-C=O), 1636 (C=N), 1580 (-N-O); HRMS (ESI-positive): [M+H] + for
C27H46NO2 found: 416.3500, calculated: 416.3528.
(1Z,2E,6E,10E)-2,6,9,9-tetramethylcycloundeca-2,6,10-trien-1-one-O-palmitoyl
oxime
NO
O
3g
Color less liquid: white solid (4 °C); yield: 178 mg (88%); 1H NMR (500
MHz, CDCl3): δ = 6.22 (d, 1H, J = 16.38 Hz), 5.61 (d, 1H, J = 16.25 Hz), 5.51 (t,
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1H, J = 5.52 Hz ), 5.15 (t, 1H, J = 7.80 Hz), 2.42 (t, 2H, J = 7.4 Hz), 2.12- 2.31 (m,
4H ), 1.67 (m, 2H ),1.21-1.30 (m, 25H ),1.95 (s, 3H ), 1.50 (s, 3H ), 1.06-1.18 (bs, 6H,
), 0.87 (t, 3H, J = 7.0 Hz) ; 13C NMR (125 MHz, CDCl3): δ = 171.27, 168.56, 156.17,
143.45, 135.52, 132.21, 123.91, 119.61, 42.41, 42.31, 39.41, 37.30, 32.76, 31.59,
30.05, 29.34, 29.12, 29.02, 28.95, 28.81, 28.60, 24.59, 23.67, 23.52, 23.44, 22.64,
22.35, 14.79, 14.70, 13.76; IR (ν cm-1): 1761 (-C=O), 1637 (C=N), 1580 (-N-O);
HRMS (ESI-positive): [M+H]+ for C31H54NO2, found: 472.4105, calculated:
472.4154.
(1Z,2E,6E,10E)-2,6,9,9-tetramethylcycloundeca-2,6,10-trien-1-one-O-(9Z,12Z)-
octadeca-9,12-dienoyl oxime
NO
O
3h
Colorless liquid: yield: 174 mg (82%); 1H NMR (500 MHz, CDCl3): δ = 6.22
(d, 1H, J = 16.38 Hz), 5.62 (d, 1H, J = 16.38 Hz), 5.52 (t, 1H, J = 5.76 Hz ), 5.31-
5.40 (m, 4H ), 5.16 (t, 1H, J = 7.73 Hz), 2.76(t, J = 6.49 Hz), 2.43 (t, 2H, J = 7.46
Hz), 2.04 (q, 4H, J = 7.04 Hz), 1.95 (s, 3H ), 1.63-1.73,(m, 3H), 1.50 (s, 3H ), 1.22-
1.45(m, 19H), 1.07-1.20 (bs, 6H, ), 0.88 (t, 3H, J = 6.63 Hz); 13C NMR (125 MHz,
CDCl3): δ = 171.64 , 168.94, 156.56, 143.82, 135.91, 132.56, 130.22, 130.04, 128.07,
127.93, 124.26, 124.07, 119.96, 42.66, 39.76, 37.66, 33.11, 31.54, 29.63, 29.36,
29.20, 29.13, 27.22, 25.65, 24.93, 24.03, 23.88, 22.58, 15.16, 15.07, 14.07: IR (ν cm-
1): 1760 (-C=O), 1636 (C=N), 1580 (-N-O); HRMS (ESI-positive): [M+H]+ for
C33H54NO2, found: 496.4119 calculated: 496.4154
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(1Z,2E,6E,10E)-2,6,9,9-tetramethylcycloundeca-2,6,10-trien-1-one-O-oleoyl
oxime
NO
O
3i
Colorless liquid, yield: 182 mg (85%); 1H NMR (500 MHz, CDCl3): δ = 6.23
(d, 1H, J = 16.36 Hz), 5.62 (d, 1H, J = 16.36 Hz), 5.52 (t, 1H, J = 5.86 Hz ), 5.32-
5.38 (m, 2H ), 5.16 (t, 1H, J = 7.88 Hz), 2.43 (t, 2H, ,J = 7.47 Hz), 2.08-2.31 (m, 4H
) 2.01 (q, 4H, J = 6.01 Hz), 1.96 (s, 3H ), 1.65-1.71,(m, 2H), 1.51 (s, 3H ), 1.25-1.36
(m, 22H), 1.08-1.22 (m, 6H), 0.88 (t, 3H, J = 7.18 Hz); 13C NMR (125 MHz, CDCl3):
δ = 171.26 , 168.56, 156.17, 143.45, 135.53, 132.23, 129.64, 129.39, 123.92, 119.61,
42.32, 39.42, 37.30, 32.75 ,31.57, 29.43, 29.37, 29.34, 29.18, 28.98, 28.85, 28.78,
26.88, 26.84, 24.58, 23.68, 23.53, 23.44, 22.33, 14.79, 14.70, 13.75; IR (ν cm-1): 1760
(-C=O), 1636 (C=N), 1580 (-N-O); HRMS (ESI-positive): [M+Na]+ for
C33H55NO2Na, found: 520.4131, calculated: 520.4130.
4.1.3 Results and Discussions
In the first step, zerumbone (1) was converted to zerumbone oxime (2) by
treating with hydroxylamine hydrochloride in ethanol (Scheme 4.1.3). The
zerumbone oxime was obtained in >90% yield. It also resulted in the formation of
inseparable syn- and anti-oximes in 1:3 ratio as measured by NMR (Figure 4.1.1).
Those peaks that were integrating to the single unit were observed having daughter
peaks next to them integrating close to 0.3 units. Hence, it was concluded that the
geometric isomeric syn/anti oximes are formed with 1:3 ratio. The difference in the
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ratio is because of steric hindrance. The syn-oxime presents more crowding, hence it
becomes less stable. This is formed in lower quantity compared to anti-oxime, which
offers lesser crowding around it and formed in the higher ratio. Zerumbone oxime
was analyzed by NMR, IR, and HRMS spectral studies.
Figure 4.1.1: NMR spectra of zerumbone oxime
Zerumbone oxime was taken for next step of oxime-ester preparation with
different fatty acids and benzoic acid. The ZOFA preparation with butyric acid was
checked with various polar aprotic, protic and chlorinated solvents in the presence of
EDCI reagent (Scheme 4.1.2). The yield of oxime esters was excellent, however, in
the case of chlorinated solvents like CH2Cl2 and CHCl3 reactions were fast (Table
4.1.1). Dichloromethane was found to be the suitable solvent for ZOFA preparation
as it gives high yield at the minimum time when compared to other solvents.
11 10 9 8 7 6 5 4 3 2 1 ppm
9.56
3.09
1.13
3.09
1.45
8.04
0.33
0.37
1.01
1.03
0.99
0.36
0.32
0.94
0.33
1.00
Zerumbone Oxime E- & Z- isomers mixture
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Scheme 4.1.2: Reaction of zerumbone oxime with butyric acid
Table 4.1.1: Reaction of zerumbone oxime with butyric acid in different solvents
Sl no Solvent Time (h) Yield (3a, %)a
1 MeOH 13 78
2 EtOH 15 75
3 CHCl3 11 80
4 CH2Cl2 10 80
5 THF 17 76
6 MeCN 15 72
a isolated yield
NOH
EDCI.HCl, DMAP
rt, solvent
NO
O
2
COOH
a 3a
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Representative Spectra of (1Z,2E,6E,10E)-2,6,9,9-tetramethylcycloundeca-2,6,10-
trien-1-one-O-benzoyl oxime (3b)
1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 ppm
6.06
3.12
1.09
3.06
6.17
1.08
1.05
1.00
1.03
2.09
1.04
2.01
7.443
7.458
7.473
7.556
7.570
7.583
8.039
8.053
2.09
1.04
2.01
5.166
5.182
5.198
5.590
5.602
5.613
5.669
5.702
6.343
6.376
1.08
1.05
1.00
1.03
1.125
1.223
1.256
1.522
1.587
2.027
6.06
3.12
1.09
3.06
6.17
1H NMR Spectra of compound 3b
ZO BENZOIC ACID ESTER
m/z250 260 270 280 290 300 310 320 330 340 350 360 370 380
%
0
100
24061307 4 (0.082) TOF MS ES+ 555360.1906
338.2216
376.1761
361.2197 377.1883
HRMS Spectra of compound 3b
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200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
125130135140145150155160165170 ppm
119.874
123.417
124.290
128.459
129.590
133.013
135.905
140.389
144.330
156.742
159.652
169.910
2025303540 ppm
15.064
15.149
24.060
37.709
39.722
42.520
13C NMR Spectral chart of compound 3b
The pure ZOFA esters were characterized by NMR, IR, and HRMS spectral
studies. In the 1H-NMR spectrum disappearance of -OH proton at 10.56 ppm and
acidic proton of different carboxylic acid in the range 9-12 ppm confirmed the
formation of oxime ester. Further, it was evidenced by IR stretching frequencies at
~1761 (-C=O), 1636 (C=N), 1580 (-N-O) cm-1 and HRMS data. The ZOFA ester,
thus prepared, have two lipophilic groups like alkyl side chain and zerumbone
skeleton with polar oxime-ester linkage. Since ZOFA esters artistically look like kites
with zerumbone as head and alkyl chain as a tail of a kite, we named these oxime
esters as ZOFA-kites (Figure 4.1.2). The products are obtained as unequal and an
inseparable mixture of syn- and anti-ZOFA esters. The ratio was identified by 1H-
NMR spectra based on the integration values of protons attached to carbon, which is
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vicinal to carbonyl functionality. The ZOFA esters were screened for their
antibacterial potential and antimutagenic potential. The results are discussed in detail
in Chapter 5.
NOH
b) EDCI.HCl,DMAP,DCM,rt
NOR
O
RCOOH
O
a) NH2OH.HCl,K2CO3, EtOH,rt
1 2 3a-3i
a
90%b
80-91%
R=CH3(CH2)n =2,4,6,8,10,14,Ph, Oleic,Lenoleic
Scheme 4.1.3: Synthesis of ZOFA Esters
Table 4.1.2: Synthesis of ZOFA-Kites
a isolated yield
Compound Carboxylic acid Time (h) Yield (%)a
3a Butyric acid 10 80
3b Benzoic acid 09 83
3c Hexanoic acid 17 91
3d Octanoic acid 15 90
3e Decanoic acid 20 84
3f Dodecanoic acid 18 89
3g Palmitic acid 12 88
3h Linoleic acid 20 82
3i Oleic acid 24 85
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NO
O
NO
O
NO
O
NO
O
NO
O
NO
O
NO
O
Figure 4.1.2: Structure of ZOFA kites
4.1.4 Conclusions
The method for the synthesis of zerumbone oxime fatty acid esters was
developed. The zerumbone oxime skeleton was tagged with different saturated,
unsaturated and aromatic acids. These derivatives possess lipophilic pockets, oxime
ester-bridge, and bioactive molecular structure. These are important molecular
features of medicinally useful compounds. They are also useful compounds as they
may diffuse easily through the lipid bilayer, and improve their effectiveness in
biological systems.
120
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Natural Compounds 45 (2009) 148.
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122
Section 4.2: A convenient practical synthesis of alkyl and aryl oxime esters
4.2.1 Introduction
The Oxime-esters are the small and important group of compounds in the
synthesis of biologically active compounds, fragrances chemicals [1,2], crop
protection agents [3], and for therapeutic studies [4]. They are also used as building
blocks in the synthesis of the peptides [5]. Oxime-esters cleave DNA under the
photolytic condition and are selective covalent inhibitors of serine hydrolase
retinoblastoma-binding protein 9 (RBBP9) [6-8]. They also exhibit biological
activities like antitumor [9], herbicidal [10], fungicidal [11] and insecticidal activities
[12]. Oxime-esters of dihydrocoumaric acid are prepared and screened for their
antibacterial activity [13]. The aromatic oxime esters of benzophenone and
dibenzosuberone are pharmacologically most important [14]. The piperidin-4-one
oxime-esters that are derived from vanillin tested for their antimicrobial and
antioxidant potential [15]. The oxime-esters obtained from nafimidone are analyzed
as potential anticonvulsant compounds [16]. The synthesis of oxime-esters has been
carried out by several methods, but there is scope for improvement in terms of
simplification of experimental methods and development of new protocols to get
desired products in high yields. An expedient synthetic protocol with easy
purification and general applicability to the synthesis of oxime-esters is in demand.
The classical method of synthesis of oxime-esters involves either the
condensation of oximes with acid chlorides under alkaline conditions or by using acid
anhydrides in the presence of strong acids [1, 7, 8, 13, 15, 16]. However, the yield of
oxime-esters are good, the functional groups that is sensitive to acid and base are
123
rarely applied. Moreover, this method requires one more additional step of
preparation of acid chloride from carboxylic acids. They are unstable compounds and
needs to be utilized immediately after the preparation. Since acid chlorides are more
prone to undergo hydrolysis, the anhydrous and inert reaction conditions have to be
maintained to get a high yield of oxime esters. Also, purification of crude products is
unwieldy and invariably needs column chromatography, which requires solvents in
large quantity. In the literature, few more methods of syntheses of oxime-esters are
reported. In the synthesis of benzoyl esters of alkyl and aryl substituted oximes,
benzoyl peroxide is used but the protocol is valid only for benzyol ester [17]. Oxime
esters are also synthesized by condensing oximes and α,β–unsaturated aldehydes
using redox esterification catalyst [3].
Owing to the significance of oxime-esters in synthetic organic chemistry, we
have developed a new facile and very efficient synthetic method that yields oxime
ester in high yield. The new method involves the reaction of alkyl or aryl substituted
oximes with aliphatic or aromatic acids in the presence of N-(3-methylaminopropyl)
N'-ethylcarbodiimide hydrochloride (EDCI) reagent (Scheme 4.2.1). The products
were obtained in excellent yield in various solvents. The reactions were carried out at
room temperature and completed in a reasonable time. The products obtained were
readily isolated by simple workup procedure and without chromatographic
purification. The solid products were separated in pure form by evaporation of
solvent after completion of the reaction and sonicating the crude product by adding
few drops of petroleum ether in a bath type sonicator. The liquid products were
purified by column chromatography technique.
The EDCI is economical, easily available and water soluble reagent. It is
commercially available as the hydrochloride salt in the pH range 4-6. EDCI activates
124
carboxyl group in the coupling reaction with amines to form amides. In phospho-
ester synthesis, phosphate groups are activated by EDCI. It is also used in the
preparation of peptides, in protein cross-linking to nucleic acids and in the preparation
of immune conjugates. However, there are no reports of using EDCI for oxime ester
preparation. Hence, we were interested in exploring its utility in the synthesis of
oxime esters. A protocol using EDCI reagent has been developed, which is more
advantageous for the synthesis of variously substituted oxime-esters.
4.2.2 Experimental
4.2.2.1 General procedure for preparation oxime [1-5]
In a 100 mL RB flask, a known quantity of aldehyde or ketone (10 mmol) was
taken. To this 50 mL distilled ethanol was added followed by the addition of
hydroxylamine hydrochloride (100 mmol) and anhydrous K2CO3 (100 mmol). The
mixture was magnetically stirred at room temperature until the completion of reaction.
The progress of the reaction was monitored by TLC using petroleum ether and ethyl
acetate mixture as an eluting solvent. After completion of the reaction, the solution
was filtered, the residue left was washed with ethanol. The filtrate collected was
evaporated and concentrated. It was then dissolved in DCM (50 mL) and washed
thoroughly with water (3×50 ml) followed by brine solution (50 mL). The organic
layer was separated and dried over anhydrous Na2SO4. Finally, the clear solution was
concentrated to get the pure product (1-5), which was taken for next step of oxime
ester preparation without further purification.
4.2.2.2 General procedure for preparation oxime esters [1-5 (a-e)]
In a 50 mL RB flask ketoxime or aldoxime (1-5, 2.0 mmol) was taken with
CH2Cl2 (20 mL) (Scheme 4.2.1). To this solution, carboxylic acid (a-e, 2.0 mmol)
was added slowly, followed by addition of EDCI (5 mmol) and DMAP (0.2 mmol)
125
reagents. The reaction mixture was stirred at room temperature under nitrogen
atmosphere until completion of the reaction. The reaction was monitored by TLC
using a mixture of petroleum ether and EtOAc as the eluting solvent. After
completion of the reaction, the mixture was diluted with water (50 mL) and the
organic layer was separated. Then traces of water were removed by adding anhydrous
Na2SO4. The clear DCM solution was evaporated to get crude product. The crude
product was treated with 2-3 mL of petroleum ether, separation of the pure solid
product occurred on sonication in a bath type sonicator. The resultant solid product
was filtered and dried under high pressure to afford the oxime esters [1-5 (a-e)] in
pure form (90-97% yield). In case of liquids, products were purified by column
chromatography. The pure products obtained were characterized by NMR, IR, and
HRMS spectral studies. The physical and spectral data of oxime esters is presented
below.
NOH
R1 R2
+ R3 CO2HEDCI.HCl
r.t.
NOCOR3
R1 R2CH2Cl21-5 a-e 1-5(a-e)
Scheme 4.2.1: Synthesis of oxime-esters
Cyclohexanone O-benzoyl oxime:
NO
O
1a
126
White solid; yield: 96% (184 mg); m.p 64-65 °C; IR (KBr): 1733, 1632 cm-1;
1H NMR (500 MHz, CDCl3): δ = 8.06 (d, J =7.27 Hz, 2H), 7.56 (t, J =7.27 Hz, 1H),
7.44 (t, J =7.94 Hz, 2H), 2.66 (t, J =6.34 Hz, 2H), 2.45 (t, J =6.34 Hz, 2H), 1.77 (pent,
J = 6.01 Hz, 2H), 1.72 (pent, J = 6.01 Hz, 2H), 1.61-1.66 (m, 2H); 13C NMR (125
MHz, CDCl3): δ = 169.2, 163.9, 132.8, 129.1, 128.1, 31.8, 26.7, 26.4, 25.5, 25.0;
HRMS (ESI): [M+Na]+ calculated for C13H15NO2Na: 240.1000; found: 240.1086
Cyclohexanone O-butyryl oxime:
NO
O
1b
Pale yellow liquid; yield: 95% (154 mg); IR (neat):1760, 1642 cm-1; 1H NMR
(500 MHz, CDCl3): δ = 2.39 (t, J =6.46 Hz, 2H), 2.21-2.28 (m,4H), 1.57-1.62 (m,
3H), 1.50-1.56 (m, 3H), 1.45-1.50 (m, 2H), 0.84 (t, J =7.48 Hz, 3H); 13C NMR (125
MHz, CDCl3): δ = 170.8, 168.1, 34.4, 31.7, 26.4, 25.4, 25.0, 18.0, 13.3; HRMS (ESI):
[M + Na]+ calculated for C10H17NO2Na: 206.1157; found 206.1208
Cyclohexanone O-4-aminobenzoyl oxime:
NO
O
NH2
1c
White solid; yield: 94% (193 mg); m.p 145-146 °C; IR (KBr): 1707, 1639 cm-
1; 1H NMR (500 MHz, CDCl3): δ = 7.84 (d, J =8.25 Hz, 2H), 6.64 (d, J =8.25 Hz,
2H), 4.48 (bs, 2H), 2.64 (t, J =6.34 Hz, 2H), 2.41 (t, J =6.34 Hz, 2H), 1.74 (q, J = 5.91
127
Hz, 2H), 1.69 (q, J = 6.10 Hz, 2H), 1.57-1.63 (m, 2H); 13C NMR (125 MHz, CDCl3):
δ = 168.5, 164.3, 151.5, 131.2, 131.1, 117.2, 113.4, 31.8, 26.6, 26.4, 25.5, 25.1;
HRMS (ESI): [M+H]+ calculated for C13H17N2O2: 233.1290; found 233.1317
Cyclohexanone O-4-methylbenzoyl oxime:
NO
O
1d
White solid; yield: 97 % (198.5 mg); m.p 75-76 °C; IR (KBr): 1730, 1636 cm-
1; 1H NMR (500 MHz, CDCl3): δ = 7.94 (d, J =8.17 Hz, 2H), 7.23 (d, J =8.08 Hz,
2H), 2.65 (t, J =6.25 Hz, 2H), 2.44 (t, J =6.54 Hz, 2H), 1.77 (pent, J = 5.93 Hz, 2H),
1.72 (pent, J = 5.93 Hz, 2H), 1.60-1.66 (m, 2H); 13C NMR (125 MHz, CDCl3): δ =
169.0,164.0, 143.5, 129.2, 128.8, 31.9, 26.8, 26.4, 25.5, 25.1, 21.3; HRMS (ESI): [M
+ Na]+ calculated for C14H17NO2Na: 254.1156; found: 254.1139.
Cyclohexanone O-4-nitrobenzoyl oxime:
NO
O
NO2
1e
Pale yellow solid; yield: 90% (209 mg); m.p 110-112 °C; IR (KBr): 1730,
1631 cm-1; 1H NMR (500 MHz, CDCl3): δ = 8.29 (d, J =8.85 Hz, 2H), 8.21 (d, J =
8.85 Hz, 2H), 2.66 (t, J =6.49 Hz, 2H), 2.46 (t, J =6.19 Hz, 2H), 1.79 (q, J = 5.81 Hz,
2H), 1.74 (q, J = 5.81 Hz, 2H), 1.66 (d, J =4.30 Hz, 2H); 13C NMR (125 MHz,
128
CDCl3): δ = 170.2, 162.0, 150.2, 134.6, 130.3, 123.3, 31.8, 26.9, 26.4, 25.5, 25.0;
HRMS (ESI): [M+Na]+ calculated for C13H14N2ONa: 285.0852; found: 285.0813
(E)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enone O-benzoyl oxime :
NO
O
2a
White solid; yield: 97% (158 mg) ; m.p 92-94 °C; IR (KBr): 1739, 1644 cm-
1; 1H NMR (500 MHz, CDCl3): δ = 8.15 (d, J =7.11 Hz, 2H), 7.66 (t, J =7.61 Hz, 1H),
7.55 (t, J =7.85 Hz, 2H), 6.32 – 6.36 (m, 1H), 4.91 (d, J =1.11 Hz, 1H), 4.89 (bs, 1H),
3.35 -3.39 (m, 1H), 2.50-2.55 (m, 1H), 2.39 -2.45 (m, 2H), 2.21 -2.27 (m, 1H), 2.10
(s, 3H), 1.85 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 164.0, 163.9, 147.1, 137.4,
133.1, 130.2, 129.5, 128.5, 110.6, 40.2, 30.4, 29.3, 27.2, 20.6, 17.7; HRMS (ESI):
[M+Na]+ calculated for C17H19NO2Na: 292.1313; found 292.1263
(E)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enone O-butyryl oxime:
NO
O
2b
Pale yellow liquid; yield: 92% (131mg); IR (neat): 1761, 1644 cm-1; 1H NMR
(500 MHz, CDCl3): δ = 6.20-6.27 (m,1H), 4.81 (d, J =1.22 Hz, 1H), 4.77(bs, 1H),
3.12-3.19 (m, 1H), 2.45 (t, J =7.50 Hz, 2H), 2.28-2.38 (m, 2H), 2.11-2.21 (m, 2H),
1.94 (t, J =0.91 Hz, 3H), 1.75 (s, 3H), 1.72 (q, J = 7.5Hz, 2H), 1.00 (t, J =7.50 Hz,
3H); 13C NMR (125 MHz, CDCl3): δ = 171.0, 162.4, 146.7, 136.6, 129.8, 110.1, 39.8,
129
34.5, 30.0, 28.7, 20.1, 18.0, 17.2, 13.3; HRMS (ESI): [M+Na]+ calculated for
C14H21NO2Na: 258.1469; found 258.1456
(E)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enone O-4-aminobenzoyl oxime :
NO
O
NH2
2c
White solid; yield: 94% (161.5 mg); m.p 192-193 °C; IR (KBr): 1717, 1631
cm-1; 1H NMR (500 MHz, CDCl3): δ = 7.90 (d, J =8.72 Hz, 2H), 6.68 (d, J =8.57 Hz,
2H), 6.26 (d, J =4.93 Hz, 1H), 4.83 (d, J =11.53 Hz, 2H), 4.16 (bs, 2H), 3.30 (dd, J1
=16.27, J2 =2.48 Hz, 1H), 2.41 -2.52 (m, 1H), 2.30-2.38 (m, 2H), 2.14 -2.20 (m, 1H),
2.03 (s, 3H), 1.79 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 163.7, 163.0, 147.0,
136.4, 131.3, 130.5, 130.1, 128.5, 118.2, 113.5, 110.1, 39.9, 30.1, 28.9, 20.3, 17.5;
HRMS (ESI): [M+H]+ calculated for C17H21N2O2: 285.1603; found 285.1636
(E)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enone O-4-methylbenzoyl oxime :
NO
O
2d
White solid; yield: 92% (157.6 mg); m.p 73-75 °C; IR (KBr): 1741, 1645 cm-
1; 1H NMR (500 MHz, CDCl3): δ = 7.96 (d, J =7.85 Hz, 2H), 7.25 (d, J =7.85 Hz,
2H), 6.25 (d, J =4.42 Hz, 1H), 4.81 (d, J =11.54 Hz, 2H), 3.28 (dd, J1 =16.20 Hz, J2
=1.96 Hz, 1H), 2.44 (d, J =12.27 Hz, 1H), 2.40 (s, 3H), 2.32 (t, J =14.48 Hz, 2H),
2.11 -2.17 (m, 1H), 2.01 (s, 3H), 1.76 (s, 3H). 13C NMR (125 MHz, CDCl3): δ =
130
163.61, 163.48, 147.06, 146.82, 143.57, 136.89, 129.94, 129.25, 128.93, 126.31,
110.28, 39.91, 30.13, 28.94, 21.35, 20.2, 17.4. HRMS (ESI): [M+Na]+ calculated for
C18H21NO2Na: 306.1469; found: 306.1495
(E)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enone O-4-nitrobenzoyl oxime:
NO
O
NO2
2e
White solid; yield: 93% (176.7 mg); m.p 97-99 °C; IR (KBr): 1744, 1642 cm-
1; 1H NMR (500 MHz, CDCl3): δ = 8.35 (d, J = 8.78 Hz, 2H), 8.26 (d, J = 8.65 Hz,
2H), 6.35 (dd, J1 =3.48, J2 =1.45 Hz, 1H), 4.87 (s, 1H), 4.83 (s, 1H), 3.23-3.29 (m,
1H), 2.46 -2.51 (m, 1H), 2.36 -2.42 (m, 2H), 2.17 -2.24 (m, 1H), 2.04 (s, 3H), 1.80 (s,
3H); 13C NMR (125 MHz, CDCl3): δ = 164.5, 161.8, 150.3, 146.6, 137.9, 134.6,
130.3, 129.6, 123.4, 110.5, 39.9, 30.1, 29.0, 20.2, 17.3; HRMS (ESI): [M + Na]+
calculated for C17H18N2O4Na: 337.1164; found: 337.1107
Benzophenone O-benzoyl oxime:
PhPh
N O
O
3a
White solid; yield: 92% (140.4 mg); m.p 103-105 °C; IR (KBr): 1739, 1645
cm-1; 1H NMR (500 MHz, CDCl3): δ = 7.82 (d, J =7.35 Hz, 2H), 7.70 (d, J =7.35 Hz,
2H), 7.54 (t, J =3.26 Hz, 4H), 7.50 (t, J =7.35 Hz, 1H), 7.44 (t, J =4.62 Hz, 3H), 7.40
(q, J =7.62 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ = 165.2, 163.4, 134.3, 132.8,
131
130.6, 129.3, 128.8, 128.5, 128.1, 127.9; HRMS (ESI): [M + Na]+ calculated for
C20H15NO2Na: 324.1000; found: 324.1046.
Benzophenone O-butyryl oxime:
Ph
Ph NO
O
3b
White solid; yield: 96% (130 mg); m.p 55-57 °C; IR (KBr): 1768, 1652 cm-1;
1H NMR (500 MHz, CDCl3): δ = 7.56 (d, J =7.23 Hz, 2H), 7.44 (d, J =2.20 Hz, 2H),
7.43 (d, J =1.26 Hz, 1H),7.39-7.42 (m, 1H), 7.33 (t, J =7.89 Hz, 2H), 7.29 (d, J
=1.99, Hz, 1H), 7.28 (d, J =4.11, Hz, 1H), 2.28 (t, J =7.40 Hz, 2H), 1.59 (sextet, J
=7.40 Hz, 2H), 0.88 (t, J =7.51 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ = 170.7,
164.5, 130.5, 129.2, 128.7, 128.4, 128.0, 127.8, 34.5, 17.9, 13.2; HRMS (ESI):
[M+Na]+ calculated for C17H17NO2Na: 290.1156; found: 290.1165.
Benzophenone O-4-aminobenzoyl oxime:
Ph
Ph
NO
O
H2N
3c
Yellow solid; yield: 94 % (150.66 mg); m.p 114-115 °C; IR (KBr): 1658, 1597
cm-1; 1H NMR (500 MHz, CDCl3): δ = 7.48-7.52 (m, 9H), 7.41 (t, J =2.44 Hz, 1H),
7.40 (t, J =1.53 Hz, 1H), 7.38 (d, J =1.35 Hz, 2H), 7.36 (d, J =1.53 Hz, 2H), 7.35 (t, J
=1.62 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ = 157.6, 135.9, 132.4, 129.2, 129.0,
128.8, 128.1, 127.9, 127.6; HRMS (ESI): [M+H]+ calculated for C20H17N2O2:
317.1290; found: 316.9080.
132
Benzophenone O-4-methylbenzoyl oxime:
Ph
Ph
NO
O
3d
White solid; yield: 91% (145.39 mg); m.p. 108-110 °C; IR (KBr): 1737, 1647
cm-1; 1H NMR (500 MHz, CDCl3): δ = 7.65 (t, J =8.46 Hz, 4H), 7.47 (t, J =2.88 Hz,
3H), 7.42 (t, J =7.11 Hz, 1H), 7.37-7.40 (m, 2H), 7.34 (t, J =7.50 Hz, 2H), 7.12 (d, J
=8.17 Hz, 2H), 2.32 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 165.0, 163.5, 143.7,
132.5, 130.6, 129.3, 128.9, 128.7, 128.5, 128.1, 127.9, 127.4, 21.3; HRMS (ESI):
[M+Na]+ calculated for C21H17NO2Na: 338.1156; found 338.1109
Benzophenone O-4-nitrobenzoyl oxime:
Ph
Ph
NO
O
O2N
3e
Pale yellow solid; yield: 95% (166.7 mg); m.p 150-152 °C; IR (KBr): 1753,
1652 cm-1; 1H NMR (500 MHz, CDCl3): δ = 8.22 (d, J = 8.97 Hz, 2H), 7.95 (d, J
=8.80 Hz, 2H), 7.69 (d, J =7.28 Hz, 2H), 7.53-7.57 (m, 3H), 7.50 (d, J =7.45 Hz, 1H),
7.42 (t, J =7.54 Hz, 4H); 13C NMR (125 MHz, CDCl3): δ = 166.3, 161.5, 150.2,
134.0, 133.7, 132.2, 131.0, 130.3, 129.6, 128.8, 128.2, 128.1, 127.9, 123.3; HRMS
(ESI): [M+Na]+ calculated for C20H14N2O4Na: 369.0851; found 369.0836
133
(E)-Acetophenone O-benzoyl oxime:
Ph NO
O
4a
White solid; yield: 91% (161 mg); m.p 85-87 °C; IR (KBr): 1743, 1647 cm-1;
1H NMR (500 MHz, CDCl3): δ = 8.08 (d, J =7.66 Hz, 2H), 7.77 (d, J =6.89 Hz, 2H),
7.55 (t, J =7.50 Hz, 1H), 7.43 (t, J =7.66 Hz, 2H), 7.34-7.40 (m, 3H), 2.44 (s, 3H);
13C NMR (125 MHz, CDCl3): δ = 163.4, 163.3, 154.8, 134.4, 133.0, 130.4, 130.3,
130.2, 129.3, 129.2, 128.7, 128.3, 128.2, 126.8, 14.1; HRMS (ESI):[M+Na]+
calculated for C15H13NO2Na: 262.0843; found: 262.0872.
(E)-Acetophenone O-butyryl oxime:
PhNO
O
4b
White solid; yield: 95% (144 mg); m.p 89-91 °C; IR (KBr): 1762, 1614 cm-1;
1H NMR (500 MHz, CDCl3): δ = 7.73 (d, J =6.84 Hz, 2H), 7.36-7.43 (m, 3H), 2.48
(t, J =7.32 Hz, 2H), 2.36 (s, 3H), 1.76 (sextet, J =7.32 Hz, 2H), 1.01 (t, J =7.32 Hz,
3H); 13C NMR (125 MHz, CDCl3): δ = 170.8, 162.2, 134.6, 130.2, 128.2, 126.6, 34.6,
18.0, 14.0, 13.4; HRMS (ESI):[M+H]+ calculated for C12H16NO2: 206.1181; found
206.1161.
(E)-Acetophenone O-4-aminobenzoyl oxime:
Ph
NO
O
H2N
4c
134
White solid; yield: 90% (169 mg); m.p 166-167 °C; IR (KBr): 1708, 1600 cm-
1; 1H NMR (500 MHz, CDCl3): δ = 7.93 (d, J =8.23 Hz, 2H), 7.81 (d, J =6.76 Hz,
2H), 7.40-7.46 (m, 3H), 6.68 (d, J =8.23 Hz, 2H), 4.28 (bs, 2H), 2.50 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ = 163.7, 162.5, 151.2, 134.8, 131.4, 130.1, 128.2, 126.7,
117.6, 113.5, 14.2; HRMS (ESI): [M+Na]+ calculated for C15H14N2O2Na: 277.0952;
found: 277.0952
(E)-Acetophenone O-4-methylbenzoyl oxime:
Ph
NO
O
4d
White solid; yield: 93% (174 mg); m.p 115-117 °C; IR (KBr): 1731, 1605 cm-
1; 1H NMR (500 MHz, CDCl3): δ = 7.93 (d, J =8.23 Hz, 2H), 7.81 (d, J =6.76 Hz,
2H), 7.40-7.46 (m, 3H), 6.68 (d, J =8.23 Hz, 2H), 4.28 (bs, 2H), 2.50 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ = 163.4, 163.0, 143.8, 134.5, 130.2, 129.2, 129.1, 128.8,
128.5, 128.1, 128.8, 126.7, 125.9, 21.2, 14.1; HRMS (ESI): [M+H]+ calculated for
C16H16NO2: 254.1181; found 254.1150.
(E)-Acetophenone O-4-nitrobenzoyl oxime:
Ph
NO
O
O2N
4e
White solid; yield: 92% (193.3 mg); m.p 167-169 °C; IR (KBr): 1744, 1604
cm-1; 1H NMR (500 MHz, CDCl3): δ = 8.31 (q, J =8.75 Hz, 4H), 7.81 (d, J =7.26 Hz,
2H), 7.42-7.49 (m, 3H), 2.54 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 164.2, 161.6,
135
150.3, 134.3, 134.0, 130.6, 130.4, 128.3, 126.8, 123.44, 14.4; HRMS (ESI): [M+ Na]+
calculated for C15H12N2O4Na: 307.0694; found: 307.0673.
(E)-Benzaldehyde O-benzoyl oxime:
Ph
H
NO
O
5a
White solid; yield: 96% (178.3 mg); m.p 105-107 °C; IR (KBr): 1743, 1652
cm-1; 1H NMR (500 MHz, CDCl3): δ = 8.54 (s, 1H), 8.13 (d, J =7.29 Hz, 2H), 7.80
(d, J =7.10 Hz, 2H), 7.59 (t, J =7.29 Hz, 1H), 7.47 (t, J =7.66 Hz, 3H), 7.42 (t, J
=7.66 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ = 163.6, 156.5, 133.1, 131.4, 129.8,
129.39, 128.6, 128.2, 128.1; HRMS (ESI): [M+Na]+ calculated for C14H11NO2Na:
248.0687; found: 248.0627.
(E)-Benzaldehyde O-butyryl oxime:
H
PhNO
O
5b
Liquid; yield: 90% (142 mg); IR (neat): 1760, 1645 cm-1; 1H NMR (500
MHz, CDCl3): δ = 8.29 (d, J =5.10 Hz, 1H), 7.67 (d, J =6.93 Hz, 2H), 7.32-7.41
(m, 3H), 2.38 (q, J =6.93 Hz, 2H), 1.65-1.74 (m, 2H), 0.96 (t, J =7.29 Hz, 3H); 13C
NMR (125 MHz, CDCl3): δ = 170.6, 155.5, 131.2, 129.8, 128.5, 127.9, 34.2, 29.3,
17.9, 13.2; HRMS (ESI): [M+Na]+ calculated for C11H13NO2Na: 214.0843; found:
214.0828.
136
(E)-Benzaldehyde O-4-methylbenzoyl oxime:
H
Ph
NO
O
5d
White solid; yield: 91% (179.6 mg); m.p 125-127 °C; IR (KBr): 1731, 1607
cm-1; 1H NMR (500 MHz, CDCl3): δ = 8.54 (s, 1H), 8.03 (d, J =7.90 Hz, 2H), 7.81
(d, J =7.90 Hz, 2H), 7.49 (t, J =6.67 Hz, 1H), 7.44 (t, J =7.55 Hz, 2H), 7.28 (d, J =
8.07 Hz, 2H), 2.42 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 163.7, 156.2, 143.9,
131.3, 131.1, 130.8, 129.9, 129.4, 129.1, 128.9, 128.5, 128.1, 125.5, 21.4; HRMS
(ESI): [M+Na]+ calculated for C15H13NO2Na: 262.0843; found: 262.0806.
(E)-Benzaldehyde O-4-nitrobenzoyl oxime:
H
Ph
NO
O
NO2
5e
Pale yellow solid; yield: 94% (209.5 mg); m.p 159-161 °C; IR (KBr): 1740,
1606 cm-1; 1H NMR (500 MHz, CDCl3): δ = 8.60 (s, 1H), 8.34 (q, J =8.86 Hz, 4H),
7.83 (d, J =7.15 Hz, 2H), 7.54 (t, J =7.26 Hz, 1H), 7.49 (t, J =7.26 Hz, 2H); 13C
NMR (125 MHz, CDCl3): δ = 161.7, 157.3, 150.4, 133.8, 131.8, 130.5, 129.3, 128.7,
128.3, 123.4; HRMS (ESI): [M+Na]+ calculated for C14H10N2O4Na: 293.0538; found:
293.0550.
137
4.2.3 Results and Discussions
In a typical reaction, cyclohexanone oxime was condensed with benzoic acid
for the oxime ester preparation. An optimization experiment was carried out to
choose the solvent for reaction using different protic, aprotic and chlorinated solvents.
In all the reactions, EDCI was used as a dehydrating agent at 2.5 equivalents and
reaction carried out at room temperature under nitrogen atmosphere (Scheme 4.2.2).
The oxime esters were obtained in all the solvents in high yields. The yield, reaction
time are summarized in Table 4.2.1. It was found that the reactions were faster and
the product yield was high (>92%) in chlorinated solvents like DCM and CHCl3 when
compared to other solvents (80-88%). The reaction carried out in DCM was found to
be the best in terms of reaction time and yield. It was chosen as the solvent of choice
for the synthesis of oxime-ester with other substrates.
The molar equivalent of the oxime to acid was then optimized. Initially,
condensation was carried out with equimolar ratios of cyclohexanone oxime and
benzoic acid in the presence of reagent EDCI (1 equivalent). The condensation
reaction was very slow, and less than 50% conversion could be realized in 24 h. The
molar ratio EDCI was increased to two equivalents, and an equimolar ratio of acid to
oxime was maintained, it was observed that the reaction was completed in 12 h with
the high yield of the product. It was also found that the reaction time could be
reduced to 8 h if 2.5 equivalents of EDCI used.
Under optimized conditions of reagent and solvent, cyclohexanone oxime (1)
was condensed with different alkyl and aryl substituted aromatic acids at room
temperature (Table 4.2.2, a-e). The reaction of cyclohexanone oxime with butyric
acid was fast while with p-toluic acid and p-amino benzoic acid took comparatively
longer time for the complete ester formation. In all the cases, the complete
138
conversion was observed and results of time, yields were shown in Table 4.2.2. In
the case of p-aminobenzoic acid (PABA), the condensation of oxime with acid group
was selectively occurred with no formation of self-condensation product between the
amine and acid group. Hence, the present method is also selective to acid group and
affords oxime-ester over the amide product, which otherwise undergo self-
condensation to form amide product. In continuing series of oxime ester preparation,
next we studied condensation reaction of carvone-oxime (2) with different acids (a-e).
The carvone oxime esters (2a-2e) were obtained in high yield (92-97%). In
this case also butyric acid reacted at a faster rate than the substituted and
unsubstituted aromatic acids. The acetophenone oxime (4) was also found to react at
the faster rate with the acids in yielding corresponding oxime esters with higher
yield. In the same way, benzophenone oxime (3) reacted with different acids to
afford oxime esters. Benzaldehyde oxime (5) did not react with p-amino benzoic
acid even at the higher temperature, but all other acids condensed to form respective
benzaldehyde oxime esters with high yield in optimum time.
N
+O
OH
EDCI.HCl
r.t. Sol
1 a
NO
1a
O
OH
Scheme 4.2.2: Reaction of cyclohexanone oxime with benzoic acid
139
Table 4.2.1: Oxime ester preparation in different solvents
Entry Solvent Time (h) Yield (1a, %)a
1 MeCN 15 82
2 THF 20 85
3 EtOH 18 88
4 MeOH 12 80
5 CH2Cl2 8 96
6 CHCl3 9 92
a isolated yield
Representative spectra of (E)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enone-O-
benzoyl oxime (2a)
1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 ppm
3.18
3.17
1.18
2.24
1.11
1.04
1.11
1.00
1.04
2.12
1.01
2.05
7.537
7.552
7.568
7.653
7.668
7.683
8.149
8.163
2.12
1.01
2.05
1.858
2.106
2.238
2.243
2.247
2.252
2.256
2.268
2.273
2.278
2.396
2.402
2.404
2.411
2.413
2.422
2.429
2.437
2.447
2.449
2.454
2.509
2.523
2.531
3.18
3.17
1.18
2.24
1.11
3.354
3.359
3.361
3.384
3.387
3.391
3.394
4.892
4.914
4.916
6.353
6.356
6.358
6.362
6.365
6.367
1.04
1.11
1.00
1.04
1H NMR Spectra of compound 2a
140
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
115120125130135140145150155160165 ppm
110.653
128.552
129.573
130.248
133.183
137.416
147.174
163.967
164.053
2022242628303234363840 ppm
17.776
20.601
27.197
29.305
30.471
40.260
13C NMR Spectra of compound 2a
CARVONE OXIME BENZOIC
m/z275 280 285 290 295 300 305
%
0
100
29111339 3 (0.063) Cm (3) TOF MS ES+ 50292.1263
HRMS Spectra of 2a
141
Table 4.2.2: Preparation of alkyl and aryl oxime esters of alkyl and aromatic acids
Oxime (1-5) Acid (a-e) Product Time (h) Yield (%)a
NOH
Benzoic 1a 08 96
Butyric 1b 06 95
4-Aminobenzoic 1c 20 94
p-Toluic 1d 20 97
4-Nitrobenzoic 1e 03 90
Benzoic 2a 10 97
Butyric 2b 08 92
4-Aminobenzoic 2c 12 94
p-Toluic 2d 10 92
4-Nitrobenzoic 2e 03 93
Benzoic 3a 12 92
Butyric 3b 10 96
4-Aminobenzoic 3c 15 94
p-Toluic 3d 14 91
4-Nitrobenzoic 3e 04 95
Benzoic 4a 06 91
Butyric 4b 07 95
4-Aminobenzoic 4c 19 90
p-Toluic 4d 12 93
4-Nitrobenzoic 4e 04 92
Benzoic 5a 12 92
Butyric 5b 10 96
4-Aminobenzoic NR - -
p-Toluic 5d 12 91
4-Nitrobenzoic 5e 04 94
a Yield of isolated product; NR: No reaction
NOH
NOH
CH3
NOH
NOH
H
142
4.2.4 Conclusion
In conclusion, we have established a facile and convenient protocol for the
synthesis of aldoxime and ketoximes esters of alkyl and aryl substituted carboxylic
acids. Both aldoximes and ketoximes afforded the oxime esters in excellent yield.
The method was operationally simple and commercially available, inexpensive EDCI
was used as the reagent for esterification reaction. The reactions were completed in
short duration and afforded the products in high yield. The selectivity of the reaction,
which avoids intramolecular condensation of acid and amine, is an important
observation. The column chromatography is completely avoided for purification of
compounds in the case of solid products. Hence, the protocol is facile, eco-friendly
and very convenient for synthesis of oxime esters that have a crucial role in bio-
organic and medicinal chemistry field.
143
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