synthesis and importance of oxime...

Chapter 4

Synthesis and Importance of Oxime esters

104

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

105

[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.

106

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.

107

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

108

(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.

109

(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

110

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 =


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.

111

(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 =


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,

112

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

113

(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

114

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

115

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

116

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

117

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

118

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

119

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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[6] T.L.J. Liu, J. Han, B. Fu, D. Wang, M. Wang, Chinese Journal Organic

Chemistry 29 (2009) 898.

[7] L.X.H. Song Bao An, Yang Song,Hu De-Yujin Lin Hong,Zhang Yu Tao,

Chinese Journal Organic Chemistry 25 (2005) 507.

[8] T. Hart, B. Sharp, Chemical Abstract, 1991, p. 92075.

[9] E. Abele, R. Abele, K. Rubina, E. Lukevics, Chemistry of Heterocyclic

Compounds 41 (2005) 137.

[10] N. Zhukovskaya, E. Dikusar, V. Potkin, O. Vyglazov, Chemistry of Natural

Compounds 45 (2009) 148.

[11] X.H. Liu, L.P. Zhi, B.A. Song, H.L. Xu, Chemical Research in Chinese

Universities 24 (2008) 454.

[12] V. Stefan, P. Muriel, B. Christophe, C. Marc, V. Andrea, Helvetica Chimica

Acta 82 (1999) 963.

121

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of Medicinal Chemistry 57 (2012) 275.

[16] S.C. Santosh Kumar, N. Vijendra Kumar, P. Srinivas, B.K. Bettadaiah,

Synthesis 46 (2014) 1847.

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-


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-


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


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


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


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


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



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



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


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


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


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


p-Toluic 2d 10 92


Benzoic 3a 12 92

Butyric 3b 10 96


p-Toluic 3d 14 91


Benzoic 4a 06 91

Butyric 4b 07 95


p-Toluic 4d 12 93


Benzoic 5a 12 92

Butyric 5b 10 96

4-Aminobenzoic NR - -

p-Toluic 5d 12 91


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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