A convenient practical synthesis of alkyl and aryl oxime esters

Article abstract of DOI:10.1055/s-0034-1378350

A facile access to the synthesis of alkyl and aryl oxime esters of ketoximes and aldoximes in high yields (90-97%) is reported. The reactions were performed using N-[3-(methylamino)propyl]-N′-ethylcarbodiimide hydrochloride (EDCI) reagent in the presence of 4-(dimethylamino)pyridine (DMAP) as a catalyst at room temperature. The isolation and purification of products is very simple and in cases where product is solid, column chromatography is avoided. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0034-1378350

PRACTICAL SYNTHETIC PROCEDURES
▌1847
pAracCticaol snynvtheetniciperoncetduPresractical Synthesis of Alkyl and Aryl Oxime Esters
Synthesis of Alkyl and Aryl Oxime Esters
S. Chandrappa Santosh Kumar, Nanjundaswamy Vijendra Kumar, Pullabhatla Srinivas,
Bheemanakere Kempaiah Bettadaiah*
Plantation Products, Spices and Flavour Technology Department,
CSIR-Central Food Technological Research Institute, Mysore 570020, India
Fax +91(821)2517233; E-mail: bettadaiah@cftri.res.in
PSP
Received: 03.02.2014; Accepted after revision: 30.05.2014
No275
Abstract: A facile access to the synthesis of alkyl and aryl oxime esters of ketoximes and aldoximes in high yields (90–97%) is reported.
The reactions were performed using N-[3-(methylamino)propyl]-N′-ethylcarbodiimide hydrochloride (EDCI) reagent in the presence of 4-
(dimethylamino)pyridine (DMAP) as a catalyst at room temperature. The isolation and purification of products is very simple and in cases
where product is solid, column chromatography is avoided.
Key words: oxime esters, aldoximes, ketoximes, EDCI, esterification, dehydration
OCOR3
OH
N
N
EDCI⋅HCl
r.t., CH2Cl2
R3CO2H
+
R2
R1
R2
R1 = alkyl, aryl
R2 = H, alkyl, aryl
R1
R3 = alkyl, aryl
24 examples
90–97%
Scheme 1 Synthesis of oxime esters
Oxime esters are a small, but important, class of biologi- are good, this route cannot be used for acid and base sen-
cally useful compounds the for synthesis of fragrances,1 sitive functionalities. Also, the methodology requires an
crop protection,2 and therapeutic studies.3 They are useful additional step, the preparation of the acid chloride from a
building blocks in peptide synthesis.4 Oxime esters are se- carboxylic acid, and the acid chloride must be used imme-
lective covalent inhibitors of serine hydrolase retinoblas- diately for oxime preparation. Since acid chlorides are
toma-binding protein 9 (RBBP9) and cleave DNA under susceptible to hydrolysis, anhydrous reaction conditions
photolytic conditions.5,6 They also possess fungicidal,7 have to be maintained to afford good yields of oxime es-
herbicidal,8 insecticidal,9 and antitumor activity.10 Oxime ters. Also, the purification of products is cumbersome and
esters of dihydrocoumaric acid have been synthesized and invariably requires column chromatography. A few alter-
they are reported to have antibacterial activity.11 Aromatic nate syntheses of oxime esters are also reported, such as
benzophenone oxime esters and dibenzosuberone oxime the preparation of benzoyl esters of alkyl- and aryl-substi-
esters are pharmacologically important.12 Vanillin- tuted oximes using benzoyl peroxide, but the method is
derived piperidin-4-one oxime esters have been tested for applicable mainly to benzoyl esters of oximes.15 Oxime
antioxidant and antimicrobial potential.13 The oxime es- esters can be prepared using α,β-unsaturated aldehydes
ters derived from nafimidone have been tested as potential and oximes using a N-heterocyclic carbene as a redox es-
anticonvulsant compounds.14 Various methods have been terification catalyst.16
used for the preparation of oxime esters, but there is scope
Owing to the importance of oxime esters, we have devel-
for improvement in the development of new methods in
oped a simple and very efficient synthetic protocol that af-
terms of simplification of the experimental protocol and
fords the product in high yields. The synthesis involves
improvement of yields. A convenient preparative protocol
the treatment of alkyl- or aryl-substituted oximes with al-
iphatic or aromatic acids in the presence of N-[3-(methyl-
with simple purification and general applicability to the
oxime esters is required (Scheme 1).
amino)propyl]-N′-ethylcarbodiimide
hydrochloride
The classic preparation of oxime esters involves either the (EDCI) reagent (Scheme 1). The products are obtained in
condensation of acid chlorides with oximes under basic high yields in most solvents. The reactions were complete
conditions or the use of acid anhydrides in presence of in a reasonable time at room temperature. The products
strong acids.1,6a,b,11,13,14 Though the yields of oxime esters were easily isolated and purification involves no chro-
matographic separation. The solid products were isolated
in pure form by simple concentration of the solvent and
treatment with few drops of petroleum ether and agitation
in a bath-type sonicator. The liquid products were purified
SYNTHESIS 2014, 46, 1847–1852
Advanced online publication: 24.06.2014
DOI: 10.1055/s-0034-1378350; Art ID: ss-2014-z0086-psp
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

1848
S. C. Santosh Kumar et al.
PRACTICAL SYNTHETIC PROCEDURES
by passing through small pad of silica gel. Since EDCI is acid and amine groups. Hence, the present protocol is also
easily available, inexpensive, and soluble in water, the selective and affords the oxime ester over the amide prod-
present protocol is very useful for the synthesis of various uct, which otherwise is the major expected product by self
oxime esters.
condensation of acid and amine groups.
An optimization experiment was carried out to select the We studied the reaction of carvone oxime (1b) with acids
solvent for the preparation of oxime esters using EDCI as 2a–e. The products 3ba–be were obtained in over 92%
the reagent. All reactions were carried out at ambient tem- isolated yield. Butanoic acid reacted faster than the unsub-
perature under a nitrogen atmosphere. The esters were ob- stituted and substituted aromatic acids. The acetophenone
tained in all solvents in excellent yields. Cyclohexanone oxime (1c) was found to react faster with the acids in af-
oxime (1a) was esterified with benzoic acid (2a) in polar fording the corresponding oxime esters in high yield. Sim-
aprotic, protic, and chlorinated solvents (Table 1). The re- ilarly, benzophenone oxime (1d) and benzaldehyde oxime
actions were faster, and the yield of the product 3aa was (1e) gave oxime esters in high yields in the optimum time.
higher (>92%) in chlorinated solvents compared to other Substituent tolerance of the reaction was checked for 3-
common solvents (80–88%). The reaction in dichloro- methylcyclohexanone and 4-chlorobenzaldehyde oxime
methane was found to be the best choice for oxime ester with benzoic acid. The product yield in both cases was
preparation.
>95% (see the Supporting Information; 1H and 13C NMR
spectra provided).
Table 1 Oxime Ester Preparation in Different Solvents
In conclusion, we have developed a convenient protocol
for preparation of oxime esters of alkyl- and aryl-substi-
tuted carboxylic acids. Both aldoximes and ketoximes
gave the title compounds in excellent yields. The protocol
is operationally simple and commercially available inex-
pensive EDCI reagent was used for esterification. The re-
actions are fast and afford products in high yield. It is
important to note the selectivity of esterification for ox-
imes with acids over intermolecular acid–amine coupling
under the present experimental conditions. The purifica-
tion of products involves no chromatography in the case
of solid products. Hence, the present protocol is facile and
very convenient for oxime esters preparations.
OH
N
OH
O
N
O
O
+
EDCI⋅HCl
r.t., solvent
1a
2a
3aa
Entry
Solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
MeCN
THF
15
20
18
12
8
82
85
88
80
96
92
EtOH
MeOH
CH2Cl2
CHCl3
Laboratory grade solvents were generally used. Petroleum ether
(PE) refers to the fraction with bp 60–80 °C. Pre-coated aluminum
silica 60 F254 plates from Merck were used for TLC analyses. Col-
umn chromatography was performed using silica gel 200–400 mesh
using PE–EtOAc mixtures (PE = petroleum ether). NMR spectra
were recorded on a 500 MHz NMR spectrometer (Bruker Avance,
Reinstetten, Germany) using CDCl3 solvent with reference to sig-
nals at δ = 7.26 (CHCl3, 1H) and δ = 77.16 (CDCl3, 13C). Mass spec-
tral analysis were carried out using HRMS (Waters Q-Tof Ultima,
Manchester, UK) in ESI positive mode. The IR spectra (KBr pel-
lets) were recorded on a FT Raman-Nicolet 5700 instrument.
9
a Isolated yield.
To optimize the reaction conditions for the stoichiometric
ratio of oxime to acid, a reaction was carried out with
equimolar quantities of cyclohexanone oxime (1a) and
benzoic acid (2a) in the presence of one equivalent of
EDCI. The reaction was very slow and only 50% conver-
sion could be realized in 24 hours. The reaction using an
equimolar ratio of acid to oxime with two equivalents of
EDCI was complete in 12 hours, but the reaction using 2.5
equivalents of EDCI was faster (8 h).
Oxime Esters 3aa-ee; General Procedure
To a solution of ketoxime or aldoxime 1 (2.0 mmol) in CH2Cl2 (20
mL) was added the carboxylic acid 2 (2.0 mmol) followed by EDCI
(5 mmol) and DMAP (0.2 mmol). The mixture was magnetically
stirred at r.t. under N2 until the reaction was complete (TLC moni-
toring, PE–EtOAc). The mixture was diluted with H2O (25 mL) and
the CH2Cl2 layer was separated, dried (anhyd Na2SO4), and concen-
trated. The crude mass obtained was treated with PE (2–3 mL); sep-
aration of a solid occurred when sonicated. The resultant solid was
filtered and dried under suction to afford the oxime esters 3 in pure
form in 90–97% yield. The physical and spectral data of compounds
are presented below.
Under the optimized conditions, cyclohexanone oxime
(1a) was treated with different alkyl- and aryl-substituted
aromatic acids 2a–e (Table 2). The reaction with butanoic
acid (2b) was fast, whereas the reactions with 4-amino-
benzoic acid (2c) and p-toluic acid (2d) took longer. In all
cases the conversion was complete and the products were
recovered in over 94% isolated yield. In the case of 4-ami-
nobenzoic acid (2d), a substrate containing both amino
and carboxylic groups, the oxime ester was selectively
formed without any self-condensation product from the
Cyclohexanone O-Benzoyl Oxime (3aa)1c
White solid; yield: 184 mg (96%); mp 64–65 °C.
IR (KBr): 1730, 1633 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.06 (d, J = 7.27 Hz, 2 H), 7.56 (t,
J = 7.27 Hz, 1 H), 7.44 (t, J = 7.94 Hz, 2 H), 2.66 (t, J = 6.34 Hz, 2
Synthesis 2014, 46, 1847–1852
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of Alkyl and Aryl Oxime Esters
1849
Table 2 Preparation of Alkyl and Aryl Oxime Esters of Alkyl and Aromatic Acids
OCOR3
OH
N
N
EDCI⋅HCl
r.t., CH2Cl2
+
R3CO2H
R2
3aa–ee
R1
R2
1a–e
R1
2a–e
Oxime R1R2C=NOH
Carboxylic acid
2
Time (h)
Product
Yielda (%)
R3
OH
N
2a
2b
2c
2d
2e
Ph
Pr
8
6
20
20
3
3aa
3ab
3ac
3ad
3ae
96
95
94
97
90
4-H2NC6H4
4-MeC6H4
4-O2NC6H4
1a
N
2a
2b
2c
2d
2e
Ph
Pr
10
8
12
10
3
3ba
3bb
3bc
3bd
3be
97
92
94
92
93
OH
4-H2NC6H4
4-MeC6H4
4-O2NC6H4
1b
OH
N
2a
2b
2c
2d
2e
Ph
Pr
12
10
15
14
4
3ca
3cb
3cc
3cd
3ce
92
96
94
91
95
4-H2NC6H4
4-MeC6H4
4-O2NC6H4
1c
OH
N
2a
2b
2c
2d
2e
Ph
Pr
6
7
19
12
4
3da
3db
3dc
3dd
3de
91
95
90
93
92
Me
4-H2NC6H4
4-MeC6H4
4-O2NC6H4
1d
OH
N
2a
2b
2c
2d
2e
Ph
Pr
12
10
–
12
4
3ea
3eb
–
3ed
3ee
96
90
–
91
94
H
b
4-H2NC6H4
4-MeC6H4
4-O2NC6H4
1e
a Yield of isolated product.
b No reaction.
H), 2.45 (t, J = 6.34 Hz, 2 H), 1.77 (pent, J = 6.01 Hz, 2 H), 1.72
(pent, J = 6.01 Hz, 2 H), 1.61–1.66 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 169.2, 163.9, 132.8, 129.1, 128.1,
Cyclohexanone O-4-Aminobenzoyl Oxime (3ac)
White solid; yield: 193 mg (94%); mp 145–146 °C.
IR (KBr): 1707, 1638 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.84 (d, J = 8.25 Hz, 2 H), 6.64 (d,
J = 8.25 Hz, 2 H), 4.48 (br s, 2 H), 2.64 (t, J = 6.34 Hz, 2 H), 2.41
(t, J = 6.34 Hz, 2 H), 1.74 (q, J = 5.91 Hz, 2 H), 1.69 (q, J = 6.10 Hz,
2 H), 1.57–1.63 (m, 2 H).
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.
31.8, 26.7, 26.4, 25.5, 25.0.
HRMS (ESI): m/z [M + Na]+ calcd for C13H15NO2Na: 240.1000;
found: 240.1086.
Cyclohexanone O-Butanoyl Oxime (3ab)
Pale yellow liquid; yield: 154 mg (95%).
IR (neat):1760, 1642 cm–1.
1H NMR (500 MHz, CDCl3): δ = 2.39 (t, J = 6.46 Hz, 2 H), 2.21–
2.28 (m, 4 H), 1.57–1.62 (m, 3 H), 1.50–1.56 (m, 3 H), 1.45–1.50
(m, 2 H), 0.84 (t, J = 7.48 Hz, 3 H).
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/z [M + H]+ calcd for C13H17N2O2: 233.1290; found:
233.1317.
Cyclohexanone O-4-Methylbenzoyl Oxime (3ad)
White solid; yield: 198.5 mg (97%); mp 75–76 °C.
IR (KBr): 1728, 1635 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.94 (d, J = 8.17 Hz, 2 H), 7.23 (d,
J = 8.08 Hz, 2 H), 2.65 (t, J = 6.25 Hz, 2 H), 2.44 (t, J = 6.54 Hz, 2
HRMS (ESI): m/z [M + Na]+ calcd for C10H17NO2Na: 206.1157;
found: 206.1208.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1847–1852

1850
S. C. Santosh Kumar et al.
PRACTICAL SYNTHETIC PROCEDURES
H), 2.39 (s, 3 H), 1.77 (pent, J = 5.93 Hz, 2 H), 1.72 (pent, J = 5.93
Hz, 2 H), 1.60–1.66 (m, 2 H).
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.
(E)-2-Methyl-5-(prop-1-en-2-yl)cyclohex-2-enone O-4-Methyl-
benzoyl Oxime (3bd)
White solid; yield: 157.6 mg (92%); mp 73–75 °C.
IR (KBr): 1741, 1645 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.96 (d, J = 7.85 Hz, 2 H), 7.25 (d,
J = 7.85 Hz, 2 H), 6.25 (d, J = 4.42 Hz, 1 H), 4.81 (d, J = 11.54 Hz,
2 H), 3.28 (dd, J1 = 16.20 Hz, J2 = 1.96 Hz, 1 H), 2.44 (d, J = 12.27
Hz, 1 H), 2.40 (s, 3 H), 2.32 (t, J = 14.48 Hz, 2 H), 2.11–2.17 (m, 1
H), 2.01 (s, 3 H), 1.76 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 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/z [M + Na]+ calcd for C14H17NO2Na: 254.1156;
found: 254.1139.
Cyclohexanone O-4-Nitrobenzoyl Oxime (3ae)
Pale yellow solid; yield: 209 mg (90%); mp 110–112 °C.
IR (KBr): 1730, 1631 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.29 (d, J = 8.85 Hz, 2 H), 8.21 (d,
J = 8.85 Hz, 2 H), 2.66 (t, J = 6.49 Hz, 2 H), 2.46 (t, J = 6.19 Hz, 2
H), 1.79 (q, J = 5.81 Hz, 2 H), 1.74 (q, J = 5.81 Hz, 2 H), 1.66 (d,
J = 4.30 Hz, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C18H21NO2Na: 306.1469;
found: 306.1495.
13C NMR (125 MHz, 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/z [M + Na]+ calcd for C13H14N2ONa: 285.0852;
(E)-2-Methyl-5-(prop-1-en-2-yl)cyclohex-2-enone O-4-Nitro-
benzoyl Oxime (3be)
White solid; yield: 176.7 mg (93%); mp 97–99 °C.
IR (KBr): 1744, 1642 cm–1.
found: 285.0813.
1H NMR (500 MHz, CDCl3): δ = 8.35 (d, J = 8.78 Hz, 2 H), 8.26 (d,
J = 8.65 Hz, 2 H), 6.35 (dd, J1 = 3.48, J2 = 1.45 Hz, 1 H), 4.87 (s, 1
H), 4.83 (s, 1 H), 3.23–3.29 (m, 1 H), 2.46–2.51 (m, 1 H), 2.36–2.42
(m, 2 H), 2.17–2.24 (m, 1 H), 2.04 (s, 3 H), 1.80 (s, 3 H).
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.
(E)-2-Methyl-5-(prop-1-en-2-yl)cyclohex-2-enone O-Benzoyl
Oxime (3ba)
White solid; yield: 158 mg (97%); mp 92–94 °C.
IR (KBr): 1739, 1641 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.15 (d, J = 7.11 Hz, 2 H), 7.66 (t,
J = 7.61 Hz, 1 H), 7.55 (t, J = 7.85 Hz, 2 H), 6.32–6.36 (m, 1 H),
4.91 (d, J = 1.11 Hz, 1 H), 4.89 (br s, 1 H), 3.35–3.39 (m, 1 H),
2.50–2.55 (m, 1 H), 2.39–2.45 (m, 2 H), 2.21–2.27 (m, 1 H), 2.10
(s, 3 H), 1.85 (s, 3 H).
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/z [M + Na]+ calcd for C17H18N2O4Na: 337.1164;
found: 337.1107.
Benzophenone O-Benzoyl Oxime (3ca)17
White solid; yield: 140.4 mg (92%); mp 103–105 °C.
IR (KBr): 1739, 1645 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.82 (d, J = 7.35 Hz, 2 H), 7.70 (d,
J = 7.35 Hz, 2 H), 7.54 (t, J = 3.26 Hz, 4 H), 7.50 (t, J = 7.35 Hz, 1
H), 7.44 (t, J = 4.62 Hz, 3 H), 7.40 (q, J = 7.62 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 165.2, 163.4, 134.3, 132.8, 130.6,
129.3, 128.8, 128.5, 128.1, 127.9.
HRMS (ESI): m/z [M + Na]+ calcd for C17H19NO2Na: 292.1313;
found: 292.1263.
(E)-2-Methyl-5-(prop-1-en-2-yl)cyclohex-2-enone O-Butanoyl
Oxime (3bb)
Pale yellow liquid; yield: 131 mg (92%).
IR (neat): 1761, 1644 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.20–6.27 (m, 1 H), 4.81 (d,
J = 1.22 Hz, 1 H), 4.77 (br s, 1 H), 3.12–3.19 (m, 1 H), 2.45 (t,
J = 7.50 Hz, 2 H), 2.28–2.38 (m, 2 H), 2.11–2.21 (m, 2 H), 1.94 (t,
J = 0.91 Hz, 3 H), 1.75 (s, 3 H), 1.72 (q, J = 7.5 Hz, 2 H), 1.00 (t,
J = 7.50 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 171.0, 162.4, 146.7, 136.6, 129.8,
110.1, 39.8, 34.5, 30.0, 28.7, 20.1, 18.0, 17.2, 13.3.
HRMS (ESI): m/z [M + Na]+ calcd for C20H15NO2Na: 324.1000;
found: 324.1046.
Benzophenone O-Butanoyl Oxime (3cb)
White solid; yield: 130 mg (96%); mp 55–57 °C.
IR (KBr): 1768, 1652 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.56 (d, J = 7.23 Hz, 2 H), 7.44 (d,
J = 2.20 Hz, 2 H), 7.43 (d, J = 1.26 Hz, 1 H), 7.39–7.42 (m, 1 H),
7.33 (t, J = 7.89 Hz, 2 H), 7.29 (d, J = 1.99, Hz, 1 H), 7.28 (d,
J = 4.11, Hz, 1 H), 2.28 (t, J = 7.40 Hz, 2 H), 1.59 (sextet, J = 7.40
Hz, 2 H), 0.88 (t, J = 7.51 Hz, 3 H).
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/z [M + Na]+ calcd for C14H21NO2Na: 258.1469;
found: 258.1456.
(E)-2-Methyl-5-(prop-1-en-2-yl)cyclohex-2-enone O-4-Amino-
benzoyl Oxime (3bc)
White solid; yield: 161.5 mg (94%); mp 192–193 °C.
IR (KBr): 1717, 1631 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.90 (d, J = 8.72 Hz, 2 H), 6.68 (d,
J = 8.57 Hz, 2 H), 6.26 (d, J = 4.93 Hz, 1 H), 4.83 (d, J = 11.53 Hz,
2 H), 4.16 (br s, 2 H), 3.30 (dd, J1 = 16.27, J2 = 2.48 Hz, 1 H), 2.41–
2.52 (m, 1 H), 2.30–2.38 (m, 2 H), 2.14–2.20 (m, 1 H), 2.03 (s, 3 H),
1.79 (s, 3 H).
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/z [M + Na]+ calcd for C17H17NO2Na: 290.1156;
found: 290.1165.
Benzophenone O-4-Aminobenzoyl Oxime (3cc)
Yellow solid; yield: 150.6 mg (94%); mp 114–115 °C.
IR (KBr): 1658, 1597 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.48–7.52 (m, 9 H), 7.41 (t,
J = 2.44 Hz, 1 H), 7.40 (t, J = 1.53 Hz, 1 H), 7.38 (d, J = 1.35 Hz, 2
H), 7.36 (d, J = 1.53 Hz, 2 H), 7.35 (t, J = 1.62 Hz, 1 H).
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/z [M + H]+ calcd for C17H21N2O2: 285.1603; found:
285.1636.
HRMS (ESI): m/z [M + H]+ calcd for C20H17N2O2: 317.1290; found:
316.9080.
Synthesis 2014, 46, 1847–1852
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of Alkyl and Aryl Oxime Esters
1851
Benzophenone O-4-Methylbenzoyl Oxime (3cd)
White solid; yield: 145.4 mg (91%); mp 108–110 °C.
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.
IR (KBr): 1737, 1647 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C16H16NO2: 254.1181; found:
1H NMR (500 MHz, CDCl3): δ = 7.65 (t, J = 8.46 Hz, 4 H), 7.47 (t,
J = 2.88 Hz, 3 H), 7.42 (t, J = 7.11 Hz, 1 H), 7.37–7.40 (m, 2 H),
7.34 (t, J = 7.50 Hz, 2 H), 7.12 (d, J = 8.17 Hz, 2 H), 2.32 (s, 3 H).
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/z [M + Na]+ calcd for C21H17NO2Na: 338.1156;
found: 338.1109.
254.1150.
(E)-Acetophenone O-4-Nitrobenzoyl Oxime (3de)
White solid; yield: 193.3 mg (92%); mp 167–169 °C.
IR (KBr): 1744, 1604 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.31 (q, J = 8.75 Hz, 4 H), 7.81 (d,
J = 7.26 Hz, 2 H), 7.42–7.49 (m, 3 H), 2.54 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 164.2, 161.6, 150.3, 134.3, 134.0,
Benzophenone O-4-Nitrobenzoyl Oxime (3ce)
130.6, 130.4, 128.3, 126.8, 123.44, 14.4.
HRMS (ESI): m/z [M + Na]+ calcd for C15H12N2O4Na: 307.0694;
found: 307.0673.
Pale yellow solid; yield: 166.7 mg (95%); mp 150–152 °C.
IR (KBr): 1753, 1651 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.22 (d, J = 8.97 Hz, 2 H), 7.95 (d,
J = 8.80 Hz, 2 H), 7.69 (d, J = 7.28 Hz, 2 H), 7.53–7.57 (m, 3 H),
7.50 (d, J = 7.45 Hz, 1 H), 7.42 (t, J = 7.54 Hz, 4 H).
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/z [M + Na]+ calcd for C20H14N2O4Na: 369.0851;
found: 369.0836.
(E)-Benzaldehyde O-Benzoyl Oxime (3ea)17
White solid; yield: 178.3 mg (96%); mp 105–107 °C.
IR (KBr): 1743, 1652 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.54 (s, 1 H), 8.13 (d, J = 7.29 Hz,
2 H), 7.80 (d, J = 7.10 Hz, 2 H), 7.59 (t, J = 7.29 Hz, 1 H), 7.47 (t,
J = 7.66 Hz, 3 H), 7.42 (t, J = 7.66 Hz, 2 H).
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/z [M + Na]+ calcd for C14H11NO2Na: 248.0687;
found: 248.0627.
(E)-Acetophenone O-Benzoyl Oxime (3da)17
White solid; yield: 161 mg (91%); mp 85–87 °C.
IR (KBr): 1743, 1647 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.08 (d, J = 7.66 Hz, 2 H), 7.77 (d,
J = 6.89 Hz, 2 H), 7.55 (t, J = 7.50 Hz, 1 H), 7.43 (t, J = 7.66 Hz, 2
H), 7.34–7.40 (m, 3 H), 2.44 (s, 3 H).
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/z [M + Na]+ calcd for C15H13NO2Na: 262.0843;
found: 262.0872.
(E)-Benzaldehyde O-Butanoyl Oxime (3eb)
Liquid; yield: 142 mg (90%).
IR (neat): 1760, 1645 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.29 (d, J = 5.10 Hz, 1 H), 7.67 (d,
J = 6.93 Hz, 2 H), 7.32–7.41 (m, 3 H), 2.38 (q, J = 6.93 Hz, 2 H),
1.65–1.74 (m, 2 H), 0.96 (t, J = 7.29 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 170.6, 155.5, 131.2, 129.8, 128.5,
(E)-Acetophenone O-Butanoyl Oxime (3db)
127.9, 34.2, 29.3, 17.9, 13.2.
HRMS (ESI): m/z [M + Na]+ calcd for C11H13NO2Na: 214.0843;
found: 214.0828.
White solid; yield: 144 mg (95%); mp 89–91 °C.
IR (KBr): 1762, 1614 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.73 (d, J = 6.84 Hz, 2 H), 7.36–
7.43 (m, 3 H), 2.48 (t, J = 7.32 Hz, 2 H), 2.36 (s, 3 H), 1.76 (sextet,
J = 7.32 Hz, 2 H), 1.01 (t, J = 7.32 Hz, 3 H).
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/z [M + H]+ calcd for C12H16NO2: 206.1181; found:
206.1161.
(E)-Benzaldehyde O-4-Methylbenzoyl Oxime (3ed)
White solid; yield: 179.6 mg (91%); mp 125–127 °C.
IR (KBr): 1730, 1608 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.54 (s, 1 H), 8.03 (d, J = 7.90 Hz,
2 H), 7.81 (d, J = 7.90 Hz, 2 H), 7.49 (t, J = 6.67 Hz, 1 H), 7.44 (t,
J = 7.55 Hz, 2 H), 7.28 (d, J = 8.07 Hz, 2 H), 2.42 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 163.7, 156.2, 143.9, 131.3, 131.1,
(E)-Acetophenone O-4-Aminobenzoyl Oxime (3dc)
130.8, 129.9, 129.4, 129.1, 128.9, 128.5, 128.1, 125.5, 21.4.
HRMS (ESI): m/z [M + Na]+ calcd for C15H13NO2Na: 262.0843;
found: 262.0806.
White solid; yield: 169 mg (90%); mp 166–167 °C.
IR (KBr): 1708, 1600 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.93 (d, J = 8.23 Hz, 2 H), 7.81 (d,
J = 6.76 Hz, 2 H), 7.40–7.46 (m, 3 H), 6.68 (d, J = 8.23 Hz, 2 H),
4.28 (br s, 2 H), 2.50 (s, 3 H).
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/z [M + Na]+ calcd for C15H14N2O2Na: 277.0952;
found: 277.0952.
(E)-Benzaldehyde O-4-Nitrobenzoyl Oxime (3ee)
Pale yellow solid; yield: 209.5 mg (94%); mp 159–161 °C.
IR (KBr): 1740, 1606 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.60 (s, 1 H), 8.34 (q, J = 8.86 Hz,
4 H), 7.83 (d, J = 7.15 Hz, 2 H), 7.54 (t, J = 7.26 Hz, 1 H), 7.49 (t,
J = 7.26 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 161.7, 157.3, 150.4, 133.8, 131.8,
(E)-Acetophenone O-4-Methylbenzoyl Oxime (3dd)
130.5, 129.3, 128.7, 128.3, 123.4.
HRMS (ESI): m/z [M + Na]+ calcd for C14H10N2O4Na: 293.0538;
found: 293.0550.
White solid; yield: 174 mg (93%); mp 115–117 °C.
IR (KBr): 1732, 1606 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.96 (d, J = 7.86 Hz, 2 H), 7.75 (d,
J = 7.73 Hz, 2 H), 7.33–7.39 (m, 3 H), 7.20 (d, J = 7.99 Hz, 2 H),
2.41 (s, 3 H), 2.34 (s, 3 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1847–1852

1852
S. C. Santosh Kumar et al.
PRACTICAL SYNTHETIC PROCEDURES
(5) Bachovchin, D. A.; Wolfe, M. R.; Masuda, K.; Brown, S. J.;
Spicer, T. P.; Fernandez-Vega, V.; Chase, P.; Hodder, P. S.;
Rosen, H.; Cravatt, B. F. Bioorg. Med. Chem. Lett. 2010, 20,
2254.
(6) (a) Hwu, J. R.; Tsay, S.; Hong, S. C.; Hsu, M.; Liu, C.; Chou,
S. P. Bioconjugate Chem. 2013, 24, 1778. (b) Bindu, P. J.;
Mahadevan, K. M.; Satyanarayan, N. D.; Ravikumar Naik,
T. R. Bioorg. Med. Chem. Lett. 2012, 22, 898.
(7) Liu, X. H.; Zhi, L. P.; Song, B. A.; Xu, H. L. Chem. Res.
Chin. Univ. 2008, 24, 454.
Acknowledgment
Author S.C.S.K. thanks University Grants Commission, New Delhi,
India, for the award of a Senior Research Fellowship. We thank Mr.
Mukund Padmere Laxman, CFTRI, Mysore, for HRMS analysis
and Mr. J. R. Manjunatha, CFTRI, Mysore for NMR spectral analy-
sis.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
(8) Li, T. G.; Liu, J. P.; Han, J. T.; Fu, B.; Wang, D. Q.; Wang,
M. G. Chin. J. Org. Chem. 2009, 29, 898.
10.1055/s-00000084.SunpfgIpi
o
o
nr
i
(9) Ma, J. A.; Huang, R. Q.; Chai, Y. X. Prog. Nat. Sci. 2002,
12, 271.
(10) Song, B. A.; Liu, X. H.; Yang, S.; Hu, D. Y.; Jin, L. H.;
Zhang, Y. T. Chin. J. Org. Chem. 2005, 25, 507.
(11) Gao, Y.; Song, J.; Shang, S.; Wang, D.; Li, J. BioResources
2012, 7, 4150.
(12) Wylie, B. B.; Isaacson, E. I.; Delgado, G. N. J. Pharm. Sci.
1965, 54, 1373.
(13) Harini, S. T.; Vijay Kumar, H.; Rangaswamy, J.; Naik, N.
Bioorg. Med. Chem. Lett. 2012, 22, 7588.
References
(1) (a) Zhukovskaya, N. A.; Dikusar, E. A.; Potkin, V. I.;
Vyglazov, O. G. Chem. Nat. Compd. 2009, 45, 148.
(b) Zhukovskaya, N. A.; Dikusar, E. A.; Vyglazov, O. G.
Chem. Nat. Compd. 2008, 44, 688. (c) Dikusar, E. A.;
Zhukovskya, N. A. Russ. J. Org. Chem. 2008, 44, 1389.
(2) Lukasczyk, A.; Martin, H.; Diel, P. J.; Föry, W.; Gätzi, K.;
Kristinsson, H.; Müller, B.; Muntwyler, J. P.; Pachlatko, H.;
Rempfler, H.; Schurter, R.; Szczepanski, H. EP 0,012,158,
1980.
(14) Karakurt, A.; Alagöz, M. A.; Sayoğlu, B.; Çaliş, Ü.; Dalkara,
S. Eur. J. Med. Chem. 2012, 57, 275.
(3) Crichlow, G. V.; Cheng, K. F.; Dabideen, D.; Ochani, M.;
Aljabari, B.; Pavlov, V. A.; Miller, E. J.; Lolis, E.; Al-Abed,
Y. J. Biol. Chem. 2007, 282, 3089.
(4) Hayashi, I.; Shimizu, K. Bull. Chem. Soc. Jpn. 1983, 56,
3197.
(15) Kundu, S. K.; Rahman, M.; Dhara, P.; Hajra, A.; Majee, A.
Synth. Commun. 2012, 42, 1848.
(16) Enders, D.; Grossmann, A.; Craen, D. V. Org. Biomol.
Chem. 2013, 11, 138.
(17) Okada, T.; Kawanisi, M.; Nazaki, H. Bull. Chem. Soc. Jpn.
1969, 42, 2981.
Synthesis 2014, 46, 1847–1852
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