A mild system for synthesis of aldoximes and ketoximes in the presence of N-hydroxyphthalimide in aqueous system

Article abstract of DOI:10.1016/j.tet.2018.08.013

An efficient method for synthesis of oximes from aldehydes or ketones with N-hydroxyphthalimide or N-hydroxysuccinimide in water has been described. It is the first time to utilize NHPI as an oximation reagent to synthesize aldoximes and ketoximes from the corresponding organic carbonyl compounds without other reagents. The reaction tolerates various functional groups and affords the corresponding oximes in 76%–98% yields. The by-product phthalic acid can be recycled from the system. In addition, this method has been successfully applied to the synthesis of the precursor of some pharmacologically active amide molecules.

Full text of DOI:10.1016/j.tet.2018.08.013

Accepted Manuscript
A mild system for synthesis of aldoximes and ketoximes in the presence of N-
hydroxyphthalimide in aqueous system
Xiaoying Jiang, Xiaohe Xu, Yuyan Lin, Yiyan Yan, Pingping Li, Renren Bai, Yuanyuan
Xie
PII:
S0040-4020(18)30964-5
10.1016/j.tet.2018.08.013
TET 29733
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 May 2018
Revised Date: 28 July 2018
Accepted Date: 10 August 2018
Please cite this article as: Jiang X, Xu X, Lin Y, Yan Y, Li P, Bai R, Xie Y, A mild system for synthesis
of aldoximes and ketoximes in the presence of N-hydroxyphthalimide in aqueous system, Tetrahedron
(2018), doi: 10.1016/j.tet.2018.08.013.
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A mild system for synthesis of aldoximes and
ketoximes in the presence of N-
Leave this area blank for abstract info.
hydroxyphthalimide in aqueous system
a
a
a
a
a
a,b
a,b,*
Xiaoying Jiang , Xiaohe Xu , Yuyan Lin , Yiyan Yan , Pingping Li , Renren Bai , Yuanyuan Xie
a
Collaborative Innovation Centre of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University
of Technology, Hangzhou, 310014, P.R. China.
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310014, P.R. China.
b
OH
O
N
NHPI or NHSI
R1 R2
R1
R2
o
H O, 90 C
2
O
O
NHPI =
N OH
O
NHSI =
N OH
O

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
A mild system for synthesis of aldoximes and ketoximes in the presence of N-
hydroxyphthalimide in aqueous system
a
a
a
a
a
a,b
Xiaoying Jiang , Xiaohe Xu , Yuyan Lin , Yiyan Yan , Pingping Li , Renren Bai and Yuanyuan Xie
a,b,
∗
a
Collaborative Innovation Centre of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, 310014, P.R. China.
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310014, P.R. China.
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient method for synthesis of oximes from aldehydes or ketones with N-
hydroxyphthalimide or N-hydroxysuccinimide in water has been described. It is the first time to
utilize NHPI as an oximation reagent to synthesize aldoximes and ketoximes from the
corresponding organic carbonyl compounds without other reagents. The reaction tolerates
various functional groups and affords the corresponding oximes in 76% to 98% yields. The by-
product phthalic acid can be recycled from the system. In addition, this method has been
successfully applied to the synthesis of the precursor of some pharmacologically active amide
molecules.
Available online
Keywords:
N-hydroxyphthalimide
oximation
2
009 Elsevier Ltd. All rights reserved.
aldoximes
ketoximes
phthalic acid
1
. Introduction
products, such as ammonium salts; (2) it may limit the
application of aldehydes or ketones which contain acid or base
sensitive functionalities, and the yield of ketoximes are usually
low due to the low reactivity of ketones (Scheme 1, a). More
recently, Hyodo and co-workers developed the synthesis of
aldoximes and ketoximes using methylethyl ketone oxime or
ethyl acetohydroxamate as substrate through oxime exchange
reaction catalyzed 5kby Brønsted acid without use of
hydroxylamine salts. (Scheme 1, b). Although the reaction
conditions were mild, it still needs hydroxylamine to produce
target oxime, thus this may not be widely applicable. In
summary, these methods still suffer from using hydroxylamine
salt or excessive acid or base catalysts. Therefore, a new method
for synthesis of oximes without hydroxylamine is required.
Oximes have attracted much attention in both pharmaceuticals
1
and synthesis in recent years. They have many biological
activities such as antimicrobial, antioxidant, antitumor, anti-
depressive and antiviral agents. And they are vital intermediates
for many functional group transformations such as be reduced to
amines, oxidized to nitrile oxides, dehydrated to nitriles or
undergo an acid-catalyzed Beckmann rearrangement to afford
2
3
amides. Hence, many methods have been developed for their
efficient construction. Among these protocols, hydroxylamine
hydrochloride is considered as a common and useful reagent for
the synthesis of oximes. In general, the classical oximation is
from carbonyl compound to oxime with hydroxylamine
hydrochloride in the presence of a stoichiometric amount of acids
or bases, such as sulfuric acid, formic acid, oxalic acid, pyridine,
sodium acetate and sodium hydroxide. Furthermore, many
improvement strategies also have been carried out with new
systems or some organic catalysts such as polyethylene glycol
Over the past years, N-hydroxyphthalimide (NHPI) has been
4
6
used as an efficient catalyst for the activation of C-H bonds and
a stoichiometric reactant for the construction of the C-O bond in
7
organic synthesis . Herein, we report the synthesis of oximes
(PEG),
O-TBS-N-tosylhydroxylamine,
3-methyl-4-oxa-5-
from aldehydes and ketones using NHPI as a new oximation
reagent without other reagents (Scheme 1, c).
azahomoadamantane, L-amino acid ionic liquid, BaCl , Al O ,
TiO , phase transfer catalysis, etc. However, these reported
2
2
3
5
2
oximation reactions have some drawbacks that restrict their
further applications: (1) the traditional procedures need a
stoichiometric amount of hydroxylamine salt and bases, or
acids/catalysts simultaneously, which may result in many by-
∗
Corresponding author. Tel.: +86-189-5805-7635; e-mail: xyycz@zjut.edu.cn

2
Tetrahedron
o
b
Most strategy:
O
(equiv)
( C)
(h)
6
(%)
ACCEPTED MANUSCRIPT
1
2
3
4
5
1.0
1.0
1.0
1.0
1.0
THF
60
100
30
N.R.
N.R.
N.R.
OH
N
toluene
DCM
6
NH OH•HCl
2
R1
R2
6
R1
R2
(a)
acid or base or catalyst
acetone
ethanol
56
6
N.R.
N.R.
trace
(15)
80
60
6
3
Hyodo's work:
c
6
1.0
ethanol/H
2
O
O
60
(24)
OH
d
OH
O
HClO 10 mol%
N
O
7
1.0
1.0
1.0
1.0
1.1
1.2
1.1
ethanol/H
2
100
100
90
3
N
4
+
R1
+
(b)
8
H
2
H
2
H
2
H
2
H
2
H
2
O
O
O
O
O
O
3
80
81
75
88
89
87
R1 R2
R2
H2O, r.t., 24h
R
H
R
H
9
3
1
0
1
80
3
Our work:
O
1
90
3
OH
12
90
3
N
NHPI or NHSI
e
1
3
90
3
R1
R2
a
b
R1 R2
O
(c)
Reaction conditions: 1a (1.0 mmol), 2, solvent (3.0 mL). Isolated yields
H2O, 90 o
O
C
c
d
e
based on 1a. Ethanol/water (9/1 v/v). Ethanol/water (5/5 v/v). NHSI was
used. N.R.= no reaction.
Various aldehydes were then investigated under optimal
conditions and the results are summarized in Table 2. The results
indicated that aldehydes 1a-j reacted smoothly with 2 to give the
corresponding products 3a-3j in good to excellent yields.
Aldehydes with electron-withdrawing groups, such as F, Br, Cl,
CF and NO , gave the desired products 3a-f in 88-98% yields.
NHPI =
N OH NHSI =
N OH
O
O
Scheme 1 Oximation reactions
3
2
2
. Results and discussion
Initially, the reaction between p-fluorobenzaldehyde 1a and
NHPI 2 was performed at 60 C in THF. Unfortunately, no
desired product 3a was obtained (Table 1, entry 1). The reaction
did not proceed in other organic solvents such as toluene, DCM,
acetone and ethanol (entries 2-5). Water is considered as an ideal
solvent for organic reactions, since it is abundant, clean, safe,
Aldehydes with electron-donating groups, such as Me and OMe,
gave the desired products 3g-h in 84-86% yields. Generally, the
electron-deficient aldehydes carried on the reaction with better
yields than that of electron-rich aldehydes (3a-f vs 3g-h). Take p-
nitrobenzaldehyde as an example, it afforded the corresponding
product (3f) in 98% yield. Furthermore, substituents at different
positions on the benzene ring (para- and ortho-position) had little
influence on the yields of corresponding products (3a, 3b). The
reaction proceeded well when benzaldehyde and heteroaryl-
contained aldehydes were used as substrates, and the desired
oximes 3i, 3j, 3m, 3n were formed in 82-91% yields. It is
noteworthy that sensitive functional group such as hydroxyl was
well tolerated in the reaction and the desired products 3k and 3l
were obtained in high yields, respectively. Moreover, aliphatic
aldehyde 3-phenylpropanal could give the corresponding oxime
3o in 92% yield.
o
non-toxic,
non-combustible,
and
the
most
benign
8
environmentally. And thus, there are many reactions reported
were carried out in water. Additionally, NHPI can be completely
dissolved in hot water. Firstly, the reaction was performed in
ethanol/water (9/1 v/v) at 60 C for 3 h and a trace amount of 3a
was found. When the reaction time was extended to 24 h, the
desired product 3a was obtained in 15% yield (entry 6). The
yield of 3a reached 80% when the reaction was carried out in
9
6
d
o
o
ethanol/water (5/5 v/v) at 100 C (entry 7). These results
indicated that water plays an important role in the reaction. To
our delight, when the reaction was performed in water at 100 C,
a
o
Table 2 Synthesis of aldoximes with various aldehydes
the desired product 3a was also obtained in 80% yield (entry 8).
o
When the temperature was lowered to 90 C, the yield of product
3
a was almost unchanged (entry 9). However, when the
o
temperature was further decreased to 80 C, the yield of 3a was
reduced to 75% due to the decreased solubility of NHPI in water
(
entry 10). Additionally, the effect of the loading of NHPI was
further examined. In the presence of 1.0 equivalent of NHPI,
0% yield of 3a was obtained (entry 8). The yield was improved
8
up to 88% when 1.1 equivalent of NHPI was added (entry 11).
No further improvement was achieved when NHPI was increased
up to 1.2 equivalent (entry 12). When NHSI was used, the
desired product was also obtained in 87% yield (entry 13).
Therefore, the optimal conditions for this reaction are p-
fluorobenzaldehyde (1mmol), NHPI or NSHI (1.1mmol) and
o
H O (3mL) at 90 C for 3h.
2
a
Table 1 Optimization of the reaction conditions
Entry
NHPI
solvent
T
t
Yield

3
O
OH
O
OH
R3
O
ACCE
R1
N
PTED MANUSC
O
RIPT
R
N
H2O
2
H O
H
+
N
OH
3
R1
H
+
N OH
0 o
R2
9
C
0 o
R2
9
C
O
O
1
2
3
R2 = H, F, Cl, CH3, NH2, etc
R3 = CH3, CH2CH3, Ph
OH
OH
H
OH
H
N
N
F
N
4
2
5
H
F
Br
OH
N
R2 = H, 5a, 86%
R2 = 4-F, 5b, 94%
R2 = 4-Cl, 5c, 86%
R2 = 3-Cl, 5d, 88%
R2 = 3-Br, 5e, 87%
R2 = 2-Br, 5f, 83%
3
a, 88%
3b, 91%
3c, 92%
R2 = 4-NO , 5g, 98%
2
OH
H
OH
H
OH
H
R2
R2 = 4-CH3, 5h, 80%
N
N
N
R2 = 4-OCH , 5i, 82%
3
R2 = 2-NH , 5j, 83%
2
Cl
d, 92%
F3C
O2N
OH
OH
N
OH
OH
N
3
3e, 94%
3f, 98%
OH
N
N
OH
H
OH
H
OH
H
N
N
N
5k, 87%b
OH
5l, 80%b
5m, 76%c
5n, 94%b,d
OH
H3C
OCH3
3
i, 90%
OH
N
OH
N
3
3
3
g, 86%
3h, 84%
N
N
OH
H
OH
H
OH
H
N
OH
N
OH
N
N
O
S
N
H3CO
5p, 86%
5q, 85%
5r, 92%
5
o, 97%
j, 82%
3k, 92%
3l, 90%
OH
H
OH
OH
N
a
o
N
N
2
General reaction conditions: 4 (1.0 mmol) and 2 (1.1 equiv) in H O at 90 C
c
b
for 10 h, isolated yields based on 4.
NHPI (1.5 equiv) was used.
H
H
d
Cyclohexanone was used as material. 1-Tetralone was used as material.
O
S
m, 89%
3n, 91%
3o, 92%
Encouraged by the above results, we further investigated the
application of this method for the synthesis of some
pharmacologically active oximes (Figure 1). For example, I is
a
o
General reaction conditions: 1 (1.0 mmol) and 2 (1.1 equiv) in H
for 3 h, isolated yields based on 1.
2
O at 90 C
10a,10b
the precursor of paracetamol
widely used as a non-narcotic
To further explore the scope of the reaction, a number of other
carbonyl compounds were employed to react with NHPI under
the standard conditions (Table 3). Acetophenones bearing
electron-withdrawing groups such as F, Cl and Br worked well
with 2, affording the corresponding desired products in good to
excellent yields (5b-5f), and nitro group increased the yield to
analgesic and antipyretic drug, which can be easily synthesized
from p-hydroxyacetophenone under our reaction conditions with
86%
yield.
II
is1
the
which
precursor
was
of
reported
N-(4-
0c
phenoxyphenyl)formamide
as
mutagenically active molecule, it can be easily synthesized from
4-phenoxybenzaldehyde. 10dIII is the precursor of N-(2-
hydroxyphenyl)acetamide which was reported as an antifungal
and mutagenically active molecule, it can be constructed via this
oximation process. At the same time, the reaction of p-
fluorobenzaldehyde with NHPI was performed at 10 mmol scale,
and 1.26g desired product 3a was formed in 91% yield.
9
8% (5g). Acetophenones with electron-donating group such as
Me and OMe decreased the yields to 80% and 83%, respectively
5h and 5i). Interestingly, acetophenone containing amino group
(
also worked effectively to deliver the product 5j in 83% yield.
Furthermore, it was found that the reaction was successfully
applied to 1-(2-aminophenyl)propan-1-one, benzophenone,
cyclohexanone and 1-tetralone, affording the corresponding
products 5k, 5l, 5m and 5n in 87%, 80%, 76% and 94% yields,
respectively. In addition, heteroaryl-contained ketones and linear
ketones were also applied to give the desired oximes 5o, 5p, 5q
and 5r in 85-97% yields. It demonstrated that this method was
well applied in ketones which have lower reactivity than
aldehydes and the yields from 76% to 98% were significantly
higher than that from Hyodo’s work (from 41% to 84%).
Fig. 1 Biologically active molecules
A plausible mechanism of this reaction is proposed (Scheme
2). Firstly, NHPI is hydrolyzed to give A, simultaneously the
nucleophilic substitution of 1a with A affords an intermediate B.
a
Table 3 Synthesis of ketoximes with various ketones
Finally, hydrolysis of
B affords the final product p-
fluorobenzaldehyde oxime 3a and releases one phthalic acid.
After the reaction of p-fluorobenzaldehyde with NHPI, HRMS
analysis of the crude product showed the existence of phthalic
acid.
Phthalic acid was recovered as byproduct after the reaction
was completed. The reaction mixture was concentrated under
vacuum, and the residue was recrystallized from
chloroform/petroleum ether (1:1 v/v) to obtain phthalic acid as
white solid with 75% yield. Phthalic acid can be reused to
11
produce NHPI by ammoximation reaction as a yellow powder
in 66% yield.

4
Tetrahedron
ACCEPTED MAhe
N
xa
U
ne
S
/E
C
tO
R
A
I
c
P
as eluent to give the product 3a as a white solid,
T
o
m.p. 87-88 C.
4
.2.1 (E)-4-Fluorobenzaldehyde oxime (3a)
o
1
White solid, yield 88%, m.p. 87-88 C. H NMR (500 MHz,
1
3
CDCl ) δ 8.16 (s,1H), 7.60-7.57 (m, 2H), 7.12-7.08 (m, 2H).
C
3
1
NMR (125 MHz, CDCl ) δ 163.8 ( J = 249.0 Hz), 149.3, 128.9
JC-F= 8.4 Hz), 128.1 ( J = 3.3 Hz), 116.0 ( JC-F= 21.9Hz). IR
3
C-F
3
4
2
(
C-F
(
1
[
KBr, neat) ν 3342.8, 2949.1, 2865.4, 1720.3, 1621.0, 1498.1,
-
1
287.3, 1249.2, 1054.4, 819.0, 671.7 cm . HRMS (ESI) calcd for
+
M+H] C H FNO, m/z 140.0506, found 140.0524.
7 7
4
.2.2 (E)-2-Fluorobenzaldehyde oxime (3b)
o
1
Yellow solid, yield 91%, m.p. 61-63 C. H NMR (500 MHz,
CDCl ) δ 9.02 (br, 1H), 8.40 (s, 1H), 7.76-7.72 (m, 1H), 7.41-
3
1
3
7
.37 (m, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.14-7.10 (m, 1H).
NMR (125 MHz, CDCl ) δ 160.8( J = 251.1 Hz), 144.5 ( J
C
=
1
4
3
C-F
C-F
3
4
3
3
.3 Hz), 131.6 ( J = 8.5 Hz), 127.3 ( J = 2.8 Hz), 124.5 ( J
C-F C-F C-
2 2
F= 3.8 Hz), 119.8 ( J = 10.5 Hz), 116.1 ( JC-F= 21.0 Hz).
C-F
Scheme 2 Plausible reaction pathway and recycle experiments
4
.2.3 (E)-4-Bromobenzaldehyde oxime (3c)
o
1
3
. Conclusions
White solid, yield 92%, m.p. 113-114 C. H NMR (400 MHz,
CDCl ) δ 8.07 (s, 1H), 7.84 (br, 1H), 7.50 (d, J = 8.8 Hz, 2H),
3
In summary, we have developed a novel, simple and efficient
13
7
1
.43 (d, J = 8.8 Hz, 2H). C NMR (100 MHz, CDCl ) δ 149.2,
31.9, 130.8, 128.3, 124.1.
3
method for the synthesis of oximes by NHPI or NHSI in water
without hydroxylamine or other acid/base/catalyst. The reaction
exhibits a good tolerance for various aldehydes, ketones
containing sensitive groups such as hydroxyl group or amino
group and gives corresponding products in good to excellent
yields. Furthermore, this protocol provides a practical synthetic
method for the synthesis of the precursor of biologically active
molecules, such as Paracetamol. NHPI is used the first time as an
oximation reagent, and the by-product phthalic acid can be
recycled and reused easily. Further synthetic applications of this
method are ongoing in our laboratory.
4.2.4 (E)-2-Chlorobenzaldehyde oxime (3d)
o
1
White solid, yield 92%, m.p. 72-74 C. H NMR (500 MHz,
CDCl ) δ 8.71 (br, 1H) 8.60 (s, 1H), 7.84 (dd, J = 7.5, 1.5 Hz,
3
1
7
1
H), 7.41 (dd, J = 7.5, 1.2 Hz, 1H), 7.34(td, J = 7.5, 1.2 Hz, 1H),
13
.31-7.28 (m, 1H). C NMR (125 MHz, CDCl ) δ 147.6, 134.0,
3
31.1, 130.0, 129.7, 127.2, 127.1.
4
.2.5 (E)-4-(Trifluoromethyl)benzaldehyde oxime (3e)
o
1
White solid, yield 94%, m.p. 100-101 C. H NMR (400 MHz,
CDCl ) δ 8.64 (br, 1H), 8.17 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H),
4
. Experimental section
3
13
7
1
(
.62 (d, J = 8.0 Hz, 2H). C NMR (100 MHz, CDCl ) δ 149.0,
3
2 4
4
.1 General
35.1, 131.6( J = 32.2 Hz), 127.7, 125.6( JC-F= 3.3 Hz), 123.7
C-F
1
JC-F= 269.8 Hz).
All reagents were obtained from commercial suppliers and
used without further purification, unless otherwise indicated.
TLC analysis was performed using pre-coated glass plates. Silica
gel for column chromatography was purchased from Qingdao
Haiyang Chemical Co., Ltd. H NMR and C NMR were
recorded with Bruker and Varianinstrument at 600, 500, 400 and
4
.2.6 (E)-4-Nitrobenzaldehyde oxime (3f)
1
White solid, yield 98%, m.p. 131-133 °C. H NMR (500 MHz,
1
13
DMSO-d ) δ 11.84 (br, 1H), 8.30 (s, 1H), 8.25 (d, J = 8.5 Hz,
2
1
6
13
H), 7.85 (d, J = 8.5 Hz, 2H). C NMR (125 MHz, DMSO-d ) δ
6
47.2, 146.5, 139.2, 127.1, 123.7.
1
50, 125, 100 MHz, respectively, and TMS was used as internal
standard. The following abbreviations (or combinations thereof)
were used to explain multiplicities: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, br = broad. Coupling constants,
J were reported in Hertz unit (Hz). Mass spectra were measured
with Thermo Finnigan LCQ-Advantage. High resolution mass
spectra (HRMS) were measured on a Brukermicr OTOF-Q II
instrument using ESI techniques. The structures of known
4
.2.7 (E)-4-Methylbenzaldehyde oxime (3g)
1
White solid, yield 86%, m.p. 76-78 °C. H NMR (400 MHz,
CDCl
7.17 (d, J = 8.0 Hz, 2H), 2.36 (s, 3H). C NMR (100 MHz,
CDCl ) δ 150.1, 140.1, 129.3, 129.0, 126.8, 21.5.
) δ 8.79 (br, 1H), 8.11 (s, 1H), 7.45 (d, J = 8.0 Hz, 2H),
3
13
3
1
4.2.8 (E)-3-Methoxybenzaldehyde oxime (3h)
compounds were further corroborated by comparing their H
13
1
NMR, C NMR and MS data with those of literature.
White solid, yield 84%, m.p. 40-43 °C. H NMR (500 MHz,
CDCl ) δ 8.88 (br, 1H), 8.16 (s, 1H), 7.32 (t, J = 7.5 Hz, 1H),
3
4
.2 General procedure for the synthesis of aldoximes
13
7
.19-7.14 (m, 2H), 6.98-6.95 (m, 1H), 3.84 (s, 3H). C NMR
p-Fluorobenzaldehyde 1a (1.0 mmol), NHPI 2 (1.1 mmol, 1.1
(125 MHz, CDCl
111.3, 55.3.
3
) δ 159.8, 150.4, 133.3, 129.8, 120.1, 116.4,
equiv.), and H O (3 mL) were mixed in a Sealed tube and then
2
o
stirred at 90 C for 3h. After the reaction was completed
4
.2.9 (E)-Benzaldehyde oxime (3i)
(
monitored by TLC), the reaction mixture was cooled to room
1
temperature and extracted with ethyl acetate (EtOAc). The
combined organic layers were dried over Na SO , then were
Yellow oil, yield 90%. H NMR (500 MHz, CDCl ) δ 9.21 (br,
3
13
2
4
1H), 8.22 (s, 1H), 7.63-7.61 (m, 2H), 7.43-7.41 (m, 3H).
C
concentrated under reduced pressure. The crude residue was
purified by flash chromatography on silica gel using
NMR (100 MHz, CDCl ) δ 150.3, 131.8, 130.0, 128.7, 127.0.
3
4
.2.10 (E)-Picolinaldehyde oxime (3j)

5
1
C
1
Yellow solid, yield 82%, m.p. 112-113 °C
A
.
H
C
N
E
M
P
R
TE(4
D
00 MAN
W
U
hi
SC
te
so
R
lid
I
,
P
y
T
ield 86%, m.p. 96-98 °C. H NMR (500 MHz,
MHz, CDCl ) δ 10.96 (br, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.34 (s,
CDCl ) δ 9.18 (s, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5
Hz, 2H), 2.30 (s, 3H). C NMR (125 MHz, CDCl ) δ 155.2,
3
3
13
1
=
H), 7.82 (d, J = 7.6 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.25 (dd, J
6.0, 5.2 Hz, 1H). C NMR (100 MHz, CDCl ) δ 151.6, 149.6,
3
13
135.3, 134.9, 128.8, 127.3, 12.2.
3
1
48.9, 136.8, 123.9, 120.9.
4
.3.4 (E)-1-(3-Chlorophenyl)ethan-1-one oxime (5d)
4
.2.11 (E)-2-Hydroxybenzaldehyde oxime (3k)
1
White solid, yield 88%, m.p. 89-91 °C. H NMR (400 MHz,
1
White solid, yield 92%, m.p. 57-58 °C. H NMR (500 MHz,
CDCl ) δ 7.59 (s, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.34-7.27 (m,
2H), 2.27 (s, 3H). C NMR (100 MHz, CDCl ) δ 154.8, 137.9,
3
13
CDCl ) δ 9.91 (br, 1H), 8.25 (s, 1H), 7.74 (br, 1H), 7.32-7.30 (m,
3
3
1
6
1
H), 7.21 (dd, J = 7.5, 1.5 Hz, 1H ), 7.02 (d, J = 7.5 Hz 1H),
134.3, 129.5, 129.1, 126.0, 124.0, 12.3.
13
.97-6.93 (m, 1H). C NMR (125 MHz, CDCl ) δ 157.1, 153.1,
3
+
4.3.5 (E)-1-(3-Bromophenyl)ethan-1-one oxime (5e)
31.4, 130.8, 119.8, 116.7, 116.4. MS (ESI): m/z 138.2 [M+H] .
1
White solid, yield 87%, m.p. 90-92 °C. H NMR 400 MHz,
4
.2.12 (E)-2-Hydroxy-4-methoxybenzaldehyde oxime (3l)
CDCl ) δ 7.72 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 7.2
3
1
13
White solid, yield 90%, m.p. 139-141 °C. H NMR (400 MHz,
Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 2.23 (s, 3H). C NMR (100
CDCl ) δ 10.02 (br, 1H), 8.14 (s, 1H), 7.43 (br, 1H), 7.05 (d, J =
MHz, CDCl ) δ 154.7, 138.3, 132.0, 129.9, 129.0, 124.5, 122.5,
12.3.
3
3
13
8
.4 Hz, 1H), 6.49-6.46 (m, 2H), 3.80 (s, 3H). C NMR (100
MHz, CDCl ) δ 162.0, 158.7, 152.5, 131.6, 109.6, 106.8, 101.3,
3
-
4.3.6 (E)-1-(2-Bromophenyl)ethan-1-one oxime (5f)
5
5.5. HRMS (ESI) calcd for [M-H] C H NO , m/z 166.0517,
8 8 3
1
found 166.0510.
White solid, yield 83%, m.p. 114-116 °C. H NMR (400 MHz,
CDCl ) δ 7.57 (d, J = 8.0 Hz, 1H), 7.33-7.28 (m, 2H), 7.24-7.19
3
4
.2.13 (E)-furan-2-carbaldehyde oxime (3m)
13
(
m, 1H), 2.25 (s, 3H). C NMR (100 MHz, CDCl ) δ 157.7,
3
1
White solid, yield 89%, m.p. 112-115 °C. H NMR (400 MHz,
DMSO-d ) δ 11.78 (s, 1H), 7.75 (s, 1H), 7.52 (s, 1H), 7.19 (d, J =
3
1
138.5, 133.0, 130.0, 127.3, 121.6, 16.1.
6
13
4.3.7 (E)-1-(4-Nitrophenyl)ethan-1-one oxime (5g)
.2 Hz, 1H), 6.63 (s, 1H). C NMR (100 MHz, DMSO-d ) δ
6
1
45.4, 143.4, 135.5, 116.5, 112.2.
White solid, yield 98%, m.p. 146-148 °C. H NMR (500 MHz,
CDCl ) δ 8.22 (d, J = 8.5 Hz, 2H), 7.91 (d, J = 8.5 Hz, 2H), 2.20
3
4
.2.14 (E)-thiophene-2-carbaldehyde oxime (3n)
13
(
s, 3H). C NMR (125 MHz, CDCl ) δ 151.8, 147.2, 143.1,
3
1
White solid, yield 91%, m.p. 133-136 °C. H NMR (400 MHz,
126.6, 123.6, 11.4.
DMSO-d ) δ 11.84 (s, 1H), 7.84 (s, 1H), 7.73 (d, J = 4.8 Hz, 1H),
6
13
4.3.8 (E)-1-(p-Tolyl)ethan-1-one oxime (5h)
7
.47 (d, J = 3.2 Hz, 1H), 7.13 (t, J = 4.0 Hz, 1H). C NMR (150
1
MHz, DMSO-d ) δ 139.8, 131.1, 131.1, 131.0, 126.2.
White solid, yield 80%, m.p. 84-86 °C. H NMR (500 MHz,
6
CDCl ) δ 7.54 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 2.39
3
4
.2.15 (E)-3-phenylpropanal oxime (3o)
White solid, yield 92%, m.p. 102-103 °C. H NMR (400 MHz,
13
(
s, 3H), 2.31 (s, 3H). C NMR (125 MHz, CDCl ) δ 156.1, 139.4,
3
1
133.6, 129.2, 126.0, 21.3, 12.3.
DMSO-d ) δ 10.82 (s, 1H), 7.29 (t, J = 7.4 Hz, 2H), 7.24-7.15
6
4
.3.9 (E)-1-(4-Methoxyphenyl)ethan-1-one oxime (5i)
(
m, 3H), 6.67 (t, J = 5.2 Hz, 1H), 2.74 (t, J = 7.6 Hz, 2H), 2.54
13
1
(q, J = 7.5 Hz, 2H). C NMR (100 MHz, DMSO-d ) δ 149.5,
White solid, yield 82%, m.p. 88-89 °C. H NMR (500 MHz,
6
1
41.1, 128.3, 128.2, 125.9, 31.4, 26.2.
CDCl ) δ 7.60 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 3.85
3
13
(s, 3H), 2.31 (s, 3H). C NMR (125 MHz, CDCl ) δ 160.5, 155.5,
3
4
.3 General procedure for the synthesis of ketoximes
Acetophenone (1.0 mmol), NHPI 2 (1.1 mmol, 1.1 equiv.),
1
29.0, 127.4, 113.9, 55.3, 12.2.
4
.3.10 (E)-1-(2-Aminophenyl)ethan-1-one oxime (5j)
and H O (3 mL) were mixed in a Sealed tube and then stirred at
2
o
1
9
0 C for 10h. After the reaction was completed (monitored by
White solid, yield 83%, m.p. 106-107 °C. H NMR (500 MHz,
TLC), the reaction mixture was cooled to room temperature and
extracted with ethyl acetate (EtOAc). The combined organic
layers were dried over Na SO , then were concentrated under
CDCl ) δ 7.37 (dd, J = 8.0, 1.5 Hz, 1H), 7.16-7.13 (m, 1H), 6.79-
3
6.76 (m, 1H), 6.73 (dd, J = 8.0, 1.0 Hz, 1H), 5.98 (br, 2H), 2.33
1
3
2
4
(s, 3H). C NMR (125 MHz, CDCl ) δ 158.2, 145.4, 129.5,
3
+
reduced pressure. The crude residue was purified by flash
chromatography on silica gel using hexane/EtOAc as eluent to
128.8, 119.2, 117.4, 116.9, 12.6. MS (ESI): m/z 151.1 [M+H] .
o
4.3.11 (E)-1-(2-Hydroxyphenyl)propan-1-one oxime (5k)
give the product 5a as a white solid, m.p. 58-60 C.
1
White solid, yield 87%, m.p. 94-95 °C. H NMR (500 MHz,
4
.3.1 (E)-1-Phenylethan-1-one oxime (5a)
CDCl ) δ 11.25 (br, 1H), 8.01 (br, 1H), 7.47 (dd, J = 8.0, 1.5 Hz,
3
1
White solid, yield 86%, m.p. 58-60 °C. H NMR (400 MHz,
1H), 7.31-7.28 (m, 1H), 7.02 (dd, J = 8.5, 1.0 Hz, 1H), 6.97-6.93
1
3
CDCl ) δ 9.44 (br, 1H), 7.67-7.65 (m, 2H), 7.44-7.42 (m, 3H),
(m, 1H), 2.92 (q, J = 7.5 Hz, 2H), 1.26 (t, J = 7.5 Hz, 3H). C
3
13
2
1
.35 (s, 3H). C NMR (125 MHz, CDCl ) δ 156.0, 136.5, 129.3,
28.5, 126.1, 12.4.
NMR (125 MHz, CDCl ) δ 164.3, 158.0, 130.8, 127.4, 119.3,
3
3
+
117.5, 117.3, 18.1, 11.2. MS (ESI): m/z 166.2 [M+H] .
4
.3.2 (E)-1-(4-Fluorophenyl)ethan-1-one oxime (5b)
4.3.12 (E)-Diphenylmethanone oxime (5l)
1
o
1
White solid, yield 94%, m.p. 71-73 °C. H NMR (500 MHz,
White solid, yield 80%, m.p. 143-145 C. H NMR (600 MHz,
13
DMSO-d ) δ 8.98 (br,1H), 7.64-7.61(m, 2H), 7.17-7.17 (m, 2H),
.30 (s, 3H). C NMR (125 MHz, DMSO-d ) δ 163.5 ( JC-F=
47.6 Hz), 155.2, 132.6 ( J = 3.4 Hz), 127.9 ( JC-F= 8.3 Hz),
CDCl ) δ 7.51-7.42 (m, 7H), 7.40-7.31 (m, 3H). C NMR (150
MHz, CDCl ) δ 158.1, 136.3, 132.8, 129.7, 129.4, 129.3, 128.5,
6
3
13
1
2
2
1
6
3
4
3
C-F
128.4, 128.0.
2
15.5 ( JC-F= 21.6 Hz), 12.4.
4
.3.13 (E)-Cyclohexanone oxime (5m)
4
.3.3 (E)-1-(4-Chlorophenyl)ethan-1-one oxime (5c)

6
Tetrahedron
1
White solid, yield 76%, m.p. 83-85 °C. H
A
N
C
M
C
R
E
(4
P
00
T
MHz, MAun
E
D
NU
de
r
S
va
C
cu
R
umIP
, then the residue was mixed with 10 mL
T
CDCl ) δ 2.51 (t, J = 6.0 Hz, 2H), 2.21 (t, J = 6.0 Hz, 2H), 1.70-
chloroform/petroleum ether (1:1 v/v) and refluxed for 30 min.
The reaction mixture was filtered to obtain phthalic acid (0.270g,
3
13
1
2
.57 (m, 6H). C NMR (100 MHz, CDCl ) δ 160.5, 32.2, 27.0,
5.9, 25.7, 24.6.
3
o
75% yield, m.p. 193-196 C). The filtrate was concentrated under
reduced pressure, and the residue was purified by flash
chromatography on silica gel using hexane/EtOAc as eluent to
give the product 3a (0.247g, 89% yield) as a white solid. The
phthalic acid (830 mg, 5 mmol) and acetic anhydride (5 mL) was
refluxed for 15 min. The solvent was removed under reduced
pressure, then the yellow residue was dissolved in anhydrous
pyridine (7.5 mL). Hydroxylamine hydrochloride (153 mg, 2.2
mmol) was added, and the mixture was stirred overnight at room
4
.3.14 (E)-3,4-Dihydronaphthalen-1(2H)-one oxime (5n)
1
White solid, yield 94%, m.p. 101-103 °C. H NMR (500 MHz,
CDCl ) δ 8.97 (br, 1H), 7.92 (dd, J = 7.5, 1.0 Hz, 1H), 7.32-7.29
3
(m, 1H), 7.26-7.23 (m, 1H), 7.19 (d, J = 7.5 Hz, 1H), 2.88 (t, J =
13
6
.5 Hz, 2H), 2.80 (t, J = 6.0 Hz, 2H), 1.95-1.89 (m, 2H).
C
NMR (125 MHz, CDCl ) δ 155.4, 139.8, 130.4, 129.2, 128.7,
1
3
26.5, 124.1, 29.8, 23.9, 21.3.
o
temperature under argon and then for 4 h at 95 C. The solvent
4
.3.15 (E)-1-(pyridin-2-yl)ethan-1-one oxime (5o)
was removed at reduced pressure, and water (5 mL) was added.
The mixture was acidified with diluted HCl (pH 1-2). The yellow
precipitate was collected by filtration, washed with water, and
dried. Crystallization from ethanol gave NHPI as a yellow
1
White solid, yield 97%, m.p. 118-120 °C. H NMR (400 MHz,
CDCl ) δ 8.64 (d, J = 4.8 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.72-
7
MHz, CDCl ) δ 156.8, 154.5, 149.0, 136.6, 123.8, 120.8, 11.0.
3
13
.67 (m, 1H), 7.29-7.27 (m, 1H), 2.41 (s, 3H). C NMR (100
o
powder (538 mg, 66% yield, m.p. 250-251 C).
3
4
.4.1 Phthalic acid
White solid, yield 75%, m.p. 193-196 C. H NMR (500 MHz,
4
.3.16 (E)-1-(furan-2-yl)ethan-1-one oxime (5p)
o
1
1
White solid, yield 86%, m.p. 102-104 °C. H NMR (400 MHz,
DMSO-d ) δ 13.13 (s, 2H), 7.69-7.67 (m, 2H), 7.59-7.57 (m, 2H).
CDCl ) δ 7.46 (s, 1H), 6.64 (d, J = 3.2 Hz, 1H), 6.45-6.43 (m,
1
1
6
3
13
13
C NMR (125 MHz, DMSO-d ) δ 168.8, 132.9, 130.9, 128.5.
H), 2.22 (s, 3H). C NMR (100 MHz, CDCl ) δ 150.3, 147.7,
6
3
+
HRMS (ESI) calcd for [M+Na] C H NaO , m/z 189.0083, found
1
43.8, 111.4, 110.1, 11.3.
8
6
4
89.0087.
4
.3.17 (E)-1-(thiophen-2-yl)ethan-1-one oxime (5q)
Acknowledgments
1
White solid, yield 85%, m.p. 114-115 °C. H NMR (400 MHz,
CDCl ) δ 7.29 (d, J = 5.2 Hz, 1H), 7.27 (s, 1H), 7.04 (t, J = 4.8
3
We are grateful for the National Natural Science Foundation
of China (No. 21576239) for financial support. We thank Dr. Qi
Shuai (Collaborative Innovation Centre of Yangtze River Delta
Region Green Pharmaceuticals, Zhejiang University of
Technology) for helpful discussions.
13
Hz, 2H), 2.33 (s, 3H). C NMR (100 MHz, CDCl ) δ 152.0,
3
1
40.3, 127.3, 127.0, 126.6, 12.5.
4
.3.18 (E)-4-phenylbutan-2-one oxime (5r)
1
White solid, yield 92%, m.p. 83-86 °C. H NMR (400 MHz,
DMSO-d ) δ 10.27 (s, 1H), 7.27 (t, J = 7.6 Hz, 2H), 7.23-7.13
6
References and notes
(
3
1
m, 3H), 2.76 (t, J = 7.6 Hz, 2H), 2.40 (t, J = 7.2 Hz, 2H), 1.76 (s,
13
H). C NMR (100 MHz, DMSO-d ) δ 154.5, 141.4, 128.3,
1. (a) Xia, J. J.; Wang, G. W. Molecules., 2007, 12, 231-236;
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R. Org. Lett., 2004, 6, 1193-1195;
6
28.2, 125.8, 37.0, 32.0, 13.3.
4
.3.19 (E)-1-(4-Hydroxyphenyl)ethan-1-one oxime (I)
(c) Kopylovich, M. N.; Kukushkin, V. Y.; Haukka, M.; Luzyanin,
K. V.; Pombeiro, A. J. L. J. Am. Chem. Soc., 2004, 126, 15040-
1
White solid, yield 86%, m.p. 148-149 °C. H NMR (500 MHz,
1
5041;
(d) Iwamura, H. J. Med. Chem., 1980, 23, 308-312;
e) Takahashi, Y.; Miyashita, Y.; Tanaka, Y.; Abe, H.; Sasaki, S.
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CDCl ) δ 8.48 (s, 1H), 7.93 (d, J = 9.0 Hz, 2H), 6.99 (d, J = 9.0
Hz, 2H), 2.61 (s, 3H). C NMR (125 MHz, CDCl ) δ 199.1,
1
3
13
(
3
61.7, 131.3, 129.3, 115.6, 26.3.
(f) Atria, A.; Michael, M. Pharmazie., 1982, 37, 551-553;
(
g) Nakayama, A.; Iwamura, H.; Niwa, A.; Nakagawa, Y.; Fujita,
4
.3.20 (E)-4-Phenoxybenzaldehyde oxime (II)
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(h) Ley, J. P.; Bertram, H. J. Eur. J. Lipid Sci. Technol., 2002,
1
1
Brown solid, yield 90%, m.p. 86-87 °C. H NMR (500 MHz,
04, 319-323;
CDCl ) δ 8.85 (br, 1H), 8.17 (s, 1H), 7.57 (d, J = 8.5 Hz, 2H),
7
J = 9.0 Hz, 2H). C NMR (125 MHz, CDCl ) δ 159.2, 156.3,
1
HRMS (ESI) calcd for [M+Na] C H NNaO , m/z 236.0567,
found 236.0579.
3
(i) Kato, M.; Nishino, S.; Ohno, M.; Fukuyama, S.; Kita, Y.;
.41- 7.38 (m, 2H), 7.20-7.17 (m, 1H), 7.08-7.07 (m, 2H), 7.02 (d,
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Eur. J. Med. Chem., 2009, 44, 2246-2251;
13
3
49.7, 133.0, 129.9, 128.7, 126.6, 124.0, 119.6, 118.5, 117.8.
+
13
11
2
2
.
4
.3.21 (E)-1-(2-Hydroxyphenyl)ethan-1-one oxime (III)
(b) Karakurt, A.; Sevim, D.; Özalp, M.; Özbey, S.; Kendi, E.;
Stables, J. P. Eur. J. Med. Chem., 2001, 36, 421-433;
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1
White solid, yield 83%, m.p. 113-114 °C. H NMR (500 MHz,
CDCl ) δ 7.46 (dd, J = 8.0, 1.5 Hz, 1H), 7.31-7.28 (m, 1H), 7.02
3
13
(dd, J = 8.0, 1.0 Hz, 1H), 6.96-6.93 (m, 1H), 2.38 (s, 3H).
C
NMR (125 MHz, CDCl ) δ 159.4, 157.3, 130.8, 127.6, 119.4,
3
(
d) Wang, T. C.; Chen, I. L.; Lu, C. M.; Kuo, D. H.; Liao, C. H.
Chem. Biodivers., 2005, 2, 253-263;
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f) Ouyang, G.; Chen, Z.; Cai, X. J.; Song, B. A.; Bhadury, P. S.;
+
1
4
18.6, 117.2, 10.7. MS (ESI): m/z 152.2 [M+H] .
(
.4 General recovery of phthalic acid
(
p-Fluoro benzaldehyde 1a (2.0 mmol), NHPI (2.2 mmol, 1.1
Yang, S.; Jin, L. H.; Xue, W.; Hu, D.Y.; Zeng, S. Bioorg. Med.
Chem., 2008, 16, 9699-9707.
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stirred at 90 C for 3 h. After the reaction was completed
2
o
3. (a) Mendelsohn, B. A.; Lee, S.; Kim, S.; Teyssier, F.; Aulakh, V.
(monitored by TLC), the reaction mixture was concentrated
S.; Ciufolini, M. A. Org. Lett., 2009, 11, 1539-1542;

7
(
b) Owston, N. A.; Parker, A. J.; Williams, J. M. J. Org. Lett.,
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ACCEPTED MANUSCRIPT
2
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(
(
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(
2
(
(
Commun., 2003, 15, 1936-1937.
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.
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(
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8, 2433-2436;
(
(
(
(
c) Ren, R. X.; Ou, W. Tetrahedron Lett., 2001, 42, 8445-8446;
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