An efficient synthesis of O-aryloxime ethers by copper fluorapatite catalyzed cross-coupling of aryloximes with arylboronic acids

Article abstract of DOI:10.1016/j.tetlet.2014.07.056

A novel, highly efficient, and mild protocol has been developed for the synthesis of O-aryloxime ethers in good to excellent yields at ambient reaction conditions. This is the first report in which NOAr linkage was achieved with ecofriendly, recyclable, heterogeneous copper fluorapatite (CuFAP) catalyst via CO cross coupling of aryloxime with arylboronic acid in the presence of Cs₂CO₃as base and methanol as solvent.

Full text of DOI:10.1016/j.tetlet.2014.07.056

Accepted Manuscript
An efficient synthesis of O-aryloxime ethers by copper fluorapatite catalyzed
cross-coupling of aryloximes with arylboronic acids
Shafeek A.R. Mulla, Santosh S. Chavan, Suleman M. Inamdar, Mohsinkhan Y.
Pathan, Taufeekaslam M.Y. Shaikh
PII:
S0040-4039(14)01220-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.07.056
TETL 44899
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 May 2014
16 July 2014
16 July 2014
Please cite this article as: Mulla, S.A.R., Chavan, S.S., Inamdar, S.M., Pathan, M.Y., Shaikh, T.M.Y., An efficient
synthesis of O-aryloxime ethers by copper fluorapatite catalyzed cross-coupling of aryloximes with arylboronic
acids, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.07.056
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An efficient synthesis of O-aryloxime ethers by copper fluorapatite catalyzed cross-
coupling of aryloximes with arylboronic acids
Shafeek A. R. Mullaa*, Santosh S. Chavana, Suleman M. Inamdar, Mohsinkhan Y.
Pathan, Taufeekaslam M. Y. Shaikha
O
OH
B(OH)2
R2
N
N
CuFAP
+
CH3
CH3
R2
Cs2CO3
Methanol, RT
R1
R1
R1= H, isobutyl,PhCH2O, Me, OMe, NO2, Halogen, etc
R2=Me, OMe, CHO, CF3, etc

An efficient synthesis of O-aryloxime ethers by copper fluorapatite
catalyzed cross-coupling of aryloximes with arylboronic acids
Shafeek A. R. Mullaa*, Santosh S. Chavana, Suleman M. Inamdar, Mohsinkhan Y.
Pathan, Taufeekaslam M. Y. Shaikha
aAcademy of Scientific & Innovative Research (AcSIR)
Chemical Engineering and Process Development Division, National Chemical Laboratory, Pashan Road,
Pune 411 008, INDIA
*Corresponding author.Tel: +91-20-25902316; Fax: +91-20-25902676; e-mail: sa.mulla@ncl.res.in
Abstract: A novel, highly efficient and mild protocol has been developed for the synthesis of O-aryloxime
ethers in good to excellent yield at ambient reaction conditions. This is the first report in which =N-O-Ar
linkage was achieved with ecofriendly, recyclable, heterogeneous copper fluorapatite (CuFAP) catalyst via
C-O cross coupling of aryloxime with aryboronic acid in the presence of Cs2CO3 as base and methanol as
solvent.
Keywords: Copper fluorapatite, O-aryl oxime ethers, Aryl boronic acid, Aryl oxime.
The O-aryloxime ethers are not only core structural constituents of a variety of natural
products, pharmaceuticals, agricultural chemicals and molecular drug design,1 but also an
important and/ or precious precursors for the synthesis of various motifs such as
benzooxazole,2 benzofurans/dihydrobenzofuran,3 pyrrolidines, piperidines, indolizidine
alkaloids,4 chiral primary amines,5 substituted pyrroles,6 trisubstituted isoxazoles,7 amino
acids,8,5b cis-1,2-amino alcohols,9,5b fluorenones10 and so on. These synthesized motifs
show wide range of biological activities such as inhibitors of protein chaperone Hsp
90,11a monoamine oxidase,11b cytokinin-like,11c neuroleptic,11d and anticholinesterase.11e
However, 1,2-oxazines and 6-aryl-3,6-dihydro-1,2-oxazines are NO-prodrugs,11f and

mGluR1 receptor antagonists,11g respectively. Recently, bisaryloxime ethers were found
to be potent inhibitors of transthyraten amyloid fibril formation.12
Owing to potential and/or wider application of O-aryloxime ethers in life sciences,
pharmaceuticals, agricultural chemicals as well as in bioorganic chemistry, researchers
have aspired to develop various methods of their synthesis by reacting oximes and/ or
sodium salt of an oxime with alkenes,13 alkyl or aryl halides,14 aryl nitrates,15a allylic sp3
C-H bonds,15b or esters,15c alcohols,16 methyl sulfate,17a activated olefins,17b
fluorobenzene derivatives,17c nitro- or fluoroarene derivatives,14b aryl nitrates,18a
diazonium salts18b etc. Moreover, the O-aryloxime ethers are synthesized conventionally
by condensation reaction of commercially available carbonyl compounds with O-
aryloxyamines,19 which must be prepared prior to its use. Due to arylboronic acid motifs
being stable and non-toxic compared to aryl halide, its use to introduce the phenyl ring in
various biologically active compounds,20 as well as copper catalyzed cross-coupling of
C-N and C-O bond forming reactions with –NH and/ or -OH functional group containing
various substrates were well documented.21 To the best of our knowledge so far only four
research groups, Meyer et al,22a Huang et al,22b Bora et al,22c and Cai et al,22d have
reported the synthesis of O-aryloxime ether via cross coupling of aryloxime with
arylboronic acid over Cu(OAc)2 and polymer-supported copper complex. However, all
these methods reported so far by reacting oxime with various substrates13-19 and/ or
arylboronic acid22a-d for the synthesis of O-aryloxime ethers lack general applicability
along with one/or other limitations and drawbacks such as use of expensive aryl or alky
halides, ligands, chlorinated solvents, high concentration of base, oxidants, moisture-free

atmosphere, high temperature, and long reaction time resulting in the formation of many
side products, hence lower yield to desired product.
As O-aryloxime ethers motifs are key constituents of structural backbone of many
pharmaceutical compounds, the construction of its structural unit by developing more
general and cost effective protocol using non-toxic, cheap, commercially available
substrates, environmentally benign solvents, cost effective recyclable catalysts at milder
reaction condition is still challenging and an active research area. As we were inspired
from our research work for the synthesis of diaryl ether over CuFAP catalyst,23a-b herein,
we further investigated an application of CuFAP catalyst and we present the first report to
achieve =N-O-Ar linkage using heterogeneous copper fluoroapatite CuFAP catalyst for
an efficient synthesis of O-aryloxime ethers via C-O cross coupling of aryloxime with
aryboronic acid in the presence of Cs2CO3 as base and methanol as solvent at ambient
reaction conditions (Scheme 1).
To develop the protocol for the synthesis of O-aryloxime ethers via cross coupling
reaction, acetophenone oxime (1 mmol) and phenyl boronic acid (1.5 mmol) was initially
treated with CuFAP (100 mg) catalyst in the presence of Cs2CO3 as base in methanol
solvent under ambient conditions to give 90 % yields to O-aryloxime ethers (Table 1
entry 1). Initially, the C-O cross coupling reaction was screened in various solvents such
as methanol, ethanol, dimethyl sulfoxide, dimethylformamide, toluene, tetrahydrofuran,
acetonitrile, dichloromethane, and dichloroethane. However, methanol gave the cross-
coupling product in high yield (Table 1, entry 1) as compared to other solvents (Table 1,
entries 2 and 6). The formation of desired coupling product was not observed using
dimethyl sulfoxide, dimethylformamide, toluene, acetonitrile, dichloromethane, and

dichloroethane as solvents (Table 1, entries 3-5 and 7-9). After the promising results in
methanol as a solvent, studies were undertaken to investigate the influence of various
bases/catalyst loading on the C-O cross coupling reaction. The Cs2CO3 shows excellent
performance as base to achieve desired product in high yield (Table 2 entry 3) as
compared to Na2CO3, K2CO3, and NaOH (Table 2, entries 1-2 and 4). However, the
organic bases such as diisopropylethylamine, pyridine, and triethylamine (Table 2, entries
5-6) were ineffective to form the desired product. Influence of catalyst loading was
investigated, by lowering the catalyst loading from 100 mg to 75 mg and 50 mg, resulting
in a drastic decrease in the yield from 90% to 73% and 39%, respectively, (Table 2,
entries 7, 8).
The excellent results on the optimized reaction conditions using Cs2CO3 base in methanol
over the CuFAP catalyst encouraged us to investigate the scope of this protocol by
coupling the wide range of substituted aryl oxime with substituted aryl boronic acid as
coupling partner for the synthesis of O-aryloxime ethers. The various substituted aryl
oximes possessing a variety of an electron donating and/ or electron withdrawing
functional groups reacted smoothly with various substituted phenyl boronic acid under
ambient reaction conditions to get various O-aryloxime ethers as desired products in good
to excellent yield (Table 3, entries 2-31). However, the formation of desired product was
not observed under the same reaction condition in the presence of CuFAP catalyst
without base and vice versa (Table 3, entry 1). The electron-rich acetophenone oximes
such as 4-methoxyacetophenone oxime, 4-methylacetophenone oxime, 4-
isobutylacetophenone oxime, and 4-benzyloxyacetophenone oxime coupled successfully
with phenyl boronic acid providing the corresponding cross coupling products in good

(83-88%) yield (Table 3, entries 3-6) and the electron-deficient acetophenone oximes
such as 4-nitroacetophenone oxime, and 4-fluoroacetophenone oxime provided the
corresponding cross coupling products in excellent (95%) yield (Table 3, entry 7, 8).
To widen the scope of this protocol a variety of substituted phenyl boronic acid with
electron donating/ electron withdrawing group such as 2-methoxy phenyl boronic acid,
2,3,4-trimethoxyphenylboronic acid, 4-carboxyl phenyl boronic acid, (4-methoxy-3,5-
dimethylphenyl)boronic acid, (3,5-bis(trifluoromethyl)phenyl)boronic acid were coupled
smoothly without any problem with acetophenone oxime/substituted acetophenone oxime
having electron donating/ electron withdrawing group such as 4-methyl acetophenone
oxime, 4-methoxy acetophenone oxime, 4-isobutyl acetophenone oxime, 3-nitro
acetophenone oxime, 4-nitro acetophenone oxime, 2-bromo acetophenone oxime 4-
bromo acetophenone oxime, 4-fluoro acetophenone oxime, 4-phenyl ether acetophenone
oxime. These reactions furnished desired cross coupling products in good to excellent
(76-96%) yield (Table 3 entries 9-29). Surprisingly, diverse coupling partners with
electron rich and deficient centre (Table 3, entries 5, 11-13, 16, 19, 20, 24,25, 27, 28)
coupled smoothly to achieve desired product via =N-O-Ar linkage in presence of CuFAP
catalyst. The promising results on diverse coupling partners prompted us to investigate
the feasibility of this protocol to hetrocyclic boronic acids. Accordingly, benzothiophene-
2-boronic acid and thiophene-2-boronic acid coupled smoothly with acetophenone oxime
under our optimized reaction conditions and delivered the desired cross coupling
products in moderate to good yield in 24 h (Table 3, entry 30, 31). The results in Table 3
indicate that a wide range of aryloximes and arylboronic acids were compatible to
achieve =N-O-Ar linkage over ecofriendly, recyclable, heterogeneous copper fluorapatite

(CuFAP) catalyst for an efficient synthesis of O-aryloxime ethers via cross coupling of
aryloxime with aryboronic acid in the presence of Cs2CO3 as base and methanol as
solvent at ambient temperature. However, the yields obtained are dependent on the nature
of substituents on the aryl oxime as well as on the aryl boronic acids.
According to our and the previous research work on O-arylation22b,23a,b and N-arylation,24
respectively, a possible mechanism is proposed in Scheme 2. The plausible mechanism
for cross coupling reaction may involve the coordination of acetophenone oxime with
CuFAP catalyst that proceeds via formation of the Cu(II) complex I. Subsequent reaction
of complex I with phenyl boronic acid formed Cu(II) complex (II) followed by
instantaneous formation of linkage =N-O-Ar to release the O-aryloxime ethers product
(III) as well as CuFAP catalyst to recycle.
The recyclability of CuFAP catalyst for an efficient synthesis of O-aryl oxime ether via
C-O cross coupling reaction was studied using acetophenone oxime and phenyl boronic
acid in the presence of Cs2CO3 as base and methanol as solvent at ambient reaction
condition, the results are shown in Table 4. The catalyst was recovered quantitatively by
filtration and reused several times without loss of catalytic activity (Table 4).
In conclusion, a highly efficient, cost effective, general and milder protocol has been
developed for the synthesis of O-aryloxime ethers in good to excellent yield via C-O
cross coupling reactions of a wide range of substituted aryl oximes with substituted aryl
boronic acids using inexpensive, ecofriendly, heterogeneous, reusable copper fluorapatite
(CuFAP) catalyst in the presence of Cs2CO3 as base, in methanol solvent at ambient
reaction conditions. This may be a practical approach for the synthesis of various natural

products, pharmaceuticals, agricultural chemicals motifs containing O-aryloxime ethers
units.
Acknowledgements
SSC, SMI, MYP and TMYS thank CSIR and UGC New Delhi for SRF and JRF. The
authors also thank to Dr. V. V. Ranade, Chair, CE-PD for their encouragement and
support.
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Scheme 1: Synthesis of O-aryl oxime ethers over CuFAP catalyst.

CH3
P
P
O
O
Cu
Ph
N
OH
O
CH3
N
Ph
N
Ph
CH3
Ph
P
P
O
(II)
Cu
III
O
O
H
H3C
I
Ph
P
P
O
(II)
Cu
N
O
O
H
A
r-B
(OH
)
2
(HO)2B
II
Scheme 2: Possible mechanism over CuFAP catalyst for the O-aryl oxime synthesis

Table 1: Effect of solvents on CuFAP catalyzed O-arylation of acetophenone oxime with
phenylboronic acida
Entry
Solvent
Methanol
Ethanol
Yieldb (%)
90
1
2
3
4
5
6
7
8
9
76
DMSO
DMF
N.R.c
N.R.c
N.R.c
18
Toluene
THF
Acetonitrile
Dichloroethane
Dichloromethane
N.R.c
N.R.c
N.R.c
a
Reaction conditions: Acetophenone oxime (1 mmol), phenyl boronic acid (1.5 mmol), Cs2CO3 (1.5
mmol), solvent (5 mL), 100 mg CuFAP catalyst (Cu content 0.73 mmolg-1), at room temperatures, 15 h.
b Isolated yields.
c No reactions
.

Table 2: Effect of base/catalyst loading on the O-arylation of acetophenone oxime with
phenylboronic acida
Entry
Base/catalyst loading
Na2CO3
K2CO3
Yieldb (%)
43
64
1
2
3
Cs2CO3
NaOH
Diisopropylethylamine
Pyridine
CuFAP (75 mg)
90
4
5
N.R.c
N.R.c
N.R.c
73
6
7d
8e
CuFAP (50 mg) 39
Reaction conditions : Acetophenone oxime (1 mmol), phenyl boronic acid (1.5 mmol), Base (1.5 mmol),
a
Methanol (5 mL), 100 mg CuFAP catalyst (Cu content 0.73 mmolg-1), at room temperatures, 15 h.
b Isolated yields.
c No reactions.
d,eEffect of catalyst loading, Cs2CO3 base was used.

Table 3: CuFAP catalyzed O-arylation of substituted acetophenone oxime with
substituted arylboronic acidsa
Sr. No.
1
Oximes
Boronic acids
Products
Yield
(%)b
N.R.c
2
90
83
3
4
88
87
86
5
6
95
7
8
95
95
B(OH)2
OMe
9
B(OH)2
OMe
10
89

Table 3 continue
11
B(OH)2
OMe
96
85
MeO
MeO
OMe
OMe
OMe
B(OH)2
OMe
O
N
12
13
14
CH3
OMe
OMe
MeO
OMe
B(OH)2
OMe
O
OMe
N
92
85
MeO
MeO
CH3
OMe
OMe
OMe
B(OH)2
OMe
O
OMe
N
OMe
CH3
OMe
O2N
B(OH)2
OMe
15
84
82
MeO
MeO
OMe
OMe
OMe
B(OH)2
OMe
O
N
16
17
CH3
Br
OMe
OMe
86
79
18
19
90
86
76
20
OH
N
CH3
21
Br

Table 3 continue
22
O
N
79
84
CH3
CHO
F
23
24
94
85
83
25
26
F3C
F3C
F3C
B(OH)2
B(OH)2
B(OH)2
83
85
81
27
28
29
CF3
CF3
CF3
O
CF3
N
CH3
CF3
Br
74
61
30
31
a Reaction conditions: substituted acetophenone oximes (1 mmol), substituted arylboronic acid (1.5 mmol),
Cs2CO3 (1.5 mmol), Methanol (5 mL), 100 mg CuFAP catalyst (Cu content 0.73 mmolg-1), at room
temperatures, 15 h.
b Isolated yields.
c No reaction with base (Cs2CO3) without CuFAP catalyst and vice versa.

Table 4: Recyclability study of CuFAP catalyzed C-O cross coupling of acetophenone
oxime with phenyl boronic acida
Entry
Yieldb (%)
1
2
3
4
90
89
88
89
a
Reaction conditions: Acetophenone oxime (1 mmol), phenyl boronic acid (1.5 mmol), Cs2CO3 (1.5
mmol), Methanol (5 mL), 100 mg CuFAP catalyst (Cu content 0.73 mmolg-1), at room temperatures,
15h.
b Isolated yields,