Cul-mediated cross-coupling of aryl halides with oximes: A direct access to O-aryloximes

Article abstract of DOI:10.1021/ol0709578

The first Cu-catalyzed cross-coupling of aromatic oximes and haloarenes is reported. This one-step formation of the =N-O-Ar linkage gives access to a range of oxime ethers in good to moderate yields.

Full text of DOI:10.1021/ol0709578

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2767-2770
CuI-Mediated Cross-Coupling of Aryl
Halides with Oximes: A Direct Access
to O-Aryloximes
Prithwiraj De, Nonappa, Komala Pandurangan, Uday Maitra,*,† and Steve Wailes*,‡
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012,
India, and Syngenta Ltd., Jealott’s Hill International Research Centre, Bracknell,
Berkshire RG42 6EY, U.K.
maitra@orgchem.iisc.ernet.in
Received April 24, 2007
ABSTRACT
The first Cu-catalyzed cross-coupling of aromatic oximes and haloarenes is reported. This one-step formation of the
access to a range of oxime ethers in good to moderate yields.
dN−O−Ar linkage gives
O-Aryloxime ethers are attractive synthetic targets because
of their considerable application potential in medicinal and
bioorganic chemistry. For example, some benzisoxazole
derivatives have been reported as inhibitors of protein
chaperone Hsp 901a and monoamine oxidase.1b Some others
show good cytokinin-like1c and neuroleptic1d activities.
1,2-Oxazines are NO-prodrugs2a and show anticholinesterase
activity,2b and molecules like 6-aryl-3,6-dihydro-1,2-oxazines
are mGluR1 receptor antagonists.2c Recently, some bisaryl-
oxime ethers were found to be potent inhibitors of trans-
thyratin amyloid fibril formation.3 Despite their potential
applications, the synthesis of O-aryloxime ethers remains a
challenge. As a result, there is a need to develop a general
synthetic method for O-aryloxime ethers.
Available literature approaches for the preparation of
O-aryl oxime ethers essentially deal with the reaction of the
sodium salt of an oxime with fluorobenzene derivatives,4a
reaction of aldehydes/ketones with O-phenylhydroxylamine,3
or reaction of oximes with aryl nitrates4b/diazonium salts.4c
However, these procedures lack generality and cannot be
used with other haloarenes such as iodo- and bromobenzenes.
A serendipitous intramolecular coupling of 2-iodo-2′,5-
dichlorobenzophenone oxime (1) to yield the corresponding
benzisooxazole derivative (1a) under standard Sonogashira
conditions was reported in the literature.5 This formed the
basis for our exploratory work to develop a simple and
general method for the synthesis of O-aryloxime ethers.
† Indian Institute of Science.
‡ Syngenta Ltd.
(1) (a) Mailliet, P.; Ruxer, J. M.; Thompson, F.; Luc, C. C. New 3-aryl-
1,2-benzisoxazole derivatives, compositions containing them and their use
for treating cancer. French Patent FR 288236, August 25, 2006. (b) Yoshimi,
K.; Kozuka, M.; Sakai, J.; Lizawa, T.; Shimizu, Y.; Kaniko, I.; Kojima,
K.; Iwata, N. Jpn. J. Pharmacol. 2002, 88, 174. (c) Ricci, A.; Carra, A.;
Torelli, A.; Maggiali, C. A.; Vicini, P.; Zani, F.; Branca, C. Plant Growth
Regul. 2001, 34, 167. (d) Strupczewski, J. T.; Allen, R. C.; Gardner, B. A.;
Schmid, B. L.; Stache, U.; Glamkowski, E. J.; Jones, M. C.; Ellis, D. B.;
Huger, F. P.; Dunn, R. W. J. Med. Chem. 1985, 28, 761.
(2) (a) Chakrapani, H.; Toone, E. J. Abstracts of Papers. 230th ACS
National Meeting; Washington, DC, Aug 28-Sept 1, 2005; American
Chemical Society: Washington, DC, 2005; MED-414. (b) Yu, Q-s; Zhu,
X.; Holloway, H. W.; Whittaker, N. F.; Brossi, A.; Greig, N. H. J. Med.
Chem. 2002, 45, 3684. (c) Clark, B. P.; Harris, J.; Richard; K.; Ann, E.
Preparation of 6-aryl-3,6-dihydro-1,2-oxazines as mGluR1 receptor antago-
nists. UK Patent WO 2000026199, May 11, 2000.
(3) (a) Johnson, S. M.; Petrassi, H. M.; Palaninathan, S. K.; Mohamed-
mohaideen, N. N.; Purkey, H. E.; Nichols, C.; Chiang, K. P.; Walkup, T.;
Sacchettini, J. C.; Sharpless, K. B. and Kelly, J. W. J. Med. Chem. 2005,
48, 1576. (b) Blake, J. A.; Pratt, D. A; Lin, S.; Walton, J. C.; Mulder, P.;
Ingold, K. U. J. Org. Chem. 2004, 69, 3112.
(4) (a) Mooradian, A.; Dupont, P. E. J. Heterocycl. Chem. 1967, 4, 441.
(b) Jacob, B. B. Synthesis 1975, 782. (c) Nesynov, E. P. Zh. Org. Khim.
1976, 12, 1955.
(5) Coffen, D. L.; Schaer, B.; Bizzarro, F. T.; Chung, J. B. J. Org. Chem.
1984, 49, 296. Reaction conditions: (PPh3)2PdCl2-CuI/Et3N-CH2Cl2.
10.1021/ol0709578 CCC: $37.00
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Published on Web 06/20/2007

We repeated the same experiment with the reported
reaction conditions,5 and to our surprise, both Pd(II) and
Pd(0) furnished product 1a in 80% yield after column
chromatography. This led us to investigate the role of Pd
and CuI. The oxime remained unchanged in control experi-
ments [either (PPh3)2PdCl2 or (PPh3)4Pd)] in the absence of
CuI. Interestingly, when only CuI (with no Pd) was used
product 1a was formed in 80% isolated yield (Scheme 1).
With N,N,N′,N′-tetramethylethylenediamine (TMEDA)6 as
the ligand for CuI, the yields improved (Table 1).
Under the reaction condition involving Cs2CO3 and
TMEDA, benzophenone oxime (4) and fluorenone oxime
(5) produced the corresponding oxime ethers 4a and 5a in
50% and 10% yields, respectively. But in both cases, along
with the oxime ether, the ketones formed by deoximation
were isolated. While the decomposition of oxime ethers by
the cleavage of the N-O bond3 to form phenol and aryl
nitriles is known, the mechanism of formation of the carbonyl
compound is not clear.
We subsequently explored the feasibility of this cross-
coupling reaction using a catalytic amount of CuI with 1,10-
phenanthroline as the ligand.7 Under these conditions,
compounds 3, 4, as well as 1-tetralone oxime (7), 4-methoxy-
acetophenone oxime (9), and 4-chloroacetophenone oxime
(10) produced the corresponding oxime ethers when reacted
with iodobenzene (2a) in good yields (Table 2). Compound
5, however, furnished 5a in only 15% yield, and a ketoxime
bearing R-benzylic hydrogens such as deoxybenzoin oxime
(8) furnished the corresponding oxime ethers (8a) in poor
yields. Under these conditions, 3 produced 3b and O-(4-
nitrophenyl)acetophenone oxime (3d) in moderate yields
when reacted with 2b and 4-nitroiodobenzene (2d). The
structure of 3d was unambiguously proved using single-
crystal X-ray diffraction (Figure 1), which also suggest the
Scheme 1. CuI-Catalyzed Intramolecular Cyclization of
2-Iodo-2′,5-dichlorobenzophenone Oxime
These experimental results clearly suggested that the use of
Pd is not necessary, and we proceeded with Cu(I) for the
intermolecular version of this reaction.
Iodobenzene (2a) and acetophenone oxime (3) were
subsequently used as model substrates to find conditions for
intermolecular coupling. Interestingly, no reaction took place
under the same conditions, and replacing the solvent by
toluene and heating to reflux was not beneficial. However,
upon replacing Et3N by K2CO3 or Cs2CO3, 3 was found to
furnish O-phenylacetophenone oxime (3a) in the presence
of CuI (1.0 equiv) at 110 °C (Table 1). 4-Chloroiodobenzene
Table 1. CuI-Catalyzed Intermolecular Cross-Coupling of
Oximes 3-5 with Iodoarenes
Figure 1. ORTEP diagram of the single-crysytal X-ray structure
of O-(4-nitrophenyl)acetophenone oxime 3d.
producta
time (h) (yield, %)
geometrical purity of the oxime ether obtained under our
experimental conditions.
entry oxime Ar-I
base/ ligand
K2CO3
1
2
3
4
5
6
7
3
3
3
3
3
4
5
2a
2a
2a
2a
2b
2a
2a
2
2
2
2
2
2
2
3a (20)
3a (40)
3a (30)
3a (56)
3b (15)
4a (50)
5a (10)
Since deoximation continued to occur, we speculated that
possibly Cu(II),8 generated during the course of the reaction,
was responsible for facile deoximation, and hence, Na,K-
tartrate (2.0 equiv with respect to CuI) was used as a
chelating agent for Cu(II). This led to an increment in the
yield of 5a (45%). Cross-coupling of 3 with various
iodobenzenes (2b-d) showed that iodobenzenes with electron-
Cs2CO3
K2CO3/TMEDA
Cs2CO3/TMEDA
Cs2CO3
Cs2CO3/TMEDA
Cs2CO3/TMEDA
a Deoximation was observed in all cases.
(6) Carril, M.; SanMartin, R.; Tellitu, I.; Dominguez, E. Org. Lett. 2006,
8, 1467.
(7) (a) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org.
Lett. 2002, 4, 973. (b) Kunz, K.; Scholz, U.; Gazner, D. Synlett 2003, 2428.
(8) When water was chosen as solvent, 1 produced 1a in comparable
yields (80%) and the aqueous extract showed a blue color, indicating the
formation of Cu(II).
(2b) also reacted with 3 in the presence of CuI and Cs2CO3
in toluene to furnish oxime ether 3b (15%).
Although Cs2CO3 seemed to give a cleaner reaction,
considerable deoximation was observed in almost all cases.
2768
Org. Lett., Vol. 9, No. 15, 2007

Table 2. Cross-Coupling of Ketoximes with Haloarenes with Catalytic CuI in Refluxing Toluene
a Refers to the time/[yield] in the absence of tartrate. b Refers to the time/[yield] for 12. c Refers to the time/[yield] for 13.
withdrawing groups (2b, 2d; entries 2 and 4, Table 2) reacted
to give good yields. But, 4-methoxyiodobenzene (2c) did
not react at all. Bromobenzene (2e) did couple with 3 to
furnish 3a, but in low yield (30%).
similar experiments were carried out using acetophenone
oxime ether 3a instead of oxime, it remained unchanged
under both experimental conditions. It thus provides two
important pieces of information: (i) it is the oxime which
is undergoing cleavage and (ii) Na,K-tartrate forms a
complex with Cu(II) and prevents it from chelating to the
oxime.
In order to investigate the role of Na,K-tartrate and the
source of ketone formed during the course of our reaction
conditions, a number of control experiments were done. It
is known in the literature that Cu(II) chelates with oximes
and subsequently results in deoximation.9 When a mixture
of acetophenone oxime 3 and CuSO4·5H2O (10 mol %) was
stirred in toluene at reflux, complete degradation of the oxime
into acetophenone was observed after 24 h. On the other
hand, when the oxime was added to a premixed CuSO4·5H2O
(10 mol %) and Na,K-tartrate (20 mol %)10 in toluene and
stirred at reflux, it remained unchanged after 24 h. When
The need for a base and a catalytic amount of CuI
suggested a possible SRNAr mechanistic pathway for this
reaction. The formation of 3b (from 2b) rules out the
possibility for an addition-elimination pathway for this
reaction, and in addition, the lack of a reaction between
2c and 3 supports the formation of an electrophilic aryl
radical followed by the facile coupling with the oximate
anion.11
A competition experiment carried out with 3 and an
equimolar mixture of 2a and 2b in the presence of Cs2CO3,
CuI (10 mol %), and 1,10-phenanthroline (20 mol %) led to
(9) (a) Kaminskaia, N. V.; Kostic´, N. M. J. Chem. Soc., Dalton Trans.
2001, 1083. (b) Attanasi, O.; Gasperoni, S.; Carletti, C.; J. Prakt. Chem.
1980, 1063. (c) Onindo, C. O.; Sliva, Y, T.; Jankowska, T. K.; Fritsky, I.
O.; Buglyo, P.; Pettit, L. D.; Kozlowski, H.; Kiss, T. J. Chem. Soc., Dalton
Trans. 1995, 3911.
(10) (a) Sing, E. J.; Dey, A. K. Z. Analyt. Chem. 1959, 165, 81. (b)
Baffi, F.; Dadone, A.; Frache, R. Chromatographia 1976, 9, 280. These
references clearly suggest that Cu(II) forms a stable complex above 2.0
equiv of tartrate.
(11) A control experiment was carried out by flushing the reaction vessel
with oxygen. The reaction was then carried out with the standard reaction
conditions under oxygen atmosphere, resulting in deoximation (up to 80%).
No oxime ether formation was observed.
Org. Lett., Vol. 9, No. 15, 2007
2769

Table 3. Cross-Coupling of Aldoximes with Haloarenes with Catalytic CuI in DMSO at 30 °C
a Refers to the time/[yield] in the absence of tartrate.
Moreover, the DMSO conditions were also found to be
the formation of 3a and 3b in a 1:3 ratio (Scheme 2). This
compatible with ketoximes. For example, 4 produced 4a
(62%, 1 h) and 7 produced 7a (56%, 1.5 h).
result supports the suggested mechanism.
In conclusion, the cross-coupling of haloarenes with
aromatic ketoximes and aldoximes has been successfully
accomplished using a catalytic amount of CuI in toluene or
in DMSO and Cs2CO3 as the base. The inter- as well as
intramolecular reactions are rapid, and O-aryloxime ethers
are produced in good to acceptable yields. The application
of this methodology on substrates having other functional
groups is being actively investigated in our laboratory, and
the results will be reported in due course.
Scheme 2. Cross-Coupling of Acetophenone Oxime (3) with a
Mixture of 2a and 2b
Acknowledgment. We thank Syngenta Ltd. for financial
support. CCD X-ray facility, IISc Bangalore, is also thanked
for their service.
The cross-coupling of aldoximes with haloarenes did not
work at all under the conditions used for ketoximes, and rapid
deoximation was observed. However, upon reaction of 14
with 2a at 30 °C in DMSO in the presence of Cs2CO3,
catalytic CuI, 1,10-phenanthroline, and Na,K-tartrate, 14a
was isolated in 45% yield. Under identical conditions,
4-methylbenzaldoxime (15), 4-chlorobenzaldoxime (16), as
well as 4-anisaldoxime (17) produced corresponding oxime
ethers with 2a (Table 3).
Supporting Information Available: Representative ex-
perimental procedures and 1H NMR, 13C NMR, and HRMS
characterization data for all new compounds; X-ray data for
compound 3d (CCDC No. CCDC 647523) (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0709578
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Org. Lett., Vol. 9, No. 15, 2007