Palladium-Catalyzed Arylation of (Di)azinyl Aldoxime Ethers by Aryl Iodides: Stereoselective Synthesis of Unsymmetrical (E)-(Di)azinylaryl Ketoxime Ethers

Article abstract of DOI:10.1002/chem.201501758

The first example of direct arylation of (di)azinyl aldoxime ethers by aryl iodides is reported. The reaction produces, in a single step, a variety of geometrically pure unsymmetrical (E)-(di)azinylaryl ketoxime ethers, a class of nitrogenated motifs that have found wide applications in medicinal and organic chemistry but are difficult to access using conventional procedure. The utility of the method is further illustrated in a formal synthesis of the Merck melanin-concentrating hormone, 1 receptor antagonist. Arylationship of convenience: Direct arylation of (di)azinyl aldoxime ethers by aryl iodides produces, in a single step, a variety of geometrically pure unsymmetrical (E)-(di)azinylaryl ketoxime ethers (see scheme), a class of nitrogenated motifs that have found wide application in medicinal and organic chemistry but are difficult to access by conventional procedures.

Full text of DOI:10.1002/chem.201501758

DOI: 10.1002/chem.201501758
Communication
&
Synthetic Methods
Palladium-Catalyzed Arylation of (Di)azinyl Aldoxime Ethers by
Aryl Iodides: Stereoselective Synthesis of Unsymmetrical
(E)-(Di)azinylaryl Ketoxime Ethers
Quan Gou, Bin Deng, and Jun Qin*[a]
Abstract: The first example of direct arylation of (di)azinyl
aldoxime ethers by aryl iodides is reported. The reaction
produces, in a single step, a variety of geometrically pure
unsymmetrical (E)-(di)azinylaryl ketoxime ethers, a class of
nitrogenated motifs that have found wide applications in
medicinal and organic chemistry but are difficult to access
using conventional procedure. The utility of the method is
Scheme 1. Medicinally active (E)-2-pyridylaryl ketoxime ethers.
further illustrated in a formal synthesis of the Merck mela-
nin-concentrating hormone 1 receptor antagonist.
this motif can be transformed into many other bioactive com-
pounds that contain the 2-benzylpyridyl nucleus.[9]
Conventional methods to prepare (di)azinylaryl ketoxime
ethers involve the following steps: Palladium-catalyzed cou-
pling of (di)azinylmethyl derivatives with aryl halides to prepare
(di)azinylaryl methanes;[10] oxidation of (di)azinylaryl methanes
to give (di)azinylaryl ketones;[11] and condensation of (di)azinyl-
aryl ketones with O-alkylhydroxylamines (Scheme 2a). This ap-
proach usually produces a mixture of E- and Z-stereoisomers
without stereocontrol.[12] Recently, an example of the synthesis
of geometrically pure diaryl ketoxime ethers was reported by
Dolliver et al., which nevertheless required a multistep se-
quence to prepare aryl N-alkoxyimidoyl iodide for subsequent
C(sp2)ÀC(sp2) bonds are widespread in pharmaceuticals, agri-
cultural chemicals, and synthetic intermediates. Direct arylation
of C(sp2)ÀH bonds for the construction of C(sp2)ÀC(sp2) bonds
avoids the need for substrate preactivation and hence is an at-
tractive strategy with respect to reduction of the overall
number of synthetic steps and of waste production. Recent
years have seen significant progress in the development of
C(sp2)ÀH activation and C(sp2)ÀC(sp2) bond formation reac-
tions.[1] Among these methods, Pd-catalyzed arylation of
C(sp2)ÀH bonds using ArI as arylation reagent is particularly
notable.[2] In addition, examples of the direct arylation of CÀH
bonds of aldehydes[3] and aldehyde equivalents including aldi-
mines[4] and hydrazones[5] have also been reported. Despite
these advances, direct arylation of CÀH bonds of aldoxime
ethers remains to be exploited.
Oxime ethers have found broad applications in organic syn-
thesis,[6] pharmaceuticals and agrochemicals.[7] They can be
transformed into functional groups including amine, hydroxy
amine, nitrile, and carbonyl. In particular, (di)azinylaryl ketoxime
ethers are a class of compounds that have shown interesting
medicinal and biological activities. Control of stereochemistry
in the synthesis of (di)azinylaryl ketoxime ethers is important,
since the E- and Z-stereoisomers frequently display distinct
physicochemical properties and biological activities, and (E)-ge-
ometry is crucial to biological activity (Scheme 1).[8] In addition,
[a] Q. Gou,+ B. Deng,+ Prof. Dr. J. Qin
Key Laboratory of Medicinal Chemistry for Natural Resource
Ministry of Education, School of Chemical Science and Technology
Yunnan University, Kunming, Yunnan 650091 (P. R. China)
E-mail: qinjun@ynu.edu.cn
[+] Both authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501758.
Scheme 2. Classical and current methods for the synthesis of geometrically
pure ketoxime ethers.
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Suzuki coupling and was not applicable to synthesis of (di)azin-
ylaryl ketoxime ethers (Scheme 2b).[13] Stereoselective synthesis
of the geometrically pure (di)azinylaryl ketoxime ethers remains
challenging and unresolved. Development of stereoselective
methods to synthesize this motif is highly desired. Herein, we
describe the first example of arylation of CÀH bonds of (di)a-
zinyl aldoxime ethers by aryl iodides under palladium catalysis.
This reaction produces a variety of geometrically pure unsym-
metrical (E)-(di)azinylaryl ketoxime ethers in a single step
(Scheme 2c).
action had a minor detrimental effect (Table 1, entry 7). Lower-
ing the reaction temperature to 1008C resulted in a sluggish
reaction (Table 1, entry 8). When one equivalent of 2a was
used, the reaction was incomplete and afforded 3aa in 42%
yield (Table 1, entry 9). The catalyst may only survive for certain
period of time during which high concentration of 2a may
promote the reaction to proceed to completion before the cat-
alytic cycle stops. In addition, replacement of 2a with phenyl
bromide or chloride failed to give any product (not shown).
Afterwards, we investigated how the steric and electronic
properties of the aldoxime ether substituent affected the aryla-
tion (Table 2). Substrate 1b, with a cyclohexyl group as the
In a program to develop new metal-catalyzed carbon–
carbon bond-forming reactions,[14] we envisioned that we
could achieve direct arylation of (di)azinyl aldoxime ethers by
aryl iodides under palladium catalysis. The coupling between
2-pyridyl aldoxime ether 1a and phenyl iodide 2a was select-
ed as a model reaction for optimization of the reaction condi-
tions (Table 1). Before optimization, we first needed to consider
Table 2. Effect of aldoxime ether substituent on the reaction efficien-
cy.[a,b]
Table 1. Optimization of the reaction conditions.[a]
Entry
PdII
Additive
Solvent
Yield [%][b]
1
2
3
4
5
6
7[c]
8[d]
9[e]
[Pd(PPh3)2Cl2]
–
[Pd(PPh3)2Cl2]
Pd(OAc)2
[Pd(PPh3)2Cl2]
[Pd(PPh3)2Cl2]
[Pd(PPh3)2Cl2]
[Pd(PPh3)2Cl2]
[Pd(PPh3)2Cl2]
AgOAc
AgOAc
–
AgOAc
Ag3PO4
AgOAc
AgOAc
AgOAc
AgOAc
dioxane
dioxane
dioxane
dioxane
dioxane
dichloroethane
dioxane
dioxane
90
0
0
55
0
15
80
20
42
[a] Optimized reaction conditions:
[Pd(PPh3)2Cl2] (10 mol%), and AgOAc (0.50 mmol) in dioxane (1.0 mL) at
1258C for 24 h with TLC monitoring; [b] yields given refer to isolated
products, E:Z>20:1 determined by 400 MHz H NMR spectroscopy.
1 (0.20 mmol), 2a (1.0 mmol),
1
oxime ether substituent, afforded the product (E)-3ba in only
48% yield due to the sluggishness of the reaction. Meanwhile,
substrates with acyclic oxime ether substituents gave varied re-
sults. Methyl derivative 1c gave product (E)-3ca in 71% yield,
whereas isopropyl compound 1d provided product (E)-3da in
85% yield. The sterically hindered tert-butyl analogue 1e deliv-
ered the product (E)-3ea in only 28% yield. Notably, substrate
1 f, with 2-(trimethylsilyl)ethyl as the oxime ether substituent
was highly efficient, delivering the product (E)-3 fa in 91%
yield. The protecting group of (E)-3 fa could potentially be re-
moved to release the ketoxime alcohol for further derivatiza-
tion and manipulation.
dioxane
[a] General procedure: 1a (0.20 mmol), 2a (1.0 mmol), PdII (10 mol%),
and additive (0.5 mmol) in solvent (1.0 mL) at 1258C for 24 h with TLC
monitoring; [b] isolated product, E/Z>20:1 determined by 400 MHz
1H NMR spectroscopy; [c] 0.60 mmol NaHCO3 added; [d] T=1008C;
[e] 0.20 mmol 2a used.
the challenge ahead. Nitrogen atoms in heterocyclic substrates
are known to coordinate strongly with palladium(II) catalysts.
The coordination can often lead to catalyst poisoning or deac-
tivation.[15] Therefore, an appropriate palladium(II) catalyst that
can survive the pyridyl substrate 1a was first sought. After
screening a series of palladium(II) catalysts, we identified
[Pd(PPh3)2Cl2] as the best catalyst (see the Supporting Informa-
tion for the details). After further investigating other parame-
ters, including additive and solvent, we found that a combina-
tion of [Pd(PPh3)2Cl2] and AgOAc in dioxane at 1258C afforded
the arylation product (E)-3aa in 90% yield as a single stereo-
isomer (Table 1, entry 1). Omitting either [Pd(PPh3)2Cl2] or
AgOAc resulted in no reaction (Table 1, entry 2 and 3). Other
palladium(II) catalysts and silver salts were less effective
(Table 1, entry 4 and 5). Dioxane was a superior solvent to di-
chloroethane (Table 1, entry 6). Addition of NaHCO3 to the re-
With the optimized conditions in hand, we then explored
the substrate scope of the reaction (Table 3). We were delight-
ed to find that a variety of aryl iodides were well tolerated to
react with 1a under the reaction conditions. Para-substituted
aryl iodides with either electron-rich or electron-deficient
groups afforded the ketoxime ethers in good to excellent
yields (3ab–ah). The conditions also tolerated meta-substituted
aryl iodides, regardless of their electronic properties (3ai and
3aj). In addition, ortho-substituted aryl iodide afforded the
coupling product in useful yield (3ak). Interestingly, sterically
hindered 2,6-dimethyliodobenzene was not effective (not
shown). With these results in hands, we further investigated
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Br, CN, CO2Me, CH2OTBS (TBS=tert-butyldimethylsilyl), OBn,
and OTs were tolerated under the reaction conditions, and
could be useful handles for further transformations. The abso-
lute configuration of (E)-3ag was unambiguously determined
by single-crystal X-ray diffraction analysis (Figure 1).[16] The ab-
solute configuration of other products were assigned by analo-
gy.
Table 3. Substrate scope of aryl iodides and aldoxime ethers.[a,b]
Figure 1. X-ray crystal structure of (E)-3ag.
The reaction can be conducted on large scale as demon-
strated for the arylation of 2.22 g of 1 f with 2a, which afford-
ed (E)-3 fa in 89% yield (Scheme 3a). Among all the options of
the synthetic applications of oxime ethers, we wished to ex-
plore the removal of the 2-(trimethylsilyl)ethyl group of (E)-
3 fa, since the resulting ketoxime alcohol (E)-4 is a useful
handle for further derivatization, for use in medicinal and syn-
thetic chemistry. We found that the protecting group can be
smoothly removed by TBAF in 90% yield. It was remarkable
that the (E)-geometry of (E)-4 was reserved during the depro-
tection without epimerization. Alkylation of (E)-4 with 2-di-
methylaminoethylchloride gave the androgen antagonist (E)-5
in 83% yield.[7a] The utility of the method was further illustrat-
ed in a formal synthesis of the Merck melanin-concentrating
hormone 1 receptor antagonist (hMCH-1R) (Scheme 3b). Con-
version of commercially available aldehyde 6 into aldoxime
ether 1o was completed in 95% yield. Arylation of 1o by 1,2-
difluoro-4-iodobenzene 2l under the reaction conditions af-
forded (E)-3ol in 53% yield, which can be transformed into
hMCH-1R in three additional steps, as shown in Merck’s synthe-
sis (Scheme 3c). Note that intermediate (E)-3ol took five steps
to prepare in 38% overall yield in Merck’s synthesis (Sche-
me 3c).[8b]
[a] Optimized reaction conditions:
1
(0.20 mmol),
2
(1.0 mmol),
[Pd(PPh3)2Cl2] (10 mol%), and AgOAc (0.50 mmol) in dioxane (1.0 mL) at
1258C for 24 h with TLC monitoring; [b] yields given refer to isolated
products, E:Z>20:1 determined by 400 MHz 1H NMR spectroscopy;
[c] 15 mol% [Pd(PPh3)2Cl2] added.
To elucidate the reaction mechanism, we conducted the fol-
lowing control experiments (Scheme 4). We found that (E)-
benzaldoxime ether 7, (E)-nicotinaldoxime ether 8, and (E)-iso-
nicotinaldoxime ether 9 were not arylated under the reaction
conditions (Scheme 4a). These results suggest that the 2-pyrid-
yl unit is crucial for the reaction to occur, presumably function-
ing as a directing group at the desired location. Pd0 catalysts,
such as [Pd2dba3] and [Pd(PPh3)4] also afforded the arylation
product (E)-3aa, but were less effective than [Pd(PPh3)2Cl2]
(Scheme 4b). We hypothesize that the active palladium cata-
lysts under these systems may be PdII species generated in situ
the scope of the aldoxime ethers in coupling with 2a. 2-Pyridyl
aldoxime ethers which were substituted by electron-rich
groups on para-position afforded the arylation products in
good yields (3ga–ia), whereas electron-deficient 2-pyridyl al-
doxime ethers were less effective (3ja and 3ka). Meta-substi-
tuted 2-pyridyl aldoxime ether also performed smoothly (3la).
Moreover, both isoquinolinyl and pyrimidyl aldoxime ethers
underwent arylation efficiently to deliver the products in good
yield (3ma and 3na). A variety of functional groups, including
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ether CÀH bonds occurs as the
rate-limiting step[17] (see the Sup-
porting Information).
Although concrete evidences
remain to be obtained, we tenta-
tively propose a PdII/PdIV catalyt-
ic cycle for the reaction based
on the above observations
(Scheme 5). The nitrogen atoms
on
1a
coordinate
with
[Pd(PPh3)2Cl2] to generate biden-
tate five-membered intermediate
A as the initial step. Subsequent-
ly, an oxidative addition of A
into the AgOAc-polarized PhÀI
bond takes place to afford PdIV
intermediate B. At the moment,
in the presence of AgOAc, an in-
tramolecular
CÀH
insertion
occurs to deliver the PdIV inter-
mediate C (Scheme 5, path I). Fi-
nally, reductive elimination of in-
termediate C affords the product
(E)-3aa. Since the C=N bond of
the substrate remains intact
throughout the process, the (E)-
geometry of substrate is re-
tained in the product. Mean-
while, an intramolecular Heck
addition mechanism[18] (Scheme
5, path II) is less likely to occur
since this pathway will generate
(Z)-3aa after steps including syn
insertion of PdIVÀPh bond into
C=N bond to form intermediate
Scheme 3. Synthetic applications of the method.
Scheme 4. Control experiments.
by oxidation of Pd0 with AgOAc, because reactions using Pd0
catalysts without AgOAc under rigorous N2 did not work
(Scheme 4c). The data of kinetic isotope experiments (parallel
intermolecular KIE=2.9) suggest that the cleavage of aldoxime
Scheme 5. Proposed reaction mechanism.
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Communication
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metrically pure (E)-(di)azinylaryl ketoxime ethers, a class of ni-
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Experimental Section
A
5 mL teflon-capped vial was charged with 1a (38.2 mg,
0.20 mmol), 2a (204.0 mg, 1.0 mmol), [Pd(PPh3)2Cl2] (14.0 mg,
0.02 mmol), AgOAc (83.0 mg, 0.50 mmol), and dioxane (1.0 mL).
The vial was then tightly capped. The mixture was stirred at RT for
1 min to enable thorough mixing of the reactants, and was then
heated at 1258C with vigorous stirring for 24 h. The progress of
the reaction was monitored by TLC. Upon completion, the reaction
mixture was cooled to RT, diluted with dichloromethane (15 mL)
and filtered through a small pad of Celite. The filtrate was concen-
trated under reduced pressure and the residue was purified by
flash chromatography (ethyl acetate/petroleum ether) to afford the
desired product (E)-3aa (48.1 mg, 90%, E/Z>20:1).
Acknowledgement
We gratefully acknowledge financial support from National
Natural Science Foundation of China (No. 21272201), Program
for Changjiang Scholars and Innovation Research Team in Uni-
versity (IRT13095), Program of High-End Science and Technolo-
gy Talents of Yunnan Province (2012A003), Program of Hun-
dred Oversea High-Level Talents of Yunnan Province
(W8110305), and Yunnan University (XT412003).
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Keywords: arylation
palladium · synthetic methods
·
cross-coupling
·
oxime ethers
·
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Communication
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3
1589.6(3) Š ; T=100(2) K; space group P1; Z=4; m(MoKa)=0.112 mmÀ1
;
¯
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matography because they have very close or the same Rf value. See the
Supporting Information for the details.
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20541 reflections measured; 7653 independent reflections (Rint =
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[16] CCDC 1023235 [(E)-3ag] contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre. Crystal data for (E)-3ag:
Received: May 5, 2015
Published online on July 21, 2015
Chem. Eur. J. 2015, 21, 12586 – 12591
www.chemeurj.org
12591
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