Palladium(0)-mediated cyclization-coupling of β,γ-unsaturated oximes and aryl iodides

Article abstract of DOI:10.1016/j.tetlet.2016.01.076

The tandem palladium(0)-mediated nucleometalation-cross coupling of β,γ-unsaturated oximes with aryl iodides has been shown to provide the expected 3,5-disubstituted 2-isoxazolines in acceptable yields (11-78%). The addition of a weak base is required for product formation. Some influence on the yield of the reaction is noted in the electronic character of the aryl iodide used in the reaction. Exploration of the substitution patterns on the reactants has led to a proposed mechanism involving a palladium(II)-catalyzed nucleometalation/cyclization followed by reductive elimination of palladium(0) with concomitant coupling to an arene.

Full text of DOI:10.1016/j.tetlet.2016.01.076

Tetrahedron Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium(0)-mediated cyclization-coupling of b,c-unsaturated
oximes and aryl iodides
⇑
Joshua Mikesell, Michael D. Mosher
Department of Chemistry and Biochemistry, University of Northern Colorado, Greeley, CO 80639, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The tandem palladium(0)-mediated nucleometalation-cross coupling of b,c-unsaturated oximes with
Received 16 November 2015
Revised 13 January 2016
Accepted 20 January 2016
Available online xxxx
aryl iodides has been shown to provide the expected 3,5-disubstituted 2-isoxazolines in acceptable yields
(11–78%). The addition of a weak base is required for product formation. Some influence on the yield of
the reaction is noted in the electronic character of the aryl iodide used in the reaction. Exploration of the
substitution patterns on the reactants has led to a proposed mechanism involving a palladium(II)-
catalyzed nucleometalation/cyclization followed by reductive elimination of palladium(0) with
concomitant coupling to an arene.
Keywords:
Isoxazoline
Palladium cyclization
Heterocycle
Ó 2016 Published by Elsevier Ltd.
Tandem reaction
Introduction
O
N O
Ph
Ph Ph
NO2 CH3OH
CH3ONa
Ph
Ph
The 2-isoxazoline ring system has been studied extensively
since its first preparation in the late 1800s. Given the utility of
these compounds as precursors for a variety of 1,3-difunctional-
ized systems,1,2 bioisosteres for the other systems,3 and as scaf-
folds for metal ligands, studies on the various methods for the
preparation of the 2-isoxazoline ring system are found throughout
the literature.4–6
Standard methods for the preparation of this heterocycle
include the 1,3-dipolar cycloaddition of a nitrile oxide and an
appropriately substituted alkene.7,8 Although some control of the
regio- and stereoselectivity is possible in specific systems,9
electronic and steric factors of the cycloaddition often dictate the
regiochemistry that is observed in the isoxazoline substitution.10
The preparation of 2-isoxazolines with regiospecificity in the
O2N
Ph
Scheme 1. Kohler synthesis.
this as a viable route to this system. For example, the reaction of
1,2,3-triphenyl-1,3-dinitropropane with sodium methoxide in
methanol gives rise to the expected 3,4,5-triphenyl-2-isoxazoline
N-oxide in 79% yield (Scheme 1).11 The mechanism of this reaction,
the Kohler synthesis, proceeds by nucleophilic displacement of a
nitro group by a nitronate intermediate.
Our interest in the formation of 3,5-disubstituted isoxazolines
via the construction of the O1–C5 bond has revealed the utility
of this method.12–14 In our efforts to further explore the possible
use of the cyclized intermediate formed during the initial addition
of the hydroxyl group to the unconjugated olefin, we have
uncovered an interesting tandem process involving cyclization of
location of substituents, then, suggests
a non-cycloaddition
approach to this useful class of heterocycles. Such non-
cycloaddition routes to the 2-isoxazoline ring system do exist.4
The majority of these alternative routes to the 2-isoxazoline
ring system involve the intramolecular construction of the O1–C5
bond or the N2–C3 bond of the isoxazoline as the key cyclization
step. The relative ease of formation of the O1–C5 bond by either
displacement of a b-leaving group by the oxygen of an oxime or
nitronate or addition of an oxime to an internal alkene suggests
a b,c-unsaturated oxime and its subsequent coupling with an aryl
halide. Given the substitution of the oxime starting material, a
wide variety of isoxazoline substitution patterns could result.
Results and discussion
A
series of the required b,c-unsaturated oxime starting
materials were prepared using a previously published procedure
⇑
Corresponding author. Tel.: +1 970 351 2559; fax: +1 970 351 2533.
E-mail address: michael.mosher@unco.edu (M.D. Mosher).
(Scheme 2).12 For example, treatment of the commercially
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2
J. Mikesell, M. D. Mosher / Tetrahedron Letters xxx (2016) xxx–xxx
OH
O
I
5
MgBr
THF
N O
NOH
H
R3
R2
2
1
PCC
MgSO4
CH2Cl2
R1
R1
Pd(PPh3)4
R2
6
K2CO3, DMF
C, 18h
4
R3
NOH
O
NH2
NaOAc
EtOH/H2O
HCl
Scheme 3. Palladium(0) catalyzed cyclization-coupling of unsaturated oximes (4)
and aryl iodides (5).
3
4
Scheme 2. Synthetic route to b,
c
-unsaturated oximes.
aryl iodide (5), 5 mol equiv of potassium carbonate, and 10% mol
equiv of Pd(PPh3)4 (tetrakis-(triphenylphosphine)palladium(0))
were added to a stirred solution of 1 mol equiv of the substituted
available substituted benzaldehyde (1) with allylmagnesium
bromide provided nearly quantitative yield of the expected
b,c-unsaturated oxime (4) in dimethylformamide. The reaction
was stirred at 80 °C over an 18 h period. Extractive isolation with
diethyl ether gave rise to the product mixture. Observation of the
product in the crude product mixture was possible using HNMR
spectroscopy. The presence of the 2-isoxazoline coupled to the aryl
group was noted by the presence of four doublet-of-doublets near
3 ppm and the complex signal near 5 ppm.
Separation of the product from the reaction mixture using low
pressure column chromatography resulted in the isolation of the
title compounds as white solids. Compound identity was con-
firmed by spectroscopic methods and the specific correlations of
each atom to its signal in the NMR spectra were determined.
Table 1 lists the specific compounds prepared by this method
and their isolated yield. In many cases, the isolated yield of the pro-
duct was significantly less than would have been predicted by
examination of the crude product mixture by HNMR spectroscopy.
This was likely due to the decomposition of the product on the
silica gel during chromatography.
1-phenyl-3-buten-1-ol (2). Oxidation of
2 using pyridinium
chlorochromate (PCC) in dichloromethane with magnesium sulfate
added as a support phase gave the expected ketone as the major
component of the product mixture. A minor component (ꢀ10%)
was determined to be the starting benzaldehyde presumably
arising via an acid-catalyzed retro-Cope rearrangement of the
unsaturated alcohol. Attempts to eliminate this byproduct through
addition of sodium acetate, sodium carbonate, and other mild
bases were unsuccessful. Purification of 2, however, was necessary
by column chromatography before continuation of the synthesis.
Interestingly, no rearrangement of the alkene into conjugation
was observed under the conditions employed during the oxidation
or subsequent oximation reactions. The resulting ketone (3) was
then treated with hydroxylamine hydrochloride and sodium
acetate in refluxing aqueous ethanol to afford the desired
b,c-unsaturated oxime in good yield as a mixture of syn and anti
isomers (4) that were not individually isolated before use in the
Examination of the yields of the palladium(0)-mediated reac-
tion led to a proposed mechanism for the reaction. In that mecha-
nism, the palladium(0) first undergoes oxidative insertion in the
aryl iodide bond.16,17 The resulting palladium(II) complex then
title reaction.
A variety of catalysts potentially suitable for mediation of the
tandem cyclization-coupling reaction were explored.15 Specifically,
attempts to effect cyclization of the unsaturated oxime with cou-
pling to another compound included the use of aluminum, boron,
titanium(IV), tin(II), lead(II), zinc(II), mercury(II), gold(I), gold(III),
palladium(0), and palladium(II). The utility of each mediator was
explored using both catalytic (10% by mol) and stoichiometric
quantities with a variety of ligands. Spectroscopic examination of
the reaction mixtures indicated that only gold(I), mercury(II), and
palladium(II) effected the formation of a 2-isoxazoline ring system
under the conditions attempted. Specifically, the isoxazoline ring
was observed in the proton NMR spectrum of the crude reaction
mixture with the use of both catalytic and stoichiometric quanti-
ties of these metals. Characteristic signals (as doublet of doublets)
for protons on C4 and the benzylic position suggested the forma-
tion of the isoxazoline ring and coupling to the arene.
forms an
g c-unsaturated system, activating
2-complex with the b,
the internal carbon of the alkene functional group for nucleophilic
attack of the oxime hydroxyl group. Then, addition to the alkene
and formation of the 2-isoxazoline ring system gives rise to
the
r-palladium complex. During this process, the loss of the
iodide ligand and deprotonation of the isoxazoline oxygen occurs.
This results in the formal production of HI during the reaction and
is the cause of the use of potassium carbonate in the reaction
mixture. In the absence of the carbonate, the yield of the reaction
is significantly reduced, likely due to the buildup of HI in the
Table 1
2-Isoxazolines prepared by Scheme 3
Attempts to isolate the trace amount of isoxazoline-containing
product from the gold(I)-mediated reaction using a variety of chro-
matographic methods were unsuccessful. However, isolation of the
isoxazoline product from the mercury(II)- and palladium(II)-medi-
ated cyclization was accomplished as expected. Yields for the pal-
ladium(II)-mediated product were unsatisfactory and the method
was not pursued further; however, mercury(II)-mediated cycliza-
tion of the unsaturated oxime gave rise to an isolable di-(2-isoxa-
zolinyl)-mercury(II) complex in moderate yield (40%). Both NMR
and XRF (X-ray fluorescence) were consistent with the formation
of the dimer. That reaction and further exploration of the use of
mercury in the formation of substituted isoxazoline products is
currently being explored in more detail and will be presented in
due time.
Compound
R1
R2
R3
Yielda
%
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
H
H
H
H
CH3
CH3
CH3
CH3
OCH3
OCH3
OCH3
OCH3
F
H
H
H
OCH3
H
H
H
OCH3
H
H
H
OCH3
H
H
H
H
53
39
28
58
53
78
39
57
29
29
57
65
58
22
11
ndb
CH3
OCH3
H
H
CH3
OCH3
H
H
CH3
OCH3
H
H
F
F
F
CH3
OCH3
H
The use of catalytic quantities of palladium(0) in the tandem
cyclization-coupling reaction of b,c-unsaturated oximes (4) gave
rise to the coupled isoxazoline product (6) in yields ranging from
11% to 78% (Scheme 3). Specifically, 5 mol equiv of a substituted
OCH3
a
The yield is of the isolated and purified product.
The expected product was not detected in the reaction mixture.
b
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J. Mikesell, M. D. Mosher / Tetrahedron Letters xxx (2016) xxx–xxx
3
substitution on both starting materials. This methodology provides
a route to the formation of the 2-isoxazoline by ring closure of the
O1–C5 bond and results in the formation of a new carbon–carbon
bond to an aryl substituent. The products are easily identifiable in
the proton NMR spectrum due to the presence of the four
doublet-of-doublets characteristic of the methylene units around
the isoxazoline ring junction.
Acknowledgments
The authors acknowledge the financial assistance of the
University of Northern Colorado and the Department of Chemistry
and Biochemistry.
Supplementary data
Supplementary data (the general procedure for the title reaction
and spectroscopic data for each of the compounds prepared by this
method) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2016.01.076. These
data include MOL files and InChiKeys of the most important
compounds described in this article.
Scheme 4. Proposed mechanism for the title reaction.
reaction mixture. Such a buildup would inhibit the cyclization and
likely aid ring-opening of any formed isoxazoline. Finally, reduc-
tive elimination of the
r-palladium(II) complex would result in
References and notes
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zoline to give compound 6 and would allow re-formation of the
palladium(0) complex (Scheme 4).
Based on the proposed mechanism, electron-donating groups
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increase the electron density at the oxime nitrogen. This would
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increase in the yield of the reaction. Similarly, electron-withdraw-
ing groups placed on the aryl iodide would be expected to decrease
electron density at the palladium center making the complex more
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Conclusion
The reaction of b,c-unsaturated oximes with aryl iodides can be
mediated by catalytic amounts of palladium(0). The yield of the
reaction is somewhat dependent upon the electronic effects of
Please cite this article in press as: Mikesell, J.; Mosher, M. D. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.01.076