Palladium-catalyzed suzuki carbonylative reaction of a-halomethyl oxime ethers: A regioselective route to unsymmetrical 1,3-oxyiminoketones

Article abstract of DOI:10.1002/adsc.201400442

The three-component reaction of a-halomethyl oxime ethers, boronic acids and carbon monoxide at atmospheric pressure catalyzed by tetrakis- (triphenylphosphine)palladium(0) gives efficiently unsymmetrical b-alkoxyimino carbonyl compounds with total control of the regioselectivity, in high yield and atomic economy. Simple commercially available starting materials are used in this synthetic procedure. The three components assembly takes place preferentially versus the competing direct coupling or other possible side reactions. The mechanism of the transformation was investigated by NMR and intermediate palladium(II) complexes were detected.

Full text of DOI:10.1002/adsc.201400442

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DOI: 10.1002/adsc.201400442
Palladium-Catalyzed Suzuki Carbonylative Reaction of
a-Halomethyl Oxime Ethers: A Regioselective Route to
Unsymmetrical 1,3-Oxyiminoketones
Bꢀrbara Noverges,a Mercedes Medio-Simꢁn,a,* and Gregorio Asensioa
a
Departamento de Quꢂmica Orgꢀnica, Universidad de Valencia, Avda. Vicent Andrꢃs Estellꢃs s/n, 46100 Burjassot,
Valencia, Spain
Fax : (+34)-96-354-4939; e-mail: mercedes.medio@uv.es
Received: May 2, 2014; Revised: June 20, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400442.
Abstract: The three-component reaction of a-halo- dure. The three components assembly takes place
methyl oxime ethers, boronic acids and carbon mon- preferentially versus the competing direct coupling
oxide at atmospheric pressure catalyzed by tetrakis- or other possible side reactions. The mechanism of
ACHTUNGTRENNUNG(triphenylphosphine)palladium(0) gives efficiently the transformation was investigated by NMR and in-
unsymmetrical b-alkoxyimino carbonyl compounds termediate palladium(II) complexes were detected.
with total control of the regioselectivity, in high yield
and atomic economy. Simple commercially available Keywords: carbonylation; cross-coupling; palladium;
starting materials are used in this synthetic proce- reaction mechanisms; synthetic methods
Introduction
the competing direct coupling, the main competing al-
ternative reaction. The main advances in this area
Transition metal-catalyzed cross-coupling reactions have been focused to the search of new catalytic sys-
are nowadays among the most simple and successful tems[10] for the purpose of (i) avoiding the use of addi-
À
C C bond forming reactions with wide functional tives, (ii) avoiding or diminishing the formation of sec-
group tolerance on both the electrophilic and nucleo- ondary products such as those derived from homocou-
philic reactive partners.[1] The three components car- pling or direct cross-coupling reactions thus expand-
bonylative version of these reactions using CO, an or- ing the range of suitable electrophiles[11] and (iii) con-
ganohalide and an organometallic derivative has been ducting the catalysis in a heterogeneous phase.[12]
widely applied to the synthesis of ketones, compounds Alkyl aryl ketones have also been synthesized by Pd/
that occupy a central role in synthetic organic chemis- light induced carbonylative cross-coupling of alkyl io-
try.[2] The palladium-catalyzed carbonylative Suzuki dides and arylboronic acids circumventing the b-elimi-
reaction is the most popular over other versions since nation reaction.[13]
boronic acids are commercially available compounds
Recently we reported that (Z)-a-halomethyl oxime
inert to oxygen and moisture, thermally stable and ethers (1) are suitable substrates for palladium-cata-
generally non-toxic.[3] Kojima et al. first reported the lyzed Suzuki cross-coupling reactions with a wide va-
synthesis of unsymmetrical ketones by this methodol- riety of aryl-, heteroaryl- and vinylboronic acids to
ogy from aryl iodides or benzyl chlorides using afford the corresponding a-substituted oxime ethers
Zn
ate RCOPd(II)ACHTUNGTRENNUNG(acac) species which undergoes trans- as synthetic equivalents of ketones in palladium-cata-
ACHTUNGTRENNUNG
(acac)2 to promote the formation of an intermedi- with good yields.[14] Compounds 1 can be considered
metallation.[4] This reaction later was extended by lyzed Suzuki reactions. This finding prompted us to
others to the preparation of unsymmetrical ketones explore the palladium-catalyzed carbonylative Suzuki
containing a wide variety of substituents.[5–9] This ap- version of this reaction which would provide the chal-
proach to the synthesis of ketones is very attractive lenging regioselective preparation of N,O-1,3-difunc-
since the efficient assembly of three simple starting tional compounds within a non-symmetrical back-
materials occurs in just one step with high atom econ- bone. Compounds with this connectivity cannot be
omy. The success of the transformation requires high prepared from direct precursors such as 1,3-dicarbon-
selectivity in the three components assembly versus yl compounds[15] and hydroxylamine O-ether due to
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Bꢀrbara Noverges et al.
the formation of mixtures of regioisomers.[16] This to afford the corresponding oxyimino ketones 3 with
type of compounds can be obtained by reaction of an good yields.
aldehyde and methyl aryl or methyl alkyl oxime ether
First, to optimize the experimental conditions, a-
in the presence of BuLi followed by oxidation of the halomethyl oxime ethers (Z)-1a or (Z)-1b and the
alcohol. Another approach to these compounds is the parent boronic acid 2a were selected as model sub-
condensation of hydroxylamine O-ether with 1,3-hy- strates and a number of Pd(0) catalytic systems with
droxy ketones and subsequent oxidation.[17] This route different ligands were essayed in several solvents (see
provides a mixture of stereoisomers of the E-/Z- Table 1). Reaction of (Z)-1a and 2a catalyzed with
oxime ether.
PdACTHUNGTERUNN(G PPh3)4 (run 3, Table 1) in THF gave high conver-
Now we report the easy synthesis of 1,3-oxyimino sion and selectivity but formation of polymers made
ketones 3 with complete regiocontrol within a non- extraction of the product difficult thus lowering the
symmetrical carbon skeleton by the three components isolated yield in this case (see the Supporting Infor-
carbonylative Suzuki–Miyaura reaction of a-halo- mation). Other ether solvents like 1,4-dioxane facili-
methyl oxime ethers 1. Compounds 3 constitute tate the formation of cross-coupled or dehalogenated
a facile entry to b-oxyimino alcohols[18] and g-amino products (E)-4aa and (E)-5a (run 4, Table 1). Reac-
alcohols[19] upon stereo- or enantioselective reduction, tions were also assayed in toluene solution (runs 5
two classes of compounds with remarkable interest and 6, Table 1). Different results were obtained in this
from the biological point of view and also as metal li- solvent depending on the nature of the halide present
gands. Furthermore, oxyimino carbonyl compounds in the starting halomethyl oxime ether 1. The oxida-
(3) have found a recent application for the synthesis tive addition reaction was easier with (Z)-1b than in
of pyrroles.[17]
the case of (Z)-1a but (E)-5a was the major product
besides the expected oxyimino ketone (E)-3aa in 23%
yield (run 6, Table 1). However, chloromethyl oxime
ether (Z)-1a gave as the major product in this solvent
the alkoxycarbonylation derivative (E)-7a from
Results and Discussion
a-Halomethyl oxime ethers 1 (Figure 1) were submit- phenol produced in the in situ decomposition of 2a
ted to reaction with boronic acids 2 (Figure 2) under (run 5, Table 1). Best yields and selectivities towards
CO contained in a balloon at atmospheric pressure in the carbonylative Suzuki–Miyaura coupling were ob-
the presence of a Pd(0) catalyst and cesium fluoride tained in chloroform as the solvent (runs 7 and 8,
Table 1).
Regarding the influence of the ligand in the catalyt-
ic system (runs 3, 7 and 9–17, Table 1), PdACHTNUTRGNE(UNG PPh3)4 was
revealed as the most effective of the tested catalysts
(runs 3 and 7, Table 1). The electron-rich monoden-
tate phosphine P
uct (E)-3aa with very low yield (run 9, Table 1). The
electron-poor phosphine P(p-FC6H4)3 did not promote
ACHTUNGTNER(NUNG o-tolyl)3 provided the desired prod-
AHCTUNGTRENNUNG
the oxidative addition reaction and most of the start-
ing material (Z)-1a was recovered unchanged after
20 h (run 10, Table 1). The results obtained with other
more sophisticated monodentate phosphines were not
satisfactory in this case (runs 11 and 12, Table 1). Bi-
dentate phosphines commonly used in other carbony-
lative reactions (runs 13–17, Table 1) were assayed in
THF (run 13, Table 1 and Table S1 in the Supporting
Information) or chloroform solution but gave in gen-
eral a poor conversion with formation of hydroxy- or
alkoxycarbonylation products. Cesium fluoride was
very effective in promoting the transmetallation of
boronic acids in the carbonylative oxime ether cou-
pling process. Use of KF or Cs2CO3 to promote the
reaction gave the desired product (E)-3aa with rela-
tively good conversion (runs 18 and 19, Table 1). By
contrast, CsOAc was less effective giving (E)-5a and
alkoxycarbonylation products (run 20, Table 1)
Figure 1. Halomethyl oxime ethers 1.
With the optimized conditions in hand, carbonyla-
tive cross-coupling reactions of representative a-halo-
Figure 2. Boronic acids 2.
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Palladium-Catalyzed Suzuki Carbonylative Reaction of a-Halomethyl Oxime Ethers
Table 1. Development of the catalytic system[a] for the Pd-catalyzed carbonylative cross-coupling reaction of a-halomethyl
oxime ethers with phenylboronic acid.[b]
Run
1
Pd catalyst
Solvent[c]
Base
(Z)-1 [%] (E)-3aa [%] (E)-4aa [%] (E)-5a [%]
1
b
b
a
a
a
b
a
b
a
a
a
a
a
a
a
a
a
a
a
a
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
N
THF
CsF
NEt3
CsF
0
0
0
55
39
0
9
0
97
97
72
99
92
10
98
49
94
26
0
47
10
43
6
27
12
3
24
0
0
4
4
1
1
1
1
1
0
1
2
1
11
30
5
15
0
60
0
12
0
2
27
0
1
5
2[d]
3
THF
THF[e]
4
1,4-dioxane CsF
5[f]
6
toluene
toluene
CHCl3
CHCl3
THF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
KF
8
23
87
84
2
0
0
0
0
0
1
1
2
64
72
16
7
8
9
(o-tolyl)3 20 mol%
E
10
11
12
13[g]
14[h]
15
16[h]
17
18
19[h]
20[h]
(p-FC6H4)3 20 mol% THF
THF
THF
THF
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
0
1
3
10
9
0
5
0
Cs2CO3
CsOAc
3
29
[a]
Reaction conditions: 0.3 mmol 1a or 1b, 0.6 mmol 2a,10 mol% Pd source, phosphine ligand, 1.2 mmol base, 10 mL solvent,
608C, 20 h. Yields were determined by H NMR analysis with acetophenone as internal standard.
Less than 15% of 1,1’-biphenyl was obtained.
All solvents were dried and distilled prior to use.
(1E,4E)-1,4-Diphenylbutane-1,4-dione O,O-dimethyl dioxime [(E,E)-6a] was obtained in 24% yield.
A polymer formed in these reaction conditions hampers the extraction of the product.
(E)-Phenyl 3-(methoxyimino)-3-phenylpropanoate [(E)-7a] was obtained in 53% yield.
(E)-7a was obtained in 6% yield.
1
[b]
[c]
[d]
[e]
[f]
[g]
[h]
Alkoxy- and hydroxycarbonylation side products were also detected.
methyl oxime ethers 1a–1f and boronic acids 2a–2h phenylboronic acid (2d) giving the expected product
with different electronic properties and substitution with slightly lower yield than the parent boronic acid
patterns were assayed. High selectivity was observed (run 4, Table 2). The reaction was general regarding
in all the cases in the carbonylative Suzuki coupling the nucleophilic partner and satisfactory results were
with regard to the undesired competing direct cou- also obtained with heteroarylboronic acids 2e–h (runs
pling. Parent boronic acid 2a and para-substituted 5–8, Table 2). Butylboronic acid was also tested in car-
electron-rich arylboronic acid 2b reacted very effi- bonylative Suzuki cross-coupling reactions in THF
ciently leading to the corresponding three compo- and CHCl3 as solvents but formation of the expected
nents product with high yields (runs 1 and 2, Table 2). carbonylated product was not observed in any case.
The position of the electron-donating group in the
Several modifications were introduced in the react-
aromatic ring did not induce noticeable differences in ing a-halomethyl oxime ethers 1 as well (runs 9–14,
the selectivity of the carbonylative reaction. The over- Table 2). Oxime (Z)-1c led to the carbonylation prod-
all conversion was only 55% with the relatively hin- ucts (E)-3ca and (E)-3ch with excellent selectivity
dered ortho-methyl substituted boronic acid 2c (run 3, over the competitive direct coupling products (E)-4ca
Table 2). The influence of electron-withdrawing and (E)-4ch (runs 9 and 10, Table 2) despite the elec-
groups in the aromatic ring was tested in the carbony- tron-releasing character of the substituent attached to
lative arylation of (Z)-1a with para-trifluoromethyl- the aryl group that could make sluggish the oxidative
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Table 2. Regioselective Pd-catalyzed three-component Suzuki–Miyaura cross-coupling reaction of a-halomethyl oxime ether
1 with boronic acids 2 in THF or CHCl3.[a]
[a]
Reaction conditions: 0.3 mmol 1, 0.6 mmol 2a–h, 0.03 mmol PdACHTUNGTREN(NUNG PPh3)4, 1.2 mmol CsF, 10 mL dry THF for heteroarylbor-
onic acids or CHCl3 for arylboronic acids, 608C, 20 h.
Isolated yields. Side products (E)-5 and (E,E)-6 were obtained in less than 7%.
In this case (E)-4da was also obtained with 37% yield.
[b]
[c]
addition step. The effect on the reactivity of an elec- Conversely, the carbonylative coupling occurs nicely
tron-withdrawing group attached to the aryl oxime in the reaction of (Z)-1d with 3-furylboronic acid (2g)
moiety depends on the type of boronic acid consid- affording with total conversion the desired product
ered. So, the direct cross-coupling is the main process (E)-3dg (run 12, Table 2). Alkyl oxime ethers (E)-1e
in the reaction of compound (Z)-1d with the parent and (Z)-1f gave excellent results in the carbonylative
boronic acid 2a affording (E)-4da as the major prod- cross-coupling reaction yielding compounds (E)-3eg
uct with a moderate conversion (run 11, Table 2).[20] and (E)-3fg with total selectivity (runs 13 and 14,
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Palladium-Catalyzed Suzuki Carbonylative Reaction of a-Halomethyl Oxime Ethers
Table 2). Complete conversion could not be achieved are in good agreement with data reported by Beller
after 20 h with the hindered oxime (Z)-1f.
and Beck et al.[23] for other acyl palladium complexes.
The equilibrating complex cis-9b could not be detect-
ed under our experimental conditions. Minor ligand
E/Z isomerization observed in complex trans-9b con-
trasts with the configurational stability shown by
Mechanism
The usual reaction sequence in Suzuki carbonylative oxime ether ligands in oxidative addition complexes
reactions between aryl halides and boronic acids, obtained in the absence of CO.[14] In the same sense,
namely, oxidative addition, CO coordination followed complexes trans-(E)- and trans-(Z)-9b were static spe-
by aryl migration and then transmetallation of the re- cies with sharp NMR signals at room temperature
sulting acylpalladium(II) complex, hardly explains our while the corresponding oxidative addition complexes
previous findings in the palladium-catalyzed carbony- (Z)-8b show a dynamic NMR behavior.[14]
lative Suzuki reaction of bromomethyl sulfoxides.
Acylpalladium complex trans-9b was quite stable
With these compounds as electrophiles the insertion and it could be stored in the NMR tube for a time.
of carbon monoxide takes place after the transmetal- Small signals corresponding to dehalogenation and re-
lation step.[21] Halomethyl oxime ethers also contain ductive homocoupling products (E)-5a and (E,E)-6a
an electron-withdrawing substituent in the a-position appeared after 5 h under an argon atmosphere. Simul-
relative to the halide. Then, to ascertain the CO inser- taneous formation of complex Pd2ACHTNUGTRENN(UG m-CO)Br2ACHTUNGTRENNUNG(PPh3)3
tion sequence in this latter case, the migratory ability was detected by 31P NMR.[24] Equimolecular amounts
of the oxime ether fragment in (Z)-1b was investigat- of compounds trans-(Z)-9b, trans-(E)-9b and (E)-5a
ed. The complexes trans- and cis-(Z)-8b were treated were formed by decomposition of the 85/15 trans-(E/
under CO at atmospheric pressure. The reaction mix- Z)-9b mixture after 72 h. It is to be noted that only
ture (see the Supporting Information) was transferred trans-(E)-9b decomposed, while the minor stereoiso-
1
to a sealed NMR tube and the H, 13C and 31P NMR mer trans-(Z)-9b remained unchanged (see the Sup-
spectra were recorded. Complete conversion of com- porting Information). Formation of direct oxidative
plexes (Z)-8b took place affording a mixture of CO addition complex (Z)-8b was never observed along
insertion complexes trans-9b containing the E- and Z- the decomposition process revealing the irreversibility
stereoisomers of the oxime ether ligand (Scheme 1). of the insertion–migration step.[25]
The most characteristic feature displayed by the
The transmetallation step was also monitored by
1H NMR spectrum of the mixture was the appearance 1H, 13C and 31P NMR in CDCl3 solution. Upon treat-
of two sets of two pairs of signals in an 85/15 ratio as- ment of the mixture of complexes trans-(E)- and
signed to the methylene (d=3.64 and 3.67 ppm) and trans-(Z)-9b with 2b and CsF only the carbonylative
methoxy (d=3.81 and 3.88 ppm) protons of the E/Z cross-coupled product (E)-3ab was observed after 3 h
diastereoisomers.[22] A small deshielded signal in the (Scheme 2). Extrusion of CO could not be even de-
13C NMR spectrum at d=226.8 ppm revealed the tected (see the Supporting Information). These ex-
presence of CO in the major component of the mix- periments allow ascertaining that the carbonylative
ture. Characteristic signals at d=19.2 and 19.4 ppm cross-coupling catalytic cycle in halomethyl oxime
were detected in the 31P NMR spectrum correspond- ethers follows the usual reaction sequence of regular
ing to square planar complexes trans-(Z)-9b and carbonylative Suzuki reactions, that is, the CO inser-
trans-(E)-9b respectively. The presence of PPh3 (d= tion precedes the transmetallation step.
À5.2 ppm), OPPh3 (d=29.1 ppm) and PdBr
G
The electron-withdrawing character of chlorine in
Scheme 2. Stoichiometric reaction between trans-(E/Z)-9b
and 2b.
Scheme 1. Carbonylation reaction of complexes (Z)-8b.
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to diminish the electron density at the methylene dium(II) complex trans-(E)-9d which exhibited an
oxime fragment decelerating the migration step. In NMR pattern similar to that of trans-(E)-9b
this case, the carbonylated product (E)-3da was ob- (Scheme 4). By contrast, E/Z isomerization could not
tained with lower yield in the coupling of (Z)-1d with be detected in transformations involving oxime ether
2a. Formation of the direct cross-coupling product (Z)-1d. Decomposition of trans-(E)-9d was monitored
(E)-4da was favored instead. However, the same by NMR as above described, affording an equimolec-
effect was not observed in the coupling of (Z)-1d with ular mixture of PdCl
the electron-rich 3-furylboronic acid (2g) whose trans- (Scheme 5).
2ACHTUGNTRENN(GNU PPh3)2 and (E)-5d after 72 h
metallation reactions[26] are known to proceed more
readily.
The cross-coupling reaction of trans-(E)-9d with
boronic acids was tested in the presence of CsF
To clarify further the different behavior of 2a and (Scheme 6 and Scheme 7). Complex trans-(E)-9d re-
2g the carbonylative cross-coupling of (Z)-1d was acted with 2g yielding the expected product (E)-3dg
studied in detail. First, oxime ether (Z)-1d was treated almost quantitatively in 10 h. The same product was
in an NMR tube with PdACHTUNGRTNEUNG(PPh3)4 in CDCl3 as solvent. obtained when complexes trans- and cis-(Z)-8d were
1H and 31P NMR spectra were recorded at room tem- submitted to reaction with 2g and CsF under a CO at-
perature in order to detect the oxidative addition mosphere at 608C after an hour, while 18 h were nec-
complex (Z)-8d (Scheme 3). Signals at d=2.41 (dd, essary in the reaction at room temperature
J=10.3, 3.9 Hz, CH2) and 3.82 (br s, CH3) ppm in the
1H NMR (400 MHz) spectrum and d=19.0 (d, J=
38.0 Hz, 1P) and 39.8 (d, J=38.0 Hz, 1P) ppm in the
proton decoupled 31P (162 MHz) spectrum revealed
the presence in solution of the square-planar complex
cis-(Z)-8d in low concentration.[27] In addition, broad
proton NMR bands centered at d=2.17 and 3.53 ppm
and a phosphorus NMR signal at d=14.1 ppm ac-
counted respectively for the oxime ether methylene
and methyl protons and the phosphorus in the oxida- Scheme 4. Carbonylation reaction of complexes (Z)-8d.
tive addition complex trans-(Z)-8d. The broad bands
suggest a fast ligand coordination–decoordination
process at room temperature in this latter complex.
The equilibrium between phosphorus-containing spe-
cies and free PPh3 was slow when the temperature de-
creased to À208C. It could finally be frozen at À608C
giving rise to two sharp phosphorus signals at d=26.2
and À7.3 ppm assigned to the square-planar complex
trans-(Z)-8d and free PPh3 respectively besides small
signals corresponding to cis-(Z)-8d.
The above mixture containing complexes (Z)-8d
was submitted to react with CO, contained in a bal-
loon at atmospheric pressure, for 1 h at room temper-
ature to afford with total conversion a new acylpalla-
Scheme 5. Decomposition reaction of complex trans-(E)-9d.
Scheme 6. Stoichiometric reactions of trans-(E)-9d and com-
plexes (Z)-8d with 2g.
Scheme 3. Oxidative addition reaction of (Z)-1d.
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Palladium-Catalyzed Suzuki Carbonylative Reaction of a-Halomethyl Oxime Ethers
Conclusions
The new palladium-catalyzed carbonylative cross-cou-
pling reaction of a-halomethyl oxime ethers described
herein allows the selective preparation of unsymmet-
rical b-alkoxyimino carbonyl derivatives bearing the
oxime ether function at a prefixed position with high
yield and atomic economy. Simple commercially
available starting materials are used in our methodol-
ogy. Each heteroatom derives from a different com-
ponent and, consequently, the regiocontrol regarding
the products is guaranteed by the unequivocal assem-
bly in the multicomponent reaction. Unsymmetrical
oxyimino carbonyl compounds 3 are synthesized in
good to moderate yields in pure stereoisomeric form.
The migrating ability of the methylene oxime ether
fragment in Suzuki carbonylative reactions of halo-
methyl oxime ethers is general and it has been clearly
established. Extrusion of CO does not occur in the in-
termediate Pd(II) complexes. Use of a boronic acid
with increased transmetallating ability may be re-
Scheme 7. Stoichiometric reactions of trans-(E)-9d and com-
plexes (Z)-8d with 2a.
(Scheme 6). In the last experiment, the quantitative quired to avoid undesired decomposition side process-
formation of trans-(E)-9d from trans- and cis-(Z)-8d es in the carbonylative Suzuki cross-coupling when
can be observed at the initial stage of the reaction. the starting halomethyl oxime ether carries an elec-
These results strongly suggest that the CO insertion tron-withdrawing substituent.
reaction precedes the transmetallation step. Converse-
These experiments allow ascertaining that the car-
ly, (E)-7d was the major product when trans-(E)-9d bonylative cross-coupling catalytic cycle with halo-
reacted with phenylboronic acid (2a) due to alkoxyla- methyl oxime ethers follows the reaction sequence of
tion of the acylpalladium(II) complex with phenol regular carbonylative Suzuki reactions, that is, the CO
generated by decomposition of 2a. Small amounts of insertion precedes the transmetallation step.
(E)-4da were also obtained by direct cross-coupling
reaction but product (E)-3da could not be even de-
tected under these reaction conditions (see the Sup-
porting Information). Alkoxycarbonylation was also
Experimental Section
the main reaction when trans- and cis-(Z)-8d were re-
acted at room temperature with 2a in the presence of
General Methods
CsF under CO at atmospheric pressure giving (E)-7d Reactions were carried out in Schlenk tubes under a CO at-
mosphere. All reagents were used as received from the com-
mercial supplier. THF was distilled from sodium/benzophe-
none. CHCl3 was distilled from P2O5. Carbonylation reac-
tions were monitored by analytical thin layer chromatogra-
phy using commercial aluminium sheets pre-coated (0.2 mm
layer thickness) with silica gel 60 F254 (E. Merck) or by gas
chromatography. GC analyses were performed with Finni-
gan Focus GC systems equipped with a glass capillary
column SGE PBX5 (30 m length, 0.25 mm inner diameter,
0.25 mm film thickness) and flame ionization detection
as the major compound besides the carbonylated
product (E)-3da. The Suzuki carbonylative reaction
took place more efficiently when the reaction was
performed under heating. In fact, at 608C the reaction
led to (E)-3da and (E)-5d in nearly equimolecular
amounts together with less than 15% of (E)-4da, the
direct cross-coupled product. It should be noted that
the low value of the ratio phenylboronic acid (2a):pal-
ladium complex in the stoichiometric reaction does
not favor the transmetallation over other side reac- under a constant flow 1 mLminÀ1 helium carrier gas. GC-
tions of 2a.[28]
MS analyses were performed with a GC Agilent 6890N
system equipped with a glass capillary column HP-5 MS UI
(30 m length, 0.25 mm inner diameter, 0.25 mm film thick-
Our experiments clearly demonstrate the migrating
ability of the methylene oxime ether fragment, how-
ness) and a low resolution quadrupole analyzer detector
ever, when it carries an electron-withdrawing substitu-
with a constant velocity of 1 mLminÀ1 helium carrier gas.
ent the success of the carbonylative Suzuki cross-cou-
Product purification by flash chromatography was per-
pling requires using a boronic acid with increased
formed using E. Merck Silica Gel (230–400 mesh). Visuali-
transmetallating ability to avoid undesired decompo-
sition side processes.
zation was carried out with UV light. Proton, phosphorus
and carbon magnetic nuclear resonance were recorded at
300, 122 and 75 MHz, respectively, with a Bruker DPX-300,
at 400, 162 and 101 MHz with a Bruker AV-400 or at 500,
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Bꢀrbara Noverges et al.
203 and 126 MHz with a Bruker DRX-500. Chemical shifts
are reported in ppm relative to TMS peak at 0.000 ppm
(1H), H3PO4 at 0.000 (31P) and CDCl3 peak at 77.00 ppm
(13C). Coupling constants (J) are given in Hertz (Hz). The
letters m, s, d, t and q stand for multiplet, singlet, doublet,
triplet and quartet respectively. The letters br indicate broad
signal. High resolution mass spectra were determined on
a TRIPLETOFT5600 (ABSciex, USA) spectrometer or on
a Fisons VG Autospec instrument. All melting points are
uncorrected and were recorded on a Cambridge Instruments
apparatus.
yield: 75%; colorless liquid; 1H NMR (300 MHz, CDCl3,
TMS): d=8.03 (dm, J=8.1 Hz, 2H), 7.67 (dm, J=8.1 Hz,
2H), 7.54–7.57 (m, 2H), 7.29–7.31 (m, 3H), 4.33 (s, 2H),
3.89 (s, 3H); 13C NMR (75 MHz, CDCl3): d=193.9, 152.1,
135.2, 129.5, 128.6, 128.3 (q, J=257 Hz), 126.3, 125.8, 125.7
(q, J=3.7 Hz), 121.9, 62.2, 38.1; HR-MS (EI): m/z (M+)=
321.0976, calcd. for C17H14F3NO2: 321.09766.
(E)-3-(Methoxyimino)-3-phenyl-1-(thiophen-3-yl)propan-
1-one (3ae): THF was used as solvent; yield: 90%; pale
yellow solid; mp 46–498C; 1H NMR (300 MHz, CDCl3,
TMS): d=8.09 (dd, J=3 Hz, 1H), 7.55–7.58 (m, 2H), 7.49
(dd, J=1.2 Hz, 1H), 7.26–7.28 (m, 3H), 7.23 (dd, J=3 Hz,
1H), 4.26 (s, 2H), 3.91 (s, 3H); 13C NMR (75 MHz, CDCl3):
d=188.8, 152.2, 141.4, 135.3, 132.5, 129.3, 128.5, 127.0, 126.4,
126.3, 62.2, 38.8; HR-MS (EI): m/z (M+)=259.0658, calcd.
for C14H13NO2S: 259.0667.
Palladium-Catalyzed Three Component Suzuki–
Miyaura Reaction with a-Halomethyl oxime Ether
(1); General Procedure
To an oven-dried 20-mL flask previously evacuated and
flushed with argon for three times, the appropriate boronic
acid 2a–h (0.6 mmol), CsF (1.2 mmol), PdACTHNUGTRNEG(UN PPh3)4
(E)-3-(Methoxyimino)-3-phenyl-1-(thiophen-2-yl)propan-
1-one (3af): THF was used as solvent; yield: 75%; pale
yellow solid; mp 54–588C; 1H NMR (300 MHz, CDCl3,
TMS): d=7.76 (dd, J=1.2 Hz, 1H), 7.57–7.60 (m, 3H),
7.28–7.30 (m, 3H), 7.07 (dd, J=3.9 Hz, 1H), 4.30 (s, 2H),
3.92 (s, 3H); 13C NMR (75 MHz, CDCl3): d=187.3, 152.0,
143.4, 135.3, 134.0, 132.4, 129.3, 128.5, 128.1, 126.3, 62.2,
38.3; HR-MS (EI): m/z (M+)=259.0659, calcd. for
C14H13NO2S: 259.0667.
(0.03 mmol), a-halomethyl oxime ether 1 (0.3 mmol) and
dry THF or dry CHCl3 (10 mL) were added. Then, a reflux
condenser and a carbon monoxide balloon were fitted under
an argon atmosphere. The system was evacuated and flushed
with carbon monoxide for three times. The mixture was
stirred at 608C in a carbon monoxide at atmospheric pres-
sure for 20 h, and then cooled at room temperature, filtered
through a celite pad and washed with CH2Cl2 (20 mL). Sol-
vents were removed under reduced pressure and the residue
purified by column chromatography yielding the corre-
sponding product 3.
(E)-1-(Furan-3-yl)-3-(methoxyimino)-3-phenylpropan-1-
one (3ag): THF was used as solvent; yield: 91%; pale yellow
1
liquid; H NMR (300 MHz, CDCl3, TMS): d=8.06 (s, 1H),
7.56–7.59 (m, 2H), 7,35 (t, J=1.5 Hz, 1H), 7.26–7.28 (m,
3H), 6.70 (d, J=1.8 Hz, 1H), 4.12 (s, 2H), 3.92 (s, 3H);
13C NMR (75 MHz, CDCl3): d=189.1, 151.9, 147.6, 146.8,
144.1, 135.2, 129.4, 128.5, 126.3, 108.8, 62.2, 39.3; HR-MS
(EI): m/z (M+)=243.0888, calcd. for C14H13NO3: 243.0895.
(E)-1-(Furan-2-yl)-3-(methoxyimino)-3-phenylpropan-1-
one[17] (3ah) [CAS: 1361387-66-7]: THF was used as solvent;
yield: 70%; pale yellow solid; mp 73–758C; 1H NMR
(300 MHz, CDCl3, TMS): d=7.60–7.54 (m, 2H), 7.52 (dd,
J=1.6, 0.7 Hz, 1H), 7.36–7.21 (m, 3H), 7.23–7.10 (m, 1H),
6.47 (dd, J=3.6, 1.7 Hz, 1H), 4.21 (s, 2H), 3.90 (s, 3H);
13C NMR (75 MHz, CDCl3): d=183.3, 152.1, 151.9, 146.4,
135.4, 129.3, 128.5, 126.3, 117.4, 112.4, 62.2, 37.6; HR-MS
(EI): m/z (M+)=243.0885, calcd. for C14H13NO3: 243.0895.
(E)-3-(Methoxyimino)-3-(4-methoxyphenyl)-1-phenylpro-
pan-1-one (3ca): CHCl3 was used as solvent; yield: 70%;
white solid; mp 76–788C; 1H NMR (300 MHz, CDCl3,
TMS): d=8.01–7.82 (m, 2H), 7.54–7.47 (m, 3H), 7.43–7.37
(m, 2H), 6.82–6.77 (m, 2H), 4.32 (s, 2H), 3.87 (s, 3H), 3.73
(s, 3H); 13C NMR (75 MHz, CDCl3): d=194.8, 160.5, 152.2,
136.4, 133.3, 128.6, 128.3, 127.7, 113.9, 62.0, 55.3, 37.7; HR-
MS (EI): m/z (M+H+)=284.1279, calcd. for C17H18NO3:
284.1281.
Characterization of compounds 3
(E)-3-(Methoxyimino)-1,3-diphenylpropan-1-one[17]
(3aa)
[CAS: 1361387-64-5]: CHCl3 was used as solvent; yield:
1
85%; white solid; mp 87–908C; H NMR (300 MHz, CDCl3,
TMS): d=7.93 (dm, J=6.9 Hz, 2H), 7.54–7.57 (m, 3H),
7.38–7.51 (m, 2H), 7.26–7.29 (m, 3H), 4.34 (s, 2H), 3.89 (s,
3H); 13C NMR (75 MHz, CDCl3): d=194.6, 152.6, 136.5,
135.5, 133.3, 129.3, 128.7, 128.5, 128.3, 126.3, 62.1, 37.8; HR-
MS (EI): m/z (M+)=253.1095, calcd. for C16H15NO2:
253.1103.
(E)-3-(Methoxyimino)-1-(4-methoxyphenyl)-3-phenylpro-
pan-1-one[29] (3ab) [CAS: 1361387-65-6]: CHCl3 was used as
solvent; yield: 80%; white solid; mp 58–608C; 1H NMR
(300 MHz, CDCl3, TMS): d=7,92 (dm, J=9 Hz, 2H), 7.54–
7,57 (m, 2H), 7.26–7.28 (m, 3H), 6.87 (dm, J=9 Hz, 2H),
4.31 (s, 2H), 3.90 (s, 3H), 3.80 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=193.1, 163.7, 152.8, 135.6, 130.6, 129.5, 129.2,
128.5, 126.3, 113.8, 62.1, 55.5, 37.5; HR-MS (EI): m/z
(M+)=283.1200, calcd. for C17H17NO3: 283.1208.
(E)-3-(Methoxyimino)-3-phenyl-1-ortho-tolylpropan-1-
one (3ac): CHCl3 was used as solvent; yield: 50%; colorless
liquid; 1H NMR (300 MHz, CDCl3, TMS): d=7.63 (d, J=
7.8 Hz, 1H), 7.52–7.55 (m, 2H), 7.27–7.30 (m, 4H), 7.15–
7.20 (m, 2H), 4.24 (s, 2H), 3.88 (s, 3H), 2.36 (s, 3H);
13C NMR (75 MHz, CDCl3): d=198.4, 152.8, 138.4, 137.3,
135.6, 131.9, 131.5, 129.3, 128.5, 128.4, 126.3, 125.5, 62.1,
40.7, 21.0; HR-MS (EI): m/z (M+)=267.1251, calcd. for
C17H17NO2: 267.1259.
(E)-1-(Furan-2-yl)-3-(methoxyimino)-3-(4-methoxyphe-
nyl)propan-1-one (3ch): THF was used as solvent; yield:
1
75%; pale yellow solid; mp 71–738C; H NMR (300 MHz,
CDCl3, TMS): d=7.57–7.45 (m, 3H), 7.20 (dd, J=3.6,
0.7 Hz, 1H), 6.80 (d, J=9.0 Hz, 2H), 6.47 (dd, J=3.6,
1.7 Hz, 1H), 4.18 (s, 2H), 3.88 (s, 3H), 3.73 (s, 3H);
13C NMR (75 MHz, CDCl3): d=183.5, 160.5, 152.0, 151.4,
146.5, 127.7, 117.6, 113.9, 112.3, 62.0, 55.3, 37.5; HR-MS
(EI): m/z (M+H+)=274.1071, calcd. for C15H16NO4:
274.1074.
(E)-3-(Methoxyimino)-3-phenyl-1-[4-(trifluoromethyl)-
phenyl]propan-1-one (3ad): CHCl3 was used as solvent;
8
asc.wiley-vch.de
ꢄ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
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FULL PAPERS
Palladium-Catalyzed Suzuki Carbonylative Reaction of a-Halomethyl Oxime Ethers
(E)-3-(4-Chlorophenyl)-3-(methoxyimino)-1-phenylpro-
pan-1-one (3da): THF was used as solvent; yield: 29%;
white solid; mp 68–708C; 1H NMR (400 MHz, CDCl3,
TMS): d=7.97–7.90 (m, 2H), 7.54–7.47 (m, 3H), 7.44–7.38
(m, 2H), 7.27–7.22 (m, 2H), 4.33 (s, 2H), 3.89 (s, 3H);
13C NMR (101 MHz, CDCl3): d=194.5, 151.6, 136.3, 135.3,
134.0, 133.5, 128.7, 128.7, 128.3, 127.6, 62.3, 37.5; HR-MS
(EI): m/z (M+H+)=288.0789, calcd. for C16H15ClNO2:
288.0786.
Chem. Rev. 2000, 100, 3187–3204; d) J. Tsuji, Transition
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2002, 653, 34–40; g) Transition Metals for Organic Syn-
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Int. Ed. 2005, 44, 4442–4489; k) A. C. Frisch, M. Beller,
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(E)-3-(4-Chlorophenyl)-1-(furan-3-yl)-3-(methoxyimino)-
propan-1-one (3dg): THF was used as solvent; yield: 86%;
1
pale yellow oil; H NMR 400 MHz, CDCl3, TMS): d=8.10–
8.01 (m, 1H), 7.56–7.45 (m, 2H), 7.38–7.29 (m, 1H), 7.27–
7.18 (m, 2H), 6.68 (dd, J=1.9, 0.7 Hz, 1H), 4.09 (s, 2H),
3.91 (s, 3H); 13C NMR (101 MHz, CDCl3): d=188.8, 150.8,
147.7, 144.2, 135.4, 133.6, 128.7, 127.6, 126.9, 108.7, 62.3,
38.9; HR-MS (EI): m/z (M+H+)=278.0577, calcd. for
C14H13ClNO3: 278.0578.
ACHTUNGTRENNUNG(E,Z)-3-[(Benzyloxy)imino]-1-(furan-3-yl)butan-1-one
(3eg): THF was used as solvent; after flash chromatography
the product was obtained with (63:37) isomeric ratio; yield:
82%; pale yellow oil; 1H NMR (300 MHz, CDCl3, TMS):
d=8.01–7.89 (m, 100/100ꢅ1H), 7.36–7.30 (m, 100/100ꢅ1H),
7.30–7.20 (m, 100/100ꢅ5H), 6.72–6.61 (m, 100/100ꢅ1H),
5.04 (s, 63/100ꢅ2H), 5.02 (s, 37/100ꢅ2H), 3.73 (s, 37/100ꢅ
2H), 3.52 (s, 63/100ꢅ2H), 1.87 (s, 37/100ꢅ3H), 1.86 (s, 63/
100ꢅ3H); 13C NMR (75 MHz, CDCl3, isomer E): d=190.5,
153.0, 148.3, 144.0, 138.1, 128.3, 127.9, 127.7, 126.8, 108.6,
75.6, 48.1, 14.7; 13C NMR (75 MHz, CDCl3, isomer Z): d=
189.3, 151.5, 148.3, 144.2, 137.4, 128.4, 128.1, 127.9, 127.1,
108.6, 75.7, 41.7, 20.5; HR-MS (EI): m/z (M+H+)=
258.1125, calcd. for C15H16NO3 258.1125.
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(E)-3-[(Benzyloxy)imino]-1-(furan-3-yl)-4,4-dimethylpen-
tan-1-one (3fg): THF was used as solvent; yield: 70%; white
1
solid; mp 64–668C; H NMR (400 MHz, CDCl3, TMS): d=
[4] Y. Wakita, T. Yasunaga, M. Akita, M. Kojima, J. Orga-
7.90 (dd, J=1.4, 0.8 Hz, 1H), 7.30 (dd, J=1.9, 1.4 Hz, 1H),
7.18–7.09 (m, 5H), 6.66 (dd, J=1.9, 0.8 Hz, 1H), 4.93 (s,
2H), 3.60 (s, 2H), 1.09 (s, 9H); 13C NMR (101 MHz,
CDCl3): d=189.5, 161.0, 147.1, 143.9, 137.6, 128.1, 128.1,
127.5, 108.8, 75.6, 37.7, 37.0, 27.6; HR-MS (EI): m/z (M+
H+)=300.1594, calcd. for C18H22NO3: 300.1594.
Data for compounds trans- and cis-(Z)-8b, trans-(E/Z)-9b,
trans- and cis-(Z)-8d, trans-(E)-9d and their decomposition
reaction are collected in the Supporting Information
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Acknowledgements
This work was supported by the Spanish Ministerio de Cien-
cia e Innovaciꢀn, European Community Founds (FEDER)
and Generalitat Valenciana grants (CTQ 2010-19999, CTQ
2011-28942-C02-02 and ACOMP-2013/185). We thank (BN)
the Ministerio de Ciencia e Innovaciꢀn for a fellowship. We
acknowledge the SCSIE (Universidad de Valencia) for access
to instrumental facilities.
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10
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Palladium-Catalyzed Suzuki Carbonylative Reaction of a-
Halomethyl Oxime Ethers: A Regioselective Route to
Unsymmetrical 1,3-Oxyiminoketones
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Bꢀrbara Noverges, Mercedes Medio-Simꢁn,*
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