Stereocontrol in Preparation of Cyclopalladated Alkylaromatic Oximes and Evaluation of Their Stereoselective Esterase-Type Catalytic Activity

Article abstract of DOI:10.1021/acs.organomet.7b00410

The stereochemistry of 2′-methylbutyrophenone oxime, the rates of ortho-palladation of its E- and Z-isomers, and catalytic activity of the respective Pd complexes were studied. The full stereoisomeric composition of oximes was established for the first time by means of supercritical fluid chromatography on chiral polysaccharide column. It was shown that enantiomeric excesses of both E/Z-isomers of (S)-2′-methylbutyrophenone oxime (1S) and (R)-2′-methylbutyrophenone oxime (1R) were equal to 92 ± 2. The cyclopalladation study revealed that while E-isomer is ortho-palladated very quickly its Z-counterpart does not enter this reaction. However, upon coordination to Pd(II), Z-oxime slowly isomerizes into E-form with fast subsequent cyclopalladation, so it was possible to perform ortho-palladation of E-oxime in kinetic resolution mode with removal of unreacted Z-oxime. Comparatively rare cis-structure of cyclopalladated oxime dimer was proved by means of single-crystal X-ray study. For the first time, it was shown that ortho-palladated chiral oximes behave as enantioselective catalyst in the hydrolysis of chiral esters.

Full text of DOI:10.1021/acs.organomet.7b00410

Article
pubs.acs.org/Organometallics
Stereocontrol in Preparation of Cyclopalladated Alkylaromatic
Oximes and Evaluation of Their Stereoselective Esterase-Type
Catalytic Activity
,
†
†
†
‡
Sergey Z. Vatsadze,* Aleksei V. Medved’ko, Sergey A. Kurzeev, Oleg I. Pokrovskiy,
Olga O. Parenago,† Mikhail O. Kostenko, Ivan V. Ananyev, Konstantin A. Lyssenko,
,‡
†,‡
§
§
†
†
†
Dmitri A. Lemenovsky, Gregory M. Kazankov, and Valery V. Lunin
†
Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia
‡
§
N.S. Kurnakov Institute of General and Inorganic Chemistry and A.N. Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences, Moscow 119991, Russia
*
S Supporting Information
ABSTRACT: The stereochemistry of 2′-methylbutyrophe-
none oxime, the rates of ortho-palladation of its E- and Z-
isomers, and catalytic activity of the respective Pd complexes
were studied. The full stereoisomeric composition of oximes
was established for the first time by means of supercritical fluid
chromatography on chiral polysaccharide column. It was
shown that enantiomeric excesses of both E/Z-isomers of
(
S)-2′-methylbutyrophenone oxime (1S) and (R)-2′-methyl-
butyrophenone oxime (1R) were equal to 92 ± 2. The
cyclopalladation study revealed that while E-isomer is ortho-
palladated very quickly its Z-counterpart does not enter this
reaction. However, upon coordination to Pd(II), Z-oxime
slowly isomerizes into E-form with fast subsequent cyclo-
palladation, so it was possible to perform ortho-palladation of E-oxime in kinetic resolution mode with removal of unreacted Z-
oxime. Comparatively rare cis-structure of cyclopalladated oxime dimer was proved by means of single-crystal X-ray study. For
the first time, it was shown that ortho-palladated chiral oximes behave as enantioselective catalyst in the hydrolysis of chiral esters.
INTRODUCTION
■
The key trends in the field of modern organic synthesis include
catalytic cross-coupling and oxidative cross-coupling reactions,
metathesis processes, design of new homogeneous and
heterogeneous catalytic systems, and the development of new
approaches to investigation of mechanisms of catalytic
1
Figure 1. General formulas of cyclopalladated oxime.
reactions. The study of new enantioselective metallocatalysts
that mimic principles of enzyme reactions is one of the most
2
important purposes of biomimetics. These catalysts usually
activity of cyclopalladated oximes in nucleophilic catalysis is due
not only to the presence of this hydroxide fragment but also to
high acidity of the hydroxyl group of oxime moiety. For
represent coordination complexes of transition metals such as
3
−5
Pd(II), Pt(II), Zn(II), and Cu(II).
Among them, cyclo-
metalated complexes seem to be extremely promising, due to
their high activity and ease with which they make structurally
diverse systems. Palladium compounds containing Pd−C bond
and stabilized by intramolecular bond with electron-donating
atom are referred to as cyclopalladated complexes or pallada-
example, pK of free acetophenone oxime is about 11, but being
a
ortho-palladated, it has a pK value of 6−7. Thus, the oximate
a
anion acting together with hydroxide as a nucleophile enhances
11
the rate of hydrolysis of the substrate significantly. While
cyclopalladation of oximes was performed for the first time
6
cycles (Figure 1). ortho-Palladated oximes are among
12,13
7
,8
more than 40 years ago,
these complexes are still popular
promising catalysts for performing cross-coupling reactions.
precursors for synthesis of more complicated palladium
If a water molecule is coordinated in the trans-position with
respect to aromatic carbon atom, then it easily loses a proton
1
4−17
complexes.
Although their catalytic properties were
(
pK ca. 4), forming a strong nucleophilic center that is
a
generally responsible for the activity of cyclopalladated
Received: June 4, 2017
9
,10
complexes in nucleophilic catalysis.
In addition, the high
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.7b00410
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Article
a
Scheme 1. General Routes for Preparation of Racemic (a) and Chiral (b, c) 2′-Methylbutyrophenone oximes
a
SAMP: (S)-N-amino-2-methoxymethylpyrrolidine.
1
1
already explored in the hydrolysis processes, no information is
found on the application of chiral oximes in such reactions.
The presence of a chiral center at the α-position with respect
to the benzene ring influences many of the structural features of
the ortho-palladated complexes including the unique formation
multistep recrystallization of diastereomeric mixture leading to
26
a large loss of oxime. In this work, we applied the oximation
of both enantiomerically pure forms of chiral ketone.
Oximation of racemic and chiral 2′-methylbutyrophenones by
hydroxylamine hydrochloride in dry pyridine gave correspond-
ing oximes in almost quantitative yields (Scheme 1), but the
question of their stereochemistry had to be solved. The
oximation of racemic 2′-methylbutyrophenone led to two pairs
of enantiomers, hereafter called (E)-1S/(E)-1R and (Z)-1S/
18
of trimeric forms in solid state and solution. In contrast, in the
case of oximes one could only have a chiral center one carbon
atom further (Figure 1). The creation of such asymmetric
carbon atom at the α-site of oxime that is located in distal
proximity to reacting Pd center (Figure 1, marked with
asterisk) might slightly influence the energy of the “substrate−
catalyst” transition complex. This idea deserves to be proved or
disproved. If we could prepare palladium complexes of both
enantiomers of such oxime, then we can try to catalyze the
hydrolysis of chiral esters. If enantiomers are being hydrolyzed
with different rates, then such complexes could be named as
enantioselective hydrolytic catalysts. Therefore, the aim of this
work was the evaluation of catalytic activity of chiral ortho-
palladated oximes. To achieve our aim, we fulfilled the
following tasks: (i) preparation of simplest chiral alkylaromatic
oxime of 2′-methylbutyrophenone, (ii) study of its stereo-
chemistry, (iii) study of its cyclopalladation, and (iv) testing
hydrolytic activity of the chiral oxime complexes in reactions
with model chiral substrates.
(
Z)-1R (Scheme 1).
First, we studied the diastereochemistry of the oximes. In our
procedure, oximes 1rac, 1S, and 1R were obtained as mixtures
of E- and Z-isomers with ratios close to 1.2:1 (on the basis of
proton NMR spectra, Figure 2b), in accordance with literature
27−29
data for similar unsymmetrical oximes.
Assignment of
isomers’ chemical shifts was based on the NMR spectrum of
pure racemic E-isomer ((E)-1rac) that spontaneously formed
from racemic E/Z mixture upon storage for ca. 1 year in a glass
29
vessel (Figure 2a).
The diastereochemistry of racemic (E)-1rac was proved by
X-ray diffraction study (Figure 3). The molecules of (E)-1rac
crystallize in the centrosymmetric space group (I4 /a, Z′=1),
1
and despite the disorder attributed to the superposition of two
enantiomers with occupancies 0.84(1) and 0.16, the crystal of
(
E)-1rac is a racemate. Note that this disorder and 1:1 ratio of
RESULTS AND DISCUSSION
■2
′-Methylbutyrophenone Preparation. Friedel−Crafts
enantiomers remains even if the crystal structure is solved and
refined in the noncentrosymmetric space group (I4 , Z′=2). In
the crystal, the (E)-1rac molecules form N···H−O hydrogen
bonds (N···O 2.751(2) Å) assembling molecules into
tetramers. A similar supramolecular motif was reported recently
for E-isomer of oxime of 2-methylpropiophenone (N···O 2.753
1
reaction is the easiest way to obtain achiral alkylaromatic
1
9,20
ketones.
However, in the case of chiral ketones this method
is limited by the commercial availability of the corresponding
enantiopure carboxylic acids as well as by the lability of the
resulting ketone toward racemization. It is known that our
target molecule 2′-methylbutyrophenone easily undergoes
30
Å)
2
1
Oxime Diastereo- and Enantiomeric Composition.
racemization in alkaline conditions even during storage in
2
2
Before proceeding to the preparation of palladium complexes,
we tried to analyze the composition of oxime stereoisomers
mixtures. The diastereo- and enantiomeric composition of
oximes was established by supercritical fluid chromatography
glass vessels. At the same time, the stereochemistry of this
19
ketone does not change in dry pyridine. In this work, racemic
′-methylbutyrophenone (1rac) and chiral (S)-2′-methylbutyr-
ophenone (1S) were obtained by acyl chloride preparation and
sequential Friedel−Crafts acylation of benzene using racemic
and chiral (S)-2-methylbutiric acid, respectively, as shown in
Scheme 1a,b.
2
19
(
SFC) using a Kromasil Amycoat column as a chiral stationary
phase and a CO −iPrOH mixture as a mobile phase. No chiral
2
separation was achieved with cellulose-based chiral phases and
methanol as a cosolvent. Enantiorecognition on amylose-based
chiral stationary phases is known to be mobile-phase-dependent
because amylose swells differently in different cosolvents, which
leads to changes in polymer conformation and hence in chiral
Enantiopure (R)-2′-methylbutyrophenone (1R) was pre-
pared by Enders’ asymmetric alkylation of propiophenone with
2
3,24
iodomethane
methods to prepare stereochemically pure ketoximes exist.
The only separation technique found in the literature includes a
(Scheme 1c). Unlike aldoximes, no general
25
31
centers accessibility.
B
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Article
stereoisomers is shown in Figure 4. The enantiomeric excesses
of both E/Z-isomers of (S)-2′-methylbutyrophenone oxime 1S
Figure 4. Separation of 2′-methylbutyrophenone oxime diastereomers
1
rac. Kromasil Amycoat 100−3 150 × 4.6, CO /iPrOH 93/7 v/v, 100
2
bar, 40 °C, 4 mL/min, 220 nm.
and (R)-2′-methylbutyrophenone oxime 1R were equal to 92 ±
2
% (Figures S2 and S3). Z- and E-oximes have different
enantiomer elution orders. For E-oxime, (S)-enantiomer elutes
earlier than (R), whereas for Z-oxime, the elution order is the
opposite. To assign the chromatographic peaks to the
corresponding isomer, enantiomerically enriched samples with
known major component were used as standards.
Oxime Cyclometalation. Since the preparation of ortho-
palladated product in fact requires only E-isomer as a starting
organic substrate, we made several attempts to increase its
content in the diastereomeric mixture. We increased bulkiness
of substituent replacing hydrogen atom attached to oxygen for a
methyl group. However, E/Z-ratio reversed to become 1:1.7 for
1
Figure 2. High-field part of H NMR spectra (400 MHz, CDCl ) of
3
racemic (E)-2′-methylbutyrophenone oxime (E)-1rac (a) and E/Z
mixture of racemic 2′-methylbutyrophenone oxime 1rac (b).
2
′-methyl-1-phenylbutan-1-one O-methyl oxime (Figure S1).
Then, we tried to improve the stereoselectivity of oximation by
performing the synthesis in the presence of α-cyclodextrin
which is known as a host molecule with hydrophobic internal
cavity, but the best E/Z isomeric ratio was 60/40 with low
chemical yield (50%).
Since no positive results in improving the diastereomeric
ratio were achieved, we decided to perform the cyclopalladation
of 1S and 1R using their respective E/Z mixtures (Scheme 2).
Surprisingly, the product distribution showed that the presence
of Pd(II) affected the ratio between nonpalladated E- and Z-
Scheme 2. Cyclopalladation of Isomeric Mixtures of 2′-
, ,
a b c
Methylbutyrophenone Oximes
Figure 3. General view of the hydrogen bonded tetramer in the
racemic crystal of (E)-1rac in representation of atoms by thermal
ellipsoids (p = 50%). The disorder corresponding to the superposition
of two enantiomers with occupancies 0.84 and 0.16 is shown only for
the asymmetric part.
a
Compound 1 is (E)-1. Reflux time is 15 min. Isolated yield corrected
b
on purity determined by NMR. Compound 1 is E/Z mixture. Reflux
time is 4 h. NMR-based yield corrected on purity determined by
NMR. Compound 1 is E/Z mixture. Reflux time is 6 h. NMR-based
yield corrected on purity determined by NMR.
This makes the choice of a cosolvent type and concentration
as the key factor of selectivity control in separations on these
stationary phases. A typical SFC separation of four oxime
c
C
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Article
isomers. The ratio was checked by NMR of crude sample with
slight excess of pyridine. Indeed, Z-oxime content in E/Z
mixture decreased from 45 to 16% during the reaction. This
means that partial isomerization of oxime occurred during
interaction of a ligand with Pd(II). We assume that the
palladium ion being bound to the N atom of oxime weakens the
CN double bond to allow easy oxime isomerization. To
enhance the degree of oxime isomerization, the cyclo-
palladation of E/Z mixture was performed in refluxing 1,4-
dioxane−water mixture.
The pure E-isomer is ortho-palladated completely after 15
min under these conditions. However, the formation of
cyclopalladated complexes is also accompanied by reduction
Figure 5. General view of one independent molecule in crystal of 2rac
in representation of atoms by thermal ellipsoids (p = 50%). The
disorders of the sec-butyl substituents are omitted for clarity. The
hydrogen bonds to chlorine atom are shown as dotted lines.
32
of Pd(II) to Pd(0) even in inert atmosphere. Oxime itself
does not reduce palladium at reflux temperature, but after
addition of basic sodium acetate, the Pd(0) formation is much
more accelerated and occurs concurrent to ortho-palladation.
NMR analysis showed that after 4 h ca. 10% of Z-oxime was
isomerized, and after 6 h, ca. 25% was isomerized. At the same
time, the complete isomerization is suppressed because free Z-
oxime could be bound by cyclopalladated product to form
Scheme 4. Sequential Cyclopalladation-Monomerization of
a
Oximes
12
byproducts shown on Scheme 3.
Scheme 3. Supposed Byproducts of Cyclopalladated Dimeric
Complex Reaction with Free Z-Oxime
a
Starting oximes are E/Z mixtures.
procedure was found to be equal to 87 ± 1 and 79 ± 1%,
respectively (Figure 6). This shows that partial isomerization
Racemic O-methyl-2′-methylbutyrophenone oxime is not
involved in cyclopalladation under these conditions. Only
adduct L PdCl is formed as proved by X-ray study (Figure S4).
2
2
The structure of racemic complex 2rac was also proved by
means of X-ray (Figure 5).
Figure 6. Separation of enantiomers of 3S. Kromasil 3-CelluCoat 4.6
This complex has cisoid arrangement of cyclopalladated
×
150 mm column with CO /methanol/isopropylamine 70/30/1
3
3−35
2
ligands,
while for other cyclopalladated complexes, i.e.,
mobile phase.
36−38
amines, the trans orientation is common.
Also, the ligand
molecule is highly bent with dihedral angle between Pd−C−N
mean planes equal to 121°. The observed bending of Pd Cl
takes place during cyclopalladation. In contrast, chiral cyclo-
palladated oximes are stable for months in solid state and give
no sign of racemization in methanol solution for at least 10 days
(Figure S25), suggesting the absence of racemization during
catalysis. The structure of pyridine-containing monomer 3S was
proved by X-ray (Figure 7) and is typical for cyclopalladated
2
2
cycle in 2rac is probably due to intramolecular O−H···Cl bonds
H···Cl 2.37−2.49 Å, O−H···Cl 138−148°). For known
dimeric palladacycles, the bending angle is close to 180° with
(
36,38−41
very few exceptions.
The fast cyclopalladation of E-isomers and significant
difference of solubility of starting oximes 1 and cyclopalladated
complexes in n-hexane allowed us to perform the reaction in
kinetic resolution mode (Scheme 4). NMR study of the
reaction mixture after separation of cyclopalladated oxime
confirmed that only E-oxime can be cyclopalladated with some
isomerization Z- to E-isomer (Figure S24). Enantiomeric
excesses of compounds 3S and 3R measured by another SFC
9
oximes.
In crystal, two independent molecules are distinguished by
two different rotation angles of a pyridine ring. Also, short
distances H(1O)...Cl(1) and H(1OA)...Cl(1A) (∼2.23 Å)
prove the existence of intramolecular hydrogen bond H···Cl,
14,15,17
which is typical for such oxime systems.
The H-bond
sustains in solution, which is clearly seen by shifting of OH
D
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Article
(
k (R)/k (S)) compared to 1.55 (k (S)/k (R)) for the first
2
2
2
2
substrate (Scheme 5).
Scheme 5. Proposed Mechanism of Ester Cleavage
Figure 7. General view of one independent molecule in crystal of 3S in
representation of atoms by thermal ellipsoids (p = 50%).
1
chemical shift from 8.2 to 10.2 ppm in H NMR spectrum in
chloroform-d.
Catalytic Activity of Oximes. The study of catalytic
activity of racemic cyclopalladated oxime 3rac in hydrolysis of
esters was started using standard substrate 2,4-dinitrophenyl
acetate. Because of low catalytic activity of cyclopalladated
oximes, the hydrolysis was carried out in pseudo-first-order
regime with variable excess of catalyst to determine k from k
Interestingly, 3R isomer was more active for Cbz-Val than
was 3S, while the latter was more active in 2,4-dinitrophenyl
(
S)-2-methylbutanoate hydrolysis. We are not going to
2
obs
1
1
11
speculate on the possible catalytic mechanism, but it seems
both reactions proceed similarly.
=
k +k [Pd], where [Pd] is palladium complex concentration.
0 2
The catalytic constant for model substrate and catalyst 3 is
−
1
−1
2
The difference found in rate constants could be only a
consequence of the difference in energy of diastereomeric
equal to 224 ± 8 M
s
(r = 0.988). It is 150 times higher
42
than the respective constants for amine-based palladacycles.
“
substrate−catalyst” transition complexes. This proves our
This proves the initial idea of using nucleophilic oxime-type
ligands. As was mentioned in the Introduction, to evaluate the
enantioselectivity of chiral palladium complexes, one should
compare the reaction rates of chiral substrate using both
enantiomeric catalysts. These reactions with chiral oxime
palladacycles 3S and 3R were tested on 2,4-dinitrophenyl
second initial idea that the creation of asymmetric carbon atom
in disital proximity to catalytic site would provide an effect on
catalytic reaction rate. What is surprising is that even such small
difference in bulkiness of methyl and ethyl groups in sec-butyl
substituent exhibits such a noticeable effect on ester cleavage
rate.
(S)-2-methylbutanoate and commercially available N-Cbz-L-
valine 4-nitrophenyl ester as substrates (Table 1).
CONCLUSIONS
Although the rate of hydrolysis of 2,4-dinitrophenyl (S)-2-
methylbutanoate by palladacycles 3S and 3R is two times lower
than that for 2,4-dinitrophenyl acetate, the reaction now
proceeds in a stereoselective manner. The second substrate was
hydrolyzed much more slowly, which was obvious because it
had only one nitro substituent on its phenolic leaving group,
but this decrease in reactivity allowed us to gain an increase in
selectivity. Indeed, the catalytic constants ratio reached 1.98
■
The oxime of the 2′-methylbutyrophenone exists as a racemic
mixture of E- and Z-isomers. Supercritical fluid chromatography
on chiral polysaccharide columns allows separating all four
oxime stereoisomers and both cyclopalladated enantiomers
within reasonable time. During the ortho-palladation reaction,
partial isomerization of Z-isomer to E-isomer occurred. ortho-
Palladated oxime adopts a very rare syn-configuration of the
a
Table 1. Hydrolysis Rate Constants
k (M− s−1
1
)
k (S)/k (R)
2 2
substrate
catalyst
2
3
3
3
3
S
119 ± 4
77 ± 2
5.6 ± 0.2
11.1 ± 0.3
2
,4-dinitrophenyl(S)-2-methylbutanoate
1.55
R
S
N-Cbz-L-valine 4-nitrophenyl ester
0.51
R
a
Rate constants were normalized to 100% enantiomer of catalysts 3S and 3R according to
R
S
S
R
k X − k X
2
S
2 S
kR =
R
S
S
R
X X − X X
R
S
R S
S
S
k − k X
2
R
R
kS =
S
XS
R
S
S
S
where k , k are catalytic constants for pure enantiomers, k , k are catalytic constants for enriched mixture of R or S enantiomer, X , X are parts of S
R
S
2
2
S
R
R
R
and R enantiomers in mixture enriched of S enantiomer, and X , X are parts of R and S enantiomers in mixture enriched of R enantiomer.
R
S
E
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Article
ligand molecules in a solid state. Pyridine-containing monomers
of ortho-palladated chiral oximes catalyze hydrolysis of chiral
esters in enantioselective manner; this finding would allow
kinetic resolution of racemic carboxylic acids in future. The
exploitation of bipy-type bidentate ligands for the synthesis of
dinuclear palladium catalysts is under current study at our
laboratories.
CH), 1.46−1.63 (m, 2H, CH
2
CH
3
), 1.70−2.08 (m, 5H, 2*CH −Pyr,
3
2
N−CHH), 2.63 (1H, m, N−CHCH ), 3.15−3.34 (3H, m), 3.37 (3H,
s, OCH ), 3.41−3.48 (1H, m), 3.61 (1H, m), 7.32−7.34 (3H, m,
3
C(3,4,5)H−Ph), 7.40−7.42 (2H, m, C(2,6)H−Ph).
24
(
R)-2-Methylbutyrophenone. A solution of 1.43 g (5.2 mmol) of
(
2′S)-2-methoxymethyl-1-((2R)-2-methyl-1-phenylbutyliden-amino)-
pyrrolidine in 21 mL of hexane was vigorously stirred with 7.4 mL of
oxalic acid saturated aqueous solution for 2 h. The organic phase was
separated and water phase was washed with 10 mL of hexane. The
organic phases were combined and dried over anhydrous magnesium
sulfate. Solvent was removed and residue was distilled in vacuum.
EXPERIMENTAL SECTION
Materials and Methods. All reagents were obtained from
commercial sources. Solvents were dried prior to use by conventional
■
Product was obtained as yellow oil (0.59 g, 60%). Bp 72−73 °C (2
45
4
3
Torr) (lit. 40−45 °C (0.01 Torr)). [α]
D
− 32.7° (c 0.2 in Et
, Me
4
2
O)
Si)
methods. 2,4-Dinitrophenyl (S)-2-methylbutanoate and (S)-N-
3
9,45
1
4
4
(lit.
0
−27.9° (c 1.0 in Et
2
O)). H NMR (400 MHz, CDCl
2
3
amino-2-methoxymethylpyrroli-dine were prepared as described
3
3
.93 (3H, t, J = 7.5 Hz, CH CH ), 1.21 (3H, d, J = 6.9 Hz, CHCH ),
3
3
elsewhere. Melting points were measured on Thermoscientific
1
13
1.47−1.54 (1H, m, CH
2
), 1.81−1.88 (1H, m, CH
2
), 3.37−3.46 (1H,
IA9100. H and C NMR spectra were processed on Bruker DRX-
00 spectrometer. J values are given in Hz. Optical rotation of
m, CH), 7.45−7.49 (2H, m, C(2,6)H), 7.55−7.58 (1H, m, C(4)H),
4
7
.95−7.97 (2H, m, C(3,5)H).
General Procedure of Oximation. First, 15 mmol of hydroxylamine
polarized light was measured on Autopol II polarimeter in a 1 dm
length cuvette.
Synthetic Procedures. General Procedure for Synthesis of
Ketones. First, 34 mmol of anhydrous aluminum chloride was mixed
with 52 mL of benzene and cooled to 5 °C. Then, 31 mmol of
chloroanhydride of (±)-2-methylbutyric acid was added dropwise for
hydrochloride was dissolved in 60 mmol of dry pyridine. Then, 4
mmol of ketone was added, and reaction mixture was left for 3 days at
rt. A solution of 5 mL of concentrated hydrochloric acid in 34 mL of
ice water was added. The product was extracted with 2 × 25 mL of
diethyl ether. The organic phase was separated and dried over
anhydrous sodium sulfate. The solvent was evaporated to dryness.
0
.5 h. The reaction mixture was stirred for 2 h in ice bath and further
at rt overnight. A solution of 5 mL of concentrated hydrochloric acid
in 45 mL of water was added. The organic layer was separated and
washed with 100 mL of ice water and 100 mL of 1% aqueous solution
of sodium hydrocarbonate. The organic layer was dried over
anhydrous calcium chloride, and the solvent was evaporated and
residue was distilled in vacuum.
2
-Methyl-1-phenylbutanone oxime (1rac). Slightly pink powder.
1
Yield 91%. E/Z mixture 1.2:1. H NMR (400 MHz, CDCl , Me Si)
3
4
3
0
.93−0.99 (5.66 H, m), 1.17 (2.55H, d, J = 6.8 Hz), 1.27 (3.00 H, d,
3
J = 7.0 Hz), 1.34−1.45 (0.90H, m), 1.51−1.69 (1.90H, m), 1.72−1.83
(
1.01H, m), 2.62 (0.83H, m), 3.41 (1.00H, m), 7.30−7.46 (9.04H, m).
1
3
3
δH (400 MHz, DMSO-d ) 0.83 (5.55H, m), 1.04 (2.46H, d, J = 6.9
(
±)-2-Methylbutyrophenone. Bp 92 °C (3 Torr) (lit. 103 °C (8
6
3
1
3
Hz), 1.15 (3.00H, d, J = 7.2 Hz), 1.22−1.31 (0.88H, m), 1.42−1.55
Torr)). H NMR (400 MHz, CDCl , Me Si) 0.84 (3H, t, J = 7.4 Hz,
3
4
3
(
(
(
1
1
1.84H, m), 1.61−1.72 (1.02H, m), 2.57 (0.81H, m), 3.21−3.30
1.00H, m), 7.21−7.43 (8.98H, m, Ph), 10.46 (0.77H, s, OH), 10.99
0.95H, s, OH). 13C NMR (100 MHz, CDCl , Me Si) 11.50, 12.40,
7.06, 17.40, 26.66, 26.80, 35.12, 41.26, 127.50, 127.56, 128.07,
28.11, 128.38, 128.45, 133.72, 136.17, 162.34, 163.82.
CH CH ), 1.12 (3H, d, J = 6.9 Hz, CHCH ), 1.37−1.47 (1H, m,
2
3
3
CH ), 1.72−1.82 (1H, m, CH ), 3.34 (1H, CH), 7.37−7.41 (2H, m,
2
2
C(3,5)H), 7.45−7.49 (1H, m, C(4)H), 7.90−7.92 (2H, m, C(2,6)H).
3
4
1
3
C (100 MHz, CDCl , Me Si) 11.42, 16.46, 26.37, 41.73, 127.90,
3
4
1
28.30, 132.46, 136.52, 203.9.
S)-2-Methylbutyrophenone. Bp 84−85 °C (3 Torr). (lit. 40−45
4
5
(S)-2-Methyl-1-phenylbutanone oxime (1S). Yield 92%. Slightly
(
1
15,19
pink powder. E/Z mixture 1.2:1. H NMR (400 MHz, CDCl , Me Si)
°C (0.01 Torr)) [α] + 36.2° (c 1.6 in Et O). (lit.
+36.6° (c 4.7 in
3
4
D
2
3
3
1
3
0.93−0.98 (5.68H, m), 1.16 (2.56H, d, J = 6.8 Hz), 1.26 (3.00H, d, J
Et2O)). H NMR (400 MHz, CDCl , Me Si) 0.93 (3H, t, J = 7.45
3
4
3
= 7.0 Hz), 1.35−1.44 (0.86H, m), 1.50−1.67 (1.94H, m), 1.71−1.82
Hz, CH CH ), 1.21 (3H, d, J = 6.9 Hz, CHCH ), 1.47−1.54 (1H, m,
2
3
3
(
1.12H, m), 2.64 (0.79H, m), 3.40 (1.00H, m), 7.29−7.46 (8.67H, m,
CH ), 1.81−1.88 (1H, m, CH ), 3.37−3.46 (1H, m, CH), 7.45−7.49
2
2
Ph), 9.09 (0.71H, br s, OH), 9.64 (0.83H, br s, OH). Elemental
composition calcd (%) for C H NO: C 74.54, H 8.53, N 7.90. Found
(
2H, m, C(3,5)H), 7.55−7.58 (1H, m, C(4)H), 7.95−7.97 (2H, m,
C(2,6)H).
2S)-2-Methoxymethyl-1-(1-phenylbutylidenamino)-pyrroli-
11 15
(
%): C 74.41, H 8.38, N 7.98.
(R)-2-Methyl-1-phenylbutanone oxime (1R). Yield 89%. Slightly
(
45
dine. 1.43 g (9.6 mmol) of butyrophenone and 1.24 g (9.6 mmol) of
S)-N-amino-2-methoxymethylpyrrolidine were dissolved in 30 mL of
1
(
pink powder. E/Z mixture 1.2:1. H NMR (400 MHz, CDCl
3
, Me
4
Si)
3
3
benzene and refluxed with Dean−Stark trap for 144 h in argon
atmosphere. The product was purified by gradient column
chromatography on silica. Eluent: benzene to benzene/acetone 10:1.
0.90−0.96 (5.51H, m), 1.13 (2.47H, d, J = 6.8 Hz), 1.23 (3.00H, d, J
= 7.0 Hz), 1.30−1.40 (0.88H, m), 1.48−1.65 (1.96H, m), 1.69−1.80
(1.09H, m), 2.62 (0.78H, m), 3.37 (1.00H, m), 7.27−7.43 (8.18H, m,
The product was obtained as a yellow oil (1.84 g, 74%). [α] + 684°
Ph). Elemental composition calcd (%) for C11H15NO: C 74.54, H
D
45
1
(
c 1.3 in benzene) (lit. +640° (c 2.1 in benzene). H NMR (400
8.38, N 7.90. Found (%): C 74.32, H 8.38, N 7.89.
MHz, CDCl , Me Si) 0.90−0.95 (3H, m), 1.46−2.08 (6H, m), 2.42−
General Procedure of Cyclopalladation. First, 0.77 mmol of
palladium chloride was dissolved in a solution of 1.76 mmol of lithium
chloride in 36 mL of water with slight heating. A solution of 0.75
mmol of (E)-oxime in 130 mL of 1,4-dioxane was added followed by
addition of 0.77 mmol of sodium acetate trihydrate in 1 mL of water.
Reaction mixture was refluxed. Suspension was cooled to rt and
filtered. Solvent was removed, 10 mL of water was added and product
was extracted with 3 × 10 mL of benzene. The organic phase was dried
over anhydrous sodium sulfate. The solvent was removed, and the
product was precipitated with hexane from benzene solution.
cis-Di-μ-chlorobis[hydroxyimino-2-methyl-1-phenylbutanone-
3
4
2
.89 (3H, m), 3.27−3.63 (7H, m), 7.32−7.38 (3H, m), 7.65−7.68
2H, m).
2′S)-2-Methoxymethyl-1-((2R)-2-methyl-1-phenylbutyliden-
(
(
45
amino)pyrrolidine. A round-bottomed flask with an addition funnel
was filled with solution of 1 mL (7.1 mmol) of diisopropylamine in 14
mL of dry diethyl ether. The solution was cooled in an ice−salt bath,
and 3.6 mL of 2 M BuLi solution in cyclohexane was added dropwise.
The solution was stirred for 15 min on cooling bath. A solution of 1.59
g (6.1 mmol) of (2S)-2-methoxymethyl-1-(1-phenylbutylidenamino)-
pyrrolidine in 1.5 mL of dry diethyl ether was added dropwise. The
suspension was stirred for 4 h on cooling bath, and the reaction
mixture was cooled to −110 °C. A solution of 0.417 mL (6.7 mmol) of
iodomethane in 1.5 mL of dry diethyl ether was added and stirred for 2
h. The solution was stirred at rt overnight and further poured in
2
2
κ C ′,N]dipalladium(II) (2rac). Reflux time 15 min. Yield 91%. Yellow
1
3
powder. H NMR (400 MHz, CDCl , Me Si) 0.93 (3H, t, J = 7.5 Hz,
3
4
3
CH CH ), 1.38 (3H, d, J = 7 Hz, CHCH ), 1.75 (1H, m, CH ),
2
3
3
2
1.94−2.05 (1H, m, CH ), 3.17 (1H, br s, CH), 6.95−6.99 (1H, m,
2
mixture of 30 mL of diethyl ether and 15 mL of water. Product was
C(5)H−Ph), 7.04−7.08 (1H, m, C(4)H−Ph), 7.12−7.14 (1H, m,
1
3
obtained as yellow oil (1.51 g, 91%). H NMR (400 MHz, CDCl ,
C(3)H−Ph), 7.35 (1H, d, J = 7.7 Hz, C(6)H−Ph), 8.14 (1H, br s,
3
3
3
Me Si) 0.94 (3H, t, J = 7.4 Hz, CH CH ), 1.08 (2H, d, J = 7 Hz,
OH). Mp 132−135 °C. Elemental composition calcd (%) for
4
2
3
F
DOI: 10.1021/acs.organomet.7b00410
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
C H Cl N O Pd : C 41.54, H 4.44, N 4.40. Found (%): C 41.83, H
consisting of CO and cosolvent pumps, Acquity UPLC autosampler
with partial loop injection, Acquity column manager for two columns
2
2
28
2
2
2
2
2
4
.63, N 4.40. X-ray quality crystals were obtained by slow evaporation
of chloroform solution.
of up to 15 cm length, Acquity convergence manager responsible for
2
General Procedure of Sequential Cyclopalladation−Monomer-
ization. First, 0.6 mmol of palladium chloride was dissolved in a
solution of 1.2 mmol of lithium chloride in 12 mL of water with slight
heating. A solution of 1.1 mmol of mixture of E/Z-oximes in 23 mL of
the conditioning of inlet and outlet CO , and Acquity UPC PDA
2
detector equipped with high-pressure flow cell. Chromatographic
separations on this system were conducted under the following
conditions: back pressure 105 bar, temperature 10 °C, flow rate 1.5
mL/min, injection volume 2 μL, and detection wavelength 210 nm.
Separation was performed on Kromasil 3-CelluCoat 4.6 × 150 mm
1
,4-dioxane was added, followed by addition of 0.6 mmol of sodium
acetate trihydrate in 6 mL of water. The reaction mixture was refluxed
for 15 min, and the suspension was cooled to rt and filtered. The
solvent was removed; 10 mL of water was added and the product
extracted with 15 mL of dichloromethane. The organic phase was
dried over anhydrous sodium sulfate. Next, 0.6 mmol of pyridine was
added, and the reaction mixture was stirred for 3 min. The solution
was evaporated to dryness. The residue was dissolved in 2 mL of
dichloromethane, and the palladacycle was precipitated by adding this
solution to 50 mL of n-hexane under vigorous stirring. Obtained
precipitate was filtered, washed with 10 mL of n-hexane, and dried.
column with CO /methanol/isopropylamine 70/30/1 mobile phase.
2
Samples were made in methanol at 1 g/L concentration.
X-ray Diffraction Experiments. Data were collected with a Bruker
Apex2 CCD diffractometer using graphite monochromated Mo Kα
radiation (λ = 0.71073 Å, ω-scans). The structures were solved by
direct method and refined by the full-matrix least-squares against F2 in
isotropic−anisotropic approximation. Hydrogen atoms positions with
the exception of OH ones were calculated using geometric criteria. All
hydrogen atoms were refined in isotropic approximation in riding
model. Crystal data and structure refinement parameters for (E)-1rac,
2rac, and 3S are given in Table S1. All calculations were performed
2
2
Chloro[hydroxyimino-2-methyl-1-phenylbutanone-κ C ′,N]-
(
pyridine)palladium(II) (3rac). Yield 85%. White powder. Mp 132−
4
6
1
4
7
35 °C. Calcd: C 48.38%, H 4.82%, N 7.05%. Found: C 48.40%, H
using the SHELXTL 2014 software. CCDC 1430829 (2rac),
1430830 (3S), and 1431462 ((E)-1rac) contain the supplementary
crystallographic data. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
CCDC, 12 Union Road, Cambridge, CB21EZ, UK, or deposit@
ccdc.cam.ac.uk).
1
3
.79%, N 6.93%. H NMR (400 MHz, CDCl , Me Si) 0.96 (3H, t, J =
3
4
3
.4 Hz, CHCH ), 1.40 (3H, d, J = 7.1 Hz, CHCH ), 1.69−1.79 (1H,
3
3
m, CH ), 1.99−2.07 (1H, m, CH ), 3.19 (1H, br s, CH), 6.23 (1H, d,
2
2
3
J = 7.5 Hz, C(6)H−Ph), 6.90 (1H, m, C(5)H−Ph), 7.06 (1H, m,
3
C(4)H−Ph), 7.21 (1H, d, J = 7.2 Hz, C(3)H−Ph), 7.47−7.50 (2H,
m, C(3,5)H−Py), 7.89−7.92 (1H, m, C(4)H−Py), 8.86−8.88 (2H, m,
Kinetic Experiments. Experiments were carried out in 0.01 M
phosphate-buffered saline at pH 8.0. Optical density was detected at 4-
nitrophenolate adsorption wavelength of 405 nm and at 2,4-
dinitrophenolate adsorption wavelength of 360 nm. Catalyst was
added as solution in acetonitrile. Final concentrations of catalyst in
1
3
C(2,6)H−Py), 10.16 (1H, br s, OH). C NMR (100 MHz, CDCl ,
3
Me Si) 12.63, 16.21, 26.03, 34.74, 124.69, 125.60, 126.02, 128.86,
4
1
31.26, 138.41, 143.29, 152.98, 153.95, 172.02.
Chloro[hydroxyimino-(S)-2-methyl-1-phenylbutanone-κ C ′,N]-
pyridine)palladium(II) (3S). Yield 76%. White powder. Mp. 129−131
C. ee 86%. [α] + 10° (c 0.2 in CH Cl ). Calcd: C 48.38%, H 4.82%,
2
2
−5
−4
(
reaction mixture were in the range of 10 −10 M. The final
concentration of acetonitrile in reaction mixture was equal to 10 vol %.
Pseudo-first-order rate constants kobs were approximated by nonlinear
regression equation using SigmaPlot 11 software.
°
D
2
2
1
N 7.05%. Found: C 48.44%, H 4.54%, N 6.99%. H NMR (400 MHz,
3
3
CDCl , Me Si) 0.95 (3H, t, J = 7.4 Hz, CH CH ), 1.40 (3H, d, J =
3
4
2
3
7
3
.1 Hz, CHCH ), 1.70−1.80 (1H, m, CH ), 1.99−2.07 (1H, m, CH ),
All kinetics curves followed this equation for more than 5 half times
3
2
2
3
.18 (1H, br s, CH), 6.23 (1H, d, J = 7.5 Hz, C(6)H−Ph), 6.90 (1H,
of reaction. Second-order rate constants k
2
were calculated from eqs 3
m, C(5)H−Ph), 7.06 (1H, m, C(4)H−Ph), 7.21 (1H, d, 3J = 7.2 Hz,
C(3)H−Ph), 7.47−7.50 (2H, m, C(3,5)H−Py), 7.89−7.92 (1H, m,
C(4)H−Py), 8.86−8.88 (2H, m, C(2,6)H−Py), 10.19 (1H, s, OH).
and 4.
kobst
D(t) = D − (D − D ) e
(3)
(4)
∞
∞
0
1
3
C NMR (100 MHz, CDCl , Me Si) 12.63, 16.21, 26.00, 34.70,
3
4
kobs = k − k [Pd]
0
2
1
1
24.69, 125.61, 126.02, 128.85, 131.24, 138.41, 143.26, 152.95, 153.93,
71.99. X-ray quality crystals were obtained by slow evaporation of
where k is the rate constant of hydrolysis of ester without catalyst and
0
chloroform solution.
[
Pd ] is the initial concentration of palladacycle.
0
2
2
Chloro[hydroxyimino-(R)-2-methyl-1-phenylbutanone-κ C ′,N]-
(pyridine)palladium(II) (3R). Yield 86%. Pale yellow powder. Mp
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.7b00410.
■
1
32−135 °C. ee 79%. [α] − 9° (c 0.2 in CH Cl ). Calcd: C 48.38%,
1
D
2
2
S
H 4.82%, N 7.05%. Found: C 48.26%, H 4.63%, N 7.03%. H NMR
3
(
(
(
400 MHz, CDCl , Me Si) 0.95 (3H, t, J = 7.4 Hz, CH CH ), 1.40
3H, d, J = 7.1 Hz, CHCH ), 1.70−1.80 (1H, m, CH ), 1.99−2.07
1H, m, CH ), 3.18 (1H, br s, CH), 6.23 (1H, d, J = 7.5 Hz, C(6)H−
3
4
2
3
3
3
2
3
2
Ph), 6.90 (1H, m, C(5)H−Ph), 7.06 (1H, m, C(4)H−Ph), 7.21 (1H,
SFC chromatograms, X-ray details, and NMR spectra
3
d, J = 7.2 Hz, C(6)H−Ph), 7.47−7.50 (2H, m, C(3,5)H−Py), 7.89−
(PDF)
7
(
.92 (1H, m, C(4)H−Py), 8.86−8.88 (2H, m, C(2,6)H−Py), 10.20
1H, s, OH). 13C NMR (100 MHz, CDCl , Me Si) 12.64, 16.22,
3
4
Accession Codes
2
1
6.03, 34.77, 124.70, 125.61, 126.02, 128.86, 131.26, 138.41, 143.29,
52.98, 153.95, 172.02.
CCDC 1430829−1430832 and 1431462 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Chiral Supercritical Fluid Chromatography. Enantiomeric compo-
sitions of oximes 1rac, 1S, and 1R were established by supercritical
fluid chromatography (SFC) using the Investigator system (Waters
Corp, Milford, MA, USA). Simultaneous separation of all four oxime
stereoisomers was performed on Kromasil 3-AmyCoat 4.6 × 150 mm
column with CO /isopropanol 93/7 mobile phase. Conditions: back
2
AUTHOR INFORMATION
Corresponding Author
E-mail: szv@org.chem.msu.ru.
pressure 100 bar, temperature 40 °C, flow rate 4 mL/min, injection
volume 2 μL, and detection wavelength 220 nm. Samples were made
in hexane at 1 g/L concentration.
Enantiomeric composition of oxime palladium complexes 3rac, 3S,
and 3R were established by supercritical fluid chromatography (SFC)
■
*
ORCID
2
Sergey Z. Vatsadze: 0000-0001-7884-8579
Ivan V. Ananyev: 0000-0001-6867-7534
using Acquity UPC system (Waters Corp, Milford, MA, USA). The
system is equipped with the following: Acquity ccBSM pump module
G
DOI: 10.1021/acs.organomet.7b00410
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Notes
(24) Enders, D.; Hundertmark, T.; Lazny, R. Synlett 1998, 1998,
21−722.
7
(
The authors declare no competing financial interest.
25) Porcheddu, A.; Giacomelli, G. In The Chemistry of Hydroxyl-
amines, Oximes and Hydroxamic Acids; Rappoport, Z., Liebman, J. F.,
Eds.; John Wiley & Sons, Ltd.: Chichester, U.K., 2009; p 164.
ACKNOWLEDGMENTS
■
(
(
26) Grob, C. A.; Ide, J. Helv. Chim. Acta 1974, 57, 2571−2583.
The synthetic, catalytic, and structural parts of this work were
supported by RFBR (grant no.# 13-03-12054-ofi-m). Parts of
the work concerning supercritical fluid chromatography and
stereochemistry assignments were supported by RSF (grant no.
27) Mizutani, Y.; Tanimoto, H.; Morimoto, T.; Nishiyama, Y.;
Kakiuchi, K. Tetrahedron Lett. 2012, 53, 5903−5906.
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John Wiley & Sons: Chichester, U.K., 2009; p 18.
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DOI: 10.1021/acs.organomet.7b00410
Organometallics XXXX, XXX, XXX−XXX