E - Z isomerization in Suzuki cross-couplings of haloenones: Ligand effects and evidence for a separate catalytic cycle

Article abstract of DOI:10.1039/c7ob02925j

Suzuki cross-coupling of haloalkenes is generally assumed to occur with retention of the alkene stereochemistry. While studying Suzuki cross-couplings on E-1,2-dichlorovinyl phenyl ketone, we were surprised to observe extensive isomerization. More surprisingly, the ligand employed strongly influenced the degree of isomerization: DPEphos and Xantphos led to 96% isomerized cross-coupled product whereas reactions in the absence of a phosphine ligand, or reactions employing t-BuXantphos, gave 94% retention of stereochemistry. While E-Z isomerization in Pd-catalyzed vinylic couplings has previously been attributed to events within the cross-coupling catalytic cycle, we present experimental and computational evidence for a separate Pd-catalyzed isomerization process in these reactions.

Full text of DOI:10.1039/c7ob02925j

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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E-Z isomerization in Suzuki cross-couplings of haloenones: Ligand
effects and evidence for a separate catalytic cycle.
Navneet K. Chehal,a Peter H.M. Budzelaara,b and Philip G. Hultin*a
Received 00th January 20xx,
Accepted 00th January 20xx
Suzuki cross-coupling of haloalkenes is generally assumed to occur with retention of the alkene stereochemistry. While
studying Suzuki cross-couplings on E-1,2-dichlorovinyl phenyl ketone, we were surprised to observe extensive
isomerization. More surprisingly, the ligand employed strongly influenced the degree of isomerization: DPEphos and
Xantphos led to 96% isomerized cross-coupled product whereas reactions in the absence of a phosphine ligand, or
reactions employing t-BuXantphos, gave 94% retention of stereochemistry. While E-Z isomerization in Pd-catalyzed vinylic
couplings has previously been attributed to events within the cross-coupling catalytic cycle, we present experimental and
DOI: 10.1039/x0xx00000x
www.rsc.org/
computational evidence for
a
separate Pd-catalyzed isomerization process in these reactions.
cyclization (Scheme 1).23-29
O
O
O
Introduction
R2
PdLn
R1
PdLn
R2
Cl
H
Cl
H
The efficient assembly of specific geometric isomers of highly
substituted alkenes remains a challenge for synthetic chemists.
1,2-Disubstituted alkenes can generally be obtained as the
thermodynamically-favoured E isomers, while Wittig reactions
and Lindlar-catalyzed hydrogenation of alkynes provide Z
isomers. However, general approaches to stereochemically
defined tri- and tetra-substituted alkenes are less well-
developed. Pd-catalyzed cross-couplings generally retain the
configuration of the vinylic C-X bond.1-6 Thus, if specific
geometric isomers of vinylic halides can be obtained, metal-
catalyzed cross-couplings offer versatile access to alkyl- or aryl-
substituted vinyl groups, as well as dienes, trienes and similar
structures. The Suzuki reaction is a particularly convenient and
reliable cross-coupling widely used in the total syntheses of
complex natural products,7-10 anticancer agents,11, 12 inhibitors
of tubulin polymerization,13-15 anti-apoptotic agents,16 insect
pheromones17 and vitamins.18
B(OH)2
B(OH)2
Cl
1
R1
R1
H
Nazarov
O
R2
R1
= aryl, vinyl, alkynyl, alkyl
Scheme 1. Planned regio- and stereo-controlled modular assembly of indanones.
R1 R2
,
Suzuki couplings of
the alkene configuration.5-19, 30-35 Further, the reactions should
favour the β- over the α-position in 1 36-42
We indeed observed
1 were expected to occur with retention of
.
the predicted regioselectivity. However, depending on the
ligand employed we obtained either nearly complete double
bond isomerization, or retention of configuration.43-47
Subsequent
investigation
revealed
some
intriguing
observations regarding the mechanism of the E-Z
Our interest in modular elaboration of alkenes starting from
trichloroethylene19-21 led us to examine Suzuki reactions of E-
1,2-dichlorovinyl phenyl ketone 122. We anticipated that the
elaborated aryl vinyl ketone products might be further
transformed, for example into indanones by Nazarov
isomerization process for our compounds, which were not
consistent with intrinsic E/Z stereochemical instability of
48, 49
vinylpalladium intermediates,43,
or paths such as Pd-H
catalysis50 or reversible addition-elimination51 that have been
proposed for related cases. Our DFT model calculations
support an alternative explanation for the rapid isomerization
observed in Suzuki reactions of these enones.
Results and discussion
E-Dichlorovinyl ketone
method of Jonczyk and Gierczak (Scheme 2).22 Our NMR
spectra of differed from their data, although our results were
internally consistent. An X-ray crystal structure verified the
structure of its precursor . Later the Z-isomer ( ) of became
1 was prepared by a modification of the
1
2
6
1
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added.
available (vide infra) and spectroscopic comparison made the E
stereochemistry of clear.
1
The reaction performed without any phosphine ligand (Entry
5) formed the expected “retention” product
3, which
subsequently partly isomerized under the reaction conditions
over 24 hours. In contrast, arylphosphine ligands (Entries 1 and
2) led to the rapid production of a ~4:96 ratio of 3:4, which
remained unchanged over time and presumably represents
the equilibrium situation. The sterically bulky and electron-rich
Scheme 2 Preparation of enone 1.
arylphosphine t-BuXantphos (Entry 4) gave predominantly
just as the “no phosphine” reaction did. This strongly suggests
that the “retention product” is formed first, and the nature
of the phosphine ligand (if present) influences the rate at
which isomerization to occurs.
Based on these observations, we were able to carry out Suzuki
couplings of with a range of arylboronic acids, using
appropriate conditions to produce predominantly the
“retention products” 3a-h (conditions or B) or the
3,
Initially we treated
1 with p-methoxyphenylboronic acid
(PMPB(OH)2) in the presence of Pd(PPh3)4 and 2M aqueous
K2CO3 in dioxane at 65 °C,52 monitoring by GC/MS (Scheme 3).
3
Consumption of
1 was complete in 25 minutes. Two products
4
of m/z 272 were obtained in a 26:74 ratio, which were
separated by flash chromatography.
chemical degradation and 1H and 13C NMR techniques assigned
A combination of
1
the minor product as 3a (E) and the major product as 4a (Z).†
3
In particular, the JC-H between the vinylic proton and the
A
“isomerized products” 4a-h (conditions C) as shown in Table
2.‡ Reactions under conditions A or B were monitored closely
and stopped as soon as tlc indicated complete consumption of
carbonyl carbon (readily observed in an HMBC experiment)
was highly diagnostic of the alkene configurations of
3 and 4. Z
3
3
isomers typically show JC-H around 5 Hz, whereas JC-H in E
isomers is 8-9 Hz.53 Eventually we were able to confirm the
structures of 3a and 4a through X-ray crystallography.
1. While timing was less critical under conditions C, we also
stopped these reactions when starting material was
consumed.
The reactions with relatively electron rich boronic acids (Table
2, entries 1-3) proceeded quickly in all cases. Electron deficient
boronic acids reacted slowly with
1;
while p-
fluorophenylboronic acid led to products 3d or 4d in 5 hours,
treatment with p-nitrophenylboronic acid failed to produce 3e
under any conditions tested (entry 5). Benzofuran-2-yl- and
thien-2-ylboronic acids reacted slowly but cleanly (entries 6
Scheme 3. Stereoisomeric products of Suzuki coupling. PMP
= 4-
methoxyphenyl.
and 7). Attempted reaction of
1
with 4-(2-
fluoropyridyl)boronic acid did not form any detectable
products under phosphine-free conditions, while only 13%
conversion leading to an 83:17 mixture favouring what we
tentatively identified as 3h was observed using t-BuXantphos
as ligand. In contrast, in the presence of DPEphos (Conditions
From a survey of conditions for the transformation shown in
Scheme 3,† we determined that using Pd2(dba)3 in the
presence of 3 equiv. of Cs2CO3 in dioxane at 85 °C gave full
conversion to products in one hour. The effect of different
phosphine ligands was the most striking feature of the
reaction, however. Selected results are presented in Table 1.
C) this boronic acid reacted slowly with
1 to form isomerized
product 4h in fair yield (entry 8). The results in Table 2
indicate that it is possible to obtain excellent results with
either retention of the initial vinyl halide configuration, or
isomerization to the thermodynamically favoured alkene
isomer.
Table 1. Effect of different phosphine ligands on product ratios
Because Pd-catalyzed cross couplings of vinylic halides are
expected to be stereospecific, we next sought to understand
how the Z arylated products were formed from the E halide,
and if possible why the stereochemistry depended on whether
a phosphine ligand was present or not.
Product ratio 3 : 4 : 5b
Liganda
After 1 hour
After 24 hours
1
2
DPEphos
Xantphos
4 : 96 : 0
4 : 96 : 0
4 : 96 : 0
6.5 : 93.0 : 0.5
3
(Cy)3P
50 : 50 : 0
7 : 93 : 0
4
5
t-BuXantphos
No phosphinec
93 : 5 : 2
94:5:1
5 : 89 : 4
55 : 43 : 2
a. Conditions: 1 (0.25 mmol), p-MeOPhB(OH)2 (0.25 mmol), Pd2(dba)3 (2.5 mol %);
Cs2CO3 (3 equiv.); Dioxane (1.5 mL), 85 °C. Ligands: DPEphos (5.0 mol %);
Xantphos (5.0 mol %); (Cy)3P (7.5 mol %); t-BuXantphos (5.0 mol %); b. Ratios
determined by GC/MS analysis; c. Pd2(dba)3 (5.0 mol %), no phosphine ligand
2 | J. Name., 2012, 00, 1-3
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thermal stereochemical stabilities of
1
and 3a were confirmed
Table 2. Stereoselective Suzuki couplings with arylboronic acids.
by extended heating in dioxane at 85 °C. No isomerization of
1
could be detected, while 3a formed only 6% of 4a after 24
hours. Chalcones may undergo photochemical isomerization,
but we verified that reactions conducted in the dark gave the
same outcomes. Phosphine ligands might promote formation
of
elimination of phosphine.51 Heating
led to 8% isomerization in 1 hour, while similar treatment of 3a
gave 3% of 4a. The slow isomerization of in the presence of
phosphines did allow us to obtain its Z isomer after either
very long reaction times (Scheme 4), or in the presence of
large excesses (ca. 500 mol%) of phosphine. Comparison of
and by NMR confirmed the E stereochemistry of
4
via Michael addition to
1
or
3
, bond rotation, and then
Aryl
Conditionsa
(hours)
3 : 4 : 5b
3JC-H
1
with 5 mol% DPEphos
(yield %)c
(Hz)d
1
A (1.0)
B (1.0)
(3a: 78)
(3a: 73)
4:96:0
8.6
6
1
2
3
p-methoxyphenyl
C (0.5)
A (2.0)
C (0.5)
A (3.5)
C (2.0)
A (7.0)
4.9
8.8
4.7
8.6
4.7
8.3
1
(4a: 80)
90:6:4
6
1.
However, these processes were too slow to account for the
observed level of isomerization under the conditions of our
Suzuki couplings.
(3b: 75)
5:92:3
p-tolyl
(4b: 76)
94:4:2
(3c: 69)
8:90:2
phenyl
(4c: 70)
91:9:0
(3d: 72)
6:94:0
4
5
6
p-fluorophenyl
p-nitrophenyl
benzofuran-2-yl
Scheme 4 Slow isomerization of 1 occurs on heating with DPEphos or other phosphines.
C (5.0)
A, B, C (24.0)
A (8.0)
4.6
-
(4d: 78)
No product
90:10:0
(3f: 76)
8:92:0
Compounds
component of the cross-coupling reaction, individually and in
combination. No detectable isomerization of occurred within
1 and 3a were each heated separately with each
8.1
1
a time window comparable to the cross-coupling reaction
time, but these studies revealed that 3a easily isomerized to
4a in the presence of both Pd2(dba)3 and DPEphos Neither the
Pd source nor the phosphine alone promoted significant
C (2.0)
4.5
8.1
5.0
(4f: 74)
95:5:0
A (24.0)
(3g: 77)
16:80:4
(4g: 62)
No product
13% conv,
83:17:0e
4:95:1
7
8
thien-2-yl
isomerization of 3a, but NMR monitoring showed that
C (24)
A (24.0)
B (24.0)
substantial isomerization took place within minutes of
exposing 3a to the ligand/catalyst mixture (Figure 1).†
-
The predominant formation of 3a in reactions employing t-
BuXantphos as ligand (see Table 1 and conditions B in Table 2)
was noteworthy. The Suzuki couplings in the presence of
DPEphos and t-BuXantphos proceeded at comparable rates,
but the rate of isomerization of 3a in the presence of t-
BuXantphos was much slower than that observed when
DPEphos was used. These experiments confirmed that loss of
stereochemical integrity was independent of the actual Suzuki
coupling process, and reflected isomerization of the initially-
2-fluoropyridin-4-yl
C (24)
4.4
(4h: 69)
a. 1 (0.5 mmol), ArylB(OH)2 (1 equiv), Dioxane (3.0 mL), 85 °C, Cs2CO3 (3
equiv.). Conditions A: Pd2(dba)3 (5.0 mol %). Conditions B: Pd2(dba)3 (2.5 mol
%), tBuXantphos (5.0 mol %). Conditions C: Pd2(dba)3 (2.5 mol %), DPEphos
(5.0 mol %). b. Ratios determined by GC/MS and/or 1H NMR of crude reaction
mixtures. c. Isolated yields of chromatographically purified major products. d.
Coupling observed by HMBC between vinylic 1H and carbonyl 13C of the major
product. e. GC/MS analysis of the crude product obtained using method B
revealed two new compounds of m/z 260 in a ratio of 83:17. Presumably the
major product was the E-isomer 3h but this was not purified and
characterized. The minor product of this reaction was identified as 4h, by
formed product 3a
.
GC/MS comparison with
characterized.
a sample prepared by method C and fully
Experimental mechanistic studies
The rapid isomerization observed in the presence of DPEphos
or Xantphos is striking when compared to the outcomes when
no phosphine was present. A few reports of similar E/Z
isomerization during Pd-catalyzed reactions of vinylic halides
have appeared.43, 48, 49, 54, 55 We investigated the isomerization
of reactant
1 and coupling product 3a in some detail. The
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100
80
60
40
20
0
3a
4a
3a
4a
150 min
0
0.1
1
5
10
60 min
30 min
15 min
3 min
Dimethyl maleate (mol %)
Figure 2 The product ratio 3a:4a from the Suzuki couplings of 1 under conditions C
t = 0
(after 1 hour) is influenced by the presence of dimethyl maleate.
NMR monitoring of the isomerization of 3a to 4a in toluene-d8
with 5 mol% of Pd/DPEphos in the presence of 2 mol% of
dimethyl maleate showed that the process was greatly
slowed.† Furthermore, when 3a was heated in toluene with 5
mol% Pd/DPEphos and 1 equivalent of dimethyl maleate,
neither 3a nor maleate isomerized at all.
Figure 1 Isomerization of 3a to 4a in the presence of Pd2(dba)3/DPEphos monitored
by1H NMR in toluene-d8 at 350 K (OCH3 region shown). More than 50% isomerization
has occurred during the addition and mixing of the catalyst.
Further evidence supporting this interpretation came from
reducing the catalyst concentrations in the Suzuki coupling
reactions. If loss of stereochemistry took place within the
cross-coupling catalytic cycle, then changing catalyst loadings
would cause parallel changes in the rates of cross-coupling and
isomerization. Instead, isomerization rates (judged by extent
of conversion at specific time points) declined much faster
than did cross-coupling rates as the catalyst concentration was
lowered.
On the other hand, Z-stilbene was not isomerized under our
cross-coupling conditions, nor did it have any effect on the
isomerization of 3a to 4a in the presence of 5 mol%
Pd/DPEphos.
Hills and Fu showed that L2PdHX species undergo reductive
elimination when exposed to tertiary amines and other
relatively strong bases.56 We observed that replacing Cs2CO3
by Et3N had no effect on the isomerization of 3a
. We also
found no effect when benzoquinone or TEMPO were added,
both of which are known to destroy Pd-H species.57, 58
A role for palladium hydride species? It seemed possible that
traces of Pd-H species might be present in our reactions and
might promote isomerization (Scheme 5). For instance,
Skrydstrup et al. reported50 that many types of alkenes
undergo positional and/or geometric isomerization in the
presence of PdL2HX compounds.
The results of our experiments with dimethyl maleate and Z-
stilbene, as well as those using triethylamine, benzoquinone or
TEMPO are inconsistent with a role for a palladium hydride
species in the isomerization process. Instead, our experiments
suggested that dimethyl maleate and product 3a might be
competing for a Pd species that promoted their isomerization,
but that Z-stilbene cannot compete in this way.
O
O
O
O
Pd
Pd
Cl
Ar
Cl
H
Cl
H
Cl
Ar
+/- PdH
+/- PdH
H
H
Ar
Ar
H
H
Is the carbonyl necessary for isomerization? The failure of Z-
stilbene to participate in the isomerization raised the question
of whether the conjugated carbonyl was essential for the
isomerization we were observing. We therefore carried out a
Scheme 5 Possible palladium hydride-mediated isomerization pathway.
In particular, they found that PdL2HX mediated the equilibria
of dimethyl maleate/fumarate and Z/E-stilbene.50 When we
exposed dimethyl maleate by itself to cross-coupling
conditions C, 80% isomerization to dimethyl fumarate was
observed in 1 hour. We then added varying amounts of
Luche reduction59 of 3a to form the allylic alcohol
7. When 7
was treated with 5 mol% Pd/DPEphos, it did not undergo any
detectable isomerization (Scheme 6). This indicates that the
conjugated carbonyl is necessary for the isomerization to occur
under these conditions.
dimethyl maleate to Suzuki cross couplings of
methoxyphenylboronic acid under conditions C, again for 1
hour. The product ratio 3a 4a formed in these reactions
1 with 4-
O
OH
:
NaBH4
CeCl3
MeOH
Pd/DPEphos
5 mol%
Cl
H
Cl
H
Ph
Ph
depended on the concentration of dimethyl maleate (Figure
2). However, in the reactions shown in Figure 2 it did not
appear that maleate was undergoing significant isomerization
to fumarate, nor did maleate undergo any isomerization when
treated with Pd2dba3 and DPEphos in toluene-d8 at 350 K (77
°C).
No change
dioxane
85 oC
PMP
3a
PMP
7
82%
Scheme 6 Allylic alcohol 7 does not isomerize under conditions that would isomerize
the enone 3a.
Computational model studies.
E/Z isomerization during Pd-catalyzed cross coupling reactions
of isolated haloalkenes has been attributed to intrinsic
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zwitterionic metal carbene character in
a
vinylpalladium syntheses of diarylallylidene oxindoles,67 and in direct C-H
48
intermediate within the catalytic cycle (Figure 3).43,
This functionalization of simple acrylamides.68 Thus, it seemed
argument was originally developed to rationalize the results of plausible that a version of this mechanism could describe our
Rh- and Pd-catalyzed carbometallation reactions of alkynes.60- situation as well but we sought some computational support
63
It suggests that the C-C π-bond is weakened sufficiently in for this hypothesis.
these structures to permit thermal E/Z isomerization,64
assuming that isomerization happens within the cross-coupling
catalytic cycle. This assumption is inconsistent with the
isomerization of 3a, which cannot undergo oxidative insertion
to form a vinylpalladium intermediate of this type.
H
O
O
O
H
CO
3
OCH
H CO
3
3
OCH
3
P
P
O
H
H
Pd(0)
H
OCH
3
OCH
R1 R2
R1 R2
R1 R2
R1 R2
3
H
H
P
L
L
L
L
L
L
L
P
O
O
Pd
Pd
Pd
H
Pd
H
H
H
Pd
Pd
P
H
E
P
E
9
H
L
X
X
X
X
11
48
Figure 3. Proposed43,
zwitterionic metal carbene character of the vinylpalladium
O
OCH
H
3
P
intermediate leading to a weakened π bond and thermal isomerization during the
Suzuki catalytic cycle.
via
TS
via
TS
Pd
1
2
P
H
E
10
A DFT computational model for the equilibrium in Figure 3
revealed that the lengths and angles of the C=C and C-Pd
bonds were not perturbed as the zwitterion model suggests.
The calculations also indicate that forced rotation of the
vinylpalladium moiety around the C=C bond has a barrier
similar to the case of a hydrogen atom at the same position,
and Pd=C double-bond character does not develop during
forced rotation.
E = CO CH
2
3
Scheme
7 The Canovese/Visentin mechanism for Pd-catalyzed fumarate/maleate
isomerization via a metallacycle intermediate.
DFT methods (TPSSh/def-TZVPP//B-LYP/def-SV(P)) were used
to compare the energetics of Scheme 7 for enone and
maleate/fumarate substrates. As a simple, generic model for a
diphosphine ligand we used DMPE. The three minima and two
transition states corresponding to Scheme 7 were located for
Metallacycle pathway. Canovese and Visentin studied the
geometric isomerization of electron-poor alkenes (including
dimethyl maleate/fumarate) in the presence of Pd(0)/ligand
complexes both experimentally and computationally.65, 66 Their
proposed mechanism involves reversible isomerization of a
Pd(0) η2-enone fragment to a cyclic Pd(II) enolate (Scheme 7).
Isomerization was found to be particularly easy with a
"hard/soft" P/N ligand at Pd, where the Pd-C bond of the
enolate intermediate develops trans to the N donor group.
While these authors only report results for symmetrically
substituted alkenes, the mechanism requires no more than a
single carbonyl or similar group conjugated to the C=C bond.
The Canovese/Visentin mechanism was recently invoked to
explain the stereochemical outcomes in tandem Pd-catalyzed
3a/4a as well as for the maleate/fumarate system studied by
Visentin. The results are summarized in Figure 4. They confirm
that enones are capable of following the same isomerization
path as maleate/fumarate. In fact, the calculated barrier for
isomerization is somewhat lower, and the enolate
intermediate for the enone substrate is more stable, in
agreement with our observations. Furthermore the
calculations suggested that the π-complexes from dimethyl
maleate or fumarate would be much more tightly bound than
those from either 3a or 4a, which is consistent with our
experimental observation that added maleate had an
inhibitory effect on the 3a
/4a isomerization (Figure 2).
Computations were also performed to seek
a
pathway
25.06
22.70
19.22
18.63
17.59
TS1
TS2
3.99
0.00
-3.94
-7.60
Maleate/Fumarate
9
TS1
10
TS2
11
9
10
11
Figure 4 DFT calculations support the Canovese/Visentin isomerization pathway depicted in Scheme 7. Energies (kcal mol-1) relative to the initial π-complexes are indicated for
each calculated stationary state. The calculated structures for the stationary states in the 3a/4a interconversion are depicted at right.
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analogous to that in Scheme 7 for isomerization of the dichloro CDCl3) δ 40.92, 74.42, 113.23, 117.45, 126.74, 128.85, 129.58,
compound . Such a pathway was in fact identified (Scheme 132.75, 135.96 ppm; HRMS: Calculated for C12H12N2Cl2:
8), and for the simplified catalyst model it appeared to be 254.0378, Found: 254.0366.
energetically reasonable. However, our calculations produced Crystal data. C12H12Cl2N2, M =
1
255.14,
monoclinic, a =
a clearly elongated Cβ-Cl bond for enolate intermediate 10' 13.368(5), b= 7.287(2), c = 14.142(5) Å, α= 90.0, β= 113.436(8),
(1.98 - 3.80 Å) indicating a tendency to directly eliminate Cl- γ= 90.0, U = 1264.0(7) Å3, T = 293 K, space group P21/c, Z = 4,
and so form 12', the equivalent of a Cβ-Cl oxidative addition 9000 reflections measured, 2353 unique (Rint = 0.0128). The
product. A proper analysis of the reaction path in Scheme 8 final wR(F2) was 0.1369 (all reflections).
would require inclusion of solvation in the geometry (2
E)-2,3-Dichloro-1-phenylprop-2-en-1-one (1).
optimizations, which goes beyond the scope of this work.
Compound was made using a modification of a procedure
1
reported by Jonczyk and Gierczak.22 The 1H NMR data
obtained for our product did not match the reported data but
was consistent with the results of COSY, HSQC and HMBC
experiments. Yield: 85%; Yellow oil; 1H NMR (500 MHz, CDCl3)
δ 6.69 (s, 1H), 7.51-7.54 (AA′BB′, 2H), 7.64-7.67 (AA′BB′C, 1H),
7.96-7.97 (AA′BB′, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ
118.89, 127.73, 129.03, 129.83, 133.50, 134.66, 188.25 ppm;
HRMS: Calculated for C9H6OCl2: 199.9796, Found: 199.9798
General procedures for Suzuki couplings with retention of
configuration (Table 2, conditions A or B, compounds 3a-g).
For reactions under conditions
A, 1 (1 eq.), the appropriate
Scheme 8 Calculated reaction path for Pd-catalyzed isomerization of 1/6 is potentially
interrupted by elimination of chloride from 10′, leading to the oxidative addition step in
the Suzuki catalytic cycle.
boronic acid (1 eq.), Pd2(dba)3 (5 mol%) and Cs2CO3 (3 eq.)
were placed in a glass tube with a screw cap.
For reactions under conditions B, 1 (1 eq.), the appropriate
boronic acid (1 eq.), Pd2(dba)3 (2.5 mol%), t-BuXantphos (5
mol%) and Cs2CO3 (3 eq.) were employed.
Conclusions
The stereochemical outcome of Suzuki cross couplings of vinyl
In either case, anhydrous dioxane (to make
concentration of of 0.166 M) was added to the glass tube.
The stirred solution was heated at 85 until consumption of
a final
chloride
ligand, to form either the kinetic “retention” product or the
thermodynamically-favoured “isomerization” product.
2 can be controlled by the appropriate choice of
1
℃
2
was complete. The reaction mixture was then cooled to room
temperature and ice-cold water was added. The reaction
mixture was extracted with ethyl acetate (ca. 5 mL × 3). The
combined organic extract was washed with brine (ca. 15 mL)
and dried over anhydrous sodium sulphate. After filtration, the
filtrate was concentrated and the product (3a-g) was isolated
from the residue by silica-gel chromatography, eluting with
97:3 hexanes:ethyl acetate.
Reactions in which no phosphine ligand is present strongly
favour retention of the vinyl halide configuration, as do
reactions using t-BuXantphos ligands. In contrast, DPEphos or
Xantphos ligands lead to rapid E/Z isomerization of the kinetic
product.
Our experimental and computational studies seem to be
inconsistent with several mechanistic rationales proposed in
the literature for related isomerizations. Instead, the results
are best explained by a mechanism first proposed by Canovese
(2
Conditions
93.1
); 1H NMR (500 MHz, CDCl3) δ 3.72 (s, 3H), 6.69-6.72
(AA′BB′, 2H), 7.09-7.12 (AA′BB′, 2H), 7.14 (s, 1H), 7.40-7.44
(AA′BB′, 2H), 7.53-7.57 (AA′BB′ , 1H), 7.96-7.98 (AA′BB′, 2H)
E)-2-Chloro-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (3a).
66
and Visentin65, for maleate and bis(sulfonyl)ethene. These
A
: 78%; Conditions : 73%; Yellow solid (mp 91.7-
B
authors noted that their calculations "emphasized the crucial
role exercised by the conjugate C=O group for the outcome of
the whole process. This evidence seems to reduce significantly
the spectrum of olefins fit for this mechanism of
rearrangement." Our observation that a single conjugated
carbonyl group is sufficient to induce easy isomerization is
significant because enones are by no means rare as reaction
partners in Pd/phosphine catalyzed chemistry.
℃
C
ppm; 13C NMR (125 MHz, CDCl3) δ 55.19, 114.03, 124.76,
125.95, 128.81, 129.90, 129.95, 132.52, 134.12, 134.15,
159.84, 191.79 ppm; HRMS: Calculated for C16H13O2Cl:
272.0604, Found: 272.0605.
Crystal data. C16H13ClO2, M = 272.71, monoclinic, a =
14.28(2), b= 9.823(14), c = 9.912(14) Å, α= 90.0, β= 98.27(2), γ=
90.0, U = 1376(3) Å3, T = 293 K, space group P21/c, Z = 4, 9855
reflections measured, 2549 unique (Rint = 0.0164). The
final wR(F2) was 0.1976 (all reflections).
Experimental
(3
This compound was prepared as described by Jonczyk and
Gierczak.22 Yield: 40%; White solid (mp 113.8-114.2 ); 1H
E)-3,4-Dichloro-2-(dimethylamino)-2-phenylbut-3-enenitrile (2).
(2
Conditions
(s, 3H), 6.97-7.07 (AA’BB’, 4H), 7.15 (s, 1H), 7.39-7.45 (AA’BB’,
2H), 7.52-7.58 (1H, AA’BB’
), 7.95-7.98 (AA’BB’, 2H) ppm; 13C
E)-2-Chloro-3-(4-methylphenyl)-1-phenylprop-2-en-1-one (3b).
A
: 75%; Yellow oil; 1H NMR (300 MHz, CDCl3) δ 2.24
℃
NMR (300 MHz, CDCl3) δ 2.32 (s, 6H), 6.35 (s, 1H), 7.39-7.43
(AA′BB′C, 3H), 7.76-7.79 (AA′BB′, 2H) ppm; 13C NMR (75 MHz,
C
6 | J. Name., 2012, 00, 1-3
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1
NMR (75 MHz, CDCl3) δ 21.23, 125.96, 128.33, 128.84, 129.35, Yield: 80%; White solid (mp 58.2-60.0 °C); H NMR (500 MHz,
129.99, 130.50, 132.73, 134.04, 134.19, 138.80, 191.66 ppm; CD3OD) δ 3.84 (s, 3H), 6.99-7.01 (AA′BB′, 2H), 7.49 (s, 1H),
HRMS: Calculated for C16H13OCl: 256.0655, Found: 256.0653.
(2 )-2-Chloro-1,3-diphenylprop-2-en-1-one (3c).
Conditions
: 69%; Yellow oil; 1H NMR (300 MHz, CDCl3) δ
7.50-7.54 (AA′BB′, 2H), 7.60-7.64 (AA′BB′C, 1H), 7.72-7.73
(AA′BB′, 2H), 7.87-7.89 (AA′BB′, 2H) ppm; 13C NMR (125 MHz,
CD3OD) δ 54.51, 113.79, 125.25, 127.55, 128.22, 128.94,
132.07, 132.71, 137.27, 140.59, 161.84, 191.75 ppm; HRMS:
Calculated for C16H13O2Cl: 272.0604, Found: 272.0604.
Crystal data. C16H13ClO2, M = 272.71, orthorhombic, a =
8.858(3), b= 11.306(5), c = 27.121(11) Å, α= 90.0, β= 90, γ=
90.0, U = 2716.0(19) Å3, T = 293 K, space group Pbca, Z = 8,
18717 reflections measured, 2525 unique (Rint = 0.0144). The
final wR(F2) was 0.1230 (all reflections).
E
A
7.17-7.20 (m, 6H), 7.39-7.45 (AA’BB’, 2H), 7.52-7.58 (AA’BB’C,
1H), 7.95-7.98 (AA’BB’, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ
127.06, 128.37, 128.63, 128.67, 128.85, 129.98, 132.77,
133.33, 133.98, 134.25, 191.43 ppm; HRMS: Calculated for
C15H11OCl: 242.0498, Found: 242.0492.
(2
Conditions
6.84-6.91 (AA’BB’, 2H), 7.13-7.18 (m, 3H), 7.40-7.46 (AA’BB’,
2H), 7.54-7.59 (AA’BB’
, 1H), 7.93-7.97 (AA’BB’, 2H) ppm; 13C
E
)-2-Chloro-3-(4-fluorophenyl)-1-phenylprop-2-en-1-one (3d).
A
: 72%; Yellow oil; 1H NMR (300 MHz, CDCl3) δ
(2Z)-2-Chloro-3-(4-methylphenyl)-1-phenylprop-2-en-1-one (4b).
1
Yield: 76%; Yellow solid (mp 58.2-58.4 °C); H NMR (300 MHz,
CDCl3) δ 2.42 (s, 3H), 7.28-7.29 (AA’BB’, 2H), 7.48-7.53 (m, 3H),
C
NMR (75 MHz, CDCl3) δ 115.60, 115.89, 127.01, 127.04,
128.91, 129.50, 129.56, 129.94, 130.17, 130.28, 131.63,
133.89, 134.39, 161.00, 164.32, 191.35 ppm; HRMS: Calculated
for C15H10OClF: 260.0404, Found: 260.0402.
7.58-7.64 (AA’BB’C
, 1H), 7.77-7.82 (AA’BB’, 4H) ppm; 13C NMR
(75 MHz, CDCl3) δ 21.59, 128.45, 129.40, 129.50, 129.67,
130.17, 130.84, 132.38, 137.14, 140.12, 141.17, 191.40 ppm;
HRMS: Calculated for C16H13OCl: 256.0655, Found: 256.0655.
Crystal data. C16H13ClO, M = 256.71, orthorhombic, a =
8.8054(8), b= 11.6093(11), c = 26.7629(15) Å, α= 90.0, β= 90,
γ= 90.0, U = 2735.8(4) Å3, T = 293 K, space group Pbca, Z = 8,
18840 reflections measured, 2543 unique (Rint = 0.0144). The
final wR(F2) was 0.1132 (all reflections).
(2
E
)-3-(Benzofuran-2-yl)-2-chloro-1-phenylprop-2-en-1-one (3f).
: 76%; Yellow solid (mp 104-105.5 °C); 1H NMR
Conditions
A
(300 MHz, CDCl3) δ 6.70 (s, 1H), 7.02 (s, 1H), 7.10-7.22 (m, 3H),
7.45-7.50 (m, 3H), 7.56-7.61 (m, 1H), 8.03-8.06 (m, 2H) ppm;
13C NMR (75 MHz, CDCl3) δ 108.16, 111.17, 120.08, 121.35,
123.23, 125.53, 127.92, 127.96, 128.86, 129.73, 134.15,
134.33, 149.86, 155.10, 190.57 ppm; HRMS: Calculated for
C17H11O2Cl: 282.0448, Found: 282.0445.
(2
Yield: 70%; Yellow oil; H NMR (300 MHz, CDCl3) δ 7.42-7.53
(m, 6H), 7.57-7.63 (1H, AA’BB’ ), 7.79-7.87 (AA’BB’, 4H) ppm;
Z)-2-Chloro-1,3-diphenylprop-2-en-1-one (4c).
1
C
Crystal data. C17H11ClO2, M = 282.71, monoclinic, a =
8.087(4), b= 6.124(4), c = 13.998(7) Å, α= 90.0, β= 91.490(9), γ=
90.0, U = 693.0(6) Å3, T = 293 K, space group P21, Z = 2, 5162
reflections measured, 2586 unique (Rint = 0.0168). The
final wR(F2) was 0.0866 (all reflections).
13C NMR (125 MHz, CDCl3) δ 128.47, 128.62, 129.54, 130.42,
130.44, 130.67, 132.53, 132.91, 136.86, 139.69, 191.28 ppm;
HRMS: Calculated for C15H11OCl: 242.0498, Found: 242.0493.
(2Z)-2-Chloro-3-(4-fluorophenyl)-1-phenylprop-2-en-1-one (4d).
1
(2
E
)-2-Chloro-1-phenyl-3-(thiophen-2-yl)prop-2-en-1-one (3g).
: 77%; Yellow oil; 1H NMR (300 MHz, CDCl3) δ
Yield: 69%; Yellow oil; H NMR (300 MHz, CDCl3) δ 7.02-7.06
(AA’BB’, 1H), 7.41 (s, 1H), 7.48-7.53 (AA’BB’, 2H), 7.59-7.65
Conditions
A
(AA’BB’C, 1H), 7.78-7.82 (AA’BB’, 2H), 8.46-8.52 (AA’BB’, 2H)
6.90-6.93 (m, 1H), 7.03-7.05 (m, 1H), 7.22-7.28 (m, 2H), 7.47-
7.52 (m, 2H), 7.59-7.65 (m, 1H), 8.01-8.05 (m, 2H) ppm; 13C
NMR (75 MHz, CDCl3) δ 124.81, 126.07, 127.34, 128.00,
128.87, 129.99, 130.02, 134.09, 134.29, 135.66, 191.19 ppm;
HRMS: Calculated for C13H9OSCl: 248.0063, Found: 248.0057.
General procedure for Suzuki couplings with inversion of
ppm; 13C NMR (75 MHz, CDCl3) δ 109.52, 110.02, 127.25,
127.31, 128.67, 129.60, 132.25, 132.28, 133.04, 133.94,
136.13, 141.89, 142.00, 150.32, 150.53, 162.18, 165.42, 190.46
ppm;
HRMS: Calculated for C14H9NOFCl: 261.0357, Found: 261.0362.
(2
Z)-3-(Benzofuran-2-yl)-2-chloro-1-phenylprop-2-en-1-one (4f).
configuration (Table 2, conditions C, compounds 4a-h).
1
C); H NMR (300 MHz,
Yield: 74%; Yellow solid (mp 62.5-65
°
Compound
1 (1 eq.), the appropriate boronic acid (1 eq.),
CDCl3) δ 7.27-7.32 (m, 1H), 7.37-7.42 (m, 1H), 7.47-7.54 (m,
3H), 7.58-7.65 (m, 2H), 7.67-7.71 (m, 1H), 7.77-7.80 (m, 3H)
ppm; 13C NMR (75 MHz, CDCl3) δ 111.48, 113.33, 122.38,
123.68, 127.0, 128.34, 128.60, 128.88, 129.42, 130.93, 132.58,
136.64, 150.26, 155.14, 190.11 ppm; HRMS: Calculated for
C17H11O2Cl: 282.0448, Found: 282.0454.
Pd2(dba)3 (2.5 mol%), DPEphos (5 mol%) and Cs2CO3 (3 eq.)
were placed in a glass tube with a screw cap. Anhydrous
dioxane (to make a final concentration of
added to the glass tube. The stirred solution was heated at 85
until tlc analysis indicated complete consumption of . The
1 of 0.166 M) was
℃
1
reaction mixture was then cooled to the room temperature
and ice-cold water was added. The reaction mixture was
extracted with ethyl acetate (ca. 5 mL × 3). The combined
organic extract was washed with brine (ca. 15 mL) and dried
over anhydrous sodium sulphate. After filtration, the filtrate
was concentrated and the product (4a-h) was isolated from
the residue by silica-gel chromatography, eluting with 97:3
hexanes:ethyl acetate.
Crystal data. C17H11ClO2, M = 282.71, orthorhombic, a =
6.1663(8), b= 12.6929(11), c = 17.4233(15) Å, α= 90.0, β= 90,
γ= 90.0, U = 1363.7(2) Å3, T = 293 K, space group P212121, Z =
4, 10108 reflections measured, 2540 unique (Rint = 0.0282).
The final wR(F2) was 0.0853 (all reflections).
(2Z)-2-Chloro-1-phenyl-3-(thiophen-2-yl)prop-2-en-1-one (4g).
1
Yield: 62%; Yellow oil; H NMR (500 MHz, CDCl3) δ 7.15-7.17
(AA’BB’, 1H), 7.46-7.52 (AA’BB’, 3H), 7.58-7.61 (AA’BB’C, 1H),
7.67-7.68 (AA’BB’, 1H), 7.74-7.78 (m, 3H) ppm; 13C NMR (125
MHz, CDCl3) δ 127.24, 127.98, 128.48, 129.24, 132.22, 132.33,
(2Z)-2-Chloro-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (4a).
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Journal Name
134.19, 134.83, 136.70, 137.22, 190.48 ppm; HRMS: Calculated of 15° while relaxing all other degrees of freedom; see the SI
for C13H9OClS: 248.0063, Found: 248.0054.
(2 )-2-Chloro-3-(2-fluoropyridin-4-yl)-1-phenylprop-2-en-1-one
(4h).
for energies and further details.
Z
For the study of enone/enolate interconversion, geometries
were fully optimized (with PQS OPTIMIZE75, 76) at the b-lyp
level77-79 with the RI approximation,80, using the def-SV(P)
81
1
Yield: 69%; Yellow oil; H NMR (300 MHz, CDCl3) δ 7.02-7.06
(AA’BB’, 1H), 7.41 (s, 1H), 7.48-7.53 (AA’BB’, 2H), 7.59-7.65
83
basis set;82,
vibrational analyses were used to check the
nature of all stationary points. Improved single-point energies
were evaluated at the TPSSh70/def-TZVPP84 level, and these
energies were combined with thermal corrections (enthalpy
and entropy, 298 K, 1 bar) and a DFT-D dispersion correction85
(zero damping) to obtain final free energies.
(AA’BB’C, 1H), 7.78-7.82 (AA’BB’, 2H), 8.46-8.52 (AA’BB’, 2H)
ppm; 13C NMR (75 MHz, CDCl3) δ 109.52, 110.02, 127.25,
127.31, 128.67, 129.60, 132.25, 132.28, 133.04, 133.94,
136.13, 141.89, 142.00, 150.32, 150.53, 162.18, 165.42, 190.46
ppm; HRMS: Calculated for C14H9NOFCl: 261.0357, Found:
261.0362.
(2
Z
)-2,3-Dichloro-1-phenylprop-2-en-1-one (6).
Acknowledgements
Compound
1
(100.0 mg, 1 mmol), DPEphos (13.5 mg, 0.025 mmol)
We thank the Faculty of Science and the Department of
Chemistry at the University of Manitoba for financial support
of this work. We also acknowledge the vital assistance of Dr.
Kirk Marat (NMR), Dr. Tom Ward (GC/MS) and Mr. Mark
Cooper (X-ray crystallography).
and anhydrous dioxane (3.0 mL) were boiled under reflux for 24 hr,
at which time tlc indicated complete conversion. The reaction
mixture was then cooled to room temperature and ice-cold water
was added. The reaction mixture was extracted with ethyl acetate
(ca. 6 mL × 3). The combined organic extract was washed with brine
(ca. 20 mL) and dried over anhydrous sodium sulphate. After
filtration, the filtrate was concentrated and the product
6 was
Notes and references
† Details are provided in the supplementary information.
obtained from the residue by silica-gel chromatography. Yield: 78%;
Yellow oil; 1H NMR (500 MHz, CDCl3) δ 7.29 (s, 1H), 7.48-7.51
‡ The E/Z geometries of all compounds in this study were
determined using the JC-H method. The results were confirmed
3
(AA′BB′, 2H), 7.60-7.63 (AA′BB′C, 1H), 7.74-7.75 (AA′BB′, 2H) ppm;
13C NMR (125 MHz, CDCl3) δ 128.68, 129.45, 133.27, 133.60, 135.45,
135.90, 187.64 ppm; HRMS: Calculated for C9H6OCl2: 199.9789,
Found: 199.9796.
from X-ray crystal structures obtained for compounds 3a, 4a, 4b,
3f and 4f. Full details are in the supplementary information.
1.
2.
A. Suzuki, Angew. Chem., Int. Ed. Engl., 2011, 50, 6722-6737.
N. Miyaura, in Metal-Catalyzed Cross-Coupling Reactions, eds. A. de
Meijere and F. Diederich, Wiley-VCH Verlag GmbH, Weinheim, Germany,
2004, ch. 2, pp. 41-123.
(2E)-2-Chloro-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-ol (7)
3.
A. Suzuki, in Handbook of Organopalladium Chemistry for Organic
Synthesis, ed. E.-i. Negishi, John Wiley & Sons, Inc., New York, USA, 2002,
ch. 16, pp. 249-262.
N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457-2483.
N. Miyaura, T. Ishiyama, M. Ishikawa and A. Suzuki, Tetrahedron Lett.,
1986, 27, 6369-6372.
N. Miyaura, K. Yamada and A. Suzuki, Tetrahedron Lett., 1979, 3437-3440.
P. J. Mohr and R. L. Halcomb, J. Am. Chem. Soc., 2003, 125, 1712-1713.
D. A. Evans and J. T. Starr, Angew. Chem., Int. Ed. Engl., 2002, 41, 1787-
1790.
N. C. Kallan and R. L. Halcomb, Org. Lett., 2000, 2, 2687-2690.
J. Uenishi, J. M. Beau, R. W. Armstrong and Y. Kishi, J. Am. Chem. Soc.,
1987, 109, 4756-4758.
V. Domingo, L. Lorenzo, J. F. Quilez del Moral and A. F. Barrero, Org.
Biomol. Chem., 2013, 11, 559-562.
D.-S. Su, D. Meng, P. Bertinato, A. Balog, E. J. Sorensen, S. J. Danishefsky,
Y.-H. Zheng, T.-C. Chou, L. He and S. B. Horwitz, Angew. Chem., Int. Ed.
Engl., 1997, 36, 757-759.
S. Ducki, G. MacKenzie, B. Greedy, S. Armitage, J. Fournier Dit Chabert, E.
Bennett, J. Nettles, J. P. Snyder and N. J. Lawrence, Biorg. Med. Chem.,
2009, 17, 7711-7722.
V. Domingo, L. Silva, H. R. Dieguez, J. F. Arteaga, J. F. Quilez del Moral and
A. F. Barrero, J. Org. Chem., 2009, 74, 6151-6156.
Compound 3a (100.0 mg, 0.37 mmol) was dissolved in MeOH
(1 mL) in a test tube. CeCl3.7H2O (136.7 mg, 0.37 mmol) was
added to the tube. NaBH4 (13.9 mg, 0.37 mmol) was carefully
added. The test tube was agitated from time to time as the
reaction was allowed to proceed until tlc indicated complete
conversion of 3a. Aqueous 0.5 M HCl was then added to the
test tube. The mixture was then extracted with ethyl acetate
(ca. 5 mL × 3). The combined organic extract was washed with
brine (ca. 20 mL) and dried over anhydrous MgSO4. After
4.
5.
6.
7.
8.
9.
10.
filtration and evaporation of the solvents, the product
7 (82.7
11.
12.
mg, 82%) was isolated from the residue by silica-gel
chromatography as a colourless, viscous oil.
1H NMR (500 MHz, CDCl3) δ 2.53 (1H, s), 3.81 (3H, s), 5.95 (1H,
s), 6.88 – 6.90 (2H, m), 7.01 (1H, s), 7.21 – 7.23 (2H, m), 7.32 –
7.35 (1H, m), 7.38 – 7.41 (2H, m), 7.47 – 7.48 (2H, m) ppm; 13C
NMR (125 MHz, CDCl3) δ 55.31, 70.90, 114.16, 126.13, 127.02,
127.94, 128.51, 129.67, 130.87, 136.07, 140.22, 159.42 ppm;
HRMS: Calculated for C16H15O2Cl: 274.0761, Found: 274.0773.
Computational methods.
13.
14.
15.
16.
D. J. Kerr, E. Hamel, M. K. Jung and B. L. Flynn, Biorg. Med. Chem., 2007,
15, 3290-3298.
A. Francais, A. Leyva, G. Etxebarria-Jardi and S. V. Ley, Org. Lett., 2010, 12,
340-343.
17.
18.
R. Rossi, A. Carpita and M. G. Quirici, Tetrahedron, 1981, 37, 2617-2623.
A. Torrado, B. Iglesias, S. Lopez and A. R. de Lera, Tetrahedron, 1995, 51,
2435-2454.
All calculations were carried out with the program
Turbomole69 coupled to an external optimizer.
For the study of forced C=C rotation, geometries were 19.
optimized at the TPSSh level,70 using the def-TZVP basis set71, 72
L. M. Geary and P. G. Hultin, Eur. J. Org. Chem., 2010, 2010, 5563-5573.
L. M. Geary and P. G. Hultin, J. Org. Chem., 2010, 75, 6354-6371.
L. M. Geary and P. G. Hultin, Org. Lett., 2009, 11, 5478-5481.
A. Jonczyk and A. H. Gierczak, Synthesis, 1998, 962-964.
E. Grenet, J. Martinez and X. J. Salom-Roig, Asian J. Org. Chem., 2017, 6,
189-198.
20.
21.
(Stuttgart ECP for Pd73). BOptimize74 was used to constrain the
22.
23.
values of H-C1-C2-C3 and H-C1-C2-Cl dihedral angles in steps
8 | J. Name., 2012, 00, 1-3
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