Pyridine-Hydrazone Ligands in Asymmetric Palladium-Catalyzed 1,4- and 1,6-Additions of Arylboronic Acids to Cyclic (Di)enones

Article abstract of DOI:10.1002/adsc.201801021

Catalysts generated by combinations of Pd(TFA)₂ and enantiomerically pure pyridine-hydrazone ligands have been applied to the 1,4-addition of arylboronic acids to β-substituted cyclic enones, building all-carbon quaternary stereocenters in high

Full text of DOI:10.1002/adsc.201801021

Title: Pyridine‒Hydrazone Ligands in Asymmetric Palladium-Catalyzed
1,4- and 1,6-Additions of Arylboronic Acids to Cyclic (Di)enones
Authors: María de Gracia Retamosa, Yolanda Álvarez-Casao, Esteban
Matador, Ángela Gómez, David Monge, Rosario Fernández,
and José Lassaletta
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801021
Link to VoR: http://dx.doi.org/10.1002/adsc.201801021

10.1002/adsc.201801021
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Pyridine‒Hydrazone Ligands in Asymmetric Palladium-
Catalyzed 1,4- and 1,6-Additions of Arylboronic Acids to Cyclic
(Di)enones
María de Gracia Retamosa,a‡ Yolanda Álvarez-Casao,b‡ Esteban Matador,b Ángela
Gómez,b David Monge,b* Rosario Fernández,b* and Josꢀ M. Lassalettaa*
a
Instituto Investigaciones Químicas (CSIC-US), Amꢀrico Vespucio 49, 41092 Sevilla, Spain
e-mail: jmlassa@iiq.csic.es
b
Departamento de Química Orgꢁnica, Universidad de Sevilla, C/Prof. García Gonzꢁlez, 1, 41012 Sevilla, Spain
e-mails: dmonge@us.es, ffernan@us.es
These authors contributed equally to this work.
‡
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. Catalysts generated by combinations of Pd(TFA)2 and enantiomerically pure pyridine-hydrazone ligands have
been applied to the 1,4-addition of arylboronic acids to β-substituted cyclic enones, building all-carbon quaternary
stereocenters in high yields and enantioselectivities (up to 93% ee). The developed methodology allows the efficient
introduction of ortho-substituted aryl groups in β-position of cyclopentanone cores, giving scaffolds present in a broad
range of biologically active natural products. These Pd(II)-complexes served also as catalysts in the 1,6-addition of
arylboronic acids to cyclic dienones, affording complete regioselectivities, moderate yields and good enantioselectivities
(up to 80% ee).
Keywords: Asymmetric Catalysis, Palladium, N Ligands, Arylboronic acids, Hydrazones
Introduction
The synthesis and practical evaluation of new chiral
ligands are essential tasks for the continuous
development of asymmetric metal catalysis.[1] In the
last twenty years, there has been an increasing
implementation of nitrogen-based ligands,[2] which
offer an extraordinary structural variability and are in
general stable and easy to handle compounds. In
particular, bidentate N-(sp2)-based ligands such as
bipyridine (I),[3] bis-imine (II),[4] bis-oxazoline
(III),[5] or pyridine-oxazoline (IV)[6] chiral ligands
(Figure 1) have allowed a vast number of asymmetric
reactions.
Alternatively, hydrazones appear as a complementary
family of chiral ligands which offer high thermal
stability, compatibility with many reagents and
distinct electronic, steric and conformational
properties. The originally designed glyoxal bis-
hydrazone L1 afforded excellent results in Cu(II)
catalyzed Diels-Alder cycloadditions[7] and Pd(0)
catalyzed Suzuki-Miyaura cross-couplings.[8] In the
original ligand design, C2-symmetric dialkylamino
groups were introduced at both ends to prevent the
loss of suitable chiral environments around the metal
by N–N bond rotations, and this design proved to be
Figure 1. N-(sp2)-based bidentate chiral ligands.
essential to reach high enantioselectivities.
1
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10.1002/adsc.201801021
Advanced Synthesis & Catalysis
Additionally, the steric crowding around the metal
center is modulated by the structure of the
dialkylamino fragment, which in turn influences the
electronic behaviour of C=N group [n→π (N-N=C)
conjugation]. This key design was subsequently
extended to phosphino-hydrazones[9] and pyridine-
hydrazones[10] (L2 and others). Pd(II) complexes of
these bidentate ligands allowed to expand the scope
of the Suzuki coupling to complementary families of
electrophilic substrates. The latter pyridine-
hydrazones, in combination with different metals,
have proved to be also useful catalysts in processes
such as RuII-catalyzed asymmetric decarboxylative
allylic etherifications[11] or, in combination with
Pd(TFA)2, 1,2-addition of arylboronic acids to
saccharin-derived cyclic ketimines (Scheme 1; A,
B).[12] Remarkably, in both cases the pyridine–
hydrazone ligand outperformed well-established
pyridyl monooxazoline (pymox) ligands: in the first
case the ligand provided substantially higher
enantioselectivities while preventing racemizations
and branched-to-linear isomerizations;[13] in the
second, it was possible to perform unprecedented
additions to diketimines,[14] reaching high yields and
enantioselectivities, along with high regioselectivities
for unsymmetrically substituted derivatives.
Pioneered by Hayashi and co–workers, different
groups have described Rh-catalyzed asymmetric
additions of arylboron reagents to β-substituted cyclic
enones.[17] Alternatively, Pd(II) catalysts in
combination with oxazoline-based ligands have also
been used for the asymmetric 1,4-addition of aryl
boronic acids to several Michael acceptors. In 2011,
Stoltz and co-workers reported the addition of
arylboronic acids to β-substituted cyclic enones
catalyzed by Pd(TFA)2/Pyrox (IVa).[18] This system
efficiently generates benzylic[19] and bis-benzylic[20]
quaternary sterocenters. Minaard and co-workers
expanded this scope to lactones and other acceptors
using PdCl2/Box (IIIa) catalyst in combination with
AgSbF6 (20 mol%).[21] A more sophisticated catalytic
system [PdCl2/IIIa (4-8 mol%), AgCF3CO2 (10-20
mol%), NH4PF6 (10-20 mol%), H2O (8 equiv.), 7
equiv. of cyclic enone] enabled reactions with ortho-
substituted aryl boronic acids in good to excellent
enantioselectivities, albeit in moderate yields.[22]
On the other hand, conjugate additions of
arylboronic acids 1 to more challenging cyclic
dienones, requires an efficient control of the
regioselectivity (1,4- vs 1,6-addition) as an additional
challenge.
Iridium/diene complexes catalyze
asymmetric 1,6-additions of aryl boroxines to cyclic
and acyclic dienones.[23] Moreover, Rhodium/diene
complexes catalyze asymmetric 1,6-addition of
sodium tetraphenylborate to cyclic dienones.[24] To
the best of our knowledge, however, the use of Pd-
based catalysts in this context remains unexplored.
Encouraged by the efficiency of [Pd(TFA)2/L2]
catalyst in related contexts, we decided to explore the
1,4- and 1,6-additions of boronic acids to cyclic
enones and dienones (Scheme 1, C); the collected
results are discussed herein.
The asymmetric 1,4-addition of organometallic
reagents to α,β-unsaturated carbonyl acceptors[15] is a
well established method for the catalytic asymmetric
formation of all-carbon quaternary stereocenters.[16]
Results and Discussion
1,4-Addition of Aryl Boronic Acids to β-Substituted Cyclic
Enones
The reaction between phenylboronic acid (1a) and 3-
methyl-2-cyclohexenone (2a) was chosen as model
system. Complexes prepared in situ from L1-L14
(7.5 mol%) and different Pd(II) sources (PdCl2,
Pd(OAc)2 and Pd(TFA)2, 5 mol%) were initially
evaluated in reactions performed at 60 °C in
dichloroethane (DCE). Pd(TFA)2 was identified as
the best catalyst precursor (Table 1, entries 2-4). Its
complex with glyoxal bishydrazone L1 was totally
inactive (entry 1), while pyridine-hydrazone ligand
L2 afforded a promising result (70% yield, 90% ee,
entry 4), showing the need for a push-pull bidentate
ligand containing a pyridine nitrogen. Subsequently,
the influence by the hydrazone chiral unit was
analyzed. (2S,6S)-2,6-Diphenylpiperidine derivative
L3 provided lower yield and enantioselectivity (42%,
40% ee, entry 5), a fact that has been repeatedly
observed in related catalysts,[7],[8],[12] and that can be
Scheme 1. Pyridine-hydrazones in asymmetric catalysis
2
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10.1002/adsc.201801021
Advanced Synthesis & Catalysis
explained by the higher conformational flexibility of
the piperidine
11). In contrast, substitution at the azomethine carbon
in L10 afforded only trace amounts of product 3a
after 60 h (entry 12). The influence of functional
groups on the pyridine ring was also investigated.
Unexpectedly, increasing the basicity of the pyridine
N atom by introduction of electron-donating groups
at C-4 (L11 and L12) decreased reactivity and
selectivity (entries 13 and 14). This can be tentatively
explained assuming that the higher donor ability of
the pyridine N-(sp2) facilitates a hemilabile behaviour
of the ligand, eventually facilitating dissociation of
the hydrazone N-(sp2) and hence giving 3a with lower
enantioselectivity [64% ee employing L12 (4-
NMe2)]. On the contrary, introduction of electron-
withdrawing groups at C-4 (L13) or at C-5 (L14) had
no drastic influence in enantioselectivity, albeit 3a
was obtained in moderate to low yields (entries 15
and 16). A survey of different solvents was also
performed (Table 2): THF as a coordinating solvent
totally inhibited the catalytic activity (entry 2). In
toluene, the reaction proceeded less efficiently than in
DCE (entry 3) while MeOH or trifluoroethanol (TFE)
afforded 3a in lower yields and enantioselectivities
(entries 4 and 5). In these polar protic solvents,
reduction of Pd(II) to catalytically irrelevant Pd(0)
species appeared as the main problem.
Table 1. Ligand screening.[a]
A further optimization of reaction temperature and
concentration was performed to reduce side reactions
such as homo-coupling, protodeboronation, and/or
partial deactivation of the Pd(II) catalysts (entries 6-
9). A poor yield was observed at 50 °C in DCE (entry
6), while running the reaction at 80 °C (entry 7) or
higher concentration (entry 8) favored the formation
of side-products. Finally, a modest improvement in
Entry
1
L*
L1
L2
L2
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L12
L13
L14
time [h]
60
60
60
60
60
60
120
120
120
60
60
60
60
60
60
60
Yield [%][b]
nr
nr
35
70
42
8
ee [%][c]
--
--
74
90
40
18
--
rac
rac
80
74
nd
84
64
84
90
2[d]
3[e]
4
5
6
7
8
nr
Table 2. Optimization of reaction conditions.[a]
36
trace
57
80
trace
65
46
28
54
9
10
11
12
13
14
15
Entry Solvent [M]
H2O
[equiv.]
t [h]
Yield
ee
[%][b] [%][c]
16
1
2
3
4
DCE (0.25)
THF (0.25)
Toluene (0.25)
MeOH (0.25)
TFE (0.25)
DCE (0.25)
DCE (0.25)
DCE (1)
-
-
-
-
-
-
-
-
-
-
-
-
1.1
0.2
60
60
60
60
60
60
36
36
40
40
36
32
24
24
70
nr
90
--
[a]
Reaction conditions: 1a (0.5 mmol), 2a (0.25 mmol), L
[b]
(7.5 mol%), Pd(TFA)2 (5 mol%), DCE (1 mL), 60 °C.
38
16
45
30
42
30
73
90
84
90
90
94
83
74
82
90
84
90
92
92
92
92
88
91
Isolated yield after column chromatography. [c] Determined
[d]
by chiral HPLC. DCE = 1,2-Dichloroethane.
PdCl2 (5
5
mol%). [e] Pd(OAc)2 (5 mol%).
6[d]
7[e]
8
moiety and the weaker n→π conjugation. (2S,5S)-2,5-
Diisopropylpyrrolidine derivative L4 was also
inadequate
9
DCE (0.5)
10[f] DCE (0.5)
11[g] DCE (0.5)
12[h] DCE (0.5)
13[h] DCE (0.5)
(entry
6).
The
(2S,5S)-2,5-
diphenylpyrrolidine unit was consequently retained
and the influence by substituents on the pyridine ring
was next explored. The presence of aryl groups at C-
6 (L5, L6 or quinoline-derived L7) had a detrimental
effect on the catalytic performance (entries 7-9). In
the best case, Pd(TFA)2/L6 afforded 3a in 36% yield
after 120 h and as racemic mixture. Substitution at C-
3 (L8 and L9) had a moderate impact, yielding 3a in
lower 80% and 74% ee, respectively (entries 10 and
14[h]
DCE (0.5)
[a]
Reaction conditions: 1a (0.5 mmol), 2a (0.25 mmol),
L2 (7.5 mol%), Pd(TFA)2 (5 mol%), solvent (M), 60 °C.
[b]
[c]
[f]
Isolated yield after column chromatography.
[d]
[e]
Determined by chiral HPLC.
Iterative addition of 1a (0.125 mmol/10 h). Pd(TFA)2
50 °C.
80 °C.
[g]
3
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10.1002/adsc.201801021
Advanced Synthesis & Catalysis
[h]
O
O
11
48 76
87
(S)-3j
(7.5 mol%), L2 (9 mol%).
(12 mol%).
Pd(TFA)2 (10 mol%), L2
yield (73%) and enantioselectivity (92% ee) was
observed at the optimal concentration (0.5M) at 60 °C
(entry 9). An iterative addition of 1a, avoiding high
concentration of boronic acid, prevented bi-phenyl
product formation and improved the yield up to 90%
(entry 10). Additionally, a higher catalyst loading of
Pd(TFA)2 (7.5/10 mol%) led to appreciably shorter
reaction times and good yields (entries 11 and 12).
The presence of water had a strong impact in both
reactivity and selectivity,[25] and was also the origin
of some irreproducibility issues. Therefore, the
remaining optimization was performed in dry DCE
with controlled amounts of added water. Addition of
stoichiometric quantities (up to 1.1-1.5 equivalents)
led to faster (24 h) and cleaner reactions, giving 3a in
Ph
12[e]
13
20 95
48 73
88
91
Ph, (S)-3k
2-MeO-C6H4,
(S)-3l
4-Me-C6H4, (S)-
3m
Me
Ar
14
48 97
60 65
88
86
15[d
]
O
O
,
(S)-3n
16
72 38
72 54
93
90
OMe
MeO
Me
good
yields
albeit
in
slightly
lower
, (S)-3o
enantioselectivities (up to 88% ee, entry 13). 0.2
Equiv. was found to be the optimal amount, affording
3a in 94% yield and 91% ee in only 24 h (entry 14).
The scope of the reaction was then explored by
using different aryl boronic acids as nucleophiles
(Table 3). In general, benzylic quaternary centers
17[f]
[a]
Reaction conditions: 1 (0.5 mmol), 2 (0.25 mmol), L2
(12 mol%), Pd(TFA)2 (10 mol%), DCE (0.5 mL), H2O (0.2
equiv.), 60 °C.
chromatography.
Iterative addition of 1 (0.125 mmol/18 h).
[b]
Isolated yield after column
[c]
[d]
Determined by chiral HPLC.
[e]
Reaction
[f]
Table 3. Substrate scope.[a]
performed with Pd(TFA)2 (7.5 mol%), L2 (9 mol%).
Reaction performed with twofold excess of enone 2d.
O
O
Pd(TFA)2 (10 mol%)
L2/ent-L2 (12 mol%)
+
ArB(OH)2
were generated in high enantioselectivities (88-92%
ee). p-Substituted aryl boronic acids were well
tolerated (entries 3-7), affording 3-aryl-3-methyl-
cyclohexanones 3b-f in variable yields depending on
the substitution pattern. p-Tolyl boronic acid reacted
slower (48 h) to give 3b in 93% yield and 91% ee
(entry 3). Arylboronic acids bearing halogens and
ethers required longer reaction times (72 h) and
iterative additions of 1 to achieve the optimal yields
(43-77%, entries 4-7). An electron-rich di-substituted
boron reagent leading to 3g (75%, 92% ee) was also a
suitable reaction partner (entry 8), while more
challenging ortho-substituted boronic acids afforded
products in lower yields. On the other hand, the
uniformity of the enantioselectivities observed herein
contrasts with the results reported with pyridine-
oxazoline IVa: electron-rich nucleophiles often
furnished products in lower enantioselectivities (Ar =
4-Me-C6H4, 3b in 87% ee; Ar = 4-MeO-C6H4, 3e in
69% ee).[18] Next, we explored the reactivity of cyclic
enones with diverse β-substitutions and ring size. The
reaction tolerated an ethyl substituent at the  carbon
(entry 9), but a phenyl group at this position kills the
reactivity (entry 10). Cyclohexenone (2d) gave (S)-3j
in 76% yield and 87% ee (entry 11), together with 3-
phenyl-cyclohex-2-enone (2c, heck-type product,
20%).[26] Finally, five-membered ring enone 2e
afforded 3k in 95% yield and 88% ee in a faster
reaction (20 h, entry 12). The superior reactivity of
this substrate allowed to reduce catalyst loading up to
7.5 mol% without practical deleterious effects and the
introduction of ortho-substituted aryl groups, as
shown for 3l (entry 13), in good yield (73%) and
enantioselectivity (91% ee).[27] A meta-para di-
R
Ar
DCE, 60 °C
H2O (0.2 equiv.)
R
n
n
1
2
3
R = Me, n = 1 (2a)
R = Et, n =1 (2b)
R = Ph, n = 1 (2c)
R = H, n = 1 (2d)
R = Me, n = 0 (2e)
Product
Ar, 3
t
Yield ee
[h] [%][b] [%][c]
O
1
24 94
91
Ph, (S)-3a
Me
Ar
2
3
24 92
48 93
91
91
Ph, (R)-3a
4-Me-C6H4, (S)-
3b
4-F-C6H4, (S)-3c
4-Cl-C6H4, (S)-3d
4-MeO-C6H4,
(S)-3e
4-CF3O-C6H4,
(S)-3f
3,5-(Me)2-C6H3,
(S)-3g
4[d]
5[d]
6[d]
72 43
72 77
72 73
90
90
90
7[d]
8
72 65
24 75
48 80
90
92
89
9[d]
O
O
(S)-3h
Et
Ph
10
72 --
--
(S)-3i
Ph
OMe
4
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10.1002/adsc.201801021
Advanced Synthesis & Catalysis
substituted boronic acid was also tolerated for the
synthesis of 3n in 65% yield and 86% ee (entry 15).
Unfortunately, alkyl (isopropyl) and heteroaryl (2-
furanyl and 2-thienyl) boronic acids were
unsuccessfully tested with 2a and 2e. The
methodology can be applied for the synthesis of
advanced intermediates en route to several
(Table 4). In contrast to the 1,4-addition pathway, the
complex L1/Pd(TFA)2 based on the bishydrazone
ligand afforded a good conversion (71%) and perfect
regioselectivity
to
3p,
albeit
with
low
enantioselectivity (entry 1). To our delight, the
pyridine-hydrazone Pd(TFA)2/L2 system provided,
also regioselectively, the 1,6-adduct 3p with a higher
biologically active natural products (Scheme 2). Thus, enantioselectivity (62% ee), although the conversion
3m [direct precursor of (−)-α-cuparenone] was
obtained in an excellent 97% yield and 88% ee (Entry
14).[27] Additionally, the synthesis of 3o, which is a
key intermediate for the synthesis of enokipodin A
and B, was accomplished in moderate yield (38%)
but remarkable enantioselectivity (up to 93% ee,
entry 16). The yield could be further improved to
54% by using a twofold excess of the enone 2e with
the same level of enantioselectivity (entry 17).[27] In
order to evaluate the practical applicability of the
remained moderate (45% after 60 h, entry 2).
Different nitrogen ligands (bipyridines, bis-
oxazolines
and
pyridine-oxazolines)
were
comparatively analyzed (See ESI), but lower
conversions and enantioselectivities were obtained in
all cases. As representative examples, bis-oxazoline
IIIb furnished 3p in 43% conversion (lower than L1
and similar to L2) in racemic form (entry 3) while
pyridine-oxazoline IVa provided 3p in 49% ee, albeit
in 20% conversion (entry 4). Structural variations of
developed methodology, the synthesis of (S)-3a (89%, the pyridine-hydrazone ligand were also investigated
88% ee) was performed on a 1.5 mmol scale under
slightly optimized reaction conditions [Pd(OTf)2 (12
mol%), L2 (14 mol%), H2O (0.1 equiv.), iterative
addition of 1a (0.5 mmol/12 h), 48 h.]
but, as in the previous 1,4-addition case, none of the
modified ligands proved to be superior than the basic
L2 (see ESI). Interestingly, none of these Pd-catalysts
yielded 1,4- or heck-type side products. Alternative
solvents, palladium salts and organoborane reagents
(boroxines and borate salts) were also evaluated
without any improvement. Increasing concentration
up to 0.8M afforded 3p with similar conversion and
slightly better enantioselectivity in a shorter reaction
time (entry 5). Iterative addition of arylboronic acid
1a had a positive effect in the outcome of the reaction,
affording 3p in yet moderate conversion (52%) but a
better 77% ee (entry 6). Then, the impact of water, as
additive in this process, was also analyzed.
Employing an excess (up to 6 equivalents) of water
accelerated the reaction, improving conversion up to
75% in 24 h, although at the expenses of a lower
enantioselectivity (entry 7). As in the 1,4-addition, a
catalytic amount of water (0.2 equiv.) were found to
be optimal, giving 3p in 61% conversion after 48 h
(entry 8) while keeping a reasonable level of
asymmetric induction (78% ee). Upon these
conditions and performing iterative additions of 1a
(0.06 mmol/12 h) during prolonged reaction times,
conversions increased up to 71% and 90% for 72 and
96 h, respectively (entries 9,10).
O
O
1 Step, ref. [21]
(-)-a-Cuparenone
3m
O
O
4 Steps, ref [22]
O
O
MeO
Enokipodin B
OMe
HO
3o
O
4 Steps, ref [22]
OH
Enokipodin A
Scheme 2. Formal synthesis of (−)-α-cuparenone and
enokipodin A and B
Table 4. Optimization of reaction conditions.[a]
The absolute configuration of the newly created
stereogenic center in products 3a-e, 3h and 3k-m was
determined to be S by chemical correlation (See ESI).
1,6-Addition of Aryl Boronic Acids to Cyclic Dienones
We initially analyzed the catalytic performance of
several Pd(TFA)2/L* complexes in the reaction
between phenylboronic acid 1a and cyclic dienone 2f
5
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10.1002/adsc.201801021
Advanced Synthesis & Catalysis
O
O
O
B(OH)2
O
Pd(TFA)2 (x mol%)
L (y mol%)
Pd(TFA)2 (15 mol%)
L2 (17 mol%)
Ar
Ph
ArB(OH)2
+
+
DCE, 60 ºC
1
DCE, 60 ºC
R
R
H2O (0.2 equiv.)
H2O (z equiv.)
2f, R = Me
2g, R = Bu
3p,s
1a
2f
3p
Ph
N N
Ph
Ph
N N
Ph
N N
O
N
N
Ph
L1
L2
Ph
O
Ph
3p
61%, 79% ee[a]
81%, 67% ee[b]
O
O
N
t (h)
N
N
tBu
CH3
OCF3
tBu
tBu
O
IVa
IIIb
O
O
Ph
H2O
[equiv.]
t (h)
Conv.
[%][b]
ee
Entry Ligand
[%][c]
1
2
3
4
-
-
-
-
60
60
60
60
71
45
43
20
10
62
rac
49
L1
L2
IIIb
IVa
3s
31%, 52% ee[a]
3q
3r
35%, 80% ee[a]
47%, 72% ee[b]
44%, 74% ee[a]
78%, 68% ee[b]
Scheme 3. 1,6-Addition to dienones. [a] Reaction time 72 h.
5[d]
-
-
36
48
44
52
67
77
L2
L2
[b] Reaction time 96 h.
6[d],[e]
7[d]
6.4
0.2
0.2
0.2
24
48
72
96
75
61
38
78
79
67
L2
L2
L2
L2
8[d],[e]
Proposed Intermediates and Stereochemical models
9[d],[f]
71 (61)[g]
10[d],[f]
90 (81)[g]
The proposed mechanism for Pd(II) catalyzed 1,4-
addition of arylboronic acids to enones mediated by
[a]
Reaction conditions: 1a (0.5 mmol), 2f (0.25 mmol), L
pyridine-oxazoline
ligands[18],[19a]
allowed
to
(12 mol%), Pd(TFA)2 (10 mol%), DCE (0.5 mL), 60 °C,
60 h.
mixtures.
conditions: 1a (0.5 mmol), 2f (0.25 mmol), L2 (17 mol%),
Pd(TFA)2 (15 mol%), DCE (0.3 mL), 60 °C.
addition of 1a (0.125 mmol/12 h). Iterative addition of
1a (0.063 mmol/12 h). [g] In parenthesis, isolated yield after
column chromatography.
Determined by 1H-NMR of crude reaction
[b]
extrapolate a plausible catalytic cycle employing
pyridine-hydrazone L2. The proposed intermediates
I/II involved in the stereocontrolling step are
depicted in Scheme 4A. In these intermediates, the
aryl group from the boronic acid should be placed
trans to the less basic hydrazone fragment after the
transmetallation step, leaving the cis position
available for the coordination of the cyclic enone.
One of the two possible orientations of enone 2 (I) is
clearly disfavoured due to a destabilizing steric
interaction with the proximal phenyl group at position
C(2’) of the ligand. The alternative orientation (in II),
however, lacks such interaction, guiding the
stereoselective C-C bond formation to the
experimentally observed major (S) enantiomer.
Coordination of water to Pd is proposed to assist the
re-generation of Pd(II)-OH catalyst (protonolysis
step). For the 1,6-addition, and according with the
stereochemical outcome, a consistent model with
similar interactions is proposed. In Scheme 4B, only
two intermediates III/IV out of other possibilities
resulting from higher conformational flexibility of
dienone, are depicted (See ESI), being IV favoured
for the lack of repulsive steric interactions.
[c]
[d]
Determined by chiral HPLC.
Reaction
[e]
Iterative
[f]
However, a decrease of enantiomeric excess over
reaction time was observed,[28] affording 3p in 81%
yield and 67% ee (entry 10). Alternatively, stopping
the reaction after 72 h afforded 3p in 61% yield and
79% ee, while some unreacted starting material was
recovered (25%). With the optimal reaction
conditions in hand, the method was extended to
different boronic acids and dienones. (Scheme 3). p-
Tolylboronic
acid
(1b)
and
[4-(trifluoromethoxy)phenyl] boronic acid (1f)
exhibited similar reaction profiles than the model
reagent 1a (see ESI). Thus, reactions after 72 h
allowed to obtain the corresponding adducts 3q and
3r in good enantioselectivities (74 and 80% ee) and
modest yields. Alternatively, higher yields were
obtained after 96 h, albeit lower enantioselectivities
were observed (68 and 72% ee).
Conclusion
Finally, when dienone 2g was used the addition of
1a proceeded with a lower enantioselectivity (52%
ee). The absolute configuration of 3s was determined
to be R by chemical correlation,[29] and those of 3p-r
were assigned by analogy assuming a uniform
stereochemical pathway.
In summary, a Pd(TFA)2/pyridine-hydrazone (L2)
precatalyst provides fairly good yields and
enantioselectivities in the 1,4-addition of arylboronic
acids to β-substituted cyclic enones, generating all-
6
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10.1002/adsc.201801021
Advanced Synthesis & Catalysis
carbon quaternary stereocenters. The developed
methodology allows the efficient synthesis of β-aryl-
β’-methylcyclopentanones bearing ortho-substituted
aryl groups, relevant precursors of biologically active
molecules. The catalytic system was also tested
employing more challenging cyclic dienones
affording 1,6-addition products with complete,
enantioselectivities. It was observed a positive effect
of catalytic amounts of water, presumably assisting in
the catalyst turnover, in both processes. The set of
results presented herein show again that readily
available
pyridine-hydrazones
constitute
an
interesting type of ligands, outperforming the well-
stablished bis-oxazoline or pyridine-oxazoline
families in some contexts.
regioselectivities
and
moderate
to
good
A (1,4-Addition)
Repulsive
interaction
O
Ph
N
O
Ph
N
N
N
(R)
N
N
O
Ph
Ph
Pd
Me
Pd
(S)
O
Ph
Me
Ph Me
Minor
Major
Me
II (favored)
I
Repulsive
interaction
B (1,6-Addition)
O
O
Ph
N
O
Ph
N
N
N
N
N
Ph
O
Ph
Pd
Me
Pd
Ph
(S)
(R)
Me
Minor
Ph
Major
Me
Me
IV (favored)
III
Scheme 4. Proposed Intermediates and Stereochemical models.
and the residue was purified by flash chromatography (n-
hexane/EtOAc). Enantiomeric excess (ee) was determined
by HPLC analysis.
Experimental Section
General Information
General Procedure for Pd(II)-Catalyzed Asymmetric
1,6-Addition of Arylboronic Acids 1 to Dienones 2f,g.
1H NMR spectra were recorded at 300 MHz or 500 MHz;
13C NMR spectra were recorded at 75.5 MHz or 126 MHz
with the solvent peak used as the internal reference (7.26
and 77.0 ppm for 1H and 13C respectively); 19F NMR
spectra were recorded at 471 MHz. Column
chromatography was performed on silica gel (Merck
Kieselgel 60). Analytical TLC was performed on
aluminum backed plates (1.5  5 cm) pre-coated (0.25
mm) with silica gel (Merck, Silica Gel 60 F254).
Compounds were visualized by exposure to UV light or by
dipping the plates in solutions of KMnO4, anisaldehyde or
phosphomolibdic acid stains followed by heating. Melting
points were recorded in a metal block and are uncorrected.
Optical rotations were measured on a Perkin-Elmer 341
MC polarimeter. The enantiomeric excess (ee) of the
products was determined by chiral stationary phase HPLC.
Solvents were purified and dried by standard procedures.
Dichloroethane was purchased from Across (99.5% Extra
Dry, Over Molecular Sieves, <0.005% H2O). Unless
otherwise noted, commercially available reagents were
used without further purification.
A test tube was charged with Pd(TFA)2 (13 mg, 0.038
mmol), L2 (13 mg, 0.04 mmol), arylboronic acid 1 (0.06
mmol), dienone 2f,g (0.25 mmol), DCE (0.5 mL) and H2O
(1 μL, 0.05 mmol). Subsequently, addition of 1 (0.06
mmol/12 h) was performed. The mixture was stirred at
1
60 °C for 72/96 h [for each substrate, conversions (by H-
NMR) and ee's (HPLC) were monitored at different times
(48, 72 and 96 h)]. The solvent was removed at reduced
pressure and the residue was purified by flash
chromatography (n-hexane/EtOAc). Enantiomeric excess
(ee) was determined by HPLC analysis.
Electronic supplementary information (ESI) contains:
experimental procedures, additional optimizations,
characterization data, NMR spectra for compounds, and
HPLC traces
Acknowledgements
General Procedure for Pd(II)-Catalyzed Asymmetric
1,4-Addition of Arylboronic Acids 1 to Cyclic Enones
2a,d.
This work was supported by the Spanish MINECO (CTQ2016-
76908-C2-1-P, CTQ2016-76908-C2-2-P and predoctoral
fellowship to E. M.), European FEDER funds and the Junta de
Andalucía (Grant 2012/FQM1078). We also thank general
NMR/MS services of the University of Sevilla.
A test tube was charged with Pd(TFA)2 (8.5 mg, 0.025
mmol), L2 (9.8 mg, 0.03 mmol), arylboronic acid 1 (0.5
mmol), cyclic enone 2a,e (0.25 mmol), DCE (0.5 mL) and
H2O (1 μL, 0.05 mmol). The mixture was stirred at 60 °C
1
for the time specified for each substrate (tlc and H-NMR
monitoring). The solvent was removed at reduced pressure
7
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10.1002/adsc.201801021
Advanced Synthesis & Catalysis
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8
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FULL PAPER
Pyridine‒Hydrazone Ligands in Asymmetric
Palladium-Catalyzed 1,4- and 1,6-Additions of
Arylboronic Acids to Cyclic (Di)enones
Adv. Synth. Catal. Year, Volume, Page – Page
María de Gracia Retamosa, Yolanda Álvarez-
Casao, Esteban Matador, Ángela Gómez, David
Monge,* Rosario Fernꢁndez,* and Josꢀ M.
Lassaletta*
9
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