Sequential rhodium/palladium catalysis: Enantioselective formation of dihydroquinolinones in the presence of achiral and chiral ligands

Article abstract of DOI:10.1002/anie.201407400

Compatible combinations of achiral and chiral ligands can be used in rhodium/palladium catalysis to achieve highly enantioselective domino reactions. The difference in rates of catalysis and minimal effects of ligand interference confer control in the dom

Full text of DOI:10.1002/anie.201407400

Angewandte
Chemie
DOI: 10.1002/anie.201407400
Multicatalytic Reactions
Sequential Rhodium/Palladium Catalysis: Enantioselective Formation
of Dihydroquinolinones in the Presence of Achiral and Chiral
Ligands**
Lei Zhang, Zafar Qureshi, Lorenzo Sonaglia, and Mark Lautens*
Abstract: Compatible combinations of achiral and chiral
ligands can be used in rhodium/palladium catalysis to achieve
highly enantioselective domino reactions. The difference in
rates of catalysis and minimal effects of ligand interference
confer control in the domino sequence. The “all-in-one” 1,4-
conjugate arylation and CÀN cross-coupling through sequen-
Taking advantage of the orthogonal ligand association, we
have recently demonstrated a number of ligand-dependent
[
4l–o]
Rh/Pd-catalyzed domino reactions,
a chiral and achiral ligand to access chiral dihydrodibenzox-
including the use of
[
4m]
epines
with high enantioselectivity, though with modest
yields and limited scope. Now we report the use of the highly
compatible Rh/Pd catalyst system with a different ligand
combination to access dihydroquinolinones in a direct and
expedient manner, affording high yields and enantioselectiv-
ities. Molecules of this class of heterocycles exhibit important
tial Rh/Pd catalysis provides access to enantioenriched dihy-
droquinolinone building blocks.
T
he use of more than one metal catalyst in a single reaction
[
7]
vessel is a recent and promising area of research. An
important advantage of multimetal catalysis is the ability to
promote various modes of catalysis that cannot be achieved
with a single catalyst. For example, bimetallic catalysis and
cooperative dual metal catalysis are modes of catalysis that
lead to transformations involving catalyst–catalyst interac-
biological activities. Current methods to access chiral C4-
substituted dihydroquinolinones include the work of Beak
[8]
and Park, through an asymmetric (À)-spartiene mediated
[9]
deprotonation [Eq. (1), Scheme 1], and that of Carreira,
[
1–3]
tions.
catalysis. However, examples of multiligand domino catal-
An alternative mode involves domino or sequential
[4]
[
4k–o]
ysis remain rare.
As metal catalysis is highly dependent on
ligands to confer specific reactivity, multiligand systems
enable transformations that can empower the domino mode
of catalysis. In this mode, independent catalytic cycles operate
with differing rates such that undesired catalytic pathways are
suppressed to afford a controlled reaction sequence, confer-
[5]
ring time resolution. In addition, the ligands should not
[
6]
interfere with subsequent steps so that combinations of
ligands can be tolerated and each ligand binds to a specific
metal to obtain highly reactive metal–ligand complexes. The
ligand may bind selectively or nonselectively, but in either
case a single reactive complex does the desired transforma-
tion. This allows similar ligands (two or more phosphines) or
different ligands (diene and phosphine) to be mixed in the
same vessel.
Scheme 1. Domino Rh/Pd catalysis strategy for the enantioselective
synthesis of dihydroquinolinones.
through a Rh-catalyzed asymmetric conjugate arylation of
a cinnamate [Eq. (2)]. Our “all-in-one” method involves
a Rh-catalyzed asymmetric conjugate arylation to an acryl-
amide followed by a Pd-catalyzed amidation of the pendant
aryl chloride [Eq. (3)]. These starting acrylamides can be
readily accessed in a reliable and straightforward manner,
thereby affording a broad substrate scope. Furthermore, these
chiral heterocyclic products are known to be functionalized
into various tetrahydroquinoline derivatives.
[
*] L. Zhang, Z. Qureshi, L. Sonaglia, Prof. Dr. M. Lautens
Davenport Laboratories, Department of Chemistry
University of Toronto
80 St. George Street, Toronto, ON, M5S 3H6 (Canada)
E-mail: mlautens@chem.utoronto.ca
[
**] The authors thank the Natural Sciences and Engineering Research
Council (NSERC), the University of Toronto, and Alphora Research
Inc for financial support. We thank NSERC/Merck for an Industrial
Research Chair (2003–2013) and the Canada Council for the Arts for
a Killam Fellowship. L.Z. thanks Ontario Graduate Scholarship for
funding. L.S. thanks the University of Genova and Prof. Andrea
Basso (University of Genova) for a research fellowship. We thank J.
Tsoung for helpful discussions.
Our initial study on the conjugate addition of phenyl-
I
boronic acid to acrylamide 1a with a Rh catalyst and
a phosphine ligand such as binap (Table 1, entry 1) did not
give the desired product. Full recovery of the starting
acrylamide was observed. The halogen substituent seemed
to have a profound effect by hindering the reaction when
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407400.
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[
a]
Table 1: Reaction Optimization.
ligand interference. Consequently we screened
a number of diene ligands in this dual metal catalysis.
[11]
The use of diene ligands developed by Genet,
[9]
[12]
Carreira, and Lam
(Table 1, entries 4–6) did
not afford the desired reactivity. L1 and L3 did not
confer enantioselectivity and the reaction stalled at
[
c]
Entry
Rh/L
Pd/L
Base
Yield [%]
a/3a
ee [%] the intermediate 2a with the use of L2. However, the
[
13]
2
(3a)
use of ligand L4 developed by Hayashi afforded
the desired product in 24% yield with an excellent
ee value of 95% (Table 1, entry 7). Significant
improvement in the yield was observed as the Rh/
L4 loading was increased to 8 mol% and KOH was
used as base (Table 1, entry 8). The use of the
Buchwald palladacycle L6-Pd-G1 as the amidation
catalyst further simplified the reaction protocol. We
realized that the use of KOH and MeOH in the
reaction conditions may hydrolyze the naphthyl ester
on the diene ligand L4, thereby stifling the conjugate
1
2
3
4
5
6
7
[Rh(cod)Cl] /binap
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(C H ) Cl] /L1
[Rh(C H ) Cl] /L2
[Rh(C H ) Cl] /L3
[Rh(C H ) Cl] /L4
[Rh(L4) Cl]2
–
–
K3PO4
K3PO4
K3PO4
0/–
–
–
–
0
–
0
95
95
95
95
2
99/–
0/99
0/76
22/0
0/16
0/24
0/63
0/68
0/89
[Pd(allyl)Cl] /L6
[Pd(allyl)Cl] /L6
[Pd(allyl)Cl] /L6
[Pd(allyl)Cl] /L6
2
2
4
2
2
2
K3PO
4
K3PO4
2
4
2
2
2
K3PO4
K3PO4
KOH
KOH
KOH
2
4
2
2
2
[Pd(allyl)Cl] /L6
2
4
2
2
2
[
b,c]
c]
8
9
1
L6-Pd-G1
L6-Pd-G1
L6-Pd-G1
2
[
[Rh(L5) Cl]2
[Rh(L5) Cl]2
2
[
d]
0
2
[
a] Representative reaction conditions: [Rh], [Pd], and respective ligands were added
to a 2-dram vial under Ar atmosphere and subsequently 1a, phenylboronic acid, and arylation. Substitution of the naphthyl to a mesityl
base (2.2 equiv) were added. The solvent was added to the vial, and the mixture was group would withstand the hydrolytic conditions.
stirred for 5 min at room temperature prior to heating at 1108C for 18 h. Yields were
Consequently, the use of Rh/L5 in lowered catalytic
1
determined by H NMR spectroscopy. [b] 8 mol% [Rh] was used. [c] 3.5 equiv KOH
loadings (5 mol%) still conferred a suitable yield and
was used. [d] 2.5 equiv phenylboronic acid was used. Yields of isolated products are
an excellent ee value (Table 1, entry 9). An increase
given. t-am-OH=2-methyl-2-butanol.
in the equivalents of the arylboronic acid gave an
excellent yield of 89% with 95% ee, exemplifying
the efficiency of the time-resolved domino-catalysis
sequence. To verify that the catalysts in the domino
sequence indeed operate in an independent manner,
we performed the individual steps separately. The
Rh-catalyzed conjugate addition was highly enantio-
selective, and no erosion of optical purity was
observed in the subsequent Pd-catalyzed amida-
[
14]
tion. Comparing the optical rotation of the prod-
[8,9]
uct to the literature,
we were able to assign the
absolute configuration of the carbon atom bearing
the phenyl group as (S).
To explore the reaction scope of the developed
Rh/Pd domino catalysis, we examined a variety of
arylboronic acids (Table 2). In general, the number of
equivalents of the substituted arylboronic acids was increased
to three to achieve consistent and improved yields. The
reaction exhibited good to high yields and enantioselectivity.
While electron-rich (Table 2, entries 3–8) and electron-poor
(entries 12–14) arylboronic acids are tolerated in the reaction,
substitution at the 3 position resulted in poorer reactivity
(Table 2, entries 4 and 13). Functionalized nucleophiles such
as thioether and fluorine-containing arylboronic acids
(Table 2, entries 6, 11, 12, and 14–16) can be readily
employed.
[
4n]
phosphine ligands were used. However, excellent reactivity
was observed once binap was omitted, and the reaction
reached completion within 30 min (Table 1, entry 2). The
conjugate addition delivers an amide that can participate in
a Buchwald–Hartwig amidation, which was readily achieved
with a Pd catalyst and the biaryl phosphine ligand XPhos (L6)
over a period of 16 h.
Because of the minimal interference of L6 with Rh in the
conjugate addition, the combination of L6, Pd, and Rh can be
used concurrently, accessing the dihydroquinolinone in
a highly efficient manner in a single operation (Table 1,
entry 3). The time resolution of the reaction sequence renders
high control over undesired reaction pathways. In particular,
the fast consumption of the phenylboronic acid minimized the
The reaction also tolerated substituents on the acryla-
mides (Scheme 2). A variety of these acrylamides can be
accessed reliably in a straightforward manner (see the
Supporting Information). Both electron-donating (3b–3d)
[
10]
Pd-catalyzed Suzuki–Miyaura cross-coupling of 1a.
As
1
cyclooctadiene was a suitable ligand for Rh in the dual
catalysis, we sought to develop the enantioselective Rh-
catalyzed conjugate arylation using chiral diene ligands. The
abundance of diene ligands in Rh catalysis and the predom-
inant use of phosphine ligands in Pd catalysis offer ortho-
and electron-withdrawing (3e–3g) groups (R ) on the aryla-
crylamide had a favourable effect, and high yields and
enantioselectivities were achieved. Heterocyclic lactam deriv-
atives can also be accessed with thiophenyl and indolyl
acrylamides with an increased Rh loading (3g–3i). While the
observed deterioration in the enantioselectivity of the con-
I
0
gonality in ligand association and minimize the ligand–metal–
2
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[
a]
Table 2: Reaction scope of arylboronic acids.
jugate addition for the thiophenyl acrylamide 3ha may be an
effect of the proximal sulfur atom, the use of an electron-rich
arylboronic acid can result in good yield and enantioselectiv-
ity (3hb). The indolyl acrylamide (3i) also exhibited poorer
reactivity at the conjugate addition step, and the formation of
by-products was noted. Nevertheless the “all-in-one” process
can give a modest yield with a high enantioselectivity.
N-Substituted acrylamides also can participate in the
reaction (3k–3m). While N-phenyl-substituted products (3m)
can be accessed with L6, substrates with other N substituents
Entry
R
Product
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
3-Me
4-Me
4-tBu
3-OMe
4-OMe
3,4-(OMe)2
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
89
88
76
56
80
80
78
70
75
72
48
61
46
94
98
96
92
96
95
94
92
95
96
92
94
82
(3j–l), including alkyl, react less readily. Switching the Pd
catalyst and the ligand to [Pd(allyl)Cl] and L7 (Brettphos),
2
modest yields were achieved while the high enantioselectivity
was retained. The ability to pair the Rh-catalyzed conjugate
addition with a number of Buchwald–Hartwig catalysts and
ligands to tailor specific reactivity demonstrates the flexibility
of the “two-catalyst” strategy.
3,4,5-(OMe)3
4-Ph
2-naphthyl
4-SMe
4-Ac
4-F
3-CF3
1
1
1
1
0
1
2
3
Further functionalization of the useful quinolinone scaf-
folds have already been demonstrated, including Friedel–
[15a]
[15b]
[8]
Crafts reaction,
amination,
and alkylation. For exam-
ple, Beak established an efficient synthesis of 3,4-disubsti-
tuted tetrahydroquinolines in a stereoselective manner in two
[
8]
steps.
In summary, we have developed a versatile “two-catalyst-
two-ligand” system, in which one ligand is chiral and the other
is achiral, that enables the direct and efficient access to chiral
dihydroquinolinone scaffolds in a single step. Selecting
ligands that demonstrate orthogonal catalyst association
behavior and the faster rate of the Rh-catalyzed enantiose-
lective conjugate addition versus Pd-catalyzed amidation
confer time resolution that gives a high degree of control on
the sequence of reactivity.
Received: July 19, 2014
Revised: August 9, 2014
Published online: && &&, &&&&
Keywords: asymmetric catalysis · domino reactions ·
.
heterocycles · palladium · rhodium
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0
2
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2
was used instead of L6-Pd-GI.
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Multicatalytic Reactions
L. Zhang, Z. Qureshi, L. Sonaglia,
M. Lautens*
&&&& — &&&&
Sequential Rhodium/Palladium
Catalysis: Enantioselective Formation of
Dihydroquinolinones in the Presence of
Achiral and Chiral Ligands
Compatible combinations of achiral and
chiral ligands and sequential rhodium/
palladium catalysis enabled highly enan-
tioselective domino reactions. The differ-
ence in rates of catalysis and minimal
ligand interference confer control in the
domino sequence. The sequential 1,4-
conjugate arylation and CÀN cross-cou-
pling provide access to enantioenriched
dihydroquinolinone building blocks.
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www.angewandte.org
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