Enantioselective α-arylation of cyclic ketones catalyzed by a combination of an unmodified Cinchona alkaloid and a palladium complex

Article abstract of DOI:10.1002/adsc.201100669

A palladium/Cinchona alkaloid-catalyzed α-arylation between cyclic ketones and aryl halides under phosphine-free conditions is presented. The use of a simple, unmodified Cinchona alkaloid results in high levels of activity and selectivity with up to 93% ee. These enantioinduction levels are comparable or even higher than the ones reported using palladium/BINAP complexes. To the best of our knowledge, this represents the first use of unmodified Cinchona alkaloids as ligands/catalysts in asymmetric transition metal complex-catalyzed cross-coupling reactions. Copyright

Full text of DOI:10.1002/adsc.201100669

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DOI: 10.1002/adsc.201100669
Enantioselective a-Arylation of Cyclic Ketones Catalyzed by
a Combination of an Unmodified Cinchona Alkaloid and a
Palladium Complex
Christian Richter,a Kalluri V. S. Ranganath,a and Frank Gloriusa,*
a
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster, Organisch-Chemisches Institut, Corrensstraße 40, 48149 Mꢁnster, Germany
Fax : (+49) 251-83-33202; e-mail: glorius@uni-muenster.de
Received: August 24, 2011; Revised: October 20, 2011; Published online: January 20, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100669.
Abstract: A palladium/Cinchona alkaloid-catalyzed
a-arylation between cyclic ketones and aryl halides
under phosphine-free conditions is presented. The
use of a simple, unmodified Cinchona alkaloid re-
sults in high levels of activity and selectivity with up
to 93% ee. These enantioinduction levels are com-
parable or even higher than the ones reported using
palladium/BINAP complexes. To the best of our
knowledge, this represents the first use of unmodi-
fied Cinchona alkaloids as ligands/catalysts in asym-
metric transition metal complex-catalyzed cross-
coupling reactions.
like ready availability, high levels of rigidity, robust-
ness and multifunctional nature render Cinchona al-
kaloids especially valuable.[6] However, whereas un-
modified Cinchona alkaloids have found prominent
applications as chiral modifiers of heterogeneous cat-
alysts,[7,8] only a few studies on Cinchona alkaloids
and their derivatives used as ligands of transition
metal complexes have been reported,[9] except for
asymmetric dihydroxylation and amino hydroxyla-
tions.[10] Herein, we report the asymmetric a-arylation
of ketones using a molecular Pd catalyst in combina-
tion with quinine as a ligand. This represents the first
formation of quarternary stereocenters by asymmetric
À
Keywords: alkaloids; asymmetric catalysis; dual cat-
alysis; enantioselective a-arylation; transition metal
catalysis
C C bond formation using an unmodified Cinchona
alkaloid (Figure 1) as chiral ligand.
We commenced our study with the a-arylation of 2-
methyl-1-tetralone (1) and iodobenzene (2) with
PdACTHNUTRGEN(UGN OAc)2 and quinine (QN) as the catalyst system.
We were pleased to find that running the reaction in
PhMe at 1008C with NaO-t-Bu as the base furnished
The metal-catalyzed a-arylation of carbonyl com- the corresponding a-arylated product 3 in 81% yield
pounds is an important cross-coupling due to the rele-
vance of the resulting carbonyl products for pharma-
ceutical and biological applications.[1] The intermolec-
ular asymmetric a-arylation is particularly attractive
for the preparation of valuable optically active car-
bonyl compounds, bearing an a-quaternary stereocen-
ter.[2] This reaction has been reported using Pd and Ni
salts in the presence of chiral phosphine ligands,
which are often expensive, toxic and sensitive.[3] In ad-
dition, a chiral heterogeneous catalyst, Pd/Fe3O4
nanoparticles modified by a chiral N-heterocyclic car-
bene (NHC), has been successfully employed in the
asymmetric a-arylation.[4]
In the past 30 years, the naturally occurring Cincho-
na alkaloids have been widely applied by themselves
or as versatile precursors for organocatalysts in asym-
metric synthesis, chromatographic selectors and NMR
discriminating agents.[5] Many attractive properties Figure 1. Structures of the applied Cinchona alkaloids.
Adv. Synth. Catal. 2012, 354, 377 – 382
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377

Christian Richter et al.
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Table 1. Effect of various Pd salts on asymmetric a-arylation
Table 2. Effect of amount of ligand on asymmetric a-aryla-
between 2-methyl-1-tetralone and iodobenzene.[a]
tion between 2-methyl-1-tetralone and iodobenzene.[a]
Entry Quinine [mol%] Time [h] Yield [%][b] ee [%][c]
Entry Pd source
Time [h] Yield [%][b] ee [%][c]
1
0
24
3
44
79
85
86
85
78
82
85
87
80
0
2
3
4
1.4
2.5
5.0
7.5
7.5
10.0
50.0
7.5
7.5
65
85
88
92
90
87
90
-89
-86
1
Pd
Pd
Pd
N
3
81
85
80
60
38
75
68
76
87
92
90
3
3
3
3
3
3
3
3
3
2
3
72
3
3[d]
4
5
[PdACHTUNGTRENNUNG
6[d]
7
5
24
3
16
16
77
90
91
93
6
7
8
Pd
Pd
Pd
G
8
G
ACHTUNGTRENNUNG
9[e]
10[f]
[a]
Ketone (0.3 mmol), PhI (0.6 mmol), Pd salt (1.4 mol%),
quinine (7.5 mol%), NaO-t-Bu (2.0 equiv.), toluene
(2.0 mL), 1008C. The absolute configuration was assigned
in analogy to entry 9 of Table 3.
Isolated yields.
The ee was measured using an chiral AD-H column (98:2
hexane:i-PrOH).
[a]
Ketone
(0.3 mmol),
PhI
(0.6 mmol),
PdACHTUNGTRENNUNG(dba)2
(1.4 mol%), quinine, NaO-t-Bu (2.0 equiv.), toluene
(2.0 mL), 1008C. The absolute configuration was assigned
in analogy to entry 9 of Table 3. Negative ee values indi-
cate the predominant formation of an R-configured prod-
uct.
Isolated yields.
The ee was measured using a chiral AD-H column (98:2
hexane:i-PrOH).
[b]
[c]
[b]
[c]
[d]
Heated at 608C.
[d]
[e]
[f]
Heated at 1508C.
Quinidine was used instead of quinine.
Cinchonine was used instead of quinine.
and a pronounced ee of 87% (Table 1, entry 1). Al-
though screening of different Pd sources resulted in
up to 93% ee, Pd
activity and selectivity with 92% ee and 85% yield
after 3 h. Naturally, no reaction was observed in the with only slightly lower ee (entry 9). A similar result
ACHTUNGERTN(NUNG dba)2 gave the best combination of
absence of palladium.
was obtained with cinchonine (entry 10).
In order to better understand the role of the Cin-
A survey of different solvents and bases revealed
chona ligand, the reaction was also carried out with- that toluene and NaO-t-Bu are a superior combina-
out any chiral ligand [Pd(dba)2 only]; this reaction tion. Employing weaker inorganic bases such as
AHCTUNGTRENNUNG
furnished the expected a-arylated product in 42% K3PO4 resulted in no product formation. The yield
yield (obviously, in racemic form) along with a signifi- and ee decreased in other solvents like THF and 1,4-
cant number of by-products like 2-methylnaphthol, dioxane (see the Supporting Information).
homocoupling products of both starting materials and
In order to test the effectiveness of the Pd/quinine-
aldol-type products (Table 2). The 7.5 mol% of qui- catalyzed arylation reaction, various aryl iodides and
nine used initially in our study were found to be opti- bromides were examined under the optimized condi-
mal in terms of selectivity and reactivity. Increasing tions in the presence of quinine. The meta- and para-
the amount of alkaloid to 50 mol% did not improve substituted aryl iodides showed good yields and good
the enantioselectivity and lowering it to 2.5 mol% re- to very good ees. However, reactivity was lower with
sulted in a significantly lower ee (Table 2). The effect bromides compared to aryl iodides in the arylation of
of temperature on the enantioselectivity of the reac- 2-methyl-1-tetralone in combination with PdACHTUNGTRENNUNG(dba)2
tion was also investigated. Interestingly, the ee only and quinine (Table 3, entry 2). There was no reaction
slightly decreased as the temperature was raised to with unactivated chloroarenes under the optimized
1508C, showing the remarkable thermal robustness of reaction conditions. Unfortunately, ester and cyano
the enantioinduction. Using twice as much catalyst groups on the aryl halide were not tolerated.
(2.8 mol% of Pd and 15.0% alkaloid) also did not in-
The absolute stereochemistry of 2-methyl-2-(3,4-di-
crease the enantioselectivity of the a-arylated prod- methoxyphenyl)-tetralone (Table 3 entry 9) could be
uct. Finally, when applying the pseudoACTHNUGRTNEUNGenantiomeric determined as (S) by comparison of the optical rota-
Cinchona alkaloid quinidine, as expected the opposite tion with literature data.[3d] It is reasonable to assume
enantiomer of the a-arylation product was formed that all products are formed with the same sense of
enantioinduction.
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Enantioselective a-Arylation of Cyclic Ketones
Table 3. Asymmetric a-arylation of ketones with aryl hal-
In order to better understand the role of quinine,
two derivatives of this alkaloid were prepared: in one
the quinuclidine nitrogen was benzylated (4), in the
other the hydroxy group was methylated (5)
(Figure 2). Then, these modified quinine ligands were
ACHTUNGTRENNUNG
ides.[a]
Entry Ketone
1
Aryl halide
Yield [%][b] ee [%][c]
85
92
2
3
4
5
6
7
8
9
70
79
76
37
72
86
91
57
77
87
89
63
77
83
Figure 2. Quinine and its N-benzylated (4) and O-methylat-
ed (5) derivatives.
83
tested in the arylation reaction between 2-methyl-1-
tetralone and iodobenzene at 1008C in the presence
of base. Interestingly, under standard conditions, the
a-arylated product was formed in 42 and 44% yield,
respectively, and each time only in racemic form. A
similar result was observed when no quinine was
added to the reaction mixture. This clearly indicates
that both functional groups (tertiary quinuclidine N
and hydroxy group) are essential for the proper mode
of action of the quinine in this asymmetric transfor-
mation, and are needed for both activity and selectivi-
ty.
According to the observation that both functional
groups are essential, we envision three fundamentally
different modes of enantioinduction (Figure 3). (A)
The formation of a catalytically active Pd/quinine
complex, where quinine acts as a bidentate ligand.
Such a kind of binding mode, although not in the con-
text of catalysis, was reported by Beck et al.[11] (B)
Quinine acts as a bridge between the Pd complex and
the substrate. A well studied example for the ability
of quinine to bring together two reactants is the Mi-
chael addition of aromatic thiols to cyclohexenones.[12]
Also Pd complexes are known where only the quinu-
clidine nitrogen is binding to the metal.[11] (C) Qui-
nine acts as an organocatalyst, binding non-covalently
to the substrate by formation of H-bonds, p interac-
tions or other weak forces. These interactions could
activate the substrate and shield one side of the car-
70 (S)[d]
10
11
86
83
85
77
12
13
76
74
72
77
58
72
14
[a]
Ketone (0.3 mmol), aryl halide (0.6 mmol), PdACTHNUTRGNEUNG(dba)2
(1.4 mol%), quinine (7.5 mol%), NaO-t-Bu (2.0 equiv.),
toluene (2.0 mL), 1008C; reaction time: aryl iodides 3–
8 h, aryl bromides 16–30 h.
[b]
[c]
Isolated yields.
The ee value was measured using a chiral AD-H column
(98:2 hexane:i-PrOH).
Comparison of the negative sign of optical rotation of
the product of entry 9 with literature data for the same
compound indicates the S-configuration of the product
formed.
[d]
Adv. Synth. Catal. 2012, 354, 377 – 382
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Christian Richter et al.
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Table 4. Asymmetric a-arylation of 2-methyl-1-tetralone cat-
alyzed by the (SIPr)PdACTHNUTRGNEUNG
(allyl)Cl complex.[a]
Entry Quinine
[mol%]
Aryl
halide
Time
[h]
Yield
[%][b]
ee
Figure 3. Possible modes of activation and enantioinduction
by quinine (QN); (S=substrate).
[%][c]
1
2
3
4
0
7.5
0
PhI
PhI
PhCl
PhCl
1.5
4
72
72
48
0
80
0
92
bonyl moiety. This kind of enantioinduction is known
for Cinchona-derived phase-transfer organocata-
lysts.[13]
33[d]
28[d]
7.5
5
[a]
Ketone (0.3 mmol), aryl halide (0.6 mmol), (SIPr)
ACHTUNGTRENNUNGPd-
Considering the different modes from A to C the
number of free coordination sites on the Pd atom is
increasing. In mode A after oxidative addition there
are no free coordination sites available. Therefore a
strongly binding additional ligand on the Pd complex
should suppress or decrease the reactivity, if the reac-
tion is processing via mode A. Mode B should be af-
fected less by blocking a coordination site and mode
C should not be affected at all. Besides their interest-
AHCTUNGTRENNUNG
(2.0 equiv.), toluene (2.0 mL), 1008C, reaction time: aryl
iodides 3–8 h, aryl bromides 16–30 h.
Isolated yields.
The ee value was measured using a chiral AD-H column
(98:2 hexane:i-PrOH).
[b]
[c]
[d]
NMR yield (CH2Br2 as internal standard).
ing electronic and steric properties, NHCs are known was quite low – no full conversion was observed after
to form stable metal-NHC complexes with many three days and reaction seemed to stop after 3 days –
metals, among them Pd.[14] Thus, in order to block and the enantioinduction was minimal at best
active sites on the Pd, the (SIPr)Pd
ACHTUNGTRENNUNG
(6) was prepared, which liberates an active NHC-
Pd(0) species under basic conditions.[15] This complex (replacing the homogeneous Pd complex) and quinine
was subjected as Pd source to our standard conditions as modifier was investigated for the described a-aryla-
(Table 4). Without any addition of quinine the reac- tion, also resulting in an active and selective catalyst
tion proceeded quickly within 90 min and a yield of system (for example, the reaction between 1 and 2
48% was obtained. In the presence of quinine full provided the product in 74% yield and 82% ee).
conversion was observed after 4 h. The slower reac- However, surprisingly, no heterogeneous system re-
tion rate could be caused by the binding of quinine to sulted, as mercury poisoning and filtration test indi-
Pd blocking active sites at the metal complex. Inter- cated a homogeneous nature of the catalytically
estingly, the yield increased to 92% and an ee of 80% active species.[4,18]
was observed, which clearly shows that the addition
In conclusion, we have developed a Pd/Cinchona-
of quinine forms a more chemoselective and enantio- catalyzed a-arylation reaction of cyclic ketones and
selective catalytically active species. The observation aryl bromides and iodides under phosphine-free con-
that the presence of quinine is lowering the reaction ditions. An unmodified Cinchona alkaloid results in
rate while still providing good levels of enantioinduc- high levels of activity and selectivity with up to 93%
tion could be aligned with mode B. The lower ee ob- ee. It is important to note that the enantioinduction
tained with complex 6 than with PdACTHNURGTNEUNG(dba)2 could be levels obtained are comparable or even higher than
explained by a faster racemic background reaction of the ones reported using Pd/BINAP complexes.[3a] To
small amounts of the free NHC-Pd(0) species, as the the best of our knowledge, this represents the first use
reaction rate without quinine is much faster for the of unmodified Cinchona alkaloids as ligands in asym-
NHC-Pd complex than for PdACHTNUTRGNEUNG(dba)2 (Table 4, entry 1 metric transition metal complex-catalyzed cross-cou-
vs. Table 2, entry 1). It must be pointed out that these pling reactions.[17]
experiments are more a hint than proof for mode B.
Since NHC-Pd complexes are known to oxidatively
[14,6]
À
add to C Cl bonds,
we also investigated the use of
(allyl)Cl complex (6).
aryl chlorides using (SIPr)Pd
U
Unfortunately the reactivity with and without quinine
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Adv. Synth. Catal. 2012, 354, 377 – 382

Enantioselective a-Arylation of Cyclic Ketones
Ranganath, F. Glorius, Catal. Sci. Technol. 2011, 1, 13–
22.
Experimental Section
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General Remarks
For detailed experimental procedures, spectral data and
characterization see the Supporting Information.
Typical Experimental Procedure for the a-Arylation
of Ketones with Aryl Halides
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An oven-dried Schlenk flask was charged with PdACTHNUTRGNEUNG(dba)2
(1.4 mol%), quinine (7.5 mol%) and NaO-t-Bu (2.0 equiv.).
Toluene (2 mL), the respective aryl halide (2 equiv.) and
ketone (1 equiv.) were added and the reaction mixture was
heated at 1008C. After completion of the reaction (moni-
tored by GC-MS), the reaction mixture was poured into sa-
turated aqueous NH4Cl (5 mL). The aqueous phase was ex-
tracted with CH2Cl2 (3ꢃ10 mL), the combined organic
phases were dried over MgSO4 and concentrated under
vacuum. Purification of the residue by flash column chroma-
tography provided the respective title compounds.
Acknowledgements
Generous financial support by Alexander von Humboldt
Foundation (KVSR) and the Deutsche Forschungsgemein-
schaft (SFB 858) is gratefully acknowledged. The research of
FG has been supported by the Alfried Krupp Prize for
Young University Teachers of the Alfried Krupp von Bohlen
und Halbach Foundation. We are grateful to Buchler GmbH
for a generous gift of Cinchona alkaloids.
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ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 377 – 382