Cationic palladium complex catalyzed highly enantioselective intramolecular addition of arylboronic acids to ketones. A convenient synthesis of optically active cycloalkanols

Article abstract of DOI:10.1021/ja0672425

An efficient and convenient synthesis of optically active cycloalkanols by utilizing the chiral cationic palladium complex as the catalyst was achieved in mild conditions with high yield and high enantioselectivity. Copyright

Full text of DOI:10.1021/ja0672425

Published on Web 12/08/2006
Cationic Palladium Complex Catalyzed Highly Enantioselective Intramolecular
Addition of Arylboronic Acids to Ketones. A Convenient Synthesis of
Optically Active Cycloalkanols
Guixia Liu and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received October 9, 2006; E-mail: xylu@mail.sioc.ac.cn
Table 1. Optimization of Asymmetric Reaction Conditions
Enantioselective addition of organometallic reagents to ketones
is a straightforward strategy for the construction of optically active
tertiary alcohols.1 While there are many reports in the enantiose-
lective addition of alkyl or aryl groups to aldehydes,2 fewer catalyst
systems will promote the analogous addition reactions to ketones
owing to its attenuated reactivity.1,3 As to the enantioselective aryla-
tion of ketones, much success has been achieved by using arylzinc
reagents.1,4 However, when considering the availability and stability
of the substrate sources, arylboronic acid is a promising alternative
arylating reagent.1b This makes transition-metal-catalyzed asym-
metric addition of arylboronic acids to ketones useful and attractive,
though successful examples of this type reaction are still rare.5,6
Recently, Hayashi and de Vries independently reported the first
example of Rh-catalyzed asymmetric addition of arylboronic acids
to R-dicarbonyl substrates, isatins.7 To the best of our knowledge,
there have been no reports for the enantioselective addition of
arylboronic acids to simple ketones catalyzed by palladium.8-10
The nonasymmetric arylation of ketones has been achieved in
Pd(0)-catalyzed intramolecular nucleophilic addition of aryl halides
to ketones reported by Yamamoto and others.9 In these reactions,
a Pd(II) species was formed after quenching an oxygen-palladium
bond. It occurred to us that if a Pd(II) complex was used as the
catalyst in this addition reaction, the catalyst system will be
simplified without the use of a redox system.11 Among kinds of
Pd(II) catalysts, cationic Pd(II) complexes have great advantages
over analogous neutral ones mainly in two dimensions: (1) vacant
coordination site for substrates or reagents and (2) stronger Lewis
acidity.12 We describe herein the application of the chiral cationic
palladium complex as a catalyst in the asymmetric intramolecular
addition of arylboronic acids to ketones (eq 1) for the highly
enantioselective synthesis of cycloalkanols.
entry
additive (equiv)
time (h)
yielda/eeb (%/%)
1c
K3PO4 (2), H2O (2)
K3PO4 (2), H2O (2)
K3PO4 (0.5)
1
1
2
1
2
89/7
2d
3d
4d
5d
6d,e
77/ 28
83/51
49/85
85/82
85/92
None
Amberlite IRA-400 (OH) (1.5)
Amberlite IRA-400 (OH) (1.5)
12
a Isolated yield. b Determined by HPLC analysis using a Chiralcel OD
column. c 4a was used as the catalyst. d 4b was used as the catalyst.
e Toluene was used as the solvent and the reaction temperature was 40 °C.
catalyst. However, with the catalysis of 4a under the optimized reac-
tion conditions, 2a was formed in high yield (89%) with extremely
low ee (7%; Table 1, entry 1). When chiral Pd complex 4b was used
instead of 4a, a slight improvement in the ee value was observed
(28%; Table 1, entry 2). Lowering the amount of K3PO4 from 2
equiv to 0.5 equiv led to significant enhancement in enantioselec-
tivity (51%; Table 1, entry 3). Surprisingly, a dramatic improvement
in enantioselectivity was obtained in the absence of a base though
the yield was not satisfied (49% yield, 85% ee; Table 1, entry 4).
These prompted us to seek for a suitable base which may have
enough basicity14 to maintain both high yield and enantioselectivity.
To our delight, while employing anion exchange resin (Amberlite
IRA 400 (OH)) as the additive, we effectively furnished the
cyclization product 2a in good yield with high enantiomeric excess
(85% yield, 82% ee; Table 1, entry 5). The solvent and temperature
effects were also examined. Finally, it turned out that a 4b/Amberlite
IRA-400(OH) combination in toluene at 40 °C provided the best
result (85% yield, 91% ee; Table 1, entry 6).
A variety of substrates16 including various aromatic, heteroaro-
matic, and aliphatic ketones could be used to afford the optically
active tertiary alcohols in good to excellent yield and high
enantioselectivity under very mild conditions (Table 2, entries 1-6).
Substituents on the arylboronic acids did not affect the additon
reaction too much (Table 2, entries 7-9). Derivatives of indan and
chroman could also be formed smoothly in moderate yields and
enantioselectivity. (Table 2, entries 10 and 11). A comparable low
enantioselectivity was observed for the formation of six-membered
ring product (Table 2, entry 11).
A plausible mechanism for the asymmetric arylation of ketones
is shown in Scheme 1. Cationic palladium complex 4b is in
equilibrium with the Pd hydroxo complex A,15c which enable smooth
transmetalation with the substrate. Two features of intermediate A
may account for its feasible transmetalation: the cationic nature of
Initially, we chose cationic palladium complex [Pd(dppp)(H2-
O)2]2+(OTf-)2 (3a)13 as the catalyst to examine the intramolecular
1,2-addition of 1a. Fortunately, upon heating at 80 °C for 1 h in
the presence of 2 equiv of K3PO4, 2 equiv of H2O, and 5 mol % of
3a in dioxane, 1a underwent addition smoothly to afford dihydro-
benzofuranol 2a in high yield (91%).14 No addition product will be
obtained in the absence of palladium catalyst. We then turned our
efforts on the asymmetric version of this addition reaction using the
easily prepared chiral cationic palladium complex 4a and 4b15 as the
9
16504
J. AM. CHEM. SOC. 2006, 128, 16504-16505
10.1021/ja0672425 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Chiral Cationic Palladium Complex 4b Catalyzed
Enantioselective Intramolecular Addition of Arylboronic Acids to
Ketonesa
the detailed mechanism and expanding the intermolecular reactions
are currently underway.
Acknowledgment. We thank the National Natural Sciences
Foundation of China (Grant 20572121) and Chinese Academy of
Sciences for financial Support.
Supporting Information Available: Experimental procedures and
characterization data of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
entry
substrate
product
yield (%)b
ee (%)c
X ) O, n ) 1, R1 ) R2 ) H
1
1a: R ) Ph
2a
85
92
90
86
84
58
92 (-)
91 (-)
87 (-)
93 (-)
84 (-)
96 (-)
2d
3d
4d
5d,f
6
1b: R ) 4-MeOC6H4
1c: R ) 4-ClC6H4
1d: R ) 4-CF3C6H4
1e: R ) 2-furyl
2b
2c
2d
2e
2f
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1k: R1 ) R2 )H
2k
a Unless otherwise indicated, all reactions were performed at 40 °C using
the substrate (0.2 mmol), Amberlite IRA-400 (OH) (1.5 eqiuv), and 4b
(2.5 mol %) in toluene (2 mL) under N2. b Isolated yield. c Determined by
HPLC analysis using a Chiralcel OD column. The sign of optical rotation
was indicated in parentheses. d Using toluene/dioxane (1:1) as solvent.
e Using toluene/DCE (1:1) as solvent. f Reaction temperature was 80 °C.
g The absolute configuration was determined to be (R) (see Supporting
Information).
Scheme 1. Plausible Mechanism for the Enantioselective
Intramolecular Addition of Arylboronic Acids to Ketones Catalyzed
by a Cationic Pd(II) Complex 4b
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metalation (step I), arylpalladium species B undergoes intramo-
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C, which upon hydrolysis (step III) forms product 2a and regen-
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group by coordination making the addition reactions easy to occur.12
It is also proposed that this coordinated intermediate B is helpful
to the enantioface discrimination of ketones resulting in high ee
values.1a When the reaction is carried out in the presence of a
coordinative solvent such as MeOH, or DMF, a competitive inter-
mediate D, which is more conformationally flexible, will produce
the low ee value. These results indicate the dual role of the cationic
palladium complex in the catalytic cycle: it acts as the transition
metal in step I and plays the role of Lewis acid in step II.18
In summary, a highly enantioselective synthesis of optically
active cycloalkanols by utilizing the chiral cationic palladium
complex 4b as catalyst was achieved. Further studies on probing
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(16) The substrates were easily synthesized by trapping the corresponding
arylmetal intermediates with borates (see Supporting Information).
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