Synthesis of chromanones: A novel palladium-catalyzed Wacker-type oxidative cyclization involving 1,5-hydride alkyl to palladium migration

Article abstract of DOI:10.1039/b711613f

A series of 2-methylchromanone derivatives have been prepared by using a novel palladium-catalyzed Wacker-type oxidative cyclization, in which a 1,5-hydride alkyl to palladium migration and a direct chirality transfer were involved. The Royal Society of Chemistry.

Full text of DOI:10.1039/b711613f

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Synthesis of chromanones: a novel palladium-catalyzed Wacker-type
oxidative cyclization involving 1,5-hydride alkyl to palladium
migration{
Zuhui Zhang, Chongfeng Pan and Zhiyong Wang*
Received (in Cambridge, UK) 30th July 2007, Accepted 20th August 2007
First published as an Advance Article on the web 29th August 2007
DOI: 10.1039/b711613f
an atmosphere of oxygen (1 atm)10 in EtOH–H2O (2 : 1) at 35 uC
A series of 2-methylchromanone derivatives have been pre-
resulted in an oxidative cyclization and the generation of 2a with a
yield of 67% (Table 1, entry 1).{ Under this mild condition, we
examined the scope and the generality of the transformation. As
can be seen from the results in Table 1, electron-donating groups
on the phenyl ring of 1 favored the reaction and the corresponding
chromanones 2 were obtained with good yields (entries 2–7) and
weak electron-withdrawing groups had little influence on the
cyclization (entries 8 and 9). On the other hand, a strong electron-
withdrawing group on the phenyl ring retarded the reaction
(entry 10), perhaps due to that the substituent group weakened the
nucleophilicity of the hydroxyl. Even 1k, which bears a C–Br bond
and is sensitive to palladium catalyst, gave the desired product with
moderate yield. Moreover, hydroxyl groups and carbon–carbon
double bonds, which can be oxidized by palladium(II) complexes,
survived in the reaction (entries 12 and 13).
pared by using a novel palladium-catalyzed Wacker-type
oxidative cyclization, in which a 1,5-hydride alkyl to palladium
migration and a direct chirality transfer were involved.
Chromanones are widely distributed in many natural products1
and have many biologic activity such as anti-HIV-1 activity.2 The
construction of these compounds have attracted much attention in
the synthetic community over the last few decades. Previously, the
conventional methods for the building of chromanones mainly
included: (a) oxo-Michael addition of o-tiglolylphenol,3 (b)
cyclization of the corresponding chromene with paraldehyde in
the presence of special base,2c (c) intramolecular Friedel–Crafts
reaction of 4-arylbutyric acid at high temperature (180 uC),4 (d)
selective reduction of chromone by calcium metal in liquid
ammonia,5 (e) oxidation of the corresponding alcohol,6 and (f)
gold catalyzed annulation of salicylaldehydes and aryl acetylenes at
150 uC for 36 h.7 However, most of these reactions are limited by
either complex starting materials or rigorous reaction conditions.
Palladium-catalyzed Wacker-type oxidative cyclization is one of
the most important processes in the synthesis of heterocycles.8 In
this communication, we report a novel palladium(II) catalyzed
Wacker-type oxidative cyclization to the synthesis of 2-methyl-
Table 1 Palladium(II)-catalyzed Wacker-type cyclizationa
chromanones
2 from easily obtained starting materials 1
(Scheme 1).9 We also describe the preliminary mechanistic
considerations for the reaction, which suggests this transformation
via an unusual 1,5-hydride alkyl to palladium migration.
Entry
Reagent
X
Y
Yield of 2b (%)
After the optimization of the reaction conditions (see ESI{), we
were delighted to find that the treatment of 1a with catalytic
Pd(OAc)2 (10 mol%) and potassium carbonate (1.2 equiv.) under
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
H
H
H
MeO
Me
Me3C
Cl
H
H
H
67
80
72
70
76
83
71
70
64
42
43
65
MeO
Me3C
Me
H
H
Me3C
H
Cl
MeCO
Br
9
10
11
12
1j
1k
1l
H
H
Scheme 1 Wacker-type oxidative cyclization of 1a.
Hefei National Laboratory for Physical Science at Microscale and
Department of Chemistry, University of Science and Technology of
China, Hefei, 230026, P. R. China. E-mail: zwang3@ustc.edu.cn;
Fax: (+86) 551-360-3185; Tel: (+86) 551-360-3185
13
1m
H
61
{ Electronic supplementary information (ESI) available: Synthesis of
substances, optimization of the reaction conditions, determination of the
absolute stereochemistry and enantiomeric excess of 1a and 2a, proposed
mechanism for pathway B and characterization data for the products. See
DOI: 10.1039/b711613f
a
b
Reaction conditions: 0.1 M of 1 in EtOH–H2O (2 : 1). Isolated
yield.
4686 | Chem. Commun., 2007, 4686–4688
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Scheme 2 Chirality transfer experiment of cyclization.
As the (+)- and (2)-chromanone derivatives have different anti-
HIV activities,2c the asymmetric synthesis of 2-methylchromones
become more valuable. We wonder whether enantioenriched 2a
could be obtained from enantioenriched 1a directly through
chirality transfer process.11 We were delighted to find that
enantioenriched (S)-1a or (R)-1a afforded enantioenriched (S)-2a
or (R)-2a, respectively, under our conditions with excellent chirality
transfer (Scheme 2). With this result in hand, it is reasonable to
believe that enantioenriched chromanone derivatives can be
realized under such mild conditions with enantioenriched starting
materials.
Afterwards, the reaction mechanism was investigated. Initially,
we envisioned the mechanism of this Wacker-type cyclization
involving b-hydride elimination/hydropalladation sequences. To
test this, a deuterium labeling experiment was designed and
performed (Scheme 3).12 To our surprise, when deuterium
substrate 1a-d was subjected to the standard reaction conditions,
it was found that deuterium was transferred from C-1 in 1a-d to
C-4 in 2a-d exclusively. This result can not be explained by the
b-hydride elimination/hydropalladation sequences. A new mechan-
ism was thus proposed on the basis of the deuterium labeling
experiment. As shown in Scheme 4, (S)-1a-d was employed as an
example to clarify the reaction process. We assumed that the
hydrogen bond between hydroxyl of (S)-1a-d and solvent would
inhibit the complexation of olefin with Pd(II) from the ‘‘hydroxyl-
face’’ but form a complex with the opposite face to form (S)-F-d.
When protic solvent was replaced with an aprotic solvent,
experimentally, a trace amount of the corresponding product
was obtained (see ESI{), which supported our assumption.
Afterwards, the palladium–oxygen bond undergoing syn-oxypal-
ladation in (S)-F-d affords (S)-G-d, which is well recognized by
deuterium-labeling studies.12a,b Then (S)-G-d gives rise to the
corresponding chromanone derivative via pathway A or B. If
followed by b-hydride elimination as outlined in pathway B, either
(R)-2a without deuterium or (R)-2a-d with deuterium at C-2,
would be generated after several rearrangements (for details of the
proposed mechanism for this pathway, see ESI{). Actually, these
products was not observed in the reaction. Another process is
feasible as described in pathway A. The palladium in (S)-G-d can
come close to the Si-face deuterium at C-1 and catches this
deuterium to form (S)-H-d. The resulting carbocation is efficiently
Scheme 4 Proposed mechanism for the Wacker-type cyclization of
(S)-1a-d involving 1,5-palladium migration.
stabilized by the hydroxy group. Then the deprotonation of (S)-H-
d produces (S)-I-d. Following reductive eliminations of deuterium
and the alkyl group from palladium leads to (S)-2a-d. Overall,
palladium at C-1 acts as a bridge which transfers a hydrogen atom
from C-1 to C-4. In this transformation, the b-hydride elimination
was suppressed absolutely by 1,5-hydride alkyl to palladium
migration. To the best of our knowledge, this is the first time of a
report of intramolecular 1,5-hydride alkyl to palladium migration.
This mechanism is also in full agreement with the chirality transfer
since the same configurations of C-1 in starting materials and C-3
in products implied an occurrence of Si-migration of the deuterium
from C-1 to C-4 via a palladium bridge.
To further support this proposed mechanism, 1n as a starting
material without b-H was investigated as shown in Scheme 5. The
cyclized product 2n was obtained in 70% yield under the
conditions. As 1n has no b-H to eliminate, 2n can not be obtained
from pathway B. In contrast, its formation can be explained by
pathway A. This result also supports the 1,5-hydride shift and
excludes the b-H elimination process.
In conclusion, we have developed a palladium(II)-catalyzed
Wacker-type oxidative cyclization for the synthesis of 2-methyl-
chromanones from readily available starting materials under mild
Scheme 3 Deuterium labelling experiment of Wacker-type cyclization.
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a novel
1,5-hydride alkyl to palladium migration. Work is currently being
undertaken to better understand the migration and extend the
scope of the reaction.
This work was supported by the National Natural Science
Foundation of China (20472078 and 30572234).
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Notes and references
{ Representative procedure for Wacker-type cyclization: To a solution of 1a
(1 mmol, 164 mg) in 6.6 mL of EtOH and 3.3 mL of H2O was added
K2CO3 (1.2 mmol, 166 mg) and Pd(OAc)2 (0.1 mmol, 22.4 mg). After the
mixture was heated at 35 uC under an atmosphere of oxygen (1 atm) for
24 h, the ethanol was removed by reduced pressure and the residue was
extracted three times with ethyl acetate. The combined organic extracts
were dried using anhydrous Na2SO4 and evaporated under reduced
pressure; the mixture was then purified by column chromatography over
silica gel to afford product 2a with high purity. 1H NMR (CDCl3,
300 MHz, ppm): d 7.88 (dd, J = 7.8 Hz, 1.5 Hz, 1 H), 7.50–7.44 (m, 1 H),
7.03–6.95 (m, 2 H), 4.63–4.56 (m, 1 H), 2.68 (d, J = 7.8 Hz, 2 H), 1.52 (d,
J = 6.3 Hz, 3 H). 13C NMR (CDCl3, 75 MHz, ppm): d 192.5, 161.7, 136.0,
127.0, 121.2, 120.9, 117.9, 74.3, 44.6, 21.0. IR (KBr film, cm21): n = 2926,
1695, 1609, 1464, 1385, 1308, 1230, 1122, 1036, 949, 764, 569. HRMS: calc.
C10H10O2 (M+): 162.0681, found: 162.0703.
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4688 | Chem. Commun., 2007, 4686–4688
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