Combined oxypalladation/C-H functionalization: Palladium(II)-catalyzed intramolecular oxidative oxyarylation of hydroxyalkenes

Article abstract of DOI:10.1002/anie.201108129

An efficient protocol has been developed for the intramolecular oxidative oxyarylation using a Pd^II-catalyzed tandem oxypalladation/C-H functionalization strategy. This methodology allows rapid access to tetrahydro-2H-indeno-[2,1-b]furan framew

Full text of DOI:10.1002/anie.201108129

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Angewandte
Communications
DOI: 10.1002/anie.201108129
À
C H Functionalization
À
Combined Oxypalladation/C H Functionalization: Palladium(II)-
Catalyzed Intramolecular Oxidative Oxyarylation of
Hydroxyalkenes**
Rong Zhu and Stephen L. Buchwald*
Originating from the classic Wacker process,[1] the palladiu-
m(II)-catalyzed oxidative difunctionalization of alkenes has
emerged as an attractive strategy for the rapid generation of
molecular complexity due to its ability to form multiple
carbon–carbon/carbon–heteroatom bonds and stereogenic
centers in a single step.[2–4] This versatility, combined with
the broad functional-group compatibility and air- and mois-
ture-tolerance, renders the PdII-catalyzed oxidative difunc-
tionalization a powerful tool for synthetic chemists. One of
the most synthetically relevant transformations of this class is
the PdII-catalyzed oxidative carboetherification of hydroxy-
alkenes, which leads to a variety of interesting oxygenated
heterocycles.[5] Pioneered by Semmelhack,[6] the oxidative
carboetherification in the presence of CO or electronically
biased olefins has been developed with wide application to
complex-molecule synthesis.[7] Mechanistically such reactions
are believed to proceed through a b-alkoxy-alkylpalladi-
um(II) intermediate 1 generated from nucleophilic oxypalla-
dation (Scheme 1). Compared to the more often reported
carbon–heteroatom bond forming processes, the scope of
oxidative carbon–carbon bond formation from 1 is still
limited.[8] It is both synthetically and mechanistically inter-
esting to expand the scope of this type of transformation in
order to access more structurally diverse molecules.
Aiming to develop a viable method for the catalytic
oxidative oxypalladation/arylation of unactivated hydroxyal-
kenes, we were inspired by the recent development in the
II
À
À
field of Pd -catalyzed directed arene C H activation/C C
bond formation.[9] Noting that 1 could undergo cyclopallada-
tion with a proximate arene ring under similar conditions
(Scheme 1), we envisioned the possibility of merging the two
PdII-catalyzed transformations, namely the oxypalladation
À
À
and C H activation/C C bond formation.
The success of this strategy lies in the identification of a
À
catalytic system efficient for both the oxypalladation and C
H functionalization steps, as well as the ability to avoid
oxidation of the alcohol functional group.[10] Herein we report
a simple and mild PdII-catalyzed method for the efficient
construction of the tetrahydro-2H-indeno-[2,1-b]furan frame-
work from acyclic hydroxyalkenes bearing unactivated
arenes.
We began our study by subjecting 4-methyl-3-phenylpent-
4-en-1-ol (2a) to a catalytic amount of palladium acetate and
a
variety of different stoichiometric oxidants. Several
Table 1: Representative optimization of the reaction conditions.[a]
Entry
Ligand
(x mol%)
Oxidant
(y equiv)
Yield
[%][b]
1
2
3
4
5
6
7
8
none
none
none
none
CuCl2 (2)
<5
18
<5
22
66
13
5
71
82
88
<5
89
Scheme 1. Scope of the PdII/Pd0-catalyzed oxidative carboetherification.
AgOAc (2)
PhI(OAc)2 (2)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
pyridine (20)
2,2’-bipyridyl (10)
1,10-phen (10)
3-cyanopyridine (20)
4-DMAP (20)
ethyl nicotinate (20)
ethyl nicotinate (20)
ethyl nicotinate (6)
[*] R. Zhu, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490, Massachusetts Institute of
Technology, Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
9
[**] We thank the National Institutes of Health (GM46059) for financial
support of this project. The Varian 400 MHz NMR spectrometer
used in this work was supported by grants from the National
Institutes of Health (1S10RR13886-01). We thank the National
Science Foundation for departmental X-ray diffraction instrumen-
tation (CHE-0946721).
10
11[c]
12
[a] Reaction conditions: Pd(OAc)2 (5 mol%), ligand (x mol%), oxidant
(y equiv), K2CO3 (0.5 equiv), 2a (0.1 mmol), toluene (1 mL), 1008C,
19 h. [b] GC yield using dodecane as an internal standard. [c] Without
Pd(OAc)2.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108129.
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Chemie
II
À
common combinations for Pd -catalyzed oxidative C H
activations such as PdII/CuII, PdII/AgI, and PdII/PhI(OAc)2
were shown to be ineffective for this transformation
(Table 1, entries 1–3).[8,11] Simple Pd(OAc)2/pyridine/O2
(1 atm) system,[12] however, was able to efficiently catalyze
the desired transformation, affording 3a in moderate yield
(entry 5). The use of bidentate pyridine-based ligands were
found to significantly retard the reaction (entries 6 and 7).[13]
Tuning the substituents on the pyridine ligand (entries 8–10)
led to the identification of ethyl nicotinate[14] as the optimal
ligand. The ligand loading could also be lowered to 6 mol%
without loss of yield (entry 12).
A variety of a-aryl-g-hydroxyalkenes could be cyclized to
the corresponding tetrahydro-2H-indeno-[2,1-b]furan deriva-
tives using this PdII-catalyzed intramolecular tandem oxy-
À
palladation/C H activation protocol. Illustrative examples of
the reaction scope are shown in Table 2. Both alkyl and aryl
substituents on the carbon–carbon double bond were toler-
ated (3b, 3c), as well as tertiary alcohol nucleophile (3d).[15]
In addition, a wide range of electron-rich, -neutral and
À
-deficient arenes were found to participate in the C H
activation process (3e–h, 3j). An aryl bromide-containing
substrate afforded the desired product (3i) in modest yield,
although additional quantities of copper(II) chloride proved
to be necessary,[16] this observed orthogonal reactivity relative
to the Pd0-catalyzed cross-coupling chemistry is useful for the
further elaboration of the arene ring. A meta-substituted
arene (entry 10) cyclized to give a 3:1 mixture of regioisomers
Table 2: PdII-catalyzed oxidative oxyarylation of hydroxyalkenes.[a]
À
favoring the cleavage of the less hindered C H bond (3j, 3j’).
Finally it was found that a pyridyl group could also participate
À
in the C H activation process with functionalization solely at
the 4-position (3k).
Lactone 4 can be accessed by one-step oxidation of the
oxyarylation adduct 3a [Equation (1)]. The relative config-
uration of 4 was confirmed by X-ray diffraction. Lactone 4 is
also structurally related to a class of sulindac-derived
biologically active molecules which have been used for
“precancerous treatment.”[17]
To gain an insight into the reaction mechanism, deuterium
labeling experiments were performed. The observed kinetic
isotope effect for both intermolecular and intramolecular
cases were found to be approximately 2 (Figure 1).[18] This
Figure 1. Observed kinetic isotope effect.
observation is consistent with a reaction mechanism in which
À
irreversible C H bond cleavage is rate-limiting. Next, treat-
ing 2a with palladium acetate under an argon atmosphere in
the presence of ethyl nicotinate also afforded cyclization
product 3a (Scheme 2). The formation of 3a in the absence of
external re-oxidant is consistent with the PdII/Pd0 catalytic
cycle depicted in Scheme 1.
[a] Reaction conditions: Pd(OAc)2 (5 mol%), ligand (x mol%), oxidant
(y equiv), K2CO3 (0.5 equiv), 2a (0.1 mmol), toluene (1 mL), 1008C,
19 h. [b] GC yield using dodecane as an internal standard. [c] Without
Pd(OAc)2.[a] Reaction conditions: Pd(OAc)2 (5 mol%), ethyl nicotinate
(6 mol%), O2 (1 atm), K2CO3 (0.5 equiv), 2 (0.5 mmol), toluene (5 mL),
1008C, 19 h. [b] Yields of isolated products, average of two runs. [c] With
5 mol% CuCl2 as co-oxidant and 30 mol% ethyl nicotinate. [d] Ratio
One of the most interesting aspects of the PdII-catalyzed
oxidative process is its orthogonal reactivity compared with
Pd0-catalyzed transformations (Scheme 3). Treating hydroxy-
1
determined by H NMR spectroscopy.
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Communications
of silica gel and concentrated in vacuo. The residue was purified by
silica gel flash column chromatography (EtOAc/hexane) to afford the
cyclization product.
Received: November 18, 2011
Published online: January 11, 2012
Scheme 2. Oxyarylation in the absence of external oxidant.
À
Keywords: C H activation · heterocyclic compounds ·
homogeneous catalysis · palladium · synthetic methods
.
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À
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II
À
the desired Pd -catalyzed oxypalladation/C H functionaliza-
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In conclusion, we have developed an efficient protocol for
the intramolecular oxidative oxyarylation of hydroxyalkenes
II
À
by using a Pd -catalyzed tandem oxypalladation/C H func-
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to tetrahydro-2H-indeno-[2,1-b]furan framework from simple
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Experimental Section
An oven-dried 50 mL Schlenk tube equipped with a Teflon-coated
magnetic stir bar was charged with palladium acetate (5.6 mg,
0.05 equiv) and potassium carbonate (34.5 mg, 0.5 equiv). The tube
was then briefly evacuated and backfilled with oxygen (this sequence
was repeated a total of four times). Ethyl nicotinate (4.5 mg,
0.06 equiv) and hydroxyalkene (0.50 mmol, 1.0 equiv) were added
to the tube followed by anhydrous toluene (5.0 mL) through a
syringe. The sealed tube was placed in a pre-heated 1008C oil bath.
After stirring at the same temperature for 19 h the mixture was
allowed to cool to room temperature. Diethyl ether (5 mL), methanol
(0.25 mL), and sodium borohydride (9.5 mg, 0.5 equiv) were then
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