Ligand-enabled reactivity and selectivity in a synthetically versatile Aryl C-H olefination

Article abstract of DOI:10.1126/science.1182512

The Mizoroki-Heck reaction, which couples aryl halides with olefins, has been widely used to stitch together the carbogenic cores of numerous complex organic molecules. Given that the position-selective introduction of a halide onto an arene is not always straightforward, direct olefination of aryl carbon-hydrogen (C-H) bonds would obviate the inefficiencies associated with generating halide precursors or their equivalents. However, methods for carrying out such a reaction have suffered from narrow substrate scope and low positional selectivity. We report an operationally simple, atom-economical, carboxylate-directed Pd(ll)-catalyzed C-H olefination reaction with phenylacetic acid and 3-phenylpropionic acid substrates, using oxygen at atmospheric pressure as the oxidant. The positional selectivity can be tuned by introducing amino acid derivatives as ligands. We demonstrate the versatility of the method through direct elaboration of commercial drug scaffolds and efficient syntheses of 2-tetralone and naphthoic acid natural product cores.

Full text of DOI:10.1126/science.1182512

Ligand-Enabled Reactivity and Selectivity in a Synthetically Versatile
Aryl C−H Olefination
Dong-Hui Wang et al.
Science 327, 315 (2010);
DOI: 10.1126/science.1182512
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Both complexes [2]4+ and [3]4+ upon mixing of the low solubility of lithium oxalate in aceto-
with LiClO4 in acetonitrile yield [4]4+ as con- nitrile, the release of the oxalate dianion from [2]4+
firmed by ESI-MS spectrometry (Fig. 2 and figs. in the presence of lithium perchlorate is instan-
S27 and S28). Therefore, in another attempt to taneous, generating the complex [4]4+. Therefore,
use the complex [2]4+ as an electrocatalyst in this for the current system the electrocatalytic reduc-
reaction, the electrochemical cell containing an tion of the copper(II) ion to copper(I) appears to
acetonitrile solution of complex [2]4+ and lithium be rate-limiting. The precipitation of the lithium
perchlorate (as supporting electrolyte) was stirred oxalate formed during the reaction onto the elec-
to precipitate all the available oxalate. Then the trode surface hampers efficient electron transfer.
solution was electrolyzed at –0.03 V versus NHE Tuning the redox potential of the copper complex
with continuous purging of CO2. The consump- by altering the ligand structure with a variety of
tion of current continued linearly for more than substituents, immobilization of the complex onto
3.3 hours, consuming three equivalents of charge the electrode surface, and improved methods for
(12 electrons) per four copper ions, with concur- the removal of oxalate may result in improved
rent crystallization of lithium oxalate. Thereafter, efficiency of the catalytic system. We believe that
the rate of the reaction gradually decreased as the our studies will instigate further development of
crystallized lithium oxalate started to cover the coordination complexes for catalytic CO2 seques-
electrode surface, thereby hampering electron tration, its selective conversion and use as fuels
transfer (fig. S29). In total, the electrocatalysis such as methanol or as feedstock in the synthesis
could be extended for more than 7 hours, with of useful organic compounds.
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J. Chem. Soc. Chem. Commun. 1995, 1223 (1995).
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supporting material on Science Online.
24. A similar reactivity of coordination complexes with
chloroform has been observed and reported before; see,
for example, (25).
25. I. M. Angulo et al., Eur. J. Inorg. Chem. 2001, 1465
(2001).
26. This work was supported by the Leiden Institute of
Chemistry. X-ray crystallographic work was supported
(M.L. and A.L.S.) by the Council for the Chemical Sciences
of The Netherlands Organization for Scientific Research
(CW-NWO). J. Reedijk and M. T. M. Koper are gratefully
acknowledged for stimulating discussions. P.B. (Ithaca
College, New York) was involved in the project through a
summer exchange program. Crystallographic data for
[2](BF4)4 and [3](BF4)4 have been deposited with the
Cambridge Crystallographic Data Center under reference
numbers 717726 and 717727.
consumption of 6 equivalents of charge (24 elec-
trons) and generating 12 equivalents of oxalate per
References and Notes
molecule of [2]4+.
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We have thus devised an electrocatalytic sys-
tem based on a copper coordination compound
that is able to activate and convert CO2 selec-
tively into oxalate at readily accessible potentials,
in the simple but very effective catalytic cycle
shown in Fig. 3. The finding that a copper(I)
system is oxidized by CO2 rather than O2 implies
that the selective binding of CO2 to the copper(I)
ions offers a low-energy pathway for the forma-
Acad. Sci. U.S.A. 105, 10654 (2008).
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Supporting Online Material
www.sciencemag.org/cgi/content/full/327/5963/313/DC1
Materials and Methods
SOM Text
Figs. S1 to S30
Tables S1 and S2
•–
tion of the CO2 radical anion. The copper(II)
oxalate complex [2]4+ is thermodynamically
favored; the binding of CO2 to the Cu(I) centers
in [1]2+ and the formation of oxalate appears to
be highly selective and relatively rapid. Because
9. B. Sarkar, B. J. Liaw, C. S. Fang, C. W. Liu, Inorg. Chem.
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References
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19 June 2009; accepted 25 November 2009
10.1126/science.1177981
tivated C–H bonds into carbon–heteroatom and
carbon–carbon (C–C) bonds (1–5). This technol-
ogy has proven to be valuable in natural products
synthesis, where several distinct C–H function-
alization strategies have been exploited (6–12).
Traditionally, C–C bonds between aryl and
olefinic fragments have been forged through the
Pd-catalyzed Mizoroki-Heck reaction, which
couples aryl halides or triflates with olefins
(Fig. 1A). Considering the prominence of this
transformation in organic synthesis (13), Pd-
catalyzed olefination of aryl C–H bonds has the
potential to emerge as a powerful platform for
more direct access to carbogenic cores of com-
plex molecules (Fig. 1, A and E), particularly in
cases in which the position-selective introduction
of a halide is problematic. However, the few
pioneering examples of Pd-catalyzed C–H olefi-
nation in total synthesis to date are restricted to
specific cases, generally including electron-rich
heterocycles, such as indoles and pyrroles, and/or
Ligand-Enabled Reactivity and
Selectivity in a Synthetically Versatile
Aryl C–H Olefination
Dong-Hui Wang, Keary M. Engle, Bing-Feng Shi, Jin-Quan Yu*
The Mizoroki-Heck reaction, which couples aryl halides with olefins, has been widely used to stitch
together the carbogenic cores of numerous complex organic molecules. Given that the position-
selective introduction of a halide onto an arene is not always straightforward, direct olefination of
aryl carbon-hydrogen (C–H) bonds would obviate the inefficiencies associated with generating
halide precursors or their equivalents. However, methods for carrying out such a reaction have
suffered from narrow substrate scope and low positional selectivity. We report an operationally
simple, atom-economical, carboxylate-directed Pd(II)-catalyzed C–H olefination reaction with
phenylacetic acid and 3-phenylpropionic acid substrates, using oxygen at atmospheric pressure as
the oxidant. The positional selectivity can be tuned by introducing amino acid derivatives as
ligands. We demonstrate the versatility of the method through direct elaboration of commercial
drug scaffolds and efficient syntheses of 2-tetralone and naphthoic acid natural product cores.
nactivated carbon–hydrogen (C–H) bonds targets for chemical transformations. Although
are among the simplest and most common C–H bonds are generally unreactive, during the
Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, CA 92037, USA.
U
structural motifs in naturally occurring past several decades transition metal catalysis has
organic molecules, and, as such, they are ideal emerged as an effective means of converting unac- yu200@scripps.edu
*To whom correspondence should be addressed. E-mail:
www.sciencemag.org SCIENCE VOL 327 15 JANUARY 2010
315

REPORTS
stoichiometric palladium (14–17). The develop-
To this end, we began by extensively screen- biaryl molecules. Several drug substrates, includ-
ment of Pd-catalyzed arene C–H olefination ing reaction conditions and optimizing with re- ing ketoprofen (4l), ibuprofen (4n), and naproxen
reactions to provide general routes to commonly spect to solvent, inorganic base, temperature, and (4o), were found to be compatible with this pro-
occurring carbogenic motifs thus remains an out- oxidant (see supporting online material). Grati- tocol, affording the respective olefinated products
standing challenge. This limitation is rooted in fyingly, we found that 4-methoxyphenylacetic 6l, 6n, and 6o. These results demonstrate the po-
two interrelated problems. First, the substrates acid could be coupled with ethyl acrylate in the tential for applying C–H olefination to effect direct
that are typically effective in palladium-catalyzed presence of 5 mol% Pd(OAc)2 (Ac, acetyl) to functionalization of existing bioactive molecular
C–H activation are synthetically restrictive, either give the desired product in high yield (Fig. 2, scaffolds in the interest of enabling drug diversi-
because they are limited to electron-rich arenes or 6a1). As a further practical advantage, 1 atm of fication for medicinal chemistry.
heterocycles, or because they possess impractical O2 could be used as the terminal oxidant, with 5
A diverse array of substitution patterns at the
chelating functional groups to promote metala- mol% benzoquinone (BQ) serving as a ligand to a position were tolerated, with a higher degree of
tion. These directing groups include those that prevent minor formation of the meta- and di- a substitution corresponding to higher activity
are irremovable and recalcitrant to undergo ortho-olefinated products.
resulting from the Thorpe-Ingold effect (6j to 6s).
further synthetic elaboration, such as pyridine, A wide range of phenylacetic acid substrates Optically pure compounds with chiral centers at
and those that are removable but require several were found to be compatible with this protocol the a position were found to racemize slightly
steps for installation and detachment, such as (Fig. 2). Products containing chlorides (6g, 6h, under our reaction conditions; for example, 6o
oxazoline (5). Second, methods for effecting 6j, 6k, and 6p), fluorides (6f and 6r), and was formed in 72% enantiomeric excess (ee). In
position-selective C–H activation on multiply ketones (6l) could be obtained in high yields. this case, the use of Li2CO3 as the base prevented
substituted arenes (18, 19), particularly via ligand Notably, the tolerance for chlorides on the aro- racemization, affording the product in 97% ee,
control, remain underdeveloped.
matic ring in this ortho-olefination offers an but also lowered the conversion to 24%.
A variety of different olefin coupling partners
Here, we report a catalytic system that ad- opportunity for subsequent cross-coupling, facil-
dresses these problems. A practical Pd-catalyzed itating expedient synthesis of highly complex were found to react well using this catalytic sys-
reaction using molecular oxygen as the terminal
oxidant has been developed to perform C–H
A
olefination with synthetically useful phenylacetic
acid and 3-phenylpropionic acid substrates. This
reaction has remarkably broad substrate scope,
which is enabled in part by the use of amino acid
ligands to enhance the reactivity of the cata-
lytically active Pd(II) species. Moreover, two
distinct methods to control the positional selec-
tivity of C–H activation with multiply substituted
arenes have been demonstrated: (i) substrate
control, by appending a protecting group (PG)
to modulate the intrinsic steric bias; and (ii)
catalyst control, by using ligands to alter the
steric and electronic properties around the metal
center (Fig. 1B). The versatility of this olefination
reaction is demonstrated by direct functionaliza-
tion of commercially available drugs (Fig. 1D)
and by atom- and step-economic syntheses of
2-tetralone derivatives (2) (key synthetic inter-
mediates for tetraline-based natural products) and
two challenging naphthoic acid components in
neocarzinostatin (1) and kedarcidin (3), highly
active antibiotics (Fig. 1E).
Mizoroki–Heck Reaction:
1
1
1
2
2
2
etc.
Arene C–H Olefination:
1
2
B
B
B
1
1
2
2
3
Position-Selective
C–H Olefination
PG-Controlled
or
Ligand-Controlled
3
A
2
2
C
D
Ligand-Enabled Reactivity
Drug Diversification
2
1
2
1
2
2
2
2
3
e.g.
2
3
As part of the overarching goal of developing
practically useful C–H functionalization reac-
tions, our laboratory has focused on discovering
reactivity with broadly useful substrates, in which
all moieties present in the starting material can be
used for subsequent synthetic applications in an
atom-economical manner. Following this phi-
losophy, we sought to develop a Pd-catalyzed
olefination protocol (20) for phenylacetic acid
substrates, as the resulting carbon skeletons are
well-established platforms for the synthesis of 2-
tetralones and naphthoic acids. Although carboxy-
directed C–H activation involving six atoms in
the coordination assembly is rare, we hypothe-
sized that our K+-promoted Pd insertion proce-
dure for benzoic and phenylacetic acids (21, 22),
which promotes C–H activation through the
complex-induced proximity effect (23), could
be exploited for subsequent olefination.
E
Synthetic Applications
i
2
1
2
2
1
Fig. 1. (A) Comparison of the Mizoroki-Heck reaction and arene C–H olefination. (B) Schematic depiction
of our position-selective C–H activation approach. (C) Substrates that were found to be unreactive under our
original conditions but could be efficiently olefinated in the presence of amino acid ligands. (D) Direct ortho-
olefination of commercial nonsteroidal anti-inflammatory drugs (NSAIDs). (E) Expedient synthesis of natural
product components using position-selective C–H olefination.
316
15 JANUARY 2010 VOL 327 SCIENCE www.sciencemag.org

REPORTS
tem (Fig. 2, 6a2 to 6a5 and 6b2). Interestingly, membered ring, which restricts the bond rotation hypothesized that tuning the steric properties of
using 1-hexene as the olefin, we found that non- necessary to align the metal for syn elimination. the metal center through the coordination of a
conjugated product 6a5 was formed predominantly Synthetically, olefinated products such as 6a5 ligand could provide the site recognition that we
(with a 5:1 ratio of E:Z alkene stereoisomers) represent a class of substrates beyond the scope sought. Extensive screening of ligands led us to
over the thermodynamically favorable conjugated of traditional Mizoroki-Heck–type chemistry.
discover that mono-N-protected amino acids were
system (observed in only trace amounts). Mech- With this highly efficient catalytic C–H effective in this respect (24). During our screening
anistically, this suggests that after 1,2 migratory olefination protocol in hand, we next sought efforts, we observed that the resulting isomeric
insertion of the Pd–aryl moiety into the olefin, the to control the positional selectivity of this reac- distribution was substantially dependent on the
resulting intermediate is conformationally restricted tion with multiply substituted arenes that yielded structure of the amino acid side chain, with
from undergoing subsequent b-hydride elimina- isomeric product mixtures under our original Boc-Leu-OH and Boc-Ile-OH giving the best
tion with the benzylic hydrogen atoms. A pos- conditions (Fig. 1B). For instance, 3-methoxy-5- selectivity (7:1 and 8:1, respectively; Boc, tert-
sible explanation is that the carbonyl oxygen methylphenylacetic acid (7) reacted to form a butoxycarbonyl) (Fig. 3A, entries 5 and 6). We
atom from the carboxylate group remains co- mixture of positional isomers without substantial were pleased to find that positional selectivity
ordinated to palladium in an unusual eight- bias (1.4:1, 8-A:8-B) (Fig. 3A, entry 1). We could be further enhanced by varying the N-
protecting group, with Formyl-Ile-OH as the best
ligand, giving a 20:1 ratio of positional isomers
(Fig. 3A, entry 12). The conversion using this
2
3
3
2
2
particular ligand was slightly lower than without
it, but by increasing the catalyst loading to 7%,
the conversion could be improved to 75%.
Allowing the reaction to run for 96 hours further
improved the conversion to 89%.
3
2
2
1
1
4
t
4
2
This ligand-controlled, position-selective C–H
olefination protocol could also be applied to other
multiply substituted arene substrates, including
natural product precursors such as 9 and drug
substrates such as flurbiprofen (11) (Fig. 3B).
With substrate 9, because the two ortho-C–H
bonds are approximately electronically equiva-
lent, the outstanding positional selectivity ob-
served with Boc-Ile-OH is likely a result of the
catalyst’s recognition of the different steric en-
vironments. In contrast, both steric and electronic
properties could be contributing to the improve-
ment in positional selectivity with substrates 7,
11, 13, and 15; the mechanistic details in these
cases remain to be fully elucidated. (Unless other-
wise noted, the reaction conditions in Fig. 3, B to
D, are identical to those described in Fig. 3A.)
To our delight, during this investigation, we
also discovered that certain Boc-protected amino
acid ligands could markedly improve the yield in
this olefination reaction (see supporting online
material), with the optimal ligand choice highly
dependent on the combination of substrate and
coupling partner. For instance, using Boc-Ile-
OH, olefinated products 6t and 17 could be
formed quantitatively, even when the catalyst
loading was reduced to 1 to 2 mol% of Pd(OAc)2
(Fig. 3C). Moreover, the use of amino acid lig-
ands allowed for efficient di-olefination, fashion-
ing product 17, for example, in quantitative yield.
Thus, our parent C–H olefination protocol and
the amino acid–ligated system offer comple-
mentary reactivity to access either the mono- or
di-olefinated products, depending on which is
more useful for a given synthetic application
(Fig. 2 and Fig. 3C, respectively).
2
2
2
2
2
2
2
2
1
1
1
2
2
2
2
2
2
2
2
*
*
2
2
2
2
2
2
2
2
*
*
*
’
’
’
2
2
2
2
i
2
2
2
2
2
2
2
2
2t
2
2
2
2
2
2
2
2
2
2
3
4
5
The strong ligand influence on reactivity in
this system encouraged us to examine whether
previously unreactive 3-phenylpropionic acid
and electron-deficient phenylacetic acid sub-
strates could now be ortho-olefinated in the
presence of amino acid ligands. Indeed, we were
pleased to find that an array of such substrates
E:Z
*The corresponding phenylacetic acid substrate was used as starting material; to simplify separation, the product was isolated as
the methyl ester following treatment of the crude reaction mixture with CH N . Racemic starting material was used. Optically pure
naproxen (4o, 97% ee) was used as the starting material. The product was obtained in 72% ee. The use of Li CO as the base
gave 24% conversion (by H NMR) and 97% ee. The ee values were determined by chiral HPLC.
†
‡
2
2
2
3
1
Fig. 2. C–H olefination of phenylacetic acid substrates with ethyl acrylate (6a1, 6b1, and 6c to 6s)
and with other olefin coupling partners (6a2 to 6a5 and 6b2).
www.sciencemag.org SCIENCE VOL 327 15 JANUARY 2010
317

REPORTS
could be olefinated in moderate to good yields
A
CO2Et
5 mol% Pd(OAc)2
5 mol% BQ
10 mol% L
2 equiv. KHCO3
(Fig. 3D). Notably, the synthetic flexibility
afforded by the extra methylene spacer in 18a
and 18b greatly expands the range of core
structures that can subsequently be accessed.
Finally, we demonstrated the synthetic utility
of this highly versatile and scalable olefination
reaction by concise syntheses of several natural
product core structures, including 2-tetralones
and naphthoic acids (Fig. 4). The synthesis of
natural products of this type is by no means
simple, but impressive efforts by several groups
(25–29) have led to a basic roadmap for how
to construct such molecules. In particular, ole-
finated arenes with structures analogous to 10-A
(Fig. 4C) often serve as key intermediates, and
the olefinic moieties are usually introduced via a
Wittig reaction with the corresponding aldehyde
or via bromination in the early stages to set up a
late-stage Mizoroki-Heck reaction. Our C–H
olefination reaction offers a departure from
these approaches both in the retrosynthetic sense
(in that it represents a different synthetic dis-
connection associated with a distinct pool of
starting materials) and in the forward sense (in
that the key transformations are highly step- and
atom-economical).
Using our original protocol (Fig. 2), commer-
cially available 2,3-dimethoxyphenylacetic acid
(4d) could be transformed to intermediate 6d2 in
high yield. A straightforward sequence of hydro-
genation, ester formation, Dieckmann condensa-
tion, and decarboxylation yielded 2-tetralone
derivative 19 (Fig. 4A) (29). Notably, nearly all
substrates described in this work could potentially
be used to synthesize a diverse range of 2-tetralones.
Next, we demonstrated the utility of both
protecting group–controlled and ligand-controlled
position-selective olefination by synthesizing the
naphthoic acid components of both neocarzino-
statin (1) and kedarcidin (3) (Fig. 4). The use of
a triisopropylsilyl (TIPS) group afforded the de-
sired positional selectivity for the preparation of
21-A (Fig. 4B). This key intermediate could then
be cyclized in accordance with literature prece-
dent (28) to give the naphthoic acid component
22 of neocarzinostatin (1) (26). On the other
hand, the ligand-controlled position-selective
olefination of 9 afforded 10-A in high yield
(Fig. 4C). 10-A could then be converted into
the desired naphthoic acid product (23) follow-
ing a two-step procedure developed by Myers
and Hirama: formation of the acid chloride and
[6p] electrocyclization (25, 27). In all three of
these cases, the reaction sequences are among
the highest-yielding and most atom- and step-
economical routes achieved to date for access-
ing these widely studied, commonly occurring
core structures.
HB
Me
Me
Me
CO2H
CO2H
CO2Et
CO2H
+
CO2Et
2 equiv.
+
HA
t-AmylOH, 85 °C
1 atm O2, 48h
OMe
OMe
8-A
OMe
7
8-B
Entry
Ligand
---
Entry
Ligand
A : B
A : B
Conv. (%)*
68
Conv. (%)*
1
2
3
1.4 : 1
2.5 : 1
5 : 1
7
8
9
50
16
24
3 : 1
6 : 1
Boc2-Leu-OH
H-Leu-OH
Boc-Tyr(Bzl)-OH
Boc-Abu-OH
Boc-Val-OH
17
17
Formyl-Leu-OH
13 : 1
4
5
6
23
6 : 1
7 : 1
8 : 1
10
11
12
Fmoc-Ile-OH
Ac-Ile-OH
16
5 : 1
10 : 1
20 : 1
Boc-Leu-OH
24
23
Boc-Ile-OH
27†
Formyl-Ile-OH
43 (75)‡
*Based on 1H NMR. The di-olefinated product was formed in less than 5% conversion. †24 h. ‡7 mol% Pd(OAc)2, 7 mol% BQ, 14
mol% L.
B
Substrate
HB
Ligand Conv. (%)*
A : B
Substrate
HB
Ligand Conv. (%)*
A : B
i-PrO
---
65†
86†
F
---
63
77
1.5 : 1
23 : 1
1.6 : 1
3.5 : 1
CO2H
CO2H
Formyl-Ile-OH
Boc-Ile-OH
MeO
HA
HA
13
9
OMe
HB Me
H
HB
F
Me
---
---
82
78
8
2.8 : 1
5.7 : 1
1.2 : 1
4.7 : 1
CO2H
CO2H
15
50‡
Formyl-Ile-OH
Formyl-Ile-OH
Ph
HA
HA
11
H
Cl
*Based on 1H NMR. Products derived from substrates 9, 11, 13, and 15 are labeled 10-A/B, 12-A/B,14-A/B, and 16-A/B respectively.
Only the major products were isolated and characterized. †t-Butyl acrylate was used as the coupling partner. ‡15 mol% Pd(OAc)2, 15
mol% BQ, 30 mol% Formyl-Ile-OH.
Me
R
C
CO2H
CO2H
17
CO2Et
R =
6t
R
MeO
R
Pd(OAc)2
Pd(OAc)2
Ligand
Conv. (%)*,†
Ligand
Conv. (%)*,†
Selectivity
---
---
mono
di
31
10
2 mol%
2 mol%
2 mol%
2 mol%
Boc-Ile-OH
>99
Boc-Ile-OH
>99
*Based on 1H NMR. †2 mol% Pd(OAc)2, 2 mol% BQ, 4 mol% Ligand.
D
Ligand
Yield (%)*
Ligand
Yield (%)*
Product
CF3
Product
CO2H
---
13
---
12
90
CO2H
CO2Et
85‡
Boc-Ile-OH
Boc-Val-OH
F3C
CO2Et
6u
6w
Me
NO2
Me
---
0
---
0
50†
57§
Boc-Val-OH
Boc-Val-OH
CO2Et
O2N
CO2Et
6v
6x
Me
CO2H
MeO
CO2H
---
22
---
8
PG1-Leu-OH||
75¶
Boc-Val-OH
60
CO2Et
CO2Et
18b
18a
*Isolated Yield. †2-Nitrophenylacetic acid was used as substrate; the product was completely decarboxylated under the reaction
conditions: 10 mol% Pd(OAc)2, 10 mol% BQ, 20 mol% Boc-Val-OH. ‡Mono:Di = 2:1. §4-Nitrophenylacetic acid was used as substrate;
¶
decarboxylated:non-decarboxylated = 2:1. ||PG1 = (
–
)-Menthyl(O2C). Mono:Di = 3:1.
Fig. 3. (A) Selected amino acid ligand screening data for position-selective C–H olefination. (The full
ligand screening data are available in table S8.) (B) Substrate scope for ligand-controlled position-
selective C–H olefination. (C) Ligand-enabled C–H olefination with 2 mol% Pd(OAc)2. (D) Amino acid
ligand–enabled C–H olefination with problematic substrates.
In this report we have attempted to demon-
strate the importance of ligand development (30)
for enabling unique reactivity and selectivity in
C–H activation, as well as to illustrate two con- synthesis: (i) versatile substrates and coupling
pate that this C–H olefination reaction and others
ceptual prerequisites for the widespread applica- partners, and (ii) precise control of positional grounded in this philosophy will find broad
applicability in multifarious synthetic endeavors.
tion of Pd-catalyzed C–H activation in organic selectivity in C–H functionalization. We antici-
318
15 JANUARY 2010 VOL 327 SCIENCE www.sciencemag.org

REPORTS
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4d
6d2
Reagents and conditions: (a) Pd(OAc)2, BQ, t-butyl acrylate, KHCO3, t-AmylOH, O2 (1 atm), 85 °C, 93%. (b) H2 (balloon), Pd/C,
MeOH, rt. (c) CH2N2, Et2O, 0 °C, 93% (two steps). (d) KOt-Bu, Et2O, rt. (e) HCl/HOAc, 110 °C, 69% (two steps).
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TIPSO
TIPSO
MeO
OH
a
b–f
CO2H
HA
CO2H
CO2Et
PG-Controlled
Position-Selective
C–H Olefination
Me
Me
Me
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22
20
21-A
Reagents and conditions: (a) Pd(OAc)2, BQ, ethyl acrylate, KHCO3, t-AmylOH, O2 (1 atm), 85 °C, 77%, A:B = 10:1. (b) H2 (balloon),
Pd/C, MeOH, rt. (c) Et3N•3HF, THF, rt. (d) MeI, K2CO3, acetone, reflux, 69% (3 steps). (e) KOt-Bu, Et2O, rt, 88%. (f) BrCCl3, DBU,
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i-PrO
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b, c
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a
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Ligand-Controlled
Position-Selective
C–H Olefination
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MeO
HA
OMe
OMe
OMe
9
R = t-Bu
10-A
R = t-Bu
23
Reagents and conditions: (a) Pd(OAc)2, BQ, t-butyl acrylate, KHCO3, Boc-Ile-OH, t-AmylOH, O2 (1 atm), 85 °C, 86%, A:B = 23:1
(without ligand, A:B = 1.5:1). (b) (COCl)2, CH2Cl2, rt. (c) i-Pr2NEt, CH2Cl2, rt, 87% (two steps).
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(J.-Q.Y.); predoctoral fellowships from NSF, the U.S.
Department of Defense, the Scripps Research Institute,
and the Skaggs Oxford Scholarship program (K.M.E.);
and the Scripps Research Institute, National Institute of
General Medical Sciences grant 1 R01 GM084019-02,
NSF grant CHE-0910014, Amgen, and Eli Lilly & Co.
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Materials and Methods
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Include this information when citing this paper.
is based on more efficient processes working
under mild conditions (low temperatures and
ambient conditions) and relying on cheap and
abundant feedstock. In this context, gold (Au)–
based catalysts have attracted considerable atten-
tion in the past decade because of their nontoxic
nature and the ability to promote selective
reactions at low temperatures. In particular, the
potentialofAuforpartialoxidationreactions,such
as the selective oxidation of alcohols (4–6) and
hydrocarbons (7, 8), was demonstrated in numer-
ous studies. Model studies on single-crystal Au
provided molecular-scale insight into the activity
of gold, showing that atomic oxygen is the key
species that promotes a range of selective oxida-
Nanoporous Gold Catalysts for Selective
Gas-Phase Oxidative Coupling of
Methanol at Low Temperature
A. Wittstock,1 V. Zielasek,1 J. Biener,2* C. M. Friend,3* M. Bäumer1*
Gold (Au) is an interesting catalytic material because of its ability to catalyze reactions, such as
partial oxidations, with high selectivities at low temperatures; but limitations arise from the low O2
dissociation probability on Au. This problem can be overcome by using Au nanoparticles supported
on suitable oxides which, however, are prone to sintering. Nanoporous Au, prepared by the
dealloying of AuAg alloys, is a new catalyst with a stable structure that is active without any support.
It catalyzes the selective oxidative coupling of methanol to methyl formate with selectivities above
97% and high turnover frequencies at temperatures below 80°C. Because the overall catalytic
characteristics of nanoporous Au are in agreement with studies on Au single crystals, we deduced that
the selective surface chemistry of Au is unaltered but that O2 can be readily activated with this
material. Residual silver is shown to regulate the availability of reactive oxygen.
1Institute of Applied and Physical Chemistry, Universität
Bremen, Bremen 28359, Germany. 2Nanoscale Synthesis and
Characterization Laboratory, Lawrence Livermore National
Laboratory (LLNL), Livermore, CA 94550, USA 3Department of
Chemistry, Harvard University, Cambridge, MA 02138, USA.
n ever-increasing demand for resources triggered a growing interest in a “green chemical
enforces the need of sustainability in all industry,” especially for the production and
*To whom correspondence should be addressed. E-mail:
mbaeumer@uni-bremen.de (M.B.), cfriend@seas.harvard.edu
A
arenas (1). This new challenge has processing of commodity chemicals (2, 3), which (C.M.F.), biener2@llnl.gov (J.B.)
www.sciencemag.org SCIENCE VOL 327 15 JANUARY 2010
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