Pd(II)-catalyzed enantioselective C-H activation/C-O bond formation: Synthesis of chiral benzofuranones

Article abstract of DOI:10.1021/ja311259x

Pd(II)-catalyzed enantioselective C-H activation of phenylacetic acids followed by an intramolecular C-O bond formation afforded chiral benzofuranones. This reaction provides the first example of enantioselecctive C-H functionalizations through Pd(II)/Pd(IV) redox catalysis.

Full text of DOI:10.1021/ja311259x

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Communication
Pd(II)-Catalyzed Enantioselective C–H Activation/C–
O Bond Formation: Synthesis of Chiral Benzofuranones
Xiu-Fen Cheng, Yan Li, Yi-Ming Su, Feng Yin, Jianyong Wang,
Jie Sheng, Harit U. Vora, Xisheng Wang, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja311259x • Publication Date (Web): 10 Jan 2013
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Xiu-Fen Cheng,†,§ Yan Li,†,§ Yi-Ming Su,† Feng Yin,† Jian-Yong Wang,† Jie Sheng,† Harit U. Vora,‡ Xi-
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†
Sheng Wang,*, and Jin-Quan Yu‡
† Department of Chemistry, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, China
‡ Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
Supporting Information Placeholder
thesis of -lactams4b and 2,3-dihydrobenzofurans.4e Herein, we re-
ABSTRACT: Pd(II)-catalyzed enantioselective C–H activation of
port the direct synthesis of ,-disubstituted benzofuran-2-ones5 via
phenylacetic acids followed by an intramolecular C–O bond
a Pd(II)/Pd(IV)-catalyzed C–H activation/C–O bond formation.6,7
formation afforded chiral benzofuranones. This reaction provides
Moreover, the use of MPAA ligands allows for the enantioselective
the first example of enantioselecctive C–H functionalizations
synthesis8,9 of benzofuran-2-ones through a desymmetrization10 to
through Pd(II)/Pd(IV) redox catalysis.
provide the respective products in excellent enantioselectivities,
thus providing a developed method providing a complimentary
strategy to current methods.11
Our study commenced by examining the C–H activation/C–O
The ability to synthesize molecules in a rapid and efficient man-
cyclization of 1-phenylcyclopentanecarboxylic acid (1a) in the pres-
ence of Pd(OAc)2 (10 mol %) and KOAc (2.0 equiv.). Although a
wide range of oxidants failed to give the desired lactone product,
such as Cu(II) and Ag(I) salts (See SI), we found that 2a could be
obtained in 42% yield with PhI(OAc)2, a generally effective oxidant
for the Pd(II)/Pd(IV) catalytic cycle.12 It should be noted that ace-
toxylation of the C–H bond, a common product obtained with this
oxidant is not observed under the optimized reaction conditions.
To improve the yield of the reaction we surveyed common addi-
tives and ligands (Table 1). Disappointingly, additives such as ben-
zoquinone and acetic acid failed to improve the yield as 2a was
obtained in 22% and 32% respectively (entry 1 and 2). Additional-
ly, the use of other common carboxylic acids (entry 4 and 5) failed
to improve the yield compared to the non-ligated conditions (entry
1).
ner still represents a major challenge in the field of organic synthe-
sis. Of significant interest are methods that provide access to fun-
damental building blocks in a chemoselective and enantioselective
manner from readily available starting materials in a step-
economical fashion. In this context, C–H bond functionalization
offers a unique opportunity to access molecules of synthetic interest
from readily available starting materials.1,2 Specifically, the func-
tionalization of phenylacetic acids and derivatives thereof have led
to the development of C–C and C–X bond forming reactions. We
envisioned that ,-disubstituted benzofuran-2-ones, a valuable
synthon and pharmacophore found in numerous natural products
and drug scaffolds could be readily attainable from the C–H bond
functionalization of phenylacetic acid derivatives (Scheme 1).3
Scheme 1. Sampling of Natural Products Containing the
Benzofuran-2-one Core and Approach to This Scaffold
Table 1. The Influence of Additives and Ligands on Reactivity
a Isolated yield. b Pd(OAc)2 (7.5 mol %).
We hypothesized that for such an approach to be successful, the
phenylacetic acid would need to undergo cyclometallation to arrive
at the 6-membered palladacycle, with subsequent reductive elimina-
tion facilitated by oxidation of the Pd(II) metallacycle to a Pd(IV)
cyclometalated intermediate by a bystanding oxidant (Scheme 1).4
Indeed, we have previously shown that addition of bystanding oxi-
dants are suitable for facilitating reductive elimination in the syn-
Guided by previous findings that C-H functionalizations can be
promoted by MPAA ligands,13 we subsequently focused on amino
acid derivatives, and under the optimized reaction conditions with
30 mol % of Ac-Ala-OH 2a was obtained in 70% yield (entry 6).
The use of 30% ligand is necessary for effective binding due to the
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presence of large excess of acetates. Replacement of Ac-Ala-OH
Subsequent substitution of the arene with electron rich substitu-
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with Boc-Ala-OH the product is obtained in 54% yield (entry 7).
Additionally, we observed that the N-protecting group on the ami-
no acid played a pivotal role as with Ac-Gly-OH provides 2a in 69%
yield while Boc-Gly-OH provides 2a in 58% yield. Surprisingly, an
increase of the steric bulk on the amino acid side chain in an effort
to improve the yield failed compared to that of Ac-Gly-OH (entries
10 through 13). It is noteworthy, that at this point very negligible
effects in yield were observed with the N-protecting group. However,
optimal results were obtained with 30 mol % Boc-Val-OH and 7.5
mol % of Pd(OAc)2 to give 2a in 92% yield (entry 14).
ent’s 2i, j, k, and 2o of ,-dimethyl phenylacetic acid are isolated
in good yields (83-94%). Additionally, the placement of electron
deficient substituents on the aromatic ring 2l, m, n and 2p provide
the respective products in slightly diminished yields (56%-70%).
Gratifyingly, when the thiophene derived phenylacetic acid is em-
ployed the cyclized product 2q is obtained in 50% yield. Moreover,
substitution of the ,-dialkyl group for di-butyl 2r and non-
symmetric alkyl groups 2s, t, u, and 2v all provide the benzo-
furanone products in good yields (84%-92%). Meanwhile, phenyl
acetic acid with either ortho-substituted group at the phenyl ring or
hydrogen at the -position is not compatible with our catalytic
system.
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Chart 1. Scope of Phenylacetic Acid Substratesa
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With the newly developed C–H lactonization protocol of phe-
nylacetic acid, we proceeded to develop a set of conditions for the
enantioselective synthesis of benzofuran-2-ones systematically with
mono-N-protected amino acid ligands that would proceed through
a desymmetrization. Although, enantioselective C–H bond func-
tionalizations still represent a considerable challenge, enantioselec-
tive desymmetrization processes have been reported through the
Pd(II)/Pd(0)8 and Pd(0)/Pd(II)9 redox manifolds to provide valua-
ble synthons in high enantioselectivities. Starting with 3a as the
model substrate we began our optimization studies and readily
identified that Boc-protected amino acids provide optimal yields in
the desymmetrization reaction. A systematic study of the side chain
of the amino acid ligand was conducted to improve upon the enan-
tioselectivities (Table 2).
Table 2. Influence of Amino Acid Ligands on Enantioselectiv-
ity
a Isolated yield. b Determined by HPLC analysis on chiral stationary
c
d
phase. Pd(OAc)2 (5 mol %) was used. Ligand (20 mol %) was
used. e Ligand (40 mol %) was used.
a
b
Isolated yield. Pd(OAc)2 (7.5 mol %) and Boc-Val-OH (30 mol
%) were used at 80 °C. c Pd(OAc)2 (10 mol %) was used. d The E/Z
ratio was determined by H-NMR. Most of S.M. was recovered
and small amount of them decomposed when the conversions were
low.
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e
Starting with Boc-L Alanine (Boc-Ala-OH) 4a is obtained in 71%
yield and 85% ee (entry 1). An increase in steric bulk of the amino
acid side chain to Boc-Val-OH provided an enantioselectivity of
95% with a yield of 58% (entry 2). However, the use of Boc-Leu-
OH affords 4a in 64% yield and 96% ee (entry 3); the use of Boc-
Ile-OH gives the desired product in 70% yield and 96% ee (entry 4).
Further investigation into the amino acid side chain (entry 5 and 6)
provided 4a in lower yields (66-68%) with good enantioselectivities
(92-96%) compared to that of Boc-Ile-OH as the ligand. Addition-
ally, lower catalyst loading to 5 mol % of Pd(OAc)2 gave 4a in 92%
ee (entry 7). Noteworthy, is the effect of ligand loading on enanti-
oselectivity, with a palladium loading of 5 mol% and 20 mol% of
Boc-Ile-OH 4a is obtained in 87% ee (entry 8). However, an in-
crease of ligand loading to 40 mol % affords 4a in 95% ee and an
improved yield of 78% (entry 9). This effect of increased ligand
loading and higher enantioselectivities is attributed to generating a
sufficient quantity of the amino acid Pd(II) catalyst; particularly as
the formation of acetic acid can facilitate ligand exchange and
giving rise to Pd(OAc)2. The non-ligated reaction can subsequently
occur to provide racemic product and lower enantioselectivities.
With the optimized reaction conditions in hand, we next inves-
tigated the substrate scope of the phenylacetic acid directed C–H
lactonization to provide a platform for subsequent enantioselective
studies. A variety of ,-disubstituted phenylacetic acids were cy-
clized to give the corresponding -lactones in modest to excellent
yield with either Boc-Val-OH or Ac-Gly-OH as suitable ligand
(Chart 1). Both electron-donating groups, such as para-Me (2b) and
para-OMe (2c) give the benzofuran-2-none products in 94% and
80% yield respectively. Additionally, electron withdrawing substit-
uent’s placed on the aromatic ring 2d and 2e give the cyclized
products with diminished yields of 67% and 58%. To survey the
influence of the Thorpe-Ingold effect on the cyclization 2f and 2g
were isolated in 56% and 90% yield. Gratifyingly, lactonization of
,-dimethyl phenylacetic acid 2h provides the desired product in
87% yield.
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Having identified a suitable amino acid ligand affording high
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enantioselectivities, we proceeded to establish the scope of the
asymmetric C–H lactonization. A diverse class of diphenylacetic
acid substrates was subjected to the reaction to provide the benzo-
furanones (Chart 2). Alkyl-substituted diphenylacetic acids 4b, c, d
were cyclized with high enantioselectivities (94-96%) and good
yields (56-86%). The reaction was also found to tolerate substrates
containing heteroatoms as 4e, f, g were isolated in moderate yields
(37-51%) with enantioselectivities of 89-95%. Lastly, replacement
of the -methyl for an ethyl undergoes cyclization to afford 4h in
85% yield and 91% ee.
xswang77@ustc.edu.cn
§ X.-F. C. and Y. L. contributed equally.
The Authors declare no competing financial interest.
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This rare example of enantioselective C–H activation/C–O
bond formation also provides valuable mechanistic insight into the
asymmetric C–H activation. The absolute configuration of 4b
(Chart 2) was confirmed to be R by X-ray crystallographic analysis,
which further support previously proposed stereochemical model
(Figure 1),8b even though these reactions proceed through different
redox catalysis.
We gratefully acknowledge the Chinese Academy of Sciences,
the Ministry of Education (SRFDP 20123402110040), the Nation-
al Science Foundation of China (No. 21102138), the National
Institutes of Health (NIGMS, 1 R01 GM084019-04), University of
Science and Technology of China (USTC) for financial support.
We thank Prof. Liu-Zhu Gong and Prof. Shi-Kai Tian from USTC
for their help of HPLC analysis.
Chart 2. Substrate Scope of the Asymmetric Pd(II)-Catalyzed
C-H Lactonization of Diphenylacetic Acidsa,b
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Isolated yield. ee was determined by HPLC analysis on chiral
stationary phase. c 70 °C, 24 h.
Figure 1. Absolute Configuration of Benzofuranone 4b
In summary, we have developed a Pd(II)-catalyzed enantioselec-
tive C–H activation/C–O cyclization of arylacetic acids to afford
chiral benzofuranones. This reaction provides the first example of
enantioselective C–H functionalizations through Pd(II)/Pd(IV)
redox catalysis.
Experimental procedure and characterization of all new com-
pounds (PDF). This material is available free of charge via the In-
ternet at http://pubs.acs.org.
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a
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ACS Paragon Plus Environment