Pd(II)-Catalyzed C-H Functionalizations Directed by Distal Weakly Coordinating Functional Groups

Article abstract of DOI:10.1021/ja5126897

Ortho-C(sp²)-H olefination and acetoxylation of broadly useful synthetic building blocks phenylacetyl Weinreb amides, esters, and ketones are developed without installing an additional directing group. The interplay between the distal weak coor

Full text of DOI:10.1021/ja5126897

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Article
Pd(II)-Catalyzed C–H Functionalizations Directed
by Distal Weakly Coordinating Functional Groups
Gang Li, Li Wan, Guofu Zhang, Dasheng Leow, Jillian Spangler, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 13 Mar 2015
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Pd(II)-Catalyzed C–H Functionalizations
Directed by Distal Weakly Coordinating
Functional Groups
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Gang Li, Li Wan, Guofu Zhang, Dasheng Leow, Jillian Spangler and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La
Jolla, California 92037
yu200@scripps.edu
RECEIVED DATE (to be automatically inserted after your manuscript is accepted
if required according to the journal that you are submitting your paper to)
Abstract Ortho-C(sp2)–H olefination and acetoxylation of broadly useful synthetic
building blocks phenylacetyl Weinreb amides, esters, and ketones are developed without
installing an additional directing group. The interplay between the distal weak
coordination and the ligand-acceleration is crucial for these reactions to proceed under
mild conditions. The tolerance of longer distance between the target C–H bonds and the
directing functional groups also allows for the functionalizations of more distal C–H
bonds in hydrocinnamoyl ketones, Weinreb amides and biphenyl Weinreb amides.
Mechanistically, the coordination of these carbonyl groups and the bisdentate amino acid
ligand with Pd(II) centers provides further evidence for our early hypothesis that the
carbonyl groups of the potassium carboxylate is responsible for the directed C–H
activation of carboxylic acids.
1. Introduction: advantages of weak coordination
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-chelation-assisted C–H palladation processes (cyclopalladation) has been extensively
exploited to develop Pd-catalyzed C–H activation/carbon-carbon and carbon-heteroatom
bond forming reactions.1 In turn, the development of these reactions has contributed to an
improved mechanistic understanding of several key redox manifolds in Pd catalysis,
namely Pd(0)/Pd(II), Pd(II)/Pd(0) and Pd(II)/Pd(IV) processes.1 However, the need for a
preinstalled strongly coordinating directing group has impeded the widespread
application of these transformations as disconnections in synthesis,2 particularly when the
installation or removal of the directing group is not operationally simple.1
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From the viewpoint of reactivity and catalysis, the broadly held notion that a strongly-
coordinating directing group is required to achieve robust cyclopalladation originates
largely from empirical observation and has generally deterred the development and
application of simple directing groups (DG).3,4 While strongly coordinating directing
groups do facilitate the formation and characterization of thermodynamically stable
palladacycles, it is debatable whether the strong coordination is necessarily advantageous
in catalytic C–H functionalization reactions.1r First, the coordination of two strongly
coordinating substrates to a Pd center can be problematic and the addition of a strong acid
is often necessary to prevent the formation of this unreactive complex.5 Second, strongly
coordinated palladacycles are often thermodynamically stable and, as such, are unreactive
towards functionalization reagents under mild conditions (Figure 1a). On the other hand,
cyclopalladation intermediates with weaker coordinating directing groups are less
favored in the thermodynamic equilibrium but should be more reactive towards a
functionalization reagent. Although present in low concentrations, the transient less stable
palladacycle intermediates can react with electrophiles or nucleophiles to give the desired
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product via kinetic control analogous to the mechanistic notion in asymmetric
hydrogenation established by Halpern (Figure 1a).6 Indeed, a weakly coordinating
substrate (phenyl acetic acid) undergoes much faster Pd-catalyzed H-D exchange in the
presence of DOAc than the strongly coordinating 2-phenylpyridine.7 Furthermore, a
weakly bound palladacycle may also undergo reversible dissociation from the directing
group to provide a coordination site that may be needed for subsequent functionalization
step (Figure 1b), for example, transmetalation with organometallic reagents or migratory
insertion with olefins. The heightened reactivity of weakly bound palladacycles may
enable the use of milder conditions and broader range of reagents for the discoveries of
new C–H functionalization processes. Indeed, a number of unprecedented Pd-catalyzed
catalytic C–H functionalization transformations were discovered recently using weakly
coordinating directing groups including hydroxylation, trifluoromethylation, and
borylation of sp2 C–H bonds, as well as olefination and alkynylation of sp3 C–H bonds.8-
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Most notably, the remote meta-C–H activation demonstrates the power of weakly
coordinating directing groups which dissociate from the Pd center to allow for the
coupling of sterically hindered disubstituted olefins.8t With this analysis in mind, we have
focused our efforts on improving our understanding of the underlying principles for the
use of weak -chelation to direct C–H activation and developing reaction conditions to
these types of C–H activation reactions.
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Figure 1. Energy diagram of weak coordination promoted C–H activation.
Towards this goal, we began to study the effect of both coordination strength and
conformation on the C–H activation step. By investigating the stereochemistry of the C–
H cleavage step through the use of a chiral oxazoline directing group, we found that the
dihedral angle between the C–H and Pd–OAc bonds is critical (Figure 2).11a A decrease
in this dihedral angle significantly favors C–H activation. In contrast, reduction of
coordination strength by increasing the steric hindrance of the directing group does not
adversely affect reactivity.1r This hypothesis was recently supported by an extensive
computational study and conformational analysis.11b
Following this primitive rationale, we systematically developed a number of C–H
activation/carbon-carbon and carbon-heteroatom bond forming reactions using a weakly-
coordinating N-Boc carbamate or an alkali carboxylate as the directing group (Figure
2).8a-c In each of these cases the carbonyl group (C=O) is proposed to coordinate to the
Pd(II) center in a geometrically similar fashion to our original oxazoline (C=N) directing
group, although the possibility of Pd(II) coordinating with carboxylate as an anion has
always been raised.8b Such coordination induces a minimum dihedral angle between the
C–H and Pd–OAc bonds with a relatively low entropic cost, and is expected to have
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superior reactivity based on the Martinez’ pioneering work on the Pd(II)-mediated C–H
deprotonation by Pd–OAc,12a,b later adopted as CMD mechanism in Pd(0)/ArI
chemistry.12c These studies led to our subsequent development of several weakly-
coordinating directing groups derived from carboxylic acids (CONHOMe8d,
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8o
CONHC6F4CF3 ) or amines (NHTf8e) (Figure 2). These directing groups can effectively
promote cyclopalladation of C(sp2)–H or C(sp3)–H bonds via five-membered
palladacycles. The superior directing power of CONHOMe group has been demonstrated
in a wide range of Pd(II)10k-p, Rh(III) and Ru(II) catalyzed-C–H activation reactions13.
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Figure 2. Systematic design and development of weakly coordinating directing groups.
The superior directing power of the carbonyl groups in carboxylate and acidic amides
promoted us to develop analogous reactions using ester, ketone and Weinreb amide
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substrates. H NMR studies of the coordination between ester, ketone and Weinreb
amides and Pd(II) show that these substrates are much less coordinative than 2-phenyl
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pyridine (see supporting information). Encouragingly, a number of ortho-C–H
functionalizations of esters, ketones, and Weinreb amides using Pd10a-j, Rh14a-i and Ru14j-r
catalysts have been successfully developed recently. However, similar to Murai’s Ru(0)-
catalyzed C–H activation reactions of acetophenone,15 the utility of these very weakly-
coordinating directing groups has been largely limited to the more reactive benzoyl
substrates. First, the conjugation of the carbonyl with the arene minimizes the dihedral
angle between the metal and C–H bonds. Second, the formation of the
thermodynamically favored five-membered palladacycle also provides a driving force
(Figure 2b). In contrast, the activation of distal C–H of esters, ketones and Weinreb
amides remains a significant challenge,10b,c,q for example, phenylacetone, Weinreb
amides of phenylpropionic acids and biphenyl carboxyl acids (Figure 2d). Compared to
the benzoic acid or acetophenone, the freely rotating sp3 carbon center between the
directing carbonyl group and the aryl C–H bonds in phenyl acetic acid and
phenylpropionic acid backbones significantly increases the entropic barrier for
assembling the desired transition state. The six- and seven-membered cyclopalldation is
also less favored in general. Herein we report Pd(II)-catalyzed ortho-C–H
functionalization of phenylacetyl or phenylpropionate backbone directed by Weinreb
amide, ester, and ketones, further demonstrating the feasibility of using simple and
ubiquitous functional groups to direct distal C–H activation reactions. The carbon
skeletons of phenylacetyl carboxylates and ketones are common in pharmaceuticals and
natural products (Figure 3). These new reactions also allows for diversification of
abundant starting materials based on phenyl acetyl backbones. Mechanistically, the
coordination of these carbonyl groups and the bisdentate amino acid ligand with Pd(II)
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centers provides further evidence for our early hypothesis that the weakly coordinating
carbonyl groups of the potassium carboxylate is responsible for the directed C–H
activation of carboxylic acids (Figure 2).
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Figure 3. Natural products and pharmaceuticals featuring the phenylacetyl scaffolds.
2. Results and Discussion
2.1. Olefination. Encouraged by our recently disclosed Pd(II)-catalyzed ortho-C–H
olefination of arenes directed by weakly coordinating alkyl ethers promoted by a
monoprotected amino acid ligands8v, we were prompted to explore the olefination of
commonly used Weinreb amide, ester, or ketone without installing additional directing
groups. Compared to the benzoyl-derived ketone, ester and amide substrates, the presence
of an extra methylene group between the aryl ring and the directing group is expected to
incur additional entropic cost during the assembly of the desired pre-transition state. We
initiated our efforts with Weinreb amide substrates as we suspected that these substrates
would be slightly more coordinative and reactive than the corresponding ester or ketone
analogue. After an survey of reaction conditions (see the Supporting Information), we
established that treatment of amide 1a with ethyl acrylate, silver carbonate, 10 mol%
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palladium acetate, and 20 mol% of the Ac-Gly-OH ligand in hexafluoroisopropanol
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(HFIP) at 80℃ for 24h provides the desired olefinated product in 87% yield (mono/di =
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1/2) (Table 1). Without addition of the Ac-Gly-OH ligand, only a trace amount of
olefinated product was detected, thus demonstrating the importance of the interplay
between the weak coordination and the ligand acceleration.8n, 16 The olefination of 1a was
also scaled up to 0.6 g (3.35 mmol) to give 62% of 3amono and 33% of 3adi products. This
reaction is compatible with phenylacetyl amides with electron-donating (1b−e) or
electron-withdrawing groups (1f−j) and can be extended to the hydrocinnamic Weinreb
amide 1k to provide the corresponding ortho-olefinated products in good yield.
Intriguingly, olefination of biphenyl benzamide 1l occurs at the remote aryl ring, which is
in marked contrast to the selective functionalization of the same substrate at the proximal
ortho-C–H bond with a Rh(III) catalyst.14h
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Table 1. Pd(II)-Catalyzed ortho-Olefination of Weinreb Amides a
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a Conditions: 1 (0.2 mmol), 2 (1.25 to 1.5 equiv), Pd(OAc)2 (10 mol%), Ac-Gly-OH
(20 mol%), Ag2CO3 (2 equiv), HFIP (2 mL), 18-48 h, 70-90°C, in 35 mL sealed tube.
Isolated yields were reported, see SI for details. b Ag2CO3 (3 equiv) was added.
Having established conditions for the olefination of Weinreb amide substrates, we
proceeded to test the feasibility of employing phenylacetyl esters as directing groups in
this transformation. Although benzoates have been applied in C–H functionalization
reactions using various transition metals, phenylacetyl esters are rarely used in these
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transformations.10b,c After a brief reaction optimization we found that desired olefinated
products can be obtained by increasing the amount of silver carbonate and lengthening
the reaction time, which implies that phenylacetyl esters are less reactive than the
corresponding Weinreb amide substrates (Table 2). These reaction conditions are
compatible with both methyl ester and isopropyl ester substrates (5a and 5b). Although a
range of electron-rich substituents (4c-e) are tolerated in this transformation, electron-
deficient phenylacetyl esters afford poor yields except for para-chloro-substituted 4f,
which gave the desired product in synthetically useful yield (5f). In contrast to the
olefination of phenylacetyl Weinreb amides, the olefination of phenylacetyl esters
displayed high mono-selectivity, presumably due to the fast off-rate of the less
coordinative products.
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Table 2. Pd(II)-Catalyzed ortho-Olefination of Phenylacetyl Esters a
a Conditions: 1 (0.2 mmol), 2 (1.5 equiv), Pd(OAc)2 (10 mol%), Ac-Gly-OH (20 mol%),
Ag2CO3 (3 equiv), HFIP (2 mL), 48 h, 80°C, in 15 mL sealed tube. Isolated yields were
reported, see SI for details. For substrates 4a-c minor amount of other isomers was also
observed. b 2 (1.25 equiv)was added. c The reaction was run at 90°C for 60 h.
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We further sought to apply this reactivity to the olefination of dialkyl ketones. To the
best of our knowledge the reactivity of these substrates in C–H functionalization has not
yet been reported (Table 3). To our delight, our reaction conditions developed for the
olefination of phenylacetyl ester substrates are also applicable for the olefination of
phenylacetone derivatives. Although a low yield was obtained with the parent
phenylacetone (6a), the reaction of benzyl ethyl ketone 6b provided the desired
olefinated product in excellent combined yield (7b). It is possible that Pd(II) coordinates
to the carbonyl on the same side of the less hindered methyl group in 6a and results a loss
of reactivity. This reaction proceeds for arylacetone derivatives with both electron-
donating (7c-e) and electron-withdrawing substitutents (7f-g) to provide the
corresponding products in moderate to good yield, albeit the reaction with highly
electron-deficient substrate 6h afforded low yield of desired product (7h). The reaction of
4-phenyl-2-butanone (6i) also provides a moderate yield of the mono-olefinated product
7i.
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Table 3. Pd(II)-catalyzed ortho-olefination of phenylacetone derivatives a
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a Conditions: 1 (0.2 mmol), 2 (1.25-2 equiv), Pd(OAc)2 (10 mol%), Ac-Gly-OH (20 mol%),
Ag2CO3 (3 equiv), HFIP (2 mL), 48 h, 80°C, in 10-35 mL sealed tube. Isolated yields were
reported, see SI for details. For substrates 6i some di-olefinated and minor amount of other
isomers was also observed. b Ag2CO3 (2 equiv) was added. c The reaction was run at 90°C.
d HFIP (1 mL) was added as solvent.
2.2 Acetoxylation of weinreb amides. In order to probe the efficacy of weak chelating
substrates in a variety of C–H functionalization reactions with different redox manifolds
we explored the application of our Weinreb amide substrates in a Pd(II)/Pd(IV)
acetoxylation reaction. We recognized that this transformation might be challenging since
as benzylic methylenes are often unstable to strongly oxidizing reaction conditions. We
were pleased to find that the desired oxidized product 8a could be obtained in 92% of
acetoxylated products (mono/di = 3.2/1) by treatment of Weireb amide 1a with
PhI(OAc)25b, 17 and Ac2O in the presence of 10 mol% Pd(OAc)2 in HFIP at 70 °C for 18h
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(Table 4). The addition of 20 equivalents of Ac2O was found to improve the efficiency of
the reaction and prevent alkoxylation with HFIP. Similar effects of Ac2O have also been
observed in Pd-catalyzed C–H oxygenation with tert-butyl peroxyacetate
(MeCOOOtBu).18 Substrates with either electron-donating (8b-e) or electron-
withdrawing groups (8f-i, m) reacted to afford the corresponding products in moderate to
good yield. An ortho-bromo-substituent is compatible with this reaction, which provided
an opportunity for further product derivatization (8m). The biphenyl Weinreb amide (1l)
was regioselectively acetoxylated at the remote ortho-C–H bond to provide 8l.
Interestingly, acetoxylation of a 3-indole Weinreb amide proceeded selectively at C4,
rather than C2, to afford indole 8n, presumably due to the steric hindrance of the N-Tosyl
protecting group. Treatment of the Weinreb amide 1o, derived from ibuprofen, with our
standard conditions provided the corresponding di-acetoxylated product in 62% yield.
Additionally, the weakly coordinating N,N-dimethyl hydrocinnamic amide 1p also
underwent the desired acetoxylation at the distal remote ortho- C–H bond. We also
found that the inexpensive oxidant ($60 per mol), tert-butyl peroxyacetate
(MeCOOOtBu), was similarly effective for acetoxylation as previously reported in the
asymmetric acetoxylation of sp3 C–H bonds (Scheme 1),18 with slightly longer reaction
times.
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Table 4. Pd(II)-Catalyzed ortho-Acetoxylation of Amides a
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a Conditions: 1 (0.2 mmol), Pd(OAc)2 (10 mol%), PhI(OAc)2 (2 equiv), Ac2O (20 equiv),
HFIP (2 mL), 18-48 h, 70-90 °C, in 35 mL sealed tube. Isolated yields were reported, see
SI for details. b Ac2O (10 equiv) and HFIP (1 mL) were added. c The reaction was run at 0.15
mmol scale, minor amount of other isomers was observed; brsm: based on recovered starting
material.
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Scheme 1. ortho-C–H Acetoxylation of Weinreb amides with inexpensive peroxides
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3. Conclusion
In summary, we have developed ortho-C(sp2)–H olefination and acetoxylation of
commonly used phenylacetyl Weinreb amides, esters, and ketones without installing a
additional directing group. The interplay between the weak coordination and the ligand-
acceleration has also enabled distal C–H functionalization reactions via a seven-
membered cyclopalldation. Functionalizations of ortho-C–H bonds in hydrocinammoyl
ketones and Weinreb amides are exemplary. Notably, both Pd(II)/Pd(0) or Pd(II)/Pd(IV)
redox catalysis are shown to be compatible with these weakly coordinating directing
groups. It is our anticipation that other C–H activation transformations of diverse range of
synthetically relevant substrates will continue to be discovered through the interplay
between the weak coordination of substrates and ligand on the metal centers.
Acknowledgements. We gratefully acknowledge The Scripps Research Institute and
the NIH (NIGMS, 2R01GM084019) for financial support.
Supporting
Information
Avialable.
Detailed
experimental
procedures,
characterization of new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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