Ligand-Enabled Monoselective β-C(sp3)-H Acyloxylation of Free Carboxylic Acids Using a Practical Oxidant

Article abstract of DOI:10.1021/jacs.0c01214

The development of C-H activation reactions that use inexpensive and practical oxidants remains a significant challenge. Until our recent disclosure of the β-lactonization of free aliphatic acids, the use of peroxides in C-H activation reactions directed by weakly coordinating native functional groups was unreported. Herein, we report C(sp³)-H β-acetoxylation and γ-, δ-, and ?-lactonization reactions of free carboxylic acids enabled by a novel cyclopentane-based mono-N-protected β-amino acid ligand. Notably, tert-butyl hydrogen peroxide is used as the sole oxidant for these reactions. This reaction has several key advantages over other C-H activation protocols: (1) exclusive monoselectivity was observed in the presence of two α-methyl groups; (2) aliphatic carboxylic acids containing α-hydrogens are compatible with this protocol; (3) lactonization of free acids, affording γ-, δ-, or ?-lactones, has been achieved for the first time.

Full text of DOI:10.1021/jacs.0c01214

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Article
Ligand-Enabled mono-Selective #-C(sp3)–H Acyloxylation
of Free Carboxylic Acids Using a Practical Oxidant
Zhe Zhuang, Alastair N. Herron, Zhoulong Fan, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c01214 • Publication Date (Web): 22 Mar 2020
Downloaded from pubs.acs.org on March 23, 2020
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Ligand-Enabled mono-Selective β-C(sp3)–H
Acyloxylation of Free Carboxylic Acids Using a
Practical Oxidant
Zhe Zhuang,† Alastair N. Herron,† Zhoulong Fan,† and Jin-Quan Yu*,†
†Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla,
California 92037, United States
*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. The development of C–H activation reactions that use inexpensive and practical oxidants
remains a significant challenge. Until our recent disclosure of the β-lactonization of free aliphatic acids,
the use of peroxides in C–H activation reactions directed by weakly coordinating native functional groups
was unreported. Herein we report C(sp3)–H β-acetoxylation and γ-, δ-, and ε-lactonization reactions of
free carboxylic acids enabled by a novel cyclopentane-based mono-N-protected β-amino acid (MPAA)
ligand. Notably, tert-butyl hydrogen peroxide (TBHP) is used as the sole oxidant for these reactions. This
reaction has several key advantages over other C–H activation protocols: (1) exclusive mono-selectivity
was observed in the presence of two α-methyl groups; (2) aliphatic carboxylic acids containing α-
hydrogens are compatible with this protocol; (3) lactonization of free acids, affording γ-, δ-, or ε-lactones,
has been achieved for the first time.
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1. Introduction
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The past two decades have witnessed significant advances in the development of carbon–carbon
and carbon–heteroatom bond-forming C–H activation reactions based on Pd(0)/Pd(II), Pd(II)/Pd(IV),
Pd(II)/Pd(0), and Pd(II)/Pd(II) catalysis.1 From a practical perspective, each catalytic cycle has inherent
advantages and limitations. For example, Pd(II)/Pd(0) catalysis enables transformations with a wide range
of coupling partners, such as organotin2a and organoboron2b,c reagents. Meanwhile in Pd(II)/Pd(IV)
catalysis, the relatively facile reductive elimination from Pd(IV) allows the reaction of C–H bonds with a
variety of electrophiles such as I2, Cl2, IOAc, PhSSPh, PhSeSePh, and BzOOBz.3 Interestingly, PhI(OAc)2
has been shown to be an effective oxidant for both C(sp2)–H4a,b and C(sp3)–H4c activation reactions.
Among a range of strong oxidants that are capable of oxidizing Pd(II) to Pd(IV), inexpensive, practical,
and readily available group 16 oxidants such as peroxides have received special attention. In 1990, van
Koten’s group reported that cyclopalladated N,N-dimethylbenzylamine complexes could be oxygenated
with tert-butyl hydrogen peroxide (TBHP).5 An unstable Pd(IV) oxo intermediate was proposed to give
oxygenated product by oxygen insertion into the Pd–C bond. Pioneering work from Canty’s group in 1998
showed that the stable Pd(IV) complex from the oxidation of Pd(II) by PhSeSePh could be isolated and
characterized (Scheme 1B).6 At higher temperatures, this Pd(IV) complex decomposed to form a carbon–
selenium bond-containing product and ethane. The analogous Pd(IV) intermediate from BzOOBz could
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also be detected by H NMR, but was too unstable to be isolated; its decomposition yielded the
corresponding oxidation products. In our early work on chiral oxazoline-directed asymmetric β-C(sp3)–
H acetoxylation (Scheme 1C),7 we proposed that the oxidative addition of AcOOtBu forms a Pd(IV)
intermediate, which undergoes subsequent reductive elimination to afford acetoxylated product. However,
despite the great value such reactions might have for synthetic chemistry, in the past decade further efforts
to develop C–H activation reactions using peroxides as the sole oxidant have led to little success outside
of C(sp2)–H functionalization reactions.8 Indeed, the use of peroxides for C–H activation reactions
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directed by weakly coordinating native functional groups was unprecedented until our recent disclosure
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of the β-lactonization of free aliphatic acids (Scheme 1D).9
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Scheme 1. Pd(IV) Chemistry Enabled by Group 16 Oxidants
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A Oxygenation of cyclopalladated complex using TBHP (van Koten, 1990)
O
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tBuOOH
O
PdII
PdII
PdIV
N
N
N
N
N
N
Me2
Me2
Me2
Me2
Me2
Me2
proposed Pd(IV) oxo species
B Pioneering synthesis of Pd(IV) complex using RXXR (Canty, 1998)
XR
Me Me
+
Me XR
N
N
Me
Me
N
N
Me
Me
RXXR
-70 oC
PdIV
XR
PdII
RXXR = PhSeSePh characterized by X-ray
= BzOOBz detected by 1H NMR
C Oxazoline-directed -C(sp3) H acetoxylation using AcOOtBu (Yu, 2005)


Me
Me
OtBu
cat. Pd(OAc)2
AcOOtBu
O
H
O
Me
Me
Me
Me
O
R1
R2
N
R1
R2
PdIV
N
N
Ac2O, 65 oC
R1
R2
OAc
OAc
4872 h
limited to tertiary acids
mixture of mono- and di-products
D Free carboxylic acid-directed -C(sp3) H acyloxylation using TBHP


L10
L12
Pd(OAc)2/
Na2CO3, TBHP
with Ac2O
Pd(CH3CN)2Cl2/
OH
M+
CsHCO3, TBHP
without Ac2O
O
R1
L
L
O
R1
R2
O
O
PdIV
OH
R2
Me
O
OtBu
R1
OAc
R2
CO2H
NHAc
CO2H
mono/di > 20/1
NHAc
L10
L12
O
R
L12
O
O
( )n
R
( )n
"standard conditions"
OH
HO
OH
without Ac2O
  and lactonization
O
H
O
Hydroxy fatty acids represent an important class of lipids that have broad applications in dietary
supplements and pharmaceuticals.10 The distance between the hydroxyl and carboxylic acid functional
groups has a remarkable effect on biological activity.11 It is therefore highly desirable to develop synthetic
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methods to selectively oxidize parent fatty acids.12,13 Recent advances in the C(sp3)–H activation of
aliphatic acid derivatives represent a powerful approach to the direct oxidation of aliphatic acids at the β
position (Scheme 1C).7 However, these reaction protocols always require exogenous directing groups
(DGs) to promote cyclometallation; thus two or three additional steps are required to install and remove
the DG.4c,7,14,15a-c Additionally, reported oxidants used in C–H oxidation are largely limited to hypervalent
iodine reagents such as PhI(OAc)2.4,14b-g,15,16 Despite the early successes in β-arylations of free acids
through the reactivity of sodium or potassium carboxylates,2c analogous acetoxylation reactions were only
recently reported by van Gemmeren’s group.16 However, this protocol requires 2.5 equivalents of excess
acid substrate and PhI(OAc)2 as the limiting reagent. In addition, aliphatic acids containing α-hydrogens
are not reactive. Despite significant advances in developing diverse C–H activation transformations for
free aliphatic acids,17 scalable and practical β-C(sp3)–H oxidations of free acids remain a significant
challenge.
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Herein we report β-C(sp3)–H acyloxylation of free carboxylic acids enabled by a newly developed
mono-N-protected β-amino acid (MPAA) ligand (Scheme 1D). This method features relatively mild
temperatures (60 °C), an inexpensive and practical oxidant (TBHP in water, $5/mol), and uses two
equivalents of Ac2O as the crucial promoter. A broad range of aliphatic acids containing α-hydrogens or
α-quaternary centers are compatible with this catalysis. Exclusive mono-selectivity was observed for acids
bearing multiple α-methyl groups. The C(sp3)–H γ-, δ-, and ε-lactonization of free carboxylic acids has
also been realized for the first time.
2. Results and Discussion
Following our earlier disclosure of the asymmetric β-acetoxylation of aliphatic acids using chiral
oxazoline directing groups,7 we have extensively investigated the possibility of extending this practically
appealing catalytic system to free carboxylic acids without success for the past 15 years. Prompted by our
recent discovery that C(sp3)–H activation of free carboxylic acids could be promoted by a bidentate
ligand,17 we began to test various ligands for reactivity using TBHP (70% in water) as the oxidant. We
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discovered that a β-amino acid ligand promoted an unprecedented β-lactonization reaction.9 This finding
prompted us to further tune the ligand and reaction conditions such that the reductive elimination pathway
of the Pd(IV) intermediate might favor an acyloxylation pathway (Scheme 1D). We selected 2-methyl
butyric acid 1a as a model substrate for ligand design and reaction development (Table 1). While no
desired acetoxylation product was detected in the absence of ligand, we were pleased to observe a 13%
1H NMR yield of β-acetoxylation product 1b when using the thioether-based bidentate ligand L2.17d
However, thioether ligand L2 was completely oxidized to sulfoxide after the reaction, which may have
contributed to the low yield of the reaction. Guided by MPAA ligand-enabled arylation17b,c,f and
lactonization9 reactions of free aliphatic acids, a series of commercially available MPAA ligands (L4–
L8) that are stable in the presence of peroxide were investigated. To our delight, the simple β-amino acid
ligand L8 further improved the yield to 44%. Further modifications to the backbone of the β-amino acid
ligand (L9–L11, with L10 being the optimal ligand from the previously reported β-lactonization reaction),
led to no further improvement in yield. Aiming to test the effect of a more rigid conformation and bite
angle on ligand reactivity,18 a series of cycloalkane-based cis-bidentate β-amino acid ligands (L12–L14)
were prepared. To our delight, the yield was improved to 61% using the cyclopentane-based ligand L12.
Furthermore, the corresponding methyl ester of the desired acetoxylation product could be isolated in 72%
yield when using TBHP in decane. However, lower catalysis loading led to lower yield: using 5 mol%
and 2 mol% Pd only gave 31% and 7% 1H NMR yield, respectively. A control experiment showed that
no reaction occurred in the presence of the γ-amino acid ligand (L15), indicating the importance of six-
membered chelation for the observed reactivity.
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Table 1. Ligand Investigation for β-C(sp3)–H Acetoxylationa,b
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Pd(OAc)2 (10 mol%)
O
O
L
ligand ( ) (20 mol%)
Me
OH
Me
OH
OAc
Na2CO3 (1.0 eq), Ac2O (2.0 eq)
TBHP (70% in water) (2.0 eq)
HFIP, 60 oC, 12 h
H
1a
2a
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AcHN
N
w/o ligand
0%
S
NHAc
Me
N
Me
L1
L2
L3
, 0%
, 0%
, 13%
Me
CO2H
NHAc
CO2H
NHAc
Me
CO2H
NHAc
L5
CO2H
Me
NHAc
, 18%
L4
L6
L7
, 25%
, 29%
, 28%
Me
Me
CO2H
NHAc
Me
Me
CO2H
CO2H
NHAc
L9
CO2H
NHAc
NHAc
L8
L10
L11
, 19%
, 44%
, 40%
, 28%
CO2H
NHAc
L12
CO2H
NHAc
L13
CO2H
NHAc
L14
AcNH
CO2H
c
L15
, 0%
, 61%(72% )
, 56%
, 43%
aConditions: 1a (0.1 mmol), Pd(OAc)2 (10 mol%), ligand (L) (20 mol%), Na2CO3 (1.0 eq), Ac2O (2.0 eq), TBHP (70%
b
1
in water) (2.0 eq), HFIP, 60 °C, 12 h. The yields were determined by H NMR analysis of the crude product using
CH2Br2 as the internal standard. cTBHP (~5.5 M in decane) (2.0 eq), isolated yield of the corresponding methyl ester.
With the optimal ligand and reaction conditions in hand, the scope of aliphatic carboxylic acids
was evaluated (Table 2). Compared to the β-lactonization reaction,9 this protocol showed broader scope
since a wide range of aliphatic carboxylic acids containing α-hydrogens were compatible with the current
conditions. Commercially available 2-methyl aliphatic acids (1a–1e) could undergo β-C(sp3)–H
acetoxylation in good yields. Less reactive propionic acid (1f) also provided the acetoxylation product in
moderate yield (51%). Aliphatic carboxylic acids bearing cyclic rings, including six- (1g–1j), five- (1k),
four- (1l), and three- (1m and 1u) membered rings, were well tolerated. Among these acids, potentially
reactive functional groups including carbonyl (1h) and tert-butyloxycarbonyl (Boc) (1j) groups were
untouched under these mild conditions. Phenyl (2n–2p, 2v, 2y, and 2ab) groups were also compatible
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with the TBHP system, and remained intact despite the potentially reactive aryl or benzylic C–H bonds.
A range of synthetically versatile functionalities such as benzoyl (Bz) protected hydroxyl (2q), ester (2r),
chloro (2s), fluoro (2w), and trifluoromethyl (2x) were all well tolerated. Aliphatic carboxylic acids
bearing α-quaternary centers (1t–1ab) consistently afforded the desired acetoxylation products in useful
yields. Notably, compared to other β-C(sp3)–H functionalization reactions, this protocol displayed
exclusive mono-selectivity (2b and 2t–2y) in the presence of two α-methyl groups, likely due to catalysis
deactivation via bidentate chelation by the installed OAc group and carboxylate group. It is noteworthy
that the low yield for several cases is due to low conversion; remaining unreacted acid substrates could
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be detected from crude H NMR, while by-products such as β-lactone and β-hydroxy acid weren’t
observed during the reaction. Besides acetic anhydride, other aliphatic acid anhydrides including
propionic, isobutyric, and pivalic anhydrides are also compatible with the reported protocol but with low
efficiency (see Supporting Information Table S7).
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Table 2. Substrate Scope for β-C(sp3)–H Acetoxylationa,b
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3
4
5
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7
8
Pd(OAc)2 (10 mol%)
L12
O
O
R1
R2
R1
R2
(20 mol%)
OH
OH
Na2CO3 (1.0 eq), Ac2O (2.0 eq)
TBHP (~5.5 M in decane) (2.0 eq)
HFIP, 60 oC, 12 h
H
1
OAc
2
9
O
O
O
O
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( )3
Me
Me
Me
Me
OH
OAc
, 72%
OH
OH
OAc
, 74%
Me
OH
OAc
, 64%
OAc
2a
2b
2c
2d
, 72%
mono/di > 20/1
O
O
O
O
O
( )4
OH
OAc
, 67%
OH
OH
OAc
, 44%
OH
OAc
, 37%
OAc
2e
2f
2g
2k
2h
, 51%
, 41%
O
O
O
O
OH
OAc
, 54%
OH
OH
OAc
, 46%
OH
OAc
, 50%
BocN
OAc
2i
2j
2l
O
O
O
O
( )3
( )5
OH
OAc
, 43%
OH
OH
OAc
, 51%
OH
OAc
2p
, 41%
OAc
, 40%
2m
2n
2o
O
O
O
O
( )4
( )4
( )5
BzO
OH
OAc
, 66%
MeO2C
OH
OAc
, 62%
Cl
OH
OAc
, 52%
Me
OH
OAc
, 45%
Me
2q
2r
2s
2t
mono/di > 20/1
O
O
O
O
( )3
Me
( )4
( )4
OH
OAc
, 33%
OH
OAc
, 43%
F
OH
F3C
OH
OAc
, 40%
Me
Me
Me
OAc
2u
2v
2w
2x
, 51%
mono/di > 20/1
mono/di > 20/1
mono/di > 20/1
mono/di > 20/1
NO2
O
O
O
O
( )3
( )3
i-Bu
O
Me
OH
OAc
Me
OH
OAc
, 52%
OH
OH
OAc
, 55%
Et
Et
Et
OAc
2y
2z
2aa
, 54%
2ab
, 55%
mono/di > 20/1
aConditions: 1 (0.1 mmol), Pd(OAc)2 (10 mol%), L12 (20 mol%), Na2CO3 (1.0 eq), Ac2O (2.0 eq), TBHP (~5.5 M in
decane) (2.0 eq), HFIP, 60 oC, 12 h. bIsolated yields of the corresponding methyl ester.
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To demonstrate the utility of the herein reported method, we performed the reaction on a 3.0 mmol
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7
8
scale with substrate 1d using TBHP in water under the aforementioned reaction conditions, yielding the
desired β-acetoxylated carboxylic acid in 55% yield. The acetyl protecting group could be removed in the
presence of K2CO3 to generate the free β-hydroxy acid in near quantitative yield (95%). (Scheme 2)
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Scheme 2. Scale-up Reaction and Deprotection of Acetyl Group
O
O
O
( )3
( )3
( )3
"std conditions"
K2CO3
Me
OH
Me
OH
Me
OH
H
OAc
OH
3
1d
2d
3.0 mmol,
55%,
95%,
We were also interested in whether this protocol could be extended to form synthetically valuable
lactones in an intramolecular fashion (Table 3). Although a single example of C(sp3)–H lactonization of
acid derivatives has been reported,14f this method was limited to the syntheses of γ-lactones and the use
of a directing group. By simply changing the base and removing Ac2O (see Supporting Information for
details), we were delighted to find that the desired lactonization product could be obtained. Different sizes
of lactones such as γ-lactones (5a), δ-lactones (5b and 5d), and ε-lactones (5c) could be formed in
moderate to good yields. Less reactive free carboxylic acids containing α-hydrogen (4d) were also
compatible with the standard conditions.
Table 3. Substrate Scope for C(sp3)–H γ-, δ-, and ε-Lactonizationa,b
O
R1
Pd(OAc)2 (10 mol%)
L12
O
O
H
( )n
R1
( )n
OH
(20 mol%)
HO
OH
K3PO4 (1.0 eq)
TBHP (~5.5 M in decane) (2.0 eq)
HFIP, 60 oC, 12 h
O
O
n = 0–2
4
5
O
O
Me
Me
O
O
Me
OH
OH
OH
OH
O
O
O
O
O
O
O
O
5a
5b
5c
5d
, 54%
, 51%
, 73%
, 59%
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aConditions: 4 (0.1 mmol), Pd(OAc)2 (10 mol%), L12 (20 mol%), K3PO4 (1.0 eq), TBHP (~5.5 M in decane) (2.0 eq),
1
2
3
HFIP, 60 oC, 12 h. bIsolated yields of the corresponding methyl ester.
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9
Based on previous literature6-9 and our results from the lactonization reaction, we propose that our
transformation proceeds via the Pd(II)/Pd(IV) catalytic cycle outlined in Scheme 3. First, coordination of
Pd(OAc)2 to an MPAA ligand generates the active LPd(II)(OAc) species. After coordination of the acid
substrate 1 to Pd, both the counteranion Na+ and the MPAA ligand accelerate the cyclopalladation of the
β-C(sp3)–H bond to form int-I. Next, oxidative addition of int-I by TBHP produces int-II. The direct
involvement of TBHP without formation of AcOOtBu by Ac2O in the oxidation addition step is supported
by 1H NMR studies of the reaction and the success of lactonization under the conditions without Ac2O.
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t
In the previously reported β-lactonization reaction, promoted by BuO- and MPAA on Pd(IV) center,
selective reductive elimination of int-II yields strained β-lactone product. In contrast, in this case, int-II
undergoes subsequent ligand exchange by Ac2O to generate int-III. Finally, reductive elimination
generates β-acetoxylation product 2 and regenerates LPd(II)(OAc) species; however, an SN2-type
reaction by AcO- that affords the final product cannot be ruled out. Similarly, for lactonization reaction,
two possible pathways of Pd(IV) center (int-II) are proposed to generate lactone product: (1) carboxylic
acid moiety on the side chain can replace OH or OtBu on Pd(IV) (int-II) by ligand exchange. Subsequent
reductive elimination affords the lactonization product; (2) it is also possible that the other carboxylate
from diacid can attack C–Pd(IV) bond of int-II by SN2-type reaction to yield lactone product. The
possibility of forming the acetoxylated product from the corresponding β-lactone was ruled out by a
control experiment: when the β-lactone analog of 2t was subjected to the standard conditions, no
acetoxylated product was observed.
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Scheme 3. Proposed Mechanism for β-C(sp3)–H Acetoxylation
1
2
3
4
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8
Pd(OAc)2
O
O
L
R1
R2
R1
R2
O-Na+
O-Na+
II
L
Pd (OAc)
H
OAc
2
1
C–H
activation
9
reductive
elimination
HOAc
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OAc
Na+
Na+
O
L
L
L
L
O
O
O
PdIV
PdII
Pd(II)/Pd(IV)
R1
R1
OAc
R2
R2 int-I
int-III
tBuOH
TBHP
oxidative
addition
OH
Na+
L
L
O
O
PdIV
Ac2O
OtBu
R1
R2int-II
ref.9
R1
O
R2
O
3. Conclusion
In summary, we have developed Pd(II)-catalyzed intra- and intermolecular C(sp3)–H
acyloxylation of carboxylic acids using inexpensive TBHP as the sole oxidant. The key to this reaction’s
success hinged on the design of a cyclopentane-based MPAA ligand. The use of the inexpensive oxidant
TBHP (70% in water) renders this reaction practical and scalable. A wide range of α-methyl aliphatic
carboxylic acids are compatible with the reported conditions and exclusive mono-selectivity is observed
in the presence of multiple α-methyl groups. An efficient method for the C(sp3)–H γ-, δ-, and ε-
lactonization of free carboxylic acids has also been realized for the first time.
4. Experimental Section
General procedure for β-C(sp3)–H acetoxylation. In the culture tube, Pd(OAc)2 (10 mol%, 2.2 mg),
ligand L12 (20 mol%, 3.4 mg), Na2CO3 (1.0 eq, 10.6 mg), and carboxylic acid 1 (0.1 mmol) in order were
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weighed in air and placed with a magnetic stir bar. Then HFIP (1.0 mL), Ac2O (2.0 eq, 19 μL), and TBHP
(~5.5 M in decane) (2.0 eq, 36 μL) were added. The reaction mixture was stirred at rt for 3 minutes, and
then heated to 60 °C for 12 hours (600 rpm). After being allowed to cool to room temperature, the mixture
was treated with AcOH (0.05 mL) and concentrated in vacuo. The resulting mixture was dissolved in
MeOH (1.0 mL), treated with TMSCHN2 (2.0 eq), and concentrated in vacuo after 1 hour. The crude
mixture was purified by pTLC or column chromatography to afford corresponding methyl esters. Full
experimental details and characterization of new compounds can be found in the Supporting Information.
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Corresponding author. *yu200@scripps.edu
Notes. The authors declare no competing financial interest.
Acknowledgements. We gratefully acknowledge The Scripps Research Institute and the NIH (NIGMS,
R01GM084019) for financial support.
Supporting Information Available. Full experimental details and characterization of new compounds.
This material is available free of charge via the internet at http://pubs.acs.org.
References
1.
For reviews on C–H functionalization, see: (a) Daugulis, O.; Roane, J.; Tran, L. D. Bidentate, Monoanionic
Auxiliary-Directed Functionalization of Carbon–Hydrogen Bonds. Acc. Chem. Res. 2015, 48, 1053−1064.
(b) Lyons, T. W.; Sanford, M. S. Palladium-Catalyzed Ligand-directed C–H Functionalization Reactions.
Chem. Rev. 2010, 110, 1147−1169. (c) He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Palladium-
Catalyzed Transformations of Alkyl C–H Bonds. Chem. Rev. 2017, 117, 8754−8786.
2.
(a) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. Palladium-Catalyzed Alkylation of Aryl C–
H Bonds with sp3 Organotin Reagents Using Benzoquinone as a Crucial Promoter. J. Am. Chem. Soc. 2006,
128, 78−79. (b) Chen, X.; Goodhue, C. E.; Yu, J.-Q. Palladium-Catalyzed Alkylation of sp2 and sp3 C–H
Bonds with Methylboroxine and Alkylboronic Acids:ꢀ Two Distinct C–H Activation Pathways. J. Am.
Chem. Soc. 2006, 128, 12634−12635. (c) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.;
ACS Paragon Plus Environment
12

Page 13 of 18
Journal of the American Chemical Society
Saunder, L. B.; Yu, J.-Q. Palladium-Catalyzed Methylation and Arylation of sp2 and sp3 C–H Bonds in
Simple Carboxylic Acids. J. Am. Chem. Soc. 2007, 129, 3510−3511.
1
2
3
4
3.
For reviews on Pd(IV) chemistry, see: (a) Xu, L.-M.; Li, B.-J.; Yang, Z.; Shi, Z.-J. Organopalladium(IV)
Chemistry. Chem. Soc. Rev. 2010, 39, 712−733. (b) Sehnal, P.; Taylor, R. J. K.; Fairlamb, I. J. S.
Emergence of Palladium(IV) Chemistry in Synthesis and Catalysis. Chem. Rev. 2010, 110, 824−889. (c)
Engle, K. M.; Mei, T.-S.; Wang, X.; Yu, J.-Q. Bystanding F+ Oxidants Enable Selective Reductive
Elimination From High-Valent Metal Centers in Catalysis. Angew. Chem., Int. Ed. 2011, 50, 1478−1491.
For selected examples using aryl iodide for Pd(IV) chemistry, see: (d) Li, B.; Seth, K.; Niu, B.; Pan, L.;
Yang, H.; Ge, H. Transient-Ligand-Enabled ortho-Arylation of Five-Membered Heterocycles: Facile
Access to Mechanochromic Materials. Angew. Chem., Int. Ed. 2018, 57, 3401−3405. (e) Li, B.; Lawrence,
B.; Li, G.; Ge, H. Ligand-Controlled Direct γ-C–H Arylation of Aldehydes. Angew. Chem., Int. Ed. 2020,
59, 3078−3082. (f) Zhang, F.-L.; Hong, K.; Li, T.-J.; Park, H.; Yu, J.-Q. Functionalization of C(sp3)–H
Bonds Using a Transient Directing Group. Science 2016, 351, 252−256. (g) Chen, G.; Gong, W.; Zhuang,
Z.; Andrä, M. S.; Chen, Y.-Q.; Hong, X.; Yang, Y.-F.; Liu, T.; Houk, K. N.; Yu, J.-Q. Ligand Accelerated
Enantioselective Methylene C(sp3)–H Bond Activation. Science 2016, 353, 1023−1027. (h) Wu, Q.-F.;
Shen, P.-X.; He, J.; Wang, X.-B.; Zhang, F.; Shao, Q.; Zhu, R.-Y.; Mapelli, C.; Qiao, J. X.; Poss, M. A.;
Yu, J.-Q. Formation of α-Chiral Centers by Asymmetric β-C(sp3)–H Arylation, Alkenylation, and
Alkynylation. Science 2017, 355, 499−503.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
4.
(a) Yoneyama, T.; Crabtree, R. H. Pd(II) catalyzed Acetoxylation of Arenes with Iodosyl Acetate. J. Mol.
Catal. A 1996, 108, 35−40. (b) Dick, A. R.; Hull, K. L.; Sanford, M. S. A Highly Selective Catalytic Method
for the Oxidative Functionalization of C−H Bonds. J. Am. Chem. Soc. 2004, 126, 2300−2301. (c) Desai, L.
V.; Hull, K. L.; Sanford, M. S. Palladium-Catalyzed Oxygenation of Unactivated sp3 C–H Bonds. J. Am.
Chem. Soc. 2004, 126, 9542−9543.
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5.
(a) Alsters, P. L.; Teunissen, H. T.; Boersma, J.; van Koten, G. The Oxygenation of Cyclopalladated N,N-
Dimethylbenzylamine Derivatives with tert-Butyl Hydroperoxide. Recl. Trav. Chim. Pays-Bas 1990, 109,
487−489. (b) Alsters, P. L.; Teunissen, H. T.; Boersma, J.; Spek, A. L.; van Koten, G. Oxygenation of
Cyclopalladated N,N-Dimethylbenzylamine Complexes by Inorganic and Organic Peroxides: Oxygen
Insertion into the Palladium–Carbon Bond. Organometallics 1993, 12, 4691−4696.
ACS Paragon Plus Environment
13

Journal of the American Chemical Society
Page 14 of 18
6.
(a) Canty, A. J.; Jin, H.; Skelton, B. W.; White, A. H. Oxidation of Complexes by (O2CPh)2 and (ER)2 (E
= S, Se), Including Structures of Pd(CH2CH2CH2CH2)(SePh)2(bpy) (bpy = 2,2‘-Bipyridine) and
MMe2(SePh)2(L2) (M = Pd, Pt; L2 = bpy, 1,10-Phenanthroline) and C···O and C···E Bond Formation at
Palladium(IV). Inorg. Chem. 1998, 37, 3975−3981. (b) Byers, P. K.; Canty, A. J.; Skelton, B. W.; White,
A. H. The Oxidative Addition of Iodomethane to [PdMe2(bpy)] and the X-ray Structure of the
Organopalladium(IV) Product fac-[PdMe3(bpy)l](bpy = 2,2′-bipyridyl). J. Chem. Soc., Chem. Commun.
1986, 1722−1724.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7.
8.
Giri, R.; Liang, J.; Lei, J.-G.; Li, J.-J.; Wang, D.-H.; Chen, X.; Naggar, I. C.; Guo, C.; Foxman, B. M.; Yu,
J.-Q. Pd‐Catalyzed Stereoselective Oxidation of Methyl Groups by Inexpensive Oxidants under Mild
Conditions: A Dual Role for Carboxylic Anhydrides in Catalytic C–H Bond Oxidation. Angew. Chem., Int.
Ed. 2005, 44, 7420−7424.
(a) Vickers, C. J.; Mei, T. S.; Yu, J.-Q. Pd(II)-Catalyzed o-C–H Acetoxylation of Phenylalanine and
Ephedrine Derivatives with MeCOOOtBu/Ac2O. Org. Lett. 2010, 12, 2511−2513. (b) Wei, Y.; Yoshikai,
N. Oxidative Cyclization of 2-Arylphenols to Dibenzofurans under Pd(II)/Peroxybenzoate Catalysis. Org.
Lett. 2011, 13, 5504−5507. (c) Duan, S.; Xu, Y.; Zhang, X.; Fan, X. Synthesis of 2,2’-Biphenols through
Direct C(sp2)–H Hydroxylation of [1,1’]-Biphenyl]-2-ols. Chem. Commun. 2016, 52, 10529−10532. (d)
Zhang, Y.; Feng, J.; Li, C.-J. Palladium-Catalyzed Methylation of Aryl C–H Bond by Using Peroxides. J.
Am. Chem. Soc. 2008, 130, 2900−2901. (e) Sharma, A. K.; Roy, D.; Sunoj, R. B. The Mechanism of
Catalytic Methylation of 2-Phenylpyridine using Di-tert-butyl Peroxide. Dalton Trans. 2014, 43,
10183−10201. (f) Lv, W.; Wen, S.; Liu, J.; Cheng, G. Palladium-Catalyzed ortho-C–H Methylation of
Benzoic Acids. J. Org. Chem. 2019, 84, 9786−9791.
9.
Zhuang, Z.; Yu, J.-Q. Lactonization as a General Route to β-C(sp3)–H Functionalization. Nature 2020, 577,
656−659.
10.
(a) Cao, Y.; Zhang, X. Production of Long-Chain Hydroxy Fatty Acids by Microbial Conversion. Appl.
Microbiol. Biotechnol. 2013, 97, 3323−3331. (b) Offermanns, S. Free Fatty Acid (FFA) and Hydroxy
Carboxylic Acid (HCA) Receptors. Annu. Rev. Pharmacol. Toxicol. 2014, 54, 407−434. (c) Kornhauser,
A.; Coelho, S. G.; Hearing, V. J. Applications of Hydroxy acids: Classification, Mechanisms, and
Photoactivity. Clin. Cosmet. Investig. Dermatol. 2010, 3, 135−142.
ACS Paragon Plus Environment
14

Page 15 of 18
Journal of the American Chemical Society
11.
(a) Kaspersen, M. H.; Jenkins, L.; Dunlop, J.; Milligan, G.; Ulven, T. Succinct Synthesis of Saturated
Hydroxy Fatty Acids and in vitro Evaluation of all Hydroxylauric Acids on FFA1, FFA4 and GPR84. Med.
Chem. Commun. 2017, 8, 1360−1365. (b) Yore, M. M.; Syed, I.; Moraes-Vieira, P. M.; Zhang, T.; Herman,
M. A.; Homan, E. A.; Patel, R. T.; Lee, J.; Chen, S.; Peroni, O. D.; Dhaneshwar, A. S.; Hammarstedt, A.;
Smith, U.; McGraw, T. E.; Saghatelian, A.; Kahn, B. B. Discovery of a Class of Endogenous Mammalian
Lipids with Anti-Diabeticand Anti-inflammatory Effects Cell 2014, 159, 318−332.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12.
For reviews on C–H oxidation reactions, see: (a) Moghimi, S.; Mahdavi, M.; Shafiee, A.; Foroumadi, A.
Transition‐Metal‐Catalyzed Acyloxylation: Activation of C(sp2)–H and C(sp3)–H Bonds. Eur. J. Org.
Chem. 2016, 3282−3299. (b) Le Bras, J.; Muzart, J. C–O Bonds from Pd‐Catalyzed C(sp3)–H Reactions
Mediated by Heteroatomic Groups. Eur. J. Org. Chem. 2018, 1176−1203. (c) Sterckx, H.; Morel, B.; Maes,
B. U. W. Catalytic Aerobic Oxidation of C(sp3)–H Bonds. Angew. Chem., Int. Ed. 2019, 58, 7946−7970.
For reviews on biocatalytic oxidation reactions, see: (a) Dong, J.; Fernandez-Fueyo, E.; Hollmann, F.; Paul,
C.; Pasic, M.; Schmidt, S.; Wang, Y.; Younes, S.; Zhang, W. Biocatalytic Oxidation Reactions: A Chemist's
Perspective. Angew. Chem., Int. Ed. 2018, 57, 9238−9261. (b) Sheldon, R. A.; Woodley, J. M. Role of
Biocatalysis in Sustainable Chemistry. Chem. Rev. 2018, 118, 801−838.
13.
14.
For C(sp3)–H oxidation of carboxylic acids using various directing groups, see: (a) Reddy, B. V. S.; Reddy,
L. R.; Corey, E. J. Novel Acetoxylation and C–C Coupling Reactions at Unactivated Positions in α-Amino
Acid Derivatives. Org. Lett. 2006, 8, 3391−3394. (b) Chen, K.; Zhang, S.-Q.; Jiang, H.-Z.; Xu, J.-W.; Shi,
B.-F. Practical Synthesis of anti‐β‐Hydroxy‐α‐Amino Acids by PdII‐Catalyzed Sequential C(sp3)–H
Functionalization. Chem. -Eur. J. 2015, 21, 3264−3270. (c) Rit, R. K.; Yadav, M. R.; Sahoo, A. K. Pd(II)-
Catalyzed Primary-C(sp3)–H Acyloxylation at Room Temperature. Org. Lett. 2012, 14, 3724−3727. (d)
Chen, F.-J.; Zhao, S.; Hu, F.; Chen, K.; Zhang, Q.; Zhang, S.-Q.; Shi, B.-F. Pd(II)-Catalyzed Alkoxylation
of Unactivated C(sp3)–H and C(sp2)–H Bonds Using a Removable Directing Group: Efficient Synthesis of
Alkyl Ethers. Chem. Sci. 2013, 4, 4187−4192. (e) Gong, W.; Zhang, G.; Liu, T.; Giri, R.; Yu, J.-Q. Site-
Selective C(sp3)–H Functionalization of Di-, Tri-, and Tetrapeptides at the N-Terminus. J. Am. Chem. Soc.
2014, 136, 16940−16946. (f) Liu, B.; Shi, B.-F. γ-Lactone Synthesis via Palladium(II)-Catalyzed
Lactonization of Unactivated Methylene C(sp3)–H Bonds. Synlett 2016, 27, 2396−2400. (g) Shan, G.; Yang,
X.; Zong, Y.; Rao, Y. An Efficient Palladium‐Catalyzed C–H Alkoxylation of Unactivated Methylene and
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15

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Page 16 of 18
Methyl Groups with Cyclic Hypervalent Iodine (I3+) Oxidants. Angew. Chem., Int. Ed. 2013, 52,
13606−13610. (h) Wu, X.; Zhao, Y.; Ge, H. Copper‐Promoted Site‐Selective Acyloxylation of Unactivated
C(sp3)–H Bonds. Chem. Asian J. 2014, 9, 2736−2739. (i) Wang, Z.; Kuninobu, Y.; Kanai, M. Copper-
Mediated Direct C(sp3)–H and C(sp2)–H Acetoxylation. Org. Lett. 2014, 16, 4790−4793. (j) Zhou, L.; Lu,
W. Palladium-Catalyzed β-Acyloxylation of Simple Amide via sp3 C–H Activation. Org. Lett. 2014, 16,
508−511.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
15.
For C–H oxidation of other classes of substrates using directing groups and PhI(OAc)2, see: (a) Zhang, S.-
Y.; He, G.; Zhao, Y.; Wright, K.; Nack, W. A.; Chen, G. Efficient Alkyl Ether Synthesis via Palladium-
Catalyzed, Picolinamide-Directed Alkoxylation of Unactivated C(sp3)–H and C(sp2)–H Bonds at Remote
Positions. J. Am. Chem. Soc. 2012, 134, 7313−7316. (b) Ye, X.; He, Z.; Ahmed, T.; Weise, K.; Akhmedov,
N. G.; Petersen, J. L.; Shi, X. 1,2,3-Triazoles as Versatile Directing Group for Selective sp2 and sp3 C–H
Activation: Cyclization vs Substitution. Chem. Sci. 2013, 4, 3712−3716. (c) Ren, Z.; Mo, F.; Dong, G.
Catalytic Functionalization of Unactivated sp3 C–H Bonds via exo-Directing Groups: Synthesis of
Chemically Differentiated 1,2-Diols. J. Am. Chem. Soc. 2012, 134, 16991−16994. For C(sp2)–H oxidation
of free mandelic acid using PhI(OAc)2, see: (d) Dastbaravardeh, N.; Toba, T.; Farmer, M. E.; Yu, J.-Q.
Monoselective o-C–H Functionalizations of Mandelic Acid and α-Phenylglycine. J. Am. Chem. Soc. 2015,
137, 9877−9884.
16.
17.
Ghosh, K. K.; Uttry, A.; Koldemir, A.; Ong, M.; van Gemmeren, M. Direct β-C(sp3)–H Acetoxylation of
Aliphatic Carboxylic Acids. Org. Lett. 2019, 21, 7154−7157.
For examples of C(sp3)–H activation reactions of free carboxylic acids, see: (a) Chen, G.; Zhuang, Z.; Li,
G.-C; Saint-Denis, T. G.; Hsiao, Y.; Joe, C. L.; Yu, J.-Q. Ligand‐Enabled β‐C–H Arylation of α‐Amino
Acids without Installing Exogenous Directing Groups. Angew. Chem., Int. Ed. 2017, 56, 1506−1509. (b)
Zhu, Y.; Chen, X.; Yuan, C.; Li, G.; Zhang, J.; Zhao, Y. Pd-Catalysed Ligand-Enabled Carboxylate-
Directed Highly Regioselective Arylation of Aliphatic Acids. Nat. Commun. 2017, 8, 14904−14911. (c)
Ghosh, K. K.; van Gemmeren, M. Pd-Catalyzed β-C(sp3)–H Arylation of Propionic Acid and Related
Aliphatic Acids. Chem. -Eur. J. 2017, 23, 17697−17700. (d) Zhuang, Z.; Yu, C.-B.; Chen, G.; Wu, Q.-F.;
Hsiao, Y.; Joe, C. L.; Qiao, J. X.; Poss, M. A.; Yu, J.-Q. Ligand-Enabled β-C(sp3)–H Olefination of Free
Carboxylic Acids. J. Am. Chem. Soc. 2018, 140, 10363−10367. (e) Shen, P.-X.; Hu, L.; Shao, Q.; Hong,
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K.; Yu, J.-Q. Pd(II)-Catalyzed Enantioselective C(sp3)–H Arylation of Free Carboxylic Acids. J. Am. Chem.
Soc. 2018, 140, 6545−6549. (f) Hu, L.; Shen, P.-X.; Shao, Q.; Hong, K.; Qiao, J. X.; Yu, J.-Q.
PdII‐Catalyzed Enantioselective C(sp3)–H Activation/Cross‐Coupling Reactions of Free Carboxylic Acids.
Angew. Chem., Int. Ed. 2019, 58, 2134−2138.
1
2
3
4
5
6
7
8
18.
(a) Jacobsen, E. N. Asymmetric Catalysis of Epoxide Ring-Opening Reactions. Acc. Chem. Res. 2000, 33,
421−431. (b) Trost, B. M.; Bunt, R. C.; Lemoine, R. C.; Calkins, T. L. Dynamic Kinetic Asymmetric
Transformation of Diene Monoepoxides: a Practical Asymmetric Synthesis of Vinylglycinol, Vigabatrin,
and Ethambutol. J. Am. Chem. Soc. 2000, 122, 5968−5976.
9
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15
16
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21
22
23
24
25
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49
50
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52
53
54
55
56
57
58
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Journal of the American Chemical Society
Page 18 of 18
TOC Graphic
1
2
3
4
5
L10
L12
Pd(OAc)2/
Na2CO3, TBHP
with Ac2O
Pd(CH3CN)2Cl2/
OH
PdIV
OtBu
CsHCO3, TBHP
without Ac2O
M+
O
R1
L
L
O
R1
R2
O
O
OH
R2
Me
O
R1
OAc
mono/di > 20/1
R2
CO2H
NHAc
L12
CO2H
NHAc
L10
6
7
8
9
O
R
L12
O
O
( )n
R
( )n
"standard conditions"
OH
HO
OH
without Ac2O
  and lactonization
O
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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40
41
42
43
44
45
46
47
48
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50
51
52
53
54
55
56
57
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60
O
n = 0–2
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