Palladium-catalyzed β-acyloxylation of simple amide via sp3 C-H activation

Article abstract of DOI:10.1021/ol403393w

β-Acyloxy amides are prepared in moderate to high yields by palladium-catalyzed acyloxylation of primary sp3 C-H bonds from simple amides without any special directing group. A catalytic system of Pd(OAc)2/CF3CO2H/ K2S2O8 is available to various amides with N-substituted by linear alkanes, cyclic alkanes, and electron-deficient benzyl compounds in this reaction. Acyloxylated products could be transformed easily to the corresponding β-hydroxy amides.

Full text of DOI:10.1021/ol403393w

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed β‑Acyloxylation of Simple Amide via sp3 C−H
Activation
Lihong Zhou and Wenjun Lu*
Department of Chemistry, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, People’s Republic of China
S
* Supporting Information
ABSTRACT: β-Acyloxy amides are prepared in moderate to
high yields by palladium-catalyzed acyloxylation of primary sp3
C−H bonds from simple amides without any special directing
group. A catalytic system of Pd(OAc)2/CF3CO2H/K2S2O8 is
available to various amides with N-substituted by linear alkanes, cyclic alkanes, and electron-deficient benzyl compounds in this
reaction. Acyloxylated products could be transformed easily to the corresponding β-hydroxy amides.
ransition-metal-catalyzed functionalization of C−H bonds
sp2 C−H bonds in both electron-rich and -deficient arenes, and
simple benzylic sp3 C−H bonds as well.4 Thus, we attempted to
apply this system to the catalytic oxygenation of sp3 C−H
bonds from simple amides. A monosubstituted amide, N-
butylpivalamide, was selected as the model substrate to test the
reaction conditions (Scheme 2). In the presence of 10 mol %
Pd(OAc)2, 5 equiv of CF3CO2H, and air (1 atm) at 80 °C, no
T
assisted by directing groups has developed rapidly in
recent years and has emerged as a powerful tool in organic
synthesis.1 Various common functional groups, such as amines,
amides, hydroxyls, carboxylic acids, etc., were found as the
directing group to improve the reactivity and regioselectivity in
transition-metal-catalyzed sp2 C−H functionalizations. How-
ever, inert sp3 C−H bonds were reluctant to cleave in the
presence of these simple directing groups compared to their sp2
counterparts. For example, in the transition-metal-catalyzed
oxygenation of sp3 C−H bonds to give alcohols, ethers, or
esters, special directing groups, which could bind to catalysts to
enhance their reactivity, were often required in these reactions
(Scheme 1).2 O-Methyl oxime,2a pyridine,2a and oxazoline
groups2b were the early class of directing groups (DG) applied
in these oxygenation reactions of sp3 C−H bonds. Recently,
removable or transformable directing groups such as amides 8-
aminoquinolines2c or o-acetyl oximes2d were also found to be
effective. However, using common functional groups (FG),
which exist naturally in both reactants and products, as
directing groups esepcially in the selective oxygenation of sp3
C−H bonds are of considerable interest. In 2012, Hartwig
reported that oxygenation of sp3 C−H bonds by the assistance
of a hydroxyl group could be achieved in the presence of an
iridium catalyst with a stoichiometric dihydridosilane reagent in
a tandem reaction.2f On the other hand, the amide group,
which is prevalent in natural products and pharmaceuticals, has
received much more attention in sp3 C−H functionalization. Yu
disclosed a series of β-functionalizations of some amides,
including arylation, alkylation, carbonylation, alkenylation,
alkynylation, and chlorination.3 In the β-oxygenation of
amide, however, special directing groups were still necessary.2h,j
Here, we report that simple amide groups could serve as the
directing groups in palladium-catalyzed acyloxylation of
unactivated sp3 C−H bonds to afford β-acyloxy amides,
which could be converted to their corresponding β-hydroxy
amides easily without loss of the amide motif during this
transformation.
1
acyloxylated product was detected by H NMR analysis (entry
1). After a series of oxidants were screened, K2S2O8 was found
to be the most effective one, giving only β-trifluoroacetoxylated
amide in 91% yield (entry 2). PhI(OAc)2 was less effective
(entry 3), and oxone or O2 was not completely suitable in this
reaction (entries 4, 5). A control test showed that Pd(OAc)2
was essential to ignite this reaction (entry 6). Selecting an
appropriate oxidant both to promote the formation of high
valent palladium species and to be compatible with this
Pd(OAc)2/CF3CO2H system was crucial in this acyloxylation.
Different carboxylic acids were also studied, showing that
trichloroacetic acid, difluoroacetic acid, or acetic acid with the
exception of pavilic acid, a weak acid, was effective in this
reaction to give the corresponding acyloxylated products in
moderate to good yields respectively (entries 7−10). The
effects of Pd(OAc)2, K2S2O8, and temperature were further
studied, showing that decreasing any one of these decreased the
yields significantly (entries 11−13). Moreover, neither non-
substituted nor disubstituted simple amides were available in
this reaction (entries 14, 15). Overall, the Pd(OAc)2/
CF3CO2H/K2S2O8 system was quite beneficial to the β-
acyloxylation of simple mono-N-substituted amides through
unactivated sp3 C−H bond cleavage.
In the investigation of the substrate scope, we found that
various monosubstituted amides could be employed in this
acyloxylation (Scheme 3). Not only linear aliphatic substituted
amides including n-butyl, cyclohexylmethyl, 1-ethylpropyl, and
tert-butyl amides but also cyclic aliphatic substituted amides
especially containing five to eight member rings performed very
In our previous work, we found that the Pd(OAc)2/
CF3CO2H system was very effective in activating simple aryl
Received: November 22, 2013
© XXXX American Chemical Society
A
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Letter
Scheme 1. Transition-Metal-Catalyzed Functionalization of
Scheme 2. Optimization of the Reaction Conditions
sp3 C−H Bonds Assisted by Directing Groups
a
1
Yields based on substrate and detected by H NMR analysis in situ
using CH2Br2 as internal standard. Alcoholysis of the β-acyloxylated
amides occurred to the corresponding β-hydroxy amides, which were
isolated by flash chromatography. For details, see Supporting
Information. Conditions: substrate (1.0 mmol), Pd(OAc)2 (0.1
mmol), K2S2O8 (2.0 mmol), CF3CO2H (5.0 mmol), 80 °C, 20 h.
b
60 °C.
well to give their corresponding products in high yields.
Although no desired product was detected in the case of
cyclopropyl substituted amide, an acyloxylated product from
highly strained cyclobutyl substituted amide was obtained in
63% yield. Notably, all acyloxylated products were β-substituted
ones for the carbonyl group rather than for the amino group of
amides and the chemical selectivity was good, giving only
mono-β-acyloxylated products in this reaction. For benzyl
substituted amides, strong electron-deficient benzyl substituted
amides such as N-(4-nitrobenzyl)pivalamide and N-(4-
trifluorobenzyl)pivalamide could afford the corresponding
acyloxylated products in high yield. Halogen atoms such as
fluorine, chlorine, or bromine attached to arenes were also
tolerated during reactions. However, either a benzyl amide
without electron-deficient groups or an aryl amide such as N-
(4-nitrophenyl)pivalamide gave biaryls as products, indicating
that activation of aryl sp2 C−H bonds was more easily
compared to that of sp3 C−H bonds under the same reaction
conditions. For the sp3 C−H bond at the β-position of the
carbonyl group, primary sp3 C−H bonds from ethyl dimethyl
amides were also effective in giving high product yields in these
reactions. However, a mono-N-alkyl substituted dimethyl amide
gave its corresponding acid as the detected product (Scheme
4). After installation of an ester methylene group to the amide
linkage, which may make the nitrogen of the amide less
electron-rich and coordinate to the Pd catalyst firmly, and
further optimization of the reaction conditions especially in
raising the reaction temperature and replenishing K2S2O8 in a
timely manner, a β-primary sp3 C−H acyloxylated amide from
dimethyl amide was obtained in 48% yield. Acyloxylation of the
secondary sp3 C−H bonds of amides was more hindered
compared to their primary counterparts since decomposition of
amides happened readily.
The β-acyloxy amide products could be mildly turned to
their corresponding β-hydroxy amides by using a regular
alcoholysis method (Scheme 5).
A reaction mechanism is proposed as follows (Figure 1).
There are three main steps involved in the catalytic cycle: (1) a
Pd(II) species coordinates with an amide group and attacks its
sp3 C−H bond to produce an alkyl−Pd(II) intermediate. Since
the highly cationic Pd(OAc)2/CF3CO2H system performs very
well in the reaction, an eletrophilic metalation process is
probably involved in this C−H activation step; (2) the formed
alkyl−Pd(II) intermediate is oxidized to its Pd(IV) state by an
oxidant K2S2O8. (3) A β-acyloxy amide product is formed by
reductive elimination from the high valent Pd(IV) species, and
B
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Scheme 3. Investigation of the Reaction Scope (1)
Scheme 4. Investigation of the Reaction Scope (2)
a
1
Yields based on substrate and detected by H NMR analysis in situ.
Conditions A: substrate (1.0 mmol), Pd(OAc)2 (0.1 mmol), K2S2O8
(2.0 mmol), CF3CO2H (5.0 mmol), 80 °C, 20 h. Conditions B:
substrate (0.5 mmol), Pd(OAc)2 (0.1 mmol), K2S2O8 (2.0 mmol),
CF3CO2H (10.0 mmol), 105 °C, 2 h; then added substrate (0.5
mmol), K2S2O8 (2.0 mmol), CF3CO2H (10.0 mmol), 105 °C, 4 h.
Conditions C: substrate (0.5 mmol), Pd(OAc)2 (0.1 mmol), K2S2O8
(2.0 mmol), CF3CO2H (10.0 mmol), 110 °C, 4 h.
Scheme 5. Alcoholysis of β-Acyloxylated Amides to the
Corresponding β-Hydroxy Amides
Figure 1. Proposed reaction mechanism.
C−H bonds at the β-position of amides were more suitable
than secondary ones for activation in the Pd(OAc)2/CF3CO2H
system. Selection of an appropriate oxidant K2S2O8 was very
important to promote this reaction and to complete the
catalytic cycle. Various amides N-substituted by linear alkanes,
cyclic alkanes, and electron-deficient benzyl compounds were
employed successfully to produce their β-acyloxy amides in this
reaction. These acyloxylated products could be easily converted
to their corresponding β-hydroxy amides using common
methods. Further research on the scope, mechanism, and
application of this acyloxylation reaction is ongoing.
a
1
Yields based on substrate and detected by H NMR analysis in situ
using CH2Br2 as internal standard. Alcoholysis of the β-acyloxylated
amides occurred to the corresponding β-hydroxy amides, which were
isolated by flash chromatography. For details, see Supporting
Information.
ASSOCIATED CONTENT
■
S
* Supporting Information
the Pd(IV) species is reduced to a Pd(II) species to fulfill the
catalytic cycle.
Text and figures giving experimental details and character-
ization data for simple amides, acyloxy amides, and hydroxy
amides. This material is available free of charge via the Internet
at http://pubs.acs.org.
In this work, we reported a palladium-catalyzed acyloxylation
of unactivated sp3 C−H bonds from simple amides. Primary sp3
C
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Letter
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: luwj@sjtu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
(Grant Nos. 20872089 and 21072129) for financial support.
■
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