Direct β-C(sp3)-H Acetoxylation of Aliphatic Carboxylic Acids

Article abstract of DOI:10.1021/acs.orglett.9b02741

The controlled construction of defined oxidation patterns is one of the key aspects in the synthesis of natural products and bioactive molecules. Towards this goal, we herein report a novel protocol for the Pd-catalyzed direct β-C(sp³)-H acetoxylation of aliphatic carboxylic acids. The protocol enables the use of free carboxylic acids in one step and without the need of introducing specialized strong directing groups. In our studies, we found that the use of a "traceless base" was crucial for the development of a synthetically useful transformation. Furthermore, the synthetic utility of the products obtained was demonstrated by their use in subsequent transformations.

Full text of DOI:10.1021/acs.orglett.9b02741

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct β‑C(sp3)−H Acetoxylation of Aliphatic Carboxylic Acids
Kiron K. Ghosh,†,§ Alexander Uttry,†,§ Aylin Koldemir,†,∥ Mike Ong,†,∥
and Manuel van Gemmeren*,†,‡
†
̈
̈
̈
̈
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster, Corrensstraße 40, 48149 Munster, Germany
‡Max Planck Institute for Chemical Energy Conversion, Stiftstraße 34-36, 45470 Mu
̈
lheim an der Ruhr, Germany
S
* Supporting Information
ABSTRACT: The controlled construction of defined oxidation
patterns is one of the key aspects in the synthesis of natural products
and bioactive molecules. Towards this goal, we herein report a novel
protocol for the Pd-catalyzed direct β-C(sp3)−H acetoxylation of
aliphatic carboxylic acids. The protocol enables the use of free
carboxylic acids in one step and without the need of introducing
specialized strong directing groups. In our studies, we found that the use
of a “traceless base” was crucial for the development of a synthetically
useful transformation. Furthermore, the synthetic utility of the products
obtained was demonstrated by their use in subsequent transformations.
arbon−oxygen bonds are ubiquitous in drugs, agro-
1
Cchemicals, and natural products. For this reason, the
introduction of new C−O bonds to form defined oxidation
patterns is often the key to success for the synthesis of natural
products and biologically active molecules.2 In this context,
reactions that oxidatively introduce C−O bonds starting from
C−H bonds are particularly attractive,3 since, if they can be
carried out selectively, these processes constitute the most
straightforward access to the desired product motifs.
In synthetic organic chemistry, aliphatic carboxylic acids are
well recognized as a fundamental building block that both
occurs in a variety of structurally complex molecules of
pharmaceutical importance and serves as a key intermediate to
access a large number of further functional groups.4
The importance of aliphatic carboxylic acids and defined
oxidation patterns highlighted above provides a strong
incentive to utilize carboxylic acids as directing groups for
the controlled introduction of C−O bonds. However, while for
example the carboxylic acid directed acetoxylation of C(sp2)−
Figure 1. Previous studies on the direct C−H arylation of aliphatic
acids and direct and indirect pathways to the β-C(sp3)−H of
carboxylic acids.
H bonds is well-known in organic chemistry, the correspond-
ing acetoxylation of C(sp3)−H bonds has not been reported to
date. It should be noted that several studies have enabled the
indirect generation of β-acetoxylated carboxylic acids through
the conversion of the carboxylic acid moiety into a stronger
specialized directing group (DG), followed by the C(sp3)−H
acetoxylation and the removal of the DG (Figure 1).5,6
Although these protocols give access to the target compounds,
a direct β-C(sp3)−H acetoxylation of carboxylic acids would
undoubtedly be desirable in terms of convenience as well as
step- and atom-economy. However, the low directing ability of
the carboxylic acid moiety poses a significant challenge. It is,
among other reasons, caused by its overall weak binding to
palladium and the presence of several competing coordination
modes, of which only the typically disfavored κ1 coordination
can lead to conformations in which C−H activation is
possible.7
Building upon the experience gained during the develop-
ment of our protocol for the direct β-C(sp3)−H arylation of
carboxylic acids,8 we became interested in the development of
a related acetoxylation process.
After an extensive screening of reaction conditions (see the
Supporting Information for details), we could indeed develop a
protocol that enables the direct β-C(sp3)−H acetoxylation of
Received: August 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02741
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Scope of the β-C(sp3)−H Acetoxylation of
Aliphatic Carboxylic Acids*
carboxylic acids. During these studies, we observed an
intriguing base effect (Table 1). When we compared the
a
Table 1. Effect of Additives
entry
H/Na
additive
NMR yield (%)
1
2
3
4
5
6
7
8
H
Na
H
H
H
H
Na
H
23
60
54
31
48
41
41
61
NaHCO3
Na2CO3
Na2HPO4
NaOMe
MeOH
NaHFIP
a
Conditions: 1a/1Na (0.5 mmol), PhI(OAc)2 (0.2 mmol), Pd(OAc)2
(3 mol %), additive (0.5 mmol), HFIP/Ac2O (9:1, 1.2 mL).
reaction outcome using pivalic acid (23%, entry 1) with that of
sodium pivalate (60%, entry 2) under otherwise optimized
conditions, we observed a dramatic difference in reaction
outcome, as expected on the basis of previous studies.9
However, attempts to employ pivalic acid together with a
suitable base led to disappointing results over a broad range of
bases (e.g., entries 3−5). In an attempt to ensure a quantitative
deprotonation of the acid substrate, sodium methanolate was
used as base (41%, entry 6), again providing a reaction
outcome well below the yield obtained with preformed sodium
pivalate. We thus hypothesized that the conjugate acid formed
after substrate deprotonation must be responsible for the
detrimental effect. In order to probe this hypothesis, sodium
pivalate was subjected to the reaction conditions in the
presence of methanol, thereby recreating the conditions of the
previous experiment (41%, entry 7). From these observations,
we concluded that in order to provide a synthetically useful
protocol that would be applicable to the easily available acid
without requiring previous salt formation, a “traceless” base
was required. Accordingly, we synthesized the sodium salt of
our main solvent, 1,1,1,3,3,3-hexafluoroisopropanol, and tested
this salt as the base in our reaction. Gratifyingly, the reaction
outcome of preformed sodium pivalate could now be achieved
using the acid as starting material (61%, entry 8).
With the optimized reaction conditions in hand, we began to
study the scope of our transformation (Scheme 1). The
product 2a derived of pivalic acid (1a) was obtained in 63%
yield. By increasing the aliphatic chain length in the substrate,
we obtained satisfactory yields of 2b (55%) and 2c (56%). Our
protocol was also found to be applicable to substrates bearing a
single methyl group and two alkyl substituents, albeit with a
moderate yield (2d, 43%). Aliphatic halide substituents like
fluoride, chloride, and even the elimination-prone bromide
were well tolerated. The respective substrates provided 2e
(59%), 2f (51%), and 2g (47%) in good yields. We were
furthermore interested in evaluating aryl-containing substrates
under our reaction conditions and found that a series of
electron-poor aryl units were tolerated under the reaction
conditions (2h−2k). As expected based on literature reports,10
electron-rich aryl groups were not tolerated due to a competing
C(sp2)−H acetoxylation under the reaction conditions. Finally,
we tested an α-nonquaternary substrate (isobutyric acid) and
*
Conditions: 1 (0.5 mmol), PhI(OAc)2 (0.2 mmol), Pd(OAc)2 (5
a
mol %), NaHFIP (0.5 mmol), HFIP/Ac2O (9:1, 1.2 mL). Isolated
after conversion to the methyl ester. Isolated after conversion to the
benzyl ester.
b
obtained the corresponding product 2l in a modest yield of
35%.9a
Next, we probed whether we can extend our protocol from
acetoxylation to further acyloxylation reactions (Scheme 2).
Scheme 2. Acyloxylation of Pivalic Acid (1a)*
*
Conditions: 1a (0.5 mmol), PhI(OCOR)2 (0.2 mmol), Pd(OAc)2
(3 mol %), NaHFIP (0.5 mmol), HFIP (1.08 mL), (RCO)2O (1.25
mmol). Isolated after conversion to the methyl ester. Isolated after
conversion to the benzyl ester.
a
b
We found that this can be achieved by replacing both the
oxidant and the anhydride employed to contain the desired
substituent. Using this approach, we could obtain the n-alkyl-
substituted products 3a (58%) and 4a (52%) in good yields.
The more sterically hindered cyclopentyl (5a, 51%), cyclohexyl
(6a, 45%), and pivaloyl (7a, 47%) analogues could likewise be
obtained.
In order to further demonstrate the synthetic utility of our
protocol, we first showed that it can be conducted on a
preparatively useful scale. Two representative products 2a
(63%) and 2c (51%) were obtained with virtually identical
results compared to the scope studies (Scheme 3a). We next
became interested in using the products of this protocol as
substrates in our previously developed arylation reaction, since
B
DOI: 10.1021/acs.orglett.9b02741
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Synthetic Utility of β-C(sp3)−H Acetoxylation of
Aliphatic Carboxylic Acids
more, the utility of NaHFIP as a “traceless base” for the β-
C(sp3)−H activation of aliphatic carboxylic acids is expected
to prove helpful in the development of further challenging
functionalizations of these substrates without the need for a
strong directing group.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02741.
Preparative procedures and analytical data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mvangemmeren@uni-muenster.de.
ORCID
Manuel van Gemmeren: 0000-0003-3080-3579
Author Contributions
§K.K.G. and A.U. contributed equally to this work.
Author Contributions
∥A.K. and M.O. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the Max
Planck Society (Otto Hahn Award to M.v.G.), FCI (Fellow-
ship to K.K.G., Liebig Fellowship to M.v.G.), the DFG (SFB
858), and the WWU Munster. We thank the members of our
̈
NMR and MS departments for their excellent service.
Furthermore, we are indebted to Prof. F. Glorius for his
generous support.
a
b
Isolated after conversion to the methyl ester. Prepared from 2a and
2c following literature protocols.15 Xanthphos added as ligand, 48 h
reaction time.
c
REFERENCES
■
this would broaden the scope of aryl-containing β-acetoxylated
acids that can be accessed based on our protocol. Indeed, we
could obtain the products 8 (71%), 9 (66%), and 10 (60%)
following this approach (Scheme 3b). Importantly, the core
motif of these compounds has served as starting point for the
synthesis of bioactive molecules.11 Finally, the synthetic utility
of carboxylic acids as precursor for photoredox initiated radical
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protocols (Scheme 3c). The compounds 12a and 12c were
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obtained from a related alkylation.12,13 Importantly, these
compounds feature otherwise challenging to obtain 1,4
oxygenation patterns. Finally, we accessed the quaternary
carbon containing homoallylic alcohol derivatives 14a and 14c,
another structural motif that is otherwise not trivial to
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