Copper-Catalyzed Oxidative Cyclization of Carboxylic Acids

Article abstract of DOI:10.1021/acs.orglett.6b03176

A method for converting C-H to C-O bonds through oxidative cyclization of carboxylic acids to generate lactone products is described. The reaction employs catalytic amounts of Cu(OAc)₂ and potassium persulfate as the terminal oxidant and is performed open to air in an aqueous acetic acid solvent system. Preliminary mechanistic studies suggest that substrate oxidation likely proceeds by sulfate radical anion and that the Cu catalyst has no influence on the product-determining step. These conclusions differ from related investigations that propose the intermediacy of a carboxylate radical.

Full text of DOI:10.1021/acs.orglett.6b03176

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Oxidative Cyclization of Carboxylic Acids
Shyam Sathyamoorthi and J. Du Bois*
Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
S
* Supporting Information
ABSTRACT: A method for converting C−H to C−O bonds through
oxidative cyclization of carboxylic acids to generate lactone products is
described. The reaction employs catalytic amounts of Cu(OAc)2 and potassium
persulfate as the terminal oxidant and is performed open to air in an aqueous
acetic acid solvent system. Preliminary mechanistic studies suggest that
substrate oxidation likely proceeds by sulfate radical anion and that the Cu
catalyst has no influence on the product-determining step. These conclusions differ from related investigations that propose the
intermediacy of a carboxylate radical.
he selective conversion of sp3 C−H to C−O bonds in
formed in reactions of linear alkanoic acids with stoichiometric
amounts of CuCl2 and Na2S2O8.7e A carboxyl radical
intermediate is posited as the active oxidant, as both CO2 and
alkyl chloride side products are detected. Intrigued by these
findings and cognizant of alternate protocols for oxidizing
carboxylate anions, we initiated studies to advance a general,
catalytic method for oxidative cyclization of carboxylic
acids.4a−c,8
T
complex molecules remains an outstanding challenge in
synthetic chemistry.1,2 The majority of methods for C−H
hydroxylation rely on a combination of intrinsic differences in
C−H bond reactivity and substrate−catalyst steric interactions
to bias reaction outcomes. A smaller number of technologies
exploit intermediate alkoxy or acyloxy radical oxidants to
promote intramolecular C−H functionalization.3,4 Such meth-
ods generally offer a level of precision in controlling site-
selectivity that is unrivaled by more conventional O-atom
transfer processes.5,6 Here, we describe our efforts to develop an
oxidation reaction that transforms carboxylic acids to lactone
products (Scheme 1). Following available precedent, this
Initial exploratory experiments to optimize conditions for
lactone formation were performed with 4-phenylbutyric acid 1 as
a model substrate. Guided by prior reports, 1 was treated with 10
mol % of Cu(OAc)2·H2O and K2S2O8 in aqueous CH3CN
(Table 1). No reaction ensued when this mixture was stirred at
room temperature; however, upon warming the solution to 65
°C, 35% of the desired lactone 2 was produced along with 10% of
ketone 3 (Table 1, entry 1). Elevating the reaction temperature
(105 °C) resulted in a slight increase in conversion of starting
material to 2 (Table 1, entry 2). Replacing CH3CN with
sulfolane as a polar cosolvent was deleterious to reaction
performance (Table 1, entry 3); in contrast, AcOH offered
demonstrable improvement, yielding ∼60% of the desired
product (Table 1, entry 4). It appears that both solvent and
temperature influence the overall efficiency of this process,
whereas the choice of copper catalyst does not (Table 1, entries 5
and 6).9 Of the terminal oxidants screened, including different
persulfate salts and Oxone, K2S2O8 was most effective (Table 1,
entries 4, 7−10). Control experiments using other transition-
metal acetates afforded substantially reduced quantities of
lactone 2 compared to reactions catalyzed with cupric ion
(Table 1, entries 10−12). These results closely mirror those
obtained in the absence of any added catalyst (Table 1, entry 13).
Finally, it is worth noting that oxidation of 1 using conditions
described by Nikishin (1 equiv CuCl2, 1 equiv Na2S2O8, neat
H2O, 90 °C) or with stoichiometric amounts of ceric ammonium
nitrate (CAN) gave only 35% and 20% of 2, respectively (Table
1, entries 14 and 15).7e,10
Scheme 1. Oxidative Cyclization of Carboxylic Acids for
Lactone Synthesis
reaction was envisioned to occur through the intermediacy of a
putative Cu carboxylate or acyloxy radical species, either of which
could effect subsequent 1,5-H atom abstraction.7 Such a process
would offer predictable control over product selectivity, avoid
complications from overoxidation of the product, and enable
direct synthesis of value-added lactone derivatives.
Our decision to explore conditions for promoting carboxylic
acid oxidative cyclization was inspired by a small number of
published reports highlighting the viability of such a process.7 In
particular, work by Nikishin and co-workers has demonstrated
that modest yields (20−40%) of γ- and δ-lactone mixtures are
Received: October 23, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03176
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Organic Letters
Letter
Table 1. Optimization of Catalytic Reaction Conditions
Table 2. Lactonization of Aliphatic Carboxylic Acids
T
a
b
c
entry
catalyst
oxidant
K2S2O8
solvent
(°C)
2/3/1
1
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(SO4)·5H2O
CuCl2·2H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
CH3CN
CH3CN
sulfolane
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
H2O
65
105
105
105
105
105
105
105
105
105
105
105
105
90
35:10:30
40:10:20
20:5:50
2
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Na2S2O8
3
4
60:10:20
60:10:20
60:10:15
50:5:25
5
6
7
8
(NH4)2S2O8
Oxone
40:5:40
9
20:10:55
20:10:15
20:10:20
25:10:30
20:10:30
35:5:50
10
11
12
13
14
15
Co(OAc)2·2H2O K2S2O8
Ni(OAc)2·4H2O K2S2O8
Zn(OAc)2·2H2O K2S2O8
none
K2S2O8
1 equiv CuCl2
none
Na2S2O8
d
CAN
AcOH
105
20:0:75
a
Reaction performed with 0.1 equiv of catalyst in a 1:1 mixture of
solvent/H2O. In the absence of H2O, no reaction is observed.
b
c
Reaction performed with 1.5 equiv of oxidant. Reaction yields and
1
product ratios estimated by H NMR integration against an internal
standard (4-nitrotoluene). CAN = ceric ammonium nitrate.
d
Our optimized catalytic C−H oxidation protocol is functional
with both aliphatic and aromatic carboxylic acids (Table 2 and
Scheme 2).11 For aliphatic derivatives, 5-membered lactone
products are formed preferentially. Isolated yields for substrates
bearing γ-benzylic centers are generally above 40%. In many
cases, reactions give few overoxidized byproducts, and unreacted
starting material accounts for the majority of the mass balance.12
Of note, electron-rich arene substrates are superior to those with
electron-withdrawing substituents (Table 2, entries 2−4), a
finding consistent with our proposed mechanism (vide infra).
Although this method shows a strong preference for benzylic
oxidation, acyloxylation of 3° C−H bonds does occur in
conformationally constrained substrates (Table 2, entry 10).
Reactions with optically active 3° substrates, however, are found
to give racemic product (Table 2, entry 11). Evident limitations
notwithstanding, the overall process uses low-cost reagents, can
be run open to air, and is easy to perform.
Oxidative cyclization of benzoic acid substrates is strongly
biased (>20:1 selectivity) toward six-membered ring lactone
formation (Scheme 2). As with aliphatic carboxylic acids,
substrates containing electron-rich arene groups engage
effectively, a feature that distinguishes this process from methods
for C−H hydroxylation.13 Benzo-fused lactones are common
elements in a number of plant-derived natural products,
including phyllodulcin and related structures.14,15
a
All reactions were conducted on a 0.5 mmol scale at a substrate
b
concentration of 0.1 M. Isolated yield after purification by
chromatography. Reaction performed in 1:1 CH3CN/H2O at 85
°C. The cis-diastereomer was formed exclusively. Product obtained
as a single trans-diastereomer. Product obtained as a 1:1 mixture of
diastereomers. Product obtained as a single diastereomer (stereo-
chemistry unassigned). Product obtained as a racemic mixture; see
the Supporting Information for details.
c
d
e
f
g
h
the 2-methylindanone product 5 or related compounds appear as
side products in the Cu(OAc)2-catalyzed reaction.
Successful lactone production in aqueous AcOH solution in
combination with the absence of detectable amounts of
decarboxylated side products in reaction mixtures has led us to
question the likelihood of a carboxylate radical as the active
oxidant in this transformation (as has been proposed for related
Cu-mediated reactions).7e We have noted that decarboxylation
occurs with 2-indanylacetic acid 4 under closely related
conditions using AgNO3 and K2S2O8 (Scheme 3).16 None of
We have performed a series of experiments to clarify the role of
the carboxylic acid in this oxidation reaction. Absent knowledge
of the rate-determining step, we have obtained kinetic isotope
effect data by conducting both intra- and intermolecular
competition experiments (Scheme 4). Under our optimized
Cu(OAc)2-catalyzed conditions, both methods give equivalent
KIE values within error of the measurements (1.9 0.1 and 2.2
B
DOI: 10.1021/acs.orglett.6b03176
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Oxidative Cyclization of Arene Carboxylic Acids
Scheme 5. Product Distribution with 5-Phenylvaleric Acid as
Substrate
compete with the rate at which H2O intercepts the putative
carbocation.20 Interestingly, a competition between 4-phenyl-
butyric acid 1 and the p-MeO derivative 14 affords a 1:6 mixture
of products, a ratio that is similar to that obtained when
Cu(OAc)2 is excluded from the reaction (Scheme 6). This final
a
Product lactones are common structural elements in natural products,
as exemplified by phyllodulcin.
Scheme 6. Competition Experiments Show No Effect of
Copper Catalyst on Product Selectivity
Scheme 3. Silver-Catalyzed Decarboxylation of 2-Indanyl-
acetic Acid
Scheme 4. Kinetic Isotope Effect Measurements Implicate
Sulfate Radical As the Active Oxidant
•−
result suggests that oxidation by SO4 is product-determining
and that Cu(OAc)2 has effectively no influence on selectivity.
The evident role of cupric salt on reaction efficiency, however, is
clear from the data shown in Table 1. Future studies will aim to
elucidate its unique function in this process.
Lactonization of aliphatic and aromatic carboxylic acids has
been shown to proceed under the action of catalytic Cu(OAc)2
and K2S2O8 as the terminal oxidant. In general, reaction
performance is highest for substrates bearing benzylic C−H
bonds and that are predisposed to furnish butyrolactone
products. The scope of this process and the identification of
conditions to effect catalytic turnover distinguish our findings
from prior art. In addition, preliminary mechanistic experiments
have provided evidence for a pathway that does not involve
carboxylate radical formation and for which the Cu catalyst has
no influence on product selectivity. Studies to reveal the
ambiguous role of cupric ion in promoting oxidative lactoniza-
tion are expected to give way to advances in this technology.
0.2, respectively). The fact that these experiments afford the
same KIE value discounts a mechanism involving rate-
determining carboxylate radical formation. Notably, a KIE of
2.1
0.1 has also been measured with substrate 7 under
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03176.
■
conditions in which Cu(OAc)2 is absent. This latter result
implicates sulfate radical, SO4 (or possibly acetoxy radical,
MeCO2 ), as the active oxidant responsible for initiating the
cyclization process.
•−
S
•
•−
A proposed mechanism involving C−H abstraction by SO4
Experimental details, characterization data, and NMR and
IR spectra (PDF)
is supported by both literature precedent and by additional
observations that we have made.17,18 Sulfate radical can be
generated from persulfate, S2O82−, and is known to react rapidly
with saturated hydrocarbons.19 In the presence of cupric ion, it is
possible that an intermediate alkyl radical is trapped and/or
oxidized to a carbocation. Formation of either a radical or
cationic species accounts for the generation of racemic lactone
from an enantiomerically pure substrate (Table 2, entry 11). This
proposal is also consistent with oxidation of 5-phenylvaleric acid
11, which gives both ketone and alcohol products (Scheme 5). In
this case, the rate of six-membered lactone formation does not
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jdubois@stanford.edu.
ORCID
Shyam Sathyamoorthi: 0000-0003-4705-7349
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b03176
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ACKNOWLEDGMENTS
■
We thank Professors T. Daniel Stack and Robert Waymouth
(Stanford University) for helpful discussions. This work has been
supported by the NSF under the CCI Center for Selective C−H
Functionalization (CHE-1205646), by generous contributions
from Novartis, and by the NIH under Award No.
T32GM007365. The content is solely the responsibility of the
authors and does not necessarily represent the official views of
the National Institutes of Health.
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