Direct Decarboxylative Functionalization of Carboxylic Acids via O-H Hydrogen Atom Transfer

Article abstract of DOI:10.1021/jacs.9b10825

Decarboxylative functionalization via hydrogen atom transfer offers an attractive alternative to standard redox approaches to this important class of transformations. Herein, we report a direct decarboxylative functionalization of aliphatic carboxylic acids using N-xanthylamides. The unique reactivity of amidyl radicals in hydrogen atom transfer enables decarboxylative xanthylation under redox-neutral conditions. This platform provides expedient access to a range of derivatives through subsequent elaboration of the xanthate group.

Full text of DOI:10.1021/jacs.9b10825

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Direct Decarboxylative Functionalization of Carboxylic Acids via
O−H Hydrogen Atom Transfer
Christina G. Na,† Davide Ravelli,‡ and Erik J. Alexanian*,†
†Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
‡PhotoGreen Lab, Department of Chemistry, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy
S
* Supporting Information
conditions. Such a process presents a significant challenge,
ABSTRACT: Decarboxylative functionalization via hy-
however: the O−H bond dissociation energy is approximately
112 kcal/mol, providing a large barrier to reaction.6
drogen atom transfer offers an attractive alternative to
standard redox approaches to this important class of
Unsurprisingly, a ground state O−H HAT of a carboxylic
transformations. Herein, we report a direct decarbox-
ylative functionalization of aliphatic carboxylic acids using
N-xanthylamides. The unique reactivity of amidyl radicals
in hydrogen atom transfer enables decarboxylative
xanthylation under redox-neutral conditions. This plat-
form provides expedient access to a range of derivatives
through subsequent elaboration of the xanthate group.
acid is unknown and would require a highly reactive species to
occur.7
We have demonstrated previously that N-functionalized
amides can serve as precursors of amidyl radicals for achieving
a range of intermolecular, site-selective aliphatic C−H bond
functionalizations.8 The key thermodynamic driving force for
these reactions is the formation of a strong amide N−H bond
(BDE ≈ 111 kcal/mol) from an unactivated aliphatic C−H
bond (BDE = 96−101 kcal/mol).9 Considering that the range
of BDEs for carboxylic acid O−H bonds (BDE ≈ 112 kcal/
mol) is similar to that of an amide N−H bond, we
hypothesized that amidyl radicals could engage carboxylic
acids directly via O−H HAT to facilitate decarboxylative
transformations. Herein, we report a direct, decarboxylative
xanthylation of carboxylic acids as a representative reaction of
this type, demonstrating the unique ability of amidyl radicals to
perform O−H HAT.10
Our studies commenced with hexanoic acid as substrate
using 440 nm blue LED photoinitiation and our previously
reported N-xanthylamide 1.8c We found that under these
conditions alkyl xanthate 3 was formed in moderate yield
(59%, Table 1, entry 1). The use of dilauroyl peroxide (DLP)
as initiator provided 3 with similar efficiency (entry 2).
Switching to the use of a pentafluorophenyl-substituted N-
xanthylamide (2) significantly increased the reaction yield
(entries 3 and 4).
ecarboxylative functionalizations constitute a diverse
Dclass of synthetic transformations that leverage the
wide availability of carboxylic acids as substrates to deliver a
variety of useful products.1 For example, the classic Barton
decarboxylation via thiohydroxamate esters is a powerful
approach to the modification of carboxylic acids.2 Oxidative
processes are also featured in many reactions, from the Kolbe
electrolysis to an array of Ag(II)-mediated transformations.
Recently, photoredox catalysis has significantly expanded the
breadth of decarboxylative transformations. These typically
involve either oxidations of carboxylate salts3 or reductions of
activated carboxylate derivatives (Figure 1).4 N-Hydroxyph-
thalimide esters in particular have found much use in this
reductive platform.5
A complementary approach to decarboxylative functionaliza-
tion would involve O−H hydrogen atom transfer (HAT) of a
carboxylic acid to generate a carboxyl radical under neutral
Chemical initiation of the xanthylation using reagent 2 was
also successful, albeit with slightly decreased efficiency (entries
5 and 6). The reaction of a carboxylate salt using Cs2CO3 as
base (entry 7) or performing a reaction in the absence of
initiator (entry 8) led to no conversion of the carboxylic acid.
We continued our studies using reagent 2 owing to its superior
performance and ease of large-scale reagent preparation.
Figure 2 details our studies demonstrating the considerable
scope of the decarboxylative xanthylation. Both chemical (10
mol % DLP) and photochemical (440 nm LEDs) modes of
initiation were successful with virtually all of the substrates
shown. The highest reaction yield of the two methods is
provided in Figure 2; all yields and the corresponding
conditions are provided in the Supporting Information.
Received: October 8, 2019
Figure 1. Decarboxylative functionalizations of carboxylic acids.
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b10825
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Journal of the American Chemical Society
Communication
stage functionalization of peptides via the carboxylic acid side
chain. As a representative example, we performed the
decarboxylative xanthylation on a tripeptide to deliver an
analogue of the antioxidant glutathione xanthate 33 in
moderate yield, albeit with good recovery of the remaining
starting material. In light of the importance of cysteine-
containing peptides in maintaining regulatory and metabolic
functions in plants, animals, fungi, and bacteria, we view the
decarboxylative xanthylation as an attractive method for
peptide modification in future biological studies.16
The xanthate functional group is readily elaborated to a wide
range of derivatives.8c,17 For example, aminolysis of lithocholic
acid-derived xanthate 26 with isopropylamine provided the
corresponding thiol in excellent yield.18 Subsequent photo-
chemical thiol−ene coupling with a glucose-derived allyl
glycoside produced the conjugation product 34 in 54% yield
over two steps. In addition, hydroxylation of gibberellic acid-
derived xanthate 30 proceeded in 55% yield using conditions
we previously developed for accessing hydroxyl or ketone
functionality from alkyl xanthates via an alkoxyamine
intermediate.8c Alternative approaches to accessing the
products of a formal decarboxylative oxidation include the
Barton decarboxylation via thiohydroxamate esters and
decarboxylative borylation using N-hydroxyphthalimide es-
ters.19,20
Table 1. Decarboxylative Xanthylation of Hexanoic Acid
a
entry
xanthylamide reagent
initiation
% yield
1
2
3
4
5
6
1 (1 equiv)
1 (1 equiv)
2 (1 equiv)
2 (1.2 equiv)
2 (1 equiv)
2 (2 equiv)
2 (1 equiv)
2 (1 equiv)
440 nm LED
10 mol % DLP
440 nm LED
440 nm LED
10 mol % DLP
10 mol % DLP
10 mol % DLP

59
49
81
86
55
70
<2
<2
b
7
8
a
Determined by 1H NMR spectroscopy of the crude reaction
mixtures using hexamethyldisiloxane as an internal standard.
b
Reaction was performed in the presence of 1 equiv of Cs2CO3.
Primary carboxylic acids were converted to alkyl xanthates 3−9
in good yields. Alkyl bromides are tolerated (4), which is
notable considering that substitution of alkyl halides is the
most common method for the preparation of alkyl xanthates
and thiols.11 The presence of aryl, ester, ketone, or alkene
functionalities was also permitted (5−8). The functionalization
of an N-Boc indole-substituted primary carboxylic acid
delivered xanthate 9 in 62% yield.
Secondary carboxylic acids were also excellent substrates
(Figure 2). The xanthylation of endonorbornane-2-carboxylic
acid provided solely the exo diastereomer of xanthate 12 in
92% yield. The reaction of 1,4-cyclohexanedicarboxylic acid
with 2 equiv of 2 provided dixanthate 13 in excellent yield
(94%) as a mixture of diastereomers. Decarboxylative
xanthylation of 3-oxocyclobutanecarboxylic acid delivered
bifunctional cyclobutane 14 (85% yield), which is an attractive
derivative for medicinal chemistry applications.12 Trans-
formations of 4-substituted tetrahydropyran and piperidine
carboxylic acids were also efficient, providing 15 and 16 in 73%
and 69% yield, respectively. Tertiary carboxylic acids were
likewise excellent substrates, providing xanthates 17−20 in
nearly quantitative yield. Ketopinic acid yielded xanthate 21 in
67% yield, which is notable considering that decarboxylation of
this substrate is known to be challenging.13
We envision the decarboxylative xanthylation herein to
significantly expand the synthetic capabilities in decarbox-
ylative functionalization via the versatile alkyl xanthate
products.
We next applied the decarboxylative xanthylation as a tool
for late-stage modification of a range of natural products and
drug derivatives (Figure 2). Xanthylation of clotting agent
tranexamic acid provided 22 in 90% yield as a mixture of
diastereomers. Reactions of the nonsteroidal anti-inflammatory
drugs (NSAIDs) ibuprofen and indomethacin delivered
xanthates 23 and 24, respectively. We hypothesize that the
decreased efficiency of these reactions is due to the increased
stability of the intermediate conjugated radicals, which may
lead to reversible xanthate transfer.14 Interestingly, ibuprofen
was the sole substrate that we examined that gave a higher
yield using xanthylamide 1. A number of complex terpenoids
and steroids were also good substrates for the xanthylation
(25−29), indicating compatibility with unprotected alcohol,
ketone, and enone functionalities.15 An AcO-derivative of
the plant hormone gibberellic acid efficiently provided xanthate
30 in 72% yield as a single diastereomer. In addition, protected
amino acids provided decarboxylative functionalization prod-
ucts 31 and 32 in good yields. Notably, glutamic acid provides
opportunities for both unnatural amino acid synthesis and late-
In order to assess the unique reactivity of the amidyl radical
in the O−H HAT process, we analyzed the reactivity of related
xanthylsulfonamide 36 (Figure 3). The parent sulfonamide has
a calculated N−H bond strength of 104 kcal/mol,9 which is
somewhat lower than that of alkyl carboxylic acid O−H bonds.
Indeed, in an attempted xanthylation of hexanoic acid using
36, no decarboxylative products were observed: a mixture of
C−H functionalization products was formed instead.21
Furthermore, in an intermolecular competition between
hexanoic acid and cyclohexane, xanthylsulfonamide 36
provided only cyclohexyl xanthate 10 (Figure 3A). In contrast,
the same experiments using xanthylamides were selective for
decarboxylative xanthylation with a selectivity (kO−H/kC−H) of
10 and 24 for reagents 1 and 2, respectively, correcting for the
number of hydrogen atoms. This marked difference in
reactivity profile between the amide and sulfonamide reagents
offers opportunities for multisite xanthylations of carboxylic
acids. As an example, adamantane carboxylic acid was
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a
b
c
Figure 2. Decarboxylative xanthylation of diverse substrates. 10 mol % DLP used as initiator. 440 nm LEDs used as initiator. Yield refers to
NMR yield with hexamethyldisiloxane as an internal standard. d50 mol % DLP used as initiator. eGC yield using dodecane as an internal standard.
fReaction performed using reagent 1.
transformed to either the decarboxylative xanthylation product
18 or the C−H xanthylation product 37 simply by selecting
the appropriate reagent (Figure 3B).
While our results are consistent with a reaction mechanism
involving direct O−H HAT, other potential mechanisms were
considered, such as oxidation of a carboxylate salt by the
xanthylamide reagent. No reaction was observed in the
presence of a noncoordinating base (Table 1, entry 7) or
with a cesium carboxylate salt as substrate, which is
inconsistent with an oxidative pathway. Furthermore, no
reaction was observed upon heating hexanoic acid and
xanthylamide 2 in the dark with no initiator. As further
evidence for the intermediacy of carbon-centered radicals, an
Figure 3. Chemoselective O−H versus C−H HAT studies.
enantioenriched carboxylic acid provided the corresponding
xanthate as a racemate (see Supporting Information for
details).
C
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With respect to the O−H HAT step, a primary kinetic
isotope effect (KIE) of 5.4 was determined from a comparison
of the initial rates of decarboxylative xanthylation between O−
H and O−D forms of 1-methyl-1-cyclohexanecarboxylic acid,
consistent with an irreversible O−H HAT (eq 3). The present
Our calculations suggested that the O−H HAT involving 2′
is slightly exergonic (ΔG = −1.68 kcal·mol−1), while that of
36′ is endergonic (ΔG = +5.90 kcal·mol−1). Similarly, the
reaction of 2′ proceeds with a lower energy barrier (ΔG⧧ =
+20.04 kcal·mol−1) than that promoted by 36′ (ΔG⧧ = +25.39
kcal·mol−1), with a ΔΔG⧧ value of 5.35 kcal·mol−1. Overall,
these computational data support a facile O−H HAT by
amidyl radical 2′, with a somewhat larger barrier for the
reaction of 36′. We also speculate that hydrogen bonding to
the carboxylic acid may play a role in facilitating the O−H
HAT step. Investigations targeting these mechanistic details
are underway.24
In conclusion, we have developed a direct decarboxylative
xanthylation of aliphatic carboxylic acids using N-xanthyla-
mides. This transformation exhibits a broad substrate scope
and excellent functional group tolerance and serves as a general
platform for decarboxylative functionalization via the synthetic
versatility of alkyl xanthates. Our studies support a pathway
involving direct O−H HAT, which complements standard
redox-based approaches to decarboxylative chemistry. We
anticipate that this unique mode of direct hydrogen atom
transfer will prove valuable in a variety of synthetic contexts.
study clearly indicates the possibility for HAT of a stronger
O−H bond in the presence of weaker C−H bonds, such as
activated benzylic, allylic, and α-heteroatom positions. We
hypothesize that this chemoselectivity stems from the kinetic
facility of HAT between heteroatoms.22
We additionally undertook a computational analysis of a
model O−H HAT process involving the relevant nitrogen-
centered radicals to support the proposed pathway. As
depicted in Figure 4A, we evaluated the O−H HAT of n-
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.9b10825.
■
S
Experimental procedures and spectral data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*eja@email.unc.edu
■
ORCID
Davide Ravelli: 0000-0003-2201-4828
Erik J. Alexanian: 0000-0002-0256-2133
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Award No. R35 GM131708 from
the National Institute of General Medical Sciences. C.G.N.
thanks the NSF for a Graduate Research Fellowship and the
Graduate School for a Royster Fellowship. We additionally
would like to thank the University of North Carolina at Chapel
Hill and the Research Computing group for providing
computational resources.
Figure 4. (A) O−H HAT processes modeled by computational
means; the reported ΔG and ΔG⧧ values were obtained at the
SMD(CH2Cl2)-UωB97XD/def2TZVP//UωB97XD/def2TZVP level
of theory (see SI for further details). (B) Optimized structure of
transition state 38 at the UωB97XD/def2TZVP level of theory (gas
phase optimization).
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