Copper-Catalyzed Decarboxylative Functionalization of Conjugated β, Γ-Unsaturated Carboxylic Acids

Article abstract of DOI:10.1021/acscatal.0c03621

Copper-catalyzed decarboxylative coupling reactions of conjugated β,γ-unsaturated carboxylic acids have been achieved for allylic amination, alkylation, sulfonylation, and phosphinoylation. This approach was effective for a broad scope of amino, alkyl, su

Full text of DOI:10.1021/acscatal.0c03621

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Research Article
Copper-Catalyzed Decarboxylative Functionalization of Conjugated
β,γ-Unsaturated Carboxylic Acids
Wei Zhang,§ Chengming Wang,§ and Qiu Wang*
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ABSTRACT: Copper-catalyzed decarboxylative coupling reac-
tions of conjugated β,γ-unsaturated carboxylic acids have been
achieved for allylic amination, alkylation, sulfonylation, and
phosphinoylation. This approach was effective for a broad scope
of amino, alkyl, sulfonyl, and phosphinoyl radical precursors as well
as various conjugated β,γ-unsaturated carboxylic acids. These
reactions also feature high regioselectivity, good functional group
tolerance, and simple operation procedure. Mechanistic studies
show that the reaction proceeds via copper-catalyzed electrophilic
addition onto an olefin followed by decarboxylation, with radical
intermediates involved. These insights present a modular and
powerful strategy to access versatilely functionalized allyl-
containing skeletons from readily available and stable carboxylic
acids.
KEYWORDS: decarboxylation, amination, alkylation, sulfonylation, radical reaction, copper catalysis
arboxylic acids represent an important class of building
blocks in organic synthesis.1 Developing decarboxylative
decarboxylation. Such an unusual decarboxylation pathway
presents an efficient strategy for regiospecific γ-functionaliza-
tion (Scheme 1). So far, only hypervalent iodine(III) agents
have been used as the precursors to introduce the functional
groups, while greater potential remains to be explored to
enable the installation of different functionalities. Herein, we
report the development of copper-catalyzed decarboxylative
coupling reactions of conjugated β,γ-unsaturated carboxylic
acids with different precursors to achieve regioselective allylic
amination, alkylation, sulfonylation, and phosphinoylation
(Scheme 1c). These transformations offer a direct approach
to access a diverse range of allyl-containing skeletons.
Our group has recently demonstrated that O-acyl-N-
hydroxylamines are effective in engaging in the copper-
catalyzed electrophilic amination onto an olefin.8 Thus, we
envisioned that O-acylzoyl-N-hydroxylamines could be used as
the amino precursors for developing a decarboxylative allylic
amination reaction of conjugated β,γ-unsaturated carboxylic
acids. Such an allylic amination transformation will greatly
expand beyond the use of chloramine salts as the nitrogen
precursors in previous work.7b With allylic amines as highly
C
functionalization strategies that utilize carboxylic acids as stable
and highly prevalent starting materials has received great
attention, offering an attractive approach to introduce versatile
functionalities and to assemble complex skeletons.2 In
comparison to numerous examples in sp- and sp2-decarbox-
ylative functionalization,3 fewer have been reported on sp3-
decarboxylative functionalization and usually required the use
of a stoichiometric strong oxidant (e.g., Hunsdiecker
reaction).4 Not until recently, remarkable advances in sp3-
decarboxylative functionalization have been achieved with
different transition-metal catalysts such as silver, copper, nickel,
palladium, and even visible-light catalysis systems under
environmentally friendly conditions.5
Decarboxylative coupling reactions of β,γ-unsaturated
carboxylic acids under mild conditions will offer an appealing
approach to construct allylic functionalized skeletons that are
of great value in organic synthesis. Among various decarbox-
ylative functionalizations, the Hu group reported copper-
catalyzed decarboxylative fluoroalkylations using Togni-type
fluoroalkylating agents (Scheme 1a).6 The Minakata group
reported decarboxylative amidation and oxygenation using
hypervalent iodine reagents or N-iodo-N-chloroamides gen-
erated in situ from chloramine salts and I2 (Scheme 1b).7
Interestingly, the reactions reported by the Hu and Minakata
groups were mechanistically distinct from classic decarbox-
ylative ipso-functionalization as they were initiated by the
addition to the olefin by an electrophile followed by
Received: August 18, 2020
Revised: October 20, 2020
https://dx.doi.org/10.1021/acscatal.0c03621
© XXXX American Chemical Society
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Na2CO3 as the base, the reaction in DCE afforded 4-(2-
phenylallyl)morpholine 3a in 62% yield (Table 1, entry 1). In
comparison, 3a was not formed without a copper catalyst
(entry 2). The absence of Na2CO3 decreased the formation of
3a to 52% yield, suggesting that the carboxylate form may
facilitate the decarboxylation (entry 3). Various solvents
(entries 4−6) and ligands (entries 7−9) were examined,
none of which gave further improvement. Among the copper
catalysts tested, Cu(OTf)2 was the most effective one (entries
10−14). Finally, the yield of 3a was increased to 76% when the
reaction was run with 2a as the limiting reagent and reversing
the ratio of 1a:2a (entry 15), which was subsequently chosen
as standard conditions to examine the generality of the
decarboxylative allylic amination reaction.
Scheme 1. Decarboxylation-Assisted γ-Functionalization of
Conjugated β,γ-Unsaturated Carboxylic Acids
With established decarboxylative amination conditions, we
studied the scope of both hydroxylamines and carboxylic acids
in this reaction (Table 2). A diverse range of piperidine and
piperazine-derived allylic amines were all formed in good yields
(3b−3f). Besides six-membered cyclic amines, five-membered
pyrrolidine 3g and seven-membered azepane derivatives 3h
were also obtained, albeit in lower yields. Acyclic O-benzoyl-N-
hydroxylamines were compatible in the formation of 3i and 3j.
The scope of carboxylic acids was also examined. Substrates
bearing a methyl group at the ortho-, meta-, and para-positions
on the phenyl ring effectively produced allylic amines 3k−3m,
respectively. Both electron-donating (3n, 3o) and electron-
withdrawing (3p−3r) substitutions were well tolerated, with
no significant impact on the outcomes. Even the free hydroxyl
group was compatible (3s). The formation of thienyl-
substituted product 3t showed the applicability of this reaction
with heteroarenes. Yet, aliphatic-substituted substrates did not
participate in the reaction, with 3u undetected. Encouragingly,
γ-methyl- and γ,γ-dimethyl-substituted carboxylic acids
afforded 3v and 3w, with lower yields resulting from the
increased steric hindrance, respectively. The cyclic dialin-
containing substrate also delivered 3x. Furthermore, α-methyl-,
α,α-dimethyl- and even α,α,γ-trimethyl-substituted substrates
afforded 3y, 3z, and 3aa successfully, respectively. Results from
α- and γ-substituted carboxylic acids suggested that the
formation of the allylic amine products was initiated by Cu-
catalyzed amination of the olefin at the γ-position of carboxylic
acid followed by the decarboxylation step to regenerate the
double bond in the products. Correspondingly, the steric
bulkiness at the γ-position hindered the efficiency of the
reactions, as seen in the poor formation of 3w. Excitingly,
when β-alkynyl- and β-vinyl-substituted carboxylic acids were
tested for this reaction, all led to the selective formation of
desired allylic amine products 3ab−3ad while other unsatu-
rated carbon−carbon bonds remained intact.
valuable building blocks in organic synthesis,9 the development
of such a direct and regioselective synthesis of allylic amines is
desired. Our studies began with the decarboxylative amination
of 3-phenylbut-3-enoic acid 1a and O-benzoyl-N-hydroxylmor-
pholine 2a (Table 1). With Cu(OTf)2 as the catalyst and
a
Table 1. Optimization for Decarboxylative Amination
b
entry
catalyst
solvent
ligand
yield (%)
c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Cu(OTf)2
none
DCE
DCE
DCE
dioxane
toluene
MeCN
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
none
none
none
none
none
none
bpy
BINAP
diamine
none
none
none
none
none
none
60 (62)
ND
52
53
47
43
43
55
d
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OAc)2
CuI
Cu(MeCN)4BF4
CuTC
Cu(acac)2
Cu(OTf)2
53
56
c
We next explored the decarboxylation-assisted allylic
functionalization by using other radical species besides O-
acyl-N-hydroxylamines. Under modified copper-catalyzed
conditions,10 we have established a decarboxylative alkylation
by using alkyl radicals derived from α-bromocarbonyl
derivatives or α-bromonitrile.11 We evaluated the scope in a
diverse range of alkyl bromides and carboxylic acids (Table 3).
When different alkyl bromides were examined in this reaction,
all successfully formed allylic alkylation products, demonstrat-
ing the generality of this decarboxylative alkylation reaction
from various α-carbonyl alkyl radical precursors, ranging from
tertiary and secondary α-bromoacetates (5a−5g), primary α-
bromonitrile (5h), α-bromoacetamide (5i), and even α-
bromoketone (5j). A range of carboxylic acids bearing different
47
45
52
55
e
c
15
76
a
Conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (0.02 mmol),
b
ligand (0.02 mmol), Na2CO3 (0.24 mmol), solvent (3.0 mL). Yields
determined by 1H-NMR with dibromomethane as an internal
c
d
e
standard. Isolation yield. Without Na2CO3. Reaction using 1a
(0.4 mmol), 2a (0.2 mmol) instead of 1a (0.2 mmol), 2a (0.4 mmol).
bpy = 1,1′-dipyridine. BINAP = ( )-2,2′-bis(diphenylphosphino)-
1,1′-binaphthalene. Diamine = trans-N,N′-dimethylcyclohexane-1,2-
diamine. ND = Not detected.
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Table 2. Decarboxylative Amination of Conjugated β,γ-
Unsaturated Carboxylic Acids
Table 3. Decarboxylative Alkylation of Conjugated β,γ-
Unsaturated Carboxylic Acids
a
a
a
Condition B: 1 (1.5 equiv.), 4 (0.3 mmol, 1.0 equiv.), Cu(OTf)2 (10
mol %), bpy (10 mol %), Na2CO3 (1.1 equiv.), dioxane, 90 °C.
b
Isolation yields. Z/E ratio determined by 1H-NMR of the crude
reaction mixture.
a
Condition A: 1 (2.0 equiv.), 2 (0.2 mmol, 1.0 equiv.), Cu(OTf)2 (10
b
mol %), Na2CO3 (1.2 equiv.), DCE, 90 °C. Isolation yields. Z/E
ratio determined by H-NMR of the crude reaction.
effectively, respectively, suggesting that steric bulkiness
significantly hampered the decarboxylative alkylation. Finally,
the reactions of β-alkynyl and β-vinyl substitutions successfully
afforded the alkylation products 5y−5aa.
We have also developed an analogous sulfur radical-initiated
decarboxylative sulfonylation reaction of conjugated β,γ-
unsaturated carboxylic acid (Table 4). The copper-catalyzed
decarboxylative conditions were found to be effective,10
promoting the formation of aromatic and aliphatic allylic
sulfone products 7a−7e using different sulfonyl chlorides.12
Carboxylic acids bearing various functional groups on the
phenyl ring all gave the desired allylic sulfones (7f−7l).
Thienyl-substituted acid gave sulfone 7m in only 29% yield. An
α-monomethyl-substituted acid smoothly formed 7n, while a γ-
1
substitutions on the phenyl ring were also investigated,
including ortho-, meta-, and para-methyl groups (5k−5m),
various electron-withdrawing groups (5n−5p), and electron-
donating groups (5q−5s). Naphthyl-substituted carboxylic
acid afforded product 5t in 52% yield, while thienyl-containing
carboxylic acid formed 5u in only 17% yield. Substitution
effects on the α- and γ-positions were also investigated in the
reactions. Although α-monomethyl-substituted acid provided
5v in 76% yield, both α,α-dimethyl-substituted acid and γ-
methyl-substituted substrates failed to deliver 5w and 5x
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Table 4. Decarboxylative Sulfonylation of Conjugated β,γ-
Unsaturated Carboxylic Acids
Scheme 2. Control Experiments and Radical Capture
a
a
Experiments
a
Condition B: 1 (1.5 equiv.), 6 (0.3 mmol, 1.0 equiv.), Cu(OTf)2 (10
mol %), bpy (10 mol %), Na2CO3 (1.1 equiv.), dioxane, 90 °C.
b
Isolation yields. Z/E ratio determined by 1H-NMR of the crude
reaction mixture.
a
Isolation yields. Condition A shown in Table 2. Condition B shown
monomethyl-substituted acid failed to deliver the desired
product 7o. Interestingly, the dialin substrate formed 7p, with
the opposite regioselectivity to the amination product 3x,
possibly resulting from a direct decarboxylation pathway.13
Carboxylic acids bearing β-alkynyl and β-vinyl groups worked
effectively, generating desired allylic sulfones 7q−7s.
Our development of the copper-catalyzed decarboxylative
functionalization began with the hypothesis that the reactions
would be initiated by electrophile addition to the olefin
followed by subsequent decarboxylation. To examine this
hypothesis, we ran a series of control experiments (Scheme 2).
First, comparative experiments were performed using β,γ-
unsaturated carboxylic acid 1a, ester 8, and simple olefin 9
under the standard conditions for decarboxylative amination,
alkylation, and sulfonylation (Scheme 2a). The results from
these experiments demonstrated that the free carboxyl group is
critical in the decarboxylation step. To probe the presence of
radical intermediates, control experiments were run with the
addition of radical inhibitors, such as TEMPO (Scheme 2b)
and butylated hydroxytoluene (BHT) (Scheme 2c). In all
cases, the presence of a radical scavenger suppressed the
b
1
in Tables 3 and 4. ND = Not detected. Yields determined by H-
NMR with dibromomethane as an internal standard.
formation of desired products. The observation of BHT-
trapped products 10−12 further supports the formation of
radical intermediates, which initiate the reaction by adding
onto the double bond in these copper-catalyzed reactions.
Note that the stereochemical outcomes observed in these
decarboxylative transformations also indicated the involvement
of radical intermediates. For example, when α-methyl-
substituted β,γ-unsaturated carboxylic acid was used, allylic
amine 3y was obtained as a mixture of E/Z isomers. Similarly,
allylic alkylation product 5v and allylic sulfone 7n were also
formed as a mixture of E/Z isomers.
Based on these experimental observations and related
studies,8,11,12 we propose that the decarboxylation-assisted
amination, sulfonylation, and alkylation of conjugated β,γ-
unsaturated carboxylic acids may involve a similar pathway as
shown in Scheme 3. First, the Cu(II) precatalyst would
generate the active Cu(I) catalyst via disproportionation. Then
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Finally, we examined the applicability of this decarbox-
ylation-assisted functionalization strategy on other radical
precursors (Scheme 5). Using N-fluorobenzenesulfonimide
Scheme 3. Proposed Reaction Pathways for Decarboxylative
Amination, Alkylation, and Sulfonylation
Scheme 5. Decarboxylative Sulfonimidation, Alkylation,
a
Phosphinoylation, and Phosphonylation
a
b
Isolation yields. Conditions: 1a (2.0 equiv.), 16 (0.1 mmol, 1.0
the oxidative addition of radical precursors X−Z (i.e., 2, 4, or
6) to Cu(I) would generate a copper complex II, which
possibly exists in an equilibrium with a Cu(II) species III. The
resultant radical intermediates can be trapped by BHT, as
shown in Scheme 2c. Subsequent addition to olefin would
occur at the γ-position of β,γ-unsaturated carboxylic acid 1a.
The resulting intermediates IV−VI would undergo decarbox-
ylation by either a one-electron or two-electron pathway to
regenerate the Cu(I) catalyst and afford the allylic-function-
alized product (i.e., 3, 5, or 7). The control experiments with
compound 9 in Scheme 2a suggest that C−H allylic
functionalization pathways unlikely contribute to the formation
of products (i.e., 3, 5, or 7) under our reaction conditions,
although allylic functionalization of α-methyl styrene has been
c
equiv.), Cu(MeCN)4PF6 (10 mol %), DCE, 60 °C, 3 h. Conditions:
1a (2.0 equiv.), 2 (0.1 mmol, 1.0 equiv.), Cu(OTf)2 (10 mol%),
Na2CO3 (1.2 equiv.), DCE, 90 °C. Conditions: 1a (2.0 equiv.), 20
d
(0.1 mmol, 1.0 equiv.), Cu(MeCN)4PF6 (10 mol %), t-BuO2H (2.0
equiv.), MeCN, 90 °C, 1 h.
(NFSI) 16 as a different type of nitrogen precursor, the
reaction of carboxylic acid 1a readily formed the allylic
sulfonimide product 17 in 73% yield under modified
conditions. The reaction of cyclobutanone O-acyloxime 18
led to the decarboxylative alkylation product 19 via a ring-
opening generation of a primary alkyl radical. We also
investigated a phosphine-centered radical generated under
copper-catalyzed oxidative conditions in this decarboxylative
approach.14 Excitingly, the decarboxylative allylic phosphinoy-
lation and phosphonylation of 1a were viable, affording
allylphosphine oxides 21a and 21b and allylphosphonate
product 21c.
In conclusion, we have developed a copper-catalyzed
decarboxylative redox-neutral and traceless approach for the
preparation of allylic amines, homoallylic carbonyl derivatives,
and allylic sulfones from conjugated β,γ-unsaturated carboxylic
acids. Decarboxylative allylic phosphinoylation and phospho-
nylation have also been achieved under oxidative conditions.
These reactions feature high regioselectivity, good functional
group tolerance, and simple operation procedure. Mechanistic
studies suggest that the reaction is initiated by copper-
catalyzed addition of radicals onto the olefin followed by
decarboxylation. These insights support a general allylic
functionalization strategy to rapidly construct diverse allyl-
containing skeletons.
reported for allylic alkylation using α-bromoesters11f or
−g
allylic sulfonylation using sulfonyl chlorides.12
With these mechanistic insights, we examined the potential
of this decarboxylative functionalization pathway further on the
diene system (Scheme 4). Encouragingly, the reactions of 13
Scheme 4. Decarboxylative Functionalization of (E)-Hexa-
a
3,5-dienoic Acid
a
b
Isolation yields. Run under condition A shown in Table 2, see the
c
Supporting Information for by-products. Run under condition B
shown in Tables 3 and 4. E/Z ratio determined by 1H-NMR of the
d
crude reaction mixture.
ASSOCIATED CONTENT
■
sı
* Supporting Information
successfully delivered products 15, under standard conditions
for the decarboxylative amination, alkylation, and sulfonylation,
presumably through the intermediate 14 via selective addition
onto the terminal double bond. The poor yield of 15a resulted
in part from the competing amino lactonization pathway (see
the Supporting Information).
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c03621.
Condition optimizations, experimental procedures,
compound characterization, and NMR spectra (PDF)
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Communications. A Convenient Synthesis of Alkyl Halides from
Carboxylic Acids. J. Org. Chem. 1961, 26, 280−280.
AUTHOR INFORMATION
Corresponding Author
Qiu Wang − Department of Chemistry, Duke University,
Durham, North Carolina 27708, United States; orcid.org/
0000-0002-6803-9556; Email: qiu.wang@duke.edu
■
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Authors
Wei Zhang − Department of Chemistry, Duke University,
Durham, North Carolina 27708, United States
Chengming Wang − Department of Chemistry, Duke
University, Durham, North Carolina 27708, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c03621
Author Contributions
§W.Z. and C.W. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support by Duke University and the
National Institutes of Health (GM118786). We thank Dr.
Peter Silinski for the assistance with high-resolution mass
spectrometry data.
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