Catalytic, Regioselective Hydrocarbofunctionalization of Unactivated Alkenes Triggered by trans-Acetoxypalladation of Alkynes

Article abstract of DOI:10.1021/acs.orglett.1c00118

Herein we demonstrate a Pd(II)-catalyzed regioselective hydrocarbofunctionalization of unactivated alkenes. The σ-vinyl-palladium(II) intermediate generated by the trans-acetoxypalladation of alkynes was added across carbon-carbon double bond to realize an efficient hydroalkenylation protocol. Bidentate auxiliary 8-aminoquinoline controls the regioselectivity of the carbopalladation step and thereby controls the regioselectivity of the hydroalkenylation. Additionally, when alkynes containing a hydroxy group at the three- or four-position were employed, the cascade sequence led to 1,6-dicarbonyl compounds via hydroalkenylation followed by intramolecular acyl migration.

Full text of DOI:10.1021/acs.orglett.1c00118

pubs.acs.org/OrgLett
Letter
Catalytic, Regioselective Hydrocarbofunctionalization of
Unactivated Alkenes Triggered by trans-Acetoxypalladation of
Alkynes
Rahul K. Shukla, Atul K. Chaturvedi, Subir Pal, and Chandra M. R. Volla*
Cite This: Org. Lett. 2021, 23, 1440−1444
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ABSTRACT: Herein we demonstrate a Pd(II)-catalyzed regiose-
lective hydrocarbofunctionalization of unactivated alkenes. The σ-
vinyl-palladium(II) intermediate generated by the trans-acetox-
ypalladation of alkynes was added across carbon−carbon double
bond to realize an efficient hydroalkenylation protocol. Bidentate
auxiliary 8-aminoquinoline controls the regioselectivity of the
carbopalladation step and thereby controls the regioselectivity of
the hydroalkenylation. Additionally, when alkynes containing a
hydroxy group at the three- or four-position were employed, the cascade sequence led to 1,6-dicarbonyl compounds via
hydroalkenylation followed by intramolecular acyl migration.
Scheme 1. Overview of the Work
ith the widespread availability of alkenes from
Wpetrochemical feedstock and renewable resources, the
catalytic hydrocarbofunctionalization of alkenes is emerging as
a powerful transformation for the construction of carbon−
carbon bonds.1 The atom- and step-economical hydro-
carbofunctionalization can be deployed in any stage of a
multistep synthesis, allowing for both the late-stage mod-
ification of alkene containing intermediates as well as the early-
stage functionalization of feedstock alkenes.2 Despite its
evident advantages, the regioselective delivery of a hydrogen
and a carbon atom across alkene is the bottleneck for its
synthetic utility. In this regard, palladium-catalyzed alkene
functionalization has witnessed tremendous growth in recent
years.3 Typically these reactions proceed by the insertion of an
alkene with the organopalladium species in a cis fashion,
leading to the generation of an alkylpalladium(II) intermediate.
Hydrocarbofunctionalization focuses on the mechanistic
strategies allowing the selective protodepalladation of this
intermediate.
Syn-carbopalladation of alkynes followed by cis−trans
isomerization was demonstrated by the groups of Werz and
Lautens as an efficient method for accessing trans-σ-vinyl-
palladium species.4 Alternatively, the trans-nucleopalladation of
alkynes has also been widely studied for generating such
organopalladium species in a stereoselective manner.5 The
coordinative insertion of these organopalladium species with
activated alkenes has been well documented (Scheme 1a).6 In
contrast, the related transformations with unactivated alkenes
have been much less explored.
Received: January 12, 2021
Published: February 2, 2021
In an effort to expand this mode of reactivity to unactivated
nonconjugated alkenes, various research groups have designed
strongly coordinating directing groups tethered to alkenes to
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© 2021 American Chemical Society
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stabilize the alkyl metal intermediate as a metallacycle.7
A
a
Table 1. Optimization of the Reaction Conditions
landmark in the this field was described by Engle and
coworkers by masking the 3-butenoic acid derivatives with an
8-aminoquinoline8 (AQ) directing group. They demonstrated
that bidentate auxiliary 8-aminoquinoline controls the
regioselectivity of the carbopalladation and also accelerates
the protodepalladation in preference to ß-hydride elimination.9
The groups of Chen, Gong, and Shi also made valiant
contributions to chelation-assisted regio- and stereoselective
alkene functionalization reactions of alkenamides.10 Given the
wide availability of alkynes and alkenes, integrating the Pd-
catalyzed trans-acetoxypalladation of alkynes and cis-migratory
insertion of alkenes would further broaden the synthetic utility
of this approach. The potential of Pd-catalyzed acetoxypalla-
dation was mostly explored either in intramolecular cyclization
reactions or with activated π-systems.11 So, the migratory
insertion of unactivated alkenes with σ-vinyl-palladium(II)
species generated by acetoxypalladation in a regioselective
manner would be of considerable importance; herein we report
the chelation-induced regiocontrol for both the acetoxypalla-
dation as well as migratory insertion (Scheme 1b). While this
work was in progress, Chen and coworkers illustrated an
efficient Pd-catalyzed hydroalkynylation of alkenamides with
terminal alkynes.12 They also studied the preliminary substrate
scope of the methodology using internal alkynes and carboxylic
acids to realize the same transformation described herein.
To test our hypothesis, we chose 3-butenoic acid as the
alkene substrate and 1,2-diphenylethyne 2a and acetic acid 3a
as potential coupling partners. Initial screening by using 10 mol
% of Pd(OAc)2 in EtOH with different directing groups such
as 2-(aminomethyl)pyridine A, 2-(methylthio)aniline B, and 2-
(4,4-dimethyl-4,5-dihydrooxazol-2-yl)aniline C did not deliver
the expected products (Table 1, entries 1−3). However, we
were pleased to observe the formation of 4a as a single
regioisomer in 30% yield when 8-aminoquinoline D was
employed as the bidentate auxiliary. The relative stereo-
chemistry of 4a was unambiguously confirmed by the single-
crystal X-ray crystallography, consistent with selective for-
mation of a trans five-membered palladacycle intermediate
upon nucleopalladation. Hence we chose bidentate 8-amino-
quinoline auxiliary as the directing group and focused our
attention on identifying suitable reaction conditions. During
preliminary screening of solvent, we found that aprotic solvent
such as DCE, toluene, CH3NO2, and CH3CN did not afford
the desired product (entries 5−8), and THF and 1,4-dioxane
delivered 4a in only trace amounts (entries 9 and 10). We then
turned our attention to the screening of polar protic solvents,
and t-amyl alcohol gave similar results to EtOH and afforded
4a in 25% yield (entry 11). However, we were delighted to
notice that trifluoroethanol (TFE) and hexafluoroisopropanol
(HFIP) improved the yield to 48 and 70%, respectively
(entries 12 and 13). We next investigated the effect of the
concentration of acetic acid and found that higher concen-
tration of acetic acid (3.0 equiv) led to the formation of 4a in
90% yield (entry 15). PdCl2 furnished the desired product in
slightly inferior yield (entry 16). Further optimization revealed
that lowering the temperature (50 °C) or reducing the catalyst
loading (5 mol %) had an adverse effect (entries 17 and 18).
The reaction did not furnish any product in the absence of the
Pd catalyst (entry 19).
b
entry
catalyst
directing group
solvent
EtOH
EtOH
EtOH
EtOH
DCE
toluene
CH3NO2
CH3CN
THF
1,4-dioxane
t-Am-OH
TFE
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
yield (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
A
B
n.r.
n.r.
n.r.
30
n.r.
n.r.
n.r.
n.r.
10
5
25
48
70
78
90
60
82
60
n.r.
n.r.
C
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
9
10
11
12
13
c
14
d
15
16
e
17
f
Pd(OAc)2
Pd(OAc)2
18
19
20
g
Pd(OAc)2
a
b
1a (0.1 mmol), 2a (0.12 mmol), 3a (0.2 mmol). NMR yield (using
1,3,5-trimethoxybenzene as internal standard). 3a (0.25 mmol). 3a
(0.3 mmol). Reaction at 50 °C. Pd(OAc)2 (5 mol %). Without 3a.
c
d
e
f
g
n.r. = no reaction.
2). To our delight, a broad range of acids were found to be
compatible under the optimized conditions, showcasing the
generality of this method. As displayed in Scheme 2 various
aliphatic primary carboxylic acids like propionic acid, 4-
phenylbutanoic acid, 3-cyclohexylpropanoic acid, and butenoic
acid delivered the corresponding products 4b−e in 80−89%
yields. Secondary (diphenyl acetic acid) and tertiary (pivalic
acid) acids were also found to be viable substrates, giving the
expected products 4f and 4g in 87 and 55% yield, respectively,
at slightly higher temperature (100 °C). The reaction could be
extended to cyclobutanecarboxylic acid, adamantanyl acetic
acid, and tetrahydrofuran-2-carboxylic acid as well (4h−j).
Vinyl carboxylic acids resulted in the corresponding function-
alized products 4k−l in synthetically useful yield (70−81%).
Additionally, aromatic acids such as benzoic acid and
naphthoic acid were as effective as their aliphatic counterparts,
affording the corresponding products 4m and 4n in 78 and
68% yield, respectively. When 3.0 equiv of deuterated acetic
acid (CD3COOD) was used in HFIP, the corresponding
product 4o was isolated in 81% yield.
To expand the synthetic utility of our hydroalkenylation
strategy, various biologically relevant carboxylic acids were
screened (Scheme 3). The anti-inflammatory drug aspirin
(acetylsalicyclic acid) was tested under the optimized
conditions to isolate 4p in 65% yield (Scheme 3). Protected
amino acids such as N-acetyl-glycine, N-phthalimide iso-
leucine, and N-boc-L-proline fared well to afford the
corresponding functionalized products 4q−s at a slightly
With the optimized reaction conditions in hand, we next
investigated the scope of carboxylic acids using alkenamide 1a
and 1,2-diphenylethyne 2a as the reaction partners (Scheme
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Scheme 2. Scope of the Carboxylic Acids
Scheme 4. Scope of Alkynes and Alkenamides
Scheme 3. Scope with Biologically Relevant Carboxylic
Acids
diynes were efficiently transformed into the corresponding
products 5g−5i in 60−68% yields. In the case of
(bromoethynyl)benzene, a single regioisomer 5j was obtained
in 78% yield. Analogous to the internal alkynes, terminal
alkynes were also compatible to deliver the desired products
with excellent regioselectivity 5k−5m. However, phenyl
propargyl ether resulted in a mixture of two regioisomers 5n
(37%) and 5n′ (28%) with a slight preference toward the anti-
Markovnikov product 5n. This change in regioselectivity is
probably due to the coordination of Pd(II) with the ethereal
oxygen. Interestingly, when nona-1,8-diyne was employed in
the reaction, bis-hydrocarbofunctionalized product 5o was
isolated in 80% yield using 2.0 equiv of 1a and 6.0 equiv of 3a.
The versatility of the reaction was further demonstrated with
8-aminoquinoline-masked pent-3-enoic acid and hex-3-enoic
acid to isolate the corresponding products 5p and 5q in 72 and
58% yield, respectively.
high temperature and longer reaction time. Gratifyingly, cholic
acid, a commonly available bile acid, could be readily
converted to the desired product 4t in 60% yield.
Next, we examined the scope of the developed protocol with
a variety of symmetrical and unsymmetrical alkynes (Scheme
4). Electron-donating methoxy and electron-withdrawing
fluoro groups on the phenyl ring were well tolerated to furnish
the corresponding products 5a, 5b in 86 and 90% yield,
respectively. We were curious to examine the regioselectivity of
the acetoxypalladation in the case of unsymmetrical diaryl
alkynes and tested 1-(4-(phenylethynyl)phenyl)ethan-1-one as
the alkyne, which resulted in a 1:0.3 mixture of 5c and 5c′ in
an overall yield of 80%. Remarkably, a single regioisomer was
observed in the case of the cyclohexadienone-tethered alkyne
5d in 90% yield, suggesting that the regioselectivity of the
trans-acetoxypalladation is controlled by the preferential
stabilization of the partial positive charge upon Pd(II)
coordination. Other unsymmetrical alkynes also indicated
similar results (5e, f). We then explored the generality of the
protocol with 1,3-diynes. A variety of diversely substituted 1,3-
Interestingly, alkynes bearing a hydroxyl group at three- or
four-position 6 under similar catalytic conditions resulted in
1,6-dicarbonyl compounds 7 by hydrocarbofunctionalization
followed by intramolecular acyl migration reaction (Scheme
5). The intramolecular migration of the acyl group was
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Scheme 5. 1,6-Dicarbonyl Compound Synthesis
Scheme 7. Proposed Mechanism
facilitated by the nucleophilic addition of the hydroxyl group
onto acyl via a five- or six-membered transition state.
Encouraged by this, we explored the cascade reactivity by
synthesizing a variety of terminal alkynes with hydroxyl
substitution at the three- or four-position to generate the
1,6-dicarbonyl compounds 7a−7g in good to excellent yields
using acetic acid (75−87%). Additionally, cyclobutanecarbox-
ylic acid was also tolerated under the optimized reaction
conditions to afford 7h in 87% yield. Interestingly, when pent-
2-yn-1-ol was employed as the alkyne, we observed the
formation of enone 7i in 77% yield. The reaction required
slightly higher temperature (110 °C) and longer reaction time
for completion (16 h) and proceeded via cascade hydro-
alkenylation and acyl migration followed by E1cb elimination.
(See the Supporting Information for the mechanism.)
In conclusion, we have demonstrated a palladium-catalyzed
regio-controlled hydrocarbofunctionalization of nonconjugated
alkenes using a cleavable 8-aminoquinoline directing group.
The reaction was triggered by the Pd-catalyzed trans-
acetoxypalladation of alkyne substrates. The operationally
simple protocol was also compatible with a variety of
biologically relevant carboxylic acids. Additionally, alkynes
having a hydroxyl group at the three- or four-position resulted
in the efficient formation of the 1,6 dicarbonyl compound by
hydrocarbofunctionalization followed by intramolecular acyl
migration.
ASSOCIATED CONTENT
* Supporting Information
To demonstrate the practical utility of this Pd(II)-catalyzed
hydrocarbofunctionalization reaction, several downstream
manipulations were performed (Scheme 6). The base-
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00118.
Scheme 6. Further Functionalizations
Additional experimental procedures, X-ray crystallo-
graphic analysis, and spectroscopic data for synthesized
compounds (PDF)
Accession Codes
CCDC 1979714−1979715 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
mediated hydrolysis of 4h resulted in the formation of ketone
8 in 92% yield. Furthermore, the aminoquinoline directing
group of 4f was converted into methyl ester 9 in 96% yield
under acidic conditions.
AUTHOR INFORMATION
Corresponding Author
■
Chandra M. R. Volla − Department of Chemistry, Indian
Institute of Technology Bombay, Mumbai 400076, India;
orcid.org/0000-0002-8497-1538; Email: chandra.volla@
chem.iitb.ac.in
A plausible mechanism for this Pd(II)-catalyzed hydro-
carbofunctionalization reaction is proposed in Scheme 7.
Initially, Pd(II) binds to the 8-aminoquinoline bidentate
directing group and coordinates with the alkyne, leading to
its π-bond activation. In the presence of a carboxylic acid, the
alkyne undergoes trans-acetoxypalladation to give the vinyl-
palladium intermediate B, which, in turn, is intramolecularly
coordinated with the alkene. Intramolecular migratory
insertion with the carbon−carbon double bond followed by
protodepalladation of C delivers the vinyl ester product 4/5. In
the case of alkynes having hydroxyl groups at the three- or
four-position, intramolecular acyl migration followed by
tautomerization results in the formation of 1,6-dicarbonyl
compound 7.
Authors
Rahul K. Shukla − Department of Chemistry, Indian Institute
of Technology Bombay, Mumbai 400076, India
Atul K. Chaturvedi − Department of Chemistry, Indian
Institute of Technology Bombay, Mumbai 400076, India;
orcid.org/0000-0002-1065-9437
Subir Pal − Department of Chemistry, Indian Institute of
Technology Bombay, Mumbai 400076, India
Complete contact information is available at:
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ChemCatChem 2018, 11 (3), 961−968. For selected examples of Ni-
catalyzed carbofunctionalization reactions, see: (b) Shrestha, B.;
Basnet, P.; Dhungana, R. K.; KC, S.; Thapa, S.; Sears, J. M.; Giri, R. J.
Am. Chem. Soc. 2017, 139, 10653−10656. (c) Basnet, P.; Dhungana,
P. K.; Thapa, S.; Shrestha, V.; KC, S.; Sears, J. M.; Giri, R. J. Am.
Chem. Soc. 2018, 140, 7782−7786. (d) Li, W.; Boon, J. K.; Zhao, Y.
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J.; Engle, K. M. ACS Catal. 2019, 9, 224−229. (j) Derosa, J.; Kang, T.;
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Xu, K. L.; Engle, K. M. Angew. Chem., Int. Ed. 2020, 59, 1201−1205.
For selected examples of Pd-catalyzed carbofunctionalization
reactions, see: (k) Liu, Z.; Zeng, T.; Yang, K. S.; Engle, K. M. J.
Am. Chem. Soc. 2016, 138, 15122−15125. (l) Liu, Z.; Wang, Y.;
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https://pubs.acs.org/10.1021/acs.orglett.1c00118
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This activity is supported by SERB, India (CRG/2019/
005059). R.K.S. is grateful to the University Grants
Commission (UGC, India) for the fellowship.
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