Pd-Catalyzed Selective Chlorination of Acrylamides at Room Temperature

Article abstract of DOI:10.1021/acs.orglett.0c02750

In this Letter, the transition-metal-catalyzed chlorination of alkenes is reported. In the presence of the commercially available and inexpensive N-chlorosuccinimide and without additive, the Pd-catalyzed chlorination of acrylamides by C-H bond activation was developed at room temperature under air. Under these mild reaction conditions, the versatility of the methodology was demonstrated as an array of acrylamides was functionalized to selectively provide the corresponding difficult-to-synthesize chlorinated olefins as a single Z stereoisomer. Mechanistic studies were conducted to get insights into the reaction mechanism, and post-functionalization reactions further demonstrated the synthetic utility of the approach toward the access to high value-added chlorinated compounds.

Full text of DOI:10.1021/acs.orglett.0c02750

pubs.acs.org/OrgLett
Letter
Pd-Catalyzed Selective Chlorination of Acrylamides at Room
Temperature
Mu-Yi Chen, Xavier Pannecoucke, Philippe Jubault, and Tatiana Besset*
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ABSTRACT: In this Letter, the transition-metal-catalyzed chlori-
nation of alkenes is reported. In the presence of the commercially
available and inexpensive N-chlorosuccinimide and without
additive, the Pd-catalyzed chlorination of acrylamides by C−H
bond activation was developed at room temperature under air.
Under these mild reaction conditions, the versatility of the
methodology was demonstrated as an array of acrylamides was functionalized to selectively provide the corresponding difficult-
to-synthesize chlorinated olefins as a single Z stereoisomer. Mechanistic studies were conducted to get insights into the reaction
mechanism, and post-functionalization reactions further demonstrated the synthetic utility of the approach toward the access to high
value-added chlorinated compounds.
hlorinated molecules are widely present in compounds of
interest such as pharmaceuticals, agrochemicals, and
(Scheme 1).9 However, the direct and regioselective synthesis
C
natural products.1 In particular, halogenation of aromatic
derivatives is at the forefront of innovation because they have
widespread applications in organic chemistry. Therefore, the
development of novel methods to access them has attracted
strong interest from the scientific community.2 Among them,
special attention has been paid to the transition-metal-catalyzed
halogenation of aromatic derivatives by C−H bond activation
with I, Br, and Cl atoms.3 Indeed, transition-metal-catalyzed C−
H bond functionalizations have completely reshaped the field of
organic chemistry.4 This straightforward tool for molecular
synthesis has further opened the chemical space, enabling
applications to various fields.5 In particular, the transition-metal-
catalyzed directed functionalization of the more challenging
vinylic derivatives by C−H bond activation has been well
studied over the years, offering straightforward and selective
access to the difficult-to-synthesize Z isomer.6 In sharp contrast,
the halogenation of vinylic derivatives by C−H bond activation6
still remains restricted to a handful of examples and requires
further investigation as it offers selective access to the
challenging and ubiquitous Z-olefinic moiety. The quest for
efficient and selective tools toward Z-olefins is of high
importance because this scaffold might be found in several
bioactive compounds, such as Selinexor.
of Z-chlorinated acrylic acid derivatives is still elusive despite the
Scheme 1. State of the Art and Present Work
In the realm of the transition-metal-catalyzed halogenation of
olefins by C−H activation, bromination and iodination
reactions have been mainly studied using various transition-
metal catalysts and have led to major contributions. In 2013,
Glorius reported the Rh(III)-catalyzed bromination and
iodination of acrylamides,7 and one year later, they depicted
the iodination of acrylamides8 via a Cp*Co(III) catalysis. In
2019, Carreira described the Pd-catalyzed iodination of
unactivated olefins using picolamide as a directing group
Received: August 17, 2020
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© XXXX American Chemical Society
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A

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clear interest in the corresponding vinyl chloride compounds.1
Therefore, the elaboration of a new synthetic approach toward
these chlorinated molecules represents a significant challenge in
modern organic chemistry and is still an unmet goal. To date, the
existing methods to synthesize Z-β-chloroacrylic acid derivatives
generally rely on a Vilsmeier−Haack reaction,10 a Wittig
reaction,11 a chloropalladation/Heck reaction sequence,12
chlorination of propagyl alcohols,13 as well as hydrochlorina-
tion,14 chloroacylation,15 and chlorocarbonylation16 reactions
of alkynes, among others. A lack of E/Z selectivity and the need
to have the proper alkynes are the main synthetic limitations of
these methods that need to be overcome. In addition, to meet
the continuous demand for more sustainable transformations,
the development of C−H activation reactions under mild
conditions (no additives, room temperature) is still highly
desirable. Keeping these considerations in mind and pursuing
our current interest in the functionalization of vinylic derivatives
by C−H bond activation,17 we report herein the unprecedented
Pd(II)-catalyzed chlorination of various α- and α,β-substituted
acrylamide derivatives at room temperature.
reaction. Finally, using nondistilled DMF or a mixture of DMF/
H2O (9:1), the reaction afforded 2a, albeit in somewhat lower
yields (Table 1, entries 8 and 9), hence showcasing the
robustness of the transformation. Note that attempts to extend
the reaction to the bromination of 1a were unsuccessful.19
With the best reaction conditions in hand, access to
trisubstituted acrylamides was achieved via the Pd-catalyzed
chlorination of an array of α-aryl-substituted acrylamides
(Scheme 2, 2a−q). When 1a was used as the substrate, the
a
Scheme 2. Scope of the Chlorination Reaction
At the outset of the study, the Pd-catalyzed chlorination of the
α-phenylacrylamide 1a was studied (Table 1). In the presence of
Table 1. Reaction of 1a with NCS: Optimization Studies
a
entry
variation from standard conditions
none
CuI instead of PdCl2
CuCl2 instead of PdCl2
5 mol % of PdCl2 instead of 10 mol %
no catalyst
yield (%)
1
2
3
4
5
6
7
8
9
85
0
0
25
b
0
82
83
75
48
16 h instead of 8 h
Ar atmosphere instead of air
no distilled DMF instead of distilled one
DMF/H2O (9:1) instead of DMF
a
Isolated yields. All reactions were performed on a 0.2 mmol scale.
Product was obtained along with the product resulting from the
b
chlorination at the C5 position of the 8-aminoquinoline part in 31%
yield.
a stoichiometric amount of NCS and using PdCl2 as a catalyst,
1a was smoothly converted into the corresponding chlorinated
product 2a in 85% yield under an air atmosphere in 8 h (Table 1,
entry 1). The reaction turned out to be completely
diastereoselective, as a single Z-isomer was obtained, as
ascertained by 2D NMR experiments.18 The replacement of
PdCl2 by other copper-based catalysts (Table 1, entries 2 and 3)
led to no expected product 2a, and only the product resulting
from the chlorination at the C5 position of the 8-aminoquino-
line part was observed. The catalyst loading was also important
to selectively get the functionalization of the olefin. Indeed,
when 5 mol % of the catalyst was used, the reaction furnished 2a
in only 25% yield, along with the chlorinated product on the
aminoquinoline part (Table 1, entry 4). A control experiment
was conducted, and in the absence of a catalyst, 2a was not
obtained, and the same side reaction was prominent (Table 1,
entry 5). Increasing the reaction time (Table 1, entry 6) or
running the reaction under an inert atmosphere (Table 1, entry
7) did not have any significant impact on the outcome of the
a
Reaction conditions: acrylamide 1 (0.2 mmol), NCS (1 equiv),
PdCl2 (10 mol %), DMF (2 mL), 25 °C, 8 h, air. Isolated yields are
given. Reaction performed on a 4 mmol scale (1.1 g of 1a), 20 h. 20
h.
b
c
reaction was efficiently 20 times scaled up, offering access to ∼1
g of 2a (0.99 g, 80%) without erosion of the yield (85% on 0.2
mmol scale). The reaction turned out to be highly regio- and
diastereoselective to the expected product, and only the
monochlorination of the olefin part was observed. Several
acrylamides bearing an arene at the α-position substituted by an
electron-donating (1b−e) group or halogens (1f−i) at the para
position were chlorinated. The reaction was also tolerant of the
trifluoromethyl group (2k). Meta- and ortho-substituted α-aryl
acrylamides (2j−o) were chlorinated, and the substitution
pattern on the arenes did not have any impact on the efficiency
B
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of the transformation (similar yields for compounds 2b, 2j, 2m).
Note that the structure of 2n was further confirmed by X-ray
analysis (CCDC 2016282). Acrylamides with disubstituted
arenes (1p and 1q) were also suitable substrates in this
transformation. The methodology was successfully extended to
the chlorination of the methacrylamide 1r, leading to the
corresponding product 2r in 53% yield.
Pleasingly, the approach was successfully applied to the
functionalization of the α,β-disubstituted acrylamides, with the
stereoselective access to the tetrasubstituted acyclic olefin still
being a synthetic challenge. α,β-Disubstituted acrylamides such
as the dimethyl acrylamide (1s) and the cyclohex-1-enecarbox-
amide (1t) were smoothly converted into the fully decorated
olefins 2s and 2t. Even the amide derived from the 5-methoxy-8-
aminoquinoline 1u was smoothly functionalized in a longer
time.
compound (6a/6b) in 75% yield, with the Z-isomer being the
major one.20 Moreover, taking advantage of the presence of an
iodine atom on the aromatic ring of 2f, a Suzuki reaction was
performed, leading to the corresponding compound 7, with the
chlorinated olefin part remaining intact at the end of the
reaction.
To gain more insight into the mechanism of the reaction,
several experiments were conducted.18 First, when scrambling
experiments were performed, an H/D exchange was observed,
suggesting that the C−H bond activation step is reversible.
Then, 1i and the isotopically labeled olefin [D]-1i were engaged
in parallel reactions, and a kinetic isotopic effect (KIE) of 2.1 was
measured. These results indicated that the rate-determining step
is most likely the palladacycle formation. Experiments
conducted with 1a in the presence of TEMPO, BHT, and 1,4-
dinitrobenezene as radical scavengers showed no significant
effect on the outcome of the reaction; the reaction was just
slowed down (remaining unreacted 1a at the end of the
reaction), explaining the slightly lower yields.18 Therefore, a
radical process might be ruled out. On the basis of these
considerations, the following plausible mechanism was
suggested: At first, coordination of the Pd(II) catalyst with the
bidentate directing group of 1a followed by the reversible
formation of the palladacycle II. This latter underwent an
oxidative addition followed by a reductive elimination to furnish
the expected product 2a and to regenerate the catalyst (Scheme
5). Note that a redox neutral Pd(II)-based mechanism might not
be excluded.21
To further illustrate the modularity of the chlorinated amides,
they were easily converted into other classes of compounds. The
directing group was cleaved under various reaction conditions
(Scheme 3). When 2a and 2u were engaged under acidic or
oxidative conditions, the corresponding ester 3 and the primary
amide 4 were obtained in 55 and 77% yields, respectively.
a
Scheme 3. Deprotection of the Directing Group
Scheme 5. Suggested Mechanism
a
Reactions were carried out on a 0.1 mmol scale. Isolated yields are
given. (i) TsOH (3 equiv), MeOH (0.2 M), 100 °C, 7 days, Ar. (ii)
CAN (3 equiv), MeCN/H2O (5:1, 0.3 M), 25 °C, 16 h, Ar.
Taking advantage of the versatility brought by the
introduction of a chlorine atom on the olefinic derivative as a
“synthetic transformable handle” for post-functionalization, we
investigated further structural modifications by the trans-
formation of the carbon−chlorine bond into other carbon-
functional groups (Scheme 4). The reaction of 2a with
morpholine led to the corresponding product 5 as the single
E-isomer, ascertained by NMR.18 The subsequent thiolation of
2a provided an inseparable Z/E mixture of the thiolated
a
Scheme 4. Synthetic Applications
In summary, we developed a new methodology allowing the
direct chlorination of acrylamide derivatives under Pd catalysis
by C−H bond activation. This approach offered access to tri-
and tetra-substituted olefins in a complete stereoselective
manner toward the Z-isomer (21 examples, up to 89% yield).
This original transformation occurred at room temperature and
was suitable for a broad variety of acrylamides. Indeed, α-
substituted and α,β-disubstituted acrylamide derivatives were
efficiently functionalized. The salient features of this chlorina-
tion transformation are the lack of additives (oxidant, ligand,
acid or base, etc.), the air and moisture tolerance, the total
a
Reactions were carried out on a 0.1 mmol scale. Isolated yields are
given. (i) Morpholine (1.5 equiv), DMF (0.2 M), 90 °C, 16 h, Ar. (ii)
3-Methylbenzenethiol (1.5 equiv), Et3N (1.5 equiv), DMF (0.2 M),
50 °C, 24 h, Ar. (iii) Pd(PPh3)4 (5 mol %), p-tolylboronic acid (2
equiv), K2CO3 (1.5 equiv), toluene (0.2 M), 100 °C, 16 h, Ar. Q = 8-
quinolyl.
C
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control of the regio- and diastereoselectivity, the very mild
reaction conditions (room temperature), and the easy scale-up.
Moreover, access to value-added scaffolds, which hinged on the
use of the chlorine atom as a linchpin, further demonstrated the
key importance of chlorinated compounds and the need to
develop methodologies to reach them. By tackling an unmet
synthetic goal, this new approach considerably extends the
portfolio of chlorinated molecules and paves the way toward
original synthetic routes to unsaturated chlorinated compounds.
thanks the French National Research Agency for a doctoral
fellowship (ANR-17-CE07-0038-01). We are thankful to Prof.
Hassan Oulyadi for his help with NMR analysis.
REFERENCES
■
(1) (a) Engvild, K. C. Chlorine Containing Natural Compounds in
Higher Plants. Phytochemistry 1986, 25, 781−791. (b) Gribble, G. W.
Naturally Occurring Organohalogen Compounds. Acc. Chem. Res.
1998, 31, 141−152. (c) Hernandes, M. Z.; Cavalcanti, S. M. T.;
Moreira, D. R. M.; de Azevedo Junior, W. F.; Leite, A. C. L. Halogen
Atoms in the Modern Medicinal Chemistry: Hints for the Drug Design.
Curr. Drug Targets 2010, 11, 303−314. (d) Jeschke, P. The Unique
Role of Halogen Substituents in the Design of Modern Agrochemicals.
Pest Manage. Sci. 2010, 66, 10−27.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02750.
(2) For selected reviews, see: (a) Petrone, D. A.; Ye, J.; Lautens, M.
Modern Transition-Metal-Catalyzed Carbon-Halogen Bond Forma-
tion. Chem. Rev. 2016, 116, 8003−8104. (b) Shi, X.; Shi, D. Recent
Advances in Transition-Metal-Catalyzed Halides Formation. Curr. Org.
Chem. 2018, 22, 2229−2255. (c) Amal Joseph, P. J.; Priyadarshini, S.
Copper-Mediated C−X Functionalization of Aryl Halides. Org. Process
Res. Dev. 2017, 21, 1889−1924. For selected examples, see: (d) Yu, P.;
Bismuto, A.; Morandi, B. Iridium-Catalyzed Hydrochlorination and
Hydrobromination of Alkynes by Shuttle Catalysis. Angew. Chem., Int.
Ed. 2020, 59, 2904−2910. (e) Shi, J.-L.; Zhang, J.-C.; Wang, B.-Q.; Hu,
P.; Zhao, K.-Q.; Shi, Z.-J. Fe-Promoted Chlorobenzylation of Terminal
Alkynes Through Benzylic C(Sp(3))-H Bond Functionalization. Org.
Lett. 2016, 18, 1238−1241. (f) Ebule, R.; Liang, S.; Hammond, G. B.;
Xu, B. Chloride-Tolerant Gold(I)-Catalyzed Regioselective Hydro-
chlorination of Alkynes. ACS Catal. 2017, 7, 6798−6801. (g) Shi, C.;
Miao, Q.; Ma, L.; Lu, T.; Yang, D.; Chen, J.; Li, Z. Room-Temperature
C-H Bromination and Iodination with Sodium Bromide and Sodium
Iodide Using N-Fluorobenzenesulfonimide as an Oxidant. Chemis-
trySelect 2019, 4, 6043−6047.
(3) For selected reviews, see: (a) Lied, F.; Patra, T.; Glorius, F. Group
9 Transition Metal-Catalyzed C−H Halogenations. Isr. J. Chem. 2017,
57, 945−952. (b) Das, R.; Kapur, M. Transition-Metal-Catalyzed Site-
Selective C−H Halogenation Reactions. Asian J. Org. Chem. 2018, 7,
1524−1541. (c) Hao, W.; Liu, Y. C−H Bond Halogenation Catalyzed
or Mediated by Copper: an Overview. Beilstein J. Org. Chem. 2015, 11,
2132−2144. (d) Li, X.; Ouyang, W.; Nie, J.; Ji, S.; Chen, Q.; Huo, Y.
Recent Development on Cp*Ir(III)-Catalyzed C−H Bond Function-
alization. ChemCatChem 2020, 12, 2358−2384.
Experimental procedures, compound characterization
data, and 1H and 13C spectra of the products (PDF)
Accession Codes
CCDC 2016282 contains the supplementary crystallographic
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.
AUTHOR INFORMATION
Corresponding Author
■
́
Tatiana Besset − Normandie Universite, INSA Rouen,
UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen,
France; orcid.org/0000-0003-4877-5270;
Email: tatiana.besset@insa-rouen.fr
Authors
́
Mu-Yi Chen − Normandie Universite, INSA Rouen,
UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen,
France
́
Xavier Pannecoucke − Normandie Universite, INSA Rouen,
UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen,
France
(4) For selected reviews, see: (a) Lyons, T. W.; Sanford, M. S.
Palladium-Catalyzed Ligand-Directed C-H Functionalization Reac-
tions. Chem. Rev. 2010, 110, 1147−1169. (b) Jazzar, R.; Hitce, J.;
Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Functionalization of
Organic Molecules by Transition-Metal-Catalyzed C(Sp3)-H Activa-
tion. Chem. - Eur. J. 2010, 16, 2654−2672. (c) Engle, K. M.; Mei, T.-S.;
Wasa, M.; Yu, J.-Q. Weak Coordination as a Powerful Means for
Developing Broadly Useful C-H Functionalization Reactions. Acc.
Chem. Res. 2012, 45, 788−802. (d) Chen, Z.; Wang, B.; Zhang, J.; Yu,
W.; Liu, Z.; Zhang, Y. Transition Metal-Catalyzed C−H Bond
Functionalizations by the Use of Diverse Directing Groups. Org.
Chem. Front. 2015, 2, 1107−1295. (e) Pototschnig, G.; Maulide, N.;
́
Philippe Jubault − Normandie Universite, INSA Rouen,
UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen,
France; orcid.org/0000-0002-3295-9326
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02750
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
Schnurch, M. Direct Functionalization of C−H Bonds by Iron, Nickel,
̈
The authors declare no competing financial interest.
and Cobalt Catalysis. Chem. - Eur. J. 2017, 23, 9206−9232.
̈
(f) Sambiagio, C.; Schonbauer, D.; Blieck, R.; Dao-Huy, T.;
ACKNOWLEDGMENTS
This work was partially supported by Normandie Universite
Pototschnig, G.; Schaaf, P.; Wiesinger, T.; Zia, M. F.; Wencel-Delord,
■
J.; Besset, T.; Maes, B. U. W.; Schnurch, M. A Comprehensive
̈
́
Overview of Directing Groups Applied in Metal-Catalysed C−H
Functionalisation Chemistry. Chem. Soc. Rev. 2018, 47, 6603−6743.
(g) Ma, C.; Fang, P.; Mei, T.-S. Recent Advances in C−H
Functionalization Using Electrochemical Transition Metal Catalysis.
́
(NU), the Region Normandie, the Centre National de la
́
Recherche Scientifique (CNRS), Universite de Rouen Nor-
mandie (URN), INSA Rouen Normandie, Labex SynOrg
(ANR-11-LABX-0029), the French National Research Agency
(ANR-17-CE07-0038-01), and Innovation Chimie Carnot
(I2C). T.B. thanks the European Research Council (ERC)
under the European Union’s Horizon 2020 research and
innovation program (grant agreement no. 758710). M.-Y.C.
ACS Catal. 2018, 8, 7179−7189. (h) Gandeepan, P.; Muller, T.; Zell,
̈
D.; Cera, G.; Warratz, S.; Ackermann, L. 3d Transition Metals for C-H
Activation. Chem. Rev. 2019, 119, 2192−2452. For an issue on C−H
bond activation, see: Crabtree, R. H.; Lei, A. Chem. Rev. 2017, 117,
8481−8482 (pp 8481−9520).
D
https://dx.doi.org/10.1021/acs.orglett.0c02750
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(5) For selected examples, see: (a) Wang, W.; Lorion, M. M.; Shah, J.;
Kapdi, A. R.; Ackermann, L. Late-Stage Peptide Diversification by
Position-Selective C−H Activation. Angew. Chem., Int. Ed. 2018, 57,
14700−14717. (b) Noisier, A. F. M.; Brimble, M. A. C-H
Functionalization in the Synthesis of Amino Acids and Peptides.
Chem. Rev. 2014, 114, 8775−8806. (c) Pouliot, J.-R.; Grenier, F.;
Reactions: Selective and Efficient Cyanation, Halogenation, and
Allylation. J. Am. Chem. Soc. 2014, 136, 17722−17725.
(9) Schreib, B. S.; Carreira, E. M. Palladium-Catalyzed Regioselective
C-H Iodination of Unactivated Alkenes. J. Am. Chem. Soc. 2019, 141,
8758−8763.
(10) Krishnaraj, K. U.; Devaky, K. S. Synthesis of 2-Hydroxy-5,6-
Diarylnicotinonitriles and 2-Chloro- 5,6-Diarylnicotinonitriles From.
Tetrahedron 2014, 70, 6450−6456.
́
Blaskovits, J. T.; Beaupre, S.; Leclerc, M. Direct (Hetero)Arylation
Polymerization: Simplicity for Conjugated Polymer Synthesis. Chem.
Rev. 2016, 116, 14225−14274. (d) Schipper, D. J.; Fagnou, K. Direct
Arylation as a Synthetic Tool for the Synthesis of Thiophene-Based
Organic Electronic Materials. Chem. Mater. 2011, 23, 1594−1600.
(e) Seki, M. A. New Catalytic System for Ru-Catalyzed C−H Arylation
Reactions and Its Application in the Practical Syntheses of
Pharmaceutical Agents. Org. Process Res. Dev. 2016, 20, 867−877.
(f) Ackermann, L. Robust Ruthenium(II)-Catalyzed C−H Arylations:
Carboxylate Assistance for the Efficient Synthesis of Angiotensin-II-
Receptor Blockers. Org. Process Res. Dev. 2015, 19, 260−269.
(g) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S.
W. The Medicinal Chemist’s Toolbox for Late Stage Functionalization
of Drug-Like Molecules. Chem. Soc. Rev. 2016, 45, 546−576.
(h) Karimov, R. R.; Hartwig, J. F. Transition-Metal-Catalyzed Selective
Functionalization of C(Sp3)−H Bonds in Natural Products. Angew.
Chem., Int. Ed. 2018, 57, 4234−4241. (i) Abrams, D. J.; Provencher, P.
A.; Sorensen, E. J. Recent Applications of C−H Functionalization in
Complex Natural Product Synthesis. Chem. Soc. Rev. 2018, 47, 8925−
8967. (j) Baudoin, O. Multiple Catalytic C-H Bond Functionalization
for Natural Product Synthesis. Angew. Chem., Int. Ed. 2020,
DOI: 10.1002/anie.202001224, and references therein..
(11) Moody, C. J.; Pass, M.; Rees, C. W.; Tojo, G. Synthesis of the
Left-Hand Unit of the Antitumour Agent CC-1065. J. Chem. Soc., Chem.
Commun. 1986, 1062−1063.
(12) Huang, J.-M.; Dong, Y.; Wang, X.-X.; Luo, H.-C. Highly Regio-
and Stereoselective Intermolecular Tandem Reaction to Synthesize
Chloro-Substituted 1,3-Butadienes. Chem. Commun. 2010, 46, 1035−
1037.
(13) Trost, B. M.; Tracy, J. S. Vanadium-Catalyzed Synthesis of
Geometrically Defined Acyclic Tri- and Tetrasubstituted Olefins From
Propargyl Alcohols. ACS Catal. 2019, 9, 1584−1594.
(14) (a) Ma, S.; Lu, X.; Li, Z. A Novel Regio- and Stereospecific
Hydrohalogenation Reaction of 2-Propynoic Acid and Its Derivatives. J.
Org. Chem. 1992, 57, 709−713. (b) Grannas, M. J.; Hoskins, B. F.;
Robson, R. A New Tetranucleating Tetra-Amino-Tetra-Phenolic
Macrocyclic Ligand and the Crystal Structure of a Zn4 Derivative. J.
Chem. Soc., Chem. Commun. 1990, 1644−1646. (c) Taniguchi, M.;
Kobayashi, S.; Nakagawa, M.; Hino, T.; Kishi, Y. β-Halovinyl Ketones:
Synthesis from Acetylenic Ketones. Tetrahedron Lett. 1986, 27, 4763−
4766.
́
(15) (a) Cano, R.; Yus, M.; Ramon, D. J. Catalyzed Addition of Acid
Chlorides to Alkynes by Unmodified Nano-powder Magnetite:
Synthesis of Chlorovinyl Ketones, Furans, and Related Cyclopentenone
Derivatives. Tetrahedron 2013, 69, 7056−7065. (b) Zhou, H.; Zeng, C.;
Ren, L.; Liao, W.; Huang, X. GaCl3-Catalyzed Chloroacylation of
Alkynes: a Simple, Convenient and Efficient Method to β-Chlorovinyl
Ketones. Synlett 2006, 2006, 3504−3506. (c) Koo, H.; Kim, H. Y.; Oh,
K. (E)-Selective Friedel−Crafts Acylation of Alkynes to β-Chlorovinyl
Ketones: Defying Isomerizations in Batch Reactions by Flow
Chemistry Approaches. Org. Chem. Front. 2019, 6, 1868−1872.
(6) For selective reviews on transition-metal-catalyzed C−H
activation of vinylic derivatives, see: (a) Besset, T.; Poisson, T.;
Pannecoucke, X. Recent Progress in Direct Introduction of Fluorinated
Groups on Alkenes and Alkynes by Means of C-H Bond
Functionalization. Chem. - Eur. J. 2014, 20, 16830−16845. (b) Wang,
K.; Hu, F.; Zhang, Y.; Wang, J. Directing Group-Assisted Transition-
Metal-Catalyzed Vinylic C-H Bond Functionalization. Sci. China:
Chem. 2015, 58, 1252−1265 and references therein.. (c) Maraswami,
M.; Loh, T.-P. Transition-Metal-Catalyzed Alkenyl Sp2 C−H
Activation: a Short Account. Synthesis 2019, 51, 1049−1062. (d) Liu,
C.; Yuan, J.; Gao, M.; Tang, S.; Li, W.; Shi, R.; Lei, A. Oxidative
Coupling between Two Hydrocarbons: An Update of Recent C−H
Functionalizations. Chem. Rev. 2015, 115, 12138−12204 and
references therein. For selected examples, see: (e) Besset, T.; Kuhl,
N.; Patureau, F. W.; Glorius, F. RhIII-Catalyzed Oxidative Olefination of
Vinylic C-H Bonds: Efficient and Selective Access to Di-unsaturated α-
Amino Acid Derivatives and Other Linear 1,3-Butadienes. Chem. - Eur.
J. 2011, 17, 7167−7171. (f) Zhang, J.; Loh, T.-P. Ruthenium- and
rhodium-catalyzed cross-coupling reaction of acrylamides with alkenes:
efficient access to (Z,E)-dienamides. Chem. Commun. 2012, 48,
11232−11234. (g) Li, F.; Yu, C.; Zhang, J.; Zhong, G. Olefination of
Electron-Deficient Alkenes with Allyl Acetate: Stereo- and Regiose-
lective Access to (2Z,4E)-Dienamides. Org. Lett. 2016, 18, 4582−4585.
(h) Wen, Z.-K.; Xu, Y.-H.; Loh, T.-P. Palladium(ii)-catalyzed cross-
coupling of simple alkenes with acrylates: a direct approach to 1,3-
dienes through C−H activation. Chem. Sci. 2013, 4, 4520−4524.
(i) Neely, J. M.; Rovis, T. Rh(III)-Catalyzed Regioselective Synthesis of
Pyridines from Alkenes and α,β-Unsaturated Oxime Esters. J. Am.
Chem. Soc. 2013, 135, 66−69. (j) Hu, X.-H.; Zhang, J.; Yang, X.-F.; Xu,
Y.-H.; Loh, T.-P. Stereo- and Chemoselective Cross-Coupling between
Two Electron-Deficient Acrylates: An Efficient Route to (Z,E)-
Muconate Derivatives. J. Am. Chem. Soc. 2015, 137, 3169−3172.
(k) Giri, R.; Yu, J.-Q. Synthesis of 1,2- and 1,3-Dicarboxylic Acids via
Pd(II)-Catalyzed Carboxylation of Aryl and Vinyl C−H Bonds. J. Am.
Chem. Soc. 2008, 130, 14082−14083.
́
(16) (a) Cantagrel, G.; de Carne-Carnavalet, B.; Meyer, C.; Cossy, J.
Iron Trichloride-Promoted Cyclization of O-Alkynylaryl Isocyanates:
Synthesis of 3-(Chloromethylene)Oxindoles. Org. Lett. 2009, 11,
4262−4265. (b) Tang, S.; Yu, Q.-F.; Peng, P.; Li, J.-H.; Zhong, P.;
Tang, R.-Y. Palladium-Catalyzed Carbonylative Annulation Reaction of
2-(1-Alkynyl)Benzenamines: Selective Synthesis of 3-
(Halomethylene)Indolin-2-Ones. Org. Lett. 2007, 9, 3413−3416.
(c) Baek, J. Y.; Lee, S.; Sim, S.; Chung, Y. Chloroesterification of
Enynes Catalyzed by NHC Rhodium Compounds. Synlett 2008, 2008,
551−554. (d) Hua, R.; Onozawa, S.-Y.; Tanaka, M. Rhodium-
Catalyzed Nondecarbonylative Addition Reaction of ClCOCOOC2H5
to Alkynes. Chem. - Eur. J. 2005, 11, 3621−3630. (e) Le, C. M.; Sperger,
T.; Fu, R.; Hou, X.; Lim, Y. H.; Schoenebeck, F.; Lautens, M.
Stereoselective Synthesis of Methylene Oxindoles via Palladium(II)-
Catalyzed Intramolecular Cross-Coupling of Carbamoyl Chlorides. J.
Am. Chem. Soc. 2016, 138, 14441−14448.
(17) (a) Chen, M.-Y.; Pannecoucke, X.; Jubault, P.; Besset, T. Access
to Isothiazolones From Simple Acrylamides by Pd-Catalyzed C-H
Bond Activation. J. Org. Chem. 2019, 84, 13194−13202. (b) Zhao, Q.;
Chen, M.-Y.; Poisson, T.; Pannecoucke, X.; Bouillon, J.-P.; Besset, T.
Pd-Catalyzed Trifluoromethylthiolation of Unsaturated Compounds: a
General Approach. Eur. J. Org. Chem. 2018, 2018, 6167−6175.
(c) Zhao, Q.; Wang, J.; Besset, T.; Pannecoucke, X.; Bouillon, J.-P.;
Poisson, T. Palladium-catalyzed synthesis of 3-trifluoromethylated 1,3-
dienes from acrylate derivatives and BTP. Tetrahedron 2018, 74, 6033−
6040. (d) Zhao, Q.; Poisson, T.; Pannecoucke, X.; Bouillon, J.-P.;
Besset, T. Pd-Catalyzed Diastereoselective Trifluoromethylthiolation
of Functionalized Acrylamides. Org. Lett. 2017, 19, 5106−5109.
(e) Zhao, Q.; Tognetti, V.; Joubert, L.; Besset, T.; Pannecoucke, X.;
Bouillon, J.-P.; Poisson, T. Palladium-Catalyzed Synthesis of 3-
Trifluoromethyl-Substituted 1,3-Butadienes by Means of Directed
C−H Bond Functionalization. Org. Lett. 2017, 19, 2106−2109.
̈
(7) Kuhl, N.; Schroder, N.; Glorius, F. Rh(III)-Catalyzed Halogen-
ation of Vinylic C-H Bonds: Rapid and General Access to Z-Halo
Acrylamides. Org. Lett. 2013, 15, 3860−3863.
́
́
(8) Yu, D.-G.; Gensch, T.; de Azambuja, F.; Vasquez-Cespedes, S.;
Glorius, F. Co(III)-Catalyzed C−H Activation/Formal SN-Type
E
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(f) Zhao, Q.; Besset, T.; Poisson, T.; Bouillon, J.-P.; Pannecoucke, X.
Palladium-Catalysed Synthesis of α-(Trifluoromethyl)Styrenes by
Means of Directed C-H Bond Functionalization. Eur. J. Org. Chem.
2016, 2016, 76−82. (g) Xiong, H.-Y.; Cahard, D.; Pannecoucke, X.;
Besset, T. Pd-Catalyzed Directed Chlorination of Unactivated C(Sp3)-
H Bonds at Room Temperature. Eur. J. Org. Chem. 2016, 2016, 3625−
3630. (h) Xiong, H.-Y.; Besset, T.; Cahard, D.; Pannecoucke, X.
Palladium(II)-Catalyzed Directed Trifluoromethylthiolation of Un-
activated C(Sp3)−H Bonds. J. Org. Chem. 2015, 80, 4204−4212.
(i) Besset, T.; Cahard, D.; Pannecoucke, X. Regio- and Diaster-
eoselective Cu-Mediated Trifluoromethylation of Functionalized
Alkenes. J. Org. Chem. 2014, 79, 413−418.
(18) See the Supporting Information for details.
(19) When phthalimide bromide was used instead of NCS, the
product resulting from the selective bromination of 1a at the C5
position of the 8-aminoquinoline moiety was isolated in 66% yield.
(20) Note that the ratio was determined on the crude mixture. The
stereochemistry was ascertained by NMR experiments; see the
Supporting Information for more details.
(21) Haines, B. E.; Xu, H.; Verma, P.; Wang, X.-C.; Yu, J.-Q.; Musaev,
D. G. Mechanistic Details of Pd(II)-Catalyzed C−H Iodination with
Molecular I2: Oxidative Addition vs Electrophilic Cleavage. J. Am.
Chem. Soc. 2015, 137, 9022−9031.
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