Palladium-Catalyzed Allenamide Carbopalladation/Allylation with Active Methine Compounds

Article abstract of DOI:10.1021/acs.orglett.1c01369

A palladium-catalyzed allenamide carbopalladation/allylation with active methine compounds has been developed. Various indoles and isoquinolinones bearing a quaternary carbon center were achieved with good efficiency, a broad substrate scope and good functional group tolerance. This reaction underwent cascade oxidative addition, carbopalladation, and allylic alkylation, and two new C-C bonds were formed in one pot.

Full text of DOI:10.1021/acs.orglett.1c01369

pubs.acs.org/OrgLett
Letter
Palladium-Catalyzed Allenamide Carbopalladation/Allylation with
Active Methine Compounds
Xiaoyi Zhu, Ruibo Li, Hequan Yao,* and Aijun Lin*
Cite This: Org. Lett. 2021, 23, 4630−4634
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A palladium-catalyzed allenamide carbopalladation/
allylation with active methine compounds has been developed.
Various indoles and isoquinolinones bearing a quaternary carbon
center were achieved with good efficiency, a broad substrate scope
and good functional group tolerance. This reaction underwent
cascade oxidative addition, carbopalladation, and allylic alkylation,
and two new C−C bonds were formed in one pot.
a b
,
Table 1. Optimization of Reaction Conditions
ll-carbon quaternary centers are widely distributed in
A
natural products and pharmaceuticals, which can greatly
increase the three-dimensionality of molecules and significantly
improve the target selectivity, metabolic stability, and other
pharmacy-related properties.1 The construction of quaternary
carbon skeleton has always been an important research topic in
organic synthetic chemistry,2 and it is also a challenging task.
Over the past several decades, the alkylation,3 arylation,4 and
allylic alkylation5 of active methine compounds have been well
explored, which has provided efficient routes to access
quaternary carbon frameworks. However, benzylation, in
particular, the heterobenzylation reaction, has rarely been
reported, and the benzylic reagents are mainly confined to
activated benzyl bromides,6 benzyl alcohols,7 and their
derivatives8 (Scheme 1a).
a
b
entry
deviation of standard conditions
yield (%)
1
2
3
4
none
92
38
trace
21
Pd(PtBu3)2 instead of Pd(PPh3)4
Pd2(dba)3 instead of Pd(PPh3)4
A2 instead of A1
Indoles and isoquinolinones are two kinds of important
heterocyclic skeletons that are frequently found in bioactive
substances exhibiting broad biological and pharmacological
effects such as antioxidant, anti-inflammatory, and antihyper-
tensive activities.9 Given the importance of quaternary carbon
skeletons and heterocycles to the pharmaceutical properties,
5
6
7
8
A3 instead of A1
26
51
12
trace
36
45
23
NR
40
53
Cs2CO3 instead of t-BuONa
K3PO4 instead of t-BuONa
Et3N instead of t-BuONa
PhMe instead of THF
MeCN instead of THF
DMSO instead of THF
without Pd(PPh3)4
9
10
11
12
13
14
Scheme 1. Benzylation of Active Methine Compounds
c
without A1
1′ instead of 1
a
Standard conditions: 1 (0.2 mmol), 2 (0.4 mmol), Pd(PPh3)4 (10.0
mol %), A1 (30.0 mol %), t-BuONa (0.2 mmol), THF (1.0 mL), 50
°C (oil bath temperature), under an Ar atmosphere for 8 h, sealed
b
c
tube. Isolated yields. NR, no reaction.
Received: April 20, 2021
Published: May 28, 2021
https://doi.org/10.1021/acs.orglett.1c01369
Org. Lett. 2021, 23, 4630−4634
© 2021 American Chemical Society
4630

Organic Letters
pubs.acs.org/OrgLett
Letter
a b
,
Scheme 2. Substrate Scope for the Synthesis of Indoles
Scheme 3. Substrate Scope for the Synthesis of
a b
,
Isoquinolinones
a
Reaction conditions: allenamide (0.2 mmol), aldehyde (0.4 mmol),
Pd(PPh3)4 (10.0 mol %), A1 (30.0 mol %), t-BuONa (0.2 mmol),
THF (1.0 mL), 50 °C (oil bath temperature), under an Ar
b
atmosphere for 8 h. Isolated yields.
a b
,
Scheme 4. Substrate Scope of Pronucleophiles
a
Reaction conditions: allenamide (0.2 mmol), aldehyde (0.4 mmol),
Pd(PPh3)4 (10.0 mol %), A1 (30.0 mol %), t-BuONa (0.2 mmol),
THF (1.0 mL), 50 °C (oil bath temperature), under an Ar
b
atmosphere for 8 h. Isolated yields.
herein we describe a palladium-catalyzed carbopalladation/
allylation of allenamides10 with active methine compounds for
the first time. Many indoles and isoquinolinones bearing a
quaternary carbon center were achieved with good efficiency
(Scheme 1b). This reaction underwent cascade oxidative
addition, carbopalladation, and allylic alkylation, and two new
C−C bonds were formed in one pot.
We commenced our study with N-(o-iodophenyl)allenamide
1 and 2-phenylpropanal 2 as the model substrates. After
systematic screening of the reaction conditions (see the
Supporting Information (SI) for details), the desired product 3
could be obtained in 92% yield by employing 10.0 mol %
Pd(PPh3)4 and 30.0 mol % diphenylmethanamine A1 as the
catalysts and t-BuONa as the base in THF at 50 °C for 8 h
(Table 1, entry 1). When Pd(PtBu3)2 was used, the reaction
proceeded in 38% yield, and Pd2(dba)3 retarded the trans-
formation (Table 1, entries 2 and 3). Proline A2 and
pyrrolidine A3 finished the reaction with low efficiency
(Table 1, entries 4 and 5). Other bases, such as Cs2CO3 and
K3PO4, offered 3 in diminished yields (Table 1, entries 6 and
7), and organic base such as Et3N failed in facilitating the
reaction (Table 1, entry 8). When the reaction was carried out
in toluene, acetonitrile, or DMSO, product 3 was isolated in
23−45% yield (Table1, entries 9−11). Control experiments
showed that the palladium catalyst was essential to this
reaction (Table 1, entry 12). A low yield of 3 was detected in
the absence of A1 (Table 1, entry 13). We also employed
a
Reaction conditions: allenamide 1 (0.2 mmol), pronucleophile (0.4
mmol), Pd(PPh3)4 (10.0 mol %), Cs2CO3 (0.4 mmol), THF (1.0
mL), 50 °C (oil bath temperature), under an Ar atmosphere for 8 h.
b
c
d
e
Isolated yields. DBU (0.4 mmol). LDA (0.4 mmol). Cs2CO3 (1.0
f
g
h
equiv). Pronucleophile (4.0 equiv). Allenamide 1 (2.0 equiv). A1
(30 mol %).
4631
https://doi.org/10.1021/acs.orglett.1c01369
Org. Lett. 2021, 23, 4630−4634

Organic Letters
pubs.acs.org/OrgLett
Letter
pound 48 was isolated in 54% yield in one pot. Compound 49
could be achieved in 88% yield through the Wittig reaction.
The N-tosyl protecting group could be expediently removed in
the presence of K2CO3 to give 50 in 62% yield. Treating
compound 39 with NiCl2·6H2O and NaBH4 offered β-amino
acid derivative 51 in 63% yield. We also attempted the
asymmetric version of this method. After screening a series of
chiral ligands and chiral amine catalysts (see the SI for details),
product 3 could be achieved in 89% yield with 40% ee.
In conclusion, we have established a palladium-catalyzed
sequential oxidative addition, carbopalladation, and allylic
alkylation of allenamides with active methine and methylene
compounds for the first time. This protocol highlighted a
generalizable strategy to construct indoles and isoquinolinones
with a quaternary carbon center with good efficiency.
Scheme 5. Synthetic Transformations
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01369.
progargylamide 1′ as the starting material, which offered 3 in
53% yield (Table 1, entry 14) (see the SI for details). The
structure of 3 was confirmed by the single-crystal X-ray
diffraction studies (see the SI for details).
Experiment procedures, detailed reaction optimization,
compound characterization, and NMR spectra (PDF)
Accession Codes
With the optimized conditions in hand, we then checked the
substrate scope for the synthesis of indole-containing
compounds (Scheme 2). The allenamides with various groups
on the benzene ring, such as methyl, methoxyl, halogen, and
carboxyl groups, performed the reaction well, offering products
4−9 in 78−98% yield. When pyridine-derived allenamide was
applied, the corresponding azaindole product 10 could be
obtained in 85% yield. The generality of α-branched aldehydes
was also examined. 2-Arylpropanals with versatile substituent
groups offered the products 11−16 and 18−21 in good to
excellent yields. Product 17 was isolated in 67% yield due to
the steric hindrance. Product 22 with two indole units was
synthesized in 96% yield. The 2-phenylbutanal, 2,2-dipheny-
lacetaldehyde, and 1,2,3,4-tetrahydronaphthalene-1-carbalde-
hyde were also good participants, affording the products 23−
25 in excellent yields. Product 3 (1.02 g) could be achieved in
98% yield on a 2.5 mmol scale under the optimal conditions.
After exploring the generality for the synthesis of indole
frameworks, we then extended this protocol to synthesize
isoquinolinones, and the corresponding products 26−35 were
achieved in 57−98% yield under the standard reaction
conditions (Scheme 3).
CCDC 2046574 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
Hequan Yao − State Key Laboratory of Natural Medicines,
Jiangsu Key Laboratory of Bioactive Natural Product
Research, Department of Medicinal Chemistry, China
Pharmaceutical University, Nanjing 210009, P. R. China;
orcid.org/0000-0003-4865-820X; Email: hyao@
cpu.edu.cn, cpuhyao@126.com
Aijun Lin − State Key Laboratory of Natural Medicines,
Jiangsu Key Laboratory of Bioactive Natural Product
Research, Department of Medicinal Chemistry, China
Pharmaceutical University, Nanjing 210009, P. R. China;
orcid.org/0000-0001-5786-4537; Email: ajlin@
cpu.edu.cn
In addition, we also extended this method to other active
methine compounds (Scheme 4), such as β-ketoester, diethyl
methylmalonate, 2-nitropropanoate, 2-cyanopropionate, cya-
nophosphonate, amide, ketone, oxindole, and azlactone, and
the corresponding products 36−44 were isolated in 43−93%
yield. Notably, this method could also be applied to active
methylene nucleophiles. The benzylic product 45 and
dibenzylic product 46 could be achieved in 68 and 67%
yield by altering the ratio of the substrates and the equivalent
of base (see the SI for details). Moreover, the dibenzylic
product 47 was obtained in 60% yield when 2-phenyl-
acetaldehyde was used.
Authors
Xiaoyi Zhu − State Key Laboratory of Natural Medicines,
Jiangsu Key Laboratory of Bioactive Natural Product
Research, Department of Medicinal Chemistry, China
Pharmaceutical University, Nanjing 210009, P. R. China
Ruibo Li − State Key Laboratory of Natural Medicines,
Jiangsu Key Laboratory of Bioactive Natural Product
Research, Department of Medicinal Chemistry, China
Pharmaceutical University, Nanjing 210009, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01369
To further demonstrate the synthetic utility of the method,
synthetic transformations of product 3 and 39 were carried out
(Scheme 5). After condensation of 3 with (4-methoxyphenyl)-
methanamine followed by reduction with NaBH3CN, com-
Notes
The authors declare no competing financial interest.
4632
https://doi.org/10.1021/acs.orglett.1c01369
Org. Lett. 2021, 23, 4630−4634

Organic Letters
pubs.acs.org/OrgLett
Letter
Chiral Acetylenes Having an All-Carbon Quaternary Center: Phase
Transfer Catalyzed Enantioselective a Alkylation of α-Alkyl-α-alkynyl
Esters. Angew. Chem., Int. Ed. 2009, 48, 5014−5017.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(NSFC22071267), the Foundation of the Open Project of
State Key Laboratory of Natural Medicines
(SKLNMZZ202023), and the Innovation Team of “the
Double-First Class” Disciplines (CPU2018GY35) for the
financial support.
(4) For selected examples, see: (a) Xie, X.; Chen, Y.; Ma, D.
Enantioselective Arylation of 2-Methylacetoacetates Catalyzed by
CuI/trans-4-Hydroxy-L-proline at Low Reaction Temperatures. J. Am.
Chem. Soc. 2006, 128, 16050−16051. (b) Martín, R.; Buchwald, S. L.
A General Method for the Direct α-Arylation of Aldehydes with Aryl
Bromides and Chlorides. Angew. Chem., Int. Ed. 2007, 46, 7236−7239.
(c) Vo, G. D.; Hartwig, J. F. Palladium-Catalyzed α-Arylation of
Aldehydes with Bromo- and Chloroarenes Catalyzed by [{Pd(allyl)-
Cl}2] and dppf or Q-phos. Angew. Chem., Int. Ed. 2008, 47, 2127−
2130. (d) Jiao, Z.; Chee, K. W.; Zhou, J. S. Palladium-Catalyzed
Asymmetric α-Arylation of Alkylnitriles. J. Am. Chem. Soc. 2016, 138,
16240−16243.
REFERENCES
■
(1) For a recent review, see: (a) Talele, T. T. Opportunities for
Tapping into Three-Dimensional Chemical Space through a
Quaternary Carbon. J. Med. Chem. 2020, 63, 13291−13315. For
selected examples, see: (b) Mould, D. P.; Alli, C.; Bremberg, U.;
Cartic, S.; Jordan, A. M.; Geitmann, M.; Maiques-Diaz, A.;
McGonagle, A. E.; Somervaille, T. C. P.; Spencer, G. J.; Turlais, F.;
Ogilvie, D. Development of (4-Cyano-phenyl)glycine Derivatives as
Reversible Inhibitors of Lysine Specific Demethylase 1. J. Med. Chem.
2017, 60, 7984−7999. (c) Zheng, X.; Liang, C.; Wang, L.; Wang, B.;
Liu, Y.; Feng, S.; Wu, J. Z.; Gao, L.; Feng, L.; Chen, L.; Guo, T.; Shen,
H. C.; Yun, H. Discovery of Benzoazepinequinoline (BAQ)
Derivatives as Novel, Potent, Orally Bioavailable Respiratory Syncytial
Virus Fusion Inhibitors. J. Med. Chem. 2018, 61, 10228−10241.
(d) Michaelides, M. R.; Kluge, A.; Patane, M.; Van Drie, J. H.; Wang,
C.; Hansen, T. M.; Risi, R. M.; Mantei, R.; Hertel, C.; Karukurichi, K.;
Nesterov, A.; McElligott, D.; de Vries, P.; Langston, J. W.; Cole, P. A.;
Marmorstein, R.; Liu, H.; Lasko, L.; Bromberg, K. D.; Lai, A.; Kesicki,
E. A. Discovery of spiro oxazolidinediones as selective, orally
bioavailable inhibitors of p300/CBP histone acetyltransferases. ACS
Med. Chem. Lett. 2018, 9, 28−33. (e) Li, Y.; Zhao, J.; Gutgesell, L. M.;
Shen, Z.; Ratia, K.; Dye, K.; Dubrovskyi, O.; Zhao, H.; Huang, F.;
Tonetti, D. A.; Thatcher, G. R. J.; Xiong, R. Novel Pyrrolopyridone
Bromodomain and Extra-Terminal Motif (BET) Inhibitors Effective
in Endocrine-Resistant ER+ Breast Cancer with Acquired Resistance
to Fulvestrant and Palbociclib. J. Med. Chem. 2020, 63, 7186−7210.
(2) For selected reviews, see: (a) Fuji, K. Asymmetric Creation of
Quaternary Carbon Centers. Chem. Rev. 1993, 93, 2037−2066.
(b) Quasdorf, K. W.; Overman, L. E. Catalytic Enantioselective
Synthesis of Quaternary Carbon Stereocentres. Nature 2014, 516,
181−191. (c) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Catalytic
Enantioselective Construction of Quaternary Stereocenters: Assembly
of Key Building Blocks for the Synthesis of Biologically Active
Molecules. Acc. Chem. Res. 2015, 48, 740−751. (d) Zeng, X.-P.; Cao,
Z.-Y.; Wang, Y.-H.; Zhou, F.; Zhou, J. Catalytic Enantioselective
Desymmetrization Reactions to All-Carbon Quaternary Stereocenters.
Chem. Rev. 2016, 116, 7330−7396. (e) Feng, J.; Holmes, M.; Krische,
M. J. Acyclic Quaternary Carbon Stereocenters via Enantioselective
Transition Metal Catalysis. Chem. Rev. 2017, 117, 12564−12580.
(f) Li, C.; Ragab, S. S.; Liu, G.; Tang, W. Enantioselective Formation
of Quaternary Carbon Stereocenters in Natural Product Synthesis: a
Recent Update. Nat. Prod. Rep. 2020, 37, 276−292.
(5) For selected examples, see: (a) Jiang, G.; List, B. Direct
Asymmetric α-Allylation of Aldehydes with Simple Allylic Alcohols
Enabled by the Concerted Action of Three Different Catalysts. Angew.
Chem., Int. Ed. 2011, 50, 9471−9474. (b) Liu, W.-B.; Reeves, C. M.;
Stoltz, B. M. Enantio-, Diastereo-, and Regioselective Iridium-
Catalyzed Asymmetric Allylic Alkylation of Acyclic β-Ketoesters. J.
Am. Chem. Soc. 2013, 135, 17298−17301. (c) Turnbull, B. W. H.;
Evans, P. A. Enantioselective Rhodium-Catalyzed Allylic Substitution
with a Nitrile Anion: Construction of Acyclic Quaternary Carbon
Stereogenic Centers. J. Am. Chem. Soc. 2015, 137, 6156−6159.
(d) Kita, Y.; Kavthe, R. D.; Oda, H.; Mashima, K. Asymmetric Allylic
Alkylation of β-Ketoesters with Allylic Alcohols by a Nickel/
Diphosphine Catalyst. Angew. Chem., Int. Ed. 2016, 55, 1098−1101.
(e) Cruz, F. A.; Dong, V. M. Stereodivergent Coupling of Aldehydes
and Alkynes via Synergistic Catalysis Using Rh and Jacobsen’s Amine.
J. Am. Chem. Soc. 2017, 139, 1029−1032.
(6) For selected examples, see: (a) Ooi, T.; Miki, T.; Fukumoto, K.;
Maruoka, K. Asymmetric Synthesis of α-Acyl-γ-butyrolactones
Possessing All-Carbon Quaternary Stereocenters by Phase-Transfer-
Catalyzed Alkylation. Adv. Synth. Catal. 2006, 348, 1539−1542.
(b) Brown, A. R.; Kuo, W.-H.; Jacobsen, E. N. Enantioselective
Catalytic α-Alkylation of Aldehydes via an SN1 Pathway. J. Am. Chem.
Soc. 2010, 132, 9286−9288. (c) Park, Y.; Lee, Y. J.; Hong, S.; Kim,
M.-h.; Lee, M.; Kim, T.-S.; Lee, J. K.; Jew, S.-s.; Park, H.-g. Highly
Enantioselective Phase-Transfer Catalytic α-Alkylation of α-tert-
Butoxycarbonyllactams: Construction of β-Quaternary Chiral Pyrro-
lidine and Piperidine Systems. Adv. Synth. Catal. 2011, 353, 3313−
3318. (d) List, B.; Coric, I.; Grygorenko, O. O.; Kaib, P. S. J.;
Komarov, I.; Lee, A.; Leutzsch, M.; Chandra Pan, S.; Tymtsunik, A.
V.; van Gemmeren, M. The Catalytic Asymmetric α-Benzylation of
Aldehydes. Angew. Chem., Int. Ed. 2014, 53, 282−285. (e) Zhu, Y.;
Zhang, W.-Z.; Zhang, L.; Luo, S. Chiral Primary Amine Catalyzed
Asymmetric α-Benzylation with In Situ Generated ortho-Quinone
Methides. Chem. - Eur. J. 2017, 23, 1253−1257.
(7) For selected examples, see: (a) Sanz, R.; Miguel, D.; Martínez,
́
A.; Alvarez-Gutiérrez, J. M.; Rodríguez, F. Brønsted Acid-Catalyzed
Benzylation of 1,3-Dicarbonyl Derivatives. Org. Lett. 2007, 9, 2027−
2030. (b) Xing, C.; Sun, H.; Zhang, J.; Li, G.; Chi, Y. R. Brønsted
Acid Catalyzed α-Alkylation of Aldehydes with Diaryl Methyl
Alcohols. Chem. - Eur. J. 2011, 17, 12272−12275. (c) Maji, T.;
Ramakumar, K.; Tunge, J. A. Retro-Claisen Benzylation: Direct Use of
Benzyl Alcohols in Pd-catalyzed Couplings with Nitriles. Chem.
Commun. 2014, 50, 14045−14048.
(8) For selected examples, see: (a) Torregrosa, R. R. P.; Ariyarathna,
Y.; Chattopadhyay, K.; Tunge, J. A. Decarboxylative Benzylations of
Alkynes and Ketones. J. Am. Chem. Soc. 2010, 132, 9280−9282.
(b) Trost, B. M.; Czabaniuk, L. C. Palladium-Catalyzed Asymmetric
Benzylation of 3-Aryl Oxindoles. J. Am. Chem. Soc. 2010, 132, 15534−
15536. (c) Trost, B. M.; Czabaniuk, L. C. Benzylic Phosphates as
Electrophiles in the Palladium-Catalyzed Asymmetric Benzylation of
Azlactones. J. Am. Chem. Soc. 2012, 134, 5778−5781. (d) Trost, B.
M.; Czabaniuk, L. C. Palladium-Catalyzed Asymmetric Benzylation of
Azlactones. Chem. - Eur. J. 2013, 19, 15210−15218. (e) Franzoni, I.;
Guénée, L.; Mazet, C. A General Pd-catalyzed α- and γ-Benzylation of
(3) For selected examples, see: (a) Sawamura, M.; Hamashima, H.;
Ito, Y. Catalytic Asymmetric Synthesis with Trans-Chelating Chiral
Diphosphine Ligand TRAP: Rhodium-Catalyzed Asymmetric Michael
Addition of α-Cyano Carboxylates. J. Am. Chem. Soc. 1992, 114,
8295−8296. (b) Hamashima, Y.; Hotta, D.; Sodeoka, M. Direct
Generation of Nucleophilic Chiral Palladium Enolate from 1,3-
Dicarbonyl Compounds: Catalytic Enantioselective Michael Reaction
with Enones. J. Am. Chem. Soc. 2002, 124, 11240−11241. (c) Mase,
N.; Tanaka, F.; Barbas, C. F., III Synthesis of β-Hydroxyaldehydes
with Stereogenic Quaternary Carbon Centers by Direct Organo-
catalytic Asymmetric Aldol Reactions. Angew. Chem., Int. Ed. 2004, 43,
2420−2423. (d) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. A Chiral
Primary Amine Thiourea Catalyst for the Highly Enantioselective
Direct Conjugate Addition of α,α-Disubstituted Aldehydes to
Nitroalkenes. Angew. Chem., Int. Ed. 2006, 45, 6366−6370. (e) Jautze,
S.; Peters, R. Enantioselective Bimetallic Catalysis of Michael
Additions Forming Quaternary Stereocenters. Angew. Chem., Int. Ed.
2008, 47, 9284−9288. (f) Hashimoto, T.; Sakata, K.; Maruoka, K. α-
4633
https://doi.org/10.1021/acs.orglett.1c01369
Org. Lett. 2021, 23, 4630−4634

Organic Letters
pubs.acs.org/OrgLett
Letter
Aldehydes for the Formation of Quaternary Centers. Org. Biomol.
Chem. 2015, 13, 6338−6343. (f) Tsuji, H.; Hashimoto, K.; Kawatsura,
M. Nickel-Catalyzed Benzylic Substitution of Benzyl Esters with
Malonates as a Soft Carbon Nucleophile. Org. Lett. 2019, 21, 8837−
8841.
(9) For selected drug molecules containing indole and isoquinoli-
none motifs, see: (a) Jagtap, P. G.; Baloglu, E.; Southan, G. J.; Mabley,
J. G.; Li, H.; Zhou, J.; van Duzer, J.; Salzman, A. L.; Szabo, C.
Discovery of Potent Poly(ADP-ribose) Polymerase-1 Inhibitors from
the Modification of Indeno[1,2-c]isoquinolinone. J. Med. Chem. 2005,
48, 5100−5103. (b) Biradar, J. S.; Sasidhar, B. S.; Parveen, R.
Synthesis, Antioxidant and DNA Cleavage Activities of Novel Indole
Derivatives. Eur. J. Med. Chem. 2010, 45, 4074−4078. (c) Pereira, R.;
Benedetti, R.; Perez-Rodríguez, S.; Nebbioso, A.; García-Rodríguez, J.;
Carafa, V.; Stuhldreier, M.; Conte, M.; Rodríguez-Barrios, F.;
Stunnenberg, H. G.; Gronemeyer, H.; Altucci, L.; de Lera, A. R.
Indole-Derived Psammaplin A Analogues as Epigenetic Modulators
with Multiple Inhibitory Activities. J. Med. Chem. 2012, 55, 9467−
9491. (d) Kaila, N.; Follows, B.; Leung, L.; Thomason, J.; Huang, A.;
Moretto, A.; Janz, K.; Lowe, M.; Mansour, T. S.; Hubeau, C.; Page,
K.; Morgan, P.; Fish, S.; Xu, X.; Williams, C.; Saiah, E. Discovery of
Isoquinolinone Indole Acetic Acids as Antagonists of Chemo-
attractant Receptor Homologous Molecule Expressed on Th2 Cells
(CRTH2) for the Treatment of Allergic Inflammatory Diseases. J.
Med. Chem. 2014, 57, 1299−1322. (e) Singh, P.; Kaur, S.; Sharma, A.;
Kaur, G.; Bhatti, R. TNF-α and IL-6 Inhibitors: Conjugates of N-
substituted Indole and Aminophenylmorpholin-3-one as Anti-
inflammatory Agents. Eur. J. Med. Chem. 2017, 140, 92−103.
(10) For selected reviews, see: (a) Lu, T.; Lu, Z.; Ma, Z.-X.; Zhang,
Y.; Hsung, R. P. Allenamides: A Powerful and Versatile Building Block
in Organic Synthesis. Chem. Rev. 2013, 113, 4862−4904. (b) Blieck,
R.; Taillefer, M.; Monnier, F. Metal-Catalyzed Intermolecular
Hydrofunctionalization of Allenes: Easy Access to Allylic Structures
via the Selective Formation of C−N, C−C, and C−O Bonds. Chem.
Rev. 2020, 120, 13545−13598. For selected examples, see: (c) Braun,
M.-G.; Katcher, M. H.; Doyle, A. G. Carbofluorination via a
Palladium-Catalyzed Cascade Reaction. Chem. Sci. 2013, 4, 1216−
1220. (d) Higuchi, Y.; Mita, T.; Sato, Y. Palladium-Catalyzed
Intramolecular Arylative Carboxylation of Allenes with CO2 for the
Construction of 3-Substituted Indole-2-carboxylic Acids. Org. Lett.
2017, 19, 2710−2713. (e) Hédouin, J.; Schneider, C.; Gillaizeau, I.;
Hoarau, C. Palladium-Catalyzed Domino Allenamide Carbopallada-
tion/Direct C−H Allylation of Heteroarenes: Synthesis of Primpri-
nine and Papaverine Analogues. Org. Lett. 2018, 20, 6027−6032.
(f) Hédouin, J.; Carpentier, V.; Renard, R. M. Q.; Schneider, C.;
Gillaizeau, I.; Hoarau, C. Regioselective Pd-Catalyzed Carbopallada-
tion/Decarboxylative Allylic Alkynylation of ortho-Iodoallenamides
with Alkynyl Carboxylic Acids. J. Org. Chem. 2019, 84, 10535−10545.
(g) Xiong, W.; Cheng, R.; Wu, B.; Wu, W.; Qi, C.; Jiang, H.
Palladium-Catalyzed Regioselective Cascade Reaction of Carbon
Dioxide, Amines and Allenes for the Synthesis of Functionalized
Carbamates. Sci. China: Chem. 2020, 63, 331−335.
4634
https://doi.org/10.1021/acs.orglett.1c01369
Org. Lett. 2021, 23, 4630−4634