Palladium-Catalyzed Regioselective Syn-Chloropalladation-Olefin Insertion-Oxidative Chlorination Cascade: Synthesis of Dichlorinated Tetrahydroquinolines

Article abstract of DOI:10.1021/acs.orglett.9b01295

A palladium catalyzed cascade process involving syn-chloropalladation, intramolecular olefin insertion, and oxidative C-Cl bond formation reactions was demonstrated for the synthesis of dichlorinated tetrahydroquinolines in high yields (up to 93%). The N-propargyl arylamines having a tethered α,β-unsaturated carbonyl moiety underwent a regioselective syn-chloropalladation followed by a Heck-type reaction to deliver the tetrahydroquinoline scaffold. The rare insertion of the second chlorine atom was rationalized comprising a Pd^II/IV catalytic cycle and oxidative cleavage of the C-Pd^II bond.

Full text of DOI:10.1021/acs.orglett.9b01295

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Regioselective Syn-Chloropalladation−Olefin
Insertion−Oxidative Chlorination Cascade: Synthesis of
Dichlorinated Tetrahydroquinolines
Perumal Vinoth,† Muthu Karuppasamy,† B. S. Vachan,† Isravel Muthukrishnan,† C. Uma Maheswari,†
Subbiah Nagarajan,‡ Vittorio Pace,§ Alexander Roller,§ Nattamai Bhuvanesh,∥
and Vellaisamy Sridharan*,†,⊥
†Department of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur-613401, Tamil Nadu
India
‡Department of Chemistry, National Institute of Technology, Warangal, Warangal-506004, Telangana, India
§Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria
∥Department of Chemistry, Texas A & M University, College Station, Texas 77843, United States
⊥Department of Chemistry and Chemical Sciences, Central University of Jammu, Rahya-Suchani (Bagla), District-Samba,
Jammu-181143, Jammu and Kashmir, India
S
* Supporting Information
ABSTRACT: A palladium catalyzed cascade process involving syn-
chloropalladation, intramolecular olefin insertion, and oxidative C−
Cl bond formation reactions was demonstrated for the synthesis of
dichlorinated tetrahydroquinolines in high yields (up to 93%). The
N-propargyl arylamines having a tethered α,β-unsaturated carbonyl
moiety underwent a regioselective syn-chloropalladation followed by
a Heck-type reaction to deliver the tetrahydroquinoline scaffold. The
rare insertion of the second chlorine atom was rationalized
comprising a PdII/IV catalytic cycle and oxidative cleavage of the
C−PdII bond.
ates, which undergo various cascade transformations including
olefin insertion via Heck-type coupling; 1,2-addition to a
carbonyl; nucleophilic addition to a nitrile group; arylation;
alkyne, carbene, isocyanide, isocyanate insertion etc. for the
generation of diverse products in a single operation. The most
common nucleopalladation reactions including amino-,13
oxy-,14 carboxy-,15 halo-,16 carbo-,17 and hydropalladation18
reactions and the subsequent cascade reactions allowed access
to a wide range of complex molecules by generating multiple
bonds in one pot.19 In continuation of our efforts in
developing nucleopalladation-initiated cascade reactions14a,15a
to access compounds of biological interest, herein, we
demonstrate the synthesis of dichlorinated tetrahydroquino-
lines bearing an exocyclic double bond at the C-3 carbon
involving a syn-chloropalladation-initiated cascade process.
Halopalladation of alkynes and the successive cascade
reactions were recognized as direct approaches for the
concurrent construction of C−X and C−C bonds in a single
operation. These reactions generate σ-vinylpalladium inter-
mediates via anti- or syn-halopalladation processes, which
could be captured with suitable reactive functionalities to
1,2,3,4-Tetrahydroquinolines, one of the most significant
nitrogen heterocycles, represent the privileged structural motifs
present in pharmaceuticals and natural products.1 Numerous
natural and synthetic analogs of tetrahydroquinolines display a
wide range of biological activities, which were summarized in
our comprehensive review.1a,b For instance, the 3-chlorotetra-
hydroquinoline alkaloids virantmycin and benzastatin C
showed antiviral,2 glutamate toxicity, and lipid peroxidation
inhibitory activities3 respectively. In addition, a large number
of synthetic analogs of tetrahydroquinolines are known to act
at chemotherapeutic targets including antiviral,4 antiparasitic,5
antimicrobial,6 antitumor7 etc., besides acting as ligands of G-
coupled protein receptors (GCPR)8 and nuclear receptors
such as androgen receptor modulators,9 glucocorticoid
receptor,10 and retinoid receptor.11 Owing to the increasing
demand of these compounds in drug discovery, several
synthetic methods have been established which include the
formation of the dihydropyridine ring comprising intra-
molecular strategies starting from suitably tethered aryl-
amines.12 Despite these advances, direct methods to access
highly functionalized tetrahydroquinolines in a single synthetic
operation are rather limited.
The nucleopalladation of alkynes, including inter- and
Received: April 14, 2019
intramolecular versions, generates σ-vinylpalladium intermedi-
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01295
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Letter
obtain complex molecules.16 Two distinctive mechanisms
involving Pd0/II and PdII/IV intermediates were proposed for
the halopalladation-initiated cascade reactions depending on
the nature of the substrates and oxidants employed.20,21 In this
context, we envisaged a chloropalladation-initiated cascade
process for the synthesis of tetrahydroquinoline derivative 2 or
3 starting from N-propargyl arylamines tethered with α,β-
unsaturated carbonyl moiety 1 (Scheme 1). The proposed
Scheme 2. Scope and Limitations of the Chloropalladation-
Initiated Cascade
a
Scheme 1. Envisioned Regioselective Syn-
Chloropalladation−Olefin Insertion−Oxidative
Chlorination Cascade
cascade involves a one-pot, three-step cascade consisting of
syn-chloropalladation, intramolecular olefin insertion, and
oxidative C−Cl bond formation or protonation steps. The
rare insertion of the second chlorine atom in 2 is rationalized
comprising a PdII/IV catalytic cycle or oxidative cleavage of C−
PdII bond.
The feasibility of the envisioned cascade was examined using
N-propargyl arylamine 1a (R1 = H, R2, Ar = Ph) as the model
substrate in the presence of palladium(II) catalysts and CuCl2·
2H2O under various reaction conditions. After an extensive
optimization study, use of 10 mol % PdCl2(MeCN)2, 4 equiv
of CuCl2·2H2O in DME at 25 °C was identified as the best
conditions to afford the product 2a in a maximum yield of 90%
(see Supporting Information for details).
a
Reaction conditions: 1 (1 equiv), PdCl2(MeCN)2 (10 mol %),
CuCl2·2H2O (4 equiv), DME, 25 °C, 4−5 h.
With the optimized conditions for the chloropalladation-
initiated cascade reaction in hand, we next investigated the
scope and limitations of the reaction. The alkynes 1a−u were
treated with 10 mol % PdCl2(MeCN)2 and 4 equiv of CuCl2·
2H2O in DME at 25 °C to obtain the corresponding
tetrahydroquinolines 2 (Scheme 2). The reaction tolerated
both electron-donating and -withdrawing groups in R1 and R2
positions (Cl: 2i; Br: 2j, o, and u; Me: 2h, j, m, and o; OMe:
2g) affording high yields of the products. Alkyne 1g having a
methoxy group in the R2 position furnished a moderate yield of
66% of the desired product. In addition, a wide variety of
substituents were introduced in the R3 aryl position including
p-methyl (2b and g), p-methoxy (2c), 2,4-dimethoxy (2d), p-
chloro (2e), and o-chloro (2f) groups. In most of the cases an
average yield of 80−90% was attained, and in the case of 2,4-
dimethoxy and o-chloro substituents, moderate yields were
observed (2d and f, 60−65%). Furthermore, 2-furyl (2k), 2-
thienyl substituted tetrahydroquinolines (2l and m) and a
couple of 2-naphthyl derivatives (2n and o) were also
synthesized in excellent yields under the optimized reaction
conditions. The methyl ketone 1p derived via Wittig reaction
was also transformed into the corresponding tetrahydroquino-
line 2p in 75% yield. The substrate containing strong electron-
withdrawing nitro group delivered the product 2q in 74% yield
with no significant change in its reactivity; however, alkyne 1r
bearing highly reactive aldehyde functionality failed to deliver
the corresponding tetrahydroquinoline 2r.
Finally, we tested the reactivity of alkynes 1s−u bearing
polar amide functionalities (both primary and secondary)
under the optimized reaction conditions. Interestingly, these
substrates underwent the chloropalladation-initiated cascade to
furnish the dichlorinated tetrahydroquinolines 2s−u in 62−
73% yields. Although this cascade approach has shown good
functional group tolerance as demonstrated in Scheme 2,
obtaining access to hydroxyl-substituted tetrahydroquinolines
was unsuccessful due to the difficulty in synthesizing the
required starting materials.
Analysis of the 1H NMR spectra of the synthesized
tetrahydroquinolines 2 showed that the hydrogens present in
the chiral carbons were trans to each other. The coupling
constants of these two doublets were 15.3 Hz thus confirming
the trans arrangement. Single crystal X-ray analysis of
B
DOI: 10.1021/acs.orglett.9b01295
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Letter
compound 2a confirmed the proposed trans stereochemistry
with a dihedral angle of 162.43° (Scheme 2). The geometry of
the exocyclic double bond was also established as the E
configuration from the crystal structure of compound 2a,
which could be explained via a syn-chloropalladation-initiated
mechanism (vide infra).
Scheme 4. Plausible Mechanism for the Chloropalladation-
Initiated Cascade
To understand the mechanism of the chloropalladation-
initiated cascade, we carried out a set of control experiments
shown in Scheme 3. Since both PdCl2 and PdCl2(MeCN)2
Scheme 3. Control Experiments for the Support of
Mechanism
catalysts furnished the products in high yields under the
optimized conditions, we selected these catalysts for the
control experiments. The reaction proceeds to afford neither
monochloro (2a) nor dichloro (3a) products in the presence
of 10 mol % or 1 equiv of PdCl2 and in the absence of CuCl2·
2H2O in dry conditions confirming the crucial role of CuCl2·
2H2O for product formation (eq 1). Interestingly, the same
reaction, using 1 equiv of PdCl2 and 8 equiv of water, delivered
only the monochloro product 3a in 90% and 86% yields in
THF and DME, respectively (eq 2). The formation of
monochloro product 3a could be explained via chloropallada-
tion−olefin insertion−protonation cascade. A mixture of
dichloro (2a, 58%) and monochloro (3a, 22%) products was
obtained when the reaction was carried out under optimized
conditions with 8 equiv of water (eq 3). Finally, the
hydration−olefin insertion product 4 was not obtained in the
presence 10 mol % of PdCl2 and 8 equiv of water (conditions
reported for hydration-olefin insertion cascade)14a and only the
monochloro product 3a was obtained in 16% yield (eq 4).
On the basis of these control experiments, we proposed a
plausible mechanism for the formation of tetrahydroquinolines
2 and 3 as depicted in Scheme 4. Initial coordination of alkyne
1 with PdCl2 followed by syn-chloropalladation would generate
σ-vinylpalladium intermediate B via palladium-coordinated
species A, which would successively undergo olefin insertion
with the pendant α,β-unsaturated carbonyl moiety to deliver
the PdII tetrahydroquinoline intermediate C (E isomer). In the
presence of water, as demonstrated in Scheme 3, eqs 2−4, the
monochloro derivative 3 has formed via protonation after
regenerating the PdII intermediate.22 However, in our
optimized experimental conditions, in the absence of water,
no protonation takes place to yield the monochloro compound
3.
The formation of the observed dichloro product 2 from
intermediate C could be visualized in three possible pathways:
(a) reductive elimination of intermediate C to deliver the
product 2 followed by oxidation of Pd0 by CuCl2 to regenerate
the PdII catalyst; (b) oxidation of PdII to PdIV by CuCl2 and
subsequent reductive elimination of PdIV intermediate D to
form the product 2 and the PdII catalyst; and (c) CuCl2
assisted oxidation of the C−PdII bond without changing the
overall oxidation state of Pd to furnish the product 2 and
release the PdII species. The reductive elimination (Path a) can
be excluded based on the control experiment (Scheme 4, eq
1), where we used 1 equiv of PdCl2 without the oxidant CuCl2
and no formation of product 2 was observed confirming the
role of CuCl2 and an oxidative mechanism. Since the
requirement of CuCl2 was established based on the control
experiments, the second pathway involving the PdII/IV catalytic
cycle could be involved in the reaction. The formation of PdIV
intermediates in the related transformations was achieved in
the presence of urea−H2O2,21a CuBr2,21b H2O2,21c and
CuX2,21d which supports the proposed pathway b. Alternative
pathway c could also be in operation as proposed by Henry
and others.21d,23 At this point, it would be difficult to
completely exclude any one of these two mechanisms. All
C
DOI: 10.1021/acs.orglett.9b01295
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Letter
the tested reactions afforded the E isomers 2 via syn-
chloropalladation presumably due to the steric nature of the
Z isomer in the transition state.
As established in Scheme 3, eq 2, we synthesized two more
derivatives of the monochloro tetrahydroquinoline 3 employ-
ing 1 equiv of PdCl2 in the presence of 8 equiv of water in
THF (Scheme 5). The structures of the synthesized
compounds were confirmed by NMR analysis and single
crystal X-ray analysis of a representative compound 3a.
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: vesridharan@gmail.com; sridharan.che@cujammu.ac.
in.
ORCID
Subbiah Nagarajan: 0000-0003-2233-4872
Vittorio Pace: 0000-0003-3037-5930
Vellaisamy Sridharan: 0000-0002-3099-4734
Scheme 5. Synthesis of Monochloro Tetrahydroquinoline
Derivatives 3
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Department of Science and
Technology−Science and Engineering Research Board, DST-
SERB (No. EMR/2016/001619) is gratefully acknowledged
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CCDC 1878155 and 1880305 contain the supplementary
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́
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DOI: 10.1021/acs.orglett.9b01295
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