Palladium-Catalyzed Regioselective Domino Spirocyclization of Carbamoyl Chlorides with Alkynes and Benzynes

Article abstract of DOI:10.1002/adsc.202000537

A palladium-catalyzed domino spiro-cyclization of carbamoyl chlorides with alkynes and benzynes, involving intramolecular C?H activation to afford valuable oxindole scaffolds bearing spiro quaternary stereocenters, has been developed. This one-step synthesis of spirooxindole is both step- and atom-economic, proceeding with high regioselectivity in moderate to excellent yields. (Figure presented.).

Full text of DOI:10.1002/adsc.202000537

Title: Palladium-Catalyzed Regioselective Domino Spirocyclization of
Carbamoyl Chlorides with Alkynes and Benzynes
Authors: Chenchen Wang, Wenyu Zhao, Xianqing Wu, Jingping Qu,
and Yifeng Chen
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000537
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10.1002/adsc.202000537
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium-Catalyzed Regioselective Domino Spirocyclization of
Carbamoyl Chlorides with Alkynes and Benzynes
Chenchen Wang, Wenyu Zhao, Xianqing Wu, Jingping Qu* and Yifeng Chen*a
a
Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and
Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for
Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of
Science and Technology, 130 Meilong Road, Shanghai, 200237, P. R. of China
E-mail: qujp@dlut.edu.cn; yifengchen@ecust.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
the addition of extra catalysts and reagents, and are
broadly applied in the pharmaceutical and other bulk
chemical industry.[4] Furthermore, transition-metal-
catalyzed domino transformations have made notable
achievements in the last few decades.[5-7]
Abstract:
A
palladium-catalyzed domino spiro-
cyclization of carbamoyl chlorides with alkynes and
benzynes, involving intramolecular C–H activation to
afford valuable oxindole scaffolds bearing spiro
quaternary stereocenters, has been developed. This one-
step synthesis of spirooxindole is both step- and atom-
economic, proceeding with high regioselectivity in
moderate to excellent yields.
Henin and co-workers demonstrated that alkene-
tethered carbamoyl chloride could undergo a Pd-
catalyzed intramolecular Heck reaction to afford -
methylene -lactam.[8-9] Since then, the intermolecular
reaction pattern of the transition metal-catalyzed
cascade cyclization/anion capture sequences of alkene
tethered carbamoyl chlorides have been widely
explored for the synthesis of valuable oxindole
employing a variety of coupling components,
including organometallic reagents,[10] B2pin2,[11]
hexamethyldisilane,[12] aldehyde,[13] iodide[14] and
carbene[15] generated in situ (Scheme 1A). Domino
Heck transformation is an astounding development
and the discovery of the ability of transition metals to
interact with intermolecular alkynes in the domino
spirocyclization would be an elegant progress in
organometallic chemistry.[16]
Keywords: Palladium; Domino reaction; Spirooxindoles;
Carbamoyl chlorides; C–H activation
Spirooxindoles are privileged structural units, with
diverse applications in numerous bioactive natural
products and pharmaceuticals (Figure 1).[1] Their
promising performance in the relevant areas and
complex skeleton have encouraged the development of
various synthetic strategies.[2] The key structural
characteristic of these compounds is the spirocyclic
scaffold with quaternary carbon center; it is still of
great of interest to develop new strategies to construct
this scaffold. Among many accessible approaches
based on the stepwise elaboration of two rings, one-
step, direct formation of spirocycles with a quaternary
center is undoubtedly an efficient and attractive
approach.[3] Alternatively, domino reactions are cost-
and time-effective and can streamline the construction
of complex molecules via formation of two or more
bonds in a single batch without
Recently, we disclosed a Pd-catalyzed domino-
Heck reaction of carbamoyl chlorides to achieve the
regiodivergent synthesis of oxindoles, obviating the
use of prefunctionalized vinyl organometallics
[17]
reagents (Scheme 1B).
Notably, when the
substitution group on the styrene moiety is an aromatic
group, the alkyl palladium intermediate, generated via
the initial Heck type insertion, undergoes a subsequent
1,4-palladium shift[18] to provide the aryl palladium
intermediate, and affords the desired product via a
second Heck reaction process. We envisaged capturing
the palladacycle intermediate with suitable reaction
component to tune the 1,4-Pd migration process.
Herein, we report a Pd-catalyzed domino process
Figure 1. Selected examples of natural products and
pharmaceuticals.
1
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10.1002/adsc.202000537
Advanced Synthesis & Catalysis
using carbamoyl chlorides as a relay switch and a
highly regioselective insertion of unsymmetrical
external alkyne to afford spirooxindole scaffolds
(Scheme 1C), exhibiting distinctive selectivity and
reactivity.
Table 1. Optimization for the reaction conditions.[a]
[a] Reaction conditions: 1a (1.0 equiv.), 2a (2.0 equiv.), base
(1.5 equiv.), [Pd] catalyst (5 mol%), ligand (10 mol%),
solvent (0.1 M), 110 °C, 4 h.
[b] Corrected GC yield.
Scheme 1. Synthesis of spirooxindoles from carbamoyl
chlorides.
[c] Pd2(dba)3 (2.5 mol%), ligand (10 mol%).
[d] Isolated yield.
[e] 20 h.
To investigate the feasibility of our hypothesis, we
initially performed the reaction of carbamoyl chlorides
(1a) and methyl 3-phenylpropiolate (2a) as model
substrates under the following conditions: 1a (0.10
mmol, 1.0 equiv.), 2a (0.20 mmol, 2.0 equiv.), Pd2dba3
(0.0025 mmol, 2.5 mol%), IPr·HCl (0.01 mol, 10
mol%) and Cs2CO3 (0.15 mmol, 1.5 equiv.) in toluene
(0.1 M) at 110 °C for 4 h, delivering the expected
product 3a in 55% yield (Table 1, entry 1). It should
be noted that a small amount of decarbonylation by-
product 7 formation was detected (Scheme 2). The
regioselectivity of 3a to 3a’ is more than 20:1.
Amongst various ligand screening, it was found that
the commercially available Pd(PPh3)2Cl2 provided the
highest yield (Table 1, entries 2-6). Under the standard
conditions, the desired product 3a was obtained with
72% isolated yield. Next, we investigated the base
screening: the yield of product 3a significantly
dropped down when K3PO4 was employed as the
inorganic base (Table 1, entry 7); When CsOPiv, a
common base for C-H activation was used, no desired
product formation was observed, and the same
scenario applied to NaOMe (Table 1, entries 8 and 9),
indicating the nucleophilicity of alkoxy group was too
strong, causing decomposition of the starting material
1a. The solvent screening revealed that toluene is the
optimal solvent for this domino transformation (Table
1, entries 10-12). Finally, lowering the reaction
temperature to 80 °C resulted in sluggish conversion
of 1a and 66% yield could be obtained by extending
reaction time to 20 h (Table 1, entry 13).
effect on the internal alkynes was first examined.
Generally, the optimized reaction conditions were
found to be suitable for various alkynes possessing
different electronic properties. For instance, the
substituted methyl 3-arylpropiolate containing both
electron donating (-OMe) and electron-withdrawing
groups (-Cl) on the aryl rings could be tolerated and
provided 3b and 3c in good isolated yields. 1,3-
Diphenylprop-2-yn-1-one was incorporated to give 3d
in 63% yield. The reaction proceeded well with alkyl-
substituted acetylate delivering the corresponding
products 3e and 3f in good to excellent isolated yields
(82–93%). Notably, it was found that the conjugated
enyne 2g, selective insertion of alkyne with the
maintenance of alkene functionality, to provide 3g in
50% yield, albeit with longer reaction time. The less
reactive diarylacetylene cannot participate this domino
reaction, and only low yield of the desired product
1
(13% crude H NMR yield) was observed when
diethyl acetylenedicarboxylate was employed under
the standard conditions. The reaction worked
efficiently on the oxindole containing methoxy (3h) or
chloride (3i) functionality. Interestingly, the substrate
bearing bromide was well-tolerated and gave moderate
reaction yield (3j). Furthermore, access to the ortho-
fluoro substituted spirooxindole (3k) indicated the
steric effect is inconspicuous. Product with para-
methyl group at the phenyl ring (3l) was formed in
good yields. Moreover, electron-withdrawing ester
and nitro groups (3m, 3n) were tolerated under the
standard conditions with 80%, 44% isolated yields.
The change of substituent on the nitrogen atom to N-
substituted benzyl substrate produced the desired
products (3o) in 66% yield. The para-substitute effect
With the optimized conditions in hand, we
investigated
the
applicability
of
domino
spirocyclization for spirooxindole synthesis (Table 2).
Unless otherwise stated, the ratio of regioisomers in all
spirooxindoles are greater than 20:1. The substituent
2
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10.1002/adsc.202000537
Advanced Synthesis & Catalysis
on the aromatic ring did not affect the selective 1,4-Pd
migration, affording the desired product 3p and 3q in
good yield. It is notable that the heterocycle thiophene
substitution could smoothly undergo the domino 1,4-
Pd shift as well to provide an expedient access of
hetero-substituted spirooxindole 3r in 72% isolated
yield.
synthesis.[20] However, these highly reaction aryne
intermediate is easy to undergo the undesired
cyclotrimerization with the transition metal catalyst to
furnish triphenylene byproduct.[21] To overcome this
challenge, a series solvent and palladium source
screenings were performed, and the yield of
triphenylenes byproduct was formed less than 5%
under the optimized conditions (see the Supporting
Information). It was found that the combination of
Cs2CO3 and CsF was the crucial for this domino
reaction, 5a was obtained in 63% isolated yield. The
substrate scope with arynes were then carried out
(Table 3). The reaction with substrates bearing methyl
(5b) or methoxy group (5c) worked well, affording the
desired products in moderate yields. To our delight,
thiophene substitution (5d) could also undergo the
domino migration and insertion reactions to generate
the desired products in 62% yield. Next, the
functionality of the carbamoyl chloride was
investigated. It was found that various functional
group could be tolerated with this cascade benzyne
insertion, including chloride (5e), methoxy (5f),
methyl (5g) and ester (5h) group, to generate the
products 5e–h in 53–69% isolated yield.
Table 2. Reaction scope with internal alkynes.[a]
Table 3. Reaction scope with arynes.[a]
[a] Standard conditions: 1 (1.0 equiv.), 4 (2.0 equiv.), Cs2CO3
(1.5 equiv.), CsF (2.5 equiv.), Pd(PPh3)2Cl2 (5 mol%),
toluene/CH3CN (v/v = 1:1, 0.1 M), 110 °C, 4 h
[a] Standard conditions: 1 (1.0 equiv.), 2 (2.0 equiv.), Cs2CO3
(1.5 equiv.), Pd(PPh3)2Cl2 (5 mol%), toluene (0.1 M),
110 °C, 4-20 h.
A plausible mechanism is shown in Scheme 2. The
domino spirocyclization commences with oxidative
addition of carbamoyl chlorides (1a) to Pd0 to afford
the carbamoyl-Pd intermediate 6. Accompanied by
decarbonylation to give the side product 7, 6
undergoes the intramolecular Heck reaction with
tethered alkene to generate the alkyl-palladium(II)
[b] 1.0 mmol scale reaction.
The
2-(trimethylsilyl)phenyl
trifluoromethanesulfonate, initially developed by
intermediate 8. The alkyl-Pd intermediate
8
Kobayashi in 1983,[19] has become an powerful aryne
subsequently performs an intramolecular C–H
precursor and was widely
applied in organic
3
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10.1002/adsc.202000537
Advanced Synthesis & Catalysis
CsF (2.5 equiv.) was evacuated and backfilled with N2 (This
process was repeated for three times). Aryne precursor 4
(2.0 equiv.) and toluene/CH3CN (v/v = 1/1, 0.1 M) were
subsequently added into the reaction mixture. The tube was
sealed with Parafilm, and allowed to stir for 4 h at 110 °C.
The mixture was quenched with sat. aq. NH4Cl and
extracted with EtOAc. The separated organic layer was
washed twice with water and once with brine, then dried
over anhydrous Na2SO4, the resulting organic layer was
concentrated under reduced pressure, and the crude product
was purified by chromatography on silica gel column
(PE/EtOAc) to afford the desired spirooxindoles 5.
activation to afford a five-membered palladacycle (9),
which undergoes a selective scission of C(sp2)-Pd
bond under kinetic control via the regioselective
migratory insertion to the activated alkynes,[16e]
followed by a final reductive elimination to provide
the desired product 3a.
Acknowledgements
This work was supported by NSFC/China (21421004, 21702060),
Shanghai Rising-Star Program, Shanghai Municipal Science and
Technology Major Project (Grant No.2018SHZDZX03) and the
Program of Introducing Talents of Discipline to Universities
(B16017), and the Fundamental Research Funds for the Central
Universities. Y.C. thank Prof. Feng Sha (ECUST) for generous
donation of benzyne precursors for product 5b and 5c. The authors
thank Research Center of Analysis and Test of East China
University of Science and Technology for the help on NMR
analysis.
References
Scheme 2. Plausible mechanism.
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In conclusion, we have demonstrated a mild and
efficient palladium-catalyzed domino spirocyclization
of carbamoyl chlorides with alkynes and arynes.
Distinguished by remarkable regioselectivity and
diverse set of substitution patterns, this protocol is a
novel strategy for synthesizing spirooxindoles and
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Experimental Section
General Experimental Procedure for the Synthesis of
Spirooxindoles 3
An oven-dried vial charged with carbamoyl chlorides 1 (1.0
equiv.), Pd(PPh3)2Cl2 (5 mol%), and Cs2CO3 (1.5 equiv.)
was evacuated and backfilled with N2 (This process was
repeated three times). Internal alkynes 2 (2.0 equiv.) and
toluene (0.1 M) were subsequently added to the reaction
mixture. The tube was sealed with Parafilm, and allowed to
stir for 4–20 h at 110 °C. The mixture was quenched with
sat. aq. NH4Cl and extracted with EtOAc. The separated
organic layer was washed twice with water and once with
brine, then dried over anhydrous Na2SO4, the resulting
organic layer was concentrated under reduced pressure, and
the crude product was purified by chromatography on silica
gel column (PE/EtOAc) to afford the desired spirooxindoles
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10.1002/adsc.202000537
Advanced Synthesis & Catalysis
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