Efficient Synthesis of Spirooxindole Pyrrolones by a Rhodium(III)-Catalyzed C?H Activation/Carbene Insertion/Lossen Rearrangement Sequence

Article abstract of DOI:10.1002/anie.201906589

A rhodium(III)-catalyzed domino annulation of simple olefins with diazo oxindoles to give spirooxindole pyrrolone products is described. This reaction can be formally viewed as the result of an anomalous tandem C?H activation, carbene insertion, Lossen rearrangement, and a nucleophilic addition process. The potential utility of this reaction was further demonstrated by the late-stage diversification of drug molecules.

Full text of DOI:10.1002/anie.201906589

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Accepted Article
Title: Rhodium(III)-Catalyzed C–H Activation/Carbene Insertion/Lossen
Rearrangement Sequence: Efficient Synthesis of Spirooxindole
Pyrrolones
Authors: Huixiong Dai, Biao Ma, Peng Wu, Xing Wang, Hai-Xia Lin,
and Zhengyu Wang
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Rhodium(III)-Catalyzed C–H Activation/Carbene Insertion/Lossen
Rearrangement Sequence: Efficient Synthesis of Spirooxindole
Pyrrolones
Biao Ma,[a],† Peng Wu,[c],† Xing Wang,[a] Zhengyu Wang,[a] Hai-Xia Lin,[c] Hui-Xiong Dai*[a,b]
Abstract: A Rh(III)-catalyzed domino annulation of simple olefins
with diazooxindole to give spirooxindole pyrrolone products was
described. This reaction can be formally viewed as the result of an
anomalous tandem C–H activation, carbene insertion, Lossen
rearrangement and nucleophilic addition process. The potential utility
of this reaction was further demonstrated by late-stage diversification
of medicinal molecules.
with diazooxindole to give spirooxindole pyrrolone products, in
good yields and with excellent regioselectivities (Scheme 1, B).
This reaction could involve a C–H activation, carbene insertion,
Lossen rearrangement, and nucleophilic addition sequence. The
potential utility of this method in late-stage diversification for
drug discovery was exemplified in the directed introduction of
spirooxindole pyrrolone skeleton into medicinal molecules
pentoxifylline, endofolliculina and pregnenolone.
Spirooxindole has been considered as the characteristic
structural centerpiece that can be found in a large number of
natural or synthetic compounds with potent bioactivity profiles1.
The introduction of spiro-containing systems not only influence
their biological activity and physicochemical property in drug
discovery program, but also increase structural novelty for
patentability2. Nowadays, common methods for synthesis of
spirooxindole include [3+2]-cycloaddition3; Mannich reaction4;
rearrangement of strained rings5 and nucleophilic substitution6.
However, many of existing methods suffer from certain
limitations such as complicated starting materials, multistep
strategies, narrow scope of substrates or harsh reaction
conditions. Great attention is still devoted to the development of
novel and simple methods for their synthesis.
Since C–H activation has demonstrated great potentials to
build complicated skeletons in a simple and an atom-economical
fashion and using readily available precursors7, the development
of an elegant one-step C(sp2)–H functionalization for
construction of spirooxindoles continuously attracts attention of
synthetic chemists. A series of Pd-catalyzed spirocyclizations
involving sequential carbopalladation, intramolecular C–H
activation, and electrophile insertion were achieved8.
Alternatively, Rh(III)-catalyzed annulation of N-pivaloyloxy
benzamides with diazo compounds to provide a facile synthesis
of isoindolones was also reported9 (Scheme 1, A). Compared
with C–H activation of arenes, C–H activation of alkenes has
also received extensive attention in recent years10. Moreover,
the multisubstituted spirooxindole pyrrolones can be synthesized
via C–H activation of simple olefins. Herein we described a
Rh(III)-catalyzed domino annulation of N-(pivaloyloxy)acrylamide
Scheme 1. C(sp2)–H Activation/Annulation to Form Spirooxindole Framework.
For construction of spirooxindole pyrrolone architecture, we
began
our
investigation
by
choosing
N-
(pivaloyloxy)methacrylamide 1a and diazooxindole 2a as the
substrates. In the presence of 2.5 mol % [RhCp*Cl2]2 and 0.2
equiv of Cs2CO3 in MeCN, the expected compound 3 was not
detected. However, rearranged product 3a and the
corresponding hydroxylated compound 3a’ were isolated in 17%
and 17% yields, respectively. The structure of 3a’ was obtained
as a single diastereomer and unambiguously confirmed by X-ray
crystallography (Scheme 2). This interesting product can be
formally viewed as the result of an anomalous tandem C–H
activation/Lossen rearrangement process (Scheme 6).
Considering its stability and further synthetic potential, we
chose to optimize conditions for the formation of spirooxindole
3a. We first sought to suppress the hydroxylation of 3a to
hemiaminal 3a’. To this end, 4Ǻ MS was added to remove H2O
in the reaction mixture. Unexpectedly, although the product ratio
almost remained unchanged, the yields were improved to 40%
(entry 2). To our delight, the yield of 3a was further increased in
the absence of any additives (entry 3). Reaction temperature
[a]
Dr. B. Ma, X. Wang, Z. Wang, Prof. Dr. H.-X. Dai
Chinese Academy of Sciences Key Laboratory of Receptor
Research, Shanghai Institute of Materia Medica, Shanghai 201203,
China. E-mail: hxdai@simm.ac.cn
[b]
[c]
Stake Key Laboratory of Natural and Biomimetic Drugs, Peking
University, Beijing, 100191, China
P, Wu, Prof. Dr. H.-X. Lin
Department of Chemistry, Innovative Drug Research Center,
Shanghai University, 99 Shangda Road, Shanghai, 200444, China
B.M. and P.W. contributed equally to this work
†
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201906589
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was essential on this annulation process (entries 3-6), and
lowering temperature to -20 C afforded the desired product 3a
in 77% yield with excellent chemoselectivity (3a/3a’ > 20/1).
Finally, modification of the concentration did not have a
detrimental effect (entries 6-8).
enamine was achieved (3ea). Subsequently, α, β-disubstituted
N-pivaloyl-acrylamides could also be converted into the
corresponding annulation products in modest to excellent yields
(3l, 3m).
o
Table 2: Substrate Scope of Aliphatic Acrylamide.[a,b]
Scheme 2. Rh(III)-Catalyzed C–H Activation/Lossen Rearrangement.
Table 1: Selected Optimization Studies.[a,b]
[a] Reaction conditions: 1 (0.1 mmol), 2a (0.1 mmol), [RhCp*Cl2]2 (2.5 mol%),
MeCN (1 mL), -20 oC, 5 h, air. [b] Isolated yields. [c] r.t. [d] After completely
conversion, aq. HCl (1 M, 1 mL) was added and kept stirring for 0.5 h.
Table 3: Substrate Scope of Aryl Acrylamide.[a,b]
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), [RhCp*Cl2]2 (2.5 mol%),
MeCN, -20 oC, 5 h, air. [b] 1H NMR yields, using CH2Br2 as an internal
standard. [c] Cs2CO3 (0.2 eq). [d] 4Ǻ MS (100 mg). [e] Isolated yield.
With optimized reaction conditions in hand, the scope of
simple aliphatic acrylamides for this reaction was explored
(Table 2). A wide range of α-substituted N-pivaloyl-acrylamides
were tolerated well, affording the corresponding annulation
products in moderate to excellent yields (62%-92%) (3a-3m). It
was noteworthy that steric hindrance of branched alkenes had
no detrimental effect on the yield (3c, 3d). Substrates containing
heteroatoms were also suitable to afford products in moderate
yields (3f-3h). The spirooxindole succinimide skeletons as a
class of important pharmacophores are widely existed in
biologically active compounds11. When an α-MeO acrylamide
was used as the substrate, the spirosuccinimide 3i was readily
afforded in 76% yield after aq. HCl (1 M, 1 mL) was added and
the resulting reaction mixture was stirred for 0.5 h. In the case of
acrylamides bearing α-benzyl, allyl or methyl ester, the exocyclic
enamines were formed exclusively due to conjugate effect (3eb,
3j, 3k). Interestingly, α-benzyl and allyl substituted substrates
gave the major products with E-configuration for steric effect
(3eb, 3j), while Z-isomer of compound 3k was highly favoured
due to the presence of intramolecular H-bond interaction. When
the reaction was carried out at room temperature, the endo acyl
[a] Reaction conditions: 1 (0.1 mmol), 2a (0.1 mmol), [RhCp*Cl2]2 (0.5 mol%),
MeCN (1 mL), r.t., 0.5 h, air. [b] Isolated yields.
Next, Aryl acrylamide substrates were also examined (Table
3). Surprisingly, reducing catalyst loading to 0.5 mol% had no
detrimental effect on the yields when the reactions were
conducted at room temperature. Variation at the meta- and para-
substituent of the aryl acrylamides had little effect on the
reaction (3nc-3ng). ortho Fluoride-substituted phenyl acrylamide
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10.1002/anie.201906589
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COMMUNICATION
proceeded the reaction smoothly, and the annulation product
3nb was isolated in
a good yield (80%). Moreover, 2-
naphthalene substrate participated in the annulation reaction to
give the products 3nm with up to 85% yield.
Furthermore, we examined the scope of diazooxindole
compounds (Table 4). A series of N- and arene substituted
diazooxindoles were applicable in this reaction to give products
in good to excellent yields 77–85% (3o-3u). It was worth noting
that the existence of N–H had no adverse effect on the yield of
adduct (3o). Moreover, chloride, bromide and trifluoromethoxy
substitution at the C5 of arene provided adducts in 83%, 85%
and 86% yields, respectively (3r, 3s, 3u), and 6-methyl
diazooxindole gave product in 82% (3t). Similarly, C7-F
substitution led to the formation of adduct in 80% (3q).
Table 4: Substrate Scope of Diazooxindole.[a,b]
Scheme 4. Late-Stage Diversification of Medicinal Molecules.
In order to gain some mechanistic insights of the reaction,
several control experiments were conducted (Scheme 5). The
reactions of isocyanate 4 with 2a were conducted under the
standard conditions (Scheme 5, A). However, there was no
desired product obtained, which indicated that isocyanate 4 may
not involved in the catalytic cycle and C–H activation could occur
before Lossen rearrangement. No deuterium incorporation was
observed for 1na in CH3CN/CD3OD (5/1) as co-solvent (Scheme
5, B), thus suggested that C–H activation was in largely
irreversible during the reaction, which was consistent with
previous reports by Rovis9. A competition experiment between
[a] Reaction conditions: 1na (0.1 mmol), 2 (0.1 mmol), [RhCp*Cl2]2 (0.5 mol%),
MeCN (1 mL), r.t., 0.5 h, air. [b] Isolated yields.
2-(4-(trifluoromethyl)phenyl)
acrylamide
1ni
and
2-(4-
methoxyphenyl) acrylamide 1nk was used to determine the
electronic preference of the reaction, and found that the C–H
activation favored the electron deficient acrylamide in a 1.5:1
ratio (Scheme 5, C). Preliminary rate kinetic isotope study
revealed a KIE value of 2.1, thus indicating that C–H bond
cleavage was involved in the rate-determining step (Scheme 5,
D).
The C(sp2)–H annulation reaction of substrate 1na with
diazooxindole 2a could be performed on a gram scale with
nearly quantitative yield by using 0.5 mol % [RhCp*Cl2]2 as the
catalyst (Scheme 3). To highlight the synthetic utility of this
transformation, we tried to apply this method to the late-stage
diversification of medicinal molecules. To our delight, N-
(pivaloyloxy)acrylamides (3v-3x) derived from pentoxifylline,
endofolliculina and pregnenolone underwent the annulation
reaction successfully to give the corresponding annulation
products in 78%, 80% and 80% yields, respectively (Scheme 4).
To determine the order of Lossen rearrangement and
carbene migratory, 1na was subjected to the standard reaction
condition with several nucleophiles such as methanol and aniline
instead of 2a, which, however, resulted in no Lossen
rearrangement/nucleophilic addition product, but only recovery
of the starting materials (Scheme 5, E). This result indicated that
the pathway B was more favorable, and was also consistent with
previous reports by Feng12b and Tanaka12a
.
Scheme 3. Gram-Scale Synthesis.
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Acknowledgements
We gratefully acknowledge Shanghai Institute of Materia Medica，
Chinese Academy of Sciences, NSFC (21472211, 21502212,
21772211), Youth Innovation Promotion Association CAS (NO.
2014229 and 2018293), Institutes for Drug Discovery and
Development, Chinese Academy of Sciences (NO.CASIMM
0120163006), Science and Technology Commission of
Shanghai Municipality (17JC1405000), Program of Shanghai
Academic Research Leader (19XD1424600), National Science
& Technology Major Project “Key New Drug Creation and
Manufacturing Program”, China (2018ZX09711002-006), the
State Key Laboratory of Natural and Biomimetic Drugs for
financial support.
Conflict of interest
The authors declare no conflict of interest.
Keywords: spirooxindole •C–H activation • Lossen
rearrangement • Rhodium(III)-catalyzed • simple olefins
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C–H Activation
Biao Ma, Peng Wu, Xing Wang,
Zhengyu Wang, Hai-Xia Lin, Hui-
Xiong Dai*
_________ Page – Page
Rhodium(III)-Catalyzed C–H
Activation/Carbene Insertion/Lossen
Rearrangement Sequence: Efficient
Synthesis of Spirooxindole
Pyrrolones
A Rh(III)-catalyzed domino annulation of simple olefins with diazooxindole to give
spirooxindole dihydropyrrole products was described. This reaction can be formally
viewed as the result of an anomalous tandem C–H activation, carbene insertion,
Lossen rearrangement nucleophilic addition process. The utility of this reaction is
also demonstrated by late-stage diversification of drug molecules.
This article is protected by copyright. All rights reserved.