Spirooxindole synthesis: Via palladium-catalyzed dearomative reductive-Heck reaction

Article abstract of DOI:10.1039/c7ob00146k

Palladium-catalyzed intramolecular dearomative reductive-Heck reaction of C2-substituted indoles is developed, which provides access to structurally diverse 3,2′-spiropyrrolidine oxindoles. By changing the hydride source to AcONa base, direct C3-arylation

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Spirooxindole Synthesis via Palladium-Catalyzed Dearomative
Reductive-Heck Reaction
Ren-Rong Liu,a Yang Xu,a Ren-Xiao Liang,a Bin Xiang,a Hu-Jun Xie,b Jian-Rong Gao,a and Yi-Xia Jia*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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the synthesis of this structural unit, while only a few methods have
been developed so far and mainly relied on 1,3-dipolar
Palladium-catalyzed intramolecular dearomative reductive-Heck
reaction of C2-substituted indoles is developed, which provides an
access to structurally diverse 3,2’-spiropyrrolidine oxindoles. By cycloaddition reactions of azomethine ylides.3 Therefore, it is highly
changing hydride source to AcONa base, direct C3-arylation
product [2,3-b]quinolinones are achieved in good yields. The
reaction of C2-substituted benzofuran is also reailzed, delivering
the desired spiro-product.
desired to explore new approach toward such unique
spirooxindoles.
Spirooxindoles are important structural moieties for their
frequent occurrence in diverse natural products and
pharmaceutical candidates.1 Amongst, 3,2’-spiropyrrolidine
oxindole scaffolds bearing nitrogen atoms at the spiro-quaternary
carbon centres received considerable attention owing to their wide
spectrum of significant bioactivities in drug discovery, such as
antibacterial, antitubercular, antitumor, and AChE inhibitor (Figure
1).2 For this reason, significant efforts have been devoted toward
Scheme 1 Palladium-catalyzed indole dearomative arylation.
Dearomative functionalization of (hetero)arenes has
recently been an attractive and efficient strategy to produce
Figure 1 3,2’-Spiropyrrolidine oxindole scaffolds in bioactive
non-aromatic cyclic compounds with
a high degree of
molecules.
stereocomplexity, which are important substructures in
bioactive molecules.4 Pioneered by Buchwald’s and Bedford’s
groups in the dearomative arylation of phenols and anilines,5
palladium-catalyzed dearomative arylation of indoles has
received much attention in last few years, which enabled facile
construction of C2- or C3-substituted indolines.6 In 2012, You
and co-workers disclosed an intramolecular arylation of C3-
substituted indoles containing a free N-H bond to construct
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C3-spiroindolines bearing quaternary carbon centers (Scheme AcONa at an elevated temperature. Moreover, the reaction of
1a).7a As shown in Scheme 1b,
series of elegant a C2-substituted benzofuran substrate 5a was also successfully
transformations of N-substituted indoles have been realized developed to afford the desired spiro-product (Scheme 4b).
via dearomative Heck arylation. Contributions included Heck Initial efforts were focused on the optimization of
reaction developed by Yao and Wu7b,7c and
recent dearomative reductive-Heck reaction of bromo-substituted
a
a
asymmetric version by Fukuyama,7d enantioselective indole-2-carboxamide (1a) (Table 1).11 It was found that the
reductive-Heck reaction by our group,7e and arylation-initiated reaction regioselectively produced spirooxindole 2a in 76%
sequential bisfunctionalizations reactions via the trapping of yield by using Pd(OAc)2 as a catalyst, HCO2Na as a hydride
benzylic-palladium species (such as Heck/cyanation,8a source, and PPh3 as a ligand in MeOH at 100 °C in 36 h (Table 1,
Heck/Suzuki8b reactions developed by Lautens’ group and entry 1). Direct C3-arylation product 3a and six-membered ring
Heck/alkynylation by Liang’s8c and our groups8d). Nevertheless, product
the aforementioned reactions mainly focused on dearomative enhance the yield (entries 2-7). A relatively lower yield was
functionalization of N- or C3-substituted indoles. As observed for tri(p-tolyl)phosphine L1 (entry 2), while to our
4 were not detected. A set of ligands was screened to
a
comparison, transformation of C2-substituted indoles toward delight the use of PCy3 ligand remarkably improved the yield to
the synthesis of C2-spiroindolines has remained much less 94% (entry 3). Comparable yield was obtained for PtBu3 (entry
explored. As
a continuous interest in developing novel 4). In comparison, bidentate phosphines were inferior for this
dearomative Heck reaction of (hetero)arenes, we report reaction. Only 48% yield of 2a was obtained when rac-BINAP
herein a palladium-catalyzed reductive-Heck reaction9 of C2- was used as a ligand (entry 5). Almost no products were
carboxamide indoles, which provides a reliable approach to isolated for dppm and Xanphos (entries 6-7). Other hydride
unique 3,2’-spiropyrrolidine oxindole structural units in good sources were then screened. HCO2K gave a comparable yield;
to excellent yields (Scheme 1c). Noteworthy, a similar reaction however, relatively lower yields were achieved with HCO2NH4
was disclosed very recently by Xu and Ma with (EtO)3SiH as or HCO2H/NEt3 as hydride sources (entries 9-10). Solvent
hydride source and only three examples were presented.10 examination revealed that poor yield was achieved in DCM and
However, we conducted
a comprehensive study under the reaction was fully suppressed in toluene and THF (entries
different reaction conditions and found direct C3-arylation 11-13). Good yields were also obtained in other alcoholic
reaction could occur to deliver [2,3-b]quinolinones in good solvents, such as EtOH and iPrOH (entries 14-15).
yields by simply changing hydride source HCO2Na to a base of
Table 1 Optimization of reaction conditionsa
entry
1
ligand
[H] source
HCO2Na
HCO2Na
HCO2Na
HCO2Na
HCO2Na
HCO2Na
HCO2Na
HCO2K
solvent
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
toluene
THF
Yield (%)b
76
PPh3
2
L1
57
3
PCy3·HBF4
PtBu3·HBF4
rac-BINAP
dppm
94
4
90
5
48
6
trace
trace
92
7
Xanphos
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
8
9
HCO2NH4
Et3N
62
10 c
11
12
13
14
15
55
HCO2Na
HCO2Na
HCO2Na
HCO2Na
HCO2Na
<5
<5
DCM
17
EtOH
iPrOH
87
90
a Reactions conditions: 0.2 mmol 1a, 5 mol% Pd(OAc)2, 10 mol%
ligand, 3.0 equiv hydride source and 2.0 mL solvent in a sealed
Schlenk tube at 100 oC (temperature of oil bath) for 36 h.
Scheme 2 Reactions conditions: 0.2 mmol 1, 5 mol% Pd(OAc)2,
10 mol% PCy3·HBF4, 3.0 equiv HCO2Na and 2.0 mL MeOH in a
sealed Schlenk tube at 100 oC (temperature of oil bath) for 36-
72 h.
b
c
Isolated yield.
tolyl)phosphine.
3.0 equiv HCO2H was added. L1 = Tri(p-
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Consequently, the optimal conditions were identified as: 5 (Scheme 5). Moreover, as a logical extension, C2-substituted
mol% Pd(OAc)2, 10 mol% PCy3·HBF4, 3.0 equiv HCO2Na in benzofuran (6a) and benzothiophene (6b) were also tested
MeOH at 100 °C for 36 h.
under the optimal reaction conditions. The desired
With the optimal conditions in hand, we investigated the spirooxindole 7a was isolated in 66% yield, while similar
scope of this reaction. Substituent effect of indoles was first
examined, and the results are shown in Scheme 2. Generally,
the reaction of indoles bearing either electron-donating or
electron-withdrawing groups on the indole ring proceeded
smoothly to furnish the desired products 2b-2j in good to
excellent yields. Steric effect of substituents at C4-, C5- or C6-
position of indole was not observed in this reaction. Moreover,
product 2k bearing a N-benzyl protecting group on indole ring
was afforded in 91% yield. As shown in Scheme 3, substituent
effect (R1) on the benzene ring of the 2-bromoaniline moiety
was then investigated. A range of functionalities at the para-
Scheme 4 Reaction example with 3-substituted indole.
(2l-2q), meta- (2r-2u) or ortho-position (2v) relative to amino
group were well-tolerated and the reactions occurred
smoothly to generate the corresponding products in 71-99%
yields. To be noted, substrate 1w bearing a pyridine moiety
was successfully employed in the reaction to produce 7-aza-
spirooxindole 2w in excellent yield. When 3-methyl indole
substrate 1x was investigated under the optimal conditions,
the desired reductive-Heck product 2x was not detected and
the Heck product
5 was isolated instead in 52% yield owing to
the easily β-H elimination (Scheme 4).
Scheme 5 Gram-scale reaction of 1a and reaction extension.
Scheme 3 Reactions conditions: 0.2 mmol 1, 5 mol% Pd(OAc)2,
10 mol% PCy3·HBF4, 3.0 equiv. HCO2Na and 2.0 mL MeOH in a
sealed Schlenk tube at 100 oC (temperature of oil bath) for 36-
72 h.
Scheme 6 Reactions conditions: 0.2 mmol 1, 5 mol% Pd(OAc)2,
10 mol% PCy3·HBF4, 3.0 equiv. AcONa and 2.0 mL MeOH in a
sealed Schlenk tube at 140 oC (temperature of oil bath).
product 7b was not detected.
Interestingly, direct C3-arylation based on indole C-H
functionaliztion12 occurred to deliver [2,3-b]quinolinone 3a in
excellent yield by simply changing HCO2Na to CH3CO2Na at an
The reaction was easily scaled up to gram quantities and
product 2a was isolated in 90% yield in the presence of 5 mol%
Pd(OAc)2 and 10 mol% PCy3·HBF4, showing its practicality
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elevated reaction temperature (Scheme 6). Other products 3b
-
3f
were also isolated in moderate to excellent yields. This
This study was supported by the National Natural Science
observation indicated that hydride source HCO2Na has a Foundation of China (21372202, 21502169, and 21522207)
significant influence on reaction regioselectivity and facilitated and the Natural Science Foundation of Zhejiang Province
the formation of spirooxindole product.
(LR14B020001 and LQ15B020003).
On the basis of above results, a plausible mechanism is
proposed in Scheme 7. As shown in path a, in situ generated
Pd(0) undergoes oxidative addition to C-Br bond of 1a to
Notes and references
afford aryl-Pd intermediate I. The followed intramolecular
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Scheme 7 Proposed mechanism.
gives rise to product [2,3-b]quinolinone product 3a (path b).
Conclusions
In summary, we have developed
a palladium-catalyzed
intramolecular dearomative reductive-Heck reaction of C2-
substituted indoles and benzofuran to synthesize structurally
diverse spirooxindoles bearing hetero atom substituted quaternary
centers. Noteworthy, by changing hydride source HCO2Na to a base
AcONa, direct C3-arylation product [2,3-b]quinolinones via indole C-
H bond activation can be synthesized in good yields.
4 | J. Name., 2012, 00, 1-3
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Synthesis of 3,2’-spiropyrrolidine oxindole scaffolds via palladium-catalyzed intramolecular
dearomative reductive-Heck reaction and [2,3-b]quinolinones through direct C3-arylation.