Enabling CO Insertion into o-Nitrostyrenes beyond Reduction for Selective Access to Indolin-2-one and Dihydroquinolin-2-one Derivatives

Article abstract of DOI:10.1021/acscatal.8b02863

The transition metal-catalyzed reductive cyclization of o-nitrostyrene in the presence of carbon monoxide (CO) has been developed to be a general synthetic route to an indole skeleton, wherein CO was used as a reductant to deoxidize nitroarene into nitrosoarene and/or nitrene with CO₂ release, but the selective insertion of CO into the heterocyclic product with higher atom economy has not yet been realized. Herein, the Pd-catalyzed reduction of o-nitrostyrene by CO and its regioselective insertion were efficiently achieved to produce synthetically useful five- and six-membered benzo-fused lactams. Detailed investigations revealed that the chemoselectivity to indole or lactam was sensitive to the nature of the counteranions of Pd²⁺ precursors, whereas ligands significantly decided the carbonylative regioselectivity by different reaction pathways. Using PdCl₂/PPh₃/B(OH)₃ (condition A), an olefin hydrocarboxylation was primarily initiated followed by partial reduction of the NO₂ moiety and cyclization reaction to give N-hydroxyl indolin-2-one, which was further catalytically reduced by CO to afford the indolin-2-one as the final product with up to 95% yield. When the reaction was conducted under the Pd(TFA)₂/BINAP/TsOH·H₂O system (condition B), complete deoxygenation and carbonylation of the NO₂ group occurred initially to yield the corresponding isocyanate followed by internal hydrocyclization to generate 3,4-dihydroquinolin-2-one with up to 98% yield. Importantly, the methodology could be efficiently applied in the synthesis of marketed drug Aripiprazole.

Full text of DOI:10.1021/acscatal.8b02863

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Article
Enabling CO Insertion into o-Nitrostyrenes beyond Reduction for
Selective Access to Indolin-2-one and Dihydroquinolin-2-one Derivatives
Li Yang, Lijun Shi, Qi Xing, Kuo-Wei Huang, Chungu Xia, and Fuwei Li
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b02863 • Publication Date (Web): 26 Sep 2018
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Enabling CO Insertion into o-Nitrostyrenes beyond Reduction for
Selective Access to Indolin-2-one and Dihydroquinolin-2-one Deriva-
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Li Yang,†,‡ Lijun Shi,† Qi Xing,† Kuo-Wei Huang,§ Chungu Xia,† and Fuwei Li†,*
†State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Lanzhou Institute of
Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, P. R. China.
‡University of Chinese Academy of Sciences, Beijing 100049, P. R. China
§KAUST Catalysis Center and Division of Physical Sciences and Engineering, King Abdullah University of Science and
Technology (KAUST), Thuwal 23955-6900, Saudi Arabia
ABSTRACT: The transition metal catalyzed reductive cyclization of o-nitrostyrene in the presence of carbon monoxide (CO) has
been developed to be a general synthetic route to indole skeleton, in which CO was used as a reductant to deoxidize nitroarene into
nitrosoarene and/or nitrene with CO2 releasing, but the selective insertion of CO into the heterocyclic product with higher atom
economy has not yet been realized. Herein, the Pd-catalyzed reduction of o-nitrostyrene by CO and its regioselective insertion were
efficiently achieved to produce synthetically useful five- and six-membered benzo-fused lactams. Detailed investigations revealed
that the chemoselectivity to indole or lactam was sensitive to the nature of the counter anions of Pd2+ precursors, while ligands sig-
nificantly decided the carbonylative regioselectivity by different reaction pathways. Using PdCl2/PPh3/B(OH)3 (Condition A), a
olefin hydrocarboxylation was primarily initiated, followed by partial reduction of NO2 moiety and cyclization reaction to give N-
hydroxyl indolin-2-one, which was further catalytically reduced by CO to afford the indolin-2-one as final product with up to 95%
yield. When the reaction was conducted under Pd(TFA)2/BINAP/TsOH·H2O system (Condition B), the complete deoxygenation
and carbonylation of NO2 group occurred initially to yield the corresponding isocyanate, followed by internal hydrocyclization to
generate 3,4-dihydroquinolin-2-one with up to 98 % yield. Importantly, the methodology could be efficiently applied in the synthe-
sis of marketed drug Aripiprazole.
KEYWORDS: o-nitrostyrene, carbonylation, heterocycle, selectivity, cascade reaction
1. INTRODUCTION
nitro group,8-14 but did not undergo further carbonylation reac-
tions, even though conceivably, the CO can be incorporated
into the resultant heterocycles without changing the reaction
substrate and atmosphere.
A Challenge for modern organic synthesis is the creation of
efficient catalytic processes that can provide the maximum
molecular complexity and diversity with a minimum number
of purification steps and chemical waste. Especially appealing
are those reactions that involve metal catalyzed construction of
heterocyclic skeletons in a selective and atom-economical
fashion, and from readily available precursors. It is known that
the potentially bioactive indole skeletons can be effectively
constructed from widespread o-nitrostyrenes using excess
reductant such as phosphine reagents,1 TiCl3 aqueous solu-
tion,2 zinc dust,3 Grignard reagent,4 etc.5-7 As a greener alter-
native, the catalytic synthesis of indole derivatives from o-
nitrostyrenes was firstly discovered in 1986 by Cenini using
metal carbonyl catalysts and carbon monoxide reductant.8
Over the last three decades, many outstanding catalysts have
been successfully developed by Cenini,9 Driver,10 Watanabe,11
Söderberg,12 Nishiyama13 and other groups14 to enhance the
catalytic efficiency and broaden the substrate scope (Scheme
1), and all these improvements have enabled this transfor-
mation to be a general indole synthesis procedure. Specifically,
nitrene and/or nitroso intermediates have been proposed to be
involved in the Pd-catalyzed CO reductive cyclization of o-
nitrostyrene into indole based on the deuterium-labeling ex-
periments,11a and CO only served as a deoxygenation agent of
Scheme 1. Metal-Catalyzed Reductive Cyclization of o-
Nitrostyrenes in the Presence of CO
It can be seen from the structure of o-nitrostyrene that it has
two possible carbonylation sites, vinyl- and NO2-group, the
former is known to undergo selective 1,2- or 2,1-CO inser-
tion,15 the latter can be converted to the isocyanate and amide
compounds through reductive carbonylation.16 Therefore, if
the CO selective insertion of o-nitrostyrenes could be enabled
by coupling these two parts in a proper cascade reaction se-
quence and under a compatible reductive condition, a novel
and powerful catalytic methodology can be developed for the
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regiodivergent synthesis of two important classes of carbonyl
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tal H2O (Supporting Information, Table S1, entry 6). Another
aryl bronsted acid, para-toluenesulfonic acid (TsOH·H2O)
gave a 90% yield of carbonylated products with around 50%
regioselectivity of 2a and 3a, respectively. It could be deduced
from these results that the addition of proper proton sources
were the key enabling factor for CO insertion, and their acidic
property had significant influence on the regio- and chemo-
selectivity, although there is no strict consistency between
catalytic performances and the properties of the tested proton
sources.
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containing heterocycles (Scheme 1), which serve as core struc-
tures of numerous natural products and marketed drugs (Fig-
ure 1).17-20 In this work, we report an unprecedented reductive
cyclocarbonylation of o-nitrostyrenes to selectively offer in-
dolin-2-one and 3,4-dihydroquinolin-2-one by different
PdX2/phosphine catalyst systems in the presence of a proper
proton source. Systematical studies were carefully conducted
to elucidate the reaction pathways and rationalize the regiose-
lectivity.
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Figure 1. Selected examples bearing the skeleton of indolin-2-one
and dihydroquinolin-2-one.
2. RESULTS AND DISCUSSION
Scheme 3. Influence of Pd Precursors for the Reductive Cy-
clocarbonylation of o-Nitrostyrenes.a aReaction conditions: 1a
(0.2 mmol), [Pd] (0.01 mmol), PPh3 (0.02 mmol), B(OH)3 (0.4
mmol), THF (2.5 mL), CO (35 atm), 80 oC, 20 h. Isolated yield.
Scheme 2. Influence of Proton Sources for the Reductive Cy-
clocarbonylation of o-Nitrostyrenes.a aReaction conditions: 1a
(0.2 mmol), PdCl2 (0.01 mmol), PPh3 (0.02 mmol), [H] (0.4
mmol), THF (2.5 mL), CO (35 atm), 80 oC, 20 h. Isolated yield.
2.1 Reaction condition optimization. It is obvious to see
that the carbonylated product, 2a and 3a, have two more hy-
drogens compared with the substrate, so the proton source was
expected to be one of the enabling keys for the reaction
chemoselectivity. With a simple catalyst system PdCl2/PPh3 at
o
Scheme 4. Ligand Effect for the Pd-Catalyzed Reductive Cy-
clocarbonylation of o-Nitrostyrenes.a aReaction conditions: 1a
(0.2 mmol), PdCl2 (0.01 mmol), Ligand (0.02 mmol for monoden-
tate ligand, 0.01 mmol for bidentate ligand), B(OH)3 (0.4 mmol),
THF (2.5 mL), CO (35 atm), 80 oC, 20 h. Isolated yield.
80 C, we initially choose 1-nitro-2-vinylbenzene (1a) as a
model substrate in the presence of different proton sources to
evaluate our proposed strategy (Scheme 2). Surprisingly, with
B(OH)3 as the proton source, 81% yield of indolin-2-one (2a)
by CO 2,1-insertion onto the vinyl group was obtained with
excellent chemoselectivity and regioselectivity, and the indole
(5a) was even not observed, which indicated the expected
carbonylation occurred perfectly beyond the well-established
reductive cyclization to indole. Acetic acid (AcOH) only gave
32% 2a yield but with high selectivity, similar and stronger
trifluoroacetic acid (TFA) provided lower 2a yield with the
formation of same amount of 4a that could be possibly further
conversed to 2a, neutral H2O also afforded lower indolin-2-
one yield. Surprisingly, no desired 2a and only 5a were ob-
tained in the presence of strong reducing SnCl2 with two crys-
It is well known that the metal precursor, particularly in
terms of its ionic or neutral nature of the counter ion, is one of
the most decisive factors in the carbonylative selectivity.21
Subsequently, we chose B(OH)3 as the necessary and opti-
mized proton source (Scheme 2), simple phosphine (PPh3) as a
standard ligand to investigate the effects of palladium precur-
sor in the reductive cyclocarbonylation synthesis of indolin-2-
one (Scheme 3). It was generally found the chemoselectivity
to indole or lactams for the conversion of o-nitrostyrene in the
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presence of CO was sensitive to the nature of the counter ani-
the Pd precursor to search for an optimal catalytic system for
the synthesis of dihydroquinolin-2-one derivatives (Scheme 5).
Counter ions of the neutral and ionic Pd salts again played a
crucial role in the catalyst performance. Pd(OAc)2 only gave
the indole product, while other tested Pd precursors all showed
good selectivity to 3a in various yields, and Pd(TFA)2 afford-
ed the best result with 98 % yield and 100 % selectivity of 3a.
With Pd(TFA)2/TsOH·H2O as the catalyst system, similarly,
monodentate phosphine and nitrogen based ligands showed no
or low catalytic activity/selectivity for the formation of 3a,
diphosphine favored to provide 3a (Scheme 6), particularly,
BINAP offered the best result. Thus, the combination of
Pd(TFA)2/rac-BINAP/TsOH·H2O was the optimized catalyst
system for the CO 1,2-insertion onto o-nitrostyrenes to pro-
duce dihydroquinolin-2-ones.
ons of Pd2+ precursors, Pd(OAc)2 and PdBr2 favored the for-
mation of indole, ionic Pd(CH3CN)4X2 (X = BF4, OTf) pro-
vided quite low five-membered 3-methyl indolin-2-one (2a)
and N-hydroxyl-3-methyl indolin-2-one (4a), to our delight,
PdCl2 gave a 81% yield of 2a and 9% yield of 4a with nearly
100% carbonylative selectivity. Pd(TFA)2 gave 2a in a slightly
lower yield of 68%, but a six-membered product 3,4-
dihydroquinolin-2(1H)-one (3a) was also isolated in 7% yield!
Interestingly, if you check the structural difference of substrate
1a with the carbonylated 2a and 3a, it seems like they were
synthesized via the reductively intramolecular cyclocarbonyla-
tion of the nitro group onto the vinyl bond, regioselectively.
And other Pd precursors showed no or poor activities for this
transformation. These results indicated that PdCl2 was an ideal
Pd catalyst precursor for enabling the CO selective insertion
for the synthesis of five-membered benzo-fused lactams.
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As illustrated in Figure S1 and Figure S2, even when the
CO pressure was reduced to 1 atm, present reductive cyclocar-
bonylation of o-nitrostyrenes did proceed, without indole (5a)
produced. And 12 % total yield of 2a and 4a were obtained
under condition A, on the other hand, it was found that the
increase of CO pressure was particularly good to the further
reductive deoxygenation of 4a to 2a.
PdCl2 was subsequently selected as the optimal Pd precur-
sor to investigate the ligand effect, another crucial factor to the
carbonylative activity and selectivity.22-25 As displayed in
Scheme 4 and Table S2, monodentate PPh3 and its derivatives
(TPAP and TPCP) provided similar and 90% - 100% yields of
carbonylated indolin-2-ones (2a and 4a) with different ratios.
Bulky and electronic-rich Cata Cxium A afforded 70% yield
of 4a with 100% selectivity under the same reaction condi-
tions. The more electron-donating trialkyl phosphine PCy3 and
P(t-Bu)3 as well as bidentate alkyl phosphine ligands and the
nitrogen-based ligands showed no catalytic activity for the
conversion of 1a. Xantphos, a widely used carbonylation lig-
and with rigid aryl skeleton, exhibited a good carbonylation
activity (total 92% yield) but with moderate regioselectivity
with 28% yield of 3a as a minor product. Interestingly, 3a
could be obtained as the major product when BINAP was used
as the complexation ligand, although its catalytic activity was
low. These results indicated that mono- and bidentate phos-
phines led to different regioselectivities for the reductive cy-
clocarbonylation of o-nitrostyrene, and PPh3, with suitable
electronic and steric properties, was selected as the best ligand
for the production of 2a in view of its cost, easy availability
and higher selectivity.
Scheme 6. Ligand Effect for the Pd-Catalyzed Reductive
Cyclocarbonylation of o-Nitrostyrenes to Dihydroquinolin-2-one.a
aReaction conditions: 1a (0.2 mmol), Pd(TFA)2 (0.01 mmol),
Ligand (0.02 mmol for monodentate ligand, 0.01 mmol for biden-
tate ligand), TsOH·H2O (0.2 mmol), THF (2.5 mL), CO (35 atm),
80 oC, 20 h. Isolated yield.
The effects of solvent and temperature were also systemati-
cally tested. In the catalytic synthesis of five-membered in-
dolin-2-one, the polarity of solvent showed striking effects on
the catalyst efficacy (Table S4), but had little influence on the
regioselectivity. Among them, the moderately polar aprotic
THF was the best solvent where 81% isolated yield of indolin-
2-one could be achieved under standard conditions. The prod-
uct yields decreased sharply at relatively lower temperatures
(Table S5), while the regioselectivity remained similar. An
o
optimal yield of 90% was obtained at 80 C, which is consid-
ered mild as the reductive cyclizations of o-nitrostyrenes to
indoles were typically carried out at higher temperatures (100
o
oC to 220 C).8-14 The effects of solvent (Table S9) and tem-
Scheme 5. Screen of Pd Catalysts for the Reductive Cyclocar-
bonylation of o-Nitrostyrenes to Dihydroquinolin-2-one.a aReac-
tion conditions: 1a (0.2 mmol), [Pd] (0.01 mmol), rac-
BINAP(0.01 mmol), TsOH·H2O (0.2 mmol), THF (2.5 mL), CO
(35 atm), 80 oC, 20 h. Isolated yield.
perature (Table S10) for the synthesis of six-membered dihy-
droquinolin-2-one were similar to the indolin-2-one.
2.2 Substrate Scope. With PdCl2/PPh3/B(OH)3 and
Pd(TFA)2/BINAP/ TsOH·H2O as the optimal catalyst for the
synthesis of indolin-2-one (2) (Scheme 7) and 3,4-
dihydroquinolin-2-one (3) (Scheme 8), respectively, their sub-
strate scopes were examined. In general, the steric hindrance
and electronic effects of substituents were different between
Since TsOH·H2O led to the production of 3a (Scheme 2 and
S6), and BINAP also preferred to afford 3a instead of 2a
(Scheme 4), we subsequently chose TsOH·H2O as the proton
source and BINAP as the ligand to investigate the effects of
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the formations of five- and six-membered benzo-fused lactams.
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Specifically, increasing steric hindrance of the vinyl group had
little effect on the formation of indolin-2-one under condition
A (2a-2d), while there was almost no corresponding dihydro-
quinolin-2-one obtained under condition B except in the syn-
thesis of 3c, wherein 90% yield of the decarboxylated product
(3a) was surprisingly isolated (3a-3c), but the decarbonylation
was not observed at all in the production of corresponding 2c.
Electron-withdrawing R2 substituents gave about 90% yield of
desired indolin-2-one (2c and 2d). Similarly, the steric-
hindrance effect of 3-position was negligible (2l and 2m), but
it was obvious under condition B (3l’ and 3m). It could be
seen that the electronic effect at 4-substitution was not very
pronounced in the synthesis of indolin-2-one (2f-2k). On the
other hand, electron-withdrawing groups at 4-position could
increase the reactivity for the production of dihydroquinolin-2-
one in 70-93% yields (3f-3h), and electron-donating groups
decreased the reactivity of the transformation (3j and 3k).
Similar reactivity differences were observed at 3-position.
Electron-withdrawing substituents only gave 2-(3-chloro-2-
nitrophenyl)propanoic acid under condition A (6n) without
any ring closed heterocycles observed, suggesting the hydro-
carboxylation of the vinyl group may be involved as the initia-
tive step in the synthesis of indolin-2-one, such key point will
be investigated and discussed later. On the contrary, the elec-
tron-withdrawing substituents at 3-position could promote the
synthesis of six-membered dihydroquinolin-2-one under con-
dition B (3n and 3n’). The steric-hindrance effect of 6-position
for synthesis of indolin-2-one was very obvious (2q and 2r),
but substituent electronic effect at this position was not signif-
icant. Both electronic and steric-hindrance effects had little
influences on the formation of 3,4-dihydroquinolin-2-one (3q
and 3r). Interestingly, the nitrogen-containing substrates also
worked smoothly under condition B (3s), although nitrogen
ligands were unfavorable to the reaction. The reaction even
could proceed when the vinyl was replaced with an allyl group
under condition B, and a seven-membered benzazepinone was
obtained in 58% yield (3t), which is the core structure of med-
icines for treating cardiovascular diseases.26
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Scheme 8. Substrate Scope for 3,4-Dihydroquinolin-2-one Syn-
thesis.a aCondition B: 1a (0.2 mmol), Pd(TFA)2 (0.01 mmol),
BINAP (0.01 mmol), TsOH·H2O (0.2 mmol), THF (2.5 mL), CO
(35 atm), 80 oC, 20 h. b3a was obtained in 90% yield.
2.3 Mechanistic insights. The above differences in steric hin-
drance and electronic effects seem to indicate that the car-
bonylative regioselectivity was resulted by different reaction
pathways. Initially, the kinetic profile of the model reaction of
1a was conducted under condition A to probe the forming
pathway of indolin-2-one (Figure 2). 4a was generated in the
beginning and then gradually increased to approx. 30% before
starting to decrease after 400 min, associated with the for-
mation of 2a, implying that N-hydroxyl indolin-2-one was
possible the intermediate for the production of N-H indolin-2-
one, and the further reduction of 4a into 2a was a slower step
compared with the formation of 4a from 1a. Similar distribu-
tions of 4a and 2a were observed when varying the CO pres-
sures above 1 atm within the reaction duration of 20 hours
(Figure S1).
Scheme 7. Substrate Scope for Indolin-2-one Synthesis.a aCondi-
tion A: 1a (0.2 mmol), PdCl2 (0.01 mmol), PPh3 (0.02 mmol),
B(OH)3 (0.4 mmol), THF (2.5 mL), CO (35 atm), 80 oC, 20 h. b40
h.
Figure 2. Kinetic profile for the reductive cyclocarbonylation of
1a to synthesize 2a.
In the substrate scope test, 2-aryl propionic acid (6n) was
isolated in nearly 100% selectivity, suggesting that the synthe-
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sis of indolin-2-one may be initiated by the hydrocarboxyla-
Given the above detailed studies on the formation of in-
dolin-2-one, we continued to examined whether 2-
nitrophenylpropionic acid was also an intermediate for the
production of 3,4-dihydroquinolin-2-one. From a controlled
experiment under standard condition B (Supporting Infor-
mation, Eq. S8), however, no reaction occurred. To probe the
plausible reaction pathway in the synthesis of 3,4-
dihydroquinolin-2-one, in situ 1H NMR experiments were
tion at the vinyl group,15b followed by the intramolecular ring
closing reaction between the carboxylic acid and the half re-
duced nitroso (N=O) species to yield N-hydroxyl indolin-2-
one. To further support this hypothesis, the reaction rate was
reduced by lowering the CO pressure as indicated above in the
model reaction, and indeed, 15% yield of 2-(2-
nitrophenyl)propanoic acid (6a) and 8% yield of 4a were ob-
tained after 1 hour without the formation of 2a at this stage. 2a
was only observed after prolonging the reaction to 5 h and 12
h with various amounts of 6a and 4a (Scheme 9, Eq. 1), im-
plying that 6a may be an intermediate before the formation of
4a during the production of indolin-2-one. When 6a and 4a
were used as the starting material, direct conversion to 2a and
dexoygenation to 2a both proceeded efficiently under the iden-
tical reaction conditions for 6a and 4a, respectively (Scheme 9,
Eq. 2 and Eq. 3). Importantly, these two controlled reactions
did not occur without the presence of catalyst or CO (as shown
in Supporting Information, Eq. S2-S5). Furthermore, a con-
trolled experiment using Pd(PPh3)4 as the catalyst without CO
was also conducted (Eq. S6), but there was no target product
2a, which indicated that CO played an important role in the
conversion of 4a into 2a, this result was also consistent with
the deuteration experiment (Eq. S10).
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conducted
using
the
corresponding
optimized
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Pd(TFA)2/BINAP/TsOH·H2O catalytic system at 80 C (Fig-
ure 3). Under 3 atm of CO for 20 minutes, new H NMR sig-
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nals formed at around 2.5 and 5.3 ppm, which could be as-
signed to the methylene hydrogen of the desired dihydroquino-
lin-2-one product and the vinyl hydrogen of a new reaction
intermediate, respectively. After 40 minutes, the 1H NMR
signals of the intermediates matched well with those of the
standard sample of 1-isocyanato-2-vinylbenzene (7a) judged
by its characteristic peaks of the two terminal C-H of vinyl
groups. At the same time, the signals of 3a also became in-
creasingly intense, particularly for its N-H characteristic peaks
at about 9.5 ppm. The concentration of isocyanate intermedi-
ate and substrate decreased gradually as the reaction proceed-
ed, and their signals disappeared completely after 80 minutes.
These results strongly indicated that 1a was reductively car-
bonylated into the 1-isocyanato-2-vinylbenzene at first, fol-
lowed by the hydrocyclization reaction to afford 3,4-
dihydroquinolin-2-one (3a). To further confirm whether 7a
was an intermediate of this transformation, a controlled con-
version of 7a was conducted under condition B (Eq. S9), and
3a was isolated in 90 % yield. In order to study the role of the
proton source, 1a and 7a were separately treated with two
equivalent amount of D2O under condition B. Intriguingly, 36%
and 90% yield of corresponding d2-3a were obtained with no
sign of deuteration on the amide N-H (Scheme 10, Eq. 4-5)!
Scheme 9. Controlled Experiments for the Synthesis of Indolin-2-
one.
Scheme 10. Deuteration Experiments for the Synthesis of 3,4-
Dihydroquinolin-2-one.
Based on our own investigations and previous reports,12,15b,27
the catalytic cycles for the formation of indolin-2-one and 3,4-
dihydroquinolin-2-one were proposed as shown in Scheme 11.
Under condition A, the reductive cyclocarbonylation of o-
nitrostyrenes was initiated by the hydrocarboxylation of the
vinyl group. The insertion of o-nitrostyrene (1a) to the in-situ
formed P2Pd-H complex (II) and the following CO coordina-
tion occurred to give the complex III,28a CO migration and
insertion into the alkyl-Pd bond of III afforded the isolated
intermediate 6a,28b which was reductively catalyzed by the
eliminated Pd(0) and CO to provide the Pd-nitrosoarene (IV)
with release of CO2,27 subsequently followed by the cycliza-
tion to give the detected 1-hydroxy-3-methylindolin-2-one
(4a).29 Finally, the target product indolin-2-one (2a) was pro-
duced by the deoxygenation of 4a using CO as the reductant,
this step could be reasonably deduced by the controlled exper-
iments (Scheme 9, Eq. 3 and Eq. S4-S6) and deuteration ex-
periment (Eq. S10).
1
Figure 3. in situ H NMR investigations in the synthesis of 3a.
Reaction conditions: 1a (0.2 mmol), Pd(TFA)2 (0.02 mmol),
BINAP (0.02 mmol), TsOH·H2O (0.2 mmol), THF-d8 (0.5 mL),
CO (3 atm), 80 oC.
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Scheme 11. Different Reaction Mechanisms for the Synthesis of
Indolin-2-one and 3,4-Dihydroquinolin-2-one (HX = B(OH)3 or
TsOH).
Scheme 12. Application in the Synthesis of Aripiprazolea and
Debromoflustramine B.37b,39 aConditions: (a) 4-bromo-1-
chlorobutane (1 equiv), K2CO3 (2 equiv), Acetonitrile (0.1 M), 30
oC. (b) 1-(2,3-Dichlorophenyl) piperazine hydrochloride (1.05
equiv), K2CO3 (2 equiv), NaI (1.5 equiv), TBAB (0.4 mol %),
Acetonitrile (0.1 M), 70 oC. (c) Condition B.
While for the synthesis of dihydroquinolinone, the reductive
deoxygenation of nitro moiety of o-nitrostyrene was firstly
initiated under condition B via Pd-nitrosoarene (V) and Pd-
nitrene (VI) complexes,27 followed by the insertion of CO into
nitrene intermediate (VI) to yield the 1-isocyanato-2-
vinylbenzene (7a) intermediate,30 which was verified by the in
3. CONCLUSIONS
1
In summary, we have developed a Pd-catalyzed chemo- and
regioselective conversion of o-nitrostyrenes, beyond the pre-
vious deoxygenation reduction of o-nitrostyrenes to indole.
The chemoselectivity was sensitive to the nature of the counter
anions of Pd2+ precursors, while ligand controlled the regiose-
lectivity. The kinetic profile and a series of controlled experi-
ments conducted under the optimal PdCl2/PPh3/B(OH)3 cata-
lytic system suggest that the catalytic conversion of o-
nitrostyrene into indolin-2-one is a tandem process involving
the hydrocarboxylation of styrene motif to give 6, the reduc-
tive deoxygenation of NO2 and intramolecular cyclization to
afford 4, and the final deoxygenation of 4 by CO to produce 2.
situ H NMR experiments. Subsequently, the hydropalladation
of 7a with the help of TsOH·H2O afforded the isocyanate in-
termediate (VII), and then VII underwent attack of the nucle-
ophilic alkyl moiety onto the electrophilic carbonyl carbon to
give a cyclic imidate (VIII),31 which was finally converted to
3a through the reductive cleavage and tautomerization.32 No-
tably, the origin of two added hydrogen of the resultant 3a
product was supported by the deuteration experiments
(Scheme 10, Eq. 4-5).
2.4 Applications. Aripiprazole (brand name Abilify) is a
new type of antipsychotic pharmaceutical and primarily used
in the treatment of schizophrenia and bipolar disorder, its sales
in 2013 ranked the first among all drugs in the United States
medicine market.33 Its conventional synthetic methods gener-
ally provided unideal yields due to the formation of isomer
which is difficult to remove (Scheme S1),34 or need excess
explosive sodium azide as the nitrogen source and corrosive
TFA as a solvent.35 With 8 as the starting substrate and our
methodology as the key catalytic procedure, 77% overall yield
of Aripiprazole could be achieved with a shorter synthetic
route and under milder reaction conditions (Scheme 12). 2c
and its derivatives have been recognized as the key intermedi-
ate in the total synthesis of pyrrolo indole alkaloids,36-37 such
as debromoflustramine B (Scheme 12), which is a selective
butyrylcholinesterase inhibitor.38 With 1c as the cheap and
easily available substrate, 2c could be synthesized in one-step
with 90% yield in 4 mmol scale. These two applications sug-
gest that our convenient and selective catalytic methodologies
have great potentials in the synthesis of five- and six- mem-
bered benzo-fused lactams.
1
The in situ H NMR studies, controlled experiments and deu-
teration experiments under the optimal Pd(TFA)2/BINAP/
TsOH·H2O catalytic system revealed that substrate 1 under-
went NO2 reduction and carbonylation into the 1-isocyanato-2-
vinylbenzene at first, followed by hydrocyclization to afford
dihydroquinolin-2-one (3). It has been further demonstrated
that our novel methodologies could be efficiently applied in
the synthesis of antipsychotic pharmaceutical aripiprazole in
gram scale with 77% overall yield, and the preparation of the
key intermediate (2c) for the total synthesis of debromoflus-
tramine B. Further detailed mechanistic studies on the synthe-
sis of indolin-2-one and dihydroquinolin-2-one to elucidate the
origin of the regioselectivity are ongoing in our laboratories.
AUTHOR INFORMATION
Corresponding Author
* E-mail for F.-W. Li: fuweili@licp.cas.cn
ORCID
Fuwei Li: 0000-0003-2895-1185
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
Supporting Information.
Full experimental details for the syntheses and characterizations
of all described compounds, Table S1-S11, Figure S1 and S2, Eq.
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ACKNOWLEDGMENT
This work was supported by the Natural Science Foundation of
China (21503242, 21522309, 21633013, and 21673269), we also
gratefully thank the Key Research Program of Frontier Sciences
from Chinese Academy of Sciences (QYZDJ-SSWSLH051).
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