B(C6F5)3-Catalyzed Highly Chemoselective Reduction of Isatins: Synthesis of Indolin-3-ones and Indolines

Article abstract of DOI:10.1021/acs.orglett.0c03150

A chemo- and site-selective reduction reaction of isatin derivatives using catalyst B(C6F5)3 and hydrosilanes is described. This transformation is operationally simple, proceeds under mild conditions, and is resistant to various functional groups. Thus, this efficient reaction using a combination of B(C6F5)3 and BnMe2SiH or B(C6F5)3 and Et2SiH2 could potentially be utilized to produce various indolin-3-ones and indolines, without the need for multistep procedures and metal catalysis conditions.

Full text of DOI:10.1021/acs.orglett.0c03150

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Letter
B(C6F5)3‑Catalyzed Highly Chemoselective Reduction of Isatins:
Synthesis of Indolin-3-ones and Indolines
Hyojin Jeong,§ Nara Han,§ Dong Wook Hwang, and Haye Min Ko*
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ABSTRACT: A chemo- and site-selective reduction reaction of
isatin derivatives using catalyst B(C6F5)3 and hydrosilanes is
described. This transformation is operationally simple, proceeds
under mild conditions, and is resistant to various functional groups.
Thus, this efficient reaction using a combination of B(C6F5)3 and
BnMe2SiH or B(C6F5)3 and Et2SiH2 could potentially be utilized to
produce various indolin-3-ones and indolines, without the need for
multistep procedures and metal catalysis conditions.
ndolin-3-ones are attractive target motifs, as they are
reduction using attractive boron Lewis acids has been
investigated by several research groups because of their low
cost, benign environmental impact, and high Lewis acid
strength (Scheme 1).3 Zhang and co-workers first used
B(C6F5)3 as the catalyst and Ph2SiH2 as the reductant for
the reduction of amides to amines.3b N-Phenylamide was
successfully reduced using this catalyst system while benzamide
did not undergo reduction. Later, the reduction of benzamides
to amines, catalyzed by B(C6F5)3 in the presence of
tetramethyldisiloxane or polymethylhydrosiloxane, was inde-
pendently realized by the research groups of Cantat and
Adronov.3c,d The reduction of diverse secondary and tertiary
benzamides to the corresponding amines was accomplished by
I
important building blocks for the synthesis of numerous
pharmaceutical compounds and natural products (Figure 1).1
́
treatment with this catalyst system. In 2018, Gagne and co-
workers reported a new (3-hexyl)B(C6F5)2 catalyst with
modified steric and electronic properties for chemoselective
amide reduction at the later stage, with no competing reaction
at other positions.3e,f A new deoxygenative reduction of amide
using the B(C6F5)3/BF3·O(C2H5)2/H3N·BH3 combination
was disclosed by Xiao et al. last year.3g In addition to
reduction using the strong Lewis acid B(C6F5)3, the selective
reduction of amide using the moderately strong Lewis acid
BPh3 was realized by Okuda et al.3h In this catalytic reaction,
tertiary amides reacted with BPh3 and PhMeSiH2 and were
transformed into amines with good chemoselectivity. The
Beller group first used a combination of boronic acid, which is
a mild Lewis acid, and hydrosilane for the synthesis of amines
from amides.3i Primary, secondary, and tertiary amides were
Figure 1. Representative examples of natural products containing the
indolin-3-one motif.
In addition, the indolin-3-one scaffold is widely studied as a
crucial starting material for the development of new synthetic
methodologies, as it exhibits varied reactivity and enables high
stereoselective transformations. However, despite their utility
and interesting structure, a few synthetic routes2 have been
developed for the construction of indolin-3-ones. Traditional
methods to construct indolin-3-ones involve several steps
consisting of 2-aminobenzoic acid alkylation, cyclization to
afford indole, and finally indole oxidation. In addition to the
conventional methods, recent approaches include visible-light-
induced radical-mediated processes,2a gold-catalyzed cycliza-
tion,2b and mercury-catalyzed enolate umpolung reactions.2c
Consequently, practical and efficient synthetic strategies for
developing the indolin-3-one framework remain desirable.
Recently, the reduction of amide groups to amines via
catalytic hydrosilylation has received immense attention owing
to its desirable chemoselectivity. Particularly, selective amide
Received: September 18, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03150
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
Scheme 1. Synthetic Strategies for the Development of
Indolin-3-one and Indoline Derivatives
Table 1. Optimization of Reaction Conditions
b
entry
solvent/temp (°C)/time (h)
2a/3a/4a (%)
1
2
3
4
5
6
7
DCM/60 °C/60 h
chloroform/60 °C/84 h
DCE/80 °C/60 h
0/0/29
N.D.
N.D.
benzene/100 °C/96 h
chlorobenzene/120 °C/84 h
dichlorobenzene/120 °C/48 h
toluene/120 °C/48 h
toluene/120 °C/60 h
toluene/120 °C/120 h
toluene/120 °C/120 h
toluene/120 °C/60 h
toluene/120 °C/12 h
toluene/120 °C/7 h
N.D.
80/12/5
57/15/8
78/6/3
48/12/0
48/27/1
31/0/0
N.D.
75/21/0
76/13/0
83/0/0
92/2/0
no rex
c
8
9
d
e
10
11
12
13
14
15
16
17
18
f
g
h
i
toluene/120 °C/3 h
h
dichlorobenzene/120 °C/2 h
dichlorobenzene/120 °C/12 h
dichlorobenzene/120 °C/12 h
toluene/120 °C/1.5 h
solvent/60 °C/2 h
h j
,
k
no rex
l
0/1/98
0/5/93
0/3/94
l m
19 ,
l n
20 ,
gradually reduced using benzothiophene-derived boronic acid
and PhSiH3 to produce the desired amines. More recently, the
chemo- and site-selective reduction of α- or β-hydroxy amides
using a combination of B(C6F5)3 and PhMeSiH2 was described
by Kanai et al.3k The hydroxy group of hydroxy amides reacted
with PhMeSiH2 to form silyl ether, and another hydride from
hydrosilane attacked the amide to synthesize amines with
functional group tolerance. Inspired by the previous study that
utilizes B(C6F5)3 and hydrosilanes, we envisioned that isatin,
which is less expensive and commercially available, is suitable
as a substrate to synthesize indolin-3-ones via chemoselective
amide reduction. Thus, we decided to investigate the chemo-
and site-selective reduction of isatins for the preparation of
indolin-3-ones. Herein, we report the first B(C6F5)3-catalyzed
selective reduction of isatins using hydrosilanes to produce
useful indolin-3-ones and indolines.
toluene/60 °C/1.5 h
a
Reactions were carried out with 1a (0.2 mmol), 10 mol % B(C6F5)3,
b
and BnMe2SiH (1.2 mmol) in solvent (0.1 M). Isolated yield.
c
d
e
f
g
Ph2MeSiH. Et3SiH. Ph3SiH. Ph2SiH2. BnMe2SiH (0.8 mmol).
h
i
j
k
BnMe2SiH (0.4 mmol). PhMe2SiH (0.4 mmol). No B(C6F5)3. No
l
m
silane. Et2SiH2 (0.4 mmol). DCE, chloroform, chlorobenzene, or
dichlorobenzene. 5 mol % B(C6F5)3.
n
result, the reaction of 1a with 2 equiv of BnMe2SiH in the
presence of 10 mol % B(C6F5)3 was performed in
dichlorobenzene at 120 °C for 2 h to provide the highest
yield of 2a (92%) and a trace amount of 3a (entry 15).
Furthermore, various catalysts such as BPh3, BEt3, and BF3·
O(C2H5)2 have been investigated, but the decomposition of 1a
was observed in all cases. The control reaction, performed
without B(C6F5)3 or BnMe2SiH, did not yield any adducts
(entries 16 and 17), and the use of Et2SiH2 instead of
BnMe2SiH allowed the formation of 4a8 in an excellent yield of
98% (entry 18). Even at a lower temperature of 60 °C, the
reactions worked well in various solvents to afford 4a (entry
19). We further examined the reaction to achieve a lower
B(C6F5)3 catalyst loading. Surprisingly, the reaction of 1a, with
Et2SiH2 in the presence of 5 mol % B(C6F5)3 in toluene at 60
°C for 1.5 h, afforded indoline 4a and indole 3a in yields of
94% and 3%, respectively (entry 20).
With the optimized reaction conditions in hand, we explored
the substrate scope of indolin-3-one synthesis, as shown in
Scheme 2. The reaction with 5-methyl-1-tosylisatin 1b,4b,5
prepared using tosyl chloride and TEA, proceeded well to
deliver 2b2b,c in a yield of 88%, while 5-methyl-1-tosylindole
3b14b,c was isolated in 7% yield by column chromatography.
Analogues 1c, 1d,5 and 1e4b,5 produced the corresponding
products 2c,2b,c 2d,2b,c and 2e2b,c in 85%, 84%, and 76% yields,
respectively; at the same time, undesired indoles 3c,14b,d,15
3d,14d,16 and 3e14b,d,15 were generated in low yields. 5-Bromo-
1-tosylisatin 1f4c reacted smoothly to deliver the desired
product 2f2b,c in 74% yield without the formation of indole
Initially, we used tosyl-protected isatin 1a4 as the standard
substrate to screen various reaction conditions, and the results
are summarized in Table 1. First, the reaction of isatin 1a,
BnMe2SiH, and 10 mol % B(C6F5)3 was performed in DCM,
chloroform, DCE, or benzene at temperatures ranging from 60
to 100 °C (entries 1−4). With the use of DCM, only indoline
4a was isolated in 29% yield (entry 1), while no desirable
products were detected in the other three solvents (entries 2−
4). Pleasingly, the expected site-selective reduction of tosyl-
protected isatin 1a occurred in chlorobenzene at 120 °C,
affording 2a,2b,c 3a,2b,8b,14 and 4a in yields of 80%, 12%, and
5%, respectively (entry 5). Several solvents were screened to
minimize the production of 3a and 4a (entries 6 and 7);
moreover, a shortening of the reaction time from 84 to 48 h
was only possible in toluene (entry 7). Next, the utility of
various hydrosilanes was evaluated; however, the yields of 2a
could not be improved (entries 8−11). Additionally, the
reaction was attempted with 2 and 4 equiv of BnMe2SiH in
toluene, where 2a was obtained in yields of 75% and 76%,
respectively (entries 12 and 13). When 2 equiv of a structurally
similar PhMe2SiH was used in toluene, 2a was produced in
83% yield without any byproducts (entry 14). Based on this
B
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a
Scheme 2. Substrate Scope of Indolin-3-one Synthesis
a
Reaction conditions: tosyl isatin 1a (0.2 mmol), BnMe2SiH (2.0 equiv), B(C6F5)3 (10 mol %), dichlorobenzene (0.1 M), 120 °C, 2 h. The yields
b
c
d
e
f
g
h
i
j
are isolated yields. 24 h. BnMe2SiH (4.0 equiv). 72 h. 84 h. 36 h. 48 h. BnMe2SiH (5.0 equiv). 6 h. BnMe2SiH (3.0 equiv).
k
l
m
n
Benzenesulfonyl chloride was used instead of tosyl chloride. 1.5 h. Naphthalenesulfonyl chloride was used instead of tosyl chloride. No
tosylation reaction.
3f.14b,17 5-Iodo-1-tosylisatin 1g was also tolerated and yielded
the adducts 2g and 3g18 in yields of 67% and 11%, respectively.
Similarly, utilizing 5-methoxy-1-tosylisatin 1h6 as the substrate
furnished 2h2b,c and 3h14b,c,15 in yields of 70% and 17%,
respectively. Interestingly, 6-methoxy-1-tosylisatin 1i produced
a mixture of regioisomers, 2i and 2i′ with 2i:2i′ = 1:0.7, which
were completely isolated by column chromatography, with a
combined yield of 65% without indole. When 1i was treated
with 3 equiv of BnMe2SiH and 10 mol % B(C6F5)3, a mixture
of regioisomers 2i and 2i′ was obtained in 34% yield with
2i:2i′ = 1:0.2. In addition to the tosyl protecting group, N-
benzenesulfonyl- and N-naphthalenesulfonylisatin generated
the desired products 2j19 and 2k in the yields of 68% and 73%,
respectively. In contrast, isatin derivatives with diverse
protecting groups such as benzyl, TBS, methyl, allyl,
butylsulfonyl, trityl, or BOC could not be converted to the
expected products. Notably, the selective reduction of isatins
was attributed to electronic effects, whereby strongly electron
withdrawing protecting groups like tosyl, benzenesulfonyl, or
naphthalenesulfonyl increased the reactivity of the substrates.
Unfortunately, 1-tosylisatin containing a methyl or fluoro
substituent at the C7 position or a nitro or trifluoromethoxy
substituent at the C5 position could not be synthesized under
various tosylation conditions due to unfavorable steric and
electronic effects.
Next, we focused on the substrate scope of the indoline
synthesis, as represented in Scheme 3. Under the optimized
reaction conditions detailed in entry 20 of Table 1, the reaction
of 5-methyl-1-tosylisatin 1b gave rise to the corresponding
product 4b8b,9 in 69% yield, without the generation of 3b.
With the use of chloro-substituted tosylisatins 1c and 1e, the
desired products 4c and 4e8b were furnished in good yields of
71% and 75%, respectively. Similarly, the expected products
4d8b and 4f8b were obtained in 76% and 71% yields,
respectively, from their respective precursors under these
reaction conditions. The reaction with 1g furnished the
product 4g10 in 77% yield, even though 3g was isolated in
17% yield. In the case of 1-tosylisatins bearing a methoxy
group at the C5 or C6 position, the targeted products 4h11 and
4i8c were prepared in moderate yields of 32% and 56%,
respectively, while in contrast to other substrates, the yields of
indoles 3h and 3i15 were higher (66% and 22%, respectively)
C
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a
Scheme 3. Substrate Scope of Indoline Synthesis
Scheme 4. Proposed Reaction Mechanism
a
Reaction conditions: tosyl isatin (0.2 mmol), Et2SiH2 (2.0 equiv),
B(C6F5)3 (10 mol %), toluene (0.1 M), 120 °C, 2 h. Above shown
b
c
yields are the isolated yields. B(C6F5)3 (5 mol %), 60 °C, 1.5 h. 60
d
°C. Et2SiH2 (4.0 equiv).
for these substrates. The reaction with N-butylsulfonyl- and N-
benzyl-protected isatins 1l4c and 1m7 led to give the
corresponding products 4l12 and 4m8b,13 in yields of 89%
and 53%, respectively.
Based on the experimental results, we propose a possible
reaction mechanism for the formation of 2a from isatin 1a via a
selective reduction reaction shown in Scheme 4. Generally, the
electrophilicities of the carbonyl groups at the C2 and C3
positions of isatin are known to be different; the carbonyl at
C3 of diverse isatins is more electrophilic than the carbonyl at
C2 (Scheme 4a). Thus, several reactions, such as reduction,
nucleophilic addition, or condensation reactions, occur at the
C3 position carbonyl group to generate the corresponding
adducts. In contrast, reversed reactivities of the carbonyl
groups in isatin toward the B(C6F5)3/BnMe2SiH catalytic
system were observed because of the introduction of a tosyl-
protecting group in nitrogen. Remarkably, the strong electron-
withdrawing protecting group had changed the distribution of
electron density in isatin, which resulted in higher reactivity at
the C2 position carbonyl group. Taking into account the
distribution of the electron density in isatin, we proposed that
the electrophilic silane associated with B(C6F5)3 coordinates
with the carbonyl groups at C2 and C3 positions to produce
intermediate i, which is attacked by the hydride from
borohydride at the more electrophilic C2 position (Scheme
4b). The generated intermediate ii20 reacts with B(C6F5)3/
BnMe2SiH again to transform 2a by releasing silyl ether. The
trace amounts of intermediate ii react with electrophilic
silylium cations at the C3 position carbonyl group to produce
iii, which is converted to iv by the abstraction of vicinal
hydrogen from hydride. Finally, 3a is synthesized by
hydrosilylation and silicon-assisted β-elimination.21 Similarly,
intermediate v is formed by treating with B(C6F5)3/Et2SiH2,
which allows continuous intramolecular hydrosilylation to give
O-silyl hemiaminal species vi. Further reaction of vi with
B(C6F5)3/Et2SiH2 produces 4a. In the case of 6-methoxy-1-
tosylisatin 1i, the unanticipated oxindole 2i′, in which the C3
position is reduced, is obtained (Scheme 4c). We believe that
the 6-methoxy substituent donates a lone-pair electron to the
isatin backbone, which activates the C3 position for reacting
with the electrophilic silylium cation. The activated species vii
is easily reduced by hydride to produce viii, which converts to
oxindole 2i′. In another possible pathway, 3h is obtained as a
major product from 1h utilizing B(C6F5)3/Et2SiH2, as
illustrated in Scheme 4d. Intermediate ix reacts with the
electrophilic silylium cation, followed by the release of silyl
ether, which is triggered by electron-donation from nitrogen.
Next, silyl ether is completely released by the activation of the
methoxy group in x; simultaneously, hydride addition occurs to
the carbon of iminium xi. Finally, to reform the aromatic
compound, benzene, a hydrogen from xii is abstracted by
borohydride, resulting in the formation of 3h.
In conclusion, we have demonstrated the first B(C6F5)3-
catalyzed selective reduction of isatins for the synthesis of
indolin-3-one and indoline derivatives. The indolin-3-one
skeleton, which is ubiquitous in pharmaceutical and natural
products, is a material of interest requiring facile, efficient, and
general synthetic approaches for its development. The
developed synthetic strategy features a simple single-step
D
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Metabolite from Aspergillusustus. Tetrahedron Lett. 1971, 12, 3331−
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reaction with metal-free conditions and broad functional group
tolerance and does not require lengthy synthetic steps to
generate the key reaction precursors. Moreover, the acidic α-
hydrogen of indolin-3-ones enables various further trans-
formations, such as aldol, carbonyl α-substitution, and oxime
formation reactions. Further investigations aimed at expanding
the substrates of this methodology are currently underway.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03150.
(3) For recent examples of the selective reduction of amides to
amines, see: (a) Fang, H.; Oestreich, M. Defunctionalisation catalysed
by boron Lewis acids. Chem. Sci. 2020, in press. DOI: 10.1039/
D0SC03712E (b) Tan, M.; Zhang, Y. An efficient metal-free
reduction using diphenylsilane with (tris-perfluorophenyl)borane as
catalyst. Tetrahedron Lett. 2009, 50, 4912−4915. (c) Blondiaux, E.;
Cantat, T. Efficient metal-free hydrosilylation of tertiary, secondary
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Experimental procedures, characterization data, and
1
copies of all H and 13C NMR spectra for all isolated
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Haye Min Ko − Department of Chemistry and Wonkwang
Institute of Materials Science and Technology, Wonkwang
University, Iksan, Jeonbuk 54538, Republic of Korea;
orcid.org/0000-0003-2807-9980; Email: hayeminko@
wku.ac.kr
́
Gagne, M. R. Late-stage chemoselective functional-group manipu-
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S. J.; Gagne, M. R. Chemoselective amide reductions by heteroleptic
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(g) Pan, Y.; Luo, Z.; Han, J.; Xu, X.; Chen, C.; Zhao, H.; Xu, L.; Fan,
Q.; Xiao, J. B(C6F5)3-Catalyzed Deoxygenative Reduction of Amides
to Amines with Ammonia Borane. Adv. Synth. Catal. 2019, 361,
2301−2308. (h) Mukherjee, D.; Shirase, S.; Mashima, K.; Okuda, J.
Chemoselective Reduction of Tertiary Amides to Amines Catalyzed
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(i) Li, Y.; Torre, J. A. M. d. L.; Grabow, K.; Bentrup, U.; Junge, K.;
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Amines by Boronic Acid Catalyzed Hydrosilylation. Angew. Chem. Int.
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12505−12512. (n) Houghton, A. Y.; Hurmalainen, J.;
Hyojin Jeong − Department of Chemistry, Wonkwang
University, Iksan, Jeonbuk 54538, Republic of Korea
Nara Han − Department of Chemistry, Wonkwang University,
Iksan, Jeonbuk 54538, Republic of Korea
Dong Wook Hwang − Department of Chemistry, Wonkwang
University, Iksan, Jeonbuk 54538, Republic of Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03150
Author Contributions
§H.J. and N.H. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF), funded by the Ministry of Science, ICT, & Future
Planning (NRF-2018R1D1A1B07042179, NRF-
2020R1A4A3079595). We thank Prof. Jeung Gon Kim of
Jeonbuk National University for the generous support of
B(C6F5)3 catalyst.
̈
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Hermeke, J.; Mohr, J. A unified survey of Si-H and H-H bond
activation catalysed by electron-deficient borane. Chem. Soc. Rev.
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