Palladium-Catalyzed Cascade Hydrosilylation and Amino-Methylation of Isatin Derivatives

Article abstract of DOI:10.1002/adsc.202000266

We demonstrate that using palladium acetate as a catalyst for reduction of DMF and isatin derivatives by hydrosilanes, a cascade hydrosilylation and amino-methylation reaction can be realized. With DMF as a reactant and a solvent, the in-situ generated siloxymethylamine intermediate, an adduct of DMF and hydrosilanes, smoothly participates in the successive stages, providing a serials of Si, N-functionalized indolin-2-ones in moderate to good yields. This strategy exhibits high chemoselectivity toward carbonyl moieties reduction among the substrates. (Figure presented.).

Full text of DOI:10.1002/adsc.202000266

Title: Palladium-Catalyzed Cascade Hydrosilylation and
Aminomethylation of Isatin Derivatives
Authors: Yue Liu, Yun-Tao Xia, Su-Hang Cui, Yi-Gang Ji, and Lei Wu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000266
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10.1002/adsc.202000266
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Palladium-Catalyzed Cascade Hydrosilylation and Amino-
methylation of Isatin Derivatives
Yue Liu,a Yun-Tao Xia,a Su-Hang Cui,a Yi-Gang Ji,a,b and Lei Wua,*
a
Jiangsu Key Laboratory of Pesticide Science and Department of Chemistry, College of Sciences, Nanjing Agricultural
University, Nanjing 210095, China
[Tel/Fax: +86-25-84395351; E-mail: rickywu@njau.edu.cn]
Jiangsu Key Laboratory of Biofunctional Molecules, Department of Life Sciences and Chemistry, Jiangsu Second
b
Normal University, Nanjing 210013, China
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))
Abstract. We demonstrate that using palladium acetate as
Scheme 1. Previous Studies on Metal-Catalyzed Reduction
a catalyst for reduction of DMF and isatin derivatives by
of Amides by Hydrosilanes (a); and This Work on Novel
hydrosilanes,
a cascade hydrosilylation and amino-
Cascade Reaction (b).
methylation reaction can be realized. With DMF as a
reactant and solvent, the in-situ generated
a
siloxymethylamine intermediate, an adduct of DMF and
hydrosilanes, smoothly participates in the successive
stages, providing a serials of Si, N-functionalized indolin-
2-ones in moderate to good yields. This strategy exhibits
high chemoselectivity toward carbonyl moieties reduction
among the substrates.
Keywords: Palladium catalysis; Hydrosilylation;
Aminomethylation; Cascade Reaction; Isatin Derivatives
The transition metal-catalyzed reduction of amides to
amines by hydrosilanes is a highly effective approach
for the synthesis of amine compounds.[1-11] This
chemistry can be retrospected to the year of 1985,
when the Voronkov group reported the first reaction
of silanes with dimethylformamide (DMF) catalyzed
by the metal complexes [Me2NH2]+[Rh(CO)2Cl2]- or
(NO)2PtCl6.[2] The research interest has been recalled
as hot topics due to the high regio-selectivity and its
broad functional group tolerance upon applying with
appropriate catalysts.
As such, various transition metals, including
carbonyl complexes of ruthenium,[3] iridium,[4]
platinum,[5] iron,[6] molybdenum,[7] manganese,[7a,8]
palladium,[9] copper,[10] the main group metal salts and
other metals,[11] have been utilized as catalysts for the
transformation. For pioneer studies, in 2009, the
groups of Pannell, Beller, Nagashima, and Nakazawa
independently documented that iron carbonyl
complexes can be used as general and efficient
catalysts for the reaction of amide and hydrosilane to
produce amine and disiloxane.[6a-d]
For a long period of time, many efforts have been
devoted to exploring novel catalytic systems,
enhancing reduction efficiency and/or broadening
substrate scopes. However, none of these works
present credible mechanistic details, but only with
postulation. Until recently, Pannell et al. successfully
intercepted
and
isolated
some
important
siloxymethyl-amine
intermediates
(R3SiOCH2NR'2),[7a] and in the presence of excess
DMF, these intermediates thermally reacted with
silanes to form trimethylamine and the corresponding
disiloxanes (Scheme 1a). Shortly afterwards, they
discovered that the isolated intermediate can act as an
excellent aminomethylation (Mannich) reagent while
being treated with E-H (E = N, O, S) species, such as
amines, alcohols, and thiols in inert solvents,
respectively.[12]
1
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10.1002/adsc.202000266
Advanced Synthesis & Catalysis
Entry
Catalyst
Solvent
Yield[b]
Inspired by the Pannell’s work, we proposed that
the siloxymethylamine, a masked analogue of
Eschenmoser’s salt [A],[13] should be an ideal “in-situ
formed intermediate” for designing novel three-
component cascade reactions. Nevertheless, to the
best of our knowledge, this chemistry has never been
reported so far. This retard may be ascribed to
difficulties in selection of appropriate cascade
components and catalyst, otherwise the third substrate
may coordinate with metal catalyst thus interrupting
the initial reduction step. As our continuing works on
heterocyclic chemistry,[14] herein, we report the first
palladium-catalyzed cascade hydrosilylation and
aminomethylation of isatin derivatives with DMF and
hydrosilanes (Scheme 1b).[15]
(2a/2a'/2a'', %)
1[c]
2[c]
3[c]
4[c]
5[c]
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Rh2(OAc)4
Fe(OAc)2
Mn(OAc)2
Pd(TFA)2
Pd/C
THF
acetonitrile
DMSO
H2O
N.R.
N.R.
0/60/0
0/0/70
18/0/0
89/0/0
38/0/0
24/63/0
0/86/0
0/<5/0
N.R.
ethyl acetate
-
-
-
-
-
-
-
-
-
-
-
-
-
-
7[d]
8[e]
9[f]
10
11
12
13
14
15
16
17
18
19
N.R.
70/0/0
69/0/0
78/0/0
72/0/0
<5/0/0
10/0/0
N.R.
The study was commenced with N-methylisatin
o
(1a), DMF and Et3SiH at 70 C under nitrogen
PdCl2
atmosphere to define the optimal reaction conditions,
as summarized in Table 1. Initial efforts focused on
screening solvents. We found that no reactions could
occur in THF or acetonitrile (entries 1-2). A N-
methyl-isatin hydrosilylation product 2a' was
obtained in 60% yield when DMSO was used as a
solvent (entry 3). The reaction in water gave only 3-
hydroxy-1-methyl-indolin-2-one (2a'') in 70% yield,
which could be a hydrolysed product of 2a' (entry 4).
Afterwards, the cascade reaction of isatin, DMF and
silane did occur in ethyl acetate, albeit 18% yield of
2a was obtained (entry 5). To our delight, the reaction
efficiency could be dramatically improved while
using the reactant DMF as a solvent, and the target
product 2a was isolated in 89% yield without the
observation of other by-products. It is noted that the
amide moiety of isatin could be a potential substrate
of hydrosilylation, but we did not detect competitive
reduction product even with excess amount of silane.
In addition, reaction temperature and the dosage of
silane also played crucial roles to keep the efficiency
and chemo-selectivity. For instance, the reaction at
room temperature delivered 2a in a lower yield of 38%
(entry 7), and reactions with 1 and 3 equivalents of
triethylsilane would bring out the unwanted 2a' as the
major product (entries 8, 9). Other transition metal
catalysts, such as rhodium acetate, ferrous acetate and
manganese acetate were applied as well, however,
none of these catalysts could compete with that of
palladium. Although palladium complexes other than
palladium acetate catalyzed the cascade reaction with
acceptable yields around 70% (entries 13-16), it is
quite clear that phosphine ligands extremely impaired
the process, leaving most of the reactants intact
(entries 17, 18). These results collectively pointed that
palladium catalyst, reaction temperature, solvent and
dosage of silane are all essential to achieve the
cascade reaction.
Pd(dba)2
Pd(PPh3)2Cl2
Pd(PPh3)4
-
[a]Reaction conditions: 1a (0.3 mmol), Et3SiH (5.0 equiv,
o
1.5 mmol), catalyst (5 mol%), DMF (3 mL) at 70 C under
N2 for 12 h;
[b]Isolated yield, N.R. = no reaction;
[c]DMF (5 equiv, 1.5 mmol);
[d]At room temperature;
[e]Et3SiH (3.0 equiv);
[f]Et3SiH (1.0 equiv).
Once the optimized reaction conditions were
identified, we then investigated the scope of N-
substituted isatins. As depicted in Scheme 2, N-alkyl
substituted isatins, including i-propyl, allyl, and n-
butyl ones, produced the corresponding products (2b-
2d) in yields above 70%. Among these substrates, the
allyl one was hydrogenated to n-propyl-substituted
product (2c). In sharp contrast, N-aryl substituted
isatins yielded the target products (2e-2f) in higher
yields over 80%. In combined with the results of N-
benzyl substitutions (p-MeO, p-Me, and p-F), it is
suggested that the cascade reactions benefit from both
electron-donating property and less steric effect.
Moreover, we demonstrated the practical synthetic
application of this protocol on a gram-scale, and the
corresponding product 2a was obtained in 75%
isolated yield.
N-Protection-free isatins are always believed to be
not applicable to metal catalytic transformations
owing to either strong coordination of N-atom to
metals or altering reaction pathways.[16] Quite
interestingly, varieties of N-protection-free isatins
performed smoothly under the standard conditions
(Scheme 2). In general, electron-deficient groups on
phenyl rings descended the reaction efficiency to
some extent. The electron-rich isatins, such as 5-
methoxy-isatin, 5-methylisatin and 7-methylisatin
could produce the corresponding products (2o, 2q and
2w) in good yields (73% to 85%), with an exception
for 2s. In comparison, isatins with electron-
withdrawing functionalities (-F, -OCF3, -CF3, -
COOCH3) at all aromatic sites were converted into
Table 1. Optimization of the Reaction Conditions.[a]
2
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10.1002/adsc.202000266
Advanced Synthesis & Catalysis
the corresponding products in medium to good yields
To further explore the substrate scope of this
(50%-74%). Notably, bromo- and chloro-substitutions method, as presented in Scheme 3, some formamides
are not compatible with the strategy since only and hydrosilanes were investigated. Since other
product 2j was isolated for both 5-bromoisatin and 6- amides and silanes would bring higher steric
chloroisatin, which could be attributed to the hindrance, it was found that modifications on the
susceptible property of chloro and bromo atoms procedure were necessary to obtain satisfactory
toward palladium-catalyzed reduction. Although results. Briefly, the amide substrate could be extended
reducible cyano group was tolerated to give to N-formyl-morpholine, where the reactions still had
corresponding product 2x in 40%, nitro-substituted good substrate adaptability and exhibited similar
substrates (1y, 1z) produced only hydrosilylation electronic effects to that of DMF. N-methylisatin, N-
products (2y′, 2z′), as well as nitro groups being formyl-morpholine, triethylsilane and
5
mol%
reduced.
palladium acetate at 100 oC delivered the adduct 3a in
74% yield. N-protection-free, N-phenyl, and N-benzyl
substituted isatins furnished the products in yields
from 55 to 70% (3b-3f). However, attempts of N,N-
diethylformamide, N,N-diphenylformamide and N-
formylpiperidine were failed even with alternative
screenings.
Scheme 2. Substrate Scope on Isatin Derivatives.[a]
When it came to exploring hydrosilanes, we found
that replace of triethylsilane with other alkylsilanes
would form only analogues of 2a’, products of ketone
hydrosilylation. Control experiments clearly indicated
that due to the difference of reducing ability, i-Pr3SiH,
t-BuMe2SiH, n-Bu3SiH and Ph3SiH could not enable
the hydrosilylation of DMF, thus no siloxymethyl-
amine would be produced (see more details in the
Supporting Information). To our delight, by
sequential using of steric hydrosilanes and
triethylsilane, i-Pr3Si, t-BuMe2Si and n-Bu3Si-
derivated products (3g-3i) were successfully achieved
in yields of 66%, 62% and 61%, respectively.
Unfortunately, dimethylphenyl silane, triphenylsilane,
phenylsilane and diphenyl-silane were not suitable
substrates.
Scheme 3. Substrate Scope on N-formylmorpholine and
Hydrosilanes.
[a]Standard conditions with isolated yields;
[b]Gram-scale synthesis;
[c]Starting from N-allylisatin.
3
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10.1002/adsc.202000266
Advanced Synthesis & Catalysis
In summary, we have established the first
palladium-catalyzed cascade hydrosilylation and
aminomethylation of isatin derivatives. The new
protocol proceeds with high selectivity in successive
hydrosilylation of carbonyl moieties in DMF and
isatin derivatives, furnishing a novel serials of Si, N-
functionalized indolin-2-ones in moderate to good
yields. Applications of siloxy-methylamine inter-
mediates in other cascade reactions are ongoing in our
laboratory.
In consideration of experimental facts and literature
reports,[6a,7a,17] we outline a plausible mechanism for
the cascade hydrosilylation and aminomethylation
(Scheme 4). Initially, palladium acetate is reduced by
hydrosilane into palladium (0) species, as well as the
formation of Et3SiOAc and H2 evolution.[17e]
Oxidative addition of triethylsilane to palladium (0)
species should generate an activated palladium-
hydride species, which hydrosilylates the carbonyl
groups of isatin derivatives (1) and DMF, respectively.
On one hand, the siloxy-methylamine intermediate
then transforms into an iminium species [A]
(Eschenmoser’s salt). On the other hand, the O-
silylated indolin-2-one tautomerizes into an enol form
[B], which then attacks the iminium species to yield
target product 2 and finalizes the cascade reaction.
Experimental Section
Typical Procedures for the Palladium-Catalyzed
Cascade Hydrosilylation and Aminomethylation of
Isatin, DMF and Hydrosilane.
To a solution of N-methylisatin (1a, 48.3 mg, 0.3
mmol) and Pd(OAc)2 (3.4 mg, 0.015 mmol) in DMF
(3 mL) was added Et3SiH (240 μL, 1.5 mmol) at room
temperature under nitrogen atmosphere. The reaction
was stirred at 70 °C for 12 h. After then, the mixture
was poured into brine (20 mL) and extracted with
petroleum ether (4×5 mL). The combined organic
phase was dried over anhydrous Na2SO4. After
filtration and evaporation of the volatiles under
reduced pressure, the crude product was purified by
column chromatography on silica gel (petroleum
ether/ ethyl acetate = 5/1(v/v)), affording product 2a
as a yellow oil. (89 mg, 89% yield, TLC: Rf = 0.35).
These compounds are unstable at room temperature,
which have to be stored in refrigerator. 1H NMR (400
MHz, CDCl3) δ 7.39 (d, J = 7.4 Hz, 1H), 7.34-7.28 (m,
1H), 7.09-7.03 (m, 1H), 6.80 (d, J = 7.8 Hz, 1H), 3.19
(s, 3H), 2.92-2.74 (m, 2H), 2.08 (s, 6H), 0.82 (t, J =
7.9 Hz, 9H), 0.46-0.30 (m, 6H). 13C NMR (101 MHz,
CDCl3) δ 177.1, 143.9, 130.9, 129.4, 124.7, 122.3,
108.0, 77.6, 66.6, 47.5, 26.2, 6.6, 5.5. HRMS (ESI):
([M+H]+) Calcd for C18H31N2O2Si+: 335.2149, Found:
335.2148. IR (film) ν 3290, 2946, 2900, 2817, 2764,
1700, 1615, 1498, 1469, 1448, 1380, 1347, 1301,
Scheme 4. Plausible Mechanism.
4
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10.1002/adsc.202000266
Advanced Synthesis & Catalysis
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Acknowledgements
This project is supported by the Foundation Research Project of
Jiangsu Province (The Natural Science Foundation, No.
BK20191305), the Fundamental Research Funds for the Central
Universities (NJAU, Grant No. KYDZ201904), the Qing-Lan
Project of Jiangsu Provincial Department of Education and the
“333 High Level Talent Project” of Jiangsu Province.
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Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
COMMUNICATION
Palladium-Catalyzed Cascade Hydrosilylation and
Amino-methylation of Isatin Derivatives
Adv. Synth. Catal. 2020, Volume, Page – Page
Yue Liu, Yun-Tao Xia, Su-Hang Cui, Yi-Gang Ji,
and Lei Wu*
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