Reduction of Benzolactams to Isoindoles via an Alkoxide-Catalyzed Hydrosilylation

Article abstract of DOI:10.1021/acs.orglett.7b02739

An alkoxide-catalyzed reduction of benzolactams to isoindoles with silanes was realized. With t-BuOK as the catalyst and Ph₂SiH₂ as the reductant, a series of benzolactams containing different functional groups were reduced to the co

Full text of DOI:10.1021/acs.orglett.7b02739

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Reduction of Benzolactams to Isoindoles via an Alkoxide-Catalyzed
Hydrosilylation
Guangni Ding, Xiaoyu Wu, Lili Jiang, Zhaoguo Zhang,* and Xiaomin Xie*
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
S
* Supporting Information
ABSTRACT: An alkoxide-catalyzed reduction of benzolactams to isoindoles with silanes was realized. With t-BuOK as the
catalyst and Ph2SiH2 as the reductant, a series of benzolactams containing different functional groups were reduced to the
corresponding isoindoles, which could be captured by N-phenyl maleimide to form Diels−Alder products in moderate to good
yields. Deuterium labeling studies and the hydrosilylation of benzolactam in DMF indicated that the deprotonation of
benzolactams took place at C3 potion during the reduction.
Scheme 1. Profiles for Hydrosilylation of Amides to
Enamines
ydrosilylation is an appealing method for the reduction of
Hcarbonyl compounds, which represents the most
important and well-established transformation in organic
chemistry.1 Hydrosilanes are air- and moisture-stable hydride
sources, and can be readily activated under mild conditions.
Various catalysts had been explored for the chemo-, regio-,
and/or stereoselective hydrosilylation of carbonyl compounds
and carboxylic acid derivatives.2 In particular, the hydro-
silylation of amides showed high chemoselectivity, which
preceded other methods.3 Moreover, by tuning the catalysts
and silanes, the hydrosilylation of amides enabled the selective
formation of different products such as amines, imines,
aldehydes, alcohols, nitriles or deacylated amines.3,4
Nagashima et al. first reported the hydrosilylation of aryl and
alkyl substituted acetamide derivatives to form enamines
efficiently, with IrCl(CO)(PPh3)2 as the catalyst and TMDS
or PMHS as the hydride source (Scheme 1a).5 The reaction
may proceed through the addition of a Si−H bond to carbonyl
group to form a silylhemiaminal as intermediate, followed by
deprotonation and elimination of the siloxy moiety to give
enamines.5 Recently, the same group realized the stepwise
synthesis of enamines by hydrosilylation of amides using
iridium complex with electron-withdrawing phosphorus ligands
as the catalyst (Scheme 1b).6 Furthermore, Adolfsson’s group
reported t-BuOK catalyzed hydrosilylation of tertiary amides to
enamines.7 However, the hydrosilylation of benzolactams has
not been reported.
Due to benzolactams having acidic hydrogen atoms at their
3-position, we envision that the selective hydrosilylation of
benzolactams may lead to the formation of isoindoles deriva-
tives, which are very important 10π-electron aromatic hetero-
Received: September 2, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02739
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
cycles,8 and have often been employed as synthetic building
blocks for highly conjugated systems in materials science and
medicinal chemistry as antibiotic and antitumor agents and
thrombin.9 Moreover, isoindoles are highly reactive intermedi-
ates in cycloaddition reactions.10 Several methods were
developed to synthesize isoindoles, such as retro Diels−Alder
reactions, 1,3-dipolar cycloadditions, oxidative processes,
alkylation and isomerization reactions of isoindolinones, and
condensation of o-phthalaldehyde or benzylic amines.8,11
Among these methods, the reduction process is the most
straightforward one. However, the noticeable over-reduction
when reducing phthalimides/lactams using metal hydrides
usually resulted in low yields of isoindoles, and instead,
substituted pyrroles were often obtained.12 Herein, we reported
an efficient procedure of base-catalyzed reduction of
benzolactams to isoindoles with hydrosilanes.
Table 1. Optimization of the Reaction Conditions of the
Base-Catalyzed Reduction of 2-Benzylisoindolin-1-one (1a)
a
entry
base
KOH
silane
solvent
conv (%) yield (%)
1
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph3SiH
THF
85
85
60
80
60
81
70
>97
59
13
24
−
2
NaOH
EtOK
THF
61
3
THF
90
4
EtONa
MeOK
MeONa
t-BuOK
t-BuONa
KHMDS
LDA
THF
66
5
THF
92
6
THF
70
7
THF
>97
60
8
THF
9
THF
44
Considering the easy removability of the benzyl group, the
hydrosilylation of 2-benzylisoindolin-1-one (1a) was chosen as
the model reaction to explore the possibility of the reduction of
benzolactams to isoindoles with hydrosilanes. Although the
metal catalyzed hydrosilylation could enable the transformation
of amides to enamines,5,6 Lewis base-catalyzed hydrosilylation
is no doubt more attractive in terms of environmental benignity
and ready availability of the catalyst.4c,13 KOH was initially
selected as the catalyst in the model reaction, on the basis of
our previous report on the hydrosilylation of imides.14 When
20.0 mol % of KOH and Ph2SiH2 (2.0 equiv) were used, 85% of
the benzolactam (1a) was converted to the desired product, N-
benzyl isoindole (2a) (Table 1, entry 1). Then, other bases
were examined in the hydrosilylation. When potassium
methoxide or ethoxide was used as the catalyst, the conversion
of the reduction increased slightly, but the yields of 2a almost
unchanged (Table 1, entries 3 and 5). Gratifyingly, t-BuOK
displayed best catalytic activity to afford almost quantitative
yield of N-benzyl isoindole (2a) (Table 1, entry 7). Comparing
with potassium alkoxides, sodium alkoxides resulted in a
decrease in conversions and yields of the hydrosilylation (Table
1, entries 2, 4, 6 and 8). In addition, potassium bis-
(trimethylsilyl) amide and lithium diisopropylamide were
inferior for the reaction (Table 1, entries 9 and 10). No
reactions occurred in the cases of using weaker bases (K2CO3
or K3PO4) as the catalyst. Omission of the base resulted in no
desired reduction of the benzolactams (1a) (Table 1, entry 11).
The yield of 2a was decreased to 80% when the t-BuOK
loading was lowered to 10.0 mol % (Table 1, entry 12).
We also screened some other silanes, solvents and reaction
temperatures during the t-BuOK catalyzed hydrosilylation of
the benzolactams. More reactive silane for example, PhSiH3,
improved the conversion of 1a, but a lower selectivity and yield
(85%) of isoindole (2a) was obtained (Table 1, entry 13).
Using less active silanes led to the compromised conversions
and yields (Table 1, entries 14−17). For example, TMDS
(tetramethyldisiloxane) and PMHS (polymethylhydrosiloxane)
gave 2a in 70% and 13% yields, respectively. Changing the
solvent from THF to DME (dimethoxyethane) decreased the
yield of 2a (Table 1, entry 18). A nearly quantitative yield of 2a
was obtained in dioxane (Table 1, entry 19). For the nonpolar
solvent, toluene, the isoindole (2a) could also be obtained in
90% yield (Table 1, entry 20). However, only 30% of lactam
(1a) was converted to isoindoles (2a) in CH3CN (Table 1,
entry 21), while no reaction occurred in DCE. When the
reaction was carried out in refluxing dioxane, the reaction time
was reduced to 10 h (Table 1, entry 22).
10
11
THF
26
−
THF
−
b
12
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
THF
82
80
85
51
53
13
51
31
>97
90
30
>97
c
13
THF
>97
52
d
14
TMDS
THF
e
15
(EtO)3SiH
(MeO)3SiH
PMHS
THF
54
e
16
THF
14
e
17
THF
52
18
19
20
21
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
DME
dioxane
toluene
CH3CN
dioxane
40
>97
>97
30
f
22
>97
a
Reaction conditions: 2-benzylisoindolin-1-one (1a, 223.3 mg, 1.0
mmol), Ph2SiH2 (368.6 mg, 2.0 mmol), base (20.0 mol %), THF (2.0
mL), 70 °C, 36 h; conversion and yields were determined by 1H NMR
b
analysis (internal standard: 4,4′-di-tert-butyl-1,1′-biphenyl). t-BuOK
c
(10.0 mol %) was used. PhSiH3 (151.3 mg, 1.4 mmol) was used.
d
e
TMDS (268.6 mg, 2.0 mmol) was used. Silane (4.0 mmol) was used.
f
The conversion was finished in 10 h at 110 °C.
Next, the scope of base-catalyzed hydrosilylation of
benzolactams (1) to isoindoles (2) was probed under the
optimized conditions. As shown in Table 2, the reduction
reactions led to efficient formation of a number of isoindoles
(2). Because of the instability of isoindoles, we listed the
isolated yields of the compound 4, which were Diels−Alder
reaction products of isoindoles (2) and N-phenyl maleimide
(3).8,15 The hydrosilylation of N-benzyl, alkyl or aryl
substituted benzolactams gave the corresponding isoindoles
(2) in moderate to good yields. N-Phenyl benzolactam (1c)
was reduced to the corresponding isoindole 2c in 92% NMR
yield and 84% isolated yield of 4c. N-Ethyl isoindole (2g) was
obtained in 87% yield. For benzolactams 1b, 1d, 1i and 1j′,
bearing an alkylated benzene ring, the hydrosilylation
proceeded smoothly to give the corresponding isoindoles
(2b, 2d, 2i and 2j′) in excellent yields. 2-(4-(tert-Butyl)phenyl)-
2H-isoindole (2d) and 2-benzyl-5-methyl-2H-isoindole (2i)
were generated in 97% and 96% yields, respectively. However,
the steric hindrance of substitutions at the nitrogen atom or C4
position of benzolactams had obvious influence on the base-
catalyzed hydrosilylation. The yield of corresponding isoindole
2h was reduced to 60% in the case of bulkier N-isopropyl
benzolactam (1h) as the substrate. The existence of propyl
group at the 4-position of benzolactam 1j inhibited the reaction
and no corresponding product (2j) was obtained. While the
isoindole 2j could be generated in 87% yield when the
B
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Organic Letters
Letter
The reduction of benzolactam with a pendant alkene group
(1p) and a Boc-protected amine (1o) proceeded smoothly with
good chemoselectivity to afford the corresponding isoindoles
(2p and 2o) in excellent yields.
Table 2. t-BuOK -Catalyzed Reduction of Benzolactams (1)
to Isoindoles (2) with Hydrosilane
a
Unlike the classical reduction process employing modified
LiAlH4 or Red-Al which result in only moderate yield and over-
reduction contaminants, the hydrosilylation of N-benzyl
benzolactam (1a) could be run effectively on a 2.0 g scale
wherein quantitative NMR yield and 86% isolated yield of 2a
was observed (Scheme S1). Isoindoles are useful building
blocks in the synthesis of functional materials and medicinal
molecules.8,9,9d,16 For example, 2a was reacted with benzyne to
form 1-benzyl-9,10-dihydro-9,10-epimino-anthracene (6) in
70% yield which may serve as a useful precursor of luminescent
materials.17 Furthermore, [4 + 3] cycloaddition of the isoindole
(1a) afford seven-membered compound (7) in 60% yield,
which occurred in many classes of natural products (Scheme
2).18
Scheme 2. Applications of Isoindoles in Materials Science
and Synthetic Chemistry
The plausible mechanism of the reduction of benzolactams 1
to isoindoles 2 via the alkoxide catalyzed hydrosilylation may be
similar to the reaction path for the hydrosilylation of tertiary
amides to enamines that was proposed by Adolfsson et al.7 The
base activates the silane via formation of a pentacoordinated
intermediate, which facilitates the transfer of the hydride to the
amide carbonyl to generate the silylhemiaminal intermediate.
Then the C3-deprotonation followed by elimination of the
siloxy moiety to generate isoindoles 2. The possibility of
deprotonation of benzolactam with t-BuOK as base was
explored. Benzolactam was reacted with t-BuOK in dioxane,
and then treated with D2O to give the C3-deuterated
benzolactam in 90% ratio (Scheme 3, A). In contrast, the
a
Reaction conditions: benzolactam (1, 1.0 mmol), Ph2SiH2 (368.6 mg,
2.0 mmol), t-BuOK (22.4 mg, 20.0 mol %), dioxane (2.0 mL), 110 °C.
b
1
Yields determined by H NMR analysis (internal standard: 4,4′-di-
Scheme 3. Experiments on the Deprotonation of
Benzolactam (1)
c
d
tert-butyl-1,1′-biphenyl). Isolated yields. Isolated yield of 2.0 g-scale
of 1a. 1.0 equiv of t-BuOK was used.
e
benzolactam 1j′ with propyl group at 7-position was used as
substrate. The electron-withdrawing groups decreased the
reactivity of benzolactams. The reduction of 2-(4-
Bromophenyl)isoindolin-1-one (1l) gave the corresponding
t
isoindole 2l in 47% yield when 20.0 mol % BuOK was used.
Increasing the loading of t-BuOK to 1.0 equiv resulted that the
yield was increased to 85% yield. 2-(4-(Trifluoro-methyl)-
phenyl)-2H-isoindole (2f) was produced in only 56% yield.
The hydrosilylation of the benzolactam with an amide group
(1n) gave the product in only 32% of yield even 1.0 equiv of t-
BuOK was used. Moreover, the reduction system showed good
tolerance of functional groups, such as halogens (1l and 1m),
alkene (1p), naphthalene ring (1k), and carbamic ester (1o).
deuteration did not occur without t-BuOK. Moreover, when
DMF was used as solvent, the hydrosilylation of benzolactam
(1a) introduced a methylene group at C3 position instead of
the formation of the isoindole (2a). In addition, on the basis of
our experimental results in Table 2, the steric hindrance of
substitution at the nitrogen atom and C4 position of
C
DOI: 10.1021/acs.orglett.7b02739
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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In summary, we have developed an alkoxide-catalyzed
hydrosilylation of benzolactams to isoindoles. With t-BuOK
(20 mol %) as the catalyst and Ph2SiH2 as the reductant,
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AUTHOR INFORMATION
Corresponding Authors
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(13) (a) Fernandez-Salas, J. A.; Manzini, S.; Nolan, S. P. Chem.
Commun. 2013, 49, 9758−9760. (b) Revunova, K.; Nikonov, G. I.
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*E-mail: zhaoguo@sjtu.edu.cn.
*E-mail: xiaominxie@sjtu.edu.cn.
ORCID
Zhaoguo Zhang: 0000-0003-3270-6617
Xiaomin Xie: 0000-0002-5798-291X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
for financial support.
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