Synthesis of new tetracyclic benzodiazepine-fused isoindolinones using recyclable mesoporous silica nanoparticles

Article abstract of DOI:10.1039/d0cc04875e

Pseudo natural products (NPs) feature structural novelty and diversity and thus are a new source of lead compounds for drug discovery. We first report the mesoporous silica nanoparticles (MSNs)-catalyzed de novo combination of benzodiazepine and isoindolinone, giving tetracyclic benzodiazepine-fused isoindolinone pseudo natural products (21 examples, 55-91% yields). The work also demonstrates that MSNs are efficient acidic catalysts for multi-component reactions.

Full text of DOI:10.1039/d0cc04875e

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Synthesis of New Tetracyclic Benzodiazepine-Fused Isoindolinones
Using Recyclable Mesoporous Silica Nanoparticles
Shuo Yuana, Ya-Le Yueb, Dan-Qing Zhanga, Jing-Ya Zhanga, Bin Yua,* and Hong-Min Liua,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
profiles. Intriguingly, Kirk et al. reported that the benzodiazepine-
fused isoindolinone MMV000917 (Figure 1C) could disrupt ion
homeostasis in the malaria parasite.13
Pseudo natural products (NPs) feature structural novelty and diversity
and thus are a new source of lead compounds for drug discovery. We
first report the mesoporous silica nanoparticles (MSNs)-catalyzed
de novo combination of benzodiazepine and isoindolinone in a
three-dimensional manner, giving biologically relevant and
Benzodiazepine-fused isoindolinone pseudo NPs show potential
for therapeutics. However, the efficient syntheses of such pseudo
NPs have not been extensively explored and remain at a very early
stage, thus limiting further biological investigation of such
compounds.14 In 1974, Kamiya et al. achieved the synthesis of
benzodiazepine-fused isoindolinones from fused hydrazinium salts
via the Stevens-type rearrangement (Scheme 1A).15 In 2004, Daïch
and co-workers successfully obtained α-hydroxylactam precursors
through two-step synthesis, which were then transformed into
benzodiazepines-fused isoindolinones through trifluoroacetic acid
(TFA)-catalyzed intramolecular substitution reaction (Scheme
1B).16 In 2013, Patil and co-workers successfully synthesized the
benzodiazepine-fused isoindolinones through Ph3PAuOTf-
catalyzed relay branching cascade strategy (Scheme 1C).17
Evidently, these approaches start from highly functionalized
precursors that need multi-step synthesis and purification and/or
use of expensive metal catalysts. Therefore, the efficient synthesis
structurally
complex
tetracyclic
benzodiazepine-fused
isoindolinone pseudo natural products (21 examples, 55-91%
yields) from readily available starting materials. The
benzodiazepine
and
isoindolinone
rings
are
formed
simultaneously, with several advantages such as no use of pre-
functionalized starting materials, metal-free conditions, gram-scale
reactions and recyclable catalysts. The work has also demonstrated
that MSNs are efficient acidic catalysts for multi-component
reactions enabling rapid access to novel scaffolds for biological
testing.
Pseudo natural products (NPs) refer to a cluster of compound
classes with structural novelty and diversity that are not accessible
through known biosynthesis pathways.1 Pseudo NPs are obtained
via the de novo combination of NP fragments derived from
biologically diverse and interesting NPs (Figure 1A),2 thus covering
larger chemical space and possessing novel bioactivities.3
Representative pseudo NPs are indomorphans,4 chromopynones,1
pyrano-furo-pyridones,5 and indotropanes6 that show interesting
biological profiles as inhibitors of glucose transporters GLUT-1/3,
mitochondrial complex I, and myosin lightchain kinase 1 (Figure 1B).
Benzodiazepine and isoindolinone scaffolds are frequently found in
many drug molecules and natural products with diverse and
interesting biological activities. Selected representative examples
are anthramycin,7 sclerotigenin,8 tilivalline,9 (±)-lennoxamine,10 (±)-
pestalachloride A,11 and fumaridine12 (Figure 1C). Due to their
interesting biological profiles of benzodiazepines and
isoindolinones, appropriate combination of these two heteroatom-
rich fragments could give new structures with novel biological
of such pseudo NPs remain highly desirable.
(A) General strategy for the design of pseudo natural products (NPs)
de novo
combination
Pseudo natural products
Not accessible through
NP
Fragmentation
existing biosynthesis pathways
NP
(B) Representative pseudo natural products
MeS
O
N
N
H
O
EtO2
C
N
O
HN
O
O
NBoc
N
N
N
HN
O
O
H
NO2
N
OMe
O
O
N
MeO
O
H
Indotropane
Pyrano-furo-pyridone
Chromopynone
Indomorphan
O
(C) Benzodiazepine-fused isoindolinone pseudo natural product
CONH2
OMe
O
HO
HN
H
OMe
OH
N
O
N
H
HO
Me
N
O
NH
HN
OH
O
MeO
HO
HN
H
Anthramycin
O
HN
(±)-Lennoxamine
N
H
OH
Me
O
OMe
O
Cl
Benzodiazepine
scaffold
Isoindolinone
scaffold
N
Me
OMe
NH
Cl
(±)-Pestalachloride A
Me
O
HN
O
N
Tilivalline
de novo
combination
O
N
O
H
Sclerotigenin
OMe
MeO
NMe2
O
O
Fumaridine
R3
R1
N
N
N
N
R2
MMV000917
benzodiazepine-fused isoindolinone
a. School of Pharmaceutical Sciences
& Key Laboratory of Advanced Drug
Me
New pseudo NPs
Preparation Technologies, Ministry of Education, Zhengzhou 450001, China. E-
mail: yubin@zzu.edu.cn; liuhm@zzu.edu.cn.
b. School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
Electronic Supplementary Information (ESI) available: General information, analytic
data, NMR spectra. See DOI: 10.1039/x0xx00000x
Figure 1. Design of biologically relevant benzodiazepine-fused
isoindolinone pseudo natural products (NPs). (A) General strategy
for the design of pseudo NPs. (B) Reported representative pseudo
NPs. (C) Benzodiazepine-fused isoindolinone pseudo NPs.
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Mesoporous silica nanoparticles (MSNs) are catalytically active size distribution are provided in supporting informatiVoinew(AFritgiculerOenSlin1e
DOI: 10.1039/D0CC04875E
because of the strong Lewis acid properties, low coordinating sites and Table S1).
and high surface area, and show excellent stability, efficient
Initially, 2-formylbenzoic acid 1a (0.5 mmol), acetophenone 2a (0.
recovery and recyclability, thus making such catalysts widely used 5 mmol) and 1,2-diaminobenzene 3a (1.5 mmol) were used as
in organic chemistry.18 Bunce and co-workers demonstrated an model substrates to optimize the reaction conditions in the
environmentally friendly Strecker approach for the construction of presence of 10-wt% MSNs (Table 1). Compound 4a was obtained
3-oxoisoindolines from 2-carboxybenzaldehyde, TMSCN and in 9% yield when the reaction was performed in DCE (Table 1,
benzylic or aliphatic amines by employing hexagonal MSN (OSU- entry1). Encouraged by this result, we further examined the
6) as the recycled catalyst.19 Subsequently, they also successfully reactivity in other solvents (Table 1, entries 2-7). To our satisfaction,
realized the metal-free synthesis of 5-benzyl and 5-aryl-1H- product 4a was afforded in 88% yield when the reaction was carried
tetrazoles through the heterogeneous OSU-6 catalyzed click out in acetic acid (Table 1, entry 7). Other solvents such as EtOH,
reaction.20 OSU-6 can also catalyze the conversion of acids and DMSO, DMF, H2O and toluene turned out to be less efficient, and
esters to amides as well as transamidations of primary amides.21 In failed to generate compound 4a (Table 1, entries 2-6). Other solid
light of the catalytic properties of MSNs, we speculate that MSNs catalysts, such as SiO2, amberlyst-15 (A-15) and montmorillonite-
could effectively catalyze the reactions, including the condensation, K10 (Mont-K10) could also catalyze this transformation, giving
amide formation, and dehydration, etc. Herein, we report the first compound 4a in 35-59% yields (Table 1, entries 8-10). We also
metal-free multi-component reactions (MCRs) for the synthesis of found that compound 4a was afforded in 33% yield when the
biologically interesting benzodiazepine-fused isoindolinone pseudo reaction was carried out in AcOH only (Table 1, entry 11), indicating
NPs from commercially available 2-formylbenzoic acid, the effectiveness of the MSNs catalysts. According to above
acetophenone and 1,2-diaminobenzene using MSNs as green and optimizations, the optimal reaction conditions entailed 2-
recyclable catalysts. In this reaction, a bicyclic pyrrolidin-2-one formylbenzoic acid 1a (0.5 mmol), acetophenone 2a (0.5
fused 1,5-diazepine ring system is formed accompanied by mmol),1,2-diaminobenzene 3a (1.5 mmol), MSNs (10-wt%), AcOH
formation of one C-C bond, two C-N single bonds, and one C-N (2 mL), 100 ℃, 24 h (Table 1, entry 7).
Table 1. Optimization of the reaction conditions a
double bond (Scheme 1D). Of note, the tetracyclic pseudo-NPs are
O
combined in a three-dimensional manner and possess multiple
O
N
NH2
NH2
COOH
CHO
Catalyst
Solvent
heteroatoms, meeting with pseudo-NP design principles.3
Compared to previously reported methods (Scheme 1A-1C), this
method has several advantages: (a) Synthesis of structurally
complex benzodiazepine-fused isoindolinone pseudo NPs from
readily available starting materials; (b) Avoids the use of precious
metal catalysts; (c) Metal-free MCRs; (d) Recyclable MSNs
N
+
+
1a
2a
3a
4a
Catalyst
(wt%)
Entry
Solvent
T (℃)
4a (%)b
1
2
MSNs
MSNs
MSNs
MSNs
MSNs
MSNs
MSNs
SiO2
DCE
EtOH
DMSO
DMF
80
80
9
0
catalysts; (e) High reactivity (up to 91% yield) and gram-scale.
(A) Sodium methoxide promoted Stevens-type rearrangement
Me
N
Me
N
N
CH3ONa
3
80
0
N
MeOH, reflux, 26 h
O
O
4
80
0
(B) Acid-promoted intramolecular nucleophilic substitution
OH
5
H2O
80
0
O
N
HN
TFA
N
6
Toluene
AcOH
AcOH
AcOH
AcOH
AcOH
80
0
rt, 12 h
O
NH
7
100
100
100
100
100
88
59
35
39
33
(C) Au-catalyzed relay branching cascade reactions
8
Ph3PAuOTf (5 mol%)
DCE, 100 °C, 24 h
N
NH2
9
A-15
+
N
N
O
OH
O
10
11
Mont-K10
(D) This work: Metal-free synthesis of benzodiazepine-fused isoindolinone pseudo NPs using MSNs
as recyclable catalysts.
R2
-
O
O
N
a
COOH
CHO
NH2
NH2
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a (1.5
MSNs (10-wt%)
+
R2
N
+
R1
AcOH, 120 °C, 24 h
b
mmol), catalyst (10-wt%), solvent (2 mL), 24 h. NMR yields
determined by 1H NMR using the triphenylmethane as an
internal standard.
R1
Tetracyclic benzodiazepine-fused
isoindolinone pseudo NPs
Scheme 1. Approaches for the synthesis of benzodiazepine-fused
isoindolinone pseudo NPs.
With the optimized reaction conditions in hand, we next
examined the scope for the synthesis of benzodiazepine fused
isoindolinones (Table 2). As shown in Table 2, compounds 4a-r
were obtained in good to excellent yields (55-91%) regardless of
their substitution patterns and electronic nature. Various R1
substitutions attached to the ketones were well tolerated in these
reactions. When R1 was halogen, the corresponding products 4b-
4g were generated in good yields (up to 91% yield), the halogen
atom could be used for further functionalization. Delightfully, both
MSNs catalysts were synthesized following a previously reported
sol-gel method,22 in which base was used as catalyst,
hexadecyltrimethylammonium bromide (CTAB) as template, and
tetraethyl orthosilicate (TEOS) as silica precursor. The preparation
and characterization including transmission electron microscopy
(TEM), scanning electron microscope (SEM), the hydrodynamic
diameter, zeta potential, nitrogen adsorption-desorption and pore
2 | J. Name., 2012, 00, 1-3
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electron-deficient and electron-rich aromatic ketones proceeded smoothly with (4-methoxyphenyl)boronic acid, affording compound
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DOI: 10.1039/D0CC04875E
well under the optimized conditions and furnished compounds 4b- 7 in 73% yield (Scheme 2C).
(A) Reduction reaction
o in moderate to excellent yields (55-91% yield). For 1,2-
O
O
diaminobenzene bearing additional substituents, the corresponding
products 4p-r were formed in 76-86% yields. Finally, 2-
formylbenzoic acid 1a (3 mmol), acetophenone 2a (3 mmol) and
1,2-diaminobenzene 3a (9 mmol) were employed to examine the
scalability. To our satisfaction, the desired product 4a was formed
in 78% yield under the standard reaction conditions. Collectively,
the MSNs catalysts could catalyze the reactions efficiently even at
a gram scale.
N
N
LiAlH4
NH
N
THF, 0 °C ~ rt
4a
5
, 90%
(B) Selective demethylation reaction
O
N
O
N
BBr3•Et2O
N
Table
2.
Construction
of
6-aryl-7,7a-dihydro-12H-
N
DCM, 0 °C ~ rt
benzo[2,3][1,4]diazepino[7,1-a]isoindol-12-ones a
OMe
OH
O
R2
N
O
NH2
NH2
COOH
CHO
MSNs
OMe
4l
OMe
, 81%
R2
N
+
+
R1
AcOH, 24 h
6
CCDC:1908638
(C) Pd-catalyzed coupling reaction
R1
B(OH)2
1
2
3
4
O
N
O
O
O
O
O
N
N
N
N
N
N
OMe
N
N
N
N
N
Pd(PPh3)4 (3 mol%)
Na2CO3, N2, 110 °C
Toluene:EtOH = 1:1
F
F
F
4a, 84% (78%)b
4b, 91%
4c, 85%
4d, 70%
Br
O
N
N
O
N
N
4g
O
N
N
O
N
N
7
, 73%
OMe
Scheme 2. Late-stage elaborations.
To gain insight into the mechanism, control experiments were
carried out (Scheme 3). Possible intermediates were synthesized
and then examined for the synthesis of compound 4a. When
chalcone 8 and 1,2-diaminobenzene 3a were treated with MSNs in
AcOH, compound 4a could not be detected (Scheme 3A). The
reaction between 9 and 1a was also tested under the standard
reaction conditions and no desired product was obtained (Scheme
3B). These results indicated that 8 and 9 were not the intermediates
in this reaction. Then the reaction between isobenzofuranone 10
and 3a was carried out in the presence of MSNs, the desired
product 4a was obtained in 93% yield (Scheme 3C). Under the
optimized reaction conditions, the imine 11 reacted with
acetophenone 2a smoothly, giving the intermediate 10 in 90% yield.
Interestingly, in the presence of 1,2-diaminobenzene 3a,
compound 4a was afforded in 87% yield (Scheme 3D). The
findings strongly suggest compounds 10 and 11 are key
intermediates during this transformation.
Br
4f, 75%
Br
Cl
4e, 63%
CF3
4h, 55%
4g
, 83%
O
N
O
N
N
O
O
N
N
N
N
N
OMe
OMe
OMe
Me
4i, 86%
OMe
4l, 75%
4j, 75%
4k, 76%
O
O
N
N
O
N
N
O
N
N
N
N
OMe
MeO
4m, 74%
Ph
4p, 86%
4o
, 88%
4n, 82%
Cl
F
O
N
N
O
Cl
F
N
N
Based on the above results, a reaction pathway of this reaction
is depicted in Scheme 4. Initially, the imine intermediate 11 was
generated in situ from 1a and 3a through the condensation reaction.
In the presence of the catalyst and/or AcOH, the intramolecular
cyclization formed the hemiacetal A, followed by addition of
acetophenone to A. The lactone intermediate 10 was then
generated accompanied by the release of 1,2-diaminobenzene 3a.
Compound 3a then reacted with the lactone 10 through the
condensation reaction to form the intermediate B (detected by LC-
MS). In the presence of the catalyst, the intermediate B underwent
the intramolecular transamidification to form the lactam species C.
Finally, dehydration of C gave the desired product 4a. In this work,
we first realized the multi-component assembly of 2-formylbenzoic
acid, acetophenones and 1,2-diaminobenzenes in the presence of
the catalyst MSNs to give structurally new and complex
benzodiazepine-fused isoindolinone pseudo natural products. We
further envisioned that the catalyst MSNs could catalyse the
condensation, dehydration and transamidification reactions and
may have wide applications in organic synthesis.
4r, 76%
4q, 81%
a
Reaction conditions:1 (0.5 mmol), 2 (0.5 mmol), 3 (1.5 mmol),
MSNs (10-wt%), AcOH (2 mL), 120 ℃, 24 h. b 1 (3 mmol), 2 (3
mmol), 3 (9 mmol), MSNs (10-wt%), AcOH (10 mL), 120 ℃, 24 h.
We next examined whether the catalyst could be recycled for the
synthesis of compound 4a under the optimal conditions. After the
completion of the reaction, the MSNs catalysts were filtered and
washed with EtOH:H2O (1:1), followed by drying at 120 ℃ under
vacuum for 24 h, and the catalytic efficiency of the MSNs slightly
decreased after five consecutive cycles (Figure S2), giving
compound 4a in 81% yield.
To showcase the synthetic utilities, late-stage diversification was
performed (Scheme 2). As shown in Scheme 2A, by treating with
LiAlH4, compound 4a was reduced to give 5 as a mixture of
diastereomers in 90% yield. Treatment of 4l with BBr3•Et2O led to
selective demethylation, yielding compound 6 in 81% yield, which
was characterized by X-ray crystallography (CCDC number:
1908638) (Scheme 2B). In the presence of Pd(PPh3)4, 4g reacted
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Journal Name
O
title compounds could undergo late-stage modificatVioienwsA,rtsichleoOwnilninge
DOI: 10.1039/D0CC04875E
the synthetic utility. We also proposed a mechanism based on the
N
(A)
COOH
NH2
MSNs
+
N
control experiments and further envisioned that MSNs may have
wide applications in organic synthesis because of the catalytic
efficiency. The title compounds are currently undergoing biological
screening for potential therapeutics based on our unbiased cell-
based phenotypic screening platforms.
AcOH, 120 °C
NH2
O
8, 0.3 mmol
3a, 0.9 mmol
4a, 0%
O
(B)
N
COOH
CHO
MSNs
+
N
N
This work was supported by the National Natural Science
Foundation of China (No. 81773562, 81973177 and 81703326),
China Postdoctoral Science Foundation (No. 2018M630840 and
2019T120641).
AcOH, 120 °C
NH2
1a, 0.3 mmol
9, 0.3 mmol
4a, 0%
O
O
(C)
O
N
NH2
NH2
MSNs
+
Conflicts of interest
There are no conflicts to declare.
References
N
O
AcOH, 120 °C
3a, 0.9 mmol
4a, 93%
10, 0.3 mmol
O
O
1 G. Karageorgis, E. S. Reckzeh, J. Ceballos, M. Schwalfenberg, S. Sievers, C.
Ostermann, A. Pahl, S. Ziegler, H. Waldmann, Nat. Chem., 2018, 10, 1103.
2 B. Over, S. Wetzel, C. Grütter, Y. Nakai, S. Renner, D. Rauh, H. Waldmann,
Nat. Chem., 2013, 5, 21.
3 G. Karageorgis, D. J. Foley, L. Laraia, H. Waldmann, Nat. Chem., 2020, 12,
227.
4 J. Ceballos, M. Schwalfenberg, G. Karageorgis, E. S. Reckzeh, S. Sievers, C.
Ostermann, A. Pahl, M. Sellstedt, J. Nowacki, M. A. Carnero Corrales, J. Wilke,
L. Laraia, K. Tschapalda, M. Metz, D. A. Sehr, S. Brand, K. Winklhofer, P.
Janning, S. Ziegler, H. Waldmann, Angew. Chem., Int. Ed., 2019, 58, 17016.
5 A. Christoforow, J. Wilke, A. Binici, A. Pahl, C. Ostermann, S. Sievers, H.
Waldmann, Angew. Chem., Int. Ed., 2019, 58, 14715.
MSNs
(D)
O
AcOH, 120 °C
O
O
OH
N
+
NH2
10, 90%
H2N
NH2
3a, 0.6 mmol
O
11, 0.3 mmol
2a, 0.3 mmol
N
MSNs
AcOH, 120 °C
N
4a, 87%
Scheme 3. Control experiments.
6 T. Schneidewind, S. Kapoor, G. Garivet, G. Karageorgis, R. Narayan, G.
Vendrell-Navarro, A. P. Antonchick, S. Ziegler, H. Waldmann, Cell Chem. Biol.,
2019, 26, 512.
7 W. Leimgruber, V. Stefanović, F. Schenker, A. Karr, J. Berger, J. Am. Chem.
Soc., 1965, 87, 5791.
O
Imine
formation
O
N
COOH
CHO
OH
N
NH2
NH2
H
N
H2N
1a
3a
11
8 M. C. Tseng, C. Y. Lai, Y. W. Chu, Y. H. Chu, Chem. Commun., 2009, 4, 445.
9 K. Unterhauser, L. Poltl, G. Schneditz, S. Kienesberger, R. A. Glabonjat, M.
Kitsera, J. Pletz, F. Josa-Prado, E. Dornisch, C. Lembacher-Fadum, S. Roier,
G. Gorkiewicz, D. Lucena, I. Barasoain, W. Kroutil, M. Wiedner, J. I. Loizou, R.
Breinbauer, J. F. Diaz, S. Schild, C. Hogenauer, E. L. Zechner, Proc. Natl. Acad.
Sci. U. S. A., 2019, 116, 3774.
10 J. R. Fuchs, R. L. Funk, Org. Lett., 2001, 3, 3923.
11 N. Slavov, J. Cvengros, J. M. Neudorfl, H. G. Schmalz, Angew. Chem., Int.
Ed., 2010, 49, 7588.
12 T. Yao, Z. Guo, X. Liang, L. Qi, J. Org. Chem., 2018, 83, 13370.
13 A. M. Lehane, M. C. Ridgway, E. Baker, K. Kirk, Mol. Microbiol., 2014, 94, 327.
14 A. G. Yaremenko, V. V. Shelyakin, D. M. Volochnyuk, E. B. Rusanov and O.
O. Grygorenko, Tetrahedron Lett., 2013, 54, 1195.
4a
Intramolecular
cyclization
MSNs
dehydration
-H2O
O
O
OH
N
H
O
N
NH2
HN
OH
Ac-OH
H
hemiacetal A
C
Intramolecular
Transamidification
Intramolecular
addition to hemiacetal
15 A. Nakamura, S. Kamiya, Studies on fused hydrazines. IV. Chem. Pharm. Bull.,
1974, 22, 2142.
O
O
NH2
O
O
16 A. Cul, A. Daïch, B. Decroix, G. Sanz, L. Van Hijfte, Tetrahedron., 2004, 60,
11029.
NH2
NH2
N
O
17 N. T. Patil, V. S. Shinde, B. Sridhar, Angew. Chem., Int. Ed., 2013, 52, 2251.
18 a) R. K. Sharma, S. Sharma, S. Dutta, R. Zboril, M. B. Gawande, Green Chem.,
2015, 17, 3207; b) A. Kokel, C. Schäfer, B. Török, Green Chem., 2017, 19,
3729; c) F. de Clippel, M. Dusselier, S. Van de Vyver, L. Peng, P. A. Jacobs,
B. F. Sels, Green Chem., 2013, 15, 1398; d) F. Hoffmann, M. Cornelius, J.
Morell, M. Fröba, Angew. Chem., Int. Ed., 2006, 45, 3216; e) M. Ferré, R.
Pleixats, M. Wong Chi Man, X. Cattoën, Green Chem., 2016, 18, 881; f) J.
Trébosc, J. W. Wiench, S. Huh, V. S. Y. Lin, M. Pruski, J. Am. Chem. Soc.,
2005, 127, 3057; g) A. Hasaninejad, M. Shekouhy, A. Zare, Catal. Catal. Sci.
Technol., 2012, 2, 201.
19 B. Nammalwar, N. P. Muddala, M. Murie, R. A. Bunce, Green Chem., 2015,
17, 2495.
20 B. Nammalwar, N. P. Muddala, R. Pitchimani, R. A. Bunce, Molecules., 2015,
20, 22757.
21 B. Nammalwar, N. P. Muddala, F. M. Watts, R. A. Bunce, Tetrahedron., 2015,
71, 9101.
22 U. Patil, A. Fihri, A.-H. Emwas, V. Polshettiwar, Chem. Sci., 2012, 3, 2224.
3a
B
lactone 10
MSNs
Imine formation
Scheme 4. Proposed reaction mechanism.
In conclusion, we have demonstrated that MSNs could catalyze
multi-component reactions that enable efficient combination of
benzodiazepine and isoindolinone NP fragments, yielding
biologically relevant benzodiazepine-fused isoindolinone pseudo
natural products (55-91% yields). Compared to previous reported
methods, this protocol does not use pre-functionalized starting
materials and is metal-free. The reaction could also be carried out
on a gram-scale, giving compound 4a in 78% yield. During this
transformation, one C-C bond, three C-N bonds and two
heterocycle ring systems (benzodiazepine and isoindolinone) were
formed simultaneously. Additionally, the catalyst could be recycled
for several times without significant loss of the catalytic activity. The
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC04875E
R2
O
O
N
COOH
CHO
NH2
MSNs (10-wt%)
AcOH, 120 °C, 24 h
N
+
R2
+
R1
NH2
R1
Tetracyclic benzodiazepine-fused
isoindolinone pseudo NPs
• Novel tetracyclic benzodiazepine-fused isoindolinone scaffold • 21 examples, up to 91% yield
• One C-C, two C-N, and one C=N bonds formed simultaneously • Metal-free conditions
• Recycle MSNs catalyst
• Readily available starting materials • Gram-scale synthesis
Mesoporous silica nanoparticles could catalyze de novo combination of benzodiazepine and
isoindolinone, giving biologically relevant benzodiazepine-fused isoindolinone pseudo natural
products.