One-pot syntheses of isoquinolin-3-ones and benzo-1,4-diazepin-2,5-diones utilizing Ugi-4CR post-transformation strategy

Article abstract of DOI:10.1021/co400001h

One-pot and efficient syntheses of structurally diverse isoquinolin-3-ones and isoquinolin-3-one-based benzo-1,4-diazepin-2,5-diones have been developed. The notable features of the process include the Ugi condensation of monomasked phthalaldehydes with a

Full text of DOI:10.1021/co400001h

Research Article
pubs.acs.org/acscombsci
One-Pot Syntheses of Isoquinolin-3-ones and Benzo-1,4-diazepin-
2,5-diones Utilizing Ugi-4CR Post-Transformation Strategy†
Chao Che,*,‡,§,∥ Song Li,‡,∥ Zhixiong Yu,§ Fangfang Li,‡ Shengchang Xin,‡ Liyan Zhou,‡ Shuo Lin,*,‡,⊥
and Zhen Yang*,‡,⊗
‡Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School,
Shenzhen 518055, China
§South China Center of Innovative Pharmaceuticals (SCCIP), Guangzhou 510663, China
∥Shenzhen Shengjie Biotech Co., Ltd., Shenzhen 518055, China
⊥Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, United States
⊗Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National Laboratory for
Molecular Science (BNLMS), College of Chemistry, Peking University, Beijing 100871, China
S
* Supporting Information
ABSTRACT: One-pot and efficient syntheses of structurally
diverse isoquinolin-3-ones and isoquinolin-3-one-based benzo-
1,4-diazepin-2,5-diones have been developed. The notable
features of the process include the Ugi condensation of
monomasked phthalaldehydes with amines, carboxylic acids,
and isonitriles, followed by HClO4-mediated intramolecular
condensation of the carbonyl with amide.
KEYWORDS: isoquinolin-3-ones, benzo-1,4-diazepin-2,5-diones, multicomponent reaction, Ugi-4CR, one-pot synthesis,
diversity-oriented synthesis
INTRODUCTION
■
Multicomponent reactions (MCRs)1 serve as a powerful tool
for the rapid and efficient assembly of complex structures from
simple starting materials and with minimized production of
wastes. These highly step-economic reactions are appealing in
both combinatorial and diversity-oriented synthesis, and are
particularly useful for the construction of diverse chemical
libraries of “drug-like” molecules.2
The isoquinolinones constitute the scaffolds of great
biological and pharmacological interest in medicinal chemistry
and exhibit an array of promising biological properties,
including antitumor,3 anti-inflammatory,4 antimalarial,5 antiar-
rhythmic,6 antithrombotics activities,7 and inhibition to NS5B
polymerase of HCV,8 PDE5,9 and PARP.10 These scaffolds are
also widely found in many biologically active alkaloids, such as
2-hydroxyaccuminatine (I)11 and oxyavicine (II) (Figure 1).12
On the other hand, benzodiazepines and its analogues are
recognized as privileged scaffolds in medicinal chemistry and
exhibit a wide scope of biological activity, known as anxiolytic
drugs,13 antitumor agents (III),14 antitubercular agents,15 and
anti-HIV agents.16 Recently, these classes of compounds were
found to hit various pharmacologically relevant targets, such as
GABAA receptor,17 histone deacetylases (HDAC),18 apoptotic
protease-activating factor 1 (Apaf-1),19 and Hdm2 protein
(IV).20
Figure 1. Medicinally important isoquinolinones and benzodiazepa-
nones.
creative biological assays.21 As part of this research objective,
we became interested in establishing a novel synthetic strategy
to construct diverse isoquinolinone and benzodiazepine-based
heterocycles. In a previous paper, we have reported a diversity-
For many years our laboratories have been involved in
developing a chemical genetic approach to analyze biological
systems by way of interfacing libraries of small molecules with
Received: January 2, 2013
Revised: February 25, 2013
© XXXX American Chemical Society
A
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ACS Combinatorial Science
Research Article
based approach for the construction of isoquinoline scaffolds
via Ugi-Heck reaction sequence.22,23 As a continuing effort, we
herein report an alternative Ugi-based MCR approach to one-
pot syntheses of diverse isoquinolinones and isoquinolinones-
based benzo-1,4-diazepin-2,5-diones.
Scheme 2. One-Pot Synthesis of Isoquinolinones
RESULTS AND DISCUSSION
■
The Ugi reaction, offering a large number of potential inputs,
has gained popularity as a powerful tool for generating diverse
compound libraries, and its union with other transformations
can further expand the structural type of compound libraries.
From a design perspective, it was envisioned that the
isoquinolinones could be assembled through an intramolecular
condensation of a carbonyl with the amide group in the α-
acylaminoamide which was in turn produced by the Ugi-4CR of
carboxylic acid, amine, isonitrile, and monomasked phthalalde-
hyde (Scheme 1, Path a), and the benzo-1,4-diazepinone could
Scheme 1. Synthetic Analysis for Isoquinolinones and
Benzo-1,4-diazepinones
products were messy and often the Passerini product was
obtained as the major product.
To profile the scope and potential of the present reaction, we
next examined a series of commercially available carboxylic
acids, amines, isonitriles with aldehyde 3a to form the
structurally diversified isoquinolinones under the optimal
reaction conditions, and their derived products are listed in
Table 1. Pleasingly, all the selected substrates underwent Ugi-
4CR/hydrolysis/intramolecular condensation transformations
smoothly to give the corresponding isoquinolinones (6b−k) in
good to excellent yields. With regard to carboxylic acid input,
the performances of aromatic acids were slightly better than
those of aliphatic acids, and aromatic or aliphatic amines appear
to be comparable in this transformation. In addition,
substituents on the amide nitrogen originating from isonitriles
did not affect the annulations, since ter-butyl, cyclohexyl, and
propyl isonitriles provided the similar results.
To further extend the reaction scope, four additional
substituted 2-(1,3-dioxolan-2-yl)benzaldehyde 3b, 3c, 3d, and
3e were made (see Supporting Information for detail), and
their annulated results are listed in Table 2. With regard to the
substituent effect on the phenyl ring of 2-(1,3-dioxolan-2-
yl)benzaldehyde, neither electron-donating groups (Table 2,
entries 1 to 6) nor electron-withdrawing groups (Table 2,
entries 7 to 10) on the phenyl ring affected the efficiency of the
reaction. Once again, all the expected products were obtained
in good to excellent yields.
As an expansion of this study, we decided to develop the
post-transformation strategy for the developed Ugi-condensa-
tion synthetic protocol to further expand the compound library
of biological interest. We envisioned that quinolin-3-one-based
benzo-1,4-diazepin-2,5-diones 7a could be synthesized starting
from nitro-substituted benzoic acid, glycine methyl ester,
aldehyde, and isonitrile, as shown in the Scheme 3. The
reaction sequence for the formation of 7a involved the Ugi-
condensation reaction followed by the intramolecular lactam-
ization which was achieved through the reduction of the nitro
group under acidic conditions. In addition, this sequence could
be achieved in one-pot fashion, which makes this process more
practical and efficient. By varying of acid, aldehyde, and
isonitrile components, a series of benzo-1,4-diazepin-2,5-diones
were generated in moderate to good yields, as listed in the
Table 3.
be built up in a similar manner using the aniline bearing a
masked carbonyl in ortho position (Scheme 1, Path b). The
proposed strategy could provide rapid access to a variety of
isoquinolones and benzo-1,4-diazepinones from simple starting
materials.
The proposed strategy was examined by the Ugi reaction of
aldehyde 3a with benzoic acid, aniline, and tert-butyl isonitrile
in MeOH at room temperature (Scheme 2), which was
followed by the treatment with various Brønsted acids. We
were pleased to find that a number of Brønsted acids including
PTSA, H2SO4, HCl, and HClO4 were able to facilitate the
desired transformation. After a preliminary survey of reaction
parameters, the use of HClO4 in acetonitrile was found to be
most effective to provide isoquinolinone 6a in 82% yield.
During our further study of benzo-1,4-diazepinone construc-
tion, we encountered difficulties in the Ugi reaction, and the
In summary, we have developed an efficient and one-pot
synthesis of structurally diverse isoquinolinones and isoquino-
B
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Research Article
Table 1. Synthesis of Compounds 6b−6k
Table 2. Synthesis of Compounds 6l−6u
linone-based benzo-1,4-diazepin-2,5-diones involving Ugi-
4CR/condensation and Ugi-4CR/condensation/reduction/lac-
tamization sequence. This developed synthetic protocol was
anticipated to be applicable in the fields of combinatorial
chemistry, diversity-oriented synthesis, and drug discovery. The
biological evaluation of the synthesized compounds is currently
underway in our lab, and the results will be reported in due
course.
EXPERIMENTAL PROCEDURES
■
General Experimental Details. Unless noted otherwise,
all reactions were performed under a nitrogen atmosphere, and
materials obtained from commercial suppliers were used
without further purification. Purification of products was
C
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ACS Combinatorial Science
Research Article
(0.5 mmol). The reaction mixture was stirred at room
temperature for 12 h, and the solvent was removed under
vacuum. To the resulting residue in CH3CN (4 mL) was added
HClO4 (70%, 6.1 μL, 0.075 mmol), and the reaction mixture
was stirred at room temperature for 8 h. The reaction mixture
was worked up by the addition of NH3·H2O to pH = 8 and
then extracted with CH2Cl2 (3 × 10 mL), and the combined
organic layers were dried over anhydrous Na2SO4. The solvent
was removed under vacuum, and the residue was purified by a
flash column chromatography on silica gel (CH2Cl2/CH3OH =
50:1) to give the desired product. 6a, yellow solid; Mp 190 °C;
IR v 3063, 2976, 2898, 1664, 1637, 1564, 1531, 1483, 1396,
1371, 1319, 1286, 856, 775 cm−1; 1H NMR (300 MHz, CDCl3)
δ 8.30 (s, 1H), 7.54−7.49 (m, 3H), 7.41−7.26 (m, 6H), 7.18−
7.08 (m, 4H), 6.92−6.87 (m, 1H), 1.71 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 158.6, 142.7, 138.0, 137.9, 137.0, 133.2, 129.6,
129.2, 128.7, 127.1, 125.6, 125.5, 123.6, 121.5, 119.3, 115.8,
64.3, 28.2; HRMS (m/z) calc. for C26H25N2O2 (+) 397.1916,
found 397.1907.
Scheme 3. One-Pot Synthesis of Isoquinolinone-Based
Benzo-1,4-diazepin-2,5-diones
Table 3. Synthesis of Compounds 7b−7u
Typical Procedure for MCR to Benzo-1,4-diazepin-2,5-
diones 7. To a mixture of glycine methyl ester hydrochloride
(0.56 mmol) and Na2CO3 (0.28 mmol) in MeOH (3 mL)
prestirring for 15 min were added 2-(1,3-dioxolan-2-yl)-
benzaldehyde (0.56 mmol), 2-nitrobenzoic acid (0.56 mmol),
and tert-butyl isocynide (0.56 mmol). The reaction mixture was
stirred at room temperature for 12 h, and the solvent was
removed under vacuum. To the resulting residue in CH3CN (4
mL) was added HClO4 (70%, 6.1 μL, 0.075 mmol), and the
reaction mixture was stirred at room temperature for 8 h. The
solvent was then removed under vacuum to give the yellow
solid, to which was added AcOH (4 mL) and Zinc powder (364
mg), and the reaction mixture was stirred at 60 °C for 8 h. The
reaction mixture was worked up by the addition of NH3·H2O to
pH = 8 and then extracted with CH2Cl2 (3 × 10 mL), and the
combined organic layers were dried over anhydrous Na2SO4.
The solvent was removed under vacuum, and the residue was
purified by a flash column chromatography on silica gel
(CH2Cl2/CH3OH = 50:1) to give the desired product. 7a,
yellow solid; Mp 165 °C; IR v 3219, 3068, 2974, 2924, 1693,
entry
R1
R2
R3
product
yield
1
H
H
H
H
H
H
H
H
H
Cy
7b
7c
7d
7e
7f
67%
62%
78%
80%
68%
54%
50%
53%
63%
56%
46%
53%
47%
45%
40%
35%
56%
54%
48%
48%
2
n-Py
n-Py
t-Bu
Cy
3
5-F
4
4-Cl
4-Cl
5-MeO
5-MeO
5-Cl
4-Cl
H
5
6
n-Py
Cy
7g
7h
7i
7
8
4,5-2MeO
4,5-2MeO
4,5-2MeO
4,5-2MeO
5-MeO
5-MeO
5-MeO
5-CF3
Cy
9
Cy
7j
10
11
12
13
14
15
16
17
18
19
20
n-Py
Cy
7k
7l
5-MeO
H
t-Bu
Cy
7m
7n
7o
7p
7q
7r
7s
7t
1
1641, 1533, 1481, 1448, 1408, 1190, 758, 698 cm−1; H NMR
5-F
(300 MHz, CDCl3) δ 8.64 (s, 1H), 8.46 (s, 1H), 8.09 (dd, J = 0.
9, 6.9 Hz, 1H), 7.51 (m, 2H), 7.32 (m, 3H), 7.18 (d, J = 8.1 Hz,
1H), 7.06 (d, J = 6.9 Hz, 1H), 6.96 (m, 1H), 4.51 (d, J = 15.3
Hz, 1H), 4.14 (d, J = 15.3 Hz, 1H), 1.86 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 172.2, 167.3, 158.0, 138.0, 137.8, 136.3, 133.4,
132.7, 132.2, 129.1, 126.1, 125.0, 122.2, 122.0, 120.9, 120.0,
116.4, 64.9, 52.3, 28.6; HRMS (m/z) calc. for C22H22N3O3 (+)
376.1661, found 376.1660.
4-Cl
5-MeO
5-F
t-Bu
t-Bu
t-Bu
Cy
5-CF3
H
5-CF3
H
5-Cl
t-Bu
t-Bu
Cy
5-Cl
5-MeO
5-Cl
5-Cl
7u
conducted by flash column chromatography on silica gel (200−
ASSOCIATED CONTENT
■
300 mesh) purchased from Qing Dao Hai Yang Chemical
1
S
* Supporting Information
Industry Co. H NMR spectra were recorded on a Bruker 300
or 500 MHz spectrometer using residual solvent (δ (CDCl3) =
7.26) as internal standard. All the coupling constants are
reported in hertz (Hz). 13C NMR spectra were recorded on the
same instruments, and chemical shifts were measured relative to
solvent resonances (δ (CDCl3) = 77.0). High-resolution mass
spectra were obtained on a quadrupole time-of-flight (QqTOF)
mass spectrometer.
Typical Procedure for Four Component Reaction to
Isoquinolinones 6. To a solution of 2-(1,3-dioxolan-2-
yl)benzaldehyde (0.5 mmol) in MeOH (3 mL) were added
amine (0.5 mmol), carboxylic acid (0.5 mmol), and isocyanide
Detailed experimental procedures, compound characterization
data, and 1H, 13C NMR spectra for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Phone: 86-755-26032530 (C.C.), 310-267-4970 (S.L.), 86-
755-26032971 (Z.Y). Fax: 86-755-26033180 (C.C.), 310-267-
4971 (S.L.), 86-755-26032163 (Z.Y.). E-mail: chec@pkusz.edu.
cn (C.C.), shuolin@ucla.edu (S.L.), zyang@pku.edu.cn (Z.Y.).
D
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ACS Combinatorial Science
Research Article
of 3,4-Dihydro-1(1H)-isoquinolinone-Based Antagonists and Ethyl
Ester Prodrugs. J. Med. Chem. 1996, 39, 4583−4591.
Funding
This work was supported by the National Natural Science
Foundation of China (Grant No. 21102006), the Natural
Science Foundation of Guangdong Province (Grant No.
S2011010000185), Guangdong Innovative Research Team
Program (Grant No. 201001Y0104701332), and Shenzhen
Science and Technology Plan Projects (Grant No.
JSA201005310118A, and GJHS20120628101219318).
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Notes
The authors declare no competing financial interest.
DEDICATION
■
†This paper is dedicated to Professor Zhongning Zhang on the
occasion of his 70th birthday.
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dx.doi.org/10.1021/co400001h | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
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dx.doi.org/10.1021/co400001h | ACS Comb. Sci. XXXX, XXX, XXX−XXX