Stereoselective Synthesis of Functionalized Benzooxazepino[5,4- a] isoindolone Derivatives via Cesium Carbonate Catalyzed Formal [5 + 2] Annulation of 2-(2-Hydroxyphenyl)isoindoline-1,3-dione with Allenoates

Article abstract of DOI:10.1021/acs.orglett.8b00382

In this work, we present a strategy for the stereoselective synthesis of functionalized benzooxazepino[5,4-a]isoindolone derivatives via a Cs₂CO₃-catalyzed domino β-addition and γ-aldol reaction of 2-(2-hydroxyphenyl)isoindoline-1,3-dione derivatives with allenoates, which offers an avenue for a combination of the structural unity between benzooxazepine and isoindolone motifs in synthetically useful yields with high stereoselectivities under mild conditions. Remarkably, it is the first example of highly stereoselective Cs₂CO₃-catalyzed formal [5 + 2] annulation of 2-(2-hydroxyphenyl)isoindoline-1,3-dione with allenoates.

Full text of DOI:10.1021/acs.orglett.8b00382

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereoselective Synthesis of Functionalized
Benzooxazepino[5,4‑a]isoindolone Derivatives via Cesium Carbonate
Catalyzed Formal [5 + 2] Annulation of 2‑(2-
Hydroxyphenyl)isoindoline-1,3-dione with Allenoates
Chao Yao, Yishu Bao, Tao Lu,* and Qingfa Zhou*
State Key Laboratory of Natural Medicines, Department of Organic Chemistry, China Pharmaceutical University, Nanjing, 210009, P.
R. China
S
* Supporting Information
ABSTRACT: In this work, we present a strategy for the
stereoselective synthesis of functionalized benzooxazepino[5,4-
a]isoindolone derivatives via a Cs2CO3-catalyzed domino β-
addition and γ-aldol reaction of 2-(2-hydroxyphenyl)-
isoindoline-1,3-dione derivatives with allenoates, which offers
an avenue for a combination of the structural unity between
benzooxazepine and isoindolone motifs in synthetically useful
yields with high stereoselectivities under mild conditions. Remarkably, it is the first example of highly stereoselective Cs2CO3-
catalyzed formal [5 + 2] annulation of 2-(2-hydroxyphenyl)isoindoline-1,3-dione with allenoates.
t is highly of interest to effectively construct diverse
heterocyclic molecules based on privileged scaffolds from
aldehydes,6 ketones,7 α, β-unsaturated carbonyl compounds,8
and azomethine imines,9 in the presence of various base or acid
catalysts. Among them, carbonate is a kind of readily available
commercial and safe normal inorganic base, and it is also used
as a catalyst in these reactions. Shi and co-workers first reported
carbonate-catalyzed reactions of ethyl allenoate with salicylic
aldehydes to access the functionalized chromenes in good
yields (Figure 2).10 Then Philipp Selig and co-workers reported
a graceful method for the synthesis of 2,3-disubstituted
quinolines via carbonate-catalyzed reaction of allenoates with
N-protected o-aminobenzaldehydes.11 Recently, phthalimide
derivatives have been disclosed as good reaction partners with
I
the viewpoints of synthetic chemistry and drug discovery.1
Benzooxazepine2 and isoindolone moieties3 are both among
important privileged ring systems because their derivatives are
valuable backbones for the discovery of new biologically active
molecules or therapeutic agents. Therefore, the chemical entry,
benzooxazepino[5,4-a]isoindolone, with a combination of the
structural unity between benzooxazepine and isoindolone
motifs may exhibit different biological characteristics in drug
discovery (Figure 1). However, the methods for the synthesis
Figure 1. Backbones of benzooxazepine and isoindolone moieties.
of these compounds are very scarce despite their potential
applications in medicinal chemistry. Accordingly, searching for
an efficient route to synthesize benzooxazepino[5,4-a]-
isoindolones would offer more promising candidates for
biological screening in a way that was neither possible nor
required before.
Figure 2. Examples for the reactions of allenoates with carbonyl
electrophiles.
Allenoates have been proven to be an important class of
substrates to construct various important heterocyclic com-
pounds with various reaction partners,4 such as imines,5
Received: February 2, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00382
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
allenoates12 or activated alkynes13 under various base catalysis
conditions. However, a cesium carbonate catalyzed reaction of
allenoates with phthalimide derivatives has never been
reported. Herein, we describe the first cesium carbonate
catalyzed domino β-addition and γ-aldol reaction of allenoates
to 2-(2-hydroxyphenyl)isoindoline-1,3-dione for the stereo-
selective construction of highly functionalized benzooxazepino-
[5,4-a]isoindolone deravatives. At the outset of our study, 2-(2-
hydroxyphenyl)isoindoline-1,3-dione 1a and allenoate 2a were
selected for the initial reaction in the presence of 20 mol %
PPh3 in DMF at 40 °C (Table 1, entry 1). No target product 3a
of benzooxazepino[5,4-a]isoindolone deravatives as follows:
use of 40 mol % Cs2CO3 as the catalyst and DMSO as the
solvent to perform the reaction at 60 °C.
With the optimized reaction conditions in hand, the
generality and efficiency of different allenoates were examined
for this transformation (Scheme 1). Overall, the desired
Scheme 1. Synthesis of Benzooxazepino[5,4-
ab
,
a]isoindolones
a
Table 1. Survey on Conditions for Formation of 3a
b
entry
catalyst
solvent
T [°C] t [h] yield [%]
1
Ph3P (20 mol %)
DMF
40
40
40
40
40
40
40
60
60
60
60
60
60
60
60
60
60
40
100
60
60
60
48
48
48
48
48
48
48
9
0
2
Bu3P (20 mol %)
DMF
0
3
Et3N (20 mol %)
DMF
0
4
Na2CO3 (20 mol %)
K2CO3 (20 mol %)
Cs2CO3 (20 mol %)
NaOH (20 mol %)
Na2CO3 (20 mol %)
K2CO3 (20 mol %)
Cs2CO3 (20 mol %)
NaOH (20 mol %)
Cs2CO3 (20 mol %)
Cs2CO3 (20 mol %)
Cs2CO3 (20 mol %)
Cs2CO3 (20 mol %)
Cs2CO3 (20 mol %)
Cs2CO3 (20 mol %)
Cs2CO3 (20 mol %)
Cs2CO3 (20 mol %)
Cs2CO3 (0 mol %)
Cs2CO3 (40 mol %)
Cs2CO3 (100 mol %)
DMF
trace
trace
trace
trace
15
17
22
5
5
DMF
6
DMF
7
DMF
8
DMF
9
DMF
9
10
11
12
13
14
15
16
17
18
19
20
21
22
DMF
10
6
DMF
DMSO
ethanol
H2O
12
48
48
48
48
48
20
1
52
0
0
DCM
THF
0
0
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
0
49
0
48
3
0
54
0
1
a
To a mixture of 1a (0.15 mmol) and 2a (0.1 mmol) in anhydrous
DMSO (1.0 mL), Cs2CO3 (0.04 mmol, 14 mg) was added. The
b
resulting solution was stirred at 60 °C. Isolated yield based on 2a.
a
To a mixture of 1 (0.15 mmol) and 2 (0.1 mmol) in anhydrous
DMSO (1.0 mL), Cs2CO3 (0.04 mmol, 14 mg) was added. The
resulting solution was stirred at 60 °C. Isolated yield based on 2.
b
was formed. Then Bu3P with relatively stronger nucleophilicity
and Et3N were also tested in the reaction, and they did not
afford any good signs of formation of product 3a. However,
product 3a was found with a negligible yield when an inorganic
base, such as Na2CO3, K2CO3, Cs2CO3, and NaOH, was used
as a reaction promoter. Gratifyingly, a moderate yield of 3a was
given using Cs2CO3 as the catalyst when the reaction was
heating at 60 °C in DMF (entry 10). Encouraged by this result,
various solvents were then evaluated to optimize the reaction
conditions. Most of them proved to be unusable for the
formation of 3a, such as ethanol, toluene, H2O, THF, and
DCM, and only DMSO gave the best result for 3a (entries 12−
17). Further examination showed that the temperature and the
amount of catalyst are crucial for the formation of 3a. Thus, we
established the optimal reaction conditions for the construction
products were formed in all the reactions of 2-(2-hydroxy-
phenyl)isoindoline-1,3-dione 1a with different α-benzyl sub-
stituted allenoates in moderate to good yields. The nature of
the substituent on the benzene ring of the α-benzyl substituted
allenoates had a slight impact on the yields. To our delight, α-
unsubstituted allenoate also reacted smoothly with 1a to give
the desired benzooxazepino[5,4-a]isoindolone derivative in a
moderate yield. However, α-ethoxycarbonylmethyl substituted
allenoate did not generate the target product. Ethyl 2-
methylbuta-2,3-dienoate and ethyl penta-2,3-dienoate were
also checked; however, they also did not give the target
products. Many 2-(2-hydroxyphenyl)isoindoline-1,3-diones
B
DOI: 10.1021/acs.orglett.8b00382
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
were then synthesized and examined in this transformation
coupling with α-benzyl substituted allenoate. The results
indicate that various substituted phenyl moieties, possessing
electron-donating or weak electron-withdrawing substituents
(F, Cl, Br), were well tolerated in this transformation. However,
for a substrate with a strong electron-withdrawing substituent
(NO2) attached on the benzene ring, no product was found. It
is worth mentioning here that, under the above conditions, the
substrate with a free anmino group could react with allenoate to
furnish the corresponding benzooxazepino[5,4-a]isoindolone
derivative 3q in a yield of 78%. The reaction was also effective
at producing the corresponding product in moderate yield
when the substrate with a large aromatic ring (naphthyl group)
instead of benzene was present. When double chlorine was
used as a substituent, the reaction did not proceed.
Figure 4. A plausible reaction mechanism for the formation of the
reaction.
intermediate IV, followed by proton transfer to produce the
desired product 3.
To demonstrate the synthetic potential of this catalytic
system, the gram-scale preparation of 3b was investigated. The
reaction of 4.2 mmol of the starting material (1a) proceeded
smoothly, delivering the corresponding product 3b in 48% yield
without a significant loss of efficiency (small scale, 58%). The
synthetic application of this methodology was demonstrated by
the reaction of 3. The dehydration products 4 were obtained in
good yields when various hydroxybenzooxazepino[5,4-a]-
isoindolones 3 were exposed at 120 °C in DMSO for 24 h
(Scheme 2).
In conclusion, an unprecedented steroselective Cs2CO3-
catalyzed domino β-addition and γ-aldol reaction of 2-(2-
hydroxyphenyl)isoindoline-1,3-dione derivatives with allenoates
has been developed. This novel process, carried out under
extremely mild conditions, provides access to functionalized
benzooxazepino[5,4-a]isoindolone deravatives. Remarkably, the
structures of these products may be attractive for potential drug
discovery.
ASSOCIATED CONTENT
* Supporting Information
■
S
Scheme 2. Gram-Scale and Synthetic Transformations
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00382.
Experimental procedures, characterization data, and
1
copies of H and 13C NMR spectra and high-resolution
mass spectrometry (PDF)
Accession Codes
CCDC 1821747 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
The structures of the products were undeniably confirmed by
X-ray crystallographic analysis of compound 4a. The ORTEP
diagram of 4a is shown in Figure 3.
*E-mail: lut163@163.com.
*E-mail: zhouqingfa@cpu.edu.cn.
ORCID
Qingfa Zhou: 0000-0001-6360-2285
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Figure 3. X-ray crystallographic analysis of 4a.
This work was financially supported by the National Natural
Science Foundation of China (Grant Nos. 21572271 and
21102179), Qing Lan Project of Jiangsu Province, and National
Science Fund for Fostering Talents in Basic Science (Grant No.
J1030830).
On the basis of our experimental observations and known
literature,10 a plausible mechanism for the reaction is shown in
Figure 4. Initially the non-nucleophilic base cesium carbonate
deprotonates 1a to generate intermediate I. The intermediate I
then undergoes Michael addition to allenoate to give
intermediate II, and the alternative resonance form III might
then undergo intramolecular nucleophilic attack to form
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DOI: 10.1021/acs.orglett.8b00382
Org. Lett. XXXX, XXX, XXX−XXX