Br?nsted acid mediated intramolecular cyclopropane ring expansion/[4 + 2]-cycloaddition

Article abstract of DOI:10.1039/c9ob02379h

A cascade reaction of 3-hydroxy-2-phenylisoindolin-1-one and cyclopropyl ketone has been developed via a Br?nsted acid-promoted ring-opening/intramolecular cross-cycloaddition/[4 + 2]-cycloaddition process. The developed methodology provides straightforward access to pentacyclic isoindolin-1-one derivatives under simple reaction conditions.

Full text of DOI:10.1039/c9ob02379h

Organic &
Biomolecular Chemistry
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Brønsted acid mediated intramolecular
cyclopropane ring expansion/[4 + 2]-
cycloaddition†
Cite this: Org. Biomol. Chem., 2019,
17, 10004
Received 4th November 2019,
Accepted 15th November 2019
Jian Li, * Shangrong Zhu, Qiuneng Xu, Li Liu and Shenghu Yan*
DOI: 10.1039/c9ob02379h
rsc.li/obc
A cascade reaction of 3-hydroxy-2-phenylisoindolin-1-one and molecular cross-cycloaddition reactions of cyclopropyl ketones
cyclopropyl ketone has been developed via a BrØnsted acid-pro- is a highly demanding goal.
moted ring-opening/intramolecular cross-cycloaddition/[4 + 2]-
Recently, we reported a copper-catalyzed cascade reaction of
cycloaddition process. The developed methodology provides 2-formylbenzonitrile, cyclopropyl ketones, and diaryliodonium
straightforward access to pentacyclic isoindolin-1-one derivatives salts via the expansion of cyclopropane/formation of
under simple reaction conditions.
N-acyliminium/the [4 + 2]-cycloaddition process.9 We envi-
sioned that dihydrofuran derivatives were produced from the
ring-opening coupling reaction of cyclopropyl ketones cata-
lyzed by copper salts. A natural extension of the work is to
explore the possibility of replacing the copper salts with other
non-metallic catalysts. Herein, we report a BrØnsted acid-pro-
moted ring-opening coupling reaction of cyclopropyl ketones
with 3-hydroxy-2-phenylisoindolin-1-one for the facile syn-
thesis of substituted pentacyclic isoindolin-1-one,10 which
usually represents an important class of pharmaceutical com-
pounds due to their various medicinal properties.
Cyclopropane derivatives have received immense attention in
organic synthesis due to their versatile activity.1 In particular,
upon activation by a Lewis acid, the donor–acceptor cyclopro-
panes could generate 1,3-zwitterions through the heterolytic
cleavage of the central C–C bond between the donating and
the electron-withdrawing moieties, which were trapped easily
by different double bonds, such as CvC, CvN, and CvO.2
This is one of the most commonly used strategies for the con-
struction of different cycles through ring expansion reactions
as the electron-donating or -accepting substituents make polar
processes more favorable.3 Thus, a number of very brilliant
examples related to intermolecular cycloadditions and intra-
molecular cross-cycloadditions have been reported (IMCC;
Scheme 1).4 Generally, cyclopropanes involved in synthetically
useful reactions contain two activating groups, and monoacti-
vated cyclopropane derivatives such as cyclopropyl ketones are
sluggish because of their low activities.5 To date, few methods
for the ring-opening reactions of cyclopropyl ketones have
been published and these methods showed severe disadvan-
tages such as harsh reaction conditions (strong Lewis acids6 or
nucleophiles7) and limited substrate scope (β-effect of the
silicon atom of a trimethylsilyl group8). Hence, the exploration
of new efficient methods for ring-opening coupling/intra-
Inspired by our previous work,9 we chose 3-hydroxy-2-phe-
nylisoindolin-1-one 1a as the 4π diene in the hetero-D–A reac-
tion as the hydroxyl group was easily removed by using cata-
lysts. Initially, the reaction conditions for the ring-opening
coupling/[4 + 2]-cycloaddition reaction from 3-hydroxy-2-phe-
nylisoindolin-1-one 1a 11 and (4-chlorophenyl)(cyclopropyl)
methanone 2a were optimized in a sealed tube (Table 1). The
catalyst-free reaction of 1a (0.3 mmol) with 2a (0.45 mmol) in
1,2-dichloroethane (DCE) at 110 °C for 30 min did not provide
Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, School of
Pharmaceutical Engineering & Life Sciences, Changzhou University, Changzhou,
213164, China. E-mail: lijianchem@cczu.edu.cn, ysh@cczu.edu.cn
†Electronic supplementary information (ESI) available: Synthetic details,
additional spectroscopic data, and characterization of the new compounds.
CCDC 1960679. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c9ob02379h
Scheme 1 Synthetic strategies of acridines with anthranils.
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Table 1 Optimization of the reaction conditionsa
Table 2 Cyclopropyl(phenyl)methanone 2 scopea,b
Entry
Catalyst
Temperature (°C)
Solvent
Yieldb (%)
1
2
3
4
—
110
110
110
110
110
110
110
110
110
110
110
110
110
r.t.
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Toluene
THF
MeCN
DMF
1,4-Dioxane
DCE
DCE
DCE
DCE
DCE
—
23
Trace
25
Trace
58
48
52
21
20
22
—
21
—
35
50
65
67
BF3·Et2O
Benzoic acid
TsOH
HOAc
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
5
6
7c
8d
9
10
11
12
13
14
15
16
17e
18f
19g
20h
80
130
110
110
110
110
a Reaction conditions: 1a (0.3 mmol), 2 (0.45 mmol) and TfOH (3.5
equiv.) in 1,2-dichloroethane (DCE) (2 mL), 110 °C, 30 min. b Isolated
yield. The diastereomeric ratio was determined by the 1H NMR analysis
of products.
DCE
DCE
69
65
a Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), catalyst
(1.5 equiv.) in solvent (2 mL), 30 min. b Isolated yield. c 15 min.
d 60 min. e TfOH (2.5 equiv.). f TfOH (3 equiv.). g TfOH (3.5 equiv.).
h TfOH (5 equiv.).
4-position, afforded 3a-phenyl-1,2,13b,13c-tetrahydrofuro[3,2-c]
isoindolo[2,1-a]quinolin-9(3aH)-ones 3a–3h in 58–75% isolated
any products (entry 1). To our satisfaction, when BF3·Et2O was yields and excellent diastereoselectivity (Table 2). For example,
used as a Lewis acid catalyst, the annulation reaction occurred cyclopropyl(phenyl)methanones bearing halogen groups such
at 110 °C in DCE, and the expected product 3a was obtained in as Cl, F and Br were compatible in this methodology to give
23% yield. To increase the yield, some BrØnsted acids, such as the halogen-containing products 3a–3c in moderate yields
TsOH, HOAc and TfOH, were employed (entries 3–6). TfOH (67–69%). Interestingly, the cascade reaction can override
was the most efficient catalyst for this reaction and the desired the ortho-effect that (2-bromophenyl)(cyclopropyl)methanone
product 3a as a single diastereoisomer (dr > 20 : 1) was formed shows giving product 3d in 66% yield. Disubstituted substrates
in 58% yield. After shortening or elongating the reaction time, also afforded the corresponding pentacyclic isoindolin-1-one
the isolated yields of 3a were not improved (48% and 55%, product 3g in an acceptable yield.
entries 7 and 8). Subsequently, a survey of other solvents was
Subsequently, the cascade reaction was carried out with
carried out with TfOH. We found that a change in the solvent differently substituted 3-hydroxy-2-phenylisoindolin-1-one 1
has a significant effect on the reaction outcome. Among the under the optimized conditions (Table 3). The results also
solvents tested, DCE appeared to be the most suitable reaction show that variation of the aromatic electronic properties of the
medium. To a large extent, the temperature affected the reac- substituent at either R1 or R2 of the 3-hydroxy-2-phenylisoindo-
tion rate and the yield of 3a was only 35% at 80 °C, while the lin-1-one 1 was tolerated, furnishing the corresponding pro-
yield was decreased to 50% at 130 °C. Gratifyingly, the reaction ducts in 55–72% yields (3i–3o). Notably, a meta-chloro substi-
can be further promoted when the loading of TfOH was tuent was also tolerated to afford the desired products 3k in
increased, and a more favorable outcome of 69% yield was 72% yield and excellent diastereoselectivity. The structure of
observed in the presence of 3.5 equiv. of TfOH (entry 19). 3m was confirmed by single-crystal X-ray diffraction.
Thus, the optimum reaction conditions for the transformation Encouraged by the above success, we then turned our attention
were as follows: 3.5 equiv. TfOH and DCE (untreated), at to apply this methodology to other cyclopropyl ketones.
110 °C for 30 min.
Remarkably, the catalytic system is applicable for the cascade
The results of the experiments run under the optimized reaction of 3-hydroxy-2-phenylisoindolin-1-one 1a with 1-cyclo-
reaction conditions to probe the scope of the tandem reaction propylethan-1-one 2p to afford the methyl product 3p in 79%
are summarized in Table 2. To our delight, all cyclopropyl yield (Scheme 2).
(phenyl)methanone 2, including electron-donating (methyl,
In order to figure out the reaction mechanism, control
dimethyl) and electron-deficient (trifluoromethyl) at the experiments were carried out (Scheme 3). To confirm whether
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Table 3 3-Hydroxy-2-phenylisoindolin-1-one 1 scopea,b
Fig. 1 Proposed reaction mechanism.
(cyclopropyl)methanone 2c with 3-hydroxy-2-mesitylisoindolin-
1-one 1b provided a non-cyclized product 5 in 49% yield. It
means that hydrogen at the ortho-position of Ar2 is necessary
for the [4 + 2]-cycloaddition process.
On the basis of the above control experiment results, a
reasonable mechanism of reaction was proposed (Fig. 1).
Initially, the removal of the hydroxyl group at the 3-hydroxy-2-
phenylisoindolin-1-one 1a generates 4π diene A with the use of
TfOH. Subsequently, the N-acyliminium cation A was attacked
by nucleophile 5-phenyl-2,3-dihydrofuran B,13 which produced
from 2a via the ring-opening/intramolecular cross-cyclo-
addition process, leading to coupling intermediate C, followed
by an intramolecular annulation to give intermediate D.
Finally, the deprotonation of intermediate D affords the final
product pentacyclic isoindolin-1-one 3a. The [4 + 2] cyclo-
addition with N-acyliminium cation A should preferentially
occur on the top face of 5-phenyl-2,3-dihydrofuran B, because
the other face of B might be shielded by the phenyl group,
which leads to the formation of (3aS,13bR,13cS)-3a as the
major diastereoisomer.
a Reaction conditions: 1 (0.3 mmol), 2d (0.45 mmol) and TfOH (3.5
equiv.) in 1,2-dichloroethane (DCE) (2 mL), 110 °C, 30 min. b Isolated
yield. The diastereomeric ratio was determined by the 1H NMR analysis
of products.
Scheme 2 Using the 1-cyclopropylethan-1-one 2p as the substrate.
In summary, a cascade reaction of 3-hydroxy-2-phenylisoin-
dolin-1-one and cyclopropyl ketone has been developed via a
TfOH mediated ring-opening/intramolecular cross-cyclo-
addition/[4 + 2]-cycloaddition process. The developed method-
ology provides straightforward access to pentacyclic isoindolin-
1-one derivatives under simple reaction conditions. Further
studies to explore the possibility for the synthesis of various
complicated isoindolinones are currently underway in our
laboratory.
Scheme 3 Experiments for mechanistic understanding.
Experimental section
General information
the ring-opening/intramolecular cross-cycloaddition process of All reactions were carried out under an air atmosphere.
cyclopropyl ketone 2 is a crucial step, we performed the reac- Various reagents were purchased from Aldrich, Acros or Alfa.
tion of 3-hydroxy-2-phenylisoindolin-1-one 1a with 5-methyl- Flash column chromatography was performed using silica gel
2,3-dihydrofuran 4 under the standard reaction conditions, (200–300 mesh). Analytical thin-layer chromatography was per-
resulting in the formation of product 3p in 50% yield. In formed using glass plates pre-coated with 200–300 mesh silica
addition, the dihydrofuran intermediate can be detected with gel impregnated with a fluorescent indicator (254 nm). NMR
GC-MS in the reaction. This result indicates that the dihydro- spectra were recorded in CDCl3 on Bruker NMR-400 (400 MHz)
furan might be the crucial intermediate, which was delivered and NMR-500 (500 MHz) spectrometers with TMS as an
from substrate 2 firstly.12 Next, treatment of (4-bromophenyl) internal reference. HRMS were recorded on an Agilent 6540
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Q-TOF mass spectrometer (ESI). MS were recorded on an
Agilent 7890A/5975C mass spectrometer (EI). Melting points
were determined on a SGW X-4B melting point apparatus.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (21402013) and the Advanced Catalysis and Green
Manufacturing Collaborative Innovation Center in Changzhou
University.
Procedure for the synthesis of compound 3-hydroxy-2-
arylisoindol-1-ones 1 14
All reactants 1 except 1h are known compounds. In a sealed
tube, to a solution of phthalic anhydride (10 mmol) in DCM
(20 mL), aniline was added (12 mmol). The reaction mixture
was stirred for 1 h at room temperature, then acetic anhydride
and sodium acetate were added, and the resulting mixture was
stirred at 90 °C for 3 h to afford the corresponding N-aryl-1H-
pyrrole-2,5-diones in 72–89% yields. Finally, to a solution of
N-aryl-1H-pyrrole-2,5-diones (0.803 g, 3.6 mmol) in THF
(36 mL) in an ice bath at 0–5 °C, NaBH4 (0.137 g, 3.6 mmol)
was added in portions over 10 min. Then, methanol (4 mL,
10 times) was added dropwise and the remaining NaBH4 was
quenched with 0.5 M HCl solution until pH 4. The solvent was
evaporated under reduced pressure and the residue was
extracted with ethyl acetate, washed with water (three times)
and dried over anhydrous Na2SO4. The organic layer was evap-
orated under vacuum to dryness, affording the pure product 1
in 68–79% yield.
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The authors declare no competing financial interest.
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