Synthesis of dibenzo[: A, d] cycloheptanoids via aryne insertion into 2-arylidene-1,3-indandiones

Article abstract of DOI:10.1039/c9ob01900f

A novel and unexpected aryne insertion cascade reaction on 2-arylidene-1,3-indandiones via conjugate addition of fluoride followed by formal C-C insertion is developed to afford dibenzo[a,d]cycloheptanoid derivatives in good yields with a single isomer. T

Full text of DOI:10.1039/c9ob01900f

Organic &
Biomolecular Chemistry
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Synthesis of dibenzo[a,d]cycloheptanoids via
aryne insertion into 2-arylidene-1,3-indandiones†
Cite this: Org. Biomol. Chem., 2019,
17, 9442
Nagaraju Payili,a,b Santhosh Reddy Rekula,a Anjaiah Aitha,a
V. V. S. R. N. Anji Karun Mutha,a Challa Gangu Naidub and
a
Satyanarayana Yennam
*
A novel and unexpected aryne insertion cascade reaction on 2-arylidene-1,3-indandiones via conjugate
addition of fluoride followed by formal C–C insertion is developed to afford dibenzo[a,d]cycloheptanoid
derivatives in good yields with a single isomer. This reaction represents a rare instance of cyclic enone
C–C bond insertion (acyl-alkenylation) in aryne chemistry. Interestingly, 2-arylidene-1,3-indandiones
bearing electron rich functional groups provided dibenz[a,c]anthracene-9,14-dione derivatives via [4 + 2]
cycloaddition followed by ring expansion.
Received 30th August 2019,
Accepted 11th October 2019
DOI: 10.1039/c9ob01900f
rsc.li/obc
Mono- and dibenzannulated carbocyclic frameworks are privi- bond of α-arylated cyclic ketones reported by Zeng et al.,9d
leged structural motifs, endowed with broad and important and similar aryne insertion into the C–C bond of cyclic 1,3-
biological activities.1 Among these, dibenzo[a,d]cyclohepta- diketones to furnish mono- and dibenzocycloheptanes and
noid scaffolds have found extensive applications in drug dis- cyclooctanes reported by Srihari et al.9e (Scheme 2). Due to
covery and attracted much attention, as they are the commonly their high importance, a flexible and rapid synthesis of diben-
occurring key structural units of biologically active natural pro- zocycloheptane libraries with further functionalization for
ducts, such as rubialatin B (1) shows cytotoxicity and a syner- high-throughput screening and further drug discovery research
gistic effect with TNF-α for NF-κB activation,2a radermachol (2) and a one-pot synthesis with multiple bond-forming trans-
is used in folk medicine,2b diptoindonesin D (3) has potent formations (MBFTs) and aryl group incorporation would be
antifungal activity and is cytotoxic against P-388 murine more practical and desirable.10
leukemia cells,2c and amurensinine (4) exhibits CNS activity
for the treatment of Parkinson’s and Alzheimer’s diseases2d bioactive scaffolds using 2-arylidene-1,3-indandiones,11 herein
(Scheme 1). we report a fluoride-anion-induced ring expansion of 2-aryl-
In continuation of our studies on the synthesis of valuable
Several synthetic approaches for the preparation of benzan- idene-1,3-indandiones by insertion of arynes into the C–C bond
nulated seven-membered frameworks have been reported. of cyclic enones for the first time (acyl-alkenylation of arynes).
These involve Friedel–Crafts reactions,3 ring-closing meta-
thesis,4 intermolecular cationic cyclization reactions,5 ene
reactions,6 intramolecular cycloadditions,7a–e [2 + 2] cyclo-
addition of alkenes and alkynes,7f–i and transition metal-
mediated hydroacylation.8 However, only a few methods have
been disclosed for the preparation of dibenzo[a,d]cyclohepta-
noids, which include the synthesis of iodo-substituted diben-
zocyclohepten-5-ones from iodine monochloride reported by
Chen et al.,9a aryne insertion into the C–C bond of cyclic
β-ketoesters to access mono- and dibenzocycloheptanes9c
recently reported by Stoltz et al.,9b aryne insertion into the C–C
aChemistry Services, GVK Biosciences Pvt. Ltd, Survey Nos: 125 (part) & 126,
IDA Mallapur, Hyderabad 500076, Telangana, India. E-mail: satya@gvkbio.com
bVignan’s Foundation for Science, Technology and Research (Deemed to be
University) (VFSTRU), Vadlamudi, Guntur 522213, Andhra Pradesh, India
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob01900f
Scheme 1 Biologically active dibenzo[a,d]cycloheptanoid derivatives.
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Table 1 Optimization of reaction conditionsa
Yieldb (%)
F− source
[equiv.]
18-c-6
[equiv.]
Time
(h)
Entry
Solvent
3a
4a
1
2
3
4
5
6
7
8
CsF (2.5)
CsF (2.5)
CsF (2.5)
CsF (2.5)c
KF (2.5)
—
—
—
—
2.5
2.5
2.5
5.0
2.5
—
MeCN
MeCN : PhMe
THF
MeCN
MeCN : PhMe
MeCN
MeCN
MeCN
THF
THF
16
16
16
8
16
16
10
16
16
6
10
5
10
5
35
74
40
62
20
10
15
35
15
15
42
5
5
10
5
KF (2.5)
KF (2.5)c
KF (5.0)d
KF (2.5)
9
10
11
5
—
5
TBAF (2.5)
TBAT (2.5)
—
THF
6
a Standard conditions: 1a (0.20 mmol), 2a (0.20 mmol), fluoride
source, solvent (3.0 mL). b Isolated yields. c Reaction temperature
80 °C. d 2a (0.40 mmol).
Scheme 2 Aryne insertion based approaches for benzannulated carbo-
cyclic motifs.
mixture of MeCN and PhMe decreased it (Table 1, entry 3).
Surprisingly, when the reaction was performed using 1.2 eq. of
It provides a straightforward, diastereoselective, and tran- 1a and 2.5 equiv. of KF/18-crown-6, dibenzo[a,d]cyclohepta-
sition-metal-free protocol for the creation of dibenzo[a,d]cyclo- noid 3a was formed in an improved yield of 74% and traces
heptanoid frameworks in a simple manner with a broad sub- of dibenz[a,c]anthracene-9,14-dione (4a) at rt in 16 h with
strate scope (Scheme 2).
complete conversion of the starting material 1a (entry 7,
As part of our research work on the development of tran- Table 1). To further optimize the yield and selectivity of the
sition metal free newer methodologies for the synthesis of bio- products, the effects of the fluoride source, temperature, addi-
active scaffolds, we sought a new synthetic route to obtain a tive, solvent, and stoichiometry were systematically studied
relatively rare and expensive polycyclic hydrocarbon, dibenz[a,c] (Table 1).
anthracene-9,14-dione (4a) from an in situ generated aryne 1a
Encouraged by these results, the generality and scope of the
and 2-arylidene-1,3-indandiones through [4 + 2]-cycloaddition domino reaction was examined by varying the electronic and
followed by ring expansion. Surprisingly, the fluoride-anion- steric properties of both 2-arylidene-1,3-indandione (1) and
induced reaction took a different course during our studies, arynes (2) (Table 2), under the optimized conditions (2-aryl-
where 2-arylidene-1,3-indandiones underwent aryne insertion idene-1,3-indandione (1a) (1.0 equiv.), aryne 2 (1.2 equiv.), KF
into the C–C bond of cyclic enone (acyl-alkenylation) to (2.5 equiv.), 18-crown-6 (2.5 equiv.), CH3CN, 25 °C, 16 h). As
provide
(E)-11-benzylidene-5H-dibenzo[a,d][7]annulene-5,10 outlined in Table 2, electronic variations in the aryl substituent
(11H)-dione (3a) as a major product. This unexpected aryne on the olefin β-position of 2-arylidene-1,3-indandiones (1) were
insertion comprised conjugate addition by fluoride, ring well tolerated. Electronically neutral as well as rich substitu-
expansion and elimination process, all occurring in a single ents on the aryl group afforded products (3a & 3b) in good to
step leading to the dibenzo[a,d]cycloheptanoid 3a in good moderate yields. Interestingly, electron withdrawing substitu-
yield as a single isomer.
ents such as fluoro, chloro, bromo, iodo, and trifluoro
Our study was initiated with the optimization of reaction methoxy groups were also tolerated and provided the desired
conditions for this unusual transformation of arynes. In an products 3c–h in good yields. Moreover, the presence of the tri-
initial experiment, the treatment of 2-benzylidene-1,3-indan- fluoro methoxy substituent on the aryl group at the ortho posi-
dione (1a) with aryne 2a (1.2 equiv.) generated in situ from tion had no steric effect on the reaction outcome and furn-
2-(trimethylsilyl)aryl triflate (2a) using CsF and MeCN as the ished the desired product (3k). It is noteworthy that the reac-
solvent resulted in the formation of dibenz[a,c]anthracene- tion of 3,4-dimethyl benzyne also provided the desired pro-
9,14-dione (4a) in 35% yield, along with dibenzo[a,d]cyclohep- ducts 3l & 3m in good yields. The reaction of unsymmetrical
tanoid 3a (10%), while 24% of 1a remained unreacted. We 4-silyl benzyne failed to furnish the expected product 3o under
noted that increasing the reaction temperature didn’t have any the optimized conditions. Most notably, unsymmetrical
remarkable effect on the yield of 3a or 4a (Table 1, entry 2), 4-fluoro benzyne resulted in the formation of a 4 : 1 insepar-
while changing the solvent from acetonitrile to THF or a able regioisomeric mixture of products 3n & 3n′ with a 72%
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Table 2 Substrate scope of dibenzo[a,d]cycloheptanoidsa,b,c
Table 3 Substrate scope of dibenz[a,c]anthracene-9,14-dionesa,b,c
a Reaction conditions:
1 (0.20 mmol), 2a (0.40 mmol), CsF
(1.00 mmol), CH3CN (3.0 mL), 80 °C and 6 h. b Yields of the isolated
products with respect to 1. c Only a negligible amount of [2 + 2] cyclo-
addition products observed. d Regioisomeric ratio determined by 1H
NMR analysis.
1.00 g) affording the product 3a (1.13 g) in 74% yield. The
structure of 3a and its E-configuration was confirmed by NMR
studies (see the ESI†).
Further experimentation and detailed analysis of the opti-
mized reaction conditions (Table 1, entry 4) indicated that this
protocol can generate dibenz[a,c]anthracene-9,14-dione (4a).
The structure of 4a was confirmed by spectroscopic analysis
and by comparison of the NMR data with structurally similar
compounds reported in the literature.13 After finding the
a Reaction conditions: 1 (0.20 mmol), 2 (0.60 mmol), KF (1.00 mmol),
18-crown-6 (1.00 mmol), CH3CN (3.0 mL), 25 °C, 6 h. b Yields of the
isolated products with respect to 1. c Only a negligible amount of optimal conditions for dibenz[a,c]anthracene-9,14-dione, we
[4 + 2] cycloaddition products observed. d Regioisomeric ratio deter-
examined the substrate scope (Table 3). Aryne precursor 2a
reacted smoothly with both 2-arylidene-1,3-indandiones 1a
mined by 1H NMR analysis.
and 1b to furnish the corresponding quinone products 4a and
4b in moderate yields. We didn’t observe products 4c and 4d
combined yield. The major regioisomeric structure of 3n was from the corresponding 2-arylidene-1,3-indandiones 1c and
further confirmed by NOE studies (ESI;† page-33). 1d. However, para methoxy substituted 2-benzylidene-1,3-
Furthermore, to gain insight into the reaction pathway and indandione 1e afforded the corresponding dibenz[a,c]anthra-
mode of addition of an enolate (nucleophilic addition) to cene-9,14-dione 4e in moderate yield. The reaction of unsubsti-
arynes, we have performed the reaction using the unsymmetri- tuted 4-methyl benzyne with 2-benzylidene-1,3-indandione 1a
cal 3-methoxybenzyne under the optimized conditions and afforded substituted quinones 4f & 4f′ with a 1 : 1 inseparable
afforded the single regioisomer 3p in 73% yield, which con- regioisomeric mixture. To our dismay, the reaction of 4-silyl
firms that the nucleophilic enolate addition on 3-methoxyben- benzyne with 2-arylidene-1,3-indandiones 1a also failed to
zyne is more favoured at the meta-position than the ortho-posi- furnish the expected product 4g under the optimized
tion,12 and the selective formation of 3p is a clear indication conditions.
that the present insertion reaction proceeds via conjugate
To clarify the reaction mechanism, the following control
addition by fluoride followed by enolate addition and ring experiments were carried out (Scheme 3): (i) the one-pot reac-
expansion. The structure of 3p was further confirmed by NOE tion of 1,3-indandione (5), benzaldehyde (6) and benzyne pro-
studies (ESI;† page-37). Unfortunately, the reaction of an elec- vided 1a and 7 and traces of 3a; the treatment of 7 with benz-
tron-rich 2-arylidene-1,3-indandione having a MeO substituent aldehyde (6) under optimized conditions failed to provide the
at the 4-position of the aryl group did not work under the stan- desired product (3a), this indicates that the reaction is not pro-
dard reaction conditions to provide the desired product (3q). ceeding through either a one pot or from dibenzocycloocta-
However, to demonstrate the practical utility of this method- none 7; (ii) further treatment of 2-benzyl-1,3-indandione (8)14
ology, this reaction was also performed on a gram scale (1a; with benzyne (2a) led to the benzyl substituted indenone
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of some push–pull electronics in the whole system that retards
fluoride addition and permits another reaction pathway (4 + 2
cycloaddition & ring expansion).
In conclusion, we have demonstrated, for the first time, the
synthesis of diastereoselectively substituted dibenzo[a,d]cyclo-
heptanoid 3a and dibenz[a,c]anthracene-9,14-diones (4) via
conjugate addition by fluoride followed by ring expansion and
[4 + 2]-cycloaddition/ring expansion of in situ generated arynes
2a with 2-arylidene-1,3-indandione (1) in moderate to good
yields. This protocol will find wide synthetic applications in
natural product synthesis and SAR (structure–activity-relation-
ship) studies. Easily accessible starting materials, milder reac-
tion conditions, good yields, and excellent diastereo-
selectivities are the salient features of the methodology.
Further studies on the mechanism, extension of the reaction
scope and medicinal chemistry are in progress in our labora-
tory and shall be reported in due course.
Scheme 3 Control experiments.
derivative 9 without opening of the 4-membered ring. These
results support that these unconventional reactions with
benzyne are taking place in a single step through different
mechanisms.
Based on the aforementioned results and literature pre-
cedent,10 a probable mechanism for the synthesis of dibenzo
General experimental procedures
[a,d]cycloheptanoid 3a and dibenz[a,c]anthracene-9,14-dione Dibenzo[a,d]cycloheptanoid derivatives 3a–o
(4a) is outlined in Scheme 4. Initially, 2-benzylidene-1,3-indan-
To a stirred solution of 2-benzylidene-1H-indene-1,3(2H)-dione
dione (1a) (electron-poor/neutral substrates) transformed into
the corresponding intermediate 10 through conjugate addition
by fluoride, which subsequently created an enolate and
attacked onto benzyne generated from 2a, thus affording an
aryl anion, which can undergo intramolecular nucleophilic
attack on the carbonyl group with the formation of cyclobu-
tene intermediate 11. Our attempts to trap compound 10 with
electrophiles failed confirming the fluoride addition. The
eventual elimination of fluoride gives rise to the desired
product with a preferred double bond geometry. However, in
the case of 2-arylidene-1,3-indandione (1) having an electron-
rich/neutral group in the presence of CsF, the 2-arylidene-1,3-
indandione (1) could undergo [4 + 2]-cycloaddition to provide
intermediate 12. Furthermore, intermediate 12 can undergo
intramolecular nucleophilic attack on the carbonyl group with
(0.200 g, 8.57 mmol) in dry MeCN (10 mL) were added
18-crown-6-ether (0.564 g, 2.13 mmol) and potassium fluoride
(0.247 g, 4258.0 mmol) under an argon atmosphere and to this
stirring solution was added appropriate aryl silyl triflate at
room temperature. Then the reaction mixture was stirred at rt
until the completion of the reaction (monitored by TLC (5%
EtOAc/pet ether)). The reaction mixture was diluted with EtOAc
(20 mL) and water (20 mL), the organic layer was separated
and then the aq. layer was extracted with EtOAc (2 × 10 mL).
The combined organic layers were washed with brine solution
(20 mL), dried over anhydrous Na2SO4 and concentrated
in vacuo. The crude reaction mixture was purified by column
chromatography using hexanes/ethyl acetate (9 : 1 v/v) as the
eluent affording compounds 3a–o.
the formation of a strained tricyclic alcohol intermediate 13, Dibenz[a,c]anthracene-9,14-dione derivatives (4a–g)
which upon retro-aldol reaction (ring expansion) and air oxi-
dation affords the dibenz[a,c]anthracene-9,14-dione (4). Overall
the fluoride addition is prompted by the electron withdrawing
To a stirred solution of 2-benzylidene-1H-indene-1,3(2H)-dione
(0.200 g, 8.57 mmol) in dry ACN (10 mL) was added cesium flu-
oride (0.389 g, 25.640 mmol), then added appropriate aryl silyl
groups on the arylidine group. When R of the arylidine is an
triflate and the reaction mixture was stirred at the same temp-
electron donating group, there is extended conjugation by way
erature for 6 h; TLC analysis (5% EtoAc/pet ether) showed the
completion of the reaction. The reaction mixture was diluted
with EtOAc (20 mL) and water (20 mL), the organic layer
was separated and then the aq. layer was extracted with EtOAc
(2 × 10 mL). The combined organic layers were washed with
brine solution (20 mL), dried over anhydrous Na2SO4 and con-
centrated in vacuo. The crude reaction mixture was purified by
column chromatography using hexanes/ethyl acetate (9 : 1 v/v)
as the eluent affording compounds 4a–f.
Conflicts of interest
Scheme 4 Proposed mechanism.
There are no conflicts to declare.
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