Regioselective quadruple domino aldolization/aldol condensation/Michael/ SNAr-cyclization: Construction of hexacyclic indeno-fused C-nor-D-homo-steroid frameworks

Article abstract of DOI:10.1016/j.tet.2014.01.059

An operationally simple and highly atom-economic anionic quadruple domino reaction sequence for the synthesis of hexacyclic indeno-fused naphthalene/quinoline molecules having structural resemblance with the C-nor-D-homo-steroid nucleus has been developed. Promoter and solvent specificity, regioselectivity and mechanistic details were experimentally established. Catalyst concentration and solvent dependent switching of domino steps creating four new C-C bonds are discussed.

Full text of DOI:10.1016/j.tet.2014.01.059

Tetrahedron 70 (2014) 2190e2194
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective quadruple domino aldolization/aldol condensation/
Michael/SNAr-cyclization: construction of hexacyclic indeno-fused
C-nor-D-homo-steroid frameworks
,
,
,
,
y
Tanmoy Chanda a y, Sushobhan Chowdhury a y, B. Janaki Ramulu a y, Suvajit Koleya
,
Raymond C.F. Jones b, Maya Shankar Singh a
,
*
a Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
b Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
An operationally simple and highly atom-economic anionic quadruple domino reaction sequence for the
synthesis of hexacyclic indeno-fused naphthalene/quinoline molecules having structural resemblance
with the C-nor-D-homo-steroid nucleus has been developed. Promoter and solvent specificity, re-
gioselectivity and mechanistic details were experimentally established. Catalyst concentration and sol-
vent dependent switching of domino steps creating four new CeC bonds are discussed.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 21 November 2013
Received in revised form 15 January 2014
Accepted 22 January 2014
Available online 5 February 2014
Keywords:
Anionic quadruple domino reaction
Regioselective
ortho-Aroylacetophenone
Indeno-fused naphthalene
Indeno-fused quinoline
1. Introduction
skeletons having structural similarity with the C-nor-D-homo-ste-
roid nucleus, an interesting framework from the synthetic per-
The design and development of new strategies with minimal
environmental impact1 is an appealing and demanding area of cur-
rent organic synthesis. Cascade/domino strategies2 being a powerful
subgroup of the broader category of one-pot reactions, have emerged
as one of the most intriguing synthetic tools due to their atom-/step-/
cost-economy, and labour effectiveness. Recently, utilizing domino
protocols several bioactive molecules and natural products have
been synthesized.3 Tietze and co-workers synthesized a variety of
hetero- and homo-steroids via domino Knoevenagel/hetero Diel-
seAlder approach for the first time.3e,f In spite of numerous articles
available on the double and triple domino reactions, there are limited
reports on quadruple domino reaction.3gej
spective (Fig. 1). Steroidal alkaloids jervine,5a,b cytotoxic
nakiterpiosin and nakiterpiosinone (isolated from the Okinawan
sponge Terpios hoshinota),5c,d and cyclopamine5e,f are some typical
representatives of C-nor-D-homo-steroids (Fig. 2).5
In this manuscript, we utilized ortho-aroylacetophenones (ac-
cessible in moderate to good yields by the reported method4) in an
anionic quadruple domino reaction that involves intramolecular-
aldolization/aldol-condensation/intermolecular-Michael/SNAr-cy-
clization, and synthesized complex hexacarbocyclic/heterocyclic
Fig. 1. Schematic representation of the quadruple domino reaction.
Eicher and Pfister first utilized substituted ortho-aroylaceto-
phenones for acid-catalyzed aldol cyclization and base-catalyzed
dehydration towards the synthesis of substituted 3-hydroxy-3-
phenylindanones and substituted 3-phenylindenones, respective-
ly.6a Harrowven and co-workers synthesized 3-arylindenone de-
rivative, isolated from the fruits of Virola sebifera by acid-mediated
aldol condensation of substituted ortho-aroylpropiophenone.6b
* Corresponding author. Tel.: þ91 542 670 2502; fax: þ91 542 236 8127; e-mail
addresses: mssinghbhu@yahoo.co.in, mayashankarbhu@gmail.com (M.S. Singh).
y
Fax: þ91 542 2368127.
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.01.059

T. Chanda et al. / Tetrahedron 70 (2014) 2190e2194
2191
continuous monitoring. It was found that the area and intensity of
the TLC spot corresponding to 4a increased continuously, whilst
those of 2a and 3a decreased simultaneously. However, complete
conversion was not observed even after 12 h. We next decided to
increase the base proportion and with 0.32 mL (4 mmol NaOH) of
aqueous NaOH (50% w/v) complete conversion of 1a to the desired
4a was observed in 86% isolated yield within 4 h. Hence, 4 equiv of
NaOH (50% w/v aq solution) in 3 mL of DMSO at room temperature
was recognized as the optimum conditions for the synthesis of 4
from 1 (Table 1, entry 3). The similar result was obtained when we
performed the reaction of pure 2a with 3a under the previously
optimized reaction conditions. Further, to gain more mechanistic
insight of the reaction, 2a and 3a separately was subjected to op-
timized domino reaction conditions. In the case of 2a, the desired
product 4a was obtained in 85% yield. However, in the case of 3a,
a complex TLC pattern showing several very close spots with no
trace of the desired molecule 4a was observed. The progress of the
reaction is illustrated in the TLC diagram shown below (Fig. 3).
Fig. 2. Natural products containing C-nor-D-homo-steroid nucleus.
Inspired by these two reports, we wish to exploit ortho-aroylace-
tophenones and selected prolines to pursue our desired domino
protocol as proline holds both an acidic and basic component.
2. Results and discussion
Initially, we attempted the desired domino reaction using ortho-
benzoylacetophenone 1a (1.0 mmol) in DMSO (3.0 mL) in the
presence of (S)-proline (0.3 mmol) at room temperature. Un-
fortunately, our supposition failed and proline was found to be
ineffective to cyclize 1a, and the starting material 1a was recovered
as such even after 24 h of stirring (Table 1, entry 1). The above
failure may be due to the inability to form the enamine in-
termediate (essential for the intramolecular aldolization) because
of steric hindrance.
Fig. 3. Progress of the desired domino reaction.
Table 1
Base catalyzed conversion of 1aa
The scope and viability of this protocol was determined by using
12 different ortho-aroylacetophenones 1 with substitutions (both
electron-donating and electron-withdrawing) at various positions.
The reaction proceeded smoothly in most of the cases affording our
desired product 4 in good yields (Table 2). Interestingly, when we
Table 2
Entry
Catalyst (mmol)
Solvent
Time
Product (yield in %)
Formation of 4 via domino aldol/Michael/SNAr-cyclizationa
2a
3a
4a
1
2
3
4
5
6
7
8
9
(S)-Proline (0.30)
50% aq NaOH (0.30)
50% aq NaOH (4.00)
50% aq NaOH (0.05)
NaOH (4.00)
DMSO
DMSO
DMSO
DMSO
Water
DMSO
DMSO
DMSO
DMSO
DMSO
24 h
3 h
4 h
2 min
4 h
4 h
5 min
4 h
3 h
nr
47
d
93
12
d
92
16
d
d
80
d
d
22
86
d
d
NaOH (4.00)
Trace
d
50% aq KOH (0.05)
50% aq KOH (4.00)
K2CO3 (0.05)
Complex TLC
94
Complex TLC
d
d
10
K2CO3 (4.00)
8 h
The bold entries signifies the optimized reaction conditions for the concerned
domino protocol.
a1 mmol of 1a was dissolved in 3 mL of solvent, appropriate proportion of catalyst
was added and stirred at room temperature; nr¼no reaction.
To minimize steric congestion, we investigated Bronsted bases,
such as NaOH, KOH and K2CO3 as catalysts (Table 1). Thus, 1a
(1.0 mmol) in 3.0 mL of DMSO was treated with 0.024 mL (0.3 mmol
NaOH) of aqueous NaOH solution (50% w/v) and the reaction mixture
was stirred at room temperature (Table 1, entry 2). Notably, 1a was
completelyconsumed within 3 h. The work up of the reaction mixture
provided 2a in 47% yield, identified as 3-hydroxy-3-phenylindanone
as major product along with 3-phenylindenone 3a in 16% yield and
the
desired
13b-phenylbenzo[a]indeno[1,2-c]fluorene-9,14-
(8bH,13bH)-dione 4a in 22% yield. The structure of 4a was assigned on
the basis of its satisfactory spectral and crystallographic analysis, and
was found tohave resemblancetotheC-nor-D-homo-steroidnucleus.7
Attracted by this result, we attempted to optimize the yield of
4a. The above reaction was stirred for a further period of time with
a1 mmol of 1 was dissolved in 3 mL of DMSO and 4 mmol of
50% aq. NaOH solution was poured and stirred at room
b
c
temperature; Isolated pure yield; Intermediate Michael adduct
4MA was the major product.

2192
T. Chanda et al. / Tetrahedron 70 (2014) 2190e2194
used 0.004 mL (0.05 mmol NaOH) of aqueous NaOH (50% w/v) in
DMSO at room temperature, 2a was obtained in quantitative yield
within 2 min (Table 1, entry 4 and Table 3). Next, when the reaction
was performed using 4 equiv of NaOH in water (3 mL), 3a was
obtained as the major product (80% isolated yield) along with 2a.
However, 4a was not formed even in trace after 4 h of stirring (Table
1, entry 5). NaOH (4 mmol) in DMSO initially triggered the reaction
and after 2 min 1a was completely converted to 2a, and a faint spot
of desired product 4a was observed. Further stirring of the reaction
provided several spots on TLC, and after 4 h only a trace of 4a was
observed (Table 1, entry 6). Next, a catalytic amount of KOH or
K2CO3 (0.05 equiv) provided 2a quite efficiently (Table 1, entries 7
and 9), but failed to produce 4a, even after employing 4 mmol of
these inorganic bases (Table 1, entries 8 and 10). Thus, from the
above observations it may be suggested that NaOH as promoter and
DMSO/H2O mixture as solvent is specific for the completion of the
desired domino reaction.
intermediates diminished and converted to the desired product 4a
(monitored by TLC) (Fig. 3).
To verify the regioselectivity of step ‘e’ in Scheme 1 of the
multiple domino reaction, we used 1e, 1f, 1g and 1j as initial sub-
strates (Scheme 2). Exclusive formation of 4f offers a proof in favour
of specific intramolecular nucleophilic attack of in situ generated
enolic nucleophile in the Michael adduct 4MAf to the less hindered
para-position with respect to the chloro group of 3-chlorophenyl. A
similar result was obtained in case of substrate 1c, where
regioisomer 4c was formed exclusively. In case of substrate 1j the
nucleophilic attack occurs exclusively at C-2 of the pyridine ring in
the intermediate 4MAj leading to the exclusive formation of 4j. A
similar trend of regioselectivity was observed in case of 4k and 4l.
The observed steric effect domination of the product formation is
mirrored in the yield, 4e greater than 4f. Structure of the exact
regioisomers (4c, 4f, 4j, 4k and 4l) has been fully characterized by
their satisfactory spectral (1H & 13C NMR and HRMS) studies along
with crystallographic analysis of one of the representative molecule
4f.7 In the case of substrate 1i a lower yield of desired product 4i
was obtained as the final SNAr step is somewhat less favourable due
to increase of electron density and steric crowding in the aromatic
ring.
Table 3
Formation of 2 via intramolecular aldolization of 1a
a1 mmol of 1 was dissolved in 3 mL of DMSO and 0.05 mmol
of 50% aq. NaOH solution (0.004 mL) was added and the
mixture stirred at room temperature; bIsolated pure yield.
Scheme 2. Regioselectivity in final domino SNAr step.
However, when we used 1g as the initial substrate, Michael
adduct 4MAg was formed after 6 h, which was isolated and fully
characterized. Interestingly, when the reaction was continued
for another 18 h, 13b-(2-chlorophenyl)benzo[a]indeno[1,2-c] flu-
orene-9,14-(8bH,13bH)-dione (4g) was obtained in very low
yield by intramolecular SNAr reaction via chloride displacement.
The similar trend was observed in the case of substrate 1h also
(Fig. 4).
On the basis of the above experimental results together with the
related reports, a plausible reaction scenario for this domino re-
action is outlined in Scheme 1. The first step in the mechanism is
believed to be intramolecular aldolization of 1a to produce 2a. Part
of 2a undergoes dehydration to complete aldol condensation fur-
nishing 3a, which further undergoes Michael addition with the
enolic form (20a) of 2a to provide the Michael adduct 4MAa. The
Michael adduct 4MAa undergoes consecutive dehydration, SNAr-
cyclization and oxidative aromatization to furnish the desired
product 4a. Intermediates 2a and 3a were isolated at the initial
stage of the reaction. With the progress of the reaction these
Fig. 4. Crystal structures of 4b, 4d and 4f.
3. Conclusion
In conclusion, we have synthesized some novel indeno-fused
naphthalene and quinoline molecules having structural similarity
with the C-nor-D-homo-steroid nucleus via an anionic quadruple
domino strategy. This domino protocol involves intramolecular-
aldolization/aldol-condensation/intermolecular-Michael/SNAr-cy-
clization sequence, which is the first of its kind. Investigation of
each step of the domino reaction was explored experimentally to
propose a reasonable mechanistic sequence.
Scheme 1. Mechanism of the anionic multiple domino reaction.

T. Chanda et al. / Tetrahedron 70 (2014) 2190e2194
2193
4. Experimental section
2H); 13C NMR (75 MHz, CDCl3)
d
203.8, 157.9, 143.7, 135.8, 135.4,
133.0, 129.4, 128.4, 126.4, 125.1, 123.0, 77.8, 55.7.
4.1. General
4.4.4. 3-(3-Chlorophenyl)-3-hydroxy-2,3-dihydro-1H-inden-1-one
1H and 13C NMR spectra were recorded at 300 and 75 MHz,
(2f). Orange sticky solid; 1H NMR (300 MHz, CDCl3)
d 7.67e7.57 (m,
respectively. Chemical shift (
d
) values are given in parts per million
2H), 7.46e7.35 (m, 3H), 7.21e7.09 (m, 3H), 3.94 (s, 1H), 3.10 (dd,
(ppm) with reference to tetramethylsilane (TMS) as the internal
standard. Coupling constant (J) values are given in Hertz (Hz). High
resolution mass spectra were recorded using ESI method. Organic
solvents used were dried by standard methods wherever necessary.
Commercially obtained reagents were used as such without further
purification. All the reactions were monitored by thin-layer chro-
matography (TLC) using silica gel 60 F254 precoated plates. Column
chromatography was carried out using silica gel with
100e200 mesh or with anhydrous alumina. Mixture of hexane/
ethyl acetate or MeOH/DCM in appropriate proportion (determined
by TLC analysis) was used as eluent solvent system.
J1¼18.9 Hz, J2¼27 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 203.7, 157.8,
147.3, 135.9, 135.5, 134.3, 129.6, 129.6, 127.4, 125.3, 125.1, 123.3,
123.1, 77.8, 55.7; HRMS (ESI-TOF) of
C15H11ClO2¼281.0340
[MþNaþ] (calculated 281.0340).
4.4.5. 6-Chloro-3-hydroxy-3-(pyridin-3-yl)-2,3-dihydro-1H-inden-
1-one (2k). Brown sticky solid; 1H NMR (300 MHz, CDCl3)
8.52
d
(broad, 1H), 8.35 (broad, 1H), 7.70e7.59 (m, 3H), 7.34e7.26 (m, 3H),
3.26 (dd, J1¼19.2 Hz, J2¼32.1 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d
201.3, 155.5, 148.2, 146.3, 140.9, 137.2, 136.4, 136.0, 133.3, 126.6,
123.5, 123.1, 76.5, 56.0; HRMS (ESI-TOF) of C14H10ClNO2¼260.0471
[MþHþ] (calculated 260.0473).
4.2. Typical procedure for the synthesis of 2
4.4.6. 3-Phenylindenone9 (3a). Orange oil; 1H NMR (300 MHz,
One mmol of 1 was taken in a round bottom flask and dissolved
in DMSO (3 mL), 0.05 mmol (0.004 mL) of freshly prepared 50%
aqueous NaOH (2.5 g in 5 mL distilled water) was added and stirred
at room temperature. After completion of the reaction (monitored
by TLC), 30 mL water was added to it and product was extracted
with ethyl acetate (20 mLꢀ3). Combined organic layer was washed
with water and brine solution and dried over anhydrous Na2SO4.
Ethyl acetate was evaporated and crude was purified by column
chromatography using EtOAc/Hexane mixture as the mobile phase
and silica gel (100/200 mesh) as the stationary phase to afford pure
2.
CDCl3)
(s, 1H).
d 7.58 (broad, 1H), 7.44 (broad, 4H), 7.32e7.09 (m, 3H), 5.93
4.4.7. 13b-Phenylbenzo[a]indeno[1,2-c]fluorene-9,14(8bH,13bH)-di-
one (4a). Orange red solid; mp 254e257 ꢁC; 1H NMR (300 MHz,
CDCl3)
1H), 7.53e7.43 (m, 6H), 7.29e7.23 (m, 4H), 7.14 (d, J¼6.3 Hz, 2H),
3.98 (s, 1H); 13C NMR (75 MHz, CDCl3)
201.4, 194.7, 156.8, 151.8,
143.2, 141.3, 137.0, 134.8, 134.1, 133.7, 133.0, 132.4, 131.7, 131.2, 130.7,
129.0, 128.8, 127.8, 127.1, 126.6, 125.6, 123.4, 122.6, 122.4, 110.0,
100.6, 66.0, 51.6; CCDC 875292.
d
8.19e8.15 (m, 2H), 7.85e7.77 (m, 2H), 7.71 (t, J¼7.35 Hz,
d
4.3. Typical procedure for the synthesis of 4
4.4.8. 2,11-Dimethyl-13b-phenylbenzo[a]indeno
9,14(8bH,13bH)-dione (4b). Red solid; mp 262e264 ꢁC; 1H NMR
(300 MHz, CDCl3)
[1,2-c]fluorene-
One mmol of 1 was taken in a round bottom flask and dissolved
in DMSO (3 mL), 4 mmol (0.32 mL) of freshly prepared 50% aqueous
NaOH (2.5 g in 5 mL distilled water) was added and stirred at room
temperature. After completion of the reaction (monitored by TLC)
30 mL water was added to it and product was extracted with ethyl
acetate (20 mLꢀ3). Combined organic layer was washed with water
and brine solution and dried over anhydrous Na2SO4. Ethyl acetate
was evaporated and crude was purified by column chromatography
using EtOAc/Hexane mixture as eluent (4aei). In case of synthesis
of 4jel extraction was performed using solvent DCM instead of
EtOAc and column was done with MeOH/DCM solvent system in
appropriate proportion using neutral alumina as stationary phase.
d
8.14 (d, J¼7.5 Hz, 1H), 8.05 (d, J¼8.1 Hz, 1H),
7.66e7.63 (m, 2H), 7.54e7.42 (m, 4H), 7.23e7.19 (m, 5H), 7.13 (d,
J¼6.6 Hz, 2H), 3.95 (s, 1H), 2.42 (s, 3H), 2.33 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 201.6, 195.1, 154.5, 151.7, 143.6, 139.4, 138.5, 138.0,
137.2, 136.1, 134.2, 133.4, 132.9, 132.8, 131.6, 131.2, 130.4, 128.8,
128.3, 127.8, 127.0, 126.7, 125.7, 123.7, 123.4, 122.3, 66.2, 51.3, 21.2,
21.0; CCDC 898556.
4.4.9. 6-Methyl-13b-(m-tolyl)benzo[a]indeno[1,2-c]fluorene-
9,14(8bH,13bH)-dione (4c). Orange red solid; mp 256e258 ꢁC; 1H
NMR (300 MHz, CDCl3)
d
8.17 (d, J¼7.8 Hz, 1H), 7.96 (s, 1H), 7.83 (t,
J¼7.35 Hz, 2H), 7.70 (t, J¼7.35 Hz, 1H), 7.42e7.24 (m, 6H), 7.15 (t,
J¼7.95 Hz, 1H), 7.02 (d, J¼7.2 Hz, 1H), 6.90 (broad, 2H), 3.94 (s, 1H),
4.4. Characterization data of the synthesized molecules
2.46 (s, 3H), 2.23 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 201.9, 194.7,
157.1, 151.8, 143.2, 141.4, 138.4, 137.5, 136.9, 134.7, 133.8, 132.9, 132.4,
132.0, 131.5, 131.2, 130.7, 129.0, 128.6, 128.0, 127.9, 127.7, 127.1, 126.3,
123.8, 123.4, 122.5, 122.4, 65.7, 51.7, 21.5, 21.5; HRMS (ESI-TOF) of
4.4.1. 3-Hydroxy-3-phenylindanone8 (2a). Yellow gelly; 1H NMR
(300 MHz, CDCl3)
7.41e7.31 (m, 2H), 7.24e7.18 (m, 5H), 3.04 (s, 2H), 2.90 (broad, 1H);
13C NMR (75 MHz, CDCl3)
203.8, 158.2, 145.1, 135.7, 129.3, 128.4,
d
7.67 (d, J¼7.5 Hz, 1H), 7.56 (t, J¼7.05 Hz, 1H),
C
32H22O2¼439.1691 [MþHþ] (calculated 439.1693).
d
127.3, 127.2, 125.2, 125.1, 124.9, 123.0, 78.3, 55.9.
4.4.10. 2,11-Dichloro-13b-phenylbenzo[a]indeno
9,14(8bH,13bH)-dione (4d). Orange red solid; mp 285e287 ꢁC; 1H
NMR (300 MHz, CDCl3)
8.10 (d, J¼8.1 Hz, 2H), 7.79e7.38 (m, 7H),
7.25 (broad, 4H), 7.10e7.08 (m, 2H), 4.00 (s, 1H); 13C NMR (75 MHz,
CDCl3) 200.1, 193.1, 154.7, 151.8, 142.4, 139.1, 138.5, 135.5, 134.8,
[1,2-c]fluorene-
4.4.2. 3-Hydroxy-6-methyl-3-phenyl-2,3-dihydro-1H-inden-1-one
d
(2b). Yellow gelly; 1H NMR (300 MHz, CDCl3)
d
7.58 (s, 1H), 7.48 (d,
J¼7.8 Hz, 1H), 7.34e7.25 (m, 6H), 3.16 (s, 2H), 2.50 (s, 1H), 2.44 (s,
3H); 13C NMR (75 MHz, CDCl3)
203.9, 155.9, 145.4, 139.5, 136.8,
d
d
134.7, 134.0,133.6, 133.2, 132.2,131.9, 131.8, 129.0,128.1, 127.6, 127.4,
126.5, 125.7, 123.3, 123.2, 66.2, 51.3; CCDC 891987.
135.9, 128.3, 127.1, 124.9, 122.8, 78.0, 56.3, 21.1; HRMS (ESI-TOF) of
C
16H14O2¼261.0886 [MþNaþ].
4.4.11. 7-Chloro-13b-(4-chlorophenyl)benzo[a]indeno[1,2-c]fluorene-
9,14(8bH,13bH)-dione (4e). Orange red solid; mp 228e230 ꢁC; 1H
4.4.3. 3-(4-Chlorophenyl)-3-hydroxy-2,3-dihydro-1H-inden-1-one
(2e). Light yellow sticky solid; 1H NMR (300 MHz, CDCl3)
NMR (300 MHz, CDCl3)
d
8.15e8.07 (m, 2H), 7.86 (d, J¼7.5 Hz, 1H),
d
7.64e7.56 (m, 2H), 7.44 (t, J¼7.2 Hz, 1H), 7.36 (d, J¼7.5 Hz, 1H),
7.73 (t, J¼7.95 Hz, 2H), 7.44 (broad, 5H), 7.32e7.22 (m, 3H), 7.06 (d,
7.26e7.23 (m, 4H), 4.04 (s, 1H), 3.09 (dd, J1¼19.05 Hz, J2¼29.9 Hz,
J¼8.4 Hz, 2H), 3.87 (s, 1H); 13C NMR (75 MHz, CDCl3þDMSO-d6)

2194
T. Chanda et al. / Tetrahedron 70 (2014) 2190e2194
d
201.1, 191.2, 157.8, 152.1, 139.2, 137.5, 137.2, 136.5, 136.4, 135.0,
124.3, 123.9, 123.7, 122.9, 122.0, 67.9, 50.2, 21.3, 21.0; HRMS (ESI-
134.6, 133.4, 133.2, 132.8, 131.0, 129.8, 128.8, 128.4, 127.6, 127.5,
126.2, 125.8, 123.1, 123.0, 121.9, 121.1, 64.7, 52.3; HRMS (ESI-TOF) of
C
TOF) C30H20N2O2¼441.1606 [MþHþ] (calculated 441.1598).
30H16Cl2O2¼517.0339 [MþKþ] (calculated 517.0159).
4.4.19. 1,30-Bis(2-chlorophenyl)-3-hydroxy-1H,10H-[1,20-biinden]-10-
one (4MAg). Orange solid; 1H NMR (300 MHz, CDCl3)
d
7.65 (d,
J¼7.2 Hz, 1H), 7.41e6.76 (m, 15H), 6.66 (d, J¼6.9, 1H), 6.39 (s, 1H);
13C NMR (75 MHz, CDCl3)
196.0, 173.2, 153.0, 145.2, 143.5, 143.1,
4.4.12. 6-Chloro-13b-(3-chlorophenyl)benzo[a]indeno[1,2-c]fluo-
rene-9,14(8bH,13bH)-dione (4f). Red solid; mp 290 ꢁC; 1H NMR
d
(300 MHz, CDCl3)
7.79e7.72 (m, 2H), 7.54e7.41 (m, 5H), 7.35e7.19 (m, 3H), 7.11e7.01
(m, 2H), 3.94 (s, 1H); 13C NMR (75 MHz, CDCl3)
200.4, 194.1, 155.7,
150.5, 145.1, 140.6, 136.7, 135.2, 134.8, 134.0, 133.4, 132.8, 132.0,
131.9, 131.0, 130.6, 130.2, 129.4, 129.3, 128.3, 127.6, 126.7, 125.6,
124.9, 123.8, 123.0, 122.4, 65.1, 51.4; CCDC 898787.
d
8.21e8.14 (m, 2H), 7.89 (d, J¼7.8 Hz, 1H),
138.5, 133.4, 132.4, 132.2, 131.8, 131.4, 131.2, 130.1, 130.0, 129.9,
129.9, 129.8, 129.7, 128.7, 128.4, 127.4, 127.0, 126.3, 122.7, 122.6,
121.8; ESI MS: m/z¼519 [MþK]þ; Anal. Calcd for C30H18Cl2O2: C,
74.85; H, 3.77. Found: C, 74.82; H, 3.19.
d
4.4.20. 1,30-Bis(2-fluorophenyl)-3-hydroxy-1H,10H-[1,20-biinden]-10-
one (4MAh). Orange solid; 1H NMR (300 MHz, CDCl3)
d 8.14 (d,
4.4.13. 13b-(2-Chlorophenyl)benzo[a]indeno[1,2-c]fluorene-
J¼7.5 Hz, 1H), 8.05 (d, J¼7.8 Hz, 1H), 7.83e7.77 (m, 2H), 7.66 (t,
J¼7.5 Hz,1H), 7.54e7.38 (m, 6H), 7.31e7.25 (m, 3H), 7.13 (t, J¼7.8 Hz,
1H), 7.04 (t, J¼7.5 Hz, 2H), 4.30 (s, 1H).
9,14(8bH,13bH)-dione (4g). 1H NMR (300 MHz, CDCl3)
d 8.80 (d,
J¼8.1 Hz, 1H), 8.61e8.58 (m, 2H), 8.25 (d, J¼7.8 Hz, 1H), 8.04 (d,
J¼7.5 Hz, 1H), 7.77e7.64 (m, 2H), 7.53e7.43 (m, 4H), 7.32e7.29 (m,
1H), 7.24e7.14 (m, 3H), 7.04 (d, J¼7.5 Hz, 1H), 5.08 (s, 1H); ESI MS:
m/z¼467 [MþNa]þ.
Acknowledgements
We gratefully acknowledge the generous financial support from
the Science and Engineering Research Board (Grant no. SB/S1/OC-
30/2013) and the Council of Scientific and Industrial Research
(Grant no. 02(0072)/12/EMR-II), New Delhi. Spectral help from Prof.
Ganesh Pandey, CBMR, Lucknow and Prof. Sandeep Verma, IIT
Kanpur is highly appreciated.
4.4.14. 13b-(2-Fluorophenyl)benzo[a]indeno[1,2-c]fluorene-
9,14(8bH,13bH)-dione (4h). 1H NMR (300 MHz, CDCl3)
d 8.83 (d,
J¼8.4 Hz, 1H), 8.61 (d, J¼8.1 Hz, 1H), 8.26 (d, J¼6.6 Hz, 2H), 8.05 (d,
J¼7.2 Hz, 1H), 7.76e7.67 (m, 2H), 7.56e7.45 (m, 5H), 7.34e7.25 (m,
4H), 5.42 (s, 1H).
Supplementary data
4.4.15. 7-Methoxy-13b-(4-methoxyphenyl)benzo[a]indeno[1,2-c]flu-
orene-9,14(8bH,13bH)-dione (4i). Red solid; mp 238e240 ꢁC; 1H
1H and 13C NMR spectra of all new compounds, experimental
procedures. Supplementary data related to this article can be found
at http://dx.doi.org/10.1016/j.tet.2014.01.059.
NMR (300 MHz, CDCl3)
d
8.20 (d, J¼7.8 Hz, 1H), 8.11 (d, J¼9 Hz, 1H),
7.82 (d, J¼7.5 Hz, 1H), 7.74e7.65 (m, 2H), 7.44e7.36 (m, 4H),
7.27e7.23 (m, 1H), 7.06e6.95 (m, 3H), 6.79 (d, J¼8.7 Hz, 2H), 3.89 (s,
4H), 3.73 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 201.4, 195.3, 162.0,
References and notes
158.5, 141.3, 136.7, 136.6, 135.5, 134.8, 132.8, 132.6, 131.3, 130.7,
130.6, 129.0, 127.8, 127.7, 127.3, 127.3, 123.4, 122.2, 121.1, 118.5, 117.2,
114.1, 113.5, 66.5, 55.4, 55.1, 51.1; HRMS (ESI-TOF) of
1. (a) Nicolaou, K. C.; Montagnon, T. Molecules that Changed the World: a Brief
History of the Art and Science of Synthesis and its Impact on Society; WILEY-VCH,
2008; (b) Russell, C. A.; Wilmot, S. A. H.; Campbell, V.; Coley, N. G. In Society and
Environment: A New History of British Chemical Industry; Russell, C. A., Ed.; The
Royal Society of Chemistry: 2000; (c) Lesch, J. E. The German Chemical Industry in
the Twentieth Century; Kluwer Academic, 2000.
C
32H22O4¼471.1596 [MþHþ] (calculated 471.1591).
4.4.16. 14b-(Pyridin-3-yl)diindeno[1,2-f:10,20-h]
5,14(5aH,14bH)-dione (4j). Brown solid; mp 148e150 ꢁC; 1H NMR
(300 MHz, CDCl3) 8.69e8.68 (broad, 1H), 8.44e8.43 (broad, 1H),
quinoline-
2. (a) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131; (b) Tietze, L. F.
Chem. Rev. 1996, 96, 115; (c) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev.
1996, 96, 195; (d) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Synthesis; WILEY-VCH, 2006; (e) Domling, A. Chem. Rev. 2006, 106, 17; (f)
Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168; (g) Ho, T.-L. Tandem
Organic Reactions; WILEY-VCH, 1992; (h) Bunce, R. A. Tetrahedron 1995, 51, 13103.
3. (a) Tietze, L. F.; Modi, A. Med. Res. Rev. 2000, 20, 304; (b) Tietze, L. F.; Rack-
elmann, N. Pure Appl. Chem. 2004, 76, 1967; (c) Grondal, C.; Jeanty, M.; Enders, D.
Nat. Chem. 2010, 2, 167; (d) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew.
Chem., Int. Ed. 2006, 45, 7134; (e) Tietze, L. F.; Beifuss, U.; Lokos, M.; Rischer, M.;
Gohrt, A.; Sheldrick, G. M. Angew. Chem., Int. Ed. Engl. 1990, 29, 527; (f) Tietze, L.
F.; Wolfling, J.; Schneider, G. Chem. Ber. 1991, 124, 591; (g) Enders, D.; Wang, C.;
Mukanova, M.; Greb, A. Chem. Commun. 2010, 2447; (h) Kotame, P.; Hong, B.-C.;
Liao, J.-H. Tetrahedron Lett. 2009, 50, 704; (i) Zhang, F.-L.; Xu, A.-W.; Gong, Y.-F.;
Wei, M.-H.; Zhang, X.-L. Chem. Eur. J. 2009, 15, 6815; (j) Enders, D.; Krull, R.;
Bettray, W. Synthesis 2010, 567.
d
8.35e8.33 (m, 2H), 8.06 (d, J¼7.8 Hz, 1H), 7.83 (d, J¼7.5 Hz, 1H),
7.68e7.62 (m, 2H), 7.50e7.37 (m, 5H), 7.27e7.18 (m, 2H), 4.21 (s,
1H); 13C NMR (75 MHz, CDCl3)
d 199.0, 193.8, 154.7, 154.0, 151.5,
150.7,147.6,147.4,147.3, 140.2,138.8,137.0,135.4, 135.3, 133.5, 132.5,
131.8, 131.4, 130.1, 129.8, 128.5, 124.0, 123.7, 123.2, 123.0, 122.2, 67.6,
50.4; HRMS (ESI-TOF) of C28H16N2O2¼435.1103 [MþNaþ] (calcu-
lated 435.1104).
4.4.17. 3,12-Dichloro-14b-(pyridin-3-yl)diindeno [1,2-f:10,20-h]quino-
line-5,14(5aH,14bH)-dione (4k). Brown solid; mp 120e122 ꢁC; 1H
NMR (300 MHz, CDCl3)
(broad, 2H), 8.09e8.02 (m, 1H), 7.84 (s, 1H), 7.69e7.63 (m, 2H), 7.42
(broad, 5H), 4.31 (s, 1H); 13C NMR (75 MHz, CDCl3)
197.9, 192.5,
d 8.75 (broad, 1H), 8.49 (broad, 1H), 8.36
4. (a) Kotali, A.; Papapetrou, M.; Dimos, V. Org. Prep. Proced. Int. 1998, 30, 177; (b)
Katritzky, A. R.; Harris, P. A.; Kotali, A. J. Org. Chem. 1991, 56, 5049; (c) Kotali, A.
Tetrahedron Lett. 1994, 35, 6753.
d
5. (a) Kupchan, S. M.; Suffness, M. I. J. Am. Chem. Soc. 1968, 90, 2730; (b) Chen, J. K.;
Taipale, J.; Cooper, M. K.; Beachy, P. A. Genes Dev. 2002, 16, 2743; (c) Teruya, T.;
akagawa, S.; Koyama, T.; Suenaga, K.; Kita, M.; Uemura, D. Tetrahedron Lett. 2003,
44, 5171; (d) Gao, S.; Wang, Q.; Chen, C. J. Am. Chem. Soc. 2009, 131, 1410; (e)
James, L. F.; Panter, K. E.; Gaffield, W.; Molyneux, R. J. J. Agric. Food Chem. 2004, 52,
3211; (f) Giannis, A.; Heretsch, P.; Sarli, V.; Stobel, A. Angew. Chem., Int. Ed. 2009,
48, 7911; (g) Brown, E.; Ragault, M. Tetrahedron 1978, 35, 911; (h) Dewick, P. M.
Medicinal Natural Products, a Biosynthetic Approach, 2nd ed.; WILEY-VCH, 2002.
6. (a) Eicher, T.; Pfister, T.; Urban, M. Chem. Ber. 1980, 113, 424; (b) Harrowven, D. C.;
Newman, N. A.; Knight, C. A. Tetrahedron Lett. 1998, 39, 6757.
153.0,151.9, 151.7, 150.7,149.0,139.3,139.2,138.6,138.1, 136.3,135.6,
135.4, 135.3, 134.3, 134.2, 133.5, 132.7, 132.5, 131.5, 124.0, 123.9,
123.8, 123.6, 123.4, 114.04, 67.9, 50.2; HRMS (ESI-TOF) of
C
28H14Cl2N2¼481.0516 [MþHþ] (calculated 481.0505).
4.4.18. 3,12-Dimethyl-14b-(pyridin-3-yl)diindeno [1,2-f:10,20-h]quin-
oline-5,14(5aH,14bH)-dione (4l). Brown solid; mp 122e124 ꢁC; 1H
NMR (300 MHz, CDCl3)
d
8.75 (d, J¼3.9 Hz, 1H), 8.48 (d, J¼3.6, 1H),
7. CCDC 875292 (4a), CCDC 898556 (4b), CCDC 891987 (4d) and CCDC 898787 (4f)
contains the supplementary crystallographic data for this paper. These data can
be obtained free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
8.40 (t, J¼6.15 Hz, 1H), 8.00 (d, J¼7.8 Hz, 1H), 7.68 (s, 1H), 7.57e7.40
(m, 3H), 7.25e7.19 (m, 4H), 4.26 (s, 1H); 13C NMR (75 MHz, CDCl3)
d
199.4, 194.2, 154.4, 154.2, 152.6, 151.2, 150.5, 148.4, 148.2, 140.2,
8. Ruan, J.; Iggo, J. A.; Xiao, J. Org. Lett. 2011, 13, 268.
138.7, 138.6, 137.5, 137.2, 136.4, 134.6, 133.3, 132.5, 132.3, 129.9,
9. Rockett, B. W.; Hauser, C. R. J. Org. Chem. 1964, 29, 1394.