FeCl3-Catalyzed Combinatorial Synthesis of Functionalized Spiro[Indolo-3,10′-indeno [1,2- b ]quinolin]-trione Derivatives

Article abstract of DOI:10.1021/acscombsci.5b00038

An efficient, inexpensive, environmentally friendly and high yield one-pot route to new spiro[indolo-3,10′-indeno [1,2-b]quinolin]-trione derivatives has been developed, involving three-component reaction of enaminones, N-substituted isatins and Indane-1,3-dione catalyzed by FeCl₃. The approach to this spiro-heterocycle is noteworthy because it results in the formation of three new σ (two C-C and one C-N) bonds in a single operation, leading to the construction of novel spiro skeleton. This method works on a large scale in excellent yields.

Full text of DOI:10.1021/acscombsci.5b00038

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Article
FeCl3-catalyzed combinatorial synthesis of functionalized
spiro[indolo-3,10´-indeno [1,2-b]quinolin]-trione derivatives
Animesh Mondal, and Chhanda Mukhopadhyay
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.5b00038 • Publication Date (Web): 18 Jun 2015
Downloaded from http://pubs.acs.org on June 23, 2015
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Graphical Abstract
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FeCl3-catalyzed combinatorial synthesis of functionalized spiro[indolo-3,10´-
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indeno [1,2-b]quinolin]-trione derivatives
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Animesh Mondala and Chhanda Mukhopadhyay a*
a Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata-700009, India;
*E-mail: cmukhop@yahoo.co.in
Phone: 09433019610
O
R5
O
N
R4
FeCl3, CH2Cl2, r.t.,
stirring
O
R4
R3
O
X
New
(38 Examples)
O
O
R4
NH
R1
X
R2
R4
R3
O
N
R2
O
R1
N
R5
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FeCl3ꢀcatalyzed combinatorial synthesis of
functionalized spiro[indoloꢀ3,10´ꢀindeno [1,2ꢀ
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b]quinolin]ꢀtrione derivatives
Animesh Mondala and Chhanda Mukhopadhyay a*
Department of Chemistry, University of Calcutta, 92 APC Road, Kolkataꢀ700009, India
Keywords: environmentally friendly, multicomponent reactions, isatins, spirocyclic compounds,
Lewis acid catalysis, ferric trichloride.
Abstract: An efficient, inexpensive, environmentally friendly and high yield oneꢀpot route to
new spiro[indoloꢀ3,10´ꢀindeno [1,2ꢀb]quinolin]ꢀtrione derivatives has been developed, involving
threeꢀcomponent reaction of enaminones, Nꢀsubstituted isatins and indaneꢀ1,3ꢀdione catalysed
by FeCl3. The approach to this spiroꢀheterocycle is noteworthy because it results in the formation
of three new σ (two CꢀC and one CꢀN) bonds in a single operation, leading to the construction of
novel spiro skeleton. This method works on a large scale in excellent yields.
INTRODUCTION
Multicomponent reactions (MCRs) are important tools for medicinal and organic chemists
because they offer significant advantages over the stepwise convergent construction of complex
molecules1. The structurally diverse enaminones have been of longstanding interest for the
construction of biologicallyꢀrelevant core structures via multicomponent reactions (MCRs).2
Examples of such heterocyclic spiroꢀfragments are shown in Figure 1,3 including those derived
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from isatin4, quinoline5, indenone6, and indole7, building blocks. Furthermore, Cꢀ3 spiroindoline
compounds8 represents an important structural unit found in many natural alkaloids9 such as
spirotryprostatins A and, B, which function as inhibitors of microtubule assembly, and
pteropodine and isopteropodine alkaloids, which interact with muscarinic serotonin receptors. In
this chemistry, our attention has been drawn to iron (III) chloride as a green and efficient Lewis
acid catalyst for CꢀC bond and carbon–heteroatom formation10,11 including MCRs under mild
reaction conditions12. Several FeCl3ꢀbased isatinꢀbased multicomponent methods have been
reported for the synthesis of spiro[indoloꢀ3,10´ꢀindeno [1,2ꢀb]quinolin]ꢀtriones heterocycles4
and related molecules13.
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OH
N
OCH3
CH3
HO
N
O
O
O
N
H3C
CH3
N
R1
O
O
O
N
N
N
R
H
H
NH
R2
O
R=OCH3 Spirotryprostatin A
R=H Spirotryprostatin B
Antimicrobial
Antitumoral
OH
H3C
H
N
Cl
O
O
H
N
OH
H
O
H
NH
COOCH3
F
N
H
O
N
Cl
Peteropodine
H
MI 219
Figure 1. Examples of biologically important fuesd spiroꢀcompounds.
We describe here the extension of FeCl3ꢀcatalyzed threeꢀcomponent coupling methodology to
commercially available cyclic1,3ꢀdicarbonyl compounds, amines and isatins for the synthesis of
highly functionalized spiroꢀderivatives (Scheme 1). This process provides good to excellent
yields of the desired compounds under mild conditions.
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Scheme 1: MCR synthesis of spiro[indoloꢀ3,10´ꢀindeno [1,2ꢀb]quinolin]ꢀtriones heterocycles.
5
6
7
R5
N
8
9
O
O
R5
N
O
O
O
R4
R2
X
FeCl3 (10 mol%)
O
R4
R4
R3
R4
R3
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O
NH
R1
X
CH2Cl2, r.t. (25ꢀ30 °C),
stirring
O
N
3
2
R2
1
R1
R1=H, Aryl and
alkyl; R2,R3=H,
ꢀCH3 and Phenyl
R4=H and ꢀCH3
R5=Allyl, Benzyl
and Alkyl
X=H, Cl, Br and NO2
4 {1,1,1}-4{1,8,1}
RESULTS AND DISCUSSION
Reaction conditions
Enaminone 1{1}, Nꢀsubstituted isatin 2{1} and indane 1,3ꢀdione 3{1} served as model
substrates to explore the threeꢀcomponent reaction conditions in the presence of various Lewis
acidic catalysts in organic solvent (Figure 2, Table 1). FeCl3 (10 mol %) was found to be the
best catalyst, giving 4{1,1,1} in 92% yield (Table 1, entry 5). While diminishing (entry 6) or
increasing (entry 7) the amount of catalyst made no significant difference, the presence of
catalyst was required (entry 1). Other Lewis acids (entries 2, 3, 4) and mild protic acids (entries
8, 9) gave the same product in moderate yield, but HCl provided only trace amounts, perhaps due
to decomposition of the product in the presence of strong acid. Among the organic solvents
tested (CH3CN, EtOH, MeOH, Toluene, THF, DMF and DMSO; entries 11ꢀ17), CH2Cl2 gave
the best yields by substantial amounts.
Table 1. Optimization of reaction conditions for the synthesis of compound 4{1,1,1}a
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N
O
O
O
O
O
conditions
N
O
H3C
H3C
O
NH
9
H3C
catalyst, r.t., 3h
N
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O
H3C
3 {1}
2{1}
CH3
1{1}
4 {1, 1, 1}
CH3
1 mmol
1 mmol
1 mmol
entry catalyst (mol %) / solvent
Yieldb4{1,1,1} (%)
1
2
3
4
5
6
7
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9
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16
17
None (ꢀ), DCM
AlCl3(10), DCM
SnCl2 (10), DCM
ZnCl2 (10), DCM
FeCl3 (10), DCM
FeCl3(5), DCM
FeCl3(20), DCM
AcOH (5), DCM
H3BO3 (5), DCM
HCl (5), DCM
FeCl3 (5), ACN
FeCl3(5), EtOH
FeCl3(5), MeOH
FeCl3(5), Tolune
FeCl3(5), THF
5
45
32
35
92
80
87
55
38
trace
75
65
52
66
55
30
25
FeCl3(5), DMF
FeCl3(5), DMSO
aReaction conditions: enaminone (1{1}, 1 mmol), isatin (2{1}, 1 mmol), indaneꢀ1,3ꢀdione
(3{1}, 1 mmol), different catalysts, different solvents. bYields of isolated products.
Substrate scope
With favorable reaction conditions established (10 mol% FeCl3, CH2Cl2 solvent, room
temperature), the substrate scope of this FeCl3ꢀcatalyzed MCRs process was explored with 27
enaminones (1{1}ꢀ1{27}), 8 Nꢀsubstituted isatins (2{1}ꢀ2{8}) and indane ꢀ1,3ꢀdione (3{1})
(Figure 2 and Table 2).
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Enaminones:
N-substituted
Isatins:
O
O
O
O
O
6
7
H3C
H3C
H3C
H3C
H3C
H3C
NH
NH
NH
NH
NH
CH3
H3C
H3C
H3C
H3C
N
CH3
8
CH3
O
N
O
9
O
1{5}
1{4}
1{2}
1{3}
1{1}
2{1}
2{3}
O
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CH3
NH
OCH3
NH
O
O
O
2{2}
O
O
H3C
H3C
H3C
H3C
H3C
H3C
H3C
H3C
H3C
NH
Br
NH
NH
H3C
N
N
O
O
O
Cl
CH3
2{4}
O
OCH3
1{10}
CH3
1{6}
1{7}
1{8}
1{9}
Cl
CH3
O
O
O
O
O
H3C
H3C
H3C
H3C
H3C
H3C
H3C
N
O
NH
N
NH
NH
CH
NH
NH
H3C
H3C
H3C
O
O
Cl
Br
Cl
Br
2{6}
2{5}
2{7}
O
1{14}
3
NO2
1{15}
1{11}
1{13}
Cl
O
1{12}
COOH
H3C
O
O
O
O
N
O
N
H3C
H3C
O
NH H3C
H3C
O
NH
NH
NH
NH
H3C
O2N
2{8}
O
H3C CH3
CH3
1{18}
1{20}
1{17}
1{19}
1{16}
CH3
O
Indane -1,3-dione:
O
O
O
O
O
O
H3C
H3C
O
H3C
H3C
NH
NH2
NH
NH
NH
NH
NH
H3C
CH3
CH3
O
1{25}
1{27}
1{23}
1{26}
1{22}
1{21}
1{24}
CH3
OCH3
3 {1}
CH3
Figure 2.
condensation.
Enaminone and isatin reagents tested in FeCl3ꢀcatalyzed multicomponent
Various 5,5 disubstituted enaminones 1 were found to give corresponding products 4{1,1,1}ꢀ
4{18,1,1}, in yields ranging from 60% to 93% (Table 2, entries 1 to 11). Unsubstituted
enaminones also gave good yields (Table 2, entries 18ꢀ20, 24, 25, 27 and 31). Phenyl
substitution at the 5 position (1{19} and 1{20}), as well as 6,6ꢀdisubstitution (1{21}) provided
lower yields (Table 2, entries 12, 16, 17, 34), the latter most probably due to steric factors. The
electronic nature of Nꢀaryl enaminone substituents had little effect, with electronꢀdonating
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(methyl, isopropyl, methoxy) or electronꢀwithdrawing (chloro, bromo, nitro, carboxylic acid)
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6
aromatic groups (R1) giving similar results (Table 2, entries 1ꢀ6).
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Table 2: Synthesized spiro compounds.
R5
O
N
R5
N
O
O
FeCl3 (10 mol%)
O
O
X
O
O
NH
R1
X
DCM (5 ml), r.t.
(25ꢀ30 °C), stirring
O
2 {1-8}
1 mmol
3 {1}
1 mmol
1 {1-27}
1 mmol
N
R1
R2=Allyl, Benzyl
and Alkyl
X=H, Cl, Br and NO2
4 {1{1-27},2{1-8},3{1}}
R1=H, Aryl
and alkyl
entry
1
product (4) / time (h) yield (%) / mp (°C)
4{1,1,1}, 3
4{2,1,1}, 3
4{3,1,1}, 4
92, 286ꢀ288
93, 280ꢀ282
86, 240ꢀ242
90, 304ꢀ305
88, 132ꢀ134
87, 310ꢀ312
74, 158ꢀ160
83, 248ꢀ250
85, 280ꢀ281
75, 238ꢀ240
84, 254ꢀ255
60, 254ꢀ256
92, 340ꢀ342
85, 278ꢀ279
86, 292ꢀ293
72, 200ꢀ202
65, 210ꢀ212
87, 328ꢀ330
70, 296ꢀ298
75, 277ꢀ278
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
4{9,1,1}, 3.5
4{12,1,1}, 4
4{13,1,1}, 4
4{14,1,1}, 5
4{15,1,1}, 3.5
4{16,1,1}, 3
4{17,1,1}, 5
4{18,1,1}, 3.5
4{20,1,1}, 6
4{23,1,1}, 3.5
4{6,2,1}, 3.5
4{10,2,1}, 3
4{19,2,1}, 5
4{20,2,1}, 6
4{23,2,1}, 3
4{24,2,1}, 4
4{25,2,1}, 5
4{2,3,1}, 3.5
4{15,3,1}, 3
4{10,4,1}, 3
4{22,4,1}, 3.5
4{25,4,1}, 6
21
22
23
24
25
88, 266ꢀ268
80, 268ꢀ270
91, 258ꢀ260
86, >350
72, 216ꢀ218
26
4{7,5,1}, 2.5
94, 328ꢀ330
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4{26,5,1}, 4
4{27,5,1}, 3.5
4{4,6,1}, 3
4{5,6,1}, 3.5
4{22,6,1}, 3
4{8,7,1}, 3
4{11,7,1}, 5
4{21,7,1}, 3
4{1,8,1}, 2
83, 336ꢀ338
82, >350
92, 308ꢀ310
88, 320ꢀ322
88, >350
90, >350
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84, 340ꢀ342
75, 318ꢀ320
92, 284ꢀ286
Nꢀalkyl enaminones also gave good yields (Table 2, entries 7ꢀ10) with this method. To further
broaden the scope of this reaction, we investigated the electronic properties of the substituents
(X= chloro, bromo and nitro) at the isatin C5 position and the Nꢀsubstituent (R5= allyl, benzyl
and nꢀbutyl). Each variation was well tolerated, giving structurally diverse spiroꢀproducts in
excellent yields (82–94%). Note that Nꢀprotected isatins bearing electronꢀwithdrawing
substituents (X) at the C5 position afforded reproducibly higher yields than other analogues,
suggesting an electronic effect (Table 2, entries 23 −38).
Enaminones derived from acyclic 1,3ꢀdiketones (5{1-3}) also proved to be effective in this
ferricꢀcaralyzed process, reacting cleanly with isatins (3{1,2,4}) and indane ꢀ1,3ꢀdione (3{1})
compounds under the same reaction conditions. The corresponding spiro[indoloꢀ3,4´ꢀindeno[1,2ꢀ
b]pyridin]ꢀ2,5´dione derivatives were isolated in good yields (75ꢀ85%, Scheme 3, 6{1,1,1}-
6{3,4,1}). All compounds were characterized by 1H, 13C NMR and IR spectroscopy analysis.
Scheme 3:Synthesis of spiro[indoloꢀ3,4´ꢀindeno[1,2ꢀb]pyridin]ꢀ2,5´diones derivatives.
R7
N
O
O
O
R7
N
O
O
X
FeCl3 (10 mol%)
O
H3C
O
H3C
X
H3C
NH
R6
CH2Cl2, r.t. (25ꢀ30 °C),
stirring, 4 h
O
H3C
N
3{1}
2{1,2,4}
5{1-3}
R6
R7=Allyl and Benzyl
X=H, Cl
R6=Aryl
6 {5{1-3},2{1,2,4},3{1}}
3 Example
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N
N
O
O
O
N
O
O
O
O
O
O
Cl
H3C
H3C
H3C
H3C
H3C
O
O
O
H3C
NH
H3C
H3C
NH
H3C
NH
9
H3C
H3C
N
N
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H3C
N
5{1}
5{2}
5{3}
6{3,4,1},
75%
6{2,2,1},
85%
Cl
6{1,1,1},
82%
CH3
OCH3
CH3
Cl
OCH3
To the best of our knowledge, this is the first report of the synthesis of spiroꢀ
heterocycle using FeCl3 as a lewis acid catalyst via multicomponent protocols and is perfectly
amenable to automation for combinatorial synthesis. Here, lewis acidic nature of FeCl3 helps to
coꢀordinate with oxygen and nitrogen atoms, thereby increasing the electrophilic character of
carbonyl carbon and finally, facilitating the dehydration process6,14 (A detailed mechanistic
pathway is proposed in Supporting Information.) The structures of the above spiroꢀcompounds
were confirmed unambiguously from single crystal Xray diffraction of the compound 4{16,1,1}
and all the compounds were well characterized by H, 13C NMR and IR spectroscopy. The
1
ORTEP plot of compound 4{16,1,1} (Figure 3) is shown in Supporting Information 1.
CONCLUSION
In summary, we have successfully developed a novel, straightforward, cheap, and
environmentally friendly oneꢀpot threeꢀcomponent reaction to synthesize highly functionalized
spiro[indoloꢀ3,10´ꢀindeno [1,2ꢀb]quinolin]ꢀ2,9´,11´triones derivatives in DCM at room
temperature (25ꢀ30 °C) in presence of the Lewis acid catalyst FeCl3 (10 mol %) . The procedure
has the following advantages: (1) it is highly efficient, has good atom economy and uses an
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ecologically benign multicomponent reaction strategy, (2) a wide variety of functional groups are
tolerated, (3) the FeCl3 catalyst is easily available and environmentally friendly, and (4) it should
be readily scalable.
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Experimental Section
Representative procedure for FeCl3ꢀcatalyzed three component synthesis of functionalized spiro
derivatives:
A 25 mL flask was charged with a mixture of enamenones (1, 1 mmol), Nꢀprotected isatin (2, 1
mmol), indaneꢀ1,3ꢀdione (3, 1 mmol), and catalytic amount of anhydrous FeCl3 (16 mg, 0.1
mmol) in dichloromethane (5 mL). The mixture was magnetically stirred at room temperature
(25ꢀ30°C) for the appropriate time mentioned in Table 2. The progress of the reaction was
monitored by TLC. After completion of the reaction the mixture was poured into water. Then it
was extracted with DCM (20 ml) for three times and followed by brine solution. Next, it was
dried over Na2SO4, and evaporated under reduced pressure to remove the excess solvent. Finally
the crude residue was directly purified by silica gel column chromatography using 30% ethyl
acetate in petroleum ether (60ꢀ80 °C) as eluant to afford the desired product as red solid. All the
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obtained products were characterized by H NMR, C NMR, and IR spectral data. The spectra
data for two representative compounds are given bellow.
1-Allyl-7´,7´-dimethyl-5´-p-tolyl-1,3,6´,7´,8´-pentahydro-5H-spiro[indolo-3,10´-indeno [1,2-
b]quinolin]-2,9´,11´triones: (Table 2, 4{1,1,1}): Yield 92 % (484 mg); red solid; Mp: 286ꢀ288
°C (EtOH); Rf [50 % EtOAc / petroleum ether (60ꢀ80°C)]: 0.60; IR (νmax, KBr, cmꢀ1): 3044,
1
2955, 2343, 1719, 1690, 1654, 1631, 1487, 1396, 1356, 1281, 1172, 1086, 897, 739, 501; H
NMR (300 MHz, CDCl3) δH: 7.30ꢀ7.04 (m, 6H, ArH), 6.94 (t, J=7.4 Hz, 2H, ArH), 6.82ꢀ6.72 (m,
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3H, ArH), 6.02ꢀ5.92 (m, 1H, allylꢀCH), 5.58ꢀ5.52 (m, 1H, NꢀCH2), 5.20 (d, J=10.5 Hz, 1H, Nꢀ
CH2), 5.12 (d, J=7.5 Hz, 1H, ArH), 4.46ꢀ4.41 (m, 2H, allylꢀCH2), 2.42 (s, 3H, ArꢀCH3), 2.18ꢀ
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2.10 (m, 2H, CH2), 1.97 (d, J=17.4 Hz, 2H, CH2), 0.84 (d, J=18.0 Hz, 6H, CH3); C NMR (75
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MHz, CDCl3) δC: 194.9, 190.1, 177.8, 154.5, 152.5, 143.3, 140.7, 136.8, 135.7, 134.6, 133.1,
132.1, 131.3, 130.7, 129.5, 129.0, 128.2, 122.4, 121.9, 121.3, 121.0, 117.2, 114.6, 110.3, 108.7,
50.0, 47.3, 43.1, 41.2, 32.2, 29.4, 26.5, 21.3; Anal. calcd. for C35H30N2O3; C: 79.82; H: 5.74; N:
5.32. Found: C: 79.98; H: 5.77; N: 5.24%.
1-Butyl-5´-(4-methoxy-phenyl)-7´,7´-dimethyl-1,3,6´,7´,8´-pentahydro-5H-spiro[indolo-
3,10´-indeno[1,2-b]quinolin]-2,9´,11´triones: (Table 2, 4{2,3,1}): Yield 88 % (492 mg); red
solid; Mp: 266ꢀ268 °C (EtOH); Rf [50 % EtOAc / petroleum ether (60ꢀ80°C)]: 0.70; IR (νmax
,
1
KBr, cmꢀ1): 2956, 2345, 1719, 1661, 1511, 1403, 1360, 1251, 1086, 986, 677; H NMR (300
MHz, CDCl3) δH: 7.44ꢀ7.35 (m, 2H, ArH), 7.28ꢀ7.20 (m, 2H, ArH), 7.12ꢀ7.06 (m, 4H, ArH),
6.95ꢀ6.90 (m, 3H, ArH), 5.33 (d, J=7.5 Hz, 1H, ArH), 3.97 (s, 3H, ꢀOCH3, 3.89ꢀ3.84 (m, 2H, Nꢀ
CH2), 2.30ꢀ2.08 (m, 4H, CH2), 1.94ꢀ1.88 (m, 2H, CH2), 1.60ꢀ1.53 (m, 2H, CH2), 1.07ꢀ1.02 (m,
9H, CH3); 13C NMR (75 MHz, CDCl3) δC: 194.8, 190.1, 177.8, 160.6, 154.7, 152.8, 143.8, 136.9,
134.9, 133.2, 131.4, 130.9, 130.8, 130.4, 129.5, 128.2, 122.5, 121.6, 121.3, 121.0, 115.2, 115.0,
114.8, 110.4, 107.8, 55.7, 50.1, 47.4, 41.3, 40.3, 32.2, 29.4, 28.9, 26.6, 20.4, 13.8; Anal. calcd.
for C36H36N2O3; C: 77.12; H: 6.47; N: 5.00. Found: C: 77.25; H: 6.46; N: 5.07%.
ASSOCIATED CONTENT
Supporting Information.
Details experimental procedures for synthesis of spiro[indoloꢀ3,10´ꢀindeno [1,2ꢀb]quinolin]ꢀ
1
2,9´,11´triones derivatives, scale up reaction and spectral data, copies of H and 13C NMR
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spectra and IR analysis data of all the new synthesised compounds are provided. This material is
available free of charge via the Internet at http://pubs.acs.org/.
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AUTHOR INFORMATION
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Corresponding Author
Eꢀmail: cmukhop@yahoo.co.in
Author Contributions
All authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported by Department of Chemistry, University of Calcutta and grateful to
the CAS Instrumentation Facility for spectral data. One of the authors (AM) thanks the
University Grants Commission (UGC), New Delhi, for the award of a Junior Research
Fellowship.
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FeCl3ꢀcatalyzed combinatorial synthesis of
functionalized spiro[indoloꢀ3,10´ꢀindeno [1,2ꢀ
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14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
b]quinolin]ꢀtrione derivatives
Animesh Mondala and Chhanda Mukhopadhyay a*
O
R5
O
N
R4
R2
FeCl3, CH2Cl2, r.t.,
stirring
O
O
R4
R3
O
X
New
(38 Examples)
O
R4
NH
R1
X
R4
R3
O
N
R2
O
R1
N
R5
ACS Paragon Plus Environment
18