Mol Divers DOI 10.1007/s11030-015-9589-z

COMPREHENSIVE REVIEW

The molecular diversity scope of 1,3-indandione in organic synthesis Shima Asadi1 · Ghodsi Mohammadi Ziarani1

Received: 30 August 2014 / Accepted: 25 March 2015 © Springer International Publishing Switzerland 2015

Abstract Indandione is an important starting material that has drawn great attention in various organic transformations because of its attributes, such as low cost, easy to handle and eco-friendliness generally affording the corresponding products in excellent yields. In this review, we summarize recent data describing the most important MCRs reactions in which one of the starting materials is indandione. This review will also present two-, three-, four-, and five-component and onepot reactions for the functionalization of indandione with the to increase awareness on the versatility of using this compound among organic chemists. Keywords Indandione · Organic synthesis · Multicomponent reaction · MCRs · Cylcization · Functionalization

Introduction Heterocyclic chemistry, as one of the most important branches of chemistry, has attracted much attention in recent years due to its increasing significance in the field of pharmaceuticals and industrial chemicals. Multicomponent reactions (MCRs) deal with the reaction of two, three, or more starting materials to form a product in one step. In many cases, indandione, as a β-diketone, plays a key role in MCRs for the synthesis of heterocyclic compound collections. Multicomponent reactions can be an ideal way for molecular diversity generation and the preparation of a library of heterocyclic compounds. For example, 100 compounds

B 1

Ghodsi Mohammadi Ziarani [email protected] Department of Chemistry, School of Sciences, Alzahra University, Vanak, Tehran, Iran

will be created from a two-component reaction when 10 different substrates are used and, similarly, 1000 different compounds will be generated with a three-component approach. Indenone-fused heterocycles and their derivatives are reported to have a wide range of pharmacological activities (Fig. 1). For example, the indenopyridine skeleton is present in the 4-azafluorenone group of alkaloids [1]. Indenopyrazoles I and indenopyridazines II are bioactive compounds that show inhibitory activity against targets such as CDK2 and CDK4 [2,3]. Indenoquinolines III are also reported to have a wide range of biological activities such as antitumor [4,5], acetylcholinesterase and steroid reductase inhibitory [6,7], and antimalarials [8] activities. Indenopyridone NSC 314622 is another biologically interesting indenone derivative attending as a main compound for the evolution of anticancer agents targeting topoisomerase I [9]. Significant efforts have been devoted to the synthesis of the above-mentioned compounds containing an indenone ring. Extensive investigations demonstrate the wide synthetic utility of indandione in MCRs. These findings have prompted us to classify them and present some interesting examples that display the effectiveness and usefulness of indandionebased MCRs.

Two-component reactions of indandione Wang et al. reported the synthesis of quinolines via the Friedländer reaction of 2-aminobenzaldehyde (2) with various ketones, such as indandione, dimedone, cyclohexandione in water [10]. This procedure was performed without using any catalyst at 70 ◦ C. Indandione (1) is one of the 1,3diketones used for the synthesis of desired product 3 with 92 % yield as shown in Scheme 1.

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Mol Divers

O

O

O

Y N

N

X

NH

N N

X

Ι

Onychnine

ΙΙ

OMe O

O

OMe

Ar

O

O N H

N Me O

O

ΙΙΙ

NSC 314622

Fig. 1 Indenone-fused heterocycles and their derivatives O

O

O H

NH2 1

O

H2O 70 °C

N

2

3 92%

Scheme 1 Two-component reaction of 2-aminobenzaldehyde (2) with indandione (1)

Rice husk ash (RiHA) as a silica source is produced from the combustion of rice husk (RiH) and can be used as an adsorbent for heavy metals. In 2013, Shirini et al. used the Friedländer reaction in the synthesis of quinoline derivatives (5) in the presence of FeCl2 ·2H2 O-RiHA as a catalyst Scheme 2 Application of the Friedländer reaction in the synthesis of quinoline derivatives (5)

[11]. The Friedländer heteroannulation occurred between indandione (1) and o-aminoaryl ketones (4) in solvent-free conditions at 90 ◦ C (Scheme 2). A one-pot synthesis of indandione was performed by the treatment of aromatic acyl chlorides (6) and malonyl dichloride (7) via a sequential cross-condensation–cycloacylation reactions. Malonyl dichloride (7) and various aromatic acyl chlorides (6) led to the desired product in the presence of AlCl3 [12]. Selective C-benzoylation followed by intramolecular electrophilic acylation gave cyclic tricarbonyl derivative (8). The dechlorocarbonylation of compound 8 during the acid quenching process affords the indandione (1) in good yields (Scheme 3). Lin’s group reported an asymmetric organocatalytic procedure in which 2-arylidene-1,3-indandiones (9) and bromonitroalkanes (10) are condensed to yield spironitrocyclopropanes (11) bearing two stereogenic centers in good yields (up to 88 %), excellent enantioselectivities (up to 98 %) and diastereoselectivities (up to 19:1) (Scheme 4) [13]. Different organocatalysts were examined in this reaction, but the best result was obtained using cinchona-derived bi-functional organocatalysts (12). The synthesis of spirocyclopropane product (14) was examined by employing a bromonitrostyrene, such as 13, as a dielectrophilic component [14,15] and 1,3-indandione (1) as a di-nucleophile group in the presence of 12. The result was not satisfactory and the adduct 14 was obtained with only 35 % ee and moderate 57 % yield (Scheme 5).

O

O

O

R

FeCl2·2H2O-RiHA R NH2 O

Scheme 3 A pathway for the synthesis of indandione (1)

N H 5 R= H; Time= 45 min, yield= 95% R= Cl; Time= 60 min, yield= 94%

4

1

Cl O Cl

O

O Cl

R

6

O

dry nitrobenzene, AlCl3

Cl Al O HCl Cl

Cl 7

COCl

R

AlCl3 O

O R= H, yield= 90% R= p-Tolyl, yield= 88% R= 2-Thienyl, yield= 78% R R= p-(NO2)C6H4, yield= 37%

123

+

H , H2O

1

O

- CO2, - HCl

COCl R

O

8

Mol Divers

reaction A 15 Sealed tube

OMe H

N

80 °C, acetone 2h, 77%

HN N HN

F3C O

CF3

12

H2O (1 eq.) toluene, -20 °C

Br

O 9a-o

10

reaction B

O

Sealed tube, 80 °C, acetone, 2h, 74%

O R 2 NO2

1

O

1

Br

NO2

O

R1 O 11a-o 15 examples

reaction C Sealed tube, 80 °C, acetone, 6h, 45%

13

O

12 (20 mol%) Na2CO3 (1 eq.) H2O (1 eq.) toluene, -20 °C 10h

NO2

Scheme 7 Preparation of 2-arylidene- 2H -indene-1,3-diones (9) via different methods

O 14 yield= 57% ee= 35%

O

O

N C O

1 Me N Ar 1

O

O 15a-d

O

O Sealed tube 80 °C, CH2Cl2 - MeNHOH

R N

O

H

B

Scheme 5 Synthesis of spirocyclopropane product (14) O

O

9

Scheme 4 Synthesis of spironitrocyclopropanes (11) O

O

MeNHOH·HCl 16

12 (20 mol%) NO2 Na2CO3 (1 eq.)

R2 R1

S

Ar

CN 16a-c

R N O

9a-d O

9a; Ar= C6H5; yield= 85% 9b; Ar= 4-MeC6H4; yield= 89% 9c; Ar= 2,4,6-Me3C6H2; yield= 87% 9d; Ar= anthracen-9-yl; yield= 80%

Scheme 6 Two component synthesis of 2-arylidene- 2H -indene-1,3diones (9)

In a green method, a catalyst-free synthesis of 2-arylidene2H -indene-1,3-diones (9) was described by the treatment of indandione (1) with different acyclic nitrones − O+ N(Me) = C(H)Ar (15) (Scheme 6). The optimized condition was reached using CH2 Cl 2 as solvent in a sealed tube at 80 ◦ C for 2 h affording the corresponding products in 80–89 % yields. Subsequently, the reaction of indandione (1) with the nitrone 15 was investigated in a sealed tube and acetone media. The desired 2-(propan-2-ylidene)-2H -indene-1,3dione (9) was afforded in 77 % yield (80 ◦ C for 2 h) (reaction A). The same reaction was examined in various conditions. In reaction B, N -methylhydroxylamine hydrochloride (16) was used instead of the nitrone (15) to afford 9 in 74 % yield. Another reaction (C) was also effected without using the nitrone 15 or 16 in a moderate yield of 45 % (Scheme 7). El-Zohry et al. reported the preparation of several new spiroindeno[1,2-b]pyran-4,3 -indolines (17), which can be

O CN

R= H, Me, Et

O

NH2

17a-c Scheme 8 Generation of new spiroindeno[1,2-b]pyran-4,3’-indolines (17)

accessed in a one-step two-component reaction between indandione (1) and 3-dicyanomethylidene-2-oxoindolines (16a–c) in refluxing ethanol (Scheme 8) [16]. This reaction was performed via a Michael addition reaction with a catalytic amount of Et3 N to give 2-amino-3-cyanospiro 5H indeno[1,2-b]pyran-4,3 -indoline derivatives (17a–c). Another transformation was examined using indoline derivatives (17a–b) that led to fused spiroheterocyclic systems and incorporated the pyrimidine nucleus in addition to indeno[1,2-b]pyran and indoline moieties. These reactions involved the treatment of 17a–b with formic acid and acetic anhydride/pyridine mixture (2/1, v/v) to give 18a,b and 19, respectively. The final products were formed via a Dimroth rearrangement as illustrated in Scheme 9. As shown in Scheme 10, this research group evaluated other indenopyrans and indenopyranopyrimidines scaffolds via the reaction of 17a,b with formamide (25) and

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Mol Divers R

R O

(28) using a few drops of glacial acetic acid to produce 20a,b, 21a,b, 22a,b and 23a,b, respectively. Finally, the reaction of 23a,b with hydrazine hydrate (29) in benzene gave 24a,b. Raoof et al. established a novel carbon–carbon bond formation method between a catechol skeleton and indandione as a diketone via an anodic oxidation in aqueous solution using cyclic voltammetry [17]. In this process, the electrogenerated benzoquinones from the electrooxidation of the catechol (CAT) (30a), 3-methylcatechol (3MCAT) (30b), and 4-methylcatechol (4MCAT) (30c) took part in a Michael addition reaction with 1 to form 31a–c (Scheme 11).

N

N O

NH

Dimorth rearrangment

O

O

O NH

O O

N

O

N

18a,b HCO2H reflux R

R

N O

N

O CN NH2

O

Ac2O/pyridine

O

O

O NH

Dimorth rearrangment

N

O

17a,b

Me

19

17a; R= H 17b; R=Me

Three-component reaction of indandione

Scheme 9 Dimroth rearrangement leading to 18a,b and 19

The reaction of mono-substituted squaraines (34) with 1 led to ring-substituted mono-squaraines (35). Squaraine dye (36) could be prepared from mono-squaraines and exhibit high molar absorptivity and long-wavelength absorption and emission (Scheme 12) [18].

malononitrile (26). This reaction was performed in the presence of pyridine or dry dioxane/Et3 N, phenyl isocyanate (27) in refluxing pyridine, triethyl orthoformate R N

CN O NC

CN O

NH2

21a,b

CH2(CN)2 26 R O

R

R

N

N

N

O

NH

O C6H5NCO

N O

N H

O

O

CN

HCONH2

O

O

NH2 N

25

27 O

NH2

O

22a,b

N

20a,b

17a,b

CH(OEt)3 28 AcOH

R

R

N

N O

O

NH2-NH2 . H2O H2N N CN O 23a,b

Scheme 10 Synthesis of various indenopyrans and indenopyranopyrimidines

123

N CHOEt

O

NH N

29 O 24a,b

N

NH2

Mol Divers O

OH OH

O

+

- 2e, 2H

R1

R1 R2

R2 30a-c O

OH H

H

H 1

O

O

OH

O

O H

O OH

O H H

R1

O

O

R2 O H

O O H

O

R1

R2

OH

OH H O

R2

R1

R1

R2 O

O

HO

OH R1 R2

O

31a-c

R1= H, CH3 R2= H, CH3

Scheme 11 Michael addition of 30a-c with 1 to form 31a-c

Scheme 12 The reaction of mono-substituted squaraines (34) with 1 to give squaraine dye (36)

O

In another procedure, 2 equvalents of indandione (1) reacted with m-phenylenediaminosulfonic acid (37a) or 2,4-diaminophenol (37b) and products with phenylenediamine fragment (38) were obtained (Scheme 13). The metal complexes were prepared via the coordination of macroheterocycles with metals, such as copper, cobalt, and zinc. Then, the desired complexes were characterized by IR and UV spectroscopic methods [19]. The Yavari group reported an efficient method for the stereoselective synthesis of spiro compounds 41 (Scheme 14) [20]. In this one-pot reaction, the treatment of quinoline (39) and dialkyl acetylenedicarboxylates (40) gave intermediate 42 which is then attacked by carbanion 43 to produce 44. This intermediate underwent a 1,3-proton shift and cyclization to produce product 41 (Scheme 15). This method was extended by using N -methylimidazole and 4-methylpyridine leading to 1,4-zwitterionic [21,22] compounds 46 and 47, and their corresponding cyclic structures 48 and 49, respectively (Fig. 2). In 2014, Habibi et al. described a three-component reaction of indandione (1), CS2 (50), triethylamine, diethyl acetylenedicarboxylate (DEAD) (40b) in CH3 CN for the synthesis of diethyl 2-(1,3-dioxo-1H-inden-2(3H)-ylidene)1,3-dithiolane-4,5-dicarboxylate (51) (Scheme 16) [23]. The reaction provides highly stable intermediates via 5-endo-trig reactions which is in contrast with Baldwin’s rule [24]. In 2014, Mukhopadhyay et al. reported the first procedure for the synthesis of fused N -substituted-2-pyridone derivatives (53) in an aqueous sodium dodecyl sulfate (SDS) solution catalyzed by L-proline [25]. The reaction was per-

Me

O

Me

O O 1

N Me

Me

TEA, 4 h

O Me

O O

N Me

OBu 34

39%

OBu 35

Me

Me

O Me N Me 51%

O Me

O

Me

Me N IMe Me

N Me

36

123

Mol Divers Scheme 13 The reaction of indandione (1) with m-phenylenediaminosulfonic acid (37a) or 2,4-diaminophenol (37b)

X O

X

C2H5OH

HN

NH

2 H2N O

1

NH2 O

O

37a: X= SO3H 37b: X= OH

2 CH3COONH4 CH3COOH

X

X 2NaOH

HN

NH

HN

NH

- 2NaCl

NH

NH

+

NH2Cl-

+

NH2Cl-

MCl2 DMF X HN

NH M = Cu2+, Co2+, Zn2+

N

N

M 38

Scheme 14 The stereoselective synthesis of spiro compounds 41

O

CO2R

r.t., 12h

N O 1

39

CH2Cl2

CO2R 40

OH N

CO2R H O H CO2R 41 R= Me; yield= 90% R= Et; yield= 85% R= t-Bu; yield= 78%

formed by the treatment of indandione (1), aromatic amines (52), and diethylacetylenedicarboxylates (DEAD) (40b) at 100 ◦ C for 15 h (Scheme 17). The proposed mechanism (Scheme 18) of the reaction include the formation of intermediate A by the reaction of indandione and an aromatic amine catalyzed by L-proline. At first, the adduction of DEAD and L-proline gave adduct B. In the second step, intermediate C was obtained by the reaction of A and B followed by removal of L-proline. Finally, the desired product D formed by intramolecular cyclization of C catalyzed by L-proline. Another three-component reaction of indandione (1) and dialkyl acetylenedicarboxylates (40) was accomplished with

123

malononitrile (26) or ethyl cyanoacetate (54) by Javanshir et al. using Na2 CO3 (20 mol%) as catalyst in refluxing ethanol [26]. This efficient method gave the corresponding products 55 with 55–66 % yields (Scheme 19). Another three-component modification of indandione was disclosed by Tu et al., which led to 4-azafluorenone (5H indeno[1,2-b]pyridin-5-one), a biologically important heterocycle [27]. In this procedure, several new poly-substituted indeno[1,2-b]pyridines derivatives (58) with mercapto or p-tolylthio groups were obtained by the treatment of arylidenemalononitrile (56), 1, and mercaptoacetic acid (or 4methylbenzenethiol) (57) under microwave (MW) irradiation (Scheme 20).

Mol Divers Scheme 15 Three-component treatment of indandione (1), quinoline (39) and dialkyl acetylenedicarboxylates (40)

O O CO2R

1

N

N

CO2R O 45

O

O

CO2Me

N

MeO2C

O

46 95% MeO2C

47 96%

CO2Me O

N N

O

MeO2C

O

O CO2Me

MeO2C 48

49

Fig. 2 1,4-Zwitterionic compounds 46 and 47, and their corresponding cyclic structures 48 and 49

O

1

O

CO2Et

CO2Et 40b

S C S 50

O

O Et3N CH3CN, r.t.

N

CO2R O 44

Three-component reaction of indandione with an aldehyde

N O

O

1,3-H shift

An efficient one-pot three-component reaction of dimethyl acetylenedicarboxylate (DMAD) (40a) and hexamethyl phosphorous triamide 60 in the presence of various CH-acids, such as indandione 1 has been reported by Maghsoodlou et al. [28]. The protocol furnished the stereospecific formation of phosphorus ylides 61 in excellent yields (Scheme 22). They found that the E-isomer was the major product over the Z-isomer because of the strong conjugation of the ylide moiety with the adjacent carbonyl group and the restriction of rotation around the partial double bond (Scheme 23).

N

N

O 43

RO2C

RO2C

MeO2C

CHCO2R 42

O 41

N RO2C

CO2R 40

39

O

S

S

O

O

EtO

OEt 51 65%

Scheme 16 Synthesis of diethyl 2-(1,3-dioxo-1H-inden-2(3H)ylidene)-1,3-dithiolane-4,5-dicarboxylate (51)

This research group used arylamines (52) instead of 57 in an alternative strategy to obtain poly-substituted indeno[1,2b]pyridines (59) in 78–91 % yield (Scheme 21).

Song and Zhu discovered that the coupling of 2-benzylideneindandiones (9) and ethyl 4,4,4-triflouoro-3-oxobutanoate (63), which are activated by a catalytic amount of piperidine, produced an unexpected fluorine containing multi substituted dispirocyclohexanes (64) (Scheme 24) [29]. At the first stage, the Knoevenagel condensation of an aromatic aldehyde 62 and 1 was obtained followed by ethyl 4,4,4-triflouoro-3oxobutanoate treatment of the 2-benzylidene-indandiones intermediate (9) in the presence of piperidine as catalyst and CH3 CN as solvent. Pyrazolo[4,3- f ]quinoline derivatives are important heterocyclic compounds with various biological effects, such as antivirals and antibacterials [30], atherosclerosis or restenosis treatment agents [31], FLT3-mediated leukemias [32], inflammatory and demyelinating disorders, and cancers [33]. Therefore, finding a suitable method for the preparation of pyrazolo[4,3- f ]quinoline derivatives is in great demand for organic and medicinal chemists. In this regard, six new series of pyrazolo[4,3- f ]quinoline derivatives (66) were synthesized by the three-component reactions of aromatic aldehydes 62, 5-aminoindazole (65), and different cyclic 1,3-dicarbonyl compounds under microwave irradiation. The

123

Mol Divers Scheme 17 Three-component reaction of indandione (1), aromatic amines (52), and DEAD (40b)

O CO2Et

O

OEt

O

NH2

H H2O, SDS (10 mM)

1

CO2Et

O

40b

52

O

N

L-proline (10 mol%) 15h, 100 °C reflux

R

R 53 R= 3,4-Me; yield= 83% R= 4-OMe; yield= 75% Scheme 18 Proposed reaction mechanism

O O N H

R-NH2

H

CO2H

- H2O O

A

NH R

O

CO2Et N H

CO2H

O N

EtO

O

H

CO2Et

B

O O

OEt

O

OEt

O

NH R

OEt

O

CO2

OEt

H

A

HO

N

EtO

CO2H

O

O

OEt N

L-proline NO R C

OEt

OEt

NH O R

N R

H CO2H H CO2Et

+ L-proline - L-proline O

OEt

O H N

O

R 53

Scheme 19 Reaction of dialkyl acetylenedicarboxylates (40) with malononitrile (26) or ethyl cyanoacetate (54)

O

RO2C

CO2R NC

R1

Na2CO3 (20 mol%) Ethanol (reflux)

1

O

CO2R 40

26 or 54

CO2RO

NC R1

O 55

R= Me, R1=CN; time= 4h, yield= 63% R= Et, R1=CN; time= 4h, yield= 55% R= Me, R1=CO 2Et; time= 4.5h, yield= 66%

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Mol Divers

O Ar 1

CN 56

O

Ar

O

NC

MW

CN

N

SR

58a-m 79-89% R= CH2COOH, 4-MeC6H4

HSR 57

Scheme 20 Preparation of poly-substituted indeno[1,2-b]pyridines derivatives (58) with mercapto or p-tolylthio groups O

Ar

O Ar 1

O

CN 56

CN

CN

MW DMF

Ar′−NH2 52

NHAr′

N

59a-n 78-91% R= 4-MeC6H4, C6H5, 4-ClC6H4

Scheme 21 Synthesis of poly-substituted indeno[1,2-b]pyridines (59)

O

O

CO2Me P[NMe2]3

O

P[NMe2]3 O H CO Me 2

60

CO2Me

1

CO2Me

Et2O r.t.

40a

61 93%

Scheme 22 Stereospecific preparation of phosphorus ylides 61

[Me2N]3P O

H

O

[Me2N]3P O

OMe CO2Me

H

O 61-(E): Major

OMe

O CO2Me O

61-(Z): Minor

Scheme 23 Two isomers of compound 61

reaction of 62, 65, and indandione (1) is shown in Scheme 25. This strategy was performed under microwave irradiation in acetic acid/DMF to obtain the desired product in 94 % yield [34]. Scheme 24 Preparation of substituted dispirocyclohexanes (64) using piperidine as catalyst

Treatment of indandione with aldehyde and 6-aminoquinoline (67) under microwave irradiation without any catalyst in water at 120 ◦ C gave indeno[2,1-b][4,7] phenanthrolines (68) in good yields (91–94 %) (Scheme 26) [35]. This group also reported the synthesis of indeno[2,1e]pyrazolo[5,4-b]pyridine (70), using 3-methyl-1-phenyl1H -pyrazol-5-amine (69) instead of 67 [36]. This procedure was performed under the same reaction conditions at 5–9 min with 92–97 % yield. Quiroga et al. in 2010 described the synthesis of pyrazolo [3,4-b]pyridine-5-spirocycloalkanediones (73a–j) via a threecomponent reaction between 5-aminopyrazoles derivatives (71a–j), paraformaldehyde (72), and cyclic β-diketones by conventional heating or microwave irradiation (Scheme 27) [37]. Ramachary et al. reported an organocatalytic threecomponent hetero-domino Knoevenagel–Diels–Alder– epimerization reactions [38]. The reaction of enones 74, arylaldehydes 62 and 1 was performed to furnish highly substituted prochiral spiro[cyclohexane-1,2 -indan]-1 ,3 ,4triones (75 and 76) in a highly diastereoselective fashion with excellent yields (Scheme 28). This reaction was catalyzed by L-Proline and pyrrolidine (77 and 78). The mechanism of the diastereospecific synthesis of cisspirane (75) in the reaction could be explained as illustrated in Scheme 29. This research group expanded this economic approach to the synthesis of highly functionalized symmetric and nonsymmetric spiro[cyclohexane-1,2 -indan]-1 ,3 ,4-triones in a diastereospecific fashion [39]. Three products (75, 80 and 81) were obtained from the reaction of 1, enone (74) and dialdehyde (79) (Scheme 30). Dihydropyrido[2,3-d]pyrimidines are some of the most important type of chemical compounds for their diverse range of biological activities, such as antitumour, anticancer, anti-inflammatory and CNS depressant activities. Agarwal et al. described the synthesis of dihydropyrido[2,3d]pyrimidines (85) in high yields (82–92 %) on solid support using microwave irradiation (Scheme 31) [40]. In 2013, the above transformation was examined in the presence of 10 mol% of Zr(HSO4 )4 as a catalyst in solvent-free condition at 80 ◦ C [41]. The catalytic nature of Zr(HSO4 )4 was attributed to the Zr4+ as a Lewis acid and the

O O

1

O

Ar

62

O

O

O

H

Ar

solvent-free grinding 9a-g

O

F3C

63

OEt

piperidine (10 mol%) CH3CN

F3C CO2Et HO Ar O O

O

Ar

O

64a-g 75-92%

123

Mol Divers Scheme 25 Three-component reaction of indandione (1), 62 and 65

O H2N

O N

1

O

65

O

R

O

N H2N

, 12

MW

O

H

O

C

N

H 2O

O R

1

0°

67

68a-l

91-94 % 6-9 min R

O

MW

,1

62

H

20

2O

°C

N N Ph 70a-j

N

N N Ph NH2 69

92-97 % 5-9 min

Scheme 26 Synthetic pathway for indeno[2,1-b][4,7]phenanthrolines (68) and indeno[2,1-e]pyrazolo[5,4-b]pyridine (70)

O

O N 1

N

N H

Ar MW or

N

EtOH (ref.)

O O

Ar

71a-j H

H

O N

N

73a-j 20-59%

72

Scheme 27 Three-component reaction of 5-aminopyrazoles derivatives (71a–j), paraformaldehyde (72), and cyclic diketones

existence of the hydrogen sulfate anion as a proton source. The products were obtained in 93–96 % yields. In 2011 a similar treatment of aldehydes 62, 1, and 6-aminouracil (83) was examined (Scheme 32) [42]. The product in dihydropyridine form (86) was obtained and then Scheme 28 Three-component reaction catalyzed by L-Proline and pyrrolidine

N H 77 O

1

O

74

O

O

HOAc/DMF (V/V= 1:1) 6 min

62

123

N 66a-h 94%

oxidized. The final product 85 could be used for the treatment of cancer cells. These products were synthesized by Shi et al. in ionic liquid 1-n-butyl-3-methylimidazolium bromide [bmim]Br with 75–93 % yields in 2–4.5 h [35]. This reaction also works well in aqueous media promoted by p-TSA (20 mol%) to produce compound 85 in 60–90 % yields in 2.5–3.5 h [43]. The use of InCl3 (20 mol%) as catalyst in refluxing water is another method for the synthesis of this compound. This procedure was expanded with various aldehydes and the products were obtained with 87–90 % yields in 60 min [44]. Gilbertson et al. described the pharmacological properties of these pyridopyrimidine derivatives and their potential to prevent the cyclic nucleotide synthesis using a stable toxin of Escherichia coli. [45]. Hassan et al. synthesized 85 without using any catalyst in 70–80 % yields in 5 h [46]. This method also works well using 6-amino-2-methylthiouracil (87) instead of 6-amino1,3-dimethyluracil (83). The product 88 was obtained in 77 % yield under the same reaction conditions (Scheme 33). Treatment of indandione with different aldehydes 62 in the presence of InCl3 or P2 O5 as catalysts followed by addition of 1,3-dimethylbarbituric acid (89) gave 5oxadiazabenzo[b]fluorenones (90) (Scheme 34) [47]. Using Fe3 O4 @SiO2 –SO3 H magnetic nanoparticles as a novel heterogeneous acid catalyzed the sequential Knoevenagel condensation and Michael addition reactions of aromatic aldehydes on 1,3-cyclic diketones such as indandione leading to tetraketone derivatives (91) (Scheme 35) [48]. When indandione was used as a source of 1,3-cyclic

H CO2H

N H 78

Cat. 2 (20 mol%) or Cat. 3 (30 mol%) Ar O CH3OH, 70 °C

Ar O

Ar O O Ar O

Ar

H

N NH

MW, 120 °C

N H

Ar H 62a-h N

Ar

75 (major product)

Ar O 76

When Cat.=77, yield= 96%, dr= >100:1, time= 2 h When Cat.=78, yield= 95%, dr= >100:1, time= 1 h

Mol Divers O H

O

CHO

O

CHO 79

O

H+

Ar O

74

Ar

CO2H

N H

A

1

O

O

L-proline or pyrrolidine MeOH (0.5 M)

Ar

O

O HO2C

CO2H N H

O O

N

O

O

Ar

H

Ar O Ar O

Ar O Knoevenagel Condensation

C

B Diels-Alder reaction C

O O O 75

80 CHO

O

81

Ar O

A

O O

CO2H N H

O

O

H

B

OH-

O

Scheme 30 Asymmetric synthesis of spiro[cyclohexane-1,2 -indan]1 ,3 ,4-triones

L-proline Ar O

Epimerization O Ar O

Scheme 29 Proposed reaction mechanism

diketones, the desired product was achieved in 81–97 % yields. After completion of the reaction, the recovered catalyst was recycled consecutively three times to produce the desired products without a significant yield variation. Wang et al. provided a novel procedure for the synthesis of cyclopropane derivatives (92) (Scheme 36) [49]. In this methodology a number of substituted aldehydes 62 with indandione (1) react to form this cyclopropanation reaction using iodine (I2 ) and dimethylaminopyridine (DMAP) under mechanical milling conditions. When an electron-withdrawing aldehyde was used the corresponding cyclopropanes (92) were obtained in good yields (75–89 %). However, when electron-rich aromatic aldehydes, aliphatic aldehydes, and heteroaromatic aldehydes were used as the aldehyde source the products were formed in low yields (60 %). Indenoquinoline derivatives (94) are important building blocks for the synthesis of biologically active compounds with the properties of 5-HT-receptor binding activity [50], anti-inflammatory activity [51], acting as antitumor agents [4, 5], steroid reductase [7] and acetylcholinesterase inhibitors [6] or antimalarials. Tu and Ji described the synthesis of these compounds with the reaction of aldehydes 62, indandione (1) and enaminones (93). In their first effort they accom-

plished the construction of the indeno[1,2-b]quinoline-9,11 (6H, 10H )-dione core [52]. In this work the reaction was accomplished in aqueous media using p-TSA as catalyst under microwave irradiation [53]. The same reaction was carried out using various enaminones derived from different amines such as cyclopropanamine, methylamine, aminoacetic acid, and aromatic amines 52 (Schemes 37 and 38). Treatment of indandione (1) with β-naphtol (96) in the presence of sulfamic acid (3 mol%) as catalyst followed by the addition of arylaldehydes 55 gave indenonaphthopyrans (97) under solvent-free conditions (Scheme 39) [54]. Further studies showed that this reaction works well in the presence of triethylammonium hydrogensulfate ([Et3 NH] [HSO4 ]) as acidic ionic liquid, 3-methyl-1-sulfonic acid imidazolium chloride ([Msim]Cl), triethylamine-bonded sulfonic acid ([Et3 N–SO3 H]Cl), 2-pyrrolidonium hydrogensulfate ([Hnhp][HSO4 ]), and 1-methylimidazolium hydrogensulfate ([Hmim][HSO4 ]) [55]. The desired products 97 were prepared with excellent yields under solvent-free conditions at 70 ◦ C. In a similar effort, silica chloride was used as a heterogeneous catalyst at 110 ◦ C without any solvent. In this case, the 13-aryl-indeno[1,2-b]naphtha [1,2-e]pyran12(13H )-ones 97 were synthesized with 84–92 % yields in 1–2 h [56]. In another study, Tu et al. generated a wide diversity of indeno[1,2-b]pyrazolo[4,3-e]-pyridin-5(1H )-one derivatives (99) via a reaction sequence of condensation, addition, cyclization, dehydration, and aromatization [57]. This procedure involved the reaction of 1, 3-methyl-1H -pyrazol5-amine (98), and aldehyde 62 in water under microwave irradiation an catalyst-free conditions (Scheme 40).

123

Mol Divers Scheme 31 Preparation of dihydropyrido[2,3d]pyrimidines (85) via microwave irradiation

O

O H3C

N

O

X

HOAc, MW

H3C

NH2 N CH3

O

1

O

X

O

N N N H CH3 84

O

83 CHO

82 TFA:CH2Cl2 (V:V, 1:1) 30 min, r.t. O X

O

O

O

and

=

H3C O

Y

OH

Scheme 32 Three-component reaction of aldehydes (62), indandione (1), and 6-aminouracil (83)

R1

and

85

N

O 1

N N H CH3

OH

O

O

N R 83 2

O

R1 NH2

AcOH/glycol (2:1) O

120 °C, 60-90%

O R

O

R

N R2

N H

O

N

85 H

62

O

N

O

=

Y

R=H, 59% R1 O

O

R

N R2

N

O

Chloranil, DMF 3-5 min 95-98%

N

86 R1=R2= H

O

O HN H3CS 1

O

O

5h N 87

NH2

62

R

N

N H

O

HN H3CS

88

H

R

O

S R=

; 77%

Scheme 33 Three-component reaction of aldehydes (62), indandione (1), and 6-amino-2-methylthiouracil (87)

In a similar method, indandione (1), aldehyde 62 and 5aminopyrazole (100) reacted to form indeno[2,1-e]pyrazolo [3,4-b]pyridine-5(1H )-one derivatives (101) in ionic liquid 94 without any catalyst (Scheme 41) [58]. The results show that the electronic nature of the substituents has no signif-

123

icant effect on this reaction; thus, aromatic aldehydes with either electron-withdrawing or electron-donating groups provide excellent yields under the same conditions (75–89 %). This efficiency is also observed when using heterocyclic aldehydes (79–80 %). The same reaction was performed using InCl3 (20 mol%) as catalyst in refluxing water. The desired products 101 were synthesized in 87–93 % yields in 45–60 min [44]. Indenopyridine-based heterocyclic scaffolds 104 can be obtained through a three-component reaction of indandione (1), aldehydes 62 and amine-containing aromatic compound (103) in acetic acid and glycol media (Scheme 42) [59]. The optimized condition requires that oxygen gas is bubbled into the reaction mixture to promote the conversion of intermediate dihydropyridine-containing compounds to

Mol Divers Scheme 34 Generation of 5-oxadiazabenzo[b]fluorenones (90) using InCl3 or P2 O5 as catalysts

O

O N

O

N

Solvent-free 100 °C

O

1

O

N

O

O

90

89

O R

R

N

InCl3 or P2O5

O

O

H 62

Scheme 35 Fe3 O4 @SiO2 −SO3 H magnetic nanoparticles catalyzed the synthesis of tetraketone derivatives (91)

O

O O 2 O

1 Scheme 36 Cyclopropane derivatives (92) synthesis

H2O, r.t., 20-245 min

OO

62

91 81-97%

O

O

O 2

R 1

R

O

I2, DMAP H

ball-milling (30 Hz) r.t., 60 min

62

O

O

Fe3O4@SiO2-SO3H H

Ar

Ar

OO 92 9 examples 60-89%

Scheme 37 Preparation of indenoquinoline derivatives (94)

O

O

O R2 R2

R1HN O

1

p-TSA H2O or MW

93

O

R2

NH2

R

N R1 94 23 examples 86-94%

62

O

O

R2

H

R

R

O

O

OH

H2O (ref.)

R

O

SA (3 mol%)

1

R1 52

O O H

R 62

or MW

R

N H 95 17 examples 93-98%

Scheme 38 The reaction of various enaminones with aldehydes (62) and indandione (1)

their aromatic counterparts. As illustrated in Scheme 42, fifteen different aldehydes (aliphatic, aromatic, heteroaromatic, formaldehyde) gave the corresponding product 104 in 33– 80 % yield. This protocol was extended to different amine-containing components 105 (Scheme 43). These novel studies led to the discovery of the novel indenoheterocycles 106 and 107 which

1

O

O

96 H

R 62

solvent-free 120 °C

O 97 10 examples 84-94%

Scheme 39 Sulfamic acid catalyzed the synthesis of indenonaphthopyrans (97)

exhibit potent cytotoxic and apoptosis inducing properties (Fig. 3). Heteropolyacids (HPAs) and their salts [60] are also efficient acidic materials to carry out many typical acidcatalyzed reactions. For instance, H6 P2 W18 O62 ·18H2 O is a kind of Wells–Dawson-type HPA catalyst that efficiently catalyzes several reactions [61–63] such as the three-component coupling of 1-naphtylamine (108), aldehydes 62 and indan-

123

Mol Divers

O

Ar H2N

O

1

O

98

N H

N

H2O

N

MW

N H

N

99 9 examples 76-83%

H

Ar

O

62

Scheme 40 The treatment of indandione (1), 3-methyl-1H -pyrazol-5amine (98), and aldehyde 62 under microwave irradiation C4H9-n N BrN [bmim]Br O

Ar N

H2N 1

102

O

N Ph 100

O

102

N

95 °C

N Ph

N

101 17 examples 75-89%

H

Ar

O

62

Scheme 41 The formation of indeno[2,1-e]pyrazolo[3,4-b]pyridine5(1H )-one derivatives (101) O

O H2N

1

O

O

R

N H

R

O

NH AcOH/glycol (2:1)

O

HN

120 °C, O2 bubbling

N H

103

N

104 15 examples 33-80%

H 62

Scheme 42 The synthetic pathway for preparation of indenopyridinebased heterocyclic scaffolds (104)

dione (1) in refluxing acetic acid to give the corresponding product 109 in 92–97 % yield (Scheme 44) [64]. Another reaction was reported by Heravi et al. which involved the reaction between indandione (1), aldehyde 62 and 2-amino benzimidazole (110) or 3-amino-1,2,4-triazole (111) (Scheme 45) [65]. This reaction was performed in refluxing acetonitrile and catalyzed by sulfamic acid (SA). Surprisingly, the Knoevenagel products 9 were obtained from the condensation of indandione and aldehyde. This reaction Scheme 43 Generation of novel indenoheterocycles 106 and 107

O

R

H2N 1

O

H 62

X 105

O

R

123

was investigated using eight different aldehydes and only the Knoevenagel products 9 were obtained. This group also reported the MCR of 1, 62 and cyclohexylisocyanide (112) in water where the reactions were catalyzed using tetraethyl ammonium chloride to give 113 (Scheme 46) [66]. As shown in Scheme 47, the synthesis of 2(cyclohexylamino)-3-aryl-indeno[1,2-b]furan-4-ones (113) likely occurs in two steps. First, the condensation reaction of 1 with an aromatic aldehyde takes place followed by the nucleophilic Michael addition of cyclohexylisocyanide to give the intermediate 114, which in turn affords the desired product 113 after an intramolecular rearrangement. The treatment of indandione (1) and aldehydes 62 with 4,5,6-triaminopyrimidine (115) via a three-component reaction leads to new regioisomeric dihydroindeno[1,2-e] pyrimido[4,5-b][1,4]diazepin-5(5aH )-ones (116a-f) (Scheme 48). This bi-component approach provided a reliable method for the preparation of 118a–f in good yields and their regioisomer (119a–c) in lower yields by using 2,4,5,6tetraaminopyrimidine (117) and 2-arylideneindandiones (9a– f) as reagents [67]. Bavantula et al. developed the new tri-molecular synthesis of stereoselective polysubstituted cyclopropane derivatives (121) via the one-pot two-step tandem reaction of 4-chloro phenacyl bromide (120), indandione (1) and aromatic aldehydes (62) with pyridine in acetonitrile using triethylamine as catalyst (Scheme 49) [68]. The mechanistic pathway of this transformation involves the reaction of 4-chloro phenacyl bromide (120) with pyridine to give pyridinium ylide. Then, the cyclopropanation of the pyridinium ylide with 2-arylidene-2H -indene1,3-dione catalyzed by triethylamine leads to the formation of trans-2-(4-chlorobenzoyl)-3-arylspiro[cyclopropane1, 2 -inden]-1 ,3 -diones (121). X-ray crystal diffraction data clearly shows the highly stereoselective formation of desired products as trans spiro-cyclopropane. Fused dihydroindeno[1,2-b]furans (123) are isolated with ease from the three-component reaction of indanedione (1), aromatic aldehyde (62) and N -phenacyl pyridinium bromide 122 in the presence of triethylamine as a catalyst (Scheme 50) [69]. It appears that the dihydroindeno[1,2-b]furans 123 formed in a diastereoselective manner with excellent yields under microwave irradiation in solvent-free conditions.

AcOH/glycol (2:1) 120 °C, O2 bubbling

R

O or

X

X N H 107

N 106 13 examples 30-72%

O

Mol Divers Fig. 3 Structures of various amines (105)

O

H2N

H2N

X

H2N

105

Me

N

N N Ph

H2N

O

Scheme 44 Three-component coupling of 1-naphtylamine (108), aldehydes 62 and indandione (1)

H2N

OMe

O

N Me

O

N H

S H2N

N H

NH

O H2N

N H

NH H2N

N H

O

H6P2W18O62 18H2O O

108

O

AcOH

N H 109 7 examples 92-97%

H

O

O

O O

O Ar

H

1

H N

N

NH2

N

111

O Ar

Ar

Ar

62

O

9

O

NH

62

N H NH2SO3H CH3CN

N N H

H2N

NH2

Ar

NH2

N

N Ph

Ar

1

1

SMe

Me

H2N

N

H2N

O NH

H2N

N Ph

OMe

Me

N H

H2N

OMe

OMe

O

N NH2SO3H CH3CN

O

H 62

O

O H

110

O

Ar N

114

O

Scheme 45 The Knoevenagel product (9) were obtained by the following reaction

C N

112

O Ar

O

O

NC

Ar H2O

1

O

O

112

Et4N+Br-

H

Ar 62

Scheme 46 Synthesis [1,2-b]furan-4-ones (113)

of

N O H 113 7 examples 91-93%

2-(cyclohexylamino)-3-aryl-indeno

The proposed mechanism shows that an initial Knoevenagel condensation occurred between indandione 1 and aromatic aldehyde 62 to give the intermediate (7) (Scheme 51). In the second step, the Michael addition between N -phenacyl

O

N H

113 Scheme 47 Proposed mechanism of reaction

pyridinium bromide 122 with triethyl amine led to pyridinium ylide (124). Finally, the latter is subjected to intermediate 7 to afford the enolate intermediate (125). The desired dihydroindeno[1,2-b]furan 123 is obtained by pyridine elimination and cyclization. The triethylamine can be released from Et3 N/HBr salt and acts as catalyst via eliminated pyridine.

123

Mol Divers

NH2 N NH2

N

N H

116a-f 71-96%

O

O

R

O

N NH2 115

N

N

R

NH2

9a-f

DMF (150 °C) MW 0.5-1.5 min

1

O

O

CHO 62

80 °C MW 6 min

R= NO2, Cl, Br, H, CH3, OCH3

R

NH2 NH2

N H2N

Three-component process

N 117

NH2 R

NH2 N

N H2N

N

N

O

N H

H2N

118a-f 65-92%

NH2 H N N

O

N

119a-c 8-20%

R

Bi-component process Scheme 48 Three-component and bi-component treatments of indandione (1) and aldehydes (62) with 115 or 117 Scheme 49 The stereoselective synthesis of polysubstituted cyclopropane derivatives (121)

R O

O

H

O

Br

O

i) CH3CN, C5H5N r.t., 30 min O

R

1

ii) Et3N 8-10 h

Cl

62

O 121

120 R= 3,4-(OMe)2; time= 9 h, yield= 58% R= 2-OH; time= 10 h, yield= 63% R= 4-OH; time= 9 h, yield= 55% R= 2-OH,3-OMe; time= 8 h, yield= 57% R= 4-OH,3-OMe; time= 8 h, yield= 60% R= 4-N(Me)2; time= 10 h, yield= 52% Scheme 50 Fused dihydroindeno[1,2-b]furans (123) formation catalyzed by triethylamine

O

O N

Br− Ph

1

R2 62

Et3N

Ar

MW O

O 122

Ar= C6H5; time= 3 min, yield= 72% Ar= 4-MeC6H4; time= 2 min, yield= 75% Ar= 4-OMeC6H4; time= 3 min, yield= 78% Ar= 2-MeC6H4; time= 6 min, yield= 68% Ar= 2-OMeC6H4; time= 5 min, yield= 69% Ar= 4-BrC6H4; time= 4 min, yield= 62%

123

R= H; time= 10 h, yield= 67% R= 2-Cl; time= 10 h, yield= 69% R= 3-Cl; time= 8 h, yield= 72% R= 4-F; time= 9 h, yield= 64% R= 3-NO2; time= 10 h, yield= 62% R= 4-Me; time= 10 h, yield= 52% R= 4-OMe; time= 9 h, yield= 62%

CHO R1

O

Cl

O

COPh

123 Ar= 4-ClC6H4; time= 4 min, yield= 63% Ar= 4-NO2C6H4; time= 5 min, yield= 54% Ar= 4-FC6H4; time= 5 min, yield= 52% Ar= 2-BrC6H4; time= 4 min, yield= 58% Ar= 2-OHC6H4; time= 7 min, yield= 60% Ar= 2-ClC6H4; time= 6 min, yield= 59%

Mol Divers Scheme 51 The mechanism of the reaction

NEt3 O

O

H

Ar

1

Ar

MW 1

N

2

Br− Ph

Et3N

O

O

9

N Ph

- Et3NH Br O 124

O 122

O

O N

Ar 3

9

Ar

COPh N

O

O

O

Ar

Ph

Scheme 52 Preparation of 2-[(aryl)-(3-hydroxy-6-methyl4-oxo-4H -pyran-2-yl) methyl]indan-1,3-dione (127)

O

O

Ar

Ar

H 62

O

IL [bmim+][BF4−]

O

O

OH

1

O

Ar= 4-ClC6H4; time= 2.3 h, yield= 90% Ar= 4-BrC6H4; time= 1.5 h, yield= 86% Ar= 3,4-Cl2C6H3; time= 1.4 h, yield= 95% Ar= 2,4-Cl2C6H3; time= 0.3 h, yield= 90% Ar= 3-ClC6H4; time= 0.8 h, yield= 74% Ar= 2-BrC6H4; time= 0.7 h, yield= 81% Ar= 2-ClC6H4; time= 0.8 h, yield= 81% Ar= 3-FC6H4; time= 0.9 h, yield= 82%

R

O O

(±) Lactic acid O

O

O

R

H

1

Ar= 2-CF3C6H4; time= 1.1 h, yield= 77% Ar= 3-CF3C6H4; time= 0.4 h, yield= 94% Ar= 2-CH3OC6H4; time= 4.3 h, yield= 76% Ar= 3,4-(CH3)2C6H3; time= 1.2 h, yield= 85% Ar= 3-CH3OC6H4; time= 1 h, yield= 75% Ar= 4-CH3C6H4; time= 2.3 h, yield= 73% Ar= 4-FC6H4; time= 0.6 h, yield= 78%

NH2

O

OH O 127

126

O

O

O

Et3N, 80 °C

O

62

2-[(Aryl)-(3-hydroxy-6-methyl-4-oxo-4H -pyran-2-yl) methyl]indan-1,3-dione derivatives 127 have also been synthesized from the reaction of indandione (1), aldehydes (62), and 5-hydroxy-2-methyl-4H -pyran-4-one (126) in the presence of Et3 N as basic catalyst and ionic liq◦ uid [bmim+ ][BF− 4 ] as solvent at 80 C (Scheme 52) [70]. Although the corresponding allomaltol derivatives were prepared in good yields with aromatic aldehydes carrying both electron withdrawing and electron-donating substituents,

COPh

123

125

124

O

Scheme 53 Treatment of indandione (1), aromatic aldehyde (62) and 4-aminocoumarin (128) leading 129

Ar

- H2O

OH

O

O

O

O

O H 62

128

O

Ethyl L-lactate 100 °C

N H 129

the reactivity of aldehydes with electron withdrawing groups was found to be faster than those with electron-donating groups. Indenodihydropyridine and dihydropyridine derivatives 129 were obtained in 2–3 h with 73–85 % yields by the treatment of indandione (1), aromatic aldehyde (62) and 4aminocoumarin (128) in the presence of an organo-catalyst (±)lactic acid (2.0 mmol) at 100 ◦ C in ethyl L-lactate as a green solvent [71] (Scheme 53).

123

Mol Divers

NH

O

O

H N

O

N

N OO 137 86%

83

TMGTf 80 °C, 5 min

R2

R1 133 91-93% R1= H, R2= H, Cl, I

R2 O H2N 134

O

TMGTf 80 °C, 5 min

O

X

TMGTf 80 °C, 5 min

O 136

Y

N 130 R1

1 O

Z

OO

O N

N H 138 94%

Z

O

R2

X= H, NH2 Y= H, NH2 131 Z= H, Br H N

H N

O

O

N

TMGTf 80 °C, 5 min

O

O

O

O

O

N

H2N

135

O

N

or

O

O N

R2

R1

R1

132 90-97% R1= H, Bn R2= Cl, Br, I, H, NO2, CH3, OCH3 Z= H, Br

Scheme 54 Diversity of three-component reaction of indandione (1) with isatin (130) and 1- or 2-naphthalenamine (134)

Three-component reaction of indandione with an isatin

H N

H N

O

N

A three-component reaction between indandione (1), isatin derivatives 130 and 1- or 2-naphthalenamine (134), catalyzed by ionic liquid N ,N ,N ,N -tetramethylguanidinium triflate (TMGTf) leads to fused spiro[1,4-dihydropyridineoxindole] compounds (132) [72]. When 2-aminouracil (83) is used instead of naphthalenamine (131) the desired product 133 is obtained. Likewise, when 2-naphthaleneamine (134) is employed instead of isatin 130 and reacted with acenaphthylene-1,2-dione (135) or 1H -indene-1,2,3-trione (136), the structurally related spirocyclic products 137 and 138 were obtained in satisfactory yields and short reaction time (Scheme 54). As shown in Scheme 54, the reaction of indandione (1), isatins 130 and 2-aminouracil (83) in the presence of (TMGTf) as catalyst leads to 133. The products were isolated in 5 mins with 91–93 % yields. This reaction was further investigated by Mohammadi Ziarani et al. in the presence of nanocarbon material as an acidic catalyst and the final products were obtained in very short reaction times (10–30 min) with good to excellent yields (70–95 %). In addition, the biological activity of the compounds was examined and the results revealed the urease inhibitory activity of these materials [73].

123

N

O O

O

O O

O Br

NH

NH

2.5h 90%

2.5h 93%

H N

H N

H N

O

H N

2.5h 91%

O O

O

O O NH

O N

NH O

O

N

N

Br

NH 2.5h 90%

Fig. 4 Structures of uracil-fused spirooxindole derivatives 133

Compound 133 was obtained through the one-pot threecomponent domino coupling of indandione (1), 6-aminouracil/4-aminocoumarin, and isatin/5-bromoisatin 130 by using PEG-SO3 H (15 mol%) as catalyst in aqueous media at 70 ◦ C [74]. The synthesized uracil-fused spirooxindole derivatives 133 are shown in Fig. 4.

Mol Divers Scheme 55 The reaction of indandione (1), various isatins (130) and 2-aminouracil (83)

X

O RN

NR1

O O O

1

O O

NH2 O

EtOH

83 O

NR

4h

135 O HN

When:

O NH

O

MeN

NH2

H2N

NMe NH2

O

HN NH2

O

78%

Ph

N O

N H Ar 141 24 examples 73-94%

EtOH (reflux) 2h

1

130

R N O

1

130

O

NR

NH2

O

O

p-TSA EtOH/H2O (1:5) 80 °C

X O

X N H 143

N N N H H 144 49% R=H,X=H

Scheme 57 Synthesis of 144 catalyzed by p-TSA

O

p-TSA 80 °C

X

NR O

O N

N

O

X

HN

NH2

N N H

100

NH2 82%

O X O

N

O N

Ph

R N

N

O

85%

N

140

HN

NH2

NR O

Ar N N

SMe

O

89%

X

X

N N R1 H 139 78-89%

O

N

142 45% R=H, X=H

Scheme 56 Formation of spiropyrazolopyridine-spiroindolinone compounds (141 and 142)

H2N

R N

X

O 1

O

130

O

NR N 145

NH2 O

O O

EtOH (reflux) 4h

NH N N H 146a-j 10 examples 73-82%

NH2

Scheme 58 Treatment of 2,6-diaminopyrimidin-4(3H )-one (145) with indandione (1) and various isatins (130) to give 146a-j

Earlier, the same method was employed to form the corresponding adducts 133 in refluxing ethanol without using a catalyst with 82–95 % yields in 3 h [75]. This protocol was extended using various isatins 130 and 2-aminouracil (83). When 130 was used instead of acenaphthylene-1,2dione (135), the adduct 139 was obtained in good yields (78–89 %) under the same reaction conditions (Scheme 55) [75]. Pyrazolo[3,4-b]pyridines are nitrogen-containing heterocycles with varied biological properties [76–79]. Spiropyrazolopyridine-spiroindolinone compounds (141, 142 and 144) are obtained by the three-component reaction of 5-aminopyrazoles (100, 140 and 143), isatin (130) and indan-

dione (1) in EtOH and no catalyst under reflux conditions [80] or in aqueous media using p-TSA as catalyst (Schemes 56 and 57) [81]. Chen and Shi developed the synthesis of 142 in the presence of 10 mol% CAN (Ceric Ammonium Nitrate) as catalyst in aqueous conditions at 80 ◦ C. Three derivatives of 142 were prepared in 88–91 % yields in 6–8 h [82]. 2,6-Diaminopyrimidin-4(3H )-one (145) was treated with indandione (1) and various isatins 130 to give 2-amino-1H spiro[indeno[1,2-b]pyrido[2,3-d]pyrimidine-5,3 -indoline]2 ,4,6(11H )-triones (146a–j) in 73–82% yields under the same reaction conditions (Scheme 58) [80].

123

Mol Divers O

O

Ph

NH2

N O

1

O

N Ar

R

NH2 EtOH (reflux) 140

O

O Ph

O

2h N H

1

N N Ar

Scheme 59 Synthesis of 1 -aryl-3 -phenyl-1 H, 2H spiro [acenaph thylene-1,4 -indeno[1,2-b]pyrazolo[4,3-e]pyridine]-2,5 (10 H ) diones (147) O

X

NH2

NR1 O

R2 1

O X

148a-c R1 N O

O 130a-e R1= H, Me, Et R2= CN, COOMe, COOEt

1-propanol L-proline (20 mol%)

O R

10 h

2

N H 149

Scheme 60 Synthesis of spiro[indeno[1,2-b]pyridine-indoline] deriva tives (149)

When isatin (130) was replaced by acenaphthylene1,2-dione (135), 1 -aryl-3 -phenyl-1 H, 2H spiro [acenaph thylene-1,4 -indeno[1,2-b]pyrazolo[4,3-e]pyridine] -2,5 (10 H ) diones (147) were obtained in good yields (Scheme 59) [80]. Looking for amino acid catalysts, L-proline (77) can catalyze two-carbon homologation and various one-pot multicomponent processes [83–86]. More recently, proline was used to produce spirooxindoles [87]. Spirooxindoles are interesting materials because their scaffolds are present in many pharmacological agents and natural alkaloids [88,89]; hence, several methods have been reported for the preparation of spirooxindole-fused heterocycles [82,90–92]. The one-pot, three-component condensation of indandione (1), isatins (130), and enamines (148) led to the formation of spiro[indeno[1,2-b]pyridine-indoline] derivatives (149) (Scheme 60) [93]. The authors report that the presence of acenaphthylene1,2-dione (135) instead of 130 gave spiro[acenaphthyleneindeno[1,2-b]pyridine] derivatives 150 in good yields under the same reaction conditions (Scheme 61). For carbon-carbon bond forming procedures, the Friedel– Crafts alkylation and acylation reactions remain the methods of choice for the introduction of substituents on arenes and heteroarenes using catalytic amounts of a Lewis acid [94].

123

O

1-propanol L-proline (20 mol%)

O

O

R

10 h N H

147 Ar= C6H5, yield= 88% Ar= 4-NO2-C6H4, yield= 89%

135

148a-c

O O

135

150 R= CN; yield= 84% R= COOMe yield= 80% R= COOEt; yield= 79%

Scheme 61 Synthesis of spiro[acenaphthylene indeno[1,2-b]pyridine] derivatives (150)

The first report for the preparation of unsymmetrical oxindoles (152–154) based on a Friedel–Crafts type threecomponent reaction was introduced by Bazgir et al. in 2011. The reaction included indandione (1), N ,N -dimethylaniline (151) and isatins (130) in ethanol using LiClO4 as catalyst [95]. Using both acenaphthylene-1,2-dione (135) and ninhydrin (136) instead of 130 provided products 152–154 in 73 and 60 % yield, respectively (Scheme 62). The spiro(dihydropyridine-oxindole) scaffold (137, 138 and 155) and its derivatives were constructed in the presence of p-TSA in a combinatorial approach via a three-component reaction (Scheme 63) [96]. In this context, indandione (1), isatin 130 and naphthalen-2-amine (134) in aqueous medium were condensed and the adduct was isolated in 78–85 % yield. Liang et al. used a novel Lewis acid-catalyzed, threecomponent method for the synthesis of spirooxindoles 157 and 159 [97]. This coupling consists of isatin derivatives 130 and two pKa differentiated 1,3-dicarbonyls to synthesize various spirooxindoles bearing a pyranochromenedione ring system. The results are shown in Schemes 64 and 65 when indandione was used as the 1,3-dicarbonyl source by two different methods. The dipolarophiles 2-arylidene-indanediones (9a–e) can be easily obtained via a three-component condensation of indandione (1) with various benzaldehydes 62 [98]. This method was introduced by the Raghunathan group and the procedure involves the reaction of tetrahydroisoquinoline-3carboxylic acid (160) with acenaphthenequinone (135) or isatin (130) under different conditions to give an azomethine ylide. The ylide intermediate undergoes a 1,3-dipolar cycloaddition with 2-arylidene-indanediones (9a–e) in a onepot three-component reaction to give a single cycloadduct (161 and 162) (Scheme 66). This group carried out this reaction using different methods: silica, BiCl3 –silica or TiO2 –silica under MW irradiation. The best results were obtained by the last method (method C). In 2014, Yan et al. described the synthesis of a series of 2 -aryl-2 -(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2 ,3 dihydro-10b H-spiro[indene -2,1 -pyrrolo[2,1-a]isoquinoli-

Mol Divers Scheme 62 Synthesis of unsymmetrical oxindoles

N O O

O

O

136 O O O

O 154 60%

O N

O

N

O

EtOH LiClO4 (10 mol%)

O

135

O 153 73%

O 1

151 R N X

NR

X

O

OO

130 O O

N

152 R= H, Me, Et, X= H, Br, NO2, Me, F,

Scheme 63 Synthesis of spiro(dihydropyridine-oxindole) scaffolds

O O

O O

136 O

O

O NH2

H2O:EtOH (5:1) p-TSA

1

N H

O

138 79%

O

135 O

60 °C O

O

134 N H

137 81%

R N X

O X

NR O

130 O O

N H 155 78-85%

123

Mol Divers Scheme 64 Synthesis of spirooxindoles 157 using two different methods

O HO

O O

N protocol A or B O

O

1

O O

156

O

N O

O

157 protocol A: time: 12h, yield: 60% protocol B: time: 80 min, yield: 39%

130 O

Protocol A: SnCl4 (10 mol%), Cl(CH2)2Cl, 60 °C Protocol B: SnCl4 5H2O (10 mol%), Cl(CH2)2Cl, MW, 80 °C O

O

O protocol A or B

1

O O

O

158

O

involves the condensation and cycloadditionreaction of an in situ generated isoquinolinium ylide. The generality of this three-component reaction was determined by treatmenting isoquinolinium salts (163), acenaphthenequinone (135) and indandione (1) under similar reaction conditions (Scheme 68). The desired 2 -acenaphthylidenespiro[indane-2,1 -pyrrolo[2,1-a] isoquinolines] 165a,b were produced in 67 and 72 % yields, respectively. Another three-component reaction was performed by Asadi et al. using indandione (1), 2-naphthol (96) and isatins (130) to give spironaphthopyrano[1,2-b]indeno-7,3 indolines (166) with 50–92 % yields [100]. The optimized conditions were found to be solvent-free and catalyst-free conditions at 130 ◦ C (Scheme 69).

N

N O O 130

O 159 protocol A: time: 16h, yield: 63% protocol B: time: 80 min, yield: 47%

Scheme 65 Synthesis of spirooxindoles 159 via two different methods

ne]-1,3-diones (164) [99]. These compounds were obtained via the three-component reactions of in situ generated N -phenacylisoquinoliniumbromides (163), indandione (1) and isatins (130) in ethanol using triethylamine as base (Scheme 67). The domino mechanism of the reaction Scheme 66 Preparation of cycloadducts (161 and 162) with various procedures

O O

O

O N O

H 135

161

R O

R R= H, Cl, Me, OMe, NO2

COOH NH

H O 9a-e

160 Method A: silica/MW Method B: BiCl3-silica/MW Method C: TiO2-silica/MW product

123

Method A

Method B

H N

NH O

O 130 O

Method C

161

time: 4.5- 8 min yield: 42-60%

time: 5- 6.9 min time: 2.5-3.6 min yield: 68-77% yield: 82-95%

162

time: 4-6.4 min yield: 50-61%

time:4.2-6 min yield: 66-78%

time: 2.3-3.6 min yield: 81-95%

O N H

O 162

R R= H, Cl, Me, OMe, NO2, NMe2

Mol Divers Scheme 67 Synthesis a series of 164

R1 O

O R1

Br O N R2

O 1

Scheme 68 The generation of 2 -acenaphthylidenespiro [indane-2,1 -pyrrolo[2,1-a] isoquinolines] 165a,b

Ar

N

O Ar

O O

R2

OH O 164

O

O

Br

Et3N

N O 1

N

EtOH, 50 °C

163

130

O

Et3N

N

Ar 163

135

EtOH, 50 °C

N O Ar

O

OH O

O 165 Ar= Ph, yield= 67% Ar= 4-ClC6H5, yield= 72%

Scheme 69 Synthesis of spironaphthopyrano[1,2b]indeno-7,3 -indolines (166)

O

OH O

O

O 130a-e

130a: R=H, X=H 130b: R=Me, X=H 130c: R=Bn, X=H 130d: R=H, X=Br 130e: R=H, X=Cl

O

O O R1 1

O

H 62

R2NH2

R3NC

167

168

HN R2

Et2O r.t., 24h

O

Solvent free

O O

130 °C

X 1

NR

X

R N

R1 HN R3 169

Scheme 70 Synthesis of 1,3-indandionylamidinium betaines (169)

Four-component reaction of indandione A novel method for the synthesis of 1,3-indandionylamidinium betaines 169 was described by Bazgir et al. The fourcomponent reaction of indandione (1), aldehydes 62, amines 167, and isocyanides (168) was carried out under mild reaction conditions and no catalyst (Scheme 70) [101]. Due to the important applications of ferrocenyl compounds in various fields such as materials chemistry [102] ferrocenecarboxaldehyde (170) was used in a same reaction to obtain new ferrocenyl amidinium betaines (171) (Scheme 71). Indeno[1,2-b]pyridines (174) were synthesized through a combination of 1, propiophenone or 2-phenylacetophenone (172), aromatic aldehydes 55, and ammonium acetate (173).

96

O 166a-e

This combination was examined by Tu et al. in 2007 using microwave-assisted synthesis in DMF as solvent at 120 ◦ C. The desired products with different substitutions were produced in 62–89 % yields [103]. In 2011, Mukhopadhyay et al. used ceric ammonium nitrate (CAN) as an inexpensive, nontoxic and readily available catalyst for the construction of carbon–carbon and carbon heteroatom bonds [104]. The optimized condition of this reaction is mentioned in Scheme 72. In order to expand the application of this catalytic system, the synthesis of 2,3,4,5,6-pentasubstituted pyridines (175) via the one-pot three-component condensation of aromatic aldehydes 62, ammonium acetate (173) and acetophenone derivatives 172 was investigated under the same reaction conditions. As depicted in Scheme 73, the products were obtained in all cases with excellent yields. In an elegant design, 4-azafluorenone (176) as an important naturally occurring alkaloids and the imidazole moiety, with pharmacophoric properties were inserted in one molecular platform (molecular hybridization) (Fig. 5) [105,106]. For preparation of the above scaffold, condensation of 1benzyl-2-butyl-4-chloroimidazole-5-carboxaldehyde (177), 1, aryl/hetero aryl methyl ketones (178) and ammonium

123

Mol Divers Scheme 71 Synthesis of new ferrocenyl amidinium betaines (171)

O CHO Fe 1

O

R2NH2

170

R3NC

167

O

Et2O

HN R2

r.t., 24h

O

HN R 3

168 Fe 171

R1 O

O

CAN (10 mol%) EtOH (5 mL)

R2

H

R1 1

O

O

NH4OAc

62

172

O R2

25-30 °C 3-5h

N

173

174 10 examples 84-94%

R1= 4-Cl, 4-NO2, 3-NO2, ... R2= CH3, Ph Scheme 72 Preparation of indeno[1,2-b]pyridines (174) Scheme 73 Synthesis of 2,3,4,5,6-pentasubstituted pyridines (175)

R1 O

H

O

CAN (10 mol%) EtOH (5 mL)

R2 NH4OAc

2 R1

62

172

R1= 4-Cl, 4-NO2, 3-NO2, ... R2= CH3, Ph

Natural product Fragment Cl O

N N

N R Fragment from Drug molecule 176

Aromatic or heterocyclic units

Fig. 5 The detailed structure of 4-azafluorenone (176)

acetate (173) under refluxing DMF was performed to produce novel 1-benzyl-2-butyl-4-chloroimidazole embodied 4-azafluorenone hybrids (176) (Scheme 74) [107]. In addition, the antimicrobial activity of the synthesized compounds was evaluated using a disk diffusion method against selected bacteria and fungal strains.

123

25-30 °C 3-5h

R2

R2 N

173 175 5 examples 88-92%

The synthesis of indeno[1,2-b]quinoline-9,11(6H, 10H )diones (180) from aldehydes 62, dimedone (179), indandione (1), and amines 52 in refluxing ethanol was reported [108]. This procedure was performed via a one-pot four-component reaction in refluxing ethanol or by the three-component reaction of 1, 62, and 5,5-dimethyl-3-arylamino-cyclohex2-enone derivatives (181) at 120 ◦ C under solvent-free conditions. Both scenarios were catalyzed using Preyssler-type heteropolyacid H14 [NaP5 W30 O110 ] (Schemes 75 and 76). In 2013, the same reaction was reported using TiO2 nanoparticles as a heterogeneous catalyst at 80 ◦ C in aqueous media. The results revealed that the reaction proceeds in a short reaction time (2 h) with excellent yields (95–98 %) [109]. Shirini et al. have established a novel method for the preparation of unsymmetrical dihydro-5H -indeno[1,2-b]quinolines (182) involving Knoevenagel reaction of indandione (1) and aldehyde 62 and sequential condensation of dimedone (179) with ammonia (173) [110]. In the next step, the condensation of these two fragments gave an acyclic Michael adduct, which finally underwent intramolecular cyclization to form dihydroindenoquinoline (182) (Scheme 77). The above reac-

Mol Divers

N

N

O

Cl

N

O

NH4OAc 173 DMF 3-4h

R1

CHO

177

1

178

O

Cl O

N N 176

R1

Scheme 74 Synthesis of 4-azafluorenone hybrids (176) Scheme 75 One-pot four-component synthesis of indeno[1,2-b]quinoline9,11(6H , 10H )-diones (180)

Ar′CHO

ArNH2 52

O

N Ar

EtOH

179

O

H14NaP5W30O110 (0.42 mol%)

O 1

Ar′

O

O

O

62

180 Scheme 76 Two steps synthesis of 180

O

O 179

ArNH2 52 Ar= Ph, 4-Me H14NaP5W30O110 (1 mol%) EtOH

O

O Ar′CHO

181

NH Ar

1

O

H14NaP5W30O110 (0.42 mol%)

62

Ar′

O

solvent-free 120 °C 180

Scheme 77 Preparation of dihydroindenoquinoline (182)

O

O

O

RCHO

NH4OAc O

1

O

62

179

173

O

N Ar

O

R

MSTA EtOH

N H 182 65-85%

tion was catalyzed by melamine trisulfonic acid (MTSA) in refluxing ethanol. The synthesized product 182 shows a sharp color change in the pH range of 9.2–12 and thus exhibited suitable properties to be used as a pH indicator (Fig. 6). Bazgir et al. reported another four-component reaction of 1, 1,3-dicarbonyl compounds, 130 or 135, and 173 in refluxing toluene in the presence of a catalytic amount of pyridine [111]. In this procedure several biologically interesting spirooxindole derivatives (184 and 185) were synthesized (Scheme 78). The same research group used a cyclo-condensation strategy for the preparation of spiro[diindeno[1,2-b:2 , 1 −

Fig. 6 The color changes of 182 in the pH range of 9.2–12

123

Mol Divers Scheme 78 Synthesis of spirooxindole derivatives (184 and 185)

O X O

X

N 130 R

N

O

O COR2

Py (15 mol%)

R1 1

N H

Toluene 24h

O R2 O

O

O 183

R

R1

184

26 examples NH4OAc 173

Py (15 mol%) Toluene 24h O

O

O COR1

O

N H

R2 185

R1= OMe, R2=Me; yield= 79% R1= OEt, R2=Me; yield= 80% R1= Me, R2=Me; yield= 75% 135

Scheme 79 Four-component reaction of isatin 130, indandione (1) (2 equiv.) and ammonium acetate (173)

R X O

O

O O 1

e]pyridine-11,3 -indoline]-triones (186) using isatin 130, 2 equivalents of indandione (1) and ammonium acetate (173) in refluxing acetic acid (Scheme 79) [112]. The proposed mechanism for this reaction is shown in Scheme 80. Initially, the addition of 1 to isatin 130 yields intermediate 187. Then 187 reacts with another indandione 1 to obtain 188, followed by addition of ammonium acetate 173, which was cyclized and dehydrated to afford the desired product 186. This method also works well when using ninhydrin (136) instated of 130 under the same reaction conditions affording desired product (189) in 78 % yield (Scheme 81). Several other MCRs via a four-component reaction of indandione (1), aromatic amines 52 and isatins 130 or acenaphthylene-1,2-dione (135) were described (Scheme 82). In 2009, this reaction was reported in refluxing acetonitrile and using p-TSA as catalyst with 75–92 % yield in 1 h [113]. The same research group examined this reaction using the ‘Grindstone method’ [114]. The ‘Grindstone method’ is a novel strategy introduced by Toda et al. based on the simply grinding of starting materials leading to the desired products in high yields [115]. This procedure was catalyzed using pTSA affording products with 80–91 % yields in only 3–4 min

N R 130

O O

O

X 2

123

N

NH4OAc

173

HOAC 24h N H 186 12 examples

as opposed to running the same reaction without a catalyst where even after 30 min the yields were low (