Synthetic routes to benzosuberone-based fused- and spiro-heterocyclic ring systems

Abstract

Natural products containing a benzosuberone nucleus are important class of medicinal and pharmaceutical compounds and have recently attracted a considerable amount of attention due to their remarkable broad-spectrum biological activity. The present review endeavors to highlight the progress in the synthesis of benzosuberones and their fused, as well as spiro, ring systems in the literature up to 2015.

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Thoraya A. Farghaly

Thoraya A. Farghaly was born in 1974 in Giza, Egypt. She graduated from Cairo University, Egypt in 1996 then she carried out his M.Sc. and Ph.D. studies in 2002 and 2005, respectively, at Cairo University in the field of organic synthesis. In 2010 she promoted to Associate Professor and in 2015 she was appointed as a full Professor of Organic chemistry at Cairo University. In 2013 she received the Cairo University Incentive Award in Chemistry. She joined the scientific school of Prof. A. S. Shawali in 1997 and she has published 76 scientific papers and reviews all in international journals in the fields of physical organic chemistry, chemistry of hydrazonoyl halides and bioactive heterocyclic chemistry.

Sobhi M. Gomha

Sobhi Mohamed Gomha is presently associate Professor of Organic Chemistry in the Chemistry Department, Faculty of Science, Cairo University. He received his B.Sc. (1995); M.Sc. (2002) and Ph.D. (2006) degrees from Cairo University. He joined the scientific school of Prof. A. S. Shawali in 1996 and he has published 74 scientific papers all in international journals in the fields of the chemistry of hydrazonoyl halides and heterocyclic chemistry of biological importance.

Kamal M. Dawood

Kamal M. Dawood graduated from Cairo University, Egypt in 1987 then carried out his M.Sc. and Ph.D. studies under the supervision of Professor Ahmad Farag, Cairo University and received his Ph.D. in 1995. In 1997 he was awarded the UNESCO Fellowship for one year and in 1999 he was awarded the JSPS (Japan Society for Promotion of Science) Fellowship for two years and worked in both periods with Professor T. Fuchigami at Tokyo Institute of Technology (TIT) in the field of ‘Electrochemical Partial Fluorination of Heterocyclic Compounds’. In addition, he was awarded the Alexander von Humboldt Fellowship at Hanover University in 2004–2005 with Prof. A. Kirschning (in the field of polymer supported palladium catalysed cross coupling reactions) and in 2007 and 2008 with Prof. Peter Metz at TU-Dresden (in the field of total synthesis of natural products). In 2002 he promoted to Associate Professor and in May 2007 he was appointed as Professor of Organic chemistry, Faculty of Science, Cairo University. In 2002 he received the Cairo University Award in Chemistry and in 2007 he received the State-Award in Chemistry. In 2012 he received the Cairo University Award for Academic Excellence. Currently he is working as a professor of Organic Chemistry at Kuwait University. He published about 110 scientific papers and reviews in distinguished international journals. There are about 1500 citations of his work from 1993 until 2015 (h-index 20).

Mohamed R. Shaaban

Mohamed R. Shaaban was born in 1971 in Cairo, Egypt. He graduated from Cairo University, Egypt in 1992 then he joined Professor Ahmad M. Farag's research group. He received his Ph.D. in 2001 at Tokyo Institute of Technology, Japan. In 2001 he was promoted to a Lecturer of Organic Chemistry at Cairo University and continued his research work on organic synthesis as well as on palladium catalyzed C–C cross-couplings. In 2009 he was promoted to Associate Professor of Organic chemistry, and in 2014 he was promoted to Professor of Organic Chemistry Faculty of Science, Cairo University.

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1. Introduction

Various methods are have been reported for the construction of the seven-membered benzosuberone derivatives, such as palladium-catalyzed intramolecular reactions, ring-closing metathesis and cycloaddition reactions.^1,2 Benzosuberone-based natural products are important class of medicinal and pharmaceutical compounds and have recently attracted a considerable amount of attention due to their remarkable biological activities. The benzosuberone unit constitutes the core structure of several natural products such as colchicine, isocolchicine, allocolchicine, theaflavin, bussealin E, demethylsalvicanol and feveline (Fig. 1), where all these natural products are clinically reported as anti-tumor agents.^3–9

Fig. 1 Some benzosuberone-based natural products.

In addition, benzosuberone derivatives possess potential bacteriostatic, anti-pyretic, anti-inflammatory, anti-ulcer, CNS-stimulant, CNS-depressant and anti-convulsant activities. Some of the derivatives are also known for anti-tumor activity in murine P388 cell line tests.¹⁰ Tricyclic antidepressants containing dibenzosuberone moieties mostly effect the autonomic and central nervous systems, and traditional anti-depressants, like imipramine,¹¹ amitriptyline¹² and noxiptiline¹³ which continue to be used as first-line drugs in treating depressive disorders.

The synthesis of benzosuberone and its fused heterocyclic derivatives is a topic of growing interest especially in medicinal chemistry. Efficient introduction of this moiety into bioactive molecules, especially in the positions responsible for their physiological profile, becomes a very important direction in pharmaceutical studies that stimulates work directed to elaboration of synthetic methodology for various compounds containing benzosuberone based fused heterocycles. The existing methods for direct synthesis of fused heterocycles do not always allow the introduction of benzosuberone based fused heterocyclic moiety in the required position of the molecule. As a result, a more flexible synthetic approach based on the application of simple and available benzosuberone derivatives is a good supplement for direct synthetic methods and is nowadays gaining importance.

In general, benzosuberone itself was obtained using different synthetic routes in quite reasonable to excellent yields, these methods include intramolecular cyclization of the corresponding carboxylic acids promoted by Brønsted acids or acyl halide. On the other hand some substituted benzosuberones were obtained from the corresponding substituted aldehydes. Metal catalyzed intramolecular hydroacylation of disubstituted alkenes afforded also the substituted benzosuberone derivatives. Other methodologies such as ring expansion of cyclic ketones were also used to access this important ring system.

The annulations of the heterocyclic ring system on the benzosuberone ring system are mainly based on the functionality of the seven membered ring fused to the benzene ring. The carbonyl group is a key function in the synthesis of the many fused systems. Active methylene group increases the reactivity and used in the construction of most of the heterocyclic ring systems fused to the seven membered ring. Sometimes the annulations occur on the benzene ring when the proper functional moiety present such as hydroxyl group. In the current review, we cast light on the main strategies for the synthesis of benzosuberone fused and spiro heterocyclic derivatives. The publications in this area over the last ten years are discussed. This review discloses the first extensive report on the methods of preparation of benzosuberone-based fused- and sprio-carbocyclic and heterocyclic ring systems. The benzosuberone-fused tricyclic, tetracyclic, pentacyclic, and heptacyclic structures as well as the benzosuberone-spiro heterocycles are comprehensively discussed in this review article.

2. Synthesis of 1-benzosuberone and its derivatives

2.1 Intramolecular cyclization of the corresponding acid derivatives

Benzosuberone 2a has been synthesized from the corresponding acid 1a by the classical intramolecular cyclization promoted by Brønsted acids (Scheme 1).^14–16 Nafion-H catalyst was also reported to effectively promote the intramolecular dehydrative cyclization of the acid 1a to yield benzosuberone 2a under mild condition.^17–24

Scheme 1

Substituted benzosuberones 2b–d were also obtained from the corresponding substituted aldehydes via three consecutive steps as shown in Scheme 2. Thus, benzaldehyde derivatives 3 were subjected to Wittig condensation with pentanoic acid phosphonium bromide using t-BuOK in DMSO to yield the aryl-pentenoic acid derivatives 4. Reduction of the double bond of 4 with H₂/PtO₂ in ethanol at room temperature followed by cyclization with polyphosphoric acid (PPA) afforded the corresponding benzosuberones 2b–d (Scheme 2).²⁵

Scheme 2

Benzosuberone 2a was alternatively obtained from the corresponding acyl halide 5 by a classical intramolecular Friedel–Crafts acylation, promoted by a Lewis acid such as AlCl₃, SnCl₄ or AgClO₄ (Scheme 3).^14–16

Scheme 3

Also, reaction of acyl chlorides with stoichiometric quantities of trifluoromethanesulfonic acid provided good yields of the benzosuberone derivatives 2 via the highly reactive sulfocarboxylic acid anhydride intermediates 6 (Scheme 4).^18,19

Scheme 4

Rhodium catalyzed intramolecular hydro-acylation of the disubstituted alkenes 7 resulted in the formation of substituted benzosuberone derivatives 2 in good yields (Scheme 5).²⁶

Scheme 5

2.2 Ring expansion of cyclic ketones

Treatment of the tetralone derivative 8 with tributyltin hydride (Bu₃SnH) in the presence of a catalytic amount of azobisisobutyronitrile (AIBN) in refluxing toluene gave two products; ethyl 1-benzosuberone-3-carboxylate 9 and ethyl 2-methyl-L-tetralone-2-carboxylate 10. Under conventional conditions (immediate addition of tributyltin hydride), the ring-expanded and non-expanded products 9 and 10 were obtained in 9% and 10% yields, respectively as depicted in Scheme 6.²⁷

Scheme 6

Reaction of 2-phenylsulfonylcyclopentanone 12 with 2-(trimethylsilyl)phenyl trifluoromethane-sulfonate 11 in THF solution in the presence of 18-crown-6 and KF yielded phenylsulfonylbenzosuberone 13 in a reasonable yield. Hydrogenolysis of phenylsulfonylbenzosuberone 13 using excess Raney Ni in ethanol at reflux afforded quantitatively 1-benzosuberone 2a ²⁸ (Scheme 7).

Scheme 7

2.3 Oxidation of the corresponding alcohols

Aerobic oxidation of alcohol 14 catalyzed by Ru@PMO-IL in TFT was reported to afford 1-benzosuberone 2a (Scheme 8, Method A).²⁹ Furthermore, an efficient Cu(I)-catalyzed oxidation of the alcohol 14 was achieved using di-tert-butyldiaziridinone under mild conditions and gave benzosuberone 2a in 91% yield (Scheme 8, Method B).³⁰ Recently, oxidation of 6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol 14 in the presence of H₂O₂ and the manganese complex Mn(S-PMB)(CF₃SO₃)₂ gave benzosuberone 2a in excellent yield (99%) as depicted in Scheme 8 (Method C).³¹

Scheme 8

In addition, the naphthoxide-bound iron (salan) complex was a good catalyst for oxidation of compound 14 (Scheme 8, Method D).³²

3. Synthesis of benzosuberone fused heterocyclic rings

3.1 Tricyclic fused systems

3.1.1 Benzosuberone fused with pyrroles. When benzosuberone 2a was treated with hydroxylamine hydrochloride in pyridine, it afforded the oxime 15 in 97% yield. Reaction of the oxime 15 with acetylene and lithium hydroxide monohydrate in DMSO gave the corresponding 1,4,5,6-tetrahydro-1-aza-benzo[e]azulene 16.³³ (Scheme 9).

Scheme 9

Synthesis of compound 21 was performed by condensation of the bromoketone 17 with ethyl cyanoacetate to give the cyanoketoester 18, which gave the pyrrole derivative 19 when treated with gaseous HCl in Et₂O. N-Methylation of 19 with Me₂SO₄ and KOH in EtOH, followed by dehalogenation of 20 with ammonium formate and Pd–C, gave the benzocycloheptapyrrole derivative 21 ³⁴ (Scheme 10).

Scheme 10

1-Benzosuberone 2a was readily converted into its epoxide 22 when treated with dimethylsulphoxonium methylide in dimethyl sulphoxide (DMSO). Treatment of the epoxide 22 with sodium azide and lithium chloride in dimethylformamide (DMF) led to the formation of the corresponding azido alcohol 23. Dehydration of the azido alcohol 23 to the vinyl azide 24, was carried out using thionyl chloride in pyridine. The cyclohepta[cd]indole 25 was obtained in 72% yield by thermolysis of the azide 24 ³⁵ (Scheme 11).

Scheme 11

3.1.2 Benzosuberone fused with furans. Alkylation of 7-hydroxybenzosuberone 2e with allyl bromide gave the allyl ether 26, which underwent rearrangement upon heating under reduced pressure to give the two isomeric hydroxybenzosuberones 27 and 28. Ozonolysis of compounds 27 and 28 followed by treatment with freshly prepared polyphosphoric acid gave the furanobenzocyclo-heptanones 29 and 30, respectively, in low yields³⁶ (Scheme 12).

Scheme 12

In a similar manner, treatment of 7-hydroxybenzosuberone 2e with 2,3-dichloropropene resulted in the formation of the allyl ether 31, which rearranged by heating in N,N-dimethylaniline to give compounds 32 and 33. Treatment of compounds 32 and 33 with polyphosphoric acid led to the formation of the corresponding methyl furanobenzosuberone derivatives 34 and 35 in low yields³⁶ (Scheme 13).

Scheme 13

3.1.3 Benzosuberone fused with thiophenes. The benzocyclohepta[2,1-b]thiophene derivative 40 was prepared starting with chlorinated benzosuberone 36. which reacted reaction 36 with potassium thioacetate gave 37 which upon treatment with the vinyl phosphonate ester 38, in the presence of lithium ethoxide, afforded the dihydrobenzocyclohepta[2,1-b]thiophene 39 via an intramolecular Horner–Emmons olefination. Aromatization of 39 with DDQ gave the corresponding benzocyclohepta[2,1-b]thiophene derivative 40 in excellent yield³⁷ (Scheme 14).

Scheme 14

Also, reaction of the benzosuberone derivative 2f with phosphoryl trichloride in dimethylformamide at 0 °C gave 5-chloro-2,3-dimethoxy-7,8,9-trihydro-benzocyclohept-5-ene-6-carbaldehyde 41 which was cyclized to the thiophene derivative 42 upon treatment with ethyl mercaptoacetate and sodium ethoxide (Scheme 15). On the other hand, the benzosuberone fused aminothiophene derivative 43 was synthesized from the reaction of compound 41 with thiourea in the presence of iodine³⁸ (Scheme 15).

Scheme 15

When the benzosuberone derivative 2g was treated with sulfur powder and ethyl cyanoacetate in the presence of diethylamine, it afforded ethyl 2-amino-5-nitro-8,9,10-trihydro-benzo[3,4]cyclohepta[1,2-b]thiophen-3-carboxylate 44 ³⁹ (Scheme 16).

Scheme 16

Recently, it was reported that cyclocondensation of the thioamide derivatives 45a and 45b with chloroacetone 46a in refluxing EtOH, in the presence of a catalytic amount of triethylamine or with phenacyl chloride 46b in DMF in the presence of potassium carbonate at room temperature gave the thiophene derivatives 48a–c via the intermediate 47 ⁴⁰ (Scheme 17).

Scheme 17

3.1.4 Benzosuberone fused with pyrazoles. Condensation of benzosuberone 2a with dimethylformamide dimethylacetal (DMF-DMA) furnished the enaminone derivative 49 (Scheme 18).⁴¹ Reaction of the enaminone 49 with hydrazine hydrate in absolute ethanol afforded the corresponding fused pyrazole derivative 50 ⁴¹ (Scheme 18).

Scheme 18

Treatment of the benzosuberone derivatives 2 with lithium hexamethyldisilazide (LiHMDS) followed by diethyl oxalate yielded the lithiated keto ester adducts 51 as isolable solid products. Subsequent reaction of 51 with the arylhydrazine 52 in acetic acid gave the benzocycloheptapyrazole esters 53 ^25,42 (Scheme 19).

Scheme 19

Treatment of the benzosuberone derivative 2f with LiHMDS and dimethyl trithiocarbonate provided the corresponding thioester derivative 54, which was then reacted with the benzylamine derivative 55 to give the thioamide derivative 56. Alkylation of 56 with methyl iodide, followed by exposure to excess hydrazine in refluxing ethanol, afforded the aminopyrazolobenzosuberane derivative 57 ⁴³ (Scheme 20).

Scheme 20

Reaction of the enol tautomers 58a and 58b with 4-methoxyphenylhydrazine led to the formation of the isomeric pyrazolobenzosuberane structures 61 and 62 via the hydrazone intermediates 59 and 60, respectively⁴² (Scheme 21).

Scheme 21

Formylation of the benzosuberone derivatives 2a,f with ethyl formate gave 6-hydroxymethylene-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ones 63, which underwent further condensation with hydrazines to give the fused pyrazolobenzosuberane derivatives 64 ⁴⁴ (Scheme 22).

Scheme 22

In the same manner, condensation of compound 65 with phenylhydrazine in the presence of triethylamine afforded the corresponding pyrazolobenzosuberane derivative 66 ³⁹ (Scheme 23).

Scheme 23

When benzosuberone 2a treated with 4-fluorophenylhydrazine it gave the corresponding hydrazone 67. The latter hydrazone reacted with two equiv. of lithium di-isopropylamide (LDA) then with methyl 4-(tetrahydropyranyloxy)-2-butenoate 68 followed by hydrolysis to give the tricyclic unsaturated alcohol 69. Oxidation of 69 with MnO₂ provided the corresponding aldehyde 70 ⁴⁵ (Scheme 24).

Scheme 24

In a similar manner, benzosuberone 2a reacted with t-butyl carbazate in refluxing ethanol using a catalytic amount of glacial acetic acid, to give the corresponding hydrazone 71. Lithiation of the latter compound with excess LDA followed by methyl 3,4,5-methoxybenzoate, afforded the corresponding pyrazolobenzosuberane derivative 72 ⁴⁶ (Scheme 25).

Scheme 25

Hexahydrobenzo[6,7]cyclohepta[l,2-c]pyrazoles 74 were synthesized by treating 2-benzylidene-1-benzosuberone 73 with hydrazine derivatives. The cis and trans isomers were distinguished by NMR techniques⁴⁷ (Scheme 26).

Scheme 26

3.1.5 Benzosuberone fused with isoxazoles. Condensation of 2-hydroxymethylene-1-benzosuberone derivatives 63, obtained from benzosuberones 2a,f, with hydroxylamine gave the corresponding fused isoxazolobenzosuberanes 75 ⁴⁴ (Scheme 27).

Scheme 27

Condensation of 3-methylbenzocycloheptan-5-one 2j with the appropriate aromatic aldehydes afforded the corresponding 6-benzylidene-3-methylbenzocycloheptan-5-one derivatives 76a–g. Reaction of 76 with hydroxylamine hydrochloride in alkaline medium gave 9-methyl-3-phenyl-3a,4,5,6-tetrahydro-3H-benzo[6,7]cyclohepta-[c]-isoxazole derivatives 77a–g (Scheme 28).⁴⁸

Scheme 28

Similarly, treatment of the enaminone 49 with hydroxylamine gave one isolable product, namely; benzo[6,7]cyclohepta[2,1-d]isoxazole 78 rather than its isomeric form benzo[6,7]cyclohepta[1,2-c]isoxazole 79 (Scheme 29).⁴¹

Scheme 29

3.1.6 Benzosuberone fused with thiazoles. Condensation of 1-benzosuberone 2a with thiourea in the presence of iodine at 100 °C yielded the seven-membered tricyclic thiazoleamine 80, which upon treatment with 2,6-difluorobenzoyl chloride 81 in dichloromethane (DCM) in the presence of triethylamine, afforded the corresponding benzamide derivative 82 ⁴⁹ (Scheme 30).

Scheme 30

Bromination of 8-fluoro-1-benzosuberone 2k with Br₂/AcOH gave 2-bromo-8-fluoro-1-benzosuberone 83. Subsequent reaction of 83 with the thiourea derivative 84 afforded the corresponding tricyclic thiazole derivative 85 in 66% yield⁵⁰ (Scheme 31).

Scheme 31

3.1.7 Benzosuberone fused with thiaphosphazulenes. Reaction of 6-benzylidene-3-methylbenzocycloheptan-5-one derivative 76a with Lawesson's reagent in xylene afforded the thiaphosphazulene derivative 86 ⁵¹ (Scheme 32).

Scheme 32

3.1.8 Benzosubrone fused triazoles. Chen et al. reported the synthesis of benzocycloheptatriazole derivative 89 by reaction of benzosuberone 2a with N-tosylhydrazine 87 followed by copper-mediated coupling with aniline. The reaction involved the spontaneous formation of a C–N bond through C–H bond cleavage and N–N bond formation⁵² (Scheme 33).

Scheme 33

3.1.9 Benzosuberone fused with thiadiazoles. When benzosuberone oxime 15 treated with the trithiazyl trichloride 90 in CCl₄ under reflux, it gave the fused thiadiazole 91 in 30% yield⁵³ (Scheme 34).

Scheme 34

Condensation of benzosuberone derivatives 2j,l with semicarbazide hydrochloride afforded the corresponding semicarbazones 92. Oxidative cyclization of 92 using SOCl₂ gave the benzosuberone-fused thiadiazoles 93 ⁵⁴ (Scheme 35).

Scheme 35

Abdel Salam et al. recently reported that, treatment of the thioamide derivatives 45a,b with C-acetyl-N-arylhydrazonoyl chlorides 94 in boiling EtOH in the presence of triethylamine, afforded the 1,3,4-thiadiazole derivatives 96a–h (Scheme 36). The structures of compounds 96 were established based on their spectral data and elemental analyses.⁴⁰

Scheme 36

3.1.10 Benzosuberone fused with selenadiazoles. Oxidative cyclization of the semicarbazones 92, obtained as shown above, afforded the corresponding benzosuberone-fused selenadiazoles 97 ⁵⁴ (Scheme 37).

Scheme 37

3.1.11 Benzosuberone fused with pyridines. Substituted benzosuberones 2a,g reacted with malononitrile, in the presence of β-alanine as a catalyst, to give the dicyanomethylidene derivatives 98 in good yield. Condensation of compounds 98 with benzaldehydes, in the presence of ammonium acetate, in refluxing acetic acid afforded the benzosuberone-fused pyridine derivatives 99 ^39,55 (Scheme 38).

Scheme 38

Menard and Zimmerman reported that, treatment of 1-benzosuberone 2a with methylmagnesium bromide gave the alcohol 100, which upon dehydration with p-toluenesulfonic acid in refluxing toluene afforded 1-methyl-1-benzosuberene 101. Reaction of 101 with butylamine hydrochloride and formaldehyde in aqueous acetic acid gave 1H-benzo[3,4]cyclohepta[1,2-c]pyridine 102 ⁵⁶ (Scheme 39).

Scheme 39

Reaction of the enaminone 49 with acetylacetone and with ethyl acetoacetate in glacial acetic acid in the presence of ammonium acetate gave the corresponding benzo-[6,7]cyclohepta[1,2-b]pyridine derivatives 103a,b ⁴¹ (Scheme 40).

Scheme 40

Farghaly et al. reported that, reaction of the enaminone 49 with malononitrile or cyanoacetamide in refluxing ethanolic sodium ethoxide solution gave 1,2-dihydro-2-oxo-benzo-[6,7]cyclohepta[1,2-b]pyridine-3-carbonitrile 104 ⁴¹ based on X-ray crystallographic analysis (Scheme 41).

Scheme 41

In a similar manner, the enaminone 49 reacted with ω-cyanoacetophenone in acetic acid in the presence of ammonium acetate to give 3-benzoyl-5,6,7-trihydrobenzo[6,7]cyclohepta[1,2-b]pyridine-2(1H)-one 105 rather than its isomeric structure 106 ⁴¹ (Scheme 42).

Scheme 42

Furthermore, benzosuberone 2a was reported to react with the enaminones 107a–c to give 5,6,7-trihydrobenzo[6,7]cyclohepta[1,2-b]pyridine derivatives 108a–c in good yields (Scheme 43).⁴¹

Scheme 43

Condensation of the substituted benzosuberones 2a,g with arylmethylene cyanoacetamide 109 in the presence of triethylamine or ammonium acetate resulted in the formation of the corresponding benzosuberone-fused cyanopyridone derivatives 110 ^39,55 (Scheme 44).

Scheme 44

3.1.12 Benzosuberone fused with pyrans. Condensation of compounds 111 with malononitrile, in the presence of pipridene, gave the fused cyanoaminopyrane derivatives 112.^39,55,57 The structure of the latter products was confirmed by alternative synthesis via reaction of the benzosuberone derivatives 2a,g with arylmethylene malononitriles 113 (Scheme 45).

Scheme 45

Reaction of benzosuberone derivatives 114 with dimethyl malonate in the presence of sodium methoxide gave the benzosuberone-fused pyranones 115 (Scheme 46).⁵⁸

Scheme 46

It was also reported that cyclization of the δ-oxo-α,β-unsaturated ester 116 gave the benzosuberone-fused pyranones 117 ⁵⁹ (Scheme 47).

Scheme 47

Treatment of the benzosuberone ester 118 with aqueous sodium hydroxide solution and acrylonitrile afforded the Michael adduct 119 in high yield. Then, synthesis of δ-hydroxynitrile 120 was performed by adding Grignard reagent to the Michael adduct 119. When the δ-hydroxynitrile 120 was treated with triflic anhydride in dichloromethane, the tricyclic imidate 121 was obtained in 40% yield⁶⁰ (Scheme 48).

Scheme 48

3.1.13 Benzosuberone fused with thiopyranone. Benzocycloheptathiopyranone derivatives 123 were prepared from the reaction of 2a,g with 3-mercaptopropanoic acid in refluxing benzene, in the presence of 4-toluenesulfonic acid (PTSA), followed by interamolecular cyclization of compounds 122 under reflux temperature using phosphorus pentoxide⁴⁰ (Scheme 49).

Scheme 49

3.1.14 Benzosuberone fused with pyridazinones. Reaction of the enol tautomer 58b with 4-methoxyphenylhydrazine gave the corresponding hydrazone intermediate 60. The resulting intermediate 60 underwent an intramolecular cyclization to give the benzosuberone-fused pyridazinone 124 ⁴² (Scheme 50).

Scheme 50

3.1.15 Benzosuberone fused with pyrimidines. Treatment of 1-benzosuberone 2a with nitriles in the presence of triflic anhydride provided the benzosuberone-fused pyrimidines 125 (Scheme 51).⁶¹

Scheme 51

When 1-benzosuberene-1-triflate 126 was heated in the presence of the appropriate cyanamides 127a–d, it afforded the corresponding 2,4-dialkylamino substituted benzocyclohepta-pyrimidines 128a–d in good yields. An alternative route to compounds 128 was also reported, where the reaction of 1-benzosuberone 2a with methylthiocyanate in the presence of triflic anhydride led to the formation of the benzosuberene[2,1-d]pyrimidine derivative 125c which under mild oxidation yielded the corresponding 2,4-bis(methylsulfonyl) derivative 129. Reaction of 129 with secondary amines (such as piperidine, morpholine and pyrrolidine), afforded the corresponding 2,4-dialkylamino derivatives 128b–d in good yields via aromatic nucleophilic substitution (Scheme 52).^61,62

Scheme 52

The reaction of β-ketoester 118 with thiourea led to the formation of the benzosuberone-fused pyrimidine derivatives 130 ⁶³ (Scheme 53).

Scheme 53

In addition, the thioxopyrimidine derivatives 131 were obtained from the reaction of the arylmethylene benzosuberone derivatives 111 with thiourea in refluxing ethanol in the presence of potassium hydroxide^39,57,64 (Scheme 54).

Scheme 54

Reaction of benzosuberone 2a with NaH/dimethyl carbonate ester gave the ester 118 which upon heating with guanidine gave 4-hydroxybenzo[6,7]-cyclohepta[1,2-d]pyrimidin-2-ylamine 132. Treatment of the latter amino alcohol with POCl₃ followed by piperazine afforded 4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl-amine 133 in a reasonable yield⁶⁵ (Scheme 55).

Scheme 55

3.1.16 Benzosuberone fused with triazine. The tricyclic triazine-N-oxide 135 was synthesized through a multistep functional group interconversions starting with benzosuberone 2a as outlined in Scheme 56.⁶⁶

Scheme 56

3.2 Tetracyclic fused systems

3.2.1 Benzosuberone fused with indole. Photocatalyzed reaction of the enolate anion of 1-benzosuberone 2a with 2-iodoaniline 136 in DMSO afforded the benzosuberone-fused-indole derivative 137 in 58% yield. However, the photostimulated reaction of 2a with 136 in liquid ammonia afforded the fused indole structure 137 in 71% isolated yield⁶⁷ (Scheme 57).

Scheme 57

The benzo[5,6]cyclohepta[b]indol-6-one derivative 139 was prepared by the intramolecular cyclization of the acid 138 in the presence of polyphosphoric acid (Scheme 58).⁶⁸

Scheme 58

3.2.2 Benzosuberone fused with quinolines. Condensation of benzosuberone 2a with anthranilic acid 140 under microwave irradiation condition gave the corresponding benzosuberone-fused quinolinone derivative 141 (Scheme 59). In order to increase the efficiency of the reaction, a small amount of N,N-dimethylacetamide (DMAC), as an excellent energy-transfer solvent with a high dielectric constant, was added to the reaction mixture.⁶⁹

Scheme 59

3.2.3 Benzosuberone fused with coumarins. Synthesis of the fused benzosuberone-coumarin derivatives 144 was easily carried out from the corresponding ketones by Vilsmeier–Haack–Arnold reaction.⁷⁰ At first, the β-chloro-enal derivatives 41 coupled with o-anisyl boronic acid using 2 mol% of palladium(II) acetate, in the presence of tetrabutylammonium bromide (TBAB) and potassium carbonate in water solvent at 45 °C for 3 h, to afford the corresponding β-aryl aldehydes 142 in 79–91% yields. Oxidation of the aldehydes 142 with sodium chlorite in the presence of 30% H₂O in acetonitrile at room temperature led to the formation of corresponding β-aryl acids 143 in 70–75% yields. Finally, the acids 143 were converted into the corresponding acyl chlorides, followed by cyclization using aluminium chloride in dichloromethane at room temperature to furnish the benzosuberone fused coumarins 144 in 82–89% yields (Scheme 60).⁷¹

Scheme 60

3.2.4 Benzosuberone fused with thieno[2,3-b]pyrimidine. Neat heating of compound 44 with phenyl isothiocyanate on a water-bath afforded 10-mercapto-2-nitro-11-phenyl-5,6,7,11-tetrahydro-12H-benzo[6′,7′]cyclohepta[1′,2′:4,5]-thieno[2,3-b]pyridine-12-one 145 ³⁹ (Scheme 61).

Scheme 61

3.2.5 Benzosuberone fused with thiazolo[3,2-a]pyrimidine. Reaction of the benzosuberone-fused thioxopyrimidine derivative 131 with chloroacetic acid in a mixture of acetic acid and acetic anhydride, in the presence of sodium acetate gave 5-(4-methoxyphenyl)-2,5,6,7,8-pentahydro-benzo[6,7]cyclohepta[1,2-d]thiazolo [3,2-a]pyrimidin-3-one 146. Treatment of compound 146 with benzaldehyde and with 3,4,5-trimethoxybenzaldehyde afforded the 5,6,7,8-tetrahydro-benzo[6,7]cyclohepta[2,1-d]thiazolo[3,2-a]pyrimidin-3-one derivatives 147 and 148, respectively. Compound 147 was alternatively prepared in one-step reaction using chloroacetic acid and benzaldehyde under the same reaction conditions (Scheme 62).⁶⁴

Scheme 62

3.2.6 Benzosuberone fused with pyrazolo[2,3-a]pyrimidine. Reaction of the enaminone 49 with 4-phenyl-5-aminopyrazole 149 in refluxing acetic acid afforded the corresponding 9,10,11-trihydrobenzo[6′,7′]cyclohepta[2′,1′-e]pyrazolo[2,3-a] pyrimidine 150 (Scheme 63).⁴¹

Scheme 63

3.2.7 Benzosuberone fused with pyrazolo[5,1-c][1,2,4]triazine. Azo-coupling reaction of the enaminone 49 with the diazonium salt of 5-amino-3-phenylpyrazole 151 in pyridine yielded 2-phenyl-7,8-dihydro-6H-benzo[6′,7′]-cyclohepta[1′,2′-e]pyrazolo[5,1-c][1,2,4]triazine 153 via the intramolecular cyclization of the hydrazone intermediate 152 (Scheme 64).⁷²

Scheme 64

3.2.8 Benzosuberone fused with triazolo[1,5-a]pyrimidines. The enaminone 49 was also reported to react with 3-aminotriazole 154 in refluxing acetic acid to give the corresponding 9,10,11-trihydrobenzo[6′,7′]cyclohepta[2′,1′-e]triazolo[2,3-a]pyrimidine 155 based on the X-ray crystallographic analysis (Scheme 65).⁴¹

Scheme 65

Reaction of benzosuberone 2a with 3-aminotriazole 154 and 2-nitro-benzaldehyde 156 in the presence of Me₃SiCl in DMF under reflux for 12 h afforded the benzosuberone-fused system 157 in moderate yield (Scheme 66).⁷³

Scheme 66

3.2.9 Benzosuberone fused with triazolo[4,3-a]pyrimidine. Reaction of the hydrazonoyl halides 94a–l with 4-(4-methoxyphenyl)-1,3,4,5,6,7-hexahydro-2-thioxo-benzo[6,7]cyclohepta[1,2-d]pyrimidine 131 in dioxane at reflux, in the presence of triethylamine, gave benzo[6,7]cyclohepta[1,2-d] triazolo[4,3-a]pyrimidine 158 (Scheme 67).⁶⁴ The latter compounds 158 were alternatively synthesized by reaction of the methylthio derivative 159 with the hydrazonoyl halides 94 under the same reaction condition (Scheme 67).⁶⁴

Scheme 67

3.2.10 Benzosuberone fused with [1,2,4]triazolo[3,4-c][1,2,4]triazine. Coupling reaction of the enaminone 49 with the diazonium salt of 3-amino-1,2,4-triazole 160 in pyridine afforded the corresponding hydrazone intermediate 161 which underwent an in situ intramolecular cyclization to give 6,7,8-trihydrobenzo[6′,7′]cyclohepta[1′,2′-e]triazolo[3,4-c][1,2,4]triazine 162 in 85% yield (Scheme 68).⁷²

Scheme 68

3.2.11 Benzosuberone fused with pyrido[4,3-b]pyridine. 3-Hydroxy-1-oxo-l,2,8,9-tetrahydro-7H-benzo[3,4]cyclohepta[1,2-c]-[1,6]naphthyridine-4-carbonitrile 165 was prepared from the reaction of the enaminone 163 with the pyridine-dione derivative 164 in refluxing acetic acid⁷⁴ (Scheme 69).

Scheme 69

3.2.12 Benzosuberone fused with pyrido[2,3-d]pyrimidine. 3-Thioxo-2,3,4,7,8,9-hexahydro-1H-benzo[6′,7′]cyclohepta-[1′,2′:4,5]pyrido[2,3-d]pyrimidin-1-one 167 was reported to be synthesized via three different routes as outlined in Scheme 70. The first route was the reaction of 2-[(dimethylamino)methylene]-1-benzosuberone 49 with 6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-one 166 in glacial acetic acid under conventional thermal heating or microwave irradiation. The second one was via reaction of 166 with dimethylformamide-dimethylacetal (DMF-DMA) followed by benzosuberone 2a in acetic acid ⁷⁵ and finally through the reaction of the enaminone 163 with 6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-one 166 ⁷⁴ (Scheme 70).

Scheme 70

3-Hydrazino-2,7,8,9-tetrahydro-1H-benzo[6′,7′]cyclohepta[1′,2′:4,5]pyrido[2,3-d] pyrimidin-1-one 169 was prepared by heating hydrazine hydrate with either 3-methylthio-2,7,8,9-tetrahydro-1H-benzo[6′,7′]cyclohepta[1′,2′:4,5]pyrido[2,3-d]pyrimidin-1-one 168 or its thiol analogue 167 ⁷⁶ (Scheme 71).

Scheme 71

The 3-hydrazinopyrido[2,3-d]pyrimidin-1-one derivative 169 reacted with 1,3-dicarbonyl compounds such as acetylacetone, diethyl malonate and ethyl acetoacetate to afford compounds 170, 171 and 172, respectively⁷⁶ (Scheme 72).

Scheme 72

3.3 Benzosuberone based pentacyclic fused systems

3.3.1 Benzosuberone fused with pyrimido[1,2-a]benzimidazole. Recently, it was reported that 9,10,11-trihydrobenzo[6′,7′]cyclohepta[2′,1′-e] pyrimido [1,2-a]benzimidazole 174 was prepared in reasonable yield through the reaction of the enaminone 49 with 2-aminobenzimidazole 173 in refluxing acetic acid (Scheme 73).⁴¹

Scheme 73

3.3.2 Benzosuberone fused with benzimidazo[2,1-c][1,2,4]triazine. Coupling of the enaminone 49 with the diazonium salt of 2-aminobenzimidazole 175 in pyridine afforded the benzosuberone-fused benzimidazo[2,1-c][1,2,4]triazine 176 via a hydrazone intermediate (Scheme 74).⁷²

Scheme 74

3.3.3 Benzosuberone fused with pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine. Heating of the hydrazonoyl halides 94 with the pyrido[2,3-d]pyrimidine-3-thione derivative 167 in the presence of triethylamine under pressurized microwave irradiation conditions or conventional heating, afforded the benzosuberone-fused pyrido[2,3-d] [1,2,4]triazolo[4,3-a]pyrimidin-15-ones 177a–g as shown in Scheme 75. The assignment of the structures of the products 167a–g was manifested by the alternate synthesis of 177a from the reaction of 2-[(dimethylamino)methylene]-1-benzosuberone 49 with 7-amino-1,3-diphenyl[1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-one 178 in acetic acid⁷⁵ (Scheme 75).

Scheme 75

Condensation of 3-hydrazinopyrido[2,3-d]pyrimidin-1-one derivative 169 with various aldehydes in acetic acid gave the corresponding hydrazone derivatives 179 (Scheme 76). Oxidative cyclization of the hydrazones 179 with bromine in acetic acid at room temperature yielded compounds 180 in moderate yields.⁷⁶

Scheme 76

3.3.4 Benzosuberone fused with pyrido[2,3-d][1,3]thiazolo[3,2-a]pyrimidine. Reactions of 3-thioxo-2,3,4,7,8,9-hexahydro-1H-benzo[6′,7′]cyclohepta[1′,2′:4,5] pyrido-[2,3-d]pyrimidin-1-one 167 with α-haloketones and with α-haloester in acetic acid in the presence of sodium acetate under various conditions (conventional heating and pressurized microwave irradiation), gave the penta-heterocyclic 6,7-dihydrobenzo[6′,7′]-cyclohepta[1′,2′:4,5]pyrido[2,3-d][1,3]thiazolo[3,2-a]pyrimidin-15(5H)-ones 181a–d ⁷⁵ (Scheme 77).

Scheme 77

3.4 Benzosuberone based heptacyclic fused systems

Reaction of 169 with isatin afforded the hepta-heterocyclic ring system 183 ⁷⁶ via the hydrazone intermediate 182 (Scheme 78).

Scheme 78

4. Benzosuberone spiro ring systems

4.1 Spiro oxiranes

2-Benzylidene-1-benzosuberone 73 slowly converted into its epoxide derivative 184 under the Julia–Colonna triphasic condition as depicted in Scheme 79.⁷⁷

Scheme 79

A simple and efficient procedure for the preparation of the trans-epoxides of 2-arylidene-1-benzosuberones 184 from the reaction of 2-arylidene-l-benzosuberones 73 was with alkaline hydrogen peroxide was reported. Dimethyldioxirane (DMD), in acetone proved also to be a convenient and powerful oxidant for the epoxidation of electron-poor functionalized olefins (Scheme 80).⁷⁸

Scheme 80

In another report, compound 185 was converted into the epoxide 186 employing using silica-supported poly-L-leucine as a catalyst with urea-H₂O₂ (UHP) as an oxidant and sub-stoichiometric quantities of BEMP (62% yield) (Scheme 81).⁷⁹

Scheme 81

4.2 Spiro lactone

Stobbe condensation of benzosuberone 2a with diethyl succinate using potassium t-butoxide led to the formation of the olefinic half-ester 187 in good yield. Use of sodium hydride instead of potassium t-butoxide gave lower yields of 187. Hydrolysis and simultaneous decarboxylation of 187 gave a mixture of the olefinic acid 188 (48%) and its isomeric lactone 189 (36%)⁸⁰ (Scheme 82).

Scheme 82

4.3 Spiro pyrazoles

Spiro-1-pyrazolines 190 were synthesized from the reaction of the Z- or E-isomers of the benzylidene derivative 73 with diazomethane in a mixture of ether and acetone⁸¹ (Scheme 83).

Scheme 83

Reaction of the 2-arylmethylene-1-benzusuberone derivatives 73 with nitrilamines [generated in situ by dehydrohalogenation of the corresponding hydrazonoyl chlorides 94 using triethylamine] in refluxing benzene, resulted in the regioselective formation of the spiro-pyrazoles 191.⁸² However, when the same reaction was carried out in chloroform, the other regioisomer 192 was obtained.⁸³ The structures of the two regioisomeric products 191 and 192 were confirmed from their X-ray crystallographic analyses (Scheme 84).

Scheme 84

Recently, the 1,3-dipolar cycloaddition reaction of the bis-hydrazonoyl chlorides 193 with 2-arylidene-1-benzosuberone derivatives 73 was reported to afford the corresponding bis-[1′,4′-diaryl-1-oxo-spiro-benzosuberane-2,5′-pyrazoline] derivatives 195 regio- and stereoselectively based on the X-ray crystallographic analysis. The yields of the reaction products were extremely affected by the heating mode, where compounds 195 were obtained in 72–91% yields after 3 h of ultrasonic irradiation and in 22–51% yields after 36 h of conventional heating⁸⁴ (Scheme 85).

Scheme 85

4.4 Spiro-dioxolane

Treatment of benzosuberenone 196 with dichlorocarbene, generated by decomposition of chloroform under basic phase-transfer conditions, furnished the cyclopropane derivative 197 in 75% yield. Protection of 197 in the form of ethylene ketal 198 (R = Cl), followed by its treatment with dimethyl copper lithium and methyl iodide led to the formation of the geminal methylated 198 (R = Me)⁸⁵ (Scheme 86).

Scheme 86

Benzosuberone-acetic acid 200 was prepared by firstly aldol condensation of benzosuberones 2 with glyoxylic acid either in alkaline medium or by fusion of at 160 °C to give the benzosuberone-carboxylic acids 199 in quantitative yields. Subsequent reduction of the olefinic acids 199 with zinc and acetic acid gave the saturated acids 200 in quantitative yields. Synthesis of the amides 202 was accomplished in good to excellent yields by reaction of the acids 200 with the piperidine derivative 201 using dicyclohexylcarbodiimide (DCC) in the presence of 1-hydroxybenzotriazole (HOBt). Ketalization of the carbonyl groups in 202 with ethylene glycol and p-TsOH in toluene gave the bis-(ethylene ketals) 203 in variable yields. Reduction of 203 with lithium aluminum hydride followed by deketalization afforded the amino ketones 204 in good to excellent yields⁸⁶ (Scheme 87).

Scheme 87

4.5 Spiro thiadiazoles

Substituted benzosuberone derivatives 2 reacted with thiosemicarbazide in ethanol catalyzed with HCl, to give the substituted benzosuberone thiosemicarbazones 205. Compounds 205 underwent cyclization in acetic anhydride to give the spiro-thiadiazole derivatives 206 (Scheme 88).⁵⁴

Scheme 88

5. Conclusion

1-Benzosuberone derivatives are of immense importance biologically and are essential to life in various ways. They can be synthesized by a variety of synthetic approaches, including the annulations of the heterocyclic ring systems via various sequences of reactions which seem to be the most attractive methodologies. We have presented in this review the main strategies for the synthesis of many kinds of fused and spiro- heterocycles to benzosuberone. The annulations of the heterocyclic ring system on the benzosuberone ring system are mainly based on the functionality of the seven membered ring fused to the benzene ring. The carbonyl group as well as its active methylene group are key function in the construction of the many fused systems. The reactions described in this review clearly demonstrate the high ability of the functional groups in the benzosuberone ring system to carry out the regioselective preparation of fused heterocycles. The highly regioselective formation of these compounds could be achieved either in intramolecular reactions, and some intermolecular reactions. The fused heterocycles mentioned in this review are arranged in an organized manner with respect to the type of heterocyclic systems. We hope that this review will be useful not only for organic synthetic chemists, but also for heterocyclic and natural products synthetic chemists.

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