Chapter 1 Dimedone: A Versatile Precursor for Annulated Heterocycles

doi:10.1016/S0065-2725(09)09801-8

Advances in Heterocyclic Chemistry

Volume 98, 2009, Pages 1-141

https://doi.org/10.1016/S0065-2725(09)09801-8 Get rights and content

Publisher Summary

This chapter explores that dimedone is a versatile precursor for annulated heterocycles. Dimedone(1) is an alicyclic compound having 1,3-dicarbonyl groups flanked by a methylene group and exists in a tautomeric transenolized form where intramolecular hydrogen bonding is not possible. Dimedone is an excellent precursor for partially hydrogenated fused heterocycles where two of the carbon atoms of dimedone are part of the backbone of the formed heterocycles. The chapter illustrates that dimedone's structural features and its reactivity to form more functionalized derivatives have led to the construction of a wide range of fused or spiral biheterocycles. Finally, this chapter emphasizes the role of 1 in the synthesis of fused heterocycles, classified according to the size of the ring and the number of heteroatoms in the heterocycle fused to the cyclohexane ring and subdivided according to the heteroatoms and their arrangement in the ring.

Introduction

Dimedone (1) is an alicyclic compound having 1,3-dicarbonyl groups flanked by a methylene group and exists in a tautomeric trans-enolized form where intramolecular hydrogen bonding is not possible (05S3468). The inherent structural features in 1 have created various reactive centers: C-1, C-2, and to a less extent C-6 in addition to C-3 in or 3-O (Figure 1). Such phenomenon attracted much attention for using it as a synthetic reagent for the characterizations of aldehydes, since its discovery, by the formation of readily crystalizable derivatives; determination of formaldehyde in textiles has been done by a colorometric method (04MIa79). Moreover, dimedone is an excellent precursor for partially hydrogenated fused heterocycles (04CUOC695), where two of the carbon-atoms of dimedone are part of the backbone of the formed heterocycles. Its structural features and its reactivity to form more functionalized derivatives have led to the construction of a wide range of fused or spiral biheterocycles.

This chapter will emphasize the role of 1 in the synthesis of fused heterocycles, classified according to the size of the ring and the number of heteroatoms in the heterocycle fused to the cyclohexane ring and subdivided according to the heteroatoms and their arrangement in the ring. The titles are given as annulated heterocycles to 1, which are mostly saturated or partially saturated heterocycles. However, for the simplicity the subtitle is given between two brackets as benzoheterocycles.

Section snippets

Dimedone-Annulated Three- and Four-Membered Heterocycles

Only few examples were reported related to these ring systems. Moreover, only those fused with three-membered ring mainly containing one heteroatom oxygen were reported. No examples can be found with a four-membered ring containing two heteroatoms.

The epoxide ring in such fused ring systems has been formed by the epoxidation with t-butylhydroperoxide/Triton-B of the respective double bond in 6 and 7, which were prepared from 2via the formation of a fused pyrrole ring, as it will be shown

Dimedone-Annulated Five-Membered Heterocycles with One Heteroatom

There are three classes of compounds that can be categorized under this title.

Dimedone-Annulated Five-Membered Heterocycles with Two Heteroatoms

There are six classes of compounds, which can be presented under this heading. These include the partially hydrogenated benzo-five-membered-heterocycles with nitrogen, oxygen or sulfur.

Annulation with triazole (synthesis of benzotriazoles)

Aryldiazonium chlorides and 1 gave 5,5-dimethylcyclohexan-1,2,3-trione-2-arylhydrazones 21985JCR(M)1076, 07MI570 which upon reaction with excess arylhydrazines in ethanol gave 5,5-dimethylcyclohexane-1,2,3-trione-1,2,3-tris(arylhydrazones) 220. Reaction of 219 with two equivalents of phenylhydrazine gave the mixed tris-hydrazones 221, and with one equivalent of phenylhydrazine gave mixed bis-hydrazone 222(93OPP569, 07MI570). Oxidation of 220 gave benzo[d]-1,2,3-triazoles 223–225 in addition to

Annulation with pyridine (synthesis of quinolines)

Dimedone has been extensively used in the synthesis of partially hydrogenated quinoline rings. Thus, 1,4,5,6,7,8-hexahydroquinolines 245 were prepared by Hantzsch-like synthesis starting from 1, aromatic or aliphatic aldehydes and β-aminocrotonates or β-aminocrotonamide (66CHE583, 89AF1393, 94IJC(B)526, 06MI109). Hexahydroquinolines 245 were also obtained by ultrasound or microwave (MW) irradiation of a mixture of 1, aromatic aldehydes and β-aminocrotonates or ethyl acetoacetate in the presence

Annulation with pyridazine (synthesis of cinnolines)

This ring system can be constructed by introducing the hydrazine moiety on C-1 or C-2 of dimedone and then heterocyclization with functionalized carbon reagents. Thus, reaction of 2-arylhydrazono-5,5-dimethylcyclohexane-1,3-dione 219, prepared from reaction of 1 with aryldiazonium chlorides, with Wittig reagents 501 afforded the respective tetrahydrocinnolinones 503. Alternatively, 503 were synthesized by the coupling of 504, obtained from reaction of 1 with Wittig reagent 501, with

Annulation with thiadiazine (synthesis of benzothiadiazines)

Reaction of 3-substituted-4-amino-5-mercapto(4H)-1,2,4-triazoles 561 with 1 gave 6,7,8,9-tetrahydro-3-substituted-1,2,4-triazolo[4,3-b][1,3,4]benzothiadiazin-9-ones 562(90H2147, 01IJC(B)828, 95MI297). The reaction can be achieved also under MW irradiation in DMF (97IJC(B)782). The bis-triazolo-benzothiadiazine 564 flanked by dihydroxyethyl was prepared from 1 and 563(05NNN1885). However, reaction of 4-amino-5-(3-chlorobenzo[b]thien-2-yl)-1,2,4-triazole-3-thiol (565) with 1 in the presence of

Annulation with oxepin (synthesis of benzoxepin)

Regioselective heterocyclization of 569–570 has been taken place on treatment with pyridine hydrotribromide, hexamethylenetetramine hydrobromide, elemental bromine, or NIS in acetonitrile and H₂SO₄ at 0–5 °C (03SC679) (Scheme 121).

Annulation with azepine (synthesis of benzazepines)

Photocyclization of the enamine 571 with a high-pressure mercury lamp in dioxane-acetonitrile in the presence of Et₃N gave the azepine 572(78CC766).

Condensation of 1 with 5-bromoindole 573 (R=Br) in the presence of hydrochloric acid gave indolyl dibenzazepinone 575

Annulation with diazepine (synthesis of benzodiazepines)

Reaction of hydrazino-cyclohexenone 580 with ethyl benzoylacetate in acetic acid afforded an equilibrium mixture of the hydrazine form 581 and the enhydrazone form 582, which upon heating in PPA produced 3-phenyl-1,8,8-trimethyl-4,5,6,7,8,9-hexahydro-1,2-benzodiazepine-5,6(1H)dione (583) (98H315).

Chlorination of 2-benzoyldimedone 584 with oxalyl chloride afforded the 3-chloro derivative 585, which upon treatment with ethylenediamine gave the respective hexahydro-1,4-benzodiazepine 586(95JHC655)

Annulation with azocine (synthesis of benzoazocines)

Treatment of the enaminone 591 (R=H) with LDEA in ether-THF afforded the tetrahydroquinoline 592, the benzazocine 593 (R=H) and a debrominated product 594 (R=H) (79JOC3985). Under similar reaction conditions the N-ethyl 591 (R=Et) gave the quinoline 595 and pyridocarbazole 596 in addition to the debrominated alcohol 597 (Scheme 126).

The dibenzazocine 599 was prepared from the photoirradiation of the enaminone 598(78JOC4420). In contrast, irradiation of a benzene solution of

Miscellaneous

3,3,7,7-Tetramethyl-1a,2,3,4,6,7,8,8a-octahydrobenzofuro[4,3,2-b,c,d]benzofuran 604 was obtained in a one-pot reaction of 1 with lithium ethylenediamine(Li/EDA), through the enolization of dimedone in the alkaline medium to give the dienol, which underwent dehydration to the diether 602. The latter formed two free-radical sites at 2,2′-positions upon attack by the nascent hydrogen formed by Li/EDA, which led to the formation of a C–C bond to give the intermediate 603 that on isomerization

Acknowledgments

The supports and encouragements from the Alexander von Humboldt in Germany, and the valuable discussions with Professor V. Whittmann at Konstanz University in Germany are highly appreciated.

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Dimedone (1) is one of the most important substrates among the active methylene compounds, having 1,3-dicarbonyl groups flanked by active methylene groups, which can exists in trans-enolized tautomer form, stabilized by intermolecular hydrogen bonding network (Mark et al., 2011; Xu et al., 2005). It has been used as a versatile synthetic precursor for the synthesis of several classes heterocyclic and spirocyclic compounds (El Ashry et al., 2009). A number of dimedone derived heterocyclic and non-heterocyclic compounds have been reported in the literature for their biological properties, such as tetrahydrobenzo[b]pyrans (Akbar and Mohammad, 2010), fused spiroketal derivatives (Giasuddin Ahmed et al., 2005), bis-spiropiperidine derivatives (Atar and Jeong, 2013), 5-aminouracil derivatives (Shaker et al., 2009), triazolo[1,2-a]indazole-triones (Nikpassand et al., 2009), fused 1,4-dihydropyridines (Mosaddegh and Hassankhani, 2012), isoquinolines (Ivanov and Nikolova, 2008), spirocarbocycles (Clavier et al., 2012), 9-aryl-1,8-dioxooctahydroxanthene derivatives (Ilangovan, et al., 2012) and others (Al-Majid et al., 2013a,b).
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Chapter 1 Dimedone: A Versatile Precursor for Annulated Heterocycles

Publisher Summary

Introduction

Section snippets

Dimedone-Annulated Three- and Four-Membered Heterocycles

Dimedone-Annulated Five-Membered Heterocycles with One Heteroatom

Dimedone-Annulated Five-Membered Heterocycles with Two Heteroatoms

Annulation with triazole (synthesis of benzotriazoles)

Annulation with pyridine (synthesis of quinolines)

Annulation with pyridazine (synthesis of cinnolines)

Annulation with thiadiazine (synthesis of benzothiadiazines)

Annulation with oxepin (synthesis of benzoxepin)

Annulation with azepine (synthesis of benzazepines)

Annulation with diazepine (synthesis of benzodiazepines)

Annulation with azocine (synthesis of benzoazocines)

Miscellaneous

Acknowledgments

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