Three Heterocyclic Rings Fused (5-5-6)

12.16 Three Heterocyclic Rings Fused (5-5-6) R. L. Riggs BASF AG, Ludwigshafen, Germany D. M. Smith University of St Andrews, St Andrews, UK ª 2008 Elsevier Ltd. All rights reserved. 12.16.1

Introduction

775

12.16.2

Ortho-Fused Tricyclic Heterocycles with No Ring-Junction Heteroatom

775

12.16.2.1

Systems with One or More Nitrogens in Each Ring

12.16.2.1.1 12.16.2.1.2 12.16.2.1.3

12.16.2.2

Systems with only one nitrogen per ring Systems with more than one nitrogen in the six-membered ring Systems with more than one nitrogen in both six- and five-membered rings

Other Two Rings

776

Systems with oxygen in the central ring – pyrrolofuropyridines Systems with sulfur in the central ring

12.16.2.3

Systems with Oxygen or Sulfur in the Outer Five-Membered Ring and One or More

12.16.2.4

Systems with Oxygen in Each Five-Membered Ring and Nitrogen in the

12.16.2.5

Systems with Sulfur in Both Five-Membered Rings and Either Nitrogen or Oxygen in

Nitrogens in the Other Two

784

the Six-Membered Ring 12.16.2.5.1 12.16.2.5.2

12.16.3

786

Thienothienopyridines and their carbocyclic fused derivatives Thienothienopyrylium salts

Systems with Oxygen in all Three Rings

12.16.2.6.1 12.16.2.6.2 12.16.2.6.3

776 780

784

Six-Membered Ring

12.16.2.7

775 775 775

Systems with Oxygen or Sulfur in the Central Ring and One or More Nitrogens in the

12.16.2.2.1 12.16.2.2.2

12.16.2.6

775

Natural products Furofurocoumarins Pyranofurooxazolines

786 788

789 789 790 792

Miscellaneous Systems

792

Ortho-Fused Tricyclic Heterocycles with Heteroatoms at the 5:5 Ring Junction

793

12.16.3.1

Introduction

793

12.16.3.2

Pyrrolizines Fused at the a-Edge to a Pyridine Ring

793

12.16.3.2.1 12.16.3.2.2 12.16.3.2.3 12.16.3.2.4

12.16.3.3

Synthesis Synthesis Synthesis Synthesis

via via via via

nucleophile–electrophile interactions Diels–Alder reactions transition metal-catalyzed reactions transformations of other ring systems

Pyrrolizines Fused at the b-Edge to a Pyridine Ring

12.16.3.3.1 12.16.3.3.2 12.16.3.3.3

Synthesis via nucleophile–electrophile interactions Synthesis via cycloaddition reactions Reactivity

773

793 794 795 795

797 797 798 798

774

Three Heterocyclic Rings Fused (5-5-6)

12.16.3.4

Pyrrolizines Fused to a Pyrimidine or Pyrazine Ring

12.16.3.4.1 12.16.3.4.2

12.16.3.5

Pyrrolizines Fused to a Pyran or Thiopyran Ring

12.16.3.5.1 12.16.3.5.2 12.16.3.5.3

12.16.3.6

12.16.4 12.16.4.1

Synthesis via 1,3-dipolar cycloadditions Synthesis via nucleophile–electrophile interactions Synthesis via photochemical reactions

Pyrroloimidazoles and Pyrrolothiazoles Fused to a Pyridine, Pyran or Thiopyran Ring

12.16.3.6.1 12.16.3.6.2

12.16.3.7

Synthesis via formation of the six-membered ring Synthesis via formation of the pyrrolizine ring system

Synthesis via 1,3-dipolar cycloaddition reactions Synthesis via nucleophile–electrophile interactions

Other Systems Ortho-Fused Tricyclic Heterocycles with Heteroatoms at the 5:6 Ring Junction Indolizines Fused at the a-Edge to a Pyrrole Ring

12.16.4.1.1 12.16.4.1.2 12.16.4.1.3 12.16.4.1.4 12.16.4.1.5

Natural products Synthesis via nucleophile–electrophile interactions Synthesis via cycloadditions Synthesis via radical processes Synthesis via transformations of other ring systems

799 799 799

801 801 803 803

804 804 805

805 806 806 806 806 807 811 812

12.16.4.2

Indolizines Fused at the b-Edge to a Pyrrole Ring

812

12.16.4.3

Indolizines a- or b-Fused to a Furan or Thiophene Ring

813

12.16.4.3.1 12.16.4.3.2

12.16.4.4

Furoindolizines Thienoindolizines

Indolizines a- or b-Fused to a Five-Membered Ring Containing Two or Three Heteroatoms

12.16.4.5

818

Pyrrolopyridazines, Pyrrolopyrimidines, and Pyrrolopyrazines Fused through the Pyrrole to a Five-Membered Heterocycle

12.16.5

813 814

Ortho-Fused Tricyclic Heterocycles with Two or More Ring Junction Heteroatoms

821 821

12.16.5.1

Two Ring Junction Heteroatoms, Both between the Five-Membered Rings

821

12.16.5.2

Two Ring Junction Heteroatoms, Both between the Five- and Six-Membered Rings

822

12.16.5.3

One Heteroatom at a 5:5-Ring Junction and the Other at a 6:5-Ring Junction

822

12.16.5.3.1 12.16.5.3.2 12.16.5.3.3 12.16.5.3.4 12.16.5.3.5

12.16.6

Pyrroloimidazo-pyridines and -pyrimidines Imidazoimidazo-pyridines and -pyrimidines Imidazotriazolopyrimidines Triazolotriazolo-pyrimidines and -triazines Other heteroatom-containing systems

Peri-Fused Tricyclic Heterocycles

822 824 825 825 825

827

12.16.6.1

Heterocycles with Three or More Heteroatoms, None at a Ring Junction

827

12.16.6.2

Heterocycles with Two or More Heteroatoms, One or More Common to Two Rings

828

12.16.6.2.1 12.16.6.2.2 12.16.6.2.3

12.16.6.3

Systems with two heteroatoms Systems with three heteroatoms Systems with more than three heteroatoms

Cycl[3.2.2]azines and Their Aza- and Diaza-Analogues

12.16.6.3.1 12.16.6.3.2 12.16.6.3.3

Synthesis Reactivity and Reactions Biologically active cycl[3.2.2]azines

828 828 828

829 830 836 838

12.16.6.4

Benzo-, Dibenzo-, and Other Fused Cycl[3.2.2]azines and Azacycl[3.2.2]azines

838

12.16.6.5

Di- and Polyhydrocycl[3.2.2]azines and Aza-Analogues

843

12.16.6.5.1 12.16.6.5.2

Dihydrocyclazines Tetrahydro- and hexahydrocyclazines: The Myrmicaria alkaloids

843 844

Three Heterocyclic Rings Fused (5-5-6)

12.16.6.6

Other Polyhydrocycl[3.2.2]azines

846

12.16.6.7

Heterocycles with Hypervalent Sulfur or Selenium at the 5:5 Ring Junction

847

12.16.7

Important Compounds and Applications

References

849 850

12.16.1 Introduction No chapter covering the fused 5-5-6 ring system was included in CHEC-II(1996). The present survey therefore attempts to fill this gap by reviewing the literature from late 1982 onwards. It is divided into a number of main sections, according to the nature of the heteroatoms, whether or not a heteroatom occupies a ring junction, and whether the rings are ortho- or peri-fused: systems containing additional heteroatoms are also included where appropriate. In view of the large number and diversity of ring systems which are covered in this chapter, the material is divided into what may be regarded, effectively, as a series of independent subchapters: each of these describes the chemistry of a group of structurally related tricyclic systems.

12.16.2 Ortho-Fused Tricyclic Heterocycles with No Ring-Junction Heteroatom 12.16.2.1 Systems with One or More Nitrogens in Each Ring 12.16.2.1.1

Systems with only one nitrogen per ring

The zwitterionic pyridinium N-arylimides 1 can undergo 1,3-dipolar cycloaddition reactions with a variety of dipolarophiles. Thus, reaction of these zwitterions with N-phenylmaleimide gives the tetrahydro-1H-pyrrolo[3949:3,4]pyrazolo[1,5-a]pyridine ring system. This system is unstable, however, and upon heating to reflux in chloroform for 1 h, or for 3 days at room temperature, a rearrangement occurs to give the tetrahydro-1Hpyrrolo[39,49:4,5]-1H-pyrrolo[3,2-b]pyridine-1,3-dione 2. The evidence is consistent with a [1,5]-sigmatropic rearrangement, as shown in Scheme 1. The tetrahydro-compound 2 can then be oxidized to the fully conjugated form 3 upon treatment with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) <2003JOC5652>.

Scheme 1

12.16.2.1.2

Systems with more than one nitrogen in the six-membered ring

Pyrrolopyrrolopyrimidines have been prepared, unexpectedly, in the course of a study of antitumor molecules. The pyrimidinopyrrolinone 4, upon treatment with BH3 in tetrahydrofuran (THF), gave a mixture of two compounds, the reduced dihydropyrrolopyrimidine 5 and the pyrrolopyrrolopyrimidine 6. It was speculated that the mechanism involved reduction of the amide to the borane complex 7, whereupon either reduction with hydride (path A) gives the expected reduced compound 5, or intramolecular attack by the amine (path B) gives 6. The tricycle could be hydrolyzed, however, to give the pyrrolopyrimidine 8 <1995CPB256> (Scheme 2).

12.16.2.1.3

Systems with more than one nitrogen in both six- and five-membered rings

Systems in which two nitrogen atoms are present only in the five-membered ring have not been described during the review period.

775

776

Three Heterocyclic Rings Fused (5-5-6)

Scheme 2

The imidazopyrroloquinoxaline derivative 9 has been prepared, due to the interest in such molecules for their potential biological activity. The amino ester 10 reacts with hydrazine hydrate to give the hydrazide 11, which can then react with nitrous acid to give the azide 12. Upon heating of this azide in dry xylene, it undergoes a Curtius rearrangement and subsequent cyclisation to give imidazo[49,59:4,5][3H,5H]pyrrolo[2,3-b]quinoxalin-2[1H]one 9 <1997PHA436, 1996M1263>, and the pyridazino analogue of 10 reacts similarly to give 13 <1999PAS135> (Scheme 3).

12.16.2.2 Systems with Oxygen or Sulfur in the Central Ring and One or More Nitrogens in the Other Two Rings 12.16.2.2.1

Systems with oxygen in the central ring – pyrrolofuropyridines

12.16.2.2.1(i) Synthesis via 1,3-dipolar cycloadditions Pyridine N-oxides react with N-arylmaleimides to give the primary adducts, pyrrolooxazolopyridines 14, which spontaneously undergo a 1,5-sigmatropic rearrangement, to give the isolated endo-pyrrolofuropyridines 15. The exo-stereochemistry of the primary adduct is determined by the ABX splitting pattern in the 1H NMR spectrum (NMR – nuclear magnetic resonance). The stereoselectivity of this reaction can be rationalized using the frontier orbital picture – the secondary interactions of the endo-transition state are antibonding, whereas for the exo they are bonding. Calculations support the experimental observation that the primary adduct is relatively unstable and that the rearrangement is energetically favorable <1983CPB2948, 1987CPB1049> (Scheme 4). Reaction of 2-alkylpyridine N-oxides with N-alkylmaleimides results in 1:3 or 1:2 ene reaction products, due to the reactive -alkyl group (Scheme 5). Initially, the same 1:1 tricyclic adduct is produced, which then undergoes a 1,3sigmatropic hydrogen shift to give the enamine 16. This may then react with another maleimide molecule, via an ene reaction, to give 17. This process may then be repeated to give 18 <1991CPB10>. The above chemistry has been applied to the synthesis of a series of derivatives which show activity against animal parasites. In order to confirm further the structure and configuration of the most active enantiomer of one of these compounds, the enantiomers were separated by chiral high-performance liquid chromatography (HPLC), and single crystal X-ray diffraction of a 2:1 CuCl2 complex was carried out <2005BML2375>.

Three Heterocyclic Rings Fused (5-5-6)

Scheme 3

Scheme 4

777

778

Three Heterocyclic Rings Fused (5-5-6)

Scheme 5

The reactivity of these pyrrolofuropyridines has been investigated through their reaction with benzenesulfinylallene. In common with certain other dihydropyridines, 19 reacts with benzenesulfinylallene in refluxing benzene to give the dihydropyridone derivative 20, whereby the sulfoxide oxygen has migrated to the pyridine ring. This seemingly unusual reaction has been explained using molecular orbital calculations, which indicate a stepwise reaction pathway involving intermediates 21 and 22 <2002CPB1525> (Scheme 6). These pyrrolofuropyridines also react with ketenes, and in this case the product is the fused -lactam derivative 23 that results from an apparent [2pþ2p] cycloaddition. In these cases only the anti-isomer was formed <2003CPB1068>.

Scheme 6

Three Heterocyclic Rings Fused (5-5-6)

12.16.2.2.1(ii)

Synthesis via nucleophile–electrophile interactions

12.16.2.2.1(ii)(a) Formation of the outer five-membered ring

The pyrido[39,49:4,5]furo[3,2-b]indole 24 can be prepared by Curtius rearrangement of 3-[5-(2-nitrophenyl)-2-furyl]propenoic azide 25, followed by reduction of the nitrophenyl functionality of the product 26, chlorination of the tetracyclic product (PCl5), then reduction (Zn/AcOH) to give the parent compound 24 <1987CCC192> (Scheme 7).

Scheme 7

12.16.2.2.1(ii)(b) Formation of the six-membered ring

In a similar way to the above, azidopropenoylfuro[3,2-b]pyrroles such as 27 can be thermolyzed in a mixture of diphenyl ether and tributylamine to give the 8-oxo-7,8-dihydropyrrolo[29,39:4,5]furo[3,2-c]pyridines 28, again via the intermediate isocyanates. The lactam 28 can be chlorinated and reduced using standard methods (POCl3 then Zn/AcOH) to give the pyrrolo[29,39:4,5]furo[3,2-c]pyridines 29 <1995M753> (Scheme 8).

Scheme 8

An alternative strategy for the synthesis of these tricyclic compounds involves the reaction of the azidoalkenylfunctionalized furo[3,2-b]pyrrole 30, which reacts with triphenylphosphine to give the corresponding iminophosphoranes 31; these upon reaction with aryl isocyanates give the pyrrolo[29,39:4,5]furo[3,2-c]pyridines 32, via the corresponding carbodiimides which are not isolated <1994H(37)1695, 1992M807> (Scheme 9).

779

780

Three Heterocyclic Rings Fused (5-5-6)

Scheme 9

12.16.2.2.2

Systems with sulfur in the central ring

12.16.2.2.2(i) Synthesis via formation of the central ring Although the pyrrolothienopyridines are a relatively little known class of compound, they exhibit a rich chemistry, in terms both of synthesis and reactivity. The first synthesis of these compounds is shown in Scheme 10: the piperidonesubstituted oxindole 33, prepared as a mixture of diastereomers by the reaction of isatin with N-ethoxycarbonyl-4piperidone, is dehydrated in acidic solution to the enaminone 34. Reaction of either 33 or 34 with phosphorus pentasulfide gives the 1,2,3,4-tetrahydro-N-ethoxycarbonyl-6H-pyrido[39,49:4,5]thieno[2,3-b]indole, hydrolysis of which at elevated temperatures in the presence of air gives the parent 6H-pyrido[39,49:4,5]thieno[2,3-b]indole 35 directly. The carbamate functionality of the primary cyclization product can also be reduced with lithium aluminium hydride to give the N-methyl derivative. Upon treatment of the latter with 10% Pd/C in refluxing decalin (197  C) in the presence of air, demethylation and aromatization occur, to give again the fully conjugated parent compound 35 <1987BSF193>.

Scheme 10

12.16.2.2.2(ii) Synthesis and reactivity of S,S-dioxo compounds The S,S-dioxopyrrolothienopyridines are also known, and can be prepared from the S,S-dioxothienopyridine 36. Reaction of 36 with the 1,3-dipole generated photochemically in situ from 2,2-dimethyl-3-phenyl-2H-azirine gives a mixture of two regioisomers, the major product being 1,1,5-trimethyl-3-phenyl-3a,8b-dihydro-1H-pyrrolo[39,49:4,5]thieno[2,3-c]-pyridine-4,4-dioxide 37 and the minor being the 3,3,5-trimethyl-1-phenyl isomer 38 <1983HCA971> (Scheme 11). The reactivity of these tricyclic compounds has been investigated in detail. Reaction of these with sodium cyanoborohydride in acetic acid reduces the imine double bonds to give the tetrahydro-derivatives, for example, 37 gives 39. Reaction of 37 with sodium methoxide results in the ring-opened sulfonate salt 40; re-acidification of this salt gives the corresponding sulfonic acid which cyclizes back to the tricycle 37. Further heating of the sulfonic acid

Three Heterocyclic Rings Fused (5-5-6)

results in loss of SO3 to give the pyridine 41. Alternatively, reduction of the sulfonic acid results in reduction of both the sulfonic acid group and the pyrrole CTC double bond, to give a mixture of the pyridinethiol 42 and the pyrrolothienopyridine 43, the latter in very low yield <1983HCA971> (Scheme 12).

Scheme 11

Scheme 12

Reaction of compound 37 with bromine in chloroform results in mono-bromination  to the sulfur. Treatment of this brominated derivative with NaBH3CN in AcOH gives a mixture of products resulting from reduction of the CTN double bond and of elimination of HBr. Reaction of 44 with sodium ethoxide results in the ethoxy-substituted derivative 45, whereas reaction with pyridine gives the dehydrobrominated derivative 46. Reaction of either 44 or 46 with sodium cyanide in dimethyl sulfoxide (DMSO) gives the cyano-derivative 47 <1983HCA971> (Scheme 13).

12.16.2.2.2(iii)

Systems with sulfur in the central ring, one nitrogen in the six-membered ring and two nitrogens in the outer five-membered ring The imidazothienopyridines can be prepared in two different ways, both starting from the same amino-nitrothienopyridine 48. This can be treated with triethyl orthoformate in acetic acid under reductive conditions to give

781

782

Three Heterocyclic Rings Fused (5-5-6)

the imidazothienopyridine directly. Alternatively, acylation of the amino group followed by reduction of the nitro group and a second acylation gives the bis-acylamino-substituted thienopyridine 49. Treatment of this diamide with polyphosphoric acid gives the 1H-imidazo[39,49:4,5]thieno[2,3-b]pyridine 50 <1984JHC587> (Scheme 14).

Scheme 13

Scheme 14

Imidazothienopyridines can be prepared from the aminohydrazide 51. Diazotisation of this compound gives the azide 52, which upon heating in xylene undergoes a Curtius rearrangement to the intermediate isocyanate; this spontaneously cyclizes to the imidazothienopyridine 53. This method appears to be general, and has been used for the synthesis of a range of differently substituted derivatives, the interest in which is due to their antibacterial and antifungal properties <1990PS(47)181, 1991CCC1749, 1991CCC1931, 1996JHC431, 1997CHE741, 2000PHA577, 2001JCCS1175, 2004JCCS335> (Scheme 15).

Three Heterocyclic Rings Fused (5-5-6)

Scheme 15

It has been reported that reactions of the cyano or amino esters, 54 and 55 respectively, with hydrazine hydrate (either neat, or in ethanol) give the pyrazolothienopyridines 56 directly <1992PS(73)127, 1995PS(106)21>. Compounds such as the hydrazide 51 have been implicated as intermediates in these reactions (Scheme 15), although not apparently being isolated in every case. More recent reports, however, claim that reaction of 54 or 55 with hydrazine hydrate gives only compound 51, and that treatment of the latter with glacial acetic acid is required to promote cyclization (presumably with loss of ammonia) to the tricycle 56 <1997PS(126)27, 2000PS(156)53, 2001JCCS1175>.

12.16.2.2.2(iv) Systems with both oxygen and nitrogen in the outer five-membered ring The oxazolothienopyridine derivative 57 can be prepared from the appropriately amino-substituted thienopyridine 58. Upon conversion of the amino group into azido, followed by heating, the oxygen of the adjacent carbonyl group attacks the azide, or the derived nitrene, to give the oxazole 57 <2004CHE377, 2000CHE494> (Scheme 16).

Scheme 16

12.16.2.2.2(v) Systems with sulfur in the central ring and two nitrogens in each of the outer rings The pyrazolothienopyrimidines are the only class of compound within this category to have been reported. These can be made by two different routes, via formation of the pyrazole ring or of the pyrimidine ring (Scheme 17). The

Scheme 17

783

784

Three Heterocyclic Rings Fused (5-5-6)

appropriately substituted thienopyrimidine 59 can be cyclized to the tricycle 61 upon treatment with acid: this involves the hydrazino group attacking the adjacent electrophilic nitrile. Alternatively, the thienopyrazole 60 can be cyclized to 61 (R1 ¼ NH2) upon treatment with hydrazine <1998PHA227>.

12.16.2.3 Systems with Oxygen or Sulfur in the Outer Five-Membered Ring and One or More Nitrogens in the Other Two This class of compound has been reported during the investigations into various heterocycle-containing photochromic materials. The thienopyrrole 62 can be prepared according to known procedures (Hemetsberger–Knittel reaction), and acylation with acetyl chloride may be achieved regioselectively, in the pyrrole ring, when SnCl4 is used as the Lewis acid catalyst. Treatment of the resulting keto ester with hydrazine hydrate gives the 4,6-dihydro-5Hthieno[29,39:4,5]pyrrolo[2,3-d]pyridazin-5-one 63 <2002OL3879, 2003RCB451> (Scheme 18).

Scheme 18

Thienopyrrolopyrimidines can be prepared by a photochemical reaction. Upon heating or irradiation of 4-azido-5(2-thienyl)pyrimidine in trifluoroacetic acid solution, the tricyclic product is formed in good yield <1989CPB2933> (Equation 1).

ð1Þ

The furopyrrolomorpholine 64 can be prepared through a reductive ring opening of the precursor 65 by highpressure hydrogenolysis over palladium hydroxide. This tetracyclic precursor can be prepared from the dioxime 66 by refluxing in toluene <1998SL277> (Scheme 19).

Scheme 19

12.16.2.4 Systems with Oxygen in Each Five-Membered Ring and Nitrogen in the Six-Membered Ring Although several more examples of this type of ring system are known in the literature, the majority of these are cyclic diacetals, which have been used for the protection of diols. These have not been included in this chapter: the reader is directed to the chapters dealing with the relevant diols. Furofuropyridines can be prepared from sugars. Starting from the doubly protected ribonolactone 67, after several steps involving addition of the pyridine group, deprotecting and other transformations, the fluoropyridyl-substituted

Three Heterocyclic Rings Fused (5-5-6)

ribose 68 can be prepared in the enantiomerically pure -form. It was found that treatment of 68 with KOH gave the tricyclic tetrahydrofuro[29,39:4,5]furo[2,3-b]pyridine in quantitative yield <1997TL203> (Scheme 20).

Scheme 20

Furofuroquinoxalinones can be prepared from an unusual reaction involving Ag2CO3/Celite as a reaction activator. Reaction of 4-hydroxy-2-quinolones with alkenes in the presence of Ag2CO3/Celite gives the corresponding dihydrofuroquinolones. Thus, reaction of 4-hydroxy-2-quinolones with 2,3-dihydrofuran gives tetrahydrofuro[29,39:4,5]furo[2,3-c]quinolones <2000T3867> (Equation 2).

ð2Þ

An unusual dimerization reaction was found to occur between anilines and 1,4:3,6-dianhydro-D-fructose 69 under acidic conditions. A 1:1 mixture of 69 with p-toluidine, stirred at room temperature with p-toluenesulfonic acid, rapidly gives the formal dimer, furofuroquinoline 70, as proved by single crystal X-ray diffraction <2005BML1821>. The proposed mechanism for this reaction is shown in Scheme 21.

Scheme 21

785

786

Three Heterocyclic Rings Fused (5-5-6)

12.16.2.5 Systems with Sulfur in Both Five-Membered Rings and Either Nitrogen or Oxygen in the Six-Membered Ring 12.16.2.5.1

Thienothienopyridines and their carbocyclic fused derivatives

12.16.2.5.1(i) Introduction The thienothienopyridines are a relatively little-known class of compound. Interest in these systems arose through the possibility that they occurred in coal-derived products and their extended p-systems initiated interest for their interesting optical properties. Additionally, several differently substituted examples have antitumor activity <2002CPB656>, and may serve as DNA intercalating agents <2005MOL279>. Three different fused systems have been reported in the literature: thieno[39,29:4,5]thieno[2,3-c]pyridine (cis-thiophenes), thieno[29,39:4,5]thieno[2,3-c]pyridine (trans-thiophenes) and thieno[3,2-g]thieno[3,2-c]pyridine derivatives. So far, the parent thienothienopyridines have only been prepared via the corresponding pyrylium salts (see below); all others are benzo or extended carbocyclic derivatives, for example, thienothienoquinolines. 12.16.2.5.1(ii) Synthesis via photocyclisation Thienothienoquinolines have been prepared from the substituted thienothiophenes such as 71 and 72. Reaction of these with an aromatic amine gives the corresponding amides, which can then undergo cyclization to the corresponding thienothienopyridones by ultraviolet irradiation in benzene solution in the presence of triethylamine <1988JHC1363, 1991H(32)2323, 1995H(41)1659>. The cyclized amides can then undergo reaction with phosphorus oxychloride to give the fully conjugated imidoyl chlorides, which in the case of the thieno[39,29:4,5]thieno[2,3-c]quinoline 73 may be reacted with sodium methoxide, to give the corresponding methoxyimine, or with hydrazine to give 74. Attempts to prepare the parent thieno[39,29:4,5]thieno[2,3-c]quinoline 75 directly from 73 were unsuccessful <1988JHC1363>; however, 75 can be prepared via the hydrazino derivative 74 by reaction of the latter with 10% copper(II) sulfate in aqueous acetic acid <1995JHC317>. In the case of thieno[29,39:4,5]thieno[2,3-c]quinoline 77, the final product may be prepared directly from the imidoyl chloride 76 by hydrogenolysis in presence of Pd/C. [1]Benzothieno[39,29:4,5]thieno[2,3-c]quinoline can be prepared in a similar way (Scheme 22).

Scheme 22

Three Heterocyclic Rings Fused (5-5-6)

Reactions of the thienothiophenecarbonyl chlorides 71 and 72 with different aromatic amines give amides which may, in principle, give more than one possible photocyclization product. The amide 79, produced by reaction of thienothiophene 78 with 1-naphthylamine, has only one cyclization possibility, and upon irradiation gives benzo[h]thieno[29,39:4,5]thieno[2,3-c]quinolin-6(5H)-one, which can then be chlorinated, then reduced to the parent ring system 80 using standard methods. However, when 2-naphthylamine is used, cyclization of the corresponding amide gives only one of the two possible isomers, namely benzo[ f ]thieno[29,39:4,5]-thieno[2,3-c]quinolin-7(6H)-one, with no trace of the benzo[g]derivative. Again this may be chlorinated then reduced to give the parent compound 81 <1991JHC737> (Scheme 23). Further examples of this type of synthesis are shown in Scheme 24 <1995JHC659, 1997JHC1597, 1996JHC119>.

Scheme 23

Scheme 24

787

788

Three Heterocyclic Rings Fused (5-5-6)

12.16.2.5.1(iii) Synthesis via nucleophile–electrophile interactions An alternative approach to thienothienopyridines involves intramolecular electrophilic attack at C-3 of the thiophene ring. In this way, the thienothiophene 82 can be cyclized to the benzothieno[2,3-f ]thieno[2,3-c]pyridine 83 upon treatment with polyphosphoric acid (PPA) at 150  C (Equation 3). Similarly, treatment of the amide 84 with POCl3 gives the corresponding 1-alkyl-3,4-dihydro-benzothieno[3,2-g]thieno[3,2-c]pyridine 85 <1999PS(153)401> (Equation 4).

ð3Þ

ð4Þ

The multifunctionalised thieno[2,3-b]thiophene 86 reacts with ethyl cyanoacetate, potassium carbonate, and tetrabutylammonium bromide (TBAB) in dimethylformamide (DMF) at 70  C to give the thienothienopyridine 87. Presumably, this reaction proceeds as shown in Scheme 25, although the published structure 88 for the final cyclisation product may not represent the major tautomer <2003PS(178)1115>.

Scheme 25

12.16.2.5.2

Thienothienopyrylium salts

These salts are useful intermediates for the synthesis of thienothienopyridines and benzothienothiophenes, as well as being an interesting class of triheterocyclic compound in their own right. Treatment of acetylacetone derivatives such as 89 or 90 with PPA results in the cyclized acetyl-substituted thienothiophenes 91 or 92. Acylation of these thienothiophenes in an aliphatic acid anhydride–perchloric acid mixture gives the corresponding thieno[29,39:4,5]thieno[2,3-c]pyrylium and thieno[29,39:4,5]thieno[2,3-c]pyrylium salts 93 or 94, which are stable crystalline solids (Scheme 26). Similarly, the thieno[39,49:4,5]thieno[2,3-c]pyrylium perchlorate isomer can be prepared from the corresponding 2,5-dialkyl substituted thiophene <2001CHE787> (Equation 5). The pyrylium ring of these salts is reactive toward nucleophiles: for example, compound 93 reacts with ammonia to give the corresponding thienothienopyridine 95, whereas reaction with amines or alkalis gives the corresponding amino- or hydroxy-substituted benzothienothiophene, 96 or 97 <1983CHE32>.

Three Heterocyclic Rings Fused (5-5-6)

Scheme 26

ð5Þ

12.16.2.6 Systems with Oxygen in all Three Rings Although many examples of this type of ring system are known in the literature, the vast majority of these are cyclic acetals, which have been used as protecting groups for diols. These have not been included in this chapter. Otherwise, the majority of the compounds which fall into this category are either natural products or derivatives of, or precursors to, the natural products.

12.16.2.6.1

Natural products

Of the three main ‘iridoid’ natural products that contain the pyranofurofuran skeleton – plumericin, 98; allamandin, 99; and allamcin, 100 – plumericin shows antifungal, antibacterial and antitumor activity, whereas allamandin, 99, shows high antitumor activity. The synthesis of these compounds each involves numerous steps, and therefore falls outwith the scope of this chapter <1983JA6755, 1984CPB2947, 1985TL1807, 1986TL1305, 1986JA4974, 1988CPB2784, 1988J(P1)1119>.

789

790

Three Heterocyclic Rings Fused (5-5-6)

12.16.2.6.2

Furofurocoumarins

Furofurocoumarins can be prepared by several methods, all of which start from 4-hydroxycoumarin. The first reported synthesis involves treatment of this with dimethoxyacetone and malononitrile to give the pyranocoumarin 101. Upon treatment of this with 2 M hydrochloric acid, a rearrangement occurs to give the furofurocoumarin 102. The mechanism proposed for this rearrangement involves firstly hydrolysis of the acetal and enamine followed by ring opening of the resulting lactone. The ring-opened compound then recyclizes to the furan, which itself undergoes cyclization to the furofuran. Finally, hydrolysis of the imine and decarboxylation gives the isolated triheterocycle 102. Compound 102 reacts with aqueous methylamine to give the ring-opened pyrrolopyrrole 103; with aqueous ammonia this ring opening is followed by decarboxylation, to give the pyrrolopyrrole 104 <1997J(P1)1323> (Scheme 27).

Scheme 27

Three Heterocyclic Rings Fused (5-5-6)

The pyranocoumarin 105 can be prepared via a three-component Diels–Alder reaction between 4-hydroxycoumarin, ethyl vinyl ether and an -dicarbonyl compound. Similarly to the above, upon treatment of 105 with sulfuric acid in THF, hydrolysis and rearrangement occur to give the furofurochromenone 106. The hemiacetal functionality in 106 may then be oxidized with pyridinium chlorochromate (PCC) to give the lactone 107 <2001EJO3711> (Scheme 28).

Scheme 28

4-Hydroxycoumarin reacts with alkenes in the presence of silver carbonate and Celite to give the corresponding dihydrofuranocoumarins. Thus, when 2,3-dihydrofuran is used as the alkene, the product obtained is the furofurocoumarin 108. Although the reaction mechanism is not certain, it has been presumed to involve oxidation of the coumarin to give the corresponding radical, to which the alkene could then add, and upon further oxidation form the cation which cyclizes and loses a proton to form the product <1998T12215> (Scheme 29).

Scheme 29

791

792

Three Heterocyclic Rings Fused (5-5-6)

12.16.2.6.3

Pyranofurooxazolines

The pyranofurooxazoline 109 can be prepared by a nitrene insertion reaction of the corresponding furan 110 upon treatment with ethyl azidoformate at 50  C under photolysis conditions. Compound 109 is moisture sensitive, and upon treatment with wet acidic THF was converted quantitatively to the more polar furanopyran 111. The structure and stereochemistry of 109 were proved unambiguously by X-ray diffraction, showing that the nitrene inserted anti to the bridgehead methyl group <1999JOC736> (Scheme 30).

Scheme 30

12.16.2.7 Miscellaneous Systems Furothienoquinolines can be produced starting from 2-chloro-3-cyanoquinoline. Treatment of this with thiourea in aqueous alkali gives the corresponding thioamide, which can then react with chloroacetonitrile and potassium carbonate in DMF to give the thienoquinoline 112. Reaction of 112 with chloroacetonitrile in PPA then gives the triheterocyclic furothienoquinoline 113 <1987JHC219> (Scheme 31).

Scheme 31

Diisopropylethylamine (Hu¨nig’s base) reacts with disulfur dichloride in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) and formic acid to give bis[1,2]dithiolo[5,4-b][59,49-e]-[1,4]thiazine 114 <1997AG283, 1997AGE281>. Upon thermolysis, 114 extrudes sulfur, to give the bis[1,2]dithiolo[4,5-b][59,49-d]pyrrole 115 in excellent yield. This reacts as a 1,3-dipole with dimethyl acetylenedicarboxylate (DMAD) to give the 1:2 adduct, the dithiolopyrrolothiopyran 116, via the intermediate 117 <1997CC879>. This reaction appears to be general, 115 reacting with a variety of alkynes containing electron-withdrawing substituents <2002JOC6439> (Scheme 32).

Three Heterocyclic Rings Fused (5-5-6)

Scheme 32

12.16.3 Ortho-Fused Tricyclic Heterocycles with Heteroatoms at the 5:5 Ring Junction 12.16.3.1 Introduction This class of tricyclic compound is dominated by the 3H-pyrrolizines (systematically named 3H–pyrrolo[1,2-a]pyrroles) and related systems, which are fused to another six-membered heterocyclic ring (Figure 1).

Figure 1 3H-pyrrolizine and fused tricyclic systems.

12.16.3.2 Pyrrolizines Fused at the a-Edge to a Pyridine Ring 12.16.3.2.1

Synthesis via nucleophile–electrophile interactions

12.16.3.2.1(i) From pyrrolopyridines Pyrrolizines fused to a pyridine ring can be prepared from pyrrolopyridinones such as 118. These can be alkylated both at the amide nitrogen and at the carbon  to that nitrogen, and so reaction of 118 with 1-bromo-3-chloropropane and sodium hydroxide under phase-transfer conditions gives the tetrahydropyrido[2,3-a]pyrrolizinone 119 <1990BCJ3047> (Equation 6).

ð6Þ

Quinolinic anhydride reacts with ethyl glycinate to give the ester-substituted pyrrolopyridine 120, which reacts with phenylacetic acid and potassium acetate to give the tricyclic pyrrolizinopyridinedione 121. Alternatively, reaction of quinolinic anhydride with phenylacetic acid gives the benzylidene-substituted lactone 122, which then reacts with different amino acids in acetic acid in the presence of potassium acetate to give the substituted pyridopyrrolizines 123 <1991CCC2999> (Scheme 33).

793

794

Three Heterocyclic Rings Fused (5-5-6)

Scheme 33

Benzo-fused pyridopyrrolizines can be prepared by an acid-induced cyclodehydration of the appropriately substituted hydroxypyrrolopyridines. In the case of 124 (Equation 7), this is best rationalized as an intramolecular electrophilic substitution at the o-carbon of the benzyl substituent <1988CC623, 1990J(P1)1757, 2001J(P1)1446>.

ð7Þ

12.16.3.2.1(ii) From pyrrolizines A variety of substituted dibenzo-fused derivatives 126 have been prepared for evaluation of their biological activities. The synthesis of these compounds involves the reaction of o-acylanilines with pyrroloindolones 125, in boiling butan1-ol with pyridinium p-toluenesulfonate as catalyst (Equation 8). Compounds such as 126 which contain the benzo[5,6]pyrrolizino[1,2-b]quinoline skeleton exhibit cytotoxicity against several cancer cell lines <2004BML2363>.

ð8Þ

12.16.3.2.2

Synthesis via Diels–Alder reactions

Aza-Wittig reactions involving N-alkenyl- or N-alkynyl-pyrrole-2-carbaldehydes give the azadiene-substituted alkenyl- 127 or alkynyl-pyrroles 128. These systems can then undergo intramolecular Diels–Alder reactions, with subsequent oxidation (spontaneous) if necessary, to give the pyridopyrrolizines 129 with a variety of ring substituents, although prolonged heating is necessary <2002JOC1941> (Scheme 34).

Three Heterocyclic Rings Fused (5-5-6)

Scheme 34

Intramolecular inverse electron-demand Diels–Alder reaction of N-propargyl-2-(pyrimidin-2-yl)pyrrolidine provides an alternative route to pyridopyrrolizines. For example, heating of 130 to 170  C in nitrobenzene affords the cyclized product with the loss of HCN <1992JOC3000> (Equation 9). The above reference includes molecular orbital (MO) calculations on relative reactivities in this series.

ð9Þ

12.16.3.2.3

Synthesis via transition metal-catalyzed reactions

Functionalized pyridopyrrolizines can be prepared from a rhodium-catalyzed decomposition and subsequent intramolecular cycloaddition reaction of a diazoimide such as 131. It has been established generally that catalytic rhodium(II) species, for example, the perfluorobutyrate, can induce decomposition of diazoimides, which are known then to undergo loss of N2 and form a rhodium carbenoid. This then cyclizes on to the neighboring amide carbonyl oxygen to generate the intermediate dipole, which in turn undergoes a 1,3-dipolar cycloaddition across the adjacent pendant alkene. In this way, treatment of 131 with a rhodium(II) reagent gives the pyridopyrrolizine 134 in high yield (Scheme 35). This reaction is thought to proceed via the primary cycloadduct 132, which undergoes ring opening to give 134, probably via the iminium ion 133 which then eliminates a proton <1994JOC1418>. Pyridopyrrolizines can be prepared by a palladium-catalyzed carbonylation-intramolecular cyclization sequence. The 2-iodo-3-pyrrolidinylquinoline derivative 135, upon treatment with Pd(0) and CO (1 atm) in the presence of TlOAc (2 equiv), gives the corresponding triheterocyclic derivative 136. This reaction is thought to involve firstly oxidative addition of the Pd into the iodine–aryl bond, followed by the addition of CO to give the acylpalladium(II) species, which can then undergo intramolecular capture by the pyrroline nitrogen. TlOAc is added to the reaction in order to promote carbonylation at atmospheric pressure <1995T295> (Scheme 36).

12.16.3.2.4

Synthesis via transformations of other ring systems

The fused indolopyrrolizidine 137 can be transformed into the tetrahydropyrrolizinoquinolone 138 upon reaction with ButOK while oxygen is bubbled into the solution. (This is an apparently general strategy for the oxidation of indoles.) Compound 138 may then be oxidized with m-chloroperbenzoic acid (MCPBA) to give the dihydropyridopyrrolizine 139 <1997TL2997> (Scheme 37).

795

796

Three Heterocyclic Rings Fused (5-5-6)

Scheme 35

Scheme 36

Scheme 37

Three Heterocyclic Rings Fused (5-5-6)

As part of a study on the synthesis of Vinca alkaloids, the polycyclic compound 140 was prepared. Treatment of 141 with aqueous alkali gives the triheterocyclic product 142, which was isolated as its perchlorate salt. The iminium functionality of 142 can then be reduced stereospecifically by treatment with sodium borohydride <1985JOC3760> (Scheme 38).

Scheme 38

12.16.3.3 Pyrrolizines Fused at the b-Edge to a Pyridine Ring 12.16.3.3.1

Synthesis via nucleophile–electrophile interactions

5-Benzylidene–2,3,4,5-tetrahydropyridine 143 reacts with nucleophiles either by a 1,2- or 1,4- (conjugate) addition. Reaction of 143 with an excess of pyrrole at 130  C for 14 h gives 5-phenyl-1,3,4,4a,5,9a-hexahydro-2H-pyrrolo[19,29:1,5]pyrrolo[2,3-b]pyridine 144. The likely mechanism of this reaction involves conjugate addition of the pyrrole (through C-2) to the imine, the product of which then cyclizes by a 5-exo-trig process to give 144 <1984BCJ1271> (Scheme 39).

Scheme 39

The 9H-pyrido[3,4-b]pyrrolizin-9-one 145 has been prepared for its photochemical properties. The preparation involves an intramolecular Friedel–Crafts acylation of the acid chloride formed from 3-(1-pyrrolyl)pyridine-4-carboxylate (Scheme 40). The product is a photosensitizer, which absorbs visible light: its absorption spectra are pH, solvent, and concentration dependent <1994SAA57>.

Scheme 40

Pyridopyrrolizines have been prepared starting from N-acylprolines such as 146. Upon treatment of this compound with acetic anhydride, the zwitterionic species 147 is produced, which can then react with DMAD to give the dihydropyrrolizine diester 148. This, upon treatment with an excess of methylamine, undergoes loss of the phthalimido protecting group, and the triheterocyclic amide 149 is isolated <1985TL1295> (Scheme 41). The scheme also shows the conversion of the N-protected diester 148 into the chloropyridopyrrolizine 150, which may then serve as a starting point for further transformations.

797

798

Three Heterocyclic Rings Fused (5-5-6)

Scheme 41

Treatment of the N-protected 4-chloro-2-pyridone 151 with sodium prolinate in hot DMSO gives a prolinylpyridone, which may then be cyclodehydrated by acetic anhydride to give the pyridopyrrolizinone 152 <1994TL6985> (Scheme 42). The acetoxy group in 152 forms the basis for further functional group transformations, as outlined in the scheme.

Scheme 42

12.16.3.3.2

Synthesis via cycloaddition reactions

Cycloaddition of the tetrahydropyrrolopyridine-2-carbaldehyde 153 with electron-depleted alkenes in the presence of a base leads to products, the 1H NMR spectra of which are consistent with their formulation as 154 rather than 155. In the case of the acrylonitrile adduct, the initially formed pyrrolizine reacts with another molecule of acrylonitrile to give a cyanoethyl-substituted derivative <1998CHE1418> (Scheme 43).

12.16.3.3.3

Reactivity

The reactivity of triflate-substituted pyridopyrrolizines has been investigated. In the presence of a polar aprotic solvent and a nucleophile, these compounds undergo SN9 reactions, leading to the -substituted 3H-3-pyrrolones. This process is thought to involve loss of the trifluoromethanesulfinate ion, formation of an acyliminium ion intermediate, and nucleophilic attack on the latter <1995JOC5382> (Scheme 44).

Three Heterocyclic Rings Fused (5-5-6)

Scheme 43

Scheme 44

12.16.3.4 Pyrrolizines Fused to a Pyrimidine or Pyrazine Ring 12.16.3.4.1

Synthesis via formation of the six-membered ring

Pyrimidine-fused pyrrolizines have been prepared from the functionalized tetrahydropyrroles 156 according to Scheme 45 <1989CHE691>. 3,3-Dimethyl-3H-indole reacts with diethyl oxaloacetate in acetic acid to give the pyrrolizine 157. Upon reaction of this product with guanidine for extended periods of time, the tetracyclic product 158 is formed in low yield <1988J(P1)451> (Scheme 46).

12.16.3.4.2

Synthesis via formation of the pyrrolizine ring system

In a one-pot reaction, 6-pyrrolidinouracils react with DMAD in refluxing ethanol to give the pyrrolizine-fused uracils 159 directly. The mechanism proposed for this reaction involves Michael addition of the uracil (through C-5) to the alkyne, to give the isolable aminodiene intermediate 160. Upon further heating, 160 undergoes a 1,6-hydride shift to give a 1,5-dipole, which is then cyclized to the final product 159, the stereochemistry of which is not reported <1998JCM502, 1998JRM2025, 1996TL1853> (Scheme 47).

799

800

Three Heterocyclic Rings Fused (5-5-6)

Scheme 45

Scheme 46

Scheme 47

Benzo-fused pyrrolizines can be prepared from the palladium-catalyzed reaction of alkynes with imines of 2-halogenoanilines. Pyrimidine-substituted alkynes react in the same way, to produce the pyrimidine-fused pyrrolizines 161 <2001JOC412> (Scheme 48).

Three Heterocyclic Rings Fused (5-5-6)

Scheme 48

Owing to the electron-withdrawing cyano groups, 2,3-dichloro-5,6-dicyanopyrazine is especially reactive toward nucleophilic attack at the chlorine-bearing carbons. For example, it reacts with 2-cyanomethyl-benzimidazole and -benzothiazole under mild conditions (DMF at room temperature, optionally in the presence of triethylamine) to give the corresponding bis-heterocycles 162 and 163 respectively, in which the central double bond may possess either (E)- or (Z)-geometry. These bis-heterocycles can be cyclized to the corresponding benzimidazopyrrolopyrazines and benzothiazolopyrrolopyrazines, 164 and 165, respectively (Scheme 49), by heating in pyridine. It is reported that these benzo-triheterocycles are yellow in color and exhibit fluorescence in solution <1999CHE1089>.

Scheme 49

12.16.3.5 Pyrrolizines Fused to a Pyran or Thiopyran Ring 12.16.3.5.1

Synthesis via 1,3-dipolar cycloadditions

Intramolecular [3þ2] cycloaddition reactions have been used for the synthesis of pyranopyrrolizines and thiopyranopyrrolizines. Azomethine ylides are prepared in situ: nonstabilized examples are derived from the condensation of -amino acids with aldehydes, and the stabilized examples from the condensation of -amino esters. These ylides react with alkenes and alkynes to give the corresponding pyrroles, by a [3þ2] cycloaddition. Thus, reaction of proline derivatives with O-allyl- or O-propargyl-salicylaldehydes (Equations 10 and 11) gives the benzo-fused triheterocyclic products 166 and 167, which may then be dehydrogenated with treatment with sulfur (Equation 12). Similarly, treatment of proline methyl ester with O-propargylsalicylaldehyde or its S or N analogues gives pyranopyrrolizines, thiopyranopyrrolizines, and pyridopyrrolizines. In these reactions the ester group is retained in the final product, whereas when the acid is used, decarboxylation occurs (Equation 13) <1984CC182, 1984JA7175, 1990T2213, 2004TL1567>.

801

802

Three Heterocyclic Rings Fused (5-5-6)

ð10Þ

ð11Þ

ð12Þ

ð13Þ

Thiopyranopyrrolizines have also been prepared for the evaluation of their biological properties: they are potent, selective, and orally active inhibitors of 5-lipoxygenase. Upon heating to 180  C with pyridinium chloride, the indole 168 is cyclized to the pyrrolizine and also the methoxy group is demethylated. Formation of the thiopyran ring may be achieved by allylation of the phenol oxygen followed by a Claisen rearrangement to give the allyl-substituted benzopyrrolizine 169: this is cyclized to the thiopyranopyrrolizine upon treatment with acid <1993JME2771> (Scheme 50).

Scheme 50

Three Heterocyclic Rings Fused (5-5-6)

12.16.3.5.2

Synthesis via nucleophile–electrophile interactions

Thiopyranopyrrolizines can be prepared readily from the enamine 170 upon treatment with DMAD. Alternatively, heating of the thiacyclooctadiene derivative 171 in methanol gives the same tricycle 172, but this time as a 5:2 mixture with the (Z,E)-isomer of the precursor 171. These reactions probably involve the the intermediacy of an unstable cyclobutene and/or a zwitterionic diene, as shown in Scheme 51 <1984JA1341>.

Scheme 51

12.16.3.5.3

Synthesis via photochemical reactions

An interesting and unusual example of 5:5:6-fused triheterocyclic systems is provided by pyranopyrrolizines fused through the outer pyrrole ring to a C60 fullerene. The interest in these systems arises from their potential biological properties. Of particular interest here is the attachment of the alkaloid tazettine, 173. Irradiation of a toluene solution of 173 and C60 with visible light gave the triheterocycle-fused C60. The mechanism of this reaction is thought to involve the photoinduced electron transfer from the tertiary amine to C60, resulting in the tertiary amine radical cation and a C60 radical anion. The latter can then deprotonate the radical cation to give the tertiary amine radical and C60H as a radical pair, which can then combine to form the first carbon–carbon bond. The product can then undergo another electron-transfer, proton-transfer, and radical combination sequence to give the isolated product <2000JOC3804> (Equation 14).

ð14Þ

Pyranopyrrolizines can be prepared from prolinylcoumarin derivatives. Treatment of the Weinreb-type amide 174 with methyllithium in THF gives a ketone intermediate, which when treated with silica gel in chloroform undergoes a cyclodehydration to give the triheterocyclic system 175 <1999T13211> (Scheme 52).

803

804

Three Heterocyclic Rings Fused (5-5-6)

Scheme 52

12.16.3.6 Pyrroloimidazoles and Pyrrolothiazoles Fused to a Pyridine, Pyran or Thiopyran Ring 12.16.3.6.1

Synthesis via 1,3-dipolar cycloaddition reactions

Pyranopyrroloimidazoles have been prepared stereospecifically by an intramolecular 1,3-dipolar cycloaddition reaction. Either enantiomer of the imidazoline derivative 176 (the S-enantiomer is shown) may react with the bromoacetyl-containing acrylate dipolarophile 177, in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), to give the diastereomerically pure tricyclic product 178 in moderate yield (Equation 15). This reaction involves quaternization of the imidazole N, reaction of the quaternary salt with base to give the 1,3-dipole, which can then react, intramolecularly and stereospecifically, with the tethered dipolarophile <1997TL1647>.

ð15Þ

Pyranopyrrolothiazoles can be prepared in a similar way to certain pyrano- and thiopyrano-pyrrolizines and pyrrolizinopyridines as discussed earlier. Thus, thiazolidine-4-carboxylic acid reacts with the aldehyde 179 to give a 2:1 mixture of 180 and 181 (Equation 16). This reaction is a 1,3-dipolar cycloaddition of the alkene to the 1,3-dipole formed from reaction of the amino acid amine with the aldehyde <1988T4953, 1990T2213>. The alkyne analogue of 179 is similarly converted into 182 (Equation 17).

ð16Þ

ð17Þ

Three Heterocyclic Rings Fused (5-5-6)

In another variant of these intramolecular 1,3-dipolar cycloadditions, the alkyne-containing amino acid amide 183, when reacted with acetic anhydride, produces a zwitterionic thiazolo-oxazolium intermediate, which may then react intramolecularly with the dipolarophile and give the triheterocycle 184 <1999J(P1)1219, 2002JOC4045> (Equation 18). The benzo-fused analogue 185 is obtained similarly (Equation 19).

ð18Þ

ð19Þ

12.16.3.6.2

Synthesis via nucleophile–electrophile interactions

Pyranopyrroloimidazoles can be prepared by a reaction sequence involving the synthesis of pyranopyrrole 186 from an intramolecular [3þ2] cycloaddition of the Grigg type discussed in the foregoing section. This compound may then react with phenyl isocyanate to give the corresponding urea, which in turn undergoes a base-induced cyclization <1998TL1685> (Scheme 53). A ‘solid-phase’ synthesis of these compounds has been developed, whereby removal of the final product 187 from the polymer is concomitant with the final cyclization step <1998JOC3081>.

Scheme 53

This cyclization reaction can be accelerated by the use of microwave irradiation, using DMF as the solvent and Ba(OH)2 as the base <1998JOC4854, 1998TL3379>.

12.16.3.7 Other Systems The hydrazinoyl-substituted imidazothiadiazole 188 under Vilsmeier–Haack–Arnold reaction conditions gives the tricyclic thiadiazoloimidazopyridazinone 189 <2006SC1837> (Equation 20).

805

806

Three Heterocyclic Rings Fused (5-5-6)

ð20Þ

12.16.4 Ortho-Fused Tricyclic Heterocycles with Heteroatoms at the 5:6 Ring Junction All compounds reported within the review period are indolizines or their hetero-substituted derivatives, fused through the a- or b-edge to a five-membered heterocyclic ring.

12.16.4.1 Indolizines Fused at the a-Edge to a Pyrrole Ring 12.16.4.1.1

Natural products

The natural products aristone, 190, bisaristone A, 191, and bisaristone B, 192, all contain an indoloindolizine unit within their polycyclic structures. These natural products have been isolated from the leaves and branches of the Australian mountain wine berry. Structural assignments are derived from spectroscopic data, and as yet no syntheses have been reported <1987JOC4527>.

12.16.4.1.2

Synthesis via nucleophile–electrophile interactions

The indolizine enol 193 (R ¼ H), when treated with phenylhydrazine in acetic acid, gives the ene-hydrazine 194, which can then undergo a Fischer indole synthesis to give the indoloindolizine 195 in low yield. However, compound 195 is obtained directly, and in much higher yield, in a ‘one-pot’ reaction of the indolizine enol ether 193 (R ¼ C3H7), phenylhydrazine and HCl in acetic acid (Scheme 54) <2001JOC426>. Attempted N-alkylation of 195 results in a mixture of oxidized products 196–199, the proportions depending on the conditions used (Figure 2). 2-Chloromethylindolizine-1-carbonitrile reacts with anilines to give the amines 200, which can then react in acidic conditions to give the cyclized pyrroloindolizines, as the hydrochloride salts, 201 <2006S349> (Scheme 55).

Three Heterocyclic Rings Fused (5-5-6)

Scheme 54

Figure 2 Products of alkylation of compound 195.

Scheme 55

12.16.4.1.3

Synthesis via cycloadditions

By far the majority of reports of pyrrolindolizines involve their synthesis via dipolar cycloaddition reactions. Thus, almost exclusively, such compounds are derived from maleimides.

12.16.4.1.3(i) [3þ2] cycloadditions between pyridinium methylides and maleimides Stereoselective [3þ2] cycloaddition reactions between pyridinium methylides and electron-deficient alkene dipolarophiles have been used for the construction of the pyrroloindolizine skeleton. 1,3-Dipolar cycloadditions give endo[3þ2]-cycloadducts, the stereoselectivity proved by spectroscopic means. These reactions proceed quantitatively after only a few minutes <1983H(20)1907>, and this chemistry has been used on a range of substrates <1990M529, 2001TL5081, 2003OBC2377, 2004T9937> (Equation 21). Use of a silyloxypyridinium methylide in the above reaction leads, after hydrolytic workup, to the hexahydropyrroloindolizine 202 <1986JOC1853> (Equation 22). These pyrroloindolizines are unstable, however, and decompose rapidly to a mixture of secondary products. The decomposition is accelerated in polar solvents: catalytic AcOH in CHCl3 or the application of silica gel gives the alkenylpyrrolidinedione 203, with the elimination of pyridine <1987BCJ1489> (Equation 23).

ð21Þ

807

808

Three Heterocyclic Rings Fused (5-5-6)

ð22Þ

ð23Þ

Reaction of isoquinolinium phenacylide with (E)-1,2-dibenzoylethene gives the indolizine 204; epimerization at the carbon (* )  to the two additional ketone groups occur upon standing in solution. Treatment of this with N-methylmaleimide gives the corresponding pyrroloindolizine 205, with the loss of dibenzoylethene, implying that the epimerization process may occur through a retro-cycloaddition <1985CL355, 1985BCJ3137> (Scheme 56).

Scheme 56

Dehydrogenation has been used as a method for azomethine ylide formation. Treatment of compound 206 with N-methylmaleimide in the presence of palladium black gives a 1:1 mixture of the endo- and exo-diastereomers 207 and 208, in 65% combined yield <1989J(P1)198> (Equation 24).

ð24Þ

Tetrahydropyridinium methylides, for example, 209, have been prepared in situ from the organotin- or organosilylsubstituted imines. These react with N-phenylmaleimides to produce the completely saturated pyrroloindolizines <1997TL5441, 2004JOC1919> (Equation 25).

Three Heterocyclic Rings Fused (5-5-6)

ð25Þ

Reaction of 5-halogenoalkanals with organotin- or organosilyl-substituted amines and maleimides gives the pyrroloindolizines directly. Condensation of the amine with the aldehyde, followed by reaction of the imine with the halogenoalkane, gives the tetrahydropyridinium salt, which can then undergo elimination of the organometallic component to give the azomethine ylide 209. This can then react with the dipolarophile in the usual way to give the tricyclic product <2004JOC1919> (Scheme 57).

Scheme 57

A solid-phase synthesis of pyrroloindolizines has been developed using this cycloaddition methodology, whereby an isoxazolopyrroloindolizine can be removed from the polymeric resin upon treatment with trifluoroacetic acid (TFA). This also results in ring opening of the isoxazole to give the isolated compound 210 (Scheme 58). A library of 96 such derivatives has been prepared in this way <1998TL5869>.

Scheme 58

12.16.4.1.3(ii) 3-Component reactions between amines, aldehydes, and maleimides Azomethine ylides can also be prepared from the condensation between aldehydes and secondary amino esters. In the same way as the azomethine ylides above, these ylides can then react with dipolarophiles to form the pyrrole ring. Thus, a stoichiometric mixture of ethyl picolinate, benzaldehyde, and N-methylmaleimide gives 211 and 212 as a 3:1 ratio of diastereomers <1985TL2775, 1988BSF143> (Equation 26). Similarly, reaction of tetrahydroisoquinoline, phenylglyoxal, and N-methylmaleimide gives a 7:1 mixture of the endo- and exo-isomers. In this case the azomethine ylide is formed through a 1,5-hydrogen shift <1986CC602> (Equation 27).

809

810

Three Heterocyclic Rings Fused (5-5-6)

ð26Þ

ð27Þ

1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid reacts with aldehydes with concomitant decarboxylation, to give the intermediate anti-dipole 213. Reaction of this with N-methylmaleimide gives the pyrroloindolizine 214 stereospecifically <1987CC47>. When tetrahydrosoquinoline 1-carboxylic acid is used in this reaction, however, the product mixture contains pyrroloindolizines resulting from both syn- and anti-dipoles <1987CC49, 1988J(P1)2693, 1988J(P1)2703> (Scheme 59).

Scheme 59

Pyrroloindolizines can be prepared from bifunctional ketones and their derivatives. For example, 3,3-dipiperidinoisoindoxyl 215 reacts with N-methylmaleimide to give the pyrroloindolizines 216 and 217. Similarly, reaction of the dipiperidinoindanedione 218 gives 219 and 220, and reaction of acenaphthenequinone with tetrahydroisoquinoline and N-methylmaleimide gives 221 and 222 <1990T6433> (Scheme 60). Further examples of the use of aldehydes and ketones in pyrroloindolizine synthesis have also been reported <1990T6449, 2001JOC7666>.

Three Heterocyclic Rings Fused (5-5-6)

Scheme 60

12.16.4.1.3(iii) Synthesis via metal-catalyzed reactions Differently substituted pyrrolopyrroles can be constructed from a 1,3-dipolar cycloaddition, between the adduct from glycines and aldehydes and maleimides. Then, for example, the initially formed N-allyl-o-bromophenyl-substituted pyrrolopyrrole mixture, 223, þ 224, can then undergo an intramolecular cyclization in the presence of catalytic palladium(0) to give the pyrroloindolizine 225 <1991TL1359> (Scheme 61).

Scheme 61

12.16.4.1.4

Synthesis via radical processes

The 2-bromoindole derivative 226 can be cyclized by a radical process upon treatment with Bu3SnH and AIBN in toluene. The proposed mechanism involves generation of the radical at C-2, which undergoes a 1,5-hydrogen abstraction to give the -imidoyl radical 227; this is followed by cyclization and hydrogen abstraction to give 228 <2001CC805> (Scheme 62).

811

812

Three Heterocyclic Rings Fused (5-5-6)

Scheme 62

12.16.4.1.5

Synthesis via transformations of other ring systems

Acylation of the polycyclic compound 229 with acetic anhydride results not only in acylation but also in a formal contraction of the central ring to give the indoloindolizine 230 <1999H(51)303>. A plausible mechanism is shown in Scheme 63.

Scheme 63

12.16.4.2 Indolizines Fused at the b-Edge to a Pyrrole Ring An intramolecular variant of the above chemistry has been used for the preparation of pyrroloindolizines. N-Allyl- and N-propargyl-glyoxals react with tetrahydroisoquinoline to give 231 and 232, respectively (Equations 28 and 29). Furthermore, these reagents have been linked through the N-substituent to a polymeric resin for further use in solidphase and combinatorial chemistry <1997JA6153>.

ð28Þ

Three Heterocyclic Rings Fused (5-5-6)

ð29Þ

12.16.4.3 Indolizines a- or b-Fused to a Furan or Thiophene Ring 12.16.4.3.1

Furoindolizines

12.16.4.3.1(i) Synthesis via nucleophile–electrophile interactions Treatment of the indolizine 233 with sulfuric acid results in hydrolysis and lactonization, and gives the furanoindolizine 234 <1984BCJ548> (Equation 30).

ð30Þ

Treatment of the indolizines 235 with a base results in furan ring formation to give furoindolizines 236. The proposed mechanism involves the intermediacy of the corresponding aldehyde resulting from a retro-aldol cleavage of the dicyanovinyl group; this aldehyde can then undergo an intramolecular aldol reaction with the enolate <1983BCJ1219> (Scheme 64).

Scheme 64

In common with many other ortho-dicarboxylic acids, indolizine-1,2-dicarboxylic acid, when treated with trifluoroacetic anhydride, gives the cyclic anhydride <2000H(53)2123> (Equation 31).

ð31Þ

The furoindolizine 237 can be prepared from the azide-tethered quinone 238. Heating 238 gives a mixture of products, the two isolated being the expected azepinedione 239 and also the furoindolizine. The proposed intermediate is the fused triazole 240, which can then either undergo a 1,2-acyl migration to the piperidine nitrogen, with concomitant loss of N2, to give 239, or undergo another series of rearrangements to give 237 <1987TL4929> (Scheme 65).

813

814

Three Heterocyclic Rings Fused (5-5-6)

Scheme 65

12.16.4.3.1(ii) Synthesis via cycloaddition reactions The isoquinolinium ylide 241 reacts with allyl alcohol in a [3þ2] cycloaddition to give the tetracyclic product 242 (Equation 32): the primary cycloaddition product spontaneously undergoes an intramolecular transesterification to give the isolated furanone. Similarly, reaction of such ylides with vinylene carbonate gives the tetracycles 243 (Equation 33) <1988BCJ2513>.

ð32Þ

ð33Þ

Reaction of the aldehyde-tethered furanone 244 with pipecolinic acid results in the formation of the oxazolopyridine derivative 245, which undergoes spontaneous decarboxylation to give the ylide 246. This in turn undergoes an intramolecular cycloaddition with the tethered exomethylene group to give 247, or with the endocyclic alkene to give the furoindolizine 248 <1997T10633> (Scheme 66).

12.16.4.3.2

Thienoindolizines

12.16.4.3.2(i)

Thiophenes fused to the a-edge

12.16.4.3.2(i)(a)

Synthesis via transformations of other ring systems

Treatment of thiopyranoindolizines 249 with an alkylating agent and a base results, unexpectedly, in the thienoindolizines 250. This unusual transformation is thought to arise through S-alkylation and ring opening, followed by rearrangement and rearomatization with the loss of ethyl cyanoacetate <1993CPB1753> (Scheme 67).

Three Heterocyclic Rings Fused (5-5-6)

Scheme 66

Scheme 67

12.16.4.3.2(i)(b) Synthesis via nucleophile–electrophile interactions

By reaction of a base with compound 251, attack of the ester enolate at the adjacent nitrile occurs, to give the aminosubstituted thienoindolizine 252 <1987CL2043> (Equation 34).

ð34Þ

815

816

Three Heterocyclic Rings Fused (5-5-6)

Thienoindolizines can be prepared by treatment of a 1,2-diacylindolizine with P4S10 <1983H(20)1525, 1988JHC1793, 1984H(21)572> (Equation 35).

ð35Þ

A reductive intramolecular cyclization of 253 gives the tricycle 254, the amino group of which can be removed upon treatment with zinc and acetic acid <1994H(37)239> (Scheme 68).

Scheme 68

12.16.4.3.2(i)(c)

Metal-catalyzed reactions

Palladium-catalyzed reactions have been used for the formation of thienoindolizines: the following reaction, which is carried out in presence of a mild base, gives different ratios of the endo- (thienopyridone) and exo- (thienoindolizine) products according to the specific catalyst and base used (Equation 36). The latter is almost exclusively formed when the base used is sodium formate or piperidine <1997TL1057>. For the conditions favoring the 5:6:6-fused product, see Section 11.17.4.1.1.3.

ð36Þ

12.16.4.3.2(ii)

Thiophenes fused to the b-edge

12.16.4.3.2(ii)(a) Synthesis via nucleophile–electrophile interactions

Whereas reaction of the cyano-substituted indolizine 251 with a base results in the a-fused product (Equation 34), the diester 255 reacts to give only the b-fused product 256 <1987CL2043> (Equation 37). Similarly, when the acylindolizines 257 are prepared (Equation 38), very small amounts of the thienoindolizines are found in the product mixture. When such indolizines are substituted with both cyano and keto groups, treatment with a base gives a mixture of products resulting from reaction of the ester enolate with either of these electrophiles <1989BCJ119> (Equation 39).

ð37Þ

Three Heterocyclic Rings Fused (5-5-6)

ð38Þ

ð39Þ

The reactivities of variously substituted derivatives are illustrated below in Scheme 69 <1989BCJ119, 1990CPB1527, 1992CPB2313>.

Scheme 69

817

818

Three Heterocyclic Rings Fused (5-5-6)

The N-thienylpyridinium salt 258 can be transformed into the thienoindolizine 259 upon treatment with HBr (dehydrogenation occurs spontaneously) <2002H(57)17>; or by treatment with DBU followed by chloranil <2003CPB75, 2003CPB1246>. These same compounds can be prepared directly from the salt 260, by treatment with DBU and chloranil <2001H(54)185> (Scheme 70).

Scheme 70

Thienoindolizines can be prepared by treatment of the alkenylindolizine 261 with bromine and a base, whereby bromination of the indolizine ring also occurs. Alternatively, reaction of 261 with a tetraalkylammonium tribromide and a base gives the tricycle 262, which can then be brominated to 263 by treatment with molecular bromine <2004CPB279> (Scheme 71).

Scheme 71

12.16.4.3.2(ii)(b) Synthesis via transformations of other ring systems

Reaction of the thiazine 264 with DDQ in chloroform does not give the dehydrogenated product 265 in every case: instead thienoindolizines, 266, may be the observed products. A possible mechanism is shown below <1987BCJ3713; 1992BCJ1244> (Scheme 72).

12.16.4.4 Indolizines a- or b-Fused to a Five-Membered Ring Containing Two or Three Heteroatoms Isoxazolidinoindolizines and pyrazolidinoindolizines, 268, can be prepared from the oximes or hydrazones 267. 1,3-Dipolar cycloadditions of oxime or hydrazone on to the adjacent alkene occur cleanly by heating the substrate in acetonitrile, or in the case of the basic aliphatic hydrazones, under acidic conditions <1987JOC226> (Equation 40).

Three Heterocyclic Rings Fused (5-5-6)

Scheme 72

ð40Þ

This method has also been applied to the pyridinium salt 269, which on heating in n-butanol gives the unstable salt 270. This can be then reduced to the stable tetrahydropyridine 271 on treatment with NaBH4 <1991T4007> (Scheme 73). Similarly, heating of the oxime 272 in a sealed tube at 180  C gives the tricycle 273 [as a 75:25 anti:syn mixture; Equation (41)], and 274 can be obtained (although only one stereoisomer has been isolated) in the same way <1989TL2289, 1991JOC2775> (Equation 42).

Scheme 73

ð41Þ

ð42Þ

819

820

Three Heterocyclic Rings Fused (5-5-6)

Condensation of p-chlorophenylhydrazine with the diacylisoxazolopyridine 275 gives the pyrazoloindolizine 276, and not the expected pyridazine. The proposed mechanism for this reaction involves a complex series of rearrangements <1997J(P1)155> (Scheme 74).

Scheme 74

Treatment of the anthraquinone-based ,-unsaturated ketone 277 with hydrazine, phenylhydrazine, and hydroxylamine is reported to give the corresponding pyrazolo- and isoxazolo-fused ring systems <2002JCCS387> (Scheme 75).

Scheme 75

A series of new pyrazoloindolizinium salts has been prepared for their interest as dyestuffs. The amide 278 undergoes an intramolecular cyclization to the tricycle 279 upon heating in an ethanol/piperidine mixture. The methylene group of this can then react with different electrophiles, for example, aldehydes, to extend the chromophore <2002JCCS571> (Scheme 76).

Three Heterocyclic Rings Fused (5-5-6)

Scheme 76

12.16.4.5 Pyrrolopyridazines, Pyrrolopyrimidines, and Pyrrolopyrazines Fused through the Pyrrole to a Five-Membered Heterocycle In the cycloaddition reactions of diaminooxindoles 215 (cf. Scheme 60), the piperidine can be replaced by morpholine, thiomorpholine, or N-methylpiperazine to give the corresponding tricycles with two heteroatoms in the sixmembered ring <1990T6433> (Equation 43).

ð43Þ

A four-component Ugi reaction between the thienopyrrole-diketo-acid 280, an isonitrile and an amine gives the fused tricycle 281 with two nitrogens in the six-membered ring <2006SC903> (Equation 44).

ð44Þ

The natural product verrucofortine, 282, contains a pyrrolopyrrolopyrazine structural unit. This compound is a major metabolite of Penicillium verrucosum var. cyclopium, the fungus that produces the mycotoxin verrucosidin <1988JNP66>.

12.16.5 Ortho-Fused Tricyclic Heterocycles with Two or More Ring Junction Heteroatoms 12.16.5.1 Two Ring Junction Heteroatoms, Both between the Five-Membered Rings Pyrazolopyrazoloquinoline derivatives can be prepared by treatment of pyrazolidin-3-one with 2-chloroquinoline-3carbaldehyde, which gives firstly the zwitterionic compound 283. Reduction with sodium borohydride followed by ring closure in basic media gives the fused tricyclic heterocycles (Scheme 77) <1991T9599>.

821

822

Three Heterocyclic Rings Fused (5-5-6)

Scheme 77

12.16.5.2 Two Ring Junction Heteroatoms, Both between the Five- and Six-Membered Rings Pyrazolopyrazolopyrazines can be prepared from a stereoselective dipolar cycloaddition between the alkene group of 284 and diazomethane (Equation 45). Ten equivalents of diazomethane are used in this reaction: when only 1 equiv is used, the corresponding methyl ester of the starting material was formed <2002OL773>.

ð45Þ

12.16.5.3 One Heteroatom at a 5:5-Ring Junction and the Other at a 6:5-Ring Junction 12.16.5.3.1

Pyrroloimidazo-pyridines and -pyrimidines

The synthesis of pyrroloimidazopyridines via photochemical reactions has been investigated in detail. Irradiation of tetrahydropyridine- and morpholine-linked succinimide and phthalimide derivatives gives the corresponding cyclised products resulting from the intramolecular reaction between the aminoalkyl and carbonyl groups <1982S1078, 1983J(P1)2857> (Equations 46–48).

ð46Þ

ð47Þ

Three Heterocyclic Rings Fused (5-5-6)

ð48Þ

In the same way, irradiation of compound 285 gives the pentacycle 286, which can be converted into the enaminol 287 on treatment with HCl (Scheme 78). This is of interest as 287 contains the same ring system as the protoberberine alkaloids <1984TL1087, 1985J(P1)1177>.

Scheme 78

Pyrroloimidazopyridines can be prepared readily by an interesting reaction between 6-aminomethyl-2-piperidone and the vinyldiketo ester 288. This initially gives compound 289, which can be converted into the pyrroloimidazopiperidine 290 upon treatment with pyridinium p-toluenesulfonate <1990JOC5821> (Scheme 79).

Scheme 79

The fused N-(pyrimidin-4-yl)proline derivative 291 undergoes cyclization to the zwitterionic pyrroloimidazopyrimidine 292 upon treatment with acetic anhydride <1985JHC187> (Equation 49).

ð49Þ

823

824

Three Heterocyclic Rings Fused (5-5-6)

A novel natural product has been isolated from the Micronesian sponge Dysidea herbacea. This material is the zwitterionic pyrroloimidazopyridine 293 and is claimed to be the first example of a simple peptide with an N,Naminal linkage <2004JOC1180>.

12.16.5.3.2

Imidazoimidazo-pyridines and -pyrimidines

Some benzimidazoimidazopyridines can be prepared from the reaction of the sulfoxide 294 with acetic acid. This unusual acid-induced rearrangement, condensation, and oxidation sequence gives the dimer 295, the proposed pathway being as shown in Scheme 80 <1987JOC4582>. In a similar way, 296 can be converted into 297 upon treatment with acid <1999PHA734> (Equation 50). The product (probably a mixture of isomers) is described as violet in color, but it is obtained in amounts too small for its potential as a colorant to be assessed.

Scheme 80

ð50Þ

Three Heterocyclic Rings Fused (5-5-6)

12.16.5.3.3

Imidazotriazolopyrimidines

Treatment of the ethanolamine derivative 298 with PPA results in a mixture of two isomeric imidazotriazolopyrimidines 299 and 300 <2002JHC319> (Equation 51), and treatment of triazoloquinazoline 301 with ethyl 2-chloroacetoacetate in ethanol gives the imidazotriazoloquinazoline 302 <2003AP560> (Equation 52).

ð51Þ

ð52Þ

12.16.5.3.4

Triazolotriazolo-pyrimidines and -triazines

Treatment of the hydrazine derivative 303 with triethyl orthoformate gives the cyclized compound 304 <1987AP765> (Equation 53). Similarly, treatment of hydrazine 305 with formic acid gives the tricycle 306: the formamide intermediate was not isolated <2001CHE1150> (Equation 54).

ð53Þ

ð54Þ

12.16.5.3.5

Other heteroatom-containing systems

(Pyridinemethylidene)dithioles can be prepared from the reaction of 2-butadiynyl-pyridines with hydrogen sulfide and sodium hydroxide in methanol. These compounds exist in equilibrium with the tricyclic dithioloisothiazolopyridines. The spectroscopic and electrochemical properties of these materials have been investigated, and they show absorption between 409–458 nm, depending on the substituent. Cyclic voltammetry shows that they can be irreversibly oxidized, possibly to the radical cation 307, and then in some cases to the dication; these materials can then dimerize upon treatment with tetracyanoquinodimethane (TCNQ) to give 308 <1992JOC3895> (Scheme 81). Thiazolotriazolothiadiazines, thiazolooxadiazolotriazines, and thiazolothiadiazolo-triazines have been prepared starting from the thiazole 309 (Scheme 82). Treatment of 309 with sodium hydroxide gives the thiazolotriazole,

825

826

Three Heterocyclic Rings Fused (5-5-6)

which can be converted into 310 on treatment with formaldehyde and an amino acid. Treatment of 309 with potassium iodide, iodine, and sodium hydroxide gives the thiazolooxadiazole, which undergoes a similar cyclization to 311 with formaldehyde and an amino acid. Treatment of 309 with acid gives the thiazolothiadiazole, which can be converted to the tricycle 312 under the same conditions as before. These compounds exhibit fungitoxic properties <1994JFA811>.

Scheme 81

Scheme 82

Three Heterocyclic Rings Fused (5-5-6)

Triazolothiadiazolopyrimidines can be prepared from the reaction of the fused hydrazinothiadiazole 313 with carbon disulfide and pyridine. The thiol product can then be alkylated using standard conditions <1994CHE495> (Scheme 83).

Scheme 83

12.16.6 Peri-Fused Tricyclic Heterocycles With the exception of cycl[3.2.2]azines and their analogues (Sections 12.16.6.3–12.16.6.5) and systems containing a sulfur(IV) ring junction (Section 12.16.6.6), these ring systems have been little investigated to date, and certainly not in a systematic manner.

12.16.6.1 Heterocycles with Three or More Heteroatoms, None at a Ring Junction This is a group of diverse ring systems, the majority of the representatives being derivatives of, or otherwise related to, a well-known class of natural product or a compound of known biological activity. Thus, for example, compound 315, the isopropylidene ketal derived from the diol 314, has been prepared in order to demonstrate the syn-relationship between the hydroxyl groups in the latter, which in turn is an intermediate in the synthesis of the mold metabolite, asteltoxin <1988TL655> (Equation 55). The anomers 316 and 317 (Figure 3) are conformationally restricted nucleoside analogues, the independent synthesis of which, in 11 steps, from diacetone-D-glucose, has been described <2000J(P1)3706>; and the fused thienoisothiazole 318 is obtained as a by-product in the synthesis of MK-0417, 319, a compound which has been used in the treatment of glaucoma <1991JOC763>.

ð55Þ

Figure 3

827

828

Three Heterocyclic Rings Fused (5-5-6)

12.16.6.2 Heterocycles with Two or More Heteroatoms, One or More Common to Two Rings This is also a diverse group, no members of which appear to have been the subject of systematic study.

12.16.6.2.1

Systems with two heteroatoms

The aza-tricyclic lactone 320 is an intermediate in the synthesis of the indolizidine 321, which is the indolizine analogue of the pyrrolizidine alkaloid platynecine <1995TL5109> (Scheme 84).

Scheme 84

12.16.6.2.2

Systems with three heteroatoms

The ketal hydrochloride 322 has been used for X-ray crystallographic analysis to establish the structure and stereochemistry of the pyrrolizidine alkaloid 1,7a-diepialexine <1990P111>, and the fused isoxazolidine 323 is an intermediate in a model synthetic approach to alkaloids such as laccarin, 324 <2002SL1344>.

12.16.6.2.3

Systems with more than three heteroatoms

The tetraaza-tricyclic compound 326 is the main product of the reaction of CS2 with the mono-protected triaminopyridylhydrazine 325 <1990JME656> (Equation 56). The lactone 328, which is fused to a hexahydro(1,2,3-triazolo)[3,4-a]pyridine, is formed by thermolysis of the azide 327 <1998TL4203> (Equation 57).

ð56Þ

Three Heterocyclic Rings Fused (5-5-6)

ð57Þ

The tricyclic guanidinium salt 329 (X ¼ MeSO2 or BPh4) has been prepared <1992CC507> but its properties are not recorded. Compounds such as 330 and 331 (Figure 4) containing the reduced imidazo[4,5-d]imidazole-2,5-dione unit (effectively a bis-urea) fused to a six-membered heterocycle are among the simpler members of a large number of compounds investigated in the course of a study of molecular self-assembly <1995JA12733, 1997JOC2234>.

Figure 4

12.16.6.3 Cycl[3.2.2]azines and Their Aza- and Diaza-Analogues This class of compound, also described in the literature as [2.2.3]cyclazines, and according to the rules of systematic nomenclature as pyrrolo[2,1,5-cd]indolizines, have been the topic of several reviews in earlier years. The seminal research work of the teams led by Boekelheide (USA), Flitsch (Germany), and Leaver (UK) was reviewed at length by Flitsch and Kra¨mer <1978AHC(22)321>, also by Flitsch in CHEC(1984) <1984CHEC(4)459> and later by Leaver <1986PAC143>. More recent results have been covered in reviews by, among others, Tominaga and his colleagues <1988H(27)2251, 2005JHC337>. The parent compound is shown, with the approved numbering system, as structure 332. Several of the theoretically possible monoaza- and diaza-analogues, viz. the ring systems 333–339 (Figure 5), have representatives which are described in the literature.

Figure 5 Cycl[3.2.2]azine and its aza- and diaza-analogues.

829

830

Three Heterocyclic Rings Fused (5-5-6)

12.16.6.3.1

Synthesis

The most frequently used synthetic route to cycl[3.2.2]azines involves the reaction of an indolizine with a dienophile, for example, DMAD, in the presence of a dehydrogenating agent such as palladium-on-carbon (Scheme 85), although the scope of the reaction is limited by the presence of substituents in one or both of the reactants, and/or the reaction conditions. If C-3 and C-5 of the indolizine are unsubstituted, the cyclazine is the main product; a 3,4-dihydrocyclazine may sometimes be isolated as a by-product (see below).

Scheme 85

If C-3 of the indolizine carries a potential leaving group as a substituent (e.g., Z ¼ CN or SR), elimination of HCN or RSH is an alternative to the final dehydrogenation step <1980CL149, 1991JHC2059, 1992JHC1473>; a few examples are also known where the eliminated substituent is CH(CN)2, although only if the dienophile is methyl propiolate (propynoate) <1996T10519>. The essential step in these processes has come to be regarded in general as an [8þ2] cycloaddition, but doubt has been cast recently on this generality <1998JPO201>, both by quantum chemical calculations and by experimental observations. The former studies led to the conclusion that three mechanisms may be postulated for such cyclisations, viz. (1) a concerted cycloaddition, (2) electrophilic attack at C-3 of the indolizine followed by intramolecular ring closure on to the six-membered ring, or (3) nucleophilic attack at C-5 of the indolizine followed by ring closure on to the fivemembered ring, and that any of these three mechanisms may be feasible according to the substituents present in one or both of the reactants. According to the calculations, the parent indolizine is predicted to react with a variety of dienophiles generally via a concerted cycloaddition process, although with nitroethene as dienophile the calculations point to (2) as the preferred mechanism; and when the six-membered moiety of the indolizine carries an electronaccepting substituent (NO2) at C-6, mechanism (3) may be preferred. These theoretical predictions find support in some experimental studies: for example, the reaction of 7-methyl-2-phenylindolizine 340 (R1 ¼ R3 ¼ H; R2 ¼ Me) with DMAD in the absence of a dehydrogenating agent yields a mixture, usually of three or more products (Scheme 86), each usually in low yield (<20%), with nonpolar solvents (benzene or DCM) favoring the formation of the cyclazine 341 or a dihydrocyclazine, for example, 342 or 343, and more polar media (e.g., EtOH) favoring the uncyclized products 344 and 345, corresponding to electrophilic addition at C-3 of the indolizine <1984H(22)705>. It was initially believed that, in common with the addition of dienophiles to many other heterocyclic systems, the initially formed zwitterion could be intercepted by a second molecule of the dienophile, with subsequent cyclization and dehydrogenation leading to the formation of a 5:6:7-fused ring system, 346 (a cycl[4.3.2]azine); but the 1:2 adducts are now recognized, in certain cases at least, as dihydroazocino[2,1,8-cd]pyrrolizines; in the presence of an excess of DMAD these may be obtained in yields of up to 35%, and may be dehydrogenated using DDQ to give the highly colored, fully conjugated compounds 347 <1991J(P1)2991>. Reactions of 3-cyanoindolizines (indolizine-3-carbonitriles) with an excess of DMAD in the absence of palladiumon-carbon lead, not to cyclazines, but to 1:2 adducts, possibly 348, which are not isolable but undergo a series of rearrangements, giving finally 3-styrylpyrroles of the type 349 <1992J(P1)2437> (Scheme 87).

Three Heterocyclic Rings Fused (5-5-6)

Scheme 86

Scheme 87

The reaction of 6-methyl-7-nitro-2-phenylindolizine with DMAD gives, not only the expected nitrocyclazine but the denitrocyclazine as the main product: the latter is formed, presumably, by loss of HNO2 from the primary cycloadduct <1997RCB609>. Also reaction of the same indolizine with the ynamine 350 gives, not the

831

832

Three Heterocyclic Rings Fused (5-5-6)

cyclazine, but an adduct assigned the unusual N-oxide structure 351, in which the zwitterion formed by initial nucleophilic attack at C-5 of the indolizine is stabilised by interaction with the adjacent nitro-oxygen <1999JOC9057> (Scheme 88).

Scheme 88

Where the indolizine bears a 2-alkenyl substituent, it is to be expected that Diels–Alder reactions involving this substituent may constitute a major side reaction, and with certain dienophiles this is indeed the case. Up to 68% has been recorded, although with careful control of the reaction conditions, yields of the side product are usually low (Scheme 89). 2-Styrylindolizine (R1 ¼ Ph, R2 ¼ H in the scheme) and DMAD (R3 ¼ CO2Me) or methyl propiolate (R3 ¼ H) in fact give the corresponding cyclazine as the main product, in reasonable yield (40–65%) <1997BSB29, 1997BSB85>.

Scheme 89

Three Heterocyclic Rings Fused (5-5-6)

A second method for the conversion of indolizines into cycl[3.2.2]azines involves the generation of the final fivemembered ring by a condensation process. 5-Methylindolizines undergo Vilsmeier–Haack–Arnold formylation at C-3, and the resulting aldehyde then undergoes base-induced condensation with the 5-methyl group. The reaction sequence may be applied also to other 3-acyl-5-methylindolizines, and yields are reportedly high, usually >60% and often >80% <2001JHC853>. 3-Aroyl-5-methylindolizines may be prepared in situ by cyclization of 2-alkynyl-6methyl-N-(aroylmethyl)pyridinium salts with base (Scheme 90) <1984CPB4666, 1988CPB3826>.

Scheme 90

A third method for the synthesis of cycl[3.2.2]azines, from N-(aroylmethyl)pyridinium salts via indolizines, involves intramolecular (reductive) McMurry coupling of the latter. For example, 3,5-dibenzoylindolizines, obtained from 2-benzoyl-N-phenacylpyridinium bromide as shown (Scheme 91), are cyclized using zinc and titanium(IV) chloride to give the 3,4-diphenylcyclazines 352 in high yield (>90%). The reaction cannot be applied, however, to 2-acetyl-N-phenacylpyridinium salts, since these undergo self-condensation in basic media to give quinolizines; and McMurry coupling of 3-benzoylindolizine-5-carbaldehyde gives a mixture of the 3-phenylcyclazine and the 3-phenylcyclazin-4-ol <2001J(P1)1820>.

Scheme 91

The initial step in Scheme 91 presumably involves deprotonation of the phenacyl substituent to give a pyridinium ylide. Such ylides may be generated as reactive (unstable) intermediates in the synthesis of cycl[3.2.2]azines from N-(trimethylsilylmethyl)-2-pyridones (Scheme 92): in the presence of an excess of DMAD, the cyclazine is the major product <2003S1398>. Cycl[3.2.2]azines which are highly functionalized in the six-membered ring may be obtained in good yield from 4-(N-pyrrolyl-4-trimethylsilyloxy)cyclobutenones and DMAD according to the following sequence (Scheme 93). The monosilylated indolizine-5,8-diols, 353, are the presumed key intermediates <1992TL7811>. Cycl[3.2.2]azines may also be obtained by the cycloaddition of a bifunctional three-carbon unit to a 3H-pyrrolizine. Vinamidinium salts have been used for this purpose <1984CB1649>, although the reactions require the use of a strong base (sodium hydride) and extended reaction times. They appear to proceed via a stepwise mechanism, since intermediates (the conjugated enamines 354 and 355) have been isolated in certain cases (Scheme 94). Synthetic routes to the various classes of azacycl[3.2.2]azines generally follow along very similar lines to the above. For example, 1-azacycl[3.2.2]azines (imidazo[5,1,2-cd]indolizines), 356, may be obtained by the [8þ2] cycloaddition

833

834

Three Heterocyclic Rings Fused (5-5-6)

Scheme 92

Scheme 93

Scheme 94

Three Heterocyclic Rings Fused (5-5-6)

of alkynes such as DMAD to imidazo[1,2-a]pyridines, although according to Tominaga et al. <1988JHC185, 1988H(27)2251> the success of these reactions may depend on the presence of a 2-substituent in the latter (Scheme 95). Such compounds are also formed in good yield from 6-alkynyl-2-aminopyridines by reaction with phenacyl bromide and then a mild base (cf. Scheme 90) <1984CPB4666, 1988CPB3826>. A third synthetic procedure involves cycloaddition of DMAD to the dibenzotetraazapentalene 357 (Scheme 96), although the scope of this method apparently remains to be explored <1986TL4129>.

Scheme 95

Scheme 96

The synthesis of 2-azacycl[3.2.2]azine (imidazo[2.1.5-cd]-indolizine), 334, by Paudler et al. <1975JOC1210> (Scheme 97) is apparently the only successful synthesis to date, and is in effect a variant of the Vilsmeier–Haack– Arnold method of Scheme 90. All attempts to synthesize the ring system by cycloadditions to imidazo[1,5-a]pyridine have been unsuccessful.

Scheme 97

5-Azacycl[3.2.2]azines (pyrimido[2,1,6-cd]pyrrolizines, 335) are relatively little known, although a synthesis has been described starting from 1-dialkylamino- or 1-methanesulfanyl-3-imino-3H-pyrrolizines <1988H(27)2791, 1990JHC647> (Equation 58). 6-Azacycl[3.2.2]azines (pyrazino[2,1,6-cd]pyrrolizines, 336) are similarly rare, but those few syntheses which are recorded (Equation 59) start from 3,5-bis-enaminopyrrolizinium salts such as 358 <1980J(P1)1319>.

835

836

Three Heterocyclic Rings Fused (5-5-6)

ð58Þ

ð59Þ

Attempts to synthesize 1,2-diazacycl[3.2.2]azines {(1,2,4-triazolo)[3,4,5-cd]indolizines}, for example, 337, have met with very limited success. To date the ring system is known only when fused on its ef-faces to a cycloheptatriene ring (see Section 12.16.6.4). It may be that the 1,2-diazacyclazine system is more strained than that of the parent cyclazines, since the N–N bond of the triazole ring is expected to be shorter than a C–C or C–N bond. Similarly, all attempts to form the N–N bond as the final step in a synthesis of the 1,2,4-triazacyclazine ring system, 359, have been unsuccessful <1987J(P1)1159>.

12.16.6.3.2

Reactivity and Reactions

Much of the interest in cycl[3.2.2]azines has centered on the extent to which the 10p-electron periphery may give rise to ‘aromatic’ characteristics. This delocalized system certainly gives rise to a ring current, as evidenced by the chemical shifts in the 1H NMR spectra: the vicinal coupling constants are also similar to those found in simpler heteroaromatic molecules, viz. 7–8 Hz in the six-membered ring and 4–5 Hz in the five-membered ring <1984CHEC(4)459>. 13C resonances for the parent cyclazine and some of its simple analogues are reproduced in Table 1.

Table 1

13

C chemical shifts () of cycl[3.2.2]azine analogues (in CDCl3)

Substituent

C-1

C-2

C-2a

C-3

C-4

C-4a

C-5

C-6

C-7

C-7a

Me

5,7-Me2 1,2-(CO2Me)2a

110.2 108.5 121.6

117.4 115.1 127.2

123.6 112.4

117.4 115.1 117.5

110.2 108.5 115.5

127.0 132.0

113.0 128.9 124.8

123.7 120.6

113.0 128.8 115.8

127.0 129.7

17.3 51.8 52.6

112.9

130.7

112.9

1,4-diazab a

124.8

124.8

Reference 1989PAS313 1988H(27)2251 1992J(P1)2437 1989PAS313

CTO, 164.2, 164.6. Nonstandard atom numbering used in this reference.

b

Some 15N resonances (ppm, in d6-DMSO, relative to nitromethane) are as follows: parent cyclazine, 192.4 <1989PAS313>; 1,4-diazacyclazine, N-1 and N-4, 102.1; central N, 165.4 <1989MI159>. Electrophilic substitution reactions, typical of aromatic compounds with enhanced electron density, occur under relatively mild conditions, and exclusively at C-1 and C-4. These reactions are summarized in earlier reviews

Three Heterocyclic Rings Fused (5-5-6)

<1984CHEC(4)459>. Positional reactivity indices, calculated for hydrogen–tritium exchange by p-electron densities, give the reactivity order 1(4) > 2(3) > 6 > 5(7), whereas calculations of localization energies give the order 1(4) > 2(3) > 5(7) > 6 <1987J(P2)591>. In the 2-azacycl[3.2.2]azine system, electrophilic substitution takes place at C-4, that is, in the other five-membered ring <1975JOC3065>, and halogens attached at C-1 are susceptible to nucleophilic substitution <1975JHC925>. Substituents attached to the cyclazine ring show the reactivity pattern expected for those attached to other aromatic rings. Since many cyclazine syntheses give initially cyclazinecarboxylate (or dicarboxylate) esters, it is of particular importance that removal of these ester functions may be achieved by hydrolysis followed by decarboxylation in the presence of the commercial ‘copper chromite’ catalyst. In other syntheses which lead to methanesulfanylcyclazines, the MeS-group may be removed by treatment with Raney nickel <1988JHC185, 1992JHC1473>. Vicinal diester groups may be transformed by reaction with hydrazine hydrate into cyclic dihydrazides (pyridazinocyclazinediones); members of this class, viz. 360, have been studied for the chemiluminescence which they exhibit when treated with hydrogen peroxide and horseradish peroxidase <1998H(48)1985> (Equation 60).

ð60Þ

Reduction of ester substituents may be effected without concomitant reduction of the ring, and the resulting alcohols may serve as the basis for further transformations. Of particular interest are the following sequences, which may be used to generate the dithiacyclazinopyridophane 361 and the dithiadicyclazinophane 362 <1990H(31)983, 1996H(43)1633> (Scheme 98), and the tetracyclazinophane 363 <1982H(17)325> (Scheme 99).

Scheme 98

837

838

Three Heterocyclic Rings Fused (5-5-6)

Scheme 99

12.16.6.3.3

Biologically active cycl[3.2.2]azines

1-Ethyl-2-( p-hydroxyphenyl)cycl[3.2.2]azine, 364 (R1 ¼ R2 ¼ H), which is also known as NNC-45-0095, is the prototype of a series of cyclazine derivatives which show oestrogen receptor-binding affinities <2000BML399>. Synthesis of a series of analogues from the appropriately substituted indolizines, essentially according to Scheme 85, indicates that the potency of such compounds is particularly high when R1 or R2 is also OH: these molecules exhibit binding and structural features closely resembling those of 17-oestradiol <2000BML2383>.

12.16.6.4 Benzo-, Dibenzo-, and Other Fused Cycl[3.2.2]azines and Azacycl[3.2.2]azines Two series of benzo-fused cycl[3.2.2]azines, viz the benzo[a]-, 365, and benzo[g]-cycl[3.2.2]azines, 366, and three dibenzoanalogues, 367–369, are theoretically possible (Figure 6). These have attracted attention since the benzo-analogues have a

Figure 6 Benzo- and dibenzo-cycl[3.2.2]azines.

Three Heterocyclic Rings Fused (5-5-6)

conjugated 14p-periphery and the dibenzo-analogues have an 18p-periphery, so in principle members of both series may be considered as potentially ‘aromatic’ molecules if the p-electrons can be delocalized, although the potential integrity of a 6p-system within the additional benzene ring may operate against such extensive delocalization. Synthetic routes to the benzocyclazines are analogues of those which lead to the cyclazines themselves. Representatives of the benzo[a]cycl[3.2.2]azine (indolizino[3,4,5-ab]isoindole, 365) ring system result from cycloaddition of, for example, DMAD to pyrido[2,1-a]isoindole-6-carbonitrile 370 <1986H(24)3071> (Scheme 100). An alternative synthesis, which starts from the cyclazine 371 and involves construction of the additional benzenoid ring by a double Horner–Wadsworth–Emmons type of reaction, apparently gives the tetracyclic product 365 in only very low yields (Scheme 101) <1988H(27)2251>.

Scheme 100

Scheme 101

Benzo[g]cycl[3.2.2]azines or pyrrolizino[3,4,5-ab]isoquinolines, for example, 366, are similarly obtained by cycloaddition of DMAD to pyrrolo[2,1-a]isoquinolines <1985CPB3038>, and 1-aza-benzo[h]cycl[3.2.2]azines are prepared by cycloaddition of DMAD to imidazo[2,1-a]iso-quinolines <1985H(23)2531> (Scheme 102). In all of the above cases, as with the simpler cyclazines, the ester functions are removable by hydrolysis in aqueous alkali followed by

Scheme 102

839

840

Three Heterocyclic Rings Fused (5-5-6)

decarboxylation in the presence of copper metal, copper(I) oxide or copper chromite, and methanesulfanyl substituents are removable at any stage by treatment with Raney nickel. The overall yields, however, are reportedly low. Representatives of all three dibenzocycl[3.2.2]azines are known. The [a,d]-fused system {benz[1,2]indolizino[3,4,5-ab]isoindole} 367 is obtained from a ‘one-pot’ reaction of pyridinium dicyanomethylide with benzyne, although the intermediate 370 may be isolated and itself reacted with benzyne <1982CL869, 1985H(23)2773> (Scheme 103). The [a,g]-fused {benzo[6,7]-pyrrolizino[3,4,5-ab]isoquinoline} system 368 is accessible (Scheme 104) from the benzo[g]cyclazine diester 372 using a variant of the Horner–Wadsworth–Emmons route of Scheme 101 <1988H(27)2251> and the[a,h]-fused {benzo[1,2]pyrrolizino[3,4,5-ab]isoquinoline} system 369 is accessible through the cycloaddition of benzyne to isoquinolinium dicyanomethylide <1987H(26)2073> (Scheme 105).

Scheme 103

Scheme 104

Scheme 105

Three Heterocyclic Rings Fused (5-5-6)

NMR spectra (1H and 13C) for certain of these tetra- and pentacyclic systems <1988H(27)2251> are illustrated in Figure 7.

Figure 7

1

H and

13

C NMR chemical shifts of some benzo- and dibenzocycl[3.2.2]azines.

Two other fused cyclazines with a conjugated 14p-periphery are pyrazino[2,1,6-cd:5,4,3-c9d9]dipyrrolizine, 373 <1984CC821>, and cycl[3.2.2]azino[1,2-a]cycl[3.2.2]azine, 374 <1997H(45)2223>: their syntheses are set out in Schemes 106 and 107. An unusual series of cycl[3.2.2]azine analogues has a cycloheptatriene ring fused to the e- and f-edges of the latter, giving molecules such as 375–378. The first three of these are produced by cycloaddition of dienophiles such as DMAD to the tricyclic precursors 379–381 <1983BCJ3703, 1987H(26)59, 1987BCJ969, 1992BCJ1784> (Scheme 108), whereas compound 378 results, as a component of a complex mixture, from the reaction of the hydrazinoazaazulene 382 with diphenylcyclopropenone (Scheme 109) <1994BCJ2487>. The generality of this last reaction, however, remains in doubt, since the hydrazinoazaazulene lacking the ester functionality fails to cyclize in this manner.

Scheme 106

841

842

Three Heterocyclic Rings Fused (5-5-6)

Scheme 107

Scheme 108

Three Heterocyclic Rings Fused (5-5-6)

Scheme 109

In principle all of these fused cyclazines may be considered as bridged analogues of [14]- and [18]annulene, and the extent to which delocalization of the p-electron periphery can contribute to stabilization of the particular system has been debated in terms of the degree of deshielding of the ring protons in the 1H NMR spectra <1988H(27)2251>. The general conclusion is, apparently, that most of these molecules do contain delocalized 14p- or 18p-systems: in the case of the dibenzo[a,d]cyclazine, the radical cation produced by one-electron oxidation using silver perchlorate has an electron spin resonance (ESR) spectrum which is consistent with delocalization of the unpaired electron virtually around the whole 18p-periphery <1985H(23)2773>. However, in the cycloheptatriene-fused compounds, although they give rise to a ring current, there is sufficient bond length alternation in the seven-membered ring to suggest that these molecules may be better regarded as butadiene-fused cyclazines rather than as a continuous cyclic conjugated p-system <1993BCJ1229, 1994BCJ2487>.

12.16.6.5 Di- and Polyhydrocycl[3.2.2]azines and Aza-Analogues 12.16.6.5.1

Dihydrocyclazines

Reference has already been made (Section 12.16.6.3.1) to the formation of dihydrocyclazines in cycloadditions involving indolizines and DMAD. These dihydrocyclazines are by-products when the reactions are conducted in the presence of palladium-on-carbon, or among the main products if dehydrogenation is impossible (e.g., if the indolizine carries a 5-substituent) and/or if no such dehydrogenating agent is present <1984H(22)705, 1991J(P1)2991>. These dihydrocyclazines are assigned the 3,4-dihydro-, 342, or the 5,7a-dihydro-structure 343, either of which may result from the original cycloadduct by double bond migration (double hydrogen shift). Compound 383, which is formally the dione tautomer of a diazadihydrocyclazinediol, is obtained from the mesoionic imidazopyrimidine 384 and DMAD <1982JHC567> (Equation 61), and salts of the type 386 are obtained from the thiazole 385 and an -halogenonitrile <1987SUP1284215> (Equation 62).

ð61Þ

ð62Þ

843

844

Three Heterocyclic Rings Fused (5-5-6)

12.16.6.5.2

Tetrahydro- and hexahydrocyclazines: The Myrmicaria alkaloids

Among a wide variety of alkaloids found in the poison gland secretions of African Myrmicaria ants, and known collectively as myrmicarins, are several derivatives of 3,4,4a,5-tetrahydro- and 3,4,4a,5,6,7–hexahydrocycl[3.2.2]azine: not only simple analogues such as myrmicarins 213A and B, 215A, B, and C, and 217, but more complex molecules such as myrmicarins 430A and B, 645, and 663: the numeral attached to each name refers to the nominal molecular formula weight (Figure 8). The simple members contain an unbranched C15 chain, which is biosynthetically derived from the acetate pool <1996T13539>. The more complex members contain two or more of these C15 units, modified in different ways <1996CC2139, 1997AG161, 1997AGE77>. A nine-step synthesis of racemic myrmicarin 217, 387, from 6-methylpyridine-2-carbaldehyde <1998T5259> (Scheme 110) has been followed by a 14-step synthesis of the (R)-(þ)- and (S)-()- enantiomers independently, using (R)- and (S)-glutamic acid, respectively, as the source of the stereogenic centre <2000JOC2824>; the synthesis of the (R)-enantiomer is shown in Scheme 111.

Figure 8 Cyclazine-containing myrmicarins.

Scheme 110

Three Heterocyclic Rings Fused (5-5-6)

Scheme 111

The stereoisomeric myrmicarins 215A and 215B have also been obtained, as a 4:1 mixture, from the simpler hexahydrocyclazine 388 by well-established transformations involving the pyrrole ring <2001JOC2522>; it is noteworthy that the first Vilsmeier–Haack–Arnold formylation in the sequence (Scheme 112) is regiospecific, like the Friedel–Crafts reaction in Scheme 111. When compound 389 is reduced using lithium aluminium hydride under milder conditions than shown above, so that the alcohol mixture 390 may be isolated, and if this is then allowed to react with acetic acid over a prolonged period, the (E)-alkene, that is, myrmicarin 215B, is the only product <2006T5287>.

Scheme 112

If, however, compound 390 is treated with a stronger acid (TFA), it undergoes diastereoselective dimerization; reduction of the initial reaction product gives 391 (Scheme 113). It is suggested that in vivo dimerization of myrmicarin 215B may provide the key to the biosynthesis of the more complex myrmicarins such as M430 <2006T5287>.

845

846

Three Heterocyclic Rings Fused (5-5-6)

Scheme 113

12.16.6.6 Other Polyhydrocycl[3.2.2]azines Fused octahydrocycl[3.2.2]azines of the type 392 are obtained by tandem cycloadditions of pyridinium phenacylide with N-substituted maleimides <1989JOC420>, and other types of fused octahydrocyclazines, viz. 394, result from the attempted preparation of the enamines 393, since these are unstable and undergo intramolecular acylation <1999T1763> (Scheme 114).

Scheme 114

In connection with a study of potential serotonin receptor antagonists, some decahydrocyclazin-6-ones and -6-ols have been synthesized from acyclic precursors <1992SC3115> (Scheme 115), but those esters derived from the latter (both epimers) which have been tested to date as potential 5-HT3 receptor antagonists have shown little biological activity <1993EJM869>. The decahydrocyclazine skeleton is also found in the alkaloid 395, currently known only by the designation 261C. This compound bears a passing resemblance to some of the myrmicarins (Section 16.6.5.2), but occurs in the skin of a totally different animal species, namely poisonous frogs of the genus Mantella <2003H(59)745>.

Three Heterocyclic Rings Fused (5-5-6)

Scheme 115

12.16.6.7 Heterocycles with Hypervalent Sulfur or Selenium at the 5:5 Ring Junction This group of heterocycles, which has attracted considerable interest over the past 50 years, was reviewed by Lozac’h in CHEC(1984) <1984CHEC(6)1049>, and interest in these ring systems has continued, mainly within the Japanese group led by Matsumura. Systems in which the 5:5-bicyclic heterocycles (1,6,6a4-trithiapentalenes and their oxa-, aza-, dioxa-, diaza-, polyaza-, and selena-analogues) fused to a six-membered heterocycle have been the subject of several investigations within the present review period. The interest in these ring systems is centered on the nature of the bonding on either side of the hypervalent atom, as determined by X-ray crystallographic analysis and molecular orbital calculation. Although the usual formulation of these compounds implies a symmetrical structure, those crystallographic measurements which have been made show that, whereas the NMR spectra indicate a symmetrical molecule, in the solid state at least, the two S–S or S–N bonds are of unequal length, implying some sort of equilibrium between structures such as shown in Figure 9.

Figure 9

Synthetic routes to these compounds vary according to the heteroatoms in the specific end-product <2001SL1129, 1986BCJ3693, 1988BCJ2419, 1989BCJ2419>. These methods are summarized in Schemes 116–118.

847

848

Three Heterocyclic Rings Fused (5-5-6)

Scheme 116

Scheme 117

Scheme 118

The high reactivity of these fused systems is shown by the ease with which one of the five-membered rings is opened by interaction with an electrophile. So, for example, compound 397 (R ¼ Me) reacts with 3-bromo-1,3diphenylpentane-2,4-dione, to produce 399, effectively (pathway a in Scheme 119) by reversing the last step in the

Scheme 119

Three Heterocyclic Rings Fused (5-5-6)

synthetic sequence in Scheme 117; although it is claimed that the mechanism of this reaction may be more complicated and involve the intermediacy of an aziridine (pathway b in Scheme 119) <1989TL2259>. The same compound 397 (R ¼ Me) is also the starting point for the synthesis of a series of macrocycles such as compound 400 <2005JHC1175> (Scheme 120).

Scheme 120

Modified neglect of diatomic overlap (MNDO) calculations can support the structures assigned to certain of these fused tricyclic systems, such as 401, where confirmatory X-ray crystallographic data are lacking <1983JCM128>.

12.16.7 Important Compounds and Applications As already mentioned in Section 12.16.1, this chapter covers a large number of diverse ring systems, and it has therefore been convenient to divide the material into several sections, according to the nature of these systems. Except for the cycl[3.2.2]azines (Section 12.16.6), an in-depth study of the properties of each individual ring system appears not to have been undertaken, and so the emphasis in each section has been on the diversity of available synthetic routes to these structural types. The same approach has been adopted in the chapter which follows (11.17), where the number and diversity of ring systems covered is even greater. The number of natural products containing these tricyclic systems is relatively small, viz. a few alkaloids from marine (compound 293), fungal (compound 282), amphibian (compound 395), insect (compound 387), and plant sources (compound 288) and also some iridoid molecules (compounds 98–100). Some of those Myrmicaria alkaloids (from ants: Section 12.16.6.5.2) which contain the 5:5:6 fused-ring system are perhaps the most extensively studied of these natural products, with several successful syntheses now recorded.

849

850

Three Heterocyclic Rings Fused (5-5-6)

Otherwise there are sporadic references to bioactive compounds with potential value as therapeutic agents, but any systematic study of the latter property appears in most cases to be lacking; and certain other individual compounds have been noted as having possible uses, for example, as photosensitisers (compound 145), photochromic materials (compound 63), or as chemiluminescent agents (compound 360). Although most of the fundamental studies of cycl[3.2.2]azines were reported in CHEC(1984) (see Section 12.16.6.3 for leading references), there is continuing interest – synthetic, spectroscopic, and theoretical – in these and their benzo- and dibenzo-fused analogues, all of which may be considered as bridged analogues of [10]-, [14]-, and [18]annulenes, respectively. The same level of theoretical interest continues to apply to those peri-fused systems with a hypervalent sulfur or selenium at the 5:5 ring junction (Section 12.16.6.6).

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851

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853

854

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Three Heterocyclic Rings Fused (5-5-6)

Biographical Sketch

Richard Riggs was born in Edinburgh, Scotland in 1980 and grew up at the nearby town of South Queensferry. He studied chemistry at the University of St. Andrews, gaining his first class M. Chem. degree in 2002 and his PhD in 2005. During this time he received the Graduate Prize from the Salters’ Institute and the Gray Scholarship from the Society of Chemical Industry. His thesis ‘Novel Aza-Heterocyclic Colourants’ was supervised by Dr. David Smith and Prof. Alex Slawin, and his research program included a brief stay at the University of Ulm, working with Prof Peter Ba¨uerle. After his doctoral studies he undertook a 1-year postdoctoral research position with Ciba Specialty Chemicals, Grenzach, Germany. In November 2006 he joined BASF at their headquarters in Ludwigshafen, Germany, where his position is Research Scientist within the Performance Chemicals research division. His research interests are broad, and currently focus on the development and application of chemical technology toward new industrially relevant materials.

David Smith was born in Paisley, Scotland, and educated at the town’s Grammar School and then at the University of Glasgow, where he graduated BSc in 1960 and PhD in 1963 following research with J. D. Loudon. He was then appointed Assistant in Chemistry (effectively Teaching and Research Fellow) in the University of St. Andrews, promoted to Lecturer in 1966, and to Senior Lecturer in 1988. In 1973, he spent a half-year’s leave in Marburg, Germany, in the group of R. W. Hoffmann, and from 1987 to 1989 he was seconded to ICI’s Materials Research Centre at Wilton, England, as the holder of a Royal Society/SERC Industrial Fellowship. He was awarded the degree of DSc by his alma mater in 1999, and since his official retirement in 2003 he has held an Honorary Senior Lectureship in St. Andrews. His research interests lie in aromatic and nitrogen heterocyclic chemistry, especially in the fields of new materials and colorants. He is the author or co-author of 85 publications to date, including several reviews and patents, and also two successful undergraduate textbooks, the second of which – Guidebook to Organic Synthesis (with R. K. Mackie and R. A. Aitken) – is now in its third edition (Longmans,1999), with total sales worldwide (including foreign translations) in excess of 36 000.

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