Tricyclic derivatives

Reaction of 2-alkyl- -pyrrolines and 2-alkyl- -piperideines with acid chlorides leads to ring-opening and formation of N-acylated amino ketones (131, = 1, 2) (211-213). Ketene reacts with J -piperideine to form a tricyclic derivative (132) (214). 

Radical cyclization of perhydro-l,3-benzoxazines 64, promoted by Bu4SuH in the presence of AIBN gave a mixture of perhydropyrido[2,l-6][1,3]benzoxazin-9-ones 65 and 66 and seven membered tricyclic derivatives 67 and 68, formed in a 6-exo and 7-endo cyclization process, respectively (99TL2421). Cyclization of parent acrylamide 64 (R = R = H) occured with moderate regioselectivity (6-exo/7-endo ratio 65 35) and poor stereoselectivity (65/66 ratio 42 43). The presence of a /3-methyl group in... 

Cycloaddition of 2-styryl-4/7-3,l-benzoxazines and malononitrile gave 1 -amino-3-aryl-2-cyano-1 //,6//-pyrido[l, 2-n][3, l]benzoxazin-4-ones (99ZN(B)923). These tricyclic derivatives were also prepared in the reaction of 2-methyl-4//-3,l-benzoxazin-4-one and arylidenemalononitrile in AcOH in the presence of NaOAc. 

Irradiation of 9-substituted 6-oxo-3,4-dihydro-2//,6//-pyrido[l,2-Z)]-[1,3]thiazine-4-carboxylate 93 in benzene afforded tricyclic derivatives 94, sometimes as a diastereomeric mixture (00JCS(P1)4373). 

Treatment of 2-hydroxy-4/7-pyrido[l,2-u]pyrimidin-4-ones 208 with TFA furnished tricyclic derivatives 209 (99ACS901, 99MI29). 

Cyclocondensation of 3-cyano-2-methylthio-4//-pyrido[l, 2-u]pyrimidin-4-ones and ethyl mercaptoacetate in boiling EtOH in the presence of NaOEt afforded 4//-pyrido[l,2-u]thieno[2,3-r/ pyrimidin-4-ones 210 (00HC571). 2-Methylthio-4-oxo-4//-pyrido[l,2-u]pyrimidine-3-carboxylates 211 and mercaptoacetates afforded tricyclic derivatives 212 (93MIP1). Cyclocondensation of 2-methylthio-4-oxo-4//-pyrido[l, 2-u]pyrimidin-3-car-bonitriles 213 with H2NNH2 H2O and with guanidine HCl afforded tricyclic derivatives 214 and 215, respectively (96FES781). 

The reaction of methane tricarboxylate with indoline 342 gave the tricyclic derivative 361 which can be transformed to the amide derivatives 362 (97JHC969). Alkylation of the iV-benzyl indoline 360 with pentafluor-oacetone gave 363 which upon debenzylation and subsequent acylation with diketene followed by cyclization gave 364. Other haloacetones were used to prepare different halogenated derivatives (79BEP872311) (Scheme 63). 

Reaction of perhydropyrido[l,2-c]pyrimidin-l-one 149 with Mc2C(OMe)2 in the presence of CSA afforded tricyclic derivative 150 (01JA8851). 

The terc-butyldimethylsilyl groups of pyrido[l,2-c]pyrimidine 154 was eliminated with BU4NF to afford 6-hydroxy-8-hydroxymethyl derivative 155 (00TL1849). Compound 155 gave tricyclic derivative 156 under Mitsunobu conditions. 

A 3,4,8,9-tetrahydropyrido[2,l-c][l,4]thiazine 336 and a benzo(A)-l,4-thiazine 335 was isolated from the reaction mixture of enaminone 334 and 2-(3-chlorobenzylidene)acetylacetate (99T7915). Reactions of enamines 334 and 337 with DMAD in MeOH yielded addition products 338 and 339 and bi- and tricyclic derivatives 340 and 341, respectively. The latters could be obtained in quantitative yields when the addition products 338 and 339 were heated in refluxing MeOH. 

Reaction of 3-(4-methylphenylamino)-4-(4-methylphenylimino)-4//-pyr-ido[l,2-a]pyrazine (373, R = 4-MePh) with ketenes 393, prepared in situ from the appropriate acetyl chloride with NEt3, yielded tricyclic derivatives... 

Reaction of 3-amino-4-imino-47/-pyrido[l,2- ]pyrazines 319 with DMAD and maleimides 321 yielded 2,2 -bipyr-idine-3,4-dicarboxylates 320, and mixtures of bi- and tricyclic derivatives 322 and 323, respectively (Scheme 27) <1996JPR430>. In the cases of maleimide reactions, higher temperature (at 160°C in xylene) in an autoclave gave only 323. When pyrido[l,2- ]pyrazine 319 (Ar = 4-MeC6H4) was reacted with W-(4-methylphenyl)-maleimide 321 (R = 4-MeC6H4), 324 could be isolated. 

Radical cyclization of perhydro-l,3-benzoxazines 518, promoted by Bu vSnI I in the presence of 2,2 -azobis(2-methylpro-pionitrile) (AIBN) gave a mixture of perhydropyrido[2,T ][l,3]benzoxazin-9-ones 519 and 520 and the seven-membered tricyclic derivatives 521 and 522, formed by a 6-exo- and a 7-rwr/o-cyclization process, respectively (Scheme 54) < 1999TL2421 >. Cyclization of parent acrylamide 518 (R = R1 = H) occurred with moderate regioselectivity (()-exo/7-endo ratio = 65 35) and poor stereoselectivity (519/520 ratio = 42 43). The presence of a [1-methyl group in crotylamide 518 (R = Me, R1 = H) disfavored the 7-/w/ -cyclization process, but did not influence the stereoselectivity of the cyclization (519/520 ratio = 66 34). The presence of an a-methyl group in methylacrylamide 518 (R=H, R1 Me) caused a retardation of the 6-oeo-attack, favoring the 7-/w/ -cyclization with a higher stereoselectivity (521/522 ratio = 75 12). 

Treatment of pyridones 638a (X = CH) <1997CHE596> and pyrazinones 638b (X = N) <1998JHC655> with - V-alkyl and W-aryl triazolidinediones provides tricyclic derivatives 639 containing the title bicyclic moiety in good yields (Equation 94). 

Diaz-Ortiz and co-workers carried out microwave cycloadditions to synthesize pyrazolo[3,4-A]pyridines, including tricyclic derivative 149 obtained from pyrrole 147 using A-methylmaleimide 148 as the dienophile (Equation 34)... 

Azomethine ylides of pyrrolo[l,2- ]pyrazine <1996JOC4655> and 3,4-dihydro pyrrolo[l,2-tf]pyrazine <1997T9341> undergo 1,3-dipolar cycloadditions with a number of dipolarophiles. For example, the ylide 178 reacts with propargylic ester 179 to give the tricyclic derivative 180 (Equation 43). 

Tricyclic derivative 186 was obtained by treating solution of 184 with tris(trimethylsilyl)silane (TTMSS) and azobisisobutyronitrile (AIBN). The pyridyl radical 185 is the suggested intermediate product (Scheme 4)... 

Proton and 13C NMR spectroscopy have been widely used to elucidate the structures of compounds discussed in this chapter. 1SN NMR investigations have been reported for some hetero tricyclic derivatives <2003JA10288>. Several more specialized studies are mentioned below. 

The Diels-Alder reaction between isothiazole-dioxides and various dienes represents an attractive approach toward a range of bi- and tricyclic derivatives containing the fused... 

Similar to the Pd-catalyzed pyrrole and thiophene annulations, an intramolecular Heck reaction of substrate 91 resulted in benzofuran 92 [80], Such an approach has become a popular means of synthesizing fused furans. Muratake et al. exploited the intramolecular Heck cyclization to establish the tricyclic core structure en route to the synthesis of a furan analog of duocarmycin SA, a potent cytotoxic antibiotic [81]. Under Jeffery s phase-transfer catalysis conditions, substrate 93 was converted to tricyclic derivatives 94 and 95 as an inseparable mixture (ca. 4 1) of two double bond isomers. 

Thiadiazoles (THDs) react with an excess of phenylethyl mercaptan at room temperature to produce the ring opening of the tricyclic derivatives <2005JOC6230, 2005JMC2266>, for THD 173 to give compound 174 in 65% yield (Equation 9). 

However, the cyclodehydration of 3-[2-aryloxymethyl-l,3,4-oxa(thia)diazol-5-yl]imino-spiro(cyclohexane)l,2-thiazolidin-4-ones 301 with concentrated sulfuric acid at 0°C furnishes tricyclic derivatives 302 (Equation 47) <2002IJC(B)1314>. 

The photochemical reaction of azide-functionalized tetrazole derivatives such as 38 leads to the formation of the 5-5 bicyclic ring system 40 (Scheme 5) in very moderate yields <1999JHC863>. This reaction is believed to proceed via the singlet nitrene intermediate 39. Attack at the aromatic substituent in ortho position leads to product 40 <1974JOG2546> by subsequent cyclization. This intermediate is deprotonated during the workup conditions to the mesoionic tricyclic derivative 41. 

The thermal cyclization of arylaminomethylenemalonates (977, R = H, X = CH, N) and their N-methyl derivatives (R = Me) in Dowtherm A at 250°C for 15 min afforded the angular tricyclic derivatives (978) in excellent yields (87CCC2918 88MI11 89CCC713). 

In the case of the enantiomers of isopropylidene N-( 1 -substituted tetra-hydroisoquinolin-2-yl)aminomethylenemalonates (1258), complete loss of chirality was observed, with racemic tricyclic derivatives (1259) being... 

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