Pyridines cyclizations with

Krogsgaard-Larsen and co-workers have protected the P-keto functionality as a ketal as a modification to the traditional conditions so attack of hydroxylamine is directed towards the ester. They prepared hydroxamic acid 10 from ester 9 then cyclized with sulfuric acid to isoxazole 11, in route to 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), a selective GABAa receptor agonist studied clinically for insomnia. 

A green chemistry variation makes use of solventless conditions to minimize the waste stream from reactions of this type. To a mortar are added aldehyde 67, ketone 68 and solid sodium hydroxide. The mixture is ground and within 5 minutes aldol product 69 is produced. Addition of the second ketone and further grinding affords the 1,5-diketone 70, which can be isolated and cyclized to pyridine 71 with ammonium acetate. The authors report that this method can substantially reduce the solid waste (by over 29 times) and is about 600% more cost effective than previously published procedures. 

Synthesis of dithieno[2,3-A2,3-,7]thiophene derivatives 122 has been accomplished through the Heck reaction of 3-(4-bromo-2-thienyl)acrylic acid 302 to afford 3-(2,4-thienylene)diacrylic acid 303 which was cyclized with thionyl chloride and a catalytic amount of pyridine to the dichloride 120 in 75% yield (Scheme 56) <2005MOL279>. 

The synthesis of diphenylmethylpyrimidotriazinones 243 was achieved (86MI2) by the reaction of 3-chloro-5,6-diphenyl[l,2,4]triazine with chlo-ro- or cyanoacetamides in pyridine to give 242, which cyclized with sodium acetate in acetic acid. 

Thiation of [l,2,4]triazino[3,2-h]quinazoline-3,10-dione 782 with phosphorus pentasulfide in pyridine proceeded selectively to give the 3-thioxo analogue 783. The latter was converted to the corresponding 3-methylthio derivative 784 by reaction with methyl iodide. Treatment of 784 with hydrazine gave 785, which was converted to 786 and 787 by cyclization with formic acid or carbon disulfide (90JHC591). Cyclization of 785 with sodium nitrite in hydrochloric acid gave 788 (90JHC591). 

MethyM-cthoxycarbonyl-5-bcnzoyl-hydrazino-l //-pyrazole 274, prepared by reacting benzoyl chloride and 3-methyM-cthoxycarbonyl-5-bcnzoyl-hydrazino-l //-pyrazole hydrochloride 273, in the presence of pyridine in acetonitrile, has been cyclized with phosphoryl chloride in benzene or toluene to give 7-ethoxycarbonyl-6-methyl-3-phenyl-l //-pyrazolo[5,l -/ 1,2,4 triazolc 55. This compound has been also synthesized through cyclization of... 

One procedure for the synthesis of these title ring systems appeared recently <2003S1079>. Yadav and Kapoor described that the transformation of some oxadiazole and thiadiazole derivatives bearing specially substituted methylsulfinyl side chain 131, when reacted with thionyl chloride, give ring-closed compounds 134. The reaction was carried out in pyridine under reflux conditions in 74-79% yield. As shown in Scheme 25, the authors assume that the first step is the formation of the sulfonium salt 132 which undergoes cyclization with hydrogen chloride and sulfur dioxide elimination to 133 and, finally, demethylation of this intermediate leads to the final product 134. 

Cyclization of mixed acetals (13,300).4 This reaction is a particularly useful route to eight-membered cyclic ethers (oxocanes) and provides the first practical route to a natural oxocene, (- )-laurenyne (3), from an optically active mixed acetal 1. Thus cyclization of 1 followed by O-desilylation affords 2 as the only cyclic product. Remaining steps to 3 involved C-desilylation, for which only HF/pyridine is useful, introduction of unsaturation into the C2-side chain, and extension of the C8-side chain. Exploratory studies showed that unsaturation at the p- or y-positions to the cite of cyclization of 1 prevent or retard cyclization with a wide variety of Lewis acids. The cyclization is apparently more tolerant of substitution in the terminator position, C3-Q, of the oxocene. 

If the amino group of an AA is transformed into an amidine, cyclization can occur either with acetic anhydride in pyridine or with hydrazine to give... 

L-Asparagine was used for the synthesis of chiral pipecolates, building blocks for the alkaloid apovincamine. The iodo compound, formed in a multistep transformation from L-asparagine, was cyclized with LDA and ethyl iodide to give the pyridine derivative with a defined configuration (Scheme 36) (85JOC1239). 

Access to pyridines from aza-l,3,5-triene units, achieved by an intramolecular aza-Wittig reaction and thermal electrocyclic cyclization with a subsequent 1,3-H shift, was mentioned in Section V,B (cf. Scheme 28) as an... 

Some recent work has made several heterocondensed furo[3,2-c]pyri-dines accessible. Starting compounds are the aldehydes of furo[3,2-c]pyri-dines, which are converted into the azides 203 (Scheme 75). Reaction with triphenylphosphane furnishes the iminophosphoranes 204, which are finally cyclized with phenyl isocyanate to afford the substituted pyrrolo[2, 3 4,5]-furo[3,2-c]pyridines 205 (92M807 94H1695). 

N-Amination of 2-[o-(l,3-dioxolan-l-yl)phenyl]pyridine (121) with O-tosylhydroxylamine gave an A-amino derivative, which underwent ring closure on the action of 70% perchloric acid to yield a pyrido[2,l-a]phthal-azinium salt (122, R = H) (92JHC1049). The 7-hydroxy derivative of a pyrido[2,l-fl]phthalalzinium salt (122, R = OH) was prepared similarly by cyclization of l-amino-2-(o-methoxycarbonylphenyl)pyridinium salt, ob-... 

Electrophilic iodine reagents have also been employed in iodocyclization. Several salts of pyridine complexes with I+ such as bis(pyiidinium)iodonium tetrafluoroborate and bis(collidine)iodonium hexafluorophosphate have proven especially effective.61 y-Hydroxy- and d-hydroxyalkcncs can be cyclized to tetrahydrofuran and tetrahydropyran derivatives, respectively, by positive halogen reagents.62 (see entries 6 and 8 in Scheme... 

On the other hand, Wyeth-Ayerst chemists ° encountered limitations with this methodology during their syntheses of spirocyclic 2,4-oxazolidinediones derived from isoindole (Scheme 6.55). For example, reaction of 246 with chlorosulfonyl isocyanate followed by cyclization with potassium terf-butoxide afforded poor to modest yields of 247 when R was a substituted benzyl group. Cyclization of 246 using ethyl chloroformate (ECF), triethylamine and 4-(dimethylamino)pyridine (DMAP) in refluxing tetrahydrofuran (THF) gave 247 in only 29% yield when R was methyl and failed completely if R was an isopropyl group. However,... 

Optically active namral and unnamral amino acids as well as various cyclic amino alcohols have been utilized in the synthesis of a wide variety of bis(oxazo-line) ligands. As previously mentioned, the first bis(oxazoline) ligands, py-box la-d, were synthesized by Nishiyama and co-workers in 1989. The common material for their syntheses was pyridine 2,6-dicarboxylic acid 19. Conversion of 19 to the acid chloride was achieved by treatment with thionyl chloride, as illustrated in Figure 9.4. This was followed by condensation with (5)-valinol in the presence of triethylamine. Conversion of the resulting bis(amidodiol) 20 to py-box-ip lb was achieved by sequential treatment of 20 with thionyl chloride at 50 °C followed by cyclization with aqueous sodium hydroxide in methanol to afford py-box-/p lb in 60% overall yield. The same synthetic scheme can be used to obtain the other... 

Imidazo[4,5- ]pyridines have also been prepared through cyclization of the requisite diamine with ethyl acetimi-date hydrochloride (Equation 43) <1996JME487> or by cyclization with 4-methylsulfonylbenzoyl chloride (Equation 44) <2001JME350>. Further examples of this type can be found in <1996CHEC-II(7)283>. 

Pyrazolo[3,4-. ]pyridines have also been formed by reaction of the appropriate chloronitrile pyridine (Equation 50) <2002BML2925>. Pyrazolo[3,4-. ]pyridines can be prepared by oxidative cyclization with PIFA (Equation 51 Table 27) <1997SC2217>. 

Polyfunctionalized pyrido[3,4- ]pyridazines 270 and 272 could be prepared by cyclization of pyridine derivatives 269 with R NHNH2 <2002RJ01548> and coupling 5-(/ra j-pyrazolylazo)pyridine 271 with -chlorobenzenediazo-nium chloride, respectively <2000IJH135>. 

An alternative synthesis of this ring system involves the conversion of the pyridine-3-sulfonic acid 229 into the pyridylsulfonylguanidine 230, then cyclization with K2CO3 in DMF (Scheme 35) <1993JME3211>. 

Synthesis (Freed and Potoski (American Home), 1971 Freed, 1973 Kleemann et al., 1999,) Dezocine is prepared through the following sequence The condensation of 1-methyl-7-methoxy-2-tetralone with 1,5-di-bromopentane by means of NaH or potassium tertbutylate affords 1 -(5-bromopentyl)-1 -methyl-7-methoxy-2-tetralone this product is cyclized with NaH to give 5-methyl-3-methoxy-5,6,7,8,9,10,11,12-octahydro-5,11 -methano-benzocyclodecen-13-one i. The ketone i, by reaction with hydroxylamine hydrochloride in pyridine, is converted into its oxime ii, which is reduced with H2 over Raney Ni to a mixture of isomeric amines which were separated by crystallization of the HCI salts giving 5-a-methyl-3-methoxy-5,6,7,8,9,11 a, 12-octahydro-5,11 -methanobenzo-cyclodecen-13p-amine, which is finally cleaved with concentrated HBr. 

The benzo[6]furan derivatives which are most easily prepared are the /3-coumaranones via cyclization with pyridine of 2-hydroxychloroketones. 

A further synthesis of thieno[2,3-6]pyridines (79JHC603) resembles quite closely the preparation of pyrrolo[2,3-fc]pyridines (76AP597). 2-Amino-3-cyanothiophenes (e.g. 268 Scheme 62) were reacted with ethyl aminocrotonate to give enamines, which were cyclized with sodium ethoxide yielding 4-aminothieno[2,3-5]pyridines. 

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