Pyridines tricyclic

The first organocatalyzed domino Michael/aldol reaction was used in the total synthesis of the natural product (—)-huperzine A [12]. This process was catalyzed by (—)-cinchonidine to convert a P-keto ester and methacrolein to a 5,9-methanocycloocta[h]pyridine tricyclic core. Two excellent reviews dealing with these processes have been recently published [8, 11], and in the field of natural products several total syntheses utilize a domino process involving a Michael reaction step [12-24]. This chapter will mainly cover the recent work in the development of novel domino reactions containing a Michael reaction published since the beginning of 2006, as the many such domino reactions were collated prior to this date by Tietze et al. in a comprehensive book [25]. 

There exist many types of azoloquinolines, and therefore it is necessary to define the objects of interest to be described in this review. The tricyclic azoloquinolines reviewed in this article have an azole ring fused to the benzene ring of quinoline (not isoquinoline derivatives) in positions / g, and h. This means that the benzene ring is between azole and pyridine rings, and all of them are ortho-peri condensed. The azole and benzene rings do not have a common heteroatom, and also a carbon... 

The Diels-Alder methodology can also be applied in the synthesis of tricyclic heterocycles, as was demonstrated by reactions of 2-(2-trimethylsilylethynylphenyl-X)pyrimidines (X = 0, S, NCOMe, CHj, CO). They are converted in good yield on heating at 160°C into tricyclic annelated pyridines (89T6511) (Scheme 37). A similar reaction was found with the 2-(2-allylphenoxy)pyrimidines affording azaxanthenes (79H665) (Scheme 37). 

As an extension of this reaction the intramolecular cycloaddition of 5-propynyloxycycloalkanepyrimidines was studied. It was found that bi-and tricyclic annelated pyridine derivatives are formed by expulsion of either X-CH2-CN and/or HCN, respectively. A marked selectivity in the product formation was observed, depending on the size of the cycloalkane ring. With cyclohexapyrimidines a mixture of A and B is formed, while with the cycloheptapyrimidine derivative exclusive formation of the tricyclic compound B takes place (92T1643, 92T1657) (Scheme 39a). 

This tricyclic ring system was prepared from the functionalized pyrazo[l,5-n]pyridines. Thus, pyrazo[l,5-n]pyridine-3-carboxylate 462 gave 465 upon mesylation and subsequent reaction with 2-ethoxy-2-lithioxyethy-lene, whose cyclization afforded 466 (94AP435). Intramolecular aldol... 

Silicon linker 76 was used for direct loading of aromatic compounds to supports for the assembly of pyridine-based tricyclics (Scheme 39) [87], Following the initial coupling of an aromatic bromide to the resin by halogen/metal exchange in the presence of tert-butyl lithium, a... 

Activation of a primary alcohol 174 by in situ mesylation and nucleophilic attack of a pyridine nitrogen atom was used in the last steps of a synthesis of cyclohexa[tf]quinolizidines 176. These compounds were obtained by direct NaBH4 reduction of intermediate pyridinium salts 175, and were proposed as tricyclic models containing the ABC-part of 8-azasteroids (Scheme 30) <1999T9269>. 

Reaction of 3-amino-4-imino-4//-pyrido[l,2- ]pyrazine 306 (R = 4-MeC6H4) with ketenes 328, prepared in situ from the appropriate acetyl chloride with NEt3, yielded tricyclic derivatives 329 (Scheme 29) <1999JPR332>. Pyridine-3,4-dicarboxylates 330 were obtained from 4//-pyrido[l,2- pyrazines 307 with DMAD in refluxing toluene. 

The compounds 93 (R = Me, Et) are extremely sensitive toward oxidation and moisture and were not isolated in a pure state. Their structures were supported by NMR spectroscopy. Treatment of 93 with pyridine also gives rise to pyridine-l-boraadamantane complex 111 and starting acetylene derivative, via 1,1-deorganoboration. Accordingly, the 1-boraadamantane-TMEDA adduct (TMEDA - bis(dimethylamino)ethane) (along with Me3SnC CSnMc() is formed when the tricyclic borane 93a (R=Me) reacts with TMEDA <2003JOM(687)108>. 

Cyclization of substituted vinylic imidazo[l,2-tf]pyridines has been used to synthesize angular tricyclic systems. For example, reaction of 136 with ethyl azidoacetate 137 to give 138 followed by cyclization furnishes 139 (Scheme 10) <2001JOC6576>. 

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)... 

Formation of a pyridine ring onto bis-heterocycles is another route to these tricyclic systems. Reaction of 4-amino-2-morpholino-5-(2-morpholinothiazoM-yl)thiazolc 154 with the Vilsmeier reagent proceeds by direct cyclization to the bis-thiazolylpyridine 155 (Equation 36) <1997JHC1291>. 

An alternative strategy for the synthesis of these tricyclic compounds involves the reaction of the azidoalkenyl-functionalized furo[3,2-A]pyrrole 30, which reacts with triphenylphosphine to give the corresponding iminophos-phoranes 31 these upon reaction with aryl isocyanates give the pyrrolo[2, 3 4,5]furo[3,2-r-]pyridines 32, via the corresponding carbodiimides which are not isolated < 1994H(37) 1695, 1992M807> (Scheme 9). 

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

Numerous examples of the synthesis of tricyclic systems based on indolizine derivative 232 have been reported <2000M959>. The product obtained from the reaction of 232 with carbon disulfide depends on the reaction medium. Thus, in aqueous potassium hydroxide the pyrimidine-dithione 233 is formed, whereas in pyridine the iminothiazine-thione 234 is obtained. In aqueous potassium hydroxide, compound 234 rearranges to 233 (Scheme 12) <2000M959>. 

Pyridine-containing tricyclic compounds have been produced via a sequence consisting of a Suzuki reaction and a subsequent annulation. Gronowitz et al. coupled 2-formylthienyl-3-boronic acid with 3-amino-4-iodopyridine. The resulting adduct spontaneously condensed to yield thieno[2,3-c]-l,7-naphthyridine 59 [47]. They also synthesized thieno[3,4-c]-l,5-naphthyridine-9-oxide (60) in a similar fashion [48]. Neither the amino nor the N-oxide functional group was detrimental to the Suzuki reactions. 

In a sequence analogous to the Suzuki reaction and annulation described in section 4.2.4, pyridine-containing tricyclic compounds have also been prepared via the Stille reaction and a ... 

Scheme 2. Traceless linkers for the solid-phase synthesis of (a) pyridine-based tricycles and (b) isoquinolines.

F. X. Woolard, J. Paetsch, J. A. Ellman, A Silicon Linker for Direct Loading of Aromatic Compounds to Supports. Traceless Synthesis of Pyridine-Based Tricyclics , J. Org Chem. 1997, 62, 6102-6103. 

Only few general methods allow for the introduction of a substituent at the C-7 position. However, treatment of cyano-enamide 335 with LiTMP followed by reaction with electrophiles has been successfully used to introduce an alkyl chain at G-7. It is worth noting that the amide obtained by acidic hydrolysis of the cyano-enamide group can be further alkylated to form tricyclic hexahydro-oxazolo[3,2- ]pyridin-5-ones 337 (Scheme 92) <1998JOC1619>. 

The most efficient routes to the cationic oxazolo[3,2- ]pyridine ring system 351 rely on the method of Bradsher and Zinn <1967JHC66> involving the cyclocondensation of iV-phenacyl-2-pyridones 349 obtained by alkylation of readily available 2-pyridones 347 (Scheme 95). This method has been used by Babaev et al. to prepare a series of 6-nitro-oxazolo[3,2- ]pyridines 355 from 5-nitro-2-pyridone 352 in excellent yields <2003MOL460>. Similarly, tricyclic oxazolo[3,2- ]pyridines 359 have been prepared from the corresponding quinolin-2(177)-ones 356 <2003H(60)131>. 

A prototypical series of monocyclic and tricyclic agents with potency in the nalidixic acid - oxolinic acid range has been reported [89]. The enantiomers of the tricycle (55), which lacks the ring fused to the 5- and 6-positions of the pyridine portion common to most quinolones, have been evaluated in vitro, and... 

From such silanol-functional cyclics, the polycyclic (ladder) siloxanes are made in a controlled manner. Thus, the reaction of (7-PrSi(0H)0)4 with ((-PrPhClSiO)2 in pyridine was described, leading to the formation of tetraphenyl tricyclic ladder siloxane. Dephenylchlorination with A1C13/HC1, and the hydrolysis allowed isolation of tetrahydroxyl tricyclic ladder siloxane in good yield. Using a similar reaction starting from tetrahydroxyl ladder siloxane, the first pentacyclic ladder siloxane was obtained.38 Abe et al. describe the synthesis of... 

The ring closure of A/-ethyl-/V-(3,4-alkylenedioxyphenylamino)methy-lenemalonates (839) in polyphosphoric acid at 120-130°C for 30 min afforded linearly fused tricyclic pyridine-3-carboxylates (840) in over 90% yields (73JAP6479). 

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