Pyridines 1,2,3,4,5,6-hexahydro

It is now applied more widely to include malonic acid derivatives, such as diethyl monoethyl-malonate, ethyl cyanacetate, etc. Various amines may be used as catalysts, and usually the most effective is piperidine (hexahydro-pyridine) a mixture of piperidine and pyridine, or pyridine alone, is also often used. 

The amino group of 8-amino-l,3,4,6,l 1,1 ln-hexahydro[l,4]oxazino[4,3-Z ] isoquinoline was reacted with 5-methyl-2-thiophenecarboximide hydroiodide in DMSO in the presence of pyridine at 50 °C for 4 h to give amidine 260 (X = 0) in 94% yield (97MIP4). 

Phthalimidobutyl)-2,3,4,4u,5,6-hexahydro-l//-pyrazino[l,2-u]quino-line was obtained in the reaction of 2,3,4,4u,5,6-hexahydro-l//-pyrazino[l,2-u]quinoline and A-(4-bromobutyl)phthalimide in boiling MeCN in the presence of K2CO3 (97MIP12). 2,3,4,4u,6,7-He-xahydro-l//-pyrazino[l,2-ujquinolines were N-alkylated with 3-dimethylaminomethyl-l//-pyrrolo[2,3-6]pyridine and a mixture of l//-pyrrolo[2,3-6]pyridine and 37% aqueous H2CO in aqueous AcOH in the presence of NaOAc (96USP5576319). 3-[3-Substituted 2-propen-l-yl]-2,3,4,4u, 5,6-hexahydro-l//-pyrazino[l,2-u]qui-... 

Hydroxy group of 8-hyd oxy-2-cycloalkyl-2,3,4,6,ll,lla-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-diones was alkylated with allyl bromide, 2-(bromodifluoromethyl)pyridines, l-(bromodifluoromethyl)- and l-(bro-momethyl)benzenes, halomethyl derivatives of different heterocycles (pyridine, pyrazine, pyrazole, pyrrole, thiazole, thiophene) in the presence of CS2CO3 or K2CO3 (98MIP7). Hydroxy group of 8-hydroxy-2-cyclopentyl-... 

A mixture consisting of 2 grams of 2-hydroxy-3-(N,N-diethylcarboxamido)-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-1 Ib-H-benzopyridocoline (OH-axial) hydrochloride (prepared by treating the base with hydrogen chloride gas in absolute ether) dissolved in 7 ml of acetic anhydride containing 3 ml of pyridine was heated at 100°C for 2 hours under a nitrogen atmosphere. At the end of this period, a crystalline precipitate had formed and the resultant mixture was subsequently diluted with an equal volume of diethyl ether and filtered. 

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). 

Isoxazolo[2,3-4]pyridines 44, isothiazolo[2,3-4]pyridines 46, and their fully saturated derivatives 45 and 47 (Scheme 16) were discussed in CHEC(1984) <1984CHEC(6)613> and CHEC-II(1996) <1996CHEC-II(8)249>. Very little information was available on the isothiazolo[2,3- ]pyridine ring system while most of the informations given on the oxygenated parent, isoxazolo[2,3- ]pyridines, concerned the fully saturated system. Careful examination of the literature clearly shows that the situation did not change much almost no references have been reported on isothiazolo[2,3- ]pyridines and most of the work done in the last decade concerns the synthesis and reactivity of hexahydro-isoxazolo[2,3- ] pyridines 45. Therefore, this chapter will briefly describe the new reactions of fully conjugated systems and will focus on the partially/completely saturated derivatives. 

NMR data for new compounds are routinely reported. The hexahydro-isoxazolo[2,3- ]pyridine ring system 48 can exist as a mixture of three conformers 48-trans, 48-cm-A, and 48-cis-B (Scheme 17). While the two conformers possessing a as ring junction 48-m-A and 48-m-B are interconverted by chair inversion, conversion of the cis-conformer 48-cis-h to 48-trans requires inversion of the nitrogen. The presence of the adjacent oxygen slows down... 

In contrast to the conjugated system, the reactivity of hexahydro-isoxazolo[2,3-tf] pyridines has been the subject of considerably more attention, which can most certainly be attributed to its greater synthetic potential, as demonstrated by the synthesis of many complex natural products. However, most of the reactions reported since 1996 have been known for many years and the last decade was in fact characterized by their use in syntheses or optimization. After a brief survey of the thermal reactions, procedures involving the reductive cleavage of the N-O bond will be detailed. 

Finally, the reversibility of the nitrone/alkene [3+2] cycloaddition, mainly used to access the hexahydro-isoxa-zolo[2,3- ]pyridine ring system (see Section 11.10.3.7), can be used to functionalize these heterocycles. Accordingly, Holmes et al. found that a cycloreversion-cycloaddition reaction could be performed from 65 by simple heating in toluene at 190 °C. Under these conditions, the product of the reaction was found to be the exo-adduct 67 (Scheme 21) <2002J(P1)1494>. 

Interestingly, both the amino and the hydroxy groups can participate in another reaction with a suitable reacting group present in the molecule as shown with the two examples in Scheme 23 <1998T11581>. Finally, it should be mentioned that this N-0 bond reduction is also efficient starting from quaternary ammonium derivatives of hexahydro-isoxazolo[2,3- ]pyridines <1999JOC1932>. 

Representative examples illustrating these concepts and general rules as well as giving an overview of all different dipolarophiles engaged in the formation of hexahydro-isoxazolo[2,3- ]pyridines are collected in Table 6. 

Various chiral dipolarophiles have been used in the asymmetric synthesis of hexahydro-isoxazolo[2,3- ]pyridines. Examples include // / -2-methylcnc-l, 3-dithiolane 1,3-dioxide 83 <1998JOC3481>, chiral vinyl sulfoxide 85 <1997TA109>, or chiral dioxolanes <2001TA1747> (Scheme 27). 

On the nitrone side, high levels of selectivities have been reached using camphorsultam-derived nitrone 87 since hexahydro-isoxazolo[2,3- ]pyridine 88 en route to (—)-histrionicotoxin was obtained as a single regio- and diaster-eoisomer <1999JA4900> (Scheme 28). A polyhydroxylated hexahydro-isoxazolo[2,3- ]pyridine could also be obtained starting from a nitrone derived from a C2-symmetric piperidine <2002TL9357>. 

If nitrones have been widely used as 1,3-dipoles in the synthesis of hexahydro-isoxazolo[2,3- ]pyridines, the use of nitroacetates such as 92 in the cycloaddition sequence allows for an efficient access to hexahydro-isoxazolo[2,3-tf] pyridin-7-ones such as 93 after spontaneous dehydration (Scheme 30) <2000JOC499>. 

An efficient preparation of hexahydro-isoxazolo[2,3- ]pyridin-2-ones relies on the anionic addition of nucleophiles at the electrophilic carbon of the nitrone followed by cyclization of the resulting Ar-oxide. As shown by results collected in Scheme 31, various nucleophiles can be engaged in the reaction and include enolates 95 <20020L3119> or 98 <2000BML1811>, silyl acetals 101 <2003TL2817>, or ynolates 103 <20020L3119> (Scheme 31). 

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