1 -substituted-1,2,3,4-tetrahydro

The Mannich reaction has been employed to obtain the pyr-N-substituted l,2,3,4-tetrahydro-j8-carboline 319, and intramolecular Mannich reactions at the pyr-N of suitably 1-substituted 1,2,3,4-tetrahydro-jS-carbohnes with formaldehyde 149,359-361... 

Reaction of homophthalic acid (377) and 3-hydroxypropylamine at 215-220°C gave l-(3-hydroxypropyl)-l,2,3,4-tetrahydro-6//-pyrimido[l,2-b]isoquinoline (376, R = CH2CH2CH2OH, R1 = H) (71GEP1960375). 1-Substituted 1,2,3,4-tetrahydro-6//-pyrimido[l, 2-b]isoquinolin-6-ones (378) were obtained from homophthalic acid (377) and 1,3-propanediamines in o-dichlorobenzene at 140-150°C with removal of water by azeotropic distillation [78JAP(K)78/130435 79CPB2372 88HCA77],... 

The factors that control diastereoselection in the construction of 1,3-disubstituted tetrahydro-p-car-bolines are not, as yet, well understood. With many aldehydes a slight preference for forming the trans diastereomer is observed. " This preference is somewhat greater when the indole nitrogen (Na) of the tryptamine is alkylated. Pictet-Spengler cyclizations of Nb-benzyltryptophan methyl ester under Cook s aprotic conditions are reported to provide nearly exclusively the rr 2ni-A b-benzyl-3-methoxycarbonyl-1 -substituted-1,2,3,4-tetrahydro-P-carbolines. ... 

The decarboxylated products are obtained directly, however, if condensation of tryptamine with the a-oxo acid is carried out in aqueous solution at elevated temperature. This direct synthesis of a 1-substituted-1,2,3,4-tetrahydro-j8-carboline has been carried out with... 

Alkylation at the ind-N of l,2,3,4-tetrahydro-j8-carbolines has been carried out with alkyl halide after treatment with sodamide in the usual manner. Cyanoethylation of a p /r-V-substituted tetrahydro-jS-carboline in the presence of Triton B yields the corresponding 9-cyanoethyl derivative. Similarly, treatment of p / -V-methyl-l,2,3,4,4a,9b-hexahydro-y-carboline with sodamide, followed by benzyl chloride, leads to the ind-A -benzyl-substituted derivatives. l-Oxo-l,2,3,4-tetrahydro-j8-carboline yields the ind-A -methyl derivative directly with dimethyl sulfate.Prolonged treatment with sodium hydride, followed by methyl iodide, yields the 2,9-dimethyl derivative. Heating with sodium hydride in acetone followed by the addition of dimethyl sulfate gives rise to the ind-V-methyl derivative. ... 

The interesting work of Hahn and Hansel, who prepared a tetracyclic lactam by intramolecular cyclization of the condensation product of tryptamine and a-ketoglutaric acid, is referred to in Section IV, B, 2. Condensation of tryptamine with a,a -diketopimelic acid (403) led, presumably by way of the 1-substituted tetrahydro-)S-carboline (404), which could not be isolated, to a product to which the tetracyclic structure 405 was assigned. 

The addition of (Z)-3-(alkylamino)-2-butenoic acid esters to nitroalkenes derived from open-chain sugars gave a 50 50 mixture of diastereomeric products 32. The reaction of chiral 2-sub-stituted l-(2-nitroethenyl)pyrrolidines with zinc enolates of 3-substituted tetrahydro-2//-pyran-2-oncs in 1,2-dimethoxyethane at — 78 °C afforded the corresponding 3,3-disubstituted products in 82-96% ee via an addition-elimination process33. The stereochemical course of the reaction was determined by chemical correlation of (S)-( )-3-ethyltetrahydro-3-(2-ni-troethenyl)-2//-pyran-2-one with ( + )-quebrachamine. 

The addition of the lithium enolates of various acetic add esters to (S)-3-(4-methylphcnyl-sulfmyl)-2(5//)-liiranone and (,S)-5,6-dihydro-3-(4-methylphenylsulfinyl)-2//-pyran-2-one gives, after desulfurization with Raney nickel, 4-substituted dihydro-2(3//)-furanoncs and 4-substituted tetrahydro-2//-pyran-2-ones, respectively, in good to quantitative enantiomeric excess. Addition of the enolate occurs via the nonchelate mode. The enolate of methyl (phenylthio)acetatc is best overall in regards to chemical yields and enantiomeric purity of the final lactone product13. 

Shat general strategies can you suggest for the synthesis of Symmetrical 2,3-di substituted tetrahydro-furans (48) ... 

The impulse to the study of these cycloadditions came from the discovery that 5-spirocyclopropane isoxazolidines (or isoxazolines) undergo a thermal rearrangement resulting in the production of selectively substituted tetrahydro-(or dihydro) pyrid-4-ones (Scheme 42) [64], In particular, cyclic nitrones gave ultimately N-bridgehead bicyclic ketones, molecular skeleton of many alkaloid families [65]. 

The substituted tetrahydro derivative of the [l,2,4]triazolo[4,3- /][l,2,4]triazine ring system 40 has also been investigated by X-ray crystallography <2002M1165>. The result showed a close similarity with that obtained with an earlier related derivative <1996CHEC-II(8)479>. 

The 4-phenyl and 4-phenyl-2-oxo analogues of (6, n = 3 R1 = R2 = Me) have been reported to exhibit sedative properties [13]. Several carboxamides (7) with a 4-phenyl group have been claimed to be useful as tranquillizers [ 14]. A variety of central effects of the 1-substituted 5-phenyl derivatives (8) has been studied [10]. The 2-(substituted aminomethyl)tetrahydro-l-benzazepine and octahydropyrazino[ l,2-c]-l-benzazepine derivatives have no pharmacological activity on the CNS [15]. 1-Substituted tetrahydro-l-benzazepines having an aminoalkyl group at position 3 are claimed to potentiate the activity of 5-hydroxytryptophan [16]. 

In all cases, mixtures of cis and trans diastereoisomers are reported. In terms of experimental observation, it is now possible to prepare 1,3-disubstituted tetrahydro-j8-carbolines and 1-substituted tetrahydro-/3-carbolines of known absolute stereochemistry. For example, if optically active A -benzyltryptophan methyl ester of known chirality reacts with aldehydes in refluxing benzene, the trans derivative is obtained. Arylglycidate was also used in the synthesis instead of aldehydes (78CPB2305). 

The conformational analysis of methyl-substituted tetrahydro-1,3-oxazines has been discussed in detail in several contexts (86MRC145,... 

The tautomerism of the 2-aryl-substituted tetrahydro-1,3-oxazines with the general structures 390, 391, 393, 394, and 396-406 has been studied in detail. Only the structures of the ring forms are shown. In all series, the ring-chain tautomeric equilibria measured in CDCl.i at room temperature can be described by the equation... 

Some A -enecarboxylic acids undergo a rapid intramolecular cyclization reaction of the 5-exo-trig type prior to the radical coupling step. Substituted tetrahydro-furans [95] and pyrrolidines [96] can be prepared by this Kolbe route. It is preferable to protect the amine function in the pyrrolidine synthesis by N-formy ation in... 

A novel route to ( )-0-methylthalisopavine (26) involves the oxidation of the properly substituted tetrahydro-3-isoquinolone of type 129 with vanadium oxy-trifluoride to furnish bridged lactam 130. Compound 130 was then reduced to the racemic isopavine alkaloid 26 in an overall yield of 4.4% (Scheme 26) 136). 

In 2004, Taylor and Jacobsen suggested a procedure for the enantioselective acetyl-Pictet-Spengler reaction, that is the cyclization of electron-rich aryl or heteroaryl groups onto N-acyliminium ion enabling access to substituted tetrahydro-P-carbolines and tetrahydroisoquinolines that are core structure elements in natural and synthetic organic compounds [202, 203]. Screening various thiourea catalyst candidates such as 47 in the formation of model product Np-acetyl-... 

Methylene-substituted tetrahydro-l,3-oxazine 141 underwent ring opening in response to nucleophilic attack by carboxylic acids or thiophenols to afford the A -acetyl derivatives of the corresponding 0-acyl-l,3-amino alcohols 168 or aminoalkyl sulfides 169 in high yields (Scheme 27) <2006JC0262>. 

The reactions of A -BOC-protected a-amino acids 424 and diazomethane in the presence of iV-methylmorpholine-polystyrene and isobutyl chloroformate resulted in formation of diazoketones 425, which, on treatment with indium(lll) triflate, were cyclized to 4-substituted-tetrahydro-l,3-oxazine-2,5-diones 426 in high overall yields (Scheme 82) <2006TL7969>. 

Additionally, the acid-catalyzed decomposition of substituted tetrahydro-l,2-dioxin-3-ols yielded adequately the substituted furan derivatives <1994JHC1219, 1998S1457>. 

Either enantiomer of a-alkylated alkanoic acids, 3-substituted dihydro-2(3//)-furanones and 3-substituted tetrahydro-2//-pyran-2-ones with known absolute configuration and high optical purities can be obtained from metalation and alkylation of chiral 4,5-dihydrooxazoles (see Section 1.1.1.4.3.). 

Recently, a variable-temperature study of the 13C-NMR of 3,4-dimethyl-hexahydro-l,3,4-oxadiazine and of the trans-fixed derivative 434 have completely clarified the conformational equilibria and allowed a rather complete energy contour to be constructed for the monocyclic oxadiazine (Fig. 17).344 The conformational analysis of other methyl-substituted tetrahydro-1,3,4-oxadiazines345,346 is consonant with these results. 

Sulfur is normally found in a tetracoordinate setting, and bivalent sulfur is quite analogous to oxygen in its general influence on the conformational preferences of the equivalent substituted tetrahydro systems. Thus, nonpolar substituents prefer to occupy equatorially-disposed positions on the preferentially chair-conformer ring. Molecular mechanics calculations have been used to derive some of the characteristics of the parent system (75JA5167). 

Heterocyclizations involving the oxygen of enolizable (3-dicarbonyl groups115 176 and of epoxides177 as the nucleophile have also been reported. Iodocyclizations of unsaturated A -oxides of tertiary amines to form substituted tetrahydro-l,2-oxazines,178al78b and iodocyclizations of A -dimethyl-W -allylbenzo-hydrazides to form substituted 4//-1,3.4-oxadiazinium saltsl78c have been reported. 

A novel acid-catalysed rearrangement of 2-hydroxy-2-phenylazo-y-butyrolactone (45) to the interesting /V-substituted tetrahydro-l,3-oxazine-2,4-dione derivative (46) has been reported.58 The photo- and thermo-chemistry of diazo(2-furyl)methane and diazo(3-furyl)methane have been investigated59 using matrix isolation techniques, and 3,7-diphenylpyrano[4,3-c]pyran-l,5-diones have been prepared60 from 5,5 -diphenyl-... 

N-substituted tetrahydro-1,3-oxazines were also studied. It has been suggested (66) that conformer 93 with the M-alkyl group in the axial orientation, is more stable than 94 when R is either a methyl or a benzyl group. It was also found that the contribution made by conformer 95 is appreciable and it may dominate conformer 96 in tetrahydro-3,4,4,6-tetramethyl-l,3-oxazine. 

Access to chiral 1-substituted tetrahydro-3-benzazepines by aysmmetric sysnthesis has been reported <2007EJ0462>. The synthesis began with o-phenylenediacetic acid and (R)-phenylglycinol, and proceeded via an acid catalyzed type a ring constmction to afford an intermediate oxazolobenzazepinone. This intermediate in turn was then subjected to lactam reduction followed by hydrogenolytic removal of the N-substituent to afford the chiral reduced 3-benzazepines, which were evaluated as NMDA receptor antagonists. 

Ward, D. E. Gai, Y. Lai, Y. A general method for the synthesis of 3-substituted tetrahydro-and 2,3-dihydro-4H-thiopyran-4-ones. Synlett 1996, 261-262. 

Another important type of sul the model reaction mixture is Eight heterocyclic thioethers first time. Both heterocyclic (3 - 1 1 are substituted by sul to the connection of a furan with a substituted tetrahydro... 

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