Amidation, with piperidine

A thioglycoside was immobilized by the following sequence of reactions. Treatment of the dibutyltin acetal of diol 36 with succinic anhydride afforded 37 in an excellent yield of 85%. Attachment of Fmoc protected glycine to TentaGel hydroxyl resin (38, 0.37 mmol/g resin) under standard conditions followed by removal of the Fmoc group by treatment with piperidine gave polymer 27. Compound 37 was immobilized by amide bond formation with 27 in the presence of... 

Reaction of 5-trichloromethyl-1,2,4-thiadiazoles with secondary amines leads to amides. For example, treatment of (84) with piperidine gives (86) which presumably arises by nucleophilic displacement of chloride ion from the trichloromethyl group, followed by hydrolysis during work up of the resulting dichloro compound (85) (Scheme 21) <86PS(26)151>. 

If the amide moiety, in lieu of the carboalkoxy group, is used, then a monooxy derivative is obtained. Thus, the simple thiophene 465 is first acylated on the amine using chloroacetyl chloride. Subsequent treatment with piperidine affords intermediate 466. Cyclization in alkali produces the thienopyrimidine 467 (no yield given) (Scheme 38) <1998JME4021>. 

The presence of the propionamide fragment in the stmcture of the anti-inflammatory agent broperamole (125-1) is reminiscent of the heterocycle-based NSAID propionic acids. The activity of this agent may trace back to the acid that would result on hydrolysis of the amide. Tetrazoles are virtually always prepared by reaction of a nitrile with hydrazoic acid or, more commonly, sodium azide in the presence of acid in a reaction very analogous to a 1,3-dipolar cycloaddition. A more recent (and safer) version of the reaction noted later (see losartan, 77-4) uses tributyltin azide. In the case at hand, reaction of the anion of mefa-bromobenzonitrile (125-1) with sodium azide and an acid affords the tetrazole (125-2). Condensation of the anion from that intermediate with ethyl acrylate leads to the product from Michael addition saponiflcation gives the corresponding carboxylic acid (125-3). This is then converted to the acid chloride reaction with piperidine affords broperamole (125-4) [136]. 

With both pyr-T and 4-HO-pyr-T, there are two additional ring analogies that are natural companions to 5-MeO-pyr-T. These are the piperidine and the morpholine counterparts, 5-MeO-mor-T and 5-MeO-pip-T. Both compounds are in the literature, and an entry reference to them can be gotten from the "known tryptamines" appendix. Along with the pyrrolidine material I had made a reasonable supply of the amides for these other two, both by way of the 5-methoxyindole and oxalyl chloride procedure given above. With piperidine, there is 5-... 

If the coumarin is heated with an amine, the amide of the coumarilic acid is isolated thus, 3-halo-4-piperidinocoumarins with piperidine (X = CH2) or morpholine (X = 0) gives the corresponding compounds 359.791... 

The reduction of amides with borane leads to the formation of borane-amine adducts, which can be resistant towards acylating agents or hydrolysis. Such borane complexes can be cleaved either by treatment with a secondary amine (e.g. piperidine, 60 °C [180]), or oxidatively, by treatment with iodine (Entry 3, Table 10.11 [181,182]). 

Pyrrolo[2,1 -d][ 1,5]benzothiazepine-6-carboxylic acid (27) was obtained via base-catalyzed cyclization of pyrrole-2-carboxaldehydes 26 and 28, each synthesized by Vilsmeier-Haack formylation of their respective pyrroles 24 and 25, prepared in turn by condensation of 18, respectively, with ethyl bromoacetate and chloroacetonitrile in the presence of sodium ethylate at room temperature. When treated with piperidine in refluxing benzene for 48 hours, 26 and 28 afforded ester 29 and nitrile 31 from which, in an alkaline medium, acid 27 could be obtained. Under similar experimental conditions, acid 27 was also formed from amide 30 (Scheme... 

Other examples include CAN oxidation of silylmethyl amines and amides with the synthesis of aryl-fused piperidine and pyrrolidine ring derivatives.360... 

When 3-chloro- or 3-bromopyridine is heated with lithium piperidide and piperidine in boiling ether, 156 is formed, which reacts further with piperidine to give a mixture of 3- and 4-piperidinopyridine in the ratio of 48 52. No 2,3-pyridyne intermediate is apparently produced under these conditions.388 Such an intermediate is probably involved in the reaction of potassium amide in liquid ammonia with 3-bromo-4-ethoxypyridine, which gives 2-amino-4-ethoxypyridine (55-60%). The reaction is, however, complicated by the fact that 2-amino-5-bromo-4-ethoxypyridine (15-20%) and 4-ethoxypyridine (25%) are also obtained.387 The formation of these two by-products may proceed by the preliminary disproportionation of some 3-bromo-4-ethoxy-pyridine to 3,5-dibromo-4-ethoxypyridine and 4-ethoxypyridine.388 The remarkable observation that both 2-amino-6-ethoxypyridine (157) (85%) and 4-amino-2-ethoxypyridine (158) (15%) are formed during the amination of 2-bromo-6-ethoxypyridine367 still requires explanation. No such rearrangement is observed with lithium piperidide.3880... 

Whereas an elimination-addition mechanism is not involved in the reaction of pyridines with alkali-metal amides, the reaction of potassium amide with 2-chloropyridine iV-oxide probably involves the intervention of 2,3-dehydropyridine N-oxide.3686 3,4-Dehydropyridine N-oxide is an intermediate in the reaction of 3-chloropyridine N-oxide with piperidine.388 ... 

Though the destabilisation is much less severe than with a nitrogen lone pair, an amide-stabilised organolithium prefers to minimise the interaction (shown below) between the C-Li bond and the 7i-system of the amide. Hindered amides of piperidines such as 37 are therefore deprotonated to give an equatorial organolithium such as 38.5 4 The equatorially substituted piperidine amide products 39 and 40 are less stable than their axially substituted products owing to the interaction between the new substituent and the pseudoequatorial amide group. Oxidation and equilibration leads to the axial substituted ketone 41.4... 

The occurrence of several new hetarynes has been indicated by rearrangements observed. 4,5-Pyrimidyne was shown to be involved as an intermediate in the conversion of 5-bromopyrimidine with piperidine 2-methyl-4,5-pyrimidyne in the reaction of 5-chloro-2-methylpyrimidine with sodium amide in liquid ammonia and a series of 6-substituted derivatives of 4,5-pyrimidyne when reacting the 5-bromo compounds of 6-amino-, 6-1-butyl-, 6-dimethylamino-,... 

The cyclization of aspartic acid residues to form aspartimide is the most likely side-reaction observed in routine SPPS (Fig. 10). This is a sequence-dependent side-reaction that occurs either during chain elongation or during final TFA cleavage when Asp(OtBu)-AA sequence (AA = Ala, Gly, Ser, Asn(Trt)) is present in the peptide. Hydrolysis of the aspartimide ring leads to a mixture of both a- and P-peptides. Its reaction with piperidine used for Fmoc removal also leads to the formation of a- and p-piperidides. Normally, in Fmoc-based SPPS, Asp (OtBu) provides sufficient protection. However, for particular sequences such as Asp(OtBu)-Asn(Trt) particularly sensitive to aspartimide formation, addition of HOBt to the piperidine solution or protection of the aspartyl amide bond with the 2-hydroxy-4-methoxybenzyl (Hmb) group should be considered (36). 

The reduction of nicotinamide (31) with NBH in diglyme at 140° C gave a low yield of tetrahydropyridine (22) and the piperidine 32. Addition of ethanol as a proton source raised the yield of 22 to 42%. The dehydration of primary amides with borohydride is known to occur in moderate yield. The reduction of 2-alkylamino- and 2-arylamino-3,5-dinitropyridines (33) in water leads to the tetrahydropyridines 34 in high yields. - The... 

Sanders, G. M., Van Dijk, M., Den Hertog, H. J. Didehydrohetarenes. XXXIV. Diversity in the course of the reactions of the 4-haloisoquinolines with potassium amide in liquid ammonia and with piperidine. Reel. Trav. Chim. Pays-Bas 1974, 93, 273-277. 

Bunnett and co-workers used sodium amide to effect condensation of sodium naphthalene-/3-sulfonate with piperidine to produce N-0-naphthylpiperidine. 

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