The Triazole Fragment

In order for this strategy to be competitive with the convergent approach, we would have to first improve the synthesis of the triazole fragment and tlien find an alternative to the Masamune chemistry to get access to P-keto amides directly. 

8) A nonexplosive form of hydrazine is used as the limiting reagent. Hydrazine is completely consumed after the addition of trifluoroacetate. In this manner, no hazardous waste containing hydrazine is generated. 

Isolated amidine 20 could be converted to 3 thermally or by acid or base catalysis. Since 3 was best isolated as its HCl salt, the reaction was run by addihon of 1 equivalent of concentrated HCl to a slurry of amidine 20 at reflux in methanol. Under optimized conditions, triazole 3 was isolated by filhation of the reachon slurry at 0°C in 92% yield [14], 

112 I 5 Synthesis of Sitagliptin, the Active Ingredient in Januvia and Janurnet Q 

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However, this approach required additional functional group manipulation steps since the chiral P-amino ester intermediate had to be hydrolyzed and activated to be converted to the desired amide. These steps could potentially be dirni-nated by introducing the triazole fragment much earlier in the synthesis and then introducing the chiral center on an enamine-amide instead of an enamine-ester (Route B on Scheme 5.8). 

With an improved synthesis of the triazole fragment in hand, which would allow for its introduction much earher in the synthesis, we started searching for a direct preparation of the P-keto amide intermediate from trifluorophenylacetic acid (9). This type of transformation has been accomplished in the past using acyl Mel-drum s acid adducts [16]. This methodology involves reaction of Meldrum s acid with activated carboxyhc acids followed by decarboxylation in the presence of nucleophiles such as alcohols or amines (Scheme 5.13). The abihty of readily avail-... 

With the improved route to prepare the triazole fragment 3 and the one-pot method to access keto amide 25 demonstrated, we set out to explore the chiral auxiliary strategy that had been demonstrated previously from keto ester 10. 

SCHEME 20 Multicomponent coupling to form the triazole fragment. 

Thermal recyclization of the 3-diazenofuroxanyl unit to form the 4-nitro-l,2,3-triazole fragment has been found in noncondensed 1,2,5-oxadiazole 2-oxide derivatives (3,3 -azofuroxans) with acetamido substituents in the 4,4 -posi-tions <1999MC17>. 

In the presence of various metal ions, 2-(fluoroenone)benzothiazoline has been found to rearrange to A-2-mercaptophenylenimine, while a free radical mechanism involving the homolysis of C-S and C-N bonds has been invoked to explain the formation of 3-phenyl-1,2,4-triazole derivatives from the thermal fragmentation and rearrangement of 2-(arylidenehydrazino)-4-(5//)-thiazolone derivatives. The cycloadducts (36) formed from the reaction of 3-diethylamino-4-(4-methoxyphenyl)-5-vinyl-isothiazole 1,1-dioxide (34) with nitric oxides or miinchnones (35) have been found to undergo pyrolytic transformation into a, jS-unsaturated nitriles (38) by way of pyrrole-isothiazoline 1,1-dioxide intermediates (37). 

In a very recent study, trialkylated 1,2,4-triazoles were shown to produce the novel bridging diylidynes with metals coordinated at C3 and C5. For example, with (cod)M (M = Rh and Ir) as the metal fragment they proved active in transfer hydrogenation, although it is possible that their activity in the cyclization of alkynoic acids may be more relevant [39]. 

These results show the greater stability of a 1,2,3-triazole compared with a 1,2,5-oxadiazole. As confirmation, CNDO/2 calculations on model compounds 76 and 77 are also reported. This approach shows that (a) the triazole 77 is about 20 kcal mol more stable than the oxadiazole 76 and (b) the 7T bond order of the O—N bond is lower than that of N—N (85HCA1748). The occurrence of a rearrangement by electronic impact is also shown in the mass spectra of 74Z the fragment at m/z (M-17) is ascribed to the formation of the rearranged product (85HCA1748). 

Cycloadditions have been carried out to 37/-indoles (222, 223) (125,126), N-arylmaleimides (224) (127,128), l,2), -azaphospholes (225) (129), 5(47/)-oxazo-lones (226) (130), and 4,5-dihydrooxazoles (230) (131). The primary cycloadducts from the reaction of oxazolones (e.g., 226 with diaryl nitrile imines), derived from tetrazoles in refluxing anisole, do not survive. They appear to lose carbon dioxide and undergo a dimerization-fragmentation sequence to give the triazole 228 and the diarylethene 229 as the isolated products (130). In cases where the two aryl substituents on the oxazole are not the same, then, due to tautomerism, isomeric mixtures of products are obtained. 

Three methods for making 4,5,6,7-tetrahydrotriazoIopyridines use two fragments to form the triazole ring. The lithium derivative of A/-nitro-sopiperidine reacts with benzonitrile to give the 3-phenyl derivative 19.28 Diazonium salts react with a-amino acids to give mesoionic triazole oxides if pipecolic acid is used, the product is a tetrahydrotriazolopyridine 3-oxide... 

The other major approach to triazolo[4,3-a]pyridines is from pyridines or from 2-halogenopyridines, with the addition of a three-atom fragment to form the triazole ring. Reaction between pyridine or 4-methylpyridine and... 

Anomalous products have been observed in several cases. Azide addition to malonodinitrile yields a triazole only when the reaction is conducted in aqueous sodium hydroxide solution,425,428 and the triazoles obtained (83 and 84) are determined by the structure of the azide (Scheme 134). The product from the action of phenylcarbamyl azide is not a triazole (Scheme 134).425 Methylmalononitrile and tosyl azide lead to fragmentation products of the triazole such as imidazolone.429... 

Phenyldesylamine,21 when heated under reflux with phenylhydrazine in acetic acid, forms the 2,4,5-triphenyl-2,5-dihydro-lH-l,2,3-triazole 10 (Scheme 6).22 The 2-pyridyldesylamine21 leads to the same triazoline (10), with the pyridine fragment being lost during the cyclization in place of the benzene.22... 

Spectroscopic analysis revealed that the thermally initiated [3 + 2] polycycloaddition produced 1,4- and 1,5-substituted triazole isomers in an approximately 1 1 ratio. This ratio appears to be statistic and dependant on the bulkiness of the organic moieties. For example, hfr-r-P[30(4)-20] with butyl spacers contained slightly more 1,4-triazole isomers than did hb-r-P[30(6)-20] with hexyl spacers. This becomes clearer if we look at the proposed transition states a and b of the [3 + 2]-dipolar cycloaddition (Scheme 16). Because of their molecular orbital symmetry, the acetylene and azide functional groups arrange in two parallel planes, a so-called two-plane orientation complex [48], which facilitates a concerted ring formation. If the monomer fragment or the polymer branch ( ) attached to the functional groups are bulky, steric repulsion will come into play and transition state a will be... 

Intermolecular isotope effects /c2h4 //c2d4 in the range 1.3 -1.9 have been reported for metastable ion decompositions effecting loss of ethylene from various triazole molecular ions with 7V-ethyl side chains [568, 573]. Subsequent elimination of N2 from the benztriazole fragment ions occurs with an isotope effect of 1.5 (unlabelled vs. perdeuterated ions), perhaps indicating that a hydrogen transfer is involved in the decomposition [573],... 

The dipole moments of nitroazoles measured in chloroform are lower than the values obtained in dioxane (Table 3.72) [1268], This effect is supposed to be caused by mutual orientation of the substrate and chloroform dipoles, which leads to partial compensation of charges and, hence, to the reduction of polarization. The substitution of hydrogen atom of the NH-fragment by a methyl group does not influence much the dipole moment value of nitroazole. Nevertheless, the dipole moment is, for example, sensitive to substitution in position 5 of the 1,2,4-triazole cycle [1268], The introduction of electron-donating substituent (methyl group)... 

The analogical fragmentation way shows the isomeric 1-chloro- and 5-chloro-3-nitro-l,2,4-triazoles herewith that the isomers have some differences. 5-Chloro... 

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