Nucleophilic addition triazole

A Sandmeyer reaction leading to the 3-chloro derivatives was observed upon treatment of 3-diazotriazoles with aqueous hydrochloric acid [1898LA33 26JCS1729 78ZN(B)216]. 3-Diazotriazole was reduced to the parent triazole by treatment at 0°C with primary and secondary alcohols [86DIS(B) (46) 3052]. The mechanism is not clear, but the process may be envisaged as involving hydride transfer from the intermediate 244 obtained by nucleophilic addition of alcohols to the diazo compound (Scheme 70). 

Triazole can undergo nucleophilic addition with aldehydes, but the reaction is reversible and the products cannot be isolated. They can be trapped, however, with acid chlorides (Scheme 7) <90CL351>. 

Some earlier contradictory results concerning the reactions of N-unsubstituted azoles have been clarified (224,225) and it has been shown that pyrazole, imidazole, 1,2,4-triazole, and benzotriazole all undergo nucleophilic addition to give (e.g., 392) from pyrazole and 373 (R, R =Ph). 

On the basis of the same principle, we developed a three-component synthesis of macrocycles starting from azido amide (46), aldehyde (47) and a-isocyanoaceta-mide (48) (the cx-isocyanoacetamides are easily available, see [84—86]) bearing a terminal triple bond (Scheme 11) [87]. The sequence is initiated by a nucleophilic addition of isonitrile carbon to the in situ generated imine 50 led to the nitrilium intermediate 51, which was in turn trapped by the amide oxygen to afford oxazole 52 (selected examples [88-94]). The oxazole 52, although isolable, was in situ converted to macrocycle 51 by an intramolecular [3+2] cycloaddition upon addition of Cul and diisopropylethylamine (DIPEA). In this MCR, the azido and alkyne functions were not directly involved in the three-component construction of oxazole, but reacted intramolecularly leading to macrocycle once the oxazole (52) was built up. The reaction created five chemical bonds with concurrent formation of one macrocycle, one oxazole and one triazole (Scheme 15). 

Phenyl- and 3,5-diphenyl-substituted triazines 154 undergo to a small extent ring contraction by action of potassium amide in liquid ammonia to yield 1,2,4-triazoles 155. Again, nucleophilic addition at C-6 is presumed to facilitate ring opening (Scheme 86) (87JOC71). 

When metronidazole (89) and other 4(5)-nitroimidazoles are treated with hydrazine the products include 4-amino-4//-1,2,4-triazole and ring-opened species. The 4-nitro isomers are less reactive than the 5-nitro compounds (which are also known to be more biologically active). A proposed rationale for the reactions (Equation (28)) involves initial nucleophilic addition of hydrazine at C-... 

The susceptibility of 1,3,5-triazine to nucleophilic attack with ring opening makes it a synthetically useful equivalent of formate, or formamide, particularly for the synthesis of other heterocycles, such as imidazoles and triazoles (see above). Despite the high susceptibility of 1,2,4-triazines to nucleophilic addition, 3-substituted-6-methoxy-l,2,4-triazines can be successfully lithiated. ... 

As outlined above, isolated acyl Meldrum s adducts react with amines to afford the corresponding [3-ketoamides. More interestingly, nonbasic amine derivatives, such as carbamates, amides, and hydroxylamines, as well as alcohols, can also react with these adducts to effectively provide the corresponding 1,3-dicarbonyl compounds. To investigate the effect of the nature of the nucleophile, we initiated these studies with BocNHOBoc, because it is nonbasic and is a much weaker bulky nucleophile than the triazole 4. Comparison of the k s with other weak or strong nucleophiles would reveal whether nucleophilic addition or the following elimination is involved in the rate-determining step. 

With nucleophilic bases 3,7,7a-trimethyl-2,3,5,6,7,7a-hexahydro-17f-imidazo[l,5-Zi][l,2,4]-triazole-2,5-dione (130) and -2,5-dithione (129) the [3 -H 2] cycloelimination of the heterocumulene moiety from the triazole ring is followed by nucleophilic addition of the base to give 4-substituted 4,5,5-trimethyl-2,3,4,5-tetrahydro-l/7-imidazol-2-ones (135) and -2-thiones (136), respectively (Scheme 7) <93TH 805-01, 95FES379). 

The isolable potassium salts (74) (available from the nucleophilic addition of 4-amino-l-methyl-3-methylthio-l -l,2,4-triazole-5(4//)-thiones (73) to aromatic nitriles in the presence of base) upon acidification with hydrochloric acid cyclize to give 7/7-[l,2,4]triazolo[4,3-fc][l,2,4]triazole-3(2//)-thiones (75) (Scheme 5) <85BCJ735>. 

Siedle et al. established that the hydrazinolysis of corresponding fluoroimine occurred via particular mechanism nucleophilic addition - HF elimination leading to the formation of 3,5-bis(heptafluoropropyl)-1,2,4-triazole 82 [81]. 

Three-component reaction of 2-ethynylaniline, sulfonyl azide, and nitroolefin also could lead to polysubstituted indole derivatives in moderate to good yields with CuBr catalyst. The reaction conditions are extremely mild and various polysubstituted indoles were obtained successfully. Initially, a triazole intermediate was formed from alkyne and sulfonyl azide in the presence of CuBr and triethy-lamine. It could convert into reactive ketenimine by the ring-opening rearrangement. Subsequently intramolecular nucleophilic addition, intermolecular Michael addition, and tautomerization could lead to the desired polysubstituted indoles [49] (Scheme 8.20). 

Quintard and Alexakis developed a double Michael addition reaction of enals, taking advantage of the high reactivity of vinyl sulfone-initiated nucleophilic addition of benzaldoxime, triazole, Angelica lactone, benzyl mercaptan, and 174. The powerful organocascade allows for the rapid construction of highly attractive synthons in high enantioselectivities (typically, 99% ee) [117]. 

In both cases, the metallotriazole can react with several electrophiles, leading to 1,4,5-triazoles in a regioselective manner. The mechanism proposed for these transformations involves a nucleophilic addition of the metal acetyhde, followed by ring closure to the metallotriazole. Preferential attack on the terminal rather than internal nitrogen of the azide explains the exclusive formation of the 4-metallo intermediate. 

Reaction of 6,7-dialkynyl-l,3-dimethylpteridine-2,4-(lH,3H)-diones 3.832 with sodium azide in DMF at room temperature produced [l,2,3]triazolo[l, 5, l,2]-pyrido[4,3-g ]-pteridine-8,10(9fi,llH)-diones 3.833 together with the isomers 3.834 (Scheme 3.107) [337]. The mechanism involves 1,3-dipolar cycloaddition of azide ion to the triple bond followed by intramolecular nucleophilic addition of the intermediate 1,2,3-triazole N-anion to the second triple bond. 

The triazole 76, which is more accurately portrayed as the nucleophilic carbene structure 76a, acts as a formyl anion equivalent by reaction with alkyl halides and subsequent reductive cleavage to give aldehydes as shown (75TL1889). The benzoin reaction may be considered as resulting in the net addition of a benzoyl anion to a benzaldehyde, and the chiral triazolium salt 77 has been reported to be an efficient asymmetric catalyst for this, giving the products (/ )-ArCH(OH)COAr, in up to 86% e.e. (96HCA1217). In the closely related intramolecular Stetter reaction e.e.s of up to 74% were obtained (96HCA1899). 

The same research group has shown that the 5-fluorophenyl-l,2,4-oxadiazoles 73 (Scheme 6) form the triazoles 74 as the major products in the presence of amine nucleophiles, together with varying amounts of side products 75-77, with product 76, for example, being formed by the competitive addition of the methanol solvent to the N-O-cleaved photolytic product <2005H(65)387>. The formation of quinazolin-4-ones 75 has been studied separately, and has been optimized to allow good yields as shown by the example in Equation (6) <1999JOC7028>. 

Unlike the 3-position, the 5-position is very susceptible to nucleophilic substitutions and additions. Thus, a series of publications report that 5-fluoroalkyl-l,2,4-oxadiazoles 94 undergo reaction with hydrazine or hydroxylamine to furnish 3-fluoroalkyl-l,2,4-triazoles 95 (X = NH) and 3-fluoroalkyl-1,2,4-oxadiazoles 95 (X = 0), a reaction that proceeds via addition of the nitrogen nucleophile to the 5-position (Scheme 9) <2005JOC3288, 2004EJ0974, 2003JOC605>. 

The aroyl-substituted heterocyclic ketene aminals 482 react with 4-chlorophenyl azide to give polysubstituted 1,2,3-triazoles 483 and imidazo[ 1. Z-r 1.2,4]triazoles 39 (Equation 112) <2000HAC387>. Polysubstituted 1,2,4-triazoles are formed by the nucleophilic attack of the ct-carbon of the azide. Then, through the cyclocondensation and aromatization sequences, the fused heterocycles resulted by a 1,3-dipolar addition at first, and then through a Dimroth rearrangement and deamination of chloroaniline <1992JOC184>. 

In the 1,2,4-triazole series, base-induced degenerate rearrangements have been reported with the aroylarylazo-l,2,4-triazolium salts 185 (87MI3) (Scheme IV.72). The reaction product is 3-aroyl-l-aryl-1,2,4-triazole 187, and its formation can be described as involving an ANRORC mechanism, initiated by an addition of the nucleophile at C-5, ring opening into 186, and subsequent heterocyclization with the former CNN side chain of the rearranging 1,2,4-triazole. 

The base-catalyzed condensation of azides with activated methylene compounds is a well-established route to IJT-triazoles. In particular, it is the best route to triazoles bearing a 5-amino or hydroxy substituent and an aryl or carbonyl-containing function in the 4-position. The addition is regiospecific. The reaction is a stepwise one, since anomerism of glycosyl azides has been observed in their reaction with activated methylene compounds, indicating the presence of an intermediate. The mechanism can be envisaged as a nucleophilic attack by the car-banion on the terminal nitrogen of the azide, followed by cyclization to a... 

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