Tautomerizable heterocycles

Phosphonium coupling of tautomerizable heterocycles and nucleophiles using the OBt-derived reagents (PyBOP, BOP) is more complicated... 

In 2004-2005, the first phosphonium coupling of tautomerizable heterocycles and amines was reported to enable the direct amination reaction. 

In recent years, direct amination of tautomerizable heterocycles with amines via phosphonium coupling has been widely utilized in the synthesis of various heterocychc compounds used for chemical building blocks or medicinal chemistry. The reaction rate of the direct amination is usually dependent upon the electronic and steric nature of the amine nucleophiles. In principle, electron-richer and sterically less-hindered alkyl amines are much more reactive than aryl amines and nitrogen heterocycles (04AP702,05JOC1957). 

In 2005-2007, Wan and coworkers described the direct amination of a number of six- and five-membered tautomerizable heterocycles using BOP in the presence of DBU or DIPEA in MeCN or DMF (05OL5877, 06OL2425,07JOC10194). 

In 2007, Bae and coworkers synthesized a fully protected DNA building block, the 0 -(benzotriazol-l-yl)-2 -deoxyinosine 5 -0-DMT 3 -0-phosphoramidite, used for potential DNA modification, via stepwise BOP-mediated coupling of the tautomerizable heterocycle, and S Ar displacement with the amine nucleophile (07JACS782). 

In 2008, in the study of adenosine derivatives as Aj adenosine receptor agonists, Ashton and coworkers prepared the structurally modified adenosine via direct amination of the tautomerizable heterocycles using PyBroP in the presence of DIPEA in DCE giving the coupling product (08BMC1861). 

In 2011, in the synthesis of a new series of tricyclic pyrimidine compounds as histamine H4 receptor antagonists, Savall and coworkers first tried to convert the pyrimidinone compound to the chloropyrimidine compound for the subsequent S Ar displacement reaction. However, this attempted chlorination was not successful with a variety of chlorination reagents. Alternatively, they synthesized this target compound via direct amination of the tautomerizable heterocycle using BOP in the presence of DBU in DMF (11BMCL6577). 

In 2011, Adcock and coworkers developed diversity-oriented synthesis for several series of fused pyrimidine compounds used for biological evaluation studies against the Gram positive bacterium Nocardia farcittia and the parasite Trypanosoma brucei hrucei.The featured chemistry relied on the direct amination of the tautomerizable heterocycles using BOP in the presence of DBU in MeCN (11T3226). 

In 2012, Verkman and coworkers identified a new class of triazolo-thienopyrimidine compounds as potent and metabolically stable inhibitors of kidney urea transporter UT-B. They synthesized these compounds via direct amination of the tautomerizable heterocycle using PyBOP in the presence of DBU in MeCN under microwave condition at 100°C (12JASN1210,13BMCL3338,12JMC5942). 

In 2004-2005, we reported direct etherification of tautomerizable heterocycles with oxygen nucleophiles via phosphonium coupling to produce biaryl ethers or alkyl aryl ethers. Phenols are moderately strong nucleophiles, therefore the NaOi-Bu-promoted phosphonium coupling condition was found to be better than the Et3N-promoted condition (04AP702,05JOC1957). 

In 2007,Wan and coworkers prepared the diaryl ether via direct etherification of the tautomerizable heterocycle using BOP in the presence of DBU in MeCN (07JOCI0I94). 

In 2010, Kokatla and coworkers screened the reaction conditions for direct etherification of tautomerizable heterocycles using BOP in the presence of CS2CO3 in THE The optimal reaction condition led to the synthesis of many alkyl aryl ethers and diaryl ethers from various pyrimidines and nucleosides under mild conditions in high yields (10OL4478). 

In 2011, Fang and coworkers prepared a series of quinazolines as inhibitors of the Rho-associated coiled-coil containing protein kinase. As the key step in the medicinal chemistry, these compounds were conveniently synthesized via direct thioesterification of the tautomerizable heterocycles using BOP in the presence of DBU in DMF (11BMCL1844). 

In 2010, Radi and coworkers reported the synthesis of isozaleplon, which is a regioisomer of the therapeutic drug Zaleplon to treat insomnia. The synthesis of isozaleplon featured the key C-C bond formation via direct arylation of the tautomerizable heterocycle with the arylboronic ester using PyBroP in the presence of PdCl2(PPh3)2 catalyst (10H1359). 

In 2012, Sharma and coworkers reported the direct arylation of tautom-erizable heterocycles with azoles under microwave conditions. This Pd/Cu catalyzed dehydrative phosphonium coupling via C—OH and C—H bond activation elegandy produced the diheteroaryl compounds via direct arylation of the tautomerizable heterocycle with boronic acids using PyBroP in the presence of Pd(OAc)2 and Cul catalysts (120L1854). 

Interestingly, during their studies on the direct arylation via dehydrative phosphonium coupling, the authors also discovered some side products, the homocoupled symmetrical biheterocycles in about 10-15% yields resulted from the tautomerizable heterocycles. This type of symmetrical biheterocycles have important applications in photochemistry... 

In 2013, Neres and coworkers reported the synthesis, biochemical, and microbiological evaluation of a series of pyrazolopyridine derivatives as nonnucleoside inhibitors of BasE, an adenylating enzyme in the sidero-phore biosynthetic pathway of the opportunistic pathogen Acinetobacter hau-mannii. Dozens of analogs on the aryl-pyrazolopyridine series were synthesized via direct arylation of the tautomerizable heterocycle with... 

In 2010, Shi and coworkers reported direct alkynylation of tautomerizable heterocycles with alkynes using PyBroP in the presence of PdCl2(PPh3)2/ Cul at rt (Condition A) or PdCl2(MeCN)2/cyclohexyl JohnPhos (Condition B) catalysts. Condition A is suitable for substrates with sensitive functional groups and Condition B is applicable to a wider range of substrates (10OL2286). 

---