Tetrasubstituted amine derivatives

An effective process for generating tetrasubstituted amine derivatives is through the use of selective, intermolecular tertiary C-H bond amination using limiting amounts of 2,6-difluorophenyl sulfamate as source of nitrogen, [Rh2(esp)2] (esp = a,a,a, a -tetramethyl-l,3-benzenedipropionate) as the catalyst, PhMe2CC02H as additive and PhI(OAc)2 as the oxidant in i-PrOAc. The inclusion of both MgO and 5 A molecular sieves further improves catalyst TONs. Competition studies with substrates possessing disparate C-H bond types reveal variations in product selectivity, which derive solely from the choice of sulfamate ester. 

Treatment of tantalum-alkyne complexes, prepared in situ from TaCls, Zn and RC=CR (R = n-C5Hn), with the lithio-imine Li N=CR Me (R = n-CgHn), followed by aqueous NaOH, gives primary ( )-allylic amines E-RCH=CR-CR Me(NH2). Treatment of these complexes with the terminal alkyne R"C=CH (R" = n-CeHis), followed by aqueous NaOH, yields tetrasubstituted benzene derivatives (99a-d). ... 

The reaction of amide chlorides with primary and secondary amines or amine derivatives yields amid-inium salts (134 Scheme IS). - In the course of the reactions HCl is produced, which converts the amino compound to its hydrochloride. The salt mixtures thus formed are difficult to separate. Provided the amidinium compound in the mixture is at most an N,A, -trisubstituted one, separation can be achieved via the free amidine, which, after separation, is easily converted to the desired amidinium salt (135) by acidification with water-free acids. From salt mixtures containing iV.. A -tetrasubstituted amidinium salts, the pure amidinium compound, e.g. (136) can sometimes be isolated via anion exchange by addition of HCIO4, NaC104 or Nal (in acetone/acetonitrile). 

R. Bossio and co-workers developed a novel method for the synthesis of tetrasubstituted furan derivatives. The Passerini reaction between arylglyoxals, isocyanides, and cyanoacetic acids led to the formation of A/-substituted 3-aryl-2-cyanoacetoxy-3-oxopropionamides, which in the presence of amine bases underwent a Knoevenagei condensation providing A/-substituted 3-aryl-cyano-2,5-dihydro-5-oxofuran-2-carboxamides. 

Carbonylation of the tetrasubstituted bispropargyiic amine 23 using PdCP and thiourea under mild conditions affords the carboxylated pyrrolidine derivatives 24a and b in good yields. Thiourea is regarded as effective for the oxidative carbonylation of alkynes, but no oxidative carbonylation was observed in this case[21]. 

Hydrolysis. Hydrolysis of zirconacyclopentadienes (103) with inorganic acid see Acids Acidity) provides, in a stereocontrolled manner, 1,2,3,4-tetrasubstituted dienes. Protonolysis with weak organic acids such as ethanol gives monoprotonated dienylzirconocene, which can be reacted with electrophiles to yield pentasubstituted diene derivative (Scheme 31). In the same way, p,y unsaturated amines are obtained by cleavage of Zr-C and Zr-N bonds of azazirconacycles. 

The reaction of amines with 1,2-diketo substrates led to a variety of substituted imidazole derivatives. Treatment of various substituted anilines 88 with glyoxals 89 gave the imine intermediate 90, which was then cyclized to the 1-arylimidazoles 91 with paraformaldehyde and ammonium chloride under acidic conditions <0382661>. A one-pot, three-component condensation of benzil 92, benzonitrile derivatives and primary amines on the surface of silica gel under solvent-free conditions and microwave irradiation provided tetrasubstituted imidazoles 93<03TL1709>. 

Tetrasubstituted imidazoles (xxviii) were also obtained in high yields by a one-pot, three-component condensation of benzyl, benzonitrile derivatives and 1° amines on the surface of silica gel under solvent free microwave condition [2]. 

Enol Amination. The Cu[(S,5)-t-Bu-box] (OTf)2 complex was found to be optimal for promoting the enantioselective conjugated addition of enolsilanes to azodicarboxylate derivatives (eq 13). This methodology provides an enantioselective catalytic route to differentially protected ot-hydrazino carbonyl compounds. Isomerically pure enolsilanes of aryl ketones, acylpyrroles, and thioesters add to the azo-imide in greater than 95% ee. The use of an alcohol additive was critical to achieve catalyst turnover. Amination of cyclic enolsilanes was also possible. For example, the enolsilane of 2-methylindanone provides the adduct containing a tetrasubstituted stereogenic center in 96% ee and high yield. Acyclic (Z)-enolsilanes react in the presence of a protic additive with enantioselection up to 99%. ... 

One of the classical methods for the synthesis of pyrazines involves dimerization of an a-amino carbonyl compound and subsequent aromatization. Oximes have often been used as the latent functionality to generate the amine by a variety of reductive processes. 3-Oxo-2-oximinobutanoic esters or the amides (146), which are formed by nitrosation of acetoacetic acid derivatives, are reduced by catalytic hydrogenation <82CPB3424, 91JHC1731> or titanium(III)-induced reduction <88H(27)il23> to give the tetrasubstituted pyrazines (147) (Equation (17)). 

Modification of the products that resulted from the aza-annulation of tetrasubstituted enamine substrates with acrylate derivatives was very limited. The aza-annulation of benzyl ester 496 with the mixed anhydride, a mixture (497) preformed from EtC CCl and sodium acrylate, provided a route to 498 in >98 2 diastereoselectivity (eq. 100), which allowed access to the carboxylic acid derivative 499 through catalytic hydrogenation.1 Further elaboration of either the ester or the acid derivative was unsuccessful, possibly due to the steric congestion around the reactive functionality. Extended hydrogenation did not reduce the enamine functionality, as observed in related substrates, and 498 was relatively stable to acidic hydrolysis conditions. In addition, DCC (N,N -dicyclohexylcarbodiimide) coupling of acid 499 with either benzyl amine or glycine ethyl ester was unsuccessful. 

Tetrasubstituted imidazoles have been prepared in high yield by one-pot three-component condensation of benzil, benzonitrile derivatives, and primary amines adsorbed on silica gel without solvent (Scheme 10.87) [169]. Under irradiation conditions yields range from 58 to 92% (8 min). 

Tetrasubstituted imidazoles 32 can also be synthesized by a three-component condensation [55]. These reactions are usually limited and cannot be performed under neutral conditions [70]. With use of MW irradiation, however, the reaction becomes possible. The procedure requires benzonitrUe derivatives, benzU, and primary amines on the surface of silica gel to obtain the tetrasubstituted imidazoles 32 in moderate to good yields (58-92%, Scheme 17.23). 

Mercapto pyrimidines 82 were synthesized from acetoacetanilide, dihydroxybenzaldehyde, and thiourea, which were readily alkylated with benzyl chloride to afford 2-benzylthio derivatives 83 (Scheme 32). 83 when reacted with different amines in acetic acid furnished 2-amino derivatives 84 (R = Ar), whereas upon reaction with hydrazine hydrate 83 afforded 2-hydrazinyl derivative 84 (R = NH2), which with different aldehydes gave hydrazones 85 (R = 2-furyl, 2-thienyl). Arylidene thiazolidinone 86 was obtained from 84 with carbon disulfide, monochloroacetic acid, and aryl aldehydes, while 84 with ethyl acetoacetate and different aromatic aldehydes provided pyrazoles 87 (Scheme 32) (10MI9). Such tetrasubstituted pyrimidines act as cyclin-dependent kinase (CDK2) inhibitors. 

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