Formamides, cycloaddition with

Preparation of the requisite Tosyl formamide 2 using the procedure of Sisko 4, 5) occurred in good yield. Dehydration of 2 with POCI3 provided the TOSMIC reagent 3 which underwent 1,3 dipolar cycloaddition with methyl imine 4 to provide imidazole 5. However, this procedure proved problematic on larger scale. The reactions turned very dark and formed several unidentified byproducts. Fortunately, the resulting mixture could be purified by silica gel chromatography to provide the desired trisubstituted imidazole in 60% yield. The installation of the piperidine substituent in the 2-position was effected in a... 

This synthesis involves Michael cycloaddition reaction of the readily available 4-hydroxycoumarine 1 with a cyanocrotonitrile 2 in ethanolic piperidine to afforded 2-amino-3-cyano-4-methyl-4H, 5H-pyrano-benzopyran-5-one (3). Treatment of 3 with acetic anhydride for 0.5 h and/or 3 h under reflux afforded N-acetyl and [l]benzopyrano[3/,4/ 5,6]pyrano(2,3-d) pyrimidine-6,8-dione derivatives (4) and (5a), respectively. Also, interaction of 3 with benzoyl chloride or formic acid gave the corresponding pyrimidine derivatives (5b,c) while its treatment with formamide afforded the aminopyrimi-dine derivative (6). 

While cycloaddition approaches have been discussed extensively in this chapter, there are certain substitution patterns that are not amendable to such approaches. In these cases, the more traditional annelative approaches are necessary. For example, the 5,6-dihydropyrrolo[3,4-rf]imidazol-4(3//)-one (286) is obtained from the diamine (285) and triethyl orthoformate. If formamide is used in excess, 6-(formamidomethylene)-5,6-dihydropyrrolo[3,4-d]imidazol-4(3//)-one (287) is obtained (Scheme 53) <70JPS1732>. A variant of the Thorpe cyclization was employed in the preparation of 3-amino-4//-pyrrolo[3,4-c]isoxazoles (289) from a-cyanooximes (288) (Equation (66)) <68JMC453>. 3-Acyltetramic acid (290 X = NR2) and 3-acyltetronic acid (292 X = O) hydrazones undergo ready cyclization in refluxing xylene with catalytic p-toluenesulfonic acid to afford 4-oxo-l,4-dihydro-6/f-pyrrolo[3,4-c]pyrazoles (291) and 4-oxo-l,4-dihydro-6//-furo[3,4-c]pyrazoles (293), respectively (Equation (67)) <82SC43l>. The novel synthesis of 5-amino-6a-hydroxydihydro-6//-pyrrolo[2,3-j]isoxazole (296) from 3,4-disubstituted 4-(amino)isoxazol-(4//)-ones (294) is hypothesized to occur by the cyclization of the ketene aminal intermediates (295) (Scheme 54) <91S127>. 

Similarly, pteridine-6-carbaldehyde 2a after conversion to the oxime 3 can be transformed to the corresponding nitrile oxide with (V-chlorosuccinimide in dimethyl formamide, followed by treatment with friethylamine in the presence of a dipolarophile, to give good yields of cycloaddition products 4.254 These adducts are hydrolyzed to the 2-amino compounds by heating to 70-80°C with 1 M hydrochloric acid in dioxane. 

Disubstituted-2-methyl-1,2,3-triazinium iodides 114a-c are demethylated to the triazines 17m,s,u by reaction with formamide and diammonium persulfate (Equation 92) < 1991H(32)2015>. This special case has already been mentioned in Section 9.01.5.6 together with the removal of 2-dicyanomethylene groups from the 1,2,3-triazinium dicyanomethylides 34 (R = H R, R = Me, Et, Ph) under the same conditions see also <1996CHEC-11(6)483>. Cycloadditions of 2-ethyl-1,2,3-triazinium tetrafluoroborates and 1,2,3-triazinium 2-dicyanomethylides have been treated in Section 9.01.5.7. 

Oxazole itself participates as a dienophile in a Diels-Alder reaction with the electron-dehcient 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine 94 to give A-[3,6-bis-(trifluoromethyl)-pyridazin-4-yl]formamide 96 in 80% yield after 55 h in refluxing toluene (Fig. 3.25). The reaction is postulated to proceed via initial cycloaddition followed by loss of nitrogen to give 95. Ring-opening aromatization of 95 then gave 96. 

Scheme 14.67 Ni-catalysed dehydrogenative cycloaddition formamides with allgrnes.

A nickel-catalysed [4-1-2] cycloaddition of formamides with allgmes through double C-H activation as shown in Scheme 14.67 was also carried out in the presence of AlMes, forming dihydropyridones along with a,p-unsaturated amides as side products. The side products were formed via insertion of alkynes into the C(0)-H bond. Use of PtBus as a ligand is crucial for the success of the reaction. If an unsymmetrical internal all ne is used, a mixture of regioisomers of dihydropyridones was obtained. ... 

In an extension of this approach, Hiyama, Nakao et al. demonstrated that N,N-bis(l-arylalkyl)formamides 203 underwent a previously unprecedented dehydroge-native [4 + 2] cycloaddition reaction with alkynes 204 using a nickel catalyst/AlMe3 Lewis acid combination in a double functionalization of C(sp )—H and C(sp )—H... 

SCHEME 5.39 Nickel-catalyzed dehydrogenative [4 -I- 2] cycloaddition of formamides with alkynes. 

Nickel-Catalyzed Dehydrogenative [4 + 2] Cycloaddition of Formamides with Alkynes... 

The dehydrogenative [4 + 2] cycloaddition of formamides with alkynes described by Hiyama, Nakao et al., and summarized in Section 5.6, as well as representing an example of C(sp )—H activation, also represents an example of C(sp )—H activation alkyl-alkenyl bond formation." " ... 

Very little information is available about the effect of ultraviolet radiation on polymers containing double bonds. However, the double bonds of polymer [80] isomerize to the all-trans configuration on irradiation (2). Dimethyl-formamide solutions of polymer [81] and of polymers with similar structures gelled upon irradiation with a low-pressure mercury lamp (50). The cross-linking was postulated to be due to cycloaddition of the double bonds forming cyclobutane rings. 

Nickel-catalyzed [4 + 2] cycloaddition using C—H bond activation was also developed by Nakao et al. (Scheme 12.27) [31], Formamide 66 reacted with 4-octyne in the presence of nickel catalyst gave substituted dihydropyridone 67 in good yield. Shiota et al. reported that chelation-assisted C—H bond activation enables [4 + 2] cycloaddition of amide 68 with alkynes to provide isoquinolone (Scheme 12.28) [32]. The key azanickelacycle intermediate 69 was generated in situ via N—H bond and C—H bond activation with chelation assistance by a 2-pyridinylmethylamine moiety. 

---