Cyanation reactions, heterocyclic

There are many other examples in the literature where sealed-vessel microwave conditions have been employed to heat water as a reaction solvent well above its boiling point. Examples include transition metal catalyzed transformations such as Suzuki [43], Heck [44], Sonogashira [45], and Stille [46] cross-coupling reactions, in addition to cyanation reactions [47], phenylations [48], heterocycle formation [49], and even solid-phase organic syntheses [50] (see Chapters 6 and 7 for details). In many of these studies, reaction temperatures lower than those normally considered near-critical (Table 4.2) have been employed (100-150 °C). This is due in part to the fact that with single-mode microwave reactors (see Section 3.5) 200-220 °C is the current limit to which water can be safely heated under pressure since these instruments generally have a 20 bar pressure limit. For generating truly near-critical conditions around 280 °C, special microwave reactors able to withstand pressures of up to 80 bar have to be utilized (see Section 3.4.4). 

The reaction of alkyl quaternary salts of pyridine and its benzo analogues with cyanide ion and subsequent loss of the alkyl substituent is known as the Reissert-Kaufmann reaction (Scheme 112). It is not of as much importance for heterocyclic cyanations or alkylations as the other reactions described in this section, chiefly because the N- substituent is such a poor leaving group. 

The iron-catalyzed [3 + 2]-cycloaddition (Huisgen reaction) of nitriles and carbonyl compounds as reported by Itoh et al. is one of the rare examples reported where an iron reagent can be utilized for the synthesis of 1,2,4-oxadiazoles (Scheme 9.35) [93]. In this reaction, methyl ketones are nitrated at the a-position by Fe(N03)3 to generate an a-nitro ketone. This intermediate rearranges to an acyl cyanate, which reacts further with the nitrile to give the heterocyclic product 48 in good to excellent yields (R1 = Ph, R2 = CH3 95% yield). 

Strecker reactions are among the most efficient methods of synthesis of a-amino nitriles, useful intermediates in the synthesis of amino acids [73] and nitrogen-containing heterocycles such as thiadiazoles, imidazoles, etc. [74]. Although classical Strecker reactions have some limitations, use of trimethylsilyl cyanide (TMSCN) as a source of cyano anion provides promising and safer routes to these compounds [73b,75]. TMSCN is, however, readily hydrolyzed in the presence of water, and it is necessary to perform the reactions under strictly anhydrous conditions. BusSnCN [76], on the other hand, is stable in water and a potential source of cyano anion, and it has been found that Strecker-type reactions of aldehydes, amines, and BuaSnCN proceed smoothly in the presence of a catalytic amoimt of Sc(OTf)3 in water [77]. No surfactant was needed in this reaction. The reaction was assumed to proceed via imine formation and successive cyanation (it was confirmed that imine formation was much faster than cyanohydrin ether formation under these reaction conditions) again the dehydration process (imine formation) proceeded smoothly in water. 

Other reactions such as the anodic cyanation or alkoxylation of electron-rich heterocycles such as pyrroles and indoles [85] or of electron-donating substituted azines [86] are important, but are not discussed in detail here, because this subject is well covered in electrochemistry textbooks. 

Thiourea (98) was first prepared in 1870 by heating ammonium thiocyanate (99) (Scheme 54). The reaction is analogous to the historic preparation of urea (Wohler, 1828) which involved heating ammonium cyanate. Thioureas generally are stable crystalline solids which are useful in the synthesis of heterocyclic compounds. Symmetrical thioureas (100) may be obtained by the action of amines on carbon disulfide, and the procedure can be extended to the synthesis of cyclic thioureas (101) (Scheme 55). The reaction occurs via the intermediate (102) which on subsequent treatment with either ammonia or an amine yields the corresponding... 

The yields of isolated products varied from 45 to 95%. It is not totally proven whether an iminium ion is involved in the formation of 7-morpholinobicyclo[4.1. OJheptane 14. All primarily formed compounds were shown to be ent/o-morpholino isomers. Some derivatives isomerized to the corresponding ejfo-isomers on heating with acidic catalysts. Starting from 13 pure endo-and exo-morpholino compounds could be obtained in the case of the azide 14f and aminal 14k with benzotetrazole as the heterocycle. Reaction of potassium cyanate with 13 gave a trimer of 14e at ambient temperature or the exo-morphohno diastereomer of 14e at higher temperature. ... 

The reaction has been shown to be of very broad scope with a multitude of nucleophiles Nu such as imides.23,24,29,32,33,36,37,42 amines,10,32 cyanide,25,32 hydroxide,10,32 alkox-ide,10,26,32 electron-rich isocyclic or heterocyclic aromatic compounds,28 carboxamides,31 lactams,31 ureas,31 sulfonamides,31 cyanate,31 formate (to give products with Nu = H),34 C-H acidic compounds,35 hydrazines and hydrazides,38 and sulfinates.38 The amino group NR R2 of cyclopropane-1,1-diamines and the nucleophile Nu in bicycles 8, 9 or 12, respectively, can be easily replaced with other nucleophiles Nu, such as water,10,32,33 alkoxide,10,32-34,42 Grignard compounds,27,42 amines,29,30,36,37,42,43 cyanide,29,33,42,44 hydride,34,42,44 and C-H acidic compounds39-41,43,44 (see Section 5.2.1.). Therefore, it is currently the most important method for the preparation of substituted bicyclic cyclopropylamines. The toxic and costly reagent methyl fluorosulfate can be avoided in a modified synthetic route, which instead of the fluorosulfate 5 proceeds via the corresponding tetraphenylborate, hexafluorophosphate, or (most conveniently) via the tosylate.23 The different steps of the method can often be combined in a one-pot procedure. Results are summarized in Table 3. 

Benzimidazol-2-amine reacts with cyanates to give selectively the 2-aminobenzimidazole-l-carboximidic esters l.56 2-Guanidinobenzimidazole 4 is prepared by reaction of ammonia with AT-cyanobenzimidazol-2-amine. Compounds 1 and 4 react with JV-sulfinylarenesulfonainides to give the corresponding unstable /V-sulfinyl derivatives 2 and 5 of the heterocyclic bases.34,31... 

Construction of the simplest fused heterocyclic system that shows some anabolic activity starts by epoxidation of the olefin at C2 in 23-1 with peracetic acid buffered with sodium acetate (23-2) (Scheme 5.23). Reaction of this intermediate with potassium thiocyanate and phosphoric acid, essentially thiocyanic acid, leads to diaxial opening of the oxirane to form the 3a-hydroxy-2/8-cyanate 23-3. Treatment of the product with base leads to formation of the /3-thioepoxide 23-5. Formation of that product can be rationalized by assuming that the first step involves removal by base of a proton on the hydroxyl group. That alkoxide then proceeds to add to the cyano group at C2 to form a transient five-membered ring as in... 

In 2010, Wan and coworkers disclosed direct cyanation of the tautomeriz-able heterocycle using BOP in the presence of DBU in MeCN.The addition of 18-crown-6 facilitated the coupling reaction and produced the product in moderate yield (07JOC10194). 

The reaction was not only limited to cyanation, but other Pd-catalyzed reactions such as Heck and Suzuki couplings were also used as the termination step to afford a variety of functionahzed carbo- and heterocycles 30 via the C-H activation/Pd migration pathway (Scheme 3.7a). Under these conditions, isochroman 25 was obtained as a single regioisomer [11] by the aforementioned intermolecular C-H activation of heterocycle as the termination step (Scheme 3.7b). 

Triazine and Other Heterocyclic Ring Formation. Several types of reactions can be used to form heterocyclic rings in which multiple C-N bonds contribute high thermal stability. When these are used to cross-link heat-stable oligomers, the resulting thermoset polymers may have high thermal stability and other useful properties. These include cyanate/cyanurate, isocyanate/isocyanurate, hexaazatriphenylene trianhydride, and phtha-lonitrile/phthalocyanine. 

A palladium-catalyzed domino reaction involving a C-H activation process to synthesize diverse carbo and heterocyclic skeletons was developed [10] (Scheme 8.10). H O was used to eontrol the regioselectivity as the cosolvent. The palladacyele intermediate was successfully trapped by cyanation, Heck reaction, secondary C-H activation, and Suzuki coupling. The regioselectivity was controlled by manipulating the leac-... 

Densely cross-linked PCN networks, synthesized by polymerization, via cy-clotrimerization reaction, of dicyanic ester of bisphenol A [159-161], consist of rigid triazine heterocycles as junctions connected with bisphenol A remainders (see a scheme in Fig. 26). At the total conversion of cyanate groups (Xcn pcn 1). PCN exhibits high Tg 300°C and rigidity, good adhesion to different substrates and chemical resistance, as well as low values of dielectric constant and water uptake. This allowed in particular its application as the matrix for glass- and aramid fiber-reinforced plastics in the electronics and aerospace industries. 

Attanasi, O. A., Bartoccini, S., Favi, G., Giorgi, G., Pemilli, F. R., and Santeusanio, S. (2012). Powerful approach to heterocyclic skeletal diversity by sequential three-component reaction of amines, isothio-cyanates, and l,2-diaza-l,3-dienes. J. Org. Chem., 77, 1161-1167. 

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