Pyridine reaction with isocyanides

In studying the reactivity of iV-fluoropyridinium fluoride 127 obtained from pyridine 126 by treatment with fluorine gas in chloroform at low temperature (Scheme 30), Kiselyov studied reactions with isocyanides in the presence of trimethylsilylazide <2005TL4851>. A mixture of products was obtained in which, besides tetrazolylpyr-idine 128 and a nicotinamide derivative 129 also tetrazolo[l,5-tf]pyridine 1 was obtained in very poor yield (5-10%). 

Mono- and dilithio derivatives of p-tosylmethyl isocyanide 297a were shown to display interesting reactions. Reaction of the monoanion with unsaturated esters was shown to give pyrrole derivatives . Dianion 297b was found to add to the carbon-nitrogen double bonds of isoquinoline, quinoline and quinoxaline affording compounds 298, 299 and 300, respectively. In the reactions with pyridine iV-oxide and pyridazine iV-oxide, unstable open-chain products 301 and 302 were obtained . 

These methylene-bridged complexes III are extremely robust, air-stable substances. We have sought without success to effect insertions into the Pd-C bonds. The complexes are unreactive toward carbon monoxide (at 5 atm at 30°C) or sulfur dioxide. Reaction with methyl isocyanide or pyridine results in displacement of the terminal halide ions and produces cations that have been isolated as hexa-fluorophosphate salts [Pd2(dpm)2( -CH2)(CNCH3)2][PF6]2( (CN) = 2217 cm-1) and [Pd2(dpm)2(/Lt-CH2)(py)2][PF6]2. Treatment of III with fluoroboric or trifluoroacetic acid slowly results in the protonation of the methylene group which is converted into a terminal methyl group. The resulting brown complex, which has been isolated as its tetra-fluoroborate salt has been shown by H-l and P-31 NMR spectroscopy and X-ray crystallography to have Structure IV. 

This reaction appears to be similar to the imidazo-pyridine formation mentioned above, most likely via a [5+1] insertion reaction of the isocyanide into the corresponding hydrazone. This reaction mechanism seems likely since only electron-rich aromatic hydrazines yielded cinnolines. The Ugi 4-CR reaction with phe-nylhydrazine is known and has been reported to give the expected Ugi-type 4-CR product. 

Almost accidentally, Bienayme and Bouzid discovered that heterocyclic amidines 9-76 as 2-amino-pyridines and 2-amino-pyrimidines can participate in an acid-catalyzed three-component reaction with aldehydes and isocyanides, providing 3-amino-imidazo[l,2-a]pyridines as well as the corresponding pyrimidines and related compounds 9-78 (Scheme 9.15) [55]. In this reaction, electron-rich or -poor (hetero)aromatic and even sterically hindered aliphatic aldehydes can be used with good results. A reasonable rationale for the formation of 9-78 involves a non-con-certed [4+1] cycloaddition between the isocyanide and the intermediate iminium ion 9-77, followed by a [1,3] hydride shift. 

A suspension of polymeric cupric dimethoxide in pyridine reacts with CO2 to yield the cupric methyl carbonate. The CO2 moiety is, however, very labile the insertion could be reversed by heating the reaction mixture at 80" under a stream of nitrogen [SO]. Another reversible carbon dioxide carrier was found in copper(I) rerr-butoxide, which was stabilized by rerr-butyl isocyanide. The rerr-butyl carbonato complex was formed during the reaction with CO2 [811. Carbon dioxide also reacts with ROCu(PPh3)2 0 produce (ROCOj)Cu(PPhj>3, Hydrolysis or thermolysis of these alkylcarbonato complexes gives the binuctear carbonato copper (I) complex (PPhj>2 CuCK Oj Cu(PPhj)2, which can be further convened into the bicarbonate complex f(HC)C02)Cu(PPh3)3] by reaction with CO2 in moist solvents [82],... 

Alternative reaction pathways exploring different synthetic possibilities have been studied. For instance, electron-rich dihydroazines also react with isocyanides in the presence of an electrophile, generating reactive iminium species that can then be trapped by the isocyanide. In this case, coordination of the electrophile with the isocyanide must be kinetically bypassed or reversible, to enable productive processes. Examples of this chemistry include the hydro-, halo- and seleno-carba-moylation of the DHPs 270, as well as analogous reactions of cyclic enol ethers (Scheme 42a) [223, 224]. p-Toluenesulfonic acid (as proton source), bromine and phenylselenyl chloride have reacted as electrophilic inputs, with DHPs and isocyanides to prepare the corresponding a-carbamoyl-(3-substituted tetrahydro-pyridines 272-274 (Scheme 42b). Wanner has recently, implemented a related and useful process that exploits M-silyl DHPs (275) to promote interesting MCRs. These substrates are reacted with a carboxylic acid and an isocyanide in an Ugi-Reissert-type reaction, that forms the polysubstituted tetrahydropyridines 276 with good diasteroselectivity (Scheme 42c) [225]. The mechanism involves initial protiodesilylation to form the dihydropyridinum salt S, which is then attacked by the isocyanide, en route to the final adducts. 

Mono-axially coordinated species are most conveniently formed by the reaction of single face-hindered Fe(II) porphyrins with isocyanide in a non-coordinating solvent, such as toluene or benzene,or when four-coordinate PFe are reacted under an inert atmosphere with nitrogen bases, such as imidazoles and pyridines in the presence of isocyanide This... 

Scheme 33 Reaction of pyridine W-oxides with isocyanides.

Pyridine iV-oxides can be aminated with isocyanides (Scheme 33). The reaction proceeds through an N-formylaminopyridine intermediate that can be isolated or hydrolyzed with acid to provide the aminopyridines.The reaction works with a number of substituted pyridines however, with electron-withdrawing groups the yields are lower. With C-3 substituted pyridine iV-oxides, a mixture of regioisomers was produced. The C-2 product predominated with aryl isocyanides. Steric hindrance did appear to impact the yield for both aryl and aliphatic isocyanides. Finally, isoquinoline AT-oxide reacted under these conditions to form the aminoisoquinoline in good yield (60%). If both the two and six positions were blocked, the reaction failed to proceed (14JOC2274). 

An intramolecular pericyclization reaction provides either di- or trisub-stituted pyridines in good yields (Scheme 14) (13EJ02537). Arynes were generated from 2-(trimethylsilyl)phenyltriflate and combined with isocyanides and 3-bromopropyne in one-pot. CsF was the best source of fluoride to provide the benzyne, but yields of the pyridine were low imtil CSCO3 was added. The rate of benzyne formation was modulated with a cosolvent of MeCN and toluene and the ratio of precursors was tweaked. With the optimized conditions, the reaction was shown to be fairly robust in the face... 

Imidazo[l,2-(j]pyridines can be prepared from a multicomponent reaction of alcohols, 2-aminopyridines, and isocyanides (Scheme 53) (13TL95). The alcohols are oxidized by DMSO and propylphosphonic anhydride, which also catalyzes the nucleophilic addition with isocyanides. Aromatic alcohols with electron-donating and electron-withdrawing groups can provide the desired... 

Amides can be readily added to the 2-position of the title compound. One account describes a direct dehydrative process, whereby the pyridine iV-oxide is activated by triflic anhydride (eq 34). The role of a base additive was determined to be key with 2-fluoropyridine, proving to be optimal. Also noteworthy is the application of a similar means of triflate activation in the addition of amine nucleophiles. A separate account describes the amidation of the title compound via reaction with activated isocyanides. The reaction requires the presence of TMSOTf, which, under these conditions, furnishes the corresponding amine directly (eq 35). 

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