Pyrazine irradiation

Microwave and fluorous technologies have been combined in the solution phase parallel synthesis of 3-aminoimidazo[l,2-a]pyridines and -pyrazines [63]. The three-component condensation of a perfluorooctane-sulfonyl (Rfs = CgFiy) substituted benzaldehyde by microwave irradiation in a single-mode instrument at 150 °C for 10 min in CH2CI2 - MeOH in the presence of Sc(OTf)3 gave the imidazo-annulated heterocycles that could be purified by fluorous solid phase extraction (Scheme 9). Subsequent Pd-catalyzed cross-coupling reactions of the fluorous sulfonates with arylboronic acids or thiols gave biaryls or aryl sulfides, respectively, albeit it in relatively low yields. 

Chemoselective cyanation in the C-3 position of 3,5-dichloro-N-(4-methoxybenzyl)-pyrazin-2(lH)-one has been described by Van der Eycken et al. [27]. The procedure is similar to that reported by Alterman and Hallberg. The only difference is that CuCN was selected as transmetal-lating agent instead of Zn(CN)2. When a mixture of 3,5-dichloro-N-(4-methoxybenzyl)-pyrazin-2(lH)-one and CuCN in DMF, using Pd(PPh3)4 as a catalyst, was irradiated for 15 min at 200 °C, the desired 5-chloro-3-cyano-N-(4-methoxybenzyl)pyrazin-2(lff)-one could be isolated with a 68% yield (Scheme 69). 

In another paper, the same authors investigated the 1,3-dipolar cycloaddition on 2-(lH)-pyrazine scaffolds 72 and electron-rich azides, using Cu(0) and CUSO4 as pre-catalysts. To demonstrate the versatility of this approach, they reported the generation of different templates (73 in Scheme 25) as an application of cUck chemistry . They also investigated the Diels-Alder reaction of the so obtained triazoles with dimethyl acetylenedicarboxylate (DMAD), under microwave irradiation. The latter reaction allowed obtaining various pyridinones in good yields (74 and 75 in Scheme 25) [57]. 

Quinoxalines have been prepared starting from common 1,2-diketones and 1,2-aryldiamines in MeOH/AcOH at 160 °C for 5 min under microwave irradiation (Scheme 81). Several differently substituted quinoxalines 223 and pyrido[2,3-b]pyrazines were prepared with this method, which Umitation may be the symmetry of the diketone 221 or the diamine 222 employed, in order to avoid the formation of a mixture of regioisomers [142],... 

Maldotti (96) studied the kinetics of the formation of the pyrazine-bridged Fe(II) porphyrin shish-kebab polymer by means of flash kinetic experiments. Upon irradiation of a deaerated alkaline water/ethanol solution of Fe(III) protoporphyrin IX and pyrazine with a short intense flash of light, the 2 1 Fe(II) porphyrin (pyrazine)2 complex is formed, but it immediately polymerizes with second-order kinetics. This can be monitored in the UV-Vis absorption spectrum, with the disappearance of a band at 550 nm together with the emergence of a new band due to the polymer at 800 nm. The process is accelerated by the addition of LiCl, which augments hydrophobic interactions, and is diminished by the presence of a surfactant. A shish-kebab polymer is also formed upon photoreduction of Fe(III) porphyrins in presence of piperazine or 4,4 -bipyridine ligands (97). 

E.s.r. showed that, X. ray irradiation of tetraalkyldiphosphine diphosphides gave phosphoranyl radicals with t.b.p. structures (39).114 A structure has been assigned to phosphiny1hydrazy1s (40). The dimethy1 ami no radical was particularly persistent.115 The e.s.r. parameters of the electrogenerated pyrazine radical cations (41) have been recorded.116 The spectra of a stable furanyl phosphate radical adduct117 and a phenalene radical anion which involves injection of spin density into half an attached cyclophosphazene ring,11 are reported. 

Ring transposition processes are well established in six-membered heteroaromatic systems. Recent studies have centered on perfluoro systems in which bicyclic and tricyclic intermediates are sufficiently stable to permit isolation or at least detection. Thus, on irradiation in CF2C1CFC12, the perfluoropyridine 207 is converted into the azabicyclo[2.2.0]hexa-2,5-diene 208 and the two azaprismanes 209 and 210.154 An azabicyclo[2.2.0]hexa-2,5-diene has also been shown to be an intermediate in the photorearrangement of substituted 2-methylpyridines to o-substituted anilines.155 Diaza-bicyclo[2.2.0]hexa-2,5-dienes have similarly been shown to be intermediates in the conversion of fluorinated pyridazines (211) into the corresponding pyrazines (212)156 the proposed pathway is outlined in Scheme 7. Photoproducts which are formally dimers of intermediate azetes have been obtained when analogous reactions are carried out in a flow system.157... 

Analogous photoadditions have been observed on irradiation of pyrimidine and purine bases in ethers and amines. Irradiation of 1,3-dimethylur-acil (314) in tetrahydrofuran leads to the formation of 5- and 6-(tetrahydro-furan-2-yl)-5,6-dihydrouracils 315 and 316.261 Similarly, solvent adducts arising by way of initial hydrogen abstraction have been obtained on irradiation of pyrazine derivatives in diethyl ether or tetrahydrofuran.262 The... 

The diazines pyridazine, pyrimidine, pyrazine, and their benzo derivatives cinnoline, phthalazine, quinazoline, quinoxaline, and phenazine once again played a central role in many investigations. Progress was made on the syntheses and reactions of these heterocycles, and their use as intermediates toward broader goals. Some studies relied on solid-phase, microwave irradiation, or metal-assisted synthetic approaches, while others focused attention more on the X-ray, computational, spectroscopic, and natural product and other biological aspects of these heterocycles. Reports with a common flavor have been grouped together whenever possible. 

A rapid one-pot synthesis of imidazo-[l,2-a]-pyridines, pyrazines and pyrimidines was described in 1999 by Varma et al. [50], who used recyclable montmorillonite clay Kio under solvent-free conditions and microwave irradiation (Scheme 8.32). 

Alternatively, arene displacement can also be photo- rather than thermally-induced. In this respect, we studied the photoactivation of the dinuclear ruthenium-arene complex [ RuCl (rj6-indane) 2(p-2,3-dpp)]2+ (2,3-dpp, 2,3-bis(2-pyridyl)pyrazine) (21). The thermal reactivity of this compound is limited to the stepwise double aquation (which shows biexponential kinetics), but irradiation of the sample results in photoinduced loss of the arene. This photoactivation pathway produces ruthenium species that are more active than their ruthenium-arene precursors (Fig. 18). At the same time, free indane fluoresces 40 times more strongly than bound indane, opening up possibilities to use the arene as a fluorescent marker for imaging purposes. The photoactivation pathway is different from those previously discussed for photoactivated Pt(IV) diazido complexes, as it involves photosubstitution rather than photoreduction. Importantly, the photoactivation mechanism is independent of oxygen (see Section II on photoactivatable platinum drugs) (83). 

Dihydropyrazolo[l,5-a]pyrazine-4,7-diones 205 were synthesized by Nikulnikov et al. using tcrt-butyl isocyanide 209 as a convertible isocyanide [62]. The Ugi reaction of tert-butyl isocyanide and pyrazole-3-carboxylic acids 208 with various aldehydes 206 and amines 207 yields tert-butyl amides 210, which undergo cycli-zation into glacial acetic acid under microwave irradiation (Scheme 37). 

Krasavin et al. described the synthesis of dihydropyrazol pyrazine diones via Ugi-4CR, employing ferf-butyl isocyanide as a convertible reagent [102], The authors reported that, under microwave irradiation, the ferf-butyl isocyanide behaves similar to Armstrong s isocyanide, furnishing the DKPs in good yields. It is noteworthy that the low priced isonitrile applied may be helpful for developing large-scale syntheses in the future (Scheme 6). 

Although there have been few new developments in the period since 1993, halogenopyrazines 42 have been convenient precursors for a variety of pyrazine derivatives. For example, the halogenopyrazines 42 are cyanated by palladium-catalyzed cross-coupling with alkali cyanide or by treatment with copper cyanide in refluxing picoline, to yield cyanopyrazines 48. Alkoxypyrazines 49 are produced by treatment with alkoxide-alcohol, and aminopyrazines 50 are prepared by amination with ammonia or appropriate amines. The nucleophilic substitution of chloropyrazine with sodium alkoxide, phenoxide, alkyl- or arylthiolate is efficiently effected under focused microwave irradiation <2002T887>. 

Tetra-r-butylpyridazine (34) is converted into its Dewar isomer (35) when irradiated in pentane with UV light of wavelength > 300 nm. Irradiation of this product at shorter wavelengths, or thermolysis, gives rise to further reaction (91TL57). Irradiation of 4-amino-2,6-dimethylpyrimidine gives the acyclic amino imine via the Dewar pyrimidine as shown in Scheme 2a. The photoisomerization of perfluoropyridazines to pyrazines is considered also to involve Dewar diazine intermediates. 

In contrast to the thermolysis reactions described above, photolysis of perfluoro (alkyl-pyridazines) leads to high yields of pyrazines.40-42 Thus, irradiation of pyridazines 33 with unfiltered light in the vapor phase gives pyrazines 34.40... 

Keywords hydrazide, phenacyl bromide, alumina, montmorillonite, silica gel, microwave irradiation, pyrazine... 

Irradiation of azido-substituted pyrazines and pyrimidines bearing strong electron-donating substituents in the presence of a base, such as MeONa or diethylamine, resulted in ring expansion with formation of 1,3,5-triazepines (Scheme 38) <1990CC723>. A similar transformation was observed on irradiation of a series of 6-azidouracils in the presence of a primary or a secondary amine <1984J(P1)1719>. 

Reactions of perhydropyrido[l,2-flJpyrazine with aldehydes in the presence of NaB(OAc)3H and NaBH3CN in AcOH (05USA2005/ 0282811) and in acidified EtOH (07USA2007/0117839) afforded 2-substi-tuted derivatives. 2-(l-Diphenylmethylazetidin-3-yl) derivative was obtained in the reaction of perhydropyrido[l,2-a]pyrazine and diphenyl-methyl-3-azetidin-3-one in the presence of (polystyrylmethyl) trimethy-lammonium cyanoborohydride in MeOH containing 10% AcOH at 120 °C for 5 min under microwave irradiation (06WOP2006/137791). 

Reaction of l-(2-oxoethyl)-4-oxo-l,4-dihydropyridine-2-carboxylate 418 and 2-methoxyethylamine in the presence of AcOH at 140 °C for 0.5 h under microwave irradiation provided l,2-dihydro-8H-pyrido[l,2-a pyrazine-1,8-dione 419 (06WOP2006/088173, 07WOP2007/049675). 

Another reaction pathway is observed in methanol [117]. Irradiation of a methanolic solution of 134 led to imidazoline 147 in 60% yield, with a possible intermediate being azomethine ylide 146 (Scheme 1.44). However, two pathways for the formation of imidazoline 147 are possible. The first one is via initial formation of an enediimine 141 (such reaction is known as a nonphotochemical process [118, 119]). The fact that addition of methanol to compound 141 obtained by irradiation of cis-d i h yd ro pyrazine or trans-dih yd ro pyrazi ne 140... 

Lindsley and co-workers developed a general procedure towards the collection of diverse heterocyclic scaffolds from common 1,2-diketone intermediates 96. Substituted quinoxalines 97, fused pyrazolo [ 4,5-g ] quinoxalines 98 and imidazolo[3,4-g]quinoxalines 99 as well as pyrido[2,3-fo]pyrazines 100 and Ihicno[3,4-fo Ipyrazincs 101 have been prepared in excellent yields [132] (Scheme 54), employing optimized reaction conditions (microwave heating of equimolar mixtures of 1,2-diketone 96 and diamine components at 160 °C for 5 min in 9 1 MeOH - AcOH). The use of microwave irradiation resulted in reduced reaction times (5 min vs. 2-12 hours), improved yields as well as the suppressed formation of polymeric species a characteristic of traditional... 

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