Azadienes, Cycloadditions

The most thoroughly investigated and widely recognized class of cat- 

The [4+ + 2] cycloadditions proceed in a regiospecific manner with the nucleophilic carbon of the electron-rich dienophile attaching to the expected electrophilic site of the aromatic quaternary salt (e.g., C-6 for acridizinium salts, C-1 for isoquinolinium salts) and the rate of reaction (ketene aminals, ketene acetals, enamines cyclopentadiene 2,3-di-methylbutadiene styrene dihydropyran 2-butene maleic anhydride) does increase as the nucleophilic character of the dienophile is enhanced [Eq. (66)].  

Two experimental techniques have improved the observed participation of simple aromatic quaternary salts in [4 + 2] cycloadditions. The addition of hydroquinone, which forms a stabilized 1 2 complex with the isoquinolinium salts, to the reaction mixture accelerates the rate of observed isoquinolinium salt [4 + 2] cycloaddition. In addition, the use of 2,4-dinitrophenyl aromatic quaternary salts, prepared from the parent base and 2,4-dinitrophenyl bromide or chloride, accentuates the electron-deficient character of the quaternary salt and accelerates their participation in [4 + 2] cycloadditions with electron-rich dienophiles. These observations of Falck and co-workers have proved useful for promoting the [4+ -I- 2] cycloaddition of isoquinolinium systems previously regarded unmanageable. The application of these observations in the total syntheses of 14-epicorynoline (16) and methyl arrnothanamide (17) have been detailed [Eq. (67)],  

A one-step synthesis of the protoberberine alkaloid karachine (18), employing a presumed Mannich reaction of 4-methyl-2-trimethylsilyloxy-2,4-pentadiene with berberine, has been detailed by Stevens and Pruitt. 

It is plausible that the initial step of the one-flask reaction sequence leading to karachine is, in fact, a [4+ + 2] cycloaddition of the quaternary aromatic salt, berberine chloride, with the terminal electron-rich olefin of the silyloxydiene [Eq. (70)]. 

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Heteroaromatic compounds such as oxazoles, diazines and triazines are useful azadienes. Cycloaddition with the dienophile gives abridged intermediate that often fragments (e.g. with loss of HCN or Ni) by a retro Diels-Alder reaction to generate a new aromatic compound (see Section 3.1.6). 

A second generation of ketene—azadiene cycloadditions involves [4 + 2] cycloaddition with chiral 2-aIkenyloxazoHnes and 2-aIkenylthiazohnes 250 (Scheme 79), which react with ketene, with excellent stereoselectivity to afford enantio-pure thiazolopyridones 251 (1999SL1379, 1979H(12)231, 2001JOC6756). 

Vapor phase pyrolysis of 2-dimethylaminoazirine (168), on the other hand, proceeds in a similar manner at 340 °C to give substituted azadiene (169) in high yield (7SJA4409). Azadiene (169) has been employed in the construction of heterocyclic rings such as pyridines via a [4-1-2] cycloaddition-elimination sequence. 

The reaction of JV,iV-dimethylhydrazones (1-amino-1-azadienes) and alkenylcarbene complexes mainly produces [3C+2S] cyclopentene derivatives (see Sect. 2.6.4.5). However, a minor product in this reaction is a pyrrole derivative which can be considered as derived from a [4S+1C] cycloaddition process [75]. In this case, the reaction is initiated by the nucleophilic 1,2-addition of the nitrogen lone pair to the metal-carbon double bond followed by cyclisation and... 

S+3C] Heterocyclisations have been successfully effected starting from 4-amino-l-azadiene derivatives. The cycloaddition of reactive 4-amino-1-aza-1,3-butadienes towards alkenylcarbene complexes goes to completion in THF at a temperature as low as -40 °C to produce substituted 4,5-dihydro-3H-azepines in 52-91% yield [115] (Scheme 66). Monitoring the reaction by NMR allowed various intermediates to be determined and the reaction course outlined in Scheme 66 to be established. This mechanism features the following points in the chemistry of Fischer carbene complexes (i) the reaction is initiated at -78 °C by nucleophilic 1,2-addition and (ii) the key step cyclisation is triggered by a [l,2]-W(CO)5 shift. 

Finally, chromium imine carbenes underwent photoreaction with imines to give azadienes (metathesis) (Eq. 36), with azobenzene to give both metathesis and cycloaddition products (Eq. 37), and with ketones to give oxazolines... 

Reactivity of 1-azadienes 87 and the regioselectivity and stereoselectivity of the cycloadditions with dienophiles 88 are strongly dependent on the type of... 

Azadienes 89, generated in situ by thermolysis of the corresponding o-aminobenzylalcohols, have been used for the derivatization of [60]-fullerene through C-N bond formation leading to tetrahydropyrido [60]-fullerenes [93]. Theoretical calculations predicted these cycloadditions to be HOMO azadiene-controlled (Equation 2.25). 

Interestingly, the cycloaddition of 2-azadiene 44 with N-methylmaleimide in 2.5m LT-DE gave predominantly exo-adduct in contrast to the thermal cycloaddition that is mainly enJo-selective (Scheme 6.27). A similar but not so dramatic increase in cxo-selectivity was also observed [47] for the cycloaddition of 44 with N-phenylmaleimide. The reaction is kinetically controlled, but the origin of the high cxo-selectivity observed in LT-DE is unclear the polar medium probably favors the more polar exo transition state. 

The first microwave-assisted hetero-Diels-Alder cycloaddition reaction was described by Diaz-Ortiz and co-workers in 1998 between 2-azadiene 198 and the same electron-poor dienophiles as for the preparation of pyrazolo[3,4-b]pyridines 200 (Scheme 72) [127]. These dienes reacted with... 

It has been shown that cross-coupling reactions constitute a very mild method to introduce different alkyl and aryl groups to the most active C-3 position of the pyrazinone ring [26]. The broadly functionahzed 2-azadiene system of the title compounds was studied in cycloaddition reactions with various electron-reach and electron-poor dienophiles to provide highly substituted heterocycles [24]. 

An interesting parallel was found while the microwave-enhanced Heck reaction was explored on the C-3 position of the pyrazinone system [29]. The additional problem here was caused by the capability of the alkene to undergo Diels-Alder reaction with the 2-azadiene system of the pyrazinone. An interesting competition between the Heck reaction and the Diels-Alder reaction has been noticed, while the outcome solely depended on the substrates and the catalyst system. Microwave irradiation of a mixture of pyrazinone (Re = H), ethyl acrylate (Y = COOEt) and Pd(dppf)Cl2 resulted in the formation of a mixture of the starting material together with the cycloaddition product in a 3 1 ratio (Scheme 15). On the contrary, when Pd(OAc)2 was used in combination with the bulky phosphine ligand 2-(di-t-butylphosphino)biphenyl [41-44], the Heck reaction product was obtained as the sole product. When a mixture of the pyrazinone (Re = Ar) with ethyl acrylate or styrene and Pd(dppf)Cl2 was irradiated at 150 °C for 15 min, both catalytic systems favored the Heck reaction product with no trace of Diels-Alder adduct. 

The 2-azadiene system of the pyrazinone scaffold undergoes inter- and intramolecular cycloaddition reactions with a variety of (functionalized) alkenes forming bicyclic adducts, leading to the stereoselective generation of a variety of natural product analogues as well as peptidomimetics [58]. These bicyclic compounds could serve as key intermediates in the synthesis... 

The JV-phosphino-l-azadiene 66 undergoes cycloaddition with DMAD in ether at -20 °C to form the bridged structure 67 <96AG(E)896>. The new compound is thermally unstable and isomerises to the alternative bridged structure 68 at 25 °C. X-ray analysis data have been interpreted to suggest that the isomer 69 co-exists in the solid state. The same ring system is also formed by protonation at the sp carbon atom neighbouring phosphorus in 67 (Scheme 15). 

For 4-nitrophenyl 2-azadiene 617, vigorous reaction conditions are necessary (110°C, sealed tube, 25h) and give bicyclic product 619. The formation of this compound could be explained by [4+2] cycloaddition reaction leading to 618 followed by dehydrogenation (Scheme 99) <1994T12375, 2003H(61)493>. 

Thermolysis of the isothiazolopyridine dioxide 223 results in loss of S02 to give an azadiene which spontaneously undergoes an intramolecular [4+2] cycloaddition with the tethered terminal alkene to give the tricycle 224 (Equation 58) <1997TL4667, 2002EJ0947>. 

Scheme6.241 Azadiene Diels—Alder cycloaddition of fulvenes.

A general hetero-Diels-Alder cycloaddition of fulvenes with azadienes to furnish tetrahydro-[l]pyrindines has been described by Hong and coworkers (Scheme 6.241 see also Scheme 6.92) [424]. A solution of the azadiene and fulvene (1.2 equivalents) precursors in chlorobenzene was heated under open-vessel microwave irradiation for 30 min at 125 °C to provide the target compounds in excellent yields and with exclusive regio- and diastereoselectivity. Performing the reactions under conventional conditions or under microwave irradiation in different solvents provided significantly reduced yields. 

Moody and coworkers have employed a biomimetic hetero-Diels-Alder-aroma-tization sequence for the construction of the 2,3-dithiazolepyridine core unit in amythiamicin D and related thiopeptide antibiotics (Scheme 6.243 a) [426]. The key cycloaddition reaction between the azadiene and enamine components was carried out by microwave irradiation at 120 °C for 12 h and gave the required 2,3,6-tris(thi-azolyl)pyridine intermediate in a moderate 33% yield. Coupling of the remaining building blocks then completed the first total synthesis of the thiopeptide antibiotic... 

Methods have been described that involve microwave-assisted graphite-supported dry media for the cycloaddition of anthracene, 1-azadienes and 1,2,4,5-tetrazines with several C-C dienophiles and carbonyl compounds in hetero-Diels-Alder reactions [35], This technique leads to a shortening of reaction times, a situation that enables work to be undertaken at ambient pressure in an open reactor to avoid the formation of unwanted compounds by thermal decomposition of reagents or products. 

Pyrazole derivatives are very reluctant to participate as dienes in Diels-Alder cycloadditions that involve the pyrazole ring, because of the loss of aromatic character during the process [79]. Microwave irradiation under solvent-free conditions, however, induces pyrazolyl 2-azadienes 96 to undergo Diels-Alder cycloadditions with ni-troalkenes 97 and 98 in 5-10 min to give good yields of pyrazolo-[3,4-b]-pyridines (Scheme 9.29) [80], Under the action of classical heating only traces of the corresponding cycloadducts were detected. 

Later, Quiroga described a similar reaction - the cycloaddition of 2-azadienes derived from pyrazoles and pyrimidones with arylvinylketones 103 as dienophiles (Scheme 9.30) [81]. 

An interesting annelation reaction of allene-derived 13-dipoles with 3-(IV-aryliminomethyl)chromones 38 affords, in fair yields, after [4 +3] cycloaddition and a subsequent cascade of rearrangements, derivatives of the novel iV-aryl-2,3-dihydro-4-ethoxycarbonylchromano[2,3-h]azepin-6-one system 39 (for example, R = Me, R1 = Cl) (Scheme 9). In the initial cycloaddition, the substituted chromone acts as an azadiene moiety <00OL2023>... 

DFT calculations have been used to study the mechanistic pathway of the intramolecular Diels-Alder cycloaddition involved in the biosynthesis of natural products paraherquamide A and VM55599. The cycloaddition involves a dihydropyrolo[l,2- ]pyrazine as the azadiene and a standard alkene as the dienophile (Scheme 1). Analysis of the results reveals that these cycloadditions take place through concerted transition structures associated with [4+2]... 

Motorina and Grierson (224) examined the use of bis(oxazoline)-Cu(II) complexes as chiral Lewis acids in the intramolecular heterocycloaddition of azadienes, Eq. 184. Very low selectivities are observed in the cycloaddition of 326. The authors speculate that monodentate coordination of the substrate to copper is responsible for the low selectivity. 

In the reaction of benzylideneaniline with cyclopentadiene, the imine functions as an azadiene to yield the rearranged Diels-Alder adduct 77 (equation SI)44,453. In a study of the effect of various Lewis acids (ZnCl2, TiCU, Et2AlCl and SnCU) on diastereoselective cycloadditions of Danishefsky s diene to the imines 79, obtained from the chiral aldehydes 78 (R = MeO or Cl), it was found that SnCLj was the most effective, giving the optically active products in high yields and excellent ee values (equation 52)46. 

Experimental Procedure 2.2.8. [4 + 3] Cycloaddition of a Chromium Vinylcarbene Complex to a 1-Azadiene rranj-i-(2-Furyl)-2-inethoxy-5-methyl-4,5-dihydro-3H-azepine [390]... 

The (diphenylmethylene)aminocyclobutenecarboxylates 109 obtained by rearrangement of the DMPA-H adducts of 1-Me, 2-Me, contain a 2-azadiene unit and a cyclobutene moiety. Indeed, the parent compound 109 a reacted with 4-phenyl-l,2,4-triazoline-3,5-dione (PTAD, [80]) at room temperature in a [4-1-2] cycloaddition mode to yield the tricyclic tetraazaundecene 132 in almost quantitative yield (Scheme 44) [8]. As substituted cyclobutenes, compounds 109 should be capable of opening up to the corresponding butadienes [1, 2b, 811. When compounds 109 were subjected to flash vacuum pyrolysis, the dihydro-isoquinolines 135 were obtained, presumably via the expected ring-opened intermediates 133, which subsequently underwent bn electrocyclization followed by a 1,5-shift, as is common for other 3-aza-l,3,5-hexatrienes [82]. 

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