1-Azabutadienes

Recognition of the electrophilic character of azadienes led to the investigation, demonstration, and subsequent development of the inverse electron demand (LUMOdiem controlled) Diels-Alder reaction. Substitution 

Alternatively, the complementary addition of strong electron-donating substituents to the azadiene system increases the nucleophilic character of the azadiene system and permits the use of conventional electron-deficient dienophiles in Diels-Alder reactions. In such instances, the azadiene systems are participating in normal (HOMOd,ene controlled) Diels-Alder reactions. The appropriate introduction of electron-donating substituents to the azadiene system raises the HOMOazadiene, reduces the magnitude of the HOMOazadiene-LUMOdienophiie energy separation, and accounts for the accelerated participation of nucleophilic azadienes in normal Diels-Alder cycloadditions. 

In many instances, the entropic assistance provided in the intramolecular Diels-Alder reaction is sufficient to promote azadiene participation in Diels-Alder reactions. The incorporation of the azadiene system, or dienophile, into a reactive or sensitive system, e.g., heterocumulene or strained olefin, allows a number of specialized azadiene Diels-Alder reactions. Many such examples may represent stepwise, polar [4 + 2] cycloaddition reactions. 

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Reaction of 4-amino-l-azabutadienes (45) with various hydrazine salts at 60°C leads to the expected pyrazoles (46) without isolation of the hydrazone intermediate (eq. 8) (39). 

For 71, ketene acetal 73 was paired with azabutadiene 74. The cycloadduct was immediately treated with base to afford 75. This compound was eventually converted into 71. 

The hetero-Diels-Alder reaction of aldehydes 12 with 2-azabutadienes 13 (Scheme 8.5) has been studied using high-level ab-initio multiconfigurational molecular orbital and density functionality calculation methods [28]. 

To determine the preferred pathway for the [4-r-2]-hetero-Diels-Alder reaction model reactions using formaldehyde (R =H for 12 in Scheme 8.5) as the carbonyl compound and 2-azabutadiene (R -R" = H for 13 in Scheme 8.5) for the hetero... 

Fig. 8.15 Calculated transition-state structure for the [4 + 2] hetero-Diels-Alder reaction of formaldehyde with 2-azabutadiene [28 ...

Another method, starting from the 4-amino-l-azabutadiene system, e.g. 19, involves initial reaction with dichlorodiphenylsilane to give 1,3,2-diazasilincs, which can normally be isolated. Further reaction with dimethyl acetylenedicarboxylate provides the silicon-substituted 1,5-di-azocines.40... 

Sulfurdiimine, Triazenido, Azabutadiene and Triatomic Hetero Anion Ligands... 

Venturini, A., Joglar, J., Fustero, S., Gonzalez, J., 1997, Diels-Alder Reactions of 2-Azabutadienes With Aldehydes Ab Initio and Density Functional Theoretical Study of the Reaction Mechanism, Regioselectivity, Acid Catalysis, and Stereoselectivity , J. Org. Chem., 62, 3919. 

Another beautiful example of an early domino process is the formation of daphnilactone A (0-19), as described by Heathcock and coworkers [17]. In this process the precursor 0-17 containing two hydroxymethyl groups is oxidized to give the corresponding dialdehyde, which is condensed with methylamine leading to a 2-azabutadiene. There follow a cycloaddition and an ene reaction to give the hexacycle 0-18, which is transformed into daphnilactone A (0-19) (Scheme 0.6). 

Neutral 2,3-dihydro-l,3,2-diazaphosphinines are straightforwardly accessible from condensation of 4-amino-1-azabutadienes with appropriately substituted dichlorophosphines or PC13 (Scheme 16). The reactions are generally carried out in benzene in the presence of triethylamine as acid scavenger, and the products are isolated in excellent yields of 86-96% [86, 87],... 

Azabutadiene systems are well-known efficient heterodienes in aza Diels-Alder additions. The presence or absence of substituents especially in the 3-position seems to play an important role in the reactivity of 2-azadienes. For example, compounds 615 with PTAD provide the corresponding products 616 usually in high yields (Equation 92) C1994T12375, 2003H(61)493>. 

The [4+2] cycloaddition of 2-amino-l-thia-3-azabutadienes, for example, 652, formed in situ from W-(trimethylsilyl)-imines and PhNCS, and PTAD leads to the regioselective formation of cycloadducts 653 with complete endo-stereoselectivity (Equation 96) <1995S985>. 

Katritzky, A.R., Zhang, G., and Jiang, J., Convenient preparations of diethyl [(acylamino)methyl]phosphonates, 2-azabutadienes, and isoquinolines from a 1,2-monoazabisylide equivalent,. Org. Chem., 59, 4556, 1994. 

In contrast with the reactions of the imino esters, the aldol condensation of imino nitriles and aromatic aldehydes in dichloromethane produces azabutadienes (Scheme 6.17), with the Z-isomers predominating often to the exclusion of the E-isomers [43, 44], Yields generally tend to be at least 10% lower when the reaction is conducted in acetonitrile. 

Derivatives of azabutadiene react with Gly-OEt to give pyrrole-2-carbox-ylates. This reaction, which is assumed to occur via an azapentadienyl anion, allows the synthesis of 3,5-diarylpyrrole-2-carboxylates in a regioselective manner (Scheme 10) (82JOC1696). 

The aza-Diels-Alder reaction is an important and versatile tool for the preparation of nitrogen-containing heterocycles present in numerous natural products and drug candidates. It involves the [4 + 2] cycloaddition of either an imine with an electron-rich diene or an azabutadiene with an electron-rich alkene (inverse electron demand). Catalytic asymmetric variants employing not only metal complexes, but also organic molecules were disclosed over the last few years. 

The reaction of aromatic imines with [Cp(PPh3)2Ru=C=C=C=CH2] gave two types of products, either l-azabuta-l,3-diene-2-ethynyl complexes or 4-ethynylquino-line complexes [52, 53]. The azabutadiene-2-ethynyl complexes were thought to be... 

Scheme 3.26 Formation of azabutadiene-2-ethynyl complexes in the reaction of butatrienylidene complexes with imines.

The azabutadiene (80), on treatment with strong base, gives 2-ethyl-3,5-dimethyltetra-hydropyridine the proposed mechanism involves dimerization and cleavage, followed by... 

Aus a-[(Dimethylamino-methyliden)-amino]- bzw. a-[(Methylthio-methyliden)-amino]-carbon-saure-nitrilen oder -estern werden durch Umsetzung mit 1,1-Dialkoxy-l-dimethylamino-alka-nen 2-Azabutadiene erhalten, die mit primaren Aminen in Eisessig252 oder mit deren Hydro-chioriden in Dimethylformamid253 zu den entsprechenden Imidazolen cyclisieren ... 

Reports on the synthesis of five-membered heterocycles by intramolecular nitrogen—nitrogen bond formation (N1—N5) came some years ago from our laboratory [79CC891 81 JCS(Pl) 1891 83JCS(P1)2273]. Thus, 4-alkyl(aryl)amino-l-azabutadienes 2, which are readily available in large scale from alkyl(aryl)imines 1 and aliphatic or aromatic nitriles (70S 142 ... 

The [4+1] annulation of 1-azadienes to pyrroles can also be achieved through their carbonyl iron complexes (Scheme 6). Novel complex (1,4-diphenyl-2-methyl-l-azabutadiene)tricarbonyliron (0) 24 was obtained in 40% yield from the corresponding azadiene 23 and Fe2(CO)9 then nucleophilic attack by methyl lithium and quenching with tert-butyl bromide, as the proton source, gave 2,5-dimethyl-l,3-diphenylpyrrole 26 in 70% yield, probably through the anionic intermediate complex 25 [88TL1425 90JCS(P1)761]. 

The formation of substituted quinolines 35 (58-90% yield) by intramolecular cyclization of 4-arylamino-l-azabutadienes 2 has been carried out at 100°C using one equivalent of aluminium chloride the reaction involves the diene moiety and one carbon—carbon double bond of the aromatic ring (87S82). The participation of the phenyl group attached to the a-... 

Similarly, Uneyama and Watanabe (91TL1459) have reported the synthesis of trifluoromethylated AI-aryl-1-azabutadienes by palladium-catalyzed coupling of trifluoroacetimidoyl iodides with alkenes as well as the transformation of the azadiene derived from methyl acrylate into the corresponding 4-methoxycarbonyl-2-trifluoromethylquinoline in quantitative yield. 

We have described (88TL4855) a simple synthesis of pyridin-2-ones by a two-step annulation of 2 with aliphatic acid chlorides (Scheme 27). The acylation of aminoazadienes 2 in pyridine furnished 4-amidoyl-l-azabutadienes 107 in high yields (85JOC802) lithium diisopropylamide-catalyzed aldol-type cyclization of 107 afforded pyridin-2-ones 108 in 83-94% yield. Extension of this reaction to methanesulfonyl chloride permitted preparation of open-chain derivatives 109 in 88-90% yield, which in turn cyclized in the presence of lithium diisopropylamide to 2//-l,2-thiazines 110 in 82-92% yield (89TL4705). Earlier work by the Komatsu-Ohshiro group showed that the reaction of simple 1-azadienes... 

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