1.2- Diazines, inverse-electron-demand Diels-Alder

Electron-deficient heteroaromatic systems such as 1,2,4-triazines and 1,2,4,5-tetrazines easily undergo inverse electron demand Diels-Alder (lEDDA) reactions. 1,2-Diazines are less reactive, but pyridazines and phthalazines with strong electron-withdrawing substituents are sufficiently reactive to react as electron-deficient diazadienes with electron-rich dienophiles. Several examples have been discussed in CHEC-II(1996) <1996CHEC-II(6)1>. This lEDDA reaction followed by a retro-Diels-Alder loss of N2 remains a very powerful tool for the synthesis of (poly)cyclic compounds. 

Pyrroles, indoles and benzo[ft]thiophene act as good dienophiles in inverse electron demand Diels-Alder reactions with 1,2-diazines, 1,2,4-triazines and sy/n/n-tetrazines. This is examplified by the formation of compounds (189) in excellent yields on interaction of indoles and benzo[c]thiophene with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate (87JOC4610 90JOC3257). There are also many examples of such intramolecular reactions, e.g. (190 — 191). 

Pyrroles are obtained by reduction of 1,2-diazines (80JMC481). This reaction has been used in conjunction with inverse electron demand Diels-Alder reactions to prepare 3,4-disubstituted pyrrole-2, 5-dicarboxylic acid derivatives(Scheme 67). Silyl enol ethers or enamines can also serve as the electron-rich dienophiles thus, silyl ethers of ester enolates give 3-methoxypyrroles (84JOC4405). 

Heterocyclic azadienes like di- and triazines have been used in the synthesis of pyridine rings. In general terms the reaction involves a regiospecific inverse electron demand Diels-Alder cycloaddition between the heterocycle and the enamine 280 followed by elimination of HCN (diazines) or N2 (triazines) and an amine from the primary cycloadduct 281 or 283, respectively, to give pyridines 282 and 284 (equation 61). At least in one case the latter type of intermediate has been isolated and fully characterized148. 

Regiospecific inverse electron demand Diels-Alder reactions of enamines with 1,3-diazines or 1,2,3- and 1,2,4-triazines (see Section III.D.l), which on elimination of HCN or N2, respectively, produce a pyridine ring, can be used with 1,3,5-triazines and 1,2,4,5-tetrazines as a useful method for the synthesis of pyrimidines214-216 (1,3-diazines) and pyridazines217-219 (1,2-diazines). Examples of the use of this methodology are the preparation of the pyrimidine substituted benzomorphane 356 (equation 77)219 and the pyridazine 359 (equation 78), intermediate in the total synthesis of cis- and trans-trikentrin A216. 

Key elements of the total synthesis of ningalin D (1) developed by Boger et al. include an inverse electron-demand Diels-Alder reaction (1,2,4,5-tetrazine 1,2-diazine) followed by a reductive ring contraction of the resultant 1,2-diazine, affording the fully substituted pyrrole core central to the structure of 1. 

Thus, the electron-deficient 1,2,4,5-tetrazine 7 reacts smoothly with the electron-rich acetylene 8 in an inverse electron-demand Diels-Alder reaction First, the [4+2] cycloaddition of 7 with 8 takes place and then the formed intermediate 9 loses N2 to provide the symmetrical 1,2-diazine 6. 

This approach to 1,2-diazine and pyrrole introduction based on the inverse electron demand Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate complements the [4 + 2] cycloaddition reactions of a range of electron-deficient heterocyclic azadienes which permits the divergent preparation of a range of heterocyclic agents employing a common dienophile precursor, Scheme I. 

All the diazines, providing they also have electron-withdrawing snbstitnents, nndergo Inverse Electron Demand Diels-Alder (lEDDA) additions with dienophiles. Intramolecnlar reactions occnr the most readily these do not even require the presence of activating snbstitnents. The immediate prodncts of snch process nsually lose nitrogen (pyridazine addncts) or hydrogen cyanide (addncts from pyrimidines and pyrazines) to generate benzene and pyridine prodncts, respectively, as illnstrated below. ... 

Probably the most useful and general reaction of all these systems is the inverse-electron-demand Diels-Alder reaction with acetylenes (or equivalents) to produce either pyridines or diazines via elimination of hydrogen cyanide, a nitrile or nitrogen. ... 

Fragmentation of an adduct with release of a nitrile, CO2 or N2 are most common and the latter provide an irreversible method for the formation of a new diene or aromatic compound. Cycloaddition of a pyran-2-one or a 1,2-diazine (pyridazine) with an alkyne gives an intermediate bridged compoimd that loses CO2 or N2 to generate a benzene derivative (see Scheme 3.46). Many other aromatic and heteroaromatic compounds can be prepared likewise. For example, a synthesis of lavendamycin made use of the inverse electron demand Diels-Alder reaction between the 1,2,4-triazine 116 and the enamine 117, followed by in situ elimination of pyrrolidine and retro Diels-Alder reaction, releasing N2 and the substituted pyridine 118 (3.88). 2... 

Scheme 3. Use of 1,2,4,5-tetrazine 8 in an inverse-electron-demand Diels-Alder reaction followed by an intramolecular 1,2-diazine/alkyne cycloaddition in Boger s total synthesis of (-i-)-CC-1065 (15).

Overall, while this excursion has been brief, the above examples should provide a preliminaiy indication of the power of azadiene-based inverse-electron-demand Diels—Alder reactions in the context of total synthesis, particularly for the synthesis of highly substituted heterocyclic systems such as pyridines, diazines, and pyrimidines. Arguably, few if any other methods enable such facile, diverse, and consistent constructions of these challenging aromatic systems. With this background in place, we are now prepared to analyze the total synthesis of isochrysohermidin (1) by Boger and Baldino. 

Synthetic efforts towards isochrysohermidin (1) commenced with exploration of the critical double inverse-electron-demand Diels- Alder union of 1,1,4,4-tetramethoxy-1,3-butadiene (28) with tetrazine 8, as shown in Scheme 6." After considerable experimentation, it was found that the desired sequence based on a double [4+2] cycloaddition reaction to produce the 1,2-diazine dimer 27 could be effected in 65 % yield upon treatment of 28 with... 

In 2014 several reports described the use of inverse-electron-demand Diels-Alder reactions to furnish naphthalene-based compounds from phthalazine-containing ring systems. Employing nonprecious metal complexes, copper(l) and nickel(O) complexes, instead of silver salts to catalyze formal [4+ 2] cycloadditions of 1,2-diazines and siloxyalkynes, Rawal and his group developed an environmentally friendlier and more economical method for preparing siloxy derivatives of naphthalene, anthracene, and phenanthrene (Scheme 16) (140L3236). In addition, the copper catalyst could also be employed for the synthesis of the corresponding quinolines and isoquinolines. This method provided the respective products in... 

Kessler, S., Neuburger, M., Wegner, H. (2012). Domino inverse electron-demand Diels-Alder/cyclopropanation reaction of diazines catalyzed by a bidentate Lewis acid. Journal of the American Chemical Society, 134, 17885-17888. 

Several methods for construction of diazine core of chain-fluorinated pyrimidines do not fall into any of the mentioned above categories. One of such approaches is discussed in Sect. 7.8, namely, inverse-electron-demand Diels-Alder reactions with fluorinated sym-triazines. Other methods that fall into category miscellaneous are too different to discuss them systematically therefore, selected examples of them are listed in this section. 

It was described in Sect. 7.8 of this chapter that chain-fluorinaled diazines can be synthesized using inverse-electron-demand Diels-Alder reactions. Some of the fused pyridazines can also undergo analogous reactions with electron-rich alkenes. In particular, Diels-Alder reactions of pyridopyrazine 1259 were smdied. It was found that 1259 reacted with enamines to give quinoline derivatives (e.g. 1260) (Scheme 291) [790]. Reaction of 1259 with ketene N,S-acetal 1261 led to a mixture of regioisomers 1262 and 1263, whereas reaction with A-methylindole gave complex mixture of products 1264-1267 (Scheme 292) [791]. 

Boger [57] has utilized inverse electron-demand Diels-Alder reaction of 3,6-bis(methylthio)-l,2,4,5-tetrazine 150 with electron-rich dienophile 151 to produce 1,2-diazine 152 (Scheme 37). Thermally conducted reaction at atmospheric pressure (xylene, 140 °C, 26h) afforded diazine 152 in lower yield (78%). Similar [4 + 2] cycloaddi-tion/nitrogen elimination methodology followed by aromatization was applied by Boger in the S5mthesis of pyridines from triazine 153 and 151 (Scheme 37) [58]. In classical conditions, pyridine 154 was produced in 72% yield (CHCI3, 22h,60°C). 

D.L. Boger, S.M. Sakya, Inverse electron demand Diels-Alder reactions of 3,6-bis(methylthio)-l,2,4,5-tetrazine. 1,2-Diazine introduction and direct implementation of a divergent l,2,4,5-tetrazine- l,2-diazine- benzene (indoUne/indole) Diels-Alder strategy, J. Org. Chem. 53 (1988) 1415-1423. 

Panl996 Panek, J.S. and Zhu, B., Synthesis of Aromatic 1,2-Diazines by Inverse Electron Demand Diels-Alder Reaction of Polymer-Supported 1,2,4,5-Tetrazines, Tetrahedron Lett., 37 (1996) 8151-8154. 

Tetrazines 1 undergo regioseleetive inverse electron demand Diels-Alder reactions with a variety of electron-rich dienophiles to yield 1,2-diazines in good yield. The process takes place in three steps (a) [4+2] cycloaddition, (b) elimination of the electron-donating group, (c) extrusion of N2 by means of a retro-Diels-Alder process. 

The ring enlargement of pyrroles providing 3-chloropyridines has already been described (see p 93). Oxazoles react as masked 2-azadienes with alkenes yielding pyridine derivatives of various types (see p 131). With enamines and ynamines, diazines and triazines undergo Diels-Alder reactions with inverse electron demand (see p 441). This leads to pyridines (e.g. 201) by the enamine cycloaddition of the 1,2,4-triazine, as shown below ... 

Diazines and triazines undergo Diels-Alder reactions with inverse electron demand with enamines and ynamines to give pyridines, as shown by the enamine cydoaddition of 1,2,4-triazine ( 211) ... 

An unusual approach to the synthesis of chain-fluorinated diazines relies on the inverse-electron-demand hetero-Zretro-Diels - Alder ihDA/rDA) sequence. The background of this method for the preparation of nitrogen-containing heterocycles in general has been reviewed recently [674], Typical dienes used for the synthesis of chain-fluorinated diazines are given in Fig. 29. Since electron-deficient dienes are necessary for the first step of the sequence - inverse-electron-danand hetero-Diels -Alder reaction, fluoroalkyl substituents of tri- and tetrazines 1111-1112 are favorable for the process. Typical electron-rich dienophiles for the reactions with 1111-1112 are enamines (including amino heterocycles) and alkynes, although other examples are also known. 

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