Inverse electron demand using enamines

These authors found that the tetrazinylhydrazone derivative 46 when reacted with pyrrolidinoenamine 47 in methanol yields the cyclopenta-fused derivative of the title ring system 48 in 94% yield. A similar transformation was carried out successfully by using morpholine-enamine in somewhat poorer yield. When the transformation was tried in acetonitrile as a solvent, a totally different reaction was observed a regular Diels-Alder reaction between the tetrazine ring and the enamine double bond (of inverse electron demand) took place to yield pyridazines. 

In addition to the reaction of vinylcarbene complexes with alkynes, further synthetic procedures have been developed in which Fischer-type carbene complexes are used for the preparation of benzenes. Most of these transformations are likely to be mechanistically related to the Dbtz benzannulation reaction, and can be rationalized as sequences of alkyne-insertions, CO-insertions, and electrocycli-zations. A selection of examples is given in Table 2.18. Entry 4 in Table 2.18 is an example of the Diels-Alder reaction (with inverse electron demand) of an enamine with a pyran-2-ylidene complex (see also Section 2.2.7 and Figure 2.36). In this example the adduct initially formed eliminates both chromium hexacarbonyl ([4 -I- 2] cycloreversion) and pyrrolidine to yield a substituted benzene. 

The Pechmann and Knoevenagel reactions have been widely used to synthesise coumarins and developments in both have been reported. Activated phenols react rapidly with ethyl acetoacetate, propenoic acid and propynoic acid under microwave irradiation using cation-exchange resins as catalyst <99SL608>. Similarly, salicylaldehydes are converted into coumarin-3-carboxylic acids when the reaction with malonic acid is catalysed by the montmorillonite KSF <99JOC1033>. In both cases the use of a solid catalyst has environmentally friendly benefits. Methyl 3-(3-coumarinyl)propenoate 44, prepared from dimethyl glutaconate and salicylaldehyde, is a stable electron deficient diene which reacts with enamines to form benzo[c]coumarins. An inverse electron demand Diels-Alder reaction is followed by elimination of a secondary amine and aromatisation (Scheme 26) <99SL477>. 

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). 

It is also worth mentioning that inverse electron demand Diels-Alder reactions are possible with pyran-2-ones and coumarins. Shown in Equation (26) is one such reaction using an electron-deficient diene of coumarin 258 with enamine 259 to give 260 <1999SL477>. 

The inverse electron demand Diels-Alder reaction between enamines and electron-deficient dienes is a useful method for the synthesis of six-membered rings. The process is considered LUMOdiene-controlled70 72, and its rate (as in the other Diels-Alder... 

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. 

In addition to 1,2,4-triazines condensed with carbocycles, 1,2,4-triazines condensed with heterocycles can also be used as dienes with inverse electron demand in Diels-Alder reactions. Thus, it has been shown that pyrimido[4,5-e]-1,2,4-triazines react with enamines to yield pyrido[2,3-tflpyrimidines 29 (5-deazapteridines).415... 

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... 

Pyrrolidine has been the common organocatalyst used by Boger and coworkers for the synthesis of highly substituted pyridines based on the inverse-electron-demand Diels-Alder reaction of in situ formed enamines and 1,2,4-triazines. Barbas and coworkers have described the amine-catalysed direct self-Diels-Alder reaction of a,p-unsaturated ketones. The inverse-electron-demand hetero-Diels-Alder reaction of nitrosoalkenes and in situ formed enamines as dienophiles was also shown to be possible. ... 

L-Pro has been used as an organocatalyst in an inverse-electron-demand Diels-Alder reaction of ketones with 1,2,4,5-tetrazines to furnish pyrazines with medicinal interest.The transformation proceeds by the reaction of the diene 1,2,4,5-tetrazine with the enamine formed in situ from the ketone and L-Pro. A retro-Diels-Alder step eliminates nitrogen and forms the pyr-azine product after catalyst elimination. The transformation is, however, not regioselective with unsymmetrical ketones. 

Inverse-electron-demand DA cycloaddition reactions retain the top position in synthetic research on 1,2,4-triazines (12CHC1153). There are several new examples of the use of the reaction for 1,2,4-triazine ring transformation. Thus, a new route to prepare pyridine derivatives 23 and 24 based on inverse-electron-demand DA/retro-DA reactions of ketones with 1,2,4-triazines 25 using the enolates of methyl ketones direcdy as a dienophile without enamine intermediates is reported, which is complementary to the classical Boger procedure (14RSCA59218). 

Dixon and co-workers [182] published an enantioselective aryloxylation of aldehydes using an inverse-electron-demand hetero-Diels-Alder reaction of in s/tM-generated enamines and o-quinones. After trying different proline-derived catalysts, imidazolidinone 120 gave the best enantioselectivities (Scheme 12.34). 

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. 

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]. 

An enantioselective inverse-electron-demand hetero-Diels-Alder reaction of o-quinones 104 and aldehydes 98 was disclosed by the Dixon group with the use of secondary amine catalyst 105 [44]. This reaction went smoothly through in situ generated enamines with o-quinone reagents to afford the corresponding products 106 (with up to 81% ee), which can be further converted into optically active 2,3-dihydro-benzo[l,4]dioxin compounds (Scheme 38.28). 

Chen and coworkers presented a highly stereoselective inverse-electron-demand aza-hetero-Diels-Alder reaction of aldehydes 137 and a, 3-unsaturated imines 136 with the use of a chiral secondary amine 36 through enamine activation [62]. Excellent enantioselectivities can be achieved for a broad range of substrates (Scheme 38.40). Water is helpful in the hydrolysis of intermediate P to release... 

When using aliphatic aldehydes tethered to arene motifs as substrates, an enan-tioselective sequential aza-hetero-Diels-Alder and Friedel-Crafts reaction was successfully achieved by the same group [63]. Similarly, optically active lactone[3,3-b] piperidine skeletons 140 can be obtained by tandem aza-hetero-Diels-Alder reaction-hemiacetal formation-oxidation from a,P-unsaturated imines 136 and glutaraldehyde (139) (Scheme 38.41) [64]. Enamine catalysis of the inverse-electron-demand aza-hetero-Diels-Alder reaction was further extended to o-benzoquinone diimide 141 by Chen s group [65]. Various hydroquinoxalinones 142 can be obtained in high yields with excellent enantioselectivities (Scheme 38.42). 

Inverse-Electron-Demand [4+2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas group s ingenious design of Diels-Alder reactions using enamine-activated dienes, Jprgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse-electron-demand hetero-Diels-Alder reaction (Scheme 1.24) [26]. 

Nitroalkenes 1 behave as heterodienes in [4+2] inverse electron demand cycloadditions with simple unactivated alkenes, enamines, or enol ethers (2) as dieno-philes. These reactions require the presence of a Lewis acid to enhance the reactivity of the nitroalkene and accelerate the process. The products obtained in such reactions are six-membered cyclic compounds called nitronates (3) (Scheme 22.1). These compounds can be used in turn, as 1,3-dipoles in [3+2] cycloaddition reactions. 

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