Cycloadditionen mit Azabenzolen, VII¹⁾ Reaktion von Pyrimidinen mit N,N‐Diäthyl‐1‐propinylamin

Abstract

Die Pyrimidincarbonsaureester 2a-2e reagieren rnit N,N-Diathyl-I-propinylamin (1) in einer Diels-Alder-Reaktion rnit inversem Elektronenbedarf zu den Pyridinderivaten 3a-3f. Es werden Regeln fur die Orientierung der beiden Reaktionspartner zueinander abgeleitet. Cycloaddition Reactions with Azabenzenes, VIL'). -Reaction of Pyrimidines with N,N-Diethyl- 1-propynylamineThe pyrimidinecarboxylates 2a-2e react with N,N-diethyl-I-propynylamine (1) via a Diels-Alder reaction with inverse electron demand to give the pyridine derivatives 3a-3f. Rules are given for the orientation of the two reactants.

Diels–Alder and Formal Diels–Alder Cycloaddition Reactions of Ynamines and Ynamides

“…Pyrimidines are not reactive dienes in general, and their cycloaddition reactions require high temperatures. Nevertheless, Neunhoeffer reported in 1974 that electron‐rich ynamines were competent partners in [4+2]/retro‐[4+2] reactions leading to aminopyridines in moderate yields (Scheme ) . The sequence proceeds through a bicyclic intermediate (e.g., 38 ; Scheme ) that spontaneously expels a nitrile.…”

“…Inspired by the elegant transformations of pyrimidines into pyridines through inverse‐electron‐demand Diels–Alder reactions reported by the groups of Neunhoeffer, Miyashita, Ohsawa,, and van der Plas, we hypothesized that ynamides 141 might be competent partners in such pericyclic sequences in either intra‐ or intermolecular fashion (Scheme ). As detailed in Section 2, pyrimidines are quite unreactive azadienes, but this downside should be balanced by their commercial availability, low cost, and unsurpassed structural diversity in relation to triazines or tetrazines.…”

“…Careful screening of the reaction conditions was required, because the classical Neunhoeffer or van der Plas conditions (nitrobenzene solution in sealed tube) were not practical and took far too long (up to several days). Model substrate 145d having been selected, variation of solvents, temperatures (and type of heating), reaction times, and additives identified that microwave irradiation for a short period of time [255 °C for 30 s (Method A) or 210 °C for 30 min (Method B)] of a sulfolane solution of the pyrimidinyl‐ynamide led to a clean reaction.…”

“…The impact of the substitution of the azadiene was further explored with different atoms or groups in the C5 position (Scheme ). These substituents are known to have a strong influence on the yields of the [4+2]/retro‐[4+2] sequences, because one of the two σ‐bonds is created at this reacting center , . Indeed, it was found that only C5–F substitution was tolerated (compound 148f ), this offering the right balance between electron‐withdrawing properties and small volume.…”

Optimized Synthesis of 7-Aza-Indazoles by Diels–Alder Cascade and Associated Process Safety

“…Diels-Alder cycloadditions between alkynes and pyrimidines are classified as inverse electron demand [4ps+2ps] cycloadditions that lead to pyridines upon spontaneous retro-Diels-Alder reaction of the primary cycloadduct. [1][2][3][4][5] A limitation of this conceptually interesting synthesis of pyridines are the high temperature (up to 280 °C under classical conditions 6 ) and very long reaction times that are required [7][8][9] to overcome the intrinsic lack of reactivity of these aza-dienes. [10][11][12][13][14][15][16][17][18][19] On the other hand, we recently reported that pyrimidines substituted in the 2-position by an (alkynyl)hydrazone could be exceptionally activated towards intramolecular [4ps+2ps] cycloadditions by a simple activation (Scheme 1, A).…”