Scope of the Inverse Electron Demand Diels–Alder Reactions of 1,2,3-Triazine

Abstract

An examination of the scope of the inverse electron demand Diels–Alder reactions of the parent unsubstituted 1,2,3-triazine is described including the first report of its unique capabilities for participating in previously unexplored [4 + 2] cycloaddition reactions with heterodienophiles.

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“…With the requisite tricyclic ketone 12 in hand, its use in a key inverse electron demand Diels–Alder reaction with 5-carbomethoxy-1,2,3-triazine 13a ( 14 , ALD00106) 22 was explored (Scheme 2). The enamine 13 was prepared by treatment of ketone 12 with pyrrolidine (4Å MS, CHCl 3 , 25 °C, 8 h) and its Diels–Alder reaction with the 1,2,3-triazine 14 (4 equiv, 0.1 M CHCl 3 , 25 °C, 3 h) 23 proceeded rapidly to provide the pyridine cycloaddition product 15 (75% from ketone 12 ) as a single regioisomer without detection of the intermediates even when conducted at room temperature.…”

“…The inclusion of 4Å MS in the reaction mixture or use of higher reaction concentrations (0.3 M) or temperatures (65 °C) even with prolonged reaction times (15 h) did not further improve the already excellent cycloaddition yield. The reaction of the 1,2,3-triazine 14 exhibited the now characteristic exclusive N1/C4 cycloaddition regioselectivity 13 with the nucleophilic carbon of the electron-rich enamine attached to C4, benefiting from the complementary azadiene substitution (C5-CO 2 Me). Importantly, the remarkable reactivity of 14 imparted by the C5 electron-withdrawing substituent provides substantially improved cycloaddition reactivity toward enamine dienophiles such that the reaction with 13 occurred at 25 °C, representing a synthetic scope not observed with 1,2,3-triazine itself.…”

“…This strategy deliberately permits additional cycloaddition reactions of the advanced electron-rich dienophile 13 with other reactive heterocyclic azadienes ( 19 – 24 ) for the late-stage, divergent preparation of a series of complementary heterocyclic derivatives (Scheme 4). Representative of this and without individual optimization, this included the reaction of 1,2,3-triazine 13d ( 19 , ALD00112), 22 5-bromo-1,2,3-triazine ( 20 ), 13a 4-carbomethoxy-1,2,3-triazine 13b ( 21 , ALD00104), 22 and 4,6-dicarboethoxy-1,2,3-triazine 13b ( 22 , ALD00110), 22 each of which displayed the 1,2,3-triazine C4/N1 mode of cycloaddition and provided the alternatively substituted pyridines 25 – 28 , 1,3,5-triazine 30 ( 23 ) 22 that provided the pyrimidine 29 , and 3,6-dicarbomethoxy-1,2,4,5-tetrazine 31 ( 24 , ALD00098) 22 that provided the substituted pyridazine 30 and served further as a precursor to the pyrrole 31 via a unique zinc-mediated reductive ring contraction. 32 It is of note that it was the exploration of the ergot alkaloids at Lilly and the preparation of their simplified ring systems that provided the first synthetic use of such heterocyclic azadiene Diels–Alder reactions (use of 30 ) and the first report of the effective zinc-mediated pyridazine to pyrrole reductive ring contraction reaction.…”

“…The first of these reactions is a powerful intramolecular Larock indole cyclization 10,11 for formation of an embedded tricyclic indole isomeric with Uhle’s 12 and Kornfeld’s 6a ketones widely used in accessing the ergot alkaloids (Figure 2). The second of the reactions is a powerful inverse electron demand Diels–Alder reaction of 5-carbomethoxy-1,2,3-triazine with a conjugated enamine for the regiospecific introduction of a functionalized pyridine, 13 serving as the precursor for a subsequent and remarkably diastereoselective reduction to the N -methylpiperidine D-ring. An additional and deliberate key feature of the approach is that use of the same advanced ketone-derived enamine and a series of inverse electron demand [4 + 2] cycloaddition reactions of heterocyclic azadienes 14 permitted the divergent 15 preparation of isomeric and alternative heterocyclic derivatives bearing deep-seated structural changes to the ergot skeleton not as readily accessible by conventional approaches.…”

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“…Whereas the Synder group showed the importance of the triazine as a diene reaction partner in the DAR inv in 1,2,4-triazine studies [47][48][49] , the Boger group systematically investigated the 1,2,3-triazines 50,51 ; earlier, the group exhibited expertise in the research of the DAR inv azadiene chemistry in the field of the total synthesis of nature identical molecules 4,5,52 .…”