Functionalization of 1N-Protected Tetrazoles by Deprotonation with the Turbo Grignard Reagent

Abstract

1N-PMB-protected tetrazole undergoes C–H deprotonation with the turbo Grignard reagent, providing a metalated intermediate with increased stability. This can be used for the reaction with electrophiles such as aldehydes, ketones, Weinreb amides, and iodine. C–H deprotonation with the turbo Grignard reagent is compatible with the PMB-protecting group at the tetrazole, which can be cleaved using oxidative hydrogenolysis and acidic conditions. The method enables the tetrazole functionalization at the fifth position by overcoming the difficulties associated with retro [2 + 3] cycloaddition of the metalated intermediates.

Functionalization of Tetrazoles Bearing the Electrochemically Cleavable 1N-(6-Methylpyridyl-2-methyl) Protecting Group

“…The proposed mechanism for the electrochemical cleavage of the 6-methyl-pyridylmethyl group from tetrazole 9 is provided in Scheme 5 in analogy to the cleavage of the O-(4-nitro)benzyl group. 16 The reduction of the pyridylmethyl group at the cathode by sacrificing the Zn anode leads to an anion radical A, which fragments to pyridylmethyl radical B and tetrazole anion [10] − . The pyridyl radical B undergoes further reactions, like hydrogen abstraction, dimerization, oxidation, and/or reduction to give a mixture of byproducts.…”

“…10a , 67%. 1 H NMR (300 MHz, CD 3 OD) δ 7.35 (d, J = 8.7 Hz, 2H, Ar), 6.92 (d, J = 8.7 Hz, 2H, Ar), 6.10 (s, 1H, −C H –OH), 3.77 (s, 3H, −OC H 3 ) …”

“…10b , 65%. 1 H NMR (300 MHz, CD 3 OD) δ 7.54 (d, J = 8.5 Hz, 2H, Ar), 7.39 (d, J = 8.4 Hz, 2H, Ar), 6.14 (s, 1H, −C H –OH) …”

“…10e , 71%. 1 H NMR (400 MHz, CD 3 OD) δ 7.79 (dd, J = 7.6, 0.9 Hz, 2H), 7.49–7.39 (m, 4H), 7.32 (td, J = 7.5, 1.1 Hz, 2H) …”

“…9c Recently, we have reported generation organomagnesiun intermediates by C–H deprotonation of 1 N -PMB protected tetrazole ( 1 , PG = PMB), which was subsequently subjected to the reaction with electrophiles ( Scheme 1 ). 10 To extend the utility of this approach, 1 N -pyridyl-2-methyl protected tetrazoles 1a and 1b were investigated as substrates to give C–H functionalization products, which can be deprotected by the electrochemical reduction ( Scheme 1 ).…”