In Situ Allene Formation via Alkyne Tautomerization to Promote [4 + 2]-Cycloadditions with a Pendant Alkyne or Nitrile

Abstract

We have explored the net-[4 + 2]-cycloadditions of a variety of aryl (or alkenyl) alkynes. Tautomerization via base-catalyzed alkyne-to-allene isomerization produces a transient allene, which undergoes stepwise cyclization with not only a pendant alkyne but also a nitrile. The operative mechanisms for these reactions were studied by density functional theory and compared with the slower thermal cyclization of the precursor alkyne.Letter pubs.acs.org/OrgLett

Intramolecular Cyclization of Alkynylheteroaromatic Substrates Bearing a Tethered Cyano Group: A Strategy for Accessing Fused Pyridoheterocycles

“…We had also examined 11a in our earlier study, but the intermediate allene was not observed in that instance as well. 5 These results implied that the rate-limiting step for these reactions is the generation of the allenes and not the subsequent, more rapid cyclization events.…”

“…These observations were consistent with the reactivity we previously reported for the gem-dimethylated analogs of 11b−11d and are reflective of a slower tautomerization to the requisite allene intermediates 12. 5 To better understand the energetic differences required to achieve the cyclization of 11a vs 11b, we undertook density functional theory (DFT) calculations. We were unable to find a concerted transition state structure (TSS) connecting either of the allenes 12 with its corresponding dearomatized intermediate 15.…”

“…f 1 h. g 22 d. h 24 h. i 12 h. j 24 h. (c) Deuterium incorporation observed in the cyclization of 5f . (d) Additional HAR compounds reported in ref .…”

“…1 H NMR (500 MHz, CDCl 3 ): δ 9.20 (dd, J = 1.5, 0.8 Hz, 1H, H5), 8.01 (td, J = 1.5, 0.9 Hz, 1H, H9), 7.26 (d, J = 0.8 Hz, 1H, H8), 4.84 (d, J = 1.6 Hz, 2H, CH 2 ), 3.05 (s, 3H, MsCH 3 ), and 1.87 [s, 6H, C(CH 3 ) 2 ]. 13 4-Methoxy-6,6-dimethyl-7-(methylsulfonyl)-7,8-dihydro-6Hpyrrolo [3,4-b] [1,5]naphthyridine (7d). A solution of nitrile 5d (25.9 mg, 0.08 mmol) and TBD (6 mg, 0.04 mmol) in CHCl 3 (1.69 mL, 0.05 M) was allowed to stir at 23 °C.…”

“…Previously we reported the net-[4 + 2]-cycloaddition of an in situ-generated allenyl arene with a pendant alkyne or nitrile, which generates a naphthalene or quinoline derivative. 5 We wanted to expand the types of substrates amenable for this cyclization reaction with the goal of producing useful classes of heterocyclic compounds using a novel and complementary method. More specifically, if the C sp2 �C sp2 bond endocyclic to the aromatic ring bearing the alkyne in a substrate is within a heteroaromatic ring (HAR), such as the 2-pyridine 5a, a wider variety of heterocyclic products can be envisioned.…”