Regio- and Stereoselective Synthesis of Isoindolin-1-ones through BuLi-Mediated Iodoaminocyclization of 2-(1-Alkynyl)benzamides

Abstract

A simple and straightforward synthesis of isoindolin-1-ones is reported. Exclusive N-cyclization of the amide functional group, an ambident nucleophile, was accomplished for the cyclization of 2-(1-alkynyl)benzamides using n-BuLi-I/ICl. The methodology works with the primary amide and affords the desired isoindolinones in yields of 38-94%. Interestingly, the isolated products exhibit a Z-stereochemistry across the C═C double bond. The reaction mechanism involving the formation of either a vinylic anion or an intimate ion pair intermediate is proposed.

Silyl Group‐Directed 6‐exo‐dig Iodocyclization of Homopropargylic Carbamates and Amides

“…[2] We also have developed 5-endo-dig-type iodocyclizationo fa ryl or vinyl group-substituted alkynes for the construction of heterocyclic compounds such as benzofuran, [3a] pyrazole, [3b] isoxazole, [3c] pyrrole, [3d] and their dihydro-derivatives. The endo-type cyclization could be also directed by nitrogen, [4a,b] sulfur, [4c,d] and selenium [4e,f] atoms.T he iodocyclization of arylalkynes tethered nucleophiles at the o-position proceeds in exo-mode for the same reason (Scheme 1b), [5] and when substituent Ro na lkyne was silyl group, not only aryl group (resonance effect) but also silyl group (b-silyl effect) might directc yclization mode to exo-type. On the other hand, solely silyl-group-directed exo-type iodocyclization of alkynes [6] by the b-silyl effect [7] has not yet been reported( Scheme 1c).…”

“…As as imilar bulky alkyl-substituent, tBu group also directed the cyclization mode to 6-exo type, however,5 -endo-dig product 3d was obtained as ab yproduct (entry 4). We have already reported that the iodocyclizationo fl ess bulky nBu group-possessing substrate 1e caused decomposition, and Ph group directed the cyclization mode to 5-endo type leading to 3f (entries [5][6]. [3d] Te rminal alkyne 1g tended to exo-type iodocyclization, [10] but the consumption of 1g was slower thant hato f1a and diiodop roduct 2g' was afforded as am ajor product in 24 % yield accompanied with 2g in 9% yield (entry 7).W econsidered that bulky substituent on alkynem ight direct 5-endo mode iodocyclization of carbamate duet ot he repulsion witha lkoxycarbonyl group when electronic effectw as scarcelya ffected( entries 4and 7),and electroniceffectstrongly workedonthese reactions (entries 1a nd 6).…”

Theoretical Insight into the Mechanism and Origin of Divergent Reactivity in the Synthesis of Benzo-Heterocycles from o-Alkynylbenzamides Catalyzed by Gold and Platinum Complexes

“…o -Alkynylbenzamides are a class of powerful dual-function building blocks synthesizing various N / O -heterocyclic architectures through chemo- and regioselective intramolecular annulations, − including base-mediated 5- exo -azo cyclization, − Lewis acid-catalyzed 6- endo -azo cyclization, , and transitional metal-catalyzed 5- exo - or 6- endo -oxy cyclization. − Excitingly, Jiang et al recently reported a controllable approach for constructing four different heterocyclic compounds from o -alkynyl- N -methoxyl-benzamides, as indicated in Scheme by a representative o -alkynylbenzamide with R 1 = Ph. Both chemo- and regioselectivities were perfectly achieved by tuning the catalyst or ligand.…”

Ring Opening/Site Selective Cleavage in N-Acyl Glutarimide to Synthesize Primary Amides

“…This result intimates that our approach can be applied in both batch and flow systems. Meanwhile, the synthetic application has been extended to the synthesis of 2ah , which is an emerging precursor for heterocyclization reactions. , First, Sonogashira coupling between 1-(2-iodobenzoyl)­piperidine-2,6-dione ( 1m ) and phenyl acetylene afforded 1ah in 85% yield. It further transformed to primary amide 2ah using our standard condition with an isolated yield of 93% (Scheme b).…”