An Alkyne–Isocyanide Cycloaddition/Boulton-Katritzky Rearrangement/Ring Expansion Reaction: Access to 9-Deazaguanines

Luo, Jianghao; Ma, Haowen; Wu, Kaifu; Ao, Yun-Lin; Zhou, Wei; Cai, Qian

doi:10.1021/acs.orglett.3c00575

Org. Lett.

2023

DOI: 10.1021/acs.orglett.3c00575

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An Alkyne–Isocyanide Cycloaddition/Boulton-Katritzky Rearrangement/Ring Expansion Reaction: Access to 9-Deazaguanines

Jianghao Luo

Haowen Ma

Kaifu Wu

et al.

Abstract: An alkyne–isocyanide [3 + 2] cycloaddition followed by a Boulton–Katritzky rearrangement and a ring expansion is demonstrated. Different from the typical Boulton-Katritzky rearrangement, which forms five-membered ring products, the rearrangement-ring expansion method provides a mild, efficient, and atom-economical access to fused 9-deazaguanine structures in high yields.

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Synthesis of Pyrrolo[3,2-d]pyrimidin-4-ones via Cascade Alkyne−isocyanide [3＋2] Cycloaddition/Boulton-Katritzky Rearrangement/Ring Expansion Process^★

Luo,

Ma,

Zhang

et al. 2023

Acta Chimica Sinica

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Pyrrolo[3,pyrimidin-4-ones are valuable structural motifs in many bioactive compounds and pharmaceuticals. Such structures have received extensive attentions from synthetic community. Two general strategies have been developed for the formation of the fused pyrimidine-pyrrole structure: one is to construct the pyrimidine ring from substituted pyrroles, and the other is to construct the pyrrole ring from 5,6-functionalized pyrimidines. However, these methods have generally required multiple synthetic steps and the use of starting materials with uncommon functional groups, and also suffered with other drawbacks such as harsh reaction conditions and limited substrate scope. Thus, it is highly desirable to develop facile and practical approaches for the construction of structural diversified pyrrolo [3,2-d]pyrimidin-4-ones. Very recently, we have developed an alkyne-isocyanide [3＋2] cycloaddition/Boulton-Katritzky rearrangement/ring expansion reaction for the synthesis of 9-deazaguanines from 1,2,4-oxadiazole-derived propiolamides with isocyanides. Different from traditional Boulton-Katritzky rearrangement (BKR), which is to form stable five-membered rings, the method provides a facile access to fused heterocycles via forming an unstable BKR spirocyclic intermediate and followed by a spontaneous ring expansion via acyl migration. In this work, to further expand the scope of this method, the [3＋2] cycloaddition/BKR-ring expansion reactions of isoxazole-derived propiolamides with isocyanides were developed. The reactions were performed with CuI as the catalyst and Cs2CO3 as the base in toluene/N,N-dimethylformamide (DMF) (1∶3, V∶V) at room temperature for the alkyne-isocyanide [3＋2] cycloaddition and then at 110 ℃ for the BKR-ring expansion process. A variety of isoxazolederived propiolamides and isocyanides were well tolerated in the reactions and afforded the desired pyrrolo [3,2d]pyrimidin-4-one products in satisfactory yields. The control experiments were performed to elucidate the reaction process: copper catalyst is used only for the alkyne-isocyanide [3＋2] cycloaddition, but no necessary for the base-promoted BKR-ring expansion process. Compared to the traditional methods for such skeletons, the approach features readily available starting materials, broad substrate scope, short steps, and structural diversification. Keywords alkyne-isocyanide [3 ＋ 2] cycloaddition; Boulton-Katritzky rearrangement (BKR); ring expansion; pyrrolo [3,2-d] pyrimidin-4-one; cascade reaction

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Synthesis of Pyrrolo[3,2-d]pyrimidin-4-ones via Cascade Alkyne−isocyanide [3＋2] Cycloaddition/Boulton-Katritzky Rearrangement/Ring Expansion Process^★

Luo,

Ma,

Zhang

et al. 2023

Acta Chimica Sinica

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An Alkyne–Isocyanide Cycloaddition/Boulton-Katritzky Rearrangement/Ring Expansion Reaction: Access to 9-Deazaguanines

Cited by 1 publication

References 63 publications

Synthesis of Pyrrolo[3,2-d]pyrimidin-4-ones via Cascade Alkyne−isocyanide [3＋2] Cycloaddition/Boulton-Katritzky Rearrangement/Ring Expansion Process^★

Synthesis of Pyrrolo[3,2-d]pyrimidin-4-ones via Cascade Alkyne−isocyanide [3＋2] Cycloaddition/Boulton-Katritzky Rearrangement/Ring Expansion Process^★

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An Alkyne–Isocyanide Cycloaddition/Boulton-Katritzky Rearrangement/Ring Expansion Reaction: Access to 9-Deazaguanines

Cited by 1 publication

References 63 publications

Synthesis of Pyrrolo[3,2-d]pyrimidin-4-ones via Cascade Alkyne−isocyanide [3＋2] Cycloaddition/Boulton-Katritzky Rearrangement/Ring Expansion Process★

Synthesis of Pyrrolo[3,2-d]pyrimidin-4-ones via Cascade Alkyne−isocyanide [3＋2] Cycloaddition/Boulton-Katritzky Rearrangement/Ring Expansion Process★

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Synthesis of Pyrrolo[3,2-d]pyrimidin-4-ones via Cascade Alkyne−isocyanide [3＋2] Cycloaddition/Boulton-Katritzky Rearrangement/Ring Expansion Process^★

Synthesis of Pyrrolo[3,2-d]pyrimidin-4-ones via Cascade Alkyne−isocyanide [3＋2] Cycloaddition/Boulton-Katritzky Rearrangement/Ring Expansion Process^★