串联炔-异氰[3＋2]环加成/Boulton-Katritzky重排/扩环反应构建吡咯并[3,2-d]嘧啶-4-酮化合物★

doi:10.6023/A23040164

摘要/Abstract

吡咯并[3,2-d]嘧啶-4-酮骨架在药物设计中广受关注, 该骨架是众多生物活性分子的核心结构单元. 目前已报道的吡咯并[3,2-d]嘧啶-4-酮骨架的合成方法有限且存在原料不易得、反应条件苛刻、合成步骤长、产率低和产物结构不易修饰等缺陷. 因此, 发展吡咯并[3,2-d]嘧啶-4-酮骨架的新型高效合成策略在合成化学与药物化学领域均具有重要的研究意义. 最近, 一种通过串联炔-异氰[3＋2]环加成/Boulton-Katritzky重排/酰基迁移扩环反应构建9-去氮鸟嘌呤化合物的新方法被报道, 该方法以氮杂异噁唑衍生的炔丙酰胺化合物和异氰化合物为原料. 鉴于异噁唑化合物也是Boulton-Katritzky重排反应常使用的底物, 此工作进一步研究了一系列异噁唑衍生的炔丙酰胺化合物与异氰化合物的上述串联反应, 成功构建了一系列吡咯并[3,2-d]嘧啶-4-酮化合物.

关键词: 炔-异氰[3＋2]环加成, Boulton-Katritzky重排, 扩环反应, [3,2-d]嘧啶-4-酮, 串联反应

Pyrrolo[3,2-d]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 isoxazole- derived propiolamides and isocyanides were well tolerated in the reactions and afforded the desired pyrrolo[3,2- d]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.

Key words: alkyne-isocyanide [3＋2] cycloaddition, Boulton-Katritzky rearrangement (BKR), ring expansion, pyrrolo[3,2-d] pyrimidin-4-one, cascade reaction

引用此文

罗江浩, 马浩文, 张杰豪, 周伟, 蔡倩. 串联炔-异氰[3＋2]环加成/Boulton-Katritzky重排/扩环反应构建吡咯并[3,2-d]嘧啶-4-酮化合物^★[J]. 化学学报, 2023, 81(8): 898-904.

Jianghao Luo, Haowen Ma, Jiehao Zhang, Wei Zhou, Qian Cai. Synthesis of Pyrrolo[3,2-d]pyrimidin-4-ones via Cascade Alkyne−isocyanide [3＋2] Cycloaddition/Boulton-Katritzky Rearrangement/Ring Expansion Process^★[J]. Acta Chimica Sinica, 2023, 81(8): 898-904.

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图/表 6

图1. 具有吡咯并[3,2-d]嘧啶-4-酮结构单元的生物活性分子

Figure 1. Examples of pyrrolo[3,2-d]pyrimidin-4-one-related bioactive compounds

图2. 炔-异氰[3＋2]环加成/BK重排/扩环反应构建吡咯并[3,2-d]嘧啶-4-酮化合物

Figure 2. An alkyne-isocyanide [3＋2] cycloaddition/BKR/ring expansion reaction for the construction of pyrrolo[3,2-d]pyrimidin-4-one derivatives

Entry	Catalyst	Solvent (V∶V)	Base
1^c	CuI	Tol/DMF (1∶3)	Cs₂CO₃	Trace	90
2^d	CuI	Tol/DMF (1∶3)	Cs₂CO₃	Trace	88
3^e	CuI	Tol/DMF (1∶3)	Cs₂CO₃	64	18
4	CuI	Tol/DMF (1∶3)	Cs₂CO₃	79	Trace
5^f	CuI	Tol/DMF (1∶3)	Cs₂CO₃	74	Trace
6	CuBr	Tol/DMF (1∶3)	Cs₂CO₃	59	Trace
7	Cu₂O	Tol/DMF (1∶3)	Cs₂CO₃	46	Trace
8	CuI	Tol	Cs₂CO₃	12	83
9	CuI	DMF	Cs₂CO₃	67	Trace
10	CuI	DMSO	Cs₂CO₃	61	Trace
11	CuI	Tol/DMF (1∶3)	LiO^tBu	42	Trace
12	CuI	Tol/DMF (1∶3)	NaOH	48	Trace

表1. 炔-异氰[3＋2]环加成/BK重排/扩环反应条件优化a

Table 1. Optimization of reaction conditions for alkyne-isocyanide [3＋2] cycloaddition/BKR/ring expansion reaction

图3. 炔-异氰[3＋2]环加成/BK重排/扩环反应底物普适性考察

Figure 3. Substrate scope for alkyne-isocyanide [3＋2] cycloaddition/BKR/ring expansion reaction

图4. 克级规模反应和产物转化

Figure 4. Gram-scale reaction and synthetic transformation of 3a

图5. 炔-异氰[3＋2]环加成/BK重排/扩环反应控制实验

Figure 5. Control experiments for alkyne-isocyanide [3＋2] cycloaddition/BKR/ring expansion reaction

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