铱催化中氮茚衍生物的Friedel-Crafts类型不对称烯丙基取代反应

doi:10.6023/A21050198

摘要/Abstract

本工作报道了金属铱催化烯丙醇与中氮茚衍生物Friedel-Crafts类型的不对称烯丙基取代反应. 该方法在温和条件下, 以优秀的收率以及对映选择性控制合成了一系列C3位烯丙基化的中氮茚衍生物, 为构建手性中氮茚化合物提供了一条新策略.

Indolizine is an important N-containing heterocyclic nucleus and their derivatives display interesting biological activities. The development of synthetic methods towards indolizine derivatives has attracted extensive attention. Despite the rapid growth in this area, asymmetric synthesis of indolizine derivatives has been rarely reported. Ir-catalyzed asymmetric allylic substitution reaction is an efficient method for the enantioselective construction of C-C or C-X bonds, furnishing terminal olefins bearing a stereogenic center at the allylic position with excellent regio- and enantioselectivities. In this regard, various electron-rich arenes, including indoles, pyrroles, naphthols, have been applied as the nucleophiles via Friedel-Crafts type process in the allylic substitution reactions. As a class of constitutional isomers of indoles, indolizines are now demonstrated as suitable nucleophiles in transition-metal-catalyzed allylic substitution reactions. Herein, an iridium- catalyzed enantioselective allylic substitution of allylic alcohol with indolizine is reported. A broad range of 3-allylindolizines were accessed with high yields (83%~95%) and excellent enantioselectivities (95%~>99%ee). A general procedure for the asymmetric allylation of indolizines is described in the following: A flame-dried Schlenk tube was cooled to room temperature and filled with argon. To this flask were added [Ir(cod)Cl]₂ (4.0 mg, 0.006 mmol, 3 mol%) and (S)-L1 (12.1 mg, 0.024 mmol, 12 mol%). After the flask was evacuated and refilled with argon for three times, freshly distilled dichloromethane (DCM) (2 mL) were added. After the mixture was stirred for 15 min at room temperature, indolizines (0.2 mmol, 1.0 equiv.), allylic alcohols (0.4 mmol, 2.0 equiv.) and (PhSO₂)₂NH (18.0 mg, 0.06 mmol, 30 mol%) were added under argon atmosphere. The reaction mixture was stirred at room temperature and monitored by thin-layer chromatography (TLC). Once indolizines were consumed, the reaction was diluted with water (5 mL), and the mixture was extracted with EtOAc (10 mL×3). The organic layer was collected, dried over Na₂SO₄ and then concentrated in vacuo to afford the crude product. This crude material was purified by column chromatography to afford the product.

Key words: iridium-catalyzed, allylic substitution reaction, enantioselectivity, indolizine, allylic alcohol

引用此文

杨普苏, 刘晨旭, 张文文, 游书力. 铱催化中氮茚衍生物的Friedel-Crafts类型不对称烯丙基取代反应[J]. 化学学报, 2021, 79(6): 742-746.

Pusu Yang, Chen-Xu Liu, Wen-Wen Zhang, Shu-Li You. Ir-Catalyzed Enantioselective Friedel-Crafts Type Allylic Substitution of Indolizines[J]. Acta Chimica Sinica, 2021, 79(6): 742-746.

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图/表 6

图1. 含中氮茚结构的代表性活性分子

Figure 1. Representative bioactive molecules containing indolizine scaffold

图2. 铱催化Friedel-Crafts类型烯丙基取代反应

Figure 2. Iridium-catalyzed Friedel-Crafts type allylic substitution reactions

Entry	Additive	Ligand	x mol%	Solvent	NMR yield^b/%	ee ^c/%
1	None	L1	0	DCM	trace	N.D.^d
2	Zn(OTf)₂	L1	100	DCM	>95	98
3	Fe(OTf)₂	L1	100	DCM	>95	99
4	Y(OTf)₃	L1	100	DCM	>95	99
5	3,5-Cl₂C₆H₃CO₂H	L1	100	DCM	94	>99
6	(PhO)₂PO₂H	L1	100	DCM	95	>99
7	(PhSO₂)₂NH	L1	100	DCM	>95	>99
8	(PhSO₂)₂NH	L1	100	THF	>95	98
9	(PhSO₂)₂NH	L1	100	MeCN	>95	95
10	(PhSO₂)₂NH	L1	100	toluene	>95	98
11	(PhSO₂)₂NH	L1	30	DCM	>95	>99
12	(PhSO₂)₂NH	L1	10	DCM	74	>99
13	(PhSO₂)₂NH	L2	30	DCM	68	>99
14	(PhSO₂)₂NH	L3	30	DCM	>95	>99
15^e	(PhSO₂)₂NH	L1	30	DCM	94	>99

表1. 反应条件优化a

Table 1. Optimization of the reaction conditions

表2. 烯丙醇底物范围考察a

Table 2. Substrate scope for allyl alcohols

表3. 中氮茚底物范围考察a

Table 3. Substrate scope for indolizine derivatives

图3. 可能的反应机理

Figure 3. Proposed reaction mechanism

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