Synthesis of Indole Analogues Based on 1,3⁃Cyclohexanedione Building Blocks

doi:10.3969/j.issn.1672-6952.2022.02.004

Abstract

Abstract:

In this paper, used cheap, easy?to?obtain and multi?reactive 2?position single?side chain substituted 1,3?cyclohexanedione compound as a synthetic building block, used phenyl tetrafluoroborate diazonium salt as raw material, and adopt classic Japp?Klingemann fischer indole synthesis method, it is ring?opening fragmentation and following ring?closing to obtain more valuable multi?substituted indole structural units. Among them, 2?methyl?1,3?cyclohexidone and a diazonium salt of phenyl tetrafluoroborate were used as raw materials, under reflux conditions of p?toluenesulfonic acid as the acid reagent and toluene as the solvent, when the reaction was carried out for 15.0 h, the closed ring indole products were obtained with a yield of 49%; Meanwhile, 2?benzyl?1,3?cyclohexidone and a diazonium salt of phenyl tetrafluoroborate were used as raw materials, under the condition of heating and refluxing in a sealed tube of 30% hydrochloric acid ethanol solution, when the reaction was carried out for 0.5 h, the closed ring indole products were obtained with a yield of 98%. This methodology can be applied to the total synthesis of indole alkaloids.

Key words: 1,3?cyclohexanedione, Indole analogs, Fragmentation, Japp?Klingemann fischer indole synthesis method

摘要：

以廉价易得和具备多种反应性的2位单侧链取代的1,3?环己二酮化合物作为合成砌块，以苯基四氟硼酸重氮盐作为原料，采用经典的Japp?Klingemann费舍尔吲哚合成法，对其进行开环碎裂化，进而环合，得到更有价值的多取代吲哚结构单元。其中，以2?甲基?1,3?环己二酮和苯基四氟硼酸重氮盐作为原料，在对甲苯磺酸作为酸试剂、甲苯为溶剂的回流条件下，反应15.0 h，能以49%的产率得到关环吲哚产物；以2?苄基?1,3?环己二酮和苯基四氟硼酸重氮盐作为原料，在体积分数为30%的盐酸乙醇溶液的封管加热回流条件下，反应0.5 h，能以98%的产率得到关环吲哚产物。该合成方法学可应用于吲哚类生物碱的全合成研究中。

关键词: 1,3?环己二酮, 吲哚类似物, 碎裂化, Japp?Klingemann 费舍尔吲哚合成法

CLC Number:

TE624

Shuang Xi, Rui Wang. Synthesis of Indole Analogues Based on 1,3⁃Cyclohexanedione Building Blocks[J]. Journal of Liaoning Petrochemical University, 2022, 42(2): 23-29.

席爽, 王锐. 基于1，3⁃环己二酮砌块的吲哚类似物合成研究[J]. 辽宁石油化工大学学报, 2022, 42(2): 23-29.

Figures/Tables 13

References 15

1	Jiricek J，Blechert S.Enantioselective synthesis of （-）⁃gilbertine via a cationic cascade cyclization［J］.Journal of the American Chemical Society，2004，126（11）：3534⁃3538.
2	Findlay S P，Dougherty G.The synthesis of certain substituted indoleacetic acids［J］.The Journal of Organic Chemistry，1948，13（4）：560⁃569.
3	Hernández⁃Benitez R I，Zárate⁃Zárate D，Francisco D，et al. Palladium⁃catalyzed synthesis of diarylamines and 1⁃and 2⁃oxygenated carbazoles：Total syntheses of natural alkaloids clauraila A，clausenal， clausine P，and 7⁃methoxy⁃O⁃methylmukonal ［J］.Synthesis，2017，49（18）：4357⁃4371.
4	Kamijo S，Dudley G B.Tandem nucleophilic addition/fragmentation reactions and synthetic versatility of vinylogous acyl triflates［J］.Journal of the American Chemical Society，2006，128（19）：6499⁃6507.
5	Ma S Q，Long D，Chen P Q，et al. Synthesis of 2，3⁃disubstituted indoles via a tandem reaction［J］.Organic Chemistry Frontiers，2020，7（18）：2689⁃2695.
6	陈和举，欧阳贵平，陈洪，等.环己二酮类化合物的研究进展［J］.精细化工中间体，2016，46（3）：1⁃9.
7	Tian C，Lei X Q，Wang Y H，et al. Total syntheses of periconiasins A⁃E［J］.Angewandte Chemie⁃International Edition，2016，55（24）：6992⁃6996.
8	Roudier M，Constantieux T，Quintard A，et al.Enantioselective synthesis of medium⁃sized⁃ring lactones by organnocatalytic michael addition followed by reductively initiated fragmentation［J］.European Journal Organic Chemistry，2015（26）：5709⁃5711.
9	Kei Y，Kosuke O，Hirofumi U，et al.A concise enantioselective total synthesis of （-）⁃deoxoapodine［J］.Angewandte Chemie International Edition，2020，59（51）：23089⁃23093.
10	Zhang Z，Xie S J，Cheng B，et al.Enantioselective total synthesis of （+）⁃arboridinine［J］.Journal of the American Chemical Society，2019，141（17）：7147⁃7154.
11	Zhou J，Tan D X，Han F S.A divergent enantioselective total synthesis of post‐iboga indole alkaloids［J］.Angewandte Chemie International Edition，2020，59（42），18731⁃18740.
12	Ryo T，Atsushi M，Hiroki O，et al.Total synthesis of alkaloids using both chemical and biochemical methods［J］.Natural Product Report，2020，37（8）：1098⁃1121.
13	Nadezhda V V，Ekaterina A V.Recent advances in total synthesis of alkaloids from α，β‐unsaturated aldehydes［J］.ChemistrySelect，2020，5（31）：9579⁃9589.
14	何龙，马金波，于芳.对甲砜基甲苯选择性氧化的研究与应用［J］.石油化工高等学校学报，2020，33（1）：12⁃16.
15	李振亚，刘志波，于芳.二胺单保护方法工艺的研究［J］.辽宁石油化工大学学报，2020，40（1）：31⁃34. （编辑宋锦玉）

序号	酸试剂	溶剂	温度/ ℃	时间/h	产率/ %
1	对甲苯磺酸	甲苯	110	15.0	49
2	对甲苯磺酸	甲苯	80	12.0	27
3	多聚磷酸	甲苯	110	12.0	痕量
4	三氟乙酸	甲苯	110	12.0	0
5	1.5%盐酸	乙酸	98	12.0	0
6	三氟甲磺酸	甲苯	100	0.5	48
7	三氟甲磺酸	甲苯	80	0.5	34
8	三氟甲磺酸	1,2⁃二氯乙烷	80	5.5	25
9	10.0%盐酸	乙醇	80	1.0	0

序号	酸试剂	溶剂	温度/ ℃	时间/h	产率/ %
1	对甲苯磺酸	甲苯	110	15.0	49
2	对甲苯磺酸	甲苯	80	12.0	27
3	多聚磷酸	甲苯	110	12.0	痕量
4	三氟乙酸	甲苯	110	12.0	0
5	1.5%盐酸	乙酸	98	12.0	0
6	三氟甲磺酸	甲苯	100	0.5	48
7	三氟甲磺酸	甲苯	80	0.5	34
8	三氟甲磺酸	1,2⁃二氯乙烷	80	5.5	25
9	10.0%盐酸	乙醇	80	1.0	0

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