A new and simple synthesis of the pyrrole ring system from Michael acceptors and tosylmethylisocyanides

Leusen, A. M. Van; Siderius, H.; Hoogenboom, Bernard E.; Leusen, Daan van

doi:10.1016/s0040-4039(01)85244-8

Cited by 234 publications

(116 citation statements)

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“…Treatment of the electrophilic alkenes 1a′-n with monomethylated p-toluenesulfonylmethyl isocyanide (TosMIC), prepared from the commercially available TosMIC under phase transfer conditions according to van Leusen's protocol, 8) afforded the 2,3,4-polysubstituted pyrroles 2a′-n in 70-96% yields. The key intermediates 3a′-n were prepared by N-alkylation of the pyrroles 2a′-n using 2-bromo-4,5-dimethoxyphenethyl 4-methylbenzenesulfonate as alkylating agent, which had been prepared from 2-(3,4-dimethoxyphenyl)ethanol in the presence of sodium hydride (NaH) as a base in dry dimethyl sulfoxide (DMSO).…”

Section: Resultsmentioning

confidence: 99%

“…The ethyl cinnamates 1a′ and 1b were obtained from m-iodobenzoic acid or m-iodoaniline through a Heck reaction 6) and a subsequent amidation reaction 7) with the corresponding cyclic amines (Chart 3). It should be noted that all the α,β-unsaturated esters prepared were obtained exclusively as the (E)-isomers in good yields (78-98%).Treatment of the electrophilic alkenes 1a′-n with monomethylated p-toluenesulfonylmethyl isocyanide (TosMIC), prepared from the commercially available TosMIC under phase transfer conditions according to van Leusen's protocol,8) afforded the 2,3,4-polysubstituted pyrroles 2a′-n in 70-96% yields. The key intermediates 3a′-n were prepared by N-alkylation of the pyrroles 2a′-n using 2-bromo-4,5-dimethoxyphenethyl 4-methylbenzenesulfonate as alkylating agent, which had been prepared from 2-(3,4-dimethoxyphenyl)ethanol in the presence of sodium hydride (NaH) as a base in dry dimethyl sulfoxide (DMSO).…”

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5,6-Dihydropyrrolo[2,1-<i>a</i>]isoquinolines as Alternative of New Drugs with Cytotoxic Activity

Chávez-Santos

Reyes‐Gutiérrez

Torres‐Ochoa

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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In this study, the pyrrolo[2,1-a] isoquinolines 4a-n were synthesized in good yields in a three steps synthesis from the corresponding α,β-unsaturated esters starting materials. These compounds were tested on six human cancer cells lines to measure the cytotoxic activity as a function of the electronic properties and aromaticity of the substituent at the C-2 position of the pyrroloisoquinoline. Our results reveal that the cytotoxic activity could be explained in terms of the distribution of electronic density across the ring joined to C-2. Also, this study identified 3-hydroxy (4d) and 3-chloro (4j) derivatives with powerful cytotoxic activities. The IC 50 values of these compounds were found to be comparable to those of the commercially available Topotecan, Irinotecan, Etoposide, Tamoxifen, and Cisplatin.Key words pyrrolo[2,1-a]isoquinoline; synthesis; cytotoxic activity Cancer is a leading cause of death worldwide, and according to the World Cancer Research Fund International (GLOBOCAN 2012), an estimated 17.1 million new cancer cases and 10.0 million cancer-related deaths will occur in 2020, compared with 15.2 million and 8.9 million, respectively, in 2015.1) The most commonly diagnosed cancers worldwide are cancers of the skin (melanoma), prostate, lung, breast, and colorectum.2) Cancer poses a challenge to researchers searching for potent drugs that are capable of controlling cancer growth while minimizing side effects or the development of drug resistance. Our group is currently engaged in a program aimed at synthesizing novel heterocyclic compounds that inhibit the growth of cancer cells. We recently synthesized the pyrroloisoquinolines I-IV 3,4) ( Table 1) in a threestep protocol, and their cytotoxic activities were tested on six tumor cell lines: PC-3 (human prostatic adenocarcinoma), U-251 (human glioblastoma), K-562 (human chronic myelogenous leukemia), HCT-15 (human colorectal adenocarcinoma), MCF-7 (human mammary adenocarcinoma), and SKLU-1 (human lung adenocarcinoma). The results of this study (Table 1), allowed us to establish preliminary structure-activity relationship (Fig. 1) that revealed the importance of the aromatic substituent at the C-2 position, particularly when the substituent was a m-(cyclohexylmethylpiperazinamide)phenyl (I), phenyl (II), or m-(amino) phenyl (III), substituent, in combination with an ethyl ester at the C-1 position. Following up on these preliminary structure-activity studies, the present work sought to synthesize the novel pyrroloisoquinolines 4a-c (Fig. 2) to evaluate the effects of modifying the cyclohexylmethylpiperazinyl moiety on the antiproliferative activity. Compounds 4d-k (Fig. 2) were evaluated to determine the role of the phenyl ring substituent on the antiproliferative activity of the compound. Compounds 4l-n (Fig. 2) were evaluated to determine the effect of modifying the aromaticity of the C-2 substituent on the antiproliferative activity. Results and DiscussionChemistry The synthetic route to compounds 4a-n is depicted in Chart 1. Compounds 4a-n wer...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

5,6-Dihydropyrrolo[2,1-<i>a</i>]isoquinolines as Alternative of New Drugs with Cytotoxic Activity

Chávez-Santos

Reyes‐Gutiérrez

Torres‐Ochoa

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…法 [14] , 以第一步得到的 α,β-不饱和酮为原料, 与对甲基苯磺酰甲基异腈(Tosylmethyl isocyanide, TosMIC)在无水碱性环境下进行 Michael 加成得到相应的目标化合物. [16] , 可尝试测定目标化合物的 COX1/COX2 抑制活性, 以发掘这一类化合物更多的生理作用.…”

Section: 由于原料活性和空间位阻不同反应时间在 15 Min 到 4 H 不等 (2)环合反应: 采用范勒森(Van Leuunclassified

Synthesis and Anti-tumor Activity of Novel 3-Substituted-benzoyl-4-substituted-thienyl-pyrroles

陈简¹,

张袁魁²,

詹晓平³

et al. 2016

Chin. J. Org. Chem.

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29 novel 3-substituted-benzoyl-4-substituted-thienyl-pyrrole compounds 2a～5c were synthesized via aldol condensation and Van Leusen pyrrole reaction using substituted acetophenone and substituted 2-thenaldehyde as raw materials, and the cell proliferation inhibition efficacy of 2a～5c against human colon cancer (HCT-116), human gastric adenocarcinoma (SGC-7901), human cervical carcinoma (Hela) and human umbilical vein endothelial (HUVEC) cell lines were estimated. Then MTT assay was used to evaluate the anti-proliferative activity. The result indicated that some target compounds exhibited) proliferation inhibition efficacy against tumor cells, meanwhile didn't have significate inhibition effect on HUVEC. Compounds 2c, 2i, 3i, 3j, 4a～4f and 5c showed strong or moderate inhibition efficacy against HCT-116. The IC 50 value of 2j was 4.3 μmol•L -1 against Hela, and compounds 2i and 3j exhibited moderate inhibition efficacy against Hela. The IC 50 value of 3j was 10.5 μmol•L -1 against SGC-7901, and compounds 2i indicated moderate inhibition efficacy against SGC-7901. Compounds 2i and 3j showed broad anti-proliferative activity against all selected tumor cells.

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“…25 [3 + 2]-cycloadditions, [26][27][28] multicomponent reactions, [29][30][31] and ring contractions 32 or cyclizations, 33-36 a novel and efficient synthetic method for the synthesis of pyrroles is currently being pursued.…”

Section: Introductionmentioning

confidence: 99%

Spectroscopic Studies of Newly Synthesized Steroidal Pyrroles

Dar¹,

Mir²,

Jan³

et al. 2017

ECB

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A new and simple synthesis of the pyrrole ring system from Michael acceptors and tosylmethylisocyanides

Cited by 234 publications

References 10 publications

5,6-Dihydropyrrolo[2,1-<i>a</i>]isoquinolines as Alternative of New Drugs with Cytotoxic Activity

5,6-Dihydropyrrolo[2,1-<i>a</i>]isoquinolines as Alternative of New Drugs with Cytotoxic Activity

Synthesis and Anti-tumor Activity of Novel 3-Substituted-benzoyl-4-substituted-thienyl-pyrroles

Spectroscopic Studies of Newly Synthesized Steroidal Pyrroles

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