HETEROCYCLES

■ Contents

■ Recent Advances in the Chemistry and Synthetic Uses of Magnesium Carbenoids

Tsuyoshi Satoh*

*Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka 1-3, Shinjuku-ku, Tokyo 162-8601, Japan

Abstract

Carbenes and carbenoids have long been recognized to be a highly reactive species and are frequently used as intermediates in organic synthesis. However, most of the carbenes and carbenoids are relatively short-lived and are too reactive to control. Recently, the author’s group found that the treatment of aryl α-chloroalkyl sulfoxides and α-chlorovinyl p-tolyl sulfoxides with a Grignard reagent at low temperature gave magnesium carbenoids via the sulfoxide-magnesium exchange reaction. Magnesium carbenoids, cyclopropylmagnesium carbenoids, cyclobutylmagnesium carbenoids, magnesium alkylidene carbenoids, and magnesium β-oxido carbenoids were generated from the corresponding α-chloro sulfoxides with a Grignard reagent at low temperature. The generated magnesium carbenoids were proved to be relatively stable and they showed very interesting reactivity with several nucleophiles to afford many unprecedented new reactions. The present review is written for the purpose of reflecting recent achievements in the areas of chemistry and synthetic application of above-mentioned magnesium carbenoids. This review mainly covers literature from 2006 to late 2011.

■ First Synthesis of 2-Heteroarylazulenes by the Electrophilic Substitution of Azulene with Triflate of N-Containing Heterocycles

Taku Shoji,* Yuta Inoue, Shunji Ito, Tetsuo Okujima, and Noboru Morita

*Department of Chemistry, Faculty of Science, Shinshu University, Asahi, Matsumoto 390-8621, Japan

Abstract

An efficient synthesis of 2-heteroarylazulene derivatives was established via electrophilic substitution. The reaction of 6-dimethylamino-1,3-di(methylthio)azulene (1a) with the triflate of N-containing heteroarenes proceeded in the presence of excess heteroarenes to afford the corresponding 2-dihydroheteroarylazulene derivatives 3−7. The 2-dihydroheteroarylazulene derivatives were readily converted into the desired 2-heteroarylazulene derivatives 8−11 by the treatment with KOH in alcohols in excellent yields, except for 4 and 5.

■ Unexpected Tandem Reaction of New Type Morita-Baylis-Hillman Adducts Promoted by [Hmim]HSO4/NaNO3 System

Weihui Zhong,* Guan Wang, and Kai Chen

*Key Laboratory of Pharmaceutical Engineering of Ministry of Educations, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310014, China

Abstract

A tandem reaction of new type Baylis-Hillman adducts 1 was prompted by ionic liquid [Hmim]HSO4/NaNO3 system and the unexpected products 6-aryl-2H-pyran-3-carboxylates 2 and imidazolium salts 3 were efficiently formed via the rearrangement and substitution reaction. While mediated by [Emim]HSO4/NaNO3 system, the key intermediates 4 were isolated. A plausible mechanism for the transformation was given.

■ 1,3-Dipolar Cycloaddition Reaction in Porphyrin Systems with Functionalized Alkyl Nitrile Oxides — Synthesis of Isoxazoline-Fused Chlorins

Przemysław Wyrębek, Agnieszka Mikus, and Stanisław Ostrowski*

*Institute of Chemistry, Uniwersytet Przyrodniczo-Humanistyczny w Siedlcach, ul. 3 Maja 54, 08-110 Siedlce, Poland

Abstract

meso-Tetraphenylporphyrin reacts at higher temperature with unstable alkyl nitrile oxides (R–C≡N→O) affording isoxazoline-fused chlorins according to dipolar [3+2]-cycloaddition pathway. The respective nitrile oxides were in situ generated from the corresponding functionalized nitroalkanes in the presence of base (NEt3, DABCO) and dehydrating agent (PhNCO, (Boc)2O). Substituent R bearing diverse of functionality allows synthesis of very attractive moieties which may be of potential use as sensitizers in photodynamic therapy. The products obtained are also suitable intermediates for further derivatization of porphyrins.

■ Iterative One Pot Reactions of a Chiral Sulfamidate with 2,4,6-Trichloropyridine: Regiocontrolled Synthesis of Linear and Angular Chiral Dipyrrolidino Pyridines

Paul Hebeisen,* André Alker, and Markus Buerkler

*Discovery Chemistry, Pharmaceutical Division, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland

Abstract

The product of the ring opening of a chiral sulfamidate with the 3-lithiopyridine species obtained by deprotonation of 2,4,6-trichloropyridine with n-BuLi can be deprotonated again in situ with n-BuLi and reacted with a second equivalent of the sulfamidate furnishing bis a β-aminoethyl pyridine derivative which can be cyclized regioselectively to linear or angular chiral dipyrrolidino pyridines.

■ Stereoselective Synthesis of Melatonin Receptor Agonist Ramelteon via Asymmetric Michael Addition

Xuan Zhang, Wei Yuan, Yu Luo, Qing-Qing Huang, and Wei Lu*

*Department of Chemistry, Room B 423, Science Building, Institute of Medicinal Chemistry, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China

Abstract

Highly enantioselective asymmetric Michael addition was used to synthesize ramelteon and its analogue. The asymmetric strategy provides an efficient approach for the medicinal modification of ramelteon with high ee value.

■ Useful Building Blocks for the Stereocontrolled Assembly of 2,3,5-Trisubstituted Pyrrolidines

Charles Dylan Turner and Marco A. Ciufolini*

*Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver B.C., V6T 1Z1, Canada

Abstract

A protected pyroglutamol derivative is converted into an all-cis, differentially protected 2,3,5-trisubstituted pyrrolidine, which is amenable to elaboration into more complex nitrogenous educts.

■ Megouraphin Glucosides: Two Yellowish Pigments from the Aphid Megoura crassicauda

Mitsuyo Horikawa,* Daisuke Kikuchi, Toshihito Imai, Masami Tanaka, Hiroto Kaku, Takeshi Nishii, Makoto Inai, Shigeru Takahashi, and Tetsuto Tsunoda*

*Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Nishihamabouji, Yamashiro-machi, Tokushima, 770-8514, Japan

Abstract

Two new yellow pigments, megouraphin glucosides A (1) and B (2), were isolated from the aphid Megoura crassicauda. Their structures were established by detailed analysis of their 1D and 2D NMR spectra and via chemical conversion.

■ Polycyclic Quinolones (Part 1) — Thieno[2,3-b]benzo[h]quinoline Derivatives: Design, Synthesis, Preliminary in vitro and in silico Studies

Abeer Ahmed and Mohsen Daneshtalab*

*School of Pharmacy, Memorial University of Newfoundland, St. John’s, NL, A1B 3V6, Canada

Abstract

Heterocyclic systems with a quinoline nucleus represent the most spectacular example of privileged molecules in medicinal chemistry, as their biological activities are surely affected by changes in structural features. Quinoline derivatives have been shown to display a wide spectrum of biological activities such as antibacterial, antifungal, antiparasitic, antiviral, cytotoxic and anti-inflammatory activities. In this study, several 7-hydroxy-8-oxo-8,9-dihydrobenzo[h]thieno[2,3-b]quinoline-9-carboxylic acids were designed, synthesized, and were further subjected to chemical reactions such as alkylation and annelation. The synthesized compounds were also subjected to docking study and biological evaluation. This work was mainly designed to shed light on the requirements for the quinoline nucleus to act as an anticancer agent. Unexpectedly, the synthesized derivatives showed weak or no cytotoxicity against cancer cell lines and the increase in the extent of aromatic/condensed rings did not increase the affinity toward the double stranded DNA. Our virtual screening demonstrated that the chelation with Mg2+ is a determining factor in the expected interaction with Topoisomerases. Key synthetic issues, crystallographic and docking studies have also been described.

■ Polycyclic Quinolones (Part 2) — Synthesis of Novel 4-Oxo-1,4-dihydrobenzo[h]-[1,3]thiazeto[3,2-a]quinoline Carboxylic Acids via Oxidative Cyclization of the Corresponding 2-Mercaptoquinoline Precursors

Abeer Ahmed, Louise N. Dawe, and Mohsen Daneshtalab*

*School of Pharmacy, Memorial University of Newfoundland, St. John’s, NL, A1B 3V6, Canada

Abstract

The first synthesis of a series of 4-oxo-1,4-dihydrobenzo[h][1,3]thiazeto[3,2-a]quinoline carboxylic acids and their esters via oxidative cyclization of ethyl 2-((2-ethoxy-2-oxoethyl)thio)-4-hydroxybenzo[h]quinoline-3-carboxylate derivatives in the presence of a vicinal dihaloalkane, KI, and K2CO3 is described. Structures of the synthesized compounds were characterized by spectrometric and X-ray crystallographic analyses.

■ Briaroxalides: Novel Diepoxybriarane Diterpenes from an Okinawan Gorgonian Briareum Sp.

Koichiro Ota, Naoko Okamoto, Hidemichi Mitome, and Hiroaki Miyaoka*

*School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

Abstract

Seven new 8,17- and 11,12-diepoxybriarane diterpenoids, briaroxalides A-G (1-7), were isolated from an Okinawan gorgonian Briareum sp. The structures of the diterpenoids were determined on the basis of spectroscopic analysis, chemical conversions and X-ray diffraction analysis.

■ Lignan Derivatives from the Leaves Nicotiana tabacum and Their Activities

Xue-Mei Gao, Xuesen Li, Xinzhou Yang, Huaixue Mu, Yongkuan Chen, Guangyu Yang,* and Qiu-Fen Hu*

*Key Laboratory of Ethnic Medicine Resource Chemistry, State Ethnic Affairs Commission & Ministry of Education, School of Chemistry and Biotechnology, Yunnan University of Nationalities, Kunming 650031, China

Abstract

Two new lignan derivatives, nicotnorlignan A and nicotlactone A (1, 2), together with two known lignan derivatives (3, 4) were isolated from the leaves of Nicotiana tabacum. Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D-NMR techniques. Compounds 1-4 were tested for their anti-HIV-1 activity and anti-tobacco mosaic virus activities. The results showed compound 2 has high anti-tobacco mosaic virus activities, and all other compounds have modest anti-HIV-1 activity and anti-tobacco mosaic virus activities.

■ A Facile One-Pot Synthesis of Sulfur-Linked Thieno[1,2,4]triazolo[4,3-c]pyrimidine Derivatives Containing Phenylpyrazole or Thienopyrimidinylpyrazole Moiety

Jina Whang and Yang-Heon Song*

*Department of Chemistry, Mokwon University, Daejeon, Doan-dong 800, 302-729, Korea

Abstract

A facile synthesis of sulfur-linked thieno[1,2,4]triazolo[4,3-c]pyrimidine derivatives containing phenylpyrazole or thienopyrimidinylpyrazole moiety via a one-pot reaction of thieno[1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-thiones, 3-chloropentane-2,4-dione and various hydrazines in the presence of potassium hydroxide in ethanol has been achieved.

■ Synthesis of 1-Amino-1-aryl-1,2-dihydropyrrolo[3,4-c]pyridin-3-one Derivatives by the Reaction of 4-Lithiopyridine-3-carbonitrile with Aromatic Tertiary Amides

Kazuhiro Kobayashi,* Kazuhiro Nakagawa, and Taketoshi Kozuki

*Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

A one-pot procedure for the preparation of 1-amino-1-aryl-1,2-dihydropyrrolo[3,4-c]pyridin-3-one derivatives from pyridine-3-carbonitrile and aromatic tertiary amides has been developed. Thus, the reaction of 4-lithiopyridine-3-carbonitrile, generated by the treatment of pyridine-3-carbonitrile with lithium 2,2,6,6-tetramethylpiperidide (LTMP), with aromatic tertiary amides in THF at –78 ˚C yields the pyrrolopyridinone derivatives in moderate yields.

■ First Synthesis of [6-15N]-Cladribine Using Ribonucleoside as a Starting Material

Norikazu Sakakibara, Ai Kakoh, and Tokumi Maruyama*

*Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki City, Kagawa, 769-2193, Japan

Abstract

We have synthesized two types of [6-15N]-deoxyadenosine analogs: [6-15N]-2′-deoxyadenosine (1) and [6-15N]-2-chloro-2′-deoxyadenosine ([6-15N]-cladribine, 2), which utilized the readily available ribonucleosides inosine and guanosine, respectively, via 3′-benzoyl-5′-trityl- (or tert-butyldimethylsilyl)-substituted intermediates (6, 15).