Synthesis of Annulated <i>γ</i>-Carbolines and Heteropolycycles by the Palladium-Catalyzed Intramolecular Annulation of Alkynes

Zhang, Haiming; Larock, Richard C.

doi:10.1021/jo0343228

Cited by 63 publications

(29 citation statements)

References 47 publications

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“…1 H NMR (CDCl 3 ): d = 1.16 (d, J = 6.8 Hz, 6 H), 1.75 (br s, 1 H), 2.44 (dt, J = 2.2 Hz, J = 6.2 Hz, 2 H), 2.55 (tsep, J = 2.2 Hz, J = 6.8 Hz, 1 H), 3.68 (t, J = 6.2 Hz, 2 H). 13…”

Section: -Methylhex-3-yn-1-ol (3)mentioning

confidence: 99%

Trimethylaluminum (TMA)-Catalyzed Reaction of Alkynyllithiums with Ethylene Oxide: Increased Yields and Purity of Homopropargylic Alcohols

Brummond¹,

McCabe²

2005

Synlett

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An efficient protocol was developed to obtain homopropargylic alcohols. Subjecting alkynyllithiums and ethylene oxide to 10-20 mol% of trimethylaluminum provided homopropargylic alcohols in good yields.Successful completion of a synthesis of a natural product possessing moderate complexity typically requires the preparation of starting materials in gram quantities. The syntheses of these relatively simple and low molecular weight precursors are usually the least interesting in a synthetic sequence that may ultimately lead to an interesting bioactive compound via a novel carbon-carbon bond forming reaction. However, low yields in the beginning stages of a synthesis can foil the best of synthetic strategies if key step precursors cannot be accessed in sufficient quantities.Recently, while working towards the synthesis of guanacastepene A, we desired the homopropargylic alcohol 3 in gram quantities. We obtained this alcohol by addition of ethylene oxide (2) to lithiated 3-methyl-1-butyne (1); 1 however, the yields of this reaction suddenly went from 95% to 10%. After some experimentation, the irreproducibility of this reaction was traced to the ethylene oxide. It was observed that an older expired lecture bottle of ethylene oxide gave 95% yields of alkynol 3. Since the older bottle had been discarded, we could only speculate that a contaminant was responsible for the higher yields. Based upon our need for a reliable and cheap protocol for the preparation of gram quantities of homopropargylic alcohol 3, we initiated a systematic investigation into the addition reaction of acetylides to ethylene oxide (Equation 1). Equation 1There are many reports of Lewis acids catalyzing the addition of acetylides to epoxides, the most common of which was developed by Yamaguchi and Hirao 2 using a stoichiometric amount of boron trifluoride etherate. In our hands this protocol was not only technically challenging upon scale up, but inseparable by-products were formed. Another reagent used to facilitate the reaction between epoxides and alkynyllithiums is catalytic amounts of trimethylgallium. 3 This methodology appears to be a very efficient way to form homopropargylic alcohols; however, it seems not to be a very well-liked protocol. It is thought that the cost ($13 per gram) of Me 3 Ga and special handling needs detract from its usefulness.Stoichiometric amounts of trimethylaluminium (TMA) have been reported to promote reaction with epoxides to give good to moderate yields; however, in some cases TMA was not reactive enough and needed to be used in conjunction with stoichiometric amounts of BF 3 ·OEt 2 . 4 In one publication, catalytic TMA could be used only if the acetylide was reacted with an epoxy ether, not a simple epoxide like 5-phenyl-1-pentene oxide. 5 There were also reports of the use of diethylaluminum chloride by Fried, 6 which gave good yields for the addition of the alkynyllithium of octyne, but low yields for more complex alkynes. Herein, we report the use of catalytic TMA for the formation of a variety of homoproparg...

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“…1 H NMR (CDCl 3 ): d = 1.16 (d, J = 6.8 Hz, 6 H), 1.75 (br s, 1 H), 2.44 (dt, J = 2.2 Hz, J = 6.2 Hz, 2 H), 2.55 (tsep, J = 2.2 Hz, J = 6.8 Hz, 1 H), 3.68 (t, J = 6.2 Hz, 2 H). 13…”

Section: -Methylhex-3-yn-1-ol (3)mentioning

confidence: 99%

Trimethylaluminum (TMA)-Catalyzed Reaction of Alkynyllithiums with Ethylene Oxide: Increased Yields and Purity of Homopropargylic Alcohols

Brummond¹,

McCabe²

2005

Synlett

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“…Within the context of the synthesis of BIMs, we speculated that the reaction could follow a similar pathway, where the first nucleophilic attack could occur intermolecularly with the external indole and the intramolecular reaction would happen in the final step. Alternatively, the cyclisation would occur first and the external indole would be added in the final step . Here we report our efforts to understand this mechanism and the implications on the reaction.…”

Section: Resultsmentioning

confidence: 99%

“…Alternatively, the cyclisation would occur first and the external indole would be added in the final step. [24] Here we report our efforts to understand this mechanism and the implications on the reaction.…”

Section: Mechanistic Investigationsmentioning

confidence: 99%

Synthesis of a Novel Type of 2,3′‐BIMs via Platinum‐Catalysed Reaction of Indolylallenes with Indoles

Cooper

Alonso

Eagling

et al. 2018

Chemistry A European J

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Optimisation, scope and mechanism of the platinum‐catalysed addition of indoles to indolylallenes is reported here to give 2,3′‐BIMs with a novel core structure very relevant for pharmaceutical industry. The reaction is modulated by the electronic properties of the substituents on both indoles, with the 2,3′‐BIMs favoured when electron donating groups are present. Although simple at first, a complex mechanism has been uncovered that explains the different behaviour of these systems with platinum when compared with other metals (e.g. gold). Detailed labelling studies have shown Pt‐catalysed 6‐endo‐trig cyclisation of the indollylallene as the first step of the reaction and the involvement of two cyclic vinyl‐platinum intermediates in equilibrium through a platinum carbene, as the key intermediates of the catalytic cycle towards the second nucleophilic attack and formation of the BIMs.

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“…In this instance the researchers described a mechanism (given for R 2 = R 1 in Scheme 66) that consisted of initial oxidative addition of Pd to the indole halogen to form the Pd intermediate 200, which reacted with the alkyne to form vinyl Pd intermedi- A similar synthetic strategy was used to prepare a series of annelated g-carbolines [181,185] and b-carbolines [180, 182 -184].…”

Section: Iminoannelation Of Acetylenes To Tert-butylimines Of N-substmentioning

confidence: 99%

Carbolines. Part I: Comparison of some methods for the synthesis of α-, γ-, and δ-carbolines (a review)

Smirnova¹,

Golovko²,

Граник³

2011

Pharm Chem J

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The main trends in the development of the chemistry of a-, g-, and d-carbolines are generalized. Syntheses of carbolines based on pyridine derivatives (including the Fischer synthesis, Graebe-Ullmann reaction, thermal decomposition of azides, photochemical cyclization of anilinopyridines, arylation of substituted pyridines and piperidones, etc.) and based on indole derivatives are described. Published data about the biological activity of compounds belonging to these series are summarized.Four classes of pyridoindoles, i.e., carbolines (1 -4), are known. Of these, b-carbolines (2) have been studied most completely. Numerous studies, including several reviews [1 -3], have addressed the synthesis and various properties of this class of compounds. The properties of the other carbolines have been studied in less detail, e.g., their syntheses and chemical and physicochemical properties have not yet been discussed and compared in the literature.A detailed comparison seems especially important because precisely such an analysis can expose the basic features that make these classes chemically and biologically significant. This is especially important during research directed at the discovery of new biologically active compounds. Because the large volume of literature dedicated to b-carbolines makes it practically impossible to discuss it in a single review, the present review is limited to a comparison of the other carbolines only, the syntheses of which have been discussed much less in the literature. We intend to discuss the main trends in the development of the chemistry of a-, g-, and d-carbolines without pretending to include all literature in its entirety in order to compare the potential of finding novel effective drugs in these series. We discuss first reviews dedicated to pyridoindoles [2 -5], including a rather recent review of g-carbolines [6]. Then we switch to chemical approaches to the synthesis of selected carboline derivatives, noting briefly publications on their biological properties.Pyridoindoles (carbolines), including pyrido[4,3-b]indoles (g-carbolines), some of which exhibit a broad spectrum of biological activity, are definitely interesting. Drugs of this class already exist, e.g., neuroleptic carbidine 5 (Carbidinum or Stobadine) and dimebon antihistamine drugs 6 (Dimebonum) and diazoline 7 (Diazolinum or Omeril) [7,8]. Furthermore, dimebon exhibited pronounced anti-NMDA (N-methyl-D-asparate, ED 50 = 42 mg/kg i.p.) and anticalcium activity (blocks calcium channels, IC 50 = 57 mM) and inhibited acetylcholinesterase (ACE) and butyrylcholinesterase (BuCE) (IC 50 = 42 and 7.9 mM, respectively) in in vitro tests. It also had pronounced cognitive-stimulant properties in in vivo tests for a neurotoxic 654 0091-150X/11/4412-0654

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Synthesis of Annulated γ-Carbolines and Heteropolycycles by the Palladium-Catalyzed Intramolecular Annulation of Alkynes

Cited by 63 publications

References 47 publications

Trimethylaluminum (TMA)-Catalyzed Reaction of Alkynyllithiums with Ethylene Oxide: Increased Yields and Purity of Homopropargylic Alcohols

Trimethylaluminum (TMA)-Catalyzed Reaction of Alkynyllithiums with Ethylene Oxide: Increased Yields and Purity of Homopropargylic Alcohols

Synthesis of a Novel Type of 2,3′‐BIMs via Platinum‐Catalysed Reaction of Indolylallenes with Indoles

Carbolines. Part I: Comparison of some methods for the synthesis of α-, γ-, and δ-carbolines (a review)

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