Synthesis of Functionalized Indolizidines through Pauson–Khand Cycloaddition of 2-Allylpyrrolidines

McCormack, Michael P.; Waters, Stephen P.

doi:10.1021/jo302734w

Cited by 10 publications

(2 citation statements)

References 55 publications

(31 reference statements)

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“…Consequently, these skeletons have attracted much attention from synthetic organic chemists, and several approaches have been developed. , The Pauson–Khand reaction, a [2 + 2 + 1]-carbonylative cyclization reaction, is one of the widely used methods to construct bicyclic fused cyclopentenones . However, the intramolecular Pauson–Khand reaction toward the synthesis of bicyclic cyclopentenones fused with a heterocyclic ring system has not been explored enough . Herein, we disclose the results of our strategy for the synthesis of novel bicyclic fused cyclpentenones from easily accessible MBH-acetates of acetylenic aldehydes.…”

Section: Introductionmentioning

confidence: 99%

Sequential Allylic Substitution/Pauson–Khand Reaction: A Strategy to Bicyclic Fused Cyclopentenones from MBH-Acetates of Acetylenic Aldehydes

2014

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An efficient approach for the construction of novel bicyclic fused cyclopentenones starting from Morita-Baylis-Hillman (MBH) acetates of acetylenic aldehydes with flexible scaffold diversity has been achieved using a two-step reaction sequence involving allylic substitution and the Pauson-Khand reaction. This strategy provided a facile access to various bicyclic cyclopentenones fused with either a carbocyclic or a heterocyclic ring system in good yield.

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Section: Introductionmentioning

confidence: 99%

Sequential Allylic Substitution/Pauson–Khand Reaction: A Strategy to Bicyclic Fused Cyclopentenones from MBH-Acetates of Acetylenic Aldehydes

2014

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“…Substrates 4-9 were first allowed to react with Co 2 (CO) 8 , under standard Pauson-Khand reaction conditions ( Table 1). Reaction of substrates 8, 9 with an equimolar amount of Co 2 (CO) 8 at room temperature, using NMO as promoter, gave only traces of the tricyclic indolizidines 10 and 11, even after a few days. Use of different promoters and even increasing the reaction temperature did not improve the reaction yield.…”

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confidence: 99%

Synthesis of tricyclic indolizidines from ethyl isocyanoacetate

Lamberto

2015

Heterocyclic Communications

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Tricyclic indolizidines were synthesized in good yields from commercially available ethyl isocyanoacetate by a novel sequential alkylation, thiol-mediated radical cyclization, N-alkylation, and microwave-assisted Pauson-Khand reaction.In this communication, we present a novel strategy for the synthesis of tricyclic indolizidines starting from a simple isocyanoacetate and using a radical cyclization/Nalkylation/Pauson-Khand [1-6] cycloaddition strategy. Recently, the synthesis of functionalized indolizidines via Pauson-Khand reaction using a stoichiometric amount of Co 2 (CO) 8 , in the presence of various promoters (CO, DMSO, NMO, and TMANO) has been reported [7-9]. Isocyanoacetates [10] have been widely used in many different areas of chemistry as efficient building blocks in the total synthesis of natural products and biologically active molecules. It was envisaged that ethyl isocyanoacetate could be used as the starting building block to access tricyclic indolizidines, useful substrates for the synthesis of indolizidine alkaloids such as asperparaline, and its derivatives (Figure 1), which exhibit potent paralytic, fungicidal, insecticidal, and antifeedant activity [11][12][13].Ethyl isocyanoacetate was first alkylated with excess allyl bromide to give isocyanide 1 in 83% yield [14]. Subsequent microwave-assisted thiol-mediated radical cyclization using 2-mercaptoethanol [15] gave pyroglutamates 2 and 3 in 88% yield (Scheme 1) as a 1:1 inseparable mixture of cis/trans diastereomers. The diastereomeric ratio was determined by 1 H NMR.The next step in our strategy was the N-alkylation of these substrates with a variety of propargyl bromides that would give access to substrates that could then be subjected to the Pauson-Khand cyclization reaction. Although NaH and NaOH, under phase transfer conditions, are the bases employed for N-alkylation of either proline or pyroglutamates in the literature [16], better yields were obtained using tert-butyliminotri(pyrrolidino)phosphorane (BTPP). Alkylation of pyroglutamates 2, 3 was then performed using BTPP and three different propargyl bromides (RX) in refluxing acetonitrile (Scheme 2). Compounds 4, 5 and 8, 9 were obtained as inseparable mixtures of diastereomers in 72% yield (1.4:1 cis/trans ratio by 1 H NMR) and 99% yield (1.7:1 cis/trans ratio by 1 H NMR), respectively. Pyroglutamates 6 and 7, with a terminal Trimrthylsilyl (TMS) group, were obtained in 30% yield only as an inseparable mixture of diastereomers (1.9:1 cis/trans ratio by 1 H NMR), due to loss of the TMS group and consequent formation of 8 and 9 (isolated in 31% yield) as a by-product. With these substrates in hand, it was possible to perform the final step in our synthetic strategy, the Pauson-Khand cycloaddition. Substrates 4-9 were first allowed to react with Co 2 (CO) 8 , under standard Pauson-Khand reaction conditions ( Table 1). Reaction of substrates 8, 9 with an equimolar amount of Co 2 (CO) 8 at room temperature, using NMO as promoter, N O NMe H N O O Asperparaline C N O NMe H HN O Brevinamide A...

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ChemInform Abstract: Synthesis of Functionalized Indolizidines Through Pauson—Khand Cycloaddition of 2‐Allylpyrrolidines.

McCormack

Waters

2013

ChemInform

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Synthesis of Functionalized Indolizidines through Pauson–Khand Cycloaddition of 2-Allylpyrrolidines

Cited by 10 publications

References 55 publications

Sequential Allylic Substitution/Pauson–Khand Reaction: A Strategy to Bicyclic Fused Cyclopentenones from MBH-Acetates of Acetylenic Aldehydes

Sequential Allylic Substitution/Pauson–Khand Reaction: A Strategy to Bicyclic Fused Cyclopentenones from MBH-Acetates of Acetylenic Aldehydes

Synthesis of tricyclic indolizidines from ethyl isocyanoacetate

ChemInform Abstract: Synthesis of Functionalized Indolizidines Through Pauson—Khand Cycloaddition of 2‐Allylpyrrolidines.

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