Vinylphosphonium Salt-Mediated Reactions: A One-Pot Condensation

Letter Cite This: Org. Lett. 2019, 21, 22−26

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Vinylphosphonium Salt-Mediated Reactions: A One-Pot Condensation Approach for the Highly cis-Selective Synthesis of N‑Benzoylaziridines and the Green Synthesis of 1,4,2-Dioxazoles as Two Important Classes of Heterocyclic Compounds Hamideh Aghahosseini,† Ali Ramazani,*,† Nastaran Safarvand Jalayer,† Zahra Ranjdoost,† Ali Souldozi,‡ Katarzyna Ślepokura,§ and Tadeusz Lis§ Downloaded via EASTERN KENTUCKY UNIV on January 11, 2019 at 20:29:11 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

†

Department of Chemistry, University of Zanjan, P.O. Box 45195-313, Zanjan, Iran Department of Chemistry, Urmia Branch, Islamic Azad University, Urmia, Iran § Faculty of Chemistry, University of Wrocław, 14 Joliot-Curie St., 50-383 Wrocław, Poland ‡

S Supporting Information *

ABSTRACT: An efficient, one-pot, and convenient approach for the reaction of the same precursors, trialkyl(aryl) phosphines, acetylene diesters, and benzhydroxamic acids has been developed to produce two important classes of heterocyclic compounds: N-benzoylaziridines and 1,4,2-dioxazoles. The strategy utilizes the intermediate solvation as a key step in product selectivity. The usefulness of the developed approach has been confirmed in the unprecedented highly cis-selective formation of the N-benzoylaziridines. In addition, the procedure provides a green alternative method for the synthesis of 1,4,2-dioxazoles employing a β-cyclodextrin nanoreactor in aqueous media.

P

Scheme 1. Efficient One-Pot Synthesis of 1,4,2-Dioxazoles (1) and N-Benzoylaziridines (2)

hosphine-mediated and phosphine-catalyzed reactions have been widely reported for more than a century.1 Phosphines can easily add onto a variety of electron-deficient species, resulting in zwitterionic compounds as the important synthetic intermediates. The reaction of phosphines with carbonyl compounds has been widely studied.2 In this regard, significant efforts have been made to exploit reactions involving zwitterions derived from activated acetylenediesters using trivalent phosphines in Wittig reactions,3 annulations4 and cycloadditions.5 Meanwhile, the reaction between trivalent phosphorus compounds and acetylenic esters in the presence of organic acids such as CH acids, NH acids, OH acids, or SH acids to give a vinyl trivalent phosphonium cation as the important intermediate has been studied extensively.2 Herein, we describe a novel, one-pot, and convenient reaction between trivalent phosphorus nucleophiles, acetylenic esters and benzhydroxamic acids as the OH-organic acids in the different solvent conditions to afford two classes of heterocyclic compounds: 1,4,2-dioxazoles (1) and cis-2,3disubstituted N-benzoylaziridines (meso structure) (2) (Scheme 1). Aziridines with structural fascination,6 pharmaceutical importance,7 and wide applications in synthetic chemistry8 have attracted particular attention from organic synthetic and medicinal chemistry communities. In particular, N-benzoyla© 2018 American Chemical Society

ziridines are an activated type of aziridines for the formation of ketyls and radical intermediates under the nucleophilic ring opening reactions.9 The development of synthetic methods for the synthesis of aziridines in the stereoselective manner is of relevance for the life-science industry.10,11 Aziridines are known as key intermediates for many diverse products,12 such as bioactive aziridines and nonaziridine containing bioactive compounds as well as natural products.13 Some possible routes for the stereoselective synthesis of aziridines featuring double bond aziridination,14 aziridination of imines,10a,15 multicomponent reactions,11b organocatalytic Received: October 23, 2018 Published: December 19, 2018 22

DOI: 10.1021/acs.orglett.8b03388 Org. Lett. 2019, 21, 22−26

Letter

Organic Letters Table 1. Optimization of Reaction Conditionsa

asymmetric reactions,10b and so on. This study reports the unprecedented catalyst-free cis-selective synthesis of Nbenzoylaziridines under operationally convenient conditions. In addition to the pharmacological importance of 1,4,2dioxazoles, such as their antiamoebic activity16 and modest central nervous system depressant activity,17 research also explored their very important synthetic aspects as protecting agents,18 nitrene precursors,19 nitrene transfer reagents,20 and amidating reagents.21 Although the synthesis of 1,4,2-dioxazole derivatives from the reaction of benzhydroxamic acids and acetylene esters has been previously reported in methanol,17 the efficient synthesis of these compounds employing βcyclodextrin (β-CD) as a nanoreactor and trialkyl(aryl) phosphine as an organocatalyst could realize the reaction in water as a green process, which has not been reported so far. Cyclodextrins have been widely used as nanoreactors in organic syntheses. They act through reversible formation of host−guest complexes with various organic compounds22 and contribute greatly to the development of catalytic processes in water.3,23 Initially, we optimized the reaction conditions for the synthesis of 1,4,2-dioxazoles. Previously the use of methanol was reported as a solvent for this reaction.17 We investigated the use of water as a green, polar protic solvent with the assistance of β-CD as a nanoreactor and trialkyl(aryl) phosphine as an organocatalyst to afford 1,4,2-dioxazoles with high yields and under green conditions (Table 1, entries 2−9). The hydrophobic cavity and the external hydrophilic surface of β-CD nanoreactor enables it to process the insoluble organic reactants reaction in aqueous media. The required amount of trialkyl(aryl) phosphine as an organocatalyst was investigated in the synthesis of 1,4,2dioxazoles (Table 1, entries 3, 7−9). It was observed that the best yield was observed with equivalent molar ratios of organocatalyst and reactants.24 It could be concluded that the higher molar ratios of catalyst could prevent side reactions,25 such as polymerization of acetylenic esters26 at the initial reaction steps. Then, some of aprotic solvents were investigated as the reaction media, and it was observed that the cis-Nbenzoylaziridines were obtained in excellent yields and only a trace amount of 1,4,2-dioxazoles was observed as the byproduct (Table 1, entries 10−16). Among the investigated aprotic solvents, we selected acetonitrile as an optimized solvent, because of its lower toxicity. Furthermore, to avoid side reactions, both types of reactions began at −10 °C and the secondary temperature was adjusted after 30 min. In aqueous media, increasing the reaction temperature leads to the conversion of dialkyl acetylenedicarboxylate to dialkyl fumarate and consequently decreases the 1,4,2-dioxazoles yields (Table 1, entry 6). Moreover, it was observed that, in the selected aprotic solvent, acetonitrile, increasing the reaction temperature above room temperature resulted in lower N-benzoylaziridines yields (Table 1, entry 14). Indeed, the higher reaction temperature directed the mechanism to an undesirable reaction between trialkyl(aryl) phosphine and 2 equiv of dialkylacetylene diester to afford a five-membered heterocyclic product.25 Encouraged by these results, we next investigated the substrate scope of the reactions under the optimized reaction conditions given in Table 1, entries 3 and 13. The scope of benzhydroxamic acids was first investigated for the synthesis of the 1,4,2-dioxazoles and N-benzoylaziridines and all of them

Product Yieldd (%)

entry

solvent

PPh3(molar ratio)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

methanol water water water water water water water water 1,4-dioxane DMSO DMF acetonitrile acetonitrile acetonitrile acetonitrile

1 1 1 1 1 1 0.5 0.1 0 1 1 1 1 1 1 0f

βCD (mg)

temperaturec (°C)

1a

2a

− 5 10 15 − 10 10 10 10 − − − − − 10 10

reflux 25 25 25 25 50 25 25 25 25 25 25 25 50 25 25

80 80 83 83 59 30e 72 64 60 trace trace trace trace trace trace trace

0 0 0 0 0 0 0 0 0 78 85 84 85 70 85 0

a

Reaction conditions: triphenylphosphine (1 mmol), dimethyl acetylenedicarboxylate (1 mmol), benzhydroxamic acid (1 mmol); solvent (0.5 mL); adjusted reaction time (12 h for dioxazoles and 72 h for aziridines). bMolar ratio of triphenylphosphine as an organocatalyst to other reactants. cIn order to avoid side reactions, the reaction began at −10 °C and the secondary temperature was adjusted after 30 min. dIsolated yields. eIncreased temperature led to the conversion of dimethyl acetylenedicarboxylate to dimethyl fumarate. fReaction in the absence of trialkyl(aryl) phosphine.

gave the corresponding products in excellent yields (Table 2). Meanwhile, the scope of acetylene diesters was investigated and the ethylacetylene dicarboxylate represented slightly better yields compared with its dimethyl analogue. Moreover the asymmetric substituted acetylene diesters were examined and they did not afford any N-benzoylaziridines (Table 2, entries 16−18). We proposed the following reaction mechanism for the synthesis of heterocyclic compounds, 1,4,2-dioxazoles (1) and N-benzoylaziridines (2) from the same reactants (Scheme 2). Initially, the addition of trialkyl(aryl) phosphine to dialkyl acetylenedicarboxylate afforded the expected reactive 1,3dipolar intermediate. Then, the hydrogen transfer from benzhydroxamic acid to 1,3-dipolar intermediate gave the benzhydroxamate as a nucleophile. In this step, the solvent nature represents its influence on the reaction pathways. In protic solvents, the solvation of the benzhydroxamate ion can significantly decrease its nucleophilicity and direct reaction pathway to the Michael addition. Subsequently, the 1,2-H shift followed by the intramolecular cyclization afford the 1,4,2dioxazole derivatives. On the other hand, when an aprotic solvent was employed, a hard acid/hard base reaction occurred between phosphonium cation and benzhydroxamate anion. The nucleophilic intramolecular cyclization leads to an 23


Letter

Organic Letters Table 2. Scope of Substrates and Product Selectivitya

Product Yieldb entry

solvent

R

R′

R′′

Ar

1 (%)

2 (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN

CH3 C2H5 CH3 C2H5 CH3 C2H5 C2H5 CH3 C2H5 C2H5 CH3 C2H5 CH3 C2H5 C2H5 CH3 C2H5 C2H5

CH3 C2H5 CH3 C2H5 CH3 C2H5 C2H5 CH3 C2H5 C2H5 CH3 C2H5 CH3 C2H5 C2H5 H H C6H5c

C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 n-C4H9 C6H5 C6H5 C6H5

C6H5 C6H5 4-BrC6H4 4-BrC6H4 4-ClC6H4 4-ClC6H4 4-IC6H4 4-PhC6H4 4-PhC6H4 3-NO2C6H4 C6H5 C6H5 4-BrC6H4 4-PhC6H4 C6H5 C6H5 C6H5 C6H5

a: 83 b: 85 c: 90 d: 95 e: 88 f: 93 g: 87 h: 97 i: 98 j: 94 trace trace trace trace trace trace trace trace

a: 0 b: 0 c: 0 d: 0 e: 0 f: 0 g: 0 h: 0 i: 0 j: 0 a: 85 b: 87 c: 80 d: 83 b: 73 k: 0 l: 0 m: 0

a

Optimized reactions conditions: trialkyl(aryl) phosphine (1 mmol), acetylene diester (1 mmol), hydroxamic acid (1 mmol); solvent (0.5 mL); reaction time (12 h for dioxazoles and 72 h for aziridines); reaction temperature (−10 °C for 30 min and then warmed to room temperature). b Isolated yields. cEthyl phenylacetylenecarboxylate.

Scheme 2. Possible Reaction Mechanism for the Synthesis of 1,4,2-Dioxazoles (1) and N-Benzoylaziridines (2)

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Organic Letters

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unstable five-membered ring, which produces N-benzoylaziridines after the elimination of trialkyl(aryl) phosphine oxide. Our proposal for the cis-selectivity in forming the Nbenzoylaziridines is based on steric factors (Figure 1). The

Letter

AUTHOR INFORMATION

Corresponding Author

*E-mail addresses: [email protected], aliramazani@znu. ac.ir. ORCID

Ali Ramazani: 0000-0003-3072-7924 Notes

The authors declare no competing financial interest.

■ ■

DEDICATION Dedicated to Professor Dr. Issa Yavari on the occasion of his 70th birthday.

Figure 1. Preferred orientation in the transition state for the cyclization.

ester groups are likely to adopt a cis-orientation preferentially to avoid unfavorable repulsive interactions with the benzoyl group on the N atom and/or R′ of trialkyl(aryl) phosphine, which results in the cis-aziridine configuration. In summary, we have disclosed the unprecedented catalystfree cis-selective synthesis of N-benzoylaziridines and efficient aqueous synthesis of 1,4,2-dioxazoles employing β-CD nanoreactor under one-pot operationally convenient conditions. The structures of both classes of compounds were confirmed via single-crystal X-ray analysis (Figure 2).

Figure 2. X-ray structures of 1h and 2b. Arbitrary chosen enantiomers are shown.

■

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03388. Detailed experimental procedures, spectral data, and full characterization (PDF) Accession Codes

CCDC 1854997 and 1854998 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. 25


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Vinylphosphonium Salt-Mediated Reactions: A One-Pot Condensation

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