Copper-mediated reaction of oxazirconacyclopentenes with dichlorophenylphosphine: a new pathway for the formation of 1,2-oxaphosphole derivatives

Abstract

Copper-mediated reaction of oxazirconacyclopentenes with dichlorophenylphosphine afforded 2,5-dihydro-1,2-oxaphosphole in high yields, in which the reaction was performed conveniently in one-pot from an alkyne, carbonyl compound and dichlorophosphine.

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Organophosphorus compounds are important intermediates in organic synthesis and have been widely used as pharmaceutical¹ and chemical agents.² Recently, phosphorus heterocycles³ have received considerable interest because of their unique biological activities⁴ and wide-ranging utilities as synthetic intermediates in organic synthesis.⁵ Consequently, much attention has been directed to the synthesis of these compounds. Among them, particular interest was paid to the oxaphosphole derivatives. Although some progress has been achieved for synthesis of the oxaphospholes,⁶ the most efficient one seems the direct transformation of oxametallacyclopentenes to oxaphospholes. In this regard especially attractive one is oxazirconacyclopentenes, which are easily prepared by the coupling reaction of alkynes and carbonyl compounds with zirconocene–ethylene species.⁷ The oxazirconacyclopentenes are useful intermediates in a number of organic reactions,^7g,8 such as reaction of the oxazirconacyclopentenes with propynoates to afford 2,5-dihydrofurans,^8a and reaction with but-2-ynedioates to afford α-methylene-δ-lactone.^8b As part of our ongoing project on the chemistry of organozirconium and organophosphorus,⁹ we herein describe a new pathway for the synthesis of 1,2-oxaphospholes based on the reaction of oxazirconacyclopentenes with dichlorophenylphosphine in the presence of CuCl (eqn (1)).

Typical procedure is as follows. To a solution of oxazirconacylopentene 1a in THF (3 mL), prepared from Cp₂ZrCl₂ (292 mg, 0.6 mmol), EtMgCl (2.0 M THF solution, 0.6 mL, 1.2 mmol), 4-octyne (78 μL, 0.5 mmol), and 3-pentanone (60 μL, 0.5 mmol) according to the reported procedure,^7a was added CuCl (100 mg, 1 mmol) and dichlorophenylphosphine (82 μL, 0.6 mmol). The reaction mixture was stirred at 50 °C for 12 h. The reaction mixture was quenched with 3 M HCl and 1,2-oxaphosphole 2a was obtained in 85% NMR yield. Direct purification of 2a by column chromatography on Al₂O₃ led to the formation of complex inseparable mixture. Since 2a was sensitive under air ambient for direct isolation, this reaction mixture with crude product was treated by addition of elemental sulfur to afford 1,2-oxaphosphole 2-sulfide 3a in 84% isolated yield (Scheme 1). In addition, the reaction mixture was treated with hydrogen peroxide and 1,2-oxaphosphole oxide 4a was isolated in 54% yield. It is notable that the reaction of oxazirconacylopentene with dichlorophosphine did not proceed in the absence of CuCl.

Scheme 1 Schematic showing the reaction of 1a and PhPCl₂.

Further study involving the using of various substituted oxazirconacylopentene bearing alkyl, aryl, and TMS groups resulted in all cases in the formation of 1,2-oxaphosphole 2-sulfide in good yields. Some representative examples of the results are summarized in Table 1. Reaction of oxazirconacyclopentenes tolerating four substituents (entries 1–8) with dichlorophenylphosphine gave the corresponding 1,2-oxaphosphole 2-sulfide derivatives in good to high yields. To our delight, the crystals of 3f were suitable for the X-ray diffraction analysis, and its structure was confirmed as 1,2-oxaphosphole 2-sulfide (Fig. 1). When acetophenone was used, trace amount of expected product was observed in GC-MS (entry 9), the starting material remained. It is noteworthy that reaction of spirocyclic oxazirconacyclopentenes with dichlorophenylphosphine gave the corresponding spiro-oxaphospholene 2-sulfide derivatives in high yields (entries 10–12). The expected products, spirooxaphospholene, are popular targets for the development of new biologically active compounds.¹⁰

Table 1 Reaction of oxazirconacycles in the presence of CuCl

Entry	Oxazirconacycles	Product	Yield^a (%)
a Isolated yield.
1			84
2			75
3			79
4			64
5			58
6			55
7			63
8			72
9			Trace
10			71
11			63
12			54

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Fig. 1 Perspective view of 3f (CCDC 1412383).

Recently, Liu and co-workers developed an improved procedure for zirconium-mediated alkyne–aldehyde coupling reactions to afford three substituents oxazirconacyclopentenes.^7g Reaction of the oxazirconacyclopentenes with dichlorophenylphosphine gave the corresponding 1,2-oxaphosphole 2-sulfide derivatives (Scheme 2). When alkyl aldehyde such as propionaldehyde and hexanal were employed and compound 5a, 5b, and 5c were formed in 84%, 64%, and 56% yield, respectively. It is noteworthy that in the reaction to obtain 5b and 5c, two diastereomers of product 5b and 5c were observed in 6 : 1 and 2 : 1 ratio, respectively. When benzaldehyde was used and the product 5d was formed in 15% yield, which could not be fully separated from unidentified by product. Together with result in entry 9 of Table 1, the aryl group on the carbon connected with oxygen in oxazirconacyclopentene gave the poor yield of desired products. That maybe attributed to bulky group.

Scheme 2 Reaction of 1 derived from aldehyde to form oxaphosphole 2-sulfide.

Based on the results obtained here, the following reaction pathway can be proposed for the formation of 2,5-dihydro-1,2-oxaphospholes (Scheme 3). In the first step the Zr–C bond of oxazirconacyclopentene 1 is transmetalated to the Cu–C bond to give 6.^11,12 It is not clear whether only the Zr–C bond is transmetalated, or also the Zr–O bond. The intermediate 6 then reacts with dichlorophosphine to give 2,5-dihydro-1,2-oxaphosphole 2.

Scheme 3 Possible reaction mechanism.

We conclude that the reaction of oxazirconacyclopentenes with dichlorophenylphosphine in the presence of CuCl gives oxaphosphole derivatives. This reaction represents a convenient pathway to substituted 2,5-dihydro-1,2-oxaphosphole in one-pot from an alkyne, carboxyl compound and dichlorophosphine with zirconocene compound.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (21272132, 21472106 and 21032004) and national basic research program of China (2012CB933402).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, NMR data and spectra of compounds for 3a–3h, 3j–3l, 4a and 5a–5c. CCDC 1412383. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra13818c

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