A Concise Synthesis of 4-Vinylphencyphos

Abstract

A fast and clean procedure has been found to prepare the 4-vinyl derivative of enantiomerically pure 2-hydroxy-5,5-dimethyl-4-phenyl-1,3,2-dioxaphosphinan-2-oxide, commonly known as phencyphos. This cyclic phosphoric acid is a popular acidic resolving agent. Functionalization opens a route to attachment to surfaces.

The conformationally rigid cyclic phosphoric acid, phencyphos 1, and derivatives thereof in enantiomerically pure form are known to be excellent resolving agents for various basic compounds.[1] [2]

We have been particularly interested in the development of derivatives of 1 that lend themselves for attachment to solids.[3] [4] [5] [6] A vinyl substituent is particularly attractive. Attachment strategies include coupling to a thiol-functionalized silicon surface[ ^7–9 ] or preparation of polymer-bound materials that might be used both for resolutions or as catalysts. We also note that chiral phosphoric acids, especially those derived from bisnaphthol, are known to catalyze a wide range of reactions.[ ^10–18 ]

Early introduction of a vinyl substituent is not attractive owing to the rather rigorous conditions required for production of the carbon framework of 1 (see further). Introduction of the vinyl group at a late stage by cross-coupling with a suitable derivative of 1 was seen as the best approach. We chose to prepare a 4-bromo-substituted derivative. The synthesis of enantiomerically pure brocyphos 5 is illustrated in Scheme [1].

Bromobenzaldehyde 2 was allowed to react under strongly basic conditions with isobutyraldehyde (3) to give diol 4, the result of a Claisen condensation followed by Cannizzaro reaction.[ ¹ ] The product 4 was treated with POCl₃ and the resulting acid chloride was hydrolyzed to provide 5 after acidification. This compound has not been described previously in the literature but was prepared according to experimental conditions described for similar compounds.[ ¹ ] Resolution was performed using quinine as a resolving agent. Compound 5 was enantiomerically pure as established by chiral HPLC (see experimental).

An X-ray crystal structure determination was performed on the obtained (+)-enantiomer of compound 5. The compound crystallizes as a monohydrate in the orthorhombic space group P2₁2₁2₁ and is therefore likely a conglomerate. The absolute configuration was confirmed by the Flack parameter[ ¹⁹ ] of 0.01(1), which allows assignment of 5 as S (see Figure [1]). Figure [2] shows also the hydrogen bonding scheme, which forms a column along the crystallographic a-axis with O–O distances between 246–273 pm (246 pm for O5–O3 and 268 or 273 pm between O5 and O4A or O4B). The six-membered ring adopts the expected chair conformation.

Somewhat surprisingly, only the enantiomerically pure form crystallizes as a hydrate whereas the racemate crystallizes in non-hydrated form. The crystal structure of the racemate has not been determined. We note that both racemic 1 as well as the pure enantiomers can occur as monohydrates and that racemic 1 has been shown to be a conglomerate that may be resolved by preferential crystallization.[ ²⁰ ]

Cross-coupling with 5 with a vinyl equivalent was expected to provide the desired product 6. This proved to be less easy than expected. Kumada coupling of (S)-5 (see Scheme [2]) using vinyl Grignard reagent was first explored.

Kumada coupling, although not described for phosphoric acids, has been reported for an unprotected carboxylic acid.[ ²¹ ] In fact, there are very few cross-coupling reactions described for molecules containing an unprotected phosphoric acid. Unfortunately, Kumada coupling with 5 stops at maximally ca. 50% conversion. Addition of extra equivalents of Grignard reagent, change of catalyst to NiCl₂(PPh₃)₂, PdEnCat, Pd(di-tert-BP-ferrocene) or PdCl₂(MeCN)₂/combiphos, change of temperature, or addition of tris(acetylacetonato) iron(III) [Fe(acac)₃][ ²² ] in THF did not improve the conversion. Purification of 6 was troublesome: crystallization was not effective and use of preparative HPLC led to loss of most material despite the promising peak separation seen in the HPLC trace.

Negishi coupling to introduce the vinyl group[23] [24] [25] [26] (see Scheme [3]) was attempted using brocyphos 5 with a zinc reagent, prepared in situ from vinylmagnesium bromide and ZnCl₂.[ ²⁶ ]

1,1′-Bis(diphenylphosphino)ferrocene palladium(II)dichloride dichloromethane complex [PdCl₂(dppf)₂ CH₂Cl₂] was used as catalyst.[ ²⁶ ] A mixture of mainly starting material and ca. 20% of an unidentified side product was obtained.

Introduction of the vinyl group via a vinyltin reagent in a Stille coupling was another possibility (Scheme [4]).

Unfortunately, Stille coupling using tributyl(vinyl)tin and Pd(PPh₃)₄ [ ²⁷ ] led to less than 50% conversion. Purification problems similar to those encountered in Kumada coupling were encountered. In addition, the toxicity of the trialkyltin compounds formed as product makes this alternative less attractive.

These disappointing results led to consideration of other alternatives. We felt that the phosphoric acid embedded in 5 might be the source of many of the problems. Hiyama coupling,[ ²⁸ ] which involves the use of a vinyl silane under basic conditions, was a particularly interesting alternative. Our attention was drawn to a paper in which the reaction of a trialkoxyvinyl silane with, for example, 4-bromobenzoic acid is reported.[ ²⁹ ] As shown in Scheme [5], the reaction with 5 was carried out (in a pressure tube) in aqueous sodium hydroxide, under which conditions the phosphoric acid segment would be in a neutral salt form before any reaction began. In fact, this reaction of 5 (racemate or pure enantiomer) catalyzed by Pd(OAc)₂ proceeded in virtually quantitative yield with complete retention of enantiopurity as established by chiral HPLC. The absolute configuration of the product should be S, identical to starting material 5. This approach is clearly a very effective way to prepare 4-vinylphencyphos 6, which was obtained pure after extraction. The reaction has been carried out on 6-mmol scale. Further scale-up is not expected to be a problem. The reagents are cheap and the reaction conditions quite simple.

Enantiomerically pure (S)-vinylphencyphos 6 is a remarkably stable compound, obtained as a white solid. It can be readily handled and stored for long periods without decomposition or polymerization. This stability of a styrene derivative that contains also a strong acid stands in contrast to observations made, for example, with 4-vinylbenzoic acid and 4-vinylphenylacetic acid[ ³⁰ ] as well as 4-vinylbenzylphosphonic acid.[ ³¹ ] The latter compound is stabilized by addition of a radical inhibitor. These styrene derivatives are reported to be quite sensitive to polymerization. The relative stability of 6 recommends it for ­applications.

Acknowledgment

The analytical department at Syncom BV carried out the analysis. The research leading to these results has received funding from the European Community’s Seventh Framework Programme under grant agreement no. NMP4-SL-2008-214340, project RESOLVE.

• References

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  Search in Google Scholar
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  Search in Google Scholar
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  CrossrefSearch in Google Scholar
• 6 Fredriksen KA, Kristensen TE, Hansen T. Beilstein J. Org. Chem. 2012; 8: 1126
  CrossrefSearch in Google Scholar
• 7 Heckel A, Seebach D. Chem. Eur. J. 2002; 8: 560
  Search in Google Scholar
• 8 Gill CS, Venkatasubbaiah K, Phan NT. S, Weck M, Jones CW. Chem. Eur. J. 2008; 14: 7306
  CrossrefSearch in Google Scholar
• 9 Baleizão C, Gigante B, Garcia H, Corma A. J. Catal. 2003; 215: 199
  CrossrefSearch in Google Scholar
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  CrossrefSearch in Google Scholar
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  CrossrefSearch in Google Scholar
• 21 Bumagin N, Luzikova EV. J. Organomet. Chem. 1997; 532: 271
  CrossrefSearch in Google Scholar
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  Search in Google Scholar
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  CrossrefSearch in Google Scholar
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  CrossrefSearch in Google Scholar
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  CrossrefSearch in Google Scholar
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  Search in Google Scholar
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  Search in Google Scholar
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  CrossrefSearch in Google Scholar

• Supplementary Material