© The Royal Society of Chemistry 2006Treatment of 1,2-diols with diphenylphosphinoyl chloride in pyridine produces beta-chloroethyl phosphinates which react with complete control of stereochemistry to give epoxides and azido-alcohols, useful intermediates in cyclopropane synthesis.David J. Fox, Daniel Sejer Pedersen, Asger B. Petersen and Stuart Warre

Asger B. Petersen

Boesen

Braun

Chandrasekhar

Chang

Daniel Sejer Pedersen

David J. Fox

Deng

Kolb

Lohray

Newman

Pearson

Richardson

Sahasrabudhe

Sayyed

Soucy

Stuart Warren

Wang

Xiong

Organic & Biomolecular Chemistry

English

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Diphenylphosphinoyl chloride as a chlorinating agent ? the selective double activation of 1,2-diols

Fox, David J.

Pedersen, Daniel Sejer

Petersen, Asger B.

Warren, Stuart

Adelaide Research & Scholarship

PAPER www.rsc.org/obc | Organic & Biomolecular ChemistryDiphenylphosphinoyl chloride as a chlorinating agent – the selective doubleactivation of 1,2-diols†David J. Fox,* Daniel Sejer Pedersen, Asger B. Petersen and Stuart WarrenReceived 15th May 2006, Accepted 21st June 2006First published as an Advance Article on the web 6th July 2006DOI: 10.1039/b606881bTreatment of 1,2-diols with diphenylphosphinoyl chloride in pyridine produces b-chloroethylphosphinates which react with complete control of stereochemistry to give epoxides and azido-alcohols,useful intermediates in cyclopropane synthesis.Stereochemically pure 1,2-diols, derived either from the catalyticasymmetric dihydroxylation of oleﬁns1 or from other sources, areimportant intermediates in asymmetric synthesis. The hydroxygroups can be activated and differentially displaced by a variety ofnucleophiles,oftenwithhighlevelsofregiocontrolduetoadjacentelectronic conjugating groups. Cyclic acylium ions, most oftengenerated by reaction of diols with orthoesters2–4 or equivalents,5can be ring opened with ﬂuoride,5 chloride2–4 and bromide to givevicinial halo-acylates.3 Along with cyclic carbonates,6 sulﬁtes7–9and sulfates,10–12 chloro- and bromo-ethyl esters are valuableintermediates in the stereoselective synthesis of epoxides,6,13 b-amino-alcohols8,9,14 diamines11 and amino-acids.7,10,15–17 In thispaper we describe a new and simple method that provides notonlytheregioselectivedifferentiationof1,2-diolsbutalsoselectivebis-activation.Duringsynthesisofcyclopropane-containingc-aminoketones18and esters19 the attempted bis-diphenylphosphinoylation of diols1 and 2 with diphenylphosphinoyl chloride in pyridine resulted ininclusion of only one phosphinoyl group. Initially it was assumedthat only one hydroxy group had reacted, but mass spectrometryandX-raycrystallographyindicatedthatchlorinehadreplacedthehydroxy at the benzylic position with stereochemical inversion togivechloro-phosphinates5and6(Scheme1).Methylanddiphenylsubstituted diols13 3 and 4 also react selectively (Table 1). Onlythe reaction of diol 1 produced a small amount (3%) of bis-phosphinateproduct18 9.Thereactionsofdiols1,2and3producedonly single stereo- and regioisomers of chloro-phosphinates.The reaction of methyl cinnamate-derived diol17 10 produced amixture of chloro-phosphinate regioisomers 11 and 12 along withbis-phosphinate 13 (Scheme 2). This result indicated that esterscan also mediate the adjacent introduction of chlorine into 1,2-diols. This was conﬁrmed when non-aryl diol20 14 produced onlythe 2-Cl isomer of chloro-phosphinate 15.X-Ray crystallography of chloro-phosphinate 6 (Scheme 1)showed that the introduction of chlorine occurred with inversionof stereochemistry,21 probably by SN2 reaction of chloride ionwith the activated diol at the more activated position adjacentto either the aryl or ester groups. Hydrobenzoin 4 was chosen asa substrate to test the mechanism as it had substituted only onceUniversity Chemical Laboratory, Lensﬁeld Road, Cambridge, UK CB21EW. E-mail: djf34@cam.ac.uk†Electronic supplementary information (ESI) available: experimentalproceduresandanalyticaldetailsfornewcompoundsandcrystallographicdata. See DOI: 10.1039/b606881b.Scheme 1 Reagents and conditions:i )P h 2POCl, pyridine, see Table 1.Inset: X-ray crystal structure of chloro-phosphinate 6 with thermalellipsoids at 50% probability.Table 1 Chloro-phosphinoylation of diols (see Scheme 1)R Diol Chloro-phosphinate Yield (%)a(CH2)2COPh 15 66b(CH2)2CO2tBu 26 83Me 37 60Ph 48 71a Isolated yield of chloro-phosphinate.b 3% biphosphinate 9 also isolated.Scheme 2 Reagents and conditions:i )P h 2POCl, pyridine, 11 : 12 : 13 =52 : 17 : 31 (by1H NMR); ii) Ph2POCl, pyridine, 45%.despite containing two benzylic alcohols. Two possible reactionpathways are either phosphinoylation of both alcohols followedby displacement of one phosphinate by chloride, or alternatively,reaction of the mono-phosphinate 16 with chloride, followed by asecond phosphinoylation (Scheme 3).This journal is © The Royal Society of Chemistry 2006 Org. Biomol. Chem., 2006, 4, 3117–3119 | 3117Scheme 3 i) Phosphinoylation; ii) SN2 diplacement by chloride.The mono- and bis-phosphinates 16 and 17 were therefore syn-thesisedfromdiol4toinvestigatetheirreactionswithchlorideionsin pyridine. Interestingly, neither the mono- nor bis-phosphinatereactswithpyridiniumchloride,suggestingthatthesereactionsdonot take place in the chloro-phosphination reaction (Scheme 4).Unlike bis-phosphinate 17, the mono-phosphinate 16 does reactwith diphenylphosphinoyl chloride to give chloro-phosphinate 8.Finally, diol 4 does not react directly with pyridinium chloride.Scheme4 Reagentsandconditions:i)Ph 2POCl,Et3N,DMAP,THF,36%;ii) Ph2POCl, Et3N, DMAP, CH2Cl2, 24%; iii) Ph2POCl, pyridine, >95%(by1H NMR); iv) pyridine·HCl, pyridine, or Ph2POCl, pyridine, 0%; v)pyridine·HCl, pyridine, 0%; vi) pyridine·HCl, pyridine, 0%.Given that mono-phosphinate 16 reacts with diphenylphos-phinoyl chloride to give chloro-phosphinate 8, but that bis-phosphinate 17 is not an intermediate, an alternative pathwayto those suggested above must be sought. In addition, as chlorideseems not to be nucleophilic enough to displace diphenylphosphi-nateinthesereactionconditions,amoreelectrophilicintermediatemust be involved. Cyclic phosphonium ion 20, formed via phos-phinoylation of phosphorane 19, is suitably reactive (Scheme 5).Scheme 5 Reagents and conditions:i )P h 2POCl, pyridine.Independent synthesis of phosphonium ion 20 and reactionwith chloride ion was achieved via the reaction of diol 4 withPh2PCl3 in pyridine (Scheme 6).22 Along with unreacted diol, themajor product of the reaction is chloro-phosphinate 8. Peaks dueto mono-phosphinate 16 can also be observed in the1HN M Rspectrum of the crude reaction mixture. These products providegood evidence for the participation of phosphonium ion 20 inthe chloro-phosphinoylation of diols with diphenylphosphinoylchloride according to the mechanism proposed in Scheme 5.Scheme 6 Reagents and conditions:i )P h 2PCl3, pyridine (4 : 8 : 16 = 43 :31 : 26, by1HN M R ) .Finally, the reactions of the chloro-phosphinates were studied(Scheme 7). Displacement of the benzylic chlorides 5, 7 and 8with azide produced mono-azide phosphinates 21–23 as singlediastereoisomers; the phosphinate neither acts as a leaving groupnor participates in the displacement of chloride. As with therelated anti-azido-phosphinate,18 syn-azido-phosphinate 21 couldbe converted into mainly trans-cyclopropane 31. anti-Chloro-phosphinates can also be converted into anti-epoxides 27 and29: treatment with potassium carbonate in methanol13 resultsin removal of the diphenylphosphinate group23 and ring closure.The synthesis of cyclopropane24 30 results from the in situ base-mediated reaction of epoxide 29. Overall, change in the order ofreagents in the conversion of chloro-phosphinate 8 into azido-alcohols 26 and 28 reverses the stereochemistry of the ﬁnal prod-uct. Overall reaction occurs with maintenance of stereochemistryvia epoxide 27, but with inversion of stereochemistry at thebenzylic position if the diphenylphosphinate is removed as thelast step.We hope to extend the simple chloro-phosphinoylation of 1,2-diols to the synthesis of more complex and widely functionalised3118 | Org. Biomol. Chem., 2006, 4, 3117–3119 This journal is © The Royal Society of Chemistry 2006Scheme 7 Reagents and conditions: i) NaN3, DMF; ii) K2CO3, MeOH;iii) K2CO3, MeOH, 86%; iv) NaN3,D M F ,7 5 % ;v )K 2CO3, MeOH, 79%;vi) LDA, THF, 47% (31 : 32 = 9:1 ) .molecules where the introduction of two different leaving groupswith deﬁned stereochemistry will have signiﬁcant use.AcknowledgementsWe thank Dr John Davies for crystallography and the EPSRCfor ﬁnancial assistance towards the purchase of the Nonius CCDdiffractometer. D. S. P. thanks the Alfred Benzon Foundation forﬁnancial support.References and notes1 H. C. Kolb, M. S. VanNieuwenhze and K. B. Sharpless, Chem. Rev.,1994, 94, 2483.2 M. S. Newman and D. R. Olson, J. Org. Chem., 1973, 38, 4203.3 M. S. Newman and C. H. Chen, J. Org. Chem., 1973, 38, 1173.4 M. S. Newman and C. H. Chen, J. Am. Chem. Soc., 1973, 95, 278.5 S. Hara and T. Fukuhara, US Pat. 2006/0014972, 2006.6 H. T. Chang and K. B. Sharpless, J. Org. Chem., 1996, 61, 6456.7 I. A. Sayyed and A. Sudalai, Tetrahedron: Asymmetry, 2004, 15,3111.8 M. Braun, R. Fleischer, B. Mai, M. A. Schneider and S. Lachenicht,Adv. Synth. Catal., 2004, 346, 474.9 K. Sahasrabudhe, V. Gracias, K. Furness, B. T. Smith, C. E. Katz, D. S.Reddy and J. Aube, J. Am. Chem. Soc., 2003, 125, 7914.10 C. Y. Xiong, W. Wang and V. J. Hruby, J. Org. Chem., 2002, 67,3514.11 P.F.Richardson,L.T.J.NelsonandK.B.Sharpless,TetrahedronLett.,1995, 36, 9241.12 B. B. Lohray, Y. Gao and K. B. Sharpless, Tetrahedron Lett., 1989, 30,2623.13 H. C. Kolb and K. B. Sharpless, Tetrahedron, 1992, 48, 10515.14 H. T. Chang and K. B. Sharpless, Tetrahedron Lett., 1996, 37, 3219.15 F. Soucy, L. Grenier, M. L. Behnke, A. T. Destree, T. A. McCormack,J. Adams and L. Plamondon, J. Am. Chem. Soc., 1999, 121, 9967.16 J. G. Deng, Y. Hamada and T. Shioiri, J. Am. Chem. Soc., 1995, 117,7824.17 Z. M. Wang, H. C. Kolb and K. B. Sharpless, J. Org. Chem., 1994, 59,5104.18 D. J. Fox, S. Parris, D. S. Pedersen, C. R. Tyzack and S. Warren, Org.Biomol. Chem., 2006, DOI: 10.1039/b606874j.19 D. J. Fox, D. S. Pedersen and S. Warren, Org. Biomol. Chem., 2006,DOI: 10.1039/b606879k.20 W. H. Pearson and M.-C. Cheng, J. Org. Chem., 1987, 52, 3176.21 Crystal data for 6.C 27H30ClO4P, M = 484.93, orthorhombic, spacegroup P212121, a = 5.8203(10), b = 11.4038(2), c = 37.8022(9) A ˚ , a =90,b =90,c =90◦,U =2509.1(4)A ˚ 3,Z =4,l(Mo-Ka)=0.247mm−1,10165 reﬂections collected at 180(2) K using an Oxford CryosystemsCryostream cooling apparatus, 4316 unique (Rint = 0.056); R1 = 0.053,wR2 = 0.127 [I > 2r(I)], absolute structure parameter 0.02(10). CCDCreference number 600429. For crystallographic data in CIF or otherelectronic format see DOI: 10.1039/b606881b.22 V. Chandrasekhar, T. Chivers, S. S. Kumaravel, A. Meetsma and J. C.van de Grampel, Inorg. Chem., 1991, 30, 3402.23 D. J. Fox, D. S. Pedersen and S. Warren, Org. Biomol. Chem., 2006,DOI: 10.1039/b606873a.24 T. Boesen, D. J. Fox, W. Galloway, D. S. Pedersen, C. R. Tyzack and S.Warren, Org. Biomol. Chem., 2005, 3, 630.This journal is © The Royal Society of Chemistry 2006 Org. Biomol. Chem., 2006, 4, 3117–3119 | 3119

Diphenylphosphinoyl chloride as a chlorinating agent - The selective double activation of 1,2-diols

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Diphenylphosphinoyl chloride as a chlorinating agent - The selective double activation of 1,2-diols

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