Alkylation of Secondary Phosphines

The asymmetric arylation or alkylation of racemic secondary phosphines catalyzed by chiral Lewis acids in many cases led to the formation of enantiomerically enriched tertiary phosphines [120-129]. Chiral complexes of ruthenium, platinum, and palladium were used. For example, chiral complex Pt(Me-Duphos)(Ph)Br catalyzed asymmetric alkylation of secondary phosphines by various RCH2X (X=C1, Br, I) compounds with formation of tertiary phosphines (or their boranes) 200 in good yields and with 50-93% ee [121]. The enantioselective alkylation of secondary phosphines 201 with benzyl halogenides catalyzed by complexes [RuH (/-Pr-PHOX 203)2] led to the formation of tertiary phosphines 202 with 57-95% ee [123, 125]. Catalyst [(R)-Difluorophos 204)(dmpe]Ru(H)][BPh4] was effective at asymmetric alkylation of secmidaiy phosphines with benzyl bromides, whereas (R)-MeOBiPHEP 205/dmpe was more effective in the case of benzyl chlorides (Schemes 65, 66, and 67) [125—127]. 

Scheme 64 Asymmetric alkylation of secondary phosphines 196 catalyzed by Pt(II) complexes...

Scriban C, Glueck DS (2006) Platinum-catalyzed asymmetric alkylation of secondary phosphines enantioselective synthesis of P-stereogenic phosphines. J Am Chem Soc 128 2788-... 

The three reactions are likely to have phosphido complexes as intermediates. Pt-, Pd- and Ln-catalysed hydrophosphination of activated alkenes and Pd-catalysed phosphination of aryl halides (a cross-coupling reaction) have been known for some time whereas Pt and Ru-catalysed alkylation of secondary phosphines are more recent. 

Scheme 6.34 Pt-catalysed enantioselective alkylation of secondary phosphines.

While the formation of a variety of carbon stereocentres has been effectively achieved, stereoselective approaches for the preparation of P-stereogenic phosphines have, until recently, been non-existent. In this context, Bergman s group has developed several chiral ruthenium catalysts to be investigated for the enantioselective ruthenium-catalysed alkylation of secondary phosphines into the corresponding chiral air- and moisture-tolerant tertiary phosphine-borane products after a subsequent treatment with BHs.THF. " These reactions proceeded through the intermediacy of nucleophilic phosphido species, which had low barriers to pyramidal inversion, allowing a DKR process. 

Glueck s group has reported catalytic DKR processes in which secondary phosphines were converted into the corresponding enantio-enriched tertiary phosphines by platinum-catalysed asymmetric hydrophosphination of acrylonitrile, or by platinum-catalysed asymmetric alkylation of secondary phosphines. The key intermediates were diastereomeric phosphide complexes with chiral ancillary ligands (L -Pd PRR )- Their relative rates of P-inversion and phosphorus-carbon bond formation controlled the enantioselectivity of the product formation. As shown in Scheme 2.66, the reactions allowed moderate enantioselectivities of up to 71% ee and 77% ee, respectively, to be achieved. 

Example 4.10 Copper-Catalyzed Alkylation of Secondary Phosphines [22]. 

The hydrophosphonylation (addition of dialkyl phosphonates), hydrophos-phinylation (addition of alkyl alkylphosphinates or alkyl phosphinates) and addition of secondary phosphine oxides to unfunctionalized alkenes and alkynes occur under free radical conditions or with transition metal catalysis.10,39 63 90... 

The action of heat on a mixture of secondary phosphine and alkyl iodide, and treatment of the product with alkali, has produced... 

Catalytic symmetric synthesis of P-stereogenic phosphines by cross-coupling of secondary phosphines with benzyl or other alkyl halides was promoted by chiral ft and Ru complexes [112-114]. The key step is believed to be the nucleophilic attack of a metal-phosphido complex on a free electrophile the background reaction of the unactivated nucleophilic substrate is much slower. The origin of enantioselec-tivity, as in the Pd-catalyzed asymmetric cross-couplings described above, is the interconversion of diastereomeric phosphido complexes, whose speciation and relative rates of nucleophilic attack determine the product ratio. In the case of ft ((R./ )-Me-DuPhos)(Ph)(PMels), as with the Pd analog in Scheme 43 above, the major product phosphine was formed from the major diastereomeric phosphido complex (Scheme 63) [112-113]. 

Examples of electrophilic addition of secondary phosphines to alkenes or alkynes were described. [114, 124, 125, 135]. Glueck [124-126] reported enantioselective tandem reaction of alkylated/arylation of primary phosphines catalyzed by platinum complex, proceeding with formation of chiral phosphaace-naphthenes. Palladium-catalyzed hydrophosphination of alkynes 219 tmder kinetic resolution conditions gave access to 1,1-disubstituted vinylphosphine boranes 220. However, despite screening several chiral ligands, temperatures, and solvents, the... 

Secondary phosphinic acids (6.254) may be prepared by the oxidation of secondary phosphine oxides (6.26) or by thermal decomposition of the latter (6.133). Air, oxygen, hydrogen peroxide, dilute nitric acid or bromine water may be used for such oxidations. Many phosphinic acids can be prepared by refluxing their alkyl esters with 20% aqueous HCl (6.255). Sulphur dioxide and phosphines may also be used (6.268). 

Tetraalkylphosphonium compounds (TAPC s). TAPC s are obtained by alkylation of secondary or tertiary phosphines with alkylhalides at temperatures of 80-100°C. Intermediarily originates a tetraalkylphosphonium halide-hydrohalide complex which, if exposed to vacuum at the elevated temperatures, releases hydrohalide and is transformed to tetraalkylphosphonium halide ... 

Woik by Leung demonstrated that palladacycles were effective catalysts for synthesis of alkyl phosphines through the addition of secondary phosphines to alkenes [67-74]. In addition, many of these reports desaibed the asymmetric synthesis of phosphines using chiral palladium complexes. For example, the use of a chiral C, A-palladacycle for the asymmetric addition of secondary phosphines to enones was outlined (Schane 4.24 and Example 4.21)... 

The complex of 10-membered cyclic triphosphine 10 has been prepared by the base catalyzed template cyclization of 1,3-bis(phosphino)propane and trivinyl-phosphine at the metal center ([( / -Me3SiC5H4)Fe]) 9 (Scheme 12.4). Hydrogenation of vinyl substituent followed by alkylation of secondary phosphino group lead to complexes 11 with three endocyclic tertiary phosphino moieties. 

Metal phosphides can be employed to direct the action of alkyl hahdes more toward primary and secondary phosphines. 

Kyba and eoworkers prepared the similar, but not identical compound, 26, using quite a different approach. In this synthesis, pentaphenylcyclopentaphosphine (22) is converted into benzotriphosphole (23) by reduction with potassium metal in THF, followed by treatment with o "t/20-dichlorobenzene. Lithium aluminum hydride reduction of 23 affords l,2-i>/s(phenylphosphino)benzene, 24. The secondary phosphine may be deprotonated with n-butyllithium and alkylated with 3-chlorobromopropane. The twoarmed bis-phosphine (25) which results may be treated with the dianion of 24 at high dilution to yield macrocycle 26. The overall yield of 26 is about 4%. The synthetic approach is illustrated in Eq. (6.16), below. 

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