Methylphosphonate esters, reaction with

Bromopyridine undergoes photoassisted SrnI reaction with a variety of stabilized carbanions <1997JOC6152>. The reaction is carried out in the presence of potassium amide in liquid ammonia at —33 °C under photoirradiation at 350 nm and proceeds in moderate to good yield with anions derived from 2-benzyl-4,4-dimethyloxazoline, 2,4-dialkylthiazoles, and dimethyl methylphosphonate and also with carboxamide and ester enolates. 

Phosphonate esters can be prepared either by the Arbuzov reaction (rearrangement) or by the alkylation of esters with DMMP (dimethyl methylphosphonate) (Scheme 4.28). Variation of the reaction conditions and reagents allows one to synthesize E- and Z-aUcenes with a high degree of stereoselectivity, as shown in Scheme 4.29. For example, 6-heptenal (4.33) on reaction with 4.34 in the presence of NaH gives -nonadienoate (4.35) on the other hand, in the presence of a base n-BuLi, Z-nonadienoate (4.36) is the major product. 

A relatively general procedure for the preparation of dialkyl 2-oxoalkylphosphonates by direct acylation of dialkyl 1-lithioalkylphosphonates has been introduced by Corey and Kwiatkowski in 1966. The use of phosphonate carbanions as nucleophiles in reaction with carboxylic esters avoids the problems associated with the Michaelis-Arbuzov reaction. The reaction sequence is initiated by the addition at low temperature of dimethyl 1-lithiomethylphosphonate (2 eq and frequently more) to a carboxylic ester (1 eq) to give the transient lithium phosphonoenolate. The dimethyl methylphosphonate, being readily available and easy to eliminate, is the most frequently used phosphonate, but other phosphonates such as diethyl and diisopropyl methylphosphonates can be used. When the resulting enolate is treated with acid, dimethyl 2-oxoalkylphosphonate is produced in moderate to good yields (45-95%, Scheme 7.20). The reaction has been achieved with... 

Commercially available dimethyl cyclopropylmalonate 30 was converted to mono ester 31 by careful saponification using sodium hydroxide. Coupling with l-amino-2-hexanol afforded the hydroxyamide 32 which was oxidized to ketone 33 under Swern conditions. Condensation to oxazole 34 was effectively achieved by utilizing a two-phase system consisting of dichloromethane and sulfuric acid. Reaction with deprotonated dimethyl methylphosphonate gave the 0-ketophosphonate 35 in an excellent overall yield. 

E)-Allylic amines. Reaction of the lithiated methylphosphonate ester with a nitrile, followed by addition of an aldehyde, furnishes a conjugated imine with an ( )-configuration. Immediate reduction (e.g., with NaBH4) gives the allylic amine. 

Amino Acids and Peptides. - Wasserman s method of one-carbon homologation of carboxylic acids to give a-ketocarboxylates involves reaction with cyanomethylenetriphenyl-phosphorane followed by ozone (Scheme 24) and has been used as a key step in a chemo-enzymatic synthesis of isotopically labelled L-valine, L-isoleucine, and o/fo-isoleucine. Alkylation of the carbanion derived from the imino-substituted methylphosphonate diphenyl ester (186) with indol-3-ylmethyl bromide followed by appropriate deprotection has been used to prepare the phosphonate analogue (187) of tryptophan (Scheme 25). The deprotected analogue (188) and derived peptides show activity as inhibitors of chymotrypsin. Two approaches to solid phase Wadsworth-Enunons reactions which have applications in combinatorial chemistry have been reported. In one diethylphosphonoacetamide is bound to PEG-PAL resin via a peptide link, while... 

The treatment of diethyl (trichloromethyl)phosphonate with BuLi in thf affords diethyl [lithio(dichloromethyl)]-phosphonate the latter undergoes reactions with aldehydes or ketones to give, not only dichloroalkenes, C12C=CR R but also, from RCHO, the saturated esters RCH=CAB (A, B = Cl or P03Et2) The products from the interaction of the (l-haloalkyl)phosphonic diesters, (EtO)2P(0)CHXR (X = Cl, Br or I R = H or Me) and alk-1-enes, H2C=CHR (R = pentyl, OEt, OBu, OAc, CN or Ac) under free radical conditions, are mixtures containing moderate amounts of the esters 658 and 659, as well as diethyl methylphosphonate, in relative amounts which depend on reaction conditions " ... 

The conjugate base of dimethyl methylphosphonate readily reacts with alcohols and carbonyl compounds in the gas phase. (Me0)2P(0) CH2" reacts with CD3OH via three pathways, each of which proceed initially via proton transfer to form the ion-molecule complex [CD3O" (Me0)2P(0)Me], which subsequently undergoes S 2 attack at carbon (equation 56a) or addition/elimination at phosphorus (equation 56b and c). (MeO)2 P(0)CH2 reacts with methyl pyruvate via proton transfer (equation 57a), addition/ elimination (equation 57b) and also via a Horner-Emmons-Wadsworth reaction (equation 57c). The latter reaction is the dominant one for benzaldehyde. Although a consideration of the reactions of phosphate esters were not a mandate for this review, it is... 

Aldol donors bearing chiral auxiliaries include cii-l-)V-tosylamino-2-indanyl esters (ami-selective with TiCyf-Pr NEt) and (-)-bis(2,2,2-trifluoroethyl) menthoxycarbonyl)methylphosphonate. A dynamic kinetic resolution of racemic a-amino aldehydes is realized during their reaction with the latter compound. 

The reaction of the ester 51 with MeLi (55) in the presence of trimethylsilyl chloride cannot be performed on a large scale in a reproducibly high yield. For the synthesis of the Ci8-ketone 51 on a large scale, an alternative, a three-step route is used (Scheme 18). First the geranylacetone (52J is coupled in an Horner-Emmons reaction with diethyl cyano-methylphosphonate (4) with NaH as a base. Reduction of the nitrile by DEB AH then gives the aldehyde 56 in 73% yield. Aldol condensation of 56 with acetone (57) in the presence of a... 

For the preparation of prostacyclin derivative ([3- " C]nonyl)SM-10902 1821. halo-decarboxylation of (35)-3-methylheptanoic acid 1781 gave key intermediate 79. Grignard reagent preparation, carboxylation with " COj, esterification and subsequent reaction of the resulting ethyl ester with lithiated dimethyl methylphosphonate afforded ketophos-phonate SI in 70% overall radiochemical yield. Homer—Wadsworth—Emmons reaction with the corresponding aldehyde derivative and reduction of the resulting a,/3-unsaturated ketone converted 81 into 82". ... 

A facile preparation of aryl or heteroaryl substituted methylphosphonate esters (470) in good yields, involving a Lewis acid mediated Michaelis-Arbuzov reaction of arylmethyl halides/alcohols (468) with triethyl phosphite (469) at room temperature, has been described by Mohanakrishnan et al. (Scheme 116). ... 

Although most of the macrocycles that contain phosphorus or arsenic which have thus far been prepared, are primarily transition metals binders, two compounds have been prepared which are essentially crown ethers containing phosphorus. Kudrya, Shtepanek and Kirsanovhave prepared two compounds which are essentially polyoxygen macrocycles but which contain one or two methylphosphonic acid esters as part of the ring. These two macrocycles are shown below as 7d and 17 and are both prepared by the reaction of 2,2 [oxybis(ethyleneoxy)] bisphenolate with methylphosphonic dichloride in a mixture of acetonitrile and benzene. The crystalline monomer 16) and dimer 17) were isolated in 17% and 11% yields respectively as indicated in Eq. (6.13). 

The rate of appearance of p-nitrophenolate ion from p-nitrophenyl methylphosphonate (7), an anionic substrate, is moderately accelerated in the presence of cycloheptaamylose (Brass and Bender, 1972). The kinetics and pH dependence of the reaction are consistent with nucleophilic displacement of p-nitrophenolate ion by an alkoxide ion derived from a cycloheptaamylose hydroxyl group to form, presumably, a phosphonylated cycloheptaamylose. At 60.9° and pH 10, the cycloheptaamylose-induced rate acceleration is approximately five. Interestingly, the rate of hydrolysis of m-nitrophenyl methylphosphonate is not affected by cycloheptaamylose. Hence, in contrast to carboxylate esters, the specificity of cycloheptaamylose toward these phosphonate esters is reversed. As noted by Brass and Bender (1972), the low reactivity of the meta-isomer may, in this case, be determined by a disadvantageous location of the center of negative charge of this substrate near the potentially anionic cycloheptaamylose secondary hydroxyl groups. 

Nolan and co-workers have extended the scope of transesterification reactions to include phosphonate esters as phosphorylating agents [137]. In this publication the authors use dimethyl methylphosphonate 273 and benzyl alcohol with a variety of imidazolylidene carbenes (Table 23). The nse of molecnlar sieves to absorb methanol leads to increased conversion however, longer reaction times lead to decreased... 

The plant bufadienolide scillarenin (500) has been synthesized. The starting material was 15a-hydroxycortexone (501), which was converted into the diketone ketal (502) by cupric acetate oxidation at C(21), followed by selective ketalization and tosylate elimination. Protection at C(3) as the dienol ether, oxiran formation at C(20) with dimethylsulphonium methylide, and regeneration of the C(3)- and C(21)-oxo-groups by acid hydrolysis then provided (503). Selective reaction at C(21) with the sodium salt of diethyl methoxycarbonyl-methylphosphonate, and boron trifluoride rearrangement of the epoxide ring to the aldehydo-unsaturated ester (504), was followed by enol lactonization to the bufadienolide (505). This was converted, in turn, to scillarenin (500) via the 14,15-bromohydrin, by standard reactions. Unsubstituted bufadienolides have also been prepared by the same method. 

The synthesis of novel HBV-specific antiviral agents, the 2-amino-6-arylthio-9-[2-(phosphonomethoxy)ethyl]purine bis (2,2,2-trifluoroethyl) esters (87a-r) has been reported. These phosphonate diesters were prepared by the reaction of substituted purines with bis-(trifluoroethyl) (2-iodoethoxy)methylphosphonate in the presence of DBU. ... 

Horner-Wadsworth-Emmons Reactions of Phosphonate Anions. - As with the Horner modification of the Wittig reaction, the principal focus of papers that mention the Horner-Wadsworth-Emmons reaction relate to synthetic applications. The use of pressure to induce the synthesis of P-amino esters, p-thioesters and P-thionitriles via tandem Horner-Wadsworth-Emmons and Michael reactions has been reported. The reagent (l-tritylimidazol-4-yl)methylphosphonate (99) has been prepared and, when treated with aldehydes and ketones, affords (E)-vinylimidazoles in high yields. ... 

Reaction of dienoaldehyde with the stabilized Wittig reagent(s) provided a triene 88, which upon high-pressure Diels-Alder cyclization furnished bicyclo[4.3.0]nonene [78]. Alternatively the aldehyde S7-E was converted into the methyl ester 89, which reacted with the dimethyl methylphosphonate anion affording the phosphonate 90. Reaction of the latter with aldehydes under mild PTC conditions yielded a (regioisomeric to the previous one) triene 91, which cyclized spontaneously to bicyclo[4.4.0]decene (O Scheme 37) [79]. 

The reaction of diphenyl methylphosphonate with lithium alkoxides gives phenyl alkyl methylphosphonates even with hindered alcohols and, in the case of chiral alcohols, with high diastereoselectivity at phosphorus. [Hydroxy(pho-sphoryloxy)X, iodo]benzenes 289, prepared from reactions of iodosobenzene with phosphonic or phosphinic acids react with ketones, esters or phenyl acetylene to give esters 290. Racemic l-hydroxy-4-(3-phenoxyphenyl)butylphosphonate diethyl ester undergoes stereoselective acetylation in the presence of a lipase to... 

A chemoenzymatic synthesis of the P-a-methyl 2 -deoxynucleoside triphosphates 122 has been described which involves reaction of the 5 -0-(methylpho-sphonyl)-N-protected nucleosides with pyrophosphate in the presence of CDI. Removal of the base protection by treatment with penicillin amidase gave compounds 122 leaving the labile a-methylphosphonate intact. A number of 2 -deoxythymidine 5 -triphosphate and 3 -azido-2, 3 -dideoxythymidine 5 -tripho-sphate analogues (123) containing a hydrophobic phosphonate group have also been synthesised and evaluated as substrates for several viral and mammalian polymerases. Some y-ester (124) and y-amide (125) derivatives of dTTP and 3 -azido-2, 3 -dideoxythymidine 5 -triphosphate (AZTTP) were also synthesized and studied. The y-phenylphosphonate triphosphate 126 and its conjugation to biotin and fluorescein labels has also been described. 

Diethyl l-(ethoxycarbonyl)methylphosphonate was obtained for the first time by A. E. Arbuzov and Dunin by the reaction of ethyl bromoacetate with triethyl phosphite. " Subsequently, the Arbuzov-Dunin method was successfully extended for the synthesis of the alkyl esters of differently substituted dialkyl phosphonoacetates (R = Me, Et, /-Pr, n-Pr, n-Bu, /-Pent, n-Pent, n-... 

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