Methyl oxalyl chloride

Stereoselective synthesis of monofluoroolefins (371) from diisopropyl(car-boethoxyfluoro-methyl)phosphonates (372) by treatment with CHsMgl or CHaCuMgBr has been described. The intermediate compounds (372) have been prepared by the action of phosphonate anion (373) on oxalyl chloride or methyl oxalyl chloride (Scheme 100). ... 

Radical Carboxylation with Methyl Oxalyl Chloride... 

Kim and Jon recently reported a unique method for the synthesis of esters via a radical reaction of alkyl iodides with methyl oxalyl chloride under in-adiation con-... 

Methyl oxalyl chloride was also employed as a radical trap for the same purpose (Scheme 18) [40c], Radical reaction of an alkyl iodide with methyl oxalyl chloride in the presence of hexabutylditin under photochemically initiated conditions affords an acid chloride along with a small amount of the corresponding methyl ester. Sequential radical reaction involving cyclization and carboxylation can be performed using methyl oxalyl chloride. 

Follow-up chemistry of azetidyl ylide 94, which was obtained by hydrolysis of ylide 84, led to various pyrrolidines and pyrazoles [68]. The reaction with methyl oxalyl chloride gave a 4-triphenylphosphoranyhdene-pyrrolidine-2,3,5-trione 95, while treatment with ethyl diazoacetate afforded 4-anilido-3-triphenylphosphoran-ylidene-pyrazole-5-carboxylic acid ethyl ester 96 (Scheme 20). 

Methyl oxalyl chloride (which was first used by Japanese workers [95]) has been claimed by Farooq, Rahman, Nasim and Siddiqui [96] to give higher yields than the ethyl ester but its higher cost—about fifteen times as much—may account for its infrequent use, even in subsequent experiments by the workers [93, 94] who earlier had recommended it. 

The 3-deoxv-3-diazo-D-arabino-oct-2.4-diulosonate derivative (47) has been synthesised by condensation of 1-diazo-D-fructose derivative (48) with methyl oxalyl chloride. In contrast to other carbohydrate diazoketones, compound (47) is relatively stable to acids, although it reverts to the precursor (48) on exposure to water. ... 

Construction of the B Ring. For construction of the penem nucleus the intramolecular Wittig-type cyclization developed by Woodward(38) as modified by Afonso(39) was employed. Compound 18 was N-acylated by treatment with methyl oxalyl chloride in the presence of triethylamine to oxalimide 19.(29) This compound without purification was then heated under reflux in xylene in the presence of triethyl phosphite(40) to yield the tribactam 7. 

A fiuorinated version of a trinem P-lactam was synthesized bearing a methyl group at position three instead of a hydroxyethyl unit. The electronic effect of the fluorine was observed during nucleophilic addition to the adjacent in situ -formed sp carbon which resulted in exclusively trans addition to the carbon-fluorine bond. The electronic effect of fluorine dominates the steric influences of flie methyl group at the same site. The addition of methyl oxalyl chloride in the cyclization process under basic conditions promotes epimerization of the C-4 stereocenter. The biological testing of the final compound is under investigation. 

The related compounds bis(2-mothyl-3-indolyl)glyoxal (263) and bis(3-methyl-l-indolyl)glyoxai (264) - have been prepared by the action of oxalyl chloride on the Grignard reagents derived from 2-methylindole and 3-methylindole, respectively, Eis(l-methyl-3-indolyl)-glyoxal (265) was prepared by the action of oxalyl chloride on 1-methyIindole in ether. 

Vilsmeier-Haack formylation of 2-(4-methyl-l-piperazinyl)-4//-pyrido-[l,2-n]pyrimidin-4-one with a mixture of POCI3 and DMF at 95°C gave a 3-formyl derivative (93FES1225) while ethyl 4-oxo-6,7,8, 9-tetrahydro-4//-pyrido[l,2-n]pyrimidine-2-acetate at 50 °C yielded a 9-dimethylaminomethylene-3-formyl derivative (01MI4). 3-Formyl-2-hydroxy-8-[2-(4-isopropyl-l,3-thiazol-2-yl)-l-ethenyl]-4//-pyrido[l,2-n]pyri-midin-4-one was obtained from the 3-unsubstituted derivative with oxalyl chloride-DMF reagent in CH2CI2 at room temperature for 3h (OlMIPl). 

Reaction of 4-hydroxyquinoline-2-one 598 with oxalyl chloride gave oxazoloquinoline 599 (970PP211). The oxazoloquinoline 600 was obtained as a byproduct during the synthesis of pyranoquinoline alkaloids 601 by reaction of 598 with 2-methyl-2-chlorobutyne under phase transfer catalysis (87JHC869) (Scheme 101). 

Treatment of N-benzoyl-L-alanine with oxalyl chloride, followed by methanolic triethylamine, yields methyl 4-methyl-2-phenyloxazole-5-carboxylate 32 <95CC2335>. a-Keto imidoyl chlorides, obtained from acyl chlorides and ethyl isocyanoacetate, cyclise to 5-ethoxyoxazoles by the action of triethylamine (e.g.. Scheme 8) <96SC1149>. The azetidinone 33 is converted into the oxazole 34 when heated with sodium azide and titanium chloride in acetonitrile <95JHC1409>. Another unusual reaction is the cyclisation of compound 35 to the oxazole 36 on sequential treatment with trifluoroacetic anhydride and methanol <95JFC(75)221>. 

DMSO or other sulfoxides react with trimethylchlorosilanes (TCS) 14 or trimefhylsilyl bromide 16, via 789, to give the Sila-Pummerer product 1275. Rearrangement of 789 and further reaction with TCS 14 affords, with elimination of HMDSO 7 and via 1276 and 1277, methanesulfenyl chloride 1278, which is also accessible by chlorination of dimethyldisulfide, by treatment of DMSO with Me2SiCl2 48, with formation of silicon oil 56, or by reaction of DMSO with oxalyl chloride, whereupon CO and CO2 is evolved (cf also Section 8.2.2). On heating equimolar amounts of primary or secondary alcohols with DMSO and TCS 14 in benzene, formaldehyde acetals are formed in 76-96% yield [67]. Thus reaction of -butanol with DMSO and TCS 14 gives, via intermediate 1275 and the mixed acetal 1279, formaldehyde di-n-butyl acetal 1280 in 81% yield and methyl mercaptan (Scheme 8.26). Most importantly, use of DMSO-Dg furnishes acetals in which the 0,0 -methylene group is deuter-ated. Benzyl alcohol, however, affords, under these reaction conditions, 93% diben-zyl ether 1817 and no acetal [67]. 

Quebrachitol was converted into iL-c/j/roinositol (105). Exhaustive O-isopropylidenation of 105 with 2,2-dimethoxypropane, selective removal of the 3,4-0-protective group, and preferential 3-0-benzylation gave compound 106. Oxidation of 106 with dimethyl sulfoxide-oxalyl chloride provided the inosose 107. Wittig reaction of 107 with methyl(triphenyl)phos-phonium bromide and butyllithium, and subsequent hydroboration and oxidation furnished compound 108. A series of reactions, namely, protection of the primary hydroxyl group, 0-debenzylation, formation of A-methyl dithiocarbonate, deoxygenation with tributyltin hydride, and removal of the protective groups, converted 108 into 7. 

The reaction of the aldehyde 174, prepared from D-glucose diethyl dithio-acetal by way of compounds 172 and 173, with lithium dimethyl methyl-phosphonate gave the adduct 175. Conversion of 175 into compound 176, followed by oxidation with dimethyl sulfoxide-oxalyl chloride, provided diketone 177. Cyclization of 177 with ethyldiisopropylamine gave the enone 178, which furnished compounds 179 and 180 on sodium borohydride reduction. 0-Desilylation, catalytic hydrogenation, 0-debenzyIation, and acetylation converted 179 into the pentaacetate 93 and 5a-carba-a-L-ido-pyranose pentaacetate (181). 

Methyl 3-acyl-l-diphenylmethyleneamino-4,5-dioxo-4,5-dihydro-l//-pyrrole-2-carboxylates 489 are formed from 488 and oxalyl chloride in good yields. Preparative thermolysis of these compounds at 130-140°C gives mixtures of dipyrazolo[l,2- l,2- [l,2,4,5]tetrazines 491 as major products and pyrazoles 492 as minor hydrolytic by-products. The intermediacy of mesoionic compound 490 is expected (Scheme 83) <2004T5319>. 

Acyl hydrazides are useful precursors for the synthesis of 1,2,4-triazoles. Reaction of acyl hydrazides 149 with imidoylbenzotriazoles 148 in the presence of catalytic amounts of acetic acid under microwave irradiation afforded 3,4,5-trisubstituted triazoles 150 <06JOC9051>. Treatment of A-substituted acetamides with oxalyl chloride generated imidoyl chlorides, which reacted readily with aryl hydrazides to give 3-aryl-5-methyl-4-substituted[ 1,2,4]triazoles <06SC2217>. 5-Methyl triazoles could be further functionalized through a-lithiation and subsequent reaction with electrophiles. ( )-A -(Ethoxymethylene)hydrazinecarboxylic acid methyl ester 152 was applied to the one-pot synthesis of 4-substituted-2,4-dihydro-3//-1,2,4-triazolin-3-ones 153 from readily available primary alkyl and aryl amines 151 <06TL6743>. An efficient synthesis of substituted 1,2,4-triazoles involved condensation of benzoylhydrazides with thioamides under microwave irradiation <06JCR293>. 

Cyclization of ethyl 3-cyano-3-methyl butyrate 201 with hydrazine hydrate gave the hydrazonopyridazine 202, which underwent ring closure with oxalyl chloride to give (85MIP1) pyridazinotriazine derivative 203. 

As second example for the scale-up of solid-phase reactions directly on solid support, we chose an arylsulfonamido-substituted hydroxamic acid derivative stemming from the matrix metalloproteinase inhibitor library (MMP) of our research colleagues (Breitenstein et al. 2001). In this case, there was already a solution-phase synthesis available for comparison (see Scheme 4). The synthesis starts with the inline formation of a benzaldehyde 18 with the glycine methyl ester, which is then reduced to the benzylamine 20 using sodium borohydride in methanol/ THF (2 1). The sulfonamide formation is carried out in dioxane/H20 (2 1) with triethylamine as the base and after neutralisation and evaporation the product 21 can be crystallised from tert. butylmethyl ether. After deprotection with LiOH, the acid is activated by treatment with oxalyl chloride and finally converted into the hyroxamic acid 23 in 33.7% yield overall. 

In the first total synthesis of the alkaloid erysotrine, the pyrroloisoquino-line ring 132 was prepared from (5 )-3,4-dimethoxyphenylalanine methyl ester and methyl chloroformylacetate, followed by ring closure and condensation with oxalyl chloride [92H(33)497]. 

Figure 2. Typical hydrodynamic radius distributions (/(RjO) of individual triblock PMMA-Z>-PS-Z>-PMMA copolymer chain end-capped with oxalyl chloride in a solvent mixture of methyl acetate and acetonitrile (10/1, v/v) at 45 °C and the aggregates formed via the self-assembly of the triblock copolymer chains at 29 °C, where the triblock copolymer concentration is 1 x 10 4 g / mL.[35]...

D. 1 -[N-Benzyloxycarbonyl-(IS)-1 -amino-2-oxoethyl]-4-methyl-2,6,7-trioxabi-cyclo[2.2.2]octane, [Cbz-L-Ser(ald) OBO ester, (4)7 Cbz-Ser OBO ester 3 (9.10 g, 28.0 mmol) (Note 21) is dissolved in dry CH2CI2 (80 mL) (Note 14) under Ar and cooled to -78°C in a 100-mL, round-bottomed flask labeled flask 1. Oxalyl chloride (3.9 mL, 45 mmol, 1.61 equiv) (Note 22) is added to dry CH2CI2 (120 mL) (Note 14) in a separate 250-mL, round-bottomed flask (flask 2) under Ar, and cooled to -78°C. Dry dimethyl sulfoxide (DMSO, 7.0 mL, 90 mmol, 3.21 equiv) (Note 23) is added to the oxalyl chloride solution (flask 2) and the mixture is stirred under Ar (magnetic stir bar) at -78°C for 15 min. The alcohol solution 3 (in flask 1) is transferred slowly by cannula to flask 2 over a period of 45 min and then rinsed with dry CH2CI2 (50 mL) (Note 14). The resulting cloudy white... 

The 7-lactam 120, which is very reactive, is obtained from the reaction of methyl 2-(2-methoxycarbonylmethyl-ene)-5-methyl-3,6-dihydro-2//-l,3-thiazine-4-carboxylate 119 with oxalyl chloride and in the presence of triethyl-amine (Scheme 5). Subsequent treatment with methanol affords 3,6-dihydro-2//-l,3-thiazine 121 as a mixture of isomers. Similar treatment of the 4-allyl carboxylate analogue with oxalyl chloride/triethylamine yielded the corresponding 7-lactam <1999J(P1)2449>. 

Other useful dehydrating agents are dimethylaminosulfur trifluoride (DAST), methyl A -(triethylammoniosulfonyl)carbamate (Burgess salt), acetic anhydride, oxalyl chloride, and phosphorous oxychloride, each one in combination with triethylamine (89). Dehydration of O-sUylated hydroxamic acids using trifluoro-methanesulfonic anhydride and triethylamine under mild conditions also gave nitrile oxides, which in the presence of olefins led to the formation of 2-isoxazolines in moderate to good yields (90). In view of the less readily available starting materials, this method probably will be of limited use. 

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