Cyanomethyl ethers

The cyanomethyl ether, formed from bromoacetonitrile (acetone, K2CO3, 97-100% yield), is cleaved by hydrogenation of the nitrile with Pt02 in EtOH, in 98% yield. The method has also been used for the protection of amines and carbamates. 

Furo[3,2-fa]benzothiophenes (37) were synthesized in an analogous way (91JHC269) by smooth cyclization of the cyanomethyl ether 36 in the presence of K2C03/DMF. The starting 2-cyano-3-hydroxybenzothiophene 35 was obtained from methyl 2-thiohydroxybenzoate and chloroacetonitrile. Under Vilsmeier conditions (POCl3/DMF), the 2-cyano-3-cyanomethoxy-... 

CH3SH and C2H5N[CH(CH3)2]2 (equation I). Under the same conditions dialkyl acetals can be converted into 0,S-acetals (equation II). MEM and MOM ethers can be converted into cyanomethyl ethers (ROCH2CN) by sequential reaction with (CH3)2BBr and Bu4NCN in 80-90% yield. 

Cyanomethyl ethers, ROCH2CN.7 Conventional methods for preparation of these ethers with C1CH2CN fail. A recent method involves reaction of (CH3)3SiCN and Znl2 (9,127-128) with methylsulfoxymethyl ethers in CH2C12. 

The C-4 hydroxy group of Neu5Ac2en was oxidized to the ketone 18, resulting in a drop in potency by a factor of over 100.72 Cyanomethyl ether 19, a key intermediate towards the synthesis of the inhibitors 20 and 21, which intended to mimic Zanamivir at C-4, was evaluated against NA.74,75 These modifications were not particularly successful, as 19-21 showed only 7-30% inhibition of catalysis at 1.0 mM compared to Zanamivir, which inhibits NA activity by over 90%. 

Cyanomethyl ethers. Methoxyethoxymethvl (MEM) ethers are converted into cy-anomethyl ethers by reaction with excess diethylaluminum cyanide in toluene at 100° (equation 1). The same reaction with methoxymethx I (MOM) ethers is considerably slower. 

Conversion of MEM-protected alcohols to related cyanomethyl ethers by use of dimethylboron bromide in dichloromethane at low temperature, followed by addition of cyanide, has also been reported. 

Functional group replacement by cyano is an important synthetic transformation since it frequently allows homologation by hydrolysis to the carboxylic acid, or by reduction to an amine. The replacement of sulphinyl by cyano via trimethyl-silylcyanide thus provides a preparation of aliphatic cyanomethyl ethers, and this useful reagent has been further employed to provide cyclic a-acylaminonitriles by the replacement of methoxy-groups. The replacement of a primary amino-group by cyano is an often sought after transformation, and... 

Dimethylindole magnesium iodide reacts with chloroacetonitrile in ether to give 3-cyanomethyl-2,3-dimethylindolenine (234). Majima and Hoshino obtained 3-(2-cyanoethyl)lndole (235) by the action of -chloropropionitrile on indole magnesium iodide. The reaction was slower with -chloropropionitrilc than with chloro-aoetonitrile. 3-(3-Cyano-w-propyl)indole (236), required as an intermediate in the synthesis of 3-indolyl-y-w-butyric acid, was prepared, but not isolated, by the action of y-chloro-w-butyronitrile on indole magnesium iodide. ... 

The reaction of l-phenyl-3-cyanomethyl-4-cyano-5-(ethyloxalyl-amino)pyrazole (60) wdth diazomethane in tetrahydrofuran-ether at... 

Reaction of 2-cyanomethyl-4H-l,3-benzothiazin-4-one with benzoylace-tonitrile at 160°C yielded 8-cyano-7-imino-9-phenyl-7//,ll//-pyrido[2,l-6][l,3]benzothiazin-l 1-one (85MI1 86MI2). Reaction of 2-ethoxy-2,3 dihydro-4//-l,3-benzothiazin-4-one with 1,2,3,4-tetramethylbutadiene and 2,4-dimethyl-l,3-pentadiene in the presence of boron trifluoride in diethyl ether gave rise to 6,7,8,9-tetramethyl- and 7,9)9-trimethyl-5a,6,9,ll-tetrahydropyrido[2,l-6][l,3]benzothiazin-ll-one, respectively (73JHC149). 

Finally, lV-(cyanomethyl)iminodiacetic acid was obtained from the ester of iminodiacetic acid and chloroacetonitrile as illustrated in Scheme l.10 The purified ester is hydrolyzed selectively at the methylester groups with zinc perchlorate in a 70% alcoholic solution and formation of the 1 1 complex (3) occurs. The substituted iminodiacetic acid is extracted with ether after zinc separation as ZnS by treatment with H2S, and crystallized in a chloroform ethanol solution. 

Interestingly, attempts to adapt either Scheme 3.10 or Scheme 3.11 to the preparation of 7-azaMTX (55) were uniformly unsuccessful (Scheme 3.12). In the former case, the alkylation product of methyl / -(methylamino)benzoate [64] with cyanomethyl tosylate was converted to the imino ether (56) as previously described for (46). Reaction of (56) with (47) produced none of the... 

To date, the last total synthesis of a sesquiterpene picrotoxane (132) is a variant of the above-described picrotoxinin/corianin synthesis by Trost et al. Again, the synthesis started with (—)-carvone and the introduction of the C-1 unit corresponds with the earlier syntheses. The choice of the protective group was governed by the discovery that the oxygen(s) of alkoxymethyl ethers had a directing effect in the following addition of (cyanomethyl)lithium. 

An anodically induced controlled-potential cycloaddition reaction between ethyl vinyl ether and A-cyanomethyl oxazolidines was recently reported, though the reaction was thought to involve oxidation of the oxazolidines rather than the vinyl ether component [154]. 

Thus irradiation of ethyl 2-cyano-4-methyl-l,2-dihydroquinoline-l-carboxylate (3a) in diethyl ether with a 350-W high-pressure mercury lamp through a Pyrex filter gave a cyclopropaindole as minor product, along with ethyl 2-cyanomethyl-3-methylindole-l-carboxylate arising from the intramolecular cyclization of an allene intermediate. 

Under a nitrogen atmosphere, dimethyl 2-cyanomethyl-2-(hex-2 -yny)malonate (3) (136 mg, 0.5 mmol) was added to a mixture of Pd(OAc)2 (5.6 mg, 0.025 mmol), 2,2 -bipyridine (4.5 mg, 0.03 mmol), HOAc (1 mL) and 1,4-dioxane (4 mL). The solution was stirred at 80 °C for 14 hours until the reaction was complete as monitored by TLC. On cooling, the reaction mixture was neutralised with saturated sodium hydrogencarbonate, and then extracted with diethyl ether (3 x 20 mL). The combined ether solution was washed with saturated sodium chloride, dried with sodium sulfate, and concentrated. The residue was purified by flash chromatography (EtOAc/petroleum ether 1/4) to give the product dimethyl 3-acetylamino-4-butyrylcyclopent-3-ene-l,l-dicarboxylate (4) in 95% yield as white solid m.p. 89.5-90.5 °C. 

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