Lewis methanol synthesis

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

Keimg et al. describes the optimization of 2-imino-piperazines using Lewis acids to catalyze the multicomponent a-amino amidine synthesis to make piperazines 39 (Scheme 6) [26]. A, Af -(jimethylethylenediamine 36 was used with an aldehyde 37 and isocyanide 38 in methanol with scandium (III) trifluoromethane sulfonate (Sc(OTf)3) as a catalyst to obtain the piperazine 39 in 57% yield. 

In the Sepracor synthesis of chiral cetirizine di hydrochloride (4), the linear side-chain as bromide 51 was assembled via rhodium octanoate-mediated ether formation from 2-bromoethanol and ethyl diazoacetate (Scheme 8). Condensation of 4-chlorobenzaldehyde with chiral auxiliary (/f)-f-butyl sulfinamide (52) in the presence of Lewis acid, tetraethoxytitanium led to (/f)-sulfinimine 53. Addition of phenyl magnesium bromide to 53 gave nse to a 91 9 mixture of two diastereomers where the major diasteromer 54 was isolated in greater than 65% yield. Mild hydrolysis conditions were applied to remove the chiral auxiliary by exposing 54 to 2 N HCl in methanol to provide (S)-amine 55. Bisalkylation of (S)-amine 55 with dichlonde 56 was followed by subsequent hydrolysis to remove the tosyl amine protecting group to afford (S)-43. Alkylation of (5)-piperizine 43 with bromide 51 produced (S)-cetirizine ethyl ester, which was then hydrolyzed to deliver (S)-cetirizine dihydrochloride, (5)-4. 

A number of related couplings have been reported during the synthesis of the alkaloid ( )-cryptopleurine149 and also intramolecular coupling of diaryl amides to dibenzazepine and dibenzazodne structures.150 A versatile method for the preparation of tetrahydroquinolines and jololidines has been developed.151 The method involves the anodic oxidation of AT,AT-dimethyl-aniline in methanol to afford a-methoxylated or a, a -dimethoxylated compounds and subsequent treatment of products with Lewis acids in the presence of olefins. 

In the report that described the synthesis of 108 (777), Whitmire also observed that the reaction between NaBi03 and methanolic [Fe(CO)s] in the presence of hydroxide afforded the trianionic species [Bi Fe(CO)4 4]3, 110, which was subsequently characterized by X-ray crystallography (775). Cluster 110 contains a central bismuth atom tetrahedrally coordinated by four Fe(CO)4 fragments and is isoelectronic with the anionic tetracobalt-indium complex, 27, and the neutral tetracobalt-germanium, - tin, and -lead complexes, 68, 71, and 72. Oxidation of 110 affords 108 (777), while acidification (772) yields the hydride-containing cluster [BiFe3(CO)9(/i-H)3], 111, which also contains a tetrahedral BiFe3 core. Johnson and Lewis (114) have... 

The palladium [Pd(Ph3)4]-catalysed 3 + 3-cycloaddition of trimethylenemethane with azomethineimines produced hexahydropyridazine derivatives under mild conditions (40 °C).171 The Lewis acid-catalysed formal oxa-[3 + 3]-cycloaddition of a,f+ unsaturated aldehydes with 6-methyl-4-hydroxy-2-pyrone, 1,3-diketones, and viny-logous silyl esters yielded a variety of pyrones at room temperature.172 Croton-aldehyde has been converted to 6-hydroxy-4-methylcyclohex-l-enecarboxaldehyde by an enantioselective 3 + 3-cycloaddition catalysed by proline. This methodology was used in the synthesis of (—)-isopulegol hydrate, (—)-cubebaol, and (—)-6-hydroxy-4-methylcyclohex-l-ene-1-methanol acetate, an intermediate in the total synthesis of the alkaloid magellanine.173... 

As an alternative to the alkylation of 113 for the preparation of compounds of type 103-105, 110, and 111, Meyers et al. developed a variant of the Com-forth oxazole synthesis. This had been used previously to prepare 113-115 (67, 70). In this scheme, the imino ether 128, the adduct of methanol, HC1, and acetonitrile, is condensed with methyl glycinate (129) to yield 130, which is for-mylated to 131. Deprotonation of the formyl anion 131 at the incipient 2-methyl position of the oxazole followed by alkylation with the electrophile of choice [in this case the acetonide 132 derived from (S)-malic acid] and Lewis acid-... 

Lewis WK, Frolich PK. Synthesis of methanol from carbon monoxide and hydrogen. Ind Eng Chem. 1928 20(285) 285-90. 

Lewis acids can also be exploited for the cleavage of isopropylidene derivatives. One of the mildest examples comes from a synthesis of Lankacidin in which cleavage of an isopropylidene acetal without harm to a p-methoxybenzyl ether was effected with copper(Il) chloride dihydrate in methanol at reflux [Scheme 3.11].13 Alternatively, zinc(II) nitrate hexahydrate in acetonitrile at 50 DC can be used in which case even a primary tert-butyldimethylsilyl ether survives [Scheme 3.12].14 During a synthesis of Quinocarin, Katoh and co-workerscleaved an isopropylidene group using iron(IIT) chloride adsorbed onto silica gel [Scheme 3.13]. 

Trost first introduced the di-fe/7-butylsilylene derivative as a means for protecting 1,2- and 1,3-diols during a synthesis of PiUaromycinone derivatives.213 Di-ferf-butylsilylene derivatives are not as robust as isopropylidene or benzylidene acetals and their use is best reserved for systems requiring deprotection under very mild conditions. Di-isopropylsiiylene derivatives are occasionally used but they usually only survive in highly crowded environments.214 Di-feri-butylsily-lene derivatives survive hydroboration with 9-BBN, mild oxidation (e g the Dess-Martin, ozone), Lewis acids such as trifluoroborane e the rate and titanium tetrachloride, mild acids (pyridinium p-toluenesulfonate). camphorsulfonic acid, strong bases such as feri-butyllithium (THF, -50 °C), DDQ, and sodium meth-oxide in methanol at 0 C — conditions used to cleave acetate esters. 

At the exotic end of the Lewis acid scale is tetrafluorosilane (mp -90 5C, bp -86 UC) first proposed by Corey and Yi as a mild and selective reagent for the cleavage of silyl-protected alcohols with the reactivity order being EtiSi > f-Bu-Me2Si f-BuPhiSi/ 1 The substrate in dichloromethane or acetonitrile, is stirred at room temperature under an atmosphere of excess tetrafluorosilane provided by a gas-filled balloon. The reaction is slow in dichloromethane but quite fast (ca. 15 min) in acetonitrile. In the final step of Yamamoto s synthesis of the Hemibrevetoxin B [Scheme 4.40]61 the secondary TIPS and TBS ethers were removed from 40.1 with tetrafluorosilane. Identical conditions were used by Nicolaou et al to remove two TBS ethers in the final step of their synthesis of Hemibrevetoxin B.62 In the example shown in Scheme 4,41, deprotection with fluoride (basic) or cerium(lV) ammonium nitrate (CAN) in methanol (neutral) isomerised the angelate to the more thermodynamically stable tiglate.63 However, with tetrafluorosilane, no isomerisation occurred during the deprotection step. 

Most Lewis acids such as zinc bromid in methanol, dichtoroethylalane in di-chloromethane, trifluoroborane etherate and ethane-1,2-dithiol in methanol,372 or iron(lll) chloride373 will also cleave trity ethers. Scheme 4.202 illustrates the use of zinc bromide in dichloromethane374 to remove a trityl ether in the presence of two a Hylic TBS ethers during a synthesis of ACRL toxin 111b.375... 

In the synthesis of the boron-capped cobalt(II) tris-dioximates, ferrocenylboronic acid was also used as a capping agent [43], Reaction of this Lewis acid with anhydrous C0CI2 and dioximes in oxygen-free methanol gave clathrochelate CoNx3(BFc)2 and CoDm3(BFc)2 complexes ... 

A formal total synthesis of ( )-morphine has been achieved by adopting the above synthetic route (Scheme 18). The tetrahydropyridine 91, prepared from the reaction of A/ -methyl-4-piperidone with 2,3-dimethoxy-phenyllithium, followed by dehydration, was converted to the bicyclic en-amine 92 by treatment with the ylic dibromide. Kinetic protonation of 92 with perchloric acid gave the trans-fused immonium salt, which upon dissolution in methanol equilibrated to the thermodynamically prefered cis isomer 93. Treatment of 93 with diazomethane brought about the formation of the aziridinium salt 94, which was readily transformed into the a-amino aldehyde 95 by its oxidation with dimethyl sulfoxide. It is also worth noting that the Komblum oxidation of aziridinium salts leads to the construction of a-amino aldehydes efficiently. Lewis-acid-catalyzed cyclization of 95 afforded the morphinan carbinol 96 in 80% yield. Successive mesylation and reduction of the mesylate derived from 96 with LiBEtjH afforded morphinan (97) in excellent yield. In this instance, direct conversion of 93 to 97 by treatment with diazomethane gave approximately 1 % of the desired product. Lemieux-Johnson oxidation of 97 under acidic conditions furnished the ketone 98, which was previously transformed into ( )-morphine by Gates. In order to confirm the structure of 98, its conversion to the known... 

---