Ethers, diethyl boron trifluoride complexes

The pharmaceutical interest in the tricyclic structure of dibenz[6,/]oxepins with various side chains in position 10(11) stimulated a search for a convenient method for the introduction of functional groups into this position. It has been shown that nucleophilic attack at the carbonyl group in the 10-position of the dibenzoxepin structure renders the system susceptible to water elimination. Formally, the hydroxy group in the enol form is replaced by nucleophiles such as amines or thiols. The Lewis acids boron trifluoride-diethyl ether complex and titanium(IV) chloride have been used as catalysts. 

Alternatively, diazomcthanc can be added to thioxanthylium perchlorate (4) over 30 minutes at 0°C, and the reaction solution then poured into propan-2-ol. After concentration, the residue is dissolved in acetic anhydride and treated with boron trifluoride-diethyl ether complex at 0 C, to provide dibenzo[6,/]thiepin in 55 % overall yield16 (cf. Houben-Weyl, Vol. 10/4, p 834). 

In acid solution 1-acyl-1//-azepines and alkyl l//-azepine-l-carboxylates undergo rapid aromatization to A-arylcarbamates,115,139,142 whereas 1/Z-azepine-l-carbonitrile suffers quantitative rearrangement and hydrolysis to phenylurea.163 Rearrangement of ethyl l//-azepine-l-carboxylate to ethyl A-phenylcarbamate is also rapid (5 min) and quantitative with boron trifluoride-diethyl ether complex in benzene.245... 

The dehydrogenation of 2,3-dihydro- and 2,5-dihydro-l//-l-benzazepines to 3//-l-benz-azepincs with heterocyclic enamines in the presence of boron trifluoride diethyl ether complex has been achieved in moderate yields (30-35%).241 In contrast, electrochemical oxidation of 2,5-dihydro-1 H- -benzazepines in buffered acetic acid solution furnishes initially 5//-l-benz-azepines in 35-45% yield.242... 

Indole and dimethyl acetylenedicarboxylate yield 2-(indol-3-yl)-2,3-dihydro-l//-l-ben-zazepine (mp 240-242 C) by addition of indole to the initially formed l//-l-benzazepinc,21 whereas 1,3-dimethylindole (10, R = H) fails to react with the diester under a variety of conditions.145 However, in the presence of boron trifluoride-diethyl ether complex at room tem-... 

The reaction of benzopentathiepin with alkenes [(fl-but- -ene, ( )-hex-3-ene, cyclopentene or cyclohexene] in the presence of the boron trifluoride-diethyl ether complex results in the formation of 3,4-dihydro-l,2,5-benzotrithiepins, e.g. formation of 3.407... 

In addition to the boron trifluoride-diethyl ether complex, chlorotrimcthylsilanc also shows a rate accelerating effect on cuprate addition reactions this effect emerges only if tetrahydrofuran is used as the reaction solvent. No significant difference in rate and diastereoselectivity is observed in diethyl ether as reaction solvent when addition of the cuprate, prepared from butyllithium and copper(I) bromide-dimethylsulfide complex, is performed in the presence or absence of chlorotrimethylsilane17. If, however, the reaction is performed in tetrahydrofuran, the reaction rate is accelerated in the presence of chlorotrimethylsilane and the diastereofacial selectivity increases to a ratio of 88 12 17. In contrast to the reaction in diethyl ether, the O-silylated product is predominantly formed in tetrahydrofuran. The alcohol product is only formed to a low extent and showed a diastereomeric ratio of 55 45, which is similar to the result obtained in the absence of chlorotrimethylsilane. This discrepancy indicates that the selective pathway leading to the O-silylated product is totally different and several times faster than the unselective pathway" which leads to the unsilylated alcohol adduct. A slight further increase in the Cram selectivity was achieved when 18-crown-6 was used in order to increase the steric bulk of the reagent. 

Addition of 15-crown-5 to the higher-order cuprate led to a reagent that is totally unrcac-tive towards 2-phenylpropanal even at room temperature18. If, however, boron trifluoride-diethyl ether complex was added as additional ingredient, the reactivity was restored and, furthermore, the Cram selectivity increased to 90 10 (Table 4). Analogous results could be obtained by placing the crown-ether effect within the cuprate itself, as in reagent 10. 

The alkynyl reagent 9 was recently introduced for the dia stereoselective synthesis of tertiary propargylic alcohols144. 9 can be prepared as a solid 1 1 complex with tetrahydrofuran by treatment of 9-methoxy-9-borabicyclo[3.3.1]nonane with (trimethylsilylethynyl)lithium, followed by addition of boron trifluoride-diethyl ether complex. The nucleophilic addition of reagent 9 to (R)-2-methoxy-2-methylhexanal (10) afforded a mixture of the diastereomers 11 with a considerable preference to the nonchelation-controlled (3S,4R)-isomer144. 

For the monoprotected a-amino aldehydes, the best results in yield and stereoselectivity were obtained under kinetic control conditions which gave the expected sw-com pounds. The addition of tin(lV) chloride did not result in increased syn selectivity, and the use of boron trifluoride diethyl ether complex did not provide the ann -isomer as the major product. 

Benzylzinc requires activation by copper(l) cyanidc/boron trifluoride-diethyl ether complex for rapid carbonyl addition29. Little information is available on the reactivity of benzyltitani-um derivatives30,31. 

To a stirred — 78 C solution of 5.85 mL (62.5 mmol) of 3-methoxy-l-prnpene in 25 mL of THf- are added 43.1 mL (50 mmol) of 1.16 M. vcc-butyllithium in cyclohexane over a 20-25 min period. The mixture is stirred at — 78 °C for an additional 10 min, and diisopinocampheyl(methoxy)borane [50 mmol prepared from (+ )-a-pinene] in 50 mL of THF is added. This mixture is stirred for 1 h, then 8.17 mL (66.5 mmol) of boron trifluoride diethyl etherate complex are added dropwise to give a solution of diisopiuocampheyl[(Z)-3-inethoxy-2-propenyl]borane. Immediately. 2.8 mL (50 mmol) of acetaldehyde are added and the mixture is stirred for 3 h at — 78 rC and then allowed to warm to r.t. All volatile components are removed in vacuo, then the residue is dissolved in pentane. The insoluble fraction is washed with additional pentane. The combined pentane extracts are cooled to 0 JC and treated with 3.0 mL (50 mmol) of ethanolamine. The mixture is stirred for 2 h at 0rC and is then seeded with a crystal of the diisopinocampheylborane-ethanolaminc complex. The resulting crystals arc filtered and washed with cold pentane. The filtrate is carefully distilled yield 5.6 g (57%) d.r. (synjanti) >99 1 (2/ ,37 )-isomer 90% ee bp 119-120 C/745 Torr. 

The diastereofacial selectivity of Lewis acid promoted reactions of allylsilancs with chiral aldehydes has been thoroughly investigated58. Aldehydes with alkyl substituted a-stereogenic centers react with a mild preference for the formation of Cram products, this preference being enhanced by the use of boron trifluoride-diethyl ether complex as catalyst58. 

The use of boron trifluoride-diethyl ether complex as the Lewis acid in these reactions promotes silyl group migration and gives rise to the formation of tetrahydrofurans with excellent stereoselectivity82. 

Effective 1,4-asymmetric induction has been observed in reactions between 2-(alkoxyethyl)-2-propenylsilanes and aldehydes. The relative configuration of the product depends on the Lewis acid used. Titanium(IV) chloride, in the presence of diethyl ether, gave 1,4-ijn-products with excellent stereoselectivity with boron trifluoride-diethyl ether complex, the amt-isomer was the major product, but the stereoselectivity was less83. 

The stereoselectivity of Lewis acid promoted reactions between 2-butenylstannanes and aldehydes has been widely studied, and several very useful procedures for stereoselective synthesis have been developed. In particular syn-products are formed stereoselectively in reactions between trialkyl- and triaryl(2-butenyl)stannanes, and aldehydes induced by boron trifluoride-diethyl ether complex, irrespective of the stannane geometry66. 

Excellent chelation control was observed using tributyl(2-propenyl)stannane and a-benzyloxy-cyclohexaneacetaldehyde with magnesium bromide or titanium(IV) chloride, whereas useful Cram selectivity was observed for boron trifluoride-diethyl ether complex induced reactions of the corresponding ferr-butyldimethylsilyl ether89. 

For a-benzyloxycyclohexaneacelaldehyde and 2-butenylstannanes, good chelation control was observed using zinc iodide and titanium(IV) chloride, but only weak synjanti selectivity. Better syn/anti selectivity was found using boron trifluoride-diethyl ether complex, but weak chelation control. Magnesium bromide gave excellent chelation control and acceptable syn/anli selectivity90. 

The boron trifluoride-diethyl ether complex induced reaction of 2-butenyl(tributyl)-stannane and 3-(/er/-butyldimethylsilyloxy)-2-methylpropanal gave predominantly the nonchelation-controlled yyn-product93, whereas with the analogous 3-benzyloxyaldehyde, 2-propenyl-tin trichloride, generated in situ from tributyl(2-propenyl)stannanc and tin(IV) chloride, gave the chelation-controlled product93. 

The reaction between 5-methyl-2-(l-methyl-1 -phenylethyl)cyclohexyl 2-oxoacetate and 2-buteny](tributyl)stannane promoted by boron trifluoride-diethyl ether complex showed a strong preference for 57-facial attack, with syn selectivity69. 

The stereoselectivity of these intermolecular reactions between 1-alkoxyallylstannanes and aldehydes induced by boron trifluoride-diethyl ether complex is consistent with an open-chain, antiperiplanar transition state. However, for intramolecular reactions, this transition state is inaccessible, and either (Z)-.yyn-products are formed, possibly from a synclinal process105, or 1,3-isomerization competes113. Remote substituents can influence the stereoselectivity of the intramolecular reaction114. 

Alkoxyallylstannanes are also available by boron trifluoride-diethyl ether complex induced isomerization of their 1-alkoxy isomers. This isomerization proceeds in an antarafacial manner with excellent stereoselectivity to give (Z)-3-alkoxyallylstannanes possibly via an intermolecu-lar exchange process119. Coupled with the asymmetric reduction of acylstannanes (see Section 1.3.3.3.2.3.1) this provides access to 1-alkyl-3-alkoxyallylstannanes of useful optical purity106. 

Boron trifluoride-diethyl ether complex induced reactions of both (E)- and (Z)-tributyI(3-methoxy-2-propenyl)stannane with aldehydes give. vj-w-products with useful slereoselectivi-... 

Alkoxyallylstannanes can be generated in situ by stannylation of allyl ethers or by 1,3-isomerization of isomers, and trapped by boron trifluoride-diethyl ether complex induced addition to aldehydes to give syn-diol derivatives 13,120. 3-Alkylthioallylstannanes can similarly be generated and trapped84. 

Pure di-2-propenylzinc2,8,9 10, bis(2-methyl-2-propenyl)zinc11 or di-2-butenylzinc11 are best prepared by the metal exchange between dimethylzinc and the appropriate triallylborane, which is produced in situ from the Grignard reagent and boron trifluoride-diethyl ether complex. The purification is accomplished by distillation, for experimental procedure, see ref 2, p619. 

Much better results are achieved in the addition of butyllithium to oxime ethers 4a, 4b and 4c activated by boron trifluoride-diethyl ether complex (BF3 OEt2) at — 78 °C (above a reaction temperature of — 30 °C complex mixtures of products are obtained) using toluene as the solvent. Furthermore, the stereoselectivity depends on the E/Z ratio of the starting oxime ethers. The reaction appears to be highly stereoselective, with the diastereoselectivity of the... 

An interesting example from carbohydrate chemistry is the boron trifluoride-diethyl ether complex catalyzed nucleophilic addition of silyl enol ethers to chiral imines (from n-glyceralde-hyde or D-serinal)22. This reaction yields unsaturated y-butyrolactones with predominantly the D-arabino configuration (and almost complete Cram-type erythro selectivity). 

In the first example of an intramolecular Sakurai reaction, a six-membered ring was formed in the presence of boron trifluoride-diethyl ether complex starting from an acyclic enone36. 

Dienones, such as 4-[4-(trimethylsilyl)-2-butenyl]-3-vinyl-2-cyclohexenone, are useful precursors for these particular transformations the allylsilane side chain is too short for effective 1,4-addition, but just right for 1,6-addition, resulting in six-ring annulation. Three different Lewis acids can be used titanium(IV) chloride, boron trifluoride diethyl ether complex, and ethylaluminum dichloride. The best chemical yields and complete asymmetric inductions were obtained with ethylaluminum dichloride. 

When the chain bearing the allylsilane is one carbon longer, i.e., by the use of pentenylsilanes, cycloheptane rings can be formed. Both the (Z)- and (A )-isoiner of the (3-pentenyl)silanes can be synthesized selectively, but only the (Z)-(3-pentenyl)silane cyclized stereospecifically (complete 1,4-asymmetric induction). Both cthylaluminum dichloride and boron trifluoride diethyl ether complex promote the seven-membered ring formation35 43-48. 

Method A A solution of 0.5 mmol of (2/ /S ,3R/S )-2,3-dialkyl-1,4-diarylbutane and 0.125 mL (1.0 mmol) of boron trifluoride-diethyl ether complex in 2 mL of trifluoroacctic acid is added to a suspension of 0.12 g (0.26 mmol) of thallium(III) oxide in 2 mL of trifluoroacetic acid at — 40°C to +25CC under an argon atmosphere. The dark colored solution is stirred until the reaction is complete, diluted with ethyl acetate, then washed successively with water (twice) and sat. aq NaCl. Evaporation of the dried extract gives the crude product. In a variant of this method the boron trifluoride-diethyl ether complex can be omitted. 

In a variant of this method the boron trifluoride-diethyl ether complex can be omitted. 

Method E To a suspension of 0.67 mM of ruthenium(IV) dioxide dihydrate in 0.8 mL of trifluoroacetic acid, 0.4 mL of trifluoroacetic anhydride, and 4 mL of CH2C12 at 0 C is added, with stirring and under argon, a solution of 0.33 mM of prestegane B in 4mL of CH2C12 and, immediately, 0.2 mL of boron trifluoride-diethyl ether complex. After 3 h. the suspended solid is removed by filtration. Evaporation and flash chromatography affords the pure crystalline product yield 84% mp 228-230°C. 

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