Tosylhydrazones ethers

The following general procedure has been used for the reduction of the tosylhydrazone derivatives of various steroidal ketones. A mixture of the tosylhydrazone (50 mg) and sodium borodeuteride (50 mg) in dry dioxane (3 ml) is heated under reflux for 2 hr, and then the excess deuteride is decomposed by the addition of a few drops of acetic acid. Ether is added and the resulting solution is washed with 2 N sodium bicarbonate solution and... 

The dry tosylhydrazone (20 g, 45.5 mmol) is dissolved in 750 ml of 1,2-dimethoxyethane (freshly distilled from lithium aluminum hydride) in a flame-dried 1 liter round bottom flask fitted with a 240 ml addition funnel, a drierite tube and a magnetic stirrer. A 2.05 M ether solution of methyllithium (130 ml, Alfa Inorganics, Inc.—Caution to avoid the mineral oil impurity the methyllithium solution is decanted from a cold solution which contains a precipitate) is placed in the dropping funnel and added over a 60 min period. The temperature of the reaction mixture increases to ca. 35° during the addition however, no cooling precautions are required. The highly colored reaction mixture is stirred for 7 hr and then poured into 1.5 liters of ice water. The flocculent precipitate is digested for 12 hr at room temperature to speed the filtration. After filtration the filter cake is washed with 500 ml water and dried under vacuum at 50° for several hr. The androsta-5,16-dien-3l5-ol is obtained in ca. 70% yield after recrystallization from methanol mp 138-139°. 

The sodium salt of tropone tosylhydrazone (14.8 g, 50 mmol) and dimethyl acetylenedicarboxylate (14.6 g, 100 mmol) in bis(2-methoxyethyl) ether (70 mL) was heated at 120 C for 15 min. The solution was poured into H20 and the mixture extracted with Et20. The extract was washed with H20, followed by brine, and dried (Na2S04). The solution was evaporated to yield the crystalline product (4.01 g), together with an oil. The latter was chromatographed (silica gel) to give additional product (0.405 g) total yield 4.415 g (34%) mp 153-154°C (cyclohexane). 

Another approach to (R)-(-)-phoracantholide I (245) used a ring enlargement of cyclohexanone (255) which had been alkylated with chiral synthon 256 (Scheme 14) [206]. Thus, compound 257 was prepared in 35% yield on a 7-g scale by alkylation of cyclohexanone with chiral 256. Cyclization with Am-berlyst A-15 provided enol ether 258 that was directly submitted to ruthenium tetroxide oxidation to give oxolactone 259 in a 47% yield. Reduction of the latter with catecholborane via its tosylhydrazone afforded (R)-(-)-phoracan-tholide I (245) in 31% yield. 

In keto steroids the reductions were also achieved by electrolysis in 10% sulfuric acid and dioxane using a divided cell with lead electrodes (yields 85-97%) [862], hy specially activated zinc dust in anhydrous solvent (ether or acetic anhydride saturated with hydrogen chloride) (yields 50-87%) [155, 86J], and by the above mentioned reduction of tosylhydrazones with sodium borohydride (yields 60-75%) [811]. 

The Shapiro reaction occurs when a tosylhydrazone 86, easily prepared from a ketone and tosylhydrazine, is treated with 2 equivalents of an ethereal solution of n-butyllithium 87, resulting first in the removal of the N—H proton to give the anion 88 and then of a one proton from the less-substituted a position to give the dianion 89. Elimination of lithium p-toluenesulfinate in the rate-limiting step gives the lithium aUtenyldiazenide 90, which suffers loss of nitrogen to afford the alkenyllithium 91 (equation 31) ° . ... 

Synthesis of novel bicyclic heterocyclic systems involving aziiidine ring formation has been described. The sodium salts of tosylhydrazones 11 decomposed by heating in benzene and gave aziridinopyrroloindoles 12 in yields up to 73% (equation 5) . Intramolecular cyclization of oxime ether 13 in the presence of base (for example, DBU) in acetonitrile afforded aziridinopyrrolidine 14 in yields up to 51% (equation 6) °. 

The most useful method synthetically involves treatment of the substrate with at least two equivalent of an organolithium compound (MeLi) in ether, hexane, or tetramethylenediamine. Tosylhydrazones of a, b-unsaturated ketones give conjugated dienes. 

Thermal decomposition of y-lactone tosylhydrazone sodium salts are reported to yield cyclobu-tanones, which can be accounted for by rearrangement of an intermediate oxycarbene. In this manner, the sodium salts of dihydrofuran-2(37/)-one tosylhydrazones 1 were decomposed as a loose powder, at 310 C in a bulb-to-bulb distillation apparatus at an initial pressure of 0.1 Torr, to give the corresponding cyclobutanones 2 in addition to enol ethers, cyclopropanes and open-chain alkenes. Condensable products (74-76%) were collected at — 78 °C, weighed and the ratio of components was determined from their relative GC peak areas.63... 

Since the first report in 1960 of the observation that sodium methoxide induced carbenoid decomposition of cyclobutanone tosylhydrazone (1) at 180 °C in either bis(2-ethoxyethyl) ether or /V-methylpyrrolidone results in an intriguing ring contraction to produce methylenecyclopropane (3),1 many experimental results have been presented invoking cyclobutylidene (2) as a key intermediate in this rearrangement. 

A number of tosylhydrazones containing an alkene have been shown to undergo intramolecular cycloaddition in the presence of acid.103 96 Boron trifluoride etherate appears to be the acid of choice.103 Bridged, rather than fused, bicyclic pyrazolines are formed under these conditions. The mechanism almost certainly involves cationic intermediates. Thus, tosylhydrazone (192a) cyclized in 87% yield to the... 

Cyclohexanone (202) was converted to compound (203) whose transformation to cyclohexanone (204) was accomplished in three steps. It underwent cyclialkylation with boron trifluoride etherate affording the cyclized product (205) (R=R,=OMe) in 64% yield along with naphthalene (206) (R=Ri= H,H). Compound (205) on heating under reflux with DDQ in benzene produced ketone (207) whose tosylhydrazone on treatment with sodium cyanoborohydride afforded reduced product (208). Deprotection of the aryl methyl ethers and oxidation with ceric ammonium nitrate led to the formation of miltirone (197). 

Tosylhydrazones of keto esters. Acid-sensjtivc a- and (3-keto esters can be converted into the tosylhydrazones in 30-80% yield by u.se of neutral alumina as catalyst. Yields are 5-10% when BF, etherate is used as catalyst. ... 

Oxidation. Triphenylbismuth carbonate suspended in CH2CI2 is a heterogeneous oxidant for a variety of functional groups. Allylic alcohols are efficiently oxidized to the corresponding unsaturated aldehydes or ketones, even in the presence of a thiol, which is itself oxidized by this reagent to a disulfide, cis- and Irani-1,2-Glycols are cleaved to dialdehydes hydrazones are oxidized to diazocompounds oximes are cleaved to ketones and 1,2-dialkylhydrazines are oxidized to azo compounds. Phenylhydrazones, semicarbazones, tosylhydrazones, aromatic and aliphatic amines, enamines, and enol ethers are inert to 1. 

Treatment of a,p-unsaturated tosylhydrazones with NaBH4 in MeOH affords principally allylic ethers from cyclic derivatives and pyrazoles with most noncyclic examples. This divergent behavior compared to saturated tosylhydrazones has been attributedto a lessening of the electrophilicity of conjugated imine ir-bonds, which allows initial abstraction of the acidic N—H proton by BH4 to compete with reduction, and gives alternative reactions related to the Bamford-Stevens process as depicted in Scheme 4. An exception to this may be the deoxygenation of conjugated vinyl triflates (entry 11, Table 6). The cyclopropanation and elimination products produced in entry 4, Table 6 also probably arise from similar, alternative reaction paths. ... 

---