Monoadducts

Another of the few selective syntheses of aLkylpyridines is one for a-picoline (2) (76). This is a two-step process (eq. 24) where acrylonitrile is used to monocyanoethylate acetone in the Hquid phase at 180°C and at autogenous pressure, 2 MPa (300 psig). The monoadduct, 5-cyano-2-pentanone, is then passed over a palladium-containing catalyst to reduce, cyclize, and dehydrogenate, in sequence. 

Ethoxyl tion. Base-cataly2ed ethoxylation of aUphatic alcohols, alkylphenols, and fatty acids can be broken down into two stages formation of a monoethoxy adduct and addition of ethylene oxide to the monoadduct to form the polyoxyethylene chain. The sequence of reactions is shown in equations 20—22 ... 

Equation 20 is the rate-controlling step. The reaction rate of the hydrophobes decreases in the order primary alcohols > phenols > carboxylic acids (84). With alkylphenols and carboxylates, buildup of polyadducts begins after the starting material has been completely converted to the monoadduct, reflecting the increased acid strengths of these hydrophobes over the alcohols. Polymerization continues until all ethylene oxide has reacted. Beyond formation of the monoadduct, reactivity is essentially independent of chain length. The effectiveness of ethoxylation catalysts increases with base strength. In practice, ratios of 0.005—0.05 1 mol of NaOH, KOH, or NaOCH to alcohol are frequendy used. 

Commercial alkylphenol ethoxylates are almost always produced by base-cataly2ed ethoxylation of alkylphenols. Because phenols are more strongly acidic than alcohols, reaction with ethylene oxide to form the monoadduct is faster. The product, therefore, does not contain unreacted phenol. Thus, the distribution of individual ethoxylates in the commercial mixture is narrower, and alkylphenol ethoxylates are more soluble in water. 

The addition of benzonitrile oxide to cyclooctatetraene produced a monoadduct which was induced to undergo valence tautomerism to produce a tricycloisoxazoline (Scheme 104). A similar reaction with tropone gave a minimum of eight adducts from which two monoadducts were isolated (Scheme 104) (70T5113). 

Monoadduct 17-ketal (43b), mp 160-162°, is hydrolyzed to the corresponding 17-ketone by treatment with methanolic 1 N hydrochloric acid for 1 hr at room temperature. The product is precipitated from the reaction mixture by careful addition of water and collected by suction filtration. Recrystallization of the crude product from acetone affords prisms mp 182-184°. 

A-Homo-estra-l 0),2,4c[-triene-4,ll-dione (45) by solvolysis of the l-keto dibromocarbene adduct (43a).A mixture of monoadduct (43a 0.25 g) and silver perchlorate (0.3 g) in aqueous acetone (1 4, 30 ml) is heated under reflux for 30 min. The reaction mixture is filtered to remove the precipi-... 

A-Homo-estra- Q>),2,Aa-triene-4, l-dione (45) from the l-ketal mono-dibromocarbene adduct (43b). A solution of monoadduct 17-ketal (43b 0.46 g) and dry pyridine (20 ml) is heated at reflux for 2 hr. After cooling the reaction mixture, the pyridine hydrobromide (0.1 g) is removed by filtration and the filtrate is concentrated under reduced pressure. The resultant gum is dissolved in ether and washed successively with water, ice-cold 4 N hydrochloric acid, water, 5% aqueous sodium bicarbonate solution, water, saturated salt solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent at reduced pressure gives 3-bromo-4-methoxy-A-homo-estra-2,4,5(10)-trien-17-one (44 0.22 g) mp 158-162° after crystallization from ether. 

Bromo-4-methoxy-A-homo-estra-2,4,5(10)-trien-17-one (44 0. 2g), is dissolved in formic acid, 2 ml of boron trifluoride etherate is added and the mixture is stirred vigorously at 0° for 2 hr. A brown mass ca. 0.12 g) is obtained after evaporation of the solvents at reduced pressure. This material is diluted with water and extracted with chloroform. The chloroform extracts are washed successively with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated at reduced pressure to give 95 mg of a product which is purified by filtration through a column of neutral alumina and crystallization of the residue after evaporation of the solvent from ethyl acetate-petroleum ether. The resulting A-homo-estra-l(10),2,4a-triene-4,17-dione (45), mp 143-146°, is identical to the tropone (45) prepared from monoadduct 17-ketone (43a). 

The method of choice for preparing tropone (45) is to treat the initial mixture of monoadducts (43a) and (43b) with methanolic 1 TV hydrochloric acid to complete ketal hydrolysis and then carry out the pyridine rearrangement to give 3-bromo-4-methoxy-A-homo-estra-2,4,5(10)-trien-17-one (44) as described above for monoadduct 17-ketone (43b). 

Bromo-A-homo-estra-4y5 0)-diene-3, l-dione (49). A solution of silver perchlorate (0.55 g, 5 mole-eq) in acetone (2 ml) is added to a refluxing solution of monoadduct (48 0.28 g) in acetone (30 ml) containing water (0.5 ml). After being heated at reflux for 25 min the reaction mixture is cooled and the precipitated silver bromide is removed by filtration, yield about 0.11 g. The filtrate is diluted with water (500 ml) and is thoroughly extracted with chloroform. The chloroform extracts are washed with water and saturated salt solution, dried over anhydrous magnesium sulfate, and evaporated at... 

It was, however, found 22) that when the pyrrolidine enamine of cyclohexanone was allowed to react with an excess of -nitrostyrene, a bis adduct (46), made up of one molecule of the enamine and two molecules of olefin, was obtained in addition to the monoadduct. That the bis adduct is not derived from the monoadduct was shown by the latter s failure to react with (9-nitrostyrene. Therefore, this adduct must be formed by the addition of the olefin to the dipolar intermediate (47), as shown in the following scheme. 

The reaction of the morpholine enamine of cyclohexanone with phenyl isothiocyanate led only to the tetrasubstituted isomer of the monoadduct (54), which failed to add any more of the phenyl isothiocyanate. The formation of only the tetrasubstituted isomer has been attributed by Hunig et al. (37) to the stronger conjugation of the C=S group with the enamine double bond than that of the C=0 group in the enamine (49). 

Benzylmercaptan reacts with diacetylenes 57 under base-catalyzed conditions in aregio- and stereoselective fashion to form diadducts Z,Z-l,4-di(benzylthio)buta-1,3-dienes (59). In this case, monoadducts 58 can be isolated (96T12677). The reaction with r-butylmercaptans gives good results for diacetylenes with aromatic substituents. 

Diacetylene homologs are involved in this reaction by terminal acetylene bond to form monoadducts 5-alkynylpyrazoles 82 (65ZOR610). 

In tlie case of 2,5-cydobexadieaone 70, witli a metlioxy and a metliyl substilueal 1 Sdieme 7.19), tlie ryn monoadduct 71 gave 3,4,4,5-tetrasubstituled cydobexanones, witli tlitee consecutive steteocealets. On employing tlie 1R, S, Sj-ligand 18 in tlie second addition step, ds-72 19896 de was found, wbeteas witli 1S, R, i j-18 in tlie second step fraiis-73 19896 de) was obtained [73]. 

A major disadvantage of this procedure is the lack of regioselectivity of the bishydroxylation which can take place on each of the four pyrrole rings of the macrotetracycle so that, in addition to the monoadduct, two bisadducts and one trisadduct are formed. The subsequent pinacol rearrangement of the diols can also occur in two directions, leading to a complex mixture of additional constitutional isomers. 

In numerous synthetic studies,9" 6 100 it has been demonstrated that porphyrins react at the chromophore periphery in cycloaddition reactions, rearrangements, conjugative additions and substitution reactions to yield interesting porphyrin derivatives. Thus, metal-free protoporphyrin IX dimethyl ester reacts in Diels-Alder reactions108a b with dienophilcs like ethenetetra-carbonitrile and acetylenedicarboxylates at the diene structural parts to yield, according to the reaction conditions, the corresponding monoadducts 2 and 3 (see also Section 1.2.) and bisadducts 1 (see also Section 1.4.), respectively. 

The different possible adducts formed between mitomycin C and DNA have been isolated by degradation of DNA after in vitro alkylation/crosslinking reactions and structurally characterized. Monoadduct 21 (Scheme 11.3), derived from alkylation at C-l only [53], and monoadducts 22 [54] and 23 [55, 56] (derived from C-10 alkylation by 16 at N-7 or N-2 of guanine, respectively) have been isolated, together with bisadducts 24 [57] and 25 [58], derived from interstrand and intrastrand crosslinks, respectively, and adduct 26 [59], formed by addition of a molecule of water to C-10 instead of the second guanine. All of these adducts have also been isolated from DNA after in vivo crosslinking [60, 61]. 

Saito et al. achieved the first direct confirmation of double alkylation of purine bases by azinomycin B [140]. They incubated azinomycin B with the self-comple-mentary DNA duplex d(TAGCTA)2 and monitored the reaction by HPLC and ion spray MS. They observed initial formation of a monoadduct that was then converted into a crosslinked bisadduct. The crosslink position was identified as between the guanine of one strand and the 5 -adenine on the other strand by thermo-lytic depurination. Further decomposition prevented structural analysis of the azi-... 

In 1988 a paper by Zard and coworkers4(, reported that xanlhates were a convenient source of alkyl radicals by reversible addition-fragmentation and used the chemistry for the synthesis of a monoadduct to monomer (a maleimide). Many applications of the chemistry in organic synthesis have now been described in papers and reviews by the Zard group.406 407... 

There is another type of multiple thermal Diels Alder reaction in which the initial monoadduct is involved, either directly or after one transformation, in a second cycloaddition that affords the final polycyclic compounds. These methodologies have been used especially in the synthesis of polycyclic cage compounds. Paquette was the first to report the conversion of 9,10-dihydroful-valene into polyfused cyclopentanoid systems [124],... 

In adding two molecules of acetone to acetylenes, there are no problems of chemoselectlvity as the dl-anion (15) of the monoadduct reacts preferentially on carbon. Diol (13) cannot bo Isolated as it cyclises under the hydration conditions. 

Analogously, the 1,3-dipolar cycloaddition reaction of 2-diazopropane with propargyl alcohol 62b, performed at 0 °C in dichloromethane, was completed in less then 10 h and led to a monoadduct 63b with the same regioselective addition mode of 59 to the triple bond. The HMBC spectrum showed correlations between the ethylenic proton and the carbons C3 and C5 and between the methyl protons and the carbons C3 and C4. 

From inspection of Figure 3, which is the Si NMR spectrum of the reaction mixture after 10 minutes, it is seen that reaction is quite rapid and that a significant amount of the trimethylsilazane monoadduct of sym-tetrachlorodisilane has formed, along with Me SiCl by-product and a small amount of the sym-1,2- diadduct. As reaction proceeds, rapid consumption of starting materials with resultant... 

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