Carbonyls additions

Ligand exchange provided a simple and effective solution to these problems. Addition of 0.5 eq. of Ti(0 Pr)4 to the trichlorotitanium homoenolate produces an alkoxytitanium species 19 which is more reactive than the original homoenolate, Eq. (30). This allows the addition to proceed under nearly neutral conditions. Preparation of 4-hydroxy esters by this method is summarized in Table 5. The structure of 19 has been studied by H NMR spectroscopy [19]. 

An even more reactive complex which is particularly useful for reactions with ketones is available by ligand exchange with Ti(0 Bu)4, Eq. (31). The 

These alkoxytitanium homoenolates show high propensity for equatorial attack in their ir reactions with substituted cyclohexanones (Table 6). The basic trend of their chemical behavior is similar to that of simple titanium alkyls [35]. Chemo-selectivity of the reagent 19 is also noteworthy. The alkoxytitanium homoenolate reacts preferentially with an aldehyde even in the presence of a ketone Eq. (32). A notable difference of rate between the reaction with cyclohexanone and that with 2-methylcyclohexanone was also observed, the latter being far less reactive toward the homoenolate. 

In line the with the chemistry of dialkylzinc [36], the zinc homoenolate is inert to carbonyl compounds in a variety of solvents, Eq. (33). Slow addition accurs only in an HMPA/THF mixture. When the reaction is conducted in halomethane in the presence of Me3SiCl, however, a very rapid addition reaction occurs [33], Control experiments indicate that the acceleration is due to the activation of the carbonyl group by Me3SiCl. The activating effect of the chlorosilane disappears in ethereal solvents. 

Interestingly, the carbonyl addition of the zinc homoenolate, in the presence of acid chloride, affords 4-acyloxyesters Eq. (35) [27]. 

1-isopropoxycyclopropane 20. Znl2 also catalyzes the reaction of acetophenone or benzaldehyde dimethyl acetal, which fail to react under ZnCl2 catalysis. Results of such of ZnXj catalyzed homo-Reformatsky reactions are summarized in Table 7. 

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Diaryl disulfides and diselenides add to alkynes to afford the (Z)-l, 2-bis(ar-ylthio)alkenes 193 and (Z)-l,2-bis(arylseleno)alkenes 194. Under CO pressure, carbonylative addition takes place to give thio esters and the selenoketones 195[I07], The selenoketones are converted into the /J-seleno-a, 3-unsaturated aldehydes 196 by Pd-catalyzed hydrogenolysis with HSnBu3[108,109],... 

Chloral forms well-crystallized adducts (126) with diaziridines containing at least one NH group (B-67MI50800). Carbonyl addition products to formaldehyde or cyclohexanone were also described. Mixtures of aldehydes and ammonia react with unsubstituted diaziridines with formation of a triazolidine ring (128). Fused diaziridines like (128) are always obtained in ring synthesis of diaziridines (127) from aldehyde, ammonia and chloramine. The existence of three stereoisomers of compounds (128) was demonstrated (76JOC3221). Diaziridines form Mannich bases with morpholine and formaldehyde (64JMC626), e.g. (129). 

Compound (253) is formed from benzaldehyde and methylhydroxylamine-O-sulfonic acid in 35% yield. With ethyl-substituted chloramine or hydroxylamine-O-sulfonic acid yields do not exceed 10%, which is assumed to be due to steric hindrance and is foreseeable for both carbonyl addition and O —N bond formation. 

The precedent is strong for the involvement of oxetanes as Intermediates in carbonyl additions to pyrroles. " NMR evidence has been obtained far an oxetane adduct of acetone and N-methylpyrrole. The initial photoadduct was shown to rearrange readily on workup to the 3-(hydroxyalkyl)pyrrole derivative. 

In general terms, there are three possible mechanisms for addition of a nucleophile and a proton to give a tetrahedral intermediate in a carbonyl addition reaction. 

Enolates can also serve as carbon nucleophiles in carbonyl addition reactions. The addition reaction of enolates with carbonyl compounds is of very broad scope and is of great synthetic importance. Essentially all of the enolates considered in Chapter 7 are capable of adding to carbonyl groups. The reaction is known as the generalized aldol addition. 

Reductions by NaBKt are characterized by low enthalpies of activation (8-13kcal/mol) and large negative entropies of activation (—28 to —40eu). Aldehydes are substantially more reactive than ketones, as can be seen by comparison of the rate data for benzaldehyde and acetophenone. This relative reactivity is characteristic of nearly all carbonyl addition reactions. The reduced reactivity of ketones is attributed primarily to steric effects. Not only does the additional substituent increase the steric restrictions to approach of the nucleophile, but it also causes larger steric interaction in the tetrahedral product as the hybridization changes from trigonal to tetrahedral. 

The borohydride reduction rate data are paralleled by the rate data for many other carbonyl addition reactions. In fact, for a series of ketones, most of which are cyclic, a linear free-energy correlation of the form... 

In the first century of "organic" chemistry much attention was given to the structures of carbogens and their transformations. Reactions were classified according to the types of substrates that underwent the chemical change (for example "aromatic substitution," "carbonyl addition," "halide displacement," "ester condensation"). Chemistry was taught and learned as transformations characteristic of a structural class (e.g. phenol, aldehyde) or structural subunit... 

There are a number of powerful synthetic reactions which join two trigonal carbons to form a CC single bond in a stereocontrolled way under proper reaction conditions. Included in this group are the aldol, Michael, Claisen rearrangement, ene and metalloallyl-carbonyl addition reactions. The corresponding transforms are powerfully stereosimplifying, especially when rendered enantioselective as well as diastereoselective by the use of chiral controller groups. Some examples are listed in Chart 20. 

Still another synthetic route to gibberellic acid has been developed which differs from those above in the transforms used to disconnect the various rings, but which also depends on the initial disconnection of ring A (using aldol and carbonyl addition transforms). ... 

Chiral Cu(ll)-complexes ofbis-oxazolines as Lewis acids for catalyzed cycloaddition, carbonyl addition, and conjugate addition reactions 99PAC1407. 

Condensation of p-chlorobenzaldehyde with 3-mercaptopropionic acid in the presence of ammonium carbonate leads to the thiazi-none, 179. The reaction very probably proceeds by the intermediacy of the carbonyl addition product, I7S lactamization completes formation of the observed product. Oxidation of 179 to the sulfone by means of potassium permanganate in acetic acid gives chlormezanone (180), a minor tranquilizer with muscle-relaxant properties. 

In an alternate approach to the preparation of compounds containing the additional ring, haloamide, 41 (obtained from the aminobenzophenone and bromoacetylbromide) is alkylated with etha-nolamine to afford 42. Treatment of the amino alcohol in acetic acid affords the carbonyl addition product, 43, at the same time... 

The oral contraceptive agent Mestranol is synthesized using a carbonyl addition reaction like that shown in Problem 8.42. Draw the structure of the ketone needed. 

The reduction of carbonyl compounds by reaction with hydride reagents (H -) and the Grignard addition by reaction with organomagnesium halides (R - +MgBr) are examples of nucleophilic carbonyl addition reactions. What analogous product do you think might result from reaction of cyanide ion with a ketone ... 

Cyanohydrin formation is somewhat unusual because it is one of the few examples of the addition of a protic acid (H—Y) to a carbonyl group. As noted in the previous section, protic adds such as H20, HBr, HC1, and H2S04 don t normally yield carbonyl addition products because the equilibrium constants ate unfavorable. With HCN, however, the equilibrium favors the cyanohydrin adduct. 

Coniine, molecular model of. 28 structure of, 294 Conjugate acid, 49 Conjugate base, 49 Conjugate carbonyl addition reaction, 725-729 amines and, 727 enamines and, 897-898 Gilman reagents and, 728-729 mechanism of, 725-726 Michael reactions and, 894-895 water and. 727 Conjugated diene, 482... 

Claisen rearrangement, 660 conjugate carbonyl addition reaction, 725-726 Curtius rearrangement, 935 cyanohydrin formation, 707 dichlorocarbene formation, 227 Dieckmann cyclization reaction, 892-893... 

Johnson s classic synthesis of progesterone (1) commences with the reaction of 2-methacrolein (22) with the Grignard reagent derived from l-bromo-3-pentyne to give ally lie alcohol 20 (see Scheme 3a). It is inconsequential that 20 is produced in racemic form because treatment of 20 with triethyl orthoacetate and a catalytic amount of propionic acid at 138 °C furnishes 18 in an overall yield of 55 % through a process that sacrifices the stereogenic center created in the carbonyl addition reaction. In the presence of propionic acid, allylic alcohol 20 and triethyl orthoacetate combine to give... 

The synthetic problem has now been substantially simplified. Retrosynthetic cleavage of the indicated carbon-carbon bond in 24 provides aldehyde 25 as a potential precursor. A simple carbonyl addition reaction could bring about the conversion of the latter substance to the former. Compound 25 could, in turn, be fashioned in a few straightforward steps from prochiral diol 26. 

The homology between 22 and 21 is obviously very close. After lithium aluminum hydride reduction of the ethoxycarbonyl function in 22, oxidation of the resultant primary alcohol with PCC furnishes aldehyde 34. Subjection of 34 to sequential carbonyl addition, oxidation, and deprotection reactions then provides ketone 21 (31% overall yield from (—)-33). By virtue of its symmetry, the dextrorotatory monobenzyl ether, (/ )-(+)-33, can also be converted to compound 21, with the same absolute configuration as that derived from (S)-(-)-33, by using a synthetic route that differs only slightly from the one already described. 

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