Y-keto

Tertiary amines capable of eliminating a secondary amine to form a conjugated system can react with hydrogen cyanide to form y-keto nitriles by amine replacement. Thus (I) yields p-benzoylpropionitrile (IV) ... 

Clearly other combinations of logical and illogical synthons could be used to make 1,4-dioxygenated compounds. How could you use cyanide ion (as the CO2H synthon) to make a y-keto acid such as... 

Similarly, 5-thiazole alkanoic acids and their salts are obtained from thioamides and /3-halo -y-keto acids (695). Thus thioarylamides condensed with 3-aroyl-3-bromopropionic acid (88) in isopropanolic solution in the presence of Na COs give first 4-hydroxy-2-aryl-A-2-thiazoline-5-acetic acid intermediates (89), which were dehydrated in toluene with catalytic amounts of p-toluene sulfonic acid to 2,4-diaryl-5-thiazole acetic acid (90) (Scheme 39) (657), with R = H or Me Ar = Ph, o-, m- or p-tolyl, o-, m-, or P-CIC6H4, 0-, m-, or p-MeOC(iH4, P-CF3C6H4, a-thienyl, a-naphthyl (657). 

The 1,3-elimination of y-keto sulfones leads to the formation of cyclopropane rings as seen in equation 4538. 

Photolysis of alkoxycarbene complexes in the presence of stabilized ylides produced allenes having a donating group at one terminus and an accepting group at the other. These were highly reactive and rearranged to 1,3-dienes under mildly acidic conditions and hydrolyzed to y-keto-a,/J-unsaturated esters (Eq.31) [117]. 

In another procedure, acyl radicals derived from phenyl selenoesters ArCOSePh I by treatment of them with Bu3SnH) add to a,P-unsaturated esters and nitriles to give y-keto esters and y-keto nitriles, respectively. ... 

This product is also obtained on alkaline hydrolysis of compounds of the formula RCOCHX2. Similar reactions have been performed on a-keto acetals and y-keto... 

The y-keto nitriles shown in Table I were prepared by the cyanide-catalyzed procedure described here. This procedure is generally applicable to the synthesis of y-diketones, y-keto esters, and other y-keto nitriles. However, the addition of 2-furancarboxaldehyde is more difficult, and a somewhat modified procedure should be employed. Although the cyanide-catalyzed reaction is generally limited to aromatic and heterocyclic aldehydes, the addition of aliphatic aldehydes to various Michael acceptors may be accomplished in the presence of thioazolium ions, which are also effective catalysts for the additions. 

Importance of enol formation for y keto ester fluorination... 

For internal olefins, the Wacker oxidation is sometimes surprisingly regioselective. By using aqueous dioxane or THF, oxidation of P,y-unsaturated esters can be achieved selectively to generate y-keto-esters (Eq. 3.18).86 Under appropriate conditions, Wacker oxidation can be used very efficiently in transforming an olefin to a carbonyl compound. Thus, olefins become masked ketones. An example is its application in the synthesis of (+)-19-nortestosterone (3.11) carried out by Tsuji (Scheme 3.5).87... 

Carbonylation of alkynes is a convenient method to synthesize various carbonyl compounds. Alper et al. found that carbonylation of terminal alkynes could be carried out in aqueous media in the presence of 1 atm CO by a cobalt catalyst, affording 2-butenolide products. This reaction can also be catalyzed by a cobalt complex and a ruthenium complex to give y-keto acids (Scheme 4.8).92... 

To date, only one example of a combination of a photochemically induced transformation with a transition metal-catalyzed reaction has been found in the literature. This hv/Pd°-promoted process allows the synthesis of five-membered cyclic y-keto esters 5-119 from 5-iodoalkenes 5-117 in the presence of CO and an alcohol 5-118 as a nucleophile (Scheme 5.24) [41]. The yields are high, and differently substituted iodoalkenes can be employed. 

Nitroalkenes react with lithium dianions of carboxylic acids or with hthium enolates at -100 °C, and subsequent treatment of the Michael adducts with aqueous acid gives y-keto acids or esters in a one-pot operation, respectively (Eq. 4.52).66 The sequence of Michael addition to nitroalkenes and Nef reaction (Section 6.1) provides a useful tool for organic synthesis. For example, the addition of carbanions derived from sulfones to nitroalkenes followed by the Nef reaction and elimination of the sulfonyl group gives a,P-unsaturated ketones (Eq. 4.53).67... 

Diverging results have been reported for the carbenoid reaction between alkyl diazoacetates and silyl enol ethers 49a-c. Whereas Reissig and coworkers 60) observed successful cyclopropanation with methyl diazoacetate/Cu(acac)2, Le Goaller and Pierre, in a note without experimental details u8), reported the isolation of 4-oxo-carboxylic esters for the copper-catalyzed decomposition of ethyl diazoacetate. According to this communication, both cyclopropane and ring-opened y-keto ester are obtained from 49 c but the cyclopropane suffers ring-opening under the reaction conditions. 

The rates of hydrolysis in 80% aqueous ethanol at 25°C were 60 and 199 times faster than that of ethyl cyclohexylacetate and cyclopentylacetate. These rate enhancements were considered to indicate the occurrence of participation by the neighbouring y-keto group. Furthermore, unusually small enthalpies of activation were found for these esters, as shown in Table 1. 

Electrooxidation of l,3,4,6-tetraaryl-2k482-thieno[3,4-c]thiophenes85 causes a thiophene ring to open with formation of y-keto thioketones. 

The unified highly convergent total and formal syntheses of ( + )-macro-sphelides B (441 X = O) and A (441 X = a-OH, p-H), respectively, have been described (483). Key features of the syntheses include the concise synthesis of the optically active S-hydroxy-y-keto a, 3-unsaturated acid fragment 442 via the direct addition of a fra/i.s-vinylogous ester anion equivalent to a readily available Weinreb amide, and the facile construction of the 16-membered macrolide core of the macrosphelide series via an INOC. 

In these studies (291, 292), the ring-chain tautomerism of silylated cations A, prepared by reversible silylation of the above mentioned nitronates (96) was suggested as an explanation for the observed transformations of y-keto-functionalized SENAs 96 (Scheme 3.80). 

In 1986, Wulff reported the first synthesis of an -vinylketene complex from the reaction between a carbene and an alkyne51 the former had of course been postulated as key intermediates in analogous reactions of chromium8 and iron97 carbenes (see Sections II.B and VI.C, respectively). On treatment of the tricarbonylcobalt carbene (84) with 3-hexyne under mild conditions, the yf-vinylketene complex (85) and the y-keto unsaturated... 

Butenolides are formed in the alkyne-CH3l--Co2(CO)3 phase transfer reaction. When the latter process is effected in the presence of ruthenium carbonyl, a second metal catalyst, y-keto acids are isolated in good yields(17). 

There are many reports describing the preparation of various butyrolac-tones from AAs. When r-butyl 2-dibenzylaminoacetate in the form of its Li-enolate was treated with (5)-0-benzyllactic aldehyde, a mixture of four diastereoisomeric hydroxy-AAs was obtained. After separation and further treatment, three lactones were obtained (Scheme 17) (87T2317). Similar compounds were obtained from a-acylamino-y-keto acids after cycliza-tion (75CC905). 

In contrast to the [2-1-2]-photocycloaddition which is a widely used method to generate four-membered rings, Koreeda and Zhang used a thermal rearrangement key step to construct the tricyclic framework of kelsoene [23]. In earlier work, it was shown that upon treatment with base, y-keto-p-toluene-sulfonate rac-32 is converted to a 44/56 mixture of bicyclo[3.1.1 ]heptanone rac-33 and bicyclo[3.2.0]heptanone rac-34 (Scheme 10) [24-26]. 

The preparation of the requisite y-keto-p-toluenesulfonate rac-35 as homo-Favorskii precursor commenced with commercially available 2,5-dihy-droanisole (36) that was protected and epoxidized to acetal rac-31 (Scheme 11). Regioselective opening of the epoxide with p-chlorophenylse-lenide followed by sequential oxidation to the selenoxide and thermal elimination generated an allylic alcohol that was protected to give pivaloate rac-38. 

With the appropriate precursor rac-35 in hand, the rearrangement key step was examined. As expected, basic treatment of y-keto-tosylate rac-35 resulted in the formation of a 56/44 mixture of the formal substitution product rac-43 and rac-44 as the product of homoallylic rearrangement (Scheme 12), in a combined yield of 95%. 

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