2,2-Disubstituted adducts

The addition of the tellurium occurs exclusively at the terminal carbon of phenylacety-lene, whereas a minor amount (11-28%) of the 2,2-disubstituted adduct (RTeR C=CH2) is formed in addition to alkylacetylenes. 

Bull and co-workers have shown that 2-(arylsulfonyl)oxetanes 43 can also easily undergo a regioselective deprotonation at the oxetane ring, assisted by the sulfonyl group, which is promoted by either LiHMDS or -BuLi in THF at —78 °C to furnish 2,2-disubstituted adducts 44 in yields of up to 93% (2014CC5203). Under the above conditions, the ori/jo-lithiation reaction competes to only a very limited extent (Scheme 12). 

Further reaction occurs with excess alkyne to yield products which may be formally considered as disubstituted adducts, Ru4(CO)u-(RC2R1)(PhC2R2) (where R = R = Ph R2 = Me R = R = Ph, R2 = Et R = Ph, R = R1 = Me). The structures of these products have not been... 

The alkylation proceeds mainly via a trans-mode giving cA-l,2-disubstituted adducts. When an excess of phenylacetylene is used, the yield of the alkylation product is raised (98%, EIZ=9 9l), indicating that the alkylation competes with the self-degradation of n-Bu4Te (to n-Bu2Te, butane and octane). 

In addition, it has been shown that the catalytic use of PS-N3PAPT (10 mol%) was very effective for Michael addition reactions of a variety of Michael donors such as p-ketoesters, ot-nitroketones and nitroalkanes with activated olefins such as methyl acrylate and methyl vinyl ketone [41] (Scheme 6.9). The recyclability of the catalyst was established after it had been used 12 times. When diethyl malonate or ethyl cyanoacetate was used as the Michael donor substrate, the expected disubstituted adducts were obtained in moderate to good yields. 

The ability of the diarylprolinol catalysts to participate in both enamine- and iminium-ion achvations makes them ideal for the sequential addition of nucleophiles and electrophiles through cascade catalysis (Scheme 2.8). Conjugate addition of a nucleophile to the iminium ion forms a transient enamine intermediate 3, which can effectively react with an electrophile in the a-position, forming an a,P-disubstituted adduct. This process commonly proceeds to afford the products in good yields and with high enantio- and diastereoselectivities. If the nucleophile and electrophile are part of the same molecule, cyclic products are obtained. The cascade concept has been widely explored and some illustrative examples are given below [13, 17]. 

This category corresponds to the construction of the carbocyclic ring by 2 + 4 cycloaddition with pyrrole-2,3-quinodimethane intermediates. Such reactions can be particularly useful in the synthesis of 5,6-disubstituted indoles. Although there are a few cases where a pyrrolequinodimethane intermediate is generated, the most useful procedures involve more stable surrogates. Both 1,5-di-hydropyrano[3,4-b]pyrrol-5(lf/)-ones[l] and l,6-dihyropyrano[4,3-b]pyrrol-6-(in)-ones[2] can serve as pyrrole-2,3-quinodimethane equivalents. The adducts undergo elimination of CO2. 

Because of the structural requirements of the bielectrophile, fully aromatized heterocycles are usually not readily available by this procedure. The dithiocarbamate (159) reacted with oxalyl chloride to give the substituted thiazolidine-4,5-dione (160) (see Chapter 4.19), and the same reagent reacted with iV-alkylbenzamidine (161) at 100-140 °C to give the 1 -alkyl-2-phenylimidazole-4,5-dione (162) (see Chapter 4.08). Iminochlorides of oxalic acid also react with iV,iV-disubstituted thioureas in this case the 2-dialkylaminothiazolidine-2,4-dione bis-imides are obtained. Thiobenzamide generally forms linear adducts, but 2-thiazolines will form under suitable conditions (70TL3781). Phenyliminooxalic acid dichloride, prepared from oxalic acid, phosphorus pentachloride and aniline in benzene, likewise yielded thiazolidine derivatives on reaction with thioureas (71KGS471). 

The imonium salt (199), obtained from ynamines and phosgeneimonium chloVide, underwent ready reaction with monosubstituted hydrazines to give the 3,5-bis(dimethyl-amino)pyrazole (200) (68T4217, 69T3453). Similarly, the adduct (201), resulting from the addition of phosgene to ynamines, likewise reacted with sym-disubstituted hydrazines to give pyrazoles (202). With hydroxylamine derivatives the isoxazolinone (203) was obtained. 

In the alternative approach.the 1,3-dipolar system can be constructed in several ways. Treatment of a-chloroacylhydrazones of diaryl ketones and certain aralkyl and dialkyl ketones (382) with NaH in anhydrous THF gives l-(disubstituted methylene)-3-oxo-l,2-diazetidinium inner salts (383). Reaction of (383) with DMAD in methylene chloride gave (384), a 2 1 adduct with loss of CO. Double bond migration in (384) occurred on heating to give (385). The intermediate in the cycloaddition was found to be (386), which on heating lost CO to form a new ylide system which in turn underwent reaction with more DMAD <81JA7743). 

An interesting probe of reactivity was presented by Burton in his study of cycloadditions of l,2-disubstituted-3,3,4,4-tetrafluorocyclobutenes and 1,2-disub-stituted-3,3,4,4,5,5-hexaf1uorocyclopentenes with butadiene, 2-methylbutadiene, and 2,3-dimethylbutadiene [86], On the basis of the extent of their conversions to adducts, the relative reactivities of the cyclobutenes and of the cyclopentenes are as shown in equation 74. A typical reaction is shown in equation 75. 

Further investigations revealed that the disubstituted indolo[3,2-fl]carbazoles 117a-b may be conveniently obtained in moderate yields simply by heating 115 with dimethyl or diethyl acetylenedicarboxylate in xylene, while the use of lower-boiling solvents (benzene, toluene) led to the formation of the presumed intermediate Michael adducts 118a-b as the major products. The reaction of 115 with 2-chloroacrylonitrile furnished the indolo[3,2-fl]carbazole derivative 119 where aromatizaticRi did not take place (99T2371). 

Due to their successful synthesis of 2-(4 -chlorophenyl)-4-iodoquinoline from the corresponding precursor acetylene, Arcadi et al. (99T13233) developed a one-step synthesis of 2,4-disubstituted quinolines via palladium-catalyzed coupling reactions. An example is the Heck reaction of 4-iodoquinoline (131) with a-acetamidoacrylate (132). This one-pot synthesis yielded adduct 133 in 50% overall yield after purification via flash chromatography. 

The aldehyde or ketone functionalities in the Michael adducts are restored by ozonolysis of the hydrazone moiety resulting in am/-3,4-disubstituted-5-oxoalkanoates 1. 

Lithiated areneacetonitriles react with a,/i-unsaturated ketones at low temperatures using short reaction times to give both 1,2- and 1,4-adducts. The 1,2-addition is reversible and under thermodynamic control (higher temperatures and longer reaction times) only the 1,4-adducts, i.e., <5-oxonitriles, arc obtained. When lithiated arylacetonitrile is added to 2-substituted 2-cy-cloalkenones in THF or in THF/HMPA mixtures at — 70-0°C, followed by protonation or alkylation under kinetically controlled conditions, predominantly cis- or fnms-2,3-disubstitut-ed cycloalkanones respectively, are obtained. 

The configuration at sulfur is mainly responsible for the sense of asymmetric induction. It is of interest to note that butylcopper and lithium dibutylcuprate undergo addition reactions in the opposite stereochemical sense. The adducts can be converted to chiral /i-disubstituted carboxylic acids1. 

PhsSnflV)] carboxylates and of some 1 1 addition compounds of PhsSnCl and 2,3-disubstituted thiazolidin-4-ones indicate that the carboxylates in the solid state are monomeric with a Sn atom = 2.14—2.54 mm s the only exception being the furan-2-carboxylic acid derivative, which is polymeric. The PhsSnCl adducts are Thp (I Ag p I = 2.97-3.08 mm s ) with the three Ph groups in a not coplanar eq plane. These complexes are effective inhibitors of C. The 2,3-disubstituted... 

The reaction can also be used synthetically for the preparation of isocyanides, though yields are generally not high. An improved procedure has been reported. When secondary amines are involved, the adduct cannot lose 2 mol of HCl. Instead it is hydrolyzed to an iV,A -disubstituted formamide ... 

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