Bromomalonates

Reaction of aniline derivatives with 4-chlorobutyroyl chloride followed by cyclization with sodium ethoxide and subsequent thionation promoted by sonication gave the corresponding A -arylpyrrolidine-2-thiones 126. Zinc-mediated condensation of diethyl bromomalonate with 126 using iodine as activator gave the vinylogous urethanes 127 whose cyclization with PPA gave the tricyclic compound 128 which upon hydrolysis afforded the acid 129 (96TL9403). 

The hydrazinolysis is usually conducted in refluxing ethanol, and is a fast process in many cases. Functional groups, that would be affected under hydrolytic conditions, may be stable under hydrazinolysis conditions. The primary amine is often obtained in high yield. The Gabriel synthesis is for example recommended for the synthesis of isotopically labeled amines and amino acids. a-Amino acids 9 can be prepared by the Gabriel route, if a halomalonic ester—e.g. diethyl bromomalonate 7—is employed as the starting material instead of the alkyl halide ... 

The regioselecdve cross-coupling between anions of bromomalonate esters or bromoacetate esters and m-dirutrobenzene proceeds in the presence of copper tfirr-bntoxide to give the 3-snbsdtiited product Without the copper salt, the4-snbsritiited isomer is the only product fEq 9 35,... 

The radical alkylation of ketones is achieved by their conversion into the desired N-silyloxy enamines 81 (Scheme 13). The reaction of 81 with diethyl bromomalonate in the presence of EtsB (0.5 equiv) in benzene was performed in open air and stirred at room temperature for 3h. With nitro compounds it is achieved by their conversion into the desired ]V-bis(silyloxy)enamines (82) (Scheme 13). When the reaction is carried out with 82 and alkyl iodides with an electron-withdrawing substituent at the a-position, using V-70 as radical initiator (2,2 -azobis(4-methoxy-2,4-dimethylvaleronitrile)), it underwent a clean radical alkylation reaction to yield an oxime ether. Successful radical alkylation of... 

An alternative synthetic approach, first developed by Bingel225 allowed the efficient nucleophilic cyclopropanation of fullerenes via their reaction with bromomalonate derivatives in the presence of base. This approach, the most reliable method for the synthesis of functionalized methanofullerenes, combined the advantages of mild... 

Compound 162 could be brominated to give the 2-bromomalonate analog (167). Reductive removal of bromine could be achieved cata-lytically,126 or by treatment with triphenylphosphine.125... 

Synthesis front Nitroso Compounds Aryl nitroso compounds (175) react easily with dimethyl bromomalonate in the presence of alkali to give the corresponding A-aryl-QC-dimethoxycarbonyl-nitrones (177) (Scheme 2.62) (333). 

Finally, Scheme 3.14 presents the Michael addition of bromomalonic ester to conjugated nitro olefins 10. This approach allows one to synthesize five-membered cyclic nitronates (5) doubly functionalized at the C-5 atom (Scheme 3.14, Eq. 5). 

Bromides are less reactive than the corresponding iodides in atom transfer processes. However, activated bromides such as diethyl bromomalonate [36] and bromomalonitrile [53] react with olefins under Et3B/02 initiation. Kha-rasch type reactions of bromotrichloromethane with alkenes are also initiated by Et3B/02 [41]. On the other hand, a remarkable Lewis acid effect was reported by Porter. Atom-transfer reactions of an a-bromooxazolidinone amide with alkenes are strongly favored in the presence of Lewis acids such as Sc(0Tf)3 or Yb(0Tf)3, this reaction was successively applied to the... 

The reaction of tetrahydro-l,3-thiazine-2-thione and diethyl 2-chloro-malonate in the presence of triethylamine in boiling methylene chloride for 1.5 hr gave tetrahydro-1,3-thiazin-2-ylidenemalonate (508) in 33% yield via 507 through Eschenmoser sulfur elimination, together with traces of the mesoionic derivative (509) [77JCS(P 1) 1107]. In a similar reaction, diethyl 2-bromomalonate afforded the mesoionic compound (509) in 80% yield. Tetrahydro-l,3-thiazin-2-ylidenemalonate (508) was also obtained in 42% yield from 509 by irradiation in the presence of tributylphosphine in ethanol for 15 hr under argon [77JCS(P1)1107]. 

The reaction of the sodium salt of imidazo[l,5-J][l,2,4]triazinethione (512) and diethyl 2-bromomalonate in dimethylformamide at room temperature overnight gave (imidazotriazinylidene)malonate (513) in 14% yield (85JMC1704). 

Dihydrothieno[2,3-/]-l,4-thiazepin-5(2//)-thione (514) was reacted with diethyl 2-bromomalonate in methylene chloride under argon for 2.5 hr. The reaction mixture was then treated with a 10% aqueous solution of potassium hydrogen carbonate for 30 min to give (thienothiazepinylide-ne)malonate (515) (86EUP183994). 

The reaction of diethyl bromomalonate with a 3 1 mixture of pyrroli-dinethiones (516 and 517) in the presence of sodium ethoxide gave a 3 1 mixture of isomeric (2- and 5-pyrrolidinylidene)malonates (518 and 519) in 73% yield (89H435). 

Direct conversion of a-bromo esters into amino esters by hydride reduction of the azido ester (without isolation) produces yields in excess of 80% [7]. However, bromomalonates fail to form the azido ester under similar conditions. Instead, oxidative dimerization occurs to yield the ethene-l,l,2,2-tetracarboxylate (see Section 6.1) [10]. 

Attempts to convert 1-bromo-l-phenylacetonitrile into the dicyano derivative under liquidrliquid two-phase conditions have been unsuccessful but, on addition of aqueous sodium hydroxide, l,2-dicyano-l,2-diphenylethene is formed by an oxidative dimerization mechanism [18], Similarly, diethyl bromomalonate fails to produce the corresponding azide with lithium azide under catalytic conditions the sole product (15%) is the ethene-l,l,2,2-tetracarboxylate [19]. 

More recent reports from Cordova [155] and Wang [156] have described the cyclopropanation of a, P-unsaturated aldehydes 99 with diethyl bromomalonates 100 and 2-bromo ethyl acetoacetate catalysed by a series of diaryIprolinol derivatives. Both describe 30 as being the most efficient catalyst in many cases and optimal reaction conditions are similar. Some representative examples of this cyclopropanation are shown in Scheme 40. The transformation results in the formation of two new C-C bonds, a new quaternary carbon centre and a densely functionalised product ripe for further synthetic manipulation. Triethylamine or 2,6-lutidine are required as a stoichiometric additive in order to remove the HBr produced during the reaction sequence. The use of sodium acetate (4.0 equivalents) as an additive led to subsequent stereoselective ring opening of the cyclopropane to give a,P-unsaturated aldehydes 101. It can be envisioned that these highly functionalised materials may prove useful substrates in a variety of imin-ium ion or metal catalysed transformations. 

In contrast, when the reaction was conducted using diethyl malonate instead of bromomalonate in the presence of Na2C03 under the HSVM conditions, there was obtained not the cyclopropanated product but a C o derivative having two bis(ethoxycarbonyl)methyl groups at the 1,4-positions 46 in 18% yield (82% based on consumed Cgo) (Scheme 21) [52]. Previously it was reported that... 

Cyclopropanation of Cjq with diethyl bromomalonate in toluene with NaH as auxiliary base proceeds smoothly at room temperature (Scheme 3.5). By-products are unreacted Cjq and higher adducts. The formahon of higher adducts is discussed in detail in Chapter 10. The monoadduct can be isolated easily from the reach on mixture by column chromatography. Saponificahon of such di(efhoxycarbonyl)-methylene adducts of Cgg is achieved by treatment with NaH in toluene at elevated temperatures and subsequent quenching with methanol (Scheme 3.6) [32], This method provides easy access to defined water-soluble fullerenes and can also be applied to higher adducts. These malonic acid derivatives of are very soluble in polar solvents, for example acetone, THF or basic water, but insoluble in aqueous acids. 

Recently, a solvent-free variation was found to be equally effective. The inorganic base Na2C03 was utilized to replace the organic base DBU in a mechanochemical reaction under high-speed vibration milling conditions [37]. The yields with diethyl bromomalonate are in the range 40-50%. 

One modification of the Bingel reaction involves DBU as a base. Initial experiments showed that exposure of CgQpjg to DBU leads to a complete loss of fluorine [71]. Fortunately this defluorination does not take place in the presence of diethyl bromomalonate. Reaction of CgQpjg with DBU and diethylbromomalonate in toluene at room temperature yields three products and unreacted CgQpjg [67, 71]. The three products are the result of mono-, bis- and tris-substitution their relative yield depends on how fast the base is added. The reaction does not - as in the usual Bingel reaction - proceed via a nucleophilic addition reaction to one double bond but as a nucleophilic substitution with a Sj.j2 -mechanism. The bromomalonate anion attacks a double bond in 5-position to one of the least sterically hindered fluorine atoms, which leads to the loss of this fluorine. The bromine atom is not replaced (Scheme 9.6). 

Scheme 10.10 Double nucleophilic cyclopropanation of all-e tetrakis-adduct 15 with second generation (G2) bromomalonates yields dendrimeric [4 2] hexakisadduct 54. (i) CHBr(COOG2)2, DBU, toluene-CH2Cl2, 3 d, room temp.

Scheme 10.13 Topochemically controlled solid-state synthesis of bisadduct 61 and subsequent cyclopropanation to give [2 4]-hexakisadduct 62. (i) 180°C, 10 min (ii) 40 equiv. diethyl bromomalonate, 40 equiv. DBU.

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