Electron-deficient alkenes, alkylation

AlkenyldQon using nitroalkanes foUowedby theselecQve reducQonof the double bends with NiCl and NdBbb, can be regarded as the addition of alkyl aruons to electron-deficient alkenes... 

Nitro compounds have been converted into various cyclic compounds via cycloaddidon reactions. In particular, nitroalkenes have proved to be nsefid in Diels-Alder reactions. Under thermal conditions, they behave as electron-deficient alkenes ind react v/ith dienes to yield 3-nitrocy-clohexenes. Nitroalkenes c in also act as heterodienes ind react v/ith olefins in the presence of Lewis acids to yield cyclic alkyl nkronates, which undergo [3- 2 cycloaddidon. Nitro compounds are precursors for nitnie oxides, alkyl nitronates, and trialkylsilyl nitronates, which undergo [3- 2 cycloaddldon reacdons. Thus, nitro compounds play important roles in the chemistry of cycloaddidon reacdons. In this chapter, recent developments of cycloaddinon chemistry of nitro compotmds and their derivadves are summarized. 

The sequence of the Michael addition of nitroalkanes and denitration provides a general method for conjugate addition of primary and secondary alkyl groups to electron deficient alkenes (Eq. 4.122).168... 

A unique nickel-catalyzed alkylative monofunctionalization of cyclic anhydrides using dialkylzinc and diphenylzinc provided 7- or f3-keto acids (Scheme 124).323 This reaction also required the use of Ni(cod)2 or Ni(acac)2 and a bidentate ligand. As it was observed by Knochel in the reactions of dialkylzinc with alkyl iodides (vide infra), addition of an electron-deficient alkene,324 for example, 4-fluoromethylstyrene, accelerated the rate of the reaction and increased the yield of the desired products. The alkylzinc reagents BuZnBr and Et02CCH2CH2ZnBr also reacted with anhydrides, although the yields were lower. 

Three-component coupling. Addition of AIBN to a benzene solution of an allylic stannane, an alkyl iodide, and an electron-deficient alkene initiates a radical process that results in 1,2-addition of the alkyl and allyl groups to the alkene.4 Example ... 

Sunlamp irradiation of butynyl iodide (6) in the presence of hexabutylditin generates an alkyl radical that reacts with an electron-deficient alkene (7) to form an (iodomethylene)cyclopentene (8) in moderate yield. This product can be reduced by Bu3SnH (AIBN) to the methylenecyclopentane (9).2... 

The base-catalysed addition of thiols to Jt-electron-deficient alkenes is an important aspect of synthetic organic chemistry. Particular use of Triton-B, in place of inorganic bases, has been made in the reaction of both aryl and alkyl thiols with 1-acyloxy-l-cyanoethene, which behaves as a formyl anion equivalent in the reaction [1], Tetra-n-butylammonium and benzyltriethylammonium fluoride also catalyse the Michael-type addition of thiols to a,P-unsaturated carbonyl compounds [2], The reaction is usually conducted under homogeneous conditions in telrahydrofuran, 1,2-dimethoxyethane, acetone, or acetonitrile, to produce the thioethers in almost quantitative yields (Table 4.22). Use has also been made of polymer-supported qua-... 

The reactivity of phenylacetic esters with electron-deficient alkenes is generally fairly poor, even under phase-transfer catalytic conditions. The reaction with cinnamic esters is often accompanied by hydrolysis and the yield of the adduct with chalcone is generally <60% [10]. The activity of the methylene group towards alkylation has been enhanced by the initial complexation of the phenyl ring with chromium tricarbonyl (see Section 6.2), but this procedure has not been applied to the Michael reaction. 

The electron-deficient alkene (5.2 mmol) in MeCN (5 ml) is added to an intimate mixture of powdered K2C03 (1 g) and NaOH (0.2 g), the (S)-menthone-protected ethyl glycine (1.27 g, 5 mmol), and TBA-Br (0.16 g, 0.5 mmol) in MeCN (20 ml). The mixture is stirred for 1 h at 0°C and then filtered. The solid is washed with MeCN (10 ml) and the combined organic solutions are evaporated and the residue is taken up in Et20. The ethereal solution is washed well with H20, dried (MgS04), and evaporated to produce the alkylated imine, which can be converted into the amino acid upon hydrolysis with aqueous acid. 

Most aryl alkyl sulphones react with electron-deficient alkenes in the expected manner [e.g. 4-8] and a-(arenesulphonyl)acetic esters undergo a catalysed one-pot double Michael addition with Michael acceptors (Scheme 6.24) [8], The two Michael acceptors can be either identical or different. 

Metal alkyl peroxides can be used for the epoxidation of electron-deficient alkenes such as enones. The use of a combination of diethylzinc, oxygen, and A-methylephedrine gave epoxides in very high yield and generally high enantio-selectivity (Figure 11.8). " ... 

The combined influences of polar and steric effects and of the strength of the newly formed bond was also recognized in the reaction of OE,0-unsaturated carbonyl compounds and similar electron deficient alkenes with organomercurials and NaBH4. For the addition of alkyl radicals to substituted styrenes, p assumed a... 

Elsewhere, Heaney et al. (313-315) found that alkenyloximes (e.g., 285), may react in a number of ways including formation of cyclic nitrones by the 1,3-APT reaction (Scheme 1.60). The benzodiazepinone nitrones (286) formed by the intramolecular 1,3-APT will undergo an intermolecular dipolar cycloaddition reaction with an external dipolarophile to afford five,seven,six-membered tricyclic adducts (287). Alternatively, the oximes may equilibrate to the corresponding N—H nitrones (288) and undergo intramolecular cycloaddition with the alkenyl function to afford five,six,six-membered tricyclic isoxazolidine adducts (289, R = H see also Section 1.11.2). In the presence of an electron-deficient alkene such as methyl vinyl ketone, the nitrogen of oxime 285 may be alkylated via the acyclic version of the 1,3-APT reaction and thus afford the N-alkylated nitrone 290 and the corresponding adduct 291. In more recent work, they prepared the related pyrimidodiazepine N-oxides by oxime-alkene cyclization for subsequent cycloaddition reactions (316). Related nitrones have been prepared by a number of workers by the more familiar route of condensation with alkylhydroxylamines (Scheme 1.67, Section 1.11.3). 

This work has been extended from aryl and alkyl substituted systems (42) (R = aryl, alkyl) to analogues where R is an amino group, so giving access to synthetic equivalents of the nonstabilized amino nitrile ylides (45). Adducts were obtained in good-to-moderate yield with A-methyhnaleimide (NMMA), DMAD, electron-deficient alkenes and aromatic aldehydes (27,28), and with sulfonylimines and diethyl azodicarboxylate (29). Similarly the A-[(trimethylsilyl)methyl]-thiocarbamates (46) undergo selective S-methylation with methyl triflate and subsequent fluorodesilylation in a one-pot process at room temperature to generate the azomethine ylides 47. 

Weinreb and co-workers (16) reported a high-pressure-induced 1,3-dipolar cycloaddition of alkyl and phenyl azides with electron-deficient alkenes at ambient temperature. As a representative example, phenyl azide underwent cycloaddition with methyl crotonate (69) at 12 kbar to give the triazoline 70 (43%) and the p-amino diazoester 71 (53%). The high-pressure conditions resulted in high yield and a shorter reaction time (Scheme 9.16). 

Hosokawa, Murahashi, and coworkers demonstrated the ability of Pd" to catalyze the oxidative conjugate addition of amide and carbamate nucleophiles to electron-deficient alkenes (Eq. 42) [177]. Approximately 10 years later, Stahl and coworkers discovered that Pd-catalyzed oxidative amination of styrene proceeds with either Markovnikov or anti-Markovnikov regioselectivity. The preferred isomer is dictated by the presence or absence of a Bronsted base (e.g., triethylamine or acetate), respectively (Scheme 12) [178,179]. Both of these reaction classes employ O2 as the stoichiometric oxidant, but optimal conditions include a copper cocatalyst. More recently, Stahl and coworkers found that the oxidative amination of unactivated alkyl olefins proceeds most effectively in the absence of a copper cocatalyst (Eq. 43) [180]. In the presence of 5mol% CUCI2, significant alkene amination is observed, but the product consists of a complicated isomeric mixture arising from migration of the double bond into thermodynamically more stable internal positions. 

A variety of geminally substituted cyclopropyl ethers are synthesized employing Fischer carbene complexes [(CO)5M=CR (OR2) M = Cr, Mo, W R1 = alkyl, alkenyl and aryl] as alkoxycarbene sources. Electron-deficient alkenes and conjugated dienes are suitable substrates for the reaction (equation 108)237-245. Electron-rich enol ethers and enamines are also... 

Upon photolysis, the alkyl nitrate (42) undergoes 1,5-H transfer to furnish the 5-radical, which in the presence of a large excess of electron-deficient alkenes undergoes addition followed by NO quenching to give (43) (Scheme 16).51... 

Houck and coworkers postulate that the origin of the regioselectivity is at the biradicalforming step and directly affected by the polarity of the alkene. The /J-carbon, considered as nucleophilic, adds rapidly to the less substituted side of the electron-deficient alkene, whereas a position considered as an a-acyl radical (more electrophilic than an alkyl radical) adds rapidly to the less substituted side of electron-rich alkenes. The calculated relative energies for the addition of jtjt triplet acrolein to different substituted alkenes at the first bond-forming step (Table 3) are found to be in good agreement with experimental values determined in the photoaddition of cyclohexenone to the related alkene. 

In designing multicomponent coupling reactions, the nature of the individual components is obviously a key factor. Generally speaking, carbon radical species, such as alkyl radicals, aryl radicals, vinyl radicals, and acyl radicals are all classified as nucleophilic radicals, which exhibit high reactivity toward electron-deficient alkenes [2]. To give readers some ideas about this, kinetic results on the addition of tert-butyl and pivaloyl radicals are shown in Scheme 6.2. These radicals add to acrylonitrile with rate constants of 2.4 x 106 M-1 s 1 and 5 x 105 M-1 s-1 at... 

Unsymmetrical ketones can be synthesized by the formal double alkylation of carbon monoxide [21] in which the three-component coupling of alkyl halides, carbon monoxide, and electron-deficient alkenes is carried out using tributyltin hydride as a radical chain mediator (Scheme 6.13) [22], The use of a slower radical mediator such as (TMS)3SiH [23] has subsequently proven to be superior to tribu-... 

Free-radical-mediated four-component coupling reactions are rare. However, when an allyltin-mediated radical carbonylation is conducted in the presence of electron-deficient alkenes, four-component coupling reactions take place efficiently to give good yields of p-functionalized <5,fi-unsaturated ketones [40]. The wide scope of this four-component coupling reaction is noteworthy Primary, secondary, and tertiary alkyl bromides and iodides can be used as well as aromatic and vinylic halides. A variety of electron-deficient alkenes, such as methyl vinyl ketone, ethyl acrylate, acrolein, acrylonitrile, and vinyl sulfone, can be used as the acyl radical trap (Scheme 6.23). Fluorous allyltin compounds can also be used in four-component coupling reactions [41]. 

Scheme 6.33 illustrates an example of some zinc-induced three-component coupling reactions of alkyl iodides, electron-deficient alkenes, and carbonyl compounds [51]. In this instance, the isopropyl radical is generated by a one-electron reduction of isopropyl iodide followed by elimination of iodide ion. The resulting radical then adds to acrylonitrile to form an a-cyano alkyl radical, which is con-... 

Similar experimental procedures can be used for the radical alkylation of electron-deficient alkenes 7 (Scheme 4). In this process, a mixture of alkene 7 and [bis(acyloxy)iodo]arenes 8 (prepared from PhI(OAc)2 and the respective... 

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