Addition of Carbon Nucleophiles

FIGURE 14.56 Preparation of Grignard and organolithium reagents and their reactions with epoxides. 

FIGURE 14.57 Reaction of a Grignard reagent with formaldehyde. 

FIGURE 14.58 Reaction of Grignard reagents with aldehydes and ketones. 

FIGURE 14.62 Mechanism of reaction of Grignard reagents with nitriles. 

CgQ readily reacts with organoHfhium and Grignard compounds with alkyl, phenyl or alkynyl groups to form the anions RCgg as primary intermediates [2-10], This 

These electron density considerations imply a preferential proton attack on position 2, which actually was observed in the experiments. Whereas only the 1,2-derivatives could be detected, after chromatographic purification, following the in 

Therefore, CjqH Bu is one of the strongest acids consisting exclusively of carbon and hydrogen. 

Owing to their stability and low nucleophilicity, metal acetylides are less reactive toward Cjq than other lithium organyls or Grignard reagents [11]. Though the reaction is slower and higher reaction temperatures are necessary, various acetylene derivatives of Cjq could be obtained. The first acetylene Cjq hybrids were (trimethyl-silyl)ethynyl- and phenylethynyl-dihydro[60]fullerene, synthesized simultaneously 

The NMR spectra of C qHR exhibits 37 resonances of the fuUerene carbons, with two of them in the sp region, proving Q-symmetry for the C oHR adducts. This is consistent with an addition to a double bond of a pole corannulene imit (1,2-addition), leading to l,2-dihydro[70]fullerene derivatives. These particular [6,6] bonds of Cyg, located between the carbons of the sets A and B, have almost the same bond length as the [6,6] bonds in Cjq [30], and the pole corannulene unit also exhibits bond alternation with longer [5,6] bonds. NMR data imply that the initial attack of the nucleophile occurred on C-1 and the protonation on C-2. 

2-Cyclohexadione was recently shown to react with a,fS-unsaturated aldehydes to form bicyclo[3.2.1]octanes 46 under Lewis base catalysis [22]. The best results were 

Organometallic reagents are well known for 1,4-additions and can hence be utilized to catalyze domino Michael/aldol reactions. Based on a methodology published by Noyori et al. [24], the group of Feringa estabhshed a catalytic enantios-elective protocol for the synthesis of (—)-prostaglandin Ej methyl ester [25]. There, 

The authors proposed a Zimmerman-Traxler type transition state 56 bearing a Z-enolate, which was based on the fact that mainly T) -haptomeric rhodium enolates exist after conjugate additions. Additionally, this concept could be extended to parallel kinetic resolution reactions with racemic unsymmetrically substituted diones. 

An intramolecular domino Michael/aldol reaction starting from the chiral Cope products 58 was developed by the group of Schneider [27], After 1,4-addition of 

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The addition of carbon nucleophile, including organometallic compounds, enolates, or enols, and ylides to carbonyl gro is an important method of formation of carbon-carbon bonds. Such reactions are- ctremely important in synthesis and will be discussed extensively in Part B. Here, we will examine some of the fundamental mechanistic aspects of addition of carbon nucleophiles to carbonyl groups. 

SECTION 8.3. ADDITION OF CARBON NUCLEOPHILES TO CARBONYL GROUPS... 

Azirines (three-membered cyclic imines) are related to aziridines by a single redox step, and these reagents can therefore function as precursors to aziridines by way of addition reactions. The addition of carbon nucleophiles has been known for some time [52], but has recently undergone a renaissance, attracting the interest of several research groups. The cyclization of 2-(0-tosyl)oximino carbonyl compounds - the Neber reaction [53] - is the oldest known azirine synthesis, and asymmetric variants have been reported. Zwanenburg et ah, for example, prepared nonracemic chiral azirines from oximes of 3-ketoesters, using cinchona alkaloids as catalysts (Scheme 4.37) [54]. 

Addition of carbon nucleophiles to vinylepoxides is of particular importance, since a new carbon-carbon bond is formed. It is of considerable tactical value that conditions allowing for regiocontrolled opening of vinyloxiranes with this type of nucleophiles have been developed. Reactions that proceed through fonnation of a rr-allyl metal intermediate with subsequent external delivery of the nucleophile, or that make use of a soft carbon nucleophile, generally deliver the SN2 product. In contrast, the Sn2 variant is often the major reaction pathway when hard nucleophiles are employed. In some methods a nucleophile can be delivered selectively at either the Sn2 or SN2 positions by changing the reaction conditions. 

Additions of carbon nucleophiles to vinylepoxides are well documented and can be accomplished by several different techniques. Palladium-catalyzed allylic alkylation of these substrates with soft carbon nucleophiles (pKa 10-20) proceeds under neutral conditions and with excellent regioselectivities [103, 104]. The sul-fone 51, for example, was cyclized through the use of catalytic amounts of Pd(PPh3)4 and bis(diphenylphosphino)ethane (dppe) under high-dilution conditions to give macrocycle 52, an intermediate in a total synthesis of the antitumor agent roseophilin, in excellent yield (Scheme 9.26) [115, 116]. 

In this chapter the addition of carbon nucleophiles to simple a,j8-unsaturated sulfoxides, a-sulfinyl-a,/ -unsaturated ketones and a-sulfmyl-a,/ -unsaturated lactones will be discussed separately, in most cases the asymmetric induction arises from the chirality at sulfur. 

Addition of Carbon Nucleophiles to Chiral a-Amino Azomethine Compounds... 

Nucleophilic addition to a, -unsaturated sulfones has long been known. For example, treatment of divinyl sulfone with sodium hydroxide has been known to afford bis( -hydroxyethyl) sulfone "", while the reaction of a- and -naphthyl allyl sulfones and allyl benzyl sulfone " with alkali hydroxide or alkoxide gave -hydroxy or alkoxy derivatives. In the latter reaction, the allyl group underwent prototropy to the 1-propenyl group, which in a subsequent step underwent nucleophilic attack . Amines, alcohols and sulfides are known to add readily to a, -unsaturated sulfones, and these addition reactions have been studied widely. In this section, the addition of carbon nucleophiles to a, ji-unsaturated sulfones and the reactions of the resulting a-sulfonyl carbanions will be examined. 

The reactions that are discussed in this section involve addition of carbon nucleophiles to carbonyl centers having a potential leaving group. The tetrahedral intermediate formed in the addition step reacts by expulsion of the leaving group. The overall... 

Among the olefination reactions, those of phosphonium ylides, phosphonate anions, silylmethyl anions, and sulfone anions are discussed. This chapter also includes a section on conjugate addition of carbon nucleophiles to a, (J-unsaturated carbonyl compounds. The reactions in this chapter are among the most important and general of the carbon-carbon bond-forming reactions. 

A number of the more characteristic addition reactions will now be studied in greater detail they will be grouped under the heads (a) simple addition, (b) addition/elimination, and (c) addition of carbon nucleophiles. 

Addition of carbon nucleophiles to furfural tosylhydrazone provides 5-substituted 2E,4E-pentadienyls in good yields <00TL2667>. The ab initio calculations at the RHF/3-21G level have been utilized to study the origins of diastereoselectivity of the vinylogous Mannich reaction of 2-methylfuran with pyrrolinium ion . A simple procedure for isomerization of 2-furylcarbinols to cyclopentenones under neutral condition was reported and a new mechanism was proposed <00H(52)185>. 

As mentioned in Section 2.3, a large number of biologically active natural products contain quaternary carbon atoms, and the addition of carbon nucleophiles to ketones has attracted increasing attention for the construction of quaternary carbon centers. 

Diastereoselectivities observed for 1,2-additions of carbon nucleophiles, and 1,4-additions of lithium diorganocuprates, to enantiomerically enriched bicyclo[m.l.O]alk-3-en-2-ones possessing 8-, 12-, and 15-membered rings have been discussed. ... 

The first organocatalyzed conjugate addition of a-substituted p-ketoester to a,P-unsaturated ketones was presented by Deng et al. [42] (Scheme 3). Although traditional Cinchona alkaloids were efficient catalysts for conjugate addition of carbon nucleophiles to nitroalkenes and sulfones, replacement of the C(9)-OH with an ester group (Q-7b) showed great improvement in stereoselectivity. The reaction is applicable to a variety of cyclic and acyclic enones (16,18). 

The asymmetric Mannich addition of carbon nucleophiles to imines catalyzed by the cyclohexane-diamine catalysts has developed significantly in the past decade. List and co-workers reported the asymmetric acyl-cyanantion of imines catalyzed by a cyclohexane-diamine catalyst [103], Using a derivative of Jacobsen s chiral urea catalyst, the authors optimized reaction conditions and obtained chiral iV-acyl-aminonitriles in high yield and enantioselectivities (Scheme 51). The scope of the reaction was explored with both aliphatic and aromatic imines, providing good to high selectivities for a variety of substrates. 

Formation of C-C bonds remains the ultimate challenge to the synthetic chemist. The employment of new synthetic methods in complex target synthesis can be frustrated by a lack of functional group tolerance and substrate specificity. These problems can be somewhat alleviated within conjugate addition reactions by the use of secondary amine catalysts where a number of important and highly selective methods have been developed. Two principle classes of nucleophile have been shown to be effective in the iminium ion activated conjugate addition of carbon nucleophiles to a,P-unsaturated carbonyl systems aryl, heteroaromatic and vinyl... 

Scheme 24. Addition of carbon nucleophiles onto chlorocyclopropylideneacetates 1,2 [9,15b, 22 b, 27,53]...

In this chapter, we wish to disclose our results on the nucleophilic addition of carbon nucleophiles to N-alkoxycarbonylamino sulfones. Both allyltrimethylsilane and silyl enolates will be considered as nucleophiles. The corresponding amines were obtained efficiently in the presence of 0.5-5 mol% of Bi(0Tf)34H20 [57,58]. 

The intramolecular addition of carbon nucleophiles to alkenes has received comparatively little attention relative to heterocyclization reactions. The first examples of Pd-catalyzed oxidative carbocyclization reactions were described by Backvall and coworkers [164-166]. Conjugaled dienes with appended al-lyl silane and stabilized carbanion nucleophiles undergo 1,4-carbochlorination (Eq. 36) and carboacetoxylation (Eq. 37), respectively. The former reaction employs BQ as the stoichiometric oxidant, whereas the latter uses O2. The authors do not describe efforts to use molecular oxygen in the reaction with allyl silanes however, BQ was cited as being imsuccessful in the reaction with stabihzed car-banions. Benzoquinone is known to activate Ti-allyl-Pd intermediates toward nucleophilic attack (see below. Sect. 4.4). In the absence of BQ, -hydride eUm-ination occurs to form diene 43 in competition with attack of acetate on the intermediate jr-allyl-Pd" species to form the 1,4-addition product 44. 

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