Addition of organometallics

Barbier-type C-alkylation of imines can be carried out with alkylstrontium halides generated from strontium metal and alkyl halide.38 IV-Alkylation competes, and RSrI is strongly nucleophilic, as shown by a-alkylation of imines derived from enolizable 

A kinetic study of the addition of n-Bul.i to a chiral aliphatic aldimine has explored the roles of TMEDA ( /V,/V,lV, lV -tetramcihylc(.hylcncdiaminc) and solvents (toluene, diethyl ether) on relative rates and diastereoselectivity41 Evidence for four mechanisms was obtained, including monomeric and dimeric n-BuLi cases, and a cooperative TMEDA-Et20 pathway. Hence the roles of chelation, aggregation, and cooperative solvation all need to be considered when solvents and additives are varied in such reactions. 

Copper-catalysed enantioselective addition of diorganozincs to phosphinoylimines has been reported42 as has enantioselective addition of diethylzinc to A-acylal- 

Asymmetric addition of organometallic reagents to imines, to produce useful optically active amines, has been reviewed.44 

Enantioselective exocyclic, endocyclic, and acyclic a-p-tolylsulfinyl ketimines have been reacted with Et2AlCN 45 The cyclic substrates exhibit good yield and diastere-oselectivity, but the acyclic cases are complicated by imine-enamine equilibria. 

The mechanism of conjugate addition of lithium dialkylcuprates to enones has been explored by the determination of 13C kinetic isotope effects by an NMR method reductive elimination from Cu is implicated as the rate-determining step.109 

Aryltrimethylstaimanes arylate aldehydes in the presence of a cationic rhodium complex, [Rh(cycloocta-l,5-diene)(MeCN)2]+, yielding secondary alcohols.114 

Schiff bases, Ar1-CH=N-Ar2, that are unreactive with triethylaluminium alone undergo ethylation in the presence of cerium(IV) the reaction site is the methine.36 The sterically sensitive reaction is favoured by electron-donating substituents. Excess Et3Al is required, or cleavage to aldehyde and amine results. 

The structure of lithiated cyclohexanone A-cyclohcxylimine (16) and its reactivity towards C-alkylation has been investigated experimentally and by DFT calculations.37 

Formed from the imine using LDA in hexane, NMR studies reveal complex solvent-dependent distributions of monomers, dimers, and trimers in several ethereal solvents, although a mono-solvated dimer can be selected by appropriate choice of solvent. Study of C-alkylation rates suggests that both monomer- and dimer-based mechanisms operate. The lithioimines were compared with the isostructural lithium dialkylamides, but were shown to be not simply vinylogous analogues thereof. 

A pseudo-C2-symmetric tertiary diamine derived from (1 S2S)-(+)-pseudoephedrinc (17, R1 = Me, R2 = Ph) has been prepared and tested in the enantioselective addition of methyllithium to aromatic imines.39 It shows comparable ee and better reactivity than a genuinely C2-symmetric relative [17, R1, R2 = -(CH2)4-]. 

A chiral rhodium(I)-diene complex catalyses the addition of dimethylzinc to N-tosylarylimines, ArCH=NTs, with ees up to 98%.40 

Several stereoselective dialkylzinc additions have been reported. The oxazolidine catalyst series (64) gives moderate ee% in the addition of diethylzinc to benzaldehyde. Substituent effects on the mechanism of induction have been explored for a range of 

Chiral amines, ArCH(R)NH2, can be prepared by addition of a dialkylzinc to A-(diphenylphosphinoyl)imines, ArCH=N—P(=0)Ph2, using a suitable auxiliary, followed by acid hydrolysis to cleave the phosphorus moiety. A series of 

2-azanorbornylmethanols (65) give ee% up to 92%, and they also induce some enantioselectivity in additions to benzaldehyde. A highly organized transition state with two zincs is proposed one coordinates the nitrogens of substrate and catalyst and the other coordinates the oxygens. 

Among other enantioselective alkylations, a series of 3-aminopyrrolidine lithium amides (67 derived from 4-hydroxy-L-proline) have been used to induce high ee% in the addition of alkyllithiums to various aldehydes. Structure-activity relationships are identified, and the role of a second chiral centre (in the R group) in determining the stereochemistry of the product is discussed. 

A template (68) containing two aluminium centres, one nucleophilic and the other electrophilic, accelerates nucleophilic alkylation of aldehydes.  

P-Chirogenic phosphinoylimines (33) have been synthesized and undergo diastereos-elective addition of Grignards.  

Aryl Grignards add to chiral A-alkyl (or A-aryl) benzenesulflnylimines, PhCH=NSOR/PhCH=NSOAr, in high yield and de, to give chiral diaryl amines (in protected sulfinyl form). A comparative smdy of the use of the familiar f-butane or p-toluene groups at sulfur with 2,4,6-triisopropylbenzene finds that the latter is significantly superior in yield and de and that results are somewhat better at room temperature versus -40 °C (g) 

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The ketones can be obtained by addition of organometallic reagents to acids and their derivatives. 

Dihydropyrazines are relatively stable, although they are easily oxidized. They are usually formed via the addition of organometallic reagents to the pyrazine ring. Similarly, 2,3-dihydropyrazines are usually easily oxidized to pyrazines and are formed during type A synthesis (see Section 2.14.3.2). 

There is another possible mechanism for addition of organometallic reagents to carbonyl compounds. This involves a discrete electron-transfer step. °... 

Table 8.2. Stereoselectivity in Addition of Organometallic Reagents to Some Chiral Aldelqrdes and Ketones"...

Analyze the factors which would determine stereoselectivity in the addition of organometallic compoimds to the following carbonyl compounds. Predict the major product. 

House investigated the role of cuprous ions in the conjugate addition of organometallic reagents. He found that the catalytic effect can be explained by the intervention of a methyl copper derivative, which reacts rapidly with the carbon-carbon double bonds of the conjugated system. 

Similarly, the addition of organometallic reagents to pyridines leads to dienamine intermediates, which can be demonstrated (167-170). 

The addition of organometallic reagents to a-amino ketones e.g., 1 normally obeys Cram s rule the dominant diastereomer is the. syrc-compound81. 

A different approach to chiral oc-hydroxy acids 4 is the nucleophilic addition of organometallic reagents to chiral oc-oxo 4,5-dihydrooxazoles 2, which can be synthesized by oxidation of the corresponding 2-alkyl-4,5-dihydrooxazoles l17,19. 

As with oxathianes 3 (R1 = CH, R2 = H), which bear a close structural resemblance to 17, the addition of organometallic reagents is highly diastereoselective with a predominant chelation-controlled attack of the nucleophile from the Rc-sidc35 -40. In the case of vinylmagnesium bromide a considerable enhancement of the diastereo selectivity could be attained by adding... 

The addition of organometallic reagents to the C —N double bond of imines 1 provides an attractive route to amines 21 2. However, due to the poor electrophilici ty of imines, this method is often plagued by competitive reactions ... 

For diastereoselective addition of organometallic agents to imines attached to arene tricar-bonylchromium or ferrocenyl moieties, see refs 26 28 and Section 1.4.1.1.2.2. 

Arylalkylamines 6 by Addition of Organometallic Reagents to 1,3-Oxazolidines 4 and Oxidative Cleavage and Hydrolysis General Procedure22 ... 

Additions of organometallic compounds to 2-azelidinones such as 1 or 4 bearing a leaving group in the 4-position preferentially or exclusively afford tram-3,4-substituted /(-lactams 3 or 6. Therefore, the participation of an A -acylinline intermediate such as 2 or 5 which is attacked from the less hindered side is probable14-16. This has been exploited for the synthesis of carbapenem antibiotics, e.g., thienamycin (7)16. 

The enantioselective addition of organometallic reagents to, V-(trimethylsilyl)benzaldehyde imine (1) in the presence of enantiomerically pure modifiers has been investigated. The best result is obtained with butyllithium (the corresponding Grignard reagent affords both lower yield and selectivity, 1 fails to react with diethylzinc) and two equivalents of the enantiomerically pure diol 2 in diethyl ether. It should be noted that the choice of the solvent is crucial for the stereoselectivity of the reaction1 2 3 5 7 8 9. 

Addition of organometallics to hydrazones provides hydrazines1, which can be converted to the corresponding amines by hydrogenolysis. Hydrazones can therefore be regarded as masked imine derivatives of ammonia. This methodology has been utilized successfully for numerous stereoselective syntheses of amines and amine derivatives2-23. 

Table 4. Addition of Organometallics to Chiral /V,jV-Dimethyl Hydrazone Aminals Sb6,7 HsCe,...

In order to synthesize 1,3-diphenyl-l, 3-diamines 3 containing a C2 axis of symmetry, which can be employed as auxiliaries and controller groups in asymmetric syntheses, the diastereoselective addition of organometallic reagents to racemic pyrazolines 2, prepared from cinnamaldehyde (l)23, was investigated. 

The synthesis of alkoxy amines 2 by addition of organometallic reagents to the C-N double bond of oxime ethers 1 is plagued by the propensity for proton abstraction a. to the C-N double bond, the lability of the N-O bond and the poor electrophilicity of the oxime ethers. Therefore, frequently no products, undesired products or complex mixtures are obtained. The result depends on the substrate, organometallic reagent, solvent, temperature and additives1 6. 

Table 6. Addition of Organometallic Reagents to Racemic Nitrones S8-9...

Table 8. 1,2-Asymmetric Induction in the Addition of Organometallics to N-Alkylimines 4, Cram Selectivity 6...

Addition of Organometallic Compounds to a,/MJnsaturated Carbonyl Compounds... 

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