Stereoselectivity electrophilic amination

Stereoselective Electrophilic Amination with Sulfonyloxycarbamates and Azodicarboxylates... 

The chemistry of nitrogen electrophiles R R2NX (I) was excellently summarized in 1989Ia. Recent studies in the field of stereoselective electrophilic amination, however, have shown that azidation with sulfonyl azides III, reactions with di-tert-butyl azodicarboxylate (II) and reactions with 1-chloro-l-nitroso reagents IV, are superior to the previously mentioned nitrogen electrophiles. 

In the latter three cases, the initially formed adducts are easily transformed into the desired amines RNH2 with very high diastereoselectivity and/or enantioselectivity3. It is thus the main purpose of this section to summarize these stereoselective electrophilic aminations and to mention reactions performed with electrophiles of the type R R2NX, I. 

Azo-ene reactions. The ene reaction provides a powerful method for C-C bond formation with concomitant activation of an allylic C-H bond. A variety of functionalized carbon skeletons can be constructed due to the range of enophiles which can be used. For example, carbonyl compounds give homoallylic alcohols and imino derivatives of aldehydes afford homoallylic amines. The azo-ene reaction offers a method for effecting allylic amination by treatment of an alkene with an azo-diester to afford a diacyl hydrazine which upon N-N cleavage furnishes a carbamate. Subsequent hydrolysis of the carbamate provides an allylic amine. Use of chiral diazenedicarboxylates provides a method for effecting stereoselective electrophilic amination. 

Theoretical studies have led to the choice of (IS, 2S)-l-phenyl-2-benzyl-2-(2-propylamino)ethanol as the chiral auxilary in the 1,3,2-oxazaphospholane 295 for use in stereoselective electrophilic amination. The experimental results confirm the theoretical studies, de values up to 83% being obtained (Scheme 33). 

Stereoselective Synthesis of a-Amino Carboxylic and Phosphonic Acids via Electrophilic Amination with Lithium tert-Butyl Af-(tosyloxy) carbamate... 

Diastereoselective enolate amination as an approach to a-aminoke-tones.42 We have demonstrated that the Mannich reaction is successful for the highly stereoselective introduction of P-aminoketone moieties (vide supra, Asymmetric Mannich Reactions24). The diastereofacially selective electrophilic amination of enolates is attractive as a complementary approach to the asymmetric... 

In summary, the electrophilic amination of lithium enolates derived from 1 with di-toT-buty] azodicarboxylate (DBAD) provides an excellent approach to the stereoselective synthesis of a-hydrazino and a-amino acids. 

Unfortunately, the yields of the amines are only moderate and the enantioselectivities are poor. Similar observations have been made with 2 as the electrophilic animating reagent. In both 1 and 2 the distance between the stereogenic centers and the electrophilic nitrogen atoms is probably too large for effective stereoselectivity to occur. Due to the high yields and stereoselectivities achieved in other electrophilic amination reactions reported in this section, the method demonstrated here is only of historical interest, although less then 15 years old. 

Related Reagents. The synthesis of chiral diazenedicarboxylates as potential chiral electrophilic aminating agents has received little attention. A series of chiral bomyl, isobomyl and menthyl diazenedicarboxylates has been reported and their reaction with achiral enolates of esters and N,N-dimethyl amides afforded a-hydrazino acid derivatives with little or no selectivity. Incorporation of a chiral azodicarboxamide unit into a chiral bridging binaphthyl moiety afforded a-hydrazino acid derivatives with high stereoselectivity in reactions with achiral oxazolidinone anions. ... 

In an interesting application of enolate chemistry associated with silyl derivative 79, electrophilic amination allows convenient access to the synthetic equivalent of 2-deoxy-2-aminotetroses. This methodology has been applied to the stereoselective synthesis of D-ribo- Ci8-phytosphingosine (96) (Scheme 11) [41]. 

Coeffard, V., Desmarchelier, A., Morel, B., Moreau, X., Greek, C. (2011). Stereoselective organocatalytic one-pot a,a-bifunctionalization of acetaldehyde by a tandem Mannich reaction/electrophilic amination. Organic Letters, 13, 5778-5781. 

It is supposed that the nickel enolate intermediate 157 reacts with electrophiles rather than with protons. The successful use of trimethylsilyl-sub-stituted amines (Scheme 57) permits a new carbon-carbon bond to be formed between 157 and electrophiles such as benzaldehyde and ethyl acrylate. The adduct 158 is obtained stereoselectively only by mixing nickel tetracarbonyl, the gem-dibromocyclopropane 150, dimethyl (trimethylsilyl) amine, and an electrophile [82]. gem-Functionalization on a cyclopropane ring carbon atom is attained in this four-component coupling reaction. Phenyl trimethyl silylsulfide serves as an excellent nucleophile to yield the thiol ester, which is in sharp contrast to the formation of a complicated product mixture starting from thiols instead of the silylsulfide [81]. (Scheme 58)... 

Substitution of a carbon monoxide ligand of complexes, such as 1, by the more electron-donating triphenylphosphane group (see Section 1.1.1.3.4.1.3.) provides chiral monophos-phane complexes, such as 3. Monophosphane complexes in general lack sufficient electrophilic-ity to react with amines or thiols, but react readily with amine anions at the /J-position, producing enolate anions such as 4, which may be quenched stereoselectively at the a-carbon by electrophiles46 (see Section 1.1.1.3.4.1.3.). The conformational and stereochemical issues involved are essentially identical to those already discussed in this section for the 1,4-additions of carbon nucleophiles. 

A7-Fluorobis(trifluoromethylsulfonyl)amine (Id) in acetic acid even reacts with deactivated a,/ -unsaturated carbonyls, which are normally unreactive with the usual electrophiles, to afford (6-acetoxy-a-fluoro derivatives 17.146 In these reactions, no stereoselectivity is observed, supporting the proposed carbocation intermediates. 

Stereoselective vicinal diamination of dihydropyridines 309 by electrophilic interaction with iodine in the presence of secondary amines leading to tetrahydropyrimidines 312 is described in [338, 339] (Scheme 3.107). The... 

Addition of nucleophiles to electrophilic glycine templates has served as an excellent means of synthesis of a-amino acid derivatives [2c, 4—6]. In particular, imines derived from a-ethyl glyoxylate are excellent electrophiles for stereoselective construction of optically active molecules [32], This research and retrosyn-thetic analysis led us to believe that amine-catalyzed asymmetric Mannich-type additions of unmodified ketones to glyoxylate derived imines would be an attractive route for synthesis of y-keto-ce-amino acid derivatives [33], Initially, L-proline-catalyzed direct asymmetric Mannich reaction with acetone and N-PMP-protected a-ethyl glyoxylate was examined in different solvents. The Mannich-type reaction was effective in all solvents tested and the corresponding amino acid derivative was isolated in excellent yield and enantioselectivity (ee >95 %). Direct asymmetric Mannich-type additions with other ketones afford Mannich adducts in good yield and excellent regio-, diastereo- and enantioselectivity (Eq. 8). 

The similarity between mechanisms of reactions between proline- and 2-deoxy-ribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggests that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes, which could add to different electrophiles such as imines [36, 37]. In fact, proline is able to mediate the direct catalytic asymmetric Mannich reaction with unmodified aldehydes as nucleophiles [38]. The first proline-catalyzed direct asymmetric Mannich-type reaction between aldehydes and N-PMP protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantioselectivity (Eq. 9). 

Electrophilic substitutions of alkenyl-, aryl-, and alkynylsilanes with heteroatom-stabilized cationic carbon species generated by the action of a Lewis or Brpnsted acid (acyl cation, oxocarbenium ion, etc.) provide powerful methods for carbon-carbon bond formation. Particularly, intramolecular reactions of alkenylsilanes with oxocarbenium and iminium ions are very valuable for stereoselective construction of cyclic ether and amine units.21-23 For example, the BFj OEt -promoted reaction of (E)- and (Z)-alkenylsilanes bearing an acetal moiety in the alkenyl ligand gives 2,6-disubstituted dihydropyrans in a stereospecific manner (Scheme l).23 Arylsilanes also can be utilized for a similar cyclization.24... 

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