Activated imine

It is well known that aziridination with allylic ylides is difficult, due to the low reactivity of imines - relative to carbonyl compounds - towards ylide attack, although imines do react with highly reactive sulfur ylides such as Me2S+-CH2-. Dai and coworkers found aziridination with allylic ylides to be possible when the activated imines 22 were treated with allylic sulfonium salts 23 under phase-transfer conditions (Scheme 2.8) [15]. Although the stereoselectivities of the reaction were low, this was the first example of efficient preparation of vinylaziridines by an ylide route. Similar results were obtained with use of arsonium or telluronium salts [16]. The stereoselectivity of aziridination was improved by use of imines activated by a phosphinoyl group [17]. The same group also reported a catalytic sulfonium ylide-mediated aziridination to produce (2-phenylvinyl)aziridines, by treatment of arylsulfonylimines with cinnamyl bromide in the presence of solid K2C03 and catalytic dimethyl sulfide in MeCN [18]. Recently, the synthesis of 3-alkyl-2-vinyl-aziridines by extension of Dai s work was reported [19]. 

This method was extended to the diastereoselective synthesis of amino acid derivatives from the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines to enones90. 

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

Chromium aminocarbenes [39] are readily available from the reaction of K2Cr(CO)5 with iminium chlorides [40] or amides and trimethylsilyl chloride [41]. Those from formamides (H on carbene carbon) readily underwent photoreaction with a variety of imines to produce /J-lactams, while those having R-groups (e.g.,Me) on the carbene carbon produced little or no /J-lactam products [13]. The dibenzylaminocarbene complex underwent reaction with high diastereoselectivity (Table 4). As previously observed, cyclic, optically active imines produced /J-lactams with high enantioselectivity, while acyclic, optically active imines induced little asymmetry. An intramolecular version produced an unusual anti-Bredt lactam rather than the expected /J-lactam (Eq. 8) [44]. 

The highly strained and reactive 2iT-azirines have been extensively studied for various synthetic purposes, such as ring expansion reactions, cycloaddition reactions, preparation of functionalized amines and substituted aziridines. The older literature on azirines in synthesis has extensively been reviewed [69]. Concerning azirines with defined chirality only scarce information is available. Practically all reactions of azirines take place at the activated imine bond. Reduction with sodium borohydride leads to cz5-substituted aziridines as is shown in Scheme 48 [26,28]. 

In the future, further studies should be addressed to improve the chemose-lectivity and diastereoselectivity of the reductive coupling process, especially searching for novel reagents and milder experimental conditions. As a matter of fact, a few novel reductive couphng procedures which showed improved efficiency and/or stereoselectivity have not been further apphed to optically active imines. For example, a new electrochemical procedure which makes use of the spatially addressable electrolysis platform with a stainless steel cathode and a sacrificial aluminum anode has been developed for imines derived from aromatic aldehydes, and the use of the N-benzhydryl substituent allowed 1,2-diamines to be obtained with good yields and dl-to-meso ratios... 

Another example of the addition of terminal alkynes to C=N in water is the coupling of alkynes with in-situ-generated A-acylimines (Eq. 4.32) and A-acyliminium ions (Eq. 4.33). In 2002, Li et al. developed a coupling reaction of alkynes with A-acylimines and A-acyliminium ions mediated by Cu(I) in water to generate propargyl amide derivatives.57 Either an activated imine derivative or imininum derivative was proposed as the intermediate, respectively. 

An unusual temperature dependence on the regioselective behavior of an allylbarium species has been demonstrated in asymmetric allylation with the optically active imine SAMP-hydrazone [SAMP = (A)-(—)-l-amino-2-meth-oxymethylpyrrolidine] (Scheme 10).322 Its reaction with prenylbarium chloride at 0°C produced an a-allylated hydrazine in 60% diastereotopic excess, but at — 78 °C, the y-adduct was generated with 98% diastereotopic excess. The temperature dependence of the ct/y ratio may reflect competition between a kinetically favored y-adduct at low temperature and a thermodynamically preferred ct-form at higher temperatures. 

Addition of organocopper reagents to imine derivatives can readily afford functionalized amine derivatives. Three recent examples are shown below (Equations (129) and (130) Scheme 102).498,498a,498b In these cases, iminium ions are employed as an activated imine. 

II. Asymmetric Aldol Reaction by the Use of Optically Active Imines... 

P-Amino carbonyl compounds containing an a-atkyUdene group are densely functionalized materials, which are widely applied in the synthesis of medicinal reagents and natural products [265]. These products are usually prepared through the classic aza-Morita-Baylis-Hillman reaction [176, 177] of activated imines and electron-deficient alkenes catalyzed by tertiary amines or phosphines. Chen and co-workers, in 2008, identified bis-thiourea 106 as a suitable catalyst for the... 

Doubly acceptor-activated imines with an intramolecular alkene moiety such as 29 can cyclize according to an electrophilic mechanism to give pyrrolidine, piperidine or azepine derivatives. This reaction is induced by stoichiometric amounts of Lewis acids, preferably trialkylsilyl triflates [38]. In certain cases FeCl3 can also be used, for example for the preparation of azepinolactone 30 from imine 29 (Scheme 8.10) [39]. Catalytic amounts of FeCl3 are required for the addition of diethyl phosphite to an... 

Non-activated imines have been pentafluorophenylated with (FsCebSiF protonation activates the inline, and chloride ions activate the silane.78... 

A direct stereoselective addition of an activated imine to jS-keto phosphonates in the presence of a chiral copper(II) catalyst has been developed 83... 

The doubly activated imines 4 can be cyclized by Lewis acids or TMS triflate to provide the cyclic amino acid derivative 5 after saponification and decarboxylation. 

The allylation of a-iV-tosylimino esters, highly activated imines, proceeds by catalytic use of a Lewis acid. Tol-BINAP-Cu(l) complexes are effective catalysts of asymmetric allylation of these imines with allylsilanes (Equation (28)).124 125 The presence of an aryl group at the position j3 to silicon improves the enantioselectivity. 

The above additions to activated imines presumably involve iminium salt/complex intermediates. Addition to preformed iminium salts can also be effective, as in the examples given here. 

The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a receptor is a valuable synthetic tool leading to the synthesis of highly funtionalized products. Acyl anion receptors include Michael acceptor (Stetter reaction), aromatic aldehyde (benzoin reaction), ketone, nitroalkene, aziridine, activated imine. Recently, nucleophilic addition of acyl anions to unactivated imines has been explored <07CC852>. Treatment of aryl aldehydes with imines 146 in the presence of triazolium salt 147 (20 mol%) and triethylamine (20 mol%) provides the a-amino ketones 148 in good yields. However, this methodology does not work for 4-pyridylaldehyde and tert-buty laldehyde. 

Optically active macrocyclics were prepared in two methods. In Method-1, the product from Step 3 was converted to an imine using (R)-l-phenylethylamine and separated by chromatography [Procedure-1]. In Method-2 the optically active imines were hydrolyzed by base into the optically active /3-diketone cyclophane entionomers [Procedure-2] and then isolated by chromatography. 

Potassium hydroxide (4.0 mmol) dissolved in 4 ml water was added to an optically active imine (1.0 mmol) dissolved in 5 ml THF and the mixture stirred at ambient temperature 20 hours. Thereafter, 2 ml 10% HCl was added, the solution made acidic, and the mixture extracted with diethyl ether. The organic layer was washed with brine, dried, concentrated, the residue either recrystallized from pentane or purified by chromatography using hexane/EtOAc, 10 1, and the product isolated. 

Scheme 25 shows representative examples of various chemotypes that can be generated with this simple and efficient strategy. Practically, all common azines and Michael acceptors react in these processes, and the range of the third component is also extremely wide. Aldehydes (such as 179), ketones and a-dicarbonyls (such as 181) afford the expected products in good yields moreover, the cyclic carbonyl derivatives 183 and 185 lead to spiro-polyheterocycles 184 and 186, respectively [160]. Interestingly, activated imines (such as 187) are also reactive, which naturally... 

Even the very efficient enantioselective catalysts used in organozinc addition reactions to carbonyl compounds failed to catalyze the corresponding addition reactions to nonactivated imines such as A-silyl-, A-phenyl-, or iV-benzyl-imines. However, enantioselective additions of diaUcylzinc compounds to more activated imines, like iV-acyl- or iV-phosphinoyl-imines, in the presence of catalytic or stoichiometric amounts of chiral (see Chiral) aminoalcohols, have been recently reported. For example, in presence of 1 equiv of (A,A-dibutylnorephedrine) (DBNE) diethylzinc reacts with masked A-acyl imines like A-(amidobenzyl)benzotriazoles, to give chiral A-(l-phenylpropyl)amides with up to 76% e.e. (equation 68). 

Doubly activated imines undergo intramolecular electrophilic cyclization reactions in the presence of Lewis acids and this provides an efficient route to annulated pyrrolidine, piperidine and azepine lactones (Sch. 32) [143]. TMSOTf and GaCls give different product ratios and yields. 

One synthetic problem in aza Diels-Alder reactions is the stability of imines under the influence of Lewis acids. It is desirable that the Lewis acid-activated imines are immediately trapped by dienes or dienophiles. In 1989, Sisko and Weinreb reported a convenient procedure for the aza Diels-Alder reaction of an aldehyde, a 1,3-diene, and A-sulfinyl p-toluenesulfonamide via A -sulfonyl imine produced in situ—a stoichiometric amount of BF3 OEt2 was used as a promoter [28a]. 

Imino lactones, such as (22), can be reduced cleanly to the morpholinone (23) in an aptotic medium using diethyl malonate as a mild proton donor (equation 9). The electroreductive behavior of this class of activated imines is presently under study. 

The influ nee of reaction conditions on the stereochemistry of the oxidation of optically act ve or racemic Af-diphenylmethylene a-methylbenzylamines 40 with chiral or achiral peroxy acids to oxaziridines was investigated. It was found that asymmetric induction at the ring nitrogen in the resulting oxaziridine from optically active imine 40 does not depend on the nature of the peroxy acid or the solvent. However, the diastereoselectivity seems to be dependent only on the reaction temperature. The ratio of the resulting oxaziridine diastereomers changed by 10% when the reaction temperature was raised from — 30°C to -t-40°C. On the other hand, the enantioselectivity was found to depend on the chirality of the peroxy acid, the temperature, and the solvent. For example, the optical yield of the major oxaziridine diastereomer decreased from 3.4 to 1.3 when the solvent was changed from chloroform to methanol in the oxidation of racemic 40. 

Further extension of the reaction pool of Schilf bases 138 was achieved by their reaction with tran -l-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (Danishefsky s diene) to give 2-substituted 5,6-didehydro-piperidin-4-ones 164 [135,136] (Scheme 10.54). The reaction is considered to be a sequence of an initial Mannich reaction between the imine and the silyl enol ether, followed by an intramolecular Michael addition and subsequent elimination of methanol. If the reaction was terminated by dilute ammonium chloride solution, then the Mannich bases 163 could be isolated and further transformed to the dehydropiperidinones 164 by treatment with dilute hydrochloric acid. This result proved that the reaction pathway is not a concerted hetero Diels-Alder type process between the electron-rich diene and the activated imine. The use of hydrogen chloride as a terminating agent resulted in exclusive isolation of the piperidine derivatives 164 formed with... 

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