Imines, preparation from aldehydes

Synthesis. - Type C Syntheses (C-C-H-C + S). Imines prepared from aldehydes and t NCR CR R X (X=leaving group,R1,R, R3,R =H, alkyl,Ar) react with S donors such as Na2S to form the corresponding thiazolidines (152)1. ... 

The imines are prepared by 16-12. The enamine salt method has also been used to give good yields of mono a alkylation of a,P-unsaturated ketones. Enamines prepared from aldehydes and butylisobutylamine can be alkylated by simple primary alkyl halides in good yields. N-alkylation in this case is presumably prevented by steric hindrance. 

Secondary allylic amines 184 have been prepared from aldehydes 181 (R1 = H, Me or Ph R2 = Me, Et or H) by the following sequence treatment with an amine R3NH2 (R3 = i-Pr, t-Bu, cyclohexyl or PhCH2) yields an imine 182, which is chlorinated by N-chlorosuccinimide. Dehydrochlorination of the resulting chloro compound with potassium t-butoxide gives an allylic imine 183, which is reduced to the product by means of methanolic sodium borohydride191. 

Organomagnesium compounds react with imines, prepared from 3-methoxy-2-naphth-aldehydes by a 1.4-addition mechanism. This reaction can be performed with high diastere-oselectivity. The method was applied for the synthesis of optically pure S-tetralones . Vinyhnagnesium bromide reacts as an acceptor with a ketone dimethyl hydrazone zincate 207, yielding a 1,1-bimetallic species, which can be reacted sequentially with two different electrophiles (equations 131 and 132) . The reaction proceeds via a metalla-aza-Claisen rearrangement, where the dimethylhydrazone anion behaves as an aza-allylic system . 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

Few additions have been attempted using imines prepared from heterocyclic aldehydes and heterocyclic amines. In the one example reported l-(3-pyridyl)-5-(2-quinolyl)-l,2,3-triazoline is obtained in 70% yield after 21 hr.329... 

Lactone 7 (derived from D-isoascorbic acid) reacted readily with the aryllithium formed from bromide 8 to produce lactol 9 (Scheme 16.3). The latter underwent a facile ring-opening and Wittig olefination with methylenetriphenylphosphorane to give 6 in excellent overall yield. After 0-trifLation, a two-carbon chain extension was performed on 10 with the azaenolate derived from A-cyclohexylacetaldimine 11 and lithium diisopropylamine (LDA). After acid hydrolysis of the product imine, aldehyde 12 was isolated in 83% yield for the two steps. The (2-azaallyl)stannane 5 was prepared from aldehyde 12 in quantitative yield by treatment with (aminomethyl)tri-n-butylstannane. 

Imine anions are superior to the corresponding enolate anions of the parent carbonyl compounds in alkylation reactions because they give only monoalkylated products of predictable regioselectivity. They can be prepared from aldehyde imines as well as from ketone imines by deprotonation with EtMgBr, LDA, or t-BuLiA ... 

An efficient, versatile protocol for the synthesis of highly enantioenriched a-aminophosphonate has been devised. The addition of lithium diethyl phosphite in THF at room temperature to imines prepared from methyl and methoxymethyl (MOM) ethers of (7 )-(-)-2-phenylglycinol and a wide variety of aldehydes has been explored. The reaction generates predominantly the (R,R) diastereomers whose hydrogenolysis produces a-aminophosphonates in good yields (Scheme 8.67). 

Aliphatic aldehydes reacted with amines and silyl enolates to give the corresponding b-amino esters in high yields. In some reactions of imines, it is known that aliphatic enolizable imines prepared from aliphatic aldehydes gave poor results. 

The imines derived from vicinal dicarbonyl substances afford cis-lactams (Scheme 2), whereas the imines prepared from aryl and alkenyl aldehydes yield trans-lactams (Schemes 3 and 4). The different basis for the stereoselection in the carbonylative cycloaddition from that of the usual base-induced process is worthy of anphasis. The mechanism of this carbonylative formal [2 + 2] cycloaddition is discussed in comparison with the results of the base-induced ketene-imine cycloaddition,... 

In conclusion, we have prepared, for the first time, chiral yV-aluminum- and N-trimethylsilyl imines starting from aldehydes and nitriles. These compounds represent interesting starting materials for the preparation of a variety of biologically active nitrogen containing compounds. 

Arylmethylamines can be oxidized to the corresponding arylamides by formation of a Schiff base with 2,6-di-t-butylbenzoquinone and base-catalysed oxygenation. Allenic alcohols are oxidized to allenic amides by nickel peroxide at -20 °C in ethereal ammonia. N-Alkyl-amides can be prepared from aldehydes in a four-step procedure consisting of imine formation and subsequent reactions with N-chlorosuccinimide, potassium cyanide, and finally alcoholic HCl. ... 

Nitriles can be prepared from aldehydes by a two-step procedure that involves formation of an imine with NH2OH, followed by dehydration with SOCI2. Show the mechanism of the reaction. 

Diastereoselective Pictet-Spengler reactions of imines prepared from tryptophan esters have been studied in great detail by Cook [9, 128, 129], The resulting trans-substituted tetrahydro-/l-carbolines have formed the cornerstone of numerous total syntheses of alkaloids. As shown in Scheme 11.25, treatment of tryptophan derivative 155 with aldehyde 156 under acidic conditions afforded 157 as a single diastereomer in 95% yield [129]. This functionalized tricyclic structure was subsequently elaborated into (-)-cory-nantheidine (158). 

A number of imine derivatives have been prepared as amine protective groups, but most of these have not seen extensive use. The most widely used are the ben-zylidene and diphenylmethylene derivatives. The less used derivatives are listed, for completeness, with their references at the end of this section. For the most part, they are prepared from the aldehyde and the amine by water removal cleavage is effected by acid hydrolysis. 

Imine formation from such reagents as hydroxylamine and 2,4-dinitro-phenylhydrazine is sometimes useful because the products of these reactions— oximes and 2,4-dinitrophenylhydrazones (2,4-DNPs), respectively—are often crystalline and easy to handle. Such crystalline derivatives are occasionally prepared as a means of purifying and characterizing liquid ketones or aldehydes. 

This review summarizes the best asymmetric methods for preparing epoxides and aziridines from aldehydes (or ketones) and imines. 

Primary and secondary halides do not perform well, mostly because N-alkylation becomes important, particularly with enamines derived from aldehydes. An alternative method, which gives good yields of alkylation with primary and secondary halides, is alkylation of enamine salts, which are prepared by treating an imine with ethylmagnesium bromide in THF ... 

For the addition of an organometailic compound to an imine to give a primary amine, R in RCH=NR would have to be H, and such compounds are seldom stable. However, the conversion has been done, for R = aryl, by the use of the masked reagents (ArCH=N)2S02 [prepared from an aldehyde RCHO and sulfamide (NH2)2S02]. Addition of R"MgX or R"Li to these compounds gives ArCHR"NH2 after hydrolysis. ... 

Double asymmetric induction operates when the azomethine compound is derived from a chiral a-amino aldehyde and a chiral amine, e.g., the sulfin-imine 144 [70]. In this case, the R configuration at the sulfur of the chiral auxihary, N-tert-butanesulfinamide, matched with the S configuration of the starting a-amino aldehyde, allowing complete stereocontrol to be achieved in the preparation of the diamine derivatives 145 by the addition of trifluo-romethyl anion, which was formed from trifluoromethyltrimethylsilane in the presence of tetramethylammonium fluoride (Scheme 23). The substituents at both nitrogen atoms were easily removed by routine procedures see, for example, the preparation of the free diamine 146. On the other hand, a lower diastereoselectivity (dr 80 20) was observed in one reaction carried out on the imine derived from (it)-aldehyde and (it)-sulfinamide. 

The Strecker reaction has been performed on the aldehyde 182 prepared from L-cysteine [86] (Scheme 28). The imine was formed in situ by treatment with benzylamine, then TMS cyanide was added to afford prevalently in almost quantitative yield the syn-diamine 183, which is the precursor of (-l-)-biotin 184. The syn selectivity was largely affected by the solvent, toluene being the solvent of choice. Since the aldehyde 182 is chemically and configurationally unstable, a preferred protocol for the synthesis of 183 involved the prehminary formation of the water-soluble bisulfite adduct 185 and the subsequent treatment with sodium cyanide. Although in this case the syn selectivity was lower, both diastereomers could be transformed to (-l-)-biotin. 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

Amines can react with various carbonyl compounds and their derivatives in aqueous media to give the corresponding imine derivatives. These reactions have been discussed in related chapters. The synthetically most useful reaction of this type is the formation of imines and imine derivatives from the condensation of amines with aldehydes and ketones. Water is an excellent solvent for such condensation reactions. For example, water was found to be an ideal solvent for a high-yield, fast preparation of easily hydrolyzable 2-pyrrolecarbaldimines.23 In the presence of Cu2+, the reaction afforded the corresponding Cu(II) chelates (Eq. 11.19). 

Benzyloxybenzylamine (BOBA) 48 is a new class of an amine support and was prepared from Merrifield resin in two steps [56]. BOBA resin was treated with an aldehyde in the presence of an acid to give an imine that subsequently reacted with Yb(OTf)3-catalyzed silyl enolates (Scheme 18). Cleavage with trimethylsilyl triflate (TMSOTf) or 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) gave either phenols or amines, respectively. 

Besides the domino Michael/SN processes, domino Michael/Knoevenagel reactions have also been used. Thus, Obrecht, Filippone and Santeusanio employed this type of process for the assembly of highly substituted thiophenes [102] and pyrroles [103]. Marinelli and colleagues have reported on the synthesis of various 2,4-disubstituted quinolines [104] and [l,8]naphthyridines [105] by means of a domino Michael addition/imine cyclization. Related di- and tetrahydroquinolines were prepared by a domino Michael addition/aldol condensation described by the Hamada group [106]. A recent example of a domino Michael/aldol condensation process has been reported by Brase and coworkers [107], by which substituted tetrahydroxan-thenes 2-186 were prepared from salicylic aldehydes 2-184 and cycloenones 2-185 (Scheme 2.43). 

These authors also found that the addition of excess MgO during the in situ preparation of allyltantalum species improved reaction outcomes, even allowing for the first example of allylation of imines derived from aliphatic amines and aliphatic aldehydes (prepared in situ at room temperature in the presence of molecular sieves) (Equation (18)). The selective addition to imines permitted three-component reactions. 

---