Imines, reaction with acid chlorides

In order to further understand how this overall transformation proceeds, a series of mechanistic experiments have been performed, in which the catalytic cycle has been broken down into individual steps (Scheme 1). Firstly, monitoring the reaction in situ by H and C NMR clearly reveals that imine 2 with acid chloride 3 react immediately upon mixing, prior to the addition of Pd2(dba)3 CHCl3, bipyridine, or carbon monoxide, to form the N-acyliminium salt 6 (Step A, Scheme 1) (10). The stmcture of 6 can be confirmed by its independent synAesis from imine and acid chloride. The conversion of 2 and 3 to this iminium salt is essentially quantitative by H NMR. 

Many examples of the usual route to /S-lactams via imines and acid chlorides, ketens, or keten equivalents have appeared.These include syntheses of 3-[bis(alkylthio)methylenamino]-2-azetidinones, ° of spiro-azetidinones and bis-azetidinones, and the use of l-methyl-2-halogenopyridinium salts to activate carboxylic acids towards coupling with imines. A non-hazardous alternative route to 3-amido-2-azetidinones, avoiding the use of azidoacetyl chloride, involves the reaction of Schiff bases with salts of [(a-methyl-/3-methoxycar-bonyl)vinylamino]acetic acid, e.g. (20), in the presence of ethyl chloroformate, as shown in Scheme 5. Formaldimines can be generated from their trimers by treatment with Lewis acids immediately prior to reaction with acid chlorides, so allowing the formation of the nocardicin nucleus which is unsubstituted at C-4. ... 

Ester 324 is hydrolyzed to acid 325 by refluxing in 10% NaOH. In a reaction with thionyl chloride, acid 325 is converted to acid chloride 326, which is isolated as a solid in 96% yield and consecutively converted into amide 327 in 85% yield. Treatment of amide 327 with LDA extracts a proton from the methyl group. The generated anion is trapped by added benzonitrile. Subsequent cyclocondensation of the obtained imine anion with the amide group provides derivative 328 in 62% isolated yield (Scheme 50) <2003EJM983>. 

An intramolecular cycloaddition brought about by reaction with acetyl chloride and di-isopropylamine converted the imine 377, presumably via 378, to a mixture of the carbazole 379 and the tetracycle 380 prolonged heating alone or brief treatment of the latter with p-toluenesulfonic acid caused elimination and the formation of 379. ... 

Staudinger reaction of imine 8 derived from 7-oxanorbomenone with 2-alkoxy-acetyl chlorides in the presence of Et3N (toluene, RT), afforded (3-lactams 9 (Scheme 3). These were obtained as single diastereomers, and no traces of the corresponding isomeric exo-(3-lactams were detected in the crude reaction products [50]. It is worth mentioning that this stereochemical outcome of (3-lactam formation with acid chlorides under Staudinger reaction conditions was opposite to the one expected from a simple [2+2]-cycloaddition reaction, which should have taken place from the exo face of compound 8. 

Rink resin derived imines have been reported to give cycloaddition reactions with acetyl chlorides (or equivalent) using triethylamine as the base and dichloro-methane as the solvent at temperature ranging from 0°C to room temperature [70], The resin-bound p-lactam could be cleaved by using 50% trifluoroacetic acid (TFA) in dichloromethane, to afford the /V-unsubstituted p-lactam. 

When irradiated in a microwave oven using chlorobenzene and triethylamine, cis (3-lactams 44 and 47 did not isomerize to trims (3-lactams 43 and 46. These experiments clearly established that there is no isomerization of the cis (3-lactams to the more stable tram (3-lactams during reaction of imines with acid chlorides at a high temperature and under microwave irradiation. Irradiation of 21, 23, and 29 with 17 under identical conditions afforded the trans product 22a, 24a, and 30a as the only isomers. Therefore, the present study clearly indicated that microwave irradiation can accelerate the synthesis of (3-lactams (e.g., see [132-139]). No... 

Intermolecular carbon-carbon bond formation of alkenylsilanes by electrophilic substitution is rather limited except for the reaction with acyl chlorides.1. The alkenylations of imines and epoxides are achieved with electronically activated alkenylsilanes (Equation (3)).2 a Alkynylsilanes have frequently been used for intermolecular alkynylation of carbon electrophiles activated by a Lewis acid.30 30a-30d... 

Lactams are readily prepared by reaction of acid chlorides or bromides with imines in the presence of a tertiary base, usually triethylamine. The method is extremely versatile. Conditions are very mild (inert solvent, room temperature) and sensitive functional groups are tolerated on both the imine and acid chloride partners (equations 2 l-W). " ... 

N-(l-Alkoxyalkyl)-aniides or -carbamates (2 X = OR), most frequently used as stable precursors for A -acyliminium ions, are usually prepared by one of the following routes (equations 7-13). For five- or six-membered cyclic cases a simple acid-catalyzed solvolysis of the hydroxy compound provides the alk-oxy derivative (equation 7). A silicon-assisted approach involves the TMSOTf-catalyzed reaction of bis(trimethylsilyl)formamide with aldehydes (equation 8). /V-(l-Trimethylsilyloxyalkyl)formamides are thus formed in good yields, which on TMSOTf-catalyzed solvolysis lead to the /V-( 1-alkoxyalkyl)form-amides. A third method is based on the NaBH4 reduction of imidates (equation 9), and has proved useful for a total synthesis of the insect poison pederine. Addition of reactive acid derivatives to imines constitutes another method (equations 10 and 11). Acylation with acid chlorides followed by treatment with ethanol in the presence of base leads to N-(l-alkoxyalkyl)amides. A one-step protocol using diethyl dicarbonate provides the corresponding carbamates. 2... 

These studies have shown that the palladium catalyzed coupling imines, CO and acid chlorides is a viable and general route for the synthesis of a new class of peptide-based imidazolines. Mechanistic studies suggest this four-component coupling reaction proceeds via the in situ formation of Miinchnone intermediates, which undergo cyclization with imines in the presence of acid to yield the ob-... 

EXPLOSION and FIRE CONCERNS dangerous fire and explosion hazard extremely flammable liquid NFPA rating Health 3, Flammability 3, Reactivity 1 vigorous or explosive reaction above -70°C with alkyl aluminum chlorides and aromatic hydrocarbons violently exothermic polymerization reaction with aluminum chloride, boron trifluoride, sulfuric acid incompatible or reacts strongly with nitric acid, ethylene imine, ethylenediamine, chlorsulfonic acid, oleum, sodium hydroxide combustion will produce carbon dioxide, carbon monoxide, and hydrogen chloride use carbon dioxide, alcohol foam, or dry chemical for firefighting purposes. 

Primary amines are transformed into amides by substitution reactions of acid chlorides, and to imines by condensation with an aldehyde in the presence of an acid catalyst. Both amides and imines may be reduced to amines amides need LiAlH4, while imines may be reduced by sodium borohydride, sodium cyanoborohydride, or hydrogenation over a palladium catalyst. 

Isomannide (80) was the core for a hexahydrofurofuran library." Primary amines were loaded onto solid-support by reductive amination and acylated with bromoacetic acid to give bromides 79 (Scheme 7.16). Alkylation of bromides 79 on solid-support with isomannide (80) gave the solid-supported alcohols 81. A Mitsunobu reaction with phthalimide (82) proceeded to furnish amines 83 in excellent yield and purity after removal of the protecting group." " Support-bound primary amines 83 were converted to secondary amines by stepwise imine formation with aldehydes 84 and reduction with sodium borohydride." The hindered secondary amines 85 were acylated with acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates to yield 87 after cleavage from solid-support. 

Chemical. A large number of chitin and chitosan derivatives have been synthesized through modification of the primary (C-6) and secondary (C-3) hydroxyl groups present on each repeat imit, including amine (C-2) functionality existing on deacetylated imits (31). Reactions typical of hydroxyl and amine groups (such as acylations with acid chlorides and anhydrides) including urethane and urea formation respectively, are feasible with isocyanates. The primary amine can be quatemized by alkyl iodides or converted to an imine with a variety of aldehydes and ketones that can subsequently be reduced to an N-alkylated derivative. Chitin and chitosan are reactive with a variety of alkyl chlorides after treatment with concentrated NaOH. Important derivatives such as carboxymethylated chitin and chitosan are commonly produced in this manner with the addition of sodium chloroacetate. 

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