Acid chloride-imine method

Among the most suitable methods for the synthesis of appropriately substituted monocyclic P-lactams [16], the chlorosulphonylisocyanate-alkene approach, the acid chloride-imine method, the ester enolate-imine condensation and the hydroxamate approach have received considerable attention in P-lactam synthesis. 

The acid chloride—imine method [48] has resulted in numerous new 0-lactams during the past decade [49,50]. In the attempted synthesis of I-aza-octam analogues of cephalosporins, the Macetylated tetrahydropyrimidines (89) were used as imine components [46] and different acid chlorides as ketene precursors in the presence of Iriethylamine (TEA). 

Scheme 2 Acylation of the Imine 2 by the Acid Chloride/Pyridine Method ...

Another occasionally used method for the preparation of acyclic A-(l-alkoxyalkyl)amides (or carbamates) proceeds via addition of reactive carboxylic acid derivatives to aldimines. In a one-pot procedure, treatment of the imine with the acid chloride (or ethyl chloroformate) and subsequent (m)ethanolysisofthe intermediary a-chloroamide leads to the oc-alkoxyamide56-58. 

A new copper-catalyzed reaction involving imines, acid chlorides, and alkynes has been applied to the synthesis of propargyl amides 160 in a single operation by Arndtsen and co-workers. The same method allows the synthesis of N-carbamate-protected propargylamines [149]. a-Substituted amides 161 may also be prepared under palladium catalysis by substituting alkynes for vinyltin (Scheme 8.71) [150]. 

The second method, referred to as the decarbonylation reaction, concerns a base-catalyzed elimination of HC1 and CO from an acid chloride.31 The amide moiety was converted into the amino acid 15 by reaction with Na202 in water.32 Alternatively, amides can be converted into the corresponding carboxylic acid by treatment with concentrated HC1.33 However, this method produced lower yields as a result of some decomposition. The carboxylic acid 15 was treated with the Vilsmeier reagent and triethylamine furnishing the imine 16 via decarbonylation. The imine 16 was then converted, in a similar manner to the retro-Strecker method, to the unprotected homoall-ylamine 17 in 75% overall yield and an ee of 98%. 

In a similar heterocyclic quinodimethane ring construction strategy, the hexacyclic adducts (64) were isolated in good yield upon condensation of appropriately functionalized indole imines with ( )-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid chloride (Equation (35)) (88JA2242). In a demonstration of the utility of this new method for indole alkaloid synthesis, further transformations conducted on compound (64 R = R2 = H, R3 = Et) were shown to lead to ( —)-16-methoxy-tabersonine. 

The synthetic importance of reaction (a) ° comes from the fact that it reduces to one step the pathway for conversion of an acid chloride into a nitrile (instead of the classical and rather inconvenient two-step route via an acid amide). Reaction is an example of a new transformation for aliphatic amines. Previously, there were no methods available for the direct transformation of an amino into a nitro group and the stepwise procedures were too cumbersome to be of practical use. Transformation of a nitro group into a carbonyl is a well-known reaction. Its modification, shown in reaction represents a welcome opportunity to obtain a protected carbonyl group as the immediate result of such a transformation. The viability of the sequential reactions (b) plus (c) enables the employment of a > CHNH2 moiety as a synthetic equivalent to a protected carbonyl group. A one-pot sequence of imine formation and its reduction with sodium triacetoxyborohydride represents a convenient... 

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... 

In addition to heterolysis of compounds of type (2), N-acyliminium intermediates (1) are also obtained by protonation of Af-acylimines (27) and by protonation of enamides or enecarbamates (28). The former method is mainly of theoretical interest, Ixcause /V-acylimines (27) are rather unstable compounds. The latter technique is occasionally applied, although compounds (28) are usually synthesized through elimination of HX from (2). Other preparatively very useful methods for the in situ generation of the N-acyliminium ion are the acid-mediated coupling of an aldehyde (or ketone) with a primary (or secondary) amide or a nitrile, and the thermal reaction between an acid chloride and an imine. ... 

Other methods for the synthesis of l,4-dihydro-l,2,4,5-tetrazines 9 which can be explained by intermediate formation of nitrile imines 8 are the photolysis of 1,2,3-triazoles 2181 and sydnones 3,182 reaction of tetrazoles 4180 with tosyl chloride, elimination of pyridine from the pyridinium compounds 5,189-190 of hydrogen chloride from the hydrazonic acid chlorides 1 s.3-i88 or elimination 0f sulfinate from the a-sulfonyl hydrazone 7.189... 

The addition of an acid chloride to an imine is an important method for the preparation of (3-lactams and is often referred to as the Staudinger reaction. The reaction allows a convenient and mild approach to the -lactam antibiotics and has therefore received considerable attention. Good stereoselectivity in favour of the cis 3,4-disubstituted product is common. For example, the p-lactam 182 was formed in reasonable yield by condensation of the acid chloride 180 and the imine 181 (3.120). The reaction is not thought to be a concerted cycloaddition with the ketene, but to take place via a zwitterionic intermediate. Almost complete asymmetric induction in the synthesis of -lactams by the Staudinger reaction using a chiral auxiliary or a chiral tertiary amine, such as benzoylquinine, has been reported. 

This method is an extension of the known ketene—imine procedure, which has been in use for -lactam formation since the beginning of the century [51]. Examples of this acid chloride - ketene route up to the end of 1971 have been reviewed by Mukerjee and Srivastava [52]. It is interesting to note that, depending upon the experimental conditions, both the concerted 1,2-cycloaddition path and another involving an acylation step and salt formation can be operative [53,54], The former is supported by the formation of by-products of dioxo-piperidine type [55,56]. Use of this procedure has provided a number of azaoctams of type (92) [46]. 

The stereoselectivity of the reaction of ketenes with imines to produce -lactams depends upon the method of ketene generation and different results are obtained in reactions involving acid chloride/NEt versus the photolysis of chromium carbene complexes. ) The complex Cr sC(CH2)2CHMeO (CO)s and aliphatic aldehydes RiR CHCHO bearing a-hydrogen atoms, in... 

An improved method for the acylation of imines with acid chlorides has been reported." "... 

Agawa et al. have modified their earlier synthesis of a-methylene-/3-lactams, which required rather severe, and thus limiting, conditions. The new method incorporates in situ production of the phenylseleno-substituted ketene (180) from the acid chloride. Reaction with imines gave a mixture of cis- and trans-fi-lactams (181) and (182). Oxidation and elimination of the seleno-moiety produced the methylene functionality. 

A new, mild method for acyl exchange in amides involves conversion to the imidoyl chloride, reduction to the imine [LiAl (OBu )3H], and acylation with an acid chloride. ... 

A very detailed report on /3-lactams, both synthetic and natural, has been published." An excellent new method for the synthesis of a-amino-/8-lactams has been described." The central feature of the synthesis is the protection of a-amino-acids as an enamine followed by acid chloride formation and annellation of imines (Scheme 86). Yields are in the region 35—45%. An unusual transformation of mesoionic thiazol-4-ones into /8-lactams has been reported. It is... 

Bell and Hall have incorporated an organometallic unit into a crown by using the ferrocenyl unit as part of the ring or as a third strand. The unit is incorporated either as the 1,1 -diformylferrocene or the corresponding acid. In the former case, the bis-imine is prepared and reduced to give the saturated crown (see structure 24). In the latter case, the acid is converted into its corresponding chloride and thence into the diamide by reaction with a diamine. Diborane reduction affords the saturated amino-crown. Structure 24 could be prepared by either of these methods but the dialdehyde approach was reported to be poor compared to the amide approach which afforded the product in ca. 60% yield . 

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