Amides disconnection

Example Optically active aldehyde (10) was needed for a synthesis of biotin. The compound has a 1,1-dlX disconnection (10a) clearly available and a C-N (amide) disconnection leaving (11) which has the same skeleton as the amino acid cysteine (12). 

Answer Amide disconnection gives chloroformate (7), made from alcohol (8) with COCl (cf p T37). Alcohol (8) is a simple acetylene adduct. 

Amide disconnection reveals (18) and FGl (amino to nitro) gives (19) which could be made by Michael addition of nitro compound (16) to an acrylate ester.. lalys-ts... 

Amide disconnection leaves simple amine (51), available by reductive amination from aldehyde (52). Analysis 2... 

A simple example is the weedkiller propanil 17 used on rice fields. Amide disconnection gives the amine 18 obviously made from 0-dichlorobenzene 20 by nitration and reduction. All positions around the ring in 20 are about the same electronically but steric hindrance will lead to 19 being the major product. 

The morpholine derivative 75 has an obvious amide disconnection to 76 and a less obvious 1,2-diX disconnection at the ether to 77. This is obviously an epoxide 78 adduct with ammonia. 

Indomethacin 87 is a Merck non-steroidal anti-inflammatory. Amide disconnection reveals a simpler indole 88 and the Fischer disconnection gives the two starting materials 89 and 90. 

Ramipril 124, the Hoechst ACE inhibitor, is obviously more complicated. The first amide disconnection is the same and we can see the structure of alanine in the acid 135. The amine 136 looks like proline but no reactions spring to mind to make the bonds corresponding to the disconnections. 

The HIV-protease inhibitors, probably the most successful drugs used to prevent HIV turning into AIDS, are all protein mimics with an unreactive C-C bond replacing an amide link. That bond is marked with a broad arrow in norvir 152, Bristol-Myers Squibb s entry in this class. Amide disconnection reveals that the key central part of the molecule 154 looks like a phenylalanine dipeptide except that it has the C C bond. So can we make 154 from phenylalanine 4 ... 

The oxazolidinones, general structure 213, such as the Upjohn compound U100766, 213 R = morpholine, are antibiotics that act by a different mechanism to all others. Amide disconnection takes us back through amine 214 and azide 215 to alcohol 216. 

There is a 1,4-relationship both between the chiral centres on the ring and between those on the side chain and the nearer on the ring. This makes the ester and amide disconnections shown on 321 attractive giving three starting materials. 

An impressive application is the total synthesis28 of the anti-tumour antibiotic (+)-macbecin I 163. The amide disconnection is obvious and the decision to make the amino quinone from an aromatic nitro compound 164 sensible. Less obvious is the synthon 165 as the anion at C-14 could be an allyl silane but the further disconnections of 165 all correspond to allyl silane chemistry. 

Bonds between carbon and various heteroatoms (e.g. O, N, S, P) which are easily generated synthetically are strategic for disconnection. Specific bonds in this category are ester, amide, imine, thioether, and acetal. 

Amine (1) was needed to study the stereochemistry of alkylation reactions. The primary alkyl group had best come from an amide or an Imine while the secondary alkyl group must come from an imine. The disconnections may be carried out in any order. 

Answer Disconnection oi the amide reveals secondary amine (4). This can be distonnected in various ways using reduction of amides (benzyl side only) or imides (either side). Again the order doesn t matter. 

Disconnecting one of the C-N bonds around the tertiary amine will help (a) is not possible, (b) would be possible after FGl to the amide but (c) separates the two nitrogens and requires the easily synthesised (16) as intermediate. We shall follow (c). Analysis... 

Kswer The primary amine might come from an amide or a cyanide, e.g, (18) a 1,3-diX disconnection (reverse Michael) is then excellent. 

AnsweT We wish to disconnect the ring-chain C-N bond but we must first go back to amide (6) to make the synthesis reliable (Chapter 8). 

Amide (1) was needed for a synthesis of an isoquinoline. Disconnecting the amide reveals the amine (2) which could be made by reduction of an unsaturated nitro compound. The a, -disconnection is simple. 

Disconnecting the amide reveals an amine (9) with two hydroxyl groups both positioned so that the corresponding nitro compound (10) could be made from nltromcthane and two aldehydes. 

Two atoms ( in 27a) occupy positions between a benzene ring and the nitrogen atom. Disconnection might be to an aldehyde, via C28), or an amide (e.g, 30). 

The initial retrosynthetic analysis of 1 resulted in the cleavage of the two amide bonds and a C-N bond leading to the four components oxadiazole carbonyl chloride 2, methyl iodide, 4-fluorobenzylamine (4-FBA) and the densely functionalized hydroxypyrimidinone 3 (Scheme 6.1). These synthetic disconnections were reasonable and should be applicable for long term route development. 

Bimolecular reactions of aniline with /V-acyloxy-/V-alkoxyamides are model Sn2 processes in which reactivity is dictated by a transition state that resembles normal Sn2 processes at carbon. Electronic influences of substituents support a non-synchronous process which has strong charge separation at the transition state and which is subject to steric effects around the reactive centre, at the nucleophile but not on the leaving group. The sp3 character of nitrogen and disconnection between the amino group and the amide carbonyl renders these reactions analogous to the displacement of halides in a-haloketones. 

The physical and spectroscopic properties of /V-acyloxy-A-alkoxyamides confirm pyramidality at nitrogen and the disconnection of the nitrogen lone pair from the amide carbonyl. The presence of an acyloxyl and an alkoxyl group at nitrogen also results in an anomeric interaction between the oxygens, which is facilitated by the sp3-hybridised nitrogen. Experimental observations, including X-ray analysis are fully supported by results from computational chemistry. 

The burner is now extinguished, the ammonia shut off, and the pot cover removed by disconnecting at H, H. The crucible is removed from the pot with tongs, and the molten amide is poured into a shallow iron tray, which has been previously heated to remove traces of moisture (Note 8). At this point it is essential to work rapidly to avoid solidification of the amide in the crucible (Note 9). As soon as the product has solidified sufficiently, the tray is transferred to a large desiccator to cool. When cold enough to handle, the tray is inverted on a clean heavy paper the amide is removed by rapping the bottom of the pan and is at once transferred to convenient wide-mouthed bottles and covered with a petroleum fraction (Notes 10 and n). The yields vary from 267 to 282 g. (90-95 per cent of the theoretical amount) (Notes 12,13, and 14). 

Such an operation represents, in the synthetic sense, the classical Williamson reaction (or its r/j/o-equivalent in the case of sulphur). However, with amines, in order to avoid polyalkylations, a FGA must be carried out beforehand, introducing a carbonyl group (=0) at the p.ro-position, and proceeding then to the ipso-disconnection to afford the amine and an acyl derivative -as an acid chloride, for instance-, since in the synthetic direction monoacylations can be easily controlled owing to the deactivation of the resulting amide, which prevents further acylations. In practice, the amide can then be reduced by UAIH4. As an alternative solution, a... 

In the particular case in which the carbonyl group belongs to a carboxylic acid derivative, such as an ester (17) or an amide (18) (or other functional groups which may be converted into it by a FGI), then they may be disconnected according to the "orthoacetate-modification" of the retro-Claisen rearrangement (Schemes 7.7 and 7.8) developed mainly by Eschenmoser [7] and Ziegler [8], independently, in the synthesis of alkaloids, and Johnson in a very simple and yet highly stereoselective synthesis of squalene [9]. 

We were interested in applications of the high level of stereocontrol associated with the asymmetric Birch reduction-alkylation to problems in acyclic and heterocyclic synthesis. The pivotal disconnection of the six-membered ring is accomplished by utilization of the Baeyer-Villiger oxidation (Scheme 7). Treatment of cyclohexanones 25a and 25b with MCPBA gave caprolactone amides 26a and 26b with complete regiocon-trol. Acid-catalyzed transacylation gave the butyrolactone carboxylic acid 27 from 26a and the bis-lactone 28 from 26b cyclohexanones 31a and 31b afforded the diastereomeric lactones 29 and 30. ... 

The bourgeoning interest in twisted or atypical amide linkages has resulted in a need to better understand the chemical and physical consequences of disconnection between the amide nitrogen lone pair and its carbonyl. To this end, Mucsi and coworkers recently defined a new amidity index, which shows some promise in quantifying relative amide character . 

A C—N disconnection of a primary amine gives rise to the carbocation and amide anion synthons. It might be predicted therefore that treatment of an alkyl halide with ammonia (reagents equivalent to the above synthons) under pressure would constitute a suitable synthesis of a primary amine. In practice, however, the yield is poor since a mixture of all three classes of amines, together with some of the quaternary ammonium salt, is obtained, owing to more ready further alkylation of the sequentially formed products. 

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