Orthoamide

Scheme 6.17 gives some examples of the orthoamide and imidate versions of the Claisen rearrangement. Entry 1 applied the reaction in the synthesis of a portion of the alkaloid tabersonine. The reaction in Entry 2 was used in an enantiospecific synthesis of pravastatin, one of a family of drugs used to lower cholesterol levels. The product from the reaction in Entry 3 was used in a synthesis of a portion of the antibiotic rampamycin. Entries 4 and 5 were used in the synthesis of polycyclic natural products. Note that the reaction in Entry 4 also leads to isomerization of the double bond into conjugation with the ester group. Entries 1 to 5 all involve cyclic reactants, and the concerted TS ensures that the substituent is introduced syn to the original hydroxy substituent. 

The orthoamide 40 reacted smoothly with 4-alkoxybenzyl bromide 208 to give the alkylated salt triazamacrocycle 209 <2000CC955> in almost quantitative yield (Scheme 32). ... 

Conformational analysis of orthoamides has been previously discussed <1996CHEC-II(8)967> and calculations of reactivity for systems containing a bridgehead nitrogen are generally consistent with experimental observations <1984CHEC(4)443>. 

The immediate precursor retains the 06-C3 bond and would have a C8-06 bond and a C8=C9 n bond. This calls for an SnI substitution at C8 to replace the C8-OMe bond with a C8-06 bond and an El elimination to make the C8=C9 k bond. The overall reaction is an orthoamide Claisen rearrangement. 

For the preparation of cephems from a protected t-butyl ce-methoxygly-cinate thioamide and an orthoamide, an azathiadiene was formed which afforded the 1,3-thiazine derivative after cycloaddition of acrolein (Scheme 42) (89JOC2889). 

The parent compound of this series (13, R = H) is readily synthesized by treatment of DAMN with orthoformates at 80-150°C under basic catalysis (Scheme 5) (50USP2534331). Orthoamides (74JOC2341), dime-thylformamide/POClj (74JOC2341), or even HCN/NHj (68JOC642) can be used in place of orthoformates. In a similar fashion, 2-alkyl or 2-aryl... 

Previous studies had indicated that, in general, although some differences were sometimes observable, the products formed by photobromination of carbohydrate derivatives using bromine or yV-bromosuccinimide were similar. When compound 31 or 32, however, was treated with the latter reagent, a major difference was found, and the main product (74% isolated) was the orthoamide 35, formed, it was concluded, by way of the bromides 33 and 34 and, thence, a cyclic 3,4-benzoxonium ion.35 Support for this route was obtained by observing that treatment of a mixture of the bromides with yV-bromosuccinimide in refluxing carbon tetrachloride without irradiation resulted in their complete conversion into the orthoamide 35. yV-Bromoacet-... 

Reaction of the ribofuranose ester 36 with jV-bromosuccinimide again resulted in C-4 substitution, to give the bromides 37 and 38 in the ratio of 3 2, and compound 35 and close analogs remain the only orthoamides encountered during these studies. 

Further experimental evidence supporting the principle of stereoelectronic control in the cleavage of hemi-orthoamide tetrahedral intermediates has been obtained from studies on the carbonyl-oxygen exchange during the basic hydrolysis of amides, and from the hydrolysis of imidate salts. These experiments are described next. 

Carbonyl-oxygen exchange has been observed in the course of the basic hydrolysis of primary amides (23, 24). The exchange, observed by using Relabeling (0 = occurs vi a a tetrahedral hemi-orthoamide intermediate... 

When a hemi-orthoamide tetrahedral intermediate exists in the T ionic form, the amide ion is not ejected previous to protonation by the solvent, to give the secondary amine. The formation of an amide ion 24-25 is a process so high in energy, that both the protonation and the ejection processes must be synchronized 24 - 26 - 27 (28). This means that in aqueous solution, the nitrogen electron pair must first be hydrogen bonded with the solvent, so that the group can leave as a secondary amine. 

The stereoelectronically controlled reaction of hydroxide ion with an anti imidate salt (62) must give the hemi-orthoamide conformer 60 where the nitrogen and the oxygen of the OR group have each an electron pair anti peri -planar to the C -OH bond also, the 0 —R bond and the N —R bond which were anti peri planar to the C-R bond in anti imidate salt 62 remain in the same relative orientation in intermediate 60. 

Stork, Jacobson, and Levitz (51) have recently reported that the reaction of the lithium carbanion 234 with benzaldehyde followed by reduction with sodium borohydride gave the phenylcarbinol 235. The sequence of events in the transformation of 234 to 23S was shown to be as depicted below. Convincing spectral evidence was obtained for 236, 238, and 239. Thus, the hemi-orthoamide tetrahedral intermediate 237 which was generated in situ gave the ami nobenzoate 238, the expected product from stereoelectronic control. 

The chemical shift of the methine proton in orthoamide 223 is 2.3 ppm. It is therefore at a much higher field than that of orthoamide 122. This remarkable difference of 2.7 ppm can be ascribed to a dramatic stereoelectronic effect. The origin of the unusual spectroscopic properties of orthoamide 123 presumably is the antiperiplanar relationship of the central C-H bond to the three lone pairs. This arrangement permits mixing of the lone pair orbital with the antibonding orbital of the central C-H bond (a ). As a result, the electron density at the methine hydrogen increases and the central C-H bond is weakened. Indeed, this hydrogen has a notably small chemical shift. 

The orthoamides 122 and 123 are therefore completely different one adopts a conformation in which the central C-H bond is synperi pi anar to the adjacent lone pairs (122A) while the other takes a conformation in which the central C —H bond is antiperiplanar (123A). These two compounds are there-... 

Orthoamide 123 cleanly reduced mercuric acetate in ethanol at 25°C to mercury or mercurous acetate. The organic product formed is guanidinium salt 129 lX= OAc). Similarly, iodine in methanolic potassium carbonate at 25°C oxidized orthoamide 123 to guanidinium iodide 129 (X= I). On the other hand, orthoamide 122 does not react with mercuric acetate even in boiling ethanol. Syn-elimination of mercury and acetic acid from complex 130 must be slow but anti-elimination from complex 131 (Y= l or HgX2) must occur readily. 

The low reactivity of the central carbon-hydrogen bond in orthoamide 123 was explained in two ways (82) ... 

Halogenation of ketones, 275 Hemi-orthoester, 63 Hemi-orthoamide, 103-105 Hemi-orthothioamide, 144 Hemi-orthothiol esters, 93-97 Hinesol, 250... 

In cases where Y is an alkoxy group, there is the possibility of forming either an ester or an amide function, and the proportion of each will depend on the conformation of the tetrahedral intermediate. The nine different gauche conformers for such a hemi-orthoamide tetrahedral intermediate are shown in Fig. 1, and the stereoelectronically controlled cleavages are described in Table 1. 

The ionic state of the hemi-orthoamide tetrahedral intermediate must also be considered (9-12). In acidic medium, the intermediate will exist in... 

Using the equilibrium constants estimated by Guthrie (12) for hemi-orthoamide tetrahedral intermediates (derived from N,N-dimethylformamide and N,N-di-methylacetamide) and the activation parameters described in Table 2, it was possible to obtain the free energy of activation for the breakdown UG ieav) and for conformational change (aG onf) of the tetrahedral interme.-diates derived from the N-benzyl-N-methyl derivatives of formamide, acetamide and propionamide. These values are the following. 

The hydrolysis of imidate salts is a technique to generate in situ hemi-orthoamide tetrahedral intermediates (44), and to observe their breakdown to yield the reaction products under kinetically controlled conditions. Such conditions can be ascertained by verifying that the reaction products are not ihterconverted (amide + alcohol ester +amine) during the reaction. This technique can therefore be used to test the principle of stereoelec-tronic control in the cleavage of tetrahedral intermediates derived from amides. 

A hemi-orthoamide tetrahedral intermediate can take several ionic forms, T+, T, T°, and T, depending on the pH of the reaction medium. In acidic medium, it will exist in the T form, in slightly basic medium (near the pKa of the intermediate, pH =10), it will exist as T and in basic medium (pH >11), as T". In systems where the nitrogen can be readily protonated, T° is neglected since it is rapidly converted into the T form which has a low energy barrier for fragmentation. 

Very unusual reactivity has been observed (82-84) with the tricyclic orthoamides 122 and 123. This can be readily explained on the basis of the stereoelectronic effects due to the three nitrogen electron pairs. 

Treatment of orthoamide 123 with equimolar amounts of aqueous hydrochloric acid yielded the salt 124 from which 123 can be regenerated by neutralization. NMR indicates that salt 124 and bicyclic formamidinium ion 126 interconvert rapidly at 70°C. This is explained by a conformational change from 124 into 125 which permits elimination of the amine group with stereoelec-tronic control (125 126). Finally, addition of excess hydrochloric acid to orthoamide 123 precipitated the bicyclic dichloride 127. 

The Passerini-3CR between bifunctional 6-oxo-4-thiacarboxylic acids and alkyl-isocyanides, in the presence of a catalytic amount of tributylamine, afforded the tetracyclic structure 171, which included the 1,4-benzothioxepin group and an unexpected oxazolidinone ring, with formation of a rare orthoamide group (Scheme 2.62) [94]. 

Although 1,4,7-triazacyclononane was first incorporated into linked macrocyclic systems around three decades ago [7], it was only in 1997 that the corresponding three-ring analogue 1 was synthesised and investigated. The synthesis of 1 [8] (Scheme 1) proceeds from the tricyclic orthoamide derivative of 1,4,7-triazacyclononane 2 [9] and involves reaction with l,3,5-tris(bromomethyl)benzene in acetonitrile in a 3 1 molar ratio followed by base hydrolytic work-up of the product. The addition of excess HBr to the reaction mixture led to isolation of 1 as its nonahydrobromide salt in 76% yield. 

Erhardt, J. M. Wuest, J. D. Transfer of hydrogen from orthoamides. Reduction of protons to molecular hydrogen./. Am. Chem. Soc. 

Scheme 10.18. Monoalkylation of a tricyclic orthoamide derived from 1,4,7-triazacyclononane[81].

The contrasting behaviour of the tricyclic orthoamides [44] and [45] towards triphenylcarbenium tetrafluoroborate has also been rationalized in terms of the necessity of adduct formation in the removal of the tertiary hydrogen (Atkins, 1980 Erhardt and Wuest, 1980). The dominant con-former of [44] has C3v symmetry, so that the central C—H is antiperi-planar with respect to all three nitrogen lone pairs. This hydrogen shows... 

Fig (19) Octalin ketal (163) is converted to kete dithioacetal (164) by the cleavage of ketal function and condensation with carbon disulfide and methyl iodide. Subjection of (164) to the action of dimethylsulfonium niethylide and acid hydrolysis leads to the formation of unsaturated lactone (165).lts furan silyl ether derivative is caused to undergo Diets-Atder reaction with methyl acrylate to obtain salicyctic ester (166) which is converted by standard organic reactions toabietane ether (167). It is converted to aiiylic alcohol (168) by epoxidation and elimination. Alcohol (169) obtained from (168) yields orthoamide which undergoes transformation to amide (170). Its conversion to the previously reported intermediate has been achieved by epoxidation, elimination and hydrolysis. 

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