Bromo ortho ester

The first total synthesis of the Stemona alkaloid (-)-tuberostemonine was accomplished by P. Wipf and co-workers. " The installation of the butyrolactone moiety commenced with the preparation of a Weinreb s amide from a methyl ester. The tricyclic methyl ester substrate was exposed to A/,0-dimethylhydroxylamine hydrochloride and Me2AICI and the tertiary amide was isolated in excellent yield. Next, the bromo ortho ester was treated with LDBB in THF to generate the corresponding primary alkyllithium species, which cleanly and efficiently added to the Weinreb s amide to afford the desired ketone. 

Tocopheryl)propionic acid (50) is one of the rare examples that the o-QM 3 is involved in a direct synthesis rather than as a nonintentionally used intermediate or byproduct. ZnCl2-catalyzed, inverse hetero-Diels-Alder reaction between ortho-qui-none methide 3 and an excess of <2-methyl-C,<9-bis-(trimethylsilyl)ketene acetal provided the acid in fair yields (Fig. 6.37).67 The o-QM 3 was prepared in situ by thermal degradation of 5a-bromo-a-tocopherol (46). The primary cyclization product, an ortho-ester derivative, was not isolated, but immediately hydrolyzed to methyl 3-(5-tocopheryl)-2-trimethylsilyl-propionate, subsequently desilylated, and finally hydrolyzed into 50. 

In summary, most of the known synthetic routes to azaadamantanes depend on condensation of an amine or ammonia with a carbonyl compound or equivalent (aldehyde, ketone, ortho ester, acetal) or other active methylene compound, such as nitromethane. The syntheses of 10 and 13 employed bromo intermediates in displacement or addition reactions. 

Substituent effects on the A,u I reaction have been studied by Bender and Chen55. These authors measured the rates of hydrolysis of a series of 4-substituted 2,6-dimethylbenzoates in 9.70 M sulphuric acid at 25°C, and found that the values for the first-order coefficients with 4-methoxy, 4-methyl, 4-unsubstituted and 4-bromo-compounds (5.0, 0.37, 0.033 and 0.01 x I0 4 sec-1, respectively) are satisfactorily correlated by the Hammett equation, following cr+ with a slope p = —3.22. Since the esters are not fully protonated in 9.70 M H2SOj, part of this factor is due to the effects of the 4-substituent on the protonation equilibrium, p for the protonation of substituted benzoic acids is about — l35, but is likely to be considerably smaller for di-ortho-substituted compounds, since the conjugative interaction of the p-substituents with the protonated carboxyl group requires coplanarity with the ring. 

Photolysis of phenyl 2-thenoate leads to a 3 2 mixture of ortho and para Fries rearrangement products (Scheme 109) (74H(2)423). The photolytic rearrangement of a thiolester to a thiopyrone has been investigated with thiophenecarbothioic acid S-aryl esters as substrates (79LA2043). In the case of the 2-carbothioic acid esters, a 3-bromo substituent is necessary for this rearrangement. On the other hand, such a substituent is not necessary for the 3-carbothioic acid derivatives. In both cases, aldehydes may also be formed, sometimes as the main products (Scheme 110). 

The procedure has been extended to the formation of difunctional compounds like 3-methyl-3-butenal diethyl acetal (24%), 1,1-diethoxy-2-butyne (80%), and /3-ethoxyethyl methyl ketone diethyl ketal (92%). A somewhat related reaction is the formation of diethyl acetals of a-formyl esters by treatment of a-bromo esters with zinc and ethyl ortho formate (45 60%). ... 

The reaction is applicable to the formation of m and p-dialdehydes, but not the ortho isomer, from the fcis-(chloromethyl)-benzenes, as well as aldehyde esters, e.g., p-carbomethoxybenzaldehyde, and halo aldehydes, e.g., l-bromo-2-naphthaldehyde. ... 

The total synthesis of the potent protein kinase C inhibitor (-)-balanol was accomplished by J.W. Lampe and co-workers. They took advantage of the anionic homo-Fries rearrangement to prepare the sterically congested benzophenone subunit. To this end, 2-bromo-3-benzyloxy benzyl alcohol was first acylated with a 1,3,5-trisubstituted benzoyl chloride to obtain the ester precursor in 84% yield. Next, the ester was treated with n-BuLi at -78 °C to perform a metal-halogen exchange. The resulting aryllithium rapidly underwent the anionic homo-Fries rearrangement to afford the desired tetra ortho-substituted benzophenone in 51% yield. 

The scope of the reaction is broadened by the use of the tetrahydrophosphepine ligand. In addition to heterocycles that were reactive with PCy3 or cyclohexyl-phobane as ligands, 4,5-dimethylthiazole can be arylated. The scope with respect to the bromoarene partner is also broadened to include electron-rich bromoarenes and heteroaryl bromides such as 3-bromothiophene, 5-bromo-iV-methylindole, 5-bromobenzofuran, and 5-bromobenzothiophene. Functional groups including sulfoxides, chlorides, fluorides, ketones, esters, primary and secondary amides, phenols, anilines, and pyridines can be tolerated under these conditions. Sterically hindered and/or ortho substituted substrates are unreactive, but meta and para substituted substrates are well-tolerated. 

In a related process an ortho bromo ester is coupled with l-tri- -butylstannyl-2-ethoxyethene then acid used to close the ring the example below shows how this sequence is applied to a pyridine ester. 

Smeets et al. synthesized para-siloxyl-substituted o-tolyl bromide and para-ethynyl-trimethyl sUyl-substituted o-tolyl bromide, i.e., l-bromo-2-methyl-4-([[(t-butyl) dimethylsilyl]oxy methyl)benzene and l-hromo-2-methyl-4-[2-(trimethylsilyl)-ethynyl]benzene (Fig. 7) [168]. The oxidative additimi of these aryl halides with Ni (PPh3)4 followed by the addition of two equivalents of dppp ligand yielded 95% Ar/H-terminated polymer chains for the sUoxyl substituent and about 80% Ar/H for the ethynyltrlmethylsilyl substituent. These results, combined with Doubina s results [169] on para-substituted phosphonate esters, confirmed the importance of the presence of an ortho substituent position on the aromatic initiator, irrespective of the presence or absence of a substituent on the para position of the phenyl ring. 

The palladium-catalysed -arylation of ester enolates with aryl bromides has been studied both experimentally and computationally. The effect of the ligand on the selectivity of the a/j9-arylation reactions of ortho- and mcta-bromofluorobenzenes has been described. While / -arylation was predominantly observed with 1-bromo-2-fluorobenzene for a range of biarylphosphine ligands, a-arylation was primarily observed with l-bromo-3-fluorobenzene. It has been shown that electronic factors play a major role in the a// -arylation selectivity, with electron-withdrawing substituents favouring 0-arylation. 

---