PROCESAMIENTO DE DATOS DE LA ENCUESTA N° 02 DIRIGIDA A LA POBLACIÓN DE HUÁNUCO:

With an adequate quantity of 147 secured, it was discovered that the desired borodesilylation reaction could not be performed. The reaction in which a solution of 147 in dichloromethane was treated with a solution of boron tribromide, also in dichloromethane, was repeated a number of times. Although the starting material was consumed, none of the resultant mixture of products could be identified and the borodesilylation route to boronic acid 138 was not pursued further.

Considering that the reason for the failure of the borodesilylation route to deliver 138 was not understood, it was perhaps rather ambitious to apply the same reaction to another attempted synthesis of borinic acid 82 from sulfide 132 (Fig. 2.21).

TMSn oTMS

B orodesilyation ? ^

OH

132 82

Figure 2.21: A borodesilylation strategy to borinic acid 82

Additionally, as the ipsoborodesilylation reaction is simply a directed electrophilic aromatic substitution, it might be expected to be retarded by the presence of the adjacent electron- withdrawing sulfone group. However, as other ipsodesilylation reactions have proceeded in the presence of electron-withdrawing groups (e.g. C02H),279 the attempted diborodesilylation of 132 appeared to be worthwhile. However, the two main products

isolated following the reaction between 132 and boron tribromide did not contain boron (as determined by mass spectrometry) and were discarded.

Before completing the study of the borodesilylation reaction, curiosity prompted two final attempts at successfully applying it in two other syntheses. We reasoned that it should be possible to synthesise borinic anhydride 117 and borinic acid 107 (perhaps isolable also as its anhydride) through diborodesilylation reactions performed on sulfide 150 and disulfide 151 respectively (Scheme 2.32). The electron-donating properties of the sulfide or disulfide groups were expected to provide an additional driving force for substitution at the positions occupied by the TMS groups.

Sulfide 150 was synthesised from sulfide 99 by sequential treatment with two equivalents each of w-BuLi and TMS chloride. Disulfide 151 was synthesised by sodium perborate oxidation,280 of the previously prepared thiol 146. However, whilst the addition of aluminium chloride enabled the synthesis of 117 in 48% yield, application of this and other methods only caused the decomposition of the second starting material, 151

Br Br 99 (i) TMS TMS 150 (ii) SH TMS 146 (iii) S-S TMS TMS 151 (ii) S -S 107

Reagents and Conditions: (i) w-BuLi, THF, -70 °C, 30 min, then TMS-Cl, -70^25 °C,

1 h, 61%; (ii) AICI3, CH2CI2, -70 °C, then BBrg, -70^25 °C, 16 h, 47% (of 117); (iii) NaB0 3.4H2 0, Aliquot 336, MeOH, 25 X , 1 h, 73%

Scheme 2.32: Application of ipso diborodesilylation to the synthesis of borinic anhydride 117, and to the attempted synthesis of borinic acid 107

2 .8 .2 Syntheses of Borinic and Borinic acids Derived from Diphenyl Sulfone, Diphenyl Sulfide and Diphenyl Ether

Finally, attention was turned to the syntheses of the two additional sets of compounds described on page 102. Of these, boronic acid 108 had already been synthesised. The related borinic acid (142) was prepared from 2-lithiodiphenyl sulfone and diwopropoxymethylborane, but was found to be unstable (Scheme 2.33). It was therefore stabilised by the formation of its ethanolamine ester (1 5 2).204 Rather frustratingly, this protection could not performed on the crude product, as an intractable viscous yellow oil was formed. Instead the derivatisation was carried out on 142 (following its purification by column chromatography). Although the ethanolamine ester 152 was obtained this way, the yield was disappointingly low (36%).

(i) 0s_.0 ^ (ii)

Me^^'OH

142

Reagents and Conditions’, (i) n-BuLi, THF, -30 °C, 30 min, then B(OPri)2Me, -30 °C, Ih, ->25 °C, 1 h; (ii) ethanolamine, ether, 0 °C, 36% (over two steps).

Scheme 2.33: Preparation of borinic acid 142 and its ethanolamine ester 152

Of the remaining four compounds, it was expected that the two based on the diphenyl ether skeleton (141 and 144) could be synthesised directly from diphenyl ether like the cyclic borinic acid 84. At the time, unfortunately, it proved impossible to obtain a quality solution of j^-BuLi. Therefore, the lithiation of diphenyl ether was attempted using f-BuLi. However, addition of difjopropoxymethylborane to the resulting solution,

afforded, after quenching the reaction, a mixture of the products 147, 153 and 83 (Scheme 2.34). + B. Me' OH 144 (7%) + 153(16%) 83 (33%)

Reagents and Conditions'. f-BuLi, THF, -70—>25 °C, 30 min, then, B(OPr^)2Me, -50 °C, 2 h, then ->25 °C, Ih.

Scheme 2.34: Products obtained from the first attempted preparation of borinic acid 144

In addition to these products, 40% of starting material was recovered intact. Although it is not known how the 2-phenoxyphenol (153) was produced, it would seem that the only way in which the borinic acid 83 could have been generated is by the dilithiation of diphenyl ether and the reaction of the 2,2'~dilithiodiphenyl ether with triwopropyl borate. This could be a contaminant in the diwopropoxymethylborane.

Because of this failure, it was decided to synthesise the 2-lithiodiphenyl sulfide and 2-lithiodiphenyl ether required to make 140 & 143 and 141 & 144, respectively, by lithiation of the appropriate bromo-compounds 154 and 155. The syntheses of these are shown in Scheme 2.35 overleaf. The preparation of the known sulfide 154,^81 was achieved using the method of Hilbert and J o h n s o n . Out of curiosity, another

preparation of 99 was attempted by a modification of this procedure. Although this was successful, only a low yield of 32% was achieved. The 2-bromodiphenyl ether 155 was prepared from 2-aminodiphenyl ether according to a known p r o ce d u r e . 2 8 3

NH2 hs + Br (i). (ii). 154 (48%) (iii) NH2 155 (73%)

a

:o

Reagents and Conditions', (i) H2S0 4(aq.), NaNÛ2, 0-3 °C, then NaOAc; (ii) NaOH, Cu, H2O, 0-5 °C, then ->90 °C, Ih.; (iii) 48% HBr, NaN0 2 , 0-5 °C, then CuBr, 48% HBr, 100 °C, 30 min; (iv) HCl(aq.), NaN0 2, 0-2 °C, then NaOAc.

Scheme 2.35: Preparation o f154, 155 and 99 from aromatic amines

Aryl bromides 154 and 155 were then used to synthesise both the boronic acids 140 and 141 and the borinic acids 143 and 144. Although like 142, these borinic acids were found to be unstable, it proved possible to prepare their corresponding ethanolamine esters (156 and 157) directly from the crude mixtures containing 143 and 144. The preparation of 140,141,156 and 157 are shown in Scheme 2.36.

Br X = S:154 X = 0:155 HO' OH X = S: 140 X = 0 : 141 X = S: 156 X = 0 :157

Reagents and Conditions: (i) w-BuLi, THF, -70 °C, 30 min, then B(OPF)3, -70 °C, 30 min, -70-^25 °C, 1 h, 80% (of 140), 84% (of 141); (ii) n-BuLi, THF, -70 °C, 30 min, then B(OPF)2Me, -70 °C, 30 min, -70-^25 °C, 1 h; (iii) ethanolamine, 2 d, 59% (of 156 from 154), 82% (of 157 from 155).

Scheme 2.36: Preparation of boronic acids 140,141 and protected borinic acids 156