EJECUCIÓN DE LA FASE DE REPORTES, LIMPIEZA Y

For a number of reasons, the initially chosen starting point to gain access to hydrophilic phthalocyanine analogues was the use of 5-ethynylisophthalic acid esters 29 (Fig. 17) as starting materials for the diketone synthesis. Firstly, previous experience has shown that sufficiently bulky substituents on the peripheral phenyl rings can be a way to deter aggregation of alkynylphthalocyanine analogues. Secondly, while derivatised as appropriate esters, the intermediates should maintain sufficient lipophilicity to allow standard work-up procedures in all steps. The hydrophilicity can then be conferred onto the chromophore at the final stage of the synthesis by a simple saponification. Thirdly, the carboxylic acid groups should provide options for further fimctionalisation, if required, for instance by the formation of amides.

H

RO2C

29

Fig. 17: 5-Ethynylisophthalic Acid Esters

Dimethyl 5-ethynylisophthalate^®*^ 29g and di-^grf-butyl 5-ethynylisophthalate 29h were prepared in three steps fi-om 5-iodoisophthalic acid (Scheme 35). Refluxing 30 in thionyl chloride generated the corresponding bis-acyl chlorides, which were not isolated but converted directly to dimethyl 5-iodoisophthalate^^®^ 31g and di-fgrr-butyl 5-

Results and Discussion 60

iodoisophthalate 31h by treatment with methanol or potassium ferr-butoxide, respectively. The acetylene moiety was then introduced employing a Sonogashira-type coupling with trimethylsilylacetylene catalysed by dichloro-bis(triphenylphosphine)- palladium(II) and copper(I) iodide in toluene/triethylamine.^^*^ These reactions were found to proceed extremely well at ambient temperature affording 5- (trimethylsilylethynyl)isophthalic acid esters 32g and 32 h in excellent yield. The free terminal acetylenes 29g and 29h were obtained in good yield by separately treating compounds 32g and 32h with potassium carbonate in THF/methanol solutions at room temperature (Scheme 35). I HO2C CO2H 30 1. SOCI2 2. MeOH (31 g) terf-BuOK (31h) RO2C -S iM e. (PPh3)2PdCl2, Cul SiM©-: H CO2R PhMe, EtgN, r.t. K2CO3. MeOH, RO2C THF, r.t. CO2R 31g: R = Me, 81%^®°’ 31 h: R = ferf-butyl, 74% 32g: R = Me, 98% 32h: R = fe/t-butyl, 97% RO2C 29g; R = Me, CO2R 88% 29h: R = fe/t-butyl, 89%

Scheme 35: Synthesis of 5-Ethynylisophthalic Acid Esters 29

However, whereas phenylacetylene itself and simple alkyl-substituted phenylacetylenes proved to be good precursors for the preparation of acetylenic diketones 13b - 13d (Scheme 14), the phenylacetylene-derived carboxylic acid esters 29 did not react accordingly. Upon treatment of 29g and 29h with butyllithium at 0 ®C in THE, a deep purple solution was obtained, which, when reacted further with copper(I) bromide and oxalyl chloride (Scheme 12) only led to the recovery of a fractional amount of starting

material along with other unidentifiable products (Scheme 36), The same results were obtained when the reaction was conducted at -78 °C. The use of different bases {tert-

butyllithium, methyllithium) did not give better results either. Several scenarios are imaginable for the failure of this reaction. The deep purple colour, which appears instantly after the addition of a trace of base even at - 78 ®C, might indicate the formation of a charge-transfer complex, altering the chemical behaviour of the acetylene. However, when the reaction is quenched at this stage vrith trimethylsilyl chloride, the formation of the corresponding silylacetylene 32 is observed, hence the lithium acetylides derived fi-om 29g, 29h must be formed. It is possible that these, in turn, could react with the electrophilic carbonyl groups of the esters, although it was thought that at least the tert-

butyl ester should provide enough steric bulk to prevent the nucleophilic attack of the acetylide. Another plausible explanation might be that the electron-withdrawing ester fimctionalities decrease the nucleophilicity of the intermediate copper acetylide, causing it to fail to attack oxalyl chloride.

R2 Ri 1. BuLi 2. CuBr, 2 LiBr 3. 0.5 (C 0 C I ) 2 THF, 0 °C , 15m in 29g; Ri = C02Me, R2= H 29h: Ri = CO2BU, R2= H 33: Ri — H, R2 — CO2B11

Scheme 36: Unsuccessful Attempts of Diketone Syntheses

To probe whether phenylacetylenes bearing fewer electron withdrawing substituents would give more satisfying results, the reaction was attempted with a mono-carboxylated phenylacetylene, namely tert-huty\ 4-ethynylbenzoate 33.^^^^ In this case, the reaction of the acetylene with butyllithium did not give rise to a purple colour, and after reaction

Results and Discussion 62

with copper(I) bromide and oxalyl chloride a yellow solid was obtained. This was, however, a complex mixture and the desired product could not be isolated or unambiguously identified (Scheme 36).

These negative results suggest that the deployment of carboxy-substituted phenylacetylenes is not compatible with the established reaction conditions of the dialkynyl dione synthesis. A solution to this problem could be envisioned by the protection of the carboxy groups as or^Ao-esters^^^^ which display an entirely different electronic behaviour (they are not electrophilic and not electron withdrawing), but this idea was not pursued further in the course of this work.

An alternative approach to access the envisaged carboxylated dyes was also examined. It was thought that the isophthalic acid ester could be introduced at the stage of the pyrazine or quinoxaline, respectively, using a Sonogashira coupling reaction (Scheme 37).^^^^

COgR RO2C N . X N RO2C N CN _RO2C 31 N CN CO2R

Scheme 37: Retrosynthetic Analysis for the Preparation of Dicarboxyalkylphenyl Substituted 2,3-Dicyano-5,6-diethynylpyrazine

The required 2,3-dicyano-5,6-diethynylpyrazine 161 and 6,7-dicyano-2,3-diethynyl- quinoxaline 251 should be accessible fi-om the corresponding triisopropylsilyl-protected derivatives 16a and 25a, respectively, by protodesilylation with tetrabutylammonium fluoride (TBAF).'’^'

However, all attempts to obtain the deprotected acetylenes 16i and 25i were ill-fated. The treatment of compound 16a in a moisturised, deoxygenated solution in THF at - 78 °C led to the decomposition of the starting material within seconds (monitored by TLC), but no identifiable product could be isolated. Similar results were obtained for the quinoxaline 25a (Scheme 38). The protodesilylation of diketone 13a to access the parent dione 13i was equally unsuccessful under these conditions, which is in agreement vsdth previous results. It suggests that either the respective fi’ee terminal acetylene derivatives or their acetylide intermediates are unstable compounds, hence this approach was deemed unfeasible under the conditions investigated.

16a or 25a TBAF, wet THF _______ A______ // -7 8 °C N . X N N 'CN CN (/■-PrlgSi O 13a

.Si(/-Pr) 3 TBAF, wet THF

f ^ -7 8 °C H O O 13i H

Results and Discussion___________________________________________________ M