Iodophenols are an invaluable class of organic compounds for medical and synthetic applications. In the first part of the Master’s thesis, direct synthesis of mono- and diiodophenols by chemoselective iodination of phenols is explored. The system I$_2$/H$_2$O$_2$/H$_2$SO$_4$ readily introduces iodine atom(s) onto phenols. Reagents are inexpensive and commercially available, 100 % iodine atom economy is enabled, and H$_2$O is the only byproduct. Chemoselectivity is achieved by choice of solvent – employing MeCN results in monoiodination, whereas EtOH effects diiodination. Utilizing our method, 15 phenols were chemoselectively iodinated. Monoiodination of phenols proceeds in 44–82 % yield. Diiodination of 4-alkylphenols proceeds in 67–78 % yield. Tuning the iodination stoichiometry allowed us to prepare four biologically relevant iodophenols: 3-iodotyramine, 3-iodotyrosine, 3,5-diiodotyramine and 3,5-diiodotyrosine, which have valuable applications in proteomics, ADMET studies, synthetic organic chemistry, and radiology.
During our exploration of iodination, formation of biaryl compounds was observed in low yields. Since their formation was unexpected, in the second part of the Master’s thesis we investigated the possibility of utilizing iodophenols in transition-metal-free coupling of aryl electrophiles. Homocoupling of 4-tert-butyl-2,6-diiodophenol (3a) occurs in the presence of 2 eq. of K$_2$CO$_3$ in THF/H$_2$O. The reaction proceeds via a radical chain mechanism. Initiation can be achieved by heating to 35 °C or by employing a substoichiometric amount of I$_2$ at room temperature. Control experiments exclude photochemical initiation or phantom reactivity. Utilizing our method, five biaryls were prepared in up to 79 % yields under transition-metal-free conditions. Heterocoupling of 3a and eight aryl iodides with varying electronic properties were unfruitful – reactions resulted in complete inhibition or homocoupling of 3a. Transition-metal-free heterocoupling of Ar–X electrophiles remains elusive.
Radical trapping experiments employing Ph$_2$Se$_2$ confirmed the radical chain mechanism via a key aryl radical intermediate. Mechanistic probe revealed the radical addition step of Ar· to the phenol ring, followed by radical chain propagation. The role of K$_2$CO$_3$ is phenol deprotonation, whereas I$_2$ mediates single electron transfer. The discovered reaction is the second example of transition-metal-free C–C coupling of Ar–X electrophiles and the first example of described reactivity at room temperature.
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