- Malaria Research
- Schisto Research
- Toxoplasma Research
- Tuberculosis Research
- General Open Research
- Getting Started
- Resources Needed
Thienopyrimidine complexities, Electrophilic aromatic quandaries and Suzuki concerns
Communitymalaria research community
Jim Cronshaw from the Todd Laboratory at the University of Sydney here again for my two monthly update.
Previously I had reported puzzlement at why the proton at the 6-position of the thieno[3,2-d]pyrimidine (aka: the α position) was proving difficult to remove with BuLi. Both n and s BuLi had been utilised at different temperatures to no effect: That proton was not going to removed. When the nitrogen was masked with a morpholine group a different story emerged. Treatment of this substrate with n-BuLi followed by iodine lead to the iodination of the desired position alongside extensive decomposition (Scheme 1).
Scheme 1: Iodonated Morpholine derivative
Interestingly, the ESI mass spectrum of this compound showed a peak corresponding to the following compound:
Figure 1: Iodonated Thienopyrimidine
Based upon this information, it was thought that perhaps the thienopyrimidine with a hydroxyl group at the 4-position might be suitable for iodination. This turned out to be the case, and the iodinated product (6-iodothieno[3,2-d]pyrimidin-4-ol) was synthesised in 30% yield (Scheme 2).
Scheme 2: Iodonated Thienopyrimdine
The ability of this reaction to proceed shed some light on why the earlier reaction, involving proton removal in the presence of the amine, didn’t work. Assuming that the above thienopyrimidine ring exists in its tautomeric keto form (as shown), then the pKa’s suggest that the proton on the 1-position of the thienopyrimidine ring shown in Figure 2 ought to be more acidic than the amine protons of thieno[3,2-d]pyrimidin-4-amine (Figure 2).
Figure 2: pKa's of relevant protons
Though the iodinated thienopyrimidine was now in my possession, I was still unsure as to where the substitution had taken place. Conventional wisdom would dictate that the substitution occurred at the 6-position, but a summary of the chemistry of thienopyrimidines indicated that thieno[3,2-d]pyrimidines are particularly reactive at the 7-position. Two lines of investigation were employed to determine where the substitution had occurred.
First, 2D NMR studies (HSQC and HMBC) were utilised. Known values for the chemical shifts of substituted carbons in thiophene rings were necessary to make a definitive judgement on where the substitution had occurred. Without these, no judgement with any certainty could be passed. An X-ray crystal structure would be needed.
An alternative way of iodinating the thiophene ring was desired to avoid the harsh conditions of the above reaction and to improve the yield. A series of experiments (Figure 3) based on reactions found in the literature were attempted but to no avail: The BuLi reaction was the only means of iodinating the thiophene ring.
Figure 3: Alternative methods of halogenation
The next step in the synthetic plan involved treating this iodinated thienopyrimidine with POCl3, but unfortunately this reaction lead to decomposition of starting material. It was thought that using bromine in place of iodine might lead to better stability. In addition, brominated aryl rings are more frequently used in Suzuki couplings (the next step in the synthetic plan). This offered additional incentive to pursue a brominated thienopyrimidine.
Surprisingly, treating 6-iodothieno[3,2-d]pyrimidin-4-ol with bromine lead to the recovery of starting material. So too did attempts utilising 1,2-dibromoethane. Treating 4-chlorothieno[3,2-d]pyrimidine with n-BuLi and bromine lead to the synthesis of a brominated thienopyrimidine ring in 50% yield (Scheme 3).
Scheme 3: Brominated 4-chloro thienopyrimdine
Suzuki reactions were attempted next, and these form the crux of my problem right now. Reactions substrates and conditions are shown below in Table 1.
Table 1: Suzuki Reactions
Once purified, only two of these reactions have yielded products that appear interesting (reactions C and F).
It’s interesting that none of the para-isomers of the boronic ester have given products that appear reasonable for this reaction. It’s also quite fortunate, since the compound that I’m interested in (reaction F) involves the meta-isomer. The typical problematic 1H-NMR spectrum is shown below. (Figure 4). The top spectrum shows peaks that are associated with the desired product (Reaction C), and the bottom spectrum shows peaks that are associated with an undesired product (Reaction D).
The primary question that needs to be solved right now is,
Why aren’t these Suzuki reactions giving the desired products? What can be done to improve the situation? What is shown in that 1H-NMR spectrum?