Date: 19 December 2024 | Category: News
Authors: Davin Cronly, Megan Smyth, Thomas S. Moody, Scott Wharry, Julia Bruno-Colmenarez, Brendan Twamley, and Marcus Baumann
The Baumann Group at University College Dublin, in partnership with Almac Sciences, have utilised photo-click chemistry, a relatively underdeveloped field of synthesis, to form structurally diverse nitrogen-rich scaffolds that are relevant to the pharmaceutical industry [1]. Of particular note is the exquisite control they had over the reaction conditions afforded through the use of a Vapourtec UV-150 photochemical reactor, where both the wavelength of light and the power used could be adjusted, enabling an elegant, chromoselective, synthetic sequence.
Figure 1: General scheme for the transformation of a tetrazole into either tricyclic pyrazoles or benzotriazepine species
The power of light: exquisite reaction control enables chromoselectivity
In order to generate the key building block that would undergo the photo-click reaction, mono-functionalisation of a benzylic methyl group with NBS was required. Although photobromination reactions have previously been reported in flow mode [2, 3], careful control of the conditions was necessary as the substrate also contained a photo-labile tetrazole species. In this case, passing the tetrazole substrate (MeCN, 0.1 M, containing 1.5 equiv. NBS, 20 minute residence time) through the UV-150 photoreactor equipped with a high-power UVA LED (365 nm, 100 W input power) ensured that the desired monobromination products were formed selectively, with neither degradation of the tetrazole nor dibromination observed, Figure 2.
Figure 2: Functionalisation of the benzylic methyl group with NBS in the presence of a high-power UVA LED (365 nm)
Photo-click reactions: an underdeveloped reaction paradigm
Once the bromination and installation of the requisite alkyne or alkene had been achieved, attention turned to photochemical degradation of the tetrazole ring to give the key nitrile imine that underwent cyclisation with alkenes, alkynes and benzylic amines. An adjustable medium-pressure Hg-lamp (set to 137 W input power) with a low-pass filter, available within the Vapourtec UV-150 photochemical reactor, was used. This set-up allowed rapid screening of reaction variables, such as solvent, residence time and substrate scope, that minimized degradation of the starting materials and formation of side-products. Importantly, it was noted that the Hg-lamp emitted high intensity UVC light, which was sufficient for fragmentation of the tetrazole to form the requisite nitrile imine for the photo-click process and, at the time of writing, there were no high intensity UVC LEDs available on the market, so the Hg lamp/filter combination was invaluable.
Use of an allyl ether tether rapidly led to tricyclic pyrazoles, some of which contained embedded benzoxazine and benzoxazocine moieties. These scaffolds are nonplanar and therefore potentially of interest to medicinal chemists. The use of tethered secondary allyl amines formed more unusual benzotriazepine-based structures which are relatively unexplored in terms of biological activity [4–6].
Photochemistry as a tool for formation of unusual scaffolds
While treatment of tetrazole substrates containing an allyl ether species led to the expected tricyclic pyrazoles, some scaffolds accessed are challenging to prepare through thermal means. Substrates containing an allyl amine furnished benzotriazepines, which were unexpected. This serendipitous discovery has enabled new avenues for exploration of benzotriazepines within drug discovery, as the only other reports of these scaffolds are as oxidised analogues [7].
Overall, the use of the Vapourtec UV-150 photochemical reactor allowed fine control over photochemical reaction conditions due to the ability to vary the light sources within the module. Conditions could be readily tuned, enabling functionalisation of one part of the molecule in the presence of photolabile groups, also known as chromoselectivity, ensuring specific functionality could be accessed. In this case, the ability to switch between LEDs or an Hg-lamp meant that particular functional groups could be targeted, and the reaction outcomes tuned. Finally, the use of the Hg-lamp in combination with a filter allowed the use of UVC light, which is not available through use of other LEDs on the market.
References:
[1] Structurally Diverse Nitrogen-Rich Scaffolds via Continuous Photo-Click Reactions (D. Cronly, M. Smyth, T. S. Moody, S. Wharry, J. Bruno-Colmenarez, B. Twamley and M. Baumann, Org. Lett., 2024, ASAP). https://doi.org/10.1021/acs.orglett.4c03953
[2] Multikilogram per Hour Continuous Photochemical Benzylic Brominations Applying a Smart Dimensioning Scale-up Strategy. (A. Steiner, P. M. Roth, F. J. Strauss, G. Gauron, G. Tekautz, M. Winter, J. D. Williams and C. O. Kappe, Org. Process Res. Dev. 2020, 24, 2208−2216). https://doi.org/10.1021/acs.oprd.0c00239
[3] Continuous photochemical benzylic bromination using in situ generated Br2: process intensification towards optimal PMI and throughput (A. Steiner, J. D. Williams, O. de Frutos, J. A. Rincón, C. Mateos and C. O. Kappe, Green Chem., 2020, 22, 448−454). https://doi.org/10.1039/C9GC03662H
[4] Facile Synthesis of Dihydro-1,2,4- benzotriazepin-5-ones. (N. I. Hindawi, J. A. Zahra, M. El-Abadelah, B. A. Abu Thaher and K.-P. Zeller, Monatsh. Chimie 2006, 137, 1349−1355). https://doi.org/10.1007/s00706-006-0532-y
[5] A new synthesis of 5-keto-1H-4,5-dihydro-1,2,4-benzotriazepines and a preliminary study of their biological properties. (M. Bianchi, A. Butti, S. Rossi, F. Barzaghi and V. Marcaria, Eur. J. Med. Chem. 1977, 12, 263−269). https://doi.org/10.1002/chin.197739271
[6] Synthesis and properties of 1H-1,2,4-benzotriazepines. (S. Conde, C. Corral and R. Madronero, Tetrahedron, 1974, 30, 195−200). https://doi.org/10.1016/S0040-4020(01)97235-7
[7] Continuous flow synthesis enabling reaction discovery. (A. Ilenia Alfano, J. García-Lacuna, O. M. Griffiths, S. V. Ley and M. Baumann, Chem. Sci., 2024, 15, 4618–4630). https://doi.org/10.1039/D3SC06808K
