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. 2021 Sep 15;12(40):13413-13424.
doi: 10.1039/d1sc04176b. eCollection 2021 Oct 20.

Flash chemistry enables high productivity metalation-substitution of 5-alkyltetrazoles

Jeff Y F Wong  1 , Christopher G Thomson  1 , Filipe Vilela  1   2 , Graeme Barker  1   2
Affiliations

Flash chemistry enables high productivity metalation-substitution of 5-alkyltetrazoles

Jeff Y F Wong et al. Chem Sci. .

Abstract

Tetrazoles play a prominent role in medicinal chemistry due to their role as carboxylate bioisosteres but have largely been overlooked as C-H functionalisation substrates. We herein report the development of a high-yielding and general procedure for the heterobenzylic C-H functionalisation of 5-alkyltetrazoles in up to 97% yield under batch conditions using a metalation/electrophilic trapping strategy. Through the use of thermal imaging to identify potentially unsafe exotherms, a continuous flow procedure using a flash chemistry strategy has also been developed, allowing products to be accessed in up to 95% yield. This enabled an extremely high productivity rate of 141 g h-1 to be achieved on an entry-level flow system.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Tetrazole containing drugs.
Scheme 1
Scheme 1. Previous alkyltetrazole lithiations vs. this work.
Scheme 2
Scheme 2. Electrophile scope.
Scheme 3
Scheme 3. Di-substitution with chloroformates and isocyanates.
Scheme 4
Scheme 4. Substrate scope. aUsing 3.2 eq. s-BuLi.LiCl. bUsing 1.5 eq. n-BuLi.
Scheme 5
Scheme 5. Lithiation-substitution of chlorophenyl substrate 29 and crystal structure of 30.
Scheme 6
Scheme 6. Synthesis of tetrazolyl lactams.aWith 3.2 eq. s-BuLi.
Scheme 7
Scheme 7. Attempted enantioselective lithiation-substitution.
Fig. 2
Fig. 2. Thermal imaging of flow metalation in THF with the reactor tubing circled in green. (A) While pumping solvent at rt. (B) While reaction is running. (C) Graph of mean and maximum reactor temperatures over time. Only solvent at rt is pumping until 0 s, at which base and starting material solutions (both at rt) are pumped to the reactor. Pumping is switched back to solvent only at rt at 140 s.
Fig. 3
Fig. 3. Thermal imaging of flow metalation in toluene/TMEDA: graph of mean and maximum reactor temperatures over time. Only solvent at rt is pumping until 0 s, at which base and starting material solutions (both at rt) are pumped to the reactor. Pumping is switched back to solvent only at rt at 60 s.
Fig. 4
Fig. 4. Flow system diagram for RTD determination.
Scheme 8
Scheme 8. Electrophile scope in flow. a34% isolated yield of 12, 20% recovered 5.
Scheme 9
Scheme 9. Synthesis of an anaesthetic agent.
Scheme 10
Scheme 10. Substrate scope in flow. a1.7 M solution of substrate used.
Scheme 11
Scheme 11. Large scale continuous flow lithiation-trapping.
See this image and copyright information in PMC

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