Published: 06 February 2025
At BioAscent we are always striving to find new ways to maximise our efficiency working on client projects to save resources. One of the most sensible approaches is to modify molecules at late stages from common advanced building blocks as opposed to synthesis of each analogue from scratch. We have previously highlighted skeletal editing as the most prominent trend in late-stage modifications that allows us to modify the core of a complex molecule selectively without disrupting its architecture.
In this blog, I wanted to talk about peripheral editing and an awesome reagent pyrylium tetrafluoroborate (Pyry-BF4) that can grease the wheels of advanced molecule modifications. Pyry-BF4 is, in a big way, a useful reagent for the activation of aromatic amino groups and subsequent functionalisation to form C−O, C−N, and C−S bonds. The transformation is characterised by remarkable chemoselectivity, which makes it an attractive tool for use in late-stage diversification.
Why opt for Pyry-BF4 instead of the classical Sandmeyer reaction?
Using Pyry-BF4 can be viewed as an advanced version of the Sandmeyer reaction for the reason that it overcomes constraints associated with diazonium salt formation such as, instability (and consequently the difficulty in determining conversion), being explosive, and the handling of potentially carcinogenic aqueous nitrite solutions. Besides that, in our experience, the Sandmeyer reaction is quite laborious to perform and can be low yielding.
In contrast, pyridinium salts are bench-stable solids and can be isolated (if necessary), analysed (by both LC-MS and NMR) and purified by recrystallisation. Moreover, in most cases, pyridinium salt formation and subsequent nucleophilic attack can be performed in a one-pot fashion under mild conditions, which leads to broad functional group tolerance. Overall, it’s a green and handy approach that benefits both the project and the environment.
Why opt for Pyry-BF4 and not its trisubstituted alternatives?
The commercial availability and chemical stability of 2,4,6-trisubstituted pyryliums pinpoints them as the best candidates for the C(sp2)-NH2 to C(sp2)-Nuc transformation. However, whilst working on a PROTAC®-related project we observed sluggish formation of a 2,4,6-triphenyl pyridinium salt (Katritzky salt) with one of the VHL ligands due to steric hindrance, whereas Pyry-BF4 showed much more promising results.
Cornella’s group1 explains that ‘The use of 2,4,6-trisubstituted pyryliums leads to highly sterically demanding pyridinium leaving groups. This substitution pattern would force the substrate into a coplanar situation, giving a disfavoured or even unfeasible trajectory for the incoming nucleophile to reach the lowest unoccupied molecular orbital (LUMO) of the pyridinium substrate’ (Scheme 1).
Scheme 1. Cornella’s lab hypothesis and experimental evidence of Pyry-BF4 superiority over 2,4,6-trisubstituted pyryliums.
‘This essential Bürgi-Dunitz angle is delivered in a perfect way using the unsubstituted pyrylium salt for activation of the heteroaryl amine. The unsubstituted pyridinium substrate would show a planar conformation presenting free space for incoming nucleophiles of different sizes. Indeed, as shown in the experiments above, the reaction of toluidine with the 2,4,6-trisubstituted pyridinium salt afforded only trace amount of product. On the other hand, the unsubstituted pyridinium delivered the C‒N product in excellent yields.’
Are there any shortcomings to using Pyry-BF4?
Well, I would say Pyry-BF4 is like Mary Poppins ‘practically perfect in every way’. The only downside that may put chemists off from using it on a regular basis is its rather high price (£103 - £693 per gram depending on the supplier). Thanks to the fantastically detailed synthetic procedure from Cornella’s lab1 we can produce Pyry-BF4 for our internal use at £34 - £40 per gram which makes it 2.5-17 times cheaper than commercially available material and, therefore, accessible for routine use.
I wanted to showcase several useful publications in the field starting from the landmark paper from Cornella’s laboratory.
Discovery and applications of Pyry-BF4 as an activating agent of aminoheterocycles for late-stage modifications
A pioneering comprehensive study of Pyry-BF4 reaction ability (including a detailed description of Pyry-BF4 synthesis as well as a Q&A section in the Experimental Part!) was published in 20181 by Cornella’s group. The authors came on the scene with a novel approach for highly selective activation of C(sp2)-NH2 bonds in heterocycles by using non-substituted pyrylium tetrafluoroborate that could easily be prepared from inexpensive pyridine sulphur trioxide (Scheme 2A).
Scheme 2. A) Synthesis of Pyry-BF4. B) Comparison of Pyry-BF4 and commonly employed pyryliums in amination of 4-aminopyridine via C-N activation.
This robust and simple approach addresses common challenges encountered previously during the Sandmeyer reaction or using trisubstituted pyrylium salts as discussed above. As shown in Scheme 2B, non-substituted Pyry-BF4 has furnished the best results during SNAr of 4-aminopyridine tolerating multiple solvents tested (THF, EtOH, acetone, MeCN, and 1,4-dioxane). One more benefit, there was no need to isolate the pyridinium salt; it could be prepared in situ and, in most cases, forwarded into the next step ‘as is’.
A large variety of structurally simple anilines (over 60 examples) were subjected to the chemoselective C(sp2)-NH2 activation via pyridinium salts followed by a nucleophilic attack affording the formation of desired C-N, C-O, C-S and C-SO2R bonds. Reactions were performed under mild to forcing conditions (DMSO or EtOH at 25°C – 150°C) either from isolated pyridinium salts or from pyridinium salts generated in situ (Figure 1).
Figure 1. Selected examples of the SNAr mediated by the Pyry-BF4 salt.
Mild conditions applied in this method enabled the use of C(sp2)-NH2 groups as sites for facile late-stage diversifications of complex pharmaceuticals, agrochemicals and natural products (Figure 2).
Figure 2. Selected examples of modified pharmaceuticals, agrochemicals and natural products.
Ditching explosive and unsafe diazonium salts: converting C(sp2)-NH2 into C(sp2)-Hal with the aid of Pyry-BF4
Another milestone publication describing a simple methodology using Pyry-BF4 as a C(sp2)-NH2 activator came out from the same laboratory in 20222. Here, the primary focus of the investigation was the transformation of the aromatic -NH2 group into a modular and versatile leaving group – heteroaryl chloride (several heteroaryl bromides and fluorides have successfully been obtained as well) by means of Pyry-BF4 and a variety of inexpensive chloride sources (Scheme 3).
Scheme 3. Development of a two-step deaminative chlorination of aminoheterocycles using various chloride sources.
This method was tested on and found to be applicable to >20 distinct types of heterocyclic scaffold (five- and six-membered rings containing N, O and S) tolerating structural complexity and a broad range of functional groups (halogens, pyridine, cinnamyl, cyano, methylsulfone or even aldehyde).
More advanced architectures also behaved well under these mild conditions. For instance, the chlorinated analogue of the lipoxygenase-activating protein antagonist (BI-665915) was obtained in 38% yield tolerating the presence of the fragile N‒O bond of the oxadiazole. Despite the presence of a Michael acceptor and a piperidinyl moiety the anti-cancer drug Ibrutinib posed no difficulties for chlorination yielding its Cl- analogue in 87% yield (Figure 3).
Figure 3. Selected substrate scope of the deaminative chlorination of aminoheterocycles.
Green and unorthodox methodology for Pyry-BF4 mediated aromatic -NH2 functionalisation using a ball mill.
Recently, I came across 2 papers that came out of Iaroshenko’s lab on mechanochemical conversion of aromatic -NH2 into aromatic -OCF33 or aromatic ketones4 mediated by Pyry-BF4. By taking inspiration from the Cornella publication2 the authors suggested that a similar approach could enable the introduction of the trifluoromethoxy group into aromatic substrates. Multiple initial attempts to engage 4-(methylsulfonyl)aniline (or its isolated pyridinium salt) in the desired transformation in various solvents failed.
In their search for greener methodologies, Iaroshenko’s group conducted the same experiment but solvent-free under mechanochemical conditions and, surprisingly, it worked! After optimising the mechanochemical reaction conditions by adjusting the reagent equivalents and the ⊝OCF3 source the authors embarked on an assessment of the method’s scope (Scheme 4).
Scheme 4. Selected examples of the reaction scope.
Several substituted anilines yielded the corresponding -OCF3 products with high isolated yields. Somewhat lower yields were observed for the ortho-substituted anilines due to steric hindrance. The technique was also feasible on gram scale, which makes it an attractive tool for building block synthesis. The unexpected drawback of this approach (for us, chemists) is that it works only in the solid state but at the same time it ensures reduced work up time and solvent economy satisfying the principles of green chemistry and contributing to the environment.
The same environmentally friendly method was used for the arylation of aryl amide substrates to broaden its versatility. Optimised conditions were applied to a diverse range of substituted arylamides using either boronic acids or trialkoxysilanes as coupling agents achieving isolated yields varying from 49% to 94% (Scheme 5).
Scheme 5. Iaroshenko’s strategy for amide bond functionalisation and reaction scope.
Rather unsurprisingly at this stage, it had been found out that these conditions were not reproducible in liquid media making Pyry-BF4 mediated mechanochemical deaminative arylation a step forward for the development of green methods in synthetic organic chemistry.
All in all, Pyry-BF4 has great potential for use in commercial laboratories due to its stability, safety and ease of use. Moreover, since it allows for one-pot reactions in liquid or solid media Pyry-BF4 might aid in saving resources and time.
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About the author
Olga Gozhina is a Senior Scientist in the Chemistry Department at BioAscent. She earned her PhD in organic chemistry from The Arctic University of Norway, focusing on synthesis of short boron-containing antimicrobial peptidomimetics. Upon completion of her postdoctoral studies at the University of São Paulo (Brazil) she made a career shift into industry. Prior to working at BioAscent she worked for several CRO’s and Biotech businesses in Canada, Russia and Norway.
