Synthetic Challenges in Miyaura Borylation of Bromo-Thienopyrimidine

[yinuowang0812]

We need some help with a Miyaura borylation reaction, so that we can make some key compounds in OSM3 (related to OSM-S-106).

We synthesised a series of final compounds using a Suzuki coupling with Br-aminothienopyrimidine (4, below) and B(pin)-aryl sulfonamides (detailed protocols can be found in Yinuo's ELN YNW5). This works fine. Problem: there are not that many B(pin)-aryl sulfonamides available. There are a lot more aryl bromides available. It'd be much better if we could convert 4 into the boronate first, then do the Suzuki. I've been trying this, but can't make it work. It should work! Help!

So here is what I've done so far:

Note: The purity of 4 and B2(Pin)2 has been checked and they were used as controls in LCMS and NMR analyses.

1. Direct borylation: (ELN YNW63):

I've tried this with various conditions for the direct Miyaura borylation of 4 and B2(Pin)2 based on papers like (this) and (this). However, the LCMS results under all the borylation conditions tested below showed m/z = 152 (dehalogenation, a known side reaction with Pd catalysts) and m/z = 255 (suggesting unreacted B2(pin)2).

Conditions tested:

(1) Pd(PPh3)4, potassium acetate, diethyl ether/H2O, 70 °C, overnight. (patent)
(2) Pd(dppf)Cl2·DCM, potassium acetate, dioxane, 70 °C /100 °C, overnight. (DMK180-1)
(3) Pd(dppf)Cl2·DCM, potassium acetate, toluene, 80 °C, 24 hrs. (lit)

2. Boc-protected borylation: (ELN YNW66)

I then protected the amine at the 4-position with a Boc group before proceeding with the borylation. The borylation results indicated both Boc deprotection and dehalogenation occurred. LCMS also found m/z = 152 (dehalogenation) and m/z = 255 (B2(pin)2 remaining). Two of my lab mates have also observed that Pd coupling can lead to the deprotection of NH-Boc groups.

3. Selective borylation: (ELN YNW68)

Referencing patents (1) and (2), the borylation showed selectivity for -Br over -Cl. So I attempted to borylate the intermediate, 6-bromo-4-chlorothienopyrimidine, but no desired product was detected in LCMS, which instead found minor traces of m/z = 170 (dehalogenation) and m/z = 255 (B2(pin)2 remaining).

In summary, all attempted borylation conditions resulted in dehalogenation. It's unclear why Miyaura borylation is ineffective on aminothienopyrimidine, yet it succeeds on thiophene and amino-aryl rings separately (both using Pd catalyst/ same base/ similar heating temperatures). Feel free to comment below (or by email at yinuo.wang.20@ucl.ac.uk (but let me know if I can post your advice below!)) if you have any ideas or advice :) (Alternatively, if you had a platform to test multiple reaction conditions, we can send materials to you).

borylation issue ChemDraw.cdxml.zip

[davidc54]

Nice work guys! I predict that the trouble here is protodeboronation rather than protodehalogenation as the major issue. The stability of 2-heteroaryl boronates to this side reaction is a notorious bugbear. Have you considered trying C-H boronation using Ir catalysis? (see https://onlinelibrary.wiley.com/doi/full/10.1002/anie.202001520) If you dont see the product from this then I would abandon future efforts to access the BPin.

Following on from this, have you considered an alternative boronate equivalent such as a trifluoroborate (https://www.sigmaaldrich.com/GB/en/technical-documents/technical-article/chemistry-and-synthesis/cross-coupling/potassium-trifluoroborate) or BMIDA (https://www.sigmaaldrich.com/GB/en/technical-documents/technical-article/chemistry-and-synthesis/cross-coupling/mida-boronates)? I was thinking of a couple of disconnections for this compound, including annulation to the benzothiophene-type system: see screenshot, what do you think?

https://pubs.acs.org/doi/10.1021/acs.joc.1c02606

[yinuowang0812]

Hi @davidc54 , thank you for your comment! Very helpful.

Do you think the protodeboronation happened after the transmetalation, and then pinacolborane gets protonolysis by H2O or something else? I wondered if the dehalogenation could result from β-elimination of acetate.

The Ir catalyst paper is very interesting. It includes examples of borylating 2-substituted pyrimidines. I will add it into my synthetic plan for sure.

Before we look into other ways of doing things, we really want to sort out this Miyaura borylation reaction. I'll dig into what's been tried before and we'd like to crack this reaction first.

[paulkingau]

I did a database search for this reaction (I searched the core structure plus boron). There are only two compounds in the entire literature with boron in that position and are both Chinese patents. You may wish to look at these patents: CN 115716840 A and CN 113214326 A.

CN 115716840 A

There does appear to be a mistake in the drawing here (they used pinacolborane).

Google Patents translation: "INT 6-1 Synthesis: n is a radical of hydrogen 2 INT 3 (1.00g, 2.01mmol), pinacolborane (5.14g, 40.20mmol), triethylamine (0.61g, 6.03mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (0.19g, 0.40mmol) and tris (dibenzylideneacetone) dipalladium (0.18g, 0.20mmol) were added to dioxane (16.0 ml) under protection, and stirring was carried out at 105 ℃ for 0.5 hour, and LC-MS monitored for the absence of a raw material. The reaction solution was used in the next step without purification."

CN 113214326 A

Espacenet

Take 5.0g (20.8mmol) of Intermediate Int.-1 prepared in the previous step and dissolve it in 100mL of dry THF. Under the protection of nitrogen, the temperature is cooled to -80℃ with liquid nitrogen, and 10.0mL of 2.5M is added dropwise. The n-butyllithium hexane solution, stirred for half an hour, added dropwise 3.2g (30.7mmol) of trimethyl borate, stirred for half an hour, warmed to room temperature and stirred for 1 hour, added 20.0mL of 2M dilute hydrochloric acid and stirred for half of the reaction After hours, it was extracted with ethyl acetate, the organic phase was collected, dried, filtered, the filtrate was concentrated and dried under reduced pressure, and n-hexane was added for dispersion and filtration to obtain 3.6 g of the intermediate compound Int.-2 as a gray solid.

I understand that patent documents can be annoying to read (you're never supposed to read all of it since most of it is there for legal reasons). However, they can be a useful place to look. Also, translations from Chinese can be a bit dodgy, so if you're a native speaker/reader, you should consider looking at the original document.

You can also get translations of patents from Espacenet which is provided by the European Patent Office. Sometimes those translations are better than Google Patents.

[davidc54]

paulkingau Great idea, its never a good sign when you see this small a number of prior examples in a SciFinder search! To me, the examples shown look more achievable anyway due to the absence of a free amino group on the pyrimidine (to my knowledge, no one has made clear "rules" for which of these compound should be stable and which should not, would be delighted to be pointed to a publication that says otherwise).

yinuowang0812 Yes I would expect that the reaction proceeds to the desired boronate (inspired by your thiophene literature result above), but under the Miyaura conditions the product is so unstable that it is destroyed before you can work it up. Dehalogenation is also possible as you suggest, perhaps you could test this by running the reaction in the absence of B2Pin2, if you see the same amount of the C-H product then you are correct :)

Protodeboronation is an interesting reaction thats been studied a fair bit due to it being the cause of problems such as this, a couple of starter refs can be found in the work of Guy Lloyd-Jones et al.:
https://pubs.acs.org/doi/10.1021/jacs.6b03283 (take a look at the thiazole example in the graphical abstract)
https://pubs.acs.org/doi/10.1021/jacs.7b07444

Other ideas for this reaction: have you tried other sources of boron, such as bis-boric acid, B2Cat2, B2Epin2 (ethyl version of pinacol)
Have you tried additives/co-catalysts for this reaction? Other solvents? Perhaps you could speed up the reaction to make it go at a lower temperature.

Have you tried deprotonative borylation using BuLi and a boronate ester such as isopropoxyBPin? (https://www.sigmaaldrich.com/GB/en/product/aldrich/417149)

[mlc-syg]

At the CRO I work for we've found the conditions in this paper with XPhos precatalysts to be superior in the majority of cases often overcoming issues with dehalogenation:
https://pubs.acs.org/doi/pdf/10.1021/acs.joc.0c01758

Alternatively, you could consider the 2-step 1 pot borylation/Suzuki method with your sulfonamide as the reagent that is borylated...

[jhjensen2]

Perhaps this paper could help?

[mattodd]

Hi @paulkingau !

[yinuowang0812]

Hi @jhjensen2 the link you shared is unfortunately 404

[jhjensen2]

Sorry, should work now

[yinuowang0812]

Hi guys, many thanks for sharing your experiences and providing diverse suggestions for my borylation issue. I’ve summarized the ideas from all platforms and compiled them here to keep everyone on the same page. Please don’t hesitate to share if you have more ideas!

1. Not Isolating the Borylated Intermediate:

   • This paper has been repeatedly mentioned with the idea of a “Two-Step, One-Pot Palladium-Catalyzed Borylation,” which involves carrying out the Suzuki coupling after borylation in one pot without isolating the boronate intermediate. It describes a direct Borylation + Suzuki coupling reaction to yield the final compounds. Both conditions below are worth trying.
   • The free amine from the theinopyrimidine (our core) could be protected by DMF·DMA, which can be removed by mild acid at the end.
   • need to be 100% sure the system is dry.
     

2. Optimising the Reagents (can also be combined with the first optimisation):

   • The stability of boronate needs to be considered. Can try altering the boronate source such as B2(OH)2, B2(EPin)2, B2Cat2, (BF3K salts along with)BMIDA…
   • Optimisation of the Base (https://pubs.acs.org/doi/10.1021/acs.joc.0c01758?ref=pdf) such as 2-ethyl hexanoate.

3. Optimise the method:

   • Use BuLi deprotonated and use Triisopropyl borate
   • Stille coupling / Stannylation (https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10.1002/ejoc.201701463)
   • Ir-catalysed C-H borylation (https://onlinelibrary.wiley.com/doi/full/10.1002/anie.202001520)
   • Ni-catalysed reductive C-B coupling of bromoborane (https://pubs.acs.org/doi/10.1021/jacs.4c01450?ref=pdf)

The lack of literature or patents on the borylation of aminopyrimidine/thienophene combo poses a challenge for this reaction. But I believe the posts here already provide a broad perspective on borylation conditions, and I will optimise the reaction next following these ideas. I'll keep you guys updated :)

[Jamesw350]

If the goal is the aryl-aryl product and med chem scale, fighting with a challenging boronation/unstable boronate isn’t a good use of time, a process chemist can solve that problem later when you have identified the clinical candidate. Stanylation seems like a suitable alternative. Li-Br exchange on either partner then charge Bu3Sn-Cl to hopefully give you a stable coupling partner. Initial deprotonation of the NH2 might be needed or 2,6-hexanedione can be used as a protecting group to hide the acidic protons. The hexanedione protecting group could also be a viable option to avoid formation of the protonated impurity in your borylations.