Potassium tert-Butoxide: Solubility, Solution Structure, and Reactivity Fundamental properties including solubility and structure–reactivity correlations of potassium tert-butoxide (KOtBu) are described in this manuscript. A combination of donor solvent titration, diffusion NMR, and DFT studies established that KOtBu exists in one of three solution structures: (1) unsolvated cubic tetramer in non-Lewis basic solvents, (2) disolvated cubic tetramer in Lewis basic solvents, and (3) solvated monomer in protic solvents. These studies dispel the notion that strong aprotic donor solvents lead to deaggregation of KOtBu cubic tetramer. In DMSO, a concentration-dependent equilibrium mixture of bis-DMSO-solvated cubic tetramer, dimsylpotassium, and tert-butanol is formed. Donor solvent association with potassium was contextualized in terms of periodic trends within the alkali metal series. The previously reported 1:1 complex of KOtBu and tert-butanol was found to be highly insoluble and affords poor availability of KOtBu when employed in a model dehydrohalogenation reaction. Reactivity can be recovered by the inclusion of strongly Lewis basic donor solvents that disproportionately stabilize the transition state.

So you think you know KOtBu…
Well my colleagues in #PfizerChemistry process chem have done some amazing work to find out a lot more about a very useful base #ChemSky

Annulative Skeletal Diversification of Pyrimidines to Expanded Heteroaromatic Space Single-atom skeletal editing has recently emerged as a powerful strategy for the direct diversification of the heterocyclic cores of various compounds. Yet, methods that enable monocycle-to-bicycle tr...

My favorite 2025 #PfizerChemistry publications #12daysOfPapers 12b:

I’m so excited how this one turned out with the @sarponggroup.bsky.social led by Philip Speiß. A one-pot fusion of 2 heterocycles - a whole new way in to key 6/5 and 6/6 pharmacophores @jacs.acspublications.org

#ChemSky #ChemChat

Oxygen migration into carbon–carbon single bonds by photochemical oxidation - Nature Synthesis Heteroatom insertions into chemically inert carbon–carbon single bonds are rare compared to their unsaturated analogues. Now, ligand-to-metal charge transfer offers a promising entry point for oxygen ...

My favorite 2025 #PfizerChemistry publications #12daysOfPapers
12a:

What a pleasure it was to work with the @uwyoongroup.bsky.social and @tehshik.bsky.social on this sp3 skeletal rearrangement paper - wonderful job by Caitlin, Cade and all - I’m still floored by this rxn #ChemSky #ChemChat

Development of a Scalable Synthesis of a HPK1 Inhibitor Featuring a Direct α-Arylation of Boc-Protected N,N-Dimethylamine by Palladium-Mediated Negishi Cross-Coupling The development of an improved synthesis of the potent HPK1 inhibitor, compound 1, is described. Two primary strategies were explored during this process: metallaphotoredox decarboxylative coupling an...

My favorite 2025 #PfizerChemistry publications #12daysOfPapers 11/n:
A super cross line/site collaboration among Groton and La Jolla medchem teams with our Process chemists comes this fantastic het synthesis w/ innovative BOCNMe2 zincate coupling #JOC #ChemSky #ChemChat

Sulfur fluoride exchange with carbon pronucleophiles Aryl alkyl sulfones are an important class of compounds in drug discovery; thus, new methods toward their synthesis are desirable. A general sulfur fluoride exchange (SuFEx) method to couple aryl sulf...

My favorite 2025 #PfizerChemistry publications #12daysOfPapers 10/n:

Alkylation of R-SO2F with carbon nucleophiles out in @chemicalscience.rsc.org
- a collaboration with the awesome @ballnchemist.bsky.social
and his amazing undergrads at @pomonacollege.bsky.social
#ChemSky #Chemchat

Accelerating Medicinal Chemistry: A C(sp3)‐Rich Fragment Toolbox for Redox‐Neutral Cross‐Coupling It is introduced in this report a unified toolbox comprising of 15 sulfonyl hydrazide reagents that enable the redox-neutral radical cross-coupling of 14 distinct C(sp3)-rich small fragments onto (he...

My favorite 2025 #PfizerChemistry publications #12daysOfPapers 9/n:

An industry collab with our Pfizer La Jolla colleagues (w/BMS+BioGen) and @BaranLabReads comes this wonderful medchem look at sulfonyl hydrazides as powerful sp2-sp3 coupling agents #ChemSky #ChemChat

A bifunctional boronic acid/phosphorus(V) organocatalyst for the direct room-temperature amidation of carboxylic acids An organocatalyst containing boronic acid and phosphine oxide groups enables the coupling of carboxylic acids and amines at room temperature to achieve a sustainable route to the amide bonds present i...

My favorite 2025 #PfizerChemistry publications #12daysOfPapers 8/n:

Room temp catalytic amide formation with this ingenious bifunctional B-P reagent from our process chem in collab with the Sandford Lab @ UTSA
#ChemSky #ChemChat

C(sp2)–C(sp3) Suzuki–Miyaura Cross-Coupling Using gem-Bis(boronates) A strategy utilizing gem-bis(boronates) as a stable and easily accessible surrogate for the analogous monoboronate and their efficient use in Suzuki–Miyaura cross-couplings to access the highly intere...

My favorite 2025 #PfizerChemistry publications #12daysOfPapers 7/n:

From my colleague Jun Xiao and our MedChem teams in collab with our WuXi partners this is a facile sp2-sp3 Suzuki with tons of het scope using alkyl gem-(bis)boronates
#ChemSky #ChemChat

Desulfinative Cross-Coupling as a Method to Overcome Problematic Suzuki–Miyaura Reactions of Pharmaceutically Relevant Heteroaromatic Boronates The well documented difficulties associated with direct (hetero)arylation of aza-aromatics (e.g., azines) at the α-position to nitrogen led to a collaborative project between the Willis group at Oxfor...

My favorite 2025 #PfizerChemistry publications #12daysOfPapers 6/n:

This wonderful review of desulfinative coupling in med chem as an alternative to traditional Suzuki - esp effective for heterocycles - collab with the Willis lab @rhpdcu.bsky.social
Uses in PMC to scale up
#ChemSky #ChemChat

Kilo-Scale-Enabled Route toward PF-07907063, a Type II Brain Penetrant cMET Inhibitor New synthetic methodologies that access complex saturated building blocks enable the synthesis of drug molecules with unique properties. Here, we report collaborative efforts between Pfizer’s Medicina...

My favorite 2025 #PfizerChemistry publications #12daysOfPapers 5/n:

From Pfizer Boulder-this #OPRD has it all-enablement, sp2/sp3 hets, cross electrophile couplings, SnAr and more - nice work from @ronhinklin.bsky.social and all
#ChemSky #ChemChat

Cu-Catalyzed C–N Couplings with Benzilamide Ligands A linker fragment used in the preparation of an oncology candidate is efficiently synthesized via Cu-catalyzed C–N coupling. The original route required a Cu-catalyzed coupling, followed by an oxidati...

My favorite 2025 #PfizerChemistry publications #12daysOfPapers 4a/n:

The Copper Crew from our Process chem department teamed up again for another #OPRD paper on Cu-catalyzed coupling this time enabling 2° amines with very mild conditions
#ChemSky #ChemChat

Alkyl sulfonyl fluorides as ambiphiles in the stereoselective palladium(II)-catalysed cyclopropanation of unactivated alkenes - Nature Synthesis The ambiphilic reactivity of alkyl sulfonyl fluorides in stereoselective cyclopropanation under Pd(II) catalysis is reported. The method provides convenient access to cis-disubstituted cyclopropanes t...

Interrupting #12DaysOfPapers to share this beauty from #PfizerChemistry, @mykhailiukchem.bsky.social Enamine, @pengliugroup.bsky.social and a host of Scripps La Jolla folks now out in @natsynth.nature.com - stereocontrolled cyclopropanes from Alkyl-SO2F & olefins with a Pd (II-IV) catalytic cycle

Cu-Catalyzed Coupling of Aryl Halides Utilizing Ammonia and Hydroxypicolinamide Ligands The hydroxypicolinamide family of ligands has previously demonstrated utility in Cu-catalyzed C–N couplings and hydroxylation of heteroaryl halides. The application of these ligands has been extended ...

My favorite 2025 #PfizerChemistry publications #12daysOfPapers 4/n:

From our Process chem colleagues comes this wonderful #OPRD paper on Cu-catalyzed ammonia/small amine couplings - tons of het scope, easy set up (even worked for me!)
#ChemSky #ChemChat

Building Efficient Diastereo- and Enantioselective Synthetic Routes to trans-Cyclopropyl Esters for Rapid Lead Scale-Up Cyclopropanes play an important role in drug discovery, and synthetic access to variedly substituted systems is an ongoing challenge for chemistry teams. A variety of scalable synthetic routes were de...

My favorite 2025 #PfizerChemistry publications #12daysOfPapers 3/n:

MedChem and Process working together to enable chiral cyclopropanes for pre-clinical scaleup - route scouting and development with great teamwork #OPRD #ChemSky #ChemChat

Palladium-Catalyzed Enantioselective Stereodivergent Desymmetrization of Cyclic 1,4-Allyldiboronates In the presence of a chiral palladium-based catalyst, 1,4-diboryl-2-alkenes undergo enantioselective cross-coupling that results in desymmetrization of the substrate structure. Depending on the reaction conditions and the choice of ligand, the reaction can occur with cis or trans selectivity, allowing the construction of an array of different substituted chiral carbocycles in an enantiomerically enriched fashion.

My favorite 2025 #PfizerChemistry publications #12daysOfPapers 2/n:
From my process chem colleagues in collaboration with the Morken lab (Boston College) - a desymmetrization of 1,4 cyclic bisboronates @jacs.acspublications.org
#ChemSky #ChemChat

Microwave-Assisted Synthesis of Heterocycles via Rhodium(III)-Catalyzed C–H Activation: Norbornadiene as an Acetylene Equivalent General procedures for the rhodium-catalyzed annulation of aryl/heteroaryl O-pivaloyl hydroxamic acids and norbornadiene have been developed. Employing norbornadiene as an acetylene equivalent enables...

My favorite 2025 #PfizerChemistry publications #12daysOfPapers 1/n: From my La Jolla colleagues this is a cool use of Rh-catalyzed C-H activation followed by retro Diels-Alder to provide useful med chem heterocycles #OrgLett
#ChemSky #ChemChat

two men are sitting at a table in a kitchen talking to each other . one of the men is wearing a beanie . ALT: two men are sitting at a table in a kitchen talking to each other . one of the men is wearing a beanie .

As 2025 comes to a close I'm taking a look back at some fantastic 2025 #PfizerChemistry publications and wanted to share a few of my favorites so watch here for the next few days #12daysOfPapers

And here it is – Annulative Editing – aka The Monster Mash. What a super collab #PfizerChemistry & @sarponggroup.bsky.social
In 1 pot, activated pyrimidines with bis-nucleophiles like amino-pyrazoles & other small hets to deliver 6/5 hets and other useful products
#MyFirstJACS
#ChemSky #ChemChat

C(sp2)–C(sp3) Suzuki–Miyaura Cross-Coupling Using gem-Bis(boronates) A strategy utilizing gem-bis(boronates) as a stable and easily accessible surrogate for the analogous monoboronate and their efficient use in Suzuki–Miyaura cross-couplings to access the highly intere...

From #JOC this is a cool and useful reaction from my #PfizerChemistry colleagues and WuXi partners using bis-boronates in sp2-sp3 Suzuki-Miyaura couplings - easy to make SM and the couplings work really well with broad scope #ChemSky

I'm excited to post an opening in our group for a principal scientist in process chemistry. | Aaron Whittaker I'm excited to post an opening in our group for a principal scientist in process chemistry. Know anyone who might be interested?

#ChemJobs #ChemSky
Opening at #PfizerChemistry Process chem in Bothell WA - looking for a Principal Scientist (ADC synthesis) PhD+4y experience (MS +10)
@chemjobber.bsky.social

Peptidylarginine Deiminase (PAD) Inhibitor Optimization through Displacement of a Trapped Water Molecule Excess protein citrullination, a post-translational modification converting arginine to citrulline, has been associated with a range of autoimmune and neurological disorders, as well as cancers. Prote...

What a great team this was here at #PfizerChemistry! Discovery of an allosteric PAD2/4 inhibitor that kicks out an embedded water and opens up additional binding pocket – fun synthetic project this one was #ACSMedChemLett asap #ChemSky

Elucidation of a Parasitic Proton-Coupled Electron Transfer in a Photocatalytic Benzylic C–H Sulfonamidation Strategies for C–H amination with sulfonamides have been dominated by stoichiometric strategies or Rh/Cu catalysis using strong oxidants, elevated temperatures, or excess equivalents of C–H partner. We developed a photocatalytic C–H amination with a bench-stable N-methoxypyridinium salt that is amenable to late-stage functionalization efforts. We discovered a competitive proton-coupled electron transfer pathway between sulfonamide and a pyridine byproduct that inhibits the reaction. Catalysis was re-established with the introduction of ZnBr2.

From the Musacchio Lab (Buffalo) and #PfizerChemistry is a new #OLasap with #PhotoChem C-H amination with sulfonamides - great scope. LA addition was key to eliminate competing pathway

Cu-Catalyzed Coupling of Aryl Halides Utilizing Ammonia and Hydroxypicolinamide Ligands The hydroxypicolinamide family of ligands has previously demonstrated utility in Cu-catalyzed C–N couplings and hydroxylation of heteroaryl halides. The application of these ligands has been extended ...

Looking to couple small amines? Even NH3? Super #OPRD from some of my #PfizerChemistry friends with picolinamide ligands for Cu couplings at low %, hi yields/scope-all those hets! So easy I used it to make [REDACTED] inhibitors
This is who I go to for advice – top chemists and friends
#ChemPubs

June 27 at Conn College New London CT #PfizerChemistry #MerckChemistry @boehringerus #BMSChemistry & @ACS_CVS are hosting the 7th Annual Symposium on Applied Synthesis featuring Ryan Shenvi (Scripps) & Martin Tomanik (NYU) Slots for student talks available #ChemSky https://www.cvs-acs.org/event-details/7th-annual-symposium-on-applied-synthesis

June 27 at Conn College New London CT #PfizerChemistry #MerckChemistry
@boehringerus #BMSChemistry & @ACS_CVS are hosting the 7th Annual Symposium on Applied Synthesis featuring Ryan Shenvi (Scripps) & Martin Tomanik (NYU)
Student talks available
#ChemSky Reg is open: www.cvs-acs.org/event-detail...

Kilo-Scale-Enabled Route toward PF-07907063, a Type II Brain Penetrant cMET Inhibitor New synthetic methodologies that access complex saturated building blocks enable the synthesis of drug molecules with unique properties. Here, we report collaborative efforts between Pfizer’s Medicinal Chemistry, Medicinal Chemistry Synthesis Development, and Pharmaceutical Sciences Small Molecule (PSSM) groups for the development of kilogram-scale-enabled synthesis of a type II brain penetrant cMET inhibitor, PF-07907063. The chemistry presented herein demonstrates the importance of implementing a green chemistry approach for developing and applying new transformations throughout the drug development pipeline. Specifically, synthetic planning rooted in the 12 Principles of Green Chemistry led to advancements in deoxygenative photoredox-nickel dual catalysis and cross-electrophile nickel catalysis. The final route significantly lowered the process mass intensity (PMI), increased the yield of the final API, and allowed for the purification of key intermediates through crystallization versus purging impurities via column chromatography, among other improvements.

Another #OPRD asap to highlight is this one from #PfizerChemistry showing a kilo scale route to complex API with all kinds of cool - small hets (pyrazoles!) cyBu, Weix cross electrophile coupling, key synthesis improvements driven by reaction safety…so much to discover in this one #ChemSky

Some Items of Interest to Process R&D Chemists and Engineers

The April 2025 edition of #OPRD Items of Interest is online chock full of useful synthesis highlights for #ChemSky - too many to list off here (but you might find a couple from #PfizerChemistry)
Definitely worth a look at the cool chem in this issue

Thermally Hazardous 1,3-Dioxolane Coupling Reaction Required for a Pharmaceutical Candidate Starting Material, Made Safer by Employing Process Safety Data as Key Design of Experiments Output Variables The optimization of a ruthenium-catalyzed catechol, terminal-alkyne coupling reaction to form a key benzodioxolane intermediate toward Lotiglipron is described. This transformation required the use of...

Wonderful #OPRD from #PfizerChemistry (UK) with Snapdragon prepping a key intermediate using process safety endpoints as part of DOE studies #MyOtherCompoundIsAKetal

Building Efficient Diastereo- and Enantioselective Synthetic Routes to trans-Cyclopropyl Esters for Rapid Lead Scale-Up Cyclopropanes play an important role in drug discovery, and synthetic access to variedly substituted systems is an ongoing challenge for chemistry teams. A variety of scalable synthetic routes were de...

Chiral cyclopropanes?
We got em - check out this new #OPRD from my #PfizerChemistry colleages from MedChem, HTE, Biocatalysis and Process coming together to enable a wonderful method to key fragments. Neat story on how it all came together (chiral Corey-Chaykovsky alert!)

Conformational Role of Methyl in the Potency of Cyclohexane-Substituted Squaramide CCR6 Antagonists CCR6 is a chemokine receptor that mediates the migration of pathogenic inflammatory leukocytes to sites of inflammation in response to its ligand, CCL20. Herein we report the design of a potent CCR6 antagonist capable of inhibiting the chemotactic migration of CCR6+ T cells in vitro. Key to this finding was the discovery of a remarkable methyl substituent effect on antagonist potency. A 365-fold improvement in potency was observed for the cis-2-methylcyclohexanamine analogue compared to the unsubstituted cyclohexanamine derivative. Evidence generated through the characterization of conformationally restricted analogues supports the conclusion that the large potency enhancement is the result of the methyl substituent biasing the cyclohexane ring ground state conformation to favor that of the bound ligand and thus decreasing the ligand strain energy.

Also in #JMedChemASAP - anyone can have a “Magic Methyl” but what about a SUPER Methyl!! Oh and a squareamide too…
#ChemSky #PfizerChemistry

Methodologies for the Formation of 2-Substituted Oxetanes: Synthesis of (S)-Oxetan-2-ylmethyl Tosylate The compound (S)-oxetan-2-ylmethyl tosylate 1 was identified as a key synthetic fragment for the introduction of the 2-substituted oxetane functionality in potential drug candidates under development ...

This is a very cool #OPRD showing some excellent enablement of a small piece of a drug candidate from my former #PfizerChemistry colleagues in Sandwich UK.

See also: “Oh cute Medchem route…here’s 6 papers with better chemistry”

[Narrator: it was the Medchem route from Scott’s lab]