James A Bull

James A Bull
Imperial College London | Imperial · Department of Chemistry

Dr

About

102
Publications
9,597
Reads
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3,698
Citations
Citations since 2016
69 Research Items
3028 Citations
20162017201820192020202120220100200300400500
20162017201820192020202120220100200300400500
20162017201820192020202120220100200300400500
20162017201820192020202120220100200300400500
Additional affiliations
January 2016 - January 2016
Imperial College London
Position
  • Royal Society University Research Fellow
January 2012 - present
Imperial College London
October 2011 - December 2016
Imperial College London
Position
  • EPSRC Career Acceleration Fellow

Publications

Publications (102)
Article
The four-membered oxetane ring has been increasingly exploited for its contrasting behaviors: its influence on physicochemical properties as a stable motif in medicinal chemistry and its propensity to undergo ring-opening reactions as a synthetic intermediate. These applications have driven numerous studies into the synthesis of new oxetane derivat...
Article
The transfer of nitrogen atoms is extremely valuable in the preparation of medicinal compounds. Here, a new system for NH transfer is developed to prepare sulfoximines, which are emerging as valuable motifs for drug discovery. This is achieved using readily available sources of nitrogen without the requirement for pre-activation or for metal cataly...
Article
Full-text available
Oxetanes offer exciting potential as structural motifs and intermediates in drug discovery and materials science. Here an efficient strategy for the synthesis of oxetane rings incorporating pendant functional groups is described. A wide variety of oxetane 2,2-dicarboxylates were accessed in high yields, including functionalized 3-/4-aryl- and alkyl...
Article
Functionalization of C(sp(3))-H bonds at the unactivated 3-position of proline derivatives has been achieved using aryl iodides and palladium catalysis. This directly affords cis-2,3-disubstituted pyrrolidines as single stereoisomers. 3-Arylation occurs in high yield under solvent-free conditions with aminoquinoline and methoxyaminoquinoline direct...
Preprint
Full-text available
4-Membered ring heterocycles oxetanes and azetidines offer exciting potential as small polar molecular motifs in medicinal chemistry but require further methods for their incorporation. Photoredox catalysis is a powerful method for the mild genera-tion of alkyl radicals for C–C bond formation. However, the effect of ring strain on radical reactivit...
Article
Sulfoximines provide aza-analogues of sulfones, with potentially improved properties for medicinal chemistry. The sulfoximine nitrogen also provides an additional vector for the inclusion of other functionality. Here, we report improved conditions for rhodium catalyzed synthesis of sulfoximine (and sulfilimine) carbamates, especially for previously...
Article
Full-text available
Sulfonimidoyl halides have previously shown poor stability and selectivity in reaction with organometallic reagents. Here we report the preparation of enantioenriched sulfonimidoyl fluorides and their stereospecific reaction at sulfur with...
Article
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Annulations that combine diacceptors with bis-nucleophiles are uncommon. Here, we report the synthesis of 1,4-dioxanes from 3-aryloxetan-3-ols, as 1,2-bis-electrophiles and 1,2-diols. Brønsted acid Tf2NH catalyzes both the selective activation of the oxetanol, to form an oxetane carbocation that reacts with the diol, and intramolecular ring opening...
Preprint
Full-text available
Transient directing groups can provide a powerful means for C–H functionalization to install medicinally valuable motifs without requiring additional steps for directing group introduction and removal. Here we report the first use of a transient directing group in combination with copper to effect C-H functionalization. The copper mediated β–C(sp2)...
Article
Full-text available
Bioisosteres provide valuable design elements that medicinal chemists can use to adjust the structural and pharmacokinetic characteristics of bioactive compounds towards viable drug candidates. Aryl oxetane amines offer exciting potential as bioisosteres for benzamides—extremely common pharmacophores—but are rarely examined due to the lack of avail...
Article
A selective Pd‐catalyzed C(3)–H cis‐functionalization of piperidine and tetrahydropyran carboxylic acids is achieved using a C(4) aminoquinoline amide auxiliary. High mono‐ and cis‐selectivity is attained by using mesityl carboxylic acid as an additive. Conditions are developed with significantly lower reaction temperatures (≤50 °C) than other repo...
Article
Recent years have seen a marked increase in the occurrence of sulfoximines in the chemical sciences, often presented as valuable motifs for medicinal chemistry. This Review covers the most recent advances in the synthesis of NH‐sulfoximines, including extensive developments in both S−N and S−C bond formations. Moreover, flow chemistry processes for...
Preprint
Full-text available
A selective Pd-catalyzed C(3)–H cis-functionalization of piperidine and tetrahydropyran carboxylic acids is achieved using a C(4) aminoquinoline amide auxiliary. High mono- and cis-selectivity is attained by using mesityl carboxylic acid as an additive. Conditions are developed with significantly lower reaction temperatures (≤50 °C) than other repo...
Preprint
A selective Pd-catalyzed C(3)–H cis-functionalization of piperidine and tetrahydropyran carboxylic acids is achieved using a C(4) aminoquinoline amide auxiliary. High mono- and cis-selectivity is attained by using mesityl carboxylic acid as an additive. Conditions are developed with significantly lower reaction temperatures (≤50 °C) than other repo...
Preprint
The copper mediated β–C(sp2)–H sulfonylation of benzaldehydes with sulfinate salts is accomplished using β-alanine as a catalytic transient directing group. A broad range of sulfonylated benzaldehydes are prepared us-ing copper fluoride as both copper source and oxidant. Both b-(ortho) and g-(peri)-sulfonylation are demon-strated. Mechanistic studi...
Article
Full-text available
Recent years have seen a marked increase in the occurrence of sulfoximines in the chemical sciences, often presented as valuable motifs for medicinal chemistry. This has been prompted by both pioneering works taking sulfoximines containing compounds into clinical trials and the concurrent development of powerful synthetic methods. This review cover...
Preprint
div> Oxetanes have received increasing interest in medicinal chemistry as attractive polar and low molecular weight motifs. The application of oxetanes as replacements for methylene, methyl, gem-dimethyl and carbonyl groups has been demonstrated to often improve chemical properties of target molecules for drug discovery purposes. The investigation...
Preprint
Vinyl sulfones and sulfonamides are valued for their use as electrophilic warheads in covalent protein inhibitors. Conversely, the S(VI) aza-isosteres thereof, vinyl sulfoximines and sulfonimidamides, are far less studied and have yet to be applied to the field of protein bioconjugation. Herein, we report a range of different synthetic methodologie...
Article
The formation of hydrazinium salts by N−N bond formation has typically involved the use of hazardous and difficult to handle reagents. Here, mild and operationally simple conditions for the synthesis of hydrazinium salts are reported. Electrophilic nitrogen transfer to the nitrogen atom of tertiary amines is achieved using iodosylbenzene as oxidant...
Article
Analysis of the use of differential scanning calorimetry (DSC) for thermal hazard assessment in 2019 shows some alarming trends. Many reports are not reproducible, do not follow established best practices and the conclusions drawn are not supported by the data presented. This Viewpoint discusses these issues and offer simple guidance on how to avoi...
Article
Differential scanning calorimetry (DSC) is increasingly used as evidence to support a favourable safety profile of novel chemistry, or to highlight the need for caution. DSC enables preliminary assessment of the thermal hazards of a potentially energetic compound. However, unlike other standard characterisation methods, which have well defined form...
Article
Full-text available
Antidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake. Structural and biochemical studies aiming to understand binding of small-molecules to conformationally dynamic transporters like SERT often require thermostabilizing mutations and antibodies to stabilize a specific conformation, leading to questions about rela...
Article
Full-text available
Antidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake. Structural and biochemical studies aiming to understand binding of small-molecules to conformationally dynamic transporters like SERT often require thermostabilizing mutations and antibodies to stabilize a specific conformation, leading to questions about rela...
Article
Full-text available
Antidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake. Structural and biochemical studies aiming to understand binding of small-molecules to conformationally dynamic transporters like SERT often require thermostabilizing mutations and antibodies to stabilize a specific conformation, leading to questions about rela...
Article
A synthesis of unprecedented and stable glycosyl sulfoximines is reported. The developed strategies represent the first example of highly stereoselective sulfoximine formation directly from thioglycosides. This synthetic protocol has been tested on several β-thioglycosides bearing different aromatics and alkyls as S-substituents, and bearing glucos...
Article
Four-membered rings remain underexplored motifs despite offering attractive physicochemical properties for medicinal chemistry. Arylacetic acids bearing oxetanes, azetidines, and cyclobutanes are prepared in two steps: a catalytic Friedel-Crafts reaction from four-membered ring alcohol substrates, followed by mild oxidative cleavage. The suitabilit...
Preprint
Full-text available
Antidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake. Structural and biochemical studies aiming to understand the binding of small-molecules to conformationally dynamic transporters like SERT often require thermostabilizing mutations and antibodies to stabilize a specific conformation. Such modifications to SERT...
Article
A hindered β-amino amide transient directing group effects di-trans-arylation of cyclohexanecarbaldehydes. The amide N-substituents are shown to affect yield and can enhance the rate of arylation compared with the α-amino acid. Addition of a pyridone ligand further enhanced reactivity. The reaction is successful for a range of aryl iodides, and var...
Article
Despite their wide use in academia as metal-carbene precursors, diazo compounds are often avoided in industry owing to concerns over their instability, exothermic decomposition and potential explosive behaviour. The stability of sulfonyl azides and other diazo-transfer reagents is relatively well understood, but there is little reliable data availa...
Article
Palladium catalysed β-C(sp3)–H activation of tertiary aldehydes using a transient imine directing group enables intramolecular arylation to form substituted indane-aldehydes. A simple amine bearing a methyl ether (2-methoxyethan-1-amine) is the optimal TDG to promote C–H activation and reaction with an unactivated proximal C–Br bond. Substituent ef...
Article
Synthetic methods that can readily access saturated heterocycles with different substitution patterns and with control of stereo- and regiochemistry are of huge potential value in the development of new medicinal compounds. Directed C–H functionalization of simple and commercially available precursors offers the potential to prepare diverse collect...
Article
Directed C(sp<sup>3</sup>)–H functionalization has made enormous progress in recent years, but has largely been restricted to catalysis using noble metals, particularly palladium. However, since 2013, there have been prominent advances that exploit the reactivity of abundant first row transition metals for a multitude of new bond formations. The us...
Article
gem‐Diarylheterocycles display a wide range of biological activity. Here we present a systematic study into the formation of 4‐ to 6‐membered O‐ and N‐heterocycles and cyclobutanes bearing the diaryl motif through a catalytic Friedel–Crafts reaction from the corresponding benzylic alcohols. 3,3‐Diaryltetrahydrofurans, 4,4‐diaryltetrahydropyrans, 3,...
Article
New small ring derivatives can provide valuable motifs in new chemical space for drug design. 3-Aryl-3-sulfanyl azetidines are synthesized directly from azetidine-3-ols in excellent yield by a mild Fe-catalyzed thiol alkylation. A broad range of thiols and azetidinols bearing electron donating aromatics are successful, proceeding via an azetidine c...
Article
2-Azido-4,6-dimethoxy-1,3,5-triazine (ADT) was reported recently as a new ‘intrinsically safe’ diazo transfer reagent. This assessment was based on Differential Scanning Calorimetry (DSC) data indicating that ADT exhibits endothermic decomposition. We present DSC data on ADT that show exothermic decomposition with an initiation temperature (Tinit)...
Article
The ring expansion of 2-ester-2-arylazetidine carbamates can be achieved using Brønsted acids to form 6,6-disubstituted 1,3-oxazinan-2-ones. The reaction is rapid at room temperature with Boc or Cbz derivatives and proceeds with excellent yield (up to 96%) and broad substrate scope. Derivatives of drug compounds and natural products are incorporate...
Article
Full-text available
The synthesis of a new functional group in the form of selenyl-substituted aziridines is described. Selenoaziridines are stereoselectively prepared by functionalization of intact aziridine precursors involving radical and anionic intermediates. Radicals are generated from cis-N-Ts iodoaziridines by activation of the C-I bond using alkoxides as a so...
Article
Azetidines are valuable motifs that readily access under explored chemical space for drug discovery. 3,3-Diarylazetidines are prepared in high yield from N-Cbz azetidinols in a calcium(II)-catalyzed Friedel-Crafts alkylation of (hetero)aromatics and phenols, including complex phenols such as β-estradiol. Electron poor phenols undergo O-alkylation....
Article
Methods that provide rapid access to new heterocyclic structures in biologically relevant chemical space provide important opportunities in drug discovery. Here, a strategy is described for the preparation of 2,2‐disubstituted azetidines, pyrrolidines, piperidines and azepanes bearing ester and diverse aryl substituents. A one‐pot rhodium catalyzed...
Article
Methods that provide rapid access to new heterocyclic structures in biologically relevant chemical space provide important opportunities in drug discovery. Here, a strategy is described for the preparation of 2,2‐disubstituted azetidines, pyrrolidines, piperidines and azepanes bearing ester and diverse aryl substituents. A one‐pot rhodium catalyzed...
Article
Full-text available
C–H Functionalization of amines is a prominent challenge due to the strong complexation of amines to transition metal catalysts, and therefore typically requires derivatisation at nitrogen with a directing group. Transient directing groups (TDG) permit C–H functionalization in a single operation, without needing these additional steps for directing...
Article
Full-text available
The selective synthesis of cis-3,4-disubstituted pyrrolidines and piperidines is achieved by a Pd-catalyzed C–H arylation with excellent regio- and stereoselectivity using an aminoquinoline auxiliary at C(3). The arylation conditions are silver free, use a low catalyst loading, and employ inexpensive K2CO3 as a base. Directing group removal is acco...
Article
C–H Functionalisation promises a paradigm shift in synthetic planning. However, the additional steps often required to install and remove directing groups currently detracts from the efficiency. The strategy of reversible installation of a directing group via an imine linkage has recently emerged, with the imine formed and hydrolysed in situ. Such...
Article
Aryl thiols can be selectively converted to sulfonimidates or sulfonamides with three new S–X connections being made selectively in one pot. Using hypervalent iodine reagents in the presence of ammonium carbamate, NH- and O-groups are transferred under mild and practical conditions. Reducing the loading of ammonium carbamate changed the product dis...
Article
Full-text available
Surface functionalisation with viscosity sensitive dyes termed 'molecular rotors' can potentially open up new opportunities in sensing, for example for non-invasive biological viscosity imaging, in studying the effect of shear stress on lipid membranes and in cells, and in imaging contacts between surfaces upon applied pressure. We have functionali...
Article
Studies on the mechanism and intermediate products in the Friedel-Crafts reaction between oxetanols and phenols are presented. The formation of O-alkylated intermediates is identified using ¹H NMR spectroscopy, in a reversible formation of the kinetic oxetane ether products. An interesting relationship between the electronic nature of the nucleophi...
Article
Full-text available
Sulfanyl-oxetanes are presented as promising novel bioisosteric replacements for thioesters or benzyl sulfides. From oxetan-3-ols, a mild and inexpensive Li catalyst enables chemoselective C-OH activation and thiol alkylation. Oxetane sulfides are formed from various thiols providing novel motifs in new chemical space and specifically as bioisoster...
Article
Sulfoximines are emerging as valuable new isosteres for use in medicinal chemistry, with the potential to modulate physicochemical properties. Recent developments in synthetic strategies have made the unprotected ‘free’ NH-sulfoximine group more readily available, facilitating further study. This account reviews approaches to NH-sulfoximines, with...
Article
Full-text available
Cyclopropanes provide important design elements in medicinal chemistry and are widely present in drug compounds. Here we describe a strategy and extensive synthetic studies for the preparation of a diverse collection of cyclopropane-containing fragments, lead-like compounds and building blocks exploiting a single precursor. The bifunctional cyclopr...
Article
Full-text available
Changes in microscopic viscosity and macromolecular crowding accompany the transition of proteins from their monomeric forms into highly organised fibrillar states. Previously, we have demonstrated that viscosity sensitive fluorophores termed ‘molecular rotors’, when freely mixed with monomers of interest, are able to report on changes in microrheo...
Article
Full-text available
Simple amine and diamine derivatives can promote the palladium catalysed direct -C–H arylation of aliphatic aldehydes via transient imine formation. Trifluoroacetate was shown to be crucial in promoting the reaction. Sub-stoichiometric quantities of simple N-tosylethylenediamine was shown to form a bidentate directing group with an imine linkage....
Article
Full-text available
The plasma membranes of cells within the eye lens play an important role in metabolite transport within the avascular tissue of the lens, maintaining its transparency over the entire lifespan of an individual. Here we use viscosity-sensitive ‘molecular rotors’ to map the microscopic viscosity within these unusual cell membranes, establishing that t...
Article
Full-text available
The microscopic viscosity plays an essential role in cellular biophysics by controlling the rates of diffusion and bimolecular reactions within the cell interior. While several approaches have emerged that have allowed the measurement of viscosity and diffusion on a single cell level in vitro, the in vivo viscosity monitoring has not yet been reali...
Article
Direct synthesis of NH-sulfoximines from sulfides has been achieved through O and NH transfer in the same reaction, occurring with complete selectivity. The reaction is mediated by bisacetoxyiodobenzene under simple conditions and employs inexpensive N-sources. Preliminary studies indicate that NH-transfer is likely to be first, followed by oxidati...
Article
1,4-Dioxenes present interesting potential as synthetic intermediates, and as unusual motifs for incorporation into biologically active compounds. Here, an efficient synthesis of functionalized 1,4-dioxenes is achieved in two steps. Using keto-diazo compounds, a ruthenium catalyzed O-H insertion with β-halohydrins followed by treatment with base r...
Article
Full-text available
The first examples of 3,3-diaryloxetanes are prepared in a lithium-catalyzed and substrate dependent divergent Friedel-Crafts reaction. para-Selective Friedel-Crafts reactions of phenols using oxetan-3-ols afford 3,3-diaryloxetanes by displacement of the hydroxy group. These constitute new isosteres for benzophenones and diarylmethanes. Conversely,...
Article
An extremely useful method for the conversion of variously substituted sulfoxides to sulfoximines using ammonium carbamate as nitrogen source is reported.
Article
Using an 8-aminoquinoline-based directing group, the Pd-catalyzed C(sp3)—H arylation of saturated hetero- and carbocycles succeeds with high regio- and stereoselectivity.
Article
In the reactions of the title compounds with Grignard reagent the oxetanylsulfinyl group is retained.
Article
Full-text available
A new system for NH transfer is developed for the preparation of sulfoximines, which are emerging as valuable motifs for drug discovery. The protocol employs readily available sources of nitrogen without the requirement for either preactivation or for metal catalysts. Mixing ammonium salts with diacetoxyiodobenzene directly converts sulfoxides into...
Article
Full-text available
A new system for NH transfer is developed for the preparation of sulfoximines, which are emerging as valuable motifs for drug discovery. The protocol employs readily available sources of nitrogen without the requirement for either preactivation or for metal catalysts. Mixing ammonium salts with diacetoxyiodobenzene directly converts sulfoxides into...
Article
Full-text available
Saturated heterocycles, such as THFs, pyrrolidines, piperidines and THPs, are essential components of many biologically active compounds. Examples of C-H functionalization on these important ring systems remain scarce, especially at unactivated positions. Here we report the development of conditions for the palladium-catalyzed stereoselective C(sp3...
Article
The synthesis of 2-sulfinyl oxetanes is described by a C-C bond-forming cyclisation strategy. Oxetanes bearing electron-poor aryl sulfoxides are shown to be viable targets using this strategy. We report investigations into the sulfoxide magnesium exchange on 2-sulfinyl oxetanes, which resulted in products formed via ligand exchange and ligand coupl...
Article
Full-text available
Di-, tri- and tetra-substituted oxetane derivatives with combinations of ester, amide, nitrile, aryl, sulfone and phosphonate substituents are prepared as fragments or building blocks for drug discovery. The synthesis of these novel oxetane functional groups, in new chemical space, is achieved via rhodium-catalysed O-H insertion and C-C bond formin...
Article
α-Iodoaziridines are unusual motifs and intriguing structures for further functionalisation of the intact aziridine. The preparation of N-protected α-iodoaziridines is achieved through an addition-cyclisation reaction of LiCHI2 with imines. The effects of varying the N-group and using different carbenoids are investigated. Excellent cis-stereochemi...
Article
Full-text available
In order to fully understand the dynamics of processes within biological lipid membranes, it is necessary to possess an intimate knowledge of the physical state and ordering of lipids within the membrane. Here we report the use of three molecular rotors based on meso-substituted boron-dipyrrin (BODIPY) in combination with fluorescence lifetime spec...
Article
Recent interest in oxetanes in medicinal chemistry and as synthetic intermediates has led to the development of a number of methods for the synthesis of more functionalized and highly substituted oxetane derivatives. Here we review cyclization approaches for the preparation of 2-substituted oxetanes. Methods involving C-O bond formation, as well as...
Article
Sulfoximines are of considerable interest for incorporation into medicinal compounds. A convenient synthesis of N-protected sulfoximines is achieved, under mild conditions, by rhodium-catalyzed transfer of carbamates to sulfoxides. The first examples of 4-membered thietane-oximines are prepared. Sulfoximines bearing Boc and Cbz groups are stable to...
Article
2-(Arylsulfonyl)oxetanes have been prepared as new structural motifs of interest for medicinal chemistry. These are designed to fit within fragment space and be suitable for screening in fragment based drug discovery, as well as being suitable for further elaboration or incorporation into drug-like compounds. The oxetane ring is constructed through...
Article
Oxetanes offer exciting potential as structural motifs and intermediates in drug discovery and materials science. Here an efficient strategy for the synthesis of oxetane rings incorporating pendant functional groups is described. A wide variety of oxetane 2,2-dicarboxylates were accessed in high yields, including functionalized 3-/4-aryl- and alkyl...
Article
The highly diastereoselective preparation of cis-N-Ts-iodoaziridines through reaction of diiodomethyllithium with N-Ts aldimines is described. Diiodomethyllithium is prepared by the deprotonation of diiodomethane with LiHMDS, in a THF/diethyl ether mixture, at -78 °C in the dark. These conditions are essential for the stability of the LiCHI2 reagen...
Article
Lithium-iodine exchange on alkyl- or aryl-substituted N-tosyliodoaziridines afforded unstabilized aziridinyllithiums, which were subsequently trapped at low temperatures with a range of carbon and heteroatom electrophiles affording cis-substituted aziridines exclusively. When using isocyanates as electrophiles, access to aziridine carboxamides or 1...
Article
Molecular rotors have emerged as versatile probes for microscopic viscosity in live cells, however, the exclusive localisation of rotors in the plasma membrane has remained elusive. We report the synthesis, spectroscopic characterisation and live cell imaging of a new BODIPY-based molecular rotor suitable for mapping viscosity in the cell plasma me...