Author Archives: Louis Morrill

Synthetic Organic Electrochemistry

Manganese-Catalyzed Electrochemical Deconstructive Chlorination of Cycloalkanols via Alkoxy Radicals

Alkoxy radicals are highly transient species that exhibit diverse reactivity, including hydrogen atom transfer, addition to pi-systems and beta-scission processes. The generation of alkoxy radicals directly from aliphatic alcohols is challenging, partly due to the high dissociation energy of RO−H bonds (~105 kcal/mol).

A manganese-catalyzed electrochemical deconstructive chlorination of cycloalkanols has been developed. This electrochemical method provides access to alkoxy radicals from alcohols and exhibits a broad substrate scope, with various cyclopropanols and cyclobutanols converted into synthetically useful beta- and gamma-chlorinated ketones (40 examples). Furthermore, the combination of recirculating flow electrochemistry and continuous inline purification was employed to access products on gram scale (Org. Lett., 2019, 21, 9241-9246). [link]

Employing enabling tools (flow and mechanochemistry) for organocatalytic processes

Expedient Organocatalytic Aza-Morita-Baylis-Hillman Reaction Through Ball-Milling

A ball-milling enabled tertiary amine catalysed aza-Morita-Baylis-Hillman reaction is reported. The reaction process does not require solvent, has significantly shorter reaction times than previous methods, and is reported on a range of imines and acrylate Michael acceptors across more than 25 examples. A 12-fold scaled-up example is also reported as well as experimental comparisons to solution based experiments and neat-stirred reactions including (ACS Sustainable Chem. Eng., 2020, 8, 17876-17881. [link])

N-Heterocyclic Carbene Acyl Anion Organocatalysis by Ball-Milling

The ability to conduct N-Heterocyclic carbene catalysed acyl anion chemistry under ball-milling conditions is reported for the first time. This process has been exemplified through applications to intermolecular-benzoin, intramolecular-benzoin, intermolecular-Stetter and intramolecular-Stetter reactions including asymmetric examples and demonstrates that this mode of mechanistically complex organocatalytic reaction can operate under solvent minimised conditions (ChemSusChem, 2019, 13, 131-135. [link] [Hot Topic: Organocatalysis]).

Organocatalytic Artificial Enzymes

Transfer Hydrogenations Catalyzed by Steptavidin-hosted Seccondary Amine Organocatalyst

Here, the streptavidin-biotin technology was applied to enable organocatalytic transfer hydrogenation. By introducing a biotin-tethered pyrrolidine to the tetrameric streptavidin (T-Sav), the resulting hybrid catalyst was able to mediate hydride transfer from dihydro-benzylnicotinamide (BNAH) to α,β-unsaturated aldehydes. Hydrogenation of cinnamaldehyde and some of its aryl-substituted analogues was found to be nearly quantitative. Kinetic measurements revealed that the T-Sav:1 assembly possesses enzyme-like behavior, whereas isotope effect analysis, performed by QM/MM simulations, illustrated the step of hydride transfer is at least partially rate-limiting. These results have proven the concept that T-Sav can be used to host secondary amine-catalyzed transfer hydrogenations. (Chem. Commun., 2021, 57, 1919-1922) [link].

Streptavidin-hosted Organocatalytic Aldol Addition

In this report, the streptavidin-biotin technology has been applied to enable organocatalytic aldol condensation. By attaching pyrrolidine to the valeric motif of biotin and introducing to streptavidin (Sav), a protein-based organocatalytic system was created, and the aldol condensation of acetone with p-nitrobenzaldehyde was tested. The conversion of substrate to product can be as high as 93%. Although the observed enantioselectivity was only moderate (33:67 er), further protein engineering efforts can be included to improve the selectivity. These results have proven the concept that Sav can be used to host stereoselective aldol condensation. (Molecules, 2020, 25, 2457) [link]. [Invited contribution to the Hybrid Catalysts for Asymmetric Catalysis Special Issue] 

Reactivity and Selectivity of Iminium Organocatalysis Improved by a Protein Host

There has been growing interest in operating organocatalysis within a supramolecular system as means of controlling reaction reactivity and stereoselectivity. In a collaborative research effort led by Dr Louis Luk, a protein is used as host for iminium catalysis; a pyrrolidine moiety is covalently linked to biotin, introduces to the protein host streptavidin and tested for organocatalytic activity (Angew. Chem. Int. Ed., 2018, 57, 12478-12482) [link]. Whereas in traditional systems, stereoselectivity is largely controlled by the substituents added to the organocatalyst, enantiomeric enrichment by the reported supramolecular system is completely controlled by the host. Also, the yield of the model reaction increases over 10-fold when streptavidin is included. A 1.1-Å crystal structure of the protein-catalyst complex and molecular simulations of a key intermediate reveal the chiral scaffold surrounding the organocatalytic reaction site. This work illustrates that proteins can be an excellent supramolecular host for driving stereoselective secondary amine organocatalysis.

Group Spatulas

Borrowing Hydrogen Catalysis

Borrowing Hydrogen for Organic Synthesis

Borrowing hydrogen is a process that is used to diversify the synthetic utility of commodity alcohols. A catalyst firstly oxidizes an alcohol by removing hydrogen to form a reactive carbonyl compound. This intermediate can undergo a diverse range of subsequent transformations before the catalyst returns the “borrowed” hydrogen to liberate the product and regenerate the catalyst. In this way, alcohols may be used as alkylating agents whereby the sole byproduct of this one-pot reaction is water. In recent decades, significant advances have been made in this area, demonstrating many effective methods to access valuable products. This outlook highlights the diversity of metal and biocatalysts that are available for this approach, as well as the various transformations that can be performed, focusing on a selection of the most significant and recent advances. By succinctly describing and conveying the versatility of borrowing hydrogen chemistry, we anticipate its uptake will increase across a wider scientific audience, expanding opportunities for further development. (ACS Cent. Sci., 2021, 7, 570-585) [link]

Transition Metal Free α-C-Alkylation of Ketones Using Secondary Alcohols

Alkylation is a fundamental transformation in synthetic chemistry that is routinely performed across the entire spectrum of chemical industries. Traditionally, hazardous alkyl (pseudo)halides are commonly employed for alkylation processes, which can result in non-selective transformations due to multiple alkylation, whilst generating stoichiometric waste products that must be separated from the target compound. As such, the development of selective alkylation methodologies that employ less toxic reagents, whilst generating benign by-products, is an important goal for improving sustainability within the synthetic community.

A base-mediated α-C-alkylation of ketones with secondary alcohols has been developed as an alternative to borrowing hydrogen-type alkylation. This transition metal free approach employs KOt-Bu as the base and exhibits a broad scope, allowing a range of commodity aliphatic secondary alcohols and 1-arylethanols to be employed as alkylating agents. Aryl methyl ketones undergo selective mono-α-C-alkylation in high isolated yields (23 examples, 65% average yield). (Tetrahedron, 2020, 76, 131571) [link] [Invited contribution to the Special Issue on Strategies for Efficient Organic Synthesis Dedicated to the Achievements of Prof. Jonathan Williams]

Manganese-Catalyzed One-Pot Conversion of Nitroarenes into N-Methylarylamines Using Methanol

N-methylamines are an important structural motif that feature within a diverse array of useful compounds, including medicines, agrochemicals, dyes and surfactants. More specifically, N-methylarylamines can be found within a broad range of pharmaceuticals, including Rosiglitazone, Clobazam and Osimertinib. Traditional methods for N-methylation of arylamines include the use of hazardous reagents such as methyl iodide, dimethyl sulfate and diazomethane, which typically produce a mixture of mono- and di-methylated arylamines whilst generating stoichiometric quantities of waste. Reductive couplings of arylamines with carbon dioxide or formic acid can also be employed for N-methylation. Alternatively, the borrowing hydrogen approach enables methanol to be employed as the methylating agent for the selective mono-N-methylation of anilines.

A manganese-catalyzed one-pot conversion of nitroarenes into N-methylarylamines has been developed. This transfer hydrogenation method employs a well-defined bench stable Mn PN3P pincer precatalyst in combination with methanol as both the reductant and the C1 source. A selection of commercially available nitroarenes was converted into N-methylarylamines in synthetically useful yields. (Eur. J. Org. Chem., 2020, 1136-1140) [link] [Invited contribution to the YourJOC Talents Special Issue]

Iron-Catalyzed Borrowing Hydrogen βC(sp3)-Methylation of Alcohols

Allylic alcohols are privileged motifs in synthetic chemistry due to their widespread availability and diverse reactivity profile. An important transformation of allylic alcohols is the redox isomerization to form synthetically useful enolizable carbonyl compounds, which can be performed using metal catalysts or Brønsted base catalysts. The subsequent incorporation of methyl groups via a-C(sp3)-methylation can significantly impact the pharmacological properties of a molecule. Many commonly employed methylation protocols utilize hazardous reagents such as methyl iodide, diazomethane, or dimethyl sulfate. However, recent advances in borrowing hydrogen catalysis have enabled methanol to be employed as an attractive alternative for ketone a-C(sp3)-methylation, using catalysts based on both precious metals and more abundant 3d transition metals.

A one-pot iron-catalyzed conversion of allylic alcohols to a-methyl ketones has been developed. This isomerization-methylation strategy utilized a (cyclopentadienone)iron(0) carbonyl complex as precatalyst and methanol as the C1 source. A diverse range of allylic alcohols undergo isomerization-methylation to form a-methyl ketones in good isolated yields (up to 84% isolated yield) (Org. Lett., 2019, 21, 7914-7918) [link].

Iron-Catalyzed Borrowing Hydrogen βC(sp3)-Methylation of Alcohols

The incorporation of methyl groups can have a significant impact upon the pharmacological properties of a molecule. Inspection of Njarđarson’s poster entitled “Top 200 Brand Name Drugs by Prescription in 2016” reveals that a significant proportion contain the C(sp3)−Me motif. As such, the development of new synthetic methods for the direct methylation of C(sp3)−H bonds is an important area of scientific endeavor. Methanol is an attractive reagent for methylation processes. It is an abundant, biodegradable liquid that is less hazardous relative to commonly employed methylation reagents such as diazomethane, dimethyl sulfate and iodomethane.

We report the iron-catalyzed β-C(sp3)-methylation of primary alcohols using methanol as a C1 building block. This borrowing hydrogen approach employs a well-defined bench stable (cyclopentadienone)iron(0) carbonyl complex as precatalyst (5 mol %) and enables a diverse selection of substituted 2-arylethanols to undergo β-C(sp3)-methylation in good isolated yields (24 examples, 65% average yield) (ACS Catal., 2019, 9, 8575-8580) [link] [Highlighted in Synfacts, 2019, 15, 1280] [link]

Iron-Catalyzed Borrowing Hydrogen C-Alkylation of Oxindoles Using Alcohols

The oxindole framework is present in a diverse array of naturally occurring compounds. Furthermore, oxindoles that are mono- or disubstituted at the C(3) position are commonly employed in drug discovery programmes, with examples including the development of HIV-1 non-nucleoside reverse transcriptase inhibitors, spircocyclic compounds with anti-cancer and anti-inflammatory properties, and antagonists of progesterone and 5-hydroxytryptamine7 (5-HT7) receptors. The traditional method for alkylation of unprotected oxindoles employs toxic alkyl halides and exhibits poor selectivity (mono- vs. dialkylation, C– vs. N-alkylation) alongside the generation of stoichiometric quantities of undesired byproducts. An alternative approach employs the borrowing hydrogen (BH) principle, also known as hydrogen autotransfer, which allows bench stable and inexpensive alcohols to be used as alkylating agents, generating water as the sole byproduct

A general and efficient iron-catalyzed C-alkylation of oxindoles has been developed. This borrowing hydrogen approach employs a (cyclopentadienone)iron carbonyl complex (2 mol %) and exhibits a broad reaction scope, allowing benzylic and simple primary and secondary aliphatic alcohols to be employed as alkylating agents. A variety of oxindoles undergo selective mono-C(3)-alkylation in good to excellent isolated yields (28 examples, 50-92% yield, 79% average yield) (ChemSusChem, 2019, 12, 2345-2349) [link].

Manganese-Catalyzed N-Alkylation of Sulfonamides Using Alcohols

The sulfonamide functional group is present in a diverse array of bioactive compounds. More specifically, N-alkylsulfonamides are commonly employed in drug discovery programmes. Classical methods for N-alkylsulfonamide synthesis include the reaction of amines with activated sulfonyl derivatives (commonly sulfonyl chlorides), N-alkylation of primary sulfonamides with alkyl halides, and reductive amidation using aldehydes. Drawbacks of these methods include limited availability and stability of specific sulfonyl chlorides, the use of toxic alkylating agents, and the stoichiometric generation of undesired by-products. In contrast, the borrowing hydrogen (BH) approach allows commodity alcohols to be employed as alkylating agents, with water generated as the only by-product. Traditionally, BH processes have employed precious metal catalysts. However, as part of ongoing efforts to reduce our dependence on precious metal catalysts, recent advances have demonstrated the use of earth-abundant first row transition metal catalysts across a variety of borrowing hydrogen processes.

An efficient manganese-catalyzed N-alkylation of sulfonamides has been developed. This borrowing hydrogen approach employs a well-defined and bench stable Mn(I) PNP pincer precatalyst, allowing benzylic and simple primary aliphatic alcohols to be employed as alkylating agents. A diverse range of aryl and alkyl sulfonamides undergoes mono-N-alkylation in excellent isolated yields (32 examples, 85% average yield) (J. Org. Chem., 2019, 84, 3715-3724) [link] [Highlighted in Organic Chemistry Portal] [link].

Recent Advances in Homogeneous Borrowing Hydrogen Catalysis Using Earth-Abundant First Row Transition Metals

The borrowing hydrogen (BH) approach, also known as hydrogen autotransfer, combines a transfer hydrogenation process with a concurrent reaction on the in situ generated reactive intermediate. This one-pot oxidation-reaction- reduction sequence has received much attention due to its inherent high atom economy, permitting alcohols or amines to be employed as alkylating agents, generating water or ammonia as the sole by-products, respectively. Traditionally, borrowing hydrogen processes have employed precious second and third row transition metal catalysts, specifically those based on Ru, Os, Rh and Ir, to perform hydrogen transfer. However, in line with the increasing global challenge to develop more sustainable catalytic methodologies for the production of chemicals for society, there has been a concerted effort within the scientific community to seek alternatives to catalysts based on precious metals by diversifying the utility of earth-abundant first row transition metals in catalysis. In this context, this review highlights the recent advances (2013-present) in the use of earth-abundant first row transition metals in homogeneous borrowing hydrogen catalysis. The utility of catalysts based on Mn, Fe, Co, Ni and Cu to promote a diverse array of important C−C and C−N bond forming reactions is described, including discussion on reaction mechanisms, scope and limitations, and future challenges in this burgeoning area of sustainable catalysis. (Org. Biomol. Chem., 2019, 17, 1595-1607) [link]. [Invited contribution to the New Talent Special Issue]

Iron-Catalyzed Methylation using the Borrowing Hydrogen Approach

Methylation is a fundamental transformation in synthetic chemistry that is widely used for the synthesis and functionalization of fine chemicals. Traditional methylation procedures often employ toxic and/or potentially explosive reagents including iodomethane, dimethyl sulfate or diazomethane, among many others. In recent years, methanol, an abundant and biodegradable liquid, has emerged as an attractive alternative reagent for methylation. Borrowing hydrogen (BH), or hydrogen autotransfer, combines a transfer hydrogenation process with a concurrent reaction on the in situ generated reactive intermediate. This one-pot oxidation-reaction-reduction sequence has received much attention due to its inherent high atom economy and minimal waste generation, allowing bench stable and inexpensive alcohols to be used as alkylating agents. In comparison to benzyl and long-chain n-alkyl alcohols, it is challenging to use methanol as the alkylating agent in BH processes, due partly to the increased energy of dehydrogenation (∆H (MeOH) = +84 kJ mol-1, cf. ∆H (EtOH) = +68 kJ mol-1) to form the required transient reactive formaldehyde intermediate.

A general iron-catalyzed methylation has been developed using methanol as a C1 building block. This borrowing hydrogen approach employs a Knölker-type (cyclopentadienone)iron carbonyl complex as catalyst (2 mol %) and exhibits a broad reaction scope. A variety of ketones, indoles, oxindoles, amines and sulfonamides undergo mono- or dimethylation in excellent isolated yields (>60 examples, 79% average yield) (ACS Catal., 2018, 8, 6440-6445) [link].

Exploring Tandem Ruthenium-Catalyzed Hydrogen Transfer and SNAr Chemistry

The carbonyl functional group is one of the most prevalent and versatile in chemistry. However, in some cases, carbonyl compounds suffer from poor stability (e.g., air oxidation of aldehydes to carboxylic acids; enolization leading to deleterious side reactions and erosion of enantiopurity) and limited commercial availability. In comparison, alcohols are typically widely available, inexpensive and relatively inert toward air, moisture and light, making them highly attractive starting materials for synthesis. Furthermore, the alcohol functional group is ubiquitous in pharmaceuticals, agrochemicals, dyes, fragrances, polymers, functional materials and catalysts. As such, the development of novel methods that directly functionalize alcohols, diversifying their reactivity profile, is an important pursuit.

Hydrogen transfer is a powerful approach that can be employed to access the diverse reactivity of carbonyl compounds from alcohol starting materials. Dehydrogenation of secondary alcohol substrates accesses ketones that can react with both nucleophiles and electrophiles (via enolization) in a variety of important reactions including C−C or C−N bond formation. Dehydrogenation of allylic and benzylic alcohols dramatically alters the properties and reactivity of the olefin and arene, respectively, via electronic activation. We have developed a hydrogen transfer strategy for the catalytic functionalization of benzylic alcohols via electronic arene activation, accessing a diverse range of bespoke diaryl ethers and aryl amines in excellent isolated yields (38 examples, 70% average yield). Taking advantage of the hydrogen transfer approach, the oxidation level of the functionalized products can be selected by judicious choice of simple and inexpensive additives (Org. Lett., 2017, 19, 6716-6719) [link].

Frustrated Lewis Pair (FLP) / Main Group Catalysis

Electron deficient borane-mediated hydride abstraction in amines: stoichiometric and catalytic processes

The manipulation of amino C–H bonds has garnered significant interest from the synthetic community due to its inherently high atom, step and redox economy. This Tutorial Review summarises the ability of boranes to mediate hydride abstraction from α-amino and γ-amino conjugated C–H bonds. Borane-mediated hydride abstraction results in the generation of reactive iminium hydridoborate salts that participate in a variety of stoichiometric and catalytic processes. The reactions that have utilised this unusual reactivity include those that manipulate amino scaffolds (including dehydrogenation, racemisation, isomerisation, α- and β-functionalisation, and C–N bond cleavage) and those that use amine-based reagents (transfer hydrogenation, and alkylation) (Chem. Soc. Rev., 2021, 50, 3720-3737). [link]

B(C6F5)3-Catalyzed Direct C3 Alkylation of Indoles and Oxindoles

Owing to their intrinsic Lewis acidity, borane catalysts have found numerous applications in synthesis and are traditionally used to activate polarized bonds. Triaryl boranes can also activate unpolarized bonds, such as H–H and Si–H bonds. In a similar vein, we considered if boranes could also be used to cleave heterolytically C(sp3)–H bonds and unveil new approaches to challenging transformations

The direct C3 alkylation of indoles and oxindoles is a challenging transformation and only a few direct methods exist. Utilizing the underexplored ability of triaryl boranes to mediate the heterolytic cleavage of α-nitrogen C–H bonds in amines, in a collaborative research effort with the Pulis and Melen labs, we have developed a catalytic approach for the direct C3 alkylation of a wide range of indoles and oxindoles using amine based alkylating agents. We also employed this borane-catalyzed strategy in an alkylation-ring opening cascade (ACS Catal., 2020, 10, 4835-4840) [link].

FLP-Catalyzed Transfer Hydrogenation of Silyl Enol Ethers

Silyl enol ethers have often served as a test bed for the development of novel FLP catalytic systems. In contrast to imines and N-heterocycles, which can serve the role of the Lewis base within an FLP-type system, the lower basicity of silyl enol ethers necessitates an additional Lewis base for dihydrogen activation and subsequent hydrogenation.

In a collaborative research effort with the Melen lab, we developed the first catalytic transfer hydrogenation of silyl enol ethers. This metal free approach employs tris(pentafluorophenyl)borane and 2,2,6,6-tetramethylpiperidine (TMP) as a commercially available FLP catalyst system and naturally occurring γ-terpinene as a dihydrogen surrogate. A variety of silyl enol ethers undergo efficient hydrogenation, with the reduced products isolated in excellent yields (29 examples, 82% average yield) (Angew. Chem. Int. Ed., 2018, 57, 12356-12359) [link].

Frustrated Lewis Pair (FLP)-Catalyzed Hydrogenation of Aza-Morita-Baylis-Hillman Adducts and Sequential Organo-FLP Catalysis

Over the past 10 years there has been a surge or research into frustrated Lewis pairs (FLPs). Of particular interest is the ability of FLPs to activate hydrogen for metal-free hydrogenation processes. Despite intensive research efforts, the substrate scope of FLP-catalyzed hydrogenation is somewhat narrow and applications of FLP catalysis in wider organic synthesis remain scarce. FLP-catalyzed hydrogenations of electron-deficient olefins are particularly challenging, often requiring the use of specialized Lewis acidic boranes, out with B(C6F5)3.

In a collaborative research effort with the Melen lab, we developed a metal-free diastereoselective FLP-catalyzed hydrogenation of aza-Morita-Baylis-Hillman (aza-MBH) adducts, accessing a diverse range of stereodefined β-amino acid derivatives in excellent isolated yields (28 examples, 89% average yield, up to 90:10 d.r.). Furthermore, the first example of sequential organo-FLP catalysis has been developed. An initial organocatalyzed aza-MBH reaction followed by in situ FLP formation and hydrogenation of the electron deficient α,β-unsaturated carbonyl compounds can be performed in one-pot, using DABCO as the Lewis base in both catalytic steps (ACS Catal., 2017, 7, 7748-7752) [link].

New Synthetic Lab

Exploring new synthetic routes towards cyanamides

Synthesis and Reactivity of N-Allenyl Cyanamides

Allenamides, also referred to as N-allenyl amides, are versatile synthetic building blocks in organic chemistry. In comparison to allenamines, which require careful preparation and handling due to their susceptibility toward hydrolysis and polymerization, allenamides exhibit enhanced stability due to delocalization of the nitrogen lone pair of electrons into the electron-withdrawing carbonyl. In addition to N-acyl allenamides, alternative classes have been introduced through variation of the electron-withdrawing N-substituent, including N-phosphoryl, N-sulfonyl, and N-heteroaryl allenamides.

Continuing our collaboration with SyngentaN-allenyl cyanamides have been accessed via a one-pot deoxycyanamidation-isomerization approach using propargyl alcohol and N-cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS). The utility of this novel class of allenamide was explored through derivatization, with hydroarylation, hydroamination and cycloaddition protocols employed to access an array of cyanamide products that would be challenging to access using existing methods (Org. Lett., 2018, 20, 5282-5285) [link].

Deoxycyanamidation of Alcohols with N-Cyano-N-Phenyl-p-Methylbenzenesulfonamide (NCTS)

Electrophilic cyanation describes the reaction of C-, N-, O– and S-based nucleophiles with electrophilic nitrile sources “+CN”. Traditionally, cyanogen halides have been employed for this purpose, but their high associated toxicity has driven the development of alternative electrophilic cyanating reagents including cyanates (O-CN), thiocyanates (S-CN), cyanamides (N-CN), nitriles (C-CN) and hypervalent iodine reagents (I-CN). Among these reagents, N-cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS), has been employed in a variety of N– and C-cyanation processes. However, the alternative desulfonylative reactivity pathway of NCTS remains largely under developed.

Continuing our collaboration with Syngenta, we developed the first one-pot deoxycyanamidation of alcohols using NCTS as both a sulfonyl transfer reagent and cyanamide source, accessing a diverse range of tertiary cyanamides in excellent isolated yields (Org. Lett., 2017, 19, 3835-3838) [link]. Mechanistic investigations (both experimental and computational) probed reaction intermediates, additive effects and the observed N– to O-sulfonyl transfer.

N-Cyanation of Secondary Amines using Trichloroacetonitrile

The cyanamide functionality is present in a variety of biologically active compounds including natural products, agrochemicals, and pharmaceuticals. Furthermore, cyanamides have diverse synthetic applications, serving as building blocks in the production of amidines, guanidines and various heterocyclic scaffolds. Despite their significance, the most commonly employed method for cyanamide synthesis remains the electrophilic N-cyanation of amines using highly toxic cyanogen bromide.

In a collaborative research effort with Syngenta, we developed a one-pot N-cyanation of secondary amines using trichloroacetonitrile as an inexpensive cyano source (Org. Lett., 2016, 18, 5528-5531) [link]. A diverse range of cyclic and acyclic secondary amines can be readily transformed into the corresponding cyanamides in good isolated yields, with the method successfully utilised in the final synthetic step of a biologically active rolipram-derived cyanamide. This approach exhibits distinct selectivity when compared to the use of highly toxic cyanogen bromide.

Celebrating group publications

Past Group Members

Postdoctoral Research Associates

Dr Shyam Basak (EPSRC Funded PDRA Oct 2019 – Nov 2020, Collaborative project with Dr Duncan Browne and Prof. Thomas Wirth; Leverhulme Trust Funded PDRA Sept 2018 – Sept 2019, Collaborative project with Dr Rebecca Melen)

Next position: Senior Scientist, Sygnature Discovery, Nottingham, UK

Group spatula: [link]

Publications:

  1. “Electron deficient borane-mediated hydride abstraction in amines: stoichiometric and catalytic processes”, S. Basak, L. Winfrey, B. A. Kustiana, R. L. Melen*, L. C. Morrill* and A. P. Pulis*, Chem. Soc. Rev., 2021, 50, 3720-3737. [link]
  2. B(C6F5)3-Catalyzed Direct C3 Alkylation of Indoles and Oxindoles”, S. Basak, A. Alvarez-Montoya, L. Winfrey, R. L. Melen*, L. C. Morrill* and A. P. Pulis*, ACS Catal., 2020, 10, 4835-4840. [link]

Dr Alex Nödling (Leverhulme Trust Funded PDRA since July 2017-July 2020, Collaborative project led by Dr Louis Luk)

Next position: Senior Scientist, Agenus, Cambridge Science Park, UK

Publications:

  1. “Reactivity and Selectivity of Iminium Organocatalysis Improved by a Protein Host”, A. R. Nödling, K. Swiderek, R. Castillo, J. W. Hall, A. Angelastro, L. C. Morrill, Y. Jin, Y-H. Tsai, V. Moliner* and L. Y. P. Luk*, Angew. Chem. Int. Ed., 2018, 57, 12478-12482. [link]

Dr Ben Allen (EPSRC Funded PDRA, Collaborative project with Dr Duncan Browne and Prof. Thomas WirthNov 2017 – Nov 2019)

Next position: Senior Scientist, Pharmaron, Cardiff, UK

Group spatula: [link]

Publications:

  1. “Manganese-Catalyzed Electrochemical Deconstructive Chlorination of Cycloalkanols via Alkoxy Radicals”, B. D. W. Allen,† M. D. Hareram,† A. C. Seastram, T. McBride, T. Wirth, D. L. Browne* and L. C. Morrill*, Org. Lett., 2019, 21, 9241-9246. [link] [Associated correction to citations] [link]
  2. Iron-Catalyzed Methylation using the Borrowing Hydrogen Approach”, K. Polidano, B. D. W. Allen, J. M. J. Williams and L. C. Morrill*, ACS Catal., 2018, 8, 6440-6445. [link]

Conference Contributions:

  1. Enabling Technologies for Synthesis Workshop, Cardiff University, 28/06/19, Presentation

Dr Imtiaz Khan (Leverhulme Trust Funded PDRA, Collaborative project with Dr Rebecca MelenJun 2016 – Jun 2018)

Next position: PDRA, The University of Manchester, Advisor: Prof. James Micklefield

Group spatula: [link]

Publications:

  1. “FLP-Catalyzed Transfer Hydrogenation of Silyl Enol Ethers”, I. Khan, B. G. Reed-Berendt, R. L. Melen* and L. C. Morrill*, Angew. Chem. Int. Ed., 2018, 57, 12356-12359. [link]
  2. Frustrated Lewis Pair (FLP)-Catalyzed Hydrogenation of Aza-Morita-Baylis-Hillman Adducts and Sequential Organo-FLP Catalysis”, I. Khan, M. Manzotti, G. J. Tizzard, S. J. Coles, R. L. Melen* and L. C. Morrill*, ACS Catal., 2017, 7, 7748-7752. [link]

Conference Contributions:

  1. RSC Organic Division South-West Regional Meeting, University of Bristol, 17/01/18, Poster
  2. 254th ACS National Meeting & Exposition, Washington, DC, 20/08/17, Presentation
  3. 10th Molecular Synthesis Section Seminar, Cardiff University, 13/07/17, Presentation

PhD Students

Benjamin Reed-Berendt (Ph.D. student Oct 2016 – Mar 2020)

Ph.D. Examiners: Dr Stephen Thomas (external), Dr Ian Fallis (internal)

Next position: Process Development Chemist, CatSci, Cardiff, UK

Group spatula: [link]

Publications:

  1. “Borrowing Hydrogen for Organic Synthesis”, B. G. Reed-Berendt,† D. E. Latham,† M. B. Dambatta and L. C. Morrill*, ACS Cent. Sci., 2021, 7, 570-585. [link]
  2. Manganese-Catalyzed One-Pot Conversion of Nitroarenes into N-Methylarylamines Using Methanol“, B. G. Reed-Berendt, N. Mast and L. C. Morrill*, Eur. J. Org. Chem., 2020, 1136-1140. [link] [Invited contribution to the YourJOC Talents Special Issue] 
  3. N-Heterocyclic Carbene Acyl Anion Organocatalysis by Ball-Milling“, W. I. Nicholson, A. C. Seastram, S. A. Iqbal, B. G. Reed-Berendt, L. C. Morrill* and D. L. Browne*, ChemSusChem, 2019, 13, 131-135. [link] [Hot Topic: Organocatalysis]
  4. “Manganese-Catalyzed N-Alkylation of Sulfonamides Using Alcohols“, B. G. Reed-Berendt and L. C. Morrill*, J. Org. Chem., 2019, 84, 3715-3724. [link] [Highlighted in Organic Chemistry Portal] [link]
  5. “Recent Advances in Homogeneous Borrowing Hydrogen Catalysis using Earth-Abundant First Row Transition Metals”, B. G. Reed-Berendt, K. Polidano and L. C. Morrill*, Org. Biomol. Chem., 2019, 17, 1595-1607. [link[Invited contribution to the New Talent Special Issue]
  6. “FLP-Catalyzed Transfer Hydrogenation of Silyl Enol Ethers”, I. Khan, B. G. Reed-Berendt, R. L. Melen* and L. C. Morrill*, Angew. Chem. Int. Ed., 2018, 57, 12356-12359. [link]
  7. Exploring Tandem Ruthenium-Catalyzed Hydrogen Transfer and SNAr Chemistry”, K. Polidano, B. G. Reed-Berendt, A. Basset, A. J. A. Watson, J. M. J. Williams and L. C. Morrill*, Org. Lett., 2017, 19, 6716-6719. [link]

Conference Contributions:

  1. 18th Annual Cardiff Chemistry Conference, Cardiff University, 15/05/19, Presentation 
  2. RSC Organic Division South-West Regional Meeting, Cardiff University, 24/01/19, Poster
  3. 13th Molecular Synthesis Section Seminar, Cardiff University, 18/01/18, Presentation
  4. RSC Organic Division South-West Regional Meeting, University of Bristol, 17/01/18, Poster

Kurt Polidano (CDT Ph.D. student since Oct 2016 – Oct 2019, CDT co-advisor: Prof. Jonathan Williams)

Ph.D. Examiners: Prof Steve Marsden (external), Dr Ben Ward (internal)

Next position: Process Development Chemist, CatSci, Cardiff, UK

Group spatula: [link]

Publications:

  1. One-Pot Conversion of Allylic Alcohols to α-Methyl Ketones via Iron-Catalyzed Isomerization-Methylation“, D. E. Latham, K. Polidano, J. M. J. Williams and L. C. Morrill*, Org. Lett., 2019, 21, 7914-7918. [link]
  2. “Iron-Catalyzed Borrowing Hydrogen β-C(sp3)-Methylation of Alcohols“, K. Polidano, J. M. J. Williams and L. C. Morrill*, ACS Catal., 2019, 9, 8575-8580. [link] [Highlighted in Synfacts, 2019, 15, 1280] [link]
  3. “Iron-Catalyzed Borrowing Hydrogen C-Alkylation of Oxindoles Using Alcohols“, M. B. Dambatta, K. Polidano, A. D. Northey, J. M. J. Williams and L. C. Morrill*, ChemSusChem, 2019, 12, 2345-2349. [link]
  4. “Recent Advances in Homogeneous Borrowing Hydrogen Catalysis using Earth-Abundant First Row Transition Metals”, B. G. Reed-Berendt, K. Polidano and L. C. Morrill*, Org. Biomol. Chem., 2019, 17, 1595-1607. [link[Invited contribution to the New Talent Special Issue]
  5. Iron-Catalyzed Methylation using the Borrowing Hydrogen Approach”, K. Polidano, B. D. W. Allen, J. M. J. Williams and L. C. Morrill*, ACS Catal., 2018, 8, 6440-6445. [link]
  6. Exploring Tandem Ruthenium-Catalyzed Hydrogen Transfer and SNAr Chemistry”, K. Polidano, B. G. Reed-Berendt, A. Basset, A. J. A. Watson, J. M. J. Williams and L. C. Morrill*, Org. Lett., 2017, 19, 6716-6719. [link]

Conference Contributions:

  1. EPSRC CDT Catalysis Spring Conference, Cardiff University, 06/06/19, Presentation and Poster
  2. RSC Organic Division South-West Regional Meeting, Cardiff University, 24/01/19, Poster
  3. 14th Molecular Synthesis Section Seminar, Cardiff University, 15/03/18, Presentation
  4. RSC Organic Division South-West Regional Meeting, University of Bristol, 17/01/18, Poster
  5. EPSRC CDT Catalysis Spring Conference, Cardiff University, 06/06/17, Presentation and Poster

James Ayres (PhD student, Oct 2015 – Sept 2018)

Ph.D. Examiners: Dr Marc Kimber (external), Prof. Thomas Wirth (internal)

Next position: PDRA, The University of Leeds, Advisor: Dr Richard Foster

Group spatula: [link]

Publications:

  1. “Synthesis and Reactivity of N-Allenyl Cyanamides”, J. N. Ayres, M. T. J. Williams, G. J. Tizzard, S. J. Coles, K. B. Ling and L. C. Morrill*, Org. Lett., 2018, 20, 5282-5285. [link]
  2. “Deoxycyanamidation of Alcohols with N-Cyano-N-Phenyl-p-Methylbenzenesulfonamide (NCTS)”, J. N. Ayres, M. W. Ashford, Y. Stöckl, V. Prudhomme, K. B. Ling, J. A. Platts and L. C. Morrill*, Org. Lett., 2017, 19, 3835-3838. [link]
  3. “N-Cyanation of Secondary Amines using Trichloroacetonitrile”, J. N. Ayres, K. B. Ling* and L. C. Morrill*, Org. Lett., 2016, 18, 5528-5531. [link]

Conference Contributions:

  1. RSC Organic Division South-West Regional Meeting, University of Bristol, 17/01/18, Poster
  2. Departmental Seminar, Indian Institute of Chemical Technology (IICT), Hyderabad, India, 22/11/17, Presentation
  3. J-NOST-13 Conference, Banaras Hindu University, Lucknow University, India, 09/11/17, Presentation
  4. 32nd Postgraduate Symposium of the RSC Heterocyclic and Synthesis Group, London, 20/09/17, Poster and Presentation
  5. 10th Molecular Synthesis Section Seminar, Cardiff University, 13/07/17, Session Chair
  6. Bio-Techne Chemistry Poster Symposium, Bristol, 25/05/17, Poster
  7. 16th Cardiff Chemistry Conference, Cardiff University, 15/05/17, Poster
  8. 8th Molecular Synthesis Section Seminar, Cardiff University, 16/03/17, Presentation
  9. RSC Organic Division South-West Regional Meeting, University of Bath, 01/02/17, Poster

CDT Research Sabbatical Students

Taniya Shandil (Catalysis CDT research sabbatical 1 student, CDT co-advisor: Prof. Jonathan Williams, Jun-Sept 2016)

Mattia Manzotti (Catalysis CDT research sabbatical 1 student, Collaborative project led by Dr Rebecca Melen, Jan-May 2016)

Next position: PhD, Bristol University, Advisor: Prof. Robin Bedford

Publications:

  1. “Frustrated Lewis Pair (FLP)-Catalyzed Hydrogenation of Aza-Morita-Baylis-Hillman Adducts and Sequential Organo-FLP Catalysis”, I. Khan, M. Manzotti, G. J. Tizzard, S. J. Coles, R. L. Melen* and L. C. Morrill*, ACS Catal., 2017, 7, 7748-7752. [link]

Jonathan Hall (Catalysis CDT research sabbatical 1 student, Collaborative project led by Dr Louis Luk, Jan-May 2016)

Next position: PhD, Bath University, Advisor: Prof. Mike Whittlesey

Publications:

  1. “Reactivity and Selectivity of Iminium Organocatalysis Improved by a Protein Host”, A. R. Nödling, K. Swiderek, R. Castillo, J. W. Hall, A. Angelastro, L. C. Morrill, Y. Jin, Y-H. Tsai, V. Moliner* and L. Y. P. Luk*, Angew. Chem. Int. Ed., 2018, 57, 12478-12482. [link]

Postgraduate Project Students

Seán O’Rourke (MSc medicinal chemistry postgraduate researcher, Jun – Aug 2019)

Undergraduate Project Students (MChem)

Joe Santos (MChem project student, Oct 2019 – May 2020)

Publications:

  1. Transition Metal Free α-C-Alkylation of Ketones Using Secondary Alcohols“, M. B. Dambatta, J. Santos, R. R. A. Bolt and L. C. Morrill*, Tetrahedron, 2020, 76, 131571. [link] [Invited contribution to the Special Issue on Strategies for Efficient Organic Synthesis Dedicated to the Achievements of Prof. Jonathan Williams]

Mark Shuttleworth (MChem project student, Oct 2019 – May 2020)

Next position: PhD, University of Bath, Advisor: Dr James Taylor

Ioan Bale (MChem project student, Oct 2019 – May 2020)

Alex Bardsley (MChem project student, Oct 2018 – May 2019)

Callum Adams (MChem project student, Oct 2018 – May 2019)

Next position: PhD, University of St Andrews, Advisor: Dr Craig Johnston

Beth Grattidge (MChem project student, Oct 2018 – May 2019)

Alex Seastram (MChem project student, Oct 2017 – May 2018)

Prizes: Outstanding 4th year MChem Performance

Next position: PhD, Cardiff University, Advisor: Dr Louis C. Morrill

Publications:

  1. N-Heterocyclic Carbene Acyl Anion Organocatalysis by Ball-Milling“, W. I. Nicholson, A. C. Seastram, S. A. Iqbal, B. G. Reed-Berendt, L. C. Morrill* and D. L. Browne*, ChemSusChem, 2019, 13, 131-135. [link] [Hot Topic: Organocatalysis]

Matthew Williams (MChem project student, Oct 2017 – May 2018)

Prizes: GSK prize for best MChem project in molecular synthesis section

Next position: PhD, Cardiff University, Advisor: Dr Louis C. Morrill, CDT co-advisors: Dr Duncan Browne and Dr Alastair Lennox

Publications:

  1. “Synthesis and Reactivity of N-Allenyl Cyanamides”, J. N. Ayres, M. T. J. Williams, G. J. Tizzard, S. J. Coles, K. B. Ling and L. C. Morrill*, Org. Lett., 2018, 20, 5282-5285. [link]

Publications:

  1. “Iron-Catalyzed Borrowing Hydrogen C-Alkylation of Oxindoles Using Alcohols“, M. B. Dambatta, K. Polidano, A. D. Northey, J. M. J. Williams and L. C. Morrill*, ChemSusChem, 2019, 12, 2345-2349. [link]

Alex Northey (MChem project student, Oct 2017 – May 2018)

Matthew Ashford (MChem project student, Oct 2016 – May 2017)

Next position: PhD, University of St Andrews, Advisor: Dr Allan Watson

Publications:

  1. “Deoxycyanamidation of Alcohols with N-Cyano-N-Phenyl-p-Methylbenzenesulfonamide (NCTS)”, J. N. Ayres, M. W. Ashford, Y. Stöckl, V. Prudhomme, K. B. Ling, J. A. Platts and L. C. Morrill*, Org. Lett., 2017, 19, 3835-3838. [link]

Daniel Moseley (MChem project student, Oct 2016 – May 2017)

Next position: PhD, Oxford Synthesis for Biology & Medicine CDT, Advisor: Prof. Michael Willis

 

Bryna Harris (MChem project student, Oct 2016 – May 2017)

 

Max Smith (MChem project student, Oct 2016 – May 2017)

Benjamin Reed- Berendt (MChem project student, Oct 2015 – May 2016)

Next position: PhD, Cardiff University, Advisor: Dr Louis C. Morrill

Matthew Jenner (MChem project student, Oct 2015 – May 2016)

Next position: PhD, University of Southampton, Advisor: Dr Ramon Rios

Tyler Woods (MChem project student, Oct 2015 – May 2016)

Undergraduate Project Students (BSc)

Adam Gage (BSc project student, Jan-May 2020)

Sam Parker (BSc project student, Jan-May 2018)

Connor Radcliffe (BSc project student, Jan-May 2018)

Thomas Lambourn (BSc project student, Jan-May 2017)

Niall Hope (BSc project student, Jan-May 2016)

Undergraduate Project Students (Cardiff Internship)

Robert Bolt (CUROP undergraduate researcher, Jun-Aug 2019)

Next position: MChem, Cardiff University

Publications:

  1. Transition Metal Free α-C-Alkylation of Ketones Using Secondary Alcohols“, M. B. Dambatta, J. Santos, R. R. A. Bolt and L. C. Morrill*, Tetrahedron, 2020, 76, 131571. [link] [Invited contribution to the Special Issue on Strategies for Efficient Organic Synthesis Dedicated to the Achievements of Prof. Jonathan Williams]

Joe Santos (CUROP undergraduate researcher, Aug-Sept 2018)

Next position: MChem, Cardiff University

Luke Ward (CUROP undergraduate researcher, Aug-Sept 2018)

Next position: MChem, Cardiff University

Ashley Ramdass (CUROP undergraduate researcher, Jun-Aug 2018)

Next position: MChem, Cardiff University

Thomas Knight (CUROP undergraduate researcher, Jun-Aug 2018)

Next position: MChem, Cardiff University

Alexi Sedikides (Internship student, Jun-Sept 2016)

Next position: MChem, Cardiff University

Vladimir Vladimirov (RSC undergraduate bursary scholar, Collaborative project led by Dr Rebecca Melen, Jun-Jul 2016)

Next position: MChem, Cardiff University

Undergraduate Project Students (Visiting Scholars)

Nicolas Mast (ERASMUS internship student May-Aug 2019)

Next position: MEng in Chemistry, ENSCR

Publications:

  1. Manganese-Catalyzed One-Pot Conversion of Nitroarenes into N-Methylarylamines Using Methanol“, B. G. Reed-Berendt, N. Mast and L. C. Morrill*, Eur. J. Org. Chem., 2020, 1136-1140. [link] [Invited contribution to the YourJOC Talents Special Issue] 

Marcus Espe (ERASMUS project student, since Sept-Dec 2017)

Next position: MSc in Chemistry, Aarhus University

Anaïs Basset (ERASMUS internship student, Jan-May 2017)

Next position: MA in Chemistry, ENSCM

Publications:

  1. Exploring Tandem Ruthenium-Catalyzed Hydrogen Transfer and SNAr Chemistry”, K. Polidano, B. G. Reed-Berendt, A. Basset, A. J. A. Watson, J. M. J. Williams and L. C. Morrill*, Org. Lett., 2017, 19, 6716-6719. [link]

Yannick Stöckl (RISE Worldwide internship student, Aug-Oct 2016)

Next position: MSc in Chemistry, University of Stuttgart

Publications:

  1. “Deoxycyanamidation of Alcohols with N-Cyano-N-Phenyl-p-Methylbenzenesulfonamide (NCTS)”, J. N. Ayres, M. W. Ashford, Y. Stöckl, V. Prudhomme, K. B. Ling, J. A. Platts and L. C. Morrill*, Org. Lett., 2017, 19, 3835-3838. [link]

Ng Yoke Yin (Internship student, Sept-Oct 2016)

Next position: Diploma in Medicinal Chemistry, Nangyang Polytechnic

Anissa Naïr (ERASMUS internship student, Jun-Aug 2016)

Next position: MA in Chemistry, ENSCCF

Vassili Prudhomme (ERASMUS internship student, Jun-Aug 2016)

Next position: MA in Chemistry, ENSCCF

Publications:

  1. “Deoxycyanamidation of Alcohols with N-Cyano-N-Phenyl-p-Methylbenzenesulfonamide (NCTS)”, J. N. Ayres, M. W. Ashford, Y. Stöckl, V. Prudhomme, K. B. Ling, J. A. Platts and L. C. Morrill*, Org. Lett., 2017, 19, 3835-3838. [link]