54 research outputs found
Microwave-mediated synthesis of N-methyliminodiacetic acid (MIDA) boronates
A library of over 20, mainly aryl or heteroaryl, N-methyliminodiacetic acid (MIDA) boronates have been synthesised. A rapid microwave-mediated (MW) method (5–10 min) has been developed using polyethylene glycol 300 (PEG 300) as solvent. However, acetonitrile (MeCN) and dimethylformamide (DMF) were found to be alternative solvents, the latter especially for 2-substituted aryl boronic acids
Access to a diverse array of bridged benzo[1,5]oxazocine and benzo[1,4]diazepine structures
The preparation of bridged benzo[1,5]oxazocines and benzo[1,4]diazepines is demonstrated from simple aniline and aldehyde starting materials. A one-pot condensation/6Ï€ electrocyclization is followed by an intramolecular trapping of the 2,3-dihydroquinoline intermediate by nitrogen or oxygen nucleophiles to give bridged seven- and eight-membered products. Using 3-hydroxypyridinecarboxaldehydes results in a stable zwitterionic structure that can undergo a diastereoselective reduction under hydrogenative conditions. A similar cyclization/hydrogenation pathway with excellent diastereoselectivity is also demonstrated from 2-pyridyl-substituted 1,2,3,4-tetrahydroquinolines.PostprintPeer reviewe
4-Ï€-Photocyclization of 1,2-Dihydropyridazines: An Approach to Bicyclic 1,2-Diazetidines with Rich Synthetic Potential.
The 4-Ï€-photocyclization of a range of 1,2-dihydropyridazines is described, generating bicyclic 1,2-diazetidines in high yields on multigram scale. The key bicyclic 1,2-diazetidines are versatile synthetic intermediates and were easily converted into a range of novel derivatives, including functionalized 1,2-diazetidines, cyclobutenes, cyclobutanes, and 1,3-dienes
N1-arylation of 1,4-benzodiazepine-2-ones with diaryliodonium salts
A library of N1-arylated 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-ones has been synthesized starting with unsymmetrical diaryliodonium salts using aqueous ammonia as a base. This can also be applied to a similar 1,3,4-benzotriazepin-2-one derivative
Gram scale laboratory synthesis of TC AC 28, a high affinity BET bromodomain ligand
TC AC 28, 6-(1H-Indol-4-yl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-4-acetic acid methyl ester, has been synthesized on a near gram scale in seven steps with notable improvements in the reported poor yielding last 2 steps enabling this key chemical probe compound to be available for researchers
A directed enolization strategy enables by-product-free construction of contiguous stereocentres en route to complex amino acids.
Homochiral α-amino acids are widely used in pharmaceutical design as key subunits in chiral catalyst synthesis or as building blocks in synthetic biology. Many synthetic methods have been developed to access rare or unnatural variants by controlling the installation of the α-stereocentre. By contrast, and despite their importance, α-amino acids possessing β-stereocentres are much harder to synthesize. Here we demonstrate an iridium-catalysed protocol that allows the direct upconversion of simple alkenes and glycine derivatives to give β-substituted α-amino acids with exceptional levels of regio- and stereocontrol. Our method exploits the native directing ability of a glycine-derived N-H unit to facilitate Ir-catalysed enolization of the adjacent carbonyl. The resulting stereodefined enolate cross-couples with a styrene or α-olefin to install two contiguous stereocentres. The process offers very high levels of regio- and stereocontrol and occurs with complete atom economy. In broader terms, our reaction design offers a unique directing-group-controlled strategy for the direct stereocontrolled α-alkylation of carbonyl compounds, and provides a powerful approach for the synthesis of challenging contiguous stereocentres
Atom and step economical synthesis of acyclic quaternary centers via iridium-catalyzed hydroarylative cross-coupling of 1,1-disubstituted alkenes
Elaboration of tetra-orthogonally-substituted aromatic scaffolds towards novel EGFR-kinase inhibitors
Nitration of three regioisomers of bromo-fluorobenzaldehyde proceeds regioselectively, notably with H2SO4/HNO3 at 0 °C. The thereby synthesized tetrasubstituted aromatics, endowed with orthogonal substituents, can be elaborated via Pd-catalysed coupling, reduction and reductive amination reactions. As a test-case, these compounds were converted into EGFR inhibitors related to Gefitinib, whose activity was rationalised by docking studies
Regioselective routes to orthogonally-substituted aromatic MIDA boronates
A series of tetrasubstituted aromatics has been synthesized, many of which are based on elaborated N-methyliminodiacetic acid (MIDA)-boronates. A sequence employing nitration, bromination, stepwise Suzuki-Miyaura (SM) coupling with a boronic acid, then base-mediated unmasking of the boronic acid from the MIDA-boronate and a second SM-coupling has led to our desired, mainly 1,2,4,5-substituted tetrasubstituted aromatic targets
Atom and step economical synthesis of acyclic quaternary centers via iridium-catalyzed hydroarylative cross-coupling of 1,1-disubstituted alkenes
Quaternary benzylic centers are accessed with high atom and step economy by Ir-catalyzed alkene hydroarylation. These studies provide unique examples of the use of non-polarized 1,1-disubstituted alkenes in branch selective Murai-type hydro(hetero)arylations. Detailed mechanistic studies have been undertaken, and these indicate that the first irreversible step is the demanding alkene carbometallation process. Structure-reactivity studies show that the efficiency of this is critically dependent on key structural features of the ligand. Computational studies have been undertaken to rationalize this experimental data, showing how more sterically demanding ligands reduce the reaction barrier via predistortion of the reacting intermediate. The key insight disclosed here will underpin the ongoing development of increasingly sophisticated branch selective Murai hydroarylations
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