Recent Advances in Minisci‐Type Reactions Proctor, Rupert S. J.; Phipps, Robert J.
Angewandte Chemie International Edition,
September 23, 2019, Volume:
58, Issue:
39
Journal Article
Peer reviewed
Open access
Reactions that involve the addition of carbon‐centered radicals to basic heteroarenes, followed by formal hydrogen atom loss, have become widely known as Minisci‐type reactions. First developed into ...a useful synthetic tool in the late 1960s by Minisci, this reaction type has been in constant use over the last half century by chemists seeking to functionalize heterocycles in a rapid and direct manner, avoiding the need for de novo heterocycle synthesis. Whilst the originally developed protocols for radical generation remain in active use today, they have been joined in recent years by a new array of radical generation strategies that allow use of a wider variety of radical precursors that often operate under milder and more benign conditions. The recent surge of interest in new transformations based on free radical reactivity has meant that numerous choices are now available to a synthetic chemist looking to utilize a Minisci‐type reaction. Radical‐generation methods based on photoredox catalysis and electrochemistry have joined approaches which utilize thermal cleavage or the in situ generation of reactive radical precursors. This review will cover the remarkably large body of literature that has appeared on this topic over the last decade in an attempt to provide guidance to the synthetic chemist, as well as a perspective on both the challenges that have been overcome and those that still remain. As well as the logical classification of advances based on the nature of the radical precursor, with which most advances have been concerned, recent advances in control of various selectivity aspects associated with Minisci‐type reactions will also be discussed.
Under control: Reactions that involve the addition of carbon‐centered radicals to basic heteroarenes, followed by formal hydrogen atom loss, have become widely known as Minisci‐type reactions. Whilst the original protocols for radical generation remain in active use today, they have been joined in recent years by a new array of radical generation strategies that allow use of a wider variety of radical precursors that often operate under milder conditions.
Catalytic enantioselective Minisci-type addition to heteroarenes Proctor, Rupert S J; Davis, Holly J; Phipps, Robert J
Science (American Association for the Advancement of Science),
2018-Apr-27, 2018-04-27, 20180427, Volume:
360, Issue:
6387
Journal Article
Peer reviewed
Open access
Basic heteroarenes are a ubiquitous feature of pharmaceuticals and bioactive molecules, and Minisci-type additions of radical nucleophiles are a leading method for their elaboration. Despite many ...Minisci-type protocols that result in the formation of stereocenters, exerting control over the absolute stereochemistry at these centers remains an unmet challenge. We report a process for addition of prochiral radicals, generated from amino acid derivatives, to pyridines and quinolines. Our method offers excellent control of both enantioselectivity and regioselectivity. An enantiopure chiral Brønsted acid catalyst serves both to activate the substrate and induce asymmetry, while an iridium photocatalyst mediates the required electron transfer processes. We anticipate that this method will expedite access to enantioenriched small-molecule building blocks bearing versatile basic heterocycles.
The Minisci reaction is one of the most direct and versatile methods for forging new carbon–carbon bonds onto basic heteroarenes: a broad subset of compounds ubiquitous in medicinal chemistry. While ...many Minisci-type reactions result in new stereocenters, control of the absolute stereochemistry has proved challenging. An asymmetric variant was recently realized using chiral phosphoric acid catalysis, although in that study the substrates were limited to quinolines and pyridines. Mechanistic uncertainties and nonobvious enantioselectivity trends made the task of extending the reaction to important new substrate classes challenging and time-intensive. Herein, we describe an approach to address this problem through rigorous analysis of the reaction landscape guided by a carefully designed reaction data set and facilitated through multivariate linear regression (MLR) analysis. These techniques permitted the development of mechanistically informative correlations providing the basis to transfer enantioselectivity outcomes to new reaction components, ultimately predicting pyrimidines to be particularly amenable to the protocol. The predictions of enantioselectivity outcomes for these valuable, pharmaceutically relevant motifs were remarkably accurate in most cases and resulted in a comprehensive exploration of scope, significantly expanding the utility and versatility of this methodology. This successful outcome is a powerful demonstration of the benefits of utilizing MLR analysis as a predictive platform for effective and efficient reaction scope exploration across substrate classes.
Minisci-type reactions constitute one of the most powerful methods for building up complexity around basic heteroarenes. The most desirable variants involve formal oxidative coupling of a C–H bond on ...each partner, leading back to the simplest possible starting materials. We herein disclose a method that enables such a coupling of linear amides and heteroarenes with full control of enantioselectivity at the newly formed stereocenter as well as site selectivity on both the heteroarene and the amide. This is achieved by the use of a chiral phosphoric acid catalyst in conjunction with diacetyl as a combined hydrogen atom transfer reagent and oxidant. Diacetyl is directly photoexcitable, and thus, no extraneous photocatalyst is required: an added feature that contributes to the simplicity and practicality of the protocol.
The Minisci reaction is one of the most valuable methods for directly functionalizing basic heteroarenes to form carbon–carbon bonds. Use of prochiral, heteroatom-substituted radicals results in ...stereocenters being formed adjacent to the heteroaromatic system, generating motifs which are valuable in medicinal chemistry and chiral ligand design. Recently a highly enantioselective and regioselective protocol for the Minisci reaction was developed, using chiral phosphoric acid catalysis. However, the precise mechanism by which this process operated and the origin of selectivity remained unclear, making it challenging to develop the reaction more generally. Herein we report further experimental mechanistic studies which feed into detailed DFT calculations that probe the precise nature of the stereochemistry-determining step. Computational and experimental evidence together support Curtin–Hammett control in this reaction, with initial radical addition being quick and reversible, and enantioselectivity being achieved in the subsequent slower, irreversible deprotonation. A detailed survey via DFT calculations assessed a number of different possibilities for selectivity-determining deprotonation of the radical cation intermediate. Computations point to a clear preference for an initially unexpected mode of internal deprotonation enacted by the amide group, which is a crucial structural feature of the radical precursor, with the assistance of the associated chiral phosphate. This unconventional stereodetermining step underpins the high enantioselectivities and regioselectivities observed. The mechanistic model was further validated by applying it to a test set of substrates possessing varied structural features.
Ratios of first-row transition elements (FRTE), such as Fe/Mn and Zn/Fe, may be fractionated differently by partial melting of peridotite than by partial melting of recycled lithologies like ...eclogite, and therefore may be useful as indicators of the source lithologies of mantle-derived basalts. Interpretation of basalt source lithologies from FRTE ratios requires accurate assessment of FRTE partitioning behavior between peridotitic minerals and coexisting melts. We present experimental determinations of partition coefficients for several of the FRTE (Sc, Ti, V, Cr, Mn, Fe, Co, Zn) and Ga and Ge between basaltic melt and olivine, garnet, pyroxenes, and spinel at 3GPa. Because mineral/melt partitioning is sensitive to phase compositions, a key feature of these experiments is that the melts and minerals are known from previous experiments to be in equilibrium at the solidus of garnet peridotite at 3GPa. Therefore, these partition coefficients are directly applicable to near-solidus partial melting of the mantle at 3GPa. We use these partition coefficients to calculate compositions of model partial melts of peridotite and compare these to natural OIB. Model partial melts of peridotite have lower Fe/Mn (<62) and higher Co/Fe (>7*10−4) than many primitive OIB, which implies that some other source lithology participates in the formation of many OIB. Alternatively, these ratios may potentially be produced by garnet peridotite if the source contains ∼0.3% Fe2O3, consistent with observations from continental xenoliths. Zn/Fe is a less sensitive indicator of non-peridotite source lithology than either Fe/Mn or Co/Fe, as Zn/Fe in partial melts of peridotite overlaps with >75% of primitive OIB. Ga and Sc are fractionated significantly by residual garnet, and high Ga/Sc may indicate the presence of garnet in basalt source regions. When taking into account several FRTE ratios simultaneously, few OIB appear to be consistent with derivation solely from a reduced peridotitic source. The source either must have a modest non-peridotitic component, be Fe-enriched, or be slightly oxidized.
Benzyl bromides and related molecules are among the most common substrates in organic synthesis. They are typically used as electrophiles in nucleophilic substitution reactions. These molecules can ...also be activated via single-electron-transfer (SET) process for radical reactions. Representative recent progress includes α-carbon benzylation of ketones and aldehydes via photoredox catalysis. Here we disclose the generation of (nitro)benzyl radicals via N-heterocyclic carbene (NHC) catalysis under reductive conditions. The radical intermediates generated via NHC catalysis undergo formal 1,2-addition with ketones to eventually afford tertiary alcohol products. The overall process constitutes a formal polarity-inversion of benzyl bromide, allowing a direct coupling of two initially electrophilic carbons. Our study provides a new carbene-catalysed reaction mode that should enable unconventional transformation of (nitro)benzyl bromides under mild organocatalytic conditions.
To determine if Sa roughness data from measuring one central location of unpolished and polished enamel were representative of the overall surfaces before and after erosion.
Twenty human enamel ...sections (4x4 mm) were embedded in bis-acryl composite and randomised to either a native or polishing enamel preparation protocol. Enamel samples were subjected to an acid challenge (15 minutes 100 mL orange juice, pH 3.2, titratable acidity 41.3mmol OH/L, 62.5 rpm agitation, repeated for three cycles). Median (IQR) surface roughness Sa was measured at baseline and after erosion from both a centralised cluster and four peripheral clusters. Within each cluster, five smaller areas (0.04 mm2) provided the Sa roughness data.
For both unpolished and polished enamel samples there were no significant differences between measuring one central cluster or four peripheral clusters, before and after erosion. For unpolished enamel the single central cluster had a median (IQR) Sa roughness of 1.45 (2.58) μm and the four peripheral clusters had a median (IQR) of 1.32 (4.86) μm before erosion; after erosion there were statistically significant reductions to 0.38 (0.35) μm and 0.34 (0.49) μm respectively (p<0.0001). Polished enamel had a median (IQR) Sa roughness 0.04 (0.17) μm for the single central cluster and 0.05 (0.15) μm for the four peripheral clusters which statistically significantly increased after erosion to 0.27 (0.08) μm for both (p<0.0001).
Measuring one central cluster of unpolished and polished enamel was representative of the overall enamel surface roughness, before and after erosion.
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