Noncryogenic Conditions Research Articles

An improved stereodivergent and practical synthesis of α- and β-pseudouridines

A simplified stereodivergent and concise route featuring non-cryogenic conditions enable access to both anomers of pseudouridine.

High-fluence and high-gain multilayer focusing optics to enhance spatial resolution in femtosecond X-ray laser imaging

With the emergence of X-ray free-electron lasers (XFELs), coherent diffractive imaging (CDI) has acquired a capability for single-particle imaging (SPI) of non-crystalline objects under non-cryogenic conditions. However, the single-shot spatial resolution is limited to ~5 nanometres primarily because of insufficient fluence. Here, we present a CDI technique whereby high resolution is achieved with very-high-fluence X-ray focusing using multilayer mirrors with nanometre precision. The optics can focus 4-keV XFEL down to 60 nm × 110 nm and realize a fluence of >3 × 105 J cm−2 pulse−1 or >4 × 1012 photons μm−2 pulse−1 with a tenfold increase in the total gain compared to conventional optics due to the high demagnification. Further, the imaging of fixed-target metallic nanoparticles in solution attained an unprecedented 2-nm resolution in single-XFEL-pulse exposure. These findings can further expand the capabilities of SPI to explore the relationships between dynamic structures and functions of native biomolecular complexes.

Noncritical phase-matching fourth- and fifth-harmonic generation of 1077 nm laser using KDP-family crystals.

We systematically demonstrated the angular and temperature acceptances of noncritical phase-matching (NCPM) fourth- and fifth-harmonic generation (FHG and FiHG) of a 1077 nm laser in NH4H2PO4 (ADP), KH2PO4 (KDP), and KD2PO4 (DKDP) crystals. In this work, a new, to the best of our knowledge, laser frequency with a wavelength of 1077 nm was generated by optical parametric amplification, in which the pump light (526.3 nm) was generated by the frequency doubling of a Nd:YLF laser (1052.7 nm), and the signal light was a Yb:YAG laser (1029.5 nm). Subsequently, the 1077 nm laser was used as the fundamental wave for FHG and FiHG to obtain a deep-ultraviolet laser source. For ADP and DKDP crystals, NCPM FHG of a 1077 nm laser was realized at 74.0∘C and 132.5∘C, respectively, and large angular acceptances of 59.8 and 61.6 mrad were measured. For the FiHG, NCPM was realized in a KDP crystal at 48.5∘C with an angular acceptance of 56.4 mrad. The results pave the way for high-energy and high-power deep-ultraviolet laser generation using KDP-family crystals under noncryogenic conditions.

Synthesis and characterization of 3-pyridylchalcogen compounds

A convenient methodology, which efficiently promoted one-pot synthesis of 3-pyridylchalcogen (Se, Te) compounds, has been developed. Under non-cryogenic conditions, 3,3′-dipyridyl diselenide/ditelluride and other unsymmetrical derivatives were prepared by the reaction of 3-bromopyridine with the isopropyl magnesium chloride (i-PrMgCl) followed by the addition of chalcogen (Se/Te) and with variety of electrophiles. The known and unknown compounds were characterized by elemental analysis, NMR (1H,13C,77Se and 125Te), FT-IR and Mass spectroscopy.

Selective Acylation of Aryl- and Heteroarylmagnesium Reagents with Esters in Continuous Flow.

A selective acylation of readily accessible organomagnesium reagents with commercially available esters proceeds at convenient temperatures and short residence times in continuous flow. Flow conditions allow us to prevent premature collapse of the hemiacetal intermediates despite noncryogenic conditions, thus furnishing ketones in good yields. Throughout, the coordinating ability of the ester and/or Grignard was crucial for the reaction outcome. This was leveraged by the obtention of several bisaryl ketones using 2-hydroxy ester derivatives as substrates.

Halogen-Metal Exchange on Bromoheterocyclics with Substituents Containing an Acidic Proton via Formation of a Magnesium Intermediate.

A selective and practical bromine–metal exchange on bromoheterocyclics bearing substituents with an acidic proton under non-cryogenic conditions was developed by a simple modification of an existing protocol. Our protocol of using a combination of i-PrMgCl and n-BuLi has not only solved the problem of intermolecular quenching that often occurred when using alkyl lithium alone as the reagent for halogen–lithium exchange, but also offered a highly selective method for performing bromo–metal exchange on dibrominated arene compounds through chelation effect.

Using Flow To Outpace Fast Proton Transfer in an Organometallic Reaction for the Manufacture of Verubecestat (MK-8931)

We report that an organolithium addition to a chiral ketimine, which because of competitive proton transfer proceeds with only modest yield in batch, can be significantly improved in flow. The transformation was discovered to be highly mixing-sensitive but remarkably temperature-independent in flow, enabling the continuous process to be performed under noncryogenic conditions. Experiments at the kilogram scale provided robust operating conditions that are amenable to implementing this chemistry for the manufacture of verubecestat (MK-8931), a drug candidate for the treatment of Alzheimer’s disease.

A Practical, Protecting-Group-Free Synthesis of a PI3K/mTOR Inhibitor

We report a practical and protecting-group-free synthesis amenable to produce multikilogram amounts of PI3K/mTOR inhibitor GDC-0980. The route employed metalation/formylation and reductive amination followed by a metal catalyzed Suzuki–Miyaura cross-coupling. The metalation was performed via triarylmagnesiate intermediates allowing formylation under noncryogenic conditions. 2-Picoline·BH3 was employed to replace Na(OAc)3BH in the reductive amination and to eliminate the use of molecular sieves. A concise one-step synthesis was developed for the selective monoamidation of piperazine with (S)-lactate to produce the piperazine lactamide starting material. The boronic acid was produced from 2-amino-5-bromopyrimidine in a one-step and protecting-group-free approach. The final crystallization in 1-propanol and water afforded the API in 59% overall yield in four steps and >99% purity by HPLC.

A Practical Synthesis of a PI3K Inhibitor under Noncryogenic Conditions via Functionalization of a Lithium Triarylmagnesiate Intermediate

We report a practical synthesis of PI3K inhibitor GDC-0941. The synthesis was achieved using a convergent approach starting from a thienopyrimidine intermediate through a sequence of formylation and reductive amination followed by Suzuki-Miyaura cross-coupling. Metalation of the thienopyrimidine intermediate involving the intermediacy of triarylmagnesiates allowed formylation under noncryogenic conditions to produce the corresponding aldehyde. We also investigated aminoalkylation via a benzotriazolyl-piperazine substrate as an alternative to the reductive amination route. We evaluated both palladium and nickel catalyzed processes for the borylation and Suzuki-Miyaura cross-coupling. Final deprotection and salt formation afforded the API.

Practical Preparation of Ethyl 2-Methylthiophene-3-carboxylate

A safe and efficient process for the preparation of ethyl 2-methylthiophene-3-carboxylate (5) was devised. This process provides several advantages over the precedents, involving operational simplicity, avoidance of the use of strong bases such as n-butyllithium and application of noncryogenic conditions, and enabled to prepare 5 in 52% overall yield from commercially available 2-methylthiophene on a multikilogram scale.

Efficient Synthesis of 5-Functionalised 2-Methoxypyridines and their Transformation to Bicyclic δ-Lactams, both Accessed Using Magnesium ‘Ate’ Complexes as Key Reagents

Simple and efficient synthesis of 5-functionalised -2-methoxypyridinesfrom 5-bromo-2-methoxypyridine using -[ N-Bu 3 Mg]Li performedin noncryogenic conditions is described. Application of 5-functionalised2-methoxypyridines in the synthesis of 1-substituted 3,6,9,9a-tetrahydroquinolizin-4-onesand 3,5,8,8a-tetrahydro-1 H-quinolin-2-onesvia allylation of the corresponding 5-functionalised N-allyl(or benzyl)pyridin-2-ones using -[allyl N-Bu 2 Mg]Li followedby ring-closing metathesis is presented.

Single-Step Symmetrical Double Alkylation of β,γ-Unsaturated δ-Lactams via Magnesium ‘Ate’ Complexes

An easy approach to symmetrically 3,3-dialkylated derivatives of 3,6-dihydro-1H-pyridin-2-one in a one-pot and a single-step procedure via magnesium 'ate' complex is described. [Bu 3 Mg]Li used as the base showed great basic potential as one equivalent of it allowed double proton abstraction from 3,6-dihydro-1H-pyridin-2-one. Deprotonation at noncryogenic conditions yielded stable magnesiates which on treatment with more than two equivalents of alkyl halides provided 3,3-dialkylated products in good yield. In some cases minor 3,5-dialkylated lactams were formed due to allylic conjugation.

Mild and Selective Synthesis of an Aryl Boronic Ester by Equilibration of Mixtures of Boronic and Borinic Acid Derivatives

Quenching of aryl Grignard reagents with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (isopropyl pinacol borate) under noncryogenic conditions can lead to mixtures of the corresponding boronic ester along with, generally undesired, borinic acid derivatives. We have found that in certain cases gentle heating of the crude reaction mixtures leads to complete equilibration to give the borinic esters as the sole product which can then be isolated in high yield. This novel equilibration can reduce the need for use of cryogenic conditions or large excesses of reagents to obtain selectivity during boronic ester syntheses.

A practical non-cryogenic process for the selective functionalization of bromoaryls

A selective and practical bromine–metal exchange process under non-cryogenic conditions was developed by a simple modification of an existing protocol. By directly adding an alkyl lithium RLi reagent to a solution of a bromoaryl substrate ArBr and an alkylmagnesium reagent RMgX, a lithium triarylmagnesiate Ar 3MgLi complex formed that allowed for various types of functionalization and more elaborate cross-coupling reactions. The simplicity and improved safety of the method represent a significant improvement over current state of the art that uses lithium trialkylmagnesiate R 3MgLi complexes, and is especially advantageous for large-scale synthesis.

Bromine–lithium exchange under non-cryogenic conditions: TMSCH2Li–LiDMAE promoted C-2 lithiation of 2,3-dibromopyridine

The first C-2 selective bromine-lithium exchange in 2,3-dibromopyridine was performed at 0 degrees C in toluene using the TMSCH(2)Li-LiDMAE reagent.

TMSCH2Li and TMSCH2Li—LiDMAE: Efficient Reagents for Noncryogenic Halogen—Lithium Exchange in Bromopyridines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Lithium–halogen exchange reaction using microreaction technology

A two-stage continuous microreactor system was use to synthesize the materials for an organic light emitting diode. The split and recombine type of micromixers were suitable for the two-stage reaction including lithium-bromo exchange reaction. The two-stage synthesis was carried out under non-cryogenic conditions by taking full advantage of microstructured reaction systems. In a first stage, the unstable intermediate, naphthyl lithium was synthesized with maximum yield and consumed immediately in the second stage micromixer. The naphthyl-substituted anthracene was obtained with 97% purity.

TMSCH2Li and TMSCH2Li−LiDMAE: Efficient Reagents for Noncryogenic Halogen−Lithium Exchange in Bromopyridines

TMSCH(2)Li and TMSCH(2)Li-LiDMAE have been used efficiently for bromine-lithium exchange in 2-bromo-, 3-bromo-, and 2,5-dibromopyridines under noncryogenic conditions, while low temperatures (-78 to -100 degrees C) are always needed with n-BuLi. The aminoalkoxide LiDMAE induced a remarkable C-2 selectivity with 2,5-dibromopyridines in toluene at 0 degrees C, which was unprecedented at such a temperature. The lithiopyridines were successfully reacted with electrophiles also under noncryogenic conditions giving the expected adducts in good yields.

Selective Metal‐Halogen Exchange of 4,4′‐Dibromobiphenyl Mediated by Lithium Tributylmagnesiate.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Bromine—Magnesium Exchange of 5‐Bromo‐2‐picoline via an Organomagnesium Complex nBu2iPrMgLi: A New Preparation Methodology of Functionalized Picolines under Noncryogenic Conditions.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.