Nickel-Catalyzed Reductive Arylation of Redox Active Esters for the Synthesis of α-Aryl Nitriles: Investigation of a Chlorosilane Additive.

A nickel-catalyzed reductive cross-coupling of redox active N-hydroxyphthalimide (NHP) esters and iodoarenes for the synthesis of α-aryl nitriles is described. The NHP ester substrate is derived from cyanoacetic acid, which allows for a modular synthesis of substituted α-aryl nitriles, an important scaffold in the pharmaceutical sciences. The reaction exhibits a broad scope, and many functional groups are compatible under the reaction conditions, including complex highly functionalized medicinal agents. Mechanistic studies reveal that reduction and decarboxylation of the NHP ester to the reactive radical intermediate are accomplished by a combination of a chlorosilane additive and Zn dust. We demonstrate that stoichiometric chlorosilane is essential for product formation and that chlorosilane plays a role beyond activation of the metal reductant.

A Dedicated Outpatient Pharmacy Improves Access to Discharge Medications in a Pediatric Emergency Department: A Quality Improvement Study.

STUDY OBJECTIVE: Following discharge from a pediatric emergency department (ED) or urgent care, many families do not pick up their prescribed medications. The aim of this quality improvement study was to increase the percentage of patients discharged home with medications in-hand from 6% to 30% within 6 months. METHODS: Due to the planned construction of a new ED, urgent care, and dedicated pharmacy, a multidisciplinary team was formed to increase access to discharge medications. We performed a pilot study in the urgent care to improve the discharge prescription process and expanded its scope to the ED. We evaluated the effect of our interventions on the percentage of patients discharged with medications in-hand through statistical process control charts. Process measures included the percentage of prescriptions electronically prescribed and directed to an on-site pharmacy. RESULTS: Between June 21, 2021 and March 27, 2022, 7,678 patients were discharged with at least 1 medication in-hand. The percentage of patients discharged with medications in-hand increased from 6.2% to 60.6%. The percentage of prescriptions e-prescribed and directed to an on-site pharmacy increased to 94.6% and 65.6% respectively. CONCLUSIONS: In this study, the availability of a 24-hour on-site pharmacy appears to be the most impactful intervention increasing access to discharge medications for families. Other interventions, such as a pilot study in the urgent care and implementing default electronic prescribing, may have potentiated the effect of the new pharmacy.

Nickel-Catalyzed Cyanation of Benzylic and Allylic Pivalate Esters.

A nickel-catalyzed cyanation reaction of benzylic and allylic pivalate esters is reported using an air-stable Ni(II) precatalyst and substoichiometric quantities of Zn(CN)2. Alkene additives were found to inhibit catalysis, suggesting that avoiding ß-hydride elimination side reactions is essential for productive catalysis. An enantioenriched allylic ester undergoes enantiospecific cross-coupling to produce an enantioenriched allylic nitrile. This method was applied to an efficient synthesis of (±)-naproxen from commercially available starting materials.

DABO Boronate Promoted Conjugate Allylation of α,ß-Unsaturated Aldehydes Using Copper(II) Catalysis.

The first catalytic method for the selective 1,4-conjugate allylation of α,ß-unsaturated aldehydes is reported. The method employs an air-stable diethanolamine-complexed boronic acid (DABO boronate) as the allyl transfer reagent and promotes conjugate addition over 1,2-addition. A variety of aryl- and alkyl-substituted enals are tolerated, providing δ,ε-unsaturated aldehyde products in good yields and selectivities under mild conditions.

Femoral cartilage ultrasound echo-intensity is a valid measure of cartilage composition.

This study aimed to create a conversion equation that accurately predicts cartilage magnetic resonance imaging (MRI) T2 relaxation times using ultrasound echo-intensity and common participant demographics. We recruited 15 participants with a primary anterior cruciate ligament reconstruction between the ages of 18 and 35 years at 1-5 years after surgery. A single investigator completed a transverse suprapatellar scan with the ACLR limb in max knee flexion to image the femoral trochlea cartilage. A single reader manually segmented the femoral cartilage cross-sectional area to assess the echo-intensity (i.e., mean gray-scale pixel value). At a separate visit, a T2 mapping sequence with the MRI beam set to an oblique angle was used to image the femoral trochlea cartilage. A single reader manually segmented the cartilage cross-sectional area on a single MRI slice to assess the T2 relaxation time. A stepwise, multiple linear regression was used to predict T2 relaxation time from cartilage echo-intensity and common demographic variables. We created a conversion equation using the regression betas and then used an ICC and Bland-Altman plot to assess agreement between the estimated and true T2 relaxation time. Cartilage ultrasound echo-intensity and age significantly predicted T2 relaxation time (F = 7.33, p = 0.008, R2 = 0.55). When using the new conversion equation to estimate T2 relaxation time from cartilage echo-intensity and age, there was strong agreement between the estimated and true T2 relaxation time (ICC2,k = 0.84). This study provides promising preliminary data that cartilage echo-intensity combined with age can be used as a clinically accessible tool for evaluating cartilage composition.

Validating a Semi-Automated Technique for Segmenting Femoral Articular Cartilage on Ultrasound Images.

OBJECTIVE: To validate a semi-automated technique to segment ultrasound-assessed femoral cartilage without compromising segmentation accuracy to a traditional manual segmentation technique in participants with an anterior cruciate ligament injury (ACL). DESIGN: We recruited 27 participants with a primary unilateral ACL injury at a pre-operative clinic visit. One investigator performed a transverse suprapatellar ultrasound scan with the participant's ACL injured knee in maximum flexion. Three femoral cartilage ultrasound images were recorded. A single expert reader manually segmented the femoral cartilage cross-sectional area in each image. In addition, we created a semi-automatic program to segment the cartilage using a random walker-based method. We quantified the average cartilage thickness and echo-intensity for the manual and semi-automated segmentations. Intraclass correlation coefficients (ICC2,k) and Bland-Altman plots were used to validate the semi-automated technique to the manual segmentation for assessing average cartilage thickness and echo-intensity. A dice correlation coefficient was used to quantify the overlap between the segmentations created with the semi-automated and manual techniques. RESULTS: For average cartilage thickness, there was excellent reliability (ICC2,k = 0.99) and a small mean difference (+0.8%) between the manual and semi-automated segmentations. For average echo-intensity, there was excellent reliability (ICC2,k = 0.97) and a small mean difference (-2.5%) between the manual and semi-automated segmentations. The average dice correlation coefficient between the manual segmentation and semi-automated segmentation was 0.90, indicating high overlap between techniques. CONCLUSIONS: Our novel semi-automated segmentation technique is a valid method that requires less technical expertise and time than manual segmentation in patients after ACL injury.

Synthesis of α-Aryl Secondary Amides via Nickel-Catalyzed Reductive Coupling of Redox-Active Esters.

The transition-metal-catalyzed α-arylation of secondary amides remains a synthetic challenge due to the presence of a free N-H bond. We report a strategy to synthesize secondary α-aryl amides via a Ni-catalyzed reductive arylation of redox-active N-hydroxyphthalimide (NHP) esters of malonic acid half amides. This transformation proceeds under mild conditions and displays excellent chemoselectivity for amide α-arylation in the presence of other enolizable carbonyls. The NHP ester substrates are readily prepared from Meldrum's acid.