Palladium-Catalyzed Addition of Aryl Halides to N-Sulfinylamines for the Synthesis of Sulfinamides.

Sulfinamides are versatile, synthetically useful intermediates, and final motifs. Traditional methods to synthesize sulfinamides generally require substrates with preinstalled sulfur centers. However, these precursors have limited commercial availability, and the associated synthetic routes often require harsh reaction conditions and highly reactive reagents, thus severely limiting their application. Herein, we report the synthesis of sulfinamides from aryl and alkenyl (pseudo)halides and N-sulfinylamines, enabled by palladium catalysis. The reactions use mild conditions and are achieved without the use of highly reactive preformed organometallic reagents, resulting in transformations of broad generality and high functional group tolerance. In particular, substrates featuring protic and electrophilic functional groups can be used successfully. The modification of complex aryl cores and natural product derivatives demonstrates the utility of this method.

Examining the impact of structural uncertainty across ten type 2 diabetes models: Results from the 2022 Mount Hood Challenge.

OBJECTIVE: The Mount Hood Diabetes Challenge Network aimed to examine the impact of model structural uncertainty on the estimated cost-effectiveness of interventions for type 2 diabetes. METHODS: Ten independent modelling groups completed a blinded simulation exercise to estimate the cost-effectiveness of three interventions in two type 2 diabetes populations. Modelling groups were provided with a common baseline population, cost and utility values associated with different model health states, and instructions regarding time horizon and discounting. We collated the results to identify variation in predictions of net monetary benefit (NMB), and the drivers of those differences. RESULTS: Overall, modelling groups agreed which interventions had a positive NMB (i.e. were cost-effective), though estimates of NMB varied substantially- by up to £23,696 for one intervention. Variation was mainly driven through differences in risk equations for complications of diabetes and their implementation between models. The number of modelled health states was also a significant predictor of NMB. CONCLUSIONS: This exercise demonstrates that structural uncertainty between different health economic models impacts cost-effectiveness estimates. Whilst it is reassuring that a decision maker would likely reach similar conclusions on which interventions were cost-effective using most models, the range in numerical estimates generated across different models would nevertheless be important for price-setting negotiations with intervention developers. Minimising the impact of structural uncertainty on healthcare decision making therefore remains an important priority. Model registries, which record and compare the impact of structural assumptions, offer one potential avenue to improve confidence in the robustness of health economic modelling.

The Modular Synthesis of Sulfondiimidoyl Fluorides and their Application to Sulfondiimidamide and Sulfondiimine Synthesis.

A modular synthesis of sulfondiimidoyl fluorides - the double aza-analogues of sulfonyl fluorides - allowing variation of the carbon and both nitrogen-substituents is reported. The chemistry uses readily available organometallic reagents, commercial sulfinylamines, simple electrophiles, and N-fluorobenzenesulfonimide (NFSI), as the starting materials. The reactions are broad in scope, efficient, and scalable. We show that the sulfondiimidoyl fluoride products can be combined with amines to provide sulfondiimidamides, and with organolithium reagents to provide sulfondiimines, and that reactivity in these transformations can be modulated by variation of the N-substituents.

Exploiting Trans-Sulfinylation for the Synthesis of Diverse N-Alkyl Sulfinamides via Decarboxylative Sulfinamidation.

Combining simple amines with the bench-stable sulfinylamine Tr-NSO allows in situ preparation of reactive alkyl sulfinylamines, which when combined with alkyl radicals generated by photocatalytic decarboxylation, provides N-alkyl sulfinamides. The reactions are broad in scope and tolerate a wide variety of functional groups on both the acid and amine components. The sulfinamide products are used to prepare a selection of challenging S(VI) products. The method provides a convenient way to use reactive and unstable alkyl sulfinylamines.

Severe Fatigue and Persistent Symptoms at 3 Months Following Severe Acute Respiratory Syndrome Coronavirus 2 Infections During the Pre-Delta, Delta, and Omicron Time Periods: A Multicenter Prospective Cohort Study.

BACKGROUND: Most research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants focuses on initial symptomatology with limited longer-term data. We characterized prevalences of prolonged symptoms 3 months post-SARS-CoV-2 infection across 3 variant time-periods (pre-Delta, Delta, and Omicron). METHODS: This multicenter prospective cohort study of adults with acute illness tested for SARS-CoV-2 compared fatigue severity, fatigue symptoms, organ system-based symptoms, and ≥3 symptoms across variants among participants with a positive ("COVID-positive") or negative SARS-CoV-2 test ("COVID-negative") at 3 months after SARS-CoV-2 testing. Variant periods were defined by dates with ≥50% dominant strain. We performed multivariable logistic regression modeling to estimate independent effects of variants adjusting for sociodemographics, baseline health, and vaccine status. RESULTS: The study included 2402 COVID-positive and 821 COVID-negative participants. Among COVID-positives, 463 (19.3%) were pre-Delta, 1198 (49.9%) Delta, and 741 (30.8%) Omicron. The pre-Delta COVID-positive cohort exhibited more prolonged severe fatigue (16.7% vs 11.5% vs 12.3%; P = .017) and presence of ≥3 prolonged symptoms (28.4% vs 21.7% vs 16.0%; P < .001) compared with the Delta and Omicron cohorts. No differences were seen in the COVID-negatives across time-periods. In multivariable models adjusted for vaccination, severe fatigue and odds of having ≥3 symptoms were no longer significant across variants. CONCLUSIONS: Prolonged symptoms following SARS-CoV-2 infection were more common among participants infected during pre-Delta than with Delta and Omicron; however, these differences were no longer significant after adjusting for vaccination status, suggesting a beneficial effect of vaccination on risk of long-term symptoms. Clinical Trials Registration. NCT04610515.

Photocatalytic Carboxylate to Sulfinamide Switching Delivers a Divergent Synthesis of Sulfonamides and Sulfonimidamides.

sulfinamides, sulfonamides, and sulfonimidamides are in-demand motifs in medicinal chemistry, yet methods for the synthesis of alkyl variants that start from simple, readily available feedstocks are scarce. In addition, bespoke syntheses of each class of molecules are usually needed. In this report, we detail the synthesis of these three distinct sulfur functional groups, using readily available and structurally diverse alkyl carboxylic acids as the starting materials. The method harnesses alkyl radical generation from carboxylic acids using acridine photocatalysts and 400 nm light with subsequent radical addition to sulfinylamine reagents, delivering sulfinamide products. Using the N-alkoxy sulfinylamine reagent t-BuO-NSO as the radical trap provides common N-alkoxy sulfinamide intermediates, which can be converted in a divergent manner to either sulfonamides or sulfonimidamides, by treatment with sodium hydroxide, or an amine, respectively. The reactions are scalable, tolerate a broad range of functional groups, and can be used for the diversification of complex biologically active compounds.

Modular Two-Step Route to Sulfondiimidamides.

Sulfur functional groups are common motifs in bioactive molecules. Sulfonamides are most prevalent but related aza-derivatives, in which oxygen atoms are replaced by imidic nitrogens, such as sulfoximines and sulfonimidamides, are gaining attraction. Despite this activity, the double aza-variants of sulfonamides, termed sulfondiimidamides, are almost completely absent from the literature. The reason for this is poor synthetic accessibility. Although a recent synthesis has established sulfondiimidamides as viable motifs, the length of the route and the capricious nature of the key sulfondiimidoyl fluoride intermediates mean that direct application to discovery chemistry is challenging. Herein, we describe a two-step synthesis of sulfondiimidamides, exploiting a hypervalent iodine-mediated amination as the key step. The starting materials are organometallic reagents, an unsymmetrical sulfurdiimide, and amines. The method allowed >40 examples to be prepared, including derivatives of three sulfonamide-based drugs. The operational simplicity, broad scope, and concise nature make this route attractive for discovery chemistry applications.

The public economic burden of suboptimal type 2 diabetes control upon taxpayers in Sweden: Looking beyond health costs.

AIM: To estimate the fiscal burden for taxpayers in Sweden associated with type 2 diabetes (T2D) attributed to diabetes-related complications in patients failing to meet HbA1c targets. MATERIAL AND METHODS: We developed a public economic framework to assess how changes in diabetes-related complications influenced projected tax contributions and government disability payments for people with T2D. The analysis applied accepted disease-modelling practices to estimate different rates of diabetes-related complications based on an HbA1c of 6.9% (52 mmol/mol) and of 6.0% (42 mmol/mol). We adjusted the employment activity rates for those experiencing T2D-related events, applying age-specific earnings to estimate lifetime tax losses. Furthermore, the likelihood of receiving payments for health-related employment inactivity was estimated. Direct healthcare costs are excluded from this analysis. RESULTS: The estimated per person earnings loss for immediate and delayed HbA1c control was Swedish krona (SEK) 42 299 and SEK 44 157, respectively, over 10 years. The lost employment activity of people with T2D translates to lost tax revenues of SEK 23 265 and SEK 24 287 for immediate and delayed control, respectively. The estimated difference in disability payments was SEK 538. Combining the tax revenue loss and excess disability payments defines the broader fiscal costs, where we observe combined fiscal losses that favour immediate and sustained control by SEK 1560 over 10 years. CONCLUSIONS: We show that conducting fiscal analysis of diabetes interventions offers an enriched perspective capturing a range of costs that fall on government in relation to lost tax revenue and disability payments. Tax-financed health systems may benefit from broadening the consideration of costs and benefits when evaluating new interventions and treatment practices.

Accelerating changes in ice mass within Greenland, and the ice sheet's sensitivity to atmospheric forcing.

From early 2003 to mid-2013, the total mass of ice in Greenland declined at a progressively increasing rate. In mid-2013, an abrupt reversal occurred, and very little net ice loss occurred in the next 12-18 months. Gravity Recovery and Climate Experiment (GRACE) and global positioning system (GPS) observations reveal that the spatial patterns of the sustained acceleration and the abrupt deceleration in mass loss are similar. The strongest accelerations tracked the phase of the North Atlantic Oscillation (NAO). The negative phase of the NAO enhances summertime warming and insolation while reducing snowfall, especially in west Greenland, driving surface mass balance (SMB) more negative, as illustrated using the regional climate model MAR. The spatial pattern of accelerating mass changes reflects the geography of NAO-driven shifts in atmospheric forcing and the ice sheet's sensitivity to that forcing. We infer that southwest Greenland will become a major future contributor to sea level rise.

Reductant-Free Cross-Electrophile Synthesis of Di(hetero)arylmethanes by Palladium-Catalyzed Desulfinative C-C Coupling.

An efficient Pd-catalyzed one-pot desulfinative cross-coupling to access medicinally relevant di(hetero)arylmethanes is reported. The method is reductant-free, and involves a sulfinate transfer reagent and a Pd-catalyst mediating the union of two electrophilic coupling partners; a (hetero)aryl halide and a benzyl halide. We establish for the first time that benzyl sulfinates, generated in situ, undergo efficient Pd-catalyzed desulfinative cross-coupling with (hetero)aryl halides to generate di(hetero)arylmethanes. The reaction can be extended to benzylic pseudohalides derived from benzyl alcohols. The reactions are straightforward to perform and scalable, and all reaction components are commercially available.

Nickel(II)-Catalyzed Addition of Aryl and Heteroaryl Boroxines to the Sulfinylamine Reagent TrNSO: The Catalytic Synthesis of Sulfinamides, Sulfonimidamides, and Primary Sulfonamides.

We report a redox-neutral Ni(II)-catalyzed addition of (hetero)aryl boroxines to N-sulfinyltritylamine (TrNSO). The reactions use a catalyst generated from the combination of commercial, air-stable NiCl2·(glyme) and a commercially available bipyridine ligand, and deliver sulfinamide products. The scope of the reaction is established using a sulfonimidamide synthesis, in which the initially formed sulfinamides undergo oxidative chlorination with the inexpensive and safe chlorinating agent, trichloroisocyanuric acid (TCCA), to produce sulfonimidoyl chlorides as key intermediates. These are combined in situ with a range of amines to deliver sulfonimidamides. The sulfonimidoyl chlorides can also be elaborated into primary sulfonamides via hydrolysis, and sulfonimidoyl fluorides via treatment with fluoride. These transformations are all achieved using one-pot procedures. Unprotected, primary sulfinamides are also available. For larger-scale reactions, the catalyst loading can be reduced to 1 mol %.

Rediscovering Sulfinylamines as Reagents for Organic Synthesis.

Sulfinylamines (R-N=S=O), monoaza analogues of sulfur dioxide, have been known for well over a century, and their reactivity as sulfur electrophiles and in Diels-Alder reactions is well-established. However, they have only rarely been used in organic synthesis in recent decades despite the increasing prominence of compounds containing N=S=O functionality, such as sulfoximines and sulfonimidamides. This Minireview aims to bring wider visibility to the unique chemistry enabled by this class of compounds. We focus on advances from the last 10 years, including the first examples of their use in the one-pot syntheses of sulfoximines and sulfonimidamides. Also covered are the reactions of sulfinylamines with carbon-centred radicals, their use for formation of heterocycles through cycloadditions, and catalytic enantioselective allylic oxidation of alkenes via a hetero-ene reaction. These examples highlight the different reactivity modes of sulfinylamines and their underappreciated potential for forming molecules which contain high- or low-valent sulfur, or even no sulfur at all.

Swedish guidelines for device-aided therapies in Parkinson's disease -Economic evaluation and implementation.

OBJECTIVES: The National Board of Health and Welfare in Sweden published the national guidelines for Parkinson's Disease 2016. The aim of this study was to summarize this evidence review and development of the guidelines, focusing on the economic evaluation of device-aided therapies (deep brain stimulation, pump-based infusion of levodopa-carbidopa intestinal gel or apomorphine) for Parkinson's disease, and the rate of implementation after 3 years in Sweden. MATERIAL AND METHODS: The evidence review underlying the guidelines-including systematic literature searches of clinical and economic evidence, model-based economic evaluation, and formal analysis and guideline development-was examined, condensed, and translated. The impact of the guidelines was assessed with treatment use statistics from 2009 to 2019. RESULTS: All device-aided therapies were assigned high priority. Based on a relatively low proportion of device-aided therapies (30%) in Parkinson's disease, a 5-year increase of 500 patients was recommended. This was estimated to reduce total costs by SEK 14 million (€1.7 million). Follow-up data found an increase of 217 patients between 2017 and 2019, following the same trend as before the guidelines. CONCLUSION: Three years after the guidelines were published, the use of device-aided therapies has increased in Sweden, albeit not in pace with recommendations. One reason for slow implementation may be poor incentivization related to budget silos in which the costs for device-aided therapies are borne by the regions but the cost offsets (eg, reduced need for home care) are reaped by local stakeholders.

Recharge of a subglacial lake by surface meltwater in northeast Greenland.

In a warming climate, surface meltwater production on large ice sheets is expected to increase. If this water is delivered to the ice sheet base it may have important consequences for ice dynamics. For example, basal water distributed in a diffuse network can decrease basal friction and accelerate ice flow, whereas channelized basal water can move quickly to the ice margin, where it can alter fjord circulation and submarine melt rates. Less certain is whether surface meltwater can be trapped and stored in subglacial lakes beneath large ice sheets. Here we show that a subglacial lake in Greenland drained quickly, as seen in the collapse of the ice surface, and then refilled from surface meltwater input. We use digital elevation models from stereo satellite imagery and airborne measurements to resolve elevation changes during the evolution of the surface and basal hydrologic systems at the Flade Isblink ice cap in northeast Greenland. During the autumn of 2011, a collapse basin about 70 metres deep and about 0.4 cubic kilometres in volume formed near the southern summit of the ice cap as a subglacial lake drained into a nearby fjord. Over the next two years, rapid uplift of the floor of the basin (which is approximately 8.4 square kilometres in area) occurred as surface meltwater flowed into crevasses around the basin margin and refilled the subglacial lake. Our observations show that surface meltwater can be trapped and stored at the bed of an ice sheet. Sensible and latent heat released by this trapped meltwater could soften nearby colder basal ice and alter downstream ice dynamics. Heat transport associated with meltwater trapped in subglacial lakes should be considered when predicting how ice sheet behaviour will change in a warming climate.

The 2-Pyridyl Problem: Challenging Nucleophiles in Cross-Coupling Arylations.

Azine-containing biaryls are ubiquitous scaffolds in many areas of chemistry, and efficient methods for their synthesis are continually desired. Pyridine rings are prominent amongst these motifs. Transition-metal-catalysed cross-coupling reactions have been widely used for their synthesis and functionalisation as they often provide a swift and tuneable route to related biaryl scaffolds. However, 2-pyridine organometallics are capricious coupling partners and 2-pyridyl boron reagents in particular are notorious for their instability and poor reactivity in Suzuki-Miyaura cross-coupling reactions. The synthesis of pyridine-containing biaryls is therefore limited, and methods for the formation of unsymmetrical 2,2'-bis-pyridines are scarce. This Review focuses on the methods developed for the challenging coupling of 2-pyridine nucleophiles with (hetero)aryl electrophiles, and ranges from traditional cross-coupling processes to alternative nucleophilic reagents and novel main group approaches.

Exploiting Configurational Lability in Aza-Sulfur Compounds for the Organocatalytic Enantioselective Synthesis of Sulfonimidamides.

Methods for establishing the absolute configuration of sulfur-stereogenic aza-sulfur derivatives are scarce, often relying on cumbersome protocols and a limited pool of enantioenriched starting materials. We have addressed this by exploiting, for the first time, a feature of sulfonimidamides in which it is possible for tautomeric structures to also be enantiomeric. Such sulfonimidamides can readily generate prochiral ions, which we have exploited in an enantioselective alkylation process. Selectivity is achieved using a readily prepared bis-quaternized phase-transfer catalyst. The overall process establishes the capability of configurationally labile aza-sulfur species to be used in asymmetric catalysis.

Base-Activated Latent Heteroaromatic Sulfinates as Nucleophilic Coupling Partners in Palladium-Catalyzed Cross-Coupling Reactions.

Heteroaromatic sulfinates are effective nucleophilic reagents in Pd0 -catalyzed cross-coupling reactions with aryl halides. However, metal sulfinate salts can be challenging to purify, solubilize in reaction media, and are not tolerant to multi-step transformations. Here we introduce base-activated, latent sulfinate reagents: ß-nitrile and ß-ester sulfones. We show that under the cross-coupling conditions, these species generate the sulfinate salt in situ, which then undergo efficient palladium-catalyzed desulfinative cross-coupling with (hetero)aryl bromides to deliver a broad range of biaryls. These latent sulfinate reagents have proven to be stable through multi-step substrate elaboration, and amenable to scale-up.

Mechanistic Studies of the Palladium-Catalyzed Desulfinative Cross-Coupling of Aryl Bromides and (Hetero)Aryl Sulfinate Salts.

Pyridine and related heterocyclic sulfinates have recently emerged as effective nucleophilic coupling partners in palladium-catalyzed cross-coupling reactions with (hetero)aryl halides. These sulfinate reagents are straightforward to prepare, stable to storage and coupling reaction conditions, and deliver efficient reactions, thus offering many advantages, compared to the corresponding boron-derived reagents. Despite the success of these reactions, there are only scant details of the reaction mechanism. In this study, we use structural and kinetic analysis to investigate the mechanism of these important coupling reactions in detail. We compare a pyridine-2-sulfinate with a carbocyclic sulfinate and establish different catalyst resting states, and turnover limiting steps, for the two classes of reagent. For the carbocyclic sulfinate, the aryl bromide oxidative addition complex is the resting state intermediate, and transmetalation is turnover-limiting. In contrast, for the pyridine sulfinate, a chelated Pd(II) sulfinate complex formed post-transmetalation is the resting-state intermediate, and loss of SO2 from this complex is turnover-limiting. We also investigated the role of the basic additive potassium carbonate, the use of which is crucial for efficient reactions, and deduced a dual function in which carbonate is responsible for the removal of free sulfur dioxide from the reaction medium, and the potassium cation plays a role in accelerating transmetalation. In addition, we show that sulfinate homocoupling is responsible for converting Pd(OAc)2 to a catalytically active Pd(0) complex. Together, these studies shed light on the challenges that must be overcome to deliver improved, lower temperature versions of these synthetically important processes.

Harnessing Sulfinyl Nitrenes: A Unified One-Pot Synthesis of Sulfoximines and Sulfonimidamides.

Sulfoximines and sulfonimidamides are promising compounds for medicinal and agrochemistry. As monoaza analogues of sulfones and sulfonamides, respectively, they combine good physicochemical properties, high stability, and the ability to build complexity from a three-dimensional core. However, a lack of quick and efficient methods to prepare these compounds has hindered their uptake in molecule discovery programmes. Herein, we describe a unified, one-pot approach to both sulfoximines and sulfonimidamides, which exploits the high electrophilicity of sulfinyl nitrenes. We generate these rare reactive intermediates from a novel sulfinylhydroxylamine (R-O-N=S=O) reagent through an N-O bond fragmentation process. Combining sulfinyl nitrenes with carbon and nitrogen nucleophiles enables the synthesis of sulfoximines and sulfonimidamides in a reaction time of just 15 min. Alkyl, (hetero)aryl, and alkenyl organometallic reagents can all be used as the first or second component in the reaction, while primary and secondary amines, and anilines, all react with high efficiency as the second nucleophile. The tolerance of the reaction to steric and electronic factors has allowed for the synthesis of the most diverse set of sulfoximines and sulfonimidamides yet described. Experimental and computational investigations support the intermediacy of sulfinyl nitrenes, with nitrene formation proceeding via a transient triplet intermediate before reaching a planar singlet species.