Indolizine, pyrrolone, and indolizinone heterocycles are easily accessed via the Pt(II)-catalyzed cycloisomerization or a tandem cyclization/1,2-migration of pyridine propargylic alcohols and derivatives. This method provides an efficient synthesis of highly functionalized heterocycles from readily available substrates. The development of efficient and versatile strategies for the synthesis of heterocycles continues to be of major significance in synthetic organic chemistry. 1 In this regard, transformations that employ readily available substrates to provide access to multiply functionalized heterocycles are highly desirable. In the last two decades, the pharmacological potential of indolizines and related derivatives has become well recognized. 2 As a result, a variety of methods for their syntheses have emerged. 3 However, there still remains a significant need for more direct methods to afford functionalized indolizine derivatives. Previously, we reported the Pt-catalyzed cyclization of an acetate nucleophile (see 1, Scheme 1) onto an activated alkyne to achieve the formation of pentannulated products (e.g., 3), via the intermediacy of a zwitterion (2). 4,5 On the basis of this precedent, we reasoned that substrates such as 4 (Scheme 2), which possess a nitrogen nucleophile, could provide a platform for metal-catalyzed cycloisomerizations to access a range of nitrogen-containing heterocycles (e.g., 6). Optimization studies of this transformation began with propargylic ester 7a (Table 1), which was easily prepared from pyridine-2-carboxaldehyde in two steps. 6 Initial attempts identified PtCl 4 (entry 1) and PtCl 2 (entry 2) to be suitable catalysts that provide moderate yields of the desired C-1 substituted indolizine 8a at 70 °C. 7 Furthermore, after a screen of various additives, we were delighted to find that the addition of 10 mol % of the bulky, electron-rich phosphine ligands 2-(di-tert-butylphosphino)-biphenyl 8 (9, entry 3) or 2-(dicyclohexylphosphino)biphenyl (10, entry 4) to the reaction mixture with PtCl 2 as catalyst led to a significant increase in the yield of the indolizine product 8a, with 10 proving to be superior (79% yield). The utility of phosphine ligands in facilitating Pt(II)-catalyzed reactions involving nitrogen nucleophiles is consistent with recent observations made by Widenhoefer during studies of the hydroamination of olefins. 9 Importantly, for the hydroamination reactions reported by Widenhoefer, a 1:1 ratio of Pt(II) salt to exogenous phosphine (Pt/PR 3) was critical to success. 10 We reasoned that the use of bulky phosphines would dictate the formation of this critical 1:1 Pt/PR 3 complex, which led to the choice of 9 and 10 as additives. Significant differences in reaction efficiency were also observed upon exposure of internal alkyne substrates (e.g., 7b) to various Pt(II)-catalyzed cycloisomerization conditions as outlined in entries 5-11. Consistent with our initial observations (entries 1-4), bulky phosphine additives provided conditions that produced higher yields of th...

No abstract

This article is based on an appraisal of Cancer Information and Support Services in Britain supported by the UK-based charity Macmillan Cancer Relief. Commissioned in 2002, the appraisal formed part of a wider review aimed at extending knowledge about Cancer Information and Support Services. It was also designed to ensure that the Macmillan Cancer Information and Support Service Model continues to reflect the needs of people whose lives are affected by cancer. The individual services reviewed for the appraisal vary widely in terms of resources, staffing and organizational structure, but many common themes emerge. The importance of outreach and networking are highlighted, along with the problem of isolation. Many post-holders saw a need to include a hospital base, while the role played by volunteers is widely acknowledged. A key aim of the review was to start to identify the factors that contribute to the success of a service, and a number of these emerge from the study. The creation of a culture that enables such a service to thrive appears to be as important as securing financial and other resources. The contribution made by Macmillan is explored, and ways in which the organization can support the dissemination of knowledge are put forward.

Several heterocycles such as furanones, pyrrolones, and indolizines, which are of pharmacological importance, are easily accessed via the Pt(II)-catalyzed heterocyclization/1,2-migration of propargylic ketols or hydroxy imine derivatives. This method sidesteps the challenges of traditional heteroaromatic oxygenation strategies such as regioselectivity and functional group tolerance in the syntheses of these heterocycles.

No abstract

Somatic and visceral nociceptive signals travel via different pathways to reach the spinal cord. Additionally, signals regulating visceral blood flow and gastrointestinal tract (GIT) motility travel via efferent sympathetic nerves. To offer optimal pain relief and increase GIT motility and blood flow, we should interfere with all these pathways. These include the afferent nerves that travel with the sympathetic trunks, the somatic fibers that innervate the abdominal wall and part of the parietal peritoneum, and the sympathetic efferent fibers. All somatic and visceral afferent neural and sympathetic efferent pathways are effectively blocked by appropriately placed segmental thoracic epidural blocks (TEBs), whereas well-placed truncal fascial plane blocks evidently do not consistently block the afferent visceral neural pathways nor the sympathetic efferent nerves. It is generally accepted that it would be beneficial to counter the effects of the stress response on the GIT, therefore most enhanced recovery after surgery protocols involve TEB. The TEB failure rate, however, can be high, enticing practitioners to resort to truncal fascial plane blocks. In this educational article, we discuss the differences between visceral and somatic pain, their management and the clinical implications of these differences.

No abstract

Indolizine, pyrrolone, and indolizinone heterocycles are easily accessed via the Pt(II)-catalyzed cycloisomerization or a tandem cyclization/1,2-migration of pyridine propargylic alcohols and derivatives. This method provides an efficient synthesis of highly functionalized heterocycles from readily available substrates.The development of efficient and versatile strategies for the synthesis of heterocycles continues to be of major significance in synthetic organic chemistry. 1 In this regard, transformations that employ readily available substrates to provide access to multiply functionalized heterocycles are highly desirable. In the last two decades, the pharmacological potential of indolizines and related derivatives has become well recognized. 2 As a result, a variety of methods for their syntheses have emerged. 3 However, there still remains a significant need for more direct methods to afford functionalized indolizine derivatives.Previously, we reported the Pt-catalyzed cyclization of an acetate nucleophile (see 1, Scheme 1) onto an activated alkyne to achieve the formation of pentannulated products (e.g., 3), via the intermediacy of a zwitterion (2). 4,5 On the basis of this precedent, we reasoned that substrates such as 4 (Scheme 2), which possess a nitrogen nucleophile, could provide a platform for metal-catalyzed cycloisomerizations to access a range of nitrogen-containing heterocycles (e.g., 6).Optimization studies of this transformation began with propargylic ester 7a (Table 1), which was easily prepared from pyridine-2-carboxaldehyde in two steps. 6 Initial attempts identified PtCl 4 (entry 1) and PtCl 2 (entry 2) to be suitable catalysts that provide moderate yields of the desired C-1 substituted indolizine 8a at 70 °C. Furthermore, after a screen of various additives, we were delighted to find that the addition of 10 mol % of the bulky, electron-rich phosphine ligands 2-(di-tert-butylphosphino)-biphenyl 8 (9, entry 3) or 2-(dicyclohexylphosphino)biphenyl (10, entry 4) to the reaction mixture with PtCl 2 as catalyst led to a significant increase in the yield of the indolizine product 8a, with 10 proving to be superior (79% yield). The utility of phosphine ligands in facilitating Pt(II)-catalyzed reactions involving nitrogen nucleophiles is consistent with recent observations made by Widenhoefer during studies of the hydroamination of olefins. 9 Importantly, for the hydroamination reactions reported by Widenhoefer, a 1:1 ratio of Pt(II) salt to exogenous phosphine (Pt/PR 3 ) was critical to success. 10 We reasoned that the use of bulky phosphines would dictate the formation of this critical 1:1 Pt/PR 3 complex, which led to the choice of 9 and 10 as additives.Significant differences in reaction efficiency were also observed upon exposure of internal alkyne substrates (e.g., 7b) to various Pt(II)-catalyzed cycloisomerization conditions as outlined in entries 5-11. Consistent with our initial observations (entries 1-4), bulky phosphine additives provided conditions that produced higher yields o...