Bifunctional isocyanates are highly reactive compounds that undergo nucleophilic attack by a variety of functional groups available in the biological system. While the etiology of the respiratory disease caused by diisocyanates is not fully understood, a great deal of research has been performed to elucidate the chemical mechanisms involved in the direct and indirect effects of these compounds. Since adducts of isocyanates are found not only to proteins along the entire respiratory tree but also to proteins in the circulatory system, it is likely that a transport mechanism for the isocyanate from the respiratory to the circulatory system exists. The initial reaction of isocyanates with cellular thiols to form thiocarbamates, which are known to release the isocyanate under physiological conditions, is believed to provide a possible carrier mechanism for the isocyanate functional group. Previous work with aliphatic mono-isocyanates and the aromatic diisocyanate toluene diisocyanate has demonstrated the feasibility of this mechanism. Adding to this database, the products of the reaction of the highly water-insoluble, low vapor pressure, methylene-bis-(phenylisocyanate) (MDI) with glutathione were synthesized, and their chemical stability under various pH and buffer conditions was tested. Novel synthetic routes were developed for both the mono- and bis-S-(glutathionyl) adducts with MDI that yielded each compound in analytically pure form. Both compounds were found to be unstable under mild basic conditions (phosphate-buffered saline, pH 7.4, and NaHCO(3), pH 8.2), however to a different degree. Furthermore, a significant influence of the pH value (the rate of degradation increases with pH) and the concentration of free glutathione (increasing thiol stabilizes the adduct) on the stability was observed, indicating a base-catalyzed mechanism of the degradation/formation of the thiocarbamate bond. Unlike the monoadduct, which forms almost exclusively the polyurea upon degradation, a variety of products were formed upon degradation of the bis adduct. Though the disappearance of the bis adduct was complete as measured by HPLC, (1)H NMR spectra showed the existence of residual thiocarbamate bonds in the final mixture. In both cases, no evidence of the free methylene-bis-phenylamine (MDA) could be detected under the applicable conditions.

1-Dialkylamino-1,3-diaryl-3-diphenylphosphanylallenes 3a-e are thermally converted into a-annulated 3,5-diarylpyrroles 6a-f and [a]-annulated benzo[c]azepines 7a,b,d. These transformations are likely to include conjugated azomethine ylide intermediates that can undergo either a 1,5- or a 1,7-electrocyclization. The periselectivity is markedly shifted toward 1,5-cyclization when the diphenylphosphanyl substituent is replaced by the diphenylphosphoryl group. Thus, 1-dialkylamino-3-(diphenylphosphoryl)allenes 4a-f yield pyrroles 6 exclusively and with improved yields, unless the 3-aryl substituent in the allene is too electron-rich (e.g., benzodioxol-5-yl, 4f --> 7f). The preparation and thermal transformation of aminoallenes 4 over three or four steps can be conducted as a one-pot procedure, thus providing a convenient synthesis of [a]-annulated 3,5-diarylpyrroles from enaminoketones.

Treatment of 4‐(1,3‐diphenyl‐l‐propynylidene)morpholinium triflate (1a) with the neutral phosphorus nucleophiles Me3Si−PPh2, Me3Si−P(Ph)C5H11, and Me3SiO−PPh2 affords (3‐morpholinoallenyl)phosphanes 4 and 5 and (3‐morpholinoallenyl)phosphane oxide 11, respectively. In contrast to these conjugate addition reactions at the ambident propyne iminium moiety of 1a, nucleophilic attack by Me3Si−PEt2 and Me3SiO−P(OEt)2 takes place at the iminium function and gives (1‐morpholinopropargyl)phosphane 6 and (1‐morpholinopropargyl)phosphonate 12, respectively. Propyne iminium salt 1b reacts with Me3Si−PPh2 to form (3‐morpholino‐1,3‐butadienyl)phosphane oxide 8. The bis(donor)‐substituted allene 4 is transformed by oxidation of the phosphorus substituent into the push‐pull substituted allenylphosphane oxide 11. Treatment of allene 4 with elemental sulfur results in the formation of betaine 16, which undergoes [3+2] cycloaddition reactions with acetylenic esters to afford 5‐benzylidene‐4,5‐dihydrothiophenes 17 and 18. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Zinc-copper reagents of the type IZnCu(CN)-(CH 2 ) n -NR 1 R 2 , obtained from N -(2-iodoethyl)phthalimide, N -(2-iodopropyl)phthalimide, and N -(2-iodoethyl)benzamide, undergo conjugate addition to propyne iminium triflate 1 . After hydrolytic workup, the β -amidoalkyl-α , β -unsaturated ketones 6a , b and 9 are obtained in moderate yield. The iodoalanine derived zinc-copper reagent IZnCu(CN)-Boc-L -Ala-OBn (11) reacts with 1 analogously and furnishes after hydrolytic work-up both N -Boc-α -amino acid ester 12 and 5-aminocyclopent-2-en-1-one 13 .Conjugate nucleophilic addition to the triple bond of propyne iminium triflates represents a versatile approach to aminoallenes and amino-1,3-dienes. Carbon nucleophiles which serve this purpose are typically supplied as organocuprates 1-3 and other organocopper reagents. 1 The shortcoming of these reagents, namely not to be compatible with most of the polar functional groups, can be overcome by the use of zinc-copper organometallic compounds which tolerate many organic functional groups. 4 In fact, we have successfully transferred cyano-and alkoxycarbonyl-substituted carbon nucleophiles via the zinc-copper reagents 2 [R c = -(CH 2 ) 2 -, -(CH 2 ) 3 -, -C 6 H 4 -, FG = CN, COOEt] to propyne iminium salts such as 1 (Scheme 1); the resulting functionalized morpholinoallenes 3 underwent further reactions such as tautomerization to form morpholino-1,3-dienes and cyclization, or were transformed into α , β -unsaturated ketones during hydrolytic workup. 5In this communication, we report that zinc-copper reagents 2 , in which FG is an amido group, also react with salt 1 to give β -( ω -aminoalkyl ) -α , β -unsaturated ketones after hydrolytic workup.Zinc-copper reagents 5a , b were prepared according to a procedure published for 5b , 6 i.e. by reaction of alkyl iodides 4a , b with activated zinc, followed by transmetalation of the organozinc iodide so formed with the THF-soluble salt CuCN • 2 LiCl.In a modification of the literature procedure, we used granulated zinc rather than zinc foil or zinc dust, and completed the activation (1,2-dibromoethane, then Me 3 SiCl) by ultrasonication for 15 minutes. While the zinc insertion into the carbon-iodine bond is usually monitored by GC analysis of a hydrolyzed aliquot of the reaction mixture, we found it convenient to follow the progress of this transformation by direct 1 H NMR control. The addition of CDCl 3 or CD 3 CN as a lock substance to the NMR sample led to the destruction of the organozinc compound, but the use of DMSO-d 6 (water content < 0.005%) 7 allowed observation of the signal of the Zn-CH 2 protons as part of an AA'XX' system at δ = 0.2-0.4 [with δ (DMSO) = 2.49], as well as the disappearance of the starting material. For 4b , zinc insertion was complete after 4 hours, while 4a had been consumed only after 24 hours.Reaction of zinc-copper reagents 5a , b with propyne iminium salt 1 in THF/dichloromethane, followed by hydrolytic workup and chromatographic separation, furnished α , β -unsaturated ketones 6a,b in moderate ...

Trimethylsilyl)phosphanes Me 3 Si-PR 2 (PR 2 = PPh 2 , PEt 2 , 1-phospholanyl) add smoothly across the CºC bond of acetylenic ketones RCOCºCPh to form (Z)-3-phosphanyl-2-(trimethylsilyl)prop-2-en-1-ones 3 (3,4-addition). Thermal isomerization of the latter yields the corresponding 3-(trimethylsilyl)oxy-allenylphosphane 6, formally the product of a 1,4-addition. Mainly 1,2addition occurs with propiolic aldehydes leading to (1-[(trimethylsilyl)oxy]propargyl)phosphanes 4. Desilylation reactions of 3b yield either (3-oxopropyl)phosphanoxide 7 or (3-oxopropenyl)phosphanoxide 8.