(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

Abstract

SummaryOrganocatalysis, now running its second decade of life, is being considered one of the main tools a synthetic chemist has to perform asymmetric catalysis. In this review the synthesis of six-membered rings, that contain multiple chiral centers, either by a ring closing process or by a functionalization reaction on an already existing six-membered ring, utilizing bifunctional (thio)ureas will be summarized. Initially, the use of primary amine-thioureas as organocatalysts for the above transformation is being discussed, followed by the examples employing secondary amine-thioureas. Finally, the use of tertiary amine-thioureas and miscellaneous examples are presented.

Direct, Microwave‐Assisted Synthesis of Isothiocyanates

“…Over the past few decades, isothiocyanates (ITCs) have become the focus of medicinal chemistry and chemical biology gaining attention as many of these natural (e.g., BITC or SFN) and synthetic heteroanulenes have chemopreventive and antiproliferative as well as antibacterial, activity. In flow cytometry and in proteomics studies, ITCs are also exploited as probes (see Scheme for selected examples); they are also useful building blocks in the synthesis of sulfur‐containing heterocycles and thiourea‐derived organocatalysts There are two basic strategies for synthesizing ITCs: the first uses organic azides as reactants, which in the tandem Staudinger/aza‐Wittig reaction with triphenylphosphane and carbon disulfide are converted into target ITCs; the second, which is most exploited due to the large availability of starting materials, achieves the goal through the direct reaction of primary amines with highly toxic thiophosgene, or its more expensive surrogates such as di(2‐pyridyl) thionocarbamate,[10a] 1,1′‐thiocarbonyldiimidazole,[10b] and 1,1′‐thiocarbonyldi‐2‐( 1H )‐pyridone. [10c] In an alternative two‐step protocol, amines are converted by reactions with carbon disulfide into dithiocarbamates followed by their decomposition to the desired ITCs under the action of the desulfurating agent.…”

Design, Synthesis, and Evaluation of ω‐(Isothiocyanato)alkylphosphinates and Phosphine Oxides as Antiproliferative Agents

“…New electrophiles-N-Boc protected w-bromoalkylamines-easily availablef rom parenta mines such as N-Boc 2-bromoethylamine( 14), [49] N-Boc 3-bromopropylamine ( 15), [50] bis-N-Boc 4-bromobutylamine (16), [51] bis-N-Boc 5-bromopentylamine (17), [52] and bis-N-Boc 6-bromohexylamine( 18) [53] were applied in the alkylation of diphenylphosphine oxide.A ll reactions were performed in pressure vials at 100 8C under microwave-assisted phase-transfer catalysis reaction (PTC) using toluene and 56 %a queousp otassium hydroxide as solvents andt etra-n-butylammonium bromide (TBABr)a sc atalyst. The protected diphenyl(w-aminoalkyl)phosphine oxides 19-23 were isolated in yields of 57-86 %a fter flash chromatography (Scheme 2).…”

“…[13] ITCs playa ni mportant role in organic synthesis, especially in the synthesis of hetero-cyclic compounds, [14] including thioamides [15] or thiourea-derived organocatalysts. [16] Among the naturali sothiocyanates such as benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC), or allyl isothiocyanate (AITC), sulforaphane( SFN)-1-(isothiocyanate)-4-(methylsulfinyl)butane (Figure 1) is the most extensively studied ITC. It was synthesized by Schmidt and Karrer [17] in 1948 and isolated from broccoli by Zhang et al [18] in 1992.…”

Chiral Bifunctional Thiosquaramides as Organocatalysts in the Synthesis of Enantioenriched 3,3‐Disubstituted Oxindoles

“…The catalytic activity of these structures is dependent on the strength of the formed hydrogen bond, and the stereoselectivity on the nature of the chiral appendage. Searching for the modification of the acidity of the catalysts, chiral ureas, thioureas, and squaramides, have been the most common organocatalysts used in different stereoselective transformations.…”