Toni Rantanen

Toxicity of hydroxylated alkyl-phenanthrenes to the early life stages of Japanese medaka (Oryzias latipes).

Polycyclic aromatic hydrocarbons (PAH) are hydrophobic environmental contaminants with petrogenic, biogenic, and pyrogenic sources. Alkylated PAH predominate in crude oils, are found in sediment downstream of pulp and paper mills, and can be more toxic than their non-alkylated homologues. The enzymatic metabolism of alkyl phenanthrenes generates ring and chain hydroxylated derivatives. The main objective of this research was to estimate the potential role of hydroxylation in PAH toxicity and secondly to better understand the relative risk of different PAH in complex mixtures. This project assessed the toxicity of ring and chain hydroxylated 1-methylphenanthrenes to the early life stages of Japanese medaka (Oryzias latipes). Phenols were more toxic than benzylic alcohols, and some phenols were more than four times more toxic than their non-hydroxylated counterpart. Ring hydroxylation can increase PAH toxicity, and metabolism may enhance alkyl-PAH toxicity through the generation of such metabolites. This paper is the first to describe the relative toxicity of a suite of hydroxylated alkyl-PAH to the early life stages of fish, proposing an association between the preferential formation of para-quinones and enhanced toxicity.

The Directed ortho Metallation-Cross- Coupling Fusion: Development and Application in Synthesis

Snieckus Innovations, Innovation Park, 945 Princess Street, Kingston, Ontario, K7L 3N6, Canada *Email: victor.snieckus@chem.queensu.ca This review constitutes a detailed but non-exhaustive examination of the directed ortho metallation (DoM)– cross-coupling fusion in its many fl avours. Special attention is paid to the application of the concept of the linked reactions and the synthetic utility that it endows, particularly in the case of one-pot reactions that can greatly increase the ease and effi ciency of the process. Personal experience of particular issues that can arise from these reactions and examples of their solutions are given, as well as illustrations of the rapid access to complex molecules that the technique encourages.

Combined Directed ortho Metalation−Halogen Dance (HD) Synthetic Strategies. HD−Anionic ortho Fries Rearrangement and Double HD Sequences

A general and efficient directed ortho metalation (DoM)-halogen dance (HD)-electrophile quench sequence for the synthesis of trisubstituted pyridyl O-carbamates is described. A second HD sequence furnishes highly functionalized tetrasubstituted pyridines. Furthermore, a hitherto unobserved double HD rearrangement is reported. Under similar LDA conditions, aromatic O-carbamates with OMe, Cl, and F substituents (4a-c) undergo either a HD-electrophile quench sequence, 4a-c --> 18-20, or a HD-anionic ortho Fries rearrangement, 4a-c --> 6a-c, respectively.

Quantitative structure–activity relationships for chronic toxicity of alkyl-chrysenes and alkyl-benz[a]anthracenes to Japanese medaka embryos (Oryzias latipes)

Alkylated polycyclic aromatic hydrocarbons (alkyl-PAHs) are a class of compounds found at significant concentrations in crude oils, and likely the main constituents responsible for the chronic toxicity of oil to fish. Alkyl substituents at different locations on the aromatic rings change the size and shape of PAH molecules, which results in different interactions with tissue receptors and different severities of toxicity. The present study is the first to report the toxicity of several alkylated derivatives of chrysene and benz[a]anthracene to the embryos of Japanese medaka (Oryzias latipes) using the partition controlled delivery (PCD) method of exposure. The PCD method maintained the desired exposure concentrations by equilibrium partitioning of hydrophobic test compounds from polydimethylsiloxane (PDMS) films. Test concentrations declined by only 13% over a period of 17 days. Based on the prevalence of signs of blue sac disease (BSD), as expressed by median effective concentrations (EC50s), benz[a]anthracene (B[a]A) was more toxic than chrysene. Alkylation generally increased toxicity, except at position 2 of B[a]A. Alkyl-PAHs substituted in the middle region had a lower EC50 than those substituted at the distal region. Except for B[a]A and 7-methylbenz[a]anthracene (7-MB), estimated EC50 values were higher than their solubility limits, which resulted in limited toxicity within the range of test concentrations. The regression between log EC50s and logKow values provided a rough estimation of structure-activity relationships for alkyl-PAHs, but Kow alone did not provide a complete explanation of the chronic toxicity of alkyl PAHs.

Twisted Amide Analogues of Tröger’s Base

Lets do the twist: The first twisted bis-amide is obtained by the benzylic oxidation of Trogers base (TB). Kinetic studies of its acidic hydrolysis reveal that the hydrolysis is to a large extent funneled through doubly protonated species.

Directed ortho metalation strategies. Effective regioselective routes to 1,2-, 2,3-, and 1,2,3-substituted naphthalenes.

The regioselective synthesis of 2,3-di- and 1,2,3-trisubstituted naphthalenes via Directed ortho Metalation (DoM) strategies of N,N-diethyl-O-naphthyl-2-carbamate (1) is presented. Sequential LiTMP metalation-electrophile quench and s-BuLi/TMEDA (or t-BuLi)-electrophile quench of naphthyl-2-carbamate 1 provides a general route to contiguously substituted naphthalenes (6) with full regioselectivity. Further derivatization via ipso-halodesilylation and Suzuki-Miyaura cross-coupling leads ultimately to substituted halonaphthalenes and benzonaphthopyranones (9).

Directed Metalation–Suzuki–Miyaura Cross-Coupling Strategies: Regioselective Synthesis of Hydroxylated 1-Methyl-phenanthrenes

A general, efficient, and regioselective synthesis of a series of hydroxylated 1-methylphenanthrenes 9 by a combined directed ortho metalation (DoM)-Suzuki-Miyaura cross-coupling-directed remote metalation (DreM) sequence is reported. Diversity to this methodology was achieved by a regioselective DoM rather than DreM reaction, affording more highly substituted phenanthrols ( Table 2 ). Application of the turbo-Grignard reagent (i-PrMgCl·LiCl) in the Ni-catalyzed Corriu-Kumada reaction gave efficient decarbamoylation ( Tables 3 and 4 ). Additional features are the TMS protecting group and halo-induced ipso-desilylation tactics applied to the regioselective synthesis of phenanthrenes ( Scheme 2 ).

Hydroarylation Approach to Phosphacoumarins

Significance: Reported is an intramolecular hydroarylation of aryl alkynylphosphonates catalyzed by gold–silver and resulting in the formation of phosphacoumarins. The starting materials are synthesized by the reaction of terminal alkynes with chlorophosphonates using a strong base (n-BuLi) at cryogenic temperatures. Optimization studies on the cyclization reaction using mixtures of different gold and silver salts led mostly to starting material recovery and/or isolation of β-ketophosphonates. Trifluoromethanesulfonic acid (TfOH) as protic acid additive was unique in effecting the hydroarylation. Control experiments in the absence of gold, or in the absence of metals altogether, led to very poor yields of products. Surprisingly, no control experiment in the absence of silver was conducted. The substrate scope was well studied, except for absence of cases with R2 = electron-withdrawing groups. The yields seem to be consistently good. Comment: Previous syntheses of phosphacoumarins, for example by the condensation of salicylaldehydes with diethylphosphonoacetates (C. H. Chen, J. L. Fox, J. L. Lippert J. Heterocycl. Chem. 1987, 24, 931) suffer from deficiencies such as poorly available starting materials and harsh reaction conditions. The current methodology offers usage of reasonably mild catalytic conditions and readily available starting materials. The synthesis of the starting chlorophosphonates, which is not reported, does not seem to be too arduous an undertaking. Mechanistic studies hint at the involvement of an allene intermediate. Refreshingly, the authors conclude that more mechanistic elucidation has to be performed rather than draw the unsupported catalytic cycle pervasive in the current literature. O P OR1 O R3

Synthesis of Phosphaisocoumarins via Ruthenium Catalysis

Significance: Presented is the ruthenium-catalyzed C–H activation–cyclization of aryl phosphonic monoester and phosphinic acids resulting in phosphaisocoumarins. An extensive screening identified the witches’ brew shown to be ideal. The reason for the effectiveness of the mixture of Ag2CO3–AgOAc–KPF6 is not identified. However, it was shown that in the absence of KPF6 the reaction does proceed, albeit with lower yields (63% vs. 97%). AgOAc alone affords a comparable yield to the Ag2CO3–AgOAc mixture, although this was established early in the optimization study with only 2 mol% ruthenium catalyst. AgOAc alone was not used with a higher catalyst loading, leading to the extrapolation that the reaction may be successful without additional KPF6 and Ag2CO3. The scope of the reaction was well studied and the yields range from moderate to good. Comment: Heterocyclic phosphorus-containing compounds can have significant biological and pharmaceutical properties. The synthesis of phosphaisocoumarins has recently been reported using rhodium-catalyzed C–H activation–cyclization of alkynes with organophosphorus compounds (Y. Unoh et al. Org. Lett. 2013, 15, 3258). The current report uses similar conditions, but with a less expensive ruthenium catalyst, albeit in a more complex overall reaction system. The reaction seems tolerant to electron-withdrawing and -donating groups on both alkyne and aryl phosphorus starting materials, although alkynes with strong electron-withdrawing groups were not tested. Some mechanistic studies were conducted using deuterium-labelled organophosphorus compounds, and a kinetic isotope effect (kH/kD = 5.67) was observed, indicating that C2–H bond cleavage is most likely involved in the rate-limiting step. A plausible mechanism was proposed, which does not include rationalization of the effect of the mixture of reagents involved in the reaction. P O

Diels–Alder Cycloaddition Approach to Indoles from Alkynol-Furans

Significance: Reported is the synthesis of 3,4-disubstituted 5-hydroxyindoles starting from NBoc-2-aminofuran using a furan-yne Diels–Alder approach. The aminofuran is easily converted into a stannane which, upon transmetalation followed by alkynone or alkynal quench, afforded alkynol intermediates in poor to moderate yields. The alkynols were subjected to microwave heating in an inert solvent to perform the intramolecular Diels– Alder reaction resulting in the formation of substituted 5-hydroxyindoles in sad to decent yields. The substrate scope was reasonably well studied and with R1 and R2 being aromatic substituents afforded higher yields of products than their aliphatic counterparts. Interestingly, when R1 = TMS, the trimethylsilyl group undergoes a 1,3-silatropic C-to-O rearrangement to afford 5-silyloxyindoles (R1 = H). These were easily desilylated to give the 5-hydroxyindoles. Comment: Indoles are ubiquitous units in bioactive molecules, and 5-hydroxyindoles especially are found in a large array of pharmacologically active agents. The Nenitzescu reaction is often reliably used for the synthesis of 5-hydroxyindoles (see Review below). The presented paper is an appropriate extension of the authors’ previous paper on a similar synthesis of 4-substituted indoles (Chem. Commun. 2009, 104). More significantly, it offers a fresh complementary route to indoles compared to the current ubiquitous Sonogashira/ cyclization approaches. Unfortunately, the starting furan does not seem to be readily available from standard suppliers, and requires synthesis via Curtius rearrangement of the corresponding furan-2-carboxylic acid. Furthermore, the overall yields are quite poor, which can hinder further applications of this protocol.