Butadiene monoepoxide

Exposure studies have been made using mice and rats (257). These experiments have demonstrated species differences in butadiene toxicity and carcinogenicity. Butadiene was found to be a potent carcinogen in the mouse, but only a weak carcinogen in the rat. The interpretations have focused on differences in toxification rates and detoxification metaboHsms as causative factors (257). The metaboHsm is beHeved to proceed through intermediates involving butadiene monoepoxide and butadiene diepoxide (257). A similar mechanism has been proposed for its biodegradation pathway (258). 

The Gabriel synthesis represents another indirect but highly valuable approach to amines. Trost has demonstrated a method for the asymmetric ring-opening of butadiene monoepoxide by use of one equivalent of phthalimide, 7t-allylpalladium chloride dimer, and the chiral bisphosphine 22 (Scheme 7.37). The dynamic kinetic asymmetric transformation proceeded through a putative achiral intermedi-... 

Epoxides will also participate in radical reactions and this usually results in ring opening of the epoxide. The addition of a radical derived from xanthate 38 to butadiene monoepoxide provides the addition product 39 in good yields as an E/Z mixture of olefins <06AG(I)6520>. This reaction presumably proceeds through the addition of the xanthate-derived radical to the olefin, which then opens the epoxide. 

Dg]-butadiene monoepoxide, 8, has been synthesized2 by treating the water solution (pH 5.5) of magnesium monoperoxyphthalate hexahydrate at room temperature with [Dg]-1,3-butadiene at 1 atmosphere in 94% yield after 50 min reaction time. Under these conditions less than 1% of butadiene diepoxide has been formed as determined by GC/MS. The concentration of the [Dg]-butadiene monoepoxide in the aqueous reaction mixture at various reaction times has been determined by selective ion monitoring of ions with mjz... 

Buta-1,3-diene (10.101, Fig. 10.24) is a gaseous chemical used heavily in the rubber and plastics industry, the presence of which in the atmosphere is also a concern. Butadiene is suspected of increasing the risks of hematopoietic cancers, and it is classified as a probable human carcinogen. Butadiene must undergo metabolic activation to become toxic the metabolites butadiene monoepoxide (10.102, a chiral compound) and diepoxybutane (10.103, which exists in two enantiomeric and one meso-form) react with nucleic acids and glutathione [160 - 163], as does a further metabolite, 3,4-epoxybutane-l,2-diol (10.105). Interestingly, butadiene monoepoxide is at least tenfold more reactive than diepoxybutane toward nucleic acids or H20. Conjugation between the C=C bond and the oxirane may account for this enhanced reactivity. 

Both the mono- and diepoxides of butadiene are substrates for epoxide hydrolase [163], In rat liver microsomes, (R)- and (S)-butadiene monoepoxides were hydrolyzed to but-3-ene-l,2-diol (10.104, Fig. 10.24) with complete retention of configuration at C(2), indicating attack at C(l) [164], In mouse liver microsomes, in contrast, 15 - 25% inversion of configuration was observed, suggesting partial attack at C(2). Preliminary results indicate that human liver microsomes are more efficient than mouse or rat liver microsomes in hydrolyzing butadiene monoepoxide [165]. The hydrolysis of diepoxybutane (10.103) yields 3,4-epoxybutan-l,2-diol (10.105), which can be further hydrated to erytritol (10.106) [163]. 

Adler, I.-D., Kliesch, U., Nylund, L. Peltonen, K. (1997) In vitro and in vivo mutagenicity of the butadiene metabolites butadiene diol epoxide, butadiene monoepoxide and diepoxybutane. Mutagenesis, 12, 339-345... 

Csanady, G.A., Guengerich, F.P. Bond, J. A. (1992) Comparison of the biotransformation of 1,3-butadiene and its metabolite, butadiene monoepoxide, by hepatic and pulmonary tissues from humans, rats and mice. Carcinogenesis, 13, 1143-1153... 

Koivisto, P, Kostiainen, R., Kilpelainen I., Steinby, K. Peltonen, K. (1995) Preparation, characterization and 32p-postlabeling of butadiene monoepoxide N -adenine adducts. Carcinogenesis, 16,2999-3007... 

Kumar, R., Vodicka, P, Koivisto, P, Peltonen, K. Hemminki, K. (1996) 32p-Postlabelling of dia-stereomeric 7-alkylguanine adducts of butadiene monoepoxide. Carcinogenesis, 17,1297-1303... 

Schmidt, L. Loeser, E. (1985) Species differences in the formation of butadiene monoepoxide from 1,3-butadiene. Arch. Toxicol., 57, 222-225... 

Sharer, J.E., Duescher, R.J. Elfarra, A. A. (1991) Formation, stability and rearrangements of the glutathione conjugates of butadiene monoepoxide evidence for the formation of stable sulfu-rane intermediates. Chem. Res. Toxicol., 4, 430 36... 

Thornton-Manning, J.R., Dahl, A.R., Beehtold, W.E., Griffith, W.C., Jr Henderson, R.F. (1995a) Disposition of butadiene monoepoxide and butadiene diepoxide in various tissues of rats andmiee following a low-level inhalation exposure to 1,3-butadiene. Carcinogenesis, 16, 1723-1731... 

The conversion of racemic butadiene monoepoxide to a single enantiomer of 54 (R=CH2OH) using Pd-catalyzed asymmetric allylic alkylation was uncovered by Trost [141]. By using a slightly modified ligand, the alkylation with phthalim-... 

Godleski etal, Utilization of Butadiene Monoepoxide as a Dienophile, Kodak Research Technical Report, pp. 1-4, (August 10, 1989)... 

SYNS BUTADIENE MONOEPOXIDE BUTADIENE MONOXIDE 1.2-EPOXYBUTENE-3 ... 

BUTADIENE, 2-ETHYL- see EGV600 BUTADIENE MONOEPOXIDE see EBJ500 BUTADIENE MONOXIDE see EBJ500 BUTADIENES, inhibited (DOT see BOPlOO... 

Rickborn [34] reported that 3,4-epoxycyclohexene 58, on addition of Grignard reagent, gave only the 8, 2 product 59 in 95% yield [see Eq. (11)]. Whereas Johnson [35] found that butadiene monoepoxide 60 reacted with methylmagnesium halides, affording the 8 2 8 2 products 61 and 62, respectively, with a ratio that strongly depended on the nature of the halide [Eq. (19)]. 

Anderson [36] reported that the product distributions of the reaction of butadiene monoepoxide 60 with Grignard reagents are also dependent on the nature of the Grignard reagent [Eq. (20)], which has been also observed by Rose et al. [37]. 

Butadiene is converted to butadiene monoepoxide, which is believed to be responsible for carcinogenesis in rodents but not in humans. In humans, butadiene monoepoxide is further converted to butenediol and conjugation with glutathione results in no toxicity. In rodents, however, there is direct conjugation of butadiene monoepoxide with glutathione, which presumably is not adequate, and thus cancer initiation occurs. In this example, it can be seen that rodent data are a poor indicator for prediction of risk in humans because the detoxification pathways differ. 

Acid-catalyzed hydrolysis of isobutylene oxide (8) is >750 times faster than that of ethylene oxide (6), and > 99% of the glycol product is from addition of solvent at the tertiary carbon.23 These results are consistent with a mechanism in which there is significant positive charge on the tertiary carbon at the transition state, as discussed in the previous section. Butadiene monoepoxide (10) is slightly less reactive than isobutylene oxide,36 and its acid-catalyzed hydrolysis can potentially proceed via a resonance-stabilized allyl cation (Scheme 6). However, the acid-catalyzed hydrolysis of 10 yields 96% of 3-buten-l,2-diol (15) and only 4% of 2-butene-1,4-diol (16),36 and the acid-catalyzed methanolysis of 10 is reported to yield only 2-methoxy-3-buten-l-ol.37 An A-2 mechanism proceeding via transition state 17 may account for the observation that 1,2-diol 15 is the predominant product from acid-catalyzed hydrolysis of 10. The minor yield of the 1,4-diol 16 may be formed from reaction of... 

Olefin epoxidation is not only important in the manufacture of bulk chemicals, e. g. ethylene and propylene oxides, but is also a widely used transformation in the fine-chemicals industry [1], Ethylene oxide is manufactured by vapor-phase oxidation of ethylene, with air or oxygen, over a supported silver catalyst [2], This method is not generally applicable as olefins containing allylic or other reactive C-H bonds give complex mixtures of products with low epoxide selectivity. The method has recently been extended to some other olefins that do not contain reactive allylic C-H bonds, e. g. butadiene, styrene, norbornene, and tert-butyl ethylene [3]. Some of these products, e. g. butadiene monoepoxide and styrene oxide, have potential applications as fine chemicals/intermediates. 

In 1999, Trost and Toste introduced the concept of dynamic kinetic asymmetric transformation (DYKAT) which is frequently referred to as DKR, since it involves the equilibration of diastereomeric intermediates generated from the racemic substrates. This concept allows for the transformation of both enantiomers of a racemic substrate in a highly enantio-enriched product. As an example. Trust s group has demonstrated that exposing butadiene monoepoxide and phthalimide to a catalyst formed in situ from a 7i-allylpalladium chloride dimer and a chiral ligand led to the corresponding chiral phthalimide... 

In 2009, Mangion et al. found that hydrazines and hydroxylamines eould be excellent nucleophiles for the Pd-catalysed allylic amination of butadiene monoepoxide in the presence of this ligand. The DYKATs afforded the corresponding amino alcohols in good yields and enantioselectivities, as shown in Scheme 2.50. The method was applicable to acyclic and heterocyclic amines, and applied towards a live-step synthesis of (f )-piperazic acid. 

Butadiene monoepoxide 166 has been used as a substrate for enantioselective allylic substitution reactions. The reaction with phthalimide has been performed with excellent regiocontrol and excellent enantiocontrol. The best results were obtained with a variant 168 of the standard ligand (Scheme 36). ° " ... 

PdL4 Complexes in the Selective 1,4 Addition of Nucleophiles to Butadiene Monoepoxide. 

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