Propylene Oxide1

[75-56-9]  · C3H6O  · Propylene Oxide  · (MW 58.09)

(monomer for polymerization; electrophile; chiral building block)

Alternate Names: 1,2-epoxypropane; methyloxirane.

Physical Data: mp -112 °C; bp 34 °C; d 0.859 g cm-3; [a]20D +14.6° for the (R)-enantiomer, corrected to 100% ee.

Solubility: sol H2O (405 g L-1); miscible with organic solvents.

Form Supplied in: colorless liquid; commercially available as a racemic mixture and as the enantiomers. Drying: distillation from calcium hydride or calcium. Upon cooling, a hydrate C3H6O.(H2O)16 of mp -3 °C is precipitated from the moist oxirane as white crystals.2

Analysis of Reagent Purity: 13C NMR (CDCl3): d 47.1, 46.8 (C-1, C-2), 17.2 (C-3) ppm; determination of ee by complexation gas chromatography on nickel(II) bis[3-heptafluorobutanoyl-(1R)-camphorate] in squalane, separation factor a 1.24 at 50 °C;3 other suitable chiral stationary phases are nickel(II) bis[2-heptafluorobutanoyl-(S)-4-methylthujan-3-onate] and manganese(II) bis[3-heptafluorobutanoyl-(1R)-camphorate].4

Preparative Methods: (R)-propylene oxide is prepared (eq 1) in three steps: diazotization of (S)-alanine with Sodium Nitrite in hydrochloric acid; to give (S)-2-chloropropanoic acid; reduction to 2-chloropropan-1-ol with Lithium Aluminum Hydride; and cyclization by distillation from Potassium Hydroxide pellets.4,5

The (S)-enantiomer is prepared from (S)-Ethyl Lactate via (S)-propane-1,2-diol, and cyclization of a mixture of (S)-2-acetoxy-1-bromopropane and (R)-2-bromo-1-acetoxypropane (eq 2).6,7

Alternatively, conversion of (S)-ethyl lactate into the mesylate is followed by reduction of the ester group with Aluminum Hydride/THF and ring closure with aqueous KOH.8 Another route to (S)-propylene oxide involves protection of the (secondary) hydroxyl group of (S)-ethyl lactate with Ethyl Vinyl Ether, followed by reduction of the ester group with LiAlH4, conversion of the primary hydroxyl group into the tosylate, acidic deprotection of the secondary hydroxyl group, and cyclization with aqueous KOH.9 By means of a combined microbial/chemical synthesis, (R)-propylene oxide is obtained from glucose with ee >99%.10 Metal-mediated access to both enantiomers is provided by either chromatographic or kinetic resolution of racemic propylene oxide, and also by asymmetric epoxidation of propylene.11

Handling, Storage, and Precautions: a suspected carcinogen for humans; it is inflammable and explosive; because of its high volatility, cooling to 0 °C before use is recommended. Use in a fume hood.

Polymerization of Propylene Oxide.

Monoalkyl-substituted oxiranes are polymerized by a great variety of initiators (cationic, anionic, or ionic-coordinated). Cationic initiators tend to give irregular enchainments, as ring opening occurs in both the a- and b-positions. With anionic initiators, such as Potassium t-Butoxide and KOH, the stereoselective formation of head-to-tail polymers is straightforward; in the case of propylene oxide, the chain ends are left unsaturated, giving rise to secondary reactions.12 Enantioselective polymerization of racemic propylene oxide is mediated by initiators formed from Diethylzinc and various chiral auxiliaries;13 the reaction proceeds with complete inversion at the stereogenic center and, with achiral initiators, an equimolar mixture of homochiral polymers (R)-(R)-(R)... and (S)-(S)-(S)... is formed.14 Oligoethers are formed with tetraphenylporphinatoaluminium chloride as initiator species (eq 3); ring opening in the b-position is followed by insertion of the monomer unit into the Al-Cl bond. In subsequent steps, the monomer is inserted into the Al-O bond, leading to a polymer that bears a secondary hydroxyl group at one chain end and a chloromethyl group at the other.15

Reaction with Carbon Dioxide.

The stereoselective reaction of propylene oxide with Carbon Dioxide to give 4-methyl-1,3-dioxolan-2-one (eq 4) is catalyzed by metal salts and also by transition metal complexes; high pressures and high temperatures are necessary.16

Reaction with Heteronucleophiles.

Nucleophiles preferentially attack the unsubstituted carbon atom; since secondary amines are more basic than primary amines, the reaction of (S)-propylene oxide with the latter leads to polyfunctional amino diols (eq 5).17

As shown in eq 6, a primary amino group is introduced into an alkyloxirane by ring opening with lithium dibenzylamide, followed by hydrogenolytic deprotection of the amine.18

(S)-Propylene oxide reacts with Hydrogen Chloride/Lithium Chloride to give (S)-1-chloro-2-propanol (eq 7). This can be converted to 1-benzylthio-2-propanol by lithiation with n-Butyllithium followed by reaction with Lithium Naphthalenide to give highly reactive C-metalated alkoxides.19

Reaction with Grignard Reagents.

The C-C-coupling reaction between oxiranes and Grignard reagents is catalyzed by copper(I) compounds. As depicted in eq 8, (R)- and (S)-sulcatol are prepared in a straightforward manner from (R)- and (S)-propylene oxide, respectively, and an allylic Grignard reagent, using Copper(I) Iodide as catalyst.20

A convenient route to (R)-a-methylene-g-lactones (eq 9) comprises reaction of a vinylic Grignard reagent with propylene oxide, electrophilic replacement of the trimethylsilyl group, and ring closure with Tetrakis(triphenylphosphine)palladium(0) and Carbon Monoxide in acetonitrile.21

In eq 10, the total synthesis of (R)-mellein is depicted via the O-methoxymethylene-protected aryl Grignard compound derived from 3-bromophenol, which is added to (R)-propylene oxide using CuBr.SMe2 (see Copper(I) Bromide) as the catalyst. After ring lithiation with n-Butyllithium and carboxylation with Carbon Dioxide, treatment with methanolic hydrochloric acid leads to the final product.22

An illustration of protection and deprotection of two hydroxy groups is displayed in eq 11. Reaction of an aliphatic bromomagnesium compound with propylene oxide in the presence of 1,4-cyclooctadiene-Copper(I) Chloride, followed by protection with 3,4-Dihydro-2H-pyran, hydrogenolytic debenzylation of the primary hydroxy group, and oxidation with Pyridinium Chlorochromate yields an aldehyde that is transformed into melochinine by a multistep procedure.23

This scheme is paralleled by eq 12, where an aliphatic chloromagnesium compound reacts with propylene oxide. In a multistep procedure, the secondary hydroxy group is protected, and the primary hydroxy group is deprotected and eventually oxidized to a carboxylic function. The final product, (S)-13-methyl-(Z)-5-tridecenolide, is a macrolide aggregation pheromone of the flat grain beetle.24

Reaction with Organoaluminum Compounds.

The macrocyclic lactone (R)-recifeiolide is prepared via ring opening of (R)-propylene oxide with a lithium vinylaluminate, and conversion of another vinyl group into a carboxymethylene function via the sequence shown in eq 13.25

Reaction with Organolithium Compounds.

(R)-2-Hydroxypropylfuran is available by lithiation of furan with n-BuLi and alkylation with (R)-propylene oxide (eq 14).26

The total synthesis of grahamimycin A1, a macrolide antibiotic, starts with ring opening of propylene oxide by means of a lithium acetylide (eq 15). Initially, (S)-propylene oxide was used to prepare the unnatural (S,S)-(+)-enantiomer;27 the use of the (R)-enantiomer to produce the natural (R,R)-(-)-grahamimycin has also been described.28

As outlined in eq 16, ring opening of (S)-propylene oxide with a lithiated sulfone serves as a key step in the synthesis of (2R,5S)-cis-2-methyl-5-hexanolide, a sex pheromone of the carpenter bee. In the same way, the (R)-enantiomer is used to prepare (2S,5R)-cis-2-methyl-5-hexanolide in high enantiomeric purity.29

Reaction with Enolates.

The pheromone components of Paravespula vulgaris, the (E)- and (Z)-isomers of 2-methyl-1,6-dioxaspiro[4.5]decane with the (S)-configuration at C-2, are obtained by alkylation of the a-acetyl-d-valerolactone dianion with (S)-propylene oxide (eq 17).30

Alkylation of methyl acetoacetate with (R)-propylene oxide yields (R)-2-acetyl-4-pentanolide. This is converted into a mixture of (E,E)- and (Z,E)-exogonic acid (eq 18).31

Related Reagents.

Ethylene Oxide; Glycidol; Isoprene Epoxide.


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29. Mori, K.; Senda, S. T 1985, 41, 541.
30. Hintzer, K.; Weber, R.; Schurig, V. TL 1981, 22, 55.
31. Nishiyama, T.; Woodhall, J. F.; Lawson, E. N.; Kitching, W. JOC 1989, 54, 2183.

Bernhard Koppenhoefer, Konrad Lohmiller & Frank V. Schurig

University of Tübingen, Germany



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