Two-fold extrusion reactions

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Twofold extrusion reactions involve the loss of two small, typically inorganic fragments bridging two atoms with the formation of a double bond between the atoms (most commonly, an alkene or imine). These reactions are particularly useful for the introduction of hindered double bonds, as extrusion can often be initiated thermally without the need for added reagents.[1]


Twofold extrusion reactions involve the loss of small, inorganic fragments from a heterocyclic ring system with the formation of a double bond between carbons in the ring (Eq. 1). This suite of reactions has been applied for the synthesis of hindered alkenes, for which other methods such as the Wittig reaction are not successful. Synthetic routes to molecular machines have also involved twofold extrusion reactions. The scopes of these reactions are limited primarily by the availability of precursors to the required cyclic starting materials. At high temperatures or in the presence of a reductant such as a phosphine, extrusion is commonly spontaneous.


Precursors to the ring systems that undergo twofold extrusion include thiones, hydrogen sulfide, selones, diazo compounds, and azines. Thia- and selenadiazoline ring systems and their oxidized analogues are the most common starting materials for the extrusion step itself; however, several different methods exist for the preparation of these substrates.

Mechanism and Stereochemistry

Alkene Formation from Thia- and Selenadiazolines

The mechanism of the thermal extrusion reaction of thiadiazolines has been studied in detail.[2] Initial loss of nitrogen from thiadiazoline 1 produces a thiocarbonyl ylide, which may be represented as a diradical, dipole, or tetravalent sulfur structure. This intermediate can be captured through 1,3-dipolar cycloaddition with alkynes or treatment with acid.[3][4] 4π-electron, conrotatory ring closure of the thiocarbonyl ylide affords thiirane 2 (Eq. 2). It is often possible to isolate the thiirane at this stage; however, subsequent treatment with tertiary phosphines,[5] phenyllithium,[6] or copper bronze[1] leads to the extrusion of sulfur and alkene formation.


Alkene Formation from Sulfenes and Diazo Compounds

Sulfenes and diazo compounds react to afford alkenes, but unlike extrusion reactions employing thiones and diazo compounds (for which thiadiazolines are intermediates; see above), the mechanism of this reaction does not directly involve thiadiazoline-1,1-dioxides. Solvent effect studies[7] and independent investigation of isolated thiadiazoline-1,1-dioxides[8] support a polar mechanism involving addition of the diazo compound to the sulfene followed by ring closure (Eq. 3). Related thiadiazoline-1,1-dioxides lose sulfur dioxide upon heating to afford the corresponding azines, not alkenes.


Imine Formation from Thiatriazolines

Azides are nitrogen-containing analogues of diazo compounds, and react with thiones to afford imines after twofold extrusion. Trapping experiments support the intermediacy of a thiocarbonyl-S-imide 3 in this mechanism, most likely generated via cycloaddition of the azide and thione followed by extrusion of nitrogen (Eq. 4).[9]


Scope and Limitations

As the scope of twofold extrusion reactions depends significantly on the availability of precursors, this section includes discussions of the scope and limitations of both precursor synthesis and twofold extrusion itself.

Preparation of Precursors

Thiones may be prepared using Lawesson's reagent in conjunction with ketones[10] or, for relatively stable thiones, treatment of the corresponding ketone with hydrogen sulfide and an acid catalyst may be used (Eq. 5).[11]


Diazo compounds for use in extrusion reactions are commonly prepared via oxidation of the corresponding hydrazone. Lead(IV) acetate is useful for the oxidation of aryl hydrazones (Eq. 6),[11] while barium manganate is commonly used to prepare hindered alkyl diazo compounds from the corresponding hydrazones.[12]


Selones, the selenium analogues of ketones, may be prepared by treating the corresponding triphenylphosphoranylidene hydrazones with elemental selenium (Eq. 7).[13] Importantly, the substrate scope of selones is strictly limited to those stabilized by conjugation or steric hindrance.


Alkene and Imine Formation

A few different methods exist for the preparation of thia- or selenadiazolines suitable for twofold extrusion reactions. The "azine addition" method is convenient for the preparation and extrusion of symmetric thiadiazolines. Treatment of the symmetric azine with hydrogen sulfide leads to addition across both π bonds of the azine, and the resulting thiadiazolidines may be oxidized with lead(IV) acetate and subjected to extrusion in the presence of a tertiary phosphine. This one-pot method, applicable to a broad array of substrates, bypasses isolation of the thiirane (Eq. 8).[14]


For the synthesis of unsymmetrical thiadiazolines, the cycloaddition of thiones and diazo compounds is commonly employed (Eq. 9).[15] Spontaneous extrusion of sulfur often occurs at high temperatures, particularly when the thiirane is unhindered. An important limitation of this chemistry concerns the synthesis of severely hindered, asymmetric thiadiazolines, which readily undergo retrocyclization to form new thiones and diazo compounds. These intermediates may in turn combine with the starting materials to afford less hindered, symmetric alkenes after extrusion.[12]


Using heteroatom-substituted thiones, the preparation of heteroatom-substituted alkenes is possible. For instance, the reaction of thiophosgene and diphenyldiazomethane at elevated temperatures produces the corresponding 1,1-dichloroalkene in good yield (Eq. 10).


Both thiones and sterically hindered selones, in combination with aryl azides, are useful for the preparation of N-aryl imines (Eq. 11).[16] The substrate scope of this reaction is limited to aryl azides.


Synthetic Applications

Twofold extrusion reactions are most commonly employed when other olefination methods are unsuccessful. Highly substituted or sterically hindered olefins are the most problematic targets for classical olefination methods, such as the Wittig, Horner-Wadsworth-Emmons, and Peterson olefinations. Although few natural products contain sterically hindered alkenes, several molecules of theoretical interest possess this structural motif (Eq. 12).[17][18][19]


Extrustion reactions have also been applied for the synthesis of molecular machines, which often include highly conjugated or strained alkenes as a design element.[20]

Comparison to Other Methods

Other olefination methods are generally inferior to extrusion reactions when sterically hindered alkenes are the target. However, extrusion methods require the preparation of exotic (and at times unstable) precursors, and the reaction does not work well for some unhindered precursors.[21] The McMurry coupling reaction (Eq. 13) is an alternative to twofold extrusion that is useful for the synthesis of hindered alkenes.[22]


Imines are most commonly prepared through dehydrative condensation of amines and carbonyl compounds. Sterically hindered imines typically require the use of a stoichiometric amount of a dehydrating agent, such as titanium(IV) chloride (Eq. 14).[23] These methods, useful for the synthesis of hindered N-alkyl imines, are a nice complement to the twofold extrusion method for the synthesis of hindered N-aryl imines.


Experimental Conditions and Procedure

Typical Conditions

Many of the substrates and reagents employed in twofold extrusion reactions are foul-smelling, toxic, and/or explosive. Care should be taken when handling sensitive reagents, and reactions should be carried out in a well-ventilated fume hood.

Anhydrous, non-polar solvents and an atmosphere of dry nitrogen or argon are employed most commonly for these reactions. Typically, for reactions involving the extrusion of sulfur, phosphines or copper bronze are added after the initial extrusion of dinitrogen and the mixture is reheated. For stabilized thiones and diazo compounds, a metal salt may be necessary to catalyze cycloaddition.

Example Procedure[24]


Hydrogen sulfide was bubbled through vigorously stirred cyclobutanone (21 g, 0.30 mol) for 20 min, and then aqueous hydrazine (20 mL, 7.5 M solution, 0.15 mol) was added dropwise over 20 min with continued passage of H2S. After completion of the addition of hydrazine, H2S was passed for a further 20 min, a solid product having formed. The crude reaction mixture was treated with CH2Cl2 (200 mL), the organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2 x 50 mL). The combined organic layers were dried (MgSO4) and the solvent removed under reduced pressure to give 5-thia-10,11-diazadispiro[]undecane (21.0 g, 82%). A sample was recrystallized from petroleum ether (bp 40–60 °C) to afford white crystals: mp 96–97 °C; IR (KBr) 3200, 2910, 1425, 1245, 1170, 1140, 1075, 850, 860, 820 cm–1; 1H NMR (CCl4) δ 3.53 (br s, 2H), 2.64–1.61 (m, 12 H); HRMS (m/z): M+ cacld for C8H14N2S, 170.0878; found, 170.0868.

5-Thia-10,11-diazadispiro[]undecane (21.0 g, 0.12 mol) was dissolved in dry petroleum ether (800 mL), and the solution was then added slowly over 40 min to a vigorously stirred suspension of powdered lead(IV) acetate (66 g, 0.15 mol) in anhydrous petroleum ether (100 mL) at 0 °C. After completion of the addition the reaction mixture was stirred for a further 40 min at 0°. The reaction mixture was filtered through a pad of filtering aid, and the solid was washed with petroleum ether (2 x 100 mL). The filtrates were combined and the solvent was removed under reduced pressure to give 5-thia-10,11-diazadispiro[]undec-10-ene as colorless crystals (19.0 g, 92%). A sample was recrystallized from MeOH to afford colorless crystals: mp 72.5–73 °C; IR (KBr) 2950, 1565, 1425, 1250, 1090, 950, 880, 800 cm–1; 1H NMR (CCl4) δ 2.96–2.24 (m, 10H), 2.14–1.85 (m, 2H); MS (m/z): 168 (M+). Anal. Calcd for C8H12N2S: C, 57.11; H, 7.19; N, 16.65. Found: C, 56.67; H 7.21; N, 17.06.

A mixture of powdered 5-thia-10,11-diazadispiro-[]undec-10-ene (4.2 g, 0.025 mol) and dry triphenylphosphine (12.5 g, 0.075 mol) was heated at 85° for 1 h under reduced pressure (100 mm). The volatile liquid product was condensed from the evolved gases and purified by distillation over MgSO4 at 85 °C (100 mm) to give cyclobutylidenecyclobutane (2.5 g, 92%): IR (KBr) 2930, 1425, 1035, 915 cm–1; 1H NMR (CCl4) δ 2.66–2.36 (m, 8H), 2.12–1.72 (m, 4H); MS (m/z): 108 (M+). Anal. Calcd for C8H12: C, 88.83; H, 11.18. Found: C, 88.86; H, 11.07.


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