(1) (E/Z) (X = Cl, Y = Cl)

[926-57-8]  · C4H6Cl2  · 1,3-Dichloro-2-butene  · (MW 125.00) (E)-(1) (X = Cl, Y = Cl)

[7415-31-8] (Z)-(1) (X = Cl, Y = Cl)

[10075-38-4] (2) (E/Z) (X = Cl, Y = Br)

[51430-83-2]  · C4H6BrCl  · 1-Bromo-3-chloro-2-butene  · (MW 169.45) (3) (E/Z) (X = Cl, Y = I)

[54201-06-8]  · C4H6ClI  · 3-Chloro-1-iodo-2-butene  · (MW 216.45) (E)-(4) (X = Br, Y = Br)

[86365-83-5]  · C4H6Br2  · 1,3-Dibromo-2-butene  · (MW 213.90) (Z)-(4) (X = Br, Y = Br)

[86365-84-6] (E)-(5) (X = I, Y = Cl)

[135663-74-0]  · C4H6ClI  · 1-Chloro-3-iodo-2-butene  · (MW 216.45) (Z)-(5) (X = I, Y = Cl)

[138174-48-8] (Z)-(6) (X = I, Y = I)

[134005-20-2]  · C4H6I2  · 1,3-Diiodo-2-butene  · (MW 307.90)

(aldol, alkenyl radical, organopalladium/Heck annulations; methyl ketone precursor; alkyne precursor; alkenyl organometallic precursor; allylic nucleophile precursor)

Alternate Name: Wichterle reagent (1).

Physical Data: (E)-(1) bp 40 °C/20 mmHg; (Z)-(1) bp 35 °C/20 mmHg; (Z)-(4) bp 66 °C/13 mmHg.

Preparative Methods: see appropriate reference: (1),2a,3 (2),7a (3),12a (4),14b,15d,e (5),15c,f (6).15a

Handling, Storage, and Precautions: reagent (1) shows an acute LD50 (inhalation, 4 h) of 546 ppm in rats.2a Acute and chronic toxicity to the kidney and other major organs is well established.2 As low molecular weight allylic halides, these reagents can be expected to be lachrymatory, irritating to and absorbed through the skin and mucous membranes, especially hazardous via inhalation, and suspect carcinogens. The usual stability order I < Br < Cl applies for both X and Y. The iodoallyl reagent (3) is photolabile;12a the iodoalkenyl reagent (Z)-(5) is reported to decompose above 25 °C.15f

Annulation (Aldol); Methyl Ketone Precursor.4-10

In 1948, Wichterle reported that treatment of a chloroalkenyl keto ester with concentrated sulfuric acid resulted in cyclization (eq 1),4a effecting a formal equivalent of the Robinson annulation with 1,3-dichloro-2-butene (1) serving as a substitute for Methyl Vinyl Ketone (MVK). The Wichterle reaction has proven useful in many syntheses in which MVK gives poor results due to polymerization or other side reactions. The alkylation step has been performed with unstabilized as well as stabilized enolates and with enamines. The Roussel-Uclaf synthesis of 19-norprogesterone, which exploited the selective condensation of pyrrolidine with a cyclohexenone in the presence of a saturated methyl ketone, is exemplary (eq 2).4b In this case, the allylic iodide (3) was formed in situ; the bromo (2) or iodo derivative (3) is often prepared in a separate Finkelstein reaction. Although (E)-(1) and (Z)-(1) are more reactive than allyl chloride to substitution with Potassium Iodide or Sodium Ethoxide,3a (3) failed a demanding test of regioselective alkylation of a sterically hindered enolate (eq 3).4c Catalytic Tetrakis(triphenylphosphine)palladium(0) has been shown to enhance the reactivity of (1), allowing regioselective alkylation of potassium enoxyborates.4d

When concentrated H2SO4 is used for solvolysis, high yields are favored by short (<1 h) reaction times at 0 °C, use of a diluent (CH2Cl2), and rapid dilution upon aqueous workup.5a,b Starting ring size, substitution, and unsaturation affect the course of cyclization.5 Saturated ketones tend to cyclize to bridged bicyclic enones, sometimes (eq 4)5a to the exclusion of the usually desired fused product. Unsaturation can prevent premature cyclization (eq 5);5a in eq (2), a bridged enone would violate Bredt's rule. Fused products can be obtained from saturated ketones by using milder acidic conditions (eq 6).5d,7a Treatment with HgII salts or Titanium(IV) Chloride is often preferred,4d giving the dione which is cyclized in a separate aldol step (e.g. eqs 7 and 8). Chloroalkenes also react with carbocations intramolecularly as cyclization terminators, but are inferior to fluoroalkenes in this role.6

Reductive alkylation by (2) of a dienone (eq 7),7b or related enedione,7a proceeded regio- and stereoselectively to provide a concise synthesis of adrenosterone. The stabilized Michael acceptor a-(trimethylsilyl)-MVK7c failed in this case. Alkylation of an optically active b-hydroxybutyrate dianion proceeded with high anti selectivity to form a quaternary chiral center (eq 8);8a,b the 1,5-diketone thereby obtained could be cyclized to either regioisomeric cyclohexenone by varying aldol conditions. Phase-transfer alkylation of a 1-indanone in the presence of a Cinchona alkaloid-derived chiral catalyst proceeded with pronounced enantioselectivity, again leading to a chiral quaternary enone after cyclization (eq 9).8c Reaction of a lithiothiomethyl phosphonate with (1), followed by a second lithiation and condensation with an aldehyde, afforded in one flask a dienic 1,4-diketone precursor (eq 10).8d

The Wichterle reaction has found use in heterocyclic synthesis, of the pyrido[1,2-a]benzimidazole system (eq 11).10a En route to camptothecin, a planned aldol cyclization route to a dihydropyridone using Methyl Magnesium Carbonate (MMC) took an unexpected course, via transient benzylic methoxycarbonylation (eq 12).10b In a model study for mesembrine synthesis, alkylation with (1) followed by a regioselective imide reduction paved the way to an iminium ion cyclization (eq 13).10c

Alkyne Precursor.11,12

Vigorous basic treatment of (1) provides vinylacetylene (eq 14).11a Under appropriate conditions, chloroalkenes derived from (1) are transformed into either the internal (eq 15)11b or terminal alkyne (eq 16).12a-c d,ε-Alkynyl ketones undergo reductive12a,b or photochemical cyclization;12c HgII-catalyzed hydration to the 1,5-diketone is an alternative to direct hydrolysis of the chloroalkene.12d

Allylic Nucleophile.13

The allyllithium derivative of (1) can be prepared at -90 °C via an allyllead intermediate;13a preparation of the Grignard reagent in the usual way, near rt, presumably results in decomposition. Electrochemical coupling of (1) with ClSiMe2Ph yields the allylsilane.13b Reaction of (3) with Ph3P gives the phosphonium salt and thence the phosphorane unexceptionally.13c

Alkenyl Radical Cyclization.14

Treatment of an iodo- or bromoalkene with Tri-n-butylstannane generates the alkenyl radical which can add intramolecularly to a double bond (eqs 17 and 18).14a,b A strong preference for enolate alkylation syn to the double bond (eq 18)14b was exploited. The (E)-bromoalkene can be used because alkenyl radical inversion is rapid.

Alkenyl Organometallic Precursor.15

Eq 1915a,b demonstrates use of a catalytic intramolecular Heck reaction of a (Z)-iodoalkene in a cyclopentene annulation sequence. Cyclization of the related (1-alkenyl) triflate using the chiral ligand S-BINAP gave the exo-methylene product in 80% ee. En route to rapamycin, reagent (E)-(5) provided an allylic sulfone that was deployed sequentially in a CrII-mediated (Nozaki-Kishi) aldehyde addition and a Julia coupling (eq 20).15c

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Raymond E. Conrow

Alcon Laboratories, Fort Worth, TX, USA

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