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Review
. 2015 Dec 21;54(52):15642-82.
doi: 10.1002/anie.201507152. Epub 2015 Dec 2.

Catalytic, Stereoselective Dihalogenation of Alkenes: Challenges and Opportunities

Alexander J Cresswell  1 , Stanley T-C Eey  2 , Scott E Denmark  3
Affiliations
Review

Catalytic, Stereoselective Dihalogenation of Alkenes: Challenges and Opportunities

Alexander J Cresswell et al. Angew Chem Int Ed Engl. .

Abstract

Although recent years have witnessed significant advances in the development of catalytic, enantioselective halofunctionalizations of alkenes, the related dihalogenation of olefins to afford enantioenriched vicinal dihalide products remains comparatively underdeveloped. However, the growing number of complex natural products bearing halogen atoms at stereogenic centers has underscored this critical gap in the synthetic chemist's arsenal. This Review highlights the selectivity challenges inherent in the design of enantioselective dihalogenation processes, and formulates a mechanism-based classification of alkene dihalogenations, including those that may circumvent the "classical" haliranium (or alkene-dihalogen π-complex) intermediates. A variety of metal and main group halide reagents that have been used for the dichlorination or dibromination of alkenes are discussed, and the proposed mechanisms of these transformations are critically evaluated.

Keywords: alkenes; catalysis; dihalogenation; enantioselective synthesis; reaction mechanisms.

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Figures

Figure 1
Figure 1
Proposed stereoinduction model.
Figure 2
Figure 2
Strategies for avoiding the use of molecular dihalogens.
Figure 3
Figure 3
Challenges in stereochemical communication between the catalyst and the alkene substrate. Cat = catalyst, X = halogen atom.
Figure 4
Figure 4
Anticipated destabilizing steric interaction in the concerted addition of SbCl5 to either cyclopentene or norbornene.
Scheme 1
Scheme 1
A racemic alkene dichlorination as the first step of Carreira’s landmark chlorosulfolipid total synthesis.
Scheme 2
Scheme 2
Snyder’s stoichiometric, enantioselective alkene dichlorination en route to (–)-napyradiomycin 7. MOM = methoxymethyl.
Scheme 3
Scheme 3
Stoichiometric, enantioselective alkene dichlorination employing a chiral, non-racemic, S-Cl sulfonium salt 9 as a chlorenium ion transfer reagent.
Scheme 4
Scheme 4
Catalytic, enantioselective alkene dichlorination.
Scheme 5
Scheme 5
Catalytic, enantioselective alkene dibromination.
Scheme 6
Scheme 6
Proposed catalytic cycle. 2-Np = 2-naphthyl.
Scheme 7
Scheme 7
Catalytic, enantioselective alkene chlorobromination. NBS = N-bromosuccinimide.
Scheme 8
Scheme 8
Enantioselective synthesis of (+)-bromochloromyrcene 14. DMP = Dess-Martin periodinane. NBS = N-bromosuccinimide.
Scheme 9
Scheme 9
Preliminary examples of catalytic, enantioselective alkene dichlorination and dibromination. NBS = N-bromosuccinimide.
Scheme 10
Scheme 10
General strategies for catalysis of halofunctionalization.
Scheme 11
Scheme 11
A Brønsted acid-catalyzed alkene dihalogenation using separate
Scheme 12
Scheme 12
A Brønsted acid-catalyzed alkene dihalogenation using an X+ reagent III in combination with a complex anion of the halide as an X− source.
Scheme 13
Scheme 13
A Brønsted acid-catalyzed alkene dihalogenation using a dihalogen equivalent XII as a single reagent.
Scheme 14
Scheme 14
A Lewis acid-catalyzed alkene dihalogenation using separate X+ and X− sources.
Scheme 15
Scheme 15
A Lewis acid-catalyzed alkene dihalogenation using a dihalogen equivalent XII as a single reagent.
Scheme 16
Scheme 16
A Lewis base-catalyzed alkene dihalogenation using separate X+ and X− sources.
Scheme 17
Scheme 17
A Lewis base-catalyzed alkene dihalogenation using a dihalogen equivalent XII as a single reagent.
Scheme 18
Scheme 18
Cationic phase transfer-catalyzed alkene dihalogenation.
Scheme 19
Scheme 19
Toste’s enantioselective halocyclization via chiral anion phase transfer catalysis.
Scheme 20
Scheme 20
Ma’s enantioselective bromocyclization via chiral anion phase transfer catalysis.
Scheme 21
Scheme 21
Anionic phase transfer-catalyzed alkene dihalogenation.
Scheme 22
Scheme 22
“Isohypsic” redox catalysis for alkene dihalogenation. M = transition metal or main group element.
Scheme 23
Scheme 23
“Oxidative” and “reductive” redox catalysis for alkene dihalogenation (note that all oxidation states are relative rather than absolute). M = transition metal or main group element.
Scheme 24
Scheme 24
Symmetry-based analysis of alkene dihalogenations (via haliranium ions), with enantiodetermining steps highlighted by bold arrows. X = halogen atom.
Scheme 25
Scheme 25
Enantiodetermining nucleophilic attack of halide ion by kinetic resolution of haliranium ions. Cat = catalyst, X = halogen atom.
Scheme 26
Scheme 26
Enantiodetermining nucleophilic attack of halide ion by regiodivergent (enantioconvergent) reaction of a racemic mixture. Cat = catalyst, X = halogen atom.
Scheme 27
Scheme 27
Alkene-to-alkene transfer illustrated for ethylene and its corresponding bromiranium ion.
Scheme 28
Scheme 28
Erosion of enantiospecificity in acetolysis from alkene-to-alkene transfer. HFIP = hexafluoroisopropanol, Tf = trifluoromethanesulfonyl, Ts = 4-toluenesulfonyl, es = (eeproduct/eestarting material) × 100%.
Scheme 29
Scheme 29
Racemization of an enantioenriched, acyclic vicinal dibromide via a Type 1 dyotropic rearrangement.
Scheme 30
Scheme 30
Correlation between alkene geometry and vicinal dihalide relative configuration for anti- and syn-selective dihalogenations.
Scheme 31
Scheme 31
A Type I dihalogenation process. Y = nucleofuge.
Scheme 32
Scheme 32
Predominant syn-dichlorination in the reaction of (E)-stilbene 28 with molecular Cl2.
Scheme 33
Scheme 33
A Type II dihalogenation mechanism.
Scheme 34
Scheme 34
A Type III dihalogenation mechanism. TS = transition state.
Scheme 35
Scheme 35
A Type IV dihalogenation mechanism.
Scheme 36
Scheme 36
A Type V dihalogenation mechanism.
Scheme 37
Scheme 37
Low-yielding dichlorination reaction of (Z)-4-octene 31 with TlCl3•H2O.
Scheme 38
Scheme 38
A thallium-catalyzed alkene dichlorination?
Scheme 39
Scheme 39
The dichlorination of excess cyclohexene 34 with in situ generated PbCl4, accompanied by extensive hydrochlorination.
Scheme 40
Scheme 40
Difluorination of pregnenolone acetate 37 using Pb(OAc)4-HF.
Scheme 41
Scheme 41
The dichlorination of excess cyclohexene 34 with NCl3.
Scheme 42
Scheme 42
The dichlorination of (E)-stilbene 28 with PCl5.
Scheme 43
Scheme 43
The dichlorination of 1,5-cyclooctadiene 39 with PCl5.
Scheme 44
Scheme 44
Syn-stereospecific dichlorination of alkenes using SbCl5.
Scheme 45
Scheme 45
Proposed equilibria in chlorocarbon solutions of SbCl5.
Scheme 46
Scheme 46
Proposed parallel mechanisms for the formation of syn- and anti-dichlorides, respectively, arbitrarily illustrated for an (E)-configured alkene.
Scheme 47
Scheme 47
Dichlorination of alkenes with SO2Cl2 via a radical chain mechanism (with Cl· depicted as the chain-carrier).
Scheme 48
Scheme 48
The dichlorination of 1,5-cyclooctadiene 39 with SO2Cl2. 1,3-DNB = 1,3-dinitrobenzene.
Scheme 49
Scheme 49
Selenium-catalyzed syn-dichlorination of alkenes.
Scheme 50
Scheme 50
Proposed catalytic cycle for the selenium-catalyzed syn-dichlorination of alkenes.
Scheme 51
Scheme 51
Dichlorination of alkenes with PhICl2 via a radical chain mechanism (with Cl· depicted as the chain-carrier).
Scheme 52
Scheme 52
The stereoconvergent dichlorination of β-methylstyrenes (E)-51 and (Z)-52 with PhICl2.
Scheme 53
Scheme 53
Mechanistic rationale for the syn-selective dichlorination of cholesterol benzoate 55 via a Type V radical chain pathway.
Scheme 54
Scheme 54
Possible reaction pathways for the ionic dichlorination of alkenes with PhICl2.
Scheme 55
Scheme 55
Trifluoroacetic acid-catalyzed alkene dichlorination with PhICl2 in CCl4.
Scheme 56
Scheme 56
Plausible active chlorinating agents in the pyridine-promoted dichlorination of alkenes with PhICl2.
Scheme 57
Scheme 57
Dihalogenation of (E)-β-methylstyrene 51 with PhI(OAc)2 and Py•HX (X = Br or Cl), and attempted enantioselective dibromination with chiral, non-racemic iodoxyarene 59.
Scheme 58
Scheme 58
Vicinal difluorination of alkene 60 with 4-TolIF2 and Et3N•5HF and the proposed Type IIinv mechanism.
Scheme 59
Scheme 59
Dichlorination of norbornene 62 using VCl4.
Scheme 60
Scheme 60
Syn-stereospecific dichlorination of alkenes using MoCl5.
Scheme 61
Scheme 61
Proposed parallel mechanisms for the formation of syn- and anti-dichlorination products, respectively, arbitrarily illustrated for an (E)-configured alkene.
Scheme 62
Scheme 62
Nugent’s protocol for molybdenum-mediated syn-dichlorination of alkenes.
Scheme 63
Scheme 63
Anti-stereospecific dichlorination of alkenes with Markó‘s reagent.
Scheme 64
Scheme 64
Experiments to probe the intermediacy of chloriranium ions as intermediates.
Scheme 65
Scheme 65
Mechanistic proposal for the anti-dichlorination of alkenes by Markó‘s reagent.
Scheme 66
Scheme 66
Alkene dichlorination mediated by Mn(III) chlorides.
Scheme 67
Scheme 67
Mn(III)-catalyzed dichlorination of alkenes.
Scheme 68
Scheme 68
Alkene dichlorination mediated by Mn(IV) chlorides.
Scheme 69
Scheme 69
Alkene dichlorination with a structurally well-characterized Mn(IV) halide.
Scheme 70
Scheme 70
Chlorine atom abstraction from CH2Cl2 to generate a Mn(IV) hypochlorite complex 88.
Scheme 71
Scheme 71
Ability of Mn(IV) hypochlorite complex 88 to dichlorinate alkenes.
Scheme 72
Scheme 72
Ruthenium-catalyzed alkene dichlorination by a Type V mechanism.
Scheme 73
Scheme 73
A palladium-catalyzed dichlorination of alkenes?
Scheme 74
Scheme 74
Stepwise dichlorination of an allene using stoichiometric palladium.
Scheme 75
Scheme 75
Palladium-catalyzed dibrominations of allenes. Cy = cyclohexyl.
Scheme 76
Scheme 76
Potential strategies for stabilizing the alkyl–Pd(II) intermediate against unproductive β-halo elimination. LB = Lewis base.
Scheme 77
Scheme 77
Pd(IV)-mediated dichlorination of alkenes.
Scheme 78
Scheme 78
The “oxychlorination” process for the dichlorination of ethylene.
Scheme 79
Scheme 79
Gas-phase dichlorination of alkenes on pumice-supported CuCl2.
Scheme 80
Scheme 80
Non-stereospecific dichlorination of 2-butenes with CuCl2 in MeOH.
Scheme 81
Scheme 81
Mechanistic proposal for the dichlorination of alkenes with stoichiometric amounts of CuCl2 in alcohol solvents.
Scheme 82
Scheme 82
A plausible mechanism for alkene dichlorinations with CuCl2 that is consistent with all of the experimental observations.
Scheme 83
Scheme 83
Stereospecific dibromination of 2-butenes with CuBr2.
Scheme 84
Scheme 84
Calculated Type IIret mechanism for alkene dibromination with CuBr2 and LiCl in MeCN:THF.
Scheme 85
Scheme 85
Sequential reactions in the dichlorination of alkenes with AuCl3.
Scheme 86
Scheme 86
Stereospecific dichlorination of 2-butenes with AuCl3.
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