2-IODOCYCLOHEXEN-2-ONE 1

2-Iodocyclohexen-2-one

I

O

[33948-36-6] C6H7IO (MW 222.02)InChI = 1/C6H7IO/c7-5-3-1-2-4-6(5)8/h3H,1-2,4H2InChIKey = IPFSJCDRYRZTJU-UHFFFAOYAO

(highly reactive and versatile intermediate for the generation ofα-substituted enones, especially important in transition metal-

mediated couplings)

Physical Data: mp 46–47 ◦C.Solubility: MeOH, EtOH, and DMSO.Form Supplied in: usually prepared by iodination of cyclohexe-

none. Light orange-yellow to colorless crystals.Purification: crude material can be recrystallized from petroleum

ether or mixtures of diethyl ether and pentane (2:1). Can alter-natively be purified using column chromatography on silica geland 10% EtOAc in petroleum ether.

Handling, Storage, and Precautions: starting material for mostreactions is 2-cyclohexenone, which is a highly toxic and com-bustible liquid. Contact with the skin, eyes, by ingestion, orinhalation may cause dermatitis, respiratory tract irritation, orgastric disturbances.

Preparation. 2-Iodocyclohexen-2-one is not commerciallyavailable, but it can be prepared by a variety of methods from2-cyclohexenone. Methods include the addition of IN3,1 theaddition of iodine in the presence of Ce(IV),2 and the sequen-tial addition of TMSN3 and a mixture of pyridine and iodine,3

iodine plus bis(tetra-n-butylammonium) peroxydisulfate,4 andiodine plus bis(trifluoroacetoxy)iodobenzene.5 A direct iodina-tion method using 2 equiv of I2 in a 1:1 mixture of pyridine andCCl4 was developed in 1992 (eq 1)6,7 and remains one of the mostpopular methods for preparation. The method was improved toillustrate that only a catalytic amount of PDC8 or pyridine9 wasrequired for good yields.

O

Ipy:CCl4

60%(1)

2 equiv I2

O

A later improvement (eq 2) replaced the catalytic pyridine withDMAP and used an aqueous–THF solvent system with K2CO3 togenerate the product in quantitative yield.10

O

IH2O–THF, K2CO3

99%(2)

2 equiv I2, 0.2 equiv DMAPO

2-Iodocyclohexen-2-one can also be prepared from 2-cyclohexenone oxide on solid-supported LiI11,12 and from2-(trimethylsilyl)-2-cyclohexenone using either 2 equiv of ICl ora 1:1 mixture of ICl/AlCl3.13

1,2-Additions. 2-Iodocyclohexen-2-one undergoes 1,2-addition with Grignard reagents (eq 3).14

I

O

IOH

MgBr

Et2O, 81%(3)

Phenylzinc can be added in the presence of a chiral,nonracemic ligand, providing the product in good yield (77%)and with good levels of asymmetric induction (ee = 93%).15

Attempted asymmetric allylation of 2-iodocyclohexen-2-one bya titanium-catalyzed Sakurai–Hosomi reaction with an in situ-generated H8-BINOLate titanium catalyst led to the formationof chiral homoallylic alcohols in modest yield and enantio-selectivities (eq 4).16 However, use of the difluorophos ligand andthe corresponding siloxane led to a substantial increase in boththe yield and the enantioselectivity.17

O

I Sn

OHI

4

H8-BINOL (30 mol %)Ti(o-i-Pr)4 (30 mol %)isopropanol (20 equiv)

+

(4)

CH3CN, rt55%, 49% ee

1,4-Additions. Standard conditions to promote conjugateaddition to 2-iodocyclohexen-2-one usually employ the use of acuprate reagent. This cuprate can be generated in situ either froma Grignard reagent (eq 5)18 or by reacting an iodo compound witht-BuLi and then CuCN.19

O

I

O

Ithen H2O, 79%cis:trans (1:2.2)

(5)CuI, MeMgBr, THF

The resulting enolate can be trapped with TMSCl, followedby oxidation with 2-iodoxybenzoic acid (IBX) or the 4-methoxy-pyridine-N-oxide complex (IBX·MPO).20 The addition can beassisted by BF3·OEt2 for sterically hindered enones.21,22 Asym-metric variants have been reported, proceeding in good yield withgood levels of asymmetric induction. It was determined that theenantioselectivity can be enhanced through the use of styreneas an additive. The ‘styrene effect’ is thought to be a result ofthe inhibition of a background and nonstereoselective conjugateaddition by trapping the initial Et radical (eq 6).23

O

I

O

OP

Ar

N

Ar

Me

MeO

I

Et

CH2Cl2, –30 °C to rt

with 0 equiv styrene87%, 88% ee, 18:82 trans/cis

with 1 equiv styrene92%, 95% ee, 19:81 trans/cis

(6)

1.5 equiv Et2Zn2% copper thiophene carboxylate

4% ligand (Ar = 2-napthyl)

Stille Cross-couplings. The Stille reaction has been usedextensively for cross-coupling reactions between 2-iodocyclo-

Avoid Skin Contact with All Reagents

2 2-IODOCYCLOHEXEN-2-ONE

hexen-2-one and alkyl stannanes,24 alkynyl stannanes,25 vinyl26

and arylstannanes (eq 7),27,28 3-tributylstannylsulfolene,29 α-stannylenamines,30,31 and PTC-protected α-hydroxystannanes.32

Typical conditions involve the use of a Pd(0) or Pd(II) catalystwith CuI and a weakly coordinating ligand, such as AsPh3 orP(o-tolyl)3, in NMP or dioxane at elevated temperatures.

O

I

O

SnBu3

PdCl2(PhCN)2 AsPh3, CuI

(7)NMP, 60%

+

1-Butyl-3-methylimidazolium tetrafluoroborate (BMIM+BF4

−), a room-temperature ionic liquid, was treated with PdCl2(PhCN)2, CuI, and AsPh3 to create a renewable solvent andcatalyst system for the Stille reaction of 2-iodocyclohexen-2-onewith vinyl and phenyl stannanes.33 Stille cross-couplings of2-iodocyclohexen-2-one and functionalized aromatic or hetero-cyclic rings have been used as initial reactions toward the synthesisof indoles34–36 and 1,2-dihydro-4(3H)-carbazole skeletons aspart of total synthesis schemes (eq 8).37,38 Reduction of the nitromoiety to the amine sets the stage for cyclization to the carbazole.

SnBu3

NO2

O

I

NO2

OPdCl2(PPh3)2AsPh3, CuI

(8) NMP, 76%

+

Suzuki Cross-couplings. The Suzuki cross-coupling reactionconditions have been used with primary alkenyl boranes withretention of stereochemistry39 and with boranes made in situ.40

Examples of aryl couplings have been performed under standardSuzuki conditions (eq 9),7,41 on soluble and insoluble polymer-supported triphenylarsine reagents,42 with heterogeneous, ligand-less conditions43 and with the use of a Pd(II) precatalyst.44

I

O

(HO)2B

OMe

OMeO

PdCl2(PhCN)2AsPh3, Ag2O

(9)

THF:H2O, 78%+

Negishi Cross-couplings. 3-Oxo-2-cyclohexen-2-ylzinciodides (or 6-oxocyclohexenylzinc iodides) can be preparedby treatment of 2-iodocyclohexen-2-one with preactivated zincdust, 1,2-dibromoethane, and TMSCl (eq 10)45 or Zn(Ag) andtetramethylenediamine (TMEDA),46 and subsequently coupledwith aryl or alkenyl halides using a Pd(0) catalyst.

O

I

O

ZnIZn dust (excess)(10)

THF

2-Iodocyclohexen-2-one can be alternatively coupled withalkenylzinc compounds to prepare α-alkenylenones (eq 11),47,48

with α-(phenylthio)alkenylzinc reagents,49 with alkyl (E)- or(Z)-2-iodo-2-alkenoates with retention of stereochemistry,50 witharylzinc chlorides,51 or with vinyl Grignards, the latter as a meansto prepare precursors for the Diels–Alder reaction.52

O

I

O

Ph

PhCH2Br + ZnPdCl2(PPh3)2 (11)DMF, 94%

Sonagashira Couplings. Sonogashira conditions have beenused to introduce an alkynyl substituent in the total synthesisof (−)-harveynone and (−)-trichloromenyn A (eq 12),53 in theattempted synthesis of a trans-lactone,54 in the synthesis of theneocarzinostatin chromophore,55,56 and to prepare highly substi-tuted furans.57,58

O

I

H TMS

O TMSPdCl2(PPh3)2CuI, iPr2NH (12)THF, 92%

A copper-free Sonogashira reaction has been used to form theenyone derivatives in situ, immediately followed by a regiose-lective benzannulation to synthesize highly substituted benzenes(eq 13).59

O

I OH PdCl2(PPh3)2

OH

OH

O

+Et3N, DMF

80 °C, 3–5 h, 75%(13)

Other Coupling Reactions. The utility of 2-haloenones hasbeen demonstrated in other types of coupling reactions thathave been successful. Grignard reagents have been used tosubstitute the α-position of 2-iodocyclohexen-2-one withFe(acac)3 as a catalyst.60 Allyl,61 allenyl,62 and vinyl homocoup-lings63 have been achieved using an in situ-generated allylindiummoiety (eq 14).

O

I

O

O

(14)LiCl, DMF

100 °C, 2 h, 85%

Pd-C, In

Ullman conditions have been used to couple o-halonitrobenzene with 2-iodocyclohexen-2-one as a pre-cursor for indole synthesis.64 A modified Ullman usinga NiCl2(PPh3)2/PPh3/Zn/NaH/toluene system was used tohomocouple 2-iodocyclohexen-2-one.65

Other Reactions. 2-Iodocyclohexen-2-one can be gem-difluorinated to provide mixtures of the 2,6- and 6,6-difluorinated-1-iodocyclohexenones using either DAST or Morph-DAST.

A list of General Abbreviations appears on the front Endpapers

2-IODOCYCLOHEXEN-2-ONE 3

However, the reaction conditions require column purification andyields are very low (16–26%).66,67 Sequential Michael addition/cyclization reactions can be used to prepare aziridines in thepresence of cesium carbonate (eq 15).68

O

I

O

N Bn

BnNH2, Cs2CO31,10-phenanthroline

(15)xylene, 88%

In the presence of tetrabutylammonium hydrogensulfate or18-crown-6, sodium benzoate adds to 2-iodocyclohexen-2-oneto give mixtures of the α- and γ-benzoyloxylated products.69

2-Iodocyclohexen-2-one can be enantioselectively reduced(93% ee) with an oxazaborolidine catalyst in the presence ofBH3·THF.70 The ethylene acetal derivative of 2-iodocyclohexen-2-one has been used in Stille cross-couplings.71,72

Related Reagents. 2-Cyclohexenone; 2-Bromocyclohexen-2-one; 2-Chlorocyclohexen-2-one; 2-Iodocyclopenten-2-one; 2-Iodocyclohexen-2-one Ethylene Acetal.

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Avoid Skin Contact with All Reagents

4 2-IODOCYCLOHEXEN-2-ONE

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Lesley A. Schmid & Carl J. LovelyThe University of Texas at Arlington, Arlington, TX, USA

A list of General Abbreviations appears on the front Endpapers