One or More CC Bond(s) by Elimination of Hydrogen, Carbon, Halogen or Oxygen Functions

1.13 One or More C1C Bond(s) by Elimination of Hydrogen, Carbon, Halogen or Oxygen Functions JONATHAN M. PERCY University of Birmingham, UK 0[02[0 BY ELIMINATION OF HYDROGEN 0[02[0[0 Dehydro`enation of Hydrocarbons 0[02[0[1 Dehydro`enation of Ketones 0[02[0[2 Dehydro`enation of Silyl Enol Ethers

443 443 443 445

0[02[1 ELIMINATION OF CARBON FUNCTIONS 0[02[1[0 Elimination of Hydro`en Cyanide 0[02[1[1 Elimination of Carbon Oxides 0[02[1[1[0 Decarboxylation 0[02[1[1[1 Didecarboxylation 0[02[1[1[2 Decarboxylation:dehydration 0[02[1[1[3 Decarboxylation:dehalo`enation

448 448 459 459 451 454 457

0[02[2 BY ELIMINATION OF HALOGEN "OR H!HAL#

457 457 469 469 460 461 463

0[02[2[0 Elimination of Dihalides 0[02[2[1 Elimination of Hydro`en Halides 0[02[2[1[0 Dehydro~uorination 0[02[2[1[1 Dehydrochlorination 0[02[2[1[2 Dehydrobromination 0[02[2[1[3 Dehydroiodination 0[02[3 BY ELIMINATION OF OXYGEN FUNCTIONS 0[02[3[0 Dehydration 0[02[3[0[0 Usin` Bur`ess| rea`ent 0[02[3[0[1 Usin` Martin|s sulfurane rea`ent 0[02[3[0[2 Dehydration by other methods 0[02[3[1 Elimination of Alcohols "H0OR# 0[02[3[2 Eliminative Rin` Openin` of Epoxides 0[02[3[3 Elimination of a Carboxylic Acid "H0OCOR# 0[02[3[4 Elimination of a Sulfonic Acid 0[02[3[5 Elimination of 0\1!Diols 0[02[3[6 Deoxy`enation of Epoxides

442

464 464 464 465 465 468 479 471 472 474 476

443

C1C Bonds by Elimination of Hydro`en\ Carbon\ Halo`en or Oxy`en

0[02[0 BY ELIMINATION OF HYDROGEN 0[02[0[0 Dehydrogenation of Hydrocarbons The most demanding dehydrogenation would involve the regioselective removal of two hydrogen atoms from an unactivated alkane[ Active iridium and rhodium catalysts have been described ð73TL0168\ 76JA7914Ł\ which achieve the transformation\ consuming an alkene oxidant during the catalytic cycle[ Unsymmetrical alkanes have been oxidized with modest regio! and stereoselectivities ð81JA8381Ł[ Though none of the current methods appear suitable for use in the synthesis of complex molecules\ the area is developing rapidly and signi_cant progress is being made[ The best known examples of reactions in this class lie outside the scope of this chapter and involve the aromatisation of polycyclic hydroaromatic compounds ð67CRV206Ł[ A number of reagents have been employed to e}ect dehydrogenations\ via hydride abstraction from benzylic or allylic positions[ The reagent of choice 1\2!dichloro!4\5!dicyano!0\3!benzoquinone "ddq#"0#\ is commercially avail! able and chemically reactive\ although the cost of the reagent is relatively high[ Chloranil "1# is a less expensive alternative[ Reactions are normally performed in inert\ high boiling solvents including toluene\ chlorobenzene\ xylene and 0\3!dioxan[ The corresponding dihydroquinol is formed during the reaction\ and can be removed by _ltration or chromatography on alumina[ Solvents must be dry to prevent nucleophilic attack by water on the quinone leading to decomposition[ Nucleophilic functional groups should be protected[ O NC NC

O Cl

Cl

Cl

Cl

Cl Cl

O (1)

O (2)

When hydride abstraction generates a highly stabilised carbenium ion\ dehydrogenations occur smoothly under mild conditions ð80TL2568Ł[ Oxidations of this type are unusual\ but appealing\ when further unwanted oxidation steps are impossible "Equation "0##[ MeO

TBDMS-O

TBDMS-O

MeO

H

ddq

(1) O

O

23 °C, 14 h 88%

TBDMS = t-butyldimethylsilyl

0[02[0[1 Dehydrogenation of Ketones The direct dehydrogenation of saturated ketones is a common and well!used reaction[ The mechanism probably involves initial enolisation of the ketone\ followed by nucleophilic attack on the quinone oxidant[ Elimination of the hydroquinol follows to form the a\b!double bond "Scheme 0#[ Bulky substituents at the b!carbon reduce the rate of oxidation\ presumably by impeding the nucleophilic addition step ð76BCJ3357Ł[ A range of ketones have been oxidised in this way "Table 0\ entries 0Ð6#[ OH (1) or (2)

O

OH

OH X

X

O

X

X

X

X

O

+ X O

X

OH

Scheme 1

A substituted cycloheptenone "entry 0# underwent e.cient dehydrogenation when re~uxed with ddq in benzene ð70JOC0Ł[ Flavanone and chromanone substrates underwent smooth oxidation to

444

Of Hydro`en Table 0 Dehydrogenations with ddq[ Entry

Substrate

Product

O

Yield (%)

O

O

O CO2Me

CO2Me

1

90

OMe

O

OMe

O

O

O 75

2 O O

HO

O Ph

O

HO

Ph 50

3 O O

MeO

Ph

O O

MeO

Ph 75

4 O

O O

O

84

5 O

O O

O

98

6

7

O

O

MeO2C

MeO2C

O

H

O

77

H

the corresponding ~avones and chromones "entries 1Ð3# ð72S209Ł[ The e}ect of the presence of a nucleophilic functional group was a reduction in yield\ possibly through nucleophilic attack on the oxidant[ The addition of an acid catalyst appeared to accelerate the reaction\ presumably by increasing the rate of enolisation ð56JCS"C#0619Ł[ Oxidation was complete within 4 hours\ when p!toluene sulfonic acid was added to the reaction mixture "entry 5#^ in the absence of the catalyst\ a reaction time of 04 hours was required "entry 4#[ The regiochemical outcome of the reaction also changed^ oxidation occurred in the B!ring when the catalyst was present[ The b!ketoester oxidation "entry 6# is unusual\ but the observation is entirely consistent with the proposed mechanism via an enol ð81JA6264Ł[ Attempts to oxidise "2# and "3# using a ddq procedure were unsuccessful[ The a!and b!faces of the steroid A!ring in "2# are both sterically hindered around the b!carbon atom\ impairing attack on the oxidant ð78T5398Ł[ In "3#\ enolisation of the b\g!unsaturated ketone may occur to generate a

445

C1C Bonds by Elimination of Hydro`en\ Carbon\ Halo`en or Oxy`en

sterically hindered enol ð81JA4848Ł[ Flavanone oxidation has been studied by a number of groups\ and alternative methods use thallium salts ð81JCS"P0#1454Ł[ O

O

NCO2Me

H

OMe O

O

H

O (4)

(3)

Ketone!to!enone conversions have been achieved by other methods[ Scheme 1 shows a fortuitous procedure\ applied to the synthesis of prostanoid intermediates ð72TL444Ł[ The straightforward one! step oxidation used commercial "88)# copper"II# bromide\ and o}ered signi_cant advantages over more conventional multistep procedures ð79JOC3691Ł[ However\ the method does not appear to have found other applications[ O CO2Me

CuBr2

O CO2Me

CHCl3, EtOAc reflux, 0.7 h 66%

O

O CO2Me

CuBr2

CO2Me

CHCl3, EtOAc reflux, 0.7 h 38%

CHO

CHO

Scheme 2

Cation radical oxidants achieved a regioselective oxidation of substituted cyclopentanones to a}ord the more substituted cyclopentenone products in modest yield "Scheme 2# ð89T1260Ł[ The salts could be preprepared or generated in situ[ An excess of oxidant was required\ and the reactions were performed in aqueous acetonitrile in the presence of collidine[ Lead tetraacetate:copper"II# acetate has been used to dehydrogenate b!ketoesters and b!ketoamides "Scheme 3#[ The amides were easy to prepare and were oxidised in better yield than the corresponding esters[ The procedure could be used on a multigramme scale ð82TL2910Ł[ O

+ •

O

R3NSbCl6–

R

R collidine H2O, MeCN

R = Me, 50% yield/65% conversion R = But, 40% yield/65% conversion Scheme 3

0[02[0[2 Dehydrogenation of Silyl Enol Ethers The oxidation of a silyl enol ether is a valuable synthetic method\ allowing the conversion of ketones to enones in a stepwise procedure[ The method combines well with the developments in regiocontrolled silyl enol ether formation[ E}ective oxidants include ddq\ palladium"II# compounds and tritylium salts[ Initial studies using ddq deployed a large excess of the oxidant to obtain enones in moderate yields ð67TL2344Ł[ Tritylium salts\ generated in situ\ oxidised enol ethers to cyclic enones in moderate yield[ The products were usually contaminated with ketone[ Acyclic silyl enol ethers were oxidised in low yield\ and ddq failed to yield oxidation products ð66JOC2850Ł[ Both methods were re_ned by Fleming and Paterson in an elegant study combining conjugate addition methods with silyl enol ether oxidation ð68S625Ł[ Table 1\ entries 0Ð6 show the scope of the reaction[ The ease of oxidation varied with level of substitution at the carbon atom b! to the carbonyl

446

Of Hydro`en O

O CO2Me

CO2Me

Pb(OAc)4, Cu(OAc)2•2H2O PhH, RT 78%

O

O

O

Pb(OAc)4, Cu(OAc)2•2H2O

NEt2

O NEt2

PhH, RT 72%

OMe O

OMe

O

Pb(OAc)4, Cu(OAc)2•2H2O

N

O

O

N

PhH, RT 55%

Scheme 4

Table 1 Dehydrogenations of silyl enol ethers with ddq[ Substrate

Entry

Product

TMS-O

Yield (%)

O

1

74

TMS-O

O

2

73

TMS-O

O

3

52

TMS-O

O

4

>80 CO2Me

CO2Me

TMS-O 5

O H

H

H

H

OMe H

OMe

OMe

>45

OMe

6

65

TMS-O

O

TMS-O

O

7

>57 SnMe3

SnMe3

447

C1C Bonds by Elimination of Hydro`en\ Carbon\ Halo`en or Oxy`en

group[ When the position was trisubstituted "entry 0#\ one equivalent of ddq a}orded high yields of enone[ When the position was less substituted\ ddq was used in excess\ and collidine was required to remove the dihydroquinol formed in the reaction "entries 1 and 2#[ Unless the oxidation was rapid\ the dihydroquinol acted as a general acid catalyst and protonated the silyl enol ether\ leading to the formation of the saturated ketone[ The oxidation has been applied in syntheses of complex molecules ð81JA6264Ł and the conditions were compatible with the presence of a methyl ester ð89TL768Ł\ an allylic ketal ð89JA8173Ł and a trialkylstannyl group ð80TL4108Ł[ A _nal example described an oxidation of an O!silyl imidate with applications in the steroid _eld ð77JA2207Ł[ Equation "1# shows the reaction\ which tolerated the presence of a range of functional groups in the D!ring of the steroid[ A four!fold excess of silylating agent was used\ so the nucleophilic functional groups were probably protected in situ[ CO2H

CO2H O-TMS F3C N-TMS

O

1.0 ddq 1,4 dioxan 20 °C, 4 h then 110 °C, 18 h 85%

N H H

(2) O

N H H

Oxidation with palladium acetate\ usually in acetonitrile\ has proved a general and valuable method[ One equivalent of the oxidant was required\ though 9[4 equivalents could be used when benzoquinone was present as a co!oxidant[ The stoichiometric method is expensive to perform but valuable products have been obtained[ The reaction conditions are very mild^ high yields of enones were obtained by stirring the enol ether and oxidant in acetonitrile^ workup was usually facile[ Small amounts "generally ð09)# of saturated ketone were also formed[ Table 2 shows a range of examples including several from recent natural product syntheses[ Acyclic silyl enol ethers were oxidised to E!enones or enals ð67JOC0900Ł[ Exposed ð78LA1040Ł and protected ð82CC508Ł hydroxyl groups were tolerated[ Other examples described steroid manipulations ð80TL2246Ł\ homochiral cyclohexenone syntheses ð82TA10Ł and a building block for an asymmetric synthesis of "−#!D8"01#!capnellene ð83T544Ł[ Catalytic versions of the reaction were developed in Tsuji|s laboratory ð72TL4524Ł[ Silyl enol ethers\ enol acetates and enol carbamates underwent e.cient oxidation in the presence of palladium acetate\ dppe and diallyl carbonate[ However\ relatively high temperatures were required to initiate the catalytic cycle^ the reactions were performed in acetonitrile or benzonitrile at re~ux "Equation "2##[ Enol acetates underwent the catalytic reaction in high yield "Equation "3##[ A range of conditions were described ð75T1860Ł\ so a careful choice may be essential for optimum yields to be obtained[ The tributyltin methoxide coreagent was required to convert the stable enol acetate to the reactive tin enolate in situ[ Enol allyl carbamates underwent dehydrogenation in the presence of catalytic amounts of palladium acetate and triphenylphosphine "Equation "4##[ The reactions were performed on a 9[0 mol scale and a}orded high isolated yields ð76S881Ł[ O-TMS

O Pd(OAc)2/dppe

(3)

diallyl carbonate/MeCN 100%

OAc

O Pd(OAc)2/dppe/MeOSnBu3

(4)

OCO2Me 97%

O

O O

CHO Pd(OAc)2/Ph3P

(5) MeCN reflux, 1.5 h 82%

Ketene acetals and aminals also underwent oxidation with catalytic palladium acetate in ace! tonitrile or benzonitrile in the presence of two equivalents of allyl methyl carbamate "Equation "5##[ The reactions in benzonitrile were performed at _ve!fold higher concentration[

448

Of Carbon Table 2 Dehydrogenations with palladium acetate[ Entry

Product

Substrate

O-TMS

Yield (%)

O

1

97 O

O-TMS

2

3

OMe

OMe

O-TBDMS

O-TBDMS

O-TMS

92

>88

O O-TMS

O

4

>74 TMS Ph

TMS Ph high

5 O-TMS

O O-TMS

O

6

84

MeO

O

MeO

O

O

O O

O-TMS 7

92

O

O O

OH

O

OH

O-TMS O

O Pd(OAc)2

O

(6)

diallyl carbonate/MeCN 70%

It is surprising that the catalytic chemistry developed by Tsuji has not found wider application in target syntheses[ Despite the higher cost of the palladium reagents\ the most popular method appears to be the stoichiometric oxidation[ 0[02[1 ELIMINATION OF CARBON FUNCTIONS 0[02[1[0 Elimination of Hydrogen Cyanide The range of examples in the literature is very limited\ re~ecting the modest nucleofugacity of the cyanide anion[ Reaction mechanisms are most likely to be E0cb or E0cb!like[ Enamines were

459

C1C Bonds by Elimination of Hydro`en\ Carbon\ Halo`en or Oxy`en

prepared by elimination of hydrogen cyanide\ following alkylation of a!aminonitriles\ a useful early class of acyl anion equivalent[ Equation "6# shows a typical result ð68S016Ł[ CN NMe2

NMe2

KOH

(7) PhMe reflux, 16 h 71%

Ph

Ph

The experimental procedure appears straightforward[ Shorter reaction times were possible when potassium t!butoxide replaced potassium hydroxide in the role of base[ Other eliminations of hydrogen cyanide are shown in Equations "7#Ð"00#[ Forcing conditions were used in most cases\ as exempli_ed in Equation "7# ð81M828Ł[ In some cases\ cyanide loss occurred directly from the enolate\ though full experimental details were not reported ð66TL2076Ł[ Equation "09# shows a typical strong base procedure ð45JA71Ł[ Equation "00# is interesting because of the high reactivity of TCNE towards neutral aromatic nucleophiles[ The very mild conditions for the elimination re~ect the high degree of carbanion stabilisation in the conjugate base ð51ACS"B#412Ł[ In other cases\ direct elimination of hydrogen cyanide occurred in the reaction mixture ð48OS"28#57Ł[

N

O

N

KOH

O (8)

NC DMF/H2O 120 °C 80%

O

O NaNH2

CN

CN

Ph Ph

Ph

(9)

PhH reflux 70%

KNH2

Ph

Ph

(10)

NH3 94%

Ph

OH

OH

ethanol/pyridine

(11) NC NC

CN CN

100 °C, 0.5 h 95%

CN

NC CN

0[02[1[1 Elimination of Carbon Oxides 0[02[1[1[0 Decarboxylation The decarboxylation of carboxylic acids to form alkenes has been achieved with lead tetraacetate[ The reagent is commercially available and inexpensive\ and its preparation is facile[ Polar solvents "acetic acid\ acetonitrile\ DMF# were used in most cases[ The literature contains many examples of successful decarboxylations using the reagent ð61OR"08#168Ł[ The ease of decarboxylation is related to the stability of the carbenium ion formed at the carboxyl!bearing carbon atom[ Tertiary acids undergo decarboxylation at room temperature with photochemical initiation at 249 nm[ Running the reaction at low temperature prevents oxidation of the nucleophilic trisubstituted alkene products[ Side reactions have proved problematic in pro! cedures using this reagent^ for example\ a\b!unsaturated ketones are oxidised at the a?!position ð81S124Ł[ The decarboxylation of secondary and even primary acids has been achieved in the

450

Of Carbon

presence of a low concentration of copper"II# acetate monohydrate to promote the oxidation of the _rst!formed alkyl radical to the corresponding carbenium ion[ Rearrangement and poor regio! selectivity have attended the decarboxylation reaction\ in common with other carbenium ion! dependent processes[ Some conversions are shown in Table 3\ entries 0Ð5[ Table 3 Decarboxylations with lead tetraacetate[ Entry

Substrate

Product

1

Yield (%) 87

CO2H CO2H

2

78

CO2H

3

84

HO2C H

H 4 N

H

N

OMe

H

90 OMe

O

O H

H

H CO2Me

5

CO2Me

+

CO2Me

56

CO2H

6

+

CO2H

19 + 37 OAc

Entries 0 to 2 ð57T1104Ł and entry 3 ð80H"21#1978Ł represent typical results[ Entry 4 displayed a low degree of regioselectivity ð50JA816Ł while\ in entry 5\ the dienic propellane was not the major reaction product ð82S359Ł[ In the absence of copper acetate\ none of the desired alkene was obtained[ Ring opening and rearrangement product predominated^ considerable strain relief resulted upon opening the propellane bond[ Non!Kolbe electrolysis of carboxylic acids has proceeded with decarboxylation to form alkenes[ Table 4 lists some examples[ Entries 0 ð79CPB171Ł\ 1 and 2 ð63JOC1375Ł are examples of e.cient syntheses of a\b!unsaturated lactones[ Electrolyses were performed in aqueous pyridine solutions containing triethylamine with graphite electrodes[ Entries 3 to 5 were performed in ace! tonitrile:ethanol containing potassium hydroxide ð77CB0040Ł[ The non!Kolbe electrolysis proceeded through a carbenium ion intermediate and was assisted by the well!known stabilising e}ect of the b carbonÐsilicon bond[ The in~uence of reaction conditions on the selectivity of the non!Kolbe process has been discussed\ though prescriptive guidelines are not yet available ð82CB0512Ł[ When a carbanion stabilising group is present\ mild catalytic decarboxylation methods become feasible[ Allyl esters of a!cyano! and b!ketocarboxylic acids underwent decarboxylation to cyano! alkenes ð76S881Ł and enones ð73S0998Ł\ respectively\ in the presence of palladium catalysts[ Some examples are shown in Schemes 4 and 5[ Direct access to an a!~uoroenone "Equation "01# is particularly appealing because the chemistry of such species is almost unexplored ð83T376Ł[ O

F

O

O O

Pd2(dba)3•CHCl3 Ph3P, MeCN reflux, 2 h 74%

F (12)

451

C1C Bonds by Elimination of Hydro`en\ Carbon\ Halo`en or Oxy`en Table 4 Decarboxylation under non!Kolbe conditions[

Entry

1

Substrate

a

HO

Product

Method

H

67

HO

H

CO2H O O

O O

O

a

2

Yield (%)

O

85

HO2C CO2H O

3

b

O

95

O

O

4

b

60

b

82

CO2H TMS TMS 5 CO2H a

Graphite electrode, aqueous pyridine, triethylamine. b Graphite electrode, ethanolic potassium hydroxide, acetonitrile.

NC

CO2allyl

CN

Pd2(dba)3•CHCl3 Ph3P, EtCN reflux, 1 h 78%

CN O

Pd2(dba)3•CHCl3 Ph3P, EtCN reflux, 1 h 68%

O O NC

(E):(Z) 8 : 1

CN (E):(Z) = 5 : 3 CN

O

Pd2(dba)3•CHCl3 Ph3P, EtCN reflux, 1 h 81%

Scheme 5

0[02[1[1[1 Didecarboxylation The strategic signi_cance of the didecarboxylation reaction has diminished with the introduction of modern alkyne equivalents for cycloaddition chemistry[ De Lucci and Modena provided an excellent survey of the area up to 0873 ð73T1474Ł[ The main methods include lead tetraacetate oxidation\ anodic oxidation and a transition metal complex!mediated procedure[ Some reactions with lead tetraacetate are shown in Table 5\ entries 0Ð3[ Both diacids and cyclic anhydrides underwent didecarboxylation with the lead reagent[ Cyclic anhydrides fused to four!membered rings were particularly reactive "entry 0# ð50JA0694Ł^ trans!0\1!dicarboxylic acids were more reactive than the cis!isomers "entries 1 and 2# ð68S006Ł[ The

452

Of Carbon O

O

O

Pd(OAc)2

O

MeCN, 80 °C 79%

O

O

O Pd(OAc)2

O

O CO2allyl

dppe, MeCN reflux, 4 h 72%

O

O

O

Pd2(dba)3•CHCl3 Ph3P, MeCN reflux, 2 h 79%

Scheme 6

Table 5 Didecarboxylations with lead tetraacetate[ Entry

Substrate

Product

Yield (%)

O O 1

O

O

56

O

O

O

O

O CO2H CO2H 18

2

CO2H HO2C 29

3

O

O 4 O O

CO2H CO2H

O O

most common experimental procedure used the diacid and the presence of oxygen was advantageous^ yields were moderate at best[ A range of other functional groups survives the conversion "entry 3# ð57JA002Ł[ Electrochemical didecarboxylations have been performed on cyclic anhydrides and dicarboxylic acids[ Moderate to good yields have been obtained\ but scales were limited and special equipment and forcing conditions were required[ Experimental details for these procedures are few and far between\ though aqueous pyridine containing triethylamine appeared to be the usual reaction medium[ Some examples are shown in Table 6\ entries 0Ð5[ A range of other functionalities including amide groups "entry 0# ð79AG"E#352Ł\ carbonÐcarbon double bonds "entry 1# ð79JOC4267Ł\ and ketone carbonyl groups "entry 2# ð70JOC0763Ł was com! patible with the electrochemical reaction conditions[ Entries 3 and 4 represent key steps in general approaches to linear and angular triquinanes ð74AG"E#862Ł[ Entry 6 provided some experimental details^ in this case\ the reaction was performed in re~uxing methanolic sodium methoxide with

453

C1C Bonds by Elimination of Hydro`en\ Carbon\ Halo`en or Oxy`en Table 6 Didecarboxylations under electrochemical conditions[ Substrate

Entry

Product

Yield (%)

O Bz 1

O N

Bz

45

N

CO2H CO2H CO2H

2

47

CO2H O O

O

3

57

O O O-MEM

O-MEM 45

4 O

CO2H CO2H

O

O-MEM

O-MEM

5

55 O

CO2H CO2H Cl Cl

O

Cl Cl Cl Cl

6

CO2H

Cl Cl 54

HO2C MEM = methoxyethoxymethyl

platinum electrodes ð83JCS"P0#682Ł[ The alkene was obtained in moderate yield "43)#^ dehy! drochlorination by elimination or reduction processes was not reported[ The complex bis"triphenylphosphine#nickel dicarbonyl "4# _rst described by Trost ð60TL1592Ł has found application in the preparation of a range of bicyclic and polycyclic systems[ The reagent is commercially available "though fairly expensive# and reacts with cyclic anhydrides in re~uxing DIGLYME[ In many cases\ an excess of the reagent was required[ Workup was usually complicated by the contamination of the product with two equivalents of triphenylphosphine which had to removed by chromatography followed by repeated recrystallisation ð73JA5691Ł[ Monocyclic alkenes were not formed cleanly^ reduction and aromatisation led to mixtures of products[ Table 7\ entries 0Ð4 show some successful and attempted conversions[ Other functional groups including ketone "entry 3# ð75LA0467Ł and ester "entries 0 and 1# ð60TL1592\ 73JA5691Ł carbonyl groups withstood the reaction conditions but some 0\3!reduction of an enone occurred "entry 2# ð80JOC886Ł[ The reagent appeared to be highly sensitive to subtle changes in the molecular architecture of the substrate[ Entries 3 and 4 di}ered only in the absence or presence of a bridgehead methyl group\ yet this minor alteration reduced the yield to zero in the latter case ð75LA0467\ 81M476Ł[ Despite the limitations and variation in reaction yield\ the nickel!mediated procedure has remained a useful method for the manipulation of architecturally complex polycyclic hydrocarbons ð76JA3515Ł[

454

Of Carbon Table 7 Nickel complex!mediated didecarboxylations[ Ph3P

CO Ni

Ph3P

CO (5)

Entry

Substrate

Equivalents of (5)

Product

CO2Me O

Yield (%)

CO2Me

1

53

O O CO2Me O 2

CO2Me 50

1.5

MeO

O

MeO

O O

O O

1.5

3

43 O

O O O 4

0.2

O

64 O

O O O 5

0

O O O

0[02[1[1[2 Decarboxylation:dehydration Decarboxylation\ coupled with loss of a hydroxyl group\ has been achieved under mild conditions making b!hydroxyacids useful alkene precursors[ Elimination can be performed directly\ or in a stepwise procedure\ via a b!lactone ð82S330Ł^ both processes are stereospeci_c[ In the more direct route\ the hydroxyacid was re~uxed with an excess "4 to 5 equivalents# of DMF dimethylacetal in dry chloroform[ Reaction times ranged from 1 to 09 hours\ and good yields of alkenes were obtained[ In some cases\ DMF neopentyl acetal was used[ The cost of both reagents is fairly high\ but valuable products have been obtained\ and workup was usually straightforward[ The reaction mechanism involves activation of the hydroxyl group followed by decarboxylation via an antiperiplanar "E1! like# transition state with signi_cant partial positive charge development at the hydroxyl!bearing carbon atom[ Substituents capable of stabilising the developing charge accelerated the reaction[ Table 8\ entries 0Ð4 show a range of examples[ Highly substituted alkenes formed smoothly "entry 0# ð64TL0434Ł[ Entry 1 described the preparation of a "Z#!alkene ð73T0158Ł In entry 2\ a pure diastereoisomer was obtained via a silylcuprate conjugate addition to an unsaturated ester\ followed by enolate trapping with an aldehyde ð81JCS"P0#2240Ł^ in the ensuing decarboxylation:dehydration the allylsilane was obtained as the pure "E#!stereoisomer[ Similar methodology a}orded "E#! or

455

C1C Bonds by Elimination of Hydro`en\ Carbon\ Halo`en or Oxy`en

"Z#!disubstituted allylstannanes ð76JCS"P0#1148Ł[ Dienes have also been prepared using the dineo! pentyl acetal reagent "entries 3 and 4# ð64HCA042\ 73JOC1968Ł[ Table 8 Dehydration:decarboxylations with amide acetals[ Entry

Substrate

Reagent

Product

Yield (%)

CO2H

OH a

1

70

OH CO2H

2

high

a Ph

Ph SiMe2Ph

SiMe2Ph CO2H 3

a

91

b

94

OH CO2H 4 OH

O

O-TBDMS b

5

O

O-TBDMS

68

CO2H OH a

DMF dimethyl acetal. b DMF dineopentyl acetal.

The reagent of choice for conversion of b!hydroxy acids to b!lactones appears to be benzene sulfonyl chloride[ Dehydration usually occurred in dry pyridine with an excess of the halide[ The rate of carbon dioxide elimination was strongly dependent on structure[ Trans!disubstituted b!lactones were more reactive than the cis!isomers[ Bulky substituents retarded the reaction\ the e}ect on the cis!isomers being more pronounced[ Substituents capable of stabilising a developing positive charge at C!1 accelerated the pyrolysis[ Forcing conditions were required in some cases and sealed tube procedures have been used ð70JOC2248Ł[ A particularly convenient procedure generated b!lactones directly in good yield by trapping thioester enolates with aldehydes and ketones "Scheme 6# ð80JOC0065Ł[ Pyrolysis was performed by Kugelrohr distillation from 129Ð399 mesh silica gel for more volatile alkenes\ or by re~uxing with silica gel in benzene or cyclohexane for the less volatile species[ The silica gel catalysis was e}ective only in highly substituted cases[ Table 09 shows some transformations achieved using this method[ Cost!e}ectiveness and ease of puri_cation were combined in this appealing alternative to Wittig and related methods for alkene assembly[ a!Methylene!b!lactones underwent rapid DielsÐAlder cycloaddition with dienes "Scheme 7#[ Pyrolysis revealed alkylidene norbornenes\ the formal products of cyclopentadiene:allene cycloaddition ð82CB0370Ł[ Simple allenes are poor dienophiles\ so the equivalence is useful even if the requirement for a pyrolysis procedure limited the scale to approximately 0 mmol[ b!Lactone pyrolyses have also been performed in DMF ð73TL3770Ł and collidine at re~ux "Equation "02##[ The developing positive charge receives some allylic stabilisation in this case[

456

Of Carbon R1

O i, LDA

R1

SPh

ii, R3COR4

R2

R3 R4

R2

∆

O O Scheme 7

R1

R3

R2

R4

Table 09 Silica!mediated b!lactone pyrolyses[ Entry

Substrate

Product

Yield (%)

O O

1

88

O O 2

95

O O CO2Et

3

97

CO2Et O O 4

93 TBDMS TBDMS O O OH

5

77

OH

O O

O

+

O

50 °C, 24 h 94%

O

7 : 3

O

400 °C flash distillation quartz tube 71%

Scheme 8

PhO

O DMF

O

(13) 100 °C, 2 h high yield

PhO

457

C1C Bonds by Elimination of Hydro`en\ Carbon\ Halo`en or Oxy`en

Alternatively\ catalytic chemistry has been developed ð81TL5672Ł allowing the direct conversion of b!hydroxy acids to alkenes and enol ethers "Equation "03##[ CO2H WOCl4/TMEDA

(14)

MeCN 73%

OH

(E):(Z) 10 : 1

0[02[1[1[3 Decarboxylation:dehalogenation Useful examples of the reaction are very limited[ b!Bromoesters were converted to alkenes in moderate to excellent yield upon heating in hexamethylphosphoramide "HMPA# at 039>C "Equation "04##[ Synthesis of the bromoesters imposed the main limitation upon this methodology ð72TL0364Ł[ The reaction was also performed successfully in the noncarcinogenic 0\2!dimethyl!1!imidazoli! dininone "5#[ A related procedure was used in a synthesis of "2#!acarenoic acid "Equation "05##[ Heating the bromoester in pentan!2!one with sodium iodide led to the formation of furanone in excellent yield[ The reaction proceeded only in the ketone solvent\ and formed part of a versatile furanone synthesis ð76BCJ1806Ł[ Ph

Ph 140 °C

Br

(15)

HMPA 95%

CO2Me

O Me N

N Me (6)

CO2Et Br CO2Me ( )10

O

O

CO2Et

NaI pentan-3-one reflux, 2 h 93%

(16) ( )10

O

O

0[02[2 BY ELIMINATION OF HALOGEN "OR H!HAL# 0[02[2[0 Elimination of Dihalides The elimination of a dihalide has only limited use in the synthetic chemist|s repertoire[ The most convenient starting material for a 0\1!dihalide is usually an alkene ð61HOU"4:0b#079Ł[ As Kocienski pointed out ð80COS"5#864Ł\ {Unless there are very pressing reasons\ one cannot advocate the synthesis of alkenes from alkenes] to travel in circles is the domain of astronomers not chemists;| Alkenes form 0\1!dibromides in high yield and under mild conditions[ A signi_cant limitation for alkene protection by dibromide formation has been the severity of the conditions required for\ and the low e.ciency of\ debromination[ Simple alkenes containing robust functional groups were obtained by heating the corresponding dibromide in DMF at 044Ð059>C ð80S716Ł[ A sodium selenite:cysteine reducing system was used to achieve debromination under mild aqueous conditions "Equation "06##[ Excellent yields of alkenes were obtained and functional groups such as the ketonic carbonyl group were tolerated[ The reaction system was odourless and exhibited a distinctive range of colour changes on progression to completion ð89CC629Ł[ An alternative procedure used a tellurium reagent and tolerated some useful and delicate functional groups ð89TL5180Ł "Scheme 8#[

Of Halo`en "or H!Hal# Br

Br

458

NH3+ HS

CO2–

(17) NaSeO3, H2O 0 °C, 5 min 99%

O

O

Br (Ph3Sn)2Te

PhO2S

CsF, MeCN RT, 5 h 97%

Br Br

O

Br

O

PhO2S

(Ph3Sn)2Te CsF, MeCN RT, 4 h 100%

O O

Scheme 9

Though the cost of reagents would be high\ chemistry of such subtlety may _nd applications in total syntheses of complex molecules[ Debromination of 0\3!dibromides to form dienes is a useful method\ particularly when ortho!quinodimethanes are formed[ A range of metals can be used to achieve the transformation[ Trapping conditions are usually employed\ so that the reaction mixture also contains a dienophile\ to allow bi! and polycyclic systems to be constructed in an e.cient manner[ Cava and co!workers reported an example in which iodide anion was used to initiate didebromination in a 0\3!sense\ forming an ortho!quinodimethane\ which was trapped in situ "Equa! tion "07## ð71JOC398Ł[ O

OMe

O

O Br

MVK, NaI

Br

DMA, 70 °C 75%

OMe

O (18)

OMe

O

OMe

MVK = methyl vinyl ketone

More forcing conditions are required for the elimination of chlorine[ However\ the reaction is worthwhile because chloroalkenes undergo e.cient photochemical ð1¦1Ł additions to enones to a}ord cyclobutane products[ Reductive dechlorination reveals the carbonÐcarbon double bond for further transformation "Scheme 09# ð82S359Ł[ High yielding free radical dechlorinations have been reported[ Equation "08# shows an application of the tin method in a simple cyclohexane derivative[ Cl i, ethane-1,2-diol, H2SO4, PhH, reflux, 5 d

Cl

ii, Na/NH3(l), diethyl ether, –78 °C, 3 h iii, dilute HCl, diethyl ether, RT, 4 d

O

O Scheme 10

Cl Cl

Bu3SnH, AIBN

(19)

xylene reflux

AIBN = 2,2'-azobisisobutyronitrile

Dechlorination occurred upon exposure of a dichlorodi~uoroenone to zinc metal in an interesting synthesis of g\g!di~uoro!b\g!enones "Equation "19## ð82JOC4052Ł[ A range of zinc!based reaction conditions were investigated^ sonication was essential for the success of the elimination[

469

C1C Bonds by Elimination of Hydro`en\ Carbon\ Halo`en or Oxy`en O

O

Cl

Zn, ZnCl2

CF2Cl

Ph

ultrasound MeOH 25 °C, 6 h 67%

F

Ph

(20)

F

Despite the high strength of the carbonÐ~uorine bond\ mild de~uorinations have been described[ Pez and co!workers ð81JOC1745Ł have described conversions of per~uorocyclohexane and per~uoro! decalin to per~uorobenzene and per~uoronaphthalene\ respectively\ with sodium:benzophenone ketal in THF[ Chambers has described a mild de~uorination procedure using either a sodium: mercury amalgam or tetrakis"dimethylamino#ethene "Equations "10# and "11## ð83JCS"P0#2004Ł[ Na/Hg 0.5% w/w amalgam

F

F

(21)

F

F

F3C

CF3


F3C

Me2N

CF3

NMe2 NMe2 NMe2

CF3

F3C O

F

F

CH2Cl2 0 °C to RT

(22) F3C

O

CF3

0[02[2[1 Elimination of Hydrogen Halides The mechanistic aspects of these reactions were studied extensively during the halcyon days of physical organic chemistry[ In simple unsymmetrical haloalkanes\ the elimination may be regio! chemically ambiguous^ it is unlikely that any modern synthetic sequence would include such a step[ The issues a}ecting such reactions ð80COS"5#838Ł and detailed mechanistic aspects ðB!78MI 002!90Ł have been reviewed[

0[02[2[1[0 Dehydro~uorination Dehydro~uorination in simple unactivated systems required the use of strong bases[ One recent systematic study revealed that lithium diisopropylamide "LDA# was required for clean dehydro! ~uorination "Equation "12## and inferred that the solvent of choice was ether or ether:hexane ð77T1744Ł[ The elimination of the ~uoride anion received some electrophilic assistance from the lithium cation^ the cation was only available for this role when weakly solvated in the less polar solvents[ LDA

(23)

diethyl ether 40 °C, 48 h 76%

F

(E):(Z) 94 : 6

Poor yields of alkene were obtained when alkoxide bases were used in alcohol solvents[ Vigorous conditions were required because ~uoride ion elimination involves a transition state with a high degree of E0cb character[ Synthetically useful dehydro~uorinations have been performed on derivatives of tri~uoroethanol[ Strategically\ these methods transform the relatively inert tri~uoromethyl group into a manipulable di~uorovinylic unit ð78TL0530\ 81CC0366Ł[ Dehydro~uorination occurred in good yield upon exposure of a tri~uoromethyl dithioketal to methyllithium in ether "Equation "13## a}ording a useful building block for the synthesis of tetrathiafulvene derivatives ð82JOC3574Ł[ S

MeLi

S

F

diethyl ether –78 °C to RT 12 h 75%

S

F

(24)

CF3 S

Of Halo`en "or H!Hal#

460

0[02[2[1[1 Dehydrochlorination As the nucleofugacity of the halide anion "X−# increases\ the character of the transition state for HX elimination becomes more E1!like\ and progressively weaker bases and milder conditions can be used[ A range of bases including sodium acetate and amines has been used to dehydrochlorinate b!chloro carbonyl compounds[ Equations "14#Ð"16# show some examples which occurred in moderate to good yields[ In Equation "14#\ the reaction required four days at room temperature with excess triethylamine in ether ð80JOC6066Ł[ Sodium acetate was used to e}ect dehydrochlorination in a useful enone synthesis "Equation "15## ð77OSC"5#216Ł[ A range of cyclic enones was prepared in high yield by this route[ In a reactive system derived from a quinone\ dehydrochlorination proceeded instantaneously with diethylamine in ether at room temperature "Equation "16## ð77OSC"5#109Ł[ The dehydrochlorination of a cyclobutane dinitrile was also performed in good yield using triethylamine "Equation "17## ð77OSC"5#316Ł[ A cyclopropene was prepared in good yield from the corresponding chlorocyclopropane upon treatment with potassium t!butoxide in THF under mild conditions "Equation "18## ð70OS"59#42Ł[ OH

OH

Et3N

Cl

CO2Et

diethyl ether RT, 4 d 43%

Cl

(25)

Cl

O

CO2Et

O NaOAc

(26) Cl

O

MeOH reflux, 3 h 80%

O

But

But

But

Et2NH

Cl

(27)

diethyl ether RT, seconds 99%

Cl O

But O

Cl

CN CN

Et3N

(28)

PhH reflux, 2 h

CN Ph

Cl

Ph

ButOK

Cl

CN

Ph

Ph (29)

THF –78 °C to RT, 16 h 88%

Ph

Ph

Unactivated substrates required more strongly basic conditions[ The multiple dehydrochlorinations performed by Stoddart and co!workers ð81JA5229Ł required a large "7[4!fold# excess of potassium t!butoxide at low temperature "Equation "29##[ Lithium carbonate has also been used in dehydro! chlorination reactions "Equation "20## ð79JOC1925Ł[ An alternative approach to dehydrochlorination was used by Viehe and co!workers ð74T2220Ł[ Treatment of a\a!dichloroamides with aluminum chloride in dichloromethane\ led to the isolation of chloroenamides in good yield "Equation "21##[ O

O Cl Cl

ButOK

Cl Cl

(30) THF 0 °C, 14 h 89%

461

C1C Bonds by Elimination of Hydro`en\ Carbon\ Halo`en or Oxy`en Cl

H Cl Cl Li2CO3 DMF 85 °C, 30 min 96%

H Cl

H Cl

Cl

n-C13H27

(31)

O

O

AlCl3

NMe2

n-C13H27

NMe2

CH2Cl2, ∆ 78%

O

(32)

O

The procedure was also applied successfully to cyclic cases[ Dehydrochlorination failed with bases such as lutidine and collidine\ even at 067>C[ Bases such as 0\4!diazabicycloð4[3[9Ł undec!4!ene "dbu# are of limited use for dehydrochlorination[ The sharp contrast between activated and unactivated systems was emphasised by a paper which described a useful synthesis of vinyl sulfones ð67JOC0197Ł[ Attempts to dehydrochlorinate at the sul_de level required prolonged reaction times at high tem! perature\ and led to mixtures of regioisomeric vinyl sul_des[ The b!chlorosulfones reacted rapidly at low temperature to a}ord quantitative yields of regioisomerically pure vinyl sulfones "Scheme 00#[ Cl

PhS

PhS

dbu

PhS

+ 120 °C, 3 h

40% Cl

PhO2S

40%

PhO2S

dbu CH2Cl2 0 °C, 0.5 h 100 %

Scheme 11

0[02[2[1[2 Dehydrobromination Bromides have proved slightly easier to eliminate than the corresponding chlorides[ Useful bases for this purpose include alkoxides\ amidines and phosphazenes[ Potassium t!butoxide has proved popular\ although the choice of solvent appears to be important[ The base has been used in petroleum ether in the presence of a phase transfer catalyst "07!crown!5# at re~ux temperature[ Hindered secondary bromides underwent elimination in excellent yield "Equation "22##[ However\ less hindered bromoalkanes were converted to t!butyl ethers in a side reaction\ accounting for 09Ð19) of the product mixture ð68S261Ł[ The importance of the antiperiplanar conformation in the E1 elimination was revealed by a study of spiroketals "Equation "23##[ ButOK, 18-crown-6

(33) petrol 120 °C, 6 h 92%

Br Br Br

O O

ButOK

+

O (34)

O O

DMSO 100 °C, 8 h 79%

O

The axial bromide was consumed within 049 minutes in DMSO containing potassium t!butoxide at 099>C[ The equatorial epimer required a four!fold longer reaction time for dehydrobromination ð82JOC1490Ł[ The product alkene underwent double bond isomerisation upon prolonged heating[ When the reaction was performed in THF\ proton abstraction occurred at the a!carbon atom\ followed by spiroketal ring opening[ The use of amide bases produced the same result[ A simple workup procedure involved saturating the DMSO solution with salt and extracting the volatile

Of Halo`en "or H!Hal#

462

spiroketal products into pentane[ The combination of dipolar aprotic solvent and hindered alkoxide base appears to represent the procedure of choice ð81JA8308Ł[ A useful desymmetrisation procedure used a potassium alkoxide base in THF[ A signi_cant degree of carbanion stabilisation was provided by the ionised carboxylate group\ allowing the elimination to proceed at low temperature "Equation "24## ð82CC005Ł[ A bromoalkane survived exposure to potassium t!butoxide in pentane at lower temperature\ allowing a useful isomerisation to be achieved "Scheme 01#[ Dehydrobromination required treatment with dbu at higher temperature ð82CC0927Ł[ This amidine base ð61S480Ł has allowed valuable alkenes to be isolated in good yield[ Alkylation of the amidine is normally slow in comparison with the elimination reaction[ In unreactive cases\ dbu has been used as the reaction solvent "Equation "25## ð82TA768Ł[ More reactive bromides underwent dehydrobromination in nonpolar solvents containing dbu "Scheme 02# ð81JA8562\ 81JOC4446Ł[ An application involving a sensitive substrate was described by Ganem during the synthesis of senepoxide "Equation "26## ð67JA5372Ł[ Dehydrobromination occurred in benzene at room temperature^ at higher temperature\ decarboxylation accompanied the elimination[ OK

But

But

Ph NMe2

CO2H

Br

(35)

THF, –90 °C 70% yield 90% ee

HO2C

Br

dbu 110 °C, 3 h 70%

O Br

O Br

ButOK pentane RT, 12 h 70%

O

•

O

Scheme 12 O

O

O

O

dbu

(36)

Br

70–75 °C, 18 h 91%

Br CO2Me CO2Me

CO2Me

dbu CHCl3 100%

TBDMS-O O Br

CO2Me TBDMS-O O

dbu PhH 90%

AcO

O

H

AcO

O

Scheme 13 O O

O OBz O

Br

dbu PhH, RT 91%

O

OBz O

(37)

463

C1C Bonds by Elimination of Hydro`en\ Carbon\ Halo`en or Oxy`en

In some applications\ even hindered amidine bases were alkylated[ Schwesinger and co!workers have described extremely hindered and yet reactive phosphazene bases which may be useful in such circumstances ð76AG"E#0056Ł[ A 85) yield of 0!octene was obtained upon treatment of 0!bromooctane with "6# after 5 hours at room temperature[ Only 2) of alkylation product was obtained[ In contrast\ the phase transfer method of von Dehmlow a}orded a 64) yield of alkene after 2 hours at 59>C accompanied by a signi_cant amount "07)# of t!butyl octyl ether[

(Me2N)3P

N

P(NMe2)3

N P NBut N

P(NMe2)3

(7)

The most reactive base for E1 elimination is phosphazenium ~uoride "7# ð80AG"E#0261Ł[ This extraordinary {naked ~uoride| reagent is unstable but e}ected the dehydrobromination of a primary substrate at −67>C; Fluoroalkane "09)# was also formed in the reaction[ The reagent found use in a synthesis of the architecturally complex and thermally sensitive isopagodane skeleton ð83AG"E#006Ł[ Me2N Me2N

NMe2 +

P N P NMe2

Me2N

F–

NMe2 (8)

Amidine bases failed to provide good yields of bromoalkenes from 0\1!dibromides[ Morpholine and DMSO were required to achieve the dehydrobromination in good yield "Equation "27## ð89S732Ł[ Br

Br

morpholine

(38) Br

DMSO reflux, 2 h 70%

Bromoalkenes were obtained when a\v!dibromides were heated in HMPA at high temperature[ Amine and amidine bases were unsuccessful in this role ð73S774Ł[

0[02[2[1[3 Dehydroiodination Examples of the elimination are relatively scarce[ An e.cient vinyl isocyanide synthesis was achieved using an excess of potassium t!butoxide at low temperature "Equation "28## ð78TL2224Ł[ Fluoroalkenes have been prepared via dehydroiodination using dbu in dichloromethane "Equation "39## ð80TL0104Ł[ O-TBDMS

O-TBDMS

I

ButOK, THF

NC

–78 °C to RT 3h 80%

(39) NC

I dbu

Ph F

CH2Cl2 RT, 12 h 93%

Ph

(40) F

464

Of Oxy`en 0[02[3 BY ELIMINATION OF OXYGEN FUNCTIONS 0[02[3[0 Dehydration 0[02[3[0[0 Using Burgess| reagent

Burgess| reagent "ðN\N!diethyl!N!ð"methoxycarbonyl#aminoŁsulphonylŁ ethanaminium hydrox! ide\ inner salt# "8# has been used to dehydrate a range of secondary and tertiary alcohols under mild conditions ð62JOC15Ł[ The reagent is crystalline\ commercially available and readily prepared in high yield on a 0[4 mol scale "Scheme 03# ð89JA7322Ł[ O Cl

S N

O

MeOH

•

O

Cl PhH 92%

O

O

Et3N

S NHCO2Me

+

Et3N

PhH 81%

O

–

S NHCO2Me O (9)

Scheme 14

Dehydration occurred smoothly in benzene or toluene at 49>C\ normally using a slight excess "0[0 to 0[4 equivalents# of the reagent[ Workup is always simple\ often involving hydrolysis and solvent extraction[ However\ when the product alkenes were volatile\ the reactions were performed neat\ allowing the alkenes to distil from the reaction mixture[ Table 00\ entries 0Ð4 show a range of alcohols dehydrated successfully using the reagent[ The products include highly acid!sensitive species "entries 0 and 1# ð62JOC15Ł\ a densely functionalised quinocarcinol methyl ester precursor "entry 2# ð74JA0310Ł and a sensitive propellane "entry 3# ð73JA0407Ł[ In entry 4\ dehydration a}orded only the nonconjugated diene in good yield ð89JA8173Ł[ Table 00 Dehydrations with Burgess| reagents[ Entry

Substrate

Method

Product

Yield (%)

OH a

1 OH

O

2

66 O

a

MeO

69

MeO

O

O N

N 3

b

NMe

CO2Me

CO2Me

OH

53

NMe

O

O OH

4

b

H

OH a

5 H a

92

O

66 H

O

Neat reagent. b Benzene solution, 50 °C.

A mechanism has been proposed for the reaction which involves a syn!elimination from an intermediate sulphamate ester[ However\ the ester is a good leaving group\ and the products of E0

465

C1C Bonds by Elimination of Hydro`en\ Carbon\ Halo`en or Oxy`en

elimination have been observed where stabilised carbenium ions are accessible[ McCague used Burgess| reagent to prepare a tamoxifen analogue\ producing the same 1[7 ] 0 mixture of "Z# and "E#!alkenes from both diastereoisomeric alcohols "Scheme 04# ð76JCS"P0#0900Ł[ Mixtures of products have been obtained where elimination could occur across a number of possible C0C bonds[ Thus endo!1!methyl!1!norborneol was converted to endo! and exo!cyclic alkenes "0 ] 0# in 55) yield "Scheme 05# ð89JA7322Ł\ while a mixture of unsaturated esters resulted upon dehydration of a pyrethroid precursor "Scheme 06# ð76T742Ł[ Ph

Ph

Ph

Ph

Ph Ph

Ph HO

HO

Ph

(9)

+

or PhH 50 °C

OMe

OMe

OMe

OMe 2.8 : 1 Scheme 15

(9)

+ MeCN 50 °C, 2.5 d 66%

OH

1:1 Scheme 16

CO2Me

CO2Me (9)

CO2Me

+

CO2Me

+

PhMe

HO

MeO2C CO2Me

CO2Me 26% Scheme 17

CO2Me 22%

2%

0[02[3[0[1 Using Martin|s sulfurane reagent Martin|s sulfurane "bis"a\a!bisðtri~uoromethylŁbenzyloxy#diphenyl sulfur# "09# is a moisture! sensitive and expensive commercial reagent[ However\ the material has been prepared on a 149 g scale\ and stored inde_nitely in the absence of moisture ð66OS"46#11Ł[ The mechanism of dehydration has been investigated ð61JA4992Ł[ Like Burgess| reagent\ tertiary alcohols reacted via an E0!like mechanism^ for secondary alcohols\ an E1!like pathway was inferred while primary alcohols formed stable ethers[ The reagent appears to be particularly useful for the dehydration of alcohols prone to carbenium ion rearrangement[ Even cyclopropyl alcohols underwent elimination[ Table 01\ entries 0Ð6 show the scope of the dehydration[ Entry 3 underwent skeletal ð2\2Ł!rearrangement following dehydration ð75JA2628Ł[ In the extreme case of entry 0\ the tricyclopropyl alcohol rearranged\ resulting in a low "21)# yield of the dehydration product ð61JA4992Ł[ The development of angle strain in the alkene retards the rate of elimination ð71TL0232\ 74JA3853Ł[ Entries 4 and 5 indicate that the more acidic proton was removed when a choice was available ð75JOC2987\ 81JOC4197Ł[ A sensitive diene was prepared in entry 6 ð77LA432Ł[

0[02[3[0[2 Dehydration by other methods Treatment of alcohols with strong acids has been used to achieve dehydration[ The method is most useful when highly stabilised carbenium ions are accessible\ and proton loss is unambiguous

466

Of Oxy`en Table 01 Dehydrations with Martin|s sulfurane reagent "09#[ F3C Ph

CF3 Ph O

Ph CF3 CF3 S

O

Ph

(10) Substrate

Entry

Temperature (°C)

Product

Yield (%)

OH 1

2

32

25

CONMe2

CONMe2

HO

–78

92

25

52

25

60

OH 3 OH OH

4

EtO2C

EtO2C OH

5

0 TBDMS-O CO2Et

80 TBDMS-O

O-TBDMS

O-TBDMS CO2Et

OH 6

25

93 O-TBDMS

O-TBDMS

MeO

O

7

O 25

MeO

O

O

>50

HO

or can be thermodynamically controlled[ An e.cient acid!catalysed dehydration will almost invariably be more economical than any other method[ A recent example involved an acid!catalysed dehydration of a tertiary benzylic alcohol[ The reaction was performed in benzene using DeanÐ Stark apparatus and a catalytic quantity of p!toluene sulfonic acid to a}ord the more stable endocyclic alkene in good yield "Equation "30## ð83JOC395Ł[

467

C1C Bonds by Elimination of Hydro`en\ Carbon\ Halo`en or Oxy`en OMe

HO

OMe TsOH

(41)

PhH, reflux 45 min 90%

OMe

OMe

Supporting the acid catalyst on silica gel allowed the e.cient dehydration of secondary and tertiary alcohols[ Re~uxing the alcohol with the supported reagent in benzene a}orded good yields of D1! and D2!steroids "Equation "31## ð74S0048Ł[ A strong acid ion exchange resin was used to dehydrate sterols[ Double bond migration accompanied dehydration when a sterol was re~uxed with Na_on!H in chloroform "Scheme 07# ð76CC389Ł[ Other dehydrations were performed with a sulfuric acid catalyst ð89OSC"6#252Ł and in tri~uoroacetic acid ð75TL0338Ł[

TsOH on silica gel

(42) PhH reflux, 8 h 97%

HO

H

H

O

O Nafion-H

OH

CHCl3 reflux, 1 d 50%

O

O

O

O H2SO4 (cat.)

O

DMF 95 °C, 3 h 70–76%

OH O

H

O O

OH TFA 4h

H

O

H

O

Scheme 18

A useful method involved generation of the expensive sulfonyl diimidazole reagent in situ[ Selective reaction at a steroidal hydroxyl group was followed by elimination[ This is an attractive method because the byproducts from the reaction are particularly easy to remove "Equation "32## ð77JPR298Ł[

OH SOCl2, imidazole

(43) THF 10 °C to 60 °C 1.5 h

O

O

Synthetically useful nitroalkenes were generated by a dehydration reaction on alumina ð81JOC1059Ł[ An unusual but general dehydration allowed the direct conversion of primary and secondary alcohols to alkenes[ The reaction produced volatile byproducts and involved an easy workup "Equation "33## ð77SC0684Ł[

468

Of Oxy`en O Cl3C

CF3

(44)

TsOH, PhH reflux, 6 h

OH

0[02[3[1 Elimination of Alcohols "H0OR# The low nucleofugacities of simple alkoxide anions means that elimination usually occurs under E0cb conditions[ Some useful reactions have been reported and are shown in Scheme 08[ Potassium t!butoxide ð81JOC0502Ł\ potassium hexamethyl disilazide "KHMDS# ð83JOC283Ł and dbu ð82T5606Ł have all found applications[ Fragmentation of the leaving group to release acetone prevented the back reaction[ In the _nal example\ the amidine proved superior to a range of hydride and amide bases[ O

O

O

O

ButOK

OH

O

SEt

O SEt SEt

EtS

OH

O O

CO2Me HN

MeO2C

Ph

O

KHMDS

CO2Me

MeO2C HN

Ph

THF –78 °C, 1 h 97%

O O i, dbu, RT

OMe

O

ii, HCl, H2O 84%

O

O

HO OMe

Ph Scheme 19

Superbase!mediated eliminations from simple homoallyl ethers form a interesting class of reac! tions[ A range of dienes and trienes were prepared by alkoxide elimination using LIDAKOR "LDA:ButOK# in THF "Scheme 19# ð89T1300Ł[ LIDAKOR

OMe THF, –50 °C 72% LIDAKOR

O

THF, –50 °C 55%

EtO EtO

HO

LIDAKOR THF, –50 °C 91%

EtO

Scheme 20

Pivalate esters underwent elimination at slightly higher rates[ Eliminations of alkoxy groups from acetals and ketals have a}orded enol ethers[ ð71TL212\ 71TL520Ł[ A method of choice which uses readily available reagents has been described ð77JOC4465Ł[ The eliminations were highly regio! selective\ with removal of the least hindered proton[ A range of substituents was tolerated in the ketal moiety "Equation "34##[ Under acidic conditions\ ethanol was eliminated from an acetal to

479

C1C Bonds by Elimination of Hydro`en\ Carbon\ Halo`en or Oxy`en

form an enol ether[ A signi_cant amount of hemiacetal was formed in the reaction "Equation "35## ð83JOC200Ł[

O O

OH

TMS-OTf

O

(45)

DIPEA CH2Cl2 –20 °C to RT 94%

DIPEA = Pri2NEt O HCl2C O

O HCl2C O

O 2,6-lutidinium tosylate

HCl2C

CO2Me

H

O

O

HCl2C

CO2Me

PhMe, ∆ 70%

OEt

H

(46)

O

0[02[3[2 Eliminative Ring Opening of Epoxides Epoxides open readily under Lewis acid or Bronsted base conditions ð73S518Ł[ Chiral amide bases have been used in desymmetrisation procedures involving epoxide opening by elimination[ Equation "36# shows an example ð82CC773Ł[ OBn

Ph

OBn OLi

LiNH THF –78 °C to 0 °C 91% yield 81% ee

O

(47) OH

The products were obtained in moderate enantiomeric excess^ changing the solvent from THF to a benzeneÐTHF mixture allowed the other enantiomer to be isolated[ Magnesium amides appear to combine basicity with Lewis acidity in a useful way\ allowing epoxides to be opened in high yield ð75TL188Ł[ The amides were prepared in toluene by reacting the lithium amide with Grignard reagent[ An excess "2Ð3 fold# of the amide was required\ reactions were run at 9>C\ and the choice of solvent was critical[ Poor yields were obtained in THF\ with and without additives such as HMPA[ Proton abstraction usually occurred from methyl groups rather than from methylene positions[ Table 02\ entries 0Ð4 show some typical examples^ the amide reagents tolerated other functional groups "entries 0Ð2# ð75TL188Ł[ In entry 2\ the less acidic proton was removed[ The regioselectivity displayed in entry 4 was exceptional ð81T09154Ł and was reversed when the elim! ination was performed in monoglyme[ The procedure was deployed in an asymmetric synthesis of R!"¦#!perrillaldehyde from limonene ð77SC0894Ł[ Epoxide opening can also occur under E0cb conditions using weak bases[ A useful sequence used arsonium ylide chemistry to prepare b\g!epoxy aldehydes^ treatment with triethylamine in ether led to the formation of g!hydroxy!a\b!unsaturated aldehydes "Equation "37## ð78TL068Ł[ OH

O CHO

Et3N diethyl ether 79%

CHO

(48)

470

Of Oxy`en Table 02 Epoxide opening with magnesium amide bases[ Entry

Substrate

Base

Product

O

Yield (%)

OH a

1

96

O-TMS

O

TrO

OH

OMe

O

TrO

OMe

a

2

94 HO

O CO2H

CO2H a

3

51 OH

O O

HO

4

b

74

H

H OH

O c

5

92

H a

H

MeMg(PriNC6H11), PhMe, 0 °C, 1.5–7.5 h. b MeMg(PriNC6H11), DME, 0 °C. c MeMgBr, LDA, PhMe, –5 °C, 6 h.

The product described in Equation "37# corresponds to the addition to aldehydes of a b!acyl vinyl anion equivalent[ Similar eliminations were used to prepare an enone intermediate during a total synthesis of "2#!breynolide ð81JA8308Ł[ Using an amidine base at low temperature ensured that the most acidic proton was removed "Equation "38##[ Epoxide opening was used to trigger an anionic cyclisation during the total synthesis of an elfamycin natural product "Scheme 10# ð74JA0580Ł[ Useful pyranone syntheses have also involved eliminative epoxide openings "Scheme 11# ð82TA0684Ł[ CO2Me

CO2Me dbu

O O

MeO2C

(49)

O

O

O

O dimsyl potassium

O

OH

MeOH, CH2Cl2 –78 °C to RT 79%

O

MeO2C

PhMe, DMSO –20 °C to RT

OH O

O

O TBDMS-Cl imidazole DMF 0 °C to RT >90%

Scheme 21

MeO2C

O-TBDMS O

O

471

C1C Bonds by Elimination of Hydro`en\ Carbon\ Halo`en or Oxy`en OH SPh

BnO OH

BuLi

O

SPh

BnO

–78 °C 81%

OH

OH

O

O

BnO Scheme 22

0[02[3[3 Elimination of a Carboxylic Acid "H0OCOR# Acetate anion has been eliminated in high yield from activated and unactivated substrates[ An alkylidene furanone synthesis combined a furan metallation procedure with a high!yielding acetate elimination in acidic media "Equation "49## ð81BCJ1255Ł\ presumably via an E0!type mechanism[ H2SO4 (cat.)

AcO

O

O

(50)

AcOH, Ac2O 80 °C, 1–2 h 95%

O

O

Acetate anion was eliminated from an unactivated substrate upon treatment with a transition metal catalyst "00# ð80T7044Ł[ The regiochemical outcome of the reaction was unexpected[ Depro! tonation occurred from a methylene position in the ring rather than from the more accessible methyl group[ Mild reaction conditions were employed to achieve this interesting transformation "Equation "40##[ Tri~uoroacetylation of a tertiary alcohol in situ led to an elimination reaction "Equation "41## ð82OSC"7#109Ł[ Conversion to the corresponding mesylate also led to a good yield of enone\ but sulfur!containing byproducts were di.cult to remove from the product[ The preparation of a particularly reactive tri~uoroacetylating agent was reported ð89OSC"6#495Ł[

Mo+ BF4–

(11)

(11)

OAc H

O

HO

(51) AcOH, 1,4-dioxan reflux, 3 h 100%

H

O

TFAA

(52) E3N, dmap CH2Cl2

Ph

Ph

dmap = 4-dimethylaminopyridine; TFAA = trifluoro acetic anhydride

A wide range of E0cb eliminations has been described[ The elimination of a pivalate unit occurred upon Kugelrohr distillation of the ester from anhydrous potassium carbonate^ this was used in a synthesis of "R#!ionone on a gramme scale "Equation "42## ð81HCA0912Ł[ Other useful bases included aqueous potassium hydroxide ð80TL2628Ł\ Hunig|s base ð78CPB1771Ł and dbu "Scheme 12# ð89CC73\ 81JOC1169\ 83JOC170Ł[ OPiv O

O K2CO3

(53) Kugelrohr 140 °C/10 mm Hg

472

Of Oxy`en OAc 1N KOH diethyl ether 100%

O

O OMe

MeO OH

H

MeO

AcO

H

OMe

O

CN

OMe

PhH 80 °C good yield

CHO CHO

BzO

O

dbu

CN

BzO BzO

AcO

DIPEA

CH2Cl2 95%

OBz

BzO

H dbu

O

BnO2C

O

O

OAc

CO2Me CONH2 O

O

AcO

O-MOM

H OAc MeO

CH2Cl2 45 °C, 15 h

U

dbu

OPiv

PhH 28 °C, 0.5 h

O

O

BnO2C

O-MOM CO2Me O

OAc

CONH2 O

O

H OAc MeO

U OPiv

U = uridine; MOM = methoxymethyl Scheme 23

0[02[3[4 Elimination of a Sulfonic Acid A popular method of alkene formation involves formation of the methanesulfonate "mesylate# ester followed by treatment with base ð89SC0352Ł[ In some cases\ isolation of the ester was unnecess! ary[ Activated substrates underwent elimination directly in high yield upon treatment with methane! sulfonyl chloride and an amine base "Scheme 13# ð81JOC2504\ 83JOC221Ł[ In hindered cases\ 3!dimethylaminopyridine "dmap# was used to facilitate the esteri_cation ð83T0286Ł[ Other mesylate

O

O MsCl

ButO2C Ph

OH

0–RT, 2 h 93%

(CO)3 Co

HO O H

Co(CO)3

MsCl

ButO2C Ph (CO)3 Co

O

Co(CO)3

Et3N, dmap 54%

O

TBDMS-O HO But

O

TBDMS-O

O

O MsCl dmap, THF reflux, 93%

Scheme 24

But

473

C1C Bonds by Elimination of Hydro`en\ Carbon\ Halo`en or Oxy`en

eliminations have been performed with alkoxide bases[ Table 03\ entries 0Ð4 provide a selection of examples[

Table 03 Mesylate eliminations with alkoxide bases[ Entry

Substrate MEM-O

Conditions

Product

MEM-O

NHPf

Yield (%) NHPf

a

78

b

58

1 OMs OMs

2

MsO

OMs O

3

b

O

OMs

H H O

OBn

4 O

O

H H b

O

OBn

O

N H

H

5

a

70

N H

MsO

O HO

84

O

H

c

76 O HO

O

MeOCH2CH2ONa, DMF, 0 °C. b ButOK, DMSO. c MeCH2C(Me)2ONa, PhH, reflux.

H

O

Ph Pf =

In entry 0\ the 8!phenyl!8!~uorenyl "Pf# protecting group was used to prevent proton abstraction a! to the amino group ð83JOC283Ł[ The regiochemical outcome was unambiguous in entries 1 ð81JA7707Ł and 2 ð81JA3017Ł[ In entry 3\ the major regioisomer is shown ð81JOC6174Ł[ In entry 4\ the mesylate was locked in an equitorial environment on the trans!fused decalin system\ and the antiperiplanar transition state required for the E1 elimination could not be reached[ Instead\ an interesting elimination reaction involving simultaneous ring expansion occurred ð83JOC263Ł[ The phosphazenium naked ~uoride base "7# converted a steroidal benzene sulfonate to the corresponding diene in excellent yield under very mild conditions "Equation "43## ð80AG"E#0261Ł[ In comparison\ only a 64) yield of the alkene was obtained after 3 days in the presence of potassium t!butoxide in DMSO at 79>C[ Amidine bases have also been used in a number of cases[ Equation "44# shows a high yielding example ð81JA8308Ł[ In Equation "45#\ aromatisation followed elimination with 0\4 diazabicycloð3[2[9Łnon!4!ene "dbn# in benzene solution ð89JA8173Ł[ Palladium!catalysed mesylate elimination in the absence of a base led to the formation of a range of interesting glycals "Scheme 14# ð81JA0380Ł[

474

Of Oxy`en

(8)

(54)

THF RT, 0.5 h 99%

BzO

MsO

H

H dbu

(55) + –

S

CO2Me

H

O

PhH 94–100%

O-MEM

H

+ –

S H

O

CO2Me O-MEM

OMs dbn

O

H

O

OH

BnO BnO

OBn

(56)

50 °C, 8 h 88%

O

O i, ii

BnO

60%

BnO

BnO

OBn

BnO O

O

i, ii

BnO

OH

BnO 87%

BnO

BnO

OBn

OBn

O

O O O

O OH

i, ii

O

15%

O

O

O

O

i, Ms2O, collidine, CH2Cl2, RT, 1 h ii, Pd(PPh3)4, 50 °C, 12 h Scheme 25

0[02[3[5 Elimination of 0\1!Diols Vicinal eliminations involving two hydroxyl groups "or their derivatives# have formed the subject of a review ð73OR"29#346Ł[ The reactions have found useful applications in the areas of carbohydrate\ nucleoside and enediyne chemistry[ The CoreyÐWinter reaction was developed to deoxygenate 0\1! diols via thionocarbonate formation followed by treatment with a diaminophosphorane ð71TL0868Ł[ Scheme 15 shows examples from the enediyne ð82TL3010Ł and nucleoside ð78JOC1106Ł _elds[ The mildness of the reaction conditions allowed a range of other functional groups to survive the dideoxygenation procedure[ Organometallic procedures using bis"cyclooctadienyl#nickel a}orded lower yields in the enediyne case\ and involves using hydrogen sul_de gas in the workup[ Table 04\ entries 0Ð4 highlight a range of vicinal eliminations performed under free radical conditions[ Treatment of a ribonucleotide bis"xanthate#ester using the usual tin method conditions a}orded a dideoxynucleoside in 82) yield "entry 0#\ o}ering a clear advantage over the CoreyÐ Winter method which a}orded the dideoxynucleoside in only 40) yield ð78JOC1106Ł[ Halides also served as e}ective leaving groups in free radical elimination[ Entries 1 ð89S300Ł and 2 ð89TL2718Ł illustrate high yielding eliminations[

475

C1C Bonds by Elimination of Hydro`en\ Carbon\ Halo`en or Oxy`en Me N PMe

O-TBS

O-TBS

N Me

O

diethyl ether 0 °C, 4 h 84%

S O

Me N

O

PPh

Ad

N

TBDMS-O

O

Me

O

O

Ad

TBDMS-O

51%

S Scheme 26

Table 04 Eliminations via free radicals[ Entry

Substrate

Conditions

Product

Yield (%)

TBDMS-O O 1

S O

Ad

93

O SMe H N N

O

O

H

NH2

O

AcO

O

a

S

MeS

2

TBDMS-O

Ad

Br

N

N

O

N N

O

O

a

NH2

58

O

AcO

N

N

S OPh TrO

O O

3

N

N H

S O

Cl

TrO

O O

b

N

84

N H

O O

PhO TBDMS-O O 4

S O

5

Ph

O

c

70

SMe O

OMe S

O

O SMe

O

SMe

O

O

c Ph

S a

Ad

O

MeS O

TBDMS-O

Ad

S

Bu3SnH, AIBN, PhMe, reflux. b Bu3SnH, AIBN, PhMe, 60 °C. c Ph2SiH2, AIBN, PhMe, reflux.

OMe 76

O

476

Of Oxy`en

Barton has developed chemistry that avoids the use of toxic tin compounds^ instead\ a silane serves as the chain carrier "entries 3 and 4# ð80TL1458Ł[ The method developed by Samuelsson et al[ "Equation "46## is particularly suitable for larger scale operations because all the byproducts from the reaction are soluble in water ð89JOC3162Ł[ Treatment of dibenzoates with samarium diiodide "Equation "47## a}orded elimination products in moderate to good yield ð81TL462Ł[ The method is noteworthy because of the routine use of benzoate esters in carbohydrate chemistry[ Short reaction times and facile workup also add to the appeal of the samarium!mediated reaction[ O

O

OMe

O

Ph

OH OH

O

O

Ph

O

O

O

BzO

THF 75 °C, 0.5 h 60%

OBz

OMe (57)

imidazole, I2 PhMe 88%

SmI2

BzO BzO

O

O

PhPCl2

(58)

0[02[3[6 Deoxygenation of Epoxides One!pot sequences are available involving nucleophilic ring opening\ followed by elimination[ An acid!sensitive glycal was prepared by a mild procedure "Equation "48## ð66CB1016Ł[ Epoxide opening was e.cient\ but the elimination step proceeded in only moderate yield[ A simple and inexpensive combination of reagents "chlorotrimethyl silane:sodium iodide in acetonitrile# converted a cis! epoxide into a "Z#!alkene in good yield ð70TL2440Ł[ A range of metals has been used in deoxygenation reactions\ including low!valent titanium ð67JOC2138Ł\ niobium ð71CL046Ł\ and samarium ð79JA1582Ł[ A procedure based on an organotungsten intermediate tolerates the presence of ester and ether groups ð70OS"59#18Ł\ but the most sensitive method involves an organotitanium reagent "Equation "59## ð89JA5397Ł[ O AcO

OMe

O

i, NaI, AcOH, 98%

(59)

ii, POCl3, pyridine, 45%

AcO

O OTr O

TrO

OTr

Cp2TiCl

OMe O

THF 66%

OMe

O TrO

(60) OMe

Attempts to deoxygenate the furanoid epoxide by other methods led exclusively to the formation of the furan\ via elimination of the alkoxy group[

Copyright

#

1995, Elsevier Ltd. All R ights Reserved

Comprehensive Organic Functional Group Transformations