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OSEM O O O O Claisen Diels-Alder O HO O HO O OH O

Aromatic Rings and the Diels-Alder Reaction

O OH MeO2C OMe HO2C H H Me Oxidation Diels-Alder Me O OMe O

MeO2C

Blake Greene Monday, May 12th After Group Meeting

Outline

I. Review of the Diels-Alder Reaction A. Mechanism B. Types of Diels-Alder Reactions C. Regioselectivity II. Background on Aromatic Compounds A. Stability of Benzene B. Molecular Orbital Theory III. Examples of Diels-Alder Reactions of Aromatic Compounds A. Benzene B. Cyclohexatriene Equivalents C. Polycyclic Aromatic Hydrocarbons D. Tandem Claisen/Diels-Alder Reactions i. General Reactivity ii. Garcinia Natural Products iii. Salvadione A E. Tandem Oxidation/Diels-Alder Reactions i. Wessely Oxidation ii. MOB's

1

Review of the Diels-Alder Reaction

Two mechanisms for the Diels-Alder reaction have been proposed: One-step (concerted): b c a d e f b c a d e f b c a d e f b c Two-step (nonconcerted): a d e f b c a d e f b c a d e f b c a d e f

or

biradical or zwitterionic Concerted mechanism supported by chemical evidence: --syn stereospecificity of the reaction --Low solvent effects on the reaction rate --Kinetic isotope effect research --Large negative values of activation entropy and activation volume

Frontier molecular orbital (FMO) theory dictates that the Diels-Alder reaction is controlled by the interaction between the two HOMO-LUMO molecular orbitals closest in energy

HOMO O H O H B A A O H

O

LUMO

Endo Transition State A: Bonding Interaction B: Secondary Orbital Interaction

Brian's class notes Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction; Wiley & Sons: New York, 1990.

Review of the Diels-Alder Reaction

There are three general types (normal, inverse, and neutral electron demand) of Diels-Alder reactions, depending upon the arrangements of the HOMO and LUMO molecular orbitals: E Diene LUMO Dienophile Diene Dienophile Diene Dienophile

HOMO Normal Inverse Neutral

Factors that lower the HOMO-LUMO distance (i.e. substituent effects) increase the reaction rate due to the fact that the smaller energy difference allows for a greater contribution to the stabilization of the transition state E LUMO D D

W W

HOMO

Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction; Wiley & Sons: New York, 1990.

W= Electron withdrawing group D = Electron donating group

2

Review of the Diels-Alder Reaction

Regioselectivity: ortho/para Rule:

ortho:

O OR O OR

ortho/endo product favored

longer interaction

O OR

O OR

O OR largely - lobe

largely + lobe closer interaction O

para:

O OR

OR

para/endo product favored

O OR

O OR

Brian's notes

Brief Background on Aromatic Compounds: A Look at Benzene

Aromatic compounds are unsaturated cyclic molecules containing additional stability caused by the arrangement of !electrons in the ring system Aromaticity accounts for the fact that benzene is 151kJ/mol more stable than cyclohexatriene

3H2 predicted energy for cyclohexatriene 2H2 3H2 Energy 360kJ/mol H2 232kJ/mol 120kJ/mol 209kJ/mol

aromatic stabilization 151kJ/mol

Hepworth, J. D. ; Waring, D. R.; Waring, M. J. Aromatic Chemistry. The Royal Society of Chemistry: Cambridge, 2002.

3

Molecular Orbital Theory of Benzene

Six carbons of benzene are sp2 hybridized Three sp2 orbitals on each carbon overlap with those on two adjacent carbons and with the s orbital of hydrogen-compose the planar !-bonded skeleton of benzene The p orbital (perpindicular to the plane of the ring) of each carbon contains one electron Six p orbitals of benzene combine to form six molecule orbitals--three bonding and three anti-bonding

"6 anti-bonding "4 "5

Energy

"2 "1 Atomic Orbitals

"3 bonding

Molecular Orbitals

Six overlapping p orbitals comprise a delocalized p-electron cloud, which result in the aromaticity of benzene

Hepworth, J. D. ; Waring, D. R.; Waring, M. J. Aromatic Chemistry. The Royal Society of Chemistry: Cambridge, 2002.

Diels-Alder Reactions with Benzene

A 20-40kcal/mol thermodynamic barrier must be overcome to induce [4+2] reactivity in benzene Due to its aromaticity, benzene is a weak diene in [4+2] cycloadditions reactions--very few successful cases have been reported with benzene as a diene in a Diels-Alder reaction

Successful Cases:

X X X X Very active dienophiles

X = CN (14%) X = CF3 (8%) O OH O O OH O X X PTAD 20oC, 138h PTAD (99%) X X X-X =

Cossu, S.; Garris, F.; DeLucchi, O. Synlett 1997, 12, 1327. Chordia, M. D. et al. JACS 2001, 123, 10756.

O neat 200oC, 1.5h O O O Destabilize aromatic ring by adding substituents

X X Destabilize aromatic ring by increasing ring strain O N N NPh O

4

Diels-Alder Reactions with Polycyclic Aromatic Hydrocarbons

Anthracene and its derivatives yield Diels-Alder reactions at diene sites C-9 and C-10, where the lowest benzenoid character exists R COOH R COOH R

COOH R CN COOH CHO NO2 OMe

ortho

65% 44% 100% 19% 100% R1

meta

35% 56% 0% 81% 0%

R

R

R1

R

R

R R1

R

R Cl CO2Me CO2Me CN

R1 Me Me CO2Me CO2Me 75% 69% 24% 1% 25% 31% 76% 99%

Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction; Wiley & Sons: New York, 1990.

Diels-Alder Reactions with Polycyclic Aromatic Hydrocarbons

Diels-Alder rate constants of polycyclic aromatic hydrocarbons with maleic anhydride increase on linear annulation and decrease on angular annulation Acene krel Acene krel

1

6 x 10-3

20.3 3 x 10-3 722.5

1447 1.5 x 10-3

= most reactive diene sites The above can be explained by Clar's sextet theory, which states that the increasing reactivity going from anthracene to hexacene is a result of a gradual loss of benzenoid character of the aromatic hydrocarbon, whereas the decreasing reactivity with the angular annulation is due to the formation of a new !-sextet with each angular benzene addition.

Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction; Wiley & Sons: New York, 1990.

5

Bicyclo[2.2.2]octene Skeleton Synthesis via Cyclohexatriene Equivalents

Y Z W cyclohexatriene equivalent Success of the above reaction requires the "temporary interruption" of the aromaticity of the benzene ring followed by the reinstallation of the double bond via the elimination of the W and Z functionalities This is not a trivial point due to the fact that the easier it is to add and/or remove the functional groups, the easier it is to aromatize. Because of this, the energy needed for the cycloaddition reaction is usually much greater than the energy of aromatization. This results in the aromatization of the substrate and no Diels-Alder product.

Cossu, S.; Garris, F.; DeLucchi, O. Synlett 1997, 12, 1327.

Y Z W -WZ X

Y X

X

Example: Barrelene Synthesis

SO2Ph O SO2Ph PhO2S PhO2S O

PhH 80oC, 48h (96%)

WCl6/n-BuLi THF, RT, 24h (90%)

PhO2S PhO2S

Na/Hg buffered MeOH (90%) Barrelene

Cossu, S.; Battaggia, S.; De Lucchi, O. JOC 1997, 62, 4162.

Rhenium Promoted Diels-Alder Reaction with Benzene

CH3 N N N N N HB N N N Re Br Br CO Nao HB N N N N N N Re N CO PhH, THF, 25oC (65%) N CH3 O N O CH3

CH3 N O N N N N HB N N N O single diastereomer Re CO O [O] and/or N CH3

O N CH3 O

O N CH3 O

Crystal structure of dihapto complexation shows dearomatization to the extent that the uncoordinated portion of the benzene ring resembles cyclohexadiene Note: Re complex dictates the stereochemistry of the cycloaddition and prevents retrocycloaddition by hindering one of the !-bonds

Chordia, M. D. et al. JACS 2001, 123, 10756.

6

Tandem Claisen/Diels-Alder Reactions of Aromatic Compounds

General Reactivity:

R R O R R O R O R

The Claisen rearrangement results in the simultaneous formation of the activated diene and the activated dienophile

Some Examples:

H N

i-BuOH, H2SO4

100oC, 1h (30%) Cl F F N F F O

Cl O

F 185oC (81%) N F

F F O

Neuschutz, K.; Velker, J.; Neier, R. Synthesis 1998, 227.

Synthesis of the Bridged Tricyclic Core of Garcinia Natural Products

O H O O O O O Morellin Lateriflorone Biologically natural products isolated from the genus Garcinia of the Guttiferae family of plants Biological activity includes antibacterial and cytotoxic activities Other products of this class are bractatin, 1-O-methylbractatin, 1-Omethyneolbractatin, forbesione, 1-Omethylforbesione, morellic acid, scortechinone A, and scortechinone B

OH

O

O

O OH

O O O

O

Tandem Claisen/Diels-Alder:

OSEM O O O O O 110oC 1h O O O OSEM O O (85%) O O O O OSEM

O

Electron donating alkoxides expedite dearomatization via the tandem Claisen/Diels-Alder reactions

Nicolaou, K.C.; Li, J. Angew. Chem. Int. Ed. 2001, 40(22), 4264. Tisdale, E. J. et al. Org. Lett. 2003, 5(9), 1491.

7

Tandem Claisen/Cope/Diels-Alder in the Stoltz Lab

HO OH

O Claisen OH OH

HO

O Cope OH

HO OH

OH OH O

HO

OH OH O Diels-Alder

HO

O

O

Salvadione A

Tandem Oxidation/Diels-Alder Reactions

Wessely Oxidation:

OH (AcO)3Pb O O OH OR

t-Bu

t-Bu

Pb(OAc)4

t-Bu

t-Bu

ROH

t-Bu

t-Bu

t-Bu

t-Bu t-Bu t-Bu

OR

t-Bu

Harrison, M. J.; Norman, R. O. C. J. Chem. Soc. 1970, C, 728.

t-Bu

Examples:

OMe OH Pb(OAc)4 H2C=CHCO2H OMe OMe O O OMe O MeO 80oC (82%) O O OMe O

CO2Et Et OH

Pb(OAc)4 AcOH (72%) Et

CO2Et OAc O

140oC (89%)

EtO2C Et O OAc

Tisdale, E. J. et al. Org. Lett. 2002, 4(6), 909. Bhamare, N. K. et al. J. Chem. Soc., Chem. Commun.. 1990, 739.

8

Masked o-benzoquinones (MOBs)

Masked o-benzoquinones (MOBs) are a highly reactive species of 6,6-dialkoxycyclohexa-2,4-dienones MOBs can be formed in situ via the oxidation of the corresponding 2-methoxyphenols with hypervalent iodine reagents in MeOH--diacetoxyiodobenzene (DAIB) or phenyliodonium (III) bis(trifluoroacetate) (PIFA)

O Rn O Rn

OMe OR' O R' = alkyl Type I Rn

OAc OR' O R' = Ac, alkyl Type II Rn

O O O O Type III

o-benzoquinones

MOBs

o-benzoquinones are generally unstable and undergo numerous reactions including dimerization

MOBs are relatively stable compared to the corresponding o-benzoquinones MOBs can participate in cycloaddition and nucleophilic additions reactions The double bonds of the diene are electronically different (due to their positioning between carbonyl and acetal functionalities), thus making regioselective reactions possible The acetal functionality can act as monoprotection for the vicinyl carbonyl group Limited methods for the synthesis of MOBs

Liao, C. C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856. Lin, K. C. et al. JOC 2002, 67, 8157.

Masked o-benzoquinones (MOBs)

Masked o-benzoquinones (MOBs) are a highly reactive species of 6,6-dialkoxycyclohexa-2,4-dienones MOBs can be formed in situ via the oxidation of the corresponding 2-methoxyphenols with hypervalent iodine reagents in MeOH--diacetoxyiodobenzene (DAIB) or phenyliodonium (III) bis(trifluoroacetate) (PIFA)

O Rn O Rn

OMe OR' O R' = alkyl Type I Rn

OAc OR' O R' = Ac, alkyl Type II Rn

O O O O Type III

o-benzoquinones

MOBs

o-benzoquinones are generally unstable and undergo numerous reactions including dimerization

MOBs are relatively stable compared to the corresponding o-benzoquinones MOBs can participate in cycloaddition and nucleophilic additions reactions The double bonds of the diene are electronically different (due to their positioning between carbonyl and acetal functionalities), thus making regioselective reactions possible The acetal functionality can act as monoprotection for the vicinyl carbonyl group Limited methods for the synthesis of MOBs

Liao, C. C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856. Lin, K. C. et al. JOC 2002, 67, 8157.

9

Intramolecular Diels-Alder (IMDA) Reactions with MOBs

Two important advantages of intramolecular vs. intermolecular Diels-Alder reactions --IMDA reactions can usually proceed under milder conditions with higher reactions rates due to lower entropic demands --IMDA reactions usually result in greater selectivities due to the reduction in the degrees of freedom of the transition state (unimolecular vs. bimolecular) Replacing methanol with an alkenol or a dienol in the oxidation of 2-methoxyphenols yields MOBs which can undergo IMDA reactions to form tricyclic ring systems O OMe R3 R' R2 n = 1, R' = H, Me, Ph n = 2, R' = H O

n

R4 R3 R2

OMe OH

R'

n

OH DAIB

R4

n

R' R4 R3 R2

O

OMe O (15-80%)

R2 = R3 = H, R4 = H, Me, CO2Me R2 = R4 = H, R3 = CO2Me R2 = OMe, R3 = H, R4 = Me, CO2Me

While the intermolecular Diels-Alder reaction of MOBs yields ortho, anti products, the IMDA reaction of MOBs yields meta, syn products--both with respect to the carbonyl group X X Rn O OMe OMe Rn O OMe OMe Rn O

n

O OMe

ortho, anti

meta, syn

Liao, C. C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856.

Diels-Alder Reactions with MOBs in Total Synthesis

cis-clerodane diterpenic acid:

OH OMe OH PIFA O OMe O O IMDA OMe O 3 steps

OBn OH

oxy-Cope H 4 steps O OR

11 steps O

H

R = Bn R = Ac

CO2H

Br

OMe OMe O MeO2C

MeO2C Br

OMe Bu3SnH OMe O AIBN

MeO2C

OMe OMe O

7 steps

BnO

OH oxy-Cope H O OBn

10 steps H O

Liao, C. C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856.

CO2H

10

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