10 Obscure Name Reactions

Whiting ReactionHO

R

OH

R'R'R

LiAlH4

Whiting, Cosmene, J. Chem. Soc. 1954, 4006

+CHO

MgBrHO HO OH

LiAlH4

Cosmene, 35%

Isler et al., 7,7'-Dihydro-ß-carotene, Helv. Chim. Acta, 1956, 454

OH

OHLiAlH480%

Dakin ReactionO R

HO

OH

ORHO

OH

HOO-

OOH

Slow

O R

HO

OH

-OHOH

OHO

OH

OH

-CO2R-

Can. J. Chem. 1977, 102

O R

O

HOR

O

HOO-

OOH

HOOH

OR

O

O

H2O

OOH

OR

O

OO

OH O R

O

O

-OOH-

-OOH-

RCO3H

O

O

Ortho-phenols speed up reaction via stabilizing intramolecular H-bonding

Unlikely other mechanismsO R

O

HOR

O

HOO-

OOH ROH

O

O+ HOOH + OH

R

OH

O

HO

OH

R OH

OH

OHO

+

Spirocyclic epoxide intermediate

O R

O

HOOH

O

OO

R OH

O

OO

+

Phenoxide radical mechanism

O R

O

O R

O

OR

O

OOH

O

ROO

H

H

+

+ O2

An example of synthetic use:A New 5 step 33% yield synthesis of an

L-DOPA derivative

J. Org. Chem., 1997, 62, 1553

OH

H2NCO2H

(tBuO2C)2OEt3Ndioxane/ H2O92%

OH

NHCO2tBuCO2H

CHCl36eq NaOH2eq H2O∆/ 4 h54%

OH

NHCO2tBuCO2H

CHOK2CO3/BnBrCHCl3/ MeOH71%

OBn

NHCO2tBuCO2H

CHO

1) 2.5eq 30% H2O2 4% (PhSe)2 CH2Cl2 18 h2) NH3/ MeOH/ 1 h 78%

OBn

NHCO2tBuCO2H

OH

Roush Coupling

B OO

CO2-iPr

CO2-iPr

R O

H

OB

R2

R3 O

O

CO2-iPr

CO2-iPr

R1

HR1

OH

R2R3R2

R3Generally 80%-90%DE~>90%EE~60%-80%

B OO

CO2-iPr

CO2-iPrn-BuLi, KtOBu, THF-78 ˚C --> -50 ˚C

1) (iPr)3B, -78 ˚C2) H3O+, Et2O3) DIPT, MgSO470-75%

B OO

CO2-iPr

CO2-iPrn-BuLi, KtOBu, THF-78 ˚C --> -25 ˚C

1) (iPr)3B, -78 ˚C2) H3O+, Et2O3) DIPT, MgSO470-75%

K+

K+

>98% E

>99% Z

Grob Fragmentation

OH

BrBase

OGeneric Structure for Grob Fragmentation:

D L D CR2 L-

R R

R RR RR

R

R

R

Fragmentation is challenged by nucleophilic substitution, elimination, or ring closure

D LR R

R RR R

D NuR R

R RR R

DR

RR R

Nu-

elim

R.C.

R

D

-L-

-L-

-L-

D LR R

R RR R

DR R

R RR Rcarbonium2-step

synch.

carbanion2-step

-L-D CR2

R

R

R

R

D CR2R

R

R

R+ L-+

+

D CR2 + LR R

R R R

R

R

R+ L-

While ample evidence intially existed for the first two mechanisms occuring regularly, the carbanion 2-step mechanism was confirmed by experiment later

Carbonium:Favored by good leaving groups, ex I>Br>Cl(kinetics of elimination are coherent with the homomorphous haloalkanesuggesting a formal ionization; however the amine is more slow to react than the alkane)Synchronous:Faster Reaction rate than the Carbonium mechanism as heteroatom bears pos. charge. Thus favorably substitutionaccelerates reaction. The reaction is concerted and requires an extended antiperiplanar arrangement of the amine and nucleofuge in space. However, sterics can make some of the reactive conformations inaccessible. Thus inaccessible coformers react via a carbonium.This acceleration in elimation by a synchronous mechanism is called the frangomeric effect.Carbanion:Generally the first step is reversible, with the ion being favored if the negative charge is stabilized while the nucleofuge remains attached.Thus this reaction is analogous to E1CB

-L-

D LR R

R RR R

DR R

R RR Rcarbonium2-step

synch.

carbanion2-step

-L-D CR2

R

R

R

R

D CR2R

R

R

R+ L-+

+

D CR2 + LR R

R R R

R

R

R+ L-

While ample evidence intially existed for the first two mechanisms occuring regularly, the carbanion 2-step mechanism was confirmed by experiment later

Carbonium:Favored by good leaving groups, ex I>Br>Cl(kinetics of elimination are coherent with the homomorphous haloalkanesuggesting a formal ionization; however the amine is more slow to react than the alkane)Synchronous:Faster Reaction rate than the Carbonium mechanism as heteroatom bears pos. charge. Thus favorably substitutionaccelerates reaction. The reaction is concerted and requires an extended antiperiplanar arrangement of the amine and nucleofuge in space. However, sterics can make some of the reactive conformations inaccessible. Thus inaccessible coformers react via a carbonium.This acceleration in elimation by a synchronous mechanism is called the frangomeric effect.Carbanion:Generally the first step is reversible, with the ion being favored if the negative charge is stabilized while the nucleofuge remains attached.Thus this reaction is analogous to E1CB

-L-

Tet. Lett. 38 (19) 3469

Proposed mechanism for GrobFragmentation

Tishchenko ReactionR

O

H R

OMCl3OCH2R

R

O

H R

OCp2Nd(SiMe3)2

OCH2R

Classic Tishchenko Reaction

Lanthanide Variant

R

O

H R

OM(OR)x, NCly

OCH2RCl210-90% depending on reaction conditions

Adkins and Child hypothesize the reaction takes place with the metal orienting and directing an auto-oxidation-reduction reaction as is seen in glyoxal (JACS47, 804).

Lanthanide variants

HO

O

R1

O

Me2HC

HR2

Sm

O

R1

OHR2CHO15% SmI2

OH

R1

O

O

R2

Yield: 82-96%JACS 112, 6447

1% Cp2Nd(SiMe3)2

Yield: 80%-quantitativeTet. 52, 4291

R

O

H R

O

OCH2R

Lanthanide DataJACS 112, 6447

Tet. 52, 4291

Nysted Reagent/Reaction

R

O

H

OZn Zn

ZnRBF3OEt2

THF, O ˚C to RT

This commerically available reagent is capable of methyenylationalone or in concert with TiCl4. While information on the reactivityof the reagent exists, the mechanistic basis of its function has yet tobe elucidated.

Methylenylation in aldehydes

Synlett, 1998, 313-15

In methylenylating chiralaldehydes, completeretention of the chiral centeris seen. Further in caseswith a ketoaldehyde, thealdehyde is methylenylatedexclusively.

Cont’d

Addition of TiClx salts

Cont’d

Cont’d

Majetich Cyclobutane annulation

Fluoride ion confers an anti orientation of the silyl alkene throughkinetic control, lewis acid confers a synclinical orientation andformation of cyclopentyl and cyclohexyl adducts. This reactiondepends on the construction of an 8-TMS-1,5-octa-diene moiety,followed by treatment with fluoride. Yields can range from 30%-65%depending on the context.

Me3Si"F-"

Grieco, Synlett. 1997, 493-94Endiandric Acid

O

PhH

H

H

H

TMSHa

Hb

65%

0.3M in DMF5.0 eq HMPA0.2 eq Bu4NF4Å mol sieves O

PhHH

H

H

H

100% eeH

PhHH

H

H

H

HO2C HEndiandric Acid

This remarkable ee is possible as fluoride induces a anti ring closure,and Ha and Hb would provide steric clash to give the oppositestereochemistry at the carbon ß to the acid group.

Grieco’s synthesis of Endiandric Acid

OO

H

HPh Br+

OHH

HH

OO

H

H

Ph

H

Ph

HO

H

H

Ph

TIPSOCl

H

H

Ph

TIPSOOAc

LDA, THF LiAlH4

SOCl210mol% DMAPMe4NOAc

OHH

HH

Ph

HO

TIPSClDMAPimidazole

1) K2CO32) MnO2

O

Ph

TIPSO

H

H

Ph

TIPSOOAc

O

PhH

H

H

H

TIPSO

Hb

O

PhH

H

H

H

Hb

O

PhH

H

H

H

TMSHa

Hb

HO

10mol% TFALiClO4, orTMSOTf CH3Ph, ∆

exo:endo=7.7:1

Bu4NF1) DMSO, (COCl)22) Seyferth's rgnt

O

PhH

H

H

H

TMSHa

Hb0.3M in DMF5.0 eq HMPA0.2 eq Bu4NF4Å mol sieves O

PhHH

H

H

H

H

PhHH

H

H

H

HO2C HEndiandric Acid

O

PhHH

H

H

H

HHO

PhHH

H

H

H

HHO

PhSeBrm-CPBA

1) Catecholboranecat. RhPPh3Cl2) NaOH, H2O2

1) TrisylNHNH20.3 eq p-TsOH10eq MgSO42) LDA

Dess-Martin periodinane

Carbon Ferrier rearrangement

O

OAcOAc

OAc

SiMe3

BF3 OEt2MeCN O

OAc

OAc

Danishefsky JOC, 1982, 3803, JACS 1987, 2082

JOC, 1997, 6985

Fritsch-Buttenberg Wiechell

Ph SO

Cl H

OMe

1) t-BuLi2) H2O

OMe

HBull. Chem. Soc. Jpn 66, 1866

Bu Bu

Br Br

Bu Bun-BuLi

Mechanistic Satiation

Bu Bu

Br Br

Bu Bun-BuLi

Bu Bu

Br Li

Bu Bu

R

R

H

XM+B- R

R

M

X

R

R-X-

R

RR R

Ph SO

Cl H

OMe

1) t-BuLi2) H2O

OMe

H

Ph SO

Li H

OMe

H

OMe

Buchner-Curtius-Schlotterback

R1

OR

H

N2R2

+ R

O

R2

R1

What is the mechanism of this reaction?

Mechanism of the Buchner-Curtius-Schlotterbeck reaction

R1

OR

H

N2R2

+ R

O

R2

R1

R2

H

N N

R1

OR R

NO

R R

N