10 obscure name reactions - scripps research · 2008. 5. 12. · tishchenko reaction r o h r mcl o...
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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
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