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Mitsunobu reaction and its application By Mohammad Mohsin Qadri 1
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Mitsunobu reactionand its application
By
Mohammad Mohsin Qadri
1
FLOW OF CONTENT
Introduction
Mechanism
Recent advances
Applications– Esterification
– Etherification
– N-alkylation
Conclusions
2
Work at the AoyamaGakuin University,Tokoyo. One of thescientist to have afamous namereaction
1934-2003
IntroductionSubstitution of primary or secondary alcohols with nucleophiles mediated
by a redox combination of a trialkyl or triarylphosphine and a dialkyl
azodicarboxylate
Converts an alcohol into a variety of functional groups using trialkyl/triarylphosphine dialkyl azodicarboxylate
OH
R1RNuH
DEAD
TPP
Nu
R1RDEAD-H2 TPPO
OH OHO R
O
Ph3P / DEAD
O
R
iPr iPr
3Tetrahedron Lett. 1999, 40, 2685-2690
• Condensation of an alcohol and a nucleophile using Triphenyl
phosphine and Dialky/diaryl azodicarboxylate
• Substrates :1º or 2º alcohols (Chiral alcohol gives inversion product)
• Nucleophile : normally acidic compound containing an -OH, -SH, -NH-
• Reagents : Trialky/triaryl phosphine and Dialkyl azodicarboxylate
• Solvents : THF, toluene, benzene, DMF, diethyl ether, acetonitrile, DCM
• Additional components such as acyl/alkyl halides or lithium/zinc halides,
convert alcohols to halides
• Intramolecular Mitsunobu reaction leads to cyclic product
Salient features
4
Tetrahedron Lett. 2003, 44, 3609-3621
J. Chem. 1992, 45, 47-67
Alternatives
ReagentsTrialkyl or triarylphosphine Azodicarboxylic acid derivatives
P
P
TPP TnBP
N
P
Ph
Ph
P
Ph
Ph
NMe2
P NMe2 PPh2Ph2P
DPPP DMDPP
TDMPP DPPE
3
O NN O
O NN O
O
O
O
O
DEAD DIAD
O NN O
N NN N
O
O
O
OADDP
DBAD
5Tetrahedron Lett. 1999, 40, 4497-4513
Mechanism
Basic scheme
R1
OH
R2
Nu H
N N
R3O2C
CO2R3
R1
Nu
R2
HN NH
R3O2C
CO2R3
PR3 R3P O
+
6Chem. Rev. 2009, 109, 2552-2553
Mechanism of reaction
N N
C
C
N N
CO2Et
EtO2CPPh3
H Nu
PPh3
H
O
R2R1
H
O
R2R1
PPh3
Nu
Nu
R2R1
Ph3P O_
O
O
OEt
EtO
N N
C
O
EtO PPh3
O
OEt
_ HN NH
CO2Et
EtO2C
7
J. Org. Chem. 2003, 68, 1176
Tetrahedron Lett. 2003, 44, 3609
Why Retention product is formed in some cases?
(1) Sterically hindered substrate(2) Acidic component with lower pKa(3) Solvent(4) Less nucleophilic phoshine (TCHP)
8
J. Org. Chem. 1989, 54, 3049
J. Am. Chem. Soc. 2005, 127, 12566
Recent advancesConventional reagents creats problem in the
separation, isolation and purification
1 Triisopropyl phosphite in place of PPh3 forms a more
water soluble phosphate
2 Replacement of OEt group in DEAD by more electron-
donating and bulky group expands the versatility of
reaction with less acidic Nu-H
3 Acidic component with lower pKa, retention product is
more favoured
9
Tetrahedron Lett. 2006, 47, 3153
J. Org. Chem. 1994, 59, 234
4 There are few publications on Microwave-promoted
Mitsunobu reaction
5 Mitsunobu reaction-Claisen rearrangement
10
OH
MeOHO
PPh3+DIAD
Toluene, 30 min
MW, 220 ºC
OH
MeO+
Tetrahedron Lett. 2005, 46, 8823
APPLICATIONS
• Reaction of alcohol with carboxylic acid in presence of Trialkyl/triaryl phosphine and azodicarboxylate
• Alcohol: Preference of reaction 1° > 2° > 3°
With chiral 2° alcohol, configuration inversion of alcohol occures
• Acid: pKa of usable acid should be < 11 ( Lower pKa favours inversionproduct). eg. 4-nitrobenzoic acid (pKa 3.4) or chloroacetic acid (pKa
2.9)
(A) Esterification
11Tetrahedron Lett. 1999, 40, 2685
In the synthesis of ( )-Gingkolide B
In the synthesis of precursor of Octalactins
12
Tetrahedron Lett. 1999, 40, 2685Tetrahedron Lett. 1995, 36, 7189
O
O
OH
H
O
O
OH
H
O
O
H
N
NN
N
Cl
(1) PPH3 + DEAD, 4-NO2-C6H4CO2H, Toluene (2) K2CO3, MeOH
(1)
(2)
(3) PPH3 + DEAD, 6-chloropurine, THF
(3)
In the synthesis of marine alkaloid ( )-Fasicularine
In the synthesis of nucleoside analogues
13
J. Am. Chem. Soc. 2000, 122, 4583
Eur. J. Org. Chem. 2005, 1444
N
O
OHHO
2C
MeO2C
PPH3 + DEAD
THF, 0 °C N
O
O
O
MeO2C
NO
OH
O
CO2MeN
HO H
OH
OH
(-)- rosmarinecine
+
In the synthesis of (-)-Rosmarinecine
14Org. Lett. 2001, 3, 1367
-Me group produces steric effect shifts equilibrium towards ‘a’ Retention product
Lactonisation
15J. Org. Chem. 2003, 68, 1176
Macrolactonisation
In the synthesis of (+)-Amphidinolide
In the synthesis of Mibemycin-β3
16
Org. Lett. 2006, 8, 3987
J. Am. Chem. Soc. 2001, 123, 765
(B) Ether formation
(Etherification)• Phenols and alcohols with strong electron withdrawing
group can act as nucleophiles
• With chiral 2 alcohol, configuration inversion of alcohol
generally occurs
(a) Etherification without cyclization
BnO
O
OH
OH
OBn
PPh3 + DIAD+
BnO
O
O
OBn
17Tetrahedron Lett. 2003, 44, 3609
CO2Me
HO OH
OHPPh3 + DIAD
THF
CO2Me
O O
THF
PPH3 + DIAD + c
O
OO
O
CO2Me
O O
more branched structure
c
LiAlH4
Synthesis of dendrimeric structure
18J. Org. Chem. 2004, 69, 7363
O
OBn
BnOBnO
OBn
OHO
OBn
BnOBnO
OBn
OCH2CF3
PPh3 + DIAD
CF3CH2OH
Toluene
OO
HO OH
HO
HO OO
RO OH
HO
HO
PPh3 + DEAD
ROH
THF + DMF
R= Me, n-propyl, allyl
OO
O O
HO
HO
Ph3P
Synthesis of fluoroalkyl/fluoroaryl glycosides
Alkylation of L-Ascorbic acid
19
Carbohydr. Res. 1999, 318, 171
J. Org. Chem. 2000, 65, 911
(b) Etherification with cyclization
Intramolecular Mitsunobu reaction results in cyclic productGenerally 3-7 member ring formation is prefered
O
O2NO2N OH
OH
PPh3+DEAD
THF
Synthesis of benzopyran
OHOH
OBenzene
n-Bu3P+TMAD
Synthesis of fused ring system
20
HO(CH2)nOHTPP + DEAD
(CH2)n O
J. Org. Chem. 1998, 63, 4116
Tetrahedron Lett. 1996, 37, 2463
OH
O
N
O NH-cycl-C6H11
OH
O
N
O NH-cycl-C6H11
O
PPh3+DEAD/Et3N
Synthesis of Dihydrobenzoxazepin-5-one
Synthesis of excitatory amino acid analogues
21
Org. Biomol. Chem. 2006, 4, 4236
Synlett 2006, 2407
N
OHOH
NPhth
Cl
Cl
PPh3 + DIAD
TolueneN
O
NPhth
Cl
Cl
OHHO
OH
OH
HO
OH
OH
OHO
OH
OHOH
OHPPh3 + DEAD
THF
Synthesis of (+)-Catechin
Synthesis of chiral substituted morpholine
derivatives
22Synlett 2006, 2151
(C) N-AlkylationAmines, Amides and Azides can act as nucleophilesNucleophiles : Phthalimides , Nucleobasides, suitably protected amino acid moieties or HN3
23
N NH
NN
N
OH
N
N N
NOH
S
F
F
PPh3+DEAD
DMFN NN
N
NN
N N
NOH
S
F
F
Synthesis of Antifungal compounds
Tetrahedron Lett. 1994, 35, 1847-1850
Chem. Abstr. 2003, 139, 3379
24
O
NH
OHN O
CN
NO2
N
N O
CN
NO2
O
N
N O
CN
NO2
HO
N
Mitsunobu
N -alkylation
pyrrolidine
+
In the synthesis of HIV inhibitor
Chem. Abstr. 2005, 144, 6778
HN NH
N N
O
O
O
O
O
O
O
O
O
O
O
O
N N
O
O
O
O
OH HO
N N
O
O
O
O
O
O
O
O
PPh3 + DEAD
THF+
Synthesis of Catenanes
25Org. Lett. 2000, 2, 449
NH
N OAc
N
H
OH
N
OHEt
H
CO2Me
Et
H
MeO2C
N
Boc
OH
CO2Me
NH(R)
OTMS
OMOMN
Boc OMOM
N
R
OTMS
CO2Men-Bu3P + TMAD
Toluene
In the synthesis of (+)-vinblastine
26Org. Lett. 2007, 9, 4737
In the synthesis of Clavizepine
analogue
27Org. Chem. 2006, 71, 3963
Synthesis of cyclic nucleoside analogues
28
Synthesis of Adenosine antagonist
N
N
N
N
N
NH
O
N
N
N
N
N
O N
Mitsunobu N -alkylation
Tetrahedron 2003, 59, 6493
29
N
N
Cl
OH
OBn
N
O
O
N
N
Cl
OBn
HN
O
O
+ Mitsunobu
N-alkylation
NH
O
N
N
Cl
OBn
In the synthesis of Tyrosine kinase inhibitors
Chem. Abstr. 2006, 144, 390946
30
SMeHN
O O
BrHN CF3
O
N O Ph
HO
O
SMeHN
O O
Br
N CF3
O
N O Ph
O
+
Mitsunobu
N-alkylation
SMeHN
O ON CF3
O
N O Ph
O
In the synthesis of Serotonergic agent
Chem. Abstr. 1996, 125, 300820
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