The Mitsunobu reaction allows the conversion of alcohols to various functional groups using trialkyl/triaryl phosphine and dialkyl azodicarboxylate reagents. It proceeds via an oxidation-reduction mechanism. Common applications include esterification, etherification, and N-alkylation reactions. Recent advances have focused on replacing conventional reagents to improve selectivity and yields. The Mitsunobu reaction has been widely used in the synthesis of natural products and pharmaceuticals.
2. FLOW OF CONTENT
Introduction
Mechanism
Recent advances
Applications 1934-2003
– Esterification Work at the Aoyama
Gakuin University,
– Etherification
Tokoyo. One of the
– N-alkylation scientist to have a
famous name
Conclusions reaction
2
3. Introduction
Substitution of primary or secondary alcohols with nucleophiles mediated
by a redox combination of a trialkyl or triarylphosphine and a dialkyl
azodicarboxylate
OH DEAD Nu
NuH DEAD-H2 TPPO
R R1 TPP R R1
Converts an alcohol into a variety of functional groups using trialkyl/triaryl
phosphine dialkyl azodicarboxylate
O O
OH HO R O R
iPr iPr
Ph3 P / DEAD
Tetrahedron Lett. 1999, 40, 2685-2690 3
4. Salient features
• 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
Tetrahedron Lett. 2003, 44, 3609-3621
J. Chem. 1992, 45, 47-67 4
5. Reagents
Trialkyl or triarylphosphine Azodicarboxylic acid derivatives
P O O
P O O
N N
O N O N
O O
DEAD DIAD
TPP TnBP
Alternatives
O
Ph Ph
N O
P P NMe 2 O N
Ph N Ph O
DPPP DMDPP
DBAD
O
P NMe 2 3 Ph2 P PPh2 N N
N N
TDMPP DPPE O
ADDP
Tetrahedron Lett. 1999, 40, 4497-4513 5
6. Mechanism
Basic scheme
PR3 R3P O
R1 R1
OH + Nu H Nu
R2 R2
CO2R3 CO2R3
N N HN NH
R3O2C R3O2C
Chem. Rev. 2009, 109, 2552-2553 6
7. Mechanism of reaction
H Nu
O
O
C OEt H CO2 Et
OEt
N N N N N N
PPh3
EtO C EtO C PPh3 EtO2C PPh3
O O
EtO2C H
PPh3
O
_ HN NH O
Nu _ Ph P O
3 CO2 Et
Nu
R1 R2 R1 R2 R1 R2
J. Org. Chem. 2003, 68, 1176
Tetrahedron Lett. 2003, 44, 3609 7
8. 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)
J. Org. Chem. 1989, 54, 3049
J. Am. Chem. Soc. 2005, 127, 12566 8
9. Recent advances
Conventional 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
Tetrahedron Lett. 2006, 47, 3153
J. Org. Chem. 1994, 59, 234 9
10. 4 There are few publications on Microwave-promoted
Mitsunobu reaction
5 Mitsunobu reaction-Claisen rearrangement
OH PPh 3+DIAD OH
MeO Toluene, 30 min MeO
+ HO
MW, 220 ºC
Tetrahedron Lett. 2005, 46, 8823 10
11. APPLICATIONS
(A) Esterification
• 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 inversion
product). eg. 4-nitrobenzoic acid (pKa 3.4) or chloroacetic acid (pKa
2.9)
Tetrahedron Lett. 1999, 40, 2685 11
12. In the synthesis of ( )-Gingkolide B
In the synthesis of precursor of Octalactins
Tetrahedron Lett. 1999, 40, 2685
Tetrahedron Lett. 1995, 36, 7189 12
13. In the synthesis of marine alkaloid ( )-Fasicularine
In the synthesis of nucleoside analogues
Cl
N N
H H H
N N
O OH (1) O OH (3) O
(2)
O O O
(1) PPH 3 + DEAD, 4-NO2 -C 6H 4CO2 H, Toluene (2) K2CO3 , MeOH
(3) PPH 3 + DEAD, 6-chloropurine, THF
J. Am. Chem. Soc. 2000, 122, 4583
Eur. J. Org. Chem. 2005, 1444 13
14. In the synthesis of (-)-Rosmarinecine
O
OH O
HO2C
PPH 3 + DEAD
+ MeO2C
N THF, 0 °C N
MeO2C
O O
O
HO OH O
H H
OH CO 2Me
N N O
(-)- rosmarinecine
Org. Lett. 2001, 3, 1367 14
15. Lactonisation
-Me group produces steric effect shifts equilibrium
towards ‘a’ Retention product
J. Org. Chem. 2003, 68, 1176 15
16. Macrolactonisation
In the synthesis of (+)-Amphidinolide
In the synthesis of Mibemycin-β3
Org. Lett. 2006, 8, 3987
J. Am. Chem. Soc. 2001, 123, 765 16
17. (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
O OH O
OH O
BnO PPh 3 + DIAD BnO
+
OBn
OBn
Tetrahedron Lett. 2003, 44, 3609 17
18. Synthesis of dendrimeric structure
CO2 Me CO2 Me
OH
PPh 3 + DIAD
THF
HO OH O O
c
LiAlH4 PPH 3 + DIAD + c
THF
CO2 Me
O O
more branched structure O O
O O
J. Org. Chem. 2004, 69, 7363 18
19. Synthesis of fluoroalkyl/fluoroaryl glycosides
OBn OBn
PPh 3 + DIAD
O CF3CH 2OH O
BnO BnO
BnO OH Toluene BnO OCH 2CF3
OBn OBn
Alkylation of L-Ascorbic acid
HO PPh3 + DEAD HO
HO O ROH HO O
O O
THF + DMF
HO OH RO OH
R= Me, n-propyl, allyl
HO
HO O
O
O O
Ph 3P
Carbohydr. Res. 1999, 318, 171
J. Org. Chem. 2000, 65, 911 19
20. (b) Etherification with cyclization
Intramolecular Mitsunobu reaction results in cyclic product
Generally 3-7 member ring formation is prefered
TPP + DEAD
HO(CH 2)nOH (CH 2)n O
Synthesis of benzopyran
O2N OH PPh 3+DEAD O2N
OH THF O
Synthesis of fused ring system
n -Bu3P+TMAD
OH O
OH Benzene
J. Org. Chem. 1998, 63, 4116
Tetrahedron Lett. 1996, 37, 2463 20
21. Synthesis of Dihydrobenzoxazepin-5-one
OH
O
OH
PPh 3+DEAD/Et3N
N N
O O
O NH-cy cl-C6 H11 O NH-cy cl-C6H11
Synthesis of excitatory amino acid analogues
Org. Biomol. Chem. 2006, 4, 4236
Synlett 2006, 2407 21
22. Synthesis of chiral substituted morpholine
derivatives
NPhth NPhth
OH OH O
PPh3 + DIAD
N N
Toluene
Cl Cl
Cl Cl
Synthesis of (+)-Catechin
OH
HO OH
OH OH
OH PPh3 + DEAD OH
HO OH HO O
THF
OH OH
Synlett 2006, 2151 22
23. (C) N-Alkylation
Amines, Amides and Azides can act as nucleophiles
Nucleophiles : Phthalimides , Nucleobasides, suitably protected amino acid
moieties or HN3
Synthesis of Antifungal compounds
S S
N OH PPh 3+DEAD N OH
N N N N
N N N N N N
N
F
H N N DMF N
F N N
OH
F F
Tetrahedron Lett. 1994, 35, 1847-1850
Chem. Abstr. 2003, 139, 3379 23
24. In the synthesis of HIV inhibitor
NO2 NO2
Mitsunobu
OH +
N O N -alkylation N O
O
N CN N CN
H
O
pyrrolidine
NO2
N O
N CN
HO
N
Chem. Abstr. 2005, 144, 6778 24
25. Synthesis of Catenanes
O O
N N
O O
O O
PPh3 + DEAD
HN NH + O O THF
O O
O O
OH HO
O O
N N
O O
O O
O O O O
N N
O O
Org. Lett. 2000, 2, 449 25
26. In the synthesis of (+)-vinblastine
NH(R) R
OTMS N OTMS
OH
n- Bu 3P + TMAD CO2Me
Toluene
N CO2Me N
Boc OMOM Boc OMOM
OH
Et
N
H N
H
N Et
H 2C
MeO OH
N OAc
H
CO2 Me
Org. Lett. 2007, 9, 4737 26
27. In the synthesis of Clavizepine
analogue
Org. Chem. 2006, 71, 3963 27
28. Synthesis of cyclic nucleoside analogues
Synthesis of Adenosine antagonist
O O N
NH N
N
N N
Mitsunobu N -alkylation
N N
N N N N
Tetrahedron 2003, 59, 6493 28
29. In the synthesis of Tyrosine kinase inhibitors
OBn OBn
O
Cl + Mitsunobu Cl O
HN
N OH N-alkylation N N
N O N
O
Chem. Abstr. 2006, 144, 390946
OBn
29
30. In the synthesis of Serotonergic agent
O
Br O Ph Mitsunobu
H N
N CF3 N-alkylation
O O +
S O
MeHN
HO
O
Ph O
N O
O Ph
N
Br
N CF3 N CF3
O O O O
S O S O
MeHN MeHN
Chem. Abstr. 1996, 125, 300820 30
Notes de l'éditeur
Custom animation effects: spotlight text(Intermediate)To reproduce the text effects on this slide, do the following:On the Home tab, in theSlides group, click Layout, and then click Blank.On the Insert tab, in the Text group, click Text Box, and then on the slide, drag to draw the text box. Enter text in the text box and select the text. On the Home tab, in the Font group, do the following:In the Font list, select Arial Black.In the Font Size box, enter 50.Click Bold. On the Home tab, in the Paragraph group, click Center to center the text in the text box.Select the text box. Under Drawing Tools, on the Format tab, in bottom right corner of the WordArt Styles, click the Format Text Effects dialog box launcher. In the Format Text Effects dialog box,click Text Fill in the left pane, select Gradient fill in the Text Fill pane, and then do the following: In the Type list, select Linear.Click the button next to Direction, and then click Linear Down (first row, second option from the left).Under Gradient stops, click Add or Remove until two stops appear in the drop-down list.Also under Gradient stops, customize the gradient stops that you added as follows:Select Stop 1 from the list, and then do the following:In the Stop position box, enter 0%.Click the button next to Color, and then under Theme Colors click Black, Text 1, Lighter 35% (third row, second option from the left).Select Stop 2 from the list, and then do the following: In the Stop position box, enter 100%.Click the button next to Color, and then under Theme Colors click Black, Text 1 (first row, second option from the left).Also in the Format Text Effects dialog box,click 3-D Format in the left pane, and then do the following in the 3-D Format pane:Under Bevel, click the button next to Top, and then under Bevel click Circle (first row, first option from the left). Next to Top, in the Width box, enter 10 pt, and in the Height box, enter 2.5 pt.Under Depth, click the button next to Color, and then select Automatic. Under Contour, click the button next to Color, click More Colors, and then in the Colors dialog box, on the Custom tab, enter values for Red: 68,Green: 113,Blue: 166. In the Sizebox, enter 0.5 pt.Under Surface, click the button next to Material, and then under Standard clickMetal (fourth option from the left). Click the button next to Lighting, and then under Neutral click Contrasting (second row, second option from the left). In the Angle box, enter 75°.Under Drawing Tools, on the Format tab, in the WordArt Styles group, click Text Effects, point to Reflection, and then under Reflection Variations click Half Reflection, touching (first row, second option from the left).Drag the text box above the middle of the slide.On the Home tab, in the Drawing group, click Arrange, point to Align, and then do the following:Click Align to Slide.Click Align Center.To reproduce the background effects on this slide, do the following:Right-click the slide background area, and then click Format Background. In the Format Background dialog box, click Fill in the left pane, select Gradient fill in the Fill pane, and then do the following:In the Type list, select Radial.Click the button next to Direction, and then click From Center (third option from the left).Under Gradient stops, click Add or Remove until two stops appear in the drop-down list.Also under Gradient stops, customize the gradient stops that you added as follows:Select Stop 1 from the list, and then do the following:In the Stop position box, enter 0%.Click the button next to Color, and then under Theme Colors click White, Background 1, Darker 5% (second row, first option from the left).Select Stop 2 from the list, and then do the following: In the Stop position box, enter 100%.Click the button next to Color, and then under Theme Colors click Black, Text 1, Lighter 35% (third row, second option from the left). To reproduce the shape effects on this slide, do the following:On the Home tab, in the Drawing group, click Shapes, and then under Basic Shapes click Oval (first row, second option from the left). On the slide, drag to draw an oval.Select the oval. Under Drawing Tools, on the Format tab, in the Size group, do the following:In the Shape Height box, enter 1.1”. In the Shape Width box, enter 2.31”.With the oval still selected, on the Home tab, in the bottom right corner of the Drawing group, click the Format Shape dialog box launcher. In the Format Shape dialog box, click Fill in the left pane, select Gradient fill in the Fill pane, and then do the following:In the Type list, select Radial.Click the button next to Direction, and then click From Center (third option from the left).Under Gradient stops, click Add or Remove until three stops appear in the drop-down list.Also under Gradient stops, customize the gradient stops that you added as follows:Select Stop 1 from the list, and then do the following:In the Stop position box, enter 0%.Click the button next to Color, and then under Theme Colorsclick White, Background 1 (first row, first option from the left).In the Transparency box, enter 21%.Select Stop 2 from the list, and then do the following: In the Stop position box, enter 51%.Click the button next to Color, and then under Theme Colorsclick White, Background 1 (first row, first option from the left).In the Transparency box, enter 73%.Select Stop 3 from the list, and then do the following: In the Stop position box, enter 100%.Click the button next to Color, and then under Theme Colorsclick Black, Text 1 (first row, first option from the left).In the Transparency box, enter 100%.Under the Drawing Tools, on the Format tab, in the Shapes Styles group, do the following:Click the arrow next to Shape Outline, and then click No Outline.Click Shape Effects, point to Soft Edges,and then click 25 Point.On the slide, drag the oval until it is centered on the first letter in the text box.To reproduce the animation effects on this slide, do the following:On the Animations tab, in the Animations group, click Custom Animation.On the slide, select the oval. In the CustomAnimation task pane, do the following:Click AddEffect, point to Entrance, and then click More Effects. In the Add Entrance Effect dialog box, under Subtle, clickFade.Select the animation effect (fade entrance effect for the oval). Under Modify: Fade, do the following:In theStart box, selectWith Previous.In the Speed box, select Fast. On the slide, select the oval. In the CustomAnimation task pane, do the following:Click AddEffect, point to Exit, and then click More Effects. In the Add Exit Effect dialog box, under Subtle, clickFade.Select the second animation effect (fade exit effect for the oval). Click the arrow to the right of the animation effect, and then click Timing. In the Fade dialog box, on the Timing tab, do the following:In theStart list, selectWith Previous.In the Delay box, enter 4.In the Speed list, select 1 seconds (Fast). On the slide, select the oval. In the CustomAnimation task pane, do the following:Click AddEffect, point to Entrance, and then click More Effects. In the Add Entrance Effect dialog box, under Subtle, clickFade.Select the third animation effect (fade entrance effect for the oval). Click the arrow to the right of the animation effect, and then click Timing. In the Fade dialog box, on the Timing tab, do the following:In theStart list, selectWith Previous.In the Delay box, enter 5.In the Speed list, select 1 seconds (Fast). On the slide, select the oval. In the CustomAnimation task pane, do the following:Click AddEffect, point to Exit, and then click More Effects. In the Add Exit Effect dialog box, under Subtle, clickFade.Select the fourth animation effect (fade exit effect for the oval). Click the arrow to the right of the animation effect, and then click Timing. In the Fade dialog box, on the Timing tab, do the following:In theStart list, selectWith Previous.In the Delay box, enter 7.In the Speed list, select 1 seconds (Fast). On the slide, select the oval. In the CustomAnimation task pane, do the following:Click AddEffect, point to Motion Paths, and then click Right. Select the fifth animation effect (motion path for the oval). Click the arrow to the right of the animation effect, and then click Effect Options. In the Fade dialog box, do the following:On the Effect tab, under Path, select Auto-reverse.On the Timing tab, do the following:In theStart list, selectWith Previous.In the Delay box, enter 0.In the Speed list, select 2 seconds (Medium).In the Repeat list, select 2.On the slide, select the motion path. Point to the endpoint (red arrow) of the motion path until the cursor becomes a two-headed arrow, press and hold SHIFT, and then drag the endpoint to the center of the last letter in the text box.