Mitsunobu reaction
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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.
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Mitsunobu reaction
- 1. Mitsunobu reaction and its application By Mohammad Mohsin Qadri 1
- 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
Editor's Notes
- 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.