Chemistry 125: Lecture 68 April 14, 2010 Mitsunobu Reaction Acids and Acid Derivatives This For copyright notice see final page of this file

Teleology Lectures (4/16,19) Topics from Chapters Acid Derivatives and Condensations Lecture 71 (4/21) Topics from Ch Carbohydrates Lecture 72 (4/23, 26? ) guest lecture(s) by Prof. Ziegler Carbohydrates - Fischer's Proof of the Configuration of Glucose Lecture 73 (4/28) Synthesis of an Unnatural Product (Review) (Anti-Aromatic Cyclobutadiene in a Clamshell) Lecture 74 (4/30) Synthesis of a Natural Product (Review) (Woodward's Synthesis of Cortisone)

Table 1 Reactions companies use now but would strongly prefer better reagents Amide formation avoiding poor atom economy reagents 6 votes OH activation for nucleophilic substitution 5 votes Reduction of amides without hydride reagents 4 votes Oxidation/Epoxidation methods without the use of chlorinated solvents 4 votes Friedel-Crafts reaction on unactivated systems 2 votes Nitrations 2 votes “Key green chemistry research areas - a perspective from pharmaceutical manufacturers” Green Chemistry, 2007, 9, Research Area Number of roundtable companies voting for this research area as a priority area Safer and more environmentally friendly Mitsunobu reactions 3 votes

Very general for acidic Nu-H (pK a < 15) e.g. R-CO 2 - (RO) 2 PO 2 - (RCO) 2 N - N 3 - “active methylene compounds” Mitsunobu Reaction Nu - Ph 3 P O R Ph 3 P O R Nu C 61% yield >99% inversion great leaving group pK a = 13 (enolate nucleophile) HO COOH C epimers? -CO 2 C C Oyo Mitsunobu ( ) H AcO (R) H HO (R) - OH OH H (S) Mitsunobu Inversion Allows correcting a synthetic “mistake”! O. Mitsunobu Synthesis (1981)

Mitsunobu Mechanism O. Mitsunobu Synthesis (1981) Nu - Ph 3 P O R Ph 3 P O R Nu great leaving group Ph 3 P H OR -3 need an oxidizing agent Diethylazodicarboxylate (DEAD) H+H+ (reduced DEAD) Eliminating H 2 O (18 m.wt.) generates 450 m.wt. of by-products. “atom inefficient” but separable only by chromatography! unless hooked to polymer beads Three Nucleophiles “tuned” just right H OR 2

Acidity of RCO 2 H (p. 836) Making RCO 2 H by Oxidation and Reduction (sec. 17.6)

RCOO-H to RCOO-R’ (p. 848) Activating RCO 2 H (sec. 17.7b,d,e) making OH a leaving group

GREEN H Milstein et al., J.A.C.S. 127, (2005) H O-CH 2 -R H H H O-C-R H Catalytic Formation of Ester + H 2 Another oxidation involving removal of an H from RCHO and one from another RCH 2 OH, plus C-O coupling, completes 2 R-CH 2 -OH  R-CO 2 -CH 2 R + 2H 2 with no other activation! H H H H H 3

Milstein et al., J.A.C.S. 127, (2005) Catalytic Formation of Ester + H 2 Thermochemistry of 2 EtOH  AcOEt + 2 H 2 HfHf HOEt -66.1±0.5 x ±1.0 AcOEt ±0.2 H 2 0  H rxn 17.4 endothermic! K 3/2 RmT  10 -1/  need p H 2 > atm

Also Amines Milstein et al., Angew. Chem. IEE. 17, 8661 (2008) Imines, Amides, etc.

Oil of Bitter Almonds Benzoic Acid O2O2

Air Oxidation of Benzaldehyde Cf. sec a

R-Li & LiAlH 4 (sec. 17.7f) stop at C=O?

End of Lecture 68 April 14, 2010 Copyright © J. M. McBride Some rights reserved. Except for cited third-party materials, and those used by visiting speakers, all content is licensed under a Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0).Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0) Use of this content constitutes your acceptance of the noted license and the terms and conditions of use. Materials from Wikimedia Commons are denoted by the symbol. Third party materials may be subject to additional intellectual property notices, information, or restrictions. The following attribution may be used when reusing material that is not identified as third-party content: J. M. McBride, Chem 125. License: Creative Commons BY-NC-SA 3.0