An Exploration of a-Cyanocinnamate as a Replacement for DEAD in the Mitsunobu Reaction Trey W. Olson (Faculty Mentor: David E. Lewis) Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, WI 54702, U.S.A.

Introduction Our Traget Transformation Our Potential Solution

• We are seeking to prepare ylide OH CN O H O R OH R O nitriles from with Ph3P R’ R’ R’ R’ inversion of configuration at 1 2 1 2 R O Ph3P O Ph3P O Ph3P O R R R R R CN CN CN CN the carbinol carbon. R1 O R1 O H R2 • This can be accomplished 2 NC OH DEAD, Ph P, KCN CN R Ph3P O by: 3 1 2 Et O-CH Cl 1 2 • (a) the Mitsunobu reaction with R R 2 2 2 R R O R’ potassium cyanide. R O

• (b) initial conversion of the NC R1 to the tosylate, followed by OH 1) TsCl, py CN dosplacement of the sulfonate by R2 NC cyanide anion. R1 R2 2) KCN, EtOH, Δ R1 R2 • Both these methods involve a the use of hazardous • The -cyanocinnamate esters are readily prepared by the cyanide anion. Doebner reaction between the aromatic and ethyl cyanoacetate in with ammonium acetate. • These esters have an electron-deficient double bond that will react like DEAD with to give a zwitterion Hazards of the Mitsunobu intermediate. • The b- position of the original is now positioned to Reaction generate a very stabilized phosphorus ylide. • We expect this ylide to react with the alcohol to give the DEAD alkylated cyanoacetate, which will then react with cyanide anion in a reaction that generates cyanide ion.

SAFETY DATA SHEET SAFETY DATA SHEET DIETHYL DIAZENE-1,2-DICARBOXYLATE DIETHYL DIAZENE-1,2-DICARBOXYLATE • We have now completed the synthesis of ethyl E-a-cyano- Page: 1 Page: 2 • The Mistunobu reaction was first reported by Oyo Compilation date: 15/09/2008 H315: Causes skin irritation. Revision date: 30/09/2014 H319: Causes serious eye irritation. 3,4-dimethoxycinnamate and ethyl E-a-cyano-2-chloro- Revision No: 3 H335: May cause respiratory irritation. Signal words: Mitsunobu in the Bulletin of the Chemical Society of Japan in Section 1: Identification of the substance/mixture and of the company/undertaking Danger Hazard pictograms: GHS01: Exploding bomb 1.1. Product identifier cinnamate from the corresponding . GHS07: Exclamation mark 1967, with a follow-up review in Synthesis in 1981. Product name: DIETHYL DIAZENE-1,2-DICARBOXYLATE CAS number: 1972-28-7 EINECS number: 217-821-7 • We have begun our preliminary explorations of the reaction Product code: OR2868 Precautionary statements: P210: Keep away from heat/sparks/open flames/hot surfaces. - No smoking. Synonyms: DIETHYL AZODICARBOXYLATE P261: Avoid breathing vapours. • A recent literature search using Web of Science reveals that P280: Wear protective gloves/protective clothing/eye protection. DIETHYL AZODIFORMATE E a Label elements under CHIP: using 2-octanol and ethyl - -cyano-3,4-dimethoxycinnam- DEAD Hazard symbols: Harmful. between them, these two papers have amassed over 5,000 1.2. Relevant identified uses of the substance or mixture and uses advised against 1.3. Details of the supplier of the safety data sheet ate, with diethyl malonate as the starter nucleophile. Company name: Apollo Scientific Ltd citations. Units 3 & 4 Risk phrases: R5: Heating may cause an explosion. Parkway R20/21/22: Harmful by inhalation, in contact with skin and if swallowed. Denton R36/37/38: Irritating to eyes, respiratory system and skin. Manchester Safety phrases: S16: Keep away from sources of ignition - No smoking. • The reaction proceeds by coupling the desired SN2 M34 3SG S23: Do not breathe vapour. MeO CHO MeO CO2Et MeO CO2Et UK S26: In case of contact with eyes, rinse immediately with plenty of water and seek NCCH2CO2Et MeI, K2CO3 Tel: 0161 337 9971 medical advice. substitution with an exothermic redox reaction and Fax: 0161 336 6932 S36/37/39: Wear suitable protective clothing, gloves and eye / face protection. AcOH, NH4OAc CN acetone, Δ CN Email: [email protected] S63: In case of accident by inhalation, remove casualty to fresh air and keep at rest. HO HO MeO

1.4. Emergency telephone number 2.3. Other hazards Δ dehydration. Other hazards: Heating may cause an explosion. Section 2: Hazards identification PBT: This substance is not identified as a PBT substance. 2.1. Classification of the substance or mixture Section 3: Composition/information on ingredients Cl Cl Classification under CHIP: -: R5; Xn: R20/21/22; Xi: R36/37/38 3.1. Substances The formation of the phosphoryl (P=O) group provides much Classification under CLP: • Self-react. A: H240; Acute Tox. 4: H302+312+332; STOT SE 3: H335; Eye Irrit. 2: H319; CHO NCCH CO Et CO2Et Skin Irrit. 2: H315 Chemical identity: DIETHYL DIAZENE-1,2-DICARBOXYLATE 2 2 Most important adverse effects: Heating may cause an explosion. Harmful by inhalation, in contact with skin and if CAS number: 1972-28-7 of the driving force for the reaction. swallowed. Irritating to eyes, respiratory system and skin. EINECS number: 217-821-7 AcOH, NH4OAc CN 2.2. Label elements Section 4: First aid measures Δ Label elements under CLP: 4.1. Description of first aid measures Hazard statements: H240: Heating may cause an explosion. Skin contact: Remove all contaminated clothes and footwear immediately unless stuck to skin. H302+312+332: Harmful if swallowed, in contact with skin or if inhaled. Drench the affected skin with running water for 10 minutes or longer if substance is still [cont...] on skin. Consult a doctor. Mechanism of the Mitsunobu Reaction [cont...]

Ph Ph Ph P O O O O O EtO N EtO N EtO N EtO N Is There a Way to Avoid the Use of N OEt N OEt N OEt N OEt Future Directions O O PPh3 OH PPh3 OH 2 H O R R2 • We will continue our preliminary examination of this P O H Both DEAD and Cyanide? Ph Ph H H Ph R1 Nu 1 R1 R2 H R Nu H reaction. • We will explore the effects of the aromatic ring substituents • The ideal reagent should: on the course of the reaction O OH H 1. Be of relatively low toxicity. • We will determine the stereochemistry of the reaction using EtO N EtO N N OEt N OEt 2. Be relatively non-volatile. a chiral alcohol of known configuration. H O OH 3. React with triphenylphosphine to generate a zwitterionic R2 H intermediate capable of reacting with the alcohol, in a manner R1 Nu similar to DEAD. 4. Maintain a low level of free cyanide anion in situ. Acknowledgments • The reaction is the method of choice for the conversion of 5. Generate low-toxicity or recyclable by-products. primary or secondary alcohols to substitution products with • It would be especially nice if the triphenylphosphine could inversion of configuration. also be replaced, but this is not viable at this time. We are happy to acknowledge the financial support of the University of • The reaction works best when the pKa of H—Nu is below 12. Wisconsin-Eau Claire Office of Research and Sponsored Programs