DEAD/DIAD - More than Simple Mitsunobu Reagents

Biographical Sketches

Arthur Eugen Kümmerle was born in Rio de Janeiro, Brazil, in 1979. He received his degree in Pharmacy (2003) and his M.Sc. in Organic Chemistry (2005) from Universidade Federal do Rio de Janeiro (UFRJ), Brazil. Currently he is in the final stage of his D.Sc. thesis at UFRJ under the supervision of Prof. Eliezer J. Barreiro and Prof. Carlos A. M. Fraga. His research interests focus on the synthesis of N-acylhydrazones and heterocyclic chemistry in the scope of medicinal chemistry aiming at anti-inflammatory and cardiovascular agents.

Introduction

Diethyl azodicarboxylate (DEAD) and diisopropyl azodicarboxylate (DIAD) (Figure  [¹] ), are widely used reagents in organic synthesis.

Figure 1

These are important reagents in the Mitsunobu reaction, [¹] [²] which is a versatile and widely used method for the dehydrative coupling of an alcohol with clean stereogenic inversion and is perhaps the most favorable reaction to invert chiral centers of secondary alcohols. [¹] [²] This kind of reaction can also be applied in aminations, cyclodehydrations, deoxygenations, and in dehydrative alkyl­ations. [³]

Besides the direct association of DEAD/DIAD with the Mitsunobu reaction, [²] there are many other reactions in which these reagents can be applied. For example, DEAD/DIAD are efficient components in Diels-Alder reactions and in click chemistry, [4a] they function as dienophiles in some cycloadditions, [4b] and they can be used in the synthesis of functionalized β-amino alcohols from aldehydes and ketones. [4c] DEAD and DIAD are commercially available or can be prepared in the laboratory in a two-step synthesis from hydrazine, first by condensation with ethyl chloroformate followed by treatment of the resulting ethyl hydrazodicarboxylate with chlorine or fuming nitric acid (Scheme  [¹] ). [5]

Scheme 1

Abstracts

(A) Alkylation can be achieved under Mitsunobu conditions (DEAD + PPh3). This reaction is an important tool in carbocyclic nucleoside chemistry for the direct coupling of alcohols with heterocycles. Ludek and Meier described the influence of the solvent [6a] and the alcohol [6b] utilized on N- vs. O-alkylation of N3-benzoylthymine.
(B) The Mitsunobu reaction can be used to induce cyclodehydratation from hydroxyphenols in good yield and diastereoisomeric excess, giving a new and easy access to cycloalkenobenzofurans. [7]
(C) DEAD can be utilized as dehydrogenation agent as demonstrated in its reaction with 5-alkoxy-8-chloro-2,3,4,6-tetrahydro-1-methyl-4-oxo-3-(2-thienyl)-1H-1,2-diazepino[3,4-b]quinoxaline compounds to give 5-alkoxy-8-chloro-4,6-dihydro-1-methyl-4-oxo-3-(2-thienyl)-1H-1,2-diazepino[3,4-b]quinoxaline compounds. [8]
(D) Cyclobutanone ring-expansion products were obtained in moderate to high yields by treatment of methylenecyclopropanes with DIAD or DEAD in acetonitrile under mild conditions in the presence of a Lewis acid such as Zr(OTf)4. [9]
(E) The selective N-debenzylation of benzylamines with DIAD in THF was achieved in the presence of azido, O-benzyl, and N-tosyl groups in reactions of benzylamines derived from 1,6-anhydro-β-d-glucopyranose. [¹0]
(F) Formal [4+2] cycloadditions were performed by reaction of symmetrically substituted 2,2′-biindole compounds with DEAD to provide 5,5′-dichloroindigo azine derivatives. [¹¹]
(G) The heterocycle ring construction of 2-amino-s-triazino[1,2-a]benzimidazole from 2-guanidinobenzimidazoles was produced by a ring annelation reaction with DEAD in EtOH. [¹²]
(H) DEAD is an efficient reagent in the production of disulfides. A one-pot procedure employing mild conditions was described in which a series of glycosyl disulfides were synthesized in excellent yields. [¹³]
(I) The reaction of aryl diazoacetates with H2O and DEAD catalyzed by dirhodium acetate gives aryl α-keto esters in high yields. [¹4]

References

• 1a Mitsunobu O. Yamada M. Bull. Chem. Soc. Jpn.  1967,  40:  2380 
• 1b Mitsunobu O. Eguchi M. Bull. Chem. Soc. Jpn.  1971,  41:  3427 
• 1c Mitsunobu O. Wada M. Sano T. J. Am. Chem. Soc.  1972,  94:  679 
• 1d Mitsunobu O. Synthesis  1981,  1 
• 2 Nune SK. Synlett  2003,  1221 
• 3 But TYS. Toy PH. Chem. Asian J.  2007,  2:  1340 
• 4a Gassman PG. Mansfield KT. Org. Synth., Coll. Vol. 5  1973,  96 
• 4b Ellis JM. King SB. Tetrahedron Lett.  2002,  43:  5833 
• 4c Chowdari NS. Ramachary DB. Barbas CF. Org. Lett.  2003,  5:  1685 
• 5a Rabjohn N. Org. Synth., Coll. Vol. 3  1955,  375 
• 5b Kauer JC. Org. Synth., Coll. Vol. 4  1963,  411 
• 6a Ludek OR. Meier C. Synlett  2006,  324 
• 6b Ludek OR. Meier C. Synlett  2005,  3145 
• 7 Bertolini F. Bussolo VD. Crotti P. Pineschi M. Synlett  2007,  3011 
• 8 Kim HS. Jeong G. Hyoung CL. Kim JH. Park YT. Okamoto Y. Kajiwara S. Kurasawa Y. J. Heterocycl. Chem.  2000,  37:  1277 
• 9 Shao L.-X. Shi M. Eur. J. Org. Chem.  2004,  426 
• 10 Kroutil J. Trnka T. Čern M. Synthesis  2004,  446 
• 11 Kuethe JT. Davies IW. Tetrahedron Lett.  2004,  45:  4009 
• 12 Dolzhenko AV. Chui W.-K. J. Heterocycl. Chem.  2006,  43:  95 
• 13 Morais GR. Falconer RA. Tetrahedron Lett.  2007,  48:  7637 
• 14 Guo Z. Huang H. Fu Q. Hu W. Synlett  2006,  2486