Di-(-)-(1R,2S)-2-phenyl-1-cyclohexyl Diazenedicarboxylate

[206359-91-3]  · C26H30N2O4  · (434.53)

(reagent used as a chiral azo-enophile in asymmetric azo-ene reactions)

Alternate Name: (1R-{1a[E(1R*,2S*)],2b})-Bis(2-phenylcyclohexyl) diazenedicarboxylate.

Physical Data: [a]D -56.9 (c 0.65, CHCl3).

Solubility: soluble in CH2Cl2, diethyl ether, and most organic solvents.

Form Supplied in: yellow oil.

Analysis of Reagent Purity: 1H NMR, IR, TLC, elemental analysis.

Preparative Methods: The title reagent is prepared1 by reaction of (1R, 2S)-2-phenyl-1-cyclohexanol with excess phosgene in the presence of quinoline to afford a chloroformate which is treated directly with hydrazine monohydrate (0.5 equiv) to afford di-(-)-(1R, 2S)-2-phenyl-1-cyclohexyl diazanedicarboxylate. Oxidation of the diazanedicarboxylate to the diazenedicarboxylate is then readily effected using N-bromosuccinimide and pyridine (1).

Purification: flash chromatography using hexane-ethyl acetate (9:1) as eluent.

Handling, Storage, and Precautions: store in closed vessels under an inert atmosphere in the refrigerator. Protect from light.

Azo-ene reactions

The ene reaction1 provides a powerful method for C-C bond formation with concomitant activation of an allylic C-H bond. A variety of functionalized carbon skeletons can be constructed due to the range of enophiles which can be used. For example, carbonyl compounds give homoallylic alcohols2 and imino derivatives of aldehydes afford homoallylic amines.3 The azo-ene reaction offers a method for effecting allylic amination by treatment of an alkene with an azo-diester to afford a diacyl hydrazine which upon N-N cleavage furnishes a carbamate. Subsequent hydrolysis of the carbamate provides an allylic amine. Use of chiral diazenedicarboxylates provides a method for effecting stereoselective electrophilic amination.

Lewis acid-mediated ene reaction of di-(-)-(1R,2S)-2-phenyl-1-cyclohexyl diazenedicarboxylate with cyclohexene using tin(IV) chloride in dichloromethane at -60 °C for 5 min afforded the azo-ene adduct in 80% yield after purification by flash chromatography (2).4 The 1H NMR spectrum of the azo-ene adduct recorded at 380 K in deuterated toluene established the presence of only one diastereomer. Further analysis of the ene adduct by HPLC on a Whatman Partisil 5 normal phase silica column using hexane-ethyl acetate (9:1) as eluent confirmed the presence of only one diastereomer.

Use of cyclopentene, trans-hex-3-ene and trans-oct-4-ene afforded the ene adducts in good yield with a diastereomeric excess of 86:14 in each case. The diastereoselectivity observed using di-(-)-(1R,2S)-2-phenyl-1-cyclohexyl diazenedicarboxylate as a chiral azo-enophile offered a significant improvement over the use of di-(-)-menthyl azodicarboxylate where the level of asymmetric induction achieved in Lewis acid-mediated ene reactions with simple alkenes was not impressive.5 Moreover, it proved difficult to cleave the N-N bond in the menthyl ester azo-ene adducts whereas sodium/liquid ammonia was used to smoothly cleave the N-N bond in the diacylhydrazine adducts formed using di-(-)-(1R,2S)-2-phenyl-1-cyclohexyl diazenedicarboxylate as azo-enophile.

The absolute stereochemistry at the newly formed stereogenic carbon of the major diastereomer of the ene adduct can be predicted by analysis of the transition model for the ene reaction (3). The (1R,2S)-2-phenyl-1-cyclohexyl chiral auxiliary adopts a chair conformation with equatorial placement of the bulky phenyl group. Complexation of the carbonyl group to the Lewis acid affords the more stable s-trans conformation about the C-N sigma bond. In this conformation, the phenyl group shields the Nb-re-face. Therefore the cyclic alkene preferentially attacks from the less hindered Nb-si-face. Ene reaction proceeds through a six-membered cyclic transition state affording the (1R)-diastereomer of the ene adduct.

Related Reagents.

The synthesis of chiral diazenedicarboxylates as potential chiral electrophilic aminating agents has received little attention. A series of chiral bornyl, isobornyl and menthyl diazenedicarboxylates has been reported6 and their reaction with achiral enolates of esters and N,N-dimethyl amides afforded a-hydrazino acid derivatives with little or no selectivity. Incorporation of a chiral azodicarboxamide unit into a chiral bridging binaphthyl moiety afforded a-hydrazino acid derivatives with high stereoselectivity in reactions with achiral oxazolidinone anions.7

1. Snider, B. B. Ene Reactions with Alkenes As Electrophiles, in Comprehensive Organic Synthesis, Trost, B. M., Ed.; Pergamon: Oxford, 1991, Vol. 5, p1.
2. (a) Snider, B. B. The Prins and Carbonyl-Ene Reactions, in Comprehensive Organic Synthesis, Trost, B. M., Ed., Pergamon: Oxford, 1991, Vol. 2, p 527; (b) Mikami, K.; Shimizu, M., Chem. Rev. 1992, 92, 1021.
3. Borzilleri, R. M.; Weinreb, S. M., Synthesis 1995, 4, 347.
4. Brimble, M. A.; Lee, C. Y. K., Tetrahedron: Asymmetry 1998, 9, 873.
5. Brimble, M. A.; Heathcock, C. H.; Nobin, G. N., Tetrahedron: Asymmetry 1996, 7, 2007.
6. Harris, J. M.; Bolessa, E. A.; Mendonca, A. J.; Feng, S.-C.; Vederas, J. C., J. Chem. Soc. Perkin Trans. 1 1995, 1945.
7. Harris, J. M.; McDonald, R.; Vederas, J. C., J. Chem. Soc. Perkin Trans. 1 1996, 2669.

Margaret A. Brimble

The University of Auckland, Auckland, New Zealand

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