C-(1-Chloroethyl) N-Cyclohexyl Nitrone1

[37898-42-3]  · C9H16ClNO  · C-(1-Chloroethyl) N-Cyclohexyl Nitrone  · (MW 189.69)

(nitrone precursor of N-cyclohexyl-N-1-propenylnitrosonium cation, i.e. N-alkyl-N-vinylnitrosonium cations1)

Alternate Names: a-(1-chloroethyl) N-cyclohexyl nitrone; a-chloro-N-cyclohexylpropanaldonitrone; N-(2-chloropropylidene-N-cyclohexylamine N-oxide.

Physical Data: mp 73-75 °C.

Solubility: sol ether, ethanol, dichloromethane, 1,2-dichloroethane, liquid sulfur dioxide.

Form Supplied in: not commercially available.

Preparative Methods: by condensation of freshly distilled 2-chloropropanal and N-cyclohexylhydroxylamine in anhydrous ether and dichloromethane in the presence of magnesium sulfate at 0 °C.2a Recrystallization is from a mixture of ether and pentane. N-Cyclohexylhydroxylamine hydrochloride is commercially available and the free base is easily liberated. The simpler aldonitrones, C-chloromethyl N-cyclohexyl and N-t-butyl nitrones, are made by chlorination of the appropriate C-methyl N-alkyl nitrone with N-chlorosuccinimide in carbon tetrachloride at 0 °C.2a

Handling, Storage, and Precautions: may be stored in a freezer under argon, but it slowly becomes yellow on standing at room temperature. For best results it should be used shortly after preparation.

[4 + 2] Cycloadditions.

Eschenmoser and co-workers introduced N-vinyl-N-alkyl-nitrosonium cations as heterodienes in reverse electron demand, Diels-Alder-type [4 + 2] cycloadditions in 1972.2 C-a-Chloroalkyl N-cyclohexyl aldonitrones are the precursors which are treated with Silver(I) Tetrafluoroborate in 1,2-dichloroethane in the presence of a suitable alkene to produce 5,6-dihydro-4H-1,2-oxazin-2-ium tetrafluoroborate cycloadducts (eq 1).2a This salt may be used directly, but the usual workup is with aqueous Potassium Cyanide to give 3-cyanotetrahydro-2H-1,2-oxazines. Exchange to the more stable tetraphenylborates is facile.2a The cycloaddition is regioselective with the oxygen of the N-vinylnitrosonium cation becoming attached to the carbon of the alkene which can best stabilize a positive charge (i.e. Markovnikov's r ule).

These cycloadducts, which may be derived from cyclic and acyclic di-, tri-, and tetrasubstituted alkenes, are useful synthetic intermediates. The preparation of g-lactones is illustrative (eq 22b and eq 33a). The mechanism probably involves base-catalyzed rearrangement of the 3-cyano adduct to an iminolactone by elimination-addition with expulsion of hydrogen cyanide. Acid-catalyzed hydrolysis leads to the products. Propellane lactones have been prepared by this method.4

When C-a,b-dichloroethyl nitrones are used as starting materials, the identical sequence of reactions leads to a-methylene-g-lactones via a 3-cyano-4-chloromethyl adduct (eq 4).3a Other contributions from the ETH laboratories have demonstrated that C-a,b-epoxy nitrones can be used for the same purpose. The reagent used to generate the vinylnitrosonium ion is a trialkylsilyl trifluoromethansulfonate, and the initially formed cyano-protected cycloadduct must be desilylated and converted to a mesylate before further reaction with base (eq 5).5 The nitrone precursors for the reactions outlined in eqs 4 and 5 are easily prepared by condensation of 2,3-dichloropropanal and epoxypropanal, respectively, with N-cyclohexylhydroxylamine.

Intramolecular examples of the epoxy nitrone-alkene reaction are known (eq 6), but further conversion into useful products was not efficient.6 Enol acetates also undergo the cycloaddition.7

When the dihydro-4H-1,2-oxazin-2-ium tetraphenylborate is allowed to react with Potassium Carbonate in dichloromethane (or with Diisopropylethylamine, Hunig's base), proton abstraction occurs to give a 5,6-dihydro-2H-1,2-oxazine which upon heating undergoes electrocyclic ring opening. The imine thus formed can be hydrolyzed, and an important synthesis of unsaturated dicarbonyl compounds is achieved (eq 7). The key feature of this sequence is that a cyclic alkene starting material is oxidatively cleaved (as in ozonolysis) to a product with carbonyl group and an extended alkylidene chain at the original alkenic carbon atoms (carboxolytic cleavage).2a A creative application of this method is the synthesis of a 4-prenylindole from 8-nitro-1,4-dihydronaphthalene.8

Enol ethers have proved somewhat problematic and unwanted side products often appear.9 A bicyclic and several benzobicyclic enol ethers gave low yields of propellane-type nitrile adducts. The major products were keto alcohols thought to be formed from fragmentation of oxonium compounds. Nevertheless, the cycloadduct nitriles underwent further conversions in good yield to form macrocyclic lactones with a formylmethylene appendage.

There are reports of ketone carbonyl groups functioning as heteroenes in [4 + 2] cycloadditions with N-vinylnitrosonium salts.10

The N-vinylnitrosonium salts also undergo facile [4 + 2] cycloadditions with alkynes.3c The first-formed adducts are N-cyclohexyl-4H-1,2-oxazin-2-ium tetrafluoroborates and subsequent hydrolysis affords a,b-unsaturated ketones, a viable alternate route route to these common products (eq 8).

Electrophilic Substitution Reactions.

The N-vinylnitrosonium ions are strongly electrophilic and their interaction with alkenes often leads to substitution in competition with cycloaddition. For example, when the reaction is conducted with trisubstituted alkenes in a highly polar solvent, such as liquid sulfur dioxide, unsaturated nitrones are formed in addition to the dihydro-4H-1,2-oxazinium salts (eq 9).3b The stereochemistry of the alkene is retained. Mild acid hydrolysis of the nitrones affords b,g-unsaturated aldehydes. Similarly, electron-rich aromatic compounds are alkylated and hydrolytic workup affords a-arylaldehydes (eq 10).3b The N-vinyl-N-cyclohexylnitrosonium ion is an a-acyl carbocation equivalent in these reactions. Analogous substitutions were successful with indole and N-methylindole, and they represent abbreviated pathways to C-(3-indolyl-1-ethyl) and C-(3-indolylmethyl) nitrones.11


1. Breuer, E. In Nitrones, Nitronates and Nitroxides; Patai, S.; Rappoport, Z., Eds.; Wiley: New York, 1989; p 189.
2. (a) Kempe, U. M.; Das Gupta, T. K.; Blatt, K.; Gygax, P.; Felix, D.; Eschenmoser, A. HCA 1972, 55, 2187. (b) Das Gupta, T. K.; Felix, D.; Kempe, U. M.; Eschenmoser, A. HCA 1972, 55, 2198. (c) Gygax, P.; Das Gupta, T. K.; Eschenmoser, A. HCA 1972, 55, 2205.
3. (a) Petrzilka, M.; Felix, D.; Eschenmoser, A. HCA 1973, 56, 2950. (b) Shatzmiller, S.; Gygax, P.; Hall, D.; Eschenmoser, A. HCA 1973, 56, 2961. (c) Shatzmiller, S.; Eschenmoser, A. HCA 1973, 56, 2975.
4. Ruttimann, A.; Ginsburg, D. HCA 1975, 58, 2237.
5. (a) Riediker, M.; Graf, W. HCA 1979, 62, 205. (b) Riediker, M.; Graf, W. HCA 1979, 62, 1586. (c) Riediker, M.; Graf, W. HCA 1979, 62, 2053. (d) Riediker, M.; Graf, W. AG(E) 1981, 20, 20.
6. Shatzmiller, S. LA 1982, 1933.
7. Denmark, S. E.; Cramer, C. J.; Dappen, M. S. JOC 1987, 52, 877.
8. Hattingh, W. C.; Holzapfel, C. W.; van Dyk, M. S. SC 1987, 17, 1477.
9. Shalom, E.; Zenou, J.-L.; Shatzmiller, S. JOC 1977, 42, 4213. See also Levinger, S.; Shatzmiller, S. T 1978, 34, 563.
10. (a) Neidlein, R.; Shatzmiller, S.; Walter, E. LA 1980, 686. (b) Hepp, L. R.; Bordner, J.; Bryson, T. A. TL 1985, 26, 595.
11. Holzapfel, C. W.; van Dyk, M. S. SC 1987, 17, 1349.

Norman A. LeBel

Wayne State University, Detroit, MI, USA



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