Significant interest has developed in recent years in the application of iminophosphoranes for various synthetically useful transformations, especially those affording C=N bond possessing compounds, which are usually referred to as aza-Wittig reactions¹. Although numerous articles have appeared on the reactions and synthetic applications of N-alkyl(aryl)triphenyliminophosphoranes², the preparative utility of analogous aza-ylides, viz. N-allyltriethoxyiminophosphoranes is almost unexplored³. Recently, we reported the one-pot preparation of N-alkyltriethoxyiminophosphoranes from alkyl bromides by azidation followed by Staudinger reaction⁴ and the application of these compounds for the synthesis of primary amines⁵. Herein we describe a route for the synthesis of secondary amines beginning with the parent alkyl bromides and employing a facile construction of the final carbon skeleton via the aza-Wittig reaction between N-alkyltriethoxyiminophosphoranes and aldehydes. Secondary amines are synthesized by the variety of methods, the reduction of imines being a very convenient and explicit route⁶. Difficulties which may be sometimes encountered in this approach are due to the properties of some imines which are unstable and therefore not easily accessible in pure state. We decided to overcome this disadvantage by preparing the respective imines under mild conditions and use them for reduction without isolation and purification. The synthetic protocol illustrating the construction of secondary amine skeleton from two simple building blocks - alkyl bromide and aldehyde is presented in the Scheme.

Azidation of alkyl bromides was performed for 3 hours at the reflux temperature of the solvent system, using a 100% excess of sodium azide. Benzene solution of crude alkyl azides 1 afforded N-alkyl- triethoxyiminophosphoranes 2 when treated with triethyl phosphite at 25-30°C.

Isolation and purification of these aza-Wittig reagents was neither necessary nor recommended. Neat 2 are extremely sensitive to traces of moisture and hydrolyze easily to diethyl N-alkylphosphoramidates which may then contaminate the target compounds. Benzene solution of 2 reacted easily with aliphatic and aromatic aldehydes to give the imines 3. If one followed the course of this reaction by ³¹P-NMR, the practically complete conversion of 2 to 3 was observed after 3 hours at room temperature. Due to the exothermic nature of this reaction, all reactions were started at 0-5°C and then run at 20-25°C.

The crude imines 3 were not isolated but immediately reduced with sodium borohydride in methanol to form the target secondary amines 4. The amines were purified by steam distillation and characterized as corresponding hydrochlorides 5. This methodology can be used to prepare a number of secondary amines as shown in Table 1. The range of substrates in Table 1 demonstrates the clear utility of this synthetic procedure in preparing a variety of secondary amines in moderate to good yields. Best results were obtained when benzaldehyde and primary alkyl bromides were used as starting materials. The overall yields of 5 were inevitably lower (entry 6 and 7) with easily enolizable butyraldehyde as carbonyl substrate, possibly due to base-promoted (by strongly basic 2) aldol condensation as a side reaction.

Although secondary alkyl bromides could be easily converted into the corresponding iminophosphoranes 24, the aza-Wittig reactions of the latter were totally ineffective (entry 8).

It is well known that reaction of azides with tertiary phosphines gives iminophosphoranes¹, useful intermediates for the synthesis of a variety of nitrogen compounds² including imines³. As part of our program on the photochemistry of some allyl imines, we directed our efforts toward their efficient preparation. Now we wish to report an effective one-pot synthesis of imines directly from alkyl bromides via azide intermediates under the conditions of the Staudinger reaction in acetonitrile.

Scheme 1

The literature reports a great number of procedures for the synthesis of alkyl azides by the nucleophilic substitution of bromide with sodium azide⁴. To obtain a corresponding imine, isolated alkyl azides are generally treated with triphenylphosphine and a carbonyl compound in a nonpolar solvent such as benzene³. Those procedures are usually too complex and so we decided to find a short, simple, and efficient method.

Acetonitrile was found to be a very practical solvent in both steps: azidation and imine formation. Thus, both steps were combined without necessity to isolate and purify any intermediate (Scheme 1). Reactive primary bromides were refluxed with an excess of sodium azide in acetonitrile. Sodium bromide and the remaining sodium azide were easily filtered off from the cooled reaction mixture because both salts are insoluble in cold acetonitrile. Since aliphatic nonyl bromide did not afford nonyl azide under those conditions, a small amount of water or a phase-transfer catalyst were used to enhance the reactivity. The presence of a phase-transfer catalyst raised the conversion, however, the reaction time was too long (over 50 hours). Reflux of the acetonitrile solution with triphenylphosphine and an aldehyde afforded the corresponding imine in a very high yield and purity (Table 1). Reaction of cinnamyl bromide provided imine with only 70% purity - some unidentified byproducts were formed. When ketone instead of aldehyde was used a longer reaction time in the second step was applied bat the conversion was still too low.

The described one-pot procedure offers relatively high overall yields and thus may serve as an helpful sequence in many procedures whom the synthesis of imines is anticipated.