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A Convergent One-Pot Synthesis of Secondary Amines via Aza-Wittig Reaction

Synth. Commun. 22(13), 1929-1938 (1992)


Secondary amines are obtained in moderate-good yields by reduction of crude imines prepared from N-alkyltriethoxyiminophosphoranes and aldehydes via the aza-Wittig reaction. N-Alkyltriethoxyiminophosphoranes are synthesized by one-pot azidation of alkyl bromides followed by Staudinger reaction.

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 25-30C.

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 0-5C and then run at 20-25C.

Table 1.
Preparation of secondary amine hydrochlorides 5

EntryRR'Yield*mp (solvent)
1 PhCH2CH2Ph77%259.5-261C (95% EtOH)
2 C6H13Ph80%214-215C (acetone)
3 CH2=CH-CH2Ph85%138-139C
4 PhCH2CH2i-Pr75.5%239-240C
5 C6H13i-Pr62% 236-238C (dec.)
6 PhCH2CH2Pr40% 215-218C (dec.)
7 C6H13Pr32% 248-250C (dec.)
8 sec-BuPr19%196-197C

* Overall yield of crude 5 calculated on alkyl bromide

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).



Unless otherwise stated, all solvents and reagents were purchased from commercial suppliers and used without further purification. Aldehydes were freshly distilled before use. Melting points were determined in open capillaries and are uncorrected. All new compounds gave satisfactory elemental analyses data. Infrared spectra were measured using a Specord M80 (C. Zeiss) instrument, and NMR spectra were recorded at 80 MHz with a Tesla BS 587FT spectrometer. All amine hydrochlorides exhibited IR and NMR spectra in accord with the expected structures.

Preparation of Secondary Amine Hydrochlorides 5; General Procedure:

A suspension of finely powdered sodium azide (6.5 g, 0.1 mol) in the mixture of alkyl bromide (0.05 mol), benzene (15 mL), and dimethylformamide (15 mL) was refluxed gently with stirring for 3 h. In the case of allyl bromide azidation should be carried out at 35-40C for 6 h. The product was cooled to room temperature and poured into cold water (200 mL). The organic layer was separated. The aqueous layer was extracted with benzene (3x15 mL); the extracts were combined with the organic phase, dried (MgSO4), and filtered. Triethyl phosphite (8.3 g, 0.05 mol) was added dropwise with stirring to a benzene solution of crude alkyl azide 1. The temperature of the slightly exothermic reaction was kept at 25-30C for 4 h and the product was left overnight at room temperature. Benzene solution of N-alkyltriethoxyiminophosphorane 2 such prepared was added dropwise with stirring and occasional external cooling (ice-water bath) to a solution of freshly distilled aldehyde (0.05 mol) in benzene (5 mL) at 0-5C. After the addition had been completed the mixture was stirred for 3 h at 20-25C. Benzene solution of crude imine 3 was then evaporated under reduced pressure end the residue was diluted with methanol (100 mL). Sodium borohydride (1.9 g, 0.05 mol) was added portion-se with stirring to the resultant solution and the temperature was kept below 30C. The mixture was then left at room temperature far 24 h, evaporated under reduced pressure and diluted with water (50 mL). The solution was made strongly alkaline With an excess of 50% aqueous sodium hydroxide and steam distilled. The distillate was acidified with 25% hydrochloric avid and evaporated to dryness. Crude amine hydrochloride 5 was dried in vacuo over P2O5 and crystallized from the suitable solvent (see Table 1). When the amine could not be distilled with steam (entry 1) the crude reduction product after evaporation of methanol was steam distilled to remove volatile contaminants.

The residue was made alkaline and extracted with ether (3x50 ml). The extracts were evaporated, the residue was treated with 25% hydrochloric acid (10 mL), and evaporated to dryness to give crude 5. Analytically pure samples were obtained by recrystallization from ethanol-ether unless otherwise stated (see Table 1).



  1. Cadogan, J.I.G. and Mackie, R.K., Chem. Soc. Revs. 3, 131 (1974)
  2. Katritzky, A.R., Jiang, J. and Urogdi, L., Synthesis 565 (1990) and references cited therein.
    1. Leyshon, L.J. and Saunders, O.C., J. Chem. Soc. Chem. Comm. 1608 (1971)
    2. Foster, S.A., Leyshon, L.J. and Saunders, D.C., J. Chem. Soc. Chem. Comm. 29 (1973)
    3. Tsuge, O., Kanemasa, S. and Matsuda, K., J. Org. Chem. 49, 2688 (1984)
  4. Gololobov, Yu.G., Zhmurova, I.N. and Kasukhin, L.F., Tetrahedron 37, 437 (1981)
  5. Koziara, A., Osowska-Pacewicka, K., Zawadzki, S., and Zwierzak, A., Synthesis 202 (1985)

One-Pot Conversion Of Alkyl Bromides Into Imines
Via The Staudinger Reaction

Synth. Commun. 30(8), 1503-1507 (2000)

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A new one-pot procedure for transforming primary alkyl bromides into the corresponding imines via the Staudinger reaction has been developed. Acetonitrile was found to be an excellent solvent for azidation as well as the reaction of organic azide with triphenylphosphine and a carbonyl compound.

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.

Table 1

ProductR1 R2 R3 Yielda
1PhCH2 PhH95% (96%)
2PhCH2 o-NO2-Ph H89% (98%)
3PhCH2 n-Bu H94% (96%)
4PhCH2 PhCH3 35%b
5PhCH=CHCH2 PhH 86% (70%)c
6n-C9H19 PhH 88% (94%)d

a. Yields of isolated compounds (purity shown in the
parenthesis was determined by NMR and/or by GC).
b. Refluxed 48 h after acetophenone addition, the
yield given is imine conversion by 1H-NMR.
c. 30% of unidentified byproducts were formed.
d. Azidation was carried out in wet acetonitrile.

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.


Synthesis of N-Benzyl-N-(phenylmethylidene)amine 1.

A stirred mixture of benzyl bromide (2.0 g, 11.7 mmol) and sodium azide (1.0 g, 15.2 mmol) in dry acetonitrile (30 ml) was refluxed for 3 h and then cooled to 20C Solid sodium bromide and remaining sodium azide were removed by filtration and the benzyl azide solution was used in the next step without further purification.

Triphenylphosphine (2.8 g, 10-5 mmol) was added and the solution was refluxed for 1 h. Freshly distilled benzaldehyde (1.1g, 10.5 mmol) was then added into the mixture and reflux continued for 2 h. Acetonitrile was evaporated in vacuo and the residue was triturated twice with dry hexane (2x40 mL). The solid that precipitated (triphenylphosphine oxide) was removed by filtration and concentration in vacuo gave imine 1. The analytically pure imine was obtained by distillation (Kugelrohr).

Compounds 2, 3, and 5 were prepared according to this procedure from the corresponding bromides and aldehydes. Synthesis of imine 4 was same as above besides that the acetonitrile solution was refluxed for 48 h after the addition of acetophenone.

Synthesis of N-Nonyl-N-(phenylmethylidene)amine 6.

A stirred mixture of nonyl bromide (2.0 g, 9.7 mmol) and sodium azide (0.8 g, 12.6 mmol) in a mixture of acetonitrile (27 ml) and water (3 ml) was refluxed for 12 h. and then cooled to 20C. The water layer was removed and the acetonitrile solution was dried with sodium sulfate. The filtered solution was used in the next step without further purification and was treated with triphenylphosphine and benzaldehyde in the same way as that described in the first procedure.



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    1. Alvarez, S. G. and Alvarez, M. T. Synthesis 413 (1997) and references cited therein.
    2. Ran,, B. C., Sarkar, A, and Chakraborty, R. J. Org. Chem. 59, 4114 (1994)
    3. Koziara, A. and Zwierak, A. Synthesis 1063 (1992)