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One Pot Conversion of Alcohols to Amines

Synth Commun 30(12), 2233-2237 (2000)

Abstract:

A convenient and efficient one pot sequence has been developed for the transformation of alcohols to amines using sodium azide and triphenylphosphine in CCl4-DMF.

Amines are a versatile class of compounds used frequently in organic synthesis, especially in the construction of heterocyclic compounds1. Therefore, transformation of alcohols to amines is an important reaction for the synthesis of a variety of organic compounds. The most common approach for their preparation involves a three steps protocol: a) conversion of alcohols to corresponding halides or sulfonates, b) nucleophilic substitution by azide anion2 and c) reduction of azide to amine by using various reagents3.

Alternatively they can be prepared by a two step methodology : a) conversion of alcohol to azide by Mitsunobu reaction using hydrazoic acid, triphenylphosphine and diethylazodicarboxylate (DEAD)4, b) reduction of azide to amine.

Although these methods works well, extra time is required to isolate intermediate products and leading to low overall yields, and involves the risk of handling explosive azides. In view of this, there is a need to develop one pot sequence. Altough there is a report of one pot method5 involving the combination of Mitsunobu and Staudinger reactions, it is less attractive as it involves the usage of toxic and expensive reagents like HN3 and DEAD respectively. Herein, we report a novel, facile one-pot protocol for the conversion of alcohols to azides/amines using NaN3 and PPh3 in CCl4-DMF (1:4).

Treatment of alcohols with NaN3 and two equivalents of PPh3 in CCl4-DMF(1:4) at 90C afforded amines in an excellent yields (85-95%). Formation of amines may be visualized as the initial azide formed would react with second equivalent of Ph3P giving the iminophosphorane which in turn converted to the amine upon treatment with water. Treatment of alcohols with one molar equivalent of Ph3P afforded azides exclusively in good yields confirming the azide intermediacy. This reaction has general applicability, the results obtained with various primary and secondary alcohols are summarized in table-1. The reaction of primary alcohols was completed within 4-6 hrs, whereas secondary alcohols required longer times (8-10 hrs). All the compounds were characterised and found to be in accordance with authentic samples.

Experimental:

A mixture of alcohol (2 mmol), sodium azide (2.4 mmol) and PPh3 (4.2 mmol) in 10 ml of CCl4-DMF (1:4) was warmed at 90C with stirring. After total disappearance of starting material (monitored by TLC), reaction mixture was brought to RT and quenched by adding 5 ml of water. After stirring for 10 min., reaction mixture was diluted with ether (25 ml) and washed thoroughly with water. By trituration of ether fraction at 0C, triphenylphosphineoxide was crystallized out and ether was filtered off. Dried over anhydrous Na2SO4, filtration and concentration of solvent afforded amines almost in pure form, which were passed through a short pad of silica gel to give pure amines.

In summary, we developed a facile and efficient one pot methodology for the conversion of alcohols to azides/amines by using readily available, cheap reagents. The major advantages of the present work are neutral reaction conditions and can be used for acid and base sensitive substrates, avoids multisteps and hazardous reagents, and offers a practical alternative to the earlier methodologies.

 

References

  1. E.C.B. Barbara, in: The chemistry of the Amino Group, Patai, S. (ed.), Wiley-interscience, London, 1968, chap 6
  2. Rolla, F. J., Org. Chem. 47 4327 (1982)
  3. Suzuki, H, Takaoka, K, Chem Lett 1733 (1984)
  4. Loibner, H, Zbiral, E, Helv Chim Acta 59, 2100 (1976)
  5. Fabiano, E, Golding, B.T., Sadeghi, M.M., Synthesis 190 (1987)

One-pot Conversion of Primary Alcohols to Amines

J. Chem. Research (S), 1989, 296-297

Although primary amines can be obtained from the corresponding alkyl halides by a variety of methods, only a few of these1 allow these compounds to be prepared directly from alcohols by a one-pot procedure. Recent approaches to this problem1,2 based on the Mitsunobu reaction, suffer from commercially inaccessible reagents and/or rather tedious work-ups. The method now reported judiciously combines several known reactions.

Having convincingly established the utility of transforming alkyl bromides into amines by a one-pot procedure involving the Staudinger reaction3, attention was focused upon a conversion of alcohols into bromides and/or chlorides which would then be suitable for use in this reaction without the need for isolation. Treatment of the alcohols with triphenylphosphine-tetrahalogenomethane was chosen as a reasonable approach to this problem, the reagent system triphenylphosphine-carbon tetrachloride having previously been proved very versatile for the conversion of alcohols into alkyl chlorides4. However, the relatively low reactivity of chlorides in comparison with bromides in the subsequent azidation step was discouraging. Replacement of carbon tetrachloride by bromotrichloromethane seemed a feasible method for increasing thc proportion of the more reactive bromides in the halogenated material. Moreover, in this new three-component system, Ph3P-CBrCl3 ROH, the formation of undesirable side-products, i.e. dichloromethylene- phosphorane, chloromethylene-phosphorane, and chloromethyltriphenyl phosphonium chloride, should be less than in the Appel system5 which involves only carbon tetrachloride. The combination of triphenylphosphine and bromotrichloromethane, but with different stoichiometry, has been successfully used for the preparation of dichloromethylidene-phosphoranes6. The third conceptually promising possibility of converting alcohols into the corresponding alkyl bromides by means of the two-component system carbon tetrabromide-triphenylphosphine was disqualified because of the formation of bromoform which on subsequent azidation could possibly afford highly explosive gem-diazides7 as undesirable side-products.

Table 1

Conversion of alcohols R-CH2OH (1) into
amines (6) and ammonium tosylates (7)
Amine R Isolation
Variant
Amine
Yield
Tosylate
Salt m.p.
6a n-C5H11
A
61%
125-126°C
6b PhCH2
A
78%
175-176°C
6c Ph
B
65%
178-180°C
6d p-MeO-Ph
B
43%
201-202.5°C
6e Me2CHCH2
B
61%
96-97°C
6f n-C7H15
C
71%
127-128°C
6g n-Bu(Et)CH
C
67%
62-65°C

 

The effectiveness of an equimolar mixture of triphenylphosphine and bromotrichloromethane in the first step of the devised one-pot sequence depicted in the Scheme was corroborated experimentally. The mixtures of the alkyl bromides and chlorides (2) formed by the action of this reagent system on the primary alcohols (1) were then subjected to azidation and subsequent Staudinger reaction with triethyl phosphite according to the previously described procedure3. The crude iminophosphorane intermediates (4) were hydrolysed by refluxing with 20% hydrochloric acid and the solutions of the amine hydrochlorides (5) were made alkaline with sodium hydroxide. The free amines (6) were formed in good overall yields (60-70%) and characterized as their crystalline ammonium toluene-p-sulphonates. Attempts at using this procedure for converting secondary alcohols into the corresponding amines were unsuccessful: the amines were formed in very low yields (e.g. cyclohexylamine, 11%; 3-aminohexane, 21.5%) even when the azidation time was prolonged to 12 h and the amount of tetrabutylammonium bromide was increased to 10 mol%.

Experimental:

The mixture of primary alcohols (1) (0.03 mol), triphenylphosphine (8.65 g, 0.033 mol), bromotrichloromethane (6.54 g, 0.033 mol), and benzene (10 ml) was refluxed gently with stirring for 2 h. It was then cooled to room temperature and, after addition of sodium azide (3.9 g, 0.06 mol), tetrabutylammonium bromide (0.48 g, 5 mol %), and dimethylformamide (10 ml), refluxed again with stirring for 6 h. The resultant mixture was then poured into water (100 ml) and extracted with benzene (2x10 ml). The organic phase was dried (MgSO4) and treated with triethyl phosphite (5.0 g, 0.03 mol) at 25-30C for 2 h. After this solution had been stood overnight at room temperature, 20% hydrochloric acid was added and the mixture was refluxed with stirring for 2 h.

The free amine was isolated and purified by one of the following variants.

Variant A - for low-molecular-weight, water-insoluble amines (6a), (6b)

The aqueous phase was separated, made strongly alkaline with solid sodium hydroxide, and steam-distilled. The distillate was salted out, extracted with diethyl ether (4x15 ml), and evaporated using a short Vigreux column to avoid undesirable losses of amine.

Variant B - for water-soluble amines (6c), (6d), (6e)

The aqueous phase was separated, decolorized with charcoal, made strongly alkaline with solid sodium hydroxide, and extracted with diethyl ether (5x15 ml). The extract was dried (Na2SO4) and evaporated.

Variant C - for higher-molecular-weight, water-insoluble amines (6t), (6g)

Benzene was evaporated from the hydrolysate and the volatile impurities were steam-distilled from the acidic solution. The solution was made strongly alkaline with solid sodium hydroxide and steam-distilled again. The distillate was extracted with diethyl ether (4x15 ml), dried (Na2SO4), and evaporated.

The free amines (6) were treated with equimolar amounts of para-toluenesulphonic acid in ethanol. Crystalline ammonium para-toluenesulphonates (7) were precipitated with diethyl ether and purified by dissolving in a small amount of ethanol and then reprecipitating with an excess of diethyl ether. The yields of the free amines (6) and the mp's and analytical data of the ammonium para-toluenesulphonates (7), are compiled in the Table.

 

References

  1. E. Fabiano, B. T. Golding, and M. M. Sadeghi, Synthesis, 1987, 190 and references cited therein.
  2. E. Slusarska and A. Zwierzak, Liebigs Ann. Chem., 1986, 402.
  3. A. Koziara, K. Osowska-Pacewicka, S. Zawadzki, and A. Zwierzak, Synthesis, 1985, 202.
  4. I. M. Downie, J. B. Lee, and M. F. S. Matough, J. Chem. Soc., Chem. Commun., 1968, 1350 and references cited therein.
  5. R. Appel, Angew. Chem., Int. Ed. Engl., 1975, 14, 801.
  6. B. A. Clement and R. L. Soulen, J. Org. Chem., 1976, 41, 556; G. Burton, J. S. Eldler, S. C. M. Fell, and A. V. Stachelski, Tetrahedron Lett., 1988, 3003.
  7. A. Hassner and M. Stern, Angew. Chem., Int. Ed. Engl., 1986, 25,478.