Utilization of the Sterically Hindered Base, 4-Hydroxy-2,2,6,6-tetramethylpiperidine, as a Hydrogen Halide Acceptor George Sosnovsky and Maria Konieczny* Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, USA Z. Naturforsch. 33 b, 792-796 (1978); received March 17, 1978 Dehydrobromination, Preparation of Alkenes, Quaternization of Amines, Sterically Hindered Bases, 4-Hydroxy-2,2,6,6-tetramethylpiperidine The synthetic utility of the sterically hindered base, 4-hydroxy-2,2,6,6-tetramethyl- piperidine (1) as a hydrogen halide acceptor was studied. HINSKT"^^ 3 3 H3C | CH3 ' RN(CH ) F H 1 2 It was shown that base 1 can be effectively used in the quaternization reaction of primary aliphatic and aromatic amines to give the corresponding trimethylammonium iodides 2 in 88-98% yield. Base 1 was used also as the dehydrobrominating agent of alkyl and cyclo- alkyl bromides to give the corresponding unsaturated compounds in 82-95% yield. A. Exhaustive Methylation 0! Amines propylaniline [6], and 1,2,2,6,6-pentamethylpiper- idine (PMP) [1, 2, 6] have been utilized in the Over the years, methods have been developed exhaustive alkylation reactions of primary amines. for the preparation of quaternary ammonium com- The organic bases are superior to inorganic bases, pounds, which are important as organic inter- such as, sodium hydroxide due to the ease of sep- mediates, detergents, insecticides, bacteriostats, aration of by-products and lack of complicated side and drugs [1, 2]. The most common method for reactions under the milder reaction conditions. preparation of these compounds is by alkylation Sommer et al. [6] have shown that, in order to be of tertiary amines [3, 4]. Primary and secondary an effective hydrogen halide acceptor, the base amines have also been quaternized, albeit less fre- which is utilized should fulfill four criteria. quently [3, 4], due to the harsh reaction conditions which are often required. In order to prepare qua- 1) In order to attain homogeneous reaction con- ternary ammonium compounds from primary a- ditions, the organic base should have solubility mines, methods have been developed to minimize characteristics similar to those of the primary unwanted side reactions and to increase the yields amines and the alkylating agents. [3, 4]. Since the reaction of a primary amine with 2) It must possess a pKa larger than the reacting an alkylating agent, such as, an alkyl halide, results amines, in order to combine preferentially with the in the formation of a hydrogen halide, various amine hydrogen halide released. hydrohalide salts will be formed as by-products, 3) The alkylation of the base should proceed at a thereby complicating the reaction. In order to sup- rate significantly slower than that of the amines to press the side reactions, various bases, such as be quaternized. sodium hydroxide [3], 2,6-lutidine [5], 1,6-lutidine 4) The by-product hydrohalide salt of the organic [5], triethylamine [5], tri-w-butylamine [6], dicyclo- base must be readily separable from the quaternary hexylamine [6], N,N-diethylaniline [6], N,N-di-w- ammonium product. Now we wish to report that the sterically hindered 4-hydroxy-2,2,6,6-tetramethylpiperidine (1), with its pKa of 10.05 [7] is a readily available, stable, Requests for reprints should be sent to Professor Dr. G. Sosnovsky, Department of Chemistry, University inexpensive and effective hydrogen halide acceptor of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, in the quaternization reaction of primary aliphatic USA. and aromatic amines [8]. The hydroxypiperidine 1 * Present address: The Ben May Laboratory for Cancer is prepared via the sodium borohydride reduction Research, The University of Chicago, Chicago, Illinois, USA. of triacetoneamine (4-oxo-2,2,6,6-tetramethylpiper- Gr. Sosnovsky-M. Konieczny • 4-Hydroxy-2,2,6,6-tetramethylpiperidine as Hydrogen Halide Acceptor 793 ^OH HÖH J-CH3 • RNH2 • 3 CH3I -OME • 2 H3C4D;CH3 • RNCH3)3R CH-J HOC Ä CHO ! 3 R = alkyl. aryl 3 J X- (x= n 1 idine) [9]. The latter compound, in turn, is prepared lower than in the presence of base 1. The yield of by the condensation of acetone with ammonia in the quaternary ammonium iodide of m-nitroaniline the presence of anhydrous calcium chloride [10-12]. increased to 83% on prolonging the reaction time Because of the solubility characteristics of the to three days. It appears that, in the case of very products and by-products (see Experimental), the weak bases, i. e., the pK of p-aminobenzoic acid is quaternary ammonium iodides 2 can be easily 2.36 [13] and the pK of m-nitroaniline is 2.6 [13], separated from the by-product, 4-hydroxy-2,2,6,6- dimethylformamide, the solvent, acts as the accep- tetramethylpiperidinium hydrogen iodide (3). The tor of the hydrogen iodide. This action on the part products 2 were obtained in 88-89% yield after of dimethylformamide is not without precedent, twenty hours at room temperature in dimethyl- since it was noted [14] that solutions of alkyl halides formamide (DMF) as solvent. Although the reaction in DMF undergo slow but significant dehydrohal- of the amines with methyl iodide in the presence ogenation on standing at room temperature. The of 1 is exothermic, the reaction mixture was left to results of the quaternization reactions of primär}*- stand overnight in order to insure complete reaction amines with methyl iodide in dimethylformamide and/or allow for total precipitation of product(s). in the presence and absence of base 1 are listed in Blank reactions, i. e., alkylation of the amines in Table I. dimethylformamide in the absence of base 1 were also made, in order to study the effectiveness of B. Dehydrohalogenation of Alkyl Bromides [8] base 1. In the case of w-butylamine, aniline, 2- Recently, considerable interest has been shown methyl-2-aminopropanol, and propanolamine, the in the utilization of sterically hindered bases in the yields of quaternary ammonium iodides 2 were low, synthesis of alkenes via the corresponding alkyl i. e., 10-14%. However, in the case of 35-amino- halides [1, 2, 5, 6, 20]. The bicyclic bases, 1,5-diaza- benzoic acid and m-nitroaniline, in the absence of bicyclo[4,3,0]non-5-ene (DBN) and 1,8-diazabi- base 1, after twenty hours in dimethylformamide, cyclo(5,4,0)undec-7-ene (DBU) [21, 22] initially the yield of 3 was 50% and 40%, respectively. became known as dehydrohalogenating agents, i. e., Although substantial, the yields were nevertheless hydrogen halide acceptors, in the syntheses of Table I. Quaternization of primary amines with methyl iodide in dimethylformamide in the presence and absence of base 1. RNH- PMF CH3I RN(CH3)3F 3 <x= 1} 2 Amine Yield [%] m.p. [°C] lit. m.p. Yield [%] Yield [%] of 2 in m.p. [°C] RNH2 2 (dec) [°C] 3 (X = I)a the absence of 1 (dec) (blank reaction) n-Butylamine 88 222-223 223-225 [5] 93 10 222-223 2-Amino-2-methyl- 1-propanol 92 240 b 93 10 240 2 - Aminoethanol 91 265 266 [15] 94 14 262-263 Aniline 90 227-228 228 [16, 17] 99 14 227-228 4-Aminobenzoic acid 98 236-238 238 [18] 93 50 236-238 3-Nitroaniline 98 207 198 [19] 95 40 207 (83)= a The m.p. of 3 was in the range 279-284 °C. Anal. Calcd. for C9H20INO: C 37.90; H 7.07; N 4.91. Found: C 37 98 • H 7.19- N 4 85. b Anal'. Calcd. for'C7Hi8INO: C 32.45; H 7.00; N 5.41. Found: C 32.28; H 6.98; N 5.26. c 3 days. 794 Gr. Sosnovsky-M. Konieczny • 4-Hydroxy-2,2,6,6-tetramethylpiperidine as Hydrogen Halide Acceptor 794 vitamin A. Subsequently, these bases have been Experimental applied to condensation reactions, rearrangements, Materials: All reagents were of the best quality and as catalysts in the synthesis of macromolecules commercially available. 4-Hydroxy-2,2,6,6-tetra- [20]. In view of the utility of 4-hydroxy-2,2,6,6- methylpi peri dine (1) was prepared by the sodium tetramethylpiperidine (1) as a hydrogen halide borohydride reduction reaction [9] of triacetone- acceptor in the exhaustive methylation reaction amine [10-12]. Dimethylformamide and dimethyl sulfoxide were dried over a molecular sieve (Linde of primary amines, we attempted to apply 1 also as a 4 Ä). dehydrohalogenating agent for the conversion of All melting points are, alkyl halides to alkenes. Analytical procedures: actually, decomposition points, and are uncorrected. Now we wish to report that sterically hindered Microanalyses were performed on a F & M Scientific amine 1 can be effectively used as a dehydrohalo- Corporation Carbon, Hydrogen, Nitrogen Analyzer, genating agent for the conversion of allylic (3- Model 185. An Aerograph 1700 dual column gas Chromatograph was used. The following overall bromocyclohexene), primary (1-bromoheptane, 1- conditions were maintained: injector temperature, bromooctane), and secondary (cyclohexylbromide) 185 °C; detector temperature, 200 °C; bridge alkyl bromides to the corresponding olefins. Di- current, 150 ma; sample size, 5 pi\ with the appro- priate attenuations. The column used was 20% H^OH HJH 1 2 Carbowax 20 M on 60/80 mesh acid washed Chroma- R CH,CHR -QMSSL» R1CH=CHR2 HjC-f^-f-CHj H3C-IJ-CH3 sorb W, 6 ft by 1/4 in. Analyses were performed iso- H3C/^CH3 Br H3C | CH3 thermally at 100 °C, with a flow rate of 60 ml of H H He/min. All identifications of products were made r1, 2 = alkyl,cyc|oalkyl,H R by the comparison of retention times and peak 3 (X=Br) enhancement ("spiking") with authentic samp- methyl sulfoxide (DMSO) was used for the reac- les.