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

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. tions, which were rapid, i. e., complete within four hours at elevated temperatures. In the same period of time, dimethylformamide was a much less effec- Reaction of amines with methyl iodide in the absence of 4-hydroxy-2,2,6,6-tetramethylpiperidine (1). Blank tive solvent, since only a trace amount of olefin Reaction was formed, as determined by gas chromatography. General procedure: A solution of the amine The olefins were obtained in 82-95% yield follow- (0.01 mol) and methyl iodide (5.68 g, 0.04 mol) in ing isolation by distillation from the reaction mix- dimethylformamide (20 ml) was left to stand at ture. Also formed as by-product in the reaction room temperature for 24 h. The mixture was concentrated on a rotating evaporator at 25-30 °C/ was the hydrobromide of I (3, X = Br) in nearly 0.2-0.5 torr. Acetone and diethyl ether were added quantitative yield. The results of these reactions to induce precipitation of the quaternary ammo- are listed in Table II. nium compounds 2 listed in Table I.

Table II. Dehydrobromination of alkyl bromides in DMSO in the presence of 4-hydroxy-2,2,6,6-tetramethyl- piperidine (1). Preparation of alkenes.

1 2 R1CH-CHR2 1 DMSO R CH=CHR • 3 (X = BR) 2I Br

R1, R2 = alkyl. cycloalkyl.H

a Alkyl bromide Yield [%] b.p. [°C] WD lit. njo> Yield [%] m.p.of 3, (X—Br) alkene (torr) 3 [°C]

1 -Bromoheptane 82 90-93 1.3981 1.3998 (20 °C)[23] 89 311-312 (760) 1-Bromooctane 93 120-123 1.4079 1.4084 (25 °C) [24] 95 310-312 (760) Cyclohexyl bromide 83 80-83 1.4483 1.4481 (25 °C)[25-27] 98 309-313 (760) 3-Bromocyclohexene 95 80-83 1.4751 1.4758 (25 °C) [28, 29] 97 311-312 (760)

a Anal. Calcd. for C5H20BrNO: C 45.39; H 8.46; N 5.88. Found: C 45.55; H 8.39; N 5.79. Gr. Sosnovsky-M. Konieczny • 4-Hydroxy-2,2,6,6-tetramethylpiperidine as Hydrogen Halide Acceptor 795

Preparation of n-butyl trimethylammonium iodide Preparation of phenyl trimethylammonium iodide (2, R = n-C^Hy) (2,i? = C6#5) To a suspension of 1 (3.14 g, 0.02 mol) and n- To a suspension of 1 (3.14 g, 0.02 mol) and aniline butylamine (0.73 g, 0.01 mol) in dimethylformamide (0.93 g, 0.01 mol) in dimethylformamide (20 ml) (20 ml) was added slowly with shaking and cooling was added slowly with shaking and cooling the the methyl iodide (5.68 g, 0.04 mol). During the methyl iodide (5.68 g, 0.04 mol). During the addi- addition, the reaction mixture became homogeneous. tion, the reaction mixture became homogeneous, On cooling, a solid separated and after 20 h at room and then heterogeneous once again. Following the temperature, the mixture was filtered. The solid addition, the reaction mixture was left to stand at was washed with acetone to give 3 (X = I; 2.04 g). room temperature for 20 h. The mixture was filtered The combined filtrates were concentrated on a to give a solid. The solid was washed with acetone rotating evaporator at 30 °C/0.2-0.5 torr, and the to give 3 (X = I; 1.12 g). The combined filtrates remaining crude solid was boiled in acetone and were concentrated on a rotating evaporator at filtered to give an additional amount of 3 (X = I; 25-30 °C/0.2-0.5 torr. Acetone was added to the 3.23 g). The total yield of 3 was 93% (5.27 g; m.p. remaining solid, and the mixture was filtered to give 281-282 °C). The acetone filtrate was concentrated additional 3 (X = I; 4.56 g). The total yield of 3 was on a rotating evaporator at 25 °C/10-15 torr to give 99% (5.68g; m.p. 282-283 °C). The filtrate was crude 2 (R = W-C4H9). The solid was washed with concentrated on a rotating evaporator at 25 °C/ ether and recrystallized from acetone/ether to give 10-15 torr to give crude 2 (R = C6H5). The solid 2.10 g (88%) of 2 (R = W-C4H9), m.p. 222-223 °C; was washed with ether and cold acetone to give lit. [5] m.p. 223-225 °C. 2.35 g (90%) of 2 (R = C6H5), m.p. 227-228 °C; lit. [16, 17] m.p. 228 °C. Preparation of the trimethylammonium iodide of 2-amino-2-methyl-l-propanol [(1,1-dimethyl- 2-hydroxyethyl) trimethylammonium iodide] Preparation of 4-carboxyphenyl trimethylammonium iodide (2, R = 4-COOH-C^H4) (2,R = C(CH3)2CH2OH) To a suspension of 1 (3.14 g, 0.02 mol) and To a suspension of 1 (3.14 g, 0.02 mol) and p- aminobenzoic acid (1.37 g, 0.01 mol) in dimethyl- 2-amino-2-methyl-l-propanol (0.89 g, 0.01 mol) in formamide (15 ml) was added rapidly with shaking dimethylformamide (10 ml) was added slowly with the methyl iodide (5.68 g, 0.04 mol). The reaction shaking and cooling the methyl iodide (5.68 g, mixture was left, with occasional shaking, at room 0.04 mol). The reaction mixture did not become temperature for 24 h. A homogeneous solution homogeneous. After 20 h at room temperature, the eventually resulted. The solution was concentrated reaction mixture was filtered to give a solid. The on a rotating evaporator at 25-30 °C/ 0.2-0.5 torr. solid was washed with a small amount of cold The solid was dissolved in boiling acetone. Diethyl acetone to give 2 (R = C(CH3)2CH2OH; 2.37 g, ether was added to precipitate 2 (R=4-COOH-CeH4; 92%) m.p. 240 °C. The combined filtrates were 3.01 g, 98%), m.p. 236-238 °C; lit. [18] m.p. 238 °C. concentrated on a rotating evaporator at 25-30 °C/ The filtrate was concentrated on a rotating evapo- 0.2-0.5 torr. The remaining solid was washed with rator at 20-25 °C/10-15 torr. The remaining solid acetone to give 3 (X = I; 5.28 g, 93%), m.p. 279 to was washed with ether to give 3 (X = I; 5.29 g, 281 °C. 93%), m.p. 282-284 °C. Preparation of (2-hydroxyethyl) trimethylammonium iodide (2, R = CH2CH2OH) Preparation of 3-nitrophenyl trimethylammonium To a suspension of 1 (3.14 g, 0.02 mol) and iodide (2, R = 3-NO^C6H4) 2-aminoethanol (0.61 g, 0.01 mol) in dimethylform- To a suspension of 1 (3.14 g, 0.02 mol) and 3- amide (10 ml) was added rapidly with shaking the nitroaniline (1.38 g, 0.01 mol) in dimethylformamide methyl iodide (5.68 g, 0.04 mol). The reaction (15 ml) was added rapidly with shaking the methyl mixture was left, with occasional shaking, at room iodide (5.68 g, 0.04 mol). Following the addition, temperature for 24 h. A homogeneous solution the reaction mixture was left, with occasional resulted, followed by precipitation of a small amount shaking, at room temperature for 20 h. The mixture of crystalline material. The reaction mixture was eventually became homogeneous, then heteroge- concentrated on a rotating evaporator at 25-30 °C/ neous once again. The mixture was concentrated on 0.2-0.5 torr. The solid was boiled in acetone and the a rotating evaporator at 25-30 °C/0.2-0.5 torr. The mixture filtered to give 3 (X = I; 5.38 g, 94%), remaining solid was boiled in acetone and the m.p. 280-282 °C. The filtrate was concentrated on a mixture filtered to give 2 (R = 3-N02-C6H4; 3.02 g, rotating evaporator at 25-30 °C/10-15 torr. The 98%), m.p. 207 °C; lit. [19] m.p. 198 °C. The filtrate remaining solid was washed with ether, then was concentrated on a rotating evaporator at recrystallized from acetone/ether to give 2 25 °C/10-15 torr. The solid was washed with cold (R = CH2CH2OH; 2.10 g, 91%), m.p. 265 °C; lit. acetone and ether to give 3 (X = I; 5.42 g, 95%), [15] m.p. 266 °C. m.p. 282-284 °C. Gr. Sosnovsky-M. Konieczny • 4-Hydroxy-2,2,6,6-tetramethylpiperidine as Hydrogen Halide Acceptor 796

Dehydrobromination of alkyl bromides in DMSO in The pot residue was concentrated on a rotating the presence of 4-hydroxy-2,2,6,6-tetramethylpiperidine evaporator at 25-30 °C/0.2-0.5 torr. The remaining 1). Preparation of alkenes solid was treated with acetone and ether, and the mixture filtered to give the hydrobromide 3 (X = Br) General procedure: A mixture of alkyl bromide (0.1 mol) and 1 (15.7 g, 0.1 mol) in dimethylsulfoxide in the yields indicated in Table II. (50 ml) was boiled with reflux for 4 h in a flask fitted with a condenser cooled by a mixture of dry ice and Dehydrobromination of cyclohexyl bromide in DMF isopropyl alcohol. Dining this time, the reaction in the presence of 4-hydroxy-2,2,6,6-tetramethyl- mixture became homogeneous, then heterogeneous piperidine (1) once again. The mixture was allowed to cool, then As described in the general procedure, a mixture the flask was fitted with a distillation setup. of cyclohexyl bromide (16.3 g, 0.1 mol) and 1 (15.7 g, Heating was resumed, and the alkenes listed in 0.01 mol) in dimethylformamide (50 ml) was re- Table II were collected in a receiver chilled by a dry fluxed for 4 h, then allowed to cool. Gas chromato- ice/isopropyl alcohol bath. The products were graphic analysis of the reaction mixture indicated checked by gas chromatography for purity and for that only trace amounts of cyclohexene had formed authenticity by comparison of retention times with during this time. commercial samples. All alkenes obtained in this This investigation was supported by a grant from manner were found to be pure, i.e., giving a single the Graduate School of the University of Wisconsin- peak by gas chromatography. Milwaukee.

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