[CONTRIBUTION FROY
THE SCHOOL OF
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OF
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THE PREPARATION OF SOME C-ALKYLMORPHOLINES' D. L. COTTLE,2 A. E. JELTSCH? T. H. STOUDT;
AND
D. R. WALTERS
Received February 8, IO&
Very few preparations of C-alkylmorpholineshave been reported, although the literature on N-alkyl and arylmorpholines is large. Morpholine itself was first prepared in 1889 by Knorr (1) by dehydration of diethanolamine with 70% sulfuric acid. MBdard (2) studied this dehydration more thoroughly, and obtained morpholine in 90-95% yield by heating diethanolamine with 95% sulfuric acid for 7-8 hours at 175-180". Krasuskii (3) applied this dehydration method to di-isopropanolamine but obtained only 22% yield of 2,6-dimethylmorpholine by heating di-isopropanolamine with 70% sulfuric acid in a sealed tube at 160170' for 8 hours. Payman and Piggott's (4) method involved the condensation of alkylene or arylalkylene halohydrins with aromatic sulfonamides to form Ndi-(8-hydroxyalky1)arylsulfonamides which when treated with sulfuric acid yielded a morpholine and an arylsulfonic acid. The preparation of 2 ,&dimethylmorpholine from 1-chloro-2propanol and p-toluenesulfonamide is recorded by these workers. 3,5-Diphenylmorpholine-2,6-dicarboxylicacid was also prepared, by treating p-chloro-6-phenyl*-hydroxypropionic acid (obtained from phenylglycidic acid and hydrochloric acid) with a sulfonamide and subsequently heating with sulfuric acid. hdams and Cairns (5) prepared the N-arylsulfonamide of 2,2,6 ,6- or 2,2,5,5-tetramethylmorpholineas a by-product of the dehydration of 1-(p-bromobensenesulfonamide)-2-methyl-2-propanolwith phosphorus pentoxide. In the present work, the Preparation of 2-methylmorpholine, 3,3-dimethyImorpholine, 3-ethylmorpholine7 2-methyl-5-ethylmorpholine,and 2-ethylmorpholine are reported. The first four compounds were prepared by dehydration of the corresponding alkanolamines, which were made by addition of the appropriate amino alcohol to an olefin oxide. In the preparation of 2-methylmorwas prepholine, the dialkanolamine, N-/3-hydroxyethyl-l-amino-2-propanol, prepared by the addition of 2-aminoethanol to propylene oxide. In the preparation of 3,3-dimethylmorpholine, the dialkanolamine, N-p-hydroxyethyl-2amino-2-methy1-1-propano1, was prepared by the addition of 2-amino-2-methyl1-propanol to ethylene oxide. The dialkanolamine used in the preparation of 3-ethylmorpholine7N-8-hydroxyethyl-2-amino-1-butanol, was prepared by the addition of 2-amino-1-butanol to ethylene oxide. The dialkanolamine used in 1 The experimental work reported in this paper was done on a volunteer basis in connection with a contract between Columbia University and the Committee on Medical Research of the Office of Scientific Research and Development as a part of their Antimalarial Research program. 2 Present address : Standard Oil Development Company, Esso Laboratories, Elizabeth, New Jersey. * Present address: The Proctor & Gamble Company, Ivorydale 17, Ohio. 4 Now serving with the United States Navy.
286
287
C-ALKYLMORPHOLINES
PREPARATION OF
the preparation of 2-methyl-5-ethylmorpholine,N-/3-hydroxy-n-propyl-2-amino1-butanol, was prepared by the addition of 2-amino-1-butanol to propylene oxide. 2-Ethylmorpholine was prepared by the following series of reactions: (CH,CH0)3 HCI ClCHzCHzOH +
+
+
CH3CHCl-O-CHzCH2Cl
+
CH~CHC~-O-CHZCH~C~ Br2 CH2BrCHBr-O-CH2CH2C1
+
+ H2 0
3
CH2BrCHBr-O-CH2CH2C1 C2H6MgBr
+ HCl
--f
+
CH~B~CH(C~HS)-~-CH~CHZC~ MgBrz CH~B~CH(CZHS)-O-CH~CHZC~ 3CsHE"z +
+
+ C6H6NH3Br+
C6H6NHsC1
/ 0 \
CH2-CHz
CH-
I
\
/NC6Hs CH2
C2HS
0/cH2-cH2
\
CH-CHz
\ NCaHs /
+
"02
-+
I
C2HS
/ 0 \
CHz- CHn
CH-CHz
\ NCJ&-NO-p /
0/CH2-cH2 \
\
CH-CH2
/
NH
+ HzO
+ p-NO-CsKOH
288
COTTLE, JELTSCH, STOUDT, AND WALTERS EXPERIMENTAL
Reagents. The 2-aminoethanol, 2-amino-2-methyl-l-propano1, and 2-amino-1-butanol were supplied generously by The Commercial Solvents Corporation. The ethylene oxide was purified by passing i t through two 4-foot towers filled with crushed sodium hydroxide. The other reagents were from common sources and were used without further purification. Preparation of N-8-hydroxyt:thyl-1-amino-2-propanol. 2-Aminoethanol (1143 g. 18.7 moles) and 765 g. of water (to make a 60% solution) were chilled by ice. To the vigorouslystirred solution, 139 g. (2.4 moles) of propylene oxide was added dropwise. Water and 2aminoethanol were removed by fractionation; the recovered 2-aminoethanol was used in subsequent runs. The dialkanolamine distilled a t 160-175"/35 mm. and was refractionated through a three-bulb Snyder column to give a yield of 268 g., or 94% of a product boiling 163-166'/35 mm.; d,261.042; nbJ 1,4670; Anal? Calc'd for CsHl3NO2: N, 11.76; Mol. Wt., 119.1. Found: N, 11.75; Mol. Wt. (by titration), 120.1. Preparation of I-methylmorpholine. I n a 3-liter 3-necked flask fitted with mercurysealed stirrer, dropping-funnel, and condenser set for distillation was placed 1700 g. of 95% sulfuric acid. To the water-cooled, vigorously-stirred acid, 620 g. (5.2 moles) of N-8hydroxyethyl-1-amino-2-propanol was added through the dropping-funnel. When all was added, the mixture was heated a t 155-165" for ten hours, allowing the water formed to distill. After cooling, a solution of 1530 g. of sodium hydroxide in 2.5 1. of water was added carefully to the acid mixture, and the resulting alkaline solution was extracted with ether in a large continuous extractor for 48 hours. The ether extract was fractionated through a three-bulb Snyder column to obtain 297 g. or 57% yield of 2-methylmorpholine boiling 133-136". The products from several runs were refractionated through an eight-bulb Snyder column to obtain a product boiling at 135136'; di6 0.939; nbJ 1.4454. Anal. Calc'd for C5HnNO: C , 59.40; H, 10.97; N, 13.85; Mol. Wt., 101.1. Found: C, 59.11; H, 10 99; N, 13.42; Mol. Wt. (by titration), 101.8. The phenylthiourea derivativc: and the p-toluenesulfonamide derivative were prepared by standard procedures (6). 'The phenylthiourea derivative melted a t 135.5-136.5" (uncorr.). Anal. Calc'd for CUHIBN~OS: N, 11.91; Found: N, 11.1. The p-toluenesulfonamide derivative melted at 88-89' (uncorr.). Anal. Calc'd for C I ~ H I ~ N ON, ~ E5.49; : Found: N, 4.99. A 60% aqueous solution Preparation of N-8-hydroxyethyl-3-amino-8-methyl-1-propanol. of 1910 g. (24.8 moles) of 2-amino-2-methyl-I-propanol was placed in a 5-1. 3-necked flask fitted with a stirrer and wide inlet tube. To the well-cooled, vigorously-stirred solution, gaseous ethylene oxide, purified as previously described, was passed in until the gain in weight of the flask corresponded to an absorption of 136 g. (3.10 moles) of the oxide. The mixture was then fractionated through a three-bulb Snyder column; the recovered amino alcohol was used in subsequent preparations. The yield of N-~-hydroxyethyl-2-amino-2methyl-I-propanol boiling a t 143--147"/10 mm. was 396 g., or 96%. This product melted a t 60-61" (uncorr.). Anal. Calc'd for CeHlsNOz: C:, 54.10; H, 11.35; K, 10.52; Mol. w t . , 133.2. Found: C, 54.63; H, 11.32; W, 10.14; Mol. Wt. (by titration), 133.9. Preparation of 3,9-dimethylmorpholine. The conditions of Mt5dard (2) were used. Four was slowly hundred grams (3.00 moles) of N-~-hydroxyethyl-2-amino-2-methyl-l-propanol added to 540 g. of 95% sulfuric acid in a water-cooled flask fitted with mercury-sealed stirrer and condenser set for distillation. The vigorously-stirred mixture was heated for 9.5 hours a t 178-180", then cooled, ms,de alkaline with sodium hydroxide solution arid extracted with ether in a large continuous iextractor. The ether extract was fractionated through a three-bulb Snyder column and 266 g., a 77% yield, of 3,3-dimethylmorpholine boiling at 6 All microanalyses were performed by Miss Lois E. May of Columbia University, New York, New York.
PREPARATION OF
CLALKYLMORPHOLINES
289
143-146" was collected. The combined yields of several runs were twice fractionated through a six-bulb Snyder column to give a product boiling a t 143-144"; di: 0.9355; n: 1.4472. Anal. Calc'd for CeHlaNO:C, 62.57; H, 11.38; N, 12.16; Mol. Wt., 115.2. Found: C, 62.76; H, 11.64; N, 11.92; Mol. Wt. (by titration), 115.9. Preparation of N-~-hydroxyethyl-2-amino-l-butanol. This compound was prepared by using 2125 g. the samiB procedure as for N-~-hydroxyethyl-2-amino-2-methyl-l-propanol, (24.0 moles) of 2-amino-1-butanol and 132 g. (3.00 moles) of ethylene oxide. The yield of product boiling a t 138-140"/12 mm. was 363 g. or 91%; d,2: 1.0153; n: 1.4677. Anal. Calc'd for CeHI6NO2:C, 54.10; H, 11.35; N, 10.52; Mol. Wt., 133.2. Found: C, 54.90; H, 11.43; N, 10.03; Mol. Wt. (by titration), 133.2. Prepcsration of 5-ethylmorpholine. This compound was prepared by the same procedure used for 3,3-dimethylmorpholine, using 400 g. (3.00 moles) of N-p-hydroxyethyl-2-amino-lbutanol and 540 g. of 95% sulfuric acid. The yield of 3-ethylmorpholine boiling at 156.5157.5' was 2-48 g., or 72%. On redistillation of the combined fractions from several runs through a six-bulb Snyder column, the fraction 156.5-157.5' was collected as pure product, d l o 0.9556; n: 1.4519. Anal. Calc'd for CBHl3NO:C, 62.57; H, 11.38; N, 12.16. Mol. Wt., 115.2. Found: C, 62.76; H, 11.64; N, 11.92; Mol. Wt. (by titration), 116.0. Preparation of N-~-hydroxy-n-propyl-2-arnino-l-butanol. This compound was prepared by the same procedure used for N-~-hydroxyethyl-l-amino-2-propanol, using 1780 g. (20.0 moles) of 2-amino-1-butanol and 110 g. (2.50 moles) of propylene oxide. The yield of dialkanolandne boiling a t 147.0-152.5"/16 mm. n a s 335 g., or 91%; &: 1.0153; n: 1.4677. Anal. Calc'd for C7H1&02: C, 57.10; H, 11.65; N, 9.51; Mol. Wt., 147.3. Found: C, 57.35; H , 12.15; N, 9.14; Mol. Wt. (by titration), 147.8. Preparation of 2-methyl-6-ethylmorpholine.This compound was prepared by the same procedure used for 2-methylmorpholine, using 147 g. (1.0 mole) of N-p-hydroxy-n-propyl-2amino-1-butanol and 330 g. of 95% sulfuric acid. The time of heating was 12 hours. The yield of 2-methyl-5-ethylmorpholineboiling a t 163-164" was 110 g., or 86%; this product was refractionated through a six-bulb Snyder column to give a product boiling a t 164.5-165.0'; d i t 0.9222; n: 1.4471. Anal. Calc'd for CrHlsNO: C, 65.07; H, 11.70; N, 10.84. Found: C, 64.53; H, 12.35; N, 10.65. Preparation of 1-chloro-1-(p-chloroethoxy)ethane. This preparation was a modification of the ones previously applied to the same substance by Grignard and Purdy (7), who obtained i t in 65y0 yields, and by Summerbell and Umhoefer (S), who obtained a crude yield of 794r0. The yield obtained by the folloning procedure in five runs averaged 68% of a product distilling at 46-48"/10-11 mm. through a five-bulb Snyder column. Dry hydrogen chloride was passed as rapidly as absorption would take place for three hours into a vigorously-stirred mixture of 350 g. (4.36 moles) of ethylene chlorohydrin and 200 g. (1.52 moles) of paraldehyde cooled i,o -10". The resulting upper layer was dried overnight over calcium chloride and fractionated. Preparation of 1,2-dibromo-l-(p-chloroethoxy)ethane. The procedure used was that of Summerbell and Umhoefer (8) except that the bromine was added at room temperature instead of a t 0" because of the slowness of the reaction a t the lower temperature. The yields from six preparations, each involving 2.68 to 3.11 moles of 1-chloro-1-(8-ch1oroethoxy)ethane averaged 82% of a product distilling a t 110-113"/13 mm. through a six-bulb Snyder column. This substance was a powerful lachrymator ,md great care had to be exercised in handling it. Preparation of l-bromo-2-(p-chloroethoxy)butane. The procedure used was a modification of one described by Summerbell and Umhoefer (8). They failed t o heat their reaction mixand obtained a ture of ethylmagnesium bromide and 1,2-dibromo-l-(P-chloroethoxy)ethane yield of 25y0. I n the present work the mixtures were refluxed a t 45-50" for one hour and allowed t o stand 12 hours or longer before hydrolysis. The yields of seven preparations involving 1.61 to 2.60 moles of 1,2-dibromo-1-(p-chloroethoxy)ethane and approximately equivalent quantities of ethylmagnesium bromide averaged 81% of a product distilling a t 91-93"/11 mni.
290
COTTLE, JELTSCH, STOUDT, AND WALTERS
Preparation of d-ethyl-4-phenylmorpholine. Although the preparation of 2-ethyl-4phenylmorpholine had not been described previously, Cretcher, Koch, and Pittenger (9) have described various 4-arylmorpholines, and their method was adapted t o this work. l-Bromo-2-(~-chloroethoxy)butane (440 g. or 2.05 moles) and 548 g. (6.15 moles) of aniline were placed in a 3-1. flask fitted with a large Hopkins condenser and heated in a n oil-bath. When the temperature reached 120-130" a vigorous reaction made removal of the oil-bath necessary. After three to four minutes the reaction subsided, the oil-bath was replaced and heating continued a t 160" for four hours, at the end of which the contents of the flask were almost completely solid. After cooling, 240 g. (6.0 moles) of sodium hydroxide in 500 ml. of water was added, the o.rganic layer removed and the water layer extracted with benzene. Distillation of the benzene removed the water, and the residue was vacuumfractionated through a three-bulb Snyder column. The recovered aniline was used in subsequent runs. The yield of product boiling at 139-140'/9 mm. was 83%. Anal. Calc'd for CI~HI.INO: C, 75.35; H, 8.96; N, 7.33. Found: C, 77.24; H, 9.23; N, 7.42. The average yield of six similar preparations involving 1.25 to 2.11 moles of dibromoether was 78%. One preparation with 1.02 moles of dihaloether which was heated for 2 hours gave a 60% yield, and one with 2.00 moles which was heated for 9 hours gave a 56% yield. TABLE I
TEENITROSATIONO F
2-ETIiYL-4-PEIENYLMORPEOLINE ~
~~
MOLES OF ÐYL4 -PHENYLMORPHOLINE
bC0LES OF HYDROCHLORIC ACID
MOLE m n o OF ACID r o PHENYLHOBPHOLINE
0.61 1.00 1.12 1.50 1.50 1.50 1.53 1.41
4.61 13.0 10.0 15.0 15.0 10.0 10.0 14.0
7.6 13.0 8.9 10.0 10.0 10.0 9.8 10.0
YIELD OF ~-ETEYLMOXPHOLINE,
%
23 57 36 45 54 47 33" 61
Ratio of NaN02/phenylmorpholine was 1.5; in all other runs i t was 1.05.
Preparation of 2-ethylmorpholine. (a) Nitrosation. The conditions given by Bennett and Bell (IO) were adapted. I n a typical run, 286 g. (1.50 moles) of 2-ethyl-4-phenylmorpholine was dissolved in 1250 ml. of concentrated hydrochloric acid (15 moles), diluted with 1250 ml. of water, and chilled to -6". A solution of sodium nitrite containing 109 g. (1.58 moles) in 150 ml. of water was ridded dropwise to the well-stirred hydrochloride solution over a period of 2.5 hours, and stirring continued for another hour. The resulting solution was treated with 605 g. (16 moles) of sodium hydroxide in 700 ml. of water, cooled, extracted with ether, the ether removed by distillation, and the residue hydrolyzed. Although the nitroso compound was not isolated as a pure substance, the following data on the nitrosations are of interest because the subsequent hydrolysis conditions were kept constant and the difference in yield of the 2-ethylmorpholine must be attributed to a difference in the nitrosation procedure. It will be noted that when the mole ratio of hydrochloric acid to phenylmorpholine was below 10.0, the yield of 2-ethylmorpholine suffered. Excess sodium nitrite was also found to decrease the yield of 2-ethylmorpholine. (b) Hydrolysis of the nitroso derivative. The conditions for hydrolyzing the nitroso compound were those used by Mr. Munch and Miss Thannhauser of this laboratory in the preparation of some diamines (11). The nitroso compound was treated with a 27% solution of sodium bisulfite in the ratio of one mole of nitroso compound to six moles of bisulfite. The mixture was heated to 35-40' for one hour and then a t 75" for one hour, with stirring
PREPARATION OF
C-AELYLMORPHOLINES
291
throughout, After cooling, the mixture was treated with 8 moles of concentrated hydrochloric acid per mole of phenylmorpholine nitrosated, and the volume reduced by distillation to about 1500 ml. The resulting solution was treated with 9 moles of sodium hydroxide per mole of phenylmorpholine nitrosated, during which addition much ammonia was given off. Extraction of the amine was performed with ether in a large continuous extractor, the ether solution was dried over potassium carbonate and the ether removed by distillation. The residue was fractionated through a three-bulb Snyder column, and the crude 2-ethylmorpholine distilled a t 155-157", or 38-40"/8 mm. The combined yields of several preparations were refractionated twice through a six-bulb Snyder column and the portion distilling a t 154" was taken as pure product. Physical constants on this fraction were as follows: di: 0.9419; n f 1.4519. Anal. Calc'd for CsHlaNO: C, 62.56; II, 11.38; N, 12.17; Mol. Wt., 115.2. Found: C, 62.44; H, 11.73; N, 11.50; Mol. Wt. (by titration), 115.5. The phenylthiourea derivative and p-toluenesulfonamide derivative were prepared by standard procedures ( 6 ) . The phenylthiourea derivative melted a t 126.4-127.2" (uncorr.) and the p-toluenesulfonamide derivative melted a t 116.0-116.7" (uncorr.)
.
SUMMARY
The preparation in quantity and in high yield of the following new compounds is reported : 2-methylmorpholine, 3 ,3-dimethylmorpholine, 3-ethylmorpholine, and 2-methyl-5-ethylmorpholine. These substances were made by dehydration of the dialkanolamines, N-j3-hydroxyethyl-l-amino-2-propanol,N-j3-hydroxyethy1-2-amino-2-methy1-1-propano1,N-j3-hydroxyethyl-2-amino-l-butanol, and N-j3-hydroxy-n-propyl-2-amino-l-butanol, which also are new substances and which were prepared by the addition of commercially available amino alcohols to olefin oxides. The preparation of 2-ethylmorpholine, a new compound, in large quantity by a five-step synthesis starting with commercially available materials is described. This synthesis involved the preparation of 2-ethyl-4-phenylmorpholine,also a new compound, its nitrosation, and the hydrolysis of the nitroso derivative. Conditions affecting the yields of 2-ethylmorpholine from this hydrolysis are discussed. NEWBRUNSWICK, N. J. REFERENCES (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11)
KNORR,Ann., 301, 1 (1889). M ~ D A R Bull. D , SOC. chim., [5] 3, 1338 (1936). KRASUSKII, J . Gen. Chem. ( U . S. S. R.), 6, 460 (1936). PAYMAN AND PIGGOTT, Chem. Abstr., 23, P2723 (1929); U. S. Patent 1,736,747 (July, 1928). ADAMSAND CAIRNS,J . Am. Chem. Soc., 61, 2464 (1939). SHRINERAND FUSON, "The Identification of Organic Compounds," Second Edition, John Wiley & Sons, Inc., New York, 1941. GRIGNARD AND PURDY, Bull. S O C . chim., [4] 31, 982 (1933). SUMMERBELL AND UMHOEFER, J . Am. Chem. SOC.,61,3016 (1939). CRETCHER, KOCH,AND PITTENQER, J. Am. Chem. Soc., 47, 1174 (1925). BENNETTAND BELL,Org. Syntheses, Coll. Vol. 11, 223 (1943). THANNRAUSER, GERTRUDE T., Master's Thesis, Rutgers University, 1944; MUNCH, ROBERTJ., Unpublished research, Rutgers University, 1943-44; cf. VON BRAUN, 111, 975 (1890-1894). HEIDER,AND MULLER,Ber., 51, 1737 (1918); FRIEDLANDER
