Dec. 5, 1958
7-CAPROLACTAMS AND
THEIR
ethanol, the volume was reduced t o one-third by boiling, and the solution then was cooled, m.p. 204.5-206.0' (with ~ i 0.2' effervescence to a clear red melt), [ a I a 3+16.2 (c 1.01 in 1 N HC1-ethanol (1:1)).
[CONTRIBUTION FROM
THE
TRANSFORMATION TO DL-LYSINE
6233
Anal. Calcd. for Cl,HlgOsN (317.3): c , 64.3; H, 6.03; N , 4.42. Found: C , 63.7; H , 6.15; N, 4.34. MADISON 5, Wrsc.
ORGANIC DIVISION,MONSANTO CHEMICAL CO.1
a-Halogenation Products of E-Caprolactam and their Transformation to DL-Lysine' BY ROBERT J. WINEMAN,Eu-PHANG T. Hsu
AND
CONSTANTINE E. ANAGNOSTOPOULOS
RECEIVED APRIL 11, 1958 Improved methods have been developed for the preparation of 3,3-dihalo-2-oxohexamethyleneimines.Conversions of the dihaloimines to the corresponding 3-halo-2-oxohexamethyleneimines, and transformations of the 3-halo- and 3,3-dihalo2-oxohexamethyleneimines to DL-lySille by amination or reductive amination and acid hydrolysis are given. The latter for comparireactions were carried out on the corresponding 1-acyl-3-halo- or 1-acyl-3,3-dihalo-2-oxohexameth~leneimines acids to DL-lysine was made. son. Similarly, the transformation of 6-acetamido-%halo- or 6-acetamido-2,2-dihalohexanoic
For the synthesis of DL-lysine, c-caprolactam methyleneimine (IIa) . By improved conditions (2-oxohexamethyleneimine) frequently has been for the halogenation of e-caprolactam and selective chosen as the starting material. I n the last decade reduction, 3-chloro-2-oxohexamethyleneiminewas the increased availability of e-caprolactam, con- prepared in yields of over SOYo from c-caprolactam. taining all the carbon atoms and one of the nitro- The best yield of m-lysine obtained by amination gen atoms required for DL-lysine in their correct and hydrolysis of 3-chloro-2-oxohexamethylenestate of oxidation, has gained in attractiveness as a imine (IIIa) was 30-33% giving an over-all yield of DL-lysine of 25% from €-caprolactam. Modistarting material for synthetic ~ ~ - 1 y s i n eUntil . recently, the lactam ring has been hydrolytically fications of this route described below gave yields cleaved, prior to halogenations and amination.2-s of 50y0over-all. As in the classic synthesis of Eck and Marvel, an additional blocking group is introduced for protection of the €-amino group. It seemed apparent that the lactam might provide sufficiently stable acyl blocking of the €-amino group to prevent its degradation in the halogenation + step and to prevent effectively its interaction with IIIa, X=CI IIa, X = C1 an a-halogen. This study deals with the halogenab. X = B r b, X = B tion and subsequent transformations of the halo/ caprolactams into DL-lysine. After this work was R I completed, Rickenbacher and Brennerg reported c=o using 3-chloro-2-oxohexamethyleneimine as an intermediate for lysine synthesis, introducing the or-amino group by interaction with sodium azide and reduction. The initial purpose of the present investigation IVa,X=Cl Va, X=C1, R =CHa was to study the conversion of e-caprolactam (I) b, X = Br, b, X = B r , R = CH3 into 3-chloro-2-oxohexamethyleneimine(IIIa), its 1 C. X=C1, R=CsHs amination t o 3-amino-2-oxohexamethyleneimine (VII), and the hydrolysis of the latter to DL- 1 / lysine (VIII). Since the 3-chloro-2-oxohexamethyleneimine could not be obtained by direct halogenation of c-caprolactam, use was made of the selective reduction of the 3,3-dichloro-2-oxohexa-
1
I
(1) Presented in part before the Organic Division of the American Chemical Society at the 133rd National Meeting, San Francisco, Calif., April 18, 1958. (2) 5. C. Eck and C. S. Marvel, J. Biol. Chem., 106, 387 (1934); J. C. Eck and C. S. Marvel, "Organic Syntheses," Coll. Vol. 11, John Wiley and Sons, Inc., h-ew York, N. Y., 1943, pp, 74, 76 and 374. (3) K. Odo and S. Himizu, J. SOC.Org. S y n t h e f . Chem. Japan, 11, 386 (1953); C. A , , 48, 1958 (1954). ( 4 ) D. C. Sayles and E. F. Degering, Tqxs JOURNAL, 71, 3161 (1949). (5) A. Galat, U. S. Patent 2,519,038. ( 6 ) A. Galat, THISJOURNAL, 69, 86 (1947). (7) E. E . Howe and E. W. Pietrusza, ibid., 71, 2581 (1949). (8) G. Steinbrunn, German Patent 855,260. (9) H. R. Rickenbacher and M. Brenner. Anxem. Chem., 69, 688 (1957); M. Brenner and H. R. Rickenbacher, Heiu. Chim. Acta. 41, 181 (1958).
L
VI
1
VI1
J
H,NCH&H2CH&H,FHCOOH-HHCl NH, VI11
The chlorination of 3-oxohexamethyleneimine was first reported by von Braun and Heymons.'O These workers used an excess of phosphorus pentachloride, xylene as solvent and reaction a t elevated temperatures. Their procedure involved a high (10) 1. v. Braun and A. Heymons, Ber., 63, 502 (1930).
(3234
R. J. WINEMAN, E.-P. T.Hsu
AND
C. E. ANAGNOSTOPOULOS
Vol. 80
vacuum distillation step and the yields of 3,3- Similarly, the l-acetyl-3-halo-2-oxohexamethylenedichloro-2-oxohexamethyleneiminewere less than imines (Va, Vb), were prepared from the cor40%. responding monohalolactams in high yield. Thcse I t was found that 3,3-dichloro-2-oxohexamethyl-compounds were also available by selective hyeneimine can be prepared in 90 to 93% yields by drogenolysis of one halogen from the l-acety1-3,3using a combination of phosphorus pentachloride dihalo-2-oxohexamet hyleneimine s. For example, and chlorine] chloroform as the solvent and much 1-acetyl-3-chloro -2 -0xohexamethyleneimine (Va) lower reaction temperatures. In addition, this was formed in over 90% yield by atmospheric procedure did not require the distillation of any pressure hydrogenation of the dihalo compound in intermediate. Furthermore, the same dichloro the presence of palladium and sodium acetate. Amination of 1-acetyl-3-chloro-2-oxohexamethylproduct can be obtained in lower yields when 2oxohexamethyleneimine is chlorinated with a eneimine with excess anhydrous ammonia for one combination of phosgene and chlorine, or phos- hour a t 120" and subsequent hydrolysis with hydrochloric acid resulted in the formation of DLphorus pentachloride and sulfuryl chloride. Using a similar procedure and employing phos- lysine in 38y0. yield. Similarly, the amination of phorus pentachloride and two equivalents of bro- the corresponding l-acetyl-3-bromo-2-oxohexamethmine, 3,3-dibromo-2-oxohexamethy1eneiminewas yleneimine resulted in 43-46y0 yields of DL-lysine. obtained in 83y0 yield. When only one equivalent Use of the benzoyl group instead of acetyl gave of bromine was used the 3-bromo-2-oxohexamethyl- poorer results; e.g., only 12y0DL-lysine was formed in amination and hydrolysis of l-benzoyl-3eneimine was formed in 377, yield. Attempts t o synthesize the 3-chloro-2-oxohexa- chloro-2-oxohexamethyleneimine(Vc). Reductive methyleneimine by direct chlorination of 2-oxo- amination conditions applied to l-acetyl-3,3hexamethyleneimine failed. However, 3,3- dichloro-2-oxohexamethyleneimine (IVa), followed dichloro-2-oxohexamethyleneiminewas easily con- by acid hydrolysis resulted in the formation of 21yo verted in almost quantitative yields to the mono- DL-lysine. Factors which might cause the relatively unchloro compound by low pressure reduction. 3,3Dibromo-2-oxohexamethyleneimine was similarly satisfactory yields in the amination and hydrolysis converted in high yield to 3-bromo-2-oxohexa- reactions are considered to be: Reactivity of ahalogen amides in nucleophilic displacement remethyleneimine. Amination of 3-chloro-2-oxohexamethyleneimine actions is lower than in the corresponding acids, with excess anhydrous ammonia a t 120" for one due t o the relatively less positive character of the hour resulted in 85-95y0 conversion of the halogen lactam carbonyl. Steric hindrance toward disto the ionic condition. Hydrochloric acid hy- placement reactions on the a-carbon is undoubtedly drolysis of the amination products resulted in greater in the cyclic lactams than in the open chain 25-33Y0 yield of DL-lysine from the lactam. Ami- 6-acylamido-2-halo-hexanoic acids. The conformation of the halogen in the mononations a t lower temperatures and longer times gave yields of the same order of magnitude. For halocaprolactams is not known. The possibility example, excess ammonia a t 70" for 12 hours re- exists that the halogen is more stable in the eyuasulted in only 4Gy0 reaction of 3-chloro-2-oxohexa- torial position. Steric hindrance due t o the ring methyleneimine, and &yoyield of crude Dr,-lysine, is greater for the displacement of halogen from the equatorial position. I n an open chain compound, based on the 3-chloro-2-oxohexamethyleneimine this is not a factor. In spite of the possible adconsumed. verse electrical and steric factors, high conversions 3-Bromo-2-oxohexamethyleneimine a t 70" for of organic to ionic halogen were possible. The 5 hours in the presence of excess ammonia under- nature of the side reactions was not investigated in went complete reaction of the halogen. Hydrolysis detail. Comparative transformations involving of this amination mixture resulted in &yoyield of the 6-acetamido-2-halohexanoic acids were macle. DL-lySine. H O Application of reductive amination conditions to 3,3-dichloro-2-oxohexamet hyleneimine followed 24,x2 by hydrolysis resulted in a low yield (8.5% of DL-lysine.) In view of the relatively low yields of DL-lysine IIa, X = C1 from the amination of 3-halo or 3,3-dihalo-2b, X = Br oxohexamethyleneimine, i t was of interest to prepare some 1-acyl-3-halo or 1-acyl-3,3-dihalo-2- HzK( CHz)
