J. Org. C h e m . 1984,49, 133-138 moved, and the reaction mixture was heated at reflux for 6 h. The ice bath was then replaced, and the reaction was quenched by dropwise addition of 3 mL of HzO. The THF solution was decanted from aluminum salts into a separatory funnel containing 75 mL of HzO. The product was extracted with CHzCl2(3 X 30 mL). The extracts were combined, dried over NaZSO4,and concentrated by rotary evaporation. Bulb to bulb distillation of the residual oil gave 0.56 g (86%) of pure carnegine as a viscous yellow oil: bp 150-160 "C (0.2 mm) [lit.14 bp 170 "C (1mm)]; 'H NMR 6 1.36 (3 H, d, J = 7.0 Hz, CH3), 2.43 (3 H, 9, NCH,), 2.48-3.12 (4 H, m, H3, H4), 3.50 (1H, q, J = 7.0 Hz, Hl), 3.80 (6 H, s, C6 and C7-OCH3),6.50 (1H, s, H5 or H8), 6.53 (1H, s, H5 or H8). Spectral data were identical with those obtained from an authentic sample of natural carnegine. 6,7-(Methylenedioxy)-2-methyl- 1,2,3,4-tetrahydroisoquinoline (Hydrohydrastinine) from 6. The general procedure described above for preparation of 10 was used to convert 0.38 g (2.0 mmol) of 6 to crude 11: 0.39 g (83%); 'H NMR 6 2.67 (2 H, t, J = 6.0 Hz, H4), 3.58 (2 H, t, J = 6.0 Hz, H3), 3.68 (3 H, s, OCH,), 4.43 (2 H, br s, Hl), 5.81 (2 H, s, OCH,O), 6.45 (1H, s, H5 or H8), 6.47 (1 H, s, H5 or H8). (14)"The Merck Index", 9th ed.; Merck & Co.: Rahway, NJ, 1976.
133
Reduction of crude 11 by LiAlH, according to the procedure for preparation of carnegine gave a pale yellow oil which wm added to a saturated solution of anhydrous HC1 in ether. Recrystallization of the crude salt from EtOH gave 0.31 g (68% from 6) of pure hydrohydrastinine hydrochloride, 270 "C dec (lit.14278 "C dec).
Acknowledgment. This research was supported by grants from the Texas Christian University Research Fund (Grant 5-23649) and The Robert A. Welch Foundation (Grant P-853). D.E.M. also thanks Prof. Manfred G. Reinecke for providing an authentic sample of natural carnegine. Registry No. 2, 119-65-3; 5, 87803-18-7; 6, 87803-19-8; 7, 87803-12-1; 8, 87803-13-2; 9, 87803-15-4; 10, 87803-14-3; 11, 87803-16-5; 11.HC1, 87803-17-6; 19, 3340-78-1; 6,7-dimethoxyisoquinoline, 15248-39-2;6,7-(methylenedioxy)isoquinoline,26944-3; carnegine, 71783-56-7;hydrohydrastinine, 494-55-3. Supplementary Material Available: Additional spectral data for compounds 5-10; full experimental details for preparations of compounds 6 , 9 , and hydrohydrastinine (4 pages). Ordering information is given on any current masthead page.
General Method for the Synthesis of Selectively N-Alkylated Polyamines J. Eric Nordlander,* Mark J. Payne, Michael A. Balk, Julia L. Gress, Frederick D. Harris, J. Scott Lane, Robert F. Lewe, Stephen E. Marshall, Dianne Nagy, and Daniel J. Rachlin Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106 Received April 28, 1983
A versatile method is presented for the synthesis of linear polyamines-in particular, the naturally ubiquitous putrescine, spermidine, and spermine-regiospecifically N-alkylated or N-polyalkylated. The new approach is based on the acylation of amines with N-(trifluoroacety1)amino acid chlorides, optional alkylation followed by selective saponification of the (trifluoroacetylhnino function, analogous reacylation, and polyamide to polyamine reduction. The naturally ubiquitous polyamines putrescine (l), spermidine (2), and spermine (3) play a complex set of roles
in cell life whose detailed understanding has become the object of extensive research.' Much of the action of the polyamines is broadly linked with their essentially complete protonation under physiological conditions and coulombic complexation of the resultant polycations with particular conformations of nucleic acids and other polyanionic molecules.' The polyamines have also been found within a variety of conjugate structures.'V2 Medical interest has been spurred by the observation of abnormal (1)Leading recent reviews: (a) Ganem, B. Acc. Chem. Res. 1982,15, 290. (b) Wasserman, H. H.; Wu, J. S. Heterocycles 1982,17,581. (c) Morris, D. R.; Marton, L. J. 'Polyamines in Biology and Medicine"; Marcel Dekker: New York, 1981. (d) Calderara, C. M.; Zappia, V.; Bachrach, U., Eds. "Advances in Polyamine Research", Raven Press: New York, 1981;Vol. 3. (e) Pegg, A. E.; Hibasami, H.; Matsui, I.; Betheli, D. R. Adv. Enzyme Regul. 1981,19,427. (0 Stevens, L.; Stevens, E. Polyamines Biomed. Res. 1980,167.(9) Morgan, D. M. L. Ibid. 1980,285.(h) Theoharides, T.H. Life Sci. 1980,27,703. (2)(a) McMillan, J. A.; Paul, I. C.; Goo, Y. M.; Rinehart, K. L., Jr.; Krueger, W. C.; Pschigoda, L. M. Tetrahedron Lett. 1981,22,39. (b) Wasaerman, H. H.; Berger, G. D.; Cho, K. R. Ibid. 1982,23,465.(c) Araki, K.; Miyazawa, K.; Hashimoto, H.; Yoshimura, J. Ibid. 1982,23, 1705.
polyamine levels in several disease states, including cystic f i b r o s i ~ ' ~and ~ ~ ?~ ~a n c e r . ' ~ * ~ Considerable progress has been made in delineating the biosynthesis of the p o l y a m i n e ~ . ' ~ ~Less ~ ~ f detail ~ ~ is known about their catabolism'a.eBgp6 as well as their vital noncovalent interactions.laJ Further advances in all three directions would be promoted by extended structure/activity (3)(a) Dearborn, D. G. In "Advances in Polyamine Research"; Raven Press: New York, 1978;Vol. 2,pp 273-279. (b) Wilson, G. B.; Fudenberg, H. H. Ibid. pp 281-305. (c) Berry, H. K.; Denton, M. D.; Glazer, H. S.; Kellogg, F. W. Ibid. pp 307-312. (d) Rosenblum, M.G.; Durie, B. G. M.; Beckerman, R. C.; Taussig, L. M.; Russell, D. H. Science 1978,200,1496. (e) Russell, D. H.; Rosenblum, M. G.; Beckerman, R. C.; Durie, B. G. M.; Taussig, L. M.; Barnett, D. R. Pediat. Res. 1979,13,1137.(0 Baylin, S. B.; h e n s t e i n , B. J.; Marton, L. J.; Lockwood, D. H. Ibid. 1980,14,921. (4)(a) Matsuda, M.; Osafune, M.; Kotake, T.; Sonoda, T.; Sobue, K.; Nakajima, T. Clin. Chim. Acta 1978,87,93.(b) Endo, Y.; Samejima, K. Igaku no Ayumi 1978,106, 282; Chem. Abstr. 1978,89,1612433. (c) Uehara, N.;Shirakawa, S.; Domae, N.; Uchino, H.; Saeki, Y. Ibid. 1978, 107, 23; Chem. Abstr. 1979,90,20465s. (d) Endo, Y.;Samejima, K.; Fujino, M.; Oda, T. Scand. J. Immunol.,Suppl. 1978,8 (Carcinoembryonic Proteins: Recent Prog.), 661. (e) Harik, S. I.; Sutton, C. H. Cancer Res. 1979,39,5010. (5)Tabor, C.; Tabor, H.; Tyagi, A. K. J. Biol. Chem. 1981,256,12156. (6)(a) Fogel, W.A.; Bieganski, T.; Ulatowska, M. Arch. Immunol. Ther. Exp. 1980,28,907.(b) Gaugas, J. M.; Dewey, D. L. J.Pathol. 1981, 134,243.(c) Bolkenius, F. N.; Seiler, N. Int. J. Biochem. 1981,13,287. (7)(a) Allison, S.A.; Herr, J. C.; Schurr, J. M. Biopolymers 1981,20, 469. (b) Burton, D. R.; Forsen, S.; Reimarsson, P. Nucleic Acids Res. 1981,9,1219.(c) Subirana, J. A.; Vives, J. L. Biopolymers 1981,20,2281. (d) Voige, W.H.; Elliott, R. I. J. Chem. Educ. 1982,59,257. (e) Kimura, E.; Kodama, M.; Yataunami, T. J. Am. Chem. SOC.1982, 104, 3182.
0022-3263/84/1949-0133$01.50/00 1984 American Chemical Society
134 J. Org. Chem., Vol. 49, No. 1, 1984
Nordlander et al. Scheme Ia
TFANH(CH2).CC1
0 II RR"H1
py
+
0 II
Me2co, 40, n = 1
d, n
= 3;
R = Et; R'
=
TFAN(CH2)nCNRR'
b, n = 2; R = H; R' = CH 2 Ph;
e, n = 3; R,R' = (CH2)5
c,n=3
4.
0 I1
I
m
60, n = 1; R,R' = CH 2 CH 2 OCH2CH2; R" = CH2Ph
50, n = 1; R,R' = CH CH OCH2CH2 2 2 b, n = 2; R = H; R' = CHZPh
b,n=2
R"
R"X, K2CO3
TFANH(CH2)nCNRR'
Ph
I
\
1)BMS 2)HCI
R
~ ( C H ~ ) ~ + , ~ H R R2 IY-
80, n = 1; R,R' = CH2CH20CH2CH2; R" = CH2Ph; Y = C1
R"NH (CH2)"CNRR'
70, n = 1; R,R' = CH 2CH2OCH2CH2; R" = CH2Ph
b, n = 2 ; R = H; R ' = CH2Ph; R" = CH
b, n = 2 ; R = H; R' = CH2Ph; R" = CH ; Y = C1 3
c, n = 3; R,R' = (CH2)5; R" Y- = 2,4,6-(02N)3Ph0-
II
1) BMS 2)HCl
3
=
H;
c, n
= 3;
R,R' = (CH2j5; R" = H
d, n = 3; R = Et; R' = Ph; R" = CF3CH2; Y = C1 a
TFA = CF,CO.
correlations, dependent in turn on methods for the systematic preparation of derivatives of the natural compounds. Novel syntheses of a number of individual Nsubstituted polyamines have been published during the past decade.la,b,s We report here the results of a further and general approach to the preparation of N-mono- and -polyalkylated polyamines.
Results Diamines. Our construction of linear polyamines has been based on the formation and subsequent reduction of peptide-type connections in conjunction with the trifluoroacetylation of amino groups for protection as well as possible intermediate mon~alkylation.~The synthesis of N-benzyl-2-(4-morpholino)ethylamine bis-hydrochloride (8a), shown in Scheme I, is illustrative. N-(Trifluoroacety1)glycyl chloride (4a)1°was prepared smoothly from (8) (a) Israel, M.; Zoll, E. C.; Muhammad, N.; Modest, E. J. J. Med. Chem. 1973,16, 1. (b) Schopp, E.: Hesse, M. Helu. Chim. Acta 1973,56, 124. (c) Doskotch, R. W.; Ray, A. B.; Kubelka, W.; Fairchild, E. H.; Hufford, C. D.; Beal, J. L. Tetrahedron 1974,30,3229. (d) Fischer, H. A. J. Labelled Compd. 1975,11, 141. (e) Guggisberg, A.; van den Broek, P.; Hesse, M.; Schmid, H.; Schneider, F.; Bernauer, K. Helv. Chim. Acta 1976, 59, 3013. (f) Egami, F.; Yanagawa, H.; Fukuda, K.; Ogawa, Y. Japanese Patent 77 118405,1977. (g) Weigert, F. J. J. Org. Chem. 1978, 43,622. (h) Guggisberg, A.; Dabrowski, B.; Kramer, U.; Heidelberger, C.; Hesse, M.; Schmid, H.Helu. Chim. Acta 1978,61, 1039. (i) Guggisberg, A.; Kramer, U.; Heidelberger, C.; Charubala, R.; Stephanou, E.; Hesse, M.; Schmid, H. Helu. Chim. Acta 1978,61,1050. 6)Andruszkiewicz, R.; Wojciechowska, H.; Borowski, E. Pol. J.Chem. 1978,52,1167. (k) Smith, R. G.; Daves, G. D., Jr. J. Org. Chem. 1978,43,2178. (1) Asatoor, A. M. Biochem. Biophys. Acta 1979, 586, 55. (m) Okada, S.; Kawashima, S.; Imahori, K. J.Biochem. (Tokyo) 1979,85,1235. (n) Chantrapromma, K.; McManis, J. S.; Ganem, B. Tetrahedron Lett. 1980,2475. (0)Yamamoto, 1981,103,4186. (p) Adams, T. C.; H.; Maruoka, K. J . Am. Chem. SOC. Combs, D. W.; Daves, G. D., Jr.; Hauser, F. M . J. Org. Chem. 1981,46, 4582. (9)Waeserman, H. H.; Berger, G. D.; Cho, K. R. Tetrahedron Lett. 1982,23,465. (r) Bergeron, R. J.; Stolowich, N. J. Synthesis 1982,8,689. (s) Hosseini, M. W.; Lehn, J. M. J. Am. Chem. SOC.1982, 104, 3525. (t) Bergeron, R. J.; Kline, S. J. Ibid. 1982, 104, 4489. (9) Nordlander, J. E.; Catalane, D. B.: Eberlein, T. H.; Farkas, L. V.; Howe, R. S.; Stevens, R. M.; Tripoulas, N. A.; Stansfield, R. E.; Cox, J. L.; Payne, M. J.; Viehbeck, A. Tetrahedron Lett. 1978, 4987. (10) Weygand, F.; Leising, E. Chem. Ber. 1954,87, 248.
N-(trifluoroacety1)glycine" and oxalyl chloride12 and reacted with morpholine in the presence of pyridine to yield the diamide 5a13 (60% from N-(trifluoroacety1)glycine). N-Benzylation was achieved (80%)by reaction of 5a with K2C03and PhCH2Br in boiling a ~ e t o n e , ~ and J * the resultant 6a was detrifluoroacetylated (50%)by treatment with K&O3 in boiling aqueous methan01.l~ Amide 7a was reduced with BH3.Me2S (BMS) in tetrahydrofuran16to give the diamine, isolated as the dihydrochloride 8a" (77%). Similarly, N-ben~yl-N'-methyl-l,3-propanediamine'~ dihydrochloride (8b) was prepared from N-(trifluoroacetyl)-@-alanylchloride (4b), PhCH2NH2,and CH31 via diamides 5b and 6b and amino amide 7b (19% overall yield from N-(trifluoroacety1)-@-alanine). N-(Trifluoroacetyl)-yaminobutyryl chloride (4c) and piperidine likewise furnished diamide 5c, which was selectively hydrolyzed directly to amino amide 7c. Reduction with BMS produced 4 4 l-piperidino)butylamine,lgisolated as the known dipicrate,20 8c (20% overall yield from N-(trifluoroacety1)-y-aminobutyric acid). BMS was found to effect normal reduction of trifluoroacetamides, as illustrated by the conversion of y(11) (a) Weygand, F.; Csendes, E. Angew. Chem. 1952, 64, 136. (b) Schallenbern. E. E.: Calvin. M. J. Am. Chem. SOC. 1955. 77. 2779. (12) Ada&, R.; Ulich, L. H. J. Am. Chem. SOC.1920; 42; 599. (13) Clerin, D.; Meyer, B.; Fleury, J.-P. Bull. SOC.Chim. Fr. 1976,2053. (14) (a) Evans, D. A,; Sacks, C. E.; Kleschick, W. A.; Taber, T. R. J. Am. Chem. SOC.1979,101,6789. See also: (b) Sugasawa, T.; Adachi, M.; Sasakura, K.; Kitagawa, A. J. Org. Chem. 1979,44, 578. (15) (a) Newman, H. J. Org. Chem. 1965, 30, 1287. (b) Kotani, E.; Takeuchi, N.; Tobmaga, S. J.Chem. SOC., Chem. Commun. 1973,550. (c) Schwartz, M. A.; Wallace, R. A. Tetrahedron Lett. 1979, 3257. (16) (a) Lane, C. F. Aldrichimica Acta 1975, 8, 20. (b) Lane, C. F. 'Aspects of Mechanism and Organometallic Chemistry"; Plenum Press: New York, 1978; p 181. (17) Baganz, H.; Milster, H. Arch. Pharm. 1958,291, 116. (18) Takehisa, M.; Watanabe, T.; Iwata, M. Japanese Patent 73 10614, 1973. (19) (a) Braun, J. V.; Zobel, F. Justus Liebigs Ann. Chem. 1925,445, 247. (b) Elslager, E. F.; Moore, A. M.; Short, F. W.; Sullivan, M. J.; Tendick, F. H. J. Am. Chem. SOC.1957, 79, 4699. (20) Whitmore, F. C.; Mosher, H. S.; Adams, R. A.; Taylor, R. B.; Chapin, E. C.; Weisel, C.; Yanko, W. J. Am. Chem. SOC.1944, 66, 728.
J. Org. Chem., Vol. 49, No. I , 1984 135
Synthesis of N-Alkylated Polyamines Scheme 11" 0 II
0
II
K2CO3 MeOH, H20
TFANH(CH2)3CNRR'
0 II
TFANH(CH2) 2CNH (CH2)3CN (CH3) 10
r' 50, R = CH3; R' = CH
0 II
H2N(CH2)3CNRR'
90, R = CH3; R' = CH
3
3
I I
b, R = 1-Ad; R' = H
f , R = l - A d ; b R' = H
K2C03, MeOH, H20
Ar
NC(CH2) 2NH(CH2) 3?NHAd-l 14
1
11
1) BMS 2 ) HC1
1
PhCOC1, K2C03, H20
0
+ + R ~ H ~ ( C H ~ ) ~ N H ~ ( C H ~ ) ~ N3 HYR- R 4 ~
BMS
II
0 I1
0 I1
PhCNH(CH2) 2CNH(CH2) 3CN(CH3)
2)HCl 12
I*,
R = CH ; R' = CH3; R" = PhCH2; Y = C1 3
b, R = 1-Ad; R ' = R"
" TFA = CF,CO.
H; Y- = 2,4,6-(0 N) PhO-
' 1-Ad = 1-adamantyl.
1-AdNH2*HC1 Et 3N
[(trifluoroacety1)amino)l-N-ethylbutyranilide(5d) from 4c and PhNHEt, to N-ethyl-N-phenyl-N'-(2,2,2-trifluoroethyl)-1,4-butanediaminedihydrochloride (8d) (70% overall yield from N-(trifluoroacety1)-y-aminobutyricacid) on treatment with excess BMS followed by HC1. Spermidines. The diamine methodology was readily extended to the synthesis of selectively substituted spermidines (Scheme 11). Reaction of N-(trifluoroacety1)-yaminobutyryl chloride (442) with anhydrous dimethylamine in the presence of pyridine produced diamide 58, which was discretely saponified to y-amino-N,N-dimethylbutyramide (9a). This amine was acylated with N-(trifluoroacety1)-&alanyl chloride (4b) to give triamide 10. Detrifluoroacetylation again and benzoylation of the resultant 11 furnished the penultimate 12, which on reduction with BMS followed by acidification with gaseous HC1 gave IP-benzyl-P,iP-dimethylspermidine trihydrochloride (13s) (46% overall yield from N-(trifluoroacety1)-yaminobutyric acid). (Trifluoroacety1)amino acid chloride 4c was analogously converted to the N-(1-adamanty1)carboxamide 5f, which was deprotected (to 9b)21 and cyanoethylated with
2
3
(CH3) 2N (CH2) 3NHZ DCCb, H O B t C , DMF
acrylonitrile*n~22 to afford cyanoamide 14. BMS treatment reduced the cyano and carboxamido functions16 concurisolated rently to produce NB-(1-adamantyl)spermidine, as the tripicrate 13b (31.5% from N-(trifluoroacety1)-yaminobutyric acid). Spermines. The present approach was applied also to the synthesis of a representative unsymmetrically subs t i t u t e d spermine, N1-(l-adamantyl)-N12,N'2-dimethylspermine (17) (Scheme 111). 3-Amino-N-(1adamanty1)propionamide (7d) was generated routinely from N-(trifluoroacety1)-8-alanyl chloride (4b) and 1aminoadamantane via diamide 5g and was acylated with succinic anhydride to produce diamido acid 15. Coupling of 15 with NJV-dimethylpropanediaminewas effected by dicyclohexylcarbodiimide in the presence of l-hydroxybenzotriazole in dimethylformamide solution to furnish the dimethylamino triamide 16. The inclusion of 1(21) Tsybma, N. M.; Ostrovskaya, R.U.;Skoldmov, A. P.Khim.-Farm. Zh. 1980, 14, 30. (22) (a) Schultz, H.P.J.Am. Chem. SOC.1948,70,2666. (b) Jackson, E.L. J. Org. Chem. 1956,21, 1374.
136
J. Org. Chem., Vol. 49, No.
1, 1984
Nordlander e t al.
hydroxybenzotriazole in this reaction was crucial, preventing what appeared to be an otherwise preemptive
-
7
cycli~ation~ to~ give the succinimide derivative
CO-
(CHz)zCON(CH2)zCONHAd-l. The reduction of 16 was carried out with LiAlH, in EtzO to yield the oily trisubstituted spermine 17 (37% overall yield from N-(trifluoroacety1)-@-alanine),characterized also as the tetrapicrate. Discussion
The strategy outlined here provides the first general access to linear di-, tri-, and tetraamines, 1-3 in particular, N-substituted with common alkyl groups in practically unlimited combinations. The utility of the trifluoroacetyl group for both the protection and the controlled monoalkylation of primary amino groups differentiates the present method from earlier approaches to polyamine construction.lab8 Products of maximum elaboration would result from the alkylation of each intermediate trifluoro6a and 5b 6b conversions) acetamide (as in the 5a followed by the ordinary alkylation of any remaining NH sites after polyamide reduction (not performed in the present work). The current method also allows for the regioselective introduction of 2H and 3Hlabels through the use of corresponding reagents for the amide reductions.
-
-
Experimental Section General Procedures. Capillary melting points are uncorrected. Infrared spectra were obtained with a Beckman IR-8 or IR-10 spectrophotometer. 'H NMR spectra were recorded at 60 MHz on a Varian EM-360A spectrometer using CDC13as solvent and Me4Si as internal standard unless otherwise noted; 2,2-dimethyl-2-silapentane-5-sulfonate (DSS) was employed as internal standard when the solvent was D20. Undecoupled l9F NMR spectra were obtained at 94.1 MHz on a Varian XL-100-15 Fourier transform spectrometer using DzO for internal lock. Elemental analyses were performed by Galbraith Laboratories, Inc., Knoxville, TN, or by Guelph Chemical Laboratories Ltd., Guelph, Ontario. Column chromatography utilized Silica Woelm 63-200 (70-230 mesh) silica gel, supplied by ICN Nutritional Biochemicals. Tetrahydrofuran (THF) was distilled from sodium benzophenone ketyl under nitrogen immediately before use.24 Pyridine was fractionally distilled from KOH pellets and stored over 4-A molecular seivesSz4 N-(Trifluoroacety1)amino Acid Chlorides. N-(Trifluoroacetyl)glycine, -@-alanine,and -7-aminobutyric acid were prepared by reaction of the amino acid (Aldrich) with ethyl trifiuoroacetate2s and triethylamine in methanol as described by Curphey.26 of oxalyl chloride12was added Typically, 4.8 mL (7.0 g, 55 "01) dropwise over 5 min to a stirred suspension of 50 mmol of the N-(trifluoroacety1)aminoacid in 50 mL of dry benzene containing 3 drops of dry pyridine. The mixture was heated under reflux for 15 min and allowed to cool to room temperature, and the benzene and excess reagent were removed by rotary evaporation, yielding the crude acid chloride as a clear yellow liquid. The acid chloride was diluted immediately with 10 mL of dry CHzClzand reacted without further purification. 4-(N-Benzyl-2-aminoethyl)morpholine Dihydrochloride (8a). N-(Trifluoroacety1)glycine (13.0 g, 76 mmol) was converted to the acid chloride as described above, diluted with 10 mL of CHzC12,and added dropwise to a stirred solution of 7.3 mL (7.3 g, 84 mmol) of freshly distilled morpholine and 6.8 mL (6.6 g, 84 mmol) of dry pyridine in 50 mL of CHzCl2at 0 "C. This stirred (23) Martinez, J.; Bodanazky, M. Znt. J. Peptide Protein Res. 1978, 12, 277. (24) Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. "Purification of Laboratory Chemicals";Pergamon Press: Oxford, 1966. (25) Kaluszner, A.; Reuter, S.;Bergmann, E. D. J . Am. Chem. SOC. 1955, 77, 4164. (26) Curphey, T. J. J. Org. Chem. 1979, 44, 2805.
solution was allowed to warm to room temperature for an additional 15 min and was made acidic with 5% HCl. The layers were separated, and the aqueous layer was extracted again with CH2Cl2. The combined organic phase was dried (MgS04)and concentrated by rotary evaporation to yield a yellow solid, which was recrystallized from 191 (v:v) ether/pentane (ice-bath cooling) to afford 11.0 g (46 mmol, 60%) of pure amide 5a: mp 108-109 "C; IR (Nujol) 3333,1727,1650,1282,1215,1149,1112,1035,901 cm-'; 'H NMR 6 3.46 (m) and 3.73 (s) (8 H, CH2CHz),4.18 (d, J = 5 Hz, 2 H, CHzCO), 7.64 (br s, 1 H, NH). To a stirred suspension of 9.6 g (70 "01) of anhydrous K2C03 in 200 mL of acetone (freshly distilled from K2CO3) was added dropwise 8.3 g (35 mmol) of carboxamide 5a in 15 mL of acetone of benzyl bromide (Aldrich). followed by 10.3 mL (15.0 g, 88 "01) The mixture was heated under reflux under Nz for 72 h, allowed to cool to room temperature, and transferred to a sepmatory funnel containing an equal volume of 10% KzCO3 solution. The solution was extracted with ether (3 X 50 mL), the organic layers were combined and dried over MgSO4, and the ether was removed by rotary evaporation to yield a yellow oil. Crystallization of the oil by trituration with pentane followed by recrystallization from 1:3 benzene/hexanes provided 9.2 g (28 mmol, 80%)of the desired benzylated amine 6a: mp 93-94 "C; IR (Nujol) 1691,1649,1276, 1248,1198,1170,1140,1110,1037,1000,964,852,744,703 cm-'; 'H NMR 6 3.55 (br s) and 3.82 (s, 8 H, CHzCHz),4.19 (s, 2 H, CH2CO),4.94 (s, 2 H, PhCHz),7.26-7.68 (m with major peaks at 7.46, 7.53, 5 H, Ph). Amine 6a (7.2 g, 22 mmol), 12.2 g (88 mmol) of potassium carbonate, 120 mL of methanol, and 6 mL of H20 in a 500-mL round-bottomed flask were boiled under reflux for 3 h. After rotary evaporation of the methanol, the residue was diluted with 30 mL of H20 and extracted with ether (3 x 50 mL). The combined ether layers were dried over K2C03, and the solvent was removed by rotary evaporation to afford 2.6 g (11 mmol, 50%) of amine 7a as a yellow oil: IR (film) 3446,2982,1641,1435,1260, 1111, 795 cm-'; 'H NMR 6 2.48 (s, 1 H, NH), 3.41 (s) and 3.67 (9) (10 H, CHZCH,, CHZCO), 3.90 (9, 2 H, PhCHz), 7.37 (s, 5 H, Ph). Amino carboxamide 7a (2.6 g, 11 mmol) was reduced with borane-methyl sulfide (BMS, Aldrich, 4.22 mL, 44 mmol) in 100 mL of dry THF as described by Lane.16 Workup yielded a brown gum, which crystallized upon trituration with ether. Recrystallization from methanol/ether yielded 2.5 g (8.5 mmol, 77%) of dihydrochloride Sa as colorless crystals: mp 248-249 "C dec; IR (Nujol) 2410, 1111,872 cm-'; 'H NMR (D20)6 3.48 (q) and 3.62 (SI (8 H, CH&H20), 3.96 (t,J = 5 Hz, 4 H, NCHZCHZN), 4.31 (9, 2 H, PhCHz), 7.54 ( 8 , 5 H, Ph). Anal. Calcd for C13H22C1zN20:C, 53.25; H, 7.56; N, 9.55. Found: C, 53.23; H, 7.70; N, 9.71. N-Benzyl-N'-methyl-l,3-propanediamine Dihydrochloride (8b). N-(Trifluoroacety1)-@-alanine(11.79 g, 64 mmol) was converted to the acid chloride and reacted with benzylamine as described for the preparation of 5a to afford 14.38 g (52 mmol, 82%) of carboxamide 5b as colorless needles (from benzene): mp 14C-141 "C; IR (Nujol) 3300,1689, 1629,1538, 1183, 1153 cm-'; 'H NMR (acetone-d,) 6 2.60 (t,J = 7 Hz, 2 H, CHzCH2CO),3.62 (q, J = 7 Hz, 2 H, CH&H2CO), 4.44 (d, J = 6 Hz, 2 H, PhCHz), 7.39 (s, 5 H, Ph), 7.70 (br s, 1 H, CF3CONH). Carboxamide 5b (5.0 g, 18 mmol) was alkylated with CH31as in the preparation of 6a to provide 3.4 g (23 mmol, 65%) of methylated amine 6b (from 1:3 toluene/heptane): mp 72-73 "C; IR (Nujol) 3279,1695, 1634, 1178,1075, 1016 cm-'; 'H NMR 6 2.42 (t, J = 7 Hz, 2 H, CH2CH2CO),2.86 (s) and 3.04 (d, J = 2 Hz) (3 H, CH,), 3.58 (t,J = 7 Hz, 2 H, CH,CHzCO), 4.30 (d, J = 6 Hz, 2 H, PhCHz), 7.21 (9, 5 H, Ph). Saponification was effected as before to give 0.23 g (4.9 mmol, 87%) of amine 7b as an amber oil: IR (film) 3311, 2976, 1678, 1543, 1200, 1171, 1126, 1026, 909, 829, 799, 719 cm-'; 'H NMR 6 2.36 (t, J = 6 Hz, 2 H, CH2CH&O), 2.40 (s, 3 H, CH3), 2.86 (t, J = 6 Hz, 2 H,CHSNHCH2),4.34 (d,J= 6 Hz, 2 H,PhCHJ, 7.33 (s, 5 H, Ph). Amino carboxamide 7b (0.4 g, 2.1 "01) was reduced with BMS as described above to yield 0.22 g (0.87 mmol, 41%) of hydrochloride salt 8b as colorless crystals: mp 272-274 "C dec; IR (Nujol) 2755,2584,2500,2463,2415,1011,909,740,694cm-'; 'H NMR (DzO) 6 2.03 (m, 2 H, CH2CH2CH2),2.59 (s, 3 H, CHJ, 2.98
J. Org. Chem., Vol. 49, No. I , 1984 137
Synthesis of N-Alkylated Polyamines (m, 4 H, CHzCH2CHz),4.12 (s, 2 H, PhCHZ), 7.33 (s, 5 H, Ph). Anal. Calcd for C1lHaoC1zNz:C, 52.60, H, 8.03;N, 11.05. Found c, 52.44; H, 8.02; N, 11.01. 4 4 1-Piperidino)butylamine Dipicrate (8c). N-(Trifluoroacetyl)-y-aminobutyricacid (6.0 g, 30 mmol) was converted to the acid chloride and reacted with piperidine to afford 6.4 g (24 mmol, 80%) of carboxamide 5c as colorless plates (from toluene/hexanes): mp 94-96 "C: IR (Nuiol) . - . 3236.3096.1725.1625. 1190, 1150 cm-'; 'H NMR 6 1.63 (s, 6 H, NCHz(CHz)&H2),1.97 (9, J = 6 Hz, 2 H. NHCH,CH,). 2.47 (t. J = 6 Hz. 2 H. COCHA. 3-20 (m, 6 H, NHCHz, CHzN??Hz), 8.46 (br s, 1 'H, NH). Compound 5c (5.3 g, 20 mmol) was saponified as usual to give 1.7 g (10 mmol, 51%) of amine 7c as a yellow oil: IR (film) 3300, 2960, 2880, 1636 cm-'; 'H NMR 6 1.26 (s, 2 H, NHz), 1.57 (8, 6 I H, NCHz(CH2)3CHz), 1.70-2.46 (m, 4 H, HzNCHzCHz),2.40 (t, J = 6 Hz, 2 H, COCHJ, 3.49 (m, 4 H, CHzNCHz). Amine 7c was reduced as described above. The isolated dihydrochloride (1.1 g, 5 mmol, 50%) was dissolved in 5 mL of 10% KzC03, and the solution was extracted with ether. Drying of the ether layer over K&O3 followed by rotary evaporation afforded the free diamine: IR (film) 3380,2960,1620,1055 cm-'; 'H NMR 6 1.50 (br s, 12 H, NCHz(CH&CHz, CHZCH~CHZNHZ), 2.35 (m, 6 H, CHzNCHz,CHzNH&,2.73 (t,J = 7 Hz, 2 H, CHzN);picraten mp 160-161 "C (lit.20mp 160.5 OC). N-Et hyl-N-phenyl-N'- (2,2,2-trifluoroethy1)-1,4-butanediamine Dihydrochloride (8d). N-(Trifluoroacety1)-y-aminobutyric acid (2.0 g, 10 mmol) was converted to the acid chloride and reacted with freshly distilled N-ethylaniline. The crude orange-brown oil was purified on a short silica gel column (1:2 EtOAc/hexanes) to yield 5d as a yellow oil: IR (film) 3257,3067, 2933,1704,1631,1408,1206,1175,1152,766,699cm-'; 'H NMR 6 1.13 (t,J = 7 Hz, 3 H, CH3), 1.65-2.36 (m, 4 H, CHzCHzCO), 3.33 (q, J = 6 Hz, 2 H, NHCHZ), 3.77 (9, J 7 Hz, 2 H, CH3CHzN),7.03-7.62 (m, 5 H, Ph), 8.21 (br 8, 1 H, CONH). Carboxamide 5d was reduced with BMS as described above to give a white solid, which was recrystallized from 1:2 EtOH/EkO to give 2.4 g (7 mmol, 70% from N-(trifluoroacety1)-y-aminobutyric acid) of 8d: mp 220 "C dec; IR (Nujol) 3398,2600,1604, 1277,1233,1172,934,760,697 cm-l; 'H NMR (DzO) 6 1.06 (t, J = 7 Hz, 3 H, CH3), 1.62 (m, 4 H, CHzCHzCHzCHz),3.10 (t, J = 7 Hz, 2 H, PhNCHzCHz), 3.63 (m, 4 H, CH3CHzN, CF3CHzNHCH2),3.88 ( q , J = 9 Hz, 2 H CF3CHz),7.50 ( 8 , 5 H, Ph); lgFNMR (DzOwith internal CF3COZHreference) 6 7.11 (t, J = 10 Hz, 2 H, CF-CH,). Anal. Calcd for C;,Hz&F3Nz: C, 48.42; H, 6.68. Found C, 48.29; H, 6.54. N1-Benzyl-Ns,Ns-dimethylspermidine Trihydrochloride (13a). N-(Trifluoroacety1)-y-aminobutyric acid (7.03g, 35 mmol) was converted to the acid chloride and reacted with gaseous (CH3),NH to afford 7.40 g (33 mmol, 93%) of 5e as pale yellow crystals (from 2:l toluene/heptane): mp 69-70 "C; IR (Nujol) 3257,3096,1720,1637,1195,1176,1144 cm-'; 'H NMR 6 2.01 (9, J = 7 H ~2, H, C H ~ C H ~ C H2.48 ~ ) , (t, J = 7 HZ, 2 H, COCH~), 3.05 (d, J = 3 Hz, 6 H, N(CH,).J, 3.43 (9,J = 7 Hz, 2 H, CHZNH), 8.55 (br s, 1 H, NH). Saponification of carboxamide 5e was effected as before to yield 3.2 g of amine 9a. A CHzClzsolution of 9a was reacted with 5.0 g (25 mmol) of N-(trifluoroacety1)-@-alanylchloride to give 6.7 g (23 mmol, 91%) of white crystalline product 10 (from CHzClz/EtO): mp 115-116 "C; IR (Nujol) 3255,3077,1706,1620, 1178,1148 cm-'; 'H NMR 6 1.90 (q, J = 6 Hz, 2 H, CHzCH2CHz), 2.42 (t,J = 6 Hz, 4 H, COCHZ), 3.03 (d, J = 4 Hz, 6 H, N(CHS)z), 3.27 (q, J = 6 Hz, 2 H, NHCHJ, 3.60 (9, J = 6 Hz, 2 H, CF3CONHCHz),7.00-7.25 (m, 1 H, CH,CONH), 7.78-8.09 (m, 1 H, CF3CONH). Carboxamide 10 was saponified as usual and the residue diluted with 5 mL of HzO. To this aqueous solution was added 3.15 mL (3.93 g, 28 mmol) of benzoyl chloride. The t- rphase system was stirred in a hot water bath until the benzoyl chloride phase disappeared, and an alkaline pH was maintained by the addition I
-
'
~
/I
7
1
.
~
(27) Picrates were prepared according to Shriner et al.: Shriner, R. L.; Fuaon, R. C.; Curtin, D. Y.; Morrill, T. C. "The Systematic Identification of Organic Compounds", 6th ed.; Wiley: New York, 1980; p 236.
of small portions of K2C03. This solution was allowed to cool, the product was extracted three times into 20 mL of CHC13,and the organic layer was dried over KzC03. Rotary evaporation of the CHC13gave a residue that crystallized upon trituration with EtzO. The solid was recrystallized from CHCl3/Et20to afford 1.25 g (4.1 mmol, 73%) of white crystalline benzamide 12: mp 130-131 "C; IR (Nujol) 3300,3080, 1660,1640,1550,1450,700 cm-'; 'H NMR 6 1.82 (q, J = 6 Hz, 2 H, CHzCHzCHz),2.35 (t, J = 6 Hz, 2 H, COCHz), 2.49 (t,J = 6 Hz, 2 H, COCHZ), 2.95 (9 with sh, 6 H, N(CH&, 3.28 (9, J = 6 Hz, 2 H, CHzCONHCHz), 3.67 (q, J = 6 Hz, 2 H, PhCONHCHz), 7.12-8.30 (m, 7 H, Ph, NH). Carboxamide 12 was reduced as described previously to give 1.05 g (2.8 "01,7576) of hydrochloride 13a as colorless crystals (from MeOH/EtzO): mp 198 OC dec; IR (Nujol) 1170,960,715 cm-l; 'H NMR (DzO) 6 1.50 (m, 6 H, NHCHz(CHz)2CHz, NHCHzCHzCHzN),2.36 (s,6 H, N(CH3)B),2.90 (m, 8 H, NHCH2(CH2)2CH2N,NHCHZCHZCHZNH),4.07 ( ~ ,H, 2 PhCHz), 7.26 (8, 5 H, Ph). Anal. Calcd for C16H32C13N3:C, 51.55;H, 8.65; N, 11.27. Found c, 51.88; H, 8.68; N, 11.18. N8-Adamantylspermidine Tripicrate (13b). N-(Trifluoroacety1)-y-aminobutyricacid (5.00 g, 25 mmol) was converted to the acid chloride as described above, and the acid chloride was reacted with 1-adamantylamine hydrochloride to afford 8.30 g (17 mmol, 67%) of carboxamide 5f as a white powder (from toluene/hexane): mp 142-144 "C; IR (Nujol) 3375,3309,3070, 1715,1660,1650,1195,1165 cm-'; 'H NMR 6 1.68,2.01 (br s, 15 H, adamantyl), 2.15 (m, 4 H, COCHz, CHzCHzCH,), 3.39 (q, J = 6 Hz, 2 H, NHCHz), 5.78 (s, 1 H, AdNH), 8.53 (br s, 1 H, NHCHZ). Saponification (as usual) of 5f gave 3.3 g (13 mmol, 84%) of amine 9b as a tan solid (from hexanes): mp 73-75 "C; IR (Nujol) 3300, 3070, 1640, 1539 cm-'; 'H NMR 6 1.49-2.47 (m, 21 H, adamantyl, CHzCHzNHz),2.72 (t, J = 6 Hz, 2 H, COCHz),5.74 (br s, 1 H, NHCO). Acrylonitrile (0.82 mL, 0.66 g, 12 mmol), amine 9b (3.23 g, 14 mmol), and absolute EtOH (70 mL) were stirred at room temperature for 48 h, and the ethanol and excess acrylonitrile were then evaporated under reduced pressure. The resulting yelloworange solid was recrystallized from hexanes to afford 3.25 g (11 mmol, 80%) of pure nitrile 14: mp 84-86 "C; IR (Nujol) 3368, 3297,2237,1659,1535 cm-'; 'H NMR 6 1.32-2.37 (m with major peaks at 1.69 and 2.01, 19 H, adamantyl, CH2CH2CHzCO), 2.42-3.17 (m, 6 H, COCHz, NCCHzCHz),5.33 (br s, 1 H, NHCO). Reduction of 14 as described previously followed by basification afforded p-adamantylspermidine as a pale yellow liquid: IR (film) 3336, 2909, 2841, 1444,1257, 1060, 788 cm-'; 'H NMR 6 1.65, 2.04 (br s, 25 H, adamantyl, NH, NCH2CHzCHzN, NCH,CHzCHzCHzN),2.60 (br m, 8 H, NCH,); picratez7mp 220 "C dec. Anal. Calcd for C3SH42N12021: C, 43.48; H, 4.38. Found: C, 42.66; H, 4.59. N'-l-Adamantyl-N'2,"'2-dimethylspermine Tetrapicrate (17). N-(Trifluoroacety1)-@-alanine(8.00 g, 43 mmol) was converted to the acid chloride and reacted with 1-adamantylamine hydrochloride to yield 12.9 g (41 mmol, 94%) of pure 5g (from 4:l toluene/heptane): mp 143-145 "C; IR (Nujol) 3360,3260,3117, 1720,1653,1555, 1211,1178,1152 cm-'; 'H NMR 6 1.67, 2.03 (br s, 15 H, adamantyl), 2.38 (t, J = 6 Hz, 2 H, CHzCO), 3.57 (4, J = 6 Hz, 2 H, NHCHz), 5.38 (br s, 1 H, AdNH), 7.80 (br s, 1 H, NHCHZ). Carboxamide 5g was saponified as usual to give 8.0 g (36 mmol, 91%) of amino amide 7d as a white powder (from toluene): mp 104-105 "C; IR (Nujol) 3295,1641,1549,1372,1355 cm-'; 'H NMR 6 1.67, 2.00 (br s, 15 H, adamantyl), 2.23 (t, J = 6 Hz, 2 H, CHzNHz),2.95 ( t , J = 6 Hz, 2 H,COCHz), 3.40 (br s, 2 H,NH2), 6.28 (br s, 1 H, NH). Freshly recrystallized succinic anhydride (1.60 g, 16 mmol) and 3.56 g (16 mmol) of 7d were combined in 25 mL of CHC13 and stirred for 24 h at room temperature. The mixture was transferred to a separatory funnel and diluted with 5% HC1. The layers were separated, and the aqueous layer was extracted with CHC1, (3 X 20 mL). The combined organic layers were dried (MgS04) F d concentrated on a rotary evaporator to afford a yellow solid, whch was recrystallized from 1:l 2-propanollethyl acetate to give 4.58
138
J. Org.Chem. 1984,49,138-140
g (14mmol, 89%) of carboxylic acid 15 as colorless crystals: mp 171-173 "C; IR (Nujol) 3358,3300,1721,1649,1220,1174 cm-'; 'H NMR (MezSO-ds)6 1.68,2.01 (br s, 15 H, adamantyl), 2.36 (m, 6 H, CHzCO,CHzNH),3.10(m, 2 H, NHCHzCHz),7.22 (br s, 1 H, AdNH), 7.76 (br s, 1 H, CHzNHCO). Carboxylic acid 15 (0.500 g, 1.55 mmol), 0.39 mL (0.32g, 3.11 mmol) of freshly distilled N,N-dimethyl-l,3-propanediamine (Aldrich),0.353g (1.71"01) of N,W-dicyclohexylcarbodiimide,28 and 0.975 g (6.37mmol) of 1-hydroxybenzotriazolem hydrate (Aldrich) were reacted in 5 mL of NJV-dimethylformamide according to Martinez and Bodanszky23 to afford 0.312g (0.77"01, 51%) of pure colorless 16 (from toluene): mp 184-186 "C; IR cm-'; 'H NMR 6 1.30 (m, 2 (Nujol) 3275,3090,1665,1635,1551 H, CHzCHzCHz),1.68,2.02 (8, 15 H, adamantyl), 2.26 (8, 6 H, N(CH3),), 2.40 (m, 4 H, COCHzCHzNH,(CH3)zNCHz),2.50 (m, 4 H, COCHzCHzCO), 3.44 (m, 4 H, COCHzCHzNH, 5.67 (br s, 1 H, AdNH), 6.87(br s, 1 H, CHzCHzCHzN(CH3)z), NHCO). Anal. Calcd for CzzH&&403: C, 64.99;H, 9.42;N, 13.78. Found C, 65.24;H, 9.52;N, 13.80. Triamide 16 (0.315g, 0.78 mmol) was added to a stirred suspension of 0.236g (6.2mmol) of LiAlH430in 10 mL of anhydrous ether. The mixture was boiled under reflux under Nz for 30 h. After the mixture had cooled to room temperature, saturated sodium potassium tartrate solution was added dropwise until no more foaming occurred. The resulting precipitates were removed by filtration and washed with EhO. The filtrate and washings were transferred to a separatory funnel, and a small amount of KzCO3 was added to basify the solution. The layers were separated, and the aqueous layer was extracted with three 10-mL portions of EhO. The combined organic solution was dried over KzC03and concentrated by rotary evaporation to yield 0.268 g (0.74mmol, 95%) of tetraamine 17 as a colorless oil: IR (film) ~
~~~
(28)SheehanJ. C.; Hess, G. P. J. Am. Chem. Soc. 1966, 77, 1067. (29)Konig, W.; Geiger, R. Chem. Ber. 1973, 106, 3626. (30)Brown, W. G.In 'Organic Reactions"; Wiley: New York, 1951; Vol. 6,pp 469-509.
3296,2916,1442 cm-'; 'H NMR 6 1.64 (br s,23 H, adamantyl, NH, CHzCH2CHz,CHz(CH2)&H2),1.99 (br s, 3 H, adamantyl), 2.22 (8, 6 H, (CH3),N), 2.59 (m, 12 H,NCHz). A portion of 17 was treated with excess saturated ethanolic picric acidz7to form a yellow powder, which resisted recrystallization but was washed several times with cold EtOH and twice with acetone to afford the crystalline tetrapicrate: mp 236 "C dec. Anal. Calcd for C46HS6N16028: C, 43.13;H, 4.41.Found: C, 43.81;H, 4.79. Acknowledgment. Support by a grant from the Rainbow Chapter of the Cystic Fibrosis Foundation and United Way of Cleveland and by National Institutes of Health Pediatric Pulmonary Training Grant HL 07415 is gratefully acknowledged. We also thank Halocarbon Products Corp. for a generous gift of trifluoroacetic acid, Prof. Dorr G. Dearborn and Prof. Miklos Bodanszky for valuable consultations, and Dr. Jerome Haky and Kirtivan Kotian for I9F NMR spectra. Registry No. 4b,87639-76-7; 5a,63066-15-9; 5b,87639-77-8; 512,87639-78-9; 5d,87639-79-0; 5e,87639-80-3; 5f,87639-81-4; 5g, 87639-82-5;6a,87655-14-9; 6b,87639-83-6; 7a,87639-84-7; 7b, 7d, 3728-77-6; Sa, 87639-87-0; 8b, 87639-85-8; 7c, 87639-86-9; 87639-881;8c (Y= Cl), 87639-89-2;8d, 87639-90-5;9a,87639-91-6; Sb,87639-92-7; 10,87639-93-8; 12,87639-94-9; 13a,87639-95-0; 14,87639-96-1; 15,87639-97-2; 16,87639-98-3; 17,87655-15-0; 17 (tetrapicrate), 87655-16-1; N-(trifluoroacety1)-8-alanine,5063282-1;N-(trifluoroacety1)-y-aminobutyricacid, 50632-83-2;1ad am a n t y lam ine hydrochloride , 665 - 66-7; N * adamantylspermidine, 87639-99-4;N8-adamantylspermidine tripicrate, 87640-00-4; N-(trifluoroacetyl)glycine,383-70-0; morpholine, 110-91-8; benzylamine, 100-46-9; piperidine, 110-89-4; N-ethylaniline, 103-69-5; dimethylamine, 124-40-3; acrylonitrile, 107-13-1;succinic anhydride, 108-30-5;N,N-dimethyl-1,3propanediamine, 109-55-7.
Chromatographic Separation of the Enantiomers of Acylated Amines on Chiral Stationary Phases' William H. Pirkle* and Christopher J. Welch School of Chemical Sciences, University of Illinois, Urbana, Illinois 61801
Received July 11, 1983 Enantiomers of acylated amines are chromatographically resolved on a stationary phase comprised of (R)N-(3,5-dinitrobenzoyl)phenylglycinecovalently bound to y-aminopropylsilanized silica. Among the acylating agents studied, a-naphthoyl chloride generally serves well and possesses desirable chromophoric properties. The a-naphthamides of a series of primary amines, amino alcohols, and amino acid derivatives have been found to be resolvable on the chiral stationary phase. Among the amines are various substituted cyclohexylamines. A chiral recognition model consistent with present data is described to rationalize the degree of sense of the observed chiral recognition. High-pressure liquid chromatography columns containing chiral stationary phases (CSP's) derived from the 3,5-dinitrobenzamides of a-amino acids are capable of separating the enantiomers of a great many compounds.24 HPLC columns packed with CSP's derived from (R)(1)This work has been deecribed at the 184th National Meeting of the American Chemical Society, Kansas City, MO, Sept 1982. (2)Pirkle, W. H.: Finn, J. M.: Schreiner, J. L.: Hamper, B. C. J. Am. Chem. SOC. 1981,103, 3964. (3)Pirkle, W. H.; Finn,J. M.; Hamper, B. C.; Schreiner, J. L.; Pribish, J. R. ACS Symp. Ser. 1982, No. 185, 246. (4)Pirkle, W. H.; House, D. W.; Finn,J. M. J. Chromutogr. 1980,192, 143.
phenylglycine (i.e., la-b) are commercially available5and, as we now report, are capable of separating the enantiomers of a great many acylated amines.6 Acylation of basic amines both facilitates their passage through the r-acidic CSP's, la-c, and provides functionality helpful in the chiral recognition process. While acylation of these amines with a variety of acylating agents ( 5 ) (a) Regis Chemical Co., 8210 Austin Avenue, Morton Grove, IL 60053. (b) J. T.Baker Chemical Co., 222 Red School Lane, Phillipsburg, NJ 08865. (6)This observation has been made independently by others as well. See: Wainer, I.; et al. J. Chromatogr., in press.
0022-3263/84/1949-0138$01.50/00 1984 American Chemical Society
