[CONTRIBUTION FROM
THE
CHEMISTRY DEPARTMENT OF LOS ANGELES]
THE
UNIVERSITY OF CALIFORNIA,
SUBSTITUTED a-DIALKYLAMINOALKYL-1-NAPHTHALENEMETHANOLS. I. AMINO KETONE METHOD1 THOMAS L. JACOBS, S. WINSTEIN, JACK W. RALLS, JOHN H. ROBSON, ROBERT B. HENDERSON, RICHARD I. AKAWIE, WARNER H. FLORSHEIM, DEXTER SEYMOUR, AND CHRISTIAN A. SEIL
Received October i6, 1946
Attempts to discover an effective antimalarial drug have been based in part on modification of the structure of quinine. Among the simplest compounds examined were ethanolamine derivatives such as quinolyl-CHOHCHzNRa and related substances in which other aryl groups, including naphthyl, replaced quinoline (1, 2, 3, 4). A thorough investigation of such compounds was undertaken a t the National Institute of Health to determine the influence of various nuclei on antimalarial action (5). It was found that, among others, compounds of this type containing the a-naphthyl nucleus possessed some antimalarial activity in avian malaria (6), although King and Work (1) had not observed activity in similar substances. The corresponding &naphthyl derivatives were much less active. As part of a cooperative project with the National Institute of Health, we have extended the work on the a-naphthyl compounds by synthesizing dialkylaminomethyl-1-naphthalenemethanolsin which the naphthalene nucleus was substituted in various positions with halogen or methoxyl and in which the dialkylamino group vaned from dimethylamino to di-ndecylamino. The conventional synthesis of such ethanolamine derivatives involves the reaction of an a-halo ketone such as I with a dialkylamine to yield an amino ketone I1 which is then reduced. COCHzX
I
COCHzNR:, I
CH( 0H)CHzNRZ I
I I1 I11 All of the compounds reported in this paper were prepared thus, although yields were often poor and k a l products difhult to purify. These difficulties led us to devise other synthetic methods which are described in later papers of this series (7, 8). It is probable that the compounds reported in the present paper could have been prepared more readily by these alternative procedures. The halo ketones, I, which served as starting materials for the synthesis, were 1 This work was done under a contract, recommended by the Committee on Medical Research, between the Office of Scientific Research and Development and the University of California, Los Angeles. The survey number, designated SN, identifies a drug in the records of the Survey of Antimalarial Drugs. The antimalarial activity of those compounds to which such numbers have been assigned will be tabulated in a forthcoming monograph.
21
22
JACOBS, WINSTEIN, ET AL.
usually prepared in excellent yield by brominating the corresponding methyl ketones which were available from the Friedel and Crafts reaction. In the case of 4-methoxy-l-chloroacetonaphthone,however, it was easier to prepare the chloro ketone directly by a Friedel and Crafts reaction of 1-methoxynaphthalene and chloroacetyl chloride. The details of the synthesis of the 4-halogen-substituted acetonaphthones are given in a separate paper (9). The reaction of naphthacyl halides with dialkylamines has been reported by Day and co-workers (10, 11) in addition to the investigators already mentioned (1, 5, 6 ) but the instability of the resulting amino ketones has not been emphasized. a-Amiio ketones are known to be unstable when the amino group is primary or secondary (10, 12), but a-dialkylamino ketones are usually easy t o isolate, although they are frequently reduced to amino alcohols without isolation, and in some cases the yields are poor (1). It was reported that piperidinomethyl 4-quinolyl ketone darkened on exposure to light (3) while a-tetrahydroisoquinoliio-@-acetonaphthone turned pink on standing in air and the yield in its synthesis decreased if the reaction mixture stood too long (11). Small and co-workers (5, 6 ) noted the ease of decomposition of aryl dialkylaminomethyl ketones, especially on heating (as in attempted distillation), and reported that purification before reduction had never been necessary in their experience. We followed their directions with but few modifications, adding the a-haloacetonaphthone slowly to two molecular equivalents of dialkylamine in dry ether to avoid quaternary salt formation, (RCOCHS)~NR~+X-.After removing the dialkylamine hydrohalide by filtration, the ether was evaporated under diminished pressure and the ketone reduced directly. It was always contaminated by a dark red impurity which made isolation of the final product difficult. When the halo ketone was 4-methoxy-1-naphthacyl halide all attempts to isolate a-dialky laminomethy l-4-met hoxy-1-naphthalenemet hanols failed until the reactions were carried out under nitrogen. In the presence of oxygen the products were largely intractable tars, although 4-methoxy-1-naphthoic acid was isolated in several instances. Time was not available for an examination of this side reaction, but it was found desirable to carry out both the condensation and reduction of the methoxyl-substituted compounds under nitrogen and even then the crude products were dark and purification difficult. With halogensubstituted naphthalene compounds the exclusion of air seemed to do little good. The reduction of a-dialkylaminomethyl aryl ketones has usually been carried out catalytically (1, 2, 3, 4, 10, 11).2 Among chemical methods of reduction may be mentioned sodium and alcohol (13, 14, 15)) sodium amalgam (16)) and sodium ethoxide in alcohol (17). Aluminum amalgam has given hydramine fission (2, 17). The aluminum isopropoxide-isopropyl alcohol method appears to have been tried first on this type of compound by Work (2), who reported that the reduction of 1,12-dipiperidino- or bisdiethylamino-2 ,11-diketododecane or the corresponding tetradecanes was impractical with this reagent. Burger 2 These references are to the reduction of naphthyl and quinolyl compounds and represent only a few of the many examples in the literature.
DIALKYLAMINOALKYLNAPHTHALENEMETHANOLS. I
23
and co-workers (18, 19,20) used the method successfully on a number of heterocyclic dialkylaminomethylketones and Mosettig and co-workers (5,6) applied it independently to a large variety of aryl dialkylaminomethyl ketones. In many cases it gives cleaner products and avoids cleavage of the C-N bond. Since most of our compounds contained nuclear halogen which might be removed by other reducing agents, aluminum isopropoxide was always used. Table. I summarizes the compounds which we prepared by the amino ketone method. EXPERIMENTAL
All melting points are corrected unless marked otherwise. Analyses were by Jack W. Ralls or Bruce Day. w-Bromo-1-acetonaphthones. To 0.5 mole of the substituted acetonaphthone in 450-500 ml. of anh. ether in a 1-liter, 3-necked flask equipped with mechanical stirrer and droppingfunnel was added 0.5 mole of bromine with stirring. The first drops of bromine were added a t the b.p. of ether, and when the solution had decolorized, the flask was cooled in ice as bromine was added dropwise. The bulk of the bromine was added a t 10-15" in fifteen to thirty minutes and the solution was then washed several times with water to remove hydrogen bromide and dried over anh. potassium carbonate or magnesium sulfate. This solution was usually diluted with anh. ether and used directly in the amine condensation, but the ether could also be removed and the solid product recrystallized. Table I1 gives the data on the compounds prepared. 2-Methoxy-o-bromo-1-acetonaphthone wag contaminated with an oily impurity which made purification necessary. The synthesis of 4-haloacetonaphthones is described in the next paper (9). One trial of Noller and Adams' directions (21) for the synthesis of 2-methoxy-1-acetonaphthoneby the Friedel and Crafts reaction between 2-methoxynaphthalene and acetic anhydride gave a low yield, and most of the material used was prepared from acetyl chloride (22) by a procedure involving remethylation of the crude reaction product with dimethyl sulfate before isolation. The yield was 50% and 21% of 2-methoxynaphthalene was recovered. 4-Methoxyw-halo-f -acetonaphthone (23, 24). The o-chloro compound was prepared according to the directions of Madinaveitia and Puyal (23) in 64-70% yield, m.p. 70.5-71' after recrystallization from alcohol. The m.p. has been reported as 70" (23) and 85" (24). The product could be distilled at 1 mm. with some decomposition. 4-Methoxyw-bromo-1-acetonaphthone(25) was prepared similarly from bromoacetyl bromide in 70% yield, m.p. 72.5-73.0' (reported 70"). It was also obtained in lower yield by using acetyl chloride in the Friedel and Crafts reaction with 1-methoxynaphthalene and brominating the product. w-Dialkylamino-1-acetonaphthones.To 0.2 mole of dialkylamine' in 150-200 ml. of anh. ether in a 500 ml., 3-necked flask equipped with a mercury-sealed stirrer, condenser, and dropping-funnel, was added 0.1 mole of substitutedw-halo-1-acetonaphthone in 75 to 100 ml. of anh. ether during fifteen minutes or longer. It was sometimes necessary to cool the solution and to add more ether to facilitate stirring. With 2- or 4-methoxyw-halo-1-acetonaphthones a nitrogen atmosphere was maintained throughout this reaction and the subsequent reduction, but with halogen-substituted o-bromo-1-acetonaphthonesthis was usually not done. After further stirring and standing for one hour or longer the dialkylamine hydrohalide, usually pure (95-99% yield), was removed by filtration. If the ethereal filtrate does not remain free from crystalline precipitate the reaction is not complete. Any hydrobromide remaining may be removed by 8 The dialkylamines were supplied in most cases by Dr. Elderfield and co-workers of Columbia University, although some were purchased commercially from Eastman or Sharples..
24
JACOBS, WINSTEIN, ET AL.
TABLE I DIALKYLAMINOMETHYL-1 -NAPHTHALENEMETHANOLS
-
3
,OLWIL ITY AT 25' OF
rj, )O
SN'
SUBSTITUENT
ON
NAPHTHALENE
DIALKYLAMINO GROUP
] &;
q
EYDBOCHLC:IDE, G., 100 ha. WATEP
15g
!" -
__
4-ChlOrO 527;
22 31
5376 524: 6761 537t
Dipropyl Dibutyl Dihexyl Piperidino
65 7 4 65 34 77 18 28
b185-187 '125-126 e 4-8.5 bdec .
8741 4-Fluor0 6716
Diethyl Dibutyl
37
b150-151 '119-121
4-Bromo
35 52
G185-186.5 b185.5-186.5
-
~ 2 . 5 2 "59.7859.11 5.735.96 18.8 d61.15 61.57 6.74 6.91
(?I
19
42
P
-
Dimethyl Diethyl
-
ANALYSES
84
0.69 0.81 0.93 37 2.2
d63.1563.437.367.45 d64.86 65.01 7.89 7.98 873.91 74.11 9.31 9.47 d62.5862.586.49 6.18
----
d64.5364.647.117.23 d67.87 68.16 8.26 8.38
----
G4.08 54.16 5.17 5.30
Dimethyl
590.
Diethyl
45
71
92-93 '200-201
2.01
d53.57 53.54 5.90 5.99
647:
Dipropyl
45
68
c40-41 b181-183
0.60
d55.89 56.09 6.52 6.65
645:
Dibutyl
55
65
"44-45 S135-150
0.55
d57.91 57.91 7.057.11
"53-54 bl0 1-1 03
0.00
a66.3466.498.598.47
b.
6451
Dihexyl
__
___-- - -
7731 2-Methoxj
Diethyl
23
37
b180.5-181. 5
7.34
d65.9065.697.81 7.51
700:
Dibutyl
46
63
'171-172
1.50
d68.9368.668.81 9.02
737!
Dihexyl
47
70
bJ113-114 128-130
0.14
d71.14 70.91 9.55 9.73
524t 4-Methoxj 640!
Diethyl )Dibutyl
25
74
- -
* See footnote a
6-3 1 65 54 8
--
b180-182 unc. '147-149 unc.
--
-
----
________-
d65.9065.84 7.81 7.91 d68.93 68.45 8.81 8.90
1.
Data for the p-toluenesulfonate. The hydrochloride could not be induced to crystal-
lize. M.p. of the hydrochloride. M.p. of the free amine. d Analysis of the hydrochloride. Analysis of the free amine. I The compound exists in two crystalline forms. p This broad m.p. is due t o a change in crystalline form. h This product was distilled in a molecular still at 10-4 mm. It has been prepared by other methods (7, 8). b c
25
DIALKYLAMINOALKYLNAPHTHALENEMETHANOLS. I
extraction with a little dilute sodium hydroxide, but this step was often omitted and the ether removed from the filtrate directly under reduced pressure. The ether may also be removed at ordinary pressure, especially with the more stable 4-bromo-w-dialkylamino-lacetonaphthones. The condensation of tetrahydroquinoline with 4-chloro-w-bromo-lacetonaphthone was not successful using these directions; the yield of tetrahydroquinoline hydrobromide was only 25% after fifteen hours. I n earlyruns, when the reaction of 4-methoxy-1-naphthacyl chloride with di-n-propyl- or di-n-butyl-amine and subsequent reduction were carried out without exclusion of air, the only pure product isolated was 4-methoxy-1-naphthoic acid, m.p. 239.5-241.5'. The literature contains melting points ranging from 230' to 239' for this compound (23, 26, 27, 28). The mixture of our sample and one, m.p. 242-243", obtained by the action of carbon dioxide on 4-methoxy-1-naphthylmagnesiumbromide (29) showed the m.p. 240-243". Aluminum isopropoxide reduction. Isopropyl alcohol was dried by refluxing over and distillation from calcium oxide, followed by distillation from aluminum isopropoxide. Aluminum isopropoxide was prepared by the method of Young, Hartung, and Crossley (30) and usually distilled before use. The dark red or brown dialkylaminoacetonaphthone was dissolved in 200-300 mi. of isopropyl alcohol in a 5 W m l . flask (standard taper neck) and 110 ml. of 1 M aluminum isopropoxide in isopropyl alcohol was added. This solution was distilled at a moderate TABLE I1 U-BROMOACETONAPHTHONES ANALYSES SUBSTITUENT
YIELD
%
M.P.,
"C
Obs. _ _ _ _ _ _ ~ -
-
4-Chloroc'. . . . . . . . . . . . . . . . . . . . . 4-Bromos. . . . . . . . . . . . . . . . . . . . 4-Fluorob. . . . . . . . . . . . . . . . . . . . . . 2-Methoxy a . . . . . . . . . . . . . . . . . . . a
b
92 92-95 72-75 60
%H
%C
50-51 68-68.5 4344 100-101
1
Calc'd
Obs.
Calc'd
50.83 43.95 53.98 55.95
51.07 43.97 54.06 55.91
2.84 2.46 3.02 3.97
3.03 2.61 3.13 4.03
Recrystallized from hexane. Recrystallized from methanol.
rate (20-30 drops per minute) through a 40-cm. all-glass Vigreux column or from the apparatus described by Lund (31), and acetone determined in the distillate by themethod of Marasco (32). If excess volatile dialkylamine is present (as diethylamine) i t interferes with this determination. The distillation was continued until the distillate contained very little acetone (usually four to eight hours), more isopropyl alcohol being added if necessary. The yields of acetone are detailed in Table I. The isopropyl alcohol was then removed from the reaction mixture under reduced pressure and the dark red product treated by one of the following methods. When the dialkylamine group was lower than dibutylamine or in all cases where the substituent on the naphthalene nucleus was methoxyl, the reduction product was treated with ice and 200 ml. of 10 N sodium hydroxide with stirring until all the solid had disappeared. With those methoxynaphthalene derivatives having dialkylamine groups above butyl this solution was steam distilled t o remove the dialkylamine (for dihexylamine, under reduced pressure), The reaction mixture was then extracted several times with ether, the ether washed with water and dried thoroughly. The product was precipitated as the hydrochloride by using dry ethereal hydrogen chloride or by passing the dry gas over the surface. It was usually necessary t o add the hydrogen chloride in several portions, separating the solid after each addition, and t o avoid a n excess of the reagent in order to avoid oils, but with the 4-bromo compounds these precautions were unnecessary. 4-Methoxy-a-dibutyl-
26
JACOBS, WINSTEIN, ET AL.
aminomethyl-1-naphthalenemethanol could not be obtained in a crystalline state by this method until it had been distilled in the molecular still. With the dimethylamino compounds the hydrochlorides were always obtained as oils and purification was accomplished through the p-toluenesulfonates. 4-Halo-dibutyl- or dihexyl-aminomethyl-1-naphthalenemethanolswere more easily purified by treating the crude reduction product with 500 g. of ice and 200-250 ml. of 3 N sulfuric acid with stirring until no solid was present. The resulting 2-phase system was extracted several times with benzene, the benzene solution washed with water, three times with 5% sodium bicarbonate, again with water and concentrated on the steam-bath t o 300 ml. Anh. ether was added and the hydrochloride precipitated as above. The yields of pure products, physical constants, and analyses are given in Table I. SUMMARY
Eighteen a-dialkylamhomethyl-1-naphthalenemethanohcontaining halogen or methoxyl in the 2- or 4-position of the naphthalene nucleus have been synthesized by condensation of the corresponding w-bromo- or -chloro-1-acetonaphthones with dialkylamines and reduction of the amino ketones by aluminum isopropoxide. Los ANGELES,CALIF. REFERENCES (1) KINGAND WORK,J. Chem. Soc., 1307 (1940); 401 (1942). (2) WORK,5. Chem. Soc., 1315 (1940). (3) KAUFMANN, Ber., 46, 1823 (1913). (4) RABE,PASTERNAK, AND KINDLER, Ber., 60, 144 (1917). ( 5 ) SMALL AND FRY, Private Communication, December, 1942. (6) FRYAND MOSETTIG, unpublished results. (7) WINSTEIN,JACOBS, HENDERSON, AND FLORSHEIM, J. Org. Chem., in press. ( 8 ) WINSTEIN,JACOBS, HENDERSON, ROBSON, AND DAY,J. Org. Chem., in press. (9) JACOBS, WINSTEIN,RALLS,AND ROBSON, J. Org. Chem., 11, 27 (1946). (10) IMMEDIATA AND DAY,J. Org. Chem., 6,512 (1940). (11) ALLEWELTAND DAY,J.Org. Chem., 6,384 (1941). 32) GABRIEL,Ber., 41, 1127 (1908). (13) RABEAND SCHNEIDER, Ann., 366,377 (1909). (14) HENLEYAND TURNER, J. Chem. SOC.,1182 (1931). (15) British Patent 371490, I. G. FARBENINDUSTRIE, Chem. Abstr., 27, 3036 (1933). (16) RUBERG AND SMALL, J. Am. Chem. Soc., 63,736 (1941). (17) HAMPTON AND POLLARD, J. Am. Chem. SOC.,69, 2570 (1937). (18) BURGER AND HARNEST, J. Am. Chem. Soc., 66, 2382 (1943). (19) BURGER, ALFRIEND, AND DEINET,J. Am. Chem. Soe., 66, 1327 (1944). (20) BURGER A N D DEINET,J. A7n. Chem. SOC., 67,566 (1945). (21) NOLLER AND ADAMS,J.Am. Chem. Soc., 46,1889 (1924). (22) GATTERMANN, EHRHARDT, AND MARSCH, Ber., 23, 1199 (1890). (23) MADINAVEITIA AND PUYAL, Anales SOC. espafi. fis. quim., 17, 125 (1925); Chem. Abstr., 14, 3406 (1920). (24) JOHANNSSEN, Dissertation, Rostock (1898) ; Bedstein, Supp. Vol. 8, 567. (25) KUNCKELL AND SCHEVEN, Ber., 31, 172 (1898). Bull. SOC. chim., (3) 17, 300 (1897). (26) ROUSSET, (27) GATTERMANN, Ann., 244, 73 (1888). AND ZERWECK,U. S. Patent 1,669,297, Chem. Abstr., 22,2170 (1928). (28) HERZ,SCHULTE, AND JACOBS, J. Org. Chem., in press. (29) SPAETH, GEISSMAN, (30) YOUNG, HARTUNG, AND CROSSLEY, J. Am. Chem. Soc., 68, 100 (1936). (31) LUND,Ber., 70, 1520 (1937). Ind. Eng. Chem., 18, 701 (1926). (32) MARASCO,
