~-~IETHYLIXDOLEH
July 1965
461
TABLEI PYRROLE
Compd.
5-Methoxy-1-methyltryptamine hydrochloride 5-Jlet hoxy-l-methyltryptamine hydrochloride 3-( 2-Acetyl-2-methylaminoethyl)-5-methox>indole (K-methylmelatonin) 5-Net hoxy-l-methyltryptophol picrate 1-Alethyltryptophol picrate Potasssium 1-metli) 1indoxyl sulfate 1,3-Dimethylindole picrate 6-11ethoxy- 1,9-dimet hyl1,2,3,4-tetrahydro-pcarboline hydrochloride Nethylyohimbine 9-Methyl-p-carboline (methylnorharman) Met hylreserpine 5-(Benzyloxy)-l-meth>Iindole 5-( Benzoyloxy )-1-methylgramine 5-( Benzyloxy )-1-methylindole-3-acetonitrile 5-(Benzyloxy)-1-methyltryptamine hydrochloride 5-Hydroxy- 1-methyltryptamine picrate (1methylserotonin ) 5-Methoxy-1-met hylindole 5-LIethoxy-1-methylgramine
N-AIETHYLINDOLES
AKD I t E L A T E D C O M P O C S D S
Formula
Method"
Carbon, 7a Found Calcd.
Hydrogen, c/o Found Calcd.
Sitrogen, 70 Found Calcd.
59 80
7.18
6.90
11.64
11.72
97-99
6Y.11
7.87
7.35
11 37
ll.3b
so
128-129
50.00
4.18
4.34
12.90
13 06
A
67
92-95
50 75
4.00
4.12
13.86
14.12
A A
40 90
40.49
3.04
3.36
5.28
5 36
.4 Ae
73 224.5-226.5
A A/
32
288-290
BY
40
131-131.5
B
93
44-45h
B
61
B
h
92
181.5-183'
13
23
176-177"
A
S
A
C12HliClX20
59 86
119 dec. 141-143d
CuHigClN20
63.03
62.77
7.18
7.20
10 50
10 45
CirHioClN,
65.02
64.93
6.36
6.09
12 64
12 bo
86.5-87
78 63
5.84
5.76
10.14
10 37
83
213-214 dec.
68 05
6.68
6.70
8.84
8 51
B
66
201-202 dec.'
48. 7 3
4.09
4 2%
16 70
16 43
B
80
B
75
100.5-101' 42-43'"
a Method -4was a methylation employing sodium in liquid KH3, method B was the procedure using methyl p-toluenesulfonate, Lit.?om.p. 176-177". LIixture melting point wit,h above, no depression. P. E. Verkade, J. Lieste, and W.RIeerburg [Rec. trav. chim., 65, 897 (1O45)] report m.p. 142.5-143.5'. e Prepared according to the method used by C. F. Huebner, R . Lucas, H. B. MacPhillamy, and H. -4.Troxell, J . Am. Chem. SOC.,77,469 (1955). / Prepared according to the method used by C. F. Huebner, ibicl., 76, 5792 (1054). Lit.lg n1.p. 130-131". Lit.1Qm.p. 48-50'. Lit.20m.p. 197-198'. J. W. Cook, J. L). London, and P. RIcCloskey [ J . C'hetti. Soc., 1203 (1951)] report m.p. 103-104". Lit.! m.p. 43-45'. Q
prepare a methylated basic intermediate by the use of methyl p-toluenesulfonate in refluxing xylene and synthesize the tryptainirie derivative from it. The preparation of I-iiiethylserotoniri was particularly successful using this latter method and is described iri Chart I. .j-~lethoxytrylptaInirie,3-methoxytryptophol, tryptophol, skatole, fi-iiiethoxy-l-niethyl-1,2,3,4-tet rahydro-pcarboline, riorharnian, yohinibine, arid reserpine all \\.ere readily 1-methylated in liquid aninioiiia. When 5-methoxytryptaniine was methylated in 1-g. quantities in this manner, the 1-methylindole was the primary product. However, preparation on a larger scale resulted i i i considerable amounts of chain N-alkylation arid quaterriization. Methylations in aninioiiia, where reaction failed to take place or tar formation occurred, were with 3-
niethoxyindole-3-acetic acid, 5-benzyloxytryptophai1, and 5-benzyloxytryptamine. Some quaternary amnioniuni iodide was isolated during the aiiimonia methylation of 6-methoxy-l-methyl-l,2,3,4-tetrahydrop-carboline. Indole S-niethylation in more complex iiiolecules such as reserpine and yohiiiibine was specific and good yields of the properly methylated indoles were isolated without quaternization. These methylations reconimend themselves for structural studies of indole alkaloids. The only compound in which methylation did not occur as expected mas melatonin; the product isolated being the chain S-methylated derivative identified by its infrared spectrum. The coiiipounds prepared and their irit eriiiediates are listed in Table I. Since use can be iiiade of sonie of these in characterization of nietabolites, their chro-
iiiatogiaphi(4 piopei tic,- c*oiiiparitig t l i v tiic~iliylatcd arialog n t 1 h t h c parent rotiipourid arc rcpoi tcd i i i Tablc
11. .\lcthylatioii iiicreased for aliiiost every ( 2 0 1 1 1 pouiid over ihc iiotiiiiet hylated arialog. l't~eviously, i t has h c ~ t iieported that iiidoles substituted on the 1tiitrogeti do iiot give a typiral Ehrlich reactioii or olse g i w a iic~gativc rcspoiiw. This has not t,ecii roilf i r t i i d w i t h tlic series desrribed heir siiire all gavv posit ivc l.:lirli(*h i'coaci toris with rolors ranging thi,ough 1hv blues, giays, purples, and hluc-gieciis uct iii'es of all coiiipounds prepared I\ ere r o r i hriiied by iiifraied spec*troscopy. On iiicthylatioii the c~hai~acteiisiic qtretchitig peal' foi* S-H i t 1 ihe region of :Z 0 p was l o h t Several ('xaiiiplea of spec8ti.a are 41on 11 111 l'igiirc~1, whet e iiiethylated iiidoles are voiiip a i d nith tlic pai(1tii (aoiiipouiid3. The csceptioti, i i i c l a i o i i i t i , is itic*ludcdh n r i i i g that pyri*ol(~ S - i i i e ~hylat l O ? l d l t l I l O t O('(~111.
P6.C. y
Pharmacological Activity 'I'hv iiiaterials were exatiiiiied priiiiartly for t h i w types of aciivtiy' effects or1 behavior, whicah were judged t o be a iesult of gross effects 011 the m i t r a l nervous systeiii : gross effects oii the cardiovascular systeiii; arid serotonin aritagoriistii oii t h e isolated rat utcrus (Table 111). The effevts on behavior consisted of i.l udyiiig coiiditioned rats on a variable-interval positive-reiriforc.ciiieiit sehedule This schedule presented the opportunity to the aniinal for reward by bar iiig (food pellets) at iritet vals of various arbitrary hs of tiiii(1. Siriw it could riot leaim the pat terii of icqueiiws of picseriicd opp(1i.tunities, it muld ohtaiii a iiiaxitiiiiiii tiuiiibci of relrards for t h e hour j i i the c~haiiitwrhy ( ~ ~ i i t i i i u i i ito g press I he bar at a steady tiidiuiii t atc. Thu., drugs either depiessed the aniiiial aiid lo\\-rred 11,s optitiiuiii worl; ratc or stimulated it t o norl, tastw iliaii thr ratc fourid chat~arteristic~ for that alii iiial. ('ardiovascular effects were studied by recording hloocl pressuro of iritact dogs anesthetized with pentoIiarhitnl diiriiig i i i i r a ~ ~ t i o i i itijci+tioir s of the c o n i poiii~d:. Seiutotiiii aiitagotiistii nab observed oii isolulod l U l l l t ~ ~ t ~II1US('lL' l s si t-tps. C'olilpoullds lvcl ( cli\-idctl tiilo thoic wliic*h ~ W I T o t o w (voiit ravt ed t h i 1
3
In an additioiial study the sei,otoiiiii-rcleasing effects platelets of iiiethylreserpiiie was conipared to that of 1-eserpine (Figure 2 ) . Effect on Behavior (Table 111). --Til gciieral, i I i ( , iiiethylated cotlipourids were qualit at ively at id quat i titatively siiiiilar to the rioiitnethylated analogs nith three except ions : 1-iinetliyliridicaii raused iiiarhetl depressioii of not'1.i rates of miditioticd aiiiiiials at (i iiig./kg., whereas iriditsan had 110 cffert at 18 iiip I;% l-.\lethylserotoriiri was about t wiw as potwit as wi*otoiiiii rreatiiiine sulfatv. It twiuired 3 . 3 iiig. kg. of 1iiiethylserotoriiti t o i d u ( ~ ethc ~ o r rates k to less t hail 25% of their Colltl.(Jl values. 111 order for serotoiiiu to achieve the saiiie effects 6.6 iiig. were requird. Tlic, I-niethylserotoriiri was used as the picrate (iiiol. wt . 419) arid the latter as the creatinine sulfate (11101. wt. 405) so the differences in potency were riot artifacts diie lo iiiolecwlar \wights of thc salts. Another variat ioii \vas bet eeii .-~-iriethoxy-l-iiietliylt ryptopliol arid ?j-tiietIioxyt rypt opliol Thc foi i i i c t raused tiiodri~atc~ depressioii of work rat (1s while the latter caused niodcr:ttc stitii~ilatioti. 'I'hesc. results are difficanlt i o ititel-
011
July 1965
METHYLIN IN DOLES
463
cnj0Cr;)cn.cn.wn. n
Figure 1.-A comparison of infrared spectra of two 1-methylated indoles with the nonmethylated analogs. The compounds, top to 3-(2bottom, are: 3-(2-rtcetylaminoethyl)-5-methoxyindole (melatonin), 3-(N-acetyl-N-methyl-2-~minoethyl)-j-metho~yind~le, aminoethyl)-5-methoxyindole hydrochloride (5-methaxytryptamine hydrochloride), and 3-(2-sminoethyl)-5-methoxy-l-methylindal~ hydrochloride. All spectra were determined with the u8e of KBr pellets.
pret; however, 5-inethoxytryptophol has been denionstrated to possess hormone-like properties in influencing the estrus cycle of rats." I n this manner, 5-methoxytryptophol could produce increases in the animal's work rates as a general endocrinological effect,. However, such interpretations must be regarded only as suggestions of a mechanism until further evidence is obtained. Effects on Blood Pressure.-A selected number of the methylindoles were paired with the nonmethylated analogs and examined for their effect on the dog's blood pressure (Table 111). In general, the methylated indoles and the nonmethylated analogs were similar in action in that 8ome were pressor, some depressor. and some were both. There were two major exceptions to the rule of similarity of action. Although yohimbinc (171 W. M. MeIasac, R. G . Taborsky. and G. Farrell, Scianee, 146. 6J (1964).
CONTROL-NO INCUBATION
0CONTROL - INCUBbTED 2 hr. RESERPINE I p p l n l . =METHYL
RESERPINE l p p . / n l .
Figure Z.-Comparison of serotonin release from platelets between reserpine and methylreserpine.
July 1965
1-nIETHYLINDOLES
methoxytryptamine and potassium 1-methylindoxyl sulfate. 1-Methylserotonin was prepared first by methylating 5-benzyloxyindole with methyl p-toluenesulfonate and then converting the methylated intermediate to the desired compound. That synthesis is described in detail below. 5-Methoxy-1-methyltryptamine Hydrochloride.-5-Methoxvtryptamine (1 g., 5.1 mmoles) was pulverized and partially dissolved in 18.0 ml. of liquid EH3, kept cold in a round-bottom flask immersed in Dry Ice-ethanol. The system was protected from atmospheric moisture. Sodium (0.15 g., 6.5 mg.-atoms), cut into small pieces was added, and the mixture was shaken for about 30 min. until all of the solids were in solution and the typical blue color disappeared. Methyl iodide (0.92 g., 6.5 mmoles) was added with shaking. A heavy white precipitate formed within 5 min. and the mixture was allowed to stand with occasional shaking for about 1 hr. more a t Dry Ice temperatures. Most of the ammonia was removed by evaporation a t room temperature; final traces were removed under vacuum in a desiccator. The product was extracted from the NaI with CHC13 and filtered. The chloroform solution (about 100 ml.) was mixed with 200 ml. of ether and filtered, and about 1.0 ml. of l5Yc methanolic HC1 was added to prepare 600 mg. of light tan 5methoxy-1-methyltryptaminehydrochloride, m.p. 174.5-176.5'. XIore ether and HCl produced a second crop of 542 mg., melting a t 166-170" to give a total yield of 937, of crude product. A portion was crystallized from 3: 1 ethyl acetate-ethanol to give an analytical sample, m.p. 182-183". The structure was confirmed by infrared spectroscopy which showed loss of the band characteristic for the indole pyrrole X-H group. Potassium 1-Methylindoxyl Sulfate (1-Methyhdican).Commercial potassium indoxyl sulfate, which is usually red by indigoid impurities was used without further purification. Potassium indoxyl sulfate (1g., 4 mmoles) was added to 20 ml. of liquid NHI in the manner described above. Pieces of sodium (120 mg., 5.2 mg.-atoms) were added; considerable agitation and stirring was required to dissolve all of the solids. Since the solution was highly colored, a glass rod was used to ensure that all of the solids were dissolved. Slethyl iodide (0.73 g., 0.32 ml., 5.2 mmoles) was added, and the rest of the reaction was carried out as described above. However, since the product was a salt, the usual method of isolation was modified. The residue was suspended in a very small quantity of cold water which dissolved most of the NaI but left much of the product in suspension. It was filtered and washed with cold ethanol and ether t o give 250 mg. of potassium 1-methylindoxyl sulfate, m.p. 122' dec., a light-colored material with a green tint. A second crop of 160 mg., m.p. 119' dec., was obtained by cooling the filtrate to give a total yield of 417,. When the material was allowed to stand or when attempts were made a t crystallization in some solvents, the color deepened to a darker green and the melting point was greatly reduced (to below 100"). Ethanol was the best solvent of crystallization found which lightened the color but had little effect on improving the melting point. ?\lost of the prodricts were white with a light green tint immediately on preparation and sharply turned deep green a t their decomposition points. 5-Benzyloxy-1-methylindole. A,-A mixture of 5-benzyloxyindole (10.0 g., 4.48 X 10-8 mole), anhydrous K&Oa (4.6 g., 4.7 X 10-2 mole), methyl-p-toluenesulfonate (8.4 g., 4.5 X mole), and xylene (40 ml.) was heated under reflux with vigorous stirring for 48 hr. After cooling, the reaction mixture was filtered, and the residue was leached thoroughly with hot xylene. The combined xylene solutions were reduced in volume by evaporation to ca. 25 ml. On cooling, yellowish crystals of the product separated out. The product was crystallized from a mixture of acetone and water to give 4.25 g. (407, yield) of material, m.p. 129.5-130.5' (lit.19 m.p. 130-131'). A second crystallization raised the melting point to 131-131.5'. B. 5-Benzyloxyindole (1.0 g., 4.5 mmoles) and sodium (150 mg., 6.5 mg.-atoms) were dissolved in anhydrous liquid PiH3 (30 ml.) with shaking. Methyl iodide (930 mg., 6.5 mmoles) was added in two equal portions over a period of 5 min., and the reaction mixture was allowed to stand overnight in the cold. The solvent was allowed to evaporate a t room temperature with stirring, and the last traces were removed in vacuo. The dark solid residue was taken up in water, the product was extracted (19) R. V. Heinzelman, W. C. Anthony, D. A. Lyttle, and J. Szmuskowiez, J. Ore. C h e n . , 26, 1548 (1960).
465
with CHCl,, and the extracts were evaporated to dryness under reduced pressure. The crude product was crystallized from acetone-water t o give 180 mg. (17%) of 5-benzyloxy-1-methylindole, m.p. 127-128.5'. Its Identity was confirmed by the fact that it did not depress the melting point of the produrt from A. 5-Benzyloxy-l-methylgramine.-Aqueous diniethylamine (25%, 3.5 nil.) was added over a period of 5 min. to a mixture of 377, aqueous formaldehyde (1.3 nil.), dioxane (16 ml.), and acetic acid (16 ml.), cooled to 10". A solution of 5-benzyloxy-lmole) in 25 ml. of dioxane was methylindole (3.50 g., 1.48 X added over 30 min. at 10". The reaction mixture was stirred in the cold for 2 hr. more, allowed to stand overnight a t room temperatiire, diluted, and filtered through Celite. An ice-cold 10% aqueous KOH solution (170 ml.) was added to the filtrate, and the mixture was cooled in an ice bath. The resulting crystals were filtered, washed thoronghly with water, and dried in the air to give 4.05 g. (1.38 x 10-2 mole, 9 3 5 ) of product, m.p. 44-45' (lit.19m.p. 48-50'). 5-Benzyloxy-1-methylgramineMethosulfate.-A solution of 5-benzyloxy-1-methylgramine (3.8 g., 1.3 X mole) in absolute tetrahydrofuran ( T H F ) (30 ml.) and glacial acetic acid (0.3,; ml.) was added dropwise over 30 min. to a stirred mistrire of dimethyl sulfate (8.2 g., 6.5 X lo-* mole), absoliite T H F (10 ml.), and glacial acetic acid (0.35 ml.) cooled to 10". il crystalline precipitate began to settle oiit in a few minutes. When addition was complete, the reaction mixture was allowed to stand in the dark a t room temperature for 2 hr. The product was collected, washed thoroughly with anhydrous ether, and dried in z)acuo to give 4.5 g. (847, yield) of the quaternary methosulfate, m.p. 136-137.5'. This compound was not further purified brit used directly in the next step. 5-Benzyloxy-l-methylindole-3-acetonitrile.-Asolution of 5benzyloxy-1-methylgramine methosulfate (3.5 g., 8 3 mmoles) and NaCN (1.1 g., 22 mmoles) in water (30 ml.) was heated a t 80" with vigorous stirring for 3 hr. During this time the reaction mixture became turbid and a yellowish oil separated out, which solidified on cooling. The product was filtered, washed with water, and dried in air to give a yield of 1.4 g. (el?), m.p. 82-84'. The filtrate from the above reaction was heated with stirring a t 80" overnight (ca. 16 hr.) and worked up as before t o give 0.5 g. more of the product, m.p. 77-82". Two crystallizations from a mixture of acetone and water yielded an analytical sample, colorless plates, m.p. 86.547'. 5-Benzyloxy-l-methyltryptamine.-A suspension of 5-benzyloxy-1-methylindole-3-acetonitrile (1.3 g., 4.7 mmoles) in anhydrous ether (160 ml.) was added dropwise to a vigorously stirred suspension of LiAlH4 (0.54 g., 11 mmoles) in anhydrous ether (40 ml.). The reaction mixture was then heated for 16 hr. under gentle reflux. The excess LiA1H4 was carefully decomposed with a few milliliters of water, and a 10% aqueous NaOH solution (55 ml.) was added to the reaction flask. The ether layer was decanted off, the aqueous layer was filtered, and the filtrite was extracted with ethyl acetate. The combined ether and ethyl acetate solutions were evaporated to dryness under reduced pressure, then dried further zn vacuo to give 1.1 g. (83%) of crude product ip the form of a brownish oil. I t was dissolved in 30 ml. of toluene, and anhydrous HC1 bubbled through the solution. The precipitate that formed was collected, washed with acetone, and dried in the air to give 0.73 g. of yellowish crystals of 5-benzyloxy-1-methyltryptamine hydrochloride (557, yield), m.p. 208-211' der. Two crystallizations from a mixture of 4: 1 toluene and ethanol gave an analytical sample, colorless crystals, m.p. 213-214" dec. 5-Hydroxy-1-methyltryptamine (l-Methylserotonin).-5Benzyloxy-1-methyltryptamine hydrochloride (113 mg., 0.357 mmole) was taken up in a 107, aqueous NaOH solution. The free base was extracted with ethyl acetate, and the extract was evaporated to dryness under reduced pressure, then dried further zn vacuo. A mixture of the free base (99 mg , 0.354 mmole), lOy0 palladium-charcoal catalyst (25 mg.), and methanol (25 ml.) was hydrogenated in a Parr apparatus a t 2.8 kg./cm.2 pressure for 16 hr. The reaction mixture was filtered, and the filtrate was reduced in volume a t reduced pressure to ea. 2 ml. The latter solution was added to a boiling solution of picric acid (70 mg.) in methanol ( 3 ml.). After cooling, the orange precipitate was filtered and dried in air to give 98 mg. (66% yield) of 5hydroxy-1-methyltryptamine picrate, m.p. 194.5-195.5' dec. (liL20 m.p. 197-198' dec.). Two crystallizations from water (20) E. Shsw. J. A m . Chem. Soc., 77, 4819 ( 1 9 5 5 ) .
