September 1966
67 5
SEDATIVE N-~~ONOALKYL-/?-ALKYLCINNAMIDES
cooling, the mixture was diluted with ether, washed several times with dilute KOH, and then extracted with dilute HCl. The acid extracts were separated ( a suspension of the hydrochloride may form) and made alkaline, and the organic base was extracted with ether. This solution was driedSsa and evaporated; the residue was crystallized as shown.
3-Phenyl-4-(4-methoxyphenylamino)cinnoline(Table IV, 5).A solution of 4.8 g (0.02 mole) of 3-phenyl-Cchlorocinnoline and 4.8 g (0.04 mole) of p-anisidine in 20 g of dimethyl sulfoxide was heated on a steam bath for 16 hr. After cooling, the solution was diluted with ether and worked up as in the previous example.
N-Monoalkyl-p-alkylcinnamamidesas Sedatives E. VANHEYNINGEN, C. N. BROWN,F. Jos6, J. K. HENDERSON, AND P. STARK The Lilly Research Laboratories, Indianapolis, Indiana 46206 Received February 21 , 1966
A series of N-monoalkyl-8-alkylcinnamideshas been prepared and tested for sedative action in hyperirritable rats. Several polymethoxylated derivatives in this series showed pronounced sedative action.
The sedative properties of carboxylic acid amides have been studied extensively. Cinnamamides have likewise received considerable attention, but studies seem to have been confined almost exclusively to derivatives with either no substitution at the a,p-carbon atoms or with substitution at the a-carbon ~ n l y . ~ Relatively little work has appeared in the literature concerning the sedative effects of the p-alkylcinnamamides.2 Lott and Christiansen2 showed that the greatest hypnotic activity among the cinnaniamides studied was obtained from p-methylcinnamamide. We have investigated numerous analogs of /?-methylcinnamamide, together with higher /?-alkyl substitutions, for the purpose of defining the structural modifications that could enhance the sedative effects of this class of compounds. The preparation of 0-alkylcinnamamides proceeded from appropriately substituted alkyl aryl ketones (I). -4few of the intermediate cinnamic acids were prepared by a Hauser condensationlo of ethyl lithoacetate with alkylphenyl or halophenyl methyl ketones (I), followed by dehydration of the hydroxy esters I1 and saponification to the acids IV. This procedure applied to polymethoxylated ketones was successful only if the usual dehydration agent, phosphorus oxychloride, was replaced by formic acid. The yield, however, was low (10%). As a consequence of poor over-all yields by this route, the Wadsworth-Enimons modificationll of the Wittig reaction using triethyl phosphonoacetate and sodium hydride was chosen as an alternate method. (1) K. 17. Wheeler, “Medicinal Chemistry,” Val. VI, E. E. Campaigne and W.H. Hartung, Ed., John Wiley and Sons, Ino., New York, N. Y., 1963,
It in general gave quite satisfactory yields and was employed for most of the acids prepared in this study. The phosphonate modification of the Wittig reaction favors formation of the trans i s ~ m e r . ~Because ~ , ~ ~ of the apparent homogeneity of most of the products - from ~ the phosphonate condensation, the acids were converted without purification to amides as indicated in Chart I. The use of thionyl chloride alone or oxalyl chloride in chloroform to make polymethoxylated cinnamoyl chlorides led to cinnanianiides that were difficult to purify. Conditions found to be successful were treatment of the acids with oxalyl chloride in benzene and conversion of the crude acid chlorides to cinnamamides. CHART1
0
-
OH
I
(EtO),P(O)CH, COOCIHi NaH
I11
Rf R n- @ k = C H C O O H
1. ClCOCOCl P
2 . R‘NH,
P 1.
(2) W. A. Lott and W. G. Christiansen, J . Am. Pharm. Assoc.,23, 788 (1934). (3) .4merioan Cyanamid Co., British P a t e n t 923,357 (1960); D e r a e n t Basic No. 7117. (4) American Cyanamid Co., French P a t e n t 1,332,352 (1961) ; Chem. Abslr., 69, 1543 (1963). Harrom, U. S.P a t e n t 2,98i.544 (1961); Chem. Abstr., 66, 4638 (5) B. (1962). (6) D. RI. Gallant, Ill. P. Bishop, and C. A. Steele, Current Therap. Res., I,598 (1963). (7) B. W.Harrom, U. S. P a t e n t 3,133,964; Chem. Abstr., 61, 3032 (1964). ( 8 ) C. M. Hofmann, German P a t e n t 1,167,818 (1964); Chem. Abstr., 6 1 , 6963 (1964). (9) Parke, D a \ i s and Co., British P a t e n t 663,903 (1949); Chem. Abstr., 46, 6336 (1952). (10) W.R. Dunnavant a n d C. R. Hauser, J . OTQ. Chem., 26, 503 (1960). (11) W.S. W a d s a o r t h , Jr., and W. D. Emmons, J. Am. Chem. SOC., 83, 1733 (1961).
W.
IV Rf R n--(-J-~=~~~~~HRf I \--I
In one preparation of 3,4,5-triniethoxy-P-niethylcinnamic acid through the modified Wittig reaction, the product, even when recrystallized several times, still contained about 3% 0, y-unsaturated acid as (12) L. Horner, H. Hoffmann, H . Wippel, and G. Klahre, Ber., 92, 2499 (1959). (13) D. H. Wadsworth, 0. E. Schupp, E. J . S e w , a n d J. A. Ford J . OW. Chem., 30, 680 (1965).
R'CHR"
RCR"
I
v
CHZCONHR
OCH, I
I
C,H
SEDATIVE ~'-R~ONOALKYL-@-ALKYLCINNAMIDES
September 1966
67 7
TABLEI1
p-METHYLCINN AMAMIDES
Yield,
R
No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
H H H H H €1 H H H H H
R' H CH3 CzHs
n-Cd51
2-CaH7 C3HKb s-CIH~ a-CaHy t-CaHs p-CsHnCI m-CsHaC1 H p-CsHaCHa H p-CsHaOCHa H CHI 4-CHa C3Hab 4-C1 C3HIb 4-C1 t-CaHi 3-C1 C3H65 3,4-C11 C3Hab 3-CF3 C3Hsb 4-CHaO C3Hsb 3,4-(CHaO)> CdHab t-CaHi 3,4-(CHaO)z 3,6-(CHa0)2 CaHs5 3,5-(CHaO)? z-CaH7 2,5-(CHaO)z C3Hsb 4-OH-3,5-(CHa0)? C3Hsb C3Ha5 H CHa C2Hs n-CaH7 i-CaHi CHnCECH C3Hsb s-CaHs i-CaHs t-CaHs CHaCaHsb
c /c
38.1 66.3 66.6 42.8 40.1 42.7 34.6 23.2 39.8 43.7 40.4 45.5 43.2 31.2 38.8 29.3 10.6
82.2 72.4 31.0 56.0 64.0 22 42.8 40.2 33.3 50.6 64.9 62.3 59.4 40.4 60.6 55 26.5 36.0 46.4
Mp, o c 115-117 117-118 105-107 6@62 91-93 126-127 77-80 49-52 77-80 129-130 123-125 96-97 127-128 49-51 128-130 146-147 101-102 108-109 125-127 95-96 155-156 172-173 128-129 153-154 125-127.5 108 160-161 127-128 162-164 140-142 74-76 66-68 106-108 131-132 123-124 102-103 92 151-152 230-235 (5.25 mmIc
Recrystn sol\ enta
7 - 7 0
d
I3 13 C C
.I
u 13
D A I3 A
.I E A A D A .I A
.I A .1 A A F A A
h F G -4
.1 F A I C -4
236-240 (2.55 m m ) c
CiiHmNOa
C 74.50 75.39 76.15 76.81 76.81 77.57 77.37 77.37 77.37 70.71 70.71 81.24 76.38 76.15 78.10 66.24 65.68 66.24 57.79 62.44 72.70 68.94 68.41 68.94 68.41 68.94 64.96 65.95 62.14 63.38 64.49 65.51 65.51 66.42 65.95 66.42 66.42 66.42 66.86
calcd-H N 6 . 8 7 8.69 7.47 7.99 7.98 7.40 8 . 4 2 6.89 8 . 4 2 6.89 7.51 6.96 8 . 8 1 6.45 8.81 6.45 8.81 6.45 5.19 5.15 5.19 5 , l 5 6.81 5.57 6.40 5.24 7.98 7.40 T.96 6 . 5 1 5.98 5.94 6 . 7 8 5.89 5.98 5.94 4 . 8 5 5.18 5.24 5.20 7.41 6.06 7.33 5.36 8.04 5.32 7.33 5.36 8.04 5.32 i . 3 3 5.36 6.90 5 . 0 5 7.27 4.81 6.82 5.57 7.22 5 . 2 8 7.58 L O 1 7.90 4 . 7 8 7.90 4.78 6 . 6 2 4.84 7 . 2 7 4.81 8 . 2 0 4.56 8 . 2 0 4.56 8.20 4 . 5 6 7.59 4 . 5 9
66.86
7.59
4.59
found-€1 N
E index
Dose, mdkg
74.26 75.25 76.40 76.91 76.93 77.30 77.19 77.29 77.15 70.54 70.52 81.56 76.46 75.98 77.85 66.42 65.58 66.05 57.60 62.65 72.85 68.86 68.88 69.10 68.46 68.93 65.04 64.80 62.14 63.16 64.35 65.75 65.45 66.59 66.02 66.38 66.66 66.55 66.60
6.82 7.38 7.99 8.65 8.60 7.73 8.T1 8.67 8.71 5.13 5.23 7.10 6.31 8.09 8.06 6.21 6.57 5 97 4.75 5.38 7.33 7 29 8 23 7.52 7.84 7.36 6.96 7.34 7.01 7.23 7.53 7.87 7.95 6.82 7.38 8.25 8.44 8.03 7.81
8.68 7.96 7.22 6.62 6.78 i.02 6 61 6.47 6.22 5.31 5 06 5.40 5.16 T.12 6.49 6.01 5.73 5.79 5.12 5.37 5.93 5.36 5 31 5.29 5.24 5 20 4.76 4.64 5.29 5.08 5.29 4.87 4 69
0.147 0 0.183
40
66.60
---% C
40 100
0
40
0 0
100
0 0,195
100 100
0.416 0
40 40
0.205
40
0.057 0 163 0.89
40 40 40
0 091 0.270
40
0.2il 0.279
40 40
4.83 4 47 4.60 4.40 4.56
0.382
40
0 0
40 40
7.82
4.35
0.278
40
0 150
40
0 ,054 0 193 0 . 310
100
0 014
40
100
80
4.54
I (CHa)iCCEC€I
-a -0
CHzCHaOH CHzCHnOCHa CHzCHzCH20CH3 (CHn)zCsHa-3,4(0CHa)z
-Q
55.6
157-159
A
68.12
7.31
4 . 4 1 69.20
7.57
4 19
45.0
122-122.5
A
67.69
7.89
4.39
67.75
8 08
4 31
68.2
140-141
A
68.44
8.16
4 . 2 0 68.42
8.26
4.03
46.2 65 3 73 4 86 3
124-126 92-94 95-96 82-86
-4
61.00 62.12 63.14 66.49
7.17 7.49 7.79 7.04
4.74 4.53 433 3.37
60.85 62.08 63.31 66.73
7.19 4 . 6 7 7.69 4 . 4 3 7.90 4.06 7.27 3.16
30.5
116-117
F
CiaHzoNnOa
65.84
6.13
8.53
65.57
6.22
80-80 5 119-120
h -1
CiaHnsN2Oa CisHnNOa
64.26 68.44
8.39 8.16
8 . 3 3 64.07 4 . 2 0 68.26
( C H I ) ~ N ( C H ~ ) > 37 0 C3Hsb 67 1
.I A
.L
40
40
8.35
8 . 4 5 8 19 8 . 2 1 4.00
Recrystallization solvents mere: A, beiizerie-petroleum ether (bp 60-71"); B, petroleum ether (bp 86-100"); C, petroleum ether (bp 60-71'); L), methaiiol-uater; E, p e i k n e ; F, benzene; G, cyclohexane. Cyclopropyl. c Boiling point. a
The formation of P,y isomers in the modified Wittig reaction niay be due merely to isoiiierization of initially fornied a,p-unsaturated ester to P,-y ester by the excess base present. If crude ester mixtures mere refluxed with sodium ethoxide in ethanol, the ratio between C U , ~and P,y isomers appeared unchanged, supporting this point of view. When the p-alkyl group is methyl, the point of equilibrium is at or very near to the a,P-unsaturated ester. This point of equilibrium shifts appreciably toward the p, y isomer with higher @-alkylgroups.
Several details of preparation of particular derivatives bear mentioning. An hydroxyethylamide was prepared by ester interchange of hydroxyethylarnine and methyl 3,4,5-trimethoxy-@-methylcinnainate,followed by a 1,2 oxygen-to-nitrogen shift. Preparation of N-cyclopropyl-3,5-dimethoxy-l-hydroxy-P-methylcinnamamide might have been difficult by the usual route. The corresponding triniethoxy derivative, however, was selectively cleaved by heating in collidine-lithium iodide solution to afford the 4hydroxy compound in adequate yield. The presence
679
SEDATIVE X-~~OKOALKYL-~~-ALKYLCINNA~\IIDES
September 1966
TABLE IV NMRS P E C T R . ~ ~ Cinnamamidesb
2,3,4 3,4,5 3,4,5 2,3,4 3,4,5 3,4,5 3,4,5 3,4,5 3,5; 4-OH
".
Vinyl
Aromatic
OCHa
414(2),397(2) 398 398 407 ( 2 ) ,394(2) 394 394 39': 380 401
.
Xethoxy
3Ietliine
232,228 232 231 228,231 230 230 231 229 234
347 361 361 339 349 340 350 333
358
Methylene
Methyl
184(4) 185 (4) 182 (4) 152( 3 ) , 87(6)
149 151 150 58(3) 64( 3 ) 63 ( 3 ) 56 ( 3 ) 65(2)
247 ( 7 )
154
RcR'
CHsO\
CH30~!-CH&ONHR..
Pentenoamides
CH30 R'
R
H CHI H CH3
Type of protons--------------Vinyl Methoxy
Aromatic
CH3d He CH3d He
392 382 393 383
23 1 231 231 230
364(4) 343 (4) 366 (4) 345 (4)
Methylene
;\Ieth,l
110(2) 103 (2) 111 (2) 102 (2)
204 192 204 191
R
.Iromatic
R
R'
CH3
OCsHs OH
CH3
Type of protons---------------Methoxy RIethylene
Vinyl
403 404
367 370
235 235
254 (4)
hIetliyl
80( 3 ) , 154 156
Miscellaneous Compd
R
.\romatic
Vinyl
Type of proo tns---RIethoxy
442 (2),416 (2) 441 (2),412 ( 2 )
370 ( m ) 368 (1)
239 237
391
331
228,236, 244
7
Methylene
Methyl
167(4)
143(2) 79 ( 3 )
170( 7 )
75 (2,
(Methine)
OCH, a \.allies are given as cycles per second nith splitting in parentheses; the integratiou gave the expected number of protons in every instance. Not all the signals are included: those due to alkyl groups on nitrogen were consistent with expectations and did not vary significantly between compounds, and the protons on nitrogen were not important for identification, so all arc omitted. Spectra were This is a "cis" isomer. e This is a "trans" isomer. Cyclopropyl. obtained on a n HA60. b All the cinnamamides are trans.
28.5%], and 3,4,5-triethoxyacetophenone~7~2~ [bp 155' (4mm), yield 67.67G]. 3,4,5-Trimethoxyisobutyropherione was prepared according to the method of Cason26 in 49.770yield, bp 134-136"(0.9mm). Preparation of p-Alkylcinnamic Acids. A. p-Methyl-3,4,5and Hauser trimethoxycinnamic Acid. 1. Dunnavant this method, 18.2g (0.206mole) of ethyl Meth~d.~~-Following acetate and 43.0g (0.206mole) of 3,4,5-trimethoxyacetophenone with 0.432mole of LiNHs in 500 ml of liquid ammonia yielded 37.8g (0.127mole, 61.6YG)of ethyl p-hydroxy-p-(3,4,5-trimethoxyphenyl)propionate, bp 161-164"(3.5mm). (27) G. A . Reynolds a n d C. R . Hauser, "Organic Sgntheses," Coll. Vol. I V , N. Rabjohn, E d . , J o h n \Tiley a n d Sons, Inc., New York, N. Y., 1963, p
708. (28) R . B. Moflett, A. R . Hanre, a n d P. H. Seay, J . M e d . Chem., 7, 178 (1964). (29) IT. R . Dunnavant a n d C. R . Hauser. J. Org. Chem., 25, 503 (1960).
Anal. Calcd for Cl5H2206: C, 60.39;H, 7.43. Found: C, 60.78;H, 7.56. This ester was treated with 189 ml of 987,formic acid a t reflux for 2 hr. The product was isolated by making the reaction mixture alkaline with Ka&03 and extracting the unsaturated ester with ether. Evaporation of the ether yielded the crude ester which, without further purification, was saponified by refluxing with 200 ml of ethanolic KOH (15.3g/200 ml) for 4 hr. The product was obtained by removal of the ethanol zn vacuo, acidification with dilute HC1, extracting three times with ether, and drying the ether extracts (RIgSO4). Removal of the ether yielded a solid acid which was recryitallized from benzene-petroleum ether (bp 60-71°),mp 153-155'. The infrared spectrum of this compound had absorption maxima a t 1690 cm-l for the carbonyl group and a strong band of almost equal intensity for the conjugated double bond a t 1625 cm-'. The nmr spectrum poqsesseb signals as indicated in Table I\'.
September 1966
SEDATIVE ~-nIoKOALKYL-L3-ALKYLCINNARIIDES
is observed. The ultraviolet spectra of these isomers are also consistent with the rule that a trans isomer has absorption a t longer wavelength and of higher intensity than a cis
N-Cyclopropyl-p-ethyl-2,3,4-trimethoxycinnamamide.-A 5-g sample of crude amide yielded two materials by chromatography. The more mobile material, recrystallized from petroleum ether (61-70"), 133 mg, mp 85-86', was proved by nmr and infrared spectra to be 4-ethyl-7,8-dimethoxgcoumarin. Anal. Calcd for CIaH1404: C, 66.65; €1, 6.02. Found: C, 66.94; 13, 6.33. The only other material isolated was the desired amide (1.08 9). The ethyl group \vas readily distinguished in the nmr spectrum. N-Cyclopropyl-p-ethy1-3,4,5trimethoxycinnamamide.Chromatography of a 5-g sample of crude amide mixture afforded the following products in the order that they were eluted from the column. All were recrystallized from benzene-petroleum ether. N-Cyclopropyl-@-ethy1-3,4,5-trimethoxycir1namamide was obtained in 252-mg yield. The presence of an ethyl group and one vinyl proton in the nmr spectrum established the identity of the compound. Ultraviolet spectrum showed Anlax 223 mp ( e 20,650), 280 mp (E 15,500). cis-N-Cyclopropyl-3-(3,4,5-trimethoxyphenyl)-3-pentenoamide (417 mg) was identified by the presence of a methylene next to carbonyl, a methyl on a double bond, and a vinyl proton iii the nmr spectrum. Ultraviolet spectrum showed Amax 255 mp ( e 10,600). trans-N-Cyclopropyl-3-( 3,4,5-trimethoxypheriyl)-3-pentenoamide (496 mg) possessed the same type of iimr spectrum except the vinyl proton signal was shifted upfield from the vinyl proton signal in the cis isomer and so determined its assignment as trans. Cltraviolet spectrum showed A, 240 mp (E 7630). N-Isopropyl-p-ethyl-3,4,5-trimethoxycinnamamide.-A 5 - g sample was chromatographed and the product,s are list,ed in the order they were eluted from the column. All were recrystallized from benzeiie-petroleum ether unless noted otherwise. Isopropyl 3,4,5-trimethoxyphenyl ketone was recovered in less than a 100-mg amount, mp 57.5", from petroleum ether. Anal. Calcd for CI3Hi,Oa: C, 64.53; IT, 7.61. Found: C, 64.42; €I, 7.43. N-Isopropyl-p-et~hyl-3,4,5-trimethoxycinnamamide was isolated in the amount of 1.22 g and displayed the expected ethyl group signals in an nmr spectrum. cas-N-Isopropyl-3-(3,4,5-trimethoxyphenyl)-3-pente1ioamide was obtained in 90.6-mg amount and differed from the trans isomer (146 mg) in the vinylic proton signal. N-Cyclopropyl-@-n-propyl-3,4,5-trime thoxycinnamamide.The only material isolated was the expected amide, 2.47 g of product being obtained from 6.7 g of crude amide after chroma(34) R. 31. Silverstein and G. C. Bassler, "Spectroscopic Identification of Organic Compounds," John W l e y and Sons, Inc., New York, N. Y . , 1963, p 99. I n this instance. trans refers t o phenyl and methyl trans and is t h e cwpentenoamide of our case.
tography and recryst'allization from benzene-petroleum An nmr spectrum supported the structural assignment.
68 1 ether.
N-Cyclopropyl-~-isopropyl-3,4,5-trimethoxycinnamamide.I n this preparat,ion 13.6 g of starting ketone yielded 5.2 g of crude amide mixt,ure which upon chromatography gave the following materials. A yellow oil (0.51 g) was isolated which was not further purified, but the analysis and rimr spectrum support,ed its structure as 3-isopropy1-5,6,7-trimethoxyiiidenone. See Table I V for chemical shift's. Anal. Calcd for ClJILa04: C, 68.68; €I, 6.92. Found: C, 68.79; H, 7.20. trans-S-Cyclopropyl-@-isopropyl-3,4,5trimethoxycinnamamide, obtained in a 1.58-1: yield, melted a t 154-155'. The nmr spectrum confirmed the structural assignment. A trace amount of S-cyclopropyl-3,4,5-trimethoxybenzamidewas alro iodated, mp 146-146.5', as deduced from its nmr spectrum. A small amount (200 mg) of a substance melting a t 121-122" was also obtained, but it,s struct,ural assignment is in doubt. Its elemental analysis checks with the theoretical values for the amide. .4 signal for one proton a t 350 cps would seem to indicate that this is the cis-cinuamamide, but the integration of the area in the cyclopropane proton sigiials is half that required for the amide. In all probability it is the cis-cinnamamide. A n d Calcd for ClaI12sN04:C, 67.69; H, 7.89; N, 4.30. Found: C, 67.78; H, 8.03; K,4.16. N-Cyclopropyl-3,4,5-trimethoxy-@-me thy1cinnamamide.A mixture of 5.8 g (0.02 mole) of N-cyclopropyl-3,4,5-trimethoxy@-methylcinnaniamide and 8.0 g (0.06 mole) of anhydrous LiI in 200 in1 of dry collidiiie was heated at 100" for 3 hr. Excess LiI was filtered off and the collidine was distilled in uucuo to leave a viscous residue. The residue when heated with dilute HC1 solidified and was ext'racted iuto chloroform. The CHClj solution was extracted wit,h dilute NaOH solution. Evaporation of the chloroform theri gave 4.2 g of starting material (72.57,). The reaction was repeated on the recovered amide, and prodL1ct.i obtained from the NaOH extractions on acidification were combined and recrystallized from benzene-petroleum ether, mp 160161", 1.2 g. Anal. Calcd for C151-119N04:C, 64.06; €1, 6.00; V, 5.05. Found: C, 65.04; H, 6.96; K,4.76. The aromatic protons occurred as a singlet indicating the ring was symmetrical and that each aromat,ic proton has a methoxyl neighbor.
Acknowledgment.-The authors are most' grateful to the following people for their assist'ance and contributions to the work: N r . W. L. Brown, JIr. G. AI. Maciak, Mr. D. L. Cline, A h . C. W. Ashbrook, JIr. H. L. Hunt'er, and I I r . A. Brown for the microanalyses; Dr. L. G. Tensmeyer, n h . L. A. Spangle, and JIr. J Klemm for the nmr spectra; N r , D. 0. Woolf for the ultraviolet spectra; and 3Ir. R. W. Kattau for the mouse behavior tests.
