6322
SEY3lOUR
L.
SHAPIRO, IRA
VOl. SI
lf. ROSEAND LOUISFREEDMAN
nents under the conditions employed in our experiments were 34, 59, 62, 77 and 95 seconds. The component with the shortest retention time is ketobicyclo[2.2.1] heptane, and the other two major products with retention times of 59 and 62 seconds are believed to be the 1-nitro- and 7-nitrobicyclo[2.2.l]heptanes. The vapor chromatogram showed that these latter two components were present in almost equal concentrations. The retention time for the alkali-soluble 2-nitrobicyclo j2.2.11 heptane under conditions identical t o those employed above was 58 seconds. The minor components of the alkali-insoluble product were eluted at retention times of 77 and 93 scconds. I n addition to the carbonyl and nitro bands found in the infrared spectrum of this sample a weak doublet at 2.83 and 2 . 8 7 ~indicated the presence of some hydroxy compound. Nitration of Decahydronaphtha1ene.-A 207-g. (1.5 ~ was moles) sample of decahydronaphthalene ( a z 61.4694) charged t o a 1-liter stainless steel autoclave, pressured to 309 p.s.i.g. and heated t o 120’. At this point 34.5 g. (0.75 mole) of nitrogen dioxide dissolved in 100 ml. of carbon tetrachloride (0-5’) n a s fed into the reaction zone by means of a Milton Roy feed pump. After a total reaction period of 1 hour (50 minutes feed and 10 minutes cook), the autoclave was cooled t o room temperature. The reaction mixture wag washed first with 150 ml. of water and then extracted Tyith a 5% sodium hydroxide solution for 18 hours. The alkaliinsoluble portion was washed with water and dried over anhydrous magnesium sulfate. Distillation of the dried solution at reduced pressure yieldzd 122.4 g. (%yorecovery) of
decahydronaphthalene, b.p. 70’ (11 m m . ) , 32.1 g. of higherboiling material ( n * j ~1.4929-1.5010), and a pot residue weighing 16.7 g. The 32.1-g. portion of the distillate was extracted by 130 ml. of 10-15y0 sodium methoxide for 2.5 hours. The mixture then was diluted with 200 ml. of water, extracted by four 75-1111. portions of diethyl ether, and dried over anhydrous magnesium sulfate. Distillation of the alkaliinsoluble material yielded 10 g. of g-nitrodecahydronaphthalene, b.p. 60-85” (0.2 mm.). This amount of product represents a 9.0% yield based on the amount of decahydronaphthalene consumed. The infrared spectrum of the product coincided with that of 9-nitrodecahydronaphthalene which was reported previously.l4 Also, the refractive index of the product ( ~ 2 1.4925) 6 ~ was in excellent agreement with that reported in the literature.l4-’8
Acknowledgments.-The author wishes to thank Mr. L. J. Lohr for the interpretation of the infrared spectra and the vapor phase chromatographic work, and Prof. J. D. Roberts for supplying infrared spectra of authentic samples of 2-nitronorbornane and norcamphor. (14) D. K. Brayn, Dissertation, Ohio State University, 19.51. (15) S. Nametkin and D. Madaev-Ssichev, Ber., 69B, 370 (1920). (16) W.Hiickel and M. Blohm, A n n . , 602, 114 (19.33).
GIBBSTOWN, N. J.
[CONTRIBUTION FROM THE ORCASK RESEARCH LABORATORIES OF THE
u. S. VITAMIN AND PHARMACEUTICAL CORP.I
a-Hydroxy Amides and Related Compounds BY SEYMOUR L. SHAPIRO, IRAhl. ROSEAND LOUISFREEDMAN RECEIVED MAY21, 1959 A series of a-hydroxyamides and the corresponding alkyl carbonate esters of type I have been synthesized and examined for anticonvulsant activity. The best activity has been noted with the N-aralkyl glycolamides. The spectra of I, where R is phenyl and substituted phenyl, have been determined and compared with the analogous acetanilides.
While a wide variety of recent studies of carboxylic acid amides hasshown pharmacological activity, there has been relatively little systematic explorntion2 of the amides of a-hydroxy acids. Studies3 of such amides, and derivatives of these conipounds of the type I are herein described. R1 0 I€
1 - /I
I
R2C-C-NR I OR3 I R = alkyl, aralkyl, aryl R3 = hydrogen RI, Rz = H,CHI, CsH5 -COOCH, -COOC*Hs (E) -COOCsH?-n (P) -COO(CHz)?Cl ( C E ) -COO( CK2)aCl (CP) Interest in the structures I (R3 = H) was indi-
{E))
related acetanilides4 and the potential for conversion of I to substituted oxazolidinediones.s I n turn, the variant of I employing the carbonate esters (R3, other than H), was introduced to afford more lipophilic structures of varying hydrolytic stability.6 In addition, the carbonate esters were required as intermediates for conversion to carbamates. The compounds prepared have been described in Table I. Some variants of I are detailed in the Experimental section. Most of the amides (I, R 3 = H ) were prepared by ammonolysis of the ethyl esters of the ahydroxy acids (method A). H
r
!-
cated from the noted therapeutic usefulness of the (1) (a) S. R. Safir, H . Dalalian, W. Fanshawe, K. Cyr, R. Lopresti, R. Williams, S. Upham, L. Goldman and S. Kushner, THISJOURNAL, 77, 4840 (1955); (b) H. Rosen, A. Blumenthal, P. N. Townsend, R. Tislow and J. Seifter, J . Pharmacal. Exp. Thcrap., 117, 488 (1956); (c) F. Ascoli Marchetti and M. L. Stein, Gass. chim. i l d . , 84, 816 (1954); (d) C. Malen and J. R. Boissier, Bull. SOC. chim. France, 923 (1956); (e) H . Martin and H. Zutter, U. S. Patent 2,773,899 (Dec. 11, 1956); ( f ) H . Martin and E. Habicht, U.S. Patent 2,848.364 (4ug. 19, 1958); ( g ) R. I. Hewitt and L. H. Taylor, U. S. Patent 2,877,156 (Mar. 10, 1959). (2) (a) H. NIcIlwain, “Chemotherapy and the Central Nervous System,” Little, Brow-n and Co., Boston, Mass., 1057, p. G7; (b) F. A. Crunwald, U. S. Patent 2,764,613 fSept. 25, 1956). (3) For related work see S. L. Shnpiro. I. hf. Rose and I,. Freedman, THISI ~ I . H N A I81. . . 3083 (1959).
0’0-
I
I
RIRIC-C-OC,€I~
I1
HhR
1
1
This is a relatively complex reaction, responsive to steric factors and the basicity of the amine, and is promoted by the a-hydroxy group in the acylating (4) A. Burger, “Medicinal Chemistry,” Interscience Publishers, Inc., New York, N. Y.,1951, pp. 196-199. (5) S. L. Shapiro, I . M. Rose, F . C . Testa, E. Roskin and L. Freedman, THISJOCRN.4L, 81, Dec. 20, (1959). (6) T h e order of decreasing hydrolytic stability would be estimated CE, M , E, P ; see (a) K . H. Vogel and J. C . Warner, i b i d . , as Rs 7 6 , 6072 (1953); Ib) A. A. Colon, K. H. Vogel, R. B. Carlin and J. C. Warner, ibid., 76, 6075 (1983).
-
6323
a-HYDROXY AMIDES
Dec. 5 , 1936
TABLE 1 0 H
I1 I
HYDROXYAM AMIDES R1R2CC-NR
I
OR:
Rg=H M (COOCHs) E (COOC2H6) P (COOCsH,-n) CE (COOCH2CHZCl) C P (COOCH2CHzCHzCl) Analyses, 6 yo
h-0.5
R
Rs
M.p.b or b.p., "C. (mm.)
RSC
Yield,d
%
Formula
Carbon Hydrogen Nitrogen Calcd. Found Calcd. Found Calcd. Found
Ri = H, R2 = H
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 26'2 27 28"s 29 3oa4 31 32"s 33 34 35 36 37 38 39 40 41 42 43 44 45 46"s 47 48 49 50 51 52"7 53 54 55 56
H
E H M E P CE CP H H E H E H E H hl E P
CP H E H
M E H
E H E H E H E
H E H E
H M E P CE CP H E H E CE i
H E H E H E H
90-llO(O.04) 50-51 103-104 101 81-82 64-66 65-66 66-67 133-134 140- 142 105-106 55-56 56-57 99- 101 76-77 74-75 62-63 67-68 56-57 66-68 75-76 79-80 95-98 146-150 122-123 91-92 76-77 63-65 93 143-145 105-106 92-94 129-130 92-95 99-101 86- 87 03-94 169-170 100-101 100-101 105-106 138 95-96 88-89 130-131 177-178 95-96 110 166-168 107-108 59-60 9599 83-84 80-81 65-67 84-85
A A A A A A A B B A A A A A A A A A A A A A A A
52.2 52.0 51.3 51.4
7.9 7.0
7.7 6.8
59.1 70.0 62.3 53.4
5.9 6.4 6.8 5.2
5.6 6.5 6.7 5.5
54.2 54.2
5.1
54.2 53.0 54.2 52.9 67.0 62.1 67.0 60 8 62.1 63.4 54.6 60.2 57.9
54.3 53.7 67.2 62.3 67.3 60.9 62.1 63.2 54.5 60.5 58.3
5.1 5.2 5.9 5.8 7.3 6.8 7.3 6.4 6.8 7.2 5.7 7.2 6.8
5.0 5.1 5.3 5.8 5.9 7.4 6.8 7.3 6.4 6.8 7.2 5.6 7.4 7.0
68.2 68.5 69.0 69.4
5.7 6.1
5.8 6.2
59.2 59.2
5.9
5.9
6 0 . 8 61 1
6.4
6.2
60.8 61.2 67.0 66 9 62.1 62.5
6.4 7.3 6.8
6.6 7.6 6.9
54.8 51.8 51.3 51.8 49.3 51.3 53.0 45.2 47.1 54.2 53.0
54.7 51.9 51.1 52.3 49.7 51.4 53.5 45.6 47.4 54.4 53.0
5.0 4.3 4.7 4.3 4 1 4.7 5.2 3.5 4.3 5 1 5 4
5.3 4.5 4.8 4.4 4.0 4.8 5.1 3.6 4.4 5.0 5.2
43.7 39.3 47.7 59.7 56.9
43.6 39.4 47.5 60 1 57.3
4.0 3.3 4.6 6.1 6.0
4.0 3.1 4.8 6.3 6.3
56.9 57.0 61.5 61.8
6.0 6.7
6.0 6.8
61.5 61.1
6.7
6.7
59.2 60.8 62.1 53.0
54.0
53.1
4.9 7.0
7.0
5.1 6.7 7.1
5.2 9.0
4,9
5.8 4.7
5.8 4.8
7.8
7.9
8.3
8.2
7.6
7.6
4.6 7.0
4.7 7.3
8.6 7.7
8.8 7.8
5.2 7.2
5.1 7.0
8.8
C A D A B A A A D A A A B A A A A A A A E A A A C A C A A A C
B
6324
SEYMOUR
Vol. 81
L. SI-IAPIRO, I R A M. ROSE.4ND LOUISFREEDRIAI*; TABLE I (Continzied)
N0.a
58 59 60 61 62 63"' 64 65 66 67 68 69 70 71
R
Rs
4-CzHjOC6Ha4-HOOCCsH44-HOOCCsH44-HOOCCsH44-HOOCCsH4CiuHi-' CloH7-7
E H M E CE H E k H 2 H rn E ( C ~ H E , ) ~ N ( C H ~ )H ~n H 0 H 2-PyridylH
H E H E H E H E H I
M E P CE CP H H E H r
E H ?
M
E CP H E H E H
11 E
H E H H E H E H H E H E H E
A1,p b or b p C (mm)
105-106 240-241 229-230 207-209 200-203 126-128 134-135 112-118(0 07) 184-188 182-183 130-134 (0 1) 89-92 (0 08) 92-93 133-134
98 (0 04) 45 43-44 81 135 (0.04) 110 (0.03) 60 97-98 47-48 101-103 92-93 83-84 66-67 93-94 78-79 56-60 90-92 86-87 94-95 135-140 97 85-89 123-124 100-101 53 63-64 69-72 71-72 85-86 105-106 56-57 100 83- 84 69- 7 2 116-117 130 (0.02) 98-103 110-1 11 146 (0 05) 119-120 150 (0 03) 139-140 122-123 85-88 83-84 118-134 (0.02) 89-90
-
Anal> ses, e % Hydrogen Xitrogen Carbon Calcd. Found Calcd. Found Calcd. Found
r-
,
Yield, R5C
. I E B
C7
H F
90 70 70 31 84 44 82 74 45 96 72 63 55 I7
Ri
CH3
F B
.1
Ax G B
D
D I
D I D
.z A\
&1 il .I -4 .\
-1 ?i .\
-4 '4 A
A A -4
2%
n A
n
x I
D -1
h A A
B X J A
I
87 7;i 91 43 91 73 50 45 61 43 47 68 53 76 78 60 62 84 65 67 58 89 61 75 43 62 80 58 81 86 54 Ti4 78 63 58 78 54 77 90 89 89 62 76 24 72 48 72
584 584 554 554 522 521 53.9540 478 481
6 4 4 7 4 4
19 4 0
6 6
45
1 2
4 6 4 8 4 3
5 5 5 2 4 6
7 5 4 4
0 3 9 7
66.0 5 . 5 5 . 3 66.7 7 . 3 7 . 0 7 . 8 7,7 64.8 3 8 5 . 8 8 . 9 9 . 1 5.6 6 . 1 6.4 60.1 5.7 55.1 10.4 1 0 . 1 1 6 . 1 15.8 8 . 9 9.1 53 4 22.4 2 1 . 8 53.3 55.2 5 . 3 5 . 3 65.9 67.0 65.0 60.3 55.1 53.1
7.5
7.0
6.9
55.3 55.6 8 . 8 8 . 6 65.6 65.8 11.5 11.7 6 1 . 5 6 2 . 1 10.0 9 . 8
6.5 7.0 5.1
6.3 6.9 5.1
9 2 8 2 O 5 9 5 5
0 6 G 6 4 9
7 0 6 9 4 8
6.5 7.2
6.6 7.3
9.0 .5.3
9.1 5.1
6.5 6.8 7.3 6.4 7.6 7 1 75.1 6 . 7 69.9 6 5
6.5 6.7 7.3 G.7 7.7
9.0
9.2
5.3
5.1
5..7
5.8
7.4 6.4 3 . 3
+7.8
53.7 53 9
Ci2H2iN04
59.2 5 9 . 5 68.4 60.8 62.1 63.4 54.6 56 1 56.2 56.2 54.6
683 608 62.0 633 549 563 567 55.8 548
69.2 69.5 63.4 6 3 . 5 69.2 62.1 63.4 57.4 61.6 59.1 75.3 69.7
8.7
8.7
6 6 6 7 5 6 5 5 5
5 6 6 7 G 6 5 5 5
1 4 8 2 1 7
7 7
69.3 62.3 63.5 67.8 61.8 59.1
62.1 62.5 68.4 6 7 . 9 63.4 63 2 68.4 63.4 59.0 56.5 54.2 53.0
7.5
68.7 63.9 59.0 56.4 54.2 53.2
6.8 7.8 7.2
6.8 8.1 7.0
7.8 8 . 0 7.2 5.5 5.5 5.1 5.2
7.4 5.7 5.7 5.2 5.1
7.3
7.2
7,3 7.3
6.9 7.0
7.7
7.5
7.0
7.1
CY-HYDROXY AMIDES
Dec. 5 , 1959
6325
TABLE I (Continued) Analyses,* % 7 Hydrogen Nitrogen Carbon Calcd. Found Calcd. Found Calcd. Found
7
R8
H M E P CE CP H E H E H H E H E H E H E H H E H H H H H H
Mpborb oc cmmP"
RSC
100-101 A A 132 101 A A 95-97 93-95 A A 118-1 19 E 104-110 97-100 A J 71-72 65-66 h 73-77 A 105-106 x 102-103 A 64-87 K 52- 53 L 94-96 R 98-99 K 117-118 A 125-126 K 221-222 E 138-139 E 73-75 A 107-1 08 L 112 (0 06) 118-120 (0 05) 94-100(0 06) H 204-205 C 113-1 15
Yield,d
%
40 76 81 64 74 73 76 75 55 70 2 73 81 65 81 60 80 65 89 30 10 90 30 84 82 47 77 5T
Ri, Rz 148 CsHii149 CQHSCHZ150 4-ClCsH4CHz151 C6HsCHCH:152 CeHjCHzCH?153 Ci0Hi302-~ 154 (CsH5)zCH155"" CsHs156 CeHs 157"23 2-CH3CeH4158 3-CH3CVH415gaZ44-CHdCsHd160 4-C1C&161 2-CH3OCsH4162 4-CHaOCsH4163 2,5-diCH30C~H3164 ZC~HSOC~HI165 3-C2HjOC&166"25 4-C?HsOCeH4167 CioHr-' ( C?HB)SS( CHa)r168 169
H H H H H H H H r
H H H H H H H H H H H H H
82-83 60-61 102-103 67-69 102-103 80-81 137-138 132-133 167-177 84-85 112-1 13 132-134 140 91-93 138-140 101-102 118-120 103-104 151-152 162-163 106-110(0.25) 126-128
D D
A D A A A M A ,4 C D E J K S
A A A K H
65 71 48 40 63 50 29 30 55 27 56 54
44 53 41 36 35 31 8 81 30
R1 = C6H5r
64-65 163 (0.04) 82-83 96-98 97-98 98-99 87-91 161-164 134-135
D I A
A A A B
A
75 80 30 89 78 80 94 56 93
Formula
CgHioCINOz CiiHizCIK04 Ci2Hi4ClN04 CisHieC1N04 C1?Hi3C12N04e1 C13HiOC1zhT04 CgH10BrX02 Cl2Hl4BrATO4 CioHi3N03 Ci3HiiNOs CiiHibN04
54.2 51.3 53.0 54.6 47.1 48.8 44.3 45.6 61.5 58.4 58.7
54.1 51.7 53.1 54.8 48.4 48.7 44.6 45.9 61.9 58.3 58.6
5.1 4.7 5.2 5.7 4.3 4.7 4.1 4.5 6.7 6.4 6.7
5.1 4.7 5.4 5.6 3.6 4.7 4.3 4.1 6.4 6.1 6.7
CiaHiix05 CiiHiaN03 CiaHisX05 CilHlsr\r03 CiaHisNOs
58.4 63.1 59.8 63.1 59.8
58.5 63.5 59.9 63.1 59.8
6.4 7.2 6.8 7.2 6.8
6.2 7.1 6.8 7.1 6.8
Ci4HigN05 CioHlihT04 CQHlOT\T204 CisH14~206
59.8 57.4 51.4 51.1
60.0 57.2 51.6 50.6
6.8 5.3 4.8 5.0
6.7 5.1 4 . 6 13.3 13.4 4.7 9.9 9.5
CI~HISNOP CgHzoNzOz C8HiaNz03 CgHisIN20z CgHigN302
7.0 5.4 5.2
7.1 5.3 5.1
5.7 4.4
5.9 4.4
6.2
6.5
6.7 5.0 6.7
6.7 5.3 7.0
7.3 6.8 1 4 . 9 14.8 55.8 5 5 . 9 34.4 3 4 . 5
9.4 6.1
9.4 5.9
8.9 9.0 2 0 . 9 21.0
CH3 6 5 . 3 1 0 . 3 10.4 6 8 . 3 7 . 8 8.1 57.8 6 . 2 6 . 3 6 9 . 3 8.3 8 . 2 8 . 3 8.1 69.4 62.5 7 . 9 7.8 7.1 6.7 75.8
6.8
6.8
5.2
5.0
68.4 6 8 . 7
6.1
6.0
9.4
9.3
CiiHisNOa
68.4 68.4
7.8
7.8
CioHizClNOz CllH16N03 C11H15NO3 Ci~Hi7N04 CizHi7N03 Cl?H17?;03
6.6
6.4
63.1 63.1 60.2 64.6 64.6
7.2 7.2 7.2 7.7 7.7
7.0 7.3 7.1 7.8 7.8
5.9
5.7
CiaHi5NOn CioHszSzOz CinHziN302
73.3 7 3 . 0 6 . 5 6 . 5 6 . 1 6 . 0 59.4 59.2 11.0 1 0 . 9 1 3 . 9 13.9 55.8 56.3 9 . 8 9 . 8 1 9 . 5 19.9
CioHiQXOz CiiHisNOz CiiHi4ClN02 Ci2H17~02 Ci2Hi7NOz Ci4HziN04 Ci7HisNOz
64.8 68.4 58.0 69.5 69.5 62.9 75.8
Ci7H18N203
63.2 63.0 60.5 64.9 64.8
RZ = H 73.0 68.0 74.7 69.0 75.3 69.7 64.2 61.2
73.2 68.3 75.0 68.7 75.2 69.7 64.3 61.2
9.6 8.7 6.3 6.1 6.7 6.5 4.6 4.8
9.9 8.8 6.6 6.2 6.8 6.4 4.7 5.2
6.8 5.3 4.1
6.6 5.1 3.8
6326
SRYhrOUR
Compounds previously reported:
L.
SHAPIRO, I R A
11.ROSEAND
h U I S FREEDX4N
lTOl.s1
0. C. Dermer and
from the a-hydroxy isobutyramides did not form, presumably because of the relative inactivity of the t-hydroxyl group to the acylation reactionI3 in Ed.,35,50(19-16),m.p. 92’; a 3 C.A. Bischoff and P.JValden, dizn., 279, 45 (1894). m.p. 67”; e 4 ibid., m.p. 143 ; X. pyridine. Lofgren and I. Fischer, Swnsk Ken?. Tidskr.,58,206 (1946), The Carbonate esters were generally solids, and m.p. 90-91’; a6 “Beilstein,” Vol. XII, p. 648, m.p. 180’; it is of interest that although these compounds Beilstein,” Yol. VIII, p. 272, m.p. 101’; “Beilstein,” 1.01. XIII, p. 173, m.p. 153 ; O 9 “Beilstein,” 1-01. X I I , p. were readily responsive to pyrolysis to the oxaa liquid carbonate (Table I , comU’.P. Ratchford and C. H. Fisher, J . z~lidinediones,~ 1246, m.p. 128”; Org. Chem., 15, 317 (1950), b.p. 86-87” (0.2 m m . ) ; ibid., pound 77) could be distilled unchanged. b.p. 104-106” (0.1 mm.), m.p. 42-48”; “12ibid., m.p. 60The ultraviolet absorption spectra of some 70 of 60.5’; @13ibid., m.p. 47.5-48.5’; a14 M . L. Fein and E. M. Filachione, THISJOURNAL, 75, 2097 (1953), m.p. 92-94”; the compounds in this series have been compared with those noted for the corresponding acetanilides’ a15ibid.,m.p. 88-87”; =16ref.all, m.p. 57-58’; “Beilstein,” 1.01. XII, p. 819, m.p. 72’; al* “Beilstein,” Vol. XII, p. 963, in Table 11. m.p. 102-103”, m;p. 109’: a19 “Beilstein,” Vol. XIII, p. 491, The spectra permit an assessment of the rem.p. 106.5”; Beilstein,” Vol. X I I I , p. 491, m.p. 117.5118”; a Z 1 “Beilstein,” Vol. X I I , p. 1246, m.p. 108’; R. placement of hydrogens on the methyl group of F. Rekker and W. T. Nauta, Rec. t m v . clzim., 70, 24 (1951). acetanilide by a hydroxy group, a hydroxy group m.2; 135”; 0 2 3 “Beilstein,” 1’01. XII, p. 820, m.p. 8 8 ” ; and one methyl group, and a hydroxy and two a 2 4 Beilstein,” Vol. XII, p. 965, m.p. 1j2-133’; a 2 5 “Beilmethyl groups, respectively, in the classes of conistein,” Vol. X I I I , p. 493, m.p. 151-152 Melting points were determined on a Fisher-Johns melting point block and pounds evaluated. UngnadeL4has shown that reRS = recrystallizing solvent; A = placement of the three hydrogens by three methyl are not corrected. ethyl acetate-hexane; B = ethyl acetate; C = ethyl acetategroups (pivalmilide) results in hypo- and hypsoether; D = ether; E = water; F = ethyl acetatebenzene; chromic effects. w-Trifluoroacetanilide shows G = ethanol; H = acetonitrile; I = hexane; J = etherhexane; K = ethanol-hexane; L = ethanol-water; M = batho- and hypochromic effects. In turn, replaceethanol-ether; N = benzene-hexane. Yields are expressed meat with one methyl group (propionanilide) as percentage of recrystallized or distilled product. e Analy- yields essentially the same spectrum as acetanilide. ses are by Weiler and Strauss, Oxford, England: not obThe availability of many of the ethyl carbonate C3Hs- is allyl. 0 CjHeO- is furtained analytically pure. furyl. CI”H1302- is 3,4-dimethoxyphenethyl. < RI is N,X- esters of the a-hydroxyamides permitted an astetramethyleneamido-. i ClaHr is a-naphthyl. -NHR sessment of the role of hydroxyl hydrogen, as well group is replaced by N-methplbenzyl, Product is the as the hydroxy group in the noted spectra. bisamide from methylenedianiline. Bis-derivative, R3 = In general, spectra reported in this series follow OCOC?Ha, of compound immediately above. -1;HR group is replaced b y N-methylpiperazyl. The amine re- trends noted with the acetanilide^,'^ but some of acted is p-IT-piperazylethylamine. It is likely that the prod- the interesting distinctions will be described in more uct reflects amidation by the primary amine group. p CsHlr detail. is 2-ethylhexyl. * CsH11- is cyclohexyl. Phenylurethan The structural feature which was of principal of compound immediately above. Methiodide of cominterest was the characterization of the hydrogen pound immediately above. bonding effects with the a-hydroxyamide. reactant as a result of stabilization of the proThe structure of a~etanilide’~ is planar, and other posed transition state I1 by hydrogen bonding.? studiesI6 l i have shown that the aniide hydrogen in While the formed ethanol catalyzes the reaction,a simple amides is trans to the carbonyl carbon. it also lowers the boiling point of the reactant mix- These factors suggest the structural model for the ture, and I t proved desirable to remove it as the a-hydroxy amides as 111,R3= H. reaction proceeded. This permitted higher reaction temperatures and was a convenient index of completion of the reaction. With the amine $-aminobenzoic acid, good results were noted when its basicity was increasedg by using the sodium salt as the reactant.’O Some The hydrogen bonding as shown between the amide of the amides were obtained through dehydration hydrogen atom and the ORs group would require of the corresponding amine salts by reflux with the proper conformation of the groups attached to benzene or xylene (method B),11,12 or reaction of the acetanilide methyl group. the amine with lactide or polyglycolide (method C) . Ungnade had noted that with selected o-subThe carbonate esters I (R3, other than H) were stituted acetanilides the acetamino group is twisted prepared by treating the a-hydroxyamide with the out of the plane of the ring with resultant decrease alkyl chlorocarbonate in pyridine-acetonitrile. in absorption intensity and hypochromic shifts. Acetonitrile was a particularly convenient solvent In Table I1 the carbonate esters of the o-substisince it solubilized the formed pyridine hydrochlo- tuted anilides of the a-hydroxy acids show virturide. ally the same spectra as the acetanilides (see 2While the carbonate esters were obtained readily CH3-, 2-C1-, 2-CH30--), while the a-hydroxyfor all variants of Ra, the comparable compounds (13) (a) J. A. Campbell, J. Org. Chcm., 22, 1259 (1957): (b) R. B. a
1. King, J . Org. Chem., 8 , 168 (1943), m.p. 103-104”; H. I;. Iwamoto and deC. Farson, J . Am. Pharm. Assoc., Sci. O2
O6
O8
f
(7) See S. L. Shapiro, I. M. Rose and L. Freedman, THISJOURNAL, 80, 6065 (1958), for discussion of the amidation reaction. (8) G. R. Wolf, J. G. Miller and A. R . Day, i b i d . , 78, 4372 (19513). (9) P. H. Bell and R . 0. Roblin, Jr., i b i d . , 64, 2905 (19421. (10) C . van der Stelt, A. J. Zwart. Voorspuij and W. T. Nauta, Araneimitlel-Forsch,, 4 , 544 (1954). (11) The mechanism of this type of amidation has not been convincingly rationalized. I t is of interest t h a t i t is not as dependent on base strength or steric factors in the amine, a s the aminolysis of esters. ( I ? ) L. F. Fieser and J. E. Jones, Org. S y w f k c s e s , 12, 66 (lQ50).
Wiberg and T. hl. Shryne, THISJOURNAL, 77, 2774 (1955); (c) S. Nakanishi, T . C. Myers and E. V . Jensen, i b i d . , 11, 5033 (1955); (d) J. L. Hales, J . I. Jones and W. Kynaston. J. Chem. Soc., 618 (1957); (e) H. K. Hall, Jr., THIS JOURNAL,79, 5439 (1957); (f) W. Gerrard and F. Schild, Chemistry b Industry, 1232 (1954). (14) H . E. Ungnade, THISJ O U K N A L , 76, 5133 (1954). (15) C. J . Brown and D. E. C . Corbridge, Acfa Cryst., 7, 711 (1924) (IG) J. E. Worsham. Jr., and hl. E. Hobbs, THISJOURNAL, 76, 200 (1954). (17) A. Kotera, S. Shibata and K. Sone, ibid.. 71, 6183 ( l Q 5 2 ) .
6327
CY-HYDROXY AMIDES
Dec. 5 , 1959
TABLE I1
Ra 0 H I I l l - y L'LTRAVIOLETABSORPTIONSPECTRA^ RI C- C - N G I ORs RI,Rz = H Ksb
H E H E H H E H E H H H E H E H M E P CE CP H E H
Y
H H 2-CHa2-CH33-CH34-CH34-CH32,4-di-CHI2,4-di-CH32,5-di-CHp2,g-di-CHa4-F 4-F 2-c1 2-c1 4-C1 4-C1 4-C1 4-C1 4-Cl 4-C1 4-Br 4-Br 2-CH3O-
Xmax, mp
c
X 10-
24 1 240 235 229
13.2 13.9 7.4 6.3
244 24 1
14.1 14.5
24 1 242 237 227 243 243 245 238 225d 241
12.9 13.7 7.8 6 5 13.0 14.4 14.9 7.5 7.3 8.1
R ~R~ ,= Xmax, mp
241
245 243
e
cna
x
X 10-8
Xmax,C m p
13.4
242
14.4
230
6.3
245 245
14.0 14.85
240
13.1
'240
10.4
249
17.8
13.7 15.0
e
10-8
e
e
238 238 243 240 247 247 247 247 247 247 250 251 245 282
RI'= CHa, Rz = H Xmax, mp e X 10-8
12.4 12.4 12.6 10.6 18.2 17.8 18.5 18.5 19.7 19.0 19.0 20.8 13.0 5.1
237 239 244 238 247
13.0 12.7 12.7 8.8 17.8
250 20.6 252 18.7 250 18.8 13.2 245 14.4 244 10.4 245 282 4.55 5.5 282 5.7 280 244 E 2- C&O11.5 282 5.5 H 248 14.8 249 4-CH3014.9 14.6 249 13.0 249 244 E 13.0 4-CH;O249 14.9 243 H 14.4 13.9 244 15.0 2- CzHbO245 282 5.4 282 5.9 4.7 2 83 244 244 E 11.9 2-C2H5011.7 28" 5.1 283 5.1 €I 11.7 244 3-CzHbO11.o 244 11.9 245 245 11.7' 280 3.3 281 3. ' I 3.0 281 3.6 280 245 E 3-CaI-IbO11.1 3.2 281 249 H 13.7 249 4-C2H.,O248 14.3 16.0 E 25!) 15.1 4-CzHbO15.4 251 H 21.2 21.2 265 267 270 4-HOOC21.9 H 4-SO2 310 13.4 316 11.4 The spectra were deterinincd in inethanol and were established using a Becktnan recording spectrophotometer, model DE;. The following spectra were establishedforcomparisoncompounds (name, Xmax, my (methanol), E X respectively); formanilide, 242, 13.3; o-chloroformanilide, 243, 12.2; propionanilide, 243, 14.1. * The abbreviations for Rt have been detailed in Table I. The spectra (ethanol) for the corresponding acetanilides have been drawn from ref. 14 and are shown in the Table to permit more ready comparison. Shoulder. * Xon-specific absorption only. f The data shown for comparison are for m-methoxyacetanilide from ref. 14.
acetanilides each reflect a spectral pattern which is bathochromic, and hyperchromic relative to the acetanilide, with the order of this efiect being CH1> C1- > CHsO-. In turn, with the 2,g-dimethylaniline derivative, only non-specific absorption is obtained. These observations suggest that in the absence of a stabilizing influence the spectra reflect some measure of free rotationle about the nitrogen with accompanying interaction between the amido hydrogen and the o-substituent. This is the case with the acetanilides and the carbonate esters in this series. Alternatively, with the a-hydroxy
anilides, conformational stabilization through drogen bonding on the side opposite to that of o-substituent as shown (IV) would account for noted effects. The alternate possibility for a Y
O
Y
hythe the hy-
O
Lil
0 drogen-bonded form involving juncture of the hydroxyl hydrogen to the electron pair of the nitrogen would be reflected by spectra which would show IV
V
6325
SEY3fOUR
L.
SHAPIRO,
IRa 11. ROSEAND LOUISF R E E D X A N
considerably less benzenoid character, and is unlikely. n‘hen the hydroxyl group is derivatized to form the carbonate esters, the electron density on the hydroxy oxygen is decreased through forms such as V and hydrogen bonding as shown for I V apparently does not make significant contributions in V Forbes and SheratleI9 have questioned Ungnade’sL4 contention that the o-methoxy substituent contributes no steric effect in the spectra of the acetanilides. Our data with o-methoxy and oethoxy substituents are in agreement with Forbes’ position in that steric effects are noted with compounds of the type V j although not with those of the preferred orientation of type 11However, the fact that order of stabilization (AX,,, [ oc-hydroxyacetanilide - acetanilide]) is CH3 > C1 > -0CH3 would suggest some measure of contribution from forms for T’ similar to those proposed by Ungnade, which are shown as VI.
o=c.,
,,OH,
A‘!,
R, These data with the o-substituents tend to emphasize the relative hypochromicity of the malkoxy substituents in this series and in spectra tabulated by other^.^^,^^ This is emphasized in that the secondary band (at about 282 mp) for the m-alkoxy derivatives is also more hypochromic than the secondary band of the corresponding oalkoxy compounds. Since m-alkoxy substituents have positive U-values in contrast to the strongly negative U-values of p-alkoxy derivatives,20 the noted spectral effects with the m-alkoxy derivatives in this series may be a result of drainage of ring electron density by these groups through the inductive effect with consequent lesser population of resonance forms contributing to the extinction coefficient. KOclear-cut effects could be ascribed to variations of R1 and Rzas hydrogen and,‘or methyl?’ within the compounds of this series, and the compounds V (Y = H) paralleled the spectrum of trimethylacetanilide. Pharmacology.-Almos t all of tlie c(I nip()ti i i tl s described in Table I were evaluated for their anticonvulsant action in inice arid the results have heen clcscribed in Table 111. With respect to the aiiticoiivulsant efiect, some interesting generalizations may be made relating structure to activity. Of the carbonate esters Ti,
(18) Evidence for this effect based on pharmacological data has been reported b y S. L. Shapiro, I. iU.Rose and L. Freedman, THIS J O W R N a L , 80, 6065 (1958). (19) W.F. Forbes and hl. B. Sheratte, Cui%. J . Chem., 33, 1829 (1955). (20) L. P. Hammett, “Physical Organic Chemistry,” McGraw-Hill Book Co., Inc., ? V e v York, X. Y . , 1940, p. 188. ( 2 1 ) A . P. de Jonge and W, den Hertog, Rec. ti’aa. c h i i n . , 75, 85 (1950). in a study of ultraviolet absorption spectra of f a t t y acid anilides have indicated that the only branched-chain acid anilide studied, isovaleranilide, had little influence on the spectra relative t o t h a t observed with the straight-chain anilides.
VOl. 81
TABLE 111 PHARMACOLOGICAL ACTIVITYOF C~MPOUSUS 4 + anticonvulsant activityezd
3 + anticonvulsant activitya
Potentiation of Evipal sleeping timeb Reduction in motor activityC
3/500, j / Z O O , 9/230, 11/300, lG1750, 20/350, 39/225, 891400, 1521750 2 5 / 1 0 0 , 3 & 4 3 0 0 , 7 2 / ~ ~S0l,/ 7 j O , 111/850,113/800,127/1~0, 14!3/300, 1 6 2 / 2 ? 5 , 170/150
3, 9, 16, 18 i o / > 1000/18%/10,94175012ti%/ 100; 120/450/23%/100
a For method of testing see S.L. Shapiro, I. bI. Rose, E. Roskin and L. Freedman, THIS JOERNAL, 80, 16-48 (1958),; ,also, S. L . Shapiro, V. -4. Parrino ancl L. Freedman, zbzd., 81, 3996 (1959). T h e data record Table I coinpound number/LD,i, in mg./kg. b The method of testing is described in footnote a. T h e compounds listed showed 50-10070 potentiation of the Evipal sleeping time when evaluated a t of the LDmi,. c For method of testing see footnote a. The data record compound numl)er/LD,,, ing./kg./% reduction in motor activity/test dose (subcutaneous) in mg./kg. The k n o w i ariticonvulsants pheiiobarbital and trimethadione show 4+ activity in this test.
showing a good response (compounds 5 , 20, 25, 127), 5 and 20 are relatable to active hydroxyamides 3 and l G , respectively. Aniong the hydroxyamides, all the 4+ compounds were derived from aralkylamides but one (compound 39). 1i-itli the substituted anilides, the following substituents in the ring were associated with good to moderate activity : halogen (compounds 34, 3 9 , ET), dimethyl (compounds 111, 113) and methoxy (compound lG2). The R1, K2 variants showed the following number of active compounds : RI, Rz = H, 9: 111 = CHa, Rs = H , (i;lil, IC2 = CH:i, 3 ; R1 = CsHj, K?= H, 1. In this series it appears that the best results are to be found with S-aralkyl glycolamides. Experimental22 Preparation of Amides (Method A).---A iiiisturc o f 0.1 inole of amine and 0.105 mole of the ethyl ester of the a-hydroxy acid was heated until the iriteriial temperatur: of tlie refluxing mixture had dropped approximately 20-30 . The formed ethanol r a s removed anc! measured. If the quantity of ethanol collected did riot approach theoretical, reflux and r e m o d of formed ethanol was repeated. The residue was recrystallized or distilled to )+Id the product. Method B.--.i mixture of 0.1 mole of 70sl, glycolic acid (or 85C,, lactic acid), 0.11 inole of amine and 50 rnl. of benzene (or xylene) was vigorously stirred and heated untlrr reflux in a 1)caii-Stark apparatus until tlic tlicoretical water tioii had been obt:iiiicd. The Iiciizene wlutioii tereci (charcoal), the benzeuc reinovccl ancl the rcsi vilved in chloruforni. Following :L \rashiiig with di tirucliioric acid a i d water, t h e ctiloriifimn was removed ; L I I ( ~ tlic liroduct rccrystallizetl or distilled. 1 \vert pi-c.liarctl u h i g T h e follo~viiigcompouiitls iii T: , .&+,!XI, J 2 , .-)A. 3i, tliis procedure: 21, 28, ,‘H), 34, ;.Xi t i 3 , 118 a t i t 1 1-40, Method C . - - l mixture of 0.1 iil(J11. of l x t i t l e (or l)o1yd>colide) and 0.15 mole of amine \vas iiiaiutained for 18 hours. When cool, the residue was pro method B to give the product. These compounds were prepared by this tnetliotl: :32, 111, 113, 114 and 116. Compound 16 was preparetl usiiig this procedure in 86‘2 yield, in.p.74-76’. p-Carboxyglycolanilide (Compound ) iiiiuture of 80 g. (0.50 mole) of sodium p-aminobeiiz e a n d 97 g. (esccxs) of ethyl glycolate was heated for 20 hours in a11 oil-hath maintained a t 110’. n’lien cool, after trituratiotl wit11 5ilO mi. of acetone, there was obtained 92 g. (XSC;) of tllc ~ o t l i u l l l salt of the product. T o obtain the frve acid, 4 1 g. of tllc sodium salt was disscilved in 730 nil. of boiling miter, 13 nil. (22) Descriptive data s h o l r n in the table are not herein reprodiiced.
Dec. 5 , 1959
COXMUNICATIONS TO
of concentrated hydrochloric acid was added, and the product crystallized; 31 g. (66y0),m.p. 242-243'. Compound 139 was obtained in a similar manner. p-Bromoglycolanilide (Compound 46).--A solution of 10.0 g. (0.066 mole) of glycolanilide (compound 26) in 125 ml. of water was maintained at SO"while treated under vigorous stirring with bromine water until a slight excess of bromine remained. The excess bromine was removed with sodium bisulfite and the product separated: 14.3 g. (94y0), m.p. 169-171". Compound 126 was prepared in a similar manner. N-p-Phenethyl-dl-pantoamidewas prepared by the method of Shive and S r ~ e l lin , ~82% ~ yield, m.p. 92-93' (ethyl acetate-hexane). N-Benzyl-dl-pantoamide was prepared in the same nianner in 7.15;:yield, m.p. 79-81' (ethyl acetate-hexane). i l n a l . Calcd. for CI3Hl9SO3: C, 65.8; H . 8.1. Found: C, 66.2; H , 7.9. N-Isobutyl--phydroxybutyramide .--A solution of 20 g. (0.232 mole) of 7-butyrolactone and 20 g. (0.273 mole) of isobutylamine was heated slowly t o 9 5 1 0 0 " and maintained a t that temperature for 3 hours. Volatiles were removed a t 100" (0.2 mm.). The yield of residue was 36.5 g. (100%) and the PH of an aqueous solution was about 5. There were indications that the material decomposes on distillation and the analysis was run on the residue. Anal. Calcd. for C8H17S02: C, 60.4; H , 10.8; N, 8.8. Found: C,60.2; H , 10.9; T\T,8.7. N-Isobutyl-yhydroxyvaleramide was prepared as above using yvalerolactone. (23) W. Shive and E. E . Snell, J . B i d . Chem., 160, 287 (1915); m.p. 90-9lo.
THE
EDITOR
6329
Anal. Calcd. for CoH19N0~:C, 62.4; H , 11.1; N, 8.1. Found: C, 62.7; H , 11.4; N,7.9. Carbonate Esters of a-Hydroxyamides (General Procedure) .-To a solution of 0.1 mole of the a-hydroxyamide in 10 ml. of pyridine and 60 ml. of acetonitrile, 0.11 mole of the alkyl (or haloalkyl) chloroformate was added slowly with continued stirring, and cooling (below 15'). After storage a t 20' for 2 hours, the reaction mixture was transferred to an open dish and the volatiles evaporated. The solid residue was triturated with dilute hydrochloric acid, then water, filtered, dried and recrystallized. Under these reaction conditions the attempted preparation of carbonate esters of the a-hydroxy-isobutyramides failed and the reactant amide was recovered. N,N-Tetramethylenecarbamate of p-Bromoglycolanilide (Compound 49).-To 1.0 g. (0.003 mole) of compound 48 in 10 ml. of acetone was added 1.0 ml. of pyrrolidine and the slowly darkening solution stored a t 20" for 20 hours. The acetone was removed, the residue was dissolved in benzene and washed with dilute hydrochloric acid, then mater. The benzene solution was filtered (charcoal), the benzene removed, and the residue, granulated under hexane, gave 0 . i 5 g. of product which was recrystallized.
Acknowledgment.-The authors are indebted to Dr. G. Ungar and his staff for the pharmacological results herein reported, to E. Roskin, J. Hinchen and F. Testa for technical assistance and t o M. Blitz and his associates for the ultraviolet absorption data. YONKERS 1, N. Y.
COMhfUNICATIONS T O T H E EDITOR A BORON-CONTAINING PURINE ANALOG
showed the presence of a CO group, but not OH, supporting the lactam formulation (111). The The preparation of boron compounds which alcoholic solution of (111) was not stable; after a might be of use in the treatment of cancer is of cur- few hours the ultraviolet spectrum became identical rent interest1 An obvious class of such compounds with that of a mixture of o-aminobenzamide and would be purine analogs containing boron in the phenylboronic anhydride. Analogous condensation of 4-amino-l-methyl-5ring. We wish to report the first preparation of imidazolecarboxamide3 with dibutyl phenylboronsuch a compound (I). ate gave a solid (62y0 yield) which appeared to be the purine analog (I). I t crystallized with difficulty from ethanol and sublimed without melting a t ca. 300'. 4naZ. Calcd. for CllHllN~OB: C, 58.41; H, 4.87; N, 24.78; B, 4.9. Found: C, 58.40; H, 4.78; N, 24.66; B, 4.9. Owing to the The possibility of preparing stable coinpounds of insolubility of the compound its molecular weight this type was indicated by recent syntheses of het- could not be determined. For the same reason the erocyclic boron compounds, in particular (11), ultraviolet spectrum could be studied only in alcowhich seemed to show aromatic properties.2 In an hol, where under all conditions it was identical with extension of this work we first prepared the quin- that of an equiniolecular mixture of the irnidazoleazolone analog (111)from o-aminobenzamide, either carboxamide and phenylboronic anhydride. Thc with phenylboron dichloride in benzene (2070 structure of (I) is established by its method of yield), or by heating with dibutyl phenylboronate preparation, analogy with (HI), analysis, and infraand removing butanol (6370 yield). (111) crystal- red spectrum (different from that of a mixture of the lized from benzene in small plates, m.p. 210-211'. imidazolecarboxamide and phenylboronic anhyAnal. Calcd. for C13HllN20B: C, 70.27; H, 4.95; dride, notably in the loss of the NH2and BO bands). N, 12.61; B, 5.0; mol. wt., 222. Found: C, The solvolysis of (I) is reversible. On mixing 70.22; H, 4.86; N, 12.68; B, 5.1; mol. wt., 213. concentrated alcoholic solutions of the imidazole Solutions of (111) in ethanol showed an ultraviolet carboxamide and phenylboronic anhydride (effecspectrum with peaks a t 260 mp (log E , 3.84) and 314 tively diethyl phenylboronate) , (I) crystallized mp (log e, 3.4). The infrared spectrum of the solid in 97y0 yield. This novel synthesis was extended t o (11) (35% yield) and (111) (8270yield). (1) E. Nyilas and A. H. Soloway, T H I S J O U R N A L , 81, 2681 (1959).
Sir:
( 2 ) 31. J . S. Dewar, V. P. Kubba a n d R. Pettit, J. Cheiu. Soc., 3076 (1958).
(3) J (1924).
Sarasin and 1%'
E
Wegmann, Hel')
Chim. Acta, 7 , 713
