340.7
NOTES TABLE I ARYLOX OXY-^-( N-HETEROCYCLICAMINO) -2-PROPANOLS
Type A Type R A Phenoxy Hydrochloride Hydrobiomide A P-Chlurophenoxy .I o-Chluruphenoxy A 5.4-Dichlorophrnoxy .I in-Tdoxy Hydrochloride A a-Tolory A a-Naphthoxy Hydrochloride H Phenoxy" Hydrochloride Hydrobromide €3 P-Chlorophpnoxy' Hydrochloride B o-Chlorophenoxy" Hydrochloride B 2.4-Dichlorophenoxy Hydrochloride n m-Toloxya Hydrochloride
n R
C C C C C C C
Type B B.P., "C. Mm.
Formula 13@-166 1 CiaHioNOz CiaHzaCINOz CisHzoBrNO? CiiHiaClNOr C~,~HisClNO? 144-14.5 0.7 C ~ H l i C h N 0 z 162-163 I 1 C i r H 2 ~ ~ 0 2 135-139 CMHZZCINOZ . . . . . . . 124-128 1 Ci IH?INOn CllH21N02 178-186 0 . 5 CiiH2zClNOz . . . . . . . 1.5.5-180 I C I4H21 0 2
CIIH?ZCINOZ
Ci*H??BrNOz CirHzoCINOz CirH21C12NOz . . . . . . . CirHd21NOz 158--159 0 9 ClrHnCltNOl . . . . . . . CIIHLOCI~PIIO~ 1 168-170 CirHzaClaNO? . . . . . . . CiaHzaNOz 139-136 1 CisH2ClNO? CnHrJNOz Hydrochloride C~sHzrClN~0r 182-187 0 3 a-NaphthoxyUZC ClsHydNOr Hydrochloride CisH?rCIN02 . . . . . . . 150-184 1 PhenoxyJ CisHigNOi P-Chlorophenoxy CiaHiaCINOa . . . . . . . 0-Chlorophenoxy CiaHisClNOa 170-177 1 2.4-Dichlorophenoxy CiaH1;ClzNOs 176-183 1 Hydrochloride CiaHisClaNOa ....... 148-152 1 m-Toloxy CidHzINOz Hydrochloride CirHznClNO~ . . . . . . 139-141 1 0-Toloxy CirHziNOa a-Naphthoxy C I I H Z I N O ~ 190-206 0.5 Hydrochloride CIrHz2CINOa . ,.., ..
hl.p., OC. cor.
Type C
Yield, 70
. . . . . . . . . .
83.2
118.2-119.2 . . 116.2-118.2 . . 90-9 1 Qtiant. 61-62 79 79.1-79,G 93.3 92.8 117.2-117.7 . . 48.7-50.2 87.8 71.5-72 5 70.4 161..i-163 .. . . . . . . . . . 84.4 1.50.9-151. 9 .. 134.1-135.1 . . 74.6-75.1 Quant. 157-158 .. 70.1-71.1 87 151.4-152.4 . . 88-89 87.6 149.9-150.9 . .
.........
183.6-184.6
, .
67.5-68 65.5-06.6
94.1
......... 147.5-149
5.43 5.31 . . . . . . 4.63 4 . 5 6 . . . . . . .5.48 5.40 255.7 250 J . 4 8 5.34 255 7 ? , A 4.83 Tr ,O? . . . . . .
. . . . . . . . . . 4.55 4.24 . . . . . .
. . . . . . . . . .
., , . 271.8 270 . . . . . . . . . .
. . . . 269.8 266. . . . . . . . . . . . . . .
269.8 267
. . . . . . . . . .
. . . .
304.2 3no
... 13.70
...
13.05
...
,
Bromine. 70 Calcd. Found
. . . . . . . . . . . .
..
2G 44
96.37
11.5'2
11.34
...
...
13.04
12.97
... ...
,
.
.,, ..,
,
.,
5.90 5.97 ,, , 5.16 5.07 271.7 27.5. 5.16 5 . 1 2 271.7 271.
. . . . . . . . . . 4.09 4.34
. . . . . .
. . . . . . . . . .
4.87 5.04 . . . . . . 5.57 5.47 251.5 252
. . . . . . . . . . 4.33 4.23
. . . . . .
. . . . .
, . .
....
. . . . . . ..,
.,.
. . . . . . . . . . . 25.27 25.03
, . .
...
11.58b Il.5lb
... ll.58b
... 12.41
... 12.41
..
i2.m
...
...
. . . . . .
90.5
. . . . . . . . . 83.3 143.9-144 9 .. 66-67 90.4 . . . . . . . . . 86.4 190.1-191.1 . .
... 13.76
10.40b
249.3 248
Quant. 88.2
..
Chlorine, % Calcd. Found
. . . . . . . . . . 5.15 4.94 . . . . . . 3.95 5 . 09 23.5.3 238
91.8
128.6-129.6 . . 59-00 80.3 134.5-13.5.5 . . 82.1-83.1 8 4 . 2
H9-70
Nitrogen, % Neut. equiv. Calcd. Found Calcd. Found
... 11.3gb
... 10.29b 12.32
... 12.29
...
I I .n2
10.89
...
...
. . . . . .
...
,..
...
. . . . . . . . . . . .
. , ,
...
...
10.3jb 1 0 . B b
...
...
12.32
12.32
...
...
10.95
10.82
. . . . . . . . . . .
...
...
... ... . . . . . . . . . . . .
. . . . . .
Since this work was completed the hydrochlorides of these compounds have been reported by H. R. Ing and W. E. Omerod, J . Pharm. Pharmacol., 4, 21 (1952). * Ionic chlorine. Reported by Fourneau, et al., BuLZ. SOC. chim., 43, 454 (1928). Reported by Geigy, Swiss Patent 227,033 (August 2, 1943).
efforts were directed toward the synthesis of compounds which were both ethers and alcohols, as shown by the general equation R-CH2-CH-CH2
f HR'
----f
R-CH?-CH--CH?-R'
I
'0' OH R = an aryloxy group R ' = 1-pyrrolidyl, 1-piperidyl or 4-morpholinyl
Twenty-one of these compounds were synthesized by slow addition of the intermediate epoxide to the amine a t gentle reflux, using catalytic amounts of water, with subsequent distillation or recrystallization. Table I shows their structures and some pertinent physical and analytical data. The hydrochlorides and hydrobromides were made by passing the dry gas into solutions of the bases in ether. Experimentals Epoxides.-The epoxides required for this investigation were prepared4 by heating a mixture of the phenol and dichlorohydrin6 to 70" and then adding a 27% solution of sodium hydroxide over a period of about two hours. temperature of the mixture was maintained below Tht 80 throughout the addition period. The mixture was then (3) All melting and boiling points are corrected. (4) Arthur Fairbourne, George Philip Gibson and David William Stephens, J . Chem. Sac., 1965 (1932). (5) Dichlorohydrin used was approximately 70% 2,3-dichloro-lpropanol and 30a7, 1.3-dichlor0-2-propanul.
heated for 15 to 60 minutes a t loo", cooled, extracted with ether, dried, and distilled a t reduced pressure. The yields varied from 22.8 to ,5675. The residues were shown to coiltain 1,3-diaryloxy-2-propanolsin two cases, and i t is suspected that analogous by-products were obtained in all similar reactions. l-(Phenoxy)-3-pyrrolidine-Z-propanol.-Thirty grams (0.20 mole) of 1,2-epoxy-3-phenoxypropane was added dropwise to 15.6 g. (0.22 mole) of boiling pyrrolidine containing catalytic amounts of water. After all of the epoxide had been added (45 minutes), the mixture was heated a t temperatures below 150" for 135 minutes. The reaction mixture was distilled in vacuo; 36.7 g. of product was collected (83.2% crude yield). The hydrochloride was prepared by saturating an ice-cold solution of the compound with dry hydrogen chloride. The insoluble hydrochloride was collected by filtration and recrystallized from butanolhexane. The same procedure was used in preparing the hydrobromide.
CHEMISTRY DEPARTMENT
UNIVERSITYOF FLORIDA GAINESVILLE, FLORIDA
Esterification of Hindered Carboxylic Acids BY RUSSELLREED,JR. RECEIVED JANUARY 11, 1956
Bourne found that trifluoroacetic anhydride was (1) E. J. Bourne, M . Stacey, J. C. Tatlow and J. Chem. Soc.. 2976 (1949).
M. 'redder, J ,
an effective and mild reagent for the esterification Experimental5 All of the methyl esters were prepared under the same of carboxylic acids, and proposed a mechanism involving the formation of the reactive acyliuni ion,? conditions. Methyl 2,6-Dimethylbenzoate.-To 105 g. (0.50 mole) of RCO +. trifluoroacetic anhydride was added 1.5.0 g. (0.10 mole) of
+ (CI'1C0120 t3 RCO
+ CF COOH
2,6-dimethylbenzoic acid (m.p. 115-116") and 4.0 g. (0.2% mole) of methanol. The clear, colorless solution was allowed 0 to stand two hours at room temperature, and the trifluoroacetic anhydride and trifluoroacetic acid were reCF1CO' moved under vacuum a t room temperature. The viscous, RCO, oily residue was dissolved in 50 ml. of ether, and the solution shaken with 25 ml. of saturated potassium bicarbonate 0 f--9 RCO' CF?COOsolution. Acidification of the bicarbonate solution gave 3.2. Fa c 0 g. (:l%) of unreacted 2,6-dimethylbenzoic acid, m.p. 114116 . Evaporation of the ether solution yielded 14.3 g. of RCO' R'OII --+ RCOOR' IT7 methyl 2,6-dimethylbenzoate; distillation gave 12.1 g. Since Newman3 has shown that the esterification (74%), b.p. 106-107' (7 mm.), TL*OD 1.5090. of certain 2,4,6-trisubstituted benzoic acids (in Anal. Calcd. for CloH1202: C, 73.14; H , 7.37. Found: 100% sulfuric acid) proceeds via the acylium ion, i t C, 73.02; H , 7.49. Attempted Esterification of 2,4,6-Trinitrobenzoic Acid.was of interest to determine whether trifluoroacetic above procedure failed to yield isolable amounts of anhydride would esterify sterically hindered car- The either methyl or p-nitrobenzyl esters. 2,4,6-Trinitrobenzoic boxylic acids. Trifluoroacetic anhydride was found acid was nearly insoluble in trifluoroacetic anhydride. A to be a very effective and convenient reagent for mixture containing 3.00 g. (0.0117 mole) of 2,4,6-trinitrothe esterification of the hindered acids : trimethyl- benzoic acid, 2.23 g. (0.014.5 mole) of p-nitrobenzyl alcohol 50 ml. of trifluoroacetic anhydride was refluxed (35" acetic, 2,6-dimethylbenzoic, and meso-cis- and and (710 mm.)) for a week and the anhydride removed under retrans-2,6-dimethylcyclohexanecarboxylic acids. duced pressure, leaving 3.10 g. of yellow crystals which were While trimethylacetic acid is slowly esterified by extracted with 3 X 100 ml. of ether. Evaporation of the the usual acid-catalyzed esterification procedures, ether gave 0.060 g. (2.1c",) of the anhydride of 2,4,!-trinitrobenzoic acid as slightly yellow crystals, m.p. > 270 . the latter acids are unreactive. Anal. Calcd. for CllH1016N~:C, 33.88; H, 0.81; K, Although 2,6-dimethylbenzoic acid may be read- 16.94. Found: C, 34.0; H , 0.94; X, 16.7. ily esterified in 100% sulfuric acid, the meso-cis- and Methyl meso-cis- and trans-2,6-Dimethylcyclohexanecartrans-2,G-dimethylcyclohexanecarboxylic acids and boxy1ates.-The yield was 2.38 g. (2870), b.p. 10PIOT,o trimethylacetic acid are more conveniently esteri- (59 mm.), n Z 51.4398 ~ (reported4n 2 5 ~1.4410 for the meSO-CiS ~ for the meso-trans) from 7.80 g. (0.050 fied using the trifluoroacetic anhydride procedure. ester and n Z 51.4393 of meso-cis-2,6-dimethylcyclohexanecarboxylic acid; Although the latter acids are also esterified in sul- mole) 4.29 g. (55%) of meso-trans acid was recovered. The yield furic acid, the reaction appears to proceed more was 2.55 g. (30T0), b.p. 104-105" (59 mm.), nZ5D 1.4394 cleanly and in higher yield in the anhydride. Only from 7.80 g. of the meso-trans acid; 4.21 g. (54Yo) of meso2,4,6-trinitrobenzoic acid failed to give an ester, truns acid was recovered. The ester from the meso-cis acid was a mixture of cis and trans since hydrolysis with 98Oi possibly because of the low solubility of the acid in sulfuric acid gave a mixture of cis and trans acids; the trans the trifluoroacetic anhydride. However, a small ester gave only trans acid. amount of the latter acid was dehydrated to the All of the p-nitrobenzyl esters were prepared under the anhydride. meso-cis-2,6- Dimethylcyclohexanecar- same conditions. p-Nitrobenzyl 2,6-Dimethylbenzoate .-A solution conboxylic acid gave a mixture of cis and trans esters; taining 1.50 g. (0.0100 mole) of 2,6-dimethylbenzoic acid a t high temperatures the meso-cis acid has been and 0.40 g. (0.0125 mole) of methanol in 10.5 g. (0.050 mole) shown by Jacobs4 to undergo acid-catalyzed inver- of trifluoroacetic anhydride was allowed to stand two hours sion to the trans form. The inversion was appar- a t room temperature. .4fter removal of the anhydride under vacuum, the mixture was dissolved in 30 ml. of ethyl ently caused by trifluoroacetic acid, since a solu- acetate and shaken with an equal volume of a saturated tion of the meso-cis acid in trifluoroacetic acid (at solution of potassium bicarbonate. Acidification of the room temperature) gave a mixture of cis and trans potassium bicarbonate solution gave 0.20 g. (14cI) of 2,(iacids. However, neither 1 0 0 ~ sulfuric o acid nor 12 dimethylbenzoic acid, m.p. 114-116". Evaporation of the ethyl acetate gave 8.39 g. of solid which \%asboiled with iV hydrochloric acid caused inversion of configura- two 50-ml. portions of water to remove unreacted p-nitrotion of the acid or its esters a t ambient tempera- benzyl alcohol, and then recrystallized from cyclohexane tures. giving 1.60 g. (!6%) of p-nitrobenzyl 2,6-dimethylbenzoate, With the exception of the meso-cis acid, trifluoro- m.p. 59.5-60.5 . Anal. Calcd. for CleH1504N: C, 67.36; H, 6.30; S , acetic acid did not affect the esterification or hydrolysis of the aforementioned acids (or their es- 4.91. Found: C, 67.73; H , 5.29; S , 5.04. p-Nitrobenzyl Trimethylacetate.-The yield was 10.0 g. ters). meso-cis-2,6-Dimethylcyclohexanecarboxylic (42'3,), m.p. 47-48' (after recrystallization from petroleum acid, methanol and trifluoroacetic acid gave approx- ether), from 10.2 g. (0.100 mole) of trimethylacetic acid; imately the same yield of methyl ester as with tri- 4.08 g. (40y0) of trimethylacetic acid was recovered. A n d . Calcd. for C12H1~0aS:C, 60.7.5; H , 6.37; S , fluoroacetic anhydride. The explanation may involve the fact that the meso-cis acid is the weakest (5.91. Found: C, 60.60; H, 6.64; S,5.80. p-Nitrobenzyl meso-cis- and trans-2,6-Dimethylcyclohexand hence probably studied (K2s0 = 2.3 X esterification procedure gave 2.21 g. the most easily protonated. Loss of water by the anecarboxy1ate.-The (76y0) of crude ester, m.p. 30-60", from 1.66 g. (0.0100 protonated form with relief of steric strain would mole) of the meso-cis-carboxylic acid, There was recovere: then lead to the reactive acylium ion, from which 0.41 g. (26%) of the meso-trans acid, m.p. 101.5-103 . Recrystallization of t h e crude ester from hexane (solution the ester is obtained. A ) gave 0.87 g. ( 3 0 c ' ; ) of the me\-o-truns ester as yellow (21 E. J. Bourne, E. B. Randles, J. C. Tatlow and J . M. Tedder, needles, m.p. 37.6-89'; two recryst:iIlizations gave 0.ti4 p., Nalirre, 168, 942 (1951). m.p. 47.,5-48.5". RCOOH
c
\\
+
/ ,
I I
+
+
(3) M. S. Newman, THISJ O U R N A L , 63, 2431 (1941). (4) T. I,. Jacubs, R . Reed and I:. Pacovska, i b i d . , 7.3, 4AUd (1951).
~~
~
( 5 ) All r n c l l i i i ~points :ire unccrr,vxcd.
NOTES
June 20, 10.55
3405
Anal. Calcd. for C16H2,01N: C, 6,5.96; H , 7.27; N, 4.81. Found: C , 66.16; H, 7.12; N, 4.98. The mother liquor of solution A (above) deposited 0.93 g. (32Yc), m.p. 63.5-65.5', of the meso-cis ester as long needles; recrystallization from O S'@ ' methanol gave 0.81 g., m.p. 69.5-70.5". A mixture of equal parts of the cis and trans esters melted a t 37-60'. Anal. Calcd. for C16Hl10aN: C, 65.96; H , 7.27; N, 4.81. Found: C, 66.17; H, 7.20; N, 4.91. Hydrolysis of the meso-cis ester with 98% sulfuric acid gave 57y0 of the meso-cis acid, m.p. 84-86": hydrolysis of the trans ester gave a 607, of the meso-trans acid, m.p. 101.5-102°. The meso-trans acid, 1.56 g., also yielded the meso-trans ester, 1.85 g. (647,), m.p. 37.7-39.0' (m:p. 47.5-48.5 after two recrystallizations; a mixed melting point with the meso-trans ester obtained from the meso-czs acid showed no depression). This ester gave meso-lranT acid by hydrolysis with sulfuric acid.
none (VI); 24% of unreacted epoxide was recovered. The dihydrocarvone might conceivably have arisen from direct acid-catalyzed isomerization of limonene monoxide through the intermediates IIIV, or through an initial cleavage of the epoxide ring to the hydroxyacetate, I X , followed by pyrolvsis of the acetate during distillation of the product with formation of carveol (VII). Isomerization of carveol in the presence of acetic acid through the intermediates I11 and IV would lead to dihydrocarvone. In another experiment, limonene monoxide : was treated with glacial acetic acid containing 1h of sulfuric acid a t 16' for a period of eight hours. The reaction mixture was neutralized and the reaction product distilled under reduced pressure to obviate the possibility of pyrolysis of an intermeORGANIC CHEMISTRY BRANCH diately formed hydroxyacetate. Under these conCHEMISTRY DIVISION U S. NAVALORDNANCE TESTSTATION ditions, 90% of the reaction product distilled below CHINALAKE,CALIFORNIA 100' a t 10 mm. indicating the presence of little or no hydroxyacetate. Fractional distillation of the reaction product led to the isolation of p-cymene, Oxygenated Derivatives of d-a-Pinene and d- dihydrocarvone and carvenone in yields of 10, 16 Limonene. Preparation and Use of Monoperphthalic and 35%, respectively. These results indicate that Acid' limonene monoxide reacts with acetic acid, particularly in the presence of sulfuric acid, according to BY E. EARLROYALS AND L. L. HARRELL, JR. the indicated isomerization scheme; ie., under acid RECEIVED OCTOBER 13, 1954 conditions, isomerization of the epoxide is faster A simplified procedure2 for the preparation of an than ring cleavage. ethereal solution of monoperphthalic acid in 65y0 In contrast to the above results in acid media, yield has been developed, and the reagent so pre- treatment of d-limonene monoxide with glacial acepared has been used to effect the epoxidations of tic acid containing sodium acetate led to the formacyclohexene, d-limonene and d-a-pinene in yields of tion of a monoacetate of 8-p-menthene-l,2-diol in 64, 71 and 48y0,respectively. The low yield of pi- 82% yield. This monoacetate was most probably nene epoxide is probably to be accounted for on the the 2-acetoxy-1-hydroxy structure, since base-catabasis of isomerization of the oxide and, perhaps, lyzed cleavage of unsymmetrical epoxides is cleavage of the oxirane ring by phthalic acid pro- known3 to preferentially involve nucleophilic atduced in the reaction mixture. Appreciable quan- tack a t carbon in the order primary > secondary > tities of campholenaldehyde, a known product of tertiary. That the product contained a t least some isomerization of pinene oxide, were isolated from of this isomer was shown by boric acid dehydration the epoxidation reaction mixture. to give carveyl acetate in 16% yield; p-cymene and
A I
A
I
A I1
A
I11
IV
I
bOH 0 J. -H+
I--OAC 0-O" I
A IX
-HOAc,
H
- H?O, aromatization_
bond 4I migration
I
C=" I
A VI1
Trea nent of limonene monoxide with glacial acetic acid a t room temperature for a period of four hours led to the formation of a small amount of dihydrocarvone (V) probably containing some carve( 1 ) Abstracted from a thesis presented by L. L. Harrell, Jr., t o t h e Graduate Faculty of Emory University in partial fulfillment of t h e requirements for t h e degree of Doctor of Philosophy, June, 5, 1954. (2) Compare, H. Bbhme, Ber., 70, 379 (1937); Org. Synfheses. 30, 70 (1940); G. B. Bachman and D. E. Cooper, J . Or#. Chcm., 9, 302 (1944).
A
VI11
A VI
dihydrocarvone were aAdoisolated in 19 and 21y0 yields. Dehydration of the hydroxyacetate with p-toluenesulfonic acid in benzene led to the isolation of p-cymene and carvenone in 31 and 37y0 yields; no carveyl acetate was isolated. Reaction of a-pinene oxide with glacial acetic (3) See S. Winstein and R. B. Henderson in R. C. Elderfield. Editor. "Heterocyclic Compounds," Vol. I , John Wiley and Sons, Inc., New York. N. Y., 1950, pp. 32-39.
