Feb. 5, 1958
7-TROPOLONE FROM SUBSTITUTED TROPANES [CONTRIBUTION FROM THE
DEPARTMENT OF CHEMISTRY,
633
CORNELL UNIVERSITY ]
Elimination Reactions of Bicyclic Quaternary Salts. 111. 7-Tropolone from Some Appropriately Substituted Tropanes BY J. MEINWALD AND 0. L. CHAPMAN’ RECEIVED JULY 26, 1957 Some unsuccessful efforts t o prepare y-tropolone ( I V ) via 6P-hydroxytropinone (V) are described briefly. The base degradation of teloidinone methobromide (VII) has been found to give IV in fair yield. T h e degradation of a number of closely related compounds also has been studied; 6,8,7P-dimethoxytropinone methobromide ( X ) was found to yield ytropolone methyl ether ( X I ) almost quantitatively. These results, coupled with Heusner’s excellent synthesis of X and the known acid hydrolysis of X I t o IV, open practical, preparative routes t o both y-tropolone and its methyl ether.
Recent studies on the elimination reactions of tropinone methiodide (I)2 and 60-hydroxytropinone methiodide (11)3to give a mixture of cycloheptadienones and tropone (111), respectively, have made i t clear that tropane derivatives may serve as quite flexible precursors for a variety of troponoid compounds. I n connection with an interest in studying some reactions of y-tropolone (IV), we have investigated several possible synthetic routes to IV starting from appropriate bicyclic precursors. The first attack on this problem involved the oxidation of 60-hydroxytropinone (V) to the corresponding ketone VI, the methiodide of which should be readily convertible to IV by a process consisting of two p-elimination reaCtions followed by enolization. This attack was never effectively launched,
E
TiT
on a preparative scale, the isolable yield was only half as good.7 ?%Thisstudy has therefore been extended, and we now wish to report the course of the elimination reactions of the methobromides of teloidinone acetonide (VJII), 60-hydroxy-70-methoxytropinone (IX) and 6P,ip-dimethoxytropinone (X). Table I summarizes the outcome of these experiments. The data for teloidinone methobromide have been included for completeness. The yields are based on the intensity of the 360 mp absorption maximum of the y-tropolone anion.4 TABLE I Yield of y-
P
as a result of our inability to accomplish the requisite oxidation of V to VI. A large number of experiments using (1) chromic oxide under a variety of conditions, (2) the Oppenauer method or (3) N-bromoacetamide resulted either in the recovery of unchanged starting material or else in the formation of products which could not be characterThis approach was abandoned, therefore, in favor of a study of the elimination reactions of the equally attractive precursor, teloidinone methobromide (BP,ip-dihydroxytropinonemethobromide, VI0.6 The initial experiments with VI1 were encouraging, and have been reported in a preliminary communication.7 A 45% yield of y-tropolone could be observed to form in dilute, basic solution, according to the equation shown below. However, (1) American Viscose Fellow, summer 1956; Procter and Gamble Fellow, 1956-1957; Dow Chemical Co. Fellow, summer 1957. (2) J. Meinwald, S. L. Emerman, N. C. Yang a n d G. Buchi, THIS J O U R N A L , 7 7 , 4401 (1955). (3) E. E. van Tamelen, P. Barlh a n d F. Lornitzo, ibid., 7 8 , 5442 (1956). (4) T h e first synthesis of I V was achieved by T. Nozoe, T. Mukai, Y. Ikegama a n d T. Toda. Chcmisfry b Indtislry, 66 (1955). Shortly thereafter, R. S. Coffey, R. B. Johns a n d A. W. Johnson, ibid.. 658 (1955), completed another synthesis. ( 5 ) In t h e interest of brevity, details of these a t t e m p t s have been omitted. (e) Teloidinone is available by total synthesis using t h e RobinsonSchdpf “biosynthetic” technique. T h e procedure leading t o teloidinone was first developed by C. Schopf and W. Arnold, A n n . , 668, 109 (1947). A more convenient preparation is described by J. C Sheehan and B. M. Bloom. THISJ O U R N A L , 74, 3825 (1952). (7) J. Mcinwald and 0. L. Chapman, ibid., 78, 4816 (1956).
tropolone, Compound Teloidinone methobromide (VI11 Teloidinone methobromide
%
Conditions 1, NaHCOa in H i 0
45
2 , Ba(O€I)z in IInO (dil.)
45
3, Ba(OI1)z in €120 (concd.)
24
4, Anhydrous yyriiiiue
23
1, NaHCOa in Hz0
41
?, h’alICOa in HzO, then acid
41
1, NaHCOa in H i 0
48
(VW Teloidinoue methobromide (VX) Teloidinone methobroniide (VW Teloidinone acetonide methobromide (VIII) Teloidinone acetonide methobromide (VIII) 68 .Hydroxy-7p-methoxytropinone mcthobromide (IX) 6p-Hydroxy-7@-methoxytropinone methobromide (1X) 6p,7@-Dimethoxytropinonr methobromide (20 Gp,7p-Dimethoxytropinone methobromide (X) a
2 , hraHCOa in
€120.
then acid
1. NaIICOa In HrO 2, NaHCOr in 1120, then acid
GD NlOOO
91
7-Tropolone methyl ether.
Degradation of the acetonide VI11 gave y-tropolone directly, albeit in yields which were no better than those obtained using VII. Some improvement could be realized in the case of the monomethoxy compound IX, where the initial yield could be increased by mild acid hydrolysis of the product. In this instance, it is apparent that ytropolone methyl ether (XI) is formed along with VI. This is in no way surprising, and simply indicates that the methoxyl and hydroxyl groups are lost with roughly comparable ease. Degradation of X, the last case studied, yields y-tropolone methyl ether (XI) nearly quantitatively. This reaction has made possible the preparation of XI
634
J. AfEINWilLD
AND
in quantity, since X is readily available by the method of Heusner.8 In view of the ready acid hydrolysis of XI to IV,9 X appears to be the pre-
cursor of choice for either y-tropolone or its iiietliyl ether. Acknowledgment.--The authors arc deeply itidebted to Dr. 31ex Heusner, C. H. Boehriiiger Sohn, Germany-, for a saniple of 6P-hydroxy-7Pmethoxytropinone as well as for a generous gift of 6/3,7,B-dimethoxytropinone methobromide. They also wish to thank the Research Corporation for the partial support of this research program through a Frank Gardner Cottrell grant. Experimental Oxidations of 68-Hydroxytropinone (V).--Tell experiments Fere carried out in an attempt t o obtain VI. The chromic acid oxidations were worked up by making the solutions basic with potassium carbonate, saturating the basic solution with salt, and continuously extracting with ether. The Oppenauer and X-brornoacetainide oxidations were worked up in the usual manner with the final step being the satne,as for the chroriiic acid oxidations. The oxidations of 6B-li.i.droxytropiiione methiodide n-ere worked u p by adding ;icetone t o precipitate the inorganic material, filtering, anti cvaporatirig the aqueous acetone to dryness. Teloidinone Acetonide Methobromide (VIII).---Tcluicliiione acetonidel0 (0.9 g.) in 10 nil. of methanol was treated with excess methyl bromide. After standing overnight in the refrigerator, t h e solution mas evaporated to dryness zn vacuo, giving a white, crystalline solid which showed only very slight absorption a t 2.9,5 p . Recrystallization from methanol-ethannl gave white crystals which when placed on a melting stage preheated t o 180" darkened above 210' and melted with severe decompositiou at 237-338". A n d . Calctl. for C,zHsoOaNBr: C, 47.10; FI, 6.34; S, 4.58; Br, 26.20. Found: C, 46.88; H , 610; N, 3.65; Ilr, 26.41. 68-Hydroxy-7fl-methoxytropinone Methobromide (IX I .A solution of 175 mg. of aiialytically pure 6P-hydroxy-7fmethoxytropinones in 2 ml. of methatiol was treated with escess methyl bromide. A.lfterstanditig overnight in the refrigerator, the solution was evaporated to dryncss in vacjro, (8) R. Zcile and A . IIerisner, Be r... 87, 1:10 (l!lZk), See iilsii the Experimental section. ( 0 ) T h e hpdroly& uf XI under vigrrri,iis conditions has been described b y A . W. johnson a n d co-workers, ref 1. This hydrolysis has also been found t o proceed under consider:ibly milder conditions (see Experimental section). (10) J. C. Sheehan and IC. R . Bi-sell. J . O r p . C'hcm.. 19, 2 i O ( l % Z l ) ; .4. Heusner, Be?., 87, lO:i2 (1954).
0. L. C€IAPllIAN
Vol. 80
giving 252 mg. of white, crystalline product, 1n.p. 183-1S5'. 6/3,7p-Dimethoxytropinone Methobromide (X) .--The @,iB-dimethoxytropinone methobromide used in these esperiments was made available to us through the courtesy of Dr. A. Heusner. It was prepared from 6~,7@-dinietlioxytropiiione, the synthesis of which has already been reported.8 The following d a t a for 68,TP-diinethoxytropinone methobromide were supplied b y its donor. Recrystallization of X from methanol-isopropyl alcohol ( 2 : 1) gives colorless plates, m . p . 207-308' dec. T h e melting point is t o s(uine extent dependent on the rate of lieatitig. .?mi.Calcd. for C1,HzoOiXBr:C. 44.91; 11, 6.85; N, Found: C, tt.ti9; I I , C,.Rt?; 4.76; Fir, 27.16; C H B O 21.10. , S.4.76:, Br,. 27.52: CHIO, 20.77. Degradation of 'Teloidinone Acetonide Methobromide (VIII) .-.I solution of teloidiiione aeetonide tnethobromidc (7.7 mg., 0.025 mmole) and sodiuni bicarbonate (4.2 mg., 0.05 mmolej in 50 ml. of distilled water was heated on :I steam-bath. AUiquot s:iuiples were withdr:i\vn every 30 minutes, diluted t o :L suitable concentration with 0.1 4 sndium hydroxide, and the intensity of absorptioil a t 360 nip determined. -1fter 121) minutes, the intensit!. of the 360 m p absorptioii innxiinum did iiot increase. Tile aiialysis iridicatcti :I 41yc yield of y-tropolone. Five I I ~ .of 18g, hydrobromic acid \vas added, and the solutioll w i s heated on a steam-bath for several hours. This did not increase the yield of IY. Degradation of 6p-Hydroxy-7P-methoxytropinone Methobromide (IX).-.i solution of Gi3-hydrox).-7B-metlI~)xytr(lpinone methobromide (7.0 ing., 0.025 inniolc~and sodium bicarbonate (4.2 mg., 0.05 mmole) in 50 ml. of distilled water m a s heated on a steam-bath. After 90 niiuutes, 111) increase in 360 n i p absorptiun intensity of a n a1 could lie detected. The :inalysis indicated a y-tropolnne. One nil. o f -is",, hydrobromic aci and the snlutioii was lieateti 011 a steam-bath acid, ;iiialvsii lis ' L ~ N J W iiidithoxytropinone Methobromide imethorytropinone methobroed above. After 60 minutes, the absorption spectrum, ' ;:A: NaoH 226 rnp (4.30) and 332 mp (1.13), did not change. One mi. 48yohydrobrornic acid was added, and the solution was heated on a steam-batli for 90 minutes to bring about hydrolysis of the methyl ether. After neutralizing the acid, analysis of this solution indicated a 91y0 yield of IV. 7-Tropolone Methyl Ether (XI) .---I solution of 6/3,7Pdimethoxytrnpinone methobromide (26.24 g., O.OS93 mole) and sodium bicarbonate (7.50 g., 0.0893 mole) in 368 ml. of distilled water \yas iieatctl on a steam-bath for 1.5 hours. The solution, which was red in color, was contiliuously extracted with ether for trvo days. Drying over auliytlrous magnesium sulfate and careful evaporation of the etlicr gave a brown oil (11.47 g., !Nybj which solidified on stnilcling in t h e refrigerator. Distillation of thi 1:iteri:d gJ\-e pure Y tropoloiir methyl ether (3.90 g . , 74 13 .p. 10.'-1--1(MO(0.:',8 i n i n . ) . Soinc tleci)nili['~itii,~~ occttr rluriiig t l i i . distilla2R--21Jo(1it.I 29-:30°) i ; I t i 22; i l l p (4.04;(1i1.4 O n staiitiitig it1 tlic ri'~ i - o ~ ) r i l o i i iri i c . f
turiiec! pale j,eIlri\v. I-rmc-A, SEIV ITo~l~
Iiyi c.tlicr
