HALOGENATED TERPENOIDS

11." THE 1,8-DIHALO-p-MEXTHANES

By R. $1. CARMAN? and H. C. DEETH?

[Manuscript received August 5, 19691

Summary

The low-melting 1,8-dichloro- and 1,8-dibromo-p-menthanes reported in the literature are shown to be mixtures. Stereochemical assignments for the various 1,8-dihalo-p-menthanes have been revised.

Recently the stereochemistry of some isomeric 8-halolabdane diterpenoids was investigated1 and the S configuration (axial halogen, equatorial methyl) assigned to the more stable C 8 isomers. This is in accord with other reported compounds containing the 1-halo-1-methylcyclohexane system. However, the more stable 1,8-dihalo-p-menthanes (dipentene dihydrohalides) (I) and (11) have been assigned= the cis (methyl/isopropyl; with equatorial halogen, axial methyl) configuration and we felt it was necessary to reinvestigate these compounds. The assignments are now ~corrected, and the more thermodynamically stable isomers are shown to have the trans (with respect to the methyl and isopropyl groups) p-menthane configuration. This latter structure is designated cis by modern nomenclature.$

Baeyer3, who first recognized the phenomenon of geometrical isomerism in the terpene series, prepared a dipentene dihydrochloride, m.p. 25", from 1,8-cineole (XVI) which differed from the known4 dipentene dihydrochloride, m.p. 50". Although Baeyer3 mistakenly assigned the 1,4-dichloro-p-menthane structure (111) to these dihydro- chlorides, he, somewhat fortuitously, allotted the cis (methyl/isopropyl) configuration to his new compound. This cisltrans assignment was subsequently reversed by Barnes2 who assumed that chlorine was a "larger substituent" than methyl, an assumption now known to be in error.

* Part I , Aust. J. Chem., 1969, 22, 1107. t Chemistry Department, University of Queensland, St. Lucia, Qld. 4067. $ The cisltrans nomenclature in the menthane series has been used by different workers to

mean different things. In this paper we follow the IUPAC tentative rules E-3.3 and E-3.4; the cis compounds are then always Z and the trans oompounds E in configuration.

Carman, R. &I., and Deeth, H. C., Aust. J. Chem., 1969, 22, 2161. Barnes, C. S., Aust . J. Chem., 1958, 11, 134. Baeyer, A., Ber. dt. chem. Ges., 1893, 26, 2861. Wallach, O., Liebigs Ann. , 1887, 239, 1 (et seq.).

Aust. J . Chem., 1969, 22, 2651-6

2652 R. M. CARMAN AND H. C. DEETH

Repetition of Baeyer's procedure for the preparation of the compound, m.p. 25", gave a product with similar characteristics to those reported, but which, by g.1.c. and p.m.r. spectroscopy, was a mixture (1: 1 : 1) of the two dipentene dihydrochloride isomers (V) and (VI). Fractional crystallization yielded the known isomer, m.p. 50°, as tabular plates, and a second isomer, m.p. 53", as needles. Treatment of the latter isomer with hydrogen chloride in acetic acid for 2 days yielded the equilibrium mixture (5.9 : 1 by g.1.c.) of the two isomers, with the compound of m.p. 50" predominating. This equilibrium constant corresponds to an energy difference of 1: 1.1 kcal/mole, in excellent agreement with the corresponding 4-t-butyl-1-chloro-1-methylcyclo- hexane5 equilibrium (IX) + (X). The isomer m.p. 50°, being the more stable, is assigned the r-1,8-dichloro-c-4-p-menthane configuration (axial chloride, equatorial methyl) (V).

Chemical evidence for the stereochemistry of the two l&dichlorides (V) and (VI) was obtained from elimination experiments. Both isomers were treated separately with aqueous potassium hydroxide. The cis compound (V) has already been shown6 to give about 90% endocyclic A1 compounds during certain elimination experiments. The p.m.r. spectra of the product mixtures each showed two broad peaks in the vinyl region, one a t 6 5 -33 (trisubstituted double bond) and one at 6 4.66 (1,l-disubstituted double bond). The ratio of these two peaks was 1: 3 : 1 for the cis isomer (C 1 axial chlorine) and 1: 3 : 2 for the trans isomer (C 1 equatorial chlorine). More exocyclic double bond isomers are expected from the trans isomer since the equatorial chlorine

AIlinger, N. L., and Liang, C. D., J. org. Chem., 1967, 32, 2391. 6 Muraleedharan, X. V., and Verghese, J., Perfum. essent. Oil Rec., 1968, 59, 275.

HALOGENATED TE~PENOIDS. 11 2653

at C 1 is trans-coplanar only with hydrogens of the C 1 methyl group, and the ring must '(flip" before it can assume a favourable position for an E2 elimination with the hydrogens on C 2 and C 6. These latter hydrogens are, however, trans-coplanar with an axial chlorine at C 1 allowing endocyclic double bond compounds from an E2 type elimination of the cis isomer. The elimination of the C8 chlorine would be similar for both isomers.

The infrared spectra of these compounds were in accord with the present assign- ment. These spectra however are complicated by the presence of the 2-chloroiso- propyl group, and an assignment of configuration on the basis of infrared spectroscopy alone would be injudicious.

Prolonged treatment ( E 3 weeks at room temperature) of the equilibrium 1,s-dichloride mixture with hydrogen chloride in acetic acid gave a mixture (1: 2 : 3) of 1,4- (111) and 1,8- (I) dichlorides. The same equilibrium was approached by starting with r-1,t-4-dichloro-p-menthane (VII). Very little of the isomeric cis-1,4-dichloride (VIII) could be detected and it is assumed that the equilibrium strongly favours the form with the 1,4-diaxial dichloride arrangement (VII).

Baeyer also described two isomeric 1,8-dibromo-p-nienthanes (11). One of these, m.p. 64", had been reported previously4 and is obtainable from 1,8-terpin, terpineol, dipentene etc., by reaction with hydrogen bromide in acetic acid. The other, m.p. 40°, was obtained "in exceedingly large quantity by the addition of a glacial acetic acid solution of hydrogen bromide to a well-cooled solution of cineole in glacial acetic

Repetition of the reaction yielded a product (m.p. c. 40") which was shown to be a mixture (1: 1 : 1 by p.m.r.) of the two isomeric 1,s-dibromides (XI) and (XII). The two isomers crystallized in different crystal habits and could be readily separated. The known isomer had m.p. 64" while the other isomer had m.p. 73". The latter compound could be converted into the isomer m.p. 64" by brief treatment with hydro- gen bromide in acetic acid (1 hr at room temperature). The compound m.p. 64" is thus the more stable and must be r,l,8-dibromo-c-4-p-menthane (XI) while the other isomer must have trans structure (XII). This reverses the assignments of Barnes2 for these compounds also.

Treatment of the 1,8-dibromide (or 1,4-dibromide) with hydrogen bromide in acetic acid for three days produced a mixture ( E 1 : 1 by p.m.r.) of the 1,4- (IV) and 1,8- (11) dibromides. Acetic acid is known8 to promote unimolecular reactions and a reasonable mechanism for the 4- to 8-halide shift consists in cleavage of the C-Hal bond to produce a carbonium ion followed by either loss of proton and addition of hydrogen halide to the resulting double bond, or migration of a hydride ion and subsequent attack by halide ion. To test the former mechanism, 1,s-dibromo- p-menthane (11) was treated with deuterium bromide. The 1,4-dibromide resulting from this rearrangement showed a single peak in the p.m.r. spectrum for the isopropyl group and was [8-Dl-r-1,t-4-dibromo-p-menthane (XIV). The incorporation of deuteri- um requires that a 4(8) double bond is formed during the rearrangement.

Authentic 1,4-dihalo-p-menthanes (111) and (IV) were prepared from 4-terpineol (XVII). These hydrohalogenations yielded mixtures (1: 7 : 3) of the 1,4- and 1,8-

Verghese, J., Perfum. essent. Oil Rec., 1968, 59, 439. Bunton, C. A., "Nucleophilic Substitution a t a Saturated Carbon Atom." p. 121. (Elsevier: New York 1963.)

2654 , R. M. CARMAN AKD H. C. DEETH

dihalides from which the former could be obtained by recrystallization. It appears that this reaction also proceeds through the intermediacy of a 4(8) double bond formed by acid-catalysed dehydration. Hydrogen halide then adds to this double bond with little directional preference.

The above reactions suggested that the carbonium ions at C 4 and C 8 had simi- lar stabilities, and it is therefore surprising that the reaction of terpinolene (XIX) with hydrogen halides in acetic acid should be reported to give the 1,8-dihalides "in good yield".s These reactions were repeated and found to give the expected mixture (1: 3 : 2) of the 1,8- and 1,4-dihalides. The addition of halogen acids to y-terpineol to produce both dihalides has also been reported.1°

During attempts to isomerize r-1,8-dibromo-t-4-p-menthane (XII) to the c is isomer (XI) with potassium bromide in dimethyl sulphoxide, r-1,t-4,s-tribromo-p- menthane (XV) was formed in about 50% yield together with unsaturated compounds. A possible mechanism for this reaction is outlined in Scheme 1, where driving force for the hydride transfer is obtained through the formation of a bromonium ion.

Scheme 1

P.m.r. spectra were recorded a t 60 MHz in CC1, solutions with tetramethylsilane (6 0.00) as internal reference. 1.r. spectra were measured in CS, solutions. 1.r. data are only given for the pertinentl1 region, below 700 om-I. Gas chromatograms were obtained on a 5% EGS column a t 100".

r-1,8-Dichloro-t-4-p-mthane ( V I ) 1,8-Cineole (XVI) (5 g) in glacial acetic acid (5 ml) was treated with HC1 gas for 1 hr a t 0'

and 2 hr a t room temperature. The mixture was poured into iced water and extracted with hexane to give a mixture ( E 1 : 1 by g.1.c.) of cis- and trans-1,s-dichloro-p-menthanes (V) and (VI). One crystallization from ethanol gave crystals which were predominantly the cis isomer (V) while the mother liquors were enriched in the trans isomer (VI). Seed crystals were obtained by hand

Simonsen, J. L., and Owen, L. N., "The Terpenes." 2nd Edn, Vol. 1. (Cambridge Uni- versity Press 1953.)

l0 Wallach, O., Liebigs Ann., 1906, 350, 160. l1 Altona, C., Hageman, H. J., and Havinga, E., Recl Trav. chim. Pays-Bas, 1968,87, 353.

HALOGENATED TERPENOIDS. I1 2655

sorting. Repeated recrystallization of the mother liquors gave r-1,8-dichloro-t-4-p-menthane (VI) asneedles, m.p. 53' (fromethanol) (lik8 m.p. 25' for a oompound which was undoubtedly a mixture) (Found: C, 57.6; H, 8.7; Cl, 34.2. CloHl,C1, requires C, 57.4; H, 8.6; C1, 34.0%). P.m.r. spectrum (6) : 1.53 (6-proton singlet; C 9, C 10 methyls), 1.59 (3-proton singlet; C 7 methyl). C: 675s; 637, 589m; 545, 520w cm-l.

r-1,s-Dichloro-o-4-p-menthane ( V ) (Dipentene Dihydrochloride)

(i) Dipentene (XVIII) (5 g) in glacial acetic acid (10 ml) was treated with a stream of HC1 for 1 hr. The mixture was poured into ice, filtered, and recrystallized from hexane to give r- 1,s-dichloro-c-4-p-menthane (V) as plates, m.p. 50' (lit.4 50'). P.m.r. spectrum (6) : 1.55 (6-proton singlet; C9, C 10 methyls), 1.59 (3-proton singlet; C7 methyl). i;: 651, 572, 551s; 618m om-l.

(ii) r-1,s-Dichloro-t-4-p-menthane (VI) in acetic acid was treated with HCl for 2 days to give the cis isomer (V), m.p. 50' (from ethanol), identical with that obtained above.

r-1,8-Dibromo-t-4-p-menthane (XII )

1,s-Cineole (XVI) (2 g) was treated with a cold solution of HBr in glacial acetic acid (5 ml). The solution was shaken a t room temperature until the initial precipitate of the cineole-HBr salt had disappeared. The reaction was quenched with iced water and filtered. Recrystallization from ethanol gave r-1,8-dibromo-t-4-p-menthane (XII) as long needles, m.p. 73' (lit.=, for a compound which was certainly a mixture, 40') (Found: C, 40.6; H, 6.3; Br, 53.4. CloHl,Br, requires C, 40.3; H, 6.0; Br, 53.7%). P.m.r. spectrum (6): 1.72 (6-proton singlet; C9, C 10 methyls), 1.81 (3-proton singlet; C7 methyl). i; 66Om; 605, 548, 527vw om-l. The oompound was not stable to gas chromatography.

r-1,8-Dibrom0-0-4-p-menthane (XI) (Dipentene Dihydrobromide)

(i) Dipentene (XVIII) (5 g) was treated with a solution of HBr in glacial acetic acid (45% w/v) (10 ml) to give r-1,s-dibromo-c-4-p-menthane (XI) as plates (from ethanol), m.p. 64' (lit.4 64"). P.m.r. spectrum (6): 1.76 (6-proton singlet; C 9, C 10 methyls), 1.82 (3-proton singlet; C 7 methyl). i;: 630, 504m; 556, 535w cm-l. The compound was not stable to gas chromatography.

(ii) r-1,s-Dibromo-t-4-p-menthane (XII) was treated with HBr in acetic acid for 1 hr to yield the cis isomer (XI), m.p. 64' (from ethanol), identical with that obtained from dipentene.

r-1,t-4-Dichloro-p-menthane (VII) (Terpinene Dihydrochloride)

Hydrochlorination of 4-terpineol (XVII) in acetic acid for 2 hr gave a mixture ( E 7 : 3 by g.1.c.) of 1,4-dichloro-p-menthane (111) and 1,8-dichloro-p-menthane (I). Recrystallization from ethanol gave r-1,t-4-dichloro-p-menthane (VII) as plates, m.p. 50-51" ( l h 9 51-52"). P.m.r. spec- trum (6) : 1.08 (6-proton doublet, J 6.5 Hz; C 9, C 10 methyls), 1.67 (3-proton singlet; C 7 methyl), 1.95 (broad singlet, 8 protons; C 2, C 3, C 5, C 6 methylenes). i;: 548s; 510m om-l.

r-1,t-4-Dibromo-p-menthane (XII I )

4-Terpineol (XVII) was treated with HBr in acetic acid to yield a mixture ( 2: 7 : 3 by p.m.r. spectrum) of 1,4,dibromo-p-menthane (IV) and 1,s-dibromo-p-menthane (11). Recrystallization from ethanol gave r-1,t-4-dibromo-p-menthane (XIII) as plates, m.p. 59" ( l h 8 m.p. 58-59"). P.m.r. spectrum (6) : 1.13 (6-proton doublet, J 6.5 Hz; C 9, C 10 methyls), 1.91 (3-proton singlet; C 7 methyl), 2.03 (broad singlet, 8 protons; C2, C 3, C 5, C 6 methylenes). i;: 544, 500, 467m om-l. The oompound partly decomposed on gas chromatography.

Rearrangement of the 1,4- and 1,8-Dihalo-p-menthanes

I n separate experiments, 1,4- and 1,s-dichloro-p-menthanes were treated with HCl in acetio aoid for 3 weeks a t room temperature. Similar products (r-1,t-4-dichloro-p-menthane (XII) (E 40%); r-1,s-dichloro-c-4-pmenthane (V) ( E 50%), r-1,s-dichloro-t-4-p-menthane (VI) (2: 10%)) were obtained from these experiments. The 1,4- and 1,s-dibromides were each treated with HBr in acetic or HBr in acetic acid-ether for three days to give 2: 1 : 1 (by p.m.r.) mix- tures of the two major dibromides. 1,s-Dibromo-p-menthane (XI) was also treated with DBr in deuteroacetic acid-ether solution. The p.m.r, of the isopropyl methyls of 1,4-dibromide in the resulting mixture appeared as a singlet a t 6 1.13.

2656 R. M. CARMAX AKD H. C. DEETH

Reaction of r-1,8-Dibromo-c-4-p-menthane ( V ) with KBr-DMSO

r-1,s-Dibromo-c-4-p-menthane (V) (0.5 g) was dissolved in a saturated solution of KBr in DMSO (20 ml). After 6 hr a t room temperature, iced water was added, and the product extracted with hexane. Recrystallization from hexane gave r-1,t-4,s-tribromo-p-menthane (XV), m.p. 108- 109' (Mg 110'). P.m.r. spectrum (6): 2.06 (6-proton singlet; C9, C10 methyls), 1.92 (3-proton singlet; C 7 methyl). 5 : 614, 495m; 453vw cm-l. The compound was identical with an authentic sample.

Dehydrochlorination of the 1,8-Dichloro-p-menthanes (I) r-1,s-Dichloro-t-4-p-menthane (VI) and r-1,s-dichloro-c-4-p-menthane (V) were subjected to

dehydrochlorination in separate identical experiments. The dichloro-p-menthane (200 mg) in aqueous KOH (2%, 20 ml) was stirred a t 90' for 3 hr. Extraction with hexane gave a mobile oil which, by g.1.c. and p.m.r, spectra, contained unsaturated hydrocarbons and alcohols. P.m.r. spectrum of oil from (V) or (VI) (6): 1.12 (CH,-C-OH), 1.63 (CH,-C=C-), 4.66 (W+ = 3.5 Hz; 1,l-disubstituted olefinic methylene), and 5.33 (mi = 8 Hz; trisubstituted olefinic methine). The ratio of the areas of the latter two peaks was c 2 : 3 for the product from (VI) and c 1 : 3 for the product from (V).