HALOGENATED TERPENOIDS By R. M. CARMAN? and B. N. VENZKE~

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R. M. CARMAN AND B. N. VENZKE bromine was introduced into the tribromide (2). As a further example,14 the diaxial dihalide 2x74sc-dibromofriedelin (8) has ...
HALOGENATED TERPENOIDS VIII.* THE HALOGENATION OF SOME AXIAL a-BROMO-p-MENTHANONES. BOAT CONFORMERS OF HALOGENATED CYCLOHEXANONES

By R. M. CARMAN? and B. N. VENZKE~ [Manuscript received I March 19731

Abstract The structures of some halogenatedp-menthan-2-ones and p-menthan-3-ones are determined. Some cyclohexanones with a-axial bromine and a'-equatorial bromine substituents exist in a boat conformation provided an additional attractive halogen+carbony1 interaction is available to stabilize the boat through a five-membered bridging ring. Some profound differences in the conformations of bromo- and chloro-cyclohexanones are noted. The a'-bromination of a-bromocyclohexanones is discussed. The configurations of the new compounds are determined chemically and the conformations are determined chiefly by p.m.r. spectroscopy.

W a l l a ~ h " reported ~ a crystalline tribromide from the addition of hydrogen bromide and bromine to ($)-carvone. Wolinsky3 et al. determined the structure (1) of this compound and prepared a cis isomer (2). Following our recent work4 on the epimeric carvone pentabromides, we have investigated the bromination of these enantiomeric tribromides. Wallach5 prepared dihydrocarvone by the reduction of (-)-carvone (3) with zinc dust in alkaline solution. With the addition of hydrogen bromide and one mole of bromine he obtained a dibromide, m.p. 69-70", while the addition of a further mole of bromine gave6 a tribromide, m.p. 88-89", Beckmann and Eickelberg7 have prepared a crystalline dibromide, m.p. 79-80", by the addition of two moles of bromine to (-)-menthone (4). The chemistry of these three bromides is related to the above compounds and their structures have been investigated concurrently.

* Part VII, Aust. J. Chem., 1973, 26, 1283. t Chemistry Department, University of Queensland, St. Lucia, Qld. 4067. Chemistry Department, Queensland Institute of Technology, Brisbane, Qld. 4000. Wallach, O., Liebigs Ann., 1899, 305, 245. Wallach, O., Liebigs Ann., 1918, 414, 240. Wolinsky, J., Hamsher, J. J., and Hutchins, R. O., J. oug. Chem., 1970, 35, 207. Carman, R. M., and Venzke, B. N., Aust. J. Chem., 1973, 26, 1283. Wallach, O., Liebigs Ann., 1894, 279, (a) p. 377; (b) p. 389. Wallach, O., Liebigs Ann., 1895, 286, 127. Beckmann, E., and Eickelberg, H., Ber. dt, chem. Ges., 1896, 29, 418.

Aust. J. Chem., 1973,26, 1977-2007

1978

R. M. CARMAN AND B. N. VENZKE

DISCUSSION AND RESULTS Both isomeric 1,6,8-tribromo-p-menthan-2-ones (1) and (2), prepared by Wallachls2and W ~ l i n s k ywere , ~ brominated in carbon tetrachloride and the products worked up within a few hours. Appreciable isomerization of the C 6 bromine did not occur in that time. The oily trihalide (1) derived from (-)-carvone (3) yielded the equatorial a'-bromo compound (5), m.p. 78", in good yield. The p.m.r. spectrum of (5) showed the C 3 proton as a doublet at 6 5.20, J 8.5 Hz, indicating an anti arrangement between the C 3 and C 4 protons. The infrared spectrum showed a C=O stretching frequency shift of A? $9 cm-l, a little smaller than that expected8 from the introduction of an a-equatorial halogen, while the rotatory dispersion curve showed a positive Cotton effect which peaked at 334 nm and crossed the zero line near the ultraviolet maximum at 308 nm. A similar absorbance maximum was found3 in the ultraviolet spectrum of the trihalide (1). The intensity of absorbance was reduced in (5) as is often observed when an equatorial a'-halogen is i n t r ~ d u c e d . ~ Bromination of the tribromide (2) under the same conditions gave a crystalline 1,3,6,8-tetrabromide, m.p. llgO,in excellent yield. The p.m.r. spectrum showed the C 6 proton as a quartet, J , , +J , .,6 = 15 Hz, normally diagnostic of an axial hydrogen and equatorial C 6 bromine. The C 6,C 1 cis dibromo relationship was retained as the compound debrominated at the rate characteristic of vicinal cis dibromides (e.g. (2)) and much slower than that of trans dibromides (e.g. (5)). The C 3 proton resonated as a doublet, J 3 a5 Hz, assignable to an equatorial proton, and so the fourth bromine had appeared to enter the tribromide (2) in an axial configuration, and the tetrabromide was tentatively assigned structure (6). The apparent C 3 axial configuration was puzzling. Bromination of ketones ~ ~ steric ~ ~ ~factors ~ ~ " (see below) cause compound often gives the axial x - b r ~ m i d e but (1) and many other ketones in this series4 all to give equatorial a-bromides, and it seemed unlikely that the equatorial C 6 bromine of (2) would have a major steric or inductive influence upon the reaction. Furthermore, a closer examination of the evidence revealed that the new tetrabromide could not have the diaxial dihalide structure (6). Examples of %,a'-dihalocyclohexanones,particularly from cholestan-3ones, are plentiful in the l i t e r a t ~ r e .The ~ angular C 19 methyl group causes an equatorial halogen to be favoured for at least one of the a-bromines. There are however, very few a,al diaxial dihalocyclohexanones recorded. The ultraviolet spectrum12 of 5a,7a-dibromo-6-oxocholestan-3-yl acetate (7), formed by the kinetically controlled dibromination13 of the ketone, does not correspond with that obtained for the terpenoid tetrabromide (Table 1). The introduction of the first axial a-halogen into the steroid ketone caused1' a bathochromic shift of approximately 28 nm in the carbonyl absorbance while the second axial halogen caused an additional bathochromic shift of similar magnitude. This additional shift was not observed when the fourth Jones, R. N., Ramsay, D. A., Herling, F., and Dobriner, K., J. Am. chem. Soc., 1952,74, 2828. Fieser, L. F., and Fieser, M., "Steroids," p. 280 (Reinhold: New York 1959). lo House, H. O., "Modern Synthetic Reactions," p. 144 (Benjamin: New York 1965). l 1 Eliel, E. L., Allinger, N. L., Angyal, S. J., and Morrison, G. A., "Conformational Analysis," (a) p. 307; (b) p. 462; (c) p. 466; (d) p. 467; (e) p. 164 (Interscience: New York 1965). l 2 Cookson, R. C., J. chem. Soc., 1954,282. l 3 Heilbron, I. M., Jackson, H., Jones, E. R. H., and Spring, F.S., J. chem. Soc., 1938, 102.

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bromine was introduced into the tribromide (2). As a further example,14 the diaxial dihalide 2x74sc-dibromofriedelin(8) has imaX332 nm (Table I), while our tetrabromide had Amax much lower at 3 17 nm. The infrared spectrum of a,af-diaxial dibromides is of little diagnostic help. The introduction of one axial bromine into the parent 6-oxocholestan-3-yl acetate causes little change15 (0 and + 2 cm-l) in the carbonyl stretching frequency, while the second axial bromine gives a small (3 cm-I) decrease. The carbonyl frequencies of (2) TABLE1 THE ULTRAVIOLET AND INFRARED ABSORBANCE MAXIMA OF HALOGENATED KETONES

Compound

Ultraviolet

C=O transmission (nm)

Infrared C = O str (cm-')

6-Oxocholestan-3-ylacetate 5a-Bromo-6-oxocholestan-3-yl acetate

7a-Bromo-6-oxocholestan-3-yl acetate 5a,7a-Dibromo-6-oxocholestan-3-yl acetate (7) 2a-Bromofriedelin 4a-Bromofriedelin 2a,4a-Dibromofriedelin(8) (1 R,4S,6R)-1,6,8-Tribromo-p-menthan-2-one (1) (lR,3S,4R,6R)-1,3,6,8-Tetrabromo-p-menthan-2one (5) (1R,4S,6R)-1,6-Dibromo-8-chloro-p-menthan-2-one (10) (1R,3S,4S,6R)-1,3,6-Tribromo-8-chloro-p-menthan-2-one (12) (lR,4S,6S)-1,6,8-Tribromo-p-menthan-2-one (2) (lR,3S,4R,6S)-1,3,6,8-Tetrabromo-p-menthan-2-0ne (9a) (1R,3S,4R,6S)-1,6,8-Tribromo-3-chloro-p-menthan-2-one (28) (lR,3S,4S,6S)-l,3,6-Tribromo-p-menthan-2-one (52) (1R,3S,4S,6S)-1,6-Dibromo-3-chloro-p-menthan-2-one (53) (1 R,4S,6S)-1,6-Dibromo-8-chloro-p-menthan-2-one (1 1) (13a) (1 R,3S,4S,6S)-1,3,6-Tribromo-8-chloro-p-menthan-2-one (1R,3S,4R,6S)-1,6-Dibromo-3,8-dich1oro-p-menthan-2-one (29) (lS,4R)-1,8-Dibromo-p-menthan-2-one (20) (lS,3S,4R)-1,3,8-Tribromo-p-menthan-2-one (16a) (1S,3S,4R)-l,8-Dibromo-3-chloro-p-menthan-2-one (30) (1S,3S,4S)-1,3-Dibromo-p-mentban-2-one (44) (1S,4R)-1,8-Dichloro-p-menthan-2-one (26) (1S,3S,4S)-3-Bromo-1,8-dichloro-p-menthan-2-one (27a) (lS,3S,4R)-1,3,8-Trichloro-p-menthan-2-one (31) (1S,3S,4S)-1,3-Dichloro-p-menthan-2-one (45) (1S,4R)-l-Bromo-8-chloro-p-menthan-2-one (32) (1S,3S,4S)-1,3-Dibromo-8-chloro-p-menthan-2-one (33a) (1S,3S,4R)-1-Bromo-3,8-dichloro-p-menthan-2-one (34) (1S,4R)-8-Bromo-l-chloro-p-menthan-2-one (35) (1S,3S,4R)-3,8-Dibromo-1-chloro-p-menthan-2-one (36a) (1S.3S.4R~-8-Bromo-1.3-dichloro-a-menthan-2-one (37)

and the bromination product of (2) are equivalent. However, it seems unlikely that these ketones are following the normal simple a-halo ketonesllb in their infrared behaviour and it is clear that the ,&bromine, whatever its orientation, causes an increase in the carbonyl frequency and possibly then also dampens out further effects due to a-halogens. Thus, (1) and (2) both absorb at around 1725 cm-' (Table I), while the parent ketone p-menthan-2-one absorbs3 at 1717 cm- l . The effect of the a-axial bromine in (1) and (2) is predictedlib to be negligible, and so the P-bromine in these compounds must cause a shift of about + 8 cm-l. The new equatorial l4 l5

Corey, E. J., and Ursprung, J. J., J. Am. chem. Soc., 1956, 78, 5041. Corey, E. J., J. Am. chem. Soc., 1954, 76, 175.

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K-brominein compound (5), and in all the compounds previously reported which also have the C 6 b r ~ m i n ethen , ~ gives a shift of 10 cm-' which is considerably smaller than the normally acceptedllb cc-equatorial bromine effect. Compound (6) is expected, due to the severe 1,3-diaxial interaction, to rearrange to the equatorial isomer (9) but our compound proved to be stable under mild conditions. The p.m.r. spectrum of the compound showed the C 6 proton as a quartet at 6 4.55. This is at much lower field than the corresponding proton of (2) (6 3.87, J c. 7 and 8.5 Hz) (Table 2). Since the addition of the C 3 bromine in going from (1)

+

P.M.R. CHEMICAL SHIFTS

Compound

C 3 proton

2 TABLE HALO-P-MENTHAN-&ONES IN CC14

(8) OF

C 6 proton

C 7 methyl

C 9, C 10 methyls

-

(1) (5) (10) (12) (2) (94 (28) (52) (53) (11) (13a) (29) (20) (16 4 (30) (44) (26) (274 (31) (45) (32) (334 (34) (35) (364 (37)

-

5.20

-

5.22 4.88 5.36 5.46 5.30 A

4.88 5.32 4.67 5.12 5.33 4.67 5.03 5 .03 4.69 5.12 4.66 5.04

4.82 4.83 4.82 4.90 3.87 4.55 3.97 3.84 3.85 3.82 4.50 3.95 -

-

-

1.98 2.08 1.98 2.08 1.92 2.13 2.03 2.02 2.02 1.90 2.13 2.02

1.83, 1.79 2.15,1.89 1.62,1.60 1.95,1.73 1 . 8 3 , l a78 1.95,1.80 2.03,1.93 1 .03,0.93 1 .03,0.95 1.62,1.60 1.73,1.63 1.83,1.77

1'8010.30 1.80,1.80 1.90,1.77

2.101 1.95 1.90

2.02,1.91 1.01,0.93

1'6010.32 1.60,1.60

1.72,1.60 1.81,1.73 0.99,0.93

-

1 1.77 1.68

-

'77)~.33 2.10 1.93

-

1'5810.33

-

1.911 1.74

A

1.60,1.60 1.73,1.62 1 .80, 1 *73 1.80,1.80 1.91,1.74 2.00,1.88

to (5) did not materially affect the C 6 proton in these two compounds (6 4.82, J 3 and 3 Hz in (1) to 6 4.83, J 3 and 3 Hz in (5)), it seemed that the addition of bromine to C 3 of (2) had not proceeded in a simple fashion and a structure such as (6) cannot explain this low-field shift. The coupling constants for H 3,H 4, H 5,H 6, and H 5',H 6 (J 3.5, 9, 6 respectively) require dihedral angles that are approximately synclinal, antiperiplanar, and synclinal respectively.16 The compound cannot exist in configural6

Jackman, L. M., and Sternhell, S., "Applications of Nuclear Magnetic Resonance Spectroscopy in Organic Chemistry," 2nd Edn, p. 280 (Pergamon: Oxford 1969).

R. M. CARMAN AND B. N. VENZKE

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tion (6) and it is not possible to rationalize the results on the basis of a boat conformer of compound (6). Neither can the compound exist as the equatorial C 3 isomer in conformer (9) as this should give a large H 3,H4 coupling, but the boat conformer (9a) fits all the available evidence. Structure (9a) shows dihedral angles H 3,H4, H 6,H 5, and H 6,H 5' of 60°, 180°, and 60" respectively. In this conformation H 6 sits in a flagpole position close to the flagpole C 3 bromine which will cause the considerable downfield shift of H6. The compound (9a) has carbonyl-bromine dihedral angles of 120" and 60" which can account for the ultraviolet shifts,''" while the Cotton effect is predicted from models to be small although possibly positive as observed. (10) and (1 I), the anaThe isomeric 1,6-dibromo-8-chloro-p-menthan-2-ones logues of tribromides (1) and (2), were brominated in carbon tetrachloride to yield the isomeric 1,3,6,84etrahalides (12) and (13). Compound (13) must also exist in the boat conformation (13a) as compounds (13a) and (9a) have many similar spectral characteristics: weak positive Cotton effect curves, infrared carbonyl stretching frequencies at 1725 cm-l, C 3 proton resonances as doublets ( J 3 a5 Hz) at 6 4.88, and C 6 proton resonances as similarly shaped quartets at 6 4.50 and 4.55 respectively. To justify the 3S configuration in structures (9a) and (13a), tetrabromide (9a) was reduced with sodium borohydride to the alcohol (14). The C 3 proton of (14) resonated as a triplet at 6 4.37 and coupled with both the C 4 and C 2 protons by 9.5 Hz. This coupling requires that the tetrabromo alcohol (14) be in a chair conformation with equatorial C 3 bromine and C 2 hydroxyl groups. The axial C 2 proton resonated as a doublet, 6 3 34 ( J 9 .5 Hz). Irradiation of 6 3 34 and 2.12 in separate experiments caused the triplet to collapse into a doublet ( J c. 9-10 Hz) and so the C 4 proton resonates at 6 2.12. The axial G 6 proton resonated as a sextet (J5,,+J5,,6 = 16 Hz). Compound (14) was unstable to recrystallization and from ethanol gave quantities of an epoxide which was also obtained in excellent yield from the alcohol (14) by the addition of sodium methoxide. The epoxide, m.p. 139-140°, is assigned structure (15). The C 2 and C 3 protons resonated as an AB system, J 3.5 Hz. The doublet 6 3 ~ 8 8which showed some broadening due to long range coupling was assigned to C 2 and the 6 3.28 doublet was assigned to the C 3 proton. No coupling was observed between the C 3 and C 4 protons and this dihedral angle must approximate 90". In order to dehydrohalogenate so readily to give an epoxide rather than a ketone, compound (14) must have17 the trans arrangement of alcohol and halogen groups at C 2 and C3. The coupling constants in the p.m.r. spectrum of (14) require that these groups be tram diequatorial, and hence the C 3 bromine in ketone (9a) must also be equatorial when the compound is written in the chair conformer (9). The diequatorial halohydrin (14) dehydrobrominated much more rapidly than is common for steroidal trans diequatorial halohydrins,17 presumably because the unfused nature of the ring in (14) allows the hydroxyl and halide groups to become trans coplanar. Negligible ketone was formed and the cis elimination between the C 2 hydroxyl and the C 1 bromine of (14) must be unimportant. The differences occurring during the bromination of (1) and (2), and of (10) and (1 I), raise some intriguing problems. Bromination of cyclohexanones normally gives axial u-halides unless axial attack on the en01 is sterically hindered, when equatorial l7

Barton, D. H. R., Lewis, D. A., and McGhie, J. F., J. chem. Soc., 1957, 2907.

HALOGENATED TERPENOIDS. VIII

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halide may result."" &-Axial bromo ketones are more stable than a-equatorial isomers unless severe 1,3-diaxial interactions are involved. Relevant figures quoted for the free energy of interactions which tend to destabilize conformers are c. 6 l8 and 4.8 kcallmol 'Id for the 1,3-Br, diaxial interaction, c. 3 6 kcal/mol for the 1,3-Br,Me diaxial interaction,lg and 2.7 kcal/mol for the 1,2-Br,CO eclipsing intera~tion.~ The ketones from the previous paper4 and (I), (2), (lo), and (1 1) all brominate to give equatorial products because of the hindered axial face in the intermediate en01 and the severe 1,3-diaxial interaction present in axial products. Whether the reaction proceeds through the axial isomer which rearranges," or directly to the equatorial isomer," is undetermined, but no axial product was isolated in any of these reactions. The products (9) and (13) suffer a carbonyl-(C 3)Br eclipsing interaction which can be relieved if the ring flips into a boat conformer (9a) and (13a). These later conformers suffer nothing worse than eclipsing bromoisopropyl-proton, proton-proton, and carbonyl-proton interactions and they appear to minimize the dipole-dipole interactions. In addition, they allow the possibility of the attractive transannular interaction discussed below (p. 1992). It is recognized22athat a twist boat form is more stable than a regular boat by about 1.6 kcal/mol, and twist forms of (9a) and (l3a) provide low-energy conformers which fit all the available evidence. In compounds with an axial C 6 bromine [i.e. (5), (12)], two further effects are operating to keep the molecule in the chair conformation. Firstly, the C 1 and C 6 bromines have a strong dipole-dipole interaction which is at a minimum when the dihedral angle between them is at 180". Secondly, any attempt to form a boat equivalent to those formed from the C6 eq-bromo isomers (9) and (13) requires that the bromines at C 3 and C 6 sit at the two flagpole positions (5a) where they must suffer a severe 1,4 interaction. Any other boat form of (5) either does not relieve the carbonyl-bromine eclipsing interaction or else reduces the C l,C 6 dibromo dihedral angle below 180". Bromination of compound (2) in carbon tetrachloride led within 10 min to (9a) as the sole product. No oily residue was obtained. If (9a) is not the kinetic product, rearrangement to (9a) must be both rapid and clean. Structure (9a) proved to be the thermodynamic product in the bromination of both (1) and (2), with isomerism at H 6 presumably occurring by the mechanism of W ~ l i n s k y . The ~ treatment of both tetrabromides (5) and (9a) separately with hydrogen bromide in acetic acid resulted in the removal of the C 3 bromine, a result similar to that observed by other workers.13 The product of this reaction was an equilibrium mixture of trihalides (1) and (2), and the halide (2) crystallized from the reaction mixture on cooling. The thermodynamically controlled bromination of the enantiomeric tribromide (-)(I) gave tetrabromide (-)(9a) as the only isolated product, while treatment of (-)(2) under the same conditions also gave (-)(9a). The above arguments imply that other simple cyclohexanones which carry an a-axial group might also brominate to give an @'-equatorialbromine and subsequently flip into a stable boat form (or alternatively, brominate directly through the en01 to Abraham, R. J., and Siverns, T. M., J. chem. Soc. Perkin 11, 1972, 1587. Hageman, H. J., and Havinga, E., Recl Trav. chim. Pays-Bas, 1969, 88, 97. 20 Corey, E. J., Experientia, 1953, 9, 329. 21 Villotti, R., Ringold, H. J., and Djerassi, C., J. Am. chem. Soc., 1960, 82, 5693. 22 Eliel, E. L., "Stereochemistry of Carbon Compounds," (a)p. 206; (b)p. 237 (McGraw-Hill: New York 1962). Is

I9

R. M. CARMAN AND B. N. VENZKE

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give the boat conformer with the appropriate bromine configuration). One bromo isomer we have investigated is (16) which has no C 6 halogen. Reduction of (-)carvone (3) with zinc and potassium hydroxide'" gave dihydrocarvone as a mixture of C 1 epimers (17). Hydrobromination and bromination of the mixture by the procedure of Wallachsbgave a crystalline dibromide, m.p. 70-71". The hydrobromination of (17) will produce a mixture of (18) and (19). The addition of bromine could produce any of six dibromides (20), (21), (22), and (23), but since a-halogenation in the absence of steric or inductive effects produces an axial bromine, structures (22) and (23) are excluded. The p.m.r. spectrum of the dibromide revealed no low-field CHBr multiplet, which excludes structure (21). The rotatory dispersion curve of the dibromide showed a strong positive Cotton effect diagnostic of an axial C 1 and the structure (20) was assigned. The ultraviolet maximum at 311 nm confirmed the axial bromine. The tertiary C 1 brominated in preference to the secondary C 3 carbon at 0°, an observation noted in the steroid series.13 In the p.m.r. spectrum all methyl protons of the dibromide (20) are equivalent. Bromination of the dibromide (20) using Wallach's procedure6 gave a crystalline tribromide, m.p. 89-90". The p.m.r. spectrum showed that the third bromine was introduced at C 3 in an apparently axial configuration. The ultraviolet maximum due to the carbonyl group could not be located exactly due to the flatness of the curve but was between 305 and 320 nm. The rotatory dispersion curve showed a positive Cotton effect of lower amplitude than that of the dibromide (20) and the curve crossed the zero line at 315 nm which must be close to the ultraviolet maximum of the tribromide. The dibromide (20) appeared to brominate to form compound (16) in the more stable conformation (l6a). The introduction of the third bromine caused a shift of 10 cmin the carbonyl stretching frequency giving a shift intermediate between that for an axial and an equatorial a-bromo ketone in line with the observed 60" dihedral angle between the carbonyl and the C 3 bromine.24 This compound now has no P-bromine and so the a-halo effects are expected to apply to the infrared spectrum, although the effect of the C 8 halogen (see below) on the carbonyl absorption in confornzer (16a) is not known. The tribromide (16a) was also reduced to an alcohol (24) which showed p.m.r. spectral characteristics similar to those of (14). The triplet at 6 4.29 ( J 9.5 Hz) showed that the C 3 proton was axial to the axial C 2 and C 4 protons. The addition of sodium methoxide rapidly converted alcohol (24) into the epoxide (25). The C 2 proton of (25) showed some broadening due to long range coupling. The C 3 proton resonated as a quartet showing couplings J 4 Hz with the C 2 proton and J 1.5 Hz with the C 4 proton. The hydrochlorination and chlorination of dihydrocarvone (17) gave the 1,8dichloride (26), m.p. 37-38". The ultraviolet spectrum showed a maximum at 302 nm ( E 47), and the introduction of an axial cc-chlorine caused a smaller bathochromic shift than introduction of an axial a-bromine. The rotatory dispersion curve of the dibromide (20) and dichloride (26) showed similar features of intensity with the maximum of the dichloride displaced about 10 nm to shorter wavelength. Bromination of (26) under conditions similar to those used to brominate (20) gave a bromo di-

+

23 24

'

Djerassi, C., Oseicki, J., Riniker, R., and Riniker, B., J. Am. chem. Soc., 1958, 80, 1216. Brutcher, F. V., Roberts, T., Barr, S. J., and Pearson, N., J. Am, chem. Soc., 1959, 81,4915.

HALOGENATED TERPENOIDS. VIII

1989

chloride, m.p. 67-68", in excellent yield. The CHBr proton at C 3 of the new trihalide resonated as a doublet (6 4.67, J 3 - 5 Hz) and from the p.m.r. spectra there is no doubt that the configurations of C 3 and C 4 in the bromo dichloride and tribromide (16a) are equivalent. The excellent yield of bromo dichloride indicated that halide exchange at C 1 did not occur on the bromination of (26) and, from the similarity of the products, we assume it did not occur during the bromination of (20) to (16a) either. The introduction of the C 3 bromine into dichloride (26) caused shifts in the infrared carbonyl maximum of 7 cm-' and in the ultraviolet carbonyl maximum of 25 nm (Table 1) and the bromo dichloride must also be assigned a boat conformation (27a) of the C 3 equatorial isomer (27). The introduction of the C 3 bromines into (20) and (26) causes low-field shifts in the p.m.r. spectra of the C 7 methyls of 6 0.30 and 0 32 in trihalides (16a) and (27a) (Table 2). The C 9 methyls show shifts of 6 0.10 and 0.12 upon the introduction of the C 3 bromine. This close correlation also indicates that (16a) has not epimerized at C 1 during the bromination. While monobromination of C 3 inp-menthan-Zones in the presence of hydrogen bromide is complete within a few hours, chlorination proceeds more slowly and requires several days in acetic acid. The chlorination of tribromide (2) in acetic acid gave a sparingly soluble tribromo chloride, m.p. 134-135", in excellent yield. The p.m.r. spectrum showed little change in the resonance of the C 6 proton (6 3.97, triplet, J 8 8 Hz). A doublet, resonating at 6 5.36 ( J 9.5 Hz), was assigned to H 3 and indicated a large dihedral angle between the C 3 and C 4 protons and an equatorial chlorine. The ultraviolet maximum occurred at 307 nm and the infrared carbonyl stretching occurred at 1735 cm-I (A? 9 cm-I). These measurements indicated that the new compound exists in a chair conformation with equatorial C 3 and C 6 halogens and C 7 methyl and the compound is assigned structure (28). The repulsive interaction between eclipsing a-chloro and carbonyl groups of c. 0 . 6 kcal/mol* is much less than the bromine-carbonyl effect and the molecule now prefers the chair form. The p.m.r. resonance of the C 3 axial proton showed a sharp doublet. This is contrasted with the C 3 proton spectra of molecules with no C 6 halogen, or with an axial halogen at C6, where broadening or additional fine structure is observed in the C 3 proton. Some halide exchange occurred with the hydrogen chloride generated in the reaction; and the C 6 b r ~ m i n e ,and ~ the C 8 tertiary bromine when not adjacent to a vicinal bromine, are labile. Compounds with either of these structural features when synthesized under conditions where hydrogen chloride was present often analysed slightly high for carbon and halogen due to halide exchange. The impurity is apparently isomorphous with the chief product and difficult to remove by recrystallization. Chlorination of the dibromo chloride (11) in acetic acid gave the bromo dichloride (29), m.p. 124-125", with equatorial C 3 chlorine. The axial C 3 proton resonated as a sharp doublet (6 5 32, J 9 . 5 Hz). The carbonyl stretching frequency showed a high-frequency shift, A 3 9 cm-I, and the ultraviolet maximum showed very little change in peak maximum or intensity. The rotatory dispersion curves of (28) and

+

+

* This value is determined as follows : Allinger et aLZ5suggest a AFof 0.2 kcal/mol in favour of the axial halogen over the equatorial halogen for 2-chlorocyclohexanone in CCl,. Since the equatorial chlorine in chlorocyclohexane is more stable than the axial conformer by about 0.4 k c a l / n ~ o this l ~ ~gives ~ a 1,2 chlorine-carbonyl eclipsing interaction of about 0.6 kcal/mol. 25 Allinger, N. L., Allinger, J., Freiberg, L. A., Czaja, R. F., and LeBel, N. A,, J. Am. chem. Soc., 1960, 82, 5876.

R. M. CARMAN AND B. N. VENZKE

1990

(29) were almost featureless, with amplitudes almost identical with the dispersion curves of (9a) and (13a). Chlorination of dibromide (20) and dichloride (26) gave the C 3 equatorial chloro compounds (30), m.p. 93-94", and (31), m.p. 75-76", both in the chair form. The C 3 axial protons resonated at 6 5 12 (Whiz8.5 Hz) and 6 5 -03 (J 8 Hz) respectively. The geometry of the ring is critical to the coupling pattern as the C 3 proton doublet of (31) showed broadening while the C 3 proton resonance of (30) displayed much fine structure. The rotatory dispersion curves of (30) and (31) were of lower intensity than the curves of the dihalides (20) and (26) but stronger than the boat conformers (16a) and (27a). Hydrochlorination and bromination of dihydrocarvone (17) afforded the 1-bromo-8-chloro-p-menthan-2-one (32), m.p. 46-47", which brominated to give trihalide (33) in the boat form (33a), m.p. 88-89". Compound (32) chlorinated to yield (34), m.p. 91-92", now in a chair conformation with an equatorial C 3 chlorine. Likewise hydrobromination and chlorination of dihydrocarvone (17) gave the 8-bromo-1-chloro-p-menthan-2-one (35), m.p. 58-59", which brominated to give the trihalide (36) in the boat form (36a), m.p. 66-67". Chlorination of (35) yielded (37), m.p. 72-73", in the chair conformation with an equatorial C 3 chlorine. When (33a) was mixed with tribromide (16a), its melting point was not depressed. P.m.r. examination of the mother liquors from the chlorination of (20), (26), (32), and (35) showed no additional low-field multiplets apart from those of the isolated trihalides and a little starting material, which provides further evidence of the clean chlorination reaction in the absence of direct sunlight or ultraviolet radiation. The mother liquors from the chlorination of dichloride (26) showed additional methyl singlets due to CH,CCl protons at 6 1.96, 1.93, and 1.85. It is likely that these absorbances are due to the tetrachloride (38). A multiplet (6 3-25, Whiz 14 Hz) was attributed to the C 4 proton of (38) but the compound could not be obtained crystalline. P.m.r. examination of the mother liquors from the bromination of (20), (26), (32), and (35) showed additional low-field multiplets apart from those of the isolated tribromides (16a), (27a), (33a), and (36a). Apart from aromatic peaks no other absorbance could be detected at fields lower than 6 4.8. Since an equatorial bromine is more effective at deshielding the C 3 proton than is a C 3 equatorial chlorine, these observations provided evidence of the absence of discrete chair conformers (16), (27), (33), and (36) in the mother liquor at concentrations higher than 10 % of solute. In all four mother liquors a multiplet occurred at 6 4.5 in the CHCl absorbance region. Additional CH,CCl protons occurred within a narrow envelope (6 1.98, 1 a93, and 1.85) in the residue from the bromination of (20). No additional peaks for any other compound or conformer were apparent in the p.m.r. spectra of very concentrated solutions of compound (9a). Neither could additional peaks be observed in the spectra of pure (16a), (27a), (33a), and (36a). No change occurred in the p.m.r. spectrum of (9a) when the temperature was varied between - 30" and 140" (in o-dichlorobenzene) and it must be concluded that all these compounds exist predominantly as one conformer in non-polar solvents. Compounds (2), (1 I), (28), and (29) examined in dimethyl sulphoxide showed a large low-field p.m.r. shift (c. 0.55 p.p.m.) in the absorbance of the axial C 6 protons, with only minor change in the absorbances of the C7, C9, C 10 methyls. The spectra

+

HALOGENATED TERPENOIDS. VIII

1991

of boats (9a) and (13a) showed a lesser solvent effect on the C 6 protons (Table 3). In a chair, the axial C 6 proton must fall within the shielding cone of the carbonyl group and in the more polar solvent the effect is much reduced due to solvation of the carbonyl group. The reduction in the shielding effect also allows for a low-field shift in the absorbance of all C 3 protons of the compounds measured in dimethyl sulphoxide (Table 3). The C 7 methyls of the compounds show a high-field shift in dimethyl sulphoxide and it is assumed that they lie in the deshielding cone of the carbonyl group. P.m.r. examination of the boats (9a) and (13a) revealed quite significant changes in the chemical shifts of the C 3 and C 6 protons, and J3, increased from 3.5 to 5.5 Hz in going from carbon tetrachloride to dimethyl sulphoxide solution.

THE CHANGE IN CHEMICAL SHIFT IN POLYSOL COMPARED WITH THE CHEMICAL SHIFT IN CARBON TETRACHLORIDE

Compound

C 3 proton

6(CC1,) C 6 proton

- S(poly~01) C7 methyl

Av. C9, C 10 methyls

It appears that the conformations of both compounds are different in the polar solvent from those in non-polar carbon tetrachloride. Boats (16a) and (33a) apparently do not adopt this new conformation as the C 3 protons and C 7, C 9, C 10 methyls change little with the change in solvent polarity and no alteration occurred in the J3,, coupling. Similarly, only very small changes were obtained with the chairs (30) and (34). In none of the compounds examined in dimethyl sulphoxide did additional peaks appear for new discrete species or conformers. The absorbance of the axial C 3 proton in tetrahalides (28) and (29) showed some broadening in dimethyl sulphoxide, and this is ascribed to long-range coupling in the new conformers. The bromo dichloride (27a) was reduced to the alcohol (39) which also showed trans orientations between protons C2,C3 and C3,C4. The C 2 proton of (39) resonated at lower field than that of (24). Since the C 1 halogen is virtually trans to the C 2 proton this effect is attributed to the stronger inductive effect of chlorine. Sodium methoxide rapidly converted (39) into epoxide (40). The C 3 proton resonated as a quartet and coupled with the C 2 proton by 3 5 Hz and the C 4 proton by 1 Hz. In each case boats (9a), (16a), and (27a) are reduced preferentially from above the plane of the boat and this side must be less hindered to borohydride attack. In these

R. M. CARMAN AND B. N. VENZKE

1992

boats the large bromoisopropyl group lies below the boat and is likely to hinder the approach of reagent from that direction. In the purification of halides by recrystallization from alcohol, much oil was obtained after the removal of solvent. Repeated recrystallization of tribromide (16a) gave the unsaturated dibromide (41), while compound (9a) in methanol for 3 weeks gave compound (42). Both compounds (41) and (42) showed the axial C 3 proton as a sharp doublet (Jc. 12 Hz), while infrared carbonyl stretching frequencies (1735 cm-I) and ultraviolet maxima (c. 306 nm) showed the C 1 bromine to be axial. The C 9 vinyl protons showed more broadening ( Whiz8 Hz) than is usual for C 9 methylene protons in carvone and limonene systems ( Whiz c. 3.5 Hz) and the equatorial C 3 bromines in (41) and (42) make the C 9 protons more non-equivalent. The alcohols (14), (24), and (39), while proving chemically unstable, also caused severe allergic and hay fever type reactions in one of the authors (B.N.V.) A boat conformation is favoured in structures (9a), (13a), (16a), (27a), (33a), and (36a) that have bromine at C 3 and either chlorine or bromine at C 1 and C 8. However, the presence of halogen at C8 was found to be vital for the above boat conformations. Hydrogenation of (-)-carvone by Wallach's method26 yielded carvomenthone (43) as a mixture of C 1 epimers. Bromination of carvomenthone by Wallach's procedure2' gave a dibromide, m.p. 80-81". The p.m.r. spectrum showed a CH,CBr absorbance at 6 1.90 and a CHBr absorbance as a doublet (6 5.33, J 12 Hz). The bromines were bonded to C 1 and C 3 and the large coupling showed the latter halogen to be equatorial. The C 3 doublet exhibited some broadening due to long-range coupling with either the C 5 or C 8 protons. The C 9 and C 10 methyls absorbed as separate doublets (6 1.01, 0.93 ; J 7 Hz). An ultraviolet maximum at 306 nm was consistent with an a,af-dihalo ketone in a chair conformation with one axial and one equatorial halogen. This dibromide is assigned structure (44). The large optical rotation and positive Cotton effect curve also favour this structure. The infrared carbonyl absorbance showed a displacement AV = +18 cm-' above that of the parent ketone (43). Treatment of carvomenthone (43) with chlorine gave a new dichloride (45), m.p. 67-68", whose C 3 proton resonated as a doublet (6 5.03, J 12 Hz) showing the chlorine to be equatorial. Spectral and rotatory dispersion data were similar to those measured for dibromide (44) and the C 1 chlorine is axial. Since dibromide (44) is in the chair conformation, it appears that a driving force in addition to the eclipsing C 3 equatorial bromine-carbonyl interaction is necessary for the stabilization of boat conformers (9a), (13a), (16a), (27a), (33a), and (36a). All these boats have a C 8 halogen and it seems that the proximity of the slightly negatively charged C 8 halogen to the S carbon of the carbonyl group in the boat conformer provides a stabilizing interaction. There is some evidence in the literaturez8 of halogens more distant than the P-carbon interacting with the carbonyl group. y-Trifluoroesters show a 20 cm-I increase in C=O stretching above that of p-trifluoroesters. The conformation required for an interaction through space is (46). An equivalent conformation (47) exists for the boats (9a), (13a), (16a), (27a), (33a), and (36a). There is no similar favourable

+

Wallach, O., Liebigs Ann., 1911, 381, 51. Wallach, O., Liebigs Ann., 1918, 414, 333. Zs Bellamy, L. J., "Advances in Infrared Group Frequencies," p. 148 (Methuen: London 1968). 26

27

HALOGENATED TERPENOIDS. VIII

1993

interaction in carvomenthone dibromide (44), or in compounds (41) or (42), which then exist in the chair conformation. The energy of interaction of the C 8 halogencarbonyl group is not known, but since compound (9) exists solely in the boat conformer (9a) while (44) exists as the chair, the interaction stabilizing the boat in (9a) must be greater than 3 kcal/mol. It is perhaps pertinent to record that the coupling constants J3,,in chair conformers of 3-eq-halo-p-menthan-2-ones fall into two distinct groups. All compounds in this paper and the previous one4 which have a C 8 halogen show J3,, of 7.5-9 5 Hz, while those compounds with no C 8 halogen give a J3,,within the range 12-12.5 Hz. Halogenated derivatives of carvotanacetone (48) and of (-)-menthone (4) were also synthesized for comparison purposes. Several methods are in the literature for the preparation of carvotanacetone (48) from carvone. The most successful method was that of Vavon3' where the monohydrogenation of carvone using platinum black catalyst gave (48) in excellent yield provided small quantities of carvone (c. 1 g) were used. Carvotanacetone can also be prepared in excellent yield from the dichloro olefin4 (49) by hydrogenation and dechlorination. No crystalline halogen derivatives of carvotanacetone are reported in the available l i t e r a t ~ r e . ~ ~ Treatment of carvotanacetone with bromine in acetic acid is reported33 to give a liquid dibromide. The structure of the dibromide is evidently (50), the addition of the bromine giving the normal trans product. Treatment of (50) with hydrogen bromide in acetic acid should cause epimerization3 at C 6 and give the equilibrium (50) (51). Carvotanacetone was treated with bromine both in the presence and absence of hydrogen bromide. No crystalline product could be obtained and both (50) and (51) appear to be oils. When the equilibrium (50) + (51) was treated with further bromine or with chlorine, two crystalline products resulted-a tribromide, m.p. 129-130°, and a dibromo chloride, m.p. 119-1 19.5". The tribromide, assigned the structure (52), showed two equatorial bromines in the p.m.r. spectrum. The C 3 proton absorbed as a sharp doublet 6 5.46 ( J 12.5 Hz), with coupling characteristic of that between two vicinal axial protons at C 3 and C4. The C 6 proton absorbed as a triplet (J,,, = J,,,, = 8 Hz), again with couplings characteristic of an axial proton. It can be assumed that the C 1 bromine stabilized by the C 6 bromine does not isomerize during the introduction of the third bromine into (51). This is confirmed by the rotatory dispersion curve of (52) which shows a reasonably strong positive Cotton effect. The ultraviolet maximum at 307 nm also confirmed the presence of one axial a-bromine atom. The tribronlide (52) exists in the chair conformation in solution and no evidence of another conformation could be found in the p.m.r. spectrum. Chlorination of (51) also gave an equatorial product with the C 3 proton resonating as a doublet 6 5.30 'J 12.5 Hz) and the dibromo chloride, m.p. 119-119.5", was assigned the chair conformation (53). In both trihalides (52) and (53) the infrared carbonyl stretching occurred at 1735 cm-l. Chlorination and bromination of the equilibrium (50) S (51) gave, besides the crystalline trihalides, much oil which did not crystallize on cooling to

+

Harries, C., Ber. dt. chem. Ges., 1901, 34, 1924. Kotz, A., and Steinhorst, H., Liebigs Ann., 1911, 379, 25. 3 1 Vavon, M. G., C. r. hebd. Sianc. Acad. Sci., Paris, 1911, 153, 68. 32 Simonsen, J. L., "The Terpenes," 2nd Edn, Vol. 2, pp. 338-44 (Cambridge University Press 1953). 33 Wallach, O., Liebigs Ann., 1918, 414, 283. 29

30

1994

R. M. CARMAN AND B. N. VENZKE

- 15". It seems likely that these oils contain the C 6 axial halides (54) and (55) from the bromination and chlorination of (50). (-)-Menthone (4) in acetic acid with two moles of bromine at room temperature produced a dibromide, m.p. 79.5". The p.m.r. spectrum showed the C 2 proton at 6 5 -22 in an axial environment, coupled with the axial C 1 proton by 12 Hz, and showing some broadening due to coupling with the C 7 methyl whose doublet was also broadened. The C 9 and C 10 methyls resonated separately as doublets. The dibromide gave a strong positive Cotton effect curve with a large specific rotation at the D line and an ultraviolet maximum at 309 nm. If the C 4 bromine is axial, in agreement with the axial halo ketone rule,'le then the structure of the crystalline dibromide is (56) and the chair conformer is the preferred one. The specific rotation of (56) at the D line changed significantly when the solvent was changed from the chloroform to carbon tetrachloride in line with the observations that the sign of rotation of rigid ketones can often be reversed by changing the solvent.34 The crystalline dibromide represented only about one-third of the total product. The oily residue consisted of aromatic material, and a dibromide characterized by a low-field doublet, 6 5 57, J 5 Hz. Bromination of (-)-menthone in carbon tetrachloride gave much less dibromide (56) but the mother liquor, when treated with hydrogen bromide, gave an excellent yield of crystalline dibromide (56). No CH,CBr protons could be assigned in the mother liquor before or after treatment with hydrogen bromide. It appears that a 2,4-dibromide described by a C 2 doublet (6 4 56, J 11 Hz) is the kinetic product of the reaction and that this dibromide rearranges to the crystalline stable dibromide (56) in the presence of bromide ion. If C 4 brominates first, two monobromides, (57) and (58), are possible. Compound (57) brominates equatorially to yield (56) while (58) brominates to give (59). The dihedral angle between the C 2 and C l hydrogens in (59) is approximately 60" and this compound, or the diaxial compound (60), is the likely origin of the low-field doublet (6 5.57, J 5 Hz). The structure of the kinetic product responsible for the peak 6 4.56, J 11 Hz is more obscure as the coupling suggests H 1 and H 2 are diaxial and that the C 2 bromine is equatorial; this may be unlikely for a kinetic product. Beckmann and Mehrlander35 investigated the addition of two moles of bromine to menthone in chloroform and also obtained an oily residue which analysed for three bromines. The oil decomposed by the loss of hydrogen bromide and after several weeks deposited crystals of a dibromide, m.p. 79-80", presumably identical with compound (56). Treatment of (-)-menthone (4) with chlorine in acetic acid gave an oil which, when seeded with dibromide (56), partly solidified to yield a strongly dextrorotatory dichloride (61), m.p. 53-54". P.m.r. examination showed, through the absence of CH3CC1protons and the presence of a doublet (6 4.87, J 11 Hz), that the two chlorines were substituted at C 2 and C 4 with the C 2 halogen equatorial. The infrared C=O stretching frequency at 1740 cm-I confirmed that one chlorine was equatorial while the large positive Cotton effect indicated an axial C 4 chlorine. Again the chair conformation was stable. Dichloride (61) and dibromide (56) gave no mixed map. depression confirming that the crystal forms were isomorphous. The crystalline Rassat, A., in "Optical Rotatory Dispersion and Circular Dichroism in Organic Chemistry," (Ed. G . Snatzke) p. 314 (Heyden: London 1967). 3 5 Beckmann, E., and Mehrlander, H., Liebigs Ann., 1896, 289, 367.

34

HALOGENATED TERPENOIDS. VIII

1995

dichloride and its solution had apleasant odour not unlike the parent ketone. Exposure of the dichloride (61) and the mother liquor separately to further chlorine gave an oily product showing no CHCl proton absorbance in the p.m.r. spectrum, which is therefore presumed to be a 2,2,4-trichloride. Even after exposure to chlorine for extended periods (>2 weeks) no CH,CCl absorbance could be detected and it appears that the tertiary C 1 and C 8 hydrogens are inert to chlorine under these conditions. The mother liquor was inert to hydrogen chloride. Models show that compounds (44), (45), (56), and (61) all have similar environments about the carbonyl group. A comparison of the properties of these four compounds is given in Table 4. COMPARISON OF THE P-MENTHAN-2-ONES AND

1.r.

P-MENTHAN-3-ONES

Compound

P.m.r. C 2, C 3 doublet

C=O str.

U.V. C=On+7ih

(56) (44)

5.22 (J 12 Hz) 5.33 (J 12 Hz)

1730 1735

309 306

(61) (45)

4.87 (J 1 1 Hz) 5.03 (J 12 Hz)

1740 1745

301 299

+ 170" + 167" + 160' + 157"

We have previously observed4 in the trihalo olefin (62) and its C 8 epimer an unusually small coupling (J 2 Hz) between the C 3 and C 4 hydrogens which cannot be explained if the dibromoisopropyl group is quasi-equatorial as in (62) but which can be rationalized if the dibromoisopropyl group is at the bow of a half-boat with an attractive interaction between one of the bromines and the carbonyl carbon (or C6) as in conformer (62a). To check the importance of the C 3 halogen in this series we synthesized the 3-chloro compounds (63) and (64). Chlorination of p-carvone tetrabromide (65) slowly gave the pentahalide (63), m.p. 87-88". Chlorination of C 3 proceeds slowly in compounds with a C 8 halogen and the effect is even more pronounced with the additional C 9 halogen. Pentahalides (63) and (66)4 have similar p.m.r. spectral characteristics but the monodebromination products (64). and (62) showed markedly different characteristics. The C 3 proton and C 10 methyl show high-field shifts of 6 0.90 and 0.26 in the reaction (63) + (64) while the changes are 6 0.61 and 0.43 in the reaction (66) -+ (62). J,,, is 4.5 Hz in compound (64), and the dihedral angles between H 3 and H 4 must be different in the two compounds (62) and (64). The C 9 methylene showed a small high-field shift in the reaction (63) -+ (64) and a small low-field shift in the reaction (66) -+ (62). It seems that a conformational effect favouring a quasi boat may exist in cyclohex-l(6)-en-2-ones equatorially brominated at C 3 and that this effect is not as prominent in compounds with the equatorial C3 chlorine. Again, this effect must be due to the adverse eclipsing C 3 bromine-carbonyl interaction in (62) which is relieved in (62a).

P.m.r. spectra were normally recorded at 60 MHz and/or 100 MHz in carbon tetrachloride solution with tetramethylsilane (6 0.00) as internal reference. Infrared data, measured as potassium bromide discs, are given only for the pertinent regions, 1800-1650 cm-l for C=O stretching and

R. M. CARMAN AND B. N. VENZKE

1996

below 800 cm-l for C-Br and C-Cl bands. Optical rotations and ultraviolet spectra were measured in chloroform and cyclohexane solutions respectively. The (-)-carvone used in these experiments had [a], - 55" (lit.36a - 62.46'). The Bromination of (IR,4S,6R)-1,6,8-Tribvomo-p-inenthan-2-one (I) Oily (1R,4S,6R)-1,6,8-tribromo-p-menthan-2-one (1) was prepared3 by the hydrobromination and bromination of (-)-carvone (3). P.m.r, spectroscopy showed >90% purity. [XI, + 66', 72", [%I546 89'3 [%I436 +20S3, [a1365 f 1070°, [%I335 +2870°, [~]3zo+900°, [%I315 -470'. Bromine (1.4 ml) was added to the oily tribromide (1) (10 g) in carbon tetrachloride (100 ml). The initial brisk evolution of hydrogen bromide subsided after c. 3 hr and the light yellow solution was washed well with 5 % NaHC03 solution and the solvent removed under reduced pressure. The residue after repeated extraction into small volumes of methanol gave crystals of (IR,3S,4R,6R)I,3,6,8-tetrabromo-p-menthan-2-otze (5) (5.7 g, 53 %), m.p. 77-78' (from cold methanol), [x], +42", 1270' (max), [XI,,, 500, [ a h +44', [a1546 +51°, [a1436 + l M O ,[al3as + 570' (c, 1,211, -950' (Found: C, 25.6; H, 3.2; Br, 67.8. CloHl,Br,O requires C, 25.5; H, 3.0; Br, 68.1 %). P.m.r. spectrum (6): 5.20 (one-proton doublet, J 8.5 Hz; ax C 3 proton); 4.83 (one-proton multiplet, Whiz 7 HZ; eq C 6 proton); 2.08 (three-proton singlet; G 7 methyl); 2.15, 1.89 (two three-proton singlets; C9, C 10 methyls). 1.r. ( V ) : 1735, 730, 650, 575,545s; 700,615,415m cm-l. U.V.(1,,,,): 232, 308 n m (6 985, 88).

+

+

+

+

The Bromination of (IR,4S,6S)-1,6,8-Tribromo-p-menthan-2-one (2) Oily (lR,4S,6R)-1,6,8-tribromo-p-menthan-2-one (1) was isomerized3 with 45% hydrogen (2), m.p. 94-96" bromide in glacial acetic acid to yield (lR,4S,6S)-1,6,8-tribromo-p-menthan-2-one -74' (min), (lit.3 94.5-96'), [KID -27", [%I578-28'5 [ ~ ] 5 4-3303 ~ [a1436 -58', -70' -210°, [a]305-440°, [a]z9o -370' (Found: C, 30.9; H, 3.9; (c, 1.04), [a]34o$25" (max), Br, 61.5. C10HljBr30 requires C , 30.7; H, 3.8; Br, 61.4%). The tribromide (2) (3 g) in carbon tetrachloride (50 ml) was treated with bromine (0.4 ml). A vigorous reaction occurred immediately. After 2 hr the solvent was removed to yield crystals of (IR,3S,4R,6S)-1,3,6,8-tetrabvomo-pmenthan-2-one (9a) (2.9 g, 81 %), m.p. 118-119' (dec.) (from ethanol), [%ID-2g0, -30°, [a1546 -35', [a1436 -7Z0, [%I365-193' b i n ) (c, 1.00), [a13zo +37" (max), 1 0 , [ M I Z ~-98' O (Found: C, 25.7; H, 3.1 ; Br, 68.1. CloH,,Br40 requires C, 25.5; H, 3.0; Br, 68.1 %). P.m.r. spectrum (6): 4.88 (one-proton doublet, J 3 '5 Hz; C 3 proton); 4.55 (one-proton quartet, J5,6+J5',6 = 15 Hz; C 6 proton); 2.13 (three-proton singlet; C 7 methyl); 1.95, 1.80 (two three-proton singlets; C9, C 10 methyls). 1.r. ( V ) : 1725,790,715,600, 525s; 755, 540,435m cm-'. U.V. (A,,,): 233, 317 nm ( E 870, 82). The bromination of oily (1) in glacial acetic acid also produced (lR,3S,4R,6S)-l,3,6,8tetrabromo-p-menthane-2-one (9a) in 26% yield as crystals directly from the crude reaction gum, when the reaction mixture was worked up after standing at 25' for 24 hr. The C 3 proton (6 5.14, J 5.5 Hz) of compound (9a) was examined in polysol by p.m.r. spectrometry at temperatures 35", 20°, lo", 0°, - loo, - 20°, - 30". The coupling constant remained unaltered. The solution froze at -40". The C 3 proton showed an invariable coupling of 3.5 Hz over the temperature range - 30' (in CCl4) to 140' (in o-C6H,Cl,). A solution consisting of (9a) (350 mg) in CDC13 (1 ml) was examined by p.m.r. spectrometry and showed no methyl satellites in the CH3CBr region. A sweep of region 6 6.0-5.0 at 10 times the amplitude did not reveal a doublet ( J c. 12 Hz).

+

(5) with Hydrogen Attempted Isomerization of (IR,3S,4R,6R)-1,3,6,8-Tetrabuomo-p-menthan-Z-one Bromide The tetrabromide (5) (0.5 g) in glacial acetic acid (15 ml) was treated with 45 % hydrogen bromide in acetic acid solution (5 ml) at 15". The solution turned yellow immediately. After 18 hr the mixture was poured into water and extracted into light petroleum. P.m.r. examination of the (1) (45 %) and concentrate showed it to be a mixture of (1R,4S,6R)-1,6,8-tribromo-p-menthan-2-one 36

Heilbron, I., "Dictionary of Organic Compounds," (a) Vol. I, p. 569; (b) Vol. 3, p. 1946 (Eyre & Spottiswoode: London 1965).

HALOGENATED TERPENOIDS. VIII

1997

(lR,4S,6S)-1,6,8-tribromo-p-menthan-2-one (2) (55%). When the tetrabromide (9a) (0.5 g) was treated with hydrogen bromide under similar conditions the same mixture of (1) and (2) was obtained. Both tetrahalides (1) and (2) were dissolved separately in carbon tetrachloride saturated with hydrogen bromide at 20". P.m.r. examination of the concentrates after 18 hr revealed starting material and a little aromatic material. (10) The Bvomination of (IR,4S,6R)-1,6-Dibuomo-8-chloro-p-menthan-2-one Oily (1R,4S,6R)-1,6-dibromo-8-chloro-p-menthan-2-one (10) was prepared by the hydrochlorination and bromination of (-)-carvone (3) as described by Wolinsky3 in the preparation of the racemate of (10). An equimolar portion of bromine was added to the oily trihalide (10) in carbon tetrachloride. Brisk evolution of hydrogen bromide occurred almost immediately. After 2 hr the solvent was removed and the oily residue was extracted several times with methanol to yield (IR,3S,4S,6R)-I,3,6-tvibromo-8-chlovo-p-menthan-2-one (12), m.p. 70-72" (from coId methanol), [aID -6 54", f 1660' (max), [%I315+152O, [%I578+55', [%I546+6g0, [~1]436+191°, [%I3651-718" (c, O.68), [a]305 - 1130' (Found: C, 28.1 ; H, 3.1 ; halogen, 3.98 equiv. ClOHl4Br3CiO requires C, 28.2; H, 3.3 %; halogen, 4.00 equiv.). P.m.r. spectrum (6): 5.22 (one-proton doublet, J 8.5 Hz; ax C 3 proton); 4.90 (one-proton multiplet, Whiz7 HZ; eq C 6 proton); 2.08, 1.95, 1.73 (three three-proton singlets; C7, C9, C10 methyls). 1.r. (c): 1735, 730, 570s; 705, 655, 625, 615, 585, 500, 420m cm-'. 228, 295-310 nm (e 900; 98). U.V. (A,, ): (11) The Bvomination of (IR,4S,dS)-1,6-Dibromo-8-chlouo-p-menthan-2-one Oily (1R,4S,6R)-1,6-dibromo-8-chloro-p-menthan-2-one (10) was isomerized with 45% hydrogen bromide in acetic acid by the method3 used to isomerize the racemate of (10). Treatment (I I), m.p. of the oily residue with methanol gave (IR,4S,6S)-1,6-dibromo-8-chlovo-p-menthan-2-one 92-93" (front methanol) (lit.3 110-1 12" (i) form), [z], - 303, - 310, [z]s46- 3j0, [a1436 - S o , [5(]380 -70' (rnin), [~]365-58' (c, 0.88), [a]340$50' (max), [z]325-210°, [ x ] -600' ~ ~ ~(Found: C, 34.5; H, 4.4; halogen, 2.99 equiv. CloH15Br,C10 requires C, 34.6; H, 4.3 %; halogen, 3.00 equiv.). U.v. (A,,,): 230, 309 nm (e 435, 114). The crystalline trihalide (1 1) (2 g) in carbon tetrachloride (30 ml) was treated with bromine (0.3 ml) and two drops of 45 % hydrogen bromide in acetic acid. After 2 11r the solvent was removed (13a) (2 g, 81 %), m.p. 122-124" to give (IR,3S,4S,6S)-I,3,6-tribromo-8-chloro-p-menthan-2-oize -287' (min) (c, 0.86), (from methanol), [%II,- 38', [x]5J8 -40°, [%I546-46O, [%]qj6-99', [~1]3~5 - 60°, [a]295- 90' (Found: C, 28.1 ; H, 3.3; halogen, 3.95 equiv. C10H14[a]32o 36" (max), Br3C10 requires C, 28.2; H, 3.3; halogen, 4.00 equiv.). P.m.r. spectrum (6): 4-88 (one-proton +J5,,6= 15 HZ; C 6 proton); 2.13, doublet, J 3.5 Hz; C 3 proton); 4.50 (one-proton quartet; J5,6 1.73, 1.63 (C7, C9, C 10 methyls). 1.r. (B): 1725, 795, 765, 715, 610, 600s; 540, 355m cm-I. U.v. (A,, ): 232, 316 nm (e 750, 75).

+

(9a) Reduction of (lR,3S,4R,6S)-1,3,6,8-Tetvabmo-p-menthan-2-one

Tetrabromide (9a) (1 g) in anhydrous ether (40 ml) was stirred at 5" and sodium borohydride (0.4 g) in absolute ethanol (15 ml) was added slowly. After 1 h r the solution was transferred dropwise to vigorously stirred aqueous hydrochloric acid ( 4 ~ 100 , n ~ l )covered by light petroleum (75 ml) at 5". Evaporation of the hydrocarbon layer under reduced pressure gave a pale lilac mass (0.9 g). P.m.r. spectrum The chief component was (IR,2R,3S,4R,6S)-1,3,6,8-tetvabvomo-p-menthan-2-01(14). in CDC13 (6): 4.37 (one-proton triplet; J 9.5 Hz; ax C 3 proton); 3.93 (one-proton sextet," J5,6fJ5f,6 = 16Hz; ax C 6 proton); 3.34 (one-proton doublet, J 9.5 Hz; ax C 2 proton), 2.80 (one-proton multiplet; OH proton); 2.11, 2.04; 1.96 (C7, C9, C l 0 methylsf). When shaken with D 2 0 the multiplet at 6 2.80 disappeared and the doublet at 6 3.34 sharpened up. Decoupling irradiation at 6 3.35 caused the triplet 6 4.37 to collapse into a doublet, J 10.0 Hz. Irradiation at 6 2.12 also collapsed the triplet 6 4.37 into a doublet, J 9-10 Hz. Irradiation at 6 2.56 collapsed the sextet 6 3.93 into a singlet. 1.r. (V): 3530, 1105, 735, 600, 555, 520, 460s; 705, 425m cm-I.

" These lines had approximate intensities 2 : 1 : 1 : 1 : 1 :2 and had field positions that were symmetrical about a midpoint. t Not necessarily respectively.

1998

R. M. CARMAN AND B. N. VENZKE

If the reduction of (9a) was carried out at higher temperatures much oil and darkened crystals were formed. Epoxide (I 5) was formed with much dark oil when (14) was recrystallized from ethanol and compound (14) was only slightly more stable in petroleum or carbon tetrachloride. Compound (14) caused a severe allergic reaction to B.N.V. with Sodium Methoxide Tveatment of (IR,2R,3S,4R,6S)-1,3,6,8-Tetrabvomo-p-menthan-2-01(14) The tetrabromo alcohol (14) (0.9 g) in ethanol (1 ml) was treated with sodium methoxide (7 ml, 0 . 5 3 ~ )at room temperature. A heavy white precipitate appeared immediately. After 10 s, (15) (0.60 g, go%), m.p. filtration gave (lR,2R,3R,4R,6S)-1,6,8-tvibuomo-2,3-epoxy-p-menthane - 163O, [a1546 - 188", [%]4,6- 337', [a]365 584O, 139-140" (dec.) (frommethanol), [aID- 156", [a],,, - 980" (c, 0.68), [a]z6o-2240' (Found: C, 30.9; H, 4.0; Br, 61.3. CloH1,Br30 requires C, 30.7; H, 3.8; Br, 61.4%). P.m.r. spectrum in CDCl, (6): 3.88 (one-proton doublet, J 3.5 Hz; C 2 proton); 3.68 (one-proton quintet,* J5,6 = Jj,,6= 7.2 HZ; ax C 6 proton); 3.28 (one-proton doublet, J 3.5 Hz; C3 proton); 2.56 (one-proton multiplet, Whiz 18.5 Hz); 2.05, 1.90, 1.87 (three three-proton singlets; C7, C9, C 10 methyls?). 1.r. (P): 3020, 3000m (epoxy methine stretching), 1120, 1095, 790, 715s; 600, 575, 565, 505, 475,405m cm-I. U.V. (A,,): 227 nm (e 440).

-

The Pvepavation of Dihydrocavvone (17) (-)-Carvone (3) (20 ml) and zinc dust (50 g) were refluxed in a solution containing water (100 ml), potassium hydroxide (25 g), and ethanol (250 ml). After 4 hr the alcohol was distilled off and the residue steam-distilled. The distillate was extracted with hexane and concentrated to give a peppermint-odoured oil whose p.m.r. spectrum indicated a mixture (>go%) of (1R,4R)-p-menth-8en-2-one (17; eq C 7 methyl) and (lS,4R)-p-menth-8-en-2-0ne (17; ax C 7 methyl) (4 : 1). P.m.r. spectrum (6): 4.77 (two-proton multiplet, Whiz4 HZ; C 9 methylene); 1.75 (three-proton singlet; C l 0 methyl), 1.02, 0.97 (two doublets, J 6.5 Hz; eq and ax C 7 methyls). The Hydvobvomination and Bvomination of Dihydvocarvone (17) Hydrogen bromide in acetic acid (45 % 10 ml) was added dropwise with stirring to dihydrocarvone (3.1 g) in glacial acetic acid (10 ml) at 0". After 1 hr, bromine (1 .1 ml) in glacial acetic acid was added dropwise and decolorized immediately. The mixture was poured into water, extracted into petroleum, and concentrated to yield an oil which solidified on cooling, giving (1S,4R)-1,8-dibromop-menthan-2-one (20) (3.7 g, 58%), m.p. 70-71' (dec.) (from cold methanol) (lit.5b 69-70'), +205", [%I578+214", [a1546 +255O, [%I436+600°, [a1365 +1860°, [%I334$4910' (max) (c, 0.71), [a]315 +960°, [a]305 -330' (Found: C, 38.5; H, 5.20; Br 51.2. C,oH16Br20requires C, 38.5; H, 5.1 ; Br, 51 .3 %). P.m.r. spectrum (6) : 1 .SO (nine-proton singlet; C 7, C9, C 10 methyls). 1.r. (0) : 1715,720,660,625, 560, 540,400s; 465, 445m cm-I. U.V. (3,,,3: 227, 311 nm (e 460, 118). (20) The Bvomination of (lS,4R)-1,8-Dibvomo-p-menthan-2-one

(lS,4R)-1,8-Dibromo-p-menthan-2-one (20) (1 g) in carbon tetrachloride (20 ml) at 20" was treated with bromine (0.2 ml). After 16 hr the solvent was evaporated to give an oil which solidified (16a) when stirred with methanol at 0" affording (lS,3S,4R)-1,3,8-tribromo-p-rnenthan-2-one ~ ~ +93', (0.82 g, 65 %), m.p. 89-90" (from methanol) (lit.6 88-89"), [RID 78", [ c ( ] ~79', [&I436+203O, [a1365 +650° (c. 1,051, [%I345+1040° (max), [~1]330+770°, [~l]j15*Oo, [ffljoj-480' (Found: C, 30.9; H,4.0; Br, 61.1. CI0H1,Br30 requires C, 30.7; H, 3.8; Br, 61.4%). P.m.r. spectrum (6): 4-67 (one-proton doublet, J 3 Hz; C 3 proton); 2.10, 1.90, 1.77 (three three-proton singlets; C7, C9, C10 methyls). 1.r. (P): 1725, 770, 605, 580, 525s; 710, 630, 485, 445, 350m cm-l. U.V.(Amad : 234, 305-320 nm (e 706,47). The above bromination was repeated in glacial acetic acid at 20" for 4 days. Compound (16a) crystallized directly from the concentrate in lower yield (c. 50%). P.m.r, spectrum of the residue: 6 7.3 (aromatic); no other absorbance below 6 4.8; 4.5 (CHBr); 1.98, 1.93, and 1.85 (methyls).

+

+

* This system is treated as the X region of an ABX system where five lines can only be obtained if

J5,6=

J5',&The lines had intensities of 2 : 1 : 2 : 1 : 2.

t Not necessarily respectively.

HALOGENATED TERPENOIDS. VIII

1999

Further bromination of (16a) did not yield crystalline compounds and p.m.r. examination of the product showed it to be complex.

Reduction of (IS,3S,4R)-1,3,8-Tribvomo-p-menthan-2-one (16a) Tribromide (16a) (1 g) in anhydrous ether (40 ml) was treated with sodium borohydride (0.4 g) in absolute ethanol (15 ml) for 20 rnin and worked up as described above to give a pink crystalline mass (350 mg) whose chief component was (lS,2R,3S,4R)-1,3,8-fvibvomo-p-menthan-2-01 (24). P.m.r. spectrum in CDC13 (6) : 4.29 (one-proton triplet with additional fine structure, J 9.5 Hz; ax C 3 proton); 3.20 (one-proton doublet, J 9.5 Hz; ax C 2 proton); 2.65 (one-proton multiplet; OH proton); 2.05, 1.94, 1.87 (three three-proton singlets; C7, C9, C10 methyls*). When shaken with DzO the multiplet 6 2.65 was removed. 1.r. (0): 3560, 1095, 690, 595, 525s cm-'. Treatment of tribromide (16a) with sodium borohydride for 1 hr produced only small quantities of tribromo alcohol (24). The alcohol (24) was unstable to recrystallization. Treatment of (lS,2R,3S,4R)-1,3,8-Tvibrorno-p-rnenthan-2-01(24) with Sodium Methoxide Tribromo alcohol (24) (350mg) in ethanol (0.5 ml) was treated with sodium methoxide (3 ml, 0 . 5 3 ~ at ) room temperature. A heavy precipitate appeared immediately. Filtration gave (IS,2R,3R,4R)-1,8-dibromo-2,3-epoxy-p-menfhane (25) (250 mg, 90 %), m.p. 94-95' (from methanol), [&ID-67'9 1x1578 -71°, [a1546 -82'9 [a1436 -154'9 [&I365-271'9 [a1315 -484" (c,0.841, [%I260 -1300" (Found: C, 38.7; H, 5.3; Br, 51.5. Ci0HI6BrZOrequires C, 38.5; H, 5.1; Br, 51.3%). P.m.r. spectrum in CDC13 (6): 3.81 (one-proton broadened doublet, J 4 Hz; C 2 proton), 3.12 (one-proton quartet, J2,3 4 HZ, J3,4 1.5 HZ; C 3 proton); 1.93, 1.86 (six-proton singlet, three-proton singlet; C7, C9, C10 methyls*). 1.r. (B): 1105, 790, 765, 645, 625, 495s; 3020, 3000, 560, 455, 395, 325 nm (e 385). 375m cm-I. U.V. (A,,):

Competitive Debvominafions Approximately 1.55 mmol of polybromide, in acetone (25 ml), was treated with sodium iodide (13.33 mmol) in acetone (25 ml). Aliquots (I0 ml) were withdrawn at intervals and titrated against sodium thiosulphate (0.100~)solution. The percentages of vicinal bromine removed at various times were compound (2):4 1.7 % (5 rnin), 5.1 % (15 min), 93.2% (3 hr); compound (9a) : 4 % (5 rnin), 11 % (15 rnin), 90 % (3 hr) ; compound (65):4 49 % (5 min), 50% (15 min), 51 % (3 hr).

Hydrochlorination and Chlorination of Dihydvocarvone (17) Dihydrocarvone (17) (5.5 g) in acetic acid (50 ml) was cooled to 0' and saturated with dry hydrogen chloride. After 2 hr, chlorine in carbon tetrachloride (31 ml; 0.085 g ml-I) was added dropwise with stirring. The chlorine was rapidly decolorized. The mixture was poured into water and extracted into light petroleum. Concentration gave a mobile light oil which solidified when (26) seeded with dibromide (20) and cooled to - 15", yielding (IS,4R)-1,8-dichloro-p-menthan-2-one 194', [&I436+435', (1.9 g), m.p. 37-38" (from light petroleum), [a], 156", [a]578 164", ~ ~ [a]300 ~ -1160' (Found: C, 53.7; H, 7.3; [a1365 +lf63' (c, 0.73), [a]325+3980° (max), [ G ( ]&Oo, C1, 31.5. C10H16C120requires C, 53.8; H, 7.2; C1,31.8%). P.m.r. spectrum(6): 1.60 (nine-proton singlet; C7, C9, C10 methyls). 1.r. (B): 1725, 800, 620, 590, 555s; 730, 670, 640, 515m cm-l. U.V. (A,,): 302 nm (8 47).

+

+

+

Bromination of (lS,4R)-I,8-Dichloro-p-menthan-2-one (26) Bromine (0.35 ml) and a few drops of 45 % hydrogen bromide in acetic acid were added to (1S,4R)-1,8-dichloro-p-menthan-2-one (26) (1 .6 g) in glacial acetic acid (40 ml) at room temperature. After 4 days the mixture was worked up to give a brown oil which solidified at 0' yielding (IS,3S,4S)3-bvomo-1,8-dichloro-p-menthan-2-one (27a) (1.4 g, 70%), m.p. 67-68' (from methanol), [XI, 73",

+

* Not necessarily respectively.

2000

R. M. CARMAN AND B. N. VENZKE

+

[a1578 $79'3 [a1546 + 93", [~]436f 2 w , [@I365+712' (c, 1'04), [~1I345 1010° (max), [a1315 f 15", [a]300 -844' (Found: C, 39.8; H, 5.0; halogen, 3.00 equiv. C1,HI5BrCl20 requires C, 39.7; H, 5 a0 %; halogen, 3 $00 equiv.). P.m.r. spectrum (6): 4.67 (one-proton doublet, J 3.5 Hz; C 3 proton); 1.92 (three-proton singlet; C 7 methyl); 1.72, 1.60 (two three-proton singlets; C9, C 10 methyls). 1.r. (6): 1732, 775, 610, 595, 580s; 725, 640, 525, 395, 355mcm-I. U.V. (A,,,): 327 nm (E 49). Dichloro bromide (27a) mixed with tribromide (16a) gave melting points of 70-83", 68-76", and 68-72". P.m.r. examination of the oily residue from the bromination of (26) showed a multiplet (CHBr proton) at 6 4.5 and a singlet (CH3CBr) at 6 1.7. No resonance occurred at lower field than 6 4.8.

Chlorination of (IR,4S,6S)-1,6,8-Tribvomo-p-menthan-2-one (2) Chlorine in carbon tetrachloride solution (4 ml; 0.1004 g ml-') was added to the cis tribromide (2) (2 g) in glacial acetic acid (50 ml). The yellow colour faded within 6 days and the (28) deposited crystals were filtered to give (IR,3S,4R,6S)-1,6,8-tribvomo-3-chloro-p-menthan-2-one -39', [&Is46-46', [ ~ ] 4 3-8g0, ~ (1.8 g, 83x1, m.p. 134-135" (from ethanol), [%ID-37", -325" (Found: [a1365 -217' (c, 0.76), [a]355-231' (min), [E],~,-lo0 (max), [a]3l5 - 1403, C, 28.6; H, 3.4; halogen, 4.02 equiv. Cl0HI4Br3Cl0requires C, 28.2; H, 3.3 %; halogen 4.00 equiv.). P.m.r. spectrum (6): 5.36 (one-proton doublet; J 9.5 Hz; ax C 3 proton); 3.97 (one-proton triplet, J 5 , 6 = J 5 ' , 6 = 8 HZ; ax C 6 proton); 2.75 (two-proton doublet of 8 Hz separation; C 5 protons); 2.03 (three-proton singlet; C 7 methyl); 2.03; 1.93 (two three-proton singlets; C9, C l 0 methyls). 1.r. (V): 1735, 795, 680, 540s; 730, 635, 560, 395, 310m cm-I. U.V. (A,,,): 226, 307 nm (E700, 130).

Chlorination of (lR,4S,6S)-1,6-Dibvorno-8-chloro-p-menthan-2-one (11) Chlorine in carbon tetrachloride solution (4 ml; 0.1004 g ml-') was added to the cis trihalide (1 1) (1.5 g) in glacial acetic acid (50 ml). After the yellow colour faded the mixture was poured into water and extracted into chloroform to give (IR,3S,4K,6S)-1,6-dibromo-3,8-dichloro-p-menthan-2-one (29) (1.5 g, 91 %), m.p. 124-125' (from ethanol), [a], - 43", [a1578 -45O, [a1546 - 51°, [a1436 - 94', -220" (min), [a],,, $42" (max), -20°, -450" (Found: [a],,, -210" (c, 0.93), C, 31.5; H, 3.8; halogen, 4.01 equiv. CloH14Br2C120requires C, 31.5; H, 3.7 %; halogen, 4.00 equiv.). P.m.r. spectrum (6): 5.32 (one-proton doublet, J 9.5 Hz; ax C 3 proton); 3.95 (one-proton = J58,6 = 8 HZ; ax C 6 proton); 2.77 (two-proton doublet of separation 8 Hz; C 5 triplet, J5,6 protons); 2.02 (three-proton singlet; C 7 methyl); 1.83, 1.77 (two three-proton singlets; C 9, C 10 methyls). 1.r. (V): 1735, 680, 585s; 795, 730, 635, 500, 360m cm-I. U.V. (A,,,): 231, 308 nm ( e 432, 124).

Chlorination of (lS,4R)-1,8-Dibromo-p-menthan-2-one (20) Chlorine in carbon tetrachloride solution (10 ml; 0.1004 g ml-I) was added to (1S,4R)-1,8dibromo-p-menthan-2-one (20) (3.9 g) in glacial acetic acid (50 ml). The yellow colour faded within 3 days and the mixture was poured into water and extracted into light petroleum. The concentrate at (30) (3 .O g, 69 %), m.p. 93-94" 0" gave crystals of (IS,3S,4R)-1,8-dibromo-3-chloro-p-menthan-2-one (from methanol), [a], +112", +900° (c, 0.79), +117O, [a1546 +14O0, [&I436 +322', [a]328+3070° (max), [ ~ ] 3 ~-520°, 5 [a],,, -1410" (Found: C, 35.0; H,4.6; halogen, 3.01 equiv. C10H15Br2C10requires C, 34.6; H, 4.3 %; halogen, 3.00 equiv.). P.m.r. spectrum (6): 5.12 (oneproton multiplet, Whiz8.5 HZ; ax C 3 proton); 2.23 (five-proton multiplet, Wh.Vhi25.5 HZ; C4, C5, C 6 protons); 1.95 (three-proton singlet; C 7 methyl); 2.02; 1.91 (two three-proton singlets;* C9, C10 methyls). 1.r. (V): 1735, 775, 665, 530s; 635, 575, 415m cm-I. U.V. (?.,,3: 233, 300-305 nm (E 190, 44).

Chlorination of (lS,4R)-1,8-Dichloro-p-menthan-2-one (26) Chlorine in carbon tetrachloride (5 ml, 0.085 g ml-I) was added to (lS,4R)-1,8-dichloro-pmenthan-Zone (26) (0.75 g) in glacial acetic acid (40 ml) containing hydrogen chloride. After 4 days

* The C9, C 10 methyls showed slight broadening compared with the C 7 methyl.

HALOGENATED TERPENOIDS. VIII

2001

the mixture was poured into water and extracted with carbon tetrachloride to give a light-coloured (31) (0.55 g, 63 %), oil which solidified at 0" yielding (IS,3S,4R)-I,3,8-trichloro-p-menthan-2-one m.p. 75-76" (from methanol), [aID +93", +9S0, [a]j46 +117O, +270°, [@I3651691' -755' (Found: C,46.4; H, 6.0; C1, 41.1. (c, 0.52), [ ~ I ~ $2940' zo (max), [a]300 +128", CloH15C130requires C, 46,6; H, 5.8; Cl, 41 a4 %). P.m.r. spectrum (6): 5.03 (one-proton doublet* J 8 Hz; a x C 3 proton); 2.22 (five-proton multiplet, Whiz 3 Hz; C4, C 5, C 6 protons); 1.77 (threeproton singlet; C 7 methyl); 1.81, 1.73 (two three-proton singlets;? C9, C 10 methyls). 1.r. (V): 1740, 775, 675, 595, 570s; 510, 425m cm-I. U.V. (3,,. ): 301 nm (e 46). P.m.r. examination of the oily residue from the chlorination of (26) showed 6 3.25 (multiplet, W,,p 14 Hz); 1.97, 1.93, 1.85 (three methyl singlets) attributed to compound (38) or a conformer. Trichloride (31) mixed with tribromide (16a) melted at 54-57'.

Hydrochlorination a n d Bromination of Dihydrocavvone (17) Dihydrocarvone (17) (5 g) in glacial acetic acid (50 ml) was cooled to 0' and saturated with dry hydrogen chloride. After 2 hr the solution was poured into water, extracted into light petroleum, and concentrated to give an oil whose chief component was (67). P.m.r. spectrum (6): 1.59, 1.57 (two three-proton singlets; C9, C10 methyls); 0.97 (three-proton doublet, J 6.5 Hz; C 7 methyl). The oily chloride (67) in glacial acetic acid (40 ml) at 0" was treated dropwise with bromine (1 - 4ml) in acetic acid (20 ml). After 1 hr the mixture was worked up to give a brown oil which solidified when (32) seeded with dichloride (26) and cooled at 0" yielding (IS,4R)-I-bromo-8-chloro-p-menthan-2-one 261°, [a1546 +309O, (3 g), m.p. 46-47' (from methanol and light petroleum), [aID +245", [a1436 +723', [a1365 +2200° (c, 0.53, [a1335 +5860 (max), +1190°, [aL10 -160°, [aI300 -4690" (Found: C, 44.5; H, 6.0; halogen, 2.00 equiv. CloHI6BrC1O requires C, 44.9; H, 6.0%; halogen, 2.00 equiv.). P.m.r. spectrum (6) : 1.77 (three-proton singlet; C 7 methyl) ; 1 .60 (six-proton singlet; C9, 6 1 0 methyls). 1.r. (V): 1715, 665, 635, 590, 555s; 725, 415m cm-'. U.V. 228, 310 nm ( 6 310, 112).

+

The Bromination of (lS,4R)-I-Bromo-8-chloro-p-menthan-2-one (32) Bromine (0.66 ml) was added to (1S,4R)-l-bromo-8-chloro-p-menthan-2-one (32) (3.3 g) in carbon tetrachloride (50 ml) at room temperature. Vigorous evolution of hydrogen bromide occurred. The solvent was removed under reduced pressure giving an oil which solidified at 0" (33a), m.p. 88-89" (from methanol), yielding (IS,3S,4S)-1,3-dibromo-8-chloro-p-menth-2-one EXID 88", [%I578$94'9 [a1546 f 109", [a1436 4- %lo, [~1]36j1-777' ( c , 0.80), [a1345 1044' @ax), L o [a]300- 770' (Found: C, 34.6; H, 4.4; halogen, 2.98 equiv. CloHI5Brz[a1315 50°, [ ~ I ~-215O, C10 requires C, 34.6; H, 4.3 %; halogen, 3.00 equiv.). P.m.r. spectrum (6) : 4.69 (one-proton doublet, J 3 - 5 Hz; C 3 proton); 2.10 (three-proton singlet; C 7 methyl); 1.73 ; 1 .62 (two three-proton singlets; C9, C10 methyls). 1.r. (V): 1725, 770, 605, 585, 560, 530s; 715, 640, 375, 355m cm-'. U.V. (A,,,): 236, 309-321 nm (e 560,46). Compound (33a) mixed with (16a) gave melting points of 87.5-9O0, 87.5-89.5", and 88-89".

+

+

+

Chlorination of (IS,4R)-I-Bromo-8-chloro-p-mentkan-2-one (32) Chlorine in carbon tetrachloride (3 ml; 0.1004 g ml-I) was added to (1S,4R)-1-bromo-8chloro-p-menthan-2-one (32) (1 g) in acetic acid (20 ml) at room temperature. After 4 days the mixture was poured into water, extracted into light petroleum, and concentrated to an oil which (34) (1 g, 88 %), m.p. 91-92' solidified at 0' to give (IS,3S,4R)-I-bromo-3,8-dichloro-p-menthan-2-one (from methanol), [EID +136", [ ~ +143', l [a1546 ~ ~+172', ~ [a1436 +4003, [&I365+1110° (c, 0.57), 15303,[a]305-6503, [a]300-1665'(Found: C, 40.0; H, 5.1; halogen, [%13z5+3750°(max), 3.01 equiv. CloH15BrCIZ0requires C, 39.7; H, 5.0%; halogen, 3.00 equiv.). P.m.r. spectrum (6): 5.12 (one-proton doublet with additional fine splitting between the outer peaks, J 8 Hz; a x C 3 proton); 2.23 (five-proton multiplet, Whiz5.5 Hz; C4, C5, C 6 protons); 1.93 (three-proton singlet; C 7 methyl); 1.80, 1.73 (two three-proton singlets;? C9, C 10 methyls). 1.r. (V): 1735,780, 665, 595, 565s; 630, 415, 370, 345m cm-I. U.V. (A,,,): 232, 305nm (e 243, 93).

+

* The C 3 proton showed broadening due to coupling with C 5 protons.

t The C9, C 10 methyls showed slight broadening in comparison with C 7 methyl.

2002

R. M. CARMAN AND B. N. VENZKE

Hydrobromination and Chlorination of Dihydrocarvone (17) Hydrogen bromide (45 %) in acetic acid (15 ml) was added dropwise to dihydrocarvone (17) (4.2 g) in glacial acetic acid (10 ml) at 0' and stirred for 3 hr. The solution was poured into water, extracted into light petroleum, and concentrated to give an oil which was redissolved in acetic acid (20 ml) and cooled to 0'. Chlorine in carbon tetrachloride (20 ml; 0.1004 g ml-I) was added dropwise with stirring. Workup as before gave a light oil which solidified at O3 yielding (IS,4R)-8-bromo-Ichloro-p-menthan-2-one (35) (1.9 g), m.p. 58-59" (from methanol and light petroleum), [aID + 144O, [a1578 +153O, [a1546 +l8l0, [a1436 +406O, [a1365 +1090° (c, 0.85), [a1325 +3630° (Inax), [8]310 t l780", [a],,, -260°, [ x ] ~ ~ -3230' , (Found: C,44.5; H, 6.1 ; halogen, 2.02 equiv. CloHi6BrC10 requires C, 44.9; H, 6.0 %; halogen, 2.00 equiv.). P.m.r. spectrum (6): 1 .80 (six-proton singlet; C9, C10 methyls); 1.58 (three-proton singlet; C 7 methyl). 1.r. (V): 1720, 665,635, 550s; 730, 630, 595, 565,415m cm-I. U.V. (A,,,): 224, 303 nm ( E 180,47). (35) The Bronzination of (lS,4R)-8-Bromo-I-chloro-p-menthan-2-one Bromine (0.2 ml) was added to 8-bromo-1-chloro-p-menthan-2-one (35) (0.9 g) in carbon tetrachloride (15 ml). Following a brief induction period, hydrogen bromide was evolved vigorously and after 4 hr the solvent was removed under reduced pressure to give an oil which solidified yielding (IS,3S,4R)-3,8-dibromo-l-clzloro-p-menthan-2-one (36a) (0.6 g), m.p. 66-67' (from methanol), +875' (max), +67', [ a l +79", ~ [a1436 183O, [a1365 4-660' (c, 0.77), [NID+64O, -210°, [alBOO -85F (Found: C, 34.3; H, 4.4; halogen, 3.02 equiv. CIOHl5BrZ+30°, C10 requires C, 34.6; H, 4.3 %: halogen, 3.00 equiv.). P.m.r. spectrum (6) : 4.66 (one-proton doublet, J 3 . 5 Hz; C 3 proton); 1.91 (three-proton singlet, C 7 methyl); 1.91, 1.74 (two three-proton singlets; C9, C10 methyls). 1.r. (V): 1730, 775, 605, 595, 565, 495s; 535m cm-l. U.v. (A,,,): 230, 325-330 nm ( E 440, 55).

+

(35) The Chlorination of (lS,4R)-8-Bromo-l-chloro-p-menthan-2-one Chlorine in carbon tetrachloride solution (2 ml; 0.1004 g ml-I) was added to 8-bromo-lchloro-p-menthan-2-one (35) (0.6 g) in glacial acetic acid (40 ml). After 5 days, the decolorized solution was poured into water, extracted into light petroleum, and concentrated to give an oil which (37) (0.4 g), m.p. soldified on cooling to yield (1S,3S,4R)-8-bromo-l,3-dichloro-p-menthan-2-one 72-73" (frommethanol), [%ID+82", [%I578+ U O ,[@I546+10l0, [a1436 +233O, [a1365 +591° (c, O.53), 105' (Found: C, 40.1 ; H, 5.4; halogen, 3 ~ 0 0equiv. [a]325 +2540° (max), [a]305 630°, CloH1,BrC120 requires C, 39.7; H, 5.0%; halogen, 3.00 equiv.). P.m.r. spectrum (6): 5.04 (oneproton doublet with additional fine splitting, J 7.5 Hz; ax C 3 proton); 2.21 (five-proton multiplet, Whiz3.5 Hz; C4, C5, C 6 protons); 2.00, 1.88 (two three-proton singlets;" C9, C10 methyls); 1.74 (three-proton singlet, C 7 methyl). 1.r. (V): 1740, 770, 675, 540s; 580, 505, 420, 350m cm-I. U.V. (A,,,) : 224, 300 nm (e 230, 48).

+

-

(27a) Reduction of (lS,3S,4S)-3-Bromo-1,8-dichloro-p-menthan-2-one Trihalide (27a) (0.5 g) in anhydrous ether (20 ml) was treated with sodium borohydride (0.2 g) in absolute alcohol (8 ml) and worked up as described above to give a pink crystalline mass P.m.r. spectrum whose chief component was (1S,2S,3S,4S)-3-bromo-1,8-dichloro-p-menthan-2-o1(39). in CDC1, (6): 4.24 (one-proton triplet, J 9 . 5 Hz; ax C 3 proton); 3 -51 (one-proton doublet, J 9 . 5 Hz; ax C 2 proton); 2.61 (one-proton multiplet; OH proton); 1 .81, 1 .78, 1 ~ 6 9(three three-proton singlets; C7, C9, C10 methyls?). 1.r. (t): 3540 (OH stretching), 1090 (CO stretching), 695, 615, 570s; 640, 390m cm- I. Treatment of (lS,2S,3S,4S)-3-Buomo-1,8-dichloro-p-menthan-2-01(39) with Sodium Methoxide Trihalo alcohol (39) in ethanol (0.5 g) was treated with sodium methoxide (2 ml, 0 . 5 3 ~ )at room temperature. After refrigeration for 1 hr the heavy precipitate was filtered to afford (IS,2R,-

* The C9, C 10 methyls showed slight broadening in comparison with the C 7 methyl.

t Not necessarily respectively.

HALOGENATED TERPENOIDS. VIII

2003

3R,4R)-I,8-dichlovo-2,3-epoxy-p-menthane (40) (280 mg), m.p. 56-57" (from light petroleum), -270' (c, 0.38) (Found: C, 53.8; -89', [a1365 - m O , -40°, [t(]578 -41°, [t(I546-'$go, H, 7.3; C1,32.1. C1&1&120 requires C, 53.8; H, 7.2; C1,31.8%). P.m.r. spectrum in CDCl, (6): 3.5 HZ, 3.70 (one-proton broadened doublet; J 3 - 5 Hz; C 2 proton), 3 13 (one-proton quartet; J2,3 J3,41 Hz; C 3 proton); 1.72, 1.66 (six-proton singlet, three-proton singlet; C7, C9, C 10 methyls*). 1.r. ( 8 ) : 1115,795,775,660,630,575,525s; 3020,3000,600,470,420,405mcm-1. U.V.: no maximum above 225 nm. The Dehydvobvomination of (IS,3S,4R)-1,3,8-Tribvomo-p-menthan-2-one (16a) Tribromide (16a) (1 g) in methanol (20 ml) was allowed to stand for 2-3 weeks at room temperature. The solvent was allowed to evaporate to give a yellow oil which crystallized on cooling (41) (300 mg), m.p. 89-90" (from methanol), to yield (IS,3S,4S)-1,3-dibvomo-p-menth-8-en-2-one ~ 5430' l ~ [RID +206', [a1578 +217O, [a1546 +260°, [a1436 +612O, [a]36s 1810' (c, 0.59), [ - 1660°, [ ~ I B-O3320°(Found: ~ C, 38.7; H, 4.8; Br, 51.6. C10H14Br20 (max), [a1310 1465', requires C, 38.7; H, 4.5; Br, 51 -6%). P.m.r. spictrum (6): 5.36 (one-proton doublet, J 12.5 Hz; ax C 3 proton), 4.83 (two-proton multiplet, Whiz 8 HZ; C 9 methylene protons); 1.88, 1.78 (two three-proton singlets; C7, C 10 methyls). 1.r. (6): 1735, 1645, 905, 800, 725, 640, 625, 530, 430s; 3070, 1820,570,470, 395, 350, 305m cm-I. U.V. (A,,,): 229, 306 nm ( E 720,130).

+

+

+

Dehydrobvomination of Compound (9a)

-

The tetrabromide (9a) (1 5 g) dissolved in methanol (120 ml) was allowed to stand for 3 weeks at room temperature. The mixture was poured into water, extracted into light petroleum, and concentrated to give crystals of (IR,3S,4S,6S)-1,3,6-tribvomo-p-menth-8-en-2-one (42) (0.9 g), m.p. 108.5-109" (from ethanol), [n], -42", [ E ] ~ -45", ,~ [a]546 -50°, [a]436 -69' (min), [a]3655 0 ' (c, 0.83), [a1335 +490° (max), [ x ] +175O, ~ ~ ~[a]320-15O0, -1750°(Found: C, 31.0; H, 3.5; Br, 62.0. CI0Hl3Br30requires C, 30.9; H, 3.4; Br, 61.7%). P.m.r. spectrum (6): 5.48 (one-proton doublet, J 12 Hz; ax C 3 proton); 4.90 (two-proton multiplet, Wh128 HZ; C 9 vinyl protons); 3.95 = 15.5 HZ; ax C 6 proton); 2.03 (three-proton singlet, C 7 methyl); (one-proton quintet, J5,6SJ5,,6 1.82 (three-proton singlet, Wh/2 3 HZ; C10 methyl). 1.r. (P): 1735, 905, 765, 660, 515s; 3075, 1815, 233, 307 nm ( E 615, 130). 1645, 725, 710, 575, 480,450m cm-I. U.v. (A,,): The dibromide (20) (1.5 g) was treated under identical conditions. No crystalline product was obtained. P.m.r. examination of the residue showed that extensive aromatization had occurred. Little terminal olefin was detected. Carvomenthone (43) (A) (-)-Carvone (12 g) in absolute ethanol (100 ml) was hydrogenated at 3 atm over 10% palladium on charcoal. The filtered solution was poured into water and extracted into hexane. The extract was shaken with sodium hydroxide solution (5 %, 50 11-11)to remove carvacrol and the hydrocarbon layer poured onto a solution consisting of water (80 ml), sodium dichromate (15 g), and sulphuric acid (7 ml), and stirred for 2 hr to oxidize carvomenthol. Concentration of the hydrocarbon layer gave a peppermint-odoured oil which showed no low-field (6 95%. The Bromination of Carvomenthone (43) Bromine (1.7 ml) in acetic acid (20 ml) was added to carvomenthone (43) (2.5 g) in acetic acid (40 ml). The bromine rapidly decolorized. The mixture was poured into water, extracted into (44) (1.7 g), petroleum, concentrated, and cooled to yield (lS,3S,4S)-1,3-dibrorno-p-menthan-2-one +213', + 317', m.p. 80-81' (from methanol) (lkZ780-81°), [X]D 167", [a]578 178", [~l]54~ [&65 $1620' (c, 0.97), +5180° (max), +1520°, [ ~ l -1500°, ] ~ ~ [~G ~ I-5800'. Z ~ ~ [alD

+

* Not necessarily respectively.

+

~

~

R. M. CARMAN AND B. N. VENZKE

2004

+ 147" (c, 0.32 in chloroform) (lit.27 - 1.53' for enantiomer in ether) (Found: C, 38.8; H, 5.2; Br, 51.2. CloH,,Br20 requires C, 38.5; H, 5.1; Br, 51.3%). P.m.r. spectrum (6): 5.33 (one-proton doublet, J 12 Hz; ax C 3 proton); 1.90 (three-proton singlet; C 7 methyl); 1.01, 0.93 (two threeproton doublets, J 7 Hz; C9, C 10 methyls). 1.r. (0): 1735, 725, 640, 630s; 790, 590,515,470,425m 225, 306 nm ( E 450, 120). The oily residue from the dibromination of carvocm-l. U.V. menthone revealed a strong doublet at 6 4.50 ( J 3 Hz) besides residues of the isolated dibromide at 6 5.33 ( J 12 Hz).

(&,a:

The Chlorination of Caraomenthone (43) Chlorine in carbon tetrachloride solution (14 ml; 0.1004 g ml-') was added dropwise with stirring to carvomenthone (43) (3 g) in acetic acid (20 ml) containing hydrogen chloride at 5'. The yellow colour was rapidly discharged. Further chlorine solution (14 ml) was added and the mixture worked up after 4 days to afford an oil which on seeding with dibromide (44) at - 15' gave (IS,3S,4S)I,3-dichloro-p-menthan-2-one (45) (0.6 g), m.p. 67-68" (from methanol), [& 157", +167O, [a1546 +200°, [%I436 4-478'9 [~]365+1338O (c, 0.44), [~]320+5110° @ax), [~]305+1475', [~]aoo -82" (Found: C, 53.7; H, 7.2; C1, 32.2. C10H16C120requires C, 53.8; H, 7.2; C1, 31.8%). P.m.r. spectrum (6): 5.03 (one-proton doublet, J 12 Hz; ax C 3 proton); 1.68 (three-proton singlet; C 7 methyl); 0.99, 0.93 (two three-proton doublets, J 7 Hz; C9, C 10 methyls). 1.r. ( i ; ) : 1745, 795, 780, 665, 505s; 655, 535,445,430,385, 350m cm-'. U.V. (A,,,) 299 nm (8 58). P.m.r. examination of the oily residue showed no low field multiplet other than that due to the crystalline dichloride (45) at 6 5.03, J 12 Hz. No effect was produced by standing the oily residue overnight in glacial acetic acid containing hydrogen bromide.

+

The Preparation of Cavvotanacetone (48) (A) Hydrogenation and dechlovination of (IR,4S,6R)-1,6-dichloro-p-menth-8-en-2-one (49).(1R,4S,6R)-1,6-Dichloro-p-menth-8-en-2-one (49) was prepared from (-)-carvone (3) as previously

de~cribed.~ Compound (49) (3 g) in absolute ethanol (40 ml) with a little platinum black was shaken with hydrogen (400 ml), initially at 45 p.s.i. until the pressure dropped to 32 p.s.i.* The filtered solution was poured into water and extracted with light petroleum. The hydrocarbon layer was stirred with water (50 ml) containing sodium dichromate (6 g) and sulphuric acid (3 ml) for 1 hr. P.m.r. examination of the concentrated organic layer showed principally (lR,4S,6R)-1,6-dichlorop-menthan-2-one (68): 4.56 (one-proton triplet, J 5 , 6 = J5,,,= 2.5 HZ; eq C 6 proton); 1 .76 (threeproton singlet; C 7 methyl); 0.98 (six-proton doublet; J 6.5 Hz; C9, ClO methyls). The oil (68) in ethanol (30 ml) was refluxed with zinc dust (5 g) for 10 min. Workup in the usual manner yielded another oil (1.5 g) composed of principally (>85%) carvotanacetone (48). P.m.r. spectrum: 6.62 (one-proton multiplet, Wh1210 HZ; C 6 proton); 1.72 (three-proton singlet; Whiz 4 HZ; C 7 methyl); 0.93 (six-proton doublet; J 5.5 Hz; C9, C 10 methyls). (B) Partial hydrogenation3' of (-)-carvone (3).-(-)-Carvone (3) (1 g)? in absolute alcohol (30 ml) with platinum black was shaken with hydrogen (400 ml), initially at 45 p.s.i. until the pressure dropped to 39 p.s.i. Hydrogen was rapidly absorbed. The filtered solution was poured into water, extracted with light petroleum, and concentrated to yield an oil whose chief component (c. 90%) was identical by p.m.r. with (48). Several other methods described in the literature for the preparation of carvotanacetone were also attempted. (c)Monobromination and dehydrobr~mination~~ of cavaomenthone (43)-Carvomenthone (43) (6.6 g) in acetic acid (40 ml) at 0' was treated with bromine (2.3 ml). Hydrogen bromide was evolved immediately and the mixture was stirred for 1 hr. The solution was poured into water, extracted into light petroleum, and concentrated; the oil was examined by p.m.r. : 1 .77 (singlet; C 7 methyl); 0.95 (doublet, J 6 Hz; C9,C 10 methyls). The chief component was monobromide (69) (>85%).

* Hydrogenation with excess hydrogen caused dechlorination and produced carvomenthone (43). With 10 % palladium on charcoal as catalyst hydrogenation proceeded at a negligible rate. t Best results were obtained by the hydrogenation of small amounts of carvone (c. 1 g).

HALOGENATED TERPENOIDS. VIII

2005

The unrefined monobromide (9.2 g) with anhydrous sodium acetate (15 g) in acetic acid (40 ml) was heated on a steam bath for 1.5 hr. NaBr was precipitated. When worked up the residue showed only small amounts of carvotanacetone (48). (D) The debromination of (4R)-8-bromo-p-menth-1(6)-en-2-one (70) (carvone hydrobromide).Carvone hydrobromide (70) from (-)-carvone was stirred with zinc dust in methanol at 0" for 2 dayszg A similar mixture was refluxed for 5 min. Both solutions produced a mixture of carvone and carvotanacetone (1 : 3) as described by Harriesz9 but the main component was aromatic-probably carvacrol (71). The 8-chloro analogue of (70) (carvone hydrochloride) refluxed with a large excess of zinc dust in ethanol showed less than 10 % dechlorination or dehydrochlorination in 15 min. The Bromination of Cart.otanacetone (48) The crude dihydrogenation product (3 .O g) containing carvotanacetone (48), in glacial acetic acid (15 ml), was treated with 45 % hydrogen bromide in acetic acid (10 ml) at 0' and then with bromine (1.1 ml). After standing for 18 hr at 0" the mixture was poured into water, extracted into light petroleum, and concentrated to give an oil which failed to crystallize on cooling to - 15'. (A) Treatment with bromine.-The oil in carbon tetrachloride (10 ml) was shaken with further bromine (1.1 ml) for 15 min. Hydrogen bromide was evolved vigorously at first and then subsided. (52) Evaporation of the solvent and refrigeration gave (IR,3S,4S,6S)-1,3,6-tribromo-p-menthan-2-0ne (2.0 g), m.p. 129-130" (fromethanol), [%ID-45", [a1578 -4g0, [I1546 -53O, [a1436 -7g0, [ E I ~ O-83' O -16", +15", +304" (max), [ I I , ~+101°, ~ [II~ZO (mid, b 1 3 6 ~-43" (c, 0.91); -101°, [ x ] , ~-1140" ~ (Found: C, 30.8; H, 3.9; Br, 61.6. CloHI5Br3Orequires C, 30.7; H, 3.8; 4 Br, 61.4 %). P.m.r. spectrum (6): 5.46 (one-proton doublet; J 12.5 Hz; ax C 3 proton); 3 ~ 8 (oneproton triplet, J5,6= J5,,6 = 8 HZ; ax C 6 proton); 2.02 (three-proton singlet; C 7 methyl); 1.03, 0.93 (two three-proton doublets, J 7.5 Hz; C9, C10 methyls). 1.r. (3): 1735, 750, 660s; 795, 715, : 231, 307 nm ( E 525, 140). 505, 470, 445, 370m cm- l. U.V. (A,,) When an equal mass of monohydrogenation product was treated with bromine (2.2 ml) in CC14 with cooling, an oily product was obtained which did not crystallize. (B) Treatment with chlorine.-The oily dibromide described above, in glacial acetic acid (20 ml), was treated with chlorine in carbon tetrachloride solution (7.5 ml; 0.16 g ml-'). After 1 day, when the colour had faded, the mixture was poured into water and the carbon tetrachloride layer concentrated to give an oil which partly solidified on cooling to yield (IR,3S,4S,6S)-1,6-dibromo-Schloro-p-menthan-2-one (53) (0.7 g), m.p. 119-119.5" (from ethanol), [I], -50°, [a1578 - 52O, -58", [El436 -85', [a1365 -43O(c, 1.09), [a]4lo -89O(min), [a]36o-13", +392' +26', (max), [a]3z5 180°, [a]3zo- 120°, [a],,, - 1340" (Found: C, 34.6; H, 4.3; halogen, 3.00 equiv. CloHl,BrzCIO requires: C, 34.6; H, 4.3 %; halogen, 3.00 equiv.). P.m.r. spectrum (6) : 5.30 (oneproton doublet, J 12.5 Hz; ax C 3 proton); 3.85 (one-proton triplet; J 5 , 6 = J5,,6 = 8 HZ; ax C 6 proton); 2.02 (three-proton singlet; C 7 methyl); 1.03, 0.95 (two three-proton doublets, J 7.5 Hz; C9, C 10 methyls). 1.r. ( V ) : 1735, 795, 715, 665s; 625, 515, 470, 445, 375, 355m cm-l. U.V. (?&: 228, 306 nm (e 490, 135).

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The Bromination of (- )-Menthone (4) (-)-Menthol (25 g) ([aID -44" (chloroform), -49.5" (ethanol) (lit.36b-50.1' (ethanol)) was oxidized by sodium dichromate to (-)-menthone (4) according to Beckmann's m e t h ~ d . Bromine ~~,~~ (10.5 ml) in acetic acid (50 ml) was added dropwise to (-)-menthone (4) (15 g) in glacial acetic acid (100 ml) at 20". After a brief induction period the bromine was rapidly consumed. The mixture was poured into water, extracted into petroleum, and concentrated to give an oil which crystallized when (56), m.p. 78-79.5" (from stirred with methanol yielding (1R,2S,4R)-2,4-dibromo-p-menthan-3-one 185" (c, 0.89 in carbon 157" (c, 0.53 in ether) (lit.27 159.6"), ethanol) ( l k 7 79-80"), [I], ~ [a]436 514', [&I365 1642' tetrachloride) (lit.7 199.4"), [a], 170°, [~~]578 17g0,[ ~ ( ] 5 4+214', (c, 0.901, [11,34 +4540° (max), 620°, [ I ] ~ 3230' ~ ~ (Found: C, 38.6; H, 5.3; Br, 51 SO.

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37 38

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Beckmann, E., Liebigs Ann., 1889, 250, 325. Sandborn, L. T., Org. Synth., 1964, Coll. Vol. I (2nd Edn), 340.

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R. M. CARMAN AND B. N. VENZKE

2006

C10H16Br20requires C, 38.5; H, 5.1 ; Br, 51.3 %). P.m.r. spectrum (6): 5.22 (one-proton doublet, J 12 Hz; ax C 2 proton); 1.27 (three-proton doublet, J 6 Hz; C 7 methyl); 1.12, 0.98 (two threeproton doublets; J 6.5 Hz; C9, C10 methyls). 1.r. (B): 1730, 725, 670, 645, 570, 460, 355s; 595, 415m cm- '. U.v. (A,,,) : 227, 309 nm (e 460, 105). P.m.r. examination of the mother liquor showed, besides aromatic material, three doublets in the CHBr region: 6 5.57 ( J 5 Hz); 5.22 ( J 12 Hz) (compound (56)) and 4.56 ( J 11 Hz). The mother liquor in acetic acid with hydrogen bromide and a trace of bromine for 1 week lost the high-field doublet and gave a further yield of (56). The low-field doublet remained. Treatment of the dibromide (56) with further bromine (1 mol. propn) gave a complex mixture yielding no crystalline product. (-)-Menthone (4) (3 g) in carbon tetrachloride (50 ml) was treated dropwise with bromine (2 ml) in carbon tetrachloride at - 10'. The bromine colour discharged almost immediately. The solution was washed with water and concentrated to give an oil which failed to crystallize when seeded with dibromide (56). P.m.r. examination of the oil revealed three low-field doublets (as above) in the ratio 1 : 2 : 2. The oil in acetic acid with a little hydrogen bromide for a few days gave a good yield of (56). Chlorination of (-)-Menthone (4) (-)-Menthone (4) (5.5 g) in glacial acetic acid (50 ml) saturated with hydrogen chloride was cooled to 0'. Chlorine in carbon tetrachloride (25.3 ml; 0.1004 g ml-l) was added dropwise with stirring. After 1 hr a small portion of solution was worked up and examined by p.m.r, spectroscopy. (72). P.m.r, spectrum (6): The chief component (>go%) was (lR,4R)-4-chloro-p-menthan-3-0ne 1.2-0.8 (nine protons, three methyl doublets). The monochlorination product was treated with further chlorine solution (25.3 ml) at room temperature for 7 days while the colour faded. The solution was poured into water and concentrated under reduced pressure to give a colourless mobile oil which solidified when seeded with dibromide (56) and cooled to Oo yielding (IR,2S,4R)-2,4dichloro-p-menthan-3-one (61) (1.85 g), m.p. 53-54.5" (from methanol), [a], + 160°, [a]s78 + 16g0, $4550' (max), +2540°, [a1546 +202O, [aL36 +464', [aI3s5 1280' (c, 1.16), -1560" (Found: C,53.6; H,7.3; C1, 31.7. C,oH,6C120 requires C,53.8; H , 7 . 2 ; C1, 31.8%). P.m.r. spectrum (6): 4.87 (one-proton doublet,* J 11 Hz; ax C 2 proton); 1 -26(three-proton doublet,* J 5.5 Hz; C 7 methyl); 1.08,0.97 (two three-proton doublets, J 6.5 Hz; C9, C 10 methyls). 1.r. (V): 1740, 770, 700, 520, 510s; 660, 580, 375, 335m cm-'. U.v. (A,, ): 301 nm (e 50). P.m.r. examination of the mother liquor obtained in the dichlorination of (-)-menthone (4) showed three doublets in the CHCl region (6): 5.42 ( J 5 Hz), 4.87 ( J 11 Hz) (residues of (61)), and 4.42 ( J 11 Hz). Treatment of the mother liquor in acetic acid with hydrogen chloride for one week did not alter the composition. Menthone dichloride (61) (1 g) was treated with chlorine in carbon tetrachloride (4 ml; 0.1004 g ml-') for 14 days. The yellow colour faded slowly. The chief component appeared to be the oily trichloride (73). P.m.r. spectrum (6): 1 a37 (three-proton doublet; J 6.5 Hz); 1.25-0.9 (two three-proton doublets, J 6.5 Hz), no low-field protons. Dichloride (61) mixed with dibromide (56) gave mixed melting points of 54.5-58" and 63-71".

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(65) (b-Caroone Tetrabromide) Chlorination of (IR,4S,6R,8S)-1,6,8,9-Tetrabromo-p-menthan-2-one (-)-Carvone (3) was brominated4 to give the crystalline tetrabromide (65). The tetrabromide (65) (5.2 g) in acetic acid (50 ml) was treated with chlorine in carbon tetrachloride (5 ml; 0.16 g ml-') for 10 days while hydrogen chloride was slowly evolved. The solution was poured into water, extracted into chloroform, and concentrated to give an oil which solidified on cooling, yielding (IR,3S,4R,6R,8S)-1,6,8,9-tetrabuomo-3-chloro-p-menthan-2-one (63), m.p. 87-88" (from ethanol), M ID +4g0, [a1578 +53O, [a1546 4-65', [a1436 +184', [a]365+680° (c, 0.72); [a]330+2000° (max), - 1760" (Found: C, 23.9; H, 2 - 6 ; halogen, 4.95 equiv. C10H13' [a1315 560°, [a1310 - 152", Br4C10 requires C, 23.8 ; H, 2.6; halogen, 5.00 equiv.). P.m.r. spectrum (6) : 5.40 (one-proton = 2.7 HZ; eq C 6 proton); doublet, J9.5 Hz; ax C 3 proton); 4.69 (one-proton triplet, J5,6= J5t,6 3.90, 3.82 (two-proton AB quartet, J 10.5 Hz; C 9 methylene); 2-10, 2.28 (two three-proton

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* Both the C 7 methyl and C 2 proton doublets showed some broadening due to intercoupling.

HALOGENATED TERPENOIDS. VIII

2007

singlets; C7, C10 methyls); 1.r. (G): 1735, 775, 575s; 710, 660, 625, 510, 435m cm-l. U.V.(A,, ): 232, 307 nm (8 800, 114).

Monodebromination of (IR,3S,4R,6R,8S)-I,6,8,9-Tetrabromo-3-choro-p-enhan-2-one (63) The pentahalide (63) (1 g) in acetone (20 ml) was treated with sodium iodide (2 g) for 0.5 hr. Iodine was eliminated readily. The solution was shaken with sodium thiosulphate solution and extracted with hexane. Concentration gave an oil with the principal component (3S,4R,8S)-8,9dibromo-3-chloro-p-menth-1(6)-en-2-one (64). P.m.r. spectrum (6): 6.61 (one-proton multiplet ; WhlZ10 HZ; C 6 proton); 4.50 (one-proton doublet, J 4 . 5 Hz; C 3 proton); 3.88, 3.75 (two-proton quartet, J 11 .5 Hz; C 9 methylene); 2 902, 1.83 (two three-proton singlets, C 10, C 7 methyls).