Halogenated Terpenoids. X* Optically Active Terpinolene Tetrabromides

Transcription

1 Aust. J. Chem., 1974,27, Halogenated Terpenoids. X* Optically Active Terpinolene Tetrabromides R. M. CarmanA and B. N. VenzkeB A Chemistry Department, University of Queensland, St. Lucia, Qld Chemistry Department, Queensland Institute of Technology, Brisbane, Qld Abstract The syntheses of optically active terpinolene tetrabromides are discussed and the chirality of these products is followed through various rearrangement reactions. Introduction The desirability of obtaining optically active p-menthane tetrabromides (1) and (2) has already been The optically active isomers are unavailable directly from terpinolene (3) as this molecule is achiral. Resolution of either (1r)t or (2r) appeared unattractive, and only racemate was obtained upon recrystallization of compound (lr) from optically active limonene (4). Neither did the partial degradation of one enantiomer with an optically active base appear attra~tive.~ Consequently the required chiral isomers have now been synthesized from optically active precursors. Several unsuccessful approaches to chiral molecules (1) and (2) have already been described. Discussion and Results (+)-ct-terpineol(5) appeared to be an attractive starting material for the synthesis of chiral (1) and (2). Initial investigations indicated that compound (1) was very difficult to separate from racemate (lr) by recrystallization, and so the synthesis of optically pure (1) required optically pure a-terpineol (5). This alcohol was obtained from (+)-limonene (4) by amodification of the procedure of Kuczynski and Kuczynski5 in which the hydrocarbon (4) is mononitrated with nitric acid and the resulting nitrate reduced with zinc in ammonia. While some care is required as vigorous conditions can lead to partly racemic product, optically pure a-terpineol (5) is readily available by this method. * Part IX, Aust. J. Chem., 1973, 26, t Structures suffixed with the letter r are racemic. Carman, R. M., and Venzke, B. N., Aust. J. Chem., 1971, 24, Carman, R. M., and Venzke, B. N., Aust. J. Chem., 1973, 26, 571. Carman, R. M., and Venzke, B. N., Aust. J. Chem., 1973, 26, Wilen, S. H., in 'Topics in Stereochemistry' Vol. 6, p. 122 (Eds N. L. Allinger and E. L. Eliel) (Wiley-Interscience: New York 1971). Kuczynski, L., and Kuczynski, H., Roczn. Chem., 1951, 25,432.

2 R. M. Carman and B. N. Venzke

3 Halogenated Terpenoids. X Bromination of a-terpineol (5) with pyridine dibromide hydrobromide has been reported6 to give a dibromo alcohol, m.p. 64.5", [a], +84". Direct reaction of (5) with elementary bromine afforded the same compound. P.m.r. examination of the dibromo alcohol showed that H2 was equatorial (6 4.73, multiplet, W,,, 5 Hz) and so normal trans diaxial addition is implied and the compound has structure (6). The racemate (6r) when prepared from (f )-a-terpineol (4r) is an oil, but when formed by mixing equal weights of (6) and (- 6) is a low-melting s01id.~ Compound Lombard, R., and Heywang, G., Bull. Soc. chim. Fv., 1954, 1210.

4 R. M. Carman and B. N. Venzke (6) was readily freed from its racemate by recrystallization and, as it gave the same specific rotation as obtained by previous workers, is considered to be optically pure. Hydrobromination or hydrochlorination of the alcohol (6) in acetic acid gave tribromide (7) and dibromo chloride (8). Both these dextrorotatory halides are oils like their racemates and were not amenable to purification, although chloride (8) was stable to chromatography over neutral well-used alumina. Dehydrobromination of tribromide (7) with pyridine gave an oil in which dibromide (9a) predominated, although this compound is presumed to be in equilibrium with the diequatorial form (9b). The bromination of the racemic oil (9r) has already been discu~sed.~ In the chiral case, bromination of (9) gave crystals, m.p ", identical by p.m.r. spectroscopy with racemic (lr), but with a rotation varying in different batches between [a], $33" and + 48". A closer examination of the elimination product from tribromide (7) indicated the presence of some terpinolene (3), which will brominate to racemic (la). Recrystallization did not free the mixture of the racemate. Chromatography of the crude material gave, from the final fractions, crystals of optically active limonene tetrabromide (10) resulting from the bromination of the other possible elimination product (1 1). Treatment of tribromide (7) with stronger bases did not improve the optical purity of the resulting tetrabromide (1). Use of butylamine followed by bromination gave racemic (la) while either methanol or sodium methoxide gave almost exclusively C 8, C 9 dehydrohalogenation leading to (1 1) although there was also considerable methyl ether formation and evidence of C 1, C 2 debromination. Debromination of vicinal dibromides with base appears to be reasonably facile in this series7 A further approach to optically active (1) from tribromide (7) involved direct freeradical bromination2 of the trihalide to give a mixture from which crystalline limonene tetrabromide (lo), m.p ", [R], +71, and stable terpinolene tetrabromide (I), m.p ", [x], +53", were separated by chromatography. While the 1,2,8,9- tetrabromide (10) was essentially optically pure, the 1,2,4,8-tetrabromide (1) again showed considerable racemization. Since the attack of bromine on the expected intermediate (12a) + (12b) [or upon rotational isomers about C4, C8 of (12a) and (12b)l leads only to optically pure (1) or (2) [which will rearrange to (I)'], the lack of optical purity of the product can only be ascribed to a competing rearrangement about C 1, C 2 and an intermediate such as (13) [or the polar bromonium ion analogue of (13) since this rearrangement also occurs in the dark] must be participating at a slow rate. After this lack of success with tribromide (7), attention was returned to the dibromo alcohol (6). Dehydration of (6) with phosphoryl chloride in pyridine gave a mixture of olefins (9) and (1 1) in the ratio c. 1 : 4. This mixture was isomerized with perchloric acid to give a further mixture in which (9) (30-50%) was the only dibromo olefin which could be identified by p.m.r, spectroscopy. Rapid mild polar bromination of the mixture in ether gave an oil from which tetrabromide (I), m.p , [a], $69", crystallized as needles. This product was spectroscopically identical with racemic stable terpinolene tetrabromide (Ir). It is considered to be optically pure since it crystallized as needles when less optically pure samples tended to crystallize as aggregates. Some precautions are necessary in the acid-catalysed isomerization of olefin (1 I), and perchloric acid treatment for extended periods led to a sharp drop in the yield of " Carman, R. M., and Venzke, B. N., Aust. J. Chem., 1974, 27, 449,

5 Halogenated Terpenoids. X tetrabromide (1) subsequently obtained. Additionally, some tribromide (7) of unknown optical purity formed during the rearrangement of (1 1) to (9), and the additional bromine can only arise by partial breakdown at C 1, C2. Treatment of the enriched olefin mixture (9) with bromine in non-polar carbon tetrachloride afforded optically active unstable terpinolene tetrabromide (2), m.p ", [a], ", spectroscopically identical with the racemate (2r). The availability of this compound then enabled the thermal rearrangement (2) + (1) to be examined. Both radioactive bromine1 and chemical studies3 in the racemic series suggest that the rearrangement occurs about C4, C8 rather than about C 1, C2, and that compound (2) should give compound (1) rather than the enantiomer (- 1). This was confirmed through optical rotation measurements as compound (2), [cc], + 92.Y, gave compound (I), m.p lo", [a], + 68", rather than laevorotatory material from boiling ethanol, and the high optical purity indicated that rearrangement about C 1, C 2 was negligible. A similar result occurred when compound (2) was rearranged to (1) with bromine radicals, again suggesting that this rearrangement occurs about C4, C 8 presumably through intermediate (12).~ Treatment of compound (1) with sodium iodide in acetone gave olefin (9) in purity > 90 %, but the compound could not be induced to crystallize. Iodobenzene dichloride on olefin (9) gave dibromo dichloride (14), m.p. 90-9l0, [a], ", which was freed from traces of diaxial isomer (15) by repeated recrystallization. Since racemic (1%) does not rearrange rapidly to racemic (14r) in boiling ethan01,~ compound (14) is considered to be optically pure. Hydrochlorination of olefin (9) gave a low yield of dibromochloride (16), m.p ", [a], + 56". Treatment of compound (16) with bromine gave an oil, [a], -43", identical by p.m.r. spectra with the oily isomer (8) but of unknown optical purity. The reaction is catalysed by excess bromine2 and is unaffected by light, but proceeds more slowly than the C4, C 8 rearrangement of (2) to (1). Bromination of 8-chlorop-menthanes in the dark can lead2 to 4,8-dibromides, hence that C4 and C 8 could possibly be involved in the rearrangement of (16) to (8). However, the strong negative rotation of the product strongly supports, from modified Brewster's Ruless (see below), the enantiomeric structure (-8) and the rearrangement (16) -t (-8) then requires a rearrangement (17) about C 1, C2. Under the operative conditions, stable terpinolene tetrabromide (1) formed in less than 5 % yield. This rearrangement of diequatorial (16) to diaxial (- 8) suggested that other vicinal diequatorial dibromides might rearrange to diaxial isomers in the presence of bromine. A rearrangement proceeding through a bridged bromonium ion such as (17) in the presence of bromine at room temperature would normally be expected to yield the diaxial vicinal dibromide as ion (17) is presumably the intermediate in the normal diaxial bromination of a double bond. However, neither 2,3-dibromocholestane (18) or (19) rearranged when treated with bromine for 24 hr. In the terpenoid case, diaxial (- 8) is more stable than diequatorial (16), while in the steroid example the diequatorial isomer (18) is the more stable due to the adverse C2, C 10 diaxial bromine/methyl interaction in isomer (19). Chiral compound (1) could conceivably racemize on treatment with bromine by concurrent rearrangement about C 4, C 8 and C 1, C 2. This racemization does in fact occur, although the loss of chirality is a slow reaction which is attended by side Carman, R. M., Aust. J. Chem., 1971, 24, 1733.

6 R. M. Carman and B. N. Venzke reactions. Presumably the C 1, C 2 rearrangement from compound (1) to high-energy isomer (- 2) is disfavoured due to the resulting 2,Cdiaxial dibromo interaction. Hydrobromination of olefin (9) gave the tribromide (20), map ", [a], + 54", in low yield. Treatment of tribromide (20) with bromine in strong sunlight gave the same mixture of (I), (2) and (7) [(-7?)] as was previously reported in the racemic serie~.~ The optical purities of (2) and (7) from this reaction are unknown as the separation of these products from the mixture was impractical. However, the isolated tetrabromide (1) had m.p ", [a], +60, suggesting partial racemization. This loss of optical activity is again ascribed to a rearrangement at C 1, C2, which would preferentially occur before the additional C 4 bromine is attached. Table 1. Comparison between found and calculated optical rotations for optically active terpinolene tetrabromides Calculated by the Brewster treatment,8 using the polarities deduced in the text. The group CBr in structure (i) becomes CBr* if either of the X groups are bromine Corn- Found Calc. pound [MID [MID (6)~ as for (8) -, Mode of calculation k[(br* - H)Z + (Br* - H)(CBr - H) + 2(Br* - H)(C - H) - (CBr - H)' + (CBr - H)(CBr* - H) - (CBr - H)(C - H) + (CBr * - H)(C - H)] k[(br* - H)(C - H) + (CBr - H)Z - (CBr - H)(CBr* - H) + (CBr - H)(C - H) - (CBr* - H)(C - H)] k[(br* - H)(C - H) + 2(CBr - H)(C - H) - 3(CBr* - H)(C - H) + (C - H)Z] k[(br* - H)Z - (Br* - H)(C - H) - 2(CBr - H)(C - H) + 2(CBr* - H)(C - H)] as for (16) k[- (CBr* - H)(C- H) + (C- H)2] as for (21) k[(br*-h)z+(br* -H)(CBr* -H)-(Br* (CBr - H)(C - H) + (C - H)'] as for (23) k[(~r* -H)(C-H)- - H)(C- H) 2(CBr - H)(C - H) -(CBr*- H)(C - H) -(C- H)Z] k[(br* - H)(C - H) + 2(CBr - H)(C - H) - 2(CBr* - H)(C - H)] as for (8) A Carman, R. M., and Venzke, B. N., Aust. J. Chem., 1971,24, ' Carman, R. M., and Venzke, B. N., Aust. J. Chem., 1974,27,441. Oil. The optical purity of this sampleis not known. Alcohol. The finding that some of these trihalides [especially (16) and (20)] can rearrange about C 1, C2 upon treatment with bromine means that it is no longer necessary to postulate cis, trans rearrangement of bridged bromine radicals to explain the results discussed in a previous paper.2 The availability of a number of optically pure crystalline compounds in this series has encouraged us to attempt a refinement of the various parameters leading to the optical rotations. The compounds are listed in Table 1, and the analysis is by the Brewster treatment as modified for vicinal dibromides.' A best fit by least squares for

7 Halogenated Terpenoids. X the first seven entries in Table 1 gave (BrLH) = 1.84, (CBr-H) = 1.23 and (CBr* -H) = 0.42 leading to k(br*- H)' = + 541, k(br* -H)(C- H) = + 180, k(cbr - H)(C - H) = and k(cbr* - H)(C - H) = The agreement between found and calculated values in Table 1 is then very good for compounds (I), (2), (lo), (16), (20), (21) and (22) and also provides reasonable agreement for the oily compounds (7), (8) and (25) and the alcohol (6). Phellandrene derivatives (23) and (24) do not agree as well. However, these two compounds are 1,2,3,4- and 1,2,3-polybromides respectively and it is not surprising if the polarities of bonds in these polyvicinal compounds are different from those in simple vicinal dibromides. These modifications to the polarity values in no way affect arguments in previous papers in this series where optical rotation has been used to support structural assignment. Experimental P.m.r. spectra were recorded at 60 MHz in carbon tetrachloride solutions with tetramethylsilane (8 0.00) as internal reference. Infrared spectra, measured as potassium bromide discs, are given for the pertinent region below 800 cm-' for C-Br bands. Ultraviolet spectra and specific rotations (except where described otherwise) were measured in cyclohexane and chloroform solutions respectively. Melting points were determined in open capillaries and are uncorrected. The (+)-limonene had [a], + 118" (neat) (lit.9 126"). Synthesis of ( + )-a- Terpineol(5) (+)-Limonene (4) (81.6 g, 0.6 mol) stirred by a high torque stirrer was cooled to -10' and fuming nitric acid (98 %, 28 ml, 0.6 mol) containing anhydrous potassium nitrate (20.7 g) was added dropwise so that the temperature did not rise above - 5". Potassium nitrate crystals separated out as the reaction proceeded. After 2 hr, the orange-yellow solution was neutralized with 5 % ammonium hydroxide (200 ml). The crude nitrate ester was added slowly in 10-ml portions to a well stirred suspension of zinc powder (102 g) in water (130 ml) and aqueous ammonia (28%, 75 ml) below 10". The foaming gradually subsided and after stirring (18 hr) the mixture was vigorously steam-distilled to give a light oil (54 g) which was redistilled at 2 mmhg pressure. The first fraction (10.2 g), b.p ", consisted of (+)-limonene (4). The second fraction (15.8 g), b.p ", was (+)-limonene and a-terpineol (c. 6 : 1). The last fraction (22.0 g), [a], f93" (neat), b.p ", consisted of a-terpineol which solidified almost completely on standing at room temperature. Recrystallization from light petroleum gave optically pure a-terpineol (5), m.p ", [a], + 103", [a],,, + logo, [ff] O, [a , [&I365 i- 335', [a] ', [a1315 $526' (c, 1.06, chloroform), [a], + 101" (c, 0.94 methanol) (lk6 m.p ', [a], + 102"). Pmr. spectrum (6): 5.35 (one-proton multiplet, Whiz 8 5 Hz; C2 proton); 2.95 (one-proton multiplet, Whiz 4 HZ, OH); 1.67 (three-proton multiplet, Whit 5 Hz; C7 methyl); 1.16 (six-proton singlet; C 9, C 10 methyls). Several variations of the procedure gave a-terpineol in approximately equal yields but with reduced optical purity: (i) The temperature during nitration was maintained at 5-10". The optical rotations of the final fractions from low pressure distillation were + 82" and + 84" (neat). (ii) The nitration was performed at - 5" in chloroform (250 ml) and gave a final fraction [a], + 87". (iii) The nitration was repeated at 5-10" with twice the amount of nitric acid and potassium nitrate. The final fraction (11 ml) had [a], $49". Bromination of (f )-a-tevpineol(5) (+)-a-terpineol (5) (70 g) in ether (250 ml) at - 15" was treated with bromine (24.5 ml) in ether (150 ml). The mixture was poured into ice-water and extracted with light petroleum. The organic Heilbron, I., 'Dictionary of Organic Compounds' 4th Edn, Vol. 3, p. 130 (Eyre & Spottiswoode: London 1965).

8 R. M. Carman and B. N. Venzke phase on concentration gave a heavy oil which readily solidified on cooling to give (1S,2S,4R)-1,2- dibromo-p-menthan-8-01 (6) (82.6 g), m.p " (from light petroleum) (lit "), [a], +84", [a1578 $88'3 [a1546 +lolo, [a g0, [a , [a O, [a ' (c, 1.60, chloroform); [RID + 81" (c, 1.26, methanol); [or], +80 (c, 1 +58, hexane) (lk6 + 84") (Found: C, 38.5; H, 5.8; Br, Calc. for CloH18Br20: C, 38.2; H, 5.7; Br, 51.OX). P.m.r. spectrum (6): 4.73 (one-proton multiplet, Wh,, 5 Hz; eq C2 proton); 2.00 (three-proton singlet, C 7 methyl); 1.20 (six-proton singlet; C 9, C 10 methyls). 1.r. (i): 3380,550,535s; 780,750, 650, 500,470m cm-i. U.V. (A,,,): 235 nm (E 380). Hydrobromination of (IS,2S,4R)-I,2-Dibromo-p-menthan-8-01(6) The dibromo alcohol (6) (33.7 g) in acetic acid (70 ml) was treated with 45 % hydrogen bromide in acetic acid (80 ml) at 5' for 3 hr. The mixture was poured into water, extracted into light petroleum and concentrated to give an oil (39.6 g) which failed to crystallize on cooling. The chief component (> 90% by p.m.r.1 was (IS,2S,4R)-1,2,8-tribrorno-p-menthane (7), [a], c. f66". P.m.r. spectrum (6): 4.73 (one-proton multiplet, Whiz 7 Hz; eq C 2 proton); 1.98 (three-proton singlet; C7 methyl); 1.79 (six-proton singlet; C 9, C 10 methyls). Hydrochlorination of (IS,2S,4R)-1,2-Dibromo-p-menthan-8-ol(6) The dibromo alcohol (6) (2 g) in acetic acid (10 ml) at 5" was treated with a stream of hydrogen chloride gas for 2 hr. The mixture was worked up and concentrated as before to give an oil which failed to crystallize on cooling. The chief component (> 90 % by p.m.r.) was (IS,2S,4R)-1,2-dibromo- 8-chloro-p-menthane (8), [a], c. + 58". P.m.r. spectrum (8): 4.72 (one-proton multiplet, 6.5 HZ; eq C 2 proton); 1.98 (three-proton singlet, C7 methyl); 1.60 (six-proton singlet; C9, C 10 methyls). An attempt was made to purify for analysis the oil containing compound (8). A sample (1.5 g) was subjected to chromatography on well used neutral alumina (200 g) and eluted with light petroleum. The trihalide (8) appeared to be stable (by p.m.r.) under these conditions but slowly yellowed and partly aromatized when the solvent was removed at 20" under reduced pressure. Synthesis of (IS,2S,4R)-1,2,4,8-Tetrabromo-p-menthane (I) (i) The dibromo alcohol (6) (48.8 g) in pyridine (180 ml) at 0" was stirred with phosphoryl chloride (72 ml) for 3 hr. The mixture was poured slowly onto ice, extracted into light petroleum and concentrated to give a colourless oil (44.0 g). P.m.r. examination showed a mixture of (11) and (9) c. 4 : 1. The oily mixture was treated with 70% perchloric acid (16 ml) in ethyl acetate (160 ml) at 20" for 15 hr and then worked up as described above. P.m.r, examination revealed the presence of (9) (30-50%) and very little (11). The mixture (39.6 g) containing compound (9) in ether (120 ml) at 0" was treated dropwise with bromine (8 ml) in ether (60 ml). Evaporation of the ether gave a partly crystalline mass which afforded (IS,2S,4R)-1,2,4,8-tetrabromo-p-menthane (1) (18.0 g), m.p " (needles from ethanol), [a], +69", [a1578 f 723, [a ', [a g0, [a ", [a ', [a1315 $421' (c, 1.02) (Found: C, 26.5; H, 3.6. C10H16Br4 requires C, 26.3; H, 3.5 %). P.m.r. and i.r. spectra of (1) and its racemate were identical. The oily residues from the bromination reaction emitted lachrymatory vapours and slowly darkened on standing. (ii) The tribromide (7) (7.1 g) in acetic acid (15 ml) was treated with bromine (1.0 ml) in bright sunlight for 8 hr. The mixture of crystals and supernatant liquid was poured into water and extracted into light petroleum. The concentrate, when allowed to stand overnight, partly crystallized and was filtered free of oil. The crystals (3.2 g) in two portions were subjected to chromatography on neutral alumina (200 g). The first few fractions gave tetrabromide (1) (0.3 g), m.p " (from ethanol), [a], + 53" (c, 0.72). Subsequent fractions gave mixtures of (1) and (10) and finally crystalline limonene tetrabromide (10) (0.9 g), m.p ' (lit.lo "), [a], $71" (c, 1.31) (lit.lo +74"), spectroscopically (p.m.r. and i.r.) identical with genuine compound. (iii) The tribromide (7) (12.6 g) in pyridine (40 ml) was stored at room temperature for 10 days. The mixture was poured into water (500 ml) and extracted into light petroleum. Concentration of the extract gave an oil (6.1 g) which contained 2040% (by p.m.r.) of dibromide (9) and very little aromatic material. The oil in ether (30 ml) at 0" was treated dropwise with bromine (1.5 ml) in ether lo Carman, R. M., and Venzke, B. N., Aust. J. Chem., 1971,24,1727.

9 Halogenated Terpenoids. X (20 ml). The solvent was removed under reduced pressure to give an oil which partly solidified on standing. The crystals, m.p " (aggregates from ethanol), [a], +48" (c, 0.83) (Found: C, 26.4; H, 3.6. C10H16Br4 requires C, 26.3; H, 3.5 %), were identical by p.m.r. with tetrabromide (1). This procedure in pyridine was repeated for 21 days. The crystalline product, identical by p.m.r. with tetrabromide (I), gave m.p " (once from ethanol), [a], + 33" (c, 1.4). (iv) The tribromide (7) (2 g) was treated with butylamine (8 ml) for 4 hr and worked up as before. The residue was treated with bromine in ether until coloration persisted, to give a crystalline mass identical (by p.m.r.) with racemic (lr), m.p " (from ethanol) (1it.l 122"), [or], +OO. Attempts were made, in separate experiments, to selectively dehydrobrominate (7) with sodium methoxide in methanol (2 days) and methanol (3 weeks). Mixtures were obtained. P.m.r. spectrum (6): 5.4 (C=C-H); 4.8 (C=CH2 and CHBr); 3.1 (OCH,); 2.0 (CH3CBr); 1.7 (C=C-CH3). The former spectrum also showed another peak, (OCH,). Compound (9) appeared to be a very minor product of these reactions but (11) may have formed in % yield. Synthesis of (IS,2S,4S)-1,2,4,8-Tetrabromo-p-menthane (2) A mixture (4 g) containing (9), obtained by the dehydration and acid isomerization of dibromo alcohol (6), was treated in carbon tetrachloride (50 ml) at - 15" with bromine in carbon tetrachloride until a pink colour persisted. The solution was washed with 5 % sodium carbonate solution (100 ml) and concentrated under reduced pressure. The partly crystalline mass was filtered free of oil to give (IS,2S,4S)-1,2,4,8-tetrabromo-p-menthane (2) (1.6 g), m.p " (fine needles from cold acetone), [E]D 192.5", [0(] O, [a Oo, [&I436 f 197'9 [a g0, [or ', [~]31s +55S0 (c, 1.20) (Found: C, 26.7; H, 3.6. C10H16Br4 requires C, 26.35; H, 3.5%). P.m.r. and i.r. spectra of (2) and the racemate (2r) were identical. Rearrangement of Tetrabromide (2) (i) The unstable tetrabromide (2) (0.6 g) was heated in boiling ethanol (7 m?) for 3 min and the solution was cooled in ice. The p.m.r. spectra of the crystals (0.3 g), m.p O0, [or], +68" (c, 0e88), and of compound (1) were identical. (ii) The unstable tetrabromide (2) (200 mg) in carbon tetrachloride (15 ml) was treated with bromine (1 ml) for 6 hr at 203 in bright sunlight. The solution was concentrated and the crystals filtered and recrystallized once from ethanol. The crystalline product (80 mg), m.p ", [a], + 66" (c, 0.80), was identical by p.m.r. with compound (1). Synthesis of (IS,2S,4R)-1,2-Dibromo-4,8-dichloro-p-menthane (14) The stable tetrabromide (1) (1-5 g) was debrominatedl to give oily (9). The dibromo olefin (9) in chloroform (15 ml) was warmed with iodobenzene dichloride (1.4 g). The solvent was removed under reduced pressure and the residue chromatographed over neutral alumina (200 g). The total crystalline fraction (0.4 g) gave (IS,2S,4R)-I,2-dibromo-4,8-dichloro-p-menthane (14) (0.2 g), m.p " (from ethanol), [a], +67.5", [a]57a +70", [a ", [& O, [or O, [or ", [or]nis +403" (c, 0.73) (Found: C, 32.6; H, 4.4. CloHI6Br2Cl2 requires C, 32.7; H, 4.4%). The p.m.r. spectra of (14) and of the racemate (14r) were superimposable. Before recrystallization the crystalline fraction gave m.p " and was a mixture of (14) and the unstable isomer (15) (c. 10%) [p.m.r. resonance (6): 2.09 (C 7 methyl)]. Synthesis of (ls,2s,4s)-i,2-dibromo-8-chloro-p-menthane (16) The stable tetrabromide (1) (6 g) was debrominated to give (9) as described above. The dibromo olefin (9) at 0" was treated dropwise (4 hr) with acetic acid (60 ml) saturated with dry hydrogen chloride. The mixture was worked up in the usual manner and the residue was refrigerated to afford (IS,2S,4S)-1,2-dibromo-8-chloro-p-menthane (16) (190 mg), m.p ' (from cold methanol), [c& [a S0, [a O, [or , [a ', [a ', [~] ' (C, 0.6) (Found: C, 36.4; H, 5-3. CloH17Br,Cl requires C, 36.1 ; H, 5.1 %). The i.r. and p.m.r. spectra of (16) and the racemate (16r) were identical. Rearrangement of Trihalide (16) The dibromochloride (16) (120 mg) in carbon tetrachloride (15 ml) was treated with bromine (3 ml) for 6 hr at 20". The solvent was removed under reduced pressure and the oily residue was

10 R. M. Carman and B. N. Venzke identical by p.m.r. with isomer (8) (c. 90% spectroscopic purity) but of unknown optical purity. A sample had [a], -43" (c, 2.13). Attempted Rearrangement of Dibromocholestanes (18) and (19) 2a,38-Dibromocholestanel (18) (100 mg) and 2,8,3a-dibromocholestanel (19) were each treated in separate experiments with bromine (3 ml) in carbon tetrachloride (15 ml) for 24 hr at 20". Evaporation of the solvent gave only starting material (18) or (19) respectively by p.m.r. examination. Partial Racemization of Compound (I) Tetrabromide (1) (550 mg) was treated in the dark with bromine (9 ml) in carbon tetrachloride (45 rnl). Aliquots were withdrawn at the times indicated and evaporated to dryness. The crystals were filtered free of oil and recrystallized once from ethanol. P.m.r. showed spectra essentially superimposable upon that from compound (1). The physical constants of the tetrabromide were: after 6 hr, m.p. 107-logo, [a], +68" (c, 0.82); after 24 hr, m.p ", [aid +65" (c, 1.22); after 48 hr, m.p ', [a], + 53" (c, 0.99). Much oily residue was obtained in the reaction. Synthesis of (IS,2S,4S)-I,2,8-Tribromo-p-menthane (20) The tetrabromide (1) (4 g) was monodebrominated to give (9) as previously described. The dibromo olefin (9) in acetic acid (5 ml) at 0' was treated with 45 % hydrogen bromide in acetic acid (10 ml) for 4 hr. The mixture was worked up in the usual manner and the residue refrigerated to give (IS,2S,4S)-1,2,8-tribromo-p-menthane (20) (0.6 g), m.p " (from cold methanol), [a], +54", [a O, +64", [a ", [a1365 +I%', [a g0, [&I ' (c, 0.96) (Found: C, 32.0; H, 4.6. CI0H1,Br3 requires C, 31.8; H, 4.5 %). The i.r. and p.m.r. spectra of (20) and of the racemate (20r) were superimposable. The tribromide (20) (230 mg) was treated with bromide (1 ml) in carbon tetrachloride (15 ml) in bright sunlight at 20" for 6 hr. The solvent was removed under reduced pressure and the residue was allowed to stand in contact with ethanol (1 ml). The p.m.r. spectra of the once recrystallized product (60 mg), m.p ", [a], +60 (c, 0.70), and of compound (1) were identical. Manuscript received 15 October 1973