107

Alkylation of Enolate Ions Generated Regiospecifically via Organocopper Reactions. Synthesis of Decalin Sesquiterpene Valerane and of Prostaglandin Model Systems' Gary H. Posner,* Jeffrey J. Sterling,2aCharles E. Whitten,zbCarl M. Lentz, and Daniel J. BrunelleZC Contribution from the Department of Chemistry, The Johns Hopkins University, Baltimore, Maryland 2121 8. Received March 18, 1974

Abstract: Results are reported on alkylation reactions of four different structural types of cycloalkanone enolate ions (1-4) each of which is generated regiospecifically via an organocopper reaction with an ol,a'-dibromo ketone or with a 2-cycloalkenone. These results provide information on the relative rates of enolate alkylation vs. equilibration in these systems, and they have led to a new total synthesis of the decalin sesquiterpene valerane and to an efficient method for construction of model systems for the E series of 1 I-deoxyprostaglandins.

Regiospecific generation and alkylation of one enolate structural isomer of an unsymmetrical ketone under nonequilibrating conditions are often difficult and yet highly d e ~ i r a b l e .Copper-catalyzed ~ conjugate addition of Grignard reagents to cyclohexenones and subsequent alkylation by reactive (e.g., benzylic) halides have been used in synthesis of lycopodine alkaloids4 and of substituted hyd r o a z ~ l e n e sStoichiometric .~ organocopper conjugate addition reactions followed by alkylation6 or followed by Michael addition' have recently been studied and have been applied to synthesis of steroids8 We have been examining alkylation reactions of four different structural types of cycloalkanone enolate ions (1-4) which are generated regiospecifically via an organocopper reaction with an cu,cu'-dibromo ketone9 or with a 2-cy~loalkenone.~~ The results presented here provide information on the relative rates of enolate alkylation vs. enolate equilibration in these systems; these reactions have led to a new total synthesis of the decalin sesquiterpene valerane (itself not a natural product) and to a highly efficient method for direct conversion of 2cyclopentenone to trans- 2,3-dialkylcyclopentanones,which are models for the E series of 1 I-deoxyprostaglandins.

Scheme I

U 5

0

t-BuO(RlCuLi

1, R = Me or n-Bu

I

9

la. R = Bu-n b. R = Me

2

3

4

Results and Discussion Enolate Ions Derived from 2,6-Dibromocyclohexanone. 2,6-Dibromocyclohexanonel is transformed by organocopper reagents, possibly via the intermediacy of a cyclopropan ~ n e ,into ~ ~enolate , ~ ~ ion 1. This specific enolate structural isomer reacts with trimethylsilyl chloride in the presence of triethylamine to give enol silyl ether 5 (Scheme I) as the only volatile product in 50% isolated yield after nonaqueous work-up. Thus cyclohexanone can be converted via 2,6-dibromocyclohexanone directly into silyl ether 5, in t h e complete absence of the more highly substituted isomeric silyl ether. l 3 Reaction of silyl ether 5 with bromine,14 ozone,15 diborane,16 methyl orthoformate,17or methylene iodide and zinci8would provide easy access to diverse types of synthetic intermediates. Aldol condensation of enolate ion 1 with n-butyraldehyde followed by dehydration produces 2-alkylidenecy-

8

clohexanone 6 in 43% yield. This reaction is the first reported aldol condensation of organocopper generated enolate ions and offers the possibility of further functionalization at the &-ethylenic center (e.g., organocopper conjugate addition to form a 2-n- butyl-6-sec- alkylcyclohexanone).19 That the double bond in enone 6 has the E configuration is established by nmr spectroscopy, which shows an absorption for the vinyl proton at 6 6.5 as a triplet of triplets with coupling constants of 7 and 2 Hz.~O Treating enolate ion la at -78' with excess methyl iodide affords 2-n- butyl-6-methylcyclohexanone(7) in only low yield. Many different reaction conditions were tried including variation of time, temperature, solvent, and cosolvent; some of these experiments are summarized in Table I. Optimal methylation results could be achieved in three ways: (1) by allowing intermediate enolate ion 1 to warm to 0' before adding methyl iodide; (2) by ahding methyllithium to enolate ion 1 at -78'; or (3) by adding tetramethylethylenediamine (TMED) to enolate ion 1 at -78'. Although the detailed effect of these procedures on the nature of enolate ion 1 is not clear, it should be noted (fifth entry, Table I) that when methyllithium is added to enolate ion 1, but methyl iodide is not added, some methylcyclohexanone 7 is still produced. This result suggests the intermediacy of Posner, et al.

/ Alkylation of Enolate Ions

108 Table I. Methylation of Enolate 1Generated from 2,6-Dibromocyclohexanone and R(n-Bu)CuLi

Equiv of Mer/

--Cyclohexanone

products,

equiv of

R

R(n-Bu)CuLi

t-BuO t-BuO t-BuO t-BuO

2

Za-2-t1-B~-

Conditions

Additive

O", 1 hr On, 1 hr

1

I

x , 6-Me2-

22 8

35 37 41

1 9 0 5

-78 -+ O", 1 hr -78+0",1 hr 21 t-BuO MeLi -78 + O", 1 hr 32 12 Z-BUO 12 MeCu,b TMED 0", 1 hr 2 70 2 n-Bu 6 TMED -78 -+ 0". 0 . 5 hr 3 50 0 Yields were determined by glpc using calibrated internal standards. Prepared from methyllithium and cuprous iodide and therefore containing lithium iodide. 12 3 0

MeLi

2-n-Bu-

MeLi, HMPA

an organocopper cluster complex which contains both enolate and methyl groups and which decomposes via coupling of some of the organic groups within the aggregate.21Long reaction times and very large excesses of methyl iodide tend to produce substantial amounts of dimethylated cyclohexanones. I n all cases, cis- 2-n- butyl-6-methylcyclohexanone (cis7) is formed in amounts equal to or greater than trans-7; the equilibrium ratio, under basic conditions starting from either pure cis-7 or pure trans-7, is 86:14 cis:trans. I n no case was 2-n- butyl-2-methylcyclohexanone formed in more than 1% yield (see Table 11). None of the conditions listed in Table I was satisfactory for n- butylation of enolate ion 1. Addition of hexamethylphosphoramide (HMPA, 20% by volume) to the solution of enolate ion 1 along with excess n-butyl iodide, however, gave the optimal yields of di-n- butylcyclohexanones 8 and 9; lithium di-n- butylcuprate and H M P A or lithium tertbutoxy(n- buty1)cuprate and H M P A produce a mixture of dibutylcyclohexanones 8 and 9 in 35 and 53% yields, respectively; the ratio of 8 to 9 in both cases is about 3:2. Thus, under these conditions the rate of equilibration of enolate ion 1 to the isomeric more highly substituted enolate ion is roughly comparable to the rate of n- butylation. Enolate structural isomers of type 1 derived from 2-alkylcyclohexanones are known to be less stable than the isomeric more highly substituted e n ~ l a t e s ,and ~ it has been shown previously that equilibration is slower than benzylation2* but faster than n- butylation23 of lithiurn enolate lb. Thus, formation of 2,6-di-n -butylcyclohexanone (8) in substantial amounts directly from enolate ion 1 may be of synthetic use.24 In all cases, cis-dibutylcyclohexanone 8 is formed in much larger amounts than trans- 8; equilibration of cis- 8 or trans- 8 under basic conditions produces a 90: 10 cistrans mixture. That some proton transfer (and enolate equilibration) is occurring during n- butylation of enolate ion 1 is further indicated by performing this n- butylation reaction in the presence of 5-nonanone; a small amount of 4-n-butyl-5nonanone is isolated. The enolate ion of 5-nonanone may be formed via interaction of 5-nonanone with enolate ion 1 or directly with a dialkylcuprate reagent.25 Treatment of enolate ion 1 with allyl bromide, alkyl tosylates,26 and cyclohexene oxide2' causes relatively little (95% pure by glpc: ir (CC4) 2950 (s), 2870 (m), 1700 (s), 1465 (m), 1380 (m), 1355 (w). 1340 (w), 1240 (w), 1210 (w), 1170 (w), 1150 cm-l (w); nrnr (cC14) 6 0.78 (s, 3 H), 0.93 (d, J = 3.5 Hz, 6 H), 1.08 (s, 3 H), 1.0-2.6 (broad m); mass spectrum [m/e (relative intensity)] 208 (14, molecular ion), 193 (60), 165 (27), 151 (13), 137 (24), 123 (24), 109 (76), 95 (73), 93 (go), 69 (loo), 55 (70), 41 (63). An analytical sample was isolated by preparative glpc (column F, 185'). Anal. Calcd for CI5Hz6O:C, 81.02; H, 11.79. Found: C, 81.17; H, 11.97. The stereochemistry of ring fusion and the relationship of the methyl groups and the isopropyl group were demonstrated by conversion of decalone 15 to dl-valerane (16). dl -2-a-Isopropyl-cis -9~,lO@-dimethyldecalin (16) (dl-Valerane). Following the procedure of R ~ o to, a~solution ~ of decalone 15 (60 mg, 0.27 mmol) in 0.5 ml of ethanedithiol was added 0.5 ml of boron trifluoride etherate. The reaction mixture was stirred overnight and then warmed to 70-75' for 4 hr. The crude dithioketal was isolated by pouring the reaction mixture into 5 ml of water and extracting with three 5-ml portions of ether. The combined ether extracts were washed with saturated, aqueous ammonium chloride and dried over magnesium sulfate. Evaporation of solvent left the crude dithioketal, and the infrared spectrum indicated the absence of the carbonyl group. Desulfurization with Raney nickel catalyst (W-2, one level teaspoonful) was carried out in 50 ml of acetone. After 4 hr of refluxing, the catalyst was separated by filtration, and the solvent was evaporated to leave 52 mg of a yellow oil. Preparative glpc (column B, 170') afforded dl-valerane (10 mg, 18%) having nmr spectral properties and glpc retention time identical with those of authentic dl- valerane and different from those of authentic dl- isovalerane (having the angular methyl groups and the isopropyl group all cis):35 ir (CC14) 2965 (sh), 2950 (sh), 2920 (s), 2860 (s), 2840 (sh), 1465 (m), 1450 (m), 1440 (m), 1380 (m), 1370 cm-I (m); nrnr (CC14) 6 0.84 (s, 3 H), 0.85 (d, J = 6 Hz, 6 H), 0.86 (s, 3 H), 6 1.0-1.6 (broad m); mass spectrum [m/e (relative intensity)] 208 (16, molecular ion), 193 (56), 165 (301, 109 (86), 95 (83), 83 (88), 69 (loo), 55 (go), 41 (58). Reaction of 2-Cyclopentenone with Lithium Methyl(viny1)cuprate. A. Allyl Bromide Quench. To a stirred suspension of 228 mg (1.2 mmol) of cuprous iodide in 4 ml of tetrahydrofuran at -35' was added 0.44 ml of 2.5 1 M (1.1 mmol) vinyllithium, followed by 0.62 ml of 1.78 M (1.1 mmol) methyllithium. The dark solution was immediately cooled to -78' and then 82 mg (1.0 mmol) of 2cyclopentenone in 1 ml of tetrahydrofuran was added. After 30 min, 0.17 ml (2 mmol) of neat allyl bromide was added via syringe, followed after 1 hr by 1 ml of absolute methanol. The reaction mixture was then allowed to warm to room temperature and poured into saturated aqueous ammonium chloride, diluted with diethyl ether, and stirred for 1 hr at which time the layers were separated; the aqueous phase was extracted once with ether and the combined organic layers were washed once with a 2% solution of sodium thiosulfate and dried over magnesium sulfate. Analytical glpc (column A, 150'. cymene internal standard) indicated five products: A (3 rnin), B (4 rnin); C (6.5 rnin), D (7 min), and E (8.2

min). A is 3-vinylcyclopentanone ( 2 mg, 2%) identified by comparing its glpc retention time with that of authentic materiaL9 Nmr, ir, and mass spectra of B are consistent with 2-allyl-3methylcyclopentanone (5 mg, 3%). C is trans- 2-allyl-3-vinylcyclopentanone(trans- 19, 108 mg, 72%) isolated vio preparative glpc (104 mg, 69%, column F, 135', 16 min): nrnr (CC14) 6 5.58-6.05 (m, 2 H); 4.90-5.30 (m, 4 H); 1.4-2.7 (m, 8 H); ir (CC14) 1744 (C=O) and 1641 cm-l (C=C); mass spectrum (70 eV) m/e 150 (20, molecular ion), 96 (loo), 79 (70), 67 (60); bp 199-200' (760 mm). See Table I1 for analysis. To 100 mg of trans- 19 in 50 ml of absolute ethanol was added 20 mg of 10% palladium on charcoal. The mixture was hydrogenated under 50 Ib of hydrogen pressure in a Parr hydrogenator at 70' for 12 hr. After that time, the one major product was isolated via preparative glpc (column F, 150', 10 min) and identified as trans- 3-ethyl-2-n- propylcyclopentanone: nrnr (CDC13) 2.0-2.3 (m, 3 H), 1.1-1.9 (m. 7 H), 0.95 (t, J = 8 Hz, 6 H); ir (cc14) 1740 cm-I (C=O); mass spectrum (70 eV) m/e 154 (4 molecular ion), 125 (4), 112 (26), 83 (loo), 55 (29). Anal. Calcd for CloH180: C, 77.87; H, 11.76. Found: C, 77.96; H, 12.02. The trans-2.3-substitution pattern was determined utilizing a combination of nrnr shift reage@ and spin-spin decoupling. When 75 mg of Eu(fod)3 ("Resolve-AI") was added to 30 mg of 3-ethyl-2-propylcyclopentanonein 0.5 ml of CDC13, the following nrnr spectrum resulted: 6 0.90 (s, shift reagent), 1.4-1.6 (pair of overlapping t, J = 7 Hz, 6 H, methyl groups), 2.3 (m, protons of n-propyl chain), 2.5-3.6 (m, cyclopentyl and ethyl protons), 3.9 (m, 2 H, methylene of propyl group adjacent to ring), 5.6 (m, 1 H, a-methine proton), 5.9 (m, 2 H, a-methylene protons). When the signal at 6 3.80 was irradiated, the signal for the a-methine proton was resolved into a doublet, J = 11 Hz. This indicates the substitution is 2.3, and that the groups are trans to one another.39 Also when the signal at 6 3.17 was irradiated, the a-methylene signals resolved into two singlets. D is cis- 2-allyl-3-vinylcyclopentanone(cis- 19, 4 mg, 3%), isolated via preparative glpc (column F, 135', 19 rnin): nrnr (CC14) 6 5.5-6.3 (m, 2 H), 4.8-5.3 (m, 4 H), 1.6-2.8 (m, 8 H); ir (CC14) 1746 (C=O) and 1643 cm-' (C=C); mass spectrum (70 eV) m/e 150 (20, molecular ion), 96 (loo), 79 (90), 67 (55). Both C and D could be equilibrated to a 98:2 mixture of C:D in refluxing absolute ethanol containing a catalytic amount of sodium acetate for 1 hr. E is spectrally consistent with 2-allyl-4-vinylcyclopentanone (20, 1 mg, 0.5%) isolated via preparative glpc (column F, 135', 21 min). When E was treated with refluxing absolute ethanol containing a catalytic amount of sodium acetate for 24 hr, no change was noted. B. 2-Butenyl Iodide Quench. To 3.75 g (25 mmol) of sodium iodide in 50 ml of acetone was added 2.7 g (20 mmol) of l-bromo-2butene in 1 ml of acetone forming an immediate precipitate.60 After 2 hr, the suspension was poured into water and extracted with diethyl ether. The organic layer was washed twice with water and once with 2% sodium thiosulfate, dried over magnesium sulfate, and concentrated to 3 g of orange oil which was distilled at 35 mm; the major fraction, collected at 48-49', is trans-l-iodo-2-b~tene: nrnr (CC14) 6 5.5-5.9 (m, 2 H), 3.8-4.0 (m, 2 H), 1.6-1.8 (m, 3 H), n Z o D 1.5506 (lit.61n Z o D 1.5500). Enolate ion 4 was prepared by treating 82 mg (1 .O mmol) of 2cyclopentenone with 1.2 mmol of lithium methyl(vinyl)cuprate at -78' for 30 min. At that time the reaction mixture was allowed to warm to -45', and 0.32 ml (2.5 mmol) of neat tetramethylethylenediamine was added, followed in 10 min by 546 mg (3.0 mmol) of trans- 1-iodo-2-butene in 4 ml of N - methylpyrrolidene. After the reaction mixture was stirred for 1 hr at -45 to -50°, 1 ml of absolute methanol was added, and the reaction mixture was allowed to warm to room temperature, poured into saturated aqueous ammonium chloride, and diluted with diethyl ether. After stirring for 1 hr the layers were separated, and the aqueous phase was extracted once with ether; the combined organic phases were washed with 2% sodium thiosulfate and dried over magnesium sulfate.55 Analytical glpc (column A, 1 70°, valerophenone internal standard) indicated five major products: A (3.5 min), B (5.5 min), C (5.7 min), D (7 min), and E (8 min). A is 3-vinylcyclopentanone (26 mg, 24%) identified by comparing retention times with that of authentic material.9

Posner, et al. / Alkylation of Enolate Ions

116 B and C are spectrally consistent with 2-( l'-buten-3'-yl)-3-vinylcyclopentanones (1.5 mg, 1%) containing the allylically rearranged side chain. B and C were incompletely resolved and thus imperfectly isolated via preparative glpc (column E, 160°, 28 and 30 min, respectively). Neither was affected by treatment with ethanolic sodium ethoxide. The nrnr spectrum of B has a doublet ( J = 6 Hz) at 6 1.1, whereas the nrnr spectrum of C has a doublet ( J = 7 Hz) at 6 1.0. D is trans-2-(trans-2'-buten-l'-yl)-3-vinylcyclopropanone (21, 56 mg, 34%) isolated via preparative glpc (column E, 160°, 36 rnin): nrnr (CC14) 6 4.8-5.8 (m, 5 H), 1.4-2.6 (m, 11 H); ir (CC14) 1745 (C=O), 1642 (C=C), 912 and 983 (terminal vinyl), and 963 cm-I (trans olefin); mass spectrum (70 eV) m/e 164 (30, molecular ion), 110 (loo), 109 (50),95 (90); bp 229' (760 mm). See Table I1 for analysis. N o change in glpc (column D, 160') was noted when 21 was treated with ethanolic sodium ethoxide. A pure sample of 21 was hydrogenated at 50 Ib of hydrogen pressure on 10% palladium on charcoal catalyst in absolute ethanol on a Parr hydrogenator. Only one product was observed, trans -2-n- butyl-3-ethylcyclopentanone 29 (vide infra). E is 2-(trans -2-buten-l-yl)-4-vinylcyclopentanone (22, 27 mg, 12%), isolated via preparative glpc (column E, 160°, 41 min): nmr (CC14) 6 4.8-5.8 (m, 5 H), 1.2-2.6 (m, 11 H); ir (CC14) 1748 (C=O), 1642 (C=C), 912 and 983 (terminal vinyl), 961 (trans olefin); mass spectrum (70 eV) m/e 164 (30, molecular ion), 110 (90). 109 (40), 95 (100). See Table I1 for analysis. If the trans - 1-iodo-2-butene-N- methylpyrrolidone is added at -78', the yield of 21 is 74 mg (45%), but there is now 7 mg (4%) of the allylically rearranged products B and C. Likewise if HMPA is substituted for N-methylpyrrolidone (at -78'), 84 mg (51%) of 21 is observed, but the yields of B and C are also increased to 14 mg (8.5%). If no cosolvent is used and trans- I-iodo-2-butene is added neat at -78O, the rearranged products predominate (61 mg, 37%) with only 30 mg (18%) of 21. Adding neat trans- l-iodo-2butene at -20' results in 41 mg (25%) of 21 with a negligible amount of rearranged B and C. In all these cases, the yield of dibutenylcyclopentanone 22 was about one-half that of 21; however, longer reaction times and higher temperatures favored other products with longer glpc retention times. C. Methyl 7-Iodo-cis-5-heptenoate Quench. To 600 mg (4 mmol) of sodium iodide dissolved in 20 ml of acetone was added 663 mg (3 mmol) of methyl 7-bromo-cis- 5 - h e ~ t e n o a t in e ~1~ml of acetone, forming an immediate white precipitate.60 Two hours later the reaction mixture was poured into water and was extracted with diethyl ether. The organic layer was washed twice with water and once with 2% aqueous sodium thiosulfate, dried over magnesium sulfate, and concentrated to 730 mg (91%) of red oily methyl 7-iodo-cis-5-heptenoate: nrnr (CCl4) 6 5.2-6.0 (m, 2 H), 3.8-4.1 (m, 2 H ) , 3.65 (s, 3 H), 1.4-2.5 (m, 6 H); ir (CC14) 1742 (C=O) and 1656 cm-I (C=C). Enolate ion 4 was prepared by treating 41 mg (0.5 mmol) of 2cyclopentenone with 0.6 mmol of lithium methyl(viny1)cuprate at -78' for 30 min a t which time the reaction mixture was allowed to warm to -20' for 5 min, and 536 mg (2.0 mmol) of methyl 7-iOdOcis- 5-heptenoate was added in 0.5 ml of THF. After the mixture was stirred for 20 min at -20°, 1 ml of absolute methanol was added; the reaction mixture was allowed to warm to room temperature, poured into saturated aqueous ammonium chloride, and diluted with diethyl ether. After stirring for 1 hr, the phases were separated, and the aqueous layer was extracted once with diethyl ether; the combined organic layers were washed with sodium thiosulfate, dried over magnesium sulfate, and concentrated in vacuo to 485 mg of a green oil. The bulk of this material seems to be methyl 7-iodo-cis-5-heptenoate as well as the products resulting from methyl coupling with that species. The crude product was column chromatographed on 20 g of silica. Following extended elution with hexane, a 10% ether-90% hexane solution eluted 25 mg of material containing three components by glpc [9 ft X % in. 5% Lexan on Chrom W (80-90) column, 190°]: A (9.5 min), B (12.5 min. small shoulder on C), and C (13.5 min). A (