Substituent effects in the hydrogenation of A""-octalins

CIRILL SCHMIDT AND TIBOR BREINING' Department of Chetnistry, Utziversity of' Pritzce Erlrvard Islatld, Chc~rlotteto~~~tz, P.E.I., Canada CIA 4P3

Received May 30. 1983

CIRILL SCHMIDT and TIBOR BREINING. Can. J. Chem. 62, 273 (1984). The presence of the 4u-methyl group in olefin 4 or in conjugated ketone 10 prevents catalytic hydrogcnation froni the u side,

leading exclusively to cis-fused decalins.

CIRILL SCHMIDT et TIBOR BREINING. Can. J. Chem. 62, 273 (1984). On rapporte que I'hydrogtnation catalytique de I'oltfine 4 ou de la cCtone conjugute 10 conduit exclusivement a la

cis-dCcaline correspondante Ctant donnC la prCsence du groupement mCthyle-4a qui empeche la rCaction dc s'effectuer du cBtC u de la molCcule.

[Traduit par le journal]

We wish to report an example which might improve the predictability of ring junctures in decalins resulting from the catalytic hydrogenation of substituted A'."-octalins 1 . The known cases are collected in Table I. They show that any particular combination of methyl groups near the double bond profoundly influences the cisltr-ans isomer ratio of the decalins formed. However, these influences are not entirely understood.

Admittedly, the predominant and exclusive formation of trans-fused decalins from octalins l a ( l ) , l c (3), and their derivatives (4) can readily be explained as the result of prefer- ential adsorption of the less hindered side of the substrate on the surface of the catalyst. On the other hand, the predominance of the cis isomer in the hydrogenation of octalin 1 b, containing an angular methyl group, is contrary to this explanation (2).

Octalin I d should also be examined in this context, but to our knowledge this compound and its hydrogenation have not been reported. We have therefore prep&ed-hydroxyketone 4 for this purpose.

The sterically hindered keto group in the recently reported dioxolane 2 (5) was reduced to the equatorial alcohol 3 with LiA1H4 in refluxing THF as evidenced by a coupling constant of 11 Hz. After deketalization, hydroxyketone 4 was hydro- genated in acetic acid, in the presence of Adam's catalyst, to a single hydroxy ketone 50, which will be shown to possess a cis-fused system.

We recently reported the preparation of the trans-fused ke- tone 11 from dimethylether 10 (5). The latter compound was hydrogenated to ketone 9 which, after elimination, led to ke- tone 8, isomeric with the authentic trans-fused ketone 11.'

Since the only possible stereochemical difference is due to the ring juncture, ketone 8 must be cis-fused. The same ketone was also obtained by elimination of mesylate 5 b to olefin 6, followed by reduction to alcohol 7 a (8), methylation to 7 b (9), and allylic oxidation to ketone 8 (10). It is to be mentioned that the only reagent which produced the pure equatorial alcohol 7 a was Na in liquid ammonia (8). With complex hydrides, the undesired axial alcohol was also present.

The catalytic hydrogenations 4 + 5 a and 10 + 9 led exclu- sively to cis-fused systenls, even under the most trans-pro- ducing conditions (1 1). This indicated that the 4a-equatorial methyl group seriously inhibited the absorption of the substrate

'On leave from Chinoin Pharmaceutical and Chemical Works Ltd., Budapest, Hungary.

'Ketone 11 was also prepared by P. Grieco et a/. by an entirely different route (6, 7).

by the a side. This stereochemical result seems similar to that found in the selective reduction of diketone 12 to keto-alcohol 13 by NaBH,, in which the hydride ion attacks from the P side (5), in spite of7 the usual a-attack encountered in the case of 6-ketosteroids (12). Clearly the 4a-methyl group seriously decreases the accessibility of the a side in both reactions.

It could be suggested that some secondary force of attraction may exist between the catalyst and the angular methyl group in octalin l b , promoting the formation of a cis-fused system (55%), and, since hydrogenation leading to the trans product is prevented by the 4a-methyl group in compound 4, the cis- decalin 5a is the only product formed. However, this attractive force between an angular methyl group and the catalyst in octalin l c cannot operate, due to the presence of the second axial group.

Experimental All melting points were taken on a Fisher-Johns melting point

apparatus and are uncorrected. Thc elemental analyses were carried out by Pascher Mikroanalytical Laboratorium, ~ o n n , West Germany, and Schwarzkopf Mikroanalytical Laboratory, Woodside, N.Y. The ir spectra were recorded on a Perkin-Elmer Model 137B infracord spcctrophotometer. The uv spectrograms were taken on a Coleman- Hitachi Model 124 double-beam grating spectrophotometer. The nmr spectra were recorded on a Varian Associates T60 spectrophotometer. The mass spectra were obtained with a Hitachi Perkin-Elmer Model RMS-4 spectrometer.

8P -Hydroxy-4a, 7a ,8aP -trimethyl-3,4,6,7,8,8a-hexahydro- tzaphthalen-l(2H)-one ethylene ketal3

A solution of 2a,Sa,8ap-trimethyl-3,6,7,8a-tetrahydronaphthalen- 1.8 (2H.5H)-dione-%ethylene ketal2 (30.00 g, 0.1 19 mol) dissolved in dry THF (150 mL) was dropped into a magnetically stirred sus- pension of LiAIH, (4.55 g, 0.119 mol) in dry THF (150 mL). The reaction mixture was stirred while refluxing for 4 h, then the stirring was continued at room temperature for 14 h. Water (50 mL) was dropped carefully into the chilled suspension. The resulting sus- pension was filtered through Celite and the filter cake was washed with ether (100 mL). After separation of the ether layer, the aqueous phase was extracted with ether (4 X 50 mL). The combined organic phase was washed with water (50 mL), dried (MgSO,), and concen- trated in vacuo leading to crystalline, tlc (silica gel, benzenelether 4: 1) homogeneous product (28.4 g, 93.9%). An analytical sample was prepared by recrystallizing from pentane. mp 78-79°C; ir: 3460, 2850,2820, 1450, 1095, 1050 cm-'; nmr (CDC13, 6 0 MHz), 6: 1.02 (d, 6, J = 6 Hz, 4-CH3 and 7-CH3), 1.50 (s, 3, 8a-CH,), 3.28 (dd, 1, J = 11 Hz, 4 Hz, 8-proton), 4.07 (m, 4, 0-CH2-CH,-O), 4.33 (d, 1, J = 4 Hz, OH), 5.47 (m, 1, olefinic proton); mass spectrum (70 eV) mle (relative intensity): 252 (9, M+), 100 (32), 99

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274 CAN. J . CHEM. VOL. 62. 1984

1 2 a R ' , R', R' = H b R ' , R G H; R3 = CH, c R ' , R', R' = CH3 d R ' = H; R', R' = CH,

(1) Li, NH3, EtOH

(2) NaOCH3 : H

(100). Anal. calcd. for C15H2403: C 71.39, H 9.59; found: C 71.31, H 9.63.

8 P -Hydroxy-4a ,7a ,8ap-trimethyl-3,4,6,7,8,8a-he-rahydro- naphthnlen-l(2H)-one 4

A solution of 8P-hydroxy-4a,7a,8aP-trimethyl-3,4,6,7,8,8a- hexahydronaphthalen-l(2H)-one-ethylene ketal 3 (15.00 g, 0.059 mol) dis3olved in diethyl ether (150 mL) was magnetically stirred for 14 h at room temperature with a solution ofp-toluenesulfonic acid (1.5 g) in water (75 mL). After separating the two phases, the water layer was extracted with ether (2 x 50 mL). The combined ether extracts were washed with 10% NaHCO, solution (20 mL), dried (MgSO,), and concentrated in vacuo furnishing a tlc (silica gel, benzenelether 4: 1) homogeneous oil (12.0 g, 96%), which was converted to 5 a without further purification; ir (CHCI,): 3500, 2960, 2930, 2880, 1678, 1655, 1460, 1045 cm-'; nmr (CDCl,, 60 MHz), 6: 1.07 (d, 3, J = 5 Hz, CH,), 1.08 (d, 3, J = 6 Hz, CH,), 1.62 (s, 3, 8a-CH,), 2.98 (after the addition of D20, d, 1, J = 1 I Hz, 8-proton), 3.85 (d, 1, J = 11 Hz, OH), 5.50 (m, 1, olefinic proton); mass spectrum (70 eV) mle (relative intensity): 208 (82, ~ + j , 15 1 (loo), 138 (60), 135 (69), 123 (78).

8P-Hydroxy-4~~ , ~ C X ,8ap-trimetllyl-3,4,4ap ,5,6,7,8,8a-octahydro- naphthalen-l(2H)-one 5 a

A solution of 8P-hydroxy-4a,7a,8aP-trimethyl-3,4,6,7,8,8a- hexahydronaphthalen-l(2H)-one 4 (10.00 g, 0.048 mol) in acetic acid

(100 mL) was hydrogenated at room temperature until the con- sumption of one equivalent hydrogen (1 152 mL) at atmospheric pres- sure in the presence of prehydrogenated Pt (obtained from 50 mg of Adam's catalyst). After filtration, most of the acetic acid was distilled off at reduced pressure (5 Torr). Traces of CH3COOH were removed by codistillation with ethyl acetate. The resulting colorless oil, ho- mogeneous in tlc (silica gel, benzenelether 4: 1) was used without further purification for the preparation of mesylate 5b; ir (CHCl,): 3510, 2995, 2950, 2930, 2870, 1680, 1450, 1050, 1036 cm-I; nmr (CDCI,, 60 MHz), 6: 1 .OO (d, 3, J = 7 Hz, CH,), 1.05 (d, 3, J = 6 Hz, CH,), 1.57 (s, 3, 8a-CH,), 2.62 (with D20, d, I, J = 10 Hz, 8-proton), 3.37 (d, 1, J = 11 Hz, OH); mass spectrum (70 eV) mle (relative intensity): 210 (67, M+) , 193 (53 , 192 (90), 159 (loo), 149 (98), 133 (73).

8 P -Methanesulfonylo,ry-4~~, 7 a ,8ap-trimethyl-3,4,4a/3,5,6,7,8,8a- octahydronaphthalen-l(2 HI-one 5b

Methanesulfonyl chloride (5 mL) was dropped into a chilled solu- tion of 8P-hydroxy-4a,7a,8aP-trimethyl-3,4,4aP,5,6,7,8,8a-octa- hydronaphthalen-l(2H)-one 5a (5.00 g, 0.024 rnol) in dry pyridine (25 mL), over a 15-min period, while stirring magnetically. The reaction mixture was stirred at room temperature for 3 h, then it was poured into a mixture of crushed ice (25 g) and 10% (25 mL). After extraction with chloroform (4 X 20 mL), the combined extracts were washed in succession with 10% H2S04 (2 X 30 mL), 10%

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SCHMIDT AND BRElNlNG

TABLE 1. The influence of substituents on the catalytic hydrogenation of A'.'-octalins

Percentage of isomers

Substrate trcrrls cis Conditions Reference

In, R1 , R', R3 = H 77 23 Pd/CH,COOH 1 10, R ' . R' = H: R' = CH, 45 55 P ~ / C ~ H , O H 2

or CH3COOH l c , R ' , R', R7 = CH3 100 0 Pt/CH,COOH 3,4 4, R1 = H; R', R, = CH, 0 100 Pt/CH,COOH This article 10, R' = H: R', R' = CH, 0 I00 Pt/CH,COOH This article

NaHCO, (20 mL), and water (20 mL). After drying (MgSOJ and concentration in I~OCLIO, diethyl ether ( I0 mL) was added to the resi- due. The product crystallized on scratching with a glass rod, after 15 min (5.35 g, 78%. mp 140- 142°C). It was used without purification for the preparation of olefin 6; ir (CHCI,); 3010, 2960, 2930, 2865, 1695, 1320, 1 158, 1 145,910,890,876 cm-'; nmr (CDCI,, 60 MHz), 6: 1.07 (d, 3, J = 7 Hz, CH3). 1.05 (d, 3, J = 6 HZ, CH,), 1.57 (s, 3. 8a-CH,), 3.10 (s. 3, CH,-SO?). 4.08 (d, I , J = 1 1 Hz, 8-proton).

4 a . 7,8n/3-Trirnetl1yl-3,4,4~5,6,8c1-l~e.r~1hy~lro1~n~~/1t/z~1le-l(2 H)- one 6

Into a stirred suspension of Li2C0, ( I .50 g) and LiBr (1.50 g) in dry DMF ( I0 mL), a solution of 8~-methanesulfonyloxy-4a,7a,-8ap- trimethyl - 3,4,4apq5,6,7,8,8a- octahydronaphthalen - l(2H) -one 5b (3.00 g, 0.0104 mol) dissolved in DMF (30 mL) was dropped at 160°C

: under an atmosphere of dry nitrogen. Thc reaction mixture was then stirred at 170°C for 30 min. After cooling to room temperature, the

; solution was diluted with water (50 mL) and extracted with benzene 1 (3 X 15 mL). The combined extracts were washed with water (2 X 30 I mL), dried (MgSO,), and concentrated ill vncuo giving a yellow tlc i (silica gel, benzene) homogeneous oil (1.97 g, 98.5%) which was 1 used without purification for the preparation of unsaturated alcohol i 70; ir (CHCI,); 2955, 2930, 2870, 1688, 1442, 1120 cm-I; nmr

/ (CDCI,, 60 MHz), 6: 1.03 (d, 3, J = 7 Hz, 4-CH,), 1.32 (s, 8a-CH,),

/ 1.72 (d, 3, J = 1 Hz, 7-CH,), 5.38 (m, I, olefinic proton); mass spectrum (70 eV) m/e (relative intensity): 192 (62, M+), 159 (27),

! 149 (loo), 135 (70). I

4a,7,8a/3-Trimethyl-1,2,3,4,4~1/3,5,6,8c1-octn/1)~~1ro11ap/1t/1a1e11- 1 /3 -01 7a

To a stirred solution of 4a,7,8ap-trimethyl-3,4,4ap,5,6,8a- ,

hexahydronaphthalen-l(2H)-one 6 (3.00 g, 0.0156 mol) in ether (I5 mL), ethanol (15 mL), and liquid ammonia (100 mL), freshly cut pieces of sodium (3 g) were added. The 500-mL three-neck flask was cooled with Dry Ice/acetone and was equipped with a Dry Ice con- denser attached to a drying tube containing soda lime. The reduction was allowed to proceed for 30 min after the appearance of the blue color. After the evaporation of ammonia ( I h), water (30 mL) was added and the product was extracted with ether (4 x 10 mL). The combined extracts were washed with water ( I0 mL), dried (MgSO,), and concentrated in vacuo giving a tlc (silica gel, benzene/ether 4: 1) homogeneous oil (2.80 g, 92.4%) which was used without further purification for the preparation of methyl ether 7b; ir (CHCI,): 3450, 2900, 1450, 1370, 1040, 1010 cm-'; nmr (CDCI,, 60 MHz), 6: 0.87 (d, 3, J = 6 Hz, 4-CH3), I .OO (s, 3, 8a-CH,), 1.63 (d, 3, J = I Hz, 7-CH,), 2.50 (broad s, I , OH), 3.65 (dd, 1, J = 10 Hz, 6 Hz, I-proton), 5.38 (m, I, olefinic proton); mass spectrum (70 eV) m/e (relative intensity): 194 (94, M+), 192 (68), 176 (94), 136 (86), 135 (100).

4 a ,7,8a/3-Trimetl~yl-l,2,3,4,4a/3,5,6,8n-octahydrorzaphlhalen- 1/3-01 mefhyl ether 7b

In a dry 100-mL three-neck flask equipped with reflux condenser, drying tube (CaCI,), dropping funnel, and magnetic stirrer, sodium hydride (as 50% oil suspension, 2.00 g, 41.66 mmol, Alfa Inorganics) was placed under an atmosphere of dry nitrogen. After washing it by

decantation with dry pentane (3 X 5 mL), the last traces of pentane were removed with a stream of dry nitrogen. Then tetrabutylam- monium iodide ( 1 g) and dry THF (20 mL) were added.

A solution of 4a,7,8ap-trimethyl- 1,2,3,4,4ap,5,6,8a-octahydro- naphthalen-ID-ol 70 (2.00 g, 10.29 mmol) dissolved in dry THF (20 mL) was dropped into the stirred suspension. The suspension was stirred at room temperature, then methyl iodide (2.0 mL) was added over a 15-min period. The reaction mixturc was stirred for 14 h at room temperature. After the addition of water (10 mL), most of the THF was removed by distillation at atmospheric pressure, using a short fractionating column. The residue was taken up in diethyl ether and the mixture of water and ether was filtered through Celite. After separation, the water phase was extracted with ether (2 X 10 mL). The combined ether extracts were washed with water (2 X 10 mL), dried (MgSO,), and concentrated in vncuo giving a tlc (silica gel, benzene) homogeneous, slightly yellow oil (1.86 g, 86.8%) which was con- verted to the unsaturated ketone 8 without further purification; ir (CHCI'): 2900, 1450, 1370, 1090 cm-I; nmr (CDCI,, 60 Hz), 6: 0.88 (d, 3, J = 7 Hz. 4-CH,), 1 .OO (s, 3 , 8a-CH,), 1.67 (d, 3, J = I Hz, 7-CH3), 3.33 (s, 3, CH,O), 5.47 (m,l . olefinic proton); mass spec- trum (70 eV) m/e (relative intensity): 208 (46, parent peak), 176 (3 I), 135 (loo), 108 (59). 107 (96).

5/3-Metho2~)1-3,4a/3 ,8a-trirnethyl-4a,5,6,7,8,8a/3-he,xa11ydro- naphthalenZ(1 H )-one 8

(a). By the allylic o.ridatiorz of methyl ether 7b 3,5-Dimethylpyrazole (1.66 g, 17.28 mmol) was added all at once

to a magnetically stirred suspension of chromium trioxide (dried over PzOs for 24 h, 1.73 g, 17.28 mmol) in dry methylene chloride (15 mL), at -20°C. The mixture was stirred for 15 min at -20°C, then a solution of 4a,7,8ap-trimethyl- l,2,3,4,4ap,5,6,8a-octahydronaph- thalen-l p-ol methyl ether 7b (300 mg, 1.44 mmol) dissolved in dry CHZC12 (5 mL) was dripped in 5 min. The reaction mixture was stirred for 4 h at - 10 to -20°C, then 5 N NaOH (10 mL) was added and the solution was stirred at O°C for I h. After extracting with ether (3 x 30 mL), the combined organic extracts were washed in succession with 10% H2S04 (2 X 10 mL) and 10% NaHC0, (10 mL). After drying (MgS04) and concentration (to 10 mL) the solution was passed through a short column of Fluorosil (10 g). The eluted colorless solution was concentrated to an oil (240 mg, 75%), whose spectroscopic properties were identical with those prepared from dimethoxy ketone 9 (see next paragraph).

(b). By the base-catalyzed elimination of dimethoxy ketone 9 To a solution of 4P,5P-dimethoxy-3a,4ap,8a-trimethyl-3,4,4a,-

5,6,7,8ap-octahydronaphthalen-2(1 H)-one 9 (300 mg, 1.17 mmol) in methanol (5 mL), a solution of sodium methylate (20 mg) in methanol (2 mL) was added. The reaction mixture was allowed to stand at room temperature for 14 h, then it was diluted with water (15 mL) and extracted with ether (4 x 5 mL). The combined ether extracts were washed with water (2 x 5 mL), dried (MgSO,), and concentrated in vacuo furnishing a slightly yellow oil (240 mg, 92%). The tlc (silica gel, benzenelether 9: 1) homogeneous oil was microdistilled, 115"C/O. I Torr. Infrared (CHCI,): 2950, 2930, 2870, 1660, 1455, 1362, 1092 cm-I; uv,,,,,,: 238 nm (E = 10 110); nmr (CDCI,, 60 MHz), 6: 0.85 (d, 3, J = 6 Hz, 8-CH,), I . 17 (s, 3, 4a-CH,), 1.78 (d,

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276 CAN. J . CHEM. VOL. 62. 1984

3, J = I Hz, olefinic 3-CH,), 3.30 (s, 3, CH,O), 6.73 (d, I , J = 1 Hz, olefinic proton); mass spectrum (70 eV) mle (relative intensity): 222 (30, parent peak), 190 (12), 175 ( 1 I), 140, (52), 123 (loo), 122 (41). Anal. calcd. for C14H2202: C 75.63, H 9.97; found: C 75.70, H 10.01.

4 P ,5P-Dimethoxy-3a ,4a~,8a-trimethyl-3,4,4a,5,6,7,8,8a/3-octa- hydronaphthalen-2(1 H)-one 9

A solution of 4P-5P-dimethoxy-3a,4ap,8a-trimethyl-4,4a,5,6,7.8- hexahydronaphthalen-2(3H)-one 10 (250 mg, 0.99 mmol) in acetic acid (2 mL) was hydrogenated at room temperature, while stirring magnetically, in the presence of prehydrogenated Pt (prepared from 50 mg of Adam's catalyst) until the consumption of one equivalent hydrogen (24 mL). After filtering the catalyst, the filtrate was dropped to a saturated solution of NaHC0, (30 mL), while stirring, and ex- tracted with chloroform (4 X 10 mL). The combined organic extracts were washed with 10% NaHCO, (10 mL), dried (MgS04), and con- centrated in vacuo, furnishing a colorless tlc (silica gel, benzenelether 4: 1) homogeneous oil (0.25 g, 99%) which was eliminated to the unsaturated ketone 8 without further purification. Infrared (CHCI,): 2990, 2930, 1703, 1452, 1092 cm-'; nmr (CDCI,, 60 MHz), 6: 0.82 (d, 3, J = 7 Hz, CH,), 1.18 (d, 3, J = 6 Hz, CH3), 1.25 (s, 3, 4a-CH3), 3.40 (s, 3, CH,O), 3.50 (s, 3, CH,O); mass spectrum (70 eV) mle (relative intensity): 254 (8, parent peak), 222 (78), 190 (24), 175 (19), 149 (loo), 139 (49), 125 (30), 123 (94).

Engineering Research Council of Canada and the Research Committee of the University of Prince Edward lsland is gratefully acknowledged.

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The financial assistance of the Natural Sciences and

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