'({JIXOAA* Laiuoaim ' ' " Adviser Department of Chemistry DEDICATION

SYNTHESIS AND REACTIONS OF

INTERMEDIATES FOR STEROID ELABORATION

DISSERTATION

Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University

Arlen B. Mekler, B.S., M.S.

• • • o o

The Ohio State University

1959

Approved by

'({JIXOAA* lAiUOAim ' ' " Adviser Department of Chemistry DEDICATION

LEV A. MEKLER

ii ACKNOWLEDGMENT

The author wishes to express his sincere appreciation to Dr. Melvin S. Newman for stimulating ideas and helpful advice, for interesting discussions and constructive criticisms, for invaluable laboratory techniques, for his personal friendship and his inspirational guidance throughout this research. The author is also grateful for the receipt of the following awards: Charles P. Kettering Founda tion Fellowship, 1956-1957; Melvin S. Newman Scholarship, 1957; U. S. Industrial Company Fellow ship, 1957-1958; Allied Chemical Company Fellowship, 1958-1959; and E. I. Du Pont Research Fellowship, 1959.

iii TABLE OP CONTENTS Page ACKNOWLEDGMENT...... ill OBJECTIVE 1 HISTORICAL BACKGROUND 4 DISCUSSION OP RESULTS 20 SUGGESTIONS FOR FURTHER WORK 39 EXPERIMENTAL «,.... 42 General Procedures, 42 2-Methyl-l, 3-cyclohexanedione 43

4-Diethylamino-3-butanone0 44 1,6-Dioxo-8a-methyl-l, 2, 3, 4, 6,7,8, 8a- oc tahydronaphthalene. ••• 44 K -(6-Methyl-3-keto-l-cyclohexene- 1-yl)-butyric acid 47 Methyl ^-(6-Methyl-3-keto-l-cyclohexene-1-yl) butyrate • 48 Methyl &"-(3-Acetoxy-6-methyl-l,3- cyclohexadien-1-yl) butyrate. 49 Methyl #-( 5-Hydroxy-2-methylphenyl) - butyrate 50 Action of Sodium Methoxide on Methyl ^-{ 5-Hydroxy-2-methylphenyl) butyrate 51 3- (4-Hydroxybutyl) - 4-me thylphenol 51 3- ( 4-Bromobutyl) - 4-me thylphenol • 52 Attempted Synthesis of 3-(4-bromobutyl)- 4-Methylphenol Employing Acetic Acid.. 52

iv Page Base-Induced Cyclization of 3-(4- Bromobutyl)-4-raethylphenol A) Action of Methanolic Sodium Me thoxi de 53 B) Action of Sodium Amide in Liquid Ammonia 54 r -(2-Hydroxy-5-methylbenzoyl)-propionic acid. 55 *^-(2-Hydroxy-5-methylphenol)-butyric acid.... 56 Methyl -(2-Hydroxy-5-methylphenyl) butyrate. 57 2- ( 4-Hydroxybutyl)-4-methylphenol 58 2- ( 4-Bromobutyl) - 4-me thylphenol 59 Attempted Synthesis of 2-(4-Bromobutyl)- 4-methylphenol Employing Acetic acid 59 Base-Induced Cyclizations of 2-(4- Bromobutyl)-4-methylphenol A) Action of Methanolic Sodium Methoxide 60 B) Action of Sodium Amide in Liquid Ammonia 61 C) Action of Lithium Amide in Liquid Ammonia 62 1,8-Dioxo-4-methyl-l, 2, 3,5,6, 7,8,8a- octahydronaphthalene 63 4-Methyl-8-oxo-5,6,7,8-tetrahydro-l-naphthol.• 65 Lithium Aluminum Hydride Reduction of 1,8-Cioxo-4-methyl-l,2, 3,5,6,7,8,8a- octahydronaphthalene 66 c<.-Methylnaphthalene 67 4-Methyl-5,6,7,8-tetrahydro-l-naphthol 67

v Page l-Oxo-4,8-dimethyl-8-hydroxy- 1,2, 3,4,6,7, 8,8a-oetahydronaphthalene 68 1, 4-Dime thylnaphthalene «...... «*.. 69 SUMMARY.. . • 70 APPENDIX 73 AUTOBIOGRAPHY 76

vl OBJECTIVE

It was the purpose of this work to study the base-induced cyclization reactions of 2-(4-bromobutyl)- 4-methylphenol, I and 5-(4-bromobutyl)-4-methylphenol, II. Upon treatment with base the bromide, I, might be expected to cyclize by one of two paths (Figure I) to give the cyclic ether, Ilia, if the chain cyclizes at position a or the spiro decadienone, Illb, if the alkylation occurs at position b.

Of particular interest to us was the path of base- induced cyclization of the bromide, II, since this might serve as an interesting path to 10-methyl-2-keto- 2,5,6,7,8,10-hexahydronaphthalene, V (path d), a possible intermediate for steroid synthesis. The cyclization could also proceed by an alternate route to yield 4-methyl-5,6,7,8-tetrahydro-l-naphthol, IV, (path c) (Figure I).

The preparation of the bromide, I, from p-cresol via '8'-(2-hydroxy-5-methylphenyl) butyric acid, VI, was straightforward and offered no synthetic problem.

1 -x

,a, OH o0 ^ CH3

Q^(CH2)3-CH2Br (CH^ CH2Br Ilia base A CH. CH.

III b

OH ,o CH ban 3 (c) IV

r (CH2)3 CH2Br 2^3^ ^2®

CH, <& CH3

Figur« I OH

,(tH2)j-C02H

0) For the synthesis of the bromide, II, it was necessary to prepare quantities of l-6-dioxo-8a~methyl-l, 2,3, 4,6V"7,8,8a-octahydronaphthalene, VII, which was then cleaved with sodium methoxide to produce the keto ester, VIII, which possessed the carbon skeleton necessary for the formation of II. The ester, VIII was aromatized and the ester grouping then reduced and treated with hydi?obromic acid to yield II. o

Ha OC*3 j. CHjOH o VII " (2.) During the course of the preparation of the keto ester, VIII, it was noted that in the presence of excess methanolic sodium methoxide, the 1,6-dione, VII, under went a novel transacylatlon reaction to yield 1,8-dioxo- 4-methyl-2,3,5,6,7,8,8a-octahydronaphthalene, IX. ° firCHj o— CH3°H JO 0, The course of this reaction, as well as the properties of IX, was investigated. HISTORICAL BACKGROUND

Because of the varied scope of the studies involved, the background material, pertinent to the investigations described herein, has been divided into the following convenient catagories: (A) Cycliza- tion of 4-p-hydroxyphenyl-l-butyl-p-bromobenzene- sulfonate; (B) Synthesis of X-(2-hydroxy-5-methylphenyl) butyric acid; (G) Synthesis of 1,6-diaxo- 8a-methyl-l,2,3,4,6,7,8,8a-octahydronaphthalene; (D) Synthesis of 1,8-decalindione; and (E) Alkylation of Hagemannfs ester and related °<. , (3 -unsaturated ketones. Only a limited amount of work related to the studies on the base-induced cyclization of the bromides I and II, has been reported by others.

l H-oNy H-0'\x' *(ctf,iJCHlBr

(CtiJ3CHz*r

I )l

4 5 Cycllzation of 4-(p-Hydroxyphenyl) - 1-butyl p-bromobenzene Sulfonate X When 4-(p-hydroxyphenyl)-1-butyl p-bromobenzene sulfonate, X, was treated with a slight excess of potassium t-butoxide in anhydrous t-butyl alcohol, spiro-(4;5)-deca-l, 4-dien-3-one, II, was isolated 1 in 50% yield. The ketone, XI, has been subjected o to the dienone-phenol rearrangement to yield 5,6, 7,8-tetrahydro-2-naphthol, XII, in quantitative yield.

No work has been reported, however, on the analogous reactions with molecules in which the alkyl side chain is on a position meta or ortho to the phenolic hydroxyl group.

Is. Winstein and R. Baird, J. Am. Chem. Soc, 79, 756 (1957). 2 A. L. Wilds and C. Djerassi, J. Am. Chem. Soc, 68, 1715 (1946). 6

The possibility that the base-catalyzed rearrangement of the bromide, II, might lead to the formation of the dienone V seemed most intriguing as V serves as an interesting model for synthesis of steroids. Compound V has been synthesized previously in low yield by the condensation of 2-methylcyclohexanone and methylethynyl ketone in the presence of sodium hydride. The ketone, V, has also been prepared in a little higher yield from 2-methyl-2-formylcyclo- hexanone by condensation with acetone in piperidine and acetic acid.

o cw, o O + CH,-C-CHCH . MaH, ether

Pi PeriJl'ine

acetic *cij (s)

1 R. B. Woodward and T. Singh, J. Am. Chem. Soc, 72, 494 (1950). 7 The dienone, V, can be rearranged by treatment with acetic anhydride and sulfuric acid to yield 4-methyl-5-,6,7,8-tetrahydro-l-naphthol, IV. XX) -±~ §0 V Crt3 (6) Synthesis of >^-(2-Hydroxy-5 methylphenyl) butyric Acid, VI ^-( 2-Hydroxy-5 methylphenyl) butyric acid was an intermediate in the synthetic route chosen for the preparation of 2~(4-bromobutyl)-4-methylphenol, I, (Figure IV). The acid, VI, has been synthesized1* 2 by treatment of p-methylanisole, XIII, with succinic acid in the presence of aluminum chloride to give @>-(2~hydroxy- 5-methylbenzoyl) propionic acid, XIV. Compound XIV was then subjected to a Clemmensen reduction to produce VI in 54% yield.

R. B. Woodward and T. Singh, J. Am. Chem. Soc, 72, 494 (1950). 2 R. D. Desai and M. A. Wali, Proc. Ind. Acad. Sc. (A) 6, 144 (1937) C. A. 32, 509 (1938). 8

OH O ort

Nitrobenzene ru_ Toluene XII)

Synthesis of l,6-Dioxo-8a-methyl- 1,2,5,4,6,7,8,8a-octahydronaphthalene, VII It was necessary to prepare l,6-dioxo-8a-methyl- 1,2, 5, 4, 6, 7, 8,8a-octahydronaphthalene, VII, in large quantity since it was a precursor in the chosen path for the synthesis of 4-(5-hydroxy-2-methyl-phenyl)- 1-bromobutane, II, (Figure III), A survey of the literature revealed that 2-methyl-l,3-cyclohexanedione, XVII, served as the starting material in all syntheses of VII. Compound 1 2 XVII has been prepared ' by high pressure hydrogenation of an alkaline solution of resorcinol, XV, to give dihydroresorclnol, XVI, in 90% yield, followed by methylation with methyl iodide employing sodium

M. Klingenfuss, XL. S. Pat. 1965, 499 (1934). *R. R. Thompson, Org. Syntheses, Coll. Vol. 3, 278 (1955). 9 1 2 methoxlde In methanol ' potassium hydroxide in 9 4 aqueous methanol, potassium methoxlde in methanol, potassium hydroxide in aqueous acetone, potassium 6 carbonate in aqueous acetone, or sodium ethoxide in 7 ethanol, but the yield of pure X was never better than 42%'.

ow o o

X\/ xv» XVII (8) 2-Methyl-l,3-cyclohexanedione, XVII, has also been prepared by embolization of ethyl 5-oxoheptanoate and g methyl 5-oxoheptanoate with sodium ethoxide and

XM. S. Newman and S. Swaminathan, Tetrahedron, 2, 88 (1958). 2E. G. Meek, J. H. Turnbull and W. Wilson, J. Chem. Soc, 811 (1953). 3H. Stetter, angew. Chemie, 67, 783 (1955). %. Stetter and W. Dierichs, Ber., 85, 61 (1952). 5H. Smith, J. Chem. Soc, 803 (1953). I. N. Nazarov, S. i. Zav'yalov, S. I. Burmistrova, M. S. Gurvich and L. I. Shmonina, J. Gen. Ghem. (U.S.S.R.) 26, 465 (1956). 7H . Born, R. Rappo and J. Szmuskovicz, J. Chem. Soc, 1779 (1953). p E. E. Blaise and M. Maire, Bull. Soc Chem., (4) 3, 421 (1908). ~ 9M. S. Newman and S. Swaminathan, Tetrahedron, 2, 88 (1958). 10 sodium methoxide respectively in about 80$ yield. The keto esters were obtained in 75-80$ yield by the reaction of the corresponding o-carboalkoxybutyryl chloride and diethyl cadmium.

tttc-CcH.v-coci £f^ifl CO.C-CCH^CO CMV c*3 J±£^ 5 eih«<- Ron

t\ ~ CH7 C j_ Hg 3, "irT* xvn (9)

The synthesis of 1,6-dioxo-8a-methyl-l,2,3,4,6,7, •* * • 1» 2 8,8a-octahydronaphthalene VII was first realized * by allowing Michael addition to occur between 2-methyl-l, 3-cyclohexadione, XVII, and methyl vinyl ketone (as the 85$ methyl vinyl ketone-water azeotrope). The reaction was run in the presence of a catalytic amount of triethylamine, either in aqueous methanol or under anhydrous conditions to produce the a dduct 2-methyl~2- (3-oxobutyl)-l,3-cyclohexanedione, XVIII, in 42$ yield. Even under these mild conditions, however, an appreci able amount of the acid XIX was formed. The adduct, (XVIII) was cyclized to the 1,6-diketone VII in 40$ yield by refluxing in benzene solution with aluminum t-butoxide. •*-H. L. Wendler, H. L. Slates and M. Tishler, J. Am. Chem. Soc, 73 3816 (19 51). o H. L. Wendler and H. L. Slates, U. S. Patent 2, 542, 223. 11

/Vll/K A\ t-S^Oe base benzene x»/u XVDJ VI)

£H, Ccri^lco2H o°; XI*

The 1,6-diketone VII was also successfully synthesized in low yield by heating XVII with acetonedicarboxyllc acid, formaldehyde and aqueous sodium hydroxide.

tCCHuCOCrivCO» tf + WCHO -t

x \/n VII 00

1P. Wieland and K. Miescher, Helv. Chim. Acta. 33 2215 (1950). 12 An alternate route involved the reaction of 2-methyl~l,3-cyclohexanedione in ethanol with 4-diethylamino-3-butanone methiodide and ethanolic sodium ethoxide, again producing VII in but low yield.

XVII GO o In another synthesis, XVII was treated with methyl vinyl ketone (MVK) and methanolic potassium hydroxide to form the adduct 2-methyl-2-(3-oxobutyl)- 1,3-cyclohexanedione, XVIII, which, when mixed with piperidine phosphate and heated to 92-98° at 26 mm. for several hours gave the 1,6-dione VII in 62.5$ yield. 2 3 In work carried out in 1952 ' VII was synthe sized in 60$ yield by refluxing a mixture of XVII, P. Wieland and K. Miescher, Helv. Chim Acta., 33, 2215 (1950). 2 M. S. Newman and S. Swaminathan, Tetrahedron, 2, 88 (1958). "" M. S. Newman and S. Swaminathan, U. S. Pat. 2, 673 872 (1954). *" 13 4-diethylamino-3-butanone, pyridine and benzene for eighteen hours.

0 CH$ O ^.CvHs Pyridine

O "* ^CjuWy behr4n€

XVII VII ov Thus, at the time this work was started the synthesis of VII had been studied by many workers. The best overall yield from resorcinol was 21.5$« Compound VII has been treated with 10%' potassium hydroxide to give V -(3-hydroxy-6~methylcyclohex-l- enyl)-butyric acid XX in1 75% yield (This constitutes an over-all yield of 15.1^ based on resorcinol). The acid, XX, it can be seen possesses the carbon skeleton for the formation of the bromide, II.

10% Kori

0+)

1 Mo S. Newman and S. Swaminathan, U. S. Pat. 2 673, 872 (1954). " 14 Synthesis of 1,8-decalindione, XXVI During the course of the preparation of the keto ester, VIII, required for the synthesis of the bromide, II, it was observed that upon treatment with excess sodium methoxide in methanol that the 1,6-dione, VII, underwent a novel transacylation reaction to yield 1,8-dioxo-4-methyl-l,2,3,5,6,7,8,8a-octahydronaphthalene, IX,

Mi oc U3 CtiyOri

v\\ IX ft)

The only other preparation of a 1,8-dioxo compound in the naphthalene ring system is that of 1,8-decalindione XXVI, which was reported subsequent to and independent of our work. (» -(3-hydroxybenzoyl)-propionic acid, XXI, was converted to ^-( 3-hydroxyphenyl)-butyric acid, XXII

%. Stetter and U. Milbers, Ber., 91;977 (1958). 15 via a Wolff-Kishner reduction. The butyric acid, XXII, was then hydrogenated, using platinum oxide catalyst to give yf"(3-hydroxycyclohexyl)-butyric acid, XXIII, which was subsequently oxidized with chromium trioxide in acetic acid to yield "2f-(3-oxocyclohexyl)-butyric acid, XXIII. The ethyl ester, XXV, was prepared and treated with alcoholic sodium ethoxide to give 1,8- decalindione, XXVI, in 71# yield (Figure II). The 1,8-dione, XXVI, exhibited only low acidity, underwent no reaction with diazomethane, formed a green- grey copper chelate, and a mono-2,4-dinitrophenylhydrazone.

The Alkylatlon of Hagemann*s Ester and Related °< , ^ -unsaturated Diketones The facile transformation of the 1,6-dione, to the 1,8-dione, in the presence of base (reaction 3) suggests that the position ortho to the carbonyl group in the cyclohexanone, VIII is more readily acylated than is

CI4,

(Ctf,) CO .CHj o0 3 l

VII I<°

OH OH

W. K. H2. P»02 O ^ -v // C-CH^Hg'COgH lCH2)3C02H

XXI XXII

O H O CrO, H, © HOAc CgH^OH

lCH2)3C02H tCH2)3-C02H

XXIII XXIV

O 0 NaO C2H5 CgHgOH

lCH2)3C02C2H5

XXV XXVI

Figure II 17 the position which is para. In this connection, it is interesting to note the work done on the alkylation-*- of 4~carbethoxy-2-cyclohexen-l-one (Hagemann's ester), XXVII.2 Compound XXVII was prepared in 50$ yield via the condensation of acetoacetic ester and paraformaldehyde under the influence of piperidine as a catalyst, followed by refluxing the condensation product with ethanolic sodium ethoxide.

HQOCZHS

XXVM

-1-L. I. Smith and G. P. Rouault, J. Am. Chem. Soc, 65, 631 (1945). 2T. L. Hagemann Ber. 26 876 (1893). 18 Hagemann's ester, XXVII, can be alkylated by action of alkylation agents such as methyl iodide or ethyl iodide in the presence of bases and it was conclusively shown that the alkyl group enters the 2-position and not the 4-position.

A/a O Cz tt$ I + c %I 2 c-z H$ OH

A COj.CtH5 C02CtHs XXVIJ oo

It is also to be noted that when 2-oxo-4a- methyl-5-tetrahydropyranyloxy-2,3,4,4a,5,6,7,8- octahydronaphthalene, XXVIII, was treated with methyl iodide and potassium t-butoxide in t-butanol that 5-hydroxy-2-oxo-l,l,10-trimethyl-l,2,3,4,4a,5, 6,7-octahydronaphthalene, XXIX was obtained.

CH3I base XXVM) 07)

-*-J. P. Cocker and T. G. Halsall, J. Chem. Soc. 3441 (1957). ' 19 Similarly, methylation of either A4-cholestenoner3, XXX, in dry t-butanol with potassium t-butoxlde and methyl iodide gave 4,4-dimethyl- ^ -cholestenone-3, XXXI, in 62% yield.1

base XXX 08)

It is then the purpose of our present work to describe (A) the base-induced cyclization of 2-(4- bromobutyl)-4-methylphenol, (B) the base-induced cyclization of 3-(4-bromobutyl)-4-methylphenol, (C) the improved synthesis of 1,6-dioxo-8a-methyl- 1,2,3,4,6,7,8,8a-octahydronaphthalene and (D) the synthesis of 1,8-dioxo-4-methyl-l,2,3,5,6,7,8*8a- octahydronaphthalene•

^-R. B. Woodward, A. A. Patchett, D. H. R. Barton, D. A. J. Ives, R. B. Kelly, J. Am. Chem. Soc. 76, 2852 (1954). ' DISCUSSION OP RESULTS

Preparation of 3-(4-Bromobutyl)- 4-methylphenol, X Inasmuch as it was necessary to synthesize large quantities of 1,6-dioxo-8a-methyl-l,2, 3,4,6,7,8,8a- octahydronaphthalene, IV as starting material for the synthesis of 4~(2-methyl-5-hydroxyphenyl)-l-bromobutane, XXIV, careful attention was given to the improvement of the conditions and yield of its preparations. (Figure III). A solution of resorcinol, I, in aqueous sodium hydroxide was subjected to high pressure catalytic hydrogenation under 1800 lbs. of hydrogen at 50°C. In the presence of Raney nickel. Since the crystallization and Isolation of the solid dihydroresorfiinol, II, in high yield was complicated by the tendency of the crude product to oil out, no attempt was made to isolate it as previous workers had done. Instead the sodium salt of dihydroresorcinol Ila (as obtained from the hydro genation reaction) was refluxed with methyl iodide in dioxane to give 2-methyl-l,3-cyclohexanedione, III, in 61$ yield.

20 :*l

OH CH I H2, Ni 3 oq. NaOH lioxanc

CH3 ° © CH3-C-(CH2)2N(CH3>2 CH3OH, H di«thyiamin« (CH^CO^ 0 benzene

in IV

(I) NBS.CCI4 CH3 isoproptnyl a c stale (2)collidin« a (CH2)3- C02CH3 \n VII

HO" "^^ ICH2)3C02CH3 ,e^ XI ° loT3 CH3-C-0 -C-O^^^^HJaCOoCH CH3 CH3 VIII LiAlH Ql *8%HBr. H O ^ •ior(CH 2)3- CH_Br {CH2)3-CH2OH ° ¥* IX

Figure III 22 The Mannich base, 4-diethylamino-3-butanone, was prepared in 88$ yield by subjecting methyl vinyl ketone to a Michael reaction with excess diethylamine. It was found that the reaction proceeded smoothly without the use of the usual acid catalyst. This simplified the work-up procedure and improved the yield. A mixture of III and the Mannich base, in benzene was refluxed for eighteen hours with diethylamine to produce the 1,6-dione IV in 66$ yield (this constitutes a 41.5$ yield based on resorcinol). The use of diethylamine in place of pyridine as base led to p cleaner products and higher yield. The 1.6-diketone IV was then cleaved by means of 10$ ethanolic sodium hydroxide to furnish the keto acid, V, in 91$ yield. The acid, V, was refluxed with methanol and sulfuric acid catalyst in methylene chloride to give the corres ponding methyl ester, VI, in 96$ yield. In subsequent work, the keto ester, VI, was prepared in higher overall yield (97.8$ based on the 1,6-dione, IV) by refluxing

A yield of 68$ of the Mannich base was obtained by Newman and Swaminathan, ref. 1, p. 9, when employing glacial acetic acid as catalyst. It is probable that the high water solubility of the product led to the lessened yield. ^The procedure of Newman and Swaminathan, ref. 1, p. 9 produced IV in a yield of 21.5$ based on resorcinol. 23 IV with the stoichiometric amount of 5$ sodium methoxide in absolute methanol. Anhydroms conditions had to be strictly maintained or substantial amounts of the keto acid, V, were formed from the attack of hydroxide ion on the carbonyl carbon of IV.

eoH

The keto e3ter, VI, was next refluxed with isopropenyl acetate to give an 87.4$ yield of the enol acetate, VII. Treatment of VII with N-bromosuccinimide, followed by heating with 2,4,6-collidine produced 4-acetoxy-2-(3-carbomethoxy- propyl) toluene, VIII, in 76.8$ yield. When VIII was reduced with lithium aluminum hydride in dry ether, the alcohol, IX, was obtained in 86.4$ yield. A sample of the acetoxy compound, VIII, was also hydrolyzed with 10$ hydrochloric acid to give the ester XI in 83$ yield. When IX was refluxed with constant boiling hydrobromic acid in sym.-tetrachloroethane, the desired bromide XIV was obtained in 82.5$ yield. 24 An attempt to synthesize the bromide, X, by refluxing IX with constant boiling hydrobromic acid in sym.-tetrachloroethane and glacial acetic acid resulted in the formation of 5-hydroxy-8-methyl- 1,2,3,4-tetrahydronaphthalene, XII in 74.3$ yield. The overall yield for the nine-step preparation of 3-(4-bromobutyl)-4-methylphenol, X, from resorclnol, I, was 17$.

Preparation of 2-(4-Bromobutyl)-4- methylpfcenol, XVIII (Figure IV) The Priedel-Crafts condensation of succinic anhydride with p-cresol afforded the keto acid, XIV in 52.1$ yield. Clemmensen reduction of XIV yielded the butyric acid, XV (93$), which was then esterified with methanol to produce the methyl ester, XVI in 92$ yield. Treatment of the alcohol, XVII with 48$ hydro bromic acid in sym.-tetrachloroebhane gave the corresponding bromide XVIII in 96$ yield. As was the case in attempting to synthesize 3-(4-bromobutyl)-4-methylphenol, X, from the corresponding alcohol, IX, when XVII was refluxed 35

O H O H O 11 Succinic C - (CH^CC^H anhydride 2n. HCl AICI3 toluene t«trachloro«than«

XIV

OH OH (CH2)3-CO2H0 ICH2)3C02CH3 CH,OH, W LiAlH, CHCU 2 c CHr

XV XVI

OH OH lCH ) CHOH (CH ) CH Br 2 3 23 2 48%H8r»

Figure IV 26 with constant boiling hydrobromic acid in sym.- tetrachloroethane and glacial acetic acid, the bromide XVIII was not formed. Rather an 82.1$ yield of XII resulted.

Cyclization Reactions

A) Treatment of 5-(4-Bromobutyl)-4-methylphenol, X, with Sodium Methoxide Two possible routes by which X might cyclize under the influence of base are shown on Figure V. When X was added to refluxing methanolic sodium methoxide, an 83.4$ yield of XII was obtained. No carbonyl compounds were isolated nor was there any evidence for dienone formation in the infrared spectrum of the reaction product.

B) Treatment of 3-(4-Bromobubyl)-4-methylphenol, X, with Sodamide in Liquid Ammonia It was hoped that the formation of the dienone, XIX, the less stable of the possible products might be achieved by carrying out the cyclization reaction at a low temperature. However, when X was reacted with sodium amide in liquid ammonia at -70 C for twenty-four hours, again the Br OH ° >8 H CH.

CH- CH. CH- CH CH. 3

XII

O H base o (CH2)3CH2Br (CH2)3CH2Br

CH.

CH -^ CH, 2 XIX Br / "CH5

Figur* V 28 tetralol, XII, (81.8$) was the only reaction product formed. Infrared analysis of the reaction product again gave no evidence for the presence of dienone.

C) Treatment of 2-(4-Bromobutyl)--4-methylphenol, XVIII, with Sodium Methoxlde The bromide, XVIII, is also capable of undergoing base^induced cyclization via two paths as shown on Figure VI. When XVIII was heated with methanol!c sodium methoxlde, 7-methyl-2,3,4, 5-tetrahydro-l-benzoxepin, XX (87.3$) was the only reaction product formed. The infrared spectra showed no absorption in the hydroxyl or in the carbonyl region. In addition the band at 6.2H , characteristic of the starting phenol and tetralol, XII, was absent.

D) Treatment of 2-( 4-Bromobutyl)-4-methylphenol, XVIII in Liquid Ammonia Reaction of XVIII with sodium amide or lithium amide in liquid ammonia for twenty-four hours, yielded the cyclic ether, XX, the sole product, in yields of 83.1$ and 85.6$ yields respectively. CHp — CH2 \ Br £ CH,

CH,

O H

(CH2)3CH2Br

Figure VI 30 Synthesis of l,8-Dioxo-4-methyl-l,2, 5, 5,6, 7,8, 8a- octahydronaphthalene, XXII When the l,6-dioxo-8a-methyl-l,2,3,4, 6,7,8, 8a- octahydronaphthalene, IV, was refluxed with about a ten-fold excess of 10$ sodium methoxide in absolute methanol under anhydrous conditions, a novel trans- 2 acyclation reaction (see Figure VII) occurred to produce the 1,8-dione, XXII in 9 3.4$ yield, along with a small amount of 4-methyl-8-oxo-4,5, 6,7-tetrahydro- 1-naphthol, XXIII. If only a stoichiometric amount of methanolic sodium methoxide were exmployed, the keto ester, VI, was formed in 97.8/'° yield. However, if VI were treated with a ten-fold excess of methanolic sodium methoxide under anhydrous conditions, the 1,8-dione, XXII, was produced in 92.8$ yield. That the keto ester, VI, forms when a stoichiometric amount of base is used, even though the base is not consumed In the reaction indicates that at lower con centrations of base, the rate of cyclization reaction

The keto acid V was formed if anhydrous conditions were not strictly maintained. 2 To the best of our knowledge, this Is the first example of an intramolecular transacylation reaction to be reported. SI

NQOCH3 ^ S~^fe ^_ CH30H T^-^A ~ V (CH2)3C0^H3 0

IV Via C^O^ CHjf "2

CH.

XXII b

XXil

XXII a

Figur* VII 52-33 is too low to accomodate the transformation to the 1,8-diketone, XXII, in the short reaction times employed. No studies were made involving longer reaction times. The 1,8-dione, XXII, gave a positive ferric chloride test and readily formed a light-tan copper chelate. The presence of <*. , & -unsaturated carbonyl group and of an enolic grouping was shown by infrared absorption peaks at 6.04/< and at 6.20/* (see Figure XI). The nuclear magnetic resonance spectrum of XXII showed that no olefinic hydrogen atoms were present and that the molecule definitely contained allylic hydrogen atoms (8.26T). Also present in nuclear magnetic resonance spectrum was an assymetric peak at 7.65f, which corresponds to a ring diene allylic methylene amoiety and a ring keto methylene grouping. The presence of a hydrogen-bonded hydroxyl group was indicated by a peak at -5.18T# The structure of XXII was established by the reaction sequence shown in Ficure VIII. Compound XXII

xThe nuclear magnetic resonance spectrum of XXII was kindly run and interpreted by Dr. G. V. D. Tiers, Minneapolis, Mining and Manufacturing Company, St. Paul, Minnesota. CH. CH,

LiAlH. Pd

220

O O O. O XXII XXIV

CH,

W.K.

CH Mgl O p ^H- XXIII

CH. CH. Pd-C olo.

CH, O O CH- ^H •••

XXIV XXV

Figure VIII 35 was reduced with lithium aluminum hydride to give a compound, XXIV, whose infrared spectrum, Indicated the presence of an <=*, (^ -unsaturated carbonyl group

(6.0M) as well as a hydroxyl group (2.96/w). Compound XXIV was dehydrated with palladium on charcoal at 220-230° to produce oC -methylnaphthalene XXV in 82.5$ yield. The identity of XXV was confirmed by mixed melting point determination of the picrate of XXV and the authentic material. When XXII was heated in xylene, a 19.3$ yield of 4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene, XXIII, was produced. Compound XXIII was then subjected to a Wolff-Kishner reduction to yield 4-methyl-5,6,7,8- tetrahydro-1-naphthol, XII in 81$ yield. The powder diffraction pattern and a mixed melting point determin ation between XII and the authentic material. It was of interest next to attempt to determine the direction of enolization in XXII (see Figure VII). Due to the near-equivalence of the enolic forms, XXIIa and XXIIb, it was impossible to distinguish between them by means of nuclear magnetic resonance spectra, although the NMR spectra did corrobrate the other features of the molecule, XXII. It was felt that if a solution of XXII were added to an excess of methyl 36 magnesium iodide that the raagnesium salt of the favored enolic form, if any, would undergo carbonyl addition with the G-rignard reagent without effecting the equilibrium between the two enolic forms. Upon carrying out the reaction, there was obtained an 89.2$ yield of a product, XXIV, which upon heating with palladium on charcoal to 220-230° for three hours gave 1,4-dimethylnaphthalene XXVI in 43$ yield. No 1,5-dimethylnaphthalene was isolated. Hence the Grignard addition product XXIV was undoubtedly 1-keto- 4,8-dimethyl-8-hydroxy 1,2,3,4,6,7,8,8a-octahydronaptha lene. On the basis of the reactions, structure XXIIb was assigned to the 1,8-dione. 37

Attempted Cyclization of Methyl 5-Hydroxy-2- methylphenyl)-butyrate In hope of carrying out a cyclization analogous to that which occured when the keto ester, VI was refluxed with excess methanolic sodium methoxide (Figure VII) the phenol ester, XI was also heated with methanolic sodium methoxide for five hours. Only starting compound, XI was recovered. It is quite possible that indeed a reaction does occur under these conditions to yield the diendione, XIX, which then undergoes methoxide ion attack at the carbonyl carbon to regenerate the starting phenol ester, XI (Figure IX). 3*

(b)_CH 3 Na OCH- 3 (b) CH3OH HO"^^(CI {CH^3C°2CH3 ©° XI XIX

(a)

CH. CH,

H —O

XXIII

CH- O X!

O ^^J^^ lc H 2)3 C 02C H3 XIX

Figur* IX SUGGESTIONS FOR FURTHER WORK

The mere presentation of the results obtained in this work would be incomplete without setting forth some problems suggested during the course of the research. 1. The s tudies on the base-induced cyclization reac ti ohs o"f~ g'-^arTd"o^-t 4-br omo butyl) - 4-methylphenol should be extended to include molecules possessing leaving groups other than bromide. Possible groups are: benzenesulfonates, alkanesulfonates, iodide and acetate.

CCHZ)3CH2-* &

It is possible that by varying the leaving groups that the path by which the cyclization occurs might be alt ere d (c.f. FIgur e ~I)• 2. It would be of interest to study the effect of different cations on the direction in which cyclization occurs. For example, treatment of 3-(4-bromobutyl)- 4-methylphenol with lithium or potassium methoxide might possibly lead to the formation of the cyclohexadienone, XIX*, rather than the tetralol, XII, which derives from

39 40 treatment with methanolic sodium methoxide. 3. A further study should be made on the effect of varying the temperature and solvent on the direction of the base-induced cyclization reaction. 4. An attempt should also be made to isolate the solid metal salt of the phenol and then heat the salt in an inert solvent. 5. A study of the reaction between the phenols and silver trifluoroacetate in an inert solvent also might provide interesting results. This work would extend the scope of the studies to include a reaction under neutral conditions. The reaction in addition would be expected to proceed via an Sjjl mechanism (all the cyclization reactions reported herein have followed a SN2 mechanism). 6. Further study should also be directed toward the formation of 5-hydroxy-0-methyl-l, 2,3,4-tetrahydronaphthalene, XII, which is formed when 2- and 3-(4- hydroxybutyl)-4-methylphenol are treated with 48$ hydrobromic and in tetrachloroethane and glacial acetic acid. It is not clear whether the acetic acid is influenc ing the reaction by allowing for the intermediate forma tion of the corresponding acetate or by a solution effect. 41 It would be desireable therefore to preform the acetates and then reflux them with hydrobromic acid in sym.-tetrachloroethane. 7. 4-Bromobutyl-2-naphthol (or a molecule with a different leaving group) upon treatment with base would also be expected to undergo a cyclization reaction.

8. Application of the base-induced cyclization reactions to suitably substituted phenaiathrols and anthrols couls also supply interesting results to the elaboration of steroids. EXPERIMENTAL

General Procedures All melting points, unless otherwise noted, were taken in a Hershberg apparatus with total immersion thermometers calibrated by the National Bureau of Standards. X-ray powder diffraction patterns were taken with a camera of 360 mm. circumference, using copper radia tion and exposure time of three hours. Because the emphasis was on .obtaining pure material, the yields after purification frequently have little relationship to the maximum obtainable yield and are therefore omitted. Microanalyses were by Gabraith Microanalytical Laboratories, Knoxville, Term.• The phrase "treated in the usual manner" used throughout this section means that the organic solvent layer was washed successively with water and saturated sodium chloride solution, filtered through anhydrous magnesium sulfate, and the solvent distilled under reduced pressure. The term ether-benzene refers to a 1:1 mixture (by volume) of diethyl ether and benzene.

42 43

2-Methyl-l, 3-cyclohexanedione, III A freshly prepared solution of 432 g. (10.8 moles) of sodium hydroxide, 1500 ml. of water and 990 g. (9.0 moles) of resorcinol was placed in a 31. hydrogenation bomb together with 180 g. of finely powdered Raney nickel catalyst. The hydrogenation was carried out under 1800 lbs. of hydrogen for twelve hours without the application of external heating. The temperature was adjusted to 50° and the reaction was continued until a total of 9.0 moles of hydrogen has been absorbed. After cooling to room temperature, the catalyst was removed by filtration and washed with two 200 ml. portions of water. The filtrate and washings were transferred to a 51. round-bottomed flask and treated with 150 ml. of concentrated hydrochloric acid (for partial neutralization), 650 ml. of dioxane and 1500 g. (9.5 moles) of methyl iodide. The reaction mixture was refluxed for fourteen hours, allowed to cool, and the dione which crystallized was collected by filtration. The mother liquors were concentrated in vacuo to one-half of the original volume and then cooled in an ice-3alt

Org. Synthesis, Coll. Vol. 3, 181 (1955). 44 bath to yield additional dione. The total yield of the dione, III m.p. 200-203° (d) was 700 g. {61%),

4-Diethylamino-5-butanone To 115 g. (1.08 moles) of diethylamine, 100 g. 1 (1.17 moles) of methyl vinyl ketone was added dropwise with stirring over a one hour period, maintaining the temperature of the reaction mixture below 0° by means of an ice-salt bath. After the addition was compile ted, the cooling bath was removed and the stirring was con tinued for seven hours, while the temperature was allowed to rise to 25-30 . The reaction mixture was fractionally distilled throurh a ten inch packed column tipped with a total condensation partial take off head to yield 150 g. (73$) of colorless 4-diethylamine-2-butanone, b.p. 69-73° (16 mm.). Redistillation of the liquid collected in the dry ice-acetone trap yielded 31 g. more of bhe desired Mannich Base. The total yield was 181 g. (88$).

1,6-Dioxo-8a-methyl-l,2,3,4,6,7,8,8a- octahydronaphthalene, IV A mixture of 100 g. (1.6 moles) of 2-methyl-l,3- cyclohexanedione, III, 40 ml. of triethylamine, 135 g.

The methyl vinyl ketone (technical grade) was used as supplied by Mabheson, Coleman and Bell. 45

(0.95 moles) of 4-diethylamino-3-butanone and 750 ml. of benzene was refluxed on a steam bath for eighteen hours, 30 ml. of water being separated during the course of the reaction by means of a phase-separating head. During the last three hours 250 ml. of benzene was distilled. The dark reaction mixture was cooled to room temperature and washed with 800 ml. of 10$ hydrochloric acid and then treated in the usual manner. Distillation of the dark-red oil gave 106 g. of a light-yellow oil, b.p. 109-115° (0.05 mm.) and 15 g. of a higher boiling fraction, b.p. 115-150° (0.05 mm.). The lower boiling fraction was cooled in ice until it solidified, triturated with about 40 ml. of either and filtered to give 66 g. of crystalline IV, m.p. 47-48°. An additional 13 g. of IV was obtained by diluting the either filtrate with petroleum ether (b.p. 30-60°) and cooling in ice. An additional 14.1 g. of diketone was obtained from this filtrate by means of oximation. The total yield of IV was 93.1 g. (66$). A sample of IV, m.p. 47-48° (w. dec), obtained after two recrystallizations from ether exhibited a U. V. spectrum with log-,Q 4.20 and an I. R. spectrum that showed two carbonyl absorptions at 5.82 and 5.98/V . 46 Oximation of IV The residual yellow oil (30 g.) from the crystalli zation of III in the above experiment, as well as higher boiling fraction, b.p. 115-140 (0.05mm.) was dissolved in 90 ml. of ethanol and heated on a steam bath for one hour with a mixture of 32 g. of hydroxylamine hydro chloride in 85 ml. of water and 80 ml. of 20% sodium hydroxide solution. After cooling, 21 g. of the crystalline dioxime of the diketone, m.p. 199-202° was collected by filtration. Regeneration of IV from its Dioxime A mixture of 21 g. dioxime, 42 ml. of glacial acetic acid, 85 ml. of water, and 29 g. of pyruvic acid was refluxed for three and one-half hours and diluted with 175 ml. of water. After neutralization with 110 g. of sodium bicarbonate, the solution was extracted with two 60 ml. portions of ether. The water layer was saturated with sodium chloride and extracted with ether again. The combined ether extracts were treated in the usual manner. Cooling of the concentrated ethereal solution afforded 10 g. of the crystalline diketone, m.p. 47-48°. The ether filtrate was freed of ether and the residual liquid distilled at 109-115° (0.05 mm.) to give 7 g. of a yellow oil from which 4.1 g. of IV m.p. 47-48° was obtained by crystallization. The total yield of IV obtained from the dioxime was 14.1 g. (10$). 47

X"(6-M6thyl-5-keto-l-cyclohexen-l-yl)- butyric Acid, V« A mixture of 51.30 g. (0.507 moles) of IV, 110 ml. of 10$ sodium hydroxide (0.307 moles) and 120 ml. of ethanol was allowed to stand at room temperature for thirty minutes, heated on a steam bath for twenty minutes, cooled, diluted with 250 ml. of water and acidified with 6N hydrochloric acid. The solution was extracted with ether-benaene and the organic layer treated in the usual manner. Upon concentration of the solution, there was obtained 51.72 g. (91$) of V, m.p. 77,5-78°.

Methyl ^-(S-Methyl-S-keto-l- cyclohexen-1-yl) butyrate, VI

A) A mixture of 57.0 g. (0.324 moles) IV 40 ml. of methanol (1.00 moles), 150 ml. of methylene chloride and 2 ml. of concentrated sulfuric acid was refluxed for twenty-four hours. The solution was then neutralized with potassium bicarbonate, and, after cooling, was filtered. The filtrate was diluted with 75 ml. of water 48 and the organic layer was separated. The aqueous fraction was extracted with ether-benzene, the combined organic fraction washed with 10% potassium bicarbonate solution and then treated in the usual manner. Upon distillation, 59.7 g. (96$) of VI, b.p. 124-126 (1 mm.) was obtained as a yellow mobile oil. The basic aqueous fraction was neutralized with hydrochloric acid, extracted with ether-benzene and the combined organic fractions treated in the usual manner. Concentration of the organic solution yielded 0.356 g. (2%) of the starting keto acid, V.

B) A mixture of 17.8 g. (0.1 moles) of IV in 100 ml. of absolute methanol was refluxed under a nitrogen atmosphere for four hours. The reaction mixture was allowed to cool and extracted with ether-benzene. The combined organic fraction was then treated in the usual manner. Distillation yielded 19.3 g. (97.8$) of VI, b.p. 124-127 (1 mm.).

•^Absolute methanol was prepared by refluxing 5 1. of analytical grade methanol with 12 g. sodium and 92 g. of dimethylphthalate. The dry methanol was then fraction ally distilled through a ten inch packed column topped with a total condensation partial take-off head. 49 Methyl *y-(3-Acetoxy-6-methyl-l,3- cyclohexadien-1-yl) butyrate, VII A mixture of 61.6 g. (0.3 moles) of VII, 325 ml. of isopropenyl acetate and 2 ml. of concentrated sulfuric acid was placed in a one-liter flask, fitted with a ten inch packed column, topped with a total condensation, partial take-off head and allowed to reflux until all of the acetone formed had been distilled (approximately ten hours). The mixture was then neutralized with sodium bicarbonate, and the excess isopropenyl acetate was removed by distillation. The residue was taken up in ether-benzene and treated in the usual manner. Distillation in vacuo yielded 68.5 g. (87.4$) of the enol acetate, VII, b.p. 131-135° (1 mm,)• Anal. Calc'd for C, „H 0 : C, 66.7; H, 7.9 14 2Ort0 4 Pound: C, 66.4; H, 7*4

All of the NBS was converted to succinimide (detected by virtue of the fact that succinimide floats in carbon tetrachloride, whereas NBS remains at the bottom of the solution) (two hours), at which point, 100 ml. of collidine was added. The reaction mixture was then stirred with refluxing for four hours, cooled, and then 50 neutralized to litmus with hydrochloric acid. The organic layer was separated, and the aqueous layer extracted with ether-benzene. The combined organic fractions were treated in the usual manner. Distilla te-0*1 in vacuo afforded 52.6 g. (76.8$) of VIII, b.p. 145-150° (1 mm.).

Anal. Calc »d for C14EL804: C, 67.2; H, 7.2 Pound: C, 67.6; H, 7.0

Methyl ^-( 5-hydroxy-2-methylphenyl) - butyrate, XI A solution of 16.8 g. (0.067 moles) of (VII) in 75 ml. of methanol was heated on a steam bath with 50 ml. of 3M hydrochloric acid. The reaction mixture was extracted with ether-benzene and the combined organic extracts treated in the usual manner. Distilla tion yielded 12.6 g. of an oil, b.p. 115-116° (0.4 mm.) which completely solidified on standing to give XI as a white powder. Crystallization from petroleum ether (b.p. 30-60°) gave 11.6 g. (83%) of pure phenol, m.p. 81-82°.

H Anal. Calc»d for C12 14°3S C, 69.2; H, 7.7 Pound: C, 69.6; H, 7.4 51

Distillation in vacuo of the mother liquors yielded 2.0 g. of starting material b.p. 143-150° (1 mm.)•

Action of Sodium Methoxide on Methyl X~(5-hydroxy-2-methylphenyl) butyrate, XI To a solution of 0.81 g. (0.004 moles) of the phenol, XI, in 15 ml. of methanol, was added 25 ml. of 1.6 M sodium methoxide in methanol and the mixture refluxed for five hours. The reaction mixture was neutralized to litmus with dry hydrogen chloride gas, dried over magnesium sulfate and distilled in vacuo to give 0.72 g. (88$) of the starting material. g- ( 4-hydroxybutyl)~ 4-methylphenol, IX A solution of 47.4 (0.192 moles) of VIII in 150 ml. of anhydrous ether was added dropwise over a one hour period to a solution of 25 g. (0.735 moles) of lithium aluminum hydride in 1 1. of anhydrous either. The reaction mixture was stirred for four hours and the excess hydride was then destroyed by addition of approximately 200 ml. of wet ether, followed by dilute hydrochloric acid to dissolve the aluminum salts. The organic layer was separated, the aqueous layer extracted with ether and the combined organic fractions worked up 52 in the usual manner. Upon concentia tion of the ethereal solution, there was obtained 29.55 g. (86.4$) of IX. Recrystallization from ethanol gave the pure alcohol, m.p. 87-88°.

Anal. Calc»d for C11H1602: C, 73.20} H, 8.88 Pound: C, 73.00; H, 8.74

5-(4-Bromobutyl)-4-me thylphenol, X A mixture of 8.00 g. (0.044 moles) of the alcohol, IX, 100 ml. of redistilled sym-tetrachloroethane and 100 ml. of 48 % hydrqbromic acid was refluxed for two hours. After cooling the reaction mixture, the organic layer was separated and the aqueous fraction extracted with 1:1 chloroform ether. The combined organic extracts were washed with potassium carbonate solution and then treated in the usual manner. Distillation in vacuo afforded 8.91 g. (82.5$) of the desired bromide, X, b.p. 142-143° (1 mm.).

Anal. CalcM for Ci:LHx5Br: C, 54.3; H, 6.2 Pound: C, 54.2; H, 5.9

Attempted Synthesis of 5-(4-Bromobutyl)-4-methylphenol, X, Employing Glacial Acetic Acid A mixture of 5.01 g. (0.028 moles) of the alcohol IX, 60 ml. of redistilled sym.-tetrachloroethane, 60 ml. of 53 48$> hydrobromic acid and 60 ml. of glacial acetic acid was refluxed for four hours. After cooling the mixture, the organic layer was separated and the aqueous layer extracted with 1:1 chloroform ether. The combined organic extracts were washed with potassium carbonate solution and then treated in the usual manner. Distillation of the organie layer in vacuo afforded 3.82 g. of 5-hydroxy-8-methyl-1,2,3,4,-tetrahydronaphthalene, XII, b.p. 107-111° (0.5mm.) which when recrystallized from petroleum ether (b.p. 30-60°) gave 3.37 g. (74.3^) white crystals, m.p. 87-88°. The identity of XII was proven by comparison of the X-ray powder diffraction pattern with authentic sample as well as by a mixed-melting point determina tion.

Anal. Calc'd for C-QH^O: C, 81.5; H, 8.6 Found: C, 81.8j H, 8.9

Base-Induced Cycllzation of 3-(4-Bromobutyl)-4-methylphenol, X

A.) Action of Methanollc Sodium Methoxide To a solution of 1.1 g. (0.0045 moles) of X in

R. B. Woodward and T. Singh, J. Amer. Chem. Soc, 72, 494 (1950). 54 absolute methanol was added 60 ml. of 10$ sodium methoxide (0.1 moles) in absolute methanol and the mixture was refluxed for four hours. After cooling, the solution was extracted with ether-benzene, and the organic layer treated in the usual manner. The alkaline extract of the reaction mixture was then neutralized with dry hydrogen chloride gas, dried over magnesium sulfate and distilled in vacuo to give a light-yellow oil, b.p. 107-109° (0.5 mm.) which solidified to give white crystals. Upon recrystallization from petroleum ether, (b.p. 30-60°), 0.41 g. (67.2$) of XII, m.p. 87-88° was obtained. No depression in melting point was observed upon admixture of the material with authentic tetralol. A higher boiling fraction, b.p. 131-133 (0.5 mm.) afforded 0.178 g. (1.62$) of starting material, X.

B) Action of Sodium Amide in Liquid Ammonia A solution of 1.15 g. (0.0048 moles) of X in 15 ml. of dry ether was added to 3.90 g. (0.10 moles) of sodium amide in 75 ml. of liquid ammonia and the reaction mixture stirred for twenty-four hours. A 100 ml. portion

Absolute methanol was prepared by refluxing 5 1. of analytical grade methanol with 12 g. sodium and 92 g. of dimethlphthalate. The dry methanol was then fractionally distilled through a 10 inch packed column topped with a total condensation partial take-off head. 55 of ether was added and the ammonia allowed to evaporate. The solution was extracted with ether-benzene and the organic layer treated in the usual manner. No neutral fraction was obtained. The reaction mixture was then neutralized with dry hydrogen chloride gas, dried over magnesium sulfate and distilled in vacuo to give a light-yellow oil, b.p. 114-118° (1.0 mm.) which solidified to give 0.532 g. of white crystals, m.p. 84-87°. Upon recrystallization from petroleum ether (b.p. 30-60°), 0.504 g. (81.8$) of XII, m.p. 87-88 was obtained. Admixture of the compound with authentic material gave no d epression in melting point.

p-(2-hydroxy~5-niethylbenzoyl) propionic acid, XIV To a stirred solution of 100 g. (QS25 moles) of p-cresol and 100 g. (1 moles) of succinic anhydride in 1 1. of redistilled sym.-tetrachloroethane at 55°0 was gradually added 268 g. (2 moles) of aluminum chloride over a period of three hours. After most of the aluminum chloride had been added, a solid began to separate from the red solution and stirring became difficult. When the addition was completed, the bath temperature was raised 56 to 135 and the reaction mixture heated for two and one-half hours. The mixture became fluid and black, evolved hydrogen chloride gas and then set to a solid mass. The reaction mixture was cooled and poured over ice and hydrochloric acid and the solvent removed by steam distillation. The solid keto acid was dissolved in warm 10$ sodium hydroxide solution, clarified with activated charcoal, reacidified with hydrochloric acid and then collected by filtration to give 99.2 g. of material, m.p. 134-136.5°. Reerystallization from benzene yielded 94.76 g. (52.1$) of the acid, m.p. 136-137°. Anal. Calc'd for CL-H^gO^ C, 68.8; H, 6.3 Pound: C, 68,7; H, 6.0

y-(2-Hydroxy-5-me thyphenyl) butyric acid, XV To a mixture of amalgamated zinc (prepared from 200 g. of mossy zinc, 15 g. of mercuric oxide and 15 ml. of concentrated hydrochloric acid)> 150 ml. of water, 350 ml. of concentrated hydrochloric acid, 50 ml. of glacial acetic acid, and 225 ml. of toluene was added 92 g. (0.5 moles) of the keto acid, (XII). The reaction mixture was refluxed briskly for thirty hours, during 57 which time, a 100 ml. portion of concentrated hydro chloric acid was added every six hours. The solution was cooled to room temperature and the aqueous layer separated, diluted with 200 ml. of water and extracted with ether-benzene. The combined organic solutions were treated in the usual manner. Distillation in vacuo gave 83.5 g. of the butyric acid, which was obtained as a colorless oil that solidified to give 84.5 g. of white crystals, m.p. 85-88° (uncorr.). Recrystallization from toluene yielded 80.0 g. (93$) of XV, m.p. 88-89°.1 Anal. CalcM for c;n%403: c> 74.0; H, 7.9 Pound: C, 73.8; H, 7.7

Methyl- ^-(2-hydroxy-5-methylphenyl) butyrate, XVI A mixture of 78.0 g. (0.424 moles) of the butyric acid, XV, 50 m.l. (1.33 moles) of methanol, 200 ml. of methylene chloride and 2 ml. of concentrated sulfuric acid was refluxed for twenty-four hours and then neutralized with sodium bicarbonate. After cooling, the

-———r i •* - ~ — — r - r - • *nn * • ~ m ' • " •" i •» i • r i • • m 11 i 11 i m - • n -* i n n n rr — r 1R. B. Woodward and T. Singh, J. Am. Chem. Soc.,72, (1950) report a m.p. of 88-89° for XV. 58 solution was filtered, the filtrate diluted with 75 ml. of water and the organic layer separated. The aqueous fraction was extracted with ether-benzene, the combined fractions washed with 10$ potassium bicarbonate solution and the original layer treated in the usual manner. Upon distillation in vacuo, 77.2 g. (92$) of XVI, b.p. 123-124 (0.5 mm.) was obtained as a yellow mobile oil. The oil was reacted without further purification with lithium aluminum hydride (see next paragraph).

2-(4-Hydroxybutyl) - 4- methylphenol, XVIII A 3D lution of 104 g. (0.562 moles) of XV in 175 ml, of dry ether was added dropwise over a one hour period to a solution of 32 g. (1.13 moles) of lithium aluminum hydride in 850 ml. of anhydrous ether. The reaction mixture was stirred for four hours and then the excess hydride was destroyed by addition of wet ether, followed by dilute hydrochloric acid to dissolved the aluminum salts. The organic layer was separated, the aqueous layer extracted with ether and the combinated organic fractions treated in the usual manner. Upon concentration of the ethereal solution, there was obtained 83.01 g. (95.3$) of XVII. 59

Recrystallization from ethanol afforded white crystals, m.p. 82-83°.

Anal. Calc'd for C11Hi602: C, 73.0; H, 8.9 Pound: C, 73.2; H, 8.7

2-(4-Bromobutyl)-4-methylphenol A mixture of 10 g. (0.056 moles) of the alcohol, XVII, 100 ml. of redistilled sym.-tetrachlorethane and 100 ml. of 48$ hydrobromic acid was refluxed for two hours. After cooling the mixture, the organic layer was separated and the aqueous layer extracted 1:1 chloroform-ether. The combined organic extracts were washed with potassium carbonate solution and then treated in the usual manner. Distillation in vacuo afforded 13.06 g. (96$) of the desired bromide, XVIII, b.p. 134-135° (1 mm.). Anal. Calc'd for C^H^OBr: C, 54.3; H, 6.2 Found: C, 54.5; H, 6.2

Attempted Synthesis of 2-(4-Bromobutyl)- 4-methylphenol, Employing Glacial Acetic Acid A mixture of 5 g. (0.028 moles) of the alcohol, XVII, 60 ml. of redistilled sym.-tetrachloroethane, 60 ml. of 48$ hydrobromic acid and 60 ml. of glacial acid was refluxed for four hours. After cooling the 60 mixture, the organic layer was separated and the aqueous layer extracted with 1:1 chloroform-ether. The combined organic extracts were washed with potassium carbonate solution and the organic layer treated in the usual manner. Distillation In vacuo afforded a yellow-oil, b.p. 108-113 (0.5 mm.) which solidified to give 4.10 g. (82.1$) of a white solid. Recrystallization from petroleum ether (b.p. 30-60 ) gave 3.82 g. of white crystals, m.p. 87-88 . No depression was observed when a mixed melting point 1 was determined with authentic material. Comparison of the X-ray powder diffraction pattern with authentic sample were identical. Anal. Calc'd for C^H 0: C, 81.5; H, 8.6 Pound: C, 81.7; H, 8.9

Base-Induced Rearrangements of 2-(4-Bromobuty1)- 4-methylphenol,XVIII

A) Action of Methanolic Sodium Methoxide To a solution of 1.2 g. (0.005 moles of XVIII in

XR. B. Woodward and T. Singh, J. Am. Chem. Soc, 72 494 (1950). 61

5 ml. of absolute methanol1 was added 50 ml. of 10$ sodium methoxide (0.1 moles) in absolute methanol1 and the mixture refluxed for four hours. After cooling, the solution was extracted with ether- benzene and the organic extracts treated in the usual manner. Distillation in vacuo afforded 0.708 g. (87.3$) of XX, as light-yellow mobile oil, b.p. 84-85° (2 mm.). Anal. Calc'd for C IL 0: C, 81.5j H, 8*6 Pound: C, 81.3; H, 8.5

Acidification of the basic aqueous solution, followed by ether-benzene extraction afforded no organic material. The infrared spectrum (see Figure XIII), showed no absorption peaks in the regions associated with hydroxyl or carbonyl functions.

1 Ref. 1, p. 8, 62

B) Action of Sodium Amide in Liquid Ammonia A solution of 1,22 g. (0.005 moles) of XVIII in 15 ml. of dry ether was added to 3.90 g. (0.10 moles) of sodium amide in 75 ml. of liquid ammonia and the reaction mixture stirred for twenty-four hours. A 100 ml. portion of ether was added and the ammonia allowed to evaporate. The solution was extracted with ether-benzene and the organic layer treated in the usual manner. Distillation in vacuo afforded 0.678 g. (83.1$) of XX as a light-yellow mobile oil, b.p. 84-86°, (2 mm.). Anal. Calc'd for C-j^, 0: C, 81.5; H, 8.6 Pound: C, 81.4; H, 8.6

Acidification of the basic aqueous solution, followed by ether-benzene extraction afforded no organic material.

C) Action of Lithium Amide in Liquid Ammonia A solution of 1.21 g. (0.005 moles) of XVIII in 15 ml» of dry ether was added to 1.9 g. (0.1 moles) of lithium amide in 75 ml. of liquid ammonia and the reaction mixture stirred for twenty-four hours. A 100 ml. portion of ether was added and the ammonia allowed to evaporate. The solution was extracted with 63

ether-benzene and the organic layer treated in the usual manner. Distillation in vacuo afforded 0.695 g. (85.6$) of XX as a light-yellow mobile oil, b.p. 84-87 (2 mm.). Acidification of the basic aqueous solution, followed by ether-benzene extraction afforded no organic material.

1,8-Dioxo-4-methyl-l,2,5,5,6,7,8,8a- octahydronaphthalene, XXII

A) A mixture of 17.80 g. (0.1 moles) of the 1,6- 1,2 diketone, IV, in 100 ml. of absolute methanol and 178 ml. of 10$ sodium methoxide (3 moles) in absolute 1,2 methanol was refluxed under nitrogen for four hours. The reaction mixture was cooled, neutralized to litmus with dry gaseous hydrogen chloride and then treated in the usual manner. Distillation in vacuo yielded 16.63 g. (93.4$) of XXII, b.p. 105-106° (0.5 mm.) and 0.71 g. of

3-The keto acid was formed of anhydrous conditions were not maintained. 2Absolute methanol was prepared by refluxing 5 1. of analytical grade methanol with 12 g. sodium and 92 g. of dimethylphthalate. The dry methanol was then fractionally distilled through a 10 inch packed column topped with a total condensation partial take-off head. 64 8-keto-4-methyl-5,6,7,8~tetrahydro-l-naphthol, XVIII, b.p. 134-136° (0.5mm.). Anal. Calc'd for ^^^Q1 C> 74#2; H» 7#9 Pound: C, 73.9; H, 7.8

To a solution of 1 g. of XXII in 10 ml. ethanol was added 10 ml. of a saturated solution of cupric acetate. A few drops of ammonium hydroxide was added to facilitate precipitation of the copper chelate. The precipitate was filtered, and recrystallized from benzene to give light-tan crystals, m.p. 198-199°, Anal. Calc»d for C H 0 Cu: C, 63.2; H, 6.2 Pound: C, 63.4; H, 6.2

To a solution of 0.9 g. of XXII in 2 ml. of glacial acetic acid, was added 1 g. of 2,4-dinitrophenylhydrazone in 25 ml. glacial acetic acid and the mixture refluxed for forty-eight hours. The reaction mixture was cooled and evaporated to dryness by means of a water pump. The solid was taken up in benzene and passed through an alumina column, employing ether as the eluent. Concentration of the organic solution produced 1.6 g. of dark-red needles of the mono-2-4- dinitrophenylhydrazone, m.p. 213-214° (w. dec). 65

Anal. Calc»d for C,JH N 0 : C, 60.4; H, 5.3; N, 16.6 ———— i. I ig 4 5 Pound: C, 60.5; H, 5.2; N, 16.2

B) A mixture of 20.12 g. (0.1 moles) of the methyl ester (V) in 100 ml. of absolute methanol and 200 ml. of 5 sodium methoxide in absolute methanol was refluxed under nitrogen for four hours. The reaction mixture was cooled neutralized with dry, gaseous hydrogen chloride and treated in the usual manner. Distillation in vacuo yielded 16.52 g. (92.8$) of the 1,8-diketone (XXII), b.p. 105-106° (0.5 mm.).

4-Methyl-8-oxo-5,6,7,8-tetrahydro- 1-naphthol, XXIII A solution of 1.00 g. (.0056 moles) of the 1,8- diketone (XXII) in 50 ml. of xylene was refluxed for thirty-six hours. Distillation of the reaction mixture in vacuo yielded 0.18 g. (19.3$) of XXIII, b.p. 134-135° (0.5mm.) plus 0.78 g. (78.6$) of starting diketone, b.p. 105-106° (0.5mm.).

Anal. Calc'd for C1:LH1202: C, 75.0; H, 7.0 Pound: C, 74.8; H, 7.0

Subsequent runs did not always lead to the formation of XVIII. 66

Lithium Aluminum Hydride Reduction of XXII A solution of 10.68 g. (0.06 moles) of the 1,8-diketone, XXII, in 60 ml. of anhydrous ether was added dropwise with stirring over a period of one hour to a suspension of 3.36 g. (0.12 moles) of lithium aluminum hydride in 120 ml. of ether. After the addition was completed, the reaction mixture was stirred for four hours, and the excess hydride was then destroyed by the addition of wet ether, followed by dilute hydrochloric acid to dissolve the aluminum salts. The organic layer was separated, the aqueous layer extracted with ether and the combined fractions treated in the usual manner. Upon concentration of the ethereal solution there was obtained 7.20 g. (72.3$) of an oil, XXIV, b.p. 94-98 (0.15 mm.) which showed infrared absorption at 3D/f and 5.98 M • It is possible that this oil was 8-hydroxy-l-oxo-4-methyl-l,2,3,4,5,6,7,8- octahydronaphthalene, however, no attempt was made to purify it or determine the structure. The oil was immediately subjected to reaction with palladium on charcoal (see next paragraph). 67

4-Methyl-5,6,7,8-tetrahydro- 1-naphthol, XII A mixture of 0.44 g. (0.025 moles) of XXIII, 1.3 g. potassium hydrochloride, 3 g. of Q5% hydrazine mono- hydrate and 35 ml. of redistilled diethylene glycol (b.p. 137-138° (18mm.)) was heated. The distillate was removed until the solution temperature reached 196°. The solution was refluxed until the nitrogen evolution had decreased sharply (about four hours.).

xThe catalyst was supplied by Baker Catalyst Company. 2 G. Darzens, Comot. rend. 183 748 (1926) reports a m.p. of 141-142° for XXV. 68

The warm reaction mixture was poured on to 50 ml. of ice and 33 ml. of 6N hydrochloric acid. The mixture was then extracted with ether-benzene and the combined organic extracts treated in the usual manner* Concentration of the organic solution yielded 0.369 g. of the tetralol, XII. Recrystallization from petroleum ether (b.p. 30-60°) gave 0.328 g. (81$) of white crystals, m.p. 87.5-88.5 • The X-ray powder diffraction photograph of the tetralol was identical with that of authentic material.

l-Oxo-4,8-dimethyl-8-hydroxy- 1,2,5,4,6,7,8,8a-octahydronaphthalene, XXIV A solution of 9.4 g. (0.053 moles) of XVII in 75 ml. of dry ether was added dropwise with stirring over a period of one hour to 200 ml. of a solution of approx imately 1.25 M methyl magnesium iodide. The reaction mixture was refluxed with stirring for two hours, cooled, and then poured onto an ice-hydrochloric acid mixture. The mixture was extracted with ether-benzene and the combined organic fractions treated in the usual

•"•R. B. Woodward and T. Singh, J. Am. Chem. Soc, 72, (1950). 69 manner. Distillation in vacuo yielded 9.27g. (89.2$) of XXIV, b.p. 104-105° (1 mm.). The 2,4-dinitrophenylhydrazone of XXIV melted at 243-245° (w. dec).

Anal. Calc»d for C18N22N405: C, 56.5;H, 5.8; N, 16.3 Pound: C, 56.7;H, 5.7; N, 16.3

1,4-Dimethylnaphthalene XXVI To 9.2 g. (0.047 moles) in a 25 ml. Claisen flask, was added 50 mg. of palladium on charcoal and the mixture heated to 220-230° for four hours. The reaction mixture was then distilled in vacuo to yield 3.18 g. (43$) of 1,4-dimethylnaphthalene, b.p. 107-110 (1 mm.). 1,3,5,- trinitrobenzene addition compound, m»p. 165-166 ; picrate o 1 m.p. 143.5-144 • A mixed melting point determination of the picrate of XXVI with authentic material was employed to prove its identity. Anal. Calc'd for C^gH^: C, 92.3; H, 7.7 Pound: C, 92.2; H, 7.7

XM. C. Kloetzel, J. Am. Chem. Soc, 62, 1708 (1940) report a m.p. of 144° for the picrate olT'XXVI. SUMMARY

An improved synthesis of l,6-dioxo-8a-methyl- l,2,3,4,6,7,8,8a-octahydronaphthalene starting from resorcinol has been carried out in an overall yield of 41.5$, an increase of 20% over that of previous workers. Resorcinol was subjected to hydrogenation, followed by treatment with methyl iodide to yield 2-methyl-l,3-cyclohexanedione. The 1,3-dione was then condensed with 4-diethylamino-3-butanone to yield l,6-dioxo-8a-methyl-l,2,3,4?6,7,8,8a-octahydro- napthalene.

The 1,6-diketone was subsequently cleaved with sodium methoxide to produce methyl K-(6-methyl-3- keto-l-cyclohexen-l»yl) butyrate (97$). This ester was aromatized and the phenol ester was reduced with lithium aluminum hydride to yield 3-(4-hydroxybutyl)- 4-methylphenol. This alcohol was then treated with hydrobromic acid to yield 3-(4-bromobutyl)-4-methyl phenol.

The base-induced cyclization of 3-(4-bromobutyl)- 4-methylphenol was found to form 7-methyl-l,2,3,4,5- tetrahydro-1-benzoxepin (81-85$) under all conditions employed.

70 71 The preparation of 2-(4-bromobutyl)-4-methyl phenol was realized in an overall yield of 41.6$ from p-cresol. A Friedel-Crafts condensation of succinic anhydride with p-cresol afforded ^ -(2-hydroxy-5-methylbenzoyl) propionic acid, which upon Clemmensen reduction gave K'-C2-hydroxy-5-methylphenyl) butyric acid. The butyric acid was esterified and the ester treated with methylphenol. The alcohol was then treated with hydrobroraic acid to yield 2-(4-bromobutyl)-4-methyl phenol . The base-induced cyclization of 2-(4-bromobutyl)- 4-methylphenol was investigated under various conditions and found to give 4-methyl-5,6,7,8~tetrahydro-l- naphthol (82-87$). It was also observed that upon treatment with excess sodium methoxide in methanol that 1,6-dioxo- 8-methyl-l,2,3,4,6,7,8,8a- underwent a novel trans- acylablon reaction to yield, l,8-dioxo-4-methyl, l,2,3,5,6,7,8,8a-octahydronaphthalene (92$). The course of this reaction, as well as the properties of the 1,8-dione was investigated. 72 Infrared and nuclear magnetic resonance spectra showed that the 1,8-dione was completely enolized and indicated the presence of hydrogen-bonding. 1,8-Dioxo- 4-methyl-l,2,3,5,6,7,8a-octahydronaphthalene was treated with methyl magnesium iodide to give an oil, which upon heating with palladium on charcoal yielded 1,4-dimethylnaphthalene. These reactions indicate that the direction of enolization is as shown: WAVE NUMBERS IN CM ' BAIRD ATOMIC, INC WAVE NUMBERS IN CM1 5000 4000 2000 1300 1200 1100 900 800 1001—L

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4OHo <*3 AUTOBIOGRAPHY

I, Arlen B. Mekler, was born in New York City, New York, May 3, 1933. I received my secondary education in the public schools of Chicago, Illinois. After spending the first two years of my undergraduate training at Reed College, I transferred to San Jose State College, where I received the degree of Bachelor of Science in 1953. I received the degree Master of Science in 1955 from Iowa State College. In 1955, I entered the Graduate School of The Ohio State University. While completing the requirements for the degree Doctor of Philosophy, I held the following positions: Assistant in the Department of Chemistry, 1955-1956; Charles F. Kettering Foundation Fellow, 1956-1957; Melvin S. Newman Scholar, Summer 1957; U. S. Industrial Company Fellow, 19 58-1959; Allied Chemical Company Fellow, 1958-19 59; and E. I. du Pont de Nemours Fellow, Spring 1959.