Xerox University Microfilms, Ann Arbor, Michigan 48106

77-2404

GILBERT3 David Philip, 1949- THE SYNTHESIS OF 2,3-DISUBSTITUTED INDOLES.

The Ohio State University, Ph.D., 1976 Chemistry, organic

Xerox University Microfilms,Ann Arbor, Michigan 48106 THE SYNTHESIS OF 2,3-DISUBSTITUTED INDOLES

DISSERTATION

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

David P. G ilbert, B.S.

* * * *

The Ohio State University

1976

Reading Committee: Approved by

Professor Paul G. Gassman Professor John A. Secrist, III Professor John S. Swenton / <.2 cast? j Adviser Department of Chemistry To Cynthia ACKNOWLEDGMENTS

The author wishes to thank Dr. Paul G. Gassman for the ideas he has given during this project. His friendship, support, and suggestions have been greatly appreciated.

Special thanks also go to Mr. Richard C. Howard, who provided an early insight into science. The author also thanks his coworkers for their help and cooperation.

The author is especially grateful for the assistance and never ending encouragement of both his and his wife's families.

The author is continually amazed by his wife's love, assistance, patience, and sacrifice. Without Cynthia, this work would not have been possible.

iii VITA

May 1 , 1949 ...... Born, Schenectady, New York

1971 ...... B.S. in Chemistry, Hobart College

1971-1972 ...... Teaching A ssistant, The Ohio State University

1972-1974 ...... Research Assistant, The Ohio State University

1974-1976 ...... Research Assistant, University of Minnesota

PUBLICATIONS

P.G. Gassman, D.P. Gilbert, and T.J. van Bergen, Chem. Commun., 201 (1974).

P.G. Gassman, T.J. van Bergen, D.P. Gilbert, and B.W. Cue, J r ., J. Amer. Chem. Soo., 96, 5495 (1974). J.H.M. Hill, D.P. Gilbert, and A. Feldsott, J. Ovg. Chem., 40, 3735 (1975).

FIELDS OF STUDY

Major field : Organic Chemistry

iv TABLE OF CONTENTS

Section Page

ACKNOWLEDGMENTS------iii

VITA------iv

LIST OF TABLES------ix

INTRODUCTION------. — 1

RESULTS AND DISCUSSION------21

PART I. Synthesis of 2,3-Disubstituted Indoles ------21 PART II. Alkaloid Synthesis ------43

EXPERIMENTAL ------6 6

General Procedure for the Preparation of 2,3-Disubstituted

In d o le s ------6 6

3-Bromo-2-butanone (62)r\y\j ------67 3-Methylthio-2-butanone (53Ja) ------67

2 ,3-Dimethyl indole (61 b ) ------6 8 ^ OA/VU 2-Bromo-3-pentanone (63) ------69

2-Methylthio-3-pentanone (53^) ------70

2-Ethyl-3-methyl indole (61^) ------70

3-Bromo-2-pentanone (64) ------71

3-Methylthio-2-pentanone (53^d) ------72

3-Ethyl-2-methylindole (b^d) ------73

4-Methyl-3-methylthio-2-pentanone (53js) ------73

3-Isopropyl-2-methylindole (61^e) ------74

v Section Page

1-Chloro-1-phenyl-2-propanone ( 6 6 ) ------75

1 -Methyl thio-l -phenyl -2-propanone (53^) ------75

2-Methyl-3-phenylindole (5 H ) ------76

1-il/-Ani lino-1-methyl thi o-l-phenyl-2-propanone (72MO ------77

a-Methylthiopropiophenone (53^) ------78

3-Methyl-2-phenylindole (61^) ------78

a-Methylthiobutyrophenone (53Ji) ------78

3-Ethyl-2-phenyl indole (jBTJi) ------79

3-Methyl-2-phenylindole by Chlorine-Sulfide Complex (61^cj) ------80

3-Methylthio-3-buten-2-one (98 d) ------82

3-Ethyl-2-methyl indole by the Chlorine-Sulfide Complex (j51^d) — 82

Tetrahydrocarbazole (78) by the Chlorine-SulfideComplex ------83

2-Methyloxindole ( 6 8 ) ------85

Methyl 4-Methylthioacetoacetate (85^) ------85

Methyl 2-(3-Methyl thioindolyl)acetate ( 8 6 ^ ) ------87

Methyl 2-Indolylacetate (8£,j0 ------87

Ethyl 4-Methylthioacetoacetate (85Jb) ------8 8

Ethyl 2-(3-Methyl thioindolyl )acetate (8J5J)) ------8 8

Ethyl 2-Indolylacetate ( 8 ^ 0 ------89

Methyl 2-Methylacetoacetate ( 8 8 ) ------89

Methyl 2-Methyl-4-methylthioacetoacetate (89) ------90

Methyl a-Methyl-2-(3-methylthioindolyl)acetate (90) ------90

Methyl a-Methyl-2-indolylacetate (91^) ------91

vi Section Page

Ethyl 4-Methylthiobutyroacetate (92) ------91 'VO y-(l-Butenyl)pi peridine (111) ------92 VXAi 4-Formylcapronitrile (112) ------93 r\y\Aj 4-Formylcapronitrile-1,3-dioxolane (113) ------93 'WO

1-Benzyl-3-ethyl-1,4,5, 6 -tetrahydropyridine (114) ------94 'O'O'O l-Benzyl-4a-ethyl-2,3,4,4a,5,6,8,8a-octahydro-7(lH)-quinolone (1 0 4 )------94 'WO 4a-Ethyl-2,3,4,4a,5,6,8,8a-octahydro-7(lH)-quinolone (115) ------94 VIA) W-Ch1oroacetyl-4a-ethyl-2,3,4,4a,5,6,8,8a-octahydro-7(lH)-quinolone (116) ------95 o/vo

6 a-Ethy1-4,5, 6 , 6 a ,7,8,9a ,9b-octahydro-9H-pyrrolo[3,2,1-ij]-qui n- olin-2,9(lH)-dione (117) ------95 x ' ‘W O

6 a-Ethyl-l,2,4, 6 , 6 a,7,8,9a,9b-decahydro-9H-pyrrolo[3,2,1-ij]- quinolin-9-one (120) ------— 96 n m Ethylene Ketal of Methyl 4-Methyl thioacetoacetate (,124). ------97

Ethylene Ketal of 1-Methylthio-4-hydroxy-2-butanone (125) ------97 'WO

1-Methylthio-4-hydroxy-2-butanone (126)'WO ------98 1-Methylthio-3-buten-2-one (,123) ------99

1-Benzyl-4a-ethyl- 8 -methylthi o-2,3,4,4a,5,6, 8 ,8a-octahydro-7- (IH)-quinolone (105) ------100

4-Ethyl-2-methylthio-4-(N-benzyl-3-ami nopropyl)-2-cyclohexen-l - one (124) ------100 'WO 5-(N-carboethoxyamino)-2-ethylperitanal-l ,3-dioxalane (1^28) ------101

5-(N-Methyl ami no)-2-ethyl pentanal-1,3-dioxalane (1^29) ------102

1-Methyl=3-ethylrl,4,5, 6 -tetrahydropyridine (V30) ------103

vii Section Page

4a-Ethy1-1-methyl- 8 -methylthi o-2,3,4,4a,5, 6 ,8,8a-octahydro-7- (lH)-quinolone ) ------104

trans-8,10-Dimethyl-1(9)-octal-2-one (,134) ------104

8,10-Dimethyl-1-methylthio-2-decalone (,133) ------105

3-Methyl -2-methyl thiocyclohexanone (53^) ------106

Methyl 4-Methyl thi obutyroacetate (53^) ------107

General Procedure for the Preparation of Aniline Azasulfonium Salts for NMR Examination ------108

Preparation of the Aniline Azasulfonium Salt 54 b via the Chloro- sulfonium Salt of 53 b ------108 W\A;

LIST OF REFERENCES ------1 1 1

APPENDIX------118 LIST OF TABLES

Table Page

I. Yields of Indoles from a-Methylthioketones and Substi tuted Anilines 16

II. Yields of 2,3-Disubstituted Indoles (61 b-h) Based on Starting Aniline ------28

III. NMR Data of the Anil in -. Azasulfonium S a l t s ------61

IV. Experimental Conditions for the Preparation of Aniline Azasulfonium Salts ------109

ix INTRODUCTION

Organic chemists have long recognized the significance of carbonium ions (1) in modern organic chemistry. These trivalent electron defi- '1/ cient species and their reactions have been extensively studied under a

variety of conditions and applications. Surprisingly, the nitrogen ana logue of 1 , the nitrenium ion ( 2 ), was not extensively discussed until rO 'Xf Gassman began exploring the area in 1962.^ The nitrenium ion is a di valent, positively-charged nitrogen species which is isoelectronic with

1. P.G. Gassman, Aeeounts Chem. Res., 3, 26 (1970).

the carbonium ion. Gassman's systematic investigations have revealed the methods of generation, nature, reactions, and synthetic utility of dialkyl nitrenium ions.

Research in the area of nitrenium ions was not limited to aliphatic cases. Aryl nitrenium ions had been postulated as intermediates related

1 2 ? to the carcinogenic properties of aromatic amines and amides. The ni trenium ion is believed to induce carcinogenic behavior by reacting with nucleophilic centers in the nucleic acids within the cell nucleus.

2. J.A. Miller, Cancer Res., 3P> 559 (1970); J.D. Scribner and N.K. Naimy, ib id ., 3^, 1159 (19/3); E.C. Miller, B.W. Butler, T.L. Fletcher, and J.A. Miller, ib id ., 34, 2232 (1974); J.D. Scribner and N.K. Naimy, ib id ., £5, 1416 (19/5); J.D. Scribner and N.K. Naimy, Experientia, ^ , 470 (1975); J.D. Scribner and N.K. Naimy, Cancer Res., 1416 (1975).

In an effort to extend the concept of nitrenium ions, Gassman and

Campbell examined the reactions of y-chioroanilines. Solvolysis of y- tert-butyl-y-chloroaniline (3) in methanol afforded o- and p-chloroanilines. Addition of silver perchlorate to the solvolysis of 3 increased

Cl AgC1 0 4 OMe

CH3 OH 3 ) 3 NC(CH^) 'nc(ch 3'3 H H 4 28% 5 6 % 7 6 %

MeO the rate and changed the reaction products. The expected chloroanilines were observed, but the major products arose from the nucleophilic attack of the solvent on the delocalized nitrenium ion to form o- and p-anisi- 3 dines. Solvolysis of a series of para substituted N-tert-butyl-N- chloroanilines correlated well with a+ values and gave a p of -6.35.

3. P.G. Gassman, G.A. Campbell, and R.C. Frederick, J. Amer. Chem. Soc., (\y\j94, 3884 (1972).

NC(CFU), nc(ch 3 ) 3 nc(ch 3 ) 3 nc(ch 3 ) 3 Cl 3 3 /

R R = H, CcH 6 5 NC(CH3 ) 3

R = H R = H

4 + 5 l + MeO

This large negative p value indicated that a positive charge had been delocalized in the aromatic ring, and the positive charge indicated the 4 4 existence of an aryl nitrenium ion. Products 9 and'O 10 VO were derived via 3 solvent addition to the delocalized nitrenium ion intermediate.

4. P.G. Gassman and G.A. Campbell, J. Amer. Chem. Soo., 94, 3891 (1972). ^

A major extension of the nitrenium ion research was made when the formation of azasulfonium salt 11 was observed in the reaction of 3 and VO O;

+ ch 3 sch 3

c h 3 + CH3 dimethylsulfide. It was hoped that compounds similar to 1^ might be useful intermediates in aromatic nucleophilic substitution as well as provide stable intermediates for the y-chloroanilines. At that time,

r few reports of azasulfonium salts of type Tj 2 had appeared.

5. P.G. Gassman, G. Gruetzmacher, and R.H. Smith, Tetrahedron Lett., 497 (1972).

6 . a) R. Appel and W. Buchner, Angew Chem., 71, 701 (1959); b) R. Appel and W. Buchner, Chem. ~Ber. , 95, 849, 8%5, 2220 (1962); c) R. Appel, H.W. Falhaber, D. Hanssgen, and R. Schollhorn, ib id ., 99, 3108 (1966); d) C.R. Johnson, J.J. Rigau, M. Hoake, D.. McCants, J r ., J.E. Keiser, and A. Gertsema, Tetrahedron Lett., 3719 (1968); e) R.E. Cook, M.D. Glick, J.J. Rigau, C.R. Johnson, J. Amer. Chem. Soo., 93, 924 (1971); f) G.F. Whitfield, H.S. Beilan, D. Saika, and D. Swern, Tetrahedron Lett., 3543 (1970); g) H. Kise, G.F. Whit field , and D. Swern, ib id ., 1761 (1971 ); h) F. Knoll, M.-F. Miiller- Kalben, and R. Appel, Chem. Ber., K)4, 3716 (1971); i) E. Vi1s- maier and W. Spriigel, Justus Liebigs'1Ann. Chem., 747, 151 (1971). In comparison, there were numerous reports of sulfi1imines7 of type 8 5 13. Since the time of this publication, many additional publications OA, Q in this area have appeared. Azasulfonium sa lt 14 was thermalized in an

7. Other commonly used names are: sulfimides, sulfidimines, sulfi- mines, and iminosulfuranes.

8 . a) R3 = H, R. Appel, W. Buchner, and E. Guth, Justus Liebigs Ann. Chem., 618, 53 (1958); references 6 a), 6 b), 6 c); b) R3 = S02 Ts, F.G. ManrTand W.J. Pope, j. Chem. Soo., 1052 (1922); K.K. Anderson, W.H. Edwards, J.B. B iasotti, and R.A. Strecker, j . Org. Chem., 31, 2859 (1966); D. Hellwinkel and G. Fahrbach, Justus Liebigs Ann.^ Chem., 715, 6 8 (1968); K. Tsujihara, N. Furukawa, K. Oae, and S. Oae, BxiCC1. Chem.Soo. Japan., 42, 2631 (1969); reference 6 d); c) R3 = COR, D.S. Torbell and C. Weaver, J. Amer. Chem. Soo., 63, 2939 (1941); M.V. Likhosherstov, Zh. Obsheh. Khim., 17, 147&A 1947), C.A. 43, 172 (1949); references 6 f) , 6 g); d ) ^ 3 = C6 H5, P. Claus and W?vycudilik, Tetrahedron Lett., 3607 (1968); P. Claus and W. Vycudilik, Monatsh. Chem., 101, 396, 405 (1970); P. Claus, W. Vy- cudilik, and W. Rieder, ibicfY) 102, 1571 (1971); U. Lerch and J.G. Moffatt, J. Org. Chem., 36, 386^1971).

9. For leading references see: a) P.K. Claus, W.Reider, P. Hofbauer, and E. Vilsmaier, Tetrahedron, 31, 505 (1975); b) R.S. Glass and J.R. Duchek, J. Amer. Chem. Soo^\ 98, 965 (1976).

effort to regenerate the nitrenium ion. The products from the thermoly sis, 15 and 16, were obtained in yields of 58% and 32%, respectively. Further studies on this reaction, though not definitive, seemed to pre

clude the generation of a nitrenium ion intermediate.^

10. G. Gruetzmacher, Ph.D. Thesis,.The Ohio State University, 1974.

It was found that azasulfonium salt 11 reacted exothermically at 'V\. room temperature with aqueous sodium hydroxide to give T7 in 95% yield.

NaOH r 'CH2 SCH3 w _ 2 1 1 . Ra-Ni nc(ch 3 ) 3 H

The ortho-alkylated product T7 was readily reduced to the o-methylaniline

1^8 by stirring with W-2 Raney nickel in ethanol.^ This series of re actions effected a net ortho-alkylation of tf-*er£-butylaniline. The

11. R. Mozingo, Org. Synthesis, Coll. Vol. 3, 181 (1955).

reactions worked excellently for a series of anilines with para sub stituents, ranging from electron-donating to electron-withdrawing. The rearrangement of azasulfonium salt 1^1 to V7 is an example of a Sommelet-Hauser type rearrangement. Many examples of Sommelet-

1 2 1 ? Hauser rearrangements have been observed in ammonium, sulfonium, 14 15 sulfoxonium, and sulfilimine ylides. The rearrangement proceeds

12. a) M. Sommelet, C.R. Acad. Sci., Paris Ser. C, 205, 56 (1937); G.C. Jones and C.R. Hauser, J. Org. Chem., 27, 357^(1962); G.C. Jones, W.Q. Beard, and C.R. Hauser, ib id ., 119 (1963); b) For reviews see: H.J. Shrine, "Aromatic Rearrangements," Elsevier Publishing Co., New York, N.Y. (1967), pp. 316, and S.H. Pine, Org. React., T8 , 403 (1970).

13. C.R. Hauser, S.W. Kantor, and W.R. Brasen, . j. Amer. Chem. Soo., 75, 2660 (1953); A.W. Johnson and R.B. LaCount, ib id ., 83, 417 (196lT; Y. Hayashi and R. Oda, Tetrahedron Lett., 5381 (196$); J.E. Baldwin and W.F. Erickson, Chem. Commun., 359 (1971).

14. M.G. Burdon and J.G. Moffatt, J. Amer. Chem. Soo., 89, 4725 (1967); P. Claus, Monatsh. Chem., 102, 913 (1971). W \j 15. P. Claus and W. Rieder, Monatsh. Chem., 103, 1163 (1972); T.E. Varkey, G.F. Whitfield, and D. Swern, J.'x/tfrg. Chem., 39, 3365 (1974) references in 8 d) and 9a). ^

via an allowed [2.3]sigmatropic shift which alkylates the ortho-position of the aromatic ring. In the case at hand, proton abstraction from aza sulfonium salt 11'\y\j generates ■* the ylideJ 19. The ylide ^ attacks the ortho- position with subsequent formation of the dienone imine 20. Product T7 is obtained after a spontaneous proton shift which rearomatizes the aromatic ring. 8

Base + I Cl' N

~~X = Me, H, Cl V~~

~~X CHgSMe~~

~~20 c(ch 3 ) 3 rV\j r\A ,~~

~~This ortho-al kylation procedure offered great advantages over other methods. One of these methods, developed by Claus, utilized sulfilim ine~~

8 d 9a 15 to ortho alkylate primary anilines. ’ ’ Treatment of an aniline with dimethylsulfoxide, phosphorous pentoxide, and triethylamine in dichloromethane or chloroform gaveJ a sulfilimine (21). OA j Treatment of 21 'W

~~DMSO p 2 05 CH^ Base i ‘3 NH2 N(C2H5^3 N ^ S^CH3 A~~

with base and heat gave the ortho-alkylated aniline ( 2 2 ) in excellent yields. The generality of this method is limited to primary anilines which can survive the strenuous reaction conditions. Gassman and Gruetzmacher have extended their ortho-alkylation pro- 1 fi cedure to primary anilines. Addition of one equivalent of te r t- butyl

~~16. P.G. Gassman and G. Gruetzmacher, j. Amer. Chem. Soo., 95, 588 (1973); P.G. Gassman and G. Gruetzmacher, ib id ., 96, (1974).~~

~~NaOCH H 3~~

~~hypochlorite to a cold (-65°) solution of aniline 23 in dichloromethane smoothly generated the y-mono-chloroaniline 24. After stirring 24 for~~

25 min, three equivalents of dimethyl sulfide were added which yielded the azasulfonium salt 25.f\Aj Solutions of 25r\y\> were stirred for 40 min before 1 . 2 equivalents of sodium methoxide in methanol was added to gene rate sulfilim ine 26f\y\, and ylide J 27. OA, Sommelet-Hauser rearrangement'J of 27 OAj gave 28, which underwent a proton transfer to give ortho-alkylated ani line 29. The yields were very good for a variety of functionalized 10 anilines with mildly electron-donating to strongly electron-withdrawing groups. Additional advantages were that no reaction intermediates were isolated, the entire reaction was carried out in one reaction vessel, and the procedure was sufficiently gentle that a variety of other functional groups were tolerated. Other sulfides could also be utilized, as is dem onstrated below. Tetrahydrothiophene reacted with aniline to generate

~~30 in 64% yield, which was followed by a Raney-nickel reduction to give~~

~~31 in 62 % yield.~~

~~3) NaOCH~~

A variety of functional groups were used successfully in the ortho- alkylation procedure. The only reported aniline which worked poorly was p-methoxyani1ine. This was due to the low stability of the corresponding tf-chloroaniline. The solvolysis of the y-chloroaniline was greatly en hanced by the participation of the lone pair electrons of the methoxyl group, thus making 24 (X = p - CH^O) extremely unstable. In an effort to prepare 29 (X = p - CH gO), an alternate preparation of azasulfonium salt

~~^5 was desired. Sulfur compounds are known to form complexes with halo- 17 gens. Addition of dimethyl sulfide to chlorine in methylene chloride~~

17. See G.E. Wilson, J r ., and R. Albert, J. Org. Chem.s 38, 2156, 2160 (1973) for leading references. ^ 11 solution at -70° generated chlorodimethylsulfonium chloride ($£). Addi tion of two equivalents of p-anisidine followed by base gave 62% of

~~(X =p-CHgO).^ This yield should be compared with a 3% yield of~~

(X =p-CHgO) prepared via the iV-chloroaniline route. Corey and others have utilized 32 and other similar reagents to effect oxidations and dis- 19 20 placements. In one case, azasulfonium salts were prepared.

18. P.G. Gassman, T.J. van Bergen, and G. Gruetzmacher, J . Amer. Chem. Soo., 95, 5608 (1973); P.G. Gassman, G. Gruetzmacher, and T.J. van Bergen, ib id . , $>, 5512 (1974). 19. E.J. Corey and C.U. Kim, J. Amer. Chem. Soo., 94, 7586 (1972); E. J. Corey, C.U. Kim, and M. Takeda, Tetrahedrontett. , 4339 (1972). 20. E. Vilsmaier and W. Sprugel, Tetrahedron Lett., 625 (1972).

~~CH3 SCH3~~

~~i- C12 _ p-C H 30 - C 6H5NH2 ?H3 CH3 V SV H2SCH3~~

~~(CH3 )2 S-C1 Cl ------*— V>MH~~

~~w.32~~

Gassman and Huang applied this ortho-alkylation reaction sequence to 21 2-aminopyridines. Reaction of ^ with te r t- butyl hypochloride, dimethylsulfide, and sodium methoxide under similar conditions to the ani line case gave a quantitative yield of sulfilimine ^ (see reference 9a for an alternate preparation of ^ ). Treatment of 34 with potassium te rt- butoxide in refluxing te r t- butanol gave a 70% yield of ortho-alkylated product Raney-nickel reduction of 3§ gave a 71% yield of 2-amino-

~~3-methylpyridine ($§).~~

~~21. P.G. Gassman and C.T. Huang, J. Amer. Chem. Soo., 95, 4453 (1973). 12~~

~~1) ( ch 3 ) 3coci ,CH2SCH3 ChL (CH 3 )3 C0K N >~~

~~2 ) CH3 SCH3^ M^Sspij (CHo)oCOH L N CH3 3 3 I'r ' NH, 3) NaOCHo 34 Ra-Ni~~

~~36 r\Aj~~

In an effort to extend the ortho-alkylation procedure, Gassman and 22 Drewes developed an ortho-benzylation reaction. A mixture of one equi valent of an aniline and two equivalents of benzyl phenyl sulfide in a 3:1

~~22. P.G. Gassman and H.R. Drewes, Chem. Commun. 3 488 (1973).~~

~~2) NaOCH 13 acetonitrile-methylene chloride solution at -40° was treated with 1.3 equivalents of te r t- butyl hypochlorite to generate the azasulfonium salt.~~

~~Addition of sodium methoxide smoothly rearranged the s a lt to 3£ in good yield. As before, Raney-nickel reduction removed the sulfur to give a diphenylmethane derivative (38).~~

~~In an extension of this work, Gassman and Drewes ortho-formylated 23 aniline by modifying the ortho-alkylation procedure. Aniline and~~

~~23. P.G. Gassman and H.R. Drewes, J. Amer. Chem. Soo. 3 96, 3002 (1974).~~

~~thioanisole were reacted to prepare 39 under reaction conditions used 22 for the previous method. The amine was protected as the diacetate and~~

~~1) (CH3 )3 C0C1 X ?C6H5 2) C6H5SCH3 /~~

~~NH2 3) N a 0 C H 3~~

~~0 II~~

~~the s-methylene group was chlorinated via a Pummerer rearrangement.~~

Treatment of a-chlorosulfide 40 with mercuric oxide-boron trifluoride- etherate generated the aldehyde group, and the monoacetate was formed 14 by mild hydrolysis with sodium carbonate in water. The mono-acetylated o-aminobenzaldehydes (4|) were prepared in 33 - 50% overall yield based on the starting aniline. A similar route was developed which utilized 23 dithiane in place of the thioamsole. Treatment of ^ with potassium 24 acetate in acetic anhydride gave high yields of carbostyrils (^)-

~~24. H.R. Drewes, Ph.D. Thesis, The Ohio State University, 1974.~~

~~Gassman and Drewes also developed an efficient synthesis of o-aminosty 24 renes by a similar sequence.~~

~~The ortho^formylation processes were applied to 2-ami nopyridine pc by Gassman and Huang, who prepared 2-amino-3-formylpyridine (43) in~~

~~25. P.G. Gassman and C.T. Huang, Chem. Commun., 685 (1974).~~

~~43 'V\>~~

~~good yield. These were readily converted into 1, 8 -napthyridine deriva tives (££) on heating with an acetic anhydride-potassium carbonate mix ture.~~

A major extension of the ortho-alkylation research was the prep- 26 27 28 aration of indoles by Gassman and van Bergen. ’ Treatment of an ani' line in methylene chloride solution at -78° with te r t- butyl hypochlorite 15

26. For detailed discussions of the chemistry and synthesis of indoles, see R.J. Sundberg, "The Chemistry of Indoles," Academic Press, New York, N.Y., 1970 and "Indoles," Parts 1 and 2, W.J. Houlihan, £d., Wiley-Interscience, New York, N.Y., 1972. 27. a) P.G. Gassman and T.J. van Bergen, J. Amer. Chem. Soo., 95, 590 (1973); b) P.G. Gassman and T.J. van Bergen, ib id ., 95, (1973). 28. P.G. Gassman, T.J. van Bergen, D.P. Gilbert, and B.W. Cue, J r ., J. Amer. Chem. Soo., 96, 5495 (1974).

generated an il7-chloroani 1 ine 24. Replacement of dimethylsulfide by a primary a-methylthioketone (45) generated an azasulfonium salt. After stirring for an hour at -78° an equivalent of triethyl amine was added to rearrange^ the azasulfonium salt to a 3-methylthioindole '/ 46 a-1.r\ s\ S\ S\ ,r\ s\,

~~1) (CH3 )3 C0C1~~

~~2 2) CH3 SCH2CR ( ^ ) H 23 a-1 47 a-1 'VVVXAA. 'W V W b 3) (C2 H5)3N WWVV~~

~~Raney-nickel desulfurization smoothly formed the 2-monosubstituted indoles~~

47 a-1. Table I lists the yields for indoles 46 a-1 and 47 a-1. With A/VWVl) ^ W W W VWbVb para-(23r vW W a-f, \ j m 1) and ortho-substituted anilines (23 0/WT3 g), the substituents can only reside in the resulting indole at the 5 and 7 positions, re spectively. Meta-substituted anilines (23^i^k) can form indoles with the substituents at either the 4 or 6 position. For example, m-toluidine

( ^ i ) gave a 58% yield of a 2:3 mixture of 4fjM and 4 6 ^ . Secondary ani lines (£^J( 0 were shown to work effectively by the preparation of 1 , 2 -d i methyl -3-methyl thioindole (46 h) in 54% yield. Replacement of 45 with 16

~~Table I. Yields of Indoles Derived from a-methylthioketones and Substi tuted Anilines.~~

~~1) (CH3 )3 C0C13 SMe~~

~~^ > y~~

~~2 2) CH3 SCH2CR (45)~~

~~23 a-k 3) (C2 H5)3N 46 a-1 47 a-1 WWW a a a a a a O/v/\ jO»0/Y>~~

~~2-Substituted- 3-methylthio- 2-Substituted- Aniline R indole % Yield indole % Yield~~

~~23a H ch 3 46a 69 79 AAA W\;~~

~~23b p-0CCH 3 ch 3 46b 6 8 47b 72 a a a AAA •W b 23c p-ch 3 ch 3 46c 60 47c 80 AAA AAA OO/b 23d p-Cl ch 3 46d 72 47d 74 AAA AAA 0.0A/~~

~~23e p-C 0 2 C2 H3 ch 3 46e 82 47e 83 AAA AAA OAA.~~

~~23f p-N0 2 ch 3 46f 30 47 f a AAA AAA OA/b~~

~~23g o-CH3 ch 3 46g 72 47g 73 AAA AAA o o /b~~

~~A7-CH3 3 54 47h 76 23h ch 46h oA /b AAA AAA h 1 23 i m -C H 3 ch 3 46i, 46j 58 62 AAAy AAA AAA ffii* 411~~

~~23 k m-N0 2 ch 3 46k 82 47 k a AAA AAA AAA 23a H 461 81 471 76 AAA C6H5 AAA AAA~~

~~a) No 49f or 49k could be isolated due to the accompanying reduction of the^rntro group under the reaction conditions. b) The yield is reported for the isomeric mixture. 23 i 46 i rVW\> moj~~

~~1-methylthioacetaldehyde (48) produced 3-methylthioindole (49) in 30% f\Aj yield. Use of the dimethylacetal of 48 improved the yield of 49 to 45%.~~

~~1) (ch 3)3coci~~

~~2) CH3 SCH2 CH0 (48) — ------ZL& 3) (C2H5)3N~~

~~The generality of the reaction sequence was further demonstrated by the use of a-methylthioacetophenone (45, R = C^H^) to prepare 3-methylthio-~~

~~2 -phenylindole (46JJ in 81% yield.~~

Indoles have been successfully prepared by the use of the chlorine- 18 sulfide complex procedure. For example, addition of chlorine to pri mary sulfide 45 (R = CH3) generated chlorosulfonium salt 50 as a white solid. Addition of two equivalents of aniline (23,j0 generated the azasulfonium salt which was rearranged by triethyl amine to indole 46^a

(X = H) in 6 8 % yield. This route enabled 5-methoxy-2-methyl-3-methylthio indole (46^, X = p-CH 3 0), a compound which could not be prepared via the itf-chloroaniline route, to be prepared in 38% yield. 18

Prior to the Gassman procedure, the most general method for pre- 29 paring indoles was the Fischer indole synthesis, especially when coupled 30 with the Japp-Klingemann reaction. Gassman1s procedure has several ad

~~vantages over the Fischer method. First, the starting materials for this~~

29. E. Fischer and F. Jourdan, Chem. B er. , 16, 2241 (1883); E. Fischer and 0. Hess, ib id ., 17, 559 (1884); E .F isch er, Justus Liebigs Ann. Chem., 236, 126 u 8 8 6 ). For a recent review, see B. Robinson, Chem. R ev., 227 (1969). 30. F.R. Japp and F. Klingeman, Chem. Ber., 20, 2942, 3284, 3398 (1887). For a review, see R.R. Phillips, Org. React., 10, 143 (1959).

new method are generally available as well as inexpensive. A large number of substituted indoles can be prepared from easily prepared sulfides and commercially available anilines. By contrast, many 2-, 3-, or 4-substi-

~~tuted hydrazones required for the Fischer method can only be obtained~~

~~through tedious synthetic pathways. The 1,1-disubstituted hydrazones~~

~~needed to prepare 1 -substituted indoles are also difficult to prepare.~~

~~The greatest advantage of Gassman's indole synthesis is the gentle re action conditions. The reactions are carried out at low temperatures 19~~

(below -30°) without the presence of strong acid or base. In contrast, the Fischer indole synthesis normally employs high temperatures (to 200°) and strong acid to effect rearrangement. These strenuous conditions pro hibit the use of many sensitive functional groups. Finally, in a com parison of the yields, Gassman's are on the average higher than those of the Fischer method.

By use of an a-methylthioester (51) in place of oxindoles were 31 readily prepared in yields comparable to those for the corresponding indoles. Use of the chlorine-sulfide complex of EH enabled 5-methoxy-

~~3-methylthiooxindole (52, X = 5 - CHgO) to be prepared in 53% yield.~~

~~i) (ch 3)3coci~~

~~3) (C2 H5)3N 4) H+ H~~

~~31. P.G. Gassman and T.J. van Bergen, J. Amer. chem. Soo., 95, 2718 (1973); P.G. Gassman and T.J. van Bergen, ib id ., 96, 5^)8 (1974).~~

~~The Gassman indole synthesis can be used to prepare a variety of sub stituted indoles,isomerically pure with substituents in the 1, 2, 5, and~~

7 positions. However, the very nature of the reaction process requires that a hydrogen, methylthio, or methylthio derived group be present in the 3-position of the indole nucleus. This is a definite limitation 20 because of the large number of indole alkaloids which are substituted in 32 both the 2 and 3 positions.

~~5 R SMe~~

~~6 R~~

~~32. See R.H.F. Manske, "The Alkaloids," Academic Press, New York, Vol. I - XV, for leading references.~~

This thesis deals with extensions of the Gassman indole synthesis to the preparation of 2,3-disubstituted indoles. It further describes synthetic approaches to indole alkaloids. Particular emphasis is given to the development of general procedures useful in further synthetic en deavors and to the understanding of reaction processes. RESULTS AND DISCUSSION

~~Part I. Synthesis of 2,3-Disubstituted Indoles.~~

~~As discussed previously, we sought a method of preparation of~~

2,3-disubstituted indoles where the group in the 3 position was alkyl or aryl. While there are numerous reports in the chemical literatu re 26 which deal with the alkylation of 3-unsubstituted indoles, the yields are often low. This reaction is often complicated by 1- and 1,3-dial

~~kylation. An alternate method for the preparation of 3-monosubstituted 31 33 indoles is available by reduction of certain oxindoles. ’~~

~~33. T. Wieland and D. Grimm, Chem. Ber., 98, 1727 (1965).~~

Examination of the general mechanism for the formation of indoles suggested a major extension of the Gassman indole synthesis. This mech anism is shown in Scheme I. It has been demonstrated that aniline (23 a),r\S\,f\jr\j in an appropriate solvent at -78°, reacted readily with te r t- butyl hypo- 3 4 5 chlorite to form the mono-y-chloroani 1 ine (24 a).'T/VTA/ ’ * Theil/-chloroani- 2 3 line reacted with 1-methylthio-2-propanone (53^a, R = CHg, R = H) to generate the azasulfonium salt 54^.5 The protons on the atoms adjacent

~~to the sulfur were fairly acidic due to the inductive effect of the posi~~

tive sulfur. Thus, triethyl amine was sufficiently basic to abstract a proton from 54 a to establish the equilibrium between the sulfilimine r WV\> 55 a and the ylide 56 a. Intramolecular attack of the nucleophilic ylide 21 0 Scheme I

~~(CH,),C0C1 SCH3~~

~~NCI w w ^ H 24 a 54 ar-h WAiO* 'VO'WW I (C2H5^3N n~~

N N ^+X CH H + CH3 57 a-h 'WWW* 56 a-h 55 a-h WiW/W* WWW*

~~R -H20~~

~~OH 60 b-h 58 a-h W/WW.~~

~~Ra-Ni~~

47 a 46 a 61 b-h o/wv o/w^ 'VW W \j 23 in a Somme!et-Hauser type rearrangement produced 5 ^ a which underwent a rapid proton shift with rearomatization of the aniline ring to generate 7d 15 58 a. 5 Intramolecular condensation of the aminoketone 58 a followed 'VWVi 'W\A» 3 by proton transfer gave 59 a. Because R = H, the a-hydroxyamine readily 'VVVV/ dehydrated to form the indole 4j5^a. Raney-nickel desulfurization of 0 7 po WVO46 a produced the 3-unsubstituted indole 47 O/Wb a. ’

The very nature of this process precluded the preparation of 3-substituted indoles since the final step involved the reductive removal of the methylthio group from the 3 position. The key intermediate for cir cumventing this lim itation was the a-hydroxyamine 5£jt. It was found that the indole 46'Tj'WXi a was formed v ia dehydration ^ of 59 'VWT, a. There existed no ob- vious method for the transformation of 46 a into a 2,3-disubstituted 'VWV 3 indole. Use of an appropriate sulfide where R = alkyl or aryl blocked the dehydration described above. For example, 3-methylthio-2-butanone p O (53Jd, R = R = CH^) could not dehydrate to form an indole. However, an alternate path for dehydration was available to the a-hydroxyamine

~~5 ^ b , where R = CHg. This aliternadte path generated the indolenine 60Jb.~~

If 60 b could be desulfurized without reducing the imine double bond, 'WV\y 3 the desired 2,3-disubstituted indole 61 b would result. The success of this procedure would allow the sulfides 53 c-h also to be transformed r O/VVWTj into indoles (61'WW\A; b-hh.

The synthesis of the requisite sulfides for this extension are shown in Scheme II. Sulfides 53 b-h were prepared from readily available rVWV\Ai r r j starting materials in 13 to 85% yields. For example, 3-bromo-2-butanone

~~(62) was prepared by treatment of 2 -butanone with phosphorous pentabromide Scheme II~~

0 0 CH 0 CH3SNa CH^ 2 CH. CH CH3 CH30H Br SCH. 62 53 b 'X/Xj ‘X/XA j'Xi 0 CuBr2 CH.SNa 0 CH. CH. jj CH ^"3^° CH n j J »' ^ ch 3oh I Br 63 53 c SCH3 'Vb W\jO/ 0 0 Br. 0 CH3SNa CH. CH. CH CH3~CH.0H Ch3 Br SCH,

~~64 53 d CH. OAj CH. m n j 1) Br. I o~~

~~CH. AA. 2) CH.SNa CH3 | CH3~~

~~sch 3 ch 3oh o/w\,53 e~~

~~ch 3sh SOgCTg ether Na.CO. CH. CH. 13 65 vci 53 f s c h 3 -Vb rXA/XAj~~

~~0 CH3SNa CH3~~

~~Y t ) ch3°h " C o~~

~~OA/VS53 g~~

~~1) Br. ^ V ^ i ) 2) CH3SNa SCH CH30H 53 h OA/W. 25 34 by the procedure of Faworsky. The methylthioketone was prepared by adding excess condensed methyl mercaptan to a cold methanol or ethanol~~

~~34. A. Faworsky and B. Issatschenke, J. Prakt. Chem., 8 8 , 655 (1913).~~

solution of one equivalent of the respective sodium alkoxide. The a- bromoketone was then slowly added,and the reaction mixture was stirred for 24 hr at room temperature before workup to give a 43% yield of 3- methylthio-2-butanone (53 b). VWV/

~~The published procedure for the preparation of 2-bromo-3-pentanone~~

(63) was tedious due to the preparation of the low boiling enol acetate 28 of 3-pentanone. An improved procedure utilized cupric bromide to pre pare 63 in a one-step reaction in 57% yield. Sulfide 53^ was prepared

~~in the manner of 5 3 in 8 6 % yield.~~

One of the remaining sulfides deserves special comment. When 1- methylthio-l-phenyl- 2 -propanone (53^) was prepared according to the standard procedure, a mixture of l-chloro-l-phenyl- 2 -propanone ( 6 6 ), 1 - phenyl-2-propanone (65), and 53^ was obtained. If a sufficient excess of sodium methylmercaptide was present, only 65 was formed. This was be lieved to arise from sodium methyl mercaptide attacking 5 ^f at sulfur to generate dimethyl disulfide and the enolate of (55 which was protonated by the solvent. Japanese workers have examined this reaction and iden- 35 tified dimethyl disulfide as a reaction product. The desired sulfide

~~35. M. Oki, W. Funakoshi, and A. Nakamura, Bull. Chem. Soo. Jap., 4£, 828, 832 (1971). 26~~

~~Cl SCH 66 53 f 65 + CH.SSCH. 'V\, 'VWV. OA, O 0~~

~~was finally prepared by adding ^ to a cold mixture of methylmercaptan and sodium carbonate in ether. Workup and distillation provided a 41%~~

~~^yield of 53 O/OO/O f.~~

~~The methylmercaptide desulfurization worked well when applied to 3- methylthiooxindoles. For example, the oxindole ( 6 8 ) was obtained in 48%~~

~~excess X •SCH CH.SNa -j ^~~

67 X = H 6 8 X O/O 0 / 0 69 X = no . 70 X f\tr\j d. 0 / 0 yield by refluxing 67 in methanol with an excess of sodium methyl mer captide. Raney nickel affected partial reduction of the nitro group in 28 31 nitroindoles and nitrooxindoles and thus proved unacceptable. ’

~~Treatment of 3-methylthio-4-nitrooxindole (69) with excess sodium meth- ' 0 /0 36 ylmercaptide gave a quantitative yield of 4-nitrooxindole (70).~~

36. P.G. Gassman and W. Ranbom, unpublished results. 27 Addition of one equivalent of te rt-b u ty ] hypochlorite to a solution of aniline (jj^a) in methylene chloride at -78° immediately generated the y-chloroaniline. The sulfide in the same solvent was then added dropwise; stirrin g at -78° was continued for 6 to 48 hr to effect complete formation of the azasulfonium salt. Treatment of the azasulfonium salt with triethylamine generated the ylide which underwent a Sommelet-Hauser type rearrangement followed by intramolecular condensation and dehydra tion to form the indolenine 60.

Due to their instability, the crude indolenines 6 j^b-h were character ized by ir and nmr spectroscopy and used without further purification. In the infrared, the most characteristic absorption was the which ap- -1 37 peared at 1550 - 1625 cm . The pmr spectra of the indolenines were

~~37. J.B. Patrick and B. Witkop, J. Amer. Chem. Soe., 72, 634 (1950); B. Witkop and J.B. Patrick, ib id ., 73, 1558, 2188^1951); M. Nakazaki and M. Maeda, Bull. Chem. &oa. Jap., 35, 1380 (1962).~~

especially informative because of the large upfield shift of the methyl thio absorption. This absorption normally was found at 2.00 - 2.10 6 in 38 the sulfides (53 b-h) and shifted up to 1.25 - 1.436 in the indolenines.

~~This enabled the estimation of the amount of unreacted sulfide that was present.~~

~~38. a) A.H. Jackson and P. Smith, J. Chem. Soo. C, 1667 (1968); b) A.H. Jackson and P. Smith, Tetrahedron, 24, 2227 (1968). 28~~

~~Whether the indolenines 60 b-h could be readily converted to the 2,3-~~

~~disubstituted indoles 6 ^1 ^b-h remained the major question. Surprisingly, a number of reducing agents could be used to effect this conversion.~~

~~Raney nickel, sodium borohydride, and lithium aluminum hydride were all effective in transforming the methylthioindolenines 60 b-h into the di- A/WWO~~

~~substituted indoles 61yi/wvo b_h. Table II lists the overall yields ^ of the di- 28 39 substituted indoles. 5 Although numerous intermediates were involved~~

~~Table II. Yields of 2,3-Disubstituted Indoles (61 b-h) Based on Startinq w o r n J Aniline (23 a). cc~~

~~Sulfide Indole R, col Hr at -78° % Yield 1~~

~~53b 61b ch 3 CH3 o/vb WO; 7 85~~

~~53c 61c ch 3 8 60 'Wl> C2H5~~

~~53d 61 d ch 3 6 81 OA/O. O/AAj C2H5 53e 61e ch 3 (ch 3)2ch 15 'W/b m 49 53f 61 f ch 3 48 34 Wb wv, C6H5 53g 61 f ch 3 27 A/VO w v C6H5 69 53h 61 h 24 41 m C6H5 C2H5~~

in the overall conversion of aniline (23 a) into 61 b-h. The yields v 'VXj'W OA.'VWti J varied from good to excellent. The sulfides were readily available and the laboratory procedures relatively simple. The overall conversion of rorv/v>j23 a to m 60 wb-h in a one-potr conversion involved only the sequential

39. P.G. Gassman, D.P. G ilbert, T.J. van Bergen, Chem. Comrnun., 201 (1974). 29 addition of 1) hypohalite, 2) the sulfide, and 3) triethyl amine to a cold solution of aniline. The only isolated intermediate, the indolenine, was irranediately reduced to the indole.

~~Several side products have been observed in this reaction sequence.~~

Azobenzenes (7|) were generated when the azasulfonium salts had not com pletely formed prior to triethyl amine addition. These products could be viewed as arising from the base reacting with the iV-chloroaniline to generate an iv-chloroanilide which attacked another molecule of N- chloroaniline followed by dehydrochlorination to form the azobenzene.

~~Occasionally, unreacted sulfide was present in the crude indolenine and was reduced to a methylthio alcohol by the lithium aluminum hydride. For~~

~~CH SCH~~

~~example, 72 was isolated in approximately 20% yield during the prepara tion of 61 d. The last major side product was believed to arise via 'W W ° r~~

Stevens ^ * 5 or Pummerer^ type rearrangements. This product arose from a [1.2] sh ift of the anilino group to generate 73Jb^h. During a prep aration of 61^f, the crude indolenine was chromatographically separated

40. For a review of the Pummerer reaction, see G.A. Russel and G.J. Mikol in B.S. Thyagarajan, Ed., "Mechanisms of Molecular Migrations," Vol. 1, Interscience Publications, New York, N.Y., 1968, Chap. 4. 73 b-h 74 b-h 'ww\j'\, mm 54 b-h

2 3 from 73 f (R = ChL, R = Cc Hr-). However, in the normal course of the a/voA, o 6 b reaction, the side product (73) was reduced to an amino alcohol, £4, which was removed during the acidic workup of the lithium aluminum hy dride reduction.

During the development of the 2,3-disubstituted indole synthesis, a definite advantage of our method over that of Fischer's became ap parent. Gassman1s procedure permitted the substituents to be placed in the 2 and 3 positions in a very specific manner with none of the isomer problems which often occur in the Fischer method. In this work no iso meric indoles were observed during the preparation of any of the in doles listed in Table II. In the cyclization of an unsymmetrical phenyl hydrazone via the Fischer method, two isomeric indoles can be generated.

~~For example, the cyclization of the phenyl hydrazone of 2-butanone (£5) 41 by zinc chloride gave a 4:1 ratio of en^b to £ 6 . Average yields of~~

41. E. Fischer, Justus Liebigs Ann. Chem., 236, 126 (1886); A. Kor- czynski, W. Brydowna, and L. Kierzek, Gass. chim. I t a l ., 56, 903 (1926). ^ 31 indoles by our method were slightly better than those obtained by

~~Fischer's method. However, Gassman's procedure prepared the indoles under milder conditions and gave a substantially cleaner product.~~

~~ZnCl.~~

~~61 b 76 AAAA, 'Vb~~

This general route was used to prepare tetrahydrocarbazolenines 28 39 and tetrahydrocarbazoles 78 by Gassman and van Bergen. 5 The sulfide 2 3 was modified so that R and R were joined as part of a cyclic struc ture. Addition of 2-methylthiocyclohexanone (53^, R^ = R 3 = - ( 0 8 2 )4 -) to a cold solution of tf-chloroaniline followed by base gave good yields

~~1 ) (CHo)oCOCl~~

~~0 SMe SMe 2 ) 53i C r AA/b ■> 3) (C2 H5)3N O n O~~

~~AA77~~

of 77. Tetrahydrocarbazolenine 77 was readily reduced with either W-2 AA> r\Aj Raney nickel, sodium borohydride, or lithium aluminum hydride to the tetrahydrocarbazole (78). A variety of substituted anilines were used to prepare substituted tetrahydrocarbazoles in overall yields of 20 - 50%. 32

Gassman and Cue extended the preparation of tetrahydrocarbazoles an additional step by using ethyl 6 -methylthiocyclohexanone- 2 -carboxylate 28 79 to prepare tetrahydrocarbazole $£ in 70% overall yield. The tetrahydrocarbazolenine 80 was shown to be in equilibrium with the enamine 81.

~~1) (CH3 )3 C0C1~~

~~0 ch 3s 2 ) CH3Sy K j ; 0 2 C2 H5~~

~~------~~

~~3) (C2 H5)3N~~

~~co 2 c 2 h 5 co 2 c2 h 5~~

~~Ra-Ni~~

Raney nickel smoothly reduced this mixture to 1-carboethoxytetrahydro- carbazole (82)- Compound 82 indicated the possibility of using the new indole synthesis to prepare alkaloids. The acetic acid unit in the 2 32 position of 82 is a very common structural unit in indole alkaloids.

Prior to the 2,3-disubstituted indole research several indole-2- acetic acid derivatives were prepared. In order to prepare these deri vatives y-methylthio-B-ketoester derivatives were required. In the sim plest case methyl 4-methylthioacetoacetate (85^0 produced methyl 2- indolylacetate after indole formation and desulfurization. Bromine addition to methyl acetoacetate proceeded to brominate exclusively the 33 42 4 position in high yield. Bromide was a powerful lachromator and was only characterized by pmr spectrometry before being used to prepare

~~0 0 . CH.SNa OR > OR~~

~~Br SCH 3 84 a , R = CH. 'b'Wb 'W W > j ■WOO, 84 b, R = C.H, W\A» VW \j d o OA/V.O.~~

~~42. A. Burger and G.E. Ullyot, J. Org. Chem., 1^2, 342 (1947); J.L. Burdett and M.T. Rogers, J. Amer. Chem. Soal, 8 6 , 2105 (1964).~~

85 a. Addition of 84 a to a cold solution of sodium methylmercaptide in W l; 'W b J r methanol gave 85 a. Sulfide 85 a was prepared in 6 8 % overall yield 3 'W b 'Vb'Vb r r sj based on methyl acetoacetate (83 a). J vWV\<

Methyl 2-(3-methylthioindolyl)acetate ( 8 6 ^a) was prepared by ad dition of 85 a to a methylene chloride solution of y-chloroaniline at 'VO'Vb -78°. After stirring the cold solution for 7 hr, triethylamine was added

~~i) (ch 3)3coci~~

~~H 2 3)(C3 H5)3N H C02R H CO2 R~~

~~« 7 a d = rw 'Vb'Vb 'VWb 34~~

~~and a 65% yield of 8 £,ji was obtained after workup and chromatography.~~

~~Raney nickel smoothly desulfurized 8 6 ^a to give a 90% yield of 8 ^ a .~~

~~This synthetic route is the method of choice for the preparation of~~

indole-2-acetic acid derivatives. This route provided an overall yield 43 of 58% of 87 a in two steps while the previous route required six rV\jfV\j r r ” steps and proceeded in much lower overall y i e l d .^

~~43. W. Schindler, Helv. Chim. Acta., 41, 1441 (1958); W. Schindler, ib id ., f\/\j40, 2156 (1957). ^ 44. R.G. Newell, Ph.D. Thesis, University of Minnesota, 1975.~~

~~Ethyl 2-(3-methylthioindolyl)acetate ( 8 6 ,Jb) was prepared from ethyl~~

~~4-methylthioacetoacetate (85Jb) in 53% yield. Raney-nickel reduction~~

~~of 8 6 Jo produced ethyl 2-indolylacetate (87Jd) in 8 8 % yield.~~

~~A second indole acetic acid was prepared from methyl 2-methyl -~~

~~acetoacetate ( 8 8 ). Bromination of 8 8 followed by treatment with sodium~~

~~CH3 AACH 3 A A 0 CH3 CH 2) Ct^SNa cpu pu OAi8 8 lm3 3 b L H 3 l h 3~~

~~aniline according to the procedure used to prepare 8j5^a generated indole~~

~~90 in 53% yield. Raney-nickel desulfurization gave a high yield of <\Aj~~

~~methyl a-methyl- 2 -indolylacetate (91^)- Preparation of 3-substituted-2-indolylacetate derivatives required~~

~~an additional substituent on the sulfide. The sulfide derived from ethyl~~

~~butyrylacetate provided a simple model. Sulfide 9£ was readily prepared~~

~~0 0 0 0 1 ) Br2 a AA» CH oc 2 h 5 3 2) CH3SNa CH 0C2H5 SCH~~

~~by treatment with bromine followed by methyl mercaptide in 81% yield.~~

~~Treatment of y-chloroaniline with 92 was expected to generate the indolenine-enamine isomers similar to those for the tetrahydrocarbazole case.~~

~~Raney-nickel reduction was expected to generate the 2,3-disubstituted~~

indole 95. Despite use of a variety of reaction conditions, times and solvents none of the desired indole was isolated. The only products observed were aniline and the starting sulfide or its reduction products.

~~The explanation for this failure was initially that intermediates 93 and 36~~

~~94 were very unstable. A more likely explanation is that the azasulfonium salt was formed very slowly, and only a small amount was present when the base was added to effect rearrangement.~~

~~2) 92 ' OA/~~

~~Vb COoC94 2H5 Ra-Ni~~

~~C02 C2 H5 95 rV\»~~

Gassman, Gruetzmacher, and van Bergen had previously shown that the chlorine-sulfide complex was useful in forming azasulfonium salts for use 18 in the ortho-alkylation, indole and oxindole reactions. We felt that the extension of this method to the preparation of 2,3-disubstituted indoles would provide a valuable alternative to the y-chloroaniline route.

The expected reaction pathway is shown in Scheme III. Addition of chlorine to a cold solution of the sulfide should generate chlorosulfonium sa lt %6. Two equivalents of aniline would be expected to react to form the azasulfonium salt 54W/ and aniline hydrochloride. Ylide 56 r\/\j would then be generated by addition of base, which would rearrange in 37

~~Scheme III~~

~~0 R C 2 V " r R SCH3 >Ss Cl S Cl + CH~~

~~VWWV53 a-i~~

~~Pummerer Rear. Cl~~

~~Stevens R R~~

~~SCH, SCH~~

~~97 a-i W73 lW a-i b WWV\j56 a-i~~

~~Indoles~~

~~a ch 3 H b ch 3 ch 3 c c 2 H5 ch 3 d ch 3 C2H5 e ch 3 (ch 3)2ch f ch 3 C6H5~~

ch 3 g C6H5 h C6H5 C2H5 i -( ch 2)4- 38 a Sommelet-Hauser type rearrangement. After condensation and dehydration the desired indolenine would be expected. Reduction in the normal man ner should thus afford the desired 2,3-disubstituted indole.

During this research only one sulfide generated a solid after the addition of chlorine, although the chlorosulfonium salts which were pre- 18 viously utilized were all white precipitates. Addition of one equi

~~valent of chlorine to 53^c| at -78° in methylene chloride solution gave~~

~~a massive precipitate. After stirring for 15 min two equivalents of~~

~~aniline were added and stirred for an additional 3 hr period. Addition~~

~~of excess triethyl amine followed by normal workup gave the crude indol~~

~~enine 60 g. Lithium aluminum hydride reduction and workup gave a 75% 'WVXi yield of 3-methyl-2-phenylindole (61^). All other sulfides reacted~~

~~with the chlorine to give clear colorless solutions. However, several~~

~~salts which had initially formed rapidly redissolved. The highest~~

~~yield of any of the other indoles prepared by this method was 25% for~~

~~61^b and many gave no indole type products. For example, sulfide 5 3 ^~~

~~gave a high yield of 73 f and none of indolenine 60 f. 'W\jrL» 'T/WO~~

~~Several experiments were carried out to examine the chlorine-sul-~~

~~fide adducts. The chlorosulfonium chloride salts were expected to be~~

~~insoluble in methylene chloride at -78°. Addition of large amounts of~~

~~pentane to the chlorine adduct of 53^ failed to precipitate any salts.~~

~~Cyclohexene was recovered unchanged when added to this same adduct.~~

~~If 96 d had been present, it could have been expected to chlorinate the W W r olefin. A third experiment involved working up 96^d directly before~~

aniline was added. A mixture of two compounds was obtained. The f i r s t 39 compound decomposed at room temperature to form the second, and i t could not be isolated in sufficient quantity for identification. However, the second was identified as 3-methylthio-3-buten-2-one (98 d) by its ir ,

~~CH CH CH.~~

SCH 3 -J 96 d Cl 97 d A/WO A/WO 98 d AiA/OAj pmr, and mass spectra. This product apparently arose from a Pummerer type reaction of 96 d to form 97 d (the unstable first compound) which r\A/\y\j < vw u r ' eliminated hydrogen chloride to form 98 d. OA/W

Further evidence for the Pummerer rearrangement of the chlorosul fonium salts was obtained by low temperature nmr. Addition of chlorine to sulfide at -60° in deuterochloroform gave a clear, colorless

~~CH 0 Cl. CH 3 \ T CH- CH.~~

~~SCH0 SCH~~

~~53 b / rt V \ M i~~

HC1 H2C CH. SCH. SCH. 98 b 'WVTj 40 solution. Examination of the proton spectra of the adduct showed only three singlets. If 96J3 had been present, a large downfield shift of the sulfonium methyl as well as a doublet for the C-4 methyl and a quartet for the C-3 proton would have been observed. After warming to room temperature overnight and reexamining the sample, sulfide 9$ was observed. This came from the dehydrohalogenation of 97 b to form 98 b J J ‘W\Aj

~~97 b to form 73 b. bA/bOi 'Wb'b~~

The Pummerer rearrangement has grown to include any of a number of reactions which involve reduction of a sulfonium sulfur with concomitant 40 oxidation of the ct-carbon. It in itia lly involved the rearrangement 45 of sulfoxides in acids to form a-hydroxy or a-chlorosulfides.

~~45. R. Pummerer, Chem. Bev. , 12, 2282 (1909) 'Vb~~

~~Because of the large variety of substrates which undergo the reaction as well as the different reaction conditions employed, i t is doubtful~~

~~that any one reaction mechanism can accurately describe the reaction for all cases. One must be careful in drawing parallels between different~~

~~Pummerer reactions. For the most part, this discussion will concentrate~~

~~on the Pummerer reactions of sulfides and their chlorination products.~~

~~Many papers have appeared which deal with the chlorination of sulfides with chlorine,^ tf-chlorosuccinimide,^ and sulfuryl and thionyl chlor- 1de.47e,48 41~~

46. a) M.A. Riche, Ann. Chim. Phys., [3] 43, 283 (1855); b) T. Zincke and W. Frohneberg, chem. Bev., 42, 272r(1909); c) F.G. Mann and W.J. Pope, J. Chem. Soa., 121, ^ 4 (1922); d) W.E. Lawson and T.P. Dawson, J. Amev. ChemY^oa., 49, 3119, 3124 (1927); e) H. Bohme, H. Fischer, and R. Frank, Justus Liebigs Ann. Chem., 563, 53 (1949); f) H. Bohme and H.-J. Gran, ib id ., 577, 6 8 (195^7; g) H. Bohme and H.-J. Gran, ib id ., 581, 133 (19?$7; h) H. Richt- zenhain and B. Alfredson, Chem. Bev.T'&S, 142 (1953); i) G.E. Wilson, J r . , j. Amev. Chem. Soa., r\y\j87, ^85 (1965); reference 17. 47. a) D.L. Tuleen and T.B. Stephens, Chem. Ind. (London), 1555(1966); b) D.L. Tuleen and V.C. Marcum, J. Ova. Chem., 32, 204 (1967); c) D.L. Tuleen, ib id ., 32, 4006 (1967); d) R.^arville and S.F. Reed, J r ., ib id ., 33, 39??) (1968); e) D.L. Tuleen and T.B. Steph ens, ib id ., 34, 31^1969); E. Vi 1 smaier and W. Sprugel, Justus Liebigs Ann.^hem., 747, 151 (1971 ). 48. a) W.E. Truce, G.H. Birum, and E.T. McBee, J. Amev. Chem. Soa., 74, 3594 (1952); b) F.G. Boardwell and B.M. P itt, ib id ., 77, S?2 (1955). ^

There is no mechanistic explanation for the success of 53 a and r W l A 53 f in forming indoles by this method and for the failure of the other sulfides. It is noteworthy that the chlorosulfonium salts of the success ful sulfides were both insoluble white precipitates while all of the other chlorosulfonium salts rapidly decomposed via a Pummerer type rearrange ment. These rearrangements proceed at approximately 50° to 100° below 46 the normal reaction temperatures. The g-keto group in 53 may facili tate the Pummerer type rearrangement. A similar enhancement has been 49 observed in the reaction of g-keto sulfoxides with acids. Mechanistic

49. H.-D. Becker and G.A. Russell, J. Ovg. Chem., 28, 1896 (1963); H.- D. Becker, G.J. Mikol, and G.A. Russell, J. Amev. Chem. Soa., 85, 3410 (1963); H.-D. Becker, J. Ovg. Chem., 29, 1358 (1964). ^ 42 studies of the Pummerer rearrangement of sulfoxides with acetic anhydride have shown the abstraction of the a-proton to be the rate determining 50 step;- thus this rate enhancement is to be expected.

~~50. M. Kise and S. Oae, Bull. Chem. Soo. Jap., 43, 1426 (1970); C.R. Johnson and W.J. P hillips, J. Amev. Chem. Soa., 91^, 682 (1969).~~

A variety of solvents and temperatures have been used in an un successful series of experimentsr designed° to utilize 96 WWW b-i in the syn- ^ thesis of indoles. The use of w-chlorosuccinimide also failed to pro duce any of the desired product. It was hoped that the addition of chlorine to a solution containing both the sulfide and aniline would per mit the azasulfonium salt to form before the chlorosulfonium salt could decompose. Chlorine was shown to react with aniline at -78°, but it was hoped that the formation of the chlorosulfonium salt would proceed at a faster rate. The aniline which was present would then displace chloride from 96 b-i to generate the desired azasulfonium salt WVOOA/ 54 b-i. Low temperature nmr experiments indicated that azasulfonium 'VWWV> r salts were efficiently generated with this procedure. Addition of chlor ine to aniline mixtures of 3-methylthio-2-butanone and 2-methylthiocyclohexanone generated 54 b and 54 i , respectively. The spectra of 54 b WWi WV\) r OA/Wi was included in the Appendix. These azasulfonium salts could not be I O prepared by the previously published chiorine-sulfide complex procedures.

~~Further evidence for the usefulness of this modification was the prepara tion of 3-ethyl-2-methylindole (53jd) in 45% yield and tetrahydrocarbazole~~

~~(78) in 25% yield by adding chlorine to an aniline-sulfide solution. Part II. Alkaloid Synthesis.~~

Upon the completion of the 2,3-disubstituted indole research, our attention turned to alkaloid synthesis. The emphasis in alkaloid research in recent years has turned away from synthesis as a means of structure proof and to the synthesis of compounds of biological activity 51 52 and biosynthetic modeled syntheses. 5 We hoped that our approach to

51. J.P, Kutney in "MTP International Review of Science, Organic Chem istry, Series One, Volume 9, Alkaloids," K. Wiesner, Ed., Univer sity Park Press, Baltimore, 1973, Chap. 2. 52. For annual reviews of alkaloid chemistry and synthesis, see "The A1kaloids,Specialist Periodical Reports," The Chemical Society, London, Volumes 1-5.

~~this area would enable us to prepare a variety of indole alkaloids which were of medicinal importance. Two interesting alkaloids are vincristine~~

~~( 1 0 0 a) and vinblastine ( 1 0 0 b) which have found important applications WlAA VWW 53 in cancer chemotherapy. These are dimeric alkaloids containing one~~

~~53. R.C. DeConti and W.A. Creasey in "The Catharanthus Alkaloids," W.I. Taylor and N.R. Farnsworth, Ed., Marcel Dekker, New York, N.Y., 1975.~~

~~molecule of vindoline (UH) and one of 18-carbomethoxy velbanamine ( 1^0 2 )~~

~~Both of these alkaloids represent a great synthetic challenge. In this initial study, the synthesis of the basic ring structure of KH was f e lt to be a worthy synthetic goal. 44~~

~~CH.~~

~~w w v 6 OAc 100 b R = CHO w m~~

~~CH. H~~

~~C0 2CH3~~

~~101 w\j VIA.1 0 2~~

The alkaloids aspidospermine (103 a) and aspidospermidine (103 b) ■'wwb both contain this same ring structure. Aspidospermine (103 a) is widely WWU distributed among the Aspidosperma and Vallesia species, while aspido spermidine (103 b) is found primarily in Aspidosperma quebracho bianco 'WWb Schlecht f. pendulae speg. Several syntheses of 103 a and 103 b

~~103 b R1 = R2 = H VWW j~~

54. "Encyclopedia of the Alkaloids," J.S. Glasby, Plenium Press, New York, Vol. I, p. 180. 55. a) G. Stork and J.E. Dolfini, J. Amev. Chem. Soa., 85, 2872 (1963); b) Y. Ban, Y. Sato, I. Inoue, M. Nagai, T. Oishi, My^Terashima, 0. Yonemitsu, and Y. Kanaoka, Tetrahedron L ett. , 2261 (1965). 56. a) J. Harley-Mason and M. Kaplan, Chem. Commun., 915 (1967); b) J.P. Kutney, N. Abdurahman, C. Gletsos, P. LeQuesne, E. Piers, and I. Vlattas, J. Amer. Chem. Soa., 92, 1727 (1970); J.-Y. La- ronze, J. Laronze-Fontaine, J. Levy, and J. LeMen, Tetrahedron L ett., 491 (1974); d) K. Seki, T. Ohnuma, T. Oishi, and Y. Ban, ibid., 723 (1975).

The initial synthetic pathway to be followed is shown in Scheme 57 IV. The route was to begin with quinolone 104 which was to be sulfenylated to generate the requisite methylthioketone 105. Utilization

~~57. R.V. Stevens, R.K. Mehra, and R.L. Zimmerman, Chem. Commun., 877 (1969).~~

~~of ^ 5 in the Gassman synthesis would generate indolenine TJ36 and indole~~

~~10£. Debenzylation of 107 followed by reaction with chloroacetyl chlor ide would prepare amide 109. Indolenine 110 was to be prepared by base Scheme IV 46~~

~~104 'VW w105 v~~

~~R 106 'WU m~~

~~110 rW\Aj 'VbOAA,103 a R1 = Ac ,N R2 = OCH' 103 b R] = R2 = H WW\ j 47 treatment of 109. The desired alkaloids would be obtained after hydride reduction of 1 1 0 .~~

~~The synthesis of quinolone |04 and the proof of its ais-ring junc ture are shown in Scheme V. Endocyclic enamine ,1m was prepared by~~

Ziegler's procedure 8 8 in 48% overall yield from ^ 1 . The methyl vinyl ketone annelation of KJ4 proceeded in 50% yield. There is strong prec edence for a cis-ring juncture to result from this annelation. Stevens and others have extensively studied similar annelations for five-mem- bered endocyclic enamines and demonstrated the presence of the cis-ring 59 juncture by the preparation of several mesembrine alkaloids. In

58. F.E. Ziegler, J.A.Kloek, P.A. Zoretic, J. Amev. Chem. Soa., 9J, 2342 (1969). See reference 57 for an alternative preparatiorf°of ^1^. 59. a) R.V. Stevens, P.M. Lesko, and R. Lapalme, J. Ovg. Chem.* 40, 3495 (1975); b) R.V. Stevens and J.T. Lai, ibid., 37, 2 1 3 8 ^9 7 2 ); c) R.V. Stevens, L.E. DuPree, J r . , and P.L. Loewens^in, -ibid., 37, 977 (1972); d) D.A..Evans, C.A. Bryan, and 6 .M. Wahl, ibid., 3S, 4122 (1970); e) R.V. Stevens and M.P. Wentland , J. Amev. ffliem. Soa., 90, 5580 (1968); f) S.L. Keely, J r ., and F.C. Tahk, ibid., 90, 5 ^ 4 (1968); g) T.J. Curphey and H.L. Kim, Tetvahedvon L ett., 1^41 (1968).

order to prove the cis-ring juncture, K)4 was transformed into the series 55a of compounds utilized by Stork to prepare lj03^a. These compounds have been extensively studied by Ban, who independently prepared all the iso- 55b 60 mers of ^20. 5 The physical and spectral data for compounds K)4 and

~~VT5 through Tj20 agreed with those of the cis-fused compounds previously . 55,57,60,61 prepared. ’ * * Scheme V~~

~~CN CN H0CH2 CH2 0H /^»o~~

~~r 0 f-f~~

~~m 'W b 112~~

~~1) LiAlH~~

~~0 Pd - C~~

~~h 2 hn~~

~~4) MgSO~~

~~104 115 m n/Vb~~

~~■Wb118~~

~~LiAlH, H3°~~

~~119 'b'b'b 120 'W b 49~~

60. a) Y. Ban, M. Akagi, and T. Oishi, Tetrahedron L ett., 2057 (1969); b) M. Akagi, T. Oishi, and Y. Ban, ibid., 2063 (1969); c) Y. Ban, I. Iijima, I. Inoue, M. Akagi, and T. Oishi, 'ibid. » 2067 (1969); d) Y. Ban and I. Iijima, ibid., 2523 (1969). 61. S.S. Klioze and F.P. Dormory, J. Org. Chem., 40, 1588 (1975).

It was hoped that conversion of 104 into methylthioquinolone 105 m * 1 fW V would be accomplished via bromination followed by treatment with sodium methyl mercaptide. Due to the eis-ring fusion in 104, bromination was

~~CO expected to produce the 8 -bromoquinolone 121. The bromination product~~

~~62. H.0. House, "Modern Synthetic Reactions," 2nd ed., W.A. Benjamin, Menlo Park, C alif., 1972, p. 470-472.~~

~~was a mixture of two bromides (apparently the 6 -bromo compound 1 2 2 was formed in addition to 121). These products were easily separated on a~~

~~104 w < Br 'wa~~

liquid chromatograph equipped with y-Bondapack C-18 columns. Both the use of bromine or pyridinium hydrobromide perbromide generated these two 50 isomers. An effort was also made to prepare the enolacetate of but this product was also a mixture of isomers.

An alternate preparation of the 8 -methylthioquinolone 105 was de vised which prepared the sulfide by means of a functionalized methylvinyl- ketone. Reaction of enamine 1^4 and 1-methylthiobut-2-en-3-one (1^3) gave K)5 in 25% yield. The requisite methyl vinyl ketone was prepared from methyl 4-methylthioacetoacetate ( 8 6 va), which had been prepared previously.

~~hoch 2 ch2oh LiAlH- 0.1 eq TsOH 3N HC1 — — ------~~

~~SCH3 co 2 ch 3 sch 3 co 2 ch 3 SCH. OH~~

~~8 6 a 124 OA/V\, 'VX-'X,~~

~~1) CH.S0.C1 ------~~

~~2) (C2 H5)3N SCH sch 3 ch 2~~

~~126 123 'Vb'V Oj'X/X,~~

~~Treatment of 8 6 ^a with ethylene glycol and 0.1 equivalent of para-toluene sulfonic acid in refluxing benzene with water removal gave a 90% yield of~~

|24. Lithium aluminum hydride reduction of lj24 followed by basic workup afforded an 80% yield of the hydroxyketal 1^25. Hydroxyketone 1^6 was rapidly generated in 80 - 90% yield by treating lj25 with 3N hydrochloric acid. The e-hydroxyketone was smoothly dehydrated by sequential addition 51 of methanesulfonyl chloride and triethyl amine to generate 1^3 in 90 -

~~95% yield. The overall yield of 123~~

~~Quinolone K)5 was prepared in 25% yield by refluxing a dioxane~~

~~solution of 114r\ n n and. 123 r\s\s\ for 4 hr. The yield ** for this conversion was low~~

~~Dioxane~~

~~AA/h~~

~~105 'W b 'Wb~~

~~because of the formation of a,B-unsaturated ketone 124.a/\/b Compound r 124 m was a very persistent impurity which complicated the purification of 105.~~

~~ch 3s~~

~~'W b~~

~~Reaction of 105 through treatment with 2V-chloroaniline under a variety V\A/ J of temperatures and solvents did not afford any indolenine 106 or indole~~

107. The only products observed were aniline and the sulfide 105 or the 'X/b'b 'W b alcohol obtained from the reduction of 105. Gel permeation chromatography gave no indication of the formation of any higher molecular weight products.

~~Use of the chlorine-sulfide complex proved ineffective in generating the desired alkaloid precursors. 52~~

The failure of the reaction was believed to be due in part to the steric bulk of the 27-benzyl group. Removal of the benzyl group by con ventional methods was complicated by the presence of sulfur in the mole cule. An alternate method for removal of this group was by the chloroformate cleavage of te rtia ry amines which forms a carbamate and an alkyl

~~r q chloride. The amine and chloroformate react to form an ammonium species~~

~~0 0 _ + H _ri- II r 3n + cico 2 r' [R3N-C0R'r' P R2NC0R' + RC1~~

~~63. A. Wu and V. Snieckus, Tetrahedron L ett., 2057 (1975); T.A. Montzka, O.D. Matiskella, and R.A. Partyka, ibid., 1325 (1974); M.G. Reinecke and R.G. Doubert, J. Org. Chem., 38, 3281 (1973).~~

which is attacked at an R group by chloride. Use of 3,3,3-trichloroethyl- chloroformate would permit the secondary amine to be generated by treat ment of the carbamate with zinc. Treatment of 105 with a variety of chlor- 'WV oformates did not produce the desired debenzylated quinolone 125 but

~~ch 3s~~

~~126 WU125 'WU 53 instead, formed the ring opened carbamate 12j5. This arose from a e- elimination of the ammonium complex of 105.w o Analogous eliminations have 59c been observed in similar systems~~

The failure of the debenzylation required the preparation of a quinolone with a smaller protecting group on the nitrogen. The simplest and smallest group available was a methyl group. The synthesis of this quinolone is shown below. Reduction of the cyanoacetal VK3 with lithium

~~LiAlH, C-HcOCCl 113' 'W b~~

~~127 m~~

~~CH 3~~

~~129 130 131 W b W b~~

aluminum hydride followed by 1 0 % sodium hydroxide solution workup gave the crude primary aminoacetal 1^7 in 100% yield. This compound was not purified but was allowed to react directly with ethyl chloroformate in dichloromethane and pyridine to give a quantitative yield of carbamate

~~128. Lithium aluminum hydride reduction of 128 required refluxing for 'W b • 'W b n 54~~

~~15 hr in order to obtain a 91% yield of ^-.methylamine Stirring of~~

~~T29 with 3N hydrochloric acid gave the enamine 1^30 directly in 76% yield.~~

~~The enamine formed immediately in the acidic solution and did not require~~

~~extended dryingJ 3 withdessicant as had 114. m Theenamine 130 readily m re-J acted with methylthiomethylvinyl ketone (1^3) in refluxing dioxane to~~

form 131 in 40% yield. The quinolone 131 wasmuch easier to handle than AAA/ J ^ AAA 114 because of its decreased acid sensitivity, and because its lower mol- AAA/ ecular weight enabled it to be easily distilled.

~~The use of 13,1 in the Gassman indole synthesis provided none of the~~

~~desired indolenine or indole. The only products which were isolated were~~

~~the sulfide, aniline, and aniline decomposition products. The reaction~~

~~was attempted with different solvents, temperatures, and reaction times.~~

~~In addition to the iv-chloroani 1 ine route, the chlorosulfonium salt route~~

~~was tried and also failed to produce the desired compounds. None of the~~

~~higher molecular weight products were observed using gel permeation~~

~~chromotography. In addition, pmr examination of the indolenine indicated~~

~~that the unreacted sulfide was present, and the absence of the indolenine~~

~~was indicated by the absence of a peak for the methylthio group in the~~

~~1.20 - 1.45 6 region.~~

~~There are several explanations which might account for the failure~~

~~of these reactions. The reaction mechanism involves several intermediates,~~

~~and the failure of any one of these species to form or react properly~~

~~would prevent the success of the reaction. The first reaction inter~~

~~mediate is the azasulfonium salt. The possible failure of this salt to~~

~~form properly might be a result of the large steric bulk of the quinolone~~

or of the tertiary amine in l^H reacting with the w-chloroaniline and removing this starting material from the reaction. The formation of the azasulfonium salt by use of the chlorosulfonium salt of 131 miqht be 'VIA/ v complicated by a Pummerer type rearrangement of the intermediate chlor

~~osulfonium salt. Once this salt has formed, the ylide is the next inter mediate. Its formation may be slowed, because the steric hindrance around~~

~~the a-position might prohibit the attack of the base. An additional~~

~~problem could arise if the sulfonium methyl were attacked to form a d if ferent ylide. Once the desired ylide is generated, it could rearrange in~~

~~a Sommelet-Hauser type rearrangement which would lead directly to the desired indole or in a Stevens type rearrangement give other products.~~

~~In an effort to study the causes of the reaction's failure, the~~

~~carbocyclic analogue of 131 was desired. This compound would test both~~

~~0 bUH3 0 sch 3~~

~~W b w u Wb~~

the steric effects and the effect of the tertiary amine. There was no direct synthesis of compound T32 containing cis-ring juncture. However, a simplified decal one with a tr a n s -ring juncture appeared to be more available. Examination of models of 131, 132, and 133 showed very l i t t l e difference in steric environment around the sulfur. The replacement of the ethyl group by a methyl group had l i t t l e effect on the sulfur. The synthetic scheme to prepare 1^33 was to use octal one previously 64 prepared in six steps by Marshall and Schaefer, in a reductive - sulfenylation reaction. Although there are no references in the literature

~~1) Li/liq NH3 ¥~~

~~2) CH3 SSCH3~~

~~0 134 bbb 'Wb133~~

~~64. J.A. Marshall and D.J. Schaefer, J. Ovg. Chem.y 30, 3642 (1965).~~

~~for the reductive - sulfenylation reaction as in 134 to 133, there are 'W b O/Vb 65 numerous examples of reductive alkylations of the type shown below.~~

~~1) Li/liq NH > nBu 2) nBuI 57~~

65. H.A. Smith, B.J.L. Huff, W.J. Powers, III, and D. Caine, J. Ovg. Chem., 32, 2851 (1967); G. Stork, P. Rosen, N. Goldman, R.V. Coombs, and J. Tsuji, J. Amev. Chem. S o o, . 87, 275 (1965); L.E. Hightower, L.R. Glasgow, K.M. Stone, D.A. Albertson, and H.A. Smith, J. Ovg. Chem., 35, 1881 (1970).

~~These alkylations involve trapping of the lithium enolate by an alkyl halide. In our case, the lithium enolate would react with dimethyldi- sulfide to generate ,133 and methyl mercaptide.~~

~~Initial tests with 2-cyclohexenone gave 30 - 40% yields of 53Ji.~~

~~Octalone 134 was reduced with two equivalents of lithium metal in liquid~~

~~1) Li/liq NH3 (ch 3)3coh~~

~~2) CH3 SSCH3 Cr~~

~~53 i 'VWb~~

~~1) Li/liq NH3 (ch3)3coh 'Wb134 2) CH3 SSCH3~~

~~135 136 'V\A> m~~

ammonia in the presence of one equivalent of t e v t - butyl alcohol. The lith ium enolate was quenched with three equivalents of freshly d istille d di- methyldisulfide. After carefully chromatographing the material on silica 58 gel, the monosulfenylated material was obtained in 65% yield. The totally reduced decalone, T35, was obtained in 16% yield and a small amount of bis-sulfenylated product, T36, was also obtained. It is worthy of note that T33 was a mixture of isomers presumably at the 1 and 8 positions.

~~Every effort to effect the preparation of indolenine 1^£ and indole~~

1^38 met with failure. The only observed products were aniline, deca lone 133,'WO chlorinated anilines, and after reduction, the alcohol derived from T33. Reaction solvents, times, temperatures, and positive chlorine sources were all varied, but no evidence of the desired products was ever observed by pmr or gel permeation chromatography.

~~CH CH~~

~~2) 133 Wb~~

~~r\jrV \i Wb~~

~~'WV>~~

The failure of the indole forming reactions to proceed as expected prompted us to examine the reaction intermediates. The azasulfonium salt which was the first intermediate was a logical starting place. Due to the 59

~~instability of these intermediates at temperatures above about - 2 0 °,~~

~~low temperature nmr was employed. A series of sulfides were used to pre~~

~~pare the azasulfonium salts of aniline because of the limited nmr data~~

~~1 C available for these salts.~~

The method of choice for the preparation of the azasulfonium salts was to use a 5-ml, side-armed flask, equipped with a magnetic spin bar, under a nitrogen atmosphere, and cooled in a dry ice - isopropanol bath.

A 0.5-ml aliquot of deuterochloroform or dideuteromethylene chloride was added, followed by one equivalent of aniline. One equivalent of t e r t- butylhypochloride was added to generate w-chloroaniline and, after stir ring for 2 min, the sulfide was added dropwise. The solution was immedi ately transferred to a precooled nmr tube by means of teflon tubing and positive nitrogen pressure. When the transfer was made rapidly, little decomposition occurred. These experiments were normally conducted on a

0.09 to 0.13 mmol scale, and the concentrations ranged from about 0.18 to 0.25 molar. The spectra were obtained using a Varian CFT-20 spectrometer operating at 80 MHz with the probe temperature set at -59 ± 2°. Tetra- methylsilane was used as an internal reference.

Addition of tert-butylhypochlorite to a cold solution of aniline in deuterochloroform rapidly generated the tf-chloroaniline (24â). The in stantaneous formation of £4â was shown by the absence of aniline in the pmr spectra when the initial spectra were taken (see Appendix). The nitro gen proton of ^â was observed to occur at 6.36 6 while the aromatic pro tons were observed to occur from 7,00 - 7.40 6 . One equivalent of t e r t- butanol was formed during the preparation of 24 a and was observed at 60

~~1.27 and 3.35 s. The solution of 24 a was light yellow initially, but WlA slowly darkened to give a black solution after several hours. However,~~

~~24 a could be observed even after 24 hr at -78°. WIAj~~

A series of sixteen sulfides were used to prepare the azasulfonium salts of aniline. The spectra of the azasulfonium salts of dimethyl sulfide (25) and 3-methylthio-2-butanone (54 b) are included in the Appen- r\/\j 'VVVu r r dix as representative examples. Examination of these spectra indicated several sim ilarities. The most intense peak was that of the methyl groups of tert-butanol. The alcohol proton of tert-butanol was occasionally observed between 3.0 and 4.0 6 . An absorption from the chloroform im purity in deuterochloroform was also observed. This peak was located in the middle of the aromatic region and caused this region to integrate slightly higher.

The methylthio group of the azasulfonium salt shifted very predict ably downfield about 1.45 ppm from 2.00 - 2.10 6 to 3.10 - 3.53 6 . This shift was greater than for simple sulfonium salts which normally shift

~~rr downfield about 1.0 ppm down to 2.84 - 3.13 6 . The azasulfonium methyls are more deshielded than those of the corresponding sulfilim ines.^’^9’^ ’*^~~

~~The methyl groups of the sulfilimines normally appear between 2.40 and~~

~~2.85 6 . Table III lists the azasulfonium salt chemical shifts.~~

~~6 6 . C. Brown in "Sulfur in Organic and Inorganic Chemistry," A. Senning, Marcel Dekker, New York, 1972, Vol. 3, p. 276. 67. A.K. Sharma and D. Swern, Tetrahedron Lett. , 1503 (1974). 61~~

~~Table III. NMR Data of the Aniline Azasulfonium Salts.~~

~~Chemical Shifts~~

~~Azasul fonium Time of Sulfide Salt ch 3sn CHSN SNH formation~~

~~— Dimethyl sulfide AA/25 3.53 9.95 *5 min 1-Methylthio-2-propanone (53^a) AAAA54 a 3.48 5.45 1 0 . 0 0 <5 min~~

5.82 a, 2 0 3-Methylthio-2-butanone^ (53 'w b) w ' AAAA54 b 3.41 10.57 min 2-Methylthio-3-pentanone (53^) AAAA54 c 3.44 5.85 10.61 a-25 min 3-Methylthio-2-pentanone (53^d) AAAA54 d 3.42 6 . 1 2 10.59 a,2 hr 10.39

4-Methyl-3-methylthi o-2-pentanone AAAA54 e, 3.37 6.17 10.70 a,2 hr (53VWl/' e) 10.54 1-Methylthio-1-phenyl-2-propanone 54 f 3.10 a 10.60 <5 min AAAAj (53'VWV' f) 6.85 a a-Methylthiopropiophenone (53^) AAAA54 a 3.53 10.61 -15 min a-Methylthiobutyrophenone (53Ji) AAAA54 h 3.55 a 10.46 a.30 min 5.62 <5 min 2-Methylthiocyclohexanone (53^) AAAA54 i 3.40 10.46

~~2-Methylthiocyclooctanone (53^)^ 3.47 6 . 1 0 10.55 ^ 2 0 min 10.35~~

~~6 . 2 0 10.50 a,35 min 3-Methyl 2-methylthiocyclohexanone fWVrO54 k 3.53 (53 k) 3.40 10.36 'WW/ Methyl 4-methylthioacetoacetate O/Wlj54 n 3.45 5.55 10.95 c (85o/w\/ a) 10.60 9.95~~

~~Methyl 2-methyl-4-methylthioaceto WVV54 o 3.48 5.65 10.70 c acetate (89) 1 0 . 1 0~~

~~1 1 . 1 2 >3 hr Methyl 4-methylthi obutyrylacetate a/wu54 1 d d (53 1)~~

8 -Methylthi o-2-carbomethoxycyclo- AAAA.54 m 3.65 5.95 11.31 >2 ..25 1 octanone (53AAAA' m)b 3.54 10.90 a) These protons were obscured by the aromatic protons. b) The author wishes to thank Dr. April J. Evans for supplying the sam ples of 5 3 ^ and 53^rn used in this investigation. c) The s a lt was formed immediately but not completely. d) Not observed because only a small amount of the sa lt formed. 62

The a-protons of the azasulfonium salts were also shifted substan tia lly to a region from 5.40 to 7.00 6 . In several cases, residual coup ling was observed between the a and 3 protons, but usually these signals were broad singlets.

~~The most characteristic resonance of the azasulfonium salts was that of the nitrogen proton. This signal appeared from about 9.95 to~~

11.31 6 . In several instances, two or more signals were observed in this region. These could have arisen from different azasulfonium s a lt conformers or diastereomers. Because a sulfonium sulfur is tetrahedral any methylthioketone with an optically active center will form an aza sulfonium s a lt which is diastereomeric.

During the nmr examination of the azasulfonium salts, different rates of formation of the sulfides were observed. Because of different concentrations, temperatures, and times involved, actual rates were not calculated but rather a time of formation was obtained. The time of formation was judged to be the time when the starting sulfide had been completely transformed into the salt. Although there were several com pounds which appeared to be out of line, the general trend was that the unhindered sulfides reacted rapidly while the bulkier sulfides reacted more slowly to form the azasulfonium salts. For example, unhindered sul fides such as dimethyl sulfide, 53 a, 53 f , and 53 i all had completely J 9 O/Wb VWb 'WVb formed the salt within the 5 min it took to prepare the sample and obtain the spectra. Sulfides which possess large bulky groups in the a-position such as 53 d, 53 e, 53 1, and 53 m all required over 2 hr to completely V W l 'T/VIA, 'WVb 'Vb'Vb n form the salt. Sulfides intermediate in steric bulk, for example 53Jb, 63

S J l - S U > and a 1 1 t00k from 1 5 t 0 3 5 m1n t 0 completely form salts. The e-ketoesters rapidly formed the azasulfonium salts but did not form these salts quantitatively as had the other sulfides.

~~Azasulfonium s a lt 5 4 ^ was prepared as described above. Its spectra is shown in the Appendix. Addition of an equivalent of triethylamine to~~

~~54^a at -59° rapidly rearranged the salt and generated 2-methyl-3-methylthioindole (46 a). The presence of 46 a was shown by the peaks at 2.23~~

~~SCH SCH- CH-~~

~~OAAyOi46 a r\jr\/\j139~~

~~and 2.54 6 of the methylthio and methyl groups of 46^a, respectively.~~

~~The peaks at 1.92 and 2.13 may be the methyl signals of the Sommelet-~~

Hauser rearrangement product f39. These la tte r peaks disappeared as the sample was warmed to room temperature while those of 46 a increased. The r r v w v spectra of the mixture of 46 a and 139 along with a spectra of the indole r 'VW\> ,w\j ° r 46 a are included in the Appendix. 'WV r r

The spectra obtained upon the addition of methylthioquinolone l^H to iV-chloroaniline (24ja) indicated no azasulfonium salt formation. Compari son of the spectrar of 131, m 24 'wvxi a, and this mixture revealed only theJ pres- r ence of unreacted 131rW\> and 24 OA/W a. After maintaining Jthe sample r at -78° for 64

~~36 hr these two materials were unchanged. Warming a sample of ,13^ and~~

~~O/Wb24 a only decomposed 24 WVb a and did not effect any ^ azasulfonium s a lt formation. Similar experiments were conducted with the methylthiodecalone~~

'Wb133 which also failed to generate any of the desired azasulfonium salt. The failure of these compounds to form azasulfonium salts appeared to be a result of the sulfur's inability to displace the chloride from 24 a.'WVb The y-methyl group in 1^31 caused a great.increase in the steric hind rance around the sulfur. This increase in steric hindrance is in accord with Newman's rule of six.

Utilization of chlorine to generate the chlorosulfonium salt of ,^3^ also proved ineffective. A test of this procedure was carried out by mixing* vw 53 o b and aniline before the chlorine was added. The spectrum r of

~~54Jd, which was generated by this method, is included in the Appendix.~~

Repeated attempts to generate the azasulfonium salt of T3^ failed to pro duce any material with the expected spectral properties. The failure to generate this azasulfonium salt explained our inability to prepare the indole of quinolone 131. This was due to the large steric bulk of the n 'W b ^ quinolone which prevented the chloride from being displaced from any chlor osulfonium salt, which might have been present, by the aniline. Attempts to utilize the chlorine - sulfide complex gave rise to Pummerer type products.r Addition of chlorine to 131 'VT/b generated * the sulfoxide 140 Wb and the a-chloroquinolone 141. Sulfoxide 140 arose from oxidation of the AA/b AA/b chlorosulfonium salt while 14^ arose v ia a Pummerer type rearrangement.

~~These products were also formed during attempts to prepare the azasul fonium salt of nn and aniline and were identified mass spectroscopically. 65~~

~~CH CH3 S~~

~~140 141 'W b 'Wb~~

The failure of these reactions indicated that steric effects play a critical role in the formation of the azasulfonium sa lt. Because of the steric bulk of quinolonesn 105 o/w and 131 o/Wi and decalone 133, '\y\y\j these compounds must be considered to be outside the scope of the indole forming reaction. However, this method of indole synthesis should be applicable to a number of other indole alkaloid groups. EXPERIMENTAL

Melting points and boiling points are uncorrected. Proton magnetic spectra were recorded on Varian T-60, A-60A, CFT-20, and XL-100 spectro meters. Carbon-13 magnetic spectra were recorded on a Varian CFT-20 spectrometer. All chemical sh ifts are reported with respect to an in ternal TMS standard. Infrared spectra were recorded on Perkin-Elmer model 137 and Beckman model 4240 instruments. High resolution mass spec tra were recorded on AEI-MS9 and AEI-MS30 double focusing spectrometers.

~~Analytical vpc work was done on a Varian Aerograph Series 1200 Chroma tograph while all preparative vpc was done on a Varian Aerograph Model~~

~~700 Chromatograph using a 10' x 1/4", 10% SE-30 on 60/80 Chrom W column.~~

~~Analytical liquid chromatography was done on a Waters model ALC/ 6 PC~~

~~202/R401 Liquid Chromatograph using y . Porosil, y Bondapak C-18, and y Sty- ragel columns. Elemental analyses were performed by the Scandinavian~~

~~Microanalytical Laboratory, Box 25, Herlev, Denmark.~~

~~General Procedure for the Preparation of 2,3-Disubstituted Indoles. To WVV^^WljWVWWWWWWWV^aAjWViWWWWWWVWWV^W^WWWVVWb a vigorously stirred solution of 4.10 g (0.044 mol) of aniline 23jj in~~

~~200 ml of dichloromethane at -78°, was added dropwise a solution of 4.78 g~~

(0.044 mol)of t e v t -butyl hypochlorite in 20 ml of the same solvent. Af ter 5 min, 0.044 mol of the sulfide, (53 b-h), in 30 ml of dichlorometh- WWVl. ’ ane was added dropwise. The stirring was continued at -78° for 6-48 hr at which time 4.4 g (0.044 mol) of triethylamine in 20 ml of the same solvent was added and the mixture permitted to warm to room temperature over a 4 - 12 hr period. A 75-ml portion of water was added and the

66 67 reaction mixture was stirred for 15 min at which time the organic layer was separated, washed three additional times with water, and twice with a saturated sodium chloride solution. The solution was then dried over anhydrous magnesium sulfate, filtered, and the solution was evaporated to give the oily, crude indolenine 60 W b-h. b m The indolenine was checked by tic, ir, and nmr, before reduction with 3.34 g (0.088 mol) of lithium aluminum hydride in ether. The reaction mixture was hydrolyzed by the addition of 0.5 N aqueous sulfuric acid and removal of the organic layer.

~~The aqueous layer was then extracted three additional times with 100-ml portions of ether. The ether extracts were combined, washed twice with~~

0.5 N aqueous hydrochloric acid, once with a 100-ml portion of water, saturated sodium bicarbonate until neutral, and twice with saturated sodium chloride solution. The solution was dried over anhydrous mag nesium sulfate, filtered, and the solution was evaporated to yield the indole 61 b-h. The crude indoles were purified by either distillation, 'W V W b r J 9 recry stallizatio n , or column chromatography over silic a gel with either dichloromethane or benzene as the eluent.

~~3-Bromo-2-butanone (62). Compound 62 was prepared by the procedure of WWVWVWWWWW/ ■'VV r 'W r r J r 34 Faworsky and Issatschenko. This~~

~~0 yielded 38.5 g (0.26 mol, 31%) of~~

~~62, bp 48-50° (24 mm) [ l i t 3 4 bp 35-~~

~~38° (12 mm)].~~

~~To a stirred solution of 14.1 g (0.255 mol) of sodium methoxide at 0° in 500 ml of methanol was added 30 ml~~

~~(0.45 mol) of methanethiol. The reaction mixture was stirred for 15 min. 68~~

~~A 38.5-g (0.255 mol) portion of 3-~~

~~bromo- 2 -butanone (62^ was added slow~~

~~ly 1 y while keeping the temperature be~~

~~f CH-ll. low 5 . The reaction mixture was 3~~

~~S C H 3 then stirred for 24 hr before being 53^b poured into 300 ml water and ex~~

~~tracted three times with 1 0 0 -ml portions of ether. The combined ether extracts were washed with water~~

until neutral, once with saturated sodium chloride solution, dried over anhydrous magnesium su lfate, filte re d , evaporated, and the re s i due was d istille d to give 12.7 g (0.0107 mol, 42%) of 53Jt>, bp 59° (19 mm) [ l i t ^ bp 45-47° (15 mm)],

~~6 8 . F. Asinger, M. Thiel, and I. Kalzendorf, Justus Liebigs Ann. Chem.y 610, 25 (1957).~~

~~2,3-Dimethylindole (61 b). Indole 61 b was prepared according to the wwvwvmwwv\J'v x~~

~~mol) of 3-methylthio-2-butanone,~~

~~(53 b) and 4.10 g (0.044 mol) of~~

~~23 a. The reaction mixture was~~

~~stirred at -78° for 7 hr before the 'VWb61 b addition of 4.45 g (0.044 mol) of~~

~~triethyl amine which was followed by warming to room temperature over a 4 hr period. Reduction of the crude~~

~~indolenine yielded, after sublimation and recrystallization (pet ether), 69~~

~~5.42 g (0.0374 mol, 85%) of enjb, mp 104-106° ( l i t 38b mp 107°).~~

~~Interruption of the procedure at an earlier stage gave 8.90 g of~~

~~the crude intermediate 2,3-dimethyl-3-methylthioindolenine (frO^b);~~

~~ir , 1712, 1610, and 1587 cm-1 ; pmr (CDC13) 6 1.29 (3H, s, SCH3), 1.51~~

~~(3H, s, 3 -CH3 ), 2.34 (3H, s, 2-CH3), and 6.55 - 7.64 (4H, m, aromatic~~

~~H).~~

~~2-Bromo-3-pentanone (63). A 1-1, 3-necked, round-bottomed flask was e- WlAWbWVWl;Wl/V\A U quipped with a mechanical s tir r e r ,~~

~~a reflux condenser, and a 125-ml~~

~~0 CH^,. 11 CHg constant-pressure addition funnel.~~

~~A 156.0-g (0.75 mol) portion of Br finely ground cupric bromide was OAy63 added to 500 ml of a 1:1 mixture of~~

~~ethyl acetate and chloroform.~~

~~A 43.0-g (0.5 mol) portion of 3-pentanone was added to this stirred suspension. Heating was begun and the reaction occurred readily at about~~

80° with the loss of the dark color of the cupric bromide. The mixture was cooled, stirred for 3 hr, filtered, and the cuprous bromide pre cipitate was washed three times with 100-ml portions of chloroform. The organic layers were combined and washed three times with 1 0 0 -ml portions of water, three times with saturated sodium bicarbonate solution, and once with saturated sodium chloride solution. The organic solution was dried over anhydrous magnesium sulfate, filtered, evaporated, and the residue was distilled to give 35.0 g (0.21 mol, 57%) of 63, bp 90° (80 mm)

~~[ l i t 6 9 bp 48° (12 mm)]. 70~~

~~69. C. Rappe and R. Kumar, Ark. Kemi., 23, 475 (1965).~~

~~2-Methylthio-3-pentanone (53 c). To a stirred solution of 3.9 g (0.072 WWWWWWVWW\/WVVWI j ■ 'W W mol) of sodium methoxide in 150 ml~~

~~of methanol was added 10 ml (0.15~~

~~CH. CH. mol) of methanethiol at 0 ° and the~~

~~reaction mixture was stirred for 15 SCH. 53 c W\A; min. A 16.5 g (0.072 mol) portion~~

~~of 2-bromo-3-pentanone (63) was added~~

~~slowly while keeping the temperature l *1 r-ft i • • oeiow tr. me reaction mixture was stirred for 1 2 hr at room temperature~~

~~before being poured into 300 ml of water and extracted three times with~~

~~50-ml portions of ether. The combined ether extracts were washed with water until neutral, once with saturated sodium chloride, dried over an~~

~~hydrous magnesium sulfate, filte re d , evaporated, and the residue was d is~~

~~tille d to give 8.18 g (0.062 mol, 8 6 %) of 53^c, bp 87° (42 mm) [ l i t ^~~

~~bp 6 6 ° (17 mm)].~~

~~70. F. Asinger, M. Thiel, and E. Pallas, Justus Liebigs Ann. Chem., 602, 37 (1957).~~

~~2-Ethyl-3-methylindole (61 c). Indole 61 c was prepared according to the WVWWWmWlMMAM; N'WW> 'VW\> r r ^ general procedure on a 0.0159 mol scale with 2.1 g (0.0159 mol) of 53 c~~

~~and 1.48 g^ (0.0159 ' mol) ' of 23 'WV a.\j All of the amounts of the reagents and solvents were reduced to keep the concentrations the same as in the rpreparation of 61 VIM b. The reaction~~

~~was stirred for 8 hr at -78° before~~

~~the addition of 1.59 g (0.0159 mol)~~

~~of treithylamine. The reaction mix-~~

~~ture was permitted to warm to room 'VWV temperature over a 4 hr period. Af~~

~~te r reduction, workup, and recrystal lization from an ether-hexane mixture, 1.52 g (0.086 mol, 60%) of 61 c, VW\j mp 64-66° (lit^ k mp 65-66°) wasisolated.~~

~~Isolationprior toreduction gave 9.0 g of the crude intermediate~~

~~2-ethyl-3-methyl-3-methylthioindolenine (60 c); ir, 1704, 1610, and rV/\A/\j~~

~~1572 cm-1 ; pmr (CDC13) 6 1.27 (3H, s, -SCH3), 1.37 (3H, t , J = 7 Hz,~~

~~-CH2 C#3), 1.48 (3H, s, -3-CH3), 2.62 (2H, m, -Ctf2 CH3), and 6.50 - 7.65~~

~~(4H, m, aromatic H).~~

~~3-Bromo-2-pentanone (64). Compound 64 was prepared by slowly adding~~

~~31.96 g (0.2 mol) of bromine in 50~~

~~q ml of acetic acid to a stirred sol~~

~~ution of 17.23 g (0.2 mol) of 2- CH i CH 3 » 3 pentanone in 100 ml of acetic acid. Br After addition was complete, the mix~~

~~ture was heated to 80° and gaseous~~

hydrogen bromide bubbled in for 2 hr. After cooling to room temperature, the mixture was poured into 200 ml of water and extracted four times with 50-ml portions of ether. The ether extracts were combined and washed sequentially with water, satura ted sodium bicarbonate until neutral, and saturated sodium chloride. 72

The solution was dried over anhydrous magnesium sulfate, filtered, e- vaporated, and the resulting residue was distilled to give 21.2 g (0.129 mol, 64.5%) of 64, bp 75-76° (47 mm) [ l i t 7 1 bp 77-78° (44 mm)].

~~71. M.D. Mehta, D. M iller, and D.J.D. Tidy, J. Chem. Soo., 4614 (1963).~~

~~3-Methylthio-2-pentanone (53 d). To a stirred solution of 6.96 g (0.129 OA/V^OA.'toyv/V/VVVVVbajaA/VVVV/Xi 'V/'W \ i~~

~~mol) of sodium methoxide in 1 0 0 ml~~

~~g of methanol was added at 0 °, 1 2 ml~~

~~(0.18 mol) of methanethiol and the~~

~~CH3 T C H 3 reaction mixture was stirred for~~

~~5 3 d 15 min. A 21.2 g (0.129 mol) por-~~

~~tion of 64 was added slowly while~~

~~keeping the temperature below 5°.~~

The reaction mixture was stirred for 24 hr at room temperature before being poured into 300 ml of water and extracted three times with 75-ml portions of ether. The ethereal extracts were combined, washed with water until neutral, and once with saturated sodium chloride. Then the ethereal solution was dried over anhydrous magnesium sulfate, filtered, evaporated, and the residue was distilled to give 15.4 g (0.117 mol,

~~91%) of 53r\y\jr\y\j d, bp 87° (-36 mm), n U„ 4 ' 4 1.4648; i r , 1705 cm"1, pmr (CDCl.) 5 0.97 (3H, t , J = 7 Hz, - C H ^ ^ ) , 1.40 - 2.00 (2H, m, -CHC^CHg), 1.91~~

~~(3H, s, -CH3), 2.26 (3H, s, -SCH3), and 3.10 (1H, t , J = 7 Hz, -C CH2~).~~

~~Anal. Calcd. for CgH^OS; C, 54.50; H, 9.19; S, 24.25. Found:~~

~~C, 54.47; H, 9.01; S, 24.24. 73~~

~~3-Ethyl-2-methylindole (61 d), Indole 61 d was prepared according to 'VV/lA/V'tA^OiOA/VVVVlAA/VAA/'VV W W i oyW\, r r 3 the general procedure using 5.81 g~~

~~(0.044 mol) of 53 d and 4.10 g (0.044 ' 'W W j 3~~

~~CH. mol) of 23 a. The mixture was stirred~~

~~at -78° for 6 hr before the addition~~

~~of 4.45 g (0.044 mol) of treithyl-~~

~~amine. The reaction mixture was then~~

allowed to warm to room temperature over an 8 -hr period. After lithium aluminum hydride reduction, workup, and distillation, there was obtained 5.7 g (0.036 mol, 81%) of 61 d, * 7 'W V b bp 107° (0.27 mm) [ l i t 3 8 5 bp 156° (12 mm)].

~~Isolation of the intermediate prior to reduction gave 8.70 g of the crude 3-ethyl-2-methyl-3-methylthioindolenine (60jd); ir, 1709,~~

~~1605, 1579 cm"1; pmr (CDC13) 6 0.52 (3H, t, J = 7 Hz, -CHgC^), 1.27~~

~~(3H, s, -SCH3), 1.98 (2H, m, -C# 2 CH3), 2.19 (3H, s, -2-CH3), and 6.50 -~~

~~7.60 (4H, m, aromatic H).~~

~~4 -Methyl-3-methylthio-2-pentanone (53 e). A 33-ml portion of bromine~~

~~was added over a 1 -hr period to a~~

~~stirred solution of 64.5 g (0.64~~

~~mol) of 4-methyl-2-pentanone in 600 3 SCH ml of dichloromethane. After the~~

~~'WW53 e addition was complete, the reaction~~

~~mixture was refluxed for 1 hr before~~

cooling to room temperature. The organic layer was washed once with water, twice with saturated sodium bicarbonate solution, and once with saturated sodium chloride solution 74 before filtering through glass wool. Evaporation of the solvent yielded

~~108.7 g of crude 3-bromo-4-methyl-2-pentanone which was used directly in the preparation of 53 e. 'Ww~~

To a stirred solution of 33.0 g (0.61 mol) of sodium methoxide in 600 ml of methanol at 0 ° was added 6 6 ml ( 1 . 0 mol) of methanethiol and the reaction mixture was stirred for 15 min. A 108.7-g portion of crude a-bromoketone was slowly added while maintaining the temperature below 5°. The reaction mixture was stirred at room temperature for

1 2 hr before acidification with a small amount of concentrated hydro chloric acid. The precipitated sodium bromide was removed by filtra tio n and the solution was concentrated to about 200 ml. After addition of

600 ml of ether, the organic layer was washed with water until neutral and twice with saturated sodium chloride solution. The ethereal solu tion was dried over anhydrous magnesium sulfate, filtered, evaporated, and the residue was distilled to give 35.8 g (0.24 mol, 38%) of 53 c, 3 3 'VVWi bp 63-64° (10 mm), [ l i t 7 2 bp 65-66° (14 mm)].

~~72. F. Asinger, W. Schafer, G. Herkelmann, H. Roemgens, B.D. Reintges, 0. Scharein, and A. Wegerhoff, Justus Liebias Ann. Chem. , 672, 156 (1964). ^~~

~~3-Isopropyl-2-methylindole (61 e). Indole 61 e was prepared according 0/\AA/\/\/V\A^'VVVVV\/V\jK/\/\A/VV\A/ Xr\/\A /\t 'VU'VTj r r to the general procedure using 3.66 g (0.025 mol) of 53^ and 2.33 g~~

(0.025 mol) of aniline in 65 ml.of dichloromethane. The mixture was stirred for 17 hr at -78° before 1.49 g (0.028 mol) of sodium methoxide was added. The solution was stirred at -78° for an additional hour and 75

~~then slowly warmed to room tempera~~

~~ture. After lithium aluminum hydride~~

~~reduction, workup, and d is tilla tio n ,~~

~~2.13 g (0.012 mol, 49%) of 61 e was~~

~~obtained, bp 90-92° (0.01 mm) [ l i t 3 3 *5 61 p bp 1 2 0 ° (0 . 8 mm)].~~

~~Isolation of the intermediate prior to reduction gave 7,0 g of crude 3-isopropyl-2-methyl-3-methylthioindolenine (jSOje); ir , 2940, 1608, 1582, 1497, 775, and 747; pmr (CDC13)~~

~~6 0.55 (3H, d, J = 6.5 Hz, CHC«3), 1.25 (3H, d, J = 6.5 Hz, CHC//3 ), 1.26~~

~~(3H, s, -SCH3), 2.32 (3H, s, 2-CH3), and 6.50 - 7.60 (4H, m, aromatic H).~~

~~1-Chloro-l-phenyl-2-propanone ( 6 6 ). Compound 6 6 was prepared according wwwvwvi/wv^n/vwiAA/m r\/\j r o/v r r 9 to the procedure of Bordwell and 73 Scamehorn. This yielded 33.5 g~~

~~(0.20 mol, 89%) of 6 6 , bp 107° pu 3 (4 mm), [ l i t bp 91° (2.5 mm)]. Cl o/v~~

~~73. F.G. Bordwell and R.G. Scamehorn, j . Amev. Chem. S o c ., 90, 6751 (1968). ^~~

1-Methylthio-1-phenyl-2-propanone (53 f). Compound 53 f was prepared by the addition of 20 ml (0.30 ml) of methanethiol to a stirred suspension of 60 g of potassium carbonate in 2 0 0 ml of ether at 0 °, which was stirred for 15 min before 41.2 g (0.244 mol) of 1-chloro-l-phenyl-2-propanone 76

~~(6 6 ) was added dropwise. The reaction~~

~~mixture was stirred at 0° for 24 hr,~~

~~at which time the reaction mixture~~

~~was poured into 300 ml of water and~~

extracted three times with 1 0 0 -ml SCH 53 f O/WO portions of ether. The ether ex tracts were combined and washed se quentially with dilute hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride solution. The organic solution was dried over anhydrous magnesium sulfate, filtered, evaporated, and the residue was distilled to give 18.8 g (0.104 mol, 43%) of 53^, bp 76° (0.25 mm), n ^ 6 1.5339, (lit 7 4 bp 140-141° (11 mm), n ^ 0 1.5572], that solidified in the refrigerator.

~~74. M. Thiel, F. Asinger, and M. Fedtke, Justus Liebigs Ann. Chem., W615, i 77 (1968).~~

~~2-Methyl-3-phenylindole (61 f), Indole 61 f was prepared according to ^vx A^v ^oaaaa /w w v w Vwvo 'T/WO r r the general procedure from 7.91 g~~

~~(0.044 mol) of 53 f and 4.10 g 7 WVb ^ (0.044mol) of 2W). The reaction~~

~~mixture was stirred for 48 hr at~~

~~-78° before the addition of 4.45~~

~~g (0.044 mol) of triethyl amine, which~~

was followed by warming to room tem perature over a 7 hr period. After reduction, workup, chromatography on 77 silica gel with dichloromethane and recrystallization from hexane, 3.1 g (0.015 mol, 34%) of 61 f mp 58-60° (lit^ mp 60.0-60.5°) was obtained.

~~75. J. Bruce and F. S utcliffe, j . Chem. Soo., 4789 (1957).~~

~~Workup prior to reduction gave 3.9 g of the crude 2-methyl-3-methylthio- 3 -phenylindolenine (OO^f) by chromatography on s ilic a gel with d i~~

~~chloromethane; i r , 1585 cm”^; pmr (CDClg) 5 1.43 (3H, s, -SCH 3 ), 2.24~~

~~(3H, s, - 3 -CH3 )., and 6.90 - 7.65 (9H, m, aromatic H).~~

~~1-y-Anilino-l-methylthio-l-phenyl-2-propanone (73 f). Stevens product WyAA/W\/WWVWW>AVWV\AAA/VW\AW(AA/WVVWV\< . ■ 'VWV> 73 f was isolated by chromatography OA/IA, ^ J~~

~~of the crude indolenine 60O/Wb f. Chrom- atography of frO^f on silica gel with~~

~~methylene chloride as eluent gave~~

~~3.64 g (0.014 mol, 33%) of 60 f as 3 ' 'VWU~~

~~'VWb73 f an unstable oil and 7.70 g (0.028~~

~~mol, 64%) of 73WVL f as a yellow ^ o il; i r , 3442, 1704, 1612, 1499, 1449, 1431, 1355, 1317, 1264, 1185, 750,~~

~~697, and 690 cm-1 ; pmr (CDCI 3 ) 6 1.68 (3H, s, COCH3 ) , 2.04 (3H, s, -SCH3 )~~

~~5.98 (1H, s, NH), and 6.46 - 7.24 (10H, m, aromatic H).~~

A nal. Calcd w/e for C1 6 H1 7 N0S: 271.1031. Found: 271.1030. 78 a-Methylthiopropiophenone (53 g). Compound 5 3 ^ was prepared by the 'W\A/WW\.'V\JI^Aaa Aa /xAa .'VVVVVi WVl -7C procedure of Bohlman and Hoffer.

~~0 This yielded 36.0 g (0.20 mol,~~

~~85%) of 53jcj, bp 70-73° (0.05 mm)~~

~~[ l i t 7 6 bp 90-95° (0.01 mm)].~~

~~76. F. Bohlmann and G. Hoffer, Chem. B ev ., r\y\y\j 102, 4017 (1969).~~

~~3-Methyl-2-phenylindole (61 g). Indole 61 g was prepared following the O/WVV\j^^V\iVb0yWV\/l/\/\;'V\j OA/Vtf v m general procedure from 7.91 g (0.044~~

~~mol) of 53jjj and 4.10 g (0.044 mol)~~

~~of 21 a. The reaction mixture was 'V\A/Oj stirred for 27 hr at -78° before~~

~~addition of 4.45 g (0.044 mol) of~~

~~triethyl amine. The reaction mixture~~

was then allowed to warm to room temperature over a 12 hr period. After reduction, workup, and recrystal lization from an ether-pentane mixture, 6.30 g (0.03 mol, 69%) of 61^g, mp 91-93° ( l i t ^ k mp 91-93?) was obtained.

~~Workup prior to reduction gave 9.20 g of 3-methyl-3-methylthio-2- phenylindolenine (6j0^), ir, 1610 cm"^; pmr (CDCI 3 )~~

1.62 (3H, s, - 3 -CH3 ), 6.30 - 7.80 (9H, m, aromatic H). nywa - . . mlobutyro ^nyvv e (53Ji). A 54.5-g (0.340 mol) portion of bromine was slowly added to a stirred solution of 50.0 g (0.337 mol) of 79

~~butyrophenone in 500 ml of carbon~~

~~tetrachloride at 0 °. After warming~~

~~to room temperature, the solution was~~

~~washed sequentially with water, sat~~

~~53 h urated sodium bicarbonate until neu r\Ay\jf\, tral, and saturated sodium chloride.~~

~~The solution was dried over anhy~~

~~drous magnesium sulfate, filtered, and the solution was evaporated to~~

~~give 76.6 g (0.337 mol, 1 0 0 %) of crude a-bromobutyrophenone, which was~~

~~used directly in the preparation of 53 h. To a stirred solution of 18.2 u r r W V b g (0.337 mol) of sodium methoxide in 450 ml of methanol was added, at~~

~~0°, 33 ml (0,5 mol) of methanethiol and the reaction mixture was stirred~~

for 15 min. A 76.6.g (0.337 mol) portion of crude a-bromobutyrophenone was added slowly while keeping the temperature below 5°. The reaction mixture was stirred at room temperature for 24 hr before being poured

~~into 500 ml of water and then extracted three times with 100-ml portions~~

~~of ether. The ether extracts were combined, washed with water until neu~~

~~tra l, once with saturated sodium chloride, dried over anhydrous magnesium~~

~~sulfate, filtered, and evaporated, The residue was distilled to yield 54.1 g (0.28 mol, 83%) of 53 h, bp 90-91° (0.11 mm) [ l i t 7 7 bp 110° (0,4 mm)].~~

~~77. F. Asinger, W. Schafer, and H. Triem, Monatsh. Chem., 97, 1510 (1966).~~

~~3-Ethyl-2-phenylindole (61 h). Indole 61 h was prepared according to the '\AAA/VVA/\A/\AAAAA/\/\yVV\/\A» aAAA/ rVW\, r r j general procedure from 8.56 g (0.044 mol) of a-methylthiobutyrophenone~~

~~(53 h), and 4.10 g (0.044 mol) of 23 a. The reaction mixture was stirred 80~~

~~at -78° for 24 hr before 4.45 g~~

~~(0.044 mol) of triethylamine was CH 3 added. The reaction mixture was~~

~~warmed to room temperature over a H 5 hr period. After reduction, work VWb61 h up, column chromatography on silic a~~

~~gel with benzene, and recry stal lization from an ether-hexane mixture, 4.007 g (0.018 ' mol, 41%)71 of 61 C\T\T\f\. h, 7 mp 74-75° ( l i t ^ mp 65°), was obtained.~~

~~78. J. Fitzpatrick and R. Hiser, J. Org. Chem., 22, 1703 (1957); A. Korczynski, W. Brydowna, and L. Kierzck, Gazf^Chim. I t a., l 56, 911 (1926). ^~~

~~Isolation prior to reduction gave 10.5 g of the impure intermediate~~

~~3-ethyl-3-methyl thio-2-phe-nyl indolenine 60Ji. The nmr (CDCI 3 ) showed~~

~~6 0.40 (3H, t , J = 7 Hz, -CH2C 3) and 6.50 - 7.70 (9H, m, aromatic H) among other absorbances.~~

~~3-Methyl-2-phenylindole by Chlorine-Sulfide Complex (61 g). Indole 61 g~~

~~was prepared by condensing 1.3 ml~~

~~(0.030 mol) of chlorine in a grad- PH 3 uated centrifuge tube. The chlorine~~

~~was added to a vigorously stirred H solution of 5.05 g (0.028 mol) of~~

~~a-methylthiopropiophenone (23 j j )~~

in 125 ml of methylene chloride at 81 -78° by connecting the centrifuge tube to a U-shaped tube and gradually warming the tube. During the addition, the chlorine was prevented from escaping from the reaction vessel by means of a small dry ice - acetone trap. The precipitated chlorosulfonium salt was stirred for 15 min before

~~5.74 g (0.062 mol) of aniline was added in 30 ml of methylene chloride.~~

After 4 hr, 8 ml (0.056 mol) of triethylamine was added. The mixture was stirre d at -78° for about 30 min before removal of the dry ice - acetone bath and the mixture was permitted to warm to room temperature over a 4-hr period. A 100-ml portion of water was added and the re action mixture was stirred for 15 min, at which time the organic layer was separated, washed three additional times with water, and twice with a saturated sodium chloride solution. The solution was then dried over anhydrous magnesium sulfate, filtered, and the solution was evaporated to give the oily, crude indolenine 60jcj- The indolenine was checked by tic, ir, and nmr, before reduction with 5.0 g (0.13 mol) of lithium aluminum hydride in ether. The reaction mixture was hydrolyzed by the addition of 0.5 N aqueous sulfuric acid and removal of the organic layer.

~~The aqueous layer was then extracted three additional times with 100-ml portions of ether. The ether extracts were combined, washed twice with~~

0.5 N aqueous hydrochloric acid, once with a 100-ml portion of water, saturated sodium bicarbonate until neutral, and twice with saturated sodium chloride. The solution was dried over anhydrous magnesium sul fate, filtered, and the solution was evaporated to yield the indole 61^.

~~The indole was purified by recrystallization from ether-pentane solution~~

~~•.«« a oc /i ( r\ noi ci ^ on qqo /i^ +38b mri Q1 n,o\ 82~~

~~3-Methylthio-3-buten-2-one (98 d). To 1.32 g (0.01 mol) of 53 d in 20 VWWWWWVVWWVWVWW\i OAA/V. WW< ml of toluene at -78° was added 0.43~~

~~q ml (0.01 mol) of chlorine. The yel-~~

~~low solution turned clear as the CH3 CH3 chlorine was added, but no precipi- 3 98^d tate appeared. Addition of 20 ml~~

~~of pentane did not precipitate any~~

chlorosulfonium salt. After 3 hr at -78°, the solution was wanned to room temperature and washed with two 50-ml portions of water and twice with 25-ml portions of saturated sodium chloride solution. After drying with anhydrous magnesium sul fate, vpc analysis indicated a small amount of 53 d plus two unidenti- r ** o /w \, r fied compounds.

~~Compound 98jd was isolated by preparative vpc at 110° and id en ti fied by its spectral properties; ir (CDC13) 2941, 1669, 1597, 1422,~~

~~1351, 1233, and 1111 cm-1 ; pmr (CDC13) 6 2.08 (3H, d, J = 7 Hz, CHC 3),~~

~~2.20 (3H, s, -SCH3), 2.39 (3H, s, CH3 C0), and 7.07 (1H, q, J = 7 Hz,~~

~~CtfCH3).~~

~~Anal. Calcd m/e for CgH-jgOS: 130.0452. Found: 130.0450.~~

3-Ethyl-2-methylindole bythe.Chlorine-Sulfide Complex (61 d). Indole VWWvWVWWWWVVV\/\jV\nA/WVVVWWVWWVVWWWV\AAAAi ' iWV\j 61^d was prepared by condensing 2.0 ml (0.044 mol) of chlorine in a graduated centrifuge tube. The chlorine was diluted with 5 ml of cold methylene chloride and added to a mixture of 8.20 g (0.088 mol) of 23 a J ' 7 'VW» and 5.82 g* (0.044 ' mol) of 53 WVb d in 150 ml of methylene chloride at -78°. The reaction immediately exothermed and darkened. After about 5 min a yellowish white precipitate formed and this was stirred for an additional 83

~~5 min. Addition of 6 . 8 ml (0.048~~

~~mol) of triethyl amine in 13 ml of~~

~~methylene chloride caused the pre~~

~~cipitate to dissolve. The reaction~~

~~OAA/'V61 d mixture was slowly warmed to room~~

~~temperature before 1 0 0 ml of water~~

~~was added. The organic layer was~~

~~separated, washed three additional times with water and twice with~~

~~saturated sodium chloride solution. The solution was filtered through~~

~~glass wool and evaporated to give 7.20 g of crude indolenine 60^. The~~

~~indolenine was checked by nmr before reduction with 3.70 g (0.097 mol)~~

~~of lithium aluminum hydride in ether. The reaction mixture was hydro~~

~~lyzed by the addition of 14.80 ml of 10% sodium hydroxide solution. The~~

~~precipitated salts were filtered and washed thoroughly with ether. The~~

~~organic layers were combined, washed three times with 5% hydrochloric~~

~~acid, once with water, twice with saturated sodium bicarbonate solution~~

~~and twice with saturated sodium chloride solution. The solution was dried~~

~~over anhydrous magnesium sulfate, filtered, and the solution was evapo~~

~~rated to yield the crude indole. D istillatio n gave 3.16 g (0.020 mol,~~

~~45%) of 61 d, bp 95-96° (0.025 mm), [ l i t 38b bp 156° (12 mm)]. 'VW\, r~~

~~Tetrahydrocarbazole (78) by the Chlorine-Sulfide Complex. Tetrahydro- W/WWVWWVWVWV 'Vb WAAA/VbmWWW\A/\MM^V\^^m carbazole (78) was prepared by condensing 2.0 ml (0.044 mol) of chlorine~~

~~in a graduated centrifuge tube. The chlorine was diluted with 5 ml of~~

~~cold methylene chloride and added to a mixture of 8 . 2 0 g(0.088 mol) of~~

~~OAAA^23 a and 6.35 j g x (0.044 mol) 9 of 53 'VWV» i in 150 ml of methylene ^ chloride at 84~~

~~-78°. The reaction immediately exo-~~

~~thermed and darkened. After about~~

~~5mi.na precipitate appeared and the~~

~~mixture was stirred for an additional~~

~~5 min. Addition of 6 . 8 ml (0.048 mol) 78 r\Aj of triethyl amine in 13 ml of methylene~~

~~chloride caused the precipitate to~~

~~dissolve. The reaction mixture was slowly warmed to room temperature~~

~~before 100 ml of water was added. The organic layer was separated, washed~~

~~three additional times with water and twice with saturated sodium chlor~~

~~ide solution. The solution was filtered through glass wool and evapo~~

~~rated to give 7.0 g of the crude tetrahydrocarbazolenine 77.r\y\j This material was checked by nmr before reduction with 3.60 g (0.095 mol) of lithium~~

~~aluminum hydride in ether. The reaction mixture was hydrolyzed by the addition of 14.40 ml of 10% sodium hydroxide solution. The precipitated~~

salts were filtered and washed thoroughly with ether. The organic layers were combined, washed three times with 5% hydrochloric acid, once with water, twice with saturated sodium bicarbonate solution and twice with

saturated sodium chloride solution. The solution was dried over an hydrous magnesium sulfate, filtered, and the solution was evaporated to yield crude tetrahydrocarbazole. Chromatography on s ilic a gel with

~~7:3 benzenerhigh boiling petroleum ether as eluent gave 1.87 g (0.011 mol, 25%) of 78, mp 109-115° ( l i t 2 8 mp 114.5-117°). 2 4 1 eth ^ ^ ( 6 8 )- ^ 100-mg (0.5 mmol) portion of 3-methyl-3-~~

~~methylthiooxindole (67) was re-~~

~~fluxed for 15 hr in 25 ml of methanol~~

~~CH^ which contained 76 mg (1.4 mmol) of~~

~~lithium methyl mercaptide. The~~

~~H solution was then poured into 100 ml 68 ^ of water and extracted three times~~

~~with methylene chloride. The organic extracts were combined and washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give~~

~~35 mg (0.24 mmol, 48%) of 6 8 , mp 121-123° ( l i t 3 1 mp 122-124°).~~

~~Methyl 4-Methylthioacetoacetate (85 a). A 655.0-g (4.10 mol) portion of V\AAj'WW\iWV'jWWWVWIjVWW\jW oaaa j r bromine was slowly added to a stirred~~

~~solution of 467.5 g (4.05 mol) of~~

~~methyl acetoacetatein 1500 ml of~~

~~carbon tetrachloride at room tem~~

~~perature. After the solution had~~

stirred overnight, it was extracted 85 a 'VO'VOi three times with 300-ml portions of saturated sodium chloridesolution, three times with 300-ml portions of saturated sodium bicarbonatesolution and three times with 300-ml portions of saturated sodium chloride. The solution was dried over an hydrous sodium sulfate, filtered and the solvent was evaporated to give

~~693.0 g (3.5 mol, 87%) of crude methyl 4-bromoacetoacetate; ir(neat) 1750, and 1720 cm"1; pmr (CDC13) 6 3.72 (2H, s, C0CH2 C02), 3.74 (3H, s, -0CH3), 86~~

~~and 4.09 (2H, s, -CH 2 Br). Because this bromide was a powerful lachro-~~

~~mator, it was used directly in the preparation of 85 a. r r~~

~~To a mechanically stirred solution of 189.3 g (3.5 mol) of sodium methoxide in 1500 ml of anhydrous methanol at 0°, was added 320 ml~~

(4.85 mol) of methanethiol and the reaction mixture was stirred for 15 min. The 693.0-g (3.5 mol) portion of crude methyl 4-bromoacetoacetate was added slowly while the temperature was maintained below 5°. The

~~reaction mixture was stirred at room temperature for 24 hr before ad dition of 400 ml of benzene and the solution was filtered through a~~

c elite pad which was subsequently washed with a 2 0 0 -ml portion of methanol. At this point the f iltr a te was checked for acidity and if necessary the pH was adjusted to 7. The filtrate was evaporated to about

~~1 1 and added to 1.5 1 of ether which was washed twice with 200-ml por~~

tions of water and eight times with 2 0 0 -ml portions of saturated sodium chloride solution. The in itia l aqueous extracts were back extracted with fresh ether and these were added to the original organic layer. The ether solution was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was distilled to yield

~~439.6 g (2.70 mol, 6 8 %) of 85 a; bp 67-69° (0.25 mm); n ^ 5 1.4885; ir (neat) rv/v\»ru U~~

~~1749 and 1715 cm-1 ; pmr (CDC13) 5 2.08 (3H, s, -SCH 3 ) , 3.37 (2H, s,~~

~~-SCH2-) , 3.71 (2H, s, C0CH2 C02), and 3.76 (3H, s, -OCH3 ).~~

~~Anal. Calcd for CgH-j^S: C, 44.43; H, 6.21; S, 19.77. Found:~~

~~C, 44.36; H, 6.23; S, 19.77. Methyl 2-(3-Methylthioindolyl)acetate ( 8 6 a). To a vigorously stirred wwwwvwwvwwwwwvwwvwwvv - - - - - ^ solution of 0.93 g (10.0 mmol) of~~

~~aniline (23 a) in 35 ml of dichloro-~~

~~SCH. methane at -78° was added dropwise~~

~~a solution of 1.08 g ( 1 0 . 0 mmol)~~

~~of t e v t -butyl hypochlorite in 5 ml~~

~~co 2 ch 3 8 6 a 'W \> rb of the same solvent. After 5 min,~~

~~1.62 g ( 1 0 . 0 mmol) of in 6 ml of the same solvent was added dropwise. The stirring was continued at~~

~~-78° for 7 hr at which time the reaction mixture had turned a dark brown.~~

~~A 1.55-ml (11.0 mmol) portion of triethyl amine was added dropwise and the reaction mixture was allowed to warm slowly to room temperature. A~~

25-ml portion of water was added and the reaction mixture was stirred for an additional 30 min at which time the organic layer was separated, washed twice with 3N hydrochloric acid, twice with 10% sodium hydroxide solution, and twice with saturated sodium chloride solution. The solution was then dried over anhydrous magnesium sulfate, filtered and evaporated to give

1.80 g of crude 8 6 a as a red o il. Chromatography on silic a gel with benzene-eluent gave 1.52 g (6.46 mmol, 65% yield) of 8 6 a, mp 92.5-93.5°; 'WVTj ir (KBr) 3360, 1723, 1436, 1318, 1211, 994, 968, and 739 cmrl ; pmr (CDC13)

~~6 2.24 (3H, s, SCH3), 3.73 (3H, s, OCH3 ), 4.02 (2H, s, CH2), 7.05 - 7.37~~

~~(3H, m, C-4, 5, and 6 H), 7.60 - 7.87 (1H, m, C-7H), and 8.93 (1H, bs, NH).~~

~~Anal. Calcd for C, 61.25; H, 5.57; N, 5.95; S, 13.63.~~

~~Found: C, 61.46; H, 5.66; N, 5.98; S, 13.53.~~

Methyl 2-Indolylacetate (87 a). A solution of 2.00 g (8.50 mol) of 8 6 a WWWWVbWbVWbWVWb 'WW * v ' 'WVC in 150 ml of anhydrous methanol was stirred with 6 teaspoonfuls of W-2 88 Raney nickel for 2.5 hr. The indole

~~containing solution was decanted, the~~

~~Raney nickel was washed six times~~

~~with methanol and the methanol washes~~

~~were evaporated. The residue was d is C02 CH3 solved in dichloromethane, dried over~~

~~anhydrous magnesium sulfate, and the~~

~~solution was filtered in vacuo. Evaporation of the solvent gave 1.44 g~~

~~(7.60 mmol, 90%) of 8 7 ^ , mp 73-75° ( l i t 7 9 mp 71-73°).~~

~~79. K.S. Bhandari and V. Snieckus, Can. J. Chem., 49, 2354 (1971).~~

~~Ethyl 4-Methylthioacetoacetate (85 b). Sulfide 85 b was prepared, ac- OA/VAAA/V\AA/\/V/l/iuaAAAA/\/V\^^ 'w \A i W/Vb r r cording to the procedure used for~~

~~the preparation of 85 a, on a r r 'V W O 0 0 0.50 mol scale to produce 53.62 g~~

~~0C2 H5 (o.30 mol, 61%) of 85Jb, bp 75-76c SCH3~~

~~(0.025 mm) [ l i t 8 0 bp 68-70° (0.09 85 b mm)].~~

~~80. B. Ladesic and D. Keglevic, Croat. Chem. Acta, 38, 155 (1966).~~

Ethyl 2-(3-Methylthioindolyllacetate ( 8 6 b). Indole 8 6 b was prepared, WVWWVVuWViAM/WVWbWWVU 'WW 'WVb according to the procedure used for the preparation of 8 6 ^a., on a 0.044 mol scale to give 5.80 g (0.023 mol, 53%) of 8 6 b, mp 69-70°; ir (KBr) 89

~~3390, 3008, 2941, 1724, 1429, 1370, 1321~~

~~SCH 1296, 1248, 1232,1202, 1020, 971, and 747cm"1; pmr (CDC13) 1.27 (3H, t , J =~~

~~7 Hz, CH2 Ctf3), 2.24 (3H, s, -SCH3 ),~~

~~4.00 (2H, s, CH2 C02), 4.20 (2H, q, J =~~

~~7 Hz, C#2 CH2) , 6.77 - 7.43 (3H, m, aro matic H), 7.53 - 7.83 (1H, m, 7-H), and 8.97 (1H, s, NH).~~

~~Anal• Calcd for C-^H-jgNOgS: C, 62.63; H, 6.06; N, 5.62; S, 12.86.~~

~~Found: C, 62.70; H, 6.16; N, 5.53; S, 12.75.~~

~~Ethyl 2-Indolylacetate (87 b) A 2.50-g (10.0 mmol) portion of was W W VW W W \i^W l/b'VW b'Vl 'WVb desulfurized according to the procedure~~

~~described above for the preparation of~~

~~87 a to yield 1.79 g ( 8 . 8 mmol, 'WW ^ 3 N ’ of 87 b, bp 110-115° (0.001 mm) [lit',.43 'W V b r ' ' u~~

~~CO2 C2 H5 bp 119-122° (0.003 mm)].~~

~~Methyl 2-Methylacetoacetate ( 8 8 ). A mixture of 151.0 g (1.30 mol) of~~

~~mol) of methyl iodide, 168.0 g ( 1 . 2 2~~

~~0 0 mol) of anhydrous potassium carbonate,~~

~~CH 0CH and 250 ml of acetone were placed~~

~~CH in a 1 - 1 , round-bottomed flask 3 fitted with an efficient reflux con~~

denser and a calcium sulfate drying tube. The material was heated under reflux for 4 hr and then allowed to cool to room temperature. The insoluble material was filtered and 90 thoroughly washed with acetone. The combined filtrate and acetone washings were concentrated and carefully d istille d through a spinning band distillation apparatus to give 50.9 g (0.39 mol, 30%) of 8 8 , greater than 98% pure; bp 80-81° (20 mm) [ l i t * 4.81 bp 76-76.5° (20 mm)].

~~81. H.M.E. Cardwell, J. Chem. S o a ., 715 (1949)~~

~~Methyl 2-Methyl-4-methylthioacetoacetate (89). Sulfide 89 was prepared W lA/VVW \j^V\AW \AW \jVbVW \/VV\JVV\/V\A/V\jW\j l\ ,r\j OA. according to the procedure used for~~

~~the preparationr r of 85 'W\ a j onO> a 0.39~~

~~0 mol scale to produce 42.8 g (0.24~~

~~0CH, mol, 62%) of 89, bp 64-65° (0.07~~

~~SCH0 CH. mm); ir (neat film) 2924, 1721, 89 1709, 1437, 1377, 1209 cm"1; pmr~~

~~(CDC13) 6 1.40 (3H, d, J = 7.5 Hz,~~

~~CHC#3) ; 2.04 (3H, s, SCH3 ) , 3.36 (2H, q, J = 13.4 Hz, SCH2), 3.74 (3H, s,~~

~~0 CH3 ), 4.07 (1H, q, J = 7.5 Hz, CtfCH3).~~

~~Anal. Calcd for C^H-^^S'- C, 47.71; H, 6.87; S, 18.19. Found:~~

~~C, 47.59; H, 6.90; S, 18.14.~~

~~Methyl a-Methyl-2-(3-methylthioindolylJacetate (90). Indole 90 was pre- VWVWVVWWl/TAAiWWWWW/WWVWWVVWV^VliV^ ,v\j W j pared according to the procedure used~~

~~for the preparation of 8 6 a on a SCH r r O/VW 0.044 mol scale to give 5.80 g~~

~~(0.023 mol, 53%) of 90, mp 80-81.5°;~~

~~ir (KBr) 3350, 2999, 1708, 1444,~~

1426, 1419, 1332, 1208, 1173, 1077, 1003, 969, 958, 864, 802, 757, 745, 710 cm"1, pmr (CDClg) 6 1.56 (3H, d, J = 7 Hz, CHCff3), 2.25 (3H, s, SCH3), 3.70 (3H, s, 0CH3), 4.53 (1H, q, J = 7 Hz, CtfCH3), 7.00 - 7.45 (3H, m, C-4, 5, 6 H), 7.55 - 7.85

~~(1H, m, 7-H), 8.87 (1H, bs, NH).~~

~~Anal. Calcd for C1 3 H1 5 N02 S: C, 62.63; H, 6.06; N, 5.62; S, 12.86.~~

~~Found: C, 62.69; H, 6.04; N, 5.55; S, 12.84.~~

~~Methyl a-Methyl-2-indolylacetate (91). A 3.90 g (15.6 mmol) portion of WlAMAimWlAAAA/\AiWbVuWl/'iA/WVb AA, 90 was desulfurized according to the~~

~~procedure used for the preparation of~~

~~87 a to yield 2.85 g (14.0 mmol,~~

~~90%) of mp 92-93°; ir (KBr)~~

~~3360, 2937, 1708, 1446, 1417,~~

~~co 2 ch 3 1325, 1259, 1190, 1085, 1064, 1025,~~

~~1006, 941, 923, 847, 798, 778, 745,~~

~~736, and 693 cm"1; pmr (CDC13) 6 1.55 (3H, d, J = 7.1 Hz, C C 3); 3.62~~

~~(3H, s, 0CH3), 3.86 (1H, q, J = 7.1 Hz, CtfCH3), 6.30 (1H, m, 3-H), 6.85 -~~

~~7.28 (3H, m, 4-, 5-, 6 -H), 7.33 - 7.63 (1H, m, 7-H), 8.45 (1H, bs, NH).~~

~~Anal. Calcd.for C^H^NO.?: C, 70.92; H, 6.45; N, 6.89. Found:~~

~~C, 70.91; H, 6.59; N, 6.78.~~

~~Ethyl. 4-Methylthiobytyroacetate (92). Sulfide 92 was prepared according AAAAA/WXAA/tAAAAAAAAAAAAAiAAAAAAA; AA/ AA. to the procedure used for the prep-~~

~~aration of 85 a on a 0.316 mol scale W\A j ch3^ V SA , c h 2h5 to give 52.4 g (0.257 mol, 81%) of~~

~~SCH0 92, bp 70° (0.1 mm); ir (neat film) 92 AA, 2994, 1748, 1707, 1366, 1314, 1242,~~

~~1149, 1028 cm”1; pmr (CDC13) 5 0.94 92~~

~~(3H, t , J = 7.0 Hz, CHCH2 C#3), 1.22 (3H, t, J = 7 Hz, OCHgCi^), 1.45 -~~

~~2.00 (2H, m, CHCtf2 CH3), 1.79 (3H, s, SCH3 ) , 3.15 (1H, t, J = 7.0 Hz,~~

~~CHS), 3.45 (2H, q, J =15.0 Hz,C0CH2 C02) , 4.03 (2H, q, J = 7.0 Hz, OCH2).~~

~~Anal. Calcd for CgH-jgOgS: C, 52.92; H, 7.90; S, 15.69. Found:~~

~~C, 52.88; H, 7.81; S, 15.45. iV-(l-ButenylIpiperidine (111). To a mixture of 409.0 g (4.80 mol) of~~

~~piperidine and 166.0 g ( 1 . 2 mol) of~~

~~potassium carbonate at 0°, 144.2 g~~

~~(2 . 0 mol) of butyraldehyde was added~~

~~si jwly over 0.5 hr and the reaction~~

~~mixture was stirred at room tempera- m PH 3 ture for 3 hr. The potassium carbon~~

ate was removed by filtra tio n in vacuo and the solid residue was washed with 400 ml of ether. The fil trate was transferred to a distillation apparatus and the ether and ex cess piperidinewere removed at atmospheric pressure. The bath tempera ture was graduallyincreased to 180° in order to decompose the inter mediate aminal and remove the piperidine. After the distillation temper ature rose above 1 1 0 °, the distillation apparatus was cooled and the residue was d istille d under reduced pressure. After d istilla tio n , 241.0 g (1.73 mol, 87%) of TH was obtained, bp 52-58° (7.0 mm) [lit*^ bp

~~70-71° (10.0 mm)].~~

~~82. C. Mannich and H. Davidson, Chem. B e r., 69, 2106 (1936). 93~~

~~4-Formylcapronitrile (112). A mixture of 185.0 g (3.50 mol) of acrylo~~

~~nitrile in 500 ml of acetonitrile was~~

~~added over a 0.5-hr period to a CN stirred solution of 241.0 g (1.73 H mol) of 111 in 1300 ml of aceto-~~

~~nitrile. The mixture was stirred U 2 for 5 hr before refluxing for 36 hr,~~

at which time 105 ml of acetic acid in 695 ml of water was added, and the reaction mixture was refluxed for an additional 8 hr. After cooling the reaction mixture to room tempera ture, solid sodium chloride was added and the saturated water layer was removed and extracted with ether. The ether extracts were combined with the organic layer and the solution was concentrated in vacuo. The residue from the evaporation was redissolved in ether and washed succes sively with 2N hydrochloric acid and saturated sodium chloride solution.

~~The ethereal solution was dried over anhydrous sodium sulfate, filtered , 58 and the solution was evaporated to give 155.1 g (1.24 mol, 71%) of V12 which was used without further purification.~~

~~4-Formylcapronitrile-l,3-dioxolane (113). Acetal 113 was prepared by 58 the procedure of Ziegler on a 1.24~~

~~mol scale. This yielded 179.2 g~~

~~CN (1.06 mol, 8 6 %) of n 3 , bp 126-~~

~~127° (8.0 mm) [ l i t 5 8 bp 147-149° Q4J>- Enan,ine was Pre- pared on a 0.27 mol scale by Ziegler~~

~~CO procedure. This yielded 33.72 g~~

~~(0.173 mol, 64%) of 114, bp 76° 'WX, r~~

~~(0.04 mm) [lit 5 8 56%, bp 91-94°~~

~~(0.24 mm)], cmr (CDC13) 6 13.2 114 'W b (-CH3), 22.7, 24.7, 28.4, 47.5~~

~~(C-6 ) , 60.1 (C6 H5 CH2), 112.5 (C-3),~~

~~127.0, 128.3, 128.4, 130.6 (aromatic C-l).~~

-Benzyl-4a-ethyl-2,3,4,4a,5,6,8,8a-octahydro-7(lH)-quinolone (104). O/VX,VV\AA/»AVW ViA/W wVW VV\jW \;W W V\jW VW V\AA/W W tfW ^W lj,VV\j'W\/ 'WU Quinolone 104 was prepared on a 10.0 o /v b r r mmol scale by the procedure of Ste-

~~vens * with the modification of~~

~~using cellvosolve as the reaction~~

~~solvent instead of ethylene glycol. m This gave 1.39 g (5.1 mol, 51%)~~

~~of 104, mp 81-82° ( l i t 5^ mp 81.5- 'Vb'b r r~~

~~82°); cmr (CDC13) 6 7.4 (CH3), 21.3, 26.2, 29.8, 33.2, 35.4, 35.9 (C-4a)~~

~~37.2, 46.1 (C-2), 58.6 (CgHgCHg), 64.6 (C- 8 a), 126.9 (p-C), 128.2~~

~~(o- or m-aromatic C), 128.6 ( o- or m-arornatic C), 139.5 (aromatic C-l) and 212.0 (C=0).~~

Q^>- To a so’u- tion of 1 . 6 ml of concentrated hydrochloric acid, 2 0 ml of acetic acid, and 173 ml of methanol, was added 2.69 g (9.91 mmol) of 104. The resul- tant solution was hydrogenated over 2 0 0 mg of 1 0 % palladium on carbon at 95

~~atmospheric pressure until uptake~~

~~ceased. After removal of the cata~~

~~lyst, the solution was concentrated,~~

~~partitioned between ether and 2 0 %~~

~~sodium carbonate solution, and the~~

~~aqueous layer was washed three addi~~

tional times with ether. The organic extracts were combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filte re d , and the solution was evaporated to give 1.70 g (9.38mmol ,95%) of VHj as an oil which crystal

~~lized, mp 51-52° ( l i t 55a,b mp 47-50°); cmr (CDC13) 6 7.2 (CH3), 21.8,~~

~~26.8, 29.0, 32.8, 34.9 (C-4a), 37.1, 44.5, 47.2 and 62.5 (C- 8 a).~~

~~il/-Chloroacetyl-4a-ethyl-2,3,4,4a,5, 6 , 8 ,8a-octahydro-7(1H)-quino!one (116). WWW\AA~~

~~Cl that Klioze and Darmory used to~~

~~prepare the hexahydro derivative of~~

~~7-quinolone. This yielded 1.80 g~~

~~116 (7,0 mmol, 85%) of 116, mp 77-80°~~

~~(1i t 55a,b mp75-77°); cmr (CDC13) 6~~

~~7.4 (CH3 ), 20.8, 24.1 , 28.9, 33.1 , 36.6, 39.8, 40.6, 41.6, 54.2 (C- 8 a),~~

~~60.6 (C1CH2), 165.8 (NC=0), and 208.8 (C-7). m6 a-_ w . aJ7J8,9a,9b-octahydro-yh-pyrroioi -quinonn-~~

2j9(lH)-dione (117). Compound 117 was prepared on a 6 . 6 mmol scale by the VW tAAlW W W V ' rVVb' r AAACl r r j procedure that Klioze and Darmory used to prepare the hexahydro-derivative 9H-pyrolo[3,2,l-ij]-quinolin-2,9(lH)dione. This yielded 0.97 g 96

~~(4.4 mmol, 67%) of 1 ^ , mp 116-~~

~~118° ( m 5 5 a ’ b ’ 6 1 mp 113-116°);~~

~~cmr (CDC13 ) 6 6.9 (CH3), 18.8,~~

~~9a 24.2, 29.1 , 32.4, 32.9,34.1 (C-4a),~~

~~35.5, 40.4, 42.5 (C-9a), 65.8 117 'W\| C-9b), 174.4 (C-2), and 209.0~~

~~(C-9).~~

6 a-Ethvl-1,2,4,5, 6 , 6 a,7,8,9a,9b-decahydro-9H-pyrrolol3,2,1 - i j 1-quinolin- WWVmWWVWWlrtAA/WWWIjWVlWWWWWVlAwiAAMlVWWbWW^WWV^ 9-one (120). Compound 120 was OAAAAj 'VIA. r V\jV k prepared on a 3.5 mmol scale by the

~~procedure that Klioze and Darmory6^ 6 a used to prepare the octahydro-de-~~

~~rivative of 9H-pyrrolo[3,2,l~z:j]- 1 2 0 quinolin-9-one. This yielded 0.30~~

~~g (1.45 mmol, 41%) of 120, bp 80- ^ 'WV r~~

~~90° (0.025 mm), [ l i t 55a,b bp 99° (0.2 mm)]; cmr (CDC13) 6 7.1 (CH3),~~

~~21.3, 26.2, 30.1, 32.9, 34.8 (C^ 6 a), 36.8, 48.2 (C-9a), 52.9 and 53.2~~

~~(C-2 and C-4), 73.6 (C-9b), and 211.0 (C-9).~~

~~Ketal-amide 118 was utilized to prepare 120; cmr (CDClo) 5 7.0 m r r W\j v 6~~

~~(CH3), 19.1, 22.8, 28.2, 30.2, 33.0, 33.0 (C- 6 a), 33.3, 38.3 (C-9a),~~

~~39.8 (C-4), 63.8 and 65.6 (-0CH 2 CH2 0-), 64.2 (C-9b), 108.8 (C-9) and~~

~~175.4 (C-2).~~

~~Acetal 119 was prepared from 118 during the preparation of 120; W\» 'WO cmr (CDC13) 7.0 (CH3), 21.4, 22.0, 23.5, 29.6, 30.9, 33.8, 34.2 (C- 6 a), 97~~

~~42.8 (C-9a), 53.4 and 53.5 (C-2 and C-4), 63.2 and 65.7 (-0CH 2 CH2 0 - ) ,~~

~~72.2 (C-9b) and 109.6 (C-9).~~

~~Ethylene Ketal of Methyl 4-Methylthioacetoacetate (124). A 2-1, one- W\/WWWWWV\;WWWVWVW\;^VWWWWWW\;WW\; 'WO necked flask was charged with 32.4~~

~~y——^ g (0.20 mol) of 85^a, 17.5 ml (0.26~~

~~mol) of ethylene glycol, 3.80 g~~

~~(0 . 0 2 mol) of para-toluene sulfonic CHoS C09Me 0 c acid monohydrate, and 1.3 1 of ben- 124 'wv- zene. The mixture was brought to~~

reflux with a Dean-Stark trap and refluxed for 2.5 hr, at which time no additional water was being re moved. The solution was cooled and washed twice with 200-ml portions of saturated sodium chloride solution, twice with 2 0 0 -ml portions of sat urated sodium bicarbonate solution, and three additional times with saturated sodium chloride solution. The solution was dried over anhydrous

~~sodium sulfate, filtered, and the solvent was evaporated. The residue was distilled to give 39.6 g (0.19 mol, 96%) of T24, bp 60° (0.025 mm);~~

~~ir (neat film) 1745 cm’^; pmr (CDC13) 6 2.20 (3H, s, -SCH3), 2.87 and~~

~~2.92 (S and S, 2H, and 2H, -SCH2- and CH 2 C02-) , 3.70 (3H, s, 0CH3) and~~

~~4.04 (4H, s, -0CH2 CH2 0-).~~

~~Anal. Calcd for Cgl-I^O^S: C, 46.59; H, 6.84; S, 15.54. Found:~~

~~C, 46.45; H, 6.92; S, 15.99.~~

Ethylene Ketal of 1-Methylthio-4-hydroxy-2-butanone (125). A slurry containing 17.27 g (0.45 mol) of lithium aluminum hydride in 950 ml of anhydrous ether was treated, dropwise with 2 0 0 ml of an ether solution containing 110.0 g (0.535 mol) of 1^24 over a 1-hr period. After 98

~~refluxing for 30 min, the mixture was~~

~~cooled and carefully treated, drop-~~

~~0 wise, with 17.3 ml of water, 17.3 ml~~

~~CH S ^0H aqueous sodium hydroxide, and 3 51.9ml of water. The reaction mix-~~

~~/w'' ture was filtered and the salts were~~

~~thoroughly washed with ether. The ethereal solution was dried over anhydrous sodium sulfate, filtered, evap~~

~~orated, and the residue was distilled to give 79.0 g (0.43 mol, 80%) of~~

~~_125, bp 87-90° (0.02 mm); ir (neat film) 3420 cm-^; pmr (CDC1 ^) 6 2.08~~

~~(2H, t, J = 6 Hz, -Ctf2 CH3 0H), 2.18 (3H, s, -SCH 3 ) ,2.65 (1H, t , J = 6 Hz,~~

~~-OH), 2.72 (2H, s, -CHgS-), 3.75 (2H, q, J = 6 Hz, -CH2 Ctf2 0H), and 4.05 (4H,~~

~~s, -0te 2 CH2 0H); pmr (CDC1 3 /D2 0) 6 2.08 (2H, t , J = 6 Hz, -Ctf2 CH2 0H), 2.18~~

~~(3H, s, -SCH3 ) , 2.72 (2H, s, -CHgS-), 3.75 (2H, t , J = 6 Hz, -CH2 Ctf2 0H), ..~~

~~and 4.05 (4H, s, -0CH 2 CH2 0-).~~

~~Anal. Calcd for C^H^O^S: C, 47.17; H, 7.92; S, 17.99. Found:~~

~~C, 47.17; H, 8.08; S, 18.21.~~

~~l-Methylthio-4-hydroxy-2-butanone (126). To 11. 6 .g (0.065 mol) of ketal VWVWWVWVVbWlWOVWl/W^WUUV^ 'V\/\ j 3 '~~

~~q ^25 was added 111 ml of 3N hydrochlor~~

~~ic acid and the homogeneous solution~~

*q|_| was stirred for 2 min before pouring CHgS

~~into 2 . 0 ml of saturated sodium chlor- 126 ide solution. The solution was quick~~

~~ly extracted with three 50-ml portions of methylene chloride. The meth ylene chloride extracts were combined and washed once with saturated 99~~

~~sodium chloride solution before filtering through glass wool. Evaporation~~

~~of the solution gave 7.42 g (0.055 mol, 85%) of crude 126, n £ 5 1.5148; 'Wb D ’~~

~~ir (neat film) 3420 and 1704 cm'1; pmr (CDC13) 6 2.04 (3H, s, -SCH3 ),~~

~~2.80 (2H, t, J = 5.5 Hz, -C#2 CH2 0H), 2 . 9 6 (1H, s, -OH, exchanges with~~

~~D2 0), 3.17 (2H, s, -CH2 S) and 3.79 (2H, t, J = 5.5 Hz, -CH 2 Ctf2 0H).~~

~~Anal. Calcd m/e for C^H-jqO^S: 134.0401. Found: 134.0399.~~

~~1-Methylthio-3-buten-2-one (123). To a solution of 3.30 g (0.025 mol) 'X/VX/X/X/X/b^/L'X/X/X/X/X/X/X/X/T/XAA/X/X/XA/V o /x /x / 0 v ' of 126 in 30 ml of dichloromethane, W Xj~~

~~cooled to 0 ° and under nitrogen,~~

~~was added a 2.09-ml (0.027 mmol)~~

~~CH3 S CH2 portion of methanesulfonyl chlor~~

~~ide all at one time. A 14.1-ml 123 'Wb . (0 . 1 0 mol) portion of triethyl-~~

amine was added dropwise, and the reaction mixture was stirred for 15 min at 0°. The reaction mixture was transferred to a separatory funnel with the aid of 25 ml of dichloro methane, and thenwashed with a50-ml portion of water, three 50-ml portions of 5%aqueous hydrochloric acid, and three 50-ml portions of saturated sodium chloride. The solution was filtered through glass wool and evaporated to give 2.70 g (0.023 mol, 92%) of crude T23. The yields varied from 85 to 95% and the crude 123 was used directly in o/x/x, ^ the next step. The material distilled with polymerization and this reduced the yield to 25 to 50%, bp 80-84° (25 mm); n^ 1.5189; ir (neat film) 1698 and 1620 cm'1; pmr (CDCI 3 ) 6 2v08 (3H, s, -SCH 3 ) , 3.40 (2H, s, -CH2 S-), 5.82 (1H, m, Cfl=CH2), and 6.42 (2H, m, CH=C#2).

Anal. Calcd m/e for CgHgOS: 116.0296. Found: 116.0293. 1-Benzyl-4a-ethyl- 8 -methylthid-2,3,4, 4a,5, 6 ,8 ,8a-octahydro-7(1H)-quino- Oy\Z\yVV\AaAiajOA;'VV\A/VVV\/ba,aA>iVO'V\jaAA/\/\j'V\/VVlA/\/W VVVVVV^^ lone (105). To a refluxing solution 'VWV 'W\> 3 of 4.30 g (21.4 mmol) of the endo- 2 cyclic enamine 114'WV in 100 ml of an- MeS hydrous dioxane was added 2.80 g 8 a (24.1 mmol) of 123 in a dropwise rW \, r 105 a/w. manner. The reaction mixture was re fluxed for 4 hr before being evapor ated in vaouo to give 3.30 g of crude product. This material was chroma tographed on neutral alumina, activity III, with benzene-pet ether as eluent to give 1.70 g (5.35 mmol, 25%) of U)5 (99% pure); n ^ 1.5606; i r (neat film) 2920, 1695, 1 2 0 0 , 730 and 690 cm-^; pmr (CDCl^) 6 0.78

~~(3H, skewed t , J = 7 Hz, -CH2 Ci?3), 2.02 (3H, s, -SCH3), 2.78 (1H, d,~~

~~J = 3Hz, -CHS-), 3.22 (1H, d, J = 3Hz, -CHN-), 3.62 (2H, q, J = 13.5 Hz,~~

~~CgHgC#2)» anc* 7.00 - 7.33 (5H, m, aromatic H). An analytical sample was prepared by evaporative distillation, bp 70° (0.01 mm).~~

~~A nal, Calcd for C-jgH2 yN0 S: C, 71.88; H, 8.57; N, 4.41. Found:~~

~~C, 71.62; H, 8.70; N, 4.45.~~

~~4-Ethy1-2-methyIthio-4-(N-benzyl-3-aminopropyl)-2-cyclohexen-lTone (124).~~

~~Extraction of the crude reaction~~

~~mixture of 105 with 3N hydrochloric~~

~~acid, followed by neutralization with~~

~~solid sodium carbonate gave a gummy~~

~~material which was totally insoluble~~

~~in ether. The solution was decanted~~

~~and the gummy material was rinsed 101~~

~~twice with ether before being dissolved in benzene. The benzene solution~~

~~was dried over anhydrous magnesium sulfate, filtered , and evaporated to yield 3.05 g (9.6 mol, 45%) of crude ,1,24 as a gold oil, ir (neat film)~~

~~1685, 1590, 1482, 1220, 1183, and 1050 cm~^; pmr (CDCI 3 ) 6 0.80 (3H, t, J = 7 Hz, CH2 Cff3), 2.10 (3H, s, -SCH3 ) , 4.07 (2H, s, CgHgCflg), 6.02~~

~~(1H, s, =CH) and 7.20 - 7.60 (5H, m, aromatic H); cmr (CDC13) 8.3 (CH3),~~

~~13.5 (-SCH3 ), 20.6, 29.8, 30.2, 30.5, 33.9, 34.4, 34.7, 39.3, 46.2, 50.5,~~

~~129.0, 129.2, 129.9, 130.3, 136.7 (aromatic C-l), 145.8 (=CH-) and 195.4~~

~~(0=0).~~

~~5-(N-carboethoxyamino)-2-ethylpentanal-l,3-dioxalane (128). To a stirred 'V\AA/OA/VVVVV\A/V vA/^aAA^'V\jOAA/VV>V\AAyV\AA»aA>^aAAAAAA»f\AA/\A/ W j ' suspension of 4.40 g (0.116 mol) of~~

~~lithium aluminum hydride in 500 ml of~~

~~ether was added 16.10 (0.095 mol) of~~

~~0C2H5 113 in 100 ml of ether at such a rate~~

~~as to maintain a gentle reflux, and~~

~~the reaction mixture was refluxed~~

for 1 hr. The reaction was cooled to room temperature and 17.60 ml of a 10% aqueous sodium hydroxide solution was added dropwise. The precipitate was collected by filtration in vacuo and washed with ether. Evaporation of the ethereal solution gave 16.48 g (0.095 mol, 100%) of crude 5-amino-2-ethylpentanol-l,3-di oxalane (^27), which was not further purified but used directly in the suc ceeding step; pmr (CDC13) 8 0.93 (3H, t , J = 7 Hz, CH2 C#3), 1.20 - 1.70

~~(9H, m), 2.67 (2H, bs, CH 2 N), 3.85 (4H, m. -0CH 2 CH2 0-) and 4.77 (1H, s,~~

0CH0). A mixture of the reaction product ( vide supra) and 9.2 ml (0.114 mol) of pyridine in 125 ml of dichloromethane was stirred at 0°, under nitrogen as 10.0 ml (0.105 mol) of ethyl chloroformate in 60 ml of di chloromethane was added dropwise. Stirring at 0° was continued for

~~1 hr and at room temperature for 2 hr. The reaction mixture was washed~~

three times with 50-ml portions of water, twice with 50-ml portions of saturated sodium chloride, and filtered through glass wool. Evaporation of the solvent in vaauo and d istilla tio n gave 23.00 g (0.094 mol, 99%) of 128, bp 120-125° (0.01 mm); ir (neat film) 3340, 2960, 2930, 2875,

~~1715, 1535, 1253 cm-1 ; pmr (CDC13) 6 0.93 (3H, t , J = 7 Hz, 2-CH 2 Cff3) ,~~

~~1.23 (3H, t, J = 7 Hz, 0CH2 C53), 1.17 - 1.83 (7H, m), 3.17 (2H, bq, J =~~

~~6 Hz, -CH2 N), 3.88 (4H, m, -0CH 2 CH2 0-), 4.11 (2H, q, J = 7 Hz, 0Ctf2 CH3),~~

~~4.80 (1H, m, -0CH0-), and 4.88 (1H, bs, NH).~~

~~Anal. Calcd for C-^H^NO^: C, 58.75; H, 9.45; N, 5.71. Found:~~

C, 59.03; H, 9.43; N, 6.03. a/v^OAA>a/\AAAA/vv\Aa/vwv\jViA/vv\jaA,aA/vv/tiaAj'vvvvvvY>'v\>5-(N-Methylamino)-2-ethylpentanal-l,3-dioxalane (129). n/vx. To a stirred suspension of 7.80 g (0.206 mol) of

~~lithium aluminum hydride in 300 ml NCH of ether was added 20.43 g (0.083~~

~~mol) of 128 in 50 ml of ether. In~~

~~order to effect complete reduction,~~

~~the reaction mixture was refluxed for~~

15 hr at which time the reaction was cooled and treated with 31.2 ml of 10% aqueous sodium hydroxide solution in a dropwise manner. The precipitated salts were collected by filtra tio n and washed with ether and the ethereal solvent was evaporated in vaauo. 103

~~Distillation of the residue gave 14.11 g (0.075 mol, 91%) of bp 114-~~

~~116° ( 8 mm); ir (neat film) 2915, 2857, 2278, 1462, and 1111 cm-1 ; pmr~~

~~(CDC13) 6 0.92 (3H, t , J 7 Hz, -CH 2 Cff3), 0.97 (1H, s, NH), 1.23 - 1.80~~

~~(7H, m), 2.42 (3H, s, NCH3), 2.57 (2H, m, CH2 N), 3.87 (4H, m, -0:CH2 CH2 Q-)~~

~~and 4.77 (1H, rn, -0CH0).~~

~~Anal. Calcd for C-jqH2 "jN02: C, 64.13; H, 11.30; N, 7.48. Found;~~

~~C, 63.97; H, 11.21; N, 7.49.~~

~~'VVV\jOAXA.OA/VV\jaAA/%'V^,V^VVVAja/V\/baA/VVVVVlaiai'\/VVV/1-Methyl-3-ethyl-1,4,5, 6 -tetrahydropyridine (130). 'w \ j A 60-ml portion r of 3N hydrochloric acid was added to~~

~~9.40 g (0.05 mol) of 129 that was~~

~~J F* 1 cooled in an ice bath and stirred~~

~~under nitrogen. After the addition~~

~~130 V was comPlete the ice bath was re- ' W V f moved and the reaction was stirred~~

~~at room temperature for 15 min before~~

the aqueous solution was neutralized with solid sodium carbonate. Ena- mine 130W l/ was extracted with three 20-ml portions r of dichloromethane which were combined and washed once with 30 ml of saturated sodium chloride.

~~The solution was filtered through glass wool and evaporated in vaauo to~~

~~give after distillation 4.76 g (0.038 mol, 76%) of (K30, bp 162-163° (743 mm); ir (neat film) 2942, 2909, 2831, 2812, 2800, 1667,and 1305 cm-1 ;~~

~~pmr (CDC13) 6 0.97 (3H, t , J = 7 Hz, -CH 2 Cff3), 1.70 - 2.13 (6 H, m), 2.50~~

~~(3H, s, NCH3), and 5.55 (1H, s, =CH-).~~

~~Anal. Calcd for CgH-j^N: C, 76.74; H, 12.07; N, 11.19. Found:~~

~~C, 76.53; H, 12.21; N, 11.11. 104~~

~~4a-Ethyl-1-methyl- 8 -methylthio-2,3,4,4a,5, 6 ,8 ,8a-octahydro-7(1H)-~~

~~quino!one (131). A 3.31-g (26.0 hiwO'WL'V^ 'W\/ J mmol) portion of enamine 130 and 6.61~~

~~g (57.0 mmol) of 123 were combined~~

~~in 1 0 0 ml of anhydrous dioxane and~~

~~the solution was brought to reflux.~~

~~IjjH After refluxing for 5 hr, evaporation~~

of the solvent left a gummy oil which was dissolved in 200 ml of 3N hydrochloric acid and thoroughly extracted with dichloromethane. The aqueous layer was treated with solid sodium carbonate until basic and reextracted with dichloromethane. The organic

~~layer was washed with saturated sodium chloride solution, filtered~~

through glass wool, and evaporated to give 3.75 g of crude T3K High vacuum distillation afforded 2.52 g (10.0 mmol, 40%) of pure 13jU bp 50-55° (1 x 10 " 5 mm); njp 1.5305; ir (neat film) 2936, 2870, 2790, and 1698 cm-1; pmr (CDCI 3 ) 6 0.81 (3H, t , J = 7.5 Hz, CH2 Cff3), 2.02

~~(3H, s, -SCH3), 2.27 (3H, s, NCH3 ) , 2.64 (1H, bs, NCH), and 3.10 (1H, bs, SCHC0); cmr (CDC13) 6 6 . 8 (CH2 CH3), 14.7 (-SCH3), 20.3, 25.1, 27.8,~~

~~28.7, 31.0, 34.9 (C-4a), 41.5 (NCH3), 46.4 (C- 8 ), 47.9 (C-2), 70.3~~

~~(C-8 a), 206.1 (C=0).~~

~~Anal. Calcd for C1 3 H2 3 N0S: C, 64.69; H, 9.60; N, 5.80; S, 13.28.~~

~~Found: C, 64.65; H, 9.62; N, 6.10; S, 13.09.~~

*rans-8,10-Dimethyl-l(9)-octal-2-one (134). Octalone 134 was prepared by the method of Marshall and Schaefer. This procedure yielded 14.98 g 105

~~(0.084 mol, 49% from 2,6-dimethyl -~~

~~cyclohexanone) of 134,W V bp 74-76° r~~

~~(0.02 mm) [lit 5 4 bp 90-99° (0.3 mm)]. 134~~

~~8,10-Dimethyl-1-methylthio-2-decalone (133). A 0.522-g (0.075 mol) por- ,V\AA»VVV/V \A »V V \/^y\A A A /\/\A aA /V V V \/^V ^aA ^rVVVV f\jr\Aj ' r tion of lithium metal was dissolved~~

~~in 2 0 0 ml of liquid ammonia and stirred~~

~~for 2 0 min before a solution con~~

~~taining 6.10 g (0.034 mol) of 17 and~~

~~2.70 g (0.034 mol) of te v t-butyl-~~

alcohol in 35 ml of ether was added 133 over a 20-min period. After the addition was complete, an additional 0.05 g (0.007 mol) of lithium was added to maintain the dark blue color. After stirring for 90 min, 9.20 ml (0.102 mol) of freshly d istille d dimethyl sulfide in 25 ml of ether was added dropwfse. The ammonia was allowed to evaporate overnight and the residue was dissolved in ether. The ethereal solution was washed with 3N hydrochloric acid, water and saturated sodium chloride solution.

The solution was dried over anhydrous magnesium sulfate, filtered , and the filtrate was evaporated to yield 7.59 g of crude product. Chromatography of this material on silica gel with benzene-pet ether as eluent gave

~~4.97 g (0.022 mol, 65%) of 15 as a yellow o il; n ^ 5 1.5262; ir (neat film)~~

~~2882, 1695, 1458, 1385, and 1232 cm"1; pmr (CDC13) 6 0.88 (3H, d, J =~~

6.3 Hz, CHCh3), 1.15 (3H, s, IO-CH 3 ), 2.03 (3H, s, SCH3 ) and 3.06 (1H, 106 d, J = 5.9 Hz, SCH). An analytical sample of K> was prepared by prepara tive vpc on a 10' x 1/4", 10% SE-30 on 60/30 Chrom W column at 190°.

~~Anal- Calcd for C-j3 ^2 2 ^*^* 68.97; H, 9.80; S, 14.16. Found:~~

~~C, 68.95; H, 9.97; S, 14.17.~~

Further elution with benzene-dichloromethane gave 0.95 g (0.005 mol, 16%) of trans-8,10-dimethyl-2-decalone (V35). The ir, pmr, and mass spectra of 135 were identical with those published in the litera- . 83 ture.

~~83. B. Maurer, M. Fracheboud, A. Grider, and G. Ohloff, Helv. Chem. Acta , r\y\j 55, 2371 (1972).~~

~~3-Methyl-2-methylthiocyclohexanone (53 k). A 1.39-g portion of lithium~~

~~metal was dissolved in 600 ml of~~

~~0 liquid ammonia and stirred for 15 SMe min before 10.0 g (0.091 mol) of 3-~~

~~methyl-2-cyclohexen-l-one and 7.19~~

~~wv\,53 k 9 (0.091 mol) of te v t- butyl alcohol~~

~~in 75 ml of anhydrous ether was added~~

~~over a 1-hr period. The reaction mixture was stirred at reflux for 1 hr, at which time 24.5 ml (0.273 mol) of freshly distilled dimethyl disulfide in 1 0 0 ml of ether was added.~~

The solution was stirred at reflux for an additional hour before re placing the dry-ice condenser with a water cooled condenser which per mitted the ammonia to evaporate (overnight). The reaction was acidified with 3N hydrochloric acid and the ether layer was separated. The aqueous 107 layer was extracted an additional time and the extract was combined with the previous extract. The ethereal solution was washed with water, sat urated sodium bicarbonate solution, and saturated sodium chloride solu tion. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated. The residue was distilled to give 6.92 g (0.044 mol, 48%) of 53kas a 1:1 mixture of cis and OAj'X, OC trans isomers, bp 94-95° (7.0 ran); n^ 1.5020; ir (neat film) 2940, 2870,

~~1670, 1430, 1381, 1350, 1328, 1253, 1197, 1050, 1040, 962, 885, and~~

~~755 cm"1; pmr (CDC13) 5 1.11 (3H, d, J = 6.5 Hz, CHC^), 2.00 and 2.03~~

~~(3H, s, twoSCH 3 ), 2.70 - 3.10 (2H, methyne H). An analytical sample was prepared via preparative vpc on a 10' x 1/4" 10% SE-30 on 60/80~~

~~Chrom W column at 150°.~~

~~Anal. Calcd for CqH^OS; C, 60.72; H, 8.92; S, 20.25. Found:~~

~~C, 60.72; H, 8.89; S, 20.54.~~

~~Methyl 4-Methylthiobutyroacetate (53 1). Sulfide 53 1 was prepared by OA^%%>V\AA/VVW\i,VV/VV\AA>^A«VVA;'V\A»aA»,Vb O/Wlf 'VW\ j refluxing 66.5 g (0.33 mol) of~~

~~crude ethyl 4-methylbutyroacetate~~

~~(92) in 3 1 of methanol containing CH. 0CH, 5 drops of sulfuric acid until the SCH. 53 1 trans - esterification was com 'WVX plete. The methanol was evaporated~~

and the residue was dissolved in ether. The ether solution was washed with saturated sodium bicarbonate until neutral, once with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solution was filte re d , the f i l trate was evaporated, and the residue was distilled to give 36.5 g 108

~~(0.19 mol, 59%) of 53^1, bp 63° (0.25 mm); 1.4763; ir (neat film)~~

~~1754 and 1715 cm"^; pmr 0.98 (3H, t , J = 7 Hz, CH 2 Cff3), 1.40 - 1.90~~

~~(2H, m, Ctf2 CH3), 1.90 (3H, s, -SCH3), 3.27 (1H, t, J = 7 Hz, Q/CH2),~~

~~3.67 (2H, q, J = 16 Hz, C#2 C02) and 3.73 (3H, s, -0CH3).~~

~~Anal. Calcd m/e for CgH-j^03 S: 190.0664. Found: 190.0661.~~

~~General Procedure for the Preparation of Aniline Azasulfonium Salts for~~

NMR Examination. The azasulfonium salts were prepared by in itia lly weiqh- mwwvvwbm . r r J ^ ing out 0.09 to 0.13 mmol of the sulfide. To a 5-ml, side-armed flask, equipped with a magnetic spin bar, under a nitrogen atmosphere and cooled in a dry ice - 2-propanol bath was added 500 pi of deuterochloroform or dideuteromethylenechloride (containing 1% TMS) and one equivalent of aniline. One equivalent of tert-butyl hypochlorite was added and the solution was stirred for 2 min before the sulfide was added dropwise.

The solution was immediately transferred to a precooled nmr tube by means of teflon tubing and positive nitrogen pressure. When the trans fer was made rapidly, little decomposition occurred. A listing of the azasulfonium salts and the experimental details for their preparation are included in Table IV. All nmr experiments were conducted on a Varianc

CFT-20 using a proton probe operating at -59 ± 2°. The spectra were collected with the following parameters: spectral width, 1000 Hz; num ber of transients, 20; acquisition time, 4.095 sec; pulse width, 14 psec; data points, 8192; and transmitter offset, 44 Hz.

~~Preparation of the Aniline Azasulfonium Salt 54 b via the Chlorosulfbnium WbWWVWWWOWmMA/WlW/l/bVmWlAAAjVVVbWOWW^WWWWWVWV^WV^~~

~~Sal^o^S^b. A 17.0-mg (0.144 mol) portion of 53 J d and 26.2 pi (0.288 mol) of aniline were dissolved in 500 pi of deuterochloroform in a 5-ml, 109~~

~~Table IV. Experimental Conditions for the Preparation of Aniline Aza sulfonium Salts.~~

~~te r t- butyl Azasulfonium Aniline hypochlorite Sulfide Sulfide sa lt yl (mmol) yl (mmol) mg (mmol)~~

~~CH3 SCH3 25 1 0 . 0 (0 . 1 1 0 ) 12.4 (0 . 1 1 0 ) 6 . 8 0 1 1 0 OAj ( . ) 53 a 54 a 9.6 (0.105) 12.3 (0.105) 11.5 (0.106)~~

~~53 b 8 . 6 1 1 . 2 VWV O/WU54 b (0.095) 10.7 (0.095) (0.095) 53 c 54 c 9.4 (0.104)~~

~~53 d 54 d 10.5 (0.115) 13.1 (0.115) (0 . 1 1 2 ) w w 'VWb 14.8~~

~~53 e 54 e 1 0 . 6 (0.116) 13.2 (0.116) 16.5 (0.113)~~

~~53 f 54 f 9.8 (0.108) 1 2 . 2 (0.108) 18.9 WW/ (0.105) 53 g 54 g 9.9 (0.109) 12.3 'WWi W\A/ (0.109) 19.0 (0.105)~~

~~53 h 54 h 1 0 . 0 (0 . 1 1 0 ) 12.4 0 1 1 0 W W i 'VO'VO ( . ) 20.7 (0.107)~~

~~53 i 54 1 8 . 0 (0.088) 1 0 . 0 'WW. (0.088) 12.7 (0.088) 54 j 9.9 (0.109) 12.3 (0.109) 18.2 (0.106) 5W/XA 3 j ; WVU 53 k 54 k 7.7 (0.084) 9.5 (0.184) 13.9 (0.084) WW OA/VA/~~

~~85 a 54 n 10.5 (0.115) 13.1 (0 . 1 1 2 ) w v \> o /v w (0.115) 18.2~~

~~89 54 o 10.3 (0.113) 1 2 . 8 (0.113) 19.3 (0 . 1 1 0 ) o/v rV\Ajf\j~~

~~53 1 54 1 10.5 (0.115) 13.1 (0.115) 21.3 (0 . 1 1 2 ) w w . 'VWX,~~

~~53 m 54 m 10.5 (0.115) 13.1 (0.115) 25.8 ( 0 . 1 1 2 )~~

~~131 — 7.7 (0.085) 9.6 (0.085) 20.5 (0.085)~~

~~133 — 8 . 2 (0.090) 1 0 . 2 (0.090) 20.4 (0.090) 110 side-armed flask, equipped with a magnetic spin bar, under a nitrogen atmosphere and cooled in a dry ice - 2-propanol bath. Chlorine gas~~

(3.6 ml, 0.144 mmol) was added v ia a gas tight syringe and the solution was transferred to a precooled nmr tube. The nmr spectra of 5 4 Jb indi cated that 54Jb was efficiently prepared by this procedure and has been included in the Appendix. LIST OF REFERENCES

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~~118 80 MHz Proton Magnetic Resonance Spectrum of 3-Methylthio-2-butanone (5,£Jb).~~

~~SCH0b 80 MHz Proton Magnetic Resonance Spectrum of 3-Chloro-3-methylthio-2-butanone (97Jb)~~

~~CH3a and CH3b CHoC~~

~~Cl 0 CH3b CH3 c SCH3a~~

~~97 b~~

~~- i ------1------r T 10 8 6 4 0 6 80 MHz Proton Magnetic Resonance Spectrum of 4-Chloro-3-methylthio-2-butanone ($$).~~

~~Ha, Hd, He~~

~~(53 b)~~

~~10 8 6 4 2 0 6 80 MHz Proton Magnetic Resonance Spectrum of Aniline (23 a).~~

~~aromatic H~~

~~10 8 6 4 2 0 6 80 MHz Proton Magnetic Resonance Spectrum of lU-Chloroaniline and te v t-Butyl Alcohol.~~

~~aromatic H~~

~~10 86 4 2 0 6 80 MHz Proton Magnetic Resonance Spectrum of the Aniline Azasulfonium Salt 25.~~

~~aromatic H~~

~~10 68 4 2 0 6 80 MHz Proton Magnetic Resonance Spectrum of the Azasulfonium Salt 54 b.~~

~~Hd 0~~

~~CH3aN' ' ^ s ^ CH3b~~

~~N >”S ^ u + CH0c~~

~~aromatic H 80 MHz Proton Magnetic Resonance Spectrum of Azasulfonium Salt generated via the Chlorosulfonium~~

~~aromatic H~~

~~T T ro CTl 10 0 6 80 MHz Proton Magnetic Resonance Spectrum of Azasulfonium Salt 54 a.~~

~~CH0a~~

~~h C1 H + 3 'VWVO54 a~~

~~aromatic H~~

~~He and Hd~~

~~10 8 6 80 MHz Proton Magnetic Resonance Spectrum of 2-Methyl-3-methylthioindole (46^) and l-(2-anilino)-l- methylthio-2-pentanone (139).WO~~

~~139 'WX/~~

~~aromatic H~~

~~ro 10 oo 8 6 4 2 0 6 80 MHz Proton Magnetic Resonance Spectrum of 2-Methvl-3-methylthioindole (46 a) ' *VWV'/~~

~~46 a 'VXA jO,~~

~~aromatic H and NH~~

~~10 8 6 80 MHz Proton Magnetic Resonance Spectrum of 4a-Ethyl-l-methyl-8-methylthio-2,3,4,4a,5,6,8,8a-octahydro-7(lH)-quinolone (131). 'V'W SCH~~

~~NCH~~

~~131 'V\jrO 80 MHz Proton Magnetic Resonance Spectrum of fl'-chloroaniline (24ja) and 4a-Ethyl-1-methyl- 8 -methylthio- 2,3,4,4a,5,6,8,8a-octahydro-7(lH)-quinolone (^3|)•~~

~~Cl H~~

~~tf-Chloroaniline~~

~~10 68 42 0 6~~