saw: fMiWECE-i {émmam a? awmmmwgzg Eflfim {m ‘1th 53¢qu a)? M. 5». MICBLGM STATE UNWEBSETY Wayneg Gain 3931mm E968- “qt-151$ LIBRARY Michigan State UDjVCI’Sit)’ r; a U" a UN o."\'“a I“ / \ v | 9 } i ' ABSTRAOT SOME MANNICH REACTIONS OF HYDROXYINDOLES by Wayne Orrin Johnson Mannich reactions with 5- and 6-hydroxyindoles are shown to result in the stereospecific substitution of the aromatic ring. The 5-hydroxyindoles furnish the C-h adducts, while 6-hydroxyindoles yield C-7 adducts (indole numbering system). It is only when the active C-S-grthgfposition is blocked, as in the case of S-methyl-6- hydroxy-l,2,3,h-tetrahydrocarbazole {a}, that condensation occurs at the indole nitrogen. If both the indole nitrogen atom and the hydroxyl function are blocked (e.g. 2), addition occurs at the C-7 positiona or particular interest is the 0-1; alkylation of 2-methyl-S- hydroxyindole (lg) to give Mannich adduct $95.35 well as the substitution at the C-h carbon atom of 5-hydroxyindole (lg) to give 'lla. These results are contrasted with the normal 0-} alkylation of unsubstituted indoles and a possible rationale is presented. Nmr spectra are offered as evidence in the structure elucidation of all the hydroxyindoles and their Mannich adducts. SOME MANNICH REACTIONS OF HYDROXYINDOLES 'Wayne Orrin Johnson A,THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE Department of Chemistry 1966 ACKNOWLEDGMENT To study at a graduate school in a department filled with professors of great integrity and who show wide ranges of interest is, to the author, one of the most exciting and productive aspects in the attainment of an advanced degree. Dr. Stephen Monti has truly displayed this vast sphere of academic awareness and has presented a most stimulating atmosphere through his guidance and counsel. I wish to thank him for the priviledge of studying under him. HW-X- ii TABLE OF CONEEN‘I‘S INTRODUCTION RESULTS AND DISCUSSION EMBE’LENTAL 6 -Hydroxy-l, 2, 5 , LL-tetrahydrocarbazole ('1) Mannich Adduct la Mannich Adduct lb» Mannich Adduct 1c 6 -Methoxy-1 , 2 , Bjmtet rahydroc arb az ole (‘22 ' Mannich Adduct 2‘s; 9 -Methyl-6 -methoxy-l,.2 , 3, u-tetrahydroc arbazole Q). Mannich Adduct is; 9 —Methyl-6 -hydroxy-1, 2, 5 , h-tetrahydroc arbazole (it; Mannich Adduct .152“- 5-Methy1-6 -hydroxy-l , 2 , 5 , A-tetrahydrocarbazole £22 Mannich Adduct 2a. Mannich Adduct 5b 7-Hydroxy-l , 2 , Bjfitetrahydroc arbaz ole (6 ) Mannich Adduct £3 M Attempted Synthesis of 8-Hydroxy-l,2,5,h4tetra- hydrocarbazole %% ' 2-Methyl-5-carbe oxy-S-hydrowbenzofuran £21 Mannich Adduct b 2—Methyl-5-hydroxyindole (g9) Mannich Adduct 19g S-Hydroxyindole (ll) Mannich Adduct 112 BIBLIOGRAPHY BIOGRAPIUCAL NOTE iii 1'? 17 17 17 18 18 . 19 19 2O 2O 2O 21 21 21 22 22 23 25 25 21+ 21+ 25 27 LIST OF TABLES TABLE I: Nmr Spectral Data of Tetrahydrocarbazoles TABLE II: Nmr Spectral Data of Mannich Adducts TABLE III: Nmr Spectra of 5-Hydroxyindoles TABLE IV: Nmr Spectra of MEnnich Adducts iv (1) l2 13 INTRODUCTION The introduction of an aminomethyl substituent into an indole nucleus by means of a Mannich condensation has been reported to give, in most cases, condensation at the 3-position of the indole nucleus.l If this position is blocked, addition generally takes place at the indole nitrogen atom.l’2 When the 5-position of the indOle nucleus as well as the nitrogen atom are blocked, bond formation has been found to occur at the 2- 5a position; with methyl substituents at all three sites of the indole ring, the Mannich addition took place on the C-2-methy1 moiety.3b The limited application of hydroxyindoles as substrates for the Mannich reaction, in contrast to work carried out on several other phenols“ and heterocyclic phenols,5 has led to further investigation on our part in this area. 4' RESULTS AND ISCUSSION The partial synthesis of Voacemine, a dimeric indole alkaloid, employed a Mannich-like reaction of a S-methoxyindole as did the Nannich condensation of 6-hydroxy-l,2,3,h-tetrahydro- 6 carbazole (I) (Table I) to give Mannich adduct 13 (Table II). In view of the preferential condensation on the benzene I ring over the indole nitrogen with piperidine and paraformaldehyde 67 in ethanol, ’ our interest turned to the synthesis of the hydroxy gramine analog 12 by usage of dimethylamine. Optimum yields were obtained by stirring the reaction mixture at room temperature to give the dimethylamino Mannich adduct ‘13 (Table II), which showed the expected two proton AB aromatic quartet (J5~8.S cps)? and 7 . infrared Spectrum, 5 6-Methoxy—l,2,5,h-tetrahydrocarbazole (2) (Table I)? did not give substitution-on the benzene ring under normal Mannich conditions with piperidine and paraformaldehyde in ethanol, but gaNe rather the Nealkylated product‘ga. The nmr spectrum showed three aromatic protons (Table II), while the disappearance of the N-H stretching mode at BATS cm."1 in the infrared confirmed such findings. The question now arose as to whether any Mannich condensation would occur if the indole nitrogen atom were also blocked. 9-Methyl- . lO . 6-methoxy-l,2,5,h-tetrahydrocarsazole (2) (Table I) gave Mannich adduct 2a (Table II) as the major product in a 55 per cent yield under forcing conditions of refluxing in glacial acetic acid. The nmr spectrum showed two aromatic one-hydrogen singlets, which indicated that the hydrogen atoms were para to each other8 and that condensation had occured at C-7. If the 6-hydroxy Mannich adduct 12 was used as a substrate for a further condensation with an equimolar amount of piperidine and paraformaldehyde in ethanol at room temperature, the N-alkylated di-Mannich adduct $3. (v3.33 Ell—22?) (Table II) was obtained. This was confirmed by the disappearance of the N-H stretching mode at 5&70 cm,.1 in the infrared and by the continued presence of the two proton aromatic AB quartet in the nmr. The next area of interest was concerned with the mode of addition to 9-methyl-6-hydroxy-1,2,5,h-tetrahydrocarbazole (5) (Table I).11 Condensation again occured at 0-5 to give M: nich adduct‘fig (Table II), which showed a two proton aromatic AB quartet and the expected infrared spectrum. The final condensation in the 6-hydroxy-mode1 system involved the reaction of S-methy1-6-hydroxy-l,2,5,A-tetrahydro- carbazole (2) (Table I). Compound’2_was prepared by hydrogenolysis of 35b. in ethanol using a Pd/C catalyst at 80° and 50 psi of hydrogen. Condensation of_§?with the piperidine-Mannich intermediate in ethanol gavelza (TableII) as the major product, which rm ulted from N-alkyla- tion. The product showed free hydroxyl stretching at 5600 cm.-1 by infrared analysis and Lisplayed a two proton aromatic AB quartet in the nmr. A second, minor product was assigned structure 2; This di-Mannich adduct showed no N-H stretching in the infrared and had a one-proton singlet in the aromatic region of the nmr spectrum. No benzene ring monoallqylated product was observed as judged by infrared analysis of the various chromatography fractions. The up- field sh 1ft of the C-methylene group of the minor product (2b) to $5.70 is in agreeilent with the chemical shift of the methylene group in Mannich adduct 52.. (also note the upfield shift of all Ha-protons in Tables I, II, III and Iv). 7-Hydroxy-l,2,5,A-tetrahydrocarbazole (6) (Table I)12 underwent condensation at 0-8 to give the piperidine-Mannich adduct 6a.. (Table II) ,1} which gave the expected infrared spectrum and showed a two proton aromatic AB quartet, typical of orig coupling,8 in the nmr spectrum. An attempt to synthesize 8-hydroxy-l,2,5,A-tetrahydrocarbazole (I) by the method employed for the preparation of 6 furnished a crystalline product. The combined chemical and spectral evidence for this material, however, are not in complete accord with the anticipated structure Z'(see Experimental Section). RH \H w The second phase of our research turned to hydroxyindoles with various substituents in the 2- and 5-positions. t has been reported that 2-r3thylindole and 2-carbcth0iyindole give 5-a1kylated ., ’ ... 11*. Mannlcn adducts Wltn dlmetnylamlne or plperldlne as bases, while , 15 and S-benzyloxyindolelo are known to give the S-methoxyindole 5-substituted gramine analogs with dimethylamine. 2-Methyl-5—carbethoxy-5-hydroxyindole (é) (Table III)17 underwent Mannich condensation with formaldehyde and piperidinel7a or dimethylamine in acetic acid to yield the c-u Mannich adducts ‘§§_and §b, respectively. The infrared spectrum of both products showed indole N-H stretching at 5AYO cm."1 and had a two-proton aromatic AB quartet indicative of ortho coupling in the nmr. TABLE I Nmr Spectral Data of Tetrahydrocarbazoles Cnemi .al 3‘: ifts a in.£prn (a) Spectra were taken in CHSOH with an internal TMS standard; (b) doublet 0I doublets (JO n8. 5 eps, 542.5 (c ) doublet (JO/V8. 5 ops); (d) doublet (Jr-2. 5 cps); (e) compound ) Ha? H5O H d NFCHS 0-033 C-CHse “i” ' 6.60 7.05 6.82 ‘2? 6.72 17.02 6.90 -—— 3.8l --- ’2? .75 7.0M 6.90 3.38 3.78 --- i: 6.6% 6.92 6.80 3.33 --- --- .13. 6.57‘3 6.88 2.1.7 ‘6? 6.55 7.03 l 6.69 —-- --- --- CPS); singlet; (f) spectra were taken in CD013 Iiiith an internal TMS standard; (g) CS-H = H5, C6-H = Ha , CB-H = Hco TABLE II IImr Spectral Data of Mannich Adducts Chemical Shifts in {ppma (a) Spectra were taken in CD013 with an internal TIE Mannich Hb Adduct b b c c c , c Ha ab HC N-CH3 0-CH3 C-CH3 CdgNRg 653 6.62 6.97 --- --- --- --- b.03 lb 6.67 6.98 --- --- --- --- n.02 M 38. 6.67 7.18 --- --- --- --- h.08, h.u3 2a 6.75 7.2a 6.9oe 3.83 1+.h6 25L --- 7.2ac 6.89C 3.53 3.83 --— 3.67 to 6.72 7.02 --- 3.43 --- --- n.03 5a 6.58 7.05 --- --- --- 2.53 u.u6 5h --- 6.85c --- -—- --- 2.55 3.70, u.u3 63: 6.60 7.17 --- —-- --- , --- 3.70 standard; (b) doublet (Jav- 8.5 cps); (c) singlet; (d) doublet of doublets (Jh 8.5 eps, Jfi-2.5 cps); (e) doublet ( Cps); (f) 05-H°= H5, C6-H = a. Jm~2.5 Also of interest was the condensation of 2-methy1-5—carbeth- oxy-5-hydroxybenzofuran £2.) (Table III)18Iwitn”dimethylamine and paraformaldehyde to give the AL-Mannich adduct 33,19 while the reaction using piperidine15 as the base gave the corresponding Mannich adduct 20 (Table IV). Compound ab showed only hydrogen- bonded hydroxyl in the infrared and displayed a two-proton aromatic AB quartet by nmr. The last phase of our investigation involved the Mannich reactions of 2-mcthy1-5-hydroxyindole (lg) (Table III)17 and 2 S-hydroxyindole (11) (Table III).0 The nmr spectrum of 19 displayed the normal aromatic ring pattern as observed for the other hydroxy- indoles, but showed in addition the C -H at 5' 6.52, which appeared 3 10 as a multiplet due to splitting by the Cé-methyl and the indole N-H. Mannich condensation of 19 with piperidine and paraformal- dehyde in ethanol at room temperature gave as the major product Mannich adduct 198 (Table Iv) in a 72 per cent yield. Compound 1 a showed a two-proton AB quartet in the aromatic region as well as the C -H-as a multiplet at $6.5A. The infrared spectrum showed 3 the expected absorptions.7 A minor product was present in too small amounts to isolate, but may well have been the C -adduet. 3 lOa 5-Hydroxyindole (11), which has five potential sites for addition (N-H, c2, 05, CL,r and 06) was next subjected to the Mannich reaction. The parent compound‘l} showed the expected aromatic protons Ha’ Rb and He (Table III) as well as the 02- hydrogen, doublet at $7.02, and the CB-hydrogen as a broadened doublet at $6.5A in the nmr. Condensation of I; with piperidine and paraformaldehyde at room temperature, or at reflux in ethanol for a shorter time, gave principally the CA- alkylated product 11a (Table IV) in an 87 per cent yield. Mannich adduct lla showed the expected infrared ll '7 spectrum‘ while tne nmr speetrum snowed a 6..o-proton alomaolc AB quartet, which is indicative of C -addition, with retention of the C -hydrogen as a douolet at;, .l5 and tne C.-hydrogen as a broader ed 2 doublet at 56.54. -./-- —~'~‘ I o—Ivoroxy-l,2,5,4-tetra- c t I O 5 O rm. “.9.— ;:n ‘gwp I..e plelercnolal alxrla ‘ rdroearoazoles at C- -5 and of 5-hydroxvindoles at C-A via the $4..) v 4 a .- -'—-' ~ ...: -. . --- (T: a-‘-' a r“;— ‘.-—- r - Inannlc. r;aeolon requires some rationalizaolOn. is has seen ...“..A ..u, ‘21 .'.f ..4. ..'_~ . - .'..:,.~ nfi;:,\ .0 ‘,,. . 'fi suggesoeo 6na6 one preferenolal or tlo akylaoio n oi phenols over orienting the *d para-alkylation is a result of the hydroxyl grou llannicn int rm diate in a quasi-six-membered chelate r:ng preceeditg carbon-carbon 00nd fo Wat ion. If one extends this arg= ant to the hydroxyindole systems, 'tne orientation by the hydrox,l gro up would seem to suggest a lion-stereospeci fie a11—ylation of ei6her of the tw ocfl-carbon atoms. Results of our work indicate a ste eosaecific alkylation at 0-5 :for 6-hydroxy-l,2,5,A-tetrahydrocarbazole (;) and ior 9-methyl-6- lrydroxy-l,2,5,4-tetrahydrocarbazole (;), and Cu-addition for 5—hydroxyindole (ll), 2-methyl-5-hld xgind 1e (£9), 2-methyl-5- n cxarbethoxy-5—hydroxyindole (a) as well as Ior 2—methfl-5- M 12 TABLE III Nmr Spectra of 5-Hydroxyi”doles Chemical shits ir. gppma ’{ H ‘ 7~ / " p I )2 \ B - Ha '\ .- F CtmL nd I1'b 1 b - c d Ha ab He 02- C.. 3 02-H 03-H ,8 6.72 7.16 7.18 2.65 --- - _ 9(N-H=O) 6.8a 7.32 7.19 2.70 -..- - _ '15; 6.62 7.10 6.90 2.33 --- 6.003?- ) y; 6.75 7.25 k 7.08 m 7.13% 6.32h (a) Spectra were taken in Cchli with an internal TMS standard; (b) doublet of doublets (Jo.r~8 5 eps, Jm.r-2 5 cps); (c) doublet (Jéf 8. 5 cps); (d) doublet (J.’2 5 cps); (e) singlet; (f) multiplet; (g) doublet (J-v5m 5 cps); (g) broadened doublet (J~5.5 cps) CM}. was" TABLE IV Nmr Spectra of Mannich Adducts Chemical Shifts in Sppma l‘Iannich . Adduct b b _ c Ha Hb Cu-CHg- C2-CH3 C2-H Cj-H 138 6.67 6.98 [b.25 2.55 --- --- .Qéd 6.67 7.00 4.25 2.52 --- --- ’;b(N-H=O) ”.73 7.15 n.15 2.58 --- --- 1‘93. 6.67 6.98 3.83 2.32 --- 6.058 ‘113 6.72 7.08 3.87 ——- 7.02f 6.3L.g (a) Spectra were taken in CD013 with an internal TMS standard; (b) doublet (J~8.S cps); (c) singlet; (d) dimethyl- amino Mannich adduct; (e? multiplet; (f) doublet (J/~5.5 cps); (g) broadened doublet (J’sjj Cps) EM] . :fHES‘ 1h carbethoxy-S-hydroxybenzofuran 93). We consequently pr0pose resonance stabilization of the developing transition state carbonium ion lg,6 involving the electron pair on the hetero atom, to be the deciding factor for our stereospecific alkylations. Alkylation in the alternate .EZEEETPOSitiOD'%2 would allow less delocalization of the positive charge and would consequently have a higaer energy of activation. A similar argument would favor the CB-alkylation of 7-hydroxy- 1,2,3,8-tetrahydrocarbazole, in which greater charge delocalization is obtained in the transition state llg'than could occur for the C6-alkylated product‘lj; Only the CP-condensation is noted for , this compound, which supports the delocalization theory. THESI 15 For 6-methoxy-l,2,5,1.L-tetrahydrocarbazole (2) one could not employ the hydrogen-bonded orientation and consequently alkylation involving the electron pair on the indole nitrogen would be expected and was observed. The interesting case at hand is that of 5-methyl-6-hydroxy- l,2,3,8-tetrahydrocarbazole (2.) where the preferred site of addition is blocked. In this case two products were obtained. The major product was the N-ali‘Q/lated Mannich adduct .25: and the second, minor product was di-adduct 1.1% first glance this appeared to be a rather strange order for addition, expecially when the hydroxyl group was present to orient the I-Iannich intermediate, but the result is cor.:iste.1t with the stereospecific addition of the hydroxyindoles. 16 It could logically be assumed that the energy of activation for the alkylation of the two ortho-carbons is significantly different and consequently the energy of activation for the alternate site is in the region of that of N-alkylation or even somewhs; higher, which would give the resulting product distribution. An explaination for the anomalous, stereospecific orientation of 9-methyl-6-methoxy-l,2,5,h-tetrahydrocarbazole L2) is not perfectly clear at this point, but is perhaps analogous to the synthesis of Voacamine.6 It might be pointed out that forcing conditions were used in this case, which were not necessary in the other Mannich reactions. Hence, it appears that orientation of the Mannich intermediate by the hydroxyl group on the indole nucleus and resonance stabiliza- tion of the intermediate carbonium ion are the two dominant factors in the steroospccific alkylation of hydroxyindoles via the Mannich reaction. 17 EXPERIIV EITTALJ 6-Hydroxy-l,2,5,h—tetrahydrocarhazole (l) was prepared by . . 8 . . . . . . the method of Milne and Tomlinson in a 60% yield. A.moa1f1cation .0 '* 1 22 -1 w 01 the method used by Asero and co-worners was also employed to give a C#% conversion to the desired product. The crude product was purified by sublimation at O.me. and l60° to yield white \ZEt OH /.max 228, 282, 295 crystals, m.p. l70-l72° (lit. 8m. p. 172° );/ (Shoulder/M e20 ,300, 7500 and 6700, resp. M1/w*Cl3 36 00, 3L70 cm.-l. See Table I for nmr. u. Mannich Adduct la was prepw° ed according to the method of , ... 1 o ‘ o I. O n o Bucni, Manning and Mbnti. The proauct was crystalllzed from ethanol to give a 75% yield of a white crystalline solid, m.p. - .. 6 . / . . l65-loh°(l1t. m.p. lo5.S-lou.5°). The reaction was also carr1ed L out at room temperature for h hours in etha aol and recrystallized to give a 78% yield, m. p. l65-l6L-° ;/%L; OH 251, 284, 295 (shoulder) 2 “e20 800 8600 ard 7500 rec ) \IC“313 3u70 c '1 7 s Ta‘l ‘ 7" ’ 2 * : OP- 9 I max _ m. . ee 0 e II for nmr. Nhnnich Adduct lb.--A.mixture of 25% dimethylamine ‘ solution (1.0mmole) and paraformaldehyde (50 mg., l.Ommole) was 'warmed in ethanol (5 ml.) on a steam bath until the solution became homogeneous. The solution was cooled to room temperature and 6-hydroxy-l,2,5,4-tetrahydrocarbazole (I) (l85 mg., l mmole) 'was added. The mixture was stirred for 5 hours at room te perature, evaporated to dryness and chromatographed over activity III alumina 'with benzene to give lL7% .(60% ) of product, thch was recrystal— 18 lized from a benzene—pet. ether mixture to give white crystals, ,XEtOH m.p. 128—155.5°; 251, 285, 295 (shoulder) mf&(€lg,800, 8000 and 7200, reSp.);)[:::l3 5h70 cm.-l.7 The nmr showed the N,N— dimethyl group as a 6-hydrogen singlet at,f2.55 in addition to the protons shown in Table II. fin§1.0alcd. for 015H2J20: C, 75.75; H, 8.25; N, ll.u7. Found: C, 72.9%; H, 8.16; N, 11.58. The reason for poor agree- ment might be due to the instability of the product. The compound has been noted by tlc to decompose on standing in alcohol. Mannich Adduct lc.--A mixture of iperidine (85 mg., 1.0 mmole) and paraformaldehyde (50 mg., 1.0 mmole) was warmed in ethanol (9 ml.) until the solution became homogenous. The mixture was cooled to room temperature and the piperidine-Mannich adduct 1a (282 mg., 1.0 mmole) was added. he reaction mixture was refluxed for 8 hours, during which time 518 mg. (8M%) of a white solid crystallized, m.p. 172-l8l°(dec.);AE"OH 252, 286, 500 (shoulder) mfix (g’ 21 ,900, 9500 and 7h00, resp. )3 :/C“Cl3 (see footnote 7). See Table II for nmr. /-MEthoxy-l,2,5,h-tetrahydrocarbazole (2) was prepared by 9 the method of Milne and Tomlinson in a 56% yield. The crude product was purified by recrystallization from ethanol to yield white crystals, m.p. 101-101.L°(11t.9 m.p. 95-105°);A§§H 229, 285, 296 (shoulder) mfiz(é25,000, 7800 and 7500, resp.);Elgigls 5u70 cm.’l. See Table I for nmr. pmpnfgthfduct 2a.--A.mixture of piperidine (85 mg., 1.0 19 -‘ mmole) and paraformaldehyde (50 mg., 1.0 mmole) was warmed in ethanol (2 ml.) to give a homogeneous solution. The mixture was cooled and the 6—methoxy-l,2,5,k-tetrahydrocarbazole (2) (199 mg., 1.0 mmole) was added. The mixture was refluxed under a nitrogen atmosphere for 2 hours and evaporated to a yellow syrup, which crystallized from ethanol to give 172 mg. (58%) of product, m.p. 5h-65°(dec.);AIEn:J—;:H 251, 285, 296 (shoulder) m/U-( 2u,000, 8500 and 7200, resp.);)/:::13 (no functional groups present). See Table II for nmr. 9-Mnthylc6-mcthoxy-1.2.5,h—tetrahydrocarhazole (5) was prepared by the method of Stevens and Tuckerlo in a 85% yield. The crude product was purified by recrystalli ation from an ethanol- water mixture to yield a white product, m.p. 86.5-88.5° (lit.lQm.p. 888°)-/\ECOH21 287 22(huld ) («'2 00 20 ‘ -9,max 5, ,9 so erm/uc5,9,75o and 6700, resp.); no identifiable functional groups in infrared Spectrum. See Table I for nmr. Nannich Adduct 5a.--A mixture of piperidine (#5 mg., 0.50 mmole) and paraformaldehyde (15 mg., 0.50 mmole) was dissolved in glacial acetic acid (6 ml.) by warming on a steam bath. The mixture was cooled to room temperature and the 9-methyl-6-methoxy-l,2,5,h- tetrahydrocarbazole (5) (108 mg., 0.50 mmole) was added. The mixture was then refluxed under a nitrogen atmosphere for one and one half hours, Huutrulincd by adding dropwisc to a sodium carbonate solution and extracted with benzene to give 86 mg. (55%) of product, which was recrystallized from ethyl acetate to give slightly yellow ' ‘ . " .7. 0‘ ~N' ’ 0 “ \ - l" . '~‘- 'v- Q . CV} LtLb) W°T' 04'0103 . bee fable ll 10v nmr. 2O 9-hbthyl-6-hydroxy-1,2,5,L-tetrnhydrocarbazole (4).--A 650 m8- sample of 9-methyl-6-methoxy-l,2,5,M-tetrahydrocarbazole (5) was ,% , ll , . . . 1 a . . demeoh lated by reflux1ng in a leture ol hydrobromlc ac1d .148” " t—T -: “O w“ n . 1" 1’. 1 ...-'4- (5 ml. of V and ace ic acid l ml. 01 lo .ours un( r nitrogen. The solution was neutralized with sodium carbonate and extracted with methylene chloride to give 250 mg.(4l%) of product. The product was purified by sublimation at 0.5 mm to give a white solid, m.p. EtO ' 112' L l} . 5° 3, 5 251, 286, 299 (shoulder) Ill/«($21,000, 7000. , .CHCl'C, / l, . -l and 5900, resp.);pmaX 5000, 5570 (oroad) cm, . See Txble I for nmr. Mannich Adduct ha.--A.mixture of piperidine (h2.5 mg., 0.50 mmole) and paraformaldehyde (15 mg., 0.50 mmole) was warmed in a mixture of acetic acid in ethanol (1:10) to effect an homo- geneous solution. The mixture was cooled and the 9-methy1-6-hydroxy- 1,2,5,h-tetrahydrocarbazole (99.5 mg., 0.50 mmole) was added. The mixture was refluxed for 90 minutes under a nitrogen atmosphere, cooled to room temperature and added dropwise into a solution f sodium carbonate and then was extracted with benzene. The crude product was recrystallized from ethyl acetate to give 125 mg. (89%) of white‘needles, m.p. 1h2-1h-4°,A:::H 252, 287-, 508 (shoulder) mfiL(¢l9,600, 7000 and 5900, resp.). The product showed the expected infrared7 and nmr spectra (Table II). 5-Met2yl-6-hydroxy-l,2,5,h-tetrahydracarbazole (5).--Mannich adduct lb_(2hh mg., 1.0 mmole) was dissolved in 50 m1. of 95% ethanol and 100 mg. of catalyst (Pd/C) was A) 2 ed. The mixture was shaken on a Paar shaker at 80° for 5 hours at a pressure of 50 psi 21 of hydrogen to give 180 mg.(90%) of the desired product, m.p. 50.5- o EtOH ‘ 1“ j _ I‘- -'\, [:7 55.5 3>\n1x 227, 279, 294 (shoulder) mrb(gl5,jvo, 5.00 and #000, resp.),zjggils 560M, 5h70 cm.-l. See Table I for nmr. Mannich Adduct 5a.--A.mixture of piperidine (85 mg., 1.0 mmole) and paraformaldehyde (50 mg., 1.0 mmole) was warmed to effect a clear solution in alcohol (6 ml.) contailing 2 drops of acetic acid. The mixture was cooled and the 5-methyl-6-hydroxy- 1,2,5,h-tetrahydrocarbazole (2) (202 mg., 1.0 mmole) was added. The mixture was stirred at room temperature for 8 hours, evaporated to dryness on Alumina III and eluted with benzene to give 195 mg. (65%) of product. his 8282: product was recrystallized from ethanol to give white crystals, m.p. 1%.5-lt7.5°;/\$:H 229, 281, 505 (shoulder) m/sz.(r311+,500, 5Ll00 and 5700, reSp. );\]C¥Cls 5600 cm.-l.7 mox See Table II for nmr. Mannich Adduct 5b.--A second minor product was obtained by chromatography of the mother liquors fromyia over Alumina III. The second fraction (50% benzene-pet ether) furnished 50 mg. (15%) of a white solid, m.p. lL6.5-1h8°; mixture melting point with,$a, 125- .155°. The absence of N-H or free hydroxyl stretches in the infrared as well as the nmr spectrum (see Table II) confirm the di-addition formulation §p_for this material. no mono-alkylation product, resulting from addition to the benzene ring only, was obtained. This was concluded by the absence of an indole N-H stretch in the infra~ . red in any of the chromatography fractions. 3 , - .. . . , f .L . 7-nydroxy-l,2,5,h-tetrahydrocaroizole (0) was prepared by the method of Jones and TomlinsonJ‘2 in a 51% yield, m.p. l62.5-l65.5° 22 12 (lit. m.p. 165 16L?) ;/(““OH 229, 275, 502 m/ (627,5 00, L200 and L700,resp.);)/C:XC18 5600, 5“70 cm.-l. See Table I for hr . 1 r 0 ~ -. . / f“ ... Mannzcn AddtCt oa.--A.mixture of nIJelidlh (05 mg., 1.0 "I H -V _ -vr\ _ , " ‘ ,, . h, A '_ nmole) and paralormaldehyde (50 mg., 1.0 nmole) uas wasmed on a ,1 steam oath to ef ‘ect an homogeneous sol tion. The mixture was coolel to room temp ratule and the 7- hfl,droxy-l 2,5, L-tetrarydio- “ .1. carbazole (6 was added. The mixture was stirred as room temper- ature for 50 min. to give 195 mg. (or 9%) of pro oduct, m. p. 161.5- 165°;;‘LU:H 250, 27L, 505 mJA(:27,000, 4600 and hLOO, resp.); \ )31-Cls 7 ’Jmax 5u75 cm. 1. See Table II for nmr. Anal. Calcd. for 018H24N20; 0, 76.02; h, 8.51; N, 9.85. Found: C, 76.07; H, 8.hl; N, 9.88. Attrmpted Synthesis of 8—Hydroxy-l,2 5,h~tetrahydro- ) carbazole (7).--An attempt was made to prepare 7 in a method similar to the preparation of;i.l2 grthofaminophenol (5.h5 g, 50 mmoles) and 2-hydroxycyclohexanone (6.00g., 50 mmoles) were warmed in the presence of three drops of hydrochloric acid to 1M0° for eight minutes in an open flask with stirring. The syrupy product crystallized from ethanol to give 6.50 g. of a white crystalline product, m.p. 161.5-165°;/x:::H 209, 245, 295 mft(g21,h00, ##00 and 2500, reSp.);)/§::la 5580 (shoulder), 5t80‘(broad), 5595 (sharp) and 5520 (shoulder) ch-l. The nmr spectrum showed a cor aplex aromatic mult iplet from S 6 . 5-6 . 7 . Anal. Calcd. for C H.3NO: c, 76. 7; H, 7.00; N, 7.L8. 121 Found: 0, 71.20; H, 7.hl; N, 7.0h. This analysis better fits 25 C12 TI15NO2 calCd°= C: 70-22; H, 7. 7; H, 6.82. '1‘ 1‘“, ' A f“ ’ I ‘ 1" fl - ‘ P-Xeuhyl—5;ca:0-tho279 (l9JL/- l7. R. J. S. Beer, K. Clarke, H. G. Davenport and A. Robertson, J. Chem. Soc., 2029 (1951). 17a. Unpublished work by Dr. S. A. Monti in this labora;cry. 18. E. Bernatek and T. Ledaal, Acta. Chem. Sca.d.. l_, 205' \ (19:18). 19' A. lg. Grillev and N. K0 KL ne’rtseva, 5110 03.2: -C1io quo ’ 35’ 820 [1965); C. A. 59: 7406a. 20. Aldrich Cr em al Company. 21. J. H. Burckhalter and B. L. Leib, g. 0:3. hem., 6, 4078 (1961). 22. s. Asero et al, Ann., y76, 69 (l952). 2 . Meltin t point3 were obseri ed on a Kofler Micro Hot Stare 31d *b ‘2 are uncorrected. Ultraxiolet spectra were measured on a Unican P.800 r to; ding ultraviolet spectrom ter, and infrared spectra were recorded on a Berlin-E ler Model 2573 G aging Infrared Spectrophotometer. The nmr spectra were taken on aVarian Associates Model A-SO nmr spectrometer and the cr em: cal shifts are reported in (S) p.p.m. downfield from an internal tetramethylsilane reference. Woelm Alumina was used as a chromatographic adsorbant. Microanalyses were performed by the Spans” Microanalytical Laboratory, Ann Arbor, Michigan. BIOGRAPHICAL NOTE ne author was born on May 26, l9k2, in Valley City, North Dakota and received his secondary education in Hannaford, North Dakota. 'He undertook undergraduate study at Concordia College of MOorhcad, Minnesota, where he received a Bachelor of a. Arts Degree in June, 1964. ne then occage a graduate student at Michigan State University, East Lansing, Michigan, where Le worked for his Master‘s Degree. Upon completion, he has teen accepted to the graduate school of the De ar.m'nt of Chemistr. of the Jniversity* of Oregon, Eugene, Oregon,in the fall oifl966. 27 II I I I] l i ll ' l l l I 'l l l I III I l l I II l l I II l I II III 062 3049 J Ill! 1293 JIHIIHHIUHIIHI 3