PAPER 267 Synthesis 2001, No. 2, 267–275 ISSN 0039-7881 © Thieme Stuttgart · New York Preparation and Reactions of 4-, 5-, and 6-Methoxy Substituted 3-Lithioindoles and 3-Indolylzinc Derivatives Mercedes Amat,* Fátima Seffar, Núria Llor, Joan Bosch Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028-Barcelona, Spain Fax +34(93)4024539; E-mail: amat@farmacia.far.ub.es Received 3 July 2000;revised 18 September 2000 Abstract: The preparation of 4-, 5-, and 6-methoxy substituted 3-lithio-1-(trialkylsilyl)indoles 4b-d by metalation of the corre- sponding 3-bromoindoles, and their reactions with iodomethane, DMF, ethylene oxide and aziridines are reported. Transmetalation of 3-lithioindoles 4b-d with ZnCl 2 afforded 3-indolylzinc chlorides 11b-d, which underwent Pd(0)-catalyzed cross-coupling reactions with 2-halopyridines to give 4-, 5-, and 6-methoxy substituted 3-(2- pyridyl)indoles. Key words: indoles, lithium, zinc, cross-coupling, pyridylindoles, silyl protecting groups In 1994 we reported that 3-lithio-1-(trialkylsilyl)indoles, prepared by halogen-metal exchange from the corre- sponding 3-bromo derivatives, are stable species that effi- ciently react with a variety of electrophiles to regioselectively give 3-substituted indoles. 1 Due to its steric requirements and non-coordinating abilities, 2 a bulky trialkylsilyl group prevents the undesired migration of the lithium atom from the 3 to the 2 position of the in- dole ring, which occurs in 3-lithioindoles bearing the more usual N-benzenesulfonyl protecting group. 3 3-Lithio-1-(trialkylsilyl)indoles have proven to be versa- tile synthetic intermediates with a variety of applications, 4 including the preparation of valuable 3-indolylboronic acids 5 and 3-indolylzinc derivatives, 6 which can undergo Pd(0)-catalyzed cross coupling reactions. In particular, 3-indolylzinc halides react in excellent yields with di- versely substituted 2-halopyridines to give 3-(2-py- ridyl)indoles, from which we have accomplished the formal total synthesis of several alkaloids of the Strychnos and uleine groups. 6b In this paper we describe the preparation of 4-, 5-, and 6-methoxy substituted 3-lithio-1-(trialkylsilyl)indoles, their reactions with electrophiles, and their conversion to the corresponding 4-, 5-, and 6-methoxy-3-indolylzinc halides. To our knowledge, 1-(benzenesulfonyl)-5-meth- oxy-3-lithioindole was the only methoxy substituted 3-lithioindole reported at the begining of our studies, 7,8 and their generation and manipulation require tempera- tures as low as -100 °C to avoid the rearrangement to the more stable 2-lithio isomer. 7 Hydroxyindoles and their methyl or benzyl ethers have acquired great importance as synthetic precursors of physiologically active hydroxy- tryptamines, such as serotonin and the pineal hormone melatonin, as well as of the naturally occurring hallucino- gens psilocin, bufotenine, and psilocybin (Figure). Hy- droxy- and methoxyindoles are also important intermediates in the synthesis of biologically active indole alkaloids, such as physostigmine and harmaline, and the more complex monoterpenoid indole alkaloids reserpine, sarpagine, mitragynine, ibogaine and vindoline. 9 Figure Structures of some naturally occurring indoles The required 3-bromo-1-(trialkylsilyl)methoxyindoles were prepared in excellent yield by silylation of the lithi- um salt of the corresponding 4-, 5-, and 6-methoxyindoles 1, followed by addition of NBS at -78 °C in a one-pot re- action. The use of t-BuMe 2 SiCl gave satisfactory results in the preparation of bromoindoles 3c and 3d (5- and 6-methoxy series), but the bromo derivative 3a proved to be unstable and decomposed during column chromatogra- phy (Scheme 1). For this reason, we prepared the 1-triiso- propylsilyl derivative 3b, since in a previous work 4b we had observed that N-(triisopropylsilyl)indoles are more stable towards hydrolysis than the N-(tert-butyldimethyl- silyl) analogs. In contrast, all attempts to prepare 7-meth- oxy-1-(trialkylsilyl)indoles 2e by treatment of the lithium or the sodium salt of 7-methoxyindole with tert-butyldi- methyl-silyl chloride or the less bulky trimethylsilyl chlo- ride were unsuccessful, due to the steric hindrance of the 7-methoxy substituent which lies in the space near to the nitrogen atom. Treatment of a THF solution of 3-bromoindoles 3b-d with 2.2 equivalents of t-BuLi at -78 °C for 10 minutes, followed by addition of a THF solution of iodomethane at -78 °C afforded the respective 3-methylindoles 5a, 7a, and 9a, which were desilylated by treatment with Bu 4 NF to give the unprotected 3-methylindoles 6a (Scheme 2), N H RO NR 1 R 2 N H N(CH 3 ) 2 OR N H N Me MeO N Me N Me H Me O MeHN O Harmaline R = H, R 1 = R 2 = H Serotonin R = H, R 1 = R 2 = Me Bufotenine R = Me, R 1 = H, R 2 = Ac Melatonin R = H Psilocin R = PO 3 H 2 Psilocybin Physostigmine