Palladium-Catalyzed Cross-Couplings of Lithium Arylzincates with Aromatic Halides: Synthesis of Analogues of Isomeridianin G and Evaluation as GSK-3β Inhibitors

Abstract

Several analogues of isomeridianin G have been synthesized using palladium-catalyzed cross-coupling reactions of lithium triorganozincates as a key step. The latter have been prepared by deprotonative lithiation followed by transmetalation using ZnCl₂˙TMEDA (0.33 equiv).

Key words

cross-coupling - heterocycles - palladium - zinc - lithium

References

• 1a Stanforth SP. Tetrahedron  1998,  54:  263 
• 1b Hassan J. Sévignon M. Gozzi C. Schulz E. Lemaire M. Chem. Rev.  2002,  102:  1359 
• 1c Handbook of Organopalladium Chemistry for Organic Synthesis   Vol. 1:  Negishi E.-i. Wiley-Interscience; New York: 2002.  Chap. III.
• 1d Chinchilla R. Nájera C. Yus M. Chem. Rev.  2004,  104:  2667 
• 1e Chinchilla R. Nájera C. Yus M. ARKIVOC  2007,  (x):  152 
• 2 Kotha S. Lahiri K. Kashinath D. Tetrahedron  2002,  58:  9633 ; and references cited therein
• 3 Stille JK. Angew. Chem., Int. Ed. Engl.  1986,  25:  508 
• 4a Negishi E.-i. King AO. Okukado N. J. Org. Chem.  1977,  42:  1821 
• 4b Negishi E.-i. Acc. Chem. Res.  1982,  15:  340 
• 4c Negishi E.-i. In Metal-Catalyzed Cross-Coupling Reactions   Diederich F. Stang PJ. Wiley-VCH; Weinheim: 1998.  Chap. 1.
• 5a Erdik E. Organozinc Reagents in Organic Synthesis   CRC Press; New York: 1996. 
• 5b Organozinc Reagents   Knochel P. Jones P. Oxford University Press; Oxford: 1999. 
• 6 Miller JA. Farrell RP. Tetrahedron Lett.  1998,  39:  7275 
• 7a Kondo Y. Takazawa N. Yamazaki C. Sakamoto T. J. Org. Chem.  1994,  59:  4717 
• 7b Kondo Y. Komine T. Fujinami M. Uchiyama M. Sakamoto T. J. Comb. Chem.  1999,  1:  123 
• 7c Uchiyama M. Furuyama T. Kobayashi M. Matsumoto Y. Tanaka K. J. Am. Chem. Soc.  2006,  128:  8404 
• 7d See also: Kneisel FF. Dochnahl M. Knochel P. Angew. Chem. Int. Ed.  2004,  43:  1017 
• 8a Kondo Y. Shilai M. Uchiyama M. Sakamoto T. J. Am. Chem. Soc.  1999,  121:  3539 
• 8b L’Helgoual’ch JM. Seggio A. Chevallier F. Yonehara M. Jeanneau E. Uchiyama M. Mongin F. J. Org. Chem.  2008,  73:  177 
• 8c See also: Wunderlich SH. Knochel P. Angew. Chem. Int. Ed.  2007,  46:  7685 
• 9 Gauthier DR. Szumigala RH. Dormer PG. Armstrong JD. Volante RP. Reider PJ. Org. Lett.  2002,  4:  375 
• 10 Mutule I. Suna E. Tetrahedron  2005,  61:  11168 
• 11 Negishi E.-i. Luo F.-T. Frisbee R. Matsushita H. Heterocycles  1982,  18:  117 
• 12 Seggio A. Jutand A. Priem G. Mongin F. Synlett  2008,  2955 
• 13 For the use of PdCl₂(dppf) as a highly effective catalyst for the coupling of organozinc reagents, see: Hayashi T. Konishi M. Kobri Y. Kumada M. Higuchi T. Hirotsu K. J. Am. Chem. Soc.  1984,  106:  158 
• For palladium-catalyzed cross-couplings of arylzinc compounds with aryl bromides, see for example:
• 14a Amatore C. Jutand A. Negri S. Fauvarque J.-F. J. Organomet. Chem.  1990,  390:  389 
• 14b Bumagin NA. Sokolova AF. Beletskaya IP. Russ. Chem. Bull.  1993,  42:  1926 
• 14c Borner RC. Jackson RFW. J. Chem. Soc., Chem. Commun.  1994,  845 
• 14d Goldfinger MB. Crawford KB. Swager TM. J. Am. Chem. Soc.  1997,  119:  4578 
• 14e Hargreaves SL. Pilkington BL. Russell SE. Worthington PA. Tetrahedron Lett.  2000,  41:  1653 
• 14f Loren JC. Siegel JS. Angew. Chem. Int. Ed.  2001,  40:  754 
• 14g Alami M. Peyrat J.-F. Belachmi L. Brion J.-D. Eur. J. Org. Chem.  2001,  4207 
• 14h Karig G. Thasana N. Gallagher T. Synlett  2002,  808 
• 14i Balle T. Andersen K. Vedsø P. Synthesis  2002,  1509 
• 14j Kondolff I. Doucet H. Santelli M. Organometallics  2006,  25:  5219 
• 14k Akao A. Tsuritani T. Kii S. Sato K. Nonoyama N. Mase T. Yasuda N. Synlett  2007,  31 
• About the direct lithiation of thiophene and benzo[b]thiophene, see also:
• 15a Jen K.-Y. Cava MP. J. Org. Chem.  1983,  48:  1449 
• 15b Surry DS. Fox DJ. MacDonald SJF. Spring DR. Chem. Commun.  2005,  2589 
• 17 Legault CY. Garcia Y. Merlic CA. Houk KN. J. Am. Chem. Soc.  2007,  129:  12664 
• 19 Roy S. Gribble GW. Tetrahedron Lett.  2005,  46:  1325 
• For Pd-catalyzed cross-couplings of arylzinc compounds with aryl chlorides, see for example:
• 20a Bracher F. Hildebrand D. Tetrahedron  1994,  50:  12329 
• 20b Amat M. Hadida S. Pshenichnyi G. Bosch J. J. Org. Chem.  1997,  62:  3158 
• 20c Herrmann WA. Bohm VPW. Reisinger C.-P. J. Organomet. Chem.  1999,  576:  23 
• 20d Dai C. Fu GC. J. Am. Chem. Soc.  2001,  123:  2719 
• 20e Simkovsky NM. Ermann M. Roberts SM. Parry DM. Baxter AD. J. Chem. Soc., Perkin Trans. 1  2002,  1847 
• 20f Li GY. J. Org. Chem.  2002,  67:  3643 
• 20g Lützen A. Hapke M. Staats H. Bunzen J. Eur. J. Org. Chem.  2003,  3948 
• 20h Stanetty P. Schnürch M. Mihovilovic MD. Synlett  2003,  1862 
• 20i Milne J. Buchwald SL. J. Am. Chem. Soc.  2004,  126:  13028 
• 20j Switzer C. Sinha S. Kim PH. Heuberger BD. Angew. Chem. Int. Ed.  2005,  44:  1529 
• 21 Benzo[b]furan has previously been metalated using t-BuLi in Et₂O at -78 ˚C: Zhang H. Larock RC. J. Org. Chem.  2002,  67:  7048 
• 23 Strekowski L. Harden DB. Grubb WBIII. Patterson SE. Czarny A. Mokrosz MJ. Cegla MT. Wydra RL. J. Heterocycl. Chem.  1990,  27:  1393 
• 24 For the lithiation of furan, see: Ramanathan V. Levine R. J. Org. Chem.  1962,  27:  1216 
• 25 Hasan I. Marinelli ER. Lin L.-CC. Fowler FW. Levy AB. J. Org. Chem.  1981,  46:  157 
• 26 Shirley DA. Johnson JR. Hendrix JP. J. Organomet. Chem.  1968,  11:  209 
• For the deprotonation of 2-fluoropyridine using a lithium amide, see:
• 27a Gribble GW. Saulnier MG. Heterocycles  1993,  35:  151 
• 27b Estel L. Marsais F. Quéguiner G. J. Org. Chem.  1988,  53:  2740 
• 28 Hernández Franco L. Bal de Kier Joffé E. Puricelli L. Tatian M. Seldes AM. Palermo JA. J. Nat. Prod.  1998,  61:  1130 
• 29 Gompel M. Leost M. Bal De Kier Joffé E. Puricelli L. Hernandez Franco L. Palermo J. Meijer L. Bioorg. Med. Chem. Lett.  2004,  14:  1703 
• 30a Avila J. Hernandez F. Expert Rev. Neurother.  2007,  7:  1527 
• 30b Jope RS. Yuskaitis CJ. Beurel E. Neurochem. Res.  2007,  32:  577 
• 30c Maccioi RB. Otth C. Concha II. Munoz JP. Eur. J. Biochem.  2001,  268:  1518 
• 31 Only one synthesis of isomeridianin C and G has been reported: Hernández Franco L. Palermo JA. Chem. Pharm. Bull.  2003,  51:  975 
• 32 For a similar conversion, see: Jaime-Figueroa S. Liu Y. Muchowski JM. Putman DG. Tetrahedron Lett.  1998,  39:  1313 
• 33 Shengule SR. Karuso P. Org. Lett.  2006,  8:  4083 
• 34 Jacquemard U. Bénéteau V. Lefoix M. Routier S. Mérour J.-Y. Coudert G. Tetrahedron  2004,  60:  10039 
• For similar conversions under microwave irradiation, see:
• 35a Luo G. Chen L. Poindexter GS. Tetrahedron Lett.  2002,  43:  5739 
• 35b Wang X. Chakrabarti PP. Ognyanov VI. Pettus LH. Tamir R. Tan H. Treanor JJS. Gavva NR. Norman MH. Bioorg. Med. Chem. Lett.  2007,  17:  6539 
• 36 Isobe M. Kondo S. Nagasawa N. Goto T. Chem. Lett.  1977,  679 
• 37 Gottlieb HE. Kotlyar V. Nudelman A. J. Org. Chem.  1997,  62:  7512 
• 38 Inahashi N. Matsumiya A. Sato T. Synlett  2008,  294 
• 39 Kumar A. Say M. Boykin DW. Synthesis  2008,  707 
• 40 Clark RD. Muchowski JM. Fisher LE. Flippin LA. Repke DB. Souchet M. Synthesis  1991,  871 
• 41 Witulski B. Buschmann N. Bergstrasser U. Tetrahedron  2000,  56:  8473 
• 42 Takahashi K. Suzuki T. Akiyama K. Ikegami Y. Fukasawa Y. J. Am. Chem. Soc.  1991,  113:  4576 
• 43 Sieber F. Wentworth PJr. Janda KD. J. Comb. Chem.  1999,  1:  540 
• 44 Denmark SE. Baird JD. Org. Lett.  2006,  8:  793 
• 45 Yasuhara A. Suzuki N. Yoshino T. Takeda Y. Sakamoto T. Tetrahedron Lett.  2002,  43:  6579 
• 46 Labadie SS. Teng E. J. Org. Chem.  1994,  59:  4250 
• 47 Denmark SE. Baird JD. Org. Lett.  2004,  6:  3649 
• 48 Brown DJ. Cowden WB. Strekowski L. Aust. J. Chem.  1982,  35:  1209 
• 49a Constable EC. Sousa LR. J. Organomet. Chem.  1992,  427:  125 
• 49b Bayh O. Awad H. Mongin F. Hoarau C. Trécourt F. Queguiner G. Marsais F. Blanco F. Abarca B. Ballesteros R. Tetrahedron  2005,  61:  4779 
• 50 Semmelhack MF. Chlenov A. Ho DM. J. Am. Chem. Soc.  2005,  127:  7759 
• 51 Ishikura M. Matsuzaki Y. Agata I. Heterocycles  1997,  45:  2309 
• 52 Mongin F. Mojovic L. Guillamet B. Trécourt F. Quéguiner G. J. Org. Chem.  2002,  67:  8991 
• 53 Li J.-H. Zhu Q.-M. Xie Y.-X. Tetrahedron  2006,  62:  10888 
• 54 Mongin F. Bucher A. Bazureau JP. Bayh O. Awad H. Trécourt F. Tetrahedron Lett.  2005,  46:  7989 
• 55 Gupton JT. Petrich SA. Hicks FA. Wilkinson DR. Vargas M. Hosein KN. Sikorski JA. Heterocycles  1998,  47:  689 
• 56 Vaitiekunas A. Miller RE. Nord FF. J. Org. Chem.  1951,  16:  1603 
• 57 Liu F. Ma D. J. Org. Chem.  2007,  72:  4844 
• 58 Molander GA. Canturk B. Kennedy LE. J. Org. Chem.  2009,  74:  973 
• 59 Shen M. Leslie BE. Driver TG. Angew. Chem. Int. Ed.  2008,  47:  5056 
• 60 Hudkins RL. Diebold JL. Marsh FD. J. Org. Chem.  1995,  60:  6218 

16

The 10% yield obtained by using 4-bromoanisole could be explained by the absence of an electron-withdrawing group at the 4-position of the phenyl ring. The competitive formation of 2,2′-bisthiophene was also observed in 40-50% yield.

18

Use of N-Boc-indole under these conditions gave after subsequent reaction with iodine the 2-iodo derivative in 68% yield as a pale yellow oil [after purification by chromatography on silica gel using heptane-CH₂Cl₂ (30:70) as eluent]: ^¹H NMR (200 MHz, CDCl₃): δ = 1.77 (s, 9 H), 7.01 (s, 1 H), 7.22-7.30 (m, 2 H), 7.48 (dd, J = 7.8, 2.0 Hz, 1 H), 8.17 (d, J = 7.2 Hz, 1 H); ^¹³C NMR (50 MHz, CDCl₃): δ = 28.3 (3 C), 74.9, 85.2, 115.4, 119.4, 121.9, 122.8, 124.2, 131.1, 137.5, 149.2; HRMS: m/z calcd for C₁₃H₁₄INO [M⁺]: 343.0069; found: 343.0070; Anal. Calcd for C₁₃H₁₄INO (343.16): C, 45.50; H, 4.11; N, 4.08. Found: C, 45.47; H, 4.10; N, 4.16. The same compound has previously been prepared in 67% yield using t-BuLi in THF at -78 ˚C; see ref. 19.

22

No reaction takes place in the absence of transition metal. Note that product 5a has previously been obtained by addition of 2-benzo[b]furyllithium at the 4-position of 2-chloropyrimidine followed by rearomatization using DDQ in 38% yield: see ref. 23. For previously described regioselective cross-coupling using 2,4-dichloropyrimidine, see for example ref. 19e.