Synthesis of Pyrrolo[1,2-b]isoquinolines through Mesityllithium-Mediated Intramolecular Carbolithiation

Abstract

Mesityllithium has proven to be an effective iodine-lithium exchange reagent. Thus, carbolithiation reactions on 2-alkenyl-substituted N-(o-iodobenzyl)pyrroles have been accomplished avoiding side reactions to afford pyrroloisoquinolines in high yields (80-92%), improving the results obtained with t-BuLi. The carbolithiation reaction requires the use of electron-deficient alkenes. Mesityllithium has also been studied as an alternative to t-BuLi in Parham cyclization with other internal electrophiles (aldehyde, ketone, ester, amide), proving to be more selective and efficient than t-BuLi.

Key words

organolithium - carbanions - carbolithiation - metalation - heterocycles

References and Notes

• 1a Wakefield BJ. The Chemistry of Organolithium Compounds   2nd ed.:  Pergamon; New York: 1990. 
• 1b Rappoport Z. Marek I. The Chemistry of Organolithium Compounds   Vol. 1:  Rappoport Z. Wiley; Chichester: 2004. 
• 1c Gribble GW. In Science of Synthesis   Vol. 8a:  Majewski M. Snieckus V. Thieme; Stuttgart: 2006.  p.357-426  
• 2 Bailey WF. Ovaska TV. In Advances in Detailed Reaction Mechanisms: Mechanisms of Importance in Synthesis   Vol. 3:  Coxon JM. JAI Press; Greenwich: 1994.  p.251-273  
• For reviews, see
• 3a Parham WE. Bradsher CK. Acc. Chem. Res.  1982,  15:  300 
• 3b Gray M. Tinkl M. Snieckus V. In Comprehensive Organometallic Chemistry II   Vol. 11:  Abel EW. Stone FGA. Wilkinson G. Pergamon; Exeter: 1995.  p.66-92  
• 3c Ardeo A. Collado MI. Osante I. Ruiz J. Sotomayor N. Lete E. In Targets in Heterocyclic Systems   Vol. 5:  Atanassi O. Spinelli D. Italian Society of Chemistry; Rome: 2001.  p.393-418  
• 3d Sotomayor N. Lete E. Curr. Org. Chem.  2003,  7:  275 
• 3e Nájera C. Sansano JM. Yus M. Tetrahedron  2003,  59:  9255 ; see also ref. 1
• 4 Parham WE. Jones LD. Sayed YA. J. Org. Chem.  1975,  40:  2394 ; see also ref. 3a
• For representative examples of our synthetic work in this area, see:
• 5a Lete E. Egiarte A. Sotomayor N. Vicente T. Villa MJ. Synlett  1993,  41 
• 5b Collado MI. Manteca I. Sotomayor N. Villa MJ. Lete E. J. Org. Chem.  1997,  62:  2080 
• 5c Osante I. Collado MI. Lete E. Sotomayor N. Eur. J. Org. Chem.  2001,  1267 
• 5d González-Temprano I. Sotomayor N. Lete E. Synlett  2002,  593 
• 5e Osante I. Lete E. Sotomayor N. Tetrahedron Lett.  2004,  45:  1253 
• 5f González-Temprano I. Osante I. Lete E. Sotomayor N. J. Org. Chem.  2004,  69:  3875 
• 5g Osante I. Sotomayor N. Lete E. Lett. Org. Chem.  2004,  1:  148 
• 5h Abdullah MN. Arrassate S. Lete E. Sotomayor N. Tetrahedron  2007,  64:  1329 
• For reviews, see:
• 6a Marek I. J. Chem. Soc., Perkin Trans. 1  1999,  535 
• 6b Mealy MJ. Bailey WF. J. Organomet. Chem.  2002,  646:  59 
• 6c Clayden J. Organolithiums: Selectivity for Synthesis   Pergamon; New York: 2002.  p.282-335  
• 6d Normant JF. Top. Organomet. Chem.  2003,  287 
• 6e Fañanás FJ. Sanz R. In The Chemistry of Organolithium Compounds   Vol. 2:  Rappoport Z. Marek I. Wiley; Chichester: 2006.  Chap. 4. p.295-379  ; see also refs. 1, 2e, and 3
• For some representative examples, see:
• 7a Chamberlin AR. Bloom SH. Cervini LA. Fotsch CH. J. Am. Chem. Soc.  1988,  110:  4788 
• 7b Funk RL. Bolton GL. Brummond KM. Ellestad KE. Stallman JB. J. Am. Chem. Soc.  1993,  115:  7023 
• 7c Bailey WF. Jiang X.-L. McLeod CE. J. Org. Chem.  1995,  60:  7791 
• 7d Krief A. Kenda B. Remacle B. Tetrahedron  1996,  52:  7435 
• 7e Coldham I. Hufton R. Price KN. Rathmell RE. Snowdem DJ. Vennall GP. Synthesis  2001,  1523 
• 7f Deng K. Bensari A. Cohen T. J. Am. Chem. Soc.  2002,  124:  12106 
• 7g Sanz R. Ignacio JM. Rodríguez MA. Fañanás FJ. Barluenga J. Chem. Eur. J.  2007,  13:  4998 
• 7h The procedure has also been extended to the corresponding alkyne derivatives. See, for instance: Wu G. Cederbaum FE. Negishi E. Tetrahedron Lett.  1990,  31:  493 
• 8a Ross GA. Koppang MD. Bartak DE. Woolsey NF. J. Am. Chem. Soc.  1985,  107:  6742 
• 8b Harrowven DC. Tetrahedron Lett.  1992,  33:  2879 
• 8c Bailey WF. Daskapan T. Rampalli S. J. Org. Chem.  2003,  68:  1334 
• For some representative examples on indoles, see:
• 9a Barluenga J. Sanz R. Granados A. Fañanás FJ. J. Am. Chem. Soc.  1998,  120:  4865 
• On indolines, see:
• 9b Bailey WF. Jiang X.-L. J. Org. Chem.  1996,  61:  2596 
• 9c Zhang D. Liebskind L. J. Org. Chem.  1996,  61:  2594 
• On azaindolines, see:
• 9d Bailey WF. Salgaonkar PD. Brubaker JD. Sharma V. Org. Lett.  2008,  10:  1071 
• 10a Bailey WF. Mealy MJ. Wiberg KB. Org. Lett.  2002,  4:  791 
• 10b Fresigné C. Girard A.-L. Durandetti M. Maddaluno J. Angew. Chem. Int. Ed.  2008,  41:  891 
• 10c Fresigné C. Girard A.-L. Durandetti M. Maddaluno J. Chem. Eur. J.  2008,  14:  5159 
• 11a Comins DL. Zhang Y.-M. J. Am. Chem. Soc.  1996,  118:  12248 
• 11b Nishiyama H. Sakata N. Sugimoto H. Motoyama Y. Wakita H. Nagase H. Synlett  1998,  930 
• 12a Bailey WF. Mealy MJ. J. Am. Chem. Soc.  2000,  122:  6787 
• 12b Sanz G. Groth UM. J. Am. Chem. Soc.  2000,  122:  6789 
• 12c Barluenga J. Fañanás FJ. Sanz R. Marcos C. Org. Lett.  2002,  4:  2225 
• 12d Mealy MJ. Luderer MR. Bailey WF. Sommer MB. J. Org. Chem.  2004,  69:  6042 
• 12e Barluenga J. Fañanás FJ. Sanz R. Marcos C. Chem. Eur. J.  2005,  11:  5397 
• 12f Groth U. Koettgen P. Langenbach P. Lindenmaier A. Schuetz T. Wiegand M. Synlett  2008,  1301 
• 13 Pedrosa R. Andrés C. Iglesias JM. Pérez-Encabo A. J. Am. Chem. Soc.  2001,  123:  1817 
• 14a Ruiz J. Sotomayor N. Lete E. Org. Lett.  2003,  5:  1115 
• 14b Ruiz J. Ardeo A. Ignacio R. Sotomayor N. Lete E. Tetrahedron  2005,  61:  3311 
• 14c Ruiz J. Sotomayor N. Lete E. Tetrahedron  2006,  62:  6182 
• 15 Mhaske SB. Synlett  2005,  184 
• 16a Beck AK. Hoekstra MS. Seebach D. Tetrahedron Lett.  1977,  18:  1187 
• 16b Yoshifuji M. Nakamura T. Inamoto N. Yamamoto Y. Tetrahedron Lett.  1987,  28:  6325 
• 16c Yamamoto Y. Maeda K. Tomimoto K. Mase T. Synlett  2002,  561 
• 17a Comins DL. Huang S. McArdale CL. Ingalls CL. Org. Lett.  2001,  3:  469 
• 17b Comins DL. Nolan JM. Org. Lett.  2001,  3:  4255 
• 17c Mhaske SB. Argade NP. J. Org. Chem.  2004,  69:  4563 
• 17d Naka H. Akagi Y. Yamada K. Imahori T. Kasahara T. Kondo Y. Eur. J. Org. Chem.  2007,  4635 
• 17e Comins DL. Odachi PW. Tetrahedron Lett.  2008,  49:  569 
• 18 Kondo Y. Asai M. Miura T. Uchiyama M. Sakamoto T. Org. Lett.  2001,  3:  13 
• For representative examples, see:
• 22a Paleo MR. Castedo L. Domínguez D. J. Org. Chem.  1993,  58:  2763 
• 22b Gould SJ. Melville CR. Cone MC. Chen J. Carney JR. J. Org. Chem.  1997,  62:  320 
• 22c Moreau A. Lorion M. Couture A. Deniau E. Grandclaudon P. J. Org. Chem.  2006,  71:  3303 
• 23a Aidhen IS. Narasimham NS. Tetrahedron Lett.  1991,  32:  2171 
• 23b Kihara M. Kashimoto M. Kobayashi Y. Tetrahedron  1992,  48:  67 

19

Mesityllithium-Mediated Carbolithiation Reactions of N -( o -Iodobenzyl)pyrroles 3b,c: Synthesis of Pyrrolo[1,2- b ]isoquinolines - Typical Procedure for the Synthesis of Benzyl 2-(7,8-Dimethoxy-5,10-dihydropyrrolo[1,2- b ]isoquinolin-10-yl)acetate (4b)
To a solution of mesityl bromide (0.1 mL, 0.65 mmol) in dry THF (5 mL), t-BuLi (1.2 mL of a 1.1 M solution in hexane, 1.3 mmol) was added at -78 ˚C, and the reaction mixture was stirred at -20 ˚C for 1 h. N-(o-Iodobenzyl) pyrroles 3b (126 mg, 0.32 mmol) in dry THF (5 mL) was added at -105 ˚C, and the resulting mixture was stirred at this temperature for 5 min. The reaction was quenched by the addition of sat. NH₄Cl (5 mL). Then, Et₂O (10 mL) was added, the organic layer was separated, and the aqueous phase was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic extracts were dried (Na₂SO₄) and concentrated in vacuo. Flash column chromatography (silica gel, 60% hexane-EtOAc) afforded 4b as a colorless oil (113 mg, 92%). IR (CHCl₃): 1734 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 2.75 (d, J = 7.1 Hz, 2 H), 3.81 (s, 3 H), 3.88 (s, 3 H), 4.61 (t, J = 7.1 Hz, 1 H), 4.58 (s, 1 H), 4.61 (s, 1 H), 4.64 (s, 2 H), 6.01 (s, 1 H), 6.18 (t, J = 2.8 Hz, 1 H), 6.70 (s, 2 H), 6.82 (s, 1 H), 7.26-7.35 (m, 5 H). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 35.3, 43.6, 47.1, 55.9, 66.2, 103.9, 108.2, 109.0, 110.7, 118.4, 124.1, 128.1, 128.4, 129.9, 135.6, 147.6, 148.1, 171.3. MS (EI): m/z (%) = 378(6) [M⁺ + 1], 377(21) [M⁺], 287(17), 286(83), 242(7), 229(16), 228(100), 212(15), 184(10), 91(16). HRMS: m/z calcd for C₂₃H₂₃NO₄: 377.1627; found: 377.1638.

20

N-Benzylpyrroles 2b-f were prepared by alkylation of the corresponding 2-acylpyrrole 5b-f with bromide 1 under standard conditions (KOH, DMSO) as described in Scheme  [¹] for 2a.

21

In fact, when the reaction described in Table  [³] , entry 6
(t-BuLi, 2 equiv, -90 ˚C, 5 min) was quenched with MeOD, incorporation of deuterium into the acetyl group could be observed by GC-MS.