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Synlett 2008(20): 3188-3192  
DOI: 10.1055/s-0028-1087411
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Sergio Lage, Irune Villaluenga, Nuria Sotomayor, Esther Lete*
Departamento de Química Orgánica II, Facultad de Ciencia y Tecnología, Universidad del País Vasco/Euskal Herriko Unibertsitatea, Apdo. 644, 48080 Bilbao, Spain
e-Mail: esther.lete@ehu.es;
Further Information

Publication History

Received 5 August 2008
Publication Date:
26 November 2008 (online)

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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

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.

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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.