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.

organolithium - carbanions - carbolithiation - metalation - heterocycles

References and Notes

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<A NAME="RD29208ST-19">19</A>

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.

<A NAME="RD29208ST-20">20</A>

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.

<A NAME="RD29208ST-21">21</A>

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.

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