Organolithium or Heck-type cyclization of N-ortho- iodobenzyl-2-alkenylpyrrolidines to give indolizidines

Carbolithiation reactions of 2-alkenyl-substituted pyrrolidines have been studied. An electron-withdrawing group in the alkene (R = CONEt 2 ) is required for the 6-exo - trig cyclization to afford hexahydropyrrolo[1,2-b ]isoquinolines. Alternatively, the cyclization of the unactivated alkene can be performed under Heck conditions


Introduction
Cyclization of organometallic species onto alkenes plays a key role in organic synthesis.Perhaps most common is the use of organopalladium species, typically formed by insertion of palladium(0) into an aromatic halide. 1 Cyclization onto an alkene is normally followed by elimination (of a palladium hydride species) to regenerate an alkene.An alternative methodology, developed extensively by Bailey and co-workers, makes use of an organolithium species, often formed by halogen-lithium exchange. 2For example, treatment of the bromide 1 (R = allyl) with two equivalents of tert-butyllithium promotes the formation of the aryllithium which cyclizes to give, after protonation, the indoline 2 (Scheme 1). 3 The same chemistry with bromide 1 (R = H), palladium acetate (3 mol%) and tris(2-tolyl)phosphine (6 mol%) is known to give (after heating for several days) the product 3 (R = H) in 60% yield (or 87% yield from the iodide). 4

Scheme 1
Our research groups have a long-standing interest in using organometallic species for cyclization onto -systems to give nitrogen-containing heterocycles. 5,6One target of interest is the preparation of 5-substituted indolizidines.Coldham and co-workers have shown that intramolecular carbolithiation of the organolithium 4 (R = H or SPh) provides a route for the preparation of the desired indolizidines 5 (Scheme 2, disconnection a).6d In this chemistry cyclization to give the six-membered ring is competitive with enantiomerization of the organolithium.On the other hand, Lete and co-workers have reported that pyrrolo [1,2b]isoquinolines can be obtained by intramolecular carbolithiation starting from 2-alkenyl N-(oiodobenzyl)pyrroles. 5c We wondered whether we could approach such biologically important indolizidine targets 7 by disconnection b (Scheme 2, M = metal).There is precedent for carrying out such chemistry using an intramolecular Heck reaction with 6, R = Me. 8We decided to explore this reaction for a selection of R groups using either Heck or intramolecular carbolithiation chemistry.

Scheme 4
Then, we studied the intramolecular carbolithiation of 11b (Scheme 5).As shown in Table 1, the introduction of the electron-withdrawing group on the alkene moiety favours the 6-exocyclization of the intermediate aryllithium, and the hexahydropyrrolo[1,2-b]isoquinoline 14 was obtained in excellent yield.Cyclization took place at low temperature, although the best results were obtained when the reaction mixture was allowed to warm to room temperature.It is noteworthy that both n-BuLi and t-BuLi effected efficient iodine-lithium exchange (in the presence of TMEDA).No products from direct addition of these reagents to the -unsaturated amide group were detected (as reported for related systems).5c The cyclization took place with complete stereoselectivity, affording in all cases product 14 as a single diastereomer. 11Attack of the intermediate aryllithium could occur as shown in Figure 1, leading to 14 with a relative 10,10a-trans configuration.This model allows possible nitrogen-lithium chelation and subsequent intramolecular carbolithiation.NOESY and COSY experiments confirmed the stereochemistry of 14.The most significant NOESY results obtained are shown in Figure 1.In particular, 2D NOESY experiments showed an enhancement between the protons H-10 and H-1, and between H-10a and the methylenic protons of the substituent at C-10.These data are consistent with a trans stereochemistry in the indolizidine system.
Finally, Heck reaction of 11b was studied.However, when 11b was treated with Pd(OAc)2, PPh3 and K2CO3 under the same conditions as used for 11a, no cyclization product could be detected, and a mixture of products was obtained.Other reaction conditions, that have been used successfully in related substrates, 5a were tested.Thus, 11b was treated with Pd(PPh3)4 (5%), n Bu4NCl (1.5 eq), NaHCO3 (2.5 eq), in refluxing CH3CN or with Pd(PPh3)4 (30%), Et3N (2.2 eq) in toluene.In these cases a cyclized product could be detected by 1 H NMR spectroscopy of the crude reaction mixtures, but it could not be isolated or characterized, possibly due to instability.Intramolecular carbolithiation reaction of a 2-alkenyl-substituted pyrrolidine leads to a hexahydropyrrolo[1,2-b]isoquinoline via a 6-exo cyclization process, though the alkene needs to be substituted with an electron-withdrawing group (R = CONEt2).Halogen-lithium exchange takes place efficiently with n-BuLi or t-BuLi, in the presence of the enamide moiety.The Heck reaction constitutes an efficient alternative to these reactions with the unsubstituted alkene.

Experimental Section
General.Melting points were determined in unsealed capillary tubes and are uncorrected.IR spectra were obtained on KBr pellets (solids) or in CHCl3 solution (oils).NMR spectra were recorded at 20-25 o C, running at 300 or 500 MHz for 1 H and 75.5 or 125.7 MHz for 13 C in CDCl3 solutions.Assignment of individual 13 C and 1 H resonances is supported by DEPT experiments and 2D experiments (COSY, HMBC, HSQC, NOESY) when necessary.Mass spectra were recorded under electron impact at 70 eV.Exact mass was obtained using a TOF detector.GC-MS analyses were performed using a TRB-1 column (methyl polysiloxane, 30 m  0.25 mm  0.25 m).TLC was carried out with 0.2 mm thick silica gel plates.Visualization was accomplished by UV light.Flash column chromatography 12 on silica gel was performed with Kiesegel 60 (230-400 mesh).All solvents used in reactions were anhydrous and purified according to standard procedures. 13Organolithium reagents were titrated with diphenylacetic acid or N-benzylbenzamide periodically prior to use.All air-or moisture-sensitive reactions were performed under argon; the glassware was dried (130 ˚C) and purged with argon.
tert-Butyl 2-formylpyrrolidine-1-carboxylate (8).A 0.5 M solution of N-Boc pyrrolidine 7 (0.315 g, 1.83 mmol) in Et2O (4 mL) at -78 ºC was treated with TMEDA (0.27 mL, 1.83 mmol) and s-BuLi (1.69 mL of a 1.3M solution in hexanes, 2.20 mmol).After 2 h at -78 ºC, the resulting solution was added dropwise via syringe over a solution of DMF (0.28 mL, 3.66 mmol) in Et2O (2 mL).The reaction mixture was warmed up to room temperature for 2 h and quenched by the addition of sat.NH4Cl solution(10 mL).The organic layer was separated and the aqueous phase was extracted with Et2O (2 x 20 mL).The combined organic extracts were dried with Na2SO4 and evaporated under reduced pressure.The crude product was purified by flash column chromatography (silica gel, petroleum ether/AcOEt 20%) to give 8 as an oil (0.323 g, 83%), whose spectroscopic data were identical to those reported: 8

N-(tert-Butoxylcarbonyl)-2-vinylpyrrolidine (9a)
. n-BuLi (5.32 mL of a 1.3 M solution in hexanes, 6.96 mmol) was added to a solution of methyltriphenylphosphine bromide (1.92 g, 5.28 mmol) in THF (15 mL) at 0 ºC, and the reaction was stirred for 30 min.The mixture was recooled at -78 ºC and a solution of N-Boc-prolinal 8 (1.05 g, 5.28 mmol) in THF (10 mL) was added.After 30 min.at -78 ºC, the reaction mixture was warmed up to room temperature overnight and quenched by the addition of sat.NH4Cl solution (10 mL).The organic layer was separated and the aqueous phase was extracted with Et2O (2 x 20 mL).The combined organic extracts were dried with Na2SO4 and evaporated under reduced pressure.The crude product was purified by flash column chromatography (silica gel, petroleum ether/AcOEt 10%) to give 9a as an oil (0.763 g, 77%) whose spectroscopic data were identical to those reported: 14

Scheme 5 Table 1 .
Carbolithiation reactions of 11b Figure 1.Possible transition state and selected NOE enhancements for 14.