Indium Mediated Isoprenylation of Carbonyl Compounds with 2-Bromomethyl-1 , 3-butadiene . A Short Synthesis of ( ± )-Ipsenol

The introduction of isoprene unit into various compounds (isoprenylation) presents an important problem in organic synthesis, since isoprene derivatives with conjugated diene system are widely distributed in nature. Metalation of 1,3-dienes has been largely applied to generate pentadienyl anion species, such as 2 and 6 (Scheme 1). Among these, previous investigations have reported varying levels of selectivity concerning the pentadienyl anion 2. However, in many circumstances, the reaction is not regioselective and the delocalized anion 2 may react at either α or γ position, resulting in a mixture of the conjugated diene 3 and nonconjugated diene 4. Examples include zinc and indium reagents. Fallis and coworkers have established that treatment of 5-bromo-1,3pentadiene 1 with indium metal, in the presence of aldehydes and ketones, results in γ-pentadienylation to generate 1,4-diene as 4, with excellent regioselectivity and respectable yields.


Introduction
The introduction of isoprene unit into various compounds (isoprenylation) presents an important problem in organic synthesis, since isoprene derivatives with conjugated diene system are widely distributed in nature.Metalation of 1,3-dienes has been largely applied to generate pentadienyl anion species, such as 2 and 6 (Scheme 1).Among these, previous investigations have reported varying levels of selectivity concerning the pentadienyl anion 2. However, in many circumstances, the reaction is not regioselective and the delocalized anion 2 may react at either α or γ position, resulting in a mixture of the conjugated diene 3 and nonconjugated diene 4. [1][2][3][4][5] Examples include zinc 5 and indium 4 reagents.Fallis and coworkers have established that treatment of 5-bromo-1,3pentadiene 1 with indium metal, in the presence of aldehydes and ketones, results in γ-pentadienylation to generate 1,4-diene as 4, with excellent regioselectivity and respectable yields. 4

Scheme 1.
][8][9][10][11][12][13] Several metals, such as Zn, [7][8][9][10][11][12] Cr(II) 13 etc, have been used for this purpose.Limitations associated with these methods include: metal activation required, [7][8][9][10][11][12] reductive conditions, 13 formation of secondary products, such as aldol condensation. 8,12nsuccessful attempts have been made to access and apply the allylic anion 6, generated from the Grignard reagent, or the lithium salt of 5. 11 In addition, the use of 5 as isoprenylating reagent, has been rather limited in application because of poor availability and thermal instability.Some methods to synthesize the important building block 5 have been reported. 10,14,16A four-step synthesis of pure 5 was reported by Yadav, as a building block for the synthesis of the taxane skeleton. 15ere we wish to report an easy isoprenylation of aldehydes and ketones mediated by selective indium insertion in a mixture of 2-bromomethyl-1,3-butadiene 5 and its vinylic bromide isomers (Scheme 2).The wide utility of the present isoprenylating system has been further demonstrated with the synthesis of (±)-ipsenol (Entry 12), an aggregation pheromone of Ips paraconfusus bark beetle. 17

Results and Discussion
A practical large scale two-step synthesis of 5, from isoprene, has recently been reported. 16The first step, 1,4addition of bromine to isoprene, gave 1,4-dibromo-2methyl-2-butane 8, in quantitative yield.Subsequent dehydrobromination, using 1,3-dimethyl-3,4,5,6tetrahydro-pyrimidinone (DMPU), gave compound 5 and its vinylic isomers.As reported before, because of the similarities of bromodiene structures, all attempts to purify compound 5 from the product mixture using normal physical separation methods such as distillation or flash chromatography have failed. 16herefore, the mixture containing 30-40% of 5 was used directly for the isoprenylation of aldehydes and ketones, promoted by selective indium insertion, in good yields (Table 1).The best condition was achieved with the reaction of carbonyl compound in the presence of indium and sodium iodide, in DMF.Performing the reaction in aqueous media resulted in failure.This result contrasts with the previously reported indium-mediated allylation reactions of carbonyl compounds, 18,19 perhaps due to the instability towards water of the particular allylic organoindium species generated.
An additional way to utilize the valuable C 5 synthon 5 has been demonstrated here by a short synthesis of (±)-ipsenol (entry 12).The indium reagent, generated from 5, reacted with isovaleraldehyde at room temperature in THF, to give ipsenol in 91 % yield.The utility of organometalic reagents, generated from synthon 5 was demonstrated before with the synthesis of ipsenol.Katzenellenbogen and Lenox have synthesized ipsenol from the reaction of 5 with zinc and isovaleraldehyde in THF reflux in 52% yield. 9Both the low yields obtained by Katzenellenbogen and the lack of further studies to apply the synthon 5 are due to the difficulty in synthesizing and purify it.
In conclusion, we have developed in this work an efficient isoprenylation reaction for aldehydes and ketones through an easy access to 9 mediated by selective indium insertion in a mixture of 2-bromomethyl-1,3-butadiene 5 and its vinylic bromide isomers.The high efficiency using simple starting materials and easy procedures are noteworthy.

Experimental
IR spectra were measured on a Mattson Galaxy Series FT-IR 3000 (model 3020). 1 H and 13 C NMR spectra, in CDCl 3 , were obtained on a Varian VXR-200 spectrometer using TMS as the internal standard.Mass spectra were obtained on a HP CG/MS 5988A instrument, operating at 70 eV.High resolution mass spectra were performed on a VG Autospec Instrument.
Purification by column chromatography was carried out on 70-230 mesh Merk silica gel 60.N,N-Dimethylformamide (DMF) was distilled over calcium hydride (CaH 2 ).Analytical thin-layer chromatography (TLC) was conducted on Merck aluminum plates with 0.2 mm of silica gel 60F-254.Anhydrous sodium sulfate was used to dry all organic extracts.Aldehydes and ketones were obtained from commercial suppliers and used without further purification.