{Synthesis of substituted allyl acetates from heterocyclic dienes by pd-promoted arylation-acetoxylation cascade} J. Serb. Chem. Soc. 82 (12) 1335–1341 (2017) UDC 547.384+542.913:547..7+ JSCS–5044 547.944/.945:66.095.11 Original scientific paper 1335 Synthesis of substituted allyl acetates from heterocyclic dienes by a Pd-promoted arylation–acetoxylation cascade MILENA R. SIMIĆ**#, MILOŠ R. PETKOVIĆ, PREDRAG M. JOVANOVIĆ, GORDANA D. TASIĆ# and VLADIMIR M. SAVIĆ*# University of Belgrade, Faculty of Pharmacy, Department of Organic Chemistry, Vojvode Stepe 450, 11221 Belgrade, Serbia (Received 17 March, revised 3 April, accepted 10 April 2017) Abstract: Pd-catalysed arylation–acetoxylation cascade, a previously reported methodology, was applied in the functionalisation of unsymmetrical dienes. Both explored classes of compounds, isoquinoline and β-carboline-derived dienes, afforded single regioisomers. Although further improvements of the process are necessary, primarily due to lower yields, the described functional- isation of the studied compounds might be useful in the synthesis of emetine and related naturally occurring compounds. Keywords: heterocycles; synthesis; emetine-like compounds; Pd-catalysis; regioselectivity. INTRODUCTION Allylic acetates are an important class of organic compounds employed in various chemical transformations.1–5 Their reactions promoted by different trans- ition metals are of particular interest.6–13 Amongst them, Pd-catalysed processes stand as the most intensively studied methodologies frequently used in the synthesis of various organic molecules, including naturally occurring substan- ces.14–22 The most common way to access allylic acetates utilizes allyl alcohols as starting materials, which are widely accessible via addition of vinyl-nucleo- philes on aldehydes or ketones or simple nucleophilic additions on α,β-unsatur- ated equivalents.23–26 Some alternative processes usually based on the acetoxylation of alkenes or related compounds have also been developed.27–31 To this end, the arylation of dienes/allenes with concomitant acetoxylation promoted by Pd-complexes as a way to produce substituted allyl acetates, Scheme 1, was recently reported.32,33 *,** Corresponding authors. E-mail: (*)vladimir.savic@pharmacy.bg.ac.rs; (**)milena@pharmacy.bg.ac.rs # Serbian Chemical Society member. https://doi.org/10.2298/JSC170317046S ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2017 SCS. 1336 SIMIĆ et al. Although the product itself is a Pd-substrate, the reaction conditions favoured the formation of the acetate in moderate to good yields. Scheme 1. Pd-promoted arylation/acetoxylation of dienes or allenes. RESULTS AND DISCUSSION In order to explore further this methodology, the present interest lay in func- tionalisation of heterocyclic, unsymmetrical diene 4, which would be potentially useful to access emetine 1 and its derivatives, such as dehydroemetine 2 or bio- logically active compound 3.34–36 In addition, related to these are also protoeme- tine or protoemetinol.36 A potential synthetic strategy towards these natural compounds is outlined in Scheme 2. Functionalisation of the diene moiety followed by the acetate to methyl transformation would provide a core skeleton, while further structural manipulation would lead towards the target compounds.37–40 Obviously, the first issue with this approach is the regioselectivity of the arylation/acetoxylation process and initial results related to this concern are outlined in this report. Start- ing from isoquinoline, diene 4 was prepared in several high yielding steps as rep- orted previously.41,42 Scheme 2. Emetine and some related derivatives. ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2017 SCS. FUNCTIONALISATION OF HETEROCYCLIC DIENES 1337 Synthesis of corresponding allylic acetate was performed under typical con- ditions employing Pd(OAc)2/PPh3 as the catalytic system and an excess of NaOAc (5 equivalents) in DMSO as a solvent (Scheme 3). A single product was isolated in 32 % yield after column chromatography. Analysis of the 1H/13C- -NMR spectra confirmed the structure of the isolated derivative with the IR and mass spectra corroborating its formation. Full signal assignment in the 1H-NMR (Fig. 1) and 13C-NMR (Supplementary material to this paper) spectra was based on 2D experiments (H−H/C correlations), while the reaction regioselectivity was unambiguously established by examining the NOESY and HMBC spectra (Sup- plementary material). Scheme 3. Synthesis of heterocyclic allyl acetate. Fig. 1. 1H-NMR spectrum of allyl acetate 5. Analysis of NOESY spectrum showed weak interactions between H-1/H-2′ and H-4/H-3′ hydrogens, supporting the proposed structure (Fig. 2). Additionally, examination of HMBC spectrum (Supplementary material) led to same conclusion since it showed correlations C-4/H-3′ and C-1/ H-2′ (Fig. 2). The isolation of only one regioisomeric product came as a surprise but detailed analysis of the 1H-NMR spectrum (200 MHz) of the crude reaction mixture, inc- luding careful TLC analysis did not reveal the presence of any other distinctive compound. Furthermore, several additional reactions, as outlined in Scheme 4, were performed. ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2017 SCS. 1338 SIMIĆ et al. Fig. 2. Key correlations in the NOESY/HMBC spectra of allyl acetate 5. Scheme 4. Synthesis of isoquinoline derived allyl acetates. All transformations were performed as already described producing a single isolatable isomer in all reactions in yields of up to 47 %. The final example was performed using β-carboline derived diene 8 that, under the described conditions, produced acetate 9, a compound structurally related to naturally occurring pseudo- tubulosine (Scheme 5).36 The indole N–H bond does not seem to influence the reaction pathway and the product was isolated in a yield similar to those outlined in Scheme 4. Scheme 5. Synthesis of the β-carboline derived allyl acetate. ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2017 SCS. FUNCTIONALISATION OF HETEROCYCLIC DIENES 1339 Although the formation of the other regioisomer in all the studied reactions cannot be ruled out completely, it was not observed during the reaction or work- -up and purification procedure. At present, it is difficult to rationalise the exclu- sive formation of the observed products. It is not clear whether the other isomer was not formed at all or it was formed but decomposed during the reaction course. The fact that the yields were relatively low might suggest the second options but it remains to be explored further. EXPERIMENTAL General The NMR spectra were recorded on a Bruker Avance III (500 MHz) spectrometer. Chemical shifts are given in parts per million (δ) downfield from tetramethylsilane as the int- ernal standard. Deuterochloroform was used as the solvent. Mass spectral data were recorded using an Agilent MSD TOF spectrometer coupled with Agilent 1200 HPLC or Agilent Tech- nologies 5975C MS coupled with Agilent Technologies 6890N GC. The IR spectra were rec- orded on an IR Thermo Scientific Nicolet iS10 (4950) spectrometer. Silica gel 60 (230– –400 mesh) was employed for the flash chromatography while thin layer chromatography was performed using alumina plates with 0.25 mm silica layer (Kieselgel 60 F254, Merck). The compounds were visualised by staining with alkaline potassium permanganate solution. The solvents were purified by distillation before use. General procedure for the synthesis of allyl acetate from dienes and aryl iodide A mixture of diene (0.1 mmol) and aryl iodide (0.15 mmol, 1.5 eq), Pd(OAc)2 (10 mol %), Ph3P (20 mol %) and NaOAc (0.5 mmol, 5 eq) in DMSO (2 mL) was heated at 85–90 °C (bath temperature) under a nitrogen atmosphere for 12 h. The reaction mixture was then cooled to room temperature, Et2O (20 mL) was added and the mixture washed with H2O (3×5 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography (petroleum ether, diethyl ether) to afford the required product. [2-(4-Methoxybenzyl)-1,6,7,11b-tetrahydro-4H-pyrido[2,1-a]isoquinolin-3-yl]methyl acetate (5). The compound was synthesised from diene 4 and 1-iodo-4-methoxybenzene following the general procedure. Flash chromatography (SiO2, 3:2 diethyl ether/petroleum ether volume ratio) afforded 5 (32 %) as a yellow oil. [2-(3,4-Dimethylbenzyl)-1,6,7,11b-tetrahydro-4H-pyrido[2,1-a]isoquinolin-3-yl]methyl acetate (7a). The compound was synthesised from diene 4 and 1-iodo-3,4-dimethylbenzene following the general procedure. Flash chromatography (SiO2, 1:1 petroleum ether/diethyl ether volume ratio) afforded the 7a (30 %) as a pale yellow oil. [2-(4-Methylbenzyl)-1,6,7,11b-tetrahydro-4H-pyrido[2,1-a]isoquinolin-3-yl]methyl acetate (7b). The compound was synthesised from diene 4 and 4-iodotoluene following the general procedure. Flash chromatography (SiO2, 2:3 petroleum ether/diethyl ether volume ratio) afforded the product 7b (47 %) as a pale yellow oil. [2-(Naphthalen-1-ylmethyl)-1,6,7,11b-tetrahydro-4H-pyrido[2,1-a]isoquinolin-3-yl]- methyl acetate (7c). The compound was synthesised from diene 4 and 1-iodonaphthalene following the general procedure. Flash chromatography (SiO2, 1:1 petroleum ether/diethyl ether volume ratio) afforded 7c (32 %) as a pale yellow oil. [2-(4-Methylbenzyl)-1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinolizin-3-yl]methyl acetate (9). Compound was synthesised from diene 8 and 4-iodotoluene following the general ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2017 SCS. 1340 SIMIĆ et al. procedure. Flash chromatography (SiO2, 2:3 diethyl ether/petroleum ether volume ratio) afforded 9 (34 %) as a yellow oil. CONCLUSION In conclusion one can say the reactions of unsymmetrical heterocyclic dienes in the arylation–acetoxylation cascade afforded allyl acetate highly regioselective products. Although further improvement of the process is necessary, the des- cribed methodology may be potentially useful in the synthesis of a series of nat- ural products or their derivatives. SUPPLEMENTARY MATERIAL Analytical and spectral data of the synthesized compounds are available electronically at the pages of journal website: http://www.shd.org.rs/JSCS/, or from the corresponding author on request. Acknowledgement. Financial support from the Ministry of Education, Science and Tech- nological Development of the Republic of Serbia (Grant No. 172009) is greatly appreciated. И З В О Д СИНТЕЗА АЛИЛНИХ АЦЕТАТА ИЗ ХЕТЕРОЦИКЛИЧНИХ ДИЕНА КАСКАДОМ АРИЛОВАЊА И АЦЕТОКСИЛОВАЊА ПРОМОВИСАНОМ ПАЛАДИЈУМОМ МИЛЕНА Р.СИМИЋ, МИЛОШ Р. ПЕТКОВИЋ, ПРЕДРАГ М. ЈОВАНОВИЋ, ГОРДАНА Д. ТАСИЋ и ВЛАДИМИР М. САВИЋ Фармацеутски факултет, Катедра за органску хемију, Војводе Степе 450, 11221 Београд У овом раду проучаване су функционализације несиметричних диена у Pd-ката- лизованим процесима заснованим на каскади ариловање/ацетоксиловање. Диенски изохинолински деривати, као и деривати који садрже β-карболински структурни фрагмент у поменутим трансформацијама дају само један региоизомер. Мада про- цес захтева даљу оптимизацију, пре свега због нижих приноса, методологија може наћи примену у синтези еметина и сродних природних производа. (Примљено 17. марта, ревидирано 3. априла, прихваћено 10. априла 2017) REFERENCES 1. D. Liu, X. 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Soc. 81 (2016) 103. ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2017 SCS. << /ASCII85EncodePages false /AllowTransparency false /AutoPositionEPSFiles true /AutoRotatePages /None /Binding /Left /CalGrayProfile (Dot Gain 20%) /CalRGBProfile (sRGB IEC61966-2.1) /CalCMYKProfile (U.S. Web Coated \050SWOP\051 v2) /sRGBProfile (sRGB IEC61966-2.1) /CannotEmbedFontPolicy /Error /CompatibilityLevel 1.4 /CompressObjects /Tags /CompressPages true /ConvertImagesToIndexed true /PassThroughJPEGImages true /CreateJobTicket false /DefaultRenderingIntent /Default /DetectBlends true /DetectCurves 0.0000 /ColorConversionStrategy /CMYK /DoThumbnails false /EmbedAllFonts true /EmbedOpenType false /ParseICCProfilesInComments true /EmbedJobOptions true /DSCReportingLevel 0 /EmitDSCWarnings false /EndPage -1 /ImageMemory 1048576 /LockDistillerParams false /MaxSubsetPct 100 /Optimize true /OPM 1 /ParseDSCComments true /ParseDSCCommentsForDocInfo true /PreserveCopyPage true /PreserveDICMYKValues true /PreserveEPSInfo true /PreserveFlatness true /PreserveHalftoneInfo false /PreserveOPIComments true /PreserveOverprintSettings true /StartPage 1 /SubsetFonts true /TransferFunctionInfo /Apply /UCRandBGInfo /Preserve /UsePrologue false /ColorSettingsFile () /AlwaysEmbed [ true ] /NeverEmbed [ true ] /AntiAliasColorImages false /CropColorImages true /ColorImageMinResolution 300 /ColorImageMinResolutionPolicy /OK /DownsampleColorImages true /ColorImageDownsampleType /Bicubic /ColorImageResolution 300 /ColorImageDepth -1 /ColorImageMinDownsampleDepth 1 /ColorImageDownsampleThreshold 1.50000 /EncodeColorImages true /ColorImageFilter /DCTEncode /AutoFilterColorImages true /ColorImageAutoFilterStrategy /JPEG /ColorACSImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /ColorImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000ColorACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000ColorImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /OK /DownsampleGrayImages true /GrayImageDownsampleType /Bicubic /GrayImageResolution 300 /GrayImageDepth -1 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /DCTEncode /AutoFilterGrayImages true /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /GrayImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000GrayACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000GrayImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasMonoImages false /CropMonoImages true /MonoImageMinResolution 1200 /MonoImageMinResolutionPolicy /OK /DownsampleMonoImages true /MonoImageDownsampleType /Bicubic /MonoImageResolution 1200 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict << /K -1 >> /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile () /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False /CreateJDFFile false /Description << /ARA /BGR /CHS /CHT /CZE /DAN /DEU /ESP /ETI /FRA /GRE /HEB /HRV (Za stvaranje Adobe PDF dokumenata najpogodnijih za visokokvalitetni ispis prije tiskanja koristite ove postavke. 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