Pd Catalysis A readily available cyclic carbamate functions as a general precursor to a range of functionalized piperidine products using a new Pd-catalyzed annulation strategy. An asymmetric catalytic variant provides a rapid and efficient means to access these heterocycles with high to excellent levels of enantiocontrol. In addition, these richly functionalized compounds are amenable to further chemoselective elaboration. For more information, see the Communication by J. P. A. Harrity et al. on page 13000 ff

Allen, B.D.W.

Connolly, M.J.

Harrity, J.P.A.

White Rose Research Online

This is a repository copy of Frontispiece: A Pd-Catalyzed Synthesis of Functionalized Piperidines.White Rose Research Online URL for this paper:http://eprints.whiterose.ac.uk/104881/Version: Accepted VersionArticle:Allen, B.D.W., Connolly, M.J. and Harrity, J.P.A. (2016) Frontispiece: A Pd-Catalyzed Synthesis of Functionalized Piperidines. Chemistry - A European Journal, 22 (37). ISSN 0947-6539 https://doi.org/10.1002/chem.201683761This is the peer reviewed version of the following article:B. D. W. Allen, M. J. Connolly, J. P.A. Harrity, Chem. Eur. J. 2016, 22, which has been published in final form at http://dx.doi.org/10.1002/chem.201683761. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving (http://olabout.wiley.com/WileyCDA/Section/id-828039.html).eprints@whiterose.ac.ukhttps://eprints.whiterose.ac.uk/Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. The publisher or other rights holders may allow further reproduction and re-use of the full text version. This is indicated by the licence information on the White Rose Research Online record for the item. Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request.  COMMUNICATION              A Pd-Catalyzed Synthesis of Functionalized Piperidines** Benjamin D. W. Allen, Matthew J. Connolly and Joseph P. A. Harrity*[a] Abstract: A readily available cyclic carbamate 1 functions as a general precursor to a range of functionalized piperidine products via a new Pd-catalyzed annulation strategy. An asymmetric catalytic variant provides a rapid and efficient means to access these heterocycles with high to excellent levels of enantiocontrol. Finally, these richly functionalized compounds are amenable to further chemoselective elaboration. Recent trends in drug discovery design have moved away from targets that are rich in aromatic sub-units, and more towards intermediates that are rich in sp3-containing scaffolds.[1] This change in target properties has led to a demand for rapid and efficient techniques for the synthesis of lead-like structures that contain functional groups that allow lead optimization to be performed in a systematic and straightforward manner. In this context, we have reported the employment of a formal [3 + 3] cycloaddition of aziridines that allows chiral piperidines to be prepared with excellent enantiocontrol.[2,3] However, this method requires enantioenriched aziridine substrates to be made available. In an effort to devise an enantioselective variant, we considered a formal [4 + 2] strategy that comprised a Pd-catalyzed allylation – condensation sequence (Scheme 1). Moreover, we envisaged that the required conjunctive reagent 2 could be accessed from carbamate 1, allowing its generation in situ and offering the potential for enantiocontrol through the employment of chiral ligands. This approach would complement existing Pd-catalysed routes to chiral heterocycles that exploit catalyst generated dipolar reagents.[4] For example, Aggarwal has recently reported a stereoselective route to chiral functionalized pyrrolidines using a formal [3 + 2] reaction of alkenyl aziridines and Michael acceptors.[5]   Scheme 1. Pd-catalyzed annulation strategy to chiral piperidines. Our first task was to devise an efficient route to compound 1, a precursor to the required dipolar intermediate. In the event we were able to adapt the sequence developed by Suzuki[6] to establish a short and scalable route to carbamate 4 that provided the opportunity to access the N-activated reagent 1 (Scheme 2).   Scheme 2. Synthesis of annulation precursor 1. Turning our attention to the key annulation reaction, a small family of 1,3-dicarbonyl substrates comprising diketones and -keto esters were employed in our preliminary scoping studies, our results are shown in Scheme 3. After preliminary catalyst optimization, we were delighted to find that carbamate 1 could be smoothly transformed into a range of products using a catalyst system comprising Pd(dba)2 and readily available phosphoramidite ligand L1. Specifically, pentane-2,4-dione 5a underwent a one-pot allylation-condensation sequence to deliver piperidine 6a in high yield. When the same procedure was employed on lactone 5b a spirocyclic heterocycle 6b was generated, whilst an ester substituted cyclic ketone 5c produced a linearly fused bicycle 6c. Therefore, these preliminary studies confirmed the potential of cyclic carbamate 1 to deliver a range of piperidine products whereby the product skeleton could be dictated by the type of 1,3-dicarbonyl compound used.  Scheme 3. Preliminary studies on the scope of the Pd-catalyzed annulation reaction. The condensation steps in reactions of 5b,c shown in Scheme 3 are chemoselective for reaction at the ketone over the ester group. We therefore wanted to establish that selective imine Mr. B. D. W. Allen, Dr. M. J. Connolly, Prof. J. P. A. Harrity Department of Chemistry University of Sheffield Sheffield, S3 7HF (U.K.) E-mail: j.harrity@sheffield.ac.uk  [**] This work was supported by the EPSRC and The Leverhulme Trust.  Supporting information for this article is given via a link at the end of the document.   COMMUNICATION              formation could also be achieved when unsymmetrical 1,3-diketones were used. Accordingly, we opted to investigate the annulation reaction of a series of -acylated cyclopentanones and our results are shown in Scheme 4. The annulation of substrates 5d-f provided a mixture of products in each case. Fortunately, the products could be separated in the case of 6e,f via flash column chromatography allowing their characterization as individual compounds.[7] The spiro:linear product ratios reflect the thermodynamic stabilities of the individual compounds, and we noted that neat samples of pure spiro and linear compounds isomerized back to the original ratios within a few days at room temperature. Interestingly however, the outcome of these condensation reactions is subject to steric control. Specifically, we subjected a family of 5-acyl-2,2-dimethylcyclopentanones 5g-i to the allylation-condensation procedure and were pleased to find that the spiropiperidine products were formed exclusively in each case (Scheme 4).  Scheme 4. 1,3-Diketone annulation reactions. [a] Ratio of crude mixtures as judged by 400 MHz 1H NMR spectroscopy; [b] Ratios of isolated products. As -keto ester substrates provided predictable reactivity patterns we decided to explore the scope of the one-pot allylation-condensation procedure on these compounds and our results are shown in Table 1. g-Acyl-け-butyrolactones 5j-l provided the corresponding spirocyclic piperidines 6j-l in good yield (entries 1-3). These compounds are of potential biological interest as they have recently been shown to exhibit acetyl-CoA carboxylase inhibitory activity.[8] Ketoester substrates 5m-o were also successfully employed, giving rise to linearly fused bicyclic products 6m-o. Finally, we were pleased to find that g-aryl cyclic ketones could also function as substrates in this annulation process. Preliminary studies in this class of compound showed that bicyclic heterocycle 6p could be formed in acceptable yield after annulation of 5p and reduction of the resulting imine group with NaBH4 (entry 7). As we envisaged that the annulation process proceeded via an intermediate Pd-ヾ-allyl intermediate, we were interested in the prospect of developing an enantioselective variant of this piperidine forming reaction. Previous studies in this area using unsymmetrical Pd-ヾ-allyl complexes have demonstrated the difficulty in inducing high degrees of enantioselectivity with 1,3-dicarbonyl substrates, in part due to the distal approach of the prochiral nucleophile to the palladium,[9] which contains all of the chiral information, but also due to the relative steric and electronic symmetry which is inherent in these substrates.[10]  Table 1. Pd-catalyzed synthesis of quaternary carbon-substituted allylic amine derivatives.  entry substrate  product yield[a] 1   R=Me; 5j  6j; 86% 2 R=tBu; 5k 6k; 56% 3 R=Ph; 5l 6l; 94% 4   6m; 75% 5    6n; 70% 6   6o; 57% 7   6p; 44%[b]  [a] Yields of isolated products; [b] Crude reaction product treated with NaBH4. [c] Step 1 was performed at reflux.  Nonetheless, an initial ligand screen indicated that L2 could perform this transformation with impressive degrees of enantiodiscrimination at -20 °C. We were interested to find that   Scheme 5. Enantioselective piperidine synthesis.  COMMUNICATION              increasing the steric encumbrance on the ketone had varying effects on the selectivity with the isopropyl group giving rise to the best enantiomeric excess we achieved. Additionally, ligands derived from chiral diarylpyrrolidines (L3 and L4) were found to be effective for the enantioselective allylation of the 1,3-diketone substrates. The sterically demanding substrate 5f was unreactive with L3 in this case, and so the ligand L4 was employed to provide the product with high enantioselectivity. Efforts to exploit enantioenriched compounds 7-9 in selective annulation reactions (cf Scheme 4) have not been successful to-date but are the subject of active investigation.   Compound 6l was used to investigate functionalization of these compounds in order to further demonstrate the utility of this chemistry. We found that treatment of 6l with NaBH4 in refluxing methanol afforded the two diastereomeric piperidine products in a 19:1 ratio. Chromatographic separation afforded only the major diastereomer 10 in an excellent yield.[11] Additionally, the imine is unusually stable and can be utilized as a directing group for C-H amidation. Indeed, using Rh-catalysis[12] we installed a trifluoroacetamide group in the ortho-position on the aromatic moiety.  Scheme 6. Imine functionalization; [a] [Cp*RhCl2]2 (2.5 mol%), AgSbF6 (10 mol%), PhI(OAc)2 (1.5 eq.), CF3CONH2 (1.0 eq.), CH2Cl2, 40 °C, o/n; [b] diastereomer ratio determined 400 MHz 1H NMR spectroscopy. In conclusion, we have demonstrated the ability of carbamate 1 to deliver a range of highly functionalised piperidine products via a simple Pd-catalyzed annulation strategy. This methodology is very versatile and allows access to a range of sp3-containing scaffolds that bear useful functionality for further derivatization. In this context, we have demonstrated that the imine group can be exploited in a diastereoselective reduction as well as in a rare example of an imine-directed C-H amidation reaction. Additionally, we have shown that chiral phosphoramidite ligands produce spiropiperidines with excellent enantioselectivities, thereby offering an expedient means to access this important class of compounds with control of the quaternary stereocenter. Experimental Section Typical allylation-condensation procedure as exemplified by the formation of 6j: To a flask charged with Pd(dba)2 (7 mg, 0.012 mmol) and L1 (11 mg, 0.035 mmol) was added CH2Cl2 (3 mL) and the mixture was allowed to stir for 5 min. Carbamate 1 (50 mg, 0.234 mmol) in CH2Cl2 (1 mL) was added, followed by g-acetyl-け-butyrolactone (60 mg, 0.469 mmol) and the reaction mixture was left to stir for 3 h at rt. TFA (1 mL) was added and the reaction mixture was left to stir for an additional 1 h. The reaction was quenched by the addition of sat. NaHCO3 (10 mL) and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined organic fractions were dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel (75% ethyl acetate in petrol) to afford 6-methyl-9-methylene-2-oxa-7-azaspiro[4.5]dec-6-en-1-one 6j (26 mg, 62%) as a colourless oil. FTIR Ȟmax (thin film/cm-1) 2966, 1732, 1655, 1455; 1H NMR (400 MHz, CDCl3) h 4.97 (s, 1H, C=CHAHB), 4.84 (s, 1H, C=CHAHB), 4.25 (d, J = 19.5 Hz, 1H, NCHAHB), 4.15 (d, J = 19.5 Hz, 1H, NCHAHB), 2.51 – 2.27 (m, 3H, C=CCHAHB, CH2), 2.21 – 1.90 (m, 5H, C=CCHAHB, 2 × CH2), 1.90 – 1.80 (m, 3H, CH3); 13C NMR (101 MHz, CDCl3) h 218.7, 166.2, 139.4, 110.8, 58.5, 55.5, 39.0, 36.7, 33.7, 23.4, 19.3; MS (ESI+) 178 (M+H+, 100%); HRMS (ESI+) C11H15NO requires M+H+ 178.1232, found 178.1235. Received: ((will be filled in by the editorial staff)) Published online on ((will be filled in by the editorial staff)) Keywords: piperidine · Pd-catalysis · enantioselective · annulation [1] a) T. J. Ritchie, S. J. F. MacDonald, Drug Discovery Today 2009, 14, 1011; b) E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57, 10257. [2] a) S. J. Hedley, W. J. Moran, D. A. Price, J. P. A. Harrity, J. Org. Chem. 2003, 68, 4286; b) K. M. Goodenough, P. Raubo, J. P. A. Harrity, Org. Lett. 2005, 7, 2993; c) L. C. Pattenden, R. A. J. Wybrow, S. A. Smith, J. P. A. Harrity, Org. Lett. 2006, 8, 3089. [3] For reviews of heterocycle syntheses via [3 + 3] reactions see: a) R. P. Hsung, A. V.; N. Sydorenko, Eur. J. Org. Chem. 2005, 23; b) J. P. A. Harrity, O. Y. Provoost, Org. Biomol. Chem. 2005, 3, 1349; c) G. S. Buchanan, J. B.  Feltenberger, R. P. Hsung, Curr. Org. Synth. 2010, 7, 363; d) X. F. Xu, M. P. Doyle, Acc. Chem. Res. 2014, 47, 1396. [4] a) B. M. Trost, D. T. M. Chan, J. Am. Chem. Soc. 1979, 101, 6429. b) B. M. Trost, Angew. Chem. 1986, 98, 1; Angew. Chem. Int. Ed. Engl. 1986, 25, 1. c) M. Lautens, W. Klute, W. Tam, Chem. Rev. 1996, 96, 49. d) B. M. Trost, S. A. King, T. Schmidt, J. Am. Chem. Soc. 1989, 111, 5902. e) B. M. Trost, C. M. Marrs, J. Am. Chem. Soc. 1993, 115, 6636; f) M. Kimura, T. Tamaki, M. Nakata, K. Tohyama, Y. Tamaru, Angew. Chem. Int. Ed. 2008, 47, 5803. [5] a) M. A. Lowe, M. Ostovar, S. Ferrini, C. C. Chen, P. G. Lawrence, F. Fontana, A. A. Calabrese, V. K. Aggarwal, Angew. Chem. 2011, 123, 6494; Angew. Chem. Int. Ed. 2011, 50, 6370; b) F. Fontana, C. C. Chen, V. K. Aggarwal, Org. Lett. 2011, 13, 3060. [6] M. Suzuki, S. Yoshida, K. Shiraga, T. Saegusa, Macromolecules 1998, 31, 1716. [7] The structures of compounds spiro-6e, linear-6e, and spiro-6i were assigned by HMBC spectroscopy. The remaining compounds are assigned by analogy, based on the characteristic signal pattern arising from the diastereotopic protons on the carbon adjacent to the nitrogen atom. See supporting information for details. [8] M. Kamata, T. Yamashita, A. Kina, M. Funata, A. Mizukami, M. Sasaki, A. Tani, M. Funami, N. Amano, K. Fukatsu, Bioorg. Med. Chem. Lett. 2012, 22, 3643. [9] B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921. [10] R. Kuwano, K. Uchida, Y. Ito, Org. Lett. 2003, 5, 2177. [11] The structure of 10 was confirmed by X-ray crystallographic analysis. CCDC-1475348 contains the supplementary crystallographic data for this compound. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. [12] a) H. Zhao, Y. Shang, W. Su, Org. Lett. 2013, 15, 5106; b) T. M. M. Maiden, S. Swanson, P. A. Procopiou, J. P. A. Harrity, Chem. Eur. J. 2015, 21, 14342.    COMMUNICATION                COMMUNICATION To cut a long story short…. A cyclic carbamate functions as a general precursor to a range of functionalized piperidine products via a new Pd-catalyzed annulation strategy. An asymmetric catalytic variant provides a rapid and efficient means to access these heterocycles with high to excellent levels of enantiocontrol.  Benjamin D. W. Allen, Matthew J. Connolly and Joseph P. A. Harrity * Page No. – Page No. A Pd-Catalyzed Annulation to Functionalized Piperidines     

Frontispiece: A Pd-Catalyzed Synthesis of Functionalized Piperidines

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