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Bis-Sonogashira cross-coupling: an expeditious approach towards longchain, phenylene-modified 1,v-diols{

Downloaded on 03 May 2012 Published on 09 March 2012 on http://pubs.rsc.org | doi:10.1039/C2RA20411H

Simon Drescher,*ab Susan Becker,a Bodo Dobnera and Alfred Blumeb Received 6th March 2012, Accepted 8th March 2012 DOI: 10.1039/c2ra20411h

The synthesis of long-chain, phenylene-modified 1,v-diols can be effectively performed in 60% overall yield using the bisSonogashira cross-coupling with 6 mol% of PdCl2(PPh3)2 and tetrabutylammonium fluoride in a copper-, amine- and solventfree setting followed by hydrogenation. An expeditious and highly efficient method for the synthesis of longchain 1,v-diols is of high importance in supramolecular chemistry. Especially in the field of bipolar lipid (bolaamphiphile1) synthesis, these diols play an important role since they represent the hydrophobic part of this class of lipids. These bolaamphiphiles were originally found in the membrane lipids of certain species of Archaea.2 In particular, the bipolar archaebacterial model lipids3 are of great interest since their thermal and chemical stability as well as their capability to form closed vesicles are outstanding properties. These properties make this class of amphiphiles applicable in biotechnology, materials science and pharmacy.4 For instance, thermally and chemically stable liposomes made from archaebacterial bolaamphiphiles (archaeosomes) are an alternative to conventional liposomes in applications as a drug delivery system.5 Long-chain, unmodified 1,v-diols with 22 or more carbon atoms have already been synthesised using established multistep procedures such as (i) bis-acylation of cyclic enamines with dicarboxylic acid dichlorides, (ii) hydrolysis of enamino ketones and subsequent ring opening, (iii) Wolff–Kishner reduction of bis(oxoacid)s and subsequent reduction with lithium aluminium hydride, or (iv) double Wittig reaction with bis(phosphorylide)s and v-functionalised aldehydes.6 In our group, we use the Grignard reaction under catalysis of dilithium tetrachlorocuprate(II)7 for the synthesis of longchain 1,v-diols. This coupling reaction can be designed as a homocoupling8 or a bis-coupling reaction.9 For the synthesis of the entitled phenylene-modified compounds we previously used the Grignard reaction in a stepwise homo-coupling procedure since the simultaneous bis-coupling reaction resulted in the formation of by-products, which were impossible to separate.10 Although this homo-coupling approach resulted in pure products and provided the opportunity for a Institute of Pharmacy, Wolfgang-Langenbeck-Str. 4, 06120, Halle/Saale, Germany. E-mail: [email protected]; Fax: +49(0) 345 5527026; Tel: +49(0) 345 5525196 b Institute of Chemistry, von-Danckelmann-Platz 4, 06120, Halle/Saale, Germany { Electronic supplementary information (ESI) available: Experimental procedures and characterization data. NMR spectra of isolated compounds. See DOI: 10.1039/c2ra20411h

4052 | RSC Adv., 2012, 2, 4052–4054

the synthesis of unsymmetrical bolalipids, it is a very time-consuming synthetic pathway.10 Therefore, the expeditious Sonogashira crosscoupling reaction is a rational alternative for the preparation of such phenylene-modified diols. Sonogashira cross-coupling11 is one of the most powerful and straightforward methods for the formation of carbon–carbon bonds in organic synthesis.12 Usually, the Pd-catalysed reaction conditions are mild, and many reactions can be carried out at ambient temperatures. However, the Sonogashira reaction often generates homo-coupling products of terminal alkynes,13 difficult to separate from the target products due to similar chromatographic properties.14 Since the formation of these by-products is due to the addition of the co-catalyst CuI, numerous copper-free catalyst systems were developed.15 Besides the ‘homo’-Sonogashira, bis-Sonogashira crosscoupling reactions have been developed using either middle-chain alkynes (up to 11 carbon atoms) and vinyl halides16 or aromatic (benzene or pyridine) dialkynes and aryl iodides.17 However, all these approaches used copper(I), bearing the risk of the formation of homo-coupling side-products. This problem has to be considered in the synthesis presented here, because long-chain 1,v-diols cannot be separated from their phenylene-modified analogues.10 The present work describes the preparation of phenylene-modified 1,v-diols starting from benzene dihalides 1 and the long-chain unprotected alkynol 2, including different substitution patterns (Scheme 1). Due to the very low solubility of compound 2 in common solvents used for Sonogashira coupling reactions, we investigated DMSO and water combined with a micellar system as solvents, and also solventfree systems. Furthermore, several Pd-catalysts were tested (see Table 1). At first, we adapted a method described by Li et al.18 using Pd(OAc)2 as catalyst combined with the relatively strong base potassium carbonate and tetra-n-butylammonium bromide (TBAB) at elevated temperatures (entries 1, 2). In addition, we changed the solvent from ethanol to DMSO in order to obtain a better solubility of compound 2. However, the desired product (3a) could be obtained only in marginal yields of about 10%. Unexpectedly, while using the bromo derivative 1a, we detected the homo-coupling product of the terminal alkynol 2, which could not be separated from the product (entry 1). When we used the iodide 1b instead (entry 2), the formation of the by-product could be avoided. In a next step (entries 3, 4), we applied the method described by Lipshutz and co-workers15a using the micelle-forming amphiphile This journal is ß The Royal Society of Chemistry 2012


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Scheme 1 Reagents and conditions: (i) PdCl2(PPh3)2, TBAF?3H2O, 1 h, 80 uC (43–63%); (ii) H2, Pd(OH)2/C (20%), heptane/ethyl acetate/ethanol, 10 atm, 18 h, rt (90–95%).

PTS19 in aqueous medium, together with Et3N as a soluble amine and X-Phos20 as ligand in the presence of catalytic amounts of PdCl2(CH3CN)2. The rationale behind this approach was that the use of a micellar system21 might enhance the solubility of the educts and, hence, should trigger the Sonogashira cross-coupling reaction. However, both reactions (entries 3, 4), using different amounts of catalyst and ligand, respectively, and working at different temperatures, gave only low yields of the desired product. In contrast with entry 1, the formation of the homo-coupling by-product was not detected. The use of PdCl2(PPh3)2 instead of PdCl2(CH3CN)2 + X-Phos (entry 5) led to no improvement regarding yield. In addition, the PTS/water system combined with the long-chain alkynol caused problems during the purification process since a gel-like suspension was formed. The next reaction conditions tested (entries 6–11) were inspired by the work of Mori and co-workers:22 they used TBAF as an activator for the amine-free Pd-catalysed Sonogashira cross-coupling reaction. However, organic solvents such as THF were still required. Based on

this procedure, Liang et al.23 used 3 mol% of PdCl2(PPh3)2 combined with TBAF under solvent-free conditions: For the long-chain alkyne (decyne) and substituted aryl mono-bromides and mono-chlorides, respectively, they obtained 51–98% isolated yields within 1 to 25 h of reaction.23 In our experiments, the reaction of dibromo benzene 1a with the alkynol 2 in a 1.2-fold excess using 6 mol% of PdCl2(PPh3)2 and 3 equivalents of TBAF (entry 6), and without any solvent as medium, afforded 42% of the desired product 3a.24 An increase in reaction temperature from 60 to 80 uC (entry 7) resulted in an increased yield (63%), whereas an increase in reaction time (entry 8) caused a slight decrease in yield. Unexpectedly, the use of diiodo benzene 1b (entry 9) resulted in lower yields of the desired product combined with a higher amount of unknown by-products. This might be due to the higher reactivity of the iodine compound compared to the bromine counterpart. A change in the substitution pattern of the bromo derivative 1a caused only small variations in product composition: the lower yield while using the ortho derivative 1d (entry 11) is due to steric hindrance during the bis-Sonogashira cross-coupling reaction. In all reactions using the PdCl2(PPh3)2/TBAF system no homocoupling products of the terminal alkynol were observed. The monocoupling Sonogashira product, which always occurred in the crosscoupling reaction in 5–20%, could successfully be separated by middle pressure liquid chromatography (MPLC). Finally, the hydrogenation of the triple bonds of compounds 3 using a solvent mixture of heptane, ethyl acetate and ethanol, to ensure complete dissolution of the product, and Pd(OH)2 on carbon resulted in the formation of the target products 4. For a complete conversion it is necessary to use increased hydrogen pressure (up to 10 atm) over several hours. Otherwise, mixtures of products with double bonds are formed. In summary, we have developed a general synthetic approach for the expeditious preparation of long-chain, phenylene-modified 1,v-diols. We found that the bis-Sonogashira cross-coupling reaction of aryl dibromides with terminal alkynols, using PdCl2(PPh3)2 and TBAF, followed by hydrogenation is the method of choice, which circumvents the formation of homo-coupling products. This synthetic approach is also applicable for other chain lengths and/or biphenyl/terphenyl core-structures, giving rise to a huge variety of different, phenylene-modified 1,v-diols important in supramolecular chemistry. The synthesis as well as the physicochemical characterisation of the corresponding bolaamphiphiles are currently underway.

Table 1 Experimental conditions for the Sonogashira cross-coupling reactionsa Entry Dihalide (mmol) 2 (mmol) Pd-catalyst (mol%)

Solvent Additives (mmol)

1 2 3 4 5 6 7 8 9 10 11

DMSO DMSO H2O H2O H2O None None None None None None

1a 1b 1a 1a 1a 1a 1a 1a 1b 1c 1d

(0.5) (0.5) (0.5) (0.5) (0.5) (1.0) (0.8) (0.5) (0.8) (0.8) (0.8)

1.2 1.2 1.2 1.2 1.2 2.4 1.9 1.2 1.9 1.9 1.9

Pd(OAc)2 (3) Pd(OAc)2 (3) Pd(CH2CN)2Cl2 (4.8), X-Phose (10.4) Pd(CH2CN)2Cl2 (2.4), X-Phose (5.2) PdCl2(PPh3)2 (3) PdCl2(PPh3)2 (6) PdCl2(PPh3)2 (6) PdCl2(PPh3)2 (6) PdCl2(PPh3)2 (6) PdCl2(PPh3)2 (6) PdCl2(PPh3)2 (6)

Temp. (uC) Time (h) Yield (%)b

K2CO3 (2), TBABc (1) K2CO3 (2), TBABc (1) PTSf (3 mL), Et3N (2.2) PTSf (3 mL), Et3N (2.2) PTSf (3 mL), Et3N (2.2) TBAFg (3) TBAFg (2.4) TBAFg (1.5) TBAFg (2.4) TBAFg (2.4) TBAFg (2.4)

55 65 rt 45 rt 60 80 80 80 80 80

6 4.5 96 8 24 1 1 2 1 1 1

10d 9 14 10 10 42 63 56 45 61 43

a Conditions: all reactions were carried out under an argon atmosphere. b Isolated yields after chromatography (MPLC). c TBAB: tetran-butylammonium bromide. d Product was contaminated with homo-coupling by-product. e X-Phos: 2-dicyclohexylphosphino29,49,69-triisopropylbiphenyl. f PTS: polyoxyethanyl-a-tocopheryl sebacate (3 wt% in H2O; Sigma Aldrich catalogue no. 698 717). g TBAF: tetran-butylammonium fluoride trihydrate.

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Acknowledgements This work was supported by grants from the Deutsche Forschungsgemeinschaft (projects Bl 182/19-3 and Do 463/4-2).

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References

14 15

1 J.-H. Fuhrhop and T. Wang, Chem. Rev., 2004, 104, 2901. 2 (a) T. A. Langworthy, Biochim. Biophys. Acta, Lipids Lipid Metab., 1977, 487, 37; (b) M. De Rosa, E. Esposito, A. Gambacorta, B. Nicolaus and J. D. Bu’Lock, Phytochemistry, 1980, 19, 827. 3 (a) T. Benvegnu, M. Brard and D. Plusquellec, Curr. Opin. Colloid Interface Sci., 2004, 8, 469; (b) A. Meister and A. Blume, Curr. Opin. Colloid Interface Sci., 2007, 12, 138. 4 (a) B. A. Cornell, V. B. L. Braach-Maksvytis, L. G. King, P. D. J. Osmann, B. Raguse, L. Wieczorek and R. J. Pace, Nature, 1997, 387, 580; (b) U. Bakowsky, U. Rothe, E. Antonopoulos, T. Martini, L. Henkel and H. J. Freisleben, Chem. Phys. Lipids, 2000, 105, 31; (c) T. Benvegnu, G. Re´thore´, M. Brard, W. Richter and D. Plusquellec, Chem. Commun., 2005, 5536; (d) G. Re´thore´, T. Montier, T. Le Gall, P. Dele´pine, S. CammasMarion, L. Lemie`gre, P. Lehn and T. Benvegnu, Chem. Commun., 2007, 2054; (e) G. P. Patel, A. Ponce, H. Zhou and W. Chen, Int. J. Toxicol., 2008, 27, 329; (f) D. A. Brown, B. Venegas, P. H. Cooke, V. English and P. L.-G. Chong, Chem. Phys. Lipids, 2009, 159, 95. 5 G. D. Sprott, D. L. Tolson and G. B. Patel, FEMS Microbiol. Lett., 1997, 154, 17. 6 (a) S. Hu¨nig, E. Lu¨cke and W. Brenninger, in Org. Synth. Coll., vol. 5, New York, 1973, p. 533; (b) I. Grechishnikova, L. B.-A. Johansson and J. G. Molotkovsky, Chem. Phys. Lipids, 1996, 81, 87; (c) R. McKiernan, S. P. Gido and J. Penelle, Polymer, 2002, 43, 3007. 7 M. Tamura and J. Kochi, Synthesis, 1971, 303. 8 (a) U. F. Heiser and B. Dobner, Chem. Commun., 1996, 2025; (b) U. F. Heiser and B. Dobner, J. Chem. Soc., Perkin Trans. 1, 1997, 809. 9 (a) K. Ko¨hler, G. Fo¨rster, A. Hauser, B. Dobner, U. F. Heiser, F. Ziethe, W. Richter, F. Steiniger, M. Drechsler, H. Stettin and A. Blume, J. Am. Chem. Soc., 2004, 126, 16804; (b) K. Ko¨hler, G. Fo¨rster, A. Hauser, B. Dobner, U. F. Heiser, F. Ziethe, W. Richter, F. Steiniger, M. Drechsler, H. Stettin and A. Blume, Angew. Chem., Int. Ed., 2004, 43, 245; (c) S. Drescher, A. Meister, A. Blume, G. Karlsson, M. Almgren and B. Dobner, Chem.–Eur. J., 2007, 13, 5300; (d) A. Meister, S. Drescher, G. Karlsson, G. Hause, U. Baumeister, G. Hempel, V. M. Garamus, B. Dobner and A. Blume, Soft Matter, 2010, 6, 1317. 10 S. Drescher, S. Sonnenberger and B. Dobner, unpublished results. 11 K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett., 1975, 16, 4467. 12 (a) H. Doucet and J.-C. Hierso, Angew. Chem., 2007, 119, 850; (b) R. Chinchilla and C. Na´jera, Chem. Rev., 2007, 107, 874; (c) E. Negishi and L. Anaytasia, Chem. Rev., 2003, 103, 1979; (d) K. Sonogashira, J. Organomet.

4054 | RSC Adv., 2012, 2, 4052–4054

16

17

18 19 20 21 22

23 24

Chem., 2002, 653, 46; (e) M. Erdelyi and A. Gogoll, J. Org. Chem., 2001, 66, 4165; (f) T. Hundertmark, A. F. Littke, S. L. Buchwald and G. C. Fu, Org. Lett., 2000, 2, 1729. (a) P. Siemsen, R. C. Livingston and F. Dieterich, Angew. Chem., Int. Ed., 2000, 39, 2632; (b) J.-H. Li, Y. Liang and X.-D. Zhang, Tetrahedron, 2005, 61, 1903. H. Kukula, S. Veit and A. Godt, Eur. J. Org. Chem., 1999, 277. (a) B. H. Lipshutz, D. W. Chung and B. Rich, Org. Lett., 2008, 10, 3793; (b) A. Soheili, J. Albaneze-Walker, J. A. Murry, P. G. Dormer and D. L. Hughes, Org. Lett., 2003, 5, 4191; (c) Y. Ma, C. Song, W. Jiang, Q. Wu, Y. Wang, X. Liu and M. B. Andrus, Org. Lett., 2003, 5, 3317; (d) K. Heuze´, D. Me´ry, D. Gauss and D. Astruc, Chem. Commun., 2003, 2274; (e) V. P. W. Bo¨hm and W. A. Herrmann, Eur. J. Org. Chem., 2000, 3679. (a) E. Quesada, A. U. Acuna and F. Amat-Guerri, Eur. J. Org. Chem., 2003, 1308; (b) E. Quesada, A. U. Acuna and F. Ama-Guerri, Angew. Chem., Int. Ed., 2001, 40, 2095. (a) T. Shoji, S. Ito, K. Toyota, M. Yasunami and N. Morita, Chem.–Eur. J., 2008, 14, 8398; (b) K. Kobayashi and N. Kobayashi, J. Org. Chem., 2004, 69, 2487; (c) M. Akhtaruzzaman, M. Tomura and B. M. Zaman, J. Org. Chem., 2002, 67, 7813; (d) A. Khatyr and R. Ziessel, J. Org. Chem., 2000, 65, 7814; (e) P. N. W. Baxter, J. Org. Chem., 2000, 65, 1257. P. Li, L. Wang and H. Li, Tetrahedron, 2005, 61, 8633. H. Borowy-Borowski, M. Sikorska-Walker and P. R. Walter, U.S. Patent 6,045,826, April 4, 2000. D. Gelman and S. L. Buchwald, Angew. Chem., Int. Ed., 2003, 42, 5993. T. Dwars, E. Paetzold and G. Oehme, Angew. Chem., Int. Ed., 2005, 44, 7174. (a) A. Mori, T. Shimada, T. Kondo and A. Sekiguchi, Synlett, 2001, 649; (b) A. Mori, J. Kawashima, T. Shimada, M. Suguro, K. HIrabayashi and Y. Nishihara, Org. Lett., 2000, 2, 2935. Y. Liang, Y.-X. Xie and J.-H. Li, J. Org. Chem., 2006, 71, 379. Experimental procedure for a typical bis-Sonogashira cross-coupling reaction: an oven-dried flask was filled with aryl dihalide 1 (0.5–1.0 mmol), alkynol 2 (1.2–2.4 mmol), PdCl2(PPh3)2 (6 mol%) and TBAF?3H2O (3 equiv.) under an argon atmosphere. The mixture was subsequently stirred at 80 uC for 1 h until consumption of the starting material was complete. Afterwards, 30 mL H2O was added and the mixture was extracted with chloroform (3 6 20 mL). The combined organic layers were washed with brine (20 mL), and water (20 mL), dried over sodium sulfate, and evaporated. The residue was purified by middle pressure liquid chromatography (MPLC) using chloroform/diethyl ether as eluents and a gradient technique to afford the diols 3 as white to light yellow crystalline powders. For the subsequent hydrogenation of the triple bonds, diols 3 were dissolved in heptane/ethyl acetate/ethanol (100 mL, 3/1/ 1, v/v/v) and Pd(OH)2 (20% on carbon, 50–100 mg) was added. The mixture was stirred under hydrogen (10 atm) at room temperature for 18 h. Afterwards, the catalyst was removed by filtration and the solvent was evaporated in vacuo to give the diols 4 as white crystalline powders.

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