Chiral secondary allylboronates are obtained in high enantioselectivities by the copper-catalyzed 1,6-boration of electron-deficient dienes with B2(pin)2. The reactions proceed efficiently using catalyst loadings as low as 0.0049 mol%. The allylboronates may be oxidized to the allylic alcohols, and can be used in stereoselective aldehyde allylborations. This process was applied to a concise synthesis of atorvastatin

Althaus

Bernardi

Bonet

Burks

Burns

Calow

Carosi

Casar

Chen

Dell’Amico

den Hartog

Evans

Farthing

Ferris

Fillion

Hartmann

Hayashi

Hong

Hénon

Ibrahem

Kawato

Kitanosono

Kliman

Kobayashi

Lennox

Lillo

Lumbroso

Moure

Murphy

Nishimura

O’Brien

Peng

Pietruszka

Pulis

Roth

Sasaki

Sawano

Schuster

Shiomi

Silvi

Sole

Takahashi

Tian

Toribatake

Uraguchi

Zhao

A 2,4,6-trialkylanilide-containing chiral diene has been identified as a superior ligand for the enantioselective rhodium-catalyzed arylation of alkenylazaarenes with arylboronic acids.</p

Roy, Iain D.

Burns, Alan R.

Pattison, Graham

Michel, Boris

Parker, Alexandra J.

Lam, Hon Wai

University of Brighton Research Portal

A second-generation ligand for the enantioselective rhodium-catalyzed addition of arylboronic acids to alkenylazaarenes

A 2,4,6-trialkylanilide-containing chiral diene has been identified as a superior ligand for the enantioselective rhodiumcatalyzed arylation of alkenylazaarenes with arylboronic acids

Name not available

A second-generation ligand for the enantioselective\ud
rhodium-catalyzed addition of arylboronic acids to\ud
alkenylazaarenes

Luo, Yunfei

Madec, Amaël G.E.

Nottingham ePrints

Enantioselective synthesis of allylboronates and allylic alcohols by copper-catalyzed 1,6-boration

Yunfei Luo

Iain D. Roy

Amaël G. E. Madec

Hon Wai Lam

Crossref

Angewandte Chemie International Edition

Enantioselective Synthesis of Allylboronates and Allylic Alcohols by Copper-Catalyzed 1,6-Boration

Alan R. Burns

Graham Pattison

Boris Michel

Alexandra J. Parker

Chemical Communications

Roy, Iain D. and Burns, Alan R. and Pattison, Graham and Michel, Boris and Parker, Alexandra J. and Lam, Hon Wai (2014) A second-generation ligand for the enantioselective rhodium-catalyzed addition of arylboronic acids to alkenylazaarenes. Chemical Communications, 50 (22). pp. 2865-2868. ISSN 1364-548X Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/43481/1/HON2%20Arylation%20of%20alkenylazaarenes%20Chem%20Commun%20submission%202.pdfCopyright and reuse: The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions.This article is made available under the University of Nottingham End User licence and may be reused according to the conditions of the licence.  For more details see: http://eprints.nottingham.ac.uk/end_user_agreement.pdfA note on versions: The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher’s version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.ukChemComm RSCPublishing COMMUNICATION This journal is © The Royal Society of Chemistry 2014 Chem. Commun., 2014, 00, 1-3 | 1 Cite this: DOI: 10.1039/x0xx00000x Received 00th January 2012, Accepted 00th January 2012 DOI: 10.1039/x0xx00000x www.rsc.org/chemcomm A second-generation ligand for the enantioselective rhodium-catalyzed addition of arylboronic acids to alkenylazaarenes Iain D. Roy,a Alan R. Burns,ab Graham Pattison,a Boris Michel,a Alexandra J. Parkerc and Hon Wai Lam*ab    A 2,4,6-trialkylanilide-containing chiral diene has been identified as a superior ligand for the enantioselective rhodium-catalyzed arylation of alkenylazaarenes with arylboronic acids.   As part of a program aimed at the preparation of enantioenriched chiral azaarene-containing compounds,1 we have focused upon an underexploited strategy in asymmetric synthesis, namely the utilization of the C=N moiety within certain azaarenes to activate adjacent functionality in enantioselective catalysis.2–4 In this context, we have reported1b the enantioselective rhodium-catalyzed 1,4-arylation5–8 of β-substituted alkenylazaarenes with arylboronic acids using a secondary amide-containing chiral diene9–11 ligand L1 (see Table 1, entry 1), which builds upon early studies by the groups of Lautens12a and Genet12b using vinylazaarenes. Although L1 was highly effective, it was of interest to determine whether a ligand of this complexity, possessing stereochemical elements additional to those of the chiral diene component, was actually necessary for optimal results.13 Herein, we report a simpler ligand that provides results superior to those obtained using L1, along with a more comprehensive evaluation of the scope of the reaction.  First, various analogues of L1 were prepared and evaluated in the enantioselective addition of 4-methylphenylboronic acid to 2-alkenylquinoline 1a (Table 1), a reaction that gave 2a in 67% yield  Table 1     Ligand evaluation for arylation of 1aa   Entry Ligand X Conversion (%) ee (%) 1b L1  67% yield 92 2 L2 NHCy >95 90 3 L3 NCy2 28 59 4 L4 NHBn >95 88 5 L5 NBn2 81 85 6 L6 NMe2 91 46 7 L7 NHPh 58 76 8 L8 NH(2,4,6-Me3C6H2) 33 96 9 L9 NH[2,4,6-(i-Pr)3C6H2] >95 99 a Reactions were conducted using 0.10 mmol of 1a (0.2 M). Conversions were determined by 1H NMR analysis of the unpurified reaction mixtures. Enantiomeric excesses were determined by chiral HPLC analysis. b Ref. 1b.  and 92% ee in our original study.1b The conditions employed were identical to those we described previously.1b Ligand L2, which lacks the pyrrole moiety on the cyclohexane, provided 2a in high conversion but the enantioselectivity was slightly lower (entry 2) compared with that obtained using L1 (entry 1). However, the dicyclohexylamide L3 was noticeably inferior (entry 3). Ligands L4 and L5, which contain one or two benzyl groups, respectively, provided reasonable results (entries 4 and 5), but the enantioselectivities were lower compared with L1. The dimethylamide L6 gave high conversion but the reaction was poorly  Table 2     Comparison of ligand L9 with L1a  a EaStCHEM, School of Chemistry, University of Edinburgh, Joseph Black Building, The King’s Buildings, West Mains Road, Edinburgh, EH9 3JJ, United Kingdom.  b School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, United Kingdom. Email: hon.lam@nottingham.ac.uk; Tel: +44-115-748-4677. c AstraZeneca Process Research and Development, Charter Way, Silk Road Business Park, Macclesfield, Cheshire, SK10 2NA, United Kingdom. † Electronic Supplementary Information (ESI) available: Experimental procedures, spectroscopic data for new compounds, and crystallographic data. CCDC 976345-976346. For ESI and crystallographic data in CIF See DOI: 10.1039/b000000x/  ChemComm Communication This journal is © The Royal Society of Chemistry 2014 Chem. Commun., 2014, 00, 1-3 | 2   a Reactions were conducted using 0.50 mmol of alkenylazaarene (0.2 M). Yields are of isolated material. Enantiomeric excesses were determined by chiral HPLC analysis. b Results taken from ref.1b c Reaction conducted using 0.30 mmol of alkenylazaarene.  enantioselective (46% ee, entry 6). Next, ligands L7–L9 containing anilide groups were studied (entries 7–9), and of these, the 2,4,6-triisopropylanilide L9 provided the best results, giving 2a in >95% conversion and 99% ee (entry 9).  Further confirmation of the superior enantioselectivities imparted by this new triisopropylanilide ligand L9 was provided by repeating representative reactions described in our original study1b using L9 in place of L1 (Table 2). These results indicate that while in most cases the isolated yields of the products with both ligands are comparable, the enantioselectivities are higher using L9 (2a, 2b, 2c, 2e, and 2f). One exception was the addition of 4-methylphenylboronic acid to a substrate containing a 4,5-diphenyloxazole as the activating group, which gave 2d in 77% ee using L9, and this result is inferior to that obtained using ligand L1 (89% ee). Interestingly, the inferiority of L9 compared with L1 with this substrate appeared to be restricted to the use of 4-methylphenylboronic acid; when 3-methylphenylboronic acid was employed, L9 provided the product 2e in a higher enantioselectivity. The reasons for these contrasting results are not currently known.  To explore the scope of the process with the second generation ligand L9 more comprehensively, a range of previously reported and new alkenylazaarenes were reacted with 4-methylphenylboronic acid (Table 3). While substrates containing pyrimidine or benzoxazole, azaarenes that have already been demonstrated to be efficient activating groups in our original study,1b underwent arylation  Table 3     Arylation of alkenylazaarenes with 4-methylphenylboronic acid   a Reactions were conducted using 0.30 mmol of alkenylazaarene (0.2 M). Yields are of isolated material. Enantiomeric excesses were determined by chiral HPLC analysis. b Enantiomeric excess determined after hydrolysis to the secondary amide. c The stereochemistry of 2m was determined by X-ray crystallography, CCDC 976346. d The structure of the alkenylazaarene substrate 1m was determined by X-ray crystallography, CCDC 976345.  efficiently with excellent enantioselectivities as expected (2g and 2k), further examples demonstrate that other azaarenes are also effective. These examples include π-deficient azaarenes such as pyrazine (2h), a chloropyrimidine (2i), and a 4,6-bis(aryl)-1,3,5- triazine (2j), as well as π-excessive azaarenes such as benzothiazole (2l), a 1,3,4-oxadiazole (2m), and a tetrazole (2o). A pyrazine-containing substrate was only moderately reactive, providing product 2h in 48% yield, though in 99% ee. Although alkenyltetrazole 1l was unreactive (none of 2n was obtained), its regioisomer 1m provided 2o in 64% yield and 95% ee. The difference in reactivities between 1l and 1m can be understood by consideration of their conjugation patterns. Whereas the alkene is conjugated only with the C=N group of the tetrazole in 1l, it is conjugated with both the C=N and N=N    Fig. 1    Difference in conjugation between alkenyltetrazoles 1l and 1m. Table 4     Arylation of alkenylazaarenes with various arylboronic acids ChemComm Communication This journal is © The Royal Society of Chemistry 2014 Chem. Commun., 2014, 00, 1-3 | 3  Entry Product  Yield (%)b ee (%)c 1 2 3  2p  Ar = Ph 2q  Ar = 2-MeC6H4 2r  Ar = 4-FC6H4 89 >95 78 99 97 99 4 5  2s Ar = 4-MeOC6H4 2t  Ar = 3-EtO2C6H4 82 62 98 93d 6 7  2u  Ar = 3,5-(F3C)2C6H3 2v  Ar = 4-O2NC6H4 92 85 96e  94 8 9  2w  Ar = 2-naphthyl  2x  Ar = 3,5-Me2C6H3 62 85 98 99 10  2y  Ar = 3-Cl-4-i-PrOC6H3 63 99 a Reactions were conducted using 0.30 mmol of alkenylazaarene (0.2 M). b Isolated yield. c Determined by chiral HPLC analysis. d Enantiomeric excess determined on a derivative obtained after treatment of 2t with LiOH in THF/MeOH/H2O. e Enantiomeric excess determined after demethylation of the methoxy groups using BBr3.  moieties in 1m, leading to a greater degree of activation (Fig. 1). With respect to the β-substituent on the alkene, the process is tolerant of simple alkyl groups (2i and 2j), a cyclopropane (2h), an ether (2g), and aryl groups (2k, 2l, 2m, and 2o). A range of arylboronic acids are compatible with this process, as demonstrated by the results presented in Table 4. Arylboronic acids containing substituents such as methyl (entries 2 and 9), halogen (entries 3 and 10), or alkoxy (entries 4 and 10) groups reacted smoothly with various alkenylazaarenes in good yields and high enantioselectivities. Arylboronic acids containing strong electron-withdrawing groups such as ester, trifluoromethyl, or even nitro substituents were also effective (entries 5–7). A sterically encumbering ortho-substituent on the arylboronic acid was also tolerated (entry 2).   This process can also be conducted on a larger scale using lower loadings of the arylboronic acid and catalyst. For example, arylation of alkenylpyrimidine 1h on a 5.0 mmol scale with 4-methoxyphenylboronic acid (1.5 equiv), using thermal heating at 70    °C in the presence of 2.0 mol% of the rhodium‒chiral diene complex, provided 2s in 75% yield (1.27 g) and 96% ee (eq 1).  In summary, a more in-depth evaluation of chiral diene ligands for the enantioselective addition of arylboronic acids to alkenylazaarenes has resulted in the identification of a second-generation ligand L9 containing a 2,4,6-triisopropylanilide moiety that is superior to our first generation ligand L1. Not only does this new chiral diene result in generally superior enantioselectivities, it is simpler in structure. A more thorough assessment of the scope of the process demonstrated that the effectiveness of ligand L9 is fairly general across a range alkenylazaarenes and arylboronic acids. Further experimental and theoretical14 investigations of anilide-containing chiral dienes in asymmetric catalysis are planned, and will be reported in due course.  This work was supported by the EPSRC, Pfizer, and the University of Edinburgh. The EPSRC is gratefully acknowledged for the award of a Leadership Fellowship to H.W.L. We thank Dr. Gary S. Nichol and Stewart Franklin at the University of Edinburgh for X-ray crystallography and technical assistance, respectively. We thank the EPSRC National Mass Spectrometry Facility for providing high-resolution mass spectra.    Notes and references  1  (a) L. Rupnicki, A. Saxena and H. W. Lam, J. Am. Chem. Soc., 2009, 131, 10386-10387. (b) G. Pattison, G. Piraux and H. W. Lam, J. Am. Chem. Soc., 2010, 132, 14373-14375. (c) A. Saxena, B. Choi and H. W. Lam, J. Am. Chem. Soc., 2012, 134, 8428-8431. (d) C. Fallan and H. W. Lam, Chem. Eur. J., 2012, 18, 11214-11218. (e) D. Best, S. Kujawa and H. W. Lam, J. Am. Chem. Soc., 2012, 134, 18193-18196. (f) A. J. Simpson and H. W. Lam, Org. Lett., 2013, 15, 2586-2589. 2  D. Best and H. W. Lam, J. Org. Chem., 2014, 79, ASAP, DOI: 10.1021/jo402414k. 3  For Ni-catalyzed additions of organometallics to 4-alkenylpyridines with low enantioselectivities (≤15% ee), see: I. N. Houpis, J. Lee, I. Dorziotis, A. Molina, B. Reamer, R. P. Volante and P. J. Reider, Tetrahedron, 1998, 54, 1185-1195. 4  For catalytic asymmetric Michael additions of nitroalkanes and anthrone to 4-nitro-5-styrylisxoxazoles, see: (a) A. Baschieri, L. Bernardi, A. Ricci, S. Suresh and M. F. A. Adamo, Angew. Chem., Int. Ed., 2009, 48, 9342-9345. (b) H.-W. Sun, Y.-H. Liao, Z.-J. Wu, H.-Y. Wang, X.-M. Zhang and W.-C. Yuan, Tetrahedron, 2011, 67, 3991-3996. ChemComm Communication This journal is © The Royal Society of Chemistry 2014 Chem. Commun., 2014, 00, 1-3 | 4  5  A seminal reference: M. Sakai, H. Hayashi and N. Miyaura, Organometallics, 1997, 16, 4229-4231. 6  The first enantioselective example: Y. Takaya, M. Ogasawara, T. Hayashi, M. Sakai and N. Miyaura, J. Am. Chem. Soc., 1998, 120, 5579-5580. 7  For reviews, see: (a) T. Hayashi and K. Yamasaki, Chem. Rev., 2003, 103, 2829-2844. (b) Yoshida, K.; Hayashi, T. In Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005; Chapter 3, p 55–77. (c) H. J. Edwards, J. D. Hargrave, S. D. Penrose and C. G. Frost, Chem. Soc. Rev., 2010, 39, 2093-2105. (d) P. Tian, H.-Q. Dong and G.-Q. Lin, ACS Catalysis, 2011, 2, 95-119. 8  For a review of Rh-catalyzed carbon–carbon bond-forming reactions of organometallic compounds, see: K. Fagnou and M. Lautens, Chem. Rev., 2003, 103, 169-196. 9  For seminal references describing chiral dienes in asymmetric catalysis, see: (a) T. Hayashi, K. Ueyama, N. Tokunaga and K. Yoshida, J. Am. Chem. Soc., 2003, 125, 11508-11509. (b) C. Fischer, C. Defieber, T. Suzuki and E. M. Carreira, J. Am. Chem. Soc., 2004, 126, 1628-1629.  10 For reviews of chiral diene ligands, see: (a) R. Shintani and T. Hayashi, Aldrichimica Acta, 2009, 42, 31-38. (b) J. B. Johnson and T. Rovis, Angew. Chem., Int. Ed., 2008, 47, 840-871. (c) C. Defieber, H. Grutzmacher and E. M. Carreira, Angew. Chem., Int. Ed., 2008, 47, 4482-4502. 11  For selected, recent examples of chiral dienes in catalytic asymmetric 1,4- and 1,6-addition reactions, see: (a) C. Shao, H.-J. Yu, N.-Y. Wu, P. Tian, R. Wang, C.-G. Feng and G.-Q. Lin, Org. Lett., 2011, 13, 788-791. (b) K. Sasaki and T. Hayashi, Tetrahedron: Asymmetry, 2012, 23, 373-380. (c) T. Nishimura, A. Noishiki and T. Hayashi, Chem. Commun., 2012, 48, 973-975. (d) Y.-C. Chung, D. Janmanchi and H.-L. Wu, Org. Lett., 2012, 14, 2766-2769. (e) K. Sasaki, T. Nishimura, R. Shintani, E. A. B. Kantchev and T. Hayashi, Chem. Sci., 2012, 3, 1278-1283. (f) T. Nishimura, Y. Takiguchi and T. Hayashi, J. Am. Chem. Soc., 2012, 134, 9086-9089. (g) Z.-T. He, Y.-B. Wei, H.-J. Yu, C.-Y. Sun, C.-G. Feng, P. Tian and G.-Q. Lin, Tetrahedron, 2012, 68, 9186-9191. (h) H.-J. Yu, C. Shao, Z. Cui, C.-G. Feng and G.-Q. Lin, Chem. Eur. J., 2012, 18, 13274-13278. (i) J. Keilitz, S. G. Newman and M. Lautens, Org. Lett., 2013, 15, 1148-1151. (j) M. M. Hansmann, A. S. K. Hashmi and M. Lautens, Org. Lett., 2013, 15, 3226-3229. (k) A. A. Friedman, J. Panteleev, J. Tsoung, V. Huynh and M. Lautens, Angew. Chem., Int. Ed., 2013, 52, 9755-9758. 12  For Rh-catalyzed additions of arylboronic acids to vinylazaarenes resulting in achiral products, see: (a) M. Lautens, A. Roy, K. Fukuoka, K. Fagnou and B. Martín-Matute, J. Am. Chem. Soc., 2001, 123, 5358-5359. (b) R. Amengual, V. Michelet and J.-P. Genêt, Tetrahedron Lett., 2002, 43, 5905-5908. 13 For application of a simpler amide-containing chiral diene L5 in enantioselective rhodium-catalyzed arylations of electron-deficient alkenylarenes, including a 5-nitro-2-alkenylpyridine, see: A. Saxena and H. W. Lam, Chem. Sci., 2011, 2, 2326-2331.  14  For computational studies of chiral diene ligands, see ref. 11e and: (a) E. A. B. Kantchev, Chem. Commun., 2011, 10969-10971. (b) S.  Gosiewska, J. A. Raskatov, R. Shintani, T. Hayashi and J. M. Brown, Chem. Eur. J., 2012, 18, 80-84. (c) Y. Luo, N. G. Berry and A. J. Carnell, Chem. Commun., 2012, 48, 3279-3281. (d) E. A. B. Kantchev, Chem. Sci., 2013, 4, 1864-1875. 

A second-generation ligand for the enantioselective

rhodium-catalyzed addition of arylboronic acids to

alkenylazaarenes

Repository@Nottingham

ChemComm RSCPublishing COMMUNICATION This journal is © The Royal Society of Chemistry 2014 Chem. Commun., 2014, 00, 1-3 | 1 Cite this: DOI: 10.1039/x0xx00000x Received 00th January 2012, Accepted 00th January 2012 DOI: 10.1039/x0xx00000x www.rsc.org/chemcomm A second-generation ligand for the enantioselective rhodium-catalyzed addition of arylboronic acids to alkenylazaarenes Iain D. Roy,a Alan R. Burns,ab Graham Pattison,a Boris Michel,a Alexandra J. Parkerc and Hon Wai Lam*ab    A 2,4,6-trialkylanilide-containing chiral diene has been identified as a superior ligand for the enantioselective rhodium-catalyzed arylation of alkenylazaarenes with arylboronic acids.   As part of a program aimed at the preparation of enantioenriched chiral azaarene-containing compounds,1 we have focused upon an underexploited strategy in asymmetric synthesis, namely the utilization of the C=N moiety within certain azaarenes to activate adjacent functionality in enantioselective catalysis.2–4 In this context, we have reported1b the enantioselective rhodium-catalyzed 1,4-arylation5–8 of β-substituted alkenylazaarenes with arylboronic acids using a secondary amide-containing chiral diene9–11 ligand L1 (see Table 1, entry 1), which builds upon early studies by the groups of Lautens12a and Genet12b using vinylazaarenes. Although L1 was highly effective, it was of interest to determine whether a ligand of this complexity, possessing stereochemical elements additional to those of the chiral diene component, was actually necessary for optimal results.13 Herein, we report a simpler ligand that provides results superior to those obtained using L1, along with a more comprehensive evaluation of the scope of the reaction.  First, various analogues of L1 were prepared and evaluated in the enantioselective addition of 4-methylphenylboronic acid to 2-alkenylquinoline 1a (Table 1), a reaction that gave 2a in 67% yield  Table 1     Ligand evaluation for arylation of 1aa   Entry Ligand X Conversion (%) ee (%) 1b L1  67% yield 92 2 L2 NHCy >95 90 3 L3 NCy2 28 59 4 L4 NHBn >95 88 5 L5 NBn2 81 85 6 L6 NMe2 91 46 7 L7 NHPh 58 76 8 L8 NH(2,4,6-Me3C6H2) 33 96 9 L9 NH[2,4,6-(i-Pr)3C6H2] >95 99 a Reactions were conducted using 0.10 mmol of 1a (0.2 M). Conversions were determined by 1H NMR analysis of the unpurified reaction mixtures. Enantiomeric excesses were determined by chiral HPLC analysis. b Ref. 1b.  and 92% ee in our original study.1b The conditions employed were identical to those we described previously.1b Ligand L2, which lacks the pyrrole moiety on the cyclohexane, provided 2a in high conversion but the enantioselectivity was slightly lower (entry 2) compared with that obtained using L1 (entry 1). However, the dicyclohexylamide L3 was noticeably inferior (entry 3). Ligands L4 and L5, which contain one or two benzyl groups, respectively, provided reasonable results (entries 4 and 5), but the enantioselectivities were lower compared with L1. The dimethylamide L6 gave high conversion but the reaction was poorly  Table 2     Comparison of ligand L9 with L1a  a EaStCHEM, School of Chemistry, University of Edinburgh, Joseph Black Building, The King’s Buildings, West Mains Road, Edinburgh, EH9 3JJ, United Kingdom.  b School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, United Kingdom. Email: hon.lam@nottingham.ac.uk; Tel: +44-115-748-4677. c AstraZeneca Process Research and Development, Charter Way, Silk Road Business Park, Macclesfield, Cheshire, SK10 2NA, United Kingdom. † Electronic Supplementary Information (ESI) available: Experimental procedures, spectroscopic data for new compounds, and crystallographic data. CCDC 976345-976346. For ESI and crystallographic data in CIF See DOI: 10.1039/b000000x/  ChemComm Communication This journal is © The Royal Society of Chemistry 2014 Chem. Commun., 2014, 00, 1-3 | 2   a Reactions were conducted using 0.50 mmol of alkenylazaarene (0.2 M). Yields are of isolated material. Enantiomeric excesses were determined by chiral HPLC analysis. b Results taken from ref.1b c Reaction conducted using 0.30 mmol of alkenylazaarene.  enantioselective (46% ee, entry 6). Next, ligands L7–L9 containing anilide groups were studied (entries 7–9), and of these, the 2,4,6-triisopropylanilide L9 provided the best results, giving 2a in >95% conversion and 99% ee (entry 9).  Further confirmation of the superior enantioselectivities imparted by this new triisopropylanilide ligand L9 was provided by repeating representative reactions described in our original study1b using L9 in place of L1 (Table 2). These results indicate that while in most cases the isolated yields of the products with both ligands are comparable, the enantioselectivities are higher using L9 (2a, 2b, 2c, 2e, and 2f). One exception was the addition of 4-methylphenylboronic acid to a substrate containing a 4,5-diphenyloxazole as the activating group, which gave 2d in 77% ee using L9, and this result is inferior to that obtained using ligand L1 (89% ee). Interestingly, the inferiority of L9 compared with L1 with this substrate appeared to be restricted to the use of 4-methylphenylboronic acid; when 3-methylphenylboronic acid was employed, L9 provided the product 2e in a higher enantioselectivity. The reasons for these contrasting results are not currently known.  To explore the scope of the process with the second generation ligand L9 more comprehensively, a range of previously reported and new alkenylazaarenes were reacted with 4-methylphenylboronic acid (Table 3). While substrates containing pyrimidine or benzoxazole, azaarenes that have already been demonstrated to be efficient activating groups in our original study,1b underwent arylation  Table 3     Arylation of alkenylazaarenes with 4-methylphenylboronic acid   a Reactions were conducted using 0.30 mmol of alkenylazaarene (0.2 M). Yields are of isolated material. Enantiomeric excesses were determined by chiral HPLC analysis. b Enantiomeric excess determined after hydrolysis to the secondary amide. c The stereochemistry of 2m was determined by X-ray crystallography, CCDC 976346. d The structure of the alkenylazaarene substrate 1m was determined by X-ray crystallography, CCDC 976345.  efficiently with excellent enantioselectivities as expected (2g and 2k), further examples demonstrate that other azaarenes are also effective. These examples include π-deficient azaarenes such as pyrazine (2h), a chloropyrimidine (2i), and a 4,6-bis(aryl)-1,3,5- triazine (2j), as well as π-excessive azaarenes such as benzothiazole (2l), a 1,3,4-oxadiazole (2m), and a tetrazole (2o). A pyrazine-containing substrate was only moderately reactive, providing product 2h in 48% yield, though in 99% ee. Although alkenyltetrazole 1l was unreactive (none of 2n was obtained), its regioisomer 1m provided 2o in 64% yield and 95% ee. The difference in reactivities between 1l and 1m can be understood by consideration of their conjugation patterns. Whereas the alkene is conjugated only with the C=N group of the tetrazole in 1l, it is conjugated with both the C=N and N=N    Fig. 1    Difference in conjugation between alkenyltetrazoles 1l and 1m. Table 4     Arylation of alkenylazaarenes with various arylboronic acids ChemComm Communication This journal is © The Royal Society of Chemistry 2014 Chem. Commun., 2014, 00, 1-3 | 3  Entry Product  Yield (%)b ee (%)c 1 2 3  2p  Ar = Ph 2q  Ar = 2-MeC6H4 2r  Ar = 4-FC6H4 89 >95 78 99 97 99 4 5  2s Ar = 4-MeOC6H4 2t  Ar = 3-EtO2C6H4 82 62 98 93d 6 7  2u  Ar = 3,5-(F3C)2C6H3 2v  Ar = 4-O2NC6H4 92 85 96e  94 8 9  2w  Ar = 2-naphthyl  2x  Ar = 3,5-Me2C6H3 62 85 98 99 10  2y  Ar = 3-Cl-4-i-PrOC6H3 63 99 a Reactions were conducted using 0.30 mmol of alkenylazaarene (0.2 M). b Isolated yield. c Determined by chiral HPLC analysis. d Enantiomeric excess determined on a derivative obtained after treatment of 2t with LiOH in THF/MeOH/H2O. e Enantiomeric excess determined after demethylation of the methoxy groups using BBr3.  moieties in 1m, leading to a greater degree of activation (Fig. 1). With respect to the β-substituent on the alkene, the process is tolerant of simple alkyl groups (2i and 2j), a cyclopropane (2h), an ether (2g), and aryl groups (2k, 2l, 2m, and 2o). A range of arylboronic acids are compatible with this process, as demonstrated by the results presented in Table 4. Arylboronic acids containing substituents such as methyl (entries 2 and 9), halogen (entries 3 and 10), or alkoxy (entries 4 and 10) groups reacted smoothly with various alkenylazaarenes in good yields and high enantioselectivities. Arylboronic acids containing strong electron-withdrawing groups such as ester, trifluoromethyl, or even nitro substituents were also effective (entries 5–7). A sterically encumbering ortho-substituent on the arylboronic acid was also tolerated (entry 2).   This process can also be conducted on a larger scale using lower loadings of the arylboronic acid and catalyst. For example, arylation of alkenylpyrimidine 1h on a 5.0 mmol scale with 4-methoxyphenylboronic acid (1.5 equiv), using thermal heating at 70    °C in the presence of 2.0 mol% of the rhodium‒chiral diene complex, provided 2s in 75% yield (1.27 g) and 96% ee (eq 1).  In summary, a more in-depth evaluation of chiral diene ligands for the enantioselective addition of arylboronic acids to alkenylazaarenes has resulted in the identification of a second-generation ligand L9 containing a 2,4,6-triisopropylanilide moiety that is superior to our first generation ligand L1. Not only does this new chiral diene result in generally superior enantioselectivities, it is simpler in structure. A more thorough assessment of the scope of the process demonstrated that the effectiveness of ligand L9 is fairly general across a range alkenylazaarenes and arylboronic acids. Further experimental and theoretical14 investigations of anilide-containing chiral dienes in asymmetric catalysis are planned, and will be reported in due course.  This work was supported by the EPSRC, Pfizer, and the University of Edinburgh. The EPSRC is gratefully acknowledged for the award of a Leadership Fellowship to H.W.L. We thank Dr. Gary S. Nichol and Stewart Franklin at the University of Edinburgh for X-ray crystallography and technical assistance, respectively. We thank the EPSRC National Mass Spectrometry Facility for providing high-resolution mass spectra.    Notes and references  1  (a) L. Rupnicki, A. Saxena and H. W. Lam, J. Am. Chem. Soc., 2009, 131, 10386-10387. (b) G. Pattison, G. Piraux and H. W. Lam, J. Am. Chem. Soc., 2010, 132, 14373-14375. (c) A. Saxena, B. Choi and H. W. Lam, J. Am. Chem. Soc., 2012, 134, 8428-8431. (d) C. Fallan and H. W. Lam, Chem. Eur. J., 2012, 18, 11214-11218. (e) D. Best, S. Kujawa and H. W. Lam, J. Am. Chem. Soc., 2012, 134, 18193-18196. (f) A. J. Simpson and H. W. Lam, Org. Lett., 2013, 15, 2586-2589. 2  D. Best and H. W. Lam, J. Org. Chem., 2014, 79, ASAP, DOI: 10.1021/jo402414k. 3  For Ni-catalyzed additions of organometallics to 4-alkenylpyridines with low enantioselectivities (≤15% ee), see: I. N. Houpis, J. Lee, I. Dorziotis, A. Molina, B. Reamer, R. P. Volante and P. J. Reider, Tetrahedron, 1998, 54, 1185-1195. 4  For catalytic asymmetric Michael additions of nitroalkanes and anthrone to 4-nitro-5-styrylisxoxazoles, see: (a) A. Baschieri, L. Bernardi, A. Ricci, S. Suresh and M. F. A. Adamo, Angew. Chem., Int. Ed., 2009, 48, 9342-9345. (b) H.-W. Sun, Y.-H. Liao, Z.-J. Wu, H.-Y. Wang, X.-M. Zhang and W.-C. Yuan, Tetrahedron, 2011, 67, 3991-3996. ChemComm Communication This journal is © The Royal Society of Chemistry 2014 Chem. Commun., 2014, 00, 1-3 | 4  5  A seminal reference: M. Sakai, H. Hayashi and N. Miyaura, Organometallics, 1997, 16, 4229-4231. 6  The first enantioselective example: Y. Takaya, M. Ogasawara, T. Hayashi, M. Sakai and N. Miyaura, J. Am. Chem. Soc., 1998, 120, 5579-5580. 7  For reviews, see: (a) T. Hayashi and K. Yamasaki, Chem. Rev., 2003, 103, 2829-2844. (b) Yoshida, K.; Hayashi, T. In Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005; Chapter 3, p 55–77. (c) H. J. Edwards, J. D. Hargrave, S. D. Penrose and C. G. Frost, Chem. Soc. Rev., 2010, 39, 2093-2105. (d) P. Tian, H.-Q. Dong and G.-Q. Lin, ACS Catalysis, 2011, 2, 95-119. 8  For a review of Rh-catalyzed carbon–carbon bond-forming reactions of organometallic compounds, see: K. Fagnou and M. Lautens, Chem. Rev., 2003, 103, 169-196. 9  For seminal references describing chiral dienes in asymmetric catalysis, see: (a) T. Hayashi, K. Ueyama, N. Tokunaga and K. Yoshida, J. Am. Chem. Soc., 2003, 125, 11508-11509. (b) C. Fischer, C. Defieber, T. Suzuki and E. M. Carreira, J. Am. Chem. Soc., 2004, 126, 1628-1629.  10 For reviews of chiral diene ligands, see: (a) R. Shintani and T. Hayashi, Aldrichimica Acta, 2009, 42, 31-38. (b) J. B. Johnson and T. Rovis, Angew. Chem., Int. Ed., 2008, 47, 840-871. (c) C. Defieber, H. Grutzmacher and E. M. Carreira, Angew. Chem., Int. Ed., 2008, 47, 4482-4502. 11  For selected, recent examples of chiral dienes in catalytic asymmetric 1,4- and 1,6-addition reactions, see: (a) C. Shao, H.-J. Yu, N.-Y. Wu, P. Tian, R. Wang, C.-G. Feng and G.-Q. Lin, Org. Lett., 2011, 13, 788-791. (b) K. Sasaki and T. Hayashi, Tetrahedron: Asymmetry, 2012, 23, 373-380. (c) T. Nishimura, A. Noishiki and T. Hayashi, Chem. Commun., 2012, 48, 973-975. (d) Y.-C. Chung, D. Janmanchi and H.-L. Wu, Org. Lett., 2012, 14, 2766-2769. (e) K. Sasaki, T. Nishimura, R. Shintani, E. A. B. Kantchev and T. Hayashi, Chem. Sci., 2012, 3, 1278-1283. (f) T. Nishimura, Y. Takiguchi and T. Hayashi, J. Am. Chem. Soc., 2012, 134, 9086-9089. (g) Z.-T. He, Y.-B. Wei, H.-J. Yu, C.-Y. Sun, C.-G. Feng, P. Tian and G.-Q. Lin, Tetrahedron, 2012, 68, 9186-9191. (h) H.-J. Yu, C. Shao, Z. Cui, C.-G. Feng and G.-Q. Lin, Chem. Eur. J., 2012, 18, 13274-13278. (i) J. Keilitz, S. G. Newman and M. Lautens, Org. Lett., 2013, 15, 1148-1151. (j) M. M. Hansmann, A. S. K. Hashmi and M. Lautens, Org. Lett., 2013, 15, 3226-3229. (k) A. A. Friedman, J. Panteleev, J. Tsoung, V. Huynh and M. Lautens, Angew. Chem., Int. Ed., 2013, 52, 9755-9758. 12  For Rh-catalyzed additions of arylboronic acids to vinylazaarenes resulting in achiral products, see: (a) M. Lautens, A. Roy, K. Fukuoka, K. Fagnou and B. Martín-Matute, J. Am. Chem. Soc., 2001, 123, 5358-5359. (b) R. Amengual, V. Michelet and J.-P. Genêt, Tetrahedron Lett., 2002, 43, 5905-5908. 13 For application of a simpler amide-containing chiral diene L5 in enantioselective rhodium-catalyzed arylations of electron-deficient alkenylarenes, including a 5-nitro-2-alkenylpyridine, see: A. Saxena and H. W. Lam, Chem. Sci., 2011, 2, 2326-2331.  14  For computational studies of chiral diene ligands, see ref. 11e and: (a) E. A. B. Kantchev, Chem. Commun., 2011, 10969-10971. (b) S.  Gosiewska, J. A. Raskatov, R. Shintani, T. Hayashi and J. M. Brown, Chem. Eur. J., 2012, 18, 80-84. (c) Y. Luo, N. G. Berry and A. J. Carnell, Chem. Commun., 2012, 48, 3279-3281. (d) E. A. B. Kantchev, Chem. Sci., 2013, 4, 1864-1875. 

1. ENANTIOSELECTIVE RHODIUM-CATALYSED 1,4-ARYLATION OF
ALKENYLAZAARENES
An extended study on the enantioselective rhodium-catalysed 1,4-arylation of
alkenylazaarenes has been conducted. The 1,4-arylation of various alkenylazaarenes
was performed with an extended range of arylboronic acids using a modified catalytic
system with a superior chiral diene ligand. The result is the generation of a large number
of b-stereocentre-containing azaarene compounds in high enantiopurity. Further studies
also enabled the completion of a reactivity index between alkenylazaarenes and more
traditional α,β-unsaturated carbonyl compounds and the incorporation of the arylation
into arylation-aldol domino processes. 

2. ENANTIOSELECTIVE RHODIUM-CATALYSED 1,4-ALKENYLATION OF
ALKENYLAZAARENES
An extensive study on the enantioselective rhodium-catalysed 1,4-alkenylation of
alkenylazaarenes has been performed. Development of the reaction parameters identified
novel heterogeneous reaction conditions in pure water with sub-stoichiometric SDS.
Subsequent ligand development identified an anilide-based chiral diene that provided the
best balance between conversion and enantiopurity. Using the novel conditions, a
selection of alkenylazaarenes underwent enantioselective rhodium-catalysed
1,4-alkenylation with two alkenyl MIDA boronates to provide the alkenylation products
in good to excellent yields and moderate to excellent enantioselectivities. 

3. ENANTIOSELECTIVE COPPER-CATALYSED 1,6-BORATION OF
ELECTRON-DEFICIENT DIENES
The development of an enantioselective copper-catalysed 1,6-boration of electrondeficient
dienes using B2(pin)2 has been achieved. The reactions provide chiral
allylboronic esters that, after oxidation, result in secondary allylic alcohols in moderate
to high yields with excellent enantioselectivities and 1,6:1,4-regioselectivities. The
1,6-borations proceed efficiently employing catalyst loadings as low as 0.0049 mol%
and their scalability has been demonstrated up to 40.4 mmol. The methodology was
applied to a concise synthesis of atorvastatin, in which the key 1,6-boration was
performed using a catalyst loading of 0.02 mol%

Roy, Iain David

Edinburgh Research Archive

Development of novel enantioselective transition metal-catalysed 1,4- and 1,6-additions

Angewandte Chemie

https://nottingham-repository.worktribe.com/725135/1/HWL Yunfei Iain Amael 16-Boration ACIE Submission (accepted).pdf

Enantioselective synthesis of allylboronates and allylic alcohols by copper-catalyzed 1,6-boration

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