A novel chiral magnesium bisamide has enabled the development of effective asymmetric deprotonation protocols at substantially more elevated temperatures. This new, structurally simple, C2-symmetric magnesium complex displays excellent levels of asymmetric efficiency and energy reduction in the synthesis of enantioenriched enol silane

Aggarwal

Alexakis

Allan

Allan J. B. Watson

Anderson

Aoki

Bassindale

Blümke

Brownbridge

Bunn

Busch-Petersen

Carswell

Clegg

Conway

Corey

Cousins

Eaton

Graf

Gronnow

Hama

Henderson

Hodgson

Kerr

Knochel

Leitner

Linsey S. Bennie

Melzig

Michael Middleditch

Mulvey

Navarro

Netherton

Sato

Shirai

Simpkins

Westerhausen

William J. Kerr

Wunderlich

Çalimsiz

English

Bennie, Linsey Sarah

Kerr, William

Middleditch, Michael

Watson, Allan

University of St. Andrews - Pure

Towards energetically viable asymmetric deprotonations

University of Strathclyde Institutional Repository

Strathprints Institutional RepositoryBennie, Linsey Sarah and Kerr, William and Middleditch, Michael and Watson, Allan (2011) Towardsenergetically viable asymmetric deprotonations : selectivity at more elevated temperatures with C2-symmetric magnesium bisamides. Chemical Communications (London), 47 (8). pp. 2264-2266.ISSN 0009-241XStrathprints is designed to allow users to access the research output of the University of Strathclyde.Copyright c© and Moral Rights for the papers on this site are retained by the individual authorsand/or other copyright owners. You may not engage in further distribution of the material for anyprofitmaking activities or any commercial gain. You may freely distribute both the url (http://strathprints.strath.ac.uk/) and the content of this paper for research or study, educational, ornot-for-profit purposes without prior permission or charge.Any correspondence concerning this service should be sent to Strathprints administrator:mailto:strathprints@strath.ac.ukhttp://strathprints.strath.ac.uk/2264 Chem. Commun., 2011, 47, 2264–2266 This journal is c The Royal Society of Chemistry 2011Cite this: Chem. Commun., 2011, 47, 2264–2266Towards energetically viable asymmetric deprotonations: selectivity atmore elevated temperatures with C2-symmetric magnesium bisamideswLinsey S. Bennie, William J. Kerr,* Michael Middleditch and Allan J. B. WatsonReceived 12th November 2010, Accepted 22nd December 2010DOI: 10.1039/c0cc04939eA novel chiral magnesium bisamide has enabled the developmentof eﬀective asymmetric deprotonation protocols at substantiallymore elevated temperatures. This new, structurally simple,C2-symmetric magnesium complex displays excellent levels ofasymmetric eﬃciency and energy reduction in the synthesis ofenantioenriched enol silanes.The ability to perform intricate chemical manipulations isessential for the continued production of the myriad organiccompounds that our society consumes. By their very nature,many of these transformations must be carried out at energyintensive temperatures. However, the energy expenditure ofchemical processes is becoming a continually more importantconsideration,1 and with escalating environmental, ﬁnancial,and political pressures, the demand for energetic eﬃciencywithin the chemical industry is only likely to increase. Theﬁnancial impact of energy input is perhaps felt most dramaticallywhen performing reactions on larger scale.2 Figures usedwithin Chemical Development at GlaxoSmithKline suggestthat performing reactions at temperatures of lower than 40 1Cincurs an additional energetic cost of at least d250 000per annum per batch tonne process.3 Moreover, this is supplementary to the initial and appreciable expense of installingthe necessary low temperature process scale equipment.Consequently, the task of alleviating the energetic burden ofthe chemical industry, through the continued development ofmore eﬀective synthetic protocols that generate a smallerenergy footprint than preceding technologies, is of globalrelevance. In this regard, contributions by several researchgroups have already illustrated the potential for consideredexperimental design in this area of enhanced sustainability.2,4,5For example, the metallation processes pioneered by Knochelenable a more convenient and widely applicable preparation ofnucleophilic organometallic species,4 while several groupshave also focused on the development of catalyst systems thatfacilitate eﬀective cross-coupling processes at more moderatetemperatures.5 As part of a wider programme targeting theproduction of eﬀective methods for use in organic synthesis, aspeciﬁc objective has been the design of more eﬃcient and,indeed, energetically viable asymmetric deprotonation processes.Asymmetric deprotonation reactions6 are useful methodsfor the preparation of enantioenriched chiral enolates and enolsilanes, which are valuable precursors for a host of powerfuldiastereoselective transformations.7 Chiral lithium amideshave been developed extensively in this area and severalsystems provide very good levels of enantioinduction at lowreaction temperatures.6,8 In this regard, it should be notedthat, while enantioselective deprotonation processes are typi-cally conducted at 78 1C, several groups have demonstratedthe ability of chiral lithium amides to aﬀord high levels ofselectivity at more elevated temperatures in the area of epoxiderearrangement.9 In addition to all of this, work within ourlaboratory has revealed that chiral magnesium amides are alsoparticularly eﬀective within the domain of asymmetric enoli-sation and, more signiﬁcantly, were found to exhibit greaterasymmetric eﬃciency than the equivalent lithium amides.10In relation to the developing applications noted above,magnesium amides are known to possess greater thermalstability11 and exhibit less complex solution aggregation thananalogous lithium amides in THF (Fig. 1).12 As such, werecently began examining the potential for exploitation ofthese unique attributes to enable eﬀective asymmetric inductionat substantially more elevated temperatures. Herein, weFig. 1 Towards energy-eﬀective asymmetric deprotonations: lithiumvs. magnesium amides.Department of Pure and Applied Chemistry, WestCHEM,295 Cathedral Street, Glasgow, G1 1XL, Scotland, UK.E-mail: w.kerr@strath.ac.uk; Fax: +44 (0)141 548 4822;Tel: +44 (0)141 548 2959w Electronic supplementary information (ESI) available: Experimentalprocedures and analytical data for products. See DOI: 10.1039/c0cc04939eChemComm Dynamic Article Linkswww.rsc.org/chemcomm COMMUNICATIONThis journal is c The Royal Society of Chemistry 2011 Chem. Commun., 2011, 47, 2264–2266 2265describe an approach towards the development of both moregenerally eﬃcient and, in addition, energy eﬀective asymmetricdeprotonations through the deployment of simple and readilyaccessible C2-symmetric chiral magnesium bisamides.Over recent years, we have probed the structure of magne-sium bisamides in eﬀorts to understand the key aspects thatengender these complexes with comparatively enhanced levelsof asymmetric eﬃciency (for example, complexes (R)-3–7,Scheme 1).10 While good levels of selectivity could be achievedin this benchmark asymmetric deprotonation process, basedon some precedent within our laboratory,10f we envisaged thatappropriate modiﬁcation of the parent amine would lead to ahighly utilisable process at less energy intensive temperatures,i.e. above 78 1C. From the outset, we considered two keyitems as essential for an energy-eﬀective chiral base system: (i)the requisite parent amine must be simple in structure and, inturn, either readily prepared or, preferably, commerciallyavailable; and (ii) the system must operate at more readilyused temperatures of 40 1C or above.Based on all of this, we next moved to evaluate the perfor-mance of the readily accessible C2-symmetric magnesium amide(R,R)-8 (Scheme 1). Pleasingly, this complex displayed greatlyimproved enantioselectivity in the benchmark asymmetricdeprotonation reaction, providing levels of enantioinductiongreater than the corresponding lithium amide, including thetypically more selective LiCl-based ate complex.13 Furthermore,the parent amine is structurally simple and is either readilyprepared via the method of Alexakis et al.14 or can be purchasedcommercially.Based on these initial screening results, base complex (R,R)-8was selected for further investigation. We next sought toascertain the temperature dependence of our developingC2-symmetric base system, in accordance with our designcriteria. As such, we evaluated the performance of complex(R,R)-8 at more elevated temperatures ranging from 60 1Cto 0 1C (Table 1). Remarkably, this C2-symmetric amidemaintained very good levels of enantioinduction over an almost80 1C temperature range (entries 1–5). In fact, base (R,R)-8demonstrates the same level of enantioselectivity at 0 1C as theanalogous lithium complex achieves at 78 1C (entry 5).z It isalso worth noting that this new reagent system is capable ofdelivering appreciable levels of enantioselection at room tem-perature (23 1C; entry 6).Encouraged by the degree of temperature tolerance ofcomplex (R,R)-8, we proceeded to further optimise the quan-tities of additive and silyl agent loading. Consequently, wefound that only one equivalent of both DMPU and Me3-SiCl17,18 provided a chiral base system that could now deliverexcellent asymmetric eﬃciency at 78 1C for a range ofsubstrates (Table 2, entries 1–5). Indeed, the levels of selecti-vity displayed here are amongst the highest levels obtained insuch deprotonation reactions. More signiﬁcantly, these experi-mental conditions have now also been shown to instil unpre-cedented levels of enantioinduction at 20 1C (entries 6–10).zThese results are especially notable when considering theoverall simplicity of the parent amine from which this reagentis derived. Additionally, yields of products were consistentregardless of the reaction temperature.The unprecedented selectivity exhibited by this simple mag-nesium base system can perhaps be explained through thethermal stability and solution aggregation of magnesiumamides in general. Magnesium amides typically exist inScheme 1 Evaluation of simple Mg amides in the asymmetric deproto-nation of 4-tert-butylcyclohexanone (1a). (Enantiomeric ratio given as(S :R), DMPU= 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone).Table 1 Performance of base (R,R)-8 over a range of temperatures inthe asymmetric deprotonation of 4-tert-butylcyclohexanone (1a)Entry Ta (1C) Conv.b (%) e.r.b (S :R)1 78 97 94 : 62 60 93 92 : 83 40 95 90 : 104 20 97 88 : 125 0 93 86 : 146 23 89 75 : 25a Bath temperature. b Determined by G.C. analysis; see ESI.Table 2 Performance of base (R,R)-8 in the asymmetric deprotona-tion of prochiral ketones at 78 and 20 1CEntry R T (1C) Yielda (%) e.r.b (S :R)1 t-Bu (a) 78 93 (66) 93 : 72 n-Pr (b) 78 92 (65) 94 : 63 i-Pr (c) 78 96 (67) 93 : 74 Me (d) 78 96 (69) 95 : 55 OTBS (e) 78 91 (68) 92 : 8c6 t-Bu (a) 20 93 (83) 88 : 127 n-Pr (b) 20 96 (68) 89 : 118 i-Pr (c) 20 95 (70) 87 : 139 Me (d) 20 96 (69) 90 : 1010 OTBS (e) 20 92 (70) 87 : 13ca Determined by G.C. analysis; values in parentheses are isolatedyields of pure products. b Determined by G.C. analysis. c Determinedby optical rotation; see ESI.2266 Chem. Commun., 2011, 47, 2264–2266 This journal is c The Royal Society of Chemistry 2011solution as monomers or dimers.11 This is in stark contrast tolithium amides that are known to display a complex mixture ofoligomeric forms that can have markedly diﬀerent reactivityand selectivity proﬁles.12b,c Considering the small diﬀerence inselectivity of complex (R,R)-8 across the temperature rangeapplied, at present we postulate that the aggregation state ofthis magnesium bisamide does not diﬀer drastically from78 to 20 1C. As such, the structurally robust nature of thismagnesium species serves to permit ‘‘warming’’ of the basesolution without signiﬁcant decomposition, and the observedtemperature independence of the solution structure enablescomparable selectivity at considerably more elevated tempera-tures. The exact nature of the active species is currently underinvestigation.In summary, utilising unique properties characteristic ofmagnesium amides, we have successfully developed a novelC2-symmetric magnesium bisamide and demonstrated itsunique ability to function eﬃciently within asymmetricdeprotonation reactions. Signiﬁcantly, this new reagent operatesextremely eﬀectively at 78 1C, as well as the substantiallymore elevated 20 1C, maintaining very good levels ofasymmetric eﬃciency and thereby presenting signiﬁcantopportunities for energy conservation in this arena. Followingthese studies, we are currently focused on the development offurther new chiral magnesium-centred bases to enable highlyselective processes at ambient temperature.We thank the EPSRC for funding (M.M.; EP/C548981/1)and the EPSRC Mass Spectrometry Service, University ofWales, Swansea, for analyses. We are also extremely gratefulto Prof. Dr Klaus Ditrich (BASF SE, Ludwigshafen) for agenerous supply of chiral amines.Notes and referencesz The corresponding Li complex (lithium (R,R)-bis-(1-phenylethyl)-amide) is reported to achieve an e.r. of 85 : 15 (S :R) at 78 1C.15 Forcomparison, we also evaluated this Li complex under conditions asestablished by Simpkins et al.,13 using both internal quench (IQ) andexternal quench with LiCl additive16 (EQ) techniques, at 20 1C and0 1C, with the following results (selectivity values given as (S :R)):20 1C: 77 : 23 (IQ), 79 : 21 (EQ); 0 1C: 76 : 24 (IQ), 74 : 26 (EQ).1 Green chemistry guidelines include the consideration of theenergetic cost of chemical processes, see: P. T. Anastas andJ. C. Warner, Green Chemistry: Theory and Practice, OxfordUniversity Press, New York, 2000.2 For the energetic consideration of selected chemical reactions, see:M. J. Gronnow, R. J. White, J. H. Clark and D. J. Macquarrie,Org. Process Res. Dev., 2005, 9, 516.3 D. Hayes, Synthetic Chemistry, Pre-Clinical Development,Chemical Development, GlaxoSmithKline, personal communication.4 For examples, see: (a) P. Knochel, W. Dohle, N. Gommermann,F. F. Kneisel, F. Kopp, T. Korn, I. Sapountzis and V. A. Vu,Angew. Chem., Int. Ed., 2003, 42, 4302; (b) H. Ila, O. Baron,A. J. Wagner and P. Knochel, Chem. Commun., 2006, 583;(c) T. D. Blu¨mke, F. M. Piller and P. Knochel, Chem. Commun.,2010, 46, 4082; (d) S. H. Wunderlich, C. J. Rohbogner, A. Unsinnand P. Knochel, Org. Process Res. Dev., 2010, 14, 339.5 For selected examples, see: (a) M. R. Netherton, C. Dai,K. Neuschu¨tz and G. C. Fu, J. Am. Chem. Soc., 2001, 123,10099; (b) A. Leitner, S. Shekhar, M. J. Pouy and J. F. Hartwig,J. Am. Chem. Soc., 2005, 127, 15506; (c) T. Hama, D. A. Culkinand J. F. Hartwig, J. Am. Chem. Soc., 2006, 128, 4976;(d) O. Navarro, N. Marion, J. Mei and S. P. Nolan, Chem.–Eur. J.,2006, 12, 5142; (e) L. Melzig, A. Metzger and P. Knochel,J. Org. Chem., 2010, 75, 2131; (f) S. C¸alimsiz, M. Sayah, D. Mallikand M. G. Organ, Angew. Chem., Int. Ed., 2010, 49, 2014.6 For a review, see: N. S. Simpkins, Top. Stereochem., 2010, 26, 1.7 For the use of enol silanes in organic synthesis, see:(a) P. Brownbridge, Synthesis, 1983, 1; (b) P. Brownbridge, Synth-esis, 1983, 85; (c) S. Kobayashi, K. Manabe, H. Ishitani andJ.-I. Matsuo, Silyl Enol Ethers in Science of Synthesis, ed.I. Fleming, Thieme, Stuttgart, 2001, vol. 4, p. 317.8 For examples of eﬀective chiral lithium amide bases, see:(a) R. Shirai, M. Tanaka and K. Koga, J. Am. Chem. Soc., 1986,108, 543; (b) R. P. C. Cousins and N. S. Simpkins, TetrahedronLett., 1989, 30, 7241; (c) K. Aoki, H. Noguchi, K. Tomioka andK. Koga, Tetrahedron Lett., 1993, 34, 5105; (d) B. J. Bunn andN. S. Simpkins, J. Org. Chem., 1993, 58, 533; (e) B. J. Bunn,P. J. Cox and N. S. Simpkins, Tetrahedron, 1993, 49, 207;(f) R. Shirai, D. Sato, K. Aoki, M. Tanaka, H. Kawasaki andK. Koga, Tetrahedron, 1997, 53, 5963; (g) K. Aoki and K. Koga,Tetrahedron Lett., 1997, 38, 2505; (h) V. K. Aggarwal,P. S. Humphries and A. Kenwick, J. Chem. Soc., Perkin Trans.1, 1999, 2883; (i) C.-D. Graf, C. Malan and P. Knochel, Angew.Chem., Int. Ed., 1998, 37, 3014; (j) C.-D. Graf, C. Malan,K. Harms and P. Knochel, J. Org. Chem., 1999, 64, 5581;(k) K. Aoki and K. Koga, Chem. Pharm. Bull., 2000, 48, 571;(l) J. Busch-Petersen and E. J. Corey, Tetrahedron Lett., 2000, 41,6941.9 For examples, see: D. M. Hodgson, A. R. Gibbs and G. P. Lee,Tetrahedron, 1996, 52, 14361. See also ref. 6.10 (a) K. W. Henderson, W. J. Kerr and J. H. Moir, Chem. Commun.,2000, 479; (b) K. W. Henderson, W. J. Kerr and J. H. Moir,Synlett, 2001, 1253; (c) K. W. Henderson, W. J. Kerr andJ. H. Moir, Chem. Commun., 2001, 1722; (d) J. D. Anderson,P. Garcı´a Garcı´a, D. Hayes, K. W. Henderson, W. J. Kerr,J. H. Moir and K. P. Fondekar, Tetrahedron Lett., 2001, 42,7111; (e) K. W. Henderson, W. J. Kerr and J. H. Moir, Tetra-hedron, 2002, 58, 4573; (f) E. L. Carswell, D. Hayes,K. W. Henderson, W. J. Kerr and C. J. Russell, Synlett, 2003,1017; (g) M. J. Bassindale, J. J. Crawford, K. W. Henderson andW. J. Kerr, Tetrahedron Lett., 2004, 45, 4175.11 (a) P. E. Eaton, H. Higuchi and R. Millikan, Tetrahedron Lett.,1987, 28, 1055; (b) P. E. Eaton, C. H. Lee and Y. Xiong, J. Am.Chem. Soc., 1989, 111, 8016; (c) J. F. Allan, K. W. Henderson andA. R. Kennedy, Chem. Commun., 1999, 1325;(d) M. Westerhausen, Inorg. Chem., 1991, 30, 96; (e) W. Clegg,F. J. Craig, K. W. Henderson, A. R. Kennedy, R. E. Mulvey,P. A. O’Neil and D. Reed, Inorg. Chem., 1997, 36, 6238;(f) K. W. Henderson and W. J. Kerr, Chem.–Eur. J., 2001, 7,3430; (g) B. Conway, E. Hevia, A. R. Kennedy, R. E. Mulvey andS. Weatherstone, Dalton Trans., 2005, 1532.12 For a review on the structure of Li amides, see: (a) R. E. Mulvey,Chem. Soc. Rev., 1991, 20, 167. For the impact of Li amideoligomers on the selectivity of asymmetric deprotonation pro-cesses, see: (b) D. Sato, H. Kawasaki, I. Shimada, Y. Arata,K. Okamura, T. Date and K. Koga, J. Am. Chem. Soc., 1992,114, 761; (c) K. Aoki, K. Tomioka, H. Noguchi and K. Koga,Tetrahedron, 1997, 53, 13641.13 The highest level of enantioselectivity recorded for the correspondingLi base with LiCl at 78 1C is 91.5 : 8.5 (S :R). See: B. J. Bunn,N. S. Simpkins, Z. Spavold andM. J. Crimmin, J. Chem. Soc., PerkinTrans. 1, 1993, 3113 and ref. 8d.14 A. Alexakis, S. Gille, F. Prian, S. Rosset and K. Ditrich, Tetra-hedron Lett., 2004, 45, 1449.15 N. S. Simpkins, J. Chem. Soc., Chem. Commun., 1986, 88.16 The use of an LiCl additive is known to enable the highest levels ofselectivity in externally quenched reactions.6,1317 For the use of only one equivalent of Me3LiCl as an internalquench within deprotonation processes, see: (a) W. J. Kerr, A. J.B. Watson and D. Hayes, Chem. Commun., 2007, 5049;(b) W. J. Kerr, A. J. B. Watson and D. Hayes, Org. Biomol. Chem.,2008, 6, 1238; (c) W. J. Kerr, A. J. B. Watson and D. Hayes,Synlett, 2008, 1386.18 Such internal quench protocols usually require an excess ofelectrophile, see: E. J. Corey and A. W. Gross, Tetrahedron Lett.,1984, 25, 495.

Towards energetically viable asymmetric deprotonations : selectivity at more elevated temperatures with C2-symmetric magnesium bisamides

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Towards energetically viable asymmetric deprotonations: selectivity at more elevated temperatures with C2-symmetric magnesium bisamides

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Towards energetically viable asymmetric deprotonations : selectivity at more elevated temperatures with C2-symmetric magnesium bisamides

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