Catalytic synthesis of amines and amides

Transcription

1 Catalytic synthesis of amines and amides Jonathan Williams University of Bath Catalytic approaches to amine synthesis Br Pd or Cu cat 2 Chem. Sci., 2011,27 ' TM or Ln cat 2 ' 2 and/or 2 ' rg. Biol. Chem., 2005, 1819 ChemCatChem, 2010,

2 eductive amination eductive amination in a flow reactor C 2 (6 atm) + 3% Pt/C 2 Toluene 105 o C 99% conversion 93% selectivity 2 Me 2 (10 atm) 5% Pd/C Toluene 20 o C then 100 o C 2 100% conversion Collaboration with Pawel Plucinski, Sumeet Sharma and Anna Sobolewska 2

3 Borrowing hydrogen methodology for amine alkylation uthenium and iridium catalysts have been widely used for this reaction Avoids the use of alkyl halides Water is the only by-product Adv. Synth. Catal., 2007, 1555, Dalton Trans., 2009, 753 ne pot synthesis of Piribedil 1.25 mol% [u(cymene)cl 2 ] mol% dppf toluene, reflux, 12 h 87% isolated yield Tetrahedron Lett., 2007, 8263, aniti amid 3

4 Catalytic approaches to amide synthesis Metal-catalysed approaches to amide bond formation C. L. Allen and J. M. J. Williams, Chem. Soc. ev., 2011, 40, 3405 Alkylation of Sulphonamides with Alcohols Tol S mol% [u(cymene)cl 2 ] 2 5 mol% DPEos 10 mol% Et 3 toluene, reflux, 24 h S Tol 92% yield Gareth Lamb, J. Am. Chem Soc., 2009, 1766 See also, Beller et al., J. Am. Chem Soc., 2009,

5 Sulphonamides/osphonamides for Primary Amine Synthesis Gareth Lamb, Tetrahedron Lett., 2009, 3374 Amide alkylation requires fairly forcing conditions Andrew Watson, J. rg. Chem., 2011, 76,

6 Amide formation from alcohols C via C mol% [u(cymene)cl 2 ] 2 5 mol% dppb 10 mol% Cs 2 C 3 C % isolated yield (2.5 equiv.) tbu, reflux, 24 h Andrew Watson, rg. Lett., 2009, 2667 See also; Milstein et al., Science, 2007, 317, 790 Gruzmacher et al., Angew. Chem., 2008, 559 Formylation using formaldehyde as oxidant and reagent 1 mol% (Cp*IrI 2 ) 2 2 formaldehyde (2 equiv) water, 115 o C, 5 h 2 C= 3 C 2 C= Me 93% 95% 93% Me (75% ee) urida Saidi 6

7 Elimination/re-arrangement reactions with 2 C 2 Ir catalysed rearrangement of oximes into amides 2.5 mol% [Cp*IrCl 2 ] 2 toluene, reflux, 4-8 h 85-95% isolated yield Cl Cl athan wston, rg. Lett., 2007, 73. 7

8 u catalysed reactions of oximes Me 0.1 mol% u(p 3 ) 3 (C) mol% dppe 0.4 mol% Ts 2 toluene, reflux, 6 h Me 94% isolated yield Me Me 2.5 mol% u(p 3 ) 3 (C) mol% Xantphos toluene, reflux, 24 h Me C 97% conversion athan wston, rg. Lett., 2007, Tetrahedron Lett., 2007, ne pot conversion of alcohols into amides Ar (1.5 equiv.) 2.5 mol% [Cp*IrCl 2 ] 2 toluene, reflux, 24h 2 92% Cl 2 88% then add 2.Cl reflux 4 h 2 2 Me 94% F 91% athan wston, rg. Lett., 2007, 73. 8

9 Cheaper metals are also effective for oxime rearrangement Some examples of Zn and In catalysed amide formation In 87% Zn 91% In 90% In 86% Zn 93% Zn 94% In 79% Zn 88% Cl In 88% Zn 90% Et 2 In 95% Zn 91% Catalyst cost (to convert 1 mol of substrate) In = 0.4 mol% In( 3 ) 3 Zn = 10 mol% ZnCl 2 ZnCl 2 In( 3 ) 3 u(p 3 ) 3 (C) mmol = mmol = mmol = Liana Allen, Tetrahedron Lett., 2010,

10 Simple copper salts also provide good reactivity 2 mol% Cu(Ac) 2 toluene, 80 o C, 1 h 2 100% conversion 93% isolated yield 10 wt% Cu/Zn/C toluene, 100 o C, 4 h 2 98% conversion eterogeneous catalyst can be successfully reused and also workswell inanx-cube flow reactor Catalyst cost of Cu(Ac) 2 (to convert 1 mol of substrate) = 0.26 Simon Bishopp and Sumeet Sharma, Tetrahedron Lett. 2011, 4252 Some mechanistic studies 5 mol% icl xylene, 155 o C, 18 h excess mol%iCl 16 2 xylene, 155 o C, 18 h 2 1equiv % Liana Allen, rg. Lett., 2010,

11 Lack of 18 incorporation with other catalysts uth Lawrence Crossover experiment suggests a bimolecular transfer Liana Allen, rg. Lett., 2010,

12 ne possibility for the mechanism of oxime re-arrangement [i 2+ ] 2-2 [i 2+ ] 2 [i 2+ ] [i 2+ ] [i 2+ ] Liana Allen, rg. Lett., 2010, 5096 Formation of the intermediate nitrile appears to be slow Me 2 mol% Cu(Ac) 2 Me Me 2 10 min, 110 o C 15 min, 110 o C 30 min, 110 o C min, 80 o C min, 80 o C min, 110 o C (+ 10 mol% Tol-C) 100 Liana Allen, Liam Emmett, uth Lawrence, Adv. Synth. Catal., 2011, in press 12

13 Working towards room temperature amide formation James Lynch Attempted Borrowing ydrogen reaction with iron catalysts + Fe() (20mol%) expected product C 110 o C, 24 h observed product Liana Allen, Tetrahedron Lett., 2009,

14 Iron-catalysed conversion of nitriles into amides Liana Allen, Tetrahedron Lett., 2009, 4262 ther catalysts may be more effective for this reaction Simge Davulcu 14

15 Conversion of aldehydes into amides? ' 2-2 C +2 ' 2 i salts catalyse formation of secondary/tertiary amides Liana Allen, rg. Lett., 2010,

16 Conversion of aldehydes into secondary and tertiary amides Liana Allen, rg. Lett., 2010, 5096 Secondary amide formation goes via the primary amide Liana Allen and Liam Emmet 16

17 What catalyses secondary amide formation? Liana Allen ydroxylamine catalyses transamidation Liana Allen 17

18 More amides from hydroxylamine catalysed transamidation C 2 Bn 87% yield, 10 mol% cat 91% yield, 10 mol% cat Me Boc 76% yield, 50 mol% cat 71% yield, 50 mol% cat C 2 Bn Liana Allen oom temperature catalytic transamidation Liana Allen 18

19 Mechanism of amide activation by hydroxylamine? + 2 ' Secondary amides do not undergo transamidation M concentration studies show association between hydroxylamine hydrochlorideand primary amide Iodide as an alternative inorganic catalyst Are acyl iodides more electrophilic than acyl chlorides? James Taylor and in collaboration with Steve Bull 19

20 Iodide catalysed acyl transfer rg. Lett., 2010, 5740, James Taylor and in collaboration with Steve Bull Iodide catalysed formation of acylsulphonamides uss Wakeham 20

21 Towards direct amide formation from acids and amines? pka ~ 4-5? + 2 Tol Tol Tol pka~10 March: When carboxylic acids are treated with amines, salts are obtained. The salts can be pyrolyzed to give amides Uncatalysed amide formation + 2 Tol Toluene, reflux 24 h Tol 100% conversion 93% yield, 93 g Liana Allen, Chem. Commun., 2011, in the press 21

22 Catalytic direct amide formation Liana Allen, osie Chhatwal Chem. Commun., 2011, in the press Acknowledgements Liam Emmett aniti amid Gareth Lamb athan wston urida Saidi Andrew Watson Steven Bull James Taylor Simon Bishopp Pawel Plucinski Sumeet Sharma Anna Sobolewska Liana Allen osie Chhatwal Simge Davulcu uth Lawrence James Lynch uss Wakeham Sarah Abou-Shehada Ben Atkinson elen Lomax Winson Ma Dominic van der Waals EPSC University of Bath GlaxoSmithKline AstraZeneca Syngenta Pfizer Brunei Government 22

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24 The Beautiful Buildings of Bath Milder conditions with ruthenium complexes 3 P C C u(c)(p 3 ) 2 (I i Pr 2 Me 2 )' (5 mol%) 89% Toluene, 70 C, 3 h J. Am. Chem. Soc., 2007, 1987, Belinda Paine 24

25 Chemistry from other groups catalyst ' ' Cho Yus Ishii Park ucl 2 (P 3 ) 3 u(dmso) 4 Cl 2 [Ir(cod)Cl] 2 /P 3 Pd(heterogeneous) J. rg. Chem, 2001, 9020 Tetrahedron, 2006, 8982 J. Am. Chem. Soc., 2004, 72 Angew. Chem. Int., 2005, 6913 Kaneda Grigg u (heterogeneous) J. Am. Chem. Soc., 2004, 5662 Cp*IrCl 2 J. rg. Chem., 2006, 8023 Angew. Chem. Int., 2007, Adv. Synth. Cat., 2007, 1555 uthenium complexes for aldol chemistry catalyst + C CtBu + 2 Ac 24 h, 110 C toluene C CtBu 2.5 mol% [Ir(cod)Cl] 2, 5 mol% dppf, 5 mol% K 2 C 3 55% 5 mol% u(p 3 ) 3 (C) 2 56% Paul Slatford 25

26 Amine formation via the Aza-Wittig reaction M ' M 2 ' 3 P=' Indirect Aza-Wittig reactions 3 P 2 mol% [Ir(cod)Cl] 2 5 mol% dppf 5 mol% K 2 C 3 Me, 110 C, 24 h 93% 84% 76% Chem. Commun., 2004, 1072, Gerta Cami-Kobeci 26

27 Simple amines are also successful 2 2 mol% [Ir(cod)Cl] 2 5 mol% dppf 5 mol% K 2 C 3 Me, 110 C, 24 h 78% elated chemistry Grigg, u(p 3 ) 4 2 Chem Comm, 1981, 611 Beller, u 3 (C) 12 / 3 P Tetrahedron Lett, 2006, 8881 Yamaguchi, Cp*IrCl 2 Synlett, 2005, 560 uthenium complexes are more active 1.2 equiv t Bu mol% [u(cymene)cl 2 ] mol% dppf toluene, reflux, 24 h 88% yield t Bu Chem. Commun. 2007, 725, aniti amid 27