Selected topics in metal- free catalysis: Carbenes (and Lewis Base) Catalysis
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1 elected topics in metal- free catalysis: Carbenes (and Lewis Base) Catalysis Mar$n mith ffice: CL 1 st floor Telephone: (2) mar$n.smith@chem.ox.ac.uk
2 ! elected topics Enamine Iminium Lewis/ Brønsted Base Brønsted Acid E u: P All of these topics are of direct relevance to contemporary synthe7c chemistry This is a very selec7ve treatment of topics that are not a focus of most undergraduate courses
3 ! Course outline and contents 1. General considera7ons: types of reac$on, scope and focus of this (truncated) course 2. - heterocyclic carbenes: This course will focus on: (i) background and history of carbene- mediated reac$ons (ii) applica$on in catalysis (both asymmetric and racemic examples) This is a very selec7ve treatment of what is a large and complex area: the aim is to focus on contemporary developments in (mostly) cataly7c reac7ons and understand how and why these processes are effec7ve
4 ! - eterocyclic Carbenes! What is a carbene? A neutral molecule containing a divalent carbon atom with six electrons in its valence shell! Two possible ground- state electronic structures:: inglet Carbene Triplet Carbene C C Filled sp 2 hybridised orbital Empty p-orbital ucleophilic and electrophilic (ambiphilic) Most important ground state for catalysis Two singly occupied orbitals eact as diradicals More reactive, but less stable f less direct relevance to synthetic chemistry tability and reac7vity of carbenes depends on electronic and steric factors
5 ! Carbene stabiliza$on! Isola7on and prepara7on of a free carbene Use bulky groups to stabilize carbene K t Bu TF 96% table solid (m.p. 240 C) in absence of 2 and 2! Electronic tabiliza7on operates in both σ- and π- framework J. Am. Chem. oc. 1991, 113, 361 π-donation into empty p-orbital from adjacent heteroatoms stabilizes electrophilic reactivity "Push-Pull" synergistic effect stabilizes singlet carbenes 1 1 diaminocarbenes imidazol-2-ylidenes σ-withdrawal by adjacent electronegative atoms stabilizes nucleophilic reactivity 1,3-thiazol-2-ylidenes 1,2,4-triazol-3-ylidenes Aldrichimica Acta 2009, 42, 55; Chem. ev. 2000, 100, 39
6 ! C reac$vity! ucleophilic character of Cs makes them good Lewis base organocatalysts 1 2 Many variations possible sterics and electronics of 1 substituents are important 2! Typical modes of reac7vity: Umpolung Acyl Transfer Enolate reactivity E E uc E E Chem. ev. 2009, 109, 3612
7 ! Thiamine catalysed benzoin reac$on! 1943: Ugai demonstrates that vitamin B1 catalyses the Benzoin reac7on (unknown mech.) ther related salts also effective: 2 2 a, Br Br I! 1958: Breslow shows that the C2 proton of thiamine undergoes /D exchange 2 C2 D 2 D 2 C2 D D uggests that Zwitterion (aka a carbene) is responsible for catalysis -eterocyclic Carbene J. arm. oc. Jpn. 1943, 63, 296; J. Am. Chem. oc. 1958, 80, 3719
8 ! Proposed mechanism ± Breslow intermediate This (postulated) intermediate acts as an acyl anion equivalent ± ± Breslow intermediate Umpolung reactivity All steps reversible to some extent o single step fully rate-determining
9 ! Isola$on of the Breslow intermediate! 2012: First direct (spectroscopic) evidence for Breslow intermediate d 8 -TF Breslow intermediate can be observed under strictly anhydrous conditions; requires very specific carbene -ray! Pyruvate decarboxylase 2 ThDP 3 P 2 3 Cofactor mediates a range of reactions via a Breslow type intermediate ThDP PP CoA C 2 Breslow Intermediate Angew. Chem. Int. Ed. 2012, 51, 12370; Angew. Chem. Int. Ed. 2013, 52, 11158; at. Prod. ep. 2003, 20, 184
10 ! Asymmetric benzoin condensa$on! First examples using chiral C reported by heehan (1966 & 1974) 2 (10 mol%) Et 3 (10 mol%) Br 9% yield 22% ee Br igher ee at the expense of yield (6% yield, 52% ee)! ther thiazolium salts examined but yield and selec7vity s7ll a problem Takagi (1980) up to 20% yield up to 35% ee Zhao (1988) up to 30% yield up to 57% ee Br I López-Calahorra (1993) 21% yield 27% ee I TB Ts Leeper (1997) up to 50% yield up to 21% ee Acc. Chem. es. 2004, 37, 534
11 ! Asymmetric benzoin condensa$on! Breakthrough using enan7ometrically pure triazolium salt (Enders, 1996) 4 2 (1.25 mol%) K 2 C 3, TF 66% yield 75% ee! A bicyclic variant can also be used to give high enan7oselec7vity (Leeper, 1998) 2 (30 mol%) Et 3 (33% mol%), 45% yield 80% ee elv. Chim. Acta 1996, 79, 1217; J. Chem. oc., Perkin Trans , 1891
12 ! Asymmetric benzoin condensa$on! Evolu7on of bicyclic triazolium (pre) catalyst gives improved yield and enen7oselc7vity BF 4 2 t Bu (10 mol%) K t Bu (10 mol%), TF 83% yield 90% ee!.and incorpora7on of a direc7ng group gives excellent overall yield and selec7vity BF 4 C 6 F 5 2 (4 mol%) b 2 C 3, 4 mol%), TF 90% yield >99% ee Angew. Chem. Int. Ed. 2002, 41, 1743; J. rg. Chem. 2009, 74, 9214
13 ! tereochemical ra$onale (for bicyclic catalysts) t Bu tereochemistry determined during attack of Breslow intermediate onto the aldehyde tereochemistry obtained from e face attack of the Breslow intermediate onto the e face of the aldehyde ± t Bu * t Bu teric block tereochemistry determined during aaack of Breslow intermediate onto π-stacking -bonding the aldehyde t Bu Breslow Intermediate ± owever, E/Z geometry of Breslow intermediate is unknown Computational work suggests an alternative transition state with no π-stacking
14 ! Crossed Benzoin! Use electrophilic components of differing reac7vity to get selec7vity TIP (10 mol%) BF 4 DBU (10 mol%), 5 C 90% yield 84% ee + CF 3 BF 4 (10 mol%) DBU (10 mol%) TF CF 3 93% yield Angew. Chem. Int. Ed. 2006, 45, 1463; Adv. ynth. Catal. 2009, 351, 1749
15 ! te[er reac$on: another acyl anion equivalent! Intramolecular teaer reac7on azolium salt precatalyst (20 mol%)! Triazolium salts are very effec7ve (pre)catalysts 4 Bn Boc BF 4 C 6 F 5 = 60% ee elv. Chim. Acta, 1996, 79, 1899 Et I = t-bu 73% ee Chem. Comm., 2005, 195 = t-bu, 94%, 97% ee JAC 2002, 124, 10299
16 ! te[er reac$on: another acyl anion equivalent! Intermolecular teaer reac7on(s): Glyoxaldehydes and alkylidene malonates + C 2 t-bu C 2 t-bu! Desymmetrisa7on of cyclohexadienones (20 mol%) BF 4 C 6 F 5 i-pr 2 Et (100 mol%) Mg 4 C 4, -10 C C 2 t-bu C 2 t-bu up to 91% ee BF 4 (20 mol%) KMD (20 mol%) toluene, rt = PMP stereoselective protonation up to 99% ee >20:1 dr J. Am. Chem. oc., 2008, 130, J. Am. Chem. oc., 2006, 128, 2522
17 ! Alterna$ve acyl anion equivalent applica$ons! Cross- coupling of aldehydes and acyl imines Tol Bn Et 3 (15 eq) Bn JAC 2001, 123, 9697! ecent Progress: ydroacyla7on of Unac7vated Double bonds 4 s 25 mol% DBU (40 mol) 1,4-dioxane 120 C s s JAC 2009, 131, 14191
18 ! Alterna$ve acyl anion equivalent applica$ons! Extension: Cascade catalysis involving hydroacyla7on of unac7vated alkynes 4 + C s 5 mol% K 2 C 3 (10 mol%) TF 70 C s s tetter s + JAC 2010, 132, 5970
19 ! Alterna$ve acyl anion equivalent applica$ons! ydroacyla7on of arynes 4 + TM Tf s 10 mol% K 2 C 3 (20 mol%) KF (2 eq) 18-crown-6 (2 eq) TF, rt s + s s Concerted or tepwise? Angew. Chem. Int. Ed, 2010, 49, 9761
20 ! omoenolate eac$vity! Principle: s s s s s s! In prac7ce: mol% DBU (15 mol%) s :1 dr 89-94% ee J. Am. Chem. oc., 2008, 130, 2416
21 ! omoenolate eac$vity! omoenolate equivalents: mechanis7c pathway: s DBU homoenolate equivalent s 2 1 s 20:1 dr 89-94% ee s 1 2 acylazolium J. Am. Chem. oc., 2008, 130, 2416
22 ! omoenolate eac$vity! ther homoenolate examples: s DBU or Et 3 s dr 85:15, 73% e.e. homoenolate equivalent C C 2 Et C 90% ee C 2 Et dr 60:40, 78% ee JAC 2008, 130, 2740; Adv. ynth. Catal., 2008, 350, 1885; JAC, 2008, 130, 2416.
23 ! Enolates from Cs! Can the reac7vity of enals be controlled by Cs to allow homoenolate or enolate reac7vity? enol enolate homoenolate
24 ! Enolates from Cs! Can the reac7vity of enals be controlled by Cs to allow homoenolate or enolate reac7vity? 2 C Ts BF 4 s (10 mol%) 2 C Ts 1 ' i-pr 2 Et (10 mol%) toluene/tf 10:1 rt 1 >20:1 dr up to 99% ee 2 C ' 1 2 C Ts s endo [4+2] 1 2 C Ts s JAC 2006, 128, 8418
25 ! Enolates from Cs! The base (or its conjugate acid) can play a determining role in the mode of reac7vity + 2 C s (10 mol%) C C 24 hours DMAP or i-pr 2 Et (0.2 eq) enolate equivalent DBU (0.2-1 eq) homoenolate equivalent 99% ee >20:1 dr up to 98% yield 2 C 2 C 99% ee 5:1 dr up to 95% yield PA 2010, 107, 20661
26 ! Enolates from Cs! The base (or its conjugate acid) can play a determining role in the mode of reac7vity Product distribution is determined by relative rates of C-C bond formation and protonation steps acyl anion homoenolate homoenolates Favoured by strong bases (DBU) Weaker conjugate acid Protonation relatively disfavoured 3 acyl azolium (activated carboxylate) enolate enolates Favoured by weak bases (DMAP, i-pr 2 Et) tronger conjugate acid Protonation relatively favoured PA 2010, 107, 20661
27 ! Enolates from Cs! Alterna7ve trategy : From aldehydes containing an adjacent leaving group ' ' ' ' v reactive ' ' ' bench stable ' ' ' base - base ' ' ' ' ' ' indirect azolium enolate formation Bode, cheidt, ovis indirect azolium enolate formation Chem. Comm. 2011, 47, 373.
28 ! Enolates from Cs! Applica$ons: asymmetric protona$on of azolium enolates BF 4 C 6 F 5 ' ' (10 mol%) K (1 eq), (10 eq) (1.2 eq) 18-crown-6 (0.5 eq) up to 93% ee Br Br asymmetric protonation F 5 C 6 F 5 C 6 JAC 2005, 127, 16406
29 ! Enolates from Cs! Applica7ons: asymmetric [4+2] cycloaddi7ons 2 3 BF 4 s 2 3 (0.5 mol%) 1 1 ' Et 3 (1.5 eq) EtAc, rt 2 3 >20:1 dr up to 99% ee K 2C 3 (aq) (3.2 eq) toluene, rt a 3 bisulfite adducts 1 ' s [4+2] F 5 C 6 JAC 2006, 128, 15088; rg. Lett. 2008, 10, 3817
30 ! Enolates from Cs! ebound catalysis : trategy incorporates a leaving group that can regenerate C E acylation C addition / tautomerisation acylazolium E rebound activation electrophile E or elimination enol enolate JAC 2009, 131, 18028
31 ! Enolates from Cs! Applica$on of rebound catalysis - asymmetric Mannich reac$on BF 4 Ts + 2 (10 mol%) s ac (1 eq) C 2 2, 0 C Ts Ts Bn 72%, ee 95% Bn 2 Ts rebound Ts JAC 2009, 131, 18028
32 ! Enolates from Cs! Co- opera7ve catalysis - can a Lewis acid and an C be beneficial to a cataly7c system? C Lewis acid weak association copoperative catalysis? early metal late metal M-C strong binding BF 4 + (10 mol%) DBU (15 mol%) Ti(i-Pr) 4 (20 mol%) i-pr (20 mol%) C 2 2, rt single diastereoisomer ee 99% = 2,6-Et 2 C 6 4 JAC 2010, 132, 5345
33 ! Enolates from Cs! a7onale: C 2 acylation Ti() 4 Ti() n Ti() n protonation/ tautomerisation/ aldol Ti() n C-C bond formation (homoenolate) Ti() n organizes reactants JAC 2010, 132, 5345
34 ! Enolates from Cs! omoenolate vs cross- benzoin - a mechanis7c ambiguity? 2 C + (10 mol%) DBU (15 mol%) DCE, rt BF 4 s 2 C dr 91:9 ee 99% lactonise and decarboxylation s s crossbenzoin oxy- Cope s s homoenolate equivalent C 2 2 C 2 C direct homoenolate attack JAC 2007, 129, 3520
35 ! Enolates from Cs! Genera7on of enolates from Ketenes (via ammonium enolates, for comparison) ammonium enolate C 3 C 3 95% yield 98% e.e.
36 ! Enolates from Cs! Genera7on of enolates from Ketenes (via ammonium enolates, for comparison) mono-substituted in-situ generated "ketene enolates" di-substituted enolates from isolable carbenes or Fe up to 93% ee elson et al. J. Am. Chem. oc., 2004, 126, up to 99% ee Lectka et al. J. Am. Chem. oc., 2006, 128, 1810 up to 99% ee Lectka et al. J. Am. Chem. oc., 2008, 130, J. rg. Chem. 2010, 75, F 1 1 Y/ 3 1 ammonium enolate For reviews 1. "ketene enolate" chemistry Lectka et al. Tetrahedron, 2009, 65, For ammonium enolates Gaunt and Johansson, Chem. ev., 2007, 107, C 2 C 2 up to 94% ee Fu et al. Angew. Chem. Int. Ed., 2007, 46, 977 up to 93% ee Fu et al. Angew. Chem. Int. Ed., 2008, 47, 7048 up to 96% ee Fu et al. Angew. Chem. Int. Ed., 2009, 48, 2391
37 ! Enolates from Cs! imilar reac7vity from azolium enolates ' ' ' ' asymmetric catalysis ' ' azolium enolate
38 ! Enolates from Cs! imilar reac7vity from azolium enolates Ts 1.3 eq Et 2 then rg. Biomol. Chem., 2008, 6, 1108 Tetrahedron: Asymmetry, 2010, 21, 582 Tetrahedron: Asymmetry, 2010, 21, hour Ts 90% 76% e.e. >99% e.e. BF 4 TB 10 mol% (i). KMD toluene 0 C then Et C 3 Et anti C 3 + Et syn C 3 dr 75:25 ee (anti) 92%, 61% ee (syn) 88%, 16%
39 ! Enolates from Cs C 6 5 CF 3 1 dr 4:1 to >20:1 1 CF % ee rg. Lett., 2009, 11, 4029 up to 60% ee Eur. J.rg. Chem., 2010, 5863 up to 84% ee Adv. ynth. Cat., 2009, 351, 3001 [4 + 2] C 3 C 3 up to 92% ee ' ' azolium enolate Et 2 C Bz Et 2 C Bz ' Ts ' = C 2 Et ' ' = C dr up to 10:1 up to 91% ee Ye et al,j. rg. Chem., 2010, 75, 6973 C 2 Et C 2 Et up to 91% ee Ye et al, J. rg. Chem., 2009, 74, 7585 Ts C up to 97% ee Ye et al, Angew. Chem. Int Ed, 2009, 48, 192 up to 95% ee Ye et al, Angew. Chem. Int Ed, 2010, 49, 8412
40 ! Q1
41 ! Q2
42 ! Q3
43 ! Q4
44 ! Q5
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