Update to 2013 Bode Research Group Topic: N-Heterocyclic carbene catalysis

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1 Update to 2013 Bode esearch Group Topic: eterocyclic carbene catalysis This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. heterocyclic carbenes (C s) are neutral species that possesses a divalent carbon atom with an electron sextet. They were recognized and isolated as stable molecules at the end of 1980 s and beginning of 1990 s but the first evidence of their existence as reactive intermediates was presented almost hundred years earlier. C s have broad field of application in organometallic chemistry (ligands for metathesis, hydrogenation not covered here) and in organocatalysis as nucleophilic catalysts. 1 C catalysis C s can be generated from the parent imidazolium, triazolium or thiazolium salts by treatment with a base and can be represented both as ylides or carbenes. X X Base X Y Y Y carbene ' thiazolylidene pka values of precatalysts and 13 C shifts C s pka in DM ylide ' imidazolylidene ' General tructures of nucleophilic carbenes triazolylidene olan ACIE 2007, 46, s s s s 13 C! (ppm) Glorius ACIE 2010, 49, 6940 C nucleophilicity: The observed reactivity of C originates from their high Lewis basicity, not nucleophilicty. The attack of Cs to the carbonyl group of aldehydes occurs under kinetic control and has a lower degree of reversibility. s s s igher nucleophilicity (kinetics data) s s s 3 P igher Lewis basicity (calculation) Mayr ACIE 2011, 50, 6915 The effect of the substitution is also of important consequence in both the properties of the C and in the catalytic pathway. 1

2 Update to 2013 Bode esearch Group This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. B 4 more Lewis acidic less Lewis acidic DBU DBU reversible triazolium salt fully deprotonated with 1 equiv DBU DBU DBU triazolium salt not fully deprotonated with 1 equiv DBU irreversible initial adduct Bode Chem. ci. 2012, 3, 192 ee also ovis Chem. Lett. 2008, 37, 2 C intermediates: While the initial Caldehyde adducts have been isolated and reported by many groups, the enaminol eslow intermediate (see Thiamine catalyzed Benzoin reaction mechanism) remains elusive. 4 4 Teles and Enders elv. Chim. Acta., 1996, 79, 61 Bu Aggarwal Chem. Commun. 2002, Cyanide ion catalyzed benzoin condensation KC The benzoin condensation was the first organic reaction with its mechanism fully elucidated. C eslow intermediate (keto form) and a dimeric species Berkessel ACIE, 2010, 49, 7120 C C C Liebig Annalen der armacie, 1833, 3, 249 or mechanism: Lapworth, J. Chem. oc., Trans. 1903, 83, 995 & 1904, 85, 1206 In the benzoin reaction (and many other Ccatalyzed reactions), the aldehyde carbon undergoes a reversed polarity from an electrophilic center to being a nucleophilic center. This concept is termed umpolung. Corey JC 1975, 40, 231 & eebach ACIE 1979, 18, Thiamine catalyzed benzoin reaction Thiamine or vitamin B1 is the first water soluble vitamin described and an important coenzyme in a number of biochemical reactions. In the beginning of 1940 s Ugai found that thiamine in the presence of a base catalyzed the benzoin reaction. ecognizing the similarities in reactivity of the cyanide anion and thiamine, eslow proposed that a stabilized carbene is responsible for the reactivity of thiamine. This work of eslow in 1950 s constitute first mechanistic description of C s. 2

3 Update to 2013 Bode esearch Group 3 C 2 3 C thiamine base 3 C ylide 3 2 A general struture of thiazolium salt precatalyst for benzoin reaction ( = alkyl or aryl) This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. 3 C Proton shift 3 C 3 C carbene ratelimiting 3 C 3 C eslow intermediate reversible Caldehyde adduct Ugai J. arm. oc. Jpn. 1943, 63, 296 & eslow JAC 1958, 80, 3719 The mechanism of the benzoin reaction is complicated, see eslow Tet. Lett., 1994, 35, 699 & Leeper, JC, 2001, 66, Acyl anion As mentioned above upon C addition to a carbonyl, the latter undergoes a reversed polarity and this newly generated acyl anion has been used in many transformations. ' Cat tetter eaction Cat 2 2 Aldehyde Imine Couping Cat 2 omatic Acylation 2 ' Cat ' 1 Thioester ynthesis Benzoin Product or a review of catalyzed reactions of acyl anion equivalents, see Johnson ACIE 2004, 43, Enantioselective 1,2 additions Benzoin reaction Early attempt by heehan: Enders: 2! (10 mol %) 3 (10 mol %), rt! 50% optical purity: 0.77% 2 B 4 (10 mol %) K (10 mol %) T, 18 C! 83% 90% ee heehan JAC 1966, 88, 3666 & Enders ACIE 2002, 41, 1743 or computation investigation, see ouk PA 2004, 101,

4 Update to 2013 Bode esearch Group A catalytic enantioselective intramolecular benzoin reaction: This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. An application in natural product synthesis: 10 mol% cat 10 mol% 3 T, T C 3 40 mol% cat 40 mol% DBU C 3 T, T 86% yield, 99%ee 73% yield, 99%ee cat= ()seragakinone A uzuki ACIE 2006, 45, 3492 & ACIE 2011, 50, 2297 A crossbenzoin between aldehydes and ketone has also been achieved using very electron poor ketone substrate. 3 C B 4 TBDP 10 mol% 1.0 equiv ipr 2 C 3 86 % 78 %ee Enders Chem. Commun. 2010, 46, 6282 A more challenging problem is the chemoselective crossbenzoin reaction between two aldehydes, due to the self condensation B 4 10 mol% 10 mol% Cs 2 C 3 10 mol% Cs 2 C 3 10 mol% Azabenzoin variant Aldehydeimine coupling via acyl anion chemistry 82 % 84 % yu and Yang rg. Lett. 2011, 3, 880 ee also: Zeitler and Connon JC, 2011, 76, 347 & ynthesis 2011, 2, I 5 (15 mol %) base 4 up to 90% up to 87% ee Miller JAC 2005, 127,

5 Update to 2013 Bode esearch Group ,4 additions tetter reaction chanism and early example This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. I C 2 20 mol% cat K 2 C 3, T % yiel, 61% ee C 2 I Enders elv. Chim. Acta. 1996, 79, 1899 The research program of Prof. Tom ovis (Colorado tate University) has established the current state of the art for enantioselective tetter reactions. C 2 2 X 94% yield, 94% ee C 2 20 mol% cat 20 mol% KMD xylenes, 25 o C, 24 h 95% yield, 87% ee C 2 C 2 2 X 63% yield, 96% ee C 2 64% yield, 82% ee tetter reaction is not as well studied mechanistically as benzoin reaction: C 2 20 mol% Intermolecular variants /D ratelimiting rate = k[ald] 1 [cat] 1 KIE = k /k D = 2.62 B 4 /D C 2 ovis JAC 2002, 124, C 2 ovis L 2011, 13, 1742 Many aldehydes can be used in tetter reaction unfortunately formaldehyde undergoes benzoin condensation too fast and can not be used as a C1 source. owever recently group of prof. Chi reported use of biomassbased carbohydrates as formal formaldehyde (C1) source for intermolecular tetter reaction: 5

6 This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. Update to 2013 Bode esearch Group C Enantioselective variants 2 65% yield, 66% ee tetter reaction 3 I (20 mol%) K 2 C 3 µw 130 C 10 mol% cat 10 mol% Cs 2 C 3 T, 0 o C, 6h 43% yield, 78% ee C % yield, 56% ee The effect of the catalyst conformation in an intermolecular tetter reaction B 4 90 % 88 %ee 2 10 mol% cat 100 mol% DIPEA B 4 95 % 95 %ee cat= retrobenzoin ingchain tautomeric forms Chi JAC, 2013, 135, 8113 B 4 TBDP Enders Chem Commun 2008, B 4 22 % 88 %ee ovis JAC 2009, 131, & ovis and ouk JAC 2011, 133, A bifunctional additive (catechol) was found to accelerate the reaction s rate 6

7 Update to 2013 Bode esearch Group 2 B 4 10 mol% cat 100 mol% DIPEA 2 This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. 80 %; 93 % ee (5 % w/o cathecol) 5 ummary: reactive intermediates generated from αfunctionalized aldehyde 2 3 eslow intermediate oxidation 2 3 carbene 3 2 Base acyl anion ylide!," unsaturated acyl azolium homoenolate acyl azolium 3 transfer 2 azolium ovis JAC 2011, 133, enolate 2 protonation ecently group of Prof. Chi reported generation and reactions of the homoenolates from saturated esters. 2!deprotonation 2 omoenolate generation proton shift tbu B 4 (20 mol%) DBU, C 4A M, rt, 24h or a full mechanism of cyclopentene formation see 6.4 or the reference above 6 omoenolate reactions 6.1 γlactone synthesis omoenolate 2 Chi at. Chem. 2013, 5, 835 or a review of Chomoenolate chemistry, see air Chem. oc. ev. 2011, 40,

8 Update to 2013 Bode esearch Group This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. 2 s s (8 mol %) DBU (7 mol %) T/tBu rt, 3!15 h 2 2 s 2 s s activated carboxylate endering γlactone formation enantioselective however remains challenging 6.2 γlactam synthesis via 3 5 mol% cat 10 mol% Cs 2 C 3 T, 0 o C, 6h s 2 s s s s s s eslow intermediate 2 s homoenolate s Bode JAC 2004, 126, 8126 and Glorius ACIE 2004, 43, 6205 C 2 18% 25% ee s s s (15 mol %) DBU (10 mol %) 2 s mol % tbu tbu s 2!,"unsaturated acyl azolium C 2 82% 23% ee You Adv. ynth. Catal. 2008, 350, !75% 2 Bode L 2005, 7, 3131 & Bode JAC 2008, 130, tbu tbu 3 cat 2 3 up to 94% yield high dr and ee 2 Bode ACIE, 2012, 51, 9433 A Lewis acid can also be used for preorganization; however, an uncommon protecting group was needed. 8

9 Update to 2013 Bode esearch Group B 4 This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. 5 mol% 2 C 5 mol% Mg() 2 TBD (10 mol%) 1 C % 8898 %ee L Mg L A onsted acid was found to improve the selectivity of a γlactam formation reaction 6.3 ther electrophilic acceptors 6.4 Cyclopentene synthesis s s 2 C B 4 C mol % M; acrylonitrile 2 C homoenolate equivalent 3 2 a 20 mol % = 2,6() 2 C 6 3 (10 mol %) K (10 mol %) ' s (20 mol %) B 4 3 (20 mol %) s 92% 92% ee dr = 14:1 3 2 s s (6 mol %) DBU (12 mol %) s, C 3 ' 55!88% L Mg L 2 C cheidt ature Chem. 2010, 2, 766 Cy C C ovis JAC 2011, 133, s 62!80% 81!93% ee cheidt JAC 2008, 130, 2416 Zhang and Ying L 2008, 10, 953 air JAC 2006, 128, 8736 Alternatively the mechanism of cyclopentene formation reaction maybe considered as Benzoin oxy Cope rearrangement, rather than homoenolate chemistry. 9

10 Update to 2013 Bode esearch Group mol% s C 2 15 mol% DBU C 2 C 2, 0!23 o C, 40 h 2 C 2 pc 3 C 6 4 npr 2 pc 6 4 %yield cis:trans 11:1 5:1 4:1 14:1 % ee This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. Cat C 2 Boatlike oxycope T Cat C 2 tautomerization Cat intramolecular aldol C 2 acyl addition decarboxylation ecently cheidt has revisited cyclopentene formation and applied the use of a Lewis acid 3 2 B 4 10 mol% 20 mol% Ti() % 9899 %ee 3 [Ti] 3 2 C 2 Bode JAC 2007, 129, 3520 [Ti] 3 2 cheidt JAC 2010, 132, 5345 or a review on CLewis acid cooperativity, see cheidt Chem. ci. 2012,3, Cyclopentane synthesis The nature of the precatalyst used controls the stereochemical outcome that results in two complex pathways with absolute control of product selectivity 2 C (10 mol %) DBU C 3 s 2 C 7 Enolate 7.1 Catalytic generation of Cbound enolate = 3 a 2 = 2 Y enolate 4 (10 mol %) DBU C 3 2 = 7.2 etero DielsAlder reaction from aldehydes and related compounds 2 2 s C 2 C Bode L 2009, 11,

11 Update to 2013 Bode esearch Group This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. 2 nc 9 19 TB C 2 2 cex d.r. >20:1 15:1 >20:1 >20:1 3:1 0.5 mol% cat 1.5 equiv M Ac, rt % yield % ee s C 2 2 C s nuc. addition 2 C s 2 C DielsAlder (Z)enolate Elimination s Bode JAC 2006, 128, etero DielsAlder reaction, a bisulfite salt variant The issue of handing and storage of chloroaldehyde was addressed by its in situ generation via a masked bisulfite salt adduct. 3 a 84% yield, 90% ee C 2 2 C % yield, >99% ee npr 2 C 1 mol% cat 1.0 M aq K 2 C 3 (3.2 equiv) 0.16 M Toluene, rt npr 78% yield, >99 %ee 2 3 C 2 65% yield, 99% ee ecently our group has demonstrated the use of enal in hetero DielsAlder reactions 2 C Cbz 98% yield, >20:1 d.r., 99% ee 2 2 C A generation of enolate via formylcyclopropanes ' 3 89% yield, >20:1 d.r., 99% ee B 4 s (12 mol %) 10 mol% DBU 10 mol% cat 15 mol% base 0.1 M C22 40 o C, 6!16 h nc C pc % yield, >20:1 d.r., 99% ee C ' Bode L 2008, 10, 3817 Bode PA 2010, 107, ' 39 95% 99 %ee Chi L 2011, 13, 5366 An azadielsalder reaction has also been achieved 11

12 Update to 2013 Bode esearch Group 2 = pc 6 4 s (10 mol %) 2 (10 mol %) Toluene/T, rt, 23 h 2 C 2 This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. 2 C 2 90% yield, 99% ee 2 C Pr 2 58% yield, 99% ee 2 C 2 71% yield, 99% ee A Mannich reaction has also been reported for the synthesis of βamino acid derivatives = 4 2 C 6 4 Ts 1) B 4 s (10 mol %) 4 2 C 6 4 a (2 euqiv) 2) 2 Ts 56!75% 88!95% ee Bode JAC 2006, 128, 8418 cheidt JAC 2009, 131, Generation of Cbound enolate via ketene Many formal [22] and [32] cycloadditions have been reported for the synthesis of β lactones and lactams Ts Ts C' TB C (10 mol %) Cs 2 C 3 (10 mol %) toluene, rt B mol% KMD B 4 12 mol% Cs 2 C 3 71% 91% ee Ts 5994% Ts C' 7399% 7899 %ee mith BC 2008, 6, 1108 Ye JC 2008, 73, 8101 B 4 = 2C 6 4 Ye has demonstrated this strategy also in many [42] cycloaddition reactions C 3 C 3 Ts C Ye ACIE 2010, 49,

13 Update to 2013 Bode esearch Group C 2 Bz 10 mol % C Cs 2 C 3 (10 mol %) T, rt Bz C 2 95% 90% ee B 4 C 3 C 3 This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. Ts C 2 1) 20 mol % C Cs 2 C 3 (40 mol %) benzene, rt, 12 h 2) DME, rt, 24 h 10 mol % C Cs 2 C 3 (10 mol %) T, rt Ts C 2 87% 91% ee 93% 94% ee = 2naphthyl 7.4 Generation of Cbound enolate for enantioselective protonation ovis has demonstrated the proof of this principle B 4 TB B 4 Ye JC 2010, 75, 6973, ACIE 2009, 121, 198, & Chem. Commun. 2011, 2381 B 4 C 6 5 (5 10 mol %) 2 2 K/18crown6 toluene, 23 C 2 or D 2 B 4 (10 mol %) 62 85% 76 93% ee 1M K 2 C 3 10 mol% Bu 4 I toluene, 23 C 6596% 9096% ee X ovis JAC 2005, 127, & JAC 2010, 132, 2860 Ketenes have also been used. Impressive results can be obtained with some substrates. This works best when the two substituents on the ketene differ greatly in size. 8 Acyl azoliums ' C cat. 40 o C ' Ye: TB B % 11 95%ee mith: B % 3384 %ee Ye BC 2009, 7, 346 & mith Adv. ynth. Catal. 2009, 351, 3001 Acyl azoliums are fascinating reactive intermediates with chemistry quite distinct from that of other activated carboxylic acid derivates. These species have long been studied for their unusual reactivity and role in biochemical pathways. Unlike other acylating agents, acyl azoliums display a high preference for ester formation or hydrolysis rather than amide formation. This is attributed to the rapid formation of kinetically important hydrates or hemiacetals that undergo general base catalyzed CC bond cleavage in the acid or ester forming step. Y X I Y X II Bode JAC 2010, 132,

14 This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. Update to 2013 Bode esearch Group Internal redox esterification Epoxy aldehyde chanism: oxidized 3 10 mol % C mol % DIPEA 2 reduced or 2 30 C, 3 15 h DIPEA 2 redoxneutral edox esterification from αbromoaldehyde was concurrently reported: 2 3 ther redox reaction of other αfunctionalized aldehydes EWG Bu 2 s (5 mol %) DBU (20 mol %) B 4 C 6 5 EWG B (20 mol %) 3 3 (1 eq) 2 84!98% 2 a 3 / TM 3 20 mol % C Bu 3 16 mol % 3 50% 55% ee 55!91% 3 Bode ACIE, 2006, 45, 6021 ovis JC 2008, 73, 9727 Bode JAC, 2004, 126, 8126 ovis, JAC, 2004, 126, B 4 s (20 mol %) 3 (1.5 equiv) T % mith Chem. Commun 2011, 47,

15 Update to 2013 Bode esearch Group Protonation of homoenolate 2 B 4 s (5 mol %) DIPEA (10 mol %) T, 60 C % This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. 2 3 eslow intermediate 2 3 homoenolate transfer 3 enolate acyl azolium Bode L 2005, 7, Catalytic amidation reactions Amidation reactions are difficult to achieve due to acyl azolium s reluctance to acylate amines. This property has been utilized in chemoselective amidation by intramolecular to transfer. 2 s (5 mol %) T s s 2 s The use of cocatalyst (i.e. At or imidazole) solves the chemoselectivity issue (A) (B) B 4 2 C6 5 (20 mol %) 2 3 At (20 mol %) DIPEA (1.2 eq) 3 72!89% EWG xidative esterification s (5 mol %) imidazole (1.1 eq) DBU (20 mol %) EWG 53!99% 2 Movassaghi L 2005, 7, 2453 & TL 2008, 49, react slowly with amine react readily with amine (A) ovis JAC 2007, 129, & (B) Bode JAC 2007, 129, Although the reaction outcomes are the same (net oxidation of aldehyde), the mechanism for each oxidant may differ (i.e. electron transfer, hydride transfer, or benzoin type addition). 15

16 Update to 2013 Bode esearch Group Azo compounds; Inoue, J.C.. Chem. Commun. 1980, 549 & Connon TL 2008, 49, eslow intermediate [] 2 3 acyl azolium (5 mol %) 1.0 equiv [] 3 (7.5 mol %) 71 % 84 % This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. (A) Quinone as oxidant ", #unsaturated aldehydes (C) Mn 2 as oxidant ", #unsaturated aldehydes PG I (2 mol %) (1.0 equiv) DBU (1.1 equiv) B 4 (10 mol %) Mn 2 (5.0 equiv) DBU (1.0 equiv) factor up to 70 C !93% PG 2457% yield 6495% ee (B) Quinone as oxidant recovered alcohols 3 saturated aldehydes 2 B 4 (10 mol %) s (1.0 equiv) Cs 2 C 3 (0.5 equiv) C 6 5 chiral acylating agent 3 C % yield 7094% ee (A) tuder JAC, 2010, 132, 1190 & (B) Chi ACIE 2013, and related work, Chi ature Chem. 2013, 5, 835 & (C) Zhao ACIE, 2013, 52, 1731 & for other K, see Maruoka L 2005, 7, 1347; uzuki Tetrahedron 2006, 62, 302; tuder ynthesis 2011, 12, 1974 & Yashima CEJ 2011, 17, αydroxyenone as aldehyde surrogate Bode and coworkers have previously acknowledged the relative difficulty of preparing cinnamaldehyde derivatives and introduced αhydroxyenones as easily prepared (one step from commercial materials via aldol condensation) and stored surrogates. urrogate concept: retrobenzoin reaction s s s retrobenzoin s s eslow intermediate 16

17 This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. Update to 2013 Bode esearch Group !99% 2:1!12:1 dr pc % 2 DBU (15 mol %) DBU (50 mol %) s (5!20 mol %) 2 C DBU (50 mol %) 3 2 DBU (50 mol %) 4 3:1 dr DIPEA (20 mol %) 1,2,4triazole (10 mol %) 10 C promoted sigmatropic rearrangement Bicycloβlactam formation Cat 2 Boatlike oxycope T 2 10 mol% s 15 mol% DBU 0.1 M Ac, rt, 15 h Cat 2 C 2 35!76% 2:1!10:1 dr 2 77% 3.5:1 dr !99% Bode JAC 2009, 131, 8714 & Chem. Commun. 2009, npr %yield Cat!lactam C 2 tautomerization formation C 2 Mannich reaction 2 % ee > Bode JAC 2008, 130, 418 aisen rearrangement via α,βunsaturated acyl azolium. A competing plausible conjugate addition between the enol and the unsaturated acyl azolium was ruled out by a detailed kinetics analysis. or Examples: 3 azolium catalyzed internal redox reaction 3 s I ",#unsaturated acyl azolium activated carboxylate C mol % 1 C 3, 40 C no added base 2 s C s!"# II aisen rearrangement C tautomerization and lactonization III s pc 6 4 TB! = kcal/mol! = cal/k.mol k obs = 3.41x10 4 s 1 rate = k obs [cat] 1 [ald] 0.5 [u] C Bu TB 74% yield 99% ee 73% yield 88% ee 79% yield 68% ee 90% yield 96% ee 78% yield 99% ee Bode JAC 2010,132, 8810 An azaaisen variant of the above reaction has also been achieved. ere, the key α,βunsaturated acyl azolium was catalytically generated via an oxidation of the eslow intermediate instead of an internal redox reaction. αhydroxyenones can also be used as aldehyde surrogate in this reaction. 17

18 Update to 2013 Bode esearch Group This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. C 60 % 96 %ee or C % 88 %ee 11 α,βunsaturated acyl azolium edox esterification or 63% yield or or X X= or (10 mol %) oxidant (1.2 equiv) oxidant 2 91 % 79 %ee C s 5 mol% s 3 equiv Toluene, 60 o C, 2 h 48% yield examples 5899% (ee = up to 96%) C 2 99 % 90 %ee X 3 2 catalytically generated unsaturated acyl azolium via 2 3 s Ccatalyzed azaaisen C 2 91 % uc E/Z ratio in all cases >95:5 90% yield α,βunsaturated acyl azolium: observation and mechanistic investigation 10 mol% D 58 % Bode rg. Lett. 2011, 13, % yield uc Zeitler L 2006, 8, 637! = kcal/mol! = 2.93 cal/k.mol k obs = 5.41x10 5 s 1 rate = k obs [cat] 0.5 [ynal] 1 [] 0.5 ammett " =

19 Update to 2013 Bode esearch Group m Chemical ormula: C m/z: (found by LCM) m/z: (calculated) o This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. acyl azolium 1!max = 355 nm C1 c C2 d s n react rapidly with, 2 but not piperidine 2D M correlations Bode ACIE 2011, 50, 1673 earrangement reaction in conjunction with electrocyclic ring opening reaction 10 mol% Toluene, 130 oc, 14 h C aisen cascade Lupton Chem. ci. 2012, 3, 380 Alternative approaches to dihydropyranone synthesis (A) (B) Toluene, 40 4 A M oc % 8598 %ee 3 I (2 mol %) 3 10 mol% % 2 3 (1.0 equiv) DBU (0.1 equiv) (A) redox approach: Xiao Adv. ynth. Catal. 2010, 352, 2455 & Chem. Commun. 2011, 47, 8670, (B) oxidative approach: tuder ACIE, 2010, 49, 9266 & You L, 2011, 13, 4080 A [42] cycloadditions via α,βunsaturated acyl azolium TM 10 mol% T 78 to 10 oc TM C C % Lupton JAC, 2011, 133, C catalyzed hydroacylation reactions ecently the group of Glorius (Uni. Munster) has contributed to many advances in this area of research. or reviews see: Glorius Chem. Lett. 2011, 40, 786 & Acc. Chem. es. 2011, 44,

20 Update to 2013 Bode esearch Group This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. ther variations intramolecular: X X = or intermolecular: TM Tf 2 s 20 mol% cat 20 mol% DBU 80 o C, 20 h X 5 mol% cat K 3 P 4 (1.5 equiv) DM (0.25 M) 40 o C, 16 h 4 s 15 mol% cat 15 mol% K 2 equiv K 4 s 5 mol% cat 1.1 equiv Cs 2 C % 99 %ee linear 1678 % concerted Coniaene branched 847 % Glorius ACIE, 2011, 50, 4983 & ACIE, 2013, 52, % 4093 % mol% cat 1.5 equiv K 3 P 4 0 o C up to 96 % > 20:1 dr up to 96 %ee 13 Dual catalysis using C IminiumC catalysis Glorius ACIE, 2010, 49, 9761 & L, 2011, 13, 98 & ACIE, 2011, 52, TM (20 mol %) B 4 C 3293% 8095 %ee C6 5 TM C 10 mol % aac (10 mol%) C C benzoin C 6 5 ovis JAC, 2009, 131,

21 Update to 2013 Bode esearch Group This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. otoredoxc catalysis product 2 eslow's intermediate C catalysis ' [u(bpy) 3 ] 2 20 mol% mda (1.2 equiv) blue LEDs : 10 mol% ' : ' 14 Chiral triazolium and imidazolium catalysts synthesis 14.1 Chiral thiazolium salts 14.2 Imidazolium salts K () 2 (2 equiv) npr 1),, chiral aminoindanolderived imidazolium salts. 2) TB, 3, DMAP u 2 u % 6292% ee otoredox catalysis TB blue LED Tf 2, pyr C 2 T. _ x x u 2 ovis JAC 2012, 134, 8094 Tf TB Leeper, TL, 1997, 38, 3611 duengo Tetrahedron 1999, 55, * 21

22 Update to 2013 Bode esearch Group 2 C 3 a, T 2 C 3 C 2 Ac C 3 xone acetone ac 3 This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License C 3 Ac C 3 Ac Ac 2 4 Ac 2 cat Chiral pyrrolidinonederived triazolium salts ldrum's acid DMAP DCC C 2 Boc Boc 2 B 4 C() 3 C Chiral aminoindanolderived triazolium salt 2 s a C() 3 /dioxane s (C) 2 DM 3 C 3 ab 4 Ac C 2 2 B 4 3 B 4 C 2 2 ; ac 3 (sat.) s 3 cat. Boc 2 C 2 2 C 3 a 14.6 Chiral triazolium and imidazolium precatalyst reactivity comparison C 3 Bode Tetrahedron 2008, 64, 6961 toluene 110 o C; TA C B 4 C 2 2 ovis JC, 2005, 70, ) (aq) 2) a 2 3) n Bode rg. ynth. 2010, 87,

23 Update to 2013 Bode esearch Group 4 imidazoluim (cat.1) 4 triazolium (cat.2) This work is licensed under a Creative Commons AttributiononCommercialhareAlike 4.0 International License. Cyclopentene forming benzoin oxy!cope reactions Butyrolactone forming annulations Intramolecular tetter reactions Intermolecular benzoin dimerization 10 mol% cat 15 mol% DBU 0.1 M C 2 C 2 0 o C, rt, 18 h 2 C 8 mol% cat 7 mol% DBU 10:1 T:tBu 40 o pc C, 15 h 6 4 C 2 20 mol% cat 20 mol% KMD 0.02 M xylene 25 o C, 24 h 10 mol% cat 10 mol% K t Bu 0.7 M T 25 o C, 16 h C 2 cat.1: 10% yield, 1.6:1.0 d.r., 99% ee cat.2: 85% yield, 7:1 d.r., 99% ee cat.1: 55% yield, 1.4:1.0 d.r. cat.2: 14% yield, 1.3:1.0 d.r. cat.1: no reaction cat.2: 94% yield, 98% ee cat.1: 11% yield cat.2: 83% yield Bode L 2008, 10,