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Myers C!N Bond-Forming Reactions: Reductive Amination Chem 115 Reviews: Reducing Agents Abel-Magid, A. F.; Mehrman, S. J. Org. Proc. Res. Devel. 2006, 10, 971–1031. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, • Common reducing agents: NaCNBH3, Na(OAc)3BH, H2/catalyst 61, 3849-3862. Bhattacharyya, S. Tetrahedron Lett. 1994, 35, 2401–2404. • Iminium ions are reduced selectively in the presence of their carbonyl precursors. Reagents Hutchins, R. O.; Hutchins, M. K., Reduction of CdN to CHNH by Metal Hydrides. In Comprehensive such as sodium cyanoborohydride and sodium triacetoxyborohydride react selectively with iminium ions and are frequently used for reductive aminations. Organic Synthesis; Trost, B. N., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 8. Overview: Reduction with Sodium Cyanoborohydride: • The reductive amination of aldehydes and ketones is an important method for the synthesis of primary, secondary, and tertiary amines. • Borch and co-workers showed that sodium cyanoborohydride and lithium cyanoborohydride are acid-stable reagents capable of rapidly reducing carbonyl compounds to alcohols at pH • Reductive amination is a powerful and reliable strategy for the formation of C–N bonds, and 3–4, presumably via a protonated carbonyl cation. can avoid the problem of overalkylation that often accompanies direct alkylation of amines with alkyl halides. NaBH CN O 3 OH Mechanism: CH3OH Ph CH3 Ph CH3 • Reductive amination involves a one- or two-step procedure in which an amine and a carbonyl pH 3, 23 °C, 1 h (±) compound condense to afford an imine or iminium ion that is reduced in situ or subsequently 93% to form an amine product. Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897–2904. R3 4 3 4 R H+ (cat.) R3 R4 R R O R3 R4 N N hydride N + N • At pH 7, reduction of carbonyl compounds with lithium cyanoborohydride is very slow, even 2 1 2 2 R1 R R R 1 2 source R1 R at reflux in methanol. H HO R R H R1, R2, R3, R4 = H, alkyl, aryl !H2O R4 = H R3 N hydride, proton source R1 R2 LiBH CN O 3 OH CH3OH Ph CH Ph CH 3 pH 7, reflux, 72 h 3 • relative rates of reductive amination: 36% (±) H N H2NR > > HNR2 > H2NAr n Borch, R. F.; Durst, H. D. J. Am. Chem. Soc. 1969, 91, 3996–3997. n = 1, 2 Jonathan William Medley, Fan Liu 1 Myers C!N Bond-Forming Reactions: Reductive Amination Chem 115 • With care to maintain a pH of 6–7, a mixture of a ketone or aldehyde reactant, an amine, and Reduction with Sodium Triacetoxyborohydride: sodium cyanohydride provides products of reductive amination selectively, without • Sodium triacetoxyborohydride has been found to be a highly selective reducing agent for competitive reduction of the carbonyl substrate. reductive amination; acetic acid is frequently employed as a proton donor. • Though the conditions of the Borch reduction are mild, sodium cyanoborohydride is highly • This protocol is generally high yielding, highly functional group tolerant, and proceeds without toxic, as are its byproducts. release of cyanide salts. The substrate scope includes aromatic and aliphatic aldehydes, ketones, and primary and secondary amines. Ammonia can be employed successfully if used in large excess as its acetate salt. NaBH3CN R3 R4 O R R CH3OH N R R 3 4 O NaHB(OAc)3 3 4 + N R3 R4 N R R a + N 1 2 H pH 6–8, 23 °C R1 R2 H R1 R2 H Method R R 1 H 2 carbonyl compound amine product isolated yield (%) carbonyl compound amine methoda product yield (%) O Ph Ph N O O O N II 96 N N 79 N N H H H O EtO N NH2 II 88 O NHCH OEt EtO 3 OEt H C H C 3 Ph CH3NH2 3 Ph 90 NH OAc CH3 CH3 cycloheptanone 4 b cycloheptylamine c (10 equiv) II 80 O H OH CH3 CH3 N N N H2NOH 66 PhNH2 I 96 O NHPh O NHPh H3C PhNH H3C 78 COOEt COOEt H 2 H OHC H CH3 CH3 N II N 95 N N O NH2 O N(i-Pr)2 HO OH NH3 HO OH 51 H (i-Pr)2NH II 88 O O O O (±) a The pH was maintained by addition of HCl and/or KOH as needed using bromocresol green as an a Method I: ClCH2CH2Cl, AcOH (1!2 equiv), NaBH(OAc)3 (1.3!1.6 equiv). Method II: ClCH2CH2Cl, indicator. b c NaBH(OAc)3 (1.3!1.6 equiv). Et3N (1.5!2.0 equiv) added. yield of HCl salt. Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897–2904. Jonathan William Medley 2 Myers C!N Bond-Forming Reactions: Reductive Amination Chem 115 Reaction with Weakly Nucleophilic Amines: Reduction with Sodium Borohydride: • Reductive amination of carbonyl compounds with primary amines can be complicated by overalkylation. In these cases, formation and isolation of the imine followed by reduction can prove NaHB(OAc) R3 R4 O R R 3 N to be a superior alternative. + 3 N 4 R1 R2 H Method R1 R H 2 • It was found that the use of methanol as solvent allows for rapid (< 3h) and nearly quantitative imine formation from aldehydes without the need for dehydrating reagents. carbonyl compound amine methoda product yield (%) R3 R3 R4 Br O CH3OH N NaBH4 N + R3 NH2 O Br !H O 10 15 min H R1 R2 2 R1 R2 ! R1 R2 III N 89b H H2N aldehyde amine product yield (%)a O Cl Cl Ph O H3CO N Cl Cl H PhNH2 84 H H IV N 95 Cl H2N O H N 89 H2N H Cl Cl O H N H IV 95 H2N NO O 2 Ph NO2 N H PhNH2 90 H O S H S H N IV N 60 O 2 t-Bu Ph H N Bn N N H t-BuNH2 83 H O H c H2N Ts IV N Ts 80 Ph H Bn Ph H BnNH2 Ph NHBn 85 O a a products isolated as HCl salts. Method III: ClCH2CH2Cl, AcOH (1 equiv), NaBH(OAc)3 (1.4 equiv). Method IV: ClCH2CH2Cl, b AcOH (2!5 equiv), carbonyl compound (1.5!2 equiv), NaBH(OAc)3 (2.0!2.8 equiv). yield of HCl Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. salt. cEt N (2.0 equiv) added. 3 1996, 61, 3849!3862. Jonathan William Medley 3 Myers C!N Bond-Forming Reactions: Reductive Amination Chem 115 Examples in Synthesis O CH3 OTBS O AcO CH3 Na(AcO)3BH, Sn(OTf)2 CH3 H C + H3C H N(CH3)2 NaBH CN 3 O O 3 CHO 4 Å MS, ClCH2CH2Cl, 0 °C CH HO N HO OCH2 3 O O OH H O O CH3 CH3OH, H OCH CH O 3 CH3 3 O OH 66% Et O OH NH O CH3 tylosin 79% OTBS AcO CH3 H3C N O O H O CH3 N Hosokawa, S.; Sekiguchi, K.; Hayase, K.; Hirukawa, Y.; Kobayashi, S. Tetrahedron Lett. 2000, CH3 41, 6435-6439. H3C N(CH3)2 O HO HO OCH2 CH3 O O O O CH3 OH OCH CH O 3 CH3 3 O OH Et O OH CH Ph Ph Ph Ph 3 O O NaBH3CN N H N H CH2O Matsubara, H.; Inokoshi, J.; Nakagawa, A.; Tanaka, H.; Omura, S. J. Antibiot. 1983, 36, 1713-1721. H CH3 CH3 H3C 84% Jacobsen, E. J.; Levin, J.; Overman, L. E. J. Am. Chem. Soc. 1988, 110, 4329-4336. H CO2Bn H CO2Bn CO2Bn H CO2Bn H CO2Bn OHC NaBH3CN H • Formic acid can also be used as a hydride donor: N OTHP N N OTHP CH3OH CO2t-Bu CO2t-Bu + 59% H H C 3 1. H , Pd/C, EtOH, N N 2 CH3 CH3 CO2Bn H3C H3C H H2O, HCl HO OH HO OH 2. TFA H C H C NH•TFA 3 OH CH 3 OH CH 3 N(CH3)2 3 N(CH3)2 H C H C H3C 3 HO H3C 3 HO O O O CH3 O O O CH3 CH2O, HCO2H CO2H H CO2H H CO2H O O OCH O O OCH H 3 3 N N OH CH3 CHCl3, 65 ºC CH3 CH3 CH3 H O OH 71% O OH CH CH 3 3 2'-deoxymugineic acid Ohfune, Y.; Tomita, M.; Nomoto, K. J. Am. Chem. Soc. 1981, 103, 2409-2410. Dokic, S.; Kobrehel, G.; Lopotar, N.; Kamenar, B.; Nagl, A.; Mrvos, D. J. Chem. Res (S). 1988, 152. Mark G. Charest, Fan Liu 4 Myers C!N Bond-Forming Reactions: Reductive Amination Chem 115 • A regioselective reductive amination using sodium triacetoxyborohydride was employed in • In a complex transformation, a tryptamine derivative and an enantioenriched dialdehyde the construction of the pyrrolidine ring of (!)-communesin A: were combined to give a cyclic bis-hemiaminal interemediate; electrophilic activation with trifluoroacetic anhydride initiated a Mannich/Sakurai cascade. Subsequent iminium reduction H3C CH 3 OH H3C CH3 with sodium cyanoborohydride afforded a pentacyclic diamine en route to (!)-aspidophytine. O O O HN H C N NH4OAc 3 H3C N H C O NaHB(OAc)3 3 H3C O OH NH CH3OH, >92% NH OHC N NH N N 2 CH3CN CH 3 CH3 OHC HO N H CO N R H3CO R 3 TMS 4 steps CH OCH CH3 OCH3 3 TMS 3 R = CH2COOi-Pr TFAA (2 equiv) H C Ac !TFA 3 CH 3 N O N N CF3COO CF3COO NH R TMS N N !CF3COOTMS CH N R 3 H3CO TMS H CO N 3 OCH CH3 (!)-communesin A CH 3 OCH3 3 Zuo, Z.; Ma, D.
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  • Comparative Total Syntheses of Strychnine

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    Comparative Total Syntheses of Strychnine N C D MacMillan Group Meeting N H O H A H B E Nathan Jui H N N H H F G July 22, 2009 O O O References: Pre-Volhardt: Bonjoch Chem. Rev. 2000, 3455. Woodward Tetrahedron, 1963, 247. Volhardt J. Am. Chem. Soc. 2001, 9324. Magnus J. Am. Chem. Soc. 1993, 8116. Martin J. Am. Chem. Soc. 2001, 8003. Overman J. Am. Chem. Soc. 1995, 5776. Bodwell Angew. Chem. Int. Ed. 2002, 3261. Kuehne J. Org. Chem. 1993, 7490. Mori J. Am. Chem. Soc. 2003, 9801. Kuehne J. Org. Chem. 1998, 9427. Shibasaki Tetrahedron 2004, 9569. Rawal J. Org. Chem. 1994, 2685. Fukuyama J. Am. Chem. Soc. 2004, 10246. Bosch, Bonjoch Chem. Eur. J. 2000, 655. Padwa Org. Lett. 2007, 279. History and Structure of (!)-Strychnine ! Isolated in pure form in 1818 (Pelletier and Caventou) ! Structural Determination in 1947 (Robinson and Leuchs) ! 24 skeletal atoms (C21H22N2O2) ! Isolated in pure form in 1818 (Pelletier and Caventou) N ! Over !25 07 -pruinbglisc,a 6ti-osntesr epoecrteaninteinrgs to structure ! Structural Determination in 1947 (Robinson and Leuchs) ! Notor!io u Ss ptoirxoicne (nletethr a(lC d-o7s) e ~10-50 mg / adult) N H H ! Over 250 publications pertaining to structure O O ! Comm!o nClyD uEs eridn gr osdyesntet mpoison ! Notorious poison (lethal dose ~10-50 mg / adult) ! Hydroxyethylidine Strychnos nux vomica ! $20.20 / 10 g (Aldrich), ~1.5 wt% (seeds), ~1% (blossoms) "For it's molecular size it is the most complex substance known." -Robert Robinson History and Structure of (!)-Strychnine ! 24 skeletal atoms (C21H22N2O2) N ! 7-rings, 6-stereocenters ! Spirocenter (C-7) N H H O O ! CDE ring system ! Hydroxyethylidine "For it's molecular size it is the most complex substance known." -Robert Robinson "If we can't make strychnine, we'll take strychnine" -R.
  • Electrochemistry and Photoredox Catalysis: a Comparative Evaluation in Organic Synthesis

    Electrochemistry and Photoredox Catalysis: a Comparative Evaluation in Organic Synthesis

    molecules Review Electrochemistry and Photoredox Catalysis: A Comparative Evaluation in Organic Synthesis Rik H. Verschueren and Wim M. De Borggraeve * Department of Chemistry, Molecular Design and Synthesis, KU Leuven, Celestijnenlaan 200F, box 2404, 3001 Leuven, Belgium; [email protected] * Correspondence: [email protected]; Tel.: +32-16-32-7693 Received: 30 March 2019; Accepted: 23 May 2019; Published: 5 June 2019 Abstract: This review provides an overview of synthetic transformations that have been performed by both electro- and photoredox catalysis. Both toolboxes are evaluated and compared in their ability to enable said transformations. Analogies and distinctions are formulated to obtain a better understanding in both research areas. This knowledge can be used to conceptualize new methodological strategies for either of both approaches starting from the other. It was attempted to extract key components that can be used as guidelines to refine, complement and innovate these two disciplines of organic synthesis. Keywords: electrosynthesis; electrocatalysis; photocatalysis; photochemistry; electron transfer; redox catalysis; radical chemistry; organic synthesis; green chemistry 1. Introduction Both electrochemistry as well as photoredox catalysis have gone through a recent renaissance, bringing forth a whole range of both improved and new transformations previously thought impossible. In their growth, inspiration was found in older established radical chemistry, as well as from cross-pollination between the two toolboxes. In scientific discussion, photoredox catalysis and electrochemistry are often mentioned alongside each other. Nonetheless, no review has attempted a comparative evaluation of both fields in organic synthesis. Both research areas use electrons as reagents to generate open-shell radical intermediates. Because of the similar modes of action, many transformations have been translated from electrochemical to photoredox methodology and vice versa.