Opening New Frontiers in Synthesis and Catalysis

VOL. 42, NO. 3 • 2009

Discovering New Reactions with N-Heterocyclic Carbene Catalysis Synthesis and Applications of Diorganozinc Reagents: Beyond Diethylzinc New Products from Aldrich R&D Aldrich Is Pleased to Offer Cutting-Edge Tools for Organic Synthesis

Phosphine for the Conversion of Azides into Diazo Compounds More NEW Solutions of Common Reagents Due to difficulties with their preparation, especially when sensitive functional Every researcher has experienced the frustration of using on a regular basis some groups are present, diazo compounds are often overlooked in synthesis despite lab reagent that is annoying to handle: It might be difficult to weigh out, extremely their synthetic versatility. Myers and Raines have developed a mild method to volatile, prone to static, or noxious. Sigma-Aldrich has designed a series of solutions convert an azido group with delicate functional groups into a diazo compound intended to make many of these common reagents easier to measure, handle, by using the phosphine reagent shown below. Formally, this reaction is a and dispense. reductive fragmentation of the azide, like the venerable Staudinger reaction, and is highly selective in most chemical environments. 2,2′-Azobis(2-methylpropionitrile) solution, 0.2 M in toluene 714887 100 mL H3C CH3 [78-67-1] N C N O N C N C8H12N4 O H3C CH3 N FW: 164.21 P O O Iodine monochloride, 1 M in acetic acid 714836 100 mL 1.05 equiv [7790-99-0] ICl 715069 ICl N N 3 1) THF/H2O (20:3), 3-12 h 2 FW: 162.36 1 2 1 2 R R 2) Sat. aq. NaHCO3, 15 min - 12 h R R 49 - 97% 4-(Dimethylamino)pyridine solution, 0.5 M in ethyl acetate 714720 H C CH 100 mL 3 N 3 [1122-58-3] C H N Myers, E. L; Raines, R. T. Angew. Chem., Int. Ed. 2009, 48, 2359. 7 10 2 FW: 122.17 N N-Succinimidyl 3-(diphenylphosphino)propionate, 95% 4-(Dimethylamino)pyridine solution, 0.5 M in THF 715069 O 1 g O 714844 H3C CH3 100 mL [170278-50-9] N 5 g N C H NO P P O [1122-58-3] 19 18 4 O C H N FW: 355.32 7 10 2 FW: 122.17 N

1,8-Diazabicyclo[5.4.0]undec-7-ene solution, 1 M in ethyl acetate 714860 100 mL Stable Precursor for Nazarov’s Reagent [6674-22-2] N Nazarov’s reagent is a commonly used annulating agent, but its synthesis is often C9H16N2 N fraught with poor yields or difficulties isolating the material. De Risi and coworkers FW: 152.24 recently reported a bench-stable powder that can be demasked under various conditions to generate Nazarov’s reagent in situ. 1,8-Diazabicyclo[5.4.0]undec-7-ene solution, 1 M in THF 714852 100 mL O [6674-22-2] N C H N O O O 9 16 2 N O H3C O FW: 152.24 H3C S OEt O KF, MeOH, rt, 24 h O Acetaldehyde solution, 5 M in THF 718327 CO2Et 719099 50 mL 50% [75-07-0] O

C2H4O H3C H Benetti, S. et al. Synlett 2008, 2609. FW: 44.05

Ethyl 5-[(4-methylphenyl)sulfonyl]-3-oxopentanoate, 95% Carbon disulfide, 5 M in THF 718327 O O 1 g 721476 50 mL O C H O S [75-15-0] 14 18 5 H3C S OEt CS2 FW: 298.35 O CS2 FW: 76.14

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VOL. 42, NO. 3 • 2009 Joe Porwoll, President Aldrich Chemical Co., Inc. Aldrich Chemical Co., Inc. Sigma-Aldrich Corporation 6000 N. Teutonia Ave. Milwaukee, WI 53209, USA Dr. Biagetti Matteo from GlaxoSmithKline kindly suggested that we make lithium diisobutyl- t-butoxyaluminum hydride (LDBBA). LDBBA is an effective reducing agent for the conversion of esters into aldehydes without the problematic over-reduction or the inconvenience of To Place Orders requiring lower temperatures. Telephone 800-325-3010 (USA) Kim, M. S.; Choi, Y. M.; An, D. K. Tetrahedron Lett. 2007, 48, 5061. FAX 800-325-5052 (USA) or 414-438-2199 Mail P.O. Box 2060 Al Milwaukee, WI 53201, USA O H Li Customer & Technical Services Customer Inquiries 800-325-3010 718386 Technical Service 800-231-8327 718386 Lithium diisobutyl-t-butoxyaluminum hydride (LDBBA), SAFC® 800-244-1173 0.5 M in THF-hexanes 25 mL Custom Synthesis 800-244-1173 100 mL Flavors & Fragrances 800-227-4563 International 414-438-3850 Naturally, we made this useful reducing agent. It was no bother at all, just a 24-Hour Emergency 414-438-3850 pleasure to be able to help. Website sigma-aldrich.com Email [email protected] Do you have a compound that you wish Aldrich could list, and that would help you in your research by saving you time and money? If so, please send us your suggestion; we will be delighted General Correspondence to give it careful consideration. You can contact us in any one of the ways shown on this page and Editor: Sharbil J. Firsan, Ph.D. on the back cover. P.O. Box 2988, Milwaukee, WI 53201, USA TABLE OF CONTENTS Subscriptions Discovering New Reactions with N-Heterocyclic Carbene Catalysis...... 55 To request your FREE subscription to the Eric M. Phillips, Audrey Chan, and Karl A. Scheidt,* Northwestern University Aldrichimica Acta, please contact us by: Phone: 800-325-3010 (USA) Synthesis and Applications of Diorganozinc Reagents: Beyond Diethylzinc...... 71 Alexandre Lemire, Alexandre Côté, Marc K. Janes, and André B. Charette,* University of Montreal Mail: Attn: Mailroom Aldrich Chemical Co., Inc. Sigma-Aldrich Corporation ABOUT OUR COVER P.O. Box 2988 Paul Cézanne (1839–1906), who painted Milwaukee, WI 53201-2988 Landscape near Paris (oil on canvas, Email: [email protected] 50.2 × 60 cm) around 1876, was born in Aix-en-Provence in 1839. His father, a International customers, please contact your local Sigma- prosperous businessman, decided that Aldrich office. For worldwide contact information,­ please see his only son should become a lawyer. the back cover. Cézanne attended the Aix law school, but preferred classes at the Musée d’Aix (now The Aldrichimica Acta is also available on the Internet at the Musée Granet) and decided on a life as sigma-aldrich.com/acta. an artist instead. In 1861, Cézanne, encouraged by his Aldrich brand products are sold through Sigma-Aldrich, Inc. boyhood friend, the novelist Émile Zola, Sigma-Aldrich, Inc., warrants that its products conform to traveled to Paris. There, he frequented the Salon, studied the old masters, and copied Photograph © Board of Trustees, National Gallery of Art, Washington. the information contained in this and other Sigma-Aldrich Delacroix at the Louvre. He also forged publications. Purchaser must determine the suitability of the friendships with many important artists, one of whom, Camille Pissarro, became a pivotal, product for its particular use. See reverse side of invoice or lifelong influence on Cézanne. packing slip for additional terms and conditions of sale. Cézanne exhibited with the impressionists in 1874 and 1877. Our cover possibly painted in the company of Pissarro in Auvers-sur-Oise, a northwestern suburb of Paris, was completed All prices listed in this publication are subject to change sometime between the two exhibitions. The work clearly denotes Cézanne’s departure from without notice. his early romantic and realist influences, and displays his enduring interest in plein-air painting. Aldrichimica Acta (ISSN 0002-5100) is a publication of In this work, Cézanne placed an emphasis on the observation of nature and the rendering of Aldrich. Aldrich is a member of the Sigma-Aldrich Group. light and atmospheric effects. He achieved structure by applying paint directly to the canvas, © 2009 Sigma-Aldrich Co. recording his response to the sensation of color. This painting is part of the Chester Dale Collection at the National Gallery of Art, Washington, DC. VOL. 42, NO. 3 • 2009 N-Heterocyclic Carbene Organocatalysts

Organocatalysis has been an active field of research with Recently, Phillips et al. reported the utilization of a chiral over 2,000 publications in the past 10 years. Interest in this triazole for the enantioselective addition of homoenolates relatively new field derives from the many advantages of to nitrones affording γ-amino esters. This reaction is very organocatalysis such as easy experimental procedures, versatile and tolerates electron-rich and electron-poor reduction of chemical waste, avoidance of metal groups on the aldehyde. Using 20 mol % of the chiral contamination in the product, and cost saving from not triazole at –25 °C affords the desired products in good yields using expensive metals for the catalysis. and selectivities. Scheidt and coworkers have developed a series of N-heterocyclic carbene organocatalysts for various BF4 reactions. These catalysts are efficient, and the chiral ones N N have given rise to good enantioselectivities. N O In 2005, Audrey Chan and Karl A. Scheidt reported the 708542 O transformation of unsaturated aldehydes into saturated O O Ph (20 mol %) H3CO OH H N esters in good yields by using as low as 5 mol % of an + N CH Cl , Et N, 25 °C Ph Ph Ph R H 2 2 3 − N-heterocyclic carbene catalyst. then NaOMe/MeOH R R = aryl, Cy 62–80% 81–93% ee I O N N Reference: O O

Phillips, E. HM.3 COet al. J. Am. Chem.OH Soc. 2008H,3 130CO, 2416. OH H3CO OH N N N Ph Ph Ph Ph 708593 Ph Ph H CO Ph (5 mol %) 3 O O PhOH (2 eq.) 70%, 93% ee 70%, 93% ee 62%, 90% ee + ROH Ph H Ph OR DBU, toluene BF4 BF4

O O O O Ph N N N N Ph OEt Ph OPh Ph O Ph O N N O O 72% 56% 57% 77% 708542 708569 Reference: Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905. I I N N N N For ordering or more information, please visit N sigma-aldrich.com

708607 708593

I BF4 N N N N N

708577 708585

sigma-aldrich.com 55 Discovering New Reactions with N-Heterocyclic Carbene Catalysis

Eric M. Phillips, Audrey Chan, and Karl A. Scheidt* Department of Chemistry Center for Molecular Innovation and Drug Discovery Chemistry of Life Processes Institute, Silverman Hall Northwestern University 2145 Sheridan Road Evanston, IL 60208, USA Dr. Audrey Chan Professor Karl A. Scheidt Mr. Eric M. Phillips Email: [email protected]

Outline fascinating Lewis base catalyzed transformations by utilizing the 1. Introduction lone pair of electrons at C-2. 2. Acyl Anions In the early 1960s, Wanzlick and co-workers realized that 2.1. Stetter Reactions the stability of carbenes could be dramatically enhanced by the 2.2. Imine Additions presence of amino substituents, and they attempted to prepare 3. Oxidation Reactions a carbene center at C-2 of the imidazole ring.15,16 However, 4. Homoenolates only the dimeric electron-rich olefin was isolated. Later on, 4.1. b Protonation Wanzlick’s group demonstrated that potassium tert-butoxide 4.2. Formal [3 + n] Cycloadditions can deprotonate imidazolium salts to afford imidazol-2-ylidenes, 5. Enolate Chemistry which can be trapped with phenyl isothiocyanate and mercury 6. Elimination Reactions salts.17–19 However, Wanzlick’s group never reported the isolation 7. Theoretical Calculations of the free carbene. Following these results, Arduengo et al. 8. Conclusions and Outlook isolated in 1991 a stable crystalline N-heterocyclic carbene by 9. Acknowledgements the deprotonation of 1,3-di(1-adamantyl)imidazolium chloride 10. References and Notes with sodium or potassium hydride in the presence of a catalytic amount of either potassium tert-butoxide or dimethyl sulfoxide.20 1. Introduction The structure was unequivocally established by single-crystal Inspired by advances in our understanding of biological processes, X-ray analysis, and the carbene was found to be thermally stable, new reactions employing organic molecules as catalysts have which stimulated extensive research in this field. grown significantly over the last two decades.1 In the broadest The nature of the stabilization is ascribed to the steric and of terms, the most successful of these catalysts can be classified electronic effects of the substituents: The two adamantyl either as Brønsted acids,2,3 hydrogen-bond donors,4–7 or Lewis substituents hinder reactions of the carbene center with external bases.8–11 Each of these catalytic manifolds activates substrates reagents as well as prevent dimerization. In 1992, Arduengo in biological settings and provides an inspiring blueprint to create et al. expanded this carbene class by successfully isolating smaller, synthetic versions of these impressive biocatalysts. the carbene from 1,3,4,5-tetramethylimidazolium chloride by Lewis base catalysis is presently an exciting area of research treating the latter with sodium hydride and catalytic amounts and encompasses a wide variety of strategies to initiate both of potassium tert-butoxide in tetrahydrofuran.21 The successful established and new chemical processes.12,13 An elegant and isolation of carbenes with less bulky substituents demonstrates key biological transformation utilizes the cofactor thiamine, a that electronic factors may have greater impact on the stability coenzyme of vitamin B1, to transform α-keto acids into acetyl of the carbene than steric ones. Such electronic factors operate CoA, a major building block for polyketide synthesis. In this in both the π and σ frameworks, resulting in a “push-pull” process, a normally electron-deficient molecule (e.g., pyruvic synergistic effect to stabilize the carbene. π donation into the acid) is converted into an intermediate that possesses electron carbene from the out-of-the-plane π orbital of the heteroatoms density on the carbon atom that was initially part of the carbonyl adjacent to C-2 stabilizes the typical electrophilic reactivity system. These carbonyl or acyl anions are unusual since they of carbenes. The electronegative heteroatoms adjacent to C-2 have “umpolung” (reversed polarity) when compared to the provide additional stability through the framework of σ bonds, initial keto acids. In 1954, Mizuhara and Handler proposed that resulting in a moderation of the nucleophilic reactivity of the the active catalytic species of thiamine-dependent enzymatic carbene (Figure 1).22 The combination of these two effects serves reactions is a highly unusual divalent carbon-containing species,14 to increase the singlet–triplet gap and stabilize the singlet-state later on referred to as an N-heterocyclic carbene (NHC). An carbene over the more reactive triplet-state one. alternative description of the active thiamine cofactor employs The electronic properties of NHCs are a key determinant of the term zwitterion, which can be viewed as a resonance form the unique reactivity of these catalysts. Lewis bases are normally of the carbene description. This unique cofactor accomplishes considered as single electron-pair donors. However, the singlet VOL. 42, NO. 3 • 2009 56

carbenes of NHCs are distinct Lewis bases that have both σ utilizes a thiamine-related NHC as a nucleophilic catalyst. In basicity and π acidity characteristics. These attributes allow for 1943, Ugai and co-workers reported that thiazolium salts can the generation of a second nucleophile in the flask. Nucleophilic catalyze the self-condensation of benzaldehyde to produce addition of the carbene to an aldehyde results in the formation of benzoin.23 This process is clearly related to the earliest reports a new nucleophile. The “doubly” nucleophilic aspect is unique of laboratory organocatalysis from Wöhler and Liebig in 1832 to the carbenes. The combination of these characteristics allows detailing the cyanide-catalyzed benzoin reaction.24 Based NHCs to react as powerful nucleophiles, which has driven the on Ugai’s report, Breslow proposed the mechanism in which development of a distinct class of catalytic processes during the the active catalytic species is a nucleophilic carbene derived last decade. This review highlights our work in this young and from a thiazolium salt to generate the carbanion known as promising field. the Breslow intermediate.1b In 1966, Sheehan and Hunneman reported the first investigations into an asymmetric variant of 2. Acyl Anions the benzoin condensation employing a chiral thiazolium salt as The earliest application of these unique Lewis bases was the precatalyst.25a Most recently, Enders and Kallfass accomplished development of the benzoin reaction.23 This umpolung process the first high-yield and highly enantioselective intermolecular benzoin condensation (Scheme 1).25b This seminal work by Enders on carbene catalysis using triazolium salts focused the π-electron donation interest of the community on these unique structures and moved interest away from thiazolium catalysts.

1 Discovering New Reactions with N-Heterocyclic Carbene Catalysis Discovering New Reactions with N-Heterocyclic R N R σ-electron 2.1. Stetter Reactions N R withdrawal In the 1970s, Stetter demonstrated that catalysis with thiazolium R1 spe cie s ca n be employed t o a ccompl ish t he a dd it ion of a cyl a n ion s to 1,4-conjugate acceptors.26 This transformation is a useful Figure 1. Proposed Stabilization of N-Heterocyclic Carbenes carbon–carbon-bond-forming strategy that has attracted the through σ and π Electronic Effects. (Ref. 22) attention of researchers interested in producing 1,4-dicarbonyl

(a) Catalysis by a Chiral Thiazolium-Derived NHC (Ref. 1b,23) species. Like the benzoin reaction, the addition of an NHC to an aldehyde generates the acyl anion equivalent, and this initial 1 R N S step is typically facile due to the highly electrophilic nature of OH O O 2 2 OH the aldehyde. However, this electrophilicity is also detrimental R R S R H R 2 R R R to processes other than dimerization in that multiple side- R H N R1 O R2 products are formed, because the aldehyde is at least as reactive Breslow as the secondary electrophile needed for a benzoin or Stetter intermediate reaction. A possible approach to circumvent this problem is to OH utilize acylsilanes.27–29 Disclosures by Heathcock’s30 and then S 31 R R2 Degl’Innocenti’s groups have shown that, upon exposure N 1 of acylsilanes to charged nucleophilic species (e.g., fluoride, R 2 R cyanide), the carbonyl carbon can participate in alkylation (b) Catalysis by a Chiral Triazolium-Derived NHC (Ref. 25b) reactions or conjugate additions. Acylsilanes have become a O OH azolium salt (10 mol %) Ar useful alternative to aldehydes in the generation of acyl anions, Ar Ar H KOt-Bu (10 mol %) because the sterically congested nature of the silyl group O anhydrous THF, 16 h precludes problematic dimerization reactions (e.g., benzoin –78, 0, or 18 oC 8–83% 80–95% ee 32,33 O N reaction). N Ph Inspired by this early acylsilane work of Heathcock N + – t-Bu BF4 and Degl’Innocenti, we began a research program in 2002 azolium salt directed toward the investigation of catalytic carbonyl addition reactions. Well-established routes to acyl anion equivalents Scheme 1. Asymmetric Benzoin Condensation. from the combination of aldehydes and NHCs have been heavily investigated,33,34 and we hypothesized that a complementary 1. DBU, azolium salt Ph O O O THF, additive O approach utilizing acylsilanes would enhance known reactions reflux + (e.g., Stetter reaction) and provide a platform for the discovery Ph SiMe3 Ph Ph 2. H O Ph Ph 2 of new reverse polarity. In this process, nucleophilic addition Me R' Azolium of an NHC to an acylsilane would facilitate a Brook 1,2 N Salt Additive Yield rearrangement35 with concomitant formation of the acyl anion X– R S 1a none 71% equivalent or Breslow intermediate. However, at the onset – a 1; R = (CH2)2OH, R' = Et, X = Br 2 none 0% 2; R = Me, R' = Bn, X = Br– 1b none 43% of our investigations, it was unknown if a nucleophile larger 3; R = Me, R' = Me, X = I– 1b i-PrOH 77% than fluoride or cyanide would add to the sterically congested 3b i-PrOH 77% Mes Me Me carbonyl carbon of the acylsilane, let alone facilitate the requisite 4b i-PrOH 0% N N N b i-PrOH – – – 5 7% 1,2 migration of the silyl group from the carbon to the oxygen. Cl N I I b N N N 6 i-PrOH 5% We first explored the NHC-catalyzed 1,4 addition of Mes Me Me a 1 equiv of 1 used. acylsilanes to chalcone. The use of stoichiometric amounts of 4 5 6 b Catalyst loading, 30 mol %. thiazolium salt 1 and DBU led to the formation of the desired 1,4-diketone in 71% yield from benzoyltrimethylsilane and eq 1 (Ref. 36–38) chalcone (eq 1).36–38 While this result was reassuring, rendering VOL. 42, NO. 3 • 2009 57 this reaction catalytic in azolium salt was not straightforward. breadth of possible reaction platforms, a successful application When the amount of 1 was reduced to 30 mol %, the isolated would produce valuable α-amino ketones directly in a particular yield became only 43%. Interestingly, no product was observed oxidation state.39–41 when one equivalent of thiazolium 2 was employed. This lack The choice of imine protecting group proved pivotal to the of catalytic activity led us to believe that the alcohol moiety in 1 success of the reaction. Attempts to incorporate N-Bz, N-sulfinyl, played a pivotal role in the reaction. Indeed, upon addition of four and N-sulfonyl imines were fruitless, whereas N-phosphinoyl equivalents of 2-propanol to an acylsilane reaction containing 30 imines provided the right balance of activation to be successful mol % 1, the isolated yield improved to 77%. A similar yield was substrates as reported by Weinreb and Orr.42 This stark contrast obtained with thiazolium 3 and four equivalents of 2-propanol, in reactivity demonstrates a crucial consideration of any reaction further supporting our contention. Attempts to incorporate other utilizing carbenes as Lewis base catalysts, namely selective azolium salt derivatives such as imidazolium, benzimidazolium, reaction of the NHC with one of two electrophiles present. and triazolium salts proved to be unsuccessful and highlighted During these carbene processes, there is the primary electrophile the importance of the catalyst structure for this sila-Stetter (e.g., the aldehyde) and a secondary electrophile, in this case the process. This divergent reactivity among different azolium salts imine. Importantly, an irreversible reaction with the imine would

provided a strong impetus to explore varying catalyst structures preclude the desired productive carbene addition to the acylsilane. Eric M. Phillips, Audrey Chan, and Karl A. Scheidt* in several different reaction pathways. This intrinsic reaction characteristic makes the development As illustrated, this catalytic acyl anion addition is compatible of new carbene-catalyzed processes a significant challenge. In with a wide range of α,β-unsaturated ketones (eq 2).36 Both contrast, when a Lewis acid fails to promote a reaction, a stronger electron-withdrawing and electron-donating substituents are Lewis acid can be employed to further activate the electrophile. accommodated on either aryl ring of the chalcone core and give However, the failure of an NHC to catalyze a reaction cannot rise to good yields. Other classes of α,β-unsaturated carbonyl electrophiles emphasized the utility of this sila-Stetter reaction.

Acylsilanes reacted with diethyl fumarate and dimethyl maleate 1. 1 (30 mol %) to furnish the corresponding conjugate addition products in DBU, i-PrOH THF, 70 oC Ph O good yields. Unsubstituted α,β-unsaturated compounds such O O O 2–24 h + as methyl vinyl ketone and ethyl acrylate were also competent Ph SiMe R R' R R' 3 2. H2O coupling partners in this process. The compatibility of a wide range of highly reactive unsaturated carbonyl components is R R' Yield an impressive feature of this reaction. These compounds are Ph Ph 77% Ph 4-MeOC6H4 80% notorious for being susceptible to polymerization reactions and Ph 4-ClC6H4 82% are exposed to multiple nucleophilic species in solution. In spite 4-MeC6H4 Ph 84% 4-ClC6H4 Ph 74% of this precarious situation, the acyl anion addition products are H Me 75% H EtO 72% isolated in good yields. (E)-EtO2C EtO 65% The reaction was then examined with respect to the acylsilane (Z)-MeO2C MeO 72% component (eq 3).36 Aromatic acylsilanes with methyl or chloro substitution are competent reaction partners, producing eq 2 (Ref. 36) the desired product in 70% and 82% yield, respectively. Interestingly, para-chloro substitution renders the acylsilane 1. 1 (30 mol %) most reactive, most likely due to the increased stabilization DBU, i-PrOH R O of the anion generated in the reaction. Acylsilanes containing O O THF, 70 oC, 12 h O + R SiMe R' Ph Ph Ph Ph enolizable protons are successful substrates for this reaction as 2 2. H2O well. Several 1,4-dicarbonyl compounds can be synthesized with R R' Yield varying substitution patterns under extremely mild conditions. Ph Me 77% The combination of an NHC and acylsilane bypasses the need for 4-ClC6H4 Me 82% 4-MeC6H4 Me 70% toxic cyanide catalysis and provides a highly practical and safe Ph Ph 61% method for the construction of 1,4-dicarbonyl products, which Me Ph 70% Cy Ph 63% can be further telescoped to provide useful furans and pyrroles (Scheme 2).37,38 eq 3 (Ref. 36) 2.2. Imine Additions We succeeded in enhancing the utility of the Stetter reaction 1. 1 (20 mol %) DBU, i-PrOH O O O Et Ph with acylsilanes in our first carbene-catalyzed reaction. These THF, 70 oC, 24 h + initial studies were a pivotal step for our catalysis program and Et SiMe Ph Ph 3 2. AcOH Ph demonstrated the ability to access Breslow-type intermediates 82% without aldehydes. Our early successful 1,4 additions allowed us 1. 1 (20 mol %) Ph to explore 1,2 additions as a means to fully realize the potential DBU, i-PrOH N O O Me Ph THF, 70 oC, 8 h of the NHC-catalyzed generation of acyl anions from acylsilanes. + Me SiMe Ph Ph Since we could access competent acyl anions without reactive 2 2. PhNH2, TsOH Ph Ph 4 Å MS, 8 h carbonyl groups present, there was a strong chance that new 71% electrophile classes could be employed to engage these useful Scheme 2. Single-Flask Furan and Pyrrole Synthesis by the nucleophilic intermediates formed in situ. An appropriate manifold Conjugate Addition of Acylsilanes to α,β-Unsaturated Ketones. for the investigation of 1,2 additions would be the reaction of (Ref. 37,38) acylsilanes with activated imines. In addition to expanding the VOL. 42, NO. 3 • 2009 58

be solved by simply increasing the nucleophilicity of the ketones in good-to-excellent yields. This initial discovery by catalyst or the electrophilicity of the reaction partner, as there our group propelled us to investigate new NHC-catalyzed are too many facets of the reaction that have to be considered, reactions and polarity reversal (umpolung) strategies. such as primary and secondary electrophiles as well as key proton-transfer events. 3. Oxidation Reactions The optimal reaction conditions turned out to be similar to The combination of NHCs and aldehydes has led to useful those of the 1,4-addition reaction. A wide variety of substitution new chemistry in our laboratory beyond the area of umpolung wa s a ccom mod at ed on t he a cylsila ne (e q 4).43 Both alkyl and aryl catalysis. While a plethora of the existing carbene catalysis acylsilanes provided the desired α-a m i no ket one s i n good y ield s. is focused on polarity reversal chemistry, alternative modes Several phosphinoyl imines with various substitution patterns, of reactivity are possible, and have indeed been explored. including both electron-withdrawing and electron-donating One different avenue is oxidation of the initial tetrahedral groups, were suitable substrates for this transformation. In intermediate formed from the addition of an NHC to an addition, aromatic heterocycles such as thiophene provided the aldehyde. Collapse of this intermediate would generate an desired products in high yields. Unfortunately, N-phosphinoyl acyl azolium species with concomitant formation of a hydride imines derived from aliphatic aldehydes do not furnish the equivalent. desired products. This limitation is attributed to the ability of In 2006, we disclosed the application of this route in the the imine to readily undergo conversion into the more stable context of an NHC-catalyzed hydroacylation (Scheme 3).44 In enamide, rendering it unsusceptible to nucleophilic addition. this Tishchenko-like process, an aromatic aldehyde–NHC adduct The strategy of employing acylsilanes with NHCs as acyl generates a hydride equivalent in the presence of an organic Discovering New Reactions with N-Heterocyclic Carbene Catalysis Discovering New Reactions with N-Heterocyclic anion precursors has allowed for the successful addition of acyl oxidant, an α-keto ester. The initial collapse of the tetrahedral anion equivalents to conjugate acceptors and activated imines. intermediate to produce an activated ester is unprecedented, This catalytic process generates 1,4-diketones and α-amino and adds an interesting facet to the potential avenues of NHC- catalyzed reactions. Once the ketone undergoes reduction, the resulting alkoxide regenerates the catalyst through addition

O to the acyl azolium intermediate. In aprotic solvents, such as O 1. 3 (30 mol %) Ph P DBU, i-PrOH Ph2P CH2Cl2, the hydroacylation products are isolated in good yields O 2 N NH CHCl3 + R1 when triazolium precatalyst 5 is used. Additionally, when the R1 SiMe H R3 R3 2 2. H2O reaction is conducted in MeOH, the α-hydroxy ester can be R2 O isolated as the sole product due to catalyst regeneration by the R1 R3 Yield solvent. One limitation of this methodology is the requirement

Ph Ph 93% that the aldehyde starting material possess a nonenolizable Ph 4-MeC6H4 94% α-carbon atom. Ph 4-MeOC6H4 86% In order to further explore this reaction pathway, a crossover Ph 2-ClC6H4 77% Ph 4-ClC6H4 85% experiment was performed with an α-keto ester and 0.5 equiv Ph thien-2-yl 80% each of deuterated benzaldehyde and p-tolualdehyde.44 In this 4-MeC6H4 Ph 81% 4-ClC6H4 Ph 90% reaction, all four potential products were observed, supporting Me Ph 87% our contention that reduction and acylation are separate steps in BnO(CH ) Ph 63% 2 3 the reaction pathway. Additionally, when benzoin is exposed to the reaction conditions, the hydroacylation product is isolated eq 4 (Ref. 43) suggesting that the benzoin reaction is reversible and may be operating under the reaction conditions. In this new reaction,

O the carbene catalyst is responsible for two distinct processes: R2 oxidation and acylation. The novelty of this reaction is further R1 O O– Me 5 (10 mol %) O illustrated through the combination of two components N Ar H DBU, CH Cl Ar 2 2 H N (aldehyde and ketone) participating in a disproportionation N Me reaction. hydride donor Following this initial report, we focused on the use of O more conventional oxidants to facilitate the formation of O Ar O Me OH acyl azoliums. An interesting, but underutilized, approach 2 N 2 R Ar + R to unsaturated esters has been the Corey–Gilman oxidation. R1 N R1 H N H In this process, an allylic alcohol is oxidized in the presence O Me O of 10 to 20 equivalents of cyanide and MnO , first to the acyl azolium 2 corresponding aldehyde and then to the ester. This streamlined Ar R1 R2 Yield process to convert alcohols into esters would be incredibly useful if the reaction avoided the use of superstoichiometric Ph Ph MeO 78% furan-2-yl Ph MeO 73% amounts of cyanide. Our previous success of replacing cyanide 4-FC6H4 Ph MeO 71% with NHCs in the context of the Stetter reaction encouraged 4-MeOC6H4 thien-2-yl EtO 73% 4-MeOC6H4 4-ClC6H4 EtO 81% us to pursue a similar strategy with regard to this oxidation. Ph Ph Ph 83% Importantly, MnO2 was chosen in order to allow the presence of the inactivated nucleophilic alcohol required for catalyst regeneration.45 Scheme 3. Hydroacylation of α-Keto Esters and 1,2-Diketones. We chose to evaluate this process to demonstrate the use of (Ref. 44) carbenes as oxidation co-catalysts and to develop a practical VOL. 42, NO. 3 • 2009 59 oxidation procedure. When butanol is used as solvent, several intriguing possibility was the “extension” of the nucleophilic allylic and benzylic alcohols are successfully oxidized to character at C-1 of the aldehyde to the distal site C-3 through a the corresponding unsaturated butyl esters with 10 mol % C–C multiple bond. In this approach, the addition of carbenes precatalyst 5 (eq 5).45 In many cases, the nucleophilic alcohol to aldehydes containing an additional unsaturation unit could may be too costly to use as solvent. In this circumstance, slight relocate the electron density in the Breslow intermediate modifications to the reaction conditions allow the alcohol to to the β carbon of the aldehyde (Scheme 5).49 This transient be used as a reagent as opposed to solvent. In toluene, just 5 nucleophile is a “vinylogous” carbonyl anion or a homoenolate. equivalents of the nucleophilic alcohol are required to facilitate ester formation. During these initial carbene-catalyzed oxidation 5 (10 mol %) OH Me investigations, we recognized that the addition of an NHC O [O] DBU, MnO2 N R1 to any aldehyde (activated or inactivated) should generate a R1 H H N CH2Cl2 N transient benzylic-type alcohol! The catalyst itself is aromatic inactivated 0.5–3.0 h Me and should induce mild oxidations of the resulting intermediate. transient benzylic-type alcohol

Indeed, the addition of azolium salt 5 to a variety of saturated Eric M. Phillips, Audrey Chan, and Karl A. Scheidt* O Me aldehydes in the presence of MnO2 and a nucleophilic alcohol O R2OH 1 N enables oxidation of the aldehydes to their respective esters R1 OR2 R N 46 N (Scheme 4). It is noteworthy that aldehydes with electron- Me rich aromatic rings are accommodated under these reaction acyl azolium conditions, whereas typical Pinnick oxidation conditions result in significant chlorination of the aromatic ring. For example, R1 R2 Yield when 3-(2,4,6-trimethoxyphenyl)propanal is oxidized using BnCH2 Me 98% Pinnick conditions a substantial amount of monochlorination BnCH2 n-Pr 82% of the aromatic trimethoxyphenyl ring occurs, whereas BnCH2 Cy 88% BnCH2 TMSCH2CH2 85% under NHC-catalyzed conditions only the desired ester is BnCH2 (S)-MeO2CCHMe 74% 47,48 produced. 2-PyCH2CH2 Me 88% 99% Interestingly, the use of a chiral NHC in this reaction 2,4,6-(MeO)3C6H2CH2CH2 Me 1-methylinden-3-ylCH2CH2 Me 90% offers the opportunity to desymmetrize meso diols through n-Pent Me 91% the in situ formation of chiral activated ester equivalents. In TBSOCH2CH2 Me 94% (S)-TBSOCH2CHMe Me 91% a proof of concept experiment, in the presence of triazolium salt 7 with the combination of K2CO3 and a proton sponge as a base, a meso diol is acylated with modest enantioselectivity Scheme 4. Oxidation of Inactivated Aldehydes to the (eq 6).45 Problems with base-catalyzed intramolecular acyl- Corresponding Esters via a Benzylic-Type Alcohol Intermediate. transfer reactions presumably inhibit higher selectivities for (Ref. 46) this process, but these initial results pave the way for carbene- catalyzed stereoselective acylation reactions using simple 7 (30 mol %) O aldehydes. OH proton sponge OH Ph H K CO , 18-crown-6 OH 2 3 O CH2Cl2, –30 °C 4. Homoenolates Ph O From 2003 onward, our substantial interest in accessing meso diol O 58%, 80% ee

Breslow intermediates with acylsilanes and understanding the N – mechanistic aspects of this process stimulated our thinking N BF4 N about new potential applications of related structures. An Mes 7

(Ref. 45) O eq 6 5, DBU, MnO2 1 R OH R1 OR2 R2OH, 23 oC, 12–48 h

R1 R2 Yielda Classic Generation of Breslow Intermediate: a1–d1 Umpolung

2 1 2 (E)-PhCH=CH Me 95% R (R )3SiO R O S N O (E)-PhCH=CH i-Pr 89% N 1 R (E)-PhCH=CH MeO(CH2)2 82% R Si(R )3 R S (E)-PhCH=CH TMS(CH2)2 74% (E)-PhCH=CH Cl3C(CH2)2 82% Proposed (2004) Generation of Extended Breslow Intermediate: (E)-PhCH=CH n-Bu 93% a3–d3 Umpolung (E)-PhCH=CMe n-Bu 91%

Ph n-Bu 88% ' X N R 2-Np n-Bu 91% O OH O furan-2-yl n-Bu 73% Y X (E)-EtCH=CH n-Bu 87% R H R R N (E)-EtO2CCH=CH n-Bu 65% Y new R' PhC≡C n-Bu 85% reactivity pattern

a Entries 1–5: 5 (15 mol %), R2OH (5 equiv) in toluene as solvent; entries 6– 13: 5 (10 mol %) in n-BuOH as solvent. Scheme 5. Envisaged Generation of Vinylogous Carbonyl Anions eq 5 (Ref. 45) (Homoenolates). (Ref. 49) VOL. 42, NO. 3 • 2009 60

This type of reactivity has been exploited by our group49 and the catalytic cycle is restarted. The obvious choice for a proton others,50,51 which has led to the disclosure of an extensive source is an alcohol that also serves as a nucleophile in the last number of NHC-catalyzed homoenolate reactions over the last step to promote catalyst turnover. four years. Initial probing of this reaction was moderately successful. Exposure of cinnamaldehyde to 30 mol % 6, DBU, and phenol 4.1. β Protonation in toluene led to a 55% isolated yield of the desired saturated Our group began investigating this electronic reorganization ester. A serendipitous discovery was made when the reaction

with the goal of intercepting this possible homoenolate was run in CHCl3, which had been passed through basic Al2O3 intermediate with a suitable electrophile for β functionalization but not distilled. With phenol being used as the proton source, and a suitable nucleophile for subsequent acylation.49,52 We a large amount of the saturated ethyl ester was isolated. In initially chose to explore this reaction with a simple electrophile: hindsight, it became clear that the source of the ethanol was a proton. The proposed pathway for this process begins with the the chloroform, which uses ethanol as a stabilizer. With the initial 1,2 addition of the NHC to the α,β-unsaturated aldehyde knowledge that two alcohols can be used simultaneously (one (Scheme 6).49,52 Following proton migration, the electron as a proton source and one as the nucleophile), we quickly density that would be typically located at the carbonyl carbon discovered that high yields could be obtained for this process is extended to the β position with formation of the extended when phenol is employed as a proton source and a second Breslow intermediate (I). Addition of a proton generates enol alcohol is used as a nucleophile. II, which tautomerizes to activated acylating agent III. In the Under these new reaction conditions, which employ 5 presence of a nucleophile, the NHC catalyst is regenerated and mol % of azolium salt 6, 2 equiv of phenol, and 4 equiv of Discovering New Reactions with N-Heterocyclic Carbene Catalysis Discovering New Reactions with N-Heterocyclic the nucleophilic alcohol, a variety of saturated esters can be synthesized (Scheme 7).49,52 Both secondary and primary H O alcohols are accommodated under the reaction conditions. O R1 b OR2 Optically active alcohols retain their integrity in this process α R N N R R1 H to generate enantioenriched esters. Not surprisingly, tert-butyl N NHC alcohol was unreactive. Additionally, the reaction tolerates a addition R2OH acylation variety of α,β-unsaturated aldehydes with both alkyl and aryl & proton of alcohol migration substitution. Aldehydes with additional substitution at the α position, as well as substrates with β,β-diaryl substitution, H O R OH R afford the corresponding products in good yields. Our group N N 1 R1 R N N has also explored asymmetric variants of this process. N I N This initial report demonstrated that homoenolate activity III R R extended Breslow could be generated and utilized in a productive fashion. The intermediate formation of simple saturated esters provided a platform for

tautomerization protonation the investigation of homoenolates and introduced our group to H OH R a new and exciting area of chemistry. Following the success 1 N R2OH of this reaction, we actively pursued new applications with R N N these atypical nucleophiles. The most significant challenge II R encountered with these reactions is the vinylogous benzoin Scheme 6. Proposed Pathway for β Protonation. (Ref. 49,52) reaction. Homoenolate addition to an equivalent of unsaturated aldehyde starting material must be avoided in these reactions if a secondary electrophile is incorporated into a new reaction 6 (5 mol %) O O PhOH (2 equiv) sequence. The most reasonable approach to this problem would + R' OH OR' be to increase the electrophilicity of this secondary electrophile. R H DBU, PhMe 100 oC, 2–6 h R This adjustment, however, can make the addition of the NHC to the secondary electrophile more likely, thus inhibiting the R R' Yield R R' Yield reaction. These complications highlight the impressive nature Ph Et 72% 4-MeOC6H4 Bn 76% of all homoenolate reactions reported to date and demonstrate Ph Ph 56% 4-ClC6H4 Bn 71% Ph Bn 82% n-Pr Bn 90% the balance of electronic and steric effects that are required for Ph Cy 57% (E)-MeCH=CH Bn 70% Ph a,b 77% c Bn 82% future reaction development. d Bn 82%

a (S)-1-Phenylethanol (99% ee) used. 4.2. Formal [3 + n] Cycloadditions b Ester product obtained with 99% ee. c A carbene-catalyzed homoenolate addition that forms new (E)-4-ClC6H4C(Ph)=CHCH=O utilized. d (E)-PhCH=C(Me)CH=O employed. carbon–carbon bonds would clearly be a valuable reaction and enhance the applicability of this process. An appropriate 8 ( 10 mol %) Me O Me O Me O EtOH (2 equiv) strategy would be to utilize an electrophile, which, upon Ph H Ph OEt Ph OEt (i-Pr)2EtN homoenolate addition, generates a transient nucleophile to aid (25 mol %) 55% ee THF, rt in catalyst regeneration (Scheme 8). In this vein, ylides contain O N 58% the appropriate functionality, and the ability of these dipolar N Mes (8) Ph N species to undergo cycloadditions is well-precedented.53–56 Ph BF – Ph 4 3-Oxopyrazolidin-1-ium-2-ides are stable compounds that can be prepared in gram quantities, and can thus be practical coupling partners57–60 for the investigation of this reaction.61 To Scheme 7. NHC-Catalyzed β Protonation. (Ref. 49,52) our gratification, a variety of azolium salts catalyzed the reaction VOL. 42, NO. 3 • 2009 61 between cinnamaldehyde and the diphenyl-substituted azomethine imine in the presence of DBU with excellent diastereoselectivity O albeit in low yields. The optimal reaction conditions were obtained O Y using 20 mol % of azolium salt 9 and DBU in CH2Cl2 while R N N Ar R1 H 62 X heating the reaction at 40 °C (eq 7). A survey of α,β-unsaturated R1 R2 N R2 NHC aldehydes revealed that a variety of electron-rich aromatic rings addition are accommodated in the reaction. Unfortunately, electron- intramolecular & proton acylation migration deficient unsaturated aldehydes are not compatible. β-Alkyl Y substitution and extended dienylic substitution are also tolerated. R2-X R2 O Ar OH Ar Investigation of the reaction with respect to the azomethine imine N N 1 R1 R N N component demonstrated that several substitution patterns are N N allowed. However, azomethine imines derived from aldehydes R R III I with enolizable protons do not afford any tetrahydropyridazinone tautomer- product. Successful azomethine imine substrates in this reaction ization Y C–C-bond 2 formation 2 typically possess phenyl substitution in the 5 position, primarily 2 X R Y R Eric M. Phillips, Audrey Chan, and Karl A. Scheidt* R OH Ar X due to the insolubility of the unsubstituted analogues. 1 N 2 R N R H We investigated this reaction platform further with the N ylide incorporation of a second 1,3-dipole: nitrones. In addition to II R being well-known partners for cycloadditions,63–66 successful homoenolate addition to these ylides would potentially produce γ-amino acid67–69 derivatives as well as γ-lactams. While we were Scheme 8. Formal [3 + 3] Cycloadditions with Homoenolates. pleased to discover that the homoenolate addition does occur, the initial 6-membered-ring heterocyclic product was unstable toward chromatography. Addition of NaOMe to the reaction mixture O O O O upon consumption of starting material helped bypass this problem H N 9 (20 mol %) N + 70 2 and afforded γ-hydroxy amino ester products (Scheme 9). The 1 R N DBU, CH2Cl2 1 N R 40 °C, 2 h R products can be manipulated further with Pd(OH)2/C and H2 to H Ph R2 Ph provide γ-amino esters. An impressive aspect of this reaction is dr = 20:1 the synthesis of optically active products with chiral azolium Mes 1 2 Yield 10. The high degree of asymmetric induction is surprising N R R I– considering the distance between the reactive carbon atom and N Ph 3-MeOC6H4 67% the stereogenic centers of the homoenolate intermediate. Me Ph 4-FC6H4 82% 9 Ph 3-BrC6H4 78% We then wondered whether this methodology could be Ph Ph 79% extended to heteroatom electrophiles such as in a homoenolate- 4-MeOC6H4 Ph 76% 2-Np Ph 77% based amination reaction, which would constitute a reverse- (E)-MeCH=CH Ph 51% polarity approach to creating β-amino carbonyl compounds. n-Pr Ph 67% These carbonyl compounds are commonly synthesized through conjugate additions of nitrogen nucleophiles.71–74 When we employed diazenes (RN=NR’) as elecrophilic amination eq 7 (Ref. 62) partners, significant complications were encountered due to the reactive nature of the diazene functional group. A notable side product in these reactions was 1-benzoyl-2-phenylhydrazine O 1. 10 (20 mol %) O [PhC(O)NHNHPh]. Based on the previously discussed O Et3N, CH2Cl2 –25 °C H 2 MeO OH hydroacylation and oxidation reactions, we posit that the initial + R N Ph 2. NaOMe, MeOH N R1 1 Ph tetrahedral aldehyde–carbene adduct can behave as a hydride H R R2 source and perform conjugate reductions on the diazene. The dr = 20:1 damage to the outcome of the reaction is heightened by not R1 R2 Yield ee only sacrificing the diazene, but an equivalent of the aldehyde Mes N N as well. Fortunately, employing precatalyst 11 and lowering Ph Ph 70% 93% – the temperature of the reaction circumvented these problems N BF4 Me Ph 73% 94% O 4-ClC H Ph 78% 90% (eq 8).75 Ph 6 4 Ph 4-MeOC6H4 Ph 72% 89% 10 Ph 4-MeC6H4 71% 90% 5. Enolate Chemistry Ph 4-BrC6H4 68% 84% Our success with generating homoenolate reactivity using NHCs led us to believe that enolate generation and utilization O Ph OH H2 O Ph H Pd(OH)2/C N γ N were possible. The current mechanistic understanding of the MeO Ph MeO β Ph MeOH α homoenolate process includes the possible generation of a short- Ph Ph 76,77 82% lived enol (Scheme 10, structure II). The tautomerization γ-amino ester of this enol followed by nucleophilic attack on the transient acyl azolium intermediate drives catalyst regeneration. This observation provides an opportunity to tap into the powerful Scheme 9. Homoenolate Additions to Nitrones and Elaboration of ability of the carbene to functionalize the α, β, and carbonyl the Resulting Products into γ-Amino Esters. (Ref. 70) carbons of an α,β-unsaturated aldehyde in a single flask! Our VOL. 42, NO. 3 • 2009 62

goal was to intercept this nucleophile (II) with a competent been observed that weaker bases, such as (i-Pr)2EtN, and their electrophile and thus expand the number of NHC-catalyzed conjugate acids, are more accommodating in this process. An reactions. intramolecular Michael addition follows the β-protonation Toward this end, we synthesized substrates that would not step and results in the construction of a five-membered ring. only maximize the potential success of the reaction but also Under these conditions, catalyst regeneration is afforded by provide interesting structural motifs (eq 9).77 This three- the O-acylation of the newly formed (second) enol. However, atom functionalization proceeded as envisaged in Scheme 10. the addition of methanol is required to avoid hydrolysis of the While the β-protonation step is not well-understood, it has initial labile lactone products and to facilitate purification. Importantly, when aminoindanol-derived precatalyst 7 is

used in combination with (i-Pr)2EtN, excellent diastereo- O R2 and enantioselectivities are achieved for a wide range of O R2 H N O 11 (20 mol %) substrates. + N N DBU, CH Cl O The success achieved with this highly diastereo- and R1 Ph 2 2 N 4 Å MS, 0 °C R1 Ph enantioselective intramolecular NHC-catalyzed Michael addition led our group to investigate an intramolecular aldol R1 R2 Yield reaction.78,79 Readily prepared symmetrical 1,3-diketones Mes Ph Ph 63% undergo intramolecular aldol reactions to afford optically active N N – 3-MeOC6H4 Ph 60% cyclopentene rings. In this reaction, the enol generated from Me BF4 N 4-ClC6H4 Ph 61% the addition of chiral, optically active NHC 10 to the aldehyde Discovering New Reactions with N-Heterocyclic Carbene Catalysis Discovering New Reactions with N-Heterocyclic Me Me 2-MeC6H4 82% Ph 4-FC H 61% performs a desymmetrization of the 1,3-diketone. Acylation of 11 6 4 Ph Pha 71% the resulting alkoxide is coupled with a decarboxylation step to a 3-MeC6H4N=NC(O)Ph used. afford the cyclopentene adducts with excellent enantiocontrol (eq 10).78,79 Importantly, degassing of the solvent leads to a dramatic increase in yield. In some cases, unsaturated acids are eq 8 (Ref. 75) observed, and they are thought to originate from the oxidation of the homoenolate intermediate.

1st H O 3rd O The high selectivity achieved with this system is believed α 1 to arise from a 6-membered hydrogen-bonded feature in the R b Nu R N N Ar R1 H E N Breslow-type intermediate. The enol proton behaves as a 2nd NHC addition bridge between the enol oxygen and the ketone oxygen, which HNu acylation & proton predisposes the complex to undergo the aldol reaction and of nucleophile migration minimizes the nonbonding interactions between the catalyst and the keto group not undergoing attack. The regeneration H O Ar OH Ar N N of the catalyst is also a result of the hydrogen bonding in the 1 R1 R N N adduct since an anti disposition of the alkoxide and acyl azolium E N I N R R III groups in the adduct would inhibit subsequent intramolecular extended Breslow intermediate acylation. b In order to demonstrate the intrinsic value of this enolate addition protonation desymmetrization process, we adapted this methodology to the H OH Ar synthesis of the bakkenolide family of natural products.80,81 The 1 N R N bakkanes are comprised of a cis-fused 6,5-cyclic system with N II R two quaternary stereogenic centers, one of which contains an angular methyl group. This key structural element provided an Scheme 10. Proposed Pathway for Enolate Formation and Three- excellent opportunity to apply our methodology and provide Atom Functionalization. (Ref. 77) a modern demonstration of the power of carbene catalysis in total synthesis.82–84 The crucial NHC-catalyzed bond-forming O O 1. 7 (10 mol %) 1 R2 (i-Pr) EtN, CH Cl R2 R R1 2 2 2 1 1 CO2Me O R 10 (10 mol %) O R H O R3 2. MeOH R3 R2 (i-Pr)2EtN (1 equiv) O R1 O dr = 20:1 H CH Cl , 40 °C, 12 h 2 99% ee (major isomer) 2 2 R R1

R1 R2 R3 Yield R1 R2 Yield ee

Ph H H 69% Ph Me 80% 93% 4-BrC6H4 H H 62% Ph H2C=CHCH2 70% 83% Ph MeO MeO 73% Ph H2C=C(Me)CH2 69% 83% Ph F H 68% Ph (E)-PhCH=CHCH2 64% 82% 4-MeC6H4 H H 80% 4-ClC6H4 Me 76% 94% H H H 68% a a 51% 96% Me H H 59%

Me a a 66% a O dr = 20:1; O a Using (E,E)- major product = O Me MeC(O)CH=CH(CH2)2CH=CHC(O)H. H

eq 9 (Ref. 77) eq 10 (Ref. 78,79) VOL. 42, NO. 3 • 2009 63 event occurs early in the synthesis and furnishes appropriate O O functionality to complete the synthesis of bakkenolides I, J, and Me 10 (5 mol %) Me S (Scheme 11).79b CHO (i-Pr)2EtN (1 equiv) CH Cl , 35 °C O 2 2 O 6. Elimination Reactions O The formation of reactive enols through carbene catalysis is 69%, dr = 20:1 an exciting area. The use of α,β-unsaturated aldehydes in this 98% ee process requires extensive atom and electronic reorganization. In addition to our continued studies along these lines, we are also O Me investigating new approaches using carbenes to generate enols O Me O or enolates. Specifically, we hypothesized that carbon–carbon- H OR O bond-forming reactions were possible with acetate-type enols Me H H RO derived from the addition of NHCs to α-aryloxyacetaldehydes. Me bakkenolides I (R = i-Bu), J (R = i-Val), S (R = H) The aryloxy (ArO) group would not only facilitate enol formation through an elimination event, but would also assist in catalyst Scheme 11. Application of the NHC-Catalyzed Desymmetrization Eric M. Phillips, Audrey Chan, and Karl A. Scheidt* regeneration by adding to the acyl azolium. While this new to the Synthesis of Bakkenolides I, J, and S. (Ref. 79b) concept to generate acetate enolates has been successful (vide infra), the initial approach requiring a functional group to behave O as both a good leaving group and a competent nucleophile was O R2 challenging. A good leaving group may initiate the formation of R2 11 (10 mol %) the enol faster, but would not be effective at catalyst regeneration.85 R1 R1 O CHO DBU O O Thus, the optimal ArO group must strike a balance between CH3CN (0.02 M) good-leaving-group ability and sufficient nucleophilicity. In order to explore the potential of this process, we chose R1 R2 Yield to incorporate enones with tethered aldehydes. The strategy of H Ph 83 tethering the conjugate acceptor to the potential nucleophile H 4-MeOC6H4 80 H 4-BrC6H4 77 not only increases the chance of a productive bond formation, 7-Me Ph 66 but also forms privileged 3,4-dihydrocoumarin structures. 6-F Ph 91 Indeed, exposure of these enones to 10 mol % 11 in MeCN 8-Me Ph 66 affords 3,4-dihydrocoumarins with varying substitution 86a patterns (eq 11). eq 11 (Ref. 86a) The fragmentation required for this reaction to occur was a strong impetus for investigating the reaction pathway. First, P the possibility of the alkoxide undergoing acylation and then NH O O ArO performing a Michael addition was a plausible route. To discount Ph OAr H V R Ar1 this option, the potential intermediate was synthesized and N N addition acylation N & proton – migration exposed to the reaction conditions. No reaction was observed, or ArO NHC thus refuting the presence of the acylated phenoxide in the P NH O Ar1 OH Ar1 catalytic cycle. A crossover experiment was also performed N rebound activation ArO Ph – N to determine if fragmentation was occurring. When two N ArO N IV N III I N R R α-aryloxy aldehydes were exposed to the reaction conditions in + a single flask, a randomized mixture of 3,4-dihydrocoumarin 1 C–C-bond OH Ar products was obtained, supporting the contention that the formation H N elimination – 86 P N of ArO starting material fractures during the reaction. N H N R These interesting enolate precursors were further applied Ph H II in Mannich-type reactions. In this case, we sought to P = protecting group synthesize an enolate precursor that would allow for facile elimination and subsequent enol formation, but yet retain Scheme 12. Proposed Pathway for the NHC-Catalyzed Mannich enough nucleophilicity to assist in catalyst regeneration Reaction of α-Aryloxy Aldehydes. (86b) (Scheme 12).86b After much optimization, we discovered that a 4-nitrophenoxide anion was the most suitable leaving group. 1. 12 (10 mol %) In contrast to the previous studies of acyl anion additions to 4-O2NC6H4ONa Ts (2 equiv), 4 Å MS Ts imines with N-phosphoryl protecting groups, N-tosylimines N O NH O 0 → 20 °C proved to be the most compatible. Additionally, as opposed ArO R H H R NHBn 2. BnNH2 to the previously described NHC-catalyzed reactions, which Ar = 4-O2NC6H4 use a consortium of amine bases to deprotonate the azolium Mes R Yield ee precatalyst, the most successful base in this process is sodium N N – Ph 72% 94% 4-nitrophenoxide. One drawback of this process is that the N BF4 O 4-MeC6H4 70% 95% initial aryl β-amino ester products are unstable toward column Ph 2-ClC6H4 64% 88% Me Me 3-MeOC6H4 64% 92% chromatography. However, addition of benzylamine upon 4-FC H 12 6 4 56% 95% consumption of the starting material circumvents this problem and affords a wide variety of β-amino amides (eq 12).86b eq 12 (Ref. 86b) Interestingly, these acetate-type enols add to imines with VOL. 42, NO. 3 • 2009 64

excellent levels of stereoselectivity despite the problems typically 8. Conclusions and Outlook associated with 1,2 additions of acetate enolates. We have constructed a large stable of azolium precatalysts, the The highly selective Mannich-type reaction of α-aryloxy divergent reactivity of which makes it possible to carry out several aldehydes provides an opportunity to synthesize products that are types of reaction (Figures 2 and 3). valuable to the chemical and biological communities. In addition Our laboratory has been inspired by nature and by the pioneering to α-unbranched β-amino amides, synthesis of the corresponding work of Ugai and Breslow to develop whole new families of acyl β-amino acids is also possible with exposure to NaOH anion, homoenolate, enolate, and redox processes. The structural (Scheme 13).86b Formation of 1,3-amino alcohols is accomplished diversity of these intriguing azolium catalysts allows them to

with LiBH4, and the synthesis of more stable esters is demonstrated effect several transformations and leads to the conclusion that their by the addition of sodium methoxide. Lastly, β-peptide formation is potential has not been realized. A high degree of stereocontrol is possible by in situ interception with benzyl-protected (S)-alanine.86b possible through the use of chiral, optically active N-heterocyclic These two reaction manifolds, the Michael and Mannich reactions, carbenes. The integration of experimental data with computational demonstrate the viability of this type of “rebound” catalysis, and analysis has provided the first study suggesting that the further will surely open doors to new reactions.

7. Theoretical Calculations Ts trapping As discussed above, the combination of NHCs with α,β-unsaturated N O TsNH O TsNH NHC reagent + ArO X aldehydes can result in two divergent pathways: (i) oxidation of Ph H H Ph OAr Ph the aldehyde or (ii) internal redox reactions through addition of Discovering New Reactions with N-Heterocyclic Carbene Catalysis Discovering New Reactions with N-Heterocyclic the homoenolate to an electrophile followed by oxidation of the Trapping aldehyde carbon. In many cases, both pathways operate under the Reagent X Yield ee 49,87 same reaction conditions. Even though NHC-promoted reactions NaOH CO2H 71% 92% NaOMe CO2Me 61% 94% have garnered significant attention in recent years, the discovery of LiBH4 CH2OH 70% 98% the conditions required for new reactions has remained empirical. HOBt, a b 61% 94% Methods to predict and control which pathway is likely to be a (S)-Alanine benzyl ester used. b operating are imperative to the development of new reactions. X = (S)-HNCHMeCO2Bn One course of action following the addition of the NHC to the aldehyde is the formation of the homoenolate. As previously Scheme 13. Investigation of Trapping Reagents for the Mannich- stated, this option requires a formal 1,2-proton shift to succeed Type Reaction of α-Aryloxy Aldehydes. (Ref. 86b) the formation of the tetrahedral intermediate. The second possible pathway includes a collapse of the tetrahedral intermediate, generating an acyl azolium intermediate and a formal reducing Umpolung equivalent. Our goal, in collaboration with Cramer’s group at Substrate with NHC Year Ref. the University of Minnesota, was to apply computational models O X = Si O toward this complex problem in order to better understand the 2004 36 R X R potential reaction pathways and factors that control the reaction acyl anion preference for one pathway or the other.88 O X = H O Using crotonaldehyde as a model system for α,β-unsaturated + H– 2006 R X R 44 aldehydes, enthalpies of the proposed intermediates were obtained hydroacylation using Density Functional Theory (DFT) calculations with solvation models providing a correction for the solution environment.89 O 1 O 2 3 The results of these calculations are in agreement with R H R the experimental findings: the homoenolate pathway is more homoenolate 2005 52 enolate 2007 dependent on the choice of catalyst, while the choice of solvent is 77 O O less influential. In the corresponding experimental studies, a 10:1 X H mixture of solvent to methanol was employed to assist in catalyst "rebound catalysis" 2009 86b turnover. Four different, but relatively simple, azolium salts were enolate surveyed as precatalysts over a narrow range of solvents. While the GC yields of these reactions were low, the ratio of oxidation product to homoenolate product was the important statistic. The Figure 2. New Concepts in Carbene Catalysis. results indicated that polar protic solvents such as methanol favor the oxidation pathway; but as solvent polarity decreases, the Reactions It Catalyzes homoenolate pathway becomes more favored.88 While catalysts 5 Year First and 9 showed that catalyst structure could be used to favor the Precatalyst Introduced Homoenolate Enolate Oxidation Ref.

oxidation pathway, the choice of solvent also played a key role in 6 2005 √ 52 the distribution of products in the case of 1,3-dimethylimidazolium 5 2006 √ 44 chloride and 1,3-dimethylbenzimidazolium iodide. 9 2007 √ 62 10 2008 √ √ 70 These initial results suggest that a desired pathway can be 12 2008 √ 70 favored with a specific choice of catalyst and solvent, a choice that 11 2008 √ √ √ 75 is informed by a rational theoretical exploration of the reaction parameters. This first computational exploration of these Lewis Figure 3. Milestones in the Growth of This Area of Organocatalysis base reactions will hopefully lead to a more systematic approach over the Past Five Years. toward the development of NHC-catalyzed reactions. VOL. 42, NO. 3 • 2009 65 development and/or optimization of carbene-catalyzed reactions (26) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639. need not be based solely on empirical approaches. With continued (27) Page, P. C. B.; Klair, S. S.; Rosenthal, S. Chem. Soc. Rev. 1990, 19, mechanistic investigation, additional insight into these powerful 147. reactions will drive further development of the carbene catalysis (28) Cirillo, P. F.; Panek, J. S. Org. Prep. Proced. Int. 1992, 24, 553. field. In the future, new discoveries that allow for lower catalyst (29) Bonini, B. F.; Comes-Franchini, M.; Fochi, M.; Mazzanti, G.; Ricci, loadings may enable the incorporation of these catalysts into A. J. Organomet. Chem. 1998, 567, 181. synthetic plans for the construction of complex molecules. (30) Schinzer, D.; Heathcock, C. H. Tetrahedron Lett. 1981, 22, 1881. Ultimately, the continued exploration of carbene catalysis will (31) Ricci, A.; Degl’Innocenti, A.; Mordini, A.; Reginato, G.; Colotta, V. undoubtedly produce new reactions and strategies, and we look Gazz. Chim. Ital. 1987, 117, 645. forward to participating in these discoveries. (32) Linghu, X.; Potnick, J. R.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 3070. 9. Acknowledgements (33) Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326. We thank Northwestern University, the National Institute of General (34) Teles, J. H.; Melder, J.-P.; Ebel, K.; Schneider, R.; Gehrer, E.; Harder, Medical Sciences (R01GM73072), 3M, Abbott Laboratories, W.; Brode, S.; Enders, D.; Breuer, K.; Raabe, G. Helv. Chim. Acta.

Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, 1996, 79, 61. Eric M. Phillips, Audrey Chan, and Karl A. Scheidt* and Novartis for their generous support of this work. A.C. thanks (35) Brook, A. G. Acc. Chem. Res. 1974, 7, 77. The Dow Chemical Company for financial support. E.M.P. is a (36) Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc. recipient of an ACS Division of Organic Chemistry Graduate 2004, 126, 2314. Fellowship Sponsored by Organic Reactions. (37) Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6, 2465. (38) Mattson, A. E.; Bharadwaj, A. R.; Zuhl, A. M.; Scheidt, K. A. J. Org. 10. References and Notes Chem. 2006, 71, 5715. (1) (a) Breslow, R. Science 1982, 218, 532. (b) Breslow, R. J. Am. Chem. (39) Di Gioia, M. L.; Leggio, A.; Liguori, A.; Napoli, A.; Siciliano, C.; Soc. 1958, 80, 3719. Sindona, G. J. Org. Chem. 2001, 66, 7002. (2) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., (40) Béguin, C.; Andurkar, S. V.; Jin, A. Y.; Stables, J. P.; Weaver, D. F.; Int. Ed. 2004, 43, 1566. (b) Adair, G.; Mukherjee, S.; List, B. Kohn, H. Bioorg. Med. Chem. 2003, 11, 4275. Aldrichimica Acta 2008, 41, 31. (41) Haustein, K.-O. Int. J. Clin. Pharmacol. Ther. 2003, 41, 56. (3) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356. (42) Weinreb, S. M.; Orr, R. K. Synthesis 2005, 1205. (4) Curran, D. P.; Lung, H. K. Tetrahedron Lett. 1995, 36, 6647. (43) Mattson, A. E.; Scheidt, K. A. Org. Lett. 2004, 6, 4363. (5) Connon, S. J. Chem.—Eur. J. 2006, 12, 5418. (44) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4558. (6) Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4102. (45) Maki, B. E.; Chan, A.; Phillips, E. M.; Scheidt, K. A. Org. Lett. (7) Biddle, M. M.; Lin, M.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 2007, 9, 371. 3830. (46) Maki, B. E.; Scheidt, K. A. Org. Lett. 2008, 10, 4331. (8) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, (47) Wilson, S. R.; Tofigh, S.; Misra, R. N. J. Org. Chem. 1982, 47, 107, 5471. 1360. (9) List, B. Chem. Rev. 2007, 107, 5413. (48) Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski, E. (10) List, B. Acc. Chem. Res. 2004, 37, 548. J. J.; Reider, P. J. J. Org. Chem. 1999, 64, 2564. (11) List, B. Synlett 2001, 1675. (49) Our preliminary studies on the generation of homoenolates using (12) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, N-heterocyclic carbenes and the protonation of these intermediates 1560. were first disclosed by K.A.S. at the 2004 Natural Products Gordon (13) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726. Research Conference (Tilton, NH) on Thursday, July 29, 2004. See (14) Mizuhara, S.; Handler, P. J. Am. Chem. Soc. 1954, 76, 571. also Maki, B. E.; Chan, A.; Scheidt, K. A. Synthesis 2008, 1306. (15) Wanzlick, H.-W. Angew. Chem., Int. Ed. Engl. 1962, 1, 75. (50) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205. (16) Wanzlick, H.-W.; Kleiner, H.-J. Angew. Chem., Int. Ed. Engl. 1964, (51) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 3, 65. 14370. (17) Schönherr, H.-J.; Wanzlick, H.-W. Chem. Ber. (presently part of (52) Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905. Eur. J. Inorg. Chem.) 1970, 103, 1037. (53) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New (18) Schönherr, H.-J.; Wanzlick, H.-W. Justus Liebigs Ann. Chem. York, 1984. (presently part of Eur. J. Org. Chem.) 1970, 731, 176. (54) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863. (19) Walentow, R.; Wanzlick, H.-W. Z. Naturforsch., B: Chem. Sci. 1970, (55) Pearson, W. H. Pure Appl. Chem. 2002, 74, 1339. 25, 1421. (56) Carruthers, W. Cycloaddition Reactions in Organic Synthesis; (20) Arduengo, A. J., III; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. Pergamon: Elmsford, NY, 1990. 1991, 113, 361. (57) Shintani, R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 10778. (21) Arduengo, A. J., III; Dias, H. V. R.; Harlow, R. L.; Kline, M. J. Am. (58) Suárez, A.; Downey, C. W.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, Chem. Soc. 1992, 114, 5530. 11244. (22) (a) Dixon, D. A.; Arduengo, A. J., III. J. Phys. Chem. 1991, 95, 4180. (59) Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 6330. (b) Arduengo, A. J., III. Acc. Chem. Res. 1999, 32, 913. (60) Suga, H.; Funyu, A.; Kakehi, A. Org. Lett. 2007, 9, 97. (23) Ugai, T.; Tanaka, S.; Dokawa, S. J. Pharm. Soc. Jpn. (Yakugaku (61) Dorn, H.; Otto, A. Chem. Ber. 1968, 101, 3287. Zasshi) 1943, 63, 296. (62) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 5334. (24) Wöhler, F.; Liebig, J. Ann. Pharm. (presently part of Eur. J. Org. (63) Confalone, P. N.; Huie, E. M. Org. React. (NY) 1988, 36, 1. Chem.) 1832, 3, 249. (64) Gothelf, K. V.; Jørgensen, K. A. Chem. Commun. 2000, 1449. (25) (a) Sheehan, J. C.; Hunneman, D. H. J. Am. Chem. Soc. 1966, 88, (65) Martin, J. N.; Jones, R. C. F. In Synthetic Applications of 1,3-Dipolar 3666. (b) Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, Cycloaddition Chemistry toward Heterocycles and Natural 1743. Products; Padwa, A., Pearson, W. H., Eds.; The Chemistry of VOL. 42, NO. 3 • 2009 66

Heterocyclic Compounds Series, Vol. 59; Wiley: Chichester, U.K., About the Authors 2002; pp 1–81. Eric Phillips was born in 1983 in Grand Rapids, MI. He (66) Osborn, H. M. I.; Gemmell, N.; Harwood, L. M. J. Chem. Soc., received his B.S. degree in chemistry from Western Michigan Perkin Trans. 1 2002, 2419. University. In 2005, he joined the laboratory of Professor Karl (67) Bryans, J. S.; Wustrow, D. J. Med. Res. Rev. 1999, 19, 149. A. Scheidt at Northwestern University, where he is currently (68) Tassone, D. M.; Boyce, E.; Guyer, J.; Nuzum, D. Clin. Ther. 2007, a fifth-year graduate student. The majority of his graduate 29, 26. work has focused on the development of reactions catalyzed by (69) Cooper, J. R.; Bloom, F. E.; Roth, R. H. The Biochemical Basis of N-heterocyclic carbenes, and has received an ACS Division of Neuropharmacology, 8th ed.; Oxford University Press: Oxford, Organic Chemistry Graduate Fellowship sponsored by Organic U.K., 2003. Reactions. Upon completion of his Ph.D. requirements, he will (70) Phillips, E. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc. join the laboratory of Professor Jon A. Ellman at the University 2008, 130, 2416. of California, Berkeley, as a postdoctoral fellow. (71) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. Audrey Chan was bor n in São Paulo, Brazil, and im mig rated 1998, 120, 6615. to Brooklyn, New York, at the age of six. She received her (72) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959. B.S. degree in chemistry in 2002 from Cornell University. (73) Horstmann, T. E.; Guerin, D. J.; Miller, S. J. Angew. Chem., Int. Ed. After working at Merck Research Laboratories as a medicinal 2000, 39, 3635. chemist, she joined the group of Professor Karl A. Scheidt (74) Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.; Tomioka, K. J. Am. at Northwestern University in 2003. As a Dow Chemical Chem. Soc. 2003, 125, 2886. Company Predoctoral Fellow, she studied N-heterocyclic Discovering New Reactions with N-Heterocyclic Carbene Catalysis Discovering New Reactions with N-Heterocyclic (75) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2008, 130, 2740. carbene catalyzed homoenolate and hydroacylation reactions. (76) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, Upon completion of her Ph.D. requirements in 2008, she joined 8418. Cubist Pharmaceuticals in Lexington, Massachusetts, where (77) Phillips, E. M.; Wadamoto, M.; Chan, A.; Scheidt, K. A. Angew. her research focuses on drug development for anti-infectious Chem., Int. Ed. 2007, 46, 3107. diseases. (78) Wadamoto, M.; Phillips, E. M.; Reynolds, T. E.; Scheidt, K. A. J. Karl Scheidt became interested early in science because of Am. Chem. Soc. 2007, 129, 10098. his father, W. Robert Scheidt, a prominant inorganic chemistry (79) (a) Phillips, E. M.; Wadamoto, M.; Scheidt, K. A. Synthesis 2009, professor at the University of Notre Dame. He received his 687. (b) Phillips, E. M.; Roberts, J. M.; Scheidt, K. A. Org. Lett. Bachelor of Science degree from Notre Dame in 1994 while 2009, 11, submitted for publication. working in the laboratory of Professor Marvin J. Miller. Under (80) Silva, L. F., Jr. Synthesis 2001, 671. the direction of Professor William R. Roush, Karl earned his (81) Wu, T.-S.; Kao, M.-S.; Wu, P.-L.; Lin, F.-W.; Shi, L.-S.; Liou, M.-J.; Ph.D. degree from Indiana University, and was a National Li, C.-Y. Chem. Pharm. Bull. 1999, 47, 375. Institutes of Health Postdoctoral Fellow with Professor David (82) Trost, B. M.; Shuey, C. D.; DiNinno, F., Jr.; McElvain, S. S. J. Am. Evans at Harvard University. Since joining Northwestern Chem. Soc. 1979, 101, 1284. University in 2002, Karl’s research has focused on the (83) Harrington, P. E.; Tius, M. A. J. Am. Chem. Soc. 2001, 123, 8509. development of new catalytic reactions and the total synthesis (84) Koyama, Y.; Yamaguchi, R.; Suzuki, K. Angew. Chem., Int. Ed. of molecules with important biological and str uctural attributes. 2008, 47, 1084. He currently holds the Irving M. Klotz Research Chair in (85) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 15088. Chemistry and is the Alumnae of Northwestern Teaching (86) (a) Phillips, E. M.; Wadamoto, M.; Roth, H. S.; Ott, A. W.; Scheidt, Professor. He is a fellow of the Alfred P. Sloan Foundation, an K. A. Org. Lett. 2009, 11, 105. (b) Kawanaka, Y.; Phillips, E. M.; American Cancer Society Research Scholar, and the recipient Scheidt, K. A. J. Am. Chem. Soc. 2009, 131, 18028. of a National Science Foundation CAREER Award. His recent (87) Zeitler, K.; Rose, C. A. J. Org. Chem. 2009, 74, 1759. honors include: The GlaxoSmithKline Scholar Award (2008), (88) Maki, B. E.; Patterson, E. V.; Cramer, C. J.; Scheidt, K. A. Org. Lett. AstraZeneca Excellence in Chemistry Award (2007), Novartis 2009, 11, 3942. Chemistry Lecture Award (2007), Amgen Young Investigator (89) Marenich, A. V.; Olson, R. M.; Kelly, C. P.; Cramer, C. J.; Truhlar, Award (2006), Boehringer Ingelheim New Investigator Award D. G. J. Chem. Theory Comput. 2007, 3, 2011. in Organic Chemistry (2005), Northwestern University Distinguished Teaching Award (2005), 3M Nontenured Faculty Keywords: catalysis; N-heterocyclic carbenes; umpolung; acyl Award (2005), Abbott Laboratories New Faculty Award (2005), anions; homoenolates. and the Amgen New Faculty Award (2004).

Correction (June 11, 2010). The two sentences that start on line 20 and end on line 26 of page 55, column 1, paragraph 1 should be amended to read: In 1954, Mizuhara and Handler proposed that the active catalytic species of thiamine-dependent enzymatic reactions is a “pseudobase” that acts through the lone pair of electrons on the tertiary thiazole nitrogen.14 However, in 1958, Breslow offered an alternative mechanism whereby the active catalytic species of thiamine-dependent enzymatic reactions is a highly unusual divalent carbon- containing species,1b later on referred to as an N-heterocyclic carbene (NHC). The authors of the review regret the confusion the original text may have caused. VOL. 42, NO. 3 • 2009 CatCart® Catalyst Products from ThalesNano

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sigma-aldrich.com 71 Synthesis and Applications of Diorganozinc Reagents: Beyond Diethylzinc

Alexandre Lemire, Alexandre Côté, Marc K. Janes, and André B. Charette* Department of Chemistry Université de Montréal P.O. Box 6128, Station Downtown Montréal, QC H3C 3J7, Canada Email: [email protected]

Dr. Alexandre Lemire Dr. Alexandre Côté

and because of the low reactivity of the byproducts of their reactions. These reagents possess very high functional-group tolerance and react sluggishly in the absence of a catalyst or the appropriate reaction conditions (Figure 1). For all these reasons, diorganozinc reagents can be viewed as privileged reagents in enantioselective catalysis.1 Our research group has been interested in diorganozinc compounds for the past 20 years, and has developed a number of enantioselective reactions using diorganozinc reagents. Like others, we have developed several asymmetric reactions using diethylzinc as the standard reagent in part because of its Dr. Marc K. Janes Professor André B. Charette good reactivity, relatively low cost and wide availability. One impediment to the widespread use of diorganozinc chemistry Outline in novel catalytic asymmetric processes has been the lack 1. Introduction of commercial availability of most diorganozinc reagents, 2. General Syntheses of Diorganozinc Reagents especially when compared to other common organometallic 2.1. Metallic Zinc Insertion and Schlenk Equilibration reagents, such as RZnX, RMgX, and RLi. 2.2. Transmetallation of an Organometallic Reagent with a It is thus not surprising to see that diethylzinc (the Zinc Salt cheapest diorganozinc reagent) accounts for 60% of all the 2.3. Transmetallation of an Organometallic Reagent with a references found in Scifinder Scholar® on diorganozinc Diorganozinc reagents! Dimethylzinc accounts for 21%, dibutylzinc for 4%, 2.4. Halogen–Zinc Exchange diisopropylzinc for 4%, diphenylzinc for 5%, and all the others 3. Synthetic Applications of Diorganozincs for the remaining 6%. 3.1. Enantioselective Additions Obviously, new methodologies employing only diethylzinc 3.1.1. Addition to Imines Leading to Chiral Amines as the reagent would only fully blossom if they could be 3.1.2. Addition to Aldehydes and Ketones Leading to shown to be more general and applicable to other diorganozinc Chiral Alcohols reagents. For example, we reported in 2003 the copper- 3.1.3. Conjugate Addition Giving Rise to β-Substituted catalyzed asymmetric addition of diorganozinc reagents to Ketones, Nitroalkanes, and Sulfones N-diphenylphosphinoylimines in the presence of (R,R)-BozPhos 3.2. Asymmetric Allylic and Propargylic Substitution (1), in which diethyl-, dimethyl-, dibutyl-, and diisopropylzincs Reactions were successfully employed (eq 1).2 The only functionalized 3.3. C–H Bond Arylation of Heteroaromatic Compounds dialkylzinc successfully utilized in this reaction was di[6-tert- 3.4. Electrophilic Amination of Organozinc Nucleophiles butyldimethylsilyloxy)hexyl]zinc (52%, 90% ee). 3.5. Carbozincation Reactions A fundamental problem associated with the preparation 3.6. Catalytic Enantioselective Addition of Dialkylzincs to of diorganozinc reagents is the removal of the reaction N-Acylpyridinium Salts byproducts. Even if numerous methods exist to synthesize 4. Conclusions and Outlook diorganozinc reagents,3 the chemist who needs a noncom mercial 5. Acknowledgements diorganozinc reagent faces a dilemma: either the diorganozinc 6. References and Notes is easily prepared in solution from simple reagents and used without purification (but two equivalents of a lithium or a 1. Introduction magnesium halide byproducts are formed), or he/she embarks Diorganozinc reagents are unique nucleophiles because of on a time-consuming purification of the diorganozinc. Most the right balance between their nucleophilicity and basicity purification methods are either difficult to realize in a normal VOL. 42, NO. 3 • 2009 72

laboratory environment, or they require the manipulation of byproducts are removed from the reaction mixture by simple pyrophoric reagents. filtration. Most of these preparation methods, as well as our In numerous cases, the byproducts can be very detrimental findings in this area, will be discussed in Section 2, whereas to subsequent catalytic asymmetric transformations, applications of diorganozinc reagents in synthesis will be since they often interfere with the catalytic cycle. For covered in Section 3. example, the addition of in situ prepared dipropylzinc to N-diphenylphosphinoylbenzaldimine gives the product with 2. General Syntheses of Diorganozinc Reagents only a 27% ee (compared to 96% ee for addition of dibutylzinc The different methods for preparing diorganozinc compounds as depicted in equation 1). The presence of even a very small can be grouped into four general approaches (Scheme 1):1,3 (a) amount of a magnesium or lithium salt affords N-protected the oxidative addition between zinc metal and an alkyl halide secondary amines with significantly reduced enantiomeric followed by Schlenk equilibration, (b) the transmetallation excesses and variable yields.4,5 of a zinc halide with an organometallic reagent, (c) the Pure diorganozinc reagents are typically obtained by transmetallation of a diorganozinc starting material with an distillation or sublimation (vide infra), and the great majority organometallic reagent, and (d) the zinc–halogen exchange have to be kept under an inert atmosphere as they react with between an alkyl halide and a diorganozinc. water or oxygen. When diorganozinc reagents are nonvolatile or thermally unstable, a preparation method is chosen to ensure 2.1. Metallic Zinc Insertion and Schlenk Equilibration that the reaction byproducts are volatile and distilled off the Von Frankland prepared diethylzinc from iodoethane and zinc reaction mixture along with excess reagents and solvents (if metal.6 Oxidative insertion of zinc into the carbon–iodine any). This approach implies that distillation of pyrophoric bond led to ethylzinc iodide, which generated diethylzinc upon diethylzinc, triethylborane, or diisopropylzinc is sometimes distillation.7 Removal of the product diethylzinc by distillation Synthesis and Applications of Diorganozinc Reagents: Beyond Diethylzinc required. Therefore, considerable effort has been expended shifted the Schlenk equilibrium towards the diorganozinc. on the development of methods in which the metal halide Since this initial work, many improvements have been made to the process, and most of these improvements concern the zinc activation protocol. A zinc–copper couple has traditionally low nucleophilicity high been used to synthesize low-boiling and thermally stable diorganozinc reagents, either from alkyl iodides or mixtures of RZnX < R2Zn < RMgX < RLi alkyl iodides and alkyl bromides (eq 2).8

Figure 1. Reactivity of Diorganozinc Reagents Relative to Those of 2.2. Transmetallation of an Organometallic Reagent Other Organometals. with a Zinc Salt The second general approach consists of reacting a zinc salt

O O with an organolithium or a Grignard reagent, which may bear Ph Ph 9 P (R,R)-BozPhos (1) P various functional groups (see Scheme 1, Part (b)). While this N Ph (3 or 5 mol %) HN Ph + R' Zn reaction is typically run in ethereal solvents, it produces lithium R H 2 R R' (2 or 3 equiv) Cu(OTf)2 (5–10 mol %) or magnesium halides as byproducts. In most cases, these PhMe, 0 °C or rt 52–98% 16–20 h 90–99% ee byproducts need to be removed if the diorganozinc reagent is to be subsequently used as a nucleophile in catalytic enantioselective R = Ph, 2-MeC6H4, 4-MeC6H4, 2-MeOC6H4, 4- MeOC6H4, 2-ClC6H4, 4-ClC6H4, furan-2-yl, c-Pr P O P processes. The detrimental effect of the salts resides in the fact that R' = Me, Et, n-Bu, i-Pr, TBDMSO(CH2)6 they can either catalyze a background racemic reaction, or inhibit (R,R)-BozPhos (1) the activity of a chiral Lewis acid through complexation with the halide anion of the salt.4 One common procedure to remove the eq 1 (Ref. 2a) salt byproducts is by distilling off the diorganozinc reagent; but, this can sometimes lead to low yields. For instance, after solvent

o removal, diisopropylzinc tolerates distillation from magnesium (a) 2 RX + 2 Zn R2Zn + ZnX2 salts under reduced pressure (60% yield). However, distillation (b) 2 RM + ZnX2 R2Zn + 2 MX from magnesium salts is less satisfactory for dicyclobutylzinc 10 (c) 2 RM + R'2Zn R2Zn + 2 R'M (28%), dicyclopentylzinc (19%), and dicyclohexylzinc (21%). In 1929, Schlenk showed that 1,4-dioxane forms insoluble (d) 2 RX + R'2Zn R2Zn + 2 R'X complexes with magnesium halides, thus allowing the preparation of diorganomagnesium reagents from Grignard reagents by Scheme 1. Four General Approaches to Diorganozinc reagents. displacement of the Schlenk equilibrium upon precipitation of (Ref. 1,3,6) the magnesium halide–dioxane complex.7,11 Seebach used this finding to develop a synthesis of diorganozinc reagents from o 12 38 C Schlenk Et2Zn Grignard reagents. Diorganozincs were thus prepared as a Et–I + EtBr EtZnI + + 1 h equilibrium BrZnI solution in 1,4-dioxane and diethyl ether. This approach allowed Zn–Cu (5–8% Cu) the synthesis of enantioenriched secondary alcohols from distillation 200 oC diorganozinc reagents that were not commercially available <30 mmHg (vide infra). More recently, Walsh and co-workers reported an alternative Et2Zn 86–89% procedure to sequester the lithium halide byproduct formed during the preparation of diarylzinc and aryl(alkyl)zinc eq 2 (Ref. 8a,b) reagents. They achieved this by using low-polarity solvents in VOL. 42, NO. 3 • 2009 73

the reaction to minimize the solubility of lithium halides and from the corresponding boranes and diethylzinc, albeit with * by adding N,N,N,N-tetraethylethylenediamine (TEEDA) to loss of stereochemistry at the carbon attached to the boron.17 scavenge the remaining salts in solution (Scheme 2, Part (a)).5d Transmetallations are quite slower with secondary alkylboranes This procedure allowed for the in situ formation of aryl(alkyl)­ (i.e., 3–40 h at rt), varying with the steric hindrance of the zinc reagents that were compatible with the catalytic asymmetric secondary alkylborane (up to 6 equiv of Et2Zn needed for bulkier preparation of enantioenriched diarylmethanols (vide infra). This secondary alkylboranes). Arylboronic acids and esters, as well approach was later extended to the synthesis of heteroaryl- and as triarylboroxines, can be transmetallated with diethylzinc to diheteroarylmethanols using ethylzinc chloride instead of zinc afford aryl(ethyl)zinc species (see Scheme 4, Part (c)),5b which can chloride to generate the heteroaryl(alkyl)zinc reagent (Scheme 2, be utilized in situ in the enantioselective arylation of aldehydes. Part (b)).5e Low-temperature transmetallation was essential as heteroaryllithiums decompose upon warming, which necessitated the use of ethylzinc chloride as this reagent is soluble at low 1. n-BuLi (1 equiv), MTBE, –78 oC, 1 h o 2. ZnCl2 (1 equiv), 0 C, 0.5 h temperatures in low-polarity solvents. (a) ArBr ArZn(n-Bu) + TEEDA•LiX Our research group recently disclosed a practical synthesis 3. n-BuLi (1 equiv), 0 oC to rt, 4.5 h 4. TEEDA (0.4 equiv), PhMe, rt, 1 h of dialkylzinc reagents from alkylmagnesium chlorides and zinc methoxide (Scheme 3).4,13 The byproduct from this reaction, Ar = Ph, 2-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-FC6H4, 3-Np, etc. methoxymagnesium chloride (MeOMgCl), precipitates from 1. n-BuLi (1 equiv), MTBE, –78 oC, 1 h 2. EtZnCl (1 equiv), –78 oC, 0.5 h the reaction mixture as it is formed. After centrifugation or (b) HetArBr HetArZnEt + TEEDA•LiX filtration, the diorganozinc is obtained as an ether solution (ca. 3. TEEDA (0.4 equiv), PhMe, 0 oC, 0.5 h 0.5 M). The absence of deleterious impurities was ascertained HetAr = thien-2-yl, thien-3-yl, benzothien-3-yl, furan-3-yl, (N-TIPS)indol-4-yl, ferrocenyl using the afforded diorganozinc reagent solutions in numerous Et N,N,N,N-tetraethylethylenediamine (TEEDA) = N Et enantioselective reactions (see Sections 3.1.1–3.1.3). The synthesis Et N Alexandre Lemire, Côté, Marc K. Janes, and André B. Charette of diorganozinc reagents from alkyl- and arylmagnesium Et bromides is also possible by using a modified procedure that Scheme 2. Walsh’s Synthesis of Mixed Aryl(butyl)zincs and is needed to remove the slightly soluble methoxymagnesium Heteroaryl(ethyl)zincs (Ref. 5d,e) bromide (MeOMgBr) and formally convert it into an insoluble mixture of magnesium methoxide and sodium bromide. o 1. Et2O, 0 C to rt, 1 h R Zn (a) 2. centrifugation or 2 2.3. Transmetallation of an Organometallic Reagent X = Cl with a Diorganozinc filtration (MeO)2Zn + RMgX Transmetallation of organoboron, organonickel, and (1.95 equiv) 1. NaOMe (2.4 equiv) X= Br o Et2O, 0 C to rt, 2 h organozirconium compounds with dimethyl-, diethyl-, or R Zn (b) R = Et, i-Pr, n-Bu, i-Bu, 2. centrifugation or 2 diisopropylzinc are valuable methods for the synthesis of n-C10H21 , PhCH 2CH2, filtration Cy 14 o functionalized diorganozinc reagents. The use of organomercury 1. Et2O, 0 C to rt, 1 h RZnEt (c) 15 2. centrifugation or and organoaluminum reagents will not be detailed here. X = Cl Boron-to-zinc transmetallation was popularized by Oppolzer filtration (MeO) Zn + RMgX + EtMgX 16 17 2 and others for alkenyl transfer, by Knochel for alkyl transfer, (0.95 equiv) (1.0 equiv) 1. NaOMe (2.4–3.0 equiv) X= Br o 5b Et2O, 0 C to rt, 2 h and by Bolm for aryl transfer. Hydroboration of alkynes and RZnEt (d) 2. centrifugation or R = Et, Ph, TBDMSO(CH ) alkenes readily affords triorganoboron compounds, which can 2 4 filtration also be accessed from the reaction of boron halides with Grignard R Zn and RZnEt were obtained as ether solutions (ca. 0.5 M) reagents.18 Transmetallation of alkenylborons to alkenyl(alkyl) 2 zincs is a rapid process and needs only a small excess of diethyl- or dimethylzinc (Scheme 4, Part (a)).16e In situ reactions, without Scheme 3. Charette’s Synthesis of Diorganozinc Reagents Using the need for removing triethyl- or trimethylborane byproducts (MeO)2Zn. (Ref. 4,13) before addition of the amino alcohol chiral ligand (vide infra) and aldehyde, provide very convenient processes for the 2 Cy BH (R )2Zn enantioselective synthesis of secondary allylic alcohols. Internal R1 2 2 (1 equiv) BCy2 (1.05–1.5 equiv) ZnR (a) (Ref. 16) alkynes have also been used in this reaction, but unsymmetrical hexanes, o R1 –78 C R1 ones can lead to more than one regioisomer being observed.16b 0 oC to rt, 1 h 1 Transmetallation of trialkylboranes with diethylzinc (2 equiv) at R = n-Bu, t-Bu, n-Hex, (CH2)4Cl, c-Pr, Cy, Ad, OEt

0 °C proceeds well in hexane, ether, or in the absence of a solvent. R (i) (iii) BEt Zn It is complete within 0.5 h with all primary diethyl(alkyl)­boranes, (b) R 2 R (Ref. 5c,17,19) (ii) (ii) 2 but requires longer reaction times with secondary diethyl(alkyl)- R = i-PrCH2, X(CH2)n (n = 1–4; X = Br, Cl, I, CN, NPhth, BPin, boranes. The byproduct, triethylborane, is distilled off to drive C(Me)2NO2, BzO, TBSO, PivO, SPh, etc.) o o the equilibrium towards the desired dialkylzincs (see Scheme (i) Et2BH (1 equiv), 0 C to rt, 3 h. (ii) Distillation (0 C, 0.1 mmHg). (iii) Et Zn (2 equiv), 0 oC, 0.5 h. 4, Part (b)).17 Under these reaction conditions, the boron–zinc 2 exchange occurs with loss of stereochemistry. Numerous Et2Zn (3 equiv) (c) ArB(OH)2 ArZnEt (Ref. 5b) research groups have successfully used this procedure to generate PhMe, 60 oC, 12 h 5c,19 Ar = Ph, 4-MeC6H4, 4-MeOC6H4, 2-MeOC6H4, 2,6-Me2C6H3, functionalized diorganozincs. The boron–zinc exchange is 4-PhC6H4, 4-ClC6H4, 2-BrC6H4, 4-BrC6H4, 1-Np dramatically accelerated when (i-Pr)2Zn is used instead of Et2Zn. This allows for the synthesis of chiral secondary dialkylzincs Scheme 4. Functionalized Diorganozincs Prepared by the with complete retention of configuration at the carbon bearing Transmetallation of Organoboron Reagents with Diethylzinc. the boron atom.20 Secondary dialkylzincs can also be prepared VOL. 42, NO. 3 • 2009 74

The catalytic hydronickellation of alkenes followed by 1. Et2Zn (0.6–3 equiv) transmetallation with diethylzinc is an alternative approach to Ni(acac) (1–5 mol %) 2 21 cod (2–10 mol %), 50–60 °C, 3 h hydroboration (eq 3). The nickel hydride species is formed in situ Zn R R R 2. distillation (0.1 mmHg) upon reacting diethylzinc with nickel(II) to generate an ethylnickel 1 2 3 4 species that undergoes β-hydride elimination. This process releases R = n-Hex, PivO(CH2)2, Tf(Bn)N(CH2)4, R R NCH2, R R C(OH) ethylene gas as a byproduct, and the excess diethylzinc and eq 3 (Ref. 21a) unreacted olefin are distilled off leaving behind the newly formed diorganozinc reagent, which can be used directly in subsequent [Cp Zr(H)Cl] (1 equiv) 2 n ZrCp Cl catalytic asymmetric additions to aldehydes. R R 2 CH2Cl2, rt Zirconium–zinc transmetallation has also been employed 22 Me2Zn (1 equiv) in the alkenylzinc addition to electrophiles. Wipf found that R = t-Bu, c-Pr, Ph, PhMe, –65 °C 1 alkenylzirconocenes, preformed by hydrozirconation of alkynes Cl(CH2)4, R (CH2)n 5 min with Cp2Zr(H)Cl (Schwartz’s reagent), readily form alkenyl(methyl) ZnMe 22a R zinc reagents upon reaction with dimethylzinc (Scheme 5). While this transformation is conceptually identical to the hydroboration– Scheme 5. Alkenyl(alkyl)zinc Reagents by the Zirconium–Zinc zinc transmetallation sequence (see Scheme 4, Part (a)), it has also Transmetallation. (Ref. 22) proven useful in the enantioselective addition of alkenylzinc reagents to ketones.22d Internal symmetrical alkynes were also successfully

Et2Zn (3–5 equiv) employed in the synthesis of an enantioenriched trisubstituted E R I R ZnEt 22b neat, 45–55 °C, 1–12 h allylic alcohol. distillation 40–50 °C Synthesis and Applications of Diorganozinc Reagents: Beyond Diethylzinc (0.1 mmHg) 2.4. Halogen–Zinc Exchange 2 h Iodine–zinc exchange allows for the conversion of functionalized R Zn R iodoalkanes into diorganozincs using diethylzinc or diisopropylzinc 23 R = n-Hep, Cl(CH2)3, EtO2C(CH2)2, pinacolboranyl, (Scheme 6). Diethylzinc was used at first for the synthesis of NC(CH2)n (n = 2, 4), AcO(CH2)n (n = 2–4), primary diorganozinc reagents. Later, Knochel found that addition of t-BuCO (CH ) (n = 0, 2) 2 2 n cuprous iodide accelerates the reaction,23b while our research group reported that UV light also facilitates the exchange.24 However, Scheme 6. Synthesis of Diorganozincs by Iodine–Zinc Exchange. as with the synthesis of dialkylzincs via alkylboron reagents, the (Ref. 23a) removal of excess diethylzinc and iodoethane by distillation is necessary to drive the equilibrium towards the products. Several Bn O H research groups have since employed this procedure to prepare 1 R N 5c,19 Bn N NHBu functionalized diorganozincs. Use of diisopropylzinc allows for H P P N O Bn 25 O PPh2 OH the synthesis of secondary dialkylzincs as well as diarylzincs, by t-BuO R2 using Li(acac) as catalyst.26 (R,R)-BozPhos (1) 2 3a; R1 = MeO, R2 = H N-phosphinoylimines N-tosylimines 3b; R1 = R2 = t-Bu Charette (Ref. 2a,4,13,30) Tomioka (Ref. 29) N-arylimines 3. Synthetic Applications of Diorganozincs Hoveyda–Snapper (Ref. 31) 3.1. Enantioselective Additions 3.1.1. Addition to Imines Leading to Chiral Amines a Ph The asymmetric synthesis of -branched chiral amines is a very Me O P N Me Ph important process, and the addition of nucleophiles to imines is a O Ph OH N versatile approach for accessing these compounds in enantiomerically Ph Ph enriched form.27,28 Diorganozinc reagents are widely utilized in 4 5 6 N-formylimines N-formylimines N-tosylimines catalytic enantioselective additions to imines as pioneered by Bräse (Ref. 32) Feringa (Ref. 33) Hayashi (Ref. 34) Tomioka. 29 A number of such methodologies, employing a diverse set of chiral ligands (Figure 2), have been reported by our research Figure 2. Chiral Ligands Employed in Efficient, Catalytic, and 2,4,13 group (1 with Cu(OTf)2, see eq 1 and eq 4), Tomioka (2 with Asymmetric Additions of Diorganozincs to Imines. 29 31 32 Cu(OTf)2), Hoveyda–Snapper (3 with Zr(O i-Pr)4), Bräse (4), 33 34 Feringa (5 with Cu(OTf)2), and Hayashi (6 with [RhCl(C2H4)2)]), O O Ph Ph Unfortunately, it is only in a few instances that a wide array of P (R,R)-BozPhos (1) P N Ph (5 mol %) HN Ph different diorganozinc reagents were tested in these reactions. + R2Zn The use of zinc methoxide and alkylmagnesium chlorides allows Ph H 1.9 equiv Cu(OTf)2 (10 mol %) Ph R PhMe, 0 °C, 16 h the in situ preparation of the corresponding diorganozinc reagents a (see Scheme 3, Part (a)) that add to imines with moderate-to- R2Zn was generated in situ from RMgCl (3.9 R Yield ee equiv) and Zn(OMe)2 (2 equiv), as described in excellent yields and excellent enantioselectivities in the presence of b the top equation in Scheme 3. Zn(OMe)2 Eta 95% 98% copper(II) and (R,R)-BozPhos (1) (see eq 4).4,13 In one case, styrene was formed in situ from ZnCl2 (2 equiv) and Etb 90% 98% c NaOMe (4.2 equiv). Zn(OMe)2 was obtained Etc 94% 94% was employed by Li and Alexakis as an additive to enhance the in situ from ZnBr2 (2 equiv) and NaOMe (4.2 Etd 96% 98% 35 d enantioselectivity of the reaction. equiv). Commercial, neat Et2Zn was n-Bua 96% 96% e 36 dissolved in Et2O. 1 (10 mol %), Cu(OTf)2 (20 i-Pr a,e 57% 95% A mixed diorganozinc reagent was also prepared from zinc mol %), and styrene (1 equiv) as additive (see n-decyla,f 73% 97% methoxide and was added to the imine under similar conditions, f reference 35). Reaction was run for 48 h. affording the protected secondary amine with moderate yield but very good enantioselectivity (Scheme 7).4,36 Methyl,22 ethyl,5a,e,16a,e eq 4 (Ref. 4,13,30) neopentyl,37 and neophyl37 groups are other typically used VOL. 42, NO. 3 • 2009 75

nontransferable alkyl groups. This strategy minimizes the potential * 1. Et2O, 0 °C to rt waste of a precious functionalized alkyl group, while providing n-C10H21MgCl ++TMSCH2MgCl Zn(OMe)2 1.9 equiv 2 equiv 2 equiv 2. centrifugation higher yields and enantioselectivities in some reactions. O The asymmetric synthesis of a-branched dialkylamines Ph P (R,R)-BozPhos (1) HN Ph was accomplished by employing a similar catalytic system, but (5 mol %) [ n-C H ZnCH TMS ] the unstable enolizable imines were generated in situ from the Ph n-C H 10 21 2 10 21 Cu(OTf)2 (10 mol %) 1.9 equiv 38 PhMe, 0 °C O corresponding sulfinic acid adducts (eq 5). A one-pot synthesis 47%, 95% ee Ph P of enantioenriched, unprotected secondary amines from aldehydes N Ph 39 was also reported using a modification of this procedure. Ph H Similar reaction conditions enabled the enantioselective addition of dimethylzinc and diethylzinc to trifluoromethyl ketimines Scheme 7. Synthesis of a Mixed Diorganozinc and Its Addition to generated in situ from the corresponding ethanol adducts (i.e., OEt N-Diphenylphosphinoylbenzaldimine. (Ref. 4) instead of Ts on the imine precursor).40 O O Ph Ph Fu, Snapper, and Hoveyda have reported a catalytic asymmetric P (R,R)-BozPhos (1) P addition of dialkylzinc reagents to aryl-, alkyl-, and trifluoroalkyl- HN Ph (5 mol %) HN Ph + Et2Zn 41,42 R Ts R Et substituted activated N-(2-methoxyphenyl)ketimines. They 2.5 equiv Cu(OTf)2 (4.5 mol %) PhMe, –20 °C to rt, 16 h utilized protected dipeptide 3a as a chiral promoter, in conjunction with zirconium tetraisopropoxide, for the enantioselective addition R Yield ee of dimethylzinc to aryl- and heteroaryl-substituted ketimines Me 97% 90% 41 i-Pr 86% 96% (eq 6). When R = Ph in the ketimine, lowering the catalyst loading i-Bu 97% 96% n-Hex 98% 95% to 1 mol % had little impact on enantioselectivity and yield (92%, c-Pent 92% 95% 93% ee). Dipeptide catalyst 3b gave the best enantioselectivities in Cy 89% 96% Alexandre Lemire, Côté, Marc K. Janes, and André B. Charette Ph(CH2)2 98% 96% the addition of dimethylzinc to alkyl-substituted a-ketimine esters Ph 87% 97% (see eq 6), as well as to aryl-substituted trifluoromethyl ketimines (not shown, 66–96%, 96–98% ee’s, 5 examples). eq 5 (Ref. 38a)

3.1.2. Addition to Aldehydes and Ketones Leading to MeO MeO 3a or 3b (5–10 mol %) Chiral Alcohols N HN Me The catalytic enantioselective alkylation of aldehydes to afford Zr(Oi-Pr)4•i-PrOH R CO2Me (5–10 mol %) R CO2Me enantioenriched secondary alcohols was extensively studied in the Me2Zn (4 equiv), PhMe 1980s. Diorganozinc reagents were the most widely used nucleophiles –15 to 22 oC, 24–120 h in this reaction, due to their low propensity to add to carbonyl 3a; R = aryl, heteroaryl; 91–98%, 88–97% ee 3b; R = alkyl; 38–85%, 82–93% ee derivatives without the presence of a suitable catalyst. In 1986, Noyori reported that catalytic quantities of 3-exo-dimethylaminoisoborneol eq 6 (Ref. 41) (DAIB, 7, Figure 3), an amino alcohol derived ligand, triggered the ethyl-transfer reaction from diethylzinc to an aldehyde to provide NHSO2CF3 secondary alcohols in high enantiomeric excesses.43 A few years N OH later, Yoshioka,44 Ohno,45 and Kobayashi46 reported a titanium(IV)- NHSO2CF3 based enantioselective addition of diethylzinc (and of di-n-butyl-, (–)-DAIB (7) 8 Noyori Yoshioka, Ohno, Kobayashi and di-n-pentylzinc) to aldehydes, using a catalytic amount (as (Ref. 43) (Ref. 44–46) low as 0.05 mol %) of a chiral bis(sulfonamide), 8. Knochel also Ph Ph O showed the potential of this methodology by using funtionalized O OH dialkylzincs as nucleophiles, which were prepared either from a N OH O OH 17 boron–zinc (see Scheme 4, Part (b)) or an iodine–zinc exchange Ph Ph 23 (see Scheme 6). Seebach employed titanium tetraisopropoxide as (–)-MIB (10) (–)-TADDOL (9) Nugent Seebach a Lewis acid in the asymmetric addition of diethylzinc to aldehydes (Ref. 48) (Ref. 47) promoted by a catalytic amount (10 mol %) of TADDOL (9).47 The scope of this reaction was greatly enhanced by the development Figure 3. Chiral Ligands for the Enantioselective Addition of of an in situ protocol for the generation of dialkylzinc derivatives Diorganozincs to Aldehydes. from Grignard reagents.12 In 1999, Nugent reported an improved amino alcohol ligand, 3-exo-morpholinoisoborneol (MIB, 10), 1. Cy2BH, t-BuOMe 0 oC to rt, 1 h H which proved to be as good as DAIB in the addition of diethylzinc R1 Cl to aldehydes.48 MIB also displayed a large positive nonlinear effect 2. t-BuLi, –78 oC to rt R1 ZnEt 3. Et Zn similar to DAIB.49 The main advantage of MIB consists in its ease 2 of preparation and its extended bench stability.50 HO 4. TEEDA (20-30%) R1 R2 hexanes Following Nugent’s report on MIB, Walsh greatly expanded 61–93% 5. (–)-MIB (10, 5 mol %) its scope by applying it in the addition of alkenyl(alkyl)zincs >20:1 dr 6. R2CHO, 0 oC to rt (prepared as in Scheme 4, Part (a)) to aldehydes.16,51 Access to 75–98% ee 1 enantiomerically enriched Z-disubstituted allylic alcohols from R = TBDPSO(CH2)2, n-Hex, Cl(CH2)4, Ph 2 1-chloroalkynes was later reported by the same group (Scheme 8).52 R = alkyl, cycloalkyl, aryl, heteroaryl tert-Butyllithium added onto the boron center to generate an ate Scheme 8. Synthesis of Enantioenriched Z-Disubstituted Allylic complex that underwent a 1,2-hydride shift to the vinylic carbon, Alcohols. (Ref. 52) followed by halide elimination, to generate the Z-alkenylboron VOL. 42, NO. 3 • 2009 76

1. HBEt , PhMe 3. R'CHO 2 OH rt, 0.5 h –78 to –10 oC, 8 h (a) ZnEt (Ref. 56a) R R R' R 2. (–)-MIB (10) 4. Et2Zn, CH2I2 (4 mol %) hexanes o 71–84% Et2Zn, hexanes 0 C to rt, 24 h >20:1 dr o –78 C 5. NH4Cl(aq) 87–99% ee

R = Ph, n-Bu, t-Bu, Cl(CH2)4, TrO(CH2)2; R' = i-Pr, Cy

1. (–)-MIB (10) 2. Et2Zn, CF3CH2OH I R3 O R3 OZnR4 R3 OH (4 mol %) hexanes, 0 oC, 10 min (b) (Ref. 56b) R2 H R2 R4 R2 R4 Zn(R4) (2 equiv) 3. CHI3, CH2Cl2, 4 Å MS 1 2 1 1 R hexanes, 0 oC, 8 h R rt, 24 h R 4. NH4Cl(aq) 60–91% 1 2 1 2 R = H, Me; R = H, Me, Ph; R ,R = (CH2)4 >20:1 dr 3 4 89–99% ee R = H, Me, TBDPSOCH2; R = Me, Et, i-Pr(CH2)4, TBDPSO(CH2)5

Scheme 9. Enantioselective Alkylation and Vinylation of Aldehydes and in Situ Cyclopropanation.

intermediate (KHB(Oi-Pr)3 was also shown to be a suitable hydride

donor). Subsequent boron–zinc exchange with Et2Zn generated the O OH Z-alkenylzinc species. Addition of TEEDA as a lithium salt scavenger H [ RZnR' ] (1.9 equiv) R (see Scheme 2) was needed to afford high enantioselectivity in the 10 (2 or 5 mol %) alkenylzinc addition to aldehydes. The synthesis of Z-trisubstituted

Synthesis and Applications of Diorganozinc Reagents: Beyond Diethylzinc PhMe, 0 °C 53,54 12 or 24 h allylic alcohols from 1-bromoalkynes was also reported. The enantioselective addition of diorganozinc reagents to RZnR' R R' Sourcea Yield ee aldehydes was also used in tandem one-pot vinylation–epoxidation reactions,55 as well as in tandem one-pot alkylation– and Et Et A 93% 98% 56 Etb Et A 95% 98% vinylation–cyclopropanation reactions (Scheme 9). The bromo- Et Et B 96% 97% and chlorocyclopropanation could also be achieved using this c n-decyl n-decyl A 63% 97% methodology, while the opposite halide epimer was obtained when Ph Et C 90% 98% 2 Ph Et D 98% 98% R was a phenyl group. Alkynes (terminal and internal) were also Ph Et E 63% 93% transformed into iodocyclopropanes. Et Et C 96% 98% TBDMSO(CH2)4 Et C 70% 98% Walsh reported a general method for preparing enantioenriched diarylmethanols in 55–96% yields and 78–99% ee’s by the catalytic a o Method A: (i) RMgCl (3.9 equiv), Zn(OMe)2 (2 equiv), Et2O, 0 C arylation of aldehydes with mixed aryl(alkyl)zincs obtained from to rt; (ii) centrifugation. Method B: Commercial, neat Et Zn was 2 5d,e,28 dissolved in Et2O. Method C: (i) RMgBr (1.9 equiv), R'MgBr (2 aryl bromides (see Scheme 2). o equiv), Zn(OMe)2 (2 equiv), NaOMe (4.8 or 6.0 equiv), Et2O, 0 C to Likewise, we have tested the dialkylzinc reagents prepared rt; (ii) centrifugation. Method D: PhZnEt was prepared by mixing from alkylmagnesium chlorides and zinc methoxide (see Scheme 3, commercially available, neat Et2Zn (0.75 equiv) with Ph2Zn (0.75 equiv). Method E: (i) EtMgBr (1.5 equiv), PhMgBr (1.45 equiv), and Part (a)), in Nugent’s MIB-catalyzed addition to 2-naphthaldehyde b ZnCl2 (1.5 equiv) in Et2O; (ii) 1,4-dioxane (14 equiv). Zn(OMe)2 13 c (eq 7). Very good yields and enantioselectivities are obtained formed in situ from ZnCl2 (2 equiv) and NaOMe (4.2 equiv). Lower yield due to reduction of the aldehyde. with diethylzinc using either preformed or in situ generated zinc methoxide. Didecylzinc also displays a very good enantioselectivity, although the isolated yield is lower due to reduction of the eq 7 (Ref. 13) aldehyde. Diorganozinc reagents prepared from organomagnesium bromides have also been utilized in the (–)-MIB-catalyzed arylation and alkylation of 2-naphthaldehyde (see eq 7). The results for the

11 (10 mol %) OH N addition of the phenyl group, generated as in Scheme 3, Part (d), (a) RCHO + Ph2Zn O are comparable to results obtained with PhZnEt generated by THF, rt, 8–16 h Ph R OH 75–96% OH mixing commercially available neat diphenylzinc and diethylzinc R = alkyl, aryl 89–98% ee O (eq 7, Method D). In comparison, freshly prepared PhZnEt, in N which the magnesium salts are removed by precipitation with 11 1,4-dioxane, results in only a slight reduction of enantioselectivity, 1. 11 (10–40 mol %) OH X Et2Zn X X I Zn o but a lower yield. Diethylzinc prepared from ethylmagnesium Li(acac) THF, 0 C, 1 h R (b) NMP, 0 °C 2. RCHO, rt, 7–48 h bromide and zinc methoxide with sodium methoxide (as in Scheme 2 12–18 h 3, Part (b)) also results in only a comparable result to that from a R = alkyl, aryl X 11 Yield ee solution of commercial reagent. Transfer of a functionalized alkyl

3-CN 40 mol % 74–87% 79 to >98% group on a mixed diorganozinc (prepared according to Scheme 4-CO2Me 20 mol % 52–97% 87–96% 3, Part (d)) generates the secondary alcohol in good yield and 3-MeO 10 mol % 85–95% 83 to >99% enantioselectivity. The enantioselective addition of diphenylzinc to aldehydes has received considerable attention in the last decade.28 Recently, Scheme 10. Enantioselective Addition of Diarylzincs to Aldehydes. Qin and Pu designed an H8-binol-based catalyst, 11, that is highly enantioselective in this arylation reaction (Scheme 10, Part (a)).57 (Ref. 57,58) Catalyst 11 is easily prepared in one step from commercially VOL. 42, NO. 3 • 2009 77

available materials and is effective for aromatic and aliphatic prepared from zinc methoxide and ethylmagnesium chloride * aldehydes. Pu’s group also succeeded in using 11 with led to results almost identical to those obtained with neat Et2Zn functionalized diarylzincs58 that were prepared according to (92%, 94% ee).13 Knochel’s procedure (Scheme 10, Part (b)).26a Sulfones possessing a stereocenter at the β carbon are powerful The enantioselective arylation that utilizes arylboron chiral synthons for preparing complex natural and biologically species as the arylzinc precursors is an alternative strategy, active molecules. These sulfones can be derivatized into a variety which takes advantage of the wide availability of arylboronic of products, including carbonyl derivatives, alkynes, alkenes, acids. Using a boron–zinc transmetallation (see Scheme 4, alkanes, and haloalkanes.77 The catalytic enantioselective Part (c)) developed by Bolm,5b even triarylboroxines can be transformed into aryl(ethyl)-zinc reagents upon heating with diethylzinc in toluene.59 This methodology has recently been Et Zn Ar O Ar 2 applied to the enantioselective arylation of an aldehyde on a B B (2.8 equiv) [ ArZnEt ] 17.6-kilogram scale, en route to a mGlu2 receptor potentiator O O PhMe B (Scheme 11).60 60 °C, 17 h Ar N 1. Ph The enantioselective synthesis of tertiary alcohols is also an 0.45 equiv Ph important research topic in contemporary organic chemistry.42 Ph OH In 1998, Dosa and Fu reported the first catalytic asymmetric OH (0.2 equiv), PhMe CN o addition of an organometallic reagent to ketones using DAIB Ar –10 C, 0.5 h 61 (7) as catalyst and diphenylzinc as nucleophile. The same year, 2. 3-NCC6H4CH=O, PhMe –5 to –10 °C, 4 h Ramón and Yus reported the first enantioselective addition of Ar = 4-TBSOCH2C6H4 diethyl- and dimethylzinc to ketones using a sulfonamide- 88%, >94% ee based catalyst.62,63 Walsh has also been quite active in this area Alexandre Lemire, Côté, Marc K. Janes, and André B. Charette 64 using bis(sulfonamide) 12 to catalyze the addition of a variety Scheme 11. Triarylboroxine Transmetallation with Diethylzinc and of alkyl- and alkenylzinc nucleophiles, as well as diphenylzinc, Enantioselective Arylation of 3-Cyanobenzaldehyde on a Large 22d,65 to ketones (eq 8). This topic has recently been reviewed Scale. (Ref. 60) quite thoroughly.66

3.1.3. Conjugate Addition Giving Rise to β-Substituted O 1 1 OH Ketones, Nitroalkanes, and Sulfones (R )2Zn (1.6–3 equiv) R Diorganozinc reagents are widely employed in asymmetric RL RS 12 (0.25–10 mol %) RL RS aryl–alkyl ketones Ti(Oi-Pr)4 (1.2 equiv) up to 99% ee 67,68 catalytic additions of nucleophiles to enones. We tested aryl–alkenyl ketones hexane–toluene alkenyl–alkyl ketones or neat a wide array of diorganozinc reagents (see Scheme 3, Part cyclic enones (a)) in the copper-catalyzed enantioselective 1,4 addition to R1 = Me, Et, i-Pr(CH ) , TBSO(CH ) , PivO(CH ) , Br(CH ) , 69,70 2 3 2 4 2 4 2 5 cyclohexenone using Feringa’s conditions. Commercially Cl(CH2)4, n-C8H17, Ph, alkenyl, etc. available diethylzinc or in situ prepared reagent from zinc methoxide and ethylmagnesium chloride gave similar yields and enantioselectivities (eq 9).4,13 The addition of long alkyl Me Me O2S NH HN SO2 chains was also possible using the boron–zinc protocol (see

Scheme 4, Part (b)). Secondary dialkylzincs reacted with very Me OH 12 HO Me good enantioselectivities upon addition of styrene as a radical inhibitor,35 while di-(t-butyl)zinc could not be added with good selectivity. eq 8 (Ref. 65) The synthesis of all-carbon stereogenic centers has been achieved with an NHC–Cu complex by the highly enantioselective O O addition of dialkyl- and diarylzincs to 3-substituted enones [ R2Zn ] (1.9 equiv) 5 (4 mol %) 71,72 (eq 10). The NHC–Cu complex is formed in situ from the Cu(OTf) (2 mol %) 2 R corresponding NHC–Ag complex, 13, and a copper(I) salt. The PhMe–Et2O (1:1), –30 °C 20 h reaction gives the antipode of the product when diarylzincs a A: (i) RMgCl (3.9 equiv), Zn(OMe) are added to enones. Hoveyda later reported another NHC–Cu 2 R2Zn o (2.0 equiv), Et2O, 0 C to rt; (ii) R Sourcea Yield ee complex that gives higher selectivities with cyclic γ-keto esters centrifugation. B: Commercial, neat 73 b (R = CO2Me or CO2t-Bu). Et2Zn was diluted in Et2O. Et A 89% >98% Nitroalkanes are very useful intermediates in organic Zn(OMe)2 was prepared in situ from Etb A 88% >98% ZnCl2 (2 equiv) and NaOMe (4.2 Etc B 86% >98% 74 c chemistry owing to the synthetic versatility of the nitro group. equiv). Feringa's group (Ref. 69) n-Bu A 94% >95% Our research group recently reported that these substrates could reported 94% (>98% ee). i-Bu A 95% 97% d Feringa's group (Ref. 69,70) reported i-Prd A 92% 85% be readily prepared with ((R,R)-BozPhos)2•CuOTf catalyzed 92–95% (72-83% ee) for reaction run i-Pre,f A 93% 94% 75,76 o e diorganozinc addition to β-nitroalkenes (eq 11). Good- at –80 C. Styrene (1 equiv) was Cy A 90% 80% to-excellent yields of highly enantioenriched nitroalkanes added as a radical inhibitor (see Ref. Cye A 94% 94% 35). f Feringa's group (Ref. 69,70) Ph(CH2)2 A 97% >98% were observed when commercial diethylzinc was added to reported 95% (94% ee) for reaction n-decylg A 97% >98% o run at –80 C in the presence of t-Bu A 84% 6% either aryl- or alkyl-substituted β-nitroalkenes. High yields g styrene. Feringa's group (Ref. 69,70 ) t-Bue A 19% 27% and enantioselectivities required an additional amount of reported 95% (95% ee) for the (R,R)-BozPhos (1) (2.5 mol %), which could be replaced by addition of di(n-heptyl)zinc. pivalamide (20 mol %) to favor a less aggregated ethylcopper eq 9 (Ref. 4,13) species (3 examples, 69–91%, 93–96% ee’s). Using diethylzinc VOL. 42, NO. 3 • 2009 78

addition of diorganozincs to vinyl sulfones is easily accomplished 78 O O with copper(I) triflate and (R)-BINAP (eq 12). The use of the 13 (2.5–15 mol %) 2-pyridyl group on the sulfone is mandatory for high reactivity + R'2Zn R' and enantioselectivity. Fortunately, 2-pyridyl sulfones had been ( ) (3 equiv) (CuOTf)2•C6H6 ( ) n R (2.5–15 mol %) n R previously identified as the optimal coupling partner in the Julia– Et O or PhMe 2 34–95% 79 –30 or –15 °C 54–97% ee Kocienski olefination to generate E,Z dienes. 6–72 h n = 1–3, R = alkyl, alkynyl, Ph It is also possible to use diorganozinc reagents prepared from R' = Me, Et, n-Bu, Ph*, 4-MeOC6H4* (* = gave enantiomer) alkylmagnesium chlorides and zinc methoxide to introduce an Ph Ph alkyl group at the β position of the sulfone. Good yields and enantioselectivities are obtained, except when dicyclohexylzinc NNMes O is used. Ag Mes (13) N Ph Ag O N 3.2. Asymmetric Allylic and Propargylic Substitution

Ph Reactions While enantioselective allylic substitution reactions with soft nucleophiles (as enolate derivatives) typically use palladium-, eq 10 (Ref. 71) molybdenum-, or iridium-based catalysts,80 the reaction with hard nucleophiles (dialkylzincs and Grignard reagents) is generally Et 68,81 Et Zn (2 equiv) catalyzed by copper salts. It was recently reported that chiral NO 2 NO R 2 R 2 N-heterocyclic carbene complexes such as 14 (eq 13) are efficient (1)2•CuOTf (1.25 mol %) 1 (2.5 mol %), Et2O 70–99% catalysts in the Cu-free enantioselective allylic alkylation using Synthesis and Applications of Diorganozinc Reagents: Beyond Diethylzinc –70 °C, 16 h 83–98% ee diorganozinc reagents and allylic phosphates.82 Generation of R = Cy, n-C7H15, furan-2-yl, Ph, 3-MeOC6H4 4-XC6H4 (X = F, Cl, CF3, Me, MeO) enantioenriched all-carbon quaternary stereogenic centers is also possible starting with trisubstituted olefins. eq 11 (Ref. 75) Smith and Fu succeeded in generating enantioenriched alkynes by employing a nickel(II) salt and a pybox ligand.83 They first utilized diphenylzinc as the nucleophilic partner, and 5b R' Zn later adapted Bolm’s method to generate phenyl(ethyl)zinc via SO (2-Py) 2 SO (2-Py) 2 (R)-BINAP (10 mol %) 2 a boron–zinc exchange in glyme as the reaction solvent. A wide (CuOTf) •PhMe (5 mol %) R H 2 R R' 60 °C array of aryl(ethyl)zinc reagents were cross-coupled with either TMS-protected propargylic bromides or nonterminal propargylic R'2ZN bromides (eq 14).83 Similar enantioselective nickel-catalyzed R R' Source Yield ee cross-coupling reactions, utilizing secondary a-bromoamides,84 a A: Et Zn (3 equiv) in THF. 2 Me Et A 93% 88% 85 86 B: Commerical, neat Me Zn secondary allylic chlorides, or benzylic halides, have also been 2 i-Pr Et A 55% 96% was employed. C: (i) R'MgCl 2-Np Et A 63% 97% developed by Fu’s group. However, they are typically achieved (5.85 equiv), Zn(OMe)2 (3 Et A 61% 98% o 4-MeOC6H4 with the more readily available alkylzinc halides as coupling equiv), Et2O, 0 C to rt; (ii) 4-F3CC6H4 Et A 57% 94% centrifugation. b Benzene partners. Ph Et A 72% 98% was substituted for THF. c 6 Phb,c Me B 81% 98% The SN2’ reaction of organozincs with propargyl mesylates equivalents of R' Zn used. 2 Phb n-Pr C 52% 89% leading to trisubstituted allenes was dramatically improved by b C Ph n-Bu 53% 90% 87 b,c Ph Ph(CH2)2 C 72% 90% using DMSO as solvent (Scheme 12, Part (a)). The stereoselective Phb Cy C 14% 17% conversion of a chiral propargyl mesylate into a trisubstituted allene was successfully achieved using LiCl-free dibutylzinc13 (Scheme 12, Part (b)).87 eq 12 (Ref. 78) 3.3. C–H Bond Arylation of Heteroaromatic Compounds R1 R2 Diphenylzinc was recently employed in the nickel-catalyzed C–H 14 (5–10 mol %) R1 + (R2) Zn R OPO(OEt) 2 R bond arylation of electron-deficient heteroaromatic compounds 2 (3 equiv) –15 °C to 22 °C or –30 °C to 0 °C THF, 24–72 h SN2':SN2 >98:2 – Ph Ph O3S ArZnEt (2 equiv) NN (14) Mes NiCl2•glyme (3.0 mol %) Br 15 (3.9 mol %) Ar R R o alkyl glyme, –20 C, 14 h alkyl R R1 R2 Yield ee R R1 R2 Yield ee racemic 39–92% R = SiR'3, Ph, alkyl 84–94% ee Ph H i-Pr 60% 81% Ph Me Et 91% 91% O 2-MeC6H4 H Et 62% 83% Ph Me n-Bu 71% 91% O N Cy H Me 54% 79% Ph Me i-Pr 52% 91% N N Cy H Et 79% 85% 4-F3CC6H4 Me Et 68% 89% Cy H i-Pr 64% 92% 4-O2NC6H4 Me Et 82% 89% PhMe2Si H Et 59% 90% Cy Me Et 58% 94% PhMe2Si H n-Bu 59% 86% t-BuO2C Me n-Bu 85% 88% 15 (3aS,8aR)-(–)-in-pybox

eq 13 (Ref. 82) eq 14 (Ref. 83) VOL. 42, NO. 3 • 2009 79

(eq 15).88 Quinoline was also arylated with aryl(ethyl)zinc * reagents that were formed by zinc–boron exchange. On the OMs 3 R3 2 (R )2Zn (2 equiv) R (a) 1 basis of preliminary experiments, the authors reported that the R 2 • R DMSO, rt, 16–24 h 1 diphenylzinc transmetallates with the nickel catalyst to form a H R H 1 2 44–100% phenylnickelate complex, which is nucleophilic enough to add to R = H, alkyl, aryl, TMS; R = H, Ph(CH2)2 3 the most electrophilic carbon of the N-heterocycles. R = Et, n-Bu OMs [ (n-Bu)2Zn ] (2 equiv) MeO2C Me (b) MeO2C • Me DMSO, rt, 24 h n-Bu 3.4. Electrophilic Amination of Organozinc H H Nucleophiles R, >99% ee 87%, 98% ee

The copper-catalyzed electrophilic amination of diorganozincs (n-Bu)2Zn was prepared in situ from n-BuMgCl (2 equiv), with O-benzoyl hydroxylamines is an alternative to the NaOMe (2 equiv), and ZnCl2 Buchwald–Hartwig cross-coupling. The electrophilic amination reagents are prepared from primary or secondary amines and Scheme 12. Stereoselective Synthesis of Trisubstituted Allenes. benzoyl peroxide (Scheme 13). Good-to-excellent yields of di- (Ref. 87) or trisubstituted amines are obtained from dialkyl- or diarylzinc reagents.89 Electrophilic amination of diorganozinc reagents by Ni(cod)2 (5 mol %) 90 oxaziridines is also possible. Very recently, another copper(I)- PCy3 (10 mol %) ArH + Ar'ZnR Ar–Ar' catalyzed amination reagent, Me C=NOSO Mes, was reported PhMe, 60–130 °C 2 2 (1.5–3 equiv) 20 h to generate aniline derivatives from aryl(ethyl)zincs in 34–66% X yields.91 N N Ar' N Ph

Ph Alexandre Lemire, Côté, Marc K. Janes, and André B. Charette 3.5. Carbozincation Reactions Ar' R Yield Xa Yield N 92 >99% N The Rhodium-catalyzed carbozincation of ynamides was very Ph Ph >99% 55% Ph Et 73% CH Ph recently reported as an expedient protocol for generating di- and b 4-MeOC H Et 97% CPh 45% 6 4 N 71% trisubstituted enamides in 49–91% yields and with good-to- 4-Me2NC6H4 Et 93% N 81% 93 3,5-Me2C6H3 Et 71% excellent regioselectivities (rr > 4:1). Addition of dibenzylzinc, a Ph 3-Cl-5-MeOC6H3 Et 51% In all 3 cases, 2-Np b 90% diarylzincs, and dialkenylzincs to the ynamide was possible Et 56% R = Ph. PPh3 used instead of using in situ generated diorganozinc reagents. The synthesis Ph Zn used in all 3 cases. PCy3. 2 of trisubstituted enamides was possible by functionalizing the dialkenylzinc intermediate obtained after the carbozincation eq 15 (Ref. 88) reaction (Scheme 14). The diastereoselective Cu-catalyzed addition of diorganozincs R1 H (PhCO2)2, K2HPO4 R1 O Ph to cyclopropenes was reported very recently.94 Ester N N DMF, rt, 1–24 h and oxazoline groups on the cyclopropene directed the addition R2 R2 O of a variety of diorganozincs with excellent facial selectivity. 61–92% 3 The regioselectivity was high for carbozincation reactions of (R )2Zn R1 R3 THF, rt, 0.25–6.0 h the carboxylate esters of 2-alkyl-substituted 2-cyclopropene N [CuOTf] •C H (1.25 mol %) 2 2 6 6 (Scheme 15, Pa r t (a)). T h e r e s u lt i n g c yclo p r o p yl z i n c i n t e r m e d i a t e s R or CuCl2 (2.5 mol %) were captured via a stereoselective reaction with electrophiles. 43–99% The commercially unavailable diorganozinc reagents utilized in R1,R2 = 1o and 2o alkyl, cycloalkyl; R3 = alkyl, aryl the carbozincation reaction were prepared in situ using Seebach’s protocol.12A chiral oxazolidinone auxiliary was effective in Scheme 13. Preparation of O-Benzoyl Hydroxylamines and Their controlling the diastereoselectivity of the carbometallation Copper-Catalyzed Amination with Diorganozinc Reagents. (Ref. 89) reaction (Scheme 15, Part (b)).

O O Et2Zn (0.55 equiv) Zn 3.6. Catalytic Enantioselective Addition of Ph Rh(cod)(acac) (5 mol %) 2 O N O N Et Dialkylzincs to N-Acylpyridinium Salts THF, 0 °C to rt, 0.25 h Substituted piperidinones are key structural units in Ph medicinal chemistry and highly versatile intermediates in Pd2(dba)3 (2.5 mol %), (2-Fu)3P (10 mol %) organic synthesis. A number of synthetic methodologies THF, 65 °C BzCl have been developed to access these useful heterocyclic 65 °C 4-I-C6H4NO2 (E)-ICH=CHCO2Me compounds. Feringa and co-workers have very recently disclosed the first highly enantioselective addition of dialkylzincs NO2 to N-acylpyridinium salts using copper–phosphoramidite CO Me catalysts (Scheme 16).95 The noncommercial dialkylzincs 2 O O O O Ph were prepared by using the new methodology introduced by Et Et Et Côté and Charette.13 The addition of diethyl-, dipropyl-, dibutyl-, O N O N O N and diphenethylzincs gave the corresponding 2,3-dihydro-4- Ph Ph Ph 54% 61% 56% pyridinones with good yields and excellent enantioselectivities. In the case of diisopropylzinc, the enantioselectivity was Scheme 14. Synthesis of Trisubstituted Enamides by the Rhodium- lower, while the less reactive Me2Zn did not provide the Catalyzed Carbozincation of Ynamides with Diorganozinc desired product at –78 °C or –55 °C (the starting material Reagents. (Ref. 93) was recovered). VOL. 42, NO. 3 • 2009 80

Chemistry of Functional Groups Series; Rappoport, Z., Series Ed.; Wiley: Hoboken, NJ, 2006; Volumes 1 and 2. 1 3 1. (R4) Zn, CuI or 1 3 R CO2R 2 R CO2R CuCN (20 mol %) (2) (a) Boezio, A. A.; Pytkowicz, J.; Côté, A.; Charette, A. B. J. Am. (a) R2 2 Chem. Soc. 2003, 125, 14260. (b) Desrosiers, J.-N.; Côté, A.; R PhMe, 0 °C to rt R4 E 3–15 h 61–85% Boezio, A. A.; Charette, A. B. Org. Synth. 2006, 83, 5. + + 2. H or E dr >83:17 (3) For reviews on the synthesis of diorganozincs, see: (a) Knochel, 1 2 R = H, Me, Ph, PhMe2Si; R = H, n-C6H13 P.; Singer, R. D. Chem. Rev. 1993, 93, 2117. (b) Knochel, P.; R3 = Me, Et; R4 = Me, Et, i-Pr, Ph, 2-MeC H , H C=CH 6 4 2 Leuser, H.; Gong, L.-Z.; Perrone, S.; Kneisel, F. F. Functionalized Ph O Ph O Organic Compounds. In The Chemistry of Organozinc Ph 1. Et2Zn (4 equiv) Ph N Compounds; Rappoport, Z., Marek, I., Eds.; The Chemistry of N CuBr•SMe2 (20 mol %) (b) O O O Functional Groups Series; Rappoport, Z., Series Ed.; Wiley: O MgBr2•OEt2 Et E o Hoboken, NJ, 2006; Part 1, Chapter 8, p 287. (c) Knochel, P.; PhMe, –78 C dr >95:5 2. H+ or E+ Leuser, H.; Gong, L.-Z.; Perrone, S.; Kneisel, F. F. Polyfunctional E = H (82%), I (66%), allyl (65%) Zinc Organometallics for Organic Synthesis. In Handbook of Functionalized Organometallics: Applications in Synthesis; Scheme 15. Copper-Catalyzed, Directed Carbozincation of Knochel, P., Ed.; Wiley-VCH: Weinheim, 2005; Vol. 1, Chapter

Cyclopropene Derivatives with Diorganozinc Reagents. (Ref. 94) 7, p 251. (d) Knochel, P.; Millot, N.; Rodriguez, A. L.; Tucker, C. E. Org. React. (NY) 2001, 58, 417. (e) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 4414. (f) Knochel, P.; Almena Perea, J. J.; Jones, P. Tetrahedron 1998, 54, OMe OMe O 8275. (g) Knochel, P.; Jones, P.; Langer, F. Organozinc Chemistry: ClCO2Bn 1. R2Zn (2.5 equiv) Synthesis and Applications of Diorganozinc Reagents: Beyond Diethylzinc (4 equiv) 16 (10 mol %) An Overview and General Experimental Guidelines. In Organozinc + Cu(OTf) (5 mol %) N THF, 0 °C N 2 N R Reagents: A Practical Approach; Knochel, P., Jones, P., Eds.; The 0.5 h Cl– THF, –78 °C, 16 h 2. HCl(aq) Practical Approach in Chemistry Series; Harwood, L. M., Moody, BnO O BnO O C. J., Series Eds.; Oxford University Press: Oxford, 1999, p 1. (h) SPh R Yield ee Knochel, P. Product Class 1: Organometallic Complexes of Zinc.

O Et 69% 95% In Compounds of Groups 12 and 11 (Zn, Cd, Hg, Cu, Ag, Au); P N (16) n-Pr 65% 88% O i-Pr 65% 56% O’Neil, I., Ed.; Science of Synthesis: Houben-Weyl Methods of n-Bu 63% 93% Molecular Transformations Series; Thieme: Stuttgart, 2003; Vol. Ph(CH2)2 50% 97% SPh 3, p 5. (4) (a) Côté, A. Additions catalytiques énantiosélectives de réactifs diorganozinciques utilisant un ligand diphosphine monoxydé. Ph.D. Thesis, University of Montréal, Montréal, Canada, September Scheme 16. Addition of Dialkylzinc Reagents to N-Acylpyridinium 2007. (b) Charette, A. B.; Côté, A. Methods for Preparing Salts. (Ref. 95) Diorganozinc Compounds. World Patent WO/2008/134890. (c) Charette, A. B.; Côté, A.; Lemire, A. Methods for Preparing 4. Conclusions and Outlook Diorganozinc Compounds. U.S. Patent Appl. 12/591,108, Nov. 9, Diorganozinc reagents are versatile nucleophiles that accommodate 2009. either Lewis base or metal catalysis in enantioselective additions (5) For other examples, see: (a) Corey, E. J.; Hannon, F. J. Tetrahedron to electrophiles. They also display a very high functional-group Lett. 1987, 28, 5237. (b) Bolm, C.; Rudolph, J. J. Am. Chem. Soc. tolerance. While a large number of diorganozinc reagents are now 2002, 124, 14850. (c) Jeon, S.-J.; Li, H.; García, C.; LaRochelle, L. readily available via simple procedures, and despite tremendous K.; Walsh, P. J. J. Org. Chem. 2005, 70, 448. (d) Kim, J. G.; Walsh, improvements in accessing functionalized diorganozincs, as P. J. Angew. Chem., Int. Ed. 2006, 45, 4175. (e) Salvi, L.; Kim, J. pioneered by Knochel, Seebach, Bolm, and others, there is still a G.; Walsh, P. J. J. Am. Chem. Soc. 2009, 131, 12483. strong need to increase their availability, which should significantly (6) (a) Von Frankland, E. Justus Liebigs Ann. Chem. (Eur. J. Org. enhance their usefulness in synthesis. Chem.) 1849, 71, 171. (b) Freund, A. Justus Liebigs Ann. Chem. It is worth mentioning that diorganozinc reagents have several (Eur. J. Org. Chem.) 1861, 118, 1. (c) Rieth, R.; Beilstein, F. K. other applications in organic synthesis, which have not been covered Justus Liebigs Ann. Chem. (Eur. J. Org. Chem.) 1863, 126, 241. (d) in this review. These include the Negishi coupling,96 oxidation to Pawlow, D. Justus Liebigs Ann. Chem. (Eur. J. Org. Chem.) 1877, alcohols,97 addition to anhydrides98 or acylation,99 cyclopropanation 188, 104. (e) Wagner, G.; Saytzeff, A. Justus Liebigs Ann. Chem. or epoxide formation (with carbenoids),100 and the allylzincation of (Eur. J. Org. Chem.) 1875, 175, 351. alkenylmetals.101 (7) (a) Schlenk, W.; Schlenk, W., Jr. Ber. Dtsch. Chem. Ges. B (Eur. J. Inorg. Chem.) 1929, 62, 920. (b) Schlenk, W., Jr. Ber. Dtsch. 5. Acknowledgements Chem. Ges. B (Eur. J. Inorg. Chem.) 1931, 64, 736. (c) Noller, C. This work was supported by NSERC (Canada), the Canada Research R.; White, W. R. J. Am. Chem. Soc. 1937, 59, 1354. Chairs Program, the Canada Foundation for Innovation and the (8) For the synthesis of diethyl-, dipropyl-, dibutyl-, and diisoamylzinc, University of Montréal. Alexandre Côté is grateful to NSERC (ES see: (a) Noller, C. R. J. Am. Chem. Soc. 1929, 51, 594. (b) Noller, D) for a postgraduate fellowship. C. R. Org. Synth. 1932, 12, 86 (Organic Syntheses; Blatt, A. H., Ed.; Wiley: New York, 1943; Collect. Vol. II, p 184). (c) Eremeev, 6. References and Notes I. V.; Danov, S. M.; Sakhipov, V. R.; Skudin, A. G. Russ. J. Appl. (1) For a recent publication on the properties, synthesis, and Chem. 2001, 74, 1410. (d) For the synthesis of dipentyl-, dihexyl-, applications of organozinc reagents, see The Chemistry of and diheptylzinc, see Hatch, L. F.; Sutherland, G.; Ross, W. J. J. Organozinc Compounds; Rappoport, Z., Marek, I., Eds.; The Org. Chem. 1949, 14, 1130. (e) For the synthesis of diisopropyl- VOL. 42, NO. 3 • 2009 81

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Naasz, R.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2002, Am. Chem. Soc. 2000, 122, 11791. 67, 7244. (c) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. In Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Trademarks: Scifinder Scholar® (American Chemical Weinheim, 2002; Chapter 7, pp 224–258. Society). (71) Lee, K.-s.; Brown, M. K.; Hird, A. W.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 7182. Keywords: diorganozinc reagents; dialkylzinc, arylzinc, and (72) For other relevant examples, see: (a) Fillion, E.; Wilsily, A. J. Am. alkenylzinc reagents; enantioselective additions; asymmetric Chem. Soc. 2006, 128, 2774. (b) Reference 35. (c) Brown, M. K.; substitutions; C–H-bond arylation; electrophilic amination; Degrado, S. J.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2005, 44, carbozincation. 5306. (73) Brown, M. K.; May, T. L.; Baxter, C. A.; Hoveyda, A. H. Angew. About the Authors Chem., Int. Ed. 2007, 46, 1097. Alexandre Lemire received his B.Sc. degree in chemistry (74) Barrett, A. G. M.; Graboski, G. G. Chem. Rev. 1986, 86, 751. in 2000 from the Université de Sherbrooke, QC, Canada. He (75) Côté, A.; Lindsay, V. N. G.; Charette, A. B. Org. Lett. 2007, 9, 85. then joined the research group of Professor André Charette at (76) For a review on conjugate addition of organozinc compounds to the Université de Montréal to work towards a Ph.D. degree in nitro-olefins, see Rimkus, A.; Sewald, N. Synthesis 2004, 135. chemistry. His graduate studies focused on the stereoselective (77) (a) El-Awa, A.; Noshi, M. N.; du Jourdin, X. M.; Fuchs, P. L. Chem. synthesis of piperidines. In 2006, he joined Professor K. C. Rev. 2009, 109, 2315. (b) Trost, B. M. Bull. Chem. Soc. Jpn. 1988, Nicolaou’s group at The Scripps Research Institute as an 61, 107. NSERC postdoctoral fellow. He conducted initial studies VOL. 42, NO. 3 • 2009 83

towards the total synthesis of BE-43472B, a bisanthraquinone for organic synthesis, and abnormal NHC palladium catalysts * antibiotic. He subsequently moved back to Montreal and worked (co-authored by Professor Steven P. Nolan). Presentation of this in the Chemical Development department at Wyeth Research. work earned him the Shire Pharmaceuticals Best Presentation He is currently in Professor Charette’s laboratory working on Award (QOMSBOC, 2003) and the Outstanding Presentation the process development of new diorganozinc reagents, with Award (CSC Conference, 2004). In 2005, he became a consultant financial support from Soluphase Inc. advising on the potential of transferring enabling technologies Alexandre Côté received his B.Sc. degree in chemistry in in the chemical industry. Since 2007, he has been co-founder 1999 from the Université Laval (Quebec City). From 2000 to and Vice President at Soluphase, Inc., a Canadian company 2002, he was a medicinal chemist at Pharmacor in Laval (near that aims to commercialize technologies that accelerate drug Montreal), where he worked on HIV protease and integrase discovery or make chemical processes easier, greener, and more inhibitors. In 2002, he entered graduate school at the Université cost-effective. de Montréal, where he earned his M.Sc. (2004) and Ph.D. André B. Charette was born in 1961 in Montréal, QC. Shortly degrees (2007) under the supervision of Professor André after obtaining his B.Sc. degree in 1983 from the Université de Charette. His dissertation research focused on the development Montréal, he moved to the University of Rochester, NY, to pursue of new catalytic methods for the preparation of chiral amines graduate studies. He earned his M.Sc. (1985) and Ph.D. (1987) and nitroalkanes using diphosphine monoxide ligands. He also degrees in organic chemistry under the supervision of Professor worked on the synthesis of salt-free diorganozinc reagents and Robert Boeckman, Jr. He began his academic career in 1989 at their applications in asymmetric catalysis. In January 2008, he the Université Laval (Québec City) following a two-year NSERC joined Professor Erik Sorensen’s group at Princeton University as postdoctoral fellowship with Professor David A. Evans at Harvard an NSERC postdoctoral fellow. His current research is centered University. In 1992, he joined the Université de Montréal, where on the total synthesis of complex natural molecules. he quickly rose through the ranks to become full professor in

Marc K. Janes was born in 1974 in Montréal, Canada. 1998. He is presently the holder of the NSERC/Merck Frosst/ Alexandre Lemire, Côté, Marc K. Janes, and André B. Charette After receiving his B.Sc. degree in chemistry in 1999 from the Boehringer Ingelheim Industrial Chair on Stereoselective Drug Université de Montréal, he worked as a researcher in medicinal Synthesis and of a Canada Research Chair on the Stereoselective chemistry at the Merck Frosst Center for Therapeutic Research. Synthesis of Bioactive Molecules. His research focuses primarily He then went on to pursue graduate studies, and earned his on the development of new methods for the stereoselective M.Sc. and Ph.D. degrees in organic chemistry under the synthesis of organic compounds and natural products. Among supervision of Professor André B. Charette, and co-directed by his recent honors are the Urgel Archambault Award (2006), Professor Hélène Lebel. Based on these studies, he published the ACS Cope Scholar Award (2007), the Prix Marie-Victorin articles on enantioselective cyclopropanation, soluble supports (2008), and the CSC Alfred Bader Award (2009).

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sigma-aldrich.com VOL. 42, NO. 3 • 2009 PhosphonicS™ Heterogeneous Metal Oxidation Catalysts

Allylic and benzylic oxidations, alcohol oxidations, conditions in the presence of a re-oxidant, PhosphonicS™ sulfoxidations and epoxidations represent key synthetic heterogeneous oxidation catalysts cleanly, efficiently, and transformations. Traditional oxidants (chromium, selectively perform key oxidative transformations. The manganese-based reagents, and peracids) are plagued by catalysts can be recovered and recycled, and are available toxicity and often present difficulties in reaction workup in large quantities. Additionally, they are amenable to high and purification, particularly from metal residues. reaction temperatures, can be utilized with commonly employed solvents, and are suitable for flow chemistry The development of new heterogeneous oxidation applications. catalysts which would circumvent the use of hazardous References: but effective stoichiometric reagents would significantly (1) Al-Haq, N. et al. Tetrahedron Lett. 2003, 44, 769. advance the field. Attributes such as simplified reaction (2) Jurado-Gonzalez, M. et al. Tetrahedron Lett. 2003, 44, 4283. (3) Jurado-Gonzalez, M. et al. Tetrahedron Lett. 2004, 45, 4465. workup, and facile product isolation, and selective (4) Al-Hashimi, M. et al. Tetrahedron Lett. 2005, 46, 4365. reaction with a broad range of substrates, which contain multiple potential sites for oxidation, would be key in the development of an efficient catalyst system. Under mild

O S R O R = CN, CH OH, CH=CH 2 2 O SR(i) (viii) OH O O OH (ii) OH F P O O OH (vii) MLn F (iii) O (vi) OH N N S (iv) OH (v) N N O OH O O N S

N

(i) & (ii) MLn = Co(II) (POCo); (iii) & (iv) MLn = VO(II) (POVO); (v)–(viii) MLn = Ce(IV) (POCe)

sigma-aldrich.com Phosphonics Oxidation Catalyst Kit 709034

Oxidation Catalyst Substrate Product Re-Oxidant

O Allylic/Benzylic CH2 Ketones t-BuOOH Allylic alcohols Enones P O O Co

O Allylic alcohols Epoxides t-BuOOH P Sulfides Sulfoxides or NaBrO3 O or H O O VO 2 2

O Allylic CH2 Ketones t-BuOOH P or O Benzylic CH O Mn 2

O 1° alcohols Acids NaBrO3 P 2° alcohols Ketones or O Sulfides Sulfoxides t-BuOOH O Ce

O Sulfides Sulfoxides NaBrO3 P or O t-BuOOH O Cr

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