2006 VOLUME 6 NUMBER 8
Privileged Ligands
DuPhos and BPE Phospholane Ligands
DSM MonoPhos™ Family
ChiralQuest Phosphine Ligands
Solvias® Ferrolcenyl-Based Ligands
(S)-MonoPhosTM: a powerful ligand for asymmetric synthesis.
sigma-aldrich.com Introduction sigma-aldrich.com asymmetric processes. asymmetric other mediate efficiently to backbone BINOL the of transformations via or nitrogen at substituting by tuned readily be can ligands MonoPhos™ base the that Note pre-catalysts. Rh(I) with combination in utilized when reactionshydrogenation enantioselective highly ( the of structure X-ray the depicts image cover The Cover Our About success. your at inquiries your welcome we efforts, sigma-aldrich.com/catalysi visit please catalysis, to relatedproducts of listing complete a For transformations. bond-forming C–O and C–N, C–C, C–H, of breadth wide a in used ligands” “privileged art state-of-the- chiral, to accessibility unprecedentedproviding to committed is Sigma-Aldrich design. the of nature modular and accessibility ready the to due community synthetic the from attention much gained and hydroformylation, and hydrogenation as such paradigms reaction useful industrially in success their proven families, Josiphos phospholanes, DuPhos the as such ligands” “privileged second-generation of design the in above requirementsstated and challenges the met productivity.high with Impressively,and enantiocontrol exceptional have groups R&D under transformations of variety wide a effect that classes ligands” “privileged original salens, Chiral system. catalyst selective and active highly a generate as well as center metal the to strongly bind should ligands the 3) and scale; kilogram to milligram from producedreadily be should family ligand the of members all) not (if most architecture;2) the in variations systematic for allow and viable economically be should synthesis the 1) platforms ligand performance high synthesis. product natural in employed directly being then products chiral the with materials, starting achiral simple frompure enantiomer desired either synthesizing of possibility the offer systems catalytic asymmetric effective Highly transformations. difficultmore ever effect to catalysts metal transition chiral efficient novel, for searching continually are Chemists Introduction Introducing... chemicalbiology. performancematerials applications and drug discovery tools for intodiverse areas of interdisciplinary research such as high- greaterfree press. Future plans will include expanding posts scientificliterature and in the catalysisas found in the broad excitingnew developments in highlightinnovative and andindustry. fromleaders in academia personneland invited posts postswritten by chemicalcommunity, with anopen forum for the global ChemBlogs Sigma-Aldrich’s Anindustry-first Web tool for open scientific discussion. 3 bisoxazolines, Tocheck out 9 1 and ChiralQuest phosphines. ChiralQuest and is designed to be Research groups have spent much well-earned effort in designing in effort well-earned much spent have groupsResearch I nitiallywe will S igma- 4 s tartrate ligands, tartrate . If you cannot find a product related to your specific researchspecific your to relatedproduct a find cannot you If . ChemBlogs, 2 A that exhibit the following general characteristics: general following the exhibit that ldrich [email protected] 5 and cinchona alkaloids cinchona and 10 visit These outstanding ligand families have families ligand outstanding These ChemBlogs S )-MonoPhos™ ligand. This ligand fuels ligand This ligand. )-MonoPhos™ chemblogs.co 7 DSM phosphoramidites, DSM and look forward to accelerating to forward look and 6 representthe m . 8 Solvias
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DuPhos and BPE Phospholane + H [((R,R)-Me-BPE)-Rh] H Ligands (S/C = 500) Ph N(H)Ac MeOH, 60 psi H2, rt, 12 h Ph N(H)Ac Introduction 95.2% ee Asymmetric hydrogenation reactions represent the ideal process SchemeScheme 1 1 for the commercial manufacture of single-enantiomer compounds, because of the ease by which these robust procedures can be Ph scaled up and because of the low levels of byproducts generated in these asymmetric processes. The most effective hydrogenation systems rely on modifications of the electronic and steric N(H)Ac N(H)Ac N(H)Ac properties of the ligands. Burk and co-workers succeeded in S O developing a highly effective chiral phospholane class of ligands called DuPhos and BPE that contain 2,5-disubstituted groups AcO O N CO2Me allowing for systematic variation of the steric environment CO2Me 11 N(H)Cbz OAc Ligands Phospholane BPE and DuPhos around the metal. Sigma-Aldrich, in collaboration with Kanata AcO N(H)Boc Chemical Technologies, is pleased to now offer a diverse array AcO of DuPhos and BPE phospholane ligands that can be ligated to O 1 metal complexes to afford highly active catalysts for asymmetric CN R R 12 hydrogenation and other innovative transformations. CO2R R2 CO2H The large-scale capacity of these robust catalysts is observed in OH NH2 OH the efficiency (substrate-to-catalyst (S/C) ratios up to 50,000) and the high activities (TOF > 5000 h-1) in a myriad of enamide and ketone reductions. Under optimized conditions, a MeO C NHBoc (R,R)-Me-BPE-Rh complex reduced N-acetyl a-arylenamides in 2 R CO2H 13 N(H)Ac >95% ee to yield valuable a-1-arylethylamines (Scheme 1). N(H)Boc OH It should be noted that Me-DuPhos-Rh complexes were equally effective in asymmetric reductions of prochiral enamides. The Scheme 2 general utility of these phospholane ligands is illustrated in the Scheme 2 incredible diversity-oriented production of a vast array of chiral compounds (Scheme 2). OTf P P Advantages of the DuPhos and BPE Ligands Rh • Superior enantiocontrol in a vast array of catalytic H H N p-Me NC H 0.2 mol % N p-Me NC H transformations N 2 6 4 HN 2 6 4
O H2 (4 atm), 2-propanol, 2 h, rt O • High activities at low catalyst loadings Ph Me Ph Me • Exceptional chemoselectivities for specific reaction paradigms 92% ee O 0 1 0 3 . 5 2 3 . 0 0 8 . 1 : r e d r • Asymmetric hydrogenations of numerous unsaturated Scheme 3 substrates Scheme 3 • First-to-market exclusivity for selected portfolio ligands • Screening kit to facilitate tuning selectivities (Fall 2006) Representative Applications The reactivity profile of these innovative, chiral ligands is covered below and highlights the impressive breadth of valuable transformations mediated by the various portfolio products. In many documented cases, specific ligands have displayed unprecedented selectivities in reactions that form, for instance, chiral centers in heteroatom-functionalized organic building blocks for drug synthesis. T l a c i n h c e Asymmetric Hydrogenation of the C=N Group Burk and co-workers exploited the high activity of the Ethyl- DuPhos ligand via a powerful catalytic reductive amination process.14 The procedure exhibits general applicability in the reduction of a wide variety of N-arylhydrazones, yielding enantioselectivies for most substrates >90% (Scheme 3). S Additionally, this Et-DuPhos-Rh catalyzed system displays 7 2 3 8 . 1 3 2 . 0 0 8 . 1 : e c i v r e exceptionally high chemoselectivies, yielding little or no reduction of unfunctionalized alkenes, alkynes, ketones, aldehydes, and imines in competition experiments. The synthetic utility of these asymmetric hydrazone reductions is enhanced by their facile reaction at ambient temperature with samarium diiodide to afford the corresponding chiral amines, which proceeds with no observable loss of optical purity.
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Catalytic Hydrogenation of Enamides Burk also pioneered the asymmetric hydrogenation of various enamido olefins affording highly enantiopure d,g-unsaturated OTf amino acid products.15 The (S,S)-Et-DuPhos-Rh catalyst system P P controls the reactivity of conjugated substrates with high Rh regioselectivies as well. Under the standard hydrogenation OTBS OTBS H CO2Me S/C = 500:1 CO Me conditions (S/C = 500, H2 pressures ranging from 60 to 90 psi, and 2 H (4 atm), MeOH, 2 h, rt 0.5–3 h), this catalyst gave less than 2% overreduction with all NHAc 2 NHAc products isolated in better than 95% yield. The authors elaborated 99%, 99.3% ee upon this outstanding catalyst reactivity by demonstrating a Scheme 4 concise and highly selective synthesis of the natural product Scheme 4 (–)-bulgecinine, preceeded by formation of the key chiral intermediate in 99% yield with 99.3% ee (Scheme 4). 1. NH2OH 2. Fe, Ac2O
Highly Asymmetric Reductive Amidation 3.
Burk and co-workers have also illustrated a rapid three-step BF4 process for reductive amidation, converting various ketones to P P the respective chiral amines with high enantioselectivity.16 Note Rh O N(H)Ac that the transformation shown involves reacting the ketone 1 with hydroxylamine followed by subsequent reduction with iron S/C = 500:1 metal. This methodology benefits from the utilization of crude H2 (200 psi), MeOH, 18 h, rt enamides isolated as crystalline solids in the direct asymmetric >99% ee catalytic hydrogenation without prior purification. The conversion of 1-acetyladamantane to the novel amine compound occurs SchemeScheme 5 5 with >99% ee and in high yield via use of cationic Rh(I) catalyst 1
DuPhos and BPE (Scheme 5). OAc OAc Rh-(Me-DuPhos) cat. 1 R OAc Me Preparation of Chiral Organics with C–O Stereogenic Centers Me H2 (30 psi), MeOH, rt H Phospholane Ligands Neil Boaz utilized rhodium(I)-(R,R)-Me-DuPhos catalyst 1 to R R H
produce chiral alcohols via the asymmetric hydrogenation of enol 2a: R = n-C5H11, 98.5% ee esters (Scheme 6). Allylic alcohol derivatives are desirable organic 2b: R = Ph, 97.8% ee building blocks in diversity-oriented synthesis, because the olefin 2c: R = CH2CH2OCH2Ph, > 98% ee can be further functionalized after the stereochemistry has been 17 Scheme 6 set in the hydrogenation. Under asymmetric hydrogenation Scheme 6 conditions, the initially formed propargylic acetate was subsequently reduced to yield the Z-allylic acetate. Impressively, the enantioselectivity observed in this reaction was very high among the general substrate class 2a-c. P P Ru Burk and co-workers have also designed highly effective catalysts Br Br for the asymmetric reduction of C=O bonds under hydrogenation O OH conditions.18 In the case shown, the methodology proceeded via 0.4 mol % CO2Me CO2Me use of a chiral [Ru(II)Br2-(i-Pr-BPE)] complex, which was prepared H2 (60 psi), MeOH/H2O, 18 h by reacting [(cod)Ru(2-methylallyl)2] with the BPE ligand followed 99% ee by treatment with methanolic HBr. A variety of esters were Scheme 7 rapidly hydrogenated as mediated by this catalyst to the hydroxyl Scheme 7 esters with very high enantioselectivities (>98%) ee for the alkyl- substituted substrates (Scheme 7).
BF4 Preparation of Chiral Organics with C–C Stereogenic Centers P P As a complement to the C–O bond-forming asymmetric synthesis, Rh
Burk and co-workers have performed highly enantioselective O O 1 MeO hydrogenations of unique substrates that are precursors to natural MeO S/C =3500:1 1 RO C CO R1 products. This methodology is highlighted by enantioselectivies RO2C CO2R H2 (20 atm), MeOH, 3 h, rt 2 2 >99% ee approaching 100% and high efficiencies (S/C > 2500), and has Scheme 8 allowed this research team to surmount the problems associated with the asymmetric synthesis of the drug Candoxitril Scheme 8 (Scheme 8).19
PF6 Novel Asymmetric [4+1] Cycloadditions P P These highly practical enantioselective reactions have been Rh CO2CH2Ph accomplished by the Murkami research group, thus expanding CO2CH2Ph 20 Me the synthetic utility of these powerful chiral ligands. The [4+1] Ph Ph Me cycloaddition between vinylallenes and carbon monoxide affords o Me CO (5 atm), DME, 24 h, 10 C O 95% ee complex cyclopentenone derivatives in a single step and with Me enantiopurities up to 95% (Scheme 9). Scheme 9 Scheme 9
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Palladium-Catalyzed Asymmetric Phosphination Conclusion Glueck and co-workers have successfully developed a catalytic asymmetric phosphination reaction utilized in the production of The modular nature of these chiral phospholane ligands has P-chirogenic phosphines (Scheme 10).21 The fast conversions, allowed variation of the electronics and sterics around the metal moderate catalyst loadings, and superb enantioselectivies allow upon complexation. These bidentate ligands perform highly for the expeditious construction of enantioenriched phosphine enantioselective reactions to produce a wide array of compounds building blocks. Metal-catalyzed routes to these valuable P-chiral containing C–C, C–O, and C–N stereogenic centers. Sigma-Aldrich ligands are rare making this methodology attractive as a viable is your dedicated source for a broad spectrum of chiral building route to synthesize other phosphine ligands. blocks that provide essential starting materials in the synthesis of complex organic molecules. Our growing portfolio of catalysis Catalytic Asymmetric Alkylation of products, supplemented by the DuPhos/BPE family, strongly N-Diphenylphosphinoylimines complements the existing Sigma-Aldrich chemical line and will Recently Charette has published a facile asymmetric synthesis accelerate your research success. For comprehensive information of various a-chiral amines via the enantioselective addition of on our most recent product launches, please visit dialkylzinc reagents to N-phosphinoylimines.22 (R,R)-Me-DuPhos, sigma-aldrich.com/duphos.
in conjunction with a Cu(OTf)2 source, yielded exceptional Ligands Phospholane BPE and DuPhos enantiomeric excess for this reaction above 90% for all aromatic substrates (Scheme 11). The mild reaction conditions, reasonable P P i-Pr i-Pr temperatures, and use of various dialkylzinc reagents all contribute Pd P P Ph to the attractiveness of this methodology. H I Ph 5 mol % Me Me i-Pr i-Pr PhI, toluene, rt i-Pr i-Pr Enantioselective Hydrogenation of Alkenes and Imines 73% ee The use of gold complexes to effect catalytic transformations is Scheme 10 Scheme 10 on the rise, with numerous reports of catalytically active gold 23 species. Sanchez and co-workers have now reported the first O O Ph example of a gold hydrogenation catalyst utilized in asymmetric Ph Cu(OTf)2 (10 mol %) P P 24 (R,R)-Me-DuPhos (5 mol %) HN Ph transformations. The authors found that the bulkiest substrate, N Ph o which incorporates a diethyl 2-naphthylidenesuccinate group, ZnEt2 (2 eq), toluene, 48 h, 0 C 4-MeO-C6H4 Et 4-MeO-C6H4 H proceeds under the reaction conditions to afford the highest 95% ee enantioselectivities due to reactant control (Scheme 12). Future Scheme 11 plans in gold-mediated asymmetric hydrogenation involve Scheme 11 substantial modifications to the ligand structure to provide higher levels of enantiocontrol. P The First Catalytic Enantioselective Allylboration of Ketones Au Cl The Shibasaki research group has also championed use of the Au Cl DuPhos ligand system for asymmetric catalysis.25 They have now P reported the first general catalytic, enantioselective allylation H
H O EtO2C S/C = 1000:1 EtO2C
reaction with ketones, which employs copper salts and a rare- 0 1 0 3 . 5 2 3 . 0 0 8 . 1 : r e d r EtO C earth lanthanide additive. Impressively, a diverse array of aromatic, EtO2C R H2 (4 atm), EtOH, rt 2 R heteroaromatic, a,b-unsaturated, and aliphatic ketones are rapidly 95% ee allylated at ambient temperature and under low catalyst loadings SchemeScheme 12 12 (Scheme 13). The enantioselectivities range from 67 to 92%, however, the reaction appears to be quite general for both the CuF . H O (3 mol %) O 2 2 OH allylation and crotylboration reactions. O (R,R)-iPr-DuPhos (6 mol %) + B i O La(O Pr)3 (4.5 mol %) DMF, 1 h, 40 oC (1.2 equiv) 99%, 91% ee
Scheme 13 Scheme 13 T Join the GOLD RUSH in Catalysis l a c i n h c e with the latest gold catalysts from Sigma-Aldrich
CF3 These gold(I) catalysts and precursors have been O BF4 Au employed extensively by the Toste group (UC-Berkeley) Ph2P AuCl S Au Au F3C P Au Cl P Au NTf2 Ph3P PPh3 7 2 3 8 . 1 3 2 . 0 0 8 . 1 : e c i v r e and others in novel carbon–carbon bond forming PPh3 Ph2P AuCl 0.5 CH C H processes such as: Conia-ene reactions, enyne 3 6 5
isomerizations, Claisen rearrangements, and CF3 ring expansions.1 665185 665142 665177 677922
(1)(a) Gorin, D. J. et al. J. Am. Chem. Soc. 2005, 127, 11260. (b) Kennedy-Smith et al. J. Am. Chem. Soc. 2004, 126, 4526. (c) Mézailles, N. et al. Org. Lett. 2005, 7, 4133.
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(+)-1,2-Bis[(2S,5S)-2,5-dimethylphospholano]benzene 8 (+)-1,2-Bis[(2R,5R)-2,5-diethylphospholano]ethane 8
C18H28P2 C18H36P2 FW: 306.36 FW: 314.43 P P [136735-95-0] P P [136705-62-9]
665266-100MG 100 mg 668478-100MG 100 mg 665266-500MG 500 mg 668478-500MG 500 mg 665266-2G 2 g 668478-2G 2 g
(–)-1,2-Bis[(2R,5R)-2,5-dimethylphospholano]benzene 8 (–)-1,2-Bis[(2S,5S)-2,5-diisopropylphospholano]- 8
C18H28P2 benzene FW: 306.36 C26H44P2 [147253-67-6] P P FW: 418.57 [147253698] P P 665258-100MG 100 mg 665258-500MG 500 mg 665258-2G 2 g 668176-100MG 100 mg 668176-500MG 500 mg 668176-2G 2 g (+)-1,2-Bis[(2R,5R)-2,5-dimethylphospholano]ethane 8 C H P 14 28 2 (+)-1,2-Bis[(2R,5R)-2,5-diisopropylphospholano]- 8 FW: 258.32 P P [129648-07-3] benzene C26H44P2 665231-100MG 100 mg FW: 418.57 DuPhos and BPE 665231-500MG 500 mg [136705652] P P 665231-2G 2 g Phospholane Ligands 668524-100MG 100 mg (−)-1,2-Bis[(2S,5S)-2,5-dimethylphospholano]ethane 8 668524-500MG 500 mg C H P 14 28 2 668524-2G 2 g FW: 258.32 P P [136779-26-5] 1,2-Bis[(2S,5S)-2,5-diisopropylphospholano]ethane 8
665207-100MG 100 mg C22H44P2 665207-500MG 500 mg FW: 370.53 P P 665207-2G 2 g
(+)-1,2-Bis[(2S,5S)-2,5-diethylphospholano]benzene 8 668435-100MG 100 mg
C22H36P2 668435-500MG 500 mg FW: 362.47 668435-2G 2 g [136779-28-7] P P 1,2-Bis[(2R,5R)-2,5-diisopropylphospholano]ethane 8
C22H44P2 668486-100MG 100 mg FW: 370.53 P P 668486-500MG 500 mg 668486-2G 2 g 668443-100MG 100 mg (−)-1,2-Bis[(2R,5R)-2,5-diethylphospholano]benzene 8 668443-500MG 500 mg
C22H36P2 668443-2G 2 g FW: 362.47 [136705-64-1] P P (–)-1,2-Bis[(2R,5R)-2,5-diphenylphospholano]ethane 8
C34H36P2 Ph Ph FW: 258.32 P P [528565799] 668494-100MG 100 mg Ph Ph 668494-500MG 500 mg 667811-100MG 100 mg 668494-2G 2 g 667811-500MG 500 mg 667811-2G 2 g (−)-1,2-Bis[(2S,5S)-2,5-diethylphospholano]ethane 8
C18H36P2 (+)-1,2-Bis[(2S,5S)-2,5-diphenylphospholano]ethane 8
FW: 314.43 C34H36P2 Ph Ph P P [136779-27-6] FW: 258.32 P P [824395677] Ph Ph 668451-100MG 100 mg 667854-100MG 100 mg 668451-500MG 500 mg 667854-500MG 500 mg 668451-2G 2 g 667854-2G 2 g
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DSM MonoPhos™ Family O Ph P N O Introduction O Ph O CuCl O PdCl2 H 4 mol% (10 mol %) KOtBu O Sigma-Aldrich, in collaboration with DSM, is pleased to offer a O 1. Cu(OTf)2 (2 mol %) DMF H2O THF, rt † o O2 range of MonoPhos™ ligands for the research market. Feringa ZnEt2, toluene, 30 C 56%, 96% ee and co-workers have invented a diverse array of these chiral, 2. Pd(PPh3)4 (4 mol %) 88%, 96% ee 65%, 96% ee OAc monodentate phosphoramidites based on the privileged BINOL Scheme 14 platform.26 The MonoPhos™ family has exhibited high levels of Scheme 14 enantiocontrol in synthetic transformations ranging from metal- catalyzed asymmetric 1,4-additions of organometallic reagents O Ph to allylic alkylations to desymmetrization of meso-cycloalkene P N oxides.27 O Ph
i 4 mol % Pr O i Advantages of the MonoPhos™ Ligands + AlMe3 Pr O Cu(TC) (1 mol %), H+ • Superior enantiocontrol in numerous transformations 1.4 equiv Family MonoPhos™ DSM Et O, 20 min, 30 oC • High activities at low catalyst loadings 2 88%, 96% ee • Hydrogenations under low-pressure conditions • Applied in tandem reactions to yield valuable chiral organics SchemeScheme 15 15 • First-to-market exclusivity for selected portfolio ligands Representative Applications O Me cat. P N The reactivity profile of these innovative chiral ligands is covered O below and highlights the impressive breadth of valuable NHAc Ph NHAc transformations mediated by the various portfolio products. CO2Et CO2Et In many documented cases, specific ligands have displayed Rh(cod)2BF4 (2 mol %) unprecedented selectivities in reactions that form, for instance, H2 (10 bar), CH2Cl2, 4 h, rt 99% ee chiral quaternary centers that cannot be readily generated via Scheme 16 alternative methodologies. Scheme 16
Asymmetric 1,4-additions of Organometallic Reagents Feringa and co-workers exploited the high activity of the (S,R,R)-phosphoramidite ligand shown in Scheme 14 in Announcing Sigma-Aldrich’s copper-catalyzed 1,4-additions of organozinc reagents to cyclohexenones.26 Interestingly, the in situ formed zinc species Newest Web-Based Seminar originating from the cyclohexenone is readily trapped via a palladium-catalyzed allylation. The Feringa group then completed Trost Bis-ProPhenol Ligands a formal annulation process through a palladium-catalyzed Wacker O • Featuring the latest innovative chemical synthesis technologies 0 1 0 3 . 5 2 3 . 0 0 8 . 1 : r e d r oxidation, followed by an aldol cyclization. The high (96%) and products enantioselectivity of this methodology is completely retained • Access directly via your desktop browser throughout this synthetic strategy (Scheme 14). • Convenient navigation High potential also exists for the use of organoaluminum reagents • Highly interactive in asymmetric conjugate addition reactions, because of their commercial availability and proof of concept in carboalumination reactions. Woodward and co-workers have now pioneered the enantioselective phosphoramidite-catalyzed 1,4-additions of organoaluminum reagents to enones.28 This methodology provides facile access to chiral ketones with excellent enantioselectivities and in good yields (Scheme 15).
Highly Asymmetric Rhodium-Catalyzed Hydrogenation T
Feringa has also gone to great lengths to develop structurally l a c i n h c e varied MonoPhos™ ligands in industrially useful transformations such as asymmetric hydrogenation.29 Impressively, the (S)-N- benzyl-N-methyl-MonoPhos™ derivative shown below has been utilized in highly selective hydrogenations of (E)-N-acylated dehydro-b-amino acid esters, affording the corresponding 29a S
enantiopure b-amino acid derivatives (Scheme 16). The 7 2 3 8 . 1 3 2 . 0 0 8 . 1 : e c i v r e authors found that this ligand, after being screened versus related chiral phosphoramidites, afforded the highest enantiocontrol in hydrogenations albeit at slightly longer reaction times. The Feringa research group has broadened the substrate scope of the asymmetric hydrogenation reaction by generating another To check out Sigma-Aldrich’s new Web-based chiral center on the amine moiety of the phosphoramidite ligand. chemistry seminar series, please visit Amazingly, this fine ligand tuning produces a very active and sigma-aldrich.com/cheminars. productive catalyst, which efficiently hydrogenates a wide range
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of acetamido derivatives in less time than the corresponding Me- DuPhos analogs.29a Note that the chiral (S,R)-phosphoramidite ligand below is the only ligand known to afford enantioselectivities O O for the substrate shown greater than 90% (Scheme 17). P N P N O O O Recently, Feringa’s research group prepared additional structurally varied phosphoramidite ligands for rhodium-catalyzed asymmetric hydrogenations. The aptly named PipPhos and MorfPhos ligands PipPhos (665479) MorfPhos (665487) (Scheme 18) contain piperidinyl and morpholinyl subunits, respectively, and are examples of easily synthesized chiral ligands SchemeScheme 18 18 for highly effective enantioselective transformations. Under mild
reaction conditions including low H2 pressure, this catalyst system yields unprecedented enantioselectivities for several substrates such as dimethyl itaconate and a-dehydroamino ester derivatives O (Scheme 19).30 P N O O O Asymmetric Regioselective Allylic Aminations 4 mol % ∗ OMe OMe Hartwig and co-workers have succeeded in developing highly HN Rh(cod) BF (2 mol %) HN selective iridium catalysts with (R,R,R)-phosphoramidite L*.27g 2 4 H (5 bar), CH Cl , rt The allylic aminations of a wide variety of achiral allylic esters O 2 2 2 O proceeded with total conversion and superb regioselectivity in >99% ee many cases. The reaction shown clearly illustrates the power of Scheme 19 this methodology, wherein cinnamyl acetate was converted to the Scheme 19 allylic benzyl amine 3 in excellent yield and enantiopurity (Scheme 20). The authors mentioned that these valuable amination reactions were mediated by air-stable Ir complexes at O Ph P N NHBn ambient temperatures, which should lead to wide acceptance of O Ph NH2 this catalyst in bench-top organic synthesis. Ph 3 (R,R,R)-L*, 2 mol % Ph OAc + + As a complement to the Hartwig chemistry, Helmchen and [Ir(cod)Cl] (1 mol %), EtOH, rt 2 4 co-workers have performed highly enantioselective iridium- Ph NHBn 3 equiv
DSM MonoPhos™ Family catalyzed intra- and intermolecular aminations with 97:3 (3:4), 95%, 95% ee 31a N-nucleophiles. Impressively, dicarbonate 5 reacts smoothly Scheme 20 under the reaction conditions to afford the pyrrolidine products Scheme 20 6a and 6b in moderate yield but with excellent selectivity (Scheme 21).
Ph O N Asymmetric Hydrovinylation – An Efficient Route to P N O Ph p-Ns All-Carbon Quaternary Centers 6a These highly practical enantioselective reactions have been + R R accomplished by RajanBabu’s research group at Ohio State [Ir(cod)Cl]2, THF, base 32 N University. The generation of all-carbon quaternary centers is 5, R = OCOOCH3 p-Ns-NH2, NEt3, 15 h p-Ns extremely attractive to drug discovery groups, as evidenced in 6b the example shown. Note that the asymmetric hydrovinylation 6a:6b = 85:15 (65%), 6a: 99% ee
of substituted vinylarenes offers an attractive, general method Scheme 21 for creating an asymmetric center (Scheme 22). The low ligand Scheme 21 loadings, excellent yields, and superb enantioselectivities ensure that this methodology can be utilized in the production of chiral building blocks and directly applied to the synthesis of natural H OH O Ph N 33 P N Me products such as Lyngbyatoxin A. O M Ph O Zhang and RajanBabu have also extended this methodology to the 1 mol % asymmetric hydrovinylation of 1,3-dienes. 1,3-dienes were found Me N [(allyl)NiBr]2, NaBARF H Me Me to be less reactive than the vinylarene derivatives, thus higher C2H4 (1 atm.), CH2Cl2, 4 h * temperatures were applied to drive adequate conversions. Under 95% ee Lyngbyatoxin A these conditions, the hydrovinylation of conjugated 1,3-diene 7 with the (S,R,R)-phosphoramidite ligand gave exquisite regio- and Scheme 22 enantioselectivities (Scheme 23).34 Scheme 22
Ph Ph O O P N P N O Ph O H NHAc NHAc * 4 mol % 1 mol % CO2Me CO2Me [(allyl)NiBr]2, NaBARF Rh(cod)2BF4 (2 mol %) F F H (10 bar), CH Cl , 20 min, rt 7 C H (1 atm.), CH Cl , 4 h 2 2 2 94% ee 2 4 2 2 99% conv., 97% ee Scheme 17 Scheme 23 Scheme 17 Scheme 23
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Asymmetric Allylic Substitution Reactions The (R)-MonoPhos™ ligand has been effectively utilized in the Me 35 O enantioselective, iridium-catalyzed allylic substitution reaction. P N O Simply mixing an iridium precatalyst and the ligand in THF in the Me CH(COOMe) OAc 2 presence of LiCl creates a highly active catalyst, which generates PhH2CH2C a stereogenic C–C bond center in good to excellent enantio- PhH2CH2C [Ir(cod)Cl]2, LiCl selectivities (Scheme 24). The high product yields and short 93% ee NaCH(COOMe)2, THF, rt, 3 h reaction times further accentuate this methodology for application Scheme 24 to the expeditious construction of chiral building blocks. Scheme 24 Conclusion A powerful family of monodentate phosphine ligands has been developed on the well known BINOL backbone, which demonstrates both higher activities and higher enantioselectivities in asymmetric transformations when compared to the majority of For comprehensive information on our bidentate chiral phosphines. These phosphoramidite ligands are most recent product launches, please visit Family MonoPhos™ DSM accessible in a concise, linear fashion and display robust stability sigma-aldrich.com/monophos. when combined with rhodium precatalysts. We have a range of phosphoramidite ligands commercially available that differ in the amine functionality of the ligand architecture, allowing for rapid optimization of catalyst performance.
(S,S,S)-(+)-(3,5-Dioxa-4-phospha-cyclohepta 8 (S)-(+)-(3,5-Dioxa-4-phospha-cyclohepta- 8 [2,1-a;3,4-a’]dinaphthalen-4-yl)bis(1-phenylethyl)amine [2,1-a;3,4-a’]dinaphthalen-4-yl)piperidine
C36H30NO2P C25H22NO2P FW: 539.6 Ph FW: 399.42 O O [380230-02-4] P N PN O O Ph
665290-100MG 100 mg 665479-100MG 100 mg 665290-500MG 500 mg 665479-500MG 500 mg 665290-2G 2 g 665479-2G 2 g
(S,R,R)-(+)-(3,5-Dioxa-4-phospha-cyclohepta 8 [2,1-a;3,4-a’]dinaphthalen-4-yl)bis(1-phenylethyl)amine (S)-(+)-(3,5-Dioxa-4-phospha-cyclohepta- 8
C36H30NO2P [2,1-a;3,4-a’]dinaphthalen-4-yl)morpholine
Ph O FW: 539.6 C24H20NO3P
O 0 1 0 3 . 5 2 3 . 0 0 8 . 1 : r e d r [415918-91-1] P N FW: 401.39 O O PN O Ph O
665363-100MG 100 mg 665363-500MG 500 mg 665487-100MG 100 mg 665363-2G 2 g 665487-500MG 500 mg 665487-2G 2 g (S)-(+)-Benzyl(3,5-dioxa-4-phospha-cyclohepta 8 [2,1-a;3,4-a’]dinaphthalen-4-yl)methylamine (R)-(−)-(3,5-Dioxa-4-phospha-cyclohepta- 8 C28H22NO2P FW: 435.45 [2,1-a;3,4-a’]di-naphthalen-4-yl)dimethylamine O Me [490023-37-5] P N C22H20NO2P O FW: 361.37 O Me Ph
P N T [157488-65-8] O
Me l a c i n h c e 665355-100MG 100 mg 665355-500MG 500 mg 668206-1G 1 g 665355-2G 2 g 668206-5G 5 g
(3aR,8aR)-(−)-(2,2-Dimethyl-4,4,8,8-tetraphenyl- 8 (S)-(+)-(3,5-Dioxa-4-phospha-cyclohepta- 8 S tetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin- 7 2 3 8 . 1 3 2 . 0 0 8 . 1 : e c i v r e 6-yl)dimethylamine [2,1-a;3,4- a’]di-naphthalen-4-yl)dimethylamine C H NO P C22H20NO2P 33 34 4 Ph Ph FW: 361.37 Me FW: 539.6 Me O O Me O P N P N [213843-90-4] [185449-80-3] O Me O O Me Me Ph Ph 665460-100MG 100 mg 668192-1G 1 g 665460-500MG 500 mg 668192-5G 5 g
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ChiralQuest Phosphine Ligands In-situ 5 mol % Ru(cod)(Met) 2 AcHN CO R Introduction AcHN CO2R 5 mol % (S)-C3-TunePhos 2 10 mol % HBF4
One of the most efficient methods for constructing chiral X MeOH, 50 atm H2, rt X compounds is asymmetric hydrogenation. Catalytic asymmetric up to 99% ee hydrogenations are among the most widely used industrial Scheme 26 catalytic processes, due to their high turnover rates, atom economy, and inexpensive material costs. Transition metal Scheme 26 complexes associated with chiral phosphine ligands are the dominant choice of catalysts for asymmetric hydrogenation, in O HO O large part due to the Nobel prize-winning, pioneering work of O 2 mol % R R Noyori and Knowles. The requirement of an electron-rich chiral [NH2Me2][[RuCl((S)-C3-TunePhos)]2(µ-Cl)3] N N phosphine ligand is at the core of this transformation. EtOH, 100 bar H2 O O Professor Xumu Zhang at Penn State has made remarkable up to >99% ee advances by creating a toolbox of chiral phosphines which can Scheme 27 be used on a variety of substrates, some of which have been historically resistant to hydrogenation. Furthermore, an additional Scheme 27 benefit in some reductions is reduced catalyst loading, due to increased turnover numbers (TON). Sigma-Aldrich is pleased to Ligands H announce an agreement with ChiralQuest to distribute research quantities of a series of Zhang’s chiral phosphines for catalytic TangPhos P H P t t asymmetric hydrogenations. Bu Bu O O Rh-(S,S,R,R)-TangPhos R1 OR2 R OR Representative Ligands and Applications H (20 psi), rt, MeOH 1 2 NHAc 2 NHAc TON 10,000 >99% ee (S)-C3-TunePhos C3-TunePhos, a member of the atropisomeric aryl bisphosphine ligand family with tunable dihedral angles, provides comparable O O ChiralQuest Phosphine Rh-(S,S,R,R)-TangPhos or superior enantioselectivities and catalytic abilities to BINAP in OCH3 OCH3 MeOH, H (1.3 atm) NHAc 2 Ru-catalyzed asymmetric hydrogenation of b-keto esters (Scheme S S NHAc 25),36 cyclic b-(acylamino) acrylates (Scheme 26),37 and >99% ee a-phthalimide ketones (Scheme 27).38 Scheme 28 (1S,1S’,2R,2R’)-TangPhos Scheme 28 A highly electron-donating, low molecular weight, and rigid P-chiral bisphospholane ligand, TangPhos proves incredibly R R efficient in the rhodium-catalyzed hydrogenation of a variety of Rh-(S,S,R,R)-TangPhos functionalized olefins such as a-dehydroamino acids (Scheme Ar NHAc H2 (20 psi), rt, MeOH Ar NHAc 39 a 39 b Up to 10,000 turnovers 28), -arylenamides (Scheme 29), -(acylamino)acrylates Up to 99% ee (Scheme 30),40 itaconic acids (Scheme 31),41 and enol acetates (Scheme 32).41 Scheme 29 This P-chiral phosphorus ligand represents a superior ligand Scheme 29 for asymmetric catalysis including hydrogenation because of its ability to force the chiral environment to encompass the O O substrate in close proximity to the reactive metal center. TangPhos [Rh(S,S,R,R-TangPhos)(nbd)]SbF exhibits substantial conformational rigidity allowing for high OR2 6 OR2 H (20 psi), rt, THF, 24 h enantioselectivities in the hydrogenation of a wide variety of R NHAc 2 R NHAc 1 Up to 10,000 turnovers 1 densely functionalized prochiral olefins, with some reaction Up to >99% ee examples approaching 100% ee. Scheme 30
Scheme 30
O PPh2 O PPh R2 R 2 O 2 O [Rh(S,S,R,R-TangPhos)(nbd)]SbF6 R1O C3-TunePhos OH R1O H2 (20 psi), rt, THF OH O up to 5,000 turnovers O O OH O O Ru[(R)-C3-TunePhos]Cl2(DMF)n (0.5 mol %) Up to >99% ee o R1 OR2 MeOH, 60 C, 750 psi H2 R1 OR2 Up to 99% ee Scheme 31 Scheme 31
O O OH O Ru(ArH)[(R)-C3-TunePhos]Cl2 Cl * Cl o OAc [Rh(S,S,R,R-TangPhos)(nbd)]SbF OAc OEt EtOH, 100 C, 6 atm H2 OEt 6 97% ee TON = 45,000 Ar H2 (20 psi), rt, EtOAc Ar Lipitor Side Chain Scheme 32 SchemeScheme 25 25 Scheme 32
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(S)-BINAPINE BINAPINE, a highly electron-donating rigid ligand, demonstrates excellent enantioselectivity and reactivity, with TON up to 10,000 tBu P for the asymmetric hydrogenation of Z-b-aryl(b-acylamino) H acrylates (Scheme 33).42 Interestingly, BINAPINE is a rare example of a bisbinaphthophosphepine ligand with P-chiral phosphine P H But atoms. High enantioselectivities have been obtained with BINAPINE substrates that contain diverse substituents ranging from electron- O O rich and electron-poor aryl groups to heteroaryl components. OCH [Rh(NBD)((S)-BINAPINE)]SbF6 OCH3 This catalyst system illustrates the incredible effects of rigidity on 3 H (20 psi), rt, THF, 24 h Ar NHAc 2 Ar NHAc stereocontrol in the hydrogenation reaction. Up to 10,000 turnovers Up to >99% ee (R)-BINAPHANE (R)-BINAPHANE shows excellent enantioselectivity (up to >99% SchemeScheme 33 33 ee) for hydrogenation of E/Z-isomeric mixtures of b-substituted 43 arylenamides (Scheme 34). This ligand incorporates a Ligands Phosphine ChiralQuest bisphosphinite backbone that displays restricted orientation of the aromatic groups proximate to the phosphines. Zhang and P P co-workers can tune BINAPHANE by modifying the groups on the aromatic and/or the phosphine, thus creating a general BINAPHANE R catalytic system useful for obtaining high enantioselectivities in the R 1 mol % Rh-(R)-BINAPHANE asymmetric hydrogenation reaction. Ar NHAc Ar NHAc H2 (20 psi), rt, CH2Cl2, 24 h (1R,1’R,2S,2’S)-DuanPhos Up to 99.5% ee DuanPhos is more rigid than the related TangPhos ligand, due to Scheme 34 the fused phenyl rings on the phospholane architecture. This self- Scheme 34 imposed conformational stability improves the enantioselectivity in the hydrogenations of a diverse array of functionalized olefins. H Furthermore, Zhang and co-workers have successfully synthesized DuanPhos both enantiomers of this electron-rich ligand through a trivial P H P resolution process. Even highly electron-rich prochiral olefins But tBu COOMe are readily hydrogenated with exceptional stereocontrol by this COOMe Rh-(S,S,R,R)-DuanPhos productive Rh-catalyst system (Scheme 35). H (20 psi), rt, 2 h, MeOH NHAc 2 NHAc TON = 10,000 TOF = 5,000 100% conv, >99% ee
Rh-(S,S,R,R)-DuanPhos OAc OAc
MeOH, H2 (1.3 atm), rt O MeO MeO 0 1 0 3 . 5 2 3 . 0 0 8 . 1 : r e d r 96% ee
SchemeScheme 35 35
(R)-C3-TunePhos 8 (R)-Binaphane 8
C39H32O2P2 C50H36P2 FW: 594.62 FW: 698.77 O PPh2 [301847-89-2] [253311-88-5] P P O PPh2
650862-100MG 100 mg 650854-100MG 100 mg 650862-500MG 500 mg 650854-500MG 500 mg T
(S,S’,R,R’)-TangPhos 8 (1R,1’R,2S,2’S)-DuanPhos 8 l a c i n h c e
C16H32P2 H C24H32P2 FW: 286.37 FW: 382.46 H [470480-32-1] P H P [528814-26-8] But tBu P H P t t 650889-100MG 100 mg Bu Bu
650889-500MG 500 mg 657697-100MG 100 mg S 657697-500MG 7 2 3 8 . 1 500 3 2 . 0 0 8 mg . 1 : e c i v r e (S)-Binapine 8
C52H48P2 FW: 734.89 tBu [610304-81-9] H P
P H But
650870-100MG 100 mg 650870-500MG 500 mg
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Solvias Ferrocenyl-Based Ligands Cy Solvias AG has demonstrated the incredible utility of chiral Ph P Cy P ferrocenyl diphosphine ligands in a wide range of reaction Fe paradigms ranging from hydrogenation9 to the aldol reaction45 to Ph Me COOMe hydroboration.46 For years, BINAP was considered the only ligand Josiphos COOMe platform that could perform at a high-level in a wide variety of [Rh(NBD)2]BF4 (1 mol %) COOMe COOMe reactions. The ferrocenyl architecture in the Solvias portfolio serves H2 (1 bar), MeOH, 30 min, rt 8 as the superstructure for a unique group of chiral ligands that 99% ee can be fine tuned electronically and/or sterically for asymmetric synthesis optimization. The Solvias ligands can be combined with Scheme 36 metal precursors to form exceptionally active catalysts that exhibit high levels of enantiocontrol in industrially useful processes such Ph as hydrogenation (Scheme 36).9 This example illustrates the high Ph P
enantioselective control exerted by the Josiphos ligand on dimethyl Ph itaconate derivative 8. The dimethyl (S)-2-methylsuccinate product P Fe was isolated in quantitative yield and with an optical purity of Ph N(CH ) 3 2 O 99%. Also of interest to synthetic chemists is the high substrate to O Taniaphos Ph OMe catalyst ratio (1000:1), while the low hydrogen pressure and fast Ph OMe CuBr (5 mol %), EtMgBr (1.5 equiv) o conversion times further improve the attractiveness of this system. CH2Cl2, 3 h, 78 C 65%, 96% ee Ligands Feringa and co-workers have pioneered the use of the Solvias Scheme 37 ligand family in the copper-catalyzed asymmetric conjugate addition of Grignard reagents to unsaturated carbonyl compounds.47 Prior to this group’s research, only meager selectivities had been observed in the conjugate addition of R'2P Grignard reagents, which stands in stark contrast to the success R2P 48 Fe H seen with the related addition of dialkylzinc reagents. The N Feringa group utilized the Taniaphos-type ligand in conjunction with Cu(I) salts to create a highly effective catalyst system. For PR2 P Taniaphos PR'2 instance, the conjugate addition of EtMgBr to methyl cinnamate CH3 Solvias Ferrocenyl-Based Fe H affords 96% enantiopure product at a modest 65% conversion P S (Scheme 37). The lower conversions in this chemistry are most
likely due to the necessity of running the reaction at –78 ºC. PR'2 Butiphane R P Walphos 2 Fe CH3 Sigma-Aldrich, in collaboration with Solvias AG, is pleased to H offer a diverse array of chiral ligands that can be ligated to metal complexes to afford highly active catalysts for asymmetric N R P H 49 2 Fe Josiphos O hydrogenation and other innovative transformations. We are P Fe excited to offer 40 different ligands and catalysts in 100 mg N H N sample sizes in both enantiomeric forms giving you access to a PR2 N total of 80 products all in one convenient kit! This kit will allow Mandyphos O PR2 Naud rapid screening of your asymmetric synthesis plans. Each individual O PR2 ligand from the unique families below can also be ordered as individual units (Scheme 38). For complete product ordering N information on our solvias ligand portfolio, please visit Solphos sigma-aldrich.com/solvias. Scheme 38
(R)-1-[(1S)-2-(Diphenylphosphino)ferrocenyl]- 8 (R)-1-{(R)-2-[2-[Bis(4-methoxy-3,5-dimethylphenyl)- 8 ethyldi-tert-butylphosphine phosphino]phenyl]ferrocenyl}ethylbis[3,5-bis-
C32H40FeP2 (trifluoromethyl)phenyl]phosphine P H C FW: 542.45 C52H44F12FeO2P2 3 OMe H C [155830-69-6] FW: 1046.68 3 F3C CF3 MeO CH3 [494227-30-4] CF Fe 3 P H3C Fe
88719-100MG 100 mg CF3 88719-500MG 500 mg 65677-100MG 100 mg 65677-500MG 500 mg (S)-1-Dicyclohexylphosphino-2-[(R)-a-(dimethylamino)- 8 65677-1G 1 g 2-(dicyclohexylphosphino)benzyl]ferrocene 65677-5G 5 g
C43H63FeNP2 FW: 711.76 [494227-38-2] P
P Fe 8 N(CH3)2 Solvias Chiral Ligands Kit 12000-1KT 1 kt 07541-100MG 100 mg 07541-500MG 500 mg
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References (24) Sanchez, F. et al. Chem. Commun. 2005, 3451. (25) Shibasaki, M. et al. J. Am. Chem. Soc. 2004, 126, 8910. (1) (a) Noyori, R., Ed. Asymmetric Catalysis in Organic Synthesis; (26) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. Wiley: New York, 1994. (27) (a) Feringa, B. L. et al. Angew. Chem. Int. Ed. Engl. 1997, 36, (b) Beller, M.; Bolm, C., Eds. Transition Metals for Organic 2620. Synthesis; 2nd ed.; Wiley-VCH: Weinheim, 2004. (b) Martina, S. L. X. et al. Tetrahedron Lett. 2005, 46, 7159. (c) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds. (c) Malda, H. et al. Org. Lett. 2001, 3, 1169. Comprehensive Asymmetric Catalysis, Springer: Berlin, 1999. (d) Alexakis, A. et al. Chem. Commun. 2005, 2843. (2) (a) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691. (e) Streiff, S. et al. Chem. Commun. 2005, 2957. (b) Gladysz, J. A. Pure Appl. Chem. 2001, 73, 1319. (f) Bertozzi, F. et al. Org. Lett. 2000, 2, 933. (3) (a) Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I., (g) Hartwig, J. F. et al. J. Am. Chem. Soc. 2002, 124, 15164. Ed.; Wiley-VCH: New York, 1993; Chapter 4.2. (28) Alexakis, A.; Albrow, V.; Biswas, K.; Augustin, M.; Prieto, O.; (b) Katsuki, T. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, Woodward, S. Chem. Commun., 2005, 2843. I., Ed.; Wiley-VCH: New York, 2000; pp 287–325. (29) (a) Pena, D. et al. J. Am. Chem. Soc. 2002, 124, 14552. (c) Katsuki, T. Adv. Synth. Catal. 2002, 344, 131. (b) Van den Berg, M. et al. Adv. Synth. Catal. 2003, 345, 308. (4) (a) Ghosh, A. K. et al. Tetrahedron: Asymmetry 1998, 8, 1. (30) Bernsmann, H. et al. J. Org. Chem. 2005, 70, 943. References (b) Jorgensen, K. A. et al. Acc. Chem. Res. 1999, 32, 605. (31) (a) Helmchen, G. et al. Chem. Commun. 2005, 3541. (5) (a) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric (b) Helmchen, G. et al. Chem. Commun. 2005, 2957. Synthesis; Ojima, I., Ed.; Wiley-VCH: New York, 1993; Chapter 4.1. (32) RajanBabu, T. V. et al. J. Am. Chem. Soc. 2006, 128, 5620. (b) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1. (33) Gerwick, W. H. et al. J. Am. Chem. Soc. 2004, 126, 11432. (c) Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. (34) RajanBabu, T. V. et al. J. Am. Chem. Soc. 2005, 127, 54. 2001, 1, 92. (35) Helmchen, G. et al. Chem. Commun. 1999, 741. (6) (a) Kolb, H. C.; Van Nieuwenzhe, M. S.; Sharpless, K. B. Chem. (36) Zhang, Z. et al. J. Org. Chem. 2000, 65, 6223. Rev. 1994, 94, 2483. (b) Bolm, C. Jacobsen, E. N. In Catalytic Asymmetric (37) Tang, W. et al. J. Am. Chem. Soc. 2003, 125, 9570. Synthesis; Ojima, I., Ed.; Wiley-VCH: New York, 2000; (38) Lei, A. et al. J. Am. Chem. Soc. 2004, 126, 1626. pp 399–428. (39) Tang, W.; Zhang, X. Angew. Chem. Int. Ed. Engl. 2002, 41, (7) (a) Burk, M. J. et al. J. Am. Chem. Soc. 1991, 113, 8518. 1612. (b) Burk, M. J., Handbook of Chiral Chemicals, Abel, Ager, D.J., (40) Tang, W.; Zhang, X. Org. Lett. 2002, 4, 4159. Ed.; Marcel Dekker: New York, 1999; Ch. 18, p 339. (41) Tang, W. et al. Org. Lett. 2003, 5, 205. (8) Feringa, B. L. et al. Adv. Synth. Catal. 2002, 344, 1003. (42) Tang, W. et al. Angew. Chem. Int. Ed. Engl. 2003, 42, 3509. (9) Togni, A. et al. J. Am. Chem. Soc. 1994, 116, 4062. (43) Xiao, D. et al. Org. Lett. 1999, 1, 1679. (10) Zhang, Z. et al. Org. Lett. 2002, 4, 4495. (44) Liu, D.; Zhang, X. Eur. J. Org. Chem. 2005, 646. (11) Burk, M. J. Acc. Chem. Res. 2000, 33, 363. (45) Togni, A. et al. J. Org. Chem. 1990, 55, 1649. (12) DuPhos and BPE ligands are sold in collaboration with Kanata (46) Togni, A. et al. Organometallics 1997, 16, 255. Chemical Technologies and licensed from E. I. Dupont for the (47) Feringa, B. L. et al. J. Am. Chem. Soc. 2006, 128, 9103. research market only. O
(48) (a) Lippard, S. J. et al. J. Am. Chem. Soc. 1988, 110, 3175. 0 1 0 3 . 5 2 3 . 0 0 8 . 1 : r e d r (13) Burk, M. J. et al. J. Am. Chem. Soc. 1996, 118, 5142. (b) Lippard, S. J. et al. Organometallics 1990, 9, 3178. (14) Burk, M. J. et al. J. Am. Chem. Soc. 1992, 114, 6266. (c) van Koten, G. et al. J. Am. Chem. Soc. 1992, 114, 3400. (15) Burk, M. J. et al. J. Am. Chem. Soc. 1998, 120, 657. (d) Pfaltz, A. et al. Tetrahedron 1994, 50, 4467. (16) Burk, M. J. et al. J. Org. Chem. 1998, 63, 6084. (e) Seebach, D. et al. Angew. Chem., Int. Ed. 2000, 39, 153. (17) Boaz, N. W. Tetrahedron Lett. 1998, 39, 5505. (f) Tomioka, K. et al. Tetrahedron Lett. 1998, 54, 10295. (g) Sammakia, T. et al. Tetrahedron 1997, 53, 16503. (18) Burk, M. J. et al. J. Am. Chem. Soc. 1995, 117, 4423. (49) Solvias ligands and kit are sold in collaboration with Solvia, AG. (19) Burk, M. J. et al. J. Org. Chem. 1999, 64, 3290. for research purposes only. (20) Murakami, M. et al. J. Am. Chem. Soc. 1995, 121, 4130. (21) Moncarz, J. R. et al. J. Am. Chem. Soc. 2002, 124, 13356. †MonoPhos™ family ligands are sold under license from DSM for (22) Charette, A. B. et al. J. Am. Chem. Soc. 2003, 125, 1692. research purposes only. Patent WO 0204466 applies. (23) Dyker, G. Angew. Chem. Int. Ed. 2000, 39, 4237. T l a c i n h c e S 7 2 3 8 . 1 3 2 . 0 0 8 . 1 : e c i v r e
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact SAFC™ at 1-800-244-1173 (USA), or visit www.safcglobal.com. N-Heterocyclic Carbene (NHC) Ligands
Emerging Class of Privileged Ligands
N N Product Highlights O 1 mol % Cu OH • Mediate an incredible breadth of transformations Me AcO OAc Me
• Provide robust stability to the metal center 2.5 equiv PMHS, 2 equiv t-BuOH, rt • More active in many reactions than the related phosphine catalysts toluene, 20 min, NaOH (aq.) 96%
• Readily modified to incorporate chirality, immobilization, and H2O solubility NHC (N-heterocyclic carbenes) have evolved to become powerful, universal ligands for the rapid synthesis of novel organometallic complexes.1 In particular, NHC ligands have found practical use when bound to metals that are know to display high catalytic activity in related organophosphane N N Cl B(OH) metal coordination chemistry.2 Heterocyclic carbenes are emerging as a 2 Cl privileged class of ligands due to several attractive features including: 1) facile 8 mol % + Me OMe tuning of the electronics and/or sterics of a metal catalyst system; 2) ease of Pd(OAc)2 (4 mol %) synthetic preparation from conveniently available starting materials; and 3) o Me OMe Cs2CO3, dioxane, 80 C 98% exhibit strong binding to the metal thus creating a highly productive catalyst. 1.5 equiv Sigma-Aldrich is pleased to offer a diverse array of NHC ligands that have been successfully applied in reactions ranging from amination3 to C–C bond formation4 to hydrosilylation.5 BF4
References: N N (1) Herrmann, W. A. Angew. Chem. Int. Ed. Engl. 2002, 41, 1290. (2) (a) Herrmann, W. + 1 mol % A. et al. Chem. Ber. 1992, 125, 1795; (b) Ofele, K. et al. J. Organomet. Chem. 1993, Pd(dba)2 459, 177; (c) Herrmann, W. A. et al. J. Organomet. Chem. 1994, 480, C7. (3) Hartwig, + HN O N O J. F. et al. Org. Lett. 2000, 2, 1423. (4) Organ, M. G. et al. Org. Lett. 2005, 7, 1991. (5) N Cl 1.5 equiv NaOt-Bu, DME, 3 h, rt N 1.2 equiv Yun, J. et al. Chem. Commun. 2005, 5181. 98%
1,3-Bis(1-adamantyl)-benzimidazolium chloride 8 1,3-Bis(2,6-diisopropylphenyl)imidazolium chloride
C27H35ClN2 C27H37ClN2 FW: 423.03 FW: 425.05 N N N N [250285-32-6] Cl Cl 574074-500MG 500 mg 673188-500MG 500 mg 574074-2G 2 g
1,3-Dicyclohexylbenzimidazolium chloride 8 1,3-Bis-(2,4,6-trimethylphenyl)imidazolinium chloride C19H27ClN2 C21H27ClN2 FW: 318.88 FW: 342.91 N N N N [173035-10-4] Cl Cl 673404-500MG 500 mg 656631-1G 1 g 656631-5G 5 g 1,3-Di-tert-butylbenzimidazolium chloride 8 1,3-Bis(1-adamantyl)imidazolium tetrafluoroborate C15H23ClN2 FW: 266.81 C23H33BF4N2 N N N FW: 424.33 N BF Cl [286014-42-4] 4 673390-500MG 500 mg 660035-1G 1 g
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sigma-aldrich.com LEADERSHIP IN LIFE SCIENCE, HIGH TECHNOLOGY AND SERVICE SIGMA-ALDRICH CORPORATION • BOX 14508 • ST. LOUIS • MISSOURI 63178 • USA 1st Generation Privileged Unlock the full potential Ligands of your asymmetric synthesis reaction plans
SALENS Hydroquinidine 2,5-diphenyl-4,6- (S)-(−)-3,3’-Dibromo-1,1’-bi-2-naphthol 8 pyrimidinediyl diether C H Br O Br (1R,2R)-(+)-N,N’-Di-p-tosyl-1,2- 20 12 2 2 C H N O Et Et OH 56 60 6 4 N N FW: 444.12 Ph OH cyclohexanediamine O O FW: 881.11 H H [119707-74-3] H H (CH C H SO NH) C H O NN O Br 3 6 4 2 2 6 10 [149725-81-5] Me Me FW: 422.56 Me O O Me N N 595837-250MG 250 mg [143585-47-1] S NH HN S O O 595837-1G 1 g 53951-250MG 250 mg 482757-1G 1 g 53951-1G 1 g 482757-5G 5 g BIPHEPS Hydroquinine 1,4-phthalazinediyl diether (R,R)-(−)-N,N’-Bis(3,5-di-tert-butylsalicylidene)- (R)-(+)-2,2’-Bis-(diphenylphosphino)- Me Me C48H54N6O4 6,6’-dimethoxy-1,1’-biphenyl 1,2-cyclohexanediamine N N FW: 778.98 O NN O H H C38H32O2P2 [[(CH3)3C]2C6H2-2-(OH)CH=N]2C6H10 H H [140924-50-1] O O FW: 546.83 Me Me FW: 582.61 MeO PPh2 N N MeO PPh2 [135616-40-9] N N [133545-16-1] t-Bu OH HO t-Bu 53959-500MG 500 mg t-Bu t-Bu 95536-250MG 250 mg 404411-1G 1 g BINAPS 95536-1G 1 g 404411-5G 5 g (S)-(−)-2,2’-Bis(di-p-tolylphosphino)- 8 (R)-(−)-5,5’-Dichloro-2,2’-bis(diphenylphosphino)- TADDOLS 1,1’-binaphthyl 6,6’-dimethoxy-1,1’-biphenyl Cl Me C38H30Cl2O2P2 C48H40P2 (4R,5R)-2,2-Dimethyl-a,a,a’,a’-tetra FW: 678.78 FW: 651.5 MeO PPh2 MeO PPh2 (2-naphthyl)dioxolane-4,5-dimethanol [100165-88-6] Me [185913-98-8] P Cl C47H38O4 P FW: 666.8 Me 76854-250MG-F 250 mg [137365-09-4] HO OH 76854-1G-F 1 g Me O O Me Me 668974-250MG 250 mg BOX 393754-250MG 250 mg 668974-1G 1 g (+)-2,2’-Isopropylidenebis[(4R)-4-benzyl-2- 393754-1G 1 g (S)-(−)-2,2’-Bis(diphenylphosphino)- oxazoline] 1,1’-binaphthalene C H N O Me (4R,5R)-2,2-Dimethyl-a,a,a’,a’- 23 26 2 2 O O [(C H ) PC H -] Me tetraphenyldioxolane-4,5-dimethanol 6 5 2 10 6 2 FW: 362.46 N N FW: 622.67 [141362-77-8] C31H30O4 P OH HO [76189-56-5] P FW: 466.57 495301-250MG 250 mg [93379-48-7] O O 495301-1G 1 g Me Me 295825-250MG 250 mg 265004-250MG 250 mg 2,2’-Methylenebis[(4S)-4-tert-butyl-2- 295825-1G 1 g 265004-1G 1 g oxazoline]
C15H26N2O2 O O BINOLS N N Cinchona Alkaloids FW: 266.38 (S)-(−)-5,5’,6,6’,7,7’,8,8’-Octahydro(1,1’binapht [132098-54-5] Hydroquinidine 1,4-phthalazinediyl diether halene)-2,2’-diol 405965-100MG 100 mg C H N O Et Et 48 54 6 4 N N C H O N N 20 22 2 O O 405965-500MG 500 mg FW: 778.98 H H OH H H FW: 294.39 O O [140853-10-7] Me Me [65355-00-2] OH N N 53954-1G 1 g 540579-1G 1 g
Sigma-Aldrich is pleased to offer a comprehensive range of privileged ligands for your catalysis research efforts. Most products shown are available in both enantiomeric forms.
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