Vol. 9, No. 6

Olefin Metathesis

Features include: Ring-Closing Metathesis Cross Metathesis First Generation Grubbs Catalyst Ring-Opening Metathesis Polymerization $

Introduction Vol. 9 No. 6 Olefin metathesis has become a well-entrenched synthetic technique, and is a powerful method for the clean construction of innumerable classes of chemical Aldrich Chemical Co., Inc. architectures. It is broadly accepted that olefin metathesis has transformed Sigma-Aldrich Corporation the landscape of synthetic chemistry, which ultimately led to the awarding 6000 N. Teutonia Ave. of the 2005 Nobel Prize in Chemistry to the pioneers in olefin metathesis: Milwaukee, WI 53209, USA Yves Chauvin, Robert H. Grubbs, and Richard R. Schrock. Late-transition metal alkylidene complexes, specifically ruthenium alkylidenes, have propelled this chemistry to the forefront of carbon–carbon bond forming reactions, owing To Place Orders largely to their functional group tolerance and ease of handling. Ruthenium Introduction alkylidenes participate in a host of olefin metathesis reactions.1 The "carbene" Telephone 800-325-3010 (USA) mechanism proposed by Herisson and Chauvin in 1971 (Figure 1)2 initiated the FAX 800-325-5052 (USA) William Sommer development of various types of olefin metathesis catalysts with well-defined Product Manager carbenes. Katz and co-workers subsequently developed one of the first catalysts Customer & Technical Services 3 for olefin metathesis based on a tungsten-carbene complex. In 1990, Schrock Customer Inquiries 800-325-3010 and coworkers developed a highly active molybdenum catalyst for olefin metathesis.4 However, early Technical Service 800-231-8327 molybdenum catalysts were challenging to prepare and often difficult to handle. In 1992, Grubbs ® and coworkers introduced a ruthenium-based air-stable olefin metathesis catalyst (termed Grubbs 1st SAFC 800-244-1173 Generation), which was tolerant of a variety of functional groups and solvents.5 After the introduction Custom Synthesis 800-244-1173 of this initial catalyst, other ruthenium-based carbene complexes were developed with variable modes Flavors & Fragrances 800-227-4563 of reactivity. International 414-438-3850 24-Hour Emergency 414-438-3850 Web Site sigma-aldrich.com Email [email protected] R R [M] R Subscriptions [M] [M] To request your FREE subscription to ChemFiles, please

R R R contact us by: Phone: 800-325-3010 (USA)

[M] Mail: Attn: Marketing Communications R R Aldrich Chemical Co., Inc. Sigma-Aldrich Corporation Figure 1 P.O. Box 2988 Milwaukee, WI 53201-2988 In this issue of ChemFiles, we are pleased to present our portfolio of ruthenium and molybdenum Email: [email protected] based metathesis catalysts. The application of these catalysts in ring-closing metathesis (RCM), ring-closing alkyne metathesis (RCAM), cross metathesis (CM), enyne metathesis (EM), ring-opening metathesis polymerization (ROMP), ring-opening cross metathesis (ROCM), acyclic diene metathesis International customers, please contact your local (ADMET), and ring expansion has transformed the field of chemistry and some representative examples are discussed. Sigma-Aldrich office. For worldwide contact information, please see back cover. If you are unable to find a catalyst or ligand for your research, "Please Bother Us" with your suggestions at [email protected]. ChemFiles are also available in PDF format on the Internet at sigma-aldrich.com/chemfiles. References: (1) (a) Schrodi, Y.; Pederson, R. L. Aldrichimica Acta 2007, 40, 45. (b) Adv. Synth. Catal. 2007, 349, 1–268 (Olefi n Metathesis Special Issue). (c) Grubbs, R. H. Tetrahedron 2004, 60, 7117. (d) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003; Vols. 1–3. (e) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (f ) Fürstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012. (g) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. 1997, 36, 2036. (2) (a) Herission, J. L.; Chauvin, Y. Makromol. Chem. 1971, 141, 161. (b) Chauvin, Y. Angew. Chem., Int. Aldrich brand products are sold through Sigma-Aldrich, Ed. 2006, 45, 3740. (3) Katz T. J.; Rothchild, R. J. Am. Chem. Soc. 1976, 98, 2519. (4) Schrock, R. R. et al. J. Am. Chem. Soc. 1990, 112, 3875. Inc. Sigma-Aldrich, Inc. warrants that its products (5) Nguyen, S. T. et al. J. Am. Chem. Soc. 1992, 114, 3974. conform to the information contained in this and other Sigma-Aldrich publications. Purchaser must determine About Our Cover the suitability of the product for its particular use. See reverse side of invoice or packing slip for additional terms The cover graphic represents the three-dimensional structure of Benzylidene-bis(tricyclohexyl­ and conditions of sale. phosphine)dichlororuthenium, better known as the Grubbs 1st Generation catalyst. The hydrogen atoms are not represented for clarity and the aromatic ring is represented. This catalyst is active in All prices are subject to change without notice. ROMP, ADMET, CM and RCM of terminal olefins. ChemFiles (ISSN 1933–9658) is a publication of Aldrich Chemical Co., Inc. Aldrich is a member of the Sigma- Aldrich Group. © 2009 Sigma-Aldrich Co.

2 $

The Grubbs Catalysts

N N

PCy Cl 3 N N N Ru Cl Cl Cl Ph The Grubbs Catalysts Ru Ru N Br Cl Ph Cl Ph PCy 3 PCy3 Br 579726 569747 682330 Grubbs 1st generation catalyst Grubbs 2nd generation catalyst Grubbs 3rd generation catalyst

PCy3 N N PCy3 Cl Cl Ru Cl Ru Ru Cl Cl Cl PCy3 O O + - BF4

577944 569755 707961 Hoveyda-Grubbs 1st generation catalyst Hoveyda-Grubbs 2nd generation catalyst Piers-Grubbs 1st generation catalyst

N N PCy Cl 3 N N Ru Cl Cl Ru Cl PCy3 Ru + Cl Cl - PCy3 PCy BF4 3

707988 578681 682365 Piers-Grubbs 2nd generation catalyst

N N N N Cl Cl Ru N N Ru Cl Cl Cl N Ru O Cl Ph PCy3

682381 682284 682373

Discover New Cross-Coupling Catalysts

NH NH2 2 Pd Cl NH2 Pd Cl i-Pr NH2 Pd Cl Pd Cl O PCy O PCy2 2 i-Pr PCy2 i-Pr Pt-Bu2

i-Pr i-Pr O O i-Pr i-Pr i-Pr 704954 (from XPhos) 704946 (from SPhos) 707589 (from RuPhos) 708739 (from t-BuXPhos)

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Ring-Closing Metathesis PCy3 Cl Ring-closing metathesis has become an essential tool for C-C bond Ru Ph Cl formation as demonstrated by the profound impact on total synthesis R PCy3 R Ph 1 X in recent years. The first examples date back to 1980 and involved the (2 - 4 mol %) X use of tungsten-based catalysts for the preparation of macrocycles C6H6, 20 °C from dialkenyl keto-esters and dialkenyl ketones (Villemin and Tsuji, X = N, C 1-2 h 2 respectively). In 1993, Grubbs and coworkers reported the first O CF 3 O OTBS example of a carbocyclization using a functional-group tolerant N N N molybdenum-based carbene catalyst (silyl ethers, esters, alcohols, and O 3 benzyl ethers were all tolerated). The Grubbs group subsequently 93% 89% 85% synthesized a new air-stable ruthenium-carbene complex which was able to catalyze the cyclization of a variety of dienes in good yields Scheme 1 (Scheme 1).4 Numerous research groups have since used RCM to synthesize highly complex molecules. What follows is a brief overview PCy3

Ring-Closing Metathesis highlighting a few representative examples of RCM. Cl Ru Cl Ph Total Synthesis of Ingenol PCy3

5 (2 mol %) In 2004, Wood and coworkers reported the synthesis of ingenol. H2C=CH2 This natural product has fascinated synthetic chemists for the past CH2Cl2, 25 °C 20 years due to its promising biological activity and structure, which O O features four distinctive ring systems. Wood and coworkers devised an 98% ingenious approach involving a ring-opening/cross metathesis and a ring-closing metathesis step (Scheme 2). With only 2 mol % of the N N Cl Grubbs catalyst (1st Generation), the norbornene derivative afforded Ru Cl the desired dienes in nearly quantitative yield. It is important to note O that the polymerization of norbornene was suppressed by using high O O O dilution conditions and excess ethylene gas. Further functionalization (25 mol %) H H of the diene set the stage for the ring-closing metathesis step. The O toluene, ∆ O O desired product was obtained in 76% yield in the presence of 25 mol % H nd PMBO of the Grubbs-Hoveyda catalyst (2 Generation). PMBO 76% Ultra-Fast Initiating Ruthenium Catalysts for O Low-Temperature Metathesis H Traditional Grubbs catalyst systems are five-coordinate ruthenium HO HO complexes containing a neutral ligand, which is typically a phosphine, HO OH or in the case of the Hoveyda-Grubbs catalysts, a styrenyl ether. Ligand ingenol dissociation is required to provide the active catalyst, but is slow at low temperatures. Therefore, traditional Grubbs catalysts are not reactive at Scheme 2 low temperatures. The Piers group developed preformed 4-coordinate cationic complexes that do not require ligand dissociation prior to reaction. The reaction progress was examined for the cyclization of N N Cl diethyldiallylmalonate to provide the corresponding cyclopentene Ru derivative using both the Piers catalyst and the Grubbs catalyst at 0 °C Cl PCy3 (Scheme 3).6 At this temperature, the Grubbs catalysts (2nd Generation) O O BF4 O O (1 mol %) was found to be a weak initiator and after 4 h, the reaction had EtO OEt EtO OEt progressed to 25% completion, while the cationic complex had CD2Cl2, 0 °C, 2h progressed to > 90% completion after 2 h. The initiation rate of the >90% conversion 25% completion with Grubbs cationic catalyst at 0 °C was found to be comparable to the initiation Catalyst (2nd Generation) rate of the Grubbs catalyst (2nd Generation) at 35 °C. In a subsequent study, Piers and coworkers examined the intermediates Scheme 3 in an olefin metathesis reaction by NMR at –50 °C (Scheme 4). This was the first direct observation of a ruthenacyclobutane intermediate and provided evidence for a symmetrical intermediate.7 It also illustrated the stabilizing effect of the N-heterocyclic carbene ligand on the N N Ru(IV) species. N N Cl Ru Cl + 2.2 H2CCH2 Ru Cl PCy3 Cl

B(C6F5)4

Scheme 4

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Sterically Accessible Catalysts for Hindered Substrates N N More recently, Stoltz and Grubbs jointly reported the use of ring- Cl Ru closing metathesis in the key step of the total synthesis of (+)–elatol, Cl a spiro[5.5]undecane-containing natural product which has drawn O Ring-Closing Metathesis significant interest due to its antibiofueling, antibacterial, and O O antifungal activity as well as its cytotoxicity. The researchers developed (5 mol %) Cl Cl Cl benzene, 60 °C an asymmetric synthesis of this molecule utilizing RCM (with Hoveyda- i-BuO i-BuO HO Grubbs 2nd Generation catalyst) in order to provide a key intermediate 97% Br en route to the natural product. (Scheme 5).8 (+)-elatol

Synthesis of Tetrasubstituted Olefins Scheme 5 In their preparation of sominone (R = OH, 22ß-O) and related analogs, Matsuya and coworkers used RCM to generate tetrasubstituted olefins. N N Cl R2 The RCM reaction was utilized in the preparation of the lactone side Ru chain (Scheme 6). While ring closure affording the tetrasubstituted R2 OH Cl OH O 22 nd olefin with the Hoveyda-Grubbs catalyst (2 Generation) proceeded O O O O H H 1 1 in low yields (15–24%), it allowed a rapid and modular entry into the R (10 mol %) R desired motif.9 H H toluene, 80 °C H H HO HO 15-88% Synthesis of Furans R1 = OTBS, R2 = Me, H; all combinations with 22α-O and 22β-O Donohoe and co-workers have developed several synthetic approaches R1 = H, R2 = Me, H; to the synthesis of furans which incorporate RCM as a key step.10 In all combinations with 22α-O and 22β-O 2007, the researchers synthesized a series of di- and tri-substituted furans using both the Hoveyda-Grubbs catalyst (2nd Generation) and Scheme 6 the Grubbs catalyst (2nd Generation), followed by addition of PPTS or TFA, respectively (Scheme 7). In 2008, Donohoe and coworkers devised a synthesis of (–)‑ N N Cl (Z)-deoxypukalide, a member in a class of marine natural products Ru which have exhibited a range of biological activities, including Cl neurotoxicity and anti-inflammatory effects. In the total synthesis of O (–)-( Z)-deoxypukalide, mixed acetal formation with acrolein diethyl (10 mol %) acetal served to install the requisite allyl group and following RCM, O O acidic hydrolysis furnished the desired furan in good overall yield. OEt toluene, 60 °C The final step of the synthesis utilized a second RCM with the Grubbs then 1 eq PPTS 60% catalyst (2nd Generation) to form the butenolide unit in 72% yield 11 (Scheme 8). N N Cl Ru Cl Ph PCy Ph 3 (10 mol %) O O H C On-Bu toluene, reflux 3 then 0.6 eq TFA 38%

Scheme 7

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Ring-Closing Alkyne Metathesis (RCAM) Alkyne metathesis has been a useful tool for C-C bond formation since the discovery of structurally well-defined metal alkylidynes by Schrock and coworkers.12 These complexes have found use in the synthesis of complex natural products and in material science.13 The limitations of these catalysts include air- and moisture-sensitivity as well as incompatibilities with substrates that contain donor sites. Fürstner and co-workers have recently developed an air-stable molybdenum catalyst for alkyne metathesis, which proved versatile and compatible with substrates containing donor sites.14 The authors also examined the use of this catalyst in the ring-closing cross metathesis (RCAM) of a variety of alkynes in generating various macrocycles in good yields (Scheme 9).

References: (1) Nicolaou, K. C. et al. Angew. Chem., Int. Ed. 2005, 44, 4490. (2) (a) Villemin, D.

Ring-Closing Metathesis Tetrahedron Lett. 1980, 21, 1715. (b) Tsuji, J. et al. Tetrahedron Lett. 1980, 21, 2955. (3) Fu, G. C. et al. J. Am. Chem. Soc. 1993, 115, 3800. (4) Fu, G. C. et al. J. Am. Chem. Soc. 1993, 115, 9856. (5) Nickel, A. et al. J. Am. Chem. Soc. 2004, 126, 16300. (6) Romero, P. E. et al. Angew. Chem. Int. Ed. 2004, 43, 6161. (7) Romero, P. E. Piers, W. E. J. Am. Chem. Soc. 2005, 127, 5032. (8) White, D. E. et al. J. Am. Chem. Soc. 2008, 130, 810. (9) Matsuya, Y. et al. Org. Lett. 2009, 11, 3970. (10) (a) Donohoe, T. J. et al. Eur. J. Org. Chem. 2005, 1969. (b) Donohoe, T. J. et al. Tetrahedron 2008, 64, 809. (c) Donohoe, T. J. et al. Org. Lett. 2006, 8, 543. (d) Donohoe, T. J. et al. Chem. Eur. J. 2008, 14, 5716. (11) Donohoe, T. J. et al. Angew. Chem. Int. Ed. 2008, 47, 7314. (12) Schrock, R. R. Chem. Rev. 2002, 102, 145. (13) (a)Fürstner, A. et al. Chem. Commun. 2005, 2307. (b) Schrock, R. R. et al. Adv. Synth. Catal. 2007, 349, 55. (14) Bindl, M. et al. J. Am. Chem. Soc. 2009, 131, 9468.

N N Cl Ru OEt OEt Cl Ph PCy3 O OH OTIPS O OTIPS OEt (7.5 mol %) MeO PPTS CH2Cl2, ∆ O O MeO O

EtO O OTIPS then PPTS O OTIPS (85% yield over two steps) MeO O MeO O O O

N N Cl CO2Me Ru CO2Me Cl Ph PCy O 3 O (15 mol %)

toluene, ∆ O 72% O O O (−)-(Z)-deoxypukalide Scheme 8

N Mo Ph3SiO OSiPh3 N Ph3SiO

(20 mol %)

O O

O N O O 87% 54%

Scheme 9

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Cross Metathesis

Cross metathesis has become an invaluable method for the O preparation of olefins.1 While cross metathesis is typically conducted under mild conditions and is tolerant of a variety of functionalities, the chemo- and stereoselectivity of the reaction were more difficult PCy3

Cl Cross Metathesis 2 to predict. However, due to advances in catalyst design and reaction Ru understanding, predictability has improved. Cl Ph PCy3 (10 mol %) Synthesis of Glabrescol CH2C2, rt O

In 2000, Corey and coworkers utilized cross metathesis to synthesize O a series of stereoisomers of glabrescol.3 Glabrescol is the biosynthetic precursor to steroids and triterpenoids. Upon preparation of the original structure proposed for glabrescol, it was realized the wrong MeH structure for the natural product was reported. Corey and coworkers H Me O O utilized a cross metathesis dimerization approach, which allowed for H HO the preparation of the various isomers of glabrescol in a single step O and ultimately lead to the correct structure assignment for glabrescol HO O H O Me (Scheme 1). H MeH Cross Metathesis Reaction of Hindered Substrates Scheme 1 Exploiting the ability of the o-tolyl-NHC Hoveyda-Grubbs catalyst to react with hindered substrates, the Grubbs group recently reported a series of cross metathesis reactions between terminal olefins.4

Reduction in steric bulk contained on the NHC ligand resulted in N N Cl successful coupling of sterically-hindered substrates (Scheme 2). The Ru authors reported that this catalyst outperformed the Hoveyda-Grubbs Cl catalyst (2nd Generation) in all cases studied. A variety of disubstituted O olefins were prepared in good yields using 5 mol % of the catalyst. OH OH Et (5 mol %) Et + R Ph Ph R CH2Cl2, ∆ Exploiting Grubbs Catalysts with Novel Reactivity OH OH OH OH Et Et Et Et OAc Ph OBz OBz The Howell group recently reported the first synthesis of Ph Ph Ph Ph tetrasubstituted olefins using cross metathesis during the course of investigating the synthesis of a-alkylidene-ß-lactams, which serve 89%, >20:1 dr 91%, >20:1 dr 98%, >20:1 dr 66%, 3:2 dr as building blocks for the preparation of ß-lactam antibiotics. The Hoveyda-Grubbs catalyst (2nd Generation) outperformed the Grubbs Scheme 2 catalyst (2nd Generation) in cross metathesis and portion-wise catalyst addition led to increased product yields.5 Using variable catalyst loadings, the desired tetrasubstituted olefin was generated in good yields (Scheme 3). NN Cl Ru Enyne Metathesis Cl O O O Enyne metathesis has emerged as a powerful method for the O 6 O N synthesis of conjugated dienes. Botta and coworkers utilized a similar N (3 x 2 mol %) + approach, where the olefin was replaced with an enol ether. Reaction CH Cl , ∆ O O 2 2 between the alkyne and the enol ether generated the ß-substituted 85% crotonaldehydes in good yields. The reaction is conducted in the E:Z = 1:1 presence of the Grubbs catalyst (2nd Generation), an aqueous solution of CuSO , and under microwave conditions. Irradiation under 4 Scheme 3 microwave conditions (3 X 10 minutes) is followed by the addition of iodine to provide the desired crotonaldehydes in good yields (Scheme 4).7 N N References: (1) Connon, S. J. et al. Angew. Chem. Int. Ed. 2003, 42, 1900. (2) Chatterjee, A. K. et al. Cl J. Am. Chem. Soc. 2003, 125, 11360. (3) (a) Xiong, Z. et al. J. Am. Chem. Soc. 2000, 122, 4831. (b) Ru Xiong, Z. et al. J. Am. Chem. Soc. 2000, 122, 9328. (4) Stewart, I. C. et al. Org. Lett. 2008, 10, 441. Cl Ph (5) Liang, Y.et al. Tetrahedron Lett. 2009, 50, 1020. (6) Diver, S. T. et al. Chem. Rev. 2004, 104, 1317. PCy3 (10 mol %) H (7) Castagnolo, D. et al. J. Org. Chem. 2009, 74, 3172. + OEt R R O 2 eq. CuSO4 t-BuOH/H2O 1:1 µW, 80 °C then, I2

H H H H BzO PMBO O O O O

51% 68% 39% 63%

Scheme 4

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Ring-Opening Metathesis Polymerization application of brush-like polymers to include new ranges of properties. In this report, the authors use the Grubbs catalyst (3rd Generation) to (ROMP) polymerize the norbornene monomers. Excellent polydispersity of the polymer was reported with PDI ranges of 1.03 to 1.15 (Scheme 1).3 ROMP has become an important reaction for the formation of well defined polymers. Ziegler and Natta's early studies on ethylene and References: (1) (a) Ziegler, H. et al. Angew. Chem. 1955, 67, 541.(b) Natta, G. Angew. Chem. 1956, polypropylene polymerization lead to extensive research efforts on 68, 393. (2) Nguyen, S. T. et al. J. Am. Chem. Soc. 1992, 114, 3974. (3) Lu, H. et al. J. Am. Chem. Soc., the investigation of transition metal catalyzed polymerization and 2009, 131, 13582. its mechanism, which ultimately lead to the development of ROMP.1 In 1992, the Grubbs group reported the synthesis of the first well defined ruthenium alkylidene, paving the way to a new generation 2 of highly functional group tolerant ROMP catalysts. These catalysts N N

are also utilized in living ROMP, allowing control of the molecular Cl weight, a low polydispersity, and clean polymer end-capping. These N Ru Cl Ph N advantages made ROMP the method of choice for the synthesis of Br complex polymeric architectures. Norbornene's strained bicyclic H H Br O O x y structure makes it an ideal monomer for ROMP and polymerization (5 mol %) + H H H H N using the Grubbs family of catalysts leads to high reaction control. N THF: CH2Cl2 (9:1) O O H H O N O N Furthermore, the monomer can be readily functionalized, which O O NHTMS many groups have exploited to synthesize polynorbornene side NHTMS chain functionalities such as catalysts, biological reagents, hydrogen 1.0 eq 2.5 eq bonding units or trapping molecules. This living character also allows polymerization of amino acid for the introduction of two monomers resulting in the formation N-carboxyanhydride of alternative, block or random copolymers. These copolymers can x y H H H H impart a wide range of properties to the bulk polymer. Ring-Opening (ROMP) Metathesis Polymerization O N O O N O

Synthesis of Brush-like Polymers via ROMP HN O O TMS Recently, Cheng and coworkers reported the synthesis of brush-like R N O H n polymers, by which the main polymer chain was prepared using brush-like polymer ROMP followed by polymerization of peptide units on the amine side Scheme 1 chain with N-carboxyanhydrides. These new materials may extend the

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Catalysts

Handbook of Metathesis, 3 volume set Hoveyda-Grubbs Catalyst 1st Generation ISBN 978-352730616-9 [203714‑71‑0] C28H45Cl2OPRu Z551570-1EA 1 ea

FW 600.61 P Catalysts Cl 2,6-Diisopro­ ­pyl­phenyl­imido-neoph­yl­idene[(S)-(−)-BIPHEN] Ru Cl molybdenum(VI), ≥97.0% (C) O H3C

[205815‑80‑1] i-Pr CH3 H3C t-Bu C46H61MoNO2 O N 577944-100MG 100 mg FW 755.92 H3C Mo i-Pr H3C O 577944-500MG 500 mg CH3 CH3 577944-2G 2 g H3C t-Bu Dichloro(3-methyl-2-buten­yl­idene)bis(tri­cyclo­hexyl­phos­phine)  purum, ring-closing metathesis catalyst ruthe­nium(II) 73022-100MG-F 100 mg [194659‑03‑5]

C41H74Cl2P2Ru Tris(tri­phenyl­silyloxy)molybdenum­ nitride pyridine­ com­plex, FW 800.95 P ≥95% Cl Ru CH3 Cl C59H50MoN2O3Si3 P CH3 FW 1015.24 Ph N N Ph Ph Si O Mo O Si Ph Ph O Ph US Patent No. 5,969,170 (and associated foreign equivalents of the foregoing) Ph Si Ph Ph apply. Sale of this product conveys to the buyer a limited-use research license.  contains up to 10 wt. % toluene For full details of this license please see sigma-aldrich.com/materialicense. For questions, please contact us at [email protected] or Materia at 719684 100 mg [email protected].

Grubbs Catalyst, 2nd Generation 578681-1G 1 g 578681-5G 5 g [246047‑72‑3] H3C CH3 C H Cl N PRu N N 46 65 2 2 H C 3 CH3 Dichloro(3-methyl-2-buten­yl­idene)bis(tri­cyclo­pentyl­phos­phine) FW 848.97 CH3 H3C Cl ruthe­nium(II) Ru Cl Ph [220883‑08‑9] P C35H62Cl2P2Ru FW 716.79 P Cl Ru CH3 US Patent No. 6,111,121 and 7,329,758 (and associated foreign equivalents Cl of the foregoing) apply. Sale of this product conveys to the buyer a P CH3 limited-use research license. For full details of this license please see sigma-aldrich.com/materialicense. For questions, please contact us at US Patent No. 5,969,170 and foreign equivalents apply. Sale of this product [email protected] or Materia at [email protected]. conveys to the buyer a limited-use research license. For full details of this 569747-100MG 100 mg license please see sigma-aldrich.com/materialicense. For questions, please 569747-500MG 500 mg contact us at [email protected] or Materia at [email protected]. 569747-2G 2 g 578703-1G 1 g 578703-5G 5 g Hoveyda-Grubbs Catalyst 2nd Generation H C st [301224‑40‑8] 3 CH3 Grubbs Catalyst, 1 generation N N C31H38Cl2N2ORu [172222‑30‑9] H3C CH3 FW 626.62 CH3 H3C Cl C43H72Cl2P2Ru Ru Cl FW 822.96 P O Cl H3C Ru Cl Ph CH3 P US Patent No. 6,921,735 and foreign equivalents apply. Sale of this product conveys to the buyer a limited-use research license. For full details of this license please see sigma-aldrich.com/materialicense. For questions, please US Patent No. 6,111,121 and foreign equivalents apply. Sale of this product contact us at [email protected] or Materia at [email protected]. conveys to the buyer a limited-use research license. For full details of this 569755-100MG 100 mg license please see sigma-aldrich.com/materialicense. For questions, please 569755-500MG 500 mg contact us at [email protected] or Materia at [email protected]. 569755-2G 2 g 579726-1G 1 g 579726-5G 5 g

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[1,3-Bis(2-methyl­phenyl)-2-imidazolidin­yl­idene]dichloro- [1,3-Bis(2,4,6-tri­methyl­phenyl)-2-imidazolidin­yl­idene]dichloro- (benzyl­idene) (tri­cyclo­hexyl­phos­phine)ruthe­nium(II) [3-(2-pyridinyl-κN)propyli­dene-κC]ruthe­nium(II)

[C42H57Cl2N2PRu CH3 [802912‑44‑3] H3C CH3 N N N N FW 792.87 C29H35Cl2N3Ru H3C CH CH3 CH H C 3 Cl FW 597.58 3 3 Ru Cl Cl Ru Ph Cl P N

Catalysts US Patent Application No. 11/094,102 and foreign equivalents apply. US Patent Nos. 6,111,121 and 7,329,758 (and associated foreign Sale of this product conveys to the buyer a limited-use research license. equivalents of the foregoing) apply. Sale of this product conveys to the For full details of this license please see sigma-aldrich.com/materialicense. buyer a limited-use research license. For full details of this license please For questions, please contact us at [email protected] or Materia at see sigma-aldrich.com/materialicense. For questions, please contact us at [email protected]. [email protected] or Materia at [email protected]. 682381-100MG 100 mg 682284-100MG 100 mg 682381-500MG 500 mg 682284-500MG 500 mg 682381-2G 2 g 682284-2G 2 g

[1,3-Bis(2,4,6-tri­methyl­phenyl)-2-imidazolidin­yl­idene] Ruthe­nium Metathesis Catalysts Kit I dichloro(benzyl­idene)bis(3-bromo­pyri­dine)ruthe­nium(II) US Patents and patents pending (and associated foreign equivalents of the foregoing) apply. Sale of this kit conveys to the buyer a limited-use C H Br Cl N Ru H3C CH 38 40 2 2 4 3 research license. For full details of this license please see FW 884.54 N N H3C CH3 sigma-aldrich.com/materialicense. For questions, please contact us CH3 H3C Cl at [email protected] or Materia at [email protected]. N Ru Cl Br N

Br US Patent No. 6,759,537 and foreign equivalents apply. Sale of this product conveys to the buyer a limited-use research license. For full details of this license please see sigma-aldrich.com/materialicense. For questions, please contact us at [email protected] or Materia at [email protected].

682330-100MG 100 mg 682330-500MG 500 mg 682330-2G 2 g Ruthenium Metathesis Catalysts Kit I [1,3-Bis(2,4,6-tri­methyl­phenyl)-2-imidazolidin­yl­idene]dichloro- (3-methyl-2-buten­yl­idene) (tri­cyclo­hexyl­phos­phine)ruthe­nium(II) Components H C st C44H67Cl2N2PRu 3 CH3 Grubbs Catalyst, 1 Generation (Aldrich 579726) 1 G N FW 826.97 N Grubbs Catalyst, 2nd Generation (Aldrich 569747) 100 MG H3C CH3 CH3 H3C Hoveyda-Grubbs Catalyst 2nd Generation (Aldrich 569755) 100 MG Cl st Ru CH3 Hoveyda-Grubbs Catalyst 1 Generation (Aldrich 577944) 100 MG Cl Dichloro(3-methyl-2-butenylidene)bis(tricyclohexylphosphine)ruthenium(II) P CH3 (Aldrich 578681) 1 G Dichloro(3-methyl-2-butenylidene)bis(tricyclopentylphosphine)ruthenium(II) (Aldrich 578703) 1 G US Patent No. 7,329,758 (and associated foreign equivalents of the [1,3-Bis(2-methylphenyl)-2-imidazolidinylidene]dichloro(benzylidene) foregoing) apply. Sale of this product conveys to the buyer a limited-use (tricyclohexylphosphine)ruthenium(II) (Aldrich 682284) 100 MG research license. For full details of this license please see sigma-aldrich.com/ [1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(benzylidene)bis(3- materialicense. For questions, please contact us at [email protected] or bromopyridine)ruthenium(II) (Aldrich 682330) 100 MG Materia at [email protected]. [1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(3-methyl-2- butenylidene) (tricyclohexylphosphine)ruthenium(II) (Aldrich 682365) 100 MG 682365-100MG 100 mg [1,3-Bis(2-methylphenyl)-2-imidazolidinylidene]dichloro(2- 682365-500MG 500 mg isopropoxyphenylmethylene)ruthenium(II) (Aldrich 682373) 100 MG 682365-2G 2 g [1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro[3-(2-pyridinyl-κN) propylidene-κC]ruthenium(II) (Aldrich 682381) 100 MG

[1,3-Bis(2-methyl­phenyl)-2-imidazolidin­yl­idene]dichloro- 687944-1KT 1 kit (2-iso­pro­poxy­phenyl­methyl­ene)ruthe­nium(II)

C27H30Cl2N2ORu CH3 FW 570.52 N N CH 3 Cl Ru Cl O H3C

CH3 US Patent No. 6,921,735 and patents pending (and associated foreign equivalents of the foregoing) apply. Sale of this product conveys to the buyer a limited-use research license. For full details of this license please see sigma-aldrich.com/materialicense. For questions, please contact us at [email protected] or Materia at [email protected].

682373-100MG 100 mg 682373-500MG 500 mg 682373-2G 2 g

10 sigma-aldrich.com TO ORDER: Contact your local Sigma-Aldrich office (see back cover) or visit sigma-aldrich.com/chemicalsynthesis. $

Dichloro(tri­cyclo­hexyl­phos­phine)[(tri­cyclo­hexyl­phos­phor­anyl)- [1,3-Bis(2,4,6-tri­methyl­phenyl)-2-imidazolidin­yl­idene]dichloro- methyl­idene]ruthe­nium tetra­fluoro­borate, 95% [(tri­cyclo­hexyl­phos­phor­anyl)methyl­idene]ruthe­nium

C37H67BCl2F4P2Ru tetra­fluoro­borate, 95% FW 832.66 [832146‑68‑6] CH3 H3C - P BF4 C40H60BCl2F4N2PRu H3C NN CH3 FW 858.67

Cl Catalysts Ru CH3 H3C Cl F P Cl Ru F B F Cl P F US Patent No. 7,365,140 (and associated foreign equivalents) owned by UTI Limited Partnership and licensed to Materia; Inc. apply. Sale of this product US Patent No. 7,365,140 (and associated foreign equivalents) owned by UTI conveys to the buyer a limited-use research license. For full details of this Limited Partnership and licensed to Materia; Inc. apply. Sale of this product license please see sigma-aldrich.com/materialicense. For questions; please conveys to the buyer a limited-use research license. For full details of this contact us at [email protected] or Materia at [email protected]. license please see sigma-aldrich.com/materialicense. For questions; please contact us at [email protected] or Materia at [email protected]. 707961-100MG 100 mg 707961-500MG 500 mg 707988-100MG 100 mg 707961-2G 2 g 707988-500MG 500 mg 707988-2G 2 g

Discover Reagents for Selective Metalations and Additions from Sigma-Aldrich

TurboGrignards for Hal/Mg Exchange of Aryl and Knochel-Hauser-Base for Selective Deprotonations Heteroaryl Compounds

Br MgCl • LiCl RMgCl • LiCl Improved reactivity and basicity H3C CH3 • (TurboGrignard) FG FG H3C N CH3 • Increased functional group compatibility FG = alkyl, alkenyl, OR', MgCl• LiCl CO2R', CN, NH2, halogen • Mild reaction conditions 703540 • Side reactions inhibited CH3 MgCl • LiCl RMgCl • LiCl = • Excellent solubility in THF H3C MgCl • LiCl 656984 703486 • Increased functional group compatibility Selective 1,2-Additions • Mild reaction conditions LaCl /LiCl • Side reactions inhibited 3 703559

Sold in partnership with • Enolizable and sterically hindered ketones

• Low H2O content and THF-soluble • Decrease in side products

For more information, visit sigma-aldrich.com/metalations

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