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16 Heterocyclic Organotin Reagents for Stille Coupling Stille reactions remain one of the most viable methods for the formation of C–C bonds in organic chemistry. 1 Their use has been highlighted in various areas, including countless natural product syntheses, material science applications, and in numerous synthetic methodology studies. The coupling of imidazolyl stannane 718793 with heterocycle (4) by process chemists at Pfi zer was reported in 2003 (Scheme 3). 2 This coupling employed Pd(PPh3)4 as the catalyst and was carried <strong>out</strong> in 67% isolated yield. Addition/elimination on the resulting functionalized thienopyridine provided bulk material of the desired VEGFR kinase inhibitor (5). It is worth noting that of several cross-couplings which were examined, the Stille coupling employing stannane 718793 was the only reaction feasible on scales >50g. Cl N S Aldrich.com I CH3 N SnBu3 N 718793 Pd(PPh3)4 (5 mol%) DMF, 95 C 40 h, 67% Cl N H3C S N N H3C t-BuOH/DCE 100 C 4 5 Scheme 3: Stille reaction in the preparation of VEGFR kinase inhibitors (5). H N 52% NH2 H3C H N NH N H3C S N N References: (1) Mascitti, Vincent. Stille coupling. Name Reactions for Homologations 2009, (Pt. 1), 133–162. (2) Ragan, J. A.; Raggon, J. W.; Hill, P. D.; Jones, B. P.; McDermott, R. E.; Munchhof, M. J.; Marx, M. A.; Casavant, J. M.; Cooper, B. A.; Doty, J. L.; Lu, Y. Org. Proc. Res. Dev. 2003, 7, 676. Organotin Reagents from Aldrich: Bu3Sn SnBu3 S Bu 3Sn Bu3Sn N N 678333 698598 Bu3Sn Bu3Sn 717703 N S H3C N Bu3Sn 683930 719366 Bu3Sn 718807 719730 706868 707031 O O N 706981 N OCH2CH3 Bu 3Sn Bu3Sn N N N N CH3 Cl Bu3Sn Bu3Sn N Cl N Cl 707813 717630 N Bu3Sn N OCH3 CH3 N N TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis. Bu 3Sn N O Bu3Sn 638617 642541 706965 Bu 3Sn N CH3 Bu3Sn 675679 719501 718793 N S N N CH3 Br N S Bu3Sn SnBu3 For a complete list of Organotin Reagents available from Aldrich Chemistry, visit Aldrich.com/organotin Selective 1,2-Additions with LaCl3·2LiCl While the 1,2-addition of Grignard reagents to ketones is undoubtedly a powerful transformation, oftentimes selectivity issues arising from competitive alpha-deprotonation detract from the use of these reagents. Various methods have been developed to address this shortcoming, including the use of CeCl3 and other Lewis acidic salts. However, because of the heterogeneous nature of these reagents, it is often diffi cult to obtain adequate selectivity. With this in mind, the lab of Professor Paul Knochel has shown that LaCl3•2LiCl (703559) may be used to attenuate the basicity of Grignard reagents, in turn preventing competitive enolization side reactions while leading to a powerful method for the selective 1,2-addition of Grignard reagents to ketones. In addition to enolizable ketones, even sterically hindered ketones, as well as Michael acceptors and unactivated imines can undergo 1,2-additions selectively to provide the desired addition products (Table 4). 1 Entry 1 2 EtO2C 3 Grignard Reagent i-PrMgCl MgCl LiCl N R1MgCl + R2 Br Ketone O Ph Ph EtO2C MgCl LiCl Ph O Ph Product i-Pr OH a Isolated yield of product based on reaction between ketone and Grignard reagent b Isolated yield of product in the presence of 1.5 eq CeCl3 (Dimitrov Method) c Isolated yield of product in the presence of 1.0 eq LaCl3 2LiCl O R 3 O 0 °C, 10 min-6h LaCl3 2LiCl 703559 Table 4: LaCl3•2LiCl mediated addition to ketones. OH N R 2 OH Bn Bn Br OMgCl R3 R1 N N CH3 with no additives a with CeCl3 b 5 72 39 11 35 Yield (%) __ with LaCl3 2LiCl c 92 92 81
Subsequent to these initial studies with LaCl3•2LiCl, Knochel and coworkers reported that sub-stoichiometric quantities of the lanthanide salt are suffi cient to promote the desired 1,2-addition, as demonstrated by the addition of i-PrMgCl•LiCl to unactivated imines (Scheme 4). This protocol is amenable to the use of alkyl, aryl, and heteroaryl Grignard reagents. 2 Ph N OMe + i-PrMgCl LiCl LaCl3 2LiCl (10 mol%) THF, rt, 12h HN Ph i-Pr Scheme 4: 1,2-Addition of organomagnesium reagents in the presence of catalytic LaCl3•2LiCl. Advantages of LaCl3•2LiCl: • No pretreatment procedures necessary Easy handling of reagents and reaction setup • Homogeneous reaction conditions • Improved selectivity and reactivity providing better yields and • decreased reaction times References: (1) Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 497. (2) Metzger, A.; Gavryushin, A.; Knochel, P. SynLett 2009, 1433. For a complete list of selective metallation reagents available from Aldrich Chemistry, visit Aldrich.com/metallations Chiral Silacycles for Enantioselective Allylation and Crotylation Reactions The asymmetric allylation and crotylation of aldehydes and other carbonyl compounds remains one of the most fundamental reactions for the construction of chiral building blocks. While numerous methods for this challenging task have been examined previously, including the use of chiral auxiliaries, chiral reagents and catalytic systems, still today a truly convenient and broadly reaching method remains elusive. With this goal in mind, the group of Professor James Leighton has developed a versatile system that has proven to be uniquely eff ective. Leighton and co-workers have harnessed the power of strained silacycles for use as allylation reagents with<strong>out</strong> the need for any further catalysts or reagents (Scheme 5). Me Ph Me N Si O Cl Me Ph Me N Si O Cl Scheme 5: Leighton’s chiral allyl silanes. H N Si N Cl H Br Br OMe 84% H N Si N Cl H These bench-stable and non-toxic reagents undergo enantioselective addition to a range of carbonyl compounds, including aldehydes, ketones, Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich offi ce, or visit safcglobal.com. Br Br Organometallics and hydrazones 1 (Table 5). Notably, all of these reactions are carried <strong>out</strong> at convenient reaction temperatures with<strong>out</strong> the need for external activating reagents, thereby simplifying reaction set-up and manipulation. Me Ph Me N Si O Cl 706671 O OH + R H R R T ( o C) yield % e.e. % -10 -10 -10 80 59 84 81 78 88 Me Ph Me N Si O Cl 706671 R + NHBz N R' NHNHBz R R' R R' T ( o C) yield % e.e. % CH3 CO2Me Table 5: Enantioselective allylation of various aldehydes and hydrazones with 706671. In addition to enantioselective allylation reactions, Leighton and co-workers have extended this concept to the enantioselective crotylation of carbonyl compounds 2 (Table 6). Importantly, these diamine derived silacycles are bench-stable crystalline solids, providing the added benefi t of simple reaction setup and purifi cation. H N Si N Cl H Br CH 3 CH3 R R -10 -10 -10 OH OH CH 3 CH 3 Silane R product yield % e.e. % A B A B A B A B A H N Si N Cl H B or H 3C BnO Br O + DBU o Br R H CH2Cl2, 0 C Br CH 3 CH 3 Table 6: Enantioselective crotylation of aldehydes. References: (1) (a) Kinnaird, J. W. H.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L. J.Am. Chem. Soc. 2002, 124, 7920. (b) Berger, R.; Duff , K.; Leighton, J. L. J. Am. Chem. Soc. 2004, 126, 5686. (2) Hackman, B. M.; Lombardi, P. J.; Leighton, J. L. Org. Lett. 2004, 23, 4375. 1 2 1 2 1 2 1 2 83 81 70 71 82 83 67 52 1 2 or 97 98 96 97 96 99 95 94 80 59 84 81 78 88 17
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