Synthesis of Novel Bulky, Electron-Rich Propargyl and Azidomethyl

Aug 5, 2009 - Synopsis. We have developed a novel and efficient approach to the synthesis of dialkyl-substituted propargyl, azidomethyl, bromomethyl, ...
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Organometallics 2009, 28, 5025–5031 DOI: 10.1021/om900545s

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Synthesis of Novel Bulky, Electron-Rich Propargyl and Azidomethyl Dialkyl Phosphines and Their Use in the Preparation of Pincer Click Ligands Elaine M. Schuster, Gennady Nisnevich, Mark Botoshansky, and Mark Gandelman* Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel Received June 23, 2009

Phosphorus-containing compounds bearing versatile functional groups are particularly attractive as synthetic building blocks, especially if these groups can be easily transformed and further diversified. We have developed a novel and efficient approach to the synthesis of novel dialkylsubstituted propargyl, azidomethyl, bromomethyl, and carboxymethyl phosphines. Importantly, the development of a synthetic route for these unprecedented compounds allowed for facile preparation of new pincer click ligands bearing phosphine donors with bulky electron-donating alkyl substituents. This represents a crucial extension of the recently established triazole-based tridentate ligand family.

Organophosphorus compounds have enjoyed a variety of important applications in numerous actively developing fields of science and technology. They have found use as agricultural insecticides, anticorrosion and fire-resistant agents,1 extractants in hydrometallurgy,2 and antimicrobial3 and chemotherapeutic4 components. In addition, phosphorus-containing compounds have received special attention due to their spectacular applications in synthetic chemistry as both reagents5 and ligands for metal-based catalysis.6 From a synthetic point of view, phosphoruscontaining precursors decorated with versatile functional groups are especially valuable, particularly if these groups can be easily interconverted and further diversified. In this paper, we present the synthesis of dialkyl-substituted propargyl, azidomethyl, bromomethyl, and carboxymethyl phosphine species. To the best of our knowledge,7 this is the first synthesis of these types of dialkyl-substituted phosphine compounds. *To whom correspondence should be addressed. E-mail: chmark@tx. technion.ac.il. (1) Quin, L.D. A Guide to Organophosphorus Chemistry; Wiley Interscience: New York, 2000; pp 12447-12457. (2) Flett, D. S. J. Organomet. Chem. 2005, 690, 2426. (3) Reddy, P. V. G.; Kiran, Y. B. R.; Reddy, C. S.; Reddy, C. D. Chem. Pharm. Bull. 2004, 52, 307. (4) (a) Stec, W. J. Organophosphorus Chem. 1982, 13, 146. (b) Zon, G. Prog. Med. Chem. 1982, 19, 205. (5) Organophosphorus Reagents in Organic Synthesis; Cadogan, J. I. G., Ed.; Academic Press: London, 1979. (6) Downing, J. H.; Smith, M. B. In Phosphorus Ligands in Comprehensive Coordination Chemistry II; Elsevier: Oxford, 2004; Vol. 1, pp 253296. (7) With the exception of dialkylphosphinyl acetic acids, these are previously unknown compounds. For examples on the preparation of dialkylphosphinyl acetic acids, see: (a) Dolhem, F; Johansson, M. J.; Antonsson, T.; Kann, N. Synlett 2006, 20, 3389. (b) Ohashi, A.; Kikuchi, S. I.; Yasutake, M.; Imamoto, T. Eur. J. Org. Chem. 2002, 15, 2535. (c) Chen, J.; Calvo, K. C. Phosphorus, Sulfur, Silicon, Relat. Elem. 1991, 63, 403. (d) Tsvetkov, E. N.; Bondarenko, N. A.; Malakhova, I. G.; Kabachnik, M. I. Synthesis 1986, 3, 19. r 2009 American Chemical Society

Apart from the intrinsic appeal of these species, the presence of these versatile pendant functionalities makes them very attractive building blocks for further incorporation of a phosphorus-containing moiety into the more complex target molecules. We will disclose in this paper the application of these new compounds in the selective and facile preparation of both symmetrically and nonsymmetrically substituted tridentate ligands based on a triazole core. These new ligands, bearing bulky, electron-donating alkyl-substituted phosphine donors, represent an essential extension of the recently established family of pincer click ligands.8 Their synthesis in an effective, combinatorial mode is possible only due to the development of synthetic protocols for alkyl-substituted propargyl and azidomethyl phosphines, which is disclosed presently. Typical pincertype coordination upon complexation of these new tridentate ligands bearing bulky electron-donating phosphine donors to transition metals is further demonstrated.

Results and Discussion Recently, we published the first combinatorial approach toward the synthesis of tridentate ligands.8 This methodology was based on the modified Cu(I)-catalyzed Huisgen [2þ3] cycloaddition of alkynes and azides, forming triazoles, as the central building tool for ligand assembly.9,10 Notably, utilization of the triazole unit for versatile ligand construction has received growing interest in recent years.11 This not only provided us with a simple, combinatorial method for ligand (8) Schuster, E.; Botoshansky, M.; Gandelman, M. Angew. Chem., Int. Ed. 2008, 47, 4555. (9) Huisgen, R. Proc. Chem. Soc. 1961, 357. (10) (a) Meldal, A.; Tornoee, C. W. Chem. Rev. 2008, 108, 2952. (b) Rostovtsev, V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596. (c) Tornoee, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057. Published on Web 08/05/2009

pubs.acs.org/Organometallics

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Organometallics, Vol. 28, No. 17, 2009 Scheme 1. “Click” Assembly of Tridentate Ligands

Schuster et al. Scheme 3. Synthesis of Alkyne Monomersa

a Conditions: (i) (Me3Si)-propargyl MgBr, 48 h, rt; (ii) NH4F, MeOH, 18 h, rt.

Scheme 2. Synthesis of Pincer Click Ligand 3 (previous work)

assembly but importantly also allowed for the selective and high-yielding synthesis of nonsymmetric ligands. In our approach, we combined a variety of azides and alkynes decorated with donor atoms to give a triazole-based pincer frame with two donor arms in 1,4-positions. The presence of a relatively acidic hydrogen allows for metal insertion to form tridentate pincer-type complexes (Scheme 1). On the basis of this synthetic route, we prepared an entirely new family of pincer click ligands (PCLs) and demonstrated their highly efficient catalytic activity in the Heck reaction. However, the phosphine-based ligands that we were able to synthesize in this family were restricted to aryl-substituted phosphines (Scheme 2). The reason was the synthetic unavailability of alkyl-substituted analogues of monomers 1 and 2 (vide infra). This represented a serious limitation in view of the fact that pincer-type ligands based on bulky, electron-donating phosphines are highly advantageous for numerous important applications based on this type of compounds. In particular, groundbreaking catalytic processes such as dehydrogenation of saturated hydrocarbons12 and dehydrogenative coupling of alcohols with amines,13 to name few,14 were developed on the basis of pincers bearing bulky electron-donating phosphorus substituents. Additionally, pincer ligands based on alkyl-substituted phosphines have recently demonstrated (11) (a) Liu, D.; Gao, W.; Dai, Q.; Zhang, X. Org. Lett. 2005, 7, 4907. (b) Dai, Q.; Gao, W.; Liu, D.; Kapes, L. M.; Zhang, X. J. Org. Chem. 2006, 71, 3928. (c) Detz, R. D.; Heras, S.; de Gelder, R.; van Leeuwen, P. W. N. M.; Hiemstra, H.; Reek, J. N. H.; van Maarseveen, J. H. Org. Lett. 2006, 8, 3227. (d) Dolhem, F.; Johansson, M. J.; Antonsson, T.; Kann, N. J. Comb. Chem. 2007, 9, 477. (e) Detz, R. D.; Delville, M. M. E.; Hiemstra, H.; van Maarseveen, J. H. Angew. Chem., Int. Ed. 2008, 47, 3777. (f) van Assema, S. G. A.; Tazelaar, C. G. J.; Bas de Jong, G.; van Maarseveen, J. H.; Schakel, M.; Lutz, M.; Spek, A. L.; Slootweg, J. C.; Lammertsma, K. Organometallics 2008, 27, 3210. (g) Rheingold, A. L.; Liable-Sands, L. M.; Trofimenko, S. Angew. Chem., Int. Ed. 2000, 39, 3321. (h) Mindt, T. L.; Schweinsberg, C.; Brans, L.; Hagenbach, A.; Abram, U.; Tourwe, D.; Garcia-Garayoa, E.; Schibli, R. ChemMedChem 2009, 4, 529. (i) Janssen, M.; M€uller, C.; Vogt, D. Adv. Synth. Catal. 2009, 351, 313. (12) For representative examples, see: (a) Maguire, J. A.; Petrillo, A.; Goldman, A. S. J. Am. Chem. Soc. 1992, 114, 9492. (b) Gupta, M.; Hagen, C.; Kaska, W. C.; Craner, R. E.; Jensen, C. M. J. Am. Chem. Soc. 1997, 119, 840. (c) Xu, W.; Rosini, G. P.; Gupta, M.; Jensen, C. M.; Kaska, W. C.; Karsten, K. J.; Goldman, A. S. Chem. Commun. 1997, 23, 2273. (d) Goldman, S. A.; Roy, A. H.; Huang, H.; Ahuja, R.; Schinski, W.; Brookhart, M. Science 2006, 312, 257. (13) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317, 790. (14) For a review on the use of pincer-based metal complexes in synthesis, see: Singleton, J. T. Tetrahedron 2003, 59, 1837.

broad use in the elucidation of reactive intermediates and elusive species.15 Importantly, the use of bulky alkyl substituents was essential for this work. Therefore, development of methodology for the preparation of PCLs bearing bulky alkyl-substituted phosphines seems to be an essential supplement to this new class of ligands. Our novel synthesis of dialkyl (propargyl and azidomethyl) phosphines overcomes this limitation and allows for the extension of the scope of our library to include these attractive bulky, electron-donating substituents In our initial attempts to expand the accessible ligand library, we examined the method by which our aryl-substituted ligands were synthesized. Ligand 3 was prepared by the coupling of 1 and 2 in the click reaction; these monomeric units were prepared according to the reported procedures, which are presented in Scheme 2.16,11c Surprisingly, when we tried to prepare analogous alkyl-substituted phosphine species according to the same routes, the desired results were not obtained. Our literature search also did not reveal the examples of alkyl-substituted azido or propargyl phosphines analogous to 1 and 2. Therefore, we developed a synthesis for the preparation of such compounds by an entirely different approach. Alkyne monomers 5 were targeted first. Reaction of lithium dialkyl phosphides with propargyl bromide resulted in an irresolvable mixture of the desired propargyl phosphine and phosphine-allene species. Employment of trimethylsilylprotected propargyl bromide also did not afford the desired results. Interestingly, attempts to directly use dialkyl phosphine in reactions with both protected and unprotected propargyl halides led to the formation of tetra-alkyl phosphonium salts via double propargylation of the secondary phosphine. Therefore, we decided to employ the phosphorus-based species as the electrophile rather than the nucleophile. Thus, the reaction of trimethylsilyl propargylmagnesium bromide17 with the dialkyl chlorophosphineborane complex provides compound 4a (Scheme 3). Protection of the alkynyl hydrogen was necessary in order to prevent the formation of allene-substituted phosphines. The following desilylation with ammonium fluoride in methanol quantitatively affords dialkyl propargyl phosphine monomers 5. Notably, utilization of more basic desilylation reagents, for example, TBAF, led to the competing deprotonation of the acidic methylene hydrogens of 5.18 The preparation of azidomethyl dialkyl phosphines 10 proved to be more challenging. Again, attempts to prepare (15) For representative examples, see: (a) van Koten, G.; Timmer, J. G.; Noltes, J. G.; Spek, A. L. J. Chem. Soc., Chem. Commun. 1978, 250. (b) Albrecht, M; Spek, A. L.; van Koten, G. J. Am. Chem. Soc. 2001, 123, 7233. (c) Gandelman, M.; Rybtchinski, B.; Ashenazi, N.; Gauvin, R. M.; Milstein, D. J. Am. Chem. Soc. 2001, 123, 5372. (d) Vigalok, A.; Milstein, D. Acc. Chem. Res. 2001, 34, 798. (e) Poverenov, E.; Efremenko, I.; Frenkel, A.; Ben-David, Y.; Shimon, L. J. W.; Leitus, G.; Konstantinovski, L.; Martin, J. M. L.; Milstein, D. Nature 2008, 455, 1093. (16) Palacios, F.; Pagalday, J. Eur. J. Org. Chem. 2003, 913. (17) Hernandez, E.; Soderquist, J. A. Org. Lett. 2005, 7, 5397. (18) Jung, M. E.; Hagenah, J. A. J. Org. Chem. 1987, 52, 1889.

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Scheme 4. Retrosynthetic Analysis of Azidomethyl Dialkyl Phosphine Oxides

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Scheme 6. Alternative Preparation of Bromide 9

Scheme 5. Preparation of Azides 10a-c

Scheme 7. Synthesis of PCLs 14-17a

this type of compound by the procedure suitable for arylsubstituted analogues 1 (see Scheme 2) did not furnish the desired results. Our novel synthetic route involves the preparation of azide 10 from the corresponding bromide 9, which can be obtained, in turn, from carboxylic acid 8 (Scheme 4). It is important to note that each of these compounds is a useful synthetic target on its own. Esters 6 and 7 could be readily accessed by reaction of dialkyl cholorophosphine with benzyl or tert-butyl 2-bromoacetate, followed by decomposition of the resulting phosphonium salt with aqueous sodium bicarbonate under aerobic conditions (Scheme 5).19 The corresponding deprotection leads to the R-phosphine oxide-substituted carboxylic acid 8 in quantitative yield. Remarkably, this approach to compound 10 is especially attractive, as it potentially opens the door to facile preparation of enantiomerically pure R-phosphinocarboxylic acids, as the corresponding racemic carboxylic acid mixture could be easily resolved. Carboxylic acid 8 can be converted to the corresponding bromide 9 by a modified Hunsdiecker-type reaction. Conditions were optimized to prevent dibromination, a process that readily occurs due to substitution of the acidic hydrogens R to the phosphine oxide. The bromide 9, in turn, reacts quantitatively with sodium azide to provide azidophosphine 10. Similarly to 5, our synthetic strategy to azides 10 is compatible with phosphines bearing bulky electron-donating substituents. Alternatively, compound 9 could be prepared by bromination of ester 7 with sodium hypobromite, followed by deprotection of the acid and decarboxylation (Scheme 6). Spontaneous dibromination was observed in the first step of this synthetic protocol, necessitating selective reduction of one bromine substituent with tin chloride. Although various applications of these new phosphinecontaining compounds could be envisioned, we were interested in demonstrating their applicability to the selective combinatorial synthesis of tridentate ligands. As was previously mentioned, our initial PCL library was restricted to aryl-substituted phosphine donors. In the interest of expanding this library to include bulky, electron-donating

(19) For a relevant procedure, see: Gladshtein, B. M.; Zimin, V. M. Zh. Obshch. Khim. 1967, 37, 2055.

a Conditions: (i) CuSO4/Na ascorbate, THF/H2O, 23 °C, 24 h; (ii) PhSiH3, 110 °C, 12 h for 15, 17. MeOH/dioxane/4 A˚ mol sieves, 110 °C, 18 h for 14, 15, 16, 17.

Scheme 8. Synthesis of Complex 18

substituents, we examined a number of dialkyl phosphine monomers 5 and 10 in the click reaction. Gratifyingly, we found that [2þ3] cycloaddition of these monomers proceeds smoothly even with phosphine species bearing bulky isopropyl and cyclohexyl substituents. Monomer 10c, however, demonstrated only sluggish reactivity in the click reaction, presumably due to extreme steric hindrance of tert-butyl substituents. The synthesis of a number of representative ligands, including symmetrically and nonsymmetrically substituted PCP and PCS species, is shown in Scheme 7. After Cu(I)-catalyzed cycloaddition and concomitant phosphine deprotection (phosphines must be protected in the course of synthesis, e.g., as the oxide or as the borane complex, in order to prevent a Staudinger-type reaction with azides), four new alkyl-substituted electron-donating phosphine-based pincer click ligands, 14, 15, 16, and 17, were prepared. In order to examine the feasibility of these compounds of behaving as tridentate ligands, we explored the reactivity of representative ligand 17 with a Pd precursor. We were pleased to find that upon gentle heating of a solution of 17 with (TMEDA)PdCl2 (TMEDA = tetramethylethylenediamine) in the presence of triethylamine, pincer complex 18 was formed. Following the reaction by 31P NMR shows complete and selective conversion of the starting ligand into the complex 18 after 18 h (Scheme 8). Compound 18 was fully characterized by multinuclear NMR techniques. The 31P NMR of 18 exhibits two doublets at 56.2 and 65.7 ppm with a coupling constant of 413 Hz, characteristic of two nonequivalent phosphorus atoms located in mutual trans positions.

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Figure 1. Perspective view of a molecule of 18. Hydrogen atoms are omitted for clarity. Selected bond lengths [A˚] and angles [deg]: Pd1-C1 1.929(6), Pd1-P1 2.317(2), Pd1-P2 2.317(2), Pd1-Cl1 2.364(2), P1-Pd1-P2 159.70(6), C1-Pd1-Cl1 178.8 (2).

The molecular structure of complex 18 was confirmed by X-ray analysis.20 Yellowish crystals of 18 suitable for singlecrystal X-ray analysis were obtained by slow cooling of a solution of the complex in a mixture of THF/hexane. The palladium atom is located in the center of a distorted squareplanar structure with the chloride group occupying a position trans to the carbon atom of the triazole (Figure 1). The two phosphine groups are located in a mutual trans position with a P-Pd-P angle of 159.71°. Interestingly, while the chlorine, C1, and phosphorus atoms form an almost ideal plane (the deviation from the mean plane is not more than 0.001 A˚), the palladium atom deviates from the mean plane by 0.02 A˚. In conclusion, we have developed an efficient novel approach to the synthesis of dialkyl-substituted propargyl, azidomethyl, bromomethyl, and carboxymethyl phosphines. We believe that these new phosphines decorated with versatile functional groups have potential implications in a wide variety of areas of chemistry. We demonstrated the utility of azidomethyl and propargyl phosphines in the click reaction. It allowed us easy, combinatorial-type, and highly selective preparation of tridentate ligands bearing phosphine donors with bulky electron-donating alkyl substituents. The classical pincer-type coordination mode of these new ligands upon reaction with late transition metal was also demonstrated. Importantly, the successful development of synthetic routes to these bulky, electron-donating monomers allowed for a crucial extension of the recently established PCL family. Studies on applications of these ligands in metal-catalyzed transformations are currently under way in our laboratories.

Experimental Section General Methods. Oxygen- and moisture-sensitive reactions were carried out under an atmosphere of purified nitrogen in a glovebox equipped with an inert gas purifier or by using standard Schlenk techniques. Dry Et3N was obtained by distillation from CaH2. Solvents were purified by passing through a column of activated alumina under inert atmosphere. All commercially available reagents were (20) CCDC 735813 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif.

Schuster et al.

used as received, unless otherwise indicated. NMR spectra were recorded at 300 MHz/75 MHz (1H/13C NMR) in CDCl3 unless otherwise stated on a Bruker AVANCE 300 MHz spectrometer at 23 °C. Chemical shifts (δ) are reported in parts per million, and the residual solvent peak was used as an internal standard (CDCl3: δ 7.261/77.0, 1H/13C NMR). 31 P NMR signals are in ppm and referenced to external 85% H3PO4. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet, br = broad), integration, and coupling constant(s) (Hz). General Procedure for the Preparation of TrimethylsilylProtected Dialkyl Propargylphosphine-Borane Complexes. 4b: To a three-necked 25 mL round-bottom flask equipped with a condenser were successively added Mg turnings (97 mg, 4 mmol), HgCl2 (25 mg), and one crystal of I2. Dry ether (2 mL) was added, and the reaction mixture was stirred at rt for 1 h. (Trimethylsilyl)propargyl bromide (382 mg, 2 mmol) was added dropwise, and the solution was then refluxed for 30 min. The reaction was cooled at room temperature and decanted through a cannula under positive pressure of argon to produce a solution of 3-(trimethylsilyl)propargylmagnesium bromide. To the prepared Grignard reagent was added dropwise a solution of Cy2PCl 3 BH3 (247 mg, 1 mmol) in toluene (1 mL). The mixture was stirred for 40 h at rt. The mixture was then poured into a solution of NH4Cl (0.56 g, 10.4 mmol) in water (1.5 mL). The obtained mixture was stirred for 10 min and extracted with EtOAc (2  20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was separated by flash chromatography, hexane/ CH2Cl2 (3:2), Rf = 0.3, to afford product 4b as a colorless oil (0.200 g, 62%). 1H NMR (CDCl3) δ: 0.09 (s, 9H, Si(CH3)3), 1.10-1.55 (m, 10H), 1.60-1.95 (m, 12H), 2.46 (d, 8.9 Hz, 2H, PCH2). 13C NMR (CDCl3) δ: 0.1, 12.4 (d, JCP = 28 Hz, PCH2), 26.2, 26.7, 26.75, 27.0, 27.1, 31.0 (d, JCP = 31 Hz, CH), 89.1, 98.8. 31P NMR (CDCl3) δ: 25.3. 4a: 1H NMR (CDCl3) δ: 0.1 (s, 9H), 1.25 (d, 6H), 1.27 (d. 6H), 2.19-2.25 (m, 2H, CH-P), 2.6 (d, JHP = 9 Hz, 2H). 13 C NMR (CDCl3) δ: 0.1, 12.5 (d, JCP = 28 Hz, CH2), 16.8, 21.3 (d, JCP = 32 Hz, CH), 88.7, 98.2. 31P NMR (CDCl3) δ: 33.5 (q, JPB = 70 Hz). General Procedure for Trimethylsilyl Removal. 5b: To a stirred mixture of Cy2PCH2CtCSiMe3 3 BH3 (161 mg, 0.5 mmol) in MeOH (1.9 mL) was added NH4F (185 mg, 5 mmol). After 16 h at rt, the mixture was concentrated in vacuo. The residue was mixed with water (10 mL) and extracted with EtOAc (2  10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give product 5b (0.100 g, 80%) as an off-white solid. 1H NMR (CDCl3) δ: 1.15-1.55 (m, 10H), 1.65-2.00 (m, 12H), 2.07 (dt, JHP = 3.8 Hz, JHH = 2.8 Hz, 1H), 2.48 (dd, JHP = 9.0 Hz, JHH = 2.8 Hz, 2H, CH2). 13C NMR (CDCl3) δ: 11.0 (d, JCP = 29.6 Hz), 28.9, 26.4 (d, JCP= 2.5 Hz), 26.6 (d, JCP = 2.5 Hz), 26.7 (d, JCP = 2.5 Hz), 26.8 (d, JCP = 10 Hz), 30.7 (d, JCP = 30.5 Hz, CH-P), 71.7 (d, JCP = 4.6 Hz), 76.4 (d, JCP = 12 Hz). 31P NMR (CDCl3) δ: 29.4 (br m). 5a: 1H NMR (CDCl3) δ: -0.03-0.9 (br m, 3H, BH3), 1.23 (d, 6H, CH3), 1.26 (d, 6H, CH3), 2.1 (q, 1H), 2.2-2.3 (m, 2H, CH-P), 2.6 (dd, JHP = 9.0 Hz, JHH = 3.0 Hz). 13C NMR (CDCl3) δ: 11.2 (d, JCP = 28.9 Hz, CH2), 16.9 (d, JCP = 12.6 Hz, CH3), 21.3 (d, JCP = 31.4 Hz, CH), 71.7 (d, JCP = 5.0 Hz, CtC-H), 76.2 (d, JCP = 12.6 Hz, CtC-H). 31P NMR

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(CDCl3) δ: 35.8. The 13C assignments were confirmed by DEPT. HRMS-ESI: (M þ H)þ 171.1495, C9H21BP calc mass 171.1474. General Procedure for the Preparation of Compounds of the General Form R2P(O)CH2COOR0 . To benzyl (or t-Bu) bromoacetate (15 mmol) was added the corresponding dialkyl chlorophosphine (10 mmol). After stirring the neat mixture for 10 min at rt, the mixture was kept for 3 days without stirring. A viscous mixture was obtained, which was dissolved in 10 mL of CHCl3. This solution was removed from the inert atmosphere and added dropwise to a stirred mixture of NaHCO3 (40 mmol). The organic layer was separated, and the aqueous phase was extracted with CHCl3 (2  10 mL). The combined organic layers were washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was separated by flash chromatography, EtOAc/MeOH (90:10), to give the title product in >90% yield. 6b: 1H NMR (CDCl3) δ: 1.05-1.46 (m, 10H, Cy), 1.511.90 (m, 12H, Cy), 2.83 (d, 14.7 Hz, 2H, P-CH2), 5.06 (s, 2H, CH2-C6H5), 7.23-7.33 (m, Ph). 13C NMR: 24.4 (d, JCP = 2.1 Hz, CH2), 24.8 (d, JCP = 2.6 Hz, CH2), 25.3, 25.8 (d, JCP = 2.6 Hz, CH2), 26.0 (d, JCP = 2.1 Hz, CH2), 31.6 (d, JCP = 47 Hz, P-CH2), 35.6 (d, JCP = 65 Hz, CH), 66.8 (CH2), 128.1, 128.2, 128.4, 134.7, 166.5. 31P NMR (CDCl3) δ: 60.0. HRMS-ESI: (M þ H)þ 363.2080, C21H32O3P calc mass 363.2089. 6a: 1H NMR (CDCl3) δ: 1.01 (d, 3H), 1.06 (d, 3H), 1.07 (d, 3H), 1.12 (d, 3H), 1.98 (m, 2H, CH), 2.83 (d, JHP = 14.7 Hz, 2H, P-CH2), 5.02 (s, 2H), 7.18-7.26 (m, 5H). 31P NMR (CDCl3) δ: 55.7. HRMS-ESI: (M þ H)þ 283.1447, C15H24O3P calc mass 283.1463. 6c: 1H NMR (CDCl3) δ: 1.26 (d, JHP = 14.1 Hz, 18H, C(CH3)3), 2.93 (d, JHP = 11.3 Hz, 2H, P-CH2), 5.15 (s, 2H), 7.25-7.40 (m, 5H). 13C NMR (CDCl3) δ: 26.3, 30.6 (d, JCP = 41 Hz, P-CH2), 36.4 (d, JCP = 60 Hz, P(O)Ct-Bu), 66.9, 127.9, 128.2, 135.2, 167.3. 31P NMR (CDCl3) δ: 56.8. HRMS-ESI: (M þ H)þ 311.1731, C17H28O3P calc mass 311.1776. 7b: 1H NMR (CDCl3) δ: 1.16-1.32 (m, 6H, Cy), 1.361.55 (m, 4H, Cy), 1.43 (s, 9H, t-Bu), 1.69 (m, 2H, Cy), 1.762.00 (m, 10H, Cy), 2.81 (d, JHP = 15.5 Hz, 2H, P-CH2). 13 C NMR (CDCl3) δ: 24.8 (d, JCP = 3.5 Hz, CH2), 25.2 (d, JCP = 3.2 Hz, CH2), 25.8 (d, JCP = 1.4 Hz, CH2), 26.3 (d, JCP = 3.5 Hz, CH2), 26.4 (d, JCP = 3.9 Hz, CH2), 27.9, 33.4 (d, JCP = 48 Hz, P-CH2), 36.0 (d, JCP = 65 Hz, CH), 81.9, 166.2. 31P NMR (CDCl3) δ: 50.6. HRMS-ESI: (M þ H)þ 329.2227, C18H34O3P calc mass 329.2246. 7a: 1H NMR (500 MHz, CDCl3) δ: 1.16 (d, J = 7.0 Hz, 3H), 1.19 (m, 6H, 2 Me), 1.22 (d, 7.2 Hz, 3H, Me), 1.39 (s, 9H, t-Bu), 2.10 (m, 2H), 2.80 (d, JHP = 15.2 Hz, 2H, P-CH2). 13 C NMR (CDCl3) δ: 15.0, 15.6, 25.9 (d, JCP = 64 Hz, CH), 27.7, 33.2 (d, JCP = 46 Hz, P-CH2), 81.9, 166.0. 31P NMR (CDCl3) δ: 53.2. HRMS-ESI: (M þ H)þ 249.1610, C12H26O3P calc mass 249.1620. General Procedure for the Reduction of Bn. Compound 6a (2.61 g, 9.2 mmol) was dissolved in absolute ethanol (25 mL) in a 100 mL Andrews Glass hydrogenator. This mixture was hydrogenated over 10% palladium charcoal (0.26 g) under 4.5 bar of H2. After 18 h, the reaction mixture was filtered and concentrated in vacuo to yield 8a (1.77 g, 100%) as white powder. 1 H NMR (CDCl3) δ: 0.96 (d, J = 7.2 Hz, 3H, Me), 0.98 (d, 3H, Me), 0.99 (d, 3H, Me), 1.02 (d, J = 7.2 Hz, 3H, Me), 2.05

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(m, 2H), 2.73 (d, JHP = 16.0 Hz, 2H, P-CH2), 11.8 (bs, H, CO2H). 13C NMR (CDCl3) δ: 14.3 (d, JCP = 2.8 Hz, 2Me), 14.9 (d, JCP = 2.8 Hz, 2Me), 24.8 (d, JCP = 65 Hz, CH), 30.8 (d, JCP = 51 Hz, P-CH2), 167.4. 31P NMR (CDCl3) δ: 62.3. HRMS-ESI: (M þ H)þ 193.0986, C8H18O3P calc mass 193.0994. 8b: 1H NMR (CDCl3) δ: 1.07-1.47 (m, 10H, Cy), 1.582.02 (m, 12H, Cy), 2.87 (d, JHP = 15.6 Hz, 2H, P-CH2), 11.90 (bs, H, CO2H); 13C NMR (CDCl3) δ: 24.4 (d, JCP = 2.1 Hz, CH2), 24.9 (d, JCP = 2.6 Hz, CH2), 25.5 (CH2), 26.0 (d, JCP = 5.7 Hz, CH2), 26.2 (d, JCP = 6.0 Hz, CH2), 31.2 (d, JCP = 50 Hz, P-CH2), 35.1 (d, JCP = 65 Hz, CH), 168.0. 31 P NMR (CDCl3) δ: 56.1. HRMS-ESI: (M þ H)þ 273.1608, C14H26O3P calc mass 273.1620. 8c: 1H NMR (CDCl3) δ: 1.14 (d, JHP = 14.3 Hz, 18H), 2.71 (d, JHP = 10.0 Hz, P-CH2), 12.0 (bs, 1H, COOH). 13 C NMR (CDCl3) δ: 25.7, 28.2 (d, JCP = 45 Hz, P-CH2), 35.9 (d, JCP = 59 Hz, P(O)Ct-Bu), 167.7. 31P NMR (CDCl3) δ: 61.6 HRMS-ESI: (M þ H)þ 221.1292, C10H22O3P calc mass 221.1307. General Procedure for Bromodecarboxylation. 9a: Mercuric oxide (1.30 g, 6.0 mmol), MgSO4 (1.46 g, 12 mmol), and i-Pr2P(O)CH2COOH (1.15 g, 6 mmol) were combined in anhydrous CH2Cl2 (15 mL) without exclusion of air. A solution of Br2 (1.92 g, 12 mmol) in CH2Cl2 (15 mL) was added dropwise to the stirred mixture. After 18 h at rt, saturated NaHSO3 (0.5 mL in H2O) was added to the stirred mixture, and the organic solvent was decanted. The solids were triturated with CH2Cl2 (25 mL), and the combined organic layers were stirred with saturated NaHCO3 until evolution of CO2 ceased entirely. The phases were separated, and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was separated by flash chromatography on activated alumina, EtOAc/MeOH (90:10), to give 9a (368 mg, 27%) as a colorless oil. 1H NMR (CDCl3) δ: 1.21 (d, J = 7.2 Hz, 3H, Me), 1.22 (d, J = 7.2 Hz, 3H, Me), 1.26 (d, J = 7.3 Hz, 3H, Me), 1.27 (d, J = 7.2 Hz, 3H, Me), 2.30 (m, J = 2H, CH), 3.36 (d, JHP = 7.3 Hz, 2H, P-CH2). 13C NMR (CDCl3) δ: 15.3 (d, JCP = 2.8 Hz, Me), 16.0 (d, JCP = 3.2 Hz, Me), 16.5 (d, JCP = 56 Hz, P-CH2), 24.4 (d, JCP = 66 Hz, CH). 31P NMR (CDCl3) δ: 55.1. HRMS-ESI: (M þ H)þ 227.0189, C7H17OPBr calc mass 227.0200. 9b: 1H NMR (CDCl3) δ: 1.06-2.00 (m, 22H, Cy), 3.19 (d, JHP = 7.0 Hz, 2H, P-CH2); 13C NMR (CDCl3) δ: 16.8 (d, JCP = 54 Hz, P-CH2), 24.9 (d, 3.2 Hz, CH2), 25.3 (d, JCP = 3.7 Hz, CH2), 25.5 (dt, JCP = 1.1 Hz, CH2), 26.0 (CH2), 26.1 (CH2), 26.3 (CH2), 34.4 (d, JCP = 66 Hz, CH). 31P NMR (CDCl3) δ: 49.2. HRMS-ESI: (M þ H)þ 307.0792, C13H25BrOP calc mass 307.0826. 9c: 1H NMR (CDCl3) δ: 1.31 (d, JHP = 13.6 Hz, 18H), 3.36 (d, JHP = 5.5 Hz, 2H, P-CH2). 13C NMR (CDCl3) δ: 16.8 (d, JCP = 46 Hz, P-CH2), 26.9 (Me), 36.4 (d, JCP = 59 Hz, P-Ct-Bu). 31P NMR (CDCl3) δ: 52.3. HRMS-ESI: (M þ H)þ 255.0499, C9H21BrOP calc mass 255.0513. General Procedure for Preparation of Azido Species. 10a: To a solution of 9a (570 mg, 2.5 mmol) in DMSO (6 mL) was added NaN3 (330 mg, 5 mmol). The reaction mixture was heated to 90 °C under argon. After 8 h, the mixture was cooled, treated with water (12 mL), and extracted with CHCl3 (3  6 mL). The combined extracts were washed with water, dried with Na2SO4, filtered, and concentrated in vacuo to give 10a (470 mg, 100% yield), which was used without further purification. 1H NMR (CDCl3) δ: 1.15 (d,

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J = 7.2 Hz, 3H, Me), 1.19 (d, J = 7.2 Hz, 3H, Me), 1.20 (d, J = 7.2 Hz, 3H, Me), 1.24 (d, J = 7.3 Hz, 3H, Me), 2.08 (m, 2H, CH), 3.59 (d, JHP = 7.9 Hz, 2H, P-CH2). 13C NMR (CDCl3) δ: 15.1 (d, JCP = 3.2 Hz, 2Me), 15.6 (d, JCP = 2.6 Hz, 2Me), 24.5 (d, JCP = 64 Hz, CH), 43.9 (d, JCP = 65 Hz, P-CH2). 31P NMR (CDCl3) δ: 56.1. HRMS-ESI: (M þ H)þ 190.1078, C7H17N3OP calc mass 190.1109. 10b: 1H NMR (CDCl3) δ: 1.07-1.42 (m, 10H, Cy), 1.561.90 (m, 12H, Cy), 3.47 (d, JHP = 7.7 Hz, 2H, P-CH2); 13 C NMR (CDCl3) δ: 24.6 (d, JCP = 3.5 Hz, CH2), 25.1 (d, JCP = 2.8 Hz, CH2), 25.5 (d, JCP = 1.1 Hz, CH2), 26.0 (d, JCP = 4.6 Hz, CH2), 26.2 (d, JCP = 4.6 Hz, CH2), 34.4 (d, JCP = 64 Hz, CH), 43.7 (d, JCP = 64 Hz, P-CH2). 31P NMR (CDCl3) δ: 51.1. HRMS-ESI: (M þ H)þ 270.1733, C13H25N3OP calc mass 270.1735. 10c: 1H NMR (CDCl3) δ: 1.28 (d, JHP = 13.8 Hz, 18H), 3.63 (d, JHP = 6.2 Hz, 2H, P-CH2). 13C NMR (CDCl3) δ: 26.5 (Me), 35.5 (d, JCP = 59 Hz, P-Ct-Bu), 43.9 (d, JCP = 59 Hz, P-CH2). 31P NMR (CDCl3) δ: 55.7. HRMS-ESI: (M þ H)þ 218.1405, C9H21N3OP calc mass 218.1422. General Procedure for Preparation of Brominated Esters 11. 11a: A solution of 50% aqueous NaOH (2.40 g) mixed with water (2.4 mL) was cooled to 0-5 °C in a water/ice bath. Br2 (2.16 g, 13.5 mmol) was added dropwise to the stirred solution at a rate that maintained the reaction mixture below 10 °C. A solution of i-Pr2P(O)CH2COOBut (0.67 g, 1.75 mmol) in 1,4-dioxane (4.5 mL) was added dropwise to the stirred solution while maintaining the reaction temperature below 10 °C. After stirring for 30 min, the reaction mixture was extracted with Et2O (4  5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford i-Pr2P(O)CBr2COOt-Bu (1.10 g, 95%) as a colorless viscous oil. The dibromide was used in the following step without further purification. To a solution of i-Pr2P(O)CBr2COOt-Bu (0.71 g, 2.17 mmol) in MeOH (4 mL) at 0 °C was added a cooled solution of tin(II) chloride dihydrate (0.39 g, 1.73 mmol) and AcOH (0.21 g) in MeOH (4 mL). After stirring for 30 min at 0-5 °C, the reaction mixture was diluted with water (16 mL) and extracted with CHCl3 (3  10 mL). The combined extracts were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo at 50 °C. The crude mixture was separated by flash chromatography, EtOAc/MeOH (90:10), to give 11a (0.42 g, 63%) as a colorless oil. 1H NMR (CDCl3) δ: 0.97-1.10 (m, 12H, Me), 1.24 (s, 9H, t-Bu), 2.24 (m, 2H, CHi-Pr), 4.21 (d, JHP = 10.0 Hz, H, P-CHBr). 13C NMR (CDCl3) δ: 15.4 (d, JCP = 2.8 Hz, Me), 15.8 (d, JCP = 3.5 Hz, Me), 15.9 (d, JCP = 3.5 Hz, Me), 16.2 (d, JCP = 2.8 Hz, Me), 24.9 (d, JCP = 65 Hz, CHi-Pr), 25.0 (d, JCP = 65 Hz, CHi-Pr), 27.2 (Met-Bu), 38.3 (d, JCP = 39 Hz, P-CHBr), 83.7 (Ct-Bu), 164.2. 31P NMR (CDCl3) δ: 54.5. HRMS-ESI (M þ H)þ 327.0724, C12H25O3PBr calc mass 327.0725. 11b: 1H NMR (CDCl3) δ: 1.07-1.24 (m, 6H, Cy), 1.321.47 (m, 4H, Cy), 1.38 (s, 9H, t-Bu), 1.61 (m, 2H, Cy), 1.662.24 (m, 10H, Cy), 4.33 (d, JHP = 9.4 Hz, 1H, P-CHBr). 13 C NMR (CDCl3) δ: 25.9 (CH2), 27.5 (Me), 35.4 (d, JCP = 64.3 Hz, CHCy), 35.5 (d, JCP = 64.3 Hz, CHCy), 38.8 (d, JCP = 37.8 Hz, P-CHBr), 83.9 (Ct-Bu), 164.6. 31P NMR (CDCl3) δ: 49.4. HRMS-ESI: (M þ H)þ 407.1358, C18H33BrO3P calc mass 407.1351. General Procedure for Removal of t-Bu Protection. 12a: To a solution of 11a (0.40 g, 1.22 mmol) in CHCl3 (1.2 mL) was added dropwise CF3COOH (1.2 mL, 16.2 mmol), and the mixture was stirred at rt for 16 h. The mixture was

Schuster et al.

concentrated in vacuo to afford crude 12a (0.33 g, 100%). This material was used in the following step without further purification. 1H NMR (CDCl3) δ: 1.18-1.29 (m, 12H, Me), 2.56 (m, 2H, 2CHi-Pr), 4.71 (d, JHP = 11.1 Hz, 1H, P-CHBr), 12.9 (s, 1H, CO2H). 13C NMR (CDCl3) δ: 15.5 (d, JCP = 2.5 Hz, Me), 15.8 (d, JCP = 3.5 Hz, Me), 15.9 (d, JCP = 3.2 Hz, Me), 16.0 (d, JCP = 2.8 Hz, Me), 25.1 (d, JCP = 63 Hz, CHi-Pr), 25.3 (d, JCP = 64 Hz, CHi-Pr), 37.1 (d, JCP = 42 Hz, P-CHBr), 166.3. 31P NMR (CDCl3) δ: 60.6. HRMS-ESI: (M þ H)þ 271.0091, C8H17O3PBr calc mass 271.0099. 12b: 1H NMR (CDCl3) δ: 1.17-2.03 (m, 2H, Cy), 2.212.45 (m, 2H), 4.71 (d, JHP = 11.1 Hz, 1H, P-CHBr-). 13 C NMR (CDCl3) δ: 25.3-25.7, 26.0-26.4, 34.9 (d, JCP = 63.0 Hz, CHCy), 35.2 (d, JCP = 63.0 Hz, CHCy), 36.7 (d, JCP = 41.9 Hz, P-CHBr), 166.1. 31P NMR (CDCl3) δ: 57. HRMS-ESI: (M þ H)þ 351.0717, C14H25BrO3P calc mass 351.0725. General Procedure for Decarboxylation of Compounds 12a, b to Give Compounds 9a,b. Acid 12a (0.33 g, 1.22 mmol) was charged in a 25 mL round-bottom flask equipped with a magnetic stirrer and condenser. The flask was heated to 160-165 °C for 30 min under vacuum (6 mmHg). The crude residue was separated by flash chromatography, EtOAc/ MeOH (90:10), to give 9a (0.19 g, 69%) as a colorless oil. General Procedure for Preparation of Pincer Click Ligands in Their Protected Form. 17P: To the propargyl precursor 5a (315 mg, 1.85 mmol) in 3 mL of THF was added azide precursor 10a (350 mg, 1.85 mmol). In a separate vessel, CuSO4 3 5H2O (230 mg, 0.925 mmol) was dissolved in 3 mL of distilled water. Upon addition of sodium ascorbate (916 mg, 4.62 mmol) to the aqueous mixture, the resulting dark brown mixture was quickly added to the reaction. The reaction mixture was stirred at room temperature for 48 h under nitrogen. The aqueous phase was extracted with CH2Cl2 (3  10 mL), and the combined organic layers were washed with water (20 mL) and brine (20 mL). The organic phase was dried with anhydrous Na2SO4. The crude mixture was separated by flash chromatography, CH2Cl2/MeOH (90:10), to give the protected form of ligand 17 (495 mg, 76%) as a white solid. 1H NMR (CDCl3) δ: 1.11-1.23 (m, 24H, CH3), 2.01-2.10 (m, 4H, CH), 3.13 (d, JHP = 10.2 Hz, 2H, P-CH2-C), 4.77 (d, JHP = 6.3 Hz, 2H, P-CH2-N), 7.84 (s, 1H, triazole-H). 13C NMR (CDCl3) δ: 15.3 (d, JCP = 22.5 Hz), 16.9, 17.9 (d, JCP = 30 Hz), 21.7 (d, JCP = 37.5 Hz), 25.1 (d, JCP= 67.5 Hz), 44.6 (d, JCP = 60 Hz), 124.6, 147. 31 P NMR (CDCl3) δ: 35.6 (d, 1P), 53.8 (s, 1P). HRMSESI: (M þ H)þ 360.2492, C16H37BN3OP2 calc mass 360.2505. 15P: 1H NMR (CDCl3) δ: 1.04-1.19 (m, 22H), 1.61-1.79 (m, 14H), 1.94-2.06 (m, 2H, CHiPr), 3.03 (d, JHP= 10.5 Hz, P-CH2-C), 4.71 (d, JHP = 6.3 Hz, P-CH2-N), 7.74 (s, 1H, triazole-H). 13C NMR (CDCl3) δ: 15.3 (d, JCP = 22.5 Hz), 17.7 (d, JCP = 30 Hz, CH2), 24.6, 25.4, 25.8, 26.4 (CH2), 26.6 (CH2), 26.7 (CH2), 31.4 (d, JCP = 30.8 Hz), 44.6 (d, JCP = 60 Hz, CH2, 124.5, 140.8. 31P NMR (CDCl3) δ: 27.6 (m, 1P), 53.9 (s, 1P). The 13C assignments were confirmed by DEPT. HRMS-ESI: (M þ H)þ 440.3105, C22H45BN3OP2 calc mass 440.3131. 16P: 1H NMR (200 MHz, CDCl3) δ: 1.44-1.58 (m, 12H), 2.20-2.39 (m, 2H), 3.76 (d, JHP = 11.4 Hz, CH2-P), 5.44 (s, 2H, CH2-S), 7.58-7.81 (m, 5H), 8.46 (s, 1H, triazole-H). 13 C NMR (CDCl3) δ: 16.1 (d, JCP = 30 Hz, CH2-P), 16.7 (d, JCP = 7.5 Hz), 22.4 (d, JCP = 30 Hz), 55.2 (CH2-S), 125.3, 129.1, 131.1, 132.4, 139.4. 31P NMR (CDCl3) δ: 38.6 (br m).

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14P: 1H NMR (CDCl3) δ: 0.2-0.7 (br m, 3H, BH3), 1.171.24 (m, 10H), 1.68-1.83 (m, 12H), 3.08 (d, JHP= 6.6 Hz, 2H, P-CH2), 5.59 (s, 2H, S-CH2), 7.65 (s, 1H, triazole-H). 13 C NMR (CDCl3) δ: 17.9 (d, JCP= 15 Hz, CH2-P), 25.8, 26.4, 26.5, 26.6, 26.7, 26.8, 31.4 (d, JCP = 11.3 Hz, CH-P), 53.8 (CH2-S), 122.4, 128.6, 129.4, 131.6, 132.2, 140.6. 31 P NMR (CDCl3) δ: 24.5 (d). The 13C assignments were confirmed by DEPT. General Procedure for Removal of Phosphine Protecting Groups. 21,22 Protected ligand 17P (285 mg, 0.79 mmol) was dissolved in 2 mL of CH2Cl2 and 5 mL of toluene. To this solution was added phenylsilane (1.47 mL, 11.9 mmol), and the reaction mixture was heated to 90 °C in a closed vessel. After 18 h, borane-dimethylsulfide complex was added, and the mixture was concentrated in vacuo. The crude mixture was separated by flash chromatography, 100:0 to 80:20 hexane/EtOAc, to afford 167 mg of the borane-protected ligand as a white powder. This was redissolved in MeOH (2 mL) and dioxane (6 mL) and was heated to 90 °C in a closed vessel over powdered 4 A˚ molecular sieves. After 18 h the reaction mixture was cooled, decanted, and evaporated to give 150 mg (60%) of the title compound as a clear oil. 1 H NMR (CD3OD) δ: 0.96-1.05 (m, 24H), 1.68-1.78 (m, 2H), 1.79-1.84 (m, 2H), 2.78 (s, 2H), 4.60 (d, JHP = 6.9 Hz, 2H), 7.69 (s, 1H, triazole-H). 13C NMR (CD3OD) δ: 19.1, 19.2, 19.3, 19.4 (CH2), 19.8, 20.0, 20.3, 23.9 (d, JCP = 13.2 Hz), 24.6 (d, JCP = 13.2 Hz), 46.3 (d, JCP = 25.4 Hz, CH2), 123.9 (dd, JCP = 3.7, 5.8 Hz, triazole-H), 147.4 (d, JCP = 11.1 Hz). 31P NMR (CD3OD) δ: 5.79 (s, 1P). 6.57 (s, 1P). HRMS-ESI: (M þ H)þ 330.2240, C16H34N3P2 calc mass 330.2228. 15: 1H NMR (C6D6) δ: 0.73-0.83 (m, 6H), 1.26-1.85 (br m, 24H), 2.99 (s, 2H, P-CH2-C), 4.13 (d, JHP = 3.6 Hz, PCH2-N), 7.45 (s, 1H, triazole-H). 13C NMR (C6D6) δ: 18.6 (d, JCP = 10.3 Hz), 19.0 (d, JCP = 20.4 Hz), 19.4 (d, JCP = 15.5 Hz), 22.8 (d, JCP = 14.0 Hz), 27.5 (d, JCP = 4.0 Hz), 27.6 (d, JCP = 7.0 Hz), 29.4 (d, JCP = 9.0 Hz), 30.3 (d, JCP = 14.0 Hz),

33.9 (d, JCP= 15.4 Hz), 44.9 (d, JCP = 25.7 Hz). 31P NMR (C6D6) δ: 0.06 (s, 1P), 8.72 (s, 1P). HRMS-ESI: (M þ H)þ 410.2880, C22H42N3P2 calc mass 410.2854. 16: 1H NMR (C6D6) δ: 1.03-1.19 (m, 12H), 1.73-1.81 (m, 2H, CH), 2.95 (s, 2H, S-CH2), 5.08 (d, JHP = 4.5 Hz, 2H, PCH2), 7.06-7.08 (m, 2H), 7.32-7.35 (m, 3H). 13C NMR (C6D6) δ: 19.0, 19.1, 19.3 (CH2), 19.9 (d, JCP = 15.4 Hz), 23.7 (d, JCP = 14.8 Hz), 52.7 (S-CH2), 120.7, 128.1, 129.4, 131.8. 31 P NMR (C6D6) δ: 5.2. 14: 1H NMR (C6D6) δ: 1.26-1.35 (m, 10H), 1.62-1.90 (m, 12H), 2.96 (s, 2H, CH2-P), 4.96 (s, 2H, CH2-S), 6.97-7.00 (m, 2H), 7.26-7.28 (m, 4H). 13C NMR (C6D6) δ: 26.7, 27.5 (d, JCP = 7.5 Hz), 29.3 (d, JCP = 7.5 Hz), 30.3 (d, JCP = 15 Hz), 33.9 (d, JCP = 30 Hz), 52.7, 129.4, 131.7. 31P NMR (C6D6) δ: -0.25. Preparation of Complex 18. Ligand 17 (18.5 mg, 0.056 mmol), (TMEDA)PdCl2 (16.3 mg, 0.056 mmol), and triethylamine (80 μL, 0.56 mmol) were combined in 1 mL of DMF. The resulting solution was heated at 70 °C for 12 h. 31P{1H} NMR showed quantitative formation of 18 as a single product. The solvent was evaporated, and the residue was washed with ether (3  3 mL) and extracted with toluene and THF (3  3 mL). The combined fractions were evaporated, resulting in pure complex 18 (20 mg, 77%). 1H NMR (CDCl3) δ: 1.151.45 (m, 24H), 2.45-2.56 (m, 4H, CH), 2.90 (d, JHP = 8.7 Hz), 4.53 (d, JHP = 5.4 Hz). 13C NMR (DMF-d7) δ: 19.5 (dd, JCP = 2.1, 4.7 Hz), 19.8 (dd, JCP = 5.0, 12.0 Hz), 20.8 (d, JCP= 27.4 Hz), 25.9 (dd, JCP = 4.3, 17.5 Hz), 26.4 (dd, JCP = 4.3, 16.9 Hz), 45.8 (d, JCP = 29.8 Hz), 164.2 (C-ipso). 31P NMR (CDCl3) δ: 56.2 (d, JPP = 413 Hz, 1P), 65.7 (d, JPP = 413 Hz, 1P). MS-ESI: m/z = 471.2 (M þ 1). Anal. Calc: C, 40.86; H, 6.86. Found: C, 40.16; H, 6.27.

(21) For phosphine oxide reduction with phenylsilane, see: Obora, Y.; Liu, Y. K.; Tokunaga, M.; Tsuji, Y. Eur. J. Inorg. Chem. 2006, 1, 222. (22) For BH3 deprotection with methanol, see: Schroder, M.; Nozaki, K.; Hiyama, T. Bull. Chem. Soc. Jpn. 2004, 77, 1931.

Supporting Information Available: Crystallographic data of compound 18 are available free of charge via the Internet at http://pubs.acs.org.

Acknowledgment. Financial support from Israel Science Foundation (Grant No. 2152-1676.5/2006) is acknowledged. E.M.S. is a recipient of the Schulich Graduate Fellowship.