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Despite their clear utility, there are only a few reported methods to synthesize any variety of α-arylated phosphonoacetates. Primarily, these compounds are generated via the Michaelis-Arbuzov reaction (Scheme 2.1).67 _{This method is quite effective for}

generating α-alkyl phosphonoacetates, but has many limitations with regard to α-aryl phosphonoacetates. This reaction requires high temperatures and is often performed without solvent. There is limited tolerance for sterically hindered substrates, by nature of the SN2 character of the mechanism. This method is also limited by the availability of the

65 _{Gaukroger, K.; Hadfield, J. A.; Hepworth, L. A.; Lawrence, N. J.; McGown, A. T., Novel}

Syntheses of Cis and Trans Isomers of Combretastatin A-4. J. Org. Chem. 2001,66 (24), 8135-

8138.

66 _{(a) Astles, P. C.; Brown, T. J.; Halley, F.; Handscombe, C. M.; Harris, N. V.; McCarthy, C.;}

McLay, I. M.; Lockey, P.; Majid, T.; Porter, B.; Roach, A. G.; Smith, C.; Walsh, R., Selective Endothelin A Receptor Antagonists. 4. Discovery and Structure−Activity Relationships of Stilbene

Acid and Alcohol Derivatives. J. Med. Chem. 1998,41 (15), 2745-2753. (b) Ohsumi, K.;

Nakagawa, R.; Fukuda, Y.; Hatanaka, T.; Morinaga, Y.; Nihei, Y.; Ohishi, K.; Suga, Y.; Akiyama, Y.; Tsuji, T., Novel Combretastatin Analogues Effective Against Murine Solid Tumors:  Design

and Structure−Activity Relationships. J. Med. Chem. 1998,41 (16), 3022-3032.

67 _{(a) Bhattacharya, A. K.; Thyagarajan, G., Michaelis-Arbuzov Rearrangement. Chem. Rev.}

1981,81 (4), 415-430. (b) Demmer, C. S.; Krogsgaard-Larsen, N.; Bunch, L., Review on Modern

Advances of Chemical Methods for the Introduction of a Phosphonic Acid Group. Chem. Rev.

2011,111 (12), 7981-8006. (c) Rajeshwaran, G. G.; Nandakumar, M.; Sureshbabu, R.;

Mohanakrishnan, A. K., Lewis Acid-Mediated Michaelis−Arbuzov Reaction at Room Temperature:

A Facile Preparation of Arylmethyl/Heteroarylmethyl Phosphonates. Org. Lett. 2011,13 (6), 1270-

56

α-halo-α-aryl acetate starting materials and tolerance of electrophilic functional groups is particularly limited. This approach has been the primary route to elaborated cinnamic acids. The analogous Michaelis-Becker reaction, which uses the corresponding phosphonic acids, proceeds in poor yield, especially for sterically hindered tertiary phosphonoacetates.67a,b _{In addition, strong bases are required to deprotonate the}

phosphonic acids, which are incompatible with many desirable functional groups. The starting phosphonic acids are also not readily available, which further limits the utility of the method.

Scheme 2.1. Michaelis-Arbuzov Reaction to Form Tertiary α-Centers54

An alternative bond disconnection to this structural class utilizes an aryl halide and phosphonoacetate (Scheme 2.2). There is extensive literature precedent for the α- arylation of acidic substrates to form tertiary centers, using activating functional groups such as esters, ketones, nitro groups, and amides.23,28b,68 _{However, in the literature to}

date, only the α-arylation of phosphonoacetates using aryl iodides has been reported, and

68 _{Reviews of activated α-arylation: (a) Bellina, F.; Rossi, R., Transition Metal-Catalyzed Direct}

Arylation of Substrates with Activated sp3_{-Hybridized C−H Bonds and Some of Their Synthetic}

Equivalents with Aryl Halides and Pseudohalides. Chem. Rev. 2010,110 (2), 1082-1146. (b)

Lloyd-Jones, G. C., Palladium-Catalyzed α-Arylation of Esters: Ideal New Methodology for

the substrate scope was not thoroughly explored.69-72 _{Iodobenzene works well in this}

transformation, but aryl bromides do not couple effectively under the reaction conditions. Since fewer aryl iodides are available relative to the bromo and chloro arenes, we targeted this transformation for study. Notably, Walsh and co-workers recently published the α- arylation of benzyl phosphonates,73 _{but we have found that the addition of an acetate}

coordinating group greatly alters the optimal reaction conditions; such acidic substrates readily form stable chelated adducts with the metal catalyst which are not productive reaction intermediates.13a

Scheme 2.2. Copper-Catalyzed α-Arylation of Triethyl Phosphonoacetate54

2.2. Results

2.2.1. Mechanistic Analysis of the Proposed Reaction

We propose a mechanism for this transformation similar to those proposed for the

69 _{Buchwald, S. L.; Klapars, A.; Antilla, J.; Job, G. E.; Wolter, M.; Kwong, F. Y.; Nordmann, G.;}

Hennessy, E. J. Copper-Catalyzed Formation of Carbon-Heteroatom and Carbo-Carbon Bonds. WO 2002/085838 A1, April 24, 2002.

70 _{Minami, T.; Isonaka, T.; Okada, Y.; Ichikawa, J., Copper(I) Salt-Mediated Arylation of}

Phosphinyl-Stabilized Carbanions and Synthetic Application to Heterocyclic Compounds. J. Org.

Chem. 1993,58 (25), 7009-7015.

71 _{Rout, L.; Regati, S.; Zhao, C.-G., Synthesis of α-Arylphosphonates using Copper-Catalyzed α-}

Arylation and Deacylative α-Arylation of β-Ketophosphonates. Adv. Synth. Catal. 2011,353 (18),

3340-3346.

72 _{For an intramolecular cyclization to form oxindoles that was only successful with iodides and}

bromides (not chlorides), see Millemaggi, A.; Perry, A.; Whitwood, A. C.; Taylor, R. J. K., Telescoped Enolate Arylation/HWE Procedure for the Preparation of 3-Alkenyl Oxindoles: The

First Synthesis of Soulieotine. Eur. J. Org. Chem. 2009,2009 (18), 2947-2952.

73 _{Montel, S.; Raffier, L.; He, Y.; Walsh, P. J., Palladium-Catalyzed α-Arylation of Benzylic}

58

α-arylations of other enolic substrates. In this case however, the palladium can coordinate to the phosphonate or the ester, or both, as shown in Figure 2.3. The different coordination modes are shown in structures C, D, and E. As proposed by Culkin and Hartwig,21-23 _and

supported computationally by our group,27 _{reductive elimination likely occurs from the ƞ}1_-

C-bound structure (C), which is accessible only in the presence of bulky ligands on the transition metal. The increased stability of the chelated form D presents the key challenge to this method, and we propose that this causes the reductive elimination step to be comparatively slow. Thus, bulky phosphine ligands could be used to promote the desired reductive elimination.

Figure 2.3. Proposed Mechanism for the α-Arylation of Phosphonoacetates62