Last modified on 9 February 2012, at 19:02

Transition-metal-catalyzed alpha-arylation of enolates

Transition-metal-catalyzed α-arylation of enolates is the cross-coupling of a nucleophilic enolate and electrophilic aryl halide in the presence of a palladium or nickel catalyst. Products of this reaction contain one or more new carbon-carbon bonds at the α-carbon(s) of a carbonyl compound.[1]

Introduction

Like other nucleophiles, enolates do not react with unactivated sp2-hybridized electrophiles in the absence of a transition-metal catalyst. However, palladium, nickel, and other metals are able to catalyze a cross-coupling process that results in nucleophilic aromatic substitution of aryl halides and pseudohalides by enolates. This valuable transformation establishes one or more new C(sp2)-C(sp3) bonds. Enolates may be generated in situ in the presence of base, or pre-formed enolates may be used without a need for base during the cross-coupling reaction (Eq. 1).

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Mechanistic studies suggest that this reaction proceeds through a classical cross-coupling mechanism involving oxidative addition, transmetalation, and reductive elimination.[2] Recent work on this reaction has led to the development of enantioselective variants employing chiral ligands; however, the origins of asymmetric induction in these processes remain unclear.[3] Because of the wide prevalence of α-aryl carbonyl compounds in natural products and pharmaceuticals, this reaction has been extensively applied for chemical synthesis. It represents a complementary approach to Suzuki cross-coupling reactions employing α-halo carbonyl compounds and aryl boronic acids.[4]

Mechanism and Stereochemistry

Prevailing Mechanism

Studies of the palladium-catalyzed arylation of enolates suggest that the mechanism most likely involves oxidative addition of the aryl halide, transmetalation of the enolate to palladium, and reductive elimination.[2] These steps are consistent with the classical mechanism of palladium-catalyzed cross-coupling processes (Eq. 2). Electronic and steric effects on the α-arylation reaction are similar to those of other cross-coupling reactions. For instance, increasing electron density at the metal center through the use of electron-rich ligands accelerates reductive elimination.[5]

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AAryl-Mech.png

Still, a number of specific issues arise when enolates are used as nucleophiles. Following the transmetalation step, the resulting palladium(II) enolate may exist as an η3 π-complex or as C- or O-bound σ-complexes. Generally, early transition metals favor the O-bound enolate, while softer late transition metals favor the C-bound form. Palladium typically favors the C-bound form, except for sterically hindered α,α'-disubstituted ketones and complexes in which the carbonyl oxygen is located trans to the aryl group. The relative stability of tautomeric palladium enolates depends most prominently on the substitution of the α-carbon. This evidence suggests, at least for unhindered enolates, that reductive elimination takes place through a concerted, three-center pathway. Studies have ruled out the most likely alternatives to this mechanism, including isomerization to an enol followed by C(sp2)-C(sp2) reductive elimination and migratory insertion of a carbon-carbon double bond in the O-bound enolate (Eq. 3).

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Either one or two phosphine ligands may be bound throughout the catalytic cycle. The use of bulky, monodentate phosphine ligands has facilitated reactions of aryl chlorides, which readily add to 12-electron [PdL] complexes containing only one bound ligand.[6]

Enantioselective Variants

Stereoselective α-arylation reactions run under basic conditions are limited to the formation of quaternary centers because the α-arylated products are typically more acidic than the starting materials and readily epimerize in the presence of base. Early examples of enantioselective α-arylation reactions involving palladium and bidentate BINAP ligands established quaternary centers with moderate enantiomeric excess.[7] The use of electron-rich, monodentate phosphines resulted in slightly higher enantioselectivities than BINAP-based methods (Eq. 4). Interestingly, the senses of stereoselectivity of reactions employing mono- and bidentate phosphines are opposite one another.[8]

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AAryl-Stereo-1.png

The use of nickel(0) instead of palladium results in a substantial increase in enantioselectivity (Eq. 5). This observation has been attributed to the more intimate chiral environment surrounding the smaller nickel center. Zinc bromide serves as a Lewis acid and removes a halide from the metal center to facilitate transmetalation.[9]

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AAryl-Stereo-2.png

Scope and Limitations

Hartwig has developed general conditions for the α-arylation of monoarylated ketones (Eq. 6).[10] These conditions work for a variety of alkyl aryl ketones, and are a good starting point for arylations of unexplored substrates.

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A judicious choice of reaction conditions can lead to multiple arylation events in a single pot. In the example in Eq. 7, three arylations take place: one α-arylation and two C-H activation processes.[11]

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Reaction of nonequivalent, enolizable α-carbons is a problem that limits the scope of α-arylations of ketones. The use of amides and esters as substrates avoids this problem; however, the high pKas of amides and esters present their own difficulties. Strong bases are needed to form these enolates, and base-sensitive functional groups are not tolerated. A recent solution involves pre-formation of less basic zinc enolates (Eq. 8).[12]

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Amino acid derivatives, such as imino esters, can be arylated in the presence of weak base (Eq. 9). It has been suggested that the nitrogen atom coordinates to palladium, facilitating transfer of the enolate to the metal center.[13]

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AAryl-Scope-4.png

A variety of other compounds containing C–H bonds acidified by an adjacent electron-withdrawing group can be arylated under cross-coupling conditions. These include nitriles, activated methylene compounds, and unsaturated carbonyl compounds. Nitriles are less acidic than ketones, and linear nitriles are subject to diarylation because the monoaryl products are more acidic than the starting materials. In this context, α-silyl nitriles have been used in the presence of a fluoride source for monoarylation with success (Eq. 10).[14]

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Activated methylene compounds require only mild bases in order to undergo α-arylation. Steric hindrance prevents reaction of tertiary malonates; however, a two-step arylation-alkylation sequence affords quaternary malonates (Eq. 11).[15]

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α,β-Unsaturated carbonyl compounds containing protons in the γ-position exclusively give products of γ-arylation, even when α-arylation at the other α-carbon is possible (Eq. 12). In addition, Heck reactions of the carbon-carbon double bond and alkene isomerization via β-hydride elimination do not compete with γ-arylation.[16]

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AAryl-Scope-7.png

Synthetic Applications

α-Arylation is useful for the preparation of a variety of carbon skeletons commonly found in natural products, including benzofurans,[17] benzothiophenes,[18] and isochromenes.[19] In some cases, it can serve as a key step in the establishment of a complex ring system. For instance, the skeleton of N-methylwelwitindoline has been synthesized through intramolecular α-arylation of a cyclic β-keto ester derivative (Eq. 13).[20]

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AAryl-Synth-2.png

The reaction has also been applied for the synthesis of pharmaceutical compounds. Trileptal is a drug commonly prescribed for the treatment of epilepsy, and is synthesized by a sequence involving α-arylation and Buchwald-Hartwig amination (Eq. 14).[21]

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AAryl-Synth.png

Comparison to Other Methods

The α-arylation of enolates employs carbonyl compounds as nucleophiles and aryl halides and pseudohalides as electrophiles. A related method involving Suzuki cross-coupling conditions employs aryl boronic acids as nucleophiles and α-halo carbonyl compounds as electrophiles (Eq. 14).[4] A limitation of this method is the need for extra synthetic steps to prepare the α-halo carbonyl compounds.

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Copper-mediated α-arylation of carbonyl compounds is an old, well-studied method, but requires stoichiometric quantities of the metal. One recent example has employed hydrazones as nucleophiles (Eq. 15).[22]

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Electrophilic chromium arene complexes may be employed in nucleophilic aromatic substitution reactions with copper enolates (Eq. 16).[23] As the chromium remains ligated to the arene after substitution, a stoichiometric amount of chromium is required and an additional step is necessary to remove chromium.

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Experimental Conditions and Procedure

Typical Conditions

α-Arylation of carbonyl compounds is typically an operationally straightfoward method. Reactions can be carried out using standard Schlenk techniques and anhydrous solvents. The most common catalysts used are Pd2dba3 and Pd(OAc)2. Sodium tert-butoxide and tri(tert-butyl)phosphine are commonly used as base and ligand (respectively) in arylations of ketones; for esters and amides, the stronger bases sodium hexamethyldisilazide (NaHMDS) and lithium dicyclohexylamide (LiNCy2) are often used.

Example Procedure[24]

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AAryl-Ex.png

Cesium carbonate (4.570 g, 14.00 mmol) was added to a flask charged with Pd2(dba)3 (0.030 g, 0.033 mmol) and Xantphos (L) (0.040 g, 0.080 mmol) under nitrogen. The reagents were suspended in anhydrous dioxane (6.4 mL), 1-bromo-2-iodobenzene (1.80 g, 6.37 mmol, 0.82 mL) and cyclohexanone (1.25 g, 12.74 mmol, 1.3 mL) were added under nitrogen, and the reaction mixture was heated at 80 °C for 24 h. After cooling, the reaction mixture was diluted with Et2O (ca. 10 mL), filtered through Celite, and the solvents removed in vacuo. The residue was purified by flash column chromatography (5–10% Et2O/petroleum ether) to give 1.26 g (78% yield) of the product shown: mp 57–58 °C (MeOH); IR (Nujol) 2920, 2855, 1709, 1566 (w), 1462, 1377, 1281, 1196, 1121, 1070, 1027, 977, 940, 769, 746, 722, 674 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.56 (td, J = 7.9, 1.5 Hz, 1H, Ar–H), 7.31 (td, J = 7.9, 1.1 Hz, 1H, Ar–H), 7.21 (dd, J = 7.9, 1.9 Hz, 1H, Ar–H), 7.12 (ddd, J = 7.9, 7.2, 1.9 Hz, 1H, Ar–H), 4.11 (app. dd, J = 12.4, 5.3 Hz, 1H, Ar–CH), 2.89–2.51 (m, 2H, CH2CO), 2.35–2.15 (m, 2H, ArCHCH2), 2.10–1.71 (m, 4H, CH2); 13C NMR (75 MHz, CDCl3) δ 208.3, 137.8, 132.1, 128.9, 127.8, 126.8, 124.6, 56.0, 41.8, 33.6, 27.1, 25.1; LRMS (CI+, NH3) m/z: [M + NH4]+ 270, [M + H:79Br]+ 253, [M – 79Br]+ 173, [M – 79Br–CO]+ 145, [M – 79Br–CO–C2H4]+ 115; HRMS (ES+): [M + H]+ calcd. for C12H14BrO, 253.0223; found, 253.0225.

References

  1. Prim, D.; Marque, S.; Gaucher, A.; Campagne, J.-M. Org. React. 2012, 76, 49. doi: (10.1002/0471264180.or076.02)
  2. a b Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.
  3. Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082.
  4. a b Goossen, L. J. Chem. Commun. 2001, 669.
  5. Galardon, E.; Ramdeehul, S.; Brown, J. M.; Cowley, A.; Hii, K. K.; Jutand, A. Angew. Chem., Int. Ed. 2002, 41, 1760.
  6. Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44, 366.
  7. Ahman, J.; Wolfe, J. F.; Troutman, M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918.
  8. Hamada, T.; Buchwald, S. L. Org. Lett. 2002, 4, 999.
  9. Spielvogel, D. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 3500.
  10. Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473.
  11. Satoh, T.; Kametani, Y.; Terao, Y.; Miura, M.; Nomura, M. Tetrahedron Lett. 1999, 40, 5345.
  12. Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 4976.
  13. Lee, S.; Beare, N. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 8410.
  14. Wu, L.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15824.
  15. Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541.
  16. Terao, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 1998, 39, 6203.
  17. Willis, M. C.; Taylor, D.; Gillmore, A. T. Org. Lett. 2004, 6, 4755.
  18. Muratake, H.; Nakai, H. Tetrahedron Lett. 1999, 40, 2355.
  19. Sole, D.; Peidro, E.; Bonjoch, J. Org. Lett. 2000, 2, 2225.
  20. MacKay, J. A.; Bishop, R. L.; Rawal, V. H. Org. Lett. 2005, 7, 3421.
  21. Carril, M.; SanMartin, R.; Churruca, F.; Tellitu, I.; Dominguez, E. Org. Lett. 2005, 7, 4787.
  22. Setsune, J.-I.; Ueda, T.; Shikata, K.; Matsukawa, K. Tetrahedron 1986, 42, 2647.
  23. Mino, T.; Matsuda, T.; Maruhashi, K.; Yamashita, M. Organometallics 1997, 16, 3241.
  24. Willis, M. C.; Taylor, D.; Gillmore, A. T. Tetrahedron 2006, 62, 11513.