Design and Synthesis of a New Generation of ‘NH’-Ni(II) Complexes of Glycine Schiff Bases and their Unprecedented C-H vs. N-H Chemoselectivity in Alkyl Halide Alkylations and Michael Addition Reactions

Abstract

Within this manuscript the synthesis of a new generation of Ni(II) complexes that contain a secondary rather than a tertiary amino group, as well as the unusual chemoselectivity, was demonstrated in alkyl halide alkylations and Michael addition reactions. The complete C-H chemoselectivity observed in these reactions suggests that coordination of nitrogen to a metal has a significant synthetic potential as protecting a group without the need of introducing a transient N-C substituent. These new complexes have also proven highly synthetically useful nucleophilic glycine equivalents for the simple and highly diastereoselective synthesis of β-sub­stituted pyroglutamic acids via their reactions with chiral Michael acceptors.

amino acids - chemoselectivity - nickel - Schiff base - chiral auxiliary

References and Notes

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<A NAME="RS10805ST-9A">9a</A> Although Professor Hegedus does mention that the complexation of a secondary amino group to Ni(II) was not sufficient to create the desired chemoselectivity of O-H over N-H acylation, he does introduce the idea of using it as a form of protection. See: Hegedus LS. Greenberg MM. Wendling JJ. Bullock JP. J. Org. Chem.  2003,  68:  4179 

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<A NAME="RS10805ST-11">11</A>

Synthesis of the Ni(II) Complexes of Glycine Schiff Bases with N -(2-Benzoylphenyl)-2-(alkylamino)acetamides 9a-c; General Procedure. A solution of KOH (10 equiv) in MeOH (7 mL/1 g of KOH) was added to a suspension of N-(2-benzoylphenyl)-2-(alkylamino)acetamides 8a-c (1 equiv), glycine (5 equiv), nickel nitrate hexahydrate (2 equiv) in MeOH (10 mL/1 g of 8a-c) at 60-70 °C. Upon complete consumption of the N-(2-benzoylphenyl)-2-(alkylamino)acetamides 8a-c, monitored by TLC, the reaction mixture was poured over slurry of ice and 5% AcOH. After the complete precipitation, product 9a-c was filtered and dried in a low temperature oven (50 °C) overnight. The product was obtained in high chemical yield (99%) and high chemical purity without further purification.
Compound 9a: mp >300 °C (decomp.). ¹H NMR (299.95 MHz, CDCl₃): δ = 1.95 (1 H, br s), 3.45 (2 H, s), 3.86 (2 H, s), 7.01 (1 H, td, J = 7.65, 0.72 Hz), 7.13-7.29 (3 H, m), 7.30-7.60 (7 H, m), 7.62-7.78 (2 H, m), 8.64 (1 H, dd, J = 8.4, 0.3 Hz), 11.66 (1 H, br s). ¹³C NMR (75.42 MHz, CDCl₃): δ = 52.90, 54.10, 121.68, 122.32, 124.82, 125.55, 125.71, 127.30, 127.40, 128.32, 128.45, 128.48, 130.17, 132.62, 132.82, 133.66, 138.47, 139.12, 139.26, 171.19, 198.32. HRMS: m/z calcd for C₂₂H₂₀N₂NaO₂: 367.1417; found: 367.1103.
Compound 9b: mp 292.3 °C (decomp.). ¹H NMR (299.95 MHz, CDCl₃): δ = 1.56 (3 H, d, J = 6.3 Hz), 1.66 (3 H, d, J = 6.3 Hz), 2.76 (1 H, br s), 3.12 (1 H, dq, J = 13.2, 6.3 Hz), 3.29 (1 H, d, J = 17.7 Hz), 3.75 (2 H, s), 3.99 (1 H, dd, J = 17.7, 7.5 Hz), 6.83 (1 H, m), 6.93 (1 H, m), 7.01 (1 H, m), 7.19 (1 H, m), 7.35 (1 H, m), 7.53-7.59 (3 H, m), 8.55 (1 H, d, J = 7.8 Hz). ¹³C NMR (75.42 MHz, CDCl₃): δ = 20.57, 21.74, 51.70, 53.33, 60.60, 121.28, 128.34, 125.69, 125.82, 136.24, 129.45, 129.75, 129.88, 132.66, 133.60, 134.66, 142.62, 173.23, 177.88, 177.91, 178.18. HRMS: m/z calcd for C₂₀H₂₁N₃NaNiO₃: 432.0828; found: 432.0837.
Compound 9c: mp >300 °C (decomp.). ¹H NMR (299.95 MHz, CDCl₃): δ = 1.54 (9 H, s), 2.60 (1 H, d, J = 7.8 Hz), 3.41 (1 H, d, J = 17.1 Hz), 3.73 (2 H, d, J = 3.9 Hz), 4.17 (1 H, dd, J = 17.1, 7.5 Hz), 6.84 (1 H, m), 6.93 (1 H, dd, J = 8.1, 1.8 Hz), 6.99 (1 H, m), 7.23 (1 H, m), 7.38 (1 H, m), 7.53-7.60 (3 H, m), 8.37 (1 H, d, J = 7.5 Hz). ¹³C NMR (75.42 MHz, CDCl₃): δ = 28.02, 50.98, 58.25, 60.42, 121.33, 124.24, 125.71, 126.27, 129.41, 129.79, 129.90, 132.72, 133.50, 134.54, 142.38, 171.74, 177.36, 177.72. HRMS: m/z calcd for C₂₁H₂₃N₃NaNiO₃: 446.0985; found: 446.1015.
The Michael Addition of the Oxazolidinone Derived Amides of Cinnamic Acid and Nucleophilic Glycine Equivalents 9a-c; General Procedure. To a flask containing 9a, 9b, or 9c (0.10 g), 3-[(E)-3-alkyl-acryloyl]oxazolidin-2-one 20a,b (1.05 equiv) and 3 mL of DMF, DBU (15 mol%) was added to the reaction mixture, which was stirred at r.t. and monitored by TLC. After disappearance of starting glycine equivalent by TLC, the reaction mixture was poured into a beaker containing 100 mL ice water. After the ice had melted the corresponding product 21a,b, 22, 23, was filtered from the aqueous solution and dried in an oven to afford the corresponding product in high chemical yields.
Compound 23: mp 146.3 °C. ¹H NMR (299.95 MHz, CDCl₃): δ = 2.66-2.89 (4 H, m), 3.25-3.42 (3 H, m), 3.85 (1 H, dd, J = 16.2, 6.0 Hz), 4.18 (1 H, dd, J = 8.7, 3.9 Hz), 4.43 (1 H, d, J = 4.2 Hz), 4.60 (1 H, t, J = 8.7 Hz), 5.18 (1 H, dd, J = 8.7, 3.9 Hz), 6.71-6.84 (3 H, m), 6.97-7.01 (2 H, m), 7.05 (1 H, d, J = 6.9 Hz), 7.11-7.14 (2 H, m), 7.23-7.47 (10 H, m), 7.56-7.59 (2 H, m), 7.67-7.73 (3 H, m), 8.38 (1 H, d, J = 8.7 Hz). ¹³C NMR (75.42 MHz, CDCl₃): δ = 36.44, 45.18, 53.08, 54.69, 57.47, 69.75, 73.38, 121.04, 123.85, 125.72, 125.86, 126.88, 126.96, 127.24, 127.97, 128.28, 128.37, 128.74, 128.89, 129.14, 129.62, 129.79, 130.72, 132.57, 133.53, 133.61, 133.98, 138.72, 132.84, 139.24, 142.93, 169.89, 171.02, 175.94, 176.60, 177.47. HRMS: m/z calcd for C₄₂H₃₆N₄NaNiO₆: 773.1880; found: 773.1813.
Compound 22: mp 183.1 °C. ¹H NMR (299.95 MHz, CDCl₃): δ = 1.29 (3 H, d, J = 6.6 Hz), 1.37 (3 H, d, J = 6.6 Hz), 2.67 (1 H, s), 2.74 (1 H, h, J = 6.6 Hz), 2.86 (1 H, d, J = 16.5 Hz), 3.18-3.30 (2 H, m), 3.56 (1 H, dd, J = 18.6, 8.7 Hz), 3.72 (1 H, dd, J = 18.6, 8.7 Hz), 4.20 (1 H, dd, J = 8.7, 3.9 Hz), 4.49 (1 H, d, J = 4.5 Hz), 4.63 (1 H, t, J = 9.0 Hz), 5.18 (1 H, dd, J = 8.7, 3.9Hz), 6.74 (1 H, d, J = 2.7 Hz), 6.99-7.05 (3 H, m), 7.24 (1 h, d, J = 2.7 Hz), 7.27 (1 H, d, J = 2.7 Hz), 7.28-7.33 (5 H, m), 7.37 (1 H, t, J = 7.2 Hz), 7.47-7.52 (3 H, m), 7.56-7.62 (3 H, m), 8.40 (1 H, d, J = 9.3 Hz). ¹³C NMR (75.42 MHz, CDCl₃): δ = 20.22, 21.44, 29.30, 44.95, 52.75, 53.78, 57.47, 69.77, 73.29, 124.67, 125.66, 125.91, 127.27, 127.95, 128.31, 128.42, 128.49, 128.75, 128.88, 129.33, 129.42, 130.32, 130.80, 132.57, 132.70, 132.86, 138.82, 139.21, 141.57, 153.35, 169.80, 169.98, 176.94, 177.08. HRMS: m/z calcd for C₃₈H₃₆N₄NaNiO₆: 759.1501; found: 759.1584.
Compound 21b: mp 183.1 °C. ¹H NMR (299.95 MHz, CDCl₃): δ = 1.28 (9 H, s), 2.67 (1 H, s), 2.97 (1 H, d, J = 16.8 Hz), 3.20-3.37 (2 H, m), 3.51 (1 H, dd, J = 17.7, 8.4 Hz), 3.74 (1 H, dd, J = 17.7, 8.4 Hz), 4.17 (1 H, dd, J = 9, 3.9 Hz), 4.46 (1 H, d, J = 4.5 Hz), 4.61 (1 H, t, J = 8.7 Hz), 5.18 (1 H, dd, J = 8.7, 3.6 Hz), 6.79 (1 H, m), 6.98-7.03 (3 H, m), 7.26-7.38 (7 H, m), 7.43-7.49 (3 H, m), 7.54-7.63 (4 H, m), 8.23 (1 H, d, J = 8.4 Hz). ¹³C NMR (75.42 MHz, CDCl₃): δ = 27.78, 36.55, 44.93, 50.81, 57.45, 59.70, 69.72, 72.53, 120.89, 123.10, 125.81, 127.34, 127.63, 128.24, 128.32, 128.82, 128.87, 129.03, 129.18, 129.97, 130.62, 132.88, 133.62, 133.94, 138.83, 139.11, 142.79, 153.29, 169.99, 170.83, 176.36, 177.20. HRMS: m/z calcd for C₃₉H₃₉N₄NiO₆: 739.2037; found: 739.2078.
Compound 21a: mp 153.7 °C. ¹H NMR (299.95 MHz, CDCl₃): δ = 1.43 (9 H, s), 1.91 (3 H, s), 3.04 (1 H, dd, J = 18.3, 7.2 Hz), 3.24 (1 H, dd, J = 18.3, 7.2 Hz), 3.39 (1 H, d, J = 17.1 Hz), 4.16 (1 H, d, J = 4.5 Hz), 4.22 (1 H, dd, J = 9.0, 3.6 Hz), 4.39 (1 H, q, J = 17.1, 7.2 Hz), 4.61 (1 H, t, J = 8.7 Hz), 5.28 (1 H, dd, J = 8.7, 3.3 Hz), 6.78 (2 H, d, J = 4.8 Hz), 6.94 (1 H, d, J = 7.8 Hz), 7.25 (2 H, m), 7.30-7.47 (7 H, m), 7.53 (1 H, t, J = 7.8 Hz), 8.37 (1 H, d, J = 8.4 Hz). ¹³C NMR (75.42 MHz, CDCl₃): δ = 16.85, 27.97, 33.75, 38.94, 51.51, 57.50, 57.89, 69.93, 72.32, 120.98, 123.04, 126.09, 127.33, 127.81, 128.59, 128.83, 129.03, 129.09, 129.85, 132.88, 133.68, 134.00, 139.23, 142.73, 153.55, 170.46, 171.24, 177.12, 177.78. HRMS: m/z calcd for C₃₄H₃₆N₄NiO₆: 677.1880; found: 677.1918.

For the general procedure for the disassembly of the Ni(II) Schiff base complexes see:

<A NAME="RS10805ST-12A">12a</A> Soloshonok VA. Ueki H. Ellis TK. Yamada T. Ohfune Y. Tetrahedron Lett.  2005,  46:  1107 

<A NAME="RS10805ST-12B">12b</A> Ellis TK. Ueki H. Soloshonok VA. Tetrahedron Lett.  2005,  46:  941