Tandem Retro-Michael Addition-Claisen Rearrangement-Intramolecular Cyclization: One-Pot Synthesis of Densely Functionalized Ethyl Dihydropyrimidine-4-carboxylates from Simple Building Blocks

Abstract

Pyrolysis of suitably functionalized oxadiazoline diesters in refluxing xylenes provided ethyl 1,2-disubstituted 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylates in moderate to good yields. Under thermal conditions, the oxadiazoline esters undergo a sequence of complex molecular reorganizations, namely retro-Michael addition, Claisen rearrangement, and cyclization, to produce the desired pyrimidinones.

Key words

retro-Michael addition - Claisen rearrangement - intramolecular cyclization - 1,6-dihydropyrimidine-4-carboxylates

References and Notes

• For reviews, see:
• 1a Brown JD. The Pyrimidine, In The Chemistry of Heterocyclic Compounds   Vol. 16:  Weissberger A. Wiley-Interscience; New York: 1962. 
• 1b Hurst DT. An Introduction to the Chemistry and Biochemistry of Pyrimidines, Purines and Pteridines   Wiley; Chichester: 1980. 
• 2 Sunderland CJ. Botta M. Aime S. Raymond KN. Inorg. Chem.  2001,  40:  6746 
• 3a Summa V. Petrocchi A. Matassa VG. Taliani M. Laufer R. Francesco RD. Altamura S. Pace P. J. Med. Chem.  2004,  47:  5336 
• 3b Stansfield I. Avolio S. Colarusso S. Gennari N. Narjes F. Picini B. Ponzi S. Harper S. Bioorg. Med. Chem. Lett.  2004,  14:  5085 
• 4 Culbertson TP. J. Heterocycl. Chem.  1979,  16:  1423 
• For related work, see:
• 5a Colarusso S. Attenni B. Avolio S. Malancona S. Harper S. Altamura S. Koch U. Narjes F. ARKIVOC  2006,  (vii):  479 
• 5b Kinzel OD. Monteagudo E. Muraglia E. Orvieto F. Pescatore G. Rico Ferreira M. Rowley M. Summa V. Tetrahedron Lett.  2007,  48:  6552 
• 5c Ferrara M. Crescenzi B. Donghi M. Muraglia E. Nizi E. Pesci S. Summa V. Gardelli C. Tetrahedron Lett.  2007,  48:  8379 
• 6 Naidu BN. Sorenson ME. Org. Lett.  2005,  7:  1391 

7

Representative Procedures
Method A: A solution of 6e (2.68 g, 7.52 mmol) in xylenes (50 mL) was heated at reflux for 1.5 h and cooled to r.t. The precipitate was filtered and dried to give 2e as an off-white solid (1.4 g, 60% yield).
Method B: A solution of 6j (9.77 g, 29.22 mmol) in xylenes (100 mL) was heated at reflux for 5 h and cooled. Then, the reaction mixture was diluted with EtOAc (100 mL) and extracted with 0.5 M Na₂CO₃ (3 × 30 mL). The combined aqueous layers were acidified with concd HCl and extracted with CH₂Cl₂ (4 × 50 mL). The combined CH₂Cl₂ layers were dried (Na₂SO₄), filtered, and concentrated to give a brown solid which was triturated with Et₂O and filtered to afford 2j as a light-brown powder (4.32 g, 51%).

8

Analytical Data for New Compounds Compound 2a: ¹H NMR (500 MHz, CDCl₃): δ = 10.76 (1 H, s), 7.49-7.46 (5 H, m), 4.48 (2 H, q, J = 7.0 Hz), 3.45 (3 H, s), 1.41 (3 H, t, J = 7.0 Hz). HRMS: m/z calcd for C₁₄H₁₅N₂O₄ [M + H]: 275.1032; found: 275.1042. Anal. Calcd for C₁₄H₁₄N₂O₄: C, 61.30; H, 5.14; N, 10.21. Found: C, 61.31; H, 5.10; N, 10.21.
Compound 2b: ¹H NMR (500 MHz, CDCl₃): δ = 10.63 (1 H, s), 7.39-7.23 (3 H, m), 4.49 (2 H, q, J = 7.0 Hz), 3.47 (3 H, s), 1.42 (3 H, t, J = 7.0 Hz). HRMS : m/z calcd for C₁₄H₁₃F₂N₂O₄ [M + H]: 311.0844; found: 311.0832. Anal. Calcd for C₁₄H₁₄N₂O₄: C, 54.19; H, 3.89; N, 9.03. Found: C, 54.21; H, 3.85; N, 8.85.
Compound 2c: ¹H NMR (500 MHz, CDCl₃): δ = 10.85 (1 H, s),), 7.06-7.01 (2 H, m), 6.98-6.94 (1 H, m), 4.50 (2 H, q, J = 7.0 Hz), 3.47 (3 H, s), 1.42 (3 H, t, J = 7.0 Hz). HRMS: m/z calcd for C₁₄H₁₃F₂N₂O₄ [M + H]: 311.0843; found: 311.0836. Anal. Calcd for C₁₄H₁₄N₂O₄: C, 54.19; H, 3.89; N, 9.03. Found: C, 54.15; H, 3.79; N, 9.15.
Compound 2d: ¹H NMR (500 MHz, CDCl₃): δ = 10.81 (1 H, s), 7.51-7.46 (1 H, m), 7.04 (2 H, td, J = 8.2, 1.8 Hz), 6.95-6.91 (1 H, m), 4.49 (2 H, q, J = 7.0 Hz), 3.42 (3 H, s), 1.41 (3 H, t, J = 7.0 Hz). HRMS: m/z calcd for C₁₄H₁₃F₂N₂O₄ [M + H]: 311.0843; found: 311.0828. Anal. Calcd for C₁₄H₁₄N₂O₄: C, 54.19; H, 3.89; N, 9.03. Found: C, 54.21; H, 3.65; N, 8.94.
Compound 2e: ¹H NMR (500 MHz, CDCl₃): δ = 10.96 (1 H, s), 7.50-7.45 (1 H, m), 7.04 (2 H, t, J = 7.3 Hz), 4.51 (2 H, q, J = 7.0 Hz), 3.41 (3 H, s), 1.41 (3 H, t, J = 7.0 Hz). HRMS: m/z calcd for C₁₄H₁₃F₂N₂O₄ [M + H]: 311.0843; found: 311.0837. Anal. Calcd for C₁₄H₁₄N₂O₄: C, 54.19; H, 3.89; N, 9.03. Found: C, 54.10; H, 3.77; N, 9.00.
Compound 2f: ¹H NMR (500 MHz, CDCl₃): δ = 10.57 (1 H, s), 7.90 (1 H, dd, J = 7.93, 2.44 Hz), 7.49-7.42 (2 H, m), 4.54-4.47 (1 H, m), 4.41-4.34 (1 H, m), 3.31 (3 H, s), 3.30 (3 H, s), 1.35 (3 H, t, J = 7.02 Hz). ESI-HRMS: m/z calcd for C₁₅H₁₆FN₂O₆S [M + H]: 371.0713; found: 371.0724.
Compound 2g: ¹H NMR (500 MHz, CDCl₃): δ = 10.65 (1 H, s), 7.57-7.52 (1 H, m), 7.28 (1 H, d, J = 7.9 Hz), 7.22 (1 H, t, J = 8.9 Hz), 4.55-4.49 (1 H, m), 4.40-4.33 (1 H, m), 3.46 (3 H, s), 3.30 (3 H, s), 2.90 (3 H, s), 1.37 (3 H, t, J = 7.0 Hz). ESI-HRMS: m/z calcd for C₁₆H₁₉FN₃O₆S [M + H]: 400.0979; found: 400.0979.
Compound 2h: ¹H NMR (500 MHz, CDCl₃): δ = 10.76 (1 H, s), 7.45 (1 H, td, J = 7.3, 1.53 Hz), 7.34 (1 H, d, J = 7.3 Hz), 7.06 (1 H, t, J = 7.3 Hz), 6.94 (1 H, d, J = 8.6 Hz), 4.55-4.41 (2 H, m), 3.79 (3 H, s), 3.34 (3 H, s), 1.40 (3 H, t, J = 7.0 Hz). HRMS: m/z calcd for C₁₅H₁₅N₂O₅ [M + H]: 303.0981; found: 303.0980.
Compound 2i: ¹H NMR (500 MHz, CDCl₃): δ = 10.83 (1 H, s), 7.35 (1 H, t, J = 8.5 Hz), 6.59 (2 H, d, J = 8.5 Hz), 4.50 (2 H, q, J = 7.0 Hz), 3.75 (6 H, s), 3.28 (3 H, s), 1.39 (3 H, t, J = 7.0 Hz). HRMS: m/z calcd for C₁₆H₁₉N₂O₆ [M + H]: 335.1243; found: 335.1240.
Compound 2j: ¹H NMR (500 MHz, CDCl₃): δ = 10.64 (1 H, s), 7.33-7.14 (5 H, m), 4.53 (2 H, q, J = 7.0 Hz), 4.17 (2 H, s), 3.41 (3 H, s), 1.46 (3 H, t, J = 7.0 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 169.5, 158.9, 149.8, 149.0, 134.7, 129.2, 128.2, 127.5, 124.7, 63.1, 42.3, 32.0, 14.3. HRMS: calcd for C₁₅H₁₇N₂O₄ [M + H]: 289.1188; found: 289.1186. Anal. Calcd for C₁₅H₁₆N₂O₄: C, 62.49; H, 5.59; N, 9.71. Found: C, 62.44; H, 5.79; N, 9.60.
Compound 2k: ¹H NMR (500 MHz, CDCl₃): δ = 10.88 (1 H, s), 7.31-7.24 (3 H, m), 7.14 (2 H, d, J = 7.3 Hz), 5.29 (2 H, s), 4.47 (2 H, q, J = 7.0 Hz), 2.43 (3 H, s), 1.41 (3 H, t, J = 7.0 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 169.1, 158.7, 149.5, 148.9, 134.6, 129.1, 128.2, 126.8, 124.7, 63.2, 48.2, 31.7, 22.6, 14.2. HRMS: m/z calcd for C₁₅H₁₇N₂O₄ [M + H]: 289.1188. Found: 289.1176.
Compound 2l: ¹H NMR (500 MHz, CDCl₃): δ = 8.89 (1 H, br s), 4.60-4.49 (1 H, m), 4.47 (2 H, q, J = 7.0 Hz), 2.57 (3 H, s), 1.63 (6 H, d, J = 6.7 Hz), 1.42 (3 H, t, J = 7.0 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 168.6, 158.7, 149.4, 149.0, 123.5, 77.7, 63.1, 22.9, 19.1, 14.1. HRMS: m/z calcd for C₁₁H₁₇N₂O₄ [M + H]: 241.1188; found: 241.1191.
Compound 2o: ¹H NMR (500 MHz, CDCl₃): δ = 10.39 (1 H, s), 4.44 (2 H, q, J = 7.0 Hz), 3.61 (3 H, s), 3.05 (1 H, qt, J = 6.7 Hz), 1.43 (3 H, t, J = 7.0 Hz), 1.30 (6 H, d, J = 6.7 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 169.5, 159.1, 155.2, 148.0, 124.9, 62.4, 32.0, 30.9, 20.7, 14.1. HRMS: m/z calcd for C₁₁H₁₇N₂O₄ [M + H]: 241.1188; found: 241.1186. Anal. Calcd for C₁₁H₁₆N₂O₄: C, 54.99; H, 6.71; N, 11.66. Found: C, 55.01; H, 6.82; N, 11.68.
Compound 2p: ¹H NMR (500 MHz, CDCl₃): δ = 10.36 (1 H, s), 4.43 (2 H, q, J = 7.0 Hz), 3.60 (3 H, s), 3.13 (1 H, qt, J = 7.9 Hz), 2.01-1.94 (4 H, m), 1.86-1.78 (2 H, m), 1.69-1.61 (2 H, m), 1.42 (3 H, t, J = 7.0 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 169.6, 159.2, 154.1, 148.0, 124.6, 62.5, 43.1, 31.3, 31.1, 25.7, 14.2. HRMS: m/z calcd for C₁₃H₁₉N₂O₄ [M + H]: 267.1345; found: 267.1337. Anal. Calcd for C₁₃H₁₈N₂O₄: C, 58.63; H, 6.81; N, 10.52. Found: C, 58.63; H, 6.72; N, 10.49.
Compound 6b: yield 75%. ¹H NMR (500 MHz, CDCl₃): δ = 7.61-7.57 (1 H, m), 7.51-7.47 (1 H, m), 7.26-7.21 (1 H, m), 4.35-4.10 (4 H, m), 3.40 (1 H, d, J _AB = 16.5 Hz), 3.17 (3 H, s), 3.02 (1 H, d, J _AB = 16.5 Hz), 1.32 (3 H, t, J = 7.0 Hz), 1.24 (3 H, t, J = 7.0 Hz). HRMS: m/z calcd for C₁₆H₁₉N₂O₅F₂ [M + H]: 357.1262; found: 357.1273. Anal. Calcd for C₁₆H₁₈N₂O₅F₂: C, 53.93; H, 5.09; N, 7.86. Found: C, 53.82; H, 4.90; N, 8.13.
Compound 6c: yield 72%. ¹H NMR (500 MHz, CDCl₃): δ = 7.29-7.25 (2 H, m), 6.99-6.95 (1 H, m), 4.35-4.12 (4 H, m), 3.40 (1 H, d, J _AB = 16.5 Hz), 3.18 (3 H, s), 3.04 (1 H, d, J _AB = 16.5 Hz), 1.32 (3 H, t, J = 7.0 Hz), 1.25 (3 H, t, J = 7.0 Hz). HRMS: m/z calcd for C₁₆H₁₉N₂O₅F₂ [M + H]: 357.1262; found: 357.1262. Anal. Calcd for C₁₆H₁₈N₂O₅F₂: C, 53.93; H, 5.09; N, 7.86. Found: C, 53.90; H, 4.84; N, 7.81.
Compound 6d: yield 60%. ¹H NMR (500 MHz, CDCl₃): δ = 7.73 (1 H, dd, J = 14.5, 8.1 Hz), 6.96 (1 H, td, J = 8.5, 2.4 Hz), 6.91 (1 H, td, J = 8.2, 2.5 Hz), 4.36-4.10 (4 H, m), 3.40 (1 H, d, J _AB = 16.5 Hz), 3.11 (3 H, s), 3.07 (1 H, d, J _AB = 16.5 Hz), 1.32 (3 H, t, J = 7.0 Hz), 1.25 (3 H, t, J = 7.0 Hz). HRMS: m/z calcd for C₁₆H₁₉N₂O₅F₂ [M + H]: 357.1262; found: 357.1253. Anal. Calcd for C₁₆H₁₈N₂O₅F₂: C, 53.93; H, 5.09; N, 7.86. Found: C, 53.91; H, 5.01; N, 7.75.
Compound 6f: yield 64%. ¹H NMR (500 MHz, CDCl₃): δ = 7.89 (1 H, dd, J = 8.1, 2.6 Hz), 7.62 (1 H, dd, J = 8.4, 5.04 Hz), 7.40 (1 H, td, J = 8.2, 2.4 Hz), 4.35-4.26 (2 H, m), 4.19-4.13 (2 H, m), 3.40 (3 H, s), 3.38 (1 H, d, J _AB = 16.2 Hz), 3.15 (1 H, d, J _AB = 16.2 Hz), 3.02 (3 H, s), 1.36-1.30 (3 H, m), 1.27-1.23 (3 H, m). HRMS: m/z calcd for C₁₇H₂₂FN₂O₇S: 417.1132; found: 417.1116.
Compound 6g: yield 56%. ¹H NMR (500 MHz, CDCl₃): δ = 7.52-7.48 (1 H, m), 7.31 (1 H, d, J = 8.2 Hz), 7.18 (1 H, t, J = 8.6 Hz), 4.35-4.25 (2 H, m), 4.18 (2 H, q, J = 7.0 Hz), 3.40 (1 H, d, J _AB = 16.5 Hz), 3.21 (3 H, s), 3.09 (1 H, d, J _AB = 16.5 Hz), 3.09 (3 H, s), 3.07 (3 H, s), 1.33 (3 H, t, J = 7.0 Hz), 1.26 (3 H, t, J = 7.0 Hz). HRMS: m/z calcd for C₁₈H₂₅FN₃O₇S: 446.1397; found: 446.1383.
Compound 6i: yield 86%. ¹H NMR (500 MHz, CDCl₃): δ = 4.32-4.19 (2 H, m), 4.14 (2 H, q, J = 7.0 Hz), 3.72-3.67 (1 H, m), 3.23 (1 H, d, J _AB = 15.9 Hz), 2.88 (1 H, d, J _AB = 15.9 Hz), 1.98 (3 H, s), 1.30 (3 H, t, J = 7.0 Hz), 1.25-1.20 (9 H, m). ¹³C NMR (125 MHz, CDCl₃): δ = 168.9, 168.4, 162.5, 102.9, 61.9, 60.9, 53.2, 42.9, 19.2, 19.0, 14.21, 14.16, 13.0. HRMS: m/z calcd for C₁₃H₂₃N₂O₅ [M + H]: 287.1607; found: 287.1606.