A Novel and Efficient Lewis Acid Catalysed Preparation of Pyrimidines: Microwave-Promoted Reaction of Urea and β-Formyl Enamides

Abstract

A novel and efficient synthesis of pyrimidine from β-formyl enamide is described. The key step involves samarium ­chloride catalysed cyclisation of β-formyl enamides using urea as source of ammonia under microwave irradiation.

β-formyl enamide - urea - microwave - pyrimidine

References and Notes

<A NAME="RD30106ST-1A">1a</A> Brown DJ. In Comprehensive Heterocyclic Chemistry   Vol. 3:  Katritzky AR. Rees CW. Scrieven EFV. Pergamon; Oxford: 1984.  Chap 2.13. p.142-155  

<A NAME="RD30106ST-1B">1b</A> Callery P. Gannett P. In Foye’s Principles of Medicinal Chemistry   Williams DA. Lemke TL. Lippincott Williams and Wilkins; Philadelphia: 2002.  p.934-935  

<A NAME="RD30106ST-1C">1c</A> Jain KS. Chitre TS. Miniyar PB. Kathiravan MK. Bendre VS. Veer VS. Shahane SR. Shishoo CJ. Curr. Sci.  2006,  90:  793 

<A NAME="RD30106ST-2">2</A> Botta M. Corelli F. Maga G. Manetti F. Renzulli M. Spadari S. Tetrahedron  2001,  57:  8357 

<A NAME="RD30106ST-3">3</A> Garg R. Gupta SP. Gao H. Babu MS. Debnath AK. Hansch C. Chem. Rev.  1999,  99:  3525 

<A NAME="RD30106ST-4">4</A> Botta M. Occhionero F. Nicoletti R. Mastromarino P. Conti C. Magrini M. Saladino R. Bioorg. Med. Chem.  1999,  7:  1925 

<A NAME="RD30106ST-5A">5a</A> Hurst D. In An Introduction to Chemistry & Biochemistry of Pyrimidines, Purines & Pteridines   Wiley; Chichester: 1988. 

<A NAME="RD30106ST-5B">5b</A> Brown DJ. In The Pyrimidines   Interscience Publishers; New York: 1994. 

<A NAME="RD30106ST-6A">6a</A> Zanatta N. Flores DC. Madruga CC. Flores AFC. Bonacorso HG. Martins MAP. Tetrahedron Lett.  2006,  47:  573 

<A NAME="RD30106ST-6B">6b</A> Jeong JU. Chen X. Rahman A. Yamashita DS. Luengo JI. Org. Lett.  2004,  6:  1013 

<A NAME="RD30106ST-6C">6c</A> Mabry J. Ganem B. Tetrahedron Lett.  2006,  47:  55 

<A NAME="RD30106ST-6D">6d</A> Peng Z. Journet M. Humphrey G. Org. Lett.  2006,  8:  395 

<A NAME="RD30106ST-6E">6e</A> Cernuchova P. Vo-Thanh G. Milata V. Loupy A. Jantova S. Theiszova M. Tetrahedron  2005,  61:  5379 

<A NAME="RD30106ST-7A">7a</A> Lin S. Danishefsky SJ. Angew. Chem. Int. Ed.  2002,  41:  512 

<A NAME="RD30106ST-7B">7b</A> Musso DL. Cochran FR. Kelley JL. McLean EW. Selph JL. Rigdon GC. Orr GF. Davis RG. Cooper BR. Styles VL. Thompson JB. Hall WR. J. Med. Chem.  2003,  46:  399 

<A NAME="RD30106ST-7C">7c</A> Petersen AB. Petersen MA. Henriksen U. Hammerum S. Dahl O. Org. Biomol. Chem.  2003,  1:  3293 

<A NAME="RD30106ST-8A">8a</A> You J. Drexler HJ. Zhang S. Fischer C. Heller D. Angew. Chem. Int. Ed.  2003,  42:  913 

<A NAME="RD30106ST-8B">8b</A> Yan Y. Zhang X. Tetrahedron Lett.  2006,  47:  1567 

<A NAME="RD30106ST-8C">8c</A> Zhang YJ. Park JH. Lee S. Tetrahedron: Asymmetry  2004,  15:  2209 

<A NAME="RD30106ST-9A">9a</A> Ahmed S. Boruah RC. Tetrahedron Lett.  1996,  37:  8231 

<A NAME="RD30106ST-9B">9b</A> Boruah RC. Ahmed S. Sharma U. Sandhu JS. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  1999,  38:  274 

<A NAME="RD30106ST-10A">10a</A> Sharma U. Ahmed S. Boruah RC. Tetrahedron Lett.  2000,  41:  3493 

<A NAME="RD30106ST-10B">10b</A> Boruah RC. Ahmed S. Sharma U. Sandhu JS. J. Org. Chem.  2000,  65:  922 

<A NAME="RD30106ST-10C">10c</A> Ahmed S. Boruah RC. Tetrahedron Lett.  1997,  38:  1845 

<A NAME="RD30106ST-10D">10d</A> Longchar M. Chetia A. Ahmed S. Boruah RC. Sandhu JS. Synth. Commun.  2001,  31:  3281 

<A NAME="RD30106ST-11A">11a</A> Varma RS. In Microwaves: Theory and Application in Material Processing IV   Clark DE. Sutton WH. Lewis DA. American Ceramic Society; Westerville / OH: 1997.  p.357-365  

<A NAME="RD30106ST-11B">11b</A> Varma RS. Dahiya R. Tetrahedron  1998,  54:  6293 

<A NAME="RD30106ST-11C">11c</A> Bora U. Saikia A. Boruah RC. Org. Lett.  2003,  5:  435 

<A NAME="RD30106ST-12">12</A> Chetia A. Longchar M. Lekhok KC. Boruah RC. Synlett  2004,  1309 

<A NAME="RD30106ST-13A">13a</A> Saikia A. Barthakur MG. Borthakur M. Saikia CJ. Bora U. Boruah RC. Tetrahedron Lett.  2006,  47:  43 

<A NAME="RD30106ST-13B">13b</A> Barhtakur MG. Chetia A. Boruah RC. Tetrahedron Lett.  2006,  47:  4925 

<A NAME="RD30106ST-14">14</A> Simon C. Constantieux T. Rodriguez J. Eur. J. Org. Chem.  2004,  4957 

<A NAME="RD30106ST-15">15</A>

Representative Procedure for the Synthesis of 2′-Methyl-5α-cholest[2,3- e ]pyrimidine ( 4a):
3-Acetamido-2-formyl-5α-cholest-2-ene (2a; 0.46 g,
1 mmol), urea (0.18 g, 3.0 mmol) and samarium chloride hexahydrate (0.55 g, 1.5 mmol) were mixed intimately in a mortar and irradiated in an open reaction vessel of a Synthwave 402 Prolabo focused microwave reactor (manufactured by M/s Prolabo, 54 rue Roger Salengro, Cedex, France) after setting the reaction temperature at 140 °C and the power at 80% (maximum output 300 Watts). On completion of reaction (vide TLC), the reaction mixture was treated with H₂O (50 mL) and extracted with CH₂Cl₂ (3 × 30 mL). The organic portion was washed with H₂O, dried over anhyd Na₂SO₄ and the solvent was removed to obtain a crude product. Column chromatography separation using EtOAc-hexane (1:9) as eluent over silica gel afforded 4a in 82% yield. This procedure was followed for the synthesis of all products listed in Table [1] .

<A NAME="RD30106ST-16">16</A>

Spectral and analytical data of selected compounds:
Compound 4a: mp 90-92 °C; R _f = 0.3 (EtOAc-hexane, 20:80). IR (KBr): 2925, 1641, 1582, 1559, 1442 cm^-1. ¹H NMR (300 MHz. CDCl₃): δ = 8.28 (br s, 1 H), 2.65 (s, 3 H), 0. 96 (s, 3 H), 0.74 (s, 3 H), 0.91-2.78 (m, 38 H). ¹³C NMR (75 MHz, CDCl₃): δ = 165.4, 165.4, 157.7, 126.3, 56.8, 54.1, 42.9 (3 × C), 39.9 (2 × C), 36.6, 36.4, 36.1 (2 × C), 35.4, 31.9, 30.0, 28.9, 28.5, 28.3, 25.8, 24.6, 24.2, 23.1, 22.9, 21.7, 19.1, 12.4, 11.9. MS (ESI): m/z = 437 [M⁺ + 1]. Anal. Calcd for C₃₀H₄₈N₂: C, 82.51; H, 11.08; N, 6.41. Found: C, 82.28; H, 10.95; N, 6.59.
Compound 4b: gum; R _f = 0.3 (EtOAc-hexane, 30:70). IR (KBr): 2925, 1631, 1578, 1552, 1440 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 8.24 (br s, 1 H), 6.19 (br s, 1 H), 2.64 (s, 3 H), 0.94 (s, 3 H), 0.88 (s, 3 H), 1.00-2.82 (m, 35 H). ¹³C NMR (75 MHz, CDCl₃): δ = 166.6, 161.9, 160.0, 154.4, 126.3, 122.5, 56.6, 56.3, 54.2, 42.8, 40.1, 39.9 (2 × C), 39.5, 38.5, 36.5, 36.4, 36.2, 32.5, 31.6, 28.6, 28.4, 26.1, 24.7, 24.2, 23.2, 23.0, 19.1, 18.0, 12.3. MS (ESI): m/z = 435 [M⁺ + 1].
Compound 4d: mp 165-67 °C; R _f = 0.3 (EtOAc-CHCl₃, 10:90). IR (KBr): 2943, 1735, 1668, 1594, 1555, 1420, 1245, 1033, 755 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 8.31 (br s, 1 H), 5.35 (br s, 1 H), 4.52 (m, 1 H), 2.62 (s, 3 H), 1.97 (s, 3 H), 1.03 (s, 3 H), 0.92 (s, 3 H), 1.06-2.66 (m, 17 H). ¹³C NMR (75 MHz, CDCl₃): δ = 181.9, 170.7, 166.5, 152.0, 140.7, 130.8, 122.1, 74.1, 56.2, 51.0, 46.3, 38.5, 37.3, 33.2, 31.7, 31.2, 29.1, 28.3, 28.1, 26.2, 21.6, 20.8, 19.7, 17.2. MS (ESI): m/z = 381 [M⁺ + 1]. Anal. Calcd for C₂₄H₃₂N₂O₂: C, 75.75; H, 8.48; N, 7.36. Found: C, 75.90; H, 8.64; N, 7.17.
Compound 4e: oil; R _f = 0.3 (EtOAc-CHCl₃, 20:80). IR (KBr): 2925, 1641, 1583, 1553, 1438 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 8.29 (s 1 H), 2.83 (t, J = 5.96 Hz, 2 H), 2.70 (t, J = 6.05 Hz, 2 H), 2.65 (s, 3 H), 1.80-1.93 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 166.1, 165.2, 157.2, 127.0, 32.1, 25.8, 25.5, 22.6, 22.5. MS (ESI): m/z = 149 [M⁺ + 1].
Compound 4h: mp 91-93 °C; R _f = 0.5 (EtOAc-CHCl₃, 10:90). IR (KBr): 2924, 1655, 1578, 1545, 1435, 825, 773 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 8.68 (d, J = 5.34 Hz, 1 H), 8.03 (d, J = 8.55 Hz, 2 H), 7.46-7.49 (m, 3 H), 2.80 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 168.9, 163.2, 158.1, 137.5, 135.7, 129.6 (2 × C), 128.9 (2 × C), 114.1, 26.7. MS (ESI): m/z = 205 [M⁺ + 1]. Anal. Calcd for C₁₁H₉N₂Cl: C, 64.55; H, 4.43; N, 13.68. Found: C, 64.41; H, 4.33; N, 13.40.

<A NAME="RD30106ST-17">17</A> Kagan HB. Namy JL. Tetrahedron  1986,  42:  6573 

<A NAME="RD30106ST-18">18</A> Cooper HBH, and Spencer HW. inventors; US Patent  6077491.