A Remarkable Rate Acceleration of the One-Pot Three-Component Cyclo­condensation Reaction at Room Temperature: An Expedient Synthesis of ­Mitotic Kinesin Eg5 Inhibitor Monastrol

Abstract

A general and practical route for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones by a one-pot condensation of ­aldehydes, β-ketoesters, and urea is described using trimethylsilyltriflate (1 mol%)-mediated cyclocondensation reaction at room temperature within 15 minutes. Yields are significantly higher than utilizing classical Biginelli reaction conditions. Synthesis of mitotic Kinesin Eg5 inhibitor monastrol has been achieved in 95% isolated yield.

mitotic - monastrol - 3,4-dihydropyrimidin-2(1H)-ones - Biginelli reaction

References

Passerini three-component and Ugi four-component condensations are the most popular among many other reactions for their wide scope and synthetic utility. For reviews, see:

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5

Biginelli stated (ref. [3] ) that his research was inspired by the earlier work of R. Behrend on the urea-ketoester coupling and U. Schiff on the urea-aldehyde coupling.

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11

Typical Procedure for the Synthesis of DHPM’s 4b: A solution of 4-methoxybenzaldehyde (272 mg, 2.0 mmol), urea (120 mg, 2.0 mmol), EtOAc (260 mg, 2.0 mmol) in MeCN (2 mL) was stirred at r.t. in the presence of a cat. amount of TMSOTf (4 mg, 1 mol%) for 15 min (progress of the reaction was monitored by TLC). The reaction mixture was then poured onto crushed ice (10 g) and stirred for 5-10 min. The resulting solid was filtered through a sintered funnel under suction, washed with ice-cold water (10 mL) and then recrystallized from hot EtOH to afford pure product (0.58 g, 95%).
This procedure was followed for the preparation of all the dihydropyrimidinones and thiones listed in Table [1] . The mp, spectral and analytical data for selected compounds are presented below.
4d: Mp 152-155 °C. IR (KBr): 3280, 3185, 2928, 1710, 1651, 1613, 1583 cm^-1. ¹H NMR: δ = 9.98 (br s, N1-H), 9.31 (br s, N3-H), 7.16 (d, J = 9.1 Hz, 2 H), 6.62 (d, J = 9.1 Hz, 2 H), 5.13 (s, 1 H), 3.60 (s, 3 H), 2.92 (s, 6 H), 2.30 (s, 3 H). ¹³C NMR: δ = 174.1, 166.2, 150.3, 144.9, 131.2, 127.4, 112.6, 101.3, 53.7, 51.3, 17.4. EIMS: m/z (%) = 305(21) [M⁺], 246 (25), 231 (8), 185 (22), 171 (18), 141 (37), 120 (32), 78 (100), 43 (87). 4g: Mp 163-165 °C. IR (KBr): 3340, 3230, 3106, 2980, 1700, 1651, 1613 cm^-1. ¹H NMR: δ = 8.90 (br s, N1-H), 7.11 (br s, N3-H), 6.72-6.89 (m, 3 H), 5.23
(s, 1 H), 4.02-4.18 (m, 2 H), 3.85 (s, 6 H), 2.73-2.78 (m, 2 H), 1.15-1.35 (m, 6 H). ¹³C NMR: δ = 164.4, 152.6, 152.0, 147.6, 147.1, 136.3, 117.5, 110.2, 109.2, 98.4, 58.4, 54.7, 54.6, 53.2, 23.7, 13.0, 11.8. EIMS: m/z (%) = 334 (67) [M⁺], 305 (100), 261 (45), 260 (22), 197 (37), 169 (7). 4h: mp 193-195 °C. IR (KBr): 3157, 3122, 2980, 1710, 1651, 1596
cm^-1. ¹H NMR: δ = 8.10 (br s, N1-H), 7.58 (br s, N3-H), 6.80 (s, 3 H), 5.33 (s, 1 H), 3.88 (s, 6 H), 2.38 (s, 3 H), 1.85 (s, 9 H). ¹³C NMR: δ = 173.9, 164.5, 149.0, 148.9, 141.6, 135.1, 118.9, 111.3, 110.1, 104.2, 81.0, 55.9, 28.0, 17.9. EIMS: m/z (%) = 364 [M⁺], 307 (100, -57) [t-Bu], 263 (52), 248 (9), 171 (46), 138 (29), 57 (35). 5a: mp 200-202 °C. IR (KBr): 3220, 3085, 1745, 1690 cm^-1. ¹H NMR: δ = 9.83 (br s, N1-H), 9.12 (br s, N1-H), 6.62-7.28 (m, 4 H), 4.53 (d, J = 2.1 Hz, 1 H), 4.15 (q, J = 7.0 Hz, 2 H), 3.28 (d, J = 2.1 Hz, 1 H), 1.78 (s, 3 H), 1.22 (t, J = 7.0 Hz, 3 H). ¹³C NMR: δ = 168.5, 155.2, 150.5, 129.5, 128.6, 125.3, 121.0, 116.5, 83.5, 61.0, 48.0, 44.2, 23.9, 14.3. EIMS: m/z (%) = 276 (62) [M⁺], 247 (81), 229 (97), 203 (71), 183 (100).

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