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Synlett 2008(1): 100-104  
DOI: 10.1055/s-2007-1000839
LETTER
© Georg Thieme Verlag Stuttgart · New York

One-Pot Four-Component Reaction for the Generation of Pyrazoles and Pyrimidines

Jeffrey P. Stonehouse*a, Dmitriy S. Chekmarevb, Natalya V. Ivanovab, Stuart Langa, Garry Pairaudeaua, Neal Smitha, Michael J. Stocksa, Sergey I. Sviridovb, Lyubov M. Utkinab
a AstraZeneca R&D Charnwood, Medicinal Chemistry, Bakewell Road, Loughborough, LE11 5RH, UK
Fax: +44(1509)645567; e-Mail: jeffrey.stonehouse@astrazeneca.com;
b ChemBridge Corporation, Malaya Pirogovskaya 1, 119435 Moscow, Russia
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Publication History

Received 27 September 2007
Publication Date:
11 December 2007 (online)

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Abstract

The palladium-catalysed four-component coupling of a halide, terminal alkyne, molybdenum hexacarbonyl and either a hydrazine or amidine has been shown to be an efficient method for the construction of highly substituted pyrazoles and pyrimidines, respectively, in a one-pot process.

Key words

carbonylations - combinatorial chemistry - heterocycles - multicomponent reactions - palladium

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General Procedure: In a 25-mL 3-neck round-bottomed flask were added halide (1.0 mmol), alkyne (1.5 mmol), molybdenum hexacarbonyl (1.5 mmol), nucleophile (2.0 mmol), palladium acetate (0.05 mmol), copper iodide (0.02 mmol), tri-tert-butylphosphine (0.1 mmol) and cesium carbonate (2.5 mmol, 5.0 mmol when nucleophile was used as a salt) in toluene (2.5 mL) and MeCN (2.5 mL) and the mixture was heated at 80 °C overnight. The solvent was removed and the residue was dissolved in CH2Cl2 and filtered through celite. This crude material was purified by flash chromatography (gradient elution with PE and EtOAc) and then by reverse-phase preparative HPLC on a Xbridge C8 19 × 50 mm column (gradient elution with 95% of 0.3% aq NH3 solution-5% MeCN to 5% of 0.3% aq NH3 solution-95% MeCN).3,5-Diphenyl-1 H -pyrazole (1a):19 mp 201-202 °C (lit. 201-203 °C). 1H NMR (400 MHz, CDCl3): δ = 6.81 (s, 1 H, pyrazole ArH), 7.28-7.37 (m, 6 H, Ph ArH), 7.70-7.71 (m, 4 H, Ph ArH). 13C NMR (100 MHz, CDCl3): δ = 100.1, 125.5, 125.6, 128.2, 128.8, 131.2.3-Phenyl-5-(thiophen-3-yl)-1 H -pyrazole (1b):20 mp 181-183 °C (lit. 183 °C). 1H NMR (400 MHz, CDCl3): δ = 6.68 (s, 1 H, pyrazole ArH), 7.27-7.39 (m, 5 H, ArH), 7.49 (dd, J = 1.2, 2.8 Hz, 1 H, ArH), 7.65-7.71 (m, 2 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 100.2, 120.9, 125.6, 125.7, 126.3, 128.2, 128.8, 131.0, 132.9, 148.2, 169.1.3-Phenyl-5-[(tetrahydro-2 H -pyran-2-yloxy)methyl]-1 H -pyrazole (1c):21 1H NMR (400 MHz, CDCl3): δ = 1.50-1.65 (m, 4 H), 1.70-1.88 (m, 2 H), 3.53-3.58 (m, 1 H), 3.88-3.93 (m, 1 H), 4.63-4.81 (m, 3 H), 6.56 (s, 1 H, pyrazole ArH), 7.29 (t, J = 7.3 Hz, 1 H, ArH), 7.36 (dd, J = 7.0, 7.3 Hz, 1 H, ArH), 7.72 (d, J = 7.0 Hz, 2 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 19.4, 25.3, 30.4, 61.1, 62.5, 98.2, 102.1, 125.6, 127.9, 128.7, 132.0.5-(4-Methoxyphenyl)-3-phenyl-1 H -pyrazole (1d):19 mp 166-168 °C (lit. 160-162 °C). 1H NMR (400 MHz, CDCl3): δ = 3.82 (s, 3 H, Me), 6.74 (s, 1 H, pyrazole ArH), 6.90 (d, J = 8.8 Hz, 2 H, ArH), 7.31 (tt, J = 2.9, 7.1 Hz, 1 H, ArH), 7.36 (dd, J = 7.1, 7.5 Hz, 2 H, ArH), 7.63 (d, J = 8.8 Hz, 2 H, ArH), 7.71 (dd, J = 2.8, 7.5 Hz, 2 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 55.3, 99.5, 104.4, 114.2, 123.9, 125.5, 126.9, 128.0, 131.5, 159.6.5-(4-Chlorophenyl)-3-phenyl-1 H -pyrazole (1e):22 mp 216-218 °C (lit. 215-217 °C). 1H NMR (400 MHz, CD3OD): δ = 6.98 (s, 1 H, pyrazole ArH), 7.33 (t, J = 7.2 Hz, 1 H, ArH), 7.40-7.44 (m, 4 H, ArH), 7.75-7.78 (m, 4 H, ArH).3-(3-Phenyl-1 H -pyrazol-5-yl)pyridine (1f):19 mp 187-189 °C (lit. 187-189 °C). 1H NMR (400 MHz, CDCl3): δ = 6.85 (s, 1 H, pyrazole ArH), 7.34-7.48 (m, 4 H, ArH), 7.67 (d, J = 7.2 Hz, 2 H, ArH), 8.10 (d, J = 7.6 Hz, 1 H, ArH), 8.60 (br s, 1 H, ArH), 9.05 (br s, 1 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 101.4, 125.5, 125.5, 126.7, 126.8, 129.6, 129.6, 130.1, 135.0, 147.3, 149.2, 149.3.5-Benzyl-3-phenyl-1 H -pyrazole (1g):23 mp 187-189 °C (lit. 187-189 °C). 1H NMR (400 MHz, CDCl3): δ = 3.96 (s, 2 H, CH2), 6.32 (s, 1 H, pyrazole ArH), 7.20-7.34 (m, 8 H, ArH), 7.65 (d, J = 7.2 Hz, 2 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 33.1, 102.0, 125.6, 126.6, 127.9, 128.6, 128.7, 128.7, 132.0, 138.5.1-Methyl-3,5-diphenyl-1 H -pyrazole (1h):24 mp 58-60 °C (lit. 58-59 °C). 1H NMR (400 MHz, CDCl3): δ = 3.92 (s, 3 H, Me), 6.60 (s, 1 H, pyrazole ArH), 7.28-7.47 (m, 8 H, ArH), 7.82-7.84 (m, 2 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 37.5, 103.2, 125.5, 127.6, 128.5, 128.6, 128.7, 128.7, 130.6, 133.4, 145.0, 150.5.1,3,5-Triphenyl-1 H -pyrazole (1i):25 mp 140-141 °C (lit. 141-142 °C). 1H NMR (400 MHz, CDCl3): δ = 6.82 (s, 1 H, pyrazole ArH), 7.28-7.44 (m, 13 H, ArH), 7.92 (d, J = 7.7 Hz, 2 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 105.2, 125.3, 125.8, 127.4, 128.0, 128.3, 128.5, 128.6, 128.7, 128.9, 130.6, 133.0, 140.1, 144.4, 151.9.3-(1,3-Diphenyl-1 H -pyrazol-5-yl)pyridine (1j):26 mp 151-152 °C (lit. 150 °C). 1H NMR (400 MHz, CDCl3): δ = 6.86 (s, 1 H, pyrazole ArH), 7.26-7.37 (m, 11 H, ArH), 8.23 (ddd, J = 2.0, 2.0, 8.0 Hz, 1 H, ArH), 8.58-8.62 (m, 1 H, ArH), 9.14 (br s, 1 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 105.1, 123.5, 125.3, 127.7, 128.5, 128.5, 128.7, 128.7, 128.9, 130.2, 132.9, 139.9, 144.7, 147.3, 149.0, 149.0.3-(1,5-Diphenyl-1 H -pyrazol-3-yl)pyridine (4j): mp 101-103 °C. IR (CH2Cl2): 2366, 1595, 1498, 1421, 1026, 764, 707 cm-1. 1H NMR (400 MHz, CDCl3): δ = 6.89 (s, 1 H, pyrazole ArH), 7.24 (dd, J = 5.2, 8.0 Hz, 1 H, ArH), 7.32-7.41 (m, 6 H, ArH), 7.43-7.46 (m, 2 H, ArH), 7.49-7.52 (m, 1 H, ArH), 7.91-7.93 (m, 2 H, ArH), 8.61 (d, J = 11.2 Hz, 2 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 105.6, 123.1, 125.4, 125.7, 126.7, 127.9, 128.2, 128.7, 128.9, 129.2, 132.6, 135.7, 139.6, 140.9, 149.3, 152.3. HRMS: m/z calcd for C20H15N3: 298.1344; found: 298.1337.2-Methyl-4,6-diphenylpyrimidine (5b):27 mp 90-91 °C (lit. 90-92 °C). 1H NMR (400 MHz, CDCl3): δ = 2.87 (s, 3 H, Me), 7.50-7.54 (m, 6 H, ArH), 7.88 (s, 1 H, pyrimidine ArH), 8.11-8.14 (m, 4 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 26.5, 110.0, 127.2, 128.9, 130.7, 137.4, 164.7, 168.5.2-Methyl-4-phenyl-6-(pyridin-3-yl)pyrimidine (5c): mp 136-137 °C. IR (CH2Cl2): 1590, 1568, 1527, 1355, 1026, 745, 707 cm-1. 1H NMR (400 MHz, CDCl3): δ = 2.88 (s, 3 H, Me), 7.45-7.49 (m, 1 H, ArH), 7.53-7.55 (m, 3 H, ArH), 7.92 (s, 1 H, pyrimidine ArH), 8.13-8.16 (m, 2 H, ArH), 8.46 (ddd, J = 2.0, 2.0, 8.0 Hz, 1 H, ArH), 8.75-8.76 (m, 1 H, ArH), 9.32 (s, 1 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 26.4, 110.0, 123.7, 127.2, 129.0, 130.9, 133.1, 134.7, 137.1, 148.5, 151.4, 162.4, 165.2, 168.9. HRMS: m/z calcd for C16H13N3: 248.1188; found: 248.1176.2,4,6-Triphenylpyrimidine (5d):28 mp 184-185 °C (lit. 184-186 °C). 1H NMR (400 MHz, CDCl3): δ = 7.51-7.59 (m, 9 H, ArH), 8.03 (s, 1 H, pyrimidine ArH), 8.28-8.31 (m, 4 H, ArH), 8.72-8.77 (m, 2 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 110.3, 127.3, 128.4, 128.4, 128.9, 130.6, 130.7, 137.5, 138.1, 164.5, 164.7.2,4-Diphenyl-6-(pyridin-3-yl)pyrimidine (5e): mp 159-161 °C. IR (CH2Cl2): 2833, 1562, 1542, 1492, 1443, 1261, 1114, 985, 757, 707 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.51-7.61 (m, 8 H, ArH), 8.04 (s, 1 H, pyrimidine ArH), 8.29-8.32 (m, 2 H, ArH), 8.60-8.63 (m, 1 H, ArH), 8.71-8.75 (m, 2 H, ArH), 8.76-8.79 (m, 1 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 110.3, 127.2, 127.3, 128.4, 128.5, 129.0, 130.9, 131.0, 134.6, 134.7, 137.1, 137.7, 148.6, 151.5, 162.4, 164.7, 163.1. HRMS: m/z calcd for C21H15N3: 310.1344; found: 310.1329.4-(4,6-Diphenylpyrimidin-2-yl)morpholine (5f): mp 172-174 °C. 1H NMR (400 MHz, CDCl3): δ = 3.84 (t, J = 4.8 Hz, 4 H, CH2), 4.02 (t, J = 4.8 Hz, 4 H, CH2), 7.32-7.35 (m, 2 H, ArH), 7.44 (s, 1 H, pyrimidine ArH), 7.47-7.50 (m, 4 H, ArH), 8.10-8.13 (m, 4 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 44.4, 67.0, 102.3, 127.1, 128.6, 130.3, 131.5, 138.1, 165.2. HRMS: m/z calcd for C20H19N3O: 318.1606; found: 318.1592.