DOI: 10.1016/s0960-894x(99)00572-7. Highly versatile solid phase synthesis of biofunctional 4-aryl-3,4-dihydropyrimidines using resin-bound isothiourea building blocks and multidirectional resin cleavage

Highly versatile solid phase synthesis of biofunctional 4-aryl-3,4-dihydropyrimidines using resin-bound isothiourea building blocks and multidirectional resin cleavage

10.1016/s0960-894x(99)00572-7

Crossref journal-article

Elsevier BV

Bioorganic & Medicinal Chemistry Letters (78)

Bibliography

Kappe, C. O. (2000). Highly versatile solid phase synthesis of biofunctional 4-aryl-3,4-dihydropyrimidines using resin-bound isothiourea building blocks and multidirectional resin cleavage. Bioorganic & Medicinal Chemistry Letters, 10(1), 49â51.

Authors 1

C.Oliver Kappe (first)

References 24 Referenced 85

10.1021/cr960010b / Chem. Rev. by Nefzi (1997)
10.1080/00304949809355320 / Org. Prep. Proced. Int. by Corbett (1998)
10.1002/prac.19973390193 / J. Prakt. Chem. by Ugi (1997)
10.2174/138620730101220118143111 / Combinatorial Chemistry & High Throughput Screening by Dömling (1998)
10.1016/S1367-5931(98)80010-0 / Curr. Opin. Chem. Biol. by Tietze (1998)
10.2174/0929867306666220208210120 / Curr. Med. Chem. by Dax (1999)
For a review on DHPMs, see: Kappe, C. O. Tetrahedron 1993, 49, 6937 (10.1016/S0040-4020(01)87971-0)
10.1021/jm00171a044 / J. Med. Chem. by Atwal (1990)
10.1021/jm00106a048 / J. Med. Chem. by Atwal (1991)
10.1097/00005344-199508000-00015 / J. Cardiovasc. Pharmacol. by Grover (1995)
Sidler, D. R.; Larsen, R. D.; Chartrain, M.; Ikemoto, N.; Roberge, C. M.; Taylor, C. S.; Li, W.; Bills, G. F. PCT Int. Appl. WO 99 07695.
Bruce, M. A.; Pointdexter, G. S.; Johnson, G. PCT Int. Appl. WO 98 33791.
10.1016/0040-4039(95)01660-A / Tetrahedron Lett. by Wipf (1995)
10.1021/jo970095w / J. Org. Chem. by Studer (1997)
10.1126/science.275.5301.823 / Science by Studer (1997)
Lewandowski, K.; Murer, P.; Svec, F.; Fréchet, J. M. J. Chem. Commun. 2237, 1998 (10.1039/a806395h)
10.1021/cc980014p / J. Comb. Chem. by Lewandowski (1999)
10.3987/R-1987-05-1185 / Heterocycles by O'Reilly (1987)
10.3987/R-1987-05-1189 / Heterocycles by Atwal (1987)
10.1016/S0040-4039(98)01197-6 / Tetrahedron Lett. by Dodd (1998)
10.1002/hlca.19970800106 / Helv. Chim. Acta by Obrecht (1997)
Obrecht, D.; Villalgordo, J. M. Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries; Pergamon Press: Oxford, 1998; pp. 98–104.
10.1021/jo00286a020 / J. Org. Chem. by Atwal (1989)
Typical procedure: A mixture of resin bound 4-(benzyloxy)benzyl chloride (4, 500 mg, 1.10 meq/g, Fluka) and thiourea (200 mg, 2.63 mmol) in anhydrous NMP (5 mL) was heated at 75°C for 16 h. The resin was successively washed with NMP (2×5 mL), THF (3×5 mL), MeOH (3×5 mL), and CH2Cl2 (3×5 mL), and subsequently dried under high vacuum for 10 h. The resulting resin 5 was treated with NMP (5 mL), enone 3a (218 mg, 1.00 mmol), and Cs2CO3 (260 mg, 0.80 mmol) at 90°C for 16 h. The resin was washed with NMP (2×5 mL), MeOH (3×5 mL), H2O (3×5 mL), MeOH (3×5 mL), and air-dried to give polymer-bound dihydropyrimidine 6a. This material was then treated (cleavage conditions A) with a mixture of dioxane (5 mL), ethanol (5 mL), AcOH (1 mL), and water (1 mL) at reflux temperature for 16 h. The cleaved material was isolated by filtration and the resin rinsed with ethanol (2×5 mL); the solvent was removed in vacuo and the resulting solid triturated with water. The solid product was collected by filtration and dried to give 7a (102 mg, 71% based on Cl loading of 4) in >95% purity (1H NMR). A second batch of the resin bound dihydropyrimidine 6a (see above) was treated with a mixture (cleavage condition C) of dioxane (4 mL), MeCN (4 mL) and NH4OAc (385 mg, 5 mmol) at reflux temperature for 8 h. The hot mixture was filtered from the resin and evaporated in vacuo. Trituration with H2O left DHPM 9 as a crystalline acetate salt in 62% yield and > 95% purity (1H NMR), mp. 230°C dec.; 1H NMR (DMSO-d6): 1.09 (t, J=7.5 Hz, 3H), 1.72 (s, 3H), 2.28 (s, 3H), 3.98 (q, J=7.5 Hz, 2H), 5.23 (s, 1H), 7.19–7.38 (m, 5H); 13C NMR (DMSO-d6): 14.1, 19.2, 23.9, 52.1, 59.1, 99.8, 126.3, 127.5, 128.5, 144.5, 151.0, 153.5, 165.4, 175.4; calcd for C16H21N3O4: C, 60.18; H, 6.63; N, 13.16. Found: C, 60.26; H, 6.65; N, 13.00. MS (EI): m/z=259.

Dates

Type	When
Created	23 years, 1 month ago (July 25, 2002, 10:48 a.m.)
Deposited	2 years, 4 months ago (April 9, 2023, 7:19 a.m.)
Indexed	2 weeks, 4 days ago (Aug. 19, 2025, 6:10 a.m.)
Issued	25 years, 8 months ago (Jan. 1, 2000)
Published	25 years, 8 months ago (Jan. 1, 2000)
Published Print	25 years, 8 months ago (Jan. 1, 2000)

Funders 0

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BibTeX

@article{Kappe_2000, title={Highly versatile solid phase synthesis of biofunctional 4-aryl-3,4-dihydropyrimidines using resin-bound isothiourea building blocks and multidirectional resin cleavage}, volume={10}, ISSN={0960-894X}, url={http://dx.doi.org/10.1016/s0960-894x(99)00572-7}, DOI={10.1016/s0960-894x(99)00572-7}, number={1}, journal={Bioorganic & Medicinal Chemistry Letters}, publisher={Elsevier BV}, author={Kappe, C.Oliver}, year={2000}, month=jan, pages={49–51} }

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