High Throughput Synthesis of Functionalised 1,3-Diones and Subsequent Heterocycle Formation

Abstract

A functionalisation of 1,3-diones using hypervalent iodine has been developed that is useful in the preparation of libraries of heterocyclic compounds.

Key words

iodosylbenzene - alcohols - combinatorial chemistry - heterocycles - diones

References

• 1 Hobbs De Witt S. In The Practice of Medicinal Chemistry   Wermuth CG. Academic Press; San Diego: 2001. 
• 2 Deegan TL. Nitz TJ. Cebzanov D. Pufko DE. Porco JA. Bioorg. Med. Chem. Lett.  1999,  9:  209 
• 3 Joule JA. Mills K. Heterocyclic Chemistry   Blackwell Science; Oxford: 2000. 
• 4 Koser GF. Aldrichimica Acta  2001,  34:  89 
• 5 Moriarty RM. Kosmeder JW. In Encyclopedia of Reagents for Organic Synthesis   Vol. 5:  Paquette LA. John Wiley and Sons; Chichester: 1995. 
• 6 Baum JS. Shook DA. Davies HML. Smith HD. Synth. Commun.  1987,  17:  1709 
• 7a Cox GC. Miller DJ. Moody CJ. Sie EH. Kulagowski JJ. Tetrahedron  1994,  50:  3195 
• 7b Kettle JG. Faull AW. Fillery SM. Flynn AP. Hoyle MA. Hudson JA. Tetrahedron Lett.  2000,  41:  6905 
• 7c Nelson TD. Song JK. Thompson AS. Zhao M. DeMarco A. Reamer RA. Huntington MF. Grabowski EJJ. Reider PJ. Tetrahedron Lett.  2000,  41:  1877 
• 8 Moriarty RM. Vaid RK. Ravikumar VT. Vaid BK. Hopkins TE. Tetrahedron  1988,  44:  1603 
• 9a Ochiai M. Sumi K. Takaoka Y. Kunishima M. Nagao Y. Shiro M. Fujita E. Tetrahedron  1988,  44:  4095 
• 9b Ochiai M. Kunishima M. Sumi K. Nagao Y. Tetrahedron Lett.  1985,  26:  4501 
• 9c Ochiai M. Ito T. Takaoka Y. Masaki Y. Kunishima M. Tani S. Nagao Y. J. Chem. Soc., Chem. Commun.  1990,  118 
• 10a Ochiai M. Takaoka Y. Nagao Y. J. Am. Chem. Soc.  1988,  110:  6565 
• 10b Ochiai M. Kunishima M. Tani S. Nagao Y. J. Am. Chem. Soc.  1991,  113:  3135 
• 10c Ochiai M. Uemara K. Masaki Y. J. Am. Chem. Soc.  1993,  115:  2528 
• 12 Moriarty RM. Vaid RK. Duncan MP. Ochiai M. Inenaga I. Nagao Y. Tetrahedron Lett.  1988,  29:  6913 

11

The reactions were conducted in 96 well plates and the experimental procedure for a representative sample was as follows: To a solution of 3-methylbenzyl alcohol (14 mg, 117 µmol) in chloroform (0.25 mL) was added 3,5-heptanedione (10 mg, 78 µmol) in chloroform (0.20 mL), boron trifluoride etherate (12 µl, 93µmol) and iodosyl-benzene (20 mg, 93 µmol). After being shaken for 12 h water (0.30 mL) was added and the plate shaken for a further
10 min. The aq layer was removed and hydrazine (5 µL,
117 µmol) added and the plate shaken for 12 h. The solvent was removed under reduced pressure and the residue purified by HPLC using a Phenomenex Luna C₈ column eluted with trifluoroacetic acid in water(0.1% v/v): acetonitrile (95:5) (10 mL/min) to furnish 3,5-diethyl-1H-pyrazol-4-yl-3-methylbenzyl ether (5 mg, 28%); retention time 3.24 min; ¹H NMR (500 MHz; CDCl₃): δ = 7.26 (1 H, dd, J = 7.4, 7.4 Hz), 7.20 (1 H, s), 7.17 (1 H, d, J = 7.4 Hz), 7.15 (1 H, d, J = 7.4 Hz), 4.78 (2 H, s), 2.53 (4 H, q, J = 7.7 Hz), 2.37 (3 H, s), 1.21 (6 H, t, J = 7.7 Hz); LRMS: m/z = 245, MH⁺.