Sonogashira reactions with propyne: Facile synthesis of 4-Hydroxy-2-methylbenzofurans from Iodoresorcinols

Organic Process Research and Development

Volumn 14, Issue 1, 2010, Pages 180-187

  Berliner, Martin A ^a   Cordi, Eric M ^a   Dunetz, Joshua R ^a   Price, Kristin E ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 77149164764     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op900263b     Document Type: Article

References (59)

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29. When investigating a Sonogashira approach to 1, our initial concerns centered on the cost and handling of propyne. While somewhat costly on research scale, propyne (which is isolated in pure form by distillation of MAPP gas) is readily available on scale from several suppliers at low cost (less than $150/kg or $6/mol). MAPP gas is composed of propyne, allene, propane, and propene.
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32. A SciFinder search revealed over 2000 unique 2-methylbenzofuran- containing compounds prepared over the past 30 years and one compound (trioxysalen) in clinical use.
33. 4) of commercial 4-bromo-3,5-dihydroxybenzoic acid (Sigma- Aldrich). Iodoresorcinols were prepared by iodination of commercial methyl 3,5-dihydroxybenzoic acid with I2. See the experimental section for details.
34. 2NEt as base in DME was chosen as a reference starting point for reaction exploration based on literature precedent.
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41. Primary resorcinol-based impurities are enyne products derived from alkynylation of the intermediate alkynylresorcinol prior to cyclization. These include adduct i and lesser amounts of higher order enynes ii.
42. When running on the Endeavor system, 100 g tanks of propyne were attached to the secondary gas port. Each reaction was purged with N2 and then placed under a propyne blanket. No propyne purges were carried out.
43. Temperature-dependent activity coefficient data are frequently obtained from binary VLE measurements. Measurement of VLE data in the laboratory can be time consuming; therefore, computational methods accounting for functional group contributions or molecular interaction potential are used to estimate composition and temperature dependent activities of components in a mixture of interest.
44. COSMOthermX, version C21-0108, software for technical computation; COSMOlogic GmbH & Co. KG: Leverkusen, Germany, 2008.
45. The non-random two-liquid (NRTL) solution model was chosen as a descriptor for mixture activity coefficients. COSMOtherm data was regressed into NRTL binary interaction parameters for each solvent pairing with propyne, which were then transferred into an Aspen Plus databank. Reference for NRTL: Seader, J. D.; Henley, E. J. Separation Process Principles; Wiley: New York, 2006; pp 55-56.
46. Aspen Plus, version 7.1 software for technical computation; Aspen Technology: Burlington, MA, 2008.
47. Complete descriptions and data on solubility calculations can be found in the supporting information.
48. The 600 mL Parr reactor used for these experiments has a dip tube for subsurface gas delivery.
49. The mass flow device installed in our kilo facility pressure reactor is calibrated for hydrogen delivery and provided incorrect information during propyne charging operations.
50. Palladium levels dropped somewhat with silica gel chromatography (3% after aqueous work up to 0.5-1.0% after chromatography).
51. On the basis of our dissolution studies, we anticipated that propyne concentrations could be as high as 13 wt%.
52. Water and saturated ammonium chloride were introduced in a 1:1 volume ratio. On scale, water was added first followed by the ammonium chloride solution.
53. As a result of the rapid degassing, when running on larger scale, the water and ammonium chloride solution should be added slowly with aN2 purge. Both the degassing and the heat increase related to the dissolution of DMAc in water were roughly dose controlled.
54. This solvent system was chosen to maximize extraction of propyne related impurities and to minimize loss of benzofuran 1 from the aqueous phase.
55. If the aqueous solution is stored at or below 20 °C, the product will crystallize and hold on to a large amount of dark nonpolar impurities.
56. Procedure reference: Denieul, M.-P.; Laursen, B.; Hazell, R.; Skryd- strup, T. J. Org. Chem. 2000, 65, 6052-6060.
57. The procedure was modified to accommodate solvent restrictions in our scaleup facilities and to improve robustness.
58. An ∼7 mL disposable glass tube purchased from Biotage for use on the Endeavor system.
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