5-fluoro-1-indanone( 99% Sigma Aldrich)

morpholine (99+% Aldrich Chemical Company)

The synthesis was performed using standard Schlenk techniques under a nitrogen atmosphere.  To a dried and nitrogen flushed glass microwave reaction vial was added  5-flouro-1-indanone (0.101 g, 0.67 mmol).  The vial's atmosphere was cycled four times. Morpholine (2.0 mL, 0.023 mol, 3.47 equivs.) was added, The reaction was then sealed and heated to 100 ^oC for 20 hours under variable watt microwave heating.  At the completion of the reaction the crude material was transferred to a 50 mL round bottom flask using 3.5 mL ethyl acetate. Silica and ethyl acetate (4.5 mL) were added to the flask and the solvent was removed under reduced pressure to yield a free flowing dry load.  The crude product was then subjected to purification via flash chromatography (75 : 25 ethyl acetate : hexanes) to yield a red solid (144 mg, 98.7%).  

We also ran a larger scale reaction (500 mg 1-indanone, 0.0033 mole) to test scale up.  We observed a reduced yield isolating 523 mg in a 73% yield.  

• The reaction discussed in the lead reference, implementing DMSO as a solvent and a reaction time of three hours, was found to be irreproducible by our group.  We observed only trace conversion using this process.
• Basic silica was critical to obtain a reproducible yield and pure product.  An basic alumina/silica blend was most effective.
• We used a Biotage Emrys Personal Chemistry Optimizer Microwave Synthesizer for microwave heating.
• Conventional heating was also shown to work, though the reaction times were increased, slightly.
• Trace amounts of the enamine have been characterized as the only minor impurity present.
• Synthesis of 5-morpholino-1-indanone via 5-chloro-1-indanone proved unsuccessful via this approach.  The enamine was obtained as the major product. 
• We have found that a variable solvent purification works best.  Running a nonpolar mix to remove the enamine and they switching to higher polarity to remove the desired product.

¹H NMR:  (CDCl₃) δ ppm 2.59-2.62 (m, 2H), 3.01 (t, J=5.7 Hz, 2H), 3.30 (t, J=5.0 Hz, 4H), 3.83 (t, J=4.7 Hz, 4H), 6.78 (m, 6.78-6.79, 1H), 6.83-6.86 (m, 1H), 7.61 (d, J=8.8 Hz, 1H).

¹³C NMR:  (CDCl₃) δ ppm 25.8, 36.3, 47.6, 66.4, 109.7, 114.0, 124.9, 128.2, 155.8, 157.7, 204.9

GCMS EI [M⁺]  Predicted: 217.2, Actual: 217

Chern, C.-Y.; Yek, Y.-L.; Chen, Y.-L.; Kan, W.-M. J. Chin. Chem. Soc. 2008, 55, 846–853.

Dinges, J.; Albert, D.H.; Arnold, L.D.; Ashworth, K.L.; et al J. Med Chem. 2007, 50, 2011-2029