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Oxidative Esterification of 3-Phenylpropanal with Hexafluoroisopropanol and an Oxoammonium Salt Oxidant

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DOI: 

Submitted: November 20, 2013, published: November 30, 2013

Authors

Christopher Kelly (christopher.b.kelly@uconn.edu)

Michael Mercadante (michael.mercadante@uconn.edu)

Rebecca Wiles (rebecca.wiles@uconn.edu)

A contribution from 

Reaction Scheme

Chemicals

4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (Prepared In-House, See Comment 1)
3-phenylpropanal (Prepared In-House, See Comment 2)
Hexafluoroisopropanol (99%,Synquest Labs) 
Pyridine (anhydrous, 99.8%, Sigma Aldrich)
 

Procedure

To a one-neck 50 mL round bottom flask equipped with a stir bar was added 3-phenylpropanal (0.671 g, 5 mmol), pyridine3 (5.04 g, 63.75 mmol, 12.75 equiv) and HFIP (2.52 g, 3 equiv). The mixture was allowed to stir at room temperature for approximately five minutes. At this time, the  oxoammonium salt (3.75 g, 12.5 mmol, 2.5 equiv) was added all at once4 and the flask was sealed with a rubber septum. The reaction mixture was stirred at room temperature and gradually turned red.5 Once the reaction was judged6 complete , the HFIP was removed in vacuo by rotary evaporation (≈ 15 mmHg, 37 oC water bath7).  To this thick residue was added pentane8 (≈ 30 mL) causing immediate precipitation of the spent oxidant, the 4-NHAc-TEMPO radical (often called the "nitroxide").   The heterogeneous solution was allowed to stir for five minutes and the solids were filtered off through a medium porosity fritted funnel washing with pentane (≈ 250 mL). The solids were saved9 and filtrate was transferred to a separatory funnel and washed with 0.5 M HCl twice (≈ 150 mL). The organic layer was washed with deionized water (≈ 150 mL) and brine (≈ 150 mL).   The organic layer was dried with Na2SO4 and the solvent was removed in vacuo by rotary evaporation (100 mmHg, 37 oC water bath6)  affording the pure ester (1.31 g, 87%) as a clear, yellow oil. 

Author Comments

1. While this oxoammonium salt is available commercially from Sigma Aldrich, we prefer to prepare in-house than to purchase it. A procedure for its preparation from inexpensive commercially available 4-amino-2,2,6,6-tetramethylpiperidine can be found in the other references section below. A Chemspider Synthetic Page for its preparation is forthcoming.
2. Prepared from 3-phenylpropan-1-ol using a catalytic amount of 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate with bleach as the terminal oxidant. A Chemspider Synthetic Page for its preparation is forthcoming for this transformation.
3. It is highly reccommended that the pyridine used is very dry. This can be accomplished by storage over 4Å molecular sieves. 
4. CAUTION: Mildly exothermic! 
5. The red coloration results from the formation of the spent oxidant, 4-acetamido-(2,2,6,6-tetramethyl-piperidin-1-yl)oxyl (the "nitroxide")
6. The appearance a deep red coloration after addition of the oxoammonium salt likely means the reaction is complete but to ensure complete conversion we typically let the reactions run for 1 hr. If so desired, reaction progress can be monitored by TLC or GC/MS.. Monitoring by NMR is complicated by the presence of the nitroxide so it is not recommended.
7.  Note it is imperative that higher pressures are used during rotary evaporation to ensure good yields. Many of the HFIP esters are highly volatile and can easily be lost during solvent removal at lower pressures.
8. Hexanes can also be used
9. The spent oxidant can be recovered from this impure mixture and used to regenerate the oxoammonium salt. The following is a representative protocol for recovery: The solid material from one 5 mmol scale oxidations was transferred to a 50 mL round bottom flask equipped with stirbar. The flask was charged with 15 mL of CH2Cl2 and stirred for 5 minutes The solution became dark red and a fine white precipitate (pyridinium tetrafluoroborate) was observed. The solution was then filtered through a medium porosity fritted funnel eluting with 40 mL of CH2Cl2. The filtrate was transferred to a 100 mL round bottom flask and the solvent was removed in vacuo by rotary evaporation. Recovery of the oxidant by this method afforded on average 2.2 g of the pure oxyl (≈ 82% recovery, mp: 144-146 °C, lit. 147-148 °C). If desired, further purification can be accomplished by recrystallization from four times its weight of either deionized water or ethyl acetate, with a loss of about 15% in water and 10% in ethyl acetate. However, we found that this was not necessary and the material isolated by this protocol can be used directly for regeneration of the oxoammonium salt according to our established protocol (found in the other references section below).. For the best results, we recommend that regeneration of the oxidant be performed only when a sufficient quantity of the oxyl has been accumulated (≈10 runs on a 5 mmol scale).

 

Data

 1H NMR (CDCl3, 400 MHz) d ppm 2.92 (t, J=7.40 Hz, 2 H) 3.11 (t, J=7.40 Hz, 2 H) 5.89 (spt, J=6.00 Hz, 1 H) 7.27 - 7.36 (m, 3 H) 7.37 - 7.44 (m, 2 H)

13C NMR (CDCl3, 100 MHz) d ppm 30.17 (CH2) 34.56 (CH2) 66.26 (spt, JC-C-F=34.50 Hz, CH) 120.20 (q, JC-F=282.40 Hz, CF3) 126.45 (CH) 127.92 (CH) 128.43 (CH) 138.92 (C) 169.35 (C)

19F NMR (CDCl3, 377 MHz) -76.25 (d, J=6.81 Hz) (Referenced to Hexafluorobenzene, -164.9 ppm)

GC-MS (EI) 300 ([M]+, 45%) 133 (11%) 105 (34) 104 (80%) 103 (15%) 91 (100%) 77 (19%) 69 (13%) 51 (10%)

HRMS (ESI+) calcd for C12H10F6O2 [M+]: 300.0585, found: 300.0609.

Lead Reference

Kelly, C. B.; Mercadante, M. A.; Wiles, R. W.; Leadbeater, N. E. Org. Lett., 2013, 15, 2222

Other References

Mercadante, M. A.; Kelly, C. B.; Bobbitt, J. M.; Tilley, L. J.; Leadbeater N. E. Nat. Protoc. 2013, 8, 666 

Keywords

aldehydes, aromatics/arenes, esters, Green Chemistry, Organic Oxidants, Organofluorine, oxidation, Oxoammonium Salts