Chemistry - A European Journal
10.1002/chem.201602609
COMMUNICATION
an aqueous wash between modules is effective for
tetrabutylammonium salt removal.42 Using this more
environmentally friendly system, pure hydantoin material was
obtained after the two-step process following removal of the
MeTHF:MeOH by evaporation. This continuous process requires
no chromatography.
solvent was removed in vacuo (water bath heated to 60 °C) and
dried under vacuum overnight using an oil bath heated to 60 °C
to obtain pure product.
Acknowledgements
With this semi-continuous process, aromatic and aliphatic
hydantoins were obtained in good yields (Table 4) directly from
primary unprotected amines. The value of this continuous
process is highlighted in entry 3. Generally, α-amino nitriles are
unstable and 2-amino-5,5,5-trifluoropentanenitrile is particularly
labile as it decomposes immediately upon purification.42
However, the continuous process converted the fluorinated
aliphatic amine directly to the corresponding hydantoin by
circumventing the unstable intermediate.
Generous financial support by the Max-Planck-Society (K.G.,
P.H.S.), DAAD (fellowship to S.V.) and the Deutsche
Forschungsgemeinschaft (DFG)-funded Research Training
Group “Fluorine as key element” (S.V., B.K.) are gratefully
acknowledged. Authors also gratefully acknowledge Dmitry B.
Ushakov for fruitful discussions, Jingjing Shao for experimental
help and Günther Hasselof for help with improving the
photoreactor apparatus.
Table 4. The semi-continuous two-step hydantoin synthesis flow process from
Keywords: hydantoins • flow chemistry • multiphase chemistry •
amines.
carbon dioxide
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Crude solution [3 equiv. Hünig’s base in MeOH (0.3 M) was added after
photooxidation] (1 mL min-1), CO2 gas (8 mL min–1) 90 °C, τres = 20 min, 6 bar
BPR. For full reaction details, see supporting information. [b] TMSCN 2.5
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In conclusion, a novel approach to the synthesis of
hydantoins has been developed using consecutive biphasic
gas/liquid reactions in continuous flow. The two-step process
transforms primary amines using highly atom economical (O2:
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environmentally friendly solvents (MeOH and MeTHF).47 Using
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Experimental Section
General Procedure for Continuous Flow Process for
Hydantoin Synthesis from Amines
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TMSCN (3.5 equiv.)48 was added to the solution of amine (0.1 M)
and TPP (1 mg per 5 mL) in MeTHF, followed by addition of a
1.0 M solution of TBAF in THF (4 mol% based on TMSCN). The
resulting solution (1.0 mL min-1) was mixed with oxygen gas (6.0
mL min-1) and pumped through the photoreactor (420 nm LED,
reactor held at -50 °C by cold bath). Hünig’s base in MeOH (0.3
M, 3 equiv. with respect to the amine) was added to the crude
mixture after photooxidative cyanation. The resulting solution
(1.0 mL min-1) was mixed with carbon dioxide gas (8 mL min-1)
and pumped through the 24 mL reactor heated to 90 °C. The
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