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J. L. Monteiro et al.
Letter
Synlett
2015, 71, 2409. (b) Matys, A.; Podlewska, S.; Witek, K.; Witek, J.;
Bojarski, A. J.; Schabikowski, J.; Otrebska-Machaj, E.; Latacz, G.;
Szymanska, W.; Kiec-Kononowicz, K.; Molnar, J.; Amaral, L.;
Handzlik, J. Eur. J. Med. Chem. 2015, 101, 313. (c) Knizhnikov, V.
O.; Voitenko, Z. V.; Golovko, V. B.; Gorichko, M. V. Tetrahedron:
Asymmetry 2012, 23, 1080. (d) Anson, M. S.; Clark, H. F.; Evans,
P.; Fox, M. E.; Graham, J. P.; Griffiths, N. N.; Meek, G.; Ramsden,
J. A.; Roberts, A. J.; Simmonds, S.; Walker, M. D.; Willets, M. Org.
Process. Res. Dev. 2011, 15, 389.
(22) General Experimental Procedure for the Continuous Buch-
erer–Bergs Reaction
Feed A consisting of the carbonyl compound 1a–k dissolved in
EtOAc was pumped with a flow rate of 70 μL min–1 and merged
in a T-shaped mixing unit with a second feed (430 μL min–1
)
containing an aqueous solution of (NH4)2CO3 (3.5 equiv) and
KCN (1.5 equiv). The combined mixture was passed through a
coil reactor made out of Hastelloy (16 mL internal volume, 32
min residence time) at 120 °C and 20 bar back pressure. To
avoid precipitation of the corresponding hydantoin, the back
pressure regulating unit was heated to 120 °C. The reaction
mixture was collected in a sealed flask and subsequently acidi-
fied with concentrated HCl. Workup by extraction with EtOAc
or crystallization afforded the respective hydantoins 2a–k in
analytical purity.
(10) Chubb, F. L.; Edward, J. T.; Wong, S. C. J. Org. Chem. 1980, 45,
2315.
(11) For recent reviews on flow chemistry, see: (a) Gutmann, B.;
Cantillo, D.; Kappe, C. O. Angew. Chem. Int. Ed. 2015, 54, 6688.
(b) Jensen, K. F.; Reizmana, B. J.; Newman, S. G. Lab Chip 2014,
14, 3206. (c) Wiles, C.; Watts, P. Green Chem. 2014, 16, 55.
(d) Newman, S. G.; Jensen, K. F. Green Chem. 2013, 15, 1456.
(e) Baxendale, I. R.; Brocken, L.; Mallia, C. J. Green Process. Synth.
2013, 2, 211. (f) McQuade, D. T.; Seeberger, P. H. J. Org. Chem.
2013, 78, 6384. (g) Pastre, J. C.; Browne, D. L.; Ley, S. V. Chem.
Soc. Rev. 2013, 42, 8849.
(12) For selected examples of multicomponent reactions in flow,
see: (a) Salvador, C. E. M.; Pieber, B.; Neu, P. M.; Torvisco, A.;
Andrade, C. K. Z.; Kappe, C. O. J. Org. Chem. 2015, 80, 4590.
(b) Silva, G. C. O.; Correa, J. R.; Rodrigues, M. O.; Alvim, H. G. O.;
Guido, B. C.; Gatto, C. C.; Wanderley, K. A.; Fioramonte, M.;
Gozzo, F. C.; de Souza, R. O. M. A.; Neto, B. A. D. RSC Adv. 2015, 5,
48506. (c) Sharma, S.; Maurya, R. A.; Min, K.-I.; Jeong, G.-Y.;
Kim, D.-P. Angew. Chem. Int. Ed. 2013, 52, 7564. (d) Pagano, N.;
Herath, A.; Cosford, N. D. P. J. Flow Chem. 2011, 1, 28.
(e) Baumann, M.; Baxendale, I. R.; Kirschning, A.; Ley, S. V.;
Wegner, J. Heterocycles 2011, 82, 1297. (f) Herath, A.; Cosford, N.
D. P. Org. Lett. 2010, 12, 5182.
Analytical Data for Compound 2a
Feed A: acetophenone (2.53 mmol, 5.0 M in EtOAc). Feed B: KCN
(1.24 M), (NH4)2CO3 (2.88 M) in H2O. Isolation by extraction
afforded the title compound in 91% yield (440 mg, 2.31 mmol)
as a colorless solid; mp 197–199 °C. 1H NMR (300 MHz, DMSO):
δ = 10.77 (s, 1 H), 8.62 (s, 1 H), 7.50–7.46 (m, 2 H), 7.43–7.30 (m,
3 H), 1.66 (s, 3 H). 13C NMR (75 MHz, DMSO): δ = 177.42, 156.69,
140.37, 128.93, 128.26, 125.77, 64.35, 25.39.
(23) The solubility of DMDH in water causes relatively low isolated
yields and recovery rates: Wagner, E. C.; Baizer, M. Org. Synth.
1940, 20, 42.
(24) (a) Khanfar, M. A.; Asal, B. A.; Mudit, M.; Kaddoumi, A.; El Sayed,
K. A. Bioorg. Med. Chem. 2009, 17, 6032. (b) Hamilton, G. S. US
20020058685, 2002.
(25) Vanzolini, K.; Vieira, L. C. C.; Cardoso, C. L.; Correa, A. G.; Cass, Q.
B. J. Med. Chem. 2013, 56, 2038.
(26) Jain, R. K.; Low, E.; Francavilla, C.; Shiau, T. P.; Kim, B.; Nair, S. K.
WO 2010054009, 2010.
(27) Very recently, a similar observation was reported for the N-
alkylation of Riboflavin derivatives: Silva, A. V.; López-Sánchez,
A.; Junqueira, H. C.; Rivas, L.; Baptista, M. S.; Orellana, G. Tetra-
hedron 2015, 71, 457.
(28) General Experimental Procedure for the Selective N(3)-
Monoalkylation of Hydantoins
(13) For continuous-flow reactions involving cyanides, see:
(a) Heugebaert, T. S. A.; Roman, B. I.; De Blieck, A.; Stevens, C. V.
Tetrahedron Lett. 2010, 51, 4189. (b) Wiles, C.; Watts, P. Eur. J.
Org. Chem. 2008, 5597. (c) Wiles, C.; Watts, P. Org. Process Res.
Dev. 2008, 12, 1001. (d) Acke, D. R. J.; Stevens, C. V. Green Chem.
2007, 9, 386.
(14) Hessel, V.; Kralisch, D.; Kockmann, N.; Noel, T.; Wang, Q. Chem-
SusChem 2013, 6, 746.
A sealed 10 mL microwave process vial containing a mixture of
the respective hydantoin (0.5–1.0 mmol), K2CO3 (1.1 equiv), and
(5-bromopenthyl)trimethylammonium bromide (1.2 equiv) in
MeCN (2 mL) was heated for 10–45 min at 120 °C using a single-
mode microwave reactor. After cooling to r.t. the reaction
mixture was concentrated. The organic material was dissolved
in MeCN, and the inorganic salts were separated by filtration.
Evaporation of the solvent resulted in a solid material which
was carefully washed with cold EtOH before drying affording
the respective N-substituted hydantoins 4a–k in analytical
purity.
(15) For selected examples of biphasic liquid/liquid reactions in flow,
see: (a) Van Waes, F. E. A.; Seghers, S.; Dermaut, W.; Cappuyns,
B.; Stevens, C. V. J. Flow Chem. 2014, 4, 118. (b) Damm, M.;
Gutmann, B.; Kappe, C. O. ChemSusChem 2013, 6, 978.
(c) Mehenni, H.; Sinatra, L.; Mahfouz, R.; Katsiev, K.; Bakr, O. M.
RSC Adv. 2013, 3, 22397. (d) Reichart, B.; Kappe, C. O.; Glasnov,
T. Synlett 2013, 24, 2393.
(16) For details about the continuous-flow setup, see the Supporting
Information.
(17) The flow regimes were monitored in a transparent perfluoro-
alkoxy tubing between the mixing unit and the Hastelloy coil.
(18) For a recent discussion on microwave assisted organic synthe-
sis, see: Kappe, C. O.; Pieber, B.; Dallinger, D. Angew. Chem. Int.
Ed. 2013, 52, 1088; and references cited therein.
(19) For details, see Table S1 and Figure S2 in the Supporting Infor-
mation.
(20) In many cases microwave chemistry examples can be directly
translated to continuous-flow applications: Glasnov, T. N.;
Kappe, C. O. Chem. Eur. J. 2011, 17, 11956.
Analytical Data for Compound 4a
Reaction time: 10 min; yield: 66% (130 mg, 0.33 mmol) as color-
less solid; mp 222–224 °C. 1H NMR (300 MHz, DMSO): δ = 8.90
(s, 1 H), 7.49–7.31 (m, 5 H), 3.43–3.33 (m, 4 H), 3.25–3.19 (m, 2
H), 3.02 (s, 9 H), 1.68 (s, 3 H), 1.60–1.50 (m, 2 H), 1.25–1.15 (m,
2 H). 13C NMR (75 MHz, DMSO): δ = 175.85, 156.11, 140.06,
129.05, 128.43, 125.81, 65.46, 63.14, 52.60, 52.56, 52.52, 37.94,
27.54, 25.40, 23.42, 22.03. HRMS (APCI): m/z calcd for
C
18H28N3O2+ [M – Br–]+: 318.217604; found: 318.217459.
(21) Obermayer, D.; Damm, M.; Kappe, C. O. Org. Biomol. Chem.
2013, 11, 4949.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 83–87