Green Chemistry
Page 4 of 5
mechanism cannot be ruled out in the elimination step.
β-amino ketone 6, followed by three possible reaction pathways
(a) Concise Synthesis of Cytotoxic Dihydrochalcone 4 in Four Steps
DOI: 10.1039/C3GC41403E
OH
O
OMe O
20 hand, a mechanism involving two radical direct coupling between
ketone and benzylamine cannot be ruled out for the generation of
intermediate 6.
4 steps
Me
OH
24.4% overall yield
HO
HO
OH
OMe
1b
4
In summary, we developed an operationally simple, metal-free
tandem CDC/elimination reaction to prepare synthetically useful
25 chalcone derivatives. A simple ammonium persulfate allows the
reaction between readily available ketones and benzylamines to
proceed with high chemo- and stereoselectivity. A wide range of
functional groups are well tolerated by the synthetic system.
Furthermore, the utility of the methodology in highly efficient
30 synthesis of biologically interesting cytotoxic dihydrochalcone
and flavonoid derivatives is demonstrated. We believe that the
methodology could provide a beneficial complementarity for
current synthetic strategies to the formation of chalcone
derivatives. Detailed mechanistic studies are ongoing in our
35 laboratory.
NHMe
H
OMe O
OMe O
OMe
2f
Me
OH
(NH4)2S2O8, tert-Amyl-OH
HO
OH
3y, 55% yield
OMe
HO
120 oC, 24 h
1c
(b) Incorporating into a Tandem Protocol for the Synthesis of Flavonoid Derivative 5
O
O
O
2b, (NH4)2S2O8 (3.0 equiv)
CuI (20 mol %)
Me
tert-Amyl-OH, 120 oC, 48 h
OH
1d
O
Ph
OH Ph
3z
one-pot operation
5, 79% yield
Scheme 2 Application to the Highly Efficient Synthesis of Biologically
Active Molecules.
Acknowledgements
without oxidant
3f
O
tert-Amyl-OH, 120 oC, 24 h
44% yielda
Support for this work by XJTU from a start-up fund and NSFC,
P. R. China (No. 21202128) is gratefully acknowledged.
H
Ph
H
(eq 1)
Ph
NHBn
3f
(NH4)2S2O8 (3.0 equiv)
61% yielda
6
Notes and references
tert-Amyl-OH, 120 oC, 24 h
40 a Center for Organic Chemistry, Frontier Institute of Science and
Technology, Xi’an Jiaotong University, Xi’an, Shaanxi, 710054, P. R.
China. Fax: (+81)-29-83395321; Tel: (+81)-29-83395321; E-mail:
† Electronic Supplementary Information (ESI) available: [Experimental
45 procedures and product characterization]. See DOI: 10.1039/b000000x/
Cope type-elimination
O
H
H
without oxidant
Ph
HSO4
NH2Bn
(eq 2)
3f
Ph
tert-Amyl-OH, 120 oC, 24 h
93% yielda
7
Hofmann type-elimination
1H NMR yield using tetrachloroethane as an internal standard.
a
5
1
For selected recent reviews, see: (a) Z. Nowakowska, Eur. J. Med.
Chem., 2007, 42, 125–137; (b) N. K. Sahu, S. S. Balbhadra, J.
Choudhary and D. V. Kohli, Curr. Med. Chem., 2012, 19, 209–225;
For selected recent examples, see: (c) J. N. Domínguez, C. León, J.
Rodrigues, N. G. de Domínguez, J. Gut and P. J. Rosenthal, J. Med.
Chem., 2005, 48, 3654–3658; (d) S. F. Nielsen, M. Larsen, T.
Boesen, K. Schønning and H. Kromann, J. Med. Chem., 2005, 48,
2667–2677; (e) R. Kachadourian, B. J. Day, S. Pugazhenti, C. C.
Franklin, E. Genoux-Bastide, G. Mahaffey, C. Gauthier, A. D. Pietro
and A. Boumendjel, J. Med. Chem., 2012, 55, 1382−1388; (f) Z.
Qiao, Q. Wang, F. Zhang, Z. Wang, T. Bowling, B. Nare, R. T.
Jacobs, J. Zhang, D. Ding, Y. Liu and H. Zhou, J. Med. Chem., 2012,
55, 3553−3557.
2-
•−
S2O8
SO4
BnHN
BnHN
BnHN
Ph
Ph
B
iminium ion
Ph
H
50
55
60
2-
H+ + SO4
SO42- + SO4
•−
2d
A
OH
OH
O
–H+
H+
H
Ph
Ph
Ph
H+
1f''
1f
1f'
path a: (NH4)2S2O8
Cope-type elimination
2
3
C. Thebtaranonth and Y. Thebtaranonth in The Chemistry of Enones,
Vol. 29 (Eds.: S. Patai and Z. Rappoport), Wiley, New York, 1989,
pp. 199–280.
(a) T. J. J. Müller, M. Ansorge and D. Aktah, Angew. Chem., Int. Ed.,
2000, 39, 1253–1256; (b) R. U. Braun, M. Ansorge and T. J. J.
Müller, Chem.–Eur. J., 2006, 12, 9081–9094.
O
O
NHBn
Ph
path b: H+
Ph
Ph
Ph
Hofmann-type elimination
3f
6
path c
– BnNH2
65 4 (a) X.-F. Wu, H. Neumann and M. Beller, Angew. Chem., Int. Ed.,
2010, 49, 5284–5288; (b) X.-F. Wu, H. Neumann, A. Spannenberg,
T. Schulz, H. Jiao and M. Beller, J. Am. Chem. Soc., 2010, 132,
14596–14602; (c) P. Hermange, T. M. Gøgsig, A. T. Lindhardt, R. H.
Taaning and T. Skrydstrup, Org. Lett., 2011, 13, 2444–2447.
70 5 (a) Y. Shang, X. Jie, J. Zhou, P. Hu, S. Huang and W. Su, Angew.
Chem., Int. Ed., 2013, 52, 1299–1303; (b) (b) J. Zhou, G. Wu, M.
Zhang, X. Jie, W. Su, Chem.–Eur. J. 2012, 18, 8032–8036.
Scheme 3 Proposed Mechanism.
Based to these preliminary study results, a viable mechanism is
proposed as shown in Scheme 3. A single electron transfer (SET)
10 from dibenzylamine 2d to persulfate anion may initially proceed
giving a radical cation A while generation of sulfate dianion and
sulfate radical anion.12 Subsequent the related iminium ion B and
acidity proton can be produced from the reaction between A and
sulfate radical anion.13 Under the acidity circumstance, the ketone
15 1f may undergo an isomerization leading to the enol compound
1f’’, which then nucleophilic attack the iminium ion B giving the
6
The CDC reaction between ketones and tertiary amines has been
reported using copper catalyst, see: Y. Shen, M. Li, S. Wang, T.
Zhan, Z. Tan and C.-C. Guo, Chem. Commun., 2009, 953–955.
For selected recent reviews on CDC reactions, see: (a) C.-J. Li, Acc.
Chem. Res., 2009, 42, 335–344; (b) C. S. Yeung and V. M. Dong,
Chem. Rev., 2011, 111, 1215–1292; (c) C. J. Scheuermann, Chem.–
75
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