NJC
Letter
temperature for 5 min. Then, NaOH (3 equiv.) was added. The
reaction mixture was stirred at room temperature overnight
until aldehyde consumption. After that, HCl (10%) was added
until neutrality. Then dichloromethane was added to dilute the
reaction mixture. The organic layer was dried over anhydrous
Na2SO4 and concentrated on Rotavapor under reduced pressure.
Finally, the residue was purified by silica gel column chromato-
graphy to give 1a.
A typical procedure for the b-amination of chalcones
A general procedure for the preparation of 2 (2a as an example): a
mixture of chalcone 1a (208 mg, 1.0 mmol), L3 (30.6 mg,
0.1 mmol), and DBU (0.18 mL, 1.2 mmol) in MeCN (2.0 mL) was
stirred at room temperature. NBS (213 mg, 1.2 mmol) was then
added to the mixture. After starting material 1a was consumed as
indicated by TLC, the reaction mixture was poured into water and
then extracted with CH2Cl2 (3 Â 10 mL). The combined organic
phase was washed with water (3 Â 10 mL), dried over anhydrous
MgSO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash chromatography.
Scheme 1 Plausible mechanism for the formation of b-aminoketones.
ortho-substituted phenyl on the phenyl ring R2, no desired
products were obtained (Table 4, entries 7–9). This may be
attributed to the effect of steric hindrance. Besides, this protocol
could also be applied to heterocyclic chalcones as exemplified by
(E)-1-phenyl-3-(pyridin-4-yl)prop-2-en-1-one in 67% yield and 64%
ee (Table 4, entry 11). We further expanded the scope of this
reaction to aliphatic chalcones. Unfortunately, we found that no
desired product was obtained when a methyl substituent was
introduced (R2 = Me) due to side reactions (Table 4, entry 10).
The reaction begins with the formation of intermediate
A from NBS and DBU via halogen bond interaction. Then A
transforms into a more electrophilic species B. Although the
precise reaction mechanism is not clear, we proposed a possible
plausible mechanism based on our work and on pertinent
literature9 (Scheme 1).
In summary, we have developed an efficient enantioselective
b-amination reaction of chalcones into b-imidoketones using NBS
as nucleophilic nitrogen source and bis(oxazoline) as ligand. A
wide variety of b-imidoketone derivatives with various functional
groups were obtained in generally good yields with high enantio-
selectivities. Further transformations of these compounds provide
access to useful intermediates with diverse functionality, such as
building blocks of drugs and biologically active compounds.
Notes and references
1 Recent examples: (a) X. F. Wang, J. An, X. X. Zhang, F. Tan,
J. R. Xiao and W. J. Chen, Org. Lett., 2011, 13, 808; (b) S.
Fustero, S. Monteagudo, S. Flores and P. Barrio, Chem. – Eur. J.,
2010, 16, 9835; (c) Z. L. Yuan, Y. Wei and M. Shi, Eur. J. Org.
Chem., 2010, 4088; (d) S. Fustero, S. Monteagudo, S. Flores
and P. Barrio, Org. Lett., 2010, 12, 5494; (e) Y. F. Cai, X. H. Liu,
Y. H. Hui, J. Jiang, W. T. Wang, W. L. Chen, L. L. Lin and
X. M. Feng, Angew. Chem., Int. Ed., 2010, 49, 6160;
( f ) Y. F. Cai, X. H. Liu, J. Jiang, W. L. Chen, L. L. Lin and
X. M. Feng, J. Am. Chem. Soc., 2011, 133, 5636; (g) W. Yang,
H. X. He, Y. Gao and D. M. Du, Adv. Synth. Catal., 2013,
355, 3670; (h) W. Yang and D. M. Du, Chem. Commun., 2013,
49, 8842.
2 (a) J. Anthony, S. G. Burke, A. Davies and G. Christopher, Org.
Biomol. Chem., 2004, 2, 1387; (b) L. Yang, L. W. Xu, W. Zhou,
L. Li and C. G. Xia, Tetrahedron Lett., 2006, 47, 7723;
(c) M. Suginome, L. Uehlin and M. Murakami, J. Am. Chem.
Soc., 2004, 126, 13196; (d) A. Zarghia, S. A. Webb and
S. Balalaieb, Eur. J. Org. Chem., 1998, 197.
Experimental section
General remarks
All reagents were purchased from commercial sources and used
without treatment, unless otherwise indicated. The products
were purified by column chromatography over silica gel. NMR 3 R. Appel, S. Chelli, T. Tokuyasu, K. Troshin and H. Mayr,
spectra were recorded at 500 MHz using CDCl3 as the solvent.
J. Am. Chem. Soc., 2013, 135, 6579.
Elemental analysis was performed on a Vario EL III recorder. 4 M. Suginome, L. Uehlin, A. Yamamoto and M. Murakami,
Mass spectra were obtained using an automated Fininigan TSQ
Org. Lett., 2004, 6, 1167.
Advantage mass spectrometer. Most of the products were 5 (a) S. A. Pishawikar and H. N. More, Int. J. Pharma Bio Sci.,
known compounds and were identified by comparison of their
physical and spectral data with those of authentic samples. The
enantiomeric excess of the b-imidoketones was determined by
HPLC on an Ultron ES-OVM column.
2013, 4, 549; (b) D. Bhosle, S. Bharambe, N. Gairola and
S. S. Dhaneshwar, Indian J. Pharm. Sci., 2006, 68, 286;
(c) S. N. Pandeya, D. Sriram and G. Nath, Sci. Pharm., 1999,
67, 10; (d) S. N. Pandeya, V. S. Lakshmi and A. Pandeya,
Indian J. Pharm. Sci., 2003, 65, 213; (e) J. V. D. Kamp and
E. Mosettig, J. Am. Chem. Soc., 1936, 58, 1568.
Synthesis of chalcones (1a as an example)
A mixture of acetophenone (10 mmol) and benzaldehyde 6 F. Han, L. Yang, L. Li and C. G. Xia, Org. Biomol. Chem., 2012,
(1.1 equiv.) in anhydrous EtOH (15 mL) was stirred at room 10, 346.
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