N-bromosuccinimide/1,8-diazabicyclo[5.4.1]undec-7-ene combination: β-amination of chalcones via a tandem bromoamination/debromination sequence

Article abstract of DOI:10.1021/ol303539u

A one-pot cascade transformation of chalcones into β-imidoketones has been developed, in which NBS provides both electrophilic bromine and nucleophilic nitrogen sources, and DBU functions as a nucleophilic reagent to activate NBS to be a more electrophilic bromine species and to further remove the bromine of α-bromoketones. The whole process involves tandem bromoamination and debromination, which represents a unique example of preparing β-aminoketones by the reaction of chalcones with the NBS/DBU combination.

Full text of DOI:10.1021/ol303539u

ORGANIC
LETTERS
2013
Vol. 15, No. 4
852–855
N‑Bromosuccinimide/
1,8-Diazabicyclo[5.4.1]undec-7-ene
Combination: β‑Amination of Chalcones
via a Tandem Bromoamination/
Debromination Sequence
Ying Wei,† Shaoxia Lin,† Fushun Liang,*,†,‡ and Jingping Zhang†
Department of Chemistry, Northeast Normal University, Changchun 130024, China, and
Key Laboratory for UV-Emitting Materials and Technology of Ministry of Education,
Northeast Normal University, Changchun 130024, China
liangfs112@nenu.edu.cn
Received December 26, 2012
ABSTRACT
A one-pot cascade transformation of chalcones into β-imidoketones has been developed, in which NBS provides both electrophilic bromine and
nucleophilic nitrogen sources, and DBU functions as a nucleophilic reagent to activate NBS to be a more electrophilic bromine species and to
further remove the bromine of R-bromoketones. The whole process involves tandem bromoamination and debromination, which represents a
unique example of preparing β-aminoketones by the reaction of chalcones with the NBS/DBU combination.
β-Aminoketones are highly valuable molecules regard-
ing their vast applications as building blocks of drugs and
biologically active compounds.1 Conventional approaches
for the synthesis of β-aminoketones include the Mannich
reaction of methyl ketones with an amine and para-
formaldehyde,2 amination of β-haloalkyl ketones, and
aza-Michael addition of an appropriate N-nucleophile to
an R,β-unsaturated ketone.3 To date, some new methods
have been developed for the synthesis of β-aminoketones.4ꢀ7
For example, the Gomtsyan group reported the addition
of vinyl Grignard reagents to N-methoxyamides.4 Tu and
co-workers developed an aziridino alcohol rearrangement
(semipinacol rearrangement) as an efficient approach to-
ward β-aminoketones.5 Additionally, the N-heterocyclic
carbene mediated reaction of enals with aziridines6 and
the CuBr/TBHP catalyzed reaction of silyl enol ethers
and N,N-dimethylaniline7 have been recently presented.
Although a variety of methods have been reported, further
development of more efficient and atom-economical routes
† Department of Chemistry.
‡ Key Laboratory for UV-Emitting Materials and Technology of Ministry
of Education.
(1) (a) Buchi, G.; Gould, S. J.; Naf, F. J. Am. Chem. Soc. 1971, 93,
2492. (b) Traxler, P.; Trinks, U.; Buchdunger, E.; Mett, H.; Meyer, T.;
€
€
Muller, M.; Regenass, U.; Rosel, J.; Lydon, N. J. Med. Chem. 1995, 38,
2441. (c) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 25, 117. (d)
Devine, P. N.; Heid, R. M.; Tschaen, D. M. Tetrahedron 1997, 53, 6739.
(2) (a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed.
1998, 37, 1044. (b) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.
(c) Miura, K.; Tamaki, K.; Nakagawa, T.; Hosomi, A. Angew. Chem.,
Int. Ed. 2000, 39, 1958.
(3) (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthe-
sis; Pergamon Press: Oxford, 1992. (b) Bartoli, G.; Bosco, M.; Marcantoni, E.;
Petrini, M.; Sambri, L.; Torregiani, E. J. Org. Chem. 2001, 66, 9052.
(c) Wabnitz, T. C.; Spencer, J. B. Tetrahedron Lett. 2002, 43, 3891.
(d) Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109.
(4) (a) Gomtsyan, A. Org. Lett. 2000, 2, 11. (b) Gomtsyan, A.;
Koening, R. J.; Lee, C.-H. J. Org. Chem. 2001, 66, 3613.
(5) (a) Wang, B. M.; Song, Z. L.; Fan, C. A.; Tu, Y. Q.; Shi, Y. Org.
Lett. 2002, 4, 363. (b) Song, Z. L.; Wang, B. M.; Tu, Y. Q.; Fan, C. A.;
Zhang, S. Y. Org. Lett. 2002, 5, 2319. (c) Song, Z. L.; Fan, C. A.; Tu,
Y. Q. Chem. Rev. 2011, 111, 7523.
(6) Yadav, L. D. S.; Rai, V. K.; Singh, S.; Singh, P. Tetrahedron Lett.
2010, 51, 1657.
(7) (a) Huang, L, H.; Zhang, X. B.; Zhang, Y. H. Org. Lett. 2009, 4,
363. (b) Gao, R. L.; Yi, C. S. ACS Catal. 2011, 1, 544.
r
10.1021/ol303539u
Published on Web 01/31/2013
2013 American Chemical Society

to β-aminoketones still remains a hot topic in modern
organic synthesis.
Table 1. Optimization of the Reaction Conditionsa
In our research on halogen (e.g., halogenation, halo-
nium, hypervalent halogen, and halogen bond) mediated
organic reactions,8 we recently reported a one-pot cascade
reaction of methyl ketones with the NBS/DBU combina-
tion affording R-aminoketones (Scheme 1a).8c In this
reaction, NBS plays a dual role in providing both electro-
philic bromine and nucleophilic nitrogen sources, and
DBU functions as a base to deprotonate methyl ketones
to be enolates and a nucleophilic promoter to activate NBS
to be a more electrophilic bromine species. In our continued
work, we became interested in exploring the reaction
with chalcone substrates. As a result, β-aminoketones were
achieved via a domino bromoamination/debromination
sequence, which provides a convenient and economic route
toward β-aminoketones (Scheme 1b). This represents a
unique example of preparing β-aminoketones by the reac-
tion of chalcones with the NBS/DBU combination.9
2a yield
entry
base
solvent
(%)b
1
NaOH
NaOEt
NaH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
n.r.
n.r.
n.r.
n.r.
n.r.
75
2
3
4
t-BuOK
DABCO
DBN
5
6
7
DBU
78
8
DBU
67
9
DBU
toluene
MeCN
DMF
51
10
11
DBU
81
DBU
70
a Reactions were carried out with 1a (1.0 mmol), NBS (1.2 equiv),
and base (1.2 equiv) in solvent (2.0 mL) for 12 h. b Isolated yield.
Scheme 1. R- vs β-Aminoketones by a Combination of NBS and
DBU
Table 2. Tandem Reactions of Chalcones with NBS and DBU
Combinationa
Initially, the model reaction of chalcone 1a with NBS
was examined under basic conditions (Table 1). No reac-
tion occurred in CH2Cl2 at rt, by the utilization of NaOH,
NaOEt, NaH, t-BuOK, and DABCO as the base (entries 1ꢀ5).
Gratifyingly, the reaction with DBN or DBU (1.2 equiv)10
as the base in CH2Cl2 gave 1-(3-oxo-1,3-diphenylpropyl)-
pyrrolidine-2,5-dione (2a) in 75% and 78% yield, respec-
tively (entries 6 and 7). When THF, toluene, and DMF
were selected as the solvent, the yields decreased (entries 8,
9, and 11). Among all the solvents tested, MeCN was
the most efficient, affording 2a in 81% yield (entry 10).
One can see that DBU and DBN worked well in the one-
pot amination reaction while other bases were inefficient.
The reason for this may be attributed to the activation of
NBS by DBU or DBN to be a more electrophilic bromine
species via halogen bond interaction.11,12 Additionally,
NIS and NCS showed similar reactivity to NBS.
entry
1
R1
R2
2
yield (%)b
1
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
2b
2c
2d
2e
2f
81
84
83
84
79
82
81
83
79
80
80
85
81
87
86
82
81
85
84
2
4-MeC6H4
4-MeOC6H4
3,4-O2CH2Ph
2-ClC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
2-NO2C6H4
3-NO2C6H4
2-furyl
2-thienyl
t-Bu
3
4
5
6
7
1g
1h
1i
2g
2h
2i
8
9
10
11
12
13
14
15
16
17
18
19
1j
2j
1k
1l
2k
2l
1m
1n
1o
1p
1q
1r
1s
2m
2n
2o
2p
2q
2r
2s
4-BrC6H4
4-ClC6H4
4-MeOC6H4
4-MeC6H4
2-naphthyl
2-pyridyl
Ph
Under the optimized conditions (Table 1, entry 10), a
range of reactions were carried out with various chalcones
Ph
Ph
Ph
Ph
(8) (a) Wei, Y.; Lin, S.; Zhang, J.; Niu, Z.; Fu, Q.; Liang, F. Chem.
Commun. 2011, 47, 12394. (b) Wei, Y.; Lin, S.; Xue, H.; Liang, F.; Zhao,
B. Org. Lett. 2012, 14, 712. (c) Wei, Y.; Lin, S.; Liang, F. Org. Lett. 2012,
14, 4202. (d) Zhang, J.; Wei, Y.; Lin, S.; Liang, F.; Liu, P. Org. Biomol.
Chem. 2012, 10, 9237.
Ph
a Reactions were carried out with 1 (1.0 mmol), NBS (1.2 equiv), and
DBU (1.2 equiv) in MeCN (2.0 mL) for 12 h. b Isolated yield.
(9) Generally, the reaction of R,β-unsaturated enones with NBS gave
haloaminated products under acidic conditions, most often with ex-
ternal amino sources. Examples with the imido moiety from NBS itself
are rare. For such a recent example of vicinal haloimination of enecar-
bamates with NBS catalyzed by phosphate salt, see: Alix, A.; Lalli, C.;
Retailleau, P.; Masson, G. J. Am. Chem. Soc. 2012, 134, 10389.
(10) It was found that a catalytic amount (e.g., 0.2 equiv) of DBU was
not enough to drive the reaction to completion.
1 and NBS (1.2 equiv) inthepresenceof DBU (1.2equiv) in
MeCN (Table 2). The reactions proceeded smoothly to
afford the corresponding β-imidoketones 2aꢀs in moder-
ate to high yields (79ꢀ87%). The R2 group of substrate
Org. Lett., Vol. 15, No. 4, 2013
853

Scheme 3. Control Experiments
Figure 1. ORTEP drawing of 2f.
1 may be either electron-rich (entries 1ꢀ4) or electron-
deficient aryl (entries 5ꢀ10), heteroaryl (entries 11 and 12),
and alkyl groups (entry 13). The R1 substituents were also
broad, including electron-deficient aryl (entries 14 and 15),
electron-rich aryl (entries 16 and 17), naphthyl (entry 18),
and heteroaryl (entry 19). The structure of 2f was con-
firmed by the single-crystal X-ray diffraction (Figure 1).13
The scope of the reaction was further explored in regard to
R,β-unsatured enone substrates (Scheme 2). Nevertheless,
when cinnamaldehyde (R = H), ethyl cinnamate (R = OEt),
and 4,4-dimethyl-1-phenylpent-1-en-3-one (R = t-Bu) were
subjected to otherwise identical conditions, no desired pro-
ducts were obtained.14
indicated that dioxygen in air might facilitate the reaction,
although the reason was still unclear.15 Comparatively,
the mixture of chalcone 1a, succimide (1.2 equiv), and
DBU (1.2 equiv) stirred in MeCN either at rt or at 60 °C
did not give the β-imidated product 2a (eq 3). The results
indicated that such a transformation cannot be readily
achieved via Michael addition, due to the weak nucleo-
philicity of the corresponding succimide anion.3
On the basis of all the results described above, along
with our previous work,8c a plausible mechanism for the
β-imidation of chalcones was proposed, as depicted in
Scheme 4.16 First, NBS reacts with DBU to form a 1:1
adduct I via halogen bond interaction,11 which further
transforms into a more electrophilic species II.17 Second,
reaction between chalcones and activated bromide II
furnishes DBU-stabilized bromonium ion III.18,19 Nucleo-
philic attack of III by the succinimide anion IV leads to
the formation of β-imino-R-brominated ketone V. Third,
Scheme 2. Further Scope Exploration
To gain insight into the mechanism, several control experi-
ments were performed (Scheme 3). In order to explore the
influence of water in the reaction system, the reaction of
chalcone 1a and NBS/DBU was conducted in dry MeCN,
(15) Indeed, in the experiment we found that all the reactions need to
be carried out in the open air. Reactions in a sealed tube would lead to a
prolonged reaction time with slightly lowered yields.
(16) The authors would like to thank the reviewers for the valuable
suggestion for the proposed mechanism.
(17) For a recent review of NBS activation by a Lewis base, see: (a)
Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew. Chem., Int. Ed.
2012, 52, 2. Selected papers: For NBS/Ph3P, see: (b) Sakakura, A.; Ukai,
˚
along with the addition of 4 A MS (eq 1). As a result,
product 2a was not observed with intact substrate 1a
retractable. It was thus concluded that a trace amount of
water is crucial for the reaction to proceed. Furthermore,
no reaction took place if the same reaction was performed
in wet MeCN under a N2 atmosphere (eq 2). This
A.; Ishihara, K. Nature 2007, 445, 900. For Et2SBr SbCl5Br, see: (c)
3
Snyder, S. A.; Treitler, D. S. Angew. Chem., Int. Ed. 2009, 48, 7899. For
the bromocollidinium ion, see: (d) Cui, X.-L.; Brown, R. S. J. Org.
Chem. 2000, 65, 5653.
(18) For Lewis base stabilized bromonium intermediates, refer to: (a)
Denmark, S. E.; Burk, M. T. Proc. Natl. Acad. Sci. U.S.A. 2010, 107,
20655. (b) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew. Chem.,
Int. Ed. 2012, 51, 10938. (c) Cheng, Y. A.; Chen, T.; Tan, C. K.; Heng,
J. J.; Yeung, Y.-Y. J. Am. Chem. Soc. 2012, 134, 16492.
(11) For halogen bond complexes formed between imines and NIS,
ꢀ
A.; Gomez-Sal, P.; Vaquero, J. J. Chem. Commun. 2007, 1281. DABCO
see: (a) Castellote, I.; Moron, M.; Burgos, C.; Alvarez-Builla, J.; Martin,
ꢀ
and NBS, see: (b) Crowston, E. H.; Lobo, A. M.; Prabhakar, S.; Rzepa,
H. S.; Williams, D. J. Chem. Commun. 1984, 276. Hexamethylenete-
tramine and NIS, see: (c) Raatikainen, K.; Rissanen, K. Chem. Sci. 2012,
3, 1235. Alkylated DABCO with Br2, see: (d) Wang, Y.-M.; Wu, J.;
Hoong, C.; Rauniyar, V.; Toste, F. D. J. Am. Chem. Soc. 2012, 134,
12928.
(12) A highly polar complex might be formed, as observed on the
TLC plate, in the mixture of NBS and DBU in solution.
(13) CCDC 879831 (2f) contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. See the Supporting Information.
(19) For Brþ transfer via an equilibrium between chalcones 1,
electrophilic bromine species II, and the resulting bromonium inter-
mediate III, see: (a) Brown, R. S. Acc. Chem. Res. 1997, 30, 131. (b) Cui,
X.-L.; Brown, R. S. J. Org. Chem. 2000, 65, 5653.
(20) For reviews and papers on halogen bonding, see: (a) Metrangolo,
P.;Resnati, G. HalogenBonding:Fundamentalsand Applications;Springer:
Berlin, 2008. (b) Metrangolo, P.; Meyer, F.; Pilati, T.; Resnati, G.; Terraneo,
G. Angew. Chem., Int. Ed. 2008, 47, 6114. (c) Metrangolo, P.; Neukirch,
H.; Pilati, T.; Resnati, G. Acc. Chem. Res. 2005, 38, 386. (d) Auffinger,
P. F.; Hays, A.; Westhof, E.; Ho, P. S. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 16789. (e) Metrangolo, P.; Resnati, G. Chem.;Eur. J. 2001, 7, 2511.
(f) Beale, T. M.; Chudzinski, M. G.; Sarwar, M. G.; Taylor, M. S. Chem.
Soc. Rev. DOI: 10.1039/c2cs35213c.
(14) The reaction of 1a with N-bromophthalimide instead of NBS led
to a complex mixture that was inseperable.
854
Org. Lett., Vol. 15, No. 4, 2013

protonation of VI by a trace amount of water. Obviously,
it was the successive bromoamination/debromination by
the NBS/DBU combination that led to the β-imidation of
chalcones. DBU functions as a nucleophilic promotor to
activate NBS (in the bromoamination step) and to further
remove the bromine (in the subsequent debromination
step).
Scheme 4. Plausible Mechanism for the Formation of
β-Aminoketones 2
In conclusion, a novel and efficient one-pot β-amination
of chalcones has been developed by using an NBS and
DBU combination, in which NBS functions as both
electrophilic bromine and nitrogen sources and DBU as
a nucleophilic promoter to activate NBS to be a more
electrophilic bromine species and toremovethe bromine of
R-bromoketone. The tandem bromoamination/debromi-
nation involved in the whole transformation makes the
reaction more intriguing. The reaction features mild con-
ditions, a relatively broad scope, and high efficiency.
Further work on the reaction of the NBS/DBU combina-
tion with alkenes and alkynes is ongoing in our laboratory.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (21172034), Pro-
gram for New Century Excellent Talents in University
(NCET-11-0611), the Department of Science and Tech-
nology of Jilin Province (201215002), the Fundamental
ResearchFunds for the Central Universities(11SSXT129),
and Open Project of State Key Laboratory of Supramole-
cular Structure and Materials (SKLSSM2013006) is grate-
fully acknowledged.
assisted by the synergistic effect from both the halogen
bond interaction20 between DBU and alkyl bromide and
the electron-withdrawing property of the carbonyl group,
a positive bromine is abstracted and enolate VI is thus
generated.21,22 Finally, imidated product 2 is formed via
Supporting Information Available. Experimental de-
tails and characterization for all new compounds and
crystal structure data (CIF file). This material is available
free of charge via the Internet at http://pubs.acs.org.
(21) In this case, DBU can be regarded as an electron donor and
ketone as an electron acceptor.
(22) Most probably, molecular oxygen plays a certain role in the
transformation of VfVI.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
855