One-pot cascade leading to direct α-imidation of ketones by a combination of N-bromosuccinimide and 1,8-diazabicyclo[5.4.1]undec-7-ene

Article abstract of DOI:10.1021/ol301871s

A one-pot cascade transformation of ketones into α-imidoketones has been developed, in which N-bromosuccinimide (NBS) provides both electrophilic bromine and nucleophilic nitrogen sources, and diazabicyclo[5.4.1]undec-7-ene (DBU) functions as a base and a

Full text of DOI:10.1021/ol301871s

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
One-Pot Cascade Leading to Direct
r‑Imidation of Ketones by a Combination
of N‑Bromosuccinimide and
1,8-Diazabicyclo[5.4.1]undec-7-ene
Ying Wei, Shaoxia Lin, and Fushun Liang*
Department of Chemistry, Northeast Normal University, Changchun 130024, China
liangfs112@nenu.edu.cn
Received July 7, 2012
ABSTRACT
A one-pot cascade transformation of ketones into r-imidoketones has been developed, in which N-bromosuccinimide (NBS) provides both
electrophilic bromine and nucleophilic nitrogen sources, and diazabicyclo[5.4.1]undec-7-ene (DBU) functions as a base and a nucleophilic
promoter for the activation of NBS. r-Bromination is supposed as the key step in the process, which takes place between more electrophilic
bromide active species and enolates.
N-Bromosuccinimide (NBS) is a versatile reagent for
synthetic organic chemistry.1 Traditionally, NBS can be
considered as a convenient source of either cationic bro-
mine used in electrophilic addition reactions2 or a bromine
radical used in radical substitution reactions.3 In general,
relatively inert succinimide would be generated as a by-
product in the reaction. From the atom economic point of
view, direct installment of the succinimido moiety of NBS
into the target molecules, as well as further transforma-
tion thereby, is highly desirable. Herein, we would like to
present a unique mode, in which both the bromine cation
and succinimide anion of NBS were involved in a one-pot
conversion of ketones into R-imidoketones.
Recently, halogen activated organic reactions (e.g.,
halonium,2 hypervalent halogen,4aÀg and halogen bond-
ing4hÀm) have attracted increasing interest, and in our re-
search on halonium-initiated cascades,5 an intramolecular
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Schumann, W.; Winkelmann, E. Ann. 1942, 551, 80. (c) Djerassi, C.
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Y.; Jiang, J.; Wang, W.; Chen, W.; Lin, L.; Feng, X. Angew. Chem., Int. Ed.
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Eur. J. 2012, 18, 2212. (f) Ochiai, M.; Miyamoto, K.; Kaneaki, T.;
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P.; Meyer, F.; Pilati, T.; Resnati, G.; Terraneo, G. Angew. Chem., Int.
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Chem. Soc. 2005, 127, 5979. (j) Denmark, S. E.; Burk, M. T. Proc. Nat.
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r
10.1021/ol301871s
XXXX American Chemical Society

Table 2. Cascade Reactions of Ketones with NBS and DBUa
Scheme 1. One-Pot Cascade Leading to R-Imidation of Ketones
by a Combination of NBS and DBU
entry
1
R1
R2
2
yield (%)b
1
1a
1b
1c
1d
1e
1f
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Et
Ph
2a
2b
2c
2d
2e
2f
87
91
90
84
81
82
83
80
85
86
83
81
77
88
86
85
2
2-MeC6H4
4-MeC6H4
4-CH3OC6H4
4-BrC6H4
4-ClC6H4
3-NO2C6H4
4-NO2C6H4
2-naphthyl
2-furyl
3
4
CÀO bond formation between carbonyl methyl and the
amide oxygen atom was developed.5a In our continued work,
we devoted our effort to the intermolecular carbonÀcarbon
and carbonÀheteroatom bond construction of ketones with
appropriate nucleophiles via halogen activation. In this con-
text, we disclosed the one-pot cascade reaction of ketones
with NBS leading to direct imidation,6 in which NBS plays a
dual role to provide both electrophilic bromine and nucleo-
philic nitrogen sources (Scheme 1a).7 Generally, the proce-
dure requires multiple steps, as exemplified in the Gabriel
synthesis (Scheme 1b).8 To the best of our knowledge, this
represents one of the rare examples of employing two compo-
nents of NBS in a one-pot cascade transformation.9
5
6
7
1g
1h
1i
2g
2h
2i
8
9
10
11
12
13
14
15
16
1j
2j
1k
1l
2-thienyl
2-pyridyl
PhCHdCH
Ph
2k
2l
1m
1n
1o
1p
2m
2n
2o
2p
Ph
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.
Table 1. Optimization of the Reaction Conditionsa
Initially, the model reaction of acetophenone (1a) with
NBS was examined under basic conditions (Table 1).
No reactions occurred in DMF at rt, by the utilization of
NaOH, NaOEt, NaH, t-BuOK, and DABCO as the base
(entries 1À5). Gratifyingly, the reaction with DBU as the
base gave 1-(2-oxo-2-phenylethyl)pyrrolidine-2,5-dione
(2a) in 52% yield (entry 6).10 Switching the solvents
from DMF to THF and toluene did not change the yields
significantly (entries 7 and 8). The yield was improved to
81% when performed in CH2Cl2 under otherwise identical
conditions (entry 9). Among all the solvents tested, MeCN
was the most efficient, affording 2a in 87% yield (entry 10).
One can see that DBU worked well in the one-pot imida-
tion reaction while other bases were inefficient. The reason
for this may be attributed to the specific interaction between
DBU and NBS.11
entry
base
solvent
2a yield (%)b
1c
2
3c
4c
5
NaOH
NaOEt
NaH
DMF
n.r.
n.r
n.r
n.r
n.r.
52
DMF
DMF
t-BuOK
DABCO
DBU
DMF
DMF
6
DMF
7
DBU
THF
59
8
DBU
toluene
CH2Cl2
MeCN
49
9
DBU
81
10
DBU
87
With the optimized conditions in hand, the scope and
generality of the one-pot cascade reaction were investigated.
Thus, the reactions of various ketones with NBS were con-
ducted (Table 2). It was found that methyl aryl ketones
containing both electron-donating groups (2-MeC6H4,
4-MeC6H4, 4-CH3OC6H4) and electron-withdrawing groups
(4-Br, 4-Cl, 3-NO2, 4-NO2) on the aryl rings could be
smoothly transformed into the desired products 2bÀh
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. c To the
mixture of 1a (1.0 mmol) and base (0.9 equiv), NBS (1.2 equiv) was
added after 30 min; no 2a was observed.
(6) For two examples of imidation of arenes with imides using iodine(III)
as an oxidant, see: (a) Kim, J.; Choi, J.; Shin, K.; Chang, S. J. Am. Chem.
Soc. 2011, 133, 16382. (b) Kantak, A. A.; Potavathri, S.; Barham, R. A.;
Romano, K. M.; DeBoef, B. J. Am. Chem. Soc. 2011, 133, 19960.
(7) For excellent work on double duty of alkynyl halides, cyanogen
bromide, and bromoperfluoroarenes, see: (a) Trofimov, A.; Chernyak,
N.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 13538. (b) Li, Z.;
Gevorgyan, V. Angew. Chem., Int. Ed. 2011, 50, 2808. (c) Li, Z.;
Gevorgyan, V. Angew. Chem., Int. Ed. 2012, 51, 1225. For excellent
work on using N-(benzylthio)succinimides as both a nucleophilic and an
electrophilic reactant, see: (d) Zhao, G.-L.; Rios, R.; Vesely, J.; Eriksson,
(8) For one example of stepwise synthesis of R-imidoketones, see:
Lei, A.; Wu, S.; He, M.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 1626.
(9) A most recent publication was found.Alix, A.; Lalli, C.; Retaileau,
P.; Masson, G. J. Am. Chem. Soc. 2012, 134, 10389.
(10) The reaction was also examined under acidic conditions
(HCO2H, PhCO2H, CuBr, etc.) but proved to be unsuccessful.
(11) A mixture of NBS and DBU may form a highly polar complex,
as observed on TLC plate.
ꢀ
L.; Cordova, A. Angew. Chem., Int. Ed. 2008, 47, 8468.
B
Org. Lett., Vol. XX, No. XX, XXXX

(80À91%, entries 2À8). In addition, 2-naphthyl methyl
ketone (1i) also provided the corresponding product 2i in
85% yield (entry 9). Encouraged by the results obtained
with aryl ketones, we turned ourattention tothe heteroaryl
ketones. The heterocycles, including furan (1j), thiophene
(1k), and pyridine (1l), were converted into the target prod-
ucts 2jÀl in 81À86% yields (entries 10À12). 4-Phenylbut-
3-en-2-one (1m) was also a suitable substrate, affording 2m
in 77% yield (entry 13). Propiophenone (1n) and butyr-
ophenone (1o) gave the corresponding products 2n and
2o in 88% and 86% yields, respectively (entries 14 and 15).
R-Phenyl acetophenone (1p) was also efficient, afford-
ing 1-(2-oxo-1,2-diphenylethyl)pyrrolidine-2,5-dione (2p)
in high yield. Nevertheless, when isobutyrophenone and
R-tetralone were used as substrates, no reactions took place,
which was probably due to the steric effect of the alkyl
substituents.12
R-imidated ketone 4 was produced in high yield.14 The
structure of 4 was confirmed by single-crystal X-ray dif-
fraction (Figure 1).15 However, when N-bromosaccharin
was subjected to the reaction conditions, no imidated
product was observed. Both pyrrolidine-2,5-dione and
isoindole-1,3-dione derivatives have been used extensively
in synthetic chemistry, with a wide range of applications,
particularly in biological and pharmaceutical chemistry.16
Scheme 3. Control Experiments
Scheme 2. Reactions of Acetophenone 1a with N-Bromoimides
Scheme 4. Possible Mechanism for the Formation of
R-Imidated Ketones 2À4
Figure 1. ORTEP drawing of 4.
Next, we investigated the efficacy of other N-haloimides
(Scheme 2).13 Similar to NBS, N-bromophthalimide (NBP)
was also a competent reagent, affording the desired isoindole-
1,3-diones 3 in high yield. For the reaction of 1a with 1,3-
dibromo-5,5-dimethylhydantoin, due to the reactivity of
the bromine attached to the imine N-atom being higher
than that on the amide N-atom, the corresponding
To gain insight into the mechanism, several control
experiments were performed (Scheme 3). No correspond-
ing R-bromoacetophenone (6) was observed in the reac-
tions of 1a and NBS with various bases like NaOH,
NaOEt, and t-BuOK, with substrate 1a recovered quanti-
tatively (eq 1). The reactions of 6 and succinimide 7 (1.2
equiv) at rt for 12 h gave product 2a, with either NaOH or
DBU (1.2 equiv) as the base (eq 2). The results indicated
(12) Reactions of fully aliphatic ketones like acetone and butanone
with NBS gave a complex mixture. Additionally, ethyl acetate was
selected as an ester substrate and subjected to otherwise identical
conditions but proved to be inefficient.
(13) NIS showed similar reactivity to NBS, but NCS was inefficient.
(14) The bromine atom on the amide nitrogen is deactivated during
the transformation.
(15) CCDC 873495 (4) contains the supplementary crystallographic
data for this paper. These 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.
Org. Lett., Vol. XX, No. XX, XXXX
C

that (i) R-bromoketone is involved in the mechanism as the
key step and (ii) DBU plays an important role in this step
(R-bromination of ketones).17
succinimide anion. The function of DBU is to deprotonate
ketones (as base) and to activate NBS (as nucleophilic
promoter).20 Such an efficient one-pot cascade transfor-
mation involves sequential NÀBr cleavage, CÀBr forma-
tion, CÀBr cleavage, and CÀN formation. With this
protocol, we achieved the in situ cross-coupling between
two (pro)nucleophiles.21
In conclusion, a novel and efficient one-pot R-imidation
of ketones has been developed by using an NBS and DBU
combination, in which NBS functions as both halogen and
nitrogen sources and DBU as both a base and a nucleo-
philic promoter to activate NBS. The activation of NBS by
DBU to be a more electrophilic bromide active species was
supposed to be the driving force for the one-pot cascade
imidation reaction. The reaction features mild conditions,
broad scope, and high efficiency. Work on further expand-
ing the substrate scope with an NBS and DBU combina-
tion is ongoing in our laboratory.
On the basis of all the results described above and
work by Vanquero et al.,18a a possible mechanism for the
R-imidation of ketones was proposed (Scheme 4). First,
enolate I is produced in the presence of DBU (1.0 equiv at
the most). At the same time, NBS reacts with DBU to form
a 1:1 adduct II via halogen bond interaction,18,4hÀ4m which
further transforms into a more electrophilic species III.19
Second, reaction between enolate I and activated bromide
III furnishesR-bromoketone IV. Finally, imidatedproduct
2 is formed via nucleophilic substitution of IV by the
(16) Some isoindole-1,3-dione derivatives display pharmacological
activities as anticonvulsants, anti-inflammatories, analgesics, and her-
bicidal and insecticidal agents. See: (a) harma, U.; Kumar, S. P.; Kumar,
N.; Singh, B. Mini-Rev. Med. Chem. 2010, 10, 678. (b) Meng, X.-B.; Han,
D.; Zhang, S.-N.; Guo, W.; Cui, J. R.; Li, Z.-J. Carbohydr. Res. 2007,
342, 1169. (c) Abdel-Hafez, A. A. Arch. Pharm. Res. 2004, 27, 495.
(d) Lima, L. M.; Castro, P.; Machado, A. L.; Fraga, C. A. M.; Lugnier,
C.; Gonc, V. L.; Barreiro, E. J. Bioorg. Med. Chem. 2002, 10, 3067.
(e) Collin, X.; Robert, J.; Wielgosz, G.; Baut, G. L.; Bobin-Dubigeon,
C.; Grimaud, N.; Petit, J. Eur. J. Med. Chem. 2001, 36, 639. (f) Groutas,
W. C.; Chong, L. S.; Venkataraman, R.; Kuang, R.; Epp, J. B.; Houser-
Archield, N.; Huang, H.; Hoidal, J. R. Arch. Biochem. Biophys. 1996,
332, 335. (g) Antune, R.; Buttista, H.; Strivastuva, R. M. Bioorg. Med.
Chem. Lett. 1998, 8, 3071.
(17) R-Bromination of ketones is an important transformation in
synthetic chemistry. For R-bromination of ketones with NBS catalyzed
by AIBN or BPO, see: (a) Tanemura, K.; Suzuki, T.; Nishida, Y.;
Satsumabayashi, K.; Horaguchi, T. Chem. Lett. 2003, 32, 932. (b) Cope,
A. C.; Burrows, E. P.; Derieg, M. E.; Moon, S.; Wirth, W.-D. J. Am.
Chem. Soc. 1965, 87, 5452. (c) Schmid, H.; Karrer, P. Helv. Chim. Acta
1946, 29, 573. For catalysis by NH4OAc, see: (d) Tanemura, K.; Suzuki,
T.; Nishida, Y.; Satsumabayashia, K.; Horaguchi, T. Chem. Commun.
2004, 40, 470. For catalysis by Mn(ClO4)2, see: (e) Yang, D.; Yan, Y.-L.;
Lui, B. J. Org. Chem. 2002, 67, 7429.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (Nos. 20972027 and
21172034), Program for New Century Excellent Talents in
University (NCET-11-0611), the Department of Science
and Technology of Jilin Province (201215002), the Fun-
damental Research Funds for the Central Universities
(11SSXT129), and Open Project of State Key Laboratory
of Supramolecular Structure and Materials (sklssm201225) is
gratefully acknowledged.
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.
(18) For halogen bond complexes formed between imines and NIS,
ꢀ
see: (a) Castellote, I.; Moron, M.; Burgos, C.; Alvarez-Builla, J.; Martin,
ꢀ
A.; Gomez-Sal, P.; Vaquero, J. J. Chem. Commun. 2007, 1281. For
DABCO and NBS, see: (b) Crowston, E. H.; Lobo, A. M.; Prabhakar,
S.; Rzepa, H. S.; Williams, D. J. Chem. Commun. 1984, 276. For
hexamethylenetetramine and NIS, see: (c) Raatikainen, K.; Rissanen,
K. Chem. Sci. 2012, 3, 1235.
(20) Under acidic conditions, both ketones and NBS may be acti-
vated by an acid catalyst and an R-brominated product can be achieved.
Under basic conditions, transformation of ketones into enolates without
the activation of NBS is probably not sufficient for R-bromination to
occur. DBU can activate both ketones (into enolates) and NBS (into a
more electrophilic active species like III). In this case R-bromination of
ketones took place.
(19) For examples of NBS activation by a Lewis base: For NBS/Ph3P,
see ref 2b. For Et2SBr SbCl5Br, see: (a) Snyder, S. A.; Treitler, D. S.
3
Angew. Chem., Int. Ed. 2009, 48, 7899. (b) Snyder, S. A.; Treitler, D. L.;
Brucks, A. P. J. Am. Chem. Soc. 2010, 132, 14303. For NBS/DABCO, see:
(c) Ghasemnejad-Bosra, H.; Haghdadi, M.; Khanmohammade, O.;
Gholipour, A. M.; Asghari, G. J. Chin. Chem. Soc. 2008, 55, 464. For
the bromocollidinium ion, see: (d) Cui, X.-L.; Brown, R. S. J. Org. Chem.
2000, 65, 5653.
(21) For a recent review on bond formation between two nucleo-
philes, see:Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX