N-bromoimide/DBU combination as a new strategy for intermolecular allylic amination

Article abstract of DOI:10.1021/ol402287n

Allylic amination reactions of alkenes, with an NBP (N-bromophthalimide) or NBS (N-bromosuccinimide)/DBU combination, were developed, in which both internal and external nitrogen nucleophiles can be installed directly. Dual activation of NBS or NBP by DBU leads to more electrophilic bromine and more nucleophilic nitrogen atoms simultaneously. This protocol may provide a novel and complementary access to allylic amination under mild conditions.

Full text of DOI:10.1021/ol402287n

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
N‑Bromoimide/DBU Combination as a
New Strategy for Intermolecular Allylic
Amination
Ying Wei,† Fushun Liang,*,†,‡ and Xintong Zhang‡
Department of Chemistry and Key Laboratory for UV-Emitting Materials and Technology
of Ministry of Education, Northeast Normal University, Changchun 130024, China
liangfs112@nenu.edu.cn
Received August 11, 2013
ABSTRACT
Allylic amination reactions of alkenes, with an NBP (N-bromophthalimide) or NBS (N-bromosuccinimide)/DBU combination, were developed, in which both
internal and external nitrogen nucleophiles can be installed directly. Dual activation of NBS or NBP by DBU leads to more electrophilic bromine and more
nucleophilic nitrogen atoms simultaneously. This protocol may provide a novel and complementary access to allylic amination under mild conditions.
Allylic amines represent an important structural motif
frequently found in natural products, pharmaceuticals, as
well as a versatile building block for the synthesis of organic
molecules of higher complexity.1 To date, commonly used
approaches for the allylic amination of olefins include (i)
metal-based oxidative allylic amination2À5 and vinylation
of imine or aminals,6 and (ii) metal-free allylic amination,7
for example, by the introduction of a selenium reagent7a,b
or a hypervalent iodine(III) reagent7c in a recent report
(Scheme 1, top). Although the above-mentioned elegant
methods appear to be general and efficient, new synthetic
methods are still required.
In our research on halogen-mediated organic reactions,8
we discovered that NBS activated by DBU via a halogen
bond interaction brings about simultaneously enhanced
† Department of Chemistry.
‡ Key Laboratory for UV-Emitting Materials and Technology of Ministry
of Education.
(1) (a) Brown, E. G. Ring Nitrogen and Key Biomolecules; Springer:
Boston, MA, 1998. (b) Hili, R.; Yudin, A. K. Nat. Chem. Biol. 2006, 2, 284.
€
(c) Henkel, T.; Brunne, R. M.; Muller, H.; Reichel, F. Angew. Chem., Int.
Ed. 1999, 38, 643.
(5) Rhodium-catalyzed allylic C;H oxidative amination: (a) Evans,
D. A.; Faul, M. M.; Bilodeau, M. T. J. Am. Chem. Soc. 1994, 116, 2742.
(b) Parker, K. A.; Chang, W. Org. Lett. 2003, 5, 3891. (c) Parker, K. A.;
Chang, W. Org. Lett. 2005, 7, 1785. (d) Zalatan, D. N.; DuBois, J. J. Am.
Chem. Soc. 2007, 129, 7242. (e) Skucas, E.; Kong, J. R.; Krische, M. J.
J. Am. Chem. Soc. 2008, 130, 9220.
(6) Selected examples: (a) Wipf, P.; Kendal, C.; Stephenson, C. R. J.
J. Am. Chem. Soc. 2003, 125, 761. (b) Kakuuchi, A.; Taguchi, T.;
Hanzawa, Y. Tetrahedron Lett. 2003, 44, 923. (c) Kochi, T.; Ellman,
J. A. J. Am. Chem. Soc. 2004, 126, 15652. (d) Patel, S. J.; Jamison, T. F.
Angew. Chem., Int. Ed. 2004, 43, 3941. For Pd-catalyzed vinylation of
aminals, see: (e) Xie, Y.; Hu, J.; Wang, Y.; Xia, C.; Huang, H. J. Am.
Chem. Soc. 2012, 134, 20613.
(2) Selected examples of palladium-catalyzed allylic amination: (a)
Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 762. (b) Du, H.;
Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 7496. (c) Reed,
S. A.; White, M. C. J. Am. Chem. Soc. 2008, 130, 3316. (d) Du, H.; Zhao,
B.; Yian, S. J. Am. Chem. Soc. 2008, 130, 8590. (e) Liu, G.; Yin, G.; Wu,
L. Angew. Chem., Int. Ed. 2008, 47, 4733. (f) Wang, B.; Du, H.; Shi, Y.
Angew. Chem., Int. Ed. 2008, 47, 8224. (g) Reed, S. A.; Mazzotti, A. R.;
White, M. C. J. Am. Chem. Soc. 2009, 131, 11701. (h) Rice, G. T.; White,
M. C. J. Am. Chem. Soc. 2009, 131, 11707. (i) Fu, R.; Zhao, B.; Shi, Y.
J. Org. Chem. 2009, 74, 7577. (j) Yin, G.; Wu, Y.; Liu, G. J. Am. Chem.
Soc. 2010, 132, 11978. (k) McDonald, R. I.; Stahl, S. S. Angew. Chem.,
Int. Ed. 2010, 49, 5529. (l) Ramirez, T. A.; Zhao, B.; Shi, Y. Chem. Soc.
Rev. 2012, 41, 931. (m) Weinstein, A. B.; Stahl, S. S. Angew. Chem., Int.
Ed. 2012, 51, 11505.
(3) Copper-catalyzed allylic amination of olefins: (a) Takada, H.;
Nishibayashi, Y.; Ohe, K.; Uemura, S.; Baird, C. P.; Sparey, T. J.;
Taylor, P. C. J. Org. Chem. 1997, 62, 6512. (b) Smith, K.; Hupp, C. D.;
Allen, K. L.; Slough, G. A. Organometallics 2005, 24, 1747. (c) Clark,
J. S.; Roche, C. Chem. Commun. 2005, 5175. (d) Srivastava, R. S.;
Bertrand, R., III; Gallo, A. A.; Nicholas, K. M. Tetrahedron Lett. 2011,
52, 3478.
(7) Metal-free allylic amination: (a) Sharpless, K. B.; Hori, T.;
Truesdale, L. K.; Dietrich, C. O. J. Am. Chem. Soc. 1976, 98, 269. (b)
Bruncko, M.; Khuong, T. A. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
~
Engl. 1996, 35, 454. (c) Souto, J. A.; Zian, D.; Muniz, K. J. Am. Chem.
ꢀ
Soc. 2012, 134, 7242. (d) Trillo, P.; Baeza, A.; Najera, C. J. Org. Chem.
2012, 77, 7344.
(8) With NBS/DBU combination: (a) Wei, Y.; Lin, S.; Liang, F. Org.
Lett. 2012, 14, 4202. (b) Wei, Y.; Lin, S.; Liang, F.; Zhang, J. Org. Lett.
2013, 15, 852. With NBS/carboxylic acid combination: (c) Wei, Y.; Lin,
S.; Zhang, J.; Niu, Z.; Fu, Q.; Liang, F. Chem. Commun. 2011, 47, 12394.
(d) Wei, Y.; Lin, S.; Xue, H.; Liang, F.; Zhao, B. Org. Lett. 2012, 14, 712.
(e) Xue, H.; Tan, H.; Wei, D.; Wei, Y.; Lin, S.; Liang, F.; Zhao, B. RSC
Adv. 2013, 3, 5382.
(4) Iron-catalyzed intra- and intermolecular allylic C;H amination:
(a) Johannsen, M.; Jørgensen, K. A. Chem. Rev. 1998, 98, 1689. (b) Liu,
Y.; Che, C.-M. Chem.;Eur. J. 2010, 16, 10494. (c) Huang, D.; Wang,
H.; Xue, F.; Shi, Y. J. Org. Chem. 2011, 76, 7269. (d) Paradine, S. M.;
White, M. C. J. Am. Chem. Soc. 2012, 134, 2036.
r
10.1021/ol402287n
XXXX American Chemical Society

Table 1. Optimization of the Reaction Conditionsa
Scheme 1. Allylic Amination Using N-Haloimide/DBU Combination
entry
N-haloimide
activator
solvent
yield (%)b
1
NBS
NBP
NBP
NBP
NBP
NBP
NBP
NBP
NBP
NBP
DBU
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
0
86
82
5
2
DBU
DBN
3
4
pyridine
DABCO
PPh3
5
0
6
0
7c
8
DBU
0
DBU
79
74
65
9
DBU
DMF
10
DBU
toluene
a Reactions were carried out with 1a (1.0 mmol), N-haloimide (1.2
equiv), and activator (1.2 equiv) in solvent (2.0 mL) at rt for 24 h.
b Isolated yield. c With 0.2 equiv of DBU.
as observed on the TLC plate, in the mixture of NBP and
DBU in CH2Cl2. To further verify the hypothesis of the
existence of the interaction between DBU and NBP,10 we
surveyed a series of Lewis bases as electrophilic activators.
DBN exhibited similar behavior to DBU (entry 3), while
pyridine, DABCO and PPh3 proved to be less effective
or even inefficient (entries 4À6). Catalytic amount of DBU
(e.g., 0.2 equiv) was not enough to drive the reaction to
completion (entry 7). Solvent screening indicates that CH2Cl2
was the most efficient. Other solvents such as MeCN, DMF,
and toluene gave relatively low yields of 2a (entries 8À10).
Under the optimized conditions (Table 1, entry 2), a
range of reactions was carried out with various alkenes 1
and NBP (1.2 equiv) in the presence of DBU (1.2 equiv) in
CH2Cl2 (Table 2). The reactions of acyclic alkenes pro-
ceeded smoothly to afford the corresponding allylamines
2aÀf in good to excellent yields (61À91%). The alkene sub-
strates investigated include substituted R-methylstyrenes
(methyl, Cl, and F), allylic benzene, and 2,3-dimethylbutene
(entries 1À6). As for tetrasubstituted alkenes, like tetra-
methylethene, the corresponding bromoamination product
was obtained in 57% yield (entry 7). Cyclic alkenes such
as cyclohexane and cyclopentene generate a mixture of
the bromoamination11 and allylic amination products (2h,
26% yield; 2i, 13% yield) (entries 8 and 9).12 To our delight,
1-methylcyclohexene and 1-phenylcyclohexene afforded
Figure 1. Dual activation mode of NBS by DBU.
electrophilic reactivity for bromine and nucleophilicity
for the imido-nitrogen atom (in a contact ion pair form,
Figure 1). As such, direct installation of nitrogen function-
ality in an economic fashion has been achieved in the
reactions of alkyl aryl ketones and R,β-unsaturated enones
with NBS/DBU combination, respectively.8a,b Intrigued
by this unique reactivity, we envisioned that it is possible to
develop the N-haloimide/DBU combination tobeone type
of atom-efficient and versatile aminating reagent applic-
able to a variety of useful transformations. With this
idea in mind, we start to explore the reaction of various
substrates with the N-haloimide/DBU combination in the
continued work. Herein, we would like to communicate
a novel NBS(P)/DBU combination strategy toward allylic
amination of alkenes (Scheme 1, bottom), in which the
nucleophilic nitrogen sources may either arise from the
internal NBP itself (with NBP/DBU combination) or
external amines having an acidic NH group (with NBS/
DBU combination). This protocol may provide a comple-
mentary access to allylic amination.
Table 1 summarizes the optimization of the reaction
conditions. Initially, the model reaction of R-methylstyr-
ene 1a with NBS (1.2 equiv) in the presence of DBU
(1.2 equiv) was examined, but no reaction occurred in
CH2Cl2 at room temperature (entry 1). To our delight,
upon simply replacing NBS by NBP, the reaction did take
place, furnishing the allylic amination product 2a in 86%
yield (entry 2).9 A highly polar complex might be formed,
(10) Examples for the formation of halogen bond complexes: (a)
€
Castellote, I.; Moron, M.; Burgos, C.; Alvarez-Builla, J.; Martin, A.;
Gomez-Sal, P.; Vaquero, J. J. Chem. Commun. 2007, 1281. (b) Crowston,
E. H.; Lobo, A. M.; Prabhakar, S.; Rzepa, H. S.; Williams, D. J. Chem.
Commun. 1984, 276. (c) Raatikainen, K.; Rissanen, K. Chem. Sci. 2012,
3, 1235. (d) Wang, Y.-M.; Wu, J.; Hoong, C.; Rauniyar, V.; Toste, F. D.
J. Am. Chem. Soc. 2012, 134, 12928.
(11) Examples with an imido moiety from NBS or NBP itself as the
N-nucleophile are scarce. For a recent example, see: Alix, A.; Lalli, C.;
Retailleau, P.; Masson, G. J. Am. Chem. Soc. 2012, 134, 10389.
(12) The bromoamination and the allylic amination products are
inseperable over silica gel chromatography. The ratio was calculated
based on 1H NMR spetra.
(9) The feeding sequence for alkenes, NBP, and DBU is vital for the
reaction to occur!
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Allylic Amination Using NBP/DBU Combinationa
Table 3. Reactions of Alkenes and NBS/DBU Combination in
the Presence of External Nitrogen Sourcesa
a Reactions were carried out with 1 (1.0 mmol), NBP (1.2 equiv), and
DBU (1.2 equiv) in CH2Cl2 (2.0 mL) for 12À24 h. b Isolated yield.
c Bromoamination product. d Bromoamination product in 41% NMR
yield. e Bromoamination product in 47% NMR yield.
exclusively the desired allylic amination product 2j and 2k in
88 and 87% yields, respectively (entries 10 and 11).
Considering that the reaction of NBS/DBU with1a gave
no allylamine product (Table 1, entry 1), we decided to
introduce external nitrogen nucleophiles to the reaction
system. First, bistosylimide was selected and subjected
to the reaction sequence. As a result, N-(2-phenylallyl)-
benzenesulfonamide (3a) was obtained in 82% yield
(Table 3, entry 1). The structure of 3a was confirmed
by the single-crystal X-ray diffraction (Figure 2). Then,
a variety of alkenes 1bÀd and 1jÀl were reacted with
bistosylimide, giving the corresponding allylamines 3bÀg
in 62À88% yields (entries 2À7). Note that, in most cases,
one tosyl group was hydrolyzed, directly giving rise to
the deprotected allylamines 3aÀf (entries 1À6). For trans-
β-methylstyrene, the corresponding bromoamination
product was obtained in 81% yield (entry 8).13 The scope
of external amines appears broad, and the reactions of
a Reactions were carried out with 1 (1.0 mmol), NBS (1.2 equiv),
DBU (1.2 equiv), and amine (1.2 equiv) in CH2Cl2 (2.0 mL) for 12À24 h.
b Isolated yield. c Bromoamination product.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Control Experiments
Figure 2. X-ray crystal structure of 3a.
R-methylstyrene 1a with O-alkyl-N-arylsulfonylcarbamates
(alkyls = methyl and benzyl; aryls = phenyl and 4-tolyl),
N-methyltosylamine, phthalimide, and substituted phthali-
mides (4-methyl and 4-NO2), saccharin, and 1H-benzo[d]-
[1,2,3]triazole afford the corresponding allylamines 4aÀc,
2a, 2l, 2m, and 5À7 in high to excellent yields (entries 9À17).
From above, one can see that the installation of the external
amino group is dependent on the pKa values of the imides
employed. For instance, succimide (pKa = 14.7) is unable to
be introduced, while amines having a more acidic NH group
can be used as the nitrogen sources in the allylic amination.14
To gain insight into the mechanism, control experiments
were performed (Scheme 2). In the absence of DBU, the
reaction of 1a with NBP gave allyl bromide 8 in 51% yield,
with a certain amount of 1a intact (eq 1). However, in the
presence of DBU, no 8 could be observed. The reaction
of allyl bromide 8, phthalimide 9 (1.1 equiv), and DBU
(1.1 equiv) at room temperature for 20 h gave product 2a
in 63% yield (eq 2). The experimental results indicate that
the allyl bromide intermediate might be involved in the
mechanism, and DBU in the reaction system listed in
Tables 1À3 is supposed to promote allyl bromide forma-
tion, as well as further nucleophilic substitution.
Scheme 3. Proposed Mechanism
Third, allyl bromide V is formed via proton elimination.
Finally, nucleophilic substitution by the phthalimide anion
leads to allylamine 2.17 The dual activation of NBP by
DBU is exemplified by providing both a more electrophilic
bromine and a more nucleophilic nitrogen source.18
In conclusion, a novel and atom-efficient one-pot allylic
amination of alkenes has been developed by using an NBP/
DBU combination, in which NBP is dual activated by
DBU to be a highly electrophilic bromine and nucleophilic
nitrogen via a preformed halogen bonding interaction.
External N-nucleophiles can also be introduced efficiently
in the cases of the utilization of NBS/DBU combination.
The tandem reaction features mild conditions, relatively
broad substrate scope, readily available reagents, and high
bond forming and atom efficiency.
On the basis of all the results described above, along with
the work by White2g and us,8a,b a possible mechanism for
the allylic amination of alkenes was proposed, as depicted
in Scheme 3. First, a highly electrophilic bromine species
II15 is generated from the 1:1 NBP/DBU halogen bond
adduct I.10 Second, alkene reacts with ion pair II to furnish
a DBU-stabilized bromonium ion III16 and its open form IV.
(13) See Supporting Information. The formation of the allylic amines
and/or bromoamination product mainly depends on the structure of
alkene substrates employed.
(14) For the pKa values of the investigated imides, please refer to: (a)
Koppel, I.; Koppel, J.; Degerbeck, F.; Grehn, L.; Ragnarsson, U. J. Org.
Chem. 1991, 56, 7172. (b) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(c) Cotton, F. A.; Stokely, P. F. J. Am. Chem. Soc. 2012, 92, 294.
(15) For a recent review of NBS activation by Lewis base, see: (a)
Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew. Chem., Int. Ed. 2012,
51, 10938. Selected papers: (b) Sakakura, A.; Ukai, A.; Ishihara, K. Nature
2007, 445, 900. (c) Snyder, S. A.; Treitler, D. S. Angew. Chem., Int. Ed. 2009,
48, 7899. (d) Cui, X.-L.; Brown, R. S. J. Org. Chem. 2000, 65, 5653.
(16) For Lewis-base-stabilized bromonium intermediates, see: (a)
Denmark, S. E.; Burk, M. T. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20655.
(b)Cheng, Y. A.;Chen, T.;Tan, C. K.;Heng, J. J.;Yeung, Y.-Y.J. Am. Chem.
Soc. 2012,134, 16492. (c) Chen, F.; Tan, C. K.; Yeung, Y.-Y. J. Am. Chem. Soc.
2013, 135, 1232. (d) Tan, C. K.; Yeung, Y.-Y. Chem. Commun. 2013, 49, 7985.
(17) The possible mechanism for the formation of 3 is given in
Supporting Information.
Acknowledgment. Financial support from NSFC (Nos.
21172034 and 21372039) and NCET-11-0611 is gratefully
acknowledged.
Supporting Information Available. Experimental details
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 double duty of alkynyl (cyanogen) halides, 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.
The authors declare no competing financial interest.
D
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