Metal-free C-N cross-coupling of electrophilic compounds and N-haloimides

Article abstract of DOI:10.1039/c5ra13708j

When DBU is added, the cross-coupling reaction between alkyl halides (halogen = Cl, Br and I) and N-haloimides (halogen = Cl, Br) occurs, resulting in the formation of aminated products. A halogen bond activated nucleophilic substitution mechanism was proposed. The methodology represents an elegant example of applying the halogen bond activation strategy in an organic transformation.

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Metal-free C―N cross-coupling of electrophilic compounds
and N-haloimides†
Cite this: DOI: 10.1039/x0xx00000x
a
a
c
,a,b
Luyan Zhang, Yanru Li, Long-Yi Jin and Fushun Liang*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
13
alkyl halides by phthalimide anion affords the imidation product.
We think that the halogen bond between 1-chloro-2,3,4,6,7,8,9,10-
When DBU is added, the cross-coupling reaction between alkyl
halides (halogen = Cl, Br and I) and N-haloimides (halogen = Cl,
Br) occurs, resulting in the formation of aminated products. A
halogen bond activated nucleophilic substitution mechanism
was proposed. The methodology represents an elegant
example of applying halogen bond activation strategy in
organic transformation.
octahydropyrimido[1,2-a]azepinium (III) and alkyl halide may
9
facilitate the nucleophilic substitution reaction. The mutual
activation induced by halogen bonding makes otherwise inert
1
4
reaction to take place.
Amine is important raw material and intermediate in medicine,
pesticide, as well as liquid crystal material. Phthalimides are
versatile synthetic tools that are primarily employed in the
1
preparation of amines via the Gabriel reaction. Gabriel reaction
has proven to be a very effective means of forming N-
alkylphthalimides. Starting from N-substituted phthalimides, for
example, the use of the Nefkens’ reagent, N-alkylphthalimides can
2
also be prepared. Adimurthy et al. found an L-proline catalyzed
transamidation method of phthalimide with amines, to achieve new
3
amines. A. K. Yadav and L. D. S. Yadav used N-tosylhydrazone and
4
phthalimides to prepare amine. Additionally, transition metal-
catalyzed C―N coupling has been developed as a powerful
5
method. Herein, we would like to report a new type of cross-
6
7
coupling reaction between alkyl halides and N-haloimides, which
provides an efficient and straightforward method for the synthesis
of amines and functionalized amines.
In our recent research, we have developed N-haloimides to be a
8
versatile amination reagent used in organic transformation. In
further work, we found that, with organobases like DBU as the
9
activator, benzyl chloride can react with N-chlorophthalimide (NCP,
1
.2 equiv), giving the corresponding imidation product in 91% yield. Scheme 1 Proposed mechanism
It was not surprising that no reaction can occur in the absence of
DBU (eq 1). The possible mechanism for the imidation is depicted in
Our initial optimization of the model reaction commences from
10
Scheme 1. The interaction between NCP and DBU gives halogen benzyl chloride (1a). The impact of various parameters on the
11
bond adduct I, which delivers an ion pair intermediate II efficiency of the reaction of 1a with NCP (2a) is summarized in Table
containing highly electrophilic chlorine cation and potentially 1. In the presence of DBU (1.2 equiv), the reaction mixture
1
2
nucleophilic phthalimide anion. The nucleophilic substitution of conducted in DCE at room temperature, afforded product 3a in 31%
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isolated yield (entry 1). Other solvents screened include MeCN, bromides like isopropyl bromide and diphenylmethyl bromide can
also afford the corresponding aminated product, albeit in low yields.
However, cyclic alkyl bromide, i.e., cyclohexyl bromide, was
inefficient. Alkyl iodide like methyl iodide worked very well. In one
word, alkyl halides RX (X = Cl, Br and I) exhibit increased reactivity in
the order of RCl, RBr and RI. The gram-scale synthesis of 3a (1.51 g)
was also achieved in 92% yield by DBU-mediated reaction of benzyl
bromide and NCP.
DMF and DMSO (entries 2–4). DMSO proved to be the most
15
efficient (85% yield) (entry 4). The reaction mixture performed at
o
6
0 C gave product 3a in improved yield (91%) and shortened
reaction time (5 min) (entry 5). Besides DBU, NaOH, t-BuONa, PPh3,
DBN, MTBD, and DABCO were selected as the activators. MTBD
gave similar reactivity and DBN exhibits relatively lower efficiency
(
entries 6 and 7). However, NaOH, t-BuONa, PPh3 and DABCO
appear to be inert (entries 8-11). Catalytic amount of DBU, e.g., 0.2
equiv, could not drive the reaction to completion (entry 12), which
may support the presence of the halogen bonding interaction
a,b
Table 2 Cross-coupling reaction of alkyl halides with NCP
between
1-chloro-2,3,4,6,7,8,9,10-octahydropyrimido[1,2-
16
a]azepinium and alkyl halide, i.e., adduct III in Scheme 1.
a
Table 1 Optimization of the reaction conditions.
Temp
b
Yield
(%)
Entry
o
Activator
Solvent
Time(min)
c
(
C)
1
2
3
4
5
6
7
8
9
rt
rt
rt
rt
DBU
DCE
180
120
120
30
31
56
57
85
91
61
88
n.r
n.r
n.r
n.r
DBU
MeCN
DMF
DBU
DBU
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
60
60
60
60
60
60
60
DBU
5
DBN
180
6
MTBD
NaOH
t-BuONa
Ph3P
180
180
180
180
10
1
1
DABCO
DBU (0.2
equiv)
1
2
60
DMSO
180
16
a
Reactions were carried out with 1a (1.0 mmol), 2a (1.2 equiv) and activator
1.2 equiv) in solvent (2.0 mL). Dry solvents were used in all cases to
prevent the hydrolysis of benzyl chloride. Isolated yield.
b
(
c
With optimized reaction conditions in hand (Table 1, entry 5), we
investigated this methodology by reacting various alkyl halides with
17
NCP (Table 2). The scope of this new coupling reaction is fairly
broad. Alkyl chlorides examined includes benzyl chloride, n-butyl
chloride, -chlorocyclopentanone and -chloro N,N-dimethyl
acetamine. Benzyl chloride is highly efficient, while n-butyl chloride
exhibits relatively lower efficiency. -Chlorocyclopentanone and -
chloro N,N-dimethylacetamine gave satisfactory yields. Primary
a
Reaction conditions: 1 (1.0 mmol), 2a (1.2 equiv) and DBU (1.2 equiv) in
b
DMSO (2.0 mL). Isolated yields.
Interestingly, we found that dihalides are also suitable for the
cross-coupling reaction (Scheme 2). In the reaction of 1,2-
dibromoethane with NCP (1.2 equiv), two types of products could
be prepared, depending the feed ratio of DBU employed. When 1.2
equiv of DBU was used, the mixture afforded monobromo
18
alkyl bromides containing various substituents like benzyl, allyl,
ethyl, homobenzyl, isobutyl are suitable substrates. A lot of
functional groups are compatible with the reaction conditions, such
as methoxy, dimethoxyacetal, carbonyl and ester. Secondary alkyl
2
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substituted amine 3q in 56% yield. In the case of 2.2 equiv of DBU, indicated relatively high efficiency and broad scope for both alkyl
further elimination of HBr occurs, giving rise to enamine 4 in 53% halides and N-haloimides.
yield. However, no elimination of HBr or HCl was observed for 1,4-
dibromobutane, 1,6-dibromooctane and 1,2-dichloroethane
substrates, even though excess amount of DBU was used. The
corresponding imidation products 3r-t with a pendant bromine or
chlorine atom were attained in low to moderate yields, which may
19
be potentially useful in further transformation. Mixed dihalides
were also subjected to the reaction sequence. For example, 1-
bromo-4-chlorobutane gave chlorine atom-tolerant imidation
product 3u as the only product, due to the different reactivity
between bromine and chlorine atoms.
Scheme 3 Cross-coupling reaction of benzyl bromide with N-
haloimides.
In summary, we have developed a highly efficient and metal-free
cross-coupling reaction of alkyl halides and N-haloimides. With this
strategy, various alkyl- and functionalized alkylamines were
synthesized. The scope of the reaction is broad in terms of both
alkyl halides and N-haloimides.
A halogen bond activated
nucleophilic substitution mechanism was proposed. This work
demonstrated the feasibility and potential of halogen bonding
activation in organic transformation.
Financial support from the National Natural Science Foundation
of China (21172034 and 21372039), and the 111 Project is gratefully
acknowledged.
Notes and references
a
Department of Chemistry, Northeast Normal University,
Changchun 130024, China. Email: liangfs112@nenu.edu.cn; Fax:
(
+86) 431-85099759
Scheme 2 Cross-coupling reaction of dihalides with NCP.
b
Key Laboratory for UV-Emitting Materials and Technology of
Ministry of Education, Northeast Normal University, Changchun
We investigated the efficacy of N-haloimides by reacting them 130024, China
c
Faculty of Chemistry, Yanbian University
with benzyl bromide (Scheme 3). Different N-haloimide exhibits
different reactivity. NBP is less efficient than NCP (65%). Similar
trend was observed for N-halosuccinimides. NCS gave product 7 in
1
2
(a) M. S. Gibson and R. W. Bradshaw, Angew. Chem. Int. Ed., 1968,
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7
5
1% yield while NBS and NIS could not react. From Scheme 1 one
Soc., 1950, 72, 2786.
can see there are two types of halogen bonding interaction, N-
haoimide and DBU (adduct I), and the resulting chlorine cation in 1-
chloro-2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepinium
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4
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competent reagent, affording 2-
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7
coupling reactions. (a) H. Togo, Advanced Free Radical 15 For halogen cation stabilized by DMSO, see: (a) Y. Ashikari, A.
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16 That DBU binding to the halogen in any step will help us to
understand why stoichiometric amount of DBU is required in
the reaction.
8
9
1
0 A possible radical pathway was excluded via a control
experiment with TEMPO as the radical trapping reagent. Also,
the model reaction worked well under dark.
11 For reviews on halogen bonding, see: (a) P. Metrangolo, H.
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3
86; (b) P. Auffinger, F. A. Hays, E. Westhof and P. S. Ho, Proc.
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1
1
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1
2 For an excellent review on halogen-bonded adducts are pre-
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4
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