Highly selective N-allylation of anilines under microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2014.03.044

An easy and rapid procedure for the preparation of a variety of mono- and bis-allylated anilines via the reaction of allyl bromide with a wide range of anilines under microwave irradiation is described. This approach allows use of mild conditions and short reaction times to give high selectivities and excellent yields.

Full text of DOI:10.1016/j.tetlet.2014.03.044

Tetrahedron Letters 55 (2014) 2711–2714
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Tetrahedron Letters
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Highly selective N-allylation of anilines under microwave irradiation
⇑
Meiyu Liu, Xie Wang, Xiaoliang Sun, Wei He
Department of Chemistry, School of Pharmacy, Fourth Military Medical University, Xi’an 710032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An easy and rapid procedure for the preparation of a variety of mono- and bis-allylated anilines via the
reaction of allyl bromide with a wide range of anilines under microwave irradiation is described. This
approach allows use of mild conditions and short reaction times to give high selectivities and excellent
yields.
Received 19 December 2013
Revised 28 February 2014
Accepted 9 March 2014
Available online 14 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Aniline
Allyl bromine
Microwave irradiation
Allylation
Selectivity
N-allylation of aniline is a well-established process for the con-
struction of CAN bonds. Bis-allylation of aniline is often used to
protect the amino group, and subsequent deprotection can be eas-
ily achieved.1 In addition, many mono- and bis-allyl substituted
anilines are frameworks for many natural products and biologically
active agents. For example, the N-substituted 1-benzazepine deriv-
ative OPC-31260 (procyanidin) has a favorable curative effect on
cardiopathy.2 Many synthetic approaches using direct allylation
are hindered by over-allylation of the aniline, which leads to low
yields and poor selectivity.3,4 Therefore, the development of new
methods to prepare N-allylanilines with high selectivity has been
of great interest over past decades.
Traditionally, bases such as Na2CO3, K2CO3, NaH, and BuLi have
been employed in the allylation of anilines, but this often leads to
long reaction times or low yields of desired products.5 Recently,
Basu and co-workers reported a new method of N-alkylation of
amines on recyclable silica with alkyl halides to give mono- or
bis-alkylated amines selectively in the absence of base.6 Metal cat-
alyzed allylation of aniline using allyl alcohol as the allylating
agent has been established as a versatile method for the formation
of CAN bonds. Palladium catalysts have been successfully used to
afford bis-allylanilines and mono-allylanilines, respectively,7 while
Pt-catalyzed reactions of allyl alcohol with primary amines have
been employed for the selective formation of secondary amines.8
While these methods have obvious advantages, the metal catalysts
are costly, and may lead to possible environmental problems.
Therefore, a selective, efficient, widely applicable, and low cost
method of N-allylation is still highly desired.
It is well known that polar compounds absorb microwave radi-
ation selectively.9 Varma and Ju have reported the selective forma-
tion of tertiary amines via N-alkylation in aqueous alkaline
medium under microwave irradiation.10 Based on the polar nature
of allyl bromide and aniline and its derivatives, we anticipated that
the nucleophilic substitution reaction would be accelerated by
microwave energy. Our studies have confirmed that allylation of
anilines can indeed be achieved efficiently in a very short period
of time under microwave irradiation conditions, and herein, we re-
port our results on the direct synthesis of secondary and tertiary
amines under these conditions. We also show that the selectivity
of the reaction is dependent on the reaction conditions.
Initially, 2-iodoaniline and allyl bromide were selected as mod-
el substrates to screen for optimal reaction conditions under con-
trolled microwave heating. The major products of these reactions
were secondary and tertiary amines, with no quaternary ammo-
nium salts being detected. The different reaction conditions inves-
tigated are outlined in Table 1. The investigation was initiated in
polar solvents under 850 W power microwave irradiation using
K2CO3 as the base. Different solvents have different boiling points.
To prevent liquid flooding under microwave irradiation, the reac-
tion temperature was chosen at different temperatures. When
the reaction was carried out in water, the mono-substituted prod-
uct was obtained selectively in moderate yield, even though a two-
fold excess of allyl bromide was used (Table 1, entry 1). DMSO and
MeCN also tended to give the mono-substituted product (Table 1,
entries 2 and 3). However, in DMF, the bis-substituted product
was obtained in 47% isolated yield, with a 3:1 ratio of bis- to
⇑
Corresponding author. Tel.: +86 2984774470.
E-mail address: heweichem@126.com (W. He).
http://dx.doi.org/10.1016/j.tetlet.2014.03.044
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2712
M. Liu et al. / Tetrahedron Letters 55 (2014) 2711–2714
Table 1
The reaction of 2-iodoaniline with allyl bromide promoted with different bases at various temperatures and solventsa
Entry
Aniline/allyl Bromide
Solvent
Base
Temp (°C)
PTC
Mono productd (%)
Bis productd (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18b
19b,c
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
H2O
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOH
80
170
60
130
90
120
80
—
—
—
—
—
—
—
CTAB
CTAB
—
—
—
—
—
—
—
50
39
38
15
NR
NR
81
92
94
18
64
21
16
21
18
22
10
10
5
Trace
Trace
Trace
47
DMSO
MeCN
DMF
Toluene
p-Xylene
H2O
NRe
NR
Trace
Trace
Trace
59
Trace
60
H2O
H2O
KOH
KOH
80
80
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
K2CO3
KOH
Cs2CO3
Na2CO3
DABCO
DBU
DMAP
Na2CO3
Na2CO3
Na2CO3
130
130
130
130
130
130
130
130
130
130
67
Trace
Trace
Trace
83
85
90
CTAB
CTAB
CTAB
a
b
c
All of the reactions were carried out under 850 W MW power for 10 min; 2 equiv of base were used.
Reaction time was 20 min.
Allyl bromide was added in two parts.
Product isolated by chromatography.
NR: No reaction was observed.
d
e
mono-substituted products (Table 1, entry 4). Less polar aromatic
solvents were almost completely ineffective in giving mono- or
bis-substituted products (Table 1, entries 5 and 6).
To compare the effect of microwave irradiation with conven-
tional heating, reactions were carried out under the optimal condi-
tions, but using heating in an oil bath for 12 h. Using condition A,
the reaction of 2-iodoaniline with allyl bromide gave an increased
yield of bis-allylated product (14%), and a decreased yield of mono-
allylated product (77%) (Table 2, entry 2 vs entry 1). Similarly, the
reaction using condition B afforded lower selectivity and the yield
of bis-allylated product was decreased dramatically (Table 2, en-
tries 3 and 4). Obviously, the microwave-assisted syntheses give
significantly reduced reaction times, higher selectivities, and high-
er yields than those using conventional heating.
Such remarkable selectivity under simple reaction conditions
prompted us to investigate the reactivity and selectivity of a series
of anilines. Firstly, mono-allylated products were successfully pre-
pared from different anilines under MW irradiation. As shown in
Table 3, the electronic effect of substituents on the aromatic ring
had a significant influence on the yields of the mono-N-allylated
anilines. All of the 2-halogenated anilines afforded the desired
mono-N-allylated anilines in high yields under condition A (Table 3,
entries 1–3). 4-chloro-2-iodoaniline also gave the mono-allylated
product in excellent yield with excellent selectivity (Table 3, entry
4). However, when another stronger electron-withdrawing group,
which do not possess resonance donating effect like chlorine atom,
Use of the stronger base KOH rather than K2CO3 in H2O solvent
gave a significantly improved yield of the mono-allylaniline while
retaining the selectivity (Table 1, entry 7). The poor solubility of
the substrate in H2O encouraged us to explore a phase transfer cat-
alyst (PTC) to further improve the yields. Addition of hexadecyl tri-
methyl ammonium bromide (CTAB)11 resulted in an excellent yield
of the mono-allylaniline with complete selectivity. (Table 1, entry
8). Therefore, the optimal reaction conditions for the production
of the mono-allylaniline was set up as follows: 850 W power
MW irradiation at 80 °C in water, a 1:2 ratio of aniline and allyl
bromide, 2 equiv of KOH and 10 mol % CTAB. This is designated
as condition A.12
Attention then turned to optimizing conditions for the produc-
tion of bis-allylanilines. We initially tried condition A with a large
excess of allyl bromide (a 1:4 ratio of aniline to allyl bromide) but
this still gave exclusive formation of the mono-allylaniline (Table 1,
entry 9 vs entry 8). Given that we had found that use of DMF as sol-
vent and K2CO3 as base gave predominant formation of the bis-
allylaniline, we further investigated this system. A 1:4 mixture of
aniline and allyl bromide afforded the bis- and mono-allylated ani-
lines in a 3:1 ratio, but with only a slight improvement in yield and
selectivity (Table 1, entry 10 vs entry 4). Surprisingly, the mono-
allylaniline was obtained exclusively in good yield when potas-
sium hydroxide, rather than K2CO3, was used as the base in DMF
(Table 1, entry 11), while both Cs2CO3 and Na2CO3 gave similar
results to K2CO3 (Table 1, entries 12 and 13). The organic bases
DABCO, DBU, and DMAP all gave low yields of mono-substituted
product with trace amounts of the bis-substituted product (Table 1,
entries 14–16). We ultimately found that use of Na2CO3 as a base in
the presence of CTAB led to a yield of bis-allylaniline of 83%
(Table 1, entry 17). While longer reaction times did not give any
further improvement (Table 1, entry 18), addition of 4 equiv of allyl
bromide in two parts gave further improved selectivity (Table 1,
entry 19). Thus, the optimal reaction conditions for the production
of bis-allylaniline was set up as: 850 W power MW irradiation at
130 °C in DMF, a 1:4 ratio of aniline to allyl bromide, 2 equiv of
Na2CO3 and 10 mol % CTAB. This is designated as condition B.13
Table 2
N-allylation of 2-iodoaniline by allyl bromide using conventional heatinga
Reaction condition
Products and yieldsb
H
N
N
I
I
MW, 80 °C, 10 min (Condition A)
H2O, KOH (2 equiv) CTAB (10% mmol) Heated 77%
92%
Trace
14%
at 80 °C, 12 h
MW, 130 °C, 20 min (Condition B)
DMF, Na2CO3 (2 equiv) CTAB (10% mmol)
Heated at 130 °C, 12 h
Trace
67%
90%
18%
a
All the reactions were carried out at 0.5 mmol of aniline scale.
Yield of the isolated product after chromatography.
b

M. Liu et al. / Tetrahedron Letters 55 (2014) 2711–2714
2713
Table 3
Table 4
Synthesis of various substituted mono-allylations of anilinesa
Synthesis of various substituted bis-allylations of anilinesa
H
N
NH2
ConditionA
N
X
NH2
Br
R2
X
R2
X
Condition B
or ConditionC
R1
Br
R1
R2
R2
X
2a-2o
1a-1o
R1
R1
3a-3m
4a-4m
Entry Condition
X
R1 R2
Product Conver. Yieldb (%)
Entry
X
I
R1
R2
Product
Conversion
Yieldb (%)
1
2
A
A
A
A
A
A
A
A
A
A
C
C
C
C
C
C
I
H
H
H
H
H
H
H
H
H
H
H
H
H
H
I
H
H
H
Cl
CF3
CN
CN
H
H
CH3
H
2a
2b
2c
2d
2e
2f
95
93
95
92
74
67
70
79
95
97
92
90
87
90
94
95
92
90
90
89
70
63
67
76
75,
90
89
88
85
88
92
93
Cl
Br
I
I
I
Br
CF3
OCH3
I
OCH3
H
H
H
H
1
2
3
4
5
6
7
8
9
10
11
12
13
H
H
H
H
F
H
H
H
Br
H
CF3
CH3
Cl
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
95
90
90
90
87
85
95
97
96
95
75
96
94
95
94
96
3
4
5
6
Cl
Br
H
H
H
H
I
H
OCH3
H
100
100
100
100
79
100
100
100
100
100
7
8
2g
2h
2i
2j
2i
H
I
9c
10d
11
12
13
14
15
16
H
H
H
H
H
H
H
4j
4k
4l
OCH3
CH3
CH(CH3)2 2m
CH3
H
2k
2l
OCH3
CH3
CH(CH3)2
H
H
4m
2n
2o
a
All the reactions were carried out with condition B.
Yield of the isolated product after chromatography.
H
H
b
a
b
c
All the reactions were carried out using 0.5 mmol of the aniline.
Yield of the isolated product after chromatography.
The bis-allylated product was isolated in 14% yield.
The bis-allylated product was isolated in 3% yield.
bis-allylation was still noteworthy (Table 4, entry 8). Aniline re-
acted to give N,N-diallylaniline in a yield of 96% under condition
B (Table 4, entry 9), while electron-rich anilines were converted
almost quantitatively into the target tertiary aniline products
(Table 4, entries 10–13).
d
was introduced to the 4-position of 2-halogenated anilines, the
overall yield of mono-N-allylated products was decreased (Table 3,
entries 5–7). Similarly, introduction of the strongly electron-with-
drawing CF3 group at the 2-position of the aniline decreased the
yield of the mono-N-allylated product (Table 3, entry 8). These re-
sults indicated that the electronic property of substrate is very
important for conversion of the reaction. Allylation of 2-methoxy-
aniline, which has an electron-donating group at the 2-position,
yielded the mono-allylated product in 75% isolated yield, but the
conversion was 95%, and the bis-allylated product was also iso-
lated in 14% yield (Table 3, entry 9). Similarly, the mono-allylated
product was obtained with the yield of 90% for 2-iodo-4-methylan-
iline, while the bis-allylated product was also isolated in 3% yield
(Table 3, entry 10). And these two product phenomena were also
observed for compounds 2k, 2l, 2m, 2n, and 2o under condition
A, and the minor bis-allylated products were not isolated.
In summary, we have reported an efficient and highly selective
method for the allylation of anilines. Most reactions gave high
yields and selectivities in a short period of time. A large range of
secondary and tertiary aniline compounds with a series of different
substituents were prepared under simple conditions using micro-
wave irradiation. The expansion of this method toward the total
synthesis of some bioactive molecules and the studies of some
other allylation reactions under MW conditions are currently
underway in our laboratory.
Acknowledgments
We gratefully acknowledge the funding support received for
this project from the National Natural Science Foundation of China
(21272272) and the Young Scholar Foundation of the Fourth
Military Medical University.
These results show that electron-poor anilines tend to undergo
mono-substitution exclusively, while the electron-rich substrate is
more active toward allylation, making it difficult to avoid some bis-
substitution. Despite this, we found the following conditions opti-
mal for the mono-N-allylation of electron-rich anilines: 600 W
power MW irradiation at 70 °C in mixed acetonitrile/water (8/1)
solvent and a 1:2 ratio of 2-iodoaniline to allyl bromide. This is
designated as condition C (Table 3, entry 11).13 For all the elec-
tron-rich anilines tested, good conversions and selectivities were
achieved in the absence of both base and a PTC (Table 3, entries
12–15). Aniline itself also reacted smoothly under condition C, to
give a 93% isolated yield of N-allylaniline (Table 3, entry 16).
Bis-allylation of various substituted anilines was achieved in
the presence of Na2CO3 and CTAB (condition B), and the results
are shown in Table 4. Both electron-poor and electron-rich anilines
displayed high conversions and selectivities, with the yields of
tertiary anilines being up to 97%. Regardless of the position of
the halogen atoms in the anilines, or a strong electron-withdraw-
ing group trifluoromethyl as a substituent group, the bis-allylation
proceeded smoothly to give excellent results (Table 4, entries 1–7).
Only 3h, which contains two halogens at the ortho- and para-
positions, showed lower conversion, but the selectivity for
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.03.
044.
References and notes
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M. Liu et al. / Tetrahedron Letters 55 (2014) 2711–2714
4. (a) Fryhle, C. B.; Solomons, T. W. G. Organic Chemistry; John Wiley & Sons Inc:
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were added to the reaction vessel stirring for 5 min. Allyl bromide (1 mmol,
2 equiv) was added, while maintaining the temperature at 80 °C for 10 min
under microwave irradiation (850 W). After completion of the reaction, the
mixture was extracted with CH2Cl2 (3 Â 15 mL). The combined organic layer
was washed with brine (20 mL), dried over Na2SO4, and evaporated. The
residue was purified by column chromatography (petroleum ether/ethyl
acetate) to afford N-allylaniline 2a–j. Compounds 2f and 2g are new
compounds. For a detailed description of spectroscopic characterization of
compounds see Supplementary data.
13. General procedure for the preparation of compound 2i–o: Aniline 1 (0.5 mmol)
was dissolved in mixed acetonitrile/water (8/1) solvent (5 mL). Allyl bromide
(1 mmol, 2 equiv) was added, while maintaining the temperature at 70 °C for
10 min under microwave irradiation (600 W). After completion of the reaction,
the acetonitrile was evaporated. The following procedures were similar with
general procedure for the preparation of compound 2a–j.
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General procedure for the preparation of compound 4a–4m: The aniline
3
(0.5 mmol) was dissolved in DMF (3 mL) in a reaction flask. Na2CO3 (2 equiv,
1 mmol) and CTAB (10% mmol) were subsequently added, and the solution was
stirred for 5 min. After allyl bromide (4 equiv, 2 mmol) was added, the reaction
mixture was exposed to MW irradiation at 130 °C for 10 min. Following,
2 equiv of allyl bromide were added to the reaction mixture solvent for another
10 min under MW irradiation (850 W). After the solution was cooled to
ambient temperature, CH2Cl2 (20 ml) was added, the solution was washed
with water (3 Â 20 ml). The organic layer was separated, washed with brine
(20 mL), dried over Na2SO4, and evaporated. The residue was purified by
column chromatography (petroleum ether/ethyl acetate) to afford N,N-
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diallylaniline 4a–m. Compound 4g is
a new compound. For a detailed
11. Tetrabutyl ammonium bromide, polyethylene glycol 400, polyethylene glycol
2000, and 18-Crown-6 were also screened, and they provided lower conversion
than CTAB.
description of spectroscopic characterization of compounds see
Supplementary data.
12. General procedure for the preparation of compound 2a–j: Aniline 1 (0.5 mmol),
H2O (5 mL), KOH (1 mmol, 2 equiv), and the CTAB (0.05 mmol, 10% mmol)