Intermolecular hydroamination and hydroarylation reactions of alkenes in ionic liquids

Article abstract of DOI:10.1016/j.tetlet.2006.07.073

Intermolecular hydroamination or hydroarylation reactions of norbornene and cyclohexadiene performed with catalytic amounts of Br?nsted or Lewis acid in ionic liquids were found to provide higher selectivity and yields than those performed in classical organic solvents. The ionic liquid increases the acidity of the media and stabilizes ionic intermediates through the formation of supramolecular aggregates.

Full text of DOI:10.1016/j.tetlet.2006.07.073

Tetrahedron Letters 47 (2006) 6775–6779
Intermolecular hydroamination and hydroarylation reactions
of alkenes in ionic liquids
Alexandre A. M. Lapis,a Brenno A. DaSilveira Neto,a Jackson D. Scholten,a
Fabiane M. Nachtigall,b Marcos N. Eberlinb and Jairton Duponta,*
aLaboratory of Molecular Catalysis, IQ, UFRGS, Porto Alegre-RS, 91501970, Brazil
bThomson Mass Spectroscopy Laboratory, IQ, UNICAMP, Campinas-SP, 13083970, Brazil
Received 22 June 2006; accepted 14 July 2006
Available online 8 August 2006
Abstract—Intermolecular hydroamination or hydroarylation reactions of norbornene and cyclohexadiene performed with catalytic
amounts of Bro¨nsted or Lewis acid in ionic liquids were found to provide higher selectivity and yields than those performed in clas-
sical organic solvents. The ionic liquid increases the acidity of the media and stabilizes ionic intermediates through the formation of
supramolecular aggregates.
Ó 2006 Elsevier Ltd. All rights reserved.
Catalytic hydroamination and hydroarylation reactions
are important synthetic methodologies for forming
nitrogen-containing compounds such as amines, imines
and enamines. Both protocols may afford these classes
of compounds in a single step from readily available
unsaturated hydrocarbons.1 Various catalysts derived
from alkali, early and late transition metals as well as
lanthanides have been developed for addition of N–H
bonds to unsaturated compounds,2 but a more general
and selective process is still to be found. Additionally,
the cost of these transition metal catalysts, ligands or
additives is also a major drawback of these protocols.3
The use of acid-catalyzed reactions could represent a less
expensive alternative for synthesis using these nitrogen-
containing products. Indeed, it has been recently
reported4 that the hydroamination/hydroarylation reac-
tion of alkenes with anilines proceeds smoothly in the
presence of Bro¨nsted acids. The catalytic activity of
these systems is strongly influenced by the counteranion
coordination ability, that is, the efficiency of the reaction
increases as the coordination ability of the counteranion
decreases. The proposed reaction pathway involves pro-
ton transfer from the anilinium salt ([PhNH3]+) to the
C@C bond—thus generating a carbocation—followed
by nucleophilic addition of neutral aniline species that
yields ionic adducts. These adducts eliminate H+ in a
process assisted by free aniline to give the N- and/or
C-arylated product. It is reasonable to assume that
counteranion coordination ability not only influences
the Bro¨nsted acidity of the medium but also the stabil-
ization/destabilization of the ionic species involved in
the process. Therefore, the catalytic activity and selectiv-
ity of this acid catalysis may be modulated by control-
ling the solvation process of the medium. In this
respect, ionic liquids (ILs)5 and especially those based
on the imidazolium cation are known to have great abil-
ity to stabilize ionic intermediates and transition states
through different types of ions pairs.6 These properties
have been recently exploited in some reactions that
involve ionic species such as Mannich-type reactions,
the Mukaiyama aldol reaction, Baylis–Hillman reac-
tions and tetrahydropyranylation.7 ILs are also very
effective media for ‘classic’ acid catalysis8 and the acidity
of acids normally increases when dissolved in ILs. Fur-
thermore, ILs are less solvating than water.9
Herein, we describe our preliminary results concerning
the performance of acid catalysis (both Lewis and Bro¨n-
sted acids) in the hydroamination/hydroarylation reac-
tions in imidazolium-based IL media as well as the
investigation by electrospray ionization mass spectro-
metry (ESI-MS) of the possible ionic species involved
in the process. The reaction conditions were optimized
for the reaction of norbornene in the presence of aniline
with different Bro¨nsted and Lewis acids (5 mol %) in
BMIÆNTf2 (Scheme 1 and Table 1).
*
Corresponding author. Tel.: +555133166321; fax: +555133167304;
e-mail: dupont@iq.ufrgs.br
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.073

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A. A. M. Lapis et al. / Tetrahedron Letters 47 (2006) 6775–6779
NH2
oroacetic acid for which no selectivity was observed
5 mol% acid
(Table 1, entry 4). In these cases, nucleophilic attack
may occur preferentially through the aniline nitrogen
atom, following reaction pathway 1 (Scheme 2). There-
fore, the hydroarylation products were formed by the
following pathway 2, which the aromatic ring acts as a
nucleophile as proposed by Bergman.4
+
+
BMI.NTf2
24h, 135˚C
X
H2N
H
N
HN
X
+
X
As already mentioned, the acid counteranion has an
important effect on the reaction efficiency and it is
assumed that the acids would rapidly react with aniline
to form an anilinium salt ([PhNH3]+) (see proposed
reaction path in Scheme 2).4 Therefore, a low coordina-
tion ability of the counteranion facilitates alkene pro-
tonation, which may imply that the IL could be acting
in this reaction step by decreasing the ionic interactions
between the cation and anion, thus facilitating the
protonation step.
X
1
2
3
Scheme 1.
Table 1. Hydroamination/hydroarylation of norbornene by aniline
(X = H) with different acids as catalyst in BMIÆNTf2
a
Entry
Acid (5 mol %)
Yield (%)b
1:2:3c
1
2
3
4
5
6
7
8
CF3SO3H
CF3SO3H in PhH4
CH3SO3H
CF3CO2H
p-TolSO3H
PhB(OH)2
HBF4
70
13
48
28
22
38
80
83
1.9:1:Trace
1:1.4:0
1.8:1:0
1:1:Trace
1.5:1:0
1.6:1:0
To determine the influence of the ILs anion in the hydro-
amination and hydroarylation reactions, other ILs
were tested with BF3ÆOEt2 and HBF4 acids (Table 2).
As expected, the acidity of the anilinium salt decreased
with increasing IL anion coorꢀdination ability
1.5:1:0
1.4:1:Trace
ꢀ
ðOTfꢀ > PF6 > BF4 > InCl4 > NTf2 Þ
and there-
ꢀ
ꢀ
7d,10
BF3ÆOEt2
by the reaction yield decreased. The BMIÆInCl4 has an
intrinsic acid pattern7d and could be used directly to
afford products 2 and 3 with reasonable selectivity for
a Reaction conditions: norbornene (1.08 mmol), aniline (2.16 mmol),
acid (0.05 mmol) and BMIÆNTf2 (0.2 mL); 135 °C; 24 h.
b Combined yield of isolated products.
c Products ratios were determined by GC.
Table 2. Hydroamination/hydroarylation of norbornene in different
ILsa
This IL fluid has been chosen since it possesses one of
the least coordinating anions of the imidazolium IL
family and has been successfully used in acid catalysis.8a
The best yields were obtained using BF3ÆOEt2 (Table 1,
entry 8) and HBF4 (Table 1, entry 7) acids. The Bro¨n-
sted acid catalyzed reactions also afforded good yields
considering that hydroamination and/or hydroaryl-
ations are difficult to perform using protic acid cata-
lysis.1 It is also quite fitting that both yield and
selectivity are higher for the reaction performed using
CF3SO3H in BMIÆNTf2 than that performed in benzene4
under the same reaction conditions (Table 1, entry 2).
Entry ILs
Acid (5 mol %) Yield (%)b 1:2:3c
1
2
3
BMIÆNTf2 HBF4
BMIÆNTf2 BF3ÆOEt2
BMIÆInCl4
80
83
37
57
12
40
7
1.5:1:0
1.4:1:Trace
2.6:1:Trace
3.3:1.6:1
2:1:0
1.4:1:Trace
2.3:1:0
4
BMIÆInCl4 InCl3
5
6
7
8
9
10
BMIÆBF4
BMIÆBF4
BMIÆPF6
BMIÆPF6
BMIÆOTf
BMIÆOTf
HBF4
BF3ÆOEt2
HBF4
BF3ÆOEt2
HBF4
35
9
2:1:0
1.3:1:0
BF3ÆOEt2
28
1.3:1:0
a Reaction conditions: norbornene (1.08 mmol), aniline (2.16 mmol),
acid (0.05 mmol) and IL (0.2 mL); 135 °C; 24 h.
b Combined yield of isolated products.
A small selectivity towards hydroamination products in
the IL was obtained in almost all cases, except for triflu-
c Products ratios were determined by GC.
X-
[PhNH3][X]
-
PhNH2
H2N
PhNH2
H
N
Ph
pathway 1
pathway 2
+ PhNH2
+ PhNH2
H2N
H2
N
- [PhNH3][X]
- [PhNH3][X]
Ph
H
Scheme 2.

A. A. M. Lapis et al. / Tetrahedron Letters 47 (2006) 6775–6779
6777
Table 4. Acid catalysis hydroarylation between 1,3-cyclohexadiene
and substituted anilines in a BMIÆNTf2
the hydroamination products. An additional amount of
InCl3 led to a slight increase in selectivity and yield
(Table 2, entry 4).
a
Entry
X
Yield (%)b
4:5c
1
2
3
4
H
Me
OMe
NO2
56
46
40
11
Only 4
1:Trace
13:1
The reaction time was optimized for the reaction of
norbornene with aniline in the presence of BF3ÆOEt2 in
BMIÆNTf2, at 135 °C (Graphic S1 in the Supplementary
material). A maximum conversion of 96% was achieved
after 6 h. The effect of temperature on the addition of
aniline to norbornene was also investigated using
BF3ÆOEt2 in BMIÆNTf2. When the reaction was per-
formed at 135 °C, the yield was 83% and preferential
hydroamination selectivity was observed (1.4:1 of prod-
ucts 1:2, Table 1, entry 8) together with small amounts
of the hydroamination and hydroarylation product 3.
The use of lower reaction temperatures of 100 °C or
70 °C decreases the products yields (30% and 16%,
respectively) and the selectivity drastically changes. At
100 °C, no preference for hydroamination or hydroaryl-
ation products was observed (product ratio of 1:1 for
1:2). However, at 70 °C, the products ratio reversed
(1:1.4 of 1:2), when compared with the first run at
135 °C.
only 4
a Reaction conditions: 1,3-cyclohexadiene (2.16 mmol), aniline
(4.32 mmol), acid (0.11 mmol) and BMIÆNTf2 (0.4 mL); 135 °C; 24 h.
b Combined yield of isolated products.
c Products ratios were determined by GC.
Cyclohexadiene undergoes similar addition reactions
(Scheme 3) yielding almost exclusively the hydroaryl-
ation product 4 (Table 4). No hydroamination product
was observed. The di-addition products 5 were only ob-
served for anilines with electron-donating substituents
(Table 4, entries 2 and 3).
To investigate the possible intervention of supramolecu-
lar ionic species, the evolution of a mixture of aniline,
norbornene, CF3SO3H or HBF4 in 0.1 mL of IL was
monitored by both ESI(+)/MS and ESI(ꢀ)/MS.5 Using
ESI(ꢀ)/MS, no ionic species directly related to the pro-
posed reaction path could be detected. However, in the
positive ion mode (ESI(+)/MS), species involving supra-
molecular interactions of the IL with other reaction mix-
ture components were indeed detected. All putatively
assigned ions were then characterized by ESI-MS/MS
experiments. The ion of m/z 187 (detected in the mixture
of equal molar proportion of norbornene, aniline,
BMIÆNTf2 and CF3SO3H—Fig. 1) was characterized
as the protonated dimer of aniline; it looses a neutral
molecule of 93 Da (neutral aniline). The supramolecular
ionic species of m/z 711 was characterized (Fig. 1) as
[(PhNH3)3(CF3SO3)(NTf2)]+; it loses [(PhNH3)CF3SO3]
preferentially, which indicates that the relative strength
of coordination of the anion is CF3SO3 > NTf2. In this
experiment, the supramolecular species that associate
with the imidazolium cation were also observed such
as the ions of m/z 382 and 513 corresponding to [(BMI)-
(PhNH3)(CF3SO3)]+ and [(BMI)(PhNH3)NTf2]+. Using
HBF4 instead of CF3SO3H, protonated aniline is also
detected as cationic dimers associated with acid count-
eranions, that is, [(PhNH3)2(BF4)]+ of m/z 275 and IL
counteranion, that is, [(PhNH3)2(NTf2)]+of m/z 468.
The ions of m/z 320 and m/z 513 correspond to the
supramolecular species H-bonded to the BMI cation
and structurally characterized by ESI-MS/MS as
[(BMI)(PhNH3)(BF4)]+ and [(BMI)(PhNH3)(NTf2)]+
(Figure S1 in the Supplementary material). ESI-MS/
MS of the ion of m/z 649 ([(PhNH3)3(BF4)(NTf2)]+) re-
veals the intrinsic relative strength of coordination of
Therefore, the hydroamination reaction is favored
at higher temperatures, whereas the hydroarylation is
favored at lower temperatures.
The electronic effect on substituted anilines was also
evaluated in the hydroamination/hydroarylation reac-
tion using the optimized reaction conditions for
aniline. The chemoselectivity of the transformation
depends on the electron density of the aniline nitrogen
atom (Table 3). Electron-donating substituents on the
aniline moiety favored the hydroarylation products in
a stereospecific way (ortho-position) while decreasing
the yield (Table 3, entries 2 and 3). Electron-withdraw-
ing substituents increased the overall reaction yield and
only the hydroamination product was obtained (Table
3, entry 4).
Table 3. Effect of aniline substitution on hydroamination and hydro-
arylation product ratiosa
Entry
X
Yield (%)b
1:2:3c
1
2
3
4
H
Me
OMe
NO2
83
74
50
94
1.4:1:Trace
1:2:0
1:1.6:0
Only 3
a Reaction conditions: norbornene (2.16 mmol), substituted aniline
(4.32 mmol), acid (0.11 mmol) and BMIÆNTf2 (0.4 mL); 135 °C; 24 h.
b Combined yield of isolated products.
c Products ratios were determined by GC.
NH2
NH2
5 mol% BF3.OEt2
+
+
NH2
BMI.NTf2
X
X
24h, 135 °C
5
4
X
Scheme 3.

6778
A. A. M. Lapis et al. / Tetrahedron Letters 47 (2006) 6775–6779
Figure 1. ESI(+)MS of a reaction mixture containing aniline, norbornene, CF3SO3H in 0.1 mL of BMIÆNTf2 (top). ESI(+)MSMS of the ion of m/z
711 assigned as [(PhNH3)3(CF3SO3)(NTf2)]+ (bottom).
the anion with protonated aniline. The preferential loss
of neutral (PhNH3)(BF4) indicates that the relative
strength of coordination of the anion is BF4 > NTf2.
The detection and characterization of supramolecular
BMI species clearly indicates that the imidazolium ILs
stabilize the charged intermediates in the proposed reac-
tion paths (Scheme 2).
ated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2006.07.073.
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