Synthetic and mechanistic studies of indium-mediated allylation of imines in ionic liquids

Article abstract of DOI:10.1021/jo062198x

(Chemical Equation Presented) Aldimines derived from aryl and non-enolizable aliphatic aldehydes were allylated with allyl bromide mediated by indium powder in [bpy][BF₄] (bpy = N-butylpyridine) to give good yields of the corresponding homoallylic amines. Selective formation of monoallylated amines can be achieved by varying the amount of bromide ion additive in the form of [bpy][Br]. The transient organoindium intermediates, allylindium-(I) and allylindium(III) dibromide formed in the reaction, were studied by NMR spectroscopy to explain the selectivity.

Full text of DOI:10.1021/jo062198x

Synthetic and Mechanistic Studies of Indium-Mediated Allylation of
Imines in Ionic Liquids
Man Chun Law,†,‡ Tin Wai Cheung,‡ Kwok-Yin Wong,‡ and Tak Hang Chan*,†,‡
Department of Chemistry, McGill UniVersity, Montreal, Quebec, Canada H3A 2K6, and Department of
Applied Biology and Chemical Technology, The Hong Kong Polytechnic UniVersity, Hung Hom,
Hong Kong SAR, China
tak-hang.chan@mcgill.ca; bcchanth@polyu.edu.hk
ReceiVed October 23, 2006
Aldimines derived from aryl and non-enolizable aliphatic aldehydes were allylated with allyl bromide
mediated by indium powder in [bpy][BF4] (bpy ) N-butylpyridine) to give good yields of the corresponding
homoallylic amines. Selective formation of monoallylated amines can be achieved by varying the amount
of bromide ion additive in the form of [bpy][Br]. The transient organoindium intermediates, allylindium-
(I) and allylindium(III) dibromide formed in the reaction, were studied by NMR spectroscopy to explain
the selectivity.
Introduction
reaction can be carried out in aqueous media.3 Indium-mediated
allylation of imines to give homoallylic amines in water, on
the other hand, has been less explored.4 This is because of the
known hydrolytic instability of imines in water5 and the fact
that indium can cause the reductive dimerization of imines.6
So far, only hydrolytically robust and activated imine analogues
Because of concern for the environment, there has been
extensive recent research into the use of environmentally benign
reaction media to replace volatile organic solvents.1 Indium-
mediated allylation of carbonyl compounds to give the corre-
sponding homoallylic alcohols has been extensively studied in
the past 2 decades,2 especially with the discovery that the
(3) (a) Li, C. J.; Chan, T. H. Tetrahedron Lett. 1991, 32, 7017. (b) Chan,
T. H.; Yang, Y. J. Am. Chem. Soc. 1999, 121, 3228. (c) For, review, see:
Li, C. J.; Chan, T. H. Tetrahedron 1999, 55, 11149.
(4) For reviews of metal-mediated allylation of imines in organic solvents,
see: (a) Bloch, R. Chem. ReV. 1998, 98, 1407. (b) Kobayashi, S.; Ishitani,
H. Chem. ReV. 1999, 99, 1069. (c) Keck, G. E.; Enholm, E. J. J. Org. Chem.
1984, 50, 146. (d) Yamamoto, Y.; Komatsu, T.; Maruyama, K. J. Org.
Chem. 1985, 50, 3115. (e) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 49,
7395. (f) Nishigaichi, Y.; Takuwa, A.; Naruta, Y.; Maruyama, K.
Tetrahedron 1993, 49, 7395. (g) Wang, D. K.; Dai, L. X.; Hou, X. L.
Tetrahedron Lett. 1995, 36, 8649. (g) Marshall, J. A. Chem. ReV. 1996,
96, 31. (i) Andrade, C. K. Z.; Oliveira, G. R. Tetrahedron Lett. 2002, 43,
1935. (j) Choucair, B.; Leon, H.; Mire, M. A.; Lebreton, C.; Mosset, P.
Org. Lett. 2000, 2, 1851.
† McGill University.
‡ The Hong Kong Polytechnic University.
(1) (a) Anastas P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press: Oxford, U.K., New York, NY, 1998.
(b) Abraham, M.; Moens, L. Clean SolVents: AlternatiVe Media for
Chemical Reactions and Processing; ACS Symposium Series No. 819;
American Chemical Society: Washington, DC, 2001.
(2) (a) Araki, S.; Ito, H.; Butsugan, Y. J. Org. Chem. 1988, 53, 1831.
For review, see: (b) Cintas, P. Synlett 1995, 1087. (c) Podlich, J.; Maier,
T. C. Synthesis 2003, 633.
10.1021/jo062198x CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/09/2007
J. Org. Chem. 2007, 72, 923-929
923

Law et al.
SCHEME 1
bis-allylated species. Similar mixtures of 2b and 3b were
obtained irrespective of the change in the reaction temperature,
the relative ratios of In to allyl bromide and imine, or the kind
of IL used (entries 2-7). In addition to [bmim][BF4], we have
used [emim][BF4] (emim = N-ethyl-N′-methylimidazolium),
[moemim][BF4] (moemim = N-(methoxyethyl)-N′-methylimi-
dazolium), and [bpy][BF4] (bpy ) N-butylpyridinium) as the
reaction media. While there were variations in the yield, the
product was invariably a mixture of 2b and 3b. In the case of
[bpy][BF4], we have also carried out the reaction with the
addition of ZnF2 or trimethylsilyl chloride ((TMS)Cl).17 The
reactions gave more or less the same mixture with similar yields
(entries 8 and 9).
In the allylation reaction in [bpy][BF4], we noticed that the
reaction was highly irreproducible, giving at times little or no
formation of the allylated amine 2 when different batches of
ionic liquids were used. We finally realized that the reaction
depended critically on the batch and purity of [bpy][BF4] as
we had previously observed for alkylzinc reactions in [bpy]-
[BF4].16c These observations prompted us to examine the ionic
liquid precursor [bpy][Br] as the additive for the reaction. The
results are summarized in Table 2. Indeed, the allylation reaction
of 1a gave no or low yield of homoallylic amine 2a in pure
[bpy][BF4] (entry 1) or with only about 4% of [bpy][Br] added
(entry 2). The yield of 2a was substantially increased when about
8% of [bpy][Br] was added and the reaction temperature was
increased (entries 4 and 5). With a lesser amount of imine 1a
relative to that of In and allyl bromide, the yield of 2a was
essentially quantitative with >8.5% bromide ion in the reaction
media (entries 5-7). An observable effect of the addition of
bromide ion (in the form of [bpy][Br]) was that the indium metal
powder did not form a cake together during the reaction when
about 8.5% of bromide ion was added.
such as sulfonimines,7 hydrazones,8 and oxime ethers9 have been
employed in aqueous indium-mediated allylation. In addition
to water,10 supercritical carbon dioxide,11 room-temperature ionic
liquids (ILs),12 and, of course, solvent-free conditions13 have
also been explored as reaction media to replace organic solvents.
Recently, it has been reported that imines 1 (Scheme 1) can
undergo allylation mediated by indium under solvent-free
conditions to give a mixture of the monoallylated species 2 and
the bis-allylated species 3.14 Indium-mediated allylation of
imines in ionic liquids has not been reported, but a similar
reaction in a nonvolatile solvent, poly(propylene glycol), has
been reported with a limited range of substrates.15 As part of
our program on the study of organometallic reactions in ionic
liquids,16 we report here our results on the indium-mediated
allylation of imines.
Results and Discussion
(1) Preliminary Studies. In the initial stage, we examined
the allylation reaction of benzaldehyde imines 1 in the ionic
liquid [bmim][BF4] (bmim = N-butyl-N′-methylimidazolium).
As we can see in Table 1, when the imine was derived from
aniline (1a, R ) Ph, entry 1), the homoallylic amine 2a was
obtained in moderate yield. However, the equivalent reaction
with imine derived from benzylamine (1b, R ) PhCH2, entry
2) gave a mixture of products 2 and 3, the mono- and
Addition of [bpy][Br] was also found to have an equally
remarkable effect on the allylation of 1b. No allylation occurred
in its absence (entry 8). When about 4.3% of bromide ion was
added, a mixture of products 2b and 3b resulted (entries 9 and
10). To our delight, in the presence of 8.5% bromide ion, the
allylation of 1b gave 2b only in excellent yield without the
formation of 3b (entries 11 and 12). The use of larger excess
of [bpy][Br] gave a similar result (entries 13 and 14). Finally,
if excess allyl bromide (2.5 equiv to In) was added to the
reaction mixture after the overnight stirring, the eventual product
was exclusively 3b (entry 16), suggesting that 3b was derived
from the allylation of 2b or more likely its precursor before
hydrolytic workup.
(5) (a) Paquette, L. A. In Green Chemistry, Frontiers in Chemically
Benign Synthesis and Processes; Anastas, P. J., Williamson, T. C., Eds.;
Oxford University Press: Oxford, U.K., New York, NY, 1998; p 261 and
footnote 49. (b) Vilaivan, T.; Winotapan, C.; Shinada, T.; Ohfune, Y.
Tetrahedron Lett. 2001, 42, 9073.
(6) Lalyanam, N.; Rao, G. V. Tetrahedron Lett. 1993, 34, 1647.
(7) (a) Chan, T. H.; Lu, W. Tetrahedron Lett. 1998, 39, 8605. (b) Lu,
W.; Chan, T. H. J. Org. Chem. 2000, 65, 8589. (c) Lu, W.; Chan, T. H. J.
Org. Chem. 2001, 66, 3467.
(8) (a) Kumar, H. M. S.; Anjaneyulu, S.; Reddy, E. J.; Yadav, J. S.
Tetrahedron Lett. 2000, 41, 9311. (b) Miyabe, H.; Ueda, M.; Nishimura,
A.; Naito, T. Org. Lett. 2002, 4, 131. (c) Miyabe, H.; Yamaoka, Y.; Naito,
T.; Takemoto, Y. J. Org. Chem. 2004, 69, 1415. (d) Cook, G. R.; Maity,
B. C.; Kargbo, R. Org. Lett. 2004, 6, 1741. (e) Cook, G. R.; Kargbo, R.;
Maity, B. Org. Lett. 2005, 7, 2767.
(9) (a) Miyabe, H.; Nishimura, A.; Ueda, M.; Naito, T. Chem. Commun.
(Cambridge) 2002, 1454. (b) Bernardi, L.; Cere, V.; Femoni, C.; Pollicino,
S.; Ricci, A. J. Org. Chem. 2003, 68, 3348.
(10) Li, C. J.; Chan, T. H. Organic Reactions in Aqueous Media; John
Wiley & Sons: New York, 1997.
(11) Jessop, P. Chemical Synthesis Using Supercritical Fluids; Wiley-
VCH: Weinheim, Germany, 1999.
(12) Rogers, R. D.; Seddon, K. R. Ionic Liquids: Industrial Applications
to Green Chemistry; Oxford University Press: Washington, DC, 2002.
(13) (a) Tanaka, K.; Toda, F. Chem. ReV. 2000, 100, 1025. (b) Varma,
R. S. Green Chem. 1999, 43.
(14) Andrews, P. C.; Peatt, A. C.; Raston, C. L. Tetrahedron Lett. 2004,
45, 243. A likely drawback associated with solvent-free reaction is that
many solid aldehydes did not give a satisfactory result as the mixture tended
to solidify readily and gave incomplete reaction.
(2) Mechanistic Investigations. (a) The Nature of the
Allylindium Intermediates in Ionic Liquids. We have also
studied the reaction mechanism of the indium-mediated ally-
lation reaction in ionic liquids. Our first task was to identify
the reactive allylindium intermediates formed. It is known from
our previous study of the reaction of indium metal with allyl
bromide in water that a transient reactive species, allylindium-
(I) (4), is formed.3b Compound 4 has a characteristic methylene
proton NMR signal at δ 1.7 ppm (d, J ) 8 Hz) in D2O (Scheme
2). In contrast, when indium metal reacts with allyl bromide in
1
an organic solvent such as dimethylformamide (DMF), the H
(15) Andrews, P. C.; Peatt, A. C.; Raston, C. L. Green Chem. 2004, 6,
119. At present, this method is applicable only to sulfonimines and aldimines
derived from aromatic anilines and aldehydes.
(16) (a) Law, M. C.; Wong, K. Y.; Chan, T. H. Green Chem. 2002, 4,
328. (b) Law, M. C.; Wong, K. Y.; Chan, T. H. Green Chem. 2004, 6, 241.
(c) Law, M. C.; Wong, K. Y.; Chan, T. H. J. Org. Chem. 2005, 70, 10434.
(d) Law, M. C.; Wong, K. Y.; Chan, T. H. Chem. Commun. (Cambridge)
2006, 2457.
NMR has two sets of allylic methylene signals at δ 1.75 (d, J
) 8 Hz) and δ 2.02 (d, J ) 8 Hz) in DMF-d7.2a,3a Previously,
the allylindium species in DMF was assigned to have the indium
sesquihalide structure 5 to account for the two sets of methylene
(17) Wang, D.; Dai, L.-N.; Hou, X.-L. Tetrahedron Lett. 1995, 36, 8649.
924 J. Org. Chem., Vol. 72, No. 3, 2007

In-Mediated Allyation of Imines in Ionic Liquids
TABLE 1. Indium-Mediated Allylation Reaction in Ionic Liquids (IL)a
yieldb (%)
entry
IL
additive
1
1/In/allylBr (mmol)
temp (°C)
2
3
1
2
3
4
5
6
7
8
9
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[emim][BF4]
[moemim][BF4]
[bpy][BF4]
/
/
/
/
/
/
/
1a, R ) Ph
1/1/1
1/1/1
1/1/1
1/2/2
1/1/1
1/1/1
1/1/1
1/1/1
1/1/1
Rt
Rt
50
rt
rt
rt
rt
rt
rt
48
27
18
43
17
35
25
32
28
0
1b, R ) CH2Ph
14
21
15
12
33
21
12
12
1b
1b
1b
1b
1b
1b
1b
[bpy][BF4]
[bpy][BF4]
ZnF2 (0.5 eqiv)
(TMS)Cl (0.5 eqiv)
a Reaction conditions: In and allyl bromide in the indicated millimoles ratios were stirred in IL (1 mL) for 1 h at room temperature. Imine 1 was then
1
added, and the stirred mixture was brought to the indicated temperature for 12 h. b Yields of 2 and 3 were determined by H NMR.
TABLE 2. Effect of Bromide Ion on Product Distribution in the Allylation of Imines 1a
isolated yieldd (%)
entry
[bpy][Br] added (% Br-)
imine 1
In/allylBr/1 (mmol)
temp (°C)
2
3
1
2
3
- (0)
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1/1/1
1/1/1
1/1/1
1/1/1
rt
rt
rt
50
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
21
43
93
100
82
100
100
0
41
29
0
0
0
0
0
0
0
0
0
39
34
0
0
0
0.05 g (4.3)
0.1 g (8.5)
0.1 g (8.5)
0.1 g (8.5)
0.1 g (8.5)
0.15 g (12.8)
0.2 g (17.1)
- (0)
4
5
1/1/0.5
1/1/0.5
1/1/0.5
1/1/0.5
1.5/1.5/1
1.5/1.5/1
1/1/1
1.5/1.5/1
1/1/0.5
1/1/0.5
1/1/1
6b
7
8
9
10
11
12
13
14
15
16c
0.05 g (4.3)
0.05 g (4.3)
0.1 g (8.5)
0.1 g (8.5)
0.1 g (17.1)
0.2 g (17.1)
0.2 g (8.5)
90
100
100
93
1/1/0.5
0
100
a Reaction conditions: In and allyl bromide in the indicated mmol ratios were stirred in pure [bpy][BF4] (1 mL with the indicated amount of [bpy][Br]
added) for 1 h at room temperature. Imine 1 prepared in ionic liquid via condensation reaction of benzaldehyde with aniline was added to the presynthesized
allylic indium compounds prepared as described above at the indicated temperature for 12 h. b Entry 6: All the starting materials including pure imine 1
were added at the beginning of the reaction in the same reaction vessel. c Entry 16: excess amount of allyl bromide (2.5 equiv to In) was added to the
1
reaction mixture after overnight stirring. d Yields were determined by H NMR.
SCHEME 2
identical to allylindium(I). It was concluded by us that the two
sets of signals at δ 1.75 and δ 2.15 in DMF were due to the
formation of two allylindium compounds, one of which at δ
1.7 was 4 and the other tentatively assigned to have allylindium-
(III) dibromide (6) or its dimer as the structure.19,20 What then
are the structures of the reactive allylindium species formed in
ionic liquids?
We had previously reported that in the ionic liquid, [emim]-
1
[BF4], indium reacted with allyl bromide to give, in the H
NMR, two sets of allylic methylene signals at δ 1.75 (d, J ) 8
Hz) and δ 2.02 (d, J ) 8 Hz).16a We have now repeated the
same reaction of allyl bromide and indium (at 1:1 ratio of 1.5
mmol) at room temperature in pure [bpy][BF4] (1 mL). In 10
min, two sets of allylic signals were revealed at δ 1.75 and δ
SCHEME 3
(19) Formation of allylindium(III) diiodide was reported by the reaction
of indium(I) iodide with allyl iodide in THF with the allylic methylene
signal at 2.1 ppm in THF-d8. Araki, S.; Ito, H.; Katsumura, N.; Butsugan,
Y. J. Organomet. Chem. 1989, 369, 291.
signals.18 The structural assignment was clearly incorrect as the
δ 1.75 species could be extracted into D2O and found to be
(20) The formation of allenylindium(I) and allenlylindium(III) dibromide
in the reaction of indium with propargyl bromide has been reported. Miao,
W.; Chung, L. W.; Wu, Y.-D.; Chan, T. H. J. Am. Chem. Soc. 2004, 126,
13326.
(18) (a) Araki, S.; Ito, H.; Butsugan, Y. J. Org. Chem. 1988, 53, 1831.
(b) Araki, S.; Shimizu, T.; Johar, P. S.; Jin, S. J.; Butsugan, Y. J. Org.
Chem., 1991, 56, 2538.
J. Org. Chem, Vol. 72, No. 3, 2007 925

Law et al.
SCHEME 4
SCHEME 5
2.04 at a ratio of about 1:2. However, the signal at δ 1.75
gradually reduced and finally disappeared completely when the
mixture was left for another 10-30 min. At the same period,
the signal at δ 2.04 was enhanced. Since we have already found
that 4 has the methylene signal at δ 1.7 ppm in D2O and at δ
1.75 ppm in DMF, we conclude therefore that the set of
methylene signals at δ 1.75 ppm in either [emim][BF4] or [bpy]-
[BF4] have the 4 structure as well. To elucidate the structure of
the second allylindium species at δ 2.04, we examined the
reaction of indium(I) bromide with allyl bromide in [bpy][BF4]/
[bpy][Br] to give allylindium dibromide (6) (Scheme 3).19 The
reaction was found to be quite slow and there was still over
50% of the starting allyl bromide left after 3 h. Informatively,
there were indeed methylene signals at δ 2.04 together with
new olefinic peaks at δ 4.71 and 4.88 identical to the second
species formed from indium and allyl bromide, indicating that
the allylindium species formed is 6.
SCHEME 6
We have also investigated the relationship of the two
allylindium species in [bpy][BF4] by 1H NMR with toluene as
the internal standard. The intensity ratio of these two signals
varied with time. The one at δ 1.75 declined gradually in
intensity, whereas the signal at 2.04 increased, suggesting that
4 can be converted to 6 in the reaction mixture. The rate of
conversion of 4 to 6 can be slowed down, however, if the ionic
liquid [bpy][BF4] contained some [bpy][Br] (between 8.5 and
17.5%).
SCHEME 7
(b) Formation of Homoallylic Amines 2. We then tried to
examine the relative reactivity of 4 and 6 toward imine
electrophiles. The reaction of allyl bromide with indium at room
temperature in the system [bpy][BF4]/[bpy][Br] (8.5% of
1
bromide) was monitored by H NMR. At the stage when both
4 and 6 were present in almost equal amounts, a small quantity
of imine 1a (0.5 equiv) was added to the mixture. The peaks
corresponding to 4 were found to be reduced in intensity, and
a new set of signals corresponding to the amido indium adduct
7a could be observed. Eventually, compound 4 completely
disappeared and only compound 6 together with the product
7a were observed. The structure of adduct 7a was confirmed
by quenching the reaction mixture at this stage to give the
monoallylic amine 2a. This experiment therefore demonstrates
that 4 reacts with imine 1a to give the homoallylic amine 2a
via the adduct 7a (Scheme 4). The alternative possibility of the
reaction of 6 with imine 1a to give the putative intermediate
8a and then 2a was either not operative or too slow to compete
with the formation of 7a with the limited amount of 1a available.
(c) Formation of Bis-allylated Amines 3. It has been
proposed, under the solvent-free reaction conditions, that the
bis-allylation product 3 was formed through an iminium salt 9
followed by nucleophilic addition of allylindium species
(Scheme 5).14 This was supported by the reaction of MeI and
N-benzylideneaniline, which generated the presumed iminium
salt.21 To elucidate whether this may account for the formation
926 J. Org. Chem., Vol. 72, No. 3, 2007

In-Mediated Allyation of Imines in Ionic Liquids
TABLE 3. Indium-Mediated Allylation Reaction of Aldiminesa
a Reaction conditions: Aldimines (0.5 mmol generated in situ in [bpy][BF4]) was added to allylindium compounds (prepared in situ from the indicated
amount of allyl bromide and indium) in [bpy][BF4] (1 mL) with the indicated amount of [bpy][Br] added. The mixture was stirred overnight at room
temperature. b Isolated yield.
of the bis-allylated amine 3 in ionic liquids, we investigated
the possibility of generating the iminium ion in situ in ionic
liquid by reacting allyl bromide and imine 1b. However, the
unchanged in intensity. This proves that the bis-allyated amine
3b can be derived from the reaction of 7b with allyl bromide
(Scheme 6).
1
There remains the question of whether allylindium(III)
dibromide (6) could react with imine 1b to give the bis-allylated
amine 3b as well. Instead of treating the above reaction mixture
containing 6 and amido-indium adduct 7b with a second aliquot
of allyl bromide, it was quenched with a second aliquot of imine
1b (0.5 equiv). Examination by 1H NMR showed that the signal
of adduct 7b was enhanced slowly. To account for the enhanced
amount of 7b, we postulate that compound 6 can undergo
reversible reaction to generate 4 which reacts rapidly with imine
1b to give adduct 7b.
iminium salt 9 was not observed by H NMR; the signals of
allyl bromide and the imine 1b remained unchanged regardless
of reaction time and temperature (up to 50 °C). Since no
iminium salt was involved in the allylation reaction, the bis-
allylated product cannot be coming from the competitive
nucleophilic attack of iminium salt by allylindium species.
We then tried to see whether the bis-allylated amine 3b could
be formed from the mono-allylated species. When 0.5 equiv of
imine 1b was added to 1.5 equiv of allylindium species (a 1:1
mixture of 4 and 6, in situ generated by reacting indium and
allyl bromide) in [bpy][BF4]/[bpy][Br] (8.5% bromide), 4 was
completely reacted. The mixture was left with unreacted 6 and
the amido-indium adduct 7b, Addition of a second aliquot of
allyl bromide (0.5 equiv) to the reaction mixture at this stage
was found to give bis-allylated product 3b with 6 more or less
(d) An Overview. From these observations, an overview of
the mechanism of indium-mediated allyation of imine in IL
(21) Bohme, H.; Viehe, H. G. Iminium Salts in Organic Chemistry.
Advances in Organic Chemistry; John Wiley & Sons: New York, 1976;
Vol. 9.
J. Org. Chem, Vol. 72, No. 3, 2007 927

Law et al.
TABLE 4. Yields of Imines from Aldehydes with Amines in Ionic Liquid Conditionsa
entry
R1
R
solvent
time
12 h
12 h
12 h
temp/0C
yieldb (%)
1
2c
3d
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Ph
Ph
Ph
Ph
Ph
p-ClPh
p-BrPh
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
[bpy][BF4]
[bpy][BF4]
[bpy][BF4]
[bpy][BF4]
[bmim][BF4]
[bpy][BF4]
[bpy][BF4]
[bpy][BF4]
[bpy][BF4]
[bpy][BF4]
[bpy][BF4]
[bpy][BF4]
[bpy][BF4]
[bpy][BF4]
[bpy][BF4]
[bpy][BF4]
[bpy][BF4]
[bpy][BF4]
rt
rt
rt
80
90
94
1 h + 2 h
1 h + 2 h
1 h + 2 h
1 h + 2 h
1 h + 2 h
1 h + 2 h
1 h + 2 h
1 h + 2 h
1 h + 2 h
1 h + 2 h
1 h + 2 h
1 h + 2 h
1 h + 2 h
3 h
rt/50
rt/50
rt/50
rt/50
rt/50
rt/50
rt/50
rt/50
rt/50
rt/50
rt/50
rt/50
rt/50
rt
(94)
(96)
(97)
(97)
(91)
(95)
91.7
100
(99)
100
100
98
2,6-dichloroPh
NCPh
p-MeOPh
p-HOPh
trans-PhCHdCH
2-furyl
2-pyridyl
Ph
p-ClPh
p-MeOPh
CH2Ph
Ph
Ph
Ph
100
(99)
100
p-MeOPhC H2
1 h + 2 h
rt
a Reaction conditions: Aldehyde (1 mmol) and amine (1 mmol) was added to the IL (2 mL) and stirred at room temperature for a specified time period
1
followed by heating under vacuum at 50 °C for specified time. b Measured by H NMR (isolated yields in parentheses). c Entry 2: 5 Å molecular sieves
(small spheres) were added to the reaction mixture. d Entry 3.: 4 Å molecular sieves (fine powder) were added to the reaction mixture.
begins to emerge. First, indium reacts with allyl bromide in IL
to give 4 together with indium(I) bromide. Subsequent reaction
of InBr with allyl bromide gives 6. There is a dynamic
equilibrium between 4 and 6, eventually with 6 predominant.
The conversion between 4 and 6 may be mediated by indium
metal and indium bromide according to Scheme 7. When
bromide ion is present in greater than 8.5%, it retards the
conversion of 4 to 6, thus facilitating the formation of the mono-
allylated amine 2 according Scheme 4.
with imines generated in situ from the aldehydes and amines
in the ionic liquids. The aldehydes used can be aryl, heteroaryl,
and R,â-unsaturated aldehydes. The amines can be substituted
anilines and benzylamines. The aldehydes and amines were
simply mixed in [bpy][BF4] (or [bmim][BF4]) and warmed to
50 °C under vacuum for a specified time. The water byproduct
was presumably removed under these conditions, and the
formation of imines was essentially quantitative. The results
are summarized in Table 4. The imines thus formed were then
allylated directly as described previously.
(3) Allylation of Aldimines Mediated by Indium. With
these mechanistic insights, we were able to devise reaction
conditions that allow monoallylation of the imines. The standard
reaction condition we have adopted involved the reaction of
aldimine, indium powder, and allyl bromide in predried ionic
liquid in a 0.5:1.5:1.5 ratio stirred overnight at room temperature.
The homoallylic amine was extracted with ethyl acetate. There
was no decomposition of starting materials or the production
of homoallylic alcohols. The reaction proceeded smoothly with
a variety of aldimines (Table 3). Both electron-rich and electron-
deficient substituents bearing imines were found to be allylated
smoothly. Heterocycles such as pyridine, furan, and thiazole
did not present any difficulty (entries 3, 5, and 8). Imine derived
from 1-naphthaldehyde worked well even though the 1-position
may be relatively sterically hindered (entry 9). In cases where
R is an R,â-unsaturated group, 1,2-addition was obtained without
1,4-addition (entry 13).22 It is noteworthy that reactions could
be performed on N-benzylidenebenzylamine and its analogues
with good yields and excellent control of mono-allylated species
formation.23
Conclusions
In conclusion, aldimines undergo nucleophilic addition with
allylindium reagents generated from indium and allyl bromide
to give the corresponding homoallylic amines in good to
excellent yields in the presence of bromide ions. [bpy][BF4]/
[bpy][Br] was found to be a suitable reaction medium for the
reaction. The nature of the allylindium species formed depends
on the solvents used. In aqueous media, only allylindium(I)
species was formed, whereas in the organic solvents and IL
system, both allylindium(I) and allylindium(III) dibromide were
observed. Allylindium(I) was found to be more reactive toward
imines and responsible for the formation of the monoallyated
amine 2. There appears to be an equilibrium between allylin-
dium(I) and diallylindium(III) dibromide, which accounts for
the formation of the bis-allylated amine 3. The presence of
bromide ion appears to affect the equilibrium and help ensure
the sufficient presence of allylindium(I) in the IL and, therefore,
on reactions with imines, a good yield of 2.
(4) Synthesis of Imines from Carbonyl Compounds and
Amines in Ionic Liquids. We can also carry out the allylation
Experimental Section
(22) This is in contrast to the reaction of organolithiums, where both
1,2- and 1,4-addition were observed. See, for examples: Tamioka, K.; Inoue,
I.; Shindo, M.; Kago, K. Tetrahedron Lett. 1990, 31, 6681.
(1) Preparation of Ionic Liquids. The crude N-butylpyridinium
tetrafluoroborate ([bpy][BF4]) was prepared by metathesis reaction
in acetonitrile (300 mL) from sodium tetrafluoroborate (121 g, 1.1
mol,) (purchased commercially with 98% purity in fine powder
form) and its bromide precursor [bpy][Br] (216 g, 1.0 mol) which
was in turn prepared from the microwave-assisted method.11 The
(23) When R has an sp3 carbon linked to nitrogen, the corresponding
aldimines are generally less reactive, leading to poor yields and incomplete
reactions or even no reaction at all. For examples, see: (a) Beuchet, P.;
Marrec, N. L.; Mosset, P. Tetrahedron Lett. 1992, 33, 5959. (b) Nakamura,
K.; Nakamura, H.; Yamamoto, Y. J. Org. Chem. 1999, 64, 2614.
928 J. Org. Chem., Vol. 72, No. 3, 2007

In-Mediated Allyation of Imines in Ionic Liquids
mixture was stirred for 3 days at room temperature and then filtered.
The filtrate was evaporated and the residue crude [bpy][BF4] was
vacuum-dried overnight at 70 °C (0.1 mmHg) and stored under
nitrogen. Pure [bpy][BF4] could be obtained by column chroma-
tography of the crude [bpy][BF4] on silica gel with dichloromethane
as eluent.12 The recovery of [bpy][BF4] after chromatography was
about 60%.
(2) Typical Procedure for the Preparation of Benzylidene-
anilines in Ionic Liquid. A 50 mL reaction tube was charged with
the ionic liquid (2 mL). A mixture of benzaldehyde (1 mmol) and
aniline (1 mmol) was added to ionic liquid (2 mL) at room
temperature under nitrogen. The reaction mixture was stirred
vigorously for the specified time and temperature as indicated in
Table 4.
stirred at rt overnight. The resulting mixture was quenched with a
few drops of saturated ammonium chloride solution followed by
extraction with ethyl acetate (3 × 10 mL). After removal of the
solvent in vacuum, the residue was purified by flash chromatog-
raphy on silica gel to yield the pure adduct amine 2.
Acknowledgment. This work was supported by a grant from
NSERC to T.H.C. and a HKRGC grant (PolyU 5002/03P) and
the Areas of Excellence Scheme established under the University
Grants Committee of the Hong Kong Special Administrative
Region, China (Project No. AoE/P-10/01). The award of a
scholarship by McGill University to M.C.L. is gratefully
acknowledged.
(3) Allyation of Imines in Ionic Liquids. Pure [Bpy][BF4] (1
mL) with the indicated amount of [bpy][Br] added was used as
reaction media. Indium and allylBr (in millimoles specified) were
added and stirred at room temperature (rt) for 1 h. Imine (0.5 mmol
generated in situ in IL) was then added to the reaction mixture and
Supporting Information Available: 1H and 13C NMR spectra
of compounds of 2a-2m and 3b and other physical data. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO062198X
J. Org. Chem, Vol. 72, No. 3, 2007 929