Indium mediated Barbier-type allylation of aldimines in alcoholic solvents

Article abstract of DOI:10.1016/S0040-4039(01)01977-3

Barbier-type allylation of unactivated aldimines with allyl bromides in the presence of indium powder took place rapidly in alcoholic solvents to give homoallylic amines in fair to good yields.

Full text of DOI:10.1016/S0040-4039(01)01977-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9073–9076
Indium mediated Barbier-type allylation of aldimines in alcoholic
solvents
Tirayut Vilaivan,a,* Chutima Winotapan,a Tetsuro Shinadab and Yasufumi Ohfuneb
aOrganic Synthesis Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University, Phayathai Road,
Patumwan, Bangkok 10330, Thailand
bDepartment of Material Science, Graduate School of Science, Osaka City University, 3-3-138, Sugimoto, Sumiyoshi-ku,
Osaka 558-8585, Japan
Received 3 August 2001; revised 2 October 2001; accepted 19 October 2001
Abstract—Barbier-type allylation of unactivated aldimines with allyl bromides in the presence of indium powder took place
rapidly in alcoholic solvents to give homoallylic amines in fair to good yields. © 2001 Elsevier Science Ltd. All rights reserved.
Carbonꢀcarbon bond formation by nucleophilic addi-
tion of carbon nucleophiles to imines is an important
tool for synthesizing complex biologically active nitro-
gen-containing compounds. While addition of a variety
of carbon nucleophiles to carbonyl compounds has
been extensively investigated and well established, con-
siderably less successful results were obtained in the
analogous reactions with imines. The major problem is
the relatively low reactivity of unactivated imines
towards nucleophilic addition and deprotonation of
imines derived from enolizable carbonyl compounds to
form enamines.1–3
has not been much studied mainly due to the instability
of imines towards hydrolysis.12,13,15 As a result, all
indium-mediated allylations of unactivated imines
reported to date have been carried out in aprotic sol-
vents such as DMF or THF under anhydrous condi-
tions.16–20 We envisioned that the use of alcoholic
solvents would not cause the undesired hydrolysis and
might provide a driving force for the forward reaction
by protonation of the metal amide initially formed.
Indeed, dramatic rate acceleration of allylation in the
presence of proton sources was previously observed.21–23
We report herein an efficient entry to homoallylic
amines by nucleophilic addition of an allylindium
reagent formed in situ from an allyl bromide and
indium metal to unactivated aldimines in alcoholic
solvents.
We consider the allyl anion to be a potentially useful
nucleophile in such addition reactions since the result-
ing homoallyic amines can be transformed into several
classes of biologically active compounds by a variety of
known procedures.4–6 Among various organometallic
species successfully employed in the allylation of CꢁO
and CꢁN systems,7 organoindium reagents possess an
interesting feature in that they are stable in the presence
of water and air, thus, their reactions can be performed
without requiring strictly anhydrous conditions nor
inert atmosphere.8–11 A number of indium-mediated
allylations of CꢁN compounds including N-sul-
fonylimines,12,13 nitrones and hydrazones14 have been
successfully performed in aqueous solvents. However,
the analogous aqueous allylation of unactivated imines
Reactions of N-benzylidenebenzylamine (1) with the
allyl indium reagent generated in situ by addition of
allyl bromide to the suspension of indium powder were
initially attempted in reagent grade THF, but the
results were variable and always suffered a long induc-
tion period (up to several hours before the indium
started to dissolve exothermically). However, the reac-
tion between indium and allyl bromide was instanta-
neous when anhydrous THF was used as solvent. In
both cases, after stirring overnight at room tempera-
ture, the desired homoallylic amine (2) was obtained in
45% yield which was comparable to that reported in the
literature (42%).16 We next tried to compare different
solvents and found that the induction period was short-
est (<30 min), and the best yield was obtained, in lower
alcoholic solvents including isopropanol, methanol and
Keywords: allylation; imines; addition reactions; indium and com-
pounds; solvents and solvent effects.
* Corresponding author. Tel.: +66-2-2184961; fax: 66-2-2541309;
e-mail: vtirayut@chula.ac.th
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01977-3

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T. Vilai6an et al. / Tetrahedron Letters 42 (2001) 9073–9076
ethanol (Table 1).24 While the reaction in water was
fast, as judged by the disappearance of the indium
metal and TLC analysis, the reaction gave 1-phenyl-3-
buten-1-ol (3) as the major product (85%). The for-
mation of the homoallylic alcohol (3) is presumably
the result of allylation of the aldehyde derived from
indium salt-catalyzed hydrolysis of the imine (1). In
order to investigate the effect of water on the extent
of imine hydrolysis, the reactions were performed in
ethanol containing varying amounts of water. It was
found that the yield of the homoallylic amine (2)
dropped from 62 to 7.7 and 3.8% on changing the
solvent from absolute ethanol to 95 and 85% ethanol,
respectively. In view of the sensitivity of the reaction
to water, it is surprising that we obtained reasonably
good yields of the desired addition product using
commercial absolute alcoholic solvents considering
that no attempts to exclude moisture and air were
made.25,26 The reaction appeared to be unique to
indium, since treatment of (1) with zinc powder/allyl
bromide or tin powder/allyl bromide in ethanol under
the same conditions gave no allylation product.
reaction was compatible with a wide variety of poten-
tially reactive functional groups (aryl halide, alkoxy,
unprotected alcoholic and phenolic hydroxy, pyridyl),
position of substitution (ortho, meta, para) and
branching of the N-substituents; (5) reactions with
substituted allyl bromides (entries 9–11) gave only the
g-adducts; (6) stereoselective addition was possible
with imines derived from chiral amines. Although the
imine derived from benzaldehyde and (R)-a-methyl-
benzylamine (1k) gave poor diastereoselectivity (entry
13), we were pleased to find that the corresponding
(R)-phenylglycinol-derived imine (1l) gave only one
diastereomer of the desired allylation products (entries
1
14 and 15) according to 400 MHz H NMR analysis.
The scope and application of stereoselective allyla-
tions of imines in alcoholic solvents will be the sub-
ject of our next investigation.
In conclusion, we have demonstrated that indium-
mediated allylation of aldimines in alcoholic medium
could provide a convenient access to homoallylic
amines and it was possible to extend to a stereoselec-
tive version simply by incorporating an optically
active amine as the chiral auxiliary.
Following the successful results with the imine (1),
the scope of the reaction was explored employing a
number of structurally different substituted aldimines
(1a–1l) and allyl bromides (Table 2). In most cases
the desired homoallylic amines (2a–2o) were obtained
in yields ranging from fair to good.27 From Tables 1
and 2, the following trends can be noted: (1) no sig-
nificant difference in reaction rates and yields was
found between methanol, ethanol and isopropanol;
(2) the rates of reaction in lower alcohols were faster
and the yields were considerably better than the reac-
tions performed in aprotic solvents; (3) imines derived
from enolizable aldehydes (entries 6 and 7) gave the
desired products albeit in a rather poor yield; (4) the
Acknowledgements
We thank the financial support from TJTTP-OECF
(TJTTP-JBIC) (under the Center for Bioactive Com-
pound, Chulalongkorn University) and Department of
Chemistry, Faculty of Science, Chulalongkorn Univer-
sity. We also thank Ittiphol Saengswang and Narisa
Bumroong (Chulalongkorn University) for technical
assistance.
Table 1. Indium mediated allylation of N-benzylidenebenzylamine (1) in different solventsa
N
OH
HN
In (2 equiv.)
H
+
Br
(3 equiv.)
1
2
3
Solvent
Product
Yield (%)
45
THF
2
–
tBuOH
–
b
b
iPrOH
2
2
70
72
62
85
MeOH (absolute)c
EtOH (absolute)c
H2O
2
3d
a All reactions were performed at 1.0 mmol scale using commercial solvents. No attempts were made to exclude air/moisture.
b The indium metal did not completely dissolve even after stirring overnight.
c Contains <0.2% water.
d Only a trace of (2) was formed.

T. Vilai6an et al. / Tetrahedron Letters 42 (2001) 9073–9076
Table 2. Indium mediated allylation of aldiminesa
9075
R2
R2
R5
In
R5
N
HN
R1
R1
H
R3
Br
R3 R4
R4
1a-1l
R1
2a-2o
Entry
Imine
Amine
R2
R3 R4 R5
Yield (%)b
Solvent
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1h
1h
1i
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
3-HOC6H4
4-ClC6H4
4-pyridyl
2-pyridyl
PhCH2
PhCH2
PhCH2
Ph2CH
Ph2CH
Ph2CH
Ph2CH
Ph2CH
Ph2CH
Ph2CH
Ph
H H H
H H H
H H H
H H H
H H H
H H H
H H H
H H H
Ph Me H
Me Me H
Me Me H
H H H
H H H
H H H
H H Me
66
69
50
79
72
61
20
40
62c
30
55
48
76d
74e
74f
EtOH
EtOH
EtOH
MeOH
MeOH
EtOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
iPrOH
iPrOH
iPrOH
2-MeOC6H4
iPr
nC7H15
Ph
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
10
11
12
13
14
15
1j
1k
1l
(CH3)2CHCH2
(R)-PhCH(Me)
(R)-PhCH(CH2OH)
(R)-PhCH(CH2OH)
1l
a All reactions were performed at 1.0 mmol scale using commercial solvents. No attempts were made to exclude air/moisture.
b Yield refers to isolated yield, all products were characterized by 1H and 13C NMR.
c Obtained as ca. 5:1 mixture of diastereoisomers.
d d.r.=2.5:1, cf. Ref 16, yield 25% d.r.=4:1.
e d.r.>9:1, [h]2D4 −31.4 (c=1.01, CHCl3).
f d.r.>9:1, [h]2D4 −25.9 (c=0.96, CHCl3).
of imines, see: Kobayashi, S.; Busujima, T.; Nagayama,
S. Chem. Commun. 1998, 19–20.
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24. Although the reaction was initially stirred overnight
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27. General procedure for the allylation of imines: To a
mixture of the imine (1.0 mmol) and indium powder
(228 mg, 2.0 mmol) in an appropriate alcoholic solvent
(5 mL) was added allyl bromide (3.0 mmol). The reac-
tion was stirred vigorously at room temperature until all
the metal had dissolved (30 min–2 h), at which time,
TLC indicated complete reaction. The reaction mixture
was diluted with aqueous NaHCO3 and extracted with
ethyl acetate. The combined organic extracts were dried,
evaporated and the residue purified by flash column
chromatography on silica gel using hexane–EtOAc as
eluant.