Barbier-type allylation of iminium ions generated in situ in aqueous medium

Article abstract of DOI:10.1016/S0040-4039(02)02667-9

Iminium ions, generated in aqueous solution from secondary amines and formaldehyde, undergo a Barbier-type allylation mediated by tin, aluminum and zinc. The reaction is catalyzed by copper and produces tertiary homoallylamines in up to 85% yield.

Full text of DOI:10.1016/S0040-4039(02)02667-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 667–670
Barbier-type allylation of iminium ions generated in situ in
aqueous medium
Ida´lia H. S. Estevama,b and Lothar W. Biebera,*
aDepartamento de Qu´ımica Fundamental, Universidade Federal de Pernambuco, Cidade Universita´ria, Recife-PE 50670-901,
Brazil
bDepartamento de Cieˆncias Exatas e da Terra, Universidade do Estado da Bahia, Cabula, Salvador-BA 40000-000, Brazil
Received 2 October 2002; accepted 25 November 2002
Abstract—Iminium ions, generated in aqueous solution from secondary amines and formaldehyde, undergo a Barbier-type
allylation mediated by tin, aluminum and zinc. The reaction is catalyzed by copper and produces tertiary homoallylamines in up
to 85% yield. © 2003 Elsevier Science Ltd. All rights reserved.
eliminate environmental damage by organic wastes.8
Therefore, organic reactions in aqueous media have
attracted great interest. Barbier-type reactions have
been used to allylate aldehydes and ketones promoted
by zinc,7,8 tin,9 indium10 and magnesium.11 Propargyl
halides add to aldehydes in the presence of tin,12
indium,13 and zinc.14 Benzylic halides15 and halo
esters16 also react with aldehydes and zinc. Even uncon-
ventional substrates such as nitrobenzene17 and
diphenyldiselenide18 undergo Barbier-type alkylations
in aqueous medium.
Iminium ions are well known as intermediates in the
Mannich reaction, commonly applied to the synthesis
of b-aminoketones, aldehydes and other derivatives.1
They also react with Grignard reagents and other
organometallic compounds giving secondary2 and
tertiary3 amines, and have been used successfully in
cyclization reactions for the synthesis of piperidines4
and in Diels–Alder reactions5 in aqueous solution.
Iminium ions can be generated classically by condensa-
tion between an ammonium salt and formaldehyde.
The protonation or alkylation of imines and enamines
also results in iminium ions. A different method is the
acid-catalyzed rearrangement of benzyl azide.6
Most frequently, as in the Mannich reaction, iminium
ions are generated in the reaction medium and react in
situ with suitable nucleophiles. Nevertheless, only few
examples with organometallic reagents in aqueous
medium have been described.19–22 Homoallylic amines
have been obtained in a three-component reaction of
aldehydes, amines and allyltributylstannane in the pres-
ence of sodium dodecylsulfate and scandium trifl-
uoromethanesulfonate as Lewis acid.19 Katritzky20 has
used a bimetallic system, Bi(III)/Al(0), in aqueous
medium in the allylation and alkylation of 1-
On the other hand, many organometallic reactions have
been demonstrated to proceed in aqueous media in
recent years.7 This is possible when the organometallic
reagent has low reactivity towards water and is formed
in the reaction medium by mixing the metal, halide and
electrophilic substrate in a one-pot reaction, commonly
known as Barbier-type reaction.
There is general agreement about the advantages of the
use of water as solvent. Water is the cheapest and safest
solvent available. In the presence of reactive functional
groups, protection and deprotection processes are often
unnecessary and frequently better selectivity is
obtained. The use of water as solvent can reduce or
Scheme 1. Barbier-type homoallylation of secondary amines
by allylation of iminium ions generated in situ. M=Sn, Al,
Zn; R=(a) -CH3, (b) -CH2CH3, (c) -CH(CH3)2, (d) -CH2-
(CH2)3CH2-, (e) -CH2(CH2)2CH2-, (f) -CH2CH2OCH2CH2-,
(g) -CH2CH2SCH2CH2-.
Keywords: Barbier reaction; allylation; iminium salts; aqueous sol-
vent.
* Corresponding author. Tel.: +55-81-32718441; fax: +55-81-
32718442; e-mail: bieberlothar@hotmail.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02667-9

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I. H. S. Este6am, L. W. Bieber / Tetrahedron Letters 44 (2003) 667–670
Table 1. Reaction of dimethylammonium hydrochloride
(1a), formaldehyde (2) and allyl bromide (4) in the pres-
ence of reactive metals
(aminoalkyl)benzotriazoles to give homoalkylated
amines in high yield; the reaction probably involves
dissociation of the benzotriazole to iminium ion which
is attacked by the organometallic intermediate.21
Iminium ions generated from primary amines and
formaldehyde in situ have been reported to react with
allyl trimethylsilane in water to give bis-homoallyl-
amines.22 In this paper we report the allylation of
iminium ions, generated in situ, promoted by zinc in
aqueous medium.
Entry Temp. (°C) Solvent
Metal Yield (%)
1
2
3
4
5
6
7
8
30
30
30
30
30
30
30
30
0
40
50
60
30
30
30
30
30
30
30
H2O
H2O
H2O
1 M HCl
Al
15
10
Sna
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
30 (22)b
30
1 M F3CCOOH
1 M HCOOH
1 M H3PO4
1 M AcOH
1 M AcOH
1 M AcOH
1 M AcOH
1 M AcOH
H2O:DMFc
H2O:dioxanec
H2O:THFc
H2O:CH3CNc
H2O:DMSOc
24
25
–
35
The allylation was carried out in micro scale as follows:
a mixture of 1 mL of water, 1 mmol of amine (1), 1.2
mmol of formaldehyde (2, 35% aq.), 2 mmol of allyl
bromide (4) and 2.5 mmol of granulated reactive metal
was stirred vigorously for 1 h at rt (30°C). The reaction
was quenched by 5 mL of NaOH 10%. The product (5)
was extracted by 1 mL of CCl4 containing 0.2 mmol/
mL of anisol as internal quantitative reference (Scheme
1). The reaction of dimethylamine hydrochloride (1a),
formaldehyde (2) and allyl bromide (4) was used as the
starting point.
9
15
10
11
12
13
14
15
16
17
18
19
42 (19)b
44
30
32
33
31
24
34
17
16
H2O:ethylene glycolc Zn
H2O:methanolc
Zn
a The reaction time with tin was 20 h.
b Yield using powdered zinc
c A 1:1 mixture was used.
Initially, three different metals, Al, Sn and Zn, were
tested and all produced moderate amounts of the
expected homoallylamine (Table 1, entries 1–3). How-
ever, the smooth reaction and better yield with zinc
directed the following efforts to this metal. The study of
granulometry of metal showed that granulated zinc is
better (Table 1, entries 3 and 10). The effect of acidity
is very important in this reaction to protonate the
secondary amine, to drive the equilibrium to iminium
formation and to avoid undesired N-alkylation.
Organic and inorganic acids were tested (Table 1,
entries 4–8). Acetic acid (AcOH) showed better yields
and no byproducts were formed. In the absence of
acetic acid some N-alkylation was observed. When the
reaction was run between 40 and 50°C, the yield
improved to 44% (Table 1, entries 10 and 11). At 0°C
and 60°C lower yields were obtained (Table 1, entries 9
and 12). The addition of different water-miscible co-sol-
vents brought no improvement (Table 1, entries 13–19).
Table 2. Effect of catalysts in the reaction of morpholine,
formaldehyde and allyl bromide promoted by Zn at 30°C
Entry
Catalysta
Solvent
Yield (%)
1
–
H2O
33
47
–
–
24
35
35
36
38
42
44
45
50
52
63
72
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
–
TlI
RuCl3
Pb(OAc)2
Fe2(SO4)3
RhI3
EuF3
InCl3
BiCl3
NiCl2
CrCl3
CdCl2
Ag2SO4
CuCl2
CuI
CuCl2 (50°C)
CuI (50°C)
CuI (50 mg)
CuI (100 mg)
CuI (200 mg)
H2O/2 mmol AcOH
H2O/2 mmol AcOH
H2O/2 mmol AcOH
H2O/2 mmol AcOH
H2O/2 mmol AcOH
H2O/2 mmol AcOH
H2O/2 mmol AcOH
H2O/2 mmol AcOH
H2O/2 mmol AcOH
H2O/2 mmol AcOH
H2O/2 mmol AcOH
H2O/2 mmol AcOH
H2O/2 mmol AcOH
H2O/2 mmol AcOH
H2O/2 mmol AcOH
H2O/2 mmol AcOH
H2O/2 mmol AcOH
H2O/2 mmol AcOH
H2O/2 mmol AcOH
H2O/2 mmol AcOH
In view of the still moderate yields and the possible
volatility of the reaction product with dimethylamine
(5a), we applied the methodology of entry 8 (Table 1)
to morpholine, because 5f was expected to be less
volatile. Indeed, a 47% yield was obtained even at room
temperature. Once more, the addition of acetic acid
proved to be crucial (Table 2, entries 1 and 2). Encour-
aged by these results we studied the effect of catalysts
using morpholine.
67
76
76
78 (54%)b
70
a Unless otherwise stated, 5 mg of catalyst were used.
b Yield using powdered zinc.
As can be seen from Table 2 (entries 2 and 3), RuCl3
and TlI suppressed the reaction completely. Most of the
other catalysts, including the Lewis acids InCl3 and
EuF3, produced lower yields than the uncatalyzed reac-
tion (Table 2, entries 5–12). CdCl2 and Ag2SO4 brought
some improvement, but only CuCl2 and CuI raised the
yields significantly to 63 and 72%, respectively (Table 2,
entries 13 and 16). Working at 50°C brought further
improvement of the yield to 67 and 76%, respectively
(Table 2, entries 17 and 18). Increasing the amount of
CuI to 100 mg (ꢀ1 equiv.), a 78% yield was obtained
at rt (Table 2, entry 20). Again, granulated zinc showed
to be more efficient than zinc powder (Table 2, entry
20).

I. H. S. Este6am, L. W. Bieber / Tetrahedron Letters 44 (2003) 667–670
669
In the latter experiments, granulated zinc was added to
a suspension of CuI in water forming a black precipi-
tate. A similar reagent has been prepared by Luche and
co-workers under sonochemical conditions and used in
conjugate additions to a,b-unsaturated carbonyl
compounds7c,23 and in the cleavage of epoxyalkyl-
halides24 in aqueous media. Because of the strong
reducing character of the zinc–copper couple,25 a radi-
cal mechanism by a single-electron transfer is most
probable in these reactions.23–26 The same reagent has
been also successfully applied in the reductive ring
opening of 2-(bromomethyl)aziridines27 and, more
recently, in the Wurtz-type coupling of organic halides
in water.28
We thank Mr. Ricardo O. da Silva for GC/MS
analyses.
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