Rate acceleration and diastereoselectivity in chelation-controlled indium-promoted Barbier allylation of pyridine-2- and quinoline-2-imines in aqueous solvents

Article abstract of DOI:10.1016/j.tetlet.2004.03.022

The imines generated in situ from 2-pyridinecarboxaldehyde/2- quinolinecarboxaldehyde and aryl amines undergo indium-mediated Barbier allylation in aqueous media to provide homoallylic amines. Crotyl and cinnamyl bromides lead to diastereoselective allyla

Full text of DOI:10.1016/j.tetlet.2004.03.022

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3413–3416
Rate acceleration and diastereoselectivity in chelation-controlled
indium-promoted Barbier allylation of pyridine-2- and quinoline-2-
imines in aqueous solvents
Subodh Kumar* and Pervinder Kaur
Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India
Received 5 December 2003; revised 23 February 2004; accepted 5 March 2004
Abstract—The imines generated in situ from 2-pyridinecarboxaldehyde/2-quinolinecarboxaldehyde and aryl amines undergo
indium-mediated Barbier allylation in aqueous media to provide homoallylic amines. Crotyl and cinnamyl bromides lead to dia-
stereoselective allylation with d.r. up to 98:2.
Ó 2004 Elsevier Ltd. All rights reserved.
Indium-promoted allyl addition reactions continue to be
regarded amongst the premier methods for carbon–
carbon bond formation under aqueous conditions.1
Significant efforts have been made to elucidate the
impact of proximal groups on the p-facial selectivity. In
the cases of a- and b-hydroxy,2 amino,3 carboxy,4
amido5 etc., substituted aldehydes and ketones, the
excellent to moderate diastereocontrol during allylation
leads to syn-a-substituted/anti-b-substituted homoallylic
alcohols. The influence of aqueous solvents in achieving
high diastereoselectivities is significant. In all these
reactions, the involvement of a chelated transition state
has been proposed and its participation is supported by
the accelerated reaction rates.
aqueous solvents. The reactions of 3-pyridinecarboxal-
dehyde 3, p-anisaldehyde 4 and p-chlorobenzaldehyde 5
have been studied to evaluate the role of co-ordination
of the pyridine and quinoline nitrogen.
The reaction of 1, p-chloroaniline, indium metal and allyl
bromide was chosen as a model reaction (Scheme 1).
On performing the reaction in water, p-chloroaniline
was converted to N-allyl-p-chloroaniline 7 and N,N-
diallyl-p-chloroaniline 8 and the homoallylic amine 6
was not formed. For the reactions carried at 30ꢀ1 °C in
THF–H2O,8 a stirred solution of 1 and p-chloroaniline
in THF was diluted with the appropriate amount of
water and stirring continued for 30–60 min. During this
period, the solid/liquid imine separated out.8 Indium
metal and allyl bromide were then added and stirring
was continued. On using the H2O–THF (1:1) solvent
system, the desired homoallylic amine 6 was isolated in
Due to the ease of hydrolysis of imines under aqueous
conditions, allylation of imines in water has met with
limited success, and only water-stable and presynthe-
sized activated imine analogs such as aryl/sulfonyl
hydrazones, sulphimines6 and oxime ethers7 have been
employed in aqueous indium-mediated allylations. In
the course of our investigations to develop new indium-
mediated allylation reactions of imines in water, we have
found that imines generated from 2-pyridinecarboxal-
dehyde 1 and 2-quinolinecarboxaldehyde 2 and aryl
amines undergo efficient Barbier-type allylation in
Br
NH2
Cl
H
In, stir
30+1 o
N
1
C
O
N
NH
Cl
N
HN
Keywords: Indium; Imines; Aqueous solvent; Allylation; Diastereo-
selective.
Cl
Cl
6
7
8
* Corresponding author. Tel.: +91-183-2556868; fax: +91-183-22588-
20; e-mail: subodh.kumar@angelfire.com
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.022

3414
S. Kumar, P. Kaur / Tetrahedron Letters 45 (2004) 3413–3416
Table 2. Synthesis of homoallylic amines using allyl bromide
81% yield along with compounds 7 and 8 (15%). On
increasing the H2O–THF ratio to 2:1 and 4:1, the yield
of homoallylic amine 6 was increased to 82% and 89%,
respectively. Significantly, in the case of the H2O–THF
4:1 system, only traces of 7 and 8 were formed. On
increasing the ratio of H2O–THF to 6:1 or 8:1, only a
mixture of 7 and 8 could be isolated. Therefore, H2O–
THF (4:1) was the optimal solvent system for the syn-
thesis of homoallylic amine 6 from 1, p-chloroaniline,
allyl bromide and indium.
Entry
Aldehydes
X
Time (h)
Yield (%)
1
2
1
1
1
1
1
1
2
3
4
5
p-Cl
o-Cl
4–5
4–5
89
86
85
80
75
78
78
0
3
p-Me
p-OMe
o-CO2Me
p-F
4–5
4–5
4
5
4–5
4–5
6
7
p-Cl
p-Cl
4–5
8
12–14
8–10
8–10
9
10
p-OMe
p-Cl
10
20
In these reactions, the increase in the water–THF ratio
resulted in an increase in reactivity of the allyl indium
reagent3b;7;9 and a decrease in the hydrolysis of water
insoluble imines. The co-ordination of the pyridine
nitrogen with indium increased the electron deficiency
on the imine and thus increased reactivity towards the
allyl indium. Therefore, the combination of the increase
in the reactivity of the allyl indium and imine due to
co-ordination and a decrease in the hydrolysis of imine
leads to more efficient allylation. The lack of allylation
of the presynthesized imine (from 1 and p-chloroaniline)
in water showed that a small amount of THF is neces-
sary for the allylation (Table 1).
H2N
Br
X
O
+
HN
In, stir
R
H
o
30+1
C
R
X
1 5
Scheme 2.
In the case of allylation of the in situ generated imine
(tlc) from 3-pyridinecarboxaldehyde and p-chloroani-
line, the reaction proceeds quite slowly8 (12–14 h). Also,
only amine allylated products 7 and 8 could be isolated
and formation of the homoallylic amine was not
observed. In the case of allylation of the in situ gener-
ated imines from p-anisaldehyde and p-chlorobenzalde-
hyde, only 10–20% of the homoallylic amine and
80–90% of homoallylic alcohol was formed (Table 2,
entries 9 and 10). Probably, in the absence of an
appropriately placed additional coordinating site, the
allyl transfer reaction is slow and therefore the hydro-
lysis of the imine to the aldehyde and amine and sub-
sequent allylation of the aldehyde predominates. It
seems that the co-ordination of pyridine and quinoline
nitrogens with allyl indium is essential for smooth allyl-
ation of their imines in water.
O
H
H
H
N
N
O
N
O
O
2
3
1
O
H
H
Cl
MeO
5
4
The reactions of 1 with other arylamines in H2O–THF
4:1 provided homoallylic amines in 75–86% yield (Table
2, entries 2–6) (Scheme 2). Contrary to reported
homoallylic amine synthesis from o- and p-chloro- and
o-nitroanilines10 and presynthesized allyl stannanes11 in
water, here the nature and position of the substituent on
the aniline appears to have little effect on the reaction.
Similarly, the in situ generated imine from 2 and
p-chloroaniline also underwent allylation to provide
homoallylic amine in 78% yield along with a homoallylic
alcohol (8%) (Table 2, entry 7).
In the case of indium-promoted allylation reactions of
carboxaldehydes, the rate of acceleration is in general
accompanied by high diastereoselectivity.2aꢁc In order to
evaluate the role of chelation on the diastereoselectivity,
the reactions of imines derived from aldehydes 1 and 2
and aryl amines with substituted allyl halides have been
studied.
The reaction of the imine derived from 1 and p-chloro-
aniline with crotyl bromide (9, R ¼ CH3) and indium in
THF–H2O (4:1) provided the homoallylic amine 10a
(63%) along with the amine allylated products (4–7%).
(Scheme 3). The 1H NMR spectrum of 10a showed that
it exists as mixture of two diastereomers in a 90:10 ratio.
On using the imine derived from o-chloroaniline, a
Table 1. Effect of the solvent system on homoallylic amine formation
Entry
Solvent
Time (h) 6 (%)
7þ8 (%)
80
1
2
3
4
5
6
7
H2O
14
4
––
81
H2O–THF (1:1)
H2O–THF (2:1)
H2O–THF (4:1)
H2O–THF (6:1)
H2O–THF (8:1)
H2Oa
15
10
R
H2N
Br
X
O
9
4
82
89
+
HN
Het
In, stir
4
Traces
90
90
Het
1/2
H
o
30+1
C
X
20
20
––
––
R
10 / 11
No reaction
a Presynthesized imine.
Scheme 3.

S. Kumar, P. Kaur / Tetrahedron Letters 45 (2004) 3413–3416
Table 3. Diastereoselective synthesis of homoallylic amines
3415
Entry
Aldehyde
R
X
10/11
syn:anti
Yield (%)
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
CH3
CH3
CH3
CH3
CH3
CH3
C6H5
C6H5
CH3
CH3
CH3
CH3
CH3
C6H5
C6H5
p-Cl
o-Cl
10a
10b
10c
10d
10e
10f
10g
10h
11a
11b
11c
11d
11e
11f
11g
90:10
88:12
86:14
90:10
86:14
80:20
98:2
63
65
64
63
45
55
22
25
69
60
66
72
61
73
20
2
3
m-Cl
p-Br
p-CH3
o-CO2Me
p-Cl
4
5
6
7
8
o-Cl
p-Cl
98:2
91:9
9
10
11
12
13
14
15
o-Cl
90:10
83:17
88:12
90:10
98:2
m-Cl
p-Br
p-F
p-Cl
o-Cl
98:2
diastereomer ratio of 88:12 was achieved and in the case
of m-chloroaniline the d.r. decreased to 86:14. The
presence of an electron donating group (Table 3, entry
5) or an additional co-ordinating group on aniline
(Table 3, entry 6) lowered both the diastereoselectivity
and the yield of the homoallylic amine. Similarly, imines
generated in situ from 2 and aryl amines underwent
diastereoselective allylation with crotyl bromide to
provide homoallylic amines 11a–e (60–72%) along with
the corresponding homoallylic alcohol (5–8%) (Table 3,
entries 9–13).
the participation of the quinoline/pyridine nitrogen in
the allylation.
In the case of the recently reported three component
allylation of aldimines in an aqueous sodium dodecyl
sulfate medium, the reactions proceeded only in the
presence of hydrated Lewis acids10 and required pre-
synthesized allylating reagents.11;13;14 Furthermore, the
reactions were limited to the transfer of the unsubsti-
tuted allyl moiety only. Therefore, the present results
not only provide a relatively simpler approach involving
four components in one reaction pot, they lead to
increased scope in terms of diastereoselective synthesis.
The further participation of other nitrogen-based
co-ordinating groups (NH2, NR2, NHR, etc.) a- or b- to
the imine in diastereoselective allylation reactions is
currently being evaluated.
The reactions of imines derived from 1 or 2 and aryl
amines, with cinnamyl bromide (9, R ¼ C6H5) and
indium provided the homoallylic amines 10g, 10h, 11f and
11g with high diastereoselectivities (d.r.>98:2)
although the yield of the homoallylic amine was, in gen-
eral, lower.
In all the homoallylic amines derived from crotyl bro-
mide, the major diastereomer showed an N–CH doublet
at a higher d value. It seems that all these reactions
follow the same mechanism for allylation. In order to
provide insight into the mechanism, the X-ray crystal
structure12 of 11f was determined. The formation of the
syn addition product (Fig. 1) in this reaction confirmed
Acknowledgements
We thank CSIR [01(1795)/02/EMR-II] for financial
assistance and DSTfor the FISTprogramme.
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Figure 1. The ORTEP view (50% ellipsoid) of 11f.
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3416
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solved in THF (1 mL) and water (4 mL) was added with
stirring. The reaction mixture was stirred at 30 1 °C for
2 h. During this period a yellow thick liquid separated out.
Indium (2 mmol) and allyl bromide (3 mmol) were added
and stirring was continued for 4 h. During this period
indium metal was consumed. The stirring was continued
for another 1 h. The reaction mixture was diluted with
water (20 mL) and extracted with ethyl acetate. The crude
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12. The X-ray crystal data was measured by using h–2h scan
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SHELX-97. 11f, C25H21ClN2, monoclinic, space group C/
ꢀ
2C, a ¼ 24:646, b ¼ 12:494, c ¼ 14:761 A; b ¼ 114:78°;
3
v ¼ 4126:4 A ; z ¼ 8; d.c. 1.239 mg mꢁ3
;
MoKa ¼
ꢀ
ꢀ
0.70930 A; The structure solution is based on 3777
reflections, which converged to R ¼ 0:04. CCDC reference
number 231880.
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