A distinct approach for the rapid synthesis of homoallylic amines starting directly from nitro compounds in water

Article abstract of DOI:10.1016/j.tetlet.2008.10.010

Three-component reactions of nitroarenes, benzaldehydes, and allyltributylstannane using indium in dilute aqueous HCl at room temperature afford the corresponding homoallylic amines in high yields within 5-10 min. The conversion in one-pot synthesis involves the following steps: (i) reduction of nitro compounds to amines, (ii) formation of imines from amines and aldehydes, and (iii) allylation of imines.

Full text of DOI:10.1016/j.tetlet.2008.10.010

Tetrahedron Letters 49 (2008) 7209–7212
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Tetrahedron Letters
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A distinct approach for the rapid synthesis of homoallylic amines
starting directly from nitro compounds in water q
*
Biswanath Das , Gandham Satyalakshmi, Kanaparthy Suneel, Boddu Shashikanth
Organic Chemistry Division—I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Three-component reactions of nitroarenes, benzaldehydes, and allyltributylstannane using indium in
dilute aqueous HCl at room temperature afford the corresponding homoallylic amines in high yields
within 5–10 min. The conversion in one-pot synthesis involves the following steps: (i) reduction of nitro
compounds to amines, (ii) formation of imines from amines and aldehydes, and (iii) allylation of imines.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 29 August 2008
Revised 27 September 2008
Accepted 3 October 2008
Available online 7 October 2008
Keywords:
Homoallylic amine
Nitroarene
In/HCl
Three-component reaction
Allylation
Homoallylic amines are important building blocks for the prep-
aration of various biologically active molecules.1 A straightforward
synthesis of homoallylic amines involves the nucleophilic addition
of allyltin reagents to imines, which are generated in situ from
aldehydes and amines in the presence of a catalyst.2 However,
the long reaction times, unsatisfactory yields, and tedious workups
are drawbacks in several of the methods employed earlier using
various catalysts. To find a suitable catalyst which is active in the
presence of amines and water (produced during the formation of
imines) is problematical.
H
N
CHO
NO2
SnBu3
In, HCl, H2O
+
R1
r. t. , 5-10 min
R2
R1
R2
3
1
2
86-92%
Scheme 1.
In connection with our work3 on the development of useful
synthetic methodologies, we have discovered that homoallylic
amines can be synthesized efficiently via the three-component
reaction of nitroarenes, benzaldehydes, and allyltributylstannane
using indium in dilute aqueous HCl at room temperature
(Scheme 1).
Initially, the reaction of nitrobenzene, benzaldehyde, and allyl-
tributylstannane was carried out using different metals such as Zn,
Sn, In, and Fe in aqueous HCl. Considering the reaction times and
yields at room temperature, In was found to be most effective
(Table 1, entry c).
Table 1
Synthesis of homoallylic amine 3a using different metalsa
Entry
Metal
Time
Yield (%)
a
b
c
Sn
Zn
In
8 h
5 h
60
68
92
20
55
5–10 min
12 h
d
Fe
2 hb
a
Conditions: nitrobenzene (1 mmol), benzaldehyde (1 mmol), allyltributylst-
annane (1.1 mmol), metal (2 mmol), 1 N HCl, rt.
Subsequently, a series of homoallylic amines were conveniently
b
prepared4 using this metal (Table 2). The products were formed in
The reaction was conducted at 80 °C.
high yields (86–92%). The impressive point of note is that the con-
version occurred very rapidly within 5–10 min. Previously, in some
reported methods, the preparation of homoallylic amines required
q
Part 172 in the series, ‘Studies on novel synthetic methodologies’.
* Corresponding author. Tel./fax: +91 40 27160512.
E-mail address: biswanathdas@yahoo.com (B. Das).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.010

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B. Das et al. / Tetrahedron Letters 49 (2008) 7209–7212
Table 2
Synthesis of homoallylic amines using indium in dilute aqueous HCl at room temperaturea
Entry
Nitroarene 1
Aldehyde 2
Product 3
Time (min)
Isolated yield (%)
H
NO2
CHO
N
a
4
88
H
N
CHO
NO2
NO2
b
5
6
91
88
Cl
Cl
H
N
CHO
c
Cl
Cl
H
N
CHO
NO2
NO2
d
5
91
F
F
H
N
CHO
e
7
86
OMe
CHO
OMe
H
N
NO2
NO2
f
6
89
CH3
CH3
H
N
CHO
g
7
87
H
N
CHO
NO2
h
5
92
NO2
NH2
H
N
NO2
CH=CH-CHO
i
6
88

B. Das et al. / Tetrahedron Letters 49 (2008) 7209–7212
7211
Table 2 (continued)
Entry
Nitroarene 1
Aldehyde 2
Product 3
Time (min)
Isolated yield (%)
H
N
NO2
O
CHO
j
7
89
87
O
H
N
NO2
CHO
k
8
H
N
CHO
NO2
NO2
l
5
7
8
92
88
87
OAc
OAc
H
N
CHO
m
HO
OH
H
N
NO2
CHO
CH3
n
HO
OH
CH3
H
N
NO2
CH=CH-CHO
o
p
q
r
10
86
88
87
HO
OH
CHO
H
N
NO2
H2N
6
NH2
CH3
H
N
CHO
H2N
NO2
NO2
8
NH2
OMe
CHO
OMe
H
N
5
5
90
89
H2N
H3C
NH2
NO2
H
N
CHO
s
CH3
a
The structures of the products were determined from their spectral (IR, 1H and 13C NMR and MS) and analytical data.

7212
B. Das et al. / Tetrahedron Letters 49 (2008) 7209–7212
several hours.2 Various derivatives of nitrobenzene were used to
prepare homoallylic amines. Both aromatic and heteroaromatic
aldehydes underwent the conversion smoothly. The presence of
electron-donating or electron-withdrawing groups on the nitro
compounds or aldehydes did not affect the reactions. The corre-
sponding alcohols, as reduction products of the aldehydes, were
not obtained. Acid sensitive aldehydes such as cinnamaldehyde
(Table 2, entry i) and furfuraldehyde (entry j) and the sterically
hindered aldehyde 2-naphthaldehyde (entry k) afforded the corre-
sponding homoallylic amines in impressive yields. The present
method is highly selective for aldehydes as ketones did not under-
go the conversion. Halogen substituents and a conjugated double
bond were unaffected by the reaction. The allyl group also re-
mained intact. The reactions with nitroamines (entries p, q, and
r) afforded only monohomoallylic amines. The structures of the
products were determined from their spectral (IR, 1H and 13C
NMR and MS) and analytical data.4
The present conversion consists of three steps in one-pot. Ini-
tially, the nitrobenzenes are reduced to anilines by In/HCl at room
temperature. These anilines then react immediately with benz-
aldehydes to form the corresponding imines. Finally, the imines
undergo allylation with allyltributylstannane to produce the
homoallylic amines.
Recently, indium has emerged as a metal of high potential in or-
ganic synthesis.5 It is unaffected by air or oxygen at room temper-
ature. It generally does not affect oxygen and nitrogen-containing
functional groups. Here, it has been utilized successfully for the
synthesis of homoallylic amines starting from nitrobenzenes. The
conversion has been carried out efficiently in water, and no addi-
tional organic solvents were required.6
References and notes
1. (a) Enders, R. D.; Reinhold, V. Tetrahedron: Asymmetry 1997, 8, 1895; (b) Bloch, R.
Chem. Rev. 1998, 98, 1407.
2. (a) Akiyama, T.; Iwai, J.; Onuma, Y.; Kagoshima, H. Chem. Commun. 1999, 2191;
(b) Aspinall, H. C.; Bissett, J. S.; Greeves, N.; Levin, D. Tetrahedron Lett. 2002, 43,
323; (c) Yadav, J. S.; Reddy, B. V. S.; Reddy, P. S. R.; Rao, M. S. Tetrahedron Lett.
2002, 43, 6245; (d) Akiyama, T.; Onuma, Y. J. Chem. Soc., Perkin Trans. 1 2002,
1157; (e) Yadav, J. S.; Reddy, B. V. S.; Raju, A. K. Synthesis 2003, 883; (f) Das, B.;
Ravikanth, B.; Laxminarayana, K.; Rac, B. V. J. Mol. Catal. A: Chem. 2006, 253,
92.
3. (a) Das, B.; Banerjee, J.; Mahender, G.; Majhi, A. Org. Lett. 2004, 6, 3349; (b) Das,
B.; Holla, H.; Venkateswarlu, K.; Majhi, A. Tetrahedron Lett. 2005, 46, 8895; (c)
Das, B.; Ramu, R.; Ravikanth, B.; Reddy, K. R. Tetrahedron Lett. 2006, 47, 779; (d)
Das, B.; Thirupathi, P.; Kumar, R. A.; Laxminarayana, K. Adv. Synth. Catal. 2007,
346, 2677.
4. General experimental procedure: To a mixture of a nitrobenzene (1 mmol), 1 N
aqueous HCl (1 mL) and indium (325 mesh, 2 mmol, 0.228 g) in water (5 mL)
were added benzaldehyde (1 mmol) and allyltributylstannane (1.1 mmol). The
resulting mixture was stirred at room temperature, and the reaction was
monitored by TLC. After completion, the mixture was washed with saturated
NaHCO3 solution (3 Â 5 mL) and water (3 Â 5 mL) and subsequently extracted
with EtOAc (3 Â 5 mL). The extract was concentrated under reduced pressure,
and the residue was subjected to column chromatography (silica gel, hexane) to
obtain pure homoallylic amine.
The spectral and analytical data of novel products are given below.
Compound 3d: IR (KBr): 3414, 1623, 1527, 1345, 1273 cmÀ1 1H NMR (CDCl3,
;
200 MHz): d 7.34–7.23 (4H, m), 7.01 (2H, t, J = 8.0 Hz), 6.61 (1H, t, J = 8.0 Hz),
6.38 (2H, d, J = 8.0 Hz), 5.72 (1H, m), 5.22–5.13 (2H, m), 4.32 (1H, br t, J = 7.0 Hz),
4.03 (1H, br s), 2.58 (1H, m), 2.45 (1H, m); 13C NMR (CDCl3, 50 MHz): d 136.5,
134.8, 129.7, 129.5, 126.1, 118.1, 117.3, 113.6, 56.5, 43.3; ESIMS: m/z 242
[M+H]+ Anal. Calcd for C16H16FN: C, 79.67; H, 6.64; N, 5.81. Found: C, 79.84; H,
6.44; N, 5.68%
Compound 3h: IR (KBr): 3400, 1641, 1514, 1434, 1203 cmÀ1
;
1H NMR (CDCl3,
7.21 (2H, d, J = 8.0 Hz), 7.08 (2H, d, J = 8.0 Hz), 7.02 (2H, t,
200 MHz):
d
J = 8.0 Hz), 6.58 (1H, t, J = 8.0 Hz), 6.41 (2H, d, J = 8.0 Hz), 5.76 (1H, m), 5.20–5.04
(2H, m), 4.34 (1H, br t, J = 6.0 Hz), 4.02 (1H, br s), 2.58 (1H, m), 2.46 (1H, m); 13C
NMR (CDCl3, 50 MHz): d 136.6, 134.9, 129.8, 129.3, 126.5, 118.3, 117.4, 116.7,
113.9, 56.6, 43.2; ESIMS: m/z 239 [M+H]+ Anal. Calcd for C16H18N2: C: 80.67; H,
7.56; N, 11.77. Found: C, 80.32; H, 7.63; N, 11.84.
In conclusion, we have developed an efficient one-pot synthesis
of homoallylic amines via three-component reaction of nitro-
arenes, benzaldehydes, and allyltributylstannane using indium in
dilute aqueous HCl at room temperature. The direct application
of nitroarenes, rapid conversion (only 5–10 min), excellent yields
(86–92%) are notable features of the present novel method. The
exploration of the scope of the present conversion with nitro-
alkanes and alkyl aldehydes is in progress.
Compound 3l: IR (KBr): 3408, 1766, 1603, 1504, 1205 cmÀ1 1H NMR (CDCl3,
;
200 MHz): d 7.32–7.18 (2H, m), 7.09–6.91 (4H, m), 6.61 (1H, t, J = 8.0 Hz), 6.40
(2H, d, J = 8.0 Hz), 5.72 (1H, m), 5.21–5.12 (2H, m), 4.33 (1H, m), 4.05 (1H, d,
J = 6.0 Hz); 2.61 (1H, m), 2.24 (3H, s); 13C NMR (CDCl3, 50 MHz): d 170.6, 140.2,
137.1, 135.0, 132.9, 130.2, 129.4, 128.7, 128.0, 127.4, 126.3, 117.5, 56.8, 37.5,
23.1; ESIMS: m/z 282 [M+H]+ Anal. Calcd for C18H19NO2: C, 76.87; H, 6.76; N,
4.98. Found: C, 76.43; H, 6.62; N, 4.82.
Compound 3o: IR (KBr): 3451, 1631, 1459, 1251 cmÀ1
;
1H NMR (CDCl3,
7.36–7.02 (7H, m), 6.69–6.51 (3H, m), 6.15 (1H, dd, J = 14.0,
200 MHz):
d
6.0 Hz), 5.81 (2H, m), 4.02 (1H, m), 3.71 (1H, br s), 2.52–2.34 (2H, m); 13C NMR
(CDCl3, 50 MHz): d 147.6, 137.2, 134.8, 131.5, 130.7, 129.2, 128.9, 127.3, 126.7,
118.5, 117.9, 113.4, 54.9, 40.6; ESIMS: m/z 266 [M+H]+ Anal. Calcd for C18H19NO:
C, 81.51; H, 7.17; N, 5.28. Found: C, 81.93; H, 7.21; N, 5.32.
5. Ranu, B. C. Eur. J. Org. Chem. 2000, 2347.
Acknowledgments
The authors thank CSIR and UGC, New Delhi for the financial
assistance.
6. Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic and Professional:
London, 1998.