A fast and highly efficient protocol for reductive amination of aromatic aldehydes using NaBH4 and isoxazole amines in an ionic liquid medium

Article abstract of DOI:10.1002/cjoc.201190155

Reductive amination of aromatic aldehydes using NaBH₄ and isoxazole amines is carried out in a Bronsted acidic ionic liquid 1-methylimidazolium tetrafluoroborate [(HMIm)BF₄]. The ionic liquid plays dual roles of solvent as well as ca

Full text of DOI:10.1002/cjoc.201190155

FULL PAPER
A Fast and Highly Efficient Protocol for Reductive Amination of
Aromatic Aldehydes Using NaBH4 and Isoxazole Amines in an
Ionic Liquid Medium
Eligeti, Rajanarendar*
Atthunuri, Siva Rami Reddy
Samala, Raju
Shaik, Firoz Pasha
Kundur, Govardhan Reddy
Department of Chemistry, Kakatiya University, Warangal, 506009 Andhra Pradesh, India
Reductive amination of aromatic aldehydes using NaBH4 and isoxazole amines is carried out in a Brønsted
acidic ionic liquid 1-methylimidazolium tetrafluoroborate [(HMIm)BF4]. The ionic liquid plays dual roles of solvent
as well as catalyst for the efficient transformation of aromatic aldehydes to heterocyclic substituted amines in ex-
cellent yields without any undesired side product formation. The newly synthesized compounds (3, 6 and 7) were
characterized by IR, 1H NMR and mass spectral techniques.
Keywords ionic liquid, green chemistry reductive amination, 1-methylimidazolium tetrafluoroborate, isoxazole
amine
Introduction
ation of aromatic aldehydes using NaBH4 for the syn-
thesis of functionalized isoxazole amines in a one-pot
method (Scheme 1).
Functionalized amines are important synthons and
have wide applications in organic synthesis.1 Reductive
amination of aldehydes is a convenient method for the
synthesis of functionalized amines. Literature survey
reveals that there are several reagents and catalysts used
for reductive amination.2-7 Many of these are associated
with expensive reagents and catalysts and mainly, large
excess of amine was used to improve the yields.8-10 In
order to develop a mild and efficient protocol for reduc-
tive amination of aldehydes, we utilize the ionic liquid
1-methylimidazolium tetrafluoroborate, which serves as
green solvent and Brønsted acid. The potential of ionic
liquid as green solvent and Brønsted acid has been es-
tablished in several functional group transforma-
tions.11,12 The dual roles of ionic liquid as solvent and
catalyst were reported in literature for a variety of func-
tional group conversions.13-15 The involvement of ionic
liquid as a catalyst in the mechanism was also de-
scribed.14 Nagaiah et al.16 reported a one-pot reductive
amination of carbonyl compounds using ionic liquid and
water as solvent. Srinivasa Reddy et al.17 described the
utility of ionic liquid as solvent and catalyst for direct
reductive amination of carbonyl compounds. However,
heterocyclic amines, especially isoxazole amines, were
not utilized for this reaction, and significantly it was
noted that the reactions reported earlier required longer
reaction periods. In the present work, we report the use
of the Brønsted acidic ionic liquid, 1-methyl-
imidazolium tetrafluoroborate [(HMIm)BF4] as a recy-
clable medium for fast and highly efficient transform-
Scheme 1
Experimental
General procedure
Reagents were commercial grade and used as supply
*
E-mail: eligeti_ rajan@yahoo.co.in
Received July 15, 2010; revised November 18, 2010; accepted December 21, 2010.
Chin. J. Chem. 2011, 29, 769— 772
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769

Eligeti et al.
FULL PAPER
or prepared according to procedures described in litera-
ture. Solvents not including analytical reagent grade
were dried and purified according to literature when
necessary. Reactions were monitored by thin-layer
chromatography (TLC) on pre-coated silica gel F254
plates from Merck and compounds visualized either by
exposure to UV light or dipping in 1% aqueous potas-
sium permanganate solution. Melting points were de-
termined through a Fisher-Johns apparatus and uncor-
rected. IR spectra were recorded using KBr disc on a
OCH3) 4.2 (brs, 1H, NH, D2O exchangeable), 4.4 (s, 2H,
CH2), 5.2 (s, 1H, isoxazole-H), 7.2 (d, J＝7 Hz, 2H,
ArH), 7.6 (d, J＝7 Hz, 2H, ArH); I＋R (KBr) vmax: 3230
－1
cm ; ESI-MS m/z: 219 [M＋H] . Anal. calcd for
C12H14N2O2: C 66.01, H 6.47, N 12.79; found C 66.05,
H 6.42, N 12.84.
N3-[4-(Dimethylamino)benzyl]-N-5-methyl-3-iso-
xazolylamine (3d) Pale yellow solid, m.p. 125—127
℃; 1H NMR (CDCl3, 300 MHz) δ: 2.2 (s, 3H, CH3), 2.8
(s, 6H, 2NCH3), 3.9 (brs, 1H, NH, D2O exchangeable),
4.2 (s, 2H, CH2), 5.4 (s, 1H, isoxazole-H), 6.6 (d, J＝7
1
Perkin-Elmer FTIR spectrometer. The H NMR spectra
were recorded on a Varian Gemini spectrometer (300
Hz, 2H, ArH), 7.2 (d, J＝7 Hz, 2H, Ar＋H); IR (KBr) vmax
:
1
－1
MHz of H NMR). Chemical shifts are reported, with
3280 cm ; ESI-MS m/z: 232 [M＋H] . Anal. calcd for
respect to TMS as internal standard and coupling con-
stants (J) are reported in Hz units. Mass spectra were
recorded on a VG micro mass 7070H spectrometer.
Elemental analyses (C, H, N) determined by means of
Perkin-Elmer 240 CHN elemental analyzer, were within
±0.4% of theory.
C13H17N3O: C 67.53, H 7.35, N 18.18; found C 67.49, H
7.30, N 18.22.
N-(4-Methylbenzyl)-N-(5-methyl-3-isoxazolyl)a-
1
mine (3e) Pale yellow solid, m.p. 118—120 ℃; H
NMR (CDCl3, 300 MHz) δ: 2.1 (s, 3H, CH3), 2.5 (s, 3H,
Ar-CH3), 4.0 (brs, 1H, NH, D2O exchangeable), 4.2 (s,
2H, CH2), 5.2 (s, 1H, isoxazole-H), 7.0 (d, J＝7 Hz, 2H,
ArH), 7.5 (d, J＝7 Hz, 2H, ArH); I＋R (KBr) vmax: 3250
The IL, [(HMIm)BF4] was prepared according to the
reported procedure.13
－1
cm ; ESI-MS m/z: 203 [M＋H] . Anal. calcd for
General procedure for one-pot synthesis of
N-benzyl-N-isoxazolyl amines (3, 6, 7)
C12H14N2O: C 71.28, H 6.93, N 13.86; found C 71.26, H
6.98, N 13.89.
3-Amino-5-methylisoxazole (2, 0.01 mol) and aro-
matic aldehyde (0.01 mol) were added into
[(HMIm)BF4] (5 mL) and the reaction mixture was
stirred at 30 ℃ for 15 min, followed by the addition of
NaBH4 (0.02 mol) and stirring continued further at
room temperature for 15 min. The reaction was moni-
tored by TLC. When the reaction ended, the reaction
mixture was extracted with ethyl acetate (10 mL×3).
The combined extracts were dried over anhydrous
Na2SO4 and evaporated. The crude product was purified
by silica gel column chromatography eluting with ben-
zene-ethyl acetate (V∶V＝50∶50). The IL was dis-
solved in CH3CN and filtered to separate NaBH4. The
organic layer was evaporated and the IL was dried un-
der vacuum for further reuse as four consecutive runs.
N-Benzyl-N-(3,5-dimethyl-4-isoxazolyl)amine (6a)
Pale yellow solid, m.p. 118—120 ℃; 1H NMR (CDCl3,
300 MHz) δ: 2.2 (s, 3H, CH3), 2.3 (s, 3H, CH3), 3.0 (brs,
1H, NH, D2O exchangeable), 4.1 (s, 2H, CH2), 6.8—7.3
－1
(m, 5H, ArH); IR (KBr) vmax: 3320 cm ; ESI-MS m/z:
203 [M＋H]＋. Anal. calcd for C12H14N2O: C 71.28, H
6.93, N 13.86; found C 71.22, H 6.96, N 13.80.
N-(4-Chlorobenzyl)-N-(3,5-dimethyl-4-isoxazolyl)-
1
amine (6b) Pale yellow solid, m.p. 97—99 ℃; H
NMR (CDCl3, 300 MHz) δ: 2.1 (s, 3H, CH3), 2.4 (s, 3H,
CH3), 3.8 (s, 2H, CH2), 5.0 (brs, 1H, NH, D2O ex-
changeable), 6.7 (d, J＝7 Hz, 2H, ArH,), 7.1 (d, J＝7
－1
Hz, 2H, ArH); IR (KBr) vmax: 3310 cm ; ESI-MS m/z:
237 [M＋H]＋. Anal. calcd for C12H13N2OCl: C 61.01, H
5.50, N 11.86; found C 61.06, H 5.55, N 11.84.
N-Benzyl-N-(5-methyl-3-isoxazolyl)amine
(3a)
N-(3,5-Dimethyl-4-isoxazolyl)-N-(4-methoxyben-
zyl)amine (6c) Pale yellow solid, m.p. 100—105 ℃;
1H NMR (CDCl3, 300 MHz) δ: 2.2 (s, 3H, CH3), 2.4 (s,
3H, CH3), 3.8 (s, 3H, OCH3), 3.9 (s, 2H, CH2), 4.8 (bs,
1H, NH, D2O exchangeable), 7.0 (d, J＝7 Hz, 2H, ArH),
1
Pale yellow solid, m.p. 88—90 ℃; H NMR (CDCl3,
300 MHz) δ: 2.2 (s, 3H, CH3), 4.1 (brs, 1H, NH, D2O
exchangeable), 4.3 (s, 2H, CH2), 5.4 (s, 1H, isoxa-
zole-H), 7.2—7.4 (m, 5H, ArH); IR (KBr) vmax: 3240
＋
－1
－1
cm ; ESI-MS m/z: 189 [M＋H] . Anal. calcd for
C11H12N2O: C 70.21, H 6.38, N 14.89; found C 70.24, H
6.42, N 14.84.
7.4 (d, J＝7 Hz, 2H, ArH); IR (KBr) vmax: 3350 cm ;
ESI-MS m/z: 216 [M＋H]＋. Anal. calcd for C13H16-
N2O2 : C 72.18, H 7.43, N 12.94; found C 72.22, H 7.40,
N 12.96.
N-(4-Chlorobenzyl)-N-(5-methyl-3-isoxazolyl)a-
1
mine (3b) Pale yellow solid, m.p. 102—104 ℃; H
N4-[4-(Dimethylamino)benzyl]-3,5-dimethyl-4-
NMR (CDCl3, 300 MHz) δ: 2.3 (s, 3H, CH3), 4.4 (brs,
1H, NH, D2O exchangeable), 4.5 (s, 2H, CH2), 5.6 (s,
1H, isoxazole-H), 7.1 (d, J＝7 Hz, 2H, ArH), 7.4 (d,
isoxazolylamine (6d)
Pale yellow solid, m.p.
1
135—137 ℃; H NMR (CDCl3, 300 MHz) δ: 2.1 (s,
3H, CH3), 2.2 (s, 3H, CH3), 2.8 (s, 6H, 2NCH3), 3.8 (s,
2H, CH2), 4.2 (brs, 1H, NH, D2O exchangeable), 6.9 (d,
J＝7 Hz, 2H, ArH), 7.3 (d, J＝7 Hz, 2H, ArH);＋IR (KBr)
－1
J＝7 Hz, 2H, ArH); IR (KBr) vmax: 3210 cm ; ESI-MS
m/z: 223 [M＋H]＋. Anal. calcd for C11H11N2OCl: C
59.45, H 4.95, N 12.61; found C 59.40, H 4.99, N 12.65.
N-(4-Methoxybenzyl)-N-(5-methyl-3-isoxazolyl)-
－1
vmax: 3300 cm ; ESI-MS m/z: 246 [M＋H] . Anal.
calcd for C14H19N3O: C 68.57, H 7.75, N 17.14; found
C 68.61, H 7.70, N 17.18.
1
amine (3c) Pale yellow solid, m.p. 108—111 ℃; H
NMR (CDCl3, 300 MHz) δ: 2.2 (s, 3H, CH3), 3.6 (s, 3H,
N-(3,5-Dimethyl-4-isoxazolyl)-N-(4-methylbenzyl)-
770
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Chin. J. Chem. 2011, 29, 769— 772

A Fast and Highly Efficient Protocol for Reductive Amination of Aromatic Aldehydes
1
amine (6e) Pale yellow solid, m.p. 128—130 ℃; H
NMR (CDCl3, 300 MHz) δ: 2.1 (s, 3H, CH3), 2.4 (s, 3H,
CH3), 2.5 (s, 3H, ArCH3), 3.6 (s, 2H, CH2), 4.0 (brs, 1H,
NH, D2O exchangeable), 7.0 (d, J＝7 Hz, 2H, ArH), 7.5
hydes and 3-amino-5-methylisoxazole (1)/4-amino-3,5-
dimethylisoxazole (3)/4-amino-3-methyl-5-styrylisoxa-
zoles (5) was carried out in an ionic liquid [(HMIm)BF4]
for 15 min, followed by the addition of NaBH4 and the
reaction mixture was stirred at room temperature for
another 15 min. The reaction progress was monitored by
TLC. Considerable formation of N-benzyl-N-isoxazolyl
amine 3/6/7 was noticed after 30 min. The reductive
amination of aromatic aldehydes with isoxazole amines
afforded the corresponding N-benzyl-N-isoxazolyl
amines in excellent yields in a one-pot reaction as an
ionic liquid within short reaction periods.
There is no appreciable loss of ionic liquid during
recovery in each stage. The product was identified as
N-benzyl-N-(5-methyl-3-isoxazolyl)amine on the basis
of spectral and analytical data.
Based on the result, a series of reactions were con-
ducted by reacting benzaldehyde, p-chlorobenzaldehyde,
－1
(d, J＝7 Hz, 2H, ArH); IR (KBr) vmax: 3340 cm ;
ESI-MS m/z: 217 [M＋H]＋. Anal. calcd for C13H16N2O:
C 72.22, H 7.40, N 12.96; found C 72.26, H 7.44 N
12.99.
N-Benzyl-N-{3-methyl-5-[(E)-2-phenyl-1-1ethenyl]-
4-isoxazolyl}amine (7a)
Pale yellow solid, m.p.
1
119—121 ℃; H NMR (CDCl3, 300 MHz) δ: 2.1 (s,
3H, CH3), 3.0 (brs, 1H, NH, D2O exchangeable), 4.2 (s,
2H, CH2), 6.6 (d, J＝12 Hz, 1H, CH＝CH), 6.8 (d, J＝
12 Hz, 1H, CH＝CH), 7.0—7.6 (m, 10H, ArH); I＋R
－1
(KBr) vmax: 3355 cm ; ESI-MS m/z: 291 [M＋H] .
Anal. calcd for C19H18N2O: C 78.62, H 6.20, N 9.65;
found C 78.58, H 5.97, N 9.70.
N-(4-Chlorobenzyl)-N-{3-methyl-5-[(E)-2-phenyl-
1-1ethenyl]-4-isoxazolyl}amine (7b)
Pale yellow
p-methoxybenzaldehyde,
p-dimethylaminobenzalde-
1
solid, m.p. 131—133 ℃; H NMR (CDCl3, 300 MHz)
δ: 2.1 (s, 3H, CH3), 2.9 (brs, 1H, NH, D2O exchange-
able), 4.2 (s, 2H, CH2), 6.7 (d, J＝12 Hz, 1H, CH＝CH),
7.0 (d, J＝12 Hz, 1H, CH＝CH), 7.2—7.5 (m, 9H,
hyde, p-tolualdehyde with different isoxazole amines of
3-amino-5-methylisoxazole, 3,5-dimethyl-4-aminoiso-
xazole and 4-amino-3-methyl-5-styrylisoxazoles, re-
spectively. All the substrates reacted smoothly to afford
the corresponding heterocyclic amines in good to excel-
lent yields.
－1
ArH); IR (KBr) vmax: 3340 cm ; ESI-MS m/z: 325
[M＋H]＋. Anal. calcd for C19H17N2OCl: C 70.37, H
5.24, N 8.64; found C 70.41, H 5.20, N 8.63.
N-(4-Methoxybenzyl)-N-{3-methyl-5-[(E)-2-phe-
nyl-1-1ethenyl]-4-isoxazolyl}amine (7c) Pale yellow
Conclusion
1
In conclusion, an efficient protocol for reductive
amination of aromatic aldehydes with different isoxa-
zole amines in IL [(HMIm)BF4] has been developed.
The reported method is mild, efficient and environ-
mental friendly and NaBH4 is selective for reduction of
imines without formation of any side product such as
benzylalcohol (which may result from reduction of aro-
matic aldehyde alone) and affords excellent yields in
solid, m.p. 140—142 ℃; H NMR (CDCl3, 300 MHz)
δ: 2.1 (s, 3H, CH3), 3.2 (brs, 1H, NH, D2O exchange-
able), 3.8 (s, 3H, OCH3), 4.3 (s, 2H, CH2), 6.5 (d, J＝12
Hz, 1H, CH＝CH), 6.7 (d, J＝12 Hz, 1H, CH＝CH),
－1
7.0—7.4 (m, 9H, ArH); IR (KBr) vmax: 3310 cm
;
ESI-MS m/z: 321 [M＋H]＋. Anal. calcd for C20H20-
N2O2: C 75.00, H 6.25, N 8.75; found C 75.03, H 6.21,
N 8.71.
N4-[4-(Dimethylamino)benzyl]-3-methyl-5-[(E)-2-
Table 1 Reductive amination of aromatic aldehydes using
NaBH4 and isoxazole amines in [(HMIm)BF4]
phenyl-1-1ethenyl]-4-isoxazolyl}amine (7d)
Pale
yellow solid, m.p. 143—145 ℃; 1H NMR (CDCl3, 300
MHz) δ: 2.1 (s, 3H, CH3), 2.8 (s, 6H, 2NCH3), 3.9 (brs,
1H, NH, D2O exchangeable), 4.2 (s, 2H, CH2), 6.6 (d,
J＝12 Hz, 1H, CH＝CH), 6.8 (d, J＝12 Hz, 1H, CH－＝
Entry Aldehyde Amine Product Reaction time/min Yield/%
1
2
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
2
2
2
2
2
4
4
4
4
4
5
5
5
5
5
3a
3b
3c
3d
3e
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
30
25
25
30
30
30
25
25
25
30
25
30
25
30
25
95
95
90
95
90
90
90
90
95
90
92
95
93
95
90
1
CH), 7.2—7.6 (m, 9H, ArH); IR (KBr) vmax: 3320 cm ;
ESI-MS m/z: 334 [M＋H]＋. Anal. calcd for C21H22N3O:
C 75.67, H 6.90, N 12.61; found C 75.70, H 6.94, N
12.57.
3
4
5
N-(4-Methylbenzyl)-N-{3-methyl-5-[(E)-2-phenyl-
6
1-1ethenyl]-4-isoxazolyl}amine (7e)
Pale yellow
7
1
solid, m.p. 134—136 ℃; H NMR (CDCl3, 300 MHz)
δ: 2.1 (s, 3H, CH3), 2.6 (s, 3H, ArCH3), 3.4 (brs, 1H,
NH, D2O exchangeable), 4.4 (s, 2H, CH2), 6.7 (d, J＝12
8
9
10
11
12
13
14
15
Hz, 1H, CH＝CH), 6.9 (d, J＝12 Hz, 1H, CH＝CH),
－1
7.0—7.4 (m, 9H, ArH); IR (KBr) vmax: 3315 cm
;
ESI-MS m/z: 305 [M＋H]＋. Anal. calcd for C20H20N2O:
C 78.94, H 6.57, N 9.21; found C 78.91, H 6.59, N 9.24.
Results and discussion
The direct reductive amination of aromatic alde-
Chin. J. Chem. 2011, 29, 769— 772
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771

Eligeti et al.
FULL PAPER
short time.
2006, 24, 807.
7
Heydari, A.; Khaksar, S.; Akbari, J.; Esfandyari, M.;
Pourayoubi, M.; Tajbakhsh, M. Tetrahedron Lett. 2007, 48,
1135, and references cited therein.
Acknowledgement
The authors are thankful to the Head, Department of
Chemistry, Kakatiya University, Warangal for the fa-
cilities and to the Director, Indian Institute of Chemical
8
9
Heydari, A.; Khaksar, S.; Esfandyari, M.; Tajbakhsh, M.
Tetrahedron 2007, 63, 3363.
Heydari, A.; Arefi, A.; Esfandyari, M. J. Mol. Catal. A:
Chem. 2007, 274, 169 and references cited therein.
1
Technology Hyderabad, for recording H NMR and
Mass spectra. One of the authors (Kundur Goverdhan
Reddy) is grateful to University Grants Commission,
New Delhi for the award of Junior Research Fellowship
(JRF).
10 Jain, N.; Kumar, A.; Chauhan, S.; Chauhan, S. M. S. Tetra-
hedron 2005, 61, 1015.
11 Wu, H.-H.; Yang, F.; Cui, P.; Tang, J.; He, M.-Y. Tetrahe-
dron Lett. 2004, 45, 4963.
12 Wang, H.; Cui, P.; Zou, G.; Yang, F.; Tang, J. Tetrahedron
2004, 60, 7899.
References
13 Zhu, H. P.; Yang, F.; Tang, J.; He, M.-Y. Green Chem. 2003,
5, 38.
14 Chu, C. D.; Qi, Y. H.; Hao, W. Catal. Commun. 2007, 8,
1527.
15 Li, D.; Shi, F.; Guo, S.; Deng, Y. Tetrahedron Lett. 2004,
245, 265.
16 Nagaiah, K.; Kumar, V. N.; Rao, R. S.; Reddy, B. V. S.;
Narsaiah, A. V.; Yadav. J. S. Synth. Commun. 2006, 36,
3345.
1
2
Cho, B. T.; Kang, S. K. Tetrahedron 2005, 61, 5725.
Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff,
C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.
Imao, D.; Fujihara, S.; Yamamoto, T.; Ohta, T.; Ito, Y. Tet-
rahedron 2005, 61, 6988.
Menche, D.; Hassfeld, J.; Menche, G.; Ritter, A.; Rudolph, S.
Org. Lett. 2006, 8, 741.
Ito, T.; Nagata, K.; Kurihara, A.; Miyazaki, M.; Ohsawa, A.
Tetrahedron Lett. 2002, 43, 3105 and references cited
therein.
3
4
5
17 Srinivasa Reddy, P.; Kanjilal, S.; Sunitha, S.; Prasad, R. B.
N. Tetrahedron Lett. 2007, 48, 8807.
6
Ravi, V.; Ramu, E.; Kumar, P. V.; Rao, A. S. Chin. J. Chem.
(E1007155 Zhao, C.; Fan, Y)
772
www.cjc.wiley-vch.de
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Chin. J. Chem. 2011, 29, 769— 772