Efficient protocol for reductive amination of aldehydes and ketones with sodium borohydride in an ionic liquid/H2O system

Article abstract of DOI:10.1080/00397910600941356

The imines were generated in situ from carbonyl compounds and amines, which undergo smooth reduction with sodium borohydride in an ionic liquid/H ₂O solvent system. The reaction conditions were very mild and neutral to afford the corresponding highly functionalized amines in excellent yields. Copyright Taylor & Francis Group, LLC.

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Efficient Protocol for Reductive Amination
of Aldehydes and Ketones with Sodium
Borohydride in an Ionic Liquid/H2O System
K. Nagaiah a , V. Naveen Kumar a , R. Srinivasa Rao a , B. V. S. Reddy a , A. V.
Narsaiah a & J. S. Yadav a
a Division of Organic Chemistry , Indian Institute of Chemical Technology ,
Hyderabad, India
Published online: 23 Nov 2006.
To cite this article: K. Nagaiah , V. Naveen Kumar , R. Srinivasa Rao , B. V. S. Reddy , A. V. Narsaiah & J. S.
Yadav (2006) Efficient Protocol for Reductive Amination of Aldehydes and Ketones with Sodium Borohydride in
an Ionic Liquid/H2O System, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 36:22, 3345-3352, DOI: 10.1080/00397910600941356
To link to this article: http://dx.doi.org/10.1080/00397910600941356
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Synthetic Communicationsw, 36: 3345–3352, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600941356
Efficient Protocol for Reductive Amination
of Aldehydes and Ketones with Sodium
Borohydride in an Ionic Liquid/H2O System
K. Nagaiah, V. Naveen Kumar, R. Srinivasa Rao,
B. V. S. Reddy, A. V. Narsaiah, and J. S. Yadav
Division of Organic Chemistry, Indian Institute of Chemical Technology,
Hyderabad, India
Abstract: The imines were generated in situ from carbonyl compounds and amines,
which undergo smooth reduction with sodium borohydride in an ionic liquid/H2O
solvent system. The reaction conditions were very mild and neutral to afford the corre-
sponding highly functionalized amines in excellent yields.
Keywords: Anilines, carbonyl compounds, ionic liquids, reductive amination
INTRODUCTION
Although several reagents[1] are available for reductive amination, most of the
reagents have some drawbacks. The most commonly used, NaCNBH3, is
flammable, expensive, and highly toxic, and generates toxic by-products
such as HCN and NaCN upon workup. Although sodium triacetoxyborohy-
dride is free from these drawbacks, it has limitations with aromatic and
unsaturated ketones. Hence, the developments of improved protocols for
milder and efficient approaches are still in demand.
In recent years, the use of room-temperature ionic liquids (ILs) as
recyclable solvents has gained considerable importance in organic synthesis
because of their high solvating ability, negligible vapor pressure, and ease
Received in India April 24, 2006
IICT Communication No. 041013.
Address correspondence to K. Nagaiah, Division of Organic Chemistry, Indian
Institute of Chemical Technology, Hyderabad 500 007, India. E-mail: nagaiah@iict.
res.in
3345

3346
K. Nagaiah et al.
Figure 1. Chemical structure of the ionic liquids.
of recyclability.[2] Especially air- and moisture-stable second-generation ionic
liquids, such as [bmim]BF4 and [bmim]PF6, are being used as green solvents
for the immobilization of transition-metal-based catalysis, Lewis acids and
enzymes. As a result of their green credentials and potential to enhance the
reaction rates and selectivites, the ionic liquids are finding increasing appli-
cations in organic synthesis (Figure 1).[3]
RESULTS AND CONDITIONS
In this article, we report the use of an ionic liquid/water system as a novel and
recyclable reaction media for the synthesis of highly functionalized amines by
a one-pot reductive amination method using sodium borohydride. For instance,
benzaldehyde and aniline was reacted with sodium borohydride in 1-butyl-3-
methylimidazolium tetrafluoroborate/water (2:1) solvent system at ambient
temperature for 1 h to yield benzyl-phenyl-amine 3 (entry 1) in 92% yield
(Scheme 1). The product was isolated by extraction with diethyl ether, and the
rest of the ionic liquid was washed with ether and reused for further reaction
without purification. Encouraged by these results, we conducted the reactions
with various imines derived from different carbonyl compounds and amines.
Several aldimines obtained by the condensation of electron-rich aromatic
aldehydes with aromatic primary amines (entries 3–7) yielded the desired
product in excellent yields. The hydride sensitive p-fluorobenzaldehyde imine
derivatives of aromatic primary amine (entry 8) and alicyclic secondary
amines (entry 9) reduced under similar reaction conditions without affecting a
Scheme 1.

Reductive Amination of Aldehydes and Ketones
3347
fluoro group. In a similar manner, cinnamaldehyde- and crotonaldehyde-derived
corresponding imines with aromatic primary amines (entries 10–13) yielded the
amino compounds without affecting the cinnamyl and crotyl double bond. Also,
the reductive amination of the cyclohexanone adduct with the aromatic primary
amine (entry 15) and alicylic secondary amines afforded the corresponding
amines in excellent yields. The results are summarized in Table 1.
Initially, we examined the reaction in ionic liquids, which proceeds very
slowly, whereas the same reaction in combination with a ionic liquid and
water (2:1) system proceeds dramatically faster. The role of water can be
explained by the solubility of NaBH4 in the ionic medium. Furthermore, the
reduction process also requires protic solvents such as alcohol or water. In
addition, this method does not require any Lewis acid additives. The ionic
liquid was easily recovered after the reaction and reused in subsequent
reactions. The use of recyclable reaction media makes this process economical
and environmentally benign. This reaction has been studied in both hydrophi-
lic [bmim]BF4 and hydrophobic [bmim]PF6 ionic liquids. Among these,
1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF4) was found to
be the most effective in terms of conversion and reaction rates. The scope
and generality of this method is illustrated with respect to various aldehydes
or ketones and a wide range of amines, and the results are presented in Table 1.
In conclusion, ionic liquid [bmim]BF4/water system proved to be an
efficient reaction medium for one-pot reductive amination of carbonyl
compounds with sodium borohydride at ambient temperature. Simple experi-
mental and product isolation procedures combined with ease of recovery and
reuse of this reaction medium is expected to contribute to the development of a
green strategy for the synthesis of highly functionalized amines.
EXPERIMENTAL
General Methods
1H NMR spectra were recorded on a Bruker Avance 300-MHz spectrometer
and Varian Gemini 200-MHz spectrometer. Mass spectra were recorded on
VG micromass 7070 H spectrometer at 70 eV. IR spectra were recorded on
Nicolet-740 FT IR spectrometer.
General Procedure for the Preparation of Amines
To a mixture of aldehyde (1.0 mmol) and amine (1.0 mmol) in 1-butyl-3-
methyl imidazoliumtetrafluoroborate/water (2:1, 3 mL), sodiumborohydride
(1.0 mmol) was added, and the mixture was stirred at ambient temperature
for the appropriate time (Table 1). After completion of the reaction as
indicated by thin-layer chromatography (TLC), the reaction mixture was

Table 1. Reductive amination in ionic liquid [bmim]BF4/H2O system with NaBH4
Entry
Aldehyde 1
Amine 2
Aminea 3
Time (h)
1.0
Yield (%)b
92
1
2
3
2.0
1.5
89
87
4
1.0
90
5
6
2.5
3.0
87
81

7
8
9
2.5
1.0
3.0
83
89
87
10
11
2.0
2.5
80
90
12
3.0
86
(continued)

Table 1. Continued
Entry
Aldehyde 1
Amine 2
Aminea 3
Time (h)
3.0
Yield (%)b
82
13
14
15
2.5
3.0
80
80
16
17
3.0
2.5
85
83
aAll products were characterized by 1H NMR, 13C NMR, IR, and mass spectroscopy.
bIsolated and unoptimized yields.

Reductive Amination of Aldehydes and Ketones
3351
extracted with ether (3 ꢀ 10 mL). The combined ether extracts were
concentrated under reduced pressure. The obtained crude products were
purified by column chromatography (silica gel 60–120 mesh) while eluting
with a mixture of ethylacetate–hexane.
Spectral Data for Selected Compounds
4-[(2,4-Difluoro-phenylamino)-methyl]-2-methoxy-phenol (5): Pale yellow
oil; IR (neat): nmax: 3423, 2927, 2852, 1603, 1516, 1431, 1271, 1034, 849,
1
797 cm21; H NMR (400 MHz, CDCl3): d 3.85 (s, 3H), 3.95–4.05 (brs,
NH, 1H), 4.20 (s, 2H), 5.40–5.50 (brs, OH, 1H), 6.58 (m, 1H), 6.70
(m, 1H), 6.78–6.85 (m, 4H); EIMS: m/z (%): 265 (10) Mþ, 137
(100), 129 (52), 94 (12), 81 (12), 77 (6), 65 (8), 51 (10). Calcd. for
C14H13F2NO2: C, 63.39; H, 4.94; F, 14.32; N, 5.28. Found: C, 63.32; H,
4.90; F, 14.27; N, 5.31.
Phenyl-(3-phenyl-allyl)-amine (10): Pale yellow oil; IR (neat): nmax: 3417,
3027, 2847, 1602, 1505, 1322, 1068, 747 cm21 1H NMR (200 MHz,
;
CDCl3): d 3.60–3.70 (brs, NH, 1H), 3.90 (d, J ¼ 6.7 Hz, 2H), 6.20–6.30
(m, 1H), 6.50–6.70 (m, 3H), 7.00–7.30 (m, 8H); EIMS: m/z (%): 209 (3)
Mþ, 183 (50), 106 (15), 91 (100), 77 (19), 65 (19), 39 (6). Calcd. for
C15H15N: C, 86.08; H, 7.22; N, 6.69. Found: C, 86.12; H, 7.17; N, 6.75.
But-2-enyl-phenyl-amine (13): Pale yellow oil; IR (neat): nmax: 2933, 2855,
1602, 1505, 1222, 1038, 828, 750 cm21; 1H NMR (200 MHz, CDCl3): d 1.80
(d, J ¼ 6.9 Hz, 3H), 3.60–3.70 (brs, NH, 1H), 3.75 (d, J ¼ 6.4 Hz, 2H), 5.60–
5.80 (m, 2H), 6.62 (d, J ¼ 8.4 Hz, 2H), 6.78 (t, J ¼ 8.2 Hz, 1H), 7.20
(t, J ¼ 8.4 Hz, 2H); EIMS: m/z (%): 147 (32) Mþ, 132 (30), 119 (17), 106
(37), 93 (92), 81 (100), 77 (75), 55 (25), 41 (30). Calcd. for C10H13N: C,
81.59; H, 8.90; N, 9.51. Found: C, 81.55; H, 8.87; N, 9.45.
Benzyl-furan-2-ylmethyl-amine (14): Pale yellow oil; IR (neat): nmax: 3323,
2928, 2852, 1600, 1497, 1452, 1147, 1008, 736, 698 cm21 1H NMR
;
(300 MHz, CDCl3): d 3.70 (s, 2H), 6.15 (m, 1H), 6.30 (m, 1H), 7.05–7.25
(m, 6H); EIMS: m/z (%): 187 (12) Mþ, 141 (3), 119 (5), 106 (20), 96 (42),
91 (100), 81 (84), 77 (5), 65 (21), 53 (33), 39 (20). Calcd. for C12H13NO:
C, 76.98; H, 7.00; N, 7.48. Found: C, 76.92; H, 6.95; N, 7.41.
4-Cyclohexyl-morpholine (16): Pale yellow oil; IR (neat): nmax: 2932, 2860,
1711, 1450, 1359, 1179, 772 cm21; 1H NMR (300 MHz, CDCl3): d 1.00–1.30
(m, 6H), 1.70–1.90 (m, 4H), 2.10–2.20 (m, 1H), 2.45–2.55 (m, 4H),
3.60–3.70 (m, 4H); EIMS: m/z (%): 169 (22) Mþ, 126 (100), 99 (25), 69
(30), 55 (40), 41 (43). Calcd. for C10H19NO: C, 70.96; H, 11.31; N, 8.28.
Found: C, 70.90; H, 11.27; N, 8.22.

3352
K. Nagaiah et al.
ACKNOWLEDGMENT
R. S. R. is thankful to Council of Scientific and Industrial Research (CSIR),
New Delhi, India, for the award of the fellowship.
REFERENCES
1. (a) Klyuev, M. V. Russ. Chem. Rev. 1980, 49, 14; (b) Cho, B. T.; Kang, S. K.
Tetrahedron 2005, 61, 5725, and references cited therein.
2. (a) Welton, T. Chem. Rev. 1999, 99, 2071; (b) Wasserscheid, P.; Keim, W. Angew.
Chem. Int. Ed. 2000, 39, 3772.
3. (a) Sheldon, R. Chem. Commun. 2001, 2399; (b) Seddon, K. R.; Stark, A.;
Torres, M. J. Pure Appl. Chem. 2000, 82, 2275; (c) Yadav, J. S.; Reddy, B. V. S.;
Naveen Kumar, V.; Srinivasa Rao, R.; Nagaiah, K. New J. Chem. 2004, 8, 335;
(d) Yadav, J. S.; Reddy, B. V. S.; Naveen Kumar, V.; Srinivasa Rao, R.;
Nagaiah, K. Synthesis 2004, 11, 1873.