Letters in Organic Chemistry, 2007, 4, 473-477
473
Reductive Amination of Carbonyl Compounds with NaBH4-H3PW12O40 in THF and Under Solvent-Free Conditions Heshmatollah Alinezhad* and Ehsan Ardestani Department of Chemistry, Mazandaran University, Babolsar, Iran Received May 05, 2007: Revised July 18, 2007: Accepted July 20, 2007
Abstract: A simple, completely chemoselective, and convenient procedure for reductive amination of aldehydes and ketones using NaBH4 in the presence of H3PW12O40 in THF and under solvent-free conditions at ambient temperature is described.
Keywords: Reductive amination, H3PW12O40, NaBH4, solvent-free conditions. INTRODUCTION
importance [15]. The possibility of performing multicomponent reactions under solvent-free conditions with solid catalysts could enhance their efficiency from an economic as well as an ecological point of view, so solvent-free chemical reactions have received much attention. The solid-state or solvent-free reactions have many advantages such as reduced pollution, low costs and simplicity in process and handling [14], and some applications have been successfully performed such as conversion of aldehydes to geminal diacetates (acylals) [16,17]and the Michael addition reaction of acetophenone with ferrocene-containing chalcones [18].
Heteropoly acids (HPAs) have been extensively studied as acids and oxidation catalysts for many reactions and have found industrial application in several processes [1]. These catalysts are very important for industries associated with fine chemicals, flavours, pharmaceuticals, and foods [2], and are also used as industrial catalysts for several liquid-phase reactions [3-6] such as alcohol dehydration [7], alkylation [8], and esterification reactions [9]. HPAs are green and efficient bifunctional catalysts [10], harmless to the environment with respect to corrosiveness, safety, quantity of waste, and separability [11]. HPAs are more active catalysts than conventional inorganic and organic acids for various reactions in solutions [12]. Among these acids, polytungstic acids are the most widely used catalysts owing to their high acid strengths, thermal stabilities, and low reducibilities. Catalysts based on HPAs as Brønsted acids have many advantages over liquid acid catalysts. They are non-corrosive and environmentally benign, presenting fewer disposal problems. Solid HPAs have attracted much attention in organic synthesis owing to easy work-up procedures, easy filtration, and minimization of cost and waste generation due to reuse and recycling of the catalysts [13]. Development of new solid-
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t s i D r
o F t o N R1
O
R2
HNR3R4
R1
R2 HO
NR3R4
Reductive amination of carbonyl compounds is the process by which amines are condensed with aldehydes or ketones to form imines which are subsequently reduced to the corresponding amines [19]. The first step is a nucleophilic addition of an amine to the carbonyl group followed by a rapid proton transfer. The resulting product, a hemiaminal, also sometimes called a carbinolamine, is generally unstable and cannot be isolated. A second reaction occurs in which water is eliminated from the hemiaminal in protic ambient, and iminium ion is formed (Scheme 1). Subsequent reduction of this iminium ion produces the alkylated amine product.
H+,-H2O H2O,-H+
R1
+ NR3R4
Reducing agent
R2
R1 NR3R4 R2
Scheme 1.
phase (solvent-free) reactions and transferring solution-phase reactions to solid-phase are subjects of recent interest in the context of generating libraries of molecules for the discovery of biologically active leads and also for the optimization of drug candidates [14]. Development of clean technologies is a major goal in green chemistry. Among the several aspects of green chemistry, the amount reduction or replacement of volatile organic solvents in the reaction media are of great *Address correspondence to this author at the Department of Chemistry, Mazandaran University, Babolsar, Iran; Fax: +98(112)5242002; E-mail:
[email protected]
1570-1786/07 $50.00+.00
For this transformation a variety of reducing agents, such as NaBH3 CN [20], NaBH(OAc)3 [21], borane-pyridine [22], tetrahydroborate exchange resin [23], Zn(BH4)2 [24], Zn (BH4)2-ZnCl2 [25], Zn(BH4)2-SiO2 [26], Ti(OiPr)4-NaBH 4 [27], NaBH4-wet clay-microwave [28], Bu3SnH [29], Bu 3 SnH-SiO2 [30], Zr(BH4)2Cl2(dabco)2 [31], NaBH4 in micellar media [32], N-methylpiperidine zinc borohydride [33], solid acid-activated NaBH4 under solvent free conditions [34], have been developed. However, most of these reagents may have one drawback or another. For example, the use of an expensive and highly toxic NaBH3CN that carries the risk of having residual cyanide in the product as well as in the work
© 2007 Bentham Science Publishers Ltd.
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Alinezhad and Ardestani
up stream makes this procedure not much attractive. Clearly the use of NaBH3CN is not acceptable in the context of green synthesis, especially in industry [20b]. Tin hydride reagents are also highly toxic and generate toxic organotin byproducts [35].
can be successfully used for anilines with electronwithdrawing groups (Table 2, entries 6-8) whose imine derivatives cannot be reduced with NaBH3CN [36] and NaBH(OAc)3 [21], most often used reagents in the reductive amination of carbonyl compounds. In the case of , unsaturated carbonyl compounds and amines such as cinnamaldehyde and allylamine, the reductive amination was successfully achieved in excellent yields without reduction of the carbon-carbon double bond (Table 2, entries 13,14,19).
Here we report an efficient and smooth reductive amination of a variety of carbonyl compounds performed by reacting aldehydes or ketones with amines and NaBH4 H3PW12O40 in THF and under solvent-free conditions. RESULTS AND DISCUSSION
CONCLUSION
First of all the reaction conditions were optimized by investigating the reaction of benzaldehyde (1 mmol) with aniline (1 mmol) in different solvents such as CH2 Cl2, MeOH, THF and Et2O in the presence of NaBH4 (1mmol) and catalytic amount of H3PW12O40 (0.1 g) at room temperature (Table 1). We observed that reaction occurred in THF and MeOH only. In the comparison between MeOH and THF, we selected THF because of MeOH toxicity. Higher yields and shorter reaction times were observed using 0.25 g of catalyst (Method ).
In summary, we have described two efficient and completely chemoselective methods (, ) for the synthesis of amines by reductive amination of carbonyl compounds with various amines in the presence of NaBH4 and H3PW12O40. The scope of the reaction has been demonstrated with aliphatic, aromatic, cyclic and acyclic carbonyl compounds and primary and secondary amines. These methods have afforded amines as the only isolated products at room temperature. The one-pot conditions, the simple work up, the high yields, and the use of efficient and eco-friendly reagents with no special handling techniques are the notable advantages of the presented methods.
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Then we studied the same reaction under solvent free conditions using 0.1 g catalyst (Method ) and we found this method better than method because method was characterized by higher yield, shorter reaction time, cleaner reaction medium, and required lesser amount of catalyst.
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We have showed that these reactions in absence of solvent (Method ) proceeded with shorter reaction times and higher yields than in solution (Method ).
The reductive amination of a wide variety of aldehydes and cyclic and acyclic ketones with primary and secondary amines in THF (Method ) and under solvent-free conditions (Method ) was successful and gave the desired products in good to excellent yields (78-97% and 84-98 % respectively) as shown in Table 2. The method is not only of interest from ecological point of view, but also proves to be a clean, rapid, and very simple procedure for carrying out this type of transformation. Under the same conditions chemoselective reductive amination of functionalized carbonyl compounds and reductive alkylation of functionalized amines were examined. Method and appeared suitable for chemoselective reduction of imines carrying cyano, nitro, or hydroxycarbonyl substituents (Table 2, entries 3,6,8).These methods
EXPERIMENTAL
o F t o N Table 1.
Materials were purchased from Fluka and Merck companies. All the products are known compounds and were identified by comparison of their spectra and physical data with those of the authentic samples. IR spectra were recorded on Bruker VECTOR 22 spectrometer. 1H NMR spectra were recorded with Bruker DRX500 AVANCE (500 MHz) and GNM-EX90A (90 MHz) spectrometers, using CDCl3 as solvent. Reaction monitoring and purity determination of the products were accomplished by TLC.
Reductive Amination of Benzaldehyde (1 mmol) Using Equimolar Amounts of Aniline and NaBH4 in the Presence of H3PW12O40
CHO +
NH2
NaBH4 Cat.
CH2
NH
Entry
H3PW12O40 (g)
Solvent
Time (min)
Yield (%)
1
0.1
CH2Cl2
120
N.R
2
0.1
MeOH
120
95
3
0.1
Et2O
120
N.R
4
0.1
THF
120
90
5
0.2
THF
8
95
6
0.25
THF
2
97
Reductive Amination of Carbonyl Compounds
Table 2.
Letters in Organic Chemistry, 2007, Vol. 4, No. 7
Reductive Amination of Aldehydes and Ketones Using NaBH4-H3PW12O40a Method c
Entry
Carbonyl Compound
Productb
Amine
CHO
1
NH2
CH2
2
Cl
CHO
NH2
Cl
3
NC
CHO
NH2
NC
CHO
4
Method d e
NH
CH2
NH
CH2 NH
CH2 NH
NH2
Time
Yield (%)
Time
Yielde (%)
2 min
97
Im.f
98
8h
88
4h
98
4h
88
1h
96
8h
87
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Cl
Cl
u rib
CH2 NH
CHO NH2
5
Cl
Cl 6
CHO
7
CHO
F t o
8
CHO
9
CHO
N
475
O2N
t s i
NH2
D or Cl
NH2
HOOC
NH2
CH2
NH
CH2
NH
CH2
CH3
10
CHO
H3C
NH2
11
CHO
H3CO
12
CHO
HN
13
CHO
H2C
CH
CH2
NH2
14
O
H2C
CH
CH2
NH2
15
CHO
16
CHO
NH2
CH2 CH3
NH
HN
O
2
87
5h
98
6 min
95
1 min
97
4.5 h
94
3.5 h
98
55min
93
25min
98
8h
85
3h
98
CH3
2.5 h
88
1.5 h
98
OCH3
3h
82
25min
96
Im.
88
Im.
94
3 min
90
3 min
96
1 min
91
1 min
96
Im.
81
Im.
85
3 min
78
2 min
84
Cl
COOH
NH
CH2
NH2
98
9h
NO2
NH
4h
H3C NH
CH2
CH2
NH
CH2
CH2
NH
N
NH
CH2 CH3
CH2 CH
CH2
CH
CH2
CH2
CH2 N
CH2 N
2
O
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Letters in Organic Chemistry, 2007, Vol. 4, No. 7
Alinezhad and Ardestani
(Table 2). Contd…..
Method c Entry
Carbonyl Compound
17
O
18
O
H
b
Amine
Product
NH
HN
O
CHO C
H
20
CH2 C
N
H
C
19
N
NH2
Time
Yielde (%)
Time
Yielde (%)
Im.
81
Im.
85
3 min
78
2 min
84
7 min
89
1 min
93
3 min
90
CH2 NH C
C H
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CH3
O
NH2
CH3
CH2
CH3 21
O
Method d
CHO
C NH H
u rib
CH3 CH2 N
NH
t s i D r
a
3 min
80
2 min
94
1 min
86
All reactions were carried out at room temperature and molar ratio of reagent/carbonyl compound/amine was 1/1/1. All products were characterized spectroscopically (1H NMR, IR) and showed physical and spectral data in accordance with their expected structure and by comparison with authentic samples. c reaction in THF. d reaction under solvent-free conditions. e Yields refer to pure isolated products. f Immediately. b
o F t o N
Reductive amination of benzaldehyde with aniline as a typical procedure for reductive amination of aldehydes and ketones with NaBH4-H3PW12O40 in THF (Method )
Benzaldehyde (0.106 g, 1 mmol) and aniline (0.093 g, 1 mmol) were mixed in THF (5 ml) and treated with NaBH 4 (0.038 g , 1 mmol) and the pH was adjusted to neutrality by addition of H3PW12O40 (0.25 g, 0.087 mmol). The mixture was stirred at room temperature. After completion of the reaction, as indicated by TLC, solvent was evaporated and crude product was purified by column chromatography on silica gel (eluent: hexane/EtOAc 10:1). After evaporation of the solvent, pure N-benzylaniline was obtained (0.178 g, 97%, Table 2, entry 1).
Reductive anilation of benzaldehyde as a typical procedure for solvent-free reductive amination of aldehydes and ketones with NaBH4-H3PW12O40 (Method ) Benzaldehyde (0.106 g, 1 mmol) was ground with aniline (0.093 g, 1 mmol) for 5 min in an agate mortar at room temperature under solvent-free conditions. NaBH4 (0.038 g, 1 mmol) and H3PW12O40 (0.1 g, 0.035 mmol) was added to the mixture and after completion of the reaction, as indicated by TLC, the mixture was extracted by Et2O (320 ml). The combined organic layers were dried on anhydrous Na2SO 4 and evaporated. The crude product was purified by column chromatography on a silica gel eluting with hexane/EtOAc (10:1). After evaporation of the solvent, pure Nbenzylaniline was obtained (0.180 g, 98%, Table 2, entry 1).
ACKNOWLEDGEMENT
Financial support of this work from the Research Council of Mazandaran University gratefully acknowledged. REFERENCES
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