Oxalic acid as a simple and efficient organocatalyst for three-component synthesis of α-amino nitriles

Article abstract of DOI:10.1016/j.cclet.2010.12.002

A simple, efficient, and general method has been developed for the synthesis of α-amino nitriles. Oxalic acid as a Br?nsted acid promotes the addition of TMSCN to various imines (generated in situ).

Full text of DOI:10.1016/j.cclet.2010.12.002

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Chinese Chemical Letters 22 (2011) 543–546
www.elsevier.com/locate/cclet
Oxalic acid as a simple and efficient organocatalyst
for three-component synthesis of a-amino nitriles
a
b
Seyed Mohammad Vahdat a, , Samad Khaksar , Maryam Khavarpour
*
a Chemistry Department, Islamic Azad University, Ayatollah Amoli Branch, P.O. Box 678, Amol, Iran
b Chemical Engineering Department, Islamic Azad University, Ayatollah Amoli Branch, P.O. Box 678, Amol, Iran
Received 30 August 2010
Available online 3 March 2011
Abstract
A simple, efficient, and general method has been developed for the synthesis of a-amino nitriles. Oxalic acid as a Brønsted acid
promotes the addition of TMSCN to various imines (generated in situ).
# 2010 Seyed Mohammad Vahdat. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Oxalic acid; TMSCN; Brønsted acid; a-Amino nitriles
Organocatalysis [1,2] has gained widespread attention as a result of the efficiency and selectivity of many
organocatalytic reactions. Novel methods employing organic molecules are advantageous from both a practical and an
environmental standpoint due to their ability to perform in wet solvents under an aerobic atmosphere and to avoid the
possibilityofmetalcontaminationthatmayoccurwithtraditionalmetalcatalystsystems.Anefficientandpracticalprocess
using organocatalysts should involve easily recoverable and reusable catalysts. In this article, we described the remarkable
catalytic activity of a novel organic Brønsted acid for the synthesis of a-amino nitriles. The Strecker reaction is an efficient
method for the synthesis of a-aminonitriles [3] which are useful precursors for the synthesis of a-amino acids, various
nitrogen containing heterocycles [4] and chiral building blocks [5]. Usually, it is carried out by the nucleophilic addition of
a cyanide anion to imines in the presence of Lewis acid/base catalyst [6]. Several modifications of the Strecker reaction
have been made and a variety of cyanating agents such as a-trimethylsiloxy nitriles and diethylphosphorocyanidates were
used under various conditions [7]. One-pot procedures were also reported for this reaction using trimethylsilylcyanide or
tributyltin cyanide as cyanating agent in the presence of different Lewis acid catalysts such as lithium perchlorate [8],
scandium triflamide [9], vanadyl triflate [10], nickel(II) chloride [11], Fe3O4 [12], ruthenium(III) chloride [13], NHC-
amidatepalladium(II)complex[14], bismuth(III)chloride[15], montmorilloniteKSF[16], sulphamicacid[17], guanidine
hydrochloride [18] and fluorinated alcohols [19]. Many of these methods required strong acidic conditions, expensive
reagents, long reaction times, harsh experimental conditions and tedious work-up procedures that generates large amount
oftoxicwaste.Apartfromthis,theseprotocolsarelimitedtoaldehydesonlyandareunsuccessfulwithketones.Hence,new
efficient, selective and green procedures are still in strong demand, and searching of cheaper, simpler, and more efficient
procedures(simple chemistry), includingmetal-freeorganocatalysts, isveryattractive. Itis well known that oxalic acidisa
* Corresponding author.
E-mail address: m.vahdat@iauamol.ac.ir (S.M. Vahdat).
1001-8417/$ – see front matter # 2010 Seyed Mohammad Vahdat. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.12.002

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S.M. Vahdat et al. / Chinese Chemical Letters 22 (2011) 543–546
relatively stable, easy to handle solid that is insensitive to small amounts of air and moisture. We have recently
demonstrated that oxalic acid efficiently activated imines and carbonyl group [20]. Very recently, Zambare et al.
demonstrated that oxalic acid efficiently catalyzed synthesis of substituted flavones [21]. However, there are no any
reports about the application in catalysis as a Brønsted acidic organocatalyst for three component Strecker type reaction.
Herein, we report the first example of the oxalic acid-catalyzed one-pot synthesis of a-aminonitrile under solvent-free
condition at 50–60 8C.
1. Experimental
Oxalic acid (20 mg, 0.2 mmol) was added to a mixture of aldehyde (2 mmol) and amine (2.2 mmol) at r.t. The
mixture was stirred for 15 min and then TMSCN (2 mmol) was added. After completion of the reaction (1 h), as
indicated by TLC, the reaction mixture was quenched with aq. satd. NaHCO3 followed by brine solution and then
extracted with CH2Cl2, dried over Na2SO4, concentrated under vacuum and the crude mixture was purified by column
chromatography on silica gel (hexane:ethylacetate 4:1) to afforded pure products. After extraction of the reaction
mixture with CH2Cl2, the aqueous layer was acidified and distilled off to leave oxalic acid.
1H NMR and 13C NMR were consistent with the assigned structures and were compared with those reported in the
literature. Spectral data for selected products:
(Scheme 1, entry 1): 1H NMR: (500 MHz, CDCl3): 4.03 (br s, NH), 5.41 (s, 1H), 6.80–6.98 (m, 3H), 7.27–7.60 (m,
7H). 13C NMR (125 MHz, CDCl3): d 50.8, 113.1, 118.2, 126.5, 127.4, 128.1, 128.2, 129.2, 130.1, 143.3. (Scheme 1,
entry 2): 1H NMR: (500 MHz, CDCl ): d 4.11 (br s, NH), 5.46 (s, 1H), 6.80–6.98 (m, 3H), 7.30–7.34 (m, 2H), 7.47 (d,
[()TD$FIG]
3
O
R1
R2
+
R3
R4
1
Oxalic acid (10 mol%)
N
R2
R1
TMSCN
H
N
Solvent-free, 40-50 C, 1h
CN
R4
R3
3
2
Entry
Aldehyde/Ketone
Amine
NH2
3 Yeild %
Entry
Aldehyde/Ketone
CHO
Amine
NH2
3 Yeild %
CHO
N
97
97
11
1
NH2
NH2
NH2
CHO
95
90
97
96
CHO
CHO
CHO
12
2
3
Cl
CHO
H N
H N
13
14
NH2
NH2
CHO
90
95
98
95
4
5
Cl
H
H
CHO
CHO
N
CHO
CHO
15
16
O
O
O
NH2
N
90
95
90
90
6
7
Cl
NH2
CHO
O
CHO
CHO
N
17
18
H
Cl
Br
NH2
NH2
90
95
95
8
9
O
O
NH2
NH2
CHO
CHO
NH2
19
20
95
96
90
NH2
10
Scheme 1.

S.M. Vahdat et al. / Chinese Chemical Letters 22 (2011) 543–546
545
2H, J = 8.5 Hz), 7.60 (d, 2H, J = 8.5 Hz). 13C NMR (125 MHz, CDCl3): d 50.1, 114.7, 118.2, 121.1, 129.1, 129.9,
131.1, 132.6, 136.1, 144.8. (Scheme 1, entry 3): 1H NMR: (500 MHz, CDCl3): d 3.9 (br s, 1H), 5.08 (d, 1H, J = 5 Hz),
6.3 (dd, 1H, J = 5 Hz, 5.5 Hz), 6.7 (d, 1H, J = 5.5 Hz), 6.9–7.1 (m, 3H), 7.0–7.4 (m, 7H). 13C NMR (125 MHz,
CDCl3): d 44.4, 105.6, 110.9, 114.5, 116.5, 119.2, 120.6, 129.5, 130.1, 143.9, 144.1, 146.1. (Scheme 1, entry 4): 1H
NMR: (500 MHz, CDCl3): d 1.20–1.27 (m, 5H), 1.67–2.62 (m, 5H), 3.79 (br s, NH), 4.05 (d, 1H, J = 6Hz), 6.71–6.92
(m, 3H), 7.22–7.27 (m, 2H). 13C NMR (125 MHz, CDCl3): d 25.7, 25.9, 29.6, 40.6, 51.7, 114.1, 118.8, 119.8, 129.5,
145.2. (Scheme 1, entry 5): 1H NMR: (500 MHz, CDCl3): d 4.29 (br s, NH), 5.53 (s, H), 6.48–6.99 (m, 4H), 7.21–7.53
(m, 4H). 13C NMR (125 MHz, CDCl3): d 44.1, 109.6, 110.9, 114.5, 116.6, 120.6, 129.7, 144.1, 144.3, 146.2. (Scheme
1, entry 10): 1H NMR: (500 MHz, CDCl3): d 2.20 (br s, NH), 4.00 (dd, 2H, J = 13Hz), 4.89 (s, 1H), 7.37–7.93 (m,
10H). 13C NMR (125 MHz, CDCl3): 51.1, 53.2, 118.6, 127.1, 128.2, 128.3, 128.4, 128.5, 128.8, 134.1, 138.4. (Scheme
1, entry 17): 1H NMR: (500 MHz, CDCl3): d 3.4 (d, 2H, J = 13.5Hz), 3.8 (d, 2H, J = 13Hz), 4.91 (s, 1H), 7.26–7.60 (m,
15H). 13C NMR (125 MHz, CDCl3): d 54.8, 57.1, 115.2, 127.1, 127.5, 128.1, 128.3, 128.4, 128.5, 128.6, 128.7, 128.8,
133.8, 137.5. (Scheme 1, entry 19): 1H NMR: (500 MHz, CDCl3): d 1.30–2.33 (m, 10H), 3.86 (br s, NH), 6.89–7.27
(m, 5H). 13C NMR (125 MHz, CDCl3): 22.1, 24.6, 36.2, 54.1, 114.9, 117.1, 121.1, 128.9, 143.6. (Scheme 1, entry 20):
1H NMR: (500 MHz, CDCl3): d 1.71–2.37 (m, 8H), 4.05 (br s, NH), 6.70–7.34 (m, 5H). 13C NMR (125 MHz, CDCl3):
d 23.7, 40.1, 57.5, 115.6, 119.7, 122.4, 129.3, 144.3.
2. Results and discussion
In the presence of 10 mol% of oxalic acid, the three component coupling reaction involving benzaldehyde, aniline
and TMSCN successively proceeded smoothly at 50–60 8C to afford the corresponding a-aminonitrile derivative in
97% yield. The new methodology allowed us to prepare the a-aminonitriles shown in Scheme 1. After this success,
reactions of several aldehydes (aliphatic, aromatic, heterocyclic, and conjugated) [21], amines (primary and
secondary), and TMSCN were examined in the presence of 10 mol% oxalic acid under solvent-free conditions. This
method is equally effective with electron-withdrawing 4-chlorobenzaldehyde and 4-chloroaniline. This method is also
effective with ketones and aliphatic aldehydes, which normally produce low yields due to their intrinsic lower
reactivity. The reaction using solid amines, such as 4-chloroaniline and 4-bromoaniline, gave corresponding a-
aminonitriles exclusively under the reaction conditions described. Thus, acetophenone gave a 90% of 17 and 4-
chloroaniline afforded a-aminonitrile 7 (Scheme 1) in 90% yield. In all cases, no undesired side products such as
cyanohydrins are obtained under these conditions. We believe that this is mainly due to the rapid formation and
activation of the imines catalyzed by oxalic acid. Although the amount of catalyst has been optimized to 10 mol%,
lesser amounts (5 mol%) also worked with longer reaction times.
3. Conclusions
In summary, this new protocol represents a safer, simpler and more environmentally friendly alternative to the usual
classical Strecker conditions, avoiding the use of expensive and/or toxic Lewis acids and therefore permitting the use
of substrates sensitive to Lewis acid conditions. The purification of products after the usual work-up was in some cases
unnecessary.
Acknowledgment
This research is supported by the Islamic Azad University, Ayatollah Amoli Branch.
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