Synthesis of 2-aminooxazolines from isonitriles and iodine

Article abstract of DOI:10.1016/j.cclet.2011.09.017

A novel one-pot protocol for the synthesis of substituted 2-aminooxazoline from isonitriles and 2-aminoethanol was developed and the reactions involved imidoyl diiodide intermediates, which were generated by mixing isonitriles and iodine in CH₂

Full text of DOI:10.1016/j.cclet.2011.09.017

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Chinese Chemical Letters 23 (2012) 130–132
www.elsevier.com/locate/cclet
Synthesis of 2-aminooxazolines from isonitriles and iodine
*
Hui Yu , Yu Zhe Li, Qiong Liu, Mei Shu Zhang, Wen Liang Sun
Department of Chemistry, Tongji University, Shanghai 200092, China
Received 24 May 2011
Available online 21 December 2011
Abstract
A novel one-pot protocol for the synthesis of substituted 2-aminooxazoline from isonitriles and 2-aminoethanol was developed
and the reactions involved imidoyl diiodide intermediates, which were generated by mixing isonitriles and iodine in CH2Cl2 at room
temperature.
# 2011 Hui Yu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 2-Aminooxazoline; Isonitrile; Imidoyl diiodide
Imidoyl dichloride, acting as an electrophilic reagent, is a versatile intermediate to the synthesis of various
heterocyclic compounds [1]. However, the preparation of imidoyl dichloride usually required toxic reagents and harsh
conditions, which limited its application in organic synthesis [2]. Recently, imidoyl dibromide and diiodide, as
efficient substitution for imidoyl dichloride, attracted more and more interests for their easy generation by mixing
isonitriles and bromine or iodine [3], and these compounds could undergo subsequent conversion in vivo without
further purification, which makes the reactions more convenient [4].
In our previous work, we reported the synthesis of substituted guanidines by guanylation of amines with isonitriles
in the presence of iodine and sodium bicarbonate and the reaction involved imidoyl diiodides intermediate [5]. We
envisaged that such an intermediate could also be trapped by a molecular containing two nucleophlic groups, and then
a heterocyclic compound would be obtained by dehydroiodination.
Initially, we investigated the reaction of 4-nitrophenylisonitrile (1a) and ethylenediamine in the presence of iodine
and sodium bicarbonate in CH2Cl2 at room temperature, but no product was found. When glycol was used instead of
ethylenediamine, a new compound could be detected as monitored by TLC, but underwent decomposition during
workup. In case of 2-aminoethanol 2a, a stable product was isolated in the yield of 82% and was identified as N-(4-
nitrophenyl)-2-aminooxizole 3a. Encouraged by such a result, we examined the scope of the reaction and the results
are summarized in Table 1. Different aryl isonitriles gave the desired products in moderate yields regardless of
electron-donating or electron-withdrawing groups linked on the benzene ring (Table 1, entries 1À8). Regrettably, alkyl
isonitriles such as p-methoxy benzyl isonitrile 1e and t-butyl isonitrile 1f failed to the reaction (Table 1, entries 9À10).
In most cases, 1-amino-2-propanol 2b gave similar yields as 2a.
The reaction of 4-nitrophenylisonitrile 1a and 3-amino-1-propanol 4 was also tested. Interestingly, guanidine 5 was
obtained as the only product and no cyclic product was detected (Scheme 1).
* Corresponding author.
E-mail address: yuhui@tongji.edu.cn (H. Yu).
1001-8417/$ – see front matter # 2011 Hui Yu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.09.017

H. Yu et al. / Chinese Chemical Letters 23 (2012) 130–132
131
Table 1
Synthesis of substituted 2-aminooxazoline from isonitriles and 2-aminoethanol.
H
N
H2N
OH
R2
I2, NaHCO3
CH2Cl2, r.t.
R1
N
+
R1NC
O
R2
2
1
3
Entry
R1
R2
Product
Yield (%)a
1
2
4-NO2C6H4 1a
4-NO2C6H4 1a
4-MeOC6H4 1b
4-MeOC6H4 1b
4-t-BuC6H4 1c
4-t-BuC6H4 1c
4-ClC6H4 1d
H 2a
CH3 2b
H 2a
3a
3b
3c
3d
3e
3f
82
74
3
52
4
CH3 2b
H 2a
61
5
76
6
CH3 2b
H 2a
72
7
3g
3h
3i
41
8
4-ClC6H4 1d
4-MeOC6H4CH2 1e
t-Bu 1f
CH3 2b
H 2a
H 2a
36
9
Trace
Trace
10
a
Isolated yields.
3j
O N
2
I , NaHCO
2
3
HN
OH
OH
HO
NH
+
O N
2
NC
2
N
N
H
CH Cl , r.t.
2
2
4
1a
5 (41 %)
Scheme 1. Reaction of 4-nitrophenylisonitrile 1a and 2-amino-1-propanol 4 in the presence of iodine and sodium bicarbonate.
1. Experimental
A mixture of isonitrile (1.0 mmol), 2-aminoethanol (1.0 mmol) and NaHCO3 (168 mg, 2.0 mmol) in CH2Cl2
(3 mL) was cooled to 0 8C, then a solution of iodine (254 mg, 1.0 mmol) in CH2Cl2 (2 mL) was added dropwise within
15 min. After stirring at room temperature for 4 h, the reaction was quenched with water. The organic layer was dried
with anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified by aluminum oxide
chromatography (Hexane/EtOAc = 2:1) to give the product. 3a [6] yellow solid, 1H NMR (300 MHz, CDCl3): d 8.03
(d, 2H, J = 8.4 Hz), 6.68 (d, 2H, J = 8.4 Hz), 4.04 (s, 1H), 3.73 À 3.68 (m, 2H), 3.60 À 3.56 (m, 2H). 3b [7] white
solid, 1H NMR (300 MHz, CDCl3): d 8.06 (d, 2H, J = 8.4 Hz), 6.66 (d, 2H, J = 8.4 Hz), 4.07 (s, 1H), 3.88 À 3.81 (m,
2H), 3.68 À 3.60 (m, 1H), 1.18 (d, 2H, J = 7.5 Hz). 3c [6] yellow solid, 1H NMR (300 MHz, CDCl3): d 7.40 (d, 2H,
J = 6.0 Hz), 6.95 (d, 2H, J = 6.0 Hz), 4.16 (s, 1H), 3.79 (s, 3H), 3.69 À 3.62 (m, 2H), 3.89 À 3.85 (m, 2H). 3d [7]
yellow solid, 1H NMR (300 MHz, CDCl3): d 7.25 (d, 2H, J = 6.0 Hz), 7.15 (d, 2H, J = 6.0 Hz), 4.30 (s, 3H), 4.12 (s,
1H), 3.88 À 3.81 (m, 2H), 3.68 À 3.60 (m, 1H), 1.23 (d, 2H, J = 7.5 Hz).
In summary, we developed a convenient method to the synthesis of 2-amino oxizoles from isonitriles and 2-
aminoethanol in the presence of iodine and sodium bicarbonate in CH2Cl2 at room temperature. The reaction is easy to
handle and the yields are moderate to good.
Acknowledgment
We thank NSFC for the financial support (No. 20802053).
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