Novel synthesis of 3-aminopropionitriles by ring opening of 2-oxazolidinones with cyanide ion

Article abstract of DOI:10.1016/j.tetlet.2009.06.014

Nucleophilic attack of cyanide ion on the 5-position of 2-oxazolidinones in the presence of 18-crown-6 gave 3-aminopropionitriles.

Full text of DOI:10.1016/j.tetlet.2009.06.014

Tetrahedron Letters 50 (2009) 4857–4858
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Tetrahedron Letters
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Novel synthesis of 3-aminopropionitriles by ring opening of 2-oxazolidinones
with cyanide ion
*
Tsuyoshi Taniguchi, Naoya Goto, Hiroyuki Ishibashi
School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Nucleophilic attack of cyanide ion on the 5-position of 2-oxazolidinones in the presence of 18-crown-6
gave 3-aminopropionitriles.
Received 28 April 2009
Revised 30 May 2009
Accepted 5 June 2009
Available online 7 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
H
N
3-Aminopropionitriles are versatile intermediates in organic
synthesis, because the nitrile group can easily be converted into
a carboxylic acid, amide or aminomethyl group (Scheme 1).1
Reaction of acrylonitrile with ammonium hydroxide seemed to
be the most convenient reaction for the synthesis of non-substi-
tuted 3-aminopropionitrile 2b,2 but this method also afforded
bis(3-cyanoethyl)amine as a by-product. 3-Aminopropionitrile 2b
was also obtained from 3-chloropropionitrile and liquid ammonia.3
Many methods for the synthesis of N-substituted 3-aminopropio-
nitrile using the Michael addition to acrylonitrile have been
reported.4 Herein, we report a novel synthesis of 3-aminopropio-
nitriles by ring-opening reaction of 2-oxazolidinones 1 with cya-
nide ion in the presence of 18-crown-6. The synthesis of optically
active 3-aminopropionitriles is also presented.
R1
CN
3-aminopropionitrile
H
N
H
N
R1
β
CO2H
NH2
R1
CONH2
H
N
-amino acid
R1
1,3-diamine
3-aminopropanamide
Scheme 1. Conversion of 3-aminopropionitrile.
Treatment of 3-phenyl-2-oxazolidinone (1a) with KCN (2 equiv)
in DMF gave no reaction product after 24 h of heating at 100 °C
(Table 1, entry 1). However, the addition of a catalytic amount
(0.1 equiv) of 18-crown-6 in the reaction media gave the desired
3-aminopropionitrile 2a in 34% yield (Table 1, entry 2). Treatment
of 1a with trimethylsilylcyanide in the presence of tetrabutylam-
monium fluoride (TBAF) (2.0 equiv) also afforded 2a in 32% yield
(Table 1, entry 3). Acetone cyanohydrin in the presence of triethyl-
amine gave no desired compound 2a (Table 1, entry 4).
Table 1
Reactions of 1a under various conditions
O
[CN] (2 equiv)
additive
H
Ph
N
N
O
Ph
CN
DMF
100 °C
24 h
2a
1a
Entry
[CN]
Additive (equiv)
Yielda (%)
Table 2 shows the results of reactions of 1a with KCN (2 equiv)
in the presence of 18-crown-6 in various conditions. The use of
DMSO or MeNO2 as a solvent did not improve the yield of 2a com-
pared with that when DMF was used (Table 2, entries 2 and 3). We
found, however, that the yield of 2a was dramatically improved
without using a solvent (Table 2, entry 4). When an excess (1 or
2 equiv) of 18-crown-6 was used, reaction time was greatly short-
ened and the yield of 2a was improved (Table 2, entries 5 and 6).
However, the reaction at a lower temperature (80 °C) took a long
2a
1a
No reaction
59
20
No reaction
1
2
3
4
KCN
KCN
TMSCN
Me2C(OH)CN
None
18-crown-6 (0.1)
TBAF (2.0)
34
32
Et3N (2.0)
a
Isolated yields.
time (Table 2, entry 7), and only a trace amount of product 2a
was obtained when the reaction was carried out at 60 °C (Table
2, entry 8).
* Corresponding author. Tel.: +81 076 234 4476; fax: +81 076 234 4474.
E-mail address: isibasi@p.kanazawa-u.ac.jp (H. Ishibashi).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.014

4858
T. Taniguchi et al. / Tetrahedron Letters 50 (2009) 4857–4858
Table 2
Table 3 shows the results of reactions of other 2-oxazolidinones
1 with KCN (2 equiv) in the presence of 18-crown-6 (1 equiv) with-
out using a solvent. The reaction of non-substituted 2-oxazolidi-
none (1b) afforded 3-aminopropionitrile (2b) in low yield (Table
3, entry 2), whereas alkyl-substituted 2-oxazolidinones 1c and 1d
led to corresponding 3-aminopropionitriles 2c and 2d in moderate
to good yields, respectively (Table 3, entries 3 and 4). The reactions
of aryl-substituted 2-oxazolidinones 1e–g with an electron-donat-
ing group or a halogen atom provided desired 3-aminopropionitr-
iles 2e–g in good yields (Table 3, entries 5–7). p-Nitrophenyl-
substituted 2-oxazolidinone (1h), however, afforded the desired
product 2h in very low yield (Table 3, entry 8). Ring opening of
optically active 2-oxazolidinones gave the synthesis of optically ac-
tive 3-aminopropionitriles. Thus, compounds 1i–l gave the corre-
sponding 3-aminopropionitriles 2i–l in moderate to good yields,
respectively (Table 3, entries 9–12).
Formation of 2a from 1a and KCN in the presence of 18-Crown-6
O
KCN (2 equiv)
3
H
N
18-crown-6 ( )
Ph
N
O
Ph
CN
solvent
1a
2a
Entry
3 (equiv)
Solvent
Temp (°C)
Time (h)
Yielda (%)
2a
1a
1b
2
3
4
5
6
7
8
0.1
0.1
0.1
0.1
1
DMF
100
100
100
100
100
100
80
24
24
24
24
10
3
34
32
5
64
82
78
77
1
59
13
61
17
2
19
9
97
DMSO
MeNO2
Neat
Neat
Neat
Neat
Neat
2
1
1
24
24
60
In conclusion, treatment of 2-oxazolidinones 1 with KCN in the
presence of 18-crown-6 resulted in a ring-opening reaction to give
3-aminopropionitriles 2. This reaction proceeds under non-solvent
conditions and the experimental procedure is very simple. Further
studies directed towards applications to reactions with other car-
bon nucleophiles are underway in our laboratory.
a
Isolated yields.
Table 1, entry 2.
b
O
–
H
CO2
Acknowledgements
Ph
N
O
N
N
Ph
CN
–CN
Ph
CN
-CO2
5
This work was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science
and Technology of Japan.
1a
4
2a
Scheme 2. Plausible mechanism for the formation of 2a from 1a.
Supplementary data
Formation of 2a was explained in terms of a ring opening of
Experimental procedure for the synthesis of 2a–l; 1H and 13C
NMR spectra of 2a–l are available. Supplementary data associated
with this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.06.014.
oxazolidinone 1a at the 5-position with cyanide ion followed by
a decarboxylation of the resulting carbamate 4 (Scheme 2). An at-
tack of nucleophiles such as aromatic amines5 or thiolate ions6 on
the 5-position of 2-oxazolidinones 1 has been reported, but, to the
best of our knowledge, no example of the use of a carbon nucleo-
phile such as cyanide ion has been reported.7
References and notes
1. For recent examples of conversion of 3-aminopropionitrile derivatives into b-
amino acid, 3-aminopropanamide, or 1,3-diamine, see: (a) Burns, M. R.; Jenkins,
S. A.; Kimbrell, M. R.; Balakrishna, R.; Nguyen, T. B.; Abbo, B. G.; David, S. A. J.
Med. Chem. 2007, 50, 877; (b) Maiti, K. K.; Lee, W. S.; Takeuchi, T.; Watkins, C.;
Fretz, M.; Kim, D.-C.; Futaki, S.; Jones, A.; Kim, K.-T.; Chung, S.-K. Angew. Chem.,
Int. Ed. 2007, 46, 5880; (c) Yanling, Y.; Ballard, C. E.; Zheng, S.-L.; Gao, X.; Ko, K.-
C.; Yang, H.; Brandt, G.; Lou, X.; Tai, P. C.; Lu, C.-D.; Wang, B. Bioorg. Med. Chem.
Lett. 2007, 17, 707; (d) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett. 2007,
48, 2471; (e) Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Sato, A.; Furusho, S.; Kanai,
M.; Shibasaki, M. Tetrahedron 2007, 63, 5820; (f) Rivara, S.; Lodola, A.; Mor, M.;
Bedini, A.; Spadoni, G.; Lucini, V.; Pannacci, M.; Fraschini, F.; Scaglione, F.; Ochoa
Sanchez, R.; Gobbi, G.; Tarzia, G. J. Med. Chem. 2007, 50, 6618; (g) Huang, Y.;
Coull, J. M. J. Am. Chem. Soc. 2008, 130, 3238; (h) Ma, D.-Y.; Wang, D.-X.; Pan, J.;
Huang, Z.-T.; Wang, M.-X. J. Org. Chem. 2008, 73, 4087; (i) Mukai, T.; Suganuma,
N.; Soejima, K.; Sasaki, J.; Yamamoto, F.; Maeda, M. Chem. Pharm. Bull. 2008, 56,
260; (j) Biswas, S.; Zhang, S.; Fernandez, F.; Ghosh, B.; Zhen, J.; Kuzhikandathil,
E.; Reith, M. E. A.; Dutta, A. K. J. Med. Chem. 2008, 51, 101.
Table 3
Formation of 2 from 1
O
KCN (2 equiv)
18-crown-6 (1 equiv)
H
N
R1
R1
CN
N
O
100 °C
R2
R2
1
2
Entry
R1
R2
1
Time (h)
2
Yielda (%)
2
1
1b
2
3
4
5
Ph
H
Me
Bn
H
H
H
H
H
H
1a
1b
1c
1d
1e
1f
10
5
8
2a
82
13
50
73
67
79
72
12
63
21
61
65f
2
—
—
—
6
5
13
31
24
—
2b
2c
2d
2e
2f
2g
2h
2i
2. Buc, S. R. Org. Synth. 1947, 27, 3.
3. Bauer, O. W.; Teter. J. W. U.S. patent 2,443,292 [ Chem. Abstr., 1948, 42, 7322.].
4. For recent examples, see: (a) Hashemi, M. M.; Eftekhari, -S. B.; Abdollahifar, A.;
Khalili, B. Tetrahedron 2006, 62, 672; (b) Munro-Leighton, C.; Blue, E. D.; Gunnoe,
T. B. J. Am. Chem. Soc. 2006, 128, 1446; (c) Munro-Leighton, C.; Delp, S. A.; Blue, E.
D.; Gunnoe, T. B. Organometallics 2007, 26, 1483; (d) Yadav, J. S.; Reddy, A. R.;
Rao, Y. G.; Narsaiah, A. V.; Reddy, B. V. S. Synthesis 2007, 3447; (e) Hussain, S.;
Bharadwai, S. K.; Chaudhuri, M. K.; Kalita, H. Eur. J. Org. Chem. 2007, 374; (f) de
Souza, R. O. M. A.; Matos, L. M. C.; Gonçalves, K. M.; Costa, I. C. R.; Babics, I.; Leite,
S. G. F.; Oestreicher, E. G.; Antunes, O. A. C. Tetrahedron Lett. 2009, 50, 2017; (g)
Corberán, R.; Marrot, S.; Dellus, N.; Merceron-Saffon, N.; Kato, T.; Peris, E.;
Baceiredo, A. Organometallics 2009, 28, 326.
4
4-Me–C6H4
4-MeO–C6H4
4-Cl–C6H4
4-NO2–C6H4
Bn
12
20
5
18
48
168
24
7
6
7
H
H
Me
Bn
Ph
1g
1h
1i
1j
1k
1l
8c
9d
10e
11e
12
Bn
Bn
2j
2k
2l
—
—
–CH2–CH2–CH2–
5. Poindexter, G. S.; Owens, D. A.; Dolan, P. L.; Woo, E. J. Org. Chem. 1992, 57, 6257;
See also: Altmann, E.; Renaud, J.; Green, J.; Earley, D.; Cutting, B.; Jahnke, W. J.
Med. Chem. 2002, 45, 2352.
6. Ishibashi, H.; Uegaki, M.; Sakai, M.; Takeda, Y. Tetrahedron 2001, 57, 2115.
7. Friedel–Crafts type reaction of 2-oxazolidinones and aromatic solvent has been
reported, see: Jouitteau, C.; Perchec, P. L.; Forestière, A.; Sillion, B. Tetrahedron
Lett. 1980, 21, 1719.
a
Isolated yield.
Table 2, entry 5.
At 70 °C.
8 equiv of KCN was used.
b
c
d
e
f
4 equiv of KCN and 2 equiv of 18-crown-6 were used.
Determined by 1H NMR analysis.