A mild and efficient catalytic Strecker reaction of N-alkoxycarbonylamino sulfones with trimethylsilyl cyanide using indium(III) chloride: A facile synthesis of α-aminonitriles

Article abstract of DOI:10.1055/s-0028-1087277

The Strecker reaction of N-alkoxycarbonylamino sulfones with trimethylsilyl cyanide in the presence of catalytic amount of indium(III) chloride at room temperature produces the corresponding protected α;-aminonitriles in high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087277

LETTER
3133
A Mild and Efficient Catalytic Strecker Reaction of N-Alkoxycarbonylamino
Sulfones with Trimethylsilyl Cyanide Using Indium(III) Chloride: A Facile
Synthesis of a-Aminonitriles1
Synthesis of
a-Aisriles wanath Das,* Kongara Damodar, Boddu Shashikanth, Yallamalla Srinivas, Itikala Kalavathi
Organic Chemistry Division – I, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Fax +91(40)7160512; E-mail: biswanathdas@yahoo.com
Received 6 August 2008
drawbacks such as requirement of longer reaction times,
Abstract: The Strecker reaction of N-alkoxycarbonylamino
sulfones with trimethylsilyl cyanide in the presence of catalytic
amount of indium(III) chloride at room temperature produces the
corresponding protected a-aminonitriles in high yields.
application of costly reagents, harsh reaction conditions,
and unsatisfactory yields. Moreover, some of the catalysts
such as boron halides used for the preparation of a-amino-
nitriles are deactivated or decomposed by amines and wa-
ter produced during imine formation. Here, we have
utilized the Strecker reaction of N-alkoxycarbonylamino
sulfones for an efficient synthesis of a-aminonitriles.
Key words: Strecker reaction, N-alkoxycarbonylamino sulfones,
trimethylsilyl cyanide, protected a-aminonitrile, indium(III)
chloride
It is known that the N-alkoxycarbonylamino sulfones,
generally referred as a-amido sulfones, can be conve-
niently prepared15 from aldehydes, sodium p-toluenesulfi-
nate or sodium benzenesulfinate, and suitable carbamates.
Most of the N-alkoxycarbonylamino sulfones are stable
solids and can be stored for prolonged times. They are
converted into the corresponding N-alkoxycarbonyl imine
derivatives on treatment with a Lewis acid16 (Scheme 1).
These derivatives possess a superior electrophilic charac-
ter because of the presence of positively charged nitrogen
atom and are highly suitable for nucleophilic reactions.17
Thus the Strecker reaction of these sulfones with trimeth-
ylsilyl cyanide in the presence of a suitable Lewis acid
constitutes an important method for the synthesis of
a-aminonitriles.
a-Aminonitriles are versatile intermediates for the prepa-
ration of a-amino acids2 and various nitrogen-containing
heterocycles such as imidazoles and thiadiazoles.3 a-Amino
acids, in turn, are of great importance in chemistry and bi-
ology and as valuable building blocks.4 The classical
Strecker reaction for the synthesis of these compounds in-
volves the treatment of carbonyl compounds with alkaline
cyanides and salts of amines in aqueous medium.5 The ex-
perimental procedure of this reaction is tedious and sever-
al modified methods have been subsequently developed
using different cyanide reagents [such as diethyl phospho-
rocyanidate, a-trimethylsiloxy nitrile, tri-n-butyltin cya-
nide, acetone cyanohydrin, diethylaluminium cyanide,
trimethylsilyl cyanide (TMSCN) etc.].6 Among these cy-
anide ion equivalents, TMSCN is more efficient and safer
in handling. The synthetic procedures to a-aminonitriles
using TMSCN are of two types: (1) the reaction of imines
to TMSCN7 and (2) the reaction of aldehydes, amines, and
TMSCN in one pot.8 However, imines in general tend to
be unstable during purification and so the first method has
limited utility. The second one, that is, the three-compo-
nent Strecker-type reaction has been studied by using var-
ious Lewis acids,9 Lewis bases,10 N-heterocyclic
carbenes,11 metal complexes and metal-salen complex-
es.12 In recent years, a number of asymmetric Strecker re-
actions using highly effective catalysts have been
reported.6d,13 Herrera et al. described6d an efficient chiral
phase-transfer-catalyzed enantioselective Strecker reac-
tion of protected a-amino sulfones with cyanohydrins as
well as KCN and TMSCN. a-Aminonitriles have also
been synthesized by Strecker methodologies using ionic
liquids and water instead of regular organic solvents.14
However, many of these methods suffer from different
R2O2CNH2
ArSO2Na
+
NHCO2R2
SO2Ar
NHCO2R2
Lewis acid
R1CHO
R1
R1
aq HCO2H
R1, R2 = alkyl, aryl
Scheme 1
In continuation of our studies18 we have observed that a
catalytic amount of InCl3 is highly effective for the reac-
tion of N-alkoxycarbonylamino sulfones with trimethyl-
silyl cyanide to afford the corresponding protected
a-aminonitriles at room temperature (Scheme 2).
NHCbz
NHCbz
TS
InCl3 (10 mol%)
TMSCN
+
R
CN
R
CH2Cl2, r.t.
2–3.5 h
79–95%
1
2
3
Scheme 2
SYNLETT 2008, No. 20, pp 3133–3136
1
6
.1
2
.2
0
0
8
Advanced online publication: 26.11.2008
DOI: 10.1055/s-0028-1087277; Art ID: D29608ST
© Georg Thieme Verlag Stuttgart · New York

3134
B. Das et al.
LETTER
Initially, we carried out the reaction of N-alkoxycarbony- Table 2 InCl3-Catalyzed Cyanation of N-Alkoxycabonylamino
Sulfone 1 with Trimethylsilyl Cyanide (2, Scheme 2)a
lamino sulfone 1a (R = Ph) with trimethylsilyl cyanide in
the presence of various Lewis acids (Table 1).
Entry R in 1 and 3
Time (h) Yield (%)b Mp (°C)
Table 1 Cyanation of N-Alkoxycabonylamino Sulfone 1a (R = Ph)
1
2
Ph
2.0
2.0
2.0
2.5
2.5
2.5
2.0
2.0
2.5
3.5
3.5
3.0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
88
91
93
87
89
88
95
93
88
82
79
85
87
87
90
83
86
84
88
89
107–109
111–113
82–84
92–94
106–108
93–95
113–115
151–154
88–90
112–114
127–129
133–135
104–106
110–112
82–84
oil
Using Different Lewis Acids at Room Temperature (Scheme 2)a
Tol
Entry
Lewis acid
x
Time
(h)
Isolated yield
(%)b
3
4-i-PrC6H4
4-FC6H4
4-BrC6H4
2,4-Cl2C6H3
PMP
(mol%)
4
1
2
CeCl3·7H2O
CeCl3·7H2O
ZnCl2
ZnCl2
ZrCl4
10
10
10
10
10
10
10
10
10
10
5
2.5
9
15
30
10
25
25
40
20
35
30
50
40
85
88
90
5
6
3
2.5
9
7
4
8
3,4,5-(MeO)3C6H2
3-MeO-4-HOC6H3
3-O2NC6H4
4-O2NC6H4
2-indenyl
2-furyl
5
2.5
9
9
6
ZrCl4
10
11
12
13
14
15
16
17
18
19
20
7
VCl3
2.5
9
8
VCl3
9
CuBr2
CuBr2
InCl3
2.5
9
10
11
12
13
14
Bn
2.5
9
(CH2)2Ph
Et
InCl3
5
InCl3
10
10
2.5
9
Pr
oil
InCl3
a Reaction conditions: N-alkoxycabonylamino sulfone 1a (1 mmol),
trimethylsilyl cyanide 2 (1.2 mmol), Lewis acid (x mol%).
b Yields of pure isolated products after column chromatography.
i-Pr
oil
(CH2)4Me
(CH2)6Me
oil
oil
Considering the amount of the catalyst, reaction time, and
yield, InCl3 (10 mol%) was found to be most effective.
Subsequently, this catalyst was utilized for the preparation
of a series of protected a-aminonitriles (Table 2).
a The structures of the products were established from their spectral
(IR, 1H NMR, 13C NMR, and MS) and analytical data.
some of the reactions were carried out with toxic KCN,
yields of several products were low, and some of the con-
versions required low temperature.20 Herrera et al. dem-
onstrated the use of cyanohydrins as well as KCN and
TMSCN as cyanide reagents but they utilized the sulfones
derived from aliphatic aldehydes only.6d
The reactions were completed within 2–3.5 hours. The
products were formed at room temperature and in high
yields.19
N-Alkoxycarbonylamino sulfones derived from various
aldehydes (aromatic, heterocyclic, and aliphatic) under-
went the present conversion smoothly. Aromatic alde-
hydes containing both electron-donating and electron-
withdrawing groups were used to prepare the sulfones.
Various functional groups such as ether, halogen, and
nitro remained intact. The sulfones derived from an acid-
sensitive aldehyde such as furfuraldehyde (Table 2, entry
13) and a sterically hindered aldehyde such as 2-naphthal-
dehyde (entry 12) also formed the corresponding protect-
ed a-aminonitriles in good yields. The structures of the
products were established from their spectroscopic (IR,
1H NMR, 13C NMR, FABMS, and HRMS) data.19
In conclusion, we have developed a mild, efficient, and
novel protocol for the synthesis of protected a-amino-
nitriles at room temperature and in high yields by apply-
ing the Strecker reaction of N-alkoxycabonylamino
sulfones (generated from both aromatic and aliphatic al-
dehydes) with TMSCN in the presence of a catalytic
amount of indium(III) chloride.
Acknowledgment
The authors thank CSIR, New Delhi for financial assistance. They
are also thankful to NMR, Mass, and IR Divisions of IICT for recor-
ding the spectra.
N-Alkoxycarbonylamino sulfones were also previously
used for the preparation of protected a-aminonitriles but
Synlett 2008, No. 20, 3133–3136 © Thieme Stuttgart · New York

LETTER
Synthesis of a-Aminonitriles
3135
(15) (a) Pearson, W. H.; Lindbeck, A. C.; Kampf, J. W. J. Am.
Chem. Soc. 1993, 115, 2622. (b) Mecozzi, T.; Petrini, M.
J. Org. Chem. 1999, 64, 8970.
References and Notes
(1) Part 179 in the series ‘Studies on novel synthetic
methodologies’.
(16) Giardina, A.; Mecozzi, T.; Petrini, M. J. Org. Chem. 2000,
(2) (a) Shafran, Y. M.; Bakulev, V. A.; Mokrushin, V. S. Russ.
Chem. Rev. 1989, 58, 148. (b) March, J. Advanced Organic
Chemistry, 4th ed.; Wiley: New York, 1999, 965.
(3) (a) Weinstock, L. M.; Davis, P.; Handelsman, B.; Tull, R.
J. Org. Chem. 1967, 32, 2823. (b) Matier, W. L.; Owens, D.
A.; Comer, W. T.; Deitchman, D.; Ferguson, H. C.;
Seidehamel, R. J.; Young, J. R. J. Med. Chem. 1973, 16, 901.
(4) (a) Duthaler, R. O. Tetrahedron 1994, 50, 1539. (b)Enders,
D.; Shilvock, P. Chem. Soc. Rev. 2000, 29, 359; and
references cited therein.
65, 8277.
(17) (a) Petrini, M. Chem. Rev. 2005, 105, 3949. (b) Petrini, M.;
Torregiani, E. Synthesis 2007, 159; and references cited
therein.
(18) (a) Das, B.; Krishnaiah, M.; Balasubramanyam, P.;
Veeranjaneyulu, B.; Kumar, D. V. Tetrahedron Lett. 2008,
49, 2225. (b) Das, B.; Kanth, B. S.; Reddy, K. R.;
Satyalaxmi, G.; Kumar, R. A. Chem. Lett. 2008, 37, 512.
(c) Das, B.; Thirupathi, P.; Kumar, R. A.; Reddy, K. R.
Catal. Commun. 2008, 9, 635.
(19) General Procedure for the Synthesis of a-Aminonitriles
Trimethylsilyl cyanide (2, 120 mg, 1.2 mmol) was added
dropwise to a solution of an N-alkoxycabonylamino sulfone
1 (1 mmol) and InCl3 (22.1 mg, 10 mol%) in CH2Cl2 (5 mL)
under nitrogen. The mixture was stirred, and the reaction
was monitored by TLC. After completion, the reaction was
quenched with distilled H2O (5 mL) and the mixture was
extracted with EtOAc (3 ×10 mL). The combined organic
portions were washed with H2O (2 × 10 mL) and sat. aq
NH4Cl solution (2 × 10 mL), dried over anhyd Na2SO4, and
concentrated under vacuum. The crude product was
subjected to column chromatography (silica gel, hexane–
EtOAc = 85:15 to 90:10) to obtain pure protected a-
aminonitrile.
(5) (a) Strecker, A. Ann. Chem. Pharm. 1850, 75, 27.
(b) Groger, H. Chem. Rev. 2003, 103, 2795; and references
cited therein.
(6) (a) Harusawa, S.; Hamada, Y.; Shioiri, T. Tetrahedron Lett.
1979, 20, 4663. (b) Mai, K.; Patil, G. Tetrahedron Lett.
1984, 25, 4583. (c) Kobayashi, S.; Ishitani, H. Chem. Rev.
1999, 99, 1069. (d) Herrera, R. P.; Sgarzani, V.; Bernardi,
L.; Fini, F.; Pettersen, D.; Ricci, A. J. Org. Chem. 2006, 71,
9869. (e) Davis, F. A.; Lee, S.; Zhang, H.; Fanelli, D. L.
J. Org. Chem. 2000, 65, 8704. (f) Mori, Y.; Kimura, M.;
Seki, M. Synthesis 2003, 2311.
(7) (a) Spino, C. Angew. Chem. Int. Ed. 2004, 43, 1764.
(b) Kantham, M. L.; Mahender, K.; Sreedhar, B.;
Choudhary, B. M. Tetrahedron 2008, 64, 3351.
(8) Kobayashi, S.; Ishitani, H.; Ueno, M. Synlett 1997, 115.
(9) (a) Surya Prakash, G. K.; Mathew, T.; Panja, C.; Alconcel,
S.; Vaghoo, H.; Do, C.; Olah, G. A. Proc. Natl. Acad. Sci.
U. S. A. 2007, 104, 3703. (b) Heydari, A.; Fatemi, P.;
Alizadeh, A.-A. Tetrahedron Lett. 1998, 39, 3049.
(c) Royer, L.; De S, K.; Gibbs, R. A. Tetrahedron Lett. 2005,
46, 4595.
(10) (a) Li, B. F.; Yuan, K.; Zhang, M. J.; Wu, H.; Dai, L. X.;
Wang, Q. R.; Hou, X. L. J. Org. Chem. 2003, 68, 6264.
(b) Takahashi, E.; Fujisawa, H.; Yanai, T.; Mukaiyama, T.
Chem. Lett. 2005, 34, 318. (c) Fetterly, B. M.; Jana, N. K.;
Verkade, J. G. Tetrahedron 2006, 62, 440.
Spectroscopic Data of some Representative Products
2-(Benzyloxycarbonylamino)-2-(phenyl)acetonitrile (3a)
White solid; mp 107–109 °C. IR (KBr): 3278, 3031, 1694,
1521, 1451 cm–1. 1H NMR (200 MHz, CDCl3): d = 7.55–
7.24 (10 H, m), 5.80 (1 H, br d, J = 8.7 Hz), 5.37 (1 H, br d,
J = 8.7 Hz), 5.12 (2H, s). 13C NMR (50 MHz, CDCl3): d =
155.2, 135.7, 133.3, 129.9, 129.6, 128.9, 128.7, 128.5,
127.1, 117.6, 68.2, 46.8. MS–FAB: m/z = 267 [M + H]+.
ESI-HRMS: m/z calcd for C16H14N2O2Na [M + Na]+:
289.0952; found: 289.0951.
2-(Benzyloxycarbonylamino)-2-(4-methoxyphenyl)-
acetonitrile (3g)
(11) (a) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem. Int.
Ed. 2005, 44, 4032. (b) Tsogoeva, S. B.; Hateley, M. J.;
Yalalov, D. A.; Meindl, K.; Weckbecker, C.; Huthmacher,
K. Bioorg. Med. Chem. 2005, 13, 5680. (c) Shibasaki, M.;
Yoshikawa, N. Chem. Rev. 2002, 102, 2187. (d) Groger, H.
Chem. Eur. J. 2001, 7, 5247.
(12) (a) Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun,
W. G.; Gleason, J. D.; Snapper, M. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 1999, 121, 4284. (b) Banphavichit, V.;
Mansawat, W.; Bhanthumnavin, W.; Vilaivan, T.
Tetrahedron 2004, 60, 10559. (c) Blacker, J.; Clutterbuck,
L. A.; Crampton, M. R.; Grosjean, C.; North, M.
Tetrahedron: Asymmetry 2006, 17, 1449. (d) Ishitani, H.;
Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem.
Soc. 2000, 122, 762.
(13) (a) Liu, B.; Feng, X.; Chen, F.; Zhang, G.; Cui, X.; Jiang, Y.
Synlett 2001, 1551. (b) Iyer, M. S.; Gigstad, K. M.; Namdev,
N. D.; Lipton, M. J. Am. Chem. Soc. 1996, 118, 4910.
(c) Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem.
Int. Ed. 2000, 39, 1279. (d) Corey, E. J.; Grogan, M. Org.
Lett. 1999, 1, 157. (e) Ooi, T.; Uematsu, Y.; Maruoka, K.
J. Am. Chem. Soc. 2006, 128, 2548.
(14) (a) Surendra, K.; Krishnaveni, N. S.; Mahesh, A.; Rao, K. R.
J. Org. Chem. 2006, 71, 2532. (b) Yadav, J. S.; Reddy,
B. V. S.; Eshwaraiah, B.; Srinivas, M.; Vishnumurthy, P.
New J. Chem. 2003, 27, 462. (c) Kobayashi, S.; Basujima,
T.; Nagayama, S. Chem. Commun. 1998, 981.
White solid; mp 113–115 °C. IR (KBr): 3296, 1688, 1612,
1519, 1253 cm–1. 1H NMR (200 MHz, CDCl3): d = 7.43 (2
H, d, J = 8.0 Hz), 7.40–7.31 (5 H, m), 6.92 (2 H, d, J = 8.0
Hz), 5.76 (1 H, d, J = 8.0 Hz), 5.22 (1 H, d, J = 8.0 Hz), 5.18
(2 H, s), 3.82 (3 H, s). 13C NMR (50 MHz, CDCl3): d =
160.7, 155.2, 135.7, 128.8, 128.7, 128.6, 128.5, 125.2,
117.8, 114.9, 68.1, 55.6, 46.3. ESI–MS: m/z = 297 [M + H]+,
319 [M+Na]+. ESI-HRMS: m/z calcd for C17H16N2O3Na [M
+ Na]+: 319.1058; found: 319.1069.
2-(Benzyloxycarbonylamino)-2-(3-nitrophenyl)aceto-
nitrile (3j)
White solid; mp 112–114 °C. IR (KBr): 3280, 3057, 1692,
1532 cm–1. 1H NMR (200 MHz, CDCl3): d = 8.37 (1 H, t,
J = 7.0 Hz), 8.33 (1 H, dd, J = 8.0, 2.0 Hz), 7.83 (1 H, dd,
J = 8.0, 2.0 Hz), 7.62 (1 H, t, J = 8.0 Hz), 7.35 (5 H, br s),
5.95 (1 H, br d, J = 8.0 Hz), 5.52 (1 H, d, J = 8.0 Hz), 5.17
(2 H, s). 13C NMR (50 MHz, CDCl3): d = 155.2, 148.9,
135.6, 135.3, 133.0, 130.7, 128.7, 128.5, 124.7, 122.2,
116.6, 68.5, 46.0. MS–FAB: m/z = 311 [M]+. ESI-HRMS:
m/z calcd for C16H13N3O4Na [M + Na]+: 334.0803; found:
334.0820.
2-(Benzyloxycarbonylamino)-2-(2-naphthyl)aceto-
nitrile (3l)
White solid; mp 133–135 °C. IR(neat): 3283, 1690, 1517,
1289 cm–1. 1H NMR (200 MHz, CDCl3): d = 7.98 (1 H, d,
J = 2.0 Hz), 7.90–7.79 (3 H, m), 7.58–7.45 (3 H, m), 7.38–
7.27 (5 H, m), 5.99 (1 H, d, J = 8.0 Hz), 5.39 (1 H, d, J = 8.0
Synlett 2008, No. 20, 3133–3136 © Thieme Stuttgart · New York

3136
B. Das et al.
LETTER
Hz), 5.18 (2 H, s). 13C NMR (50 MHz, CDCl3): d = 155.1,
135.5, 133.5, 133.0, 130.2, 129.6, 128.7, 128.6, 128.3,
128.2, 127.8, 127.3, 127.1, 126.5, 123.9, 117.5, 68.0, 46.8.
ESI-MS: m/z = 317 [M + H]+. ESI-HRMS: m/z calcd for
C20H16N2O2Na [M + Na]+: 339.1109; found: 339.1125.
2-(Benzyloxycarbonylamino)-2-(2-furyl)acetonitrile
(3m)
Pale grey solid; mp 104–106 °C. IR(neat): 3270, 1694, 1532,
1255 cm–1. 1H NMR (200 MHz, CDCl3): d = 7.42 (1 H, d,
J = 1.5 Hz), 7.39–7.22 (5 H, m), 6.52 (1 H, d, J = 3.0 Hz),
6.38 (1 H, dd, J = 3.0, 1.5 Hz), 5.89 (1 H, d, J = 8.0 Hz), 5.45
(1 H, d, J = 8.0 Hz), 5.14 (2 H, s). 13C NMR (50 MHz,
CDCl3): d = 154.8, 145.0, 144.1, 135.3, 128.6, 128.5, 128.2,
115.6, 110.9, 109.8, 68.0, 40.5. ESI-MS: m/z = 257 [M +
H]+. ESI-HRMS: m/z calcd for C14H12N2O3Na [M + Na]+:
279.0745; found: 279.0742.
2-(Benzyloxycarbonylamino)-3-methylbutyronitrile (3r)
Colorless oil. IR(neat): 3324, 3035, 1706, 1527, 1266, 1237
cm–1. 1H NMR (200 MHz, CDCl3): d = 7.35–7.26 (5 H, br s),
5.16 (1 H, br d, J = 8.0 Hz), 5.12 (2 H, s), 4.50 (1 H, t, J = 8.0
Hz), 2.03 (1 H, m), 1.11 (3 H, d, J = 7.0 Hz), 1.07 (3 H, d,
J = 7.0 Hz). 13C NMR (50 MHz, CDCl3): d = 155.5, 135.8,
128.8, 128.7, 127.0, 117.9, 67.8, 49.0, 31.8, 18.9, 18.2. MS–
FAB: m/z 233 [M + H]+. ESI-HRMS: m/z calcd for
C13H16N2O2Na [M + Na]+: 255.1109; found: 255.1102.
(20) (a) Banphavichit, V.; Chaleawlertumpon, S.;
Bhanthumnavin, W.; Vilaivan, T. Synth. Commun. 2004, 34,
3147. (b) Ooi, T.; Uematsu, Y.; Fujimoto, J.; Fukumoto, K.;
Maruoka, K. Tetrahedron Lett. 2007, 48, 1337.
Synlett 2008, No. 20, 3133–3136 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.