Vanadyl triflate as an efficient and recyclable catalyst for the synthesis of α-aminonitriles

Article abstract of DOI:10.1081/SCC-200061547

Vanadyl triflate to catalyzed Strecker-type reactions were successfully carried out by simply mixing aldehydes, amines, and trimethylsilyl cyanide at room temperature to afford α-aminonitriles in good yields. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200061547

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Vanadyl Triflate as an Efficient
and Recyclable Catalyst for the
Synthesis of α‐Aminonitriles
Surya Kanta De a
a Department of Medicinal Chemistry and Molecular
Pharmacology , School of Pharmacy, Purdue Cancer
Center, Purdue University , West Lafayette, Indiana,
USA
Published online: 16 Aug 2006.
To cite this article: Surya Kanta De (2005) Vanadyl Triflate as an Efficient and
Recyclable Catalyst for the Synthesis of α‐Aminonitriles, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry,
35:12, 1577-1582, DOI: 10.1081/SCC-200061547
To link to this article: http://dx.doi.org/10.1081/SCC-200061547
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Synthetic Communicationsw, 35: 1577–1582, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200061547
Vanadyl Triflate as an Efficient and
Recyclable Catalyst for the Synthesis of
a-Aminonitriles
Surya Kanta De
Department of Medicinal Chemistry and Molecular Pharmacology,
School of Pharmacy, Purdue Cancer Center, Purdue University,
West Lafayette, Indiana, USA
Abstract: Vanadyl triflate to catalyzed Strecker-type reactions were successfully
carried out by simply mixing aldehydes, amines, and trimethylsilyl cyanide at room
temperature to afford a-aminonitriles in good yields.
Keywords: a-Aminonitriles, aldehydes, amines, recyclability, trimethylsilyl cyanide,
vanadyl triflate
INTRODUCTION
In view of the tremendous versatility of a-aminonitriles in synthetic organic
chemistry as important intermediates for the synthesis of amino acids[1] and
nitrogen-containing heterocycles,[2] a plethora of procedures has been
reported for their preparation.[3–10] The classical Strecker reaction is
generally carried out with alkaline cyanides in an aqueous solution. Among
various cyanide-ion sources, trimethysilyl cyanide is a safer and more easily
handled reagent compared with hydrogen cyanide, sodium cyanide, or
potassium cyanide. However, many of these methods have some drawbacks,
such as low yields of the products, long reaction times, harsh reaction con-
ditions, difficulties in workup, the requirement for an inert atmosphere, and
Received in the USA February 11, 2005
Address correspondence to Surya Kanta De, Department of Medicinal Chemistry
and Molecular Pharmacology, School of Pharmacy, Purdue Cancer Center, Purdue
University, West Lafayette, IN 47907, USA. Fax: 765-494-1414; E-mail: skd125@
pharmacy.purdue.edu
1577

1578
S. K. De
the use of stoichiometric and/or relatively expensive reagents. Moreover,
many of the catalysts used for these reactions are deactivated or sometimes
decomposed by amines and water that exist during imine formation.
Therefore, there is reason to search a better catalyst in terms of operational
simplicity and reusability.
Most recently, vanadyl triflate has been introduced as promising mild and
selective reagent in organic synthesis.[11] The catalyst vanadyl triflate is
[11]
readily prepared using a reported method
and can be used for the prep-
aration of a-aminonitriles through a one-pot, three-component coupling of
aldehydes, amines, and trimethylsilyl cyanide. Although most conventional
Lewis acids are decomposed in the presence of water, VO(OTf)2 is stable
in water and does not decompose under aqueous workup conditions. Thus,
recyclization is often possible. In continuation of my work to develop new
synthetic methodologies,[12] I herein report that vanadyl triflate, which acts
as a mild Lewis acid, might be an important and reusable catalyst for the
synthesis of a-aminonitrile.
RESULTS AND DISCUSSION
The reaction of benzaldehyde and aniline with trimethylsilyl cyanide
(TMSCN) in the presence of a catalytic amount of VO(OTf)2 afforded the cor-
responding 2-(N-anilino)-2-phenylacetonitrile in 94% yield (Scheme 1). Thus,
various aromatic, aliphatic, and heterocyclic aldehydes were coupled with a
wide range of amines and trimethylsilyl cyanide in a one-pot operation in
the presence of a catalytic amount of VO(OTf)2 to give the corresponding
a-aminonitriles. However, ketones did not give any satisfactory results. On
the other hand, all types of primary and secondary amines are readily
coupled to give good yields. Moreover, acid-sensitive aldehydes such as
furfuraldehyde afforded the desired product in high yield. The results shown
in Table 1 clearly indicate the scope and generality of the reaction with
respect to various aldehydes and amines.
CONCLUSION
In conclusion, a very simple, mild, and practical method has been developed
for the synthesis of a-aminonitriles through a one-pot, three-component
coupling of aldehydes, amines, and trimethylsilyl cyanide using a catalytic
Scheme 1.

Vanadyl Triflate
1579
Table 1. VO(OTf)2-catalyzed synthesis of a-amino nitriles with trimethylsilyl
cyanide
Time
(h)
Yielda
(%)
Entry
Aldehyde
Benzaldehyde
Amine
1
2
Aniline
Aniline
12
14
12
14
10
7
94
88
79
75
92
85
89
88
85
74
89
4-Chlorobenzaldehyde
Isobutyraldehyde
Decylaldehyde
3
Benzyl amine
Aniline
4
5
3-Methoxybenzaldehyde
Furfural
Benzyl amine
Benzyl amine
Benzyl amine
Morpholine
Pyrrolidine
Furfurylamine
3-Methoxybenzyl
amine
6
7
Thiophene 2-carboxaldehyde
Benzaldehyde
Butyraldehyde
8
8
11
9
9
10
11
Benzaldehyde
Benzaldehyde
11
10
12
13
Benzaldehyde
2,4-Dimethoxybenzaldehyde
Butylamine
3,4,5-Trimethoxy-
aniline
14
11
91
95
14
4-Methylbenzaldehyde
Aniline
10
91
1
aAll products were characterized by H NMR and mass spectra.
amount of vanadyl triflate. Further, the catalyst can be readily recovered and
reused, thus making the procedure more environmentally acceptable.
EXPERIMENTAL
NMR spectra were recorded on a Bruker ARX 300 (300 MHz) instrument.
Low-resolution mass spectra (CI, EI) were recorded on a Finnigan 4000
mass spectrometer. High-resolution mass spectra (HRMS, EI, CI, ESI) were
recorded on Finnigan MAT XL95 mass spectrometer. The reactions were
monitored by TLC and visualized with UV light, followed by development
using 15% phosphomolybdic acid in ethanol. All solvents and reagents
were purchased from Aldrich in high-grade quality and used without any
purification. All yields refer to isolated products.
Typical Procedure
A mixture of benzaldehyde (212 mg, 2 mmol), benzyl amine (214 mg,
2 mmol), and trimethylsilyl cyanide (300 mg, 3 mmol) in dry acetonitrile
(2 mL) was stirred in the presence of vanadyl triflate (15 mol%) at room temp-
erature. After completion of the reaction (TLC), the reaction mixture

1580
S. K. De
was extracted with ethyl acetate (2 ꢀ 20 mL). The organic layer was washed
with water (20 mL) and brine (20 mL), dried (MgSO4), and concentrated. The
residue was chromatographed over silica gel (20% ethyl acetate in hexane) to
afford the pure product. The aqueous layer containing the catalyst can be evap-
orated under reduced pressure (30 mm at 808C) to give a solid, which was
reused for the next reaction. The catalyst can be reused three times without
significant loss of activity.
Product Characterization Data
2-(N-Anilino)-2-phenylacetonitrile (entry 1). 1H NMR (300 MHz, CDCl3)
d 4.02 (br s, 1H), 5.40 (s, 1H), 6.74 (d, J ¼ 7.8 Hz, 2H), 6.89 (t, J ¼ 7.8 Hz,
1H), 7.24 (t, J ¼ 7.8 Hz, 2H), 7.41–7.49 (m, 3H): 13C NMR (75 MHz,
CDCl3) d 50.6, 114.8, 118.8, 120.6, 127.7, 129.7, 130.1, 130.2, 134.5,
145.6. EIMS m/z 208 (Mþ), 180, 116, 91, 77, 55. HRMS calcd. for
C14H12N2 208.1004, found 208.1006.
1
2-(N-Anilino)-2-(4-chlorophenyl)acetonitrile (entry 2). H NMR (300MHz,
CDCl3) d 4.01 (br s, 1H), 5.39 (s, 1H), 6.75 (d, J ¼ 8 Hz, 2H), 6.91
(t, J ¼ 7.8 Hz, 1H), 7.15 (t, J ¼ 7.9 Hz, 2H), 7.38 (d, J ¼ 7.8 Hz, 2H), 7.61
(d, J ¼ 8 Hz, 2H): 13C NMR (75 MHz, CDCl3) d 49.7, 114.2, 117.7, 120.8,
128.5, 129.4, 129.6, 132.3, 135.5, 144.4. EIMS m/z 242 and 244 (Mþ), 149,
114, 91, 77, 59. HRMS C14H11ClN2 242.0610, found 242.0608.
2-(N-Benzylamino)-2-isopropylacetonitrile (entry 3). 1H NMR (300 MHz,
CDCl3) d 1.08 (d, J ¼ 6.5 Hz, 3H), 1.09 (d, J ¼ 6.5 Hz, 3H), 1.56 (br s, 1H),
1.97–2.02 (m, 1H), 3.24 (d, J ¼ 6 Hz, 1H), 3.80 (d, J ¼ 13 Hz, 1H), 4.07
(d, J ¼ 13 Hz, 1H), 7.24–7.43 (m, 5 H); 13C NMR (75 MHz, CDCl3) d 18.2,
19.3, 31.3, 51.8, 56.3, 119.3, 127.5, 128.4, 128.7, 138.4. EIMS m/z 188
(Mþ). HRMS calcd. for C12H16N2 188.1313, found 188.1316.
2-(N-Anilino)-2-decylacetonitrile (entry 4). 1H NMR (300 MHz, CDCl3) d
0.91 (t, J ¼ 6.7 Hz, 3H), 1.18–1.38 (m, 12H), 1.50–1.64 (m, 2H), 1.81–1.91
(m, 2H), 3.81 (br s, NH), 4.02–4.15 (m, 1H), 6.61 (d, J ¼ 8 Hz, 2H), 6.81
(t, J ¼ 7.8 Hz, 1H), 7.21 (t, J ¼ 7.8 Hz, 2H). EIMS m/z 258 (Mþ), 185,
155, 121, 77, 55. HRMS calcd. for C17H26N2 258.2095, found 258.2092.
2-(N-Benzylamino)-2-(3-methoxyphenylacetonitrile (entry 5). 1H NMR
(300 MHz, CDCl3) d 1.84 (br s, 1H), 3.76 (s, 3H), 3.95 (AB, q, J ¼ 13 Hz,
2H), 4.65 (s, 1H), 6.85 (dd, J ¼ 2.4, 9 Hz, 1H), 7.14–7.36 (m, 2H), 7.28–
7.43 (m, 6 H): 13C NMR (75 MHz, CDCl3) d 51.6, 53.9, 55.7, 113.4, 114.8,
119.2, 119.8, 128.5, 129.7, 128.8, 130.4, 136.7, 138.6, 160.4. EIMS m/z
252 (Mþ), 122, 91, 77. HRMS calcd. for C16H16N2O 252.1262, found
252.1258.
2-(N-Benzylamino)-2-furfurylacetonitrile (entry 6). 1H NMR (300 MHz,
CDCl3) d 1.95 (br s, 1H), 3.94 (AB, q, J ¼ 13 Hz, 2H), 4.75 (s, 1H),

Vanadyl Triflate
1581
6.27–6.32 (m, 1H), 7.16–7.52 (m, 7 H): 13C NMR (75 MHz, CDCl3) d 47.9,
51.4, 109.2, 111.5, 127.5, 127.8, 128.5, 128.9, 138.2, 143.8, 147.9. EIMS
m/z 212 (Mþ). HRMS calcd. for C13H12N2O 212.0950, found 212.0955.
2-(N-Benzylamino)-2-thiophenylacetonitrile (entry 7). 1HNMR(300 MHz,
CDCl3) d 2.02 (br s, 1H), 3.96 (AB, q, J ¼ 13 Hz, 2H), 4.91 (s, 1H), 6.94–6.98
(m, 1H), 7.21–7.45 (m, 7 H): 13C NMR (75 MHz, CDCl3) d 49.7, 51.4, 118.4,
126.7, 127.3, 128.3, 128.7, 128.9, 129.2, 138.4, 138.9. EIMS m/z 228 (Mþ).
HRMS calcd. for C13H12N2S 228.0721, found 228.0725.
2-(N-Morpholino)-2-phenylacetontrile (entry 8). 1H NMR (300 MHz,
CDCl3) d 2.51–2.63 (m, 4 H), 4.68–4.79 (m, 5 H), 7.35–7.56 (m, 5 H): 13C
NMR (75 MHz, CDCl3) d 50.4, 62.1, 62.8, 115.7, 128.5, 129.4, 129.8,
133.1. EIMS m/z 202 (Mþ). HRMS calcd. for C12H14N2O 202.1106, found
202.1109.
2-n-Propyl-2-(N-pyrrolidino)acetonitrile (entry 9). 1H NMR (300 MHz,
CDCl3) 0.98 (t, J ¼ 7.7 Hz, 3H), 1.42–1.51 (m, 2H), 1.69–1.89 (m, 6 H),
2.62–2.71 (m, 4 H), 3.75 (t, J ¼ 7.5 Hz, 1H): 13C NMR (75 MHz, CDCl3) d
11.6, 17.4, 21.4, 32.9, 47.9, 53.2, 94.4. EIMS m/z 152 (Mþ). HRMS calcd.
for C9H16N2 152.1313, found 152.1311.
2-(N-furfurylamino)-2-phenylacetonitrile (entry 10). 1H NMR (300 MHz,
CDCl3) 1.82 (br s, 1H), 4.01 (s, 2H), 4.79 (s, 1H), 6.21–6.41 (m, 2H),
7.31–7.56 (m, 6 H). EIMS m/z 212 (Mþ), 186, 81, 77. HRMS calcd for
C13H12N2O 212.0949, found 212.0951.
2-(N-3-Methoxybenzylamino)-2-phenylacetonitrile (entry 11). 1H NMR
(300 MHz, CDCl3) d 1.86 (br s, 1H), 3.81 (s, 3H), 3.94 (AB, q, J ¼ 13 Hz,
2H), 4.71 (s, 1H), 6.81–6.96 (m, 3H), 7.24 (t, J ¼ 7.8 Hz, 1H), 7.30–7.58
(m, 5 H); 13C NMR (75 MHz, CDCl3) 51.4, 53.7, 55.6, 96.6, 113.4, 114.2,
119.1, 120.9, 127.6, 129.4, 130.1, 135.4, 140.1, 160.2. EIMS m/z 252
(Mþ), 122, 91, 77. HRMS calcd. for C16H16N2O 252.1262, found 252.1265.
2-(N-n-Butylamino)-2-phenylacetonitrile (entry 12). 1H NMR (300 MHz,
CDCl3) d 0.92 (t, J ¼ 7.2 Hz, 3H), 1.25–1.47 (m, 4 H), 2.68–2.78 (m, 2H),
4.74 (s. 1H), 7.38–7.38 (m, 3H), 7.65–7.71 (m, 2H): 13C NMR (75 MHz,
CDCl3) d 14.2, 20.6, 32.3, 47.5, 54.8, 119.4, 127.7, 129.3, 135.5. EIMS m/z
188 (Mþ). HRMS calcd. for C12H16N2 188.2689, found 188.2693.
2-(N-3,4,5-Trimethoxyanilino)-2-(2,4-dimethoxyphenyl)acetonitrile (entry
13). 1H NMR (300 MHz, CDCl3) d 3.76 (s, 3H), 3.81 (s, 3H), 3.82 (s, 6 H),
3.86 (s, 3H), 4.18 (br s, 1H), 5.44 (s, 1H), 6.01 (s, 2H), 6.46–6.53 (m, 2H),
7.39 (d, J ¼ 9 Hz, 1H). EIMS m/z 358 (Mþ). HRMS calcd. for C19H22N2O5
358.1529, found 358.1531.
2-(N-Anilino)-2-(4-methylphenyl)acetonitrile (entry 14). 1H NMR
(300 MHz, CDCl3) d 2.41 (s, 3H), 3.90 (s, 1H), 5.41 (s, 1H), 6.78
(d, J ¼ 8 Hz, 2H), 6.91 (t, J ¼ 7.8 Hz, 1H), 7.21–7.31 (m, 4 H), 7.50

1582
S. K. De
(d, J ¼ 8 Hz, 2H), 7.51 (d, J ¼ 8 Hz, 2H); EIMS m/z 222 (Mþ), 176, 103, 77.
HRMS calcd. for C15H14N2 222.1156, found 222.1158.
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