MgI2 etherate-catalysed Strecker reaction: A facile and efficient synthesis of α-aminonitriles from aldimines and trimethylsilyl cyanide

Article abstract of DOI:10.3184/174751913X13817705381783

A mild and efficient procedure for the synthesis of a-aminonitriles is achieved by treatment of aldimines with trimethylsilyl cyanide catalysed by MgI₂ etherate.

Full text of DOI:10.3184/174751913X13817705381783

JOURNAL OF CHEMICAL RESEARCH 2013
NOVEMBER, 709–711
RESEARCH PAPER 709
MgI2 etherate-catalysed Strecker reaction: a facile and efficient synthesis of
α-aminonitriles from aldimines and trimethylsilyl cyanide
Yongping Lu, Yanping Wang and Xingxian Zhang*
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310032, P.R. China
A mild and efficient procedure for the synthesis of α-aminonitriles is achieved by treatment of aldimines with trimethylsilyl
cyanide catalysed by MgI2 etherate.
Keywords: aldimines, trimethylsilyl cyanide, Strecker, MgI2 etherate
The Strecker synthesis is one of the most atom-economical
methods for the synthesis of α-amino acids, and the intermediate
α-aminonitriles are also very useful precursors for the synthesis
of various nitrogen-containing heterocycles.1 The first stage of
the classical Strecker synthesis is the reaction of KCN with
an imine to yield an α-aminonitrile. Several modifications of
this nucleophilic addition reaction have been reported using
a variety of cyanating agents such as Bu3SnCN,2 Et2AlCN,3
EtOCOCN,4 K2[Fe (CN)6]5 and (EtO)2P (O)CN.6 The use of
trimethylsilyl cyanide (TMSCN) is a promising alternative
cyanation reagent for nucleophilic addition reactions, due to its
nature as an effective, easily-handled, relatively safe and one of
the simplest and highly soluble cyanide ion sources.
TMSCN and stirred for 3 h, the desired α-aminonitrile was
obtained in 95% yield. Encouraged by these results, a variety
of aldimines were subjected to similar reaction conditions.
The results are summarised in Table 1. Cyanation of aldimines
1b, 1c and 1d, prepared from benzaldehyde and, respectively,
4-methyl-, 2-methyl and 4-methoxyaniline, produced the
corresponding α-aminonitriles 2b–d in nearly quantitative
yield (Table 1, entries 2–4). Furthermore, the cyanation of imine
1e, prepared from benzaldehyde and benzylamine, also worked
well and gave the desired product in good yield (Table 1, entry
5). Four aldimines 1f–i, the products of condensation of aniline
with variously substituted benzaldehydes, also gave excellent
yields of the corresponding products, 2f–i (Table 1, entries
6–9). Moreover, the reaction of heteroaryl imines 1j–m, also
proceeded in good yields (Table 1, entries 10–13). In addition,
the use of benzylamine as the imine component was examined
and the cyanation products 2n–o were obtained in good yields
(Table 1, entries 14 and 15). As can be seen, the use of an
aromatic amine as the imine component gave, in general, better
results than the use of a benzylamine. The reaction of TMSCN
with a chiral imine catalysed by MgI2 etherate was also studied
(Table 1, entry 16). The cyanation with a chiral imine employing
the R-l-phenyl-ethylamine auxiliary afforded 2p with moderate
stereoselection in excellent yield. The procedure could not be
applied to ketimines, for it was found that neither (1; Me for H;
R, R’=Ph) nor (1; Me for H; R=4-NO2C6H4, R’=4-MeOC6H4)
reacted with TMSCN in the presence of MgI2 etherate.
All but three of the 16 α-aminonitriles that were synthesised
were characterised by comparison of melting point, if a solid,
and 1H NMR with literature data. The three new compounds, 2j,
2k and 2l were additionally characterised by HRMS analysis.
To examine the halide anion effect, halogen analogues
of MgI2 etherate, MgCl2 etherate and MgBr2 etherate were
compared under similar reaction conditions were found to be
less effective. Probably, the greater reactivity of MgI2 etherate
can be attributed to the dissociative character of the iodide
counterion and the greater Lewis acidity of the [MgI]+ species.
In conclusion, we have shown for the first time that MgI2
etherate can be used in the Strecker reaction for the synthesis
of α-aminonitriles from aldimines and TMSCN. This catalytic
reaction enables cyanation to be carried out under essentially
neutral conditions at room temperature in good to excellent
yields. The study of asymmetric Strecker reactions catalysed
by MgI2 etherate is on-going in our lab.
Recently, many methods for the synthesis of α-aminonitriles
from imines with TMSCN have been developed in the
presence of various Lewis acid catalysts, such as Fe (CP)2PF6,7
RhI3•H2O,8 Ga (OTf)3,9 GaCl3, Pr (OTf)3,11 NiCl2,12 RuCl3,13
10
InI3,14 BiCl3,15 GdCl3•H2O,16 Cu (OTf)2,17 CeCl318 and FeCl3.19
However, the traditional methods using Lewis acids must be
carried out under strictly anhydrous conditions, which can
be problematical especially if carried out on a large scale.
Water-tolerant Lewis acids such as lanthanide triflates are
rather expensive. From these viewpoints, the development of
less expensive, environmentally benign, and easily handled
promoters for cyanation of aldimines is still highly desirable.
MgI2 etherate is easily prepared, inexpensive and more easily
handled than other metal halides such as InCl3, TiCl4 and SnCl4.
To the best of our knowledge, there is no report of the use of
MgI2 etherate as a mild catalyst for cyanation. In continuation
of our research, we now describe a simple cyanation of
aldimines to α-aminonitriles with TMSCN catalysed by MgI2
etherate under mild reaction conditions in good to excellent
yields (Scheme 1).
R'
R'
.
HN
N
(OEt2)n
10 mol% MgI2
+
TMSCN
R
CN
R
H
CH2Cl2 , r.t.
2
1
R = aryl, heteroaryl; R' = alkyl, aryl
Scheme 1
Results and discussion
Initially, we prepared a variety of aldimines derived from
aromatic aldehydes and alkyl and aryl-amines. We carried out
our initial studies into the cyanation of an aldimine employing
the product of condensation of benzaldehyde and aniline, 1a
(R, R’=Ph). When a solution of 1a (R, R’=Ph) and 10 mol% of
MgI2 etherate in CH2Cl2 at room temperature was treated with
Experimental
For product purification by flash column chromatography, silica gel
(200–300 mesh) and light petroleum ether (PE, b.p. 60–90 °C) were
used. 1H NMR spectra were taken on a Bruker AM-500 spectrometer
with TMS as an internal standard in CDCl3. Reaction monitoring was
accomplished by TLC on silica gel polygram SILG/UV 254 plates.
Melting points were measured on a BUCHI B‑540 and uncorrected.
* Correspondent. E-mail: zhangxx@ zjut.edu.cn
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710 JOURNAL OF CHEMICAL RESEARCH 2013
a
Table 1 Yields of α-aminonitriles 2a–p from aldimines 1a–p treated with TMSCN catalysed by 10 mol% MgI2• (OEt2)n
Aldimine
Entry
Time/h
Productb
Yield/%c
R
R’
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
2-MeC6H4
4-MeOC6H4
Bn
3
2
3
1
4
4
3
2
2
2
3
3
3
2
4
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
97
94
99
94
80
92
99
95
94
85
83
87
86
97
84
4-MeOC6H4
4-MeC6H4
4-BrC6H4
3-NO2C6H4
2-thiophenyl
2-Thiophenyl
2-Furfuryl
4-Methylthiazolyl
4-BrC6H4
2-Thiophenyl
Ph
Ph
Ph
Ph
1j
4-MeOC6H4
4-FC6H4
4-Meoc6h
4-Meoc6h4
Bn
1k
1l4
1m
1n
1o
Bn
86d
16
1p
Ph
R-C6H4CH (Me)
2
2p
(dr=72:28)
aThe reaction was carried out by addition of TMSCN (0.6 mmol) to aldimine (0.5 mmol) and 10 mol% MgI2• (OEt2)n in CH2Cl2
at room temperature.
bAll products were identified by their 1H NMR spectra.
cYields of products isolated by column chromatography.
dThe ratio of dr value was determined by 1H NMR analysis.
FT-IR spectra were recorded on a Bruker Tensor 27 spectrometer.
HRMS were determined on a Waters GCT Premier spectrometer. All
starting materials and reagents were purchased from Sigma-Aldrich.
2-(4-Methylphenyl)-2-(phenylamino)acetonitrile (2g):20 White solid,
m.p. 94–95 °C [lit.20 95–96 °C]; IR (KBr): 3345, 2213, 1524, 1490,
1
1140 cm–1; H NMR: δH 2.44 (s, 3H), 4.07 (d, J=8.3 Hz, 1H), 5.40 (d,
J=8.3 Hz, 1H), 6.80 (d, J=8.0 Hz, 2H), 6.92–6.95 (m, 1H), 7.29–7.33 (m,
Synthesis of α-aminonitriles; typical procedure
4H), 7.51 (d, J=8.1 Hz, 2H).
Freshly prepared MgI2 etherate (0.05 mmol) was added to a stirred
solution of benzylideneaniline 1a (0.5 mmol) in CH2Cl2 (5 mL) at
room temperature. After stirring for 10 min, a solution of TMSCN
(0.6 mmol) was added dropwise via a syringe. The resulting
homogeneous reaction mixture was stirred at room temperature for
3.0 h and quenched by saturated NaHCO3 aqueous solution. Extractive
work-up with ethyl acetate and chromatographic purification of the
crude product on silica gel gave the aminonitriles 2a in 97% yield.
2-Phenyl-2-(phenylamino)acetonitrile (2a):20 White solid, m.p. 74–
75 °C [lit.20 74–76 °C]; IR (KBr): 3369, 2234, 1604, 1490, 1240, 1120 cm–1;
1H NMR: δH 4.27 (d, J=8.4 Hz, 1H), 5.46 (d, J=8.5 Hz, 1H), 6.83 (d,
J=7.9 Hz, 2H), 6.97–6.70 (m, 1H), 7.33–7.36 (m, 1H), 7.50–7.51 (m, 3H),
7.63–7.65 (m, 2H).
2-Phenyl-2-(4-methylphenylamino)acetonitrile (2b):21 White solid,
m.p. 103–105 °C [lit.21 104–106 °C]; IR (KBr): 3375, 2245, 1614, 1590,
1256, 1128 cm–1; 1H NMR: δH 3.14 (s, 3H), 3.98 (d, J=8.6 Hz, 1H), 5.42 (d,
J=8.7 Hz, 1H), 6.7 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.3 Hz, 1H), 7.47–7.48
(m, 3H), 7.61–7.63 (m, 2H).
2-Phenyl-2-(2-methylphenylamino)acetonitrile (2c):22 Light yellow
solid, m.p. 71–73 °C [lit.22 72–73 °C]; IR (KBr): 3419, 2236, 1615, 1580,
1250, 1127 cm–1; 1H NMR: δH 2.26 (s, 3H), 4.18 (d, J=8.4 Hz, 1H), 5.55 (d,
J=8.3 Hz, 1H), 6.97–7.02 (m, 2H), 7.28 (d, J=7.5 Hz, 1H), 7.33–7.36 (m,
1H), 7.55–7.59 (m, 3H), 7.74–7.75 (m, 2H).
2-(4-Bromophenyl)-2-(phenylamino)acetonitrile (2h):20 Light yellow
solid, m.p. 86–87 °C [lit.20 m.p. 87–88 °C]; IR (KBr): 3340, 2234, 1604,
1
1490, 1240, 1120 cm–1; H NMR: δH 4.08 (d, J=5.0 Hz, 1H), 5.40 (d,
J=5.0 Hz, 1H), 6.76 (m, 2H), 6.91–6.94 (m, 1H), 7.26–7.29 (m, 3H), 7.47–
7.49 (m, 2H), 7.58–7.60 (m, 2H).
2-(3-Nitrophenyl)-2-(phenylamino)acetonitrile (2i):20 Yellow oil; IR
(KBr): 3260, 2220, 1600, 1499, 1219 cm–1; 1H NMR: δH 4.50 (s, 1H), 5.56
(s, 1H), 6.68–6.70 (m, 1H), 6.78 (dd, J=6.0, 7.8 Hz, 3H), 7.26–7.29 (m,
3H), 6.96 (t, J=7.5 Hz, 1H), 7.16–7.19 (m, 1H), 7.29 (dd, J= 7.5, 8.4 Hz,
2H), 7.61 (t, J=8.0 Hz, 1H).
2-(Thiophen-2-yl)-2-(4-methoxyphenylamino)acetonitrile (2j): Yellow
oil; IR 3362, 2349, 1612, 1556, 1491, 1313, 1160 (KBr): cm–1; 1H NMR:
δH 3.81 (s, 3H), 4.43 (d, J=10.0 Hz, 1H), 5.61 (d, J=10.0 Hz, 1H), 6.84–
6.91 (m, 2H), 6.91–6.93 (m, 2H), 7.09 (dd, J=5.0, 10.0 Hz, 1H), 7.38–7.42
(m, 2H). HRMS (EI) calcd for C13H12N2OS: 244.0670, found for [M]+:
244.0653.
2-(Thiophen-2-yl)-2-(4-fluorophenylamino)acetonitrile (2k): Yellow
oil; IR (KBr): 3364, 2261, 1644, 1590, 1502, 1227, 1151 cm–1; δH 4.82
(d, J=10 Hz, 1H), 5.71 (d, J=5.0 Hz, 1H), 6.97–7.00 (m, 2H), 7.40 (d,
J=5.0 Hz, 2H), 7.43 (d, J=5.0 Hz, 1H), 7.76–7.79 (m, 2H). HRMS (EI)
calcd for C12H9FN2S: 232.0470, found for [M]+: 232.0454.
2-(Furan-2-yl)-2-(4-methoxyphenylamino)acetonitrile (2l):24 Brown
solid, m.p. 93–95 °C [lit.23 94–95 °C]; IR (KBr): 3362, 2251, 1600, 1556,
1490, 1310, 1141 cm–1; 1H NMR: δH 3.83 (s, 3H), 5.47 (d, J=10.0 Hz, 1H),
6.48 (m, 2H), 6.61 (d, J=10.0 Hz, 2H), 6.84 (d, J=10.0 Hz, 2H), 6.91 (d,
J=10.0 Hz, 1H).
2-(4-Methylthiazol-5-yl)-2-(4-methoxyphenylamino)acetonitrile (2m):
Yellow oil; IR (KBr): 3325, 2249, 1602, 1504, 1440, 1248, 1172 cm–1; 1H
NMR: δH 2.49 (s, 3H), 3.73 (s, 3H), 5.47 (d, J=10.0 Hz, 1H), 6.74–6.82
(m, 4H). HRMS (EI) calcd for C13H13N3OS: 259.0779, found for [M]+:
259.0761.
2-(4-Bromophenyl)-2-(benzylamino)acetonitrile (2n):25 Light yellow oil;
IR (KBr): 3332, 2221, 1600, 1503, 1431, 1240, 1212 cm–1; 1H NMR: δH 3.95
(d, J=15.0 Hz, 2H), 4.80 (s, 1H), 7.26–7.35 (m, 7H), 7.35–7.60 (m, 2H).
2-(Thiophen-2-yl)-2-(benzylamino)acetonitrile (2o):22 Light yellow oil;
IR (KBr): 3374, 2251, 1602, 1592, 1502, 1222, 1121 cm–1; 1H NMR: δH 3.89
(d, J=15.0 Hz, 2H), 5.13 (s, 1H), 7.01–7.09 (m, 2H), 7.32–7.49 (m, 6H).
2-Phenyl-2-(4-methoxyphenylamino)acetonitrile (2d):23 Dark green
solid, m.p. 68–70 °C; IR (KBr): 3379, 2224, 1519, 1492, 1240, 1100 cm–1;
1H NMR: δH 3.76 (s, 3H), 5.34 (d, J=10 Hz, 1H), 6.75–6.76 (m, 2H), 6.84–
6.85 (m, 2H), 7.43–7.69 (m, 2H).
2-Phenyl-2-(benzylamino)acetonitrile (2e):20 Colourless oil, IR (KBr):
3363, 2232, 1612, 1501, 1450, 1260 cm–1; 1H NMR: δH 4.02–4.05 (m, 1H),
5.02 (d, J=10.0 Hz,1H), 7.07–7.09 (d, J=10.0 Hz, 1H), 7.26–7.40 (m,
2H), 7.42–7.45 (m, 3H), 7.52–7.54 (m, 5H).
2-(4-Methoxyphenyl)-2-(phenylamino)acetonitrile (2f):20 Yellow solid,
m.p. 70–71 °C [lit.20 69–71 °C]; IR (KBr): 3359, 2130, 1504, 1480, 1220,
1
1150 cm–1; H NMR: δH 3.85 (s, 3H), 4.04 (d, J=8.2 Hz, 1H), 5.37 (d,
J=8.2 Hz, 1H), 6.79–6.80 (d, J=7.9 Hz, 2H), 6.91–6.94 (m, 1H), 6.98 (d,
J=8.8 Hz, 2H), 7.28–7.31 (m, 2H), 7.52–7.53 (m, 2H).
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JOURNAL OF CHEMICAL RESEARCH 2013 711
2-Phenyl-2-((R)-1-phenylethylamino)acetonitrile (2p):26 Colourless
8
9
A. Majhi, S.S. Kim and S.T. Kadam, Tetrahedron, 2008, 64, 5509.
G.K.S. Prakash, T. Mathew, C. Panja, S. Alconcel, H. Vaghoo, C. Do and
G.A. Olah, Proc. Natl. Acad. Sci. USA, 2007, 104, 3703.
1
oil; IR (KBr): 3360, 2233, 1602, 1500, 1460, 1240 cm–1; H NMR: δH
1.43–1.46 (m, 3H), 1.89 (s, 1H), 4.02 (d, J=10.0 Hz, 1H), 4.72 (s, 1H),
10 D. Kumar, A. Saini and S.S. Jagir, J. Chem., 2008, 1, 639.
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7.36–7.50 (m, 10 H).
This work was supported by the Program for Zhejiang Leading
Team of Science and Technology Innovation (2012R10044).
13 S.K. De, Synth. Commun., 2005, 35, 653.
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Received 20 August 2013; accepted 9 September 2013
Paper 1302142 doi: 10.3184/174751913X13817705381783
Published online: 11 November 2013
18 M.A. Pasha, A. Nanjundaswamy and V.P. Jayashankara, Synth. Commun.,
2007, 37, 4371.
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