Strecker-type reaction of nitrones using cyanohydrin

Article abstract of DOI:10.1246/bcsj.20110270

Strecker-type reaction of nitrones using acetone cyanohydrin as a cyanide source was developed. By treating nitrones with acetone cyanohydrin in the presence of n-BuMgCl, transcyanation from the cyanohydrin to the nitrones smoothly proceeded in THF at 35 °C. The amount of n-BuMgCl could be reduced to 0.2 equiv to give the corresponding α-cyanohydroxylamines in up to 98% yields.

Full text of DOI:10.1246/bcsj.20110270

© 2012 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 85, No. 2, 231-235 (2012)
231
Strecker-Type Reaction of Nitrones Using Cyanohydrin
Takahiro Sakai, Takahiro Soeta, Katsuhiko Inomata, and Yutaka Ukaji*
Division of Material Sciences, Graduate School of Natural Science and Technology,
Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192
Received September 20, 2011; E-mail: ukaji@se.kanazawa-u.ac.jp
Strecker-type reaction of nitrones using acetone cyanohydrin as a cyanide source was developed. By treating
nitrones with acetone cyanohydrin in the presence of n-BuMgCl, transcyanation from the cyanohydrin to the nitrones
smoothly proceeded in THF at 35 °C. The amount of n-BuMgCl could be reduced to 0.2 equiv to give the corresponding
¡-cyanohydroxylamines in up to 98% yields.
The Strecker-type hydrocyanation of carbon-nitrogen dou-
ble bonds is one of the oldest methods for the preparation of
¡-amino nitriles,1 which are versatile synthetic intermediates
for ¡-amino acids and various nitrogen-containing heterocycles
such as imidazoles and thiadiazoles.1,2 Among organic nitrogen
compounds bearing a carbon-nitrogen double bond, a nitrone
seems to be a suitable substrate as it possesses electronegative
oxygen, which is coordinatable to metals and polarizes a
carbon-nitrogen double bond to effectively enhance the elec-
trophilic reactivity. Nucleophilic addition to nitrones affords
various types of hydroxylamines, which are useful compounds
for the preparation of nitrogen-containing chemicals.3 We have
developed various types of nucleophilic addition reactions to
nitrones.4 The Strecker-type reaction of nitrones is also a useful
way to prepare ¡-amino nitrile derivatives, however, only a
few reports have appeared for the addition to nitrone using
hydrogen cyanide that was generated in situ from potas-
sium cyanide5 or trimethylsilyl cyanide6 as a cyanide source.
Hydrogen cyanide and trimethylsilyl cyanide are the most
commonly used cyanide sources for the Strecker-type reaction,
however, some problems such as high toxicity, volatility,
expense, and difficulty to handle, are still associated with these
approaches. In this regard, the development of other cyanide
sources for Strecker-type reaction has been explored including
the use of tributyltin cyanide,7 diethylaluminum cyanide,8
diethyl phosphorocyanidate,9 ethyl cyanoformate,10 and acyl
cyanide.11 Among such cyanide compounds, acetone cyano-
hydrin is one of the simplest, stable, relatively less toxic, easy
to handle, and readily available cyanide sources.12 Herein we
disclose the Strecker-type reaction of nitrones by the use of
acetone cyanohydrin as a cyanide source.
Table 1. The Strecker-Type Reaction of Nitrone 1a Using
Acetone Cyanohydrin (2A) as a Cyanide Source
Bn
O
OH
N
NC
H
Ph
(1.0 equiv)
(1.0 equiv)
1a
2A
Bn
OH
RM (1.0 equiv)
N
CH Cl , rt, Time
2
2
NC
Ph
(Bn = PhCH )
2
3a
Entry
RM
Time/h
Yield/%
1
2
3
4
5
6
7
8
9
®
NaH
MeMgBr
n-BuMgCl
n-Bu2Mg
Me3Al
Et2AlCl
Me2Zn
MeZnBrb)
(i-PrO)4Ti
(i-PrO)3Sm
17
45
20
43
18
65
43
44
41
43
20
no reaction
no reaction
16
54
17a)
48
29
no reaction
no reaction
no reaction
10
11
c)
®
a) By-product 4 was obtained in 18% yield. b) MeZnBr was
prepared in situ from 0.5 equiv of Me2Zn and 0.5 equiv of
ZnBr2. c) An imine 5 was obtained in less than 17% yield.
Ph
Bn
OH
Ph
N
N
Results and Discussion
n-Bu
NC
Ph
4
First acetone cyanohydrin (2A) was treated with (Z)-
benzyl(benzylidene)amine N-oxide (1a) in CH2Cl2 at rt. The
reaction did not occur at all and the nitrone 1a was recovered
after 17 h (Table 1, Entry 1). Then the Strecker-type reaction
was carried out via generation of the corresponding metal
alkoxide of acetone cyanohydrin (2A) by the treatment with
appropriate metallic reagents (Entries 2-11).13 When 2A was
5
treated with NaH, the Strecker-type reaction did not proceed
either (Entry 2). A desired cyano-transferred product 3a was
observed when 2A was treated with MeMgBr (Entry 3). By the
use of n-BuMgCl as a metal source, the reaction proceeded
Published on the web January 28, 2012; doi:10.1246/bcsj.20110270

232
Bull. Chem. Soc. Jpn. Vol. 85, No. 2 (2012)
Strecker-Type Reaction of Nitrones
Table 3. The Strecker-Type Reaction of Nitrones 1
Table 2. The Transcyanation of Cyanohydrin 2 by the
Treatment with n-BuMgCl
2
2
R
O
R
OH
OH
n-BuMgCl (0.2 equiv)
THF, 35 °C, Time
N
N
Bn
O
Bn
OH
Ph
OH
n-BuMgCl (n equiv)
N
N
NC
1
1
R
H
R
NC
R
NC
Solvent, Temp., Time
R
H
Ph
NC
(1.0 equiv)
(1.0 equiv)
1
2A
3
(1.0 equiv)
(1.0 equiv)
1a
2
3a
Entry
R1
Ph
R2
1
Time/h
Yield/%
Entry
R
R
2
n Solvent Temp/°C Time/h Yield/%
1
2
3
4
5
6
7
8
Bn
Bn
Bn
Bn
Bn
Bn
Me
Ph
a
b
c
d
e
f
g
h
23
14
14
16
18
16
16
18
90
73
81
98
84
93
86
85
p-MeOC6H4
p-ClC6H4
Me
1
2
3
4
5
6
7
8
9
CH3 CH3
CH3 CH3
CH3 CH3
CH3 CH3
CH3 CH3
CH3 CH3
CH3 CH3
CH3 CH3
CH3 CH3
A
A
A
A
A
A
A
A
A
B
B
1.0 toluene
1.0 CH2Cl2
1.0 MeCN
1.0 Et2O
1.0 THF
1.0 THF
1.0 THF
0.2 THF
0.1 THF
1.0 THF
0.2 THF
rt
rt
rt
rt
rt
35
60
35
35
35
35
43
43
43
43
49
26
29
23
115
20
67
54
41
59
75
81
81
90
23
60
c-Hex
t-Bu
Ph
Ph
a)
9
i
18
®
N
O
10 -(CH2)5-
11 -(CH2)5-
44 no reaction
a) A dehydrated product 6 was obtained in less than 13% yield.
N
more smoothly to give 3a in 54% yield (Entry 4). The reaction
using n-Bu2Mg gave a butylated by-product 414 in addition to
the desired product 3a (Entry 5). Generation of aluminum
alkoxide by the treatment with Me3Al or Et2AlCl was also
effective to give 3a in 48% or 29% yield, respectively (Entries
6 and 7). Zinc reagents, Me2Zn and MeZnBr, and titanium
alkoxide, (i-PrO)4Ti were not effective at all (Entries 8-10). In
the case of (i-PrO)3Sm, the expected cyanation itself proceed-
ed, but was followed by the dehydration to give an imine 515
in less than 17% yield (Entry 11).
6
CN
t-butyl-substituted nitrones 1e and 1f also proceeded smoothly
(Entries 5 and 6). The substituents on the nitrogen atom of
nitrone 1 did not affect the reaction (Entries 7 and 8).
Cyanation of a cyclic nitrone, 3,4-dihydroisoquinoline N-oxide
(1i), was sluggish and gave a dehydrated imine 65c in poor
yield (Entry 9).
Next the Strecker-type reaction of nitrone 1a was carried out
with acetone cyanohydrin (2A) and 1.0 equiv of n-BuMgCl in
other solvents. Among the solvents examined, THF realized the
highest chemical yield as shown in Table 2. When n-BuMgCl
was treated with cyanohydrin 2A in THF, the solution became
cloudy probably due to the formation of chloromagnesium
salt of 2A. However, after the addition of the nitrone 1a, the
reaction mixture gradually became clear. In order to promote
the reaction, temperature was raised up to 35 °C. The product
3a was obtained in 81% yield (Entry 6). Enhancement of the
temperature to 60 °C did not improve the chemical yield any
more (Entry 7). Furthermore, the amount of n-BuMgCl could
be decreased to 0.2 equiv producing 3a in 90% yield (Entry 8),
however, the use of less n-BuMgCl lowered the chemical yield
remarkably (Entry 9). As a cyanide source, cyclohexanone
cyanohydrin (2B) was not so effective (Entries 10 and 11):
Even when 1.0 equiv of n-BuMgCl was used, the yield of 3a
was only 60%.
The magnesium-mediated Strecker-type cyanation of various
nitrones 1 was performed with 1.0 equiv of acetone cyano-
hydrin (2A) and 0.2 equiv of n-BuMgCl in THF at 35 °C,
and the results are summarized in Table 3. The reaction of
p-methoxy- and p-chloro-substituted nitrones on aromatic ring
1b and 1c gave the products 3b and 3c in good yields (Entries 2
and 3). In the case of nitrone 1d derived from acetaldehyde,
the Strecker-type reaction proceeded well to afford the product
3d in 98% yield (Entry 4). The cyanation of cyclohexyl- and
In order to prepare the 1-cyano-substituted isoquinoline
skeleton, other acceptors were surveyed. It was found that an
azomethine imine 716 instead of the nitrone 1i afforded the
corresponding ¡-cyanated product 8 without elimination in
good yield (eq 1).
OH
N
NC
NBz
(1.0 equiv)
(1.0 equiv)
7
2A
n-BuMgCl (n equiv)
THF, 35 °C, t h
ð1Þ
N
NHBz
(Bz = COPh)
CN
8
n = 1.0 15 h
0.3 18 h
93%
80%
58%
0.2 18 h
For the present Strecker-type reaction, two types of mech-
anism might be possible; one is a cyclic transfer mechanism
A and another is a mechanism B via magnesium cyanide
generated from chloromagnesium salt of cyanohydrin accom-
panied by release of the corresponding ketone. In order to
confirm the mechanism, the Strecker-type reaction was carried
out using optically active (R)-mandelonitrile (2C). When 2C

T. Sakai et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 2 (2012)
Table 4. Reactions of Cyanohydrins 2 with 2 equiv of Grignard Reagent
233
OH
OMgCl
MgCl
MgCl
R
R
R
R
Ph
Ph
NC
NC
THF, 0 °C
(1.0 equiv)
(2.0 equiv)
(1.0 equiv)
(1.0 equiv)
2
O
OH
MgCl
MgCl(CN)
R
R
Ph
R
R
Ph
35 °C, Time
9
Entry
R
R
Time/h
Yield of 9/%
1
2
3
CH3
CH3
CH3
CH3
A
A
B
16
26
16
55
52
94
-(CH2)5-
was treated with 0.2 equiv of n-BuMgCl, transcyanation to 1a
did not proceed.17 Therefore 1.0 equiv of n-BuMgCl was used
toward (R)-2C, but the resulting adduct 3a obtained in 33%
yield was racemic and chiral induction was not observed
(eq 2). This result seemed to support the mechanism B.
Table 5. The Transcyanation by Pretreatment of Cyano-
hydrin 2 with n-BuMgCl
Bn
O
N
H
Ph
1a
Bn
OH
Ph
OH
R
n-BuMgCl (1.0 equiv)
THF, 35 °C, 24 h
(1.0 equiv)
Cl
N
R
Bn
H
O
Bn
H
O
Mg
N
NC
O
N
MgCl
35 °C, Time
NC
R
C
N
3a
C
N
(1.0 equiv)
1
1
R
R
R
2
A
B
Entry
R
R
2
Time/h
Yield/%
Bn
H
O
Bn
OH
Ph
OH
n-BuMgCl (1.0 equiv)
THF, 35 °C, 14 h
N
N
1
2
CH3
-(CH2)5-
CH3
A
B
26
20
84
73
Ph
ð2Þ
NC
H
Ph
NC
33%, 0% ee
(1.0 equiv)
(1.0 equiv)
1a
2C
3a
In order to get further information, several reactions were
carried out. First, cyanohydrins 2 were treated with 2 equiv of
chloro(2-phenylethyl)magnesium. If chloromagnesium cyanide
is generated with the release of ketones, the ketones could be
trapped by excess Grignard reagent to give tertiary alcohols 9.
In the case of acetone cyanohydrin (2A), the alcohol 9A18a was
obtained in 55% yield after 16 h. However, the production of
9A was not increased after 26 h (Table 4, Entries 1 and 2). In
the case of cyclohexanone cyanohydrin (2B), 9B18b was
obtained in over 90% yield after 16 h (Entry 3). These results
suggested that chloromagnesium cyanide was produced in
ca. 50% yield from 2A and almost quantitatively from 2B,
respectively.
In the reaction using 0.2 equiv of Grignard reagent,
regeneration of the chloromagnesium salt of cyanohydrin by
the reaction of the produced chloromagnesium salt of 3 with
unreacted cyanohydrin makes the catalytic cycle possible.
As described above, the efficient Strecker-type reaction of
nitrones using acetone cyanohydrin could be developed.
Transformation of acetone cyanohydrin into its chloromagne-
sium salt by treating with n-BuMgCl was effective to afford the
cyanated products in high yields. In the case of 3,4-dihydro-
isoquinoline derivative, the corresponding azomethine imine
instead of the nitrone was the suitable substrate for the present
cyanation to afford the ¡-cyanotetrahydroisoquinoline com-
pound in good chemical yield.
Next, the Strecker-type reaction was performed by pretreat-
ment of cyanohydrins 2 with Grignard reagent at 35 °C for 24 h
to produce chloromagnesium cyanide before the addition of the
nitrone. In the case of acetone cyanohydrin (2A), the reaction
appeared to proceed similarly and it took almost the same
reaction time to complete the reaction (Table 5, Entry 1 and
Table 2, Entry 6). By the use of cyclohexanone cyanohydrin
(2B), from which chloromagnesium cyanide might be gener-
ated in situ almost quantitatively, chemical yield was enhanced,
but still lower than that using 2A (Table 5, Entry 2 and
Table 2, Entry 10).
Experimental
The 1H NMR spectra were recorded on a JEOL ECS
400 NMR (400 MHz) spectrometer. The chemical shifts were
determined in the ¤-scale relative to TMS (¤ = 0) as an inter-
nal standard. The IR spectra were measured on a JASCO
FT/IR-230 spectrometer. THF and Et2O were freshly distilled
over sodium diphenyl ketyl. All other solvents were distilled
and stored over drying agents. Merck silica gel 60 PF254 (Art.
7749) and Cica silica gel 60N, spherical neutral (37563-84)
were used for thin-layer chromatography (TLC) and flash
column chromatography, respectively. All of the melting points
were determined with a micro melting apparatus (Yanagimoto-
Seisakusho) and are uncorrected.
Although the precise mechanism is still not fully understood,
the present reaction would proceed via both transition states
A and B based on the results described above.

234
Bull. Chem. Soc. Jpn. Vol. 85, No. 2 (2012)
Strecker-Type Reaction of Nitrones
A Representative Procedure for the Strecker-Type Re-
action of 1a. To a solution of acetone cyanohydrin (2A)
(43 mg, 0.5 mmol) in THF (3 mL), a solution of n-BuMgCl in
THF (0.91 M, 0.11 mL, 0.1 mmol) was added at 0 °C under an
argon atmosphere, and the mixture was allowed to stir for 1 h.
The reaction mixture was warmed to 35 °C, and a solution
of (Z)-benzyl(benzylidene)amine N-oxide (1a) (106 mg, 0.5
mmol) in THF (3 mL) was added. After 23 h, the reaction was
quenched with a saturated aqueous solution of NaHCO3 and
extracted with AcOEt. The combined organic extracts were
washed with brine, and then dried over Na2SO4. The solvent
was evaporated and the residue was separated by TLC on SiO2
(Hexane/AcOEt = 3/1, v/v) to afford 3a (107 mg, 0.45 mmol)
in 90% yield as a white solid.
J = 12.6 Hz), 4.14 (d, 1H, J = 12.6 Hz), 5.09 (br, 1H), 7.27-
7.35 (m, 5H). Found: C, 71.31; H, 8.41; N, 12.67%. Calcd for
C13H18N2O: C, 71.53; H, 8.31; N, 12.83%.
2-[Hydroxy(methyl)amino]-2-phenylacetonitrile
(3g):
Mp 118-119 °C (from i-PrOH). IR (KBr): 3242, 2968, 2930,
2883, 2241, 1496, 1455, 1422, 1138, 1060, 967, 939, 748,
696 cm¹1. 1H NMR (CDCl3): ¤ 2.68 (s, 3H), 4.84 (s, 1H), 5.95
(br, 1H), 7.38-7.45 (m, 3H), 7.48-7.50 (m, 2H). Found: C,
66.61; H, 6.30; N, 17.16%. Calcd for C9H10N2O: C, 66.65; H,
6.21; N, 17.27%.
2-[Hydroxy(phenyl)amino]-2-phenylacetonitrile
(3h):
Mp 120-121 °C (from i-PrOH). IR (KBr): 3271, 3054, 2245,
¹1
1594, 1489, 1454, 1187, 1170, 1010, 947, 768, 738 cm
.
1H NMR (CDCl3): ¤ 5.38 (s, 1H), 5.56 (br, 1H), 7.15 (t, 1H,
J = 7.3 Hz), 7.26 (d, 2H, J = 8.2 Hz), 7.35 (dd, 2H, J = 8.2,
7.3 Hz), 7.41-7.51 (m, 3H), 7.54-7.60 (m, 2H). Found: C,
75.13; H, 5.46; N, 12.48%. Calcd for C14H12N2O: C, 74.98; H,
5.39; N, 12.49%.
In a similar manner, ¡-cyanohydroxylamines 3b-3h and
1-cyanotetrahydroisoquinoline derivative 8 were prepared from
the corresponding nitrones 1b-1h and azomethine imine 7,
respectively.
2-[Benzyl(hydroxy)amino]-2-phenylacetonitrile
(3a):
N-[1-Cyano-3,4-dihydroisoquinolin-2(1H)-yl]benzamide
Mp 116-117 °C (from i-PrOH). IR (KBr): 3400, 2919, 2864,
2245, 1604, 1496, 1453, 1070, 1031, 1011, 757, 740, 693
cm¹1. 1H NMR (CDCl3): ¤ 3.87 (s, 2H), 4.72 (s, 1H), 5.91 (br,
1H), 7.30-7.39 (m, 5H), 7.40-7.43 (m, 3H), 7.45-7.48 (m, 2H).
Found: C, 75.42; H, 6.00; N, 11.46%. Calcd for C15H14N2O: C,
75.61; H, 5.92; N, 11.76%.
(8): Mp 146-147 °C (from AcOEt). IR (KBr): 3207, 3050,
¹1
2225, 1640, 1536, 1454, 1311, 921, 769, 745, 728, 692 cm
.
1H NMR (CDCl3): ¤ 1.63 (br, 1H), 2.94-3.00 (m, 1H), 3.28-
3.37 (m, 2H), 3.51-3.57 (m, 1H), 5.50 (s, 1H), 7.19-7.33
(m, 4H), 7.47 (t, 2H, J = 7.3 Hz), 7.56 (t, 1H, J = 7.3 Hz), 7.82
(d, 2H, J = 7.3 Hz). Found: C, 73.74; H, 5.52; N, 15.14%.
Calcd for C17H15N3O: C, 73.63; H, 5.45; N, 15.15%.
2-[Benzyl(hydroxy)amino]-2-(4-methoxyphenyl)aceto-
nitrile (3b): Mp 98-100 °C (from i-PrOH). IR (KBr): 3426,
¹1
2234, 1612, 1513, 1456, 1244, 1021, 804, 751, 699 cm
.
The present work was financially supported in part by Grant-
in-Aid for Scientific Research (C) from Japan Society for the
Promotion of Science (JSPS).
1H NMR (CDCl3): ¤ 3.77 (s, 3H), 3.81 (s, 2H), 4.59 (s, 1H),
6.23 (br, 1H), 6.89 (d, 2H, J = 8.7 Hz), 7.27-7.35 (m, 7H).
Found: C, 71.69; H, 6.06; N, 10.39%. Calcd for C16H16N2O2:
C, 71.62; H, 6.01; N, 10.44%.
References
2-[Benzyl(hydroxy)amino]-2-(4-chlorophenyl)acetonitrile
(3c): Mp 114-116 °C (from i-PrOH). IR (KBr): 3366, 3030,
2911, 2844, 2251, 1600, 1578, 1494, 1405, 1094, 795, 757,
727, 700 cm¹1. 1H NMR (CDCl3): ¤ 3.88 (d, 1H, J = 12.6 Hz),
3.96 (d, 1H, J = 12.6 Hz), 4.74 (s, 1H), 5.64 (br, 1H), 7.28-
7.41 (m, 9H). Found: C, 66.04; H, 4.83; N, 10.20%. Calcd for
C15H13N2OCl: C, 66.06; H, 4.80; N, 10.27%.
1
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S. H. R. Abdi, S. Agrawal, R. V. Jasra, Coord. Chem. Rev. 2008,
252, 593.
2-[Benzyl(hydroxy)amino]propanenitrile (3d): Mp 97-
2
L. M. Weinstock, P. Davis, B. Handelsman, R. Tull, J. Org.
99 °C (from i-PrOH). IR (KBr): 3237, 3033, 2944, 2899,
¹1
Chem. 1967, 32, 2823; W. L. Matier, D. A. Owens, W. T. Comer,
D. Deitchman, H. C. Ferguson, R. J. Seidehamel, J. R. Young,
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2238, 1496, 1457, 1446, 1376, 1113, 829, 739, 701 cm
.
1H NMR (CDCl3): ¤ 1.44 (d, 3H, J = 7.3 Hz), 3.65 (q, 1H,
J = 7.3 Hz), 3.80 (d, 1H, J = 12.4 Hz), 3.99 (d, 1H, J =
12.4 Hz), 6.17 (br, 1H), 7.27-7.37 (m, 5H). Found: C, 68.28;
H, 6.85; N, 15.91%. Calcd for C10H12N2O: C, 68.16; H, 6.86;
N, 15.90%.
2-[Benzyl(hydroxy)amino]-2-cyclohexylacetonitrile (3e):
Mp 124-125 °C (from i-PrOH). IR (KBr): 3402, 2929, 2851,
¹1
2242, 1495, 1452, 1408, 738, 698 cm
.
1H NMR (CDCl3):
¤ 0.83-0.93 (m, 1H), 0.97-1.07 (m, 1H), 1.10-1.34 (m, 3H),
1.66-1.89 (m, 4H), 1.99-2.05 (m, 2H), 3.26 (d, 1H, J =
10.1 Hz), 3.82 (d, 1H, J = 12.8 Hz), 4.09 (d, 1H, J = 12.8 Hz),
5.42 (br, 1H), 7.28-7.34 (m, 5H). Found: C, 73.55; H, 8.29; N,
11.37%. Calcd for C15H20N2O: C, 73.74; H, 8.25; N, 11.47%.
2-[Benzyl(hydroxy)amino]-3,3-dimethylbutanenitrile (3f ):
Mp 112-113 °C (from i-PrOH). IR (KBr): 3418, 2965, 2889,
3
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