Catalyst-free Strecker reaction in water: A simple and efficient protocol using acetone cyanohydrin as cyanide source

Article abstract of DOI:10.1002/ejoc.201100089

A simple, convenient, and practical method for the synthesis of α-amino nitriles through a one-pot, three-component Strecker reaction of a carbonyl compound, amine, and acetone cyanohydrin in water has been developed. Reactions proceed very efficiently without any catalyst at room temperature with high chemoselectivity and give, in some cases, the expected α-amino nitrile pure after direct separation from water. The protocol is particularly efficient for both aliphatic and aromatic aldehydes, and cyclic ketones, in combination with primary and secondary amines. An unusual application of the Strecker reaction to 1,2-diamines to obtain 1,2-diamino nitriles, and to cyclic secondary amines is reported. Copyright

Full text of DOI:10.1002/ejoc.201100089

FULL PAPER
DOI: 10.1002/ejoc.201100089
Catalyst-Free Strecker Reaction in Water: A Simple and Efficient Protocol
Using Acetone Cyanohydrin as Cyanide Source
Paola Galletti,*[a] Matteo Pori,[a] and Daria Giacomini*[a]
Keywords: Multicomponent reactions / Aldehydes / Ketones / Amines / Cyanides
A simple, convenient, and practical method for the synthesis
of α-amino nitriles through a one-pot, three-component
Strecker reaction of a carbonyl compound, amine, and acet-
one cyanohydrin in water has been developed. Reactions
proceed very efficiently without any catalyst at room tem-
perature with high chemoselectivity and give, in some cases,
the expected α-amino nitrile pure after direct separation from
water. The protocol is particularly efficient for both aliphatic
and aromatic aldehydes, and cyclic ketones, in combination
with primary and secondary amines. An unusual application
of the Strecker reaction to 1,2-diamines to obtain 1,2-diamino
nitriles, and to cyclic secondary amines is reported.
Introduction
ethylamine as catalyst.[11] Paraskar and Sudalai reported
the use of acetone cyanohydrin in a one-pot amino nitrile
synthesis in organic solvents with a base as catalyst.[15]
The original protocol developed by Strecker used water
as reaction solvent, but, in modified Strecker protocols,
water was replaced by organic solvents, such as toluene,
dichloromethane, or acetonitrile, especially with TMSCN
as cyanide source, to improve the solubility of organic rea-
gents. As an example of the use of nonconventional sol-
vents, a Strecker reaction in ionic liquid was also re-
ported.[16] These modifications significantly improved the
performance of the reaction in terms of yields and reaction
time, but, in some cases, the modified protocols required
tedious workup to separate toxic Lewis acids as well as their
hydrolysis products and organic solvents, leading to the
generation of a large amount of waste. Therefore, there was
scope to develop milder conditions to render the Strecker
reaction even more attractive.
The Strecker reaction was a milestone in organic synthe-
sis and is still the classical method used to obtain α-amino
nitriles,[1] which, in turn, are very important precursors of
natural and non-natural α-amino acids,[2] 1,2-amino
alcohols, 1,2-diamines, and intermediates for several trans-
formations.[3] The classical Strecker reaction is a three-com-
ponent reaction between a carbonyl compound, ammonia,
and an alkaline cyanide, and is usually performed in aque-
ous solution; in terms of atom economy the reaction is a
model.[4] Several modifications of the original protocol have
been reported, and these are referred to as modified
Strecker reactions. Such modifications concern the cyanide
source, the presence of a catalyst, and the reaction solvent.
Hydrogen cyanide (HCN) is the most straightforward cy-
anating agent, but its toxicity and volatility severely limits
its widespread and practical application in organic synthe-
sis. To avoid the use of toxic HCN, a variety of cyanating
agents, such as trimethylsilyl cyanide (TMSCN),[5] (EtO)2P-
(O)CN,[6] Et2AlCN,[7] Bu3SnCN,[8] MeCOCN,[9] K4[Fe-
(CN)6],[10] and acetone cyanohydrin,[11] have been used.
TMSCN is widely used in the Strecker reaction, but
Brönsted or Lewis acids or bases are often required as cata-
lysts.[12] Interestingly, solvent- and/or catalyst-free condi-
tions with TMSCN were recently reported.[13] Acetone
cyanohydrin in water is frequently used in chemoenzymatic
synthesis of cyanohydrines through transhydrocyanation,[14]
but, surprisingly, it has found few applications in the
Strecker reaction. A recent application in a synthesis of
amino nitriles was reported starting from aldimine alanes
generated in situ from diisobutylaluminium hydride and tri-
As part of our interest in chemoenzymatic syntheses,[17]
we recognized the advantages of using acetone cyanohydrin
in water for a one-pot Strecker protocol under catalyst-free
conditions, and here we report our results. We optimized
the reaction protocol with three model aldehydes and
benzylamine, then explored the scope of the reaction with
a series of α-amino nitriles and with an unusual application
of the Strecker reaction on 1,2-diamines and secondary
amines (Scheme 1).
[a] Department of Chemistry “G. Ciamician”, University of
Bologna,
Via Selmi 2, 40126 Bologna, Italy
Fax: +39-051-2099456
E-mail: paola.galletti@unibo.it
daria.giacomini@unibo.it
Scheme 1. Three-component Strecker reaction.
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Catalyst-Free Strecker Reaction in Water
solution to give the amino nitrile B of acetone; (iii) it can
react with the starting aldehyde to give the corresponding
cyanohydrin C (Figure 2). The latter route can be regarded
as a competitive transcyanation reaction between acetone
cyanohydrin and the aldehyde. We began our investigation
by studying the multicomponent reaction with acetone
cyanohydrin under catalyst-free conditions with benzyl-
amine and tested three aldehydes: benzaldehyde, butanal,
and racemic 2-phenylpropanal (a model for a chiral compo-
nent).
Results and Discussion
Acetone cyanohydrin is an important chemical interme-
diate[18] for the manufacture of methacrylates; it is inexpen-
sive and is a large-scale, commercially available cyanide
source.[19] Acetone cyanohydrin is highly soluble in water,
where its dissociation to give acetone and hydrogen cyanide
reaches equilibrium in 18 h.[20] In the presence of an amine,
establishment of the equilibrium is almost instantaneous.[21]
In an attempt to reproduce one-pot Strecker reaction condi-
tions and to study the influence of the parent amine and
of the corresponding imine intermediate, we monitored the
1
dissociation of acetone cyanohydrin in D2O by H NMR
analysis following the formation of acetone, and tested the
effect of additives such as benzylamine and its imine with
benzaldehyde (N-benzylidene-1-phenylmethanamine). In an
NMR tube, acetone cyanohydrin (10 μL) was added to D2O
1
(0.7 mL), and a H NMR spectrum was quickly recorded.
The reaction time course was sampled every 5 min for a
total time of 35 min. The same conditions were used with
5 mol-% benzylamine or the imine N-benzylidene-1-phenyl-
methanamine. The data were obtained by digital integration
of the acetone signal (Ia at δ = 2.11 ppm), which was com-
pared to the integration of the acetone cyanohydrin signal
(Iac at δ = 1.51 ppm) and were plotted as the ratio Ia/Iac
against time (Figure 1). The data clearly showed that the
equilibrium conditions were established more rapidly in the
presence of additives than in D2O alone. The presence of
either benzylamine or imine facilitated rapid acetone cya-
nohydryn decomposition in situ, thus establishing suitable
conditions for an efficient one-pot Strecker reaction.
Figure 2. Competitive reactions in a one-pot Strecker synthesis
with acetone cyanohydrin in water.
The reaction was tested in a series of solvents, binary
aqueous mixtures, and neat conditions. Reactions were car-
ried out in closed vials to minimize the loss of volatiles and
stirred in an orbital shaker. The crude reaction mixtures
from reactions carried out in organic solvents were directly
concentrated and analyzed; those in water were extracted
into ethyl acetate. In Table 1, Entries 1–20, the amount of
acetone cyanohydrin was 1.5 equiv. with respect to the car-
bonyl compound, whereas it was reduced to 1 equiv. in En-
tries 22–24. Reactions were monitored by either HPLC or
NMR analysis, and the reaction times reported in Table 1
correspond to a maximum conversion of the starting alde-
hyde.
In the organic solvents (CH2Cl2, tBuOMe, and CH3CN),
the yields of amino nitriles 1–3 ranged from moderate to
poor (Table 1, Entries 1–9). With benzaldehyde, the imine
intermediate A (see Figure 2) was recovered in a significant
amount and, in the case of tBuOMe, it was the only product
(Table 1, Entry 4). With butanal and 2-phenylpropanal, the
by-products B and C were also recovered (Table 1, En-
tries 2, 3, 5, 8, and 9). Under neat conditions without any
Figure 1. Effect of additives on the decomposition of acetone
cyanohydrin in D2O. Dependence of the ratio of integrals for the
resonance lines of acetone Ia and acetone cyanohydrin Iac over time. solvent, the reactions were very fast, but only 2-phenyl-
Data in D2O (dots), D2O and 5 mol-% BnNH2 (triangles), D2O
and 5 mol-% N-benzylidene-1-phenylmethanamine (squares).
propanal gave the α-amino nitrile 3 in almost quantitative
yield; benzaldehyde gave 1 in 53% yield with 46% recovery
of the unreacted imine. Butanal gave 2 in 30% yield to-
Decomposition of acetone cyanohydrin in water gives gether with a series of unidentified by-products, perhaps
HCN, which, in a one-pot procedure, can participate in due to aldehyde polymerization (Table 1, Entries 10–12).
three concurrent and competitive reaction pathways: (i) it Better results were obtained with homogeneous or biphasic
can react with the imine intermediate A (Figure 2) to give solvent mixtures composed of an organic solvent and water.
the expected Strecker amino nitrile; (ii) it can react with The biphasic mixture tBuOMe/H2O (1:1) gave good results,
the ketimine derived from acetone and the amine present in with lower amounts of by-product, except for the reaction
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P. Galletti, M. Pori, D. Giacomini
Table 1. Optimization of reaction conditions for the one-pot Strecker reaction with acetone cyanohydrin.[a]
FULL PAPER
Entry
R
Solvent
Time [h]
Product (yield [%])
By-product (yield [%])
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Ph
Bu
CH2Cl2
CH2Cl2
CH2Cl2
tBuOMe
tBuOMe
tBuOMe
CH3CN
CH3CN
CH3CN
Neat
20
20
20
20
20
20
20
20
20
0.5
0.5
0.5
2
1 (76)
2 (76)
3 (76)[b]
1 (0)
A (24)
B (20)
CH(CH3)Ph
B (10)
A (99)
B (33), C (33)
Ph
Bu
2 (33)
3 (20)
1 (36)
2 (67)
3 (68)[b]
1 (54)
2 (30)
3 (99)
1 (67)
2 (90)
3 (87)
1 (99)
2 (93)
3 (99)
1 (96)
2 (90)
3 (90)[b]
1 (99)
2 (99)
3 (99)[d]
CH(CH3)Ph
n.d.
A (64)
B (33)
Ph
Bu
CH(CH3)Ph
B (11), C (12)
Ph
Bu
A (46)
n.d
–
Neat
Neat
CH(CH3)Ph
Ph
Bu
tBuOMe/H2O
tBuOMe/H2O
tBuOMe/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
H2O
A (12), B (8), C (12)
2
2
B (5)
CH(CH3)Ph
B (4), C (9)
Ph
0.5
0.5
0.5
2
0.5
20
2
–
Bu
CH(CH3)Ph
Ph
B (7)
–
–
Bu
H2O
B (10)
CH(CH3)Ph
Ph
H2O
–
–
–
–
H2O[c]
Bu
H2O[c]
20
20
CH(CH3)Ph
H2O[c]
[a] Reagents and conditions: aldehyde (1 mmol), benzylamine (1 mmol), acetone cyanohydrin (1.5 mmol), solvent (4 mL), room temp. See
notes for exceptions. [b] Traces of acetophenone derived from decomposition of the starting aldehyde.[17a] [c] 1 mmol acetone cyanohydrin.
[d] Diastereomeric ratio 65:35 determined by HPLC analysis on a chiral column of the trifluoroacetamide derivatives (IC, hexane/iPrOH,
85:15).
with benzaldehyde (Table 1, Entries 13–15). However, the often used as a model aldehyde in nucleophilic addition re-
amount of by-products A, B, and C were further reduced actions, did not work; however, arylaldehydes bearing elec-
by using the homogeneous solvent mixture CH3CN/H2O tron-donating groups gave better results (Table 2, Entry 14
(1:1), in which the reaction was even faster (30 min for com- vs. Entries 9 and 12). Salicylaldehyde and 4-hydroxybenzal-
plete conversion; Table 1, Entries 16–18). Finally, we tested dehyde gave interesting results under neat conditions with
the reaction protocol in water alone and found that, al- 2 equiv. of acetone cyanohydrin (Table 2, Entries 8 and 11);
though the reaction mixture was heterogeneous, it afforded however, better results were obtained when the phenol
α-amino nitriles in high yields. Benzaldehyde and 2-phenyl- group was protected as the methoxy derivative (Table 2, En-
propanal gave good results, whereas butanal gave a residual try 9). Aniline and 1,2-benzenediamine gave modest yields
amount of the benzylamino nitrile of acetone, by-product with benzaldehyde and no reaction with butanal (Table 2,
B (Table 1, Entries 19–21). By reducing the amount of acet- Entries 1, 2, and 19). When yields were not quantitative, no
one cyanohydrin to 1 equiv., all three aldehydes were ef- traces of the amino nitrile B of acetone or cyanohydrines
ficiently transformed into the corresponding α-amino ni- C were detected in the reaction mixtures. Recognized by-
triles 1–3 in high overall yields and with the suppression of products included the starting aldehydes, unreacted inter-
the by-product B (Table 1, Entries 22–24).
mediate imines A, or autocondensation products of enoliz-
The experimental conditions were thus standardized to able aldehydes. The reaction of 1,2-ethylenediamine was
carbonyl compound, amine, and acetone cyanohydrin, successful with both benzaldehyde and butanal, giving the
which were used in a 1:1:1 molar ratio, and the scope was corresponding diamino nitriles as a 1:1 diastereomeric mix-
widened to include further amines, carbonyl components, ture (Table 2, Entries 3 and 16). Piperidine, as a model for
aldehydes (Table 2) or ketones (Table 3).
a secondary amine, gave excellent results (Entries 5 and 21),
Benzylamine and allylamine gave excellent results with whereas morpholine and piperazine gave lower yields (En-
benzaldehyde and aliphatic aldehydes (Table 1, Entries 22 tries 4, 6, 20, and 22). Remarkably, no traces of mono-α-
and 23; Table 2, Entries 17, 23, and 24); in particular, pival- amino nitriles were detected in the reaction with diamines.
aldehyde (Entry 24) is of great importance, because hydroly-
It is noteworthy that the majority of substrates and prod-
sis of its α-amino nitrile gives access to the non-natural ucts were not soluble in water. Complete reactions and ex-
amino acid tert-leucine. p-Nitrobenzaldehyde, which is cellent yields of the desired products reflect the fact that the
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Catalyst-Free Strecker Reaction in Water
Table 2. One-pot Strecker reaction in water with 1 equiv. of acetone cyanohydrin in combination with aliphatic and aromatic aldehydes
and primary and secondary amines.[a]
[a] Reagents and conditions: aldehyde (1 mmol), amine (1 mmol) or diamine (0.5 mmol), acetone cyanohydrin (1 mmol), water (4 mL),
room temp., 20 h. [b] For compounds 5, 6, 9, 17, and 23 the diastereomeric ratio refers to the meso stereoisomer vs. the racemic pair;
configurations were not assigned. [c] Neat conditions, 2 equiv. of acetone cyanohydrin.
substrates efficiently react without the aid of an organic co-
solvent. Enforced hydrophobic interactions could play a pound that, in the one-pot procedure, worked either as the
significant role here.[22]
amino component with butanal to afford α-amino nitrile
Piperidin-4-one is a quite interesting bifunctional com-
Dialkyl and alkyl aryl ketones gave unsatisfactory results 26, or as the carbonyl component with benzylamine to give
(Table 3 Entries 1–8), but cyclic ketones gave excellent 36 (Scheme 2; Table 2, Entry 25; Table 3, Entry 15).
yields, which is in line with the reactivity and the internal
With increasing concern for the environment, the need
strain effect (I-strain) of linear versus cyclic ketones in nu- for more sustainable synthetic methods has become of sig-
cleophilic addition reactions (Table 3, Entries 9, 10, and 12– nificant importance for reactions on any scale, from indus-
14).[23] Cyclohexenone did not react under these conditions, try to academia. Unquestionably, all cyanide sources are
either in 1,2 or 1,4 reaction modes (Table 3, Entry 11).
potentially noxious and must be used with precautions due
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P. Galletti, M. Pori, D. Giacomini
FULL PAPER
Table 3. One-pot Strecker reaction in water with 1 equiv. of acetone absence of catalysts, the use of water, and the straightfor-
cyanohydrin in combination with ketones and benzylamine.[a]
ward procedure. In particular, the use of 1 equiv. of acetone
cyanohydrin to obtain α-amino nitriles in high to optimum
yields with acetone as the unique by-product makes this
protocol more competitive from the atom economy point
of view than any other cyanide source, including TMSCN,
which is also much more expensive. HCN would be more
favorable but, unquestionably, liquid acetone cyanohydrin
is easier to quantify and handle than gaseous HCN. In or-
der to reduce the environmental impact of the overall pro-
cess as much as possible, another important favorable as-
pect of the protocol is the possibility to completely avoid
the use of organic solvents, even in the workup and isola-
tion of the products. The heterogeneous reaction conditions
used in this procedure have the additional advantage that,
at the end of reaction, the product can be removed by a
simple phase separation. When the one-pot reaction in
water is scaled up to 4 mmol, extraction with an organic
solvent was no longer necessary because the hydrophobic
nature of the liquid products allowed them to be separated
from the water and dried under reduced pressure; solid
products were simply filtered off and dried (Figure 3). Scal-
ing up with no workup was tested with a number of sub-
strates to give the expected products with unaltered yields
(Table 1, Entry 24; Table 2, Entries 2, 16, 19, 20, 22; Table 3,
Entry 13).
[a] Reagents and conditions: ketone (1 mmol), benzylamine
(1 mmol), acetone cyanohydrin (1 mmol), H2O (4 mL). [b] For
compounds 33, 34 and 35, diastereomeric ratio refers to trans vs.
cis stereoisomers. [c] 1.5 equiv. of acetone cyanohydrin.
Figure 3. Examples of heterogeneous reaction conditions for the
scaled-up, one-pot Strecker synthesis with acetone cyanohydrin in
water; reaction product 3 (left); 34 (centre), and 16 (right).
Conclusions
We have demonstrated a simple, convenient, and practi-
cal method for the synthesis of racemic α-amino nitriles
through a one-pot, three-component Strecker reaction of a
carbonyl compound, an amine, and acetone cyanohydrin in
water. Reactions proceeded very efficiently at room tem-
perature with high selectivity and gave, in some cases, the
expected α-amino nitrile pure by direct separation from
water. The mild reaction conditions and the operational
simplicity make this atom-economic cyanation process ex-
Scheme 2. Reaction with piperidin-4-one.
to the high toxicity of HCN that can be released. However, tremely attractive to the development of cleaner and envi-
the protocol developed here has several favorable aspects ronmentally more friendly processes for the synthesis of α-
concerning the atom economy of the reaction as well the amino nitriles of synthetic importance. Moreover, in view
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Catalyst-Free Strecker Reaction in Water
2.98 (m, 4 H, NCH2CH2N), 4.76 (s, 2 H, 2 CHCN), 7.33–7.45 (m,
10 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 46.0, 46.2 (2nd
diastereoisomer), 54.1, 54.2 (2nd diastereoisomer), 118.7, 127.2,
of the importance of natural and unnatural α-amino acids
in the fine chemicals and pharmaceutical industries, the
current methodology offers the possibility of utilizing the
Strecker reaction economically for large-scale syntheses.
129.0, 129.1, 134.5 ppm. IR: ν = 3330, 2223 cm–1.
˜
{4-[(Cyano)(phenyl)methyl]piperazin-1-yl}(phenyl)acetonitrile
(9):
Yield: 70%; major stereoisomer; oil. 1H NMR (400 MHz, CDCl3):
δ = 2.60–2.70 (m, 8 H, 2 NCH2CH2), 4.88 (s, 1 H, CHCN), 4.90
(s, 1 H, CHCN), 7.35–7.45 (m, 6 H, ArH), 7.52–7.57 (m, 4 H, ArH)
ppm. 13C NMR (100 MHz, CDCl3): δ = 49.3 (broad signal), 61.9,
Experimental Section
General: Commercial reagents were used as received without ad-
ditional purification, N-benzyl-4-piperidone was prepared accord-
ing to the literature.[24] 1H and 13C NMR spectra were recorded
with an INOVA 400 or a GEMINI 200 instrument with a 5 mm
probe. All chemical shifts are quoted relative to deuterated solvent
signals (δ in ppm and J in Hz). FTIR spectra were recorded with
a Thermo Nicolet 380 instrument and measured as films between
NaCl plates; wave numbers are reported in cm–1. TLC was con-
ducted with Merck 60 F254 plates. Column chromatography was
conducted with Merck silica gel 200–300 mesh. GC-MS was con-
ducted with an Agilent Technologies MSD1100 single-quadrupole
mass spectrometer, EI voltage 70 eV, gradient from 50 to 280 °C in
30 min, column HP5 5% Ph-Me Silicon. HPLC-MS was conducted
with an Agilent Technologies HP1100 instrument, with a ZOB-
RAX-Eclipse XDB-C8 Agilent Technologies column; mobile
phase: H2O/CH3CN, gradient from 30 to 80% of CH3CN in 8 min,
80% of CH3CN until 25 min, 0.4 mL/min, coupled with an Agilent
Technologies MSD1100 single-quadrupole mass spectrometer, full-
scan mode from m/z = 50 to 2600, scan time 0.1 s in positive ion
mode, ESI spray voltage 4500 V, nitrogen gas 35 psi, drying gas
flow 11.5 mL/min, fragmentor voltage 20 V. Elemental analyses
were carried out with a Thermo Flash 2000 CHNS/O Analyzer.
115.2, 127.7, 128.7, 128.9, 132.6 ppm. IR: ν = 2224, 1600 cm–1.
˜
C20H20N4 (316.40): calcd. C 75.92, H 6.37, N 17.71; found C 76.03,
H 6.44, N 17.74. GC-MS: m/z (tr = 25.6 min) = 316 [M]+, 290
[M+ – CN], 200, 116. HPLC-MS: m/z (tr = 10.55 min) = 339 [M +
Na]+, 317 [M + 1]+.
(Benzylamino)(2-hydroxyphenyl)acetonitrile (10): Yield: 65%; oil.
1H NMR (400 MHz, CDCl3): δ = 2.78 (br. s, 1 H, NH), 3.94 (d,
JAB = 12.8 Hz, 1 H, CHHPh), 4.12 (d, JAB = 12.8 Hz, 1 H,
CHHPh), 5.02 (s, 1 H, CHCN), 6.83–6.89 (m, 2 H, ArH), 7.19–
7.37 (m, 7 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 50.6,
51.5, 117.6, 120.2, 125.7, 127.5, 128.2, 128.5, 128.6, 131.0,
156.3 ppm. IR: ν = 3350, 2221, 1620 cm–1. C H N O (238.28):
˜
15 14
2
calcd. C 75.61, H 5.92, N 11.76; found C 75.58, H 5.86, N 11.83.
(Benzylamino)(4-hydroxyphenyl)acetonitrile (12): Yield: 75%;
orange solid; m.p. 79 °C. 1H NMR (400 MHz, CDCl3): δ = 1.82
(br. s, 1 H, NH), 3.86 (d, JAB = 12.8 Hz, 1 H, CHHPh), 3.97 (d,
JAB = 12.8 Hz, 1 H, CHHPh), 4.61 (s, 1 H, CHCN), 6.76 (m, 2 H,
ArH), 7.26–7.33 (m, 7 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 50.9, 52.6, 115.8, 118.9, 125.7, 127.5, 128.2, 128.5,
128.6, 137.6, 156.7 ppm. IR: ν = 3300, 2200, 1654, 1612, 1465 cm–1.
˜
C15H14N2O (238.28): calcd. C 75.61, H 5.92, N 11.76; found C
75.48, H 5.83, N 11.72.
General Procedure for the Synthesis of Amino Nitriles 1–37: The
chosen aldehyde (or ketone) (1 mmol) and amine (1 mmol,
0.5 mmol in the case of diamines) were mixed in an orbital shaker
at room temp. in a 5 mL vial equipped with a screw cap. After
10 min, water (4 mL) and acetone cyanohydrin (1 mmol) were
added, and the cap was closed. The mixture was stirred in an or-
bital shaker for 20 h or until the reaction was complete (TLC moni-
toring). The reaction mixture was poured into brine (5 mL) and
extracted with EtOAc (2ϫ10 mL), dried with Na2SO4, and concen-
trated. When necessary, products were purified by flash chromatog-
raphy. When the reaction was performed on a higher scale, the
workup was not necessary; the product separated from the aqueous
phase when liquid or could be recovered by filtration when solid.
Spectra of amino nitriles 1,[25] 2,[25] 3,[27] 4,[13a] 7,[28] 8,[29] 11,[30]
13,[30] 14,[26] 19,[26] 24,[28] 25,[30] 27,[31] 30,[13b] 31,[32] 34 (trans/cis,
88:12),[13b] and 37[33] were consistent with data reported in the lit-
erature.
(Benzylamino)(pyridin-2-yl)acetonitrile (16): Yield: 98%; oil. 1H
NMR (400 MHz, CDCl3): δ = 2.75 (br. s, 1 H, NH), 3.97 (d, JAB
= 12.8 Hz, 1 H, CHHPh), 4.04 (d, JAB = 12.8 Hz, 1 H, CHHPh),
4.79 (s, 1 H, CHCN), 7.25–7.48 (m, 7 H, ArH), 7.76 (dd, J = 10.0,
10 Hz, 1 H, ArH), 8.60 (d, J = 8.0 Hz, 1 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 51.4, 54.9, 122.0, 123.9, 127.7, 128.5, 128.6,
128.8, 137.4, 138.0, 149.9, 153.7 ppm. IR: ν = 3300, 2228,
˜
1673 cm–1. C14H13N3 (223.27): calcd. C 75.31, H 5.87, N 18.82;
found C 75.44, H 5.94, N 18.98. HPLC-MS: m/z (tr = 7.1 min) =
224 [M + 1]+.
2-({2-[(1-Cyanobutyl)amino]ethyl}amino)pentanenitrile (17): Yield:
65%; mixture of diastereoisomers, dr = 50:50 (determined by GC-
MS analysis of trifluoroacetamide derivatives), diastereoisomers
separated by flash chromatography. 1st diastereoisomer: Oil. 1H
NMR (400 MHz, CDCl3): δ = 0.97 (t, J = 7.2 Hz, 6 H, CH3), 1.47–
1.59 (m, 6 H, NH, CH2), 1.70–1.76 (m, 4 H, CHCH2), 2.72–2.81
(m, 2 H, NCHHCHHN), 2.97–3.05 (m, 2 H, NCHHCHHN), 3.51–
3.56 (m, 2 H, CHCN) ppm. 13C NMR (100 MHz, CDCl3): δ =
13.4, 18.9, 35.3, 35.4, 46.2, 46.8, 50.0, 50.4, 120.1, 120.2 ppm. IR:
[(2-{[(Cyano)(phenyl)methyl]amino}phenyl)amino](phenyl)aceto-
nitrile (5): Yield: 33%; mixture of diastereoisomers, dr = 95:5 (de-
termined by NMR spectroscopy on crude material). Major stereo-
isomer: pale-yellow solid; m.p. 98 °C. 1H NMR (400 MHz, CDCl3):
δ = 3.07 (br. s, 2 H, NH), 5.39 (s, 2 H, CHCN), 7.02–7.05 (m, 2
H, ArH), 7.13–7.29 (m, 6 H, ArH), 7.36–7.42 (m, 3 H, ArH), 7.60–
7.63 (m, 2 H, ArH), 7.80–7.82 (m, 1 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 48.1, 110.5, 119.3, 122.8, 123.1, 125.7,
127.6, 128.6, 128.8, 129.2, 130.0, 135.4, 135.9, 142.1, 153.9 ppm.
ν = 3316, 2225, 1464 cm–1. C H N (222.23): calcd. C 64.83, H
˜
12 22
4
9.97, N 25.20; found C 64.91, H 10.02, N 25.28. HPLC-MS: m/z
(tr = 7.02 min) = 245 [M + Na]+, 223 [M + 1]+, 196 [M – HCN]+.
2nd diastereoisomer: Oil. 1H NMR (400 MHz, CDCl3): δ = 0.98
(t, J = 7.6 Hz, 6 H, CH3), 1.51–1.64 (m, 6 H, NH, CH2), 1.72–1.78
(m, 4 H, CHCH2), 2.74–2.82 (m, 2 H, NCHHCHHN), 3.07–3.00
(m, 2 H, NCHHCHHN), 3.53–3.60 (m, 2 H, CHCN) ppm. 13C
NMR (100 MHz, CDCl3): δ = 13.5, 19.0, 35.4, 35.5, 46.3, 46.9,
IR: ν = 3400, 2232, 1605, 1453 cm–1. C H N (338.41): calcd. C
˜
22 18
4
78.08, H 5.36, N 16.56; found C 77.92, H 5.32, N 16.41.
[(2-{[(Cyano)(phenyl)methyl]amino}ethyl)amino](phenyl)acetonitrile 50.1, 50.5, 120.2, 120.3 ppm. IR: ν = 3312, 2224, 1464 cm–1.
˜
(6): Yield: 99%; mixture of diastereoisomers, dr = 50:50 (deter-
mined by GC-MS analysis on trifluoroacetamide derivatives); oil.
1H NMR (400 MHz, CDCl3): δ = 1.80 (br. s, 2 H, 2 NH), 2.83–
C12H22N4 (222.23): calcd. C 64.83, H 9.97, N 25.20; found C 64.76,
H 9.92, N 25.18. HPLC-MS: m/z (tr = 7.05 min) = 223 [M + 1]+,
196 [M – HCN]+.
Eur. J. Org. Chem. 2011, 3896–3903
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3901

P. Galletti, M. Pori, D. Giacomini
FULL PAPER
1
2-(Allylamino)pentanenitrile (18): Yield: 99%; yellow oil. H NMR 7.6, 29.0, 48.9, 60.5, 121.8, 127.3, 128.3, 128.5, 139.4 ppm. IR: ν =
˜
(400 MHz, CDCl3): δ = 0.90 (t, J = 7.6 Hz, 3 H, CH3), 1.40 (br. s, 3320, 2218, 1457 cm–1. C13H18N2 (202.30): calcd. C 77.18, H 8.97,
1 H, NH), 1.44–1.51 (m, 2 H, CH2CH3), 1.68 (dt, J = 7.2, 7.6 Hz, N 13.85; found C 77.17, H 8.91, N 13.78. HPLC-MS: m/z (tr =
2 H, CH2CH2CH), 3.23 (ddt, J = 1.2, 6.4, 13.6 Hz, 1 H,
CH2CHCN), 3.43–3.49 (m, H, NHCH2), 5.10 (m, H,
9.8 min) = 203 [M + 1]+, 176 [M – HCN]+.
2
1
2-(Benzylamino)-2-methylhexanenitrile (29): Yield: 47%; oil. 1H
NMR (400 MHz, CDCl3): δ = 0.95 (t, J = 7.2 Hz, 3 H, CH3), 1.39
(quint, J = 7.2 Hz, 2 H, CH2CH2CH2), 1.44–1.57 (m, 6 H, NH,
CH2,CH3), 1.67–1.82 (m, 2 H, CH2), 3.90 (s, 2 H, CH2Ph), 7.27–
7.40 (m, 5 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.7,
22.5, 24.6, 25.8, 39.5, 49.0, 55.6, 122.1, 127.2, 128.1, 128.3,
CH=CHH), 5.21 (m, 1 H, CH=CHH), 5.79 (m, 1 H, CH=CHH)
ppm. 13C NMR (100 MHz, CDCl3): δ = 13.3, 18.8, 35.3, 49.3, 50.1,
117.3, 120.1, 134.9 ppm. IR: ν = 3321, 2220, 1644, 1465 cm–1.
˜
C8H14N2 (138.21): calcd. C 69.52, H 10.21, N 20.27; found C 69.44,
H 10.16, N 20.26.
2-(Morpholin-4-yl)pentanenitrile (21): Yield: 30%; yellow solid;
m.p. 159 °C. 1H NMR (400 MHz, CDCl3): δ = 0.94 (t, J = 7.2 Hz,
3 H, CH3), 1.41–1.56 (m, 2 H, CH2), 1.65–1.79 (m, 2 H, CH2),
2.43–2.48 (m, 2 H, 2 NCHH), 2.62–2.68 (m, 2 H, NCHH), 3.37 (t,
139.1 ppm. IR: ν = 3318, 2219, 1455 cm–1. C H N (216.32):
˜
14 20
2
calcd. C 77.73, H 9.32, N 12.95; found C 77.82, H 9.41, N 12.91.
1-(Benzylamino)-4-methylcyclohexanecarbonitrile (33): Yield: 99%;
mixture of diastereoisomers, dr = 72:28 (determined by HPLC
J = 7.6 Hz, 1 H, CHCN), 3.66–3.76 (m, 4 H, CH2OCH2) ppm. 13
C
1
NMR (50 MHz, CDCl3): δ = 13.4, 19.2, 32.5, 50.0, 33.0, 57.9, 66.6,
analysis of the crude product). H NMR (400 MHz, CDCl3): δ =
116.9 ppm. IR: ν = 2223, 1455 cm–1. C H N O (168.24): calcd. C
˜
0.86 (d, J = 6.0 Hz, 3 H, CH3, minor diast.), 0.88 (d, J = 6.0 Hz,
9
16
2
64.25, H 9.59, N 16.65; found C 64.39, H 9.67, N 16.47. GC-MS:
m/z (tr = 11.7 min) (%) = 168 (2) [M]+, 153 (1) [M – 15]+, 125 (100)
[M – 43]+.
3
H, CH3, major diast.), 1.23–1.50 (m, 6 H, NH, CH,
CH2CHCH2), 1.66–1.69 (m, 2 H, CHH, CHH, major diast.), 1.69–
1.79 (m, 2 H, CHH, CHH, minor diast.), 1.86–1.93 (m, 2 H, CHH,
CHH, minor diast.), 2.01–2.01 (m, 2 H, CHH, CHH), 3.76 (s, 2 H,
CH2Ph, minor diast), 3.84 (s, 2 H, CH2Ph, major diast), 7.19–7.28
(m, 5 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.7, 28.0
(minor diast.), 31.1 (major diast.), 31.8, 34.0 (minor diast.), 36.2
(major diast.), 48.5 (minor diast.), 48.7 (major diast.), 57.7, 121.9
(major diast.), 123.0 (minor diast.), 127.2, 128.3, 128.4, 139.3 ppm.
2-(Piperidin-1-yl)pentanenitrile (22): Yield: 99%; oil. 1H NMR
(400 MHz, CDCl3): δ = 0.89 (t, J = 7.6 Hz, 3 H, CH3), 1.36–1.76
(m, 10 H, 5 CH2), 2.29–2.34 (m, 2 H, 2 NCHH), 2.53–2.59 (m, 2
H, NCHH), 3.37 (dd, J = 6.8, 8.8 Hz, 1 H, CHCN) ppm. 13C NMR
(50 MHz, CDCl3): δ = 13.3, 19.2, 23.9, 25.7, 33.0, 50.8, 58.3,
117.3 ppm. IR: ν = 2220, 1465 cm–1. C H N (166.26): calcd. C
˜
10 18
2
IR: ν = 3313, 2218, 1453 cm–1. HPLC-MS: m/z [t = 10.4 min
˜
r
72.24, H 10.91, N 16.85; found C 72.35, H 10.96, N 16.80. HPLC-
MS: m/z (tr = 8.8 min) = 189 [M + H2O]+, 167 [M + 1]+, 140 [M –
HCN]+.
(major diast.), 11.1 min (minor diast.)] = 229 [M + 1]+, 202 [M –
HCN]+.
2-[4-(1-Cyanobutyl)piperazin-1-yl]pentanenitrile (23): Yield: 50%;
mixture of diastereoisomers, dr = 80:20. Diastereoisomers were sep-
arated by flash chromatography. Major diastereoisomer: White so-
lid; m.p. 153 °C. 1H NMR (400 MHz, CDCl3): δ = 0.94 (t, J =
7.2 Hz, 6 H, 2 CH3), 1.41–1.54 (m, 4 H, 2 CH2CH), 1.65–1.80 (m,
4 H, 2 CH2CH2), 2.50–2.55 (m, 4 H, 2 NCHHCHHN), 2.62–2.72
(m, 4 H, 2 NCHHCHHN), 3.49 (t, J = 7.6 Hz, 2 H, 2 CHCN)
ppm. 13C NMR (100 MHz, CDCl3): δ = 13.4, 19.2, 32.8, 49.2, 57.3,
1-(Benzylamino)-2-methoxycyclohexanecarbonitrile (35): Yield:
61%; mixture of diastereoisomers, dr = 57:43 (separated by flash
chromatography). Major diastereoisomer: Oil. 1H NMR
(400 MHz, CDCl3): δ = 1.20–1.30 (m, 1 H, CH2CHH), 1.35–1.38
(m, 1 H, CH2CHH), 1.48 (br. s, 1 H, NH), 1.53–1.76 (m, 5 H,
CHHCH2CH2), 2.10–2.14 (m, 1 H, CHCHH), 3.38 (s, 3 H, OCH3),
3.39 (dd, J = 4.4, 9.6 Hz, 1 H, CHOCH3), 3.73 (d, JAB = 12.0 Hz,
1 H, CHHPh), 3.79 (d, JAB = 12.0 Hz, 1 H, CHHPh), 7.18–7.32
(m, 5 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.2, 23.0,
24.8, 32.3, 48.0, 57.5, 59.4, 81.8, 121.9, 127.2, 128.3, 128.4,
116.9 ppm. IR: ν = 3344, 2222 cm–1. C H N (248.37): calcd. C
˜
14 24
4
67.70, H 9.74, N 22.56; found C 67.82, H 9.77, N 22.58. HPLC-
MS: m/z (tr = 9.4 min) = 271 [M + Na]+, 249 [M + 1]+, 222 [M –
HCN]+. GC-MS: m/z (tr = 18.9 min) = 248 [M]+, 221 [M –
HCN]+. Minor diastereoisomer: 1H NMR (400 MHz, CDCl3): δ =
0.94 (t, J = 6.8 Hz, 6 H, 2 CH3), 1.44–1.52 (m, 4 H, 2 CH2CH),
139.5 ppm. IR: ν = 3334, 2210, 1454 cm–1. C H N O (244.33):
˜
15 20
2
calcd. C 73.74, H 8.25, N 11.47; found C 73.64, H 8.12, N 11.31.
HPLC-MS: m/z (tr = 10.6 min) = 245 [M + 1]+, 218 [M – HCN]+.
Minor diastereoisomer: White solid; m.p. 69 °C. 1H NMR
(400 MHz, CDCl3): δ = 1.15–1.27 (m, 1 H, CH2CHH), 1.29–1.42
(m, 1 H, CH2CHH), 1.53–1.76 (m, 2 H, CHHCH2CH2), 1.64–1.70
(m, 1 H, CHCHH), 1.76–1.81 (m, 1 H, CHCHH), 2.08–2.13 (m, 1
H, CHCHH), 2.18–2.22 (m, 1 H, CHCHH), 2.48 (br. s, 1 H, NH),
3.08 (dd, J = 4.4, 10.8 Hz, 1 H, CHOCH3), 3.31 (s, 3 H, OCH3),
3.77 (d, JAB = 12.0 Hz, 1 H, CHHPh), 3.84 (d, JAB = 12.0 Hz, 1
H, CHHPh), 7.19–7.32 (m, 5 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 22.0, 23.3, 26.5, 33.6, 48.4, 56.7, 62.8, 83.4, 120.0,
1.69–1.74 (m,
4 H, 2 CH2CH2), 2.50–2.55 (m, 4 H, 2
NCHHCHHN), 2.65–2.72 (m, 4 H, 2 NCHHCHHN), 3.48 (t, J =
7.6 Hz, 2 H, 2 CHCN) ppm. 13C NMR (100 MHz, CDCl3): δ =
13.4, 19.1, 32.8, 49.3, 57.3, 116.9 ppm. HPLC-MS: m/z (tr
=
9.2 min) = 249 [M + 1]+.
2-(4-Oxopiperidin-1-yl)pentanenitrile (26): Yield: 30%; oil. 1H
NMR (400 MHz, CDCl3): δ = 0.93 (t, J = 7.2 Hz, 3 H, CH3), 1.44–
1.51 (m, 2 H, CH2), 1.71–1.78 (m, 2 H, CH2), 2.38–2.51 (m, 4 H,
CH2COCH2), 2.66–2.72 (m, 2 H, CHHNCHH), 2.89–2.95 (m, 2
H, CHHNCHH), 3.58 (t, J = 7.6 Hz, 1 H, CHCN) ppm. 13C NMR
(50 MHz, CDCl3): δ = 13.3, 19.2, 33.3, 40.8, 49.4, 56.9, 116.6,
127.3, 128.4, 128.5, 139.5 ppm. IR: ν = 3319, 2219, 1456 cm–1.
˜
C15H20N2O (244.33): calcd. C 73.74, H 8.25, N 11.47; found C
73.58, H 8.14, N 11.27. HPLC-MS: m/z (tr = 9.5 min) = 267 [M +
Na]+, 245 [M + 1]+.
207.2. IR: ν = 2223, 1780, 1720 cm–1. C H N O (180.25): calcd.
˜
10 16
2
C 66.63, H 8.95, N 15.54; found C 66.58, H 8.94, N 15.67. GC-
MS: m/z (tr = 14.0 min) (%) = 180 (5) [M]+, 153 (100) [M –
HCN]+, 137.
2-(Benzylamino)-2-ethylbutyronitrile (28): Yield: 48%; oil. 1H NMR
4-(Benzylamino)piperidine-4-carbonitrile (36): Yield: 50%; m.p.
70 °C. H NMR (400 MHz, CDCl3): δ = 1.61 (ddd, J = 4.0, 11.2,
13.2 Hz, 2 H, 2 CHHCH2N), 1.72 (br. s, 2 H, 2 NH), 1.94–2.00
(m, 2 H, 2 CHHCH2N), 2.82 (ddd, J = 2.8, 10.8, 13.6 Hz, 2 H,
1
(400 MHz, CDCl3): δ = 1.04 (t, J = 7.2 Hz, 6 H, CH3), 1.43 (br. s, NCHHCH2), 3.04 (ddd, J = 4.0, 4.4, 13.6 Hz, 2 H, NCHHCH2),
1 H, NH), 1.77 (non, J = 7.2 Hz, 4 H, CH2), 3.81 (s, 2 H, CH2Ph), 3.85 (s, 2 H, PhCH2), 7.23–7.37 (m, 5 H, ArH) ppm. 13C NMR
7.19–7.33 (m, 5 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = (100 MHz, CDCl3): δ = 36.4, 42.6, 48.2, 56.3, 121.5, 127.4, 128.3,
3902
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3896–3903

Catalyst-Free Strecker Reaction in Water
128.5, 139.1 ppm. IR: ν = 3313, 2218 cm–1. C H N (215.29):
2005, 37, 279–294; c) M. Paravidino, M. J. Sorgedrager,
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5762.
˜
13 17
3
calcd. C 72.52, H 7.96, N 19.52; found C 72.61, H 8.04, N 19.41.
[16] J. S. Yadav, B. V. S. Reddy, B. Eshwaraiah, M. Srinivas, P. Vish-
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thank Mrs. Elisa Bellicchi for her kind technical assistance.
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Received: January 20, 2011
Published Online: April 5, 2011
Eur. J. Org. Chem. 2011, 3896–3903
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3903