Strecker reactions with hexacyanoferrates as non-toxic cyanide sources

Article abstract of DOI:10.1039/c9gc00720b

The Strecker reaction is the most widely applied three-component reaction. Although highly useful for the preparation of α-amino nitriles, α-amino acids, hydantoins and numerous related compounds, the need for the application of toxic sources of HCN limits its application in both academic and industrial settings. Here, we present a facile protocol for Strecker reactions using a mixture of potassium ferri- and ferrocyanides as a non-toxic substitute.

Full text of DOI:10.1039/c9gc00720b

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DOI: 10.1039/C9GC00720B
ARTICLE
Strecker Reactions with Hexacyanoferrates as non-toxic Cyanide
Sources
Caroline Grundke*a and Till Opatz b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The Strecker reaction is the most widely applied three-component reaction. Although highly useful for the
preparation of α-amino nitriles and α-amino acids, hydantoins and numerous related compounds, the need for the
application of toxic sources of HCN limits its application in both academic and industrial settings. Here, we present a
facile protocol for Strecker reactions using a mixture of potassium ferri- and ferrocyanide as a non-toxic substitute.
In 2015, we reported that potassium ferricyanides can be used both
Introduction
as an oxidant and as a cyanide source in the oxidative α-cyanation
Even today, almost 170 years after its discovery by Adolph Strecker,
the famous three-component reaction of aldehydes or ketones,
amines, and HCN remains to be the most widely applied
of tertiary amines.[5a] To the best of our knowledge, the only reports
on non-oxidative Strecker-type reactions using ferri- or ferrocyanide
as the source of HCN require prior activation through reaction with
benzoyl chloride and intermediate formation of benzoyl cyanide as
b]
multicomponent reaction.[1a, It produces α-amino nitriles which
proved to be versatile intermediates in organic synthesis due to
the actual HCN source or through mechanochemical activation in a
their various modes of reactivity.[2a,
Functional group
b, c]
ball mill.[3e,
The latter methodology has been proposed by the
6a]
interconversions on α-amino nitriles can afford α-amino amides,
α-amino acids, α-substituted amines or 1,2-diamines while they also
Bolm group to be of potential relevance for the origin of life on
planet earth as HCN is believed to be an integral element of
prebiotic chemistry.[6a-e] One of the first examples for the direct use
of ferrocyanide as an HCN source is the synthesis of
dibromoacrylonitriles.[5b] Ferro- and ferricyanides are stable,
inexpensive and essentially non-toxic (their oral LD50 values in the
rat are even higher than the corresponding value for NaCl),
nevertheless they are known to release cyanide under thermal,
photochemical or mechanochemical conditions.[6a, 7a-f]
α
represent stable precursors of iminium ions or nitrile-stabilized
-amino carbanions. Moreover, α-amino nitriles proved to be useful
building blocks for the synthesis of nitrogen heterocycles or
complex natural products.[2d-k]
Numerous alternative procedures for the synthesis of α-amino
nitriles have been developed but variants of the original Strecker
reaction prevail. Unfortunately, the vast majority of them requires
highly toxic cyanide sources[3a,c], yet some notable exceptions have
been reported.[3b, d, e, f] In view of the concept of “green chemistry”,
including eco-friendliness, sustainability of chemical procedures and
avoidance of toxic reagents, the search for ecologically acceptable,
non-toxic alternatives instead of classical reagents is worthwhile.[4]
Our goal was to develop a simple, environmentally benign
α
method for the one-pot-synthesis of -amino nitriles in a
biphasic solvent mixture using aldehyde, amine, K3[Fe(CN)6]
and K4[Fe(CN)6] as possible non-toxic cyanide sources[8]. It was
found that biphasic solvent mixtures can avoid solubility issues
which may be a problem in homogeneous solution.
a. Institute of Organic Chemistry, Johannes Gutenberg University Mainz, 55128
Mainz, Germany; fax: (+49)-6131-39-22338; phone: (+49)-6131-39-22272; email:
opatz@uni-mainz.de
† Both authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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In the standard protocol, 1.0 equivalent of hexacyanoferrate was
Results and Discussion
View Article Online
DOI: 10.1039/C9GC00720B
employed. All reactions were performed in homogeneous or
℃
As a model system, the Strecker reaction of benzaldehyde and heterogeneous water/solvent mixtures at 80 under the exclusion
aniline using K3[Fe(CN)6] and K4[Fe(CN)6] as non-toxic cyanide of light and without inert gas atmosphere unless otherwise stated.
sources was studied under various reaction conditions (table 1).
α
As -amino nitriles are formed through nucleophilic attack of the
Table 1: Optimization of reaction conditions for the Strecker reaction using
K3[Fe(CN)6] and K4[Fe(CN)6].(a)
cyanide ion on in-situ formed iminium ions, the preformed imine of
benzaldehyde and aniline was first used to optimize the desired
procedure (entries 1-9). The formation of amino nitriles under
concomitant formation of Prussian blue (Fe4[Fe(CN)6]3) could be
observed. Both K3[Fe(CN)6] and K4[Fe(CN)6] proved suitable for the
reaction (entries 1-4), but their combination in the theoretical 3:4
ratio for prussian blue formation afforded a higher yield (entry 9).
As simplicity in handling was one goal of our method development,
no inert gas atmosphere (entries 1 and 3) was used as no change in
yield was observed. Nevertheless, a nitrogen atmosphere should be
used to avoid the risk of ignition of the vapor phase when working
cyanide source,
solvent mixture,
HOAc, 80 °C
H
N
O
Ph
NH2
Ph
+
Ph
1
2
3
Ph
CN
Entry
Inert
gas
Solvent
Cyanide source
Time
[h]
Yield
[%](c)
1(b)
2(b)
3(b)
4(b)
5(b)
+
―
+
―
―
tBuOH:H2O
tBuOH:H2O
tBuOH:H2O
tBuOH:H2O
tBuOH:H2O
K3[Fe(CN)6]
K3[Fe(CN)6]
K4[Fe(CN)6]
K4[Fe(CN)6]
2
2
5
5
2
65
56
65
59
54
K3[Fe(CN)6]:K4[Fe(CN)6]
(1:1)
6(b)
7(b)
8(b)
9(b)
tBuOH:H2O
tBuOH:H2O
tBuOH:H2O
tBuOH:H2O
K3[Fe(CN)6]:K4[Fe(CN)6]
(2:1)
K3[Fe(CN)6]:K4[Fe(CN)6]
(1:2)
K3[Fe(CN)6]:K4[Fe(CN)6]
(3:4)
K3[Fe(CN)6]:K4[Fe(CN)6]
(3:4)
K3[Fe(CN)6]
K4[Fe(CN)6]
K3[Fe(CN)6]:K4[Fe(CN)6]
(3:4)
2
2
2
5
53
56
64
72
―
―
―
―
on
a larger scale. As stated above, the 3:4-mixture of
K3[Fe(CN)6]:K4[Fe(CN)6] afforded optimal results (entries 8+9), so
this cyanide source was chosen for further method development of
10
11
12
tBuOH:H2O
tBuOH:H2O
tBuOH:H2O
4
4
4
58
63
72
―
―
―
a
one-pot reaction starting from benzaldehyde and aniline.
Performing the reaction in a one-pot fashion, the two pure
ferricyanides K3[Fe(CN)6] and K4[Fe(CN)6] were used for further
method development in addition to the previously selected mixture
(entries 10+11). The mixed cyanide source proved most suitable for
running a one-pot procedure (entry 12). Different solvent mixtures
were studied for application (entries 13-19), where pyridine
afforded the highest yield, but since it is not eco-friendly enough
and cannot be readily obtained from biomass, it was rejected as a
solvent (entry 17).[9] Ethyl acetate as a co-solvent afforded the
second highest yield so another experiment was performed with an
extended reaction time to 13 h (entry 20) affording a yield of 84%. It
was also investigated whether smaller quantities of the cyanide
source could be used for the reaction (entries 21-26). However, the
initially chosen amount of 1.0 eq. proved to be ideal. Without the
addition of acetic acid to promote HCN release and iminium
formation or of the cyanide source, no product formation could be
observed. Running the reaction at room temperature also did not
lead to product formation.
13
14
15
16
17
18
19
20
21
22
23
24
25
26
(a)
EtOAc:H2O
K3[Fe(CN)6]:K4[Fe(CN)6]
(3:4)
K3[Fe(CN)6]:K4[Fe(CN)6]
(3:4)
K3[Fe(CN)6]:K4[Fe(CN)6]
(3:4)
K3[Fe(CN)6]:K4[Fe(CN)6]
(3:4)
K3[Fe(CN)6]:K4[Fe(CN)6]
(3:4)
K3[Fe(CN)6]:K4[Fe(CN)6]
(3:4)
K3[Fe(CN)6]:K4[Fe(CN)6]
(3:4)
K3[Fe(CN)6]:K4[Fe(CN)6]
(3:4)
K3[Fe(CN)6]:K4[Fe(CN)6]
(3:4) (0.25 eq.)
K3[Fe(CN)6]:K4[Fe(CN)6]
(3:4) (0.50 eq.)
K3[Fe(CN)6]:K4[Fe(CN)6]
(3:4) (0.75 eq.)
K3[Fe(CN)6]:K4[Fe(CN)6]
(3:4) (1.00 eq.)
K3[Fe(CN)6]:K4[Fe(CN)6]
(3:4) (1.50 eq.)
K3[Fe(CN)6]:K4[Fe(CN)6]
(3:4) (2.00 eq.)
5
5
59
26
31
33
64
42
―
―
―
―
―
―
―
―
―
―
―
―
―
―
―
cyclohexane:H2O
toluene:H2O
heptane:H2O
pyridine:H2O
n-hexane:H2O
2-butanone:H2O
EtOAc:H2O
5
5
5
5
5
13
13
13
13
13
13
13
84
43
48
27
84
88
86
EtOAc:H2O
EtOAc:H2O
EtOAc:H2O
EtOAc:H2O
EtOAc:H2O
EtOAc:H2O
Reaction conditions: cyanide source (2.00 mmol, 1.0 eq.), 1 (2.00 mmol,
1.0 eq.), 2 (2.00 mmol, 1.0 eq.), HOAc (0.20 mL), 6 mL solvent mixture (1:1),
The scope of the optimized one-pot Strecker reaction using
non-toxic hexacyanoferrates, benzaldehyde and aromatic amines is
summarized in table 2.
℃
80 , exclusion of light.
(b) Imine reagent N-benzylidenaniline (4) instead of 1 and 2.
(c) Isolated yields.
2 | J. Name., 2012, 00, 1-3
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ARTICLE
Table 3: Scope of one-pot Strecker reaction using N-substituted aniline and
Table 2: Scope of one-pot Strecker reaction using aromatic amine
substrates.(a)
View Article Online
benzylamine substrates.(a)
DOI: 10.1039/C9GC00720B
K3[Fe(CN)6]:K4[Fe(CN)6] (3:4),
K3[Fe(CN)6]:K4[Fe(CN)6] (3:4),
R2
N
EtOAc:H2O (1:1),
HOAc, 80 °C, 13 h
EtOAc:H2O (1:1),
HOAc, 80 °C, 13 h
H
O
O
H
N
N
Ph
R1
NH2
Ph
R3
+
+
R
R2
R3
R1
1, 7
Ph
CN
CN
9a-k
8a-j
1
2, 5a-m
3, 6a-m
Entry
1
2
3
4
5
6
7
8
Product, R =
3: R = Ph
6a: R = p-Tol-
Yield [%]
NC
N
84
97(b)
88
68
22
83
70
85
51
52
49
―
NC
6b: R = 4–tBu–C6H4–
6c: R = 4-MeO–C6H4–
6d: R = 4-HO–C6H4–
6e: R = 4-F–C6H4–
6f: R = 4-Cl–C6H4–
6g: R = 4-Br–C6H4–
6h: R = 4-I–C6H4–
6i: R = 4-HO2C–C6H4–
6j: R = 4-F3C–C6H4–
6k: R = 4-O2N–C6H4
6l: R = 4–Pyridyl–
6m: R = 2–Pyridyl–
N
9b
50%
9a
31%
9
NC
N
10
11
12
13
14
N
CN
9d
94%
―
―
9c
68%
(a)
reaction conditions: cyanide source (2.00 mmol, 1.0 eq.), benzaldehyde
(2.00 mmol, 1.0 eq.), amine (2.00 mmol, 1.0 eq.), HOAc (0.20 mL), 6 mL
EtOAc:H2O (1:1); isolated yields.
(b) 99% yield after crystallization instead of chromatography.
CH3
CN
N
N
For para-substituted anilines 5a-m, the corresponding amino
nitriles 6a-m were obtained in high yields. Notable exceptions are 4-
aminophenol (entry 5), 4-nitroaniline (entry 12) as well as 4- and 2-
aminopyridine (entries 13 and 14). In general, electron-deficient
anilines appeared to be less reactive (entries 10-11), possibly due to
inefficient formation of the iminium intermediate. For
N-substituted anilines and primary benzylamines, slightly lower
yields were observed than for the para-substituted anilines. The
scope is summarized in table 3. Secondary benzylic amines afforded
the corresponding amino nitriles in excellent yields instead
(compounds 9d+9e). The presence of at least one free hydrogen on
the amino nitrile’s amine nitrogen atom favors the tendency
towards HCN elimination to form the neutral imine (retro-Strecker
reaction) and therefore affords less stable products than in the case
of Strecker reactions with secondary amines. Due to the known
decomposition of the amino nitriles during workup and purification,
yields were determined via 1H-NMR spectroscopy using
dimethylsulfone as an internal standard. NMR-based yields of up to
84%(b) could be obtained. Changing the aldehyde substrate to
3-phenylpropanal did not lead to a higher yield while even the
sterically highly hindered triphenylmethylamine resulted in a 13%(b)
NMR-yield of the corresponding amino nitrile 9k.
NC
9e
93%
9f
52%, d.r. 1:1.5
H
N
H
N
CN
CN
9g
47%(b)
9h
84%(b), d.r. 0:100
H
N
N
MeO
MeO
CN
CN
CN
9i
17%(b)
9j

H
N
NC
9k
13%(b)
(a)
Reaction conditions: cyanide source (2.00 mmol, 1.0 eq.), aldehyde
(2.00 mmol, 1.0 eq.), amine (2.00 mmol, 1.0 eq.), HOAc (0.20 mL), 6 mL
EtOAc:H2O (1:1); isolated yields.
(b) calculated yield (1H-NMR, internal standard dimethylsulfone).
The scope of aliphatic amines was also investigated. Primary
aliphatic amines generally lead to unstable products so yields were
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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moderate and again had to be determined by 1H-NMR Extending the scope to cyclic aliphatic amineVsiewanArdticleliOnnelianer
DOI: 10.1039/C9GC00720B
spectroscopy. Increasing the lipophilicity of the amine component aliphatic amines with additional functional groups, yields up to
or the use of secondary aliphatic amines afforded the 74% could be achieved. The method is not suitable for
corresponding amino nitriles in up to 89% isolated yield instead. 1,2-aminoalcohols and low to moderate yields were observed
The protocol could not be extended to bulky aliphatic amines for acetals of aminoacetaldehyde (possibly due to partial
(11i-m).
α-
acetyl deprotection). The synthesis of amino nitriles in pure
Table 4: Scope of one-pot Strecker reaction using aliphatic amine
substrates.(a)
water has been investigated applying a non-water-soluble
carbonyl component but yields were significantly lower than
performing the reaction using the developed biphasic
procedure (see the supporting information).
K3[Fe(CN)6]:K4[Fe(CN)6] (3:4),
R2
N
EtOAc:H2O (1:1),
HOAc, 80 °C, 13 h
O
H
N
R1
R3
+
R2
N
R3
R1
1, 7
CN
In summary, a versatile method for a one-pot Strecker reaction
10a-j
11a-m
using ferricyanides as
a non-toxic cyanide source was
N
developed. The scope of the reaction is broad and the
procedure operationally simple. Due to the use of a non-toxic
cyanide source and of an environmentally benign solvent
system, the entire procedure can be considered “green”
according to the principles of sustainable chemistry. Both, the
cyanide source and the organic co-solvent can be produced
from biomass so that no fossil resources are required.
NC
NC
11a
89%
11b
63%
N
H
N
NC
CN
11c
9%(b)
11d
36(b)
H
N
Table 5: Scope of one-pot Strecker reaction using cyclic aliphatic amines and
linear aliphatic amines with additional functionalities.(a)
CN
11e

K3[Fe(CN)6]:K4[Fe(CN)6] (3:4),
H
N
EtOAc:H2O (1:1),
R1
O
HOAc, 80 °C, 13 h
R1
HN R2
11f
18%(b)
CN
N
Ph
+
R2
Ph
CN
1
12a-i
13a-i
H
N
H
N
N
N
N
CN
CN
11h
9%(b)
11g
48%(b)
CN
13b
50%
CN
NC
13a
22%
13c
59%
H
N
OMe
OMe
H2N
NC
H
N
N
N
MeO
MeO
CN
CN
CN
CN
13d
26%
13f
22%(b)
13e

11i
3%(b)
11j
8%(b)
N
CN
HO
OH
N
11m

H
N
H
N
CN
OH
N
O
N
CN
CN
CN
NC
11k
traces
13g
74%
13h

13i

11l

(a)
(a)
Reaction conditions: cyanide source (2.00 mmol, 1.0 eq.), aldehyde
Reaction conditions: cyanide source (2.00 mmol, 1.0 eq.), aldehyde
(2.00 mmol, 1.0 eq.), amine (2.00 mmol, 1.0 eq.), HOAc (0.20 mL), 6 mL
EtOAc:H2O (1:1); isolated yields.
(2.00 mmol, 1.0 eq.), amine (2.00 mmol, 1.0 eq.), HOAc (0.20 mL), 6 mL
EtOAc:H2O (1:1); isolated yields.
(b) calculated yield (1H-NMR, internal standard dimethylsulfone).
(b) calculated yield (1H-NMR, internal standard dimethylsulfone).
4 | J. Name., 2012, 00, 1-3
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ARTICLE
Strecker procedures using KCN was not intended here, an
Experimental Section
View Article Online
arbitrarily chosen example (compoundD3O)I: 1g0a.1v0e39a/C89G4C%00y7i2e0ldB
with hexacyanoferrates instead of an 51% yield with KCN (for
details, see the Supporting Information). Thus, the presented
procedure can have additional benefits over the avoidance of a
toxic cyanide source. The absence of a mechanochemical
component may have additional implications on prebiotic
chemistry as mentioned above.
General procedure for amino nitrile synthesis
A mixture of K4[Fe(CN)6] (420 mg, 1.14 mmol) and K3[Fe(CN)6]
(283 mg, 0.86 mmol) was dissolved in a mixture of water (3 mL) and
acetic acid (0.2 mL). The aldehyde (2.00 mmol, 1.0 eq.) and the
amine (2.00 mmol, 1.0 eq.) were dissolved in ethyl acetate (3 mL)
and added to the aqueous solution. The reaction mixture was then
℃
heated to 80 under magnetic stirring and exclusion of light and
neutralized with saturated NaHCO3 solution after 13 h of reaction
time (the adaption of the reaction time to the reactivity of Conflicts of interest
There are no conflicts to declare.
amine/aldehyde pair is an obvious optimization parameter but has
not been changed here for simplicity). The mixture was then
extracted with ethyl acetate and washed with brine. The combined
organic layers were dried over sodium sulfate. After evaporation of
the solvent in vacuo, the crude product was purified by column
chromatography using silica gel or alumina (basic or neutral). We
chose column chromatography as a uniform purification procedure
applicable to all synthesized amino nitriles. Nevertheless, the retro-
Strecker may occur under these conditions and crystallization can
provide superior results. As a test, compound 6a was recrystallized
Acknowledgements
We thank Dr. J. C. Liermann for NMR spectroscopy and Dr. C. J.
Kampf for mass spectroscopy.
Notes and references
1. a) A. Strecker, Justus Liebigs Ann. Chem. 1850, 75, 27; b) A.
Strecker, Justus Liebigs Ann. Chem. 1854, 91, 349;
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Chem. Soc. Rev. 2000, 29, 359; c) J. D. Albright, Tetrahedron
1983, 39, 3207; d) N.Otto, T. Opatz, Chem. Eur. J. 2014, 20,
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Chem. Rev. 1989, 58, 148; f) G. Gosmann, D. Guillaume, H.-P.
Husson, Tetrahedron Lett. 1996, 37, 4369-4372; g) A. Madin, C.
J. O'Donnell, T. Oh, D. W. Old, L. E. Overman, M. J. Sharp,
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Wood, J. Deitch, M. W. Lodewyk, D. J. Tantillo, R. Sarpong, Nat.
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N. Vierengel, D. Schollmeyer, H. J. Schäfer, S. R. Waldvogel, T.
Opatz, Angew. Chem. Int. Ed. 2018, 57, 11055-11059; Angew.
Chem. 2018, 130, 11221-11225; j) N. Otto, D. Ferenc, T. Opatz,
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to give
a 99% yield compared to 97% obtained after
chromatography.
CAUTION! Toxic HCN is liberated in the course of the reaction.
Corresponding safety measures should be taken to prevent contact
with this agent. The use of an inert atmosphere instead of air is
recommended to reduce the risk of explosion.
Conclusions
The developed method represents a new approach towards
α-amino nitriles using potassium hexacyanoferrates as non-
toxic cyanide sources. Including a biphasic reaction system in a
one-pot reaction, this facile protocol is highly useful for
preparative chemistry. Additionally, working with non-toxic
cyanide sources where HCN is released in-situ through thermal
activation and using environmentally friendly solvents, this
method corresponds to the principles of green chemistry. It
was possible to show a variety of α-amino nitriles using
aromatic and aliphatic amines as well as an aliphatic aldehyde.
The developed method was also applied in pure water using a
non-water-soluble carbonyl component affording slightly
lower yield. While an extensive comparison with “classical”
3. a) Y. Zhang, H. Peng, M. Zhang, Y. Cheng, C. Zhu, Chem.
Commun. 2011, 47, 2354; b) W. Han, A. R. Ofial, Chem.
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Catal. 2016, 6, 5989; d) H. Shen, L. Hu, Q. Liu, I. Hussain, J. Pan,
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Green Chemistry
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