Mechanochemical Strecker Reaction: Access to α-Aminonitriles and Tetrahydroisoquinolines under Ball-Milling Conditions

Article abstract of DOI:10.1002/chem.201603057

A mechanochemical version of the Strecker reaction for the synthesis of α-aminonitriles was developed. The milling of aldehydes, amines, and potassium cyanide in the presence of SiO₂gave the corresponding α-aminonitriles in good to high yields. The high efficiency of the mechanochemical Strecker-type multicomponent reaction allowed the one-pot synthesis of tetrahydroisoquinolines after a subsequent internal N-alkylation reaction.

Full text of DOI:10.1002/chem.201603057

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Accepted Article
Title: Mechanochemical Strecker Reaction: Access to α-Aminonitriles and Tetrahy-
droisoquinolines under Ball Milling Conditions
´
´
Authors: Jose Hernandez; Mathias Turberg; Ingo Schiffers; Carsten Bolm
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Chemistry - A European Journal
10.1002/chem.201603057
SHORT COMMUNICATION
Mechanochemical Strecker Reaction: Access to -Aminonitriles
and Tetrahydroisoquinolines under Ball Milling Conditions
José G. Hernández,* Mathias Turberg, Ingo Schiffers, and Carsten Bolm*[a]
hydrolysis of the nitrile group.[12] In fact, -aminonitriles have
been considered as key intermediates in the classical Miller
experiment to explain the formation of amino acids under
Abstract: A mechanochemical version of the Strecker reaction for
the synthesis of -aminonitriles was developed. The milling of
simulated early earth conditions (methane, ammonia, water, and
aldehydes, amines and potassium cyanide in the presence of SiO2
hydrogen) in spark-discharge flasks.[13] Therefore, due to the
afforded the corresponding -aminonitriles in good to high yields.
The high efficiency of the mechanochemical Strecker-type
fundamental importance of the Strecker reaction and particularly
to the simple conditions required for the mechanochemical
activation of a system in an early earth scenario (e.g. the
collision of two stones), we wondered about the potential of ball
multicomponent reaction allowed the one-pot synthesis of tetra-
hydroisoquinolines after a subsequent internal N-alkylation reaction.
milling to develop a mechanochemical version of the Strecker
reaction for the formation of -aminonitriles.
Introduction
Results and Discussion
Mechanosynthesis of organic molecules has grown rapidly over
the past two decades providing new alternatives to conduct
chemical transformations faster, cleaner and more selectively.[1]
The current state of mechanochemical organic syntheses by
milling, grinding or shearing, includes organocatalytic
reactions,[2] peptide syntheses,[3] numerous metal-catalyzed
reactions[4] including C–H functionalizations,[5] polymer
formation,[6] enzymatic reactions[7] among others.[8] Particularly
interesting are the reports on mechanochemical multicomponent
reactions (MCRs),[9] which allow the efficient coupling of several
building blocks in a single step to afford highly functionalized
To test the idea of a mechanochemical version of the Strecker
reaction, we began conducting a simple experiment milling
benzaldehyde (1a), ammonium chloride and potassium cyanide
(1.0:1.1:1.1 equiv) in a planetary ball mill using stones as the
milling media (Scheme 1). To our delight, after 3 h of milling at
700 rpm the analysis of the reaction mixture by 1H NMR
revealed complete consumption of 1a and the presence of the -
aminonitrile 2 (65%), imine 3 (7%) and cyanohydrin 4 (27%)
(Scheme 1). With the aim to suppress the formation of
cyanohydrin 4, a step-wise experiment was conducted in the ball
mill by first preforming the imine 3 (1 h of milling), followed by
the addition of KCN (2 h of milling). The -aminonitrile 2 formed
upon milling was then acetylated by subsequent addition of
Ac2O into the milling vessel (1 h of milling), to facilitate its
isolation as Ac-2 in 80% yield over three successive
mechanochemical steps, representing an improvement to the
typical solution-based procedures.[14]
organic
molecules.
Recently,
examples
of
the
mechanochemically induced Biginelli,[9a] Ugi and Passerini
reactions[9b] have exemplified some of the advantages of
mechanochemistry such as the reduction or elimination of the
solvent, shorter reaction times, clean reaction mixtures and
simple work-up procedures. Consequently, the combination
between MCRs and mechanochemistry clearly strengthen the
well-known advantages of both approaches in the effort to
develop environmentally friendly synthetic strategies, since the
generation of large amounts of waste, especially from solvents
used in the reactions or during the purification of the
intermediates is avoided.
NH2
CN
NH
OH
CN
O
Stones
NH4Cl
KCN
+
+
+
+
H
H
Ball milling
3 h, 700 rpm
The first documented, and perhaps the most symbolic MCR in
organic synthesis is the Strecker reaction reported by Adolph
Strecker as early as 1850.[10] This three-component reaction
between aldehydes, ammonia and hydrogen cyanide yields -
aminonitriles, which are extremely valuable intermediates for the
synthesis of nitrogen containing heterocycles and natural
products.[11] However, probably the most important application of
-aminonitriles is found in the synthesis of-amino acids upon
1a
2
3
4
65%
7%
27%
Scheme 1. Mechanosynthesis of the -aminonitrile 2 using stones as milling
media.
The formation of 2 under such simple ball milling conditions
prompted us to carry out a systematic study of the mechano-
chemical Strecker reaction. In order to expand the potential
application of this approach, NH4Cl was then replaced by
benzylamine (5a) and the reaction was repeated (Table 1, entry
1). Also this time, the analysis of the reaction mixture by 1H NMR
after 3 h of milling indicated the complete consumption of
benzaldehyde (1a) and showed the presence of the expected -
aminonitrile 6a in 16% (Table 1, entry 1). In contrast, a control
experiment in solution (acetonitrile) under similar conditions
generated mainly imine 7a and only traces of the -aminonitrile
6a (<2%). In order to favor the formation of the -aminonitrile,
[a]
Dr. J. G. Hernández, M. Turberg, Dr. I. Schiffers, Prof. Dr. C. Bolm
Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, D-52074 Aachen (Germany)
E-mail: carsten.bolm@oc.rwth-aachen.de;
Fax: +49 241 80 92 391; Tel: +49 24 80 94 675
Supporting information for this article is given via a link at the end of
the document.

Chemistry - A European Journal
10.1002/chem.201603057
SHORT COMMUNICATION
Table 1. Screening of the mechanochemical reaction conditions.[a]
readily available silica gel (denoted as SiO2) was added to the
milling vessel along with the stones. SiO2 is a common milling
auxiliary in mechanochemistry,[9b,15] and due to its intrinsic acidic
properties and the ability to absorb moisture, SiO2 was thought
to be appropriate here to facilitate the formation of the imine and
to enhance the cyanation step in the ball mill. Moreover, unlike
many of the typical Brønsted and Lewis acid catalysts used for
the Strecker reaction,[11b] silica gel is inexpensive, easy to handle,
Ratio of
6a:7a
[%][b]
Vessel/ball
bearing
Conv.
[%][b]
Entry
Additive
non-toxic, and potentially
a
reusable promoter for this
transformation. Pleasantly, in the presence of SiO2, the milling of
1a, 5a, and KCN for 3 h led exclusively to the formation of the -
aminonitrile 6a (Table 1, entry 2).
1
2
3
4
5
---
ZrO2/stones[c]
ZrO2/stones
Agate[d]
99
98
99
98
97
16:84
99:1
SiO2
The use of inexpensive stones as the milling media in ball mills
is perceived very advantageous from a practical and economical
point of view. However, the difference in hardness between the
milling vessels and the stones could in principle cause abrasion,
thereby altering the total mass of the stones and potentially
affecting the outcome of the experiments. In our case, however,
the use of stones in combination with ZrO2 milling vessels
resulted in minimal wear of the milling media after several
reactions, causing no effect on the selectivity or in the yield of
the reaction. Nevertheless, in order to assure consistency in the
following experiments, the mechanochemical Strecker reaction
was subsequently conducted in stone-based agate milling
vessels with balls of the same material giving identical results
(Table 1, entries 2-3).
Intrigued by the excellent results observed using SiO2 as a
promoter, other additives such as fused sand and powder quartz
were also tested in the ball mill. These additives also facilitated
the formation of the -aminonitrile 6a, although to a lesser extent
(Table 1, entries 4-5). Then, montmorillonite clays, which are
known to function as Brønsted or Lewis solid acids were
examined as potential activators of the mechanochemical
Strecker reaction.[11c,d] Under milling conditions, the commercial
available montmorillonite K10 proved to be highly active
affording -aminonitrile 6a almost exclusively (Table 1, entry 6).
Similarly, other solid catalysts with Lewis acid sites such as
titanium oxide and alumina were screened. Unfortunately, after 3
h of milling these oxides displayed a lower activity than SiO2 to
mediate the formation of the product 6a (Table 1, entries 8-9).
Anhydrous MgSO4, commonly used as a drying agent, was also
found to promote efficiently the Strecker reaction yielding almost
exclusively -aminonitrile 6a (Table 1, entry 10). A control
experiment in the ball mill using anhydrous Na2SO4 instead, led
to a mixture containing mainly imine 7a featuring the importance
of the Lewis acidity of MgSO4 to facilitate the cyanation step
(Table 1, entries 10-11). Recently, the properties of MgSO4 as
Lewis acid in the N-alkylation of primary amides were observed
to overweigh the originally intended role of MgSO4 as desiccant
in the reaction in toluene.[16]
SiO2
99:1
Powder quartz[e]
Sand
Agate
47:53
38:62
Agate
Montmorillonite
K10[f]
6
7
Agate
Agate
97
98
97:3
Montmorillonite
K30[f]
87:13
[g]
8
TiO2
Agate
Agate
Agate
Agate
99
99
99
99
33:67
68:32
98:2
[h]
9
Al2O3
10
11
MgSO4
Na2SO4
9:91
[a] Reaction conditions: 1a (53.1 mg, 0.5 mmol), 5a (53.6 mg, 0.5 mmol),
KCN (35.8 mg, 0.55 mmol), and the additive (240 mg) were milled in a
planetary ball mill. [b] Determined by 1H NMR spectroscopy. [c] Use of a
12 mL ZrO2 milling vessel with 5 stones (5.50 g). [d] Use of a 12 mL agate
milling vessel with 20 agate balls of 5 mm in diameter. [e] Powder quartz
obtained after milling a natural quartz crystal. [f] The montmorillonite was
dried at 120°C for 4 h prior to use. [g] TiO2 as anatase. [h] Neutral Al2O3.
stirring in solution or under neat conditions were found to be less
efficient leading to lower conversion and selectivity even after 3
h of reaction (Figure 1).
Subsequently, the recyclability of SiO2 and scalability of the
mechanochemical Strecker were evaluated. Both filtration and
100"
90"
80"
70"
60"
50"
40"
30"
20"
10"
0"
Out of the set of potential activators, which included typically
considered “inert” milling auxiliaries, SiO2 was chosen as the
ideal promoter for the Strecker reaction based on its
performance, availability and matching nature with the agate
milling media (silicon dioxide). Further screening of the reaction
conditions made evident one of the advantages of the
mechanochemical Strecker approach when the milling time of
the reaction was reduced from 3 h to 1 h without affecting the
formation of 6a. In contrast, control experiments by conventional
Neat"(3"h)"
Imine"7a"
Acetonitrile"(3"h)"
Planetary"mill"(1"h)"
αBAminonitrile"6a"
Planetary"mill"(3"h)"
Conversion"
Figure 1. SiO2-promoted Strecker reaction between 1a, 5a and KCN under
neat, solution and ball milling conditions.

Chemistry - A European Journal
10.1002/chem.201603057
SHORT COMMUNICATION
Table 3. Mechanochemical Strecker reaction of aldehydes, ketones and
various amines.[a]
Table 2. Mechanochemical Strecker reaction of aromatic and aliphatic
aldehydes with benzylamine.[a]
NHBn
NHBn
CN
NHBn
CN
Carbonyl
compound
Yield
[%][b]
Entry
Amine
Product
CN
OMe
6c
79%
Me
6a
90%
6b
88%
NHBn
CN
NHBn
CN
NHBn
CN
F
Cl
Br
6f
6e
6d
97%
93%
91%
NHBn
CN
NHBn
CN
NHBn
CN
S
MeO
N
6i
6g
6h
O
89%
NHBn
CN
91%
90%
NHBn
CN
NHBn
CN
O
6l
93%
6j
79%
6k
70%
[a] Reaction conditions: 1a-l (0.5 mmol), 5a (53.6 mg, 0.5 mmol), KCN (35.8
mg, 0.55 mmol), and SiO2 (240 mg) were milled in a planetary ball mill at 700
rpm for 3 h using a 12 mL agate jar with 20 agate balls of 5 mm in diameter.
centrifugation of the reaction mixture with a minimal amount of
organic solvent allowed an easy separation of the silica gel,
which upon washing with deionized water and drying at 120 °C
for 4 h was reused. This recovered silica gel remained active in
two subsequent milling cycles with just slight erosion in activity
(2nd cycle: conv. 99%, 6a:7a; 95:5; 3rd cycle: conv. 96%, 6a:7a
87:13). On the other hand, a 10-fold scaled-up experiment in the
planetary ball mill using a 45 mL milling vessel afforded the -
aminonitrile 6a in 88% yield, which was consistent with the 90%
of 6a obtained in the standard 0.5 mmol scale reaction (Table 2,
entry 1).
Next, the substrate scope of the mechanochemical Strecker
reaction was evaluated. Again, benzylamine (5a) was used as
the amine component and a series of aldehydes were tested in
the presence of KCN and SiO2 (Table 2). Various
benzaldehydes bearing electron-donating groups afforded the
corresponding -aminonitriles 6a-c in good yields (79-90%) after
3 h of milling. Aromatic aldehydes with electron-withdrawing
substituents on the arene led to the formation of the -amino-
nitriles 6d-g in high yields (91-97%). In the case of heterocyclic
[a] Reaction conditions: carbonyl compound (0.5 mmol), amine (0.5 mmol),
KCN (35.8 mg, 0.55 mmol), and SiO2 (240 mg) were milled in a planetary ball
mill at 700 rpm for 3 h using a 12 mL ZrO2 milling jar with 20 agate balls of 5
mm in diameter. [b] Milling of 1a, 5e and KCN in the absence of silica also
generated the product 8d.
components in the presence of SiO2 afforded the corresponding
-aminonitriles 8a-d in yields ranging from 70% to 95%. In
addition, the more challenging p-toluenesulfonamide (5f)[17] was
utilized as amino component. After 3 h of milling sulfonylamido-
nitrile 8e was obtained in 45%. (Table 3, entry 5). This result
was remarkable considering the low nucleophilicity of the
sulfonamide. In accord with this notion the formation of 8e was
not observed when the reaction was performed in solution
confirming the superiority of the ball milling process. Thus,
stirring a mixture of 1a, 5f, KCN, and SiO2 in acetonitrile-d3 at
ambient temperature for 3 h afforded none of the expected
sulfonylamidonitrile but the corresponding sulfonylimine in trace
quantities (as observed by 1H NMR spectroscopy).
aldehydes,
3-pyridinecarboxaldehyde
(1h),
2-thiophene-
carboxaldehyde (1i) and furfural (1j) the products (6h-j) were
isolated in good yields (79-90%). Finally, cyclohexanecarbox-
aldehyde and cinnamaldehyde reacted with 5a and KCN
providing the corresponding -aminonitriles 6k and 6l in 70%
and 93% yield respectively.
Then, the Strecker reaction was evaluated using different
amines [aniline (5b), piperidine (5c), morpholine (5d) and
methylammonium chloride (5e)] with benzaldehyde (1a) and
KCN (Table 3, entries 1-4). Once again, the milling of the three

Chemistry - A European Journal
10.1002/chem.201603057
SHORT COMMUNICATION
Next, the potential use of ketones as carbonyl components
was investigated. Pleasantly, substrates such as acetophenone
(7a) and cyclohexanone (7b) proved also to be suitable for the
mechanochemical Strecker reaction affording the corresponding
-aminonitriles 8f and 8g in good yields (Table 3, entries 6 and
7). On the other hand, benzophenone (7c) was found to be
unreactive under neat the milling conditions, and no product
formation was observed (Table 3, entry 8). Also the attempts to
facilitate the Strecker reaction by liquid-assisted grinding
(LAG),[18] using either nitromethane or acetonitrile ( = 0.25)
remained unsuccessful. As 7c, 4-fluorobenzophenone and 3,3'-
bis(trifluoromethyl)benzophenone did not react with benzylamine
and KCN, indicating a general insufficient reactivity of diaryl
ketones due to steric effects and increased aryl/carbonyl
conjugation.
Experimental Section
Caution! Potassium cyanide is toxic and may also release
highly toxic hydrogen cyanide. All operations involving KCN
should be conducted in a well-ventilated fume hood.
Typical procedure for the Strecker reaction in the planetary mill:
A
mixture of benzaldehyde (1a) (53.1 mg, 0.50 mmol),
benzylamine (5a) (53.6 mg, 0.50 mmol), KCN (35.8 mg, 0.55
mmol) and SiO2 (240 mg) was milled in a 12 mL agate milling
vessel with 20 agate milling balls of 5 mm in diameter at 700
rpm for 3h. After the milling was complete, the resulting powdery
reaction mixture was extracted with ethyl acetate or CH2Cl2,
washed with aqueous saturated NaHCO3 solution and brine. The
combined organic layers were dried over anhydrous Na2SO4,
concentrated in vacuo and further dried under reduced pressure
to furnish the product.
Finally, we decided to demonstrate the value of the
mechanochemical approach by conducting a one-pot Strecker
N-alkylation sequence synthesis. Milling o-formyl phenethyl
bromide (6m) with benzylamine or aniline and KCN in the
presence of SiO2, afforded tetrahydroisoquinolines (THIQs) 9a-b
in high yields (Scheme 2). This one-pot three-component
sequential reaction exemplifies an advance in complexity of
mechanochemical design to generate privileged structural
scaffolds such as THIQs, which are known for their broad
biological activities and importance as building blocks in the
synthesis of natural products containing the THIQ core.[19]
Acknowledgements
We thank RWTH Aachen University for support from the
Distinguished Professorship Program funded by the Excellence
Initiative of the German federal and state governments.
Keywords: Mechanochemistry • Ball milling • Strecker reaction •
SiO2 • Tetrahydroisoquinolines.
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Conclusions
In summary, we developed an efficient mechanochemical
approach to synthesize -aminonitriles through a one-pot three-
component Strecker reaction. The use of readily available
materials such as Montmorillonite, MgSO4 and, in particular,
SiO2, proved to enhance the cyanation step affording the -
aminonitriles derived from aldehydes, ketones, diverse amines
and KCN in good to high yields. The high efficiency of the
Strecker reaction allowed the one-pot synthesis of tetrahydro-
isoquinolines in excellent yields after a subsequent internal N-
alkylation reaction. Finally, it is important to point out the
remarkable chemical reactivity observed in the mechano-
chemical Strecker reaction by typically considered “inert” milling
auxiliaries. This observation clearly indicates the latent potential
of common additives to induce transformations in the ball mills.
Hence, the intrinsic properties of added auxiliaries should also
be taken into account during the early planning stage of a
mechanosynthesis. The successful synthesis of -aminonitriles
in the ball mill now opens the possibility to explore the
mechanochemical formation of -amino acids upon enzymatic[7]
or chemical hydrolysis[20] of the nitrile group, and research along
these lines is currently ongoing in our group.
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Chemistry - A European Journal
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Chemistry - A European Journal
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