Acetone Cyanohydrin: A Convenient Alternative
883
communication we wish to report a successful application
of acetone cyanohydrins as a convenient and efficient
source of in situ HCN for the oxidative cyanation of ter-
tiary amines 2 to a-aminonitriles 3 by using hydrogen
peroxide as oxidant and ruthenium trichloride as catalyst
under mild reaction conditions (Scheme 1). Although
Murahashi et al. [24] have reported the detailed results and
mechanism for this transformation using ruthenium tri-
chloride as catalyst with H2O2 with NaCN in acetic acid.
acid is essential. We have used methanol as solvent for this
reaction, albeit the reaction could be proceeded well with
comparable results under solvent free conditions as shown
in Table 1, entry 1. The effect of catalyst was confirmed by
carrying out a blank experiment without using any catalyst
under otherwise similar reaction conditions. The reaction
did not occur in the absence of catalyst even after pro-
longed reaction time (24 h). In addition, the drop wise
addition of hydrogen peroxide to the reaction mixture was
found to be better than its addition in one portion.
Further, we extended the scope of the developed method
by using various tertiary amines 2 as substrates with ace-
tone cyanohydrin 1 under described reaction conditions at
50 °C. As shown in Table 1, all the substrates were effi-
ciently converted into the corresponding a-aminonitriles,
affording higher product yields with selective formation of
the desired products. Reaction of substituted N,N-dime-
thylanilines having both electron-donating and electron-
withdrawing substituents were gave better yields of cor-
responding cyanated products (entries 2–5) without any
evidence of the formation of by-products. Similarly, the
reaction could also be applied efficiently to cyclic amines:
Piperidine, pyrrolidine, and tetrahydroisoquinoline deriva-
tives under described reaction conditions (Table 1, entries
6–8). Tertiary amines such as tributylamine did not
undergo any reaction under these reaction conditions and
the substrates could be recovered at the end (Table 1, entry
9). We also repeated the selected experiments at room
temperature and compared with the results reported in the
literature by using NaCN/acetic acid as shown in Table 1
(entries 1, 2, 4, 6).
2 Results and Discussion
Acetone cyanohydrin was synthesized by using the stan-
dard method [27] and stored at room temperature without
taking any special care. Initially the oxidative cyanation of
N,N-dimethylaniline was studied for comparing the effi-
ciency of acetone cyanohydrin with NaCN/CH3COOH
under the similar reaction conditions as developed by
Murahashi et al. at room temperature. The results of these
experiments are summarized in Table 1 (entry 1). The use
of acetone cyanohydrin was found to be as efficient as
NaCN/acetic acid system and afforded comparable results.
The important advantage of the acetone cyanohydrin was
its slow and controlled addition to the reaction mixture,
which provided an improved and efficient cyanation of
tertiary amines in the present reaction. By using a syringe
pump acetone cyanohydrin could easily be added to the
reaction mixture continuously in a slow and controlled
manner, which further avoids the accumulation of excess
cyanide into the reaction mixture. At the end the reaction,
the reaction mixture was quenched with 1 N HCl in order
to decompose excess acetone cyanohydrin. The aqueous
layer was extracted with dichloromethane and subjected to
usual work-up, afforded the corresponding nitrile selec-
tively without any by-product being observed.
Although, the mechanism of reaction is not clear at this
stage, the probable mechanistic pathway for the reaction
will be in analogy with the mechanism proposed by
Murahashi et al. [24] as shown in Scheme 2.
While at 50 °C the reaction was found to be faster and
afforded better product yield without any significant effect
on the selectivity of the desired product. However, further
increase in reaction temperature affected the product
selectivity adversely (Table 1, entry 1). It is worthy to
mention that we did not use acetic acid in case of acetone
cyanohydrin, whereas, with NaCN the presence of acetic
3 Conclusion
In summary, we have demonstrated the first successful
application of acetone cyanohydrin as the convenient
source of in situ HCN for the oxidative cyanation of var-
ious tertiary amines to the corresponding a-aminonitriles
without using acetic acid as solvent. The presented method
is more advantageous than the existing methods since
acetone cyanohydrin is cheap and comparatively safer in
handling than NaCN/acetic acid for an organic reaction
which not only avoids the use of toxic reagent but also its
liquid nature provides the controlled addition of the cya-
nide in the reaction mixture. We believe that the presented
work will provide new opportunities and open up new
possibilities for the use of acetone cyanohydrin as a con-
venient source of HCN for other organic transformations.
CN
O
HCN
+
OH
1
R1
R1
RuCl3.nH2O (5 mol%)
H2O2
CH3OH, reflux
N CH2R3
1
N CHR3
CN
+
R2
R2
2
3
Scheme 1 Oxidative cyanation of tertiary amines
123
Verma, Sanny
