Magnetically recyclable iron oxide nanoparticles for the α-cyanation of amines under acid-free conditions and the formal synthesis of praziquantel

Article abstract of DOI:10.1039/c5ra10552h

A sustainable protocol for the α-cyanation of amines has been developed using cheap and affordable iron oxide nanoparticles under acid free conditions with an easy-to-handle, user-friendly cyanide source, ethyl cyanoformate. The magnetic property of the i

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Magnetically recyclable iron oxide nanoparticles for
the α-cyanation of amines under acid free conditions
and the formal synthesis of Praziquantel†
Cite this: DOI:
10.1039/x0xx00000x
Received 00th June 2015,
Accepted 00th June 2015
Mahendra Patil, Anant R. Kapdi and A. Vijay Kumar*
DOI: 10.1039/x0xx00000x
A sustainable protocol for the
αꢀcyanation of amines has been developed using cheap and
affordable iron oxide nanoparticles under acid free conditions with an easyꢀtoꢀhandle, userꢀ
friendly cyanide source, ethyl cyanoformate. The magnetic property of the iron oxide
nanoparticles facilitated their easy recovery and the recovered particles were found to be
reusable up to five cycles with no loss of activity. Further this methodology was applied for the
formal synthesis of antiꢀschitosome drug Praziquantel. The use of nonꢀtoxic, affordable and
recyclable iron oxide nanoparticles as a catalyst makes this a green protocol.
www.rsc.org/
The CrossꢀDehydrogenativeꢀCoupling (CDC) reaction is a cyanoformate,16 D/Lꢀlactonitrile, malononitrile,17 benzyl
19
versatile tool for the synthesis of various molecules and nitrile18 and KSCN
in combination with oxidants such as
precursors which are medicinally and biologically important.1 H2O2, tertꢀButyl hydrogen peroxide (TBHP), O2 under solvent
The CDC strategy for the synthesis of ꢀcyanated amines is and solventꢀfree conditions.
α
NC
N
advantageous since the imines are generated in situ via CꢀH
N
bond activation thus precluding their separate synthesis from
nano-Fe2O3,TBHP
O
their respective amines. The αꢀcyanation of amines is reported
(or)
with various catalytic systems viz Ru,2 Cu,3 V,4 Au,5 Mo,6 Co,7
Fe,8 I2,9 photo redox conditions,10 acetic acid,11 TEMPO/acetic
acid12 along with nonꢀuser friendly cyanide sources. The
protocols not only generate metal wastes but also require
specialized metal scavengers to make the final products free of
metal salt contaminations. These requisites thus escalate the
cost and render them from being adopted for making
pharmaceuticals and drug molecules. Due to the shortcomings
of the existing protocols, a robust protocol more suitable to be
adopted for industry and academia with features such as easy
recoverability of catalyst, less harsh conditions and user
friendly reagents is highly desirable. Over the recent years
magnetically retrievable nanoparticles based catalysts have
received much attention owing to the advantages of easy
recoverability and nonꢀtoxicity.13 Iron being cheap, abundant
and nonꢀtoxic makes it an affordable catalyst of choice to be
employed in organic synthesis and subsequently qualify them to
be adopted for large scale syntheses. Considering the above
facts, herein we present a protocol based on easily recyclable
iron oxide nanoparticles for the αꢀcyanation of amines under
milder acid free conditions with a user friendly cyanide source ꢀ
ethyl cyanoformate (Scheme 1). Taking into consideration of
these advantages we have screened different iron based
catalysts like nanoꢀFe3O4, FeꢀBTC MOF (Basolite Fꢀ300™),14
bulk Fe2O3, FeIII(OH)(OAc)2, FeCl3, nanoꢀFe2O3, CuFe2O4, etc.
for the alphaꢀcyanation of N,NꢀDimethylaniline with various
cyanide sources such as TMSCN,15 mandelonitrile, ethyl
(or)
NC
OEt
R
R
N
N
R'
R'
CN
Scheme 1. NanoꢀFe2O3 as catalyst for
αꢀcyanation of amines
Table 1. Fe2O3 nps catalysed αꢀcyanation of amines
a isolated yield, Fe2O3 nps (10 mol%), ethyl cyanoformate (2 equiv), TBHP
(2 equiv), MeOH (2 mL), 65o and 16 hrs.
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Of all the catalysts, oxidants and cyanide sources screened,
Fe2O3 nanoparticles (Fe2O3 nps) and ethyl cyanoformate
combination in methanol solvent were found to be best
conditions which afforded the cyanated product in 80%
isolable yield (Table, supporting information).With these
optimized conditions we have further explored the scope of the
method by varying different amine precursors. We were able to
achieve the smooth conversions of different amines like
tetrahydroisoquinolines, pyrrolidines, piperidines, N,
Nꢀ
dimethylanilines, and morpholines to their respective cyanated
products. Almost all of them gave good to moderate yields of
mono cyanated products (Table 1&2).
Figure 1. Images of Iron Oxides recovery a) after b) before reaction
Table 2. Fe2O3 nps catalysed αꢀcyanation of tetrahydroisoquinolines
O
R
nano Fe2O3,TBHP
65oC,18 h
N
R
N
98%
98%
99%
97%
97%
NC
OEt
R'
100%
90%
80%
70%
60%
R'
CN
80%
80%
79%
78%
78%
Yield (%)a
Substrate
Product
R = H, R' = H
R = H, R' = H
80
78
yield (%)
R = H, R' = p-Cl
R = H, R' = p-Cl
50%
40%
30%
20%
10%
0%
R = H, R' = p-OMe
R = H, R' = p-OMe
85
72
70
R = 6.7-OMe, R' = H
R = 6.7-OMe, R' = p-Cl
R = 6.7-OMe, R' = H
R = 6.7-OMe, R' = p-Cl
a isolated yield, isolated yield, Fe2O3 nps (10 mol%), ethyl cyanoformate (2
equiv), TBHP (2 equiv), MeOH (2 mL), 65o and 18 h
1
2
3
4
5
Cycles
Our primary goal in choosing iron oxide nps as catalyst for this
transformation was to bring them in utility to be useful as
recyclable catalysts. So initially the recovered particles were
checked for their recyclability. The particles were easily
recovered with the aid of a simple external laboratory magnet
after the completion of the reactions without the need of any
specialised equipment like ultracentrifuge (or) nanofilters
(Figure 1). The collected particles were used for the next cycle
after methanol wash followed by simple oven drying at 70oC.
The particles were recyclable for five cycles with no loss of
activity and gave the comparable product yields for each cycle
(Figure 2). The surface degradation of nanoparticles and
subsequent leaching is possible in nanocatalysis. Hence it is
mandatory to investigate for surface modifications and
crystallinity of the particles. This was investigated with the help
of techniques like TEM imaging, XRD and ICP studies. Firstly,
the native and the used nanoparticles (fifth cycle) were
analysed by Transmission Electron Microscopy (TEM) for any
possible degradations of surface. Both the TEM images were
almost comparable with no signs of surface degradation, thus
confirming the intactness of particles shape and size (Figure 3).
Similarly the Powder Xꢀray patterns of native and reused
catalysts showed no extra peaks strongly suggesting no
modification in crystallinity despite their usage for several
cycles (Figure 4).
Catalyst recovered
% yield of product
Figure 2. Recyclability of Fe2O3 nanoparticles
Figure 3. TEM images of Iron Oxides (iꢀii) native (iiiꢀiv) after five cycles
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DOI: 10.1039/C5RA10552H
Thus these two spectroscopic techniques endorsed that the detail to understand the mechanism. Having studied the
particles are tolerant and nonꢀdegradative to the reagents and substrate scope and recyclability, we were interested in the
conditions employed. Even though the catalyst is found to be synthesis of a bioactive compound (or) drug using this protocol.
unchanged as seen by XRD,20 FTIR21 and TEM, it is always Surprisingly, amongst the substrates studied in this
advisory to probe for the chances of leached metal species in methodology, the tetrahydroisoquinoline derivatives afforded
the reaction mixture.
the maximum yields, so our attention was drawn into the
synthesis of a tetrahydroisoquinoline ring containing drug
molecule Praziquantel. It is also noteworthy to mention that
Praziquantel is the sole drug for the treatment of
Schistosomiasis, a parasitic infectious disease which is very
prevalent amongst the regions of Africa and SouthꢀEast Asia
and for these reasons the drug is enlisted in the World Health
Organization's List of Essential Medicines.22 We also found
that the CDC cyanation strategy was seldom put to utility for
this drug’s synthesis except a few.23 The retrosynthetic analysis
for the drug synthesis as elucidated could be fragmented to the
4000
(3 1 1)
reused
fresh
3000
2000
1000
0
(2 2 0)
(4 4 0)
(5 1 1)
(4 2 2)
(4 0 0)
respective synthetic equivalents i.e. the
NꢀPMP protected
diamine precursor which can be synthesised by the reduction of
cyanated product, which in turn could be synthesised by using
the developed CDC cyanation of the
tetrahydroisoquinoline (Scheme 2).
NꢀPMP protected
5
10 15 20 25 30 35 40 45 50 55 60 65 70
2θ
Figure 4. Xꢀray powder diffractograms of the fresh and reused γꢀFe2O3
nanoparticles
To find out this we have carefully filtered the particles from
reaction mixtures after the complete conversion of the reactants
and subjected them to ICPꢀAES analysis for Fe species coming
off the particles. The amount of Fe leached into the solution
was found to be only negligible (4ppm) as revealed by ICPꢀ
AES analysis. In another control experiment, the catalyst was
removed from the reaction after 50% conversion of the starting
materials and the reaction was continued without catalyst. No
progress of the starting material conversion was observed even
after prolonged heating. All these results strongly suggests that
the reaction is catalyzed by the Fe nps heterogeneously and the
true catalyst being the iron nps and not the leached species. It is
noteworthy to mention that the reaction did not proceed when
only Fe and peroxides are added separately. The combination of
both Fe and peroxides was essential for the smooth conversion
of the substrates. When TEMPO was added to the reaction
mixture the reaction was found to be nonꢀprogressive, which
suggests that the reaction proceeds through a radical pathway.
Thus, based on all these findings, we envisage that there might
be a synergistic effect of iron nps and peroxides which dually
activates the cyanide reagent and amine (imine generation
through the electrophilic radical intermediate followed by
proton abstraction) and subsequent cyanide addition leading to
the product formation (refer Supporting information for
possible mechanism). This can be the only possible explanation
we can offer at this moment and foresee to further investigate in
Scheme 2. Retrosynthetic analysis of Praziquantel
The synthesis was carried out as planned according to our
retrosynthetic analysis. The cyanated derivative was
synthesized using our Fe nps protocol without any difficulty.
Scheme 3. Formal Synthesis of Praziquantel
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Further reduction using Lithium Aluminium hydride (LAH) of
the cyanated derivative in dry diethyl ether gave the ꢀPMP
8
9
(a) A. Wagner, W. Han, P. Mayer, A.R. Ofial, Adv. Synth.
Catal., 2013, 355, 3058; D. Verma, S. Verma, A. K. Sinha,
S.L. Jain, ChemPlusChem, 2013, 78, 860.
N
protected diamine derivative in 63% yield and the final overall
yield for the two steps is 74% (Scheme 3).24 Finally, we have
succeeded in applying the cyanation methodology developed by
us for the formal synthesis of Praziquantel. Further studies to
elucidate the mechanism of the reaction and to utilise the
methodology for the synthesis of various natural products, drug
molecules is being pursued in our group.
(a) T. Nobuta , N. Tada , A. Fujiya , A. Kariya , T. Miura , A.
Itoh, Org. Lett., 2013, 15, 574; (b) J. D. Kumar, M. Lamani, K.
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Commun., 2011, 47, 12709.
In conclusion we have developed a recyclable protocol
11 H. Ueda, K. Yoshida, H. Tokuyama, Org. Lett., 2014, 16,
for the
α
ꢀcyanation of amines by a CDC reaction under acid
4194.
free conditions using benign and affordable Iron oxide
nanoparticles in combination with a user friendly cyanide
source ꢀ ethyl cyanoformate. The mild reaction conditions and
recyclability of the catalyst makes this a sustainable protocol
12 C. Yan, Y. Liu, Q. Wang, RSC Adv. 2014, 4, 60075.
13 For recent reviews, books and articles on magnetically
recoverable catalysts and nanocatalysis please refer these and
the references cited therein (a) B. Karimi, F. Mansouri, H. M.
Mirzaei, ChemCatChem 2015, doi 10.1002/cctc.201403057;
for the synthesis of αꢀcyanated amines. Also the formal total
synthesis of the antiꢀSchistosomiasis drug Praziquantel was
achieved with the developed cyanation method as the key step.
(b) R. B. N. Baig, R. S. Varma, Chem. Commun., 2013, 49
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The authors are grateful to SAIFꢀIITB for the providing
the TEM, ICPꢀAES and XRD analysis. MP is grateful to CSIR,
Govt. of India for the research fellowship. AVK is thankful to
DST, Govt. of India for the INSPIRE Faculty Award [IFA12ꢀ
CHꢀ40] and research funding. Institute of Chemical Technology
(ICT) is acknowledged for providing the research facilities.
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†
Electronic Supplementary Information (ESI) available: Experimental
procedures, 1HꢀNMR, 13CꢀNMR for all compounds are available. See
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Raney®Ni afforded the decyanated
tetrahydroisoquinoline.
NꢀPMP protected
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