Reactions of 3-(p-substituted-phenyl)-5-chloromethyl-1,2,4-oxadiazoles with KCN leading to acetonitriles and alkanes via a non-reductive decyanation pathway

Article abstract of DOI:10.3762/bjoc.14.280

The present work describes an unfamiliar reaction of 5-(chloromethyl)-3-substituted-phenyl-1,2,4-oxadiazoles with KCN affording trisubstituted 1,2,4-oxadiazol-5-ylacetonitriles and their parent alkanes, namely, 1,2,3-trisubstituted-1,2,4-oxadiazol-5-ylpro

Full text of DOI:10.3762/bjoc.14.280

Reactions of 3-(p-substituted-phenyl)-5-chloromethyl-1,2,4-
oxadiazoles with KCN leading to acetonitriles and alkanes
via a non-reductive decyanation pathway
Akın Sağırlı* and Yaşar Dürüst
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 3011–3017.
Department of Chemistry, Faculty of Arts & Sciences, Bolu Abant
Izzet Baysal University, Bolu, TR14030, Turkey
doi:10.3762/bjoc.14.280
Received: 06 October 2018
Accepted: 28 November 2018
Published: 10 December 2018
Email:
Akın Sağırlı* - sagirli_a@ibu.edu.tr
* Corresponding author
Associate Editor: J. A. Murphy
Keywords:
© 2018 Sağırlı and Dürüst; licensee Beilstein-Institut.
decyanation; KCN; 1,2,4-oxadiazole
License and terms: see end of document.
Abstract
The present work describes an unfamiliar reaction of 5-(chloromethyl)-3-substituted-phenyl-1,2,4-oxadiazoles with KCN affording
trisubstituted 1,2,4-oxadiazol-5-ylacetonitriles and their parent alkanes, namely, 1,2,3-trisubstituted-1,2,4-oxadiazol-5-ylpropanes.
To the best of our knowledge, the current synthetic route leading to decyanated products will be the first in terms of a decyanation
process which allows the transformation of trisubstituted acetonitriles into alkanes by the incorporation of KCN with the associa-
tion of in situ-formed HCN and most likely through the extrusion of cyanogen which could not be detected or isolated. In addition,
the plausible mechanisms were proposed for both transformations. The structures of the title compounds were identified by means
of IR, 1H NMR, 13C NMR, 2D NMR spectra, TOF–MS and X-ray measurements.
Introduction
Heterocyclic scaffolds bearing 1,2,4-oxadiazole rings have been On the other hand, arylacetonitriles are known as valuable inter-
the subject of an increasing and remarkable attention due to mediates that are generally obtained by the reaction of benzyl
their various bioactivities, such as anticancer [1], antimicrobial halides with appropriate cyanating agents such as KCN [14],
[2], antifungal [3], anti-inflammatory [4], tyrosine kinase inhibi- TMSCN [15], K4(Fe(CN)6 [16]. Deprotonation of the α-carbon
tion [5] and histamine H3 antagonism properties [6]. In addi- (adjacent to nitrile) by strong bases, especially lithiated ones,
tion, these five-membered heterocycles were widely used as resulted in an anionic species that easily undergoes a substitu-
components of organic light emitting diodes (OLEDs), poly- tion reaction with various alkyl halides to afford mono-, di- or
mers, liquid crystals, and solar cells [7-10]. Taking into account trialkylated acetonitriles [17]. Most recently, Strzalko and
the above considerations, new synthetic protocols to develop co-workers disclose mono and dialkylation of the benzylic car-
1,2,4-oxadiazole-based heterocycles have gained an increasing bon of phenylacetonitrile with a poor selectivity by benzyl and
attention over the recent decades [11-13].
methyl halides in the presence of LiHMDS, LDA or n-BuLi
3011

Beilstein J. Org. Chem. 2018, 14, 3011–3017.
(Figure 1) [18]. However, such alkylation methods need harsh alkali metals in a variety of solvents [26]. Generally, they
reaction conditions, most particularly lithiated bases and inert require mostly an inert atmosphere as well as harsh reaction
atmosphere.
conditions. These facts constitute challenges to the develop-
ment of mild reaction conditions in the reduction of nitrilated
compounds.
In the light of the above considerations, we report here an unfa-
miliar example of non-reductive decyanation through the reac-
tion of 5-(chloromethyl)-3-(substituted-phenyl)-1,2,4-oxadia-
zoles 1 with 2 equiv of KCN at 100 °C in a single step transfor-
mation.
Figure 1: Synthesis of mono- or dialkylated acetonitriles.
In order to get a deeper understanding of the limitation step of Results and Discussion
alkylation processes and to extend their scope in the synthesis In the first part of this work, 5-(chloromethyl)-3-(substituted-
of mono-, di- or trialkylated structures, cyanation attempts of phenyl)-1,2,4-oxadiazoles 1 were obtained via a previously
5-(chloromethyl)-3-phenyl-1,2,4-oxadiazoles 1 with excess published literature procedure by reacting p-substituted benz-
KCN at room temperature in CH3CN have been investigated amidoximes with chloroacetyl chloride in refluxing benzene
leading to trisubstituted acetonitrile 3 instead of anticipated [27]. After having been obtained the starting oxadiazoles, our
product 2. This result is in accord with a previous report where goal was to replace the chlorine atom with a CN− anion by a
only one example (3a) has been exploited by providing very simple SN2 reaction. For this purpose, 5-chloromethyl-1,2,4-
limited structural data [19]. Interestingly, increasing the reac- oxadiazole 1a was reacted with 10 equiv of KCN in CH3CN at
tion temperature to 100 °C yielded 1,2,4-oxadiazole-substituted reflux, after completion of the reaction on the basis of TLC, sur-
propanes 4 as the major products which can only be interpreted prisingly we obtained a mixture of products 4 (major) and 3
via a decyanation pathway of cyanated oxadiazoles 3 (Figure 2). (minor, Table 1, entry 1). This unexpected product distribution
of the reaction prompted us to investigate the reaction of
Up to date, various methods have been reported for the conver- 5-(chloromethyl)-3-(p-substituted-phenyl)-1,2,4-oxadiazoles 1
sion of organic nitriles into the parent alkanes; such as oxida- with KCN.
tive decyanation [20], dehydrocyanation [21] and more com-
monly, reductive decyanation [22]. Among them, the reductive Our initial effort was to investigate the limitation of the reac-
decyanation is a widely used method employing metal hydrides tion. For this, the effect of temperature on this reaction was ex-
[23], electrolysis [24], transition metal complexes [25], and amined in CH3CN with various equivalents of KCN and
Figure 2: Cyanation through 5-chloromethyl-3-(p-substituted-phenyl)-1,2,4-oxadiazole.
3012

Beilstein J. Org. Chem. 2018, 14, 3011–3017.
Table 1: Optimisation of reaction conditions.
Yield (%)b
Entry
KCN (equiv)a
Conditions
4a
3a
1
2
10
10
10
10
2
CH3CN, 80 °C, 3 h
CH3CN, 80 °C, 12 h
CH3CN, 100 °C, 12 h
CH3CN, 110 °C, 12 h
CH3CN, 100 °C, 24 h
CH3CN, rt, 12 h
55
70
32
15
3
75
trace
trace
trace
85
4
75
5c
6
75
10
6
trace
trace
trace
–
7
CH3CN, rt, 20 h
85
8d
9
4
CH3CN, rt, 24 h
85
2
CH3CN, rt, 24 h
52
aEquivalent of KCN respect to 1a. bAll yields were calculated after purification by flash chromatography. cThe most effective method for the formation
of 4a. dThe most effective method for the formation of 3a.
varying reaction times (Table 1, entries 2–6). Treatment of 1a substituents in compounds 1f and 1g with 2 equiv of KCN at
with 10 equiv of KCN at 100 °C gave mainly product 4a with a 100 °C (method A) afforded only the products 4f and 4g, re-
yield of 75%, as well as product 3a in trace amounts even when spectively, in a shorter reaction time (Table 2, entries 6 and 7).
heating at 110 °C. Due to the toxic nature of KCN, the
minimum amount of KCN was determined for optimal forma- However, due to the replacement of the nitrile group with
tion of 4a. When 2 equiv of KCN was used instead of 10 equiv hydrogen after decyanation in product 4, the methylenic protons
at 100 °C in CH3CN, the reaction proceeded to give compound and the methinic proton resonates at around 4–5 ppm as
4a with a yield of 75% again, but 24 h for completion of the doublets and 5 ppm as pentet, respectively (Figure 3). The ali-
reaction were needed.
phatic protons of title compounds 3 and 4 were also assigned on
the basis of HSQC and HMBC NMR experiments. The
In further trials, we aimed to decrease the reaction temperature expanded HSQC spectrum of 3a showed the C2 carbon at 35
from 100 °C to room temperature in CH3CN using 10 equiv of ppm which corresponds to the methylenic hydrogens H2. In ad-
KCN. In this case, the reaction ended with the formation of dition, the HSQC spectrum of 4a showed that the H1 proton lo-
compound 3a as a major product (85%) and decyanated prod- cated between the methylene coupled with the C1 carbon and
uct 4a was obtained in trace amounts. To optimize the reaction that the methylene protons H2 were incorporated in the C2 car-
conditions for compound 3a, different equivalents of KCN have bon signal.
been tried. We were pleased to find that the use of 4 equiv KCN
in CH3CN gave the desired product 3a in high yield with a trace Fortunately, the exact structures of compounds 3a and 4e were
amount of decyanated product 4a.
also confirmed by X-ray structures (Figure 4). The CIF data of
3a and 4e have been deposited at Cambridge Crystallographic
After having the optimized reaction conditions, 5-(chloro- Data Centre with the deposition numbers 1844118 and
methyl)-3-(p-substituted-phenyl)-1,2,4-oxadiazoles 1 were 1832133.
reacted sequentially with 2 equiv of KCN in CH3CN at 100 °C
and 4 equiv of KCN in CH3CN at room temperature giving the We propose a plausible mechanism for the transformation of
title compounds 3 and 4 as major products in high yields chloromethyloxadiazoles 1 into the title products 3 and 4. Ac-
(75–85%, Table 2). Interestingly, incorporation of electron-poor cordingly, the reaction of 1 with a CN− anion gives
3013

Beilstein J. Org. Chem. 2018, 14, 3011–3017.
Table 2: Formation of 3 and their parent alkanes 4.
Yield (%)
Method Aa
Method Bb
Entry
Substrate
4
3
3
4
3
4
1
2
3
4
5
6
7
8
9
1a: R = H
4a: R = H; X = H
3a: R = H; X = CN
3b: R = Cl; X = CN
3c: R = I; X = CN
trace
75
70
68
65
72
82c
78d
70
72
85
78
72
70
82
78
75
78
76
5
1b: R = Cl
4b: R = Cl; X = H
4c: R = I; X = H
7
trace
trace
trace
5
1c: R = I
5
1d: R = F
4d: R = F; X = H
3d: R = F; X = CN
3e: R = CH3; X = CN
3f: R = NO2; X = CN
3g: R = CF3; X = CN
3h: R = OCH3; X = CN
3j: R = SCH3; X = CN
7
1e: R = CH3
1f: R = NO2
1g: R = CF3
1h: R = OCH3
1j: R = SCH3
4e: R = CH3; X = H
4f: R = NO2; X = H
4g: R = CF3; X = H
4h: R = OCH3; X = H
4j: R = SCH3; X = H
trace
–
–
5
7
15
12
trace
trace
aCH3CN, 2 equiv KCN, 100 °C, 12 h bCH3CN, 4 equiv KCN, rt, 24 h cCH3CN, 2 equiv KCN, 100 °C, 6 h dCH3CN, 2 equiv KCN, 100 °C, 8 h.
Figure 4: X-ray ORTEP plots of 3a and 4e.
cyanomethyloxadiazole by simple SN2 reaction. Then, the
acidic hydrogen adjacent to the nitrile group in the intermediate
product is sequentially abstracted by a CN− anion with the
extrusion of an HCN molecule and a carbanion alpha to the
nitrile group bearing a 1,2,4-oxadiazole ring is formed. The
Figure 3: Expanded HSQC spectrum of 4a and 3a.
resulted carbanion undergoes a substitution reaction with
3014

Beilstein J. Org. Chem. 2018, 14, 3011–3017.
another molecule of 1, affording di-1,2,4-oxadiazole-substi- sion) possibly since it is the only proton source in the reaction
tuted acetonitrile, which then undergoes a second substitution medium. This unfamiliar decyanation reaction presumably
reaction with another molecule of 1, in the same manner, finally proceeds through product 3. First, in the presence of CN−
affording title compound 3 (Scheme 1).
anions, cyanoimine salt intermediate A forms by addition to a
nitrile. Then, a possible cyanogen release would occur to form
Considering the formation of product 4, as we believe, the tem- intermediate B. The imine–enamine tautomerization of B by the
perature plays a significant role upon formation of it and in situ- effect of in situ-generated HCN results in the desired
formed HCN facilitates the decyanation (nitrile–alkane conver- decyanated product 4 (Scheme 2).
Scheme 1: Plausible mechanism for the formation of 3.
Scheme 2: Plausible mechanism for the formation of 4 via decyanation of 3.
3015

Beilstein J. Org. Chem. 2018, 14, 3011–3017.
8. Li, Q.; Cui, L.-S.; Zhong, C.; Jiang, Z.-Q.; Liao, L.-S. Org. Lett. 2014,
16, 1622–1625. doi:10.1021/ol5002494
Conclusion
In summary, we reported a convenient one-pot protocol for the
synthesis of 3 and its transformation into 4 via a decyanation
pathway by the reaction of 5-(chloromethyl)-3-(p-substituted-
phenyl)-1,2,4-oxadiazoles 1 with KCN at different tempera-
tures. This decyanation method is the first example for the
conversion of a nitrile group into an alkane by using
KCN–HCN associates through a possible release of cyanogen
which is not detected or isolated. This synthetic protocol seems
to be applicable for further decyanation processes containing a
1,2,4-oxadiazole moiety.
9. Guo, J.; Hua, R.; Sui, Y.; Cao, J. Tetrahedron Lett. 2014, 55,
1557–1560. doi:10.1016/j.tetlet.2014.01.066
10.Li, Q.; Cui, L.-S.; Zhong, C.; Yuan, X.-D.; Dong, S.-C.; Jiang, Z.-Q.;
Liao, L.-S. Dyes Pigm. 2014, 101, 142–149.
doi:10.1016/j.dyepig.2013.09.029
11.Wang, W.; Xu, H.; Xu, Y.; Ding, T.; Zhang, W.; Ren, Y.; Chang, H.
Org. Biomol. Chem. 2016, 14, 9814–9822. doi:10.1039/c6ob01794k
12.Kuram, M. R.; Kim, W. G.; Myung, K.; Hong, S. Y. Eur. J. Org. Chem.
2016, 438–442. doi:10.1002/ejoc.201501502
13.Grant, D.; Dahl, R.; Cosford, N. D. P. J. Org. Chem. 2008, 73,
7219–7223. doi:10.1021/jo801152c
14.Chidambaram, M.; Sonavane, S. U.; de la Zerda, J.; Sasson, Y.
Tetrahedron 2007, 63, 7696–7701. doi:10.1016/j.tet.2007.05.017
15.Ren, Y.; Dong, C.; Zhao, S.; Sun, Y.; Wang, J.; Ma, J.; Hou, C.
Tetrahedron Lett. 2012, 53, 2825–2827.
Supporting Information
Supporting Information File 1
doi:10.1016/j.tetlet.2012.03.109
16.Brunel, J.-M.; Holmes, I. P. Angew. Chem., Int. Ed. 2004, 43,
2752–2778. doi:10.1002/anie.200300604
Experimental details, characterization data and copies of
NMR spectra.
17.Tsao, J.-P.; Tsai, T.-Y.; Chen, I.-C.; Liu, H.-J.; Zhu, J.-L.; Tsao, S.-W.
Synthesis 2010, 4242–4250. doi:10.1055/s-0030-1258301
18.Strzalko, T.; Wartski, L.; Corset, J.; Castellà-Ventura, M.; Froment, F.
J. Org. Chem. 2012, 77, 6431–6442. doi:10.1021/jo300758g
19.Jaunin, R. Helv. Chim. Acta 1966, 49, 412–419.
doi:10.1002/hlca.660490146
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-280-S1.pdf]
Acknowledgements
TÜBİTAK (Turkish Scientific and Technological Research
Council, grant no. 115Z581) is gratefully acknowledged for
financial support
20.Parker, K. A.; Kallmerten, J. L. Tetrahedron Lett. 1979, 20, 1197–1200.
doi:10.1016/s0040-4039(01)86101-3
21.Ahlbrecht, H.; Raab, W.; Vonderheid, C. Synthesis 1979, 127–129.
doi:10.1055/s-1979-28587
22.Too, P. C.; Chan, G. H.; Tnay, Y. L.; Hirao, H.; Chiba, S.
Angew. Chem., Int. Ed. 2016, 55, 3719–3723.
References
doi:10.1002/anie.201600305
1. Moniot, S.; Forgione, M.; Lucidi, A.; Hailu, G. S.; Nebbioso, A.;
Carafa, V.; Baratta, F.; Altucci, L.; Giacché, N.; Passeri, D.;
Pellicciari, R.; Mai, A.; Steegborn, C.; Rotili, D. J. Med. Chem. 2017,
60, 2344–2360. doi:10.1021/acs.jmedchem.6b01609
23.Marshall, J. A.; Bierenbaum, R. J. Org. Chem. 1977, 42, 3309–3311.
doi:10.1021/jo00440a029
24.Franck-Neumann, M.; Miesch, M.; Lacroix, E.; Mertz, B.; Ken, J.-M.
Tetrahedron 1992, 48, 1911–1926.
2. O’Daniel, P. I.; Peng, Z.; Pi, H.; Testero, S. A.; Ding, D.; Spink, E.;
Leemans, E.; Boudreau, M. A.; Yamaguchi, T.; Schroeder, V. A.;
Wolter, W. R.; Llarrull, L. I.; Song, W.; Lastochkin, E.; Kumarasiri, M.;
Antunes, N. T.; Espahbodi, M.; Lichtenwalter, K.; Suckow, M. A.;
Vakulenko, S.; Mobashery, S.; Chang, M. J. Am. Chem. Soc. 2014,
136, 3664–3672. doi:10.1021/ja500053x
doi:10.1016/s0040-4020(01)88514-8
25.Chang, K.-J.; Rayabarapu, D. K.; Cheng, C.-H. J. Org. Chem. 2004,
69, 4781–4787. doi:10.1021/jo049506g
26.Yamada, S.-i.; Tomioka, K.; Koga, K. Tetrahedron Lett. 1976, 17,
61–64. doi:10.1016/s0040-4039(00)71323-2
27.Ağırbaş, H.; Sümengen, D.; Dürüst, Y.; Dürüst, N. Synth. Commun.
1992, 22, 209–217. doi:10.1080/00397919208021295
3. Karad, S. C.; Purohit, V. B.; Thummar, R. P.; Vaghasiya, B. K.;
Kamani, R. D.; Thakor, P.; Thakkar, V. R.; Thakkar, S. S.; Ray, A.;
Raval, D. K. Eur. J. Med. Chem. 2017, 126, 894–909.
doi:10.1016/j.ejmech.2016.12.016
4. Heimann, D.; Börgel, F.; de Vries, H.; Bachmann, K.; Rose, V. E.;
Frehland, B.; Schepmann, D.; Heitman, L. H.; Wünsch, B.
Eur. J. Med. Chem. 2018, 143, 1436–1447.
doi:10.1016/j.ejmech.2017.10.049
5. Leite, A. C. L.; Vieira, R. F.; de Faria, A. R.; Wanderley, A. G.;
Afiatpour, P.; Ximenes, E. C. P. A.; Srivastava, R. M.;
de Oliveira, C. F.; Medeiros, M. V.; Antunes, E.; Brondani, D. J.
Farmaco 2000, 55, 719–724. doi:10.1016/s0014-827x(00)00099-9
6. Yang, X.; Liu, G.; Li, H.; Zhang, Y.; Song, D.; Li, C.; Wang, R.; Liu, B.;
Liang, W.; Jing, Y.; Zhao, G. J. Med. Chem. 2010, 53, 1015–1022.
doi:10.1021/jm9011565
7. Wei, H.; He, C.; Zhang, J.; Shreeve, J. N. M. Angew. Chem., Int. Ed.
2015, 54, 9367–9371. doi:10.1002/anie.201503532
3016

Beilstein J. Org. Chem. 2018, 14, 3011–3017.
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0). Please note
that the reuse, redistribution and reproduction in particular
requires that the authors and source are credited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(https://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.14.280
3017