Catalyst-free synthesis of 4-acyl-NH-1,2,3-triazoles by water-mediated cycloaddition reactions of enaminones and tosyl azide

Article abstract of DOI:10.3762/bjoc.14.210

The synthesis of 4-acyl-NH-1,2,3-triazoles has been accomplished with high efficiency through the cycloaddition reactions between N,N-dimethylenaminones and tosyl azide. This method is featured with extraordinary sustainability by employing water as the s

Full text of DOI:10.3762/bjoc.14.210

Catalyst-free synthesis of 4-acyl-NH-1,2,3-triazoles by
water-mediated cycloaddition reactions of
enaminones and tosyl azide
Lu Yang1, Yuwei Wu1, Yiming Yang1, Chengping Wen*2 and Jie-Ping Wan*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2348–2353.
1College of Chemistry and Chemical Engineering, Jiangxi Normal
University, Nanchang 330022, P. R. China and 2College of Basic
Medical Sciences, Zhejiang Chinese Medical University, Hangzhou
310053, P. R. China
doi:10.3762/bjoc.14.210
Received: 03 July 2018
Accepted: 22 August 2018
Published: 07 September 2018
Email:
Chengping Wen* - cpwen.zcmu@yahoo.com; Jie-Ping Wan* -
wanjieping@jxnu.edu.cn
Associate Editor: L. Vaccaro
© 2018 Yang et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
additive-free; catalyst-free; cycloaddition; enaminones; on water;
1,2,3-triazole
Abstract
The synthesis of 4-acyl-NH-1,2,3-triazoles has been accomplished with high efficiency through the cycloaddition reactions be-
tween N,N-dimethylenaminones and tosyl azide. This method is featured with extraordinary sustainability by employing water as
the sole medium, free of any catalyst or additive, authentically mild conditions (40 °C stirring) as well as practical scalability.
Introduction
Discovering sustainable chemical syntheses constitutes one research of water-mediated or promoted organic syntheses, in-
central issue of modern organic chemistry. A large number of cluding those reactions involving valuable C–C [7-11],
strategies and concepts promoting sustainable syntheses have C–heteroatom [12-16], heteroatom–heteroatom [17,18] bond
been conceived over the past decades. Methods employing formation as well as divergent cascade reactions [19-23], are
water as reaction medium are amongst the most promising ones presently taking place to guide the progress of sustainable
by avoiding the application of volatile organic solvents during organic synthesis.
the reaction process [1-3]. Besides acting as a safer and envi-
ronmentally benign alternative to organic solvents, on water 1,2,3-Triazole is a heterocyclic moiety showing exceptionally
reactions are known for their accelerated reaction rates and im- broad and important applications as privileged structure in the
proved synthetic selectivity [4-6]. Being inspired by these com- discovery of biologically functional scaffolds, organic materi-
monly recognized green features, flourishing advances in the als preparation, as directing group in transition-metal-catalyzed
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Beilstein J. Org. Chem. 2018, 14, 2348–2353.
transformations and as key building block in the synthesis of Results and Discussion
numerous organic compounds [24-28]. The amazingly rapid and To start the work, the reaction of enaminone 1a and tosyl azide
broad permeation of 1,2,3-triazoles to multidisciplinary areas (2) was tentatively run in water by heating at 60 °C in the pres-
can majorly be attributed to the occurrence of robust synthetic ence of t-BuONa, which provided NH-1,2,3-triazole product 3a
methods toward this heterocycle. The copper-catalyzed click with 52% yield together with N,N-dimethyl tosyl amide as by-
[3 + 2] cycloaddition of azides and alkynes [29-32], for exam- product (entry 1, Table 1). Varying the additive to AcOH didn’t
ple, has served enormously to the advances in both the prepara- lead to an improved result (entry 2, Table 1). To our delight, the
tion and application of 1,2,3-triazoles. In addition, the discovery parallel entry without using any catalyst or additive afforded 3a
of other metal-catalyzed alkyne–azide cycloadditions (MAAC) with identically good yield (entry 3, Table 1). With this encour-
providing 1,2,3-triazoles with diverse substitution patterns trig- aging result, we then carried out a systematic screen of the reac-
gers the continuous development of these metal-catalyzed tion parameters using water as the fixed reaction medium. First,
cycloaddition strategies [33-35]. Alongside the vast progress a slight increase in the loading of tosyl azide was able to
happened in MAAC-based 1,2,3-triazole synthesis, the past evidently enhance the yield of 3a (entries 4 and 5, Table 1).
decade has witnessed the emergence of another powerful cyclo- Furthermore, the examination on the impact of the reaction tem-
addition tool for the 1,2,3-triazole synthesis: the metal-free perature led to the observation of an excellent product yield by
cycloaddition of azides with activated dipolarophiles. As syn- running the reaction at 40 °C (entries 6–8, Table 1). The varia-
thetic tools being able to provide 1,2,3-triazoles using an tion on the volume of the water, on the other hand, gave no
organocatalyst or other non-metal catalysts, this method shows better reaction results (entries 9 and 10, Table 1). Finally, a
distinctive advantages in enabling the production of 1,2,3-tri- control experiment employing EtOH as the reaction medium
azoles free of any heavy metal contamination [36-38].
gave 3a with evidently lower yield than the equivalent reaction
using water (entry 11, Table 1).
Generally, the cycloaddition of azides with activated dipolaro-
philes such as strained cyclic alkynes, enamines, enolates, elec-
tron-deficient olefins, ylides, iminium cations and alkyne
anions, etc., have been identified as reliable approaches to
access 1,2,3-triazole scaffolds with multiple substitution
patterns [39-44]. In addition, the azide-free annulation has
evolved also as another sustainable strategy for the synthesis of
many 1,2,3-triazoles in the past decade [45-50]. More notably,
besides occurring as active intermediate in the enamine-medi-
ated cycloaddition for 1,2,3-triazole construction, enamines
with good stability and easy availability such as enaminones
have exhibited also conspicuously versatile application in the
metal-free synthesis of divergent 1,2,3-triazoles by directly
acting as starting materials [51-54]. In 2016, Dehaen and
co-workers [55] reported the synthesis of N-substituted 1,2,3-
triazoles via the reactions of organoazides and the in situ pre-
pared N,N-dimethylenaminones by 150 °C microwave irradia-
tion and subsequent heating in toluene at 100 °C, providing an
effective protocol of enaminone-based 1,2,3-triazole synthesis.
Interestingly, our continuous adventure in enaminone-based
organic transformations has led us to the discovery that the
cycloaddition of N,N-dimethylenaminones and tosyl azide effi-
ciently affords NH-1,2,3-triazoles with water as the only medi-
um, and not any catalyst or additive is required. Considering the
featured functions of NH-1,2,3-triazoles [56-61] as well as the
Table 1: Screen and optimization of the reaction conditions.a
entry
T (°C)
additive
yield (%)b
1
60
60
60
60
60
80
100
40
40
40
40
t-BuONa
52
45
52
75
76
80
72
89
83
83
22
2
AcOH
3
–
–
–
–
–
–
–
–
–
4c
5d
6c
7c
8c
9c,e
10c,f
11c,g
aGeneral conditions: enaminone 1a (0.2 mmol), tosyl azide (2,
0.2 mmol), additive (1 equiv) were stirred for 20 h in water (2.0 mL).
bYield of isolated product based on 1a. c0.3 mmol 2. d0.24 mmol 2.
eH2O (3 mL) was used. fH2O (1 mL) was used. gEtOH was used as al-
ternative reaction medium.
urgent desire in finding more sustainable methods enabling To examine the scope of this water-mediated 1,2,3-triazole syn-
1,2,3-triazole synthesis, we report herein our results in the thesis, a broad range of enaminones 1 was then employed to
water-mediated, catalyst-free synthesis of NH-1,2,3-triazoles react with tosyl azide under the optimal conditions. According
through the cycloaddition of enaminone and sulfonyl azide with to the acquired results (Figure 1), satisfactory tolerance of this
mild heating (40 °C) and simple operation.
water-mediated, catalyst-free protocol was verified by the
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Beilstein J. Org. Chem. 2018, 14, 2348–2353.
Figure 1: Scope of the water-mediated synthesis of 4-acyl-NH-1,2,3-triazoles. General conditions: enaminone 1 (0.2 mmol), tosyl azide 2 (0.3 mmol)
and water (2 mL), stirred at 40 °C for 20 h (yields of isolated products are based on 1).
smooth synthesis of the 4-acyl-NH-1,2,3-triazoles 3a–t contain- substituent in the aryl ring of 1. However, when methyl-functio-
ing versatile substructures (Figure 1). Besides the successful nalized enaminone, N,N-dimethyl nitroenaminone, N,N-
reactions employing enaminones independently containing elec- dimethyl cyanoenaminone, or pyridine-3-yl-functionalized
tron-withdrawing and donating groups in the phenyl ring (H, enaminone was individually utilized, the expected reaction did
alkyl, alkoxyl, halogen, CF3 and cyano, etc.), the substitution in not take place (3u–x, Figure 1). Moreover, it is notable that no
ortho- (3n, 3o, Figure 1) and meta-position of the phenyl ring N-sulfonyl-1,2,3-triazole was isolated from any of the above ex-
(3k–m, Figure 1) were also readily compatible with the synthe- periments, indicating the excellent chemoselectivity of the
sis. More notably, those enaminones functionalized with disub- present synthetic method.
stituted phenyls (3p–r, Table 2) as well as heteroaryl-based
enaminones (3s and 3t, Figure 1) also participated in the reac- In order to illustrate the potential application of this authenti-
tion to provide the divergently functionalized NH-1,2,3-tri- cally green synthetic method, a gram scale synthesis of product
azoles. The products were generally furnished with good to 3a was conducted starting from enaminone 1a and tosyl azide
excellent yield, and the variation of product yields was found to (2). As expected, this entry turned out to be highly efficient
associate with both the electron property and the sites of the affording product 3a with excellent yield (Scheme 1). In addi-
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Beilstein J. Org. Chem. 2018, 14, 2348–2353.
Scheme 1: The gram scale synthesis of 3a: (a) before reaction; (b) completed reaction; (c) the purified product 3a.
tion, the appearance of the reaction mixture before and after the the acidic C–H bond at the α-position of the acyl group, which
reaction indicated the reaction as a heterogeneous “on water” affords N-tosyl-1,2,3-triazole 5. Under the present reaction
process (Scheme 1).
conditions, the intermediate 5 can undergo aminolysis and/or
hydrolysis to provide the target products 3. The participation of
Based on the known works employing organic solvents for sim- water throughout the reaction also explains the high efficiency
ilar synthesis and the present results [55], a possible mecha- of the method using water as reaction medium.
nism for the reaction is proposed (Scheme 2). The reaction
starts from the cycloaddition of enaminones 1 and tosyl azide Conclusion
(2) to provide 1,2,3-triazoline 4 which couples to water by In summary, by means of the cycloaddition reactions between
strong hydrogen bond effect [51]. The presence of the hydro- tertiary enaminones and tosyl azide employing water the sole
gen bonds may promote the elimination of the amino group and reaction medium, a series of 4-acyl-NH-1,2,3-triazoles has been
Scheme 2: The proposed reaction mechanism.
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Beilstein J. Org. Chem. 2018, 14, 2348–2353.
13.Xiao, F.; Chen, S.; Tian, J.; Huang, H.; Liu, Y.; Deng, G.-J.
efficiently synthesized under catalyst-free and very mild heating
conditions, thus providing the first water-mediated metal-free
method toward the synthesis of 4-acyl-NH-1,2,3-triazoles. The
present method benefits from unique sustainability not only due
to the metal/additive-free cycloaddition reaction, but also by
applying the completely green reaction medium water and mild
reaction temperature.
Green Chem. 2016, 18, 1538. doi:10.1039/C5GC02292D
14.Liu, K.-J.; Fu, Y.-L.; Xie, L.-Y.; Wu, C.; He, W.-B.; Peng, S.; Wang, Z.;
Bao, W.-H.; Cao, Z.; Xu, X.; He, W.-M. ACS Sustainable Chem. Eng.
2018, 6, 4916. doi:10.1021/acssuschemeng.7b04400
15.Wu, C.; Xin, X.; Fu, Z.-M.; Xie, L.-Y.; Liu, K.-J.; Wang, Z.; Li, W.;
Yuan, Z.-H.; He, W.-M. Green Chem. 2017, 19, 1983.
doi:10.1039/C7GC00283A
16.Li, W.; Yin, G.; Huang, L.; Xiao, Y.; Fu, Z.; Xin, X.; Liu, F.; Li, Z.; He, W.
Green Chem. 2016, 18, 4879. doi:10.1039/C6GC01196A
17.Tang, L.; Yang, Y.; Wen, L.; Yang, X.; Wang, Z. Green Chem. 2016,
18, 1224. doi:10.1039/C5GC02755A
Supporting Information
18.Lin, Y.-m.; Lu, G.-p.; Wang, G.-x.; Yi, W.-b. J. Org. Chem. 2017, 82,
382. doi:10.1021/acs.joc.6b02459
Supporting Information File 1
General experimental information, experimental details of
the synthesis of products 3, full characterization data as
well as 1H/13C NMR spectra of all products.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-210-S1.pdf]
19.Köhling, S.; Exner, M. P.; Nojoumi, S.; Schiller, J.; Budisa, N.;
Rademann, J. Angew. Chem., Int. Ed. 2016, 55, 15510.
doi:10.1002/anie.201607228
20.Chen, D.; Feng, Q.; Yang, Y.; Cai, X.-M.; Wang, F.; Huang, S.
Chem. Sci. 2017, 8, 1601. doi:10.1039/C6SC04504A
21.Yang, J.; Mei, F.; Fu, S.; Gu, Y. Green Chem. 2018, 20, 1367.
doi:10.1039/C7GC03644B
22.Liu, J.; Lei, M.; Hu, L. Green Chem. 2012, 14, 2534.
doi:10.1039/c2gc35745c
Acknowledgements
This work is financially supported by the National Natural
Science Foundation of China (no. 21562025), Natural Science
Foundation of Jiangxi Province (20161ACB21010) and an
Open Project of the Key Laboratory of Rheumatic Diseases of
Traditional Chinese Medicine in Zhejiang Province.
23.Reddy, G. T.; Kumar, G.; Reddy, N. C. G. Adv. Synth. Catal. 2018,
360, 995. doi:10.1002/adsc.201701063
24.Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2003, 8, 1128.
doi:10.1016/S1359-6446(03)02933-7
25.Nandivada, H.; Jiang, X.; Lahann, J. Adv. Mater. 2007, 19, 2197.
doi:10.1002/adma.200602739
26.Thirumurugan, P.; Matosiuk, D.; Jozwiak, K. Chem. Rev. 2013, 113,
4905. doi:10.1021/cr200409f
ORCID® iDs
Jie-Ping Wan - https://orcid.org/0000-0002-9367-8384
27.Chen, Z.; Liu, Z.; Gao, G.; Li, H.; Ren, H. Adv. Synth. Catal. 2017, 359,
202. doi:10.1002/adsc.201600918
28.Xie, L.-Y.; Qu, J.; Peng, S.; Liu, K.-J.; Wang, Z.; Ding, M.-H.; Wang, Y.;
Cao, Z.; He, W.-M. Green Chem. 2018, 20, 760.
doi:10.1039/C7GC03106H
References
1. Lipshutz, B. H.; Ghorai, S.; Cortes-Clerget, M. Chem. – Eur. J. 2018,
24, 6672. doi:10.1002/chem.201705499
29.Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565.
doi:10.1002/anie.196305651
2. Simon, M.-O.; Li, C.-J. Chem. Soc. Rev. 2012, 41, 1415.
doi:10.1039/C1CS15222J
30.Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001,
40, 2004.
3. Anastas, P.; Eghbali, N. Chem. Soc. Rev. 2010, 39, 301.
doi:10.1039/B918763B
doi:10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO
;2-5
4. Gawande, M. B.; Bonifácio, V. D. B.; Luque, R.; Branco, P. S.;
Varma, R. S. Chem. Soc. Rev. 2013, 42, 5522.
doi:10.1039/c3cs60025d
31.Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057. doi:10.1021/jo011148j
5. Butler, R. N.; Goyne, A. G. Chem. Rev. 2010, 110, 6302.
doi:10.1021/cr100162c
32.Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302.
doi:10.1039/b904091a
6. Chanda, A.; Fokin, V. V. Chem. Rev. 2009, 109, 725.
doi:10.1021/cr800448q
33.Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams, I. D.;
Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127,
15998. doi:10.1021/ja054114s
7. Guo, W.; Wu, B.; Zhou, X.; Chen, P.; Wang, X.; Zhou, Y.-G.; Liu, Y.;
Li, C. Angew. Chem., Int. Ed. 2015, 54, 4522.
34.Destito, P.; Couceiro, J. R.; Faustino, H.; López, F.; Mascareñas, J. L.
Angew. Chem., Int. Ed. 2017, 56, 10766. doi:10.1002/anie.201705006
35.Johansson, J. R.; Lincoln, P.; Nordén, B.; Kann, N. J. Org. Chem.
2011, 76, 2355. doi:10.1021/jo200134a
doi:10.1002/anie.201409894
8. Li, Y.; Huang, Y.; Gui, Y.; Sun, J.; Li, J.; Zha, Z.; Wang, Z. Org. Lett.
2017, 19, 6416. doi:10.1021/acs.orglett.7b03299
9. Zhang, F.-Z.; Tian, Y.; Li, G.-X.; Qu, J. J. Org. Chem. 2015, 80, 1107.
doi:10.1021/jo502636d
36.Ramasastry, S. S. V. Angew. Chem., Int. Ed. 2014, 53, 14310.
doi:10.1002/anie.201409410
10.Álvarez, M.; Gava, R.; Rodríguez, M. R.; Rull, S. G.; Pérez, P. J.
ACS Catal. 2017, 7, 3707. doi:10.1021/acscatal.6b03669
11.Zhang, N.; Yang, D.; Wei, W.; Yuan, L.; Nie, F.; Tian, L.; Wang, H.
J. Org. Chem. 2015, 80, 3258. doi:10.1021/jo502642n
12.Xie, L.-Y.; Li, Y.-J.; Qu, J.; Duan, Y.; Hu, J.; Liu, K.-J.; Cao, Z.;
He, W.-M. Green Chem. 2017, 19, 5642. doi:10.1039/C7GC02304A
37.Lima, C. G. S.; Ali, A.; van Berkel, S. S.; Westermann, B.;
Paixão, M. W. Chem. Commun. 2015, 51, 10784.
doi:10.1039/C5CC04114G
38.Thomas, J.; Jana, S.; John, J.; Liekens, S.; Dehaen, W.
Chem. Commun. 2016, 52, 2885. doi:10.1039/C5CC08347H
2352

Beilstein J. Org. Chem. 2018, 14, 2348–2353.
39.Ramachary, D. B.; Shashank, A. B.; Karthik, S. Angew. Chem., Int. Ed.
2014, 53, 10420. doi:10.1002/anie.201406721
License and Terms
40.Li, W.; Wang, J. Angew. Chem., Int. Ed. 2014, 53, 14186.
doi:10.1002/anie.201408265
This is an Open Access article under the terms of the
Creative Commons Attribution License
41.Agard, N. J.; Preschner, J. A.; Bertozzi, C. R. J. Am. Chem. Soc. 2004,
126, 15046. doi:10.1021/ja044996f
(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.
42.Ramachary, D. B.; Ramakumar, K.; Narayana, V. V. Chem. – Eur. J.
2008, 14, 9143. doi:10.1002/chem.200801325
43.Belkheira, M.; Abed, D. E.; Pons, J.-M.; Bressy, C. Chem. – Eur. J.
2011, 17, 12917. doi:10.1002/chem.201102046
44.Kwok, S. W.; Fotsing, J. R.; Fraser, R. J.; Rodionov, V. O.; Fokin, V. V.
Org. Lett. 2010, 12, 4217. doi:10.1021/ol101568d
45.Wan, J.-P.; Hu, D.; Liu, Y.; Sheng, S. ChemCatChem 2015, 7, 901.
doi:10.1002/cctc.201500001
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(https://www.beilstein-journals.org/bjoc)
46.Chen, Z.; Cao, G.; Song, J.; Ren, H. Chin. J. Chem. 2017, 35, 1797.
doi:10.1002/cjoc.201700459
The definitive version of this article is the electronic one
which can be found at:
47.van Berkel, S. S.; Brauch, S.; Gabriel, L.; Henze, M.; Stark, S.;
Vasilev, D.; Wessjohann, L. A.; Abbas, M.; Westermann, B.
Angew. Chem., Int. Ed. 2012, 51, 5343. doi:10.1002/anie.201108850
48.Chen, Z.; Yan, Q.; Liu, Z.; Zhang, Y. Chem. – Eur. J. 2014, 20, 17635.
doi:10.1002/chem.201405057
doi:10.3762/bjoc.14.210
49.Cai, Z.-J.; Lu, X.-M.; Zi, Y.; Yang, C.; Shen, L.-J.; Li, J.; Wang, S.-Y.;
Ji, S.-J. Org. Lett. 2014, 16, 5108. doi:10.1021/ol502431b
50.Wan, J.-P.; Cao, S.; Liu, Y. J. Org. Chem. 2015, 80, 9028.
doi:10.1021/acs.joc.5b01121
51.Bakulev, V. A.; Beryozkina, T.; Thomas, J.; Dehaen, W.
Eur. J. Org. Chem. 2018, 262. doi:10.1002/ejoc.201701031
and references cited therein.
52.Cheng, G.; Zeng, X.; Shen, J.; Wang, X.; Cui, X.
Angew. Chem., Int. Ed. 2013, 52, 13265. doi:10.1002/anie.201307499
53.Wan, J.-P.; Cao, S.; Liu, Y. Org. Lett. 2016, 18, 6034.
doi:10.1021/acs.orglett.6b02975
54.Efimov, I.; Bakulev, V.; Beliaev, N.; Beryozkina, T.; Knippschild, U.;
Leban, J.; Zhi-Jin, F.; Eltsov, O.; Slepukhin, P.; Ezhikova, M.;
Dehaen, W. Eur. J. Org. Chem. 2014, 3684.
doi:10.1002/ejoc.201402130
55.Thomas, J.; Goyvaerts, V.; Liekens, S.; Dehaen, W. Chem. – Eur. J.
2016, 22, 9966. doi:10.1002/chem.201601928
56.Thomas, J.; Jana, S.; Liekens, S.; Dehaen, W. Chem. Commun. 2016,
52, 9236. doi:10.1039/C6CC03744E
57.Cohrt, A. E.; Jensen, J. F.; Nielsen, T. E. Org. Lett. 2010, 12, 5414.
doi:10.1021/ol102209p
58.Hu, Q.; Liu, Y.; Deng, X.; Li, Y.; Chen, Y. Adv. Synth. Catal. 2016, 358,
1689. doi:10.1002/adsc.201600098
59.Qvortrup, K.; Nielsen, T. E. Chem. Commun. 2011, 47, 3278.
doi:10.1039/c0cc05274d
60.Deng, X.; Lei, X.; Nie, G.; Jia, L.; Li, Y.; Chen, Y. J. Org. Chem. 2017,
82, 6163. doi:10.1021/acs.joc.7b00752
61.Bakulev, V. A.; Beryozkina, T. A. Chem. Heterocycl. Compd. 2016, 52,
4. doi:10.1007/s10593-016-1821-y
2353