Isothiourea-catalysed transfer hydrogenation of α,β-unsaturated para-nitrophenyl esters

Article abstract of DOI:10.1016/j.tet.2020.131758

A protocol for the isothiourea-catalysed transfer hydrogenation of α,β-unsaturated para-nitrophenyl esters using Hantzsch ester has been developed. Good to excellent yields are observed using α,β-unsaturated aryl esters bearing electron-withdrawing β-subs

Full text of DOI:10.1016/j.tet.2020.131758

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Isothiourea-catalysed transfer hydrogenation of α,β-unsaturated para-nitrophenyl
esters
Wu Jiufeng, Claire M. Younga, Andrew D. Smitha
PII:
S0040-4020(20)30992-3
https://doi.org/10.1016/j.tet.2020.131758
TET 131758
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 October 2020
Revised Date: 30 October 2020
Accepted Date: 5 November 2020
Please cite this article as: Jiufeng W, Younga CM, Smitha AD, Isothiourea-catalysed transfer
hydrogenation of α,β-unsaturated para-nitrophenyl esters, Tetrahedron, https://doi.org/10.1016/
j.tet.2020.131758.
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Isothiourea-catalyzed transfer
hydrogenation of α,β-unsaturated para-
nitrophenyl esters
Jiufeng Wu,a Claire M. Young,a, and Andrew D. Smitha*
Leave this area blank for abstract info.
aEastCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife, UK, KY16 9ST

1
Tetrahedron
journal homepage: www.elsevier.com
Isothiourea-catalysed transfer hydrogenation of α,β-unsaturated para-nitrophenyl
esters
Jiufeng Wu,a Claire M. Young,a, and Andrew D. Smitha*
aEastCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife, UK, KY16 9ST
ARTICLE INFO
ABSTRACT
Article history:
Received
Abstract: A protocol for the isothiourea-catalysed transfer hydrogenation of α,β-unsaturated
para-nitrophenyl esters using Hantzsch ester has been developed. Good to excellent yields are
Received in revised form
Accepted
Available online
observed using α,β-unsaturated aryl esters bearing electron-withdrawing β-substituents. The aryl
ester products can either be isolated directly in moderate to excellent yields (7 examples, 16–
98%) or converted to the corresponding methyl esters (2 examples, 68–70% yield) or benzyl
amides (2 examples, 44–88% yield) after in situ reaction of the hydrogenated ester with the
appropriate nucleophile. Preliminary experiments showed that modest enantioinduction (76:24
er) is possible when a chiral isothiourea catalyst was used.
This manuscript is dedicated to the memory of Professor
Jon Williams who was a leader and inspiration in the field
of organic chemistry and catalysis.
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Transfer hydrogenation
Isothiourea
Organocatalysis
Hantzsch ester
1. Introduction
Hantzsch esters, for example 2, are often considered as
NADPH analogues and have found particular prevalence in
organocatalysis
The hydrogenation of carbon-carbon double bonds is an
important transformation both in Nature and in synthetic
chemistry. The general synthetic approach uses a metal catalyst
and hydrogen gas. Although useful, this technique has associated
drawbacks, in particular the use of highly flammable hydrogen
gas, often at high pressure. The hydrogenation of carbon-carbon
double bonds conjugated with electron withdrawing groups (such
as carbonyl-containing esters or ketones) can be approached
differently due to the polarisation of the target bond. While the
presence of this additional functionality can lead to
chemoselectivity issues due to multiple reactive sites in the
molecule, there are many reported methods that overcome this
issue. For example, metal catalysts and hydrogen gas can be
used, as demonstrated in Stryker’s seminal publication where
reactive copper hydride selectively reduces the carbon-carbon
double bond of α,β-unsaturated enones.1 Avoiding the use of
hydrogen gas, catalytically generated metal hydrides can be
accessed using a range of metals (eg. Cu, Co, Rh) and various
reducing agents (eg. borohydrides, silanes).2,3,4 Importantly,
metal-catalysed hydrogenations have been extended to α,β-
unsaturated esters and amides5 while the use of chiral ligands
allows for the stereoselective reduction of prochiral substrates.6
An alternative strategy involves the use of transfer
hydrogenation, with significant contributions in this area found
from the pioneering work of Williams.7

2
Tetrahedron
Figure 2: Reactivity of α,β-unsaturated acyl ammonium intermediates
At the onset of these studies, α,β-unsaturated para-nitrophenyl
(PNP) ester 7 was proposed as a model substrate on which to
perform reaction optimisation (Table 1). Using Hantzch ester 2 as
the formal hydrogen source and DHPB 6 as Lewis base catalyst
in CH2Cl2 at 40 °C, no conversion to hydrogenated product 10
was observed (Entry 1). Increasing reaction temperature was next
probed, with solvents of higher boiling point used to facilitate
this. Pleasingly, around 30% conversion to 10 was observed in
CHCl3 (60 °C) and THF (66 °C) (Entries 2 and 3). Moving to
benzene allowed the reaction to be performed at 80 °C and
resulted in 63% conversion (Entry 4). In an effort to increase
conversion, increasing equivalents of 2 were used. Moving to 2
equivalents gave 10 in improved 75% yield but increasing further
to 4 equivalents led to low 42% conversion that was ascribed to
the heterogeneous nature of the reaction mixture (Entries 5 and
6). Performing the reaction with archetypal Lewis base catalyst
DMAP 13 led to no conversion, while increasing the loading of
DHPB 6 to 20% gave an increased conversion of 80% (Entries 7
and 8). As a control, performing the reaction in the absence of 6
again led to no conversion to product (Entry 9). A further control
reaction was performed to determine if catalyst deactivation was
occurring through direct reaction between 2 and 6, however
heating a stoichiometric mixture of 2 and 6 in benzene at 80 °C
led to no reaction. Alternative aryl esters 8 and 9, that have been
successfully employed as α,β-unsaturated acyl isothiouronium
precursors, were also tested but no product conversion was
observed (Entries 10 and 11). Taking the conditions in Entry 8 as
optimal, 10 was isolated in 60% yield (Entry 9) but it was noted
that some hydrolysis of both the starting material and ester
products was occurring.
Figure 1: Organocatalytic transfer hydrogenations
for conjugate reductions (Figure 1a).8,9 Important classes of
organocatalysts used in tandem with this class of reagent include
thioureas, phosphoric acids and Lewis bases, for example
secondary amines.9 An early example of Lewis base catalysed
hydrogen transfer was reported by List in 2004 (Figure 1b).10
N,N-Dibenzylamine was shown to catalyse the reduction of enals
under mild reaction conditions using Hantzsch ester 2 as the
reducing agent and significantly showed that the reaction could
proceed enantioselectively when a chiral catalyst 1 was used
giving aldehyde 4 in 81% yield and 90:10 er. Further
developments followed this initial proof of concept using the
same principle for the enantioselective hydrogenation of enals,11
enones12 and nitroalkenes.13
Despite these advances, to the best of our knowledge the
organocatalysed transfer hydrogenation of α,β-unsaturated esters
has not been demonstrated to date. To allow such a process to
proceed, we proposed the use of catalytically generated α,β-
unsaturated acyl isothiouronium intermediates. In early reports of
catalysis via α,β-unsaturated acyl isothiouronium species,
cyclisation products were required to allow catalyst turnover.14 In
recent publications, we have demonstrated that apposite choice of
electron deficient aryl esters can facilitate addition of carbon
Table 1: Scope of isolated amides
nucleophiles
to
α,β-unsaturated
acyl
isothiouronium
intermediates, with catalyst release promoted by the aryl oxide
initially derived from the acylating agent (Figure 2a).15 Building
upon this work, in this manuscript we demonstrate the
organocatalytic transfer hydrogenation of α,β-unsaturated aryl
esters using isothiourea catalysis (Figure 2b).
Entry
Ester Solvent
T /
°C
Cat.
(mol%)
2
Yield /
%
a
(equiv)

3
1
7
7
7
7
7
7
7
7
7
8
9
CH2Cl2
CHCl3
40
60
66
80
80
80
80
80
80
80
80
6 (10)
6 (10)
6 (10)
6 (10)
6 (10)
6 (10)
13 (10)
6 (20)
-
1.3
1.3
1.3
1.3
2.0
4.0
2.0
2.0
2.0
2.0
2.0
0
to column chromatography. Therefore, for further exploration
of the scope, addition of coupling agent (EDCI) and benzylamine
after the hydrogen transfer was complete gave stable amide
products 22 and 23 (Figure 4). Using this protocol, β-aryl ester
substrates containing electron withdrawing substituents could be
used, leading to the formation of amides 23 and 24 in excellent to
moderate yields (88% and 44%, respectively). Substrates with β-
aryl substituents bearing electron-donating groups 24 and 25 as
well as β-furyl 26, led to no product formation consistent with the
requirement for an electron withdrawing β-substituent observed
previously (Figure 4).
2
32
3
THF
29
4
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
63
5
75
6
42
7
0
8
80(60)b
9
0
0
0
i) 2 (4.0 eq.), 6 (20 mol%)
benzene, 80 °C, 16 h
O
O
10
11
6 (20)
6 (20)
Ar
OPNP
Ar
NHBn
ii) EDCI (1.0 eq.)
i-Pr2NEt (1.0 eq.)
BnNH2 (5.0 eq.)
22-23
PNP = 4-NO2C6H4
a Determined by 1H NMR analysis of the crude material. b isolated yield
O
O
The scope and limitations of this process under the developed
NHBn
NHBn
conditions was explored. Despite high conversion of starting
material for a range of substrates (all > 80%), the isolated yields
were variable (16–89%) and highly substrate dependent (Figure
3). First, variation of β-substituent (R1) was explored. Substrates
substituted with an electron-withdrawing group were suitable for
the reaction. Ester 14 was formed in only 16% yield. Pleasingly,
15 could be isolated in good 64% yield from β-methyl substituted
starting material. Trifluoromethyl substituted 16 was isolated in
excellent 89% and notably, the reaction was not limited to the p-
nitrophenyl ester, with 2,4,6-trichlorophenyl (TCP) ester 17
isolated in good 67% yield. Significantly, a disubstituted
substrate could be successfully used, giving chiral ester 18 in
73% isolated yield. Some limitations were also observed with
β,β-dimethyl substituted variant 19 and β-isopropyl 20 giving no
conversion, presumably indicative of the requirement for an
electron withdrawing β-substituent within the substrate for
effective reduction. α-Methyl 21 also led to no conversion despite
the expected high reactivity of the terminal alkene but is
consistent with past observations that α-substituted α,β-
unsaturated esters are typically unreactive in isothiourea
catalysis.
22 88%
23 44%
F3C
Br
Unsuccessful substrates
O
O
O
O
OPNP
OPNP
OPNP
24
25
26
H3C
MeO
Figure 4: Scope of amides from in situ derivatisation. All yields given are
isolated yields after flash column chromatography.
Despite promising results, the use of benzene as solvent was
recognised as non-ideal due to its toxicity. Toluene is generally
accepted as a safer alternative to benzene, in terms of both
environmental impact and human toxicity.16 While no reactivity
was observed using toluene at 80 °C, further optimisation showed
that upon heating to reflux good conversion to product was
observed, allowing the isolation of model compound 10 in 55%
yield (Figure 5). Using this protocol, substrates with electron-
withdrawing β-substituents
R2
O
R2
O
2 (2.0 eq.)
R1
OPNP
R1
OPNP
6 (20 mol%)
PNP = 4-NO2C6H4
10, 14-18, 27-30
PNP = 4-NO2C6H4
were well tolerated, giving 14 and 27 in good 55 and 59% yields.
Pleasingly, 15 was isolated in excellent 98% yield, while both
PNP and TCP esters could be used to give trifluoromethyl
examples 16 and 17 in 78% and 67% yields respectively. Again,
a disubstituted substrate could be successfully used, giving chiral
ester 18 in 70% yield. The scope of β-aryl substituents was also
explored, with 28 formed in 59% yield. As an alternative
approach to in situ derivatisation, a selection of examples was
treated with methanol after completion of the transfer
hydrogenation, leading to the formation of methyl esters 29 and
30 in very good yields (68% and 70%, respectively).
benzene, 80 °C, 16 h
O
O
N
O
OPNP
H3C
OPNP
14 16%
15 64%a
Cl
Cl
O
O
CH3 O
F3C
OPNP F3C
O
F3C
OPNP
Cl
16 89%
17 67%
18 73%
Unsuccessful substrates
CH3
O
O
O
H3C
OPNP i-Pr
OPNP
OPNP
21
19
20
CH3
Figure 3: Scope of isolated esters. All yields given are isolated yields
after flash column chromatography.
The inconsistent isolated yields of p-nitrophenyl esters was
proposed to be a result of both hydrolysis of the starting esters
and ester products, as well as the instability of the product esters

4
Tetrahedron
O
O
2 (2.0 eq.)
6 (20 mol%)
R
OPNP
R
OPNP
PNP = 4-NO2C6H4
10, 14-18, 27-30
PNP = 4-NO2C6H4
toluene, 110 °C, 16 h
O
O
O
N
Ph
Ph
OPNP
OPNP
OPNP
O
O
27 59%
10 55%
14 59%
Cl
O
Cl
O
O
H3C
OPNP F3C
15 98%
OPNP F3C
16 78%
O
Cl
17 67%
O
CH3
O
OPNP
F3C
OPNP
O
18 70%
28 59%
Br
O
OMe
OMe
O2N
29 68%
30 70%
Figure 5: Scope of isolated para-nitrophenyl esters and methyl esters
from in situ derivatisation. All yields given are isolated yields after flash
column chromatography
The successful formation of chiral ester 18, provided the
attractive prospect of performing the transfer hydrogenation
enantioselectively. Use of chiral isothiourea 31 in toluene at
reflux led to 18 in 74% yield but with limited stereocontrol
(56:44 er, Table 2, Entry 1).17 Reduction of the temperature and
performing the reaction in both toluene and benzene at 80 °C was
next investigated. In toluene, a lower isolated product yield was
obtained (49%) but with an increase in er observed (63:37 er)
(Entry 2). In benzene a higher yield (70%) and slightly increased
er (71:29 er) was observed (Entry 1). Lowering the reaction
temperature to 60 °C in benzene gave an increase in er (75:25)
but led to a significant decrease in yield (40%) (Entry 4).
Although this demonstrates proof of concept for the
enantioselective transfer hydrogenation protocol, the high
temperature required was concluded to be incompatible with high
enantioselectivity so no further experiments were performed.

5
Table 2: Enantioselective transfer hydrogenation
Research Merit Award. We also thank the EPSRC UK National
Mass Spectrometry Facility at Swansea University.
iPr
N
S
References and notes
Ph
N
CH3
O
CH3 O
32 (10 mol%)
F3C
OPNP
F3C
OPNP
1. For seminal examples, see: a) W. S. Mahoney, J. M. Stryker, J.
Am. Chem. Soc. 1989, 111, 8818–8823; b) J. M. Grosselin, C.
2 (2.0 eq.)
solvent, T °C, 16 h
31
(S)-18
PNP = 4-NO2C6H4
PNP = 4-NO2C6H4
Yield %a
Mercier, G. Allmang, F. Grass, Organometallics, 1991, 10, 2126–
2133; c) V. V. Grushin, H. Alper, Organometallics, 1991, 10,
831–833.
Entry
Solvent
T / °C
110
erb
1
2
3
4
Toluene
Toluene
74
49
70
40
56:44
63:37
71:29
75:25
2. a) B. H. Lipshutz, B. A. Frieman, A. E. Tomaso Jr., Angew. Chem.
2018, 130, 6637–6641; Angew. Chem. Int. Ed. 2006, 45, 1259 –
1264; b) B. H. Lipshutz, B. A. Frieman, J. B. Unger, D. M. Nihan,
Can. J. Chem., 2005, 83, 606–614; c) B. A. Baker, Ž. V.
Bošković, B. H. Lipshutz, Org. Lett. 2008, 10, 289–282; d) B. H.
Lipshutz, J. M. Servesko, B. R. Taft, J. Am. Chem. Soc. 2004, 126,
8352–8353.
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M. Kikuchi, Y. Yamamoto, H. Nishiyama, Chem. Eur. J., 2006,
12, 69–71
80
Benzene
Benzene
80
60
a Isolated yield after flash column chromatography. b Enantiomeric ratio
determined by HPLC analysis on a chiral stationary phase.
Consistent with previous studies,15a,18 the reaction is proposed
to proceed via acylation of catalyst 6 by ester 7 to form α,β-
unsaturated acyl isothiouronium I, which along with
intermediates II and III contains a stabilising intramolecular 1,5-
4. U. Leutenegger, A. Madin, A. Pfaltz, Angew. Chem. 1989, 101,
61–62; Angew. Chem. Int. Ed. 1989, 28, 60–61.
5. For selected examples, see: a) W. S. Mahoney, D. M. Brestensky,
J. M. Stryker, J. Am. Chem. Soc. 1988, 110, 291-293; b) D. H.
Appella, Y. Moritani, R. Shintani, E. M. Ferreira, S. L. Buchwald,
J. Am. Chem. Soc. 1999, 121, 9473-9474; c) G. Hughes, M.
Kimura, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125, 11253–
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Zhang, ACS Catal. 2018, 8, 4824−4828.
6. For a review, see: D. J. Ager, A. H. M de Vries, J. G. de Vries,
Chem. Soc. Rev. 2012, 41, 3340–3380; M. Shevlin, M. R.
Friedfeld, H. Sheng, N. A. Pierson, J. M. Hoyt, L.-C. Campeau, P.
J. Chirik, J. Am. Chem. Soc. 2016, 138, 3562–3569.
OꢀꢀꢀS interaction.19 Hydride transfer from
2 leads to
intermediate II which can subsequently be protonated to give
acyl isothiouronium III. Formally, the Hantzsch ester serves as
the source for this proton via pyridinium V but involvement of 4-
nitrophenol, the conjugate acid if aryl oxide IV, in this proton
transfer is also possible and cannot be ruled out. Subsequent
reaction of intermediate III with aryl oxide IV leads to the
formation of the ester product 10 and release of catalyst 6.
7. For selected examples, see: a) P. J. Black, M. G. Edwards, J. M. J.
Williams, Eur. J. Org. Chem. 2006, 2006, 4367–4378; b) P. J.
Black, G. Cami-Kobeci, M. G. Edwards, P. A. Slatford, M. K.
Whittlesey J. M. J. Williams, Org. Biomol. Chem. 2006, 4, 116–
125; c) A. E. W. Ledger, P. A. Slatford, J. P. Lowe, M. F. Mahon,
M. K. Whittlesey, J. M. J. Williams, Dalton Trans. 2009, 716–
722.
8. A. Hantzsch, Ber. Dtsch. Chem. Ges., 1881, 14, 1637
9. A. M. F. Phillips, A. J. L. Pombeiro, Org. Biomol. Chem. 2017,
15, 2307–2340.
10. J. W. Yang, M. T. Hechavarria Fonseca, B. List, Angew. Chem.
2004, 116, 6829 –6832; Angew. Chem. Int. Ed., 2004, 43, 6660–
6662.
11. For selected examples of organocatalytic transfer hydrogenation
of enals, see: a) J. W. Yang, M. T. Hechavarria Fonseca, N.
Vignola, B. List, Angew. Chem. 2005, 117, 110 –112; Angew.
Chem. Int. Ed., 2005, 44, 108–110; b) J. W. Yang, M. T.
Hechavarria Fonseca, B. List, J. Am. Chem. Soc., 2005, 127,
15036–15037; c) S. G. Ouellet, J. B. Tuttle, D. W. C. MacMillan,
J. Am. Chem. Soc. 2005, 127, 32–33; d) Y.-H. Chen, D.-H. Li, Y.-
K. Liu, ACS Omega, 2018, 3, 16615–16625.
12. a) N. J. A. Martin, B. List, J. Am. Chem. Soc., 2006, 128, 13368–
13369; b) J. B. Tuttle, S. G. Ouellet, D. W. C. MacMillan, J. Am.
Chem. Soc., 2006, 127, 12662–12663.
13. a) N. J. A. Martin, L. Ozores and B. List, J. Am. Chem. Soc., 2007,
129, 8976–8977; b) N. J. A. Martin, X. Cheng and B. List, J. Am.
Chem. Soc., 2008, 130, 13862–13863; c) J. F. Schneider, M. B.
Lauber, V. Muhr, D. Kratzer and J. Paradies, Org. Biomol. Chem.,
2011, 9, 4323–4327.
14. For a review, see: a) S. Vellalath, D. Romo, Angew. Chem. Int.
Ed, 2016, 55, 13934–13943 and references therein. For seminal
examples see: b) E. R. T. Robinson, C. Fallan, C. Simal, A. M. Z.
Slawin, A. D. Smith, Chem. Sci. 2013, 4, 2193–2200; c) S.
Vellalath, K. N. Van, D. Romo, Angew. Chem. 2013, 125, 13933 –
13938; Angew. Chem. Int. Ed. 2013, 52, 13688–13693; d) G. Liu,
M. E. Shirley, K. N. Van, R. L. McFarlin, D. Romo, D. Nat.
Chem. 2013, 5, 1049–1057. For selected recent examples, see: e)
Y.-C. Zhang, R.-L. Geng, J. Song, L.-Z. Gong, Org. Lett., 2020,
22, 2261–2265; f) J.-H. Jin, X.-Y. Li, X. Luo, W.-P. Deng,
Tetrahedron, 2018, 74, 6804–6808; g) D. M. Leace, M. R. Straub,
B. A. Matz, V. B. Birman, J. Org. Chem.. 2019, 84, 7523–7531;
h) Y. Fukata, K. Yao, R. Mitaji, K. Asano, S. Matsubata, J. Org.
Chem., 2017, 82, 12655–12668; i) M. E. Abbasov, B. M. Hudson,
D. J. Tantillo, D. Romo, Chem. Sci. 2017, 8, 1511–1524; j) G.
Scheme 1: Proposed catalytic cycle.
In conclusion, an isothiourea catalysed transfer hydrogenation
of α,β-unsaturated aryl esters has been developed. The reaction
proceeds well in both benzene and toluene giving aryl ester
products in moderate to excellent yields (7 examples, 16–98%) as
well as methyl esters (2 examples, 38–70% yield) and benzyl
amides (2 examples, 44–88% yield) after in situ reaction of the
hydrogenated ester with the appropriate nucleophile. Preliminary
experiments showed that enantioinduction was possible when a
chiral isothiourea catalyst was used however, the observed
enantioselectivity (75:25 er) was only modest.
Acknowledgments
The research leading to these results (JW) has received
funding from the ERC under the European Union's Seventh
Framework Programme (FP7/2007–2013)/ERC grant agreement
no 279850. ADS thanks the Royal Society for a Wolfson

6
Tetrahedron
Kang, M. Yamagami, S. Vellalath, D. Romo, Angew. Chem.
2018, 130, 6637–6641; Angew. Chem. Int. Ed. 2018, 57, 6527–
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Smith, Synthesis, 2017, 49, 409-423.
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Z. Slawin, A. D. Smith, Angew. Chem. 2017, 129, 12450–12455;
Angew. Chem. Int. Ed., 2017, 56, 12282–12287; b) C. Shu, H. Liu,
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3879–3890.
17. The absolute configuration of 34 was not unambiguously
assigned, but the major enantiomer was predicted based on known
stereochemical models that rely upon the known configuration of
HyperBTM and the predictable sense of enantioinduction at C(3)
using α,β-unsaturated ester starting materials. See electronic
supporting information for details.
18. M. D. Greenhalgh, S. Qu, A. M. Z. Slawin, A. D. Smith, Chem.
Sci., 2018, 9, 4909–4918; E. R. T. Robinson, D. M. Walden, C.
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Sci., 2016, 7, 6919–6927.
19. For selected discussions of S···O interactions in isothiourea
catalysis: a) V. B. Birman, X. Li, Z. Han, Org. Lett. 2007, 9, 37–
40; b) P. Liu, X. Yang, V. B. Birman, K. N. Houk, Org. Lett.
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Tantillo, D. Romo, J. Am. Chem. Soc. 2014, 136, 4492–4495; d)
E. R. T. Robinson, D. M. Walden, C. Fallan, M. D. Greenhalgh, P.
H.-Y. Cheong, A. D. Smith, Chem. Sci. 2016, 7, 6919–6927; e) M.
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20. The research data underpinning this publication can be found at:
DOI: 10.17630/b25b27ef-dca3-4590-b92d-221c243dde43
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Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: