Development of novel triazole based dendrimer supported spiroborate chiral catalysts for the reduction of (: E)-O-benzyl oxime: An enantioselective synthesis of (S)-dapoxetine

Article abstract of DOI:10.1039/c9nj03217g

Novel dendrimer supported spiroborate catalysts 2 and 3 have been synthesized using a click reaction as a key step. The catalytic efficiency of the catalysts have been verified with reduction of (E)-O-benzyl oxime 13 as a model substrate. Catalyst 3 was found to be better than catalyst 2 as the chemical yield and enantiomeric excess were significantly high with the former catalyst. Thus, catalyst 3 has been successfully used in the efficient synthesis of (S)-dapoxetine 14 with 94% ee and 46% overall yield in three steps. These catalysts could be easily recovered from the reaction solution by the solvent precipitation technique and could be reused five times without significant loss of activity and enantioselectivity.

Full text of DOI:10.1039/c9nj03217g

NJC
View Article Online
View Journal
LETTER
Development of novel triazole based dendrimer
supported spiroborate chiral catalysts for the
reduction of (E)-O-benzyl oxime: an
Cite this:DOI: 10.1039/c9nj03217g
Received 20th June 2019,
Accepted 23rd August 2019
enantioselective synthesis of (S)-dapoxetine†
a
a
b
Ramasamy Anandhan, * Mandapati Bhargava Reddy and Murugesan Sasikumar
DOI: 10.1039/c9nj03217g
rsc.li/njc
Novel dendrimer supported spiroborate catalysts 2 and 3 have been
synthesized using a click reaction as a key step. The catalytic
efficiency of the catalysts have been verified with reduction of
(E)-O-benzyl oxime 13 as a model substrate. Catalyst 3 was found
to be better than catalyst 2 as the chemical yield and enantiomeric
excess were significantly high with the former catalyst. Thus,
catalyst 3 has been successfully used in the efficient synthesis of
Fig. 1 Selective serotonin reuptake inhibitors (SSRIs).
(S)-dapoxetine 14 with 94% ee and 46% overall yield in three
steps. These catalysts could be easily recovered from the reaction
7
–9
solution by the solvent precipitation technique and could be reused procedures
has been reported. However, most of the
five times without significant loss of activity and enantioselectivity. reported synthetic methods have some disadvantages such as
tedious, complex synthetic procedures, expensive or not readily
(S)-Dapoxetine, (R)-citalopram, (R)-fluoxetine and (S,S)-sertraline available chiral catalysts, and poor yield coupled with poor
are a class of selective serotonin reuptake inhibitors (SSRIs) optical purity. Later, in an asymmetric synthesis approach, Lee
1
typically used for the treatment of Premature Ejaculation (PE),
et al. have reported the synthesis of (S)-dapoxetine using a
2
depression and anxiety disorder (Fig. 1). Among these drugs, only Du Bois C–H amination reaction catalyzed by a chiral valerolactam-
the (S)-dapoxetine serotonin transport inhibitor has a short half- derived, dirhodium(II) complex and M. D. Nikalje et al. have
life, rapid absorption and elimination with minimal dosage. It is reported the synthesis of (S)-dapoxetine using a Sharpless asym-
extensively metabolized by multiple enzymes, and was developed metric epoxidation reaction and a Mitsunobu reaction. However,
for the treatment of premature ejaculation, which was the first this route also suffers from low enantiomeric excess and use of an
drug approved by the FDA for treatment of men. Other SSRIs expensive chiral catalyst. In view of the importance of chiral
10
11
3
such as (R)-citalopram, (R)-fluoxetine, and (S,S)-sertraline have amines, development of a simple, efficient and expedient method
been prescribed for depression and psychiatric disorders and for the synthesis of chiral amines is still in demand.
also used for treatment of PE, but they have relatively slower
absorption.
Chiral spiroborate esters are known as most effective and
efficient catalysts for the asymmetric borane reduction of
1
2
(
S)-Dapoxetine has a chiral amine centre, which is responsible prochiral ketones to alcohols and O-benzyl oxime to the
4
13
for its drug action. Hence it is important to develop a method for primary amine. Remarkably, spiroborate esters, in contrast
the creation of the asymmetric amine centre via reduction of to other chiral reducing catalysts, are stable to air and moisture
the respective oxime in an enantioselective manner. Previously, and moreover have advantages such as being easy to prepare,
synthesis of (S)-dapoxetine including resolution of racemic purify, store and handle.
5
6
intermediates, chemoenzymatic routes, or stereospecific
The utilization of dendrimer supported chiral catalysts has
received much attention in the catalytic asymmetric reduction
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai reaction in organic synthesis and are less explored. Dendrimer
a
14
6
00 025, India. E-mail: ananthanramasamy@gmail.com; Tel: +91 044 22202881
supported chiral catalyst have several advantages, and excellent
catalytic activity as compared to other catalysts. The enhanced
catalytic behaviour is due to the catalytic site at the periphery
of the dendrimers exhibiting better activity owing to a uniform
arrangement and higher degree of active sites. Further it increases
b
Department of Chemistry, Vel Tech Rangarajan Dr. Sagunthala R&D Institute of
Science and Technology, Avadi, Chennai, 600062, India
†
Electronic supplementary information (ESI) available: Experimental proce-
dures, spectral data for all new compounds, and HPLC spectra for selected
compounds. See DOI: 10.1039/c9nj03217g
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2019
New J. Chem.

View Article Online
Letter
NJC
chiral induction, changing the mode of attack and independence oxime 13 has been tested as shown in Scheme 2. Accordingly,
1
5
for a variety of catalytic groups. Thus, these chiral catalyst can be treatment of oxime 13 with 4.0 equiv. of BH
3
ÁX [X = DMS/THF]
easily separable and recyclable and hence purification of products in dry dioxane/THF afforded the crude amine, which was
is very simple. Our group has explored the synthesis of various treated with a mixture of formaldehyde and formic acid at
types of dendrimers for optical and electrochemical sensors and 95–100 1C to give the desired product of (S)-dapoxetine 14.
anti-inflammatory, anti-arthritis and anti-diabetic activity. To The ee was determined by HPLC with a Chiralcel OD–H column
the best of our knowledge, there is no report on the synthesis of using the optimal condition established with the racemic
a dendrimer supporting a spiroborate ester as a catalyst for the dapoxetine 14.
1
9
16
asymmetric reduction of (E)-oxime benzyl ether into chiral
To optimize the reaction conditions, initially we examined
amines. Therefore, herein we report the synthesis of triazole the reduction of (E)-O-benzyl oxime 13 without a catalyst
based dendrimer supported spiroborate ester chiral catalysts 2 (Table 1, entry 1), which afforded the racemic compound 14
and 3 and their successful asymmetric reduction of (E)-oxime in 64% yield. Next, we screened for asymmetric reduction of
benzyl ether to the primary amine. Further, the present method (E)-O-benzyl oxime 13 using 10 mol% of spiroborate ester 1 and
was extended for the stereoselective synthesis of (S)-dapoxetine 4.0 equiv. of BH
Fig. 2). which was found to be the best solvent (entries 2 and 3).
Initially, to accomplish the development of dendrimer Reduction of oxime 13 with BH –THF in dioxane followed by
supported spiroborate esters 2 and 3, a click reaction of dimethylation improved the selectivity of (S)-dapoxetine 14 with
.0 equiv. of diazide 4/triazide 5 with 2.1/4.1 equiv. of cyclized- 52% ee and 75% yield (entry 4). To test the effect of tempera-
O-propargylproline 6 afforded the proline dendrimers 7 and 8 in ture, the reaction was carried out at 25 1C, 20 1C, 10 1C and 0 1C
8% and 97% yields, respectively. Subsequently, the proline (entries 4–7). Notably, reaction at 0 1C significantly improved
dendrimers 7 and 8 were refluxed independently with aq. KOH the yield and selectivity up to 85% ee. However, the reaction
3
–DMS in dry THF and dioxane as a solvent,
(
3
1
9
18
in EtOH/THF, which furnished dendrimer supported prolinols 9
requires a longer time of up to 48 h to get complete conversion
and 10 in 80% and 78% yields, respectively. Further, the dendri- of 13 to the primary amine intermediate. Therefore, 48 h was
mer supported spiroborate ester catalysts 2 and 3 were obtained found to be the optimum reaction time. Loading of 20 mol% of
in 97% and 96% yields, respectively, by gentle heating of 1 equiv. the spiroborate ester catalyst 1 at 0 1C did not enhance any
i
of B(O Pr)
3
and 1 equiv. of glycol with respect to the amino alcohol selectivity.
To test and compare the catalysts’ efficiency, the reduction
dropwise addition of 1.0 equiv. of prolinol 9 and 10 in toluene study was extended to dendrimer supported catalysts 2 and 3.
Scheme 1). All the reported compounds are characterized with IR, These dendrimer supported catalysts 2 and 3 significantly
in toluene until a clear solution is obtained, followed by the
(
1
1
1
13
B, H and C NMR and mass spectra.
improved the yields to 86% and 88% and selectivity up to 90
Applying the dendrimer supported spiroborate ester and 91% ee (entries 11 and 14) respectively. It has been
catalysts 1–3 for the asymmetric reduction of (E)-O-benzyl observed that the increased yield and selectivity of the products
of dendrimer supported catalysts are in the order of 1 o 2 o 3
and the reason may be due to the increased bulkiness and
availability of catalytic sites in the catalysts. Experiments with
5
mol% of catalysts 2 and 3 in the reaction showed an improve-
ment of selectivity up to 91% and 94% ee (entries 10 and 13)
respectively, and lower 89% and 90% ee (entries 11 and 14) were
observed with 20 mol% of catalysts 2 and 3.
The synthesis of biologically important serotonin transport
inhibitor (S)-dapoxetine is shown in Scheme 3; we have completed
the total synthesis of (S)-dapoxetine using the optimized condi-
tions shown in Table 1. Thus, initially we carried out the reaction
17
of naphthyl ketone 11 with hydroxyl amine and sodium carbo-
nate in ethanol at 65 1C under weakly acidic pH, to give only the
13e
(
E)-oxime 12 in 75% yield after recrystallization. Subsequently,
the benzylation of compound (E)-oxime 12 using NaH/BnBr
afforded (E)-O-benzyl oxime 13 in 72% yield (Scheme 3). The
desired (S)-dapoxetine 14 in 94% ee was obtained by asymmetric
reduction of (E)-O-benzyl oxime 13 with 5 mol% of dendrimer
supported spiroborate ester 3/BH ÁTHF in dry dioxane at 0 1C.
3
Another advantage of designing the dendrimer supported
catalyst is the opportunity to recover and recycle the catalyst. To
investigate the catalyst recovery and reuse, catalysts 2 and 3
with borane reagents were tested for the reduction of asym-
metric (E)-O-benzyl oxime 13.
Fig. 2 Proposed spiroborate ester 1 and dendrimer supported spiroborate
esters 2 and 3.
New J. Chem.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2019

View Article Online
NJC
Letter
Scheme 1 Reagents and conditions: (a) CuSO
4
(5 mol%), sodium ascorbate (10 mol%), H
2
O–MeOH (1 : 1), r.t., 12 h, 7 (98%) and 8 (97%); (b) KOH in H
2
O,
i
EtOH, 9 (80%) and 10 (78%); (c) B(O- Pr)
3
, ethylene glycol, toluene, reflux, 2 (97%) and 3 (96%).
losing their optical purity and then recovered by precipitation
and washed with diethyl ether. Thus, the recovered amino
alcohols 9 and 10 were recycled to regenerate the spiroborate
ester catalysts. The recyclability of catalysts 2 and 3 was tested
for 5 cycles, up to 2 cycles without any deleterious effect in yield
and enantioselectivity. As shown in Chart 1, a slight decrease in
the ee was observed after the third cycle, however there was no
change in the chemical yield.
Scheme 2 Reagents and conditions: (a) 1/2/3, BH
dioxane/THF, 0 1C, 48 h; (b) HCOOH, 37% aq. formaldehyde, 90 1C, 6 h.
3
ÁX [X = DMS/THF],
In conclusion, synthesis of dendrimer supported spirobo-
On consumption of the oxime, the reaction mixture was rate catalysts 2 and 3 with triazole as the bridging unit has been
quenched with MeOH, the boron nitrogen bond was cleaved achieved through click chemistry. The catalytic activity of
and catalyst 2 and 3 were converted to the corresponding amino catalysts 2 and 3 has been tested for asymmetric reduction of
alcohols 9 and 10 with almost quantitative yield (98%) without (E)-O-benzyl oxime 13 as a model substrate. Total synthesis
Table 1 Screening of catalysts 1–3 and borane reagents for the reduction of oxime 13
a
b
Entry
Cat. (mole)
Borane reagent
Solvent
Temp. (1C)
Time (h)
Yield (%)
ee
1
2
3
4
5
6
7
8
9
—
BH
BH
BH
BH
BH
BH
BH
BH
BH
BH
BH
BH
BH
BH
3
3
3
3
3
3
3
3
3
3
3
3
3
3
ÁDMS
ÁDMS
ÁDMS
ÁTHF
ÁTHF
ÁTHF
ÁTHF
ÁTHF
ÁTHF
ÁTHF
ÁTHF
ÁTHF
ÁTHF
ÁTHF
THF
THF
25
25
25
25
20
10
0
0
0
0
0
24
32
32
32
32
40
48
48
48
48
48
48
48
48
64
67
70
75
75
80
82
85
85
85
86
88
88
87
0
45
49
52
60
75
85
85
91
90
89
94
91
90
1 (10%)
1 (10%)
1 (10%)
1 (10%)
1 (10%)
1 (10%)
1 (20%)
2 (5%)
2 (10%)
2 (20%)
3 (5%)
3 (10%)
3 (20%)
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
1
1
1
1
1
0
1
2
3
4
0
0
0
a
b
4
.0 equiv. of borane reagent was used. Determined by chiral HPLC (chiralcel OD–H column).
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2019
New J. Chem.

View Article Online
Letter
NJC
Germany, 2004, p. 242; (d) D. T. Wong, K. W. Perry and
F. P. Bymaster, Nat. Rev. Drug Discovery, 2005, 4, 764;
(e) A. Cipriani, T. A. Furukawa, G. Salanti, J. R. Geddes,
J. P. T. Higgins, R. Churchill, N. Watanabe, A. Nakagawa,
I. M. Omori, H. McGuire, M. Tansella and C. Barbui, Lancet,
2
009, 373, 746; ( f ) A. L. Montejo-Gonz ´a lez, G. Llorca,
J. A. Izquierdo and F. Rico-Villademoros, J. Clin. Psychiatry,
001, 62, 10; (g) M. A. Katzman, CNS Drugs, 2009, 23, 103.
2
Scheme 3 Reagents and conditions: (a) NH
2
OHÁHCl, Na
2
CO
3
, EtOH,
3 (a) D. W. Robertson, D. C. Thompson and D. T. Wong,
US5135947A, 1992; (b) W. J. G. Hellstrom, Neuropsychiatr.
Dis. Treat., 2009, 5, 37.
reflux, 75%; (b) BnBr, THF, NaH, 72%; (c) 3 (5 mol%), BH
1C; (d) HCOOH, 37% aq. formaldehyde, 90 1C, 6 h, 88%.
3
ÁTHF, dioxane,
0
4
(a) C. G. McMahon, Ther. Adv. Urol., 2012, 4, 233; (b) N. Modi,
R. Nath, P. Staehr, S. Gupta, J. Aquilina and D. Rivas, J. Clin.
Pharmacol., 2009, 49, 634; (c) P. Clement, J. Bernabe, P. Gengo,
P. Denys, M. Laurin, L. Alexandre and F. Giuliano, Eur. Urol.,
2
007, 51, 825.
(a) W. J. Wheeler and D. D. O’Bannon, Radiopharmacy, 1992,
1, 305; (b) L. A. Sarbera, J. Castaner and R. M. Castaner,
5
3
Drugs Future, 2004, 29, 1201.
6
7
O. Torre, V. Gotor-Fernadaz and V. Gotor, Tetrahedron:
Asymmetry, 2006, 17, 860.
(a) S. A. Siddiqui and K. V. Srivasan, Tetrahedron: Asymmetry,
Chart 1 Recyclability of catalysts 2 and 3.
2007, 18, 2099; (b) S. K. Srinivasan and K. Venkatesan,
ARKIVOC, 2008, 16, 302.
8
(a) P. M. Chincholkar, A. S. Kale, V. K. Gumaste and A. R. A. S.
Deshmukh, Tetrahedron, 2009, 65, 2605; (b) R. D. Mahale,
S. P. Chaskar, K. E. Patil, G. C. Maikap and M. K. Gurjar, Org.
Process Res. Dev., 2012, 16, 710.
of (S)-dapoxetine 14 from naphthyl ketone 11 in three steps has
been achieved with spiroborate catalyst 3 with an overall yield
of 46% and 94% ee. Significantly, the dendrimer supported
spiroborate catalysts 2 and 3 are found to be better than catalyst
9 J. W. Yang, C. Chandler, M. Stadler, D. Kampen and B. List,
1
with respect to enantioselectivity and recyclability. Further
Nature, 2008, 452, 453.
utilization of the developed catalysts for asymmetric catalysis is 10 S. Kang and H. K. Lee, J. Org. Chem., 2010, 75, 237.
underway.
11 M. Sasikumar and M. D. Nikalje, Synth. Commun., 2012,
2, 3061.
2 (a) T. J. Dickerson, N. N. Reed and K. D. Janda, Chem. Rev.,
002, 102, 3325; (b) K. Zeitler and I. Mager, Adv. Synth.
4
1
Conflicts of interest
2
Catal., 2007, 349, 1851; (c) G. Chouhan, D. Wang and
H. Alper, Chem. Commun., 2007, 4809; (d) D. Font,
S. Sayalero, A. Bastero, C. Jimeno and M. A. Pericas, Org. Lett.,
2008, 10, 337; (e) D. E. Bergbreiter, J. Tian and C. Hongfa,
Chem. Rev., 2009, 109, 530; ( f ) A. Schatz, M. Hager and
O. Reiser, Adv. Funct. Mater., 2009, 19, 2109; (g) K. Huang,
M. Ortiz-Marciales, W. Correa, E. Pomales and X. Y. L ´o pez,
J. Org. Chem., 2011, 76, 1883; (h) V. S. Shende, P. Singh and
B. M. Bhanage, Catal. Sci. Technol., 2018, 8, 955.
There are no conflicts to declare.
Acknowledgements
The authors thank DST-SERB for a young scientist start-up
research grant (vide Grant No: YSS/2014/000561) and DST-FIST
for providing NMR and HRMS facilities to the Department of
Organic chemistry. MBR acknowledges DST-SERB, New Delhi,
for a fellowship.
1
3 (a) X. Huang, M. Ortiz-Marciales, K. Huang, V. Stepanenko,
F. G. Merced, A. M. Ayala and M. De Jes u´ s, Org. Lett., 2007,
9
, 1793; (b) K. Huang, F. G. Merced, M. Ortiz-Marciales,
Notes and references
H. J. Mel ´e ndez, W. Correa and M. De Jes u´ s, J. Org. Chem.,
2008, 73, 4017; (c) K. Huang, M. Ortiz-Marciales, V. Stepanenko,
M. De Jes u´ s and W. Correa, J. Org. Chem., 2008, 73, 6928;
(d) K. Huang and M. Ortiz-Marciales, Org. Synth., 2010, 87, 36;
(e) W. Ou, S. Espinosa, H. J. Mel ´e ndez, S. M. Farr ´e , J. L. Alvarez,
V. Torres, I. Mart ´ı nez, K. M. Santiago and M. Ortiz-Marciales,
J. Org. Chem., 2013, 78, 5314.
1
(a) C. Carson and K. Gunn, Int. J. Impotence Res., 2006,
8, S5; (b) H. Porst, F. Montorsi, R. C. Rosen, L. Gaynor,
S. Grupe and J. Alexander, Eur. Urol., 2007, 51, 816;
c) M. D. Waldinger, Adv. Psychosom Med., 2008, 29, 50.
(a) D. T. Wong, F. P. Bymaster and E. A. Engleman, Life Sci.,
1
(
2
1995, 57, 411; (b) I. M. J. Anderson, J. Affective Disord., 2000,
58, 19; (c) Antidepressants: Past, Present and Future, ed. S. H. 14 (a) F. Cozzi, Adv. Synth. Catal., 2006, 348, 1367; (b) M. Benaglia,
Preskorn, R. Ross and C. Y. Stanga, Springer-Velarg, Berlin,
New J. Chem., 2006, 30, 1525; (c) M. Gruttadauria, F. Giacalone
New J. Chem.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2019

View Article Online
NJC
Letter
and R. Noto, Chem. Soc. Rev., 2008, 37, 1666; (d) F. T.
Alexandre, M. P. Pedro Gois and A. M. A. Carlos, Chem. Rev.,
009, 109, 418; (e) B. Altava, M. Isabel Burguete, E. Garc ´ı a-
(d, J = 6 Hz, 6H), 4.02–3.95 (m, 2H), 3.10–2.97 (m, 4H),
1
3
1.76–1.68 (m, 2H), 1.66–1.51 (m, J = 6 Hz, 2H); C NMR
(75 MHz, CDCl ): d 147.6, 145.7, 144.9, 135.2, 128.7, 128.2,
2
3
C
Verdugo and S. V. Luis, Chem. Soc. Rev., 2018, 47, 2722.
5 (a) G. R. Newkome, E. He and C. N. Moorefield, Chem. Rev.,
128.0, 126.6, 126.4, 125.9, 125.4, 122.4, 79.9, 76.6, 63.3, 62.2,
+
1
53.6, 52.3, 32.9; HRMS: (M + H) calculated for C H N O :
4
8
48 8 5
1999, 99, 1689; (b) S. Hecht and M. J. Frechet, Angew. Chem.,
803.4033, found: 803.4016.
Int. Ed., 2001, 40, 74; (c) D. Astruc, E. Boisselier and 19 (S)-Dapoxetine 14: yield: 88%; yellow oily liquid, specific
2
5
C. Ornelas, Chem. Rev., 2010, 110, 1857.
6 (a) P. Rajakumar, R. Anandhan and V. Kalpana, Synlett,
rotation: [a]
D
3
= +60.03 (C 0.3, CHCl ), literature value
2
5
1
[a]
D
= +63.0 (C 0.3, CHCl
(Daicel OD–H, 2% isopropanol/hexanes, 0.7 mL min
3
); HPLC condition: 94% ee
À1
2009, 1417; (b) P. Rajakumar, R. Anandhan, D. Manoj and
,
J. Santhanalakshimi, RSC Adv., 2014, 4, 4413; (c) P. Rajakumar
and R. Anandhan, Eur. J. Med. Chem., 2011, 46, 4687;
210 nm, tr (major) = 7.76 min, tr (minor) = 6.8 min);
1H NMR (400 MHz, CDCl ): d 8.15–8.13 (m, 1H), 7.71–
3
H
(d) P. Rajakumar, R. Anandhan, P. V. Gangadhara and
7.43 (m, 1H), 7.29–7.18 (m, 9H), 6.56 (d, J = 5.7 Hz, 1H),
V. Elangovan, Carbohydr. Polym., 2014, 99, 403.
3.99–3.96 (m, 1H), 3.83–3.78 (m, 1H), 3.58–3.54 (m, 1H),
1
3
1
7 D. M. Rajendra, P. C. Sudhir, E. P. Kiran, C. M. Golak and
K. G. Mukund, Org. Process Res. Dev., 2012, 16, 710.
8 Dendrimer supported amino alcohol 9: yield: 85%; IR (KBr)
2.61–2.55 (m, 1H), 2.39–2.20 (m, 1H), 2.19 (s, 6H); C NMR
(100 MHz, CDCl ): d 154.5, 134.4, 128.6, 128.3, 127.5,
127.4, 126.5, 126.3, 125.8, 125.0, 122.0, 120.0, 104.5, 67.5,
3
C
1
À1
1
+
nmax: 3515, 3405, 3031, 2240 cm
;
H NMR (300 MHz,
65.5, 42.7, 32.8; HRMS: (M + H) calculated for C21
306.1858, found: 306.1832.
H23NO:
CDCl ): d 7.48–7.04 (m, 26H), 5.41 (s, 4H), d 4.45
3
H
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2019
New J. Chem.