Cinchona derivatives as sustainable and recyclable homogeneous organocatalysts for aza-Markovnikov addition

Article abstract of DOI:10.1039/c8nj01277f

Three cinchona derivatives have shown remarkable activity to catalyze the aza-Markovnikov addition reaction of N-heterocycles to vinyl esters. The synthesis of aza-Markovnikov adducts possessing valuable biological activity was thoroughly optimized. By studying the ratio of the starting materials, bases and solvents, we achieved a new and efficient protocol, which could be performed under mild conditions with a small excess of vinyl ester affording products with excellent yields and high regioselectivity. This optimization reduced Sheldon's E-factor of the reaction by 42%. Furthermore, membrane separation for catalyst recycling was assessed to further improve the sustainability of the synthesis.

Full text of DOI:10.1039/c8nj01277f

View Article Online
View Journal
NJC
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. Nagy, Z. Fehér,
P. Kisszékelyi, P. Huszthy and J. Kupai, New J. Chem., 2018, DOI: 10.1039/C8NJ01277F.
Volume 40 Number
1
January 2016 Pages 1–846
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
NJC
New Journal of Chemistry
www.rsc.org/njc
A journal for new directions in chemistry
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
rsc.li/njc

Page 1 of 9
Pl Ne ae swe Jd oo u nr no at l ao df j Cu sh te mm ai sr tgr iyn s
View Article Online
DOI: 10.1039/C8NJ01277F
New Journal of Chemistry
ARTICLE
Cinchona derivatives as sustainable and recyclable homogeneous
organocatalysts for aza-Markovnikov addition
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
a,†
Sándor Nagy, Zsuzsanna Fehér, Péter Kisszékelyi, Péter Huszthy, and József Kupai
DOI: 10.1039/x0xx00000x
Three cinchona derivatives have shown remarkable activity to catalyze the aza-Markovnikov addition reaction of N-
heterocycles to vinyl esters. The synthesis of the aza-Markovnikov adducts possessing valuable biological activity was
thoroughly optimized. Studying the ratio of the starting materials, bases and solvents, we achieved a new and efficient
protocol, which could be performed under mild conditions with small excess of vinyl ester obtaining products with
excellent yields and high regioselectivity. This optimization reduced Sheldon’s E-factor of the reaction by 42%.
Furthermore, membrane separation for catalyst recycling was assessed to further improve the sustainability of the
synthesis.
www.rsc.org/
the reported synthetic protocols are associated with the use of
harsh chemical conditions in which bases, acids and intense heating
were usually
Introduction
Catalytic transformations play an increasingly important role in
organic chemistry today, both in academic laboratories and in
industry. Organocatalysts, enzymes and homogeneous metal
catalysts are expensive, therefore new strategies have to be
developed to obtain maximum catalyst performance with regards
to selectivity and turnover numbers. Membrane separation in
organic media is a sustainable separation technology to achieve
these goals, along with process intensification and a cleaner
product stream.
Cinchona alkaloids, originally isolated from the bark of Cinchona
trees, are amongst the most well-known natural products with
exceptional medical history and their derivatives have emerged as
Fig. 1 Biologically active 1-(N-heterocycle) alkyl esters.
1
-4
applied to promote the reaction. In many cases, the yield and
selectivity are far from satisfactory due to several side reactions.
Many efforts have been made regarding green syntheses. In the
mid-2000s, a new enzymatic strategy to perform Markovnikov
addition was developed with the use of penicillin G acylase as
powerful organocatalysts, which are reported in several reviews
5
, 6
and recently in books.
The widespread usage of cinchona
alkaloids has been attributed to their non-toxicity, ease of use,
stability, cost effectiveness, recyclability, and practical utilization in
7
-10
industry.
1
6, 17
catalyst.
Later, Lin and his co-workers applied K
3 4
PO as a mild
The aza-Markovnikov addition is a useful nitrogen–carbon bond-
forming reaction, in particular for the synthesis of bioactive N-
heterocycle derivatives. 1-(N-Heterocycle) alkyl esters which could
be achieved by this reaction, possess valuable biological
11
base, and recently Chen and his co-workers used ionic liquids as
1
8
reaction media and catalysts. However, it is unsustainable to scale
up this modified synthesis due to the high excess of the vinyl ester
and the application of problematic solvents such as DMF.
1
1
12, 13
14
properties and can act as, acaricide (A)
, antitumor drug (B),
+
+
15
A serious practical problem with homogeneous catalysis is the
separation of reactants and products from the catalyst, which are
all in the same phase. The applicability of membrane-based
separation for the recovery of the homogeneous organocatalysts
was explored. Membrane-based separations in organic media is a
green technology that allows size-exclusion based separation of
(
H –K )-ATPase inhibitor (C) and are also used to treat gout and
1
6
certain types of kidney stones (D) (see Fig. 1.). Consequently,
many researchers have focused on developing new methodologies
-
1
solutes in the range of 50 and 2000 g mol by applying a pressure
1
9
gradient. Recent development in this field resulted in membranes,
which can withstand aggressive solvents and exhibit high flux, while
quasi completely rejecting relatively small solutes at the lower end
for the synthesis of 1-(N-heterocycle) alkyl esters. However, most of
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 2 of 9
View Article Online
DOI: 10.1039/C8NJ01277F
ARTICLE
Journal Name
2
0, 21
Scheme 1. Two model reactions for optimizing the aza-Markovnikov reaction.
of the nanofiltration range.
Homogeneous catalyst recovery by
membranes is an emerging field due to its mild operating
conditions, low cost and easy implementation in continuous
Table 1. Effect of solvent and reaction conditions on the aza-Markovnikov addition
a,b
3 4
reaction of N-heterocycles 1 or 2 and vinyl acetate 3 with catalyst K PO .
2
2, 23
processing.
Here, we report a new application of cinchona alkaloids for the
catalysis of aza-Markovnikov addition. The addition of N-
heterocycles (imidazole, benzimidazole, pyrazole or 1,2,3-triazole)
to vinyl esters (vinyl acetate or vinyl 4-tert-butylbenzoate) was
studied and a mechanism is suggested. Our aim was to develop a
new method for efficient synthesis of biologically active
aza-Markovnikov adducts, avoiding the tedious and expensive
repeated purifications and using homogeneous catalysts, which
could be easily recycled after the reaction. Furthermore, our new
synthesis of aza-Markovnikov adducts was evaluated through
Entry
Reagent
Solvent
Temperature
[°C]
Equivalent
of catalyst
Equivalent
of vinyl
ester
Yield
b
[%]
1
2
1
1
DMF
DMF
50
25
0.3
0.3
8
8
65
63
3
4
5
1
1
1
DMF
DMF
MeCN
25
25
25
0.05
0.05
0.3
8
1.2
8
62
52
63
6
7
8
9
1
1
2
2
MeCN
MeCN
DMF
25
25
50
25
0.05
0.05
0.3
8
1.2
8
58
48
61
57
DMF
0.3
8
1
0
2
2
2
DMF
DMF
MeCN
25
25
25
0.05
0.05
0.3
8
1.2
8
55
50
60
2
4, 25
Sheldon's E-factor.
11
1
1
1
2
3
4
2
2
MeCN
MeCN
25
25
0.05
0.05
8
55
44
1.2
Results and discussion
a
The aza-Markovnikov addition reaction of N-heterocycle 1 or 2 (0.6 mmol) and vinyl
To turn the aza-Markovnikov reaction more eco-friendly, two model
reactions were chosen (Scheme 1.) using N-heterocycles (1 and 2)
as substrates and vinyl acetate (3) as a reagent resulting in two aza-
Markovnikov adducts (4 and 5).
b
3 4
acetate 3, with catalyst K PO in 1.2 mL of solvent after 48 h. Isolated yield of purified
material.
Table 2. Effect of different methods on the Sheldon’s E-factor of aza-Markovnikov
addition reaction of N-heterocycle 1 or 2 and vinyl acetate 3.
At first, it was observed that decreasing the reaction temperature
a
(
from 50 °C to 25 °C) had no significant effect on the yield of the
Entry
Reagent
E-factor
Reference
reaction, (see Table 1., entries 1, 2 and 8, 9) and aza-Markovnikov
1
2
3
4
5
6
1
1
1
2
2
2
2.51
3.05
1.46
2.26
2.52
1.58
[11]
[30]
our work
[11]
[30]
our work
addition could proceed at room temperature. Then, the influence of
solvent, the molar ratio of vinyl acetate and catalyst (K
3 4
PO ) to N-
heterocycle was investigated. DMF was replaced by a greener
26-28
alternative,
acetonitrile (see Table 1.), providing an easier work-
up process due to its lower boiling point. According to the recent
a
To achieve meaningful comparisons of the different processes, solvent is generally
2
9
critical review by Byrne et al. about solvent selection, substitution excluded from the E-factor calculation. It was not possible to include the materials used
for chromatographic purification in this comparison, since amounts of those materials
of DMF is required, and acetonitrile is a suitable replacement. The
are never reported in journal articles.
amounts of catalyst and reagent were also decreased (see Table 1.).
The optimized process was compared to previous references by
available versatile organocatalyst. The latter was converted into its
means of Sheldon's E-factor. The optimization was carried out
amine derivative (7) after a mesylation, an azide formation and a
considering the load of all input materials. The results are
catalytic hydrogenation. Amine
7
was reacted with the
summarized in Table 2., the E-factor for each process is expressed
as the mass ratio of waste to desired aza-Markovnikov adduct.
As a summary of the optimization, the yields were a bit lower (in
case of imidazole: from 65% to 48%, and in case of benzimidazole:
from 61% to 44%). As a positive result, the decreases of E-factor
calculated over the aza-Markovnikov addition to imidazole and
benzimidazole are 42% and 30%, respectively. Therefore our results
suggest, that this method is greener than the ones previously
condensation product of 3,5-bis(trifluoromethyl)aniline and
dimethyl squarate to give bifunctional cinchona-squaramide
31
catalyst 8.
Cinchona alkaloids are well-known asymmetric catalysts giving
products with high enantiomeric excesses. In the beginning of our
study, we tried to prepare aza-Markovnikov adducts
enantioselectively. According to our latest experiments, the
enantiomeric excess is higher when reactions are performed at
lower temperature. Therefore, the cinchona-based organocatalysts
1
1, 30
reported.
Three cinchona catalysts (6–8, see Fig. 2.) were also applied as were tested and compared to the potassium phosphate first at 0 °C
homogeneous catalysts in aza-Markovnikov additions of these N- under the previously optimized circumstances in the aza-
heterocycles to vinyl esters. Hydroquinine (6) is a commercially
Markovnikov addition of four different N-heterocycles (1, 2, 9, 10,
see Table 3.) to vinyl acetate (3) or vinyl 4-tert-butylbenzoate (11).
Mostly, the yields were lower using cinchona catalysts instead of
potassium phosphate and the reactions gave racemic (ee lower
than 5%) products (4, 5, 12–19, see Table 3.).
2
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 9
Pl Ne ae swe Jd oo u nr no at l ao df j Cu sh te mm ai sr tgr iyn s
View Article Online
DOI: 10.1039/C8NJ01277F
Journal Name
ARTICLE
a
The aza-Markovnikov addition reaction of various N-heterocycles 1 or 2 or 9 or 10 (0.6
mmol) and vinyl esters 3 or 11 (0.72 mmol, 1.2 eq.), with catalysts K
3
c
PO or 6 or 7 or 8,
4
b
in 1.2 mL of acetonitrile at 0 °C. Isolated yield of purified material. After unsuccessful
results were observed in case of products 4 and 5, catalyst 8 was not applied in the
d
other reactions. Starting from vinyl acetate (3) or vinyl 4-tert-butylbenzoate (11), and
Fig. 2. Schematics of the applied cinchona organocatalysts 6–8.
1
,2,3-triazole (10) two products (13 and 14) or (16 and 17) formed in about 1:1 ratio.
The results suggest, that the acyloyl part of the reagent has no
influence on the reactivity: there was no significant difference
between the aliphatic and aromatic reagents. Using cinchona
catalysts 6–8 we achieved better yields only in case of reactions
with imidazole (1) and benzimidazole (2). Hence, we continued the
optimization using N-heterocycles 1 and 2 and vinyl acetate (3) at
elevated temperature to produce aza-Markovnikov adducts 4 and 5
with higher yields.
Finally, cinchona-based organocatalysts 6–8 were applied at 25
°
C and 50 °C, and the results were compared to those of obtained
using potassium phosphate. As the results show in Table 4.,
applying cinchona amine 7 we obtained the aza-Markovnikov
adducts with two times higher yields, than in the case of using
potassium phosphate. Consequently, based on our experimental
results, aza-Markovnikov reaction can be most environmentally
friendly
Fig. 3. Separation performance of the nanofiltration membranes in acetonitrile at 10–
0 bar pressure.
3
Table 4. Catalytic aza-Markovnikov addition reaction of N-heterocycles (1 or 2) and
a
vinyl acetate (3) at different temperatures.
Table 3. Catalytic aza-Markovnikov addition reaction of various N-heterocycles (1 or 2
a,b,c,d
or 9 or 10) and vinyl esters (3 or 11) under optimized conditions.
Catalyst
Catalyst
Yields (%)
Yields (%)
of 4 at:
of 5 at:
K
3 4
PO
6
7
8
K
3
PO
4
6
7
8
4
8
9
5
9
8
3
5
8
1
32
0
31
44
89
29 41
39 92
4
0
2
5
°C
0 °C
4
35
57
0
4
5 °C
0 °C
25 °C
50 °C
9
77
60 96 74
a
The aza-Markovnikov addition reaction of N-heterocycles 1 or 2 (0.6 mmol) and vinyl
acetate 3, with catalysts K PO or cinchona catalysts 6–8 in 1.2 mL of acetonitrile at
different temperatures for 48 h.
3
4
performed at 25 °C, using acetonitrile as a solvent, and 5 mol% of
cinchona amine 7. The high yield obtained by using cinchona amine
7
, can be attributed to mechanistic reasons. The above
3
2
experimental results, in accordance with the literature suggest a
mechanism for the aza-Markovnikov addition reaction catalyzed by
cinchona amine 7 as achieved in Scheme 2. In a similar manner as
3
3
aminocatalysis, first the quinuclidine nitrogen of the cinchona
amine 7 deprotonates the imidazole, then the primary amino group
of cinchona amine 7 forms an enamine-type intermediate with vinyl
acetate (3). After that, the non-bonding electron pair of the
deprotonated imidazole attacks the electron poor carbon atom of
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 4 of 9
View Article Online
DOI: 10.1039/C8NJ01277F
ARTICLE
Journal Name
Scheme 2. Suggested mechanism for aza-Markovnikov reaction using cinchona amine 7
In summary, a series of reported (
4, 5, 12) and novel (13–19) 1-
as a catalyst.
(
N-heterocycle) alkyl esters were synthesized and
characterized. The aza-Markovnikov reactions were performed
environmentally friendly at room temperature, replacing the
undesirable dimethyl formamide by acetonitrile, and
decreasing the amount of the catalyst (from 30% to 5%) and
the vinyl ester (from 8 equivalent to 1.2 equivalent). The
reductions of Sheldon’s E-factor calculated for the aza-
Markovnikov addition to imidazole and benzimidazole were
4
2%, and 30%, respectively.
Cinchona-based organocatalysts were synthesized and
successfully applied in aza-Markovnikov addition as
homogeneous catalysts. Using cinchona amine
7 as a catalyst,
we obtained more than twice as high yield (92–95%) as using
potassium phosphate. In the former case
mechanism was suggested.
a reaction
Fig. 4. Purification performance for single-stage and two-stage diafiltration processes
using the PBI membrane in acetonitrile. Solid and dashed lines represent the simulated
performance based on rejections, while symbols signify experimental points to validate
the model used for the simulation. Dotted lines indicate 99% product removal from the
The homogeneous catalytic implementation of the
aza-Markovnikov addition made this reaction more
environmentally friendly by using OSN as its work up process.
system, which requires about 8.7 and 10 diavolumes for single-stage and two-stage Due to the OSN technique, the applied catalysts were quasi
diafiltration, respectively.
completely recycled from the reaction mixture. The feasibility
of membrane-based separation for catalyst recovery was
vinyl acetate (3). Finally, with the elimination of the product (4) the
demonstrated with a potential to keep the catalyst loss below
starting cinchona amine 7 is recovered.
1
% using a two-stage cascade configuration.
Organic solvent nanofiltration (OSN) for recycling the cinchona
catalysts 6–8 was explored. Commercial GMT-oNF and in-house
fabricated PBI (poly[2,2’-(m-phenylene)-5,5’-bisbenzimidazole]) Experimental - Materials
membranes were screened in acetonitrile at 10–30 bar pressure to
GMT-oNF-1, GMT-oNF-2 and GMT-oNF-3 membranes were
determine their separation potential (Fig. 3.). Efficient catalyst
recovery requires as high catalyst rejection as possible, ideally
purchased from Borsig Membrane Technology GmbH (Germany). 26
wt% polybenzimidazole dissolved in N,N-dimethylacetamide
1
00%. GMT-oNF-3 and PBI membranes at 30 bar showed the
(
DMAc) was purchased from PBI Performance Products Inc. (USA).
highest catalyst rejection of 98.3% and 99.1%, respectively. The
latter membrane was selected for the purification process because
of the lower product rejection (17%) compared to GMT-oNF-3. The
rejection of the vinyl acetate (3), resulting from the 0.2 molar
Non-woven polypropylene fabric Novatexx 2471 was obtained from
Freudenberg Filtration Technologies (Germany).
excess, was found to be as low as 13%, which allows rapid purge Experimental - Membrane screening and
from the system.
diafiltration
The single stage diafiltration allowed 99% product removal in 8.7
The polybenzimidazole (PBI) membrane was prepared from a 26
diavolumes at the cost of 8% catalyst lost (Fig. 4.). The simplified
wt% dope solution on a non-woven support sheet using a casting
membrane cascade developed by Kim et al. offers a sustainable
34
knife set to a thickness of 100 μm at a temperature of 20 °C based
approach to improve the catalyst recovery. Application of their
process configuration resulted in a two-stage diafiltration cascade
that requires about 10 diavolumes to obtain 99% product removal
and at the same time the catalyst loss can be kept as low as 1% (Fig.
3
7
on literature procedure. The feed solution for the membrane
screening comprised of a mixture of catalyst, product, and substrate
-1
each of them in 0.1 g L concentration in acetonitrile. The pressure
range for the screening was 10–30 bar and the tests were carried
out in across-flow nanofiltration rig (Fig. 5.). The feed solution was
recirculated for 24 h followed by collection of samples from the
permeate and the retentate streams. By definition, the rejection of
a solute is the relative concentration decrease between the two
sides of the membrane (Eq. 1.):
4
.). The purity of recycled cinchona catalyst 7 was confirmed by
NMR, which confirmed that these catalysts do not degrade under
the mild conditions applied during these reactions. The
sustainability of the diafiltration can be further improved by in situ
35, 36
solvent recovery as recently demonstrated by Szekely et al.
ꢇ
ꢇ
ꢈ,ꢁ
ꢀ
ꢁ
ꢂ ꢃꢄꢄ% ∙ ꢅꢃ ꢆ
ꢊ
Eq. 1
ꢉ,ꢁ
Conclusions
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 9
Pl Ne ae swe Jd oo u nr no at l ao df j Cu sh te mm ai sr tgr iyn s
View Article Online
DOI: 10.1039/C8NJ01277F
Journal Name
ARTICLE
where R
i
is the rejection of the solute in percentage, CR,i and CP,i are Vinyl ester (0.72 mmol, 1.2 eq.) was added to a solution of the
the concentrations of the solute in the retentate and permeate, catalyst (0.03 mmol, 0.05 eq.) and N-heterocycle (0.6 mmol) in
-1
respectively, usually given in g L . Flux is defined as volume of solvent (1.2 mL, see Table 1.). The reaction mixture was stirred at
solvent that permeates the membrane per unit area in a given time room temperature while monitored by TLC. After two days the
(
Eq. 2.):
solvent was removed. The crude product was purified by
preparative thin layer chromatography on silica gel to obtain the
aza-Markovnikov adduct as a pale yellow oil (yields can be seen in
Tables 1., 3. and 4.).
ꢌ
ꢈ
ꢋ ꢂ
Eq. 2
ꢍꢎꢏ
where F is the solvent flux, VP is the permeate volume, A is the
membrane area and t is the time of permeation. The diafiltration
was carried out by collecting the permeate separately and keeping
the retentate volume constant.
1
-(1H-Imidazol-1-yl)ethyl acetate (4)
Aza-Markovnikov adduct 4 was prepared as described in the
General procedure starting from vinyl acetate (3, 66 μL, 62 mg, 0.72
Experimental - Preparation of organocatalysts
and aza-Markovnikov reactions
General
3 4
mmol, 1.2 eq.), imidazole (1, 40.8 mg, 0.6 mmol) and catalyst (K PO
or 6 or 7, 0.03 mmol, 0.05 eq.) in different solvents (1.2 mL) (see
Table 1). The crude product was purified by preparative thin layer
chromatography on silica gel using dichloromethane:methanol
Infrared spectra were recorded on a Bruker Alpha-T FT-IR
spectrometer. Optical rotations were measured on a Perkin-Elmer
(
10:1) mixture as an eluent to give aza-Markovnikov adduct 4 as a
2
41 polarimeter. NMR spectra were recorded in CDCl
3
either on a
pale yellow oil (yields can be seen in Tables 1., 3. and 4.). Product 4
1
Bruker DRX-500 Avance spectrometer (at 300 or 500 MHz for H
so obtained had the same spectroscopic data than those of
1
3
and at 75.5 or 125 MHz for C spectra). Mass spectra were
38
reported.
recorded on CAMAG TLC-MS Interface (HPLC pump: Shimadzu LC-
2
0AD Prominence SQ MS: Shimadzu LCMS-2020 MS settings:
Detector
Voltage: 1.10 kV, m/z: 105–1000, Scan speed: 1075 u/sec, DL Aza-Markovnikov adduct 5 was prepared as described above in the
1
-(1H-Benzo[d]imidazol-1-yl)ethyl acetate (5)
temperature: 250 °C, Nebulizing Gas Flow: 1.5 L/min, Drying Gas
General procedure starting from vinyl acetate (3, 66 μL, 62 mg, 0.72
mmol, 1.2 eq.), benzimidazole (2, 70.9 mg, 0.6 mmol) and catalyst
(
K
3
PO
mL, see Table 1.). The crude product was purified by preparative
thin layer chromatography on silica gel using
4
or 6 or 7 or 8, 0.03 mmol, 0.05 eq.) in different solvents (1.2
dichloromethane:methanol (10:1) mixture as an eluent to give aza-
Markovnikov adduct 5 as a pale yellow oil (yields can be seen in
Tables 1., 3. and 4.). Product 5 so obtained had the same
3
8
spectroscopic data than those of reported.
1
-(1H-Pyrazol-1-yl)ethyl acetate (12)
Aza-Markovnikov adduct 12 was prepared as described above in the
General procedure starting from vinyl acetate (3, 66 μL, 62 mg, 0.72
Fig. 5. Schematic of the experimental set-up for cross-flow membrane filtration.
Flow: 15 L/min. eluent: acetonitrile: 0.1 v/v% formic acid 95:5,
3 4
mmol, 1.2 eq.), pyrazole (9, 40.8 mg, 0.6 mmol) and catalyst (K PO
1
.500 mL/min). Elemental analyses were performed on a Vario EL III
or 6 or 7, 0.03 mmol, 0.05 eq.) in acetonitrile (1.2 mL). The crude
product was purified by preparative thin layer chromatography on
silica gel using dichloromethane:methanol (20:1) mixture as an
eluent to give aza-Markovnikov adduct 12 as a pale yellow oil
instrument (Element analyze Corp., Germany) in the Microanalytical
Laboratory of the Department of Organic Chemistry, Institute for
Chemistry, L. Eötvös University, Budapest, Hungary. Starting
materials were purchased from Aldrich Chemical Company unless
otherwise noted. Silica gel 60 F254 (Merck) plates were used for TLC.
Silica gel 60 (70–230 mesh, Merck) was used for column
chromatography. Ratios of solvents for the eluents are given in
volumes (mL/mL). Evaporations were carried out under reduced
pressure unless otherwise stated. The cinchona-based
organocatalysts (7 and 8) were synthesized based on the
(
yields can be seen in Table 3.). Product 12 so obtained had the
3
8
same spectroscopic data than those of reported.
1
2
-(1H-1,2,3-Triazol-1-yl)ethyl acetate (13) and 1-(1H-1,2,3-triazol-
-yl)ethyl acetate (14)
Aza-Markovnikov adducts 13 and 14 were prepared as described
above in the General procedure starting from vinyl acetate (3, 66 μL,
2
5
experiments of Bae and co-workers.
6
2 mg, 0.72 mmol, 1.2 eq.), 1,2,3-triazole (10, 41.4 mg, 0.6 mmol)
General procedure for the aza-Markovnikov additions
and catalyst (K
3
PO
4
or 6 or 7, 0.03 mmol, 0.05 eq.) in acetonitrile
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 6 of 9
View Article Online
DOI: 10.1039/C8NJ01277F
ARTICLE
Journal Name
(
1.2 mL). The crude product was purified by preparative thin layer 0.6 mmol) and catalyst (K PO or 6 or 7, 0.03 mmol, 0.05 eq.) in
3 4
chromatography on silica gel using hexane:ethyl acetate (1:1) acetonitrile (1.2 mL). The crude product was purified by preparative
mixture as an eluent to give aza-Markovnikov adduct 13 and 14 as a thin layer chromatography on silica gel using
pale yellow oil (yields can be seen in Table 3.). TLC (SiO2 TLC; dichloromethane:methanol (20:1) mixture as an eluent to give aza-
hexane:ethyl acetate = 1:1, R =0.62, UV). Markovnikov adduct 16 as a pale yellow oil (yields can be seen in
-(1H-1,2,3-Triazol-1-yl)ethyl acetate (13) IR (neat) νmax/cm 3132, Table 4.). TLC (SiO TLC; dichloromethane:methanol = 20:1, R =0.68,
002 (C=CH), 2946 (CH), 2094, 1751 (C=O), 1485, 1444, 1371, 1301, UV). IR (neat) νmax/cm 3058 (C=CH), 2997 (C=CH), 2963 (CH), 2869,
284, 1220, 1196, 1071. δH(500 MHz; CDCl ; Me
Si) 1.96 (3 H, d, 2748, 2720, 2684, 1938, 1726 (C=O), 1609 (C=C), 1496, 1483, 1459,
), 7.06 (1 H, q, J 6.5, N-CH- 1409, 1282, 1273, 1219, 1185, 1116, 1089, 1062 δH(500 MHz;
; Me Si) 1.34 (9 H, s, tBu CH groups), 2.11 (3 H, d, J 6.0,
), 7.30–7.37 [3 H, m, J 6.0, N-CH-O, BimC(5)-H, BimC(6)-H],
23.43 [TriazC(5)], 133.73 [TriazC(4)], 169.39 (COO); MS (ESI): Exact 7.46 and 7.96 (2×2H, AA' BB', JAB 8.5, Ph-H), 7.70 [1 H, d, J 8.0,
7.5, BimC(4)-H or
: C, 46.45; H, 5.85; N, 27.08. Found: C, BimC(7)-H], 8.24 [1 H, s, BimC(2)-H]; δC(125 MHz; CDCl ; Me Si)
20.10 (CH-CH group), 31.05 (tBu CH groups), 35.18 (tBu C-CH ),
f
-1
1
2
f
-1
3
1
3
4
3
J
H
,
H
= 6.5 Hz, CCH
3
), 2.08 (3 H, s, CH
3
H H
,
O), 7.71 [1 H, s, TriazC(5)-H], 7.79 [1 H, s, TriazC(4)-H]; δC(75.5 MHz; CDCl
CDCl ; Me Si) 19.64 (CH-CH group), 20.79 (CH
), 77.64 (N-CH-O), CCH
,
H H
3
4
3
H H
,
3
4
3
3
3
1
H H
,
+
mass calcd for C
6 9 3 2
H N O
H H
: 155.16. Found m/z 156.200 (M , 56.47%). BimC(4)-H or BimC(7)-H], 7.84 [1 H, s, J ,
Anal. calcd for C
6
H
N
9 3
O
2
3
4
4
6.26; H, 5.94; N, 27.07.
3
3
3
-
1
1
-(1H-1,2,3-Triazol-2-yl)ethyl acetate (14) IR (neat) νmax/cm 3124, 75.43 (N-CH-O), 110.98 [BimC(7)], 120.62 [BimC(4)], 122.86
001 (C=CH), 2945 (CH), 1745 (C=O), 1447, 1414, 1370, 1344, 1214, [BimC(5), BimC(6)], 123.62 [BimC(5), BimC(6)], 125.55 [PhC(3)],
117, 1079, 1064. δH(300 MHz; CDCl ; Me Si) 1.93 (3 H, d, J , 6.5, 126.00 [PhC(1)], 129.77 [PhC(2)], 132.47 [Bim(8)], 141.13 [Bim(9)],
3
1
3
4
H H
CCH
3
), 2.09 (3 H, s, CH
3
H H
), 7.15 (1 H, q, J ,
6.0, N-CH-O), 7.70 [2 H, s, 143.97 [Bim(2)], 157.62 [PhC(4)], 165.08 (COO); MS (ESI): Exact
+
TriazC-H]; δC(75.5 MHz; CDCl ; Me Si) 19.28 (CH-CH group), 20.84 mass calcd for C20
H
22
N
2
O
2
: 322.17, found m/z 323.200 (M , 100%).
: C, 74.51; H, 6.88; N, 8.69. Found: C,
3
4
3
(CH
3
), 81.25 (N-CH-O), 135.17 [TriazC], 169.12 (COO); MS (ESI): Anal. calcd for C20
H
22
N
2
O
2
+
Exact mass calcd for C
6
H
9
N
3
O
2
: 155.16, found m/z 156.132 (M , 74.49; H, 6.90; N, 8.68.
4
4.78%). Anal. calcd for C H N O : C, 46.45; H, 5.85; N, 27.08.
6
9
3
2
Found: C, 46.26; H, 5.94; N, 27.07.
1-(1H-Pyrazol-1-yl)ethyl 4-(tert-butyl)benzoate (17)
Aza-Markovnikov adduct 17 was prepared as described above in the
General procedure starting from vinyl 4-(tert-butyl)benzoate (11,
1-(1H-Imidazol-1-yl)ethyl 4-(tert-butyl)benzoate (15)
Aza-Markovnikov adduct 15 was prepared as described above in the 147 μL, 147.1 mg, 0.72 mmol, 1.2 eq.), pyrazole (9, 40.8 mg, 0.6
General procedure starting from vinyl 4-(tert-butyl)benzoate (11, mmol) and catalyst (K PO or 6 or 7, 0.03 mmol, 0.05 eq.) in
47 μL, 147.1 mg, 0.72 mmol, 1.2 eq.), imidazole (1, 40.8 mg, 0.6 acetonitrile (1.2 mL). The crude product was purified by preparative
mmol) and catalyst (K PO
or 6 or 7, 0.03 mmol, 0.05 eq.) in thin layer chromatography on silica gel using hexane:ethyl acetate
acetonitrile (1.2 mL). The crude product was purified by preparative (4:1) mixture as an eluent to give aza-Markovnikov adduct 17 as a
thin layer chromatography on silica gel
using pale yellow oil (yields can be seen in Table 3.). TLC (SiO TLC;
dichloromethane:methanol (20:1) mixture as an eluent to give aza- hexane:ethyl acetate = 4:1, R =0.41, UV). IR (neat) νmax/cm 3122,
Markovnikov adduct 15 as a pale yellow oil (yields can be seen in 2964 (CH), 2906 (CH), 2870 (CH), 2427, 2296, 2097, 1931, 1806,
Table 3.). TLC (SiO TLC; dichloromethane:methanol = 20:1, R
=0.48, 1719 (C=O), 1609 (C=C), 1519, 1441, 1398, 1256, 1188, 1113, 1089,
UV). IR (neat) νmax/cm 3115, 2963 (CH), 2905 (CH), 2869 (CH), 1718 1066, 1041, 1014. δH(500 MHz; CDCl ; Me Si) 1.34 (9 H, s, tBu CH
C=O), 1608 (C=C), 1493, 1261, 1223, 1188, 1071, 1033, 1014. groups), 2.02 (3 H, d, J 6.5, CCH ), 6.31 [1 H, t, J 2.0, PyrC(4)],
δH(500 MHz; CDCl ; Me Si) 1.35 (9 H, s, tBu CH groups), 1.95 (3 H, 7.10 (1 H, q, J 6.0, N-CH-O), 7.45 and 7.98 (2×2H, AA'BB', JAB 8.5,
6.0, N-CH-O), 7.10 [1 H, s, ImC(4)- Ph-H), 7.62 [1 H, s, PyrC(3)-H], 7.75 [1 H, d, J 2.5, PyrC(5)-H];
group), 31.07 (tBu CH
), 79.24 (N-CH-O), 106.15 [PyrC(4)], 125.40
3
4
1
3
4
2
-1
f
2
f
-1
3
4
3
(
H
,
H
3
H H
,
H H
,
3
4
3
d, J
H], 7.29 [1 H, s, ImC(5)-H], 7.48 and 7.95 (2×2H, AA' BB', JAB 8.5, Ph- δC(125 MHz; CDCl
H), 7.85 [s, 1 H, ImC(2)-H]; δC(125 MHz; CDCl ; Me
Si) 20.44 (CH- groups), 35.13 (tBu C-CH
CH group), 31.06 (tBu CH groups), 35.18 (tBu C-CH
O), 116.85 [ImC(5)], 125.53 [PhC(3)], 126.08 [PhC(1)], 129.68 [PyrC(3)], 157.30 [PhC(4)], 165.35 (COO); MS (ESI): Exact mass calcd
H
,
H
6.5, CCH
3
), 6.99 (1 H, q, J
H
,
H
H H
,
3
; Me
4
Si) 19.42 (CH-CH
3
3
3
4
3
), 75.63 (N-CH- [PhC(3)], 126.46 [PhC(1)], 129.81 [PhC(2)], 129.87 [PyrC(5)], 140.46
3
3
3
+
[
ImC(4)], 129.74 [PhC(2)], 136.50 [ImC(2)], 157.61 [PhC(4)], 165.04 for C16
COO); MS (ESI): Exact mass calcd for C16
: 272.15, found m/z for C16
: C, 70.56; H, 7.40; N, N, 10.23.
H
20
N
2
O
2
: 272.15, found m/z 273.200 (M , 100%). Anal. calcd
(
H
20
N
2
O
2
H
20
N
2
O
2
: C, 70.56; H, 7.40; N, 10.29. Found: C, 70.49; H, 7.45;
+
2
73.200 (M , 100%). Anal. calcd for C16
H
20
N
2
O
2
10.29. Found: C, 70.48; H, 7.59; N, 10.19.
1
-(1H-Triazol-1-yl)ethyl 4-(tert-butyl)benzoate (18) and 1-(1H-
1-(1H-Benzo[d]imidazol-1-yl)ethyl 4-(tert-butyl)benzoate (16)
triazol-2-yl)ethyl 4-(tert-butyl)benzoate (19)
Aza-Markovnikov adduct 16 was prepared as described above in the Aza-Markovnikov adducts 18 and 19 were prepared as described
General procedure starting from vinyl 4-(tert-butyl)benzoate (11, above in the General procedure starting from vinyl 4-(tert-
1
47 μL, 147.1 mg, 0.72 mmol, 1.2 eq.), benzimidazole (2, 70.9 mg, butyl)benzoate (11, 147 μL, 147.1 mg, 0.72 mmol, 1.2 eq.), 1,2,3-
6
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 9
Pl Ne ae swe Jdoo u nr no at l ao df j Cu sh te mm ai sr tgr iyn s
View Article Online
DOI: 10.1039/C8NJ01277F
Journal Name
ARTICLE
triazole (10, 41.4 mg, 0.6 mmol) and catalyst (K PO or 6 or 7, 0.03 1.
S. France; D. J. Guerin; S. J. Miller and T. Lectka, Chem.
2003, 103 2985.
K. Kacprzak and J. Gawronski, Synthesis-Stuttgart
3
4
mmol, 0.05 eq.) in acetonitrile (1.2 mL). The crude product was rev.
,
,
purified by preparative thin layer chromatography on silica gel using 2.
,
hexane:ethyl acetate (1:1) mixture as an eluent to give aza- 2001, 961.
Markovnikov adduct 18 and 19 as a pale yellow oil (yields can be 3.
T. Marcelli and H. Hiemstra, Synthesis-Stuttgart, 2010,
1
4
229.
.
seen in Table 3.).
E. M. O. Yeboah; S. O. Yeboah and G. S. Singh,
2011, 67 1725.
M. North, Sustainable Catalysis: Without Metals or
Other Endangered Elements, Part 2 2016
C. E. Song, Cinchona Alkaloids in Synthesis and
Catalysis: Ligands, Immobilization and Organocatalysis
Weinheim, 2009
G. Tanriver; B. Dedeoglu; S. Catak and V. Aviyente,
Accounts Chem. Res. 2016, 49 1250.
D. Susam and C. Tanyeli, New J. Chem.
T. Penaska; K. Ormandyova; M. Meciarova; J. Filo and
2017, 41 5506.
S. Karahan and C. Tanyeli, New J Chem
S. W. Lin; Q. Sun; R. T. Li; T. M. Cheng and Z. M. Ge,
2007, 1933.
Chem. Abstr. 1992, 116
T. Yano; H. Tomioka; T. Ishiwatari and N. Hirata, JP
1991.
S. Ozaki; Y. Watanabe; T. Hoshiko; H. Mizuno; K.
609 (C=C), 1572, 1463, 1410, 1365, 1343, 1267, 1242, 1188, 1089, Ishikawa and H. Mori, Chem. Pharm. Bull. 1984, 32 733.
061, 1015. δH(500 MHz; CDCl ; Me Si) 1.33 (9 H, s, tBu CH
15. J. C. Sih; W. B. Im; A. Robert; D. R. Graber and D. P.
Blakeman, J. Med. Chem. 1991, 34 1049.
1
-(1H-Triazol-1-yl)ethyl 4-(tert-butyl)benzoate (18) TLC (SiO
2
TLC; Tetrahedron
=0.48, UV). IR (neat) νmax/cm 3130, 5.
f
,
,
-1
hexane:ethyl acetate = 1:1, R
,
,
2
963 (CH), 2870 (CH), 2389, 2300, 2096, 1938, 1719 (C=O), 1608
6
.
(
C=C), 1573, 1460, 1409, 1365, 1339, 1262, 1187, 1078, 1034, 1011.
1
,
H NMR (500 MHz, CDCl
3
): δ (ppm) 1.34 (9 H, s, tBu CH
), 7.32 (1 H, q, J 6.5, N-CH-O), 7.48 and
.98 (2×2H, AA'BB', JAB 8.5, Ph-H), 7.74 [1 H, s, TriazC(5)-H], 7.90 [1
; Me Si) 19.69 (CH-CH group),
groups), 35.20 (tBu C-CH ), 77.98 (N-CH-O), 125.58
3
groups),
,
2.13 (3 H, d, J
H
,
H
6.5, CCH
3
H H
,
7
.
7
,
,
H, s, TriazC(4)-H]; δC(125 MHz; CDCl
1.04 (tBu CH
3
4
3
8
9
.
.
, 2017, 41, 3555.
3
3
3
[
PhC(3)],123.63 [TriazC(3)], 126.19 [PhC(1)], 129.89 [PhC(2)], 135.15
R. Sebesta, New J. Chem.
,
,
[
TriazC(4)], 157.86 [PhC(4)], 164.95 (COO); MS (ESI): Exact mass
1
1
0.
1.
, 2017, 41, 9192.
+
calcd for C15
H
19
N
3
O
2
: 273.15, found m/z 274.100 (M , 177.43%).
Anal. calcd for C H N O : C, 65.91; H, 7.01; N, 15.37. Found: C,
15
19
3
2
Synthesis-Stuttgart,
65.82; H, 7.18; N, 15.35.
1
1
2.
3.
,
.
1
-(1H-1,2,3-Triazol-2-yl)ethyl 4-(tert-butyl)benzoate (19) TLC (SiO
2
1
-
TLC; hexane:ethyl acetate = 1:1, R =0.82, UV). IR (neat) νmax/cm
03232805
,
f
3
1
1
428, 2964 (CH), 2869 (CH), 2399, 2281, 2098, 1939, 1724 (C=O), 14.
,
,
3
4
3
,
,
groups), 2.06 (3 H, d, J
H
,
H
6.5, CCH ), 7.42–7.44 [1 H, m, N-CH-O],
3
1
6.
W. B. Wu; N. Wang; J. M. Xu; Q. Wu and X. F. Lin, Chem.
7.44 and 7.98 (2×2H, AA'BB', JAB 8.5, Ph-H), 7.72 [2 H, s, TriazC(4)-H,
Commun., 2005, 2348.
TriazC(5)-H]; δC(125 MHz; CDCl ; Me Si) 19.38 (CH-CH group),
3
4
3
1
7.
W. B. Wu; J. M. Xu; Q. Wu; D. S. Lv and X. F. Lin, Adv.
3
1.06 (tBu CH groups), 35.14 (tBu C-CH ), 81.46 (N-CH-O), 125.42
3
3
Synth. Catal. 2006, 348 487.
,
,
[
PhC(3)], 126.19 [PhC(1)], 129.90 [PhC(2)], 135.15 [TriazC(4),
8. X. W. Chen; X. H. Li; H. B. Song; Y. Qian and F. R. Wang,
TriazC(5)], 157.38 [PhC(4)], 164.67 (COO); MS (ESI): Exact mass
Tetrahedron Lett. 2011, 52 3588.
1
+
,
,
calcd for C15
Anal. calcd for C15
5.79; H, 7.20; N, 15.34.
H
19
N
3
O
2
: 273.15, found m/z 274.200 (M , 91.42%).
1
9. G. Szekely; M. F. Jimenez-Solomon; P. Marchetti; J. F.
Kim and A. G. Livingston, Green Chem. 2014, 16 4440.
0. J. F. Kim; G. Szekely; M. Schaepertoens; I. B. Valtcheva;
M. F. Jimenez-Solomon and A. G. Livingston, ACS Sustain. Chem.
Eng. 2014, 2371.
1. G. Szekely; I. B. Valtcheva; J. F. Kim and A. G. Livingston,
React. Funct. Polym. 2015, 86 215.
L. Peeva; J. D. Burgal; S. Vartak and A. G. Livingston, J.
2013, 306 190.
W. E. Siew; C. Ates; A. Merschaert and A. G. Livingston,
Green Chem. 2013, 15 663.
R. A. Sheldon, Green Chem
R. A. Sheldon, Chem. Commun.
C. M. Alder; J. D. Hayler; R. K. Henderson; A. M.
Innovation office (former OTKA, grant number K112289), Servier- Redman; L. Shukla; L. E. Shuster and H. F. Sneddon, Green
H N O : C, 65.91; H, 7.01; N, 15.37. Found: C,
19 3 2
,
,
6
2
,
2,
2
Conflicts of interest
,
,
There are no conflicts to declare.
22.
Catal.
,
,
2
3.
Acknowledgements
,
,
2
2
4.
5.
,
2007,
9, 1273.
2008, 3352.
,
Financial supports of the National Research, Development and 26.
Beregi PhD Research Fellowship and the New Széchenyi Chem.
,
2016, 18, 3879.
D. Prat; J. Hayler and A. Wells, Green Chem.
Development Plan (TÁMOP_4.2.1/B-09/1/KMR-2010-0002) are 27.
,
2014, 16
,
gratefully acknowledged.
4546.
2
1
8.
.
T. Welton, P. Royal Soc. London Math. Phy.
,
2015, 471,
Notes and references
29.
Clark; T. J. Farmer; A. J. Hunt; C. Robert McElroy and J.
Sherwood, Sus. Chem. Proc. 2016, 7.
F. P. Byrne; S. Jin; G. Paggiola; T. H. M. Petchey; J. H.
,
4,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 8 of 9
View Article Online
DOI: 10.1039/C8NJ01277F
ARTICLE
Journal Name
3
2
3
0.
M. Kidwai; N. K. Mishra and A. Jahan, Chin. Chem. Lett.
417.
H. Y. Bae; S. Some; J. H. Lee; J. Y. Kim; M. J. Song; S. Lee;
2011, 353 3196.
A. Moran; A. Hamilton; C. Bo and P. Melchiorre, J. Am.
Chem. Soc,. 2013, 135 9091.
3. P. Melchiorre; M. Marigo; A. Carlone and G. Bartoli,
Angew. Chem. Int. Edit. 2008, 47 6138.
4. J. F. Kim; G. Szekely; I. B. Valtcheva and A. G. Livingston,
Green Chem. 2014, 16 133.
5. C. Didaskalou; S. Buyuktiryaki; R. Kecili; C. P. Fonte and
G. Szekely, Green Chem. 2017, 19 3116.
6. M. Schaepertoens; C. Didaskalou; J. F. Kim; A. G.
Livingston and G. Szekely, J. Membr. Sci. 2016, 514 646.
7. M. Razali; C. Didaskalou; J. F. Kim; M. Babaei; E. Drioli;
Y. M. Lee and G. Szekely, ACS Appl. Mater. Inter. 2017, 11279.
8. M. Kidwai; M. Lal; N. K. Mishra and A. Jahan, Green
Chem. Lett Rev 2013, 63.
,
011, 22
,
1.
Y. J. Zhang and C. E. Song, Adv. Synth. Catal.
2.
,
,
3
,
3
,
,
3
,
,
3
,
,
3
,
,
3
,
9,
3
,
6,
8
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 9
New Journal of Chemistry
View Article Online
DOI: 10.1039/C8NJ01277F
Table of contents
Cinchona derivatives as sustainable and recyclable homogeneous organocatalysts for aza-
Markovnikov addition.
Sándor Nagy, Zsuzsanna Fehér, Péter Kisszékelyi, Péter Huszthy and József Kupai
Aza-Markovnikov additions were achieved with up to 98% yields using cinchona based
organocatalysts that were recycled by organic solvent nanofiltration.