Stereoselectivity Inversion by Water Addition in the ?SO3H-catalyzed Tandem Prins-Ritter Reaction for Synthesis of 4-amidotetrahydropyran Derivatives

Article abstract of DOI:10.1002/cctc.202000070

A range of heterogeneous -SO₃H functionalized catalysts including carbon and halloysite nanotubes, commercial K10 clay, Amberlyst-15 etc. was investigated for the first time using as a model the Prins-Ritter reaction of (?)-isopulegol with benzaldehyde and acetonitrile producing 4-amido derivatives of octahydro-2H-chromenes (as (S)- and (R)-diastereomers). A strong effect of water addition prior the reaction on the overall selectivity and the ratio of isomers in the case of heterogeneous and homogeneous (p-toluenesulfonic acid) catalysis was found for the first time. The yield of the (R)-diastereomer sharply increased with increasing amount of added water, while the S-isomer prevailed with a minimum amount of added water. Experimental results and DFT calculations clearly indicate a kinetic control for R-amide formation. Typically synthesis of 4-amidooctahydro-2H-chromenes requires subzero temperatures and toxic catalysts, which were avoided in the current work. Nevertheless, the yield of the desired products (up to 83 %) at 30 °C after water addition exceeded the values reported previously. Thus, adding water is a simple and a very effective method for controlling both the yield and stereoselectivity of the Prins-Ritter reaction products under mild conditions.

Full text of DOI:10.1002/cctc.202000070

Accepted Article
Title: Stereoselectivity inversion by water addition in the -SO3H
catalyzed tandem Prins-Ritter reaction for synthesis of 4-
amidotetrahydropyran derivatives
Authors: Alexander Sidorenko, Nikolai Li-Zhulanov, Päivi Mäki-Arvela,
Thomas Sandberg, Anna Kravtsova, Andreia Peixoto, C.
Freire, Konstantin Volcho, Nariman Salakhutdinov, Vladimir
Agabekov, and Dmitry Murzin
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemCatChem 10.1002/cctc.202000070
Link to VoR: http://dx.doi.org/10.1002/cctc.202000070
A Journal of
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10.1002/cctc.202000070
ChemCatChem
Stereoselectivity inversion by water addition in the -SO3H catalyzed tandem Prins-Ritter reaction
for synthesis of 4-amidotetrahydropyran derivatives
A.Yu. Sidorenkoa,b*, N.S. Li-Zhulanova,c,d, P. Mäki-Arvelaa, T. Sandberga, A.V. Kravtsovab, A.F.
Peixotoe, C. Freiree , K.P. Volchoc,d, N.F. Salakhutdinovc,d, V.E. Agabekovb, D.Yu. Murzina*
a Åbo Akademi University, 20500 Turku/Åbo, Finland
bInstitute of Chemistry of New Materials of National Academy of Sciences of Belarus, 220141,
Skaryna str, 36, Minsk, Belarus
cNovosibirsk Institute of Organic Chemistry, Lavrentjev av. 9, 630090, Novosibirsk, Russian
Federation,
dNovosibirsk State University, Pirogova st. 1, 630090, Novosibirsk, Russian Federation
eLAQV-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências,
Universidade do Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal
Corresponding authors
Professor Dr. D.Yu. Murzin
Åbo Akademi University
Biskopsgatan 8, 20500, Turku/Åbo, Finland
Ph: + 358 2 215 4985
e-mail: dmurzin@abo.fi
Dr. A.Yu. Sidorenko
e-mail: Sidorenko@ichnm.basnet.by;
Ph:+375 17 268 63 08
Address: Institute of Chemistry of New Materials of National Academy of Sciences of Belarus,
220141, Skaryna str., 36, Minsk, Belarus
1
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10.1002/cctc.202000070
ChemCatChem
Abstract
A range of heterogeneous -SO3H functionalized catalysts including carbon and halloysite
nanotubes, commercial K10 clay, Amberlyst-15 etc. was investigated for the first time using as a
model the Prins-Ritter reaction of (-)-isopulegol with benzaldehyde and acetonitrile producing 4-
amido derivatives of octahydro-2H-chromenes (as (S)- and (R)-diastereomers). A strong effect of
water addition prior the reaction on the overall selectivity and the ratio of isomers in the case of
heterogeneous and homogeneous (p-toluenesulfonic acid) catalysis was found for the first time. The
yield of the (R)-diastereomer sharply increased with increasing amount of added water, while the S-
isomer prevailed with a minimum amount of added water. Experimental results and DFT calculations
clearly indicate a kinetic control for R-amide formation. Typically synthesis of 4-amidooctahydro-
2H-chromenes requires subzero temperatures and toxic catalysts, which were avoided in the current
work. Nevertheless, the yield of the desired products (up to 83%) at 30°C after water addition
exceeded the values reported previously. Thus, adding water is a simple and a very effective method
for controlling both the yield and stereoselectivity of the Prins-Ritter reaction products under mild
conditions.
Keywords: Prins-Ritter reaction, tetrahydropyran amides, stereoselectivity, sulphonated materials,
carbon nanotubes
2
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Tetrahydropyran (THP) is a common scaffold in a large number of biologically active
compounds [1, 2]. Octahydro-2H-chromene is a heterocycle with tetrahydropyran moiety occurring
in many important natural products and biologically active molecules [3,4]. Some of compounds with
the octahydro-2H-chromene scaffold exhibit antiviral and analgesic activities [5,6]. Recently it has
been found that octahydro-2H-chromenols with different amide moieties exhibit activity against
DNA repair enzyme, tyrosyl-DNA phosphodiesterase 1, a promising target for antitumor therapy [7].
A flexible method for the synthesis of variable THP derivatives is the Prins cyclization [8–
10]. Thus, synthesis of octahydro-2H-chromenes can be realized using terpenoid (-)-isopulegol
condensation with aldehydes [11, 12]. The Prins reaction could be utilized as an initiator of a tandem
(cascade) reaction to build the 4-amidotetrahydropyran derivatives (Fig. 1) [13,14]. The technique of
a cascade reaction is also a valuable tool in the synthesis of “natural product-like” molecules [15-18].
Note that the 4-nitrogen-substituted THP motif is present in some biologically active compounds [19–
22].
In general, the Prins-Ritter reaction has been reported with acetonitrile (both as a nucleophile
and as a solvent) or in CH2Cl2, in the case of other nitriles [13, 23–27]. The commonly used catalysts
for this transformation are Lewis (Bi(OTf)3, BF3·Et2O, I2/AcCl etc.) and Brønsted (TfOH) acids [13,
14, 28–31].
To the best of our knowledge, heterogeneous catalysts for the tandem Prins-Ritter reaction
have not been reported, whereas utilization of homogeneous catalysis is associated with difficulties
of the catalyst separation, toxicity and, often, high costs (as triflates, for example). At the same time,
heterogeneous materials such as zeolites and modified clays are effective catalysts for Prins
cyclization [32–34].
Considering that in a number of cases it was found that the biological activity of terpenoid-
based compounds depends on the configuration of the functional group in the fourth position in THP
(Fig. 1) [12], finding stereoselective catalytic methods for the synthesis of terpenoids-derived amides
is a very important task.
3
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Fig. 1. Prins-Ritter reaction for aliphatic (a) and terpene (b) alcohols
In this work, -SO3H functionalized K10 clay, carbon (CNT) and halloysite (HNT) nanotubes,
Na+-cloisite (CLOI) as well as a commercial Amberlyst-15 resin were studied as acid catalysts for
Prins-Ritter reaction of (-)-isopulegol with benzaldehyde and acetonitrile at mild (30°C) conditions.
For comparison, as a homogeneous catalyst, p-toluenesulfonic acid (p-TSA) was used.
Functionalization of the materials was carried out by treating them with chlorosulphonic acid
(CSA) or 2-(4-chlorosulfonylphenyl)ethyltrimethoxysilane (CSP). A schematic representation of
some investigated solids is given in Fig. 2. Functionalized clays were characterized by TEM, SEM,
XRD, XPS, FTIR with pyridine, N2 adsorption in the previous work [34]. A detailed experimental
procedure and characterization results are presented in Supporting Information (SI).
Fig. 2. Schematic representation of some -SO3H functionalized materials
4
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The products of (-)-isopulegol 1 reaction with benzaldehyde 2 and acetonitrile were amides 3,
chromenols 4, and dehydration compounds 5 (Fig. 3). The initial tests of heterogeneous catalysts
using acetonitrile of HPLC grade demonstrated that the main products were amides 3 with 66–76 %
selectivity and a predominance of the (S)–diastereomer (Table S1). The highest (-)-isopulegol 1
conversion after 3 h (78%) was achieved on K10-CSA exhibiting the highest acidity (Table S1, entry
1). In the case of carrying out the reaction in anhydrous acetonitrile on the same catalyst, there was a
sharp decrease in the amides selectivity to 32% and simultaneously an increase in the S/R isomers
ratio (Table S1, entry 2). On the contrary condensation of (-)-isopulegol with various aldehydes and
dry acetonitrile in the presence of TfOH at -25°C led to the predominance of (R)-acetamide in all
cases [14]. The preliminary results revealing the effect of water on selectivity in the Prins-Ritter
reaction (Table S1) were further explored in a more detailed study with a systematic addition of water.
Fig. 3. The products of the Prins-Ritter reaction over studied catalysts
The effect of water addition before the reaction was investigated in the presence of
functionalized with chlorosulfonic acid (CSA) materials K10-CSA, CNT-CSA, which showed quite
high activity and selectivity to amides as well as on a commercial resin Amberlyst-15 and p-TSA for
comparison.
For all heterogeneous catalysts studied in this work, addition of water to the reaction mixture
led to a sharp increase in selectivity for amides 3 and a decrease in the dehydration products 5 (Table
1). Moreover, an increase in the amount of introduced water results in a change in the ratio of the
5
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10.1002/cctc.202000070
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resulting stereoisomers of amides 3. Thus, selectivity to (R)-3 continuously increased with an increase
of water content, while the largest (S)-3 yield was observed when 2.2 mmol of H2O was added before
the reaction (Fig. 4). The (R)-amide became the predominant product after introduction of 17.3 mmol
of water, i.e. an inversion of the reaction stereoselectivity was observed. The highest selectivity
towards the target amides 3 (83 %) with a R/S isomers ratio of 5.1 was observed on CNT-CSA (Table
1, entry 10).
The achieved overall selectivity was significantly higher than that at -25 °C in the presence of
triflic acid (62 %, R/S of 5.0) [14]. Note that although water addition led to a slight increase in
selectivity to chromenols 4, there were no significant changes in the ratio of isomers contrary to
amides (Table 1).
Table 1. Distribution of reaction productsa over heterogeneous catalysts depending on water
addition
Selectivity to reaction products, %
r0,
mmol/
(g·min)
0.02
0.06
0.10
0.15
0.20
0.04
0.015
0.10
0.13
0.09
0.89
1.1
Added H2O,
mmol
Entry
Catalyst
Amides 3 Chromenols 4
Dehydration
products 5
43.8
Total
41.7
61.7
68.3
74.1
76.3
71.1
82.7
38.1
70.7
82.7
13.5
48.9
47.4
(S)-3
33.8
45.9
45.5
38.9
23.8
12.9
45.6
29.0
41,2
13.6
11.2
32.1
12,6
(R)-3
7.9
R/S
Total
14.5
16.8
17.8
17.6
19.8
26.0
7.7
R/S
5.0
4.1
3.9
3.7
3.9
4.3
3.8
4.1
3.0
3.4
2.8
3.3
4.1
1b
2
0
1:4.3
1:2.9
1:2.0
1:1.1
2.2:1
4.5:1
1:1.2
1:3.2
1:1.4
5.1:1
1:4.9
1:1.9
2.8:1
2.2
4.3
8.7
17.3
43.3
2.2
0
15.8
22.8
35.2
52.5
58.2
37.1
9.1
21.5
3
13.9
K10-CSA
4
8.3
5
4.8
6
2.9
7c
8.9
8
18.0
18.4
15.2
13.0
20.0
35.0
43.9
9
CNT-CSA
2.2
17.3
0
29.5
69.1
2.3
10.9
10
11
12
13
2.1
71.5
Amberlyst-15
2.2
17.3
16.8
34,8
30.2
0.56
16.7
Reaction conditions: 0.65 mmol of (-)-isopulegol, 1.95 mmol of benzaldehyde, 0.1 g of dry catalyst, anhydrous acetonitrile was used
both as a reactant and solvent, total volume of the reaction mixture was 20 ml, temperature was 30 °C
aAt 50 % (-)-isopulegol conversion; bAt 34 % conversion for 5 h; cAt 0°C and 20 % conversion for 3 h
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Fig. 4. Selectivity to amides for the Prins-Ritter reaction over K10-CSA as a function of water
added before the reaction.
The Prins-Ritter reaction in the presence of p-TSA as a homogeneous catalyst led to results
similar to those obtained with heterogeneous catalysts (Table 2). Thus, introduction of 2.2 mmol of
water before the reaction gave mainly (S)-amide, while in the case of large additions of H2O, a
practically quantitative inversion of stereoselectivity was observed (Table 2).
Table 2. Distribution of reaction products over homogeneous catalysts studied depending on water
on water addition
Selectivity to reaction products, %
Added H2O,
mmol
Conversion
after 3 h, %
Entry
Catalyst
Amides 3
Chromenols 4
Dehydration
products 5
18.0
Total
64.1
70.3
67.7
79.4
(S)-3
(R)-3
14.9
50.6
57.4
52.9
R/S
Total
17.9
20.6
26.9
10.1
R/S
4.1
3.9
4.3
4.9
1
2
2.2
17.3
43.3
2.2
100
100
100
100
49.2
19.7
10.3
26.5
1:3.3
2.6:1
5.6:1
2.0:1
9.1
p-TSA
3
5.4
4a
10.6
Reaction conditions: 0.65 mmol of (-)-isopulegol, 1.95 mmol of benzaldehyde, 0.53 mmol of catalyst, anhydrous acetonitrile
was used both as reactant and solvent, total volume of reaction mixture was 20 ml, temperature was 30 °C
aAt temperature 0 °C
It is important to note that both introduction of water and elevation in its amount led to an
increase in the initial reaction rate and selectivity for amides 3, while the yield of compounds 5
decreased (Table 1, entry 2–5). In this case, a continuous increase in selectivity for (R)-3 was
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10.1002/cctc.202000070
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observed. This may indicate a kinetic control for this isomer formation. To confirm this assumption,
the reaction was carried out at 0°C. Indeed, in the presence of both K10-CSA (Table 1, entry 7) and
p-TSA (Table 2, entry 4), a decrease in temperature to 0°C led to an increase in the yield of (R) -
amide, however, inverse stereoselectivity was observed for the homogeneous catalyst. These results
are consistent with the conclusions made in [35] based on the Alder calculation model [36] that for
4-methyl-substituted tetrahydropyranyl compounds, formation of cis-isomer is kinetically controlled.
Note that the initial reaction rate on K10-CSA sharply decreases with an increase in the
amount of water from 17.3 to 43.3 mmol (Table 1, entry 5, 6), which can be explained by interactions
of the catalytically active sites with water, resulting in a decrease in acidity and, subsequently,
activity.
The role of water in the Prins-Ritter reaction can be rationalized based on the hypothesis of
different stability of the intermediates. Thus, interactions of (-)-isopulegol 1 with aldehyde 2 lead to
the intermediate cation 3-A, which can undergo multivariate transformations (Fig. 5a). In the case of
nitrile capture, 3-A is converted to 3-B and 3-C ions, which are precursors of amides 3. Note that the
selectivity towards amides 3 was not dependent on isopulegol conversion (Fig. S1), which indicates
the parallel formation of (R)- and (S)-3 compounds.
The reason for the selectivity inversion may be different stability of the cations 3-B and 3-C.
Without addition of water or when its amount is small, (S)-amide is formed from the more stable 3-
C ion. At the same time, the kinetically unstable 3-B cation tends to be converted into 3-A and then
into dehydration products 5, as can be seen from the selectivity data (Table 1). With an increase in
the amount of water, an increase in selectivity to (R)-amide and in the reaction rate is observed,
illustrating a kinetically controlled formation of this isomer from 3-B. To confirm this conclusion
quantum-mechanical calculations have been performed.
B3LYP/6-31G** DFT calculations performed with the Jaguar 9.9 program [37] both for gas
phase and acetonitrile by the Jaguar’s Poisson-Boltzmann finite element method (solvation model)
gave the calculated energies difference between (S)-3 and (R)-3 isomers in the gas phase and
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acetonitrile of only 2.8 and 1.1 kJ/mol, respectively (Table S2). The energies for the intermediates
were calculated taking the (S)-3 energy level as zero. The energy difference between 3-C and 3-B
intermediates in acetonitrile was 17.4 kJ/mol (Fig. 5b), which clearly indicates a kinetic control for
(R)-3 amides formation being completely consistent with the experimental data.
All species were characterized using full geometry optimization followed by frequency
calculations at the B3LYP/6-31G** level. Compounds (S)-3 and (R)-3 were also studied using the
DMol3 module in the software Materials Studio 2019 [38] on DFT/B3LYP/TZVP level of theory.
Grimme’s method in DMol3 SEDC module was implemented for DFT-D (dispersion) correction
[39]. Dielectric coefficient of acetonitrile, 37.5 was used with COnductorlike Screening Model
(COSMO) [40]. The (S)-isomer was found to be more stable by 4.7 kJ/mol, which establishes the
previous conclusion. Optimized structures of diastereomer are shown in Fig. S2.
Fig. 5. Mechanism of the Prins-Ritter reaction (a) and DFT calculated energy diagram
for amides formation (b).
Note that the highest amides yield (83%) was observed in the presence of CNT-CSA catalyst
with a lower acidity compared to K10-CSA and Amberlyst-15. In the case of the strong Brønsted acid
9
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(Amberlyst-15), formation of a significant amount of dehydration products (Table 1, entry 11), or
chromenols after the addition of water (Table 1, entry 13) was observed. Therefore, strong acids apart
from formation of amides promoted the proton cleavage (without water) or capture a weaker
nucleophile (H2O) to the 3-A cation (Fig. 5a).
Thus, in the present work, –SO3H functionalized heterogeneous catalysts were studied for the
first time in the Prins-Ritter reaction for the synthesis of octahydro-2H-chromene amides with a
pharmaceutical potential. The inversion of stereoselectivity in amides formation by water addition to
the reagents was found in the case of both heterogeneous and homogeneous catalysis.
The yield of (R)-amide increased with an increase in the amount of water introduced or a
decrease in the reaction temperature, which suggests kinetic control of its formation as confirmed by
DFT calculations. A mechanistic discussion about the role of water in the reaction was presented.
Adding water to the reagents allows stereoselective synthesis of octahydro-2H-chromene amides
under mild conditions (30 °C), avoiding the use of toxic catalysts and subzero temperatures.
Acknowledgments
The research visit of A.S. to ÅAU was financially supported by Research Mobility Program of the
University. The research visit of N.L.Z. to the same place was supported by the EDUFI Fellowship
programme, funded by the Finnish National Agency for Education. A part of this work was also
funded by the BRFFR (grant Kh19RM-002) and RFBR (19-53-04005 Bel_mol_a) as well as by
Fundação para
a
Ciência
e
a
Tecnologia (FCT): PTDC/BII-BIO/30884/2017,
UID/QUI/50006/2019 and DL57/2016 - Norma transitória (AFP).
Conflict of interest
The authors declare no conflict of interest.
10
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The Prins-Ritter reaction: No temperatures below zero, no toxic catalysts, just add water! A
range of heterogeneous -SO3H functionalized catalysts were investigated for the first time using the
Prins-Ritter (-)-isopulegol reaction with benzaldehyde and acetonitrile as a model producing 4-amido
derivatives of octahydro-2H-chromenes (as S- and R-diastereomers). A strong effect of water addition
prior the reaction on the overall selectivity and the ratio of isomers was found.
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