Delineating the Mechanism of Ionic Liquids in the Synthesis of Quinazoline-2,4(1H,3H)-dione from 2-Aminobenzonitrile and CO2

Article abstract of DOI:10.1002/anie.201705438

Ionic liquids (ILs) are versatile solvents and catalysts for the synthesis of quinazoline-2,4-dione from 2-aminobenzonitrile and CO₂. However, the role of the IL in this reaction is poorly understood. Consequently, we investigated this reaction and showed that the IL cation does not play a significant role in the activation of the substrates, and instead plays a secondary role in controlling the physical properties of the IL. A linear relationship between the pK_a of the IL anion (conjugate acid) and the reaction rate was identified with maximum catalyst efficiency observed at a pK_a of >14.7 in DMSO. The base-catalyzed reaction is limited by the acidity of the quinazoline-2,4-dione product, which is deprotonated by more basic catalysts, leading to the formation of the quinazolide anion (conjugate acid pK_a 14.7). Neutralization of the original catalyst and formation of the quinazolide anion catalyst leads to the observed reaction limit.

Full text of DOI:10.1002/anie.201705438

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Accepted Article
Title: Delineating the Mechanism of Ionic Liquids in the Synthesis of
Quinazoline-2,4(1H,3H)-dione from 2-Aminobenzonitrile and CO2
Authors: Martin Hulla, Sami Manoubi Armand Chamam, Gabor
Laurenczy, Shoubhik Das, and Paul J. Dyson
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Angewandte Chemie International Edition
10.1002/anie.201705438
Delineating the Mechanism of Ionic Liquids in the Synthesis of
Quinazoline-2,4(1H,3H)-dione from 2-Aminobenzonitrile and CO
2
Martin Hulla, Sami M. A. Chamam, Gabor Laurenczy, Shoubhik Das and Paul J. Dyson*
Abstract: Ionic liquids (ILs) are versatile solvents and catalysts for
([TBP][Arg]) requires high CO
Although at 1 bar CO extended reaction times were required,
pressures and temperatures.[37]
2
the synthesis of quinazoline-2,4-dione from 2-aminobenzonitrile and
2
CO
2
. However, the role of the IL in this reaction is poorly understood.
tetrabutylammonium tungstate ([TBA]
relevant activity.[38,39]
2
[WO
4
]) also demonstrated
Consequently, we investigated this reaction and showed that the IL
cation does not play a significant role in the activation of the
substrates, and instead plays a secondary role in controlling the
physical properties of the IL. A linear relationship between the pKa
of the IL anion (conjugate acid) and the reaction rate was identified
with maximum catalyst efficiency observed at a pKa of > 14.7 in
DMSO. The base catalyzed reaction is limited by the acidity of the
quinazoline-2,4-dione product, which is deprotonated by more basic
catalysts leading to the formation of the quinazolide anion (conjugate
acid pKa 14.7). Neutralization of the original catalyst and formation
of the quinazolide anion catalyst leads to the observed reaction limit.
With the exception of [TBA]
2
[WO
4
], all the ILs were
used as dual catalyst-solvent media at high catalyst loadings (up
to 500 mol%). Although this approach eliminates the need of a
volatile organic solvent, it makes it difficult to assess the role of
the IL. Optimized reaction conditions have been reported for
each group of ILs studied, with reaction temperatures ranging
from 25 to 120°C, reaction times from 6 to 144 h and CO
2
pressures from 1 to 100 bar. These diverse conditions make the
search for the optimal IL catalyst challenging. Hence, we decided
to investigate systematically the catalytic role of ILs in the
conversion of 2-aminobenzonitrile to quinazoline-2,4-dione
under fixed reaction conditions in order to identify the key
features of the IL catalyst and the reaction mechanism.
Ionic liquids (ILs) are low melting salts,[1] often composed of
organic cations and inorganic anions, exhibiting diverse
properties and applications.[2,3] ILs are now often used as
Table 1: Cation effects on the catalytic activity of various acetate and fluoride
salts on the synthesis of quinazoline-2,4-dione.
[4–7]
catalysts for the transformations of CO
including, for example, the cycloaddition of CO
N-formylation of amines [10–12] and the synthesis of quinazoline-
,4-dione from 2-aminobenzonitrile.[13] The synthesis of
2
into fine chemicals
to epoxides,[8,9]
2
2
quinazoline-2,4-dione is important due to its wide range
biological activity and use as a precursor in the synthesis of
drugs, e.g. Prazosin, Bunazosin, Doxazosin and Zenarestat.[14]
The synthesis of quinazoline-2,4-dione from 2-
Entry
Catalyst
Catalyst loading (mol%)
Yield (%)
aminobenzonitrile and CO
2
was first reported with 1,8-
1
2
3
4
5
6
7
8
9
[BMIm][OAc]
[BMP][OAc]
[TBA][OAc]
[HOEMIm][OAc]
[HDBU][OAc]
KOAc
10
10
46
45
46
45
44
45
0
diazabicyclo[5.4.0]undec-7-ene (DBU).[
15–19]
Subsequently, a
variety of base catalysts were used for this reaction,[
20–23]
as well
as lanthanide complexes combined with DBU[ and a range of
24]
10
polymeric, ceramic and nanocatalysts.[
25–29]
However, the
10
catalysts that have attracted the most attention are ILs. The initial
IL catalyst, 1-butyl-3-methylimidazolium hydroxide
[BMIm][OH]),[ was shown to proceed via a self-deprotonation
10
30]
(
10
[
31]
mechanism and NHC-carbene formation.
Other stable IL
LiF
<10a
catalysts have subsequently been reported, such as 1-butyl-3-
methylimidazolium acetate ([BMIm][OAc]), which catalyzes the
KF
<10a
25
46
69
24
24
0
reaction at 1 bar CO
2
and 90°C.[32] The discovery that ILs
<10a
CsF
prepared by the protonation of DBU ([HDBU][X])[
33,34]
catalyze
10
[TBA]F
10
2
the reaction under ambient conditions led to the investigation of
protic ILs including 1,1,3,3-tetramethylguanidinium imidazolide
11
CsF
(
[HTMG][Im]),
Tetrabutylphosphonium 2-methylimidazolide ([TBP][2-MIm]) can
also catalyze the reaction at 1 bar CO at slightly elevated
temperatures,[36] whereas tetrabutylphosphonium arginine
which
showed
similar
activity.[35]
12
[TBA]F
2
13
-
-
2
Reaction conditions: 2-aminobenzonitrile (1 mmol), DMSO (1 ml), catalyst (10
mol%), CO (1 bar), 90°C, 20 h, average yield of isolated product from three
2
runs. a) 10 mol% catalyst added but salts not fully dissolved decreasing the
actual catalyst loading <10 mol%.
[
a]
M. Hulla, S. M. A. Chamam, Prof. Dr. G. Laurenczy, Prof. Dr. P. J.
Dyson Institut des Sciences et Ingénierie Chimiques, École
Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne
Both the cation and the anion of the IL were proposed to
synergistically activate the 2-aminobenzonitrile substrate,
leading to considerably different reactivities in different ILs.[
(Switzerland)
33,35]
E-mail: paul.dyson@epfl.ch
[
b]
Dr. S. Das Institut für Organische und Biomolekulare Chemie,
Georg-August-Universität Göttingen, Göttingen, Germany
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Angewandte Chemie International Edition
10.1002/anie.201705438
To verify this hypothesis we prepared a series of acetate ILs and
evaluated them under standardized catalytic reaction conditions
anions generated from weak acids (Figure 1) demonstrated
some catalytic activity towards the formation of quinazoline-2,4-
dione (Table 3, entries 7-11 and 13-16). A plot of the IL anion
pKa versus the product yield reveals a linear relationship with an
onset pKa value of 9.2 (Figure 2). A conversion limit of 68-69%
(under the conditions used), obtained with a number of stronger
bases, e.g. [TBA]F, tetrabutylphosphinum benzoimidazolide
([TBP][BenIm]) and imidazolide ([TBP][Im]), is marked by a
plateau (Figure 2). Notably, even uncharged bases such as DBU
fit the linear relationship indicating that the dependency of 2-
aminobenzonitrile conversion (and mechanism) is the same for
both ILs and uncharged bases. In addition, it should be noted
that bases with pKa values close to the observed reaction onset,
(
[
10 mol% catalyst loading in DMSO, 1 bar CO
BMIm][OAc] yielded the desired product in 46% yield (Table 1,
entry 1). Similarly, 1-butyl-1-methylpyrrolidinium acetate
[BMP][OAc]) and tetrabutylammonium acetate ([TBA][OAc])
resulted in comparable yields of 45% and 46%, respectively
Table 1, entries 2 and 3). The hydroxyl functionalized IL, 1-
hydroxyethyl-3-methylimidazolium acetate ([HOEMIm][OAc]),
2
, 90°C, 20 h).
(
(
2
which can potentially hydrogen bond with CO or the proposed
carbamate intermediate[40], also resulted in 45% yield (Table 1,
entry 4). The protic IL [HDBU][OAc] also yielded the product in
44% (Table 1, entry 5). Notably, even potassium acetate
exhibited similar activity with the product isolated in 45% yield
e.g. triethylamine and diphenylguanidine, were found to only
pressures,[
18,22]
and
(
Table 1, entry 6). In contrast to reactions conducted in pure ILs,
catalyze the reaction at elevated CO
2
where large differences in catalytic activity are observed,[
under catalytic conditions no significant differences are observed
as the IL cation is varied, indicating that the cation does not play
a significant role in the activation of the substrates or in
interactions with intermediates.
32,33,35]
weaker bases with pKa values much lower than the onset value,
e.g. pyridine, were inactive even in supercritical CO
.[18] The
positive effect of CO pressure together with the observed pKa
2
2
dependency supports a proposed reaction mechanism, where
the catalyst promotes carbamate salt formation via partial amine
deprotonation and nucleophilic attack on CO
2
.[40]
The lack of influence of the IL cation on the reaction
does not completely mitigate its role in the overall efficiency of
the catalyst. Experiments with alkali metal fluoride salts and
tetrabutylammonium fluoride ([TBA]F) reveal that the cation can
strongly influence catalyst performance. With 10 mol% of the
fluoride salt the quinazoline-2,4-dione product was extracted in
yields ranging from 0 to 69%, in the order LiF < KF < CsF <
Table 2: Dependency of the yield of quinazoline-2,4-dione on the basicity
characterized by pKa) of the catalyst.
(
Entry
Catalyst
pKa of Conjugate
Acid (BH+)[a]
Yield (%)
[
TBA]F (Table 1, entries 7-10). However, as the alkali fluoride
1
2
3
4
5
6
7
8
9
[TBA]Br
[TBA]Cl
Pyridine
0.9
1.8
0
0
salts are not fully soluble, the reaction yield is a reflection of the
catalysts solubility. With 2 mol% of CsF or [TBA]F, at which both
salts are fully soluble, comparable catalytic activity is observed
with the product isolated in 24% (Table 1, entries 11 and 12).
Thus, the efficiency of the catalyst can be limited by its solubility,
as proposed for metal carbonates.[20] Hence, the differences in
reaction rate in pure ILs may be attributed to differences in
physical properties such as viscosity or substrate solubility rather
3.4
0
[TBA][NO
Diphenylguanidine
Et
[HDBU][DioxoCy]
[TBA][PhCO
2
]
7.5
0
8.6
0
3
N
9.0
0
10.3
11.1
11.9
12.6
13.4
13.9
15.0
16.4
18.6
19.8
16
22
38
45[b]
55
65
69
69
68
68
than to the synergistic activation of the substrate by the cation
and anion.[33,35]
2
]
[TBP][BenTriz]
[X][OAc]
1
0
1
2
3
4
5
6
1
1
1
1
1
1
[TBA][Pth]
DBU
[TBA]F
[TBP][BenIm]
[TBP][Im]
[TBP][Pyr]
Reaction conditions: 2-aminobenzonitrile (1 mmol), DMSO (1 ml), catalyst (10
mol%), CO (1 bar), 90°C, 20 h, average yield of isolated product from three
2
runs. [a] Values were taken from Bordwell’s pKa tables, for ILs only the basicity
of the anion in DMSO was considered. [b] Average value for all acetate ILs
and KOAc.
Figure 1: Structures of catalytically active organic anions for the conversion of
2-aminobenzonitrile to quinazoline-2,4-dione.
The base catalyzed reaction yield reaches a limit with a
maximum efficiency between pKa 13.9 and 15, marked by a
plateau (Figure 2). From a linear extrapolation, the most efficient
catalysts will have a pKa around 14.4 or above in DMSO.
Although full deprotonation of the 2-aminobenzonitrile starting
material (pKa 24.3)[ cannot be achieved with such a catalyst,
higher yields are not observed with substantially stronger bases.
To rationalize this limit we determined the acidity of the
Since the reported organocatalysts are all bases[15–19,22] and the
cation has limited influence on the catalytic cycle, we
hypothesized that the catalytic activity of ILs is determined by the
basicity of the anion. We prepared and tested a series of ILs with
anions of varying basicity. ILs with anions derived from strong
acids are inactive (Table 2, entries 1 and 2). In contrast, ILs with
41]
2
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Angewandte Chemie International Edition
10.1002/anie.201705438
quinazoline-2,4-dione product using UV-vis spectroscopy (SI).[42]
The measured pKa of 14.7 is in excellent agreement with the
estimated pKa limit of the catalyst of 14.4. Presumably, the
acidity of quinazoline-2,4-dione results in its deprotonation by ILs
and bases with pKa values above 14.7. Hence, the original base
catalyst is neutralized and a new IL catalyst containing a
quinazolide anion is formed (Scheme 1). Thus, all catalysts with
pKa values above 14.7 only act as pre-catalysts towards the
formation of the quinazolide IL catalysts explaining the uniform
reaction yield observed for all ILs with a pKa above this value.
gives the product in 73% yield (cf. 69% is without acid). To
confirm the proposed transformation, the [TBP][Quinazolide] IL
was prepared and evaluated as a catalyst, resulting in a 74%
yield even with an aqueous work-up.
Scheme 1 Reaction of quinazoline-2,4-dione with a tetrabutylphosphonium IL,
X = fluoride, benzoimidazolide, imidazolide, pyrrazolide and other anions with
pka >14.7 in DMSO.
The pKa of a compound is solvent dependent and a linear
relationship between acidities in DMSO and a range of ILs was
recently demonstrated.[43–46] Hence, while the limiting pKa value
of 14.7 is only valid in DMSO, the pKa value is readily convertible
to ILs. Consequently, unless a base is present in excess, the
deprotonation of quinazoline-2,4-dione to the quinazolide anion
leads to the strongest base available in both organic solvents
and ILs. Similarly, in the case of substituted quinazoline-2,4-
diones the strongest available base would be the respective
quinazolide anion. Due to the linear relationship between pKa
and the yield (see above), bases stronger than quinazoline-2,4-
dione (or the quinazolide anion) are the most active catalysts for
the synthesis of quinazoline-2,4-dione (assuming they proceed
via a base-catalyzed mechanism (Scheme 2).
Figure 2: Reaction yield dependency on the pKa of the catalyst in DMSO.
Linear dependency is observed in the range 9.2-14.4; R = 0.99
Based on calculations a reaction mechanism was
proposed for the base catalyzed synthesis of quinazoline-2,4-
Once the product quinazolide-2,4-dione starts to form
2
diones from CO and 2-aminobenzonitrile (Scheme 2, cycle
[
TBP][BenIm], [TBP][Im], [TBP][Pyr] and [TBA]F are transformed
1 [
). In the first step (1), a carbamate salt is formed via a base
40]
into the tetrabutylphosphonium or tetrabutylammonium
quinazolide ([TBP][Quinazolide] and [TBA][Quinazolide]) ILs
with comparable activity. Some of the quinazolide-2,4-dione
product is lost (equivalent to the catalyst loading), which is only
partially recovered during aqueous work-up. Hence, using
2
promoted reaction between 2-aminobenzonitrile and CO . The
observed pKa dependency further supports the proposed
carbamate salt formation step as stronger bases enhance the
2
nucleophilicity of the amine favoring its reaction with CO .
[
TBP][BenIm] as a pre-catalyst followed by an acidic work-up
Scheme 2: Proposed catalytic cycle for the preparation of quinazoline-2,4-diones by catalysts with a pKa <14.7 (cycle 1, adapted from reference [40]) and the cycle
for catalysts with a pKa >14.7 (cycle 2). The IL cation was omitted for clarity.
3
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Angewandte Chemie International Edition
10.1002/anie.201705438
Intramolecular cyclisation (2), followed by
a
series of
[17] T. Mizuno, Y. Ishino, Tetrahedron 2002, 58, 3155–3158.
intramolecular rearrangement steps (3), leads to the formation of
a quinazolide anion. However, the final step (4), where the
quinazolide anion is protonated by the conjugate acid of the base
catalyst (eliminated in step 1), is only possible for catalysts with
a pKa < 14.7. For catalysts with pKa > 14.7 the quinazolide anion
is insufficiently basic to extract a proton from the original catalyst.
Presumably, the quinazolide anion then becomes the new base
catalyst in a second cycle (Scheme 2, cycle 2). The second cycle
follows the same steps, as the quinazolide anion is also a base,
with the exception that the product is formed simultaneously with
the carbamate salt in step (5) and the catalyst is regenerated by
a series of intramolecular rearrangement steps (7).[40]
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aminobenzonitrile, CO or the intermediates in the catalytic
2
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Angewandte Chemie International Edition
10.1002/anie.201705438
COMMUNICATION
Keywords: Carbon dioxide,
organocatalysis, base catalysis,
ionic liquids, sustainable chemistry
Martin Hulla, Sami M. A. Chamam,
Gabor Laurenczy, Shoubhik Das and
Paul J. Dyson*
†
Page No. – Page No.
Delineating the Mechanism of Ionic
Liquids in the Synthesis of
Quinazoline-2,4(1H,3H)-dione from
2-Aminobenzonitrile and CO
2
5
This article is protected by copyright. All rights reserved.