Syntheses of polyalkylated imidazoles

Article abstract of DOI:10.1080/00397911.2017.1330416

We have developed improved general simple methods for large-scale preparation of polyalkylated imidazoles by improved multicomponent synthesis from commercially available starting materials. A large range of NH- and N-alkyl-polyalkylimidazoles (40 in total, including novel compounds) has been synthesized.

Full text of DOI:10.1080/00397911.2017.1330416

Synthetic Communications
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Syntheses of Polyalkylated Imidazoles
Sigvart Evjen & Anne Fiksdahl
To cite this article: Sigvart Evjen & Anne Fiksdahl (2017): Syntheses of Polyalkylated Imidazoles,
Synthetic Communications, DOI: 10.1080/00397911.2017.1330416
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Date: 17 May 2017, At: 20:10

Syntheses of Polyalkylated Imidazoles
Sigvart Evjen1, Anne Fiksdahl1
1Department of Chemistry, Norwegian University of Science and Technology, NTNU,
Trondheim, Norway
Corresponding author Anne Fiksdahl E-mail: anne.fiksdahl@chem.ntnu.no
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic CommunicationsR for the following free supplementary resources:
Full experimental details and product characterization.]
Abstract
We have developed improved general simple methods for large scale preparation of
polyalkylated imidazoles by improved multi-component synthesis from commercially
available starting materials. A large range of NH- and N-alkyl-polyalkylimidazoles (40 in
total, including novel compounds) has been synthesised.
Graphical Abstract
KEYWORDS: new polyalkylimidazoles, improved preparation method, CO2 absorbents
1.
INTRODUCTION
Imidazoles represent one of the most important classes of five-membered heterocycles,
which have a great diversity of functions and applications, such as drugs, bioactive
1

natural products,[1] and acylating reagent. In addition, imidazolium salts are used as ionic
liquids [2a,b] and precursors for stable carbene NHC-ligands [2c] in organometallic
chemistry. Imidazoles have also been suggested as absorbents[3a,b] for improvement of
current technologies for carbon dioxide capture and storage (CCS). The well-established
amine CCS process is based on formation of carbamates from primary and secondary
amines (eq I), while tertiary amines form unstable carbamates, leading to formation of
bicarbonate (eq II).[4] Consequently, tertiary amines have higher theoretical CO2 loading
capacity. Regeneration of tertiary amines requires less heat energy than
primary/secondary amines.
Primary / secondaryamines:2 RR’NH CO2
RR’NCOO RR’NH2
(1)
(2)
Tertiaryamines: RR’R”N CO2 H2O RR‘R”NH
HCO3
A major challenge with the presently used amine absorbent systems is still the
requirement of substantial amounts of energy to regenerate the solvent. Improved
absorbents with lower heat of absorption of CO2 are one of the main targets in the search
for new absorbents in CCS in order to minimize energy consumption during solvent
regeneration.[5]. Due to imidazoles’ low heat of absorption and potentially high CO2
loading capacity as well as tunable chemical and physical properties and low vapour
pressure, they are proposed as alternative absorbents for CCS. N-alkylimidazoles would
absorb CO2 by a mechanism similar to the tertiary amines in aqueous solutions to give
bicarbonate adducts (eq II), allowing absorption of up to 1 mol CO2/mol imidazole and
low-temperature / low-energy regeneration of the solvent. However, the main difficulty
concerning CO2 capture with most imidazoles is the low absorption rates and absorption
2

capacities, due to low acid dissociation constant, pKa (7-8.5). It has been proposed that
CO2 absorption rates and absorption capacities for amine absorption of CO2 correlate
with the acid dissociation constant, pKa.[6] Hence, imidazoles with larger pKa values are
expected to absorb CO2 more readily. In order to obtain imidazole derivatives with higher
pKa (up to 9) than imidazole (pKa 7), we decided to introduce a variety of electron-
donating activating alkyl groups in the target imidazole products. Thus, we were aiming
at developing improved effective, low-cost, scalable general simple methods for
preparation of a range of polyalkylated N-H and N-alkyl imidazoles (3-5, Schemes 1-3),
as potential new absorbents for CO2 capture.
There are no general standard ways of synthesizing imidazole derivatives, but a variety of
cyclization reactions are used to produce specifically substituted imidazoles. Some new
cyclization methodologies have emerged the last decade.[7] However, the target products
are mainly polyaryl-substituted imidazoles. Other improved methods have been reported
the last few years on simple three-component reactions to form polyaryl-substituted
imidazoles[8] by use of a number of advanced catalytic systems (e.g. metal catalysis), but
the reaction conditions are less suitable for large scale low-cost production. The aryl-
products are prepared from aryl-substituted carbonyl building blocks, which readily
undergo the desired cyclization reactions. In contrast, preparation of polyalkylated
imidazoles from appropriate alkylcarbonyl substrates are more challenging, as competing
enolate aldol reactions may take place.
3

To develop simple scalable processes for preparation of polyalkylimidazoles, a one-pot
multi-component method was used, based on appropriate commercially readily available
alkyldicarbonyl compounds and suitable alkyl aldehydes and ammonia. This is a general
approach for preparation of alkyl-substituted imidazoles, but previous limited number of
reports on alkyl-imidazoles show that the syntheses are often suffering from low yields (<
30%), complex product mixtures, challenging work-up and isolation of water-soluble
products.[8l] Therefore, improved straightforward routes for the construction of polyalkyl-
substituted imidazole molecules are still highly attractive. Our modified procedures for
the synthesis of polyalkylated N-H and N-alkyl imidazoles are discussed below.
2. RESULTS AND DISCUSSION
A large range of NH- and N-alkyl-imidazoles (3, 4, 5; approx. 40), including novel
structures, were prepared (Schemes 1-3) as potential new absorbents for CO2 capture.
2.1. N-H Imidazoles
The preparation method used for the synthesis of NH-di- and tri-alkylimidazoles has
generally been based on reaction of aldehyde and diketone with ammonium acetate in
acetic acid. However, the reaction gives complex work-up and low yields (15-30%).[9]
We also experienced the inefficiency of the conventional procedure in acetic acid, since
corresponding low yields of several NH-trialkylimidazoles initially were obtained. Non-
substituted imidazole (3, R1,2,3 = H) has been synthesized in high yields (85%) in aqueous
solutions from glyoxal, formaldehyde and ammonium chloride.[10] Therefore, in order to
develop more efficient reaction conditions for the synthesis of NH-trialkylimidazoles, our
4

introductory optimization studies were based on reactions of aldehydes, 1,2-diketones
and ammonium salts in water. A series of ammonium salts, such as sulfate, chloride,
nitrate, carbonate and bicarbonate, were tested. Ammonium chloride readily gave clean
products, but in quite low yields (<10%). Ammonium carbonate and ammonium
bicarbonate gave rapid formation of imidazole products, but mixtures of aldol
condensation by-products were observed, and work-up was consequently challenging. By
using stoichiometric amounts of ammonium sulfate as the ammonia source, the NH-
trimethylimidazole 3e was obtained in moderate yield (41%) from 1a and 2b. Somewhat
lower yields were obtained using ammonium nitrate. Hexamethylenetetramine[11] was
tested as a replacement for formaldehyde, giving 45% yield of 4,5-dimethylimidazole 3a.
It has been reported that the yield of imidazole (3, R1,2,3 = H) from glyoxal, formaldehyde
and ammonium chloride in water, was increased by reducing the pH to 1-2.[10] We
observed no improvement of the yields of imidazole products by reducing the initial pH
of the ammonium sulfate, nitrate or chloride reactions by addition of the corresponding
acid. On the contrary, the yields decreased in ammonium sulfate reactions when the
initial pH was reduced to 1. As the imidazole cyclization reaction proceeds through
release of acidic protons, the pH of the reaction mixture will decrease. Hence, the amount
of ammonium sulfate was increased to two equivalents. This would allow gradual in situ
generation of ammonium bisulfate, which would act as a buffer. The modified condition
successfully increased the yield of NH-trimethylimidazole 3e significantly (from 41%
above, to 61% yield, Scheme 1). Applying these reaction conditions, 4,5-disubstituted
and 2,4,5-trisubstituted NH-imidazoles (3a-j) were prepared in aqueous ammonium
sulfate solutions from the appropriate diketone (1a-d) and aldehyde (2a-d) (ratio 2:1:1) in
5

up to 69% yield (Scheme 1). Non-substituted imidazole (3, R1,2,3 = H) was obtained in
high yield (86%) by the same procedure.
In general, a tendency of decreasing yields with increased alkyl chain lengths was
observed for the NH-imidazoles. It was particularly apparent that the yields decreased
with increasing chain length (Me/73% to Et/nPr/18%) in the 2-position (Scheme 1,
3e3i3j). Also, the yields dropped by increased 4,5-substituent chain length (Scheme
1, e.g. 3a3c and 3e3f3g), showing the influence of the diketone source. This trend
may be explained by increased electron density of the α-positions of diketone substrates
1b-d, which would favor aldol condensation and polymeric by-product formation. Lower
yields could also be due to low solubility of the diketone substrates. It was seen that the
hexyl diketones 1c and 1d formed two-phase systems with water. Gradual addition of
methanol until precipitation of ammonium sulfate appeared, increased the yields of 3d by
approximately 10%. Preparation in larger scale allowed improved product isolation, due
to more efficient distillation. As demonstrated by a ten-fold up-scaling of the imidazole
3e synthesis from 0.2 to 2 mol scale, an increase of the yield was obtained, from 61 to
73%, respectively, giving up to 160 g of imidazole product 3e.
2.2. N-Alkyl Imidazoles
The preparation of N-alkyl imidazoles has typically been performed by initial preparation
of imidazole (3, R1,2,3 = H) and subsequent alkylation with alkylhalide under alkaline
conditions with e.g. NaOH.[12] Some N-alkyl imidazoles have also been prepared in 30-
40% yield in a continuous flow system from diketone, aldehyde, alkylamine
6

hydrochloride and ammonium acetate in methanol in a pressurized vessel at high
temperatures (120 °C).[13] In contrast to NH-imidazoles (Part 2.1, Scheme 1), we obtained
low yields of N-alkyl imidazole 4a (<10%) when using the procedure based on aqueous
ammonium sulfate (2 eq), due to formation of a mixture of NH- and N-alkyl imidazole
(3a/4a) from diketone 1a, formaldehyde 2a, ammonium sulfate and methylammonium
sulfate in water. Modified reaction conditions, replacing water and ammonium sulfate
with methanol and stoichiometric amounts of ammonium carbonate, respectively,
afforded significantly improved yields of N-alkyl imidazoles (Schemes 2 and 3). The
aldehyde and the alkylamine were initially mixed equimolarly or with a slight excess of
amine. Ammonium carbonate was subsequently added before the diketone. Excess
aldehyde led to darkening of the solution, which occurred quickly upon addition of the
diketone. The yields remained, however, constant. As a substantial amount of heat was
generated upon mixing the substrates, temperature control (0-10 C) was essential for
successful reactions to avoid evaporation of volatile substrates.
Base on this optimised ammonium carbonate procedure, N-alkylimidazoles (4a-o) were
readily prepared from formaldehyde, the appropriate diketone (1a,d) and alkylamine in
methanol in up to 62% yield (Scheme 2). The method also allowed the formation of OH-
functionalized trialkylated imidazole, N-(2-OH-ethyl)-imidazole 4i (41%). In contrast to
iPr-amine, which afforded N-iPr imidazole 4j in good yield (55%), the more bulky tBu-
amine failed to undergo cyclization to give N-tBu-imidazole 4k. N-Phenylimidazole (4m,
37%) could also be prepared by this method. However, poorer nucleophilicity of the
aniline substrate resulted in competing formation of NH-imidazole byproduct (3a). In
7

contrast to the NH-imidazoles, the yields of the N-alkyl imidazoles did not vary with
increased alkyl chain lengths.
The optimized ammonium carbonate / methanol reaction conditions also allowed the
preparation of N-alkyl imidazoles with an additional 2-substitution (5a-q) from the
appropriate diketone (1a,d), C2-4-aldehyde (2b-d) and alkylamine in up to 39% yield
(Scheme 3). Corresponding yields were obtained for N-phenylimidazole (5m, 29%).
Similar to the unsuccessful preparation of N-tBu-imidazole 4k (Scheme 2), the bulky
tBu-amine failed to give N-tBu-imidazole 5k. N-(2-OH-Ethyl)-imidazole 5i was readily
prepared (43%). In general, higher yields were obtained for N-alkyl imidazoles 4 (37-
62%, Scheme 2), than for the corresponding more highly substituted N-alkyl products (5,
17-43%, Scheme 3).
Preliminary imidazole pKa measurements showed that pKa increased from average pKa 7-
8.3 for mono/di-substituted NH-imidazoles (3) up to pKa 8-9 for tri-/tetra-substituted
imidazoles (4, 5), respectively. A similar increasing tendency was observed for absorption
capacities, CO2 loadings, ranging from 0.2-1 mol CO2/mol imidazole ( pCO2 < 1.0 bar) at
40 °C for aqueous imidazole solutions. Further complete screening of important
properties of the polyalkylimidazoles 3-5 are in progress, also including studies on key
physical thermodynamic and chemical properties, such as vapour-liquid equilibrium, heat
of reaction, kinetics, viscosity, density, cyclic capacities and biological activity.
3.
CONCLUSION
8

With the aim of obtaining imidazole derivatives with higher pKa (7-9) as potential new
absorbents for CO2 capture, we have developed improved low-cost, general simple
methods for large scale preparation of polyalkyl NH- and N-alkyl-imidazoles by multi-
component syntheses. In order to provide easy scale-up procedures, relevant reaction
parameters, such as solvent, temperature, molar ratios, ammonium source, pH and
isolation procedure (e.g. vacuum distillation), have been optimized. A large range of di-,
tri- and tetra-substituted imidazole derivatives (40 in total; 22 novel structures) have been
synthesised by more efficient one-pot procedures in improved yields (up to 73%) from
commercially available starting materials. Up-scaling of the processes (from < 20 g to <
200 g product) allowed, generally, higher % yields, due to more efficient product
isolation. The methods do not involve the use of advanced catalytic systems, technology
or equipment and are therefore well suited for large scale low-cost production of
polyalkylimidazole derivatives, as potential new absorbents for CO2 capture.
4.
EXPERIMENTAL
4.1. General
Commercial grade reagents were used as received. Dry solvents were collected from a
solvent purification system. 1H and 13C NMR spectra were recorded using a 400 MHz
spectrometer. Chemical shifts are reported in ppm (δ) downfield from tetramethylsilane
(TMS) as internal standard. Coupling constants (J) are reported in Hertz (Hz). The
attributions of the chemical shifts were determined by means of COSY, HMQC and
HMBC experiments. Melting points for solids (m.p.) were determined using a Stuart
apparatus and are uncorrected. Accurate mass determination (HRMS) was performed on
9

a “Synapt G2-S” Q-TOF instrument from Waters. Samples were ionized with the use of
ASAP probe, no chromatography separation was used before the mass analysis. IR
spectra were obtained using a Bruker Alpha FTIR spectrometer.
4.2. General Procedure 1; Preparation Of Di- And Tri-Substituted NH-Imidazoles
(Scheme 1)
Ammonium sulfate (2 eq.) was dissolved in water (4 M) and the appropriate aldehyde
(2a-d, 1 eq.) was added. Diketone (1a-d, 1 eq.) was added to the solution and the reaction
mixture was stirred for 16 h at r.t. (or refluxed for 1h when formaldehyde 2a was used).
The reaction was cooled and made alkaline with NaOH (2 eq.), extracted with EtOAc
(3x100 mL) and dried over MgSO4. Solvent was removed in vacuo and the product was
purified.
4.3. General Procedure 2; Preparation Of Tri- And Tetra-Substituted N-Alkyl/Aryl
Imidazoles (Schemes 2, 3)
The appropriate amine (1 eq.) was added slowly to a cold (0 °C) solution of aldehyde
(2a-d, 1 eq.) in MeOH, (4 M). Ammonium carbonate (1 eq.) and diketone (1a,d) 1 eq.) in
MeOH (4 M) was added slowly to the reaction mixture while keeping the temperature
below 10 °C. The reaction mixture was stirred at 0 °C for 1 h and then in 15 h at r.t. The
solvent was removed under reduced pressure. Water (100 mL) was added and the product
was extracted with EtOAc (3x100 mL), dried over MgSO4 and the solvent removed in
vacou. In general. purification was performed by vacuum distillation.
10

SUPPORTING INFORMATION
Characterization of compounds (3a-3j, 4a-4o and 5a-5q; 1H / 13C NMR, IR, HRMS), as
well as copies of 1H and 13C NMR spectra can be found via the Supplementary Content
section of this article’s Web page.
ACKNOWLEDGEMENTS
We thank the Research Council of Norway, Climit program, grant 233776, for financial
support.
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Scheme 1. Preparation of di- and tri-substituted NH-imidazoles 3 (* indicates new
compound). a) the reaction was perfomed at reflux, 1h; b) the reaction was perfomed at rt,
16h; c) large scale (2 mol) preparation of >160 g of 3e
14

Scheme 2. Preparation of N-alkyl/aryl imidazoles 4 (* indicates new compound).
15

Scheme 3. Preparation of N-alkyl/aryl imidazoles 5 (* indicates new compound).
16