Experimental and computational study of metal-free Br?nsted acidic ionic liquid catalyzed benzylic C(sp3)–H bond activation and C–N, C–C cross couplings

Article abstract of DOI:10.1016/j.molliq.2019.02.035

Metal and solvent free synthesis of tetrasubstituted imidazoles and tetrasubstituted pyrazines from 1,2-diketones and aliphatic amines is studied experimentally and computationally. Various ionic liquids (ILs) are taken as a catalyst in 10 mol% for the re

Full text of DOI:10.1016/j.molliq.2019.02.035

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Experimental and computational study of metal-free Brønsted
acidic ionic liquid catalyzed benzylic C(sp3)-H bond activation
and C-N, C-C cross couplings
Isa Valiyev, Yusif Abdullayev, Sevinj Yagubova, Shamkhal
Baybekov, Cavanshir Salmanov, Jochen Autschbach
PII:
S0167-7322(18)36245-7
DOI:
Reference:
https://doi.org/10.1016/j.molliq.2019.02.035
MOLLIQ 10436
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Journal of Molecular Liquids
Received date:
Revised date:
Accepted date:
30 November 2018
4 February 2019
7 February 2019
Please cite this article as: I. Valiyev, Y. Abdullayev, S. Yagubova, et al., Experimental
and computational study of metal-free Brønsted acidic ionic liquid catalyzed benzylic
C(sp3)-H bond activation and C-N, C-C cross couplings, Journal of Molecular Liquids,
https://doi.org/10.1016/j.molliq.2019.02.035
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Experimental and computational study of metal-free Brønsted acidic ionic liquid catalyzed benzylic
C(sp3)–H bond activation and C-N, C-C cross couplings.
Isa Valiyeva, Yusif Abdullayev*[b, c], Sevinj Yagubova[b], Shamkhal Baybekov[b], Cavanshir Salmanov[b] and
Jochen Autschbach*[d]
[a] Department of Chemistry and Biology, University of Siegen, Adolf-Reichwein str. 2, D-57068, Siegen,
Germany
[b] Department of Chemical Engineering, Baku Engineering University, Hasan Aliyev str. 120, Baku,
Absheron, AZ0101, Azerbaijan. Email: yabdullayev@beu.edu.az
[c] Institute of Petrochemical Processes, Azerbaijan National Academy of Sciences, Baku Az1025,
Azerbaijan
[d] Department of Chemistry, University at Buffalo, State University of New York, Buffalo, New York
14260-3000, United States. Email: jochena@buffalo.edu
Abstract
Metal and solvent free synthesis of tetrasubstituted imidazoles and tetrasubstituted pyrazines from 1,2-
diketones and aliphatic amines is studied experimentally and computationally. Various ionic liquids (ILs)
are taken as a catalyst in 10 mol% for the reaction. The best conversion to products is achieved in the
presence of two ILs: [taH4][I4] and[deaH][HSO4]. The low-cost, simple Brønsted acidic IL [deaH][HSO4]
catalyzed reaction yields 75% PRO1(1-benzyl-2,4,5-triphenyl-1H-imidazole) and 18% PRO2 (2,3,5,6-
tetraphenylpyrazine) at 90oC in 1 hour. Further optimization with the IL shows that the products yield can
be tuned with changing parameters: time, catalyst loading, and temperature. Optimization shows that
PRO2 formation becomes predominant after 3 hours. Density functional calculations show that PRO1
formation occurs via condensation to diimine, and further C(sp3)–H activated cyclization stages. An
unusual hydrogen shift transition state (∆G‡=29.8 kcal) has a crucial role in the ring closure and
subsequent annulation to the five- and six-membered rings (PRO1, PRO2).
1. Introduction
C(sp3)–H bond activation is attractive to scientists because of easy access to synthesis of pharmaceuticals
and other important chemicals. Effective catalyst exploration is still a challenge in order to render passive
C-H bond functionalization economically viable. Transition metal catalyzed activation of the C(sp3)–H bond
is a widely applied method for synthesis of functionalized value-added chemicals[1-4]. However, the
application of metal catalysis in C-H activation has disadvantages such as high cost of precious metals and
environmental concerns. This is why the development and application of metal-free catalysts is very
important. So far, ionic liquids as a metal-free alternative are rarely utilized as catalysts for C-H bond
activation[5].
1-butylpyridinium iodide/tert-butyl peroxide[6] and quaternary butylammonium
iodide/tert-butyl peroxide[7] catalyzed metal-free oxidative esterification of the benzyl C(sp3)–H bond
have been studied. Both methods were assisted by the oxidant (tert-butyl peroxide) as a co-catalyst, and
it can be applicable only when iodine bearing ILs are available. Benzylic C(sp3)–H bond was activated with
metal catalysts[8-12].
Our previous experimental[13] and computational[3] studies on the catalytic effect of [Et2NH2][HSO4] IL
in a one-pot four component cyclocondensation reaction inspired us to examine the IL on a different
atom-economic reaction that was previously carried out with Ag2CO3 and NiCl2 catalysts[14, 15] and
yielded tetrasubstituted imidazole via benzylic C(sp3)–H bond activation. Multisubstituted imidazoles are
1

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an important class of compounds that have, for instance, been utilized as anti-inflammatory[16], anti-
fungial[17] agents, and a drug in the treatment of Alzheimer’s disease[18]. An imidazole moiety was used
as a cation component of various ILs[19]. Pyrazine scaffolds are another important class of compounds
found in natural products[20], with applications as metal–organic framework materials[21] and regulators
of estrogen receptors[22]. In the present study, we utilize Brønsted ILs as catalysts for the cyclization
reaction of 1,2-diketones with aliphatic amines to tetrasubstituted imidazoles and as a byproduct
tetrasubstituted pyrazines. (Scheme 1, S1). Multisubstituted imidazoles were previously accessed via a
metal and an ionic liquid catalyzed one-pot four component cyclocondensation reaction[23-26].
Multisubstituted pyrazines were previously synthesized via the Suzukie-Miyaura reaction[27] in two steps:
Preparation of tetrachloropyrazine from piperazine-2,5-dione and toxic chemicals (PCl5/POCl3), followed
by arylation of the tetrachloropyrazine with expensive palladium catalysts/ligands and phenylboronic
acid. AuCl3 catalyzed fused pyrazine derivatives were synthesized through two steps[28]. Herein, we
propose an atom economic, solvent- and metal-free, one-step protocol for the synthesis of
multisubstituted imidazole and pyrazine rings. We also optimized the benzil and benzylamine reaction
conditions for the PRO1 and PRO2 yield to a remarkable level. A detailed description of the catalytic
mechanism and a diagram with the reaction steps is provided in Section 3.6 below.
Scheme 1 IL (this work) and metal (previous works) catalyzed C-H activated annulation reactions.
2. Experimental
2.1 Synthesis and characterization of ILs
Chemicals (99%) were purchased from Sigma Aldrich for the synthesis PRO1, PRO2 and other products.
The ILs in Table 1 were utilized as catalysts in the reaction described in Scheme 1. ILs at entry 7, 8, and 9
were purchased from Alfa Aeser in 98%, 95%, and 97% purity respectively. The ILs were synthesized
according to literature procedures[29] and characterized by NMR, GC-MS, and IR.
Number Structure
Name
Abbreviation
1,3,5,7-tetraazaadamantane-1,3,5,7-
tetraium tetraiodide
[taH4][I4]
1
2

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ethane-1,2-diaminium hydrogen
phosphate
[edaH2][HPO4]
2
diethylammonium hydrogen sulfate
diethylammonium iodide
[deaH][HSO4]
[deaH][I]
3
4
4-ammoniopyridin-1-ium diiodide
[apyrH2][I2]
5
6
7
N1,N1-diethylbenzene-1,4-diaminium
hydrosulfate
[debeaH2][(HSO4)2]
N1,N1-dimethylbenzene-1,4-diaminium [dmbeaH2][Cl2]
dichloride
2-chlorobenzene-1-amino-4-aminium
Hydrosulfate
[cabeaH][HSO4]
8
4-(diethylamino)benzenaminium
hydrosulfate
1-methyl-2-oxopyrrolidin-1-ium
Hydrosulfate
[debeaH][HSO4]
[mopH][HSO4]
9
10
1H-benzo[d]imidazole-1,3-diium
Diodide
bimH2][I2]
11
Table 1. IL catalysts examined for the benzil and benzylamine cyclization reaction.
1
[taH4][I4]: H NMR (300 MHz, D2O) δ 4.69 (s, 4H), 2.53 (s, 12H). 13C NMR (75 MHz, D2O) δ 24.81. EI-MS (m/z):
144.137. FT-IR (KBr, cm-1): 930, 1014, 1199, 1411, 3419.
[edaH2][HPO4]: 1H NMR (300 MHz, D2O) δ 4.69 (s, 6H), 3.12 (s, 4H). 13C NMR (75 MHz, D2O) δ 36.91. EI-MS (m/z):
62.084. FT-IR (KBr, cm-1): 528, 824, 956, 1054, 1544, 12938.
[deaH][HSO4]: 1H NMR (300 MHz, D2O) δ 4.76 (s, 2H), 2.80 (q, 4H), 0.98 (t, 6H). 13C NMR (75 MHz, D2O) δ 42.15, δ
10.44. EI-MS (m/z): 74.096. FT-IR (KBr, cm-1):573, 853, 1032, 1155, 1457, 2843, 2991, 3426.
[deaH][I]: 1H NMR (300 MHz, D2O) δ 4.69 (s, 2H), 3.00 (q, J = 7.3 Hz, 4H), 1.19 (t, J = 7.3 Hz, 6H). 13C NMR (75 MHz,
D2O) δ 42.35, 10.69. EI-MS (m/z): 74.096. FT-IR (KBr, cm-1): 729, 892, 1036, 1154, 1432, 1449, 2798, 2956, 3447.
1
[apyrH2][I2]: H NMR (300 MHz, D2O) δ 7.90 (d, J = 7.1 Hz, 2H), 6.75 (d, J = 7.1 Hz, 2H), 4.69 (s, 4H). 13C NMR (75
MHz, D2O) δ 159.90, 139.36, 109.12. EI-MS (m/z): 96.068. FT-IR (KBr, cm-1): 728, 985, 1184, 1368, 1518, 1640, 3173,
3288.
[debeaH2][(HSO4)2]: 1H NMR (300 MHz, D2O) δ 7.72 – 7.25 (m, 4H), 4.71 (s, 4H), 3.50 (s, 4H), 0.88 (s, 6H). 13C NMR
(75 MHz, D2O) δ 137.15, 131.80, 125.55, 124.29, 53.77, 9.50. EI-MS (m/z): 166.147. FT-IR (KBr, cm-1): 572, 863,
1010, 1150, 1501, 1601, 2729, 2942, 3415.
[mopH][HSO4]: 1H NMR (300 MHz, D2O) δ 4.81 (s, 1H), 3.15 (t, 2H), 2.46 (s, 3H), 2.11(t, 2H), 1.66 (quint, 2H). 13C NMR
(75 MHz, D2O) δ 177.77, 50.52, 30.27, 29.43, 16.70. EI-MS (m/z): 100.076. FT-IR (KBr, cm-1): 565, 854, 1013, 1115,
1405, 1492, 1690, 2943.
3