Base-Promoted Nitrile-Alkyne Domino-Type Cyclization: A General Method to Trisubstituted Imidazoles

Article abstract of DOI:10.1021/acs.orglett.9b03782

An efficient base promoted nitrile-alkyne domino-type cyclization for multicomponent assembly of imidazoles from alkynes, nitriles, and tBuOK has been developed, which could run even in the absence of solvent on a gram scale with complete atom economy. This method contributes directly to reaching the synthesis of valuable imidazole derivatives from readily available raw materials.

Full text of DOI:10.1021/acs.orglett.9b03782

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Base-Promoted Nitrile−Alkyne Domino-Type Cyclization: A General
Method to Trisubstituted Imidazoles
Qiang Wang, Xi Chen, Xin-Gang Wang, Hong-Chao Liu, and Yong-Min Liang*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P.R. China
*
S Supporting Information
ABSTRACT: An efficient base promoted nitrile-alkyne domino-type
cyclization for multicomponent assembly of imidazoles from alkynes,
nitriles, and tBuOK has been developed, which could run even in the
absence of solvent on a gram scale with complete atom economy.
This method contributes directly to reaching the synthesis of valuable
imidazole derivatives from readily available raw materials.
ultisubstituted imidazoles are one of the crucial five-
Activating terminal alkynes seems to be the critical
transformation in achieving multicomponent assembly of
imidazoles through nitrile−alkyne cycloaddition. The most
popular protocols of activating terminal alkynes are to form
transition-metal acetylide under the catalysis of metal salts such
M
membered nitrogen heterocycles used in daily life
1
because of their biological activity (anti-inflammatory,
2
3
antibacterial derivatives, especially anti-HIV ), material
properties, As valuable intermediates, imidazoles are generally
4
9
10
11
12
13
14
15
used in organic synthesis. Imidazole contains two N-donor
coordination sites, which made it shine in coordination
chemistry, and has widely served as excellent candidates for
as Mg, Zn, Fe, Cu, Pd, Ag, and Au salts. Ligands
and bases are almost essential in these methods. In 2013,
oligsubstituted pyrroles were efficiently assembled through the
Ag CO -mediated oxidative cyclization of alkynes with
5
targeted metal−organic frameworks (MOFs).
2
3
14a
Substantial advances in the development of transition-metal-
catalyzed and transition-metal-free synthetic methods for
multisubstituted imidazoles have been achieved over the past
isocyanides by Bi and co-workers.
Given that isocyano
6
7
and nitrile have similar properties and our enthusiasm for
environmentally friendly reactions, we initially tested that
8
16
few decades. Compared to transition-metal-catalyzed methods,
most of these transition-metal-free reactions are eco-environ-
mentally friendly. However, luxuriant complex substrates are
required in the large reactions for the synthesis of imidazole.
Therefore, the door-to-door construction of imidazole from
elemental compounds is still an important research area.
Alkynes, nitriles, and potassium tert-butylate are three classes
of commercially available starting materials and generally used
in organic synthesis. The atom-economical cycloaddition from
these substrates is a perfect strategy to construct multi-
substituted imidazole (Scheme.1). Further demand for green
potassium tert-butylate, as a robust base to replace the
Ag CO , might activate terminal alkynes to complete the
2
3
17
nucleophilic cyclization reaction directly with nitrile.
Phenylacetylene (1a, 1.0 equiv), benzonitrile (2a, 3.0 equiv),
and potassium tert-butylate were used as substrates (3a, 2.0
equiv), and we first examined the reaction under the
conditions shown in Table 1. 2,4,5-Trisubstituted imidazole
4a was isolated in 55% yield in heptane at 100 °C under Ar
18
(entry 1). Encouraged by this result, we continued to
optimize the reaction conditions. The yield of imidazole 4a
was reduced while the amount of 2a was reduced to 2.2 equiv
or the temperatures were lowered to room temperature
(entries 2 and 3). Beyond this, shortening the reaction time
to 1 h led to a trace amount of imidazole 4a (entry 4).
Delightfully, by adjusting the ratio of 1a/2a/3a to 1.0/4.0/2.5,
the reaction afforded imidazole 4a with a better yield (66%,
entry 5). High yields of imidazole 4a were achieved, while the
solvents of n-pentane and cyclohexane were examined in this
ratio (entries 6 and 7). Remarkably, cyclohexane as solvent in
this nitrile−alkyne domino-type cyclization reaction afforded
imidazole 4a in 93% yield. It is noteworthy that the imidazole
Scheme 1. Nitrile−Alkyne Domino-Type Cyclization
chemistry is to design an atom-economical reaction that does
not require a solvent, and the aimed product would be
obtained on a gram scale within a few minutes at room
temperature under air. The synthesis strategy of imidazole is
still elusive. Herein, we hope to demonstrate a novel base-
promoted nitrile-alkyne domino-type cyclization for a multi-
component assembly of imidazole with complete atom
economy and versatile compatibility.
4
a was still isolated with 48% yield in the absence of the
solvent (entry 8). A series of bases were finally screened
entries 9−14), and the results showed that there was no more
(
Received: October 24, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03782
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Screening for the Reaction Conditions
Scheme 2. Substrate Scope for Nitrile−Alkyne Domino-
a
Type Cyclization
b
1
a/2a/3a
time
(h)
yield of 4a
entry
(equiv)
base
solvent
(%)
1
2
3
4
5
6
7
8
9
1/3.0/2.0
1/2.2/2.0
1/2.2/2.0
1/3.0/2.0
1/4.0/2.5
1/4.0/2.5
1/4.0/2.5
1/4.0/2.5
1/4.0/2.5
1/4.0/2.5
1/4.0/2.5
1/4.0/2.5
1/4.0/2.5
1/4.0/2.5
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOLi
tBuONa
PhCOOK
heptane
heptane
heptane
heptane
heptane
hexane
11
11
11
1
11
11
11
1
11
11
11
11
11
11
55
42
31
trace
66
80
c
cyclohexane
93
48
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
trace
38
NR
NR
NR
NR
10
11
12
13
14
CH ONa
3
CH OK
3
PhOK
a
Unless otherwise noted, the reactions were performed as follows: 1a
0.20 mmol, 1.0 equiv), 2a (4.0 equiv), 3a (2.5 equiv), solvent (1.5
(
b
c
mL), Ar. Isolated yields. The reaction was performed at room
temperature.
suitable base for this transformation than potassium tert-
butylate.
Using these optimized reaction conditions (Table 1, entry
), the nitrile−alkyne domino-type cyclization reactions with
7
various alkynes were explored (Scheme 2). A range of
substituted alkynes were investigated (4a−4y). Phenylacety-
lenes bearing different electron-donating and electron-with-
drawing groups furnished the corresponding products with
good yields (4a−4w). The position of the substituents on the
phenyl ring has no effect on this reaction. The reaction also has
a good response to multisubstituted phenylacetylenes (4t−4u).
Ethynylnaphthalene, -benzothiopyran, and -thiophene partici-
pated efficiently and afforded the corresponding imidazoles
4
v−4x in 58%, 65%, and 49% yields, respectively. Remarkably,
an aliphatic alkyne such as tert-butylacetylene was a suitable
substrate, and the reaction successfully proceeded at 60 °C in
THF (4y). In order to reveal the broadness of the reaction, N-
heteroaryl nitriles were also examined with phenylacetylene
a
Unless otherwise noted, the reactions were performed: alkyne (1a−
1
y) (0.20 mmol), benzonitrile or cyano compound (4.0 equiv),
(
1a) for this domino-type cyclization reaction (4A−4E). Good
tBuOK (2.5 equiv), cyclohexane (1.5 mL), 100 °C, 11 h, Ar, isolated
results were obtained when 2- and 4-pyridylnitrile were used
under the optimized reaction conditions (4D−4E). In
particular, there is potential to employ the imidazole 4E as a
ligand to build metal-catalyzed reaction.
To further demonstrate the utility of this reaction, we
performed this approach on a large scale to produce imidazole
b
yields. The reactions were performed on a large scale in the
c
optimized condition reactions. The 5 mmol scale reaction was run
d
without a solvent at room temperature for 5 min, air. The reaction
was performed in THF (1.5 mL) as solvent at 60 °C for 11 h.
4
a, 4n, and 4B. The reaction runs smoothly and gave the
verted to other ethers. The imidazoles 4a1−4a3 were isolated
in mild conditions with high yields (Scheme 3), which greatly
broadened the utility of this atom-economical strategy for
imidazole synthesis.
corresponding products in moderate yields at 100 °C in
b
b
b
cyclohexane for 11 h (4a , 4n , 4B ). Importantly, the reaction
still occurred and was isolated in 50% yield in the absence of
solvent on a 5 mmol scale, which proceeded violently at room
temperature for 5 min since a large amount of heat released
during the reaction.
To understand the nitrile−alkyne domino-type cyclization
reaction pathway better, critical mechanistic information was
collected by experimental investigations (Scheme 4). First, the
alkynes could easily transform to [d]-alkynes under the
influence of tBuOK in cyclohexane at room temperature for
The drawback is that no other base has been found to be
suitable for this reaction at present, and it only reacts with
potassium (sodium) tert-butoxide to build tert-butyl ether
compounds. Fortunately, tert-butyl ethers were easily con-
17c,d
30 min (eq 1).
The results reveal that an alkynyl anion
could be an intermediate in the reaction. When deuterated
B
DOI: 10.1021/acs.orglett.9b03782
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Further Synthetic Derivation
Scheme 5. Plausible Mechanism
a
Conditions A: HCl/ROH = 1:7, 70 °C, 2 h, air, isolated yields.
Conditions B: HCl:CH Cl = 1:7, ROH (5.0 equiv), 60 °C, 2 h, air,
isolated yield.
2
2
Scheme 4. Mechanistic Investigations
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03782.
Experimental procedures, product characterizations,
1
13
crystallographic data, and copies of the H and
C
spectra (PDF)
Accession Codes
CCDC 1961140−1961141 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
alkynes ([d]-1f, 74% deuterium content, [d]-1t, 60%
deuterium content) were run with benzonitrile and potassium
tert-butylate, 43% and 30% deuterium content for imidazoles
4
f and 4t were observed, respectively (eq 2).
A plausible mechanism for the base-promoted nitrile−alkyne
AUTHOR INFORMATION
Corresponding Author
■
domino-type cyclization among alkynes, benzonitrile, and
tBuOK is described on the basis of the above experiments
and literature precedents
*
E-mail: liangym@lzu.edu.cn.
ORCID
7a,14a,16
in Scheme 5. The reaction
begins with activation of a C−H bond of alkynes with the help
of tBuOK, which furnishes the alkynyl anion A. Then anion A
continues to react with two molecules of benzonitrile and
affords the intermediate B, which undergoes molecular
nucleophilic addition to produce intermediate C. Intra-
molecular isomerization occurs while the tBuO anion attacks
the double bond of intermediate C and gives product D with
the participation of potassium ions. The desired imidazole is
obtained when worked up with acid silica gel.
In summary, we have successfully developed a novel base-
promoted metal-free multicomponent reaction to synthesize
trisubstituted imidazole by coupling the readily available
alkynes, nitriles, and tBuOK under mild conditions. The
transformation features excellent functional group tolerance,
simple operation, and atom-economic ability. Even without the
solvent, the reaction is isolated in moderate yield at room
temperature for 5 min on a gram scale, which has significant
synthetic potential and is very helpful for green chemical
synthesis under the current environmental protection policy.
Qiang Wang: 0000-0001-9250-3067
Yong-Min Liang: 0000-0001-8280-8211
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was received from the National Science
Foundation of China (NSFC21772075, NSFC21532001, and
NSFC21272101).
REFERENCES
■
(
1) For selected examples, see: (a) Li, Q.; Hu, Q.; Wang, X.; Zong,
Y.; Zhao, L.; Xing, J.; Zhou, J.; Zhang, H. Chem. Biol. Drug Des. 2015,
8
6 (4), 509−516. (b) Laufer, S. A.; Zimmermann, W.; Ruff, K. J. J.
Med. Chem. 2004, 47 (25), 6311−6325. (c) Silva, V. G.; Silva, R. O.;
Damasceno, S. R. B.; Carvalho, N. S.; Prudencio, R. S.; Aragao, K. S.;
Guimaraes, M. A.; Campos, S. A.; Veras, L. M. C.; Godejohann, M.;
̂
̃
̃
́
Leite, J. R. S. A.; Barbosa, A. L. R.; Medeiros, J.-V. R. J. Nat. Prod.
2013, 76 (6), 1071−1077.
C
DOI: 10.1021/acs.orglett.9b03782
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
2) Wang, P.-Y.; Wang, M.-W.; Zeng, D.; Xiang, M.; Rao, J.-R.; Liu,
R. A.; Verma, M. K.; Singh, P. P. J. Org. Chem. 2018, 83 (20), 12420−
12431.
(15) (a) Lustosa, D. M.; Clemens, S.; Rudolph, M.; Hashmi, A. S. K.
Adv. Synth. Catal. 2019, DOI: 10.1002/adsc.201900824. (b) Xia, Z.;
Q.-Q.; Liu, L.-W.; Wu, Z.-B.; Li, Z.; Song, B.-A.; Yang, S. J. Agric. Food
Chem. 2019, 67 (13), 3535−3545.
(
3) Ganguly, S.; Vithlani, V.; Kesharwani, A.; Kuhu, R.; Baskar, L.;
Mitramazumder, P.; Sharon, A.; Dev, A. Acta Pharm. 2011, 61 (2),
87−201.
4) For selected examples, see: (a) Shima, K.; Mutoh, K.; Kobayashi,
Corce,
́
V.; Zhao, F.; Przybylski, C.; Espagne, A.; Jullien, L.; Le Saux,
-Mansuy, V.; Ollivier, C.;
1
(
T.; Gimbert, Y.; Dossmann, H.; Mouries
̀
Fensterbank, L. Nat. Chem. 2019, 11 (9), 797−805. (c) Alsalme, A.;
Jaafar, M.; Liu, X.; Dielmann, F.; Hahn, F. E.; Al-farhan, K.; Reedijk, J.
Polyhedron 2015, 88, 1−5. (d) Wan, X.-K.; Xu, W. W.; Yuan, S.-F.;
Gao, Y.; Zeng, X.-C.; Wang, Q.-M. Angew. Chem., Int. Ed. 2015, 54
Y.; Abe, J. J. Am. Chem. Soc. 2014, 136 (10), 3796−3799. (b) Chen,
W.-C.; Zhu, Z.-L.; Lee, C.-S. Adv. Opt. Mater. 2018, 6 (18), 1800258.
(
5) For selected examples, see: (a) Chen, S.-S. CrystEngComm 2016,
8 (35), 6543−6565. (b) Chen, Q.; Chang, Z.; Song, W.-C.; Song,
H.; Song, H.-B.; Hu, T.-L.; Bu, X.-H. Angew. Chem., Int. Ed. 2013, 52
44), 11550−11553. (c) Eddaoudi, M.; Sava, D. F.; Eubank, J. F.;
Adil, K.; Guillerm, V. Chem. Soc. Rev. 2015, 44 (1), 228−249.
d) Luo, H.-B.; Ren, Q.; Wang, P.; Zhang, J.; Wang, L.; Ren, X.-M.
ACS Appl. Mater. Interfaces 2019, 11 (9), 9164−9171.
6) For transition-metal-catalyzed reactions for the synthesis of
imidazoles, see: (a) Hu, Z.; Dong, J.; Xu, X. Adv. Synth. Catal. 2017,
59 (20), 3585−3591. (b) Pardeshi, S. D.; Sathe, P. A.; Vadagaonkar,
K. S.; Melone, L.; Chaskar, A. C. Synthesis 2018, 50 (02), 361−370.
c) Li, S.; Li, Z.; Yuan, Y.; Peng, D.; Li, Y.; Zhang, L.; Wu, Y. Org.
(
33), 9683−9686.
16) Chatterjee, B.; Gunanathan, C. Chem. Commun. 2016, 52 (24),
509−4512.
17) For use of base to activate terminal alkynes, see: (a) Zhang, J.-
S.; Zhang, J.-Q.; Chen, T.; Han, L.-B. Org. Biomol. Chem. 2017, 15
1
(
4
(
(
(
(
26), 5462−5467. (b) Dhara, K.; Kapat, A.; Ghosh, T.; Dash, J.
Synthesis 2016, 48 (23), 4260−4268. (c) Bew, S. P.; Hiatt-Gipson, G.
(
D.; Lovell, J. A.; Poullain, C. Org. Lett. 2012, 14 (2), 456−459.
(d) Sabot, C.; Kumar, K. A.; Antheaume, C.; Mioskowski, C. J. Org.
3
Chem. 2007, 72 (13), 5001−5004. (e) Wang, H.; Li, Y.; Tang, Z.;
Wang, S.; Zhang, H.; Cong, H.; Lei, A. ACS Catal. 2018, 8 (11),
(
1
0599−10605.
18) The reactions were purified by acid silica gel column, and the
imidazole 4a was isolated, not the potassium salt of imidazole.
Lett. 2012, 14 (4), 1130−1133. (d) Xu, L.; Li, H.; Liao, Z.; Lou, K.;
(
Xie, H.; Li, H.; Wang, W. Org. Lett. 2015, 17 (14), 3434−3437.
(
(
e) Xiao, Y.; Zhang, L. Org. Lett. 2012, 14 (17), 4662−4665.
f) Tjutrins, J.; Arndtsen, B. A. Chemical Science 2017, 8 (2), 1002−
1
007.
(
7) For transition-metal-free reactions for the synthesis of
imidazoles, see: (a) Das, U. K.; Shimon, L. J. W.; Milstein, D.
Chem. Commun. 2017, 53 (98), 13133−13136. (b) Gulevich, A. V.;
Balenkova, E. S.; Nenajdenko, V. G. J. Org. Chem. 2007, 72 (21),
7
878−7885. (c) Wu, J.; Zhang, H.; Ding, X.; Tan, X.; Shen, H. C.;
Chen, J.; He, W.; Deng, H.; Song, L.; Cao, W. Eur. J. Org. Chem.
2
018, 2018 (47), 6758−6763. (d) Naidoo, S.; Jeena, V. Eur. J. Org.
Chem. 2019, 2019 (5), 1107−1113. (e) Yang, D.; Shan, L.; Xu, Z.-F.;
Li, C.-Y. Org. Biomol. Chem. 2018, 16 (9), 1461−1464.
(
8) Review on imidazole synthesis, see: Rossi, R.; Angelici, G.;
Casotti, G.; Manzini, C.; Lessi, M. Adv. Synth. Catal. 2019, 361 (12),
737−2803.
9) Magre, M.; Maity, B.; Falconnet, A.; Cavallo, L.; Rueping, M.
Angew. Chem., Int. Ed. 2019, 58 (21), 7025−7029.
10) (a) Osano, M.; Kida, T.; Yonekura, K.; Tsuchimoto, T. Adv.
2
(
(
Synth. Catal. 2019, 361 (12), 2825−2831. (b) Huang, T.; Liu, X.;
Lang, J.; Xu, J.; Lin, L.; Feng, X. ACS Catal. 2017, 7 (9), 5654−5660.
(
c) Zavesky, B. P.; Johnson, J. S. Angew. Chem., Int. Ed. 2017, 56 (30),
8
1
805−8808. (d) Kuang, J.; Ma, S. J. Am. Chem. Soc. 2010, 132 (6),
786−1787. (e) Okura, K.; Kawashima, H.; Tamakuni, F.; Nishida,
N.; Shirakawa, E. Chem. Commun. 2016, 52 (97), 14019−14022.
(
Catal. 2018, 8 (9), 7973−7982. (b) Field, L. D.; Turnbull, A. J.;
Turner, P. J. Am. Chem. Soc. 2002, 124 (14), 3692−3702.
(
11) (a) Gorgas, N.; Stoger, B.; Veiros, L. F.; Kirchner, K. ACS
̈
12) (a) Alonso, F.; Yus, M. ACS Catal. 2012, 2 (7), 1441−1451.
(
b) Hazra, A.; Lee, M. T.; Chiu, J. F.; Lalic, G. Angew. Chem., Int. Ed.
018, 57 (19), 5492−5496. (c) Dong, X.-Y.; Zhang, Y.-F.; Ma, C.-L.;
Gu, Q.-S.; Wang, F.-L.; Li, Z.-L.; Jiang, S.-P.; Liu, X.-Y. Nat. Chem.
019, DOI: 10.1038/s41557-019-0346-2. (d) Su, L.; Ren, T.; Dong,
J.; Liu, L.; Xie, S.; Yuan, L.; Zhou, Y.; Yin, S.-F. J. Am. Chem. Soc.
019, 141 (6), 2535−2544. (e) Gallego, D.; Bruck, A.; Irran, E.;
Meier, F.; Kaupp, M.; Driess, M.; Hartwig, J. F. J. Am. Chem. Soc.
013, 135 (41), 15617−15626.
13) Ha, H.; Shin, C.; Bae, S.; Joo, J. M. Eur. J. Org. Chem. 2018,
018 (20−21), 2645−2650.
14) (a) Liu, J.; Fang, Z.; Zhang, Q.; Liu, Q.; Bi, X. Angew. Chem.,
2
2
2
̈
2
(
2
(
Int. Ed. 2013, 52 (27), 6953−6957. (b) He, C.; Hao, J.; Xu, H.; Mo,
Y.; Liu, H.; Han, J.; Lei, A. Chem. Commun. 2012, 48 (90), 11073−
1
1075. (c) He, C.; Guo, S.; Ke, J.; Hao, J.; Xu, H.; Chen, H.; Lei, A. J.
Am. Chem. Soc. 2012, 134 (13), 5766−5769. (d) Mitsudo, K.;
Shiraga, T.; Mizukawa, J.-i.; Suga, S.; Tanaka, H. Chem. Commun.
2010, 46 (48), 9256−9258. (e) Sharma, S.; Kumar, M.; Vishwakarma,
D
DOI: 10.1021/acs.orglett.9b03782
Org. Lett. XXXX, XXX, XXX−XXX