Microwave enabled umpulong mechanism based rapid and efficient four- and six-component domino formations of 2-(2′-azaaryl)imidazoles and anti-1,2-diarylethylbenzamides

Article abstract of DOI:10.1021/jo902204s

(Chemical Equation Presented) Concise and efficient six-component and four-component domino approaches to anti-1,2-diarylethylbenzamides and highly substituted 2-(2′-azaaryl)imidazoles have been developed under solvent-free and microwave-irradiation condi

Full text of DOI:10.1021/jo902204s

pubs.acs.org/joc
Microwave Enabled Umpulong Mechanism Based Rapid and
Efficient Four- and Six-Component Domino Formations of
2-(20-Azaaryl)imidazoles and anti-1,2-Diarylethylbenzamides
Bo Jiang,†,‡ Xiang Wang,† Feng Shi,† Shu-Jiang Tu,*,†,‡ Teng Ai,§ Austin Ballew,§ and
Guigen Li*,§
†School of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou, 221116, Jiangsu,
P. R. China, ‡College of Chemistry, Chemical Engineering, and Materials Science, Suzhou University,
Suzhou, 215123, Jiangsu, P. R. China, and §Department of Chemistry and Biochemistry,
Texas Tech University, Lubbock, Texas 79409-1061
laotu@xznu.edu.cn; guigen.li@ttu.edu
Received October 22, 2009
Concise and efficient six-component and four-component domino approaches to anti-1,2-diary-
lethylbenzamides and highly substituted 2-(20-azaaryl)imidazoles have been developed under sol-
vent-free and microwave-irradiation conditions. The reactions showed a broad scope of substrates in
which a wide range of common commercial aromatic aldehydes and heteroaryl nitriles can be used.
The syntheses were finished within short periods (15-34 min) with good to excellent chemical yields
and stereoselectivity that avoided tedious workup isolations. New mechanisms involving an
umpolung have been proposed for these two reaction processes.
Introduction
modern organic chemistry.1 In this regard, multicomponent
domino reactions serving for the total synthesis of natural
products and challenging building blocks are highly desired.2
These reactions can avoid time-consuming and energy-cost-
ing processes that involve multistep syntheses, protec-
tion-deprotection, tedious workup, and purifications.
Therefore, domino reactions are environmentally friendly
and often proceed with excellent stereo- and chemoselec-
tivities.2,3
The development of efficient approaches to chemically
and biologically important products from readily available
inexpensive starting materials has been an active topic in
(1) (a) Tietze, L. F.; Hautner, F. In Stimulating Concepts in Chemistry;
Vogtle, F., Stoddart, J. F., Shibasaki, M., Eds.; Wiley-VCH: Weinheim, 2000; pp
39-64. (b) Nicolaou, K. C.; Yue, E. W.; Oshima, T. in The New Chemistry; Hall,
N., Ed.; Cambridge University Press: Cambridge, 2001; p186. (c) Tietze, L. F.;
Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis; Wiley-VCH:
Weinheim, 2006. (d) New Avenues to Efficient Chemical Synthesis. Emerging
Technologies; Seeberger, P. H., Blume, T., Eds.; Springer: Heidelberg, 2007; Ernst
Schering Foundation Symposium Proceedings 2006-3. (e) Tietze, L. F. Chem.
Rev. 1996, 96, 115–136.
In the past several years, we have been engaging in the
development of new multicomponent domino reactions that
(2) (a) Snyder, S. A.; Breazzano, S. P.; Ross, A. G.; Lin, V; Zografos, S. L.
J. Am. Chem. Soc. 2009, 131, 1753–1765. (b) Nicolaou, K. C.; Edmonds,
D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134–7186. (c) Diguez-
Vzquez, A.; Tzschucke, C. C.; Lam, W. Y.; Le, S. V. Angew. Chem., Int. Ed.
2008, 47, 209–212. (d) Muller, F. L.; Constantieux, T.; Rodriguez, J. J. Am.
Chem. Soc. 2005, 127, 17176–17177.
(3) (a) Barluenga, J.; Jimenez-Aquino, A.; Valdes, C.; Aznar, F. Angew.
Chem., Int. Ed. 2007, 46, 1529–1532. (b) Alex, K.; Tillack, A.; Schwarz, N.;
Beller, M. Angew. Chem., Int. Ed. 2008, 47, 2304–2307. (c) Xia, M.; Xiang,
G.-F.; Wu, B.; Han, Y.-F. Adv. Synth. Catal. 2008, 350, 817–821. (d)
Waldmann, H.; Kuhn, M.; Liu, W.; Kumar, K. Chem. Commun. 2008,
1211–1213.
9486 J. Org. Chem. 2009, 74, 9486–9489
Published on Web 11/25/2009
DOI: 10.1021/jo902204s
r
2009 American Chemical Society

Jiang et al.
JOCArticle
SCHEME 1. Four-Component Domino Synthesis of 2-(20-Azaaryl)-
TABLE 1. Optimization of Reaction Conditions
imidazolesa
entry
ammonium salt
solvent
equiv
yield (%)
1
2
3
4
ammonium carbonate
ammonium chloride
ammonium formate
ammonium acetate
solvent-free
solvent-free
solvent-free
solvent-free
3.0
3.0
3.0
3.0
59
38
47
88
formation of 2-(pyridin-2-yl)imidazoles (Pyim) is limited
to the use of 1,2-diketones as starting materials that require
multistep preparations involving benzoic condensation
and oxidation reactions. We thus planned an alternative
approach to these important compounds under more concise
and efficient conditions.
aAr: 1a, 2-pyridinyl; 1b, 5-bromopyridine-2-yl; 1c, 3-methylpyridine-2-yl; 1d,
2-pyrazinyl; 1e, 2-pyrimidinyl.
SCHEME 2. Six-Component Domino Synthesis of anti-Stilbe-
nediamines
Results and Discussion
We started this synthesis by conducting the reaction of
pyridine-2-carbonitrile 1a with 4-chlorobenzaldehyde 2a as
the model case for condition optimization. As shown in
Table 1, the use of ammonium acetate allowed the direct
conversion of pyridine-2-carbonitrile 1a into the correspond-
ing 2-(20-pyridinyl)imidazole 3a in a yield of 88% under
solvent-free and microwave-irradiation condition (Table 1,
entry 4). Other ammonium salts gave much lower yields of
38-59% (Table 1, entries 1-3). The use of more than 3 equiv
of ammonium acetate did not enhance chemical yields. We
next studied solvent effects for this synthesis and found that
DMF, benzene, acetic acid, and water resulted in moderate
to good yields under MW irradiation for 20 min. However,
higher yields were obtained when the reaction was performed
under solvent-free condition.
We then investigated the substrate scope of this synthesis
by subjecting the series of aromatic aldehyde 2b-k to the
reactions with pyridine-2-carbonitrile 1a under the optimal
condition. As shown in Table 2, the reaction of thiophene-2-
carbaldehyde with pyridine-2-carbonitrile 1a was complete
within 20 min to give thienyl-substituted 2-(20-azaaryl)-
imidazoles 3l in 72% yield. Similarly, 2-(20-zaaryl)imidazoles
3b-k were formed within 20-32 min in good to excellent
yields of 74-90% (Table 2, entries 2-11). The similar
situation exists for heteroaryl nitriles 1b-e (5-bromopyri-
dine-2-carbonitrile, 1b; 3-methylpyridine-2-carbonitrile, 1c;
pyrazine-2-carbonitrile, 1d; and pyrimidine-2-carbonitrile,
1e) in which the reactions occurred rapidly to give the desired
products 3r-v in 76-84% yields (Table 2, entries 18-22).
Among the products shown in Table 2, 2-(pyridin-2-yl)-
imidazoles (entries 10, 11, 14, 22, and 25) are indeed
very difficult to obtain via the known methods because
4-dimethylaminobenzaldehyde and 2-hydroxybenzaldehyde
cannot serve as guest substrates to form symmetrical ben-
zoins.
can provide easy access to new core structures of chemical
and pharmaceutical interest.4,5 During our study of this
topic, we found an efficient microwave-accelerated synthesis
of trisubstituted imidazoles (Scheme 1).6 These products can
serve not only as synthetic building blocks but also for
supermolecular research on π-stacking and H-bonding for-
mations.7 In addition, the ligands containing 2-(20-azaaryl)-
imidazoles have also attracted widespread interest due
to their ability to form complexes with transition metals.8
In this paper, we would like to report a rapid four-
component domino formation of 2-(20-azaaryl)imidazoles
and six-component domino formation of anti-1,2-diary-
lethylbenzamides9 under microwave irradiation without
the use of any organic solvents (Schemes 1 and 2).
It has been known that the synthesis of highly functiona-
lized 2-(20-azaaryl)imidazoles can be achieved via Negishi-
type cross-coupling of 2-iodopyridine with imidazol-4-yl-
zinc reagent,8a three-component cyclocondensation of 1,2-
diketones with picolinaldehydes in the presence of ammo-
nium acetate,8b and the NaBH4-catalyzed cyclization of
2-cyanopyridines.8c However, some limitations exist in
these known methods. For example, Seto’s method8b for
(4) (a) Jiang, B.; Tu, S.-J.; Kaur, P.; Wever, W.; Li, G. J. Am. Chem. Soc.
2009, 131, 11660–11661. (b) Li, G.; Wei, H. X.; Kim, S. H.; Carducci, M.
Angew. Chem., Int. Ed. 2001, 40, 4277–4280.
(5) (a) Tu, S.-J.; Jiang, B.; Jia, R. H.; Zhang, J. Y.; Zhang, Y.; Yao, C. S.;
Shi, F. Org. Biomol. Chem. 2006, 4, 3664–3668. (b) Tu, S. J.; Jiang, B.; Zhang,
Y.; Jia, R. H.; Zhang, J. Y.; Yao, C. S.; Shi, F. Org. Biomol. Chem. 2007, 5,
355–359. (c) Tu, S.-J.; Li, C. M.; Li, G. G.; Cao, L. J.; Shao, Q. Q.; Zhou,
D. X.; Jiang, B.; Zhou, J. F.; Xia, M. J. Comb. Chem. 2007, 9, 1144–1148.
(6) (a) Lombardino, J. G.; Wiseman, E. H. J. Med. Chem. 1974, 17, 1182–
1188. (b) Phillips, A. P.; White, H. L.; Rosen, S. Eur. Pat. Appl. EP 58890, 1982;
Chem. Abstr., 1983, 98, 53894z.
(7) (a) Wang, K.-Z.; Gao, L.-H.; Bai, G.-Y.; Jin, L.-P. Inorg. Chem.
Commun. 2002, 5, 841–843. (b) Kimura, M.; Morioka, M.; Tsunenaga, M.;
Hu, Z. Z. New Technol. Med. 2000, 1, 418–421. (c) Drew, M. G. B.; Tocher,
D. A.; Chowdhury, K.; Chowdhury, S.; Datta, D. New J. Chem. 2004, 28,
323–325. (d) Pachhunga, K.; Therrien, B.; Kreisel, K. A.; Yap, G. P. A.;
Kollipara, M. R. Polyhedron 2007, 26, 3638–3644.
(8) (a) Dobler, M. R. Tetrahedron Lett. 2003, 44, 7115–7117. (b) Seko, N.;
Yoshino, K.; Yokota, K.; Tsukamoto, G. Chem. Pharm. Bull. 1991, 39, 651–
657. (c) Yemada, M. K.; Kikugawa, Y. Tetrahedron Lett. 1969, 36, 3101–
3104. (d) Chiswell, B.; Lions, F.; Morris, B. S. Inorg. Chem. 1964, 3, 110–114.
(e) Kori, S.; Narisawa, S. Asahi Garasu Kenkyu Hokoku 1962, 12, 55–70.
(9) For the synthesis of syn-1,2-diarylethylbenzamides under different
conditions and mechanism (longer reaction time and lower yields), see:
Proskurnina, M. V.; Lozinskaya, N. A.; Tkachenko, S. E.; Zefirov, N. S.
Russ. J. Org. Chem. 2002, 38, 1149–153.
All starting materials of pyridine-2-carbonitriles and aryl
aldehydes 2 employed for this synthesis are common inex-
pensive commercial chemicals, which avoids the use of 1,2-
diketones and R-hydroxyketones for this synthesis. Our next
plan is to choose special heteroaryl nitriles and aldehydes as
the substrates to make lophine peroxides that are of parti-
cular interest to material sciences because of their wide range
of chemiluminogenic activity10 and to employ amino acid
(10) (a) White, E. H.; Harding, M. J. C. J. Am. Chem. Soc. 1964, 86, 5686–
5687. (b) Kang, P.; Foote, C. S. J. Am. Chem. Soc. 2002, 124, 9629–9638.
J. Org. Chem. Vol. 74, No. 24, 2009 9487

Jiang et al.
JOCArticle
TABLE 2. Domino Synthesis of 2-(20-Azaaryl)imidazoles
aIsolated yields.
attached aromatic heteroaryl nitriles to generate unusual
amino acids for peptide drug design and synthsis.11
16-30 min; these products are can be readily hydrolyzed by
using sulfuric acid to give anti-stilbenediamines.12-14
After we achieved the above heteroaryl nitrile-based
domino reaction, we then subjected benzonitrile to
the reaction with aromatic aldehydes 2 under the similar
conditions. Surprisingly, the unexpected products of anti-
1,2-diarylethylbenzamides 4 were generated as a single
stereoisomer in good to excellent yields of 81-92%
(Scheme 2). Obviously, benzonitrile did not participate
in the reaction with aromatic aldehydes.9 The products
have been unambigeously determined by X-ray structural
analysis of single crystals of 3k and 4i, which were
obtained by carefully evaporating solvents (see Support-
ing Information).
We then utilized various aromatic aldehydes to react with
ammonium acetate under solvent-free and MW irradiation
condition without the use of benzonitrile. As revealed in
Table 3, 10 substituted anti-1,2-diarylethylbenzamides 4
were obtained in good to excellent yields (80-92%) within
On the basis of the above results, possible mechanisms
have been proposed for the formations of trisubstituted
2-(20-azaaryl)imidazole derivatives and 1,2-diarylethylben-
zamides as shown in Schemes 3 and 4, respectively. The
former involves the ring-closure cascade reactions that con-
sist of initial condensation, nucleophilic addition, umpolung
(A to B),15 intramolecular nucleophilic addition (B to C), and
(12) Corey, E. J.; Kuhnle, F. N. M. Tetrahedron Lett. 1997, 38, 8631–
8634.
(13) (a) Kotti, S. R. S. S.; Timmons, C.; Li, G. Chem. Biol. Drug Des.
2006, 67, 101–114. (b) Lucet, D.; Gall, T. L.; Mioskowski, C. Angew. Chem.,
Int. Ed. 1998, 37, 2580–2627. (c) Samanta, S.; Liu, J.; Dodda, R.; Zhao, C.-G.
Org. Lett. 2005, 7, 5321–5323. (d) Costa, A. M.; Jimeno, C.; Gavenonis, J.;
Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 6929–6941.
(14) (a) Bessonov, I. V.; Lozinskaya, N. A.; Katashova, V. R.; Proskurnina,
M. V.; Zefirov, N. S. Russ. Chem. Bull. 2005, 54, 211. (b) Trippett, S. J. Chem.
Soc. 1957, 4407–4408.
(15) (a) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534–541. (b)
Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606–5655. (c)
Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326–1328. (d) Nair, V.;
Bindu, S.; Sreekumar, V. Angew. Chem., Int. Ed. 2004, 43, 5130–5135. (e)
Christmann, M. Angew. Chem., Int. Ed. 2005, 44, 2632–2634. (f) Zeitler, K.
Angew. Chem., Int. Ed. 2005, 44, 7506–7510. (g) Marion, N.; Diez-Gonzalez,
S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988–3000.
(11) (a) Schiller, P. W. Prog. Med. Chem. 1991, 28, 301–340. (b) Hruby,
V. J.; Li, G.; Haskell-Luevano, C.; Shanderovich, M. Pept. Sci.-Biopolym.
1997, 43, 219–266.
9488 J. Org. Chem. Vol. 74, No. 24, 2009

Jiang et al.
JOCArticle
TABLE 3. Synthetic Results of 1,2-Diarylethylbenzamides
SCHEME 4. Mechanism of the Formation of anti-Diarylethyl-
benzamides
then successively added. Subsequently, the reaction vial was
capped and then stirred for 20 s. The mixture was irradiated
(initial power 100 W and maximum power 200 W) at 150 °C until
TLC (petroleum ether/acetone, 4:1 v/v) revealed that conversion
of the starting material 2a was complete (20 min). The reaction
mixture was then cooled to room temperature and diluted with
aIsolated yields.
SCHEME 3. Mechanism of the Formation of Trisubstituted
2-(20-Azaaryl)imidazoles
€
cold water (40 mL). The solid product was collected by Buchner
filtration and was purified by flash column chromatography
(silica gel, mixtures of petroleum ether/ethyl acetate, 10:1 v/v) to
afford the desired pure products 3a as an pale green solid. Mp:
210-212 °C. IR (KBr, ν, cm-1): 3056 (brs), 2959, 1594, 1565,
1
1505, 1401, 1293, 1244, 1130, 1092, 1012, 883, 823. H NMR
(DMSO-d6, 400 MHz) (δ, ppm): 9.21 (s, 1H, NH), 8.45 (d, J =
7.2 Hz, 1H, Py-H), 8.03 (d, J = 8.4 Hz, 2H, Ar-H), 7.93 (d, J =
8.8 Hz, 2H, Ar-H), 7.86 (d, J = 8.8 Hz, 1H, Py-H), 7.64 (d, J =
8.8 Hz, 2H, Ar-H), 7.56 (d, J = 8.8 Hz, 2H, Ar-H), 7.03-7.00
(m, 1H, Py-H), 6.85-6.82 (m, 1H, Py-H). 13C NMR (DMSO-d6,
100 MHz) (δ, ppm): 151.3, 137.9, 135.7, 134.8, 133.4, 129.7,
129.5, 129.0, 128.8, 128.3, 127.0, 122.6, 121.3, 117.6, 114.7.
HRMS (ESI), 366.0560: m/z calcd for C20H14Cl2N3, found
366.0559.
N-(E-2-(4-Chlorobenzylideneamino)-1,2-bis(4-chlorophenyl)-
ethyl)-4-chlorobenzamide (4a). 4-Chlorobenzaldehyde (2a, 4
mmol, 0.59 g, 4.0 equiv) was introduced in a 10-mL Emrys
reaction vial, and NH4OAc (8 mmol, 0.616 g, 4.0 equiv) was then
added. Subsequently, the reaction vial was capped and then
stirred for 20 s. The mixture was irradiated (initial power 100 W
and maximum power 200 W) at 150 °C until TLC (petroleum
ether/acetone, 4:1) revealed that conversion of the starting
material 2a was complete (16 min). The reaction mixture was
then cooled to room temperature and then diluted with cold
dehydration (Scheme 3). The latter involves the condensa-
tion reaction to give imines, which is followed by subsequent
intermolecular nucleophilic addition, umpolung (D to
E), and nucleophilic reaction (E to F). The last step of
latter mechanism involves 1,3-H transfer (F to G) leading
to thermodynamically stable anti-diarylethylbenzamides 4
(Scheme 4).
In summary, umpolung mechanism based concise and
efficient six-component and four-component domino ap-
proaches to anti-1,2-diarylethylbenzamides and highly sub-
stituted 2-(20-azaaryl)imidazoles were developed under
solvent-free and microwave irradiation condition. The reac-
tions showed a broad scope of substrates in which a wide
range of common commercial aromatic aldehydes and hetero-
aryl nitriles can be used. The syntheses were complete within
short periods (15-34 min) with good to excellent chemical
yields and stereoselectivity that avoided tedious workup iso-
lations. New mechanisms involving umpolung intermediates
have been proposed for these two reaction processes.
€
water (40 mL). The solid product was collected by Buchner
filtration and was purified by recrystallization from 95% EtOH
to afford the desired pure products 4a as a white solid. Mp:
242-243 °C (lit. mp 249 °C).14b IR (KBr, ν, cm-1): 3365, 3084,
1
1651, 1578, 1510, 1493, 1487, 1276, 1143, 1009, 971, 893. H
NMR (400 MHz, DMSO-d6) (δ, ppm): 8.98(d, J = 9.2 Hz, 1H,
NH), 8.07 (s, 1H, CH), 7.67-7.31 (m, 16H, ArH), 5.55 (t, J =
9.2 Hz, 1H, CH), 4.80(d, J = 9.6 Hz, 1H, CH).
Acknowledgment. We are grateful for financial support
from the National Science Foundation of China (20672090,
20810102050, and 20928001), Natural Science Foundation
of the Jiangsu Province (BK2006033), Six Kinds of Profe-
ssional Elite Foundation of the Jiangsu Province (06-A-039),
the Qing Lan Project (08QLT001), National Institutes of
Health (R03DA026960), and the Robert A. Welch Founda-
tion (D-1361).
Experimental Section
General. Microwave irradiation was carried out with micro-
wave oven Emrys Creator from Personal Chemistry, Uppsala,
Sweden.
Representative Example. 4,5-Bis(4-chlorophenyl)-1H-2-(20-
pyridyl)imidazole (3a). Microwave Heating. 2-Cyanopyridine
(1a, 1.1 mmol, 0.111 g, 1.1 equiv) was introduced in a 10-mL
Emrys reaction vial, and 4-chlorobenzaldehyde (2a, 2 mmol,
0.28 g, 2.0 equiv) and NH4OAc (6 mmol, 0.46 g, 3.0 equiv) were
Supporting Information Available: 1H and 13C NMR spec-
tra of all pure products. This material is available free of charge
via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 24, 2009 9489