Synthesis of 2-keto-imidazoles utilizing N -arylamino-substituted N-heterocyclic carbenes

Article abstract of DOI:10.1021/jo102244x

A new method for the synthesis of 2-aroyl-, 2-heteroaroyl-, and 2-cinnamoyl-substituted imidazoles in very good yields has been developed. The reaction employs novel nitrogen heterocyclic carbenes (NHCs), namely, N-arylamino-substituted NHCs, formed in situ from the corresponding imidazolium salts, and subsequent reaction with aromatic, heteroaromatic, and cinnamic aldehydes without utilizing transition metals or expensive specialized catalysts.(Figure Presented)

Full text of DOI:10.1021/jo102244x

pubs.acs.org/joc
antiulcerative agent cimetidine,2 the proton pump inhib-
Synthesis of 2-Keto-imidazoles Utilizing
N-Arylamino-Substituted N-Heterocyclic Carbenes
itor omeprazole,3 the fungicide ketoconazole,4 and the
benzodiazepine antagonist flumazenil5 are imidazole deriva-
tives. Recent advances in the imidazole-tailored ionic liquids,6
stable nucleophilic carbenes,7 and organic catalysts8 are
other applications of imidazole derivatives. Consequently,
efforts are focused on the development of new methodolo-
gies for the synthesis and functionalization of imidazoles.
Relative to functionalizing imidazole at the 2-position,
2-lithioimidazoles are generated with n-BuLi at low tem-
peratures under anhydrous conditions and then captured by
electrophiles.9 2-Substituted imidazoles are also prepared by
reacting 2-trimethylsilyl-1-alkylimidazoles with aldehydes10
and by direct vinylation of 1-substituted imidazoles.11 Very
recently, C2-funcionalization by a vinyl ether group of
1-substituted imidazoles has been reported.12 In addition,
imidazoles can be thermally condensed with isocyanates,13
whereas it was found that they can also be directly acylated in
the 2-position by using either benzoylchloride and triethyl-
amine14 or 4-acetylmorpholine and n-BuLi.15 However, when
direct benzoylation was applied to the 4,5-dimethyl deriva-
tive, the corresponding 2-benzoylimidazole was formed in
poor yield (19%).16
Tryfon Zarganes-Tzitzikas, Constantinos G. Neochoritis,
Julia Stephanidou-Stephanatou,* and
Constantinos A. Tsoleridis*
Department of Chemistry, Laboratory of Organic Chemistry,
University of Thessaloniki, Thessaloniki 54124,
Macedonia, Greece
ioulia@chem.auth.gr; tsolerid@chem.auth.gr
Received November 12, 2010
Concerning imidazole carbenes, their studies date back
to the 1960s work of Wanzlick17 and Ofele,18 who although
€
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A new method for the synthesis of 2-aroyl-, 2-heteroaroyl-,
and 2-cinnamoyl-substituted imidazoles in very good yields
has been developed. The reaction employs novel nitrogen hetero-
cyclic carbenes (NHCs), namely, N-arylamino-substituted
NHCs, formed in situ from the corresponding imidazolium
salts, and subsequent reaction with aromatic, heteroaro-
matic, and cinnamic aldehydes without utilizing transition
metals or expensive specialized catalysts.
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1468 J. Org. Chem. 2011, 76, 1468–1471
Published on Web 01/20/2011
DOI: 10.1021/jo102244x
r
2011 American Chemical Society

Zarganes-Tzitzikas et al.
JOCNote
SCHEME 1. Synthesis of Benzoylimidazole 6aa via Carbene 4a
TABLE 1. Preparation of 2-Keto-Substituted Imidazoles
were unsuccessful in isolating any carbenes at that time, their
work provided the conceptual framework for the develop-
ment of chemistry of these species. The current growth in the
chemistry of NHCs is mainly ascribed to the pioneering work
of Arduengo and co-workers, who in 1991 isolated the first
stable diamino carbene.19 The role of NHCs as excellent
ligands for transition metals20 and their ability to catalyze
various C-C coupling reactions, namely, benzoin condensa-
tion, transesterification,21 and Stetter reaction,22 have con-
tributed significantly to the enormous interest in these
compounds. Recently, there is also a growing awareness of
their potential application as reagents in organic reactions23
and especially in multicomponent reactions.24
Contrary to this literature background, with it being well-
established that 2-acyl substitution in polysubstituted imi-
dazoles is a rather difficult task, we sought to establish a new
reaction for C2-functionalization of imidazoles involving
formation of nitrogen heterocyclic carbenes (NHCs) and
subsequent trapping with electrophiles to afford diverse
2-substituted imidazoles.
(17) (a) Wanzlick, H.-W. Angew. Chem., 1962, 74, 129; Angew. Chem.,
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Schonherr, H.-J. Liebigs Ann. Chem. 1970, 731, 176.
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M. J. Am. Chem. Soc. 1992, 114, 5530.
€
The 4,5-dimethyl-3-phenylaminoimidazolium salt 3a,
formed in quantitative yield by methylation of 2a with
methyl iodide,25 was chosen as a model compound because
it would lead to the formation of a new Arduengo-type
carbene with a liable 3-phenylamino substituent, arising thus
the possibility of novel reactions and consequently offering
to the whole scheme a new perspective.
Thus, 3a was allowed to react with benzaldehyde in dry
THF in the presence of either sodium hydride for 1 h or DBU
for 4 h, whereupon the 2-benzoylimidazole 6aa was isolated
in 85% yield (Scheme 1). When the phenylamino salt 3e was
used, the reaction proceeded analogously, though much longer
times (12 h) were necessary for the completion of the reaction.
The reaction also proceeded successfully with several
3-phenylaminoimidazolium salts and substituted aldehydes,
including heterocyclic and R,β-unsaturated ones, with the
corresponding 2-substituted imidazoles 6 always being
isolated in very good yields (Table 1), proving thus the
(20) For selected reviews, see: (a) Herrmann, W. A. Angew. Chem., Int.
€
Ed. 2002, 41, 1290. (b) Herrmann, W. A.; Kocher, C. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2162. (c) De Fremont, P.; Marion, N.; Nolan, S. P. Coord.
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Chem. Rev. 2009, 253, 862.
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(b) Connor, E. F.; Nyce, G. W.; Myers, M.; Mock, A.; Hedrick, J. L.
J. Am. Chem. Soc. 2002, 124, 914. (c) Grasa, G. A.; Kissling, R. M.; Nolan,
€
S. P. Org. Lett. 2002, 4, 3583. (d) Grasa, G. A.; Guveli, T.; Singh, R.; Nolan,
S. P. J. Org. Chem. 2003, 68, 2812. (e) Kano, T.; Sasaki, K.; Maruoka, K.
Org. Lett. 2005, 7, 1347.
(22) (a) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639. (b) Enders,
D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534. (c) Johnson, J. S. Angew.
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43, 5130. (b) Smith, M. R.; Blake, A. J.; Hayes, C. J.; Stevens, M. F. G.;
Moody, C. J. J. Org. Chem. 2009, 74, 9372. (c) Cheng, Y.; Ma, Y.-G.; Wang,
X.-R.; Mo, J.-M. J. Org. Chem. 2009, 74, 850.
(24) (a) Nair, V.; Bindu, S.; Sreekumar, V.; Rath, N. P. Org. Lett. 2003, 5,
665. (b) Nair, V.; Sreekumar, V.; Bindu, S.; Suresh, E. Org. Lett. 2005, 7,
2297. (c) Nair, V.; Menon, R. S.; Sreekumar, V. Pure Appl. Chem. 2005, 77,
1191. (d) Cheng, Y.; Peng, J.-H.; Li, J.-Q. J. Org. Chem. 2010, 75, 2382.
(e) Pan, H.-R.; Li, Y.-J.; Yan, C.-X.; Xing, J.; Cheng, Y. J. Org. Chem. 2010,
75, 6644.
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ARKIVOC 2007, xv, 101.
J. Org. Chem. Vol. 76, No. 5, 2011 1469

Zarganes-Tzitzikas et al.
JOCNote
SCHEME 2. Reaction of Imidazolium Salt 3e with (Z)-R-
Chlorocinnamaldehyde
TABLE 2. Preparation of 2-Imidazole Derivatives 13 and 14
SCHEME 3. Proposed Mechanism for the Reaction of Carbene
4a with Benzaldehyde
generality of the reaction. Moreover, in order to support
the regioselectivity of the reaction leading exclusively to
2-substituted and not to the isomeric 4- or 5-keto-imidazoles,
the nonsubstituted 1-phenylaminoimidazolium salt 3c was
prepared, which upon reaction with aldehydes 5a and 5f
furnished the 2-keto-imidazoles 6ca and 6cf as the only
reaction products.
The reaction of (Z)-R-chlorocinnamaldehyde (7) with
carbenes 4 was also investigated, leading in the case of the
reaction with the nonmethylated exonitrogen imidazolium
salt 3e to the unsaturated imidazolyl ketone 8 in 94% yield
(Scheme 2). To the contrary, an unidentified mixture of resi-
nous products was formed from the reaction with the methyl-
ated imidazolium salt 3a.
FIGURE 1. HMBC correlations between protons and carbons (via
2JC-H and 3JC-H) in compounds 6al and 8.
An unidentified mixture of resinous products was also
formed when 3a was allowed to react with sodium hydride in
dry THF in the absence of aldehydes.
imidazoles 6. The formation of 8 possibly proceeds through
an intramolecular nucleophilic vinylic substitution28 reac-
tion of the vinylic chlorine by the phenylamino group.
Finally, the reaction was studied with the bisaldehydes,
isophthalaldehyde 12a and terephthalaldehyde 12b, where-
upon depending on the molar ratio of the reactants either 13
or 14 was isolated in almost quantitative yield (Table 2).
All isolated 2-substituted imidazoles, with the exception of
6aa, are novel compounds, and their structures were estab-
lished by analysis of their IR, MS, NMR (1H, 13C, COSY,
HMQC, HMBC), and elemental analysis data. In Figure 1,
the HMBC correlations between protons and carbons (via
2JC-H and 3JC-H) in compounds 6al and 8 are depicted.
Concerning the reaction mechanism (Scheme 3), the in-
itially formed Breslow intermediate tautomerizes to its more
stable keto form (recently isolated and studied26 in the case of
the triazolydene carbene and benzaldehyde). However, due
to the presence of the 3-arylamino substituent, the reaction
does not follow the usual pathway to benzoin reaction.27
Instead, aromatization through loss of the arylamino group,
isolated and identified in the reaction products as N-methy-
laniline, results in the formation of the 2-aroyl-substituted
(26) Berkessel, A.; Elfert, S.; Etzenbach-Effers, K.; Teles, J. H. Angew.
Chem., Int. Ed. 2010, 49, 6.
(27) (a) Moore, J. L.; Rovis, T. Top. Curr. Chem. 2010, 77. (b) Enders, D.;
Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606. (c) Simonovic, S.;
Frison, J.-C.; Koyuncu, H.; Whitwood, A. C.; Douthwaite, R. E. Org. Lett.
2009, 11, 245.
(28) (a) Bernasconi, C. F.; Rappoport, Z. Acc. Chem. Res. 2009, 42, 993.
(b) Shen, S.-S.; Lei, M.-Y.; Wong, Y.-X.; Tong, M.-L.; Teo, P. L.-Y.; Chiba,
S.; Narasaka, K. Tetrahedron Lett. 2009, 50, 3161. (c) Khamri, S.; Amri, H.
Tetrahedron 2009, 65, 4890.
1470 J. Org. Chem. Vol. 76, No. 5, 2011

Zarganes-Tzitzikas et al.
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The reaction described herein shows a new potential
concerning carbene chemistry, leading to the synthesis of
a variety of 2-substituted imidazoles. Furthermore, the
incorporated 2-substituent can also be used as a convenient
handle for further manipulation of the functionalized het-
erocycle. The facile and convenient reaction conditions,
compared to existing procedures, make this reaction the
method of choice in the preparation of 2-substituted imi-
dazoles without utilizing transition metals or expensive
specialized catalysts.
(214.26): C, 72.87; H, 6.59; N, 13.07%. Found: C, 72.99; H,
6.45; N, 13.21%.
2-(3-Formylbenzoyl)-1,4,5-trimethyl-1H-imidazole (13a): White
solid, 92% yield; mp 68-70 °C; IR (KBr) νmax 1701, 1630 cm-1
;
1H NMR (300 MHz, CDCl3) δ 2.26 (s, 6H, 4-CH3, 5-CH3), 3.96
(s, 3H, 1-CH3), 7.63 (t, J = 7.7 Hz, 1H, 50-H), 8.06 (d, J = 7.7 Hz,
1H, 40-H), 8.50 (d, J = 7.7 Hz, 1H, 60-H), 8.74 (s, 1H, 20-H), 10.1
(s, 1H, 40-CHO); 13C NMR (75 MHz, CDCl3) δ 9.1 (5-CH3), 13.0
(4-CH3), 33.2 (1-CH3), 128.8 (C-50), 131.3 (C-5), 131.9 (C-20),
133.2 (C-40), 136.1 (C-4), 136.5 (C-60), 136.7 (C-30), 139.0 (C-10),
141.0 (C-2), 182.0 (CO), 191.9 (40-CO); MS (LCMS) m/z (%) 297
(100, Mþ þ MeOH þ Na), 275 (60, Mþ þ MeOH þ H), 265 (50,
Mþ þ Na), 243 (65, Mþ þ H). Anal. Calcd for C14H14N2O2 (242.27):
C, 69.41; H, 5.82; N, 11.56%. Found: C, 69.58; H, 5.69; N, 11.47%.
1,3-Bis[1,4,5-trimethyl-1H-imidazol-2-yl)carbonyl]benzene
(14a): Yellowish solid, 91% yield; mp 147-149 °C; IR (KBr)
Experimental Section
General Procedure for the Preparation of 2-Keto-Imidazoles 6
and 13 and of Bisimidazoles 14 from Phenylaminoimidazoles 2.
A solution of 1 mmol of 2 and of 1.5 mmol of methyl (or ethyl)
iodide in 15 mL of dry toluene was refluxed for 30 min, and the
precipitated solid was filtered off, affording almost quantita-
tively the ammonium salt 3.
To a solution of 1 mmol of 3 and 1 mmol of aldehyde 5 (or 12)
in dry THF (20 mL) under argon atmosphere was added 1.1
mmol of sodium hydride (60% in oil), and the reaction mixture
was stirred at rt for 1 h. After completion of the reaction (fol-
lowed by TLC), it was quenched with water, and the organic
layer was separated, washed with water, dried with sodium
sulfate, filtered, and concentrated in vacuo. Flash chromatog-
raphy on silica gel eluted with hexane-ethyl acetate (3:1) gave
the substituted imidazoles 6 (or 13). Using a half molar ratio of
aldehyde 12, only compounds 14 were obtained.
3,4,5-Trimethyl-1-[methyl(phenyl)amino]-1H-imidazol-3-ium
iodide (3a): Light brown solid (97% yield); mp 143-145 °C; IR
(KBr) νmax 1638, 1595 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.09
(s, 3H, 5-CH3), 2.35 (s, 3H, 4-CH3), 3.56 (s, 3H, 1-NCH3), 4.03
(s, 3H, 3-CH3), 6.69 (d, J = 8.4 Hz, 2H, 20, 60-H), 7.04 (t, J =
7.4 Hz, 1H, 40-H), 7.29-7.35 (m, 2H, 30,50-H), 9.88 (s, 1H, 2-H);
13C NMR (75 MHz, CDCl3) δ 8.1 (5-CH3), 9.1 (4-CH3), 35.2
(3-CH3), 42.7 (1-NCH3), 114.2 (C-20,60), 122.8 (C-40), 127.1
(C-5), 127.4 (C-4), 129.7 (C-30,50), 135.9 (C-2), 146.6 (C-10);
MS (LCMS) m/z (%) 216 (100, Mþ - I). Anal. Calcd for
C13H18IN3 (343.21): C, 45.49; H, 5.29; N, 12.24%. Found: C,
45.38; H, 5.40; N, 12.12%.
ν
max 1619 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.23 (s, 6H, 5,500-
CH3), 2.25 (s, 6H, 4,400-CH3), 3.94 (s, 6H, 1,100-CH3), 7.55 (t, J =
7.8 Hz, 1H, 50-H), 8.44 (dd, J = 7.8, 1.6 Hz, 2H, 40,60-H), 9.06 (d,
J = 1.6 Hz, 1H, 20-H); 13C NMR (75 MHz, CDCl3) δ 9.1 (5,500-
CH3), 13.1 (4,400-CH3), 33.1 (1,100-CH3), 127.7 (C-50), 130.6
(C-5,500), 133.3 (C-20), 134.5 (C-40,60), 136.2 (C-4,400), 137.9
(C-10,30), 141.4 (C-2,200), 182.9 (2 ꢀ CO); MS (LCMS) m/z
(%) 373 (50, Mþ þ Na), 351 (100, Mþ þ H). Anal. Calcd for
C20H22N4O2 (350.41): C, 68.55; H, 6.33; N, 15.99%. Found: C,
68.39; H, 6.28; N, 16.05%.
By the same experimental procedure as above, reacting imida-
zolium salt 3e and aldehyde 7 in 1:1 molar ratio imidazole
derivative, 8 was obtained.
2-[(2Z)-2-Anilino-3-phenylprop-2-enoyl]-1,4,5-trimethyl-1H-
imidazole (8): Yellow solid, 94% yield; mp 62-64 °C; IR (KBr)
1
νmax 1649 cm-1; H NMR (300 MHz, CDCl3) δ 2.18 (s, 3H,
5-CH3), 2.26 (s, 3H, 4-CH3), 3.83 (s, 3H, 1-CH3), 6.65 (dd, J =
8.7, 1.1 Hz, 2H, 200,600-H), 6.70 (tt, J = 7.4, 1.1 Hz, 1H, 400-H),
7.05 (ddt, J = 8.5, 7.4, 1.9 Hz, 2H, 300,500-H), 7.12-7.25 (m, 3H,
30,40,50-H), 7.51-7.54 (m, 2H, 20,60-H), 7.65 (s, 1H, β-H), 8.27
(br s, 1H, N-H); 13C NMR (75 MHz, CDCl3) δ 9.1 (5-CH3), 12.9
(4-CH3), 33.1 (1-CH3), 116.4 (C-200,600), 119.4 (C-400), 126.9
(C-β), 128.11 (C-30,50), 128.16 (C-40), 128.7 (C-300,500), 130.2
(C-5), 130.6 (C-20,60), 135.1 (C-10), 135.3 (C-4), 136.3 (C-R),
140.9 (C-2), 142.8 (C-100), 181.1 (CO) (double-primed values refer
to N-Ph); MS (LCMS) m/z (%) 332 (100, Mþ þ H). Anal. Calcd
for C21H21N3O (331.41): C, 76.11; H, 6.39, N, 12.68%. Found:
C, 75.95; H, 6.45, N, 12.47%.
2-Benzoyl-1,4,5-trimethyl-1H-imidazole (6aa): Yellowish oil,
1
85% yield; IR (neat) νmax 1634 cm-1; H NMR δ 2.23 (s, 3H,
5-CH3), 2.25 (s, 3H, 4-CH3), 3.92 (s, 3H, 1-CH3), 7.42-7.47 (m,
2H, 30,50-H), 7.52 (tt, J = 7.2, 1.5 Hz, 1H, 40-H), 8.22 (d, J = 8.1
Hz, 2H, 20,60-H); 13C NMR δ 9.1 (5-CH3), 13.0 (4-CH3), 33.1
(1-CH3), 128.0 (C-30,50), 130.4 (C-5), 130.9 (C-20,60), 132.3 (C-40),
136.0 (C-4), 138.1 (C-10), 141.6 (C-2), 183.6 (CO); MS (LCMS)
m/z (%) 215 (100, Mþ þ H). Anal. Calcd for C13H14N2O
Supporting Information Available: Experimental details,
compound characterization with full assignments of chemical
1
shifts, and copies of H NMR and 13C NMR spectra for all
novel compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 5, 2011 1471