Superelectrophilic chemistry of imidazoles

Article abstract of DOI:10.1021/jo802798x

The mechanistic and synthetic chemistry of imidazole-based superelectrophiles has been studied. The protonated imidazole ring, or imidazolium group, is shown to enhance the electrophilic reactivity of an adjacent carboxonium group (compared to a related m

Full text of DOI:10.1021/jo802798x

Superelectrophilic Chemistry of Imidazoles
Matthew R. Sheets, Ang Li, Edward A. Bower, Andrew R. Weigel, Matthew P. Abbott,
Robert M. Gallo, Adam A. Mitton, and Douglas A. Klumpp*
Department of Chemistry and Biochemistry, Northern Illinois UniVersity, DeKalb, Illinois 60115
dklumpp@niu.edu
ReceiVed December 23, 2008
The mechanistic and synthetic chemistry of imidazole-based superelectrophiles has been studied. The
protonated imidazole ring, or imidazolium group, is shown to enhance the electrophilic reactivity of an
adjacent carboxonium group (compared to a related monocationic species). This leads to efficient
condensation reactions between imidazole aldehydes and ketone with arenes in the Brønsted superacid
CF3SO3H. The imidazole-based superelectrophiles are shown to be useful in other reactions leading to
functionalized heterocycles. The imidazolium group may also trigger charge migration reactions in
dicationic species.
Introduction
istry.5 As reactive intermediates, it is expected that superelec-
trophiles can be the basis for new synthetic methods leading to
functionalized imidazoles. In this Article we describe the
chemistry of superelectrophiles having the imidazole ring
system. We demonstrate that the imidazolium cation may
significantly activate adjacent electrophilic sites. This super-
electrophilic activation represents a useful structure-reactivity
The concept of superelectrophilic activation was first proposed
by Olah and co-workers in the 1970s.1 Since these pioneering
studies, there have been many example of superelectrophiles
described in the literature.2 As a consequence of their high
reactivities, superelectrophiles can be used in synthetic trans-
formations with very weak nucleophiles, including alkanes and
deactivated arenes. A number of studies have shown that
N-heterocyclic systems may also be a part of superelectrophilic
systems.3 These superelectrophilic reactions have been used to
prepare a variety of functionalized N-heterocyclic products.
Imidazoles are well-known for their diverse biological
activities and consequently are a privileged class of compounds
among pharmaceutical substances.4 Little work has been done
to determine the scope of superelectrophilic imidazole chem-
(4) (a) Hong, S.-S.; Romstedt, K. J.; Feller, D. R.; Hsu, F.-L.; Cupps, T. L.;
Lyon, R. A.; Miller, D. D. J. Med. Chem. 1994, 37, 2328. (b) Karjalainen, A.;
Kalapudas, A.; So¨dervall, M.; Pelkonen, O.; Lammintausta, R. Eur. J. Pharm.
Sci. 2000, 11, 109. (c) Vlahakis, J. Z.; Kinobe, R. T.; Bowers, R. J.; Brien, J. F.;
Nakatsu, K.; Szarek, W. A. J. Med. Chem. 2006, 49, 4437. (d) Rahman, M. N.;
Vlahakis, J. Z.; Szarek, W. A.; Nakatsu, K.; Jia, Z. J. Med. Chem. 2008, 51,
5943. (f) Rivara, M.; Baheti, A. R.; Fantini, M.; Cocconcelli, G.; Ghiron, C.;
Kalmar, C. L.; Singh, N.; Merrick, E. C.; Patel, M. K.; Zuliani, V. Bioorg. Med.
Chem. Lett. 2008, 18, 5460. (g) Kumar, S.; Jaller, D.; Patel, B.; LaLonde, J. M.;
DuHadaway, J. B.; Malachowski, W. P.; Prendergast, G. C.; Muller, A. J. J. Med.
Chem. 2008, 51, 4968. (h) Gemma, S.; Campiani, G.; Butini, S.; Kukreja, G.;
Joshi, B. P.; Persico, M.; Catalanotti, B.; Novellino, E.; Fattorusso, E.; Nacci,
V.; Savini, L.; Taramelli, D.; Basilico, N.; Morace, G.; Yardley, V.; Fattorusso,
C. J. Med. Chem. 2007, 50, 595. (i) Chegaev, K.; Lazzarato, L.; Tosco, P.; Cena,
C.; Marini, E.; Rolando, B.; Carrupt, P.-A.; Fruttero, R.; Gasco, A. J. Med. Chem.
2007, 50, 1449. (j) For a general reference, see: Xi, N.; Huang, Q.; Liu, L. In
ComprehensiVe Heterocyclic Chemistry III; Katritzky, A. R., Ramsden, C. A.,
Scriven, E. F. V., Taylor, R. J. K., Joule, J., Eds.; Elsevier: London, 2008; Vol.
4, pp 145-362.
(1) Olah, G. A.; Germain, A.; Lin, H. C.; Forsyth, D. J. Am. Chem. Soc.
1975, 97, 2928.
(2) (a) Olah, G. A.; Prakash, G. K. S.; Lammertsma, K. Res. Chem. Intermed.
1989, 12, 141. (b) Olah, G. A. Angew. Chem., Int. Ed. Engl. 1993, 32, 767. (c)
Olah, G. A.; Klumpp, D. A. Acc. Chem. Res. 2004, 37, 211. (d) Olah, G. A.;
Klumpp, D. A. Superelectrophiles and Their Chemistry; Wiley & Sons: New
York, 2008; pp 1-301.
(3) (a) Li, A.; Gilbert, T. M.; Klumpp, D. A. J. Org. Chem. 2008, 73, 3654.
(b) Prakash, G. K. S.; Paknia, F.; Chacko, S.; Mathew, T.; Olah, G. A.
Heterocycles 2008, 76, 783. (c) Sai, K. K. S.; Torkarz, M. J.; Malunchuk, A. P.;
Zheng, C.; Gilbert, T. M.; Klumpp, D. A. J. Am. Chem. Soc. 2008, 130, 14388.
(d) See also ref 2d.
(5) (a) Zhang, Y.; McElrea, A.; Sanchez, G. V.; Klumpp, D. A.; Do, D.;
Gomez, A.; Aguirre, S. L.; Rendy, R. J. Org. Chem. 2003, 68, 5119. (b) Klumpp,
D. A.; Rendy, R.; Zhang, Y.; Gomez, A.; McElrea, A.; Dang, H. J. Org. Chem.
2004, 69, 8108. (c) Rendy, R.; Zhang, Y.; McElrea, A.; Gomez, A.; Klumpp,
D. A. J. Org. Chem. 2004, 69, 2340.
2502 J. Org. Chem. 2009, 74, 2502–2507
10.1021/jo802798x CCC: $40.75 2009 American Chemical Society
Published on Web 02/12/2009

Superelectrophilic Chemistry of Imidazoles
TABLE 1. Hydroxyalkylation Reactions of Imidazole Derivatives
relationship with imidazole-based electrophiles. It is used to
prepare novel products by synthetic reactions on the imidazole
side chains.
1-5 with Acid and Arenea
Results and Discussion
The hydroxyalkylation reaction involves the acid-catalyzed
condensations of aldehydes and ketones with aromatic com-
pounds.6 It is used industrially to prepare polymers, fine
chemicals, and pharmaceutical substances. Recently, several
hydroxyalkylation reactions have been reported involving N-
heterocycle-based superelectrophiles (pyridines, thiazoles, and
quinolines).3a,b We have found that imidazole-based superelec-
trophiles are also very efficient reactants in the hydroxyalky-
lation reaction (Table 1). Similar diarylalkylimidazoles have
shown activity as aromatase inhibitors,7 and this condensation
chemistry involves a simple and improved route to these
products. A mechanism is proposed in which the acid initially
protonates the imidazole ring and an equilibium is established
with the diprotonated superelectrophile (eq 1). The involvement
of the superelectrophile 13a,b is consistent with need for strong
and superacidic media for good conversions (entry 3).
Superelectrophile 13 is capable of reacting with moderately
deactivated arenes, such as 1,3-dichlorobenzene (entry 4). In
contrast, benzaldehyde does not react with 1,3-dichlorobenzene
in CF3SO3H under similar reaction conditions, demonstrating
that the imidazolium cation activates the adjacent carboxonium
ion in dication 13. When compound 4 is reacted with CF3SO3H
and C6H6, the condensation product is formed in good yield,
suggesting that the imidazolium ion is capable of activating the
carboxonium ion despite being separated by the phenyl group
(14). The acetyl-substituted imidazole (5) also condenses with
benzene in CF3SO3H (entry 6). This observation is notable
because a similar condensation reaction cannot be done with
acetophenone. In triflic acid, acetophenone is almost completely
protonated;8 however, cation 15 is not sufficiently electrophilic
to react with benzene. The imidazole system 5 forms a
carboxonium ion (16) with an adjacent imidazolium cation,
leading to the observed superelectrophilic reactivity. When 1-(4-
(1H-imidazol-1- yl)phenyl)acetophenone (17) is reacted with
triflic acid and benzene, no condensation reaction is observed.
In contrast to dication 14, the distant imidazolium ion in dication
19 does not sufficiently activate the carboxonium ion for reaction
with benzene.
a For entries 1-3, 5, and 6 reaction was with benzene; for entry 4
reaction was with 1,3-dichlorobenzene.
reactions involving olefinic imidazoles, including intra- and
intermolecular reactions.3a,5a As extensions of these methodolo-
gies, we have found that intramolecular reactions are capable
of producing the H-imidazo[5,1-a]isoquinoline type of ring
system. For example, 4,5-diphenylimidazole reacts with styrene
oxide to give the benzylic alcohol (20), which upon ionization
in superacid gives the cyclization product 23 (eq 2). The
conversion involves formation of the superelectrophilic dication
21, cyclization to 22, ipso-protonation of the phenyl group on
22, and benzene elimination to give product 23. In an attempt
to prepare the imidazo[2,1-a]isoquinoline ring system (26),
alcohol 24 was ionized in superacid (eq 3). The cyclized product
25is formed in good yield at 25 °C; however, little or no
imidazo[2,1-a]isoquinoline (26) is produced. At higher temper-
atures, the reaction of 24 in CF3SO3H leads to a complex
mixture of decomposition products. With the allyl-substituted
imidazoles (27 and 30), reaction in superacid leads to efficient
formation of the dicationic superelectrophiles (28 and 31), and
the cyclization products (29 and 32) are formed in reasonably
good yield (eqs 4 and 5). Besides generating superelectrophilic
carbocationic centers from olefins and alcohols, the ether group
In addition to the above condensation reactions, imidazole-
based superelectrophiles may possess very reactive carbocationic
centers. Previously, we have described Friedel-Crafts-type
J. Org. Chem. Vol. 74, No. 6, 2009 2503

Sheets et al.
FIGURE 1. Charge migration experiments with imidazoles 40 and 45.
of the antifungal drug miconazole (33) reacts in superacid to
give the dicationic species (34, eq 6). In the presence of benzene,
superelectrophile 34 further reacts to give the Friedel-Crafts
product 35.
hyde directly provided compound 40, whereas a similar reaction
with 1-methyl-1H-imidazole-5-carboxaldehyde did not provide
the desired alcohol 45. Instead, compound 45 was prepared via
a triisopropylsilyl-imidazole derivative following a published
procedure.10 Compounds 40 and 45 give the respective substitu-
tion products (42 and 46) from reactions at 25 °C in CF3SO3H
and C6H6. In the case of compound 40, it ionizes to the 1,3-
dication (41) and then mainly reacts with benzene to give 42.
Only minor amounts of the rearrangement product (44) could
be detected by GC-MS. If the imidazole substrates (40 and
45) are reacted in superacid and allowed to equilibrate (1 h at
50 °C) and the benzene is subsequently added, then the
respective charge rearrangement products (44 and 47) are formed
as major products. Thus for ionization of 40, the 1,3-dication
(41) isomerizes to the 1,4-dication (43) and the charge-separated
dication reacts with benzene. Unfortunately, high yields of the
rearranged products (44 and 47) are precluded by their
decomposition in heated superacid.
The superacid-promoted acyl-transfer reactions of imidazoles
have also been studied. Previous work by Keumi and co-workers
demonstrated that N-acylimidazoles were capable of acylating
electron-rich aromatic compounds in CF3CO2H solution.11
However, using CF3CO2H, N-benzoylimidazole did not react
with benzene and produced only a 5% yield of benzoylated
product from toluene (2- and 4-methylbenzophenone). We have
found that N-acetylimidazole (48a) and N-benzoylimidazole
(48b) react with benzene in CF3SO3H solution to give the
corresponding Friedel-Crafts products (eq 8). In the earlier
studies by Keumi, a mechanism was proposed involving the
We have also studied imidazole-carbodications and their
tendency to undergo charge migration reactions. Recently, our
group described the charge migration reactions of various
dicationic N-heterocyclic systems, such as in the pyridine
derivative 36 (eq 7).9 The charge migration converts an initial
1,3-dication (37) to the 1,4-dication (38), a transformation driven
largely by charge-charge repulsive effects. Two imidazole-
based systems were examined in the present study and showed
some tendency for charge migration (Figure 1). The imidazole
substrates (40 and 45) were prepared from reactions of the
aldehydes using benzylmagnesium chloride.10 Reaction of the
Grignard reagent with 1-methyl-1H- imidazole-2-carboxalde-
(6) (a) Hofmann, J. E.; Schriesheim, A. In Friedel-Crafts and Related
Reaction; Olah, G. A., Ed.; Wiley: New York, NY, 1964; Vol. 2, pp 597-640.
(b) March, J. AdVanced Organic Chemistry, 4th ed.; Wiley: New York, NY,
1992; pp 548-549.
(7) (a) Millet, R.; Domarkas, J.; Houssin, R.; Gilleron, P.; Gooseens, J.-F.;
Chavatte, P.; Loge, C.; Pommery, N.; Pommery, J.; Henichart, J.-P. J. Med.
Chem. 2004, 47, 6812. (b) Le´ze´, M. P.; Palusczak, A.; Hartmann, R. W.; Le
Borgne, M. Bioorg. Med. Chem. Lett. 2008, 18, 4713.
(8) Ohwada, T.; Yamagata, N.; Shudo, K. J. Am. Chem. Soc. 1991, 116,
1364.
(9) (a) Li, A.; Kindelin, P. J.; Klumpp, D. A. Org. Lett. 2006, 8, 1233. (b)
Klumpp, D. A. Chem. Eur. J. 2008, 14, 2004.
(10) Tanaka, A.; Ryuno, A.; Okada, S.; Satake, A.; Kobuke, Y. Israel
J. Chem. 2005, 45, 2810.
(11) Keumi, T.; Saga, H.; Kitajima, H. Bull. Chem. Soc. Jpn. 1980, 53, 1638.
2504 J. Org. Chem. Vol. 74, No. 6, 2009

Superelectrophilic Chemistry of Imidazoles
formation of mixed anhydrides (i.e., 51) from CF3CO2H and
the N-acylimidazole (48b). It was further suggested that 51 is
the active acyl-transfer agent from 48b in CF3CO2H. In order
to gain further mechanistic insights, N-acetylimidazole (48a)
was dissolved in CF3CO2H and CF3SO3H solutions and studied
by 1H NMR using NOE experiments.12 Compound 48a exhibits
prominent NOE enhancements between Ha, Hb, and the methyl
group in CDCl3 solution. In CF3CO2H and CF3SO3H solutions,
ion 49a initially shows the same NOE enhancements. The
CF3SO3H solution of 49a was found to be indefinitely stable,
with no new imidazole/acetyl signals observed in the NMR and
no diminished NOE effects (at 25 and 50 °C). However, the
CF3CO2H solution of 49a degraded rapidly with new imidazole/
Crafts acylation reactions, it has been shown that superelectro-
philic amides may undergo acyl transfer to benzene and other
arenes.13 In the present case, the imidazolium cation is too
distant from the (protonated) amide to generate the necessary
superelectrophilic activation for acyl transfer to the arenes.
The N-(trifluoroacetyl)imidazole (56) was also studied in
superacidic reactions with benzene. Upon reaction of compound
56 with CF3SO3H and C6H6 (24 h at 25 °C), the only significant
product was determined to be 1,1,1-trifluoro-2,2,2-triphenyl-
ethane (57, eq 12). This product is the result of an initial acyl-
transfer reaction to benzene to give 2,2,2-trifluoroacetophenone.
Further reaction at the carbonyl provides compound 57, a known
conversion of 2,2,2-trifluoroacetophenone in triflic acid.14
Product 57 is formed in low yield (13%), likely a consequence
of the low basicity of 56 and its inability to form the
superelectrophilic carboxonium ion.
1
acetyl signals forming in the H NMR. Within 24 h at 50 °C,
only about 10% of the 49a remained in the CF3CO2H solution,
and the new imidazole/acetyl signals did not exhibit NOE
enhancements.
Conclusion
We have found evidence that the imidazolium ion can
significantly enhance the reactivities of adjacent electrophilic
centers (i.e., carboxonium ions). This may be an important
structure-reactivity element in some imidazole-based com-
pounds. In superacidic reactions, imidazole-based superelec-
trophiles may be involved in the conversions. The high
reactivities of imidazole-based superelectrophiles can be ex-
ploited in synthetic methodologies leading to functionalized
imidazole products.
These results suggest divergent mechanisms for acetyl-transfer
reactions involving 48a, depending on the acid strength. In
CF3CO2H, NOE experiments clearly show that N-acetylimida-
zole (48a) is cleaved in the mildly acidic solution (Ho -2.7).
This can occur as a result of the relatively strong nucleophile
strength of the trifluoroacetate anion, allowing for nucleophilic
attack on the imidazolium ion 49 and formation of the mixed
anhydride (similar to 51). The mixed anhydride may then react
with activated, electron-rich arenes. However, triflic acid is a
much stronger Brønsted acid, and the triflate anion is a
considerably weaker nucleophile (compared to the trifluoroac-
etate anion), so formation of a mixed anhydride is prevented.
The NOE experiments also argue against the involvement of a
free acetyl cation (CH3CO+) or its protosolvated superelectro-
phile (CH3COH2+), because these ionizations would lead to
Experimental Section
Trifluoromethanesulfonic acid was obtained from a commercial
supplier and distilled under an Ar atmosphere prior to use. The
imidazolecarboxaldehydes 1-4, ketone 17, and other reagents/
solvents were obtained from commercial suppliers. Imidazole 5 was
prepared using a published procedure,15 and imidazoles 40 and 45
were prepared using a modified literature procedure.10 1H and 13
C
NMR spectra were recorded on a 500 MHz NMR spectrometer,
and low-resolution mass spectra were obtained from a capillary
GC (DB-5 column) equipped with a mass selective detector.
General Procedure A for the Condensations of Imidazole
Alcohols, Aldehydes, and Ketones with Arenes. The imidazole
substrate (0.1 g) is dissolved in benzene (or other arene; 1.0 mL)
and CF3SO3H (1-2 mL) is added. The reaction is stirred at least
2 h, and then the mixture is poured over several grams of ice. The
mixture is made basic (pH paper) with the slow addition of 10 M
NaOH. The resulting solution is extracted twice with CHCl3, and
the combined organic extracts are further washed with water (once)
and then brine (twice). If purification is necessary, the product
mixture is subjected to column chromatography (silica gel; hexane/
ether).
1
diminished NOE effects in the H NMR spectra. Thus, super-
acid-promoted acyl transfer to benzene involves either the
imidiazolium ion 49a or, perhaps more likely, one of the
superelectrophilic derivatives 52 or 53.
A histamine derivative (54) was also studied for its tendency
to undergo acyl-transfer reactions with arene nucleophiles. In
reactions with benzene, toluene, or naphthalene, in CF3SO3H,
there are no acetylated arenes formed (eq 11). On the basis of
the acid strength of CF3SO3H (Ho -14.1), it is likely that both
the imidazole and amide groups are fully protonated. However,
dication 55 is not sufficiently electrophilic to acetylate the
arenes. Although amides are generally not reactive in Friedel-
(12) If the N-acetylimidazole (48a) is dissolved in CF3SO3H at 25°C, roughly
10% of the 48a undergoes an immediate cleavage reaction, while the remaining
49a remains stable under the reaction conditions. If 48a is slowly and carefully
added to CF3SO3H at -30°C, then no cleavage products are observed. Presum-
ably, solvation of 48a at 25°C can generate intense localized heating, which
leads to some cleavage of 48a or 49a (even in CF3SO3H).
(13) Klumpp, D. A.; Rendy, R.; Zhang, Y.; Gomez, A.; McElrea, A. Org.
Lett. 2004, 6, 1789.
(14) Rusanov, A. L.; Chebotarev, V. P.; Lovkov, S. S. Russ. Chem. ReV.
2008, 77, 547.
(15) Myers, M. C.; Bharadwaj, A. R.; Milgram, B. C.; Scheidt, K. A. J. Am.
Chem. Soc. 2005, 127, 14675.
J. Org. Chem. Vol. 74, No. 6, 2009 2505

Sheets et al.
2-Benzhydryl-1-methyl-1H-imidazole (6). Using general proce-
dure A, compound 1 is reacted with C6H6 and CF3SO3H. Product
6 is isolated. 1H NMR (CDCl3): δ 3.47 (s, 3H), 5.51 (s, 1H), 6.87
(s, 1H), 7.05 (s, 1H), 7.20-7.35 (m, 10H). 13C NMR (CDCl3): δ
32.9, 49.5, 121.0, 126.9, 127.6, 128.6, 128.9, 141.0, 148.7. Low
resolution MS (EI): 248 (M+), 247, 165. High resolution MS (EI),
C17H16N2 calcd: 248.13135, found 248.13070.
5-Benzhydryl-4-methyl-1H-imidazole (8). Using general proce-
dure A, compound 3 is reacted with C6H6 and CF3SO3H. Product
8 is isolated. 1H NMR (CDCl3): δ 2.07 (s, 3H), 5.39 (s, 1H),
7.10-7.44 (m, 10), 11.7 (m, 1H). 13C NMR (CDCl3): δ 10.0, 48.3,
126.2, 128.4, 129.2, 133.7, 122.5, 145.1. Low resolution MS (EI):
248 (M+), 247, 233, 171. High resolution MS (EI), C17H16N2 calcd:
248.13135, found 248.13140.
δ 44.7, 49.9, 119.3, 123.6, 127.1, 127.5, 127.9, 128.2, 128.3, 128.6,
128.9, 129.4, 135.4, 140.8, 144.1. Low resolution MS (EI): 246
(M+), 245, 169, 128. High resolution MS (EI), C17H14N2 calcd:
246.1157, found 246.1153.
6-Methyl-1-phenyl-5,6-dihydroimidazo[5,1-a]isoquinoline (29).
4,5-Diphenyl-imidazole (0.5 g, 2.2 mmol) is dissolved in 20 mL
of anhydrous ether, and KOtBu (0.27 g, 2.4 mmol) is then added
at 25 °C. The mixture is stirred at 25 °C for 30 min, and then allyl
bromide (0.2 mL, 2.3 mmol) is added. After 30 min of stirring, the
solution is partitioned between ether and water. The organic phase
is then washed twice with brine and dried over magnesium sulfate.
Further purification is achieved by column chromatography (silica
gel; hexane/ether). The 1-allyl-4,5-diphenyl-1H-imidazole (27) is
reacted with CF3SO3H according to general procedure B. Product
1
5-(Bis(2,4-dichlorophenyl)methyl)-4-methyl-1H-imidazole (9). Us-
29 is isolated. H NMR (CDCl3): δ 1.35 (d, J ) 7.0 Hz, 3H),
ing general procedure A, compound 3 is reacted with 1,3-
3.22-3.29 (m, 1H), 3.91 (dd, J ) 12.2, 5.7 Hz, 1H), 4.14 (dd, J )
12.2, 4.4 Hz, 1H), 7.12-7.15 (m, 1H), 7.20-7.23 (m, 1H),
7.29-7.31 (m, 1H), 7.33-7.36 (m, 1H), 7.41-7.44 (m, 2H), 7.60 s,
1H), 7.64 (d, J ) 7.8 Hz, 1H), 7.74-7.76 (m, 2H). 13C NMR
(CDCl3): δ 18.1, 34.1, 48.4, 123.6, 124.3, 126.7, 127.0, 127.2, 127.3,
128.4, 128.4, 135.7, 135.7, 137.2, 138.0, 143.6. Low resolution MS
(EI): 260 (M+), 259, 218, 115. High resolution MS (EI), C18H16N2
calcd: 260.13135, found 260.13086.
1
dichlorobenzene and CF3SO3H. Product 10 is isolated. H NMR
(CDCl3): δ 2.11 (s, 1H), 5.98 (s, 1H), 7.08-7.16 (m, 4H), 7.39 (s,
3H). 13C NMR (CDCl3): δ 9.8, 41.7, 127.0, 129.4, 131.2, 133.1,
133.5, 134.7, 138.3. Low resolution MS (EI): 388/386/384 (M+),
351/349, 313, 239. High resolution MS (EI), C17H12Cl4N2 calcd:
383.97545, found 383.97563.
1-Methyl-2-(1,1-diphenylethyl)-1H-imidazole (11). Using general
procedure A, compound 5 is reacted with C6H6 and CF3SO3H.
6-Methyl-5,6-dihydroimidazo[2,1-a]isoquinoline (32). Similar to
the procedure for compound 25, 1-allyl-2-phenyl-1H-imidazole (30)
is prepared by reaction of 2-phenylimidazole and allyl bromide and
it is reacted with CF3SO3H according to general procedure B.
1
Product 11 is isolated. H NMR (CDCl3): δ 2.23 (s, 1H), 2.90 (s,
3H), 6.78 (d, J ) 1.0 Hz, 1H), 7.06, (d, J ) 1.0 Hz, 1H), 7.14-7.31
(m, 10H). 13C NMR (CDCl3): δ 32.7, 34.9, 50.6, 122.7, 126.5,
126.6, 127.9, 128.4, 145.0, 152.0. Low resolution MS (EI): 262
(M+), 261, 246, 171, 103. High resolution MS (EI), C18H18N2 calcd:
262.1470, found 262.1470.
1
Product 32 is isolated. H NMR (CDCl3): δ 1.33 (d, J ) 7.0 Hz,
3H), 3.27-3.31 (m, 1H), 3.91 (dd, J ) 12.4, 5.9 Hz, 1H), 4.21
(dd, J ) 12.4, 5.1 Hz, 1H), 6.94 (s, 1H), 7.17 (s, 1H), 7.27-7.37
(m, 3H), 8.05-8.07 (m, 1H). 13C NMR (CDCl3): δ 19.0, 33.2, 49.6,
119.3, 123.7, 126.3, 126.4, 127.5, 128.6, 129.2, 137.6, 143.9. Low
resolution MS (EI): 184 (M+), 169, 128, 84. High resolution MS
(EI), C12H12N2 calcd: 184.1001, found 184.0996.
General Procedure B for the Intramolecular Cyclizations of
Imidazole Alcohols and Olefins. The imidazole substrate (1 mmol)
is dissolved in CHCl3, and CF3SO3H (3 mL, 33 mmol) is added.
Depending on the substrate the solution may be heated. The reaction
is stirred at least 2 h and then poured over several grams of ice. The
mixture is made basic (pH paper) with the slow addition of 10 M
NaOH. The resulting solution is extracted twice with CHCl3, and the
combined organic extracts are further washed with water (once) and
then brine (twice). If purification is necessary, the product mixture is
subjected to column chromatography (silica gel; hexane/ether).
1-Phenylimidazo[5,1-a]isoquinoline (23). 4,5-Diphenylimidazole
(0.5 g, 2.3 mmol) is dissolved in 20 mL of anhydrous THF, KOtBu
(0.26 g, 2.3 mmol) is added, and the mixture is stirred at 25 °C for
1 h. To this mixture is added dropwise a styrene oxide (0.3 g, 2.5
mmol) solution in 10 mL of THF, and the final solution is then
refluxed for 1 h. The product mixture is then diluted with water
and extracted three times with ether. The combined organic extracts
are then washed three times with brine solution, dried over
anhydrous Na2SO4, and concentrated by removal of the solvent.
Further purification is achieved by column chromatography (silica
gel; hexane/ether/NH4OH (trace)). The 2-(4,5-diphenyl-1H-imida-
zol-1-yl)-1-phenylethanol (20) is reacted with CF3SO3H according
to general procedure B. Compound 23 is isolated. 1H NMR (CDCl3):
δ 6.82 (d, J ) 7.3 Hz, 1H), 7.31-7.35 (m, 1H), 7.38-7.41 (m,
1H), 7.43-7.45 (m, 1H), 7.51-7.58 (m, 3H), 7.75-7.78 (m, 3H),
8.12 (d, J ) 8.3 Hz, 1H), 8.14 (s, 1H). 13C NMR (CDCl3): δ 114.3,
121.0, 122.6, 123.1, 125.5, 127.0, 127.3, 127.7, 127.9, 128.0, 128.6,
129.6, 135.5, 136.4. Low resolution MS (EI): 244 (M+), 243, 216,
189, 108. High resolution MS (EI), C17H12N2 calcd: 244.09979,
found 244.10005.
1-(2-(2,4-Dichlorophenyl)-2-phenylethyl)-1H-imidazole (35). Mi-
conazole nitrate salt (0.2 g, 4.2 mmol) is suspended in 4 mL of
CHCl3, and the solution is washed with 1.0 M NaOH and then
brine. The chloroform solution is then dried over MgSO4, filtered,
and added directly to a solution of C6H6 (1 mL) and CF3SO3H (3
mL) with stirring. After stirring at 25 °C for 4 h, the reaction is
worked up according to general experimental procedure A. Com-
1
pound 35: H NMR (CDCl3): δ 4.58 (d, J ) 7.8 Hz, 2H), 4.86 (t,
J ) 7.8 Hz, 1H), 6.81 (s, 1H), 6.99 (s, 1H), 7.20 (d, J ) 7.1 Hz,
2H), 7.25-7.33 (m, 5H), 7.39 (d, J ) 2.0 Hz, 1H), 7.49 (m, 1H).
13C NMR (CDCl3): δ 48.1, 51.0, 119.1, 127.6, 127.7, 128.0, 128.5,
129.0, 129.2, 130.0, 133.7, 135.0, 136.8, 137.2, 138.8. Low
resolution MS (EI): 283/281 (M-35/37), 235/237, 165. High
resolution MS (EI), C17H14N2Cl2 calcd: 316.0534, found 316.0536.
2-(1,2-Diphenylethyl)-1-methyl-1H-imidazole (42). Using general
procedure A, compound 40 is reacted to give product 42 as the
1
major product. Compound 42: H NMR (CDCl3): δ 3.26 (s,3H),
3.29 (dd, J ) 13.4, 8.0, Hz, 1H), 3.75 (dd, J ) 13.4, 8.1 Hz, 1H),
4.14-4.17 (m, 1H), 6.75 (s, 1H), 7.03 (d, J ) 7.0 Hz, 2H), 7.06
(s, 1H), 7.13-7.29 (m, 8H). 13C NMR (CDCl3): δ 32.4, 42.2, 46.1,
120.8, 126.1, 126.7, 127.1, 128.0, 128.1, 128.5, 129.3, 140.1, 141.3,
149.1. Low resolution MS (EI): 262 (M+), 171, 130. High
resolution MS (EI), C18H18N2 calcd: 262.14700, found 262.14696.
2-(2,2-Diphenylethyl)-1-methyl-1H-imidazole (44). Using general
procedure A (modified by dissolving 40 in CHCl3, heating to 50
°C for 1 h, and then adding C6H6), compound 40 is reacted to give
product 44 as the major product. Compound 44: 1H NMR (CDCl3):
δ 3.05 (s, 3H), 3.38 (d, J ) 7.7 Hz, 2H), 4.65 (t, J ) 7.7 Hz, 1H),
6.44 (s, 1H), 6.98 (s, 1H), 7.17-7.21 (m, 6H), 7.26-7.29 (m, 4H).
13C NMR (CDCl3): δ 32.0, 33.3, 50.1, 120.0, 126.3, 127.5, 128.0,
128.3, 144.0, 146.7. Low resolution MS (EI): 262 (M+), 167, 95.
High resolution MS (EI), C18H18N2 calcd: 262.1470, found 262.1469.
5-(1,2-Diphenylethyl)-1-methyl-1H-imidazole (46). Using general
procedure A, compound 45 is reacted to give product 46 as the
major product. Compound 46: 1H NMR (CDCl3): δ 3.13 (dd, J )
6-Phenyl-5,6-dihydroimidazo[2,1-a]isoquinoline (25). Similar to
the preparation of compound 20, 2-phenylimidazole is reacted with
styrene oxide to prepare 1-phenyl-2-(2-phenyl-1H-imidazol-1-
yl)ethanol (24). Compound 24 is reacted with CF3SO3H according
to general procedure B. Product 25 is isolated. 1H NMR (CDCl3):
δ 4.22 (dd, J ) 7.6, 12.4 Hz, 1H), 4.32 (dd, J ) 5.7, 12.4 Hz, 1H),
4.39 (m, 1H), 6.82 (s, 1H), 6.95 (d, J ) 7.7 Hz, 1H), 7.12 (d, J )
6.9 Hz, 2H), 7.15 (s, 1H), 7.20-7.23 (m, 1H), 7.25-7.28 (m, 3H),
7.34-7.37 (m, 1H), 8.14 (d, J ) 7.7 Hz, 1H). 13C NMR (CDCl3):
2506 J. Org. Chem. Vol. 74, No. 6, 2009

Superelectrophilic Chemistry of Imidazoles
13.4, 8.8, 1H), 3.19 (s, 3H), 3.44 (dd, J ) 13.4, 6.4, 1H), 4.88 (dd,
J ) 8.7, 6.5 Hz, 1H), 6.98-7.00 (m, 4H), 7.16-7.22 (m, 7H), 7.34
(s, 1H). 13C NMR (CDCl3): δ 31.3, 42.3, 44.3, 126.2, 126.7, 128.0,
128.1, 128.5, 129.1, 134.1, 138.1, 139.3, 141.8. Low resolution MS
(EI): 262 (M+), 171, 103. High resolution MS (EI), C18H18N2 calcd:
262.1470, found 262.1467.
5-(2,2-Diphenylethyl)-1-methyl-1H-imidazole (47). Using general
procedure A (modification: dissolved 45 in CHCl3, heated to 50
°C for 1 h, and then added C6H6), compound 45 is reacted to give
product 47 as the major product. Compound 47: 1H NMR (CDCl3):
δ 3.34 (d, J ) 19.3 Hz, 2H), 3.49 (s, 3H), 4.27 (t, J)19.3 Hz, 1H),
6.70 (s, 1H), 7.14-7.40 (m, 10H), 8.18 (s, 1H). 13C NMR (CDCl3):
δ 29.7, 30.4, 51.4, 126.6, 127.8, 128.3, 128.5, 143.8. Low resolution
MS (EI): 262 (M+), 167, 152, 95. High resolution MS (EI),
C18H18N2 calcd: 262.1470, found 262.1465.
Acknowledgment. Grateful acknowledgement is made to the
donors of the American Chemical Society Petroleum Research
Fund (PRF 44697-AC1), the National Science Foundation
(CHE-0749907), and the Department of Chemistry and Bio-
chemistry at Northern Illinois University for support of this
work; this research was conducted in part by the students of
the CHEM 339 laboratory class.
Supporting Information Available: NMR spectra of new
compounds, experimental procedures, and characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO802798X
J. Org. Chem. Vol. 74, No. 6, 2009 2507