Synthesis of 2-aroyl-1-methyl-1H-imidazoles using aryl carboxylic acids

Article abstract of DOI:10.3987/COM-16-S(S)66

A new and useful reaction for the synthesis of 2-aroyl-1-methyl-1H-imidazoles using free aryl carboxylic acids was developed. This method was applicable to naphthoic acid and benzoic acid derivatives to give each target compound with up to 80% yield.

Full text of DOI:10.3987/COM-16-S(S)66

HETEROCYCLES, Vol. 95, No. 2, 2017
1177
HETEROCYCLES, Vol. 95, No. 2, 2017, pp. 1177-1183. © 2017 The Japan Institute of Heterocyclic Chemistry
Received, 1st September, 2016, Accepted, 14th November, 2016, Published online, 24th January, 2017
DOI: 10.3987/COM-16-S(S)66
SYNTHESIS OF 2-AROYL-1-METHYL-1H-IMIDAZOLES USING ARYL
CARBOXYLIC ACIDS‡
Kin-ichi Oyama,a,* Noriyuki Watanabe,b and Kumi Yoshidab,*
aChemical Instrumentation Facility, Research Center for Materials Science,
bGraduate School of Information Science, Nagoya University, Chikusa, Nagoya
464-8601,
Japan;
E-mail:
oyama@cic.nagoya-u.ac.jp,
yoshidak@is.nagoya-u.ac.jp
Abstract
–
A
new and useful reaction for the synthesis of
2-aroyl-1-methyl-1H-imidazoles using free aryl carboxylic acids was developed.
This method was applicable to naphthoic acid and benzoic acid derivatives to give
each target compound with up to 80% yield.
2-Aroylimidazoles are common structural motifs found in natural products1 and pharmacologically active
compounds.2 In addition, they serve as precursors in useful organic reactions3 and as synthons for the
synthesis of more complicated bioactive compounds.4 2-Aroyl-1-methyl-1H-imidazoles have been
classically prepared by reacting N-methylimidazole with aroyl chlorides in the presence of triethylamine.5
Additionally, several methods based on the addition of 2-lithioimidazole to ketones have been
developed.6 Recently, synthesis using N-arylamino-substituted N-heterocyclic carbene7 and a
palladium-catalyzed synthesis8 have been reported. However, to the best of our knowledge, synthesis
using unmodified aryl carboxylic acids remains unexplored. Herein, we report a first synthetic route of
2-aroyl-1-methyl-1H-imidazoles using N-methylimidazole and free aryl carboxylic acids.
We have been interested in esterification reactions of hindered and low-reactive hydroxy groups with
carboxylic acids; inspired by Tanabe’s report,9 we developed an effective synthetic method of
5-acylquinic acids using unmodified carboxylic acids in the presence of TsCl, N-methylimidazole, and
i-Pr2NEt (Scheme 1).10 During that study, an unexpected product 2 was obtained (Scheme 1). This
esterification might involve an acylammonium intermediate which may be formed after tosylation.9 Based
on these observations, we sought to establish
a
new synthetic methodology of
2-aroyl-1-methyl-1H-imidazoles using unmodified aryl carboxylic acids.

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Scheme 1. Esterification with 2-naphthoic acid (1) in the presence of
TsCl, N-methylimidazole, and i-Pr2NEt
Table 1. Optimization of the condensation between 2-naphthoic acid (1)
and N-methylimidazole in the presence of TsCl and i-Pr2NEt

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First, the effect of i-Pr2NEt in the condensation reaction of N-methylimidazole and 2-naphthoic acid (1)
was examined. In the presence of TsCl in 1,2-dichloroethane at 40 °C, the reaction with i-Pr2NEt for 1 h
gave the desired aroylimidazole 2 in 28% yield (Table 1, entry 1). However, the reaction without i-Pr2NEt
for 2 h gave no 2 at all despite a longer reaction time (Table 1, entry 2). These results indicated that
i-Pr2NEt as an amine base was essential to promote the reaction. To increase the yield, the reaction time,
temperature, and equimolar amount of N-methylimidazole were further examined. The optimized reaction
conditions were 2 h at 40 °C (Table 1, entries 2-6). By addition of 6 eq. of N-methylimidazole at 40 °C
for 2 h, 2 was obtained in 65% yield (Table 1, entry 7).
Table 2. Synthesis of 2-aroyl-1-methyl-1H-imidazoles (8-12)
with various aryl carboxylic acids (3-7)

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Using the optimized reaction conditions (6 eq. of N-methylimidazole, 4 eq. of TsCl, and 6 eq. of i-Pr2NEt
in 1,2-dichloroethane at 40 °C for 2 h) we carried out the reaction using various aryl carboxylic acids to
evaluate the applicability of the reaction (Table 2). In each reaction, 2-aroyl-1-methyl-1H-imidazoles
were obtained with satisfactory yields (Table 2). The difference between an electron-donating group
(6-methoxy-2-naphthoic acid, 3) and an electron-withdrawing group (6-acetoxy-2-naphthoic acid, 4) at
the 6-position of naphthoic acid did not cause an obvious difference in yields (Table 2, entries 1 and 2).
Among the naphthoic acid derivatives, unsubstituted 1 afforded the highest yield (65%, Table 1, entry 7).
On the other hand, with benzoic acid derivatives, an increase in the electron-withdrawing effect at the
4-position increased the yield to 48% with benzoic acid, 56% with 5-fluorobenzoic acid, and 80% with
4-nitrobenzoic acid (Table 2, entries 3-5).
In summary, we developed a new methodology for the synthesis of 2-aroyl-1-methyl-1H-imidazoles
using unmodified aryl carboxylic acids. This method was applicable to naphthoic acid and benzoic acid
derivatives with up to 80% yield.
EXPERIMENTAL
Melting points (mp) were determined on a Yanaco MP-3 instrument and are uncorrected. Infrared (IR)
1
spectra were recorded on a JASCO FT/IR 6100 spectrometer. H and 13C NMR spectra were recorded on
1
a JNM ECA-500 spectrometer. Chemical shifts for H NMR are reported in parts per million (ppm)
13
downfield from tetramethylsilane (TMS: δ 0.00 ppm) as an internal reference. Chemical shifts for C
NMR were reported in the scale relative to the NMR solvent (CDCl3: δ 77.0 ppm) as an internal reference.
High resolution mass spectra (HRMS) were recorded on a JEOL JMS-700 (FAB) and Bruker
micrOTOF-QII (ESI) spectrometer. Flash column chromatography was performed on Fuji Silysia silica
gel (PSQ 60B). Analytical thin layer chromatography (TLC) was performed on Merck precoated
analytical plates, 0.25 mm thick, silica gel 60 F254. All commercially available reagents and solvents were
used directly without further purification. All reactions were carried out under an argon atmosphere. MS
4A were dried in the following manner: MS 4A was placed in a round-bottom flask. MS 4A was heated in
a regular microwave for 1.5-2.0 min, and the flask was immediately evacuated. After being cooled to
room temperature, the flask was backfilled with argon. The above procedure was repeated three times.
Compound 2: To a solution of 2-naphthoic acid (1) (86 mg, 0.5 mmol), TsCl (381 mg, 2.0 mmol), and
MS 4A (ca. 0.8 g) in 1,2-dichloroethane (3.0 mL) was added i-Pr2NEt (523 μL, 3.0 mmol) at room
temperature. After the resulting mixture was stirred at room temperature for 30 min, N-methylimidazole
(239 μL, 3.0 mmol) was added to the reaction mixture. After stirring for 2 h at 40 °C, the reaction mixture
was quenched with saturated aqueous NH4Cl. The crude products were extracted with AcOEt. The
combined extracts were washed with saturated aqueous NaHCO3 and dried over anhydrous Na2SO4. The

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solvent was concentrated under reduced pressure and the residue was purified by flash column
chromatography (30% AcOEt in hexane) to give 2 (77 mg, 65%) as a pale yellow oil; IR (neat) 3058,
1
2957, 1638, 1466, 1401, 1274, 1236, 1162, 1118, 903, 781 cm–1; H NMR (500 MHz, CDCl3) δ 4.12 (s,
3H), 7.14 (s, 1H), 7.28 (s, 1H), 7.53 (ddd, J = 8.3, 7.0, 1.0 Hz, 1H), 7.59 (ddd, J = 8.3, 7.0, 1.0 Hz, 1H),
7.88 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 8.27 (dd, J = 8.5, 1.5 Hz, 1H),
13
8.99 (brs, 1H); C NMR (125 MHz, CDCl3) δ 36.4, 125.9, 126.4, 126.7, 127.6, 127.8, 128.3, 129.3,
129.9, 132.4, 133.3, 134.5, 135.4, 143.3, 183.9; HRMS (ESI) Calcd for C15H13N2O [M+H]+ 237.1022.
Found 237.1034.
Compound 8: According to the procedure described for 2, the reaction of 6-methoxy-2-naphthoic acid
(3) (101 mg, 0.5 mmol) was carried out to afford 8 (64 mg, 48%) as a white solid (solvent used for flash
column chromatography: 25% acetone in hexane); mp 83–85 °C; IR (KBr) 1618, 1475, 1389, 1268, 1212,
1
1166, 1142, 1024, 878 cm–1; H NMR (500 MHz, CDCl3) δ 3.96 (s, 3H), 4.11 (s, 3H), 7.13 (brs, 1H),
7.16-7.20 (m, 2H), 7.27 (brs, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 8.27 (dd, J = 8.5, 1.5
13
Hz, 1H), 8.94 (brs, 1H); C NMR (125 MHz, CDCl3) δ 36.3, 55.3, 105.6, 119.3, 126.5, 126.6, 126.7,
127.7, 129.1, 131.6, 132.4, 133.3, 137.1, 143.4, 159.7, 183.6; HRMS (FAB) Calcd for C16H15N2O2
[M+H]+ 267.1134. Found 267.1132.
Compound 9: According to the procedure described for 2, the reaction of 6-acetoxy-2-naphthoic acid (4)
(115 mg, 0.5 mmol) was carried out to afford 9 (74 mg, 50%) as a yellow solid (solvent used for flash
column chromatography: 25% acetone in hexane); mp 106–108 °C; IR (KBr) 1766, 1625, 1396, 1189,
1136, 1010, 888 cm–1; 1H NMR (500 MHz, CDCl3) δ 2.37 (s, 3H), 4.12 (s, 3H), 7.15 (brs, 1H), 7.28 (brs,
1H), 7.30 (dd, J = 9.0, 2.0 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 8.03 (d, J = 9.0 Hz,
13
1H), 8.30 (dd, J = 9.0, 2.0 Hz, 1H), 9.01 (brs, 1H); C NMR (125 MHz, CDCl3) δ 21.2, 36.4, 118.3,
121.7, 126.7, 126.8, 127.5, 129.2, 130.3, 131.5, 133.1, 134.4, 135.9, 143.2, 150.2, 169.2, 183.4; HRMS
(FAB) Calcd for C17H15N2O3 [M+H]+ 295.1083. Found 295.1073.
Compound 10: According to the procedure described for 2, the reaction of benzoic acid (5) (61 mg, 0.5
mmol) was carried out to afford 10 (45 mg, 48%) as pale yellow oil (solvent used for flash column
1
chromatography: 30% AcOEt in hexane); IR (neat) 1643, 1447, 1399, 1262, 1168, 902 cm–1; H NMR
(500 MHz, CDCl3) δ 4.08 (s, 3H), 7.10 (s, 1H), 7.23 (s, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.56 (t, J = 7.5 Hz,
13
1H), 8.26 (d, J = 7.5 Hz, 2H); C NMR (125 MHz, CDCl3) δ 44.5, 116.8, 117.8, 118.8, 120.0, 121.5,
125.2, 129.9, 162.7; HRMS (FAB) Calcd for C11H11N2O [M+H]+ 187.0871. Found 187.0868.
Compound 11: According to the procedure described for 2, the reaction of 4-fluorobenzoic acid (6) (70
mg, 0.5 mmol) was carried out to afford 11 (57 mg, 56%) as a yellow solid (solvent used for flash column
chromatography: 25% AcOEt in hexane); mp 63–66 °C; IR (KBr) 3050, 1649, 1599, 1397, 1268, 1214,
1
1152, 905, 774 cm–1; H NMR (500 MHz, CDCl3) δ 4.08 (s, 3H), 7.12 (s, 1H), 7.16 (t, J = 9.0 Hz, 2H),

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7.23 (s, 1H), 8.38 (dd, J = 9.0, 5.8 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 36.5, 115.1 (d, J = 21.5 Hz),
126.9, 129.3, 133.5 (d, J = 9.5 Hz), 142.9, 165.6 (d, J = 252.6 Hz), 182.3; HRMS (FAB) Calcd for
C11H10FN2O [M+H]+ 205.0777. Found 205.0779.
Compound 12: According to the procedure described for 2, the reaction of 4-nitrobenzoic acid (7) (84
mg, 0.5 mmol) was carried out to afford 12 (92 mg, 80%) as a yellow solid (solvent used for flash column
chromatography: CHCl3); mp 166–167 °C; IR (KBr) 3107, 1640, 1599, 1514, 1352, 1251, 1141, 906
cm–1; 1H NMR (500 MHz, CDCl3) δ 4.12 (s, 3H), 7.17 (d, J = 1.0 Hz, 1H), 7.27 (d, J = 1.0 Hz, 1H), 8.31
13
(d, J = 9.0 Hz, 2H), 8.45 (d, J = 9.0 Hz, 2H); C NMR (125 MHz, CDCl3) δ 36.6, 123.1, 127.8, 130.0,
131.7, 142.4, 142.5, 149.8, 181.9; HRMS (ESI) Calcd for C11H9N3O3Na [M+Na]+ 254.0536. Found
254.0544.
ACKNOWLEDGMENTS
This work was financially supported in part by a SUNBOR GRANT (Suntory Institute for Bioorganic
Research) and the Ministry of Education, Culture, Sports, Science and Technology, Japan (Global COE in
Chemistry, Nagoya University, Priority Areas No. 18032037, Creative Scientific Research (B) No.
24380062, and Young Scientists (B) No. 18780086).
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This paper is dedicated to Prof. Masakatsu Shibasaki on the occasion of his 70th birthday.
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