A novel multi-component reaction to imidazo[4,5-g]-quinazolines

Article abstract of DOI:10.3390/molecules18055697

The trace impurities discovered after extended storage of a 5-aminobenzimidazole library were determined as imidazo[4,5-g]quinazoline derivatives by extensive spectroscopic data analysis. The formation of this highly aromatic heterocyclic ring involved a

Full text of DOI:10.3390/molecules18055697

Molecules 2013, 18, 5697-5705; doi:10.3390/molecules18055697
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
A Novel Multi-Component Reaction to Imidazo[4,5-g]-quinazolines
Li Li 1,†,*, Qianqian Zhang 1,†, Bo Liu 1 and Gang Liu 2,*
1
Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation,
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College,
1 Xian Nong Tan Street, Beijing 100050, China; E-Mails: zhangqianqian@imm.ac.cn (Q.Z.);
liubo@imm.ac.cn (B.L.)
2
Tsinghua-Peking Center for Life Sciences and Department of Pharmacology and Pharmaceutical
Sciences, School of Medicine, Tsinghua University, Haidian District, Beijing 100084, China
†
These authors contributed equally to this work.
* Authors to whom correspondence should be addressed; E-Mails: annaleelin@imm.ac.cn (L.L.);
gangliu27@tsinghua.edu.cn (G.L.); Tel./Fax: +86-10-6316-5247 (L.L.).
Received: 19 April 2013; in revised form: 8 May 2013 / Accepted: 10 May 2013 /
Published: 16 May 2013
Abstract: The trace impurities discovered after extended storage of a 5-amino-
benzimidazole library were determined as imidazo[4,5-g]quinazoline derivatives by
extensive spectroscopic data analysis. The formation of this highly aromatic heterocyclic
ring involved a novel multi-component reaction, using which several novel compounds
were prepared. Its mechanism was deduced as a cascade of chemical transformations,
including the formation of a Schiff’s base, intramolecular hetero-Diels-Alder reaction,
defluorination and dehydrogenation.
Keywords: multi-component reaction; heterocyclic compounds; imidazo[4,5-g]-quinazoline;
structure determination; hetero Diels-Alder reaction
1. Introduction
Benzimidazole has been regarded as a privileged sub-structure in fragment-based drug design and
its derivatives have achieved great importance in pharmacology [1–4]. As a part of our program to
prepare versatile chemical libraries from 1,5-difluoro-2,4-dinitrobenzene (DFDNB), we have disclosed
a multistep parallel solution-phase synthesis of 5-aminobenzimidazole derivatives [5]. Then, a

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chemical library including 2,000 members was prepared. Most of the compounds showed high purity
in the quality control by high-performance liquid chromatography/electrospray ionization mass
spectroscopy (HPLC-ESIMS) method. However, it was found that trace impurities could often be
detected in the wells containing 1-substituted-6-fluoro-2-(pyridin-4-yl)-1H-benzo[d]imidazol-5-amines
(3, Scheme 1) after extended storage. All of them have positive mode MS peaks at 173 a.m.u. higher
than the corresponding normal products 3. This greatly stirred our interest in determining their
chemical structures and establishing their origin. A systematic study including structure identification
and chemical synthesis of these novel compounds was thus carried out and the results are presented here.
Scheme 1. Chemical pathway to compounds 412.
2. Results and Discussion
2.1. Structure Elucidation of the Trace Impurity
To obtain the trace impurity, the multi-step synthesis of 5-aminobenzimidazole derivatives was
first performed on a larger scale than for the library preparation. 4-Pyridinylaldehyde and
3-isopropoxypropyl-1-amine were used in the model reaction. When the content of the M+173
impurity 4 was more than 1% by HPLC-ESIMS analysis, it was isolated by silica column
chromatography. Then, its chemical structure was established by extensive spectroscopic data analysis.
Compound 4 was obtained as a yellow powder. Its molecular formula was determined as
C30H27N7O from the HRESIMS ion at m/z 502.2353 [M+H]+ (calcd. 502.2349), which indicated
21 degrees of unsaturation. Since the normal product 6-fluoro-1-(3-isopropoxypropyl)-2-(pyridin-4-
yl)-1H-benzo[d]imidazolyl-5-amine should have a molecular formula C18H21FN4O with 10 degrees of
unsaturation, three nitrogen atoms and 11 degrees of unsaturation should have been introduced in the
formation of compound 4. It was noticed that 4-pyridinecarbaldehyde was added in twice the amount
of reduction intermediate 2 and might still stay with compound 3, even after adequate washing with
aqueous sodium bicarbonate solution. Ammonia was also thought to be in the reaction mixture because
of its release from residual ammonium formate. Thus, two more pyridinyl groups and a new aromatic
ring containing an additional nitrogen atom were presumed to exist in the chemical structure of
compound 4 compared with 3.

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1
The H-NMR spectrum of 4 confirmed the existence of an alkyl chain, three pyridinyl rings and a
large conjugated aromatic ring. All signals in the high-field region could be attributed to the
3-isopropoxypropyl group. Six pairs of aromatic protons should be assigned to the three pyridinyl
rings. It was obvious that both signals of H-3 and H-6 appeared as singlets, which should be split into a
doublet because of heteronuclear coupling with the fluorine atom in compound 3 [5]. This indicated
13
the absence of a fluorine atom in 4, consistent with the HRESIMS results. The C-NMR and DEPT
spectra of 4 showed 30 signals, including two primary carbons, three secondary carbons, 15 tertiary
carbons and 10 quaternary carbons. These spectroscopic data suggested that 4 was a highly aromatic
heterocyclic compound. Thus, two possible chemical structures 4a and 4b were proposed for 4, which
differed in the positions of one aromatic nitrogen atom and one pyridinyl ring (Figure 1).
Figure 1. Two possible chemical structures of compound 4.
The structure of 4 was further determined by comprehensive 2D NMR data analysis. In the NOESY
spectrum, the correlation of H-6 with H-17 and H-18 indicated they were on the same side of the core
aromatic ring. Meanwhile, NOESY correlation of H-6 with H-19 was observed, revealing that they
were also on the same side and relatively close. In the optimized conformations of 4a and 4b using the
MMFF94 molecular mechanical force field, the distances between H-6 and H-19 were 2.30 and 4.41 Å,
respectively. This indicated that 4a was the right chemical structure of compound 4, which was further
confirmed by gCOSY, gHSQC and HMBC spectra. Therefore, the chemical structure of 4 was
established as 1-(3-isopropoxypropyl)-2,6,8-tri(pyridin-4-yl)-1H-imidazo[4,5-g]quinazoline.
2.2. Preparation of Imidazo[4,5-g]quinazoline Derivatives
Quinazolines represent a large family of compounds with significant pharmacological properties
and other industrial uses [6–8]. Many methods for preparing quinazolines have been reported in the
literature ([9,10], but to the best of our knowledge, there are no reports on the synthesis of 2,6,8-triaryl-
1H-imidazo[4,5-g]quinazoline derivatives). Thus, the chemical transformation from 6-fluoro-1H-
benzo[d]imidazol-5-amines to imidazo[4,5-g]quinazolines was investigated. Besides 4-pyridine
carbaldehyde, three kinds of 4-substituted benzaldehyde and thiophene-2-carbaldehyde were used to
give compounds 5–12 (Figure 2).

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Figure 2. Chemical structures of compounds 5–12.
Though no impurity was discovered in the wells of the counterpart in the 5-aminobenzimidazole
library, all aromatic aldehydes could give the anticipated product after prolonged heating. It was found
that the addition of ammonium hydroxide could promote the transformation, indicating that ammonia
might participate in the reaction as supposed above. When aliphatic 2-ethylbutanal was used, no
corresponding tricyclic product was detected. Meanwhile, it seemed that the substituents on the
nitrogen atom have little effect on the reactivity of the intermediate 3.
The experimental procedure was similar to that of the preparation of 5-aminobenzimidazole library
and performed in a sequential manner [5]. The reduction intermediate 2 was not purified and directly

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condensed with aldehyde to give condensation intermediate 3, which was further reacted with
additional aldehyde and ammonia. The total yield of the typical compound 4 might vary from 16.8% to
63.4% because of the instability of the key intermediate 2,4,5-benzenetriamines 2.
2.3. Possible Mechanism of the Novel Multi-Component Reaction
Multi-component reactions have attracted considerable interest for their high synthetic efficiency [11–13].
This novel multi-component reaction might involve the formation of a Schiff’s base, intramolecular
hetero Diels-Alder reaction, defluorination and dehydrogenation, as shown in Scheme 2. The loss of a
fluorine atom might be a little difficult to explain, but all the supposed intermediates could be detected
during the course of reaction. In the synthesis of 4 monitored by HPLC-ESIMS analysis, the main
component at 2 h was a 5-amino-6-fluorobenzimidazole derivative with a positive mode MS peak at
m/z 329.3. However, intermediates corresponding to positive mode MS peaks at 524.2, 506.2 and
504.2 appeared as the reaction progressed. In the end, a molecule corresponding to a positive mode MS
peak at m/z 502.2 was the final product. Thus, the proposed mechanism was supported by the
experimental evidence.
Scheme 2. Plausible mechanism of the multi-component reaction.
R2
R1
N
R1
F
Formation of
Schiff's base
F
NH
R2
N
CHO
+
R2
R2
+
R2
N
N
N
NH2
NH3
R2
R2
R1
N
R1
F
Diels-Alder
reaction
1) - F-
2) + H+
N
NH
R2
NH
R2
R2
R2
N
N
N
H
N
R2
R1
N
- 2H2
N
R2
N
N
R2
The hetero-Diels-Alder reaction has been regarded as one of the most convenient routes to
N-heterocycles and has been used in the synthesis of many natural products [14–17]. It was also
deduced as the key step in the present process, where the dienophile was the Schiff’s base formed
between ammonia and the aldehydes.
3. Experimental
3.1. General
All chemical reagents were of reagent grade and used as purchased. Auto HPLC-ESIMS analysis
was performed on a ThermoFinnigan, LCQ-Advantage mass spectrometer equipped with an Agilent

Molecules 2013, 18
5702
1100 HPLC system and a flow splitter. HPLC-HRESIMS were recorded on an Agilent 1100 series
1
LC/MSD trap mass spectrometer (ESI-TOF). H-NMR and 13C-NMR spectra were recorded on a
Mercury 300 or Inova 500 MHz NMR spectrometers equipped with an auto sampler. Infrared spectra
were recorded using KBr pellets on a Nicolet Impact 400 spectrometer. Flash column chromatography
was carried out on silica gel (200–300 mesh).
3.2. General Synthesis Procedure
To a solution of 0.5 mmol of the substituted dinitro compound 1 in tetrahydrofuran (8 mL) and
ethanol (8 mL), HCOONH4 (800 mg) and 10% Pd-C (100 mg) were added under stirring. When the
reaction mixture turned colorless, the catalyst and insoluble excess HCOONH4 were filtered off. The
filtrate was added directly into a solution of aldehyde (1.5 mmol) and glacial acetic acid (1.2 mL) in
tetrahydrofuran (4 mL). After stirring at room temperature overnight, the reaction mixture was heated
to 90 C for 36 h or longer. The reaction mixture was then evaporated to dryness, and the residue was
further purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether. For a
typical product, 1-(3-isopropoxypropyl)-2,6,8-tri(pyridin-4-yl)-1H-imidazo[4,5-g]-quinazoline (4),
159 mg of yellow powder was obtained (63.4% overall yield for three steps). M.p. > 300 C;
1H-NMR (500 MHz, DMSO-d6):  0.79 (6H, d, J = 6.5 Hz), 1.88 (2H, m), 3.16 (2H, m), 3.20 (1H, m),
4.55 (2H, t, J = 7.5 Hz), 7.94 (2H, d, J = 5.5 Hz), 7.97 (2H, d, J = 5.5 Hz), 8.28 (1H, s), 8.46 (2H, d,
J = 6.0 Hz), 8.56 (1H, s), 8.80 (2H, d, J = 5.5 Hz), 8.86 (2H, d, J = 5.5 Hz), 8.91 (2H, d, J = 5.5 Hz).
13C-NMR (125 MHz, DMSO-d6):  21.63 (2C), 29.37 (1C), 41.92 (1C), 63.42 (1C), 70.47 (1C),
106.90 (1C), 117.24 (1C), 117.91 (1C), 121.79 (2C), 123.53 (2C), 124.36 (2C), 136.80 (1C), 137.81
(1C), 144.70 (1C), 144.76 (1C), 146.40 (1C), 148.14 (1C), 150.18 (2C), 150.39 (2C), 150.45 (2C),
154.94 (1C), 158.06 (1C), 166.53 (1C). HRMS (ESI): m/z 502.2353 [M+H]+ (calcd 502.2349).
1-Pentyl-2,6,8-tri(pyridin-4-yl)-1H-imidazo[4,5-g]quinazoline (5): m.p. > 300 C; yield: 31.2%.
1H-NMR (300 MHz, DMSO-d6):  0.72 (3H, t, J = 6.6 Hz), 1.13 (4H, m), 1.69 (2H, m), 4.46 (2H, t,
J = 7.5 Hz), 7.90 (2H, d, J = 4.5 Hz), 7.97 (2H, d, J = 4.5 Hz), 8.28 (1H, s), 8.45 (2H, d, J = 4.5 Hz),
8.56 (1H, s), 8.80 (2H, d, J = 4.5 Hz), 8.87 (2H, d, J = 4.5 Hz), 8.91 (2H, d, J = 4.5 Hz). 13C-NMR (75
MHz, DMSO-d6):  13.58 (1C), 21.31 (1C), 27.98 (1C), 28.40 (1C), 44.33 (1C), 106.82 (1C), 117.16
(1C), 117.78 (1C), 121.68 (2C), 123.41 (2C), 124.35 (2C), 136.74 (1C), 137.50 (1C), 144.54 (1C),
144.62 (1C), 146.20 (1C), 147.94 (1C), 150.08 (2C), 150.33 (2C), 150.44 (2C), 154.77 (1C), 157.87
(1C), 166.30 (1C). HRMS (ESI): m/z 472.2249 [M+H]+ (calcd 472.2244).
1-(3-Isopropoxypropyl)-2,6,8-tris(4-methoxyphenyl)-1H-imidazo[4,5-g]quinazoline (6): m.p. > 300 C;
1
yield: 45.1%. H-NMR (300 MHz, CDCl3):  0.97 (6H, d, J = 6.3 Hz), 2.03 (2H, m), 3.28 (2H, m),
3.35 (1H, m), 3.90 (6H, s), 3.95 (3H, s), 4.46 (2H, t, J = 7.2 Hz), 7.04 (2H, d, J = 6.9 Hz), 7.08 (2H, d,
J = 6.9 Hz), 7.15 (2H, d, J = 6.9 Hz), 7.84 (2H, d, J = 8.7 Hz), 7.94 (2H, d, J = 8.7 Hz), 8.10 (1H, s),
13
8.51 (1H, s), 8.69 (2H, d, J = 8.7 Hz). C-NMR (125 MHz, CDCl3):  22.11 (2C), 30.37 (1C), 42.51
(1C), 55.60 (1C), 55.70 (2C), 64.27 (1C), 71.89 (1C), 106.20 (1C), 114.02 (2C), 114.31 (2C), 114.62
(2C), 116.93 (2C), 118.27 (2C), 122.08 (1C), 130.38 (2C), 131.31 (2C), 131.49 (1C), 131.92 (2C),
136.95 (1C), 148.24 (1C), 158.08 (1C), 160.04 (1C), 161.27 (1C), 161.67 (1C), 161.81 (1C), 167.81
(1C). HRMS (ESI): m/z 589.2815 [M+H]+ (calcd 589.2809).

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2,6,8-Tris(4-fluorophenyl)-1-(3-isopropoxypropyl)-1H-imidazo[4,5-g]quinazoline (7): m.p. > 300 C;
yield: 48.3%. 1H-NMR (300 MHz, DMSO-d6):  0.97 (6H, d, J = 6.0 Hz), 2.02 (2H, m), 3.29 (2H, m),
3.35 (1H, m), 4.45 (2H, t, J = 7.2 Hz), 7.21 (6H, m), 7.93 (4H, m), 8.06 (1H, s), 8.56 (1H, s), 8.72 (2H,
13
m). C-NMR (100 MHz, DMSO-d6):  21.61 (2C), 29.31 (1C), 41.75 (1C), 63.43 (1C), 70.47 (1C),
106.75 (1C), 115.40 (1C), 115.60 (1C), 115.86 (1C), 115.90 (1C), 115.96 (1C), 116.12 (1C), 117.33
(1C), 125.95 (2C, d, J = 2 Hz), 130.22 (2C, d, J = 9 Hz), 132.33 (2C, d, J = 9 Hz), 134.26 (2C, d, J = 2 Hz),
134.31 (2C, d, J = 2 Hz), 137.09 (1C), 146.71 (1C), 148.02 (1C), 155.72 (1C), 159.15 (1C), 163.24
(1C, d, J = 246 Hz), 163.47 (1C, d, J = 248 Hz), 163.70 (1C, d, J = 246 Hz), 167.00 (1C). HRMS
(ESI): m/z 553.2215 [M+H]+ (calcd 553.2211).
1-(3-Isopropoxypropyl)-2,6,8-tri(thiophen-2-yl)-1H-imidazo[4,5-g]quinazoline (8): m.p. > 300 C;
1
yield: 28.5%. H-NMR (300 MHz, CDCl3):  1.08 (6H, d, J = 6.0 Hz), 2.22 (2H, m), 3.46 (2H, m),
3.50 (1H, m), 4.68 (2H, t, J = 7.5 Hz), 7.21 (1H, d, J = 4.8 Hz), 7.25 (1H, d, J = 4.8 Hz), 7.32 (1H, d,
J = 5.1 Hz), 7.51 (1H, d, J = 4.8 Hz), 7.65 (1H, d, J = 5.1 Hz), 7.69 (1H, d, J = 4.5 Hz), 7.93 (1H, d,
13
J = 3.3 Hz), 8.00 (1H, d, J = 3.3 Hz), 8.25 (1H, s), 8.48 (2H, s). C-NMR (125 MHz, DMSO-d6): 
22.10 (2C), 30.16 (1C), 41.48 (1C), 63.06 (1C), 70.13 (1C), 107.15 (1C), 119.25 (1C), 120.53 (1C),
125.16 (1C), 126.57 (1C), 127.95 (1C), 128.49 (1C), 129.05 (1C), 135.29 (1C), 136.91 (1C), 143.84
(1C), 143.62 (1C), 146.08(1C), 146.35 (1C), 146.82 (1C), 146.91 (1C), 149.05 (1C), 150.11 (1C),
155.04 (1C), 157.64 (1C), 167.42 (1C). HRMS (ESI): m/z 517.1190 [M+H]+ (calcd 517.1185).
1-(3-Isopropoxypropyl)-2,6,8-tris(4-nitrophenyl)-1H-imidazo[4,5-g]quinazoline (9): m.p. > 300 C;
yield: 23.9%. 1H-NMR (300 MHz, DMSO-d6):  0.77 (6H, d, J = 6.6 Hz), 1.86 (2H, m), 3.15 (2H, m),
3.22 (1H, m), 3.88 (6H, s), 3.92 (3H, s), 4.48 (2H, m), 7.35 (2H, d, J = 7.2 Hz), 7.49 (2H, d, J = 7.2 Hz),
8.01 (2H, d, J = 7.2 Hz), 8.26 (2H, d, J = 7.2 Hz), 8.46 (1H, s), 8.55 (2H, d, J = 7.2 Hz), 8.67 (1H, s),
8.90 (2H, d, J = 7.2 Hz). 13C-NMR (75 MHz, DMSO-d6):  23.04 (2C), 30.98 (1C), 42.19 (1C), 64.27
(1C), 75.21 (1C), 107.29 (1C), 116.38 (1C), 116.72 (1C), 117.19 (1C), 117.56 (1C), 119.12 (1C),
123.84 (2C), 124.08 (2C), 129.47 (2C), 130.47 (2C), 137.35 (2C), 137.69 (1C), 137.98 (2C), 142.18
(1C), 150.55 (1C), 161.01 (1C), 161.84 (1C), 162.61 (1C), 163.09 (1C), 164.16 (1C), 170.62 (1C).
HRMS (ESI): m/z 634.2049 [M+H]+ (calcd 634.2045).
1-(tert-Pentyl)-2,6,8-tri(pyridin-4-yl)-1H-imidazo[4,5-g]quinazoline (10): m.p. > 300 C; yield: 53.7%.
1H-NMR (300 MHz, DMSO-d6):  0.67 (3H, t, J = 7.2 Hz), 1.49 (6H, s), 2.05 (2H, m), 3.41 (6H, s),
3.44 (3H, s), 7.90 (2H, d, J = 4.5 Hz), 7.95 (2H, d, J = 4.5 Hz), 8.21 (1H, s), 8.43 (2H, d, J = 4.5 Hz),
8.50 (1H, s), 8.83 (2H, d, J = 4.5 Hz), 8.81 (2H, d, J = 4.5 Hz), 8.90 (2H, d, J = 4.5 Hz). 13C-NMR (75 MHz,
DMSO-d6):  8.15 (1C), 29.22 (2C), 33.26 (1C), 61.15 (1C), 106.90 (1C), 117.19 (1C), 117.83 (1C),
121.28 (2C), 123.06 (2C), 124.13 (2C), 136.42 (1C), 137.39 (1C), 144.01 (1C), 144.48 (1C), 146.10
(1C), 147.69 (1C), 150.32 (2C), 150.43 (2C), 150.95 (2C), 154.70 (1C), 157.64 (1C), 166.15 (1C).
HRMS (ESI): m/z 472.2247 [M+H]+ (calcd 472.2244).
2,6,8-Tris(4-methoxyphenyl)-1-(tert-pentyl)-1H-imidazo[4,5-g]quinazoline (11): m.p. > 300 C; yield:
41.8%. 1H-NMR (300 MHz, CDCl3):  0.56 (3H, t, J = 7.5 Hz), 1.46 (6H, s), 2.02 (2H, m), 3.78 (6H,
s), 3.80 (3H, s), 7.03 (2H, d, J = 7.2 Hz), 7.07 (2H, d, J = 7.2 Hz), 7.12 (2H, d, J = 7.2 Hz), 7.78 (2H,
d, J = 7.2 Hz), 7.89 (2H, d, J = 8.4 Hz), 8.09 (1H, s), 8.50 (1H, s), 8.64 (2H, d, J = 8.4 Hz). 13C-NMR

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(125 MHz, CDCl3):  8.09 (1C), 29.14 (2C), 33.17 (1C), 55.14 (1C), 55.57 (2C), 61.19 (1C), 106.18
(1C), 114.05 (2C), 114.26 (2C), 114.65 (2C), 116.28 (2C), 118.01 (2C), 121.95 (1C), 130.16 (2C),
131.09 (2C), 131.32 (1C), 131.83 (2C), 136.90 (1C), 148.12 (1C), 158.00 (1C), 160.07 (1C), 161.05
(1C), 161.59 (1C), 161.72 (1C), 167.56 (1C). HRMS (ESI): m/z 559.2708 [M+H]+ (calcd 559.2704).
1
2,6,8-Tri(pyridin-4-yl)-1H-imidazo[4,5-g]quinazoline (12): m.p. > 300 C; yield: 27.2%. H-NMR
(300 MHz, DMSO-d6):  7.93 (2H, d, J = 4.8 Hz), 7.99 (2H, d, J = 4.8 Hz), 8.26 (1H, s), 8.49 (2H, d,
J = 4.8 Hz), 8.54 (1H, s), 8.81 (2H, d, J = 4.8 Hz), 8.86 (2H, d, J = 4.8 Hz), 8.92 (2H, d, J = 4.8 Hz),
11.90 (1H, s). 13C-NMR (75 MHz, DMSO-d6):  106.78 (1C), 117.01 (1C), 117.69 (1C), 121.57 (2C),
123.28 (2C), 124.21 (2C), 136.56 (1C), 137.47 (1C), 144.29 (1C), 144.53 (1C), 146.16 (1C), 147.88
(1C), 150.26 (2C), 150.41 (2C), 150.49 (2C), 154.69 (1C), 157.76 (1C), 166.19 (1C). HRMS (ESI):
m/z 402.1459 [M+H]+ (calcd 402.1462).
4. Conclusions
In conclusion, a novel multi-component reaction, which led to the formation of the unexpected trace
impurities detected in a 5-aminobenzimidazole chemical library after extended storage, has been
investigated. The possible reaction mechanism is thought to involve a cascade of chemical
transformations, with the key step being a hetero Diels-Alder reaction. Its application to the
preparation of other 6-halo-1H-benzo[d] imidazol-5-amines and ortho-haloanilines will be fully
investigated in the future.
Acknowledgments
This study was financially supported by the Natural Sciences Foundation of China (No. 81001365).
Conflict of Interest
The authors declare no conflict of interest.
References
1. Rees, D.C.; Congreve, M.; Murray, C.W.; Carr, R. Fragment-based lead discovery. Nat. Rev.
Drug Discov. 2004, 3, 660–672.
2. Murray, C.W.; Rees, D.C. The rise of fragment-based drug discovery. Nat. Chem. 2007, 1, 187–192.
3. Miller, J.F.; Turner, E.M.; Gudmundsson, K.S.; Jenkinson, S.; Spaltenstein, A.; Thomson, M.;
Wheelan, P. Novel N-substituted benzimidazole CXCR4 antagonists as potential anti-HIV agents.
Bioorg. Med. Chem. Lett. 2010, 20, 2125–2128.
4. Kumar, K.; Awasthi, D.; Lee, S.Y.; Zanardi, I.; Ruzsicska, B.; Knudson, S.; Tonge, P.J.;
Slayden, R.A.; Ojima, I. Novel trisubstituted benzimidazoles, targeting Mtb FtsZ, as a new class
of antitubercular agents. J. Med. Chem. 2011, 54, 374–381.
5. Li, L.; Liu, G.; Wang, Z.G.; Yuan, Y.Y.; Zhang, C.X.; Tian, H.Y.; Wu, X.H.; Zhang, J. Multistep
parallel synthesis of substituted 5-aminobenzimidazoles in solution phase. J. Comb. Chem. 2004,
6, 811–821.

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6. Rohini, R.; Reddy, M.; Shanker, K.; Hu, A.; Ravinder, V. Antimicrobial study of newly
synthesized 6-substituted indolo[1,2-c]quinazolines. Eur. J. Med. Chem. 2010, 45, 1200–1205.
7. Marzaro, G.; Guiotto, A.; Chillin, A. Quinazoline derivatives as potential anticancer agents:
A patent review (2007–2010). Expert Opin. Ther. Pat. 2012, 22, 223–252.
8. Marson, C.M. Targeting the histamine H4 receptor. Chem. Rev. 2011, 111, 7121–7156.
9. Chioua, R.; Benabdelouahab, F.; Chioua, M.; Martínez-Alvarez, R.; Fernández, A.H. Synthesis of
novel quinazoline derivatives via pyrimidine ortho-quinodimethane. Molecules 2002, 7, 507–510.
10. Ohta, Y.; Tokimizu, Y.; Oishi, S.; Fujii, N.; Ohno, H. Direct synthesis of quinazolines through
copper-catalyzed reaction of aniline-derived benzamidines. Org. Lett. 2010, 12, 3963–3965.
11. Weber, L. Multi-component reactions and evolutionary chemistry. Drug Discov. Today 2002, 7,
143–147.
12. Kumar, A.; Sharma, S.; Maurya, R.A. A novel multi-component reaction of indole, formaldehyde,
and tertiary aromatic amines. Tetrahedron Lett. 2009, 50, 5937–5940.
13. D’Souza, D.M.; Muller, T.J.J. Multi-component syntheses of heterocycles by transition-metal
catalysis. Chem. Soc. Rev. 2007, 36, 1095–1108.
14. Tietze, L.F. Domino-reactions: The tandem-knoevenagel-hetero-diels-alder reaction and its
application in natural product synthesis. J. Heterocyclic Chem. 1990, 27, 47–69.
15. Zhou, S.L.; Li, J.L.; Dong, L.; Chen, Y.C. Organocatalytic sequential hetero-Diels-Alder and
Friedel-Crafts reaction: constructions of fused heterocycles with scaffold diversity. Org. Lett.
2011, 13, 5874–5877.
16. Powell, D.A.; Batey, R.A. Total synthesis of the alkaloids martinelline and martinellic acid via a
hetero Diels-Alder multicomponent coupling reaction. Org. Lett. 2002, 4, 2913–2916.
17. Twin, H.; Batey, R.A. Intramolecular hetero Diels-Alder (Povarov) approach to the synthesis of
the alkaloids luotonin A and camptothecin. Org. Lett. 2004, 6, 4913–4916.
Sample Availability: Samples of the compounds 4–12 are available form the authors.
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