One-pot regioselective synthesis of imidazole and 2,3-dihydroquinazolinone derivatives - An easy access to 'nature-like molecules'; Part XIII in the series: 'Studies on novel synthetic methodologies'

Article abstract of DOI:10.1055/s-0033-1339466

A mild and highly practical regioselective synthesis of imidazole and 2,3-dihydroquinazolinone derivatives from 5-alkyl-4-hydroxyisophthalaldehydes with suitable substrates in acetic acid is reported. Further exploration of the molecular diversity of 2,3-dihydroquinazolinone is demonstrated by the synthesis of diverse pharmacologically relevant natural-product-like scaffolds. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1339466

LETTER
▌1795
letter
One-Pot Regioselective Synthesis of Imidazole and 2,3-Dihydroquinazolinone
Derivatives – An Easy Access to ‘Nature-Like Molecules’; Part XIII in the
Series: ‘Studies on Novel Synthetic Methodologies’
Imidazole and 2,3-Dihydroquinazolinone Derivatives
Koneni V. Sashidhara,*a Gopala Reddy Palnati,a Ranga Prasad Dodda,a Srinivasa Rao Avula,a Priyanka Swamib
a
Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR-CDRI, Lucknow 226 001, India
Fax +91(522)2623405; E-mail: sashidhar123@gmail.com; E-mail: kv_sashidhara@cdri.res.in
b
Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli 229 010, India
Received: 15.04.2013; Accepted after revision: 21.06.2013
multicomponent reactions is whether their selectivity is
Abstract: A mild and highly practical regioselective synthesis of
chemo- or regioselective or both, due to the several possi-
imidazole and 2,3-dihydroquinazolinone derivatives from 5-alkyl-
ble parallel reaction pathways, which result in the forma-
4-hydroxyisophthalaldehydes with suitable substrates in acetic acid
is reported. Further exploration of the molecular diversity of 2,3-di-
tion of different products.8 Many factors modulate the
hydroquinazolinone is demonstrated by the synthesis of diverse selectivity of synthetic transformations, such as tempera-
ture, pressure, solvent, and catalyst.9 Addressing these re-
pharmacologically relevant natural-product-like scaffolds.
quirements with the choice of appropriate reaction
conditions is often a challenge.
Key words: one-pot synthesis, regioselective synthesis, imidazole,
2,3-dihydroquinazolinone, 5-alkyl-4-hydroxyisophthalaldehydes,
nature-like molecules
O
N
OMe
N
H
H2N
Br
Imidazole and 2,3-dihydroquinazolinone derivatives are
an important class of highly cited heterocyclic moieties as
they are key skeletons in many biologically active natural
products like oroidin, kealiinine A, evodiamine, as well as
numerous pharmacologically interesting compounds, as
exemplified by fenquizone.1 Moreover, 2,3-dihydroquin-
azolinone derivatives can be easily oxidized to their quin-
azolin-4(3H)-one analogues, which occur in several
natural products like rutaecarpine2 and luotonin F.3 Figure
1 shows chemical structures of some pharmaceuticals and
natural products that contain the imidazole and 2,3-dihy-
droquinazolinone skeletons in their molecular make-up.
HN
HN
Br
OH
N
N
oroidin1b
H2N
OMe
O
Me
N
kealiinine A1c
N
N
H
Me
H
N
evodiamine1d
Cl
HN
O
In general, the conventional literature approaches for the
synthesis of these scaffolds involve the use of multistep
reaction sequences. These are typically associated with
low yields, high cost, and tedious isolation of the resulting
products thereby their approach seldom becomes com-
mercially viable. The use of multicomponent reactions
(MCR) has become a modern approach to synthesize such
novel compounds of biological significance.4 The MCR
strategy, where three or more simple and flexible mole-
cules are brought together to rapidly introduce structural
complexity and diversity, offers significant advantages
over conventional linear-type syntheses.5 Moreover, di-
versity-oriented synthesis (DOS) is an important area of
research in synthetic organic chemistry to address the de-
mand posed by chemical biology programs for a huge
number of small molecules.6 DOS has many advantages
including accessible complexity of molecules, consecu-
tive reaction patterns, high reaction rate, efficiency, and
minimal environmental impact.7 An unresolved issue in
S
NH2
O
N
O
O
fenquizone1e
N
O
H
O
HN
N
rutaecarpine2
N
N
luotonin F3
Figure 1 Some marketed drugs and natural products with imidazole
and 2,3-dihydroquinazolinone core skeletons
Integrating the strategies of DOS10 into the realm of MCR
in acetic acid11 can be visualized as an elegant synthetic
approach to achieve diverse molecular skeletons. In con-
nection with our continuing studies on the development of
one-pot MCR to synthesize biologically important hetero-
cyclic scaffolds,12 herein we present a straightforward
convergent one-pot synthesis of imidazole and 2,3-dihy-
droquinazolinone in acetic acid. We have created skeletal
diversity and complexity by integrating the single reactant
SYNLETT 2013, 24, 1795–1800
Advanced online publication: 01.08.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339466; Art ID: ST-2013-D0338-L
© Georg Thieme Verlag Stuttgart · New York

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K. V. Sashidhara et al.
LETTER
replacement13 (SRR) strategy with MCR. The 5-alkyl-4- lective product, a series of solvents like DCM, DMF,
hydroxyisophthalaldehyde derivatives can be considered DMSO, AcOH, 1,4-dioxane, and H2O (Table 1, entries 2–
as the SRR variant of imidazoles and 2,3-dihydroquinaz- 7) were investigated. However, to our delight, the reaction
olinones. The key starting material, that is, 5-alkyl-4-hy- efficiency was greatly improved in acetic acid (Table 1,
droxyisophthalaldehydes (1a–g) required for our study entry 5) at 110 °C and the desired product 4b was ob-
were prepared from commercially available 2-alkyl phe- tained in 85% yield,15 subsequent increase and decrease in
nols following a reported Duff formylation reaction.
temperature did not enhance the reaction yield any further
(Table 1, entries 8 and 9). Next we looked at reaction time
(Table 1, entries 10 and 11) and best results were obtained
at 4.0 hours. Further efforts to improve the yield of 4b
were unsuccessful, when the reaction was performed in a
mixture of acetic acid and water (Table 1, entries 12–14).
Our approach toward the design and development of new
MCR involves the use of well-known difference in reac-
tivity between the two aldehydic groups in aromatic dial-
dehydes such as 1b. To find the optimized reaction
conditions for the synthesis of our designed strategy, a
systematic study considering different variables affecting To confirm the regioselectivity and to now bring the free
the reaction yield was carried out for the reaction of 5-eth- hydroxyl and the aldehyde group into reaction we em-
yl-4-hydroxyisophthalaldehyde (1b), ammonium acetate ployed the Knoevenagel condensation on 4a by reacting
(2), and 4,4′-dimethoxybenzil (3, molar ratio = 1:1.5:1) as with diethyl malonate in ethanol (Scheme 1).16 Pleasingly,
the model reaction. The conditions of temperature and the Knoevenagel product 6 was obtained in 80% yield. In
time were also optimized to produce compound 4b. The the 1H NMR spectrum of 6 the disappearance of both sig-
results are summarized in Table 1. Initially, the reaction nals at δ = 11.01 and 10.14 ppm and the presence of a sin-
was carried out in ethanol at 90 °C (Table 1, entry 1), this glet at δ = 8.72 ppm, a quartet at δ = 4.29 ppm, and a triplet
afforded the desired product in 45% yield and other un- at δ = 1.31 ppm confirmed the regioselective synthesis
identified products.14 To improve the yield of the regiose- and the formation of coumarin derivative. The ESI-MS
Table 1 Optimization of the Reaction Conditionsa
OMe
MeO
Et
OH
N
NH
Et
CHO
OH
CHO
O
conditions
MeCOONH4
+
+
O
CHO
MeO
1b
2
3
4b
MeO
Entry
Solvent
EtOH
Temp (°C)
Time (h)
Yield (%)b
1
2
90
90
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
4.0
3.0
5.0
5.0
5.0
45
35
30
30
85
40
30
85
56
85
80
60
73
80
CH2Cl2
DMF
3
110
110
110
110
100
130
90
4
DMSO
AcOH
1,4-dioxane
H2O
5
6
7
8
AcOH
AcOH
AcOH
AcOH
9
10
11
12
13
14
110
110
100
100
110
AcOH–H2O (5:5)
AcOH–H2O (7:3)
AcOH–H2O (9:1)
a 5-Ethyl-4-hydroxyisophthalaldehyde (1b, 1.0 mmol), NH4OAc (2, 1.5 mmol), 4,4′-dimethoxybenzil (3, 1.0 mmol), and solvent (3 mL).
b Yields after purification by column chromatography (EtOAc–hexane, 2:8).
Synlett 2013, 24, 1795–1800
© Georg Thieme Verlag Stuttgart · New York

LETTER
Imidazole and 2,3-Dihydroquinazolinone Derivatives
1797
MeO
MeO
Me
Me
O
O
N
N
i
O
OH
CHO
+
EtO
OEt
N
O
H
N
H
MeO
O
MeO
4a
5
6
EtO
Scheme 1 Synthesis of 6 from 4a. Reagents and conditions: (i) piperidine (cat.), EtOH, 80 °C, 1 h.
spectrum gave a molecular ion peak at m/z = 511 [M + A plausible mechanism for the formation of 2,4,5-triaryl
H]+, indicating the formation of the required product. It is imidazoles is shown in Scheme 3.17 The first step is the
rational to hypothesize that the observed regioselectivity formation of a diamine intermediate I via nucleophilic at-
is due to the presence of the hydroxyl group α to the alde- tack of ammonia, derived from NH4OAc (2) on the self-
hyde and will better stabilize (chelation) the benzenoid activated carbonyl group of aldehyde 1a. Next, the 4,4′-
rather than the quinoid form under the given reaction con- dimethoxybenzil (3) condenses with the intermediate I, in
ditions.
the presence of acetic acid, to form the intermediate II,
which undergoes cyclization, dehydration, and finally re-
arranges to a trisubstituted imidazole 4a by a [1,5]-hydro-
gen shift.
Under the optimized reaction conditions, the generality of
the reaction was investigated by using 5-alkyl-4-hydroxy-
isophthalaldehydes 1a–g and a variety of imidazoles were
synthesized in excellent yields, which underscores the ef- Encouraged by the success of the above reactions and to
ficiency of the present methodology (Scheme 2).
explore further the synthetic utility of 5-alkyl-4-hydroxy-
isophthalaldehydes, the methodology was extended to-
OMe
MeO
R
MeO
OH
N
N
R
CHO
OH
CHO
O
OH
CHO
i
O
+
MeCOONH4
+
NH
N
H
CHO
MeO
MeO
1a–g
2
3
4a R = Me 84%
4b R = Et 85%
4c R = Pr 85%
4d R = i-Pr 84%
4g 84%
OMe
4e R = t-Bu 83%
4f R = s-Bu 84%
Scheme 2 Reaction of 5-alkyl-4-hydroxyisophthalaldehydes 1a–g with NH4OAc (2) and 4,4′-dimethoxy benzil (3). Reagents and conditions:
(i) AcOH, 110 °C, 4 h; yields after purification by column chromatography (EtOAc–hexane, 2:8).
MeO
OH
OH
Me
CHO
O
Me
CHO
+
MeCOOH
O
MeCOONH4
+
CHO
H2N
NH2
3
2
I
1a
OMe
OMe
– 2H2O
OMe
OHC
HO
OHC
HO
N
N
N
H
N
H
Me
Me
4a
II
OMe
OMe
Scheme 3 Plausible mechanism for the formation of trisubstituted imidazole derivatives
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1795–1800

1798
K. V. Sashidhara et al.
LETTER
R
Me
O
O
O
OH
N
Me
R
CHO
N
OH
CHO
i
O
+
MeNH2
+
NH
N
H
N
H
O
CHO
OH
1a–g
7
8
9a R = Me 80%
9b R = Et 80%
9c R = Pr 78%
9d R = i-Pr 78%
9e R = t-Bu 76%
9f R = s-Bu 75%
9g 75%
CHO
Scheme 4 Reaction of 5-alkyl-4-hydroxyisophthalaldehydes 1a–g with methylamine (7) and isataoic anhydride (8). Reagents and conditions:
(i) AcOH, 110 °C, 2.0 h; yields after purification by column chromatography (CH2Cl2–hexane, 4:6).
wards the synthesis of 2,3-dihydroquinazolinones by azolinone
derivatives
from
5-alkyl-4-
substituting 4,4′-dimethoxybenzil with isataoic anhydride hydroxyisophthalaldehydes. This methodology has the
under similar reaction conditions. Also the replacement of advantage of good yields, high regioselectivity, and em-
ammonium acetate with methylamine, as the nitrogen ploys readily accessible substrates.
source, gave the desired product in good yield and shorter
To illustrate the utility of these synthons, the diversity-ori-
reaction time (2.0 h).18 A variety of 2,3-dihydroquinazolin-
ented synthesis on the 2,3-dihydroquinazolinone scaffold
ones were successfully synthesized, and the results are
was undertaken to afford various analogues in a straight-
summarized in Scheme 4.
forward way (Scheme 6). Thus, the Knoevenagel conden-
On the basis of these results, a mechanistic proposal for sation on synthon 9a resulted in the formation of its
the formation of 2,3-dihydroquinazolinone derivatives is coumarin derivatives (Scheme 6, a),16 while the 3-aryl-
outlined in Scheme 5.12a,d,19 The transformation begins coumarins were easily obtained by the condensation of 9a
with the intermediate I, which is generated in situ by nu- and phenylacetic acid derivatives promoted by cyanuric
cleophilic ring opening of isataoic anhydride (8) with me- chloride in DMF (Scheme 6, b).12b The benzofuran core
thylamine (7). Subsequent reaction with aromatic was synthesized by treatment of quinazolinone 9a with
dialdehyde 1a gives regioselective imine II, which under- phenacyl bromide derivatives in acetonitrile and K2CO3
goes intramolecular cyclization to form the desired 2,3-di- as a base (Scheme 6, c),20 furthermore ketoenamines were
hydroquinazolinone 9a.
obtained by the reaction of 9a and aniline derivatives in
ethanol (Scheme 6, d).21 The structures of the synthesized
compounds were unambiguously confirmed using 1H
NMR, 13C NMR, and 2D NMR spectroscopy (please refer
to the Supporting Information). The purity of these com-
pounds was ascertained by TLC and spectral analysis.
The strategies described in Scheme 2 and 4 provided us
with an easy access to a diverse set of imidazole and 2,3-
dihydroquinazolinone derivatives in one pot. To the best
of our knowledge this constitutes the first example of re-
gioselective synthesis of imidazoles and 2,3-dihydroquin-
Me
O
NH2
N
7
H
H
O
MeCOOH
N
Me
Me
NH
O
HO
– CO2
N
O
NH2
O
H
O
8
I
Me
OH
CHO
OHC
1a
Me
NH
O
Me
Me
O
N
N
OH
CHO
N
H
Me
II
OHC
OH
9a
Scheme 5 Plausible mechanism for the formation of 2,3-dihydroquinazolinone derivatives
Synlett 2013, 24, 1795–1800
© Georg Thieme Verlag Stuttgart · New York

LETTER
Imidazole and 2,3-Dihydroquinazolinone Derivatives
1799
Me
Me
O
O
Me
N
Me
N
O
O
O
O
O
R
NH
O
NH
RO
RO
O
O
R
OR
OH
11a R = 4-Me 82%
11b R = 4-OMe 83%
11c R = 2-Cl 82%
a
10a R = OMe 80%
10b R = OEt 80%
b
O
Me
N
Me
OH
N
H
R
R
NH2
O
CHO
Br
c
Me
d
Me
O
N
O
Me
Me
O
O
N
R
NH
NH
NH
O
R
12a R = 4-Me 75%
12b R = 4-Cl 78%
13a R = 4-Me 82%
13b R = 4-Cl 81%
Scheme 6 Access to nature-like molecules by diversity-oriented synthesis on the 2,3-dihydroquinazolinone synthon 9a. Reagents and condi-
tions: (a) piperidine (cat)., EtOH, 80 °C, 1.0 h; (b) cyanuric chloride, NMM, DMF, 110 °C, 1.0 h; (c) K2CO3, MeCN, reflux, 4.0 h; (d) EtOH,
r.t., 15 min.
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In conclusion, we report a practical and easy approach for
regioselective synthesis of imidazole and 2,3-dihydro-
quinazolinone in an efficient and convergent one-pot
MCR sequence. In addition, the synthons illustrates an ex-
ample of diversity-oriented synthesis of nature-like mole-
cules. One of the major advantages of this protocol is the
ease with which one can explore the chemical diversity
around the scaffold. This transformation will be of great
importance to medicinal chemists to generate a library of
pharmacologically relevant molecular scaffolds.
(3) (a) Zhu, Y. P.; Fei, Z.; Liu, M. C.; Jia, F. C.; Wu, A. X. Org.
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Acknowledgment
The authors are grateful to the Director, CDRI, Lucknow, India for
constant encouragement, S.P. Singh for technical support, SAIF for
NMR, IR, and MS data. G.R.P, R.P.D. and A.S.R. are thankful to
CSIR, New Delhi, India, and P.S. is thankful to the Department of
Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govern-
ment of India. This is CDRI communication number 8480.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
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LETTER
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CHCl3 (2 × 25 mL). The combined extracts were dried over
Na2SO4 and dried under high vacuum to afford the crude
product. It was subjected to further purification by column
chromatography (silica 100–200) using 20% EtOAc–hexane
as eluent. The desired product 4b was obtained as a yellow
solid; yield 85%; mp 135–137 °C. IR (KBr): 3527, 3010,
2964, 1660, 1239, 1032 cm–1. 1H NMR (300 MHz, DMSO-
d6): δ = 12.51 (s, 1 H), 11.09 (s, 1 H), 10.12 (s, 1 H), 8.30 (d,
J = 2.1 Hz, 1 H), 8.18 (d, J = 2.0 Hz, 1 H), 7.45 (d, J = 8.6
Hz, 4 H), 7.00–6.89 (m, 4 H), 3.78 (s, 3 H), 3.77 (s, 3 H),
2.70 (q, J = 7.4 Hz, 2 H), 1.23 (t, J = 7.4 Hz, 3 H). 13C NMR
(75 MHz, DMSO-d6): δ = 197.7, 159.0, 144.9, 133.4, 133.2,
129.8, 128.2, 123.6, 121.7, 115.0, 114.7, 56.0, 22.8, 14.6.
ESI-MS: m/z = 429 [M + H]+.
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(18) General Procedure for the Preparation of 9c via MCR
A mixture of 4-hydroxy-5-propylisophthalaldehyde (1c, 1.0
mmol), methylamine (7, 1.5 mmol), and isatoicanhydride (8,
1.0 mmol) in AcOH (5.0 mL) was stirred in a round-bottom
flask for 2.0 h at 110 °C (initially effervescence was
observed due to the generation of CO2 gas). Upon
completion of the reaction, the reaction mixture was diluted
with H2O (25 mL), followed by extraction with CHCl3
(2 × 25 mL). The combined organic phases were dried over
anhyd Na2SO4 and concentrated in vacuo. The crude product
was purified by column chromatography on silica gel (100–
200) in 40% CH2Cl2–hexane solvent system. The required
compound was obtained as a white solid; yield 78%; mp
173–175 °C. IR (KBr): 3516, 3412, 3015, 2934, 1650, 1190,
1042 cm–1. 1H NMR (300 MHz, CDCl3): δ = 11.39 (s, 1 H),
9.84 (s, 1 H), 7.96 (d, J = 7.7 Hz, 1 H), 7.48 (s, 1 H), 7.42 (s,
1 H), 7.31–7.28 (m, 1 H), 6.90–6.85 (m, 1 H), 6.59 (d,
J = 7.8 Hz, 1 H), 5.72 (s, 1 H), 4.59 (s, 1 H), 2.88 (s, 3 H),
2.64 (t, J = 7.4 Hz, 2 H), 1.66–1.59 (m, 2 H), 0.94 (t, J = 7.2
Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 196.5, 163.8,
160.7, 145.4, 135.3, 133.7, 132.7, 130.6, 129.6, 128.5,
119.8, 115.6, 114.3, 73.5, 31.8, 31.2, 22.4, 13.9. ESI-MS:
m/z = 325 [M + H]+.
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MCR
A mixture of 5-ethyl-4-hydroxyisophthalaldehyde (1b, 1.0
mmol), NH4OAc (2, 1.5 mmol), and 4,4′-dimethoxybenzil
(3, 1.0 mmol) in AcOH (5 mL) was heated at 110 °C with
stirring for 4.0 h (progress of the reaction was monitored by
TLC). After completion of the reaction, the reaction mixture
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Synlett 2013, 24, 1795–1800
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