Sustainable methine sources for the synthesis of heterocycles under metal- and peroxide-free conditions

Article abstract of DOI:10.1039/c8gc03839b

Alcohols and ethers were identified as sustainable methine sources for synthesizing quinazolinone and benzimidazole derivatives using a combination of TsOH·H₂O/O₂ and appropriate bis-nucleophiles for the first time. Deuterium labeling studies clearly proved that the C₂ hydrogen of the synthesized heterocycles came from the methine source. These unique reaction conditions were successfully applied to the synthesis of echinozolinone (2e′), 2f′ (a common precursor of rutaecarpine and (±) evodiamine), and dimedazole (6d). Notable features of this method include its low toxicity, use of commercial feedstocks as substrates, low cost, broad functional group tolerance and suitability for a wide range of bis-nucleophilic starting materials.

Full text of DOI:10.1039/c8gc03839b

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DOI: 10.1039/C8GC03839B
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Sustainable Methine Sources for the Synthesis of Heterocycles
under Metal- and Peroxide-Free Conditions
Gopal Chandru Senadi, a†‡ Vishal Suresh Kudale,a† and Jeh-Jeng Wang*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Alcohols and ethers were identified as sustainable methine
sources for synthesizing quinazolinone and benzimidazole
derivatives using a combination of TsOH.H2O/O2 and appropriate
bis-nucleophiles for the first time. Deuterium labeling studies
clearly proved that the C2 hydrogen of the synthesized
heterocycles came from the methine source. These unique
reaction conditions were successfully applied to the synthesis of
echinozolinone (2e’), 2f’ (a common precursor of rutaecarpine and
(±) evodiamine), and dimedazole (6d). Notable features of this
method include its low toxicity, use of commercial feedstocks as
substrates, low cost, broad functional group tolerance and
suitability for a wide range of bis-nucleophilic starting materials.
O
S
O
vi
R
O
O
ii
O
i
CO CO2 R2NC
iii iv
H
N
R
R
H
H
O
vii
O
v
H
R
R1
O
COOH
COOH
O
R
O
O
OH
xi
N
R3
R1
O R'
R2
OH
viii
ix
x
xii
xiii
Figure 1. Previously developed C1 synthons
expensive metal catalysts and explosive peroxides as oxidants,
which can hamper their synthetic practicality.
On the other hand, quinazolinone and benzimidazoles are
heteroaromatic scaffolds that are commonly encountered in
natural products and pharmaceuticals.16 In particular,
quinazolin-4(3H)-ones and 1H-benzo[d]imidazoles have shown
significant bioactivity.17 For example, febrifugine and
isofebrifugine, alkaloids isolated from the Chinese herb
dichroafebrifuga belonging to the saxifragaceae family, have
antimalarial activity.17a-c Halofuginone, a synthetic analogue of
febrifugine, is used as an antiprotozoal agent,17d an inhibitor of
type 1 collagen biosynthesis and an anticancer agent.17e
Crenolanib is used as a type 1 tyrosine kinase inhibitor.17f
Galeterone is a steroidal antiandrogen used for the treatment
of prostate cancer.17g Liarozole is used to treat lamellar
ichthyosis,17h as an CYP2S1 inhibitor17i and as an antitumoral
agent.17j Considering their importance, several synthetic
routes has been devised for the preparation of quinazolin-
4(3H)-ones, such as the reaction of o-aminobenzamides with
trialkyl orthoformate,18a,b triethylamine,19 CO2 (Scheme 1a),20
dicumylperoxide,21a,22 oxalic acid,15 methanol (Scheme 1b),23
DMF,21b and CO.24 In addition, these compounds can also be
prepared from the reaction of o-bromobenzamides with
formamide25 and from the reaction of indoles with amines.26
Similarly, 1H-benzo[d]imidazoles are commonly prepared from
the reaction of o-phenylene diamines with trialkyl
orthoformate,18c,d,e oxalic acid,15 CO2 (Scheme 1c)20,27 and
DMF.28 Despite these key advancements, some of those
methods suffer from (i) limited substrate scopes and (ii)
The development of sustainable chemical methods that uses
inexpensive, readily available feedstocks and nontoxic
reagents remains a top priority for the effective synthesis of
organic molecules.1 In particular, the replacement of
hazardous and waste-generating reagents with greener and
renewable alternatives is an important task for both industry
and academia.1b,d,e,g,h,i In the past few years, a variety of
reagents and solvents such as trialkyl orthoformate,2
paraformaldehyde,3 carbon monoxide,4 in situ-5a-j or ex situ-
generated5k CO, CO2,6 isocyanide,7 dimethylformamide,8
dimethyl sulfoxide,9 ethers,10 trialkylamines,11 peroxides,12
methanol,13 glyoxalic14 and oxalic acid,15 have been developed
as one-carbon (C1) sources (Figure 1) to introduce -CH3, -CH2-, -
CH-, –CHO and –CN units for the synthesis of organic
molecules. Among these species, DMF, DMSO and MeOH have
attracted a significant amount of attention due to their low
costs, low toxicity and high availability.8,9,13 However, the
reaction conditions developed for these solvents use
a. Department of Medicinal and Applied Chemistry, Kaohsiung Medical University,
No. 100, Shiquan 1st Rd, Sanmin District, Kaohsiung City, 807, Taiwan.
b. Department of Medical Research, Kaohsiung Medical University Hospital, No. 100,
Tzyou 1st Rd, Sanmin District, Kaohsiung City, 807, Taiwan.
† These two authors contributed equally.
‡ Present addresses: Department of Chemistry, SRM Institute of Science and
Technology, Kattankulathur, Chennai - 603203, India
Electronic Supplementary Information (ESI) available: CCDC 1881809–1881810.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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requiring strong acids, (iii) metal catalysts, (iv) explosive yield of product 2a decreased to 80% yield (TableV1iew, eArntitcrleyO1n1lin)e.
DOI: 10.1039/C8GC03839B
peroxides and (v) long reaction times.
This was likely due to the low oxidation potential of ethylene
glycol in the presence of oxygen at a lower temperature. At
higher temperatures (Table 1, entry 12), the rate of the
reaction was similar to that of entry 5. The reaction gave
traces of product under a N2 atmosphere, confirming the
importance of oxygen in product formation (Table 1, entry 13).
Thus, the conditions screened (Table 1, entry 5) were chosen
as the optimum reaction conditions for further studies.
Scheme 1. Previous works and this work on new methine sources and their uses
Selected Previous Work
O
O
ref. 20
IPR 5.0 mol%
3 PMHS,
R1
R1
N
O
N
(a)
(b)
(c)
C
O2
R
R
H
N
NH2
70 oC, 24 h
O
ref. 23
R1
R1
N
[Cp*Ir(2,2'bpyO)(H2O)]
OH
(1 mol %)
N
H
R
N
Me
R
N
NH2
Table 1 Studies of the reaction parametersa
Cs2CO3 (0.3 equiv.)
MW, 130 oC, 2 h
NH2
ref. 27b
R
O
R
O
C
O2
H2
Au/TiO2
373K
N
R1
NH
R1
Additive (1.0 equiv.)
Ph
Ph
N
N
H
NH2
A
Ethylene Glycol ( ):H2O
This Work
(9:1, 0.25 M)
O2,110 oC
(d)
TsOH.H2O
N
2a
(e)
TsOH.H2O
X
O
O
N
1a
R1
R1
R
(1.0 equiv.)/O2
"Methine
(1.0 equiv.)/O2
Ethylene
N
N
R
NH2
H
R
Yield (%)b
NH2
X = CH2NH2, CN
Entry
Additives (x equiv)
Time, h
Sources":H2O
(9:1, 0.25 M), 110 o
glycol:H2O
(9:1, 0.25 M), 110 o
C
C
1
2
3
4
5
CH3COOH (1.0)
TFA (1.0)
TfOH (1.0)
BF3.Et2O (1.0)
TsOH.H2O (1.0)
KOH (1.0)
TsOH.H2O (0.5)
TsOH.H2O (2.0)
---
TsOH.H2O (1.0)
TsOH.H2O (1.0)
TsOH.H2O (1.0)
TsOH.H2O (1.0)
8
6
6
6
4
15
12
4
78
80
85
82
96
75
77
93
40
94
80
95
trace
TsOH.H2O
H
N
NH2
(1.0 equiv.)/O2
R
R
2-Methoxy
ethanol:H2O (9:1, 0.25 M), 110 o
(f)
N
NH2
C
"Methine Sources"
OH
OH
OH
HO
OH
O
OH
HO
O
6
7c
8d
9
O
O
O
NO2
CH3
O
O
O
O
In this regard, we wish to disclose the combination of
TsOH.H2O and O2 as generalized reaction conditions to use
commercial feedstocks such as alcohols and ethers as a
potential methine source (-CH-) for the construction of
quinazolinones and benzimidazoles with appropriate bis-
nucleophiles (Scheme 1d-f). To date, the only methods that
use primary alcohols, ethers and nitromethane as methine
sources for the synthesis of azaheterocycles are those using
methanol.23 This newly developed method could replace
traditional methine C1 synthons that require expensive metal
catalysts and toxic oxidants.21
10e
11f
12g
13h
8
15
4
24
a
Reaction conditions: Compound 1a (0.15 mmol), TsOH.H2O (1.0 mmol) and
ethylene glycol A (0.25 M) were stirred at 110 °C under a balloon of O2 for the
b
c
indicated time unless otherwise noted. Isolated yields. 50 mol% of TsOH.H2O
d
e
was used. 2.0 equiv of TsOH.H2O was used. Only ethylene glycol was used
f
g
without water. Reaction was performed at 90 °C. Reaction was performed at
120 °C. h Reaction was performed under a N2 atmosphere.
The preliminary investigation of this methodology began using
2-amino-N-phenylbenzamide (1a) as the starting material with
1.0 equiv of CH3COOH and ethylene glycol as an
environmentally benign C1 source under an oxygen balloon. To
our surprise, 3-phenylquinazolin-4(3H)-one (2a), generated
from oxidative C-O and C-C cleavages, was isolated in 78%
yield (Table 1, entry 1). Replacing acetic acid with other
Brønsted acids, such as TFA, TfOH and BF3.Et2O, also gave
desired compound 2a in 80%-85% yields (Table 1, entries 2-4).
In particular, the reaction proceeded smoothly with 1.0 equiv.
of TsOH.H2O, affording 2a in 96% yield in 4 h (Table 1, entry 5).
Performing the reaction with 1.0 equiv. of strong base like KOH
resulted in longer time (15 h) and low product yield (Table 1,
entry 6). Similarly, the yield of compound 2a was reduced
when 50 mol% of TsOH.H2O was used, and no major change
was observed when increasing to 2.0 equiv. (Table 1, entries 7-
8. In the absence of additives, only 40% of the product was
formed after 24 h (Table 1, entry 9). The reaction took longer
(8 h) to reach completion using neat ethylene glycol (Table 1,
entry 10). When the temperature was decreased to 90 °C, the
With the success of ethylene glycol as a “methine” source, we
next investigated the use of other alcohols and ethers under
the standard conditions shown in Table 1, as presented in
Scheme 2. The reaction worked well, and compound 2a was
generated from 1,3-propane diol (D), 2-methoxy ethanol (F)
and propargyl alcohol (H) in good to excellent yields and short
reaction times. However, the reaction failed with methanol (B)
and isopropyl alcohol (E) perhaps because of the low oxidation
potential of methanol under these conditions and the
formation of propene from isopropyl alcohol under acidic
conditions. A moderate yield of 2a was observed with ethanol
(C), and trace amounts of product were formed with 2-
aminoethanol (G) and with morpholine (O). On the other hand,
the reaction proceeded smoothly to afford compound 2a in
50%-95% yields with 1,2-dimethoxyethane (K), diglyme (L),
1,4-dioxane (M) and 3-methyltetrahydro-2H-pyran (N).
Unfortunately, trace or no product was observed with diethyl
ether (I) and tetrahydrofuran (J). These low yields could be due
to the formation of the amine salt and the low oxidation
2 | J. Name., 2012, 00, 1-3
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potentials under these reaction conditions. Interestingly, the unambiguously confirmed by X-ray analysis.31 Since the
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reaction was successful with nitromethane (P), albeit in low formation of compound 2a was achievDeOdI:i1n0.310039m/Ci8nGuCs0i3n8g39HB
yield. Despite the efficacy of several alcohols and ethers as with a high yield (Scheme 2), the substrate scope of the
methine sources, ethylene glycol is the most desirable methine reaction with propargyl alcohol as a methine source was
source because of its environmentally friendliness,29b,c examined with 7 random substrates, and their yields are given
sustainability, low cost, low toxicity, high abundance and in brackets in Scheme 3. Furthermore, to emphasize the
scalability.29
importance of this method, 1,4-dioxane was also tested as a
methine source for 24 derivatives, and a plausible reaction
mechanism was proposed (See ESI, Scheme S1).
Scheme 2. Scope of methine sources
O
N
O
Scheme 3. Scope of o-amino benzamide derivatives with ethylene glycola,b
Additive (1.0 equiv.)
Ph
Ph
N
N
H
Methine Source:H2O
(9:1, 0.25 M)
O
O
R1
TsOH.H2O (1.0 equiv.)
R1
NH2
(0.15 mmol)
N
N
H
Ethylene Glycol:H2O
(9:1, 0.25 M)
O2,110 oC, 4 - 36 h
R
O2,110 o
C
R
1a
2a
N
NH2
2a
1a z; 1a' f'
2a z; 2a' f'
- -
-
-
CH3 OH
OH
OH
HO
OH
, 90%, 8 h
O
O
N
N
O
O
N
O
N
B
C
D
E
, 0%, 16 h
OH
, 40%, 40 h
, 0%, 15 h
N
N
H2N
N
N
OH
O
O
OH
, 5%, 24 h
2a
2b,
2c
2d
, 96%
88%
, 82%
, 90%
F
G
H
I
, 95%, 4 h
, 96%, 0.5 h
, 0%, 24 h
O
O
O
F
O
O
O
O
O
O
O
O
O
O
O
N
O
N
N
O
N
O
N
N
N
J
K
L
M
, 0%, 24 h
, 50%, 16 h
, 75%, 20 h
, 95%, 4 h
N
2g
H
c
2e,
2f
2h
90%
, 93%(91%, 1 h)
, 79%
N
, 83%
N
O
Cl
Br
O
NO2
CH3
O
O
N
N
N
O
N
O
N
O
N
O
P
, 30%, 24 h
N
, 85%, 8 h
, 10%, 24 h
N
c
2i
2j
2k
2l
, 81%
, 86%
, 87%
, 88% (88%, 2 h)
The scope of ethylene glycol as a methine source has been
investigated for the synthesis of 4(3H)-quinazolinone
derivatives as presented in Scheme 3. The reaction proceeded
smoothly with aromatic R1 functionalities, such as p-Me-Ph
(1b), 2,4-diMe-Ph (1c), o-MeO-Ph (1d), m-MeO-Ph (1e), p-
MeO-Ph (1f), 3,4,5-tri-MeO-Ph (1g), 4-F-Ph (1h), 4-Cl-Ph (1i)
and 4-Br-Ph (1j), and afforded desired compounds 2b-2j in
79%-93% yields, respectively. Changing from an aryl
functionality to Bn- (1k) and 4-MeO-Bn (1l) produced
corresponding 4(3H)- quinazolinones 2k-2l in 81%-88% yields.
Aliphatic R1 functionalities, such as Et- (1m), Pr- (1n), Bu- (1o),
1-Ad- (1p), allyl (1q), propargyl (1r) and heteroalkyl groups
such as 1-Bu-OH (1s) and MeO- (1t), worked well and afforded
4(3H)-quinazolinone derivatives 2m-2t in 71%-89% yields.
Interestingly, unsubstituted compound 2u was isolated in 78%
yield from the standard conditions using primary amide
substrate 1u. To elucidate the applicability of the reaction
conditions, R groups with various electronic and steric
properties were investigated using substrates 1v-1d’. The
reactions smoothly afforded 8-Me- (2v), 6-MeO- (2w), 7-NO2-
(2x), 7-F- (2y), 7-Cl- (2z), 6-Br- (2a’), 6-I- (2b’) and 6-Ph (2c’) in
73%-89% yields. The reaction with a fused ring substrate,
namely, naphthyl (1d’), resulted in desired tricyclic derivative
2d’ in 76% yield. Considering the importance of the 4(3H)-
quinazolinone core30 in many natural products, we applied this
method to the concise synthesis of echinozolinone30b (2e’)
from 1e’ and the synthesis of 2f’, a precursor of both
rutaecarpine and ± evodiamine, from 1f’.30a,c Both reactions
proceeded smoothly and provided the desired products in
70%-71% yields. The structures of compounds 2a and 2h were
O
N
N
O
O
N
N
O
N
N
N
N
c
c
2m
2n
2r
2o
2p
, 73% (79%, 4 h)
, 89% (78%, 4 h)
O
, 71%
, 76%
O
O
O
O
N
N
N
N
N
N
N
N
c
c
2q
2s
2t
, 73% (73%, 4 h)
, 77% (84%, 1 h)
O
, 78%
, 75%
OH
O
O
O
Ph
N
Ph
O
Ph
NH
N
N
N
N
O2N
N
N
c
2u
2v
2w
2x
, 78% (82%, 4 h)
, 77%
, 79%
, 74%
O
O
N
O
N
O
N
N
Ph
N
Ph
Br
Ph
I
Ph
F
N
Cl
N
N
2y
2z
2a'
2b',
, 78%
, 89%
, 76%
73%
O
O
O
O
OH
N
N
Ph
Ph
Ph
N
N
N
N
N
N
HN
2c'
2d',
2e'
2f',
71%
, 80%
76%
83%
a
Reaction conditions: Compound 1 (0.15 mmol), TsOH.H2O (1.0 mmol) and
ethylene glycol A:H2O (9:1, 0.25 M) were stirred at 110 °C under a balloon of O2
for 4 – 36 h. Isolated yields. Yields were obtained using 0.25 M propargyl
b
c
alcohol H as the methine source.
Replacing the o-amide functionality with benzylamine 3 under
standard conditions gave compound 2u in 67% yield rather
than the expected quinazoline via benzylic oxidation in the
presence of O2 (eq (1)). Similarly, nitrile derivative
4
underwent hydrolysis under acidic conditions to form 2-
aminobenzamide derivative 1u, which eventually underwent
further cyclization to form desired product 2u in 70% yield (eq
This journal is © The Royal Society of Chemistry 20xx
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2
(2)). These results demonstrate that the synthesis of 4(3H)- (Scheme 5a). In the presence of TsOH.H2O, an SN VrieewaAcrttiicolenOcnlainne
DOI: 10.1039/C8GC03839B
quinazolinone derivatives 2 can be achieved using 3 different occur between compounds 1a and ethylene glycol (A) to form
starting substrates, 1, 3 and 4, under the same reaction 2-((2-hydroxyethyl)amino)-N-phenylbenzamide (1’a) via either
conditions. Thus, this method can be adopted by industry and hydration or tosylation of the ethylene glycol. However, when
academia and applied to various substrates.
compound 1’a was synthesized and treated under standard
The scope of this methodology has been extended to other conditions, the starting material remained unreacted, and no
O
product was formed (Scheme 5b). Next, we hypothesized that
TsOH.H2O (1.0 equiv.)
formaldehyde can be formed via the degradation of ethylene
NH2
N
NH
NH
1
( )
Ethylene Glycol:H2O (9:1)
O2,110 oC 12 h
glycol under acidic/aerobic conditions, and the formaldehyde
could act as the methine source. However, using 3.0 equiv of
37% aq. formalin gave only 30% of the desired product after 6
h (Scheme 5c). Another possibility would be the in situ
formation of the N-formylation intermediate followed by
intramolecular annulation and dehydration. In this regard, N-
formylated compound 7a was synthesized and subjected to
NH2
N
N
2u (67%)
Expected
3
(0.15 mmol)
O
TsOH.H2O (1.0 equiv.)
Ethylene Glycol:H2O (9:1)
O2,110 oC 16 h
CN
2
( )
NH2
N
2u (70%)
4
(0.15 mmol)
heterocycles by replacing the o-amide functionality, as shown
in Scheme 4. In this regard, o-phenylene diamine 5 was
subjected to the standard reaction conditions and afforded
1H-benzo[d]imidazole 6a. Unfortunately, only trace product
was formed after 24 h. To overcome this problem, 2-methoxy
ethanol F was chosen based on results shown in Scheme 2 and
utilized as an environmentally benign methine source.
Surprisingly, the reaction afforded 1H-benzo[d]imidazole 6a in
82% yield after 7 h. The scope of o-phenylene diamine
derivatives with electron-donating and electron-withdrawing
functional groups, such as 3-Me-(5b), 3,4-di-Me-(5c), 4,5-di-
Me- (5d), 4-Cl- (5e), 4-COOMe- (5f) and 4-NO2- (5g), has been
investigated. The reaction proceeded smoothly in all cases
regardless of the electronic and steric properties of the
substituents and afforded 1H-benzo[d]imidazole derivatives
6b-6g in 74%-88% yields. In particular, the synthesis of
dimedazole drug 6d was achieved in 77% yield. However, the
reaction failed to generate benzoxazole and benzothiazole
derivatives with o-aminophenol (5h) and o-aminothiophenol
(5i) under the standard conditions with ethylene glycol, 2-
methoxyethanol and 1,4-dioxane as methine sources.
Scheme 5. Mechanistic studies
O
N
O
"Standard
Conditions"
4 h
Ph
Ph
N
N
(a)
H
NH2
: 2a
TEMPO (10.0 equiv)
, 85%
1a
1a
1a
(0.5 mmol)
(0.5 mmol)
(0.5 mmol)
O
2a
BHT (10.0 equiv) : , 85%
2a
1,4-CHD (10.0 equiv) : , 88%
O
"Standard
Conditions"
24 h
Ph
Ph
N
N
(b)
H
OH
N
N
H
1'a
2a, 0%
(0.25 mmol)
O
N
O
TsOH.H2O
(1.0 equiv.)
O
Ph
Ph
N
N
(c)
(d)
PhCl
H
H
H
O2, 110 °C, 24 h
NH2
(0.5 mmol)
O
(37% in H2O)
(3.0 equiv)
2a
, 30%
1a
O
"Standard
Conditions"
10 mins
Ph
Ph
N
N
1a
H
N
N
O
H
2a
, 80%
7a
(0.25 mmol)
O
Scheme 4. Scope of methine sourcesa,b
O
TsOH.H2O
(1.0 equiv.)
PhCl
Ph
O
N
Ph
N
TsOH.H2O (1.0 equiv.)
2-Methoxyethanol:H2O
HO
(e)
(f)
OH
H
XH
N
N
(9:1, 0.25 M),O2,110 o
C
O2, 110 °C, 24 h
R
R
NH2
(0.15 mmol)
O
2a
, 90%
NH
6a 6i
-
7-15 h
NH2
1a
8a
(5.0 equiv)
5a 5i
-
X = NH, O, S
O
"Standard
Conditions"
2 h
Ph
N
Cl
N
NH
N
N
Ph
N
N
N
N
H
N
N
H
N
H
H
N
N
(trace)c 82%
H
6b
6c
6h
6d
6e
, 87%
, 84%
, 87%
, 77%
6a,
O
2a
, 0.15 mmol
, 88%
O2N
N
N
N
N
O
O
O
O
S
D
D
N
H
Ph
NH
Ph
N
TsOH.H2O
(1.0 equiv.)
0.05 µl H2O
N
6f
6g
6i
, 0%
, 88%
, 74%
, 0%
OH
(g)
(h)
H
HO
D
D
a
N
NH2
Compound 5 (0.15 mmol), TsOH.H2O (1.0 mmol) and 2-methoxyethanol F:H2O
D
O2, 110 °C, 12 h
2a D
-
. 72%
(9:1, 0.25 M) were stirred at 110 °C under a balloon of O2 for 7 – 15 h. b Isolated
yields. c Ethylene glycol was used.
EG-D4 0.45 µl
1a
1a
, 0.15 mmol
81% D incorporation
O
O
TsOH.H2O
(1.0 equiv.)
0.05 µl H2O
O2, 110 °C, 2 h
Ph
N
(D)H H(D)
Ph
N
To elucidate the reaction mechanism, several control studies
were performed as presented in Scheme 5. Initial radical
inhibition studies using TEMPO (10.0 equiv), BHT (10.0 equiv)
and 1,4-CHD (10.0 equiv) under standard conditions revealed
that the reaction does not proceed through a radical pathway
HO
OH
H
NH2
(D)H H(D)
D/H
, 19%
KH/KD = 3
N
2a 2a D
+
-
0.450 µl
(1:1)
, 30 mg
4 | J. Name., 2012, 00, 1-3
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the standard conditions. To our surprise, the reaction rapidly oxygen was used as an environmentally benign oxidant as well
View Article Online
gave deformylation product 1a in 10 min, which upon further as the oxygen donor for the oxidation DoOfI:a1l0c.o10h3o9l/sC8oGrCe0t3h8e3r9sB.
heating gave desired compound 2a (Scheme 5d). On the other This is the first report to document that alcohols and ethers
hand, ethylene glycol can undergo thermal or acidic aerobic can function as methine sources. Kinetic isotope effect studies
oxidative conversion to formic acid, acetic acid, glycolic acid, revealed that the C-O and C-C cleavages of the methine
oxalic and glyoxalic acid.32 It is also known that glycolic acid sources could be the rate determining step. This unique
can easily be converted into glyoxalic acid under aerobic reaction strategy avoids expensive metal catalysts and, most
conditions at elevated temperatures.32 Based on these facts, importantly, explosive peroxides as oxidants and thus has the
the reaction was carried out with glycolic acid in potential to replace the current industrial strategies for the
chlorobenzene as the solvent under standard conditions, and selective synthesis of quinazolin-4(3H)-ones and 1H-
desired product 2a was obtained in 90% yield (Scheme 5e). benzo[d]imidazoles. Further studies on the synthesis of other
Similarly, 3-phenyl-2,3-dihydroquinazolin-4(1H)-one 8a was heterocyclic motifs and natural alkaloids are underway.
reacted under the standard conditions for 2 h, and the desired
4(3H)-quinazolinone was obtained in 88% yield (Scheme 5f).
These results confirm that glyoxalic acid could be the
Conflicts of interest
intermediate in the reaction and that decarboxylation occurs
after annulation. Deuterium labeling studies proved that the C2
hydrogen originated from the ethylene glycol (-CH2-) as 81%
“D” incorporation was observed (Scheme 5g). Competitive KIE
studies showed KH/KD= 3 (Scheme 5h) and parallel KIE studies
showed a KH/KD= 1.94 (See ESI), suggesting that degradation
and oxidation of the ethylene glycol to glyoxylic acid could be
the rate determining step.
“There are no conflicts to declare”.
Notes and references
The authors gratefully acknowledge funding from the Ministry of
Science and Technology (MOST), Taiwan, and the Centre for
Research and Development of Kaohsiung Medical University for
400 MHz NMR, LC-MS and GC-MS analyses.
From the mechanistic studies and previous literature
reports,29,32 a possible mechanism was proposed as shown in
Scheme 6. Initial oxidation of ethylene glycol with TsOH.H2O
under an O2 atmosphere generated unstable glyoxalic acid
intermediate B via the formation of glycolic acid intermediate
A. Then, compound B condensed with compound 1 to form
imine intermediate C. Intramolecular annulation of
intermediate C resulted in the formation of 4-oxo-1,2,3,4-
1
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tetrahydroquinazoline-2-carboxylic
acid
D.
Thermal
decarboxylation of D resulted in penultimate product 8.
Aerobic oxidation of compound 8 gave the desired 4(3H)-
quinazolinone derivative.
2
O
R1
N
R
H
1
O
N
NH2
O
O
D
D
D
R1
D
D
N
TsOH.H2O
O2
OH
TsOH.H2O
O2
OH
OH
R
H
HO
O
HO
D
D
O
3
4
O
H2O
A
B
D
COOH
C
O
O
O
R1
N
R1
R1
O
N
N
D
D
H
-CO2
-H2
N
H
N
H
D
N
2
COOH
8
D
Scheme 6. Plausible reaction mechanism
Conclusions
We developed a metal-free, aerobic oxidative C-O and C-C
cleavage cascade of alcohols and ethers for the synthesis of
quinazolinone and benzimidazole derivatives from o-amino
benzamides, o-amino benzylamines, o-amino benzonitriles and
o-phenylene diamines in the presence of TsOH.H2O. Molecular
5
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This journal is © The Royal Society of Chemistry 20xx
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