Solvent-dependent regio- and stereo-selective reactions of 3-formylchromones with 2-aminobenzothiazoles and transacetalization efficiency of the product 3-((benzo[: D] thiazol-2-ylimino)butyl)-4 H -chromen-4-one

Article abstract of DOI:10.1039/c9ra02763g

Using 2-propanol as the solvent, 3-formylchromones and 2-aminobenzothiaoles formed corresponding imines, while 1° and 2°-alcohols formed the corresponding 2-alkoxy-3-enamines with selectivity for the Z-isomer. Changing the substrates with similar molecules such as 3-formylchromone with quinoline-, quinolone- and indole-3-carbaldehydes sometimes resulted in the formation of the corresponding imines, whereas replacing 2-aminobenzothiazole with amides resulted in the formation of acetals. Considering the effect of the solvent, replacing alcohols with the aprotic solvents THF and CH₂Cl₂ resulted in the formation of imines and enamines, which are the characteristic reactions of 2-propanol and other 1° and 2°-alcohols, respectively. 2-Alkoxy-3-enamines were found to undergo transacetalization with both short and long chain alcohols. The novelty of these reactions is that they did not require an external catalyst, all the reactions were performed at the same temperature, and purification was achieved by filtration. The transacetalization we performed herein is a new concept, which has not been reported to date. In contrast, other similar reactions, such as transalkoxylation, transalkylation, and transetherification, are performed on a commercial scale using expensive catalysts such as Otera's catalyst. The highly sensitive nature of 3-formylchromones towards variations in the substrates and solvents to form different products and the reason behind the selective formation of the Z-isomer of 2-alkoxy-3-enamines and its transacetalization efficiency need further studies to understand the reaction mechanism and possibly other factors such as solvent effects.

Full text of DOI:10.1039/c9ra02763g

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Solvent-dependent regio- and stereo-selective
reactions of 3-formylchromones with 2-
aminobenzothiazoles and transacetalization
efficiency of the product 3-((benzo[d]thiazol-2-
ylimino)butyl)-4H-chromen-4-one†
b
Cite this: RSC Adv., 2019, 9, 20573
Owais Ahmed,ab Vandana Cherkadu,c Praveen Kumar Kalavagunta
*
b
*
and Jing Shang
Using 2-propanol as the solvent, 3-formylchromones and 2-aminobenzothiaoles formed corresponding
imines, while 1ꢀ and 2ꢀ-alcohols formed the corresponding 2-alkoxy-3-enamines with selectivity for the
Z-isomer. Changing the substrates with similar molecules such as 3-formylchromone with quinoline-,
quinolone- and indole-3-carbaldehydes sometimes resulted in the formation of the corresponding
imines, whereas replacing 2-aminobenzothiazole with amides resulted in the formation of acetals.
Considering the effect of the solvent, replacing alcohols with the aprotic solvents THF and CH2Cl2
resulted in the formation of imines and enamines, which are the characteristic reactions of 2-propanol
and other 1ꢀ and 2ꢀ-alcohols, respectively. 2-Alkoxy-3-enamines were found to undergo
transacetalization with both short and long chain alcohols. The novelty of these reactions is that they did
not require an external catalyst, all the reactions were performed at the same temperature, and
purification was achieved by filtration. The transacetalization we performed herein is a new concept,
which has not been reported to date. In contrast, other similar reactions, such as transalkoxylation,
transalkylation, and transetherification, are performed on a commercial scale using expensive catalysts
such as Otera's catalyst. The highly sensitive nature of 3-formylchromones towards variations in the
substrates and solvents to form different products and the reason behind the selective formation of the
Z-isomer of 2-alkoxy-3-enamines and its transacetalization efficiency need further studies to understand
the reaction mechanism and possibly other factors such as solvent effects.
Received 12th April 2019
Accepted 16th May 2019
DOI: 10.1039/c9ra02763g
rsc.li/rsc-advances
advantageous scaffolds in drug discovery. Similar to 2-naphthols,
they are also bicyclic compounds. Towards our aim of developing
Introduction
single molecules as angiotensin converting enzyme (ACE) inhibi-
tors and calcium channel blockers (CCB), which are denoted as
ACE and CCB dual inhibitors, we designed, synthesized and
screened several diarylalkylamines, such as 2-amino-
benzothiazolobenzylnaphthols,7,8 xanthones9 and phenols,10
together with their corresponding arylalkylamine counterparts,
i.e., 2-aminobenzothiazolomethylnaphthols, xanthones and
phenols, which are under different stages of synthesis and
screening. In search of bicyclic compounds with antihypertensive
properties, we found that 3-(aminomethyl)chromone derivatives
have potential antihypertensive properties, and a Scinder search
for commercially available 3-(aminomethyl)chromone derivatives
with antihypertensive property listed hundreds of compounds.
Narrowing down the results by eliminating compounds with
substructures, such as avone, isoavone, and xanthone, resulted
in 7 compounds. The structures of two of them are shown in Fig. 1.
Based upon these reports, we expected 2-amino-
Chromones are naturally occurring oxygen heterocyclic
compounds, which are widely distributed in plants and form the
basic nucleus of important compounds such as avones, iso-
avone, xanthones, and anthocyanins, and new natural products
in this category are still being discovered regularly.1,2 Due to their
wide range of pharmacological activities such as anti-
inammatory and antidiabetic activities,3–6 they are considered
aSchool of Life Sciences and Technology, China Pharmaceutical University, Nanjing
211198, China
bState Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of TCM
Evaluation and Translational Research, School of Traditional Chinese Pharmacy,
China Pharmaceutical University, Nanjing 211198, China. E-mail: shangjing21cn@
163.com; kgpk81@gmail.com
cR&D Centre, CJEX Biochem, 7&8, 2nd Cross, Muniswamappa Layout, Hosur Road,
Bommanahalli, Bangalore 560 068, India
† Electronic supplementary information (ESI) available. CCDC 1908522. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c9ra02763g
benzothiazolobenzylchromones
and
2-
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recrystallization was found to be suitable.11 Further, these
publications described that the purication is difficult. The
limited number of samples obtained were screened for their
antimycobacterial12 and antifungal11,12 properties and found to
do so.
These results indicate the possible wide range of biological
applications of these compounds and the necessity to develop
a method for their synthesis (Fig. 3). Due to the structural
similarities of these compounds with our designed 2-amino-
benzothiazolomethyl chromones (Fig. 2), we decided to develop
a method for the synthesis of imine 3a and 2-alkoxy-3-enamine
3b, which is necessary for the screening of their ACE and CCB
dual inhibition activities.
Fig. 1 Representative examples of commercially available 3-(amino-
methyl)chromones with antihypertensive properties.
aminobenzothiazolomethylchromones, which are chromone
analogues of our previous studies7 (Fig. 2), to have ACE and CCB
dual inhibition properties.
Several of our attempts to synthesize 2-amino-
benzothiazolobenzylchromones 2a using our previous protocols
in different solvents and temperatures were futile. Thus,
temporarily putting their synthesis aside, we moved on to the
synthesis of the corresponding methyl derivatives 2b. From
a literature search, we found that the corresponding imines
(Fig. 3a) can be synthesized in dry toluene with a catalytic
amount of PTSA under Dean–Stark conditions with the possible
formation of 1,4-adducts by the same amine or EtOH depending
on the conditions with 60–65% step-wise yield.11 Moreover, 2-
alkoxy-3-enamines (Fig. 3b) were found to be formed in EtOH
using a catalytic amount of PTSA and heating at 50 ꢀC for
30 min, followed by the addition of an ethanolic solution of the
2-aminobenzothiazole derivative and further stirring at RT, and
ltration followed by recrystallization.12 Spectral data revealed
that this method is applicable only to unsubstituted chro-
mones. In the case of substituted chromones, imine formation
in dry toluene under Dean–Stark conditions, followed by
Results and discussion
2-Aminobenzothiazoles and 3-formylchromes in alcohols
Synthesis of (Z)-3-((benzo[d]thiazol-2-ylamino)methylene)-2-
methoxychroman-4-ones (3aa–bh) and 3-((benzo[d]thiazol-2-
ylimino)methyl)-4H-chromen-4-one (4a–e). In general, imines
can be synthesized by reuxing their corresponding aldehydes
and amines in EtOH with PTSA. The existing literature on the
designed compounds suggests that 2-alkoxy-3-enamine 3b can
be formed under heating in EtOH. Thus, to start the reaction
with the simplest possible protocol, we attempted to reux
a mixture of equimolar quantities of 2-aminobenzothiazole and
3-formylchrome in 20 mL MeOH (Table 1, Entry 1). The solution
slowly turned into a yellow suspension. Aer 2 h, the product
was formed in good yield. The as-formed solid was ltered and
washed with MeOH and dried under vacuum to obtain the
product in low yield (45%). 1H NMR analysis revealed the
formation of the compound, but with slight impurities.
However due to the possibility of three possible structures
1
(Fig. 4) for the H NMR data obtained (notes and ESI-Page S5
and S18†), the structure assignment became difficult without
single-crystal X-ray diffraction. Our further experiments to
develop a method for the synthesis of pure product revealed
that further heating the reaction mixture resulted in the
decomposition of the product, which made the purication
more difficult. Finally, we found that the purity of the product
obtained was best when the reaction was performed at 30–40 ꢀC,
above which the products slowly decomposed, and below
Fig.
benzothiazolobenzylchromones
aminobenzothiazolomethylchromones.
2
Structures
of
the
designed
and
2-amino-
2-
Table
1 Stabilization of temperature for the reaction of 3-for-
mylchromone and 2-aminobenzothiazole in MeOH
Entry
Temperature (ꢀC)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
Reux
50
45
40
35
30
25
20
15
2
2
2.5
3
3.5
4
6
9
12
90a
85a
87a
86
90
87
81
72a
56a
Fig. 3 Structurally similar chromone derivatives to our designed
compounds.
a
Presence of impurities.
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a variety of substituents in both 3-formylchromone and 2-
aminobenzothiazole. The solubility of imine 4 was found to be
very low in any given solvent. However, in case of other 2ꢀ-
alcohols, such as 2-butanol and cyclohexanol, product 3 was
formed (Table 2, Entries 38–40). Using 3ꢀ-alcohols (tert-
butanol), phenols and benzyl alcohols as the alcohol source,
multiple products were formed, which could not be separated.
It is noteworthy to mention that even though the reactions
with phenols were not successful, 3-formylchromones with
phenolic protons successfully formed the corresponding 2-
alkoxy-3-enamines and imines in MeOH and 2-propanol,
respectively (Table 2, Entries 15 and 37). To further study the
applicability of this method to other amines, we successfully
synthesized and puried the 2-alkoxy-3-enamine 3 using 4-
chloroaniline as the amine source (Table 2, Entry 38), but at
a low yield, which was due to purication losses. The product
formed with benzylamines could not be puried, even through
column due to its decomposition.
Fig. 4 Possible regio- and stereo-selective isomers of the compound
obtained by heating 3-formylchromone and 2-aminobenzothiazole in
MeOH under reflux.
which, the reaction was a bit slow to consume all the substrates
(Table 1). We now understood that both the substrate and the
products formed are sensitive to changes in temperature.
To study the applicability of the method so developed, we
performed reactions with a variety of 3-formylchromones, 2-
aminobenzothiazoles and primary alcohols (Table 2, Entries 1–
39), including branched alcohols and diols (Table 2, Entries 27–
30). The products were obtained in good yields in about 10 h.
However, with an increase in the carbon chain length, the rate
of the reaction decreased slowly, and beyond propanol the
yields slowly decreased due to purication losses (Table 2,
Entries 22–30). The products from nitro-substituted 3-for-
mylchromones were found to be difficult to purify and the nitro-
substituted 2-aminobenzothiazoles did not react to form the
product (Table 2, Entries 31 and 32). Finally, to identify the exact
structure of the product formed, we successfully grew a crystal
from one of the compounds, 3as (Table 2, Entry 19). Single
crystal analysis revealed that the Z-isomer of 2-alkoxy-3-
enamine was formed as a product with 100% regio- and
stereo-selectivity, as shown in Fig. 4b, and its crystal structure is
shown in Fig. 5. The reaction is schematically represented in
Scheme 1.‡
3-Formylchromones and amides in alcohols: synthesis of
acetals
In continuation experiments for the synthesis of derivatives
of compound 3 with different amines, we found that the
reactions with amides (acetamide, formamide and benza-
mide) resulted in corresponding acetals, irrespective of the
alcohol and amide used (Table 3, Entries 1–6), with good
yields (71–82%) and even in the absence of amide (Table 3,
Entry 7). These acetals are known to be formed by reactions in
alcohols under both acidic13 and basic14,15 conditions mostly
using Lewis acids as catalysts. However, their formation was
unexpected when a primary amide is available as a substrate
and this behaviour is contrary to its amine counter parts.
Further, in the presence of amides, the formation of acetals
was found to be fast. These results suggest that amides, such
as formamide and acetamide, which are cheap and easy to
purify from the reaction mixtures, can be used as catalysts in
certain types of reactions, which in the present case replaced
Lewis acids. The reaction is represented schematically in
Scheme 2.
Quinoline-, quinolone- and indole-3-carbaldehydes with 2-
aminobenzothiazole in alcohol: synthesis of imines but not 2-
alkoxy-3-enamines. To study the applicability of the method
used for the synthesis of 2-alkoxy-3-enamine derivatives 3 to
quinoline-, quinolone- and indole-3-carbaldehydes, which are
the structural analogues of 3-formylchromone, we found that 4-
chloroquinoline-3-carbaldehyde (Q1) and ethyl 3-formyl-4-oxo-
quinoline-1(4H)-carboxylate (Q4) both formed 4-oxo-1,4-
dihydroquinoline-3-carbaldehyde (Q2), irrespective of the
alcohol (20 mL) used. However, Q1 required reux to form the
product (Table 4, Entries 1–6 and 9). 4-Oxo-1,4-
In continuation of the experiments with other alcohols, we
found that the reaction with the simplest 2ꢀ-alcohol, i.e., 2-
propanol, gave imine 4, which was otherwise difficult to
synthesize according to the reports11,12 in 6 h at about 95%
yield (Scheme 1) (Table 2, Entries 33–37), while it was formed
in just 2 h under reux (Table 2, Entries 35 and 36) with
‡ Single crystal data for the compound 3as can be found in CCDC, depository
number: 1908522. Spectral data for the compound (Z)-3-((benzo[d]
thiazol-2-ylamino)methylene)-2-methoxychroman-4-one (3aa): Color
& state:
lemon yellow solid. Yield 90%, m.p.: 144–146 ꢀC. 1H NMR (CDCl3, 500 MHz):
d 12.29 (d, 1H, J ¼ 10.9 Hz), 8.05–7.95 (m, 2H), 7.79–7.71 (m, 2H), 7.52 (t, 1H, J dihydroquinoline-3-carbaldehyde (Q2) formed the correspond-
¼ 8.4 Hz), 7.43 (t, 1H, J ¼ 7.9 Hz), 7.28 (t, 1H, J ¼ 7.6 Hz), 7.13 (t, 1H, J ¼ 7.5
Hz), 7.06 (d, 1H, J ¼ 8.1 Hz), 5.72 (s, 1H), 3.54 (s, 3H); 13C NMR (DMSO-d6, 75
MHz): d 188.3, 174.9, 166.4, 163.4, 155.6, 152.7, 135.2, 130.9, 126.7, 125.4, 125.3,
124.6, 120.8, 120.0, 118.8, 117.7, 48.6; IR: nmax, 2929, 1649, 1588, 1529, 1465,
1267, 1207, 1146, 1066, 1015, 967, 938, 752, 717 cmꢁ1. EI-MS: M–H, 337.
EI-HRMS: calcd for. C18H14N2O3S ¼ 338.0725. Found: 338.0724.
ing acetal 3-(dimethoxymethyl)quinolin-4(1H)-one (Q8) under
reux, while the reaction was sluggish under normal reaction
conditions. The BoC-quinolone tert-butyl 3-formyl-4-oxoquino-
line-1(4H)-carboxylate (Q3) and its indole analogues Q6 and Q7
formed the corresponding imines Q9, Q10 and Q11 under reux
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Table 2 Reactions of chromone-3-carbaldehydes (1) with 2-aminobenzothiazoles (2) in alcohols (20 mL) at 30–40 ꢀ
C
Entry
1
2
Alcohol
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
12
12
12
12
24
48
48
96
96
144
48
48
24
72
24
24
6
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
90
88
91
79
86
83
89
82
83
88
91
92
87
88
82
84
85
83
84
86
79
75
76
64
59
38
74
78
76
53
—
—
95
95
96
95
96
74
76
45
29
6-Br
6-OMe
4,6-F2
H
6-Cl
6-Br
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
6-Br
6-Br
6-Br
6-OH
6-Cl-8-Br
H
H
6-OMe
6-OCF3
4,6-F2
6-Br
6-Me
6-Br
4,6-F2
5-Cl-7-F
H
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
3aj
3ak
3al
3am
3an
3ao
3ap
3aq
3ar
3as
3at
4-Cl
H
EtOH
EtOH
EtOH
EtOH
H
H
6-OMe
4-Cl
6-Me
4-Cl
4-Cl
6-OMe
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
H
4-Cl
H
6-NO2
H
6-Me
H
H
6-Br
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
H
6-Cl
6-Cl
6-Cl
6-NO2
H
1-Propanol
1-Butanol
1-Butanol
1-Hexanol
1-Heptanol
1-Octanol
Isobutanol
Isobutanol
1,2-Ethanediol
1,5-Pentanediol
MeOH
3au
3av
3aw
3ax
3ay
3az
3ba
3bb
3bc
3bd
a
—
b
MeOH
—
H
H
2-Propanol
2-Propanol
2-Propanol
2-Propanol
2-Propanol
2-Butanol
2-Butanol
Cyclohexanol
MeOH
4a
4b
4c
4d
6
6-Cl
6-Br
6-OH
6-Cl
H
6c
6c
H
6
4e
4-Cl
4-Cl
4-Cl
48
48
48
24
3be
3bf
3bg
3bh
6-Cl
6-Cl
d
—
a
d
Difficult to purify. b No reaction. c Reaction completed in 2 h under reux. 4-Chloroaniline.
and at 30–40 ꢀC, respectively. However, the products formed
from 4-chloroaniline decomposed in the column. The reactions
are schematically represented in Scheme 3.
3-Formylchromone, 2-aminobenzothiazole and solvents
except alcohols: synthesis of 2-alkoxy-3-enamines (3) in DCM
and imines (4) in THF. To develop a method for the synthesis of
2-alkoxy-3-enamine derivatives 3 from viscous and solid alco-
hols, such as long chain unsaturated alcohols, benzylalcohols,
and phenols, we made several attempts using 6-chloro-3-
formylchromone and 2-amino-6-methoxybenzothiazole (Table
5) using different aprotic solvents (20 mL) (DMF, DMSO,
CH3CN, THF, DCM, and xylene) and found that in THF, the
imine product 4 is exclusively formed (Table 5, Entry 2). A
detailed study on the effect of alcohols in the THF-mediated
synthesis of imines 4 revealed that these imines are formed
irrespective of the presence or absence of alcohol at tempera-
tures ranging between RT to reux (Table 6), even with chro-
mones with phenolic protons (Table 6, Entry 8). Due to the very
Fig. 5 Crystal structure of compound 3as.
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Table 4 Reactions of quinolone and indole-3-carbaldehyde deriva-
tives Q1–Q7 with 2-aminobenzothiazole in MeOH (20 mL) at 30–40
ꢀC
Entry
Q1–Q7
Time (h)
Product
Yield (%)
a
1
2
3
4
5
6
7
8
Q1
Q1
Q1
Q1
Q1
Q2
Q2
Q3
Q4
Q5
Q5
Q5
Q5
Q6
Q6
Q6
Q7
144
16b
30b
144d
12b,d
12
—
—
85
Q2
c
—
a
—
87
87
<10
83
55
77
—
—
—
—
81
—
—
51
Q2
Q8
Q8
Q9
Q2
8b
24
9
24
a
10
11
12
13
14
15
16
17
12d
4b,d
12
—
Scheme 1 Schematic representation of the reactions between 3-
formylchromones (1) and 2-aminobenzothiazoles (2) using a variety of
alcohols as the solvent at 30–40 ꢀC.
c
—
a
—
c
4b
—
12
Q10
f
12e
12b,e
48
—
g
—
Table 3 Reactions of 3-Formylchromones with amides in alcohols (20
mL) at 30–40 ꢀC over a period of 12 h
Q11
a
b
c
d
No reaction. Reux. Reaction mixture decomposed. 2-propanol
Entry
1
Amide (eq.)
Alcohol
Product
Yield (%)
e
was used as the solvent. 4-Chloroaniline was used as the amine.
f
Very slow reaction. g Decomposed in column.
1
2
3
4
5
6
7
8
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
H
Acetamide (1)
Acetamide (5)
Acetamide (5)
Formamide
Benzamide
Acetamide
Formamide
—
MeOH
MeOH
MeOH
MeOH
5a
5a
5a
5a
5a
5b
5b
5a
81
80
82
86
71
72
76
80
MeOH
1-Propanol
1-Propanol
MeOH
H
6-Cl
Scheme 2 Reactions of 3-formylchromones with alcohols in the
presence and absence of amides.
Scheme 3 Schematic representation of reactions of quinolone and
indole derivatives Q1–Q7 with 2-aminobenzothiazole in MeOH (20
mL).
low solubility of derivatives of 4, we studied the effects of
different alcohols without changing the substrates. The reac-
tion is schematically represented in Scheme 4. On the other
hand, the reactions in DCM with long chain unsaturated alco-
hols formed the expected 2-alkoxy-3-enamine in about 10%
yield (Table 5, Entry 6). Further studies revealed that the prod-
ucts formed with phenols and benzyl alcohols were difficult to
purify (Table 7, Entries 4 and 5) and long chain unsaturated
alcohols formed the required 2-alkoxy-3-enamine in low yields
(Table 7, Entries 6 and 7). The reaction is schematically repre-
sented in Scheme 5.
and 3bi. During the purication of the derivatives of 2-alkoxy-3-
enamines (3) formed from long chain alcohols and diols, which
are highly viscous, we made several attempts to purify them by
ltration under different conditions using different solvents.
During this process, we observed that washing these highly
viscous liquids with MeOH resulted in the displacement of that
long chain alkoxy group with the methoxy group, which can be
called transacetalization. We are well-versed with the commer-
cial importance of transesterications for the synthesis of
polyesters16 using catalysts such as Otera's catalyst17 and
transalkylations using zeolites,18 transamidications19 and even
Trans-acetalization of 2-alkoxy-3-enamines: reactions of (Z)-
2-butoxy-6-chloro-3-((6-methoxybenzo[d]thiazol-2-lamino)
methylene)chroman-4-one (3aw) in MeOH (20 mL) and 1-octa-
nol (20 mL) for the synthesis of corresponding derivatives 3ag
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Table 5 Study of the influence of different solvents (20 mL) on the Table 7 Study of the synthesis of 2-alkoxy-3-enamine derivatives of
reactions between 6-chloro-3-formylchromone (1 mmol), 2-amino- long chain, unsaturated alcohols in DCM (20 mL) using 6-chloro-3-
6-methoxybenzothiazole (1 mmol) and alcohols (2 mmol)
formylchromone (1) and 2-amino-6-methoxybenzothiazole (2) as
substrates
Entry
Alcohol
Solvent
Time
Product
Yield (%)
Entry
Alcohol (eq.)
Time
Product
Yield (%)
a
1
2
3
4
6
7
8
9
n-Butanol
n-Butanol
n-Butanol
n-Butanol
1-Octanol
1-Octanol
1-Octanol
1-Octanol
DCM
THF
DMF
CH3CN
DCMb
DMF
DMSO
Xylene
12 h
4 h
—
—
94
—
—
10
—
—
—
4f
—
—
3bic
—
—
1
2
3
4
5
6
7
1-Octanol (1)
1-Octanol (5)
1-Octanol (10)
Benzyl alcohol (1)
4-ChloroPhenol (1)
Geraniol (1)
10 h
10 h
10 h
7 h
10 h
10 h
10 h
3bi
3bi
3bi
11
12
12
—
—
7
b
12 h
12 h
10 h
12 h
12 h
12 h
b
a
—
—
3bjb,c
b
a
b
b
—
5-Hexyne-1-ol (1)
3bkb,c,d
6
a
b
c
a
b
c
Difficult to purify.
Decomposed.
Puried by column
Difficult to purify. 2-Amino-4-chlorobenzothiazole. Puried by
d
chromatography.
column chromatography. 3-Formylchromone.
Table 6 Study of the influence of 1ꢀ,2ꢀ-alcohols on the formation of
imines from 6-chloro-3-formylchromone (1) and 2-amino-
benzothiazole (2) in THF (20 mL) at RT (10 h) and reflux (2 h)
Entry
Alcohol
Eq.
Product
Yield (%)
1
2
3
4
5
6
7
8
1-BuOH
1-BuOH
2-BuOH
1
10
1
1
—
1
—
—
4f
4f
4f
4f
4f
4g
4g
4e
96
95
96
95
96
95
96
95
Cyclohexanol
a
—
MeOHb
a,b
Scheme 5 Schematic representation of the synthesis of 2-alkoxy-3-
enamine derivatives of long chain, unsaturated alcohols in CH2Cl2.
—
a,b,c
—
a
b
c
No alcohol was used.
formylchromone.
2-Aminobenzothiazole.
6-Hydroxy-3-
increase in temperature beyond 50 ꢀC (Table 8). The reaction is
schematically represented in Scheme 6, and the structural
features favouring this transacetalization is expected to be the
(Z)-3-(aminomethylene)-2-methoxy-2H-pyran-4(3H)-one
skel-
eton, which is shown in Fig. 6 (brown square). Thus, further
studies are necessary to understand how to exploit this
property.
Materials and methods
Synthesis of quinoline- and quinolone-3-carbaldehydes (Q1,
Q2, Q4 and Q5) and BoC-protected derivatives Q3 and Q7
Scheme
4 Schematic representation of condensation of 3-for-
The experiments were performed following the existing litera-
ture.24 BoC protections were performed using the general
mylchromones with 2-aminobenzothiazoles in THF (20 mL).
transetherications20,21 with limited substrate scope, i.e., either
vinyl esters or vinyl ethers using expensive catalysts. The liter-
ature for the synthesis of unsymmetrical acetals22,23 are very
limited and their transacetalization was not found to be re-
ported. Thus, we made use of the 2-butoxy derivative 3aw as
a substrate, dissolved it in either MeOH or 1-octanol (20 mL)
with stirring at 30–40 ꢀC over a period of 5 days. The corre-
sponding products 3ag and 3bi were formed in good yields, but
as usual, the purication losses were found to be more in
octanol reactions and resulted in a nal yield of12%. Using 1–
10 mmol of alcohol (MeOH or 1-octanol) and using xylene (20
mL) as the solvent did not result in the formation of any
product, but the substrate started decomposing with a gradual
Table 8 Studies on the transacetalization efficiency of 2-alkoxy-3-
enamines using (Z)-2-butoxy-6-chloro-3-((6-methoxybenzo[d]thia-
zol-2-ylamino)methylene)chroman-4-one (3aw) as a substrate
Entry Alcohol (20 mL) Solvent
Time (h) Product Yield (%)
1
2
3
4
5
MeOH
MeOH
1-Octanol 120
Xylene
Xylene
Xylene
24
3ag
3bi
91
12
—
—
—
1-Octanol
1-Octanola
24
6
—
b
c
d
—
—
c
b
—
6e
—
a
b
c
d
e
1 eq. of 1-Octanol. Decomposed. No alcohol. No reaction. 50–
100 ꢀC.
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formed was ltered. The solid was dissolved in 400 mL CHCl3
and washed with water. The organic layer was concentrated, and
the resulting solid was puried by column chromatography
using CH2Cl2 as the eluent, and crystallized from a mixture of
ethyl acetate and hexane to afford 4-chloroquinoline-3-
carbaldehyde (Q1) as a white solid (3.8 g; 49%). A suspension
of 3.3 g of Q1 (17.3 mmol) in 40 mL of 54% aqueous formic acid
was heated at 50 ꢀC for 2 h. The resulting suspension was
frozen, and the solid formed was ltered and washed with
water. Pure 1,4-dihydro-4-oxoquinoline-3-carbaldehyde (Q2)
was collected as a white solid without further purication (2.7 g,
95%).
Scheme 6 Transacetalization reactions of 2-alkoxy-3-enamine (3).
tert-Butyl 3-formyl-4-oxoquinoline-1(4H)-carboxylate (Q3)
and tert-butyl 3-formyl-1H-indole-1-carboxylate (Q7). To a solu-
tion of 1,4-dihydro-4-oxoquinoline-3-carbaldehyde (Q2, 386 mg,
2.23 mmol) or indole-3-carbaldehyde (Q6, 324 mg, 2.23 mmol)
and TEA (1.24 mL, 8.93 mmol) in CH2Cl2 (20 mL), (BoC)2O
(1.46 g, 6.7 mmol) was added under an N2 atmosphere at 5–
10 ꢀC. The reaction mixture was stirred overnight at RT, diluted
with water and extracted with CH2Cl2. The organic layer was
washed with water and brine, and dried over Na2SO4 and
concentrated to obtain the corresponding tert-butyl 3-formyl-4-
oxoquinoline-1(4H)-carboxylate (Q3, 384 mg, 63%) or tert-butyl
3-formyl-1H-indole-1-carboxylate (Q7, 361 mg, 66%) in good
yields.
Fig. 6 Position of unsymmetrical acetal in a representative compound
3aw (blue square) and possible structural features driving the trans-
acetalization reaction (brown square).
protocols. The reactions are schematically represented in
Scheme 7.
Ethyl 3-formyl-4-oxoquinoline-1(4H)-carboxylate (Q4). To
a
suspension of 1,4-dihydro-4-oxoquinoline-3-carbaldehyde
Synthesis of 4-chloroquinoline-3-carbaldehyde (Q1) and 1,4-
dihydro-4-oxoquinoline-3-carbaldehyde (Q2). To 50 mL of dry
DMF, POCl3 (23 mL, 246.8 mmol, 6 eq.) was added dropwise at
(Q2) (701 mg, 4.05 mmol, 1 eq.) in 50 mL acetone, anhydrous
K2CO3 (1.12 g, 8.10 mmol, 2 eq.) was added and the mixture was
stirred at RT for 30 min. To this mixture, 3 ethyl chloroformate
(0.61 mL, 6.08 mmol, 1.5 eq.) was added, and the mixture was
stirred at RT for 30 min. The reaction mixture was ltered,
washed with acetone, and the ltrate was concentrated and
extracted with water and chloroform. The organic layer was
concentrated under vacuum to obtain pure ethyl 3-formyl-4-
0
ꢀC, and stirred for 15 min under nitrogen at RT. To this
mixture, 2-aminoacetophenone (5 mL, 41.1 mmol, 1 eq.) was
added dropwise and heated at 60 ꢀC for 4 h. The reaction
mixture was then quenched with the slow addition of ice,
neutralized with saturated NaHCO3 solution, and the solid
oxoquinoline-1(4H)-carboxylate (Q4) as
a yellowish solid
(920 mg, 94%).
1,4-Dihydro-4-oxo-1-(4-toluolsulfonyl)quinoline-3-carbaldehyde
(Q5). To suspension of 1,4-dihydro-4-oxoquinoline-3-
a
carbaldehyde (200 mg, 1.16 mmol, 1 eq.) in 20 mL acetone,
anhydrous K2CO3 (320 mg, 2.32 mmol, 2 eq.) was added, and
stirred at RT for 30 min. To this mixture, p-toluenesulfonyl chlo-
ride (332 mg, 1.74 mmol, 1.5 eq.) was added, and the resulting
mixture was stirred at RT for 3 h. The reaction mixture was ltered,
the solid was washed with acetone and the ltrate was concen-
trated. The residue was puried by column chromatography (silica
gel, 60–120 mesh), using CH2Cl2 as the eluent followed by
a mixture of CH2Cl2–acetone (5 : 1). The solid obtained was
recrystallized from a mixture of CH2Cl2-light petroleum to give 1,4-
dihydro-4-oxo-1-(4-toluolsulfonyl)quinoline-3-carbaldehyde (Q5) as
a white solid (369 mg, 97%).
(Z)-3-((Benzo[d]thiazol-2-ylamino)methylene)-2-methoxychroman-
4-one and its aliphatic alcohol derivatives (3aa–3bh)
Scheme 7 Schematic representation of the synthesis of derivatives of
quinoline-, quinolone- and indole-3-carbaldehyde derivatives Q1–Q5
and Q7.
Equimolar quantities of chromone-3-carbaldehyde (174.2 mg, 1
mmol) and 2-aminobenzothiazole (150.2 mg, 1 mmol) were
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ꢀ
dissolved in MeOH (20 mL) and stirred at 30–40 C for about which otherwise took about 10 h. The reaction was completed in
12 h. The yellow as-formed solid was ltered, washed with less than 2 h under reux conditions, resulting in good yields
a little MeOH and dried under vacuum to obtain pure 3aa as (Table 2).
a yellow solid (304 mg, 90% yield). The same conditions were
applicable to a variety of 3-formyl chromones, 2-amino-
benzothiazoles and 1ꢀ,2ꢀ-alcohols, except 2-propanol where
formation of imine 4 was observed. The reaction time may very
between 10 h to 3 days depending on the substituents and the
alcohol used (Table 2). An increase in the alcohol chain length
was found to be associated with an increase in reaction time. It
is noteworthy that even though a few substrates were able to
withstand a higher temperature (ꢂ60 ꢀC), a few of them
decomposed at this temperature and purication of the product
was difficult and sometimes not possible. This stability was
found to be completely dependent on the substituents on both
6-Chloro-3-(dimethoxymethyl)-4H-chromen-4-one (5)
To a solution of 6-chloro-3-formylchromone (209 mg, 1 mmol)
in MeOH (20 mL), acetamide (59 mg, 50 mL, 1 mmol) was added
and stirred at for 30–40 ꢀC 12 h. The wheat-brown solid ob-
tained was ltered, washed with MeOH (20 mL ꢃ 3) and dried
under vacuum to obtain 5a in 81% yield (Table 3). This method
was applicable to other amides, such as formamide and ben-
zamide, and other alcohols such as 1-propanol.
4-Oxo-1,4-dihydroquinoline-3-carbaldehyde (Q2) from 4-chloro-
quinoline-3-carbaldehyde (Q1) and ethyl 3-formyl-4-oxoquinoli-
ne-1(4H)-carboxylate (Q4)
the
chromone-3-carbaldehyde
(1
mmol)
and
2-
aminobenzothiazole.
Equimolar quantities of Q1 (192 mg, 1 mmol) or Q4 (245 mg, 1
mmol) and 2-aminonenzothiazole (150 mg, 1 mmol) were dis-
solved in MeOH (20 mL) and stirred under reux for 12 h, and
the as-formed solid was ltered and washed with 15 mL of
MeOH to yield the product Q2 as a wheat-brown solid in 85%
(147 mg) and 77% (133 mg) yield, respectively (Table 4).
(Z)-6-Chloro-3-((6-methoxybenzo[d]thiazol-2-ylamino)methylene)-
2-(octyloxy)chroman-4-one and its long chain unsaturated alcohol
derivatives (3bi–3bk)
Equimolar quantities of 6-chloro-4-oxo-4H-chromene-3-
carbaldehyde (209 mg,
1
mmol) and 2-amino-6-
methoxybenzothiazole (180 mg, 1 mmol) were dissolved in
20 mL of CH2Cl2. To this mixture, 2 eq. of 1-octanol (260 mg,
320 mL) was added and stirred at 30–40 ꢀC for about 12 h, the as-
formed yellow solid was refrigerated overnight, ltered, washed
with small quantities of ice cold MeOH (20 mL ꢃ 3) and dried
under vacuum, then puried by ash column to obtain pure 3bi
as a lemon-yellow solid in 11% (55 mg) yield. It is noteworthy to
mention that these compounds readily decomposed in the
column, and hence rapid column chromatography is suggested.
We were not able to purify the products formed from phenols
and benzylalcohols due to their decomposition.
3-(Dimethoxymethyl)quinolin-4(1H)-one (Q8)
To a solution of Q2 (173 mg, 1 mmol) in MeOH (20 mL), 2-
aminobenzothiazole (150 mg, 1 mmol) was added and stirred
under reux for 8 h. The solid obtained was ltered and washed
with a minimum amount of MeOH to obtain the product Q8 as
a yellow solid in 83% (182 mg) yield.
3-((Benzo[d]thiazol-2-ylimino)methyl)quinolin-4(1H)-one (Q9)
A solution of equimolar quantities of tert-butyl 3-formyl-4-oxo-
quinoline-1(4H)-carboxylate (Q3) and 2-aminobenzothiazole in
MeOH was stirred at RT for 24 h. Even though multiple impurity
spots were visible from TLC, ltration of the reaction mixture
followed by washing with a minimum amount of MeOH yielded
pure Q9 as a light-yellow solid in 55% yield. This method was
applicable to indole derivatives Q6 and Q7 for the synthesis of
their imines N-((1H-indol-3-yl)methylene)benzo[d]thiazol-2-
amine (Q10) and tert-butyl 3-((4-chlorobenzo[d]thiazol-2-yli-
mino)methyl)-1H-indole-1-carboxylate (Q11) with 81% and 51%
yields over a period of 12 h and 48 h, respectively.
Synthesis of 3-((benzo[d]thiazol-2-ylimino)methyl)-4H-chromen-
4-one (4a) and its derivatives (4a–g)
Method A: equimolar quantities of chromone-3-carbaldehyde
(174 mg, 1 mmol) and 2-aminobenzothiazole (150 mg, 1
mmol) were dissolved in IPA (20 mL) and stirred at 30–40 ꢀC for
about 6 h. The as-formed pale-yellow solid was ltered, washed
with a little MeOH (20 mL ꢃ 2) and dried under vacuum to
obtain 291 mg of pure 4a (95% yield). The reaction was
completed in just 2 h under reux conditions and resulted in
good yield (Table 2). It is important to note that the solubility of
these imines was very low in any given solvent, including CHCl3,
acetone, DMSO and DMF.
Conclusions
In conclusion, using 2-propanol as the solvent, 3-for-
Method B: equimolar quantities of chromone-3- mylchromone and 2-aminobenzothiazole were found to form
carbaldehyde (174 mg, 1 mmol) and 2-aminobenzothiazole imines; whereas, with other 1ꢀ and 2ꢀ-alcohols they formed the
(150 mg, 1 mmol) were dissolved in THF (20 mL), and to this Z-isomer of 2-alkoxy-3-enamine. Replacing 3-formylchromone
mixture, 2 eq. of alcohol was added and stirred at 30–40 ꢀC for with quinoline and indole derivatives did not yield the corre-
about 6 h. The as-formed pale-yellow solid was ltered, washed sponding 2-alkoxy-3-enamines as expected, whereas replacing
with a little MeOH and dried under vacuum to obtain 291 mg of 2-aminobenzothiazole with an amide formed the correspond-
pure 4a (95% yield). Even though the reaction did not need an ing acetal. Replacing alcohols with aprotic solvents THF and
alcohol to proceed, adding a little alcohol, such as MeOH, CH2Cl2 and an alcohol as the substrate formed corresponding
EtOH, and IPA, allowed the reaction to be completed in 6 h, imines and 2-alkoxy-3-enamines. This highlights the reactivity
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differences and highly selective nature of 3-formylchromones.
Further the 2-alkoxy-3-enamines formed above were found to
have the unique ability to undergo transacetalization, which is
rst of its kind. In addition, these reactions do not require any
external catalyst and all the reactions were performed at or just
above room temperature, and purication was achieved by
ltration. Transacetalization, which was successfully performed
here, is a new concept with no previous reference in the litera-
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There are no conicts to declare.
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Acknowledgements
OA is thankful to China Scholarship Council (CSC) for awarding
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