The first chemical synthesis of 6-thio-d-fructo-pyranose via methyl 6-bromo-6-deoxy-1,3-o-isopro-pylidene-α-d-fructofuranoside as a key intermediate

Article abstract of DOI:10.3987/COM-06-10965

Selective bromination of sucrose, followed by acetalation with 2,2-dimethoxypropane in 1,4-dioxane in the presence of p-toluenesulfonic acid, afforded methyl 6-bromo-6-deoxy-1,3-O-isopropylidene-α-d-fructofuranoside (4). The first chemical synthesis of 6-

Full text of DOI:10.3987/COM-06-10965

HETEROCYCLES, Vol. 71, No. 3, 2007
569
HETEROCYCLES, Vol. 71, No. 3, 2007, pp. 569 - 576. © The Japan Institute of Heterocyclic Chemistry
Received, 24th November, 2006, Accepted, 25th January, 2007, Published online, 26th January, 2007. COM-06-10958
2 3
A CONVENIENT K CO CATALYSED REGIOSELECTIVE SYNTHESIS
FOR BENZOPYRANO[4,3-c]PYRAZOLES IN AQUEOUS MEDIUM
Mazaahir Kidwai,* Priya, Kavita Singhal, and Shweta Rastogi
*
Green Chemistry Research Laboratory, Department of Chemistry,
University of Delhi, Delhi-110007, India
Telefax : (91 11) 27666235; Email: kidwai.chemistry@gmail.com
Abstract – This synthetic approach features heterocondensation reaction between
in situ generated 3-arylidene-2,4-chromanediones and N-substituted hydrazine
moiety avoiding the use of organic solvents at any stage. Water as solvent is taken
for the synthesis of selective benzopyranopyrazole derivatives under microwaves
(
MWs). Hydroxy coumarin moiety is employed for this ecofriendly strategy.
INTRODUCTION
The environment calls on the entire research edifice to define long term strategic goals for clean chemistry
and to reduce the amount of pollutants produced including organic solvents whose recovery is mandated by
evermore strict laws. To reduce the dependence on ecologically unsafe chemicals, it is advantageous to
carryout reactions in aqueous media. Water is the abundantly available solvent, indeed a cheaper medium
for many reactions but is often-appears as a nature’s enemy to be kept away from the reaction mixture until
work up. Reactions in aqueous media are environmentally benign, easy to handle and devoid of any
corrosive or carcinogenic effects. Moreover, this leads to shorter reaction times with enhanced yield and
1
,2
greater ease of manipulation. Therefore, the development of an efficient synthetic methodology to form
carbon-nitrogen bond in aqueous media appears to be necessary. Being polar, water serves as an excellent
3
-4
solvent for microwave assisted reactions too.
5
-7
Coumarin (benzopyran) is one of the most interesting molecule as it exhibits diverse chemical and
8
-12
biological properties. In addition, pyrazole nucleus in fusion with benzopyrans confers pharmacological
13-16
properties.
Keeping in view the medicinal importance of benzopyranopyrazoles and in continuation of our ongoing
1
7
program towards aqueous mediated ecofriendly green synthesis, it was thought worthwhile to
regioselectively synthesize benzopyrano[4,3-c]pyrazoles under microwaves using water as solvent.
We herein report a regiocontrolled conversion of arylidene derivatives of benzopyran into substituted
benzopyrano[4,3-c]pyrazoles (4a-g) by reaction with phenylhydrazine hydrochloride in refluxing water.

570
HETEROCYCLES, Vol. 71, No. 3, 2007
1
3
By help of C NMR, it has been proved that cycloaddition would proceed in such a manner that union
occurs between C9b of coumarins and amino group of phenylhydrazine to give resulting product.
RESULTS AND DISCUSSION
Various methods reported for Benzopyrano[4,3-c]pyrazole derivatives so far, employ the use of hazardous
1
8
19
20
21
22
solvents like diphenylnitrilimine , acetic acid , pyridine , xylene , with harmful catalysts like HCl ,
2
3
triethylamine . To greenify the above procedures for the synthesis of biologically active
benzopyrano[4,3-c]pyrazoles using environmentally benign reagents, we explored a new route for the
synthesis of regioselective benzopyrano[4,3-c]pyrazoles 4a-g with K
Firstly, 4-hydroxy-2H[1]benzopyran-2-one (4-hydroxycoumarin) 1 was taken with different aldehydes
a-g in water to yield 3-arylidenechromane-2,4-diones 3a-g. In this preliminary study, we were pleased to
2 3
CO as base and water as solvent.
2
find that in this Knoevenagel condensation reaction using water, base was not required. The arylidene
derivatives thus obtained were in high yield. The structures of these known α,β-unsaturated carbonyls were
2
5
found to be in consistency with the spectroscopic data. Further these compounds were easily obtained as
they precipitated out as an insoluble solid in water. Since 4-hydroxy-2H[1]benzopyran-2-one 1 exists in
2
7
tautomeric form (Figure 1) with corresponding 2-hydroxy-4-pyrone and is an active methylene reagent,
thus the plausible mechanism of our protocol involves the condensation of one mole of aromatic aldehydes
2
a-g with one mole of 4-hydroxy-2H[1]benzopyran-2-one 1 in water to give arylidene derivatives 3a-g.
O
O
O
O
OH
O
1
(enol form)
1 (keto form)
Figure 1
Then these intermediates 3a-g were reacted as an α,β-unsaturated carbonyl moiety with phenylhydrazine
hydrochloride in the presence of catalytic amounts of K CO in hot water. Here, the use of K CO served as
a mild water soluble inorganic base which obviated the requirement of the removal of acidic components
formed in the reaction medium and excess of K CO gets easily washed off with water. Moreover, the use
of K CO is found to be necessary to solubilise the chalcones 3a-g as well as to release phenylhydrazine
2
3
2
3
2
6
2
3
2
3
from its hydrochloride salt. The product can be obtained after cooling in 10-15 minutes. The presence of
K CO makes easier the formation of pure phenylhydrazine from its hydrochloride and then the amino
2
3
group of phenylhydrazine condensed with the carbonyl group of arylidene derivatives lead to cyclisation
for benzopyrano[4,3-c]pyrazoles (4a-g).

HETEROCYCLES, Vol. 71, No. 3, 2007
571
O
O
O
O
O
water
+
RCHO
a-g
µν
step 1
2
CH–R
OH
1
3
a-g
R
µν
step 2
PhNHNH .HCl
2
a C H
6
5
K CO , water
2
3
b 4-ClC H
c thiophen-2-yl
d 3-NO C H
6
4
O
O
2
6 4
e 4-OCH C H
3
6 4
f benzo[1,3]dioxol-5-yl
g 2-chloroquinolin-3-yl
C R
N
N
4a-g
Scheme 1
Table 1. Reaction times and yields for 3-arylidene-chromane-2,4-diones (step 1) and benzopyrano-
[4,3-c]pyrazoles (step 2)
R
Step 1
Compound mp/°C
Step 2
Method B Method C
time (hr) / time (hr) / time (min) /
Time (min) / Compound mp/°C
Yield (%)
Method D
yield (%)
yield (%)
yield (%)
Ph
3a
234-236
0.50/78
4a
130-135
6/50
5.5/68
2.0/77
2
4
[
>230]
4
-ClC
6
H
4
3b
3c
3d
3e
220-225
202-206
170-175
210-214
0.75/80
1.0/85
1.5/76
1.5/80
4b
4c
4d
4e
103-104
120-124
105-108
98-102
7/53
5.0/70
5.0/78
5.5/70
4.0/72
3.0/77
2.5/85
3.5/75
2.5/78
thiophen-2-yl
-NO
-OCH
6.5/45
7.0/40
5.5/45
3
2 6 4
C H
C H
3 6 4
4
2
4
[
212]
benzo[1,3]dioxol-5-yl
-chloroquinoline-3-yl
3f
3g
265-270
246-248
1.75/75
2.0/75
4f
4g
270-273
190-192
7.0/52
8.0/58
4.5/68
5.5/68
2.5/75
4.5/76
2
No minor reaction side products could be isolated from the reaction mixture.
The structures of the synthesized compounds 4a-g were confirmed on the basis of their spectroscopic data.
-1
The infrared spectrum of products 4a-g showed two bands at 1593-1608 cm for C=N stretching and
-1
1
1
665-1677 cm for C=O stretching. The significant H NMR and mass spectrum further satisfied the
1
proposed product of benzopyranopyrazoles. However, IR, mass and especially H NMR spectra did not
confirm the final product structure 4a-g. Since the reaction pathway followed in the scheme resulted in two
1
3
types of products i.e. structure I and II as shown in Figure 2, thus C NMR was found to be informative.
O
O
O
O
9b
3
3
R
9b R
N
N
N
N
Ph
Ph
I
Figure 2
II

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HETEROCYCLES, Vol. 71, No. 3, 2007
1
3
C NMR confirms the sole product (I) obtained in our protocol (Table 2). This can be explained simply.
Had C-9b bonded with substituted nitrogen one side, this would have upfield its signal by 12-20 ppm and
makes its appearance nearby the signal of C carbon atom i.e. 143-145 (structure II, Figure 2). But our
3
spectras does not consist of such type of signals. Whereas, the spectra shows the difference of C-9b and
C-3 signals with range of 12-15 ppm apart which entirely eliminates the possibility of structure II and
indicates that the unsubstituted nitrogen is attached to C9b atom, which leads to the appearance of its signal
~
153-160 ppm. The purity of compounds were determined by CHN data.
Knowing widespread application of benzopyrano[4,3-c]pyrazoles, their synthesis has been scaled up
towards green chemistry domain by circumventing the use of any organic solvent and harmful catalysts.
Water has been proved here as a suitable green solvent for the synthesis of benzopyranopyrazoles. In this
protocol the products obtained in high yield, pure and easily isolable. Diversified point is the variation of
the aryl group on the arylidene derivative which led to a library synthesis for wider role in pharmaceuticals.
This is beneficial for synthetic chemist which involves only water as a solvent for the desired target
synthesis.
1
3
Table 2. C chemical shifts of compounds (4a-g)
6
5
a
a
O
4
17
6
18
19 22
O
7
8
17
6
18
19
17
16
18
19
1
17
8
19
20
21
1
1
4e : R =
4f : R =
OCH
3
3
2
a
4a : R =
4c : R =
4d : R =
N
9b
3
21
16
9
S
20
9
C
R
21
20
18
19
Cl
4g : R =
2
2
O
1
8
22
23
N
17
16
17 18 NO2
19
17
16
N 10
24
Cl
1
16
1
3
1
O
4
b : R =
1
20
9
1
5
21
21
21
12
20
20
1
4
1
Carbon 4a
4b
4c
4d
4e
4f
4g
3
3
4
5
6
7
8
9
9
1
1
1
1
1
1
1
144.4 144.7 144.7 144.5 144.43 144.4 144.9
105.3 105.8 105.6 105.6 105.2 105.3 105.7
162.0 162.4 162.3 162.6 162.2 162.4 162.7
150.0 150.6 150.2 150.4 150.0 150.2 150.6
121.3 121.9 121.6 121.4 121.4 121.6 121.9
128.2 128.6 128.4 128.2 128.1 128.3 128.7
124.5 124.9 124.7 124.8 124.6 124.9 124.1
129.1 129.4 129.2 129.5 129.2 129.5 130.1
150.0 159.0 158.6 158.9 153.5 156.6 158.6
138.2 138.4 138.2 138.0 138.4 138.6 138.8
120.7 120.8 120.9 120.8 120.9 120.4 121.2
129.0 129.2 129.0 129.4 129.1 129.3 129.7
125.3 125.5 125.3 125.5 125.6 125.8 126.1
129.2 129.4 129.2 129.3 129.3 129.3 129.6
120.7 120.9 120.9 120.8 120.7 120.9 120.7
135.7 136.6 139.0 135.9 128.0 129.4 158.2
a
a
a
b
0
1
2
3
4
5
6

HETEROCYCLES, Vol. 71, No. 3, 2007
573
17
18
19
20
21
22
23
24
126.8 127.4 121.7 124.4 128.4 114.2 145.9
129.2 129.6 127.7 149.0 114.9 148.9 128.7
128.8 133.0 125.5 124.0 160.0 146.9 128.9
129.4 129.6
126.6 127.5
-
-
-
-
-
130.2 115.0 115.2 126.7
134.0 128.6 120.1 125.1
-
-
-
-
-
-
-
-
-
56.4
-
-
90.7
-
-
125.4
134.1
125.0
H1
H1
O
O
O
H2
O
H2
H3
H13
H12
S
H12
H11
H14
H15
H3
OC
H4
H4
H16
N
N
N
N
H11
H10
H9
H10
H5
H6
H5
H6
H9
H8
H8
H7
H7
4c
4e
Figure 3
This is further confirmed with NOESY NMR spectra of compounds 4c and 4e in Figure 3. The cross
correlation peaks due to coupling between aromatic protons (δ > 7) and thienyl proton (δ < 7) (H-9/H-10) in
the case of 4c and between aromatic proton of phenyl attached to N (δ > 7) and aromatic proton of
methoxyphenyl group (δ < 7) (H-9/H-10) in the case of 4e have been found. Hence, the synthetic method
adopted in the work has been found to be regioselective favouring compound having structure I (shown in
Figure 2).
EXPERIMENTAL
Melting points were taken on a Thomas Hoover melting point apparatus and are uncorrected. IR (in Nujol)
1
were recorded on a model Perkin-Elmer FTIR-1710 spectrophotometer using KBr pellets. H NMR was
1
3
recorded on a Bruker Avance spectrospin 300 (300 MHz) and C NMR was recorded on a Bruker Topspin
00 (300 MHz) spectrometer using TMS as internal standard. The purity of compounds were checked on
3
silica gel coated aluminium plates (Merck). A Kenstar microwave oven, Model No. OM9925E at (2450
MHz, 800W) was used for MWI. Temperature of the reaction was measured through AZ, Mini Gun Type,
Non-Contact IR Thermometer, Model No. 8868. Elemental analyses were performed using Heraeus
CHN-Rapid Analyzer. EI mass spectra were recorded on a JEOL-JHS-DX 303 mass spectrometer.
General procedure for the synthesis of 3-Arylidene-chromane-2,4-diones 3a-g (STEP 1)

574
HETEROCYCLES, Vol. 71, No. 3, 2007
Method A
To the mixture of 4-hydroxycoumarin 1 (0.01 mol), aromatic/heteroaromatic aldehyde 2a-g (0.01 mol), 3-4
mL of water was added. Irradiate the reaction mixture for appropriate time in microwave. Progress of the
reaction was monitored by TLC examination. The solid obtained was filtered, washed with water and
recrystallised with EtOH.
General procedure for the synthesis of 2-Phenyl-3-aryl[1]benzopyrano[4,3-c] pyrazol-4(2H)-ones 4a-g
(STEP 2)
Method B (Conventional method)
To the mixture of 3-arylidenechromane-2,4-diones 3a-g (0.01 mol), phenylhydrazine hydrochloride (0.015
2 3
mol) and K CO , 10 mL of EtOH was added. Refluxed the reaction mixture for appropriate time with
constant stirring. Reaction was monitored by TLC examination. Upon completion of reaction, the solid
obtained was filtered, washed with water. Then product was purified by column chromatography [column
of silica gel, elution with Benzene:EtOAc 8:2 (v/v) preceded by recrystallisation with EtOH.
Method C (Conventional Method)
To the mixture of 3-arylidenechromane-2,4-diones 3a-g (0.01 mol), phenylhydrazine hydrochloride (0.015
2 3
mol) and K CO , 10 ml of water was added. Refluxed the reaction mixture for appropriate time with
constant stirring. Rest is same as above.
Method D (Microwave assisted synthesis)
In an Erlenmeyer flask, 3-arylidenechromane-2,4-diones 3a-g, phenylhydrazine hydrochloride (0.015 mol)
2 3
and K CO with 2-3 mL of water were taken. The reaction mixture was subjected to microwave irradiation
(
MWI) for a specific time (Table 1) at low power (560 W). The progress of the reaction was monitored by
TLC at an interval of every 30 sec. On completion, the reaction mixture was cooled and filtered, washed
with cold water and dried. Rest is same as above.
-1
1
2
,3-Diphenyl[1]benzopyrano[4,3-c]pyrazol-4[2H]-one 4a; IR ν (cm ) 1593 (C=N), 1666 (C=O); H NMR
+
(
300 MHz, CDCl ) δ (ppm): 7.09-7.52 (m, 14H, Ar-H). MS: m/z 338 (M ). Anal. Calcd for C H N O : C,
3
22 14
2
2
78.1; H, 4.14; N, 8.28. Found: C, 78.23; H, 4.36; N, 8.36.
-1
2
-Phenyl-3-(4-chlorophenyl)[1]benzopyrano[4,3-c]pyrazol-4[2H]-one 4b; IR ν (cm ) 1608 (C=N), 1674
1
(
C=O); H NMR (300 MHz, CDCl
3
) δ (ppm): 6.92 (m, 3H, Ar-H), 7.01 (d, 2H, Ar-H), 7.12 (d, 2H, Ar-H),
+
7
.21-7.34 (m, 6H, Ar-H). MS: m/z 372 (M ). Anal. Calcd for C22
13 2 2
H N O Cl: C, 70.96; H, 3.49; N, 7.52.
Found: C, 70.99; H, 3.64; N, 7.72.
-1
2
-Phenyl-3-(thiophen-2-yl)[1]benzopyrano[4,3-c]pyrazol-4[2H]-one 4c; IR ν (cm ) 1599 (C=N), 1663
1
(
C=O); H NMR (300 MHz, CDCl
3
) δ (ppm): 6.76-6.81 (m, 1H, thienyl H), 6.94 (d, 2H, Ar-H), 7.00 (d, 2H,
+
thienyl H), 7.16-7.21 (m, 5H, Ar-H), 7.34-7.44 (m, 2H, Ar-H). MS: m/z 344 (M ). Anal. Calcd for

HETEROCYCLES, Vol. 71, No. 3, 2007
575
20 12 2 2
C H N O S: C, 69.76; H, 3.55; N, 8.14; S 9.75. Found: C, 69.99; H, 3.62; N, 8.37; S 9.70. NOE
correlations: H-1/H-2, H-3/H-2, -4, H-5/H-6, H-7/H-6, -8, H-9/H-8, -10, H-11/H-10, -12.
-1
2
-phenyl-3-(3-nitrophenyl)[1]benzopyrano[4,3-c]pyrazol-4[2H]-one 4d; IR ν (cm ) 1601 (C=N), 1665
1
(
C=O); H NMR (300 MHz, CDCl
3
) δ (ppm): 7.23-7.41 (m, 8H, Ar-H), 7.67-7.8 (m, 4H, Ar-H), 8.23 (s, 1H,
+
Ar-H). MS: m/z 383 (M ). Anal. Calcd for C H N O : C, 68.92; H, 3.39; N, 10.96. Found: C, 70.12; H,
22
13
3
4
3.78; N, 10.99.
-1
2
-Phenyl-3-(4-methoxyphenyl)[1]benzopyrano[4,3-c]pyrazol-4[2H]-one 4e; IR ν (cm ) 1605 (C=N), 1677
1
(
(
C=O); H NMR (300 MHz, CDCl
3
3
) δ (ppm): 3.84 (s, 3H, OCH ), 6.86-7.53 (m, 13H, Ar-H). MS: m/z 368
+
M ). Anal. Calcd for C H N O : C, 75.00; H, 4.34; N, 7.60. Found: C, 75.42; H, 4.73; N, 7.82. NOE
23
16
2
3
correlations: H-1/H-2, H-3/H-2, -4, H-5/H-6, H-7/H-6, -8, H-9/H-8, -10, H-11/H-10, -OCH
3
/H-11, -12,
H-13/H-12.
-1
2
-Phenyl-3-(benzo[1,3]dioxol-5-yl)[1]benzopyrano[4,3-c]pyrazol-4[2H]-one 4f; IR ν (cm ) 1599 (C=N),
1
1
660 (C=O); H NMR (300 MHz, CDCl
3
2
) δ (ppm): 5.92 (s, 2H, O-CH -O), 6.72 (d, 2H, Ar-H), 7.14-7.39
+
(
m, 10H, Ar-H). MS: m/z 382 (M ). Anal. Calcd for C H N O : C, 72.25; H, 3.66; N, 7.32. Found: C,
23
14
2
4
72.47; H, 3.84; N, 7.46.
-1
2
-Phenyl-3-(2-chloroquinolin-3-yl)[1]benzopyrano[4,3-c]pyrazol-4[2H]-one 4g; IR ν (cm ) 1608 (C=N), 1670
1
(
C=O); H NMR (300 MHz, CDCl
3
) δ (ppm): 6.91-7.45 (m, 10H, Ar-H), 7.56-7.68 (m, 4H, Ar-H). MS: m/z 423
+
(
M ). Anal. Calcd for C H N O Cl: C, 70.84; H, 3.3; N, 9.91. Found: C, 70.96; H, 3.62; N, 10.09.
25 14 3 2
ACKNOWLEDGEMENTS
The authors are thankful to the Council of Scientific and Industrial Research, New Delhi for the financial
assistance.
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