Glycerol as a promoting medium for electrophilic activation of aldehydes: Catalyst-free synthesis of di(indolyl)methanes, xanthene-1,8(2H)-diones and 1-oxo-hexahydroxanthenes

Article abstract of DOI:10.1039/b916015a

Glycerol was used, for the first time, as a green and effective promoting medium for electrophilic activation of aldehydes, and with which, a catalyst-free system for some reactions that conventionally carried out using acid catalysts, such as synthesis o

Full text of DOI:10.1039/b916015a

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PAPER
www.rsc.org/greenchem | Green Chemistry
Glycerol as a promoting medium for electrophilic activation of aldehydes:
catalyst-free synthesis of di(indolyl)methanes, xanthene-1,8(2H)-diones and
1-oxo-hexahydroxanthenes
Fei He,a Peng Li,a Yanlong Gu*a,b and Guangxing Lia,b
Received 17th July 2009, Accepted 4th August 2009
First published as an Advance Article on the web 7th September 2009
DOI: 10.1039/b916015a
Glycerol was used, for the first time, as a green and effective promoting medium for electrophilic
activation of aldehydes, and with which, a catalyst-free system for some reactions that
conventionally carried out using acid catalysts, such as synthesis of di(indolyl)methanes,
3,4,5,6,7,9-hexahydro-9-aryl-1H-xanthene-1,8(2H)-dione and 1-oxo-hexahydroxanthenes, was
developed.
production of glycerol offers a good opportunity to chemists to
Introduction
use it as renewable material to prepare green and biomass-based
The biodiesel industry generates a tremendous amount of crude
solvents, for example, new ionic liquids.4 Taking the inherent
glycerol as a by-product. The large surplus of glycerol, which has
properties of glycerol, such as a long liquid range, nonflamma-
entered the chemical market, has caused the closure of existing
bility and unique solubility for polar organic compounds, into
glycerol plants and the discovery of processes that use glycerol
consideration, the direct use of glycerol as a solvent for organic
as a raw material for the production of value-added chemicals
reactions would, if realized, fit perfectly the requirements of a
and even of energy. It is undoubted that increasing demand
green solvent. It should be noted that, as a solvent, data about
of biodiesel will put an additional pressure upon the glycerol
the toxicity and environmental compatibility have to be collected
market in the future. Therefore, rational utilizations of glycerol
before its utilizations on a large scale. In this respect, a good
have gained much attention recently. Today, most of the efforts
understanding of glycerol, as well as positive data, is helpful for
in this area are focusing on the development of an alternative
the commercialization of the processes related to glycerol sol-
way, starting from glycerol, to prepare old chemicals that have
vents. However, the necessity and effectiveness of glycerol solvent
either been prepared from petrochemicals or suffered from envi-
have not been well-recognized yet, owing to a lack of successful
ronmental problems during their preparation. Many successful
examples. Wolfson’s group5 reported that glycerol could be used
examples could be found in some comprehensive reviews.1 It
as alternative solvent for Pd-catalyzed Heck C–C coupling and
should be noted that although some promising approaches were
Suzuki reactions. Although isolation of product is relatively easy,
developed, the large-scale synthesis of new molecules starting
no significant improvement in terms of reaction behaviour or
from glycerol necessitates a systematic evaluation of toxicity,
catalytic performance was identified in glycerol. Quite recently,
capacity and stability of the product, which will inevitably
we and Je´roˆme,6 observed that glycerol can be used as a
cost a lot of time and also make a hard task for researchers.
promising medium for organic reactions, such as the aza-
Therefore, synthesis of new compounds using glycerol as starting
material is, to some extent, not favorable from the perspective of
Michael reaction, Fridel–Crafts type addition of indole to a,b-
unsaturated ketones and ring-opening of epoxide with amine,
industry. Although chemical conversions of glycerol have gained
under catalyst-free conditions. These observations verified that
much attention, importance of non-transformative technologies
glycerol can indeed be used as an effective solvent for develop-
have rarely been mentioned in literature. Confronted with huge
ment of new synthetic methodologies. In a continuation of our
pressure coming from biodiesel industry, more efforts are needed
research on the use of glycerol as a solvent for organic reaction,
to allow the development of new and innovative processes by
using glycerol.2
On the other hand, development of green solvents from
we report here that glycerol can be used as an effective medium
for promoting the electrophilic activity of aldehydes. Some
condensation reactions of aldehydes that are conventionally
renewable resources has gained much attention recently, because
carried out using acid catalysts could be performed in catalyst-
of the extensive uses of solvents in almost all of the chemical
free conditions in glycerol. It is particularly useful for the
industry, and of the predicted disappearance of fossil oil.3 Huge
synthesis of di(indolyl)methanes, 3,4,5,6,7,9-hexahydro-9-aryl-
1H-xanthene-1,8(2H)-dione and 1-oxo-hexahydroxanthenes.
aInstitute of Physical Chemistry and Industrial Catalysis, School of
Chemistry and Chemical Engineering, Huazhong University of Science
Results and discussion
and Technology (HUST), 1037 Luoyu road, Hongshan District, Wuhan,
430074, China; Fax: +86 (0)27 87 54 45 32. E-mail: klgyl@hust.edu.cn
Initially,
reaction
between
4-nitrobenzaldehyde
and
bHubei Key Laboratory of Material Chemistry and Service Failure,
Huazhong University of Science and Technology, Wuhan, 430074,
P R China
2-methylindole was investigated in different solvents under
catalyst-free conditions, and the results are listed in Table 1.
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Table 1 Reaction between 4-nitrobenzaldehyde and 2-methylindole in
Table 2 Reaction between 2-methylindole and aldehydes in glycerola
different solventsa
Entry Aldehyde
Product Time/h Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12b
13
14
15
16b
17
18
Benzaldehyde
p-Tolualdehyde
4-Methoxybenzaldehyde
4-Hydroxybenzaldehyde
2-Methoxybenzaldehyde
4-Chlorobenzaldehyde
Veratraldehyde
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
21.0
2.5
1.5
1.5
2.0
24.0
5.0
7.5
1.5
4.0
3.0
5.0
9.0
4.0
9.0
15.0
8.0
14.0
98
98
95
98
97
75
85
97
93
95
98
96
87
94
90
75
98
0
Entry
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
10
11b
12c
13d
Toluene
DMF
DMSO
n-Butyl acetate
No solvent
n-Butanol
Polyethylene glycol 400
Ethylene glycol
Water
Glycerol
Glycerol
Glycerol
Glycerol
< 5
< 5
< 5
< 5
< 5
38e
85
Salicyladehyde
3-Ethoxysalicylaldehyde
5-Bromosalicylaldehyde
Vanillin
4-Acetoxybenzaldehyde
4-Acetamidobenzaldehyde
2-Nitrobenzaldehyde
3-Phenylpropionaldehyde
4-Dimethylaminobenzaldehyde 3q
Furfural
Propiophenone
85
76e
95
64e
62e
91
3u
—
a 1a: 1 mmol; 2a: 2.0 mmol; solvent: 2.0 ml. b Glycerol: 1.0 ml. c 1.5 h.
d The reaction was performed on the 10.0 mmol scale, e Product was
obtained after PTLC.
a 2-Methylindole: 1.0 mmol, aldehyde: 0.5 mmol; glycerol: 1.0 ml, 90 ◦C.
b 100 ◦C.
Only a trace amount of product was detected in toluene, DMF,
DMSO, n-butyl acetate and in neat conditions (entries 1 to 5).
While the reaction proceeded sluggishly in n-butanol, a huge
improvement was observed in polyethylene glycol and ethylene
glycol (entries 6 to 8). Although water was proved to be capable
of promoting the reaction, in this case, solvent extraction and
silica chromatography needed to be used in order to separate
and purify the product (entry 9).
Because glycerol is highly hydrophilic, separation of the product
from glycerol could be realized by adding water at 60 ◦C. In order
to completely remove glycerol from solid product, washing with
water was necessary.7 This simple procedure allows easy scale-
up of our methodology. Indeed, 91% yield was obtained in the
10.0-mmol-scale reaction (entry 13).
Inspired by the observed determinant effect of alcoholic
solvents on the reaction, we then investigated the feasibility of
using glycerol as the solvent for this reaction. As we expected, the
reaction proceeded very well, and 95% yield was obtained under
identical conditions (entry 10). Further investigation revealed
that the result is affected by amount of glycerol and reaction
time, and the optimal conditions, we found, were 2.0 ml of
glycerol and 3.0 h (entries 11 and 12). Interestingly, in the
beginning of the reaction, a solution, which seems to be nearly
transparent, was observed because both 4-nitrobenzaldehyde
and 2-methylindole are soluble in glycerol (Fig. 1a). The later
formed a product, which is a solid at reaction temperature, was
found to be insoluble in glycerol, and consequently, with progress
of the reaction, a yellow solid was observed (Fig. 1b); and at the
end of the reaction, large amount of solid product was formed.
This makes stirring of the reaction mixture difficult (Fig. 1c).
It should be noted that reactions between aldehydes and
indoles are generally carried out in the presence of acids,
such as HCl,8 P2O5,9 Amberlyst-1510 and other solid acids,11
or metal-containing catalysts including Bi(NO3)3,12 Sc(OTf)3,13
14
Dy(OTf)3 and InCl3,15 with the aid of organic solvents or
ionic liquids.16 Obviously, synthesis with these reported methods
not only generates a lot of organic or inorganic wastes during
the work-up procedure, but also suffers from the difficulty of
removing trace amount of residue metal species from the product
when it is applied in pharmaceutical synthesis. Particularly, when
solid acids are used as catalysts, owing to the fact that both the
catalyst and the product are solid, in order to separate them and
recover the catalyst, a large amount of organic solvent has to
be used.17 Performing the model reaction in glycerol not only
offers a high reaction yield, but also avoids: (i) generation of
toxic wastes; (ii) the use of large amount of organic solvent or
catalyst; and (iii) tedious post-treatment. Therefore, our system
is an attractive strategy for the synthesis of the target compound
from the viewpoint of green synthesis.
With these results in hand, we then investigated the substrate
scopes and limitations of glycerol-mediated synthesis of
di(indolyl)methane, and the results are listed in Table 2
and Table 3. Many aldehydes including benzaldehyde, p-
tolualdehyde, 4-methoxybenzaldehyde, 4-hydroxybenzaldehyde,
vanillin,
veratraldehyde,
3-ethoxysalicylaldehyde,
2-methoxybenzaldehyde,
4-chlorobenzaldehyde,
5-bromosalicylaldehyde,
salicylaldehyde,
Fig. 1 Progress of the model reaction in glycerol (a: beginning of the
reaction; b: running of the reaction; c: the end of the reaction).
4-acetoxybenzaldehyde,
4-
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Table 3 Reaction between aldehyde and different indole derivatives in glycerola
Entry
1
Indole
Aldehyde
Product
Temp./◦C
100
Time/h
12.5
Yield (%)
3v
82
2
3w
90
8.5
89
3
3r
3s
3t
90
7.0
97
75
65
4b
5b
120
120
32.0
32.0
a aldehyde: 0.5 mmol, indole derivative: 1.0 mmol, glycerol: 1.0 ml; b product was obtained by PTLC.
acetamidobenzaldehyde and 2-nitrobenzaldehyde reacted
readily with 2-methylindole to afford the corresponding
products in good to excellent yields (Table 2, entries 1 to 14).
Not only aromatic aldehydes, but also aliphatic aldehydes, such
as 3-phenylpropionaldehyde, were applicable in this system,
and the product was obtained in 90% yield (entry 15). Because
no acid or metal containing catalysts were used, our system
thus allows the use of acid-labile substrates. For example,
4-dimethylaminobenzaldehyde, which tends to poison acid or
metal-containing species by means of acid–base interaction
or coordination, can be converted into the desired product in
high yields without damage to the tertiary amine group (entry
16). Furthermore, furfural, which was known as acid-sensitive
species, was also proved to be applicable in the glycerol system
(entry 17), indicating the usefulness of our methodology.
Limitations were found in the reactions of ketone, such as
acetophenone, which is generally less reactive in the model
reaction compared with aldehydes (entry 18).
When salicylaldehyde, 4-acetamidobenzaldehyde or 2-
hydroxy-1-naphthaldehyde was used as substrate, the reac-
tions of indole, 2-methyl-5-methoxyindole and 1-methylindole
proceeded smoothly in glycerol to afford the corresponding
products in moderate to good yields (Table 3, entries 1 to 3).
However, indoles with a phenyl group in C2 position showed,
unfortunately, a relatively lower reactivity compared with that
of indoles with methyl group. For example, while 87% yield was
obtained with 2-methylindole after 9 h at 90 ◦C, only 75% of
yield was achieved with 2-phenylindole after 32 h of reaction
at 120 ◦C (entry 4). The reasoning behind this low reactivity
is 2-fold: (i) steric hindrance of the phenyl group; and (ii) the
electron withdrawing effect.
The obtained results have clearly shown that glycerol can
be used as a promoting medium for electrophilic activation
of aldehydes. Encouraged by these promising results, we
then investigated another electrophilic reaction of aldehyde
in glycerol: condensation between aromatic aldehyde and
1,3-cyclohexanedione that gives 3,4,5,6,7,9-hexahydro-9-aryl-
1H-xanthene-1,8(2H)-dione exclusively. In the literature,
this reaction has been extensively investigated. The reported
examples showed that either Lewis acids or protic acids
have to be used in order to make the reaction proceed.18
It was very interesting to find that reaction between 4-
acetamidobenzaldehyde and 1,3-cyclohexanedione proceeded
well in glycerol without the use of any catalyst, and the
desired product was obtained in 85% yield (Table 4, entry
1). Glycerol was proven to be an unique promoting solvent
again, as a lesser amount of product was detected in DMF,
DMSO, n-butanol, toluene, nitromethane, polyethylene glycol,
ethylene glycol and water under the identical conditions
(entries 2 to 9). Because of the fact that the obtained product
is not soluble in glycerol, it could be separated easily with
the same procedure in the first part of this work (Fig. 2).
Other aldehydes, such as benzaldehyde, p-tolualdehyde,
4-methoxybenzaldehyde, 2-methoxybenzaldehyde, vanillin,
4-hydroxybenzaldehyde, 4-chlorobenzaldehyde, veratraldehyde,
4-nitrobenzaldehyde and 2-nitrobenzaldehyde were proven
to be applicable in this system (entries 10 to 19). Identical
to the previous system, neutral conditions in the glycerol
system allow the successful use of some acid-labile substrates,
such as 4-acetoxybenzaldehyde, furfural, cinnamaldehyde and
4-dimethylaminobenzaldehyde, indicating again the usefulness
of our system (entries 20 to 23). Other 1,3-cyclohexanediones,
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Table 4 Condensation between aldehydes and 1,3-cyclohexanedione in
Table 5 Reaction between salicylaldehydes and 1,3-cyclohexanedione
different solventsa
in glycerola
Entry Aldehyde
1
Product Time/h Yield (%)
Entry Indole
1
Product
Time/h
12.5
Yield (%)
84
4a
1.0
85
5a
2b
3c
4d
5e
6f
7g
8h
9i
10
11
12
13
14
15
16
17
18
19
20
21
22
23
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
3.0
2.5
6.0
5.5
2.5
3.0
2.5
6.0
3.0
4.0
6.0
3.0
3.5
6.0
<10
<10
<10
<10
42
47
75
77
87
90
92
91
90
92
95
99
77
83
82
2
5b
12.5
90
3
5c
5d
5e
6.0
88
78
98
Benzaldehyde
p-Tolualdehyde
4-Hydroxybenzaldehyde
4-Chlorobenzaldehyde
4-Methoxybenzaldehyde
2-Methoxybenzaldehyde
Vanillin
4
12.5
3.5
5b
Veratraldehyde
4-Nitrobenzaldehyde
2-Nitrobenzaldehyde
4-Acetoxybenzaldehyde
a Salicylaldehyde: 0.5 mmol, 1,3-cyclohexanedione: 1.0 mmol, glycerol:
1.0 ml. b 100 ◦C.
4-Dimethylaminobenzaldehyde 4m
88
50
98
Cinnamaldehyde
Furfural
4n
4o
a A◦ldehyde: 0.5 mmol, 1,3-cyclohexanedione: 1.0 mmol, glycerol: 2.0 g,
90 C. b Solvent: toluene. c Solvent: DMF. d Solvent: DMSO. e CH3NO2.
f Solvent: n-butyl acetate. g Solvent: polyethylene glycol. h Ethylene
glycol. i Solvent: water.
such as dimedone and 5-methyl-cyclohexane-1,3-dione, also
reacted readily with 4-nitrobenzaldehyde in glycerol to afford
the corresponding products in excellent yields (Scheme 1).
Scheme 1 Reactions between 4-nitrobenzaldehyde and different 1,3-
cyclohexanediones in glycerol.
1-oxo-hexahydroxanthenes, which makes the methodology quite
attractive from the viewpoints of waste minimization and conve-
nient product separation. In glycerol system, other salicylaldehy-
des, such as 5-bromosalicylaldehyde, 3-methoxysalicylaldehyde,
3-ethoxysalicylaldehyde and 2-hydroxy-1-naphthaldehyde have
also been converted smoothly, and the desired 1-oxo-
hexahydroxanthenes were obtained in moderate to high yields
(entries 2 to 5). These results further verified the effectiveness of
glycerol solvent in promoting electrophilic activity of aldehydes.
Fig. 2 Progress of the reaction between 4-acetamidobenzaldehyde and
1,3-cyclohexanedione in glycerol without any catalysts [(a): beginning
of the reaction; (b): after 30–40 min of reaction at 90 ◦C; (c): the end of
the reaction].
Furthermore, when salicylaldehyde was used in the re-
action of 1,3-cyclohexanedione, 1-oxo-hexahydroxanthene,
which has been proven to be bioactive recently,19 was ob-
tained instead of 3,4,5,6,7,9-hexahydro-9-(2-hydroxyphenyl)-
1H-xanthene-1,8(2H)-dione (Table 5, entry 1). This reaction
has been recognized as an acid-catalyzed reaction, and the aid of
organic solvents is necessary in the previous reported systems.20
Our system offers a catalyst-free method for the synthesis of
Conclusions
In conclusion, glycerol was proved to be an effective medium to
promote electrophilic activity of aldehydes. In glycerol and in
the absence of any catalyst, many aldehydes reacted readily with
indoles and 1,3-cyclohexanedione to afford the corresponding
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di(indolyl)methane derivatives, 3,4,5,6,7,9-hexahydro-9-aryl-
1H-xanthene-1,8(2H)-diones and 1-oxo-hexahydroxanthenes in
good to excellent yields. Compared with previously reported
systems composedof acid catalysts and organic solvents, glycerol
solvent not only makes the product separation much easier,
but also shows higher environmental compatibility and sustain-
ability considering the following two factors: (i) avoidance of
quenching step allows the use of less amount of toxic organic
solvent and minimization of waste; and (ii) glycerol is, currently,
a by-product of the biodiesel industry and its utilization needs
to be extended urgently. These observations also promote the
advance of solvent innovations. Despite these good results, we
are uncertain as to the reasons behind the significant effects of
glycerol on these reactions, though it is likely due to the strong
hydrogen bonds between the carbonyl of the aldehyde and the
alcoholic solvent. This is, no doubt, the next issue needing to be
addressed. The unique ability of glycerol might also be useful
for other catalytic or organic reactions, and the investigations
on these lines are underway in our group.
8.0 Hz, Jb= 10.0 Hz, 3H), 6.89 (t, J = 7.2 Hz, 2H), 7.05 (d,
J = 2.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 3H), 9.55 (s, 1H), 10.70
(s, 2H); 13C NMR: 12.3, 33.4, 110.1, 110.8, 111.8, 117.5, 118.5,
120.0, 128.9, 130.0, 132.3, 132.5, 133.9, 135.4, 155.1; IR (cm-1):
3398, 3055, 2916, 1616.3, 1460, 1426, 1340, 1303, 1263, 1221,
1103, 1017, 819, 744; anal. calcd for C25H21BrN2O: C: 67.42; H:
4.75; N: 6.29; found: C: 67.09; H: 4.56; N: 6.51.
Bis(2-methyl-3-indolyl)(4-acetoxyphenyl)methane
(3m).
White solid, mp: 284–286 ◦C; 1H NMR (DMSO-d6): 2.10 (s,
6H), 2.24 (s, 3H), 5.96 (s, 1H), 6.70 (t, J = 7.2 Hz, 2H), 6.85
(d, J = 8.0 Hz, 2H), 6.90 (t, J = 7.2 Hz, 2H), 7.01 (d, J =
8.4 Hz, 2H), 7.23 (t, J = 7.6 Hz, 4H), 10.76 (s, 2H); 13C NMR:
12.4, 21.3, 38.6, 110.8, 112.6, 118.5, 119.0, 120.1, 121.7, 128.7,
130.0, 132.6, 135.6, 142.2, 149.0, 169.7; IR (cm-1): 3391, 3058,
1737, 1503, 1461, 1428, 1369, 1347, 1304, 1224, 1194, 1164,
1097, 1016, 941, 915, 866, 844, 745, 611, 597; anal. calcd for
C27H24N2O2: C: 79.39; H: 5.92; N: 6.86; found: C: 79.61; H:
5.94; N: 6.83.
Bis(2-methyl-3-indolyl)(4-acetamidophenyl)methane
(3n).
◦
1
Experimental
White solid, mp: 275–277 C; H NMR (DMSO-d6): 2.04 (s,
3H), 2.09 (s, 6H), 5.89 (s, 1H), 6.70 (t, J = 7.2 Hz, 2H), 6.85
(d, J = 8.0 Hz, 2H), 6.90 (t, J = 8.0 Hz, 2H), 7.11 (d, J =
8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H),
9.89 (s, 1H), 10.73 (s, 2H); 13C NMR: 12.4, 24.4, 38.6, 110.8,
112.8, 118.4, 119.0, 119.2, 120.0, 128.8, 129.3, 132.5, 135.5,
137.6, 139.3, 168.5; IR (cm-1): 3386, 3294, 3052, 2918, 2868,
1672, 1613, 1556, 1513, 1458, 1405, 1356, 1305, 1246, 1180,
1155, 1128, 1096, 1015, 836, 750, 669, 629, 501; anal. calcd for
C27H25N3O: C: 79.58; H: 6.18; N: 10.31; found: C: 79.66; H:
6.01; N: 10.42.
All the reactions were conducted in a 10 mL V-type flask
equipped with triangle magnetic stirring. In a typical reaction,
glycerol (2.0 ml) was mixed with 2-methylindole (262 mg, 2.0
mmol) and p-nitrobenzaldehyde (151 mg, 1.0 mmol) under air.
◦
The mixture was stirred for 3.0 h at 90 C. After reaction, the
mixture was mixed at 60 ◦C with water (6 mL). After 15 min of
stirring, the crude mixture was filtered and washed with water.
After drying at room temperature, the product was obtained in
95% of yield.
Spectroscopic data of new compounds
3,3¢-(3-Phenyl)propylidenebis[2-methyl-1H-indole]
(3p).
◦
1
White solid, mp: 188–190 C, H NMR (DMSO-d6): 2.31 (s,
6H), 2.62 (s, 4H), 4.39 (s, 1H), 6.82 (t, J = 7.6 Hz, 2H), 6.91 (t,
J = 7.2 Hz, 2H), 7.09-7.18 (m, 3H), 7.18-7.27 (m, 4H), 7.49 (d,
J = 8.0 Hz, 2H), 10.65 (s, 2H); 13C NMR: 12.8, 34.1, 34.8, 36.6,
118.4, 119.0, 119.9, 126.1, 128.2, 128.7, 128.7, 131.7, 135.6,
142.8; IR (cm-1): 3497, 3058, 3044, 2932, 1590, 1551, 1479,
1452, 1426, 1369, 1327, 1269, 1236, 1226, 1201, 1178, 1162,
1152, 1129, 1117, 1084, 1058, 1010, 868, 805, 747, 553; anal.
calcd for C27H26N2: C: 85.68; H: 6.92; N: 7.40; found: C: 85.89;
H: 6.71; N: 7.66.
Bis(2-methyl-3-indolyl)(2-methoxyphenyl)methane
(3f).
◦
1
White solid, mp: 240–242 C; H NMR (DMSO-d6): 1.92 (s,
3H), 3.59 (s, 3H), 6.04 (s, 1H), 6.60 (t, J = 7.2 Hz, 2H), 6.74 (t,
J = 6.8 Hz, 3H), 6.81 (t, J = 7.2 Hz, 2H), 6.91 (d, J = 7.6 Hz,
1H), 7.01 (d, J = 7.2 Hz, 1H), 7.14 (d, J = 7.6 Hz, 3H), 10.59
(s, 2H); 13C NMR: 12.3, 33.1, 56.0, 110.7, 111.2, 112.4, 118.3,
118.7, 119.9, 120.3, 127.8, 129.1, 130.2, 132.1, 132.7, 135.4; IR
(cm-1): 3392, 3055, 2919, 2835, 1619, 1596, 1488, 1461, 1434,
1346, 1302, 1244, 1163, 1103, 1018, 783, 744, 603; anal. calcd
for C27H24N2O2: C: 82.07; H: 6.36; N: 7.36; found: C: 82.21; H:
6.24; N: 6.33.
1-(Di-1H-indol-3-ylmethyl)-2-naphthalenol
(3v). White
solid, mp: 224–226 ◦C; 1H NMR (DMSO-d6): 6.83 (t, J =
7.6 Hz, 4H), 6.91 (s, 1H), 7.01 (t, J = 7.2 Hz, 2H), 7.05-7.15
(m, 2H), 7.32 (t, J = 8.8 Hz, 5H), 7.68 (dd, Ja = 4.0 Hz, Jb =
9.2 Hz, 2H), 8.34 (t, J = 4.4 Hz, 1H), 9.91 (bs, 1H), 10.72 (d,
J = 1.6 Hz, 2H); 13C NMR: 30.6, 111.8, 117.4, 118.5, 118.8,
119.7, 121.3, 121.7, 122.3, 124.3, 125.0, 127.8, 128.5, 128.7,
129.4, 134.1, 136.8, 152.3; IR (cm-1): 3469, 3407, 3050, 1620,
1600, 1517, 1455, 1414, 1398, 1356, 1337, 1263, 1211, 1148,
1121, 1093, 1027, 1009, 949, 826, 780, 750, 598, 512; anal. calcd
for C27H20N2O: C: 83.48; H: 5.19; N: 7.21; found: C: 82.44; H:
5.01; N: 7.50.
2-[Bis(2-methyl-1H-indol-3-yl)methyl]-3-ethoxyphenol (3j).
◦
1
White solid, mp: 248–250 C; H NMR (DMSO-d6):1.31 (t, J
= 6.4 Hz, 3H), 2.02 (s, 6H), 4.0 (dd, Ja = 6.8 Hz, Jb = 12.8 Hz,
2H), 6.09 (s, 1H), 6.59 (t, J = 7.6 Hz, 1H), 6.65 (t, J = 7.6 Hz,
1H), 6.83 (quint, J = 7.2 Hz, 5H), 7.18 (d, J = 8.0 Hz, 2H),
8.09 (s, 1H), 10.61 (s, 2H), 13C NMR: 12.3, 15.2, 33.2, 64.6,
110.6, 111.3, 112.7, 118.2, 118.3, 118.8, 119.8, 122.5, 129.2,
131.3, 132.1, 135.4, 144.8, 146.5; IR (cm-1): 3473, 3389, 3052,
2980, 1612, 1463, 1344, 1271, 1220, 1057, 742; anal. calcd for
C27H26N2O2: C: 79.00; H: 6.38; N: 6.82; found: C: 79.32; H:
6.21; N: 7.03.
2-[Bis(2-methyl-1H-indol-3-yl)methyl]-4-bromophenol (3k).
White solid, mp: 228–230 C, H NMR (DMSO-d6): 2.08 (s,
2-[Bis(2-methyl-5-methox◦y-1H-indol-3-yl)methyl]phenol (3w).
◦
1
1
White solid, mp: 246–248 C, H NMR (DMSO-d6): 2.08 (s,
6H), 6.01 (s, 1H), 6.73 (t, J = 6.8 Hz, 2H), 6.79 (dd, Ja
=
6H), 3.34 (s, 6H), 5.92 (s, 1H), 6.24 (d, J = 2.4 Hz), 6.50 (dd,
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Ja = 2.4 Hz, Jb = 8.8 Hz, 2H), 6.68 (t, J = 7.6 Hz, 1H), 6.80
(d, J = 7.6 Hz, 1H), 7.05 (dd, Ja = 8.8 Hz, Jb = 14.4 Hz, 4H),
9.07 (s, 1H), 10.47 (s, 2H); 13C NMR: 12.3, 33.3, 55.1, 101.6,
109.0, 111.1, 112.5, 115.4, 118.7, 127.3, 129.5, 130.3, 130.6,
130.9, 132.9, 152.7, 155.7; IR (cm-1): 3475, 3383, 2950, 2832,
1622, 1583, 1484, 1451, 1350, 1298, 1252, 1212, 1087, 1033, 963,
841, 803, 618; anal. calcd for C27H26N2O3: C: 76.03; H: 6.14; N:
6.57; found: C: 76.27; H: 5.98; N: 6.79.
149.2, 165.4, 169.7, 196.8; IR (cm-1): 2959, 2929, 1748, 1664,
1628, 1506, 1423, 1360, 1221, 1201, 1173, 1129, 1015, 957, 920,
856, 537; anal. calcd for C22H22O4: C: 75.41; H: 6.33; found: C:
75.58; H: 6.09.
Acknowledgements
The authors thank for the initiatory financial support from
HUST. The authors are also grateful for Ms Ping Liang and
all the other stuffers in the Analytical and Testing Center of
HUST, for their supportive and constant contributions to our
works.
3,3¢-[(4-Acetamidophenyl)methylene]bis[1-methyl-1H-indole]
(3r). White solid, mp: 198–200 ◦C; 1H NMR (DMSO-d6):
2.02 (s, 3H), 3.67 (s, 6H), 5.78 (s, 1H), 6.79 (s, 2H), 6.90 (t, J =
7.6 Hz, 2H), 7.09 (t, J = 7.6 Hz, 2H), 7.28 (dd, Ja = 8.0 Hz, Jb
= 13.2 Hz, 4H), 7.35 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz,
2H), 9.87 (s, 1H); 13C NMR: 24.4, 32.7, 118.0, 118.8, 119.4,
119.7, 121.5, 127.4, 128.3, 128.9, 137.5, 137.7, 139.9, 168.5; IR
(cm-1): 3316, 3049, 2932, 2827, 1666, 1600, 1539, 1513, 1473,
1406, 1370, 1323, 1267, 1233, 1155, 1119, 1061, 1013, 862, 794,
740, 526; anal. calcd for C27H25N3O: C: 79.58; H: 6.18; N: 10.31;
found: C: 79.81; H: 6.33; N: 10.55.
Notes and references
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acceptable way to use or treat the generated aqueous solution of
glycerol.
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3,3¢-[(4-Acetamidophenyl)methylene]bis[2-phenyl-1H -indole
(3s). White solid, mp > 300 ◦C (decomposed); 1H NMR
(DMSO-d6): 2.04 (s, 3H), 5.96 (s, 1H), 6.72 (t, J = 7.6 Hz,
2H), 6.98 (d, J = 8.0 Hz, 2H), 7.03 (t, J = 8.0 Hz, 2H), 7.09
(d, J = 8.0 Hz, 2H), 7.16–7.29 (m, 6H), 7.35 (d, J = 2.4 Hz,
2H), 7.33 (s, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz,
2H), 9.93 (s, 1H), 11.35 (s, 2H); 13C NMR: 19.0, 24.4, 111.8,
114.9, 119.0, 119.4, 121.4, 121.4, 127.7, 128.5, 128.7, 128.8,
129.3, 133.3, 135.8, 136.8, 137.7, 140.6, 168.6; IR (cm-1): 3392,
3058, 1675, 1657, 1603, 1543, 1512, 1452, 1425, 1405, 1373,
1315, 1273, 1042, 1024, 823, 767, 745, 698, 509; anal. calcd for
C37H29N3O: C: 83.59; H: 5.50; N: 7.90; found: C: 83.66; H: 5.39;
N: 8.05.
2-[Bis(1-methyl-2-phe◦nylindol-3-yl)methyl]phenol (3t). Yel-
low solid, mp: 170–172 C, 1H NMR: 3.42 (s, 6H), 5.09 (s, 1H),
5,68 (s, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.77–6.88 (m, 7H), 7.03
(d, J = 8.0 Hz, 2H), 7.09–7.17 (m, 8H), 7.19–7.21 (m, 1H), 7.22
(s, 1H), 7.23–7.26 (m, 2H); 13C NMR: 30.8, 35.7, 109.3, 116.1,
119.5, 120.6, 120.9, 121.4, 127.5, 127.7, 127.9, 128.0, 129.8,
130.3, 130.6, 131.4, 137.3, 154.4; anal. calcd for C37H30N2O:
C: 85.68; H: 5.83; N: 5.40; found: C: 85.89; H: 5.69; N: 5.67.
3,4,5,6,7,9-Hexahydro-9-(4-acetamidophenyl)-1H-xanthene-
◦
1
1,8(2H)-dione (4a). White solid, mp: 226–228 C; H NMR
(DMSO-d6): 1.77–1.90 (m, 2H), 1.90–1.97 (m, 2H), 1.95 (s, 3H),
2.19–2.35 (m, 4H), 2.53–2.71 (m, 4H), 4.53 (s, 1H), 7.08 (d,
J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 9.81 (s, 1H); 13C
NMR: 20.3, 24.3, 26.9, 30.7, 36.9, 39.4, 116.0, 119.4, 128.6,
137.8, 139.8, 165.1, 168.5, 196.8; IR (cm-1): 3536, 3306, 2959,
2926, 1665, 1607, 1548, 1512, 1413, 1358, 1326, 1274, 1201, 1175,
1130, 1014, 958, 905, 762; anal. calcd for C22H23NO3: C: 75.62;
H: 6.63; N: 4.01; found: C: 75.83; H: 6.49; N: 4.27.
15 (a) G. Babu, N. Sridhar and P. T. Perumal, Synth. Commun., 2000, 30,
1609–1614; (b) R. Nagarajan and P. T. Perumal, Tetrahedron, 2002,
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2003, 345, 349–352; (b) D. -G. Gu, S. -J. Ji, Z. -Q. Jiang, M. -F. Zhou
and T. -P. Loh, Synlett, 2005, 959–962.
3,4,5,6,7,9-Hexahydro-9-(4-acetoxyphenyl)-1H -xanthene-
◦
1
1,8(2H)-dione (4l). White solid, mp: 227–228 C; H NMR
(DMSO-d6): 1.78–1.91 (m, 2H), 1.91–2.01 (m, 2H), 2.05–2.13
(m, 2H), 2.22 (s, 3H), 2.25–2.33 (m, 3H), 2.55–2.72 (m, 3H),
4.60 (s, 1H), 6.95 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H);
13C NMR: 20.3, 21.3, 26.9, 30.9, 36.8, 115.9, 121.7, 129.4, 142.4,
17 V. T. Kamble, K. R. Kadam, N. S. Joshi and D. B. Muley, Catal.
Commun., 2007, 8, 498–502.
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18 (a) B. Das, M. Krishnaiah, K. Laxminarayana, K. Damodar and
D. N. Kumar, Chem. Lett., 2008, 37, 1000–1001; (b) S. Kantevari, R.
Bantu and L. Nagarapu, J. Mol. Catal. A: Chem., 2007, 269, 53–57;
(c) G. I. Shakibaei, P. Mirzaei and A. Bazgir, Appl. Catal., A, 2007,
325, 188–192; (d) A. John, P. J. P. Yadav and S. Palaniappan, J. Mol.
Catal. A: Chem., 2006, 248, 121–125; (e) B. Das, P. Thirupathi, I.
Mahender, V. S. Reddy and Y. K. Rao, J. Mol. Catal. A: Chem.,
2006, 247, 233–239.
19 N. Sato, M. Jitsuoka, T. Shibata, T. Hirohashi, K. Nonoshita, M.
Moriya, Y. Haga, A. Sakuraba, M. Ando, T. Ohe, H. Iwaasa, A.
Gomori, A. Ishihara, A. Kanatani and T. Fukami, J. Med. Chem.,
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4474–4479.
This journal is
The Royal Society of Chemistry 2009
Green Chem., 2009, 11, 1767–1773 | 1773
©