Efficient non-catalytic synthesis of substituted 2,3,4,9-tetrahydro-1H-xanthen-1-ones from salicylaldehydes and dimedone

Article abstract of DOI:10.1016/j.mencom.2015.01.006

Thermally induced non-catalytic assembling of salicylaldehydes and dimedone in water or ethanol affords 9-(2-hydroxy-4,4-dimethyl- 6-oxo-1-cyclohexen-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-ones in 85-95% yields as a sequence of Knoevenagel and

Full text of DOI:10.1016/j.mencom.2015.01.006

Mendeleev
Communications
Mendeleev Commun., 2015, 25, 19–20
Efficient non-catalytic synthesis of substituted 2,3,4,9-tetrahydro-
H-xanthen-1-ones from salicylaldehydes and dimedone
1
a
b
a
Michail N. Elinson,* Olga O. Sokolova, Ruslan F. Nasybullin,
c
a
Tatiana A. Zaimovskaya and Mikhail P. Egorov
a
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: + 7 499 135 5328; e-mail: elinson@ioc.ac.ru
Higher Chemical College, Russian Academy of Sciences, 125047 Moscow, Russian Federation
A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, 119991 Moscow, Russian
Federation
b
c
DOI: 10.1016/j.mencom.2015.01.006
Thermally induced non-catalytic assembling of salicylaldehydes and dimedone in water or ethanol affords 9-(2-hydroxy-4,4-dimethyl-
-oxo-1-cyclohexen-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-ones in 85–95% yields as a sequence of Knoevenagel and
6
Michael reactions.
Neuropeptide Y (NPY) is a powerful stimulant of food intake
and is proposed to activate a hypothalamic ‘feeding’ receptor
Me Me
1
distinct from previously cloned Y-type receptors. Six distinct
R1
O
O
2
OH
O
types of G-protein-coupled NPY receptors (Y1–Y6) are known.
O
EtOH
O
+
2
Correlations between the in vitro function and the binding activity
78°C,
3 min
R1
OH
of different peptide agonists and their potent stimulation of food
R2
a–f
Me Me
Me
Me
3
intake have found the Y5 receptor as a major feeding receptor.
O
a–f
2
Recently it was revealed that 9-(2-hydroxy-4,4-dimethyl-6-oxo-
R2
1
1
-cyclohexen-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-
1
-ones 1 (Scheme 1) are the orally active and selective Y5
4–6
1
2
1
2
antagonists. Moreover, xanthene derivatives occur in natural
products and occupy a prominent position in medicinal chemistry.
a R = R = H
d R = NO2, R = H
7
8
1
2
1
2
b R = Me, R = H
c R = Br, R = H
e R = H, R = OMe
1
2
1
2
f
R = Br, R = OMe
The usual access to tetrahydro-1H-xanthen-1-ones 1 is tandem
Knoevenagel–Michael reaction of salicylaldehydes with two
molecules of dimedone with further cyclization. For this cycliza-
Me Me
9
10
11
tion, CeCl3, KF/Al O , p-toluenesulfonic acid, triethyl-
2
3
1
2
13
benzylammonium chloride and Zn[(L)proline]2 were used as
catalysts. However, these catalytic methods require refluxing in
different solvents (among them in water) and long reaction time
O
O
OH
O
OH
(
2–8 h) and often lead to insufficient yields of the products.
Me
Me
Solvent-free method using 2,4,6-trichloro-1,3,5-triazine as catalyst
also demanded heating to 120°C for 2–3 h as well as final
crystallization from ethanol.
O
2g
1g
14
In terms of green chemistry, the ‘best catalyst is no catalyst’.15
Scheme 1
Recently, non-catalytic synthesis of tetrahydro-1H-xanthen-1-ones
1
6
1
in water (reflux, 4–5 h) was suggested. Among the all known
Table 1 Tandem assembling of salicylaldehyde 2a and dimedone into
tetrahydro-1H-xanthen-1-one 1a.a
tandem procedures for the synthesis of compounds 1, the most
obvious Knoevenagel–Michael one has not been well developed
yet. Recently we have found that non-catalytic multicomponent
assembling of isatin, cyclic C–H acids and malononitrile in
alcohols (80–95°C) gives rapidly (10 min) rise to substituted
spirooxoindoles in 90–97% yields.17
Taking into consideration the above result, we anticipated that
tetrahydro-1H-xanthen-1-ones 1 can be accessed by Knoevenagel–
Michael tandem reaction between salicylaldehydes 2 and 2 equiv.
of dimedone (Scheme 1, Tables 1, 2).†
Catalyst
(quantity/mmol)
Solvent
(volume/ml)
Isolated yield
of 1a (%)
Entry
T/°C t/min
1
2
3
4
5
6
7
8
9
NaOAc (3)
EtOH (2)
EtOH (2)
78
78
80
78
78
78
78
80
80
60
80
5
5
5
5
5
3
1
5
5
3
3
93
91
86
90
88
90
83
82
71
75
84
NaOAc (1)
NaOAc (3)
H O (2)
2
–
–
–
–
–
–
–
–
EtOH (2)
EtOH (1)
EtOH (2)
EtOH (2)
†
Tetrahydro-1H-xanthen-1-ones 1 (general procedure). A solution of
H O (2)
2
salicylic aldehyde (5 mmol) and dimedone (10 mmol) in ethanol (2 ml)
was stirred under reflux for 3 min and cooled. The precipitated product
was filtered off, rinsed with an ice-cold ethanol–water solution (1:1, 2 ml)
and dried under reduced pressure. For characteristics of tetrahydro-1H-
xanthen-1-ones 1a–g, see Online Supplementary Materials.
–
1
1
0
1
MeOH (2)
PrOH (2)
a
Salicylaldehyde 2a (5 mmol), dimedone (10 mmol).
©
2015 Mendeleev Communications. Published by ELSEVIER B.V.
–
19 –
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.

Mendeleev Commun., 2015, 25, 19–20
Sodium acetate is an advantageous catalyst for a number of
condensation of dimedone anion A with salicylaldehyde 2 occurs
with elimination of hydroxide anion and formation of the adduct
3. The subsequent Michael addition of dimedone to electron
deficient adduct 3 with further cyclization results in ultimate
tetrahydro-1H-xanthen-1-one 1 and ethoxide anion.
1
8–21
organic reactions.
Therefore, we used it in our initial experi-
2
3
ments (Table 1, entries 1–3) in ethanol or water at 78–80°C and
obtained tetrahydro-1H-xanthen-1-one 1a in 86–93% yields within
yet 5 min. Surprisingly, in ethanol at 78°C in the absence of
sodium acetate the yield of product 1a was as high as 90% in
–5 min (entries 4, 6). Under solvent-free conditions (80°C,
min) compound 1a was formed in 71% yield (entry 9). Methanol
and n-propanol were less effective solvents (entries 10, 11).
Under the optimum conditions (boiling ethanol, 3 min), the
variety of tetrahydro-1H-xanthen-1-ones 1a–g was prepared in
excellent yields (Table 2).
In conclusion, the herein developed facile and efficient pro-
cedure provides very fast (neutral conditions, 3 min) and selective
multicomponent assembling of salicylaldehydes and dimedone
into tetrahydro-1H-xanthen-1-ones 1 (85–95% yields), which are
3
5
4
the orally active and selectiveY5 antagonists and seem promising
for other biomedical applications. The procedure is valuable
from the viewpoint of environmentally benign diversity-oriented
large-scale processes.
Table 2 Tandem transformation of salicylaldehydes 2a–g and dimedone
a
into tetrahydro-1H-xanthen-1-ones 1a–g.
This work was supported by the Russian Foundation for Basic
Research (project nos. 14-03-31918 and 13-03-00096a).
Entry
Salicylaldehyde
Product
Isolated yield (%)
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
1a
1b
1c
1d
1e
1f
90
91
93
89
95
88
85
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2015.01.006.
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Scheme 2
Received: 2nd April 2014; Com. 14/4342
–
20 –