CuI-ionic liquids as efficient reaction media for the synthesis of pyran skeleton via domino knoevenagel-hetero-diels-alder reaction with unactivated alkynes

Article abstract of DOI:10.1080/00397911.2012.669874

The article describes ionic liquids [bmim][NO₃] in the presence of 30% mol CuI as efficient media for the domino Knoevenagel-hetero-Diels-Alder reaction of o-propargyloxy benzaldehydes as unactivated terminal alkynes with some active methylene

Full text of DOI:10.1080/00397911.2012.669874

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Cui - Ionic Liquids as an Efficient Reaction Media
for the Synthesis of Pyran Skeleton Via Domino
Knoevenagel–Hetero–Diels-Alder Reaction with Non-
Activated Alkynes
Saeed Balalaie a , Javad Azizian b , Abolghasem Shameli b & Hamid Reza Bijanzadeh c
a Peptide Chemistry Research Center, K. N. Toosi University of Technology, Tehran, Iran
b Department of Chemistry, Science and Research Branch, Islamic Azad University, Tehran,
Iran
c Department of Chemistry, Tarbiat Modares University, Tehran, Iran
Accepted author version posted online: 27 Dec 2012.
To cite this article: Saeed Balalaie , Javad Azizian , Abolghasem Shameli & Hamid Reza Bijanzadeh (2012): Cui - Ionic Liquids
as an Efficient Reaction Media for the Synthesis of Pyran Skeleton Via Domino Knoevenagel–Hetero–Diels-Alder Reaction with
Non-Activated Alkynes, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, DOI:10.1080/00397911.2012.669874
To link to this article: http://dx.doi.org/10.1080/00397911.2012.669874
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ACCEPTED MANUSCRIPT
CuI - Ionic liquids as an Efficient Reaction Media for the Synthesis of Pyran
Skeleton via Domino Knoevenagel–Hetero–Diels-Alder Reaction with Non-activated
Alkynes
Saeed Balalaie1, Javad Azizian2, Abolghasem Shameli2, Hamid Reza Bijanzadeh3
1Peptide Chemistry Research Center, K. N. Toosi University of Technology, Tehran,
Iran, 2Department of Chemistry, Science and Research Branch, Islamic Azad University,
Tehran, Iran,3Department of Chemistry, Tarbiat Modares University, Tehran, Iran
Peptide Chemistry Research Center, K. N. Toosi University of Technology, P. O. Box
15875-4416, Tehran, Iran. Fax:+98-21-22853650; E-mail: balalaie@kntu.ac.ir
Abstract
The paper describes ionic liquids [bmim][NO3] in the presence of 30% mol CuI as an
efficient media for the domino Knoevenagel -hetero- Diels-Alder reaction of o-
propargyloxy benzaldehydes as non-activated terminal alkynes with some active
methylene compounds. Short reaction time, an easy work-up, good to high yields, and
carrying out the reaction under mild condition are advantages of this new media.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications® to view the free supplemental file.
X
X
X
O
CuI (30% mol)
O
O
O
O
O
[Bmim][NO3]
K2CO3 (20%mol)
O
CHO
O
O
500C
2a-f
1a-f
[I]
3a-m
KEYWORDS: Ionic liquids, Domino Knoevenagel – hetero – Diels - Alder reaction,
Pyran skeleton , Non-activated Alkynes, CuI.
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INTRODUCTION
The design and developing of novel reactions which allowing to highly selective access
to elaborated molecular scaffolds while combining structural diversity with economically
and ecologically are great challenges for organic chemists.[1] With increasing global
environmental safety regulations, the room temperature ionic liquids (RTILs) were used
as alternatives to conventional organic solvents in various field of chemistry and resulted
in a considerably growing interest.[2] Ionic liquids have some unique properties such as
good solvating ability, variable polarity, negligible vapor pressure, increased thermal
stability, ability to dissolve a wide range of organic compounds and long shelf lives and
ease of recyclables.[3] From this perspective, combining properties of RTILs as solvents
and promoters results in different organic synthesis procedures.[4]
The hetero- Diels–Alder reaction using 1-oxo-1,3-butadiene is one of the most efficient
and powerful synthetic tools for the synthesis of chroman and isochroman derivatives,
which are important classes of oxygenated heterocycles and also some natural products[5]
showing a broad range of biological and pharmaceutical activity.[6] Tietze et al.
extensively described the domino-Knoevenagel–hetero–Diels–Alder reaction (DKHDA)
of unsaturated aromatic- and aliphatic aldehydes with several 1,3-dicarbonyl compounds
for the synthesis of heterocycles with a pyran ring.[7] In most reported domino–
Knoevenagel -hetero-Diels-Alder reactions, alkenes were used as dienophile. The use of
alkynes was limited due to their low reactivity compared to alkenes.[8] The activation of
alkynes toward a variety of organic transformations is an interesting field in organic
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synthesis.[9] Recently, CuI was reported in our group as efficient Lewis acid for various
domino–Knoevenagel-hetero-Diels-Alder reactions with non-activated alkynes in
different organic solvents.[10] Nevertheless, many of the reported domino-Knoevenagel-
hetero-Diels-Alder reactions with unactivated alkynes involve heating at high
temperatures, leading to low or moderate yields of products, longer reaction times, and in
some cases are limited to type of substituents in the structure of starting materials.
Due to the importance of domino–Knoevenagel-hetero-Diels-Alder reactions and the
biological activities of the synthesized products, optimizing the conditions such as
environmentally friendly, good to high yields, shorter reaction times, and mild reaction
conditions are parts of the necessary research in organic synthesis. Given the unique
properties of ILs, we wondered whether performing domino–Knoevenagel-hetero-Diels-
Alder reactions in ILs could be beneficial in terms of yield and “green aspect” of the
reaction. The first example of ionic liquids-promoted domino Knoeveneagel hetero-
Diels-Alder reaction with alkenes as dienophile was reported by Yadav et al.[11] To the
best of our knowledge, there is no report about the effect of ionic liquids in DKHDA
reactions with unactivated alkynes. Herein, we wish to report the DKHDA reaction of O-
propargyloxy benzaldehydes with some active methylene compounds to construct
polycyclic compounds which contain pyran skeleton in ionic liquids.
Results and Discussion
Initially, O-propargylated salicylaldehydes (1) as the starting material were prepared in
excellent yields using reaction of propargyl bromide and salicylaldehyde derivatives in
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dimethylformamide and in the presence of K2CO3.[12] It was reported that combining the
metal catalysts and ionic liquid could improve their activity, meanwhile, copper (I)
containing ionic liquid could improve their activity and they were used for the
electrodepositing.[13] The existence of catalyst is very essential in this reaction and
without catalyst; the product was not formed. We would like to know the efficiency of
different catalysts in ionic liquids in DKHDA reaction with unactivated alkynes. Initially,
the reaction of O-propargyloxy benzaldehyde (1a) and barbituric acid (2a) was chosen as
the model reaction to optimize the reaction conditions. The effects of catalysts, solvents,
type of ionic liquids, bases and reaction temperature were investigated. As shown in
Table 1, We initially checked Sc(OTf)3, Ag-nano powder, titanium dioxide nanopowder
and also CuI in different ionic liquids [bmim][BF4], [bmim][NO3], and [omim][BF4]
(Table 1). The best result for this reaction was obtained in the presence of CuI in
[bmim][NO3] as reaction medium. The existence of catalyst is very essential in this
reaction and the product was not formed without catalyst in ionic liquids. According to
these data, CuI was selected as a suitable catalyst for this reaction. Further optimization
of the molar ratios of CuI revealed that the yields of product of 3a with 20, 30 and 40%
CuI were 80, 83 and 84% respectively. In the next step, we examined potassium
carbonate and triethyl amine as the base which led to better results with potassium
carbonate. The optimized temperature for the reaction was 50 °C. So, the reactions for the
synthesis of compound 3a were conducted under the optimized conditions of 30% CuI,
20 % K2CO3 in [bmim][NO3] as IL. The scope of this reaction was evaluated with
different O-propargyloxy benzaldehydes (1a-f) and active methyle compounds (2a-f) to
construct polycyclic compounds (3a-m) which contained pyran skeleton.
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The reactions were checked with different active methylene compounds; such as
barbituric acid, dimethyl barbituric acid, indandione, and benzoyl acetonitrile which were
synthesized in our research group.[10] To explore the reaction diversity, different O-
propargyloxy benzaldehydes with electron-donating and electron-withdrawing
substituents were used and the results were summarized in table 2.
In all cases, the reactions were completed after 3-120 min and the products were easily
separated by extraction with Et2O. A comparison of the results with previous related
investigations clearly verifies the superiority of the current method. This encouraged us
to further investigation the applicability of the procedure in engaging other substrates
such as benzoyl acetonitrile, and phenyl pyrazolone. The same acceleration in the
reaction time and also yields of reactions was observed.
The structures of the products were confirmed by their spectroscopic data and HR-Mass
spectrometric method and were compared with the synthesized samples.
CuI could play two different roles in the reaction: being the Lewis acid or formation of
copper acetylide. To find the major contribution, 2-(but-2-yn-1-yloxy)benzaldehyde was
formed by reaction of salicylaldehyde with 1-bromo-2-butyne. Reaction of 2-(but-2-yn-1-
yloxy)benzaldehyde with dimethyl barbituric acid in the presence of CuI (30%) in
[bmim]NO3 under the same condition as before was investigated. But, it didn't give the
desired skeleton and reaction doesn’t proceed. This confirms that the reaction goes to the
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next step through the formation of acetylide intermediates. The role of CuI as the Lewis
acid and the chemoselectivity observed in the reaction were rationalized by the quantum-
mechanics calculations.[14] The energy difference between the HOMO and LUMO plays a
major role for the rate of a Diels-Alder reaction. According to our studies, we showed
that the reaction could proceed via formation of copper acetylide and it seems that ionic
liquids with high polarity could affect the energy gap of the heterodiene and alkyne as
dienophile which accelerate the formation of the desired product.
We have also examined the reusability of the catalyst system. The product could be
separated from the reaction mixture using extraction with diethylether. Final extraction
was done using dry EtOAc. Then, the ionic liquid was dried at 80 °C under reduced
pressure for 1h and in this way, it is ready for the further reactions. The reactions were
carried out with several batches of the recovered catalyst. The repetition with 5 times
indicated that its efficiency is almost similar to that of the first time and the yields were
reduced 10% after five times.
Experimental
Commercially available materials were used without further purification. Melting points
were determined on an Electrothermal 9100 apparatus and were uncorrected. IR spectra
were obtained on an ABB FT-IR FTLA 2000 spectrometer. 1H-NMR and 13C-NMR
spectra were run on Bruker DRX-500 AVANCE spectrometer at 500 MHz for 1H-NMR,
and 125 MHz for 13C-NMR. CDCl3 was used as solvent. HR-MS was recorded on Mass-
ESI-POS (Apex Qe-FT- ICR instrument) spectrometer.
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General Procedure For The Synthesis Of Products 3a-I
A mixture of 1a-c (1 mmol), 2a-e (1.1 mmol), K2CO3 (20 mol%, 28 mg) and CuI (30
mol%, 87 mg) in [bmim][NO3] (1 mL) was heated at 50 °C for the appropriate time.
After completion of the reaction, based on TLC monitoring, the reaction mixture was
extracted with Et2O (3×10 mL). The organic phase was washed with brine (20 mL), dried
over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was
purified by recrystallization in EtOAc: Petroleum ether (10:3). IL was recovered by
removing its ether content (under reduced pressure at 50 °C for 1 h using a rotary
evaporator) and reused in subsequent reactions. The products are known and their
identity was confirmed by comparison of their spectroscopic data with those available in
our recent papers.[10]
Complete experimental details are available online in the Supporting Information.
CONCLUSIONS
In conclusion, we have described a convenient route to synthesis of polycyclic
compounds which contained pyran skeleton from the reaction of o-propargyloxy
benzaldehydes with active methylene compounds in bmim[NO3]. The attractive features
of this protocol are: simple procedure, short reaction time, mild reaction media,
environmental friendly character, the reuse of the reaction medium, good to high yields
and its adaptability for synthesis of a diverse set of pyran skeletons.
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ACKNOWLEDGMENT
S.B. gratefully acknowledges Alexander von Humboldt Foundation for the research
fellowship. We are also thanking Prof. R. Gleiter for his invaluable comments.
Dedicated to Prof. Mohammad Raouf Darvich on the occasion of his 70th birthday.
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Table 1. Optimization of the conditions for the CuI catalyzed domino –Knoevenagel -
hetero- Diels-Alder reaction of O-propagyloxy benzaldehyde (1a) with barbituric acid
(2a).
Entry Lewis acid
(mol%)
Base
Solvent
Yield% Temperature Time(h)
(ºC)
1
2
3
4
4
4
5
6
7
Sc(OTf)3 (40)
Ag (50)
-
K2CO3 [omim]BF4
K2CO3 [omim]BF4
K2CO3 [bmim][NO3]
K2CO3 [bmim][NO3]
K2CO3 [bmim][NO3]
K2CO3 [bmim][NO3]
K2CO3 [bmim][NO3]
K2CO3 [bmim][NO3]
trace
trace
trace
trace
40
100
100
100
100
25
24
24
24
24
6
TiO2
CuI (20)
CuI (20)
CuI (30)
CuI (40)
CuI (30)
70
50
1
85
50
1
85
50
1
Et3N
[bmim][NO3]
60
100
1
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Table 2. Domino –Knoevenagel -hetero- Diels-Alder reaction of O-propargyloxy
benzaldehydes with active methylene compounds wth CuI (30%) in bmim[NO3] at 50 °C.
Substrates
Products
CuI(%)a,b in different solvents
Cu(30%) in
[Bmim]NO3
Solvent Yield(%) Time(min) Yield(%) Time(min)
85a
600
85
120
O
H2O
CHO
O
H
O
N
O
O
N
H
O
H
N
Ref. 10a
O
N
H
O
1a
2a
3a
O
H2O
81b
240
78
90
O2N
CHO
O
H
N
O
N
H
O
Ref. 10a
1b
2a
Br
3b
3c
O
H2O
H2O
77b
1440
1200
75
82
90
90
CHO
O
H
N
O
N
H
O
Ref. 10a
1c
2a
84a
O
CHO
N
O
N
O
O
O
N
O
N
Ref. 10b
O
O
1a
2b
3d
O
80a
360
80
60
O2N
H2O
O2N
CHO
O
N
O
N
O
O
N
O
Ref. 10b
O
N
O
1b
ACCEPTED MANUSCRIPT
14

ACCEPTED MANUSCRIPT
2b
3e
O
N
Br
H2O
70a
1500
70
40
Br
CHO
O
N
O
O
O
O
N
Ref. 10b
O
N
O
1c
2b
3f
Substrates
Products
CuI(%)a,b in different solvents
Cu(20%) in
[Bmim]NO3
Solvent Yield(%) Time(min) Yield(%) Time(min)
O
O
CH3CN 85a
Ref. 10c
600
85
82
20
30
O2N
O
CHO
1b
2c
3g
3h
CH3CN 80a
Ref. 10c
1500
O
O
O
CHO
1a
2c
Br
CH3CN 80a
Ref. 10c
1440
480
80
95
20
3
O
O
O
CHO
1c
2c
3i
Br
N
CH3OH 82a
Ref. 10d
N
O
Br
CHO
O
N
O
N
O
Cl
ClC6H4
ACCEPTED MANUSCRIPT
15

ACCEPTED MANUSCRIPT
1c
3j
2d
CH3OH 85a
Ref. 10d
480
95
90
5
O2N
N
O
O2N
CHO
O
N
O
N
N
ClC6H4
Cl
O
1b
2d
Br
3k
O
CH3OH 65b
Ref. 10e
1920
90
Br
CHO
CN
O
O
NC
Ph
O
1a
2e
3m
aAll reactions were carried out using 20% mol of CuI.
bAll reactions were carried out using 40% mol of CuI.
cThe optimized mol% of CuI in ionic liquids as reaction media was 20%.
ACCEPTED MANUSCRIPT
16

ACCEPTED MANUSCRIPT
Scheme 1.
X
X
X
O
CuI (30% mol)
O
O
O
O
O
[Bmim][NO3]
K2CO3 (20%mol)
O
CHO
O
O
500C
2a-f
1a-f
[I]
3a-m
ACCEPTED MANUSCRIPT
17