Simple approach to access tricyclic spiro dihydrofurans in a one-pot reaction

Article abstract of DOI:10.1080/00397911.2017.1326141

A simple and efficient one-pot protocol is accomplished to access tricyclic spiro dihydrofurans (4) by the reaction of β-enamino ketones (1) and dimedone (2) in ethanol followed by sequential addition of N-chlorosuccinimide at ambient temperature for the

Full text of DOI:10.1080/00397911.2017.1326141

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A Simple Approach to Access Tricyclic Spiro
Dihydrofurans in a One Pot Reaction
Chiranjeevi Bingi, Ashok Kale, Jagadeesh Babu Nanubolu & Krishnaiah
Atmakur
To cite this article: Chiranjeevi Bingi, Ashok Kale, Jagadeesh Babu Nanubolu & Krishnaiah
Atmakur (2017): A Simple Approach to Access Tricyclic Spiro Dihydrofurans in a One Pot Reaction,
Synthetic Communications, DOI: 10.1080/00397911.2017.1326141
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Date: 11 May 2017, At: 02:38

A Simple Approach to Access Tricyclic Spiro Dihydrofurans in a One Pot Reaction
1
1
2
1,3
Chiranjeevi Bingi , Ashok Kale , Jagadeesh Babu Nanubolu , Krishnaiah Atmakur
1
Crop Protection Chemicals Division, CSIR-Indian Institute of Chemical Technology,
2
Tarnaka, Hyderabad, India Laboratory of X-ray Crystallography, CSIR-Indian Institute
3
of Chemical Technology, Tarnaka, Hyderabad, India Academy of Scientific and
Innovative Research, CSIR- Indian Institute of Chemical Technology, Tarnaka,
Hyderabad, India
Corresponding author Krishnaiah Atmakur E-mail: krishnu.iict@gov.in
Abstract
A simple and efficient one pot protocol is accomplished to access tricyclic spiro
dihydrofurans (4) by the reaction of β-enamino ketones (1) and dimedone (2) in ethanol
followed by sequential addition of N-chloro succinimide (NCS) at ambient temperature
for the first time. The Selectivity in desired product formation in good yields is the
advantage of this protocol.
Graphical Abstract
1

KEYWORDS: β-Enamino ketones, Dimedone, N-Chloro succinimide, Spiro
dihydrofurans
INTRODUCTION
[
1]
Furan scaffolds occupy a prominent position in modern heterocyclic chemistry. Among
these class of compounds; dihydrofurans are one of the important compounds generally
[
2]
found naturally occurring substances. Specifically, spiro dihydrofurans are prevalent in
[
3]
diverse class of natural products having biological importance and pharmaceutical.
Further, synthetic spirocycles with a spiro furan frame work has drawn significant
[
4]
[5]
attention owing to their antibacterial, antitumor and hypocholesterolemic
[
6,7]
activities.
Based on the importance of these compounds, numerous methods have been reported for
the synthesis of spiro dihydrofurans. For example, three step reaction of cyclic 1,3-diones
[8]
with aldehydes involving addition, halogenaton and cyclodehydrohalogenation gave the
[
9]
spiro dihydrofurans. Sahu’s group reported by reacting aldehydes and dimedone using
iodine and ammonium acetate. Further, some more reports found on the synthesis of spiro
[
10]
dihydrofurans promoted by 1,4-diazabicyclo[2.2.2]octane (DABCO), Dess-Martin
[
11]
Periodinane (DMP) and tetraethyl ammonium bromide. Furthermore, molecular iodine
and dimethylaminopyridine mediated reaction of aldehydes with dimedone and 1,3-
[
12]
indanedione independently through ball-milled approach selectively gave spiro
dihydrofuran and cyclopropane derivatives. On the other hand, ceric ammonium nitrate
[
13]
mediated 1,3-dipolar cycloaddition of 1,3-diketones with exocyclic alkenes gave spiro
2

dihydrofuran oxindole derivatives. Additionally, a pseudo multi-component electro
[
14]
chemical synthesis of spiro dihydrofurans was reported by C.Yao and coworkers.
However, most of them are from benzaldehyde and cyclic 1,3-dione and uses either a
base, combination of bases or organic solvents which are derived from non-renewable
resources.
In order to come out with an alternate approach and also based on our ongoing research
[
15]
program on synthesis of new bioactive molecules and utilization of β-enamino
ketones, we have come out with a simple methodology for the synthesis of tricyclic spiro
dihydrofurans by a novel, efficient and one pot reaction from β-enamino ketones for the
first time. In fact, β-Enamino ketones were reported to use in the preparation of different
kind of heterocyclic building blocks in organic chemistry. For example, Perumal et al.,
reported the synthesis of highly functionalized tetrahydroquinolines by a four component
[
16]
domino reaction involving β-enamino ketones. Further, it was also used in
synthesizing the substituted pyridines and dihydro-6H-quinolin-5-ones along with 1,3-
[
17]
diketone and ammoniumacetate.
On the other hand, multi component reactions (MCRs) have become a powerful tool in
organic synthesis because of their atom economy, multiple bond forming efficiency,
convergence etc. These features are important aspects from the green chemistry point of
[
18]
view. In this context, MCRs based on "bio-solvents" such as ethanol which is
[
19]
produced from renewable resources is an increasingly important parameter as it is one
of the best alternate to hazardous solvents owing to the EHS (Environment, Health,
3

Safety) properties such as increased biodegradability or reduced ozone depletion
[20]
potential. With this idea, we report herein, a novel protocol to access tricyclic spiro
dihydrofurans starting from β-enamino ketones and dimedone followed by sequential
addition of N-chlorosuccinimide (NCS) in ethanol and the results are as follows.
RESULTS AND DISCUSSION
Initially, β-ketoenaminone (1a) was prepared by condensing acetophenone and dimethyl
[
21]
formamide dimethyl acetal (DMF-DMA) in xylene by a literature procedure. Thus
obtained compound 1a was reacted with dimedone in ethanol under reflux condition and
obtained di-enol compound (3a) (Scheme 1).
By looking at the structure of 3a, we conceptualized the possible formation of a spiro
furan skeleton from 3a. On this account, initially, compound 3a was treated with NCS at
room temperature. Interestingly, the desired spiro furan product 4a was obtained in 86%
yield exclusively. Earlier, when 3a was refluxed in acetic acid, a bicyclic product was
obtained. Notably, the same compound when refluxed in toluene in presence of
[19b]
trifluoroacetic acid gave xanthenes.
Structure of 4a was confirmed by the spectral
1
data. It is interesting to mention that, the H NMR of compound 4a (recorded in 500
MHz) was found to be quite complex especially from δ 2.19 to 2.75 and 3.23 to 3.60 ppm
even after purification. However, entire signal pattern was found to be same at par with
[
12]
the similar compound reported. To confirm it further, a spectra was recorded in high
resolution (700 MHz) and also observed to be the same. Then we presumed that the
complexity may be due to methylene protons between dihydrofuran ring on one side and
4

benzoyl group on the other side. These two characteristic methylene protons were
resonating at δ 3.56 and 2.35 ppm as doublets of doublet by coupling with the
dihydrofuran ring proton. Except this, all other signals were clearly comparable with
1
3
aforesaid report. Surprisingly, the same compound gave a very clean C NMR where
four carbonyl carbon signals were observed at δ 203.6, 201.2, 199.0, 194.1 ppm (four
clear signals) and the methylene carbon which is attached to dihydrofuran ring and
carbonyl carbon on either side resonating at δ 38.6 ppm, rest of the signals are at a par
with reported data. Finally, the structure of compound 4a was also unambiguously
[
22]
confirmed by X-ray crystallography (Fig-1).
Enticed by the exclusive formation of 4a; studies were directed to prepare 4a in a one pot
reaction. Accordingly, the compound 1a was reacted with dimedone followed by
sequential addition of NCS in toluene and obtained the desired product 4a. Further,
solvent scrutiny studies (table-1) pronounced that, ethanol medium gave the enhanced
yields 88%. Having obtained the compound 4a in a one pot reaction in ethanol, reactions
were also carried out in ethanol and water solvent mixtures (entry 11 & 12) also.
However, there was no progress in the reaction after formation of 3a. On the other hand,
formation of 4a was observed in combination of ethanol and water medium in decreased
yields. Next, studies were conducted to optimize the NCS ratio to determine the best
optimal reaction condition. However, best yields were obtained in ethanol with 1.0
equivalent of NCS (table 1, entry 3). Alternately, a reaction was also conducted by
replacing NCS with NBS and NIS independently and observed the decrease in yields.
(Table-1& Scheme 2)
5

Fascinated by formation of 4 in one pot reaction in high yields, scope and generality of
this protocol was next explored (Scheme 2). To our satisfaction, this protocol
demonstrated wide scope as a range of enamino ketones were highly compatible under
these set of reaction conditions and provided 4 in high yields. Electronic and steric nature
of enamino ketones has shown no influence on the reaction efficiency. However, nominal
variations in the yield were observed. Compounds bearing electron withdrawing groups
gave near to 90 % yields. Whereas, electron donating groups gave up to 85% yields. This
method was found to be mild enough to be compatible with the enamino ketones bearing
naphthalene and hetero rings such as furan, thiophene and gave excellent yields up to
8
8% yield (4m-o). Further, reaction with 1,3-cyclohexanedione under similar reaction
[19b]
conditions gave xanthenes
whereas, with acetyl acetone no reaction was observed.
A plausible mechanism was proposed for the formation of 4a where the active methylene
functional of diketone initially attack on β-carbon of enamino ketone in Michael fashion
to give A (elimination of N,N-dimethylamine in the form of gas was observed by dipping
the outlet vent of the reaction flask in water and also confirmed with litmus paper during
the course of the reaction). Subsequently, attack of second molecule of diketone on β-
carbon of A lead to dienol compound 3a (isolated). Next, addition of chloronium ion
[
15b,15c]
from NCS at active methylene carbon followed by attack of lone pair electrons
from hydroxy functional and successive dehydrohalogenation gives 4',4',6,6-tetramethyl-
3
2
-(2-oxo-2-phenylethyl)-6,7-dihydro-3H-spiro[benzofuran- 2,1'-cyclohexane]-
',4,6'(5H)-trione(4a) (Scheme 3).
6

CONCLUSIONS
In conclusion, we have developed a new protocol to accomplish the synthesis of tricyclic
spiro dihydrofurans in a three component one pot reaction in ethanol at ambient
temperature for the first time. This simple and efficient protocol is an alternate to the
existing methodologies which may find good utility.
EXPERIMENTAL
General
Melting points were measured by CINTEX programmable melting point apparatus and
1
13
are uncorrected. H and C NMR spectra of samples in CDCl recorded on AVANCE-
3
3
00 MHz, 400 MHz, 500 MHz and 700 MHz spectrometers. Chemical shifts (δ) are
reported relative to TMS (δ = 0.0) as the internal standard. Mass spectra were recorded in
ESI spectrometers. All high resolution mass spectra were recorded on QSTAR XL hybrid
ms/ms system (Applied Bio systems/MDS sciex, foster city, USA), equipped with an ESI
source (IICT, Hyderabad). TLC was performed on Merck 60 F-254 silica gel plates. The
chemicals used in this work were obtained from commercial channels and were used
without purification.
General Procedure For The Synthesis Tricyclic Spiro Dihydrofurans (4)
To a round bottomed flask equipped with a reflux condenser and stopper was added β-
keto enaminone viz (E)-3-(dimethylamino)-1-aryl prop-2-en-1-one derivatives (1, 2.85
mmol), dimedone (2, 5.71 mmol), ethanol (10 mL) and was heated to reflux while
7

stirring. After refluxing reaction mixture for 5 to 6 hours, the homogenous mass was
allowed to come down to room temperature and to this was added NCS (2.7 mmol) and
continued the stirring at RT open to air for 1 hour. After completion of reaction as
indicated by TLC, the separated solid was filtered, washed with water (2×5mL) followed
by hexane (2×5mL) and was purified by flash column chromatography to get pure
products 4.
4
',4',6,6-Tetramethyl-3-(2-Oxo-2-Phenylethyl)-6,7-Dihydro-3H-Spiro[Benzofuran-2,1'-
Cyclohexane]-2',4,6'(5H)-Trion (4a).
Isolated as a white solid; Yield 88%; m.p.148-149°C; IR (KBr) νmax: 2959, 1734, 1708,
–
1 1
1
671, 1631, 1467, 1397, 1246, 1143, 1041, 938, 770, 694 cm ; H NMR (700 MHz,
CDCl ): δ 7.88 (d, J = 7.6 Hz, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 4.14
3
(d, J = 9.9 Hz, 1H), 3.65-3.60 (m, 1H), 3.56 (dd, J = 19.0, 1.9 Hz, 1H), 3.30-3.23 (m,
1
2
2
3
H), 2.75-2.69 (m, 1H), 2.57-2.46 (m, 3H), 2.35 (dd, J = 16.2, 3.1 Hz, 1H), 2.29-2.19 (m,
1
3
H), 1.21 (s, 3H), 1.16 (s, 6H), 0.91 (s, 3H) ppm; C NMR (100 MHz, CDCl ): δ 203.6,
3
01.2, 199.0, 194.1, 176.8, 135.9, 133.7, 128.6, 128.0, 111.5, 97.8, 53.0, 51.2, 49.8, 43.3,
+
8.6, 37.3, 34.2, 30.5, 30.2, 28.6, 28.4, 26.7 ppm; ESI-MS: m/z 409 [M+H] ; HRMS
+
(
ESI) Anal. calcd. for C H O m/z 409.2009 [M+H] , found 409.2003.
2
5
29
5
SUPPLEMENTARY DATA
Experimental procedures, characterization and Spectral data for all the synthesized
compounds and X-ray diffraction crystallographic data for the compound 4a which has
been deposited on CCDC with deposition number 1450194 can be available free of
8

charge at www.ccdc.cam.ac.uk/conts/retrieving.html[or from the Cambridge
Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44(0) 1223 336 033;
email: www.ccdc.cam.ac.uk/data_request/cif.
ACKNOWLEDGEMENTS
We are grateful to SERB-DST New Delhi for financial support (grant no. SB / EMEQ-
0
75 / 2013). BCJ is thankful to UGC, New Delhi for SRF.
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[
2
[
[
1
[
This data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html[or
from the Cambridge Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44(0) 1223 336 033;
email: www.ccdc.cam.ac.uk/data_request/cif.
1
1

Table 1. Optimization of reaction conditions for the synthesis of tricyclic spiro
a
dihydrofuran (4a).
S. No Solvent
Additive Temp Quantity Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
Toluene
MeOH
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NBS
NIS
Reflux 1 eq
Reflux 1 eq
Reflux 1 eq
Reflux 1 eq
Reflux 1 eq
Reflux 1 eq
Reflux 0.5 eq
Reflux 1.2 eq
Reflux 1 eq
Reflux 1 eq
Reflux 1 eq
Reflux 1eq
86
86
88
84
80
83
55
88
75
86
80
77
EtOH
Acetonitrile
Ethyl acetate
1,2-DCE
EtOH
EtOH
EtOH
0
1
2
EtOH
EtOH,H O (1:1) NCS
2
EtOH,H O (1:2) NCS
2
a;
Reaction conditions: β-ketoenaminone (2.8 mmol) and dimedone (5.7 mmol) in solvent
(
10 ml) refluxed for 5 hours then followed by sequential addition of N-halo succinimide
halo = Cl, Br, I) at RT. Yields refer to isolated pure products.
(
1
2

Scheme 1. Preaparation of 2,2'-(3-oxo-3-phenylpropane-1,1-diyl)bis(3-hydroxy-5,5-
dimethylcyclohex-2-enone) (3a).
1
3

a
Scheme 2. Preparation of tricyclic spiro dihydrofuran derivatives (4).
a
Reaction conditions: β-ketoenaminone (2.8 mmol) and dimedone (5.7 mmol) in ethanol (10 ml) reflux for
5
hours then followed by sequential addition of NCS (2.8 mmol) at RT. Yields refer to pure products after
flash column chromatography.
1
4

Scheme 3. Plausible mechanism for formation of compound (4a).
1
5

Figure 1. Crystal structure of the compound 4a (ORTEP diagram of compound 4a).
1
6