Chemoselective Synthesis of 2,2′-Arylmethylene bis-(3-Hydroxy-2-cyclohexenes) ("Tetraketones") in Hexafluoro-2-propanol

Full text of DOI:10.1080/00304948.2016.1127102

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: 0030-4948 (Print) 1945-5453 (Online) Journal homepage: http://www.tandfonline.com/loi/uopp20
Chemoselective Synthesis of 2,2′-Arylmethylene
bis-(3-Hydroxy-2-cyclohexenes) (“Tetraketones”) in
Hexafluoro-2-propanol
Behrooz Maleki, Massomeh Raei, Elahe Akbarzadeh, Hassan Ghasemnejad-
Bosra, Alireza Sedrpoushan, Samaneh Sedigh Ashrafi & Mohammad Nabi
Dehdashti
To cite this article: Behrooz Maleki, Massomeh Raei, Elahe Akbarzadeh, Hassan Ghasemnejad-
Bosra, Alireza Sedrpoushan, Samaneh Sedigh Ashrafi & Mohammad Nabi Dehdashti
(2016) Chemoselective Synthesis of 2,2′-Arylmethylene bis-(3-Hydroxy-2-cyclohexenes)
(“Tetraketones”) in Hexafluoro-2-propanol, Organic Preparations and Procedures International,
48:1, 62-71, DOI: 10.1080/00304948.2016.1127102
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Date: 01 March 2016, At: 09:37

Organic Preparations and Procedures International, 48:62–71, 2016
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2016.1127102
Chemoselective Synthesis of 2,20-Arylmethylene
bis-(3-Hydroxy-2-cyclohexenes) (“Tetraketones”)
in Hexafluoro-2-propanol
Behrooz Maleki,1 Massomeh Raei,1 Elahe Akbarzadeh,2 Hassan
Ghasemnejad-Bosra,3 Alireza Sedrpoushan,4 Samaneh Sedigh
Ashrafi,1 and Mohammad Nabi Dehdashti4
1Department of Chemistry, Hakim Sabzevari University, Sabzevar, 96179-
76487, Iran
2Young Researchers and Elite Club, Islamshahr Branch, Islamic Azad
University, Islamshahr, Iran
3Department of Chemistry, Babol Branch, Islamic Azad University, Babol, Iran
4Institute of Industrial Chemistry, Iranian Research Organization for Science and
Technology, Tehran, Iran
Some fluorous alcohols are useful as solvents, co-solvents, and additives because of their
very useful properties in synthesis, in various formulations and of the ease of isolation of
products. Fluorinated alcohols possess interesting physiochemical properties such as
lower boiling points and higher melting points than their non-fluorinated counterparts;
they are also strong hydrogen bond donors and have high polarity and the propensity to
solvate water. The use of fluorinated solvents as reaction media instead of conventional
volatile organic solvents, has grown dramatically in recent years.1–3 Among several fluo-
rinated alcohols, the most inexpensive and commonly utilized are 2,2,2-trifluoroethanol
(TFE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) which are available commercially.
In spite of the strong electron-withdrawing power of the trifluomethyl group, these com-
pounds are essentially non-acidic (pKa 9.3 and 14.4 respectively).4 These fluorinated
alcohols are neither nucleophilic nor hydrogen bond acceptors. Compared to other sol-
vents, HFIP (bp. 59ꢀC) and TFE, (bp. 74ꢀC) are unique due their due to the extensive
hydrogen bonding inter-network between the fluorines and the hydroxy groups. In addi-
tion, they can be easily separated from reaction mixtures and re-used subsequenly.5
2,20-Arylmethylene bis-(3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one (3) are impor-
tant for the synthesis of xanthenes which display biological and therapeutic properties
such as anti-bacterial and anti-viral activities and also are useful in laser technology.6,7
One of the simplest and general method for the preparation of this type of compounds
involves the condensation of aromatic aldehydes (1 equiv.) with 1,3-cyclohexanediones
(2 equiv.) under a variety of con-ditions. This reaction has been carried out using a num-
ber of catalysts such as sodium dodecylsulfate (SDS),8 HClO4–SiO2 or PPA–SiO2,9
Received July 5, 2015; in final form August 15, 2015.
Address correspondence to Behrooz Maleki, Department of Chemistry, Hakim Sabzevari Uni-
versity, Sabzevar, 96179-76487. E-mail: malekibehrooz@gmail.com
62

2,20-Arylmethylene bis-(3-Hydroxy-2-cyclohexenes)
63
Scheme 1
molecular iodine,10 L-histidine in an ionic liquid,11 SmCl3,12 polyvinylpyrrolidone(PVP)-
stabilized nickel nanoparticles,13 KF/Al2O3,14 catalyst-free,15,16 triethylbenzylammonium
chloride (TEBA),17,18 FeCl3.6H2O/TMSCl/[bmim]-[BF4],19 In(OTf)3,20 Yb(OTf)3-
SiO2,21 cetyltrimethylammonium bromide (CTMAB),22 nano-particles of Pd,23 choline
chloride/urea (2:1),24 silica/HBF4,25ultrasonic,26–28 and microwave.29,30 However, many
of these catalysts have disadvantages such as low yields, the utilization of expensive
reagents of toxic metals and harsh reaction conditions, tedious work-up procedures, the
need to use high catalyst loading, high temperature and of alternative energy source
(ultrasonic and microwave). The development of methods that involve the use of re-
usable catalysts under mild and environmentally friendly conditions is one of the major
goals in green and sustainable chemistry. Methods that lead to various organic com-
pounds are in high demand for both academic and industrial applications.31–35 As a con-
tinuation of our development of efficient and environmentally benign and catalyst,36–49
we now report that the reaction of aldehydes with 1,3-cyclohexanediones proceeds at
reflux in HFIP without any catalyst to give 3 in excellent yields and without the formation
of by-products.
Table 1
Various Conditions Used for the Synthesis of 3f
Entry
Conditions
Time (min)
Yield (%)
1
2
3
4
5
6
HFIP/Reflux
HFIP/50ꢀC
HFIP/40ꢀC
HFIP/25ꢀC
140
180
210
330
360
140
95
82
81
82
a
b
–
TFE/Reflux
–
89
aIn the absence of HFIP at 60ꢀC.
bNo reaction.

64
Maleki et al.
In our initial experiments, the condensation of 3-nitrobenzaldehyde (1 equiv.), dime-
done (2 equiv.) in 1 mL of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) was performed as a
model reaction under different conditions (Table 1, Entries 1–4). Table 1 shows that
heating at reflux (59ꢀC) afforded the best yield (95%) after 140 min. In the absence of
HFIP, the reaction did not proceed at all. even upon prolonged heating (Entry 5).
Since 2,2,2-trifluoroethanol (TFE) has similar physicochemical properties as
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP),. its catalytic activity in this reaction was exam-
ined with 3-nitrobenzaldehyde at reflux (74ꢀC). After 120 min, 3f was obtained in 90%
yield (Table 1, Entry 6).
Based on these results, the reaction of various aldehydes with cyclic 1,3-dicarbonyl
compounds was carried out under these optimized conditions. The results are summarized
in Table 2. In all cases, the corresponding products 3a-r were obtained in good to excel-
lent yields (76–95%) as well. Formaldehyde and acetaldehyde (Entries 14 and 15) as
well as cinnamaldehyde (Entry 13) also gave good yields of the expected products. How-
ever, butyralde-hyde, isobutyraldehyde and crotonaldehyde gave only poor yields (26%,
32% and 37% re-spectively) of the expected products. The reaction did not proceed with
acetylacetone, a non-cyclic b-diketone.
Chemoselectivity is one of the most desirable aspects in organic synthesis. In all the
cases, the expected compounds (3a-r) were obtained in high yields as the major products.
For example, none of the corresponding xanthene (4g) was formed on heating 2,20-[(3-
nitrophenyl)-methylene] bis-(3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one) (3g, 1 equiv.)
in HFIP (1 mL) at reflux; only starting material was recovered (Figure 1).
Upon completion of the reaction, HFIP is easily separated (by distillation) and may
be re-used without decrease in its activity. For example, the reaction of dimedone (2
equiv.) with 3-nitrobenzaldehyde (1equiv.) afforded the corresponding 2,20-(3-nitrophe-
nylmethylene) bis-(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-one) (3g) in 95%, 95%,
94%, 92%, and 90% yields over five cycles.
In order to illustrate the efficacy of our procedure, results for the preparation of
2,20-arylmethylene bis-(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-one) derivatives
reported previous-ly are compared with our data (Table 3). Our process using HFIP
offers several advantages such as excellent yields, a simple procedure, facile work-
up and recyclability.
In conclusion, we have developed an efficient procedure for the synthesis of
“tetraketone” derivatives 3 via the condensation of various aldehydes and 1,3-cyclic
dicarbonyl compounds catalyzed by HFIP. The main advantages of this procedure are
that it (i) avoids the use of any base, metal, or Lewis acid catalysts, (ii) involves an facile
separation and re-use of the catalyst from the reaction medium, (iii) leads to the easy iso-
lation of the product without aqueous work-up, (iv) proceeds in high chemoselectivity
and (v) there are no side-reactions.
Experimental Section
All reagents were obtained from commercial sources and were used without purification.
IR spectra were recorded as KBr pellets on a Shimadzu 435-U-04 spectrophotometer. 1H
and 13C NMR spectra were determined on a Bruker DRX-300 Avance spectrometer in
DMSO-d6 or CDCl3, and shifts are given in d downfield from tetramethylsilane (TMS) as
an internal standard. Melting points were determined using an Electrothermal 9200 appa-
ratus and are uncorrected.

2,20-Arylmethylene bis-(3-Hydroxy-2-cyclohexenes)
65
Table 2
Synthesis of Tetraketone Derivatives
mp (ꢀC)
Lit.
186–18812
Found
Entry
1
Products (3a-r)
Yield (%)
90
Time (min)
180
190–191
2
3
4
5
6
92
90
88
93
90
120
180
180
180
120
142–143
156–158
143–145
167–168
190–192
146–14812
158–15913
142–14412
167–16813
194–19612
(Continued on next page)

66
Maleki et al.
Table 2
Synthesis of Tetraketone Derivatives (Continued)
mp (ꢀC)
Found
Lit.
Entry
Products (3a-r)
Yield (%)
Time (min)
7
8
9
95
90
82
140
120
150
199–200
175–177
188–190
201–20312
178–18012
185–1879
10
11
12
80
79
90
240
240
240
138–140
192–194
140–142
139–14112
195–19613
139–14112
(Continued on next page)

2,20-Arylmethylene bis-(3-Hydroxy-2-cyclohexenes)
67
Table 2
Synthesis of Tetraketone Derivatives (Continued)
mp (ꢀC)
Found
Lit.
Entry
Products (3a-r)
Yield (%)
Time (min)
13
14
85
87
300
300
204–206
20413
190
192–19315
15
16
76
92
360
120
180–182
209–212
182–18415
207–20816
17
90
110
238–240
240–24116
(Continued on next page)

68
Maleki et al.
Table 2
Synthesis of Tetraketone Derivatives (Continued)
mp (ꢀC)
Found
198–200
Lit.
Entry
18
Products (3a-r)
Yield (%)
90
Time (min)
90
194–19613
Typical Procedure for the Synthesis of Compounds 3
Hexafluoroisopropanol (1 mL) was added to a mixture of the aldehyde (1 mmol), and
1,3-cyclohexanedione (0.23 g, 2 mmol) in a 5 mL flask fitted with a reflux condenser.
The resulting mixture was heated to reflux (an oil bath) for the time shown in Table 2
with stirring (spin bar). After the completion of the reaction as determined by TLC (hex-
ane-ethyl acetate, 4:1), the products were isolated by distillation of HFIP and
Table 3
Comparison of the Efficiency of Various Catalysts in the Synthesis of Tetraketone
Derivatives
Entry Tetraketones
Conditions
Time (min) Yield (%)
3a
HClO4–SiO2/acetonitrile/reflux9
SmCl3/water/rt12
KF/Al2O3/solvent-free/rt14
Catalyst-free/solvent-free/rt15
p-Dodecylbenzenesulfonic acid/
water/us/25–30ꢀC28
360
30
54
91
86
86
89
840
2880
60
Present work
180
30
90
91
90
91
88
88
94
3g
SmCl3/water/rt12
PVP-Ni NPs/ ethylene glycol/rt13
KF/Al2O3/solvent-free/rt14
Catalyst-free/water/rt16
Pd(0) NPs/water/rt23
10
840
2880
25
p-Dodecylbenzenesulfonic acid/
water/us/25–30ꢀC28
Present work
60
140
95

2,20-Arylmethylene bis-(3-Hydroxy-2-cyclohexenes)
69
Figure 1
recrystallization of the solid residue from 96% ethanol (8 ml) to afford the pure
“tetraketone” derivatives.
Analytical Data for Selected Compounds
2,20-Phenylmethylene bis(3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one) (3a): IR:
1
3080, 2956, 2929, 2870, 1610, 1520, 1400, 1350, 850; H NMR (300 MHz, CDCl3): d
1.11 (s, 6H), 1.24 (s, 6H), 2.31–2.47 (m, 8H), 5.56(s, 1H), 7.10 (d, 2H), 7.18 (t, 1H), 7.28
(t, 2H), 11.91 (s, 2H); 13C NMR (75 MHz, CDCl3): d 27.62, 29.86, 31.63, 32.96, 46.66,
47.28, 115.80, 126.05, 126.98, 128.42, 138.27, 189.59, 190.66.
2,20-[(4-nitrophenyl)methylene] bis(3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one)
1
(3f): IR: 3325, 3060, 2956, 1725, 1634, 1380, 1200, 1050, 950; H NMR (300 MHz,
CDCl3): d 1.12 (s, 6H), 1.24 (s, 6H), 2.32–2.51 (m, 8H), 5.55(s, 1H), 7.24 (d, 2H), 8.13
(d, 2H), 11.80 (s, 2H); 13C NMR (75 MHz, CDCl3): d 27.62, 29.79, 31.63, 32.62, 46.64,
47.26, 115.55, 128.r0, 128.55, 131.80, 136.91, 189.63, 190.84.
Acknowledgements
The author thanks the Research Council of Hakim Sabzevari University for partial sup-
port of this work.
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