Synthesis of 5-(trifluoromethyl)cyclohexane-1,2,3-trione (cVTC): new trifluoromethyl building block

Article abstract of DOI:10.1016/j.tetlet.2016.10.043

A simple synthesis of 5-(trifluoromethyl)cyclohexane-1,2,3-trione is demonstrated in one step, by reacting 5-(trifluoromethyl)cyclohexane-1,3-dione with cerium(IV)ammonium nitrate (CAN) in methanol. The compound represents a highly functionalized oxygen-r

Full text of DOI:10.1016/j.tetlet.2016.10.043

Tetrahedron Letters 57 (2016) 5259–5261
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Tetrahedron Letters
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Synthesis of 5-(trifluoromethyl)cyclohexane-1,2,3-trione (cVTC): new
trifluoromethyl building block
⇑
Chibuike D. Obi, Cosmas O. Okoro
Department of Chemistry, Tennessee State University, 3500 John A. Merritt Blvd., Nashville, TN 37209-1561, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple synthesis of 5-(trifluoromethyl)cyclohexane-1,2,3-trione is demonstrated in one step, by react-
ing 5-(trifluoromethyl)cyclohexane-1,3-dione with cerium(IV)ammonium nitrate (CAN) in methanol. The
compound represents a highly functionalized oxygen-rich reactive intermediate for the synthesis of
organic and heterocyclic compounds containing fluorine.
Received 19 August 2016
Revised 6 October 2016
Accepted 12 October 2016
Available online 13 October 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Trifluoromethyl
Vicinal tricarbonyl
Cycloalkanone
Fluorinated Cyclohexane-1,2-3-trione
Triketone
Introduction
functionalization, followed by oxidation of the central carbon of
the 1,3-dicarbonyl compound using singlet oxygen, dimethyldioxi-
The chemistry and synthesis of aliphatic vicinal tricarbonyl
compounds (VTC) have been extensively studied.1 However, only
a few reports exist for the corresponding cyclic counterparts
derived from dimedone, cyclohexane-1,3-dione, or 1H-indene-1,3
(2H)-dione.2 Vicinal tricarbonyl compounds possess three consec-
utive carbonyl groups, with the central one being the most electron
deficient and therefore more susceptible to nucleophilic attack.
Takeshi Endo et al. reported that VTC easily reacts in a reversible
manner with water, alcohols, amines, and thiols without the aid
rane, ozone,11 DMSO, SeO2,12 and Dess–Martin periodinane,13 syn-
thesis by oxidation of Morita–Baylis–Hillman (MBH) adducts,14
and single-step synthesis using cerium(IV)ammonium nitrate
(CAN).2 It is well established that the introduction of fluorine (s),
difluoromethyl, or trifluoromethyl group to bioactive molecules
often leads to improved pharmacological properties,15 due to
increased membrane permeability and stability against metabolic
oxidation. Moreover, fluorine, and most notably trifluoromethyl
can have significant effects on the binding affinity in protein–ligand
complexes. To the best of our knowledge, VTC containing a fluorine
substituent, particularly a trifluoromethyl group on a cycloalka-
none ring appears not to have been reported in the literature. In this
short communication, we report the synthesis of trifluoromethy-
lated cyclic vicinal tricarbonyl compounds starting from our previ-
ously reported 5-trifluoromethyl-1,3-cyclohexanedione.16 We
envisioned that fluorinated VTC with its high reactivity would not
only serve as a synthetically useful fluorine building block, but will
also provide the route to fluorine-containing compounds.
of
a catalyst to form gem-diol, hemiketal, hemiaminal, and
hemithioketal compounds respectively. The triketone feature of
VTC reflects its’ multi-reactivity or multifunctional nature, as it
gives a wide range of options in the organic synthesis of different
natural products, such as awajanomycin,3 wailupemycin A4, and
cladoniamide.5 Some important compounds with antibiotic,
immunosuppressive,6 and bronchodilator7 activities have also
been successfully synthesized from VTCs. In addition, heterocyclic
derivatives of quinoxaline, pyrazine, thiane, pterin,8 and furan9
have all been synthesized from VTC. It is also interesting to note
that VTC has been used as a ‘redox-controlled’ molecular rotor.10
b-dicarbonyl compounds have been demonstrated to be the most
effective precursor in the synthesis of vicinal tricarbonyl com-
pounds, which can be achieved via several routes. These
methods include a two-step procedure that proceeds with initial
Result and discussion
According to previous research work2 on the synthesis of vicinal
tricarbonyl compounds from b-dicarbonyl compounds, the process
was most viable using 10 mol % of cerium(IV)ammonium nitrate
(CAN) as the catalyst, and dry acetonitrile as the solvent. The
stated process leads to a model reaction in the synthesis of
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.tetlet.2016.10.043
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

5260
C. D. Obi, C. O. Okoro / Tetrahedron Letters 57 (2016) 5259–5261
O
O
O
O
O
O
O
O
Oxidant
CAN (10 mol %)
CH3CN (dry)
solvent
temperature
time
O
O
F3C
F3C
3
4
1
2
0oC to r.t.; 4 h
Scheme 1. Model reaction.2
Scheme 2. Synthesis of 5-(trifluoromethyl)cyclohexane-1,2,3-trione.
cyclohexane-1,2,3-trione 2 from cyclohexane-1,3-dione 1 under
the same reaction conditions (Scheme 1), which proceeded to yield
the product as proposed.
Table 2
Oxyalkylation reaction conditions
However, our major aim in synthesizing 5-(trifluoromethyl)cy-
clohexane-1,2,3-trione 4 in this experiment did not yield any sig-
nificant product under the same condition as the model reaction
(entry 1), thereby resulting to the modification of reaction condi-
tions in order to achieve our goal in synthesizing a trifluoromethy-
lated cyclicVTC 4 (Table 1) as shown in Scheme 2. Increase in the
concentration of cerium(IV)ammonium nitrate (CAN) to 20 mol %
Entry
Oxidant
mol %
Solvent
Temp
Time (h)
Yield (%)
15
16
17
18
19
20
21
22
23
CAN
CAN
CAN
FeCl3
CAN
CAN
CAN
FeCl3
CAN
20
50
100
20
20
50
100
20
20
EtOH
EtOH
EtOH
EtOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
n-PrOH
rt
rt
rt
Reflux
rt
rt
rt
Reflux
rt
4.5
3.5
3.5
3.5
10
10
10
4.5
6
73
69
68
32
47
43
42
35
55
and the application of
a common oxidizing agent K2Cr2O7
(10 mol %) did not yield any product (entries 2 and 5), but with
50 mol % of CAN and the use of another single electron oxidant
such as FeCl3, the reaction proceeded with a long reaction time
and very low product yields (entries 3 and 4). On a further inves-
tigative experiment to obtain a higher product yield, methanol
was used as the solvent with 10 mol % CAN and a moderate pro-
duct yield of 53% was achieved (entry 6).
Further increase in the concentration of the catalyst (CAN) to
20 mol % gave the highest product yield of 69% (entry 2) as a vis-
cous yellow liquid, after subjecting the crude residue to a column
chromatography with a solvent system of dichloromethane and
methanol in a ratio of 9:1 respectively.17 We observed from the
GC/MS analysis of 4 after extraction of the crude product with
brine solution and dichloromethane showed a little trace of the
gem-diol (dihydroxylated) form of the product, but did not appear
when the crude product was analyzed before extraction. This
revealed the tendency of the electrophilic central carbonyl group
to readily react with a slight trace of water as stated earlier.1c
The experiment was also carried out using higher concentrations
of CAN, FeCl3 as the oxidant, and similar conditions using DMF as
the solvent, but the reactions gave low product yields (entries 8,
9, 10, 12, 13). Also, other solvents such as dichloromethane, THF,
DMSO, and dioxane were also investigated, but the reaction was
not viable.
retention time of 5.4 min and m/z of 208, which was assigned as
6-methyl-5-trifluoromethyl-1,2,3-cyclohexanetrione 6. From the
data analysis of product, we observed that an oxyalkylation reac-
tion (Scheme 3) took place instead of the expected oxidation of 3
to 4. The 1H NMR and 13C NMR data also corresponded with our
proposed product as they verified the presence of the methyl group
with peaks at 1.33 ppm and 13.88 ppm respectively.
The oxyalkylation reaction was further investigated by using
propanol as the solvent under the same reaction conditions (entry
23). Remarkably, an alkylated trifluoromethylated-cyclic VTC 5
was also observed as the product. GC–MS analysis showed a peak
in the chromatogram with retention time of 6 min and m/z of 223
[M++H], which was assigned as 6-ethyl-5-trifluoromethyl-1,2,3-
cyclohexanetrione 5. The 13C NMR showed the ethyl peaks at
21.76 ppm and 10.25 ppm. The oxyalkylation reaction performed
using 2-propanol involved a long reaction time with low yield,
while the use of 1-propanol as the solvent increased gave higher
yield with shorter reaction time (entry 23). This indicates the cru-
cial role the solvent plays in this oxyalkylation reaction. The sol-
vent appears to be the primary source of the alkyl groups.
Further exploratory experiments to understand the reaction mech-
anism on this novel oxyalkylation reaction of 5-(trifluoromethyl)-
cyclohexane-1,3-dione, using alcohols ([CnH2n+1OH] ‘n’ = 2 and
above) as the solvent and single electron oxidants as catalyst is still
under study.
In addition, while optimizing the reaction conditions we also
studied the reaction in ethanol with the lead we got by using
methanol as the solvent, ethanol was also used along with single
electron oxidants CAN and FeCl3 (Table 2) (entries 15 to 18).
GC–MS analysis showed
a peak in the chromatogram with
Table 1
Optimization of reaction conditions
Entry
Oxidant
mol %
Solvent
Temp
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
CAN
CAN
CAN
FeCl3
K2Cr2O7
CAN
CAN
CAN
10
20
50
20
10
10
20
50
100
20
10
20
50
20
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
DMF
0 °C–rt
0 °C–rt
0 °C–rt
rt–reflux
0 °C–reflux
0 °C–rt
0 °C–rt
0 °C–rt
0 °C–rt
rt–reflux
0 °C–reflux
rt
10
10
6
12
12
4
69
3.5
3.5
3.5
12
18
10
10
0
0
11
19
0
53
40
37
41
0
30
21
19
9
CAN
10
11
12
13
14
FeCl3
K2Cr2O7
CAN
CAN
FeCl3
DMF
DMF
rt
Reflux

C. D. Obi, C. O. Okoro / Tetrahedron Letters 57 (2016) 5259–5261
5261
O
O
O
CAN/FeCl3
O
O
O
O
CAN/FeCl3
i-PrOH or
n-PrOH
EtOH
F3C
O
F3C
F3C
3
r.t, 4.5 h
6
5
r.t., 4-10 h
Scheme 3. Oxyalkylation reaction of 5-(trifluoromethyl)cyclohexane-1,2,3-trione.
O
OH
O
OH
O
O
H2N
H2N
N
N
+
F3C
F3C
4
7
8
Scheme 4. Potential application of novel fluorinated cyclic triketone 4.
2. Akhil, S.; Ani, D. Tetrahedron Lett. 2014, 55, 1890–1893.
3. Wohlfahrt, M.; Harms, K.; Koert, U. Eur. J. Org. Chem. 2012, 2260–2265.
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5311.
6. Wasserman, H. H.; Lombardo, L. J. Tetrahedron Lett. 1989, 30, 1725–1728.
7. Wasserman, H. H.; Kuo, G. H. Tetrahedron Lett. 1991, 32, 7131–7132.
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The reaction is presumed to proceed by initial keto–enol equi-
librium of 3, followed by oxidation of the enol form by CAN and
subsequent steps as reported in the literature.2,18
Scheme 4 describes a potential application of compound 4 as
synthetically useful fluorine building block for the synthesis of
phenazine and other biologically interesting derivatives. Some
phenazine derivatives have been reported as dual topoisomerase
I and II inhibitors.19
Conclusion
In summary, we have developed a simple one step protocol
toward the synthesis of 5-trifluoromethyl-1,2,3-cyclohexanetri-
one, a novel class of compound with potential as fluorine building
block. The reaction in methanol was facile giving the expected flu-
orinated VTC. The reactions in n-propanol, isopropanol, or ethanol
gave fluorinated cyclic C-alkylated products respectively. The syn-
thetic application is shown by the synthesis of phenazine deriva-
tive (Scheme 4).
14. Santos, M. S.; Coelho, F. RSC Adv. 2012, 2, 3237–3241.
15. Park, B. K.; Kitterringham, N. R.; O’Neill, P. M. Annu. Rev. Pharmacol. Toxicol.
2001, 41, 443–470.
16. Fadeyi, O. O.; Okoro, C. O. Tetrahedron Lett. 2008, 49, 4725–4727.
17. Procedure for 5-(trifluoromethyl)cyclohexane-1,2,3-trione 4: 10 mmol of 5-
(trifluoromethyl)cyclohexane-1,3-dione 3 and 20 mol % of CAN were added
to 12 ml of methanol. The solution was initially stirred in an ice bath and
gradually adjusted to room temp. The reaction was monitored using TLC and
upon completion (4 h), the solvent was rotary evaporated. 15 ml of
dichloromethane was added to the extracted crude residue, washed with
brine solution (3 Â 10 mL) and dried with anhydrous magnesium sulfate.
The dried organic phase was concentrated in vacuo. Subjecting the crude
Acknowledgment
We are grateful to the US Department of Education Title III
Grant, Tennessee State University for financial support.
Supplementary data
residue to
a
column chromatography with
a
solvent system of
dichloromethane and methanol in a ratio of 9:1 respectively gave 4 as a
yellow oil. Yield: 69%; IR (cmÀ1): 2948, 1736, 1652, 1601, 1365, 1226, 1168,
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.10.
043.
1112, 921 cmÀ1 1H NMR (400 MHz, DMSO): dH 5.31 ppm (OH, gem-diol),
.
3.06–3.2 (m, 1H), 2.4 (d, J = 7.93 Hz, 4H). 13C NMR (100 MHz, CDCl3): dC
195.25, 175.60, 102.02, 56.03 (C–(OH)2, gem-diol), 34.91, 27.51 ppm. EIMS
m/z: 194 [M]+.
18. Song, J.; Zhang, H.; Chen, X.; Li, X.; Xu, D. Synth. Commun. 2010, 40, 1847.
19. Yao, Bing-Lei; Mai, Yan-Wen; Chen, Shuo-Bin; Xie, Hua-Ting; Yao, Pei-Fen;
Tian-Miao, Ou; Tan, Jia-Heng; Wang, Hong-Gen; Li, Ding; Huang,
Shi-Liang; Lian-Quan, Gu; Huang, Zhi-Shu Eur. J. Med. Chem. 2015, 92,
540–553.
References and notes
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Ikuyoshi, T.; Takeshi, E. Tetrahedron Lett. 2016, 72, 4783–4788.