A Highly Efficient Approach for the Synthesis of Novel Trifluoroacetylated Enaminones using DBU as a Base

Article abstract of DOI:10.1055/s-0036-1588865

An efficient methodology has been developed for the synthesis of a variety of novel trifluoroacetylated enaminones by using trifluoroacetic anhydride in DCE as solvent and DBU as a base via electrophilic trifluoroacetylation. X-ray crystallographic studie

Full text of DOI:10.1055/s-0036-1588865

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
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A
en
P. Kumari et al.
Letter
Synlett
A Highly Efficient Approach for the Synthesis of Novel Trifluoro-
acetylated Enaminones using DBU as a Base
P. Kumari
N. Sharma
O
SMe
R2
A. Kumar
O
HN
R2
R1
F3C
N
H
TFAA, DBU
S. C. Mohapatra
S. Bhagat*
R1
SMe
DCE, 0 °C to r.t.
O
19 examples, 88–95% yield
R1 = aryl, heteroaryl
Organic Synthesis Research Laboratory, Department of
Chemistry, A.R.S.D. College, University of Delhi, New Delhi
110021, India
R
2 = Ph, 4-OMeC6H4, 2-FC6H4, 3-FC6H4,
cyclohexyl, n-propyl, i-propyl
sunitabhagat28@gmail.com
Received: 12.04.2017
Accepted after revision: 12.05.2017
Published online: 21.06.2017
functionalized heterocycles12,13 bearing a trifluoromethyl
or trifluoroacetyl group. However in spite of their wide
scope of application, enaminones have not been heavily ex-
ploited in trifluoroacetylation reactions and there is only
scanty information available on these important syn-
thons.11 In continuation of our research interest in enami-
nones,14–16 we report herein an efficient synthesis of triflu-
oroacetylated synthons, by using the non-toxic and non-
hazardous base DBU.
The enaminones 2a–s were easily prepared by direct
amination from α-oxoketene dithioacetals15 and substitut-
ed amines by refluxing in toluene.17 Compounds 2a–s were
isolated as single E stereoisomers as previously reported.14
Compounds 3a–s were efficiently synthesized18 from
enaminones 2a–s by using TFAA in the presence of DBU as a
base at room temperature (Scheme 1).
DOI: 10.1055/s-0036-1588865; Art ID: st-2017-d0251-l
Abstract An efficient methodology has been developed for the syn-
thesis of a variety of novel trifluoroacetylated enaminones by using tri-
fluoroacetic anhydride in DCE as solvent and DBU as a base via electro-
philic trifluoroacetylation. X-ray crystallographic studies confirmed the
trifluoroacetylation and E stereoisomeric form of the novel compounds.
The synthetic strategy has the advantage of using an inexpensive and
non-toxic base for producing excellent yields. Synthons bearing variety
of functional groups may be further extended for the formation of het-
erocyclic compounds.
Keywords trifluoroacetylation, electrophilic, enaminones, trifluoro-
acetic anhydride, DBU
Development of new methodologies for the synthesis of
fluorine-containing compounds is of great interest due to
their importance in pharmaceuticals,1 polymers2 and agro-
chemicals.3 Among them, trifluoroacetylated compounds
are of significant interest as pesticides.4,5 Incorporation of
the trifluoroacetyl group can increase solubility, binding
site interaction and hydrophobicity.6 A survey of the litera-
ture reveals various methods for trifluoroacetylation, using
pyridine as base.7 However, due to the problem of environ-
mental hazards and toxicity,8 it is desirable to replace the
pyridine with a less toxic, non-hazardous base. Thus, we
have concentrated on the development of new and efficient
synthetic methods for trifluoroacetylation. DBU is very in-
teresting as it can be used as an efficient base.9
Enaminones are versatile synthons for the synthesis of
various heterocyclic compounds10 because the olefinic link-
age is activated by electron-releasing alkylthio and amino
groups through p–π conjugation. This makes it reactive to-
wards electrophiles such as trifluoroacetic anhydride to af-
ford trifluoroacetylated enaminones.11 These synthons
could serve as useful building blocks in the construction of
O
SMe
R2
R2
O
HN
R1
N
H
TFAA, DBU
R1
SMe
DCE, 0 °C to r.t.
2 h
F3C
3a–s
O
2a–s
Scheme 1 Synthesis of trifluoroacetylated enaminones
The optimized reaction conditions were established by
attempting a model reaction for the synthesis of 3l (Scheme
2). The reaction was screened using various solvents, bases
and by varying time of the reaction for the synthesis of
(E)-1-(4-chlorophenyl)-2-[(cyclohexylamino)(methylthio)-
methylene]-4,4,4-trifluorobutane-1,3-dione (3l) from (E)-
1-(4-chlorophenyl)-3-(cyclohexylamino)-3-(methylthio)prop-
2-en-1-one (2l). First, we carried out the reaction with
TFAA in CHCl3 in the presence of DBU as base at room tem-
perature. The progress of the reaction was monitored by
TLC and was found to be complete after two hours and 3l
was obtained in 74% yield after workup (Table 1, entry 1).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
P. Kumari et al.
Letter
Synlett
tion of 2l with TFAA in the absence of base, no product was
obtained (Table 1, entry 14). The effect of reagent amount
on the reaction time and yield of the product was also ex-
amined. There was no significant effect on the product
yields under these conditions (Table 1, entries 15 and 16).
Thus, on the basis of these observations, the optimal reac-
tion conditions for the synthesis of 3l were established to
be DBU in DCE at room temperature for two hours.
With the optimal conditions in hand, we next turned
our attention to explore the substrate scope by testing vari-
ous enaminones 2a–s, and the results are summarized in
Table 2. All the reactions were complete in less than three
hours with both electron-rich and electron-deficient enam-
inones affording the desired products 3a–s in high yields
(Scheme 3). When unsubstituted phenyl rings were present
on both sides, product 3a was obtained in 90% yield (Table
2, entry 1). When R1 and R2 bore electron-rich or electron-
deficient phenyl groups, enaminones 2b–g were trans-
formed smoothly into the desired products 3b–g in 88–92%
yield (Table 2, entries 2–7). A yield of 89% was obtained
O
SMe
O
HN
TFAA, base
solvent, 0 °C to r.t
N
H
SMe
Cl
F3C
O
Cl
Scheme 2 Screening of optimal reaction conditions for 3l
The above reaction was then carried out using carbon
tetrachloride, dichloromethane and dichloroethane as sol-
vents under identical conditions. The reactions were com-
plete in 2–3 hours and gave 75%, 73% and 94% yield of prod-
uct 3l, respectively (Table 1, entries 2–4). The same reaction
was then explored in tetrahydrofuran, acetonitrile under
similar conditions. The reaction was found to be complete
in six hours and seven hours and gave 62% and 65% yields of
the desired product 3l, respectively (Table 1, entries 5 and
6). As the best results were obtained when the reaction was
attempted in DCE, it was chosen for further exploration of
this reaction. To determine the effect of bases other than
DBU, the reaction was attempted using DABCO, triethyl-
amine, diethylamine and DIPEA in DCE at room tempera-
ture. The reactions were found to be complete in 3–4 hours
and gave 3l in 86%, 40%, 42%, and 70% yields, respectively
(Table 1, entries 7–10). Then same reaction was repeated
with inorganic bases, sodium carbonate, potassium carbon-
ate and cesium carbonate, but the desired product was only
formed in 40–42% yield even after running the reaction for
eight hours (entries 11–13). When we carried out the reac-
O
SMe
R2
R2
O
HN
TFAA, DBU
R1
F3C
N
H
R1
SMe
DCE, 0 °C to r.t.
2 h
O
3a–s
2a–s
Scheme 3 Substrate scope of the synthesis of novel trifluoroacetylat-
ed enaminones
Table 1 Preparation of Trifluoroacetylated Enaminones
Entry
Solvent
Base
DBU
Reagent TFAA (equiv)
Temp. (°C)
Time (h)
Yield (%)b
1
2
CHCl3
CCl4
CH2Cl2
DCE
THF
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
2
3
3
2
6
7
3
4
4
4
8
8
8
8
3
2
74
75
73
94
62
65
86
40
42
70
42
40
42
–
DBU
3
DBU
4
DBU
DBU
5
6
MeCN
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DBU
7
DABCO
TEA
8
9
DEA
10
11
12
13
14
15
16
DIPEA
Na2CO3
K2CO3
Cs2CO3
–
DBU
88
90
DBU
3.5
a Reaction conditions: 2l (1.0 equiv), DBU (2 equiv), TFAA (2.5 equiv), DCE, reaction at 0 °C to r.t.
b Isolated yield.
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C
P. Kumari et al.
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with a cyclopropyl group present as R1 (entry 8). Moreover
when heteroaryl groups were present as R1, 3i, and 3j were
furnished in 88% and 87% yield, respectively (Table 2, en-
tries 9 and 10). Substrates with an electron-deficient aro-
matic substituent R1 and a cyclohexyl group as R2 gave in-
triguing trifluoroacetylated products 3k–m in 94–95% yield
(Table 2, entries 11–13); whereas substrates with R1 con-
taining electron-donating groups (4-MeC6H4 or 4-
OMeC6H4) and a cyclohexyl group as R2 gave yields of 90%
and 88%, respectively (Table 2, entries 14 and 15). However
a yield of 90–95% was observed when isopropyl and n-pro-
pyl groups were present as R2 (Table 2, entries 16–19).
Table 2 Synthesis of Novel Trifluoroacetylated Enaminones
Entry
Substrate
Product
Yields (%)
O
SMe
O
HN
N
H
1
90
SMe
F3C
O
3a
3b
2a
OMe
OMe
O
SMe
O
HN
N
H
2
3
4
5
6
92
92
90
88
89
SMe
F3C
O
2b
O
SMe
O
HN
N
H
SMe
F
F3C
O
F
2c
3c
O
SMe
O
HN
N
H
SMe
Cl
3d
F3C
O
Cl
2d
O
SMe
O
HN
F
N
H
F
SMe
Br
3e
F3C
O
Br
2e
F
O
SMe
O
HN
N
H
SMe
F
Br
F3C
O
3f
Br
2f
O
SMe
O
HN
N
H
7
89
SMe
MeO
F3C
O
MeO
2g
3g
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Table (continued)
Entry
Substrate
Product
Yields (%)
O
SMe
O
HN
N
H
8
9
89
88
SMe
F3C
O
3h
3i
2h
O
SMe
O
HN
N
H
S
F3C
SMe
O
S
2i
OMe
OMe
O
SMe
O
HN
N
H
10
11
87
95
S
SMe
HN
F3C
O
S
3j
2j
O
SMe
O
N
H
SMe
Br
F3C
O
Br
2k
3k
O
SMe
O
HN
N
H
12
13
14
94
95
90
SMe
Cl
F3C
O
Cl
2l
3l
O
SMe
O
HN
F3C
N
H
F3C
SMe
F3C
O
3m
2m
O
SMe
O
HN
N
H
SMe
MeO
F3C
O
MeO
2n
3n
O
SMe
O
HN
N
H
15
88
SMe
F3C
O
3o
2o
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P. Kumari et al.
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Table (continued)
Entry
Substrate
Product
Yields (%)
O
SMe
O
HN
N
H
16
17
90
95
SMe
F
3p
F3C
O
F
2p
O
SMe
NH
O
HN
F3C
F3C
SMe
F3C
O
3q
2q
O
SMe
O
HN
N
H
18
19
95
94
SMe
F
3r
F3C
O
F
2r
O
SMe
NH
O
HN
SMe
Cl
F3C
O
Cl
2s
3s
Structural assignments of 3l were made on the basis of
1
IR, H, 13C, 19F NMR and HRMS data. Disappearance of the
1
vinylic peak at δ = 5.49 ppm was observed in the H NMR
spectrum. In the 13C NMR spectrum of compound 3l, dis-
placement of the peak corresponding to the olefinic carbon
at δ = 85.55 ppm with simultaneous appearance of a peak
at δ = 174.01 (COCF3), 115.88 (COCF3) and 107.74 (=CCOCF3)
ppm confirmed the incorporation of a trifluoroacetyl group
at the olefinic position. In the 19F NMR spectrum, appear-
ance of a peak at δ = –70.68 ppm confirmed the presence of
a trifluoromethyl group. HRMS data of the 3l compound
showed the [M + 1] peak at m/z = 406.0853. An X-ray crys-
tallographic study of compound 3q confirmed the single E-
stereoisomeric form of the final product (Figure 1).
Figure 1 ORTEP diagram of 3q (CCDC 1515192)
In conclusion, a convenient and efficient strategy has
been developed for the synthesis of novel trifluoroacetylat-
ed enaminones using DBU as base. The easy accessibility of
the starting materials, simplicity of execution and mild re-
action conditions make this strategy convenient. The condi-
tions tolerate a wide variety of functional groups which can
be further extended for the synthesis of heterocycles such
as pyrazoles, pyrimidines or benzodiazepines.
Acknowledgment
The authors are grateful to SERB, Department of Science & Technolo-
gy, India for providing financial support and USIC, University of Delhi
for providing instrumentation facilities. PK, AK and NS are grateful to
CSIR and SERB for fellowships respectively.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
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Letter
Synlett
Supporting Information
(14) Sharma, N.; Chundawat, T. S.; Mohapatra, S. C.; Bhagat, S. Syn-
thesis 2016, 48, 4495.
(15) Sharma, N.; Chundawat, T. S.; Mohapatra, S. C.; Bhagat, S. RSC
Adv. 2013, 3, 16336.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588865.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(16) Sharma, N.; Kumari, N.; Chundawat, T. S.; Bhagat, S. RSC Adv.
2017, 7, 10150.
(17) Yang, C. W.; Bai, Y. X.; Zhang, N. T.; Zeng, C. C.; Hua, L. M.; Tian,
H. Y. Tetrahedron 2012, 68, 10201.
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Nishigaki, T. Synthesis 1986, 340. (b) Hojo, M.; Masuda, R.;
Okada, E.; Mochizuki, Y. Synthesis 1992, 455. (c) Moriguchi, T.;
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(18) General Procedure for the Synthesis of Trifluoroacetylated
Enaminones 3a–s: To a solution of enaminones 2a–s (1 equiv)
in DCE (5 mL) was added DBU (2 equiv) under a N2 atmosphere.
TFAA (2.5 equiv) was added dropwise over 10 min, keeping the
temperature at 0 °C. When addition was complete, the mixture
was allowed to warm slowly to r.t. and stirred for 2 h, monitor-
ing by TLC. After completion of the reaction, the mixture was
quenched with aq NaHCO3, then washed with dilute HCl and
finally H2O. The mixture was extracted with CH2Cl2 and the
organic layer was dried over anhyd Na2SO4. After filtering and
concentrating by rotary evaporation,
a solid product was
obtained that was crystallized from Et2O–pentane (5%) to give
the pure compounds 3a–s.
(E)-1-(4-Chlorophenyl)-2-[(cyclohexylamino)(meth-
ylthio)methylene]-4,4,4-trifluorobutane-1,3-dione (3l): The
compound was obtained as a white solid; mp 108–110 °C;
yield: 0.36 g (94%). IR (KBr): 3448, 2933, 1726, 1654, 1574, 1460
cm–1. 1H NMR (400 MHz, CDCl3): δ = 12.07 (br s, 1 H, NH), 7.75
(t, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.4 Hz, 2 H), 3.95 (s, 1 H, NHCH),
2.19 (s, 3 H, SMe), 1.87–1.90 (m, 3 H), 1.72–1.74 (m, 2 H), 1.55–
1.57 (m, 1 H), 1.24–1.46 (m, 4 H). 13C NMR (100 MHz, CDCl3):
δ = 191.17, 174.01 (COCF3), 167.94, 139.44, 137.82, 130.57,
128.83, 128.64, 128.44, 118.75, 115.88 (COCF3), 107.74
(=CCOCF3), 55.21, 33.36, 24.95, 24.16, 19.43 (SMe). 19F NMR
(376 MHz, CDCl3): δ = –70.68 (s, 3 F, COCF3). HRMS (ESI): m/z [M
+ H]+ calcd for C18H19ClF3NO2S: 406.0855; found: 406.0853.
(E)-4,4,4-Trifluoro-2-1-(4-chlorophenyl)-2[(meth-
ylthio)(propylamino)methylene]-1-[3-(trifluoromethyl)phe-
nyl]butane-1,3-dione (3q): The compound was obtained as a
white solid; mp 60–62 °C; yield: 0.37 g (95%). IR (KBr): 3418,
2903, 1723, 1621, 1562, 1464 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 11.95 (br s, 1 H, NH), 8.06 (s, 1 H), 7.99 (d, J = 7.6 Hz, 1 H),
7.74 (d, J = 7.6 Hz, 1 H), 7.54 (d J = 7.6 Hz, 1 H), 3.58 (q, J = 6.1 Hz,
2 H), 2.15 (s, 3 H, SMe), 1.65–1.74 (m, 2 H), 1.00 (t, 3 H). 13C
NMR (100 MHz, CDCl3): δ = 190.76, 174.42 (COCF3), 169.21,
140.03, 132.26, 129.21, 128.08, 125.77, 115.78 (COCF3), 107.67
(=CCOCF3), 48.06, 23.14, 18.48 (SMe), 11.29 (Me). 19F NMR (376
MHz, CDCl3): δ = –63.73 (s, 3 F, ArCF3), –71.87 (s, 3 F, COCF3).
HRMS (ESI): m/z [M + H]+ calcd for C16H15F6NO2S: 400.0806;
found: 400.0801.
(11) Zhang, L.; Dong, J.; Xu, J.; Liu, Q. Chem. Rev. 2016, 116, 287.
(12) Hojo, M.; Masuda, R.; Okada, E.; Yamamoto, H.; Morimoto, K.;
Okada, K. Synthesis 1990, 195.
(13) Barabanov, M. A.; Sevenard, D. V.; Sosnovskikh, V. Y. Russ. Chem.
Bull., Int. Ed. 2012, 61, 1646.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F