Synthesis of 1,1,1-trifluorobut-3-yn-2-ones and their reactions with N-nucleophiles

Article abstract of DOI:10.1016/j.mencom.2014.11.009

Bromination of 4-aryl-1,1,1-trifluorobut-3-yn-2-ones gives 4-aryl-3,4-dibromo-1,1,1-trifluorobut-3-en-2-ones whose reactivity towards N-nucleophiles (hydrazine and ethylenediamine) was investigated.

Full text of DOI:10.1016/j.mencom.2014.11.009

Mendeleev
Communications
Mendeleev Commun., 2014, 24, 342–344
Synthesis of 1,1,1-trifluorobut-3-yn-2-ones
and their reactions with N-nucleophiles
Vasiliy M. Muzalevskiy,a Anton A. Iskandarova and Valentine G. Nenajdenko*a,b
a Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation.
Fax: +7 495 932 8846; e-mail: nen@acylium.chem.msu.ru
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5085; e-mail: nenajdenko@gmail.com
DOI: 10.1016/j.mencom.2014.11.009
Bromination of 4-aryl-1,1,1-trifluorobut-3-yn-2-ones gives 4-aryl-3,4-dibromo-1,1,1-trifluorobut-3-en-2-ones whose reactivity towards
N-nucleophiles (hydrazine and ethylenediamine) was investigated.
Br
O
The importance of fluorinated compounds for medicinal chemistry
can be hardly overestimated.1 Among them, trifluoromethylated
pyrazoles (e.g., Celecoxib) are important type of pharmaco-
logically relevant compounds.2–5
O
Br2
R
CF3
R
CH2Cl2
Br
CF3
1
2
a,b-Unsaturated trifluoromethyl ketones are the versatile
building blocks for the synthesis of various fluorinated mole-
cules, especially heterocyclic ones.6 Heterocyclization of tri-
fluoromethyl-containing building blocks (for example, enones or
1,3-diketones) with hydrazines7 is a common access to trifluoro-
methylated pyrazoles. Here, we report the synthesis of novel
fluorinated building blocks, a,b-dibromo-CF3-enones, and their
reactions with hydrazine and ethylenediamine.
a R = H, 92%, 80:20
b R = Cl, 97%, 75:25
c R = MeO, 95%, 72:28
d R = But, 92%, 77:23
e R = Me, 93%, 79:21
Scheme 1
The presence of three electrophilic centers (trifluoroacetyl
group, activated double bond and carbon adjacent with halogens)
in the structure of a,b-dibromo-CF3-enones led us to expect high
activity of these compounds towards nucleophiles to open wide
possibilities of incorporating a trifluoromethyl group into target
compounds with the desired position of CF3 group. Heterocycles
of various sizes can be prepared using these building blocks
depending on the nature of binucleophiles (1,2-, 1,3- and 1,4-bi-
nucleophiles).
for 1a). The configuration of isomers was not assigned. Com-
pounds 2 with both electron-donating and electron-withdrawing
substituents in the phenyl ring were thus prepared.
3,4-Dibromo-4-(4-chlorophenyl)-1,1,1-trifluorobut-3-en-2-one 2b.Yield
1.905 g (97%). Major isomer: 1H NMR, d: 7.27 (d, 2H, Ar, J 8.6 Hz), 7.36
(d, 2H, Ar, J 8.6 Hz). 13C NMR, d: 114.4, 114.9 (q, CF3, J 291.9 Hz),
129.2, 130.0, 135.6, 136.7, 137.2, 179.5 (q, C=O, J 38.3 Hz). 19F NMR,
d: –73.9. Minor isomer: 1H NMR, d: 7.44 (d, 2H, Ar, J 8.7 Hz), 7.48 (d,
2H, Ar, J 8.7 Hz). 13C NMR, d: 105.7, 114.9 (q, CF3, J 291.9 Hz), 123.3,
129.0, 130.3, 134.8, 179.4 (q, C=O, J 39.1 Hz). 19F NMR, d: –73.8.
3,4-Dibromo-1,1,1-trifluoro-4-(4-methoxyphenyl)but-3-en-2-one 2c.
Yield 1.840 g (95%). Major isomer: 1H NMR, d: 3.82 (s, 3H, MeO), 6.88
(d, 2H, Ar, J 8.8 Hz), 7.29 (d, 2H, Ar, J 8.8 Hz). 13C NMR, d: 55.3, 112.4,
114.8 (q, CF3, J 292.3 Hz), 114.2, 129.6, 130.7, 138.6, 161.7, 180.4 (q,
CF3-ynones 1 were prepared from lithiated terminal alkynes
and ethyl trifluoroacetate.8 Their bromination in CH2Cl2 afforded
a,b-dibromo-CF3-enones 2 in almost quantitative yields (Scheme 1) †
.
The reaction was stereoselective and gave mixtures of E,Z-iso-
mers in which content of a major isomer reached 80% (the ratio
of the isomers was determined by 1H NMR for 1b–e or 19F NMR
1
C=O, J 38.4 Hz). 19F NMR, d: –73.8. Minor isomer: H NMR, d: 3.86
(s, 3H, MeO), 6.96 (d, 2H, Ar, J 8.9 Hz), 7.53 (d, 2H, Ar, J 8.9 Hz).
13C NMR, d: 103.5, 113.8, 114.8 (q, CF3, J 291.9 Hz), 124.9, 128.2, 130.8,
161.2, 179.8 (q, C=O, J 38.4 Hz). 19F NMR, d: –73.6.
†
1H (400.1 MHz), 13C (100.6 MHz) and 19F (376.3 MHz) NMR spectra
in CDCl3 were recorded on a Bruker AVANCE 400 MHz spectrometer.
IR spectra were recorded on ThermoNicolet IR 200. The GC/MS analyses
were performed with a Shimadzu GCMS-QP5050A instrument (EI, 70 eV).
ESI-MS spectra were measured with a MicroTOF Bruker Daltonics
instrument.
a,b-Dibromo-CF3-enones 2 (general procedure). 1 m solution of Br2 in
CH2Cl2 (5.1 ml) was added dropwise to a solution of the corresponding
CF3-ynone 1 (0.005 mol) in CH2Cl2 (10 ml) on cooling with water bath.
After stirring for 0.5 h, the volatiles were removed in vacuo and the residue
was purified by column chromatography (silica gel, 230–400 Mesh, hexane–
CH2Cl2, 3:1). All of products 2a–e were obtained as yellowish viscous
oils and as mixtures of isomers which were not resolved. Isomer ratios
are specified in Scheme 1.
3,4-Dibromo-4-(4-tert-butylphenyl)-1,1,1-trifluorobut-3-en-2-one 2d.
Yield 1.908 g (92%). Major isomer: 1H NMR, d: 1.33 (s, 9H, But), 7.28
(d, 2H, Ar, J 8.5 Hz), 7.40 (d, 2H, Ar, J 8.5 Hz). 13C NMR, d: 31.0, 34.9,
113.0, 114.8 (q, CF3, J 292.3 Hz), 125.8, 128.7, 134.3, 138.5, 154.7, 180.2
(q, C=O, J 38.3 Hz). 19F NMR, d: –73.9. Minor isomer: 1H NMR, d: 1.37
(s, 9H, But), 7.47 (d, 2H, Ar, J 8.9 Hz), 7.51 (d, 2H, Ar, J 8.9 Hz). 13C NMR,
d: 31.1, 35.0, 104.2, 114.8 (q, CF3, J 291.1 Hz), 124.9, 125.5, 128.8, 133.3,
154.1, 179.8 (q, C=O, J 38.7 Hz). 19F NMR, d: –73.7.
3,4-Dibromo-1,1,1-trifluoro-4-(p-tolyl)but-3-en-2-one 2e. Yield 1.736 g
1
(93%). Major isomer: H NMR, d: 2.38 (s, 3H, Me), 7.19 (d, 2H, Ar,
J 8.2 Hz), 7.25 (d, 2H, Ar, J 8.2 Hz). 13C NMR, d: 21.3, 113.0, 114.6
(q, CF3, J 292.3 Hz), 128.8, 129.5, 134.5, 138.5, 141.6, 180.2 (q, C=O,
J 38.7 Hz). 19F NMR, d: –73.9. Minor isomer: 1H NMR, d: 2.43 (s, 3H,
Me), 7.27 (d, 2H, Ar, J 8.2 Hz), 7.46 (d, 2H, Ar, J 8.2 Hz). 13C NMR, d:
21.4, 104.3, 125.0, 128.8, 129.2, 133.5, 141.0. Other signals are identical to
those of major isomer. 19F NMR, d: –73.7.
3,4-Dibromo-1,1,1-trifluoro-4-phenylbut-3-en-2-one 2a. Yield 1.792 g
(92%). For the mixture of isomers: IR (neat, n/cm–1): 1589 (C=C), 1745
(C=O). H NMR, d: 7.34–7.56 (m, 5H, Ph). 13C NMR, d: 105.0, 113.7,
1
114.8 (q, CF3, J 291.9 Hz), 124.6, 128.6, 128.8, 130.5, 130.9, 136.5, 137.2,
138.0, 179.9 (q, C=O, J 38.7 Hz). 19F NMR, d: –74.0 (major), –73.8 (minor).
© 2014 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2014, 24, 342–344
(a)
(b)
20
9
d
C 90.2 ppm
dC 101.2 ppm
11
19
8
13
21
H
Br
Br
O
7
10
2 equiv.
N2H4·H2O
CF3
NH
CF3
NH
12
5
4
Ph
Ph
Ph
CF3
solvent,
reflux
6
N
N
3
Br
1
2a
4a
3a
Scheme 2
Table 1 Reaction of 2a with hydrazine hydrate in different solvents.
2
Figure 1 (a) The optimized geometry of enone 2a and (b) the diagram of
the electrostatic potential of the molecule.
Solvent
Yield of 3a + 4a (%) Yield of 3a (%)
3a:4a ratio
difference was very small. The analysis of atomic charges
(Mulliken and Levden) showed that both bromine atoms have a
localized positive charge (Figure 1). Consequently, the calcula-
tions confirmed our assumption about the possibility of halophilic
reaction for dibromoenones 2.
Halophilic attack of hydrazine hydrate, which is also strong
reducing agent, on bromine atom in 2a gives intermediate anions
5 or 6, which are transformed into acetylenic ketone 1a by elimina-
tion of bromide. The subsequent reaction of 1a with hydrazine
hydrate affords pyrazole 4a. This is confirmed by the presence of
traces of acetylene 1a in the reaction mixture (m/z 198, GC-MS,
the signal at –77.8 ppm in 19F NMR spectrum). Moreover, hetero-
cyclization of similar ynones with hydrazine hydrate to pyrazoles
is known.9
THF
36
68
95
75
50
97
72
25
20
35
15
61
27
58
77
64
40
85
56
22
16
31
6
76:24
86:14
81:19
86:14
82:18
87:13
77:23
87:13
80:20
89:11
41:59
75:25
BuOH
EtOH
EtOHa
EtOHb
Toluene
MeOH
PriOH
AcOH
CF3CH2OH
NEt3
CHCl3
46
a 1 equiv. of N2H4·H2O and 1 equiv. of AcONa. b 1 equiv. of N2H4·H2O and
1 equiv. of NEt3.
Br
O
O
Br
O
N2H4
Ph
CF3
Ph
CF3 or Ph
CF3
We assumed that treatment of a,b-dibromo-CF3-enones with
hydrazine hydrate should afford the corresponding 3-bromo-
2-trifluoromethylpyrazoles. Using compound 2a as a model, we
found that the highest yields (up to 85%, 19F NMR monitoring)
of the target bromopyrazole 3a were achieved in boiling ethanol
or toluene (Scheme 2, Table 1).‡ Surprisingly, in all cases a
formation of pyrazole 4a containing no bromine atom (up to
25%) also occurred. Structures of both products were confirmed
by GC-MS (molecular ions with m/z 212 for H-pyrazole 4a and
doublet with m/z 290, 292 for bromopyrazole 3a). Additionally
1H, 13C and 19F NMR spectra of 3a and 4a are in total agreement
with published ones. The most characteristic are signals of C3
carbons in the pyrazole ring (C–Br of 3a, 90.2 ppm and C–H of
4a, 101.2 ppm).
We suppose that pyrazole 4a is formed through the halophilic
mechanism including an attack of a nucleophile to a bromine
atom of reactant 2a. Steric hindrance caused by bromine atoms
in compound 2a at the double bond creates difficulties for
nucleophile attack at the double bond (Michael addition) as
well as at the carbonyl group. To confirm this assumption, we
performed DFT (B3LYP) quantum-chemical calculations and
estimated charges on atoms in molecules of 2a, which showed
that the Z isomer was more stable by 0.23 kcal mol–1 but the
– N2H3Cl
Br
2a
Br
5
6
H
CF3
O
N2H4·H2O
Ph
Ph
N
NH
CF3
1a
4a
Scheme 3
Compound 2a also reacted unusually with ethylenediamine§ to
form E-a,b-dibromostyrene 7 and 2-trifluoromethylimidazoline
8 as a result of C–C bond cleavage. The possible mechanism
includes an attack of ethylenediamine to the carbonyl group to
produce trifluoromethylimine 9, which cyclizes into trifluoro-
Br
O
Br
N
H
CF3
H2N
+
+
Ph
CF3
Ph
NH2
N
H
Br
2a
Br
10 equiv.
7
8
36%
‡
Br
Reaction of compound 2a with hydrazine hydrate. A mixture of com-
Br
N
HN
pound 2a (1.0 mmol) and hydrazine hydrate (2.0 mmol) in appropriate
solvent (2 ml, see Table 1) was stirred at reflux for 10–12 h. The volatiles
were evaporated in vacuo, the residue was purified by column chromato-
graphy on silica gel (eluent, hexane–CH2Cl2, 1:2). The pyrazoles 3a and
4a were not separated. NMR data of 3a11 and 4a12 are consistent with
those in the literature.
4-Bromo-5-(trifluoromethyl)-3-phenyl-1H-pyrazole 3a. 1H NMR,
d: 7.48–7.83 (m, 5H, Ar), 14.39 (br.s, 1H, NH). 13C NMR, d: 88.8, 122.1
(q, CF3, J 291.9 Hz), 126.8, 127.8, 129.0, 129.7, 139.9 (q, CCF3, J 36.1
Hz), 142.5. 19F NMR, d: –61.9.
Ph
Br
NH2
Ph
N
H
CF3
F3C
Br
9
10
Scheme 4
§
Reaction of compound 2a with ethylenediamine. A mixture of com-
pound 2a (1.0 mmol) and ethylenediamine (1.0 ml) was kept at room
temperature for 12 h. The volatiles were evaporated in vacuo, the residue
was purified by column chromatography on silica gel (eluent, hexane–
CH2Cl2, 1:1) to afford 0.094 g (36%) of E-a,b-dibromostyrene 7 as a
colorless oil. 1H NMR, d: 6.81 (s, 1H, =CH), 7.36–7.54 (m, Ar) (cf. ref. 13).
1
5-(Trifluoromethyl)-3-phenyl-1H-pyrazole 4a: H NMR, d: 7.48–7.83
(m, 5H, Ar), 14.09 (br.s, 1H, NH). 13C NMR, d: 101.0, 117.0, 118.4 (q,
CF3, J 291.9 Hz), 125.6, 127.8, 129.1, 129.3, 135.8 (q, CCF3, J 36.1 Hz),
144.0. 19F NMR, d: –61.3.
– 343 –

Mendeleev Commun., 2014, 24, 342–344
4 (a) S. K. Singh, P. G. Reddy, K. S. Rao, B. B. Lohray, P. Misra, S.A. Rajjak,
methylimidazolidine 10, followed by cleavage of the C–C bond
to furnish compounds 7 and 8. Similar examples of cleavage of
C–C bonds were described for unsaturated compounds bearing
electron-withdrawing substituents in reactions with ethylene-
diamine.10 However, a significant difference with the published
data should be noted. In the case of compound 2a the cleavage of
single C–C bond is observed, whereas previously formal cleavage
of multiple C–C bonds proceeded.
In conclusion, synthesis of previously unknown a,b-dibromo-
CF3-enones by bromination of CF3-ynones was elaborated. Their
reactivity towards N-nucleophiles was examined, which opens
prospects to new useful fluorinated compounds.
Y. K. Rao and A. Venkateswarlu, Bioorg. Med. Chem. Lett., 2004, 14, 499;
(b) S. K. Singh, S. Vobbalareddy, S. R. Kalleda, S. A. Rajjak, S. R. Casturi,
S. R.Datla,R.N.V.S.Mamidi,R.Mullangi,R.Bhamidipati,R.Ramanujan,
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6 (a) V. G. Nenaidenko and E. S. Balenkova, Zh. Org. Khim., 1992, 28, 600
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2007, 63, 12481; (f) A.Yu. Rulev, V. M. Muzalevskiy, E. V. Kondrashov,
I. A. Ushakov, A. R. Romanov, V. N. Khrustalev and V. G. Nenajdenko,
Org. Lett., 2013, 15, 2726; (g) V. G. Nenajdenko, A. V. Sanin and E. S.
Balenkova, Molecules, 1997, 2, 186; (h) V. G. Nenajdenko, A. V. Sanin
and E. S. Balenkova, Russ. Chem. Rev., 1999, 68, 437 (Usp. Khim., 1999,
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ARKIVOC, 2011, 246.
This work was supported by the Russian Science Foundation
(grant no. 14-13-00083).
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Received: 15th September 2014; Com. 14/4465
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