Three-component synthesis of substituted β-(trifluoromethyl)pyrroles via Grob cyclization of 1,1,1-trifluoro-3-nitrobut-2-ene with 1,3-dicarbonylic compounds and ammonia or primary amines

Article abstract of DOI:10.1016/j.jfluchem.2012.03.012

A variety of substituted β-(trifluoromethyl)pyrroles were easily synthesized in good yields by a one-pot, three-component Grob cyclization of 1,1,1-trifluoro-3-nitrobut-2-ene with 1,3-dicarbonyls (ethyl acetoacetate, acetylacetone, benzoylacetone) and amm

Full text of DOI:10.1016/j.jfluchem.2012.03.012

Journal of Fluorine Chemistry 138 (2012) 42–47
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Three-component synthesis of substituted
b-(trifluoromethyl)pyrroles via Grob
cyclization of 1,1,1-trifluoro-3-nitrobut-2-ene with 1,3-dicarbonylic compounds
and ammonia or primary amines
*
Vladislav Yu. Korotaev, Alexey Yu. Barkov, Ivan V. Kotovich, Vyacheslav Ya. Sosnovskikh
Department of Chemistry, Ural Federal University, pr. Lenina 51, 620083 Ekaterinburg, Russian Federation
A R T I C L E I N F O
A B S T R A C T
Article history:
A variety of substituted
b
-(trifluoromethyl)pyrroles were easily synthesized in good yields by a one-pot,
Received 1 February 2012
Received in revised form 11 March 2012
Accepted 12 March 2012
Available online 20 March 2012
three-component Grob cyclization of 1,1,1-trifluoro-3-nitrobut-2-ene with 1,3-dicarbonyls (ethyl
acetoacetate, acetylacetone, benzoylacetone) and ammonia or primary aliphatic amines.
ß 2012 Elsevier B.V. All rights reserved.
Keywords:
a
-(Trifluoroethylidene)nitroethane
1,3-Dicarbonyls
Primary amines
Three-component reaction
Grob cyclization
b
-(Trifluoromethyl)pyrroles
1. Introduction
this procedure to the preparation of 3-acetyl-4-(polyfluoroalk-
yl)pyrroles in somewhat lower yields [7]. 1,3-Dipolar cycloaddi-
Much attention has been addressed to trifluoromethylated
heterocyclic compounds because they often show unique biological
and physiological activities [1]. In particular, trifluoromethyl-
substituted pyrroles and other five-membered heterocycles have
drawn considerable attention [2]. The search for a simple and
efficient access to such compounds with a CF3 group at a specific
position is one of the important goals in this area. However, there are
a limited number of regioselective syntheses of CF3-containing
tion of munchnones (1,3-oxazolium 5-olates) to
b
-chloro-
b-
(trifluoromethyl)vinyl phenyl ketone, butyl -chloro-g,g,g
b
-tri-
fluorocrotonate and polyfluoroacetylenic esters proceeds in a
regiospecific manner under mild reaction conditions, followed by
simultaneous decarboxylation to afford 4-(polyfluoroalkyl)pyr-
role-3-carboxylate derivatives [8]. Cyclodehydration of the
products obtained by oxygen-nitrogen exchange reaction of 4-
alkoxy-1,1,1-trifluoro-3-buten-2-ones with esters of
a-aminoa-
heteroaromatic compounds in good yield. In the case of
b-
cids, -aminoacetophenone and 2,2-dimethoxyethylamine into
a
(trifluoromethyl)pyrroles, only a few synthetic concepts have been
developed [1e].
fluorine-containing pyrroles is also described [9]. In addition, the
introduction of a polyfluoroalkyl group in moderate yield was
These compounds have been synthesized by the modified Knorr
condensation from ethyl trifluoroacetoacetate and 1,3-dicarbonyls
achieved by 1,2-addition of Me3SiCN to b-alkoxyvinyl polyfluor-
oalkyl ketones, followed by reduction with LiAlH4 and subsequent
hydrolysis with intramolecular cyclization [10]. Although these
reaction sequences have been developed for the regioselective
introduction of a RF group in the pyrrole ring, there are remaining
problems to be solved, such as the handling of the materials and
availability of reagents. Herein we wish to demonstrate utility of
readily available (E)-1,1,1-trifluoro-3-nitrobut-2-ene 1 [11] as a
novel building block for the construction of 4-(trifluoromethyl)-
pyrroles bearing different electron-withdrawing substituents at
the 3-position via addition of push–pull enamines.
in strong acid media [3]. Reaction of
a-(trifluoromethyl)alkenyl
sulfones with ethyl isocyanoacetate in the presence of a base gave 4-
(trifluoromethyl)pyrrole-2-carboxylates in moderate to good yields
[4]. A one-step formation of the pyrrole ring from Michael acceptors
and tosylmethylisocyanide under basic conditions was reported by
van Leusen et al. [5]. The application of this procedure to the alkyl
(E)-4,4,4-trifluorobutenoates led to the corresponding 4-(trifluor-
omethyl)pyrrole-3-carboxylates [6]. Ogoshi and coworkers applied
Nucleophilic addition of enamines to conjugated nitroalkenes is
an efficient method for preparation of cyclobutanes, 1,2-oxazine N-
oxides and nitroalkylated enamines or g-nitroketones [12] that, in
* Corresponding author. Fax: +7 343 2615978.
E-mail address: Vyacheslav.Sosnovskikh@usu.ru (V.Ya. Sosnovskikh).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2012.03.012

V.Y. Korotaev et al. / Journal of Fluorine Chemistry 138 (2012) 42–47
43
Table 1
F3C
Me
Synthesis of compounds 7a–r.
7
R1
R2
Yield (%)a
NO2
a
b
c
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Me
Me
Me
Me
Me
Me
Me
Ph
H
28
66
42
50
75
69
57
24
48
51
66
64
52
48
25b
54
50
48
CO2Et
1
+
+
Me
Et
d
e
f
HO(CH2)2
N
N
Me
Bn
X
X
Ph(CH2)2
2a
2b
g
h
i
3,4-(MeO)2C6H3(CH2)2
ref.14
ref.15
H
Me
j
Et
CF3
CF3
H
k
l
HO(CH2)2
Me
O
EtO2C
Me
Me
O
Bn
m
n
o
p
q
r
Ph(CH2)2
N
N
3,4-(MeO)2C6H3(CH2)2
O
O
H
N
X
N
X
Ph
Bn
Ph
Ph(CH2)2
Ph
3,4-(MeO)2C6H3(CH2)2
3a
3b
a
Isolated yield.
b
In propan-1-ol.
X
N
reaction was complete after 1 h and the products could be isolated
by column chromatography over silica gel. The similar reaction of
25% aqueous solution of ammonia afforded N-unsubstituted
pyrroles 7a,h,o, albeit in lower yields (24–28%). The progress of
the reaction was monitored by 1H and 19F NMR spectroscopy, and
the results are summarized in Table 1. In the case of benzoyla-
cetone, the regiochemistry was controlled by the more reactive
acetyl group, which underwent preferential attack on the amine.
The structure of the benzoyl derivative 7q was confirmed by X-ray
crystal structure analysis (Fig. 1) [19]. A plausible pathway leading
to the formation of these compounds via intermediate aminoe-
nones 6 is outlined in Scheme 2 [16b]. In contrast to its homologue
1, (E)-3,3,3-trifluoro-1-nitropropene, lacking the methyl group,
failed to give the corresponding pyrroles on reaction with 1,3-
dicarbonyls and aliphatic amines under the same conditions. This
indicated that cyclization in the case of a primary nitronate is not
efficient.
EtO2C
Me
CF3
Me
NO2
H
CF3
N
Me
N
O
OH
4
X
5
X = CH2, O, NMe
Scheme 1. Compounds 3–5 obtained previously from nitrobutene 1.
turn, are widely used in organic synthesis [12,13]. We have
recently investigated the reaction of nitrobutene 1 with tertiary
enamines 2a,b and described the first example of spontaneous
ring-contraction–rearrangement of 1,2-oxazine N-oxides 3a into
1-pyrroline N-oxides
4
[14] and
a
new type of ring-ring
This approach is the first example of successful three-
tautomerism between 1,2-oxazine N-oxides 3b and cyclobutanes
5 [15] (Scheme 1).
component Grob synthesis of fully substituted b-(trifluoro-
methyl)pyrroles 7 and has advantages with regard to ease of
operation and the ready availability of starting materials. It should
be noted that primary and secondary push–pull enamines 6 could
be employed directly under these conditions to give pyrroles 7 in
40–65% yields, however, a one-pot three-component reaction is
much more convenient. Note that in contrast to enamines 6,
In this paper we report a general method for the preparation of
b
-(trifluoromethyl)pyrroles, which is based on the three-compo-
nent variant of Grob cyclization. In this pyrrole synthesis,
nitroalkenes are commonly employed because the nitro group
can act both as a powerful stabilizer of the intermediate anion and
as a good nucleofuge in the aromatization forming a pyrrole ring. In
view of the utility of this reaction in synthetic chemistry [16], we
envisioned the use of nitrobutene 1 as a synthon for trifluor-
omethylated pyrroles, some of which represent a new class of
insect control agents [17]. Although there is one report on the
preparation of
b-(trifluoromethyl)pyrroles by reaction of active
methylene compounds with 3,3,3-trifluoro-1-nitropropene, fol-
lowed by the reduction of the nitro group and subsequent
cyclization [18], the use of nitrobutene 1 in the synthesis of
CF3-containing heterocycles has not been reported, except for
compounds 3 and 4.
2. Results and discussion
We found that nitrobutene 1, which is easily obtainable from
fluoral hydrate and nitroethane [11], reacted with 1,3-dicarbonyls
(ethyl acetoacetate, acetylacetone and benzoylacetone) and
primary aliphatic amines at reflux in ethanol to give
b-
Fig. 1. Molecular structure of pyrrole 7q.
(trifluoromethyl)pyrroles 7 in 42–75% yields. In most cases, the

44
V.Y. Korotaev et al. / Journal of Fluorine Chemistry 138 (2012) 42–47
F3C
Me
onto the acyl group in intermediates A (R1 = Me, Ph) than in A,
which bearing ethoxycarbonyl substituent. This delocalization
may prevent nucleophilic intramolecular attack and ring closure
[16f]. Substituents R2 on amine had no great effect on the reaction
course to give pyrroles 7a–r (Scheme 2, Table 1).
NO2
1
R1
Me
The above results prompted us to examine the reaction with
aromatic amines. However, in the case of nitroalkene 1,
acetylacetone and anisidine or 3,4-xylidine, the reaction resulted
in preferential formation of the previously known diastereomeric
+
R2 NH2
O
O
EtOH
adducts 8s,t [20], with formation of
b-(trifluoromethyl)pyrroles
R1
7s,t in 18–27% yields, based on the 1H NMR spectra of a crude
reaction mixture. All our attempts to obtain 7s,t as the sole
O
CF3
Me
R1
Me
R2
1
products were fruitless. Thus,
b-(trifluoromethyl)pyrroles from
anilines are formed more slowly than the corresponding Michael
adducts. A similar reaction of dimedone enamine with 1 yielded
exclusively compound 9 in 31% yield as a 75:25 mixture of
diastereomers without formation of any detectable amounts of the
corresponding pyrrole (Scheme 3).
-H2O,
-HNO
O
N
Me
H
N
6
R2
7a-r
-H2O,
-HNO
1
The structures of pyrroles 7 were confirmed by elemental
analysis, 1H, 19F, 13C NMR, and IR spectroscopy. In the 19F NMR
R1
R1
spectra the trifluoromethyl group appeared as a quartet at d 107.4–
5
O
Me
CF3
Me
O
CF3
108.6 ppm (C6F6) with JF,H = 1.7–2.5 Hz for 7a–g and 109.4–
5
111.1 ppm with JF,H = 1.3–1.5 Hz for 7o–r; the CF3 group of 7i–n
Me
manifests itself as a slightly broadened singlet at
d 110.5–
O
Me
OH
111.0 ppm. The 13C NMR spectra of 7b,f,n showed that the C-3,
C-5 and C-4 atoms were coupled with the fluorine atoms of the
trifluoromethyl group with 3JC,F = 1.7–1.8, 3.5–3.7 Hz and
2JC,F = 34.7–35.1 Hz, respectively; the Me-5 group was also coupled
N
N
OH
NH
R2
N
R2
OH
A
B
4
Scheme 2. Synthesis of
b-(trifluoromethyl)pyrroles 7a–r.
with JC,F = 2.7–3.1 Hz. The intensive absorption bands in the IR
spectra in the ranges 1684–1706 cmꢀ1 and 1616–1665 cmꢀ1 were
attributed to the ester and ketone carbonyl groups.
tertiary push–pull enamines 2b, lacking the labile hydrogen atom,
react with 1 to give compounds 3b and 5 (Scheme 1).
3. Conclusion
The reaction slightly depends on the substituent of the active
methylene compound. One possible explanation is a greater
capacity in delocalizing the electron pair of enamine nitrogen atom
In conclusion, we have shown that the three-component Grob
cyclization of (E)-1,1,1-trifluoro-3-nitrobut-2-ene with 1,3-dicar-
bonyls and primary aliphatic amines provides a simple and
convenient approach to substituted 4-(trifluoromethyl)pyrroles
bearing different electron-withdrawing substituents at the 3-
NH2
position. This new synthesis of
b-(trifluoromethyl)pyrroles
Me
Me
proceeds under mild conditions and the starting materials are
readily available.
+
O
O
R1
R2
1
4. Experimental
Ac
CF3
Me
NMR spectra were recorded on a Bruker DRX-400 (1H –
400 MHz, 13C – 100 MHz, and 19F – 376 MHz) and AVANCE-500 (1H
– 500 MHz and 13C – 126 MHz) spectrometers in DMSO-d6 and
CDCl3 with TMS and C6F6 as internal standards, respectively. IR
spectra were recorded on a Perkin-Elmer Spectrum BX-II instru-
ment as KBr discs. Elemental analyses were performed at the
Microanalysis Services of the Institute of Organic Synthesis, Ural
Branch, Russian Academy of Sciences. All solvents used were dried
and distilled per standard procedures. The starting (E)-1,1,1-
trifluoro-3-nitrobut-2-ene 1 was prepared according to described
procedure in 53% overall yield [11].
Me
NO2
F3C
Me
N
NH
+
R2
R1
R1
R2
7s,t
8s,t
R1 = H, R2 = MeO (s); R1 = R2 = Me (t)
4.1. General procedure for the synthesis of pyrroles 7a–r
O
O
CF3
A solution of the corresponding 1,3-dicarbonyl (2.0 mmol),
amine (2.0 mmol) and nitroalkene 1 (0.31 g, 2.0 mmol) in ethanol
(1 mL) was refluxed for 1 h. After removal of the solvent under
reduced pressure, the residue was chromatographed on silica gel
(eluted with chloroform) to give compound 7 as an yellow oil or
solid. The solid formed was recrystallized from the corresponding
solvent to yield a colourless powder or needles.
Me
1
Me
Me
Me
Me
NO2
NH2
NH2
9
Scheme 3. Reactions of 1 with anilines and dimedone enamine.

V.Y. Korotaev et al. / Journal of Fluorine Chemistry 138 (2012) 42–47
45
4.1.1. 3-Ethoxycarbonyl-2,5-dimethyl-4-(trifluoromethyl)-1H-
pyrrole (7a)
Yield 28%, mp 151–152 8C (CH2Cl2–hexane), colourless needles;
IR (KBr) 3312, 1687, 1608, 1559, 1544, 1478, 1449 cmꢀ1; 1H NMR
(400 MHz, CDCl3) 1.34 (t, J = 7.1 Hz, 3H, Me), 2.32 (q,
4.1.7. 3-Ethoxycarbonyl-1-(3,4-dimethoxyphenethyl)-2,5-dimethyl-
4-(trifluoromethyl)-1H-pyrrole (7g)
Yield 57%, mp 67–68 8C (hexane), colourless powder; IR (KBr)
1684, 1592, 1545, 1516, 1434 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d
d
1.33 (t, J = 7.1 Hz, 3H, Me), 2.16 (q, 3H, Me-5, 5JH,F = 2.0 Hz), 2.32 (s,
3H, Me-2), 2.83 (t, J = 7.0 Hz, 2H, CH2), 3.77 (s, 3H, MeO), 3.86 (s, 3H,
MeO), 4.00 (t, J = 7.0 Hz, 2H, CH2), 4.27 (q, J = 7.1 Hz, 2H, CH2O), 6.31
(d, J = 1.9 Hz, 1H, H-20), 6.63 (dd, J = 8.1, 1.9 Hz, 1H, H-60), 6.79 (d,
5JH,F = 2.4 Hz, 3H, Me-5), 2.45 (s, 3H, Me-2), 4.28 (q, J = 7.1 Hz,
2H, CH2O), 8.08 (br s, 1H, NH); 19F NMR (376 MHz, CDCl3)
(q, JF,H = 2.5 Hz, CF3). Anal. Calcd for C10H12F3NO2: C, 51.07; H,
d 107.4
5
5.14; N, 5.96. Found: C, 50.84; H, 5.03; N, 5.85.
J = 8.1 Hz, 1H, H-50); 19F NMR (376 MHz, CDCl3)
5JF,H = 2.0 Hz, CF3); 13C NMR (126 MHz, CDCl3)
4JC,F = 3.1 Hz, Me-5), 11.2 (Me), 14.0 (Me), 36.1, 45.1, 55.8, 56.0,
60.0, 109.5(q, 2JC,F = 35.0 Hz, C-4), 110.2 (q, 3JC,F = 1.8 Hz, C-3), 111.6,
112.0, 120.7, 124.1 (q, 1JC,F = 267.3 Hz, CF3), 129.5 (q, 3JC,F = 3.5 Hz, C-
5), 129.7, 135.8, 148.3, 149.2, 164.5 (C55O). Anal. Calcd for
d
d
108.6 (q,
10.8 (q,
4.1.2. 3-Ethoxycarbonyl-1,2,5-trimethyl-4-(trifluoromethyl)-1H-
pyrrole (7b)
Yield 66%, mp 75–76 8C (60% propan-1-ol), colourless needles; IR
(KBr) 1706, 1583, 1539, 1460, 1441 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
1.33 (t, J = 7.1 Hz, 3H, Me), 2.32 (q, 5JH,F = 1.7 Hz, 3H, Me-5), 2.47 (s,
C20H24F3NO4: C, 60.14; H, 6.06; N, 3.51. Found: C, 59.97; H, 6.17;
N, 3.59.
3H, Me-2), 3.41 (s, 3H, MeN), 4.27 (q, J = 7.1 Hz, 2H, CH2O); 19F NMR
(376 MHz, CDCl3) d
108.4 (q, 5JF,H = 1.7 Hz, CF3); 13C NMR (126 MHz,
CDCl3)
d
11.0 (q, 4JC,F = 3.1 Hz, Me-5), 11.4, 14.0, 30.3, 59.9, 109.1 (q,
4.1.8. 3-Acetyl-2,5-dimethyl-4-(trifluoromethyl)-1H-pyrrole (7h)
Yield 24%, mp 212–213 8C (ethanol), colourless needles; IR
2JC,F = 35.1 Hz, C-4), 109.7 (q, JC,F = 1.7 Hz, C-3), 124.1 (q,
3
1JC,F = 267.1 Hz, CF3), 129.8 (q, JC,F = 3.5 Hz, C-5), 136.1 (C-2),
(KBr) 3230, 3183, 1633, 1604, 1530, 1441, 1418 cmꢀ1 1H NMR
;
3
164.4 (C55O). Anal. Calcd for C11H14F3NO2: C, 53.01; H, 5.66; N,
5.62. Found: C, 52.88; H, 5.59; N, 5.65.
(400 MHz, DMSO-d6)
Me-2), 2.38 (s, 3H, Ac), 11.54 (br s, 1H, NH); 19F NMR (376 MHz,
CDCl3)
111.0 (q, 5JF,H = 2.7 Hz, CF3). Anal. Calcd for C9H10F3NO: C,
d
2.23 (q, 5JH,F = 2.6 Hz, 3H, Me-5), 2.32 (s, 3H,
d
4.1.3. 3-Ethoxycarbonyl-1-ethyl-2,5-dimethyl-4-(trifluoromethyl)-
1H-pyrrole (7c)
52.69; H, 4.91; N, 6.83. Found: C, 52.59; H, 4.72; N, 6.69.
Yield 42%, yellow oil; IR (KBr) 1704, 1578, 1548, 1436,
4.1.9. 3-Acetyl-1,2,5-trimethyl-4-(trifluoromethyl)-1H-pyrrole (7i)
1408 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
1.26 (t, J = 7.3 Hz, 3H,
Yield 48%, colourless crystals; IR (KBr) 1662, 1573, 1540,
MeCH2), 1.33 (t, J = 7.1 Hz, 3H, MeCH2O), 2.34 (q, 5JH,F = 1.9 Hz, 3H,
Me-5), 2.48 (s, 3H, Me-2), 3.87 (q, J = 7.3 Hz, 2H, CH2N), 4.27 (q,
1432 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
2.32 (q, JH,F = 1.8 Hz, 3H,
5
Me-5), 2.35 (s, 3H, Me-2), 2.43 (q, 6JH,F = 1.2 Hz, 3H, Ac), 3.41 (s, 3H,
MeN); 19F NMR (376 MHz, CDCl3)
110.6 (s, CF3). Anal. Calcd for
10H12F3NO: C, 54.79; H, 5.52; N, 6.39. Found: C, 54.59; H, 5.51; N,
6.35.
J = 7.1 Hz, 2H, CH2O); 19F NMR (376 MHz, CDCl3)
5JF,H = 1.9 Hz, CF3). Anal. Calcd for C12H16F3NO2: C, 54.75; H, 6.13;
d
108.6 (q,
d
C
N, 5.32. Found: C, 54.73; H, 6.30; N, 5.44.
4.1.4. 3-Ethoxycarbonyl-1-(2-hydroxyethyl)-2,5-dimethyl-4-
(trifluoromethyl)-1H-pyrrole (7d)
4.1.10. 3-Acetyl-1-ethyl-2,5-dimethyl-4-(trifluoromethyl)-1H-
pyrrole (7j)
Yield 50%, yellow oil; IR (KBr) 3447, 1733, 1698, 1578, 1548, 1436,
Yield51%, yellowoil;IR(KBr)1664, 1569, 1531, 1433, 1403 cmꢀ1
;
1405 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
1.33 (t, J = 7.1 Hz, 3H, Me),
1H NMR (400 MHz, CDCl3)
d
1.27 (t, J = 7.3 Hz, 3H, MeCH2), 2.34 (q,
3H, Me-5, 5JH,F = 1.8 Hz), 2.37 (s, 3H, Me-2), 2.44 (q, 6JH,F = 1.2 Hz, 3H,
Ac), 3.86 (q, J = 7.3 Hz, 2H, CH2); 19F NMR (376 MHz, CDCl3)
110.7
2.36 (q, 5JH,F = 1.8 Hz, 3H, Me-5), 2.49 (s, 3H, Me-2), 3.83, 4.00 (both t,
J = 5.7 Hz, 2H, CH2), 4.27 (q, J = 7.1 Hz, 2H, CH2O); 19F NMR (376 MHz,
d
CDCl3)
d
108.4 (q, 5JF,H = 1.8 Hz, CF3). Anal. Calcd for C12H16F3NO3: C,
(sept, JF,H = 1.4 Hz, CF3). Anal. Calcd for C11H14F3NO: C, 56.65;H, 6.05;
51.61; H, 5.78; N, 5.02. Found: C, 51.32; H, 6.08; N, 4.79.
N, 6.01. Found: C, 56.27; H, 6.10; N, 5.88.
4.1.5. 1-Benzyl-3-ethoxycarbonyl-2,5-dimethyl-4-(trifluoromethyl)-
1H-pyrrole (7e)
4.1.11. 3-Acetyl-1-(2-hydroxyethyl)-2,5-dimethyl-4-
(trifluoromethyl)-1H-pyrrole (7k)
Yield 75%, yellow oil; IR (KBr) 1705, 1651, 1601, 1583, 1548,
Yield 66%, mp 73–74 8C (CH2Cl2–hexane), colourless powder; IR
1434, 1407 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
1.35 (t, J = 7.1 Hz,
(KBr) 3330, 1639, 1568, 1528, 1432, 1396 cmꢀ1
;
1H NMR
3H, Me), 2.25 (q, 5JH,F = 1.9 Hz, 3H, Me-5), 2.42 (s, 3H, Me-2), 4.30
(q, J = 7.1 Hz, 2H, CH2O), 5.08 (s, 2H, CH2), 6.89 (d, J = 7.2 Hz, 2H,
(400 MHz, CDCl3)
3H, Me-5), 2.36 (s, 3H, Me-2), 2.43 (q, JH,F = 1.1 Hz, 3H, MeCO),
3.83, 3.99 (both t, J = 5.6 Hz, 2H, CH2); 19F NMR (376 MHz, CDCl3)
d
2.00 (br s, 1H, OH), 2.35 (q, JH,F = 1.9 Hz,
5
6
Ph), 7.26–7.35 (m, 3H, Ph); 19F NMR (376 MHz, CDCl3)
5JF,H = 1.9 Hz, CF3). Anal. Calcd for C17H18F3NO2: C, 62.76; H, 5.58;
d
108.5 (q,
d
110.5 (s, CF3). Anal. Calcd for C11H14F3NO2: C, 53.01; H, 5.66; N,
5.62. Found: C, 52.71; H, 5.46; N, 5.75.
N, 4.31. Found: C, 62.53; H, 5.36; N, 4.74.
4.1.6. 3-Ethoxycarbonyl-2,5-dimethyl-4-(trifluoromethyl)-1-
phenethyl-1H-pyrrole (7f)
4.1.12. 3-Acetyl-1-benzyl-2,5-dimethyl-4-(trifluoromethyl)-1H-
pyrrole (7l)
Yield 69%, mp 90–91 8C (hexane), colourless powder; IR (KBr)
Yield 64%, yellow oil; IR (KBr) 1665, 1607, 1563, 1532, 1432,
1687, 1647, 1595, 1550, 1499, 1455, 1430 cmꢀ1
;
1H NMR
1402 cmꢀ1; 1H NMR (500 MHz, CDCl3) 2.25 (q, 5JH,F = 1.6 Hz, 3H,
d
(400 MHz, CDCl3)
d
1.34 (t, J = 7.1 Hz, 3H, Me), 2.20 (q,
Me-5), 2.30 (s, 3H, Me-2), 2.48 (q, 6JH,F = 0.6 Hz, 3H, Ac), 5.07 (s, 2H,
CH2), 6.90 (d, J = 7.4 Hz, 2H, Ph), 7.27 ꢀ 7.37 (m, 3H, Ph); 19F NMR
5JH,F = 2.0 Hz, 3H, Me-5), 2.39 (s, 3H, Me-2), 2.88, 4.01 (both t,
J = 7.6 Hz, 2H, CH2), 4.28 (q, J = 7.1 Hz, 2H, CH2O), 7.04–7.08 (m, 2H,
(376 MHz, CDCl3)
d 110.6 (s, CF3). Anal. Calcd for C16H16F3NO: C,
Ph), 7.25–7.33 (m, 3H, Ph); 19F NMR (376 MHz, CDCl3)
d
108.5 (q,
65.08; H, 5.46; N, 4.74. Found: C, 64.94; H, 5.36; N, 4.98.
5JF,H = 2.0 Hz, CF3); 13C NMR (126 MHz, CDCl3)
d 10.8 (q,
4JC,F = 3.1 Hz, Me-5), 11.2, 14.0, 36.7, 45.1, 60.0, 109.5 (q,
4.1.13. 3-Acetyl-2,5-dimethyl-4-(trifluoromethyl)-1-phenethyl-1H-
pyrrole (7m)
2JC,F = 35.0 Hz, C-4), 110.1 (q, JC,F = 1.7 Hz, C-3), 124.1 (q,
3
1JC,F = 267.3 Hz, CF3), 127.2, 128.7, 128.9, 129.4 (q, JC,F = 3.5 Hz,
Yield 52%, mp 70–71 8C (hexane), colourless powder; IR (KBr)
3
C-5), 135.7, 137.2, 164.5 (C55O). Anal. Calcd for C18H20F3NO2: C,
1655, 1577, 1526, 1498, 1452, 1436 cmꢀ1 1H NMR (400 MHz,
;
63.71; H, 5.94; N, 4.13. Found: C, 63.76; H, 5.88; N, 4.23.
CDCl3) d 2.19 (s, 3H, Me-5), 2.27 (s, 3H, Me-2), 2.44 (s, 3H, Ac), 2.89,

46
V.Y. Korotaev et al. / Journal of Fluorine Chemistry 138 (2012) 42–47
4.00 (both t, J = 7.5 Hz, 2H, CH2), 7.06 (d, J = 6.4 Hz, 2H, Ph),
NMR (400 MHz, CDCl3) d
1.88 (s, 3H, Me-2), 2.23 (q, 5JH,F = 1.3 Hz,
7.25 ꢀ 7.34 (m, 3H, Ph); 19F NMR (376 MHz, CDCl3)
d
110.6 (s, CF3);
3H, Me-5), 2.89 (t, J = 6.8 Hz, 2H, CH2), 3.81 (s, 3H, MeO), 3.87 (s,
3H, MeO), 4.03 (t, J = 6.8 Hz, 2H, CH2), 6.41 (s, 1H, H-20), 6.63 (d,
J = 8.2 Hz, 1H, H-60), 6.81 (d, J = 8.2 Hz, 1H, H-50), 7.41 (t, J = 7.5 Hz,
13C NMR (126 MHz, CDCl3)
d
10.6 (q, 4JC,F = 2.6 Hz, Me-5), 11.3, 31.0
(4JC,F = 3.7 Hz, MeCO), 36.7, 45.1, 108.5 (q, JC,F = 34.7 Hz, C-4),
120.8 (q, JC,F = 1.5 Hz, C-3), 124.4 (q, JC,F = 267.3 Hz, CF3), 127.2,
2
3
1
2H, H-300, H-500), 7.53 (t, J = 7.4 Hz, 1H, H-400), 7.75 (d, J = 7.5 Hz, 2H,
3
5
128.7, 128.9, 129.4 (q, JC,F = 3.7 Hz, C-5), 133.1, 137.1, 196.9
H-200, H-600); 19F NMR (376 MHz, CDCl3)
d
109.4 (q, JF,H = 1.3 Hz,
(C55O). Anal. Calcd for C17H18F3NO: C, 66.01; H, 5.87; N, 4.53.
Found: C, 66.00; H, 5.88; N, 4.55.
CF3); 13C NMR (126 MHz, CDCl3)
d
10.6 (q, 4JC,F = 1.7 Hz, Me-5), 11.3
2
(Me-2), 36.2, 45.3, 55.8, 56.0, 110.0 (q, JC,F = 35.0 Hz, C-4), 111.6,
112.1, 118.8 (q, 3JC,F = 1.7 Hz, C-3), 120.9, 124.1 (q, 1JC,F = 267.8 Hz,
CF3), 128.2, 129.4 (q, 3JC,F = 3.8 Hz, C-5), 129.5, 129.8, 130.7, 132.6,
139.4, 148.3, 149.2, 193.1 (C55O). Anal. Calcd for C24H24F3NO3: C,
66.81; H, 5.61; N, 3.25. Found: C, 66.65; H, 5.51; N, 3.38.
4.1.14. 3-Acetyl-1-(3,4-dimethoxyphenethyl)-2,5-dimethyl-4-
(trifluoromethyl)-1H-pyrrole (7n)
Yield 48%, mp 92–93 8C (hexane), colourless powder; IR (KBr)
1661, 1591, 1579, 1516, 1467, 1436 cmꢀ1
;
1H NMR (400 MHz,
5
CDCl3)
d
2.14 (q, JH,F = 1.8 Hz, 3H, Me-5), 2.24 (s, 3H, Me-2), 2.43
4.1.19. 3-Amino-5,5-dimethyl-2-[2-nitro-1-
6
(q, JH,F = 1.1 Hz, 3H, Ac), 2.84 (t, J = 7.1 Hz, 2H, CH2), 3.78, 3.86
(both s, 3H, MeO), 4.00 (t, J = 7.1 Hz, 2H, CH2), 6.34 (d, J = 1.9 Hz,
1H, H-20), 6.62 (dd, J = 8.1, 1.9 Hz, 1H, H-60), 6.80 (d, J = 8.1 Hz, 1H,
H-50); 19F NMR (376 MHz, CDCl3)
(trifluoromethyl)propyl]-2-cyclohexen-1-one (9)
Yield 31%, mp 212–213 8C (decomp.) (propan-1-ol), colourless
powder; IR (KBr) 3432, 3356, 3186, 1677, 1608, 1548, 1454, 1422,
1410, 1390, 1369, 1361 cmꢀ1; 1H NMR (400 MHz, DMSO-d6) major
d
110.6 (s, CF3); 13C NMR
10.7 (q, 4JC,F = 2.7 Hz, Me-5), 11.4 (Me-2), 31.0
(126 MHz, CDCl3)
d
isomer (75%)
d 0.96 (s, 6H, 2Me), 1.29 (d, J = 6.5 Hz, 3H, Me), 2.04 (s,
5
(q, JC,F = 3.7 Hz, MeCO), 36.1, 45.1, 55.8, 55.9, 108.4 (q,
2H, CH2), 2.31 (d, J = 16.6 Hz, 1H, CHH), 2.33 (d, J = 16.6 Hz, 1H,
2JC,F = 34.7 Hz, C-4), 111.5, 111.9, 120.7 (q, JC,F = 1.8 Hz, C-3),
CHH), 4.06 (dq, JH,H = 9.9 Hz, JF,H = 9.0 Hz, 1H, H-10), 5.84 (dq,
3J = 9.9, 6.5 Hz, 1H, H-20), 7.38 (br s, 2H, NH2); minor isomer (25%)
0.94 (s, 6H, 2Me), 1.27 (d, J = 7.1 Hz, 3H, Me), 2.15 (s, 2H, CH2), 2.31
(d, J = 16.6 Hz, 1H, CHH), 2.33 (d, J = 16.6 Hz, 1H, CHH), 5.23 (quint,
J = 10.8 Hz, 1H, H-10), 5.90–6.00 (m, 1H, H-20), 6.81 (br s, 2H, NH2);
3
3
3
1
3
120.8, 124.4 (q, JC,F = 267.4 Hz, CF3), 129.5 (q, JC,F = 3.7 Hz, C-5),
129.6, 133.3, 148.2, 149.1, 196.8 (C55O). Anal. Calcd for
C
19H22F3NO3: C, 61.78; H, 6.00; N, 3.79. Found: C, 61.69; H,
5.94; N, 3.81.
19F NMR (376 MHz, DMSO-d6) major isomer (75%)
d 96.8 (d,
4.1.15. 3-Benzoyl-2,5-dimethyl-4-(trifluoromethyl)-1H-pyrrole (7o)
Yield 25%, mp 182–183 8C (ethanol), colourless powder; IR
3JF,H = 9.0 Hz, CF3), minor isomer (25%) 97.2 (d, 3JF,H = 11.0 Hz, CF3).
Anal. Calcd for C12H17F3N2O3: C, 48.98; H, 5.82; N, 9.52. Found: C,
48.59; H, 5.72; N, 9.31.
(KBr) 3243, 3196, 1616, 1596, 1580, 1535, 1450, 1423 cmꢀ1 1H
;
NMR (400 MHz, DMSO-d6)
d 1.90 (s, 3H, Me-2), 2.29 (q,
5JH,F = 1.5 Hz, 3H, Me-5), 7.46–7.68 (m, 5H, Ph), 11.63 (br s, 1H,
Acknowledgement
NH); 19F NMR (376 MHz, DMSO-d6)
d
111.1 (q, 5JF,H = 1.5 Hz, CF3);
13C NMR (126 MHz, DMSO-d6)
d
11.6 (q, 4JC,F = 1.5 Hz, Me-5), 12.3
This work was financially supported by the Russian Foundation
for Basic Research (Grant 11-03-00126-a).
2
3
(Me-2), 108.0 (q, JC,F = 34.7 Hz, C-4), 118.0 (q, JC,F = 1.6 Hz, C-3),
124.4 (q, 1JC,F = 266.9 Hz, CF3), 128.4, 128.7, 128.9 (q, 3JC,F = 4.2 Hz,
C-5), 131.3, 132.3, 139.6, 191.4 (C55O). Anal. Calcd for C14H12F3NO:
C, 62.92; H, 4.53; N, 5.24. Found: C, 62.71; H, 4.30; N, 5.33.
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4.1.16. 3-Benzoyl-1-benzyl-2,5-dimethyl-4-(trifluoromethyl)-1H-
pyrrole (7p)
Yield 54%, yellow oil; IR (KBr) 1651, 1599, 1582, 1557, 1497,
1449, 1435 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
2.04 (s, 3H, Me-2),
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2.29 (q, JH,F = 1.4 Hz, 3H, Me-5), 5.09 (s, 2H, CH2), 6.95 (d,
J = 7.2 Hz, 2H, Ph), 7.28–7.85 (m, 8H, Ph); 19F NMR (376 MHz,
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109.5 (q, 5JF,H = 1.4 Hz, CF3). Anal. Calcd for C21H18F3NO: C,
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1H-pyrrole (7q)
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(KBr) 1659, 1646, 1623, 1597, 1580, 1542, 1450, 1440, 1406 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d 1.89 (s, 3H, Me-2), 2.25 (q, 3H, Me-5,
5JH,F = 1.4 Hz), 2.95, 4.03 (both t, J = 7.2 Hz, 2H, CH2), 7.07 (d,
J = 7.0 Hz, 2H, Ph), 7.27–7.56 (m, 6H, Ph), 7.77 (dd, J = 7.0, 8.2 Hz,
2H, Ph); 19F NMR (376 MHz, CDCl3)
d
109.4 (q, 5JF,H = 1.4 Hz, CF3);
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d
4
2
3
36.8, 45.3, 110.1 (q, JC,F = 35.1 Hz, C-4), 118.8 (q, JC,F = 1.7 Hz, C-
3), 124.1 (q, 1JC,F = 267.7 Hz, CF3), 127.2, 128.2, 128.9, 129.0, 129.2
(q, JC,F = 3.9 Hz, C-5), 129.6, 130.7, 132.6, 137.3, 139.5, 193.3
3
(C55O). Anal. Calcd for C22H20F3NO: C, 71.15; H, 5.43; N, 3.77.
Found: C, 71.41; H, 5.28; N, 3.97.
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pyrrole (7r)
Yield 48%, mp 81–82 8C (CH2Cl2–hexane), colourless powder; IR
(KBr) 1639, 1595, 1579, 1530, 1515, 1466, 1446, 1398 cmꢀ1 1H
;

V.Y. Korotaev et al. / Journal of Fluorine Chemistry 138 (2012) 42–47
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methods and refined with full-matrix least-squares calculation on F2 using
SHELX-97 [21]. All non-hydrogen atoms were refined anisotropically. The hydro-
gen atoms were located geometrically using a riding model. Crystal data for
compound 7q C22H20F3NO: M = 371.39, collourless prism, triclinic crystals space
˚
˚
˚
˚
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group Pꢀ1, a = 10.1911(8) A, b = 10.4231(11) A, c = 18.644(3) A, a = 84.088(10)8,
3
b = 81.408(9)8, g = 77.059(8)8, V = 1903.5(4) A , Z = 4, Dcalc = 1.296, 7581 inde-
pendent reflections (Rint = 0.0354), R1 = 0.0518, wR2 = 0.0955, GOF = 1.000. Crys-
tallographic data (excluding structure factors), reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 858061 can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033; depos-
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´
´
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