Synthesis of 1-(4-trifluoromethoxyphenyl)-2,5-dimethyl-3-(2-rthiazol-4-yl)- 1H-pyrroles via chain heterocyclization

Article abstract of DOI:10.3390/molecules15020997

The title compounds, (4-trifluoromethoxyphenyl)-2,5-dimethyl-3-(2-R- thiazol- 4-yl)-1H-pyrroles, were prepared in four steps starting from commercially available 4- trifluoromethoxyaniline. The pyrrole (second ring) was added in one step using the Paal- K

Full text of DOI:10.3390/molecules15020997

Molecules 2010, 15, 997-1006; doi:10.3390/molecules15020997
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of 1-(4-Trifluoromethoxyphenyl)-2,5-dimethyl-3-(2-R-
thiazol-4-yl)-1H-pyrroles via Chain Heterocyclization
Mykhaylo V. Vovk 1,*, Oleksandr M. Pinchuk 1, Andrij O. Tolmachov 2 and Andrei A. Gakh 3,*
1
Institute of Organic Chemistry, NAS of Ukraine, Murmanska 5, 02094 Kyiv, Ukraine
2
National Taras Shevchenko University, Volodymyrs`ka 62, 01033 Kyiv, Ukraine
3
Oak Ridge National Laboratory, Oak Ridge, TN 37831-6242, USA
* Authors to whom correspondence should be addressed; E-Mails: mvovk@ioch.kiev.ua (M.V.V.);
gakhaa@ornl.gov (A.A.G.).
Received: 26 December 2009; in revised form: 22 February 2010 / Accepted: 22 February 2010 /
Published: 23 February 2010
Abstract: The title compounds, (4-trifluoromethoxyphenyl)-2,5-dimethyl-3-(2-R-thiazol-
4-yl)-1H-pyrroles, were prepared in four steps starting from commercially available 4-
trifluoromethoxyaniline. The pyrrole (second ring) was added in one step using the Paal-
Knorr method. The thiazole (third ring) was added in three steps using chloroacylation
with chloroacetonitrile followed by heterocyclization with thioamides/thioureas.
Keywords: pyrrole; fluorinated heterocycles; Paal-Knorr reaction; trifluoromethoxy group;
chain heterocyclization
1. Introduction
In the course of our search for new anti-cancer compounds that can be used in chemotherapy of late
androgen-independent stages of prostate cancer, we turned our attention to the specific class of
fluoroheterocyclic systems containing three linked rings, A-B-C, where B is a heterocyclic ring, and A
and C are either a heterocyclic or an aromatic ring. Typically, these heterocyclic systems are produced
by connecting of one heterocyclic and two aromatic or heterocyclic fragments together using
appropriate linking methods. Unfortunately, many common linking procedures cannot be used for
direct ring connections. An alternative approach entails chain heterocyclization where heterocyclic
moieties are being added in one-by-one fashion using appropriate alicyclic components. Here we

Molecules 2010, 15
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report the results of successful application of this strategy for the synthesis of A-B-C
fluoroheterocyclic systems with pyrrole as the central unit B.
The pyrrole ring is a part of many natural compounds [1–3] as well as synthetic biologically active
molecules [4,5]. For example, dialkylaminoalkyl esters of N-(4-hydroxyphenyl)pyrrole exhibit
anesthetic and hypotensive properties [6], N-(3-carboxyphenyl)pyrroles are known as antiphlogistic
compounds [7], and N-(4-phenoxyphenyl)pyrroles have anticholesteremic properties [8]. Some
derivatives of 4-(2,5-dimethylpyrrolyl)benzoic acid inhibit Anthrax Lethal Factor (LF) [9] and
Serotonin N-Acetyltransferase [10]. The trifluoromethoxy group is known for its utility in synthesis
[11] and usefulness in the optimization of biologically active compounds [12–15]. Moreover,
heterocyclic systems bearing the СF3O group are especially attractive, given their presence in, among
others, the insecticide indoxacarb 16], the acaricide flufenerim [17], the plant growth regulator
flurprimidol [18], and the neurologic drug riluzole [19]. At the same time, little is known about
heterocyclic systems containing CF3O-group(s) and pyrrole rings. Our research in this area started
with the synthesis of 1-(4-trifluoromethoxyphenyl)-2,5-dimethyl-3-chloroacetylpyrrole – a new
building block for the synthesis of extended heterocyclic libraries containing the 1-(4-
trifluoromethoxyphenyl)pyrrole fragment [20].
2. Results and Discussion
The Paal-Knorr method [21] (which entails condensation of 1,4-diketones with anilines) is the most
frequently used method for the synthesis of 1-aryl-2,5-dialkyl(aryl) substituted pyrroles. For example,
1-(4-trifluoromethoxyphenyl)-2,5-dimethylpyrrole (3) can be prepared in 76% yield from readily
available 2,5-hexanedione (1) and 4-trifluoromethoxyaniline (2) by this route. According to the
literature data [22,23], Friedel-Crafts acylation of 1-phenyl-2,5-pyrrole with alkylcarboxylic acid
chlorides yields bis-acylated products (3,4-diketones), whereas acylation with aryl carboxylic acid
chlorides results in a mixture of mono- (3–acylated) and bis- (3,4–acylated) products. It appears that
direct acylation with chloroacetyl acid chloride cannot be used for selective preparation of the desired
3-chloroacetyl-2,5-dimethylpyrrole (5).
We developed a new preparative method for the synthesis of 3-chloroacetylpyrroles using mild and
selective chloroacetylimidoyl chloride [24] that can be prepared in situ from chloroacetonitrile and
hydrogen chloride. The desired iminium salt precipitates directly from the reaction mixture in 87%
yield. Subsequent hydrolysis gives the target product 5 in 69 % yield (Scheme 1). The presence of a
reactive chloroacetyl group in pyrrole 5 makes this compound an attractive building block for the
preparation of various nitrogen-, oxygen- and sulfur-containing compounds containing a 4-
trifluoromethoxyphenyl fragment. For example, N-alkylation of imidazole, isothiazole, tetrazole
derivatives; O-alkylation of hetarylcarboxylic and hetarylacetic acids; S-alkylation of thiazole, 1,3,4-
oxadiazole and tetrazole derivatives proceed easily and in mild conditions in DMSO or DMF solutions.
The use of thioamides and thioureas in reactions with chloroacetylpyrrole (5) allowed us to add the
desired third heterocyclic ring (thiazole fragment) as the last step of chain heterocyclization. As a
result, new 4-trifluoromethoxyphenyl substituted pyrroles 6a-c, 7a-c, 8a-c, 9a-g functionalized with a
set of pharmacophoric heterocyclic groups were successfully prepared using this approach (Scheme 2,
Table 1).

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Scheme 1. Synthesis of 3-chloroacetylpyrrole (5).
NH2
N
a
+
O
O
OCF3
OCF3
1
2
3
b
Cl
Cl
O
.
NH HCl
c
B
N
N
A
OCF3
OCF3
5
4
Reagents and conditions: (a) AcOH, 120 oC, 4 h; (b) ClCH2CN, HCl (gas), 5–10 oC, 24 h; (c) H2O,
100 °C, 1 h
Scheme 2. Synthesis of 4-trifluoromethoxyphenyl substituted pyrroles 6-9 (R1-R5: see
Table 1).
NR1R2
O
OC(O)R3
O
N
N
Cl
O
R1R2NH
R3C(O)OH
(b)
(a)
OCF3
OCF3
N
6a-c
7a-c
SR4
O
S
R5
R5C(S)NH2
(d)
R4SH
OCF3
5
C
N
(c)
B
N
N
A
OCF3
OCF3
8a-c
9a-g
Conditions: (a) 6a-c: DMF, Et3N, 75–80 °C, 2 h; (b) 7a-c: DMSO, K2CO3, 45–50 °C, 4 h; (c) 8a-c:
DMF, K2CO3, 60–70 °C, 2 h; (d) EtOH, 80 °C, 5 h

Molecules 2010, 15
Table 1. Yields and melting points of the synthesized compounds.
1000
Yield,
%
Yield,
%
Product
6a
R
Mp
Product
8c
R
Mp
O
Me
N
S
76
174-175
N
92
106
N
N
N
Me
O
O
N
(SR4)
(R1R2N)
O
6b
81
232-234
9a
Me (R5)
62
134–135
N
S
O
O
(R1R2N)
N
N
N
6c
7a
70
71
126-127
143-144
9b
9c
2-Thienyl
(R5)
65
69
115–116
131–132
N
MeO
(R1R2N)
O
O
N
H
O
N
Me
O
(R5)
[OC(O)R3]
O
7b
7c
74
78
110-111
103
9d
9e
NH2
(R5)
71
64
126–127
166–167
O
O
N
Me
O
[OC(O)R3]
MeNH
(R5)
O
N
O
O
[OC(O)R3]
N
N
O
NH
8a
8b
84
89
132-133
165-166
9f
70
65
129–130
108–109
S
S
(SR4)
(R5)
(R5)
O
N
N
9g
S
NH
N
N
O
N
(SR4)
3. Experimental
3.1. General
Melting points were determined with a Kofler micro hot-stage (Reichert, Wien) and were
1
19
uncorrected. H- and F-NMR spectra were recorded in DMSO-d6 on a Varian-Gemini spectrometer
13
at 299.94 and 188.14 MHz, respectively, with TMS (1H) and CCl3F (19F) as internal standards. C-
NMR spectra were recorded on a Bruker Arano DRX-500 spectrometer (125.75 MHz), with TMS as
internal standard. APCI MS data were obtained on an Agilent 1100\DAD\MSD VL G1965a instrument.

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2,5-Dimethyl-1(4-(trifluoromethoxyphenyl)-1H-pyrrole (3). A mixture of 4-trifluoromethoxyaniline
(30 g, 170 mmol) and 2,5-hexanedione (22.8 g, 200 mmol) in acetic acid (150 mL) was refluxed for 4
h. The reaction mixture was cooled and poured into water (500 mL), the precipitated solid was filtered
and dried. Yield 32.9 g (76 %); mp 68 °C; 1H-NMR: δ 1.98 (s, 6H), 5.76 (s, 2H), 7.34 (d, 2H, J = 9.0
13
Hz), 7.41 (d, 2H, J = 9.0 Hz); C-NMR: δ 12.66 (2 CH3), 106.18 (pyrrole, 3,4-C), 120.57 (q, CF3,
J = 254.6 Hz), 121.64 (4-CF3O-C6H4, 3,5-C), 127.60 (pyrrole, 2,5-C), 129.90 (4-CF3O-C6H4, 2,6-C),
19
137.32 (4-CF3O-C6H4, 1-C), 147.33 (4-CF3O-C6H4, 4-C); F-NMR: δ -57.75 (F3CO); MS: m/z 256.0
(M+1)+; Anal. Calcd. for C13H12CF3NO: C 61.18; H 4.74; N 5.49. Found: C 61.31; H 4.77; N 5.61.
2-Chloro-1-{2,5-dimethyl-1-[(4-trifluoromethoxy)phenyl]-1H-pyrrol-3yl}-ethanimine hydrochloride
(4). Dry hydrogen chloride was bubbled through
a
solution of 2,5-dimethyl-1[4-
(trifluoromethoxy)phenyl]-1H-pyrrole (32.9 g, 130 mmol ) and chloroacetonitrile (15 g, 200 mmol) in
diethyl ether (200 mL) for 2 hours with vigorous stirring at 5-10 оС. The reaction mixture was left for
12 hours at room temperature. The precipitated solid was collected by filtration, washed with diethyl
ether and dried in air. Yield 41.4 g (87 %); mp 220o C; 1H-NMR: δ 2.23 (s, 3H), 2.36 (s, 3H), 5.11 (s,
2H), 7.015 (s, 1H), 7.44 (d, 2H, J = 9.0 Hz), 7.51 (d, 2H, J = 9.0 Hz), 11.62 (s, 1H), 11.96 (s, 1H); 19F-
NMR: δ – 57.14 (F3CO); Anal. Calcd. for C15H15Cl2F3NO2: C 49.07; H 4.19; Cl 19.31. Found: C 49.23;
H 4.08; Cl 19.17.
2-Chloro-1-{2,5-dimethyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrrol-3-yl}-ethanone (5). A suspension
of 2-chloro-1-{2,5-dimethyl-1-[(4-trifluoromethoxy)phenyl]-1H-pyrrol-3yl}-ethanimine hydrochloride
(4, 41.4 g, 110 mmol) in water (200 mL) was heated under reflux for 1 h. The reaction mixture was
cooled to room temperature; the precipitated solid was collected, washed with water, and dried. The
o
1
product was crystallized from methanol. Yield 25.8 g (69 %); mp 147 C; IR (KBr, cm-1) 1685; H-
NMR: δ 1.94 (s, 3H), 2.22 (s, 3H), 4.75 (s, 2H), 6.48 (s, 1H), 7.49 (d, 2H, J = 9.0 Hz), 7.56 (d, 2H,
J = 9.0 Hz); 13C-NMR: δ 12.28 (CH3), 12.49 (CH3), 47.80 (CH2), 107.40 (pyrrole, 4-C), 117.04
(pyrrole, C-5), 121.45 (q, CF3, J =257.8 Hz), 123.19 (4-CF3O-C6H4, 3,5-C), 128.73 (pyrrole, 3-C),
130.02 (4-CF3O-C6H4, 2,6-C), 135.35 (4-CF3O-C6H4, 1-C), 136.09 (pyrrole, 2-C), 148.15 (q, 4-CF3O-
C6H4 , 4-C, J = 1.3 Hz), 186.80 (C=O); 19F-NMR: δ -56.89 (F3CO); MS: m/z 332.0 (M+1)+; Anal.
Calcd. for C15H13ClF3NO2: C 54.31; H 3.95; N 4.22. Found: C 54.20; H 3.87; N 4.11.
3.2. General method for synthesis of 2,5-dimethyl-3-(2-N-substituted-1-oxoethyl)-1-[4-(trifluoro-
methoxy)phenyl]-1H-pyrroles 6a-c
An appropriate heterocyclic compound (5 mmol) and triethylamine (1.0 mL, 7.5 mmol) were
added to a solution of 2-сhloro-1-{2,5-dimethyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrrol-3-yl}-
ethanone (5, 1.66 g, 5 mmol) in DMF (50 mL). The reaction mixture was heated at 75–80 °С with
stirring for 2 h, and then it was cooled and poured into water (100 mL). The precipitated solid was
filtrated and crystallized from dioxane.

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1-{2-[2,5-Dimethyl-1(4-trifluoromethoxyphenyl)-1H-pyrrol-3-yl]-2-oxoethyl}-3-methylinidazolidine-
2,4,5-trione (6a). 1H-NMR: δ 1.99 (s, 3H), 2.23 (s, 3H), 3.07 (s, 3H), 4.81 (s, 2H), 6.63 (s, 1H), 7.48 (d,
2H, J = 9.0 Hz), 7.54 (d, 2H, J = 9.0 Hz); 19F-NMR: δ - 57.47 (F3CO); MS: m/z 424.0 (M+1)+; Anal.
Calcd. for C19H16F3N3O5: C 55.93; H 3.81; N 9.93. Found: C 56.04; H 3.88; N 9.80.
2-{2-[2,5-Dimethyl-1-(4-trifluoromethoxyphenyl)-1H-pyrrol-3-yl]-2-oxoethyl}-1,1-dioxo-1,2-dihydro-
1
1λ6-benzo[d]isothiazol-3-one (6b). H-NMR: δ 2.01 (s, 3H), 2.24 (s, 3H), 4.97 (s, 2H), 6.67 (s, 1H),
7.47 (d, 2H, J = 7.7 Hz), 7.53 (d, 2H, J = 8.8 Hz), 8.05 (m, 3H), 8.38 (d, 1H, J = 8.8 Hz); 19F-NMR:
δ - 57.44 (F3CO). MS: m/z 479.0 (M+1)+; Anal. Calcd. for C22H17F3N2O5S: C 55.23; H 3.58; N 5.86.
Found: C 55.35; H 3.68; N 5.97.
1-[2,5-Dimethyl-1-(4-trifluoromethoxyphenyl)-1H-pyrrol-3-yl]-2-[5-(3-methoxyphenyl)-tetrazol-2-yl]-
ethanone (6c). 1H-NMR: δ 2.02 (s, 3H), 2.25 (s, 3H), 3.86 (s, 3H), 6.19 (s, 2H), 6.65 (s, 1H), 7.09 (dd,
1H, J = 7.4 Hz, J = 2.3 Hz), 7.59 (m, 7H). 19F-NMR: δ - 57.49 (F3CO); MS: m/z 472.0 (M+1)+; Anal.
Calcd. for C23H20F3N5O3: C 58.60; H 4.28; N 14.86. Found: C 58.93; H 4.09; N 14.64.
3.3. General method for synthesis of 2,5-dimethyl-3-(2-O-substituted 1-oxoethyl)-1-[4-
(trifluoromethoxy)-phenyl]-1H-pyrroles 7 a-c
An appropriate acid (5 mmol) and potassium сarbonate (1.4 g, 10 mmol) were added to a solution
of 2-сhloro-1-{2,5-dimethyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrrol-3-yl}-ethanone (5, 1.66 g, 5
mmol) in DMSO (50 mL). The reaction mixture was heated at 45-50оС with stirring for 4 h. The
reaction mixture was cooled and poured into water (100 mL). The precipitated solid was collected,
dried and recrystallized from 2-propanol.
3-Methylisoxazole-5-carboxylic acid 2-[2,5-dimethyl-1(4-trifluoromethoxyphenyl)-1H-pyrrol-3-yl]-2-
1
oxoethyl ester (7a). IR (KBr, cm-1) 1700, 1775; H-NMR: δ 1.99 (s, 3H), 2.25 (s, 3H), 2.36 (s, 3H),
5.41 (s, 2H), 6.50 (s, 1H), 7.21 (s, 1H), 7.49 (d, 2H, J = 9.0 Hz), 7.54 (d, 2H, J = 9.0 Hz); 19F-NMR: -
57.47 (F3CO); MS: m/z 423.0 (M+1)+; Anal. Calcd. for C20H17F3N2O5: C 56.88; H 4.06; N 6.63. Found:
C 56.79; H 4.10; N 6.59.
(5-Methylisoxazol-3-yloxy)acetic acid 2-[2,5-dimethyl-1-(4-trifluoromethoxyphenyl)-1H-pyrrol-3-yl]-
2-oxoethyl ester (7b). IR (KBr, cm-1) 1695, 1770; 1H-NMR: δ 1.97 (s, 3H), 2.24 (s, 3H), 2.33 (s, 3H),
4.95 (s, 2H), 5.21 (s, 2H), 6.03 (s, 1H), 6.46 (s, 1H), 7.47 (d, 2H, J = 8.7 Hz), 7.52 (d, 2H, J = 8.7 Hz);
19F-NMR: - 57.50 (F3CO); MS: m/z 453.0 (M+1)+; Anal. Calcd. for C21H19F3N2O6: C 55.76; H 4.23; N
6.19. Found: C 55.65; H 4.24; N 6.12.
(2-Oxo-2H-pyridin-1-yl)acetic acid 2-[2,5-dimethyl-1-(4-trifluoromethoxyphenyl)-1H-pyrrol-3-yl]-2-
oxoethyl ester (7c). IR (KBr, cm-1) 1670, 1695, 1770;1H-NMR: δ 1.96 (s, 3H), 2.23 (s, 3H), 4.86 (s,
2H), 5.22 (s, 2H), 6.27 (t, 1H, J = 5.4 Hz), 6.42 (d, 1H, J = 9.0 Hz), 6.49 (s, 1H), 7.46 (dd, 1H, J = 6.3
Hz, J = 2.1 Hz), 7.50 (d, 2H, J = 8.8 Hz), 7.57 (d, 2H, J = 8.8 Hz), 7.73 (dd, 1H, J = 5.1 Hz, J = 1.9

Molecules 2010, 15
1003
19
Hz); F-NMR: - 57.16 (F3CO); MS: m/z 449.2 (M+1)+; Anal. Calcd for C22H19F3N2O5: C 58.93; H
4.27; N 6.25. Found: C 58.82; H 4.24; N 6.16.
3.4. General method for synthesis of 2,5-dimethyl-3-(2-S-substituted 1-oxoethyl)-1-[4-
(trifluoromethoxy)phenyl]-1H-pyrroles 8 a-c
An appropriate thione (5 mmol) and potassium сarbonate (1.4 g, 10 mmol) were added to a solution
of 2-сhloro-1-{2,5-dimethyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrrol-3-yl}-ethanone (5, 1.66 g,
5 mmol) in DMF (50 mL). The reaction mixture was heated at 65-70 °С with stirring for 2 h, and then
it was cooled and poured into water (100 mL). The precipitated solid was collected, dried and
recrystallized from ethanol/DMF 4:1.
1-[2,5-Dimethyl-1-(4-trifluoromethoxyphenyl)-1H-pyrrol-3-yl]-2-([1,3,4]thiadiazol-2-ylsulfanyl)-
1
ethanone (8a). H-NMR: δ 1.99 (s, 3H), 2.25 (s, 3H), 4.77 (s, 2H), 6.57 (s, 1H), 7.45 (d, 2H, J =7.6
19
Hz), 7.50 (d, 2H, J = 7.6 Hz), 9.50 (s,1H) F-NMR: - 57.50 (F3CO); MS: m/z 414.0 (M+1)+; Anal.
Calcd. for C17H14F3N2O2S2: C 59.45; H 4.99; N 12.23 Found: C 59.58; H 4.91; N 12.32.
1-[2,5-Dimethyl-1-(4-trifluoromethoxyphenyl)-1H-pyrrol-3-yl]-2-(5-[1,2,4]triazol-1-ylmethyl-[1,3,4]-
oxadiazol-2-ylsulfanyl)ethanone (8b). 1H-NMR: δ 1.99 (s, 3H), 2.24 (s, 3H), 4.73 (s, 2H), 5.80 (s, 2H),
6.52 (s, 1H), 7.49 (d, 2H, J = 9.0 Hz), 7.52 (d, 2H, J = 9.0 Hz), 7.95 (s, 1H), 8.60 (s, 1H). 19F-NMR: -
57.47 (F3CO); MS: m/z 479.0 (M+1)+; Anal. Calcd. for C20H17F3N6O3S: C 50.21; H 3.58; N 17.56.
Found: C 50.32; H 3.52; N 17.63.
1-[2,5-Dimethyl-1-(4-trifluoromethoxyphenyl)-1H-pyrrol-3-yl]-2-(1-methyl-1H-tetrazol-5-
ylsulfanyl)ethanone (8c). 1H NMR (DMSO-d6): δ 1.99 (s, 3H), 2.24 (s, 3H), 4.00 (s, 3H), 4.75 (s, 2H),
6.54 (s, 1H), 7.47 (d, 2H, J = 9.0 Hz), 7.53 (d, 2H, J = 9.0 Hz). 19F NMR (DMSO-d6): - 57.47 (F3CO).
MS: m/z 412.0 (M+1)+. Anal. Calcd. for C17H16F3N5O2S: C 49.63; H 3.92; N 17.02. Found: C 49.75;
H 3.82; N 17.13.
3.5. General method for synthesis of 4-[2,5-dimethyl-1-(4-trifluoromethoxyphenyl)-1H-pyrrol-3-
yl]thiazoles 9a-g
A mixture of 2-сhloro-1-{2,5-dimethyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrrol-3-yl}-ethanone
(5, 1.66 g, 5 mmol) and thioamide/thiourea (5 mmol) in ethanol (40 mL) was refluxed for 5 h. The
solid separated on cooling was collected by filtration, dried and recrystallized from ethanol.
4-[2,5-Dimethyl-1-(4-trifluoromethoxyphenyl)-1H-pyrrol-3-yl]-2-methylthiazole (9a). 1H-NMR: δ 2.00
(s, 3H), 2.25 (s, 3H), 2.67 (s, 3H), 6.24 (s, 1H), 7.15 (s, 1H), 7.44 (d, 2H, J = 9.0 Hz), 7.50 (d, 2H,
J = 9.0 Hz); 19F-NMR: - 57.43 (F3CO); MS: m/z 353.0 (M+1)+; Anal. Calcd. for C17H15F3N2OS: C
57.95; H 4.29; N 7.95. Found: C 57.86; H 4.21; N 8.04.

Molecules 2010, 15
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1
4-[2,5-Dimethyl-1-(4-trifluoromethoxyphenyl)-1H-pyrrol-3-yl]-2-thiophen-2-ylthiazole (9b). H-NMR:
δ 2.03 (s, 3H), 2.32 (s, 3H), 6.35 (s, 1H), 7.12 (t, 1H, J = 5.6 Hz), 7.20 (s, 1H), 7.42 (d, 2H,
J = 8.7 Hz), 7.47 (d, 2H, J = 8.7 Hz), 7.70 (m, 2H); 19F-NMR (DMSO-d6): - 57.69 (F3CO); MS: m/z
421.0 (M+1)+; Anal. Calcd. for C20H15F3N2OS2: C 57.13, H 3.60; N 6.66. Found: C 57.19; H 3.55; N
6.74.
2-{4-[2,5-Dimethyl-1-(4-trifluoromethoxyphenyl)-1H-pyrrol-3-yl]thiazol-2-yl}-N-phenylacetamide
1
(9c). H-NMR: δ 1.99 (s, 3H), 2.24 (s, 3H), 4.25 (s, 2H), 6.28 (s, 1H), 7.03 (t, 1H, J =7.6 Hz), 7.31
(m,2H) 7.41 (s, 1H), 7.48 (d, 2H, J =9.0 Hz), 7.52 (m, 2H), 7.64 (d, 2H, J =9.0 Hz), 10.55 (s,1H); 19F-
NMR: - 57.43 (F3CO). MS: m/z 472.0 (M+1)+; Anal. Calcd. for C24H20F3N3O2S: C 61.14, H 4.28; N
8.91. Found: C 61.29; H 4.21; N 8.84.
4-[2,5-Dimethyl-1-(4-trifluoromethoxyphenyl)-1H-pyrrol-3-yl]thiazol-2-ylamine (9d). 1H-NMR: δ
2.02 (s, 3H), 2.12 (s, 3H), 6.27 (s, 1H), 6.49 (s, 1H), 7.43 (d, 2H, J = 8.7 Hz), 7.48 (d, 2H, J = 8.7 Hz),
9.10 (br s, 2H). 19F-NMR: - 57.70 (F3CO). MS: m/z 354.0 (M+1)+; Anal. Calcd. for C16H14F3N3OS: C
54.38; H 3.99; N 11.89. Found: C 54.46; H 4.07; N 11.80.
{4-[2,5-Dimethyl-1-(4-trifluoromethoxyphenyl)-1H-pyrrol-3-yl]thiazol-2-yl}methylamine (9e). 1H-
NMR: δ 1.90 (s, 3H), 2.25 (s, 3H), 3.00 (s, 3H), 6.24 (s, 1H), 6.65 (s, 1H), 7.45 (d, 2H, J = 9.0 Hz),
19
7.51 (d, 2H, J = 9.0 Hz), 9.34 (br s, 1H); F-NMR: - 57.43 (F3CO). MS: m/z 368.0 (M+1)+; Anal.
Calcd. for C17H16F3N3OS: C 55.58; H 4.39; N 11.44. Found: C 55.67; H 4.31; N 11.50.
{4-[2,5-Dimethyl-1-(4-trifluoromethoxyphenyl)-1H-pyrrol-3-yl]thiazol-2-yl}-(2-methoxyethyl)amine
(9f). 1H-NMR: δ 1.99 (s, 3H), 2.24 (s, 3H), 3.29 (s, 3H), 3.43 (t, 2H, J = 5.4 Hz), 3.52 (t, 2H, J = 5.4
19
Hz), 6.12 (s, 1H), 6.23 (s, 1H), 7.40 (d, 2H, J = 9.0 Hz), 7.48 (d, 2H, J =9.0 Hz); F-NMR: - 57.70
(F3CO); MS: m/z 412.0 (M+1)+; Anal. Calcd for C19H20F3N3O2S: C 55.47; H 4.80; N 10.21. Found: C
55.58; H 4.79; N 10.09.
{4-[2,5-Dimethyl-1-(4-trifluoromethoxyphenyl)-1H-pyrrol-3-yl]thiazol-2-yl}-(tetrahydrofuran-2-yl-
1
methyl)amine (9g). H-NMR: δ 1.62 (m, 1H), 1.73 (m,2H), 1.85 (m, 1H), 1.96 (s, 3H), 2.23 (s, 3H),
3.25 (s,2H), 3.64 (m, 1H), 3.77 (m, 1H), 4.03 (m, 1H), 6.13 (s, 1H), 6.27 (s, 1H), 7.41 (d, 2H, J = 8.7
Hz), 7.47 (d, 2H, J = 8.7 Hz), 8.56 (m, 1H); 19F-NMR: - 57.47 (F3CO); MS: m/z 438.0 (M+1)+; Anal.
Calcd for C21H22F3N3O2S: C 57.66; H 4.5.07; N 9.60. Found: C 57.79; H 5.09; N 9.49.
4. Conclusions
In summary, we developed a successful chain heterocyclization strategy for the synthesis of A-B-C
fluoroheterocyclic systems with pyrrole as the central unit B. These compounds were prepared in four
steps starting from commercially available 4-trifluoromethoxyaniline. The pyrrole ring was added in
one step using Paal-Knorr method, and the third thiazole ring was added in three steps using
chloroacylation with cloroacetonitrile followed by heterocyclization with thioamide/thiourea. We are
currently evaluating biological profiles of these new fluorinated heterocyclic systems.

Molecules 2010, 15
1005
Acknowledgements
This research was supported by the Global IPP program through the Science and Technology
Center in Ukraine (STCU). Oak Ridge National Laboratory is managed and operated by UT-Battelle,
LLC, under U.S. Department of Energy contract DE-AC05-00OR22725. This paper is a contribution
from the Discovery Chemistry Project.
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Sample Availability: Samples of the compounds are available from the authors.
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