Regioselective synthesis of stable 2-(trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ols and derived fluorinated heterocycles

Article abstract of DOI:10.1055/s-2001-17510

1,2-Diaza-1,3-butadienes react regioselectively with trifluoromethylated β-dicarbonyl compounds to give stable 2-(trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol derivatives, which upon treatment with trifluoromethanesulphonic anhydride or with heterogeneous catalysts give rise to fluorinated 1-aminopyrrole derivatives in good to excellent yields. The reaction of 2-(trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol derivative with 2-haloketone affords fluorinated furo[2,3-b]pyrroline derivative, while that of diethyl 1-[(anilinocarbonyl)amino]-2-methyl-5-(trifluoromeihyl)-1H-pyrrole-3,4- dicarboxylate with hydrazine hydrate affords fluorinated pyrrolo[3,4-d]pyridazindione derivative.

Full text of DOI:10.1055/s-2001-17510

PAPER
1837
Regioselective Synthesis of Stable 2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-
2-ols and Derived Fluorinated Heterocycles
R
egioselective Syn
r
thesis
o
a
f
Stable 2-(
z
T
rifluorome
i
thyl)-2
o
,3-dihydro-1
H
-pyr
A
rol-2-ols . Attanasi, Paolino Filippone,* Barbara Guidi, Fabio Mantellini, Stefania Santeusanio*
Organic Chemistry Institute, University of Urbino, Piazza della Repubblica 13, 61029 Urbino, Italy
Fax +39(0722)2907; E-mail: attanasi@uniurb.it
Received 14 May 2001; revised 10 July 2001
withdrawing ability, the trifluoromethyl group lead to sig-
Abstract: 1,2-Diaza-1,3-butadienes react regioselectively with tri-
fluoromethylated b-dicarbonyl compounds to give stable 2-(trifluo-
romethyl)-2,3-dihydro-1H-pyrrol-2-ol derivatives, which upon
treatment with trifluoromethanesulphonic anhydride or with heter-
nificant changes in the regiochemistry when compared
with non-fluorinated analogues.34 Therefore, we decided
to study in detail the reaction between 1,2-diaza-1,3-buta-
ogeneous catalysts give rise to fluorinated 1-aminopyrrole deriva- dienes and trifluoromethylated 1,3-dicarbonyl com-
tives in good to excellent yields. The reaction of 2-
(trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol derivative with 2-ha-
pounds.
In the presence of catalytic amounts of CH3ONa in THF
loketone affords fluorinated furo[2,3-b]pyrroline derivative, while
at room temperature, 1,2-diaza-1,3-butadienes (1a–c) re-
acted with 1,1,1-trifluoro-2,4-pentanedione (2a) to give 3.
The reaction pathway showed regioselective spontaneous
heteroring closure at the -CO-CF3 group giving stable 2-
(trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol derivatives
(4a–c) (80–83%). In fact, pyrrole derivatives (5a–c) de-
riving from the ring closure of the -CO-CH3 group and
subsequent loss of trifluoroacetic acid molecule were
present only in smaller amount (4–6%) (Scheme 1,
Table 1). Under the same reaction conditions, 1,2-diaza-
1,3-butadienes (1a–f) reacted regiospecifically with
hexafluoroacetylacetone (2b), and trifluoromethyl-substi-
tuted 1,3-dicarbonyl compounds (2c–e) affording stable
2-(trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol deriva-
tives (4d–o) (61–93%) (Scheme 1, Table 1).
that of diethyl 1-[(anilinocarbonyl)amino]-2-methyl-5-(trifluorom-
ethyl)-1H-pyrrole-3,4-dicarboxylate with hydrazine hydrate affords
fluorinated pyrrolo[3,4-d]pyridazindione derivative.
Key words: 1,2-diaza-1,3-butadienes, Michael additions, regiose-
lectivity, 2-(trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ols, hetero-
cycles
1,2-Diaza-1,3-butadienes1–12 have been demonstrated as
powerful building blocks in heterocycle ring assem-
bly.13–23 Pyrrole ring systems are important in organic
chemistry,24–26 because they constitute the skeleton of nat-
ural products, antibiotics and polymers. As a part of our
research program directed towards the synthesis of five-
membered heterocycles, we have developed a very effi-
cient protocol for the preparation of 1-aminopyrrole de-
rivatives.13,14 The nucleophilic attack of the methylene
group of 1,3-dicarbonyl compounds at the heterodiene
system of conjugated azoalkenes resulted in a hydrazone
intermediate via Michael-type addition. The subsequent
ring closure by the hydrazone nitrogen on the keto group
of b-dicarbonyl compounds provided 2,3-dihydro-1H-
pyrrol-2-ol derivatives, rarely isolable or even detectable
as stable compounds because of the prompt dehydration
process producing pyrrole heterocycles.27 Indeed, 2,3-di-
hydro-1H-pyrrol-2-ol derivatives as stable compounds
were achieved only in the reaction of conjugated azoalk-
enes with b-dicarbonyl compounds having an activated
methinic group where the lack of a hydrogen atom in a-
position with respect to hydroxyl function can not initiate
the dehydration process.28–30 Since the introduction of a
fluorine atom into organic molecules often results in con-
siderable modification of their physical, chemical and bi-
It is worthy of emphasizing that 2-(trifluoromethyl)-2,3-
dihydro-1H-pyrrol-2-ol derivatives 4a,c,d,f,h,i (Table 1)
were also advantageously obtained also in solvent-free
conditions by using a molar ratio 1:7 between 1,2-diaza-
1,3-butadienes 1a–d and trifluoromethylated b-dicarbon-
yl compounds 2a–c, respectively. In particular, com-
pounds 4a,d,f precipitate spontaneously from the reaction
medium and were easily isolated by filtration. In all cases
derivatives 4a–o were obtained as diastereomeric mix-
tures (diastereomeric ratio ranging from 50:50 to 69:31).
Spectroscopical data exclude intramolecular ring closure
of 3 into 3-(trifluoroacetyl)-2,3-dihydro-1H-pyrrol-2-ol
derivatives as shown by the absence of -CO-CF3 group in
the 13C NMR spectra of compounds 4a–c,g–o, while the
presence of -CO-CF3 carbon in the 13C NMR spectra of
2
4d–f is clearly detectable (d = 186–187 ppm, JCF = 35
Hz).
.
ological activity,31–33 it is not surprising that the Even in the presence of CuCl2 2H2O as catalyst, the reac-
investigation of methods for the preparation of fluorine- tion between 1 and 2 produced 4 within several weeks and
containing compounds has been an area of intensive activ- any attempt of dehydration at room temperature according
ity in the past few decades. Due to its powerful electron- to the methodology used with success in our previous
investigation27 did not result in the aromatization confirm-
ing the stability of 4a–o.
Synthesis 2001, No. 12, 25 09 2001. Article Identifier:
1437-210X,E;2001,0,12,1837,1845,ftx,en;E03501ss.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1838
O. A. Attanasi et al.
PAPER
Table 1 Yield and Reaction Time of 2-(Trifluoromethyl)-2,3-dihy-
dro-1H-pyrrol-2-ol Derivatives 4a–o
O
O
O
CH3
N
R2
R1O
R3
CF3
+
N
Prod- Yield Reac-
ucts
O
1
R1
R2
2
R3
(%)a tion
1a-f
2a-e
Time
(h)
THF, r.t.
MeONa
1a CH3
NH2
2a CH3
2a CH3
4a/5a 83/4 68
4a
79b
3b
1b CH2CH3 NHC6H5
4b/5b 80/4
5
O
O
CH3
H
N
R2
R1O
R3
N
1c CH3
OC(CH3)3 2a CH3
4c/5c 81/6 25
4c
80b
4b
CF3
O
1a CH3
NH2
2b CF3
4d
84/
92b
72/4b
O
3
1b CH2CH3 NHC6H5
2b CF3
2b CF3
4e
4f
77
67
1d CH3
OCH3
61/
91b
48/1b
1a CH3
NH2
2c OCH2CH3 4g
2c OCH2CH3 4h
89
25
O
O
O
CH3
CH3
N
O
O
NH
1b CH2CH3 NHC6H5
64/
89b
1/4b
R1O
R3
R1O
R2
R2
N
NH
+
1c CH3
OC(CH3)3 2c OCH2CH3 4i
85/
94b
3/1b
R3
CF3
HO
4a-o
5a-c
1d CH3
1e CH3
OCH3
2d 2-Thienyl 4j
2d 2-Thienyl 4k
2d 2-Thienyl 4l
91
82
61
93
87
82
5
Scheme 1
NHC6H5
5
1f CH2CH3 NH2
1a CH3 NH2
1b CH2CH3 NHC6H5
1c CH3
115
78
14
18
Since trifluoromethylated nitrogen-containing aromatic
heterocycles are of great interest in biological32,33,35,36 and
agrochemical37 fields, we made efforts to find an efficient
route for the aromatization process of the title compounds
4a–o. Among the methods available in the literature for
this purpose, we selected the transformation of hydroxyl
function to a better leaving group. The treatment of 4h,k,n
with Tf2O (trifluoromethanesulphonic anhydride) in the
presence of an excess of anhydrous pyridine (anhydrous
2e 2-Furyl
2e 2-Furyl
4m
4n
4o
OC(CH3)3 2e 2-Furyl
a Yield of pure isolated products.
b Refers to solvent-free conditions.
CH2Cl2, r.t.), showed to successfully provided 1-ami- Surprisingly, under the same reaction conditions, 4a af-
nopyrrole derivatives 7h,k,n (72–86%) (Scheme 2, forded 1-aminopyrrole derivative 8a, likely via ring re-
Table 2).
opening to yield the intermediate 3a, subsequent ring
closure at COCH3 group, and final aromatization by water
elimination (Scheme 3).
O
O
O
CH3
N
O
CH3
N
O
Therefore, we decided to explore the dehydration of 4a,c
by using Montmorillonite KSF38 or Amberlyst 15 as het-
erogeneous catalysts in view of eco-friendly work-up pro-
cedures (Scheme 3). The results obtained with 4a under
these conditions were comparable with those observed in
the reaction performed with Tf2O leading to 1-aminopyr-
role derivative 8a with the trifluoroacetyl group in posi-
tion 3. Similarly, the treatment of 4c with Amberlyst 15
afforded a mixture of two 3-(trifluoroacetyl)-1H-pyrrole
derivatives 8c (52%) and 9c (46%), while the reactions
carried out with clay catalysis or by using Tf2O led exclu-
sively to methyl 1-amino-2,5-dimethyl-4-(2,2,2-trifluoro-
R1O
R3
R1O
R3
R2
R2
NH
NH
Tf2O, Py
CH2Cl2, r.t.
CF3
CF3
TfO
HO
O
O
4h,k,n
6
CH3
N
O
72-86%
R1O
R3
R2
NH
CF3
O
7h,k,n
acetyl)-1H-pyrrole-3-carboxylate
9c
in
almost
Scheme 2
comparable yields (65–71% respectively) (Scheme 3).
Synthesis 2001, No. 12, 1837–1845 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Regioselective Synthesis of Stable 2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ols
1839
Table 2 Yield and Reaction Time of 2-(Trifluoromethyl)-1H-pyr-
role Derivatives 7h,k,n
amino group occurred with simultaneous dehydration un-
der acidic conditions.39 This finding prompted us to apply
the Baxter’s methodology to compounds 4c,o and to com-
pare his results with ours. While the acidic cleavage of 1-
amino Boc residue and subsequent reductive diazotization
of 4o gave 2-(trifluoromethyl)-1H-pyrrole derivative 11o
in agreement with Baxter, a different behavior was ob-
served for 4c that afforded 3-(trifluoroacetyl)-1H-pyrrole
derivative 10c (Scheme 4).
R1
R2
R3
Com- Yield Reaction
pound (%)a Time (h)
4h CH2CH3 NHC6H5
4k CH3 NHC6H5
4n CH2CH3 NHC6H5
a Yield of pure isolated products.
OCH2CH3 7h
86
72
83
2
2
1
2-Thienyl 7k
2-Furyl
7n
O
O
O
O
CH3
N
CH3
NH
i
Boc
NH
H3CO
H3C
H3CO
F3C
58%
Under these latter conditions, both the aromatization pro-
cess and cleavage of the Boc group of 2-(trifluoromethyl)-
2,3-dihydro-1H-pyrrol-2-ol derivative 4c were observed.
CF3
CH3
HO
O
10c
4c
In a previous paper, Baxter et al. reported an example of
stable 1-NH-Boc protected 2-(trifluoromethyl)-2,3-dihy-
dropyrrol-2-ol derivative in which the removal of the Boc-
CH3
N
O
O
CH3
NH
Boc
NH
H3CO
O
i
H3CO
O
CF3
61%
O
O
O
O
CH3
CH3
N
O
H
OH
CF3
O
N
NH2
N
H3CO
H3C
H3CO
H3C
NH2
Method A
or B or C
NH
CF3
O
4o
11o
CF3
HO
O
Scheme 4 i = a) MeOH/concd HCl, 65 °C, 2–3 h; b) EtOH/aq HCl/
NaNO2, 10 °C to r. t., 1–3 h
3a
4a
All methods explored for the aromatization of 4a,c pro-
duced 3-(trifluoroacetyl)-1H-pyrrole derivatives 8a,c, 9c
and 10c via ring reopening to intermediate 3, subsequent
ring closure at COCH3, and final aromatization. Any at-
tempts for the aromatization of derivatives 4d–f by using
Tf2O or Montmorillonite KSF or Amberlyst 15 failed. In
fact, the presence of two trifluoromethyl groups in 4d–f
enhances their stability and does not permit conversion to
the corresponding aromatic derivatives.
O
CH3
O
H3CO
F3C
NH2
N
NH
CH3
8a
O
Method A = Amberlist 15, THF, ∆, 10 h, 94%
Method B = KSF, anhyd toluene, 11 h, 61%
Method C = Tf2O, anhyd Py, anhyd CH2Cl2, 2 h, 82%
The unusual stability of 2-(trifluoromethyl)-2,3-dihydro-
1H-pyrrol-2-ol derivatives encouraged us to explore the
synthesis of more complex fluorinated heterocyclic sys-
tems. The reaction between 4a and 2-bromoacetophenone
in the presence of K2CO3 provided fluorinated furo[2,3-
b]pyrroline derivative 12a as a diastereomeric mixture
(diastereomeric ratio 75:25) (Scheme 5). Efforts to dehy-
drate compound 12a by using acidic heterogeneous cata-
lysts (KSF clay or Amberlyst 15) failed.
O
CH3
Boc
H3CO
N
NH
H3C
CF3
HO
O
4c
Method A
Method B or C
O
O
O
CH3
N
CH3
N
O
O
CH3
N
O
Boc
NH
H3CO
F3C
H3CO
F3C
H3CO
CH
3 O
NH
NH2
H3CO
H3C
NH2
+ 9c 46%
NH
NH2
HO
i
N
CH3
CH3
O
H3C
CF3
77%
8c 52%
9c
HO
CF3
O
O
Ph
Method A = Amberlist 15, THF, ∆, 27 h
O
12a
4a
Scheme 3
Scheme 5 i = PhCOCH2Br, K2CO3, THF, D, 3 h
Synthesis 2001, No. 12, 1837–1845 ISSN 0039-7881 © Thieme Stuttgart · New York

1840
O. A. Attanasi et al.
PAPER
2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol Derivatives
4a–o and 2,5-Dimethyl-1H-pyrrole Derivatives 5a–c by
Reaction of 1a–f with 2a–e; General Procedure
1,2-Diaza-1,3-butadienes 1a–f (1.0 mmol) dissolved in THF (10
mL) were added to a stirred solution of 2a (1.2 mmol, 184.9 mg), or
2b (1.3 mmol, 270.4 mg), or 2c–e (1.0 mmol) with a catalytic
amount of CH3ONa (0.05 equiv with respect to 2) in THF (10 mL).
The mixture was magnetically stirred until the disappearance of the
reagents (monitored by TLC). The solvent was evaporated and
products 4a–o were obtained as diastereomeric mixtures by chro-
matographic purification (cyclohexane–EtOAc) and/or crystalliza-
tion. After the filtration of 4a–c, purification by flash
chromatography of the liquor mothers provided 5a–c as oils.
The reaction of pyrrole derivative 7h with a stoichiomet-
ric amount of NH2NH2◊H2O in THF–EtOH under reflux
allowed the formation of fluorinated pyrrolo[3,4-d]py-
ridazindione derivative 13h. The spectroscopic data of the
solid formed during the reaction (40 hours) confirmed the
structure of the expected fused heterocyclic system
(Scheme 6).
O
CH3
N
O
Ph
EtO
EtO
N
NH
H
CF3
O
2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol Derivative 4a
Yield: 270 mg (83%); white powder (EtOAc–Et2O).
7h
dr = 58:42.
IR (nujol): 3530, 3388, 3200, 1727, 1695, 1673, 1646, 1592 cm–1.
1) THF, ∆
2) NH2NH2 H2O, EtOH, ∆
1H NMR (200 MHz, DMSO-d6): d = 2.12 (s, 6 H, 2 CH3), 3.55 (s, 3
H, OCH3), 3.81 and 3.91* (2 br s, 1 H, CH), 6.18* and 6.42 (2 br s,
2 H, NH2), 7.69, 7.91 and 8.83 (3 br s, 2 H, NH and OH).
13C NMR (50.32 MHz, DMSO-d6): d = 11.7 (q), 29.6 and 29.9 (2 q),
O
O
CH3
N
O
2
50.8 (q), 56.7 and 56.8 (2 d), 90.2 and 90.8 (2 s, JCF = 32.0 Hz),
Ph
HN
HN
95.9 (s), 123.1 (s, 1JCF = 284.3 Hz), 158.1 and 160.6 (2 s), 160.9 and
161.4 (2 s), 164.9 (s), 202.8 and 203.1 (2 s).
MS: m/z (%) = 325 (M+, 10), 307 (1), 294 (2), 282 (37), 264 (100).
N
NH
H
CF3
13h
61%
Anal. Calcd for C11H14F3N3O5: C, 40.60; H, 4.34; N, 12.92. Found:
C, 40.69; H, 4.32; N, 12.89.
Scheme 6
2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol Derivative 4b
Yield: 332 mg (80%); white powder (EtOAc–petroleum ether).
Considering the electronic effects of incorporation of the
trifluoromethyl group and the increased lipophilicity of
compounds bearing this functionality,36,40,41 the reactions
and the compounds reported here should be of biological
and agrochemical interest. In addition, the simple, high-
yielding and, in some cases, environmentally friendly
methods for the preparation of fluorine-containing hetero-
cycles described in this paper are worthy of industrial ap-
plication.
dr = 68:32.
IR (nujol): 3422, 3318, 3216, 3100, 1732, 1725, 1704, 1689, 1654,
1598, 1550 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 1.15 (t, 3 H, J = 7.0 Hz,
OCH2CH3), 2.17 (s, 3 H, CH3), 2.19 (s, 3 H, CH3), 3.72 and 3.96*
(2 br s, 1 H, CH), 4.01-4.13 (m, 2 H, OCH2CH3), 6.93–7.02 (m, 1
H, Ar-H), 7.21–7.31 (m, 2 H, 2 Ar-H), 7.37–7.45 (m, 2 H, 2 Ar-H),
7.97, 7.99, 8.72 and 8.92 (4 br s, 3 H, 2 NH and OH).
MS: m/z (%) = 415 (M+, 42), 397 (14), 372 (46), 354 (100).
Anal. Calcd for C18H20F3N3O5: C, 52.03; H, 4.86; N, 10.12. Found:
C, 52.06; H, 4.88; N, 10.09.
1,2-Diaza-1,3-butadienes 1a–f were synthesized as isomeric mix-
tures according to previously reported procedures.42–44 1,1,1-Triflu-
oroacetylacetone (2a), 1,1,1,5,5,5-hexafluoroacetylacetone (2b),
ethyl 4,4,4-trifluoroacetoacetate (2c), 1-(2-thenoyl)-3,3,3-trifluoro-
acetone (2d) and 1-(2-furoyl)-3,3,3-trifluoroacetone (2e), Am-
berlyst 15 (Carlo Erba), Montmorillonite KSF (Lancaster), and
other reagents and solvents were purchased and used without fur-
ther purification with the exception of THF which was distilled
from NaOH. Melting points were determined in open capillary
tubes and are uncorrected. FT-IR spectra were obtained as Nujol
mulls. Mass spectra were determined at an ionizing voltage of 70
2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol Derivative 4c
Yield: 310 mg (81%); white powder (Et2O–n-pentane).
dr = 50:50.
IR (nujol): 3320, 3259, 1751, 1714, 1689, 1632 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 1.38, 1.40 and 1.43 (3 s, 9 H,
OBut), 2.13 (br s, 6 H, 2 CH3), 3.55 (s, 3 H, OCH3), 3.86 (br s, 1 H,
CH), 7.86, 8.00 and 8.41 (3 br s, 1 H, NH), 8.78 and 9.42 (2 br s, 1
H, OH).
1
eV. H NMR spectra were recorded at 200 MHz and 400 MHz in
DMSO-d6 or CDCl3, and 13C NMR at 50.32 MHz and 100.64 MHz
in the same solvents. Chemical shifts (d) are reported relative to
TMS as internal standard. The abbreviations used are as follows: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; all
the NH and OH exchanged with D2O. Diastereomeric ratios (dr) of
compounds 4a–o and 12a (unassigned configuration) were deter-
mined from 1H NMR spectrum in DMSO-d6; the NMR data of the
major diastereomer are marked with asterisk. Precoated silica gel
plates (0.25 mm) were employed for analytical TLC and silica gel
(35–70 m) for column chromatography.
MS: m/z (%) = 382 (M+, 21), 364 (6), 351 (4), 339 (11), 326 (12),
283 (92), 265 (100).
Anal. Calcd for C15H21F3N2O6: C, 47.10; H, 5.54; N, 7.33. Found:
C, 47.05; H, 5.49; N, 7.36.
2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol Derivative 4d
Yield: 318 mg (84%); white powder (Et2O).
dr = 50:50.
Synthesis 2001, No. 12, 1837–1845 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Regioselective Synthesis of Stable 2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ols
1841
IR (nujol): 3533, 3506, 3353, 3211, 3110, 1770, 1712, 1675, 1589
cm–1.
1H NMR (200 MHz, DMSO-d6): d = 2.16 (s, 3 H, CH3), 3.57 (s, 3
H, OCH3), 4.54 (br s, 1 H, CH), 6.21 and 6.48 (2 br s, 2 H, NH2),
7.89, 8.64 and 9.00 (3 br s, 2 H, NH and OH).
dr = 64:36.
IR (nujol): 3488, 3275, 3207, 3143, 1733, 1723, 1695, 1680, 1625,
1602, 1562 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.14–1.22 (m, 6 H, 2
OCH2CH3), 2.17 (s, 3 H, CH3), 3.90 and 3.93* (2 s, 1 H, CH), 4.04–
4.15 (m, 4 H, 2 OCH2CH3), 6.93–7.00 (m, 1 H, Ar-H), 7.22-7.28 (m,
2 H, 2 Ar-H), 7.44-7.47 (m, 2 H, 2 Ar-H), 7.79 (s, 1 H, NH), 7.97
(s, 1 H, NH), 8.95 and 9.02* (2 br s, 1 H, OH).
MS: m/z (%) = 445 (M+, 62), 427 (3), 400 (8), 372 (3), 354 (40), 326
(100).
13C NMR (50.32 MHz, DMSO-d6): d = 11.7 (q), 51.0 (q), 51.8 and
2
52.1 (2 d), 90.6 and 91.4 (2 s, JCF = 32.3 Hz), 93.7 (s), 115.1 (s,
1JCF = 290.4 Hz), 122.7 (s, 1JCF = 284.8 Hz), 157.8 and 160.6 (2 s),
161.8 and 162.9 (2 s), 164.1 (s), 187.3 (s, 2JCF = 35.0 Hz).
MS: m/z (%) = 379 (M+, 17), 361 (4), 348 (6), 282 (18), 264 (100).
Anal. calcd. for C11H11F6N3O5: C, 34.82; H, 2.92; N, 11.08. Found:
C, 34.91; H, 2.93; N, 11.11.
Anal. Calcd for C19H22F3N3O6: C, 51.22; H, 4.98; N, 9.44. Found:
C, 51.30; H, 5.00; N, 9.40.
2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol Derivative 4e
Yield: 361 mg (77%); white powder (EtOAc–Et2O).
2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol Derivative 4i
Yield: 350 mg (85%); white powder (Et2O–n-pentane).
dr = 65:35.
dr = 68:32.
IR (nujol): 3382, 3224, 3107, 1773, 1702, 1667, 1657, 1598, 1553
cm–1.
IR (nujol): 3308, 3215, 1745, 1716, 1701, 1658, 1522 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 1.14 (t, 3 H, J = 7.0 Hz,
OCH2CH3), 1.40 and 1.42 (2 s, 9 H, OBut), 2.10 (br s, 3 H, CH3),
3.58 (s, 3 H, OCH3), 3.88 (br s, 1 H, CH), 4.01–4.11 (m, 2 H,
OCH2CH3), 7.88 and 8.05* (2 s, 1 H, NH), 9.02* and 9.36 (2 s, 1 H,
OH).
MS: m/z (%) = 412 (M+, 24), 381 (9), 367 (5), 356 (30), 339 (16),
312 (54), 281 (100).
1H NMR (200 MHz, DMSO-d6): d = 1.13 (t, 3 H, J = 7.0 Hz,
OCH2CH3), 2.22 (s, 3 H, CH3), 3.99–4.09 (m, 2 H, OCH2CH3), 4.51
and 4.61* (2 br s, 1 H, CH), 6.97 (t, 1 H, J = 7.5 Hz, Ar-H), 7.26 (t,
2 H, J = 7.4 Hz, 2 Ar-H), 7.44 (d, 2 H, J = 7.5 Hz, 2 Ar-H), 8.14 (s,
1 H, NH), 8.70 (s, 1 H, NH), 8.82 and 8.97* (2 br s, 1 H, OH).
MS: m/z (%) = 469 (M+, 40), 451 (7), 424 (11), 382 (2), 354 (100),
350 (72), 334 (81).
Anal. Calcd for C16H23F3N2O7: C, 46.59; H, 5.62; N, 6.80. Found:
C, 46.66; H, 5.64; N, 6.78.
Anal. Calcd for C18H17F6N3O5: C, 46.04; H, 3.65; N, 8.96. Found:
C, 46.10; H, 3.62; N, 8.92.
2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol Derivative 4j
Yield: 371 mg (91%); white powder (EtOAc–petroleum ether–n-
pentane).
2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol Derivative 4f
Yield: 240 mg (61%); white powder (EtOAc–petroleum ether).
dr = 56:44.
dr = 66:34.
IR (nujol): 3260, 3220, 1774, 1734, 1675, 1635 cm–1.
IR (nujol): 3492, 3302, 1740, 1716, 1670, 1653, 1646, 1552, 1538
cm–1.
1H NMR (200 MHz, DMSO-d6): d = 2.16 (br s, 3 H, CH3), 3.43 and
3.46 (2 s, 3 H, NHCOOCH3), 3.65 (s, 3 H, OCH3), 4.53 and 4.90*
(2 br s, 1 H, CH), 7.20–7.27 (m, 1 H, Ar-H), 7.84–8.03 (m, 3 H, 2
Ar-H and NH), 8.64 and 8.80* (2 br s, 1 H, OH).
1H NMR (200 MHz, DMSO-d6): d = 2.13 and 2.16* (2 s, 3 H, CH3),
3.55 and 3.57* (2 s, 3 H, NHCOOCH3), 3.64 (s, 3 H, OCH3), 4.41
and 4.52* (2 br s, 1 H, CH), 8.68 and 8.90* (2 br s, 1 H, NH), 9.42*
and 9.72 (2 br s, 1 H, OH).
MS: m/z (%) = 394 (M+, 38), 363 (22), 335 (2), 319 (17), 297 (72),
279 (100).
MS: m/z (%) = 408 (M+, 8), 390 (4), 377 (2), 297 (87), 279 (100).
Anal. Calcd for C12H12F6N2O6: C, 36.54; H, 3.07; N, 7.11. Found:
C, 36.59; H, 3.06; N, 7.13.
Anal. Calcd for C15H15F3N2O6S: C, 44.11; H, 3.70; N, 6.86. Found:
C, 44.21; H, 3.69; N, 6.89.
2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol Derivative 4g
Yield: 316 mg (89%); white powder (EtOAc–petroleum ether).
2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol Derivative 4k
Yield: 384 mg (82%); white powder (CH2Cl2–petroleum ether).
dr = 50:50.
dr = 69:31.
IR (nujol): 3425, 3314, 3199, 1721, 1687, 1673, 1630, 1598 cm–1.
IR (nujol): 3404, 3337, 3226, 3102, 1707, 1682, 1662, 1599, 1547
cm–1.
1H NMR (200 MHz, DMSO-d6): d = 1.16 (t, 3 H, J = 7.0 Hz,
OCH2CH3), 2.10 and 2.12 (2 s, 3 H, CH3), 3.58 (s, 3 H, OCH3), 3.85
(br s, 1 H, CH), 4.05–4.15 (m, 2 H, OCH2CH3), 6.19 and 6.54 (2 br
s, 2 H, NH2), 7.45, 7.88 and 8.94 (3 br s, 2 H, NH and OH).
1H NMR (200 MHz, DMSO-d6): d = 2.23 (s, 3 H, CH3), 3.48 (s, 3
H, OCH3), 4.84 and 5.02* (2 br s, 1 H, CH), 6.93–7.06 (m, 1 H, Ar-
H), 7.22–7.35 (m, 3 H, 3 Ar-H), 7.43–7.53 (m, 2 H, 2 Ar-H), 7.84
(br s, 1 H, NH), 7.99–8.12 (m, 3 H, 2 Ar-H and NH), 8.99 and 9.10*
(2 br s, 1 H, OH).
13C NMR (50.32 MHz, DMSO-d6): d = 11.5 and 11.6 (2 q), 14.0 (q),
50.7 (q), 51.9 and 52.2 (2 d), 60.6 and 60.9 (2 t), 90.1 (s, 2JCF = 32.6
1
Hz), 95.3 (s), 122.8 (s, JCF = 284.1 Hz), 157.8 and 160.1 (2 s),
13C NMR (50.32 MHz, DMSO-d6): d = 12.0 (q), 50.7 (q), 52.1 (br
2
161.2 and 164.5 (2 s), 164.6 (s), 167.5 (s).
MS: m/z (%) = 355 (M+, 59), 337 (2), 324 (10), 312 (25), 281 (100),
264 (94).
d), 91.1 (s, JCF = 30.8 Hz), 97.1 (s), 118.7 and 119.0 (2 d), 122.3
and 122.8 (2 d), 123.2 (s, 1JCF = 283.7 Hz), 128.8 (2 d), 133.8 and
134.4 (2 d), 135.6 and 135.7 (2 d), 138.9 and 139.5 (2 s), 144.0 and
144.4 (2 s), 154.4 and 156.3 (2 s), 160.3 and 161.4 (2 s), 164.7 (s),
187.8 and 188.5 (2 s).
Anal. Calcd for C12H16F3N3O6: C, 40.55; H, 4.54; N, 11.83. Found:
C, 40.67; H, 4.53; N, 11.81.
MS: m/z (%) = 469 (M+, 18), 451 (5), 358 (36), 350 (7), 340 (100).
2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol Derivative 4h
Yield: 285 mg (64%); white powder (EtOAc–petroleum ether).
Anal. Calcd for C20H18F3N3O5S: C, 51.16; H, 3.87; N, 8.96. Found:
C, 51.22; H, 3.85; N, 8.92.
Synthesis 2001, No. 12, 1837–1845 ISSN 0039-7881 © Thieme Stuttgart · New York

1842
O. A. Attanasi et al.
PAPER
2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol Derivative 4l
Yield: 248 mg (61%); white powder (THF–petroleum ether).
Methyl 1-[(Aminocarbonyl)amino]-2,5-dimethyl-1H-pyrrole-3-
carboxylate (5a)
Yield: 8 mg (4%); oil.
dr = 55:45.
1H NMR (400 MHz, DMSO-d6): d = 2.01 (s, 3 H, CH3), 2.28 (s, 3
H, CH3), 3.67 (s, 3 H, OCH3), 6.07 (s, 1 H, CH), 6.19 (br s, 2 H,
NH2), 9.09 (1 H, NH).
IR (nujol): 3493, 3420, 3347, 3306, 3241, 1696, 1685, 1650, 1590
cm–1.
1H NMR (200 MHz, DMSO-d6): d = 0.91 (t, 3 H, J = 7.0 Hz,
OCH2CH3), 2.17 (s, 3 H, CH3), 3.85–3.95 (m, 2 H, OCH2CH3), 4.82
and 4.95* (2 br s, 1 H, CH), 6.21 (br s, 2 H, NH2), 7.23–7.27 (m, 1
H, Ar-H), 7.66 (br s, 1 H, NH), 7.98–8.06 (m, 2 H, 2 Ar-H), 8.68*
and 8.76 (2 br s, 1 H, OH).
MS: m/z (%) = 211 (M+, 44), 195 (4), 180 (11), 168 (81), 152 (100).
Anal. Calcd for C9H13N3O3: C, 51.18; H, 6.20; N, 19.89. Found: C,
51.20; H, 6.20; N, 19.78.
Methyl 1-[(Anilinocarbonyl)amino]-2,5-dimethyl-1H-pyrrole-
3-carboxylate (5b)
Yield: 12 mg (4%); oil.
1H NMR (200 MHz, DMSO-d6): d = 1.23 (t, 3 H, J = 7.1 Hz,
OCH2CH3), 2.04 (s, 3 H, CH3), 2.31 (s, 3 H, COCH3), 4.14 (q, 2 H,
J = 7.1 Hz, OCH2CH3), 6.10 (s, 1 H, CH), 6.97 (t, 1 H, J = 7.7 Hz,
Ar-H), 7.26 (t, 2 H, J = 7.8 Hz, 2 Ar-H), 7.45 (d, 2 H, J = 7.6 Hz, 2
Ar-H), 9.28 (br s, 1 H, NH), 9.38 (s, 1 H, NH).
MS: m/z (%) = 407 (M+, 12), 389 (4), 346 (4), 296 (78), 278 (100).
Anal. Calcd for C15H16F3N3O5S: C, 44.22; H, 3.96; N, 10.32.
Found: C, 44.32; H, 3.94; N, 10.35.
2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol Derivative 4m
Yield: 350 mg (93%); white powder (THF).
dr = 50:50.
IR (nujol): 3498, 3460, 3345, 3294, 3238, 3170, 1705, 1674, 1655,
1646, 1593, 1570 cm–1.
Anal. Calcd for C16H19N3O3: C, 63.76; H, 6.36; N, 13.95. Found: C,
63.80; H, 6.33; N, 13.94.
1H NMR (400 MHz, DMSO-d6): d = 2.16 (s, 3 H, CH3), 3.46 (s, 3
H, OCH3), 4.72 and 4.82 (2 br s, 1H, CH), 6.19 (br s, 2 H, NH2),
6.74 (br s, 1 H, Ar-H), 7.47 and 7.53 (2 br s, 1 H, Ar-H), 7.68 (br s,
1 H, NH), 8.03 (br s, 1 H, Ar-H), 8.62 and 8.88 (2 br s, 1 H, OH).
13C NMR (100.64 MHz, DMSO-d6): d = 11.8 (q), 50.7 (q), 51.6 (br
d), 90.9 (s, 2JCF = 30.2 Hz), 96.2 (s), 112.8 (d), 119.2 (d), 121.7 (s,
1JCF = 283.7 Hz), 148.2 (d), 148.6 (s), 152.2 and 152.4 (2 s), 160.5
and 162.0 (2 s), 164.5 (s), 182.8 (s).
Methyl 1-[(tert-Butoxycarbonyl)amino]-2,5-dimethyl-1H-
pyrrole-3-carboxylate (5c)
Yield: 16 mg (6%); oil.
IR (nujol): 3280, 1709, 1681, 1595 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 1.36 (s, 9 H, OBut), 2.00 (s, 3
H, CH3), 2.27 (s, 3 H, CH3), 3.67 (s, 3 H, OCH3), 6.10 (s, 1 H, CH),
10.21 (s, 1 H, NH).
13C NMR (50.32 MHz, DMSO-d6): d = 10.2 (q), 10.5 (q), 27.8 (q),
50.4 (q), 80.7 (s), 104.3 (d), 108.0 (s), 128.3 (s), 135.4 (s), 154.2 (s),
164.6 (s).
MS: m/z (%) = 377 (M+, 18), 359 (9), 327 (7), 282 (65), 264 (100).
Anal. Calcd for C14H14F3N3O6: C, 44.55; H, 3.74; N, 11.14. Found:
C, 44.64; H, 3.73; N, 11.17.
MS: m/z (%) = 268 (M+, 60), 253 (7), 237 (14), 211 (100).
2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol Derivative 4n
Yield: 406 mg (87%); white powder (CH2Cl2–petroleum ether).
Anal. Calcd for C13H20N2O4: C, 58.18; H, 7.52; N, 10.44. Found: C,
58.25; H, 7.55; N, 10.48
dr = 64:36.
IR (nujol): 3332, 3143, 1683, 1668, 1651, 1601, 1559 cm–1.
2-(Trifluoromethyl)-1H-pyrrole Derivatives 7h,k,n; General
Procedure
1H NMR (400 MHz, DMSO-d6): d = 0.92 (t, 3 H, J = 7.0 Hz,
OCH2CH3), 2.20 (s, 3 H, CH3), 3.86–3.94 (m, 2 H, OCH2CH3), 4.74
and 4.90* (2 br s, 1 H, CH), 6.73 (br s, 1 H, Ar-H), 6.92–6.97 (m, 1
H, Ar-H), 7.22–7.27 (m, 2 H, 2 Ar-H), 7.43–7.49 (m, 3 H, 3 Ar-H),
7.63 (br s, 1 H, NH), 7.77 (br s, 1 H, NH), 8.03 (br s, 1 H, Ar-H),
8.98* and 9.12 (2 br s, 1 H, OH).
To stirred solutions of 2-(trifluoromethyl)-2,3-dihydro-1H-pyrrol-
2-ols 4h,k,n (1 mmol) in anhyd CH2Cl2 (30 mL) were added anhyd
pyridine (1.1 mmol) and Tf2O (1.05 mmol). The resulted solutions
were magnetically stirred at r.t. for 1–2 h (Table 2). The crude reac-
tion mixtures were washed with 10% HCl (3 ¥ 10 mL), and brine,
and dried (Na2SO4). After removal of the solvent, compounds 7h,k
were obtained by crystallization from appropriate solvents (see be-
low), while 7n was obtained after chromatographic purification (cy-
clohexane–EtOAc) of the crude reaction mixture.
MS: m/z (%) = 467 (M+, 18), 449 (9), 422 (2), 372 (28), 354 (100).
Anal. Calcd for C21H20F3N3O6: C, 53.95; H, 4.31; N, 8.99. Found:
C, 53.89; H, 4.30; N, 8.97.
Diethyl 1-[(Anilinocarbonyl)amino]-2-methyl-5-(trifluoro-
methyl)-1H-pyrrole-3,4-dicarboxylate (7h)
Yield: 367 mg (86%); white powder.
2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ol Derivative 4o
Yield: 356 mg (82%); foam.
dr = 65:35.
Mp 163–165 °C (Et2O–n-pentane).
IR (nujol): 3326, 3183, 1740, 1719, 1661, 1599, 1564, 1556 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.22–1.28 (m, 6 H, 2
OCH2CH3), 2.35 (s, 3 H, CH3), 4.17–4.28 (m, 4 H, 2 OCH2CH3),
7.02 (t, 1 H, J = 7.8 Hz, Ar-H), 7.29 (t, 2 H, J = 7.8 Hz, 2 Ar-H),
7.45 (d, 2 H, J = 7.8 Hz, 2 Ar-H), 9.55 (br s, 1 H, NH), 9.93 (s, 1 H,
NH).
IR (nujol): 3310, 3148, 1749, 1715, 1684, 1653, 1568 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.40* and 1.43 (2 s, 9 H,
OBut), 2.15* and 2.19 (2 s, 3 H, CH3), 3.46 (s, 3 H, OCH3), 4.59 and
4.75* (2 br s, 1 H, CH), 6.73 (br s, 1 H, Ar-H), 7.45 (m, 1 H, Ar-H),
7.63* and 7.71 (2 br s, 1 H, NH), 8.01 (br s, 1 H, Ar-H), 8.18 and
8.52* (2 br s, 1 H, OH).
MS: m/z (%) = 434 (M+, 17), 416 (1), 403 (2), 378 (11), 360 (8), 334
(30), 316 (4), 283 (65), 265 (96), 239 (100).
13C NMR (100.64 MHz, DMSO-d6): d = 10.1 (q), 13.8 (q), 14.0 (q),
2
60.2 (t), 61.4 (t), 108.0 (s), 117.3 (s, JCF = 37.3 Hz), 118.4 (d),
118.9 (s), 119.8 (s, 1JCF = 267.3 Hz), 122.8 (d), 128.8 (d), 139.0 (s),
Anal. Calcd for C18H21F3N2O7: C, 49.77; H, 4.87; N, 6.45. Found:
C, 49.75; H, 4.90; N, 6.43.
141.7 (s), 153.3 (s), 162.3 (s), 163.8 (s).
Synthesis 2001, No. 12, 1837–1845 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Regioselective Synthesis of Stable 2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ols
1843
MS: m/z (%) = 427 (M+, 35), 381 (100), 354 (11), 334 (5), 308 (5),
Method C
262 (76).
See general procedure for the synthesis of 7h,k,n.
Anal. Calcd for C19H20F3N3O5: C, 53.38; H, 4.72; N, 9.84. Found:
C, 53.42; H, 4.74; N, 9.88.
Methyl 1-[(Aminocarbonyl)amino]-2,5-dimethyl-4-(2,2,2-
trifluoroacetyl)-1H-pyrrole-3-carboxylate (8a)
Method A: Yield: 288 mg (94%); white powder; mp 194–196 °C
(EtOAc–Et2O).
Methyl 1-[(Anilinocarbonyl)amino]-2-methyl-4-(2-thenoyl)-5-
(trifluoromethyl)-1H-pyrrole-3-carboxylate (7k)
Yield: 325 mg (72%); white powder.
Method B: Yield: 187 mg (61%).
Mp 142–145 °C (dec.) (EtOAc–n-pentane).
Method C: Yield: 252 mg (82%).
IR (nujol): 3310, 3266, 3143, 1721, 1693, 1646, 1606, 1574, 1549
cm–1.
IR (nujol): 3435, 3327, 3269, 3206, 1700, 1679, 1580, 1550 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 2.11 (s, 3 H, CH3), 2.27 (s, 3
H, CH3), 3.70 (s, 3 H, OCH3), 6.55 (s, 2 H, NH2), 9.41 (s, 1 H, NH).
13C NMR (50.32 MHz, DMSO-d6): d = 9.6 (q), 9.8 (q), 51.2 (q),
108.4 (s), 111.9 (s), 115.6 (s, 1JCF = 289.7 Hz), 137.7 (s), 138.4 (s),
156.4 (s), 163.7 (s), 181.3 (s, 2JCF = 34.6 Hz).
1H NMR (400 MHz, DMSO-d6): d = 2.42 (s, 3 H, CH3), 3.55 (s, 3
H, OCH3), 7.03 (t, 1 H, J = 7.6 Hz, Ar-H), 7.22 (t, 1 H, J = 4.4 Hz,
Ar-H), 7.30 (t, 2 H, J = 7.6 Hz, 2 Ar-H), 7.36–7.41 (m, 1 H, Ar-H),
7.48 (d, 2 H, J = 7.7 Hz, 2 Ar-H), 8.08 (d, 1 H, J = 4.8 Hz, Ar-H),
9.59 (br s, 1 H, NH), 9.98 (s, 1 H, NH).
13C NMR (100.64 MHz, DMSO-d6): d = 10.3 (q), 51.3 (q), 108.8
(s), 117.7 (s, 2JCF = 37.8 Hz), 118.9 (d), 119.8 (s, 1JCF = 269.8 Hz),
122.8 (d), 123.6 (s), 128.7 (d), 128.8 (d), 134.4 (d), 135.7 (d), 138.9
(s), 141.9 (s), 144.4 (s), 153.3 (s), 162.8 (s), 183.0 (s).
MS: m/z (%) = 307 (M+, 87), 275 (100), 248 (81), 238 (80).
Anal. Calcd for C11H12F3N3O4: C, 42.99; H, 3.94; N, 13.68. Found:
C, 43.01; H, 3.93; N, 13.72.
Methyl 1-[(tert-Butoxycarbonyl)amino]-2,5-dimethyl-4-(2,2,2-
trifluoroacetyl)-1H-pyrrole-3-carboxylate (8c)
Method A: Yield: 189 mg (52%); white powder; mp 118–120 °C
(Et2O–petroleum ether).
MS: m/z (%) = 451 (M+, 25), 419 (31), 367 (15), 332 (13), 316 (4),
300 (100).
Anal. Calcd for C20H16F3N3O4S: C, 53.21; H, 3.57; N, 9.31. Found:
C, 53.30; H, 3.58; N, 9.27.
IR (nujol): 3234, 1748, 1692, 1584, 1546 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 1.47 (s, 9 H, But), 2.11 (s, 3 H,
Methyl 1-[(Anilinocarbonyl)amino]-2-methyl-5-(trifluoro-
methyl)-1H-pyrrole-carboxylate (7n)
Yield: 372 mg (83%); foam.
IR (KBr): 3321, 3275, 1713, 1671, 1601, 1550 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.04 (t, 3 H, J = 7.2 Hz,
OCH2CH3), 2.38 (s, 3 H, CH3), 3.98–4.05 (m, 2 H, OCH2CH3), 6.48
(dd, 1 H, J = 3.6, 1.2 Hz, Ar-H), 6.97–7.02 (m, 2 H, 2 Ar-H), 7.20
(t, 2 H, J = 8.0 Hz, 2 Ar-H), 7.29 (d, 2 H, J = 8.0 Hz, 2 Ar-H), 7.55
(br s, 1 H, Ar-H), 8.00 (s, 1 H, NH), 8.90 (s, 1 H, NH).
CH3), 2.28 (s, 3 H, CH3), 3.71 (s, 3 H, OCH3), 10.68 (s, 1 H, NH).
13C NMR (50.32 MHz, DMSO-d6): d = 9.3 (q), 9.6 (q), 27.7 (q),
1
51.2 (q), 81.8 (s), 108.8 (s), 112.4 (s), 115.7 (s, JCF = 291.2 Hz),
137.0 (s), 137.2 (s), 154.0 (s), 163.6 (s), 181.6 (s, 2JCF = 35.3 Hz).
MS: m/z (%) = 364 (M+, 48), 333 (6), 308 (60), 295 (4), 291 (5), 276
(100).
Anal. Calcd for C15H19F3N2O5: C, 49.43; H, 5.26; N, 7.69. Found:
C, 49.51; H, 5.25; N, 7.68.
13C NMR (100.64 MHz, CDCl3): d = 10.8 (q), 14.4 (q), 61.2 (t),
2
Methyl 1-Amino-2,5-dimethyl-4-(2,2,2-trifluoroacetyl)-1H-
pyrrole-3-carboxylate (9c)
Method A: Yield: 121 mg (46%); white powder; mp 132–134 °C
(Et2O–petroleum ether).
110.5 (s), 113.4 (d), 113.6 (s), 119.7 (s, JCF = 38.8 Hz), 120.2 (s,
1JCF = 268.1 Hz), 121.2 (d), 123.4 (d), 125.0 (d), 129.6 (d), 137.7
(s), 142.7 (s), 148.7 (d), 153.4 (s), 154.5 (s), 163.7 (s), 180.5 (s).
MS: m/z (%) = 449 (M+, 27), 403 (33), 381 (12), 354 (4), 330 (19),
284 (100).
Method B: Yield: 172 mg (65%).
Method C: Yield: 187 mg (71%).
IR (nujol): 3359, 3296, 3233, 1685, 1542 cm–1.
Anal. Calcd for C21H18F3N3O5: C, 56.11; H, 4.04; N, 9.35. Found:
C, 56.29; H, 4.05; N, 9.33.
1H NMR (400 MHz, DMSO-d6): d = 2.25 (s, 3 H, CH3), 2.41 (s, 3
3-(2,2,2-Trifluoroacetyl)-1H-pyrrole Derivatives 8a,c and 9c;
Method A
H, CH3), 3.67 (s, 3 H, OCH3), 5.83 (s, 2 H, NH2).
13C NMR (100.64 MHz, DMSO-d6): d = 10.1 (q), 10.3 (q), 51.0 (q),
107.8 (s), 111.4 (s), 115.9 (s, 1JCF = 290.9 Hz), 137.6 (s), 138.3 (s),
164.0 (s), 181.2 (s, 2JCF = 35.2 Hz).
To a solution of 4a (or 4c) (1 mmol) in THF (40 mL), Amberlyst 15
(215 mg) was added and the mixture was heated under reflux for 10
h (or 27 h). The resin was filtered off and washed with THF (4 ¥ 15
mL). The filtered extract was evaporated under reduced pressure
and the residue was purified by crystallization to furnish 8a or by
flash chromatography (cyclohexane–EtOAc, 9:1) to provide 8c and
9c.
MS: m/z (%) = 264 (M+, 91), 249 (3), 232 (100), 204 (12), 195 (94).
Anal. Calcd for C10H11F3N2O3: C, 45.44; H, 4.20; N, 10.61. Found:
C, 45.61; H, 4.18; N, 10.58.
Synthesis of Derivatives 10c and 11o (According to Baxter39)
Concd HCl (1 mL) was added to a refluxing solution of 2-(trifluo-
romethyl)-2,3-dihydro-1H-pyrrol-2-ol 4c or 4o (1.1 mmol) in
MeOH (16 mL). After 2–3 h, EtOH (7 mL) was added and the solu-
tion was cooled quickly to 10 °C. HCl (5 M, 7 mL) was added fol-
lowed by NaNO2 (0.167 g) in H2O (2 mL). After 1–3 h at r.t., H2O
was added and the alcohols were evaporated. The aqueous solution
was extracted with EtOAc. The organic extract was washed with
sat. aq NaHCO3, dried (Na2SO4) and the solvent was evaporated.
The crude product 10c or 11o was purified by column chromatog-
Method B
To a solution of 4a (or 4c) (1 mmol) in anhyd toluene (20 mL),
Montmorillonite KSF (600 mg) activated for 3 h at 100 °C was add-
ed and the suspension was refluxed for 11 h (or 5 h). The solution
was filtered and the clay washed with THF (3 ¥ 20 mL). The filtrate
was dried (Na2SO4) and the solvents were removed in vacuo. The
crude product 8a (or 9c) was purified by column chromatography
(cyclohexane–EtOAc).
Synthesis 2001, No. 12, 1837–1845 ISSN 0039-7881 © Thieme Stuttgart · New York

1844
O. A. Attanasi et al.
PAPER
raphy (cyclohexane–EtOAc) and crystallized from the appropriate
MS: m/z (%) = 443 (M+, 25), 425 (6), 412 (100), 399 (6), 384 (3),
solvents.
322 (6).
Anal. Calcd for C19H20F3N3O6: C, 51.45; H, 4.55; N, 9.48. Found:
C, 51.61; H, 4.57; N, 9.45.
Methyl 2,5-Dimethyl-4-(2,2,2-trifluoroacetyl)-1H-pyrrole-3-
carboxylate (10c)
Yield: 145 mg (58%); white powder.
N-(5-Methyl-1,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydro-
6H-pyrrolo[3,4-d]pyridazin-6-yl)-N’-phenylurea (13h)
To compound 7h (1 mmol) refluxed in THF (20 mL), a stoichiomet-
ric amount of hydrazine monohydrate (1 mmol), dissolved in EtOH
(2 mL), was added dropwise within 0.5 h. The reaction mixture was
refluxed until the disappeareance of the pyrrole derivative (moni-
tored by TLC). The pale yellow solid formed during the reaction
was filtered off after completion (40 h), and recrystallized from
THF–EtOH (9:1) yielding pure 13h.
Mp 142–143 °C (Et2O).
IR (nujol): 3304, 1698, 1672, 1546 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.22 (s, 3 H, CH3), 2.35 (s, 3
H, CH3), 3.66 (s, 3 H, OCH3), 12.1 (s, 1 H, NH).
13C NMR (100.64 MHz, DMSO-d6): d = 11.5 (q), 11.7 (q), 50.8 (q),
110.7 (s), 114.2 (s), 115.9 (s, 1JCF = 290.7 Hz), 135.2 (s), 136.5 (s),
164.2 (s), 181.0 (s, 2JCF = 34.7 Hz).
MS: m/z (%) = 249 (M+, 100), 216 (64), 217 (93), 189 (61), 180
(83).
Yield: 224 mg (61%); pale yellow powder.
Mp >300 °C (dec.) (THF–EtOH).
IR (nujol): 3272, 3198, 3143, 1661, 1602, 1569 cm–1.
Anal. Calcd for C10H10F3NO3: C, 48.18; H, 4.05; N, 5.62. Found: C,
48.30; H, 4.07; N, 5.61.
1H NMR (400 MHz, DMSO-d6): d = 2.48 (s, 3 H, CH3), 7.02 (t, 1
H, J = 7.7 Hz, Ar-H), 7.29 (t, 2 H, J = 7.7 Hz, 2 Ar-H), 7.46 (d, 2 H,
J = 7.6 Hz, 2 Ar-H), 9.60 (br s, 1 H, NH), 10.04 (s, 1 H, NH), 11.08
(s, 2 H, NH).
13C NMR (100.64 MHz, DMSO-d6): d = 9.6 (q), 110.8 (s), 114.0
(s), 114.4 (s, 2JCF = 38.3 Hz), 118.5 (d), 120.2 (s, 1JCF = 267.4 Hz),
122.1 (d), 128.7 (d), 135.5 (s), 139.6 (s), 151.8 (s), 154.2 (s), 155.2
(s).
Methyl 4-(2-Furoyl)-2-methyl-5-(trifluoromethyl)-1H-pyrrole-
3-carboxylate (11o)
Yield: 184 mg (61%); white powder.
Mp 121–123 °C (Et2O–n-pentane).
IR (nujol): 3263, 3140, 1714, 1641, 1584, 1566, 1533 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.48 (s, 3 H, CH3), 3.50 (s, 3
H, OCH3), 6.68 (dd, 1 H, J = 3.6, 2.0 Hz, Ar-H), 7.09 (d, 1 H,
J = 3.6 Hz, Ar-H), 7.97 (br s, 1 H, Ar-H), 12.10 (br s, 1 H, NH).
MS: m/z (%) = 367 (M+, 42), 248 (64), 232 (100).
Anal. Calcd for C15H12F3N5O3: C, 49.03; H, 3.29; N, 19.07. Found:
C, 49.12; H, 3.28; N, 19.12.
13C NMR (100.64 MHz, DMSO-d6): d = 12.4 (q), 51.0 (q), 111.5
2
(s), 112.6 (d), 115.9 (s, JCF = 39.0 Hz), 119.2 (d), 120.6 (s,
1JCF = 268.0 Hz), 124.3 (s), 137.9 (s), 148.0 (d), 152.9 (s), 163.4 (s),
178.2 (s).
Acknowledgement
MS: m/z (%) = 301 (M+, 83), 269 (100), 241 (82), 234 (54).
This investigation was supported by the financial assistance from
the Università degli Studi di Urbino, Ministero dell'Università e del-
la Ricerca Scientifica e Tecnologica and Consiglio Nazionale delle
Ricerche.
Anal. Calcd for C13H10F3NO4: C, 51.82; H, 3.35; N, 4.65. Found: C,
51.89; H, 3.32; N, 4.63.
Methyl 2-Benzoyl-3-hydroxy-3,5-dimethyl-6-
[(aminocarbonyl)amino]-6a-(trifluoromethyl)-3,3a,6,6a-
tetrahydro-2H-furo[2,3-b]pyrrole-4-carboxylate (12a)
References
To a stirred solution of 4a (1 mmol) in THF (20 mL), K2CO3 (2
mmol) and 2-bromoacetophenone (1.01 mmol) were added. The re-
action mixture was stirred at r.t. for 5 min and then was heated under
reflux for 3 h. After removal of the solvent under reduced pressure
the crude reaction mixture was extracted with EtOAc (80 mL),
washed with brine, dried (Na2SO4), and evaporated. Silica gel col-
umn chromatography (cyclohexane–EtOAc) on the residue afford-
(1) Attanasi, O. A.; Caglioti, L. Org. Prep. Proced. Int. 1986,
18, 299; and references cited therein.
(2) Banert, K. In Targets in Heterocycles Systems-Chemistry
and Properties, Vol. 3; Attanasi, O. A.; Spinelli, D., Eds.;
Società Chimica Italiana: Rome, 2000, Chap. 1, 1.
(3) Polanc, S. In Targets in Heterocycles Systems-Chemistry
and Properties, Vol. 3; Attanasi, O. A.; Spinelli, D., Eds.;
Società Chimica Italiana: Rome, 2000, Chap. 2, 33; and
references cited therein.
ed 12a, which was crystallized from EtOAc–Et2O as
a
diastereomeric mixture.
(4) Gilchrist, T. L.; Sanchez Romero, O. A.; Wasson, R. C. J.
Chem. Soc., Perkin Trans. 1 1989, 353.
(5) Vors, J. J. Heterocycl. Chem. 1990, 27, 579.
(6) Ferguson, G.; Lough, A. J.; Mackay, D.; Weeratunga, G. J.
Chem. Soc., Perkin Trans. 1 1991, 3361.
Yield: 341 mg (77%); white powder (EtOAc–Et2O).
dr = 75:25.
IR (nujol): 3456, 3332, 3279, 3206, 1696, 1676, 1623, 1598, 1518
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.22 (br s, 3 H, CH3), 2.09*
and 2.14 (2 s, 3 H, CH3), 3.58 and 3.59* (2 s, 1 H, CH), 3.63* and
3.65 (2 s, 3 H, OCH3), 4.61 and 5.07* (2 s, 1 H, CH), 5.52* and 5.61
(2 s, 1 H, OH), 6.06 (br s, 2 H, NH2), 7.39–7.62 (m, 3 H, 3 Ar-H),
7.92–8.02 (m, 2 H, 2 Ar-H), 8.08 and 8.47* (2 s, 1 H, NH).
(7) Clarke, S. J.; Gilchrist, T. L.; Lemos, A.; Roberts, T. G.
Tetrahedron 1991, 47, 5615.
(8) Gilchrist, T. L.; Lemos, A. J. Chem. Soc., Perkin Trans. 1
1993, 1391.
(9) Baccolini, G.; Orsolan, G.; Mezzina, E. Tetrahedron Lett.
1995, 36, 447.
(10) South, M. S.; Jakuboski, T. L.; Westmeyer, M. D.;
Dukesherer, D. R. J. Org. Chem. 1996, 61, 8921.
(11) Caposcialli, N.; Dell’Erba, C.; Novi, M.; Petrillo, G.;
Tavani, C. Tetrahedron 1998, 54, 5315.
13C NMR (100.64 MHz, DMSO-d6): d = 11.8 and 12.1 (2 q), 20.3
and 20.5 (2 q), 50.4 and 50.5 (2 q), 58.8 and 58.9 (2 d), 82.8 and 82.9
2
(2 s), 89.1 and 90.1 (2 d), 94.0 (s), 98.1 (s, JCF = 39.4 Hz), 122.3
and 122.6 (2 s, 1JCF = 284.2 and 283.2 Hz), 127.9 and 128.0 (2 d),
129.4 and 129.5 (2 d), 132.9 (d), 137.1 and 137.2 (2 s), 158.5 (s),
162.2 (s), 165.2 and 165.4 (2 s), 196.9 (s).
Synthesis 2001, No. 12, 1837–1845 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Regioselective Synthesis of Stable 2-(Trifluoromethyl)-2,3-dihydro-1H-pyrrol-2-ols
1845
(12) Palacios, F.; Aparicio, D.; de los Santos, J. M. Tetrahedron
1999, 55, 13767; and references cited therein.
(28) Attanasi, O. A.; Santeusanio, S.; Serra-Zanetti, F. Gazz.
Chim. Ital. 1989, 119, 631.
(13) Attanasi, O. A.; Filippone, P. Synlett 1997, 1128; and
references cited therein.
(14) Attanasi, O. A.; DeCrescentini, L.; Filippone, P.; Perrulli, F.
R.; Santeusanio, S. Synlett 1999, 339.
(15) Attanasi, O. A.; Filippone, P.; Fiorucci, C.; Foresti, E.;
Mantellini, F. J. Org. Chem. 1998, 63, 9880.
(16) Attanasi, O. A.; DeCrescentini, L.; Filippone, P.; Guidi, B.;
Perrulli, F. R.; Santeusanio, S. Synlett 1999, 1367.
(17) Arcadi, A.; Attanasi, O. A.; Guidi, B.; Rossi, E.;
Santeusanio, S. Eur. J. Org. Chem. 1999, 3117.
(18) Attanasi, O. A.; Filippone, P.; Foresti, E.; Guidi, B.;
Santeusanio, S. Tetrahedron 1999, 55, 13423.
(19) Attanasi, O. A.; Ballini, R.; DeCrescentini, L.; Filippone, P.;
Mantellini, F. J. Org. Chem. 1999, 64, 9653.
(20) Attanasi, O. A.; DeCrescentini, L.; Filippone, P.; Foresti, E.;
Mantellini, F. J. Org. Chem. 2000, 65, 2820.
(29) Attanasi, O. A.; DeCrescentini, L.; McKillop, A.;
Santeusanio, S.; Serra-Zanetti, F. J. Chem. Soc., Perkin
Trans. 1 1992, 3099.
(30) Attanasi, O. A.; Ballini, R.; Liao, Z.; Santeusanio, S.; Serra-
Zanetti, F. Tetrahedron 1993, 49, 7027.
(31) (a) Welch, J. T. Selective Fluorination in Organic and
Bioorganic Chemistry; ACS Symposium Series 456:
Washington D. C., 1991. (b) Welch, J. T.; Eswarakrishnan,
S. Fluorine in Bioorganic Chemistry; Wiley: New York,
1991.
(32) Tipping, A. E.; Jimenez, P.; Ballesteros, E.; Abboud, J.-L.
M.; Yànez, M.; Essefar, M.; Elguero, J. J. Org. Chem. 1994,
59, 1039.
(33) Jones, B. G.; Branch, S. K.; Thompson, A. S.; Threadgill, M.
D. J. Chem. Soc., Perkin Trans. 1 1996, 2685.
(34) Alvernhe, G.; Langlois, B.; Laurent, A.; Le Drean, I.; Selmi,
A.; Weissenfels, M. Tetrahedron Lett. 1991, 32, 643.
(35) Katsuyama, I.; Funabiki, K.; Matsui, M.; Muramatsu, H.;
Shibata, K. Tetrahedron Lett. 1996, 37, 4177.
(36) (a) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M.
Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications; Elsevier: Amsterdam, 1993.
(b) Filler, R.; Kobayashi, Y. Biomedicinal Aspects of
Fluorine Chemistry; Kodansha/Elsevier: New York, 1982.
(37) (a) Uneyama, K.; Sugimoto, K. J. Org. Chem. 1992, 57,
6014. (b) Yoshioka, H.; Nakayama, C.; Matsuo, N. J. Synth.
Org. Chem. Jpn. 1984, 42, 809.
(21) Attanasi, O. A.; DeCrescentini, L.; Filippone, P.; Mantellini,
F. Synlett 2001, 557.
(22) Attanasi, O. A.; Filippone, P.; Guidi, B.; Perrulli, F. R.;
Santeusanio, S. Synlett 2001, 144.
(23) Attanasi, O. A.; Filippone, P.; Perrulli, F. R.; Santeusanio, S.
Tetrahedron 2001, 57, 1387.
(24) Cirrincione, G.; Almerico, A. M.; Aiello, E.; Dattolo, G.
Pyrroles Part Two: The Synthesis, Reactivity, and Physical
Properties of Substituted Pyrroles, Aminopyrroles, The
Chemistry of Heterocyclic Compounds; Jones, R. A., Ed.;
John Wiley & Sons: New York, 1992, Chap. 3, 299.
(25) Gribble, G. W. Pyrroles and Benzo Derivatives:
Applications; Bird, C., Ed., In Comprehensive Heterocyclic
Chemistry II Vol. 2, Katritzky, A. R.; Rees, C. W.; Scriven,
E. F. V., Eds.; Pergamon-Elsevier Science: Amsterdam,
1996, Chap. 4.
(26) Sundberg, R. J. Pyrroles and Benzo Derivatives: Synthesis;
Bird, C., Ed., In Comprehensive Heterocyclic Chemistry II
Vol. 2, Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon-Elsevier Science: Amsterdam, 1996, Chap. 3.
(27) Attanasi, O. A.; Grossi, M.; Serra-Zanetti, F.; Foresti, E.
Tetrahedron 1987, 43, 4249.
(38) Meshram, H. M. Synthesis 1992, 943.
(39) Baxter, A. J. G.; Fuher, J.; Teague, S. J. Synthesis 1994, 207.
(40) Threadgill, M. D.; Heer, A. K.; Jones, B. G. J. Fluorine
Chem. 1993, 65, 21.
(41) Jones, B. G.; Branch, S. K.; Threadgill, M. D.; Wilman, D.
E. V. J. Fluorine Chem. 1995, 74, 221.
(42) Sommer, S. Tetrahedron Lett. 1977, 18, 117.
(43) Attanasi, O. A.; Filippone, P.; Mei, A.; Santeusanio, S.
Synthesis 1984, 671.
(44) Attanasi, O. A.; Filippone, P.; Mei, A.; Santeusanio, S.
Synthesis 1984, 873.
Synthesis 2001, No. 12, 1837–1845 ISSN 0039-7881 © Thieme Stuttgart · New York