Lithium bromide/triethylamine promoted tandem cycloaddition-oxidation reaction: A convenient access to 3-trifluoroacetyl pyrroles from N-alkylidene 2-amino esters and β-trifluoroacetyl vinyl ethyl ether

Article abstract of DOI:10.1016/j.jfluchem.2010.02.008

A convenient lithium bromide/triethylamine promoted tandem cycloaddition-oxidation reaction was developed to afford 3-trifluoroacetyl pyrroles in moderate to good yields from N-alkylidene 2-amino esters and β-trifluoroacetyl vinyl ethyl ether.

Full text of DOI:10.1016/j.jfluchem.2010.02.008

Journal of Fluorine Chemistry 131 (2010) 642–645
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Lithium bromide/triethylamine promoted tandem cycloaddition–oxidation
reaction: A convenient access to 3-trifluoroacetyl pyrroles from N-alkylidene
2-amino esters and
b
-trifluoroacetyl vinyl ethyl ether
Yong Xin a, Jingwei Zhao a,b, Jianwei Han a, Shizheng Zhu a,
*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, PR China
b College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, 53 Zhengzhou Road, Qingdao 266042, PR China
A R T I C L E I N F O
A B S T R A C T
Article history:
A convenient lithium bromide/triethylamine promoted tandem cycloaddition–oxidation reaction was
developed to afford 3-trifluoroacetyl pyrroles in moderate to good yields from N-alkylidene 2-amino
Received 3 December 2009
Received in revised form 17 January 2010
Accepted 20 February 2010
Available online 26 February 2010
esters and
b-trifluoroacetyl vinyl ethyl ether.
ß 2010 Elsevier B.V. All rights reserved.
Keywords:
N-alkylidene 2-amino esters
b
-Trifluoroacetyl vinyl ether
Cycloaddition
Oxidation
Pyrrole derivatives
1. Introduction
synthesis of pyrrolidines and proline derivatives. Herein, we report
a convenient access to 3-trifluoroacetyl pyrroles from easily
Owing to the increasing importance of fluorine-containing
heterocycles in the fields of biology and pharmacology, the
development of efficient methods for the synthesis of these motifs
have long been an interesting subject [1]. Among those well-
developed methodologies for constructing 5-membered hetero-
cycles, 1,3-dipolar cycloaddition represents one of the most
available N-alkylidene 2-amino esters and
ethyl ether.
b-trifluoroacetyl vinyl
2. Results and discussion
Initial study was investigated from (E)-4-ethoxy-1,1,1-trifluor-
obut-3-en-2-one 1 and (E)-methyl 2-(benzylideneamino)acetate 2a
in the presence of one equivalent of pyridine (Table 1, entry 1).
However, the reaction proceeded rather tediously. And no
significant acceleration was observed with addition of AgNO3 [6],
which may be due to the low solubility of AgNO3 in THF. When
lithium bromide hydrate was employed as catalyst, to our delight,
the reaction could be finished within 3 h. Investigation of the 1H
NMR and 19F NMR suggested that the ethoxyl group was eliminated
during the reaction while trifluoroacyl group remained intact
(À73.7 ppm). Moreover, the mass spectrum indicated a loss of two H
atoms of the cycloaddition product, which was also proved bythe 1H
NMR. Concerning with other spectra, the structure was determined
as a pyrrole cycle [7]. It should be noted that the synthesis of 3-
trifluoroacetyl substituted pyrroles were normally reported by
multiple-step reactions, either through a protection–acylation–
deprotection or addition–oxidation process [8a,b].
versatile tools [2].
b-Trifluoroacetyl vinyl ethers were first
prepared in 1967 [3], and the existence of polarized C55C and
reactive trifluoroacetyl group have made them widely used as
building blocks for the synthesis of fluorine-containing hetero-
cycles [4].
Recently, 1,3-dipolar cycloaddition reactions have been devel-
oped based on N-alkylidene 2-amino esters, which are known as
stabilized azomethine yields. Many catalyst such as Cu(I), Ag(I),
lithium salts, Fesulphos, organocatalysts and composite catalysts
are commonly used in the reactions between N-alkylidene 2-
amino esters and electron-deficient or polarized double bond in a
stereoselective and regioselective manner [5a–f]. Considering
about the efficiency and versatility of the reaction, it becomes
one of the most convergent and practical approaches to the
In order to improve the yield, the effect of bases was
investigated and the results are summarized in Table 1. It is
* Corresponding author. Tel.: +86 21 54925185; fax: +86 21 64166128.
E-mail address: zhusz@mail.sioc.ac.cn (S. Zhu).
0022-1139/$ – see front matter ß 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2010.02.008

Y. Xin et al. / Journal of Fluorine Chemistry 131 (2010) 642–645
643
Table 1
Effect of bases on the reaction azomethine yield 2a and 1.
.
Entry
Cat/base
Yield (%)a
Fig. 1. Molecular structure of compound 3e.
1
2
AgNO3/pyridine
N.R.
15
LiBrÁH2O/pyridine
LiBrÁH2O/quinine
LiBrÁH2O/N,N-dimethylaniline
LiBrÁH2O/N,N-diethylaniline
LiBrÁH2O/NEt3
3
24
With the optimized reaction condition in hand, we then
extended the reaction with a series of N-alkylidene 2-amino esters.
All the results are summarized in Table 2. It is implied that with an
EWG attached on Ph, the reaction proceeded faster and led to a
higher yield.
4
Trace
12
5
6
73
7
LiBrÁH2O/NaOAc
18
8
LiBrÁH2O/NaCO3
Trace
3
9
LiBrÁH2O/LiCO3
The molecular structure of 3e was further confirmed by an X-
ray crystal structure analysis (Fig. 1).
10
11
12
LiBrÁH2O/K2CO3
30
LiBrÁH2O/NaOH
77
The pyrrole products might be generated as shown in Scheme 1.
Lithium enolate a was generated from 2 in the presence of LiBr and
NEt3. Then, under the chelation effect of lithium [5d], which highly
contributed to the acceleration of the reaction, concerted 1,3-
dipolar cycloaddition led to c. The following elimination of ethanol
afforded d [9]. Then, as a result of the tendency of aromatization
[1,10], spontaneous air oxidation led to a substituted pyrrole.
When there is an EWG attached on Ph, the chelation complex b can
be generated easier than there is an EDG.
LiBrÁH2O/KOH
63
Determined by 19F NMR except entry 2, adding 0.5 mmol trifluoromethylben-
a
zene as standard.
obvious that stronger base led to a relatively higher yield whether
it is organic or inorganic. In view of the feasibility and efficiency,
triethylamine was chosen as optimal base (entry 6), although KOH
and NaOH both led to a satisfactory yield (entries 11 and 12).
Table 2
Synthesis of CF3CO-bearing Pyrroles.
.
Entry
Ar
3b–i
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
4-MeO–Ph (2b)
4-Br–Ph (2c)
3b
3c
3d
3e
3f
18
12
3
62
59
73
58
75
77
81
47
4-Cl–Ph (2d)
4-F–Ph (2e)
3
2-F–Ph (2f)
10
4
3-F–Ph (2g)
3g
3h
3i
4-CF3–Ph (2h)
4-N,N-dimethylamino–Ph (2i)
4
20
a
Isolated yield.
Scheme 1. Mechanism of the cycloaddition–oxidation.

644
Y. Xin et al. / Journal of Fluorine Chemistry 131 (2010) 642–645
3. Conclusion
19F NMR (282 MHz, CDCl3):
d
= À73.6 (s). ESI-MS: m/z
[M+H]+ = 328. HRMS: m/z calcd. for C15H12F3N1O4 [M+Na]:
In conclusion, we have developed
a
convenient tandem
350.0611; found: 350.0614.
cycloaddition–oxidation reaction in the presence of lithium
bromide. 3-Trifluoroacetyl substituted pyrroles could be synthe-
sized in good yields from easily available N-alkylidene 2-amino
4.1.3. Methyl 5-(4-bromophenyl)-4-(2,2,2-trifluoroacetyl)-1H-
pyrrole-2-carboxylate 3c
esters and
b-trifluoroacetyl vinyl ethyl ethers. The mild condition
Colorless crystals. Mp = 176 8C. FTIR (KBr) cmÀ1: 3258, 2958,
and satisfactory yield will provide this reaction as a useful method
for the construction of chemical library with pyrrole motifs.
1689, 1571, 899, 782, 720. 1H NMR (300 MHz, CDCl3):
d = 10.15 (br
s, 1H, NH), 7.61 (d, 2H, J = 8.7 Hz, ArH), 7.50 (d, 2H, J = 8.7 Hz, ArH),
7.45 (s, 1H, Hpyrrole), 3.85 (s, 3H, COOCH3). 13C NMR (75 MHz,
CDCl3):
d = 175.3 (q, J = 34.0 Hz), 159.9, 143.5, 131.7, 131.1, 129.0,
4. Experimental
124.2, 123.6, 117.2 (q, J = 4.0 Hz), 116.9 (q, J = 290.0 Hz), 113.9,
Melting points are measured on a Temp-Melt apparatus and are
uncorrected. 1H (300 MHz), 13C NMR (75 MHz) and 19F NMR
(282 MHz) spectra were recorded on a Bruker AM-300 ultra shield,
300 MHz, high performance digital FT-NMR spectrometer with
Me4Si and CFCl3 as the internal and external standards, respectively.
13C NMR (100 MHz) spectra were recorded on a Bruker AV-400 ultra
shield plus, 400 MHz, high performance digital FT-NMR spectro-
meter with Me4Si as the internal standard. FTIR spectra were
obtained with a Nicolet AV-360 spectrophotometer. Low resolution
mass spectra (LRMS) and high resolution mass spectra (HRMS) were
obtained on a Finnigan GC–MS 4021 and a Finnigan MAT-8430
instrument using the electron impact ionization technique (70 eV)
or electrospray ionization. Elemental analyses were performed by
this institute. Single crystal X-ray structure analysis was performed
on a Bruker P4 instrument. All solvents and reagents were used
without further purification unless otherwise stated.
51.3. 19F NMR (282 MHz, CDCl3):
d
= À73.73 (s). ESI-MS: m/z
m/z calcd. for
[M]+
[MÀH]À = 374:376 = 1:1.
HRMS:
C14H9Br1F3N1O3: 374.9718, found: 374.9721; calcd.: 376.9697,
found: 376.9699.
4.1.4. Methyl 5-(4-chlorophenyl)-4-(2,2,2-trifluoroacetyl)-1H-
pyrrole-2-carboxylate 3d
Colorless crystals. Mp = 179–180 8C. FTIR (KBr) cmÀ1: 3259,
2964, 1915, 1704, 152, 1345, 1029, 1004, 898, 860, 784, 645. 1H
NMR (300 MHz, CDCl3):
ArH), 7.43 (m, 3H, ArH and Hpyrrole), 3.78 (s, 3H, COOCH3). 13C NMR
(100 MHz, acetone-d6): = 174.8 (q, J = 34.0 Hz), 160.0, 143.6,
d = 10.6 (br s, 1H, NH), 7.57 (d, 2H, J = 6.6 Hz,
d
135.3, 131.4, 128.6, 128.1, 124.3, 117.3 (q, J = 4.0 Hz), 116.9
(q, J = 290.0 Hz), 112.6, 51.3. 19F NMR (282 MHz, CDCl3):
d
= À73.8 (s). ESI-MS: m/z [M+H]+ = 332:334 = 3:1. HRMS: m/z
[M]+ calcd. for C14H9N1O3Cl1F3: 331.0223; found: 331.0220.
4.1. General procedure
4.1.5. Methyl 5-(4-fluorophenyl)-4-(2,2,2-trifluoroacetyl)-1H-
pyrrole-2-carboxylate 3e
Colorless crystals. Mp = 189–190 8C. FTIR (KBr) cmÀ1: 3354,
2968, 1713, 1681, 1570, 90, 843, 761, 736. 1H NMR (300 MHz,
The
a
-imino esters were prepared following the literature
procedure [5a].
To a single-necked flask containing THF (15 mL) was added 4-
ethoxy-1,1,1-trifluorobut-3-en-2-one 1 (504 mg, 3 mmol), corre-
sponding N-alkylidene 2-amino ester 2 (3 mmol), lithium bromide
hydrate (315 mg, 3 mmol) and triethylamine (303 mg, 3 mmol) in
one portion at room temperature. When the reaction was
completed monitored by TLC, the reaction was quenched by
saturated NH4Cl (15 mL) and extracted by ethyl ether (30 mL Â 3),
and the organic layer was dried over anhydrous Na2SO4. After
removal of the solvent under reduced pressure, the residue was
purified by flash chromatography on silica gel (ethyl acetate–n-
hexane, 1:5) to afford 3.
CDCl3):
7.44 (s, 1H, Hpyrrole), 7.16 (t, 2H, J = 8.1 Hz, ArH), 3.83 (s, 3H,
COOCH3). 19F NMR (282 MHz, CDCl3):
110.0 (t, 1F, J = 8.5 Hz, ArF). ESI-MS: m/z (%) = 315 (M+, 42), 284 (6),
246 (34), 214 (100), 158 (26). Anal. Calcd. for C14H9F4NO3: C, 53.34;
H, 2.88; N, 4.44. Found: C, 53.50; H, 2.92; N, 4.42.
d = 10.17 (br s, 1H, NH), 7.63 (dd, 2H, J = 5.7, 3.0 Hz, ArH),
d
= À73.9 (s, 3F, CF3CO),
Structural parameters for 3e: C14H9F4NO3, yellow block, crystal
dimension 0.26 mm  0.22 mm  0.15 mm, monoclinic, space
˚
˚
group P2(1)/n, a = 13.355 (2) A, b = 7.6243 (14) A, c = 13.642
3
˚
˚
(2) A,
a
= 90.008,
b
= 109.211 (2)8,
(Mo-Ka) = 0.71073 A. CCDC reference number
g
= 90.008, V = 1311.7 (4) A ,
Dc = 1.596 Mg/m3,
l
˚
748896.
4.1.1. Methyl 5-phenyl-4-(2,2,2-trifluoroacetyl)-1H-pyrrole-2-
carboxylate 3a
4.1.6. Methyl 5-(2-fluorophenyl)-4-(2,2,2-trifluoroacetyl)-1H-
pyrrole-2-carboxylate 3f
Colorless crystals. Mp = 183 8C. FTIR (KBr) cmÀ1: 3260, 1691,
1567, 1462, 1211, 1137, 895, 762, 695. 1H NMR (300 MHz, CDCl3):
Colorless crystals. Mp = 170 8C. FTIR (KBr) cmÀ1: 3248, 2958,
1700, 1620, 1572, 1005, 900, 801, 759, 677. 1H NMR (300 MHz,
d
= 9.96 (br s, 1H, NH), 7.64–7.61 (m, 2H, ArH), 7.49–7.45 (m, 4H,
ArH and Hpyrrole), 3.86 (s, 3H, COOCH3). 13C NMR (75 MHz, CDCl3):
= 175.6 (q, J = 34.0 Hz), 161.0, 144.6, 130.2, 129.6, 129.1, 128.5,
CDCl3):
7.37–7.29 (m, 2H, ArH), 3.86 (s, 3H, COOCH3). 13C NMR (100 MHz,
acetone-d6): 175.1 (q, J = 35.0 Hz), 160.1 (d, J = 247.0 Hz), 160.2,
d = 10.73 (br s, 1H, NH), 7.67–7.54 (m, 3H, ArH and Hpyrrole),
d
123.2, 118.1 (q, J = 4.0 Hz), 116.7 (q, J = 290.0 Hz), 114.4, 52.2. 19F
d
NMR (282 MHz, CDCl3):
m/z [M+NH4]+ = 315, m/z [M+Na]+ = 320. HRMS (ESI): m/z calcd. for
d
= À73.7 (s). ESI-MS: m/z [M+H]+ = 298,
137.7, 132.1 (d, J = 9.0 Hz), 131.8, 124.6, 124.2 (d, J = 3.0 Hz), 118.2
(d, J = 15.0 Hz), 117.3, 116.7 (q, J = 289.0 Hz), 116.4 (q, J = 4.0 Hz),
C
14H10F3N1O3 [M+Na]: 320.0505; found: 320.0504.
115.6 (d, J = 22.0 Hz), 51.7. 19F NMR (282 MHz, CDCl3):
d
= À74.2 (s,
3F, CF3CO), À113.3 (s, 1F, ArF). ESI-MS: m/z (%) = 315 (M+, 36), 284
(6), 214 (100), 158 (26). HRMS: m/z [M]+ calcd. for C14H9N1O3F4:
315.0519; found: 315.0515.
4.1.2. Methyl 5-(4-methoxyphenyl)-4-(2,2,2-trifluoroacetyl)-1H-
pyrrole-2-carboxylate 3b
Colorless crystals. Mp = 171–172 8C. FTIR (KBr) cmÀ1: 3280,
2444, 1746, 1689, 1611, 1545, 1442, 892, 758, 734. 1H NMR
4.1.7. Methyl 5-(3-fluorophenyl)-4-(2,2,2-trifluoroacetyl)-1H-
pyrrole-2-carboxylate 3g
(300 MHz, CDCl3):
d = 9.65 (br s, 1H, NH), 7.60 (d, 2H, J = 9.0 Hz,
ArH), 7.44 (s, 1H, Hpyrrole), 6.99 (d, 2H, J = 9.0 Hz, ArH), 3.90 (s, 3H,
Ar–OCH3), 3.87 (s, 3H, COOCH3). 13C NMR (75 MHz, CDCl3):
Colorless crystals. FTIR (KBr) cmÀ1: 3262, 2964, 1933, 1719,
1570, 902, 786, 786, 643, 603. 1H NMR (300 MHz, CDCl3):
d = 10.74
d
= 174.6 (q, J = 33.0 Hz), 161.1, 160.1, 145.3, 131.2, 123.7, 121.9,
(br s, 1H, NH), 7.46–7.39 (m, 3H, ArH), 7.36 (s, 1H, Hpyrrole), 7.19–7.14
(m, 1H, ArH), 3.77 (s, 3H, COOCH3). 13C NMR (100 MHz, acetone-d6):
117.3 (q, J = 4.0 Hz), 117.1 (q, J = 290.0 Hz), 113.4, 113.2, 54.9, 51.2.

Y. Xin et al. / Journal of Fluorine Chemistry 131 (2010) 642–645
645
d
= 174.9 (q, J = 36.0 Hz), 162.2 (d, J = 242.0 Hz), 159.9, 143.2, 132.0
308 (100), 183 (88), 119 (35), 91 (12). HRMS: m/z [M]+ calcd. for
C16H15N2O3F3: 340.1035; found: 340.1039.
(d, J = 9.0 Hz), 129.9 (d, J = 8.0 Hz), 125.8 (d, J = 3.0 Hz), 124.4, 117.2
(q, J = 4.0 Hz), 116.7 (q, J = 290.0 Hz), 116.6 (d, J = 47.0 Hz), 116.5 (d,
J = 3.0 Hz), 114.0, 51.3. 19F NMR (282 MHz, CDCl3):
CF3CO), À112.7 (s, 1F, ArF). ESI-MS: m/z [M+H]+ = 316, m/z
[M+NH4]+ = 333. HRMS: m/z [M]+ calcd. for C14H9N2O3F4:
315.0519; found: 315.0521.
d
= À73.9 (s, 3F,
Acknowledgements
This work is financially supported by the National Natural
Science Foundation of China (NNSFC) (Nos. 20532040 and
20972178). We express our gratitude to Professor Yuepeng Cai
from South China Normal University for his help on the single
crystal X-ray diffraction analysis.
4.1.8. Methyl 4-(2,2,2-trifluoroacetyl)-5-(4-
(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxylate 3h
Colorless crystals. Mp = 181–182 8C. FTIR (KBr) cmÀ1: 3346,
2968, 1966, 1716, 1678, 1453, 1289, 917, 845, 760, 663. 1H NMR
(300 MHz, CDCl3):
and Hpyrrole), 7.47–7.46 (m, 1H, ArH), 3.72 (s, 3H, COOCH3). 13C
NMR (100 MHz, acetone-d6): 175.0 (q, J = 34 Hz), 159.9, 142.9,
References
d = 10.71 (br s, 1H, NH), 7.76–7.73 (m, 4H, ArH
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d
133.9, 130.8 (q, J = 32 Hz), 130.6, 124.3 (q, J = 270 Hz), 124.8 (q,
J = 4 Hz), 124.7, 117.8 (q, J = 290 Hz), 117.2 (q, J = 4 Hz), 114.3, 51.4.
19F NMR (282 MHz, CDCl3):
d
= À63.4 (s, 3F, ArCF3), À73.9 (s, 3F,
CF3CO). ESI-MS: m/z [M+H]+ = 366, m/z [M+NH4]+ = 383. HRMS: m/
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trifluoroacetyl)-1H-pyrrole-2-carboxylate 3i
Light yellow crystals. Mp = 208–209 8C FTIR (KBr) cmÀ1: 3276,
2955, 1687, 1610, 1568, 896, 824, 770, 733. 1H NMR (300 MHz,
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CDCl3):
1H, Hpyrrole), 6.75 (d, 2H, J = 8.7 Hz, ArH), 3.89 (s, 3H, COOCH3), 3.04
(s, 6H, N(CH3)2). 13C NMR (75 MHz, CDCl3):
= 175.2 (q,
d = 9.61 (br s, 1H, NH), 7.57 (d, 2H, J = 8.7 Hz, ArH), 7.42 (s,
d
J = 34.0 Hz), 161.2, 151.3, 150.0, 130.2, 117.1 (q, J = 284.0 Hz),
122.3, 118.5 (q, J = 12.0 Hz), 116.8, 113.4, 111.6, 52.1, 40.2. 19F NMR
(282 MHz, CDCl3):
d
= À73.44 (s). ESI-MS: m/z (%) = 340 (M+, 62),