One-Pot Metal-Free Cascade Synthesis of 2-(Perfluoroalkyl)pyrroles

Article abstract of DOI:10.1002/ejoc.201501010

An efficient synthesis of 2-(perfluoroalkyl)pyrroles that employs a sequential one-pot three-component reaction between substituted ω-bromoacetophenones, anilines, and methyl perfluoroalk-2-ynoates has been developed. This transition-metal-free cascade pr

Full text of DOI:10.1002/ejoc.201501010

FULL PAPER
DOI: 10.1002/ejoc.201501010
One-Pot Metal-Free Cascade Synthesis of 2-(Perfluoroalkyl)pyrroles
Xuechun Sun,[a][‡] Jing Han,[a][‡] Jie Chen,[a] Hongmei Deng,[b] Min Shao,[b] Hui Zhang,*[a,b]
and Weiguo Cao*[a,c,d]
Keywords: Synthetic methods / Nitrogen heterocycles / Fluorine / Domino reactions / Regioselectivity
An efficient synthesis of 2-(perfluoroalkyl)pyrroles that em-
transition-metal-free cascade process provides a practical
ploys a sequential one-pot three-component reaction be- way to construct perfluoroalkylated pyrroles in moderate to
tween substituted ω-bromoacetophenones, anilines, and
good yields.
methyl perfluoroalk-2-ynoates has been developed. This
ported a one-pot cascade synthesis for polysubstituted
pyrroles. Under metal-free conditions in polyethylene glycol
400 (PEG-400) and water in the presence of β-cyclodextrin,
they utilized a variety of phenacyl bromides and different
anilines with dialkyl acetylenedicarboxylates (symmetrical
alkynes).[7]
Enlightened by their elegant results and as a continua-
tion of our research of the synthesis of perfluoalkylated het-
erocycles,[8] we herein report the one-pot metal-free synthe-
sis of perfluoalkylated pyrroles by using methyl perfluoro-
alk-2-ynoates (unsymmetrical alkynes) as fluorinated build-
ing blocks. This protocol is mild, efficient, and regioselec-
tive and affords a variety of 2-(perfluoroalkyl)pyrroles.
Introduction
Many pharmaceutical compounds and natural products
that contain a perfluoroalkylated pyrrole moiety have been
found to exhibit significant insecticidal and medicinal ac-
tivities, including the insecticide chlorfenapyr, general anes-
thesia inducers, and antitumor compounds.[1] It is well es-
tablished that the these qualities result from the unique
physical and chemical properties of the fluorine atom.[2]
A few successful synthetic methods have recently been
developed for the construction of trifluoromethyl-substi-
tuted pyrroles.[3] Despite these advances, however, most are
limited with respect to the regioselectivity of the reaction
and the need for stoichiometric amounts of catalysts, pre-
cious transition metals, multistep synthetic operations, and
harsh reaction conditions.[4] Furthermore, transition metals
result in heavy-metal contamination of the products, which,
complicates any purification for pharmaceutical applica-
tions. In this regard, the development of transition-metal-
free, direct, and regioselective methods that employ readily
available substrates is highly desirable.[5]
Results and Discussion
Initially, we selected ω-bromoacetophenone (1a), aniline
(2a), and methyl 4,4,4-trifluorobut-2-ynoate (3a) to investi-
gate the synthesis of 2-perfluoroalkylated pyrroles under
the reaction conditions employed by Nagarapu or Nages-
war (Scheme 1). In both cases, only a complex mixture was
obtained, and none of the desired product was isolated.
Further experiments were carried out to probe the mecha-
nism of this one-pot transformation. 1-Phenyl-2-(phen-
ylamino)ethanone (5), which was generated from 1a and 2a
in the presence of NaHCO3, readily underwent a reaction
with 3a in dimethyl sulfoxide (DMSO) at room temperature
for 20 h to afford methyl 1,4-diphenyl-2-(trifluoromethyl)-
1H-pyrrole-3-carboxylate (4a) in 86% yield [Equation (1)].
In contrast, no desired product was detected from the reac-
tion of ester 9 and ω-bromoacetophenone (1a), which was
performed in DMSO using the same base [Equation (2)].
Gratifyingly, when 1a, 2a, and 3a were subjected to a one-
pot two-step cascade process, the expected product was de-
livered in moderate yield [Equation (3)].
Cascade reactions are synthetically efficient processes
that are used for the construction of complex molecules.[6]
Nagarapu and Nageswar employed this approach and re-
[a] Department of Chemistry, Innovative Drug Research Center,
Shanghai University,
Shanghai 200444, P. R. China
E-mail: wgcao@staff.shu.edu.cn
yehao7171@shu.edu.cn
http://www.shu.edu.cn
[b] Instrumental Analysis and Research Center, Shanghai
University,
Shanghai 200444, P. R. China
[c] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
[d] Key Laboratory of Organofluorine Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
[‡] With equal contribution to this work
Supporting Information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201501010.
On the basis of the above results, the sequential transfor-
mation is proposed to involve: (i) a nucleophilic substitu-
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7086–7090

One-Pot Metal-Free Cascade Synthesis of 2-(Perfluoroalkyl)pyrroles
Scheme 1. One-pot synthesis under the reaction conditions employed by Nagarapu or Nageswar (β-CD = β-cyclodextrin).
(1)
(2)
(3)
Scheme 2. Possible reaction pathway for one-pot two-step cascade reaction.
tion of 1a with aniline (2a) to generate 5, (ii) a subsequent (Table 1). A series of organic and inorganic bases were ex-
Michael addition of 5 and 3a to give intermediate 6, (iii) an amined, but only NaHCO3 produced the best result
intramolecular cyclization that is driven by the electron-rich (Table 1, Entry 1). Upon examination, it appeared that the
amino group of 6,[9] and (iv) the dehydration of 7 to afford reaction was sensitive to the solvent medium. Among the
8 followed by deprotonation and aromatization to give 2- various solvents examined, only DMSO was practical for
trifluoromethyl pyrrole 4a (Scheme 2).
this transformation. Experiments performed in other sol-
To improve the yield of the one-pot two-step cascade se- vents resulted in recovered starting material or only a trace
quence, the reaction of 1a, 2a, and 3a was chosen as a amount of the desired product (Table 1, Entry 1 vs. En-
model to screen for the optimum reaction conditions tries 9–15). The influence of the amount of base was also
Eur. J. Org. Chem. 2015, 7086–7090
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FULL PAPER
Table 1. Screening for optimum reaction conditions.[a]
Entry
Solvent
Base
Mole ratio [1a/2a/3a/base]
Temperatur [°C][b] Time [h][c]
Yield [%][d]
1
2
3
4
5
6
7
8
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DCM[e]
CH3CN
THF[e]
NaHCO3
DIPEA[e]
Et3N
1:1.2:1.2:0.5
1:1.2:1.2:0.5
1:1.2:1.2:0.5
1:1.2:1.2:0.5
1:1.2:1.2:0.5
1:1.2:1.2:0.5
1:1.2:1.2:0.5
1:1.2:1.2:0.5
1:1.2:1.2:0.5
1:1.2:1.2:0.5
1:1.2:1.2:0.5
1:1.2:1.2:0.5
1:1.2:1.2:0.5
1:1.2:1.2:0.5
1:1.2:1.2:0.5
1:1.2:1.2:0.1
1:1.2:1.2:1.0
1:1.2:1.2:1.5
1:1.2:1.2:1.0
1:1.2:1.2:1.0
1:1.2:1.2:1.0
1:1.2:1.2:1.0
1:1.2:1.2:1.0
1:1.2:1.2:1.0
1:1.2:1.5:1.0
1:1.2:2.0:1.0
1:1.2:2.5:1.0
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
40
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
8
52
46
23
50
5
12
27
34
12
0
K2CO3
DABCO[e]
pyridine
NaOH
K3PO4
9
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
11
8
0
toluene
EtOH
DMF[e]
1,4-dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
15
11
14
57
41
44
57
62
69
61
69
73
89
74
60
80
100
120
100
100
100
100
8
8
8
[a] Reagents and conditions: ω-bromoacetophenone (1a), aniline (2a), and base were stirred in solvent (10 mL) at room temperature for
4 h, and then methyl 4,4,4-trifluorobut-2-ynoate (3a) was added. The mixture was stirred at the temperature reported above for another
8 or 20 h. [b] Reaction temperature for the second step. [c] Reaction time for the second step. [d] Isolated yield. [e] DIPEA = N,N-
diisopropylethylamine, DABCO = 1,4-diazabicyclo[2.2.2]octane, DCM = dichloromethane, THF = tetrahydrofuran, DMF = N,N-dimeth-
ylformamide.
investigated, and we determined that 1.0 equiv. of base was (e.g., Cl, NO2, or F) attached to the benzene ring of the
most effective (Table 1, Entry 17). The reaction temperature aniline decreased the nucleophilicity of intermediate 5,
and time for the second step had a clear effect on the reac- which resulted in the lower yields of 4 (Table 2, Entries 11,
tion, and carrying out this step at 100 °C for 8 h afforded 14, and 15). The yield remained high when the R2 group
the best results. In addition, the yield of 4a increased to a was either meta- or para-substituted (Table 2, Entries 7 and
remarkable 89% when 2.0 equiv of 3a were employed. 8). However, an ortho-substituted R2 group afforded a
(Table 1, Entry 26 vs. Entries 24, 25, and 27). Therefore, we much lower yield of the desired product (Table 2, Entry 6).
concluded that the optimum reaction conditions for the In addition, aliphatic amines failed to give the correspond-
preparation of 4a involved a metal-free process in DMSO ing products in satisfying yields under the standard reaction
with a mole ratio (1a/2a/3a/base) of 1:1.2:2.0:1.0 along with conditions (Table 2, Entries 16 and 17). The lower yields
conducting the second step at 100 °C for 8 h.
that resulted from aliphatic amines might be caused by its
Having established the optimum reaction conditions, the reaction with 3a to form 9. However, dimethyl-substituted
scope of substrates for our protocol was explored (Table 2). anilines were successfully employed as substrates to gener-
ω-Bromoacetophenone 1 that was either unsubstituted or ate 4l and 4m in 76 and 61% yield, respectively (Table 2,
para-substituted with electron-donating (e.g., Me and OMe) Entries 12 and 13). Interestingly, the length of the per-
and electron-withdrawing (e.g., Cl and NO2) groups af- fluoroalkyl carbon chain in compound 3 did not influence
forded the corresponding 2-(trifluoromethyl)pyrroles 4a–4e the efficiency of the transformation. When RF was C2F5
in appreciable yields (76–91%, Table 2, Entries 1–5). How- or n-C3F7, the reaction proceeded smoothly and gave the
ever, a change to the aniline substrate showed that the reac- corresponding pyrroles in 84 and 71% yield, respectively
tion was sensitive to the electronic nature of its aromatic (Table 2, Entries 18 and 19). The structures of compounds
ring, that is, the R2 group. An electron-withdrawing group 4 were then confirmed by 1H, 13C, and 19F NMR spec-
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One-Pot Metal-Free Cascade Synthesis of 2-(Perfluoroalkyl)pyrroles
Table 2. One-pot cascade protocol for the synthesis of 2-(perfluoroalkyl)pyrroles 4.[a]
Entry
R1
R2
RF
Product 4
4a
Yield [%][b]
1
2
3
4
5
6
7
8
H
Ph
Ph
Ph
Ph
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
C2F5
n-C3F7
89
88
91
81
76
34
92
89
51
90
23
76
61
0
4-Me
4-OMe
4-Cl
4-NO2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
Ph
2-MeC6H4
3-MeC6H4
4-MeC6H4
3-MeOC6H4
4-MeOC6H4
4-ClC6H4
2,4-(CH3)2C6H3
2,5-(CH3)2C6H3
4-NO2C6H3
3-Cl-4-FC6H3
benzyl
9
10
11
12
13
14
15
16
17
18
19
23
18
34
84
71
cyclopentyl
4-MeOC6H4
4-MeOC6H4
[a] Reagents and conditions: substituted ω-bromoacetophenone 1 (1.0 mmol), primary amine 2 (1.2 mmol), and NaHCO3 (1.0 mmol)
were stirred in DMSO (10 mL) at room temperature for 4 h, and then methyl perfluoroalk-2-ynoate 3 (2.0 mmol) was added. The mixture
was stirred at 100 °C for another 8 h. [b] Isolated yield.
troscopy as well as the MS, HRMS, and IR spectra. Fur- ular nucleophilic substitution, a Michael addition, and an
ther confirmation of the product structure was achieved by intramolecular cyclization reaction sequence. This is the
X-ray crystal structure analysis of compound 4b (Fig- first one-pot example of the synthesis of perfluoroalkylated
ure 1).[10] X-Ray crystallography of 4b demonstrates that pyrroles that uses methyl perfluoroalk-2-ynoates as the
the ester unit is attached at the 3-position of the pyrrole, fluorinated building block. This is an attractive complemen-
and the RF group is attached at the 2-position.
tary method to access perfluoroalkylated pyrroles. The easy
and efficient strategy should attract much attention from
both academic and industrial researchers.
Experimental Section
General Methods: All reagents and solvents were purchased from
commercial sources and used without further purification with the
exception of the methyl perfluoroalk-2-ynoates 3, which were pre-
pared according to a reported procedure.[11] Melting points were
recorded on a WRS-1 instrument. The 1H, 19F, and 13C NMR spec-
troscopic data were recorded with a Bruker DRX-500 MHz spec-
trometer. All chemical shifts were reported in parts per million
downfield (positive) of the standard, which was C6F6 for 19F NMR
1
and TMS for the H and 13C NMR. IR spectra were obtained on
an AVATAR370 FTIR spectrometer. LRMS (lower resolution mass
spectra) and HRMS were obtained on Apex-III and Bruker Dal-
tonics APEXIII 7.0 TESALA FTMS instruments, respectively. X-
Ray crystal structure analysis was performed on a Bruker Smart
Apex2 CCD spectrometer. Isolate yields are reported, and the pu-
Figure 1. ORTEP diagram of compound 4b.
Conclusions
1
rity of the compounds was determined by H NMR spectroscopy.
A new and useful metal-free method for the synthesis
of 2-(perfluoroalkyl)pyrrole derivatives has been developed
that uses inexpensive and readily available starting materials
and affords the corresponding products in moderate to
Preparation for 5 from 1a and 2a:[12] A solution of ω-bromoaceto-
phenone (1a, 1.0 mmol), aniline (2a, 1.2 mmol), and NaHCO3
(1.0 mmol) in DMSO (10 mL) was stirred at room temperature for
4 h. After the usual workup, compound 5 was isolated by column
good yields. The reaction pathway includes an intermolec- chromatography on silica gel to give 5 in 93% yield.
Eur. J. Org. Chem. 2015, 7086–7090
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General Procedure for Preparation of 2-(Perfluoroalkyl)pyrroles 4:
A mixture of substituted ω-bromoacetophenone 1 (1.0 mmol), pri-
mary amine 2 (1.2 mmol), and NaHCO3 (1.0 mmol) was stirred in
DMSO (10 mL) at room temperature for 4 h, and methyl per-
fluoroalk-2-ynoate 3 (2.0 mmol) was then added. The reaction mix-
ture was stirred at 100 °C for an additional 8 h and was then
quenched with water. The mixture was extracted with ethyl acetate
(3ϫ 5 mL). The combined extracts were washed with brine, dried
with anhydrous Na2SO4, and filtered. The filtrate was concen-
trated, and the residue was purified by flash chromatography on a
silica gel (petroleum ether/ethyl acetate) to give 4. All of the new
compounds were characterized by 1H, 19F and 13C NMR spec-
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Acknowledgments
The authors are grateful to the National Natural Science Founda-
tion of China (NSFC) (grant number 21272152) and the Science
and Technology Commission of Shanghai Municipality for their
financial support.
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4b: a = 12.0055(14) Å, b = 15.3801(17) Å, c = 9.6624(11) Å, α
= 90°, β = 97.047(2)°, γ = 90°, monoclinic, space group: Cc.
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Received: August 1, 2015
Published Online: October 2, 2015
7090
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Eur. J. Org. Chem. 2015, 7086–7090