Perfluoroalkyl-substituted thiophenes and pyrroles from donor-acceptor cyclopropanes and heterocumulenes: Synthesis and exploration of their reactivity

Article abstract of DOI:10.1021/jo500534t

A methyl 2-trifluoromethyl-2-siloxycyclopropanecarboxylate was smoothly deprotonated by lithium diisopropylamide and reacted with carbon disulfide and methyl iodide to afford a dihydrothiophene derivative. The crucial step in this transformation is a ring-expansion of the anionic intermediate by [1,3] sigmatropic rearrangement. The dihydrothiophene was converted into the corresponding 5-trifluoromethylthiophene derivative by phosphoryl chloride in refluxing pyridine. A one-pot version of the reaction sequence efficiently provided the thiophene in good yield. Analogously, aryl- and alkyl-substituted isothiocyanates instead of carbon disulfide afforded the corresponding trifluoromethyl-substituted pyrroles in moderate to very good overall yields. Explorative reactivity studies with the methylthio-substituted thiophene and pyrrole derivatives demonstrate that they are precursors of a range of interesting trifluoromethyl-substituted products, including new members from the thienothiophene and thienopyrrole class.

Full text of DOI:10.1021/jo500534t

Article
pubs.acs.org/joc
Perfluoroalkyl-Substituted Thiophenes and Pyrroles from Donor−
Acceptor Cyclopropanes and Heterocumulenes: Synthesis and
Exploration of their Reactivity
Daniel Gladow and Hans-Ulrich Reissig*
Institut fur Chemie und Biochemie, Freie Universitat Berlin, Takustrasse 3, D-14195 Berlin, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A methyl 2-trifluoromethyl-2-siloxycyclopropanecarboxylate was smoothly deprotonated by lithium diisopropy-
lamide and reacted with carbon disulfide and methyl iodide to afford a dihydrothiophene derivative. The crucial step in this
transformation is a ring-expansion of the anionic intermediate by [1,3] sigmatropic rearrangement. The dihydrothiophene was
converted into the corresponding 5-trifluoromethylthiophene derivative by phosphoryl chloride in refluxing pyridine. A one-pot
version of the reaction sequence efficiently provided the thiophene in good yield. Analogously, aryl- and alkyl-substituted
isothiocyanates instead of carbon disulfide afforded the corresponding trifluoromethyl-substituted pyrroles in moderate to very
good overall yields. Explorative reactivity studies with the methylthio-substituted thiophene and pyrrole derivatives demonstrate
that they are precursors of a range of interesting trifluoromethyl-substituted products, including new members from the
thienothiophene and thienopyrrole class.
small volume, hydrophobicity, and small polarizability of the
fluorine atom and from its very strong bond to carbon atoms.13
The activation of cyclopropane derivatives, strained three-
membered rings, by suitable electron-donating and electron-
withdrawing substituents in a vicinal relationship makes these
compounds valuable building blocks in organic synthesis. After
introducing the concept of donor−acceptor cyclopropanes,14,15
our group and others reported a broad range of interesting
reactions of this class of compounds. Recent efforts were
devoted to [3 + 2] and [3 + 3] cycloadditions; however, many
reactions with nucleophiles, electrophiles, or radicals are also
feasible.16 In this context, Lewis acid mediated cycloadditions of
donor−acceptor cyclopropanes affording five-membered het-
erocycles have been described.17,18
INTRODUCTION
■
In the constantly growing field of heterocyclic compounds,
specifically substituted thiophenes and pyrroles have diverse
biological activities1 and have found frequent applications in
medicine,2 agriculture,3 and material science.4 Prominent
examples are the broad-spectrum insecticide Chlorfenapyr,5
the multitargeted receptor tyrosine kinase (RTK) inhibitor
Sutent,6 and the cholesterol lowering blockbuster drug Lipitor.7
This importance renders the need for new methods for the
synthesis of these heterocycles.8 Traditional reactions for the
preparation of thiophenes are the Fiesselmann, Gewald,
Hinsberg, or Paal−Knorr reactions, whereas pyrroles are
commonly prepared by protocols according to Knorr,
Hantzsch, Piloty−Robinson, Madelung, Bischler−Mohlau,
̈
Nenitzescu, Brunner, and Graebe−Ullmann.9 In recent years,
organosulfur-10 and trifluoromethyl-substituted11 pyrroles and
thiophenes received great attention. It is well-established that
the incorporation of fluorine atoms into organic molecules
leads to new and often superior biological, chemical, and
physical properties that are highly desirable in pharmaceutical,
agrochemical, and materials research and industry.12 This
dramatic influence originates from the high electronegativity,
We demonstrated that deprotonation of alkyl 2-siloxycyclo-
propanecarboxylates and reaction of the generated ester
enolates with carbon disulfide or aryl isothiocyanates provides
substituted thiophene19 or pyrrole20 derivatives in a one-pot
fashion. The crucial step of this transformation was an
Received: March 6, 2014
Published: April 14, 2014
© 2014 American Chemical Society
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Scheme 1. One-Pot Transformations of Alkyl 2-Siloxycyclopropanecarboxylates Yielding Pyrroles and Thiophenes
unexpected ring-enlargement of cyclopropane intermediates A;
this anionic [1,3] sigmatropic rearrangement occurred already
at −78 °C to provide thia- or azacyclopentene derivatives B
(Scheme 1). S-Methylation and subsequent acid-mediated
elimination of trimethylsilanol afforded the aromatic hetero-
cycles. In this context, a theoretical study of [1,3] sigmatropic
rearrangements of vinylcyclopropanes and heteroanalogues was
published.21 In addition, rearrangements of substituted donor−
acceptor cyclopropanes forming furan,22a,b thiophene,22c as well
as pyrrole22d,e derivatives were reported and the susceptibility
of certain donor−acceptor cyclopropanes for rearrangements
was studied.22f Examples of ring-expansion of donor−acceptor
cyclopropanes affording other heterocycles were also re-
ported.23
Scheme 2. Preparation of Dihydrothiophene 2 and
Subsequent Elimination Affording Trifluoromethyl-
Substituted Thiophene Derivative 5
Although perfluoroalkyl- and perfluoroaryl-substituted silyl
enol ethers are considerably less nucleophilic,24a the corre-
sponding donor−acceptor cyclopropanes were easily accessible
by rhodium-catalyzed reactions with methyl diazoacetate.24b
Their subsequent deprotonation with lithium diisopropylamide
also proceeded smoothly, leading, after C-1 alkylation with alkyl
halides, to substituted derivatives. The ring-opening of these
cyclopropanes, either in situ or directly, afforded valuable γ-oxo
esters that were isolated or immediately converted into
perfluoroalkylated or perfluoroarylated lactones and pyridazi-
nones in good yields.24b,c We envisioned that heterocycles with
fluorinated substituents should be accessible by reaction of the
corresponding ester enolates with appropriate heterocumu-
lenes, analogously to the transformations depicted in Scheme 1,
if the crucial ring-enlargement also proceeds in the presence of
the strongly electron-withdrawing perfluorinated moieties.
These substituents could also hamper the final elimination of
trimethylsilanol, and hence, it was not obvious whether
conditions to overcome these issues could be established.
RESULTS AND DISCUSSION
■
First, we turned our attention to the preparation of thiophene
derivatives by deprotonation of 2-trifluoromethyl-substituted
siloxycyclopropane 1 and reaction with carbon disulfide.
Deprotonation of 1 with lithium diisopropylamide and
sequential addition of carbon disulfide and methyl iodide
afforded the desired dihydrothiophene 2 in 41% yield (Scheme
2). Along with 2, the corresponding desilylated thiophene
derivative 3 was obtained in approximately 30% yield, but it
could not be easily purified. We, therefore, explored conditions
to convert dihydrothiophene 2 into desilylated compound 3 or
to induce elimination to compound 5. Treatment of 2 with
tetra-n-butylammonium fluoride afforded a complex product
mixture. However, trifluoroacetic acid smoothly desilylated
dihydrothiophene derivative 2 and provided the corresponding
5-hydroxy-substituted compound 3 in excellent yield. On the
other hand, under harsh conditions employing p-toluenesul-
fonic acid monohydrate at 90 °C, the thioacetal moiety of 2 was
hydrolyzed to give thiolactone 4 in 51% yield as a mixture of
diastereomers. Moreover, elimination to thiophene 5 did not
occur even if the reaction of 2 with trifluoroacetic acid was
performed in refluxing toluene. This process seems to require
harsher conditions compared to the examples published
before.19 Gratifyingly, phosphoryl chloride in boiling pyridine25
enabled the elimination and converted compound 2 into the
desired thiophene derivative 5 in quantitative yield. At lower
temperatures or with Eaton‘s reagent (methanesulfonic acid/
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Scheme 3. Influence of Other Perfluorinated Substituents of Siloxycyclopropanes on the Preparation of Thiophene Derivatives
P2O5),26 no dehydration occurred. After having established
Scheme 4. Selective Oxidations of Methylthio-Substituted
these conditions, we performed all four steps in a one-pot
fashion and obtained thiophene derivative 5 in 62% overall
yield.
Thiophene Derivative 5 to the Corresponding Sulfinyl
Thiophene 11 and Sulfonyl Thiophene 12
Since we could show earlier that perfluoropentyl- and
perfluorophenyl-substituted cyclopropanecarboxylates could
successfully be deprotonated and alkylated,24c we were also
interested in the preparation of thiophene derivatives with these
substituents. When 2-perfluoropentylcyclopropane 6 was
subjected to the optimized one-pot procedure, the desired
thiophene derivative 7 was isolated in 31% yield. Unexpectedly,
the C-alkylated product 8 was also obtained in 10% yield,
although analogous compounds were never detected in the
reactions of trifluoromethyl-substituted siloxycyclopropane 1.
Surprisingly, a complex product mixture was obtained when 2-
perfluorophenylcyclopropane 9 was subjected to the procedure,
and the desired thiophene derivative 10 was not isolated
(Scheme 3). Different conditions during the deprotonation/
addition reaction did not give other results. At the moment, we
can only speculate about the moderate regioselectivity of
alkylation in the case of 6 and the failure of substrate 9 in
providing the expected product.
Scheme 5. Magnesation of Thiophene 11 by a Sulfoxide−
Magnesium Exchange and Subsequent Protonation
The methylthio group of compounds such as 5 and 7 should
allow various transformations leading to new functional groups.
Compounds with a sulfinyl moiety are biologically relevant
compounds27 and have also found various applications in
organic synthesis.28 However, selective oxidation of thio ethers
to sulfoxides is challenging and frequently overoxidation to
sulfones is observed.29 Recently, Xu et al. reported the mild
oxidation of aliphatic and aromatic thio ethers to sulfoxides
using hydrogen peroxide in phenol.30 Applying this method, we
achieved selective oxidation of compound 5 to sulfinyl
thiophene 11 in quantitative yield (Scheme 4). On the other
hand, sulfonyl thiophene 12 was quantitatively generated from
5 by treatment with m-chloroperoxybenzoic acid (mCBPA).
We also note that treatment of thio ether 5 with N-
bromosuccinimide (NBS) in acetic acid also furnished sulfoxide
11 in high yield.31
Sulfoxides undergo facile exchange with Grignard reagents or
alkyllithium reagents, and the resulting organometallic com-
pounds readily react with different electrophiles.32 Treatment
of sulfinyl thiophene 11 with a slight excess of isopropylmag-
nesium chloride for 1 h at −50 °C generated the corresponding
metalated thiophene intermediate that was quenched with
methanol to afford the desulfinated thiophene 13 in 45% yield
(Scheme 5).33
The increased acidity of sulfones compared to sulfoxides
allows smooth deprotonation of these compounds with amide
bases.34 Sulfonyl thiophene 12 was successfully deprotonated
by 2 equiv of lithium diisopropylamide, and ring closure with
the adjacent ester group afforded thienothiophene derivative 14
in 99% yield (Scheme 6). Because of the higher acidity of
product 14 compared to that of precursor 12, 2 equiv of base
was required for complete transformation. To the best of our
knowledge, this procedure represents a novel access to this
scarcely explored compound class.35,36 A first attempt to
introduce an allyl substituent by addition of allyl bromide to the
intermediate carbanion was not successful and gave a complex
product mixture.
Thio ether moieties can act as leaving groups in transition-
metal-catalyzed C−C coupling reactions. First reports by Takei
et al. and Wenkert et al. involved a low-valent nickel catalyst
and Grignard reagents that were later substituted by alkylzinc
reagents.37 Iron- and palladium-catalyzed versions have also
been reported.38 Liebeskind et al. and Guillaumet et al.
reported efficient palladium-catalyzed copper(I)-promoted
cross-couplings of functionalized heteroaromatic thio ethers
with boronic acids and organostannanes.39 We first attempted
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Scheme 6. Preparation of a Thienothiophene Derivative 14 by Deprotonation and Cyclization of Sulfonyl Thiophene 12
the Suzuki-type coupling of thiophene 5 with phenylboronic
acid under the reported conditions (cat. Pd(dba)2, trifur-
ylphosphane, copper(I) 2-thiophenecarboxylate (CuTC), THF,
50 °C, 18 h), but the reaction was very sluggish and the desired
coupling product 15 was isolated in only 10% yield.40 We,
therefore, turned our attention to a Stille coupling with
phenyltributylstannane as the reaction partner. Gratifyingly,
under these conditions, 5 was converted into 15 in 81% yield
(Scheme 7); however, to achieve full conversion, the stannane
Scheme 8. Synthesis of Trifluoromethyl-Substituted γ-
Lactam 16
Scheme 7. Copper(I)-Mediated Stille-type Cross-Coupling
of Thio Ether 5 with Phenyltributyltin Leading to Thiophene
Derivative 15
Whereas the experiments with the two isocyanates indicate
that the scope of this reaction is possibly limited,
isothiocyanates behaved reliably as already shown in our
studies with siloxycyclopropanes without perfluorinated sub-
stituents.20 Deprotonation of compound 1 and successive
treatment with phenyl isothiocyanate, methyl iodide, and
pyridine/phosphoryl chloride afforded the desired pyrrole
derivative 17a in very good yield of 85% (Scheme 9). We
investigated the substrate scope and performed the reactions
with 3,5-bis(trifluoromethyl)phenyl and 4-methoxyphenyl
isothiocyanate. The corresponding pyrroles 17b and 17c were
isolated in 45% and 44% yield, respectively. It is not clear
whether the electronic nature of the aryl substituents really
influences the efficacies of the transformation. Interestingly,
ethyl isothiocyanate provided a 87:13 mixture of the desired S-
methylated pyrrole derivative 17d and the C-alkylated
thiolactam 18 in 74% yield. Cyclopropyl isothiocyanate
afforded pyrrole 17e in 63% yield, but with t-butyl
isothiocyanate as electrophile, the expected pyrrole 17f was
not formed, possibly due to the steric bulk of the t-butyl group.
As observed with the thiophene derivatives, the thio ether
moiety of pyrrole 17a was quantitatively oxidized with
hydrogen peroxide to give the corresponding sulfinyl pyrrole
19 or with m-chloroperoxybenzoic acid the sulfonyl pyrrole 20
(Scheme 10).45
We also investigated the metalation of pyrrole 19 by
sulfoxide−magnesium exchange. Thus, treatment of sulfinyl
pyrrole 19 with isopropylmagnesium chloride and protonation
with methanol afforded desulfinated pyrrole 21 in 54% yield
(Scheme 11).
Sulfonyl pyrrole 20 was successfully deprotonated by 2 equiv
of lithium diisopropylamide, and ring closure with the adjacent
ester group afforded thienopyrrole derivative 22 in very good
yield (Scheme 12). To the best of our knowledge, there is only
one literature report for the preparation of compounds with a
similar SO2 moiety, which provide access to unique functional
materials.46
and the catalysts had to be added in two portions to the
reaction mixture (for details, see the Experimental Section).
The transformation was not accurately reproducible with yields
ranging between 40% and 80%. The efficacy of the cross-
coupling of 5 seems to be strongly dependent on the exact
reaction conditions and the addition of reagents.41,42 This
example demonstrates that coupling reactions of thiophenes
such as 5 should provide access to a variety of new
compounds.43
Consequently, we were also interested in the analogous
reactions of trifluoromethyl-substituted siloxycyclopropane 1
with other heterocumulenes in order to generate different
heterocycles. Pyrrole derivatives can be obtained by Lewis acid
promoted [3 + 2] cycloadditions of donor−acceptor cyclo-
propanes with nitriles.18 We, therefore, investigated the
reaction of cyclopropane 1 and benzonitrile under different
reaction conditions, employing trimethylsilyl triflate or tin
tetrachloride as Lewis acids. However, either complex product
mixtures were obtained or the corresponding γ-oxo ester
resulting from simple acid-induced ring-opening of 1 was
isolated. Thus, we employed the route described in Scheme 1
and investigated the additions of enolates derived from
cyclopropane 1 to nitrogen-containing heterocumulenes. In
the reaction of deprotonated 1 with dicyclohexyl carbodiimide,
followed by addition of methyl iodide, no pyrrole derivative was
identified, and the analogous reaction employing ethyl
isocyanate afforded a complex product mixture.44 Gratifyingly,
deprotonation of 1, followed by addition of phenyl isocyanate
and methyl iodide, selectively afforded the C-methylated γ-
lactam derivative 16 in 50% yield (Scheme 8). The expected O-
methylated compound could not be detected; methylation of
the anionic intermediate derived from 1 and the isocyanate with
methyl triflate did not influence the regioselectivity and
afforded 16 in 25% yield.
SUMMARY
■
One-pot procedures for the preparation of perfluoroalkyl-
substituted thiophenes and pyrroles from the corresponding
siloxycyclopropanes were established. Like their nonfluorinated
analogues, ester enolates of 2-perfluoroalkyl-substituted cyclo-
propanes 1 and 6 readily added to carbon disulfide and the
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Scheme 9. Synthesis of Trifluoromethyl-Substituted Pyrrole Derivatives 17 and 18 by Variation of the Isothiocyanate
Scheme 10. Selective Oxidations of Trifluoromethyl-
Substituted Pyrrole Derivative 17a to the Corresponding
Sulfinyl Pyrrole 19 and Sulfonyl Pyrrole 20
under forcing conditions. Nevertheless, thiophene derivatives 5
and 7 were obtained in good overall yields, whereas the
perfluorophenyl-substituted cyclopropane 9 did not afford the
corresponding thiophene. Aryl and alkyl isothiocyanates also
proved to be suitable electrophiles, which efficiently afforded 5-
trifluoromethylpyrroles 17a−17e with different substituents at
the nitrogen atom. In exceptional cases, C-methylated instead
of S-methylated isomers were obtained. The reaction of the
enolate of 1 with phenyl isocyanate/methyl iodide afforded
solely the C-methylation product 16.
In explorative fashion, we investigated possible trans-
formations of the prepared methylthio-substituted 5-trifluoro-
methylthiophene and -pyrrole derivatives. Oxidations of the
methylthio moiety selectively produced sulfoxides 11 and 19 or
sulfones 12 and 20 in excellent yields. Sulfoxide−magnesium
exchange reactions furnished desulfinated products 13 and 21.
The sulfones could smoothly be cyclized to obtain
thienothiophene 14 and thienopyrrole 22, both belonging to
scarcely explored classes of compounds. Trifluoromethyl-
substituted thiophene derivative 5 was also coupled with
phenyltributylstannane in a copper(I)-promoted Stille-type
reaction. All of these transformations prove that compounds
such as 5 and 17 allow the preparation of quite a number of
different perfluoroalkyl-substituted heterocycles. In our ap-
proach, simple commercially available fluorinated compounds
are the precursors.47 This method nicely complements the
common strategy for preparing perfluoroalkyl-substituted
heterocycles by the late stage introduction of the appropriate
fluorinated group, frequently by use of organometallic species.48
Scheme 11. Conversion of Compound 19 into Pyrrole 21 by
Sulfoxide−Magnesium Exchange and Subsequent
Protonation
Scheme 12. Preparation of a Thienopyrrole Derivative 22 by
Deprotonation of 20 and Subsequent Cyclization
EXPERIMENTAL SECTION
■
General. Compounds 1, 6, and 9 were prepared according to
literature procedures.24b Diisopropylamine was stored over solid
NaOH for several days before being used; all other reagents were
purchased and used without further purification. All reactions sensitive
to moisture and/or air were carried out under an atmosphere of argon,
and solvents were purified with an MB SPS-800-dry solvent system.
Melting points were determined on a melting point apparatus and are
uncorrected. 1H, 13C, and 19F [frequency calibrated lock with 1 ppm
deviation] NMR spectra were recorded on 250, 400, 500, and 700
MHz instruments in CDCl3 solutions, and chemical shifts (δ) are
reported in parts per million (ppm) referenced to tetramethylsilane or
the internal (NMR) solvent signals. 13C{19F} NMR spectra were
recorded to enable correct assignment. The high-resolution mass
resulting anionic intermediates underwent ring-expansion to
afford the corresponding dihydrothiophenes. Because of the
strong electron-withdrawing effect of the perfluoroalkyl
moieties, dehydration of these intermediates occurred only
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spectra were obtained with an ESI-TOF spectrometer. Silica gel
(0.040−0.063 mm) was used for column chromatography. IR spectra
were recorded on an FT-IR spectrometer.
organic layer was dried with Na2SO4 and concentrated under reduced
pressure to afford 5 (37 mg, quant.) as a yellow solid. mp 58−60 °C;
1H NMR (400 MHz, CDCl3) δ 7.74 (q, JHF = 1.2 Hz, 1H), 3.88 (s,
3H), 2.62 (s, 3H) ppm; 13C NMR (176 MHz, CDCl3) δ 163.0, 156.9,
Methyl 2-(Methylthio)-5-(trifluoromethyl)-5-(trimethyl-
siloxy)-4,5-dihydrothiophene-3-carboxylate (2). A 1 M LDA
solution was freshly prepared: n-BuLi (2.5 M in hexanes, 470 μL, 1.17
mmol) was added at −78 °C to a solution of diisopropylamine (118
mg, 1.17 mmol) in THF (1.20 mL), and the resulting mixture was
stirred for 20 min. A solution of cyclopropane 1 (200 mg, 0.780
mmol) in THF (1 mL) was added, and the reaction mixture was
stirred for 2 h at −78 °C. Carbon disulfide (149 mg, 1.95 mmol) was
added, and stirring was continued for 1 h at −78 °C and for 4 h at 21
°C. After addition of methyl iodide (277 mg, 1.95 mmol), the mixture
was stirred at 21 °C for 16 h, then diluted with Et2O (100 mL) and sat.
aqueous NH4Cl solution (50 mL), and the phases were separated. The
organic layer was washed with brine (30 mL), dried with Na2SO4, and
concentrated under reduced pressure. The crude product was purified
by column chromatography (silica gel, 10−100% AcOEt in hexanes)
to afford 2 (111 mg, 41%) as a yellow oil and an impure sample of 3
131.0 (q, JCF = 3.9 Hz), 126.2 (q, JCF = 39.5 Hz), 125.1, 121.9 (q, JCF
=
269 Hz), 52.0, 18.4 ppm; 19F NMR (376 MHz, CDCl3) δ −55.8 (d,
JFH = 1.2 Hz) ppm; HRMS (ESI-TOF) [M + Na]+ calcd for
C8H7F3NaO2S2 278.9732; found 278.9722; IR (neat) ν 3180−2835
(C−H, C−H), 1710 (CO), 1550, 1450, 1425 (CC), 1295,
1240, 1195, 1150, 1120 (C−F) cm−1. Anal. Calcd for C8H7F3O2S2: C,
37.49; H, 2.75; S, 25.02. Found: C, 37.50; H, 2.79; S, 25.09.
From Cyclopropane 1. A 1 M LDA solution was freshly prepared:
n-BuLi (2.5 M in hexanes, 230 μL, 0.585 mmol) was added at −78 °C
to a solution of diisopropylamine (59 mg, 0.585 mmol) in THF (590
μL), and the resulting mixture was stirred for 20 min. A solution of
cyclopropane 1 (100 mg, 0.390 mmol) in THF (1 mL) was added, and
the reaction mixture was stirred for 2 h at −78 °C. Carbon disulfide
(74 mg, 0.98 mmol) was added, and stirring was continued for 1 h at
−78 °C and for 4 h at 21 °C. After addition of methyl iodide (138 mg,
0.975 mmol), the mixture was stirred at 21 °C for 16 h. The mixture
was diluted with both Et2O (100 mL) and sat. aqueous NH4Cl
solution (100 mL), and the phases were separated. The organic layer
was washed with brine (50 mL), dried with Na2SO4, and concentrated
under reduced pressure. The residue was dissolved in pyridine (3 mL),
POCl3 (420 mg, 2.70 mmol) was added, and the solution was heated
to reflux for 1 h. The heating bath was replaced by an ice bath, and
after dilution with Et2O (10 mL), water (1 mL) was added carefully via
syringe to quench the excess of POCl3. The reaction mixture was
further diluted with Et2O (100 mL), and the soluble parts were
decanted from the remaining black slurry. This ether solution was
washed with aqueous 1 M HCl (100 mL) and brine (50 mL). The
organic layer was dried with Na2SO4 and concentrated under reduced
pressure. The crude product was purified by column chromatography
(silica gel, 5% AcOEt in hexanes) to afford 5 (62 mg, 62%) as a pale
yellow solid. Larger scale experiments with 1−2 g of cyclopropane 1
afforded 5 in yields ranging between 55% and 60%.
Methyl 2-(Methylthio)-5-(perfluoropentyl)thiophene-3-car-
boxylate (7) and Methyl 3-Methyl-5-(perfluoropentyl)-2-thio-
xo-2,3-dihydrothiophene-3-carboxylate (8). A 1 M LDA solution
was freshly prepared: n-BuLi (2.5 M in hexanes, 460 μL, 1.15 mmol)
was added at −78 °C to a solution of diisopropylamine (116 mg, 1.15
mmol) in THF (1.20 mL), and the resulting mixture was stirred for 20
min. A solution of cyclopropane 6 (350 mg, 0.77 mmol) in THF (2
mL) was added, and the reaction mixture was stirred for 2 h at −78
°C. Then, carbon disulfide (88 mg, 1.15 mmol) was added, and stirring
was continued for 1 h at −78 °C and for 4 h at 21 °C. After addition of
methyl iodide (272 mg, 1.92 mmol), the mixture was stirred at 21 °C
for 16 h. The mixture was diluted with both Et2O (100 mL) and sat.
aqueous NH4Cl solution (100 mL), and the phases were separated.
The organic layer was washed with brine (50 mL), dried with Na2SO4,
and concentrated under reduced pressure. The residue was dissolved
in pyridine (5 mL), POCl3 (823 mg, 5.37 mmol) was added, and the
solution was heated to reflux for 1 h. The heating bath was replaced by
an ice bath, and after dilution with Et2O (15 mL), water (2 mL) was
added carefully via syringe to quench the excess of POCl3. The
reaction mixture was further diluted with Et2O (150 mL), and the
soluble parts were decanted from the remaining black slurry. This
ether solution was washed with aqueous 1 M HCl (150 mL) and brine
(50 mL). The organic layer was dried with Na2SO4 and concentrated
under reduced pressure. The crude product was purified by column
chromatography (silica gel, 7% AcOEt in hexanes) to afford 7 (109
mg, 31%) as a brown solid and 8 (32 mg, 10%) as a brown oil.
Analytical Data of 7. mp 90−92 °C; 1H NMR (400 MHz, CDCl3)
δ 7.72 (s, 1H), 3.87 (s, 3H), 2.62 (s, 3H) ppm; 13C NMR (101 MHz,
CDCl3) δ 162.9, 158.0 (t, JCF = 1.3 Hz), 132.7 (t, JCF = 6.0 Hz), 125.6,
124.2 (t, JCF = 29.9 Hz), 117.3 (tq, JCF = 33.1 Hz, 289 Hz), 114.3,
110.8, 110.6, 108.6 (4 mc), 52.0, 18.3 ppm; 19F NMR (376 MHz,
CDCl3) δ −80.7 (t, J = 9.7 Hz, 3F), −101.8 (t, J = 13.9 Hz, 2F),
−121.7, −122.2, −126.2 (3 mc, 6F) ppm; HRMS (ESI-TOF) [M +
Na]+ calcd for C12H7F11NaO2S2 478.9604; found 478.9625; IR (neat)
1
(75 mg, ∼30%). H NMR (250 MHz, CDCl3) δ 3.74 (s, 3H), 3.56,
3.26 (2 d, J = 17.3 Hz each, 2H), 2.47 (s, 3H), 0.20 (s, 9H) ppm; 13C
NMR (101 MHz, CDCl3) δ 163.5, 154.6, 123.7 (q, JCF = 283 Hz),
112.6, 93.3 (q, JCF = 31.9 Hz), 51.5, 47.2, 17.2, 1.3 ppm; 19F NMR
(376 MHz, CDCl3) δ −79.0 (s) ppm; HRMS (ESI-TOF) [M + Na]+
calcd for C11H17F3NaO3S2Si 369.0233; found 369.0262; IR (neat) ν
3050−2805 (C−H), 1700 (CO), 1540, 1435 (CC), 1315, 1250,
1175, 1120 (C−F) cm−1. Anal. Calcd for C11H17F3O3S2Si: C, 38.13;
H, 4.95; S, 18.51. Found: C, 38.08; H, 5.03; S, 18.59.
Methyl 5-Hydroxy-2-(methylthio)-5-(trifluoromethyl)-4,5-di-
hydrothiophene-3-carboxylate (3). Thiophene derivative 2 (10
mg, 0.029 mmol) and trifluoroacetic acid (30 mg, 0.260 mmol) were
stirred for 48 h at 21 °C. The reaction mixture was diluted with Et2O
(50 mL) and washed with water (2 × 20 mL). The organic layer was
washed with brine (20 mL), dried with Na2SO4, and concentrated
under reduced pressure to afford 3 (7.8 mg, 99%) as a yellow solid. mp
105−108 °C; 1H NMR (400 MHz, CDCl3) δ 3.75 (s, 3H), 3.57, 3.34
(2 d, J = 17.2 Hz each, 2H), 2.47 (s, 3H) ppm; 19F NMR (376 MHz,
CDCl3) δ −78.0 (s) ppm.
Methyl 5-Hydroxy-2-oxo-5-(trifluoromethyl)tetrahydrothio-
phene-3-carboxylate (4). Thiophene derivative 2 (92 mg, 0.266
mmol) and p-toluenesulfonic acid monohydrate (56 mg, 0.292 mmol)
were stirred in toluene (5 mL) for 24 h at 90 °C. The reaction mixture
was diluted with Et2O (50 mL) and washed with water (2 × 20 mL).
The organic layer was dried with Na2SO4 and concentrated under
reduced pressure. The crude product was purified by column
chromatography (silica gel, 20% AcOEt in hexanes) to afford 4 (33
mg, 51%) as a yellow oil. d.r. = 83:17; HRMS (ESI-TOF) [M + Na]+
calcd for C7H7F3NaO4S 266.9909; found 266.9903; IR (neat) ν 3650−
3110 (O−H), 2990−2830 (C−H), 1745, 1720 (CO), 1285, 1180,
1120 (C−F) cm−1.
1
Spectroscopic Data of the Major Diastereomer. H NMR (500
MHz, CDCl3) δ 6.30 (s, 1H), 3.97 (d, J = 8.0 Hz, 1H), 3.89 (s, 3H),
2.81 (dd, J = 8.0, 14.4 Hz, 1H), 2.67 (d, J = 14.4 Hz, 1H) ppm; 13C
NMR (101 MHz, CDCl3) δ 196.5, 170.8, 123.4 (q, JCF = 283 Hz),
94.4 (q, JCF = 32.8 Hz), 58.8, 54.7 (q, JCF = 2.0 Hz), 36.7 ppm; 19F
NMR (376 MHz, CDCl3) δ −79.3 (s) ppm.
1
Spectroscopic Data of the Minor Diastereomer. H NMR (500
MHz, CDCl3) δ 6.30 (s, 1H), 4.16 (dd, J = 7.0, 12.4 Hz, 1H), 3.82 (s,
3H), 2.91 (dd, J = 12.4, 13.3 Hz, 1H), 2.68 (dd, J = 7.0, 13.3 Hz, 1H)
ppm; 13C NMR (101 MHz, CDCl3) δ 196.6, 166.9, 123.5 (q, JCF
=
282 Hz), 90.3 (q, JCF = 33.3 Hz), 56.5, 53.4 (q, JCF = 1.4 Hz), 36.3
ppm; 19F NMR (376 MHz, CDCl3) δ −79.1 (s) ppm.
Methyl 2-(Methylthio)-5-(trifluoromethyl)thiophene-3-car-
boxylate (5). From Thiophene 2. Thiophene derivative 2 (50 mg,
0.144 mmol) was dissolved in pyridine (3 mL), POCl3 (165 mg, 1.07
mmol) was added, and the solution was heated to reflux for 1 h. The
heating bath was replaced by an ice bath, and after dilution with Et2O
(20 mL), water (1 mL) was added carefully by syringe to quench the
excess of POCl3. The mixture was further diluted with Et2O (50 mL)
and washed with aqueous 1 M HCl (50 mL) and brine (50 mL). The
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ν 3185−2840 (C−H, C−H), 1700 (CO), 1540, 1445, 1420
(CC), 1230, 1190, 1140 (C−F) cm−1. Anal. Calcd for C12H7-
F11O2S2: C, 31.59; H, 1.55; S, 14.05. Found: C, 31.89; H, 1.61; S,
13.74.
layer was washed with brine (30 mL) and dried with Na2SO4. Removal
of all volatile components in vacuo afforded 14 (44 mg, 99%) as a
yellow solid. mp 140−142 °C; 1H NMR (400 MHz, CDCl3:CD2Cl2 =
10:1) δ 7.72 (q, JHF = 1.1 Hz, 1H), 4.45 (s, 2H); 13C NMR (101 MHz,
CDCl3:CD2Cl2 = 10:1) δ 179.8, 159.5, 146.8, 143.3 (q, JCF = 40.0 Hz),
122.3 (q, JCF = 3.7 Hz), 121.3 (q, JCF = 272 Hz), 64.4 ppm; 19F NMR
(376 MHz, CDCl3:CD2Cl2 = 10:1) δ −57.1 (s) ppm; HRMS (ESI-
TOF) [M − H]− calcd for C7H2F3O3S2 254.9403; found 254.9413; IR
(neat) ν 3150−2770 (C−H, C−H), 1730 (CO), 1540 (CC),
1325, 1290, 1210, 1140 (C−F, SO2) cm−1.
Analytical Data of 8. 1H NMR (400 MHz, CDCl3) δ 7.18 (t, JHF
=
1.0 Hz, 1H); 3.86 (s, 3H); 2.62 (s, 3H) ppm; 13C NMR (176 MHz,
CDCl3) δ 162.7, 160.9, 140.8 (t, JCF = 34.6 Hz), 116.3 (t, JCF = 3.5
Hz), 117.4, 114.0, 111.0, 110.7, 110.6, 108.6 (5 mc), 52.0, 13.5 ppm;
19F NMR (376 MHz, CDCl3) δ −80.7 (t, J = 8.6 Hz, 3F), −111.4 (t, J
= 11.2 Hz, 2F), −122.7, −126.1 (2 mc) ppm; HRMS (ESI-TOF) [M +
Na]+ calcd for C12H7F11NaO2S2 478.9604; found 478.9623; IR (neat)
ν 3120−2800 (C−H, C−H), 1720 (CO), 1600, 1515 (CC),
1230, 1200, 1140, 1105 (C−F) cm−1.
Methyl 2-Phenyl-5-(trifluoromethyl)thiophene-3-carboxy-
late (15). Thiophene derivative 5 (50 mg, 0.195 mmol), Pd(PPh3)4
(11 mg, 9.76 μmol), and copper(I) thiophene-2-carboxylate (48 mg,
0.254 mmol) were placed in a flask, and after flushing with argon,
degassed DMF (5 mL) and tributylphenyltin (86 mg, 0.234 mmol)
were added. The mixture was stirred at 80 °C for 8 h. Then, another
portion of tributylphenyltin (86 mg, 0.234 mmol) was added, and
stirring was continued for 14 h. Then, Pd(PPh3)4 (11 mg, 9.76 μmol)
was added, and after an additional 14 h, copper(I) thiophene-2-
carboxylate (48 mg, 0.254 mmol) was added. The mixture was then
stirred at 21 °C for 12 h. The reaction mixture was diluted with AcOEt
(80 mL) and washed with sat. aqueous NaHCO3 (80 mL). The
organic layer was dried with Na2SO4, and the solvent was removed in
vacuo. The crude product was purified by column chromatography
(silica gel, 5% AcOEt in hexanes) to afford 15 (45 mg, 81%) as a
Methyl 2-(Methylsulfinyl)-5-(trifluoromethyl)thiophene-3-
carboxylate (11). Thiophene derivative 5 (46 mg, 0.180 mmol),
phenol (507 mg, 5.39 mmol), and hydrogen peroxide (30% in water,
24 mg, 0.72 mmol) were stirred at 50 °C for 20 h. The mixture was
diluted with AcOEt (80 mL) and washed with sat. aqueous Na2SO3
solution (2 × 50 mL). The organic layer was washed with 10%
aqueous NaOH solution (2 × 50 mL) and brine (50 mL). Drying with
Na2SO4 and removal of the solvent afforded 11 (49 mg, quant.) as a
pale yellow liquid. 1H NMR (400 MHz, CDCl3) δ 7.78 (mc, 1H), 3.91
(s, 3H), 3.03 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ 166.3,
161.6, 134.5 (q, JCF = 39.5 Hz), 130.7 (q, JCF = 3.7 Hz), 129.1, 121.5
(q, JCF = 270 Hz), 52.9, 44.2 ppm; 19F NMR (376 MHz, CDCl3) δ
−56.4 (s) ppm; HRMS (ESI-TOF) [M + Na]+ calcd for C8H7-
F3NaO3S2 294.9681; found 294.9679; IR (neat) ν 3160−2785
(C−H, C−H), 1710 (CO), 1550, 1465 (CC), 1290, 1240,
1125, 1060 (C−F, SO) cm−1.
1
colorless oil. H NMR (400 MHz, CDCl3) δ 7.85 (q, JHF = 1.2 Hz,
1H), 7.54−7.39 (m, 5H), 3.76 (s, 3H) ppm; 13C NMR (101 MHz,
CDCl3) δ 162.7, 154.4, 131.8, 131.3 (q, JCF = 3.9 Hz), 129.9, 129.7,
128.4, 129.6 (q, JCF = 39.6 Hz), 127.6, 122.0 (q, JCF = 269 Hz), 52.1
ppm; 19F NMR (376 MHz, CDCl3) δ −55.9 (s) ppm; HRMS (ESI-
TOF) [M + Na]+ calcd for C13H9F3NaO2S 309.0168; found 309.0194;
IR (neat) ν 3160−2765 (C−H, C−H), 1730 (CO), 1560, 1470,
1400 (CC), 1295, 1260, 1210, 1125 (C−F) cm−1.
Methyl 2-(Methylsulfonyl)-5-(trifluoromethyl)thiophene-3-
carboxylate (12). To a solution of thiophene derivative 5 (50 mg,
0.195 mmol) in CH2Cl2 (1 mL) was added at 0 °C mCPBA (144 mg,
0.585 mmol), and the resulting suspension was stirred at 21 °C for 12
h. The mixture was diluted with CH2Cl2 (80 mL) and washed with sat.
aqueous NaHCO3 solution (2 × 50 mL). The organic layer was dried
with Na2SO4, and the solvent was removed in vacuo. The crude
product was purified by column chromatography (silica gel, 25%
AcOEt in hexanes) to afford 12 (56 mg, quant.) as a colorless solid.
mp 68−70 °C; 1H NMR (400 MHz, CDCl3) δ 7.84 (q, JHF = 0.9 Hz,
1H), 3.95 (s, 3H), 3.53 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ
160.6, 151.0 (q, JCF = 1.2 Hz), 135.9 (q, JCF = 39.9 Hz), 133.7, 131.9
(q, JCF = 3.6 Hz), 121.1 (q, JCF = 271 Hz), 53.3, 44.3 ppm; 19F NMR
(376 MHz, CDCl3) δ −56.5 (s) ppm; HRMS (ESI-TOF) [M + Na]+
calcd for C8H7F3NaO4S2 310.9630; found 310.9616; IR (neat) ν
3075−2760 (C−H, C−H), 1730 (CO), 1555, 1465, 1370
(CC), 1300, 1245, 1125, 1015 (C−F, SO2) cm−1.
Methyl 3-Methyl-2-oxo-1-phenyl-5-(trifluoromethyl)-2,3-di-
hydro-1H-pyrrole-3-carboxylate (16). A 1 M LDA solution was
freshly prepared: n-BuLi (2.5 M in hexanes, 470 μL, 1.17 mmol) was
added at −78 °C to a solution of diisopropylamine (120 mg, 1.17
mmol) in THF (1.20 mL), and the resulting mixture was stirred for 20
min. A solution of cyclopropane 1 (200 mg, 0.781 mmol) in THF (1
mL) was added, and the reaction mixture was stirred for 2 h at −78
°C. Then, phenyl isocyanate (140 mg, 1.17 mmol) was added, and
stirring was continued for 1 h at −78 °C and for 4 h at 21 °C. After
addition of methyl iodide (277 mg, 1.95 mmol), the mixture was
stirred at 21 °C for 16 h. The mixture was diluted with both Et2O (100
mL) and sat. aqueous NH4Cl solution (100 mL), and the phases were
separated. The organic layer was washed with brine (50 mL), dried
with Na2SO4, and concentrated under reduced pressure. The residue
was dissolved in pyridine (4 mL), POCl3 (838 mg, 5.47 mmol) was
added, and the solution was heated to reflux for 1 h. The heating bath
was replaced by an ice bath, and after dilution with Et2O (10 mL),
water (1 mL) was added carefully via syringe to quench the excess of
POCl3. The reaction mixture was further diluted with Et2O (100 mL),
and the soluble parts were decanted from the remaining black slurry.
This ether solution was washed with aqueous 1 M HCl (100 mL) and
brine (50 mL). The organic layer was dried with Na2SO4 and
concentrated under reduced pressure. The crude product was purified
by column chromatography (silica gel, 5% AcOEt in hexanes) to afford
16 (116 mg, 50%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ
7.51−7.19 (m, 5H), 6.00 (q, JHF = 1.5 Hz, 1H), 3.79 (s, 3H), 1.66 (s,
3H) ppm; 13C NMR (101 MHz, CDCl3) δ 175.4 (q, JCF = 1.0 Hz),
168.4 (q, JCF = 1.2 Hz), 136.1 (q, JCF = 37.5 Hz), 133.7, 129.5, 129.4,
128.4, 118.9 (q, JCF = 271 Hz), 114.1 (q, JCF = 5.0 Hz), 56.2, 53.5, 19.1
ppm; 19F NMR (376 MHz, CDCl3) δ −64.4 (s) ppm; HRMS (ESI-
TOF) [M + Na]+ calcd for C14H12F3NNaO3 322.0661; found
322.0669; IR (neat) ν 3190−2750 (C−H, C−H), 1750, 1730
(CO), 1485, 1400 (CC), 1240, 1175, 1135, 1110 (C−F) cm−1.
Anal. Calcd for C14H12F3NO3: C, 56.19; H, 4.04; N, 4.68. Found: C,
56.18; H, 4.15; N, 4.73.
Methyl 5-(Trifluoromethyl)thiophene-3-carboxylate (13).
Isopropylmagnesium chloride (2.0 M in THF, 110 μL, 0.220 mmol)
was added dropwise at −50 °C to a stirring solution of sulfinyl
thiophene 11 (20 mg, 0.073 mmol) in THF (2 mL). The resulting
solution was stirred for 1 h, and then methanol (50 μL, 1.24 mmol)
was added. The reaction mixture was warmed to 21 °C within 12 h
and stirred for an additional 12 h. This mixture was diluted with Et2O
(50 mL) and washed with water (50 mL). The organic layer was dried
with Na2SO4, and the solvent was removed in vacuo. The crude
product was purified by column chromatography (silica gel, 10%
1
AcOEt in hexanes) to afford 13 (7 mg, 45%) as a colorless oil. H
NMR (400 MHz, CDCl3) δ 8.22 (d, J = 1.4 Hz, 1H), 7.85 (mc, 1H),
3.88 (s, 3H) ppm. The NMR data are in agreement with literature
data.49
5-(Trifluoromethyl)thieno[2,3-b]thiophen-3(2H)-one 1,1-Di-
oxide (14). A 1 M LDA solution was freshly prepared: n-BuLi (2.5 M
in hexanes, 170 μL, 0.434 mmol) was added at −78 °C to a solution of
diisopropylamine (44 mg, 0.434 mmol) in THF (440 μL), and the
resulting mixture was stirred for 20 min. A solution of sulfonyl
thiophene 12 (50 mg, 0.173 mmol) in THF (2 mL) was added, and
the reaction mixture was stirred for 2 h at −78 °C. Upon addition of
12, the reaction mixture turned yellow and eventually wine red. The
reaction mixture was diluted with AcOEt (100 mL) and sat. aqueous
NH4Cl solution (50 mL), and the phases were separated. The organic
General Procedure for the One-Pot Synthesis of Pyrroles
17a−17e and 18. A 1 M LDA solution was freshly prepared: n-BuLi
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(2.5 M in hexanes, 1.5 equiv) was added at −78 °C to a solution of
diisopropylamine (1.5 equiv) in THF, and the resulting mixture was
stirred for 20 min. A THF solution of cyclopropane 1 (1.0 equiv) was
added, and the reaction mixture was stirred for 2 h at −78 °C. The
corresponding isothiocyanate (1.5 equiv) was added, and stirring was
continued for 1 h at −78 °C and for 4 h at 21 °C. After addition of
methyl iodide (2.5 equiv), the mixture was stirred at 21 °C for 16 h.
The mixture was diluted with both Et2O and sat. aqueous NH4Cl
solution, and the phases were separated. The organic layer was washed
with brine, dried with Na2SO4, and concentrated under reduced
pressure. The residue was dissolved in pyridine, POCl3 (7.0 equiv) was
added, and the solution was heated to reflux for 1 h. The heating bath
was replaced by an ice bath, and after dilution with Et2O, water was
added carefully by syringe to quench the excess of POCl3. The
reaction mixture was further diluted with Et2O, and the soluble parts
were decanted from the remaining black slurry. This ether solution was
washed with aqueous 1 M HCl and brine. The organic layer was dried
with Na2SO4 and concentrated under reduced pressure. The crude
product was purified by silica gel column chromatography to afford the
pure product.
−58.1 (s) ppm; HRMS (ESI-TOF) [M + Na]+ calcd for C15H14-
F3NNaO3S 368.0539; found 368.0533; IR (neat) ν 3215−2775
(C−H, C−H), 1720 (CO), 1560, 1475 (CC), 1255, 1220,
1150, 1115, 1055 (C−F) cm−1. Anal. Calcd for C15H14F3NO3S: C,
52.17; H, 4.09; N, 4.06; S, 9.29. Found: C, 52.44; H, 3.92; N, 4.12; S,
8.90.
Methyl 1-Ethyl-2-(methylthio)-5-(trifluoromethyl)-1H-pyr-
role-3-carboxylate (17d) and Methyl 1-Ethyl-3-methyl-2-thio-
xo-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrole-3-carboxylate
(18). According to the general procedure, n-BuLi (470 μL, 1.17 mmol)
and diisopropylamine (118 mg, 1.17 mmol) in THF (1.20 mL),
cyclopropane 1 (200 mg, 0.781 mmol), ethyl isothiocyanate (102 mg,
1.17 mmol), methyl iodide (277 mg, 1.95 mmol), pyridine (3 mL),
and POCl3 (838 mg, 5.47 mmol) afforded a mixture of 17d and 18
(155 mg, 74%, 17d:18 = 83:17); eluent 5% AcOEt in hexanes;
separation of the mixture by HPLC (silica gel, 3% AcOEt in hexanes)
afforded 17d (95 mg, 45%) and 18 (17 mg, 8%), both as yellow oils.
1
Analytical Data of 17d. H NMR (400 MHz, CDCl3) δ 7.05 (q,
JHF = 0.6 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 2.47 (s, 3H),
1.34 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ 163.4,
134.4 (q, JCF = 2.0 Hz), 122.2 (q, JCF = 38.8 Hz), 120.6 (q, JCF = 267
Hz), 114.1 (q, JCF = 3.8 Hz), 51.4, 41.2 (q, JCF = 1.5 Hz), 19.7, 16.8
ppm; 19F NMR (376 MHz, CDCl3) δ −59.3 (s) ppm; HRMS (ESI-
TOF) [M + Na]+ calcd for C10H12F3NNaO2S 290.0433; found
290.0444; IR (neat) ν 3100−2800 (C−H, C−H), 1720 (CO),
1560, 1480 (CC), 1240, 1210, 1110, 1060 (C−F) cm−1. Anal. Calcd
for C10H12F3NO2S: C, 44.94; H, 4.53; N, 5.24; S, 12.00. Found: C,
44.91; H, 4.45; N, 5.53; S, 11.87.
Methyl 2-(Methylthio)-1-phenyl-5-(trifluoromethyl)-1H-pyr-
role-3-carboxylate (17a). According to the general procedure, n-
BuLi (470 μL, 1.17 mmol) and diisopropylamine (118 mg, 1.17
mmol) in THF (1.20 mL), cyclopropane 1 (199 mg, 0.778 mmol),
phenyl isothiocyanate (158 mg, 1.17 mmol), methyl iodide (276 mg,
1.94 mmol), pyridine (3 mL), and POCl3 (835 mg, 5.44 mmol)
afforded 17a (208 mg, 85%) as an orange solid. mp 78−80 °C; eluent
15% AcOEt in hexanes; 1H NMR (400 MHz, CDCl3) δ 7.62−7.45 (m,
3H), 7.27, 7.25 (2 mc, 2H), 7.18 (q, JHF = 0.6 Hz, 1H), 3.89 (s, 3H),
2.28 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ 163.5, 136.5 (q, JCF
= 1.9 Hz), 136.3, 129.8, 128.9, 128.7, 124.4 (q, JCF = 38.8 Hz), 120.1
Analytical Data of 18. 1H NMR (400 MHz, CDCl3) δ 6.27 (q, JHF
= 1.5 Hz, 1H), 4.05 (q, J = 7.1 Hz, 2H), 3.69 (s, 3H), 1.59 (s, 3H),
1.28 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ 204.7,
167.7 (q, JCF = 1.0 Hz), 136.8 (q, JCF = 37.9 Hz), 122.4 (q, JCF = 4.9
Hz), 119.0 (q, JCF = 270 Hz), 67.2, 53.6, 41.5 (q, JCF = 1.7 Hz), 23.2
(q, JCF = 0.8 Hz), 11.6 (q, JCF = 1.2 Hz) ppm; 19F NMR (376 MHz,
CDCl3) δ −64.7 (s) ppm; HRMS (ESI-TOF) [M + Na]+ calcd for
C10H12F3NNaO2S 290.0433; found 290.0440; IR (neat) ν 3180−2760
(C−H, C−H), 1750 (CO), 1450 (CC), 1230, 1185, 1130,
1055 (C−F) cm−1.
(q, JCF = 268 Hz), 118.5, 114.1 (q, JCF = 3.5 Hz), 51.6, 19.6 ppm; 19
F
NMR (376 MHz, CDCl3) δ −57.9 (s) ppm; HRMS (ESI-TOF) [M +
Na]+ calcd for C14H12F3NNaO2S 338.0433; found 338.0438; IR (neat)
ν 3190−2775 (C−H, C−H), 1715 (CO), 1560, 1500, 1475,
1420 (CC), 1255, 1220, 1150, 1115, 1055 (C−F) cm−1. Anal. Calcd
for C14H12F3NO2S: C, 53.33; H, 3.84; N, 4.44; S, 10.17. Found: C,
53.33; H, 3.86; N, 4.43; S, 10.15.
Methyl 1-Cyclopropyl-2-(methylthio)-5-(trifluoromethyl)-
1H-pyrrole-3-carboxylate (17e). According to the general
procedure, n-BuLi (470 μL, 1.17 mmol) and diisopropylamine (118
mg, 1.17 mmol) in THF (1.20 mL), cyclopropane 1 (199 mg, 0.778
mmol), cyclopropyl isothiocyanate (116 mg, 1.17 mmol), methyl
iodide (277 mg, 1.95 mmol), pyridine (3 mL), and POCl3 (838 mg,
5.47 mmol) afforded 17e (138 mg, 63%) as a yellow oil; eluent 15%
Methyl 1-[3,5-Bis(trifluoromethyl)phenyl]-2-(methylthio)-5-
(trifluoromethyl)-1H-pyrrole-3-carboxylate (17b). According to
the general procedure, n-BuLi (470 μL, 1.17 mmol) and diisopropyl-
amine (118 mg, 1.17 mmol) in THF (1.20 mL), cyclopropane 1 (200
mg, 0.781 mmol), 3,5-bis(trifluoromethyl)phenyl isothiocyanate (317
mg, 1.17 mmol), methyl iodide (277 mg, 1.95 mmol), pyridine (3
mL), and POCl3 (838 mg, 5.47 mmol) afforded 17b (158 mg, 45%) as
1
1
AcOEt in hexanes. H NMR (400 MHz, CDCl3) δ 7.01 (q, JHF = 0.8
an orange oil; eluent 15% AcOEt in hexanes. H NMR (400 MHz,
Hz, 1H), 3.82 (s, 3H), 3.14 (tt, J = 4.6, 6.8 Hz, 1H), 2.48 (s, 3H),
1.26−1.15 (m, 4H) ppm; 13C NMR (101 MHz, CDCl3) δ 163.3, 137.9
(q, JCF = 2.0 Hz), 124.6 (q, JCF = 32.6 Hz), 121.2 (q, JCF = 268 Hz),
117.7, 114.6 (q, JCF = 4.2 Hz), 51.4, 28.7, 19.3, 8.9 (q, JCF = 2.3 Hz)
ppm; 19F NMR (376 MHz, CDCl3) δ −57.8 (s) ppm; HRMS (ESI-
TOF) [M + Na]+ calcd for C11H12F3NNaO2S 302.0433; found
302.0432; IR (neat) ν 3200−2785 (C−H, C−H), 1720 (CO),
1560, 1475 (CC), 1255, 1220, 1190, 1160, 1150, 1115, 1060 (C−F)
cm−1. Anal. Calcd for C11H12F3NO2S: C, 47.31; H, 4.33; N, 5.02; S,
11.48. Found: C, 47.26; H, 4.29; N, 5.17; S, 11.53.
Methyl 2-(Methylsulfinyl)-1-phenyl-5-(trifluoromethyl)-1H-
pyrrole-3-carboxylate (19). Pyrrole derivative 17a (20 mg, 0.064
mmol), phenol (179 mg, 1.90 mmol), and hydrogen peroxide (30% in
water, 29 mg, 0.254 mmol) were stirred at 50 °C for 5 h. The mixture
was diluted with AcOEt (80 mL) and was washed with sat. aqueous
Na2SO3 solution (2 × 50 mL). The organic layer was washed with
10% aqueous NaOH solution (2 × 50 mL) and brine (50 mL). Drying
with Na2SO4, removal of the solvent, and filtration (silica gel, 30%
then 50% AcOEt in hexanes) afforded 19 (21 mg, quant.) as a
colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.60−7.30 (m, 5H), 7.17
(s, 1H), 3.89 (s, 3H), 3.01 (s, 3H) ppm; 13C NMR (101 MHz,
CDCl3) δ 162.9, 140.8 (q, JCF = 1.4 Hz), 135.0, 130.5, 129.0, 128.9,
128.8, 128.1, 126.7 (q, JCF = 38.7 Hz), 119.8 (q, JCF = 269 Hz), 117.1,
114.0 (q, JCF = 3.3 Hz), 52.2, 44.5 ppm; 19F NMR (376 MHz, CDCl3)
CDCl3) δ 8.06, 7.75 (2 s, 3H), 7.24 (q, JHF = 0.7 Hz, 1H), 3.91 (s,
3H), 2.32 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ 163.1, 137.8,
136.7 (q, JCF = 2.0 Hz), 132.9 (q, JCF = 34.5 Hz), 129.4 (q, JCF = 2.8
Hz), 124.5 (q, JCF = 39.2 Hz), 123.9, 123.8 (2 q, JCF = 3.7 Hz each),
122.9 (q, JCF = 272 Hz), 119.86 (q, JCF = 269 Hz), 119.86, 115.1 (q,
JCF = 3.5 Hz), 51.8, 19.7 ppm; 19F NMR (376 MHz, CDCl3) δ −57.6
(s, 3F), −62.8 (s, 6F) ppm; HRMS (ESI-TOF) [M + Na]+ calcd for
C16H10F9NNaO2S 474.0181; found 474.0192; IR (neat) ν 3150−2790
(C−H, C−H), 1725 (CO), 1565, 1470 (CC), 1280, 1250,
1175, 1120, 1060 (C−F) cm−1. Anal. Calcd for C16H10F9NO2S: C,
42.58; H, 2.23; N, 3.10; S, 7.10. Found: C, 42.22; H, 2.30; N, 3.45; S,
7.01.
Methyl 1-(4-Methoxyphenyl)-2-(methylthio)-5-(trifluoro-
methyl)-1H-pyrrole-3-carboxylate (17c). According to the general
procedure, n-BuLi (470 μL, 1.17 mmol) and diisopropylamine (118
mg, 1.17 mmol) in THF (1.20 mL), cyclopropane 1 (200 mg, 0.781
mmol), 4-methoxyphenyl isothiocyanate (194 mg, 1.17 mmol), methyl
iodide (277 mg, 1.95 mmol), pyridine (3 mL), and POCl3 (838 mg,
5.47 mmol) afforded 17c (119 mg, 44%) as a yellow oil; eluent 5%
1
AcOEt in hexanes. H NMR (400 MHz, CDCl3) δ 7.22−6.96 (m,
5H), 3.883, 3.879 (2 s, 6H), 2.28 (s, 3H) ppm; 13C NMR (101 MHz,
CDCl3) δ 163.6, 160.4, 136.8 (q, JCF = 2.0 Hz), 129.7, 128.9, 124.6 (q,
JCF = 38.5 Hz), 120.1 (q, JCF = 268 Hz), 118.3, 114.04, 113.95 (q, JCF
= 3.6 Hz), 55.5, 51.6, 19.6 ppm; 19F NMR (376 MHz, CDCl3) δ
4499
dx.doi.org/10.1021/jo500534t | J. Org. Chem. 2014, 79, 4492−4502

The Journal of Organic Chemistry
Article
δ −57.8 (s) ppm; HRMS (ESI-TOF) [M + Na]+ calcd for
C14H12F3NNaO3S 354.0382; found 354.0402; IR (neat) ν 3220−
2760 (C−H, C−H), 1715 (CO), 1560, 1485, 1420 (CC),
1225, 1125, 1045 (C−F, SO) cm−1. Anal. Calcd for C14H12F3NO3S:
C, 50.75; H, 3.65; N, 4.23; S, 9.68. Found: C, 50.78; H, 3.78; N, 4.02;
S, 11.51.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of the 1H-, 13C-, and 19 F-NMR spectra for compounds
2−5, 7, 8, 11, 12, and 14−22. This material is available free of
charge via the Internet at http://pubs.acs.org.
Methyl 2-(Methylsulfonyl)-1-phenyl-5-(trifluoromethyl)-1H-
pyrrole-3-carboxylate (20). To a solution of pyrrole derivative 17a
(50 mg, 0.159 mmol) in CH2Cl2 (1 mL) was added at 0 °C mCPBA
(117 mg, 0.476 mmol), and the resulting suspension was stirred at 21
°C for 12 h. The mixture was diluted with CH2Cl2 (100 mL) and
washed with sat. aqueous NaHCO3 solution (3 × 50 mL). The organic
layer was dried with Na2SO4, and the solvent was removed in vacuo.
The crude product was purified by column chromatography (silica gel,
30% AcOEt in hexanes) to afford 20 (55 mg, quant.) as a colorless
solid. mp 130−132 °C; 1H NMR (400 MHz, CDCl3) δ 7.58−7.30 (2
m, 5H), 7.13 (s, 1H), 3.91 (s, 3H), 3.31 (s, 3H) ppm; 13C NMR (101
MHz, CDCl3) δ 162.8, 134.7 (q, JCF = 1.6 Hz), 135.3, 130.4, 128.8,
128.2, 127.1 (q, JCF = 38.9 Hz), 121.0, 119.4 (q, JCF = 269 Hz), 113.5
(q, JCF = 3.3 Hz), 52.7, 45.5 ppm; 19F NMR (376 MHz, CDCl3) δ
−58.0 (s) ppm; HRMS (ESI-TOF) [M + Na]+ calcd for C14H12-
F3NNaO4S 370.0331; found 370.0351; IR (neat) ν 3160−2775
(C−H, C−H), 1730 (CO), 1560, 1490, 1430, 1365 (CC),
1320, 1235, 1125, 1055 (C−F, SO2) cm−1. Anal. Calcd for
C14H12F3NO4S: C, 48.41; H, 3.48; N, 4.03; S, 9.23. Found: C,
48.43; H, 3.64; N, 3.75; S, 9.77.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hans.reissig@chemie.fu-berlin.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Deutsche Forschungsgemeinschaft
(GRK 1582, Fluorine as Key Element) and Bayer HealthCare
for generous support. We also thank Luise Schefzig and
Christiane Groneberg for experimental support and Dr.
Reinhold Zimmer for valuable discussions and assistance
during preparation of this manuscript. Professor Michael C.
Willis and his co-workers (University of Oxford) are thanked
for examining rhodium-catalyzed reactions of our compounds.
REFERENCES
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MHz, CDCl3) δ 7.49−7.34 (m, 6H), 7.14 (s, 1H), 3.83 (s, 3H) ppm;
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organic layer was washed with brine (20 mL) and dried with Na2SO4.
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́
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