Synthesis of trifluoromethyl-containing polysubstituted aromatic compounds by diels-alder reaction of ethyl 3-benzamido-2-oxo-6-(trifluoromethyl)-2H-pyran-5-carboxylate

Article abstract of DOI:10.1002/ejoc.201500032

Diels-Alder reactions of ethyl 3-benzamido-2-oxo-6-(trifluoromethyl)-2H-pyran-5-carboxylate (1a) with electronically different dienophiles, including cyclic enol ethers, cycloalkenes, α,β-unsaturated ketones, and terminal acetylenes, are useful for the ef

Full text of DOI:10.1002/ejoc.201500032

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FULL PAPER
DOI: 10.1002/ejoc.201500032
Synthesis of Trifluoromethyl-Containing Polysubstituted Aromatic Compounds
by Diels–Alder Reaction of Ethyl 3-Benzamido-2-oxo-6-(trifluoromethyl)-2H-
pyran-5-carboxylate
Ivan S. Kondratov,[a,b] Nataliya A. Tolmachova,[a] Violetta G. Dolovanyuk,[a] Igor I. Gerus,[a]
Constantin-Gabriel Daniliuc,[c] and Günter Haufe*[c,d]
Keywords: Synthetic methods / Alkenes / Alkynes / Cycloaddition / Carbocycles / Amino acids / Fluorine
Diels–Alder reactions of ethyl 3-benzamido-2-oxo-6-(tri-
fluoromethyl)-2H-pyran-5-carboxylate (1a) with electroni-
cally different dienophiles, including cyclic enol ethers,
preparation of trifluoromethyl-containing aromatic com-
pounds such as 3-aminobenzoic acid derivatives. We pre-
sume that the presence of the trifluoromethyl group is the
cycloalkenes, α,β-unsaturated ketones, and terminal acetyl- main factor in determining the regioselectivity of the initial
enes, are useful for the efficient and selective three-step
cycloaddition.
Previously, we have reported a couple of Diels–Alder re-
actions of CF3-containing pyrones 1a–1c[6] (Figure 1) with
selected dienophiles.[5b,7] In particular, the reactions of
pyrone 1a with 1-alkoxy alkenes were studied in detail, and
were shown to be an effective synthetic approach to tri-
fluoromethyl-containing 3-aminobenzoic acid derivatives.[7]
Continuing our investigations in this field, in this paper we
describe Diels–Alder reactions of pyrone 1a with a variety
of electronically different alkenes such as cyclic enol ethers,
cycloalkenes, and cyclic α,β-unsaturated ketones and alk-
ynes. In this way, we explore the scope and limitations of
this approach for the synthesis of new trifluoromethyl-con-
taining aromatic amino acid derivatives.
Introduction
Trifluoromethyl-containing aromatic compounds are of
considerable interest for medicinal chemistry, agrochemis-
try, and materials science since the selective introduction of
a CF3 group at a key position of a particular molecule can
result in desirable changes of its biological and physical-
chemical properties.[1] Consequently, a variety of synthetic
methods for the formation of trifluoromethyl-containing
aromatic compounds have been developed. The direct tri-
fluoromethylation of aromatic compounds[2] and also sev-
eral building-block-based methods[3] are among the most
useful of these methods. The latter protocols are most suit-
able for the preparation of polyfunctionalised aromatic
compounds, whose synthesis by other methods is rare.
2-Pyrones are important building blocks in organic syn-
thesis, especially as diene components for Diels–Alder reac-
tions with alkenes (with subsequent CO2 elimination and
dehydrogenation) or with alkynes (followed by CO2 elimi-
nation) for the synthesis of substituted benzenes.[4] How-
ever, there are only a few examples of the use of this strat-
egy to synthesise polyfluoroalkylated aromatic compounds
using polyfluoroalkylated pyrones as dienes.[5]
Figure 1. Pyrones 1a–1c as potent dienes for Diels–Alder reac-
tions.[5b,7]
Results and Discussion
[a] Institute of Bioorganic Chemistry and Petrochemistry, National
Ukrainian Academy of Science,
Initially, we studied the reactions of 1a with cyclic dieno-
philes 2a–2e under microwave irradiation. The initially
formed bicyclic adducts (i.e., endo/exo-3a–3e) eliminated
CO2 under forcing conditions to form stable cyclohexa-
dienes 4a–4e as the major products (Scheme 1). Com-
pounds endo-3a and exo-3a (dr≈30:70 by 19F NMR spec-
troscopic analysis of the reaction mixture) were obtained
under mild conditions (120 W, 120 °C, 10 min) as the major
products. These products were separated and fully charac-
Murmanska St. 1, Kyiv 02660, Ukraine
[b] Enamine Ltd.,
78 Chervonotkatska St, Kyiv 02094, Ukraine
[c] Organisch-Chemisches Institut, Universität Münster,
Corrensstraße 40, 48149 Münster, Germany
E-mail: haufe@uni-muenster.de
http://www.uni-muenster.de/Chemie.oc/haufe/haufe.html
[d] Cells-in-Motion Cluster of Excellence, Universität Münster
Waldeyerstraße 15, 48149 Münster, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500032.
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Scheme 1. Reaction of pyrone 1a with cyclic alkenes 2a–2e (see text and Table 1).
terised. The exo configuration of exo-3a was confirmed by Table 1. Synthesis of compounds 4a–4c, 5d, and 5e: conditions and
X-ray analysis (Figure 2).[8] Similar products have pre-
yields.
viously been isolated and characterised from the reactions
of pyrone 1a with other alkoxyalkenes,[7] whereas similar
compounds were not isolated from the reactions of pyrone
1b with dienophiles 2a and 2b.[5b]
Figure 2. Crystal structure of compounds exo-3a and 8 (thermal
ellipsoids are shown at 50% probability).[8]
We aimed to find conditions for the transformation of
compounds 3 into dienes 4 (Table 1), and also for their fur-
ther transformation into aromatic compounds 9 (Table 2).
Bicyclic adducts 3 were easily formed in all cases, but the
subsequent elimination of CO2 required prolonged micro-
wave irradiation (1–2 h, see Table 1). The reactions with
dienophiles 2a–2c proceeded smoothly to give the expected
dienes (i.e., 4a–4c) in moderate yields. In contrast, the reac-
tions with cyclohexene (2d) and cycloheptene (2e) led to the
isomeric dienes (i.e., 5d and 5e), which are supposed to be
more stable than isomers 4. The spectra of compounds 4
Most time-consuming was the reaction of cyclohexene
and 5 are similar, but the presence or absence of particular (2d), which required ca. 2 h heating for complete conversion
peaks allows the two structures to be distinguished. For (Table 1, entry 4). Products 4a–4c as well as 5d and 5e are
compounds 4a and 4c, the 1H NMR spectra contain a sing- stable, and were isolated in moderate yield and character-
let (1 H, CH) between δ = 6.90 and 7.14 ppm, and the 13C ised. The reaction conditions can be used for the multigram
NMR spectra have a characteristic signal between δ = 103.1 preparation of compounds 4 and 5.
and 104.4 ppm; neither of these signals is present in the
Besides other side-products, 3–12% (by 19F NMR spec-
spectra of compounds 5. The 1H NMR spectra of 5 contain troscopy) of 6a–6e were also identified in each of the crude
an AB system (2 H, CH2) between δ = 3.00 and 3.60 ppm reaction mixtures. We presume that these products are
with JH,H = 20.5–21.7 Hz. The corresponding signal in the formed by partial isomerisation of 4 at elevated temperature
13C NMR spectra appears between δ = 31.6 and 32.2 ppm. (Figure 3). Compounds 6a–6e could easily be identified in
In addition, the structures of compounds 5d and 5e were the reaction mixtures by 19F NMR spectroscopy,[9] but all
1
1
confirmed by H,13C HMBC and H,13C HSQC spectra.
attempts to isolate them in pure form failed.
2
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Trifluoromethyl-Containing Polysubstituted Aromatic Compounds
Table 2. Synthesis of compounds 9 by DDQ-mediated dehydroge-
nation starting from pure cyclohexenes 4a–4c, 5d, or 5e, or the
crude mixtures from the Diels–Alder reaction.
Figure 3. General structure of by-products 6a–6e (for the nature of
X, see Table 1).
major product under these conditions was aromatic com-
pound 7 (38% yield). The structure of 7 was proved by the
fact that its spectroscopic data were identical to those of an
authentic sample obtained earlier by the reaction of pyrone
1a with 2-methoxypropene.[7]
Two more isolated side-products were diene 6f (10%
yield) and bis-adduct 8 (15% yield). The simplicity of the
NMR spectra of 8 indicated that this compound had a meso
structure, and this was confirmed by X-ray analysis (Fig-
ure 2).[8] All our attempts to optimise the reaction condi-
tions for selective formation of diene 4f from pyrone 1a and
2,5-dihydrofuran (2f) failed. Compound 7 was always
formed as the major product.
Compounds 4a–4c, 5d, and 5e were easily transformed
into aromatic amino acid derivatives 9a–9e (68–92% yield)
by heating with DDQ (2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone; Scheme 3, Table 2).
[a] Yield of products 9a–9e by DDQ-mediated dehydrogenation of
dienes 4a–4c, 5d, or 5e. [b] Overall yield of 9a–9e (based on 1a) by
the “one-pot” approach.
Unexpectedly, the reaction of 1a with 2,5-dihydrofuran
(2f) took a different route (Scheme 2). Under mild condi-
tions (120 W, 120 °C, 10 min), the formation of bicyclic ad-
ducts exo/endo-3f was observed (the major product, i.e.,
exo-3f, was isolated), whereas under forcing conditions
Scheme 3. Synthesis of compounds 9a–9e.
Despite the anomalous results of the cycloaddition of 1a
(150 W, 150 °C, 60 min), a complex mixture of products was with 2,5-dihydrofuran (2f), the two-step approach, i.e.,
formed. Cyclohexadiene 4f was isolated in 6% yield. The Diels–Alder reaction of 1a with alkenes 2a–2e, with imme-
Scheme 2. Reaction of pyrone 1a with 2,5-dihydrofuran (2f) (isolated yields are given in parentheses).
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diate elimination of CO2 to form compounds 4 or 5, and the corresponding intermediate tricyclic adducts (i.e., 11a
subsequent DDQ-mediated dehydrogenation, is a conve- and 11b) were not isolated. Unexpectedly, we also failed to
nient method for the synthesis of protected bicyclic aro- isolate the corresponding cyclohexadienes (i.e., 12a and
matic amino acids such as 9. Moreover, we found that this 12b), which were not stable under the reaction conditions.
approach can be realised as a “one-pot” process without Dehydrogenation took place immediately to give the corre-
isolating cyclohexadienes 4 or 5. In this case, the crude mix- sponding aromatic compounds (i.e., 13a and 13b) in 31–
ture from the Diels–Alder reaction (after removing the ex- 45% yield.[11]
cess of 2a–2e) was directly dehydrogenated by treatment
Most intriguing, considering the electronic structures of
with DDQ to give the corresponding products (i.e., 9). The diene 1a and dienophiles 10a and 10b, the reverse regio-
overall yield (based on starting compound 1a) of the “one- selectivity was expected. However, regioisomers 15a and
pot” process was higher than that of the reaction sequence 15b were not isolated. Presumably, repulsion between the
including the purification of compound 4 or 5. The “one- electron-rich C=O and CF3 groups disfavours the transition
pot” approach can be used for the multigram synthesis of state leading to tricyclic intermediates 14a and 14b, and
compounds 9a–9e.
thus prevents the formation of 15a and 15b (Scheme 4). On
We also studied the reaction of 1a with cycloalkenones the other hand, hydrogen bonding between the NHCOPh
10a and 10b. Only a few examples of Diels–Alder reactions moiety and the ketone group might facilitate the formation
of 2-pyrones with α,β-unsaturated ketones have been re- of intermediates 11a and 11b.
ported in the literature.[10] In this way, we could synthesise
Bearing in mind that pyrone 1a is a good diene for reac-
CF3-containing 1-indanones and 1-tetralones 13. The reac- tions with electron-rich enol ethers, ordinary alkenes, and
tions were carried out under microwave irradiation (150 W, α,β-unsaturated cyclic ketones, we were also interested in
150 °C, 60 min), with the addition of a catalytic amount of reactions with terminal acetylenes 16a–16l as dienophiles.
hydroquinone in order to avoid polymerisation of com- With these substrates, the oxidation step to give the final
pounds 10a and 10b (Scheme 4). Under these conditions, aromatic compounds can be avoided.
Scheme 4. Reaction of pyrone 1a with cycloalkenones 10a and 10b.
Scheme 5. Regioselectivity of the Diels–Alder reaction between pyrone 1a and acetylenes 18a–18l.
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Trifluoromethyl-Containing Polysubstituted Aromatic Compounds
The reactions took place regioselectively under mild alkyl chain of the acetylenes, which disfavours the forma-
microwave irradiation (Scheme 5) via non-isolable interme- tion of intermediate 19. Single crystals of compound 18g
diates 17 to give aromatic products 18a–18l in moderate to were grown from toluene/hexane (1:1), and X-ray analysis
high yields (Table 3). The other regioisomers (i.e., 20) were confirmed the substituent pattern on the benzene ring (Fig-
not observed.
ure 4).[8]
Table 3. Synthesis of compounds 18a–18l: conditions and yields.
Figure 4. Crystal structure of compound 18g (thermal ellipsoids
are shown at 30% probability).[8]
Most of the acetylenes reacted smoothly, and the method
can be used for multigram syntheses of compounds 18a–
18l. Only in the case of tert-butylacetylene (16d) (Table 3,
entry 4) did the reaction require a longer heating time (3 h)
for complete conversion. In the reaction of propargyl
alcohol 16f (Table 3, entry 6), it was important to use
milder conditions to obtain a reasonable yield, since at
150 °C resinification occurred.
In contrast, all attempted reactions between 1a and pent-
3-yn-1-ol (16m) failed. Under different conditions, insepa-
rable complex mixtures were formed (Scheme 6). Presum-
ably, once again, unfavourable repulsion between the CF3
group and the alkyl groups of the acetylene prevents the
formation of the transition state.
Scheme 6. Attempted reaction between pyrone 1a and pent-3-yn-
1-ol (16m).
Compounds 18g–18l contain neighbouring N-benzo-
ylamido and hydroxyalkyl groups, which might be involved
in an intramolecular cyclisation to form bicyclic com-
pounds 22 (Scheme 7). The most efficient approach to such
a cyclisation involved an initial mesylation of the hydroxy
group, and subsequent intramolecular nucleophilic substi-
tution promoted by Cs2CO3 in dioxane.[12] This sequence
was used to cyclise compounds 18g and 18h to give indoline
22a and the tetrahydroquinoline 22b, respectively. In con-
trast, our attempts to cyclise compounds 18i–18l failed. The
We suppose that in this case, the high regioselectivity is corresponding mesylates did not undergo further transfor-
due to a steric repulsion between the CF3 group and the mation under the conditions used.
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Scheme 7. Synthesis of compounds 22a, 22b, and 24 by intramolecular cyclisation.
at 300 MHz, and an Agilent DD2 instrument at 500 and 600 MHz
(1H), at 25 °C. Tetramethylsilane (for 1H and 13C NMR) and
CCl3F (for 19F NMR) were used as internal standards. IR spectra
were recorded with a Bruker Vertex 70 instrument. Mass spectra
(ESI-MS) were measured with a MicroTof Bruker Daltonics instru-
ment. The progress of reactions was monitored by TLC (silica gel
60 F254, Merck). Column chromatography was carried out on silica
gel 60 (Merck, particle size 0.040–0.063 mm). Elemental analyses
are correct within the limits of Ϯ0.3% for C, H, N. Reactions un-
der microwave irradiation were carried out in sealed tubes. Reac-
Furthermore, compound 18g could be used for the syn-
thesis of indole 24. Oxidation of the OH group with PCC
(pyridinium chlorochromate) led directly to 24 via interme-
diate aldehyde 23, which could not be isolated. Compound
24 was also obtained by dehydrogenation of 22a with DDQ.
Formally, the compounds obtained (i.e., 9a–9e, 13a, 13b,
18a–18l, 22a, and 22b) are aromatic γ-amino acid deriva-
tives. We have previously shown for similar compounds that
the N-benzoyl group and/or the ethyl ester moiety can be
hydrolysed selectively (or both in one step) under acidic or tions using microwave heating were carried out using a Discover
basic conditions.[7] For instance, compound 22a was hydro-
lysed by heating in refluxing aqueous (6 n) HCl to give 5-
(trifluoromethyl)indole-6-carboxylic acid (25) in 66% yield
(Scheme 8).
BenchMate from CEM Corporation (for the conditions, see
Tables 1 and 3). All starting materials were of the highest commer-
cially available quality, and were used as supplied. Pyrone 1a was
prepared as described.[5b]
General Procedure for the Diels–Alder Reaction of Pyrone 1a with
Alkenes 2a–2e, 10a, 10b, and 16a–16m: A mixture of pyrone 1a
(355 mg, 1 mmol) and the corresponding dienophile 2a–2e, 10a,
10b, and 16a–16m (0.5 mL, 5–6 equiv.) was heated without solvent
in a sealed tube under microwave irradiation (see Tables 1 and 3,
main text). The excess of the dienophile was removed under re-
duced pressure, and the product was purified by crystallisation or
by column chromatography.
Scheme 8. Complete hydrolysis of compound 22a.
Ethyl exo-1-Benzamido-9-oxo-7-(trifluoromethyl)-3,8-dioxatricyclo-
[5.2.2.02,6]undec-10-ene-11-carboxylate (exo-3a): Obtained as the
major product from pyrone 1a and 2,3-dihydrofuran (2a) under
Conclusions
mild microwave irradiation (120 W, 120 °C, 10 min) as a mixture
Diels–Alder reactions of trifluoromethyl-substituted
with isomer endo-3a (exo-3a/endo-3a ca. 30:70 by 19F NMR spec-
pyrone 1a with cycloalkenes and acetylenes represent a con-
troscopic analysis of the crude reaction mixture), and isolated by
column chromatography (EtOAc/cyclohexane, 1:4, Rf = 0.32), yield
venient method for the preparation of a variety of trifluoro-
methyl-substituted, polyfunctionalised aromatic com-
89 mg (21%), colourless solid, m.p. 122 °C. IR (KBr): ν = 3403,
˜
pounds. Compounds accessible by this method include pro-
tected bicyclic 5-amino-2-(trifluoromethyl)benzoic acids
9a–9e (via bicyclic cyclohexadienes 4a–4c, 5d, or 5e), in-
danone and tetralone derivatives 13a and 13b, 4-alkyl-5-
benzoylamino-2-(trifluoromethyl)-benzoates 18a–18l, and
22a and 22b. The reactions proceed with high regioselectiv-
ity. We presume that the presence of the CF3 group deter-
mines the regioselectivity of the reaction.
2992, 2846, 1790, 1741, 1662, 1580, 1512, 1484, 1318, 1284, 1195,
1
1099, 979, 895, 725, 630, 524 cm–1. H NMR (300 MHz, CDCl3):
δ = 1.32 (t, J = 7.2 Hz, 3 H, CH3), 2.07–2.34 (m, 2 H, CH2), 3.22
(dd, J = 16.8, J = 9.0 Hz, 1 H, CH), 3.79 (ddd, J = 15.6, J = 9.7,
J = 5.9 Hz, 1 H, Ha of CH2O), 4.14 (ddd, J = 9.7, J = 7.7, J =
3.2 Hz, 1 H, Hb of CH2O), 4.21–4.33 (m, 2 H, CH2O), 5.10 (d, J
= 9.0 Hz, 1 H, CHO), 7.38 (br. s, 1 H, NH), 7.45–7.55 (m, 4 H, Ph
and CH), 7.84–7.95 (m, 2 H, Ph) ppm. 13C NMR (76 MHz,
CDCl3): δ = 13.9, 26.2, 46.1, 62.1, 64.7, 71.6, 78.4, 83.0 (q, J =
31.5 Hz), 121.8 (q, J = 281.0 Hz), 127.3, 128.8, 132.6, 132.8, 135.5,
142.2, 160.9, 166.0, 167.2 ppm. 19F NMR (283 MHz, CDCl3): δ =
–70.99 (s, CF3) ppm. HRMS (ESI): calcd. for C20H19F3NO6
426.1159; found 426.1157. C20H18F3NO6 (425.36): calcd. C 56.47,
H 4.27, N 3.29; found C 56.33, H 4.38, N 3.26.
Experimental Section
General Remarks: NMR spectra were recorded with a Bruker Av-
ance II instrument at 300 and 400 MHz, a Bruker DRX instrument
6
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Trifluoromethyl-Containing Polysubstituted Aromatic Compounds
Ethyl
endo-1-Benzamido-9-oxo-7-(trifluoromethyl)-3,8-dioxatri-
General Procedure for the Aromatisation of Compounds 4a–4c, 5d,
cyclo[5.2.2.02,6]undec-10-ene-11-carboxylate (endo-3a): Obtained as and 5e
the major product from pyrone 1a and 2,3-dihydrofuran (2a) under
Method A: A mixture of DDQ (340 mg, 1.5 mmol) and the appro-
mild microwave irradiation (120 W, 120 °C, 10 min) as a mixture
with isomer endo-3a (exo-3a/endo-3a ca. 30:70 by 19F NMR spec-
troscopic analysis of the reaction mixture), and isolated by column
chromatography (EtOAc/cyclohexane, 1:4, Rf = 0.15), yield 191 mg
priate pure compound 4a–4c, 5d, or 5e (1 mmol) was stirred in
toluene (5 mL) under reflux (4–18 h). Reaction progress was moni-
tored by TLC and NMR spectroscopic analysis of the crude mix-
tures. After conversion was complete, the solvent was removed, and
the corresponding product (i.e., 9a–9e) was purified by column
chromatography or crystallisation.
(45%), colourless solid, m.p. 98 °C. IR (KBr): ν = 3336, 3260, 1799,
˜
1715, 1528, 1489, 1369, 1271, 1194, 1165, 1138, 1100, 1078, 1011,
960, 713, 696, 628 cm–1. H NMR (300 MHz, CDCl3): δ = 1.33 (t,
1
Method B: As for Method A, but instead of pure compound 4a–
4c, 5d, or 5e, the crude product of the Diels–Alder reaction of
pyrone 1a with cycloalkene 2a–2e (see general procedure above)
was used after removing the excess cycloalkene 2a–2e.
J = 7.1 Hz, 3 H, CH3), 1.75–1.92 (m, 1 H, Ha of CH2), 2.20–2.34
(m, 1 H, Hb of CH2), 3.40 (ddd, J = 17.0, J = 9.2, J = 7.9 Hz, 1
H, CH), 3.78 (dt, J = 9.3, J = 6.6 Hz, 1 H, Ha of CH2O), 4.05 (td,
J = 8.6, J = 3.4 Hz, 1 H, Hb of CH2O), 4.22–4.36 (m, 2 H, CH2O),
4.51 (d, J = 7.9 Hz, 1 H, CH), 6.94 (s, 1 H, NH), 7.44–7.61 (m, 3
H, Ph), 7.63 (s, 1 H, CH), 7.87–7.93 (m, 2 H, Ar) ppm. 13C NMR
(76 MHz, CDCl3): δ = 14.0, 28.4, 46.0, 62.1, 64.7, 70.6, 79.6, 82.9
(q, J = 31.0 Hz), 121.0 (q, J = 280.0 Hz), 127.4, 128.7, 129.8, 132.5,
144.5, 161.1, 165.1, 167.3 ppm. 19F NMR (283 MHz, CDCl3): δ =
–73.61 (s, CF3) ppm. HRMS (ESI): calcd. for C20H19F3NO6
426.1159; found 426.1158. C20H18F3NO6 (425.36): calcd. C 56.47,
H 4.27, N 3.29; found C 56.40, H 4.21, N 3.41.
Ethyl
7-Benzamido-4-(trifluoromethyl)-2,3-dihydrobenzofuran-6-
carboxylate (9a): Obtained by Method A from compound 4a
(381 mg, 1 mmol) or by Method B from the crude product of the
Diels–Alder reaction of pyrone 1a (355 mg, 1 mmol) with 2,3-di-
hydrofuran (2a) (reaction time: 5 h), and isolated by column
chromatography (EtOAc/cyclohexane, 1:4, Rf = 0.38), yield by
Method A (from 4a): 303 mg (80%); yield by Method B (from 1a):
262 mg (69%), colourless solid, m.p. 76 °C. IR (KBr): ν = 3226,
˜
2980, 1727, 1652, 1616, 1533, 1488, 1427, 1374, 1337, 1286, 1244,
1193, 1126, 1016, 987, 912, 884, 691 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 1.38 (t, J = 7.1 Hz, 3 H, CH3), 3.48 (td, J = 8.8, J =
1.6 Hz, 2 H, CH2), 4.36 (q, J = 7.1 Hz, 2 H, CH2O), 4.74 (t, J =
8.8 Hz, 2 H, CH2O), 7.45–7.61 (m, 3 H, Ph), 7.83–7.91 (m, 2 H,
Ph), 8.09 (s, 1 H, NH), 8.70 (s, 1 H, Ar) ppm. 13C NMR (76 MHz,
CDCl3): δ = 14.0, 30.6, 61.8, 72.7, 120.5 (q, J = 31.5 Hz), 120.7,
123.6 (q, J = 273.5 Hz), 124.9, 125.4 (q, J = 2.2 Hz), 126.3 (q, J =
2.5 Hz), 127.1, 128.9, 132.4, 133.9, 150.7, 165.4, 167.1 ppm. 19F
NMR (283 MHz, CDCl3): δ = –57.40 (s, CF3) ppm. HRMS (ESI):
calcd. for C19H16F3NNaO4 402.0924; found 402.0920.
C19H16F3NO4 (379.33): calcd. C 60.16, H 4.25, N 3.69; found C
60.02, H 4.36, N 3.80.
Ethyl
cis-7-Benzamido-4-(trifluoromethyl)-2,3,3a,7a-tetrahydro-
benzofuran-6-carboxylate (4a): Obtained as the major product from
pyrone 1a and 2,3-dihydrofuran (2a) under microwave conditions
(150 W, 150 °C, 60 min, see Table 1, entry 1), and purified by crys-
tallisation from CCl4, yield 285 mg (75%), colourless solid, m.p.
81 °C. IR (KBr): ν = 3275, 3098, 2985, 2901, 1729, 1682, 1601,
˜
1531, 1448, 1373, 1290, 1227, 1192, 1143, 1112, 1078, 1047, 1020,
854, 792, 506 cm–1. H NMR (300 MHz, CDCl3): δ = 1.33 (t, J =
1
7.2 Hz, 3 H, CH3), 2.06 (dt, J = 11.9, J = 9.2 Hz, 1 H, Ha of CH2),
2.29–2.51 (m, 1 H, Hb of CH2), 3.09 (dd, J = 18.8, J = 10.0 Hz, 1
H, CH), 3.74–4.01 (m, 2 H, CH2O), 4.29 (q, J = 7.2 Hz, 2 H,
CH2O), 4.98 (d, J = 10.0 Hz, 1 H, CH), 7.09 (s, 1 H, CH), 7.38–
7.67 (m, 3 H, Ar), 7.72–7.93 (m, 2 H, Ar), 8.30 (s, 1 H, NH) ppm.
13C NMR (76 MHz, CDCl3): δ = 13.9, 31.7, 36.7, 61.9, 66.3, 75.4,
103.1, 119.6 (q, J = 34.2 Hz), 123.3 (q, J = 273.5 Hz), 127.0, 128.9,
132.4, 132.9 (q, J = 4.5 Hz), 133.9, 136.2, 166.0, 166.9 ppm. 19F
NMR (283 MHz, CDCl3): δ = –62.20 (s, CF3) ppm. HRMS (ESI):
calcd. for C19H18F3NNaO4 404.1080; found 404.1078.
C19H18F3NO4 (381.35): calcd. C 59.84, H 4.76, N 3.67; found C
59.70, H 4.86, N 3.60.
Ethyl 7-Benzamido-1-oxo-4-(trifluoromethyl)-2,3-dihydro-1H-ind-
ene-5-carboxylate (13a): Obtained as the major product from
pyrone 1a and cyclopent-2-enone (10a) by the general procedure
for a Diels–Alder reaction in the presence of hydroquinone (3–
5 mg) under microwave conditions (150 W, 150 °C, 60 min, see
Scheme 4). After concentration in vacuo, the mixture was dissolved
in Et2O, the insoluble solid was removed by filtration, the filtrate
was concentrated in vacuo, and the resulting residue was crystal-
lised from Et2O/cyclohexane, 2:1, yield 176 mg (45%), yellow solid,
Ethyl 4-Benzamido-1-(trifluoromethyl)-3,5,6,7,8,8a-hexahydronaphth-
alene-2-carboxylate (5d): Obtained as the major product from
pyrone 1a and cyclopentene (2d) under microwave conditions
(250 W, 150 °C, 120 min, see Table 1, entry 4), and purified by crys-
tallisation from CCl4, yield 228 mg (58%), colourless solid, m.p.
m.p. 52 °C. IR (KBr): ν = 3276, 2955, 1729, 1682, 1591, 1523, 1493,
˜
1408, 1285, 1244, 1132, 1056, 1026, 901, 838, 713, 611 cm–1. 1H
NMR (300 MHz, CD2Cl2): δ = 1.40 (t, J = 7.2 Hz, 3 H, CH3),
2.84–2.87 (m, 2 H, CH2), 3.34–3.38 (m, 2 H, CH2), 4.43 (q, J =
7.2 Hz, 2 H, CH2O), 7.55–7.67 (m, 3 H, Ph), 8.04–8.08 (m, 2 H,
Ph), 8.81 (s, 1 H, CH), 11.72 (s, 1 H, NH) ppm. 13C NMR
(76 MHz, CD2Cl2): δ = 13.7, 25.4 (q, J = 3.0 Hz), 36.1, 62.6, 116.7,
118.5 (q, J = 32.5 Hz), 123.6 (q, J = 276.0 Hz), 123.9, 127.4, 129.0,
132.7, 133.3, 140.2, 141.5, 154.7, 165.7, 166.9, 208.2 ppm. 19F
NMR (283 MHz, CD2Cl2): δ = –59.20 (s, CF3) ppm. HRMS (ESI):
calcd. for C20H16F3NNaO4 414.0924; found 414.0927.
C20H16F3NO4 (391.34): calcd. C 61.38, H 4.12, N 3.58; found C
61.46, H 4.00, N 3.72.
84 °C. IR (KBr): ν = 3271, 3063, 2936, 2855, 1730, 1639, 1515,
˜
1486, 1368, 1288, 1268, 1184, 1128, 1094, 1072, 1011, 749,
710 cm–1. H NMR (300 MHz, CD2Cl2): δ = 1.31 (t, J = 7.1 Hz, 3
1
H, CH3), 1.33–1.43 (m, 2 H, CH2), 1.49–1.59 (m, 1 H, H of CH2),
1.81–1.91 (m, 2 H, CH2), 2.18 (d, J = 11.9 Hz, 1 H, H of CH2),
2.73 (d, J = 11.5 Hz, 1 H, H of CH2), 3.03–3.10 (m, 1 H, CH),
3.39 (d, J = 20.5 Hz, 1 H, Ha of CH2), 7.30 (br. s, 1 H, NH), 7.45–
7.57 (m, 3 H, Ph), 7.79–7.84 (m, 2 H, Ph) ppm. 13C NMR
(76 MHz, CD2Cl2): δ = 13.6, 26.2, 27.3, 28.7, 31.6, 34.0, 39.5, 61.7,
120.0, 123.2 (q, J = 275.5 Hz), 126.6 (q, J = 28.0 Hz), 127.0, 128.6,
130.4, 131.7, 134.3 (q, J = 4.0 Hz), 134.4, 166.0, 167.5 ppm. 19F
Ethyl 5-(Benzamido)-4-propyl-2-(trifluoromethyl)benzoate (18a):
Obtained as the major product from pyrone 1a and pent-1-yne
NMR (283 MHz, CD2Cl2): δ = –60.31 (s, CF3) ppm. HRMS (ESI): (16a) under microwave irradiation (150 W, 150 °C, 60 min, see
calcd. for C21H22F3NNaO3 416.1444; found 416.1449. Table 3, entry 1), and purified by column chromatography (EtOAc/
C21H22F3NO3 (393.40): calcd. C 64.11, H 5.64, N 3.56; found C
64.02, H 5.70, N 3.68.
cyclohexane, 1:4, Rf = 0.45), yield 340 mg (90%), pale yellow solid,
m.p. 77 °C. IR (KBr): ν = 3277, 2970, 2934, 1718, 1645, 1573, 1521,
˜
Eur. J. Org. Chem. 0000, 0–0
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G. Haufe et al.
1482, 1408, 1316, 1132, 1029, 926, 910, 692, 501 cm–1. 1H NMR 169.0 ppm. 19F NMR (283 MHz, CDCl3): δ = –59.16 (s, CF3) ppm.
FULL PAPER
(300 MHz, CDCl3): δ = 1.03 (t, J = 7.3 Hz, 3 H, CH3), 1.39 (t, J
= 7.1 Hz, 3 H, CH3), 1.65–1.80 (m, 2 H, CH2), 2.70 (t, J = 7.6 Hz,
2 H, CH2), 4.39 (q, J = 7.1 Hz, 2 H, CH2O), 7.48–7.65 (m, 4 H,
CH and Ph), 7.83–7.94 (m, 3 H, CH and Ar), 8.61 (s, 1 H, NH)
ppm. 13C NMR (76 MHz, CDCl3): δ = 13.9, 14.0, 22.5, 33.3, 61.9,
123.4 (q, J = 272.0 Hz), 124.0, 124.6 (q, J = 31.5 Hz), 127.0, 128.1
(q, J = 6.0 Hz), 129.1, 130.3 (q, J = 1.8 Hz), 132.5, 134.5, 135.1,
138.4, 165.5, 166.4 ppm. 19F NMR (283 MHz, CDCl3): δ = –58.90
(s, CF3) ppm. HRMS (ESI): calcd. for C20H20F3NNaO3 402.1287;
found 402.1282. C20H20F3NO3 (379.37): calcd. C 63.32, H 5.31, N
3.69; found C 63.20, H 5.44, N 3.80.
HRMS (ESI): calcd. for C19H16F3NNaO3 386.0980; found
386.0976. C19H16F3NO3 (363.33): calcd. C 62.81, H 4.44, N 3.86;
found C 62.68, H 4.59, N 3.98.
Ethyl 1-Benzoyl-5-(trifluoromethyl)-1H-indole-6-carboxylate (24)
Method A. From 18g: A mixture of compound 18g (381 mg,
1 mmol) and PCC/silica gel (1:1; 450 mg) in CH2Cl2 (10 mL) was
stirred at room temp. for 8 h. Reaction progress was monitored by
TLC and NMR spectroscopic analysis of the crude mixture. After
the conversion was complete, the mixture was filtered through a
short pad of silica gel. The filtrate was evaporated in vacuo, and
the residue was purified by column chromatography (EtOAc/cyclo-
hexane, 1:2, Rf = 0.66), yield 225 mg (62%).
Ethyl 5-(Benzamido)-4-(2-hydroxyethyl)-2-(trifluoromethyl)benzoate
(18g): Obtained from pyrone 1a and homopropargyl alcohol (16g)
under microwave conditions (150 W, 150 °C, 60 min, see Table 3,
entry 7), and purified by column chromatography (EtOAc/hexane,
1:2, Rf = 0.45), yield 282 mg (74%), colourless solid, m.p. 64–65 °C.
Method B. From 22a: A mixture of compound 22a (363 mg,
1 mmol) and DDQ (340 mg, 1.5 mmol) in toluene (5 mL) was
stirred at room temp. for 8 h. Reaction progress was monitored by
TLC and NMR spectroscopic analysis of the crude mixture. After
the conversion was complete, the solvent was removed in vacuo,
and the residue was purified by column chromatography, yield
IR (KBr): ν = 3384, 2992, 1740, 1662, 1589, 1550, 1369, 1345, 1317,
˜
1
1269, 1232, 1018, 910, 715 cm–1. H NMR (300 MHz, CDCl3): δ =
1.36 (t, J = 7.1 Hz, 3 H, CH3), 2.92 (t, J = 5.2 Hz, 2 H, CH2Ar),
3.50 (br. s, 1 H, OH), 4.02 (t, J = 5.2 Hz, 2 H, CH2OH), 4.35 (q,
J = 7.1 Hz, 2 H, OCH2Me), 7.36–7.50 (m, 3 H, Ph), 7.51 (s, 1 H,
Ar), 7.86–7.91 (m, 2 H, Ph), 8.44 (s, 1 H, Ar), 10.27 (s, 1 H, NH)
ppm. 13C NMR (76 MHz, CDCl3): δ = 13.9, 35.0, 62.1, 64.5, 123.3
(q, J = 272.9 Hz), 124. 3 (q, J = 32.1 Hz), 124.9, 127.3, 128.7, 129.2
(q, J = 5.3 Hz), 130.3, 132.2, 133.8, 134.9, 140.4, 165.9, 166.8 ppm.
19F NMR (283 MHz, CDCl3): δ = –59.37 (s, CF3) ppm. HRMS
(ESI): calcd. for C19H18F3NNaO4 404.1080; found 404.1084.
C19H18F3NO4 (381.35): calcd. C 59.84, H 4.76, N 3.67; found C
59.76, H 4.69, N 3.91.
210 mg (58%), colourless solid, m.p. 54–55 °C. IR (KBr): ν = 3295,
˜
1721, 1658, 1613, 1593, 1536, 13212, 1232, 1142, 1109, 1039, 1019,
1
847, 714, 691 cm–1. H NMR (300 MHz, CDCl3): δ = 1.39 (t, J =
6.9 Hz, 3 H, CH3), 4.40 (q, J = 6.9 Hz, 2 H, CH2O), 7.49–7.64 (m,
3 H, Ph), 7.75 (d, J = 8.7 Hz, 1 H, Ar), 7.85–7.91 (m, 2 H, Ph),
7.96 (s, 1 H, Ar), 8.05 (s, 1 H, Ar), 8.07 (d, J = 8.7 Hz, 1 H, Ar)
ppm. 13C NMR (76 MHz, CDCl3): δ = 13.5, 61.8, 120.5, 121.0,
122.9 (q, J = 272.0 Hz), 123.7 (q, J = 31.2 Hz), 126.7, 127.7 (q, J
=
5.4 Hz), 128.6, 132.0, 132.1, 132.3, 133.7, 140.6, 165.3,
165.9 ppm. 19F NMR (283 MHz, CDCl3): δ = –59.27 (s, CF3) ppm.
HRMS (ESI): C19H14F3NNaO3 384.3038; found 384.3042.
C19H14F3NO3 (361.31): calcd. C 63.16, H 3.91, N 3.88; found C
63.02, H 4.07, N 3.68.
Synthesis of Compounds 22a and 22b: Mesyl chloride (124 mg,
1.1 mmol) was added to a solution of compound 18g (381 mg,
1 mmol) or 18h (395 mg, 1 mmol) and Et3N (111 mg, 1.1 mmol) in
CH2Cl2 (10 mL) at 0 °C. The reaction mixture was stirred overnight
at room temp., then it was poured into water, and the mixture was
extracted with CH2Cl2 (3ϫ 20 mL). The organic layer was dried
with MgSO4, and concentrated in vacuo to give crude 21a (410 mg)
or 21b (425 mg), which were used for the next step without purifica-
tion.
5-(Trifluoromethyl)indoline-6-carboxylic Acid (25): A mixture of
compound 22a (3.63 g, 10 mmol) and HCl (6 n; 50 mL) was stirred
at reflux for 48 h. Reaction progress was monitored by TLC and
1H NMR spectroscopic analysis of the reaction mixture. After the
conversion was complete, the mixture was cooled, and the precipi-
tate of benzoic acid was removed by filtration. The water solution
was evaporated. The resulting solid residue was washed with hot
CCl4 to give pure compound 25 (as its hydrochloride salt), yield
A mixture of crude compound 21a (410 mg) or 21b (425 mg) and
Cs2CO3 (390 mg, 1.2 mmol) was heated at reflux with vigorous stir-
ring for 6 h. The reaction was monitored by TLC and NMR spec-
troscopy of the crude mixtures. After conversion was complete, the
solvent was removed, and the product (i.e., 22a or 22b) was purified
by column chromatography.
1.77 g (66%), pale brown solid, m.p. 66 °C. IR (KBr): ν = 3393,
˜
2858, 1727, 1697, 1623, 1594, 1503, 1428, 1382, 1298, 1252, 1215,
1136, 1100, 1025, 964, 901, 836, 745, 713, 645, 612, 536, 457,
1
419 cm–1. H NMR (300 MHz, D2O): δ = 3.25 (t, J = 7.2 Hz, 2 H,
CH2), 3.84 (t, J = 7.2 Hz, 2 H, CH2), 7.72 (s, 1 H, Ar), 7.73 (s, 1
2-(Benzamido)-4-(ethoxycarbonyl)-5-(trifluoromethyl)phenethyl
H, Ar) ppm. 13C NMR (76 MHz, D2O): δ = 28.5, 46.1, 120.0, 122.3
1
Methanesulfonate (21a): H NMR (300 MHz, CDCl3): δ = 1.38 (t, (q, J = 275.1 Hz), 124.7 (q, J = 5.5 Hz), 128.5 (q, J = 32.5 Hz),
J = 7.1 Hz, 3 H, CH3), 2.94 (s, 3 H, CH3), 3.20 (t, J = 6.2 Hz, 2 131.8, 138.5, 139.4, 169.0 ppm. 19F NMR (283 MHz, CDCl3): δ
H, CH2), 4.40 (q, J = 7.1 Hz, 2 H, CH2O), 4.53 (t, J = 6.2 Hz, 2 = –59.68 (s, CF3) ppm. HRMS (ESI): calcd. for C10H8F3NNaO2
H, CH2O), 7.48–7.66 (m, 4 H, Ar), 7.93–8.01 (m, 2 H, Ar), 8.38 (s,
1 H, Ar), 8.43 (s, 1 H, NH) ppm. HRMS (ESI): calcd. for
C20H20F3NNaO6S 482.0861; found 482.0856.
254.0399; found 254.0401. C10H8F3NO2·HCl (267.63): calcd. C
44.88, H 3.39, N 5.23; found C 44.99, H 3.25, N 5.11.
X-ray Diffraction: Data sets for compounds 3a and 8 were collected
with a D8 Venture Dual Source 100 CMOS diffractometer. Pro-
grams used: data collection: APEX2 V2014.5–0 (Bruker AXS Inc.,
2014); cell refinement: SAINT V8.34A (Bruker AXS Inc., 2013);
data reduction: SAINT V8.34A (Bruker AXS Inc., 2013); absorp-
Ethyl 1-Benzoyl-5-(trifluoromethyl)indoline-6-carboxylate (22a):
Purified by column chromatography (EtOAc/cyclohexane, 1:1, Rf
= 0.34), yield 230 mg (63% from 18g), colourless solid, m.p. 37–
38 °C. IR (CH Cl ): ν = 2985, 1733, 1657, 1614, 1496, 1394, 1337,
˜
2
2
1294, 1134, 1106, 1079, 965 cm–1. H NMR (300 MHz, CDCl3): δ tion correction, SADABS V2014/2 (Bruker AXS Inc., 2014); struc-
1
= 1.33 (t, J = 6.9 Hz, 3 H, CH3), 3.19 (t, J = 7.8 Hz, 2 H, CH2), ture solution SHELXT-2014 (Sheldrick, 2014); structure refine-
4.15 (t, J = 7.8 Hz, 2 H, CH2N), 4.33 (q, J = 6.9 Hz, 2 H, CH2O),
ment SHELXL-2014 (Sheldrick, 2014); and graphics, XP (Bruker
7.40–7.60 (m, 7 H, Ar) ppm. 13C NMR (76 MHz, CDCl3): δ = AXS Inc., 2014). For compound 18g, the data sets were collected
13.5, 27.6, 50.3, 61.6, 117.4, 122.8, 123.0 (q, J = 275.0 Hz), 123.4 with a Nonius KappaCCD diffractometer. Programs used: data
(q, J = 36.2 Hz), 126.6, 128.4, 130.5, 131.2, 134.7, 145.1, 166.2, collection, COLLECT (R. W. W. Hooft, Bruker AXS, 2008, Delft,
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Trifluoromethyl-Containing Polysubstituted Aromatic Compounds
The Netherlands); data reduction Denzo-SMN;[13a] absorption cor-
rection, Denzo;[13b] structure solution SHELXS-97;[13c] structure
refinement SHELXL-97.[13d] R values are given for observed reflec-
tions, and wR2 values are given for all reflections.
group P21/c (No. 14), λ = 1.54178 Å, T = 223(2) K, ω and φ scans,
12725 reflections collected (Ϯh, Ϯk, Ϯl), 3213 independent (Rint
=
0.053) and 2617 observed reflections [IϾ2σ(I)], 250 refined param-
eters, R = 0.051, wR2 = 0.144, max. (min.) residual electron density
0.27 (–0.21) eÅ–3. The hydrogen at N1 was refined freely; others
were calculated and refined as riding atoms.
X-ray Crystal Structure Analysis of exo-3a: A colourless prism-
like specimen of C20H18F3NO6, approximate dimensions
0.114ϫ0.178ϫ0.328 mm3, was used for the X-ray crystallographic
analysis. The X-ray intensity data were measured. A total of 1674
frames were collected. The total exposure time was 13.12 h. The
frames were integrated with the Bruker SAINT software package
using a wide-frame algorithm. The integration of the data using a
triclinic unit cell yielded a total of 23043 reflections to a maximum
θ angle of 68.35° (0.83 Å resolution), of which 3333 were indepen-
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG) (Ha 2145/9-1; AOBJ: 560896). The authors also thank En-
amine Ltd., Kiev for technical and financial support. The authors
are grateful to Dr. R. Fröhlich (University of Münster) for the X-
ray analysis of compound 18g, and express their appreciation to
Dr. S. I. Vdovenko and O. A. Fedorenko (Institute of Bioorganic
Chemistry and Petrochemistry, National Academy of Sciences,
Ukraine) for measuring the IR spectra.
dent (average redundancy 6.914, completeness: 99.8%, Rint
=
3.93%, Rsig = 2.35%) and 3128 (93.85%) were greater than 2σ(F2).
The final cell constants of a = 7.9321(3) Å, b = 10.7244(3) Å, c =
11.5725(4) Å, α = 70.9960(10)°, β = 88.2530(10)°, γ = 77.8510(10)°,
volume: 909.16(5) Å3, are based upon the refinement of the
XYZ centroids of 9906 reflections above 20σ(I) with
8.087°Ͻ2θϽ136.7°. Data were corrected for absorption effects
using the multi-scan method (SADABS). The ratio of minimum to
maximum apparent transmission was 0.934. The calculated mini-
mum and maximum transmission coefficients (based on crystal
size) are 0.7010 and 0.8790. The final anisotropic full-matrix least-
squares refinement on F2 with 276 variables converged at R1 =
3.03%, for the observed data and wR2 = 7.57% for all data. The
goodness-of-fit was 1.054. The largest peak in the final difference
electron density synthesis was 0.311 eÅ–3 and the largest hole was
–0.235 eÅ–3 with an RMS deviation of 0.043 eÅ–3. On the basis of
the final model, the calculated density was 1.554 gcm–3 and F(000),
440 e.
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X-ray Crystal Structure Analysis of 8:
A colourless prism-
like specimen of C23H24F3NO5, approximate dimensions
0.250ϫ0.270ϫ0.291 mm3, was used for the X-ray crystallographic
analysis. The X-ray intensity data were measured. A total of 498
frames were collected. The total exposure time was 3.59 h. The
frames were integrated with the Bruker SAINT software package
using a wide-frame algorithm. The integration of the data using an
orthorhombic unit cell yielded a total of 10906 reflections to a
maximum θ angle of 68.21° (0.83 Å resolution), of which 3684 were
independent (average redundancy 2.960, completeness: 99.7%, Rint
= 2.20%, Rsig = 2.49%) and 3638 (98.75%) were greater than
2σ(F2). The final cell constants of
a = 9.6869(3) Å, b =
14.1210(5) Å, c = 15.0292(5) Å, volume: 2055.82(12) Å3, are based
upon the refinement of the XYZ centroids of 9928 reflections above
20σ(I) with 5.880°Ͻ2θϽ136.7°. Data were corrected for absorp-
tion effects using the multi-scan method (SADABS). The ratio of
minimum to maximum apparent transmission was 0.909. The cal-
culated minimum and maximum transmission coefficients (based
on crystal size) are 0.7550 and 0.7840. The final anisotropic full-
matrix least-squares refinement on F2 with 294 variables converged
at R1 = 2.42%, for the observed data and wR2 = 6.07% for all
data. The goodness-of-fit was 1.074. The largest peak in the final
difference electron density synthesis was 0.222 eÅ–3 and the largest
hole was –0.166 eÅ–3 with an RMS deviation of 0.034 eÅ–3. On
the basis of the final model, the calculated density was 1.459 gcm–3
and F(000), 944 e.
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6364–6365.
X-ray Crystal Structure Analysis of 18g: Formula C19H18F3NO4,
M
= 381.34, colourless crystal, 0.25ϫ0.20ϫ0.05 mm, a =
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13.2281(7), b = 10.4600(7), c = 13.7512(9) Å, β = 107.237(5)°, V =
1817.2(2) Å3, ρcalc = 1.394 gcm–3, μ = 1.013 mm–1, empirical ab-
sorption correction (0.785ՅTՅ0.951), Z = 4, monoclinic, space
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Pages: 11
G. Haufe et al.
FULL PAPER
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Haufe, Synthesis 2005, 1269–1278.
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[8] CCDC-1037629 (for exo-3a), -1037630 (for 8), and -1037631
(for 18g) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
[10]
[11]
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NMR spectra as quartets at δ = 25.4 (J = 3.0 Hz, 10a) and
28.2 (J = 3.2 Hz, 10b) ppm, which indicates the proximity of
this moiety to the CF3 group.
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Received: January 9, 2015
[9] The most characteristic signals in the NMR spectra of com-
pounds 6 are the doublets in the 19F NMR spectra between δ
= –64.5 and –67.5 (J = 8.5–9.0 Hz) ppm. These can easily be
identified in the NMR spectra of the reaction mixtures.
Published Online: ᭿
10
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Eur. J. Org. Chem. 0000, 0–0

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Date: 25-02-15 12:37:28
Pages: 11
Trifluoromethyl-Containing Polysubstituted Aromatic Compounds
Fluorinated Compounds
I. S. Kondratov, N. A. Tolmachova,
V. G. Dolovanyuk, I. I. Gerus, C.-
G. Daniliuc, G. Haufe* ................... 1–11
Synthesis of Trifluoromethyl-Containing
Polysubstituted Aromatic Compounds by
Diels–Alder Reaction of Ethyl 3-Benz-
amido-2-oxo-6-(trifluoromethyl)-2H-pyran-
5-carboxylate
Keywords: Synthetic methods / Alkenes /
Alkynes / Cycloaddition / Carbocycles /
Amino acids / Fluorine
Reactions of ethyl 3-benzamido-2-oxo-6-
(trifluoromethyl)-2H-pyran-5-carboxylate
with cyclic alkenes and terminal acetylenes
are useful for the efficient and selective
preparation of trifluoromethyl-containing
polyfunctionalised aromatic amino acid de-
rivatives.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11