Diels-Alder reaction of ethyl 3-benzamido-2-oxo-6-(trifluoromethyl)-2H- pyran-5-carboxylate with alkoxyalkenes as an effective approach to trifluoromethyl-containing 3-aminobenzoic acid derivatives

Article abstract of DOI:10.1002/ejoc.201301485

The Diels-Alder reactions of ethyl 3-benzamido-2-oxo-6-(trifluoromethyl)- 2H-pyran-5-carboxylate with ethyl vinyl ether, 2-methoxypropene, and 1-ethoxypropene were investigated. Under different reaction conditions, intermediate oxabicyclo[2.2.2]octenones,

Full text of DOI:10.1002/ejoc.201301485

FULL PAPER
DOI: 10.1002/ejoc.201301485
Diels–Alder Reaction of Ethyl 3-Benzamido-2-oxo-6-(trifluoromethyl)-2H-
pyran-5-carboxylate with Alkoxyalkenes as an Effective Approach to
Trifluoromethyl-Containing 3-Aminobenzoic Acid Derivatives
Ivan S. Kondratov,[a] Nataliya A. Tolmachova,[a] Violetta G. Dolovanyuk,[a] Igor I. Gerus,[a]
Klaus Bergander,[b] Constantin-Gabriel Daniliuc,[b] and Günter Haufe*[b]
Keywords: Synthetic methods / Oxygen heterocycles / Cycloaddition / Fluorine / Aromatization
The Diels–Alder reactions of ethyl 3-benzamido-2-oxo-6-(tri-
fluoromethyl)-2H-pyran-5-carboxylate with ethyl vinyl ether,
2-methoxypropene, and 1-ethoxypropene were investigated.
Under different reaction conditions, intermediate oxabi-
cyclo[2.2.2]octenones, alkoxycyclohexadienes, or aromatic
products [5-benzamido-2-(trifluoromethyl)benzoates] were
formed. The reaction is useful for the preparation of some
hitherto unknown trifluoromethyl-containing derivatives of
3-aminobenzoic acid.
Introduction
2H-Pyran-2-ones are widely used in organic synthesis as
convenient 1,3-dienes for Diels–Alder reactions, the cyclo-
adducts of which usually provide aromatic compounds
upon the elimination of CO2.[1] Although there are few re-
ports that consider Diels–Alder reactions with trifluoro-
methyl-containing pyrones,[2] the reaction might be a conve-
nient method to prepare new trifluoromethylated aromatic
building blocks, which include those of interest for medici-
nal chemistry and agrochemistry.
In addition to our earlier investigations of [4+2] cycload-
dition reactions of fluorinated compounds,[3] we have de-
scribed the synthesis of 3-benzamido-6-(trifluoromethyl)-
2H-pyran-2-ones 1–3 from readily available β-alkoxy en-
ones[4] and the Diels–Alder reactions[2b] of 1–3 with various
dienophiles to lead to compounds 4–6 (see Scheme 1).
Herein, we present our results of the Diels–Alder reac-
tions between pyrone 2 and vinyl ethers as well as the appli-
cation of this reaction to the synthesis of trifluoromethyl-
substituted 3-aminobenzoic acid 7 and its derivatives. 3-
Aminobenzoic acid moieties are common structural ele-
ments of biologically active compounds. The anesthetic
Scheme 1. Diels–Alder reactions of pyrones 1–3 with different
dienophiles as described in the literature.[2b]
Metabutethamine, the antihypertensive drug Tienoxolol,
and the antibiotic Ertapenem are commercialized drugs
that contain this motif (see Figure 1). Therefore, compound
7 and its derivatives are of interest as building blocks for
medicinal chemistry as the introduction of fluorine and
fluorinated groups into biologically active compounds is a
generally effective strategy to design new drugs.[5]
[a] Institute of Bioorganic Chemistry and Petrochemistry, National
Ukrainian Academy of Science,
Murmanska 1, 02660 Kiev 94, Ukraine
[b] 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
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301485.
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1
1
Figure 2. H{1H}- and H{19F}-NOE of compounds 8a and 8b.
Figure 1. Commercialized drugs that contain the 3-aminobenzoic
acid skeleton.
Results and Discussion
We began our investigation with the reaction of pyrone
2 and ethyl vinyl ether under conventional heating or micro-
wave irradiation (see Scheme 2 and Table 1). The outcome
of the reaction was analyzed by 19F NMR spectroscopy.
As expected, the reaction proceeded regioselectively to give
initially a mixture of endo- and exo-bicyclic adducts 8a and
8b, which upon elimination of carbon dioxide formed cyclo-
Figure 3. X-ray crystal structures of compound 8a, 12a, and 13b
(from left to right, 30% probability).[6]
Compound 9 was formed predominantly under forced
hexadiene derivative 9. Finally, N-benzoyl aminobenzoic es- conditions (see Table 1, Entry 5) and was identified in the
1
ter 10 was formed by the elimination of ethanol. Depending product mixture by using H and 19F NMR spectroscopic
on the conditions, the predominant formation of one of the analysis as well as HRMS.[7] However, our attempts to iso-
products 8, 9, or 10 was observed.
late this compound by column chromatography or by
Bicyclic adduct 8a was found as major product after recrystallization failed. Only aromatic product 10 was iso-
gentle heating (see Table 1, Entry 1) or mild microwave irra- lated in up to 64% yield (based on 2, see Table 1, Entry 5).
diation (see Table 1, Entry 2). At elevated temperatures with This product was also obtained in 60% yield through the
microwave irradiation, mixtures of 8a and up to 20% of reaction of pyrone 2 with ethyl vinyl ether under more forc-
exo-adduct 8b (see Table 1, Entries 3 and 4) were formed. ing conditions (see Table 1, Entry 6) and even then under
Products 8a and 8b were easily isolated and separated by stronger forcing thermal conditions (see Table 1, Entry 7).
column chromatography. The regiochemistry and relative The reaction could be scaled up to prepare 20 g amounts
configuration of these compounds were assigned by of 10 in one batch. Compound 10 was also formed by heat-
1H{1H}- and 1H{19F}-NOE experiments (see Figure 2). ing 8a and 8b at 180 °C.
Furthermore, the major product 8a was crystallized from
toluene (87% yield), and the structure was proved by X-ray pound 9 were recently investigated by Kocˇevar and co-
crystal structure analysis (see Figure 3).
workers,[8] who were also faced with their low stability and
Nonfluorinated cyclohexa-1,3-dienes similar to com-
Scheme 2. Diels–Alder reaction of 2H-pyran-2-one 2 with ethyl vinyl ether (for product ratios and yields from different reaction condi-
tions, see Table 1; DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone).
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Trifluoromethyl-Containing 3-Aminobenzoic Acid Derivatives
Table 1. Reaction of pyrone 2 with alkoxy alkenes (see Schemes 2 and 3).
[a] The ratios of the products were determined by 19F NMR spectroscopic analysis of the crude product mixtures. [b] The starting pyrone
2 was not isolated from the product mixtures. [c] Cyclohexadienes 9 and 15 were completely transformed into compounds 10 and 16,
respectively, during isolation by column chromatography.
1
1
aromatization during column chromatography. The more respectively) and by using H{1H}- and H{19F}-NOE ex-
stable bicyclic cyclohexa-1,3-dienes 5 were formed from the periments (see Supporting Information). In addition, the
reaction with pyrone 1 (see Scheme 1).[2b]
structure of the major isomer 12a was confirmed by X-ray
Alternatively, compound 9 (in a mixture with 10) can be crystal structure analysis (see Figure 3). Thus, trans-1-
thermally dehydrogenated by treatment with DDQ or mi- ethoxypropene predominantly underwent the reaction.
crowave irradiation. Aryl ethyl ether 11 was separated from
Heating pyrone 2 with 2-methoxypropene at 120 °C for
compound 10 by column chromatography and isolated in 90 min resulted in low conversion (see Table 1, Entry 12).
56% yield (based on pyrone 2). It is worth noting that upon However, under mild microwave irradiation, a mixture of
reaction of pyrone 1 with ethyl vinyl ether, neither bicyclic diastereomers 13a and 13b (see Figure 4) was formed. These
adducts analogous to 8 nor cyclohexa-1,3-diene derivatives compounds were separated by column chromatography and
analogous to 9 were isolated.[2b]
isolated in good yield (see Table 1, Entry 13). NOE data
Next, the reactions of pyrone 2 with cis/trans-1-ethoxy- for 13a and 13b were not sufficient to establish the relative
propene and 2-methoxypropene were investigated (see configuration of each of the stereoisomers unambiguously.
Scheme 3). Gentle heating or microwave irradiation of Thus, the structure of the crystalline minor product 13b was
pyrone 2 with an excess amount of cis/trans-1-ethoxyprop- confirmed by using X-ray crystal analysis (see Figure 3).
ene (3:1) gave mixtures of diastereomers 12 (see Table 1,
Cyclohexa-1,3-dienes 14a and 14b (ratios from 1:3 to 1:5)
Entries 8 and 9). Only 12a and 12b with the Me and EtO with the methyl and ethoxy groups in a cis or trans orienta-
groups in the trans orientation (see Figure 4) were iso- tion were formed by the reaction of pyrone 2 with cis/trans-
lated,[9] and their configurations were assigned according 1-ethoxypropene. Compounds 14a and 14b were isolated in
to the small vicinal coupling constants of 2.3 and 2.6 Hz, 12 and 67% (see Table 1, Entries 10 and 11, respectively),
respectively, (compared to 2.0 and 2.6 Hz for 8a and 8b, whereas the trans cycloadducts 12a and 12b were isolated
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Scheme 3. Reaction of pyrone 2 with 2-methoxypropene and cis/trans-1-ethoxypropene (for product ratios and yields from different
reaction conditions, see Table 1, MW = microwave).
under milder conditions (see Table 1, Entries 8 and 9).[9] On
the other hand, the reaction with 2-methoxypropene under
the same conditions led to a mixture of cyclohexadiene 15
and aromatized product 16 (see Table 1, Entries 14 and 15).
Compound 15 (just as cyclohexa-1,3-diene 9) was identified
1
in the mixture by H and 19F NMR spectroscopic analysis
as well as HRMS,[10] but could not be isolated because of
its easy aromatization into 16. The latter compound was
isolated in yields up to 66%.
In contrast, there was no significant aromatization of
compounds 14a and 14b through the elimination of eth-
anol, even after further heating under forced microwave ir-
radiation conditions (see Scheme 4). Only by heating com-
pounds 14a and 14b at reflux in toluene in the presence of
p-toluenesulfonic acid for 1 h led to the formation of aro-
Figure 4. Confirmed structures of compounds 12a, 12b, 13a, and
13b.
Scheme 4. Steric and electronic factors that prevent thermal EtOH elimination.
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Trifluoromethyl-Containing 3-Aminobenzoic Acid Derivatives
matic compound 17 in 89% yield (see Scheme 5). To explain
the stability of compounds 14a and 14b (in comparison to
the thermolabile compound 9), we examined the conforma-
tions of each isomer.
Scheme 5. Mechanism of acid-catalyzed EtOH elimination from
compounds 14a and 14b.
For a thermal E2 elimination, the favored conformation
for the elimination of EtOH is the antiperiplanar orienta-
tion of the hydrogen atom and the ethoxy group at the 3-
and 4-positions, respectively. This orientation is possible in
conformation A of the minor cis-isomer 14a, but this geom-
etry is disfavored because of the repulsive interaction be-
tween the neighboring CF3 and Me groups. In conforma-
tion B, these groups are gauche to each other (see
Scheme 4). In the case of trans-isomer 14b, conformer C is
also destabilized because of a steric repulsion between the
bulky groups. In conformer D, however, the neighboring
hydrogen atom and ethoxy group at the 3- and 4-positions,
respectively, are again in the gauche conformation. Thus,
all of the structures A through D are disfavored for the E2
elimination of ethanol. On the other hand, an E1 elimi-
nation in the absence of an acid also seems unlikely, as the
C–O scission is not assisted by the conjugated double bond.
This might explain the thermal stability of 14a and 14b.
The most stable conformations of compounds 14a and
14b were established by the NMR spectroscopic data (see
Figure 5), which demonstrate and equatorial-axial orienta-
Figure 5. NMR spectroscopic data for compounds 14a and 14b.
Scheme 6. Dehydrogenation of compounds 14a and 14b by treat-
ment with DDQ.
48 h) to give compound 7 in 56% yield (see Scheme 7). Ad-
ditionally we found that the hydrolysis of the benzamide
group proceeded more easily than that of the ester function
under milder acidic conditions, and this allowed the isola-
tion of amino ester 20 with 73% yield. On the other hand,
the ester group was selectively hydrolyzed by using “anhy-
drous hydroxide”[12] that was generated by tBuOK in tetra-
hydrofuran (THF)/H2O to give amido ester 21 in 88% yield.
The same conditions were used to hydrolyze the ester func-
tion of compound 20 to lead to compound 7 in 85% yield.
tion of the H-3 and H-4 atoms in compound 14a (JH,H
=
6.5 Hz, strong H{H}-NOE between H-4 and H-3, no
H{H}-NOE between H-4 and CH3-3) and an equatorial-
equatorial orientation of the H-3 and H-4 atoms in 14b
(JH,H = 2.3 Hz, strong H{H}-NOE between H-4 and H-3
as well as H-4 and CH3-3).
In the presence of p-toluenesulfonic acid, however, the
E1 elimination becomes probable, as protonation of the
ether oxygen and EtOH elimination lead to the formation
of the carbocationic intermediate E, which deprotonates to
give aromatic compound 17. Under these conditions, the
relative configuration and favored conformation of 14 do
not influence the aromatization process significantly (see
Scheme 5). Furthermore, compounds 14a and 14b (just as
compound 9) can be oxidized by treatment with DDQ to
give compound 18 in 51% yield (see Scheme 6).
To obtain amino acid 7, we hydrolyzed compound 10.
Under strong basic conditions, the hydrolysis of the ester
and amide functions occurred, but the CF3 group was also
converted into a carboxylic acid to give compound 19 in
75% yield.[11] In contrast, compound 10 was entirely hy-
Scheme 7. Hydrolysis reactions of compound 10.
Conclusions
The Diels–Alder reactions of ethyl 3-benzamido-2-oxo-
drolyzed under strong acidic conditions (6 n HCl, reflux, 6-(trifluoromethyl)-2H-pyran-5-carboxylate (2) with ethyl
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160.0, 165.3, 167.3 ppm. 19F NMR (564 MHz, CDCl3): δ = –74.92
(s, CF3) ppm. MS (ESI): calcd. for C20H20F3NNaO6 450.1135;
found 450.1137.
vinyl ether, cis/trans-1-ethoxypropene, and 2-methoxy-
propene under different reaction conditions was used for
the preparation of bicyclic adducts 8, 12, and 13. Under
forced conditions, the elimination of CO2 from these
cycloadducts formed cyclohexa-1,3-diene derivatives 9, 14,
and 15, respectively, followed by the elimination of ethanol
to give aromatic N-benzoylamino esters 10 and 17 and the
elimination of methanol to give 16. Compounds 11 and 18
were formed by the oxidation of compounds 9 as well as
14a and 14b by treatment with DDQ. Moreover, compound
10 was selectively hydrolyzed under different reaction con-
ditions to give either trifluoromethylated amine 20, carb-
oxylic acid 21, or amino acid 7. The Diels–Alder reactions
of pyrone 2 with other dienophiles and the applications of
these cycloadducts for the synthesis of promising fluorin-
ated building blocks are under investigation.
Ethyl exo-4-Benzamido-8-ethoxy-3-oxo-1-(trifluoromethyl)-2-oxa-
bicyclo[2.2.2]oct-5-ene-6-carboxylate (8b): The reaction of pyrone 2
and ethyl vinyl ether under microwave irradiation (see Table 1, En-
tries 3 and 4) gave the crude product that was purified by column
chromatography (EtOAc/Hex, 1:2; Rf = 0.60). The most appropri-
ate conditions were microwave heating (200 W) at 120 °C for
60 min to give the minor product 8b (47 mg, 11% yield) as a color-
less solid; m.p. 116–118 °C. IR (KBr): ν = 1016, 1047, 1109, 1137,
˜
1177, 1194, 1217, 1255, 1289, 1371, 1517, 1582, 1739, 1779, 2890,
1
2932, 2987, 3308 cm–1. H NMR (600 MHz, CDCl3): δ = 1.10 (t,
J = 7.0 Hz, 3 H, CH3), 1.31 (t, J = 7.2 Hz, 3 H, CH3), 2.32 (dd, 1J
2
1
= 13.6 Hz, J = 2.6 Hz, 1 H, Ha of CH2), 2.61 (dd, J = 13.5 Hz,
2J = 8.8 Hz, 1 H, Hb of CH2), 3.48 (dq, J = 9.7 Hz, J = 6.9 Hz,
1
2
1
2
1 H, Ha of CH2O), 3.55 (dq, J = 9.7 Hz, J = 6.9 Hz, 1 H, Hb of
CH2O), 4.23–4.29 (m, 2 H, CH2O), 4.74 (dd, 1J = 8.8 Hz, 2J =
2.6 Hz, 1 H, CHO), 7.41 (br. s, 1 H, NH), 7.50–7.54 (m, 2 H, Ph),
7.58–7.60 (m, 1 H, Ph), 7.61 (s, 1 H, CH), 7.87–7.90 (m, 2 H,
Ph) ppm. 13C NMR (150 MHz, CDCl3): δ = 13.9, 15.1, 35.5, 62.0,
65.2, 67.0, 71.5, 81.4 (q, J = 35.5 Hz), 121.6 (q, J = 282.0 Hz),
127.1, 128.9, 132.5, 133.0, 133.8, 143.4, 159.9, 106.2, 167.3 ppm.
19F NMR (564 MHz, CDCl3): δ = –75.00 (s, CF3) ppm. MS (ESI):
calcd. for C20H20F3NNaO6 450.1135; found 450.1134.
Experimental Section
General Methods: The NMR spectroscopic data were recorded with
a Bruker Avance II at 300 or 400 MHz, a Bruker DRX at
1
300 MHz, and an Agilent DD2 at 500 or 600 MHz (for H NMR)
1
at 25 °C. TMS (for H and 13C NMR) and CCl3F (for 19F NMR)
Ethyl 5-Benzamido-2-(trifluoromethyl)benzoate (10): The reaction
of pyrone 2 and ethyl vinyl ether under microwave irradiation (see
Table 1, Entries 5–7) gave the crude product that was purified by
crystallization (toluene) or column chromatography (EtOAc/Hex,
1:4; Rf = 0.26). The most appropriate conditions were microwave
heating (250 W) at 180 °C for 30 min to give the main product 10
(216 mg, 64% yield) as a colorless solid; m.p. 109–110 °C. IR
were used as internal standards. IR spectra were recorded with a
Bruker Vertex 70. Mass spectra (ESI-MS) were measured with a
Bruker Daltonics MicroTof. The progress of the reactions was
monitored by TLC (silica gel 60 F254, Merck). Column chromatog-
raphy 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, and N. Reactions under microwave irradiation
were carried out in sealed tubes. The microwave oven was a Dis-
cover BenchMate from CEM Corporation (for the conditions, see
Table 1). All starting materials were of the highest commercial
quality and were used without further purification. Pyrone 2 was
prepared as described.[4]
(KBr): ν = 1111, 1141, 1265, 1320, 1596, 1659, 1723, 2995,
˜
1
3296 cm–1. H NMR (300 MHz, CDCl3): δ = 1.38 (t, J = 7.2 Hz,
3 H, CH3), 4.37 (q, J = 7.2 Hz, 2 H, CH2O), 7.46–7.63 (m, 3 H,
Ph), 7.74 (d, J = 8.4 Hz, 1 H, CH), 7.85–7.91 (m, 2 H, Ph), 7.96
1
2
(d, J = 2.3 Hz, 2 H, CH), 8.09 (dd, J = 8.4 Hz, J = 2.3 Hz, 1 H),
8.20 (s, 1 H, NH) ppm. 13C NMR (76 MHz, CDCl3): δ = 13.9,
62.3, 121.0, 121.5, 123.4 (q, J = 275.0 Hz), 124.0 (q, J = 33.2 Hz),
127.1, 128.1 (q, J = 5.1 Hz), 129.0, 132.5, 134.0, 141.1, 166.0,
166.6 ppm. 19F NMR (283 MHz, CDCl3): δ = –59.28 (s, CF3) ppm.
MS (ESI): calcd. for C17H14F3NNaO3 360.0818; found 360.0818.
General Procedure for Diels–Alder Reactions of Pyrone 2 with Alk-
oxyalkenes: A mixture of pyrone 2 (355 mg, 1 mmol) and the corre-
sponding alkoxyalkene (ethyl vinyl ether, 1-ethoxypropene, or 2-
methoxypropene; 0.5 mL, 5–6 equiv.) was heated without solvent
in a sealed tube or microwave irradiated (see Table 1). The excess
amount of the alkoxyalkene was removed, and the corresponding
product was purified by crystallization or column chromatography.
Ethyl 5-Benzamido-4-ethoxy-2-(trifluoromethyl)benzoate (11):
A
mixture of crude compound 9 [obtained from pyrone 2 and ethyl
vinyl ether under microwave irradiation (250 W, 180 °C, 30 min; see
Ethyl endo-4-Benzamido-8-ethoxy-3-oxo-1-(trifluoromethyl)-2-oxa- General Procedure and Table 1)] and DDQ (340 mg, 1.5 mmol) in
bicyclo[2.2.2]oct-5-ene-6-carboxylate (8a): The reaction of pyrone 2
and ethyl vinyl ether with conventional heating or microwave irra-
diation (see Table 1, Entries 1–4) gave the crude product that was
purified by crystallization (toluene) or column chromatography
(EtOAc/Hex, 1:2; Rf = 0.34). The most appropriate conditions were
heating at 120 °C for 90 min to give the main product 8a (372 mg,
toluene (5 mL) was stirred and heated at reflux for 12 h or heated
in a sealed tube under microwave heating (250 W, 120 °C, 60 min).
The solvent was removed, and the corresponding product was puri-
fied by column chromatography (EtOAc/Hex, 1:4, Rf = 0.36) to
give 11 (214 mg, 56%) as a colorless solid; m.p. 105–107 °C. Com-
pound 10 (115 mg, 34%) was also isolated also as a byproduct. IR
87% yield) as a colorless solid; m.p. 206–208 °C. IR (KBr): ν = (CH Cl ): ν = 1155, 1245, 1295, 1354, 1373, 1502, 1535, 1591, 1685,
˜
˜
2
2
1106, 1138, 1164, 1208, 1254, 1486, 1518, 1663, 1734, 1784, 2911,
1730, 2855, 2927, 3428 cm–1. 1H NMR (300 MHz, CDCl3): δ =
2991, 3397 cm–1. 1H NMR (600 MHz, CDCl3): δ = 1.21 (t, J = 1.40 (t, J = 7.1 Hz, 3 H, CH3), 1.55 (t, J = 7.1 Hz, 3 H, CH3), 4.26
1
7.1 Hz, 3 H, CH3), 1.31 (t, J = 7.1 Hz, 3 H, CH3), 2.07 (dd, J =
14.0 Hz, J = 2.0 Hz, 1 H, Ha of CH2), 2.77 (dd, J = 14.0 Hz, J
= 7.3 Hz, 1 H, Hb of CH2), 3.49–3.66 (m, 2 H, CH2O), 4.22 (dd,
(q, J = 7.1 Hz, 2 H, CH2O), 4.39 (q, J = 7.1 Hz, 2 H, CH2O), 7.22
(s, 1 H, CH), 7.47–7.64 (m, 3 H, Ph), 7.84–7.94 (m, 2 H, Ph), 8.66
(s, 1 H, CH), 9.07 (s, 1 H, NH) ppm. 13C NMR (76 MHz, CDCl3):
2
1
2
1J = 7.3 Hz, 2J = 2.0 Hz, 1 H, CHO), 4.27 (q, J = 7.1 Hz, 2 H, δ = 14.1, 14.7, 61.8, 65.2, 108.9, 121.3, 122.8 (q, J = 285.0 Hz),
CH2O), 6.81 (s, 1 H, NH), 7.47–7.50 (m, 2 H, Ph), 7.55–7.59 (m, 2 124.5 (q, J = 33.5 Hz), 127.1, 129.0, 130.3, 132.2, 134.5, 135.2,
H, Ph and CH), 7.85–7.88 (m, 2 H, Ph) ppm. 13C NMR (150 MHz,
148.3, 165.2, 166.2 ppm. 19F NMR (283 MHz, CDCl3): δ = –59.19
CDCl3): δ = 14.0, 15.1, 35.3, 61.8, 64.7, 66.1, 80.8 (q, J = 34.5 Hz), (s, CF3) ppm. MS (ESI): calcd. for C19H18F3NNaO4 404.1080;
122.0 (q, J = 285.0 Hz), 127.3, 128.8, 131.1, 132.4, 133.2, 144.8, found 404.1082.
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Trifluoromethyl-Containing 3-Aminobenzoic Acid Derivatives
Ethyl 5-Amino-2-(trifluoromethyl)benzoate (20): A mixture of com-
pound 10 (3.37 g, 10 mmol) and HCl (6 n solution, 50 mL) was
heated at reflux as it stirred for 6 h. Upon full conversion, the mix-
ture was cooled, and the precipitate of benzoic acid was removed
by filtration. The water solution was treated with 10% NaHCO3
to give a pH Ͼ 7, and the resulting solution was then extracted
with EtOAc (3ϫ 20 mL). The combined organic layers were dried
with MgSO4 and concentrated in vacuo. The residue was washed
with CCl4 to give the pure compound 20 (1.70 g, 73% yield) as a
light brown solid; m.p. 171–173 °C. IR [attenuated total reflectance
compound 13b, over two positions, one disordered CF3 and CO-
OEt group were found in the asymmetric unit. Several restraints
(SIMU, SADI, SAME, ISOR, and DFIX) were used to improve
refinement stability.
X-ray Crystal Structure Analysis of 8a: Formula: C20H20F3NO6, M
=
427.37, colorless crystal, 0.40ϫ0.10ϫ0.03 mm,
a
=
14.0597(4) Å, b = 8.6177(3) Å, c = 17.2698(5) Å, β = 111.470(2)°, V
= 1947.25(10) Å3, ρcalcd. = 1.458 gcm–3, μ = 1.089 mm–1, empirical
absorption correction (0.669 Յ T Յ 0.968), Z = 4, monoclinic,
space group P21/n (No. 14), λ = 1.54178 Å, T = 223(2) K, ω and φ
scans, 13697 reflections collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] =
0.60 Å–1, 3378 independent (Rint = 0.062) and 2635 observed reflec-
tions [I Ͼ 2σ(I)], 276 refined parameters, R = 0.044, wR2 = 0.111,
max. (min.) residual electron density 0.18 (–0.20) eÅ–3, the hydro-
gen atom at N1 was refined freely, others were calculated and re-
fined as riding atoms.
(ATR)]: ν = 1034, 1098, 1247, 1271, 1306, 1580, 1610, 1630, 1719
˜
1
2986, 3232, 3384 cm–1. H NMR (300 MHz, CDCl3): δ = 1.39 (t,
J = 7.1 Hz, 3 H, CH3), 4.38 (q, J = 7.1 Hz, 2 H, OCH2), 4.10–5.10
(br. s, 2 H, NH2), 6.76 (d, J = 8.1 Hz, 1 H, Ar), 6.99 (s, 1 H, Ar),
7.50 (d, J = 8.1 Hz, 1 H, Ar) ppm. 13C NMR (76 MHz, CDCl3): δ
= 13.9, 61.9, 115.6, 117.9 (q, J = 33.2 Hz), 118.6, 124.0 (q, J =
275.0 Hz), 130.2, 132.8, 149.1, 167.4 ppm. 19F NMR (283 MHz,
X-ray Crystal Structure Analysis of 12a: Formula: C21H22F3NO6,
CDCl3):
δ = –58.36 (s, CF3) ppm. MS (ESI): calcd. for
M
= 441.40, colorless crystal, 0.40ϫ0.15ϫ0.02 mm, a =
C10H10F3NNaO2 256.0556; found 256.0555. C10H10F3NO2
(233.19): calcd. C 51.51, H 4.32, N 6.01; found C 51.39, H 4.25, N
5.87.
14.0824(5) Å, b = 8.8231(3) Å, c = 17.3409(5) Å, β = 106.919(2)°,
V = 2061.4(1) Å3, ρcalcd. = 1.422 gcm–3, μ = 1.047 mm–1, empirical
absorption correction (0.679 Յ T Յ 0.979), Z = 4, monoclinic,
space group P21/n (No. 14), λ = 1.54178 Å, T = 223(2) K, ω and φ
scans, 16978 reflections collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] =
0.60 Å–1, 3624 independent (Rint = 0.047) and 3221 observed reflec-
tions [I Ͼ 2σ(I)], 287 refined parameters, R = 0.039, wR2 = 0.104,
max. (min.) residual electron density 0.25 (–0.19) eÅ–3, the hydro-
gen atom at N1 was refined freely, others were calculated and re-
fined as riding atoms.
5-Amino-2-(trifluoromethyl)benzoic Acid (7)
Method A (from Compound 10): A mixture of compound 10 (3.37 g,
10 mmol) and HCl (6 n solution, 50 mL) was heated at reflux as it
stirred for 48 h. The reaction progress was monitored by TLC and
1H NMR spectroscopic analysis. Upon complete conversion, the
mixture was cooled, and the precipitate of benzoic acid was re-
moved by filtration. The water solution was evaporated, and the
solid residue was washed with hot CCl4 to give pure compound 7
as hydrochloride (1.35 g, 56% yield).
X-ray Crystal Structure Analysis of 13b: Formula: C20H20F3NO6,
M
10.3933(2) Å, 16.6644(5) Å, 22.9674(8) Å,
=
427.37, colorless crystal, 0.35ϫ0.35ϫ0.08 mm,
a
V
=
=
Method B (from Compound 20): To a stirred suspension of tBuOK
(2.66 g, 26 mmol) in dry THF (50 mL) was added water (0.12 mL)
through a syringe at 0 °C. This slurry was stirred for 5 min, and
then compound 20 (0.70 g, 3 mmol) was added in several portions.
The reaction mixture was stirred at room temp. overnight and then
quenched by the addition of ice water until two clear layers were
formed. The aqueous layer was separated, acidified with 15% citric
acid, and then extracted with EtOAc (3ϫ 20 mL). The combined
organic layers were washed with water, dried with MgSO4, and con-
centrated in vacuo. The residue was treated with concentrated hy-
drochloric acid (5 mL), and the mixture was then concentrated and
washed with hot CCl4 to give pure compound 7 as hydrochloride
b
=
c
=
3977.9(2) Å3, ρcalcd. = 1.427 gcm–3, μ = 1.066 mm–1, empirical ab-
sorption correction (0.706 Յ T Յ 0.919), Z = 8, orthorhombic,
space group Pbca (No. 61), λ = 1.54178 Å, T = 223(2) K, ω and φ
scans, 21334 reflections collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] =
0.60 Å–1, 3425 independent (Rint = 0.045) and 2910 observed reflec-
tions [I Ͼ 2σ(I)], 345 refined parameters, R = 0.040, wR2 = 0.111,
max. (min.) residual electron density 0.17 (–0.17) eÅ–3, the
hydrogen atom at N1 was refined freely, others were calculated and
refined as riding atoms.
Supporting Information (see footnote on the first page of this arti-
cle): Spectroscopic and mass spectrometric data, elemental analy-
(0.62 g, 85% yield) as a colorless solid; m.p. 86–88 °C. IR (KBr): ν
˜
ses, and copies of H, 13C, and 19F NMR spectra of all new com-
1
= 1039, 1109, 1145, 1264, 1322, 1536, 1658, 1721, 2909, 2995, 3111,
3296 cm–1. 1H NMR {300 MHz, deuterated dimethyl sulfoxide
([D6]DMSO}: δ = 6.04–6.80 (br. s, 4 H, NH3+, CO2H), 6.81 (dd,
pounds 1–18, 20, and 21.
2
1J = 2.2 Hz, J = 8.4 Hz, 1 H, Ar), 6.97 (d, J = 2.2 Hz, 1 H, Ar),
Acknowledgments
7.45 (d, J = 8.4 Hz, 1 H, Ar) ppm. 13C NMR (76 MHz, [D6]
DMSO): δ = 113.6 (q, J = 31.9 Hz), 114.7, 114.9, 124.4 (q, J =
271.0 Hz), 127.8 (q, J = 4.9 Hz), 133.4, 150.4, 168.2 ppm. 19F
NMR (283 MHz, [D6]DMSO): δ = –55.46 (s, CF3) ppm. MS (ESI):
This work has been supported by the Deutsche Forschungsgemein-
schaft (DFG) (Ha 2145/9-1 and AOBJ: 560896). Enamine Ltd.
(Kiev) is thanked for the technical and financial support. The au-
thors are thankful to Dr. R. Fröhlich (Universität Münster) for the
X-ray analysis of compound 8a and express our 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.
calcd.
for
C8H6F3NO2Na
228.0248;
found
228.0243.
C8H7ClF3NO2 (241.59): C 39.77, H 2.92, N 5.80; found C 39.91,
H 2.80, N 5.88.
X-ray Crystal Structure Determination: Data sets were collected
with a Nonius KappaCCD diffractometer. Programs were used for
data collection (COLLECT[13]), data reduction (Denzo-SMN[14]),
absorption correction (Denzo[15]), structure solution (SHELXS-
97[16]), structure refinement (SHELXL-97[17]), and graphics (XP
Bruker AXS, 2000). Thermals ellipsoids are shown with 30% prob-
ability. R values are given for observed reflections, and wR2 values
are given for all reflections. Exceptions and special features: For
[1] a) K. Afarinkia, V. Vinader, T. D. Nelson, G. H. Posner, Tetra-
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Eur. J. Org. Chem. 2014, 2443–2450
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2449

G. Haufe et al.
FULL PAPER
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[6] CCDC-933172 (for 8a), -963174 (for 12a), and -933173 (for
13b) contain the supplementary crystallographic data for this
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Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
[7] The most characteristic data of compound 9 are as follows: 1H
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NMR (300 MHz, CDCl3): δ = 2.46 (tq, 1J = 16.5 Hz, 2J =
1
2
2.4 Hz, 1 H, Ha of CH2), 2.81 (dd, J = 16.5 Hz, J = 7.9 Hz,
1 H, Hb of CH2), 4.42 (dd, 1J = 16.5 Hz, 2J = 7.9 Hz, 1 H,
CHOEt) ppm. 19F NMR (300 MHz, CDCl3): δ = –63.65 (s,
CF3) ppm. MS (ESI): calcd. for C19H20F3NNaO4 406.1242;
found 406.1237.
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ethoxypropene, only compounds 12a and 12b were isolated.
The signals of another diastereomer (probably with the endo-
cis configuration) were also observed in the 1H NMR spectrum
1
[The most characteristic signals are as follows: H NMR: δ =
3
3
3
2.79 (dq, J = 9.0 Hz, J = 7.0 Hz, 1 H, CHMe), 4.62 (d, J =
9.0 Hz, 1 H, CHOEt) ppm. Both signals have a large coupling
constant of 9 Hz for the cis arrangement of the protons.] and
in the 19F NMR spectrum of the reaction mixture [19F NMR:
–69.39 (s, CF3) ppm] with a relative integral of 5–8%. However,
our attempts to isolate and confirm its structure failed.
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1H NMR (300 MHz, CDCl3): δ = 2.49 (d, J = 16.8 Hz, 1 H,
1
Ha of CH2), 2.80 (d, J = 16.8 Hz, 1 H, Hb of CH2) ppm. 19F
NMR (300 MHz, CDCl3): δ = –64.20 (s, CF3) ppm. MS (ESI):
calcd. for C19H20F3NNaO4 406.1242; found 406.1240.
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Received: October 1, 2013
Published Online: January 23, 2014
2450
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2443–2450