Thermal Diels-Alder reactions of 3-(benzoylamino)-6-(polyfluoroalkyl)pyran- 2-ones - New synthesis of p-(polyfluoroalkyl)anilines

Article abstract of DOI:10.1002/ejoc.200600408

A new practical method for the regioselective synthesis of the N-benzoyl-4-(polyfluoroalkyl) anilines 5a-g by thermal Diels-Alder cycloaddition of 5-substituted 3-(benzoylamino)-6-(polyfluoroalkyl)pyran-2-ones 1a-e with fluorostyrenes 2 and 7, acetylenes

Full text of DOI:10.1002/ejoc.200600408

FULL PAPER
DOI: 10.1002/ejoc.200600408
Thermal Diels–Alder Reactions of 3-(Benzoylamino)-6-(polyfluoroalkyl)pyran-
2-ones – New Synthesis of p-(Polyfluoroalkyl)anilines
Nataliya A. Tolmachova,[a] Igor I. Gerus,*[a] Sergey I. Vdovenko,[a] Michael Essers,[b]
Roland Fröhlich,[b][‡] and and Günter Haufe*[b]
Keywords: Cycloaddition / Pyrones / 4-(Polyfluoroalkyl)anilines / Fluorostyrenes / Alkynes
A new practical method for the regioselective synthesis of
the N-benzoyl-4-(polyfluoroalkyl)anilines 5a–g by thermal
Diels–Alder cycloaddition of 5-substituted 3-(benzoylamino)-
6-(polyfluoroalkyl)pyran-2-ones 1a–e with fluorostyrenes 2
and 7, acetylenes 8a–c or vinyl ethers 10 and 13a and 13b is
described. In the case of the reactions of pyrone 1a with cy-
clic vinyl ethers 13a and 13b, the dihydrobenzenes 14a and
14b were obtained. Free 4-(polyfluoroalkyl)anilines 16a–c
were smoothly formed in good yields by DBU-assisted ben-
zoyl deprotection.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
acroleins or acrylic esters,[5a–5c] and recently we described
an enantioselective Diels–Alder reaction mediated by
enantiopure titanium catalysts.[10] Moreover, inverse-elec-
tron demand [4+2] cycloadditions of polyfluorinated 2,4-
cyclohexadienones with α- or β-fluorostyrenes gave the cor-
responding endo/exo-isomeric bicyclo[2.2.2]oct-2-en-5-ones
in good yield.[11]
Until now, 4-(polyfluoroalkyl)anilines have not yet been
synthesized by a Diels–Alder reaction as the key step. Such
compounds have previously been prepared by the replace-
ment of a halogen atom of halo(trifluoromethyl)benzenes
with an amino group[12] or by reduction of trifluoromethyl-
ated nitroaromatics.[13] Trials to introduce a CF3 group se-
lectively into an aniline ring failed.[14] It is known that ani-
lines without polyfluoroalkyl groups are available from elec-
tron-deficient 2-pyrones and electron-rich ynamines.[15]
This paper reports on a new and practical method for
the general and regioselective synthesis of N-benzoyl-4-(po-
lyfluoroalkyl)anilines 5a–e by thermal Diels–Alder cycload-
dition of the 2-pyrones 1a–e with the fluorostyrenes 2 and
7, the acetylenes 8a–c or vinyl ethers 10 and 13a and 13b.
Also, the physicochemical properties of synthesized 4-(poly-
fluoroalkyl)anilines 5a–e and some theoretical calculations
of the reaction mechanism are presented.
Introduction
Diels–Alder reactions have attracted much interest for
the syntheses of six-membered unsaturated rings, which can
be applied to the synthesis of complex pharmaceuticals and
other biologically active compounds.[1] 2-Pyrones have suc-
cessfully been used as conjugated dienes in Diels–Alder cy-
cloadditions[2] with alkenes or alkynes.[3,4] However, there
are few [4+2] cycloadditions known that lead to fluorinated
products, and only a few examples with monofluorinated
dienophiles[5] or dienes[6] have been described. On the other
hand, the introduction of a fluorine atom or a CF3 group
into organic molecules has often been performed to obtain
new biologically active compounds,[7] but there are only a
few examples of syntheses of CF3-substituted benzenes
starting from 6-CF3-containing 2-pyrones and alkynes or
alkenes.[8]
Recently, we have shown that simple vinyl fluorides such
as α- or β-fluorostyrene do not react with normal dienes
like furan, cyclopentadiene or Danishefsky’s diene neither
under thermal conditions nor at high pressure. These reac-
tions were also unsuccessful in the presence of Lewis acids
or radical cation initiators. Only with the highly reactive
diene diphenylisobenzofuran were the thermal reactions
successful, leading to a 60:40 mixture of the diastereomeric
cycloadducts in about 80% yield.[5d,9] On the other hand,
several [4+2] cycloadditions are known with α-fluorinated
Results and Discussion
[a] Institute of Bioorganic Chemistry and Petrochemistry NAS of
Ukraine,
We found that the heating of pyrone 1a[16] with α-fluoro-
styrene (2)[9] in toluene gave only one of the possible re-
gioisomeric products, the phenyl-substituted N-benzoyl-4-
(trifluoromethyl)aniline 5a in a very slow reaction (toluene,
sealed tube, 120 °C, 34 d, 43% yield, 32% of pyrone 1a was
recovered) (Scheme 1). Interestingly, the reaction of β-fluo-
rostyrenes 7[17] with pyrone 1a gave the same product in
Murmanska 1, Kiev, 02094, Ukraine
E-mail: igerus@hotmail.com
[b] Organisch-Chemisches Institut der Universität Münster,
Corrensstraße 40, 48149 Münster, Germany
E-mail: haufe@uni-muenster.de
[‡] X-ray analysis.
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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New Synthesis of p-(Polyfluoroalkyl)anilines
FULL PAPER
Scheme 1.
54% yield after 40 d at 120 °C (34% of pyrone 1a was reco-
vered).
In the key step of the synthesis, obviously only one of
the possible regioisomeric intermediate bicyclic adducts, 3
or 4, was formed. However, the bicyclic adduct was ther-
mally labile and easily eliminated CO2, followed by hydro-
gen fluoride loss, resulting in aromatization to form a 4-
(trifluoromethyl)aniline 5a or 6a. In the 19F NMR spectrum
of the crude reaction mixture, only one signal of a CF3
group at δ = –62.7 ppm was observed. Thus, the reaction
proceeded regioselectively, and only one of the possible iso-
meric anilines 5a or 6a was formed (Scheme 1). The struc-
ture of the compound obtained was easily confirmed as a
phenyl-substituted N-benzoyl-4-(trifluoromethyl)aniline by
Figure 1. Single-crystal X-ray structure of N-benzoyl-2-phenyl-4-
(trifluoromethyl)aniline (5a).
1
elemental analysis, GC-MS, IR and H, 19F and 13C NMR
spectra. However, the position of phenyl ring in the formed
aniline could not be determined by NMR spectroscopy. The
1H, as well as the 13C NMR, spectrum of the product was
quite complicated, showing many aromatic signals with
very similar chemical shifts.
Consequently, we tried to get some information from
semiempirical calculations. PM3 and AM1 calculations of
the frontier orbital energies implied a Diels–Alder reaction
with inverse-electron demand, because in all cases
∆[LUMOdiene – HOMOdienophile] was smaller (0.84–1.44 eV)
than ∆[HOMOdiene – LUMOdienophile]. However, the rel-
evant orbital coefficients of the double bond carbon atoms
are almost identical, and therefore, did not deliver unam-
biguous information about the regiochemistry of the cyclo-
addition (see Supporting Information).
Finally, crystals of the product suitable for X-ray analysis
were grown and showed the structure of aniline 5a (Fig-
ure 1), which bears the phenyl ring attached to the ortho
position. Steric demand of the CF3 group, which is compar-
able in size to an isopropyl group,[18] seems to direct the
attack of the dienophiles 2 or 7 to the diene 1.
It is known that acetylenes can react as synthetic equiva-
lents of electron-rich haloalkene dienophiles in Diels–Alder
reactions.[19,20] Thus, heating of pyrones 1 with an excess of
acetylenes 8 gave the products 5 in high yields (Scheme 2
and Table 1).
Scheme 2.
Table 1. Products of cycloaddition reactions of pyrones 1a–e with
acetylenes 8a–c.
Product
R
RЈ
Rf
Yield [%]
5a
5b
5c
5d
5e
5f
Ph
H
H
H
H
CF3
CF3
CF3
CF2Cl
C3F7
CF3
91
68
62
86
80
91
76
n-C5H11
CH2Cl
Ph
Ph
Ph
H
CO2Et
C(O)CF3
The reaction of 1a with 8a proceeded with high regiose-
lectivity. Similarly, the 4-(trifluoromethyl)anilides 5b and 5c,
5g
Ph
CF3
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FULL PAPER
containing alkyl groups ortho to the benzamido function- signed to a bicyclic 1,4-hexadiene. However, the bicyclic ad-
ality, were obtained by heating 1a with heptyne (8b) or pro- duct 11 was not stable enough to be purified by column
pargyl chloride (8c) in good yields. The reaction was also chromatography.
successful with other 6-(polyfluoroalkyl)pyrones such as 1b
The cycloaddition of the pyrone 1a with the cyclic vinyl
and 1c. The yields of the corresponding derivatives 5d and ethers 13a and 13b required harsher conditions than those
5e were not influenced by the different substituents. More- of the reactions of the above-mentioned dienophiles. The
over, the introduction of electron-withdrawing substituents reaction did not start below 160 °C, and at this temperature,
(ethoxycarbonyl or trifluoroacetyl) in position 5 of the py- we did not expect to observe cycloadducts analogous to 11.
rone ring (compounds 1d and 1e) increased the reactivity However, we isolated products from the reaction mixture
of the pyrone 1a, and the corresponding benzanilides 5f and which, in the 19F NMR spectrum, exhibited signals from a
5g were obtained in high yields under milder conditions CF3 group with chemical shifts of about –66 ppm, which is
(1 d, 100 °C) in the reaction with phenylacetylene (8a) slightly different from that of benzanilide 12 (δ
=
1
(Table 1).
–60.92 ppm). Moreover, in the H NMR spectrum, the us-
The progress of the Diels–Alder reactions was easily ual signals from the three new aromatic protons were not
monitored by 19F NMR spectroscopy of the reaction mix- observed. Instead, two signals in the typical region for ole-
tures, as the signals from polyfluoroalkyl groups of pyrones finic protons appeared. For example, for 14b a doublet of
1a–e and 4-(polyfluoroalkyl)anilides 5a–g are significantly doublets was found at δ = 7.05 ppm (J = 6.3 and 1.8 Hz),
different [e.g. the signal of the CF3 group of pyrone 1a (δ and a doublet of a quartet appeared at δ = 6.47 ppm (J =
= –70.01 ppm) was shifted downfield by 8–9 ppm in the 4- 6.3 and 2.0 Hz). Obviously, in the case of the cyclic vinyl
(trifluoromethyl)anilides 5a–e]. No other isomers have been ethers 13a and 13b, the reaction was accompanied by CO2
detected in the crude reaction mixtures by this method. We elimination but without aromatization, which would ne-
suppose that intermediates 9a–g are formed in the first step cessitate an elimination of an alcohol (Scheme 4). Earlier,[22]
of the cycloaddition (Scheme 2), since the formation of sim- ethyl 2-oxo-5,6,7,8-tetrahydro-2H-chromene-3-carboxylate,
ilar intermediate bicyclic structures has been established for with a similar cyclohexadiene structure to that of 14, was
the Diels–Adler cycloaddition of other pyrones.[2b] How- obtained by the Diels–Alder reaction of methyl 2-oxo-6-
ever, we did not observe any polyfluoroalkyl group signals (trifluoromethyl)-2H-pyran-4-carboxylate with dihydrofu-
that could be assigned to bicyclic 1,4-hexadienes 9a–g in ran 13a in a sealed tube at 160 °C.
the reaction mixtures.
It is well known that alkyl vinyl ethers react with pyrones
as dienophiles under milder conditions than acetyl-
enes.[21a,21b] Thus, we suspected that the reaction of pyrone
1a with alkyl vinyl ethers might allow us to identify bicyclic
adducts in reaction mixtures. However, after heating pyrone
1a with isobutyl vinyl ether (10), only the aromatic product
12 was obtained after 48 h at 100 °C, as a result of cycload-
dition with subsequent elimination of CO2 and isobutyl
alcohol (Scheme 3). As the bicyclic adduct 11 was not stable
at 100 °C, we tried to find milder reaction conditions in
Scheme 4.
order to detect the intermediate compound 11. However,
we did not observe any product by 19F NMR spectroscopy
1H, 19F and 13C NMR spectra of products 14a and 14b
after boiling the reactants in dichloromethane. We increased are very similar, and their stereochemistry was proven, as
the reaction temperature gradually and found that the reac- exemplified for product 14b by COSY NMR and X-ray
tion of neat reactants did not start below 80 °C. After 12 h techniques (Figure 2 and Figure 3).
at this temperature, a new signal from a CF3 group ap-
In order to verify the exact structure of the bicyclic ad-
peared at about –80 ppm in the crude reaction mixture (ca. ducts 14a and 14b and to define the regiochemistry of the
10%), together with signals from pyrone 1a (ca. 72%) and Diels–Alder cycloaddition unambiguously, we grew crystals
the aromatic product 12 (ca. 18%). This signal can be as- of dihydrobenzene 14b suitable for X-ray analysis. The X-
Scheme 3.
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New Synthesis of p-(Polyfluoroalkyl)anilines
FULL PAPER
Conclusion
A simple and highly regioselective method for the synthe-
sis of various 4-(polyfluoroalkyl)anilides 5 is presented. The
key reaction step is a Diels–Alder reaction of a 3-(benzo-
ylamino)-6-(polyfluoroalkyl)-2-pyrone of type 1 with an α-
or β-fluorostyrene 2 or 7 or with an acetylenes of type 8a–
c. Moreover, Diels–Alder reactions of the 3-(benzo-
ylamino)-6-(polyfluoroalkyl)-2-pyrones with alkyl vinyl
ethers 10 and 13a and 13b were studied. Gentle heating of
1a with isobutyl vinyl ether (10) allowed a spectroscopic
proof of the primary bicyclic Diels–Alder adduct. In case
of the reactions of pyrone 1a with cyclic alkyl vinyl ethers
13a and 13b, the bicyclic dihydrobenzenes 14a and 14b were
isolated as stable products. Removal of the N-benzoyl group
of amides 5 by heating in methanol with DBU gave the p-
CF3-containing anilines 16a–c in high yields. These prod-
ucts may serve as bioactive substances themselves or as
building blocks for the synthesis of fluorinated bioactive
compounds.
Figure 2. Characteristic COSY correlations for adduct 14b.
Figure 3. Single-crystal X-ray structure of N-[5-(trifluoromethyl)-
3,4,4a,8a-tetrahydro-2H-chromen-8-yl]benzamide (14b).
Experimental Section
General: Melting points are uncorrected. NMR spectra were re-
corded with a Varian VXR-300 spectrometer at 300 MHz (1H),
75.4 MHz (13C) and 282.3 MHz (19F) or with a Bruker AMX-400
spectrometer at 400 MHz (1H) and 100.6 MHz (13C) at 25 °C. TMS
(for 1H and 13C NMR) and CCl3F (for 19F NMR) were used as
internal standards. Mass spectra were recorded with a combination
of a Varian GC 3400 gas chromatograph and Finnigan MAT 8230
mass spectrometer (70 eV, EI). IR spectra were recorded with a
Specord M-80 spectrometer. Column chromatography was per-
formed on silica gel 60 (Merck).
ray analysis proved that the benzamido group and the oxy-
gen atom were attached in an ortho relationship, and that
the H15 and H16 protons have a cis configuration (Figure 3).
Some chemical transformations with p-(trifluoromethyl)
anilides 5a, 5f and 5g have also been investigated. Thus, the
ester 5f gave the N-protected m-aminobenzoic acid 15 in
52% yield by heating in 10% aq. HCl at 60 °C (Scheme 5).
Starting Materials: Starting materials were of the highest commer-
cial quality and were used without further purification. The N-[2-
oxo-6-(polyfluoroalkyl)-2H-pyran-3-yl]benzamides[16] and fluoro-
styrenes[9,17] were prepared according to literature procedures.
General Procedures for Diels–Alder Reaction
Scheme 5.
Method 1. Diels–Alder Reaction of Pyrone 1a with Fluorostyrenes 2
or 7 (Benzamide 5a): α-Fluorostyrene (2, 49 mg, 0.40 mmol) or β-
fluorostyrenes (7, 96 mg, 0.79 mmol) and 2-pyrone 1a (80 mg,
0.28 mmol, or 160 mg, 0.56 mmol) in anhydrous toluene (3 mL or
6 mL) were heated in a sealed glass tube at 120 °C for 34 or 40 d
(fluorostyrenes 2 or 7, respectively). The solvent was evaporated
in vacuo, and the oily residue was purified by silica gel column
chromatography with cyclohexane/ethyl acetate (10:1) as the eluent.
Yields: 41 mg (43%) of 5a and 26 mg (32%) of recovered 1a or
104 mg (54%) of 5a and 26 mg (32%) of recovered 1a for fluorosty-
renes 2 and 7, respectively.
On the other hand, under basic conditions, the amide
functionality can be deprotected. Thus, conventional heat-
ing (6–10 h) or microwave irradiation (1–3 min) of p-(tri-
fluoromethyl)anilides 5a, 5f or 5g with two equiv. of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU)[23] in methanol gave
the free 4-(trifluoromethyl)anilines 16a–c in good yields
(Scheme 6).
Method 2. Diels–Alder Reaction of Pyrones 1a-e with Acetylenes 8a–
c (Benzamides 5a–g): The acetylenes 8 (0.60 mmol) and 2-pyrone 1a
(0.28 mmol) were heated without solvent in a sealed glass tube at
100–120 °C for 1–7 d. The excess of acetylene was removed in
vacuo, and the residue was dissolved and filtered through a short
silica gel column with hexane/ethyl acetate (2:1) as the eluent. After
evaporation of the solvent in vacuo, the products were crystallized
from hexane/toluene (5:1).
N-(5-Trifuoromethyl)biphenyl-2-yl)benzamide (5a): Method 1 or 2.
White crystals, m.p. 155–156 °C The product was purified by
Scheme 6.
Eur. J. Org. Chem. 2006, 4704–4709
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N. A. Tolmachova, I. I. Gerus, S. I. Vdovenko, M. Essers, R. Fröhlich, G. Haufe
FULL PAPER
chromatography with cyclohexane/ethyl acetate as the eluent or
crystallized from hexane/toluene. Yield: 829 mg (91%, method 2).
1H NMR (300 MHz, [D6]acetone): δ = 8.50 (d, J = 8.6 Hz, 1 H),
7.78 (m, 3 H), 7.66 (br. s, 1 H), 7.51 (m, 9 H) ppm. 19F NMR
(282.3 MHz, [D6]acetone): δ = –62.71 (s, CF3) ppm. 13C NMR
(75.4 MHz, [D6]acetone): δ = 165.01, 143.22, 140.43, 138.21,
136.74, 134.35, 132.12, 129.86, 129.30, 128.93, 127.60 (q, J =
267.9 Hz), 126.91, 126.44 (q, J = 30.1 Hz), 125.82, 125.04, 120.61
ppm. GC-MS (70eV) m/z (%) = 341 (25) [M]+, 235 (8), 216 (3), 167
(67), 105 (100), 77 (38), 51 (6). C20H14F3NO (341.3): calcd. C 70.38,
(39), 78 (4), 77 (46), 59 (25), 44 (3). C17H16F3NO2 (323.32): calcd.
C 63.15, H 4.99, N 4.33; found C 63.08, H 5.00, N 4.27. IR
(CHCl ): ν = 3396, 3047, 2989, 2887, 1690, 1510, 1490, 1300, 1267,
˜
3
1163, 1110, 1060, 1025 cm–1.
2-(Benzoylamino)-5-(trifluoromethyl)biphenyl-4-carboxylic
Acid
(15): A mixture of ester 5f (500 mg, 1.2 mmol) and HCl (10%,
15 mL) was refluxed for 6 h. The reaction mixture was cooled to
room temperature, and the precipitated acid 15 was filtered and
crystallized from 2-propanol: Yield: 239 mg (52%), white crystals,
1
m.p. 163 °C. H NMR (300 MHz, [D6]DMSO): δ = 10.01 (br. s, 1
H 4.13, N 4.10; found C 70.19, H 3.94, N 3.73. IR (CHCl ): ν =
˜
3
H), 8.76 (d, J = 8.6 Hz, 1 H), 8.14 (br. s, 1 H), 7.67 (dd, J = 8.6,
1.4 Hz, 1 H), 7.34–7.61 (m, 10 H) ppm. 19F NMR (282.3 MHz,
[D6]DMSO): δ = –59.10 (s, CF3) ppm. 13C NMR (75.4 MHz, [D6]-
DMSO): δ = 172.36, 165.45, 141.67, 140.72, 134.10, 132.73, 132.42,
132.00, 130.10, 129.71, 129.42, 129.39, 128.94 (q, J = 6.0 Hz),
127.20, 124.15 (q, J = 33.1 Hz), 122.98 (q, J = 127.1 Hz) ppm. GC-
MS (70eV) m/z (%) = 386 (10) [M]+, 385 (2), 265 (3), 223 (2), 105
(100), 74 (2), 73 (5), 60 (43), 59 (10) ppm. C21H14F3NO3 (385.35):
calcd. C 65.46, H 3.66, N 3.63; found C 65.51, H 3.61, N 3.70. IR
3020, 1808, 1683, 1600, 1522, 1472, 1416, 1336, 1312, 1212, 1168,
1131, 1072, 840, 704 cm–1.
N-[4-(Trifluoromethyl)phenyl]benzamide (12): A mixture of pyrone
1a (320 mg, 1.13 mmol) and an excess of isobutyl vinyl ether 10
(1 mL) was heated without solvent in a sealed glass tube at 100 °C
for 2 d. The product was purified by silica gel column chromatog-
raphy with chloroform/hexane (2:1) as the eluent. Yield: 239 mg
1
(80%). H NMR (300 MHz, [D6]acetone): δ = 9.85 (s, 1 H), 8.09
(d, J = 8.5 Hz, 2 H), 8.01 (m, 2 H), 7.70 (d, J = 8.5 Hz, 2 H), 7.55
(m, 3 H) ppm. 19F NMR (282.3 MHz, [D6]acetone): δ = –61.63 (s,
CF3) ppm. 13C NMR ([D6]acetone, 75.4 MHz): δ = 166.79, 143.77,
135.70, 132.66, 129.29, 128.39, 126.70 (q, J = 3.6 Hz), 125.48 (q, J
= 31.7 Hz), 125.46 (q, J = 271.0 Hz), 120.74 ppm. GC-MS (70eV)
m/z (%) = 266 (6) [M]+, 160 (4), 141 (2), 105 (100), 77 (38), 51 (6).
C14H10F3NO (265.24): calcd. C 63.40, H 3.80, N 5.28; found C
(CHCl ): ν = 3240, 1810, 1740, 1584, 1559, 1523, 1477, 1310, 1260,
˜
3
1249, 1208, 1152, 1128, 1100, 1050, 1019 cm–1.
General Procedure for Deprotection of the Amides 5a,f,g to Amines
11a–c with DBU: A solution of the amide 5 (0.2 mmol) and DBU
(0.091 g, 0.6 mmol) in methanol (10 mL) was refluxed until the
amide was completely consumed (TLC). The reaction mixture was
cooled to room temperature and poured into water (25 mL). The
amine 11 was filtered, suctioned and recrystallized.
63.46, H 3.93, N 5.21. IR (KBr): ν = 3335, 1656, 1616, 1528, 1488,
˜
1408, 1341, 1262, 1160, 1111, 1072, 1016, 834, 719 cm–1.
5-(Trifluoromethyl)biphenyl-2-ylamine (16a): Yield: 402 mg (85%).
White crystals, m.p. 85 °C (hexane). H NMR (300 MHz, CDCl3):
N-[5-(Trifluoromethyl)-3,4,4a,8a-tetrahydro-2H-chromen-8-yl]-
benzamide (14a): A mixture of pyrone 1a (766 mg, 2.70 mmol) and
2,3-dihydrofuran 13a (227 mg, 3,24 mmol) in dry toluene (10 mL)
was heated in a sealed glass tube at 160 °C for 7 d. The solvent was
evaporated, and the oily residue was purified by silica gel column
chromatography with chloroform/hexane (2:1) as the eluent. Yield:
535 mg (64%), white crystals, m.p. 85 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.23 (s, 1 H), 7.82 (m, 2 H), 7.51 (m, 3 H), 7.00 (d, J
= 6.0 Hz, 1 H), 6.51 (dq, J = 6.7, 1.9 Hz, 1 H), 4.99 (d, J = 9.6 Hz,
1 H), 3.86 (m, 2 H), 3.03 (q, J = 9.9 Hz, 1 H), 2,40 (m, 1 H), 1.98
(m, 1 H) ppm. 19F NMR (282.3 MHz, CDCl3): δ = –66.32 (s, CF3)
ppm. 13C NMR (75.4 MHz, CDCl3): δ = 166.00, 135.57, 134.28,
132.21, 128.87, 127.04, 125.56 (q, J = 6.2 Hz), 124.22 (q, J =
271.0 Hz), 122.43 (q, J = 31.3 Hz), 103.30, 76.15, 66.38, 36.31,
32.64 ppm. GC-MS (70eV) m/z (%) = 310 (3) [M]+, 309 (6), 191(2),
172 (4), 105 (100), 81 (25), 78 (40), 47 (12), 31 (2). C16H14F3NO2
(309.29): calcd. C 62.14, H 4.56, N 4.53; found C 62.09, H 4.60, N
1
δ = 7.33–7.51 (m, 7 H), 6.76 (dd, J = 7.8, 0.7 Hz, 1 H), 4.03 (s, 2
H) ppm. 19F NMR (282.3 MHz, CDCl3): δ = –61.39 (s, CF3) ppm.
13C NMR (CDCl3, 75.4 MHz): δ = 147.99, 138.56, 130.01, 129.77,
129.43, 128.09 (q, J = 3.6 Hz), 127.43, 126.02 (q, J = 3.6 Hz),
125.33 (q, J = 270.3 Hz), 120.60 (q, J = 32.6 Hz), 115.21 ppm. GC-
MS (70eV) m/z (%) = 238 (2) [M]+, 237 (6), 224 (10), 205 (4), 156
(61), 79 (17). C13H10F3N (237.23): calcd. C 65.82, H 4.25, N 5.90;
found C 66.00, H 4.14, N 5.73. IR (CHCl ): ν = 3500, 3407, 1684,
˜
3
1625, 1523, 1492, 1423, 1335, 1261, 1206, 1168, 1149, 1117, 1078,
1040, 1020, 907, 824, 704 cm–1.
X-ray Crystallographic Study: Data sets were collected with Enraf–
Nonius CAD4 and Nonius KappaCCD diffractometers. Programs
used: data collection: EXPRESS (Nonius B.V., 1994) and COL-
LECT (Nonius B.V., 1998), data reduction: MolEN (K. Fair, En-
raf–Nonius B.V., 1990) and Denzo-SMN,[24] absorption correction
for CCD data: SORTAV,[25] structure solution: SHELXS-97,[26]
structure refinement: SHELXL-97,[27] graphics: SCHAKAL.[28]
4.43. IR (CHCl ): ν = 3403, 3051, 2986, 2888, 1680, 1513, 1488,
˜
3
1305, 1260, 1165, 1107, 1056, 1029 cm–1.
N-[4-(Trifluoromethyl)-2,3,3a,7a-tetrahydro-1-benzofuran-7-yl]-
benzamide (14b): A mixture of pyrone 1a (320 mg, 1.13 mmol) and
3,4-dihydro-2H-pyran 13b (0.42 mL, 1.97 mmol) was heated in a
sealed glass tube at 160 °C for 5 d. The product was purified by
silica gel column chromatography with chloroform/hexane (2:1) as
the eluent. Yield: 262 mg (72%), white crystals, m.p. 90 °C. 1H
NMR (300 MHz, CDCl3): δ = 8.51 (s, 1 H), 7.81 (m, 2 H), 7.56
(m, 1 H), 7.49 (s, 2 H), 7.07 (dd, J = 6.3, 2.1 Hz, 1 H), 6.49 (dq, J
= 6.3, 2.1 Hz, 1 H), 4.86 (d, J = 7.7 Hz, 1 H), 3.91 (m, 1 H), 3.52
CCDC-600000 and -600001 contain the supplementary crystallo-
graphic 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.
Theoretical Calculations: The semiempirical calculations (AM1 and
PM3) were performed with MOPAC93, as implemented in
Chem3D.[29]
(m, 1 H), 2.70 (m, 1 H), 1.75 (m, 4 H) ppm. 19F NMR (282.3 MHz, Supporting Information (see also the footnote on the first page of
CDCl3): δ = –66.28 (s, CF3) ppm. 13C NMR (75.4 MHz, CDCl3):
δ = 165.00, 134.21, 131.24, 127.98, 125.88, 125.80 (q, J = 7.0 Hz),
123.21 (q, J = 270.0 Hz), 122.84 (q, J = 30.6 Hz), 103.70, 71.88,
62.91, 31.45 (q, J = 1.2 Hz), 24.13, 21.97 ppm. GC-MS (70eV)
this article): i. Melting points, NMR, IR, mass spectroscopic data
of benzanilides 5b–g and anilines 16b and 16c. ii. X-ray Crystallo-
graphic Study data of compounds 5a and 14b. iii. Theoretical calcu-
lation data for the Diels–Alder reaction. iv. COSY experiment data
m/z (%) = 324 (10) [M]+, 323 (6), 218 (10), 199 (3), 105 (100), 80 for adduct 14b.
4708
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4704–4709

New Synthesis of p-(Polyfluoroalkyl)anilines
FULL PAPER
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Received: May 10, 2006
Published Online: August 24, 2006
Eur. J. Org. Chem. 2006, 4704–4709
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4709