New synthesis of 3-fluoropyrroles

Article abstract of DOI:10.1021/jo802272n

5-Alkoxymethyl-2-aryl-3-fluoro-1H-pyrroles and 2-aryl-3-fluoro-1H-pyrrole- 5-carbaldehydes were efficiently prepared from the corresponding 2-aryl-5-(bromomethyl)-1-pyrrolines via electrophilic α, α-difluorination of the imino bond, using Selectfluor (1-c

Full text of DOI:10.1021/jo802272n

pyrrole-3-diazonium tetrafluoroborates,3 or via bromine-lithium
exchange of 3-bromo-1-(triisopropylsilyl)pyrroles followed by
treatment with N-fluorobenzenesulfonimide (NFSI).6 The use
of difluorine gas in He and chloroform at -60 °C to fluorinate
1-methylpyrrole resulted in a mixture of 2- and 3-fluoro-1-
methylpyrroles (1:4).7 Cyclization strategies starting from
acyclic precursors toward 3-fluoropyrroles included a cyclo-
condensation reaction of γ-iodo-R,R-difluorocarbonyl com-
pounds with ammonia,8,9 cyclization and dehydrofluorination
of R,R-difluoro-γ-iodo-γ-trimethylsilanyl ketones with am-
monium hydroxide9 or primary amines,10 dehydrofluorination
and dehydration of 3,3-difluoro-5-hydroxypyrrolidines,11 and a
rhodium(II) acetate-catalyzed intramolecular N-H insertion of
5-amino-4,4-difluoro-2-diazo-3-ketoesters followed by dehy-
drofluorination.12
New Synthesis of 3-Fluoropyrroles
Riccardo Surmont,†,§ Guido Verniest,† Filip Colpaert,†
Gregor Macdonald,‡ Jan Willem Thuring,‡
Frederik Deroose,‡ and Norbert De Kimpe*,†
Department of Organic Chemistry, Faculty of Bioscience
Engineering, Ghent UniVersity, Coupure Links 653, B-9000
Ghent, Belgium, and Johnson & Johnson Pharmaceutical
Research & DeVelopment, a DiVision of Janssen
Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse,
Belgium
norbert.dekimpe@ugent.be
ReceiVed October 10, 2008
Rhodium complexes also catalyze the reaction between
isonitriles and 2-fluoro-1,3-diketones to give R,ꢀ-unsaturated
formamides that undergo cyclocondensation after decarbony-
lation to yield 3-fluoropyrroles.13 Synthetically less important
routes to 3-fluoropyrroles include the thermal isomerization of
N-[(2,2-difluoro-1-arylcyclopropyl)methylidene]amines,14 the
ring contraction of 1-azidocyclobutenes followed by nucleophilic
attack of arenes,15 and the ring contraction of fluorinated
dihydrooxazines with Zn.16
Finally, 4-fluoro-1H-pyrrole-2-carboxylates can be synthe-
sized by oxidation of 4,4-difluoropyrrolidine-2-carboxylates
which were prepared from proline derivatives with use of
diethylaminosulfur trifluoride (DAST).6b It is clear that no
general method to synthesize functionalized 3-fluoropyrroles is
available. Although the above-mentioned methodologies each
have their benefits, the use of not readily available fluorinated
starting materials, expensive or difficult to handle fluorinating
agents (DAST, F2-gas), or the need for photolysis clearly is a
disadvantage when a multigram scale synthesis of 3-fluoropy-
rroles is envisaged. Moreover, arylated 3-fluoropyrroles bearing
an aldehyde or alkoxymethyl function at the C-5 position have
not been synthesized before, despite the interest of the phar-
maceutical industry in such compounds. Because of the fact
that we recently disclosed a methodology to synthesize R,R-
difluoroimines,17 it was proposed to use 1-pyrrolines as precur-
sors for polyfunctionalized 3-fluoropyrroles. Although R-flu-
orinated imines can hardly be compared to R-chlorinated imines
in terms of synthesis and reactivity, the above-mentioned
synthetic strategy resulted previously in the synthesis of
5-Alkoxymethyl-2-aryl-3-fluoro-1H-pyrroles and 2-aryl-3-
fluoro-1H-pyrrole-5-carbaldehydes were efficiently prepared
from the corresponding 2-aryl-5-(bromomethyl)-1-pyrrolines
via electrophilic R,R-difluorination of the imino bond, using
Selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-
[2.2.2]octane bistetrafluoroborate) and subsequent aromati-
zation by dehydrofluorination. This methodology provides
a new and easy entry toward various new 3-fluorinated
pyrroles.
Fluorinated pyrroles have already proven to be important
building blocks for the preparation of potent pharmaceutical and
agrochemical compounds, such as drugs against cytokine
mediated diseases,1 fungicides and bactericides,2 porphyrines,3
and antithrombosis4 agents. However, the selective synthesis
of fluoropyrroles remains a difficult task,5 especially to access
3-fluoropyrroles. Only a limited number of papers reported a
direct fluorination toward 3-fluoropyrroles via photolysis of
(6) (a) Barnes, K. D.; Hu, Y.; Hunt, D. A. Synth. Commun. 1994, 24, 1749.
(b) Leroy, J.; Porhiel, E.; Bondon, A. Tetrahedron 2002, 58, 6713.
(7) Grimmett, M. R. AdV. Heterocycl. Chem. 1993, 57, 291.
(8) Qiu, Z.-M.; Burton, D. J. Tetrahedron Lett. 1994, 35, 4319.
(9) Qiu, Z.-M.; Burton, D. J. Tetrahedron Lett. 1995, 36, 5119.
(10) Kwak, K. C.; Oh, H.; Chung, D.-S.; Lee, Y.-H.; Baik, S.-H.; Kim, J.-
S.; Chai, K. Y. J. Korean Chem. Soc. 2001, 45, 100.
(11) Shi, G.; Cai, W. J. Org. Chem. 1995, 60, 6289.
(12) Wang, Y.; Zhu, S. Org. Lett. 2003, 5, 745.
* Corresponding author. Phone: +32 (0)9 264 59 51. Fax: +32 (0)9 264 62
43.
† Ghent University.
‡ Johnson & Johnson Pharmaceutical Research & Development.
§ Aspirant of the Research Foundation-Flanders (FWO-Vlaanderen).
(1) De Laszlo, S. E.; Liverton, N. J.; Ponticello, G. S.; Selnick, H. G.; Mantlo,
N. B. U.S. Patent, US5837719 A19981117, 1998.
(2) Eli Lilly and Company, Fr. Demande 1 549 829; 1968: Chem. Abstr.
1970, 72, 121357s.
(13) Takaya, H.; Kojima, S.; Murahashi, S. Org. Lett. 2001, 3, 421.
(14) Kagabu, S.; Ando, C.; Ando, J. J. Chem. Soc., Perkin Trans. I 1994, 6,
739.
(3) Onda, H.; Toi, H.; Aoyama, Y.; Ogoshi, H. Tetrahedron Lett. 1985, 26,
4221.
(15) Buhr, G. Chem. Ber. 1973, 106, 3544.
(4) Zhu, B.-Y.; Su, T.; Li, W.; Goldman, E. A.; Zhang, P.; Jia, Z. J.;
Scarborough, R. M. PCT Int. Appl. WO2002026734 A1 20020404, 2002.
(5) Gozzo, F. C.; Ifa, D. R.; Eberlin, M. N. J. Org. Chem. 2000, 65, 3920.
(16) Schlosser, M.; Shi, G. Tetrahedron 1993, 49, 1445.
(17) Verniest, G.; Van Hende, E.; Surmont, R.; De Kimpe, N. Org. Lett.
2006, 8, 4767.
10.1021/jo802272n CCC: $40.75
Published on Web 12/30/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1377–1380 1377

SCHEME 1. Synthesis of r(,r)-(Di)fluoro-1-pyrroline
SCHEME 3. Synthesis of
Derivatives 3a
5-(Alkoxymethyl)-3-fluoro-1H-pyrroles 4a
a Conditions: (a) 5 equiv of 2 M aq NaOH, R2OH, ∆, 1 h; (b) excess 1
M NaOR2 in R2OH, ∆, 1 h.
SCHEME 4. Synthesis of
3-Fluoro-1H-pyrrole-5-carbaldehydes 8a
a Not Isolated, See Table 1.
SCHEME 2. Fluorination of
2-(4-Methoxyphenyl)-1-pyrroline 2e
a 5e and 5f (ratio 56:44); 6e and 6f (ratio 49:51); 8e and 8f (ratio 57:43)
could not be separated via flash chromatography.
complex due to the presence of numerous unidentified com-
pounds. Analogously, when 1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bistetrafluoroborate (Selectfluor,
1.2 equiv) was used as a fluorination agent in acetonitrile at
reflux temperature for 48 h, monofluorination of pyrroline 2a
could not be driven to completion. However, the use of a
catalytic amount of trifluoroacetic acid to facilitate enamine
formation indeed accelerated the reaction of 2a with Selectfluor.
Reacting 5-(bromomethyl)-2-phenyl-1-pyrroline 2a with 2.5
equiv of Selectfluor in acetonitrile at reflux temperature for 2
days finally led to complete conversion and yielded 32% of 3,3-
difluoro-1-pyrroline 3a after flash chromatography. This syn-
thetic methodology also afforded other derivatives with a
different substitution pattern of the aryl group, which proves
the generality of the method. It should be noted that the R,R-
difluorination of 2-(4-fluorophenyl)-1-pyrroline 2d resulted in
an exceptionally clean reaction mixture, giving rise to a high
yield of difluoropyrroline 3d (purity >95%, determined via 1H
NMR).
On the other hand, the fluorination of 2-(4-methoxyphenyl)-
1-pyrroline 2e by using an excess of Selectfluor resulted in a
fluorination of the 3′-position of the phenyl group and led to a
mixture of di- and trifluorinated pyrroline 3e and 3f (57:43 ratio),
which could not be separated via flash chromatography (Scheme
2).
A simultaneous nucleophilic substitution on the brominated
carbon atom and dehydrofluorination of 2-aryl-5-(bromomethyl)-
3,3-difluoro-1-pyrrolines 3a and 3d could be accomplished by
heating these compounds in a mixture of 2 M aqueous sodium
3-chloropyrroles starting from the corresponding 3,3-dichloro-
1-pyrrolines.18
2-Aryl-5-(bromomethyl)-1-pyrrolines 2 were used as starting
materials because of the interesting bromomethyl group at the
5-position, which allows further transformations. These func-
tionalized 1-pyrrolines were prepared from benzonitriles 1 by
reaction with 3-butenylmagnesium bromide and subsequently
with N-bromosuccinimide, both in THF as solvent.19 In a first
attempt to fluorinate pyrroline 2a, N-fluorobenzenesulfonimide
(NFSI) was used as an electrophilic fluorination reagent (Scheme
1). In contrast to the fluorination of acyclic N-alkylimines,
1-pyrroline 2a could not be fluorinated under the same mild
conditions, using NFSI in acetonitrile with dimethylformamide
as a cosolvent (5/2) at 0 °C for 2.5 h or room temperature for
15 h (Table 1), probably due to the more difficult enamine
formation. Increasing the temperature (50 °C to reflux temper-
ature) and the reaction time (until 15 h) in acetonitrile without
cosolvent resulted in a mixture of starting material 2a and
monofluorinated 1-pyrroline 3g (a 2a:3g ratio of 95:5 to 75:25,
see Table 1); however, the reaction mixture became more
(18) (a) De Kimpe, N.; Abbaspour Tehrani, K.; Stevens, C.; De Cooman, P.
Tetrahedron 1997, 53, 3693, and references cited therein. (b) Abbaspour Tehrani,
K.; Borremans, D.; De Kimpe, N. Tetrahedron 1999, 55, 4133, and references
cited therein. (c) Verniest, G.; Claessens, S.; De Kimpe, N. Tetrahedron 2005,
61, 4631.
(19) Dechoux, L.; Jung, L.; Stambach, J.-F. Synthesis 1995, 242.
1378 J. Org. Chem. Vol. 74, No. 3, 2009

TABLE 1. Fluorination of Pyrroline 2a, Using NFSI or Selectfluor
reaction conditions
ratio 2a:3g:3aa
1.2 equiv of NFSI, 3 equiv of K2CO3, CH3CN/DMF 5/2, 0 °C, 2.5 h
1.2 equiv of NFSI, 3 equiv of K2CO3, CH3CN/DMF 5/2, rt, 15 h
1.2 equiv of NFSI, 3 equiv of K2CO3, CH3CN, 50 °C, 6.5 h
1.2 equiv of NFSI, 3 equiv of K2CO3, CH3CN, ∆, 3.5 h
1.2 equiv of NFSI, 3 equiv of K2CO3, CH3CN, ∆, 15 h
1.2 equiv of Selectfluor, CH3CN, ∆, 48 h
no reaction
no reaction
no reaction
95:5:0
75:25:0
40:60:0
2.5 equiv of Selectfluor, cat. TFA, CH3CN, ∆, 48 h
0:0:100
a
1
Ratio determined by H NMR analysis.
SCHEME 5. Possible Mechanisms for the Synthesis of
3-Fluoro-1H-pyrrole-5-carbaldehydes 8
SCHEME 6. Synthesis of
5-(3,4-dimethoxybenzyl)-1H-pyrrole 15
nation is an initial dehydrofluorination of pyrroline 6 followed
by substitution of the bromomethyl group by methoxide and
elimination of methanol to give compound 12. Most probably,
the resulting reactive azafulvene intermediate 12 is immediately
attacked by methoxide giving rise to pyrroles 7.
hydroxide in a suitable alcoholic solvent or in a mixture of 1
M sodium alkoxide in the corresponding alcohol (Scheme 3).
Both methods led to new fluorinated 5-(alkoxymethyl)-1H-
pyrroles 4 in comparable yields.
Finally 3-fluoro-1H-pyrrole-5-carbaldehyde 8a was further
derivatized to demonstrate the versatility of this building block
in the field of organic and medicinal chemistry (Scheme 6).
Direct N-alkylation of pyrrole carbaldehyde 8a with cyclopro-
pylmethyl bromide with use of sodium hydride in dimethylfor-
mamide at 60 °C gave N-(cyclopropylmethyl)pyrrole carbalde-
hyde 13 in good yield. Treatment of aldehyde 13 with (3,4-
dimethoxyphenyl)lithium (prepared in situ from 4-bromoveratrole
with tert-butyllithium at -78 °C in THF) resulted in (pyrrol-
5-yl)methanol 14. This unstable carbinol 14 was not purified
but directly reduced by using sodium borohydride in trifluoro-
acetic acid leading to the new fluorinated 5-(3,4-dimethoxy-
benzyl)pyrrole 15.
In conclusion, a convenient synthetic route to new fluorinated
pyrroles was developed, which are interesting building blocks
for the preparation of physiological active compounds in
medicinal chemistry and agrochemistry. The common precur-
sors, i.e., 3,3-difluoro-1-pyrrolines 3, were prepared via elec-
trophilic fluorination of the corresponding 1-pyrrolines by
Selectfluor. Reaction of these difluoropyrrolines 3 with sodium
alkoxides yielded new fluorinated 5-(alkoxymethyl)pyrroles in
good yields. In addition, a new synthesis of new fluorinated
pyrrole-5-carbaldehydes via intermediate fluorinated 5-methyl-
ene-1-pyrrolines was accomplished.
It was observed that during the R,R-difluorination of pyrroline
2a for 48 h, a trace amount of 5-methylene-1-pyrroline 5a was
formed via dehydrobromination of difluoropyrroline 3a. The
latter conversion could be optimized by using potassium
carbonate as base and yielded almost quantitatively the new
2-aryl-3,3-difluoro-5-methylene-1-pyrrolines 5, which are in-
teresting building blocks for further transformations (Scheme
4). The reactivity of these cyclic azadienes was investigated by
using N-bromosuccinimide in methanol. Reaction of 2-aryl-3,3-
difluoro-5-methylene-1-pyrrolines 5 with N-bromosuccinimide
in methanol at room temperature for 4 h provided a vicinal
bromomethoxylation of the exocyclic double bond, affording
5-(bromomethyl)-3,3-difluoro-5-methoxy-1-pyrrolines 6 in ex-
cellent yields (93-100%). The relatively unstable hemiaminal-
type compounds 6 were not purified by flash chromatography
to avoid decomposition, but were treated directly with an excess
of 2 M sodium methoxide in methanol at room temperature to
target fluorinated azaheterocyclic compounds. Surprisingly, these
mild conditions gave access to new fluorinated 5-(dimethoxym-
ethyl)-1H-pyrroles 7 in good yields. A mild hydrolysis of the
dimethoxymethyl group of pyrroles 7 could be established
through flash chromatography on wet silica gel, resulting in new
3-fluoro-1H-pyrrole-5-carbaldehydes 8 directly.
The conversion of 5-(bromomethyl)-3,3-difluoro-5-methoxy-
1-pyrrolines 6 into 2-aryl-5-(dimethoxymethyl)-3-fluoro-1H-
pyrroles 7 can be rationalized via an initial addition of methoxide
across the imino bond of the starting material 6 (Scheme 5)
and expulsion of bromide resulting in bicyclic aziridine inter-
mediate 9, which is attacked by methoxide at the less hindered
carbon atom to form azafulvene 12 after dehydrofluorination
and elimination of methanol. An alternative mechanistic expla-
Experimental Section
Synthesis of 2-Aryl-5-(bromomethyl)-1-pyrrolines 2. Com-
pounds 2a, 2b, and 2e were synthesized according to literature
procedures in 38%, 29%, and 28% yield, respectively (lit. yields:
2a, 51%; 2b, 56%; 2e, 63%).19 New compounds 2c and 2d were
synthesized analogously.
J. Org. Chem. Vol. 74, No. 3, 2009 1379

Difluorination of Pyrrolines 2. In a dry 250 mL flask equipped
with a reflux condenser and CaCl2-tube, 4.23 g (17.78 mmol) of
5-(bromomethyl)-2-phenyl-1-pyrroline 2a was dissolved in 150 mL
of dry acetonitrile (dest. from CaH2). Under stirring at room
temperature was added 15.75 g (44.46 mmol, 2.5 equiv) of
Selectfluor and 0.5 mL of trifluoroacetic acid. The solution was
heated under reflux for 2 days. After cooling, the heterogeneous
mixture was filtered over Celite, and the filtrate was poured into
150 mL of aq 0.5 M NaOH followed by extraction with 3 × 100
mL of diethyl ether. The combined organic phases were dried over
MgSO4, and after filtration, the solvent was evaporated in vacuo.
The crude product (dark brown) was purified by flash chromatog-
raphy to yield 1.56 g (5.70 mmol) of pure 5-(bromomethyl)-3,3-
difluoro-2-phenyl-1-pyrroline 3a: flash chromatography (hexane/
EtOAc 98:2, Rf 0.10). Yield 32%. Mp 57.3 °C. White crystals. 1H
NMR (CDCl3) δ 2.34-2.55 (1H, m, CHaHbCF2), 2.61-2.80 (1H,
m, CHaHbCF2), 3.62 (1H, dd, J ) 10.5, 6.6 Hz, CHaHbBr), 3.75
(1H, dd, J ) 10.5, 3.9 Hz, CHaHbBr), 4.50-4.62 (1H, m, CHN),
7.39-7.53 (3H, m, 3 × CHar), 7.99-8.05 (2H, m, 2 × CHar). 19F
NMR (CDCl3) δ -91.1 (1F, ddt, J ) 269.7, 17.5, 9.2 Hz), -92.0
(1F, ddt, J ) 269.7, 17.1, 2.6 Hz). 13C NMR (CDCl3) δ 35.8 (d, J
) 2.3 Hz), 38.7 (t, J ) 24.8 Hz), 66.4 (t, J ) 6.8 Hz), 128.3,
128.7, 128.9, 129.8 (dd, J ) 256.1, 253.8 Hz), 131.8, 167.0 (t, J )
26.0 Hz). IR (KBr, cm-1) ν 1626 (CdN). MS (ES+) m/z (%) 274/
276 (M + H+, 100). Anal. Calcd for C11H10BrF2N: C, 48.20; H,
3.68; N, 5.11. Found: C, 48.61; H, 4.01; N, 4.62.
Synthesis of 2-(Alkoxymethyl)-1H-pyrroles 4 (Method 1). In
a flame-dried 10 mL flask, 0.10 g (0.36 mmol) of 5-(bromomethyl)-
3,3-difluoro-2-phenyl-1-pyrroline 3a was dissolved in a mixture of
3 mL of methanol and 3 mL of aq 2 M NaOH. The solution was
heated under reflux for 1 h. After cooling, the mixture was poured
in 30 mL of water and the aqueous phase was extracted with 3 ×
15 mL of diethyl ether. The combined organic phases were dried
over MgSO4, and after filtration, the solvent was evaporated in
vacuo to yield 0.07 g (0.36 mmol) of pure and crystalline 3-fluoro-
5-(methoxymethyl)-2-phenyl-1H-pyrrole 4a. Yield 100%. Mp
115.7 °C. Orange crystals. 1H NMR (CDCl3) δ 3.37 (3H, s, MeO),
4.39 (2H, s, CH2), 6.00 (1H, d, J ) 3.0 Hz, CHCF), 7.17-7.23
(1H, m, CHar), 7.35-7.42 (2H, m, 2 × CHar), 7.48-7.53 (2H, m,
2 × CHar), 7.96-8.16 (1H, s (broad), NH). 19F NMR (CDCl3) δ
-161.7 (1F, s). 13C NMR (CDCl3) δ 57.4, 67.2, 98.7 (d, J ) 16.5
Hz), 115.0 (d, J ) 19.6 Hz), 123.8 (d, J ) 4.6 Hz), 124.9 (d, J )
5.8 Hz), 125.9, 128.8, 130.4 (d, J ) 4.6 Hz), 148.7 (d, J ) 244.6
Hz). IR (KBr, cm-1) ν 3228 (NH), 1609. MS (ES-) m/z (%) 204
(M - H+, 100). Anal. Calcd for C12H12FNO: C, 70.23; H, 5.89; N,
6.82. Found: C, 70.29; H, 5.72; N, 6.73.
Synthesis of 1H-Pyrrole-5-carbaldehydes 8. In a dry 50 mL
flask containing 25 mL of 2 M sodium methoxide in methanol (50
mmol; freshly prepared from Na and MeOH) was added 0.33 g
(1.09 mmol) of 5-(bromomethyl)-3,3-difluoro-5-methoxy-2-phenyl-
1-pyrroline 6a (for the synthesis of compounds 6 refer to the
Supporting Information). The solution was stirred at room temper-
ature for 4 h and subsequently poured in 25 mL of water and
extracted with 3 × 30 mL of dichloromethane. The combined
organic phases were dried (MgSO4), filtered, and evaporated in
vacuo to yield 0.19 g (0.81 mmol) of 5-(dimethoxymethyl)-3-
1
fluoro-2-phenyl-1H-pyrrole 7a. Yield 74%. Red oil. H NMR
(CDCl3) δ 3.34 (6H, s, 2 × MeO), 5.46 (1H, s, CH(OMe)2), 6.06
(1H, d, J ) 2.8 Hz, CHCF), 7.16-7.25 (1H, m, CHar), 7.34-7.41
(2H, m, 2 × CHar), 7.49-7.55 (2H, m, 2 × CHar), 8.20-8.43 (1H,
s (broad), NH). 19F NMR (CDCl3) δ -160.9 (1F, s). 13C NMR
(CDCl3) δ 52.5, 97.4 (d, J ) 17.3 Hz), 98.1 (d, J ) 2.3 Hz), 114.2
(d, J ) 19.6 Hz), 123.9 (d, J ) 4.6 Hz), 125.2 (d, J ) 5.8 Hz),
126.0, 128.9, 130.4 (d, J ) 3.5 Hz), 149.1 (d, J ) 244.6 Hz). IR
(NaCl, cm-1) ν 3280 (NH), 1614. MS (ES-) m/z (%) 188 (M -
Me - OMe - H+, 100).
3-Fluoro-2-phenyl-1H-pyrrole-5-carbaldehyde 8a. During chro-
matography (hexane/EtOAc 9:1, Rf 0.17), 5-(dimethoxymethyl)-
1H-pyrrole 7a was converted to 1H-pyrrole-5-carbaldehyde 8a.
1
Yield 42%. Mp 157.6 °C. Pink crystals. H NMR (CDCl3) δ 6.74
(1H, d, J ) 0.6 Hz, CHCF), 7.32-7.39 (1H, m, CHar), 7.41-7.49
(2H, m, 2 × CHar), 7.70-7.76 (2H, m, 2 × CHar), 9.44 (1H, s,
CHO). 19F NMR (CDCl3) δ -157.4 (1F, s). 13C NMR (CDCl3) δ
107.9 (d, J ) 16.2 Hz), 124.3 (d, J ) 18.5 Hz), 125.6 (d, J ) 4.6
Hz), 127.0 (d, J ) 4.6 Hz), 128.4 (d, J ) 4.6 Hz), 128.6, 129.1,
149.5 (d, J ) 249.2 Hz), 178.8 (d, J ) 3.5 Hz). IR (KBr, cm-1) ν
3117 (NH), 1638 (CdO). MS (ES+) m/z (%) 190 (M + H+, 100).
Anal. Calcd for C11H8FNO: C, 69.83; H, 4.26; N, 7.40. Found: C,
69.68; H, 4.33; N, 7.44.
Acknowledgment. The authors are indebted to the Research
Foundation-Flanders (FWO-Flanders), Ghent University (GOA,
BOF), and Janssen Pharmaceutica (Johnson & Johnson) for
financial support.
Supporting Information Available: General experimental
methods and 1H NMR and 13C NMR spectra of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO802272N
1380 J. Org. Chem. Vol. 74, No. 3, 2009