Gold-catalyzed synthesis of 2-aryl-3-fluoropyrroles

Article abstract of DOI:10.1021/ol900953n

The gold-catalyzed cyclizatlon and dehydrofluorination of gem-dlfluorohomopropargylamlnes provides a novel access to 2-aryl-3- fluoropyrroles. Difluorinated homopropargylamines are prepared by the addition of gem-difluoropropargyllithium reagents to aryla

Full text of DOI:10.1021/ol900953n

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2920-2923
Gold-Catalyzed Synthesis of
2-Aryl-3-fluoropyrroles
Riccardo Surmont,† Guido Verniest,‡ and Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent
UniVersity, Coupure Links 653, B-9000 Ghent, Belgium
norbert.dekimpe@ugent.be
Received April 30, 2009
ABSTRACT
The gold-catalyzed cyclization and dehydrofluorination of gem-difluorohomopropargylamines provides a novel access to 2-aryl-3-fluoropyrroles.
Difluorinated homopropargylamines are prepared by the addition of gem-difluoropropargyllithium reagents to arylated N-tosylimines.
Fluorine as a substituent can drastically affect the physical,
chemical, and biological properties of a molecule. The
use of fluorine substitution in drug design has resulted in
enhanced binding efficiencies and selectivities of phar-
maceuticals. These advantages led to a growing interest
in organofluorine chemistry and stimulated the research
for selective syntheses of fluorinated heterocylic com-
pounds.1 In particular, fluorinated pyrroles represent a
class of important structural units in pharmaceutical and
agrochemical products such as drugs against cytokine-
mediated diseases,2 fungicides and bactericides,3 porphy-
rins,4 and antithrombosis agents.5 In contrast to the large
number of syntheses for nonfluorinated pyrroles, only
limited synthetic pathways are available to synthesize
3-fluoropyrroles selectively.6,7 Recently, our research group
developed a convenient synthetic route to 2-aryl-3-fluoro-
1H-pyrrole-5-carbaldehydes and 5-alkoxymethyl-2-aryl-3-
fluoro-1H-pyrroles via electrophilic fluorination of the cor-
responding 1-pyrrolines.7 Because of the importance of
fluorinated pyrroles, the search for new and efficient synthetic
pathways was continued. Therefore, the gold-catalyzed
5-endo-dig cyclization of 2,2-difluorobut-3-yn-1-amines 3
toward 3,3-difluoropyrrolines 4 was investigated. Dehydro-
fluorination of the obtained pyrrolines 4 should lead to 2,5-
† Aspirant of the Research Foundation-Flanders (FWO-Vlaanderen).
‡ Postdoctoral Fellow of the Research Foundation-Flanders (FWO-
Vlaanderen).
(1) (a) O’Hagan, D. Chem. Soc. ReV. 2008, 37, 308. (b) Purser, S.;
Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. ReV. 2008, 37, 320.
(c) Kirk, K. L. Org. Process Res. DeV. 2008, 12, 305. (d) Mu¨ller, K.; Faeh,
C.; Diederich, F. Science 2007, 317, 1881. (e) Isanbor, C.; O’Hagan, D. J.
Fluorine Chem. 2006, 127, 303. (f) Be´gue´, J.-P.; Bonnet-Delpon, D. J.
Fluorine Chem. 2006, 127, 992. (g) Kirk, K. L. J. Fluorine Chem. 2006,
127, 1013.
(6) Gozzo, F. C.; Ifa, D. R.; Eberlin, M. N. J. Org. Chem. 2000, 65,
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(7) For an overview of known synthetic pathways to 3-fluoropyrroles,
see: (a) Surmont, R.; Verniest, G.; Colpaert, F.; Macdonald, G.; Thuring,
J. W.; Deroose, F.; De Kimpe, N. J. Org. Chem. 2009, 74, 1377, and
(2) De Laszlo, S. E.; Liverton, N. J.; Ponticello, G. S.; Selnick, H. G.;
Mantlo, N.B. U.S. Patent US5837719 A19981117, 1998; Chem. Abstr. 1998,
130, 10663.
references therein.
(8) (a) Verniest, G.; Padwa, A. Org. Lett. 2008, 10, 4379. (b) Hashmi,
A. S. K. Chem. ReV. 2007, 107, 3180. (c) Gorin, D. J.; Toste, F. D. Nature
2007, 446, 395. (d) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D.
Science 2007, 317, 496. (e) Jimenz-Nunez, E.; Echavarren, A. M. Chem.
Commun. 2007, 333. (f) Hoffman-Roder, A.; Krause, N. Org. Biomol. Chem.
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Scarborough, R. M. PCT Int. Appl. WO 2002026734 A1 20020404, 2002;
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.
10.1021/ol900953n CCC: $40.75
Published on Web 06/09/2009
 2009 American Chemical Society

disubstituted 3-fluoropyrroles 5 in a mild and convergent way
(Scheme 1).
1-Bromo-1,1-difluoro-3-phenylprop-2-yne 2a could be
isomerized into the corresponding compound 9 using indium
in THF/H2O (1:4) at room temperature, but a substantial
amount of dimerization product 10 (3,3,4,4-tetrafluoro-1,6-
diphenylhexa-1,5-diyne) was formed after 2 h, making this
solvent- and substrate-dependent route unattractive (Scheme
3).10
Scheme 1
Scheme 3
Despite the successful application of homogeneous gold
catalysis in organic synthesis for the preparation of heterocyclic
compounds,8 gold-catalyzed cycloisomerizations using fluori-
nated starting materials have been scarcely investigated. Re-
cently, difluorinated dihydropyranones have been synthesized
from ꢀ-hydroxy-R,R-difluoroynones via gold-catalyzed 6-endo-
dig cyclization.9
Only one example of a 2,2-difluorobut-3-yn-1-amine 3,
notably a silyl derivative, is known in literature (R1 ) Ph, R2
) CH2Ph, R3 ) Si(i-Pr)3), and its synthesis consists of an
indium-mediated propargyl-allene isomerization of (3-bromo-
3,3-difluoroprop-1-ynyl)triisopropylsilane and subsequent attack
to N-(phenylmethylidene)benzylamine.10 For the synthesis of
amines 3, it was decided to use more activated N-sulfonylimines
7 that were easily prepared from (dimethoxymethyl)benzenes
6 via condensation with arylsulfonamides.11 Substituted di-
fluoropropargyl bromides 2 were synthesized via reaction of
lithium acetylides, derived from alkynes 8, with CF2Br2
(Scheme 2).12
In contrast to imines, the addition of difluoropropargyl
bromides across aldehydes resulting in the corresponding
alcohols is far more investigated in the literature. Therefore,
the addition of difluoropropargyl bromide 2a across N-
tosylimine 7a was investigated to establish a new entry
toward fluorinated N-heterocycles. Unfortunately, the metal-
mediated condensation of 2a with N-tosylimine 7a using
indium,13,14 tin,15 magnesium,12,16-18 or zinc19-23 did not
result in the corresponding addition product 11a in acceptable
yields. Finally, when difluoropropargyl bromide 2a was
transmetalated with 1.1 equiv of butyllithium (2.5 M in
hexane) in THF at -78 °C, the organolithium reagent was
reactive enough to attack N-tosylimine 7a leading to sulf-
onamide 11a in 100% conversion after 30 min without
formation of byproducts (Scheme 4).
Scheme 4
Scheme 2
Toourknowledge,thisisthefirstreportonlithium-bromine
exchange of gem-difluoropropargyl bromides, and it
proceeds analogously to the synthesis of gem-difluoroal-
lyllithium reagents.24 Sulfonamide 11a was easily purified
Org. Lett., Vol. 11, No. 13, 2009
2921

via crystallization without necessity of chromatography.
Derivatives 11a-d were prepared by reaction of (3-bromo-
3,3-difluoroprop-1-yn-1-yl)benzene 2a with various aro-
matic N-sulfonylimines 7a-d, and the yields varied
between 36% and 54% depending on the R1-substitution
pattern of the aromatic imine. Better yields were obtained
when (3-bromo-3,3-difluoroprop-1-ynyl)trimethylsilane 2b
was treated with butyllithium and imine 7a to form
sulfonamide 11e (77%). The trimethylsilyl group of
sulfonamide 11e was almost quantitatively hydrolyzed
toward sulfonamide 11f after 5 min of stirring in 1.5 M
NaOH in diethyl ether at room temperature (Scheme 5).
from gem-difluoropropargyl alcohols using AgNO3 by
Hammond et al.26 Therefore, we tried to cyclize sulfon-
amide 11a to pyrrole 15a using 0.1 equiv of AgNO3 in
CH2Cl2 with or without NaOAc as a base, but unfortu-
nately no reaction was observed. Recently, a DBU-
promoted cyclization of gem-difluorohomopropargyl al-
cohols was reported for the synthesis of 2,5-disubstituted
3-fluorofurans.27 However, the reaction of sulfonamide
11a with 3 equiv of DBU in THF under reflux gave only
dehydrofluorination product 12 that did not cyclize to
fluorinated pyrroles even after 100 h. Finally, treatment
of sulfonamides 11a-d with 10 mol % AuCl3 in aceto-
nitrile at room temperature resulted in a smooth cyclization
and in situ dehydrofluorination, forming 2,5-aryl-1-(aryl)-
sulfonyl-3-fluoro-1H-pyrroles 15a-d in 50-69% yield.
The gold-catalyzed cyclization of [(trimethylsilanyl)bu-
tynyl]sulfonamide 11e proved to be more difficult but
could be driven to completion by reaction with AuCl3 for
3 days. However, during this long reaction time the TMS
group of 11e was removed via protodesilylation, resulting
in 2-(4-chlorophenyl)-3-fluoropyrrole 15e. In order to
determine the feasibility of removing the N-p-toluene-
sulfonyl group of pyrroles 15, the hydrolysis of 2-(4-
chlorophenyl)-3-fluoro-1-[(4-methylphenyl)sulfonyl]-5-
phenyl-1H-pyrrole 15a was carried out using NaOH in
EtOH to provide 2-(4-chlorophenyl)-3-fluoro-5-phenyl-
1H-pyrrole 16 in 75% yield.
Scheme 5
In conclusion, a gold-catalyzed cyclization reaction of
electron-deficient gem-difluorohomopropargylamines and
simultaneous dehydrofluorination of intermediate difluo-
ropyrrolines to new 2(,5)-(di)substituted 3-fluoropyrroles
was developed. Difluorinated homopropargylamines, an
almost unknown class of compounds, were successfully
prepared via lithium bromine exchange of difluoroprop-
argyl bromides and subsequent reaction with N-to-
sylimines.
(10) Wang, Z.; Hammond, G. B. J. Org. Chem. 2000, 65, 6547.
(11) Albrecht, R.; Kreaze, G.; Mlakar, B. Chem. Ber. 1964, 97, 483.
Chem. Abstr. 1964, 60, 52474.
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(13) Xu, B.; Mashuta, M. S.; Hammond, G. B. Angew. Chem., Int. Ed.
2006, 45, 7265.
(14) You, Z.-W.; Jiang, Z.-X.; Wang, B.-L.; Qing, F.-L. J. Org. Chem.
2006, 71, 7261.
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Tetrahedron 2000, 56, 8275.
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Lett. 2005, 46, 1787.
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Hammond, G. B. Org. Lett. 2007, 9, 4251.
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1-Bromo-1,1-difluoronon-2-yne 2c, however, could not be
coupled to imine 7a under various reaction conditions.
Besides gold catalysts, silver(I) salts also form stable
π-complexes with acetylenes. Silver(I)-promoted cycliza-
tions of N-(2-hydroxybut-3-yn-1-yl)toluenesulfonamides
to substituted pyrroles in excellent yields were reported
previously.25 3-Fluoro-4,5-dihydrofurans were synthesized
(23) Audouard, C.; Barsukov, I.; Fawcett, J.; Griffith, G. A.; Percy, J. M.;
Pintat, S.; Smith, C. A. Chem. Commun. 2004, 1526.
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2922
Org. Lett., Vol. 11, No. 13, 2009

Acknowledgment. The authors are indebted to the
FWO-Flanders, Ghent University (GOA), and Johnson &
Johnson Pharmaceutical Research & Development, a
Division of Janssen Pharmaceutica NV for financial
support.
Supporting Information Available: General experimen-
tal conditions and spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL900953N
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