Microwave-assisted fluorination of 2-acylpyrroles: Synthesis of fluorohymenidin

Article abstract of DOI:10.1021/ol2029993

Treatment of mono- and nonbrominated 2-acylpyrroles with Selectfluor under microwave conditions leads to fluorination of the pyrrole ring in the 5-position. In particular, 2-trichloroacetylated pyrrole can be fluorinated. As an example, dihydrofluorohymenidin was synthesized and dehydrogenated to fluorohymenidin as the first fluorinated pyrrole-imidazole alkaloid. Introduction of the vinyl double bond was achieved by chlorination of the 2-aminoimidazole moiety, followed by dehydrochlorination at 100 °C in DMF.

Full text of DOI:10.1021/ol2029993

ORGANIC
LETTERS
2012
Vol. 14, No. 2
468–471
Microwave-Assisted Fluorination of
2-Acylpyrroles: Synthesis of
Fluorohymenidin
Benjamin Troegel and Thomas Lindel*
TU Braunschweig, Institute of Organic Chemistry, Hagenring 30, 38106 Braunschweig,
Germany
th.lindel@tu-braunschweig.de
Received November 7, 2011
ABSTRACT
Treatment of mono- and nonbrominated 2-acylpyrroles with Selectfluor under microwave conditions leads to fluorination of the pyrrole ring in the
5-position. In particular, 2-trichloroacetylated pyrrole can be fluorinated. As an example, dihydrofluorohymenidin was synthesized and
dehydrogenated to fluorohymenidin as the first fluorinated pyrrole-imidazole alkaloid. Introduction of the vinyl double bond was achieved by
chlorination of the 2-aminoimidazole moiety, followed by dehydrochlorination at 100 °C in DMF.
Pyrrole-imidazole alkaloids constitute a prominent
group of marine natural products exclusively isolated
from sponges.1 Fluorinated pyrrole-imidazole alkaloids
such as fluorohymenidin (1, Figure 1), an analog of the
natural product hymenidin (2),2 may be of interest for
biosynthetic studies3 and for monitoring complex chem-
ical reactions by 19F NMR spectroscopy. Surprisingly,
fluorinated pyrrole-imidazole alkaloids have never been
synthesized.
In this communication, we report on the microwave-
assisted electrophilic fluorination of 2-acylpyrroles em-
ploying Selectfluor (3).4 Selectfluor has been used for the
fluorination of pyrazole,5 thiophene,6 thiazole,7 and indole8
derivatives. Regarding the fluorination of pyrrole with
Selectfluor, there is only one paper reporting the fluorode-
carboxylation of pyrrole-2-carboxylic acids.9 Other methods
(5) (a) Skinner, P. J.; Cherrier, M. C.; Webb, P. J.; Shin, Y.-J.;
Gharbaoui, T.; Lindstrom, A.; Hong, V.; Tamura, S. Y.; Dang, H. T.;
Pride, C. C.; Chen, R.; Richman, J. G.; Connoly, D. T.; Semple, G.
Bioorg. Med. Chem. Lett. 2007, 17, 5620–5623. (b) Sloop, J. C.; Jackson,
J. L.; Schmidt, R. D. Heteroat. Chem. 2009, 20, 341–345. (c) Teegarden,
B. R.; Li, H.; Jayakumar, H.; Strah-Pleynet, S.; Dosa, P. I.; Selaya, S. D.;
Kato, N.; Elwell, K. H.; Davidson, J.; Cheng, K.; Saldana, H.; Frazer,
J. M.; Whelan, K.; Foster, J.; Espitia, S.; Webb, R. R.; Beeley, N. R. A.;
Thomsen, W.; Moriarty, S. R.; Kilduff, T. S.; Al-Shamma, H. A. J. Med.
Chem. 2010, 53, 1923–1936.
(1) Reviews on the pyrrole-imidazole alkaloids: (a) Al-Mourabit, A.;
Potier, P. Eur. J. Org. Chem. 2001, 237–243. (b) Hoffmann, H.; Lindel,
T. Synthesis 2003, 1753–1783. (c) Jacquot, D. E. N.; Lindel, T. Curr. Org.
Chem. 2005, 9, 1551–1565. (d) Weinreb, S. M. Nat. Prod. Rep. 2007, 24,
931–948. (e) Forte, B.; Malgesini, B.; Piutti, C.; Quartieri, F.; Scolaro,
A.; Papeo, G. Mar. Drugs 2009, 7, 705–753. (f) Al-Mourabit, A.;
Zancanella, M. A.; Tilvi, S.; Romo, D. Nat. Prod. Rep. 2011, 28,
1229–1260.
(6) (a) Kobarfard, F.; Kauffman, J. M.; Boyko, W. J. J. Heterocycl.
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Chem. 1999, 36, 1247–1251. (b) Badland, M.; Compere, D.; Courte, K.;
Dublanchet, A.-C.; Blais, S.; Manage, A.; Peron, G.; Wrigglesworth, R.
Bioorg. Med. Chem. Lett. 2011, 21, 528–530.
(2) First isolation: Kobayashi, J.; Ohizumi, Y.; Nakamura, H.;
Hirata, Y. Experientia 1986, 42, 1176–1177.
(7) (a) Campbell, T. F.; Stephens, C. E. J. Fluorine Chem. 2006, 127,
1591–1594. (b) Antipas, A. S.; Blumberg, L. C.; Brissette, W. H.; Brown,
M. F.; Casavant, J. M.; Doty, J. L.; Driscoll, J.; Harris, T. M.; Jones,
C. S.; McCurdy, S. P.; McElroy, E.; Mitton-Fry, M.; Munchhof, M. J.;
Reim, D. A.; Reiter, L. A.; Ripp, S. L.; Shavnya, A.; Smeets, M. I.;
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(3) Recent studies on the biosynthesis of the pyrrole-imidazole
alkaloids: (a) Wang, Y.-G.; Morinaka, B. I.; Reyes, J. C. P.; Wolff,
J. J.; Romo, D.; Molinski, T. F. J. Nat. Prod. 2010, 73, 428–434. (b)
Genta-Jouve, G.; Cachet, N.; Holderith, S.; Oberhaensli, F.; Teyssie, J.-L.;
Jeffree, R.; Al-Mourabit, A.; Thomas, O. P. ChemBioChem 2011, 12, 2298–
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r
10.1021/ol2029993
Published on Web 12/22/2011
2011 American Chemical Society

Scheme 1. Fluorination of 2-Acylpyrroles (starting material 0.1
M, isolated yields, RSM = recovered starting material)
Figure 1. Structures of hymenidines and Selectfluor (3).
of pyrrole fluorination include the Schiemann reaction,10
anodic fluorination,11 and use of fluorine,12 XeF2,13
and N-fluorobenzenesulfonimide (NFSI).14 Microwave-
assisted reactions with Selectfluor have led to aryl fluorina-
tion of anisole15 and pyrazole derivatives,5b R-fluorination
of carbonyl compounds,16 and desilylation of aliphatic
silylethers.17
As starting materials, we chose eight mono- and non-
brominated 2-acylpyrrol derivatives. Trichloromethylke-
tones 4 and 5 were synthesized as described.18 Esters 6, 7
and amides 8, 9, 10, 11 were obtained by reaction of 4 and 5
with isobutanol, isobutylamine, and aqueous ammonia/
MeCN,19 respectively.
At room temperature, the reaction of 4 with 1 equiv of
Selectfluor (3) was sluggish with only poor yields of
product formed after 24 h. However, reactions with Select-
fluor (3, 1 equiv) under microwave conditions (continuous
power input, 0ꢀ500 W) under reflux (no sealed tube) in
acetonitrile (0.1 M) gave a single product (Scheme 1).
GC analysis showed that fluorination of ester 6 was over
after 5 min with an almost equal amount of starting
material remaining, together with minor side products.
Similar behavior was observed for all other entries. With
the exception of the pyrrole-2-carboxamides 10 and 11,
yields of more than 40% were obtained, comparing well
with other examples of electrophilic fluorination with
Selectfluor.5a,7b Fluorinated pyrroles 13ꢀ19 are new com-
pounds. Trichloromethylketone 12 has been obtained by
Wang and Scott via fluorodecarboxylation of 5-(2,2,2-
trichloroacetyl)-1H-pyrrole-2-carboxylic acid with XeF2
(33%).13a Under nonmicrowave reflux conditions longer
reaction times were needed leading to formation of higher
(10) Onda, H.; Toi, H.; Aoyama, Y.; Ogoshi, H. Tetrahedron Lett.
1985, 35, 4221–4224.
(11) Tajima, T.; Ishii, H.; Fuchigami, T. Tetrahedron Lett. 2001, 42,
4857–4860.
(12) Crestoni, M. E. J. Labelled Compd. Radiopharm. 1990, 28, 1109–
1112.
amounts of side products. Dibrominated pyrroles did not
react.
We had no success on employing N-fluorobenzene-
sulfonimide (NFSI), which had been used by Yamamoto
and co-workers for the 2-fluorination of free pyrrole in the
presence of substoichiometric amounts of ZrCl4 (53%).14
The yield of 5-fluoropyrroles could not be enhanced by
using more than 1 equiv of Selectfluor. Instead, formation
of 2-hydroxypyrrolones was observed. Starting from tri-
chloromethylketone 4 in MeCNꢀwater (50:1), product
20 was isolated in a yield of more than 30% (Scheme 2).
The presence of water increased the yield. The reaction was
also successful for monobrominated trichloromethylketone
(13) (a) Wang, J.; Scott, A. I. Tetrahedron Lett. 1994, 35, 3679–3682.
(b) Wang, J.; Scott, A. I. Tetrahedron 1994, 50, 6181–6192.
(14) Zhang, Y.; Shibatomi, K.; Yamamoto, H. Synlett 2005, 2837–
2842.
(15) Bluck, G. W.; Carter, N. B.; Smith, S. C.; Turnbull, M. D.
J. Fluorine Chem. 2004, 125, 1873–1877.
(16) (a) Xiao, J.-C.; Shreeve, J. M. J. Fluorine Chem. 2005, 126, 475–
478. (b) Thvedt, T. H. K.; Fuglseth, E.; Sundby, E.; Hoff, B. H.
Tetrahedron 2009, 65, 9550–9556.
(17) Shah, S. T. A.; Singh, S.; Guiry, P. J. J. Org. Chem. 2009, 74,
2179–2182.
(18) Bailey, D. M.; Johnson, R. E. J. Med. Chem. 1973, 16, 1300–
1302.
€
(19) Poverlein, C. Dissertation, LMU Munich, 2008.
Org. Lett., Vol. 14, No. 2, 2012
469

of a second equivalent of F would lead to 5-fluoro-5H-
3
pyrrole 24, followed by tautomerization to 5-fluoro-1H-
pyrrole 12. Overall, 2 equiv of Selectfluor would be consumed,
limiting the yield to 50%. An SET mechanism is corroborated
by an earlier finding by Wang and Scott,9 who reported
fluorodecarboxylation of a series of pyrrole-2-carboxylic acids
on treatment with Selectfluor in DCMꢀaqueous NaHCO3.
It was not possible to convert a 5-fluoropyrrole to the cor-
responding hydroxypyrrolone by treatment with Selectfluor,
indicating the possibility of two distinct reaction pathways
starting from nonfluorinated pyrrole.
Scheme 2. Oxidation of Trichloromethylketones 4 and 5
5 affording 21 (25%). Mixtures of starting material 4,
monofluorinated product 12, and hydroxypyrrolone 20 were
obtained when less than 3 equiv of Selectfluor were used.
The structures of the 5-fluoropyrroles and hydroxypyr-
rolones were deduced from 2D NMR spectra. Coupling
constants of vicinal protons 3-H and 4-H were determined
as 4.3 Hz (12) and 10.3 Hz (20), respectively, with 3-H
exhibiting HMBC correlations to the exocyclic carbonyl
Scheme 4. Synthesis of Fluorohymenidin (1) via One-Step De-
hydrogenation of Dihydrofluorohymenidin (26)
1
carbon in both series. FꢀC coupling constants JFC
ꢀ259.2 Hz, 2JFC 12.0 Hz (to C-4), and 3JFC 3.7 Hz (to C-3)
and 1.0 Hz (to C-2) were measured for 5-fluoropyrrole 16,
agreeing with the literature.20
Scheme 3. Possible SET Mechanism of 5-Fluorination
We used 5-fluorinated trichloromethylketone 13 for the
synthesis of fluorohymenidin 1 (Scheme 4). Coupling of
diamine 2522 with the fluorinated building block 13 gave
access to fluorodihydrohymenidin (26, 31%). For the in-
troduction of the vinyl double bond we employed a new
procedure via electrophilic chlorination of the 2-aminoi-
midazole moiety.23 Addition of NCS (1 equiv) to 26 in
DMF at room temperature selectively formed the corre-
sponding chloroimidazole. After complete conversion
(monitored by TLC), elimination of HCl was induced by
heating to 100 °C. At higher temperatures, decomposition
occurred. Reversed phase chromatography (H2O/MeOH/
HCOOH) afforded fluorohymenidin formate (1, 73%).
The 1H NMR spectrum of 1shows the characteristic doublet
(3JHH 16.1 Hz) and doublet of triplets (3JHH 16.1 Hz and
3JHH 5.5 Hz) of the side chain E-double bond. The 13C
Interestingly, electrophilic bromination of trichloro-
methylketone 4 with bromine in HOAc occurs at C4,21
whereas fluorination with Selectfluor takes place at C5.
Scheme 3 outlines anSET mechanism which could account
for the formation of 5-fluoropyrroles. Electrophilic fluo-
rination agents other than Selectfluor and congeners are
generally expected to be sources of atomic fluorine, rather
than of 00Fþ00, as summarized by Wong and co-workers.4
For Selectfluor-type agents, it is considered to be very
difficult to prove the intermediacy of F with the currently
available methods.
3
Oxidation of trichloromethylketone 4 may afford radi-
cal cation 22 which is deprotonated to radical 23. Addition
(22) Olofson, A.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 1998,
63, 1248–1253.
(23) Moldovan, R.-P.; Lindel, T. Z. Naturforsch., B: J. Chem. Sci.
2009, 64b, 1612–1616.
ꢀ
(20) Dvornikova, E.; Bechcicka, M.; Kamienska-Trela, K.;
ꢀ
ꢀ
Krowczynski, A. J. Fluorine Chem. 2003, 124, 159–168.
(21) Grube, A.; Lichte, E.; Kock, M. J. Nat. Prod. 2006, 69, 125–127.
€
470
Org. Lett., Vol. 14, No. 2, 2012

NMR signal of C4 is shifted from 97.5 ppm for 2to 74.9 ppm
for 1.
gift of chromatography materials. BASF Group
(Ludwigshafen, Germany) and Honeywell Specialty
Chemicals Seelze GmbH (Seelze, Germany) are thanked
for the donation of solvents. Dr. Kerstin Ibrom (Institute
of Organic Chemistry, TU Braunschweig, Germany)
is thanked for measurement and discussion of 19F NMR
spectra.
In summary, use of Selectfluor under microwave condi-
tions makes 5-fluorinated 2-acylpyrrole derivatives acces-
sible, in particular trichloromethylketone 13, which may
become of use for the synthesis of other pyrrole-imidazole
alkaloids carrying a fluorine label at the pyrrole ring.
Acknowledgment. Financial support of this research
by the Deutsche Forschungsgemeinschaft (DFG, Li
597/5-1) is gratefully acknowledged. We also thank
Merck KGaA (Darmstadt, Germany) for the generous
Supporting Information Available. Experimental pro-
cedures, characterization data, NMR spectra for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Org. Lett., Vol. 14, No. 2, 2012
471