Preparation of pentafluorosulfanyl (SF5) pyrrole carboxylic acid esters

Article abstract of DOI:10.1021/jo9007699

(Chemical Equation Presented) Pyrrole derivatives bearing a pentafluorosulfanyl group are currently unknown. In this paper, a facile preparation of SF₅-substituted pyrrole carboxylic acid esters in good yield is reported. Utilizing the cycloadd

Full text of DOI:10.1021/jo9007699

pubs.acs.org/joc
the pentafluorosulfanyl (SF5) group has increasingly at-
Preparation of Pentafluorosulfanyl (SF5) Pyrrole
Carboxylic Acid Esters
tracted interest as a novel fluorine-containing substituent.
The “discovery” of this substituent by organic, agrochem-
ical, and pharmaceutical chemists has led to a number of
recent papers and patents that have confirmed the idea that
the SF5 substituent might indeed provide unique advantages
in terms of biological activity.6-8 According to a SciFinder
search, whereas in the eight years prior to 2005 there was an
average of only 5-6 patents per year related to biologically
active SF5-containing compounds, since 2005, there has been
an average of 25 such patents submitted per year.9 Research
in this area has, however, generally been hampered by a
lack of availability of key SF5-containing building blocks.
Recently, the commercial availability of SF5-benzene deri-
vatives has facilitated exploratory work with these com-
pounds,10 with the result that most of the encouraging
studies mentioned above were carried out using SF5-aro-
matics as the building blocks.
William R. Dolbier Jr.* and Zhaoyun Zheng
Department of Chemistry, University of Florida, PO Box
117200, Gainesville, Florida 32611-7200
wrd@chem.ufl.edu
Received April 13, 2009
Heterocycles are very important potential components of
pharmaceuticals However, to our knowledge few hetero-
cycles bearing an SF5-group are known: furans,11 pyra-
zoles,12 and triazoles.12 There do not appear to be any
mention in the journal literature of ring-substituted SF5-
thiophenes, pyrroles, or pyridines, although there is mention
in a patent application of a preparation of SF5-pyridines13
and in a patent of SF5-thienylthiophenes.14
Pyrrole derivatives bearing a pentafluorosulfanyl group
are currently unknown. In this paper, a facile preparation
of SF5-substituted pyrrole carboxylic acid esters in good
yield is reported. Utilizing the cycloaddition of an azo-
methine ylide to pentafluorosulfanylalkynes, a series of
dihydropyrroles were prepared and oxidized to the re-
spective 1-tert-butyl-4-(pentafluorosulfanyl)pyrrole-2-
carboxylic acid esters in good yield. Further treatment
of these pyrroles with catalytic triflic acid allowed re-
moval of the tert-butyl group.
The search for synthetic pathways to additional classes of
SF5-heterocycles has therefore become an ongoing goal of
our research program. At this time, we would like to report
the first general method for preparation of SF5-substituted
pyrrole derivatives, namely 4-(pentafluorosulfanyl)pyrrole-
2-carboxylic acids. Most of the well-known methods for
preparing pyrroles,15 such as the Paal-Knorr synthesis,
the Knorr synthesis, the Hantzsch synthesis, the van Leusen
synthesis, etc., all involve ring formation via condensation
reactions via carbanionic intermediates. All such methods
have thus far failed when using SF5-substituted substrates,
probably because of the instability of anionic intermediates
bearing an R- or β-SF5 group. For example, in an attempt to
utilize a van Leusen approach to prepare SF5-pyrroles, the
reaction of TosMIC with SF5-substituted R,β-unsaturated
ester 1 led only to a fluorine-free product, presumably
pyrrole 2, formed by preferential elimination of SF5- rather
than loss of Tos-, which is the usual final, pyrrole-forming
step of a van Leusen synthesis (Scheme 1).
Because of the acknowledged effect of fluorine on the
physical and chemical properties of organic compounds1,2
and in particular its potential influence on the biological
activity of pharmaceutical and agrochemical compounds,3-5
(1) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308–319.
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Metcalf, B. (Incyte Corp.) WO 2009012259, 2009; Chem. Abstr. 2009, 150,
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G. M. (Pfizer Ltd) US 20080146643, 2008; Chem. Abstr. 2008, 149, 79598.
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2008058641, 2008; Chem. Abstr. 2008, 148, 561912.
þ
There is also no electrophilic source of SF5 (i.e., an SF5
reagent), so one cannot prepare SF5-pyrroles directly from
pyrroles by electrophilic substitution.
(10) Lal, G. S.; Syvret, R. G. Chim. Oggi 2008, 26, 26–27.
(11) Dolbier, W. R. Jr.; Mitani, A.; Xu, W.; Ghiviriga, I. Org. Lett. 2006,
8, 5573–5575.
(12) Ye, C.; Gard, G. L.; Winter, R. W.; Syvret, R. G.; Twamley, B.;
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5626 J. Org. Chem. 2009, 74, 5626–5628
Published on Web 06/25/2009
DOI: 10.1021/jo9007699
r
2009 American Chemical Society

Dolbier and Zheng
JOCNote
SCHEME 1. Attempted van Leusen Synthesis of SF5-Pyrroles
SCHEME 3. Preparation of SF5-Alkynes
SCHEME 4. Preparation of SF5-Pyrroles
SCHEME 2. Azomethine Methodology for Synthesis of Pyrroles
SCHEME 5. Removal of tert-Butyl Group
alkynes, followed by base-catalyzed elimination of HCl
(Scheme 3),21-23 and when such alkynes were allowed to
react with aziridine ester 3 as depicted in Scheme 4, SF5-
substituted pyrrolines, 5, were obtained. Although crude
pyrroline 5b was isolated and characterized, and its regio-
chemistry of cycloaddition determined, generally the pyrro-
lines were not fully characterized but were simply isolated
and immediately subjected to oxidation by DDQ to form the
tert-butyl pyrroles 6 (53 to 78% yield), which were them-
selves fully characterized.
To demonstrate the efficacy of the procedure, the tert-
butyl group of pyrrole 6a was cleanly removed by treatment
with catalytic quantities of triflic acid in methylene chloride
to produce pyrrole 7 in a nonoptimized yield of 72%
(Scheme 5).
Thus far there has been but one ring-forming approach
that has been demonstrated to tolerate SF5 on the building
block, and that is cycloaddition chemistry.16 Diels-Alder
reactions of both SF5-alkenes17-19 and SF5-alkynes,11 have
been reported, as have 1,3-dipolar cycloadditions of the
alkynes.12,18 A Diels-Alder approach was used in our pre-
paration of SF5-furans.11
The 1,3-dipolar cycloaddition of azomethine ylides to SF5-
alkynes, followed by oxidation of the intermediate pyrro-
lines, appeared to be a reasonable approach to the synthesis
of SF5-pyrroles, such a method having been successfully
implemented by La Porta and co-workers in their prepara-
tion of (trifluoromethyl)pyrroles from trifluoromethyl al-
kynes (Scheme 2).20
The procedure reported in this paper for the first time
makes a wide variety of SF5-substituted pyrrole building
blocks available for potential incorporation into possible
bioactive compounds.
Experimental Section
One advantage of this specific aziridine precursor is the
ability to readily remove the tert-butyl group from the
pyrrole nitrogen.
The required analogous pentafluorosulfanyl alkynes, 4,
were readily available by the addition of SF5Cl to terminal
NMR spectra were obtained in CDCl3 using TMS and CFCl3
as the internal standards for 1H/13C NMR and 19F NMR
respectively; melting points were uncorrected. Aziridine 3 and
SF5-alkyne starting materials 4b and 4c were prepared accord-
ing to the previous literature.20,21
Procedure for Preparation of Alkynes 4a and 4d21. Into a flask
equipped with a dry ice reflux condenser were added at -40 °C
20 mL of anhydrous hexane, alkyne (3-4 mmol), and SF5Cl
(1.2 equiv). The solution was stirred at this temperature for
10 min, and Et3B (0.1 equiv, 1 M in hexane) was added slowly
using a syringe. The solution was stirred for 1 h at -30 °C, and
then warmed to rt. The mixture was quenched with aqueous
NaHCO3, and the organic phase was dried with MgSO4. After
removing the solvent, 20 mL of DMSO was added to the residue
along with 5 equiv of LiOH. The solution was stirred at rt for 2 h,
after which the mixture waspouredintoice water and neutralized
with 2 M HCl. The product was extracted with ether twice, dried
with MgSO4, and finally purified by column chromatography.
(16) Lentz, D.; Seppelt, K. In Chemistry of Hypervalent Compounds;
Akiba, K., Ed.; Wiley-VCH: New York, 1999; pp 295-326.
(17) Brel, V. K. Synthesis 2006, 339–343.
(18) Hoover, F. W.; Coffman, D. D. J. Org. Chem. 1964, 29, 3567–3570.
(19) Winter, R. W.; Gard, G. L. J. Fluorine Chem. 2007, 128, 896–901.
(20) La Porta, P.; Capuzzi, L.; Bettarini, F. Synthesis 1994, 287–290.
(21) Dolbier, W. R. Jr.; Ait-Mohand, S.; Schertz, T. D.; Sergeeva, T. A.;
Cradlebaugh, J. A.; Mitani, A.; Gard, G. L.; Winter, R. W.; Thrasher, J. S.
J. Fluorine Chem. 2006, 127, 1302–1310.
(22) Mitani, A.; Dolbier, W. R. Jr. WO 2007106818, 2007; Chem. Abstr.
2007, 147, 386101.
(23) Lal, G. S.; Minnich, K. E. (Air Products) USP 6479645, 2002;
Chem. Abstr. 2002, 137, 353172.
J. Org. Chem. Vol. 74, No. 15, 2009 5627

Dolbier and Zheng
JOCNote
Data for 4a (43%). 1H NMR: δ 2.55-2.62 (m, 2H), 2.85-2.90
(t, J =10 Hz, 2H), 7.18-7.33 (m, 5H). 13C NMR: δ 20.4, 33.5,
127.0, 128.5, 128.8, 139.2. 19F NMR: δ þ77.4(m, 1F), þ82.6
(d, J = 160 Hz, 4F).
4F). HRMS: calcd for C16H18F5NO2S, 383.0978; found,
383.0973. Anal. Calcd for C16H18F5NO2S: C, 50.13; H, 4.73;
N, 3.65. Found: C, 50.42; H, 4.61; N, 3.36.
Methyl 1-tert-Butyl-4-pentafluorosulfanyl-3-butylpyrrole-2-
1
Data for 4d (45%). 1H NMR: δ 2.40 (s, 3H), 7.20-7.22 (d, J =
7.8 Hz, 2H), 7.44-7.47 (d, J = 7.8 Hz, 2H). 13C NMR: δ 21.9,
129.7, 132.7, 142.1. 19F NMR: δ þ77.3 (p, J = 162 Hz, 1F),
þ83.05 (d, J = 177 Hz, 4F).
carboxylate, 6c. (54%) mp 41-44 °C. H NMR: δ 0.88-0.93
(t, J =14.4 Hz, 3H), 1.13-1.50 (m, 4H), 1.64 (s, 9H), 2.63-2.69
(t, J =15.9 Hz, 2H), 3.86 (s, 3H), 7.26(s, 1H). 13C NMR: δ 14.0,
23.3, 25.9, 30.8, 33.8, 52.1, 59.7, 121.1 (m), 122.7 (m), 128.1 (m),
134.9 (m), 163.7. 19F NMR: δ þ88.8 (m, 1F), þ74.3 (d, J = 155
Hz, 4F). HRMS: calcd for C14H22F5NO2S, 363.1291; found,
363.1316. Anal. calcd for C14H22F5NO2S: C, 46.27; H, 6.10; N,
3.85. Found: C, 46.39; H, 6.40; N, 3.93.
Procedure for Preparation of Pyrroles 6a-d. A mixture of 3
(2.05 mmol, 3 equiv), 4 (0.68 mmol, 1 equiv), and 2.5 mL of
xylene was heated at about 130-140 °C for 24 h (monitored by
NMR). Product 5 was separated from excess 3 by flash chro-
matography, and then 5 mL of CCl4 and 310 mg of DDQ were
added to the crude 5 at rt, and the mixture was stirred for 3 h
(monitored by TLC). The solvent was then removed by distilla-
tion, and the residue submitted to column chromatography to
obtain 6 as a white solid.
Methyl 1-tert-Butyl-4-pentafluorosulfanyl-3-p-tolylpyrrole-2-
1
carboxylate, 6d. (78%) mp 114-116 °C. H NMR: δ 1.68 (s,
9H), 2.36 (s, 3H), 3.41(s, 3H), 7.12 (s, 4H), 7.33 (s, 1H). 13C
NMR: δ 21.4, 30.7, 52.1, 59.7, 121.5 (m), 122.7 (m), 126.8 (m),
128.2, 130.0, 131.1, 135.3 (m), 137.0, 164.1. 19F NMR: δ þ87.6
(p, J = 152 Hz, 1F), þ75.4 (d, J = 152 Hz, 4H). HRMS: calcd
for C17H20F5NO2S, 397.1135; found, 397.1120. Anal. calcd for
C17H20F5NO2S: C, 51.38; H, 5.07; N, 3.52. Found: C, 51.40; H,
5.25; N, 3.30.
Although the intermediate dihydropyrroles were not gener-
ally isolated but were directly converted to the respective
pyrroles by treatment with DDQ, the structure of one dihydro-
pyrrole intermediate, 5b, was demonstrated unambiguously by
NMR analysis prior to its oxidative conversion to pyrrole 6b.
Methyl 1-tert-Butyl-4-pentafluorosulfanyl-3-phenyl-2,5-dihy-
dro-2H-pyrrole-2-carboxylate, 5b. 1H NMR: δ 1.12 (s, 9H),
3.48 (s, 3H), 4.18 (dd, J = 14.1, 5.1 Hz, 1H), 4.35 (dd, J =
Procedure for Removal of tert-Butyl Group. Methyl 4-Penta-
fluorosulfanyl-3-(2-phenylethyl)pyrrole-2-carboxylate, 7. Two
drops of CF3SO3H was added to a flask containing 80 mg of
6a and 2 mL of CH2Cl2 at rt, and the mixture was stirred for
about 2 h (monitored by TLC). The mixture was purified
directly by column chromatograph to obtain 7 as a white solid
(78%): mp 165-167 °C. 1H NMR: δ 2.78-2.84 (dd, J = 8.1 and
4.2 Hz, 2H), 3.16-3.22 (dd, J=8.1 and 4.2 Hz, 2H), 3.92 (s, 3H),
7.19-7.34 (m, 6H), 9.34 (s, 1H). 13C NMR: δ 28.4, 37.5, 52.1,
118.8 (m), 122.0 (m), 126.2, 128.0 (m), 128.6, 128.6, 138.5 (m),
142.1, 161.3. 19F NMR: δ þ88.9 (p, J = 148 Hz, 1H), þ73.6 (d, J
= 148 Hz, 4H). HRMS: calcd for C14H14F5NO2S, 355.0665;
found, 355.0648. Anal. calcd for C14H14F5NO2S: C, 47.32; H,
3.97; N, 3.94. Found: C, 47.04; H, 3.68; N, 3.86.
14.1. 6.6 Hz, 1H), 4.70 (m, 1H), 7.10 (m, 2H), 7.34 (m, 3H). 13
C
NMR: δ 25.0, 51.2, 53.4, 54.6 (C-5), 72.6 (C-2), 126.4, 127.1,
127.6, 131.1, 139.7 (C-3), 147.4 (SF5-C), 171.4 (CdO). 19F
NMR: δ þ67.2 (d, J = 148 Hz, 4F), þ76.1 (m, 1F).
Methyl 1-tert-Butyl-4-pentafluorosulfanyl-3-(2-phenylethyl)
pyrrole-2-carboxylate, 6a. (60%) mp 115-117 °C. 1H NMR: δ
1.67 (s, 9H), 2.77-2.83 (dd, J = 6.6 and 4.5 Hz, 2H), 2.96-3.02
(dd, J = 6.6 and 4.5 Hz, 2H), 3.91 (s, 3H), 7.21-7.34 (m, 6H).
13C NMR: δ 28.8, 30.7, 37.9, 52.2, 60.0, 121.4 (m), 123.1 (m),
126.2, 127.1 (m), 128.5, 128.6, 135.0 (m), 142.2, 163.6. 19F NMR:
δ þ88.7 (m, 1F), þ74.3 (d, J =150 Hz, 4F). HRMS: calcd for
C18H22F5NO2S, 411.1291; found, 411.1277. Anal. Calcd for
C18H22F5NO2S: C, 52.55; H, 5.39; N, 3.40. Found: C, 52.73;
H, 5.42; N, 3.28.
Acknowledgment. The authors gratefully acknowledge
Dr. Ion Ghiviriga for assistance with NMR spectroscopy,
and Dr. Robert Syvret for generous contributions of SF5Cl.
Methyl 1-tert-Butyl-4-pentafluorosulfanyl-3-phenylpyrrole-2-
1
carboxylate, 6b. (53%) mp 108-110 °C. H NMR: δ 1.66 (s,
9H), 3.34 (s, 3H), 7.18-7.31 (m, 6H). 13C NMR: δ 30.7, 52.0,
59.8, 121.7 (m), 122.7 (m), 126.9 (m), 127.4, 127.4, 130.1, 134.3,
135.2 (m), 163.9. 19FNMR: δþ87.4 (m, 1F), þ75.4 (d, J =153 Hz,
Supporting Information Available: 1H, 13C and 19F NMR
spectra of compounds 4a and d, 5b, 6a-d and 7. This material is
available free of charge via the Internet at http://pubs.acs.org.
5628 J. Org. Chem. Vol. 74, No. 15, 2009