Probing the hydrolytic reactivity of 2-difluoromethyl pyrroles

Article abstract of DOI:10.1039/C6OB01441K

α-Difluoromethyl pyrroles were found to be stable while N-protected with an electron-withdrawing group. Due to the propensity of pyrroles to access azafulvenium-like intermediates, the C-F bonds of an α-difluoromethyl substituent are labile under hydrolytic conditions. The presence of certain electron-withdrawing substituents about the pyrrolic ring can accelerate this process, as determined through a kinetic comparison of the deprotection and subsequent hydrolysis reactions of N-protected β-aryl α-difluoromethyl pyrroles.

Full text of DOI:10.1039/C6OB01441K

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Probing the hydrolytic reactivity of
2-difluoromethyl pyrroles†
Cite this: DOI: 10.1039/c6ob01441k
Jennifer A. Melanson, Carlotta Figliola, Deborah A. Smithen,
Aleksandra K. Kajetanowicz and Alison Thompson*
α-Difluoromethyl pyrroles were found to be stable while N-protected with an electron-withdrawing
group. Due to the propensity of pyrroles to access azafulvenium-like intermediates, the C–F bonds of an
α-difluoromethyl substituent are labile under hydrolytic conditions. The presence of certain electron-
withdrawing substituents about the pyrrolic ring can accelerate this process, as determined through a
kinetic comparison of the deprotection and subsequent hydrolysis reactions of N-protected β-aryl
α-difluoromethyl pyrroles.
Received 5th July 2016,
Accepted 4th November 2016
DOI: 10.1039/c6ob01441k
www.rsc.org/obc
group on nitrogen-containing heteroaromatic compounds
Introduction
via a radical mechanism (Scheme 1, top):19 N-unsubstituted
Porphyrinogens have been intensely studied, particularly as 2- and 3-acyl pyrroles 1a–b were shown to react promptly with
regards to chemical and biological relevance of the corres- ZnDFMS in the presence of tBuOOH and gave the
ponding porphyrins.1–4 Although spontaneous oxidation of α-difluoromethyl-substituted analogues 2a–b in moderate
porphyrinogens to porphyrins can render the isolation of yield. Note that 2a and 2b both feature conjugated electron-
these precursors rather challenging,5 calix[4]pyrroles6 bear withdrawing acyl groups that serve to stabilise the heterocyclic
eight alkyl or aryl groups at the meso positions of the tetra- core.
pyrrolic skeleton and thus resist oxidation.7–14 The presence of
In 1995 Scott reported the fluorination of several 2-formyl
a meso sp3 carbon confers to the structure a significant confor- pyrroles using DAST, with the goal of synthesising an inhibitor
mational freedom,5 enabling potential binding of these macro- of the uroporphyrinogen III cosynthase.24 Pyrrole 3, which fea-
cycles for a wide range of applications.7–14 As part of an tures a substitution pattern matching that of the enzyme sub-
ongoing effort to develop functionalised dipyrrolic structures, strate, uroporphomethene, reacted with DAST to render 4 in
we began to investigate the synthesis of pyrroles featuring a high yield (87%, Scheme 1, middle). Subsequent deprotection
–CF2– moiety at the α-position, contrasting with the –CR2– unit of 4 under standard hydrolysis conditions was reported to give
(R = alkyl or aryl) used as precursors to calix[4]pyrroles. The the desired α-difluoromethyl pyrrole 5 apparently without loss
strength of the C–F bond,15 alongside its ability to sterically of fluorine. However, experimental conditions or isolated
mimic the C–H unit, has driven growing interest in the use of yields for this step are not described, nor does the report
fluorine as an isostere of hydrogen, a common strategy in agro- include any evidence for the stated maintenance of fluoro sub-
chemical16 and pharmaceutical industries.17,18 In tandem, the stituents. As reported by Haufe (Scheme 1, bottom),25 upon
development of more efficient and diverse methods through exposure to acid the stability of the difluoromethyl group is
which to incorporate this functional moiety, either directly19–22 strongly influenced by the electronic nature of ring substi-
or via the fluorination of existing functionality,23 renders this tution. Indeed, in the presence of the electron-donating
group even more suitable for incorporation into a wide variety methyl group the difluoromethyl group was hydrolysed to the
of frameworks. However, there are few reports describing corresponding 2-formyl pyrrole 6a, while, under the same reac-
pyrroles bearing a difluoromethyl substituent directly appended tion conditions, pyrrole 6b was reported to be stable
to the heterocyclic core. Baran and co-workers developed a (Scheme 1). With the backdrop of these limited reports, we
fluorinating reagent for the installation of a difluoromethyl report herein upon the reactivity of α-difluoromethyl pyrroles
under hydrolytic conditions,24 as well as an approach for the
preparation of β-aryl-α-difluoromethyl pyrroles. Furthermore,
Department of Chemistry, Dalhousie University, P.O. Box 15000, Halifax, NS, B3H
the influence of the pyrrolic ring substitution pattern upon the
4R2, Canada. E-mail: Alison.Thompson@dal.ca
reactivity of the α-difluoromethyl functional group is
†Electronic supplementary information (ESI) available: Data regarding rates of
discussed.
reaction; copies of NMR spectra. See DOI: 10.1039/c6ob01441k
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Scheme 1 Examples of α-difluoromethyl-substituted pyrroles.
exposed to the same conditions.26 Xtalfluor-M® was used to
fluorinate the 2-formyl pyrrole 9, giving the α-difluoromethyl
Results and discussion
The procedure for the synthesis of pyrrole 5 was repeated pyrrole 10 in high yield (90%, Scheme 3). The use of a stabilis-
according to Scott’s method (Scheme 1, middle).24 However, ing N-protecting group proved essential for the fluorination
upon N-deprotection of 4 the isolated product corresponded to reaction to be successful. To study the N-deprotection, aliquots
the N-unprotected aldehyde 8 (75%, Scheme 2), with the two from the reaction of 10 with 2 M aqueous NaOH in MeOD at
pendant esters of course hydrolysed to the corresponding car- 50 °C were analysed using 1H and 19F NMR spectroscopy. As
boxylic acids. As this result clearly contradicts the literature observed previously for 4, the rapid appearance of the
report,24 the reaction was repeated in deuterated solvents and N-unprotected material 11 was followed by methoxide displace-
1
progress was followed via H and 19F NMR spectroscopic ana- ment of the fluoro substituents, to give the acetal 12, which
lysis. The initial N-deprotection of the α-difluoromethyl pyrrole hydrolysed to the aldehyde 13 (Scheme 3 and Fig. 2 in ESI†).
4 was determined to occur immediately upon addition of 2 M
Although some N-unprotected α-difluoromethyl pyrroles
NaOH. The N-deprotected product 5 is unstable under these featuring electron-withdrawing substituents on the heterocycle
reaction conditions, forming first the α-dimethylacetal pyrrole are stable (Scheme 1),19 such systems are clearly different to
7 which then hydrolyses to the α-formyl pyrrole 8 (Scheme 2 pyrroles such as 5 and 11, whereupon hydrolysis to result in
and Fig. 1 in the ESI†).
loss of fluorine is facile. In order to investigate the influence of
In order to exclude the possibility that the two alkanoate the electronic properties of substituents about the pyrrolic
moieties influence the hydrolytic reactivity of the ring upon the deprotection and hydrolysis reactions, a series
α-difluoromethyl group, the unsubstituted variant 10 was of N-(2-nosyl)-β-aryl-substituted pyrroles were synthesised.
Moving away from the tosyl and –SO2Ph protecting groups, the
2-nosyl group was selected thus enabling the N-deprotection to
Scheme 2 N-Deprotection and hydrolysis of pyrrole bearing
2-difluoromethyl group.
a
Scheme 3 Formation and hydrolysis of α-difluoromethyl pyrrole 11.
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be monitored via release of 2-nitrophenyl phenyl sulfide (14, flow of nitrogen gas in the sample chamber of the spectro-
Scheme 4).27,28 Moreover, N-deprotection of the 2-nosyl group photometer, the presence of phenyl disulfide (17 in Scheme 4)
would be achieved under anhydrous conditions. However, was noted upon careful inspection of the reaction mixture
despite 2,4-dinitrophenol (2,4-DNP) being commonly used as a arising from the N-deprotection of 19a–e. Several pathways to
reporter for measuring reaction rates, we were unable to find 17 may be at play during the reaction, e.g. thiophenol affords
reports of monitoring reaction rates through detection of disulfide in the presence of an oxidising agent and a base;33,34
yellow 2-nitrophenyl, 4-nitrophenyl or 2,4-dinitrophenyl phenyl the reaction by-product sulfur dioxide 18 acts as an oxidising
sulfides. Furthermore, although 2-nitrophenyl phenyl sulfide agent. As the disulfide 17 also absorbs at 368 nm, the absor-
is known,29–31 full characterisation proved elusive in the litera- bance reading at this35 wavelength is representative of both
ture. Compound 14 was, therefore, prepared via deprotection products. Since the interference from 17 is constant across the
of 15 using PhSH and NEt3. The ejected sulfide 14 was isolated sample set, the relative production of 14 (Table 1, in ESI†) rep-
in quantitative yield (Scheme 4), thereby demonstrating that resents a qualitative estimation of the N-deprotection rate
this anhydrous method is viable for the needed N-deprotection (Table 1). The starting materials provide no interference at the
of N-(2-nosyl) pyrroles.27,28,32 The absorption maximum of 14 monitoring wavelength. The production of 14 was monitored
occurs at 368 nm (CH3CN), with an extinction coefficient of via its absorbance at 368 nm (Table 1 in ESI†), and the relative
4000 L mol−1 cm−1
.
rate constants of deprotection were thus calculated:
ꢀ
ꢁ
α-Difluoromethyl pyrroles 19a–f featuring various aryl
groups at the β-position of the ring were synthesised according
to Scheme 5. Suzuki coupling between N-(2-nosyl)-3-bromo-2-
formyl pyrrole 20 and boronic acids a–f gave the corresponding
β-aryl pyrroles 21a–f. Subsequent fluorination yielded the
desired α-difluoromethyl pyrroles 19a–f (Scheme 5).
Upon N-deprotection of pyrroles 19a–e with PhSH and NEt3
under anhydrous conditions, the resulting pyrroles (22a–e)
proved to be stable providing the material remained under an
inert and anhydrous environment (Scheme 5). As such, the de-
protection and subsequent hydrolysis reaction could be
studied separately. The first step was studied using UV-Vis
spectroscopy under pseudo-first order conditions using 400
equivalents of PhSH and 560 equivalents of NEt3 in CH3CN at
0 °C under an inert atmosphere. Despite maintaining a steady
KR
KH
log
¼ ρσ
As shown in Table 1, the presence of electron-withdrawing
character in the aryl substituent causes an increase in the rate
of N-deprotection (19a, R = CF3). In contrast, electron-donating
character (19e, R = OCH3) impedes the reaction rate. Fig. 1
shows a Hammett reaction constant (ρ) of 0.4, suggesting an
increase of negative charge in the reaction intermediates.
These features support the reaction mechanism proposed
in Scheme 6. After nucleophilic attack by PhSH,37,38 the
Meisenheimer-type intermediate 23 presumably collapses to
give the reaction intermediate 24 and the development of
anionic character in the orthogonal p-orbital of the pyrrolide
Scheme 4 Synthesis of 2-nitrophenyl phenyl sulfide 14.
Scheme 5 Synthesis and N-deprotection of 19a–f.
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Table 1 Relative rate constants and Hammett parameters for the deprotection of 19a–e
ꢀ
ꢁ
KR
KH
Compound
Substituent (R)
[Starting material] (M)
Rate constantsa (s−1
)
Hammett substituent constants (σb)
log
19a
19b
19c
19d
19e
CF3
F
H
CH3
OCH3
4.03 × 10−4
4.11 × 10−4
4.08 × 10−4
4.15 × 10−4
3.57 × 10−4
(1.96 0.01) × 10−2
(1.23 0.04) × 10−2
(1.24 0.08) × 10−2
(1.19 0.03) × 10−2
(0.81 0.02) × 10−2
0.54
0.06
0
−0.17
−0.27
0.19
−0.01
0.000
−0.02
−0.19
a Rate constants calculated on two replicates of each substrate using Kaleidagraph v 4.1.3 and error on replicates calculated using XLSTAT v
2015.4.01.21576. b As reported.36
ing R substituents are somewhat distant from the developing
anionic nitrogen atom, their effects in stabilising the tran-
sition state are small and thus the ρ value (Fig. 1) is small.
Having determined successful N-deprotection conditions,
attention was turned to the hydrolysis of the α-difluoromethyl
group. Hydrolysis was monitored using 19F NMR spectroscopy
under pseudo first-order conditions. Pyrroles 19 were first
N-deprotected in an NMR tube using 1.8 equivalents of PhSH
and 2.5 equivalents of NEt3, dissolved in CD3CN.
Subsequently, hydrolysis was initiated through the injection of
1000 equivalents of water at 40 °C. As the hydrolysis reaction
progressed, the decreasing intensity of the 19F doublet arising
from the –CF2H group, with respect to the inert internal stan-
dard (hexafluorobenzene, 0.5 equiv., 0.4 solution in
Fig. 1 Hammett plot for N-deprotection of 19a–e.
M
CD3CN), was measured and the rates of hydrolysis calculated
(Table 2). The disappearance of the –CF2H group signal in
each case was accompanied by the expected appearance of the
HF singlet, which derives from hydrolysis of the –CF2H group
(Fig. 3–7 in the ESI†).
Although the variation in the rates of hydrolysis are subtle,
the Hammett plot (Fig. 2) resembles a concave up parabola
with a minimum at R = H (22c). To confirm the concave up
parabola, we synthesized and analysed 22f (R = CN), following
the same protocols as previously, and were delighted to
observe an excellent fit with the data generated from 22a–22e.
The non-linear relationship39,40 revealed on the Hammet plot
points to the influence of the electronic features of the substi-
tuents on the aryl ring of pyrroles 22. The ρ value for electron-
donating groups was found to be −0.4, suggesting a build-up
of positive charge (or neutralisation of negative charge, nega-
tive slope, Fig. 2). In contrast, the ρ value for electron-with-
drawing groups was found to be 0.4, suggesting an increase of
the negative charge character in the transition state of the rate-
determining step (positive slope, Fig. 2).
Scheme 6 Proposed mechanism for the N-deprotection of 19.
Based on these results, and the concave up parabola of the
Hammet plot, two competing reaction pathways are proposed
for the hydrolysis of 22 (Scheme 7). In the case of R being an
electron-donating group (R = CH3 and OCH3), the rate-deter-
mining step is considered to be the loss of fluoride and for-
mation of the positively charged azafulvenium intermediate
25, whose methylene carbon atom is activated towards the fast
addition of water and the return of aromaticity to the pyrrole
ring in 26.41–44 After proton loss, the intermediate 27 would
collapse into the isolated aldehyde 28, again through loss of
nitrogen atom.27 The ability of the substituent (R) within the
aryl group to stabilise the transition state leading to 24 thus
plays an important role in the rate of deprotection. Indeed,
electron-withdrawing groups serve to stabilize the forming
pyrrolide anion, thereby enhancing the reaction rate, yet electron-
withdrawing groups serve to destabilise the transition state
en route to 24. As the electron-donating and electron-withdraw-
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Table 2 Rates and Hammett parameters for the hydrolysis of 22a–f
ꢀ
0.27
0.02
0.00
0.05
0.12
0.28
ꢁ
KR
KH
Compound
Substituent (R)
[Starting material] (M)
Rate constanta (s−1
)
Hammett substituent constants (σb)
log
22a
22b
22c
22d
22e
22f
CF3
F
H
CH3
OCH3
CN
1.400 × 10−2
1.408 × 10−2
1.501 × 10−2
1.422 × 10−2
1.450 × 10−2
1.488 × 10−2
(1.712 0.092) × 10−3
(0.966 0.108) × 10−3
(0.914 0.094) × 10−3
(1.021 0.013) × 10−3
(1.195 0.025) × 10−3
(1.749 0.040) × 10−3
0.54
0.06
0.00
−0.17
−0.27
0.66
a Rate constants calculated using Kaleidagraph v 4.1.3 and error is calculated using XLSTAT v 2015.4.01.21576. b As reported.36
resonance contributor 29. In this case, loss of a proton, to
form pyrrolide 30, is proposed as the rate-determining step.
The transition state en route to 30 would be stabilised by elec-
tron-withdrawing substituents on the aryl ring. Loss of fluoride
would then generate the azaulvene 32, followed by addition of
water to give 33. Proton exchange would provide 27, which
would collapse into the isolated aldehyde 28, presumably
again via initial pyrrolide formation and subsequent gene-
ration of the corresponding azafulvene. Akin to the
N-deprotection step, as the electron-donating and electron-
withdrawing substituents (R) are somewhat distant from the
developing azafulvenium and pyrrolide cores, their effects in
stabilising the transition states are small and consistent with
the small ρ values (Fig. 2) for the two constituent slopes of the
concave up parabola.
Fig. 2 Hammett plot for the hydrolysis of 19a–f following
N-deprotection.
To summarise, the tendency for α-difluoromethyl pyrroles
to react with water is significant, particularly in the absence of
significant electron-withdrawing N-protection. As such, the
electronic nature of substituents about α-difluoromethyl
fluoride via azafulvenium formation. In the case of R being an
electron-withdrawing group (R = CF3, F and CN) the generation
of 25 would be slow, as appreciated upon consideration of the
Scheme 7 Proposed mechanisms for the hydrolysis of 22.
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pyrroles influences the reactivity, and hence the stability, of the not reported because of the instability of 8 in CDCl3, C(O)
α-difluoromethyl group. Driven by azafulvenium formation, (CD3)2, and CD3OD for prolonged periods of time and its in-
the loss of fluoride is facile,41 yet a significant electron-donat- solubility in THF-d8 and CD3CN.
ing character on the pyrrolic ring serves to make azafulvenium
General procedure (GP1) for fluorination using XtalFluor®
character (via loss of fluoride) less favourable. In these cases,
hydrolysis is proposed to rely upon N-deprotonation, followed XtalFluor-E® (3 equiv.) or XtalFluor-M® (3 equiv.) was added,
by azafulvene formation via loss of fluoride. Therefore, the as indicated, to a solution of NEt3·3HF (4 equiv.) and NEt3
design of air-stable difluoromethyl pyrroles must consider the (2 equiv.) in 1,2-DCE [0.3 M], with stirring at room temperature
incorporation of units with significant pyrrole stabilising under N2 atmosphere at 70 °C. The 2-formylpyrrole substrate
ability,42–44 and/or electron-withdrawing capacity via N-protec- (1 equiv.) was then added in one portion and the reaction
tion, in order to avoid hydrolysis.
mixture was stirred under N2 at room temperature overnight,
before quenching with sat. aqueous NaHCO3 (10 mL) and then
stirring for 15 minutes. The reaction mixture was then diluted
with CH2Cl2 (30 mL) and washed with H2O (30 mL) and brine
(30 mL). The organic phase was dried over anhydrous Na2SO4,
concentrated in vacuo and purified via column
Experimental
General information
1
All H and 13C NMR spectra were obtained using a 500 MHz chromatography.
NMR spectrometer (operating at 500 MHz and 125 MHz,
2-(Difluoromethyl)-1-(phenylsulfonyl)-pyrrole (10). Using
respectively) and CDCl3 as solvent. Chemical shifts were GP1 and XtalFluor-M® with gentle heating (35 °C) in CH2Cl2,
recorded in parts per million (ppm) with internal reference to the title compound was synthesised from 1-(phenylsulfonyl)-
CDCl3 (1H NMR at 7.26 ppm, 13C NMR at 77.16 ppm) and to pyrrole-2-carbaldehyde (9)46 (0.13 g, 0.57 mmol). The title com-
(CD3)2CO (1H NMR at 2.05 ppm, 13C NMR at 29.84 and pound was isolated as a white solid (0.13 g, 92% yield) after
206.26 ppm). 19F NMR spectra were obtained using a 500 MHz column chromatography (10% Et2O/hexanes). M.p.: 64–66 °C;
NMR instrument (operating at 470 MHz) using trifluoroacetic 1H NMR (CDCl3, 500 MHz): δ 7.89 (d, 2H, J = 8.0 Hz), 7.63 (t,
acid (TFA, 19F NMR at −76.55 ppm vrs. CFCl3). Splitting pat- 1H, J = 8.0 Hz), 7.53 (t, 2H, J = 8.0 Hz), 7.32 (br s, 1H), 7.12 (t,
terns are indicated as follows: a, apparent, br, broad; s, singlet; 1H, JHF = 55 Hz, CF2H), 6.66 (br s, 1H), 6.31 (at, 1H, J = 1.8 Hz)
d, doublet; t, triplet; q, quartet; m, multiplet. Coupling con- ppm; 19F NMR (CDCl3, 470 MHz) δ −110.8 (d, JFH = 55.0 Hz,
stants (J) are reported in units of Hertz (Hz). High and low CF2H) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 138.6, 134.5,
resolution ESI+ mass spectra were recorded using ion trap 129.6, 127.9, 127.4, 125.1 (t, JCF = 3.0 Hz), 115.6 (t, JCF = 5.0
instruments. Column chromatography was performed using Hz), 112.2, 108.9 (t, JCF = 233 Hz, CF2H) ppm; HRMS-ESI (m/z):
230–400 mesh ultrapure silica. TLC was performed using silica [M + Na]+ calcd 280.0214 for C11H9F2NNaO2S; found 280.0201.
gel or neutral aluminum oxide plates and were visualised
(2-Nitrophenyl)(phenyl) sulfide (14). A solution of PhSH
using UV light (254 nm) and/or developed with vanillin stain. (0.30 mL, 3.21 mmol) and 1-(2-nitrophenylsulfonyl)-1H-
UV analysis was carried out with the baseline manually cor- pyrrole-2-carbaldehyde (15)47 (0.50 g, 1.78 mmol) in anhydrous
rected for the solvent used. Moisture-sensitive reactions were CH3CN (89 mL) was bubbled with N2 for 10 minutes, after
performed in flame-dried glassware under a positive pressure which anhydrous NEt3 (0.62 mL, 4.46 mmol) was added under
of nitrogen. Solutions of air- and moisture-sensitive com- N2. The reaction mixture was stirred for 30 minutes before the
pounds were introduced via syringe or cannula through a solvent was removed in vacuo. The crude residue was then dis-
rubber septum. Compounds 4,45 9,46 and 1547 were prepared solved in CH2Cl2 (200 mL) and washed with brine (200 mL).
according to literature procedures.
The organic layer was dried over Na2SO4, concentrated in vacuo
3-(4-(Carboxymethyl)-5-formyl-1H-pyrrol-3-yl)propanoic acid and purified via column chromatography (0 → 5% EtOAc/
(8). Compound 445 (0.050 g, 0.120 mmol) was added to a solu- CH2Cl2). The title compound was isolated as a yellow solid
1
tion of 1 M NaOH in 1 : 1 H2O/MeOH (1 mL). The reaction (0.41 g, quant.). M.p.: 69–70 °C; H (500 MHz, CDCl3): δ 8.21
mixture was heated to 50 °C until TLC analysis showed com- (d, 1H, J = 8.0 Hz), 7.59–7.51 (m, 2H), 7.50–7.46 (m, 3H), 7.33
plete consumption of the starting material. The reaction (t, 1H, J = 8.0 Hz), 7.21 (t, 1H, J = 8.0 Hz), 6.87 (d, 1H, J = 8.0
mixture was diluted with H2O (50 mL) and acidified to pH 4 by Hz), comparable to previously reported data;48 13C{1H}: NMR
use of 2 M aq. HCl at 0 °C. The reaction mixture was then (CDCl3, 125 MHz): δ 145.2, 139.5, 136.0, 133.5, 131.2, 130.2,
extracted with CH2Cl2 (3 × 50 mL), and the combined organic 130.1, 128.5, 125.8, 125.1 ppm; HRMS-ESI (m/z): [M + Na]+
fractions were washed with brine, dried over anhydrous calcd 254.0246 for C12H9NNaO2S; found 254.0239; ε368
Na2SO4, concentrated in vacuo and purified via column chrom- 4000 L mol−1 cm−1 in CH3CN.
=
nm
atography (50% EtOAc/hexanes). The title compound was iso-
2-(Difluoromethyl)-1-(2-nitrophenylsulfonyl)-4-(4-(trifluoro-
lated as a white solid (0.012 g, 27% yield). H (300 MHz, C(O) methyl)phenyl)-pyrrole (19a). Using GP1 and XtalFluor-M®,
(CD3)2): δ 10.81 (br s, 1H), 9.70 (s, 1H), 7.07 (as, 1H), 3.85 (s, the title compound was synthesised from 21a (0.32 g,
2H), 2.78 (t, J = 8.0 Hz, expected 2H but overlaps with water 0.75 mmol). The title compound was isolated as a beige solid
peak), 2.59 (t, J = 8.0 Hz, 2H) ppm; HRMS-ESI (m/z): [M + Na]+ (0.29 g, 85% yield) after column chromatography (50%
1
Calcd 248.0529 for C10H11NNaO5; found 248.0528. 13C NMR is CH2Cl2/hexanes). M.p.: 80–81 °C; H NMR (CDCl3, 500 MHz):
1
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δ 7.88 (ad, 1H), 7.80–7.84 (m, 1H), 7.71–7.76 (m, 3H), 7.64–7.67
2-(Difluoromethyl)-4-(4-methoxyphenyl)-1-(2-nitrophenyl-
(m, 4H), 7.09 (s, 1H), 7.08 (t, 1H, JHF = 55 Hz, CF2H) ppm; 19F sulfonyl)-1H-pyrrole (19e). Using GP1 and Xtalfluor-E®, the
NMR (CDCl3, 470 MHz) δ −63.7 (s), −113.1 (d, JFH = 55 Hz, title compound was synthesised from 21e (0.30 g, 0.78 mmol).
CF2H) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 147.9, 135.8, The title compound was isolated as a beige solid (0.20 g, 62%
135.6, 133.1, 132.5, 130.3, 129.8 (q, JCF = 27 Hz), 126.3 (q, JCF
=
yield) after column chromatography (50% CH2Cl2/hexanes).
256 Hz, CF3), 126.2 (aq., JCF = 3.0 Hz), 126.1, 125.5, 122.6, M.p.: 145–148 °C; 1H NMR (CDCl3, 500 MHz): δ 7.88 (d, 1H J =
114.3 (t, JCF = 5.0 Hz), 108.7 (t, JCF = 235 Hz, CF2H) ppm, two 8.0 Hz), 7.78 (t, 1H, J = 8.0 Hz), 7.69 (t, 1H, J = 8.0 Hz), 7.56 (d,
carbon signals missing; HRMS-ESI (m/z): [M + Na]+ calcd 1H, J = 1.8 Hz), 7.53 (d, 1H, J = 8.0 Hz), 7.46 (d, 2H, J = 9.0 Hz),
469.0257 for C18H11F5N2NaO4S; found 469.0241.
7.07 (t, 1H, JHF = 55 Hz, CF2H), 7.03 (s, 1H), 6.94 (d, 2H, J = 9.0
2-(Difluoromethyl)-4-(4-fluorophenyl)-1-(2-nitrophenylsulfo- Hz), 3.84 (s, 3H) ppm; 19F NMR (CDCl3, 470 MHz) δ −113.0 (d,
nyl)-pyrrole (19b). Using GP1 and Xtalfluor-E®, the title com- JFH = 55 Hz, CF2H) ppm; 13C{1H}: NMR (CDCl3, 125 MHz):
pound was synthesised from 21b (0.29 g, 0.78 mmol). The title δ 159.6, 147.7, 135.2, 133.1, 129.6, 129.3, 129.1, 127.5, 127.1,
compound was isolated as a beige solid (0.19 g, 61% yield) 125.4, 124.7, 120.7, 114.7 (t, JCF = 5.0 Hz), 114.6, 108.8 (t, JCF
=
after column chromatography (50% CH2Cl2/hexanes). M.p.: 235 Hz, CF2H), 55.5 ppm; HRMS-ESI (m/z): [M + Na]+ calcd
86–88 °C; 1H NMR (CDCl3, 500 MHz): δ 7.88 (d, 1H, J = 8.0 Hz), 431.0489 for C18H14F2N2NaO5S; found 431.0491.
7.80 (t, 1H, J = 8.0 Hz), 7.71 (t, 1H, J = 8.0 Hz), 7.63 (d, 1H, J =
2-(Difluoromethyl)-4-(4-cyanophenyl)-1-(2-nitrophenylsulfonyl)-
8.0 Hz), 7.59 (d, 1H, J = 1.8 Hz), 7.49–7.52 (m, 2H), 7.09 (t, 2H, 1H-pyrrole (19f). Using GP1 and Xtalfluor-E®, the title com-
J = 9.0 Hz), 7.06 (t, 1H, JHF = 55 Hz, CF2H), 7.02 (s, 1H) ppm; pound was synthesised from 21f (0.13 g, 0.33 mmol). The title
19F NMR (CDCl3, 470 MHz) δ −113.0 (d, JFH = 55 Hz, CF2H), compound was isolated as a beige solid (0.12 g, 86% yield)
−(115.0–115.1) (m) ppm; 13C{1H} NMR (CDCl3, 125 MHz): after column chromatography (90% CH2Cl2/hexanes). M.p.:
1
δ 162.6 (d, JCF = 248 Hz, CF), 147.8, 135.4, 133.1, 132.8, 171–173 °C; H NMR (CDCl3, 500 MHz): δ 7.88 (d, 1H J = 8.0
130.0, 129.4, 128.3 (d, JCF = 3.0 Hz), 127.6 (d, JCF = 8.0 Hz), Hz), 7.81–7.85 (m, 1H), 7.74–7.80 (m, 3H), 7.69 (d, 1H, J = 8.3
126.8, 125.4, 121.4, 116.1 (d, JCF = 22 Hz), 114.6 (t, JCF
5.0 Hz), 108.8 (t, JCF = 235 Hz, CF2H) ppm; HRMS-ESI (m/z): 7.07 (s, 1H) ppm; 19F NMR (CDCl3, 470 MHz) δ −112.0 (d, JFH
[M
Na]+ calcd 419.0289 for C17H11F3N2NaO4S; found 55 Hz, CF2H) ppm; 13C{1H}: NMR (CDCl3, 125 MHz): δ 147.9,
419.0287. 136.8, 135.8, 133.1, 133.0, 132.2, 130.6, 129.7 (t, JCF = 31.5 Hz),
=
Hz), 7.64 (d, 2H, J = 8.3 Hz), 7.07 (t, 1H, JHF = 55 Hz, CF2H),
=
+
2-(Difluoromethyl)-1-(2-nitrophenylsulfonyl)-4-phenyl-1H- 126.3, 125.6, 125.5, 123.1, 118.8, 114.1 (t, JCF = 5.0 Hz), 111.4,
pyrrole (19c). Using GP1 and Xtalfluor-E®, the title compound 108.6 (t, JCF = 235 Hz, CF2H) ppm; HRMS-ESI (m/z): [M + Na]+
was synthesised from 21c (0.23 g, 0.65 mmol). The title com- calcd 426.0331 for C18H11F2N3NaO4S; found 426.0341.
pound was isolated as a beige solid (0.22 g, 90% yield) after
4-Bromo-1-(2-nitrophenylsulfonyl)-pyrrole-2-carbaldehyde (20).
column chromatography (50% CH2Cl2/hexanes). M.p.: 4-Bromo-2-formyl pyrrole49 (2.72 g, 15.6 mmol), 2-nitrobenzene-
1
100–103 °C; H NMR (CDCl3, 500 MHz): δ 7.89 (d, 1H, J = 8.0 sulfonylchloride (3.15 g, 14.2 mmol) and NEt3 (2.97 mL,
Hz), 7.79 (t, 1H, J = 8.0 Hz), 7.70 (t, 1H, J = 8.0 Hz), 7.65 (as, 21.3 mmol) were dissolved in CH2Cl2 (55 mL).
1H), 7.54–7.57 (m, 3H), 7.41 (t, 2H, J = 8.0 Hz), 7.32 (t, 1H, J = Dimethylaminopyridine (0.17 g, 1.42 mmol) was added to the
7.0 Hz), 7.09 (s, 1H), 7.07 (t, 1H, JHF = 55 Hz, CF2H) ppm; 19F stirring reaction mixture, and the solution was stirred over-
NMR (CDCl3, 470 MHz) δ −113.0 (d, JFH = 55 Hz, CF2H) ppm; night. The reaction mixture was washed with H2O (60 mL) and
13C{1H} NMR (CDCl3, 125 MHz): δ 135.3, 133.1, 133.0, 129.8, brine (60 mL). The organic layer was dried over Na2SO4, con-
129.4, 129.2, 128.0, 127.7, 125.9, 125.4, 121.6, 114.7 (t, JCF = 5.0 centrated in vacuo and purified via column chromatography
Hz), 108.8 (t, JCF = 235 Hz, CF2H) ppm 2 C missing; HRMS-ESI (50% CH2Cl2/hexanes). The title compound was isolated as an
1
(m/z): [M + H]+ calcd 379.0564 for C17H13F2N2O4S; found off-white solid (4.17 g, 82% yield). M.p.: 143–145 °C; H NMR
379.0544.
(CDCl3, 500 MHz): δ 9.57 (s, 1H), 8.47–8.49 (m, 1H), 7.83–7.85
2-(Difluoromethyl)-1-(2-nitrophenylsulfonyl)-4-p-tolyl-1H-pyrrole (m, 3H), 7.71 (s, 1H), 7.16 (s, 1H) ppm; 13C{1H} NMR (CDCl3,
(19d). Using GP1 and Xtalfluor-E®, the title compound was syn- 125 MHz): δ 176.9, 148.2, 136.0, 133.8, 133.5, 132.7, 131.1,
thesised from 21d (0.24 g, 0.65 mmol). The title compound 130.7, 129.5, 125.3, 100.9 ppm; HRMS-ESI (m/z): [M + H]+ calcd
was isolated as a beige solid (0.18 g, 70% yield) after column 358.9337 for C11H8BrN2O5S; found 358.9325.
1
chromatography (50% CH2Cl2/hexanes). M.p.: 114–115 °C; H
NMR (CDCl3, 500 MHz): δ 7.88 (d, 1H, J = 8.0 Hz), 7.78 (t, 1H,
J = 8.0 Hz). 7.69 (t, 1H, J = 8.0 Hz), 7.61 (d, 1H, J = 1.8 Hz), 7.53
General procedure (GP2) for the Suzuki cross-coupling of
4-bromopyrroles
(d, 1H, J = 8.0 Hz), 7.43 (d, 2H, J = 8.0 Hz), 7.21 (d, 2H, J = 8.0 4-Bromo-1-(2-nitrophenylsulfonyl)-pyrrole-2-carbaldehyde (20)
Hz), 7.06 (s, 1H), 7.06 (t, 1H, JHF = 55 Hz, CF2H), 2.37 (s, 3H) (1 equiv.) was dissolved in toluene [0.1 M], along with a
ppm; 19F NMR (CDCl3, 470 MHz) δ −113.0 (d, JFH = 55 Hz, boronic acid a–e (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) under
CF2H) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 137.9, 135.2, N2 atmosphere with stirring. K2CO3 (4 equiv.) was prepared as
133.1, 129.8, 129.7, 129.3, 129.2, 127.8, 125.8, 125.4, 121.3, an aqueous solution [1.1 M], and then purged with N2 for
114.7 (t, JCF = 5.0 Hz), 108.8 (t, JCF = 235 Hz, CF2H), 21.3 ppm, 15 minutes. The K2CO3 aqueous solution was then added to
two carbon signals missing; HRMS-ESI (m/z): [M + Na]+ calcd the stirring reaction mixture, which was subsequently heated
415.0540 for C18H14F2N2NaO4S; found 415.0522.
with stirring at 90 °C overnight. The reaction mixture was then
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partitioned and the aqueous layer was extracted with CH2Cl2
4-(4-Methoxyphenyl)-1-(2-nitrophenylsulfonyl)-pyrrole-2-carb-
(equivalent volume to aqueous layer × 3). The combined aldehyde (21e). Using GP2 and 4-methoxyphenylboronic acid,
organic layers were dried over Na2SO4, filtered, concentrated the title compound was synthesised from 20 (0.50 g,
in vacuo and then purified via column chromatography.
1.39 mmol). The title compound was isolated as an off-white
1-(2-Nitrophenylsulfonyl)-4-(4-(trifluoromethyl)phenyl)-pyrrole- solid (0.35 g, 65% yield) after column chromatography
1
2-carbaldehyde (21a). Using GP2 and 4-(trifluoromethyl)phenyl- (CH2Cl2). M.p.: 165–166 °C; H NMR (CDCl3, 500 MHz): δ 9.68
boronic acid, the title compound was synthesised from (s, 1H), 8.43–8.45 (m, 1H), 7.87 (s, 1H), 7.80–7.82 (m, 3H), 7.49
20 (0.50 g, 1.39 mmol). The title compound was isolated as an (d, 2H, J = 9.0 Hz), 7.43 (d, 1H, J = 2.0 Hz), 6.96 (d, 2H, J =
off-white solid (0.36 g, 62% yield) after column chromato- 9.0 Hz), 3.84 (s, 3H) ppm; 13C{1H} NMR (CDCl3, 125 MHz):
graphy (CH2Cl2). M.p.: 187–189 °C; 1H NMR (CDCl3, 500 MHz): δ 177.7, 159.7, 148.2, 135.6, 134.0, 133.3, 132.6, 131.6, 127.6,
δ 9.70 (s, 1H), 8.56–8.60 (m, 1H), 8.03 (s, 1H), 7.85–7.88 (m, 127.2, 126.8, 126.0, 125.1, 124.3, 114.7, 55.5 ppm; HRMS-ESI
3H), 7.68–7.72 (m, 4H), 7.49 (d, 1H, J = 2.0 Hz) ppm; 19F NMR (m/z): [M + Na]+ calcd 409.0470 for C18H14N2NaO6S; found
(CDCl3, 470 MHz) δ −62.6 (s) ppm; 13C{1H} NMR (CDCl3, 409.0464.
125 MHz): δ 177.3, 176.9, 148.3, 135.9, 135.4, 134.2, 133.9,
4-(4-Cyanophenyl)-1-(2-nitrophenylsulfonyl)-pyrrole-2-carb-
132.6, 131.2, 130.1 (q, JCF = 33 Hz), 128.3, 126.3 (q, JCF = 270 aldehyde (21f). Using GP2 and 4-cyanophenylboronic acid, the
Hz, CF3), 126.2 (ad JCF = 3.5 Hz), 126.2, 125.8, 125.3 ppm; title compound was synthesised from 20 (0.25 g, 0.70 mmol).
HRMS-ESI (m/z): [M
+
Na]+ calcd 447.0238 for The title compound was isolated as an off-white solid (0.085 g,
C18H11F3N2NaO5S; found 447.0235.
32% yield) after column chromatography (CH2Cl2). M.p.:
4-(4-Fluorophenyl)-1-(2-nitrophenylsulfonyl)-pyrrole-2-carbalde- 195–197 °C with decomp.; 1H NMR (CDCl3, 500 MHz): δ 9.69 (s,
hyde (21b). Using GP2 and 4-fluorophenylboronic acid, the title 1H), 8.60–8.61 (m, 1H), 8.04 (d, 1H, J = 1.4 Hz), 7.85–7.88 (m,
compound was synthesised from 20 (0.50 g, 1.39 mmol). The 3H), 7.73 (d, 2H, J = 8.3 Hz), 7.68 (d, 2H, J = 8.3 Hz), 7.48 (d, 1H,
title compound was isolated as an off-white solid (0.45 g, 86% J = 1.4 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 177.5, 148.3,
yield) after column chromatography (CH2Cl2). M.p.: 136.4, 136.0, 134.3, 134.1, 133.1, 132.7, 132.0, 128.7, 126.4,
172–175 °C; 1H NMR (CDCl3, 500 MHz): δ 9.68 (s, 1H), 125.6, 125.5, 125.3, 118,7, 111.7 ppm; HRMS-ESI (m/z): [M +
8.51–8.53 (m, 1H), 7.90 (s, 1H), 7.83–7.85 (m, 3H), 7.53–7.55 Na]+ calcd 404.0312 for C18H11N3NaO5S; found 404.0305.
(m, 2H), 7.42 (d, 1H, J = 2.0 Hz), 7.12 (t, 2H, J = 9.0 Hz) ppm;
19F NMR (CDCl3, 470 MHz) δ −(113.6–113.7) (m) ppm; 13C{1H}
NMR (CDCl3, 125 MHz): δ 177.6, 162.8 (d, JCF = 248 Hz, CF),
135.7, 134.1, 133.7, 132.6, 131.4, 129.6, 128.0 (d, JCF = 3.0 Hz),
Acknowledgements
127.7 (d, JCF = 8.0 Hz), 127.5, 126.8, 126.0, 125.2, 116.3 (d, JCF
22 Hz); HRMS-ESI (m/z): [M + Na]+ Calcd 397.0270 for Engineering Research Council of Canada (NSERC) and the Nova
C17H11FN2NaO5S; found 397.0271. Scotia Health Research Foundation (NSHRF). The authors
=
This work was supported by the Natural Sciences and
1-(2-Nitrophenylsulfonyl)-4-phenyl-pyrrole-2-carbaldehyde (21c). thank Professor Norman P. Schepp (Dalhousie University) for
Using GP2 and phenylboronic acid, the title compound was assistance as regards to determining rates of reaction.
synthesised from 20 (0.87 g, 2.78 mmol). The title compound
was isolated as an off-white solid (0.65 g, 66% yield) after
1
column chromatography (CH2Cl2). M.p.: 177–178 °C; H NMR
Notes and references
(CDCl3, 500 MHz): δ 9.69 (s, 1H), 8.48–8.50 (m, 1H), 7.96 (s,
1H), 7.83 (ad, 3H), 7.58 (d, 2H, J = 8.0 Hz), 7.49 (s, 1H), 7.43 (t,
2H, J = 8.0 Hz), 7.34 (t, 1H, J = 7.0 Hz) ppm; 13C{1H} NMR
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131.5, 129.3, 128.2, 127.7 (×2C), 126.2, 126.0, 125.2 ppm, one
carbon signal missing; HRMS-ESI (m/z): [M + H]+ calcd
357.0540 for C17H12N2NaO5S; found 357.0553.
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