PhI(OAc)2and iodine-mediated synthesis ofN-alkyl sulfonamides derived from polycyclic aromatic hydrocarbon scaffolds and determination of their antibacterial and cytotoxic activities

Article abstract of DOI:10.1039/d0ob02429e

The development of new approaches toward chemo- and regioselective functionalization of polycyclic aromatic hydrocarbon (PAH) scaffolds will provide opportunities for the synthesis of novel biologically active small molecules that exploit the high degree of lipophilicity imparted by the PAH unit. Herein, we report a new synthetic method for C-X bond substitution that is speculated to operateviaa N-centered radical (NCR) mechanism according to experimental observations. A series of PAH sulfonamides have been synthesized and their biological activity has been evaluated against Gram-negative and Gram-positive bacterial strains (using a BacTiter-Glo assay) along with a series of mammalian cell lines (using CellTiter-Blue and CellTiter-Glo assays). The viability assays have resulted in the discovery of a number of bactericidal compounds that exhibit potency similar to other well-known antibacterials such as kanamycin and tetracycline, along with the discovery of a luciferase inhibitor. Additionally, the physicochemical and drug-likeness properties of the compounds were determined experimentally and usingin silicoapproaches and the results are presented and discussed within.

Full text of DOI:10.1039/d0ob02429e

Organic &
Biomolecular Chemistry
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PAPER
PhI(OAc)2 and iodine-mediated synthesis of
N-alkyl sulfonamides derived from polycyclic
aromatic hydrocarbon scaffolds and determination
of their antibacterial and cytotoxic activities†
Cite this: Org. Biomol. Chem., 2021,
19, 1133
Megan D. Hopkins, Garett L. Ozmer, Ryan C. Witt, Zachary C. Brandeburg,
David A. Rogers, Claire E. Keating, Presley L. Petcoff, Robert J. Sheaff* and
Angus A. Lamar
*
The development of new approaches toward chemo- and regioselective functionalization of polycyclic
aromatic hydrocarbon (PAH) scaffolds will provide opportunities for the synthesis of novel biologically
active small molecules that exploit the high degree of lipophilicity imparted by the PAH unit. Herein, we
report a new synthetic method for C–X bond substitution that is speculated to operate via a N-centered
radical (NCR) mechanism according to experimental observations. A series of PAH sulfonamides have
been synthesized and their biological activity has been evaluated against Gram-negative and Gram-posi-
tive bacterial strains (using a BacTiter-Glo assay) along with a series of mammalian cell lines (using
CellTiter-Blue and CellTiter-Glo assays). The viability assays have resulted in the discovery of a number of
bactericidal compounds that exhibit potency similar to other well-known antibacterials such as kanamy-
cin and tetracycline, along with the discovery of a luciferase inhibitor. Additionally, the physicochemical
and drug-likeness properties of the compounds were determined experimentally and using in silico
approaches and the results are presented and discussed within.
Received 3rd December 2020,
Accepted 7th January 2021
DOI: 10.1039/d0ob02429e
rsc.li/obc
peptide mimetics (murepavadin) to treat multi-drug resistant
Gram-negative bacterial infections.3 It has recently been
Introduction
Due to the indiscriminate use of antimicrobial agents and a reported that fluorenylmethyloxycarbonyl (Fmoc)-conjugated
relatively slow developmental pace of new antibacterial agents, amino acids and peptides demonstrate considerable anti-
the emergence of drug-resistant bacterial infections has been microbial activity.4 It is believed that the potency of the bac-
listed by the World Health Organization as one of the top terial inhibition is directly related to the hydrophobic nature
10 health threats in the world.1 The search for novel che- of the amino acid side chains and lipophilicity of the fluore-
motherapeutics and/or new antibacterial mechanisms for nyl portion of the Fmoc group.4 Although the exact nature of
treating drug-resistant bacterial infections is therefore an the mode of action is unknown, it is believed that the amphi-
urgent need amongst the scientific community. In general, pathic Fmoc-amino acid compounds target bacterial mem-
multi-drug resistant bacterial cells are able to repel current branes in a surfactant-like behavior.4 Investigation of fluor-
chemotherapeutic agents through one of the following mecha- ene as a lipophilic, polycyclic aromatic hydrocarbon (PAH)
nisms: (1) enzymatic destruction of the antibiotic; (2) scaffold in the development of bioactive small molecules as
reduction in cell membrane permeability; (3) efflux pumps; potential antibacterial agents is a desirable pursuit that has
and (4) modification of the drug target site.2 Targeting or dis- the potential to lead to new areas of research in medicinal
rupting the bacterial cell membrane is an approach that can chemistry.
circumvent many of the bacterial resistance mechanisms, and
Polycyclic aromatic hydrocarbons have a variety of appli-
recent advances have been made in the classes of polymyxins cations, including use as light-emitting devices, organic tran-
(colistin and polymyxide B), β-lactams (cefiderocol), and sistors, biosensors, and organic photovoltaic cells, among
others.5 Fluorene, one of the simplest PAH cores, is a rigid,
planar biphenyl core that has been observed as a substructure
within a variety of bioactive molecules, most notably when
Department of Chemistry and Biochemistry, The University of Tulsa, 800 South
Tucker Drive, Tulsa, Oklahoma, 74104, USA. E-mail: angus-lamar@utulsa.edu
substituted with a nitrogen-containing functionality at the
9-position (Fig. 1).4,6
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0ob02429e
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Fig. 1 Selected examples of pharmaceuticals and bioactive compounds
that contain polycyclic aromatic hydrocarbon (PAH) scaffolds. The
fluorene core is shown in red.
Scheme 1 Current approaches for installation of a N-alkyl sulfonamide
unit to a hydrocarbon core.
The majority of PAH-containing bioactive molecules take
advantage of lipophilic properties imparted by the hydro-
carbon core to engage central nervous system (CNS) and/or
neurological targets.7 Inspired by the notable examples of bio-
active compounds containing a fluorene core with amino-sub-
stitution at the 9-position shown in Fig. 1, and following our
interest in the development of new methods for sulfonamide
insertion,8–11 we aimed to generate sulfonamide analogs from
commercially available halogenated PAH scaffolds to test for
biological activity.
namide, formed in situ under visible-light conditions from an
iminoiodinane reagent (PhIvNSO2R) and molecular iodine.8
We envisioned that a NCR approach could also be applied to
sterically hindered 2° (sp3) halogenated PAH substrates in
order to directly produce a wide variety of N-sulfonylamino
analogs from hydrocarbon scaffolds under mild, operationally
simple conditions.
The synthesis of 9-aminosulfonylfluorene derivatives have
been reported from intramolecular Aza-Friedel–Crafts reaction
pathways using 2-formyl biphenyl substrates in the presence of
a Lewis acid catalyst,20 albeit with relatively limited scope of
sulfonamide substrate. In addition, C–H activation approaches
have been reported, but with limited scope and/or modest
yields.21 More recently, examples of 9-aminofluorene deriva-
tives have been reported using a Pd-catalyzed cross-coupling/
annulation pathway,22 however, sulfonamide was not
employed as a N-substrate. The direct, non-metal promoted
installation of a wide range of sulfonamide units into a 2° C–X
bond using a commercially available, air-stable oxidant (PhI
(OAc)2) and I2 provides a new method for forming sulfona-
mides from PAH scaffolds. Herein we report the development
of a practical reaction to add to the synthetic toolkit for regio-
selective functionalization of PAH scaffolds along with the cre-
ation of an initial library of N-alkyl sulfonamides to screen for
biological activity.
Sulfonamides are an important bioisosteric functionality
within the science of drug discovery and development, as evi-
denced by the number of pharmaceutical and bioactive com-
pounds that contain a sulfonamide unit.12 As a class of thera-
peutic agent, sulfonamides have displayed a broad pharmaco-
logical profile that includes anti-inflammatory, antiparasitic,
antibacterial, antithyroid, antiviral, hypoglycemic, diuretic,
and anticancer activities.13 Despite having a plethora of
options for the installation of a sulfonamide moiety to a hydro-
carbon substrate,14 synthetic limitations still exist that warrant
the development of new approaches. Current methods to
directly install a sulfonamide unit into a molecular scaffold
include: (A) reaction of pre-installed amines with sulfonyl
chlorides (Scheme 1A);15 (B) reduction of N-sulfonyl imines
formed from carbonyl-containing precursors (Scheme 1B);16
(C) alkyl halides reacting with nucleophilic sulfonamides
(Scheme 1C);16 (D) Lewis-acid catalyzed N-sulfonamidation of
1° and 2° benzylic alcohols (Scheme 1D);16 (E) benzylic C–H
activation using transition-metals or nitrene precursors
(Scheme 1E);16 (F) oxidation of sulfinimides;17 or (G) oxidative
coupling between sulfinate salts and amines.18 Recently, our
lab developed a synthetic method to incorporate N-sulfonyl
units into 3° (sp3) C–X positions under ambient conditions
Results and discussion
Synthesis of PAH sulfonamide library compounds 2–23
(20 °C) to form α-tertiary amines.8 According to mechanistic To begin our investigation, we selected 9-bromofluorene as a
investigations, the reaction is speculated to operate through a representative PAH scaffold. Our initial attempt to activate
nitrogen-centered radical (NCR)19 precursor, N,N-diiodosulfo- 9-bromofluorene 1 for N-sulfonamide substitution under a
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an excess of 1 (entries 5 and 6). When heated to 50 °C, the
reaction performed with similar efficiency (entries 5 and 7),
however, stoichiometric modifications resulted in a dramati-
cally improved yield of 3 (entries 7–9). When using 2–5 equiva-
lents of 1, the best results were obtained from allowing the
reaction to proceed for 24 hours (entries 8, 10 and 11). Further
stoichiometric modifications were attempted (entries 12–14),
though substantial improvements beyond entry 8 were not
observed. Thus, the optimized reaction conditions are as
follows: 2 equivalents 1, 1 equiv. N-sulfonamide, 1 equiv. I2, in
CH2Cl2 at 50 °C for 24 hours.
Scheme 2 Initial attempt to form 9-aminosulfonyl products from
9-bromofluorene.
In order to verify that the PhI(OAc)2/I2/N-sulfonamide
system is operating through the hypothesized NCR-mediated
radical pathway, the following control/mechanistic experi-
ments were conducted (Table 2). When using 9-chlorofluorene
as alkyl halide substrate (Table 2, entry 2), the reaction
resulted in a decreased yield, analogous to the previously
reported study using 3° alkyl halides.8 This result offers indir-
ect evidence regarding the ease of homolytic C–X bond clea-
vage by an NCR species based upon C–X bond strengths. In
the absence of I2, the reaction proceeds with drastically
reduced efficiency (entry 3). Similarly, when PhI(OAc)2 is
excluded, a reduction in the yield of 3 is also observed (entry
4). When both I2 and PhI(OAc)2 are excluded (entry 5), the reac-
tion is completely halted. This indicates that sulfonamide will
not act as a nucleophile in SN2-type mechanism with 9-bromo-
fluorene under the reaction conditions, nor will 9-bromofluor-
ene undergo SN1-type substitution at 50 °C. Lastly, a known
visible-light-promoted, radical pathway using an iminoiodi-
nane (PhIvNNs) resulted in formation of 2 in good yield
(Scheme 2A). Stoichiometry and reaction conditions were
based upon our earlier report of 3° C–X activation. Although
iminoiodinane reagents have proven to be valuable N-sources
for C–N bond-forming NCR reactions, the requirement to pre-
form the reagent and store at low temperatures limits the prac-
ticality of the approach. In order to circumvent the use of a
pre-formed iminoiodinane reagent, an additional experiment
was conducted to determine if the production of 3 could result
from the use of commercially available, temperature stable
reagents such as molecular iodine, PhI(OAc)2 and
a
N-sulfonamide. To our delight, a moderate yield of 3 was
obtained (Scheme 2B) indicating that a more convenient reac-
tion than our previous PhIvNSO2R/I2 system could potentially
be established.
radical
inhibitor,
2,2,6,6-tetramethyl-1-piperidinyloxy
The optimization of reaction conditions using 9-bromo-
fluorene 1 and a PhI(OAc)2/I2/N-sulfonamide system is shown
in Table 1. Dichloromethane was determined to be the
optimal solvent (entries 1–5). At room temperature, the yield
of 3 was limited to 47% yield and was not improved by using
(TEMPO), was added to the standard reaction conditions, and
the formation of product 3 was drastically reduced (entry 6).
Attempts to isolate a TEMPO-fluorene adduct were unsuccess-
ful, however evidence of trace amount of the adduct was
observed by MS. The attenuated yield of 3 provides additional
Table 1 Optimization of stoichiometry and reaction conditions
Entry
Equiv. 1
Equiv. Ts-NH2
Equiv. PhI(OAc)2
Equiv. I2
Solvent
Temp. (°C)
Time (h)
Light (LED)
Yield 3a (%)
1
2
3
4
5
6
7
8
1
1
1
1
1
5
1
2
5
5
2
5
1
2
1
1
1
1
1
1
1
1
1
1
1
1
2
1
2
2
2
2
2
2
2
2
2
2
2
2
2
1
1
1
1
1
1
1
1
1
1
1
1
0.2
1
CHCl3
DCE
Et2O
20
20
20
20
20
20
50
50
50
50
50
50
50
50
24
24
24
24
24
24
24
24
24
8
White
White
White
White
White
White
—
—
—
—
—
35
20
6
THF
13
47
39
46
83
85
80
62
31
58
65
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9
10
11
12
13
14
8
24
24
24
—
—
—
1
a All yields are isolated.
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Table 2 Mechanistic/control experiments
species can then combine with the N-centered radical B to
directly form the 9-aminosulfonylfluorene product
E or
abstract an iodine atom (from either I2, species A, AcOI, or I–
Br) to form a highly reactive 9-iodofluorene intermediate D.
Species D would be more susceptible than 9-bromofluorene to
nucleophilic attack from a sulfonamide (with release of HI),
and could undergo reaction to form product E. Evidence of the
benzylic radical species C is supported by observation of trace
amounts of trapped species F and G by MS.
With an optimized set of reaction conditions, the scope of
the N-sulfonamide reagent was explored (Fig. 2). A variety of
4-substituted aryl sulfonamides were tested, and yields were
consistently moderate to good (Fig. 2, products 2–7).
Compound 5 was prepared in gram scale (1.2 g isolated)
without a decrease in efficiency. The use of electron deficient
3-substituted aryl sulfonamides, however, resulted in lower
yields (9–11) when compared to analogous 4-substituted or
2-substituted aryl sulfonamide substrates. A notable exception
to this trend was observed from the use of 3,5-difluorobenze-
nesulfonamide, which resulted in an acceptable 54% yield of
product 16. Utilization of the majority of 2-substituted aryl sul-
fonamides resulted in moderate yields ranging from 44–74%
(12–15, and 17–18). An alkyl sulfonamide was also shown to be
a viable reacting partner, resulting in product 19. In addition
to 9-bromofluorene, 2,9-dibromofluorene was employed to
produce 20, albeit in low yield which we suspect is a result of
Entry
X
Deviation from standard conditions
% 3a
1
2
3
4
5
6
Br
Cl
Br
Br
Br
Br
No deviation
No deviation
0 equiv. I2
0 equiv. PhI(OAc)2
0 equiv. I2, 0 equiv. PhI(OAc)2
1 equiv. TEMPO added
83
33
20
22
0
10
a All yields are isolated.
indirect evidence for the formation of a benzylic radical that is
generated by activation from the PhI(OAc)2/I2/N-sulfonamide
system via in situ formation of the NCR precursor, N,N-
diiodosulfonamide.
A mechanistic pathway is proposed in Scheme 3 on the
basis of literature reports of related systems and the experi-
mental observations described in Table 2.8,23 Upon generation
of N-iodosulfonamide species A, the labile N–I bond under-
goes homolytic cleavage in the presence of ambient light or
heat to form N-centered radical species B and iodine radical.
Abstraction of the bromine from the representative 9-bromo-
fluorene is most likely facilitated by the liberated iodine
radical to form a relatively stable benzylic radical at the 9-posi-
tion of fluorene (species C). The stabilized carbon radical
Fig. 2 Substrate scope of 9-aminosulfonyl fluorene and heteroanthra-
cene products. aAll yields are isolated. bIsolated yield of gram-scale
reaction.
Scheme 3 Plausible mechanism for PhI(OAc)2 and I2-mediated syn-
thesis of 9-aminosulfonylfluorene compounds.
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poor solubility, with selectivity for N-substitution occurring
exclusively at the 9-Br position. Lastly, a 9-bromo-9H-thiox-
anthene substrate, prepared from thioxanthen-9-one, was
tested as a representative 9-bromoheteroanthracene substrate,
resulting in a 66% yield of 22.
In vitro antibacterial screening of 2–23
To test the bactericidal effects of the library compounds, repre-
sentative Gram-positive and Gram-negative bacterial strains
were selected for screening. An initial bacterial cell viability
screening of library compounds (50 μM) against Staphylococcus
aureas (MicroKwik Culture from Carolina), a Gram-positive
bacteria, was conducted using BacTiter-Glo Cell Viability
(Promega) assay, which is an assay that measures cell viability
by indirectly measuring a protease released by dying cells that
cleaves a peptide conjugated to firefly luciferin. The released
luciferin is oxidized to luciferase, releasing light which can be
correlated with the number of dead cells. The bacterial cells
were treated with library compounds at 50 μM concentration
for 8 hours, and none of the compounds displayed consider-
able activity relative to the DMSO background. The concen-
tration was adjusted to 500 μM and compounds 17 and 23
demonstrated activity comparable to known antibacterials
kanamycin and tetracycline (Fig. 3).
In a separate control reaction performed (based upon litera-
ture precedent)11,24 in which exogenous ATP was added to
media in the absence of cells, it was confirmed that com-
pounds 2–22 (50 μM, 10 min exposure) do not inhibit the
CellTiter-Glo luciferase assay itself (CellTiter-Glo is similar to
BacTiter-Glo but without a buffer to lyse bacterial cells).
However, compound 23 displayed substantial activity as a luci-
ferase inhibitor (Fig. 4) and this effect may account for the
activity displayed against S. aureas at 500 μM. Due to the use of
luciferase in reporter systems, there is interest in the scientific
community in understanding luciferase activity and its regu-
lation.25 The development of new small molecules that block
luciferase activity has been a topic of pursuit,24,26 and further
study of compound 23 as a luciferase inhibitor is warranted.
A bacterial cell viability screening of library compounds
(50 μM; approximately 15–20 μg mL−1) against E. coli (JM109
strain), a representative Gram-negative bacteria, was also con-
Fig. 4 Control experiment performed at 10 minutes exposure of 50 μM
of compounds using luciferase-producing CellTiter-Glo assay with
exogenous ATP added. Values are shown as percent of DMSO control
(POC). Values below 50% (stronger activity) are highlighted in red.
Fig. 5 Bacterial cell viability assay (E. coli) using compounds 2–23 at
50 μM (BacTiter-Glo kit, Promega) and 8 h exposure. Values are shown
as percent of DMSO control (POC). Values below 50% (stronger activity)
are highlighted in red.
ducted using BacTiter-Glo Cell Viability (Promega) assay.
Compounds 2, 5, and 22 all displayed comparable, albeit less
potent, activity to known antibacterials carbenicillin and kana-
mycin. Compounds 17 and 23, which showed activity against
Gram-positive S. aureas, were virtually inactive at 50 μM
against Gram-negative E. coli (Fig. 5).
With regard to structural variations of 2–23, the presence of
an electron-withdrawing substituent at the 4-position of the
benzene portion of the sulfonamide such as a nitro group
(compound 2) or chloro (compounds 5 and 22) appears to have
some effect when comparing to analogous electron-donating
substituents (for example, compound 22 vs. 23). However, this
structural feature is not solely responsible for activity, as evi-
denced by the inactivity of compounds 6 and 7, which also
contain an electron-withdrawing substitutent at the 4-position.
In addition, the observed activity is not solely due to the pres-
ence of a nitro or chloro substituent on the aromatic ring of
the sulfonamide. For example, when a nitro or chloro group is
located at the 2- or 3-position (compounds 9, 10, and 12)
instead of the 4-position, loss of activity is observed. The pres-
ence of a substituent on the fluorene core also resulted in det-
rimental bactericidal effect as observed when comparing com-
pound 5 with analogous compounds 20 and 21. Although a
predictable trend in structural features is unclear at this time,
it is clearly evident that bactericidal effect is observed from sul-
fonamides generated from PAH scaffolds.
Fig. 3 Bacterial cell viability assay (S. aureas) using compounds 2–23 at
500 μM (BacTiter-Glo kit, Promega) and 8 h exposure. Values are shown
as percent of DMSO control (POC). Values below 75% (stronger activity)
are highlighted in red.
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In vitro cytotoxicity screening of 2–23
In order to determine cytotoxicity towards mammalian cells,
an initial cytotoxicity screening of library compounds (50 μM)
using a variety of cell lines (diploid fibroblast – HDF; kidney –
H293; cervical – HeLa; prostate – PC3; and pancreatic – BxPC3)
was conducted using CellTiter-Blue Cell Viability (Promega)
assay. The CellTiter-Blue assay is based upon the conversion of
resazurin to the fluorescent resorufin by living cells, allowing
for the quantification of living cells by fluorescence emission.
The cells (∼20 000 in 20 μL PBS) were treated with library com-
pounds for 24 hours and the results are shown in Table 3 as
percent of DMSO control (POC).
Fig. 6 Cell viability screening of compounds 14, 15, 17, 21 and 22 from
Table 3 performed at 50 μM with HDF, H293, HeLa, PC3, and BxPC3 cell
lines. Values are shown as POC (percent of control).
The results of the cell viability assays were verified by using
an additional viability assay that has been reported to give
comparable/similar results.27 CellTiter-Glo operates similarly positive S. aureas (compounds 17 and 23), only compound 17
to BacTiter-Glo by measuring cell viability via quantification of shows cytotoxicity towards the five cell lines at 50 μM.
ATP released from living cells by measurement of photolumi- Regarding eukaryotic cytotoxicity of compounds 2–23, moder-
nescent luciferase. The results obtained from cell viability ate activity was observed from 14, 15, 21, and 22, and the
screening using compounds 2–23 (50 μM) against the five cell strongest hit (defined herein as compounds with cell viability
lines using a CellTiter-Glo assay kit (ESI Table S1†) are in <50% POC) was compound 17 (Fig. 6).
agreement with results from the CellTiter-Blue assay (Table 3).
Of the three compounds that displayed activity against
E. coli at 50 μM (compounds 2, 5, and 22), compounds 2 and 5
appear to be almost completely inactive against eukaryotic
cells at 50 μM. However, compound 22 displays moderate
activity against 4 of the 5 of the cell lines tested, with no
activity observed against PC3 at 50 μM. With respect to the
compounds that displayed bactericidal effect against Gram-
Experimental and in silico predictions for drug-likeness and
physicochemical properties of 2–23
Several approaches have recently been developed for the pre-
diction of drug-likeness of bioactive compounds based upon
certain properties such as molecular weight, water solubility,
lipophilicity, topological factors, and adherence to general
drug-likeness parameters. Using two open-source programs,
OSIRIS Property Explorer28 and SwissADME,29 the in silico
assessment of the properties and drug-likeness of compounds
Table 3 Cytotoxicity of compounds 2–23 at 50 μM
2–23 was explored and is summarized in Table 4 and in
Table S2 in the ESI.†
Percent of DMSO control (POC)a of various cell lines
With regard to molecular weight, it is estimated that the
majority of drugs have a molecular weight ranging from 200 to
450 g mol−1. All library compounds, with the exception of the
iodine-containing 21, fall into this acceptable range.
Topological polar surface area (TPSA) is a metric commonly
used to predict a drug’s ability to permeate cells. Molecules
with a TPSA below 140 angstroms are considered within range
for cell permeation, and compounds 2–23 all have values lower
than 140 (Table 4). TPSA values lower than 90 are also used to
predict the capability of a molecule to cross the blood–brain
barrier. The fluorene scaffold imparts a significant lipophili-
city to the overall molecule in each example, and this is evi-
denced by the clog P values experimentally determined for
2–23. The log P value of a compound is the logarithm of its
partition coefficient between n-octanol and water [log(coctanol)/
(cwater)]. It has been established that most drugs have clog P
values less than 5.0, and compounds 2–23, with the exceptions
of 18 and 21, are all determined to be within acceptable range.
The clog P values predicted using SwissADME software closely
matched the values experimentally obtained (Table S2, ESI†).
In addition, the vast majority of drugs on the market have
log S (water solubility) values that range between 0.0 and −6.0.
The majority of compounds 2–23 fall within this range, includ-
Cmpd HDF
H293
HeLa
PC3
BxPC3
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
99.1 1.5 96.8 7.1 92.1 4.8
80.8 0.4 93.8 7.0 87.7 2.6
74.6 2.7 93.0 7.6 82.8 0.3
81.0 1.7 95.3 5.5 81.8 0.2
93.0 5.2 69.6 0.7 87.7 2.1
76.9 4.7 70.2 2.0 81.0 7.2
81.6 4.6 94.7 1.0 82.5 1.7
104.5 7.4 84.4 0.5 89.0 0.6
94.0 2.0 67.4 0.2 85.7 3.4
97.0 9.0 82.4 3.2 82.2 0.1
81.4 0.8 102.4 4.4 78.1 0.2
81.0 9.0 100.5 8.9 72.4 0.1
41.2 0.8 67.4 0.5 37.4 1.0
49.3 4.5 71.3 11.9 54.7 4.4
69.5 2.0 59.4 2.7 75.9 1.9
30.7 5.3 19.0 2.9 34.1 0.5
74.4 2.6 68.5 0.0 68.5 5.9
99.0 8.0 99.5 8.4 88.5 0.9
87.5 8.2 82.4 0.5 86.1 3.4
100.9 1.6 80.2 9.3
99.1 0.5
81.8 0.5
88.4 2.8
103.3 1.4 91.5 2.2
84.1 0.1
91.7 1.6
75.8 0.1
74.7 2.9
81.3 2.9
72.1 0.2
74.0 5.7
102.2 5.0 93.6 0.5
100.2 1.2 101.6 0.5
89.9 2.2
79.5 1.7
75.0 0.9
66.3 6.1
66.7 1.4
81.8 4.2
36.4 0.8
93.6 2.5
84.2 1.3
77.0 3.2
69.0 4.5
70.0 1.7
34.3 5.7
56.6 4.3
60.6 0.5
12.8 0.6
73.7 2.7
84.9 5.5
100.4 1.6 83.6 5.1
55.9 4.4 38.1 4.4 69.2 10.6 99.3 1.7
34.2 3.8 61.7 7.1 46.5 3.7
106.0 4.8 83.5 13.6 78.4 0.2
46.9 3.5
65.3 2.0
98.2 4.0
99.2 1.9
91.1 2.3
a All values (%) against 5 cell lines were obtained as an average of
duplicate measurements via the CellTiter-Blue (Promega) assay at
50 μM (24 h). Lower values of POC indicate stronger hits. POC values
below 50% are highlighted in bold.
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Paper
Table 4 Drug-likeness and physicochemical properties of compounds
2–23 as experimentally determined or predicted by OSIRIS and
SwissADME
viability assay with Gram-positive (Staphylococcus aureas) and
Gram-negative (E. coli) bacterial strains. Compounds 17 and 23
are active (comparable to positive controls) at 500 μM against
S. aureas and compounds 2, 5, and 22 are active at 50 μM
against E. coli (comparable to positive controls). In addition to
screening for bactericidal activity, the effect of the compounds
on a series of mammalian cell lines (HDF, H293, HeLa, PC3,
and BxPC3) was determined using CellTiter-Blue and CellTiter-
Glo cell viability assays. Bactericidal compounds 2, 5, 22, and
23 have significantly lower, or negligible, activity against mam-
malian cell lines at 50 μM concentration. In addition, com-
pound 23 was discovered as a luciferase inhibitor. Finally, the
experimental determination of compound 2–23 lipophilicity
values (c log P) along with in silico-generated physicochemical
properties and predictions are provided. Although product
yields in some examples are relatively modest, we believe this
work will serve to support the consideration of fluorene-
scaffold compounds as potential antibacterial drugs that
warrant further synthetic exploration.
d
Cmpd
MW
TPSAa
c log Pb
log Sc
log Kp
Drug scoree
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
368
335
351
356
389
339
321
366
356
339
356
339
357
357
357
411
425
259
435
482
388
383
100.4
54.6
63.8
54.6
54.6
54.6
54.6
100.4
54.6
54.6
54.6
54.6
54.6
54.6
54.6
54.6
54.6
54.6
54.6
54.6
79.9
89.1
3.69
3.96
3.57
4.30
4.48
3.70
3.49
3.59
4.29
3.77
3.67
3.38
3.67
3.13
4.16
4.43
5.17
1.80
4.99
5.08
2.15
0.86
−4.04
−5.10
−4.77
−5.49
−5.53
−5.07
−4.75
−5.21
−5.49
−5.07
−5.49
−5.07
−5.38
−5.38
−5.38
−6.32
−6.96
−4.51
−6.32
−6.50
−5.19
−4.47
−6.06
−5.40
−5.78
−5.34
−5.36
−5.62
−5.58
−5.97
−5.34
−5.62
−5.34
−5.62
−5.65
−5.65
−5.65
−5.77
−4.87
−6.31
−5.33
−5.65
−5.22
−5.66
0.38
0.10
0.11
0.09
0.08
0.11
0.11
0.11
0.09
0.11
0.09
0.11
0.10
0.10
0.10
0.08
0.04
0.14
0.11
0.12
0.46
0.57
Experimental
Materials and instrumentation (synthesis)
a TPSA = Topological polar surface area; calculated by SwissADME.
b Experimentally obtained. c Solubility (log S) calculated by OSIRIS.
d Indicates skin permeation in cm s−1; calculated by SwissADME.
e Calculated by OSIRIS.
All reagents and solvents were purchased from commercial
sources and used without further purification. I2 was pur-
chased from Alfa Aesar in 99.99+% purity (metals basis). 1H
and 13C NMR spectra were recorded on a Varian 400/100
(400 MHz) spectrometer in deuterated chloroform (CDCl3) or
deuterated acetone ((CD3)2CO) with the solvent residual peak
as internal reference unless otherwise stated (CDCl3: 1H =
7.26 ppm, 13C = 77.02 ppm; (CD3)2CO: 1H = 2.05 ppm, 13C =
29.84 ppm). Data are reported in the following order:
Chemical shifts (δ) are reported in ppm, and spin–spin coup-
ling constants (J) are reported in Hz, while multiplicities are
abbreviated by s (singlet), bs (broad singlet), d (doublet), dd
(doublet of doublets), t (triplet), dt (double of triplets), td
(triplet of doublets), m (multiplet). Infrared spectra were
recorded on a Nicolet iS50 FT-IR spectrometer, and peaks are
reported in reciprocal centimeters (cm−1). Melting points were
recorded on a Mel-Temp II (Laboratory Devices, USA) and were
uncorrected. MS (EI) were obtained using a Shimadzu GC-2010
Plus with GCMS-QP2010. Accurate mass spectrum
(HRMS-High Resolution Mass Spectrometry) was performed
using a Thermo Scientific Exactive spectrometer (Waltham,
MA, USA) operating in positive and negative mode (ESI-electro-
spray ionization).
ing the bactericidal compounds 2, 5, 22, and 23. Additional
graphical summaries and BOILED-Egg plots30 of 2–23 gener-
ated by SwissADME are found within the ESI.†
In terms of drug-likeness, 5 different sets (Lipinski, Ghose,
Veber, Egan, and Muegge) of rules and/or parameters used
within medicinal chemistry to predict the likelihood of a mole-
cule to be a drug candidate were applied using SwissADME
(Table S2, ESI†).29 The bactericidal compounds 2, 5, and 23
display no violations of any of the drug-likeness parameters.
Lastly, the drug score calculated by OSIRIS combines drug-like-
ness, clog P, log S, MW, and toxicity risks into one composite
value in order to predict a compound’s overall potential as a
drug.28 Interestingly, the three highest drug scores calculated
from compounds 2–23 belong to the bactericidal compounds,
2, 22, and 23.
Conclusions
In conclusion, a new method for direct substitution of a 2°
C(sp3)–X bond with a sulfonamide unit using a PhI(OAc)2/I2
system is reported. The method is speculated to operate via a
General procedure for the synthesis of N-alkyl sulfonamides
mechanism involving a NCR species according to experimental To an oven-dried reaction tube was added polycyclic hydro-
observations. Key aspects of the approach include mild reac- carbon substrate (0.5 mmol, equiv.), sulfonamide
2
tion temperature, non-metal activation, and the use of readily (0.25 mmol, 1 equiv.), iodobenzene diacetate (0.5 mmol, 2
available and stable reagents. Using the new method, a series equiv.), I2 (0.25 mmol, 1 equiv.) in dry DCM (3–4 mL). The
of 9-aminosulfonyl fluorene analogs as well as heteroanthra- mixture was stirred at 50 °C under argon for 24 hours. After
cene products were generated. Biological activity of the syn- 24 hours, the reaction was cooled to room temperature and
thesized compounds was evaluated using a BacTiter-Glo cell the solvent was removed under vacuum. Crude sulfonamide
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was purified by flash chromatography using hexanes : EtOAc. the formula [k′ = (tR − tm)/tm] where tR is the retention time of
In some cases, a minimal amount of DCM was used to help the sample compound and tm is the retention time of the
solubilize the solid prior to chromatography.
solvent (ethyl acetate). To create a reference calibration curve,
the log of the capacity factors was plotted against the reported
partition coefficient (log P) values for 6 reference compounds
Procedure for gram scale synthesis of product 5
To an oven-dried reaction flask was added 9-bromofluorene (Fig. S3, ESI†). Using the reference calibration curve, linear
(2.45 g, 10.0 mmol), 4-chlorobenzenesulfonamide (0.958 g, regression coefficients “a” and “b” were determined. For
5.0 mmol), iodobenzene diacetate (3.22 g, 10.0 mmol), I2 library compounds 2–23, the partition coefficient (log P) was
(1.27 g, 5.0 mmol) in dry DCM (50 mL). The mixture was determined by using the experimentally determined capacity
stirred at 50 °C under argon for 24 hours. After 24 hours, the factor (k′) and the linear regression coefficients obtained from
reaction was cooled to room temperature and the solvent was the calibration curve in the formula [log P = a + b (log k′)].
removed under vacuum. Crude sulfonamide was purified by
flash chromatography using 4 : 1 hexanes/EtOAc resulting in
isolation of 1.207 g (68%) of product 5.
Compound characterization
N-(9H-Fluoren-9-yl)-4-nitrobenzenesulfonamide (2). White
solid (44 mg, 48%). M.p. 228–230 °C. Purification
Materials and methods (Bioactivity assays)
E. coli (JM109) and S. aureas (MicroKwik) were each (separ- (hexanes : EtOAc, 80 : 20). Rf = 0.32. 1H NMR (400 MHz, CDCl3):
ately) grown overnight in Circle Grow broth plus 50 μg mL−1 δ = 8.46 (dt, J1 = 9.0 Hz, J2 = 2.0 Hz, 2H), 8.24 (dt, J1 = 9.0 Hz, J2
Amp. The overnight culture (10 μL) was diluted into 21 mL of = 2.0 Hz, 2H), 7.65 (d, J1 = 7.4 Hz, 2H), 7.39 (m, 2H), 7.24 (m,
fresh Circle Grow plus Amp. Aliquots were withdrawn (approxi- 4H), 5.47 (d, J1 = 9.4 Hz, 1H), 4.95 (d, J1 = 9.4 Hz, 1H) ppm. 13
C
mately 10 000 cells), treated with DMSO or 50 μM library com- NMR (100 MHz, CDCl3): δ 147.3, 142.5, 140.1, 129.4, 128.4,
pounds, then placed in a 96-well plate at 37 °C with shaking to 128.1, 125.0, 124.7, 124.6, 120.2, 58.7 ppm. IR (neat): ν = 3283,
initiate cell growth for 8 hours. After 8 hours, cell viability was 3109, 1519, 1334, 1313, 1157, 1059, 854, 737, 611 cm−1. HRMS
determined by adding 10 μL BacTiter-Glo reagent (Ultra-Glo (ESI): calculated for C19H13N2O4S [M − H]+ requires m/z
Recombinant Luciferase) for 5–10 minutes (following protocol 365.05961, found m/z 365.05890.
issued by Promega). Luminescence was measured using a
Promega Glomax Multi + detection system.
N-(9H-Fluoren-9-yl)-4-methylbenzenesulfonamide
White solid (70 mg, 83%). M.p. 198–200 °C. Purification
(3).20b
Cell-based Glo kits, such as CellTiter-Blue and CellTiter-Glo (hexanes : EtOAc, 80 : 20). Rf = 0.37. 1H NMR (400 MHz, CDCl3):
were obtained from Promega (Madison, WI, USA). All cell cul- δ = 7.94 (dt, J1 = 8.6 Hz, J2 = 2.0 Hz, 2H), 7.60 (d, J1 = 7.4 Hz,
tures were obtained from the American Type Culture 2H), 7.41 (d, J1 = 8.2 Hz, 2H), 7.34 (m, 2H), 7.20 (m, 4H), 5.38
Collection (ATCC, Manassas, VA, USA). All other materials and (d, J1 = 9.4 Hz, 1H), 4.78 (d, J1 = 9.4 Hz, 1H), 2.51 (s, 3H) ppm.
supplies were purchased from commercial sources and used 13C NMR (100 MHz, CDCl3): δ 143.8, 143.3, 140.0, 138.4, 130.0,
without additional purification. Cell cultures were maintained 129.0, 127.8, 127.3, 125.2, 119.9, 58.3, 21.6 ppm. IR (neat): ν =
in DMEM (Fisher Scientific) supplemented with 10% fetal 3304, 3032, 2919, 1597, 1448, 1324, 1153, 1093, 756, 543 cm−1
.
bovine serum and Penn/Strep. Cultures were maintained in a HRMS (ESI): calculated for C20H17NO2SNa [M + Na]+ requires
37 °C water-jacketed incubator with 5% CO2. For experiments m/z 358.08777, found m/z 358.09146.
in 96-well plates, proliferating cells were removed from the
N-(9H-Fluoren-9-yl)-4-methoxybenzenesulfonamide
(4).
stock plate using PBS plus 2.5 mM EDTA. The desired number White solid (60 mg, 68%). M.p. 178–181 °C. Purification
of cells (∼20 000) were distributed in a 96-well plate containing (hexanes : EtOAc, 80 : 20). Rf = 0.21. 1H NMR (400 MHz, CDCl3):
100 μL DMEM plus 10% FBS and allowed to attach overnight. δ = 8.01 (dd, J1 = 7.0 Hz, J2 = 2.3 Hz, 2H), 7.63 (d, J1 = 7.4 Hz,
After 24 hours, cells were treated with the indicated library 2H), 7.36 (m, 2H), 7.25 (m, 4H), 7.08 (dd, J1 = 7.0 Hz, J2 = 2.3
compound 2–23 or DMSO control (5%). After a set time Hz, 2H), 5.39 (d, J1 = 9.4 Hz, 1H), 4.75 (d, J1 = 9.4 Hz, 1H), 3.93
(24 hours for CellTiter-Blue and 2 hours for CellTiter-Glo), cell (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 163.1, 143.4, 140.0,
viability was determined by adding 10 μL CellTiter-Blue or 132.9, 129.5, 129.0, 127.9, 125.2, 120.0, 114.5, 58.4, 55.7 ppm.
CellTiter-Glo reagent for 1–4 hours. Fluorescence was IR (neat): ν = 3282, 2928, 2842, 1594, 1327, 1180, 1094, 743,
measured either on a TECAN Safire plate reader (ex560/em590
or using a Promega Glomax Multi + detection system.
)
570 cm−1. HRMS (ESI): calculated for C20H17NO3SNa [M + Na]+
requires m/z 374.08269, found m/z 374.08749.
4-Chloro-N-(9H-fluoren-9-yl)benzenesulfonamide
White solid (63 mg, 70%). M.p. 202–205 °C. Purification
(5).20b
Experimental c log P Determination
The method of log P determination followed literature pre- (hexanes : EtOAc, 80 : 20). Rf = 0.43. 1H NMR (400 MHz, CDCl3):
cedent.31 Samples were prepared by dissolving approximately δ = 7.99 (dt, J1 = 9.0 Hz, J2 = 2.4 Hz, 2H), 7.60 (m, 4H), 7.36
1 mg of library compound in 1 mL of ethyl acetate. Samples (ddd, J1 = 7.8 Hz, J2 = 4.7 Hz, J3 = 3.5 Hz, 2H), 7.23 (m, 4H),
were analyzed by HPLC (Agilent 1100 Series, 210 nm) using an 5.40 (d, J1 = 9.4 Hz, 1H), 4.85 (d, J1 = 9.4 Hz, 1H) ppm. 13C
isocratic, 75% methanol/25% water mobile phase at a rate of NMR (100 MHz, CDCl3): δ 142.9, 140.0, 132.2, 129.8, 129.7,
1 mL min−1 over a 25 cm Discovery C18 stationary phase. The 129.2, 128.7, 128.0, 125.1, 120.1, 58.5 ppm. IR (neat): ν = 3272,
capacity factors (k′) of the compounds were calculated using 3090, 2925, 1399, 1328, 1164, 1084, 745 cm−1. HRMS (ESI): cal-
1140 | Org. Biomol. Chem., 2021, 19, 1133–1144
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culated for C19H13ClNO2S [M − H]+ requires m/z 354.03555, (neat): ν = 3279, 3067, 2922, 1427, 1337, 1159, 1050, 742 cm−1
found m/z 354.03586.
HRMS (ESI): calculated for C19H13ClNO2S [M − H]+ requires
N-(9H-Fluoren-9-yl)-4-(trifluoromethyl)benzenesulfonamide (6). m/z 354.03555, found m/z 354.03619.
.
White solid (57 mg, 58%). M.p. 206–209 °C. Purification
N-(9H-Fluoren-9-yl)-3-fluorobenzenesulfonamide (11). Off-
(hexanes : EtOAc, 80 : 20). Rf = 0.44. 1H NMR (400 MHz, CDCl3): white solid (27 mg, 32%). M.p. 152–155 °C. Purification
1
δ = 8.18 (d, J1 = 7.8 Hz, 2H), 7.89 (d, J1 = 7.8 Hz, 2H), 7.63 (d, J1 (hexanes : EtOAc 80 : 20). Rf = 0.39. H NMR (400 MHz, CDCl3):
= 7.4 Hz, 2H), 7.37 (td, J1 = 7.3 × (2) Hz, J2 = 1.4 Hz, 2H), 7.21 δ = 7.86 (d, J1 = 7.0 Hz, 1H), 7.77 (dt, J1 = 8.0 Hz, J2 = 2.2 × (2)
(m, 4H), 5.44 (d, J1 = 9.8 Hz, 1H), 4.89 (d, J1 = 9.4 Hz, 1H) ppm. Hz, 1H), 7.62 (m, 2H), 7.38 (m, 4H), 7.22 (m, 4H), 5.42 (d, J1 =
13C NMR (100 MHz, CDCl3): δ 145.1, 142.7, 140.1, 132.3, 129.3, 9.4 Hz, 1H), 4.87 (d, J1 = 9.4 Hz, 1H) ppm. 13C NMR (100 MHz,
128.0, 127.7, 126.6 (q, J1 = 3.7 × (3) Hz), 125.0, 120.1, 58.6 ppm. CDCl3): δ 162.6 (d, J1 = 250.8 Hz), 143.5 (d, J1 = 7.0 Hz), 142.9,
IR (neat): ν = 3296, 3059, 1404, 1327, 1123, 1062, 711, 140.0, 131.3 (d, J1 = 7.7 Hz), 129.2, 128.0, 125.1, 123.0 (d, J1 =
607 cm−1. HRMS (ESI): calculated for C20H13F3NO2S [M − H]+ 3.3 Hz), 120.2 (d, J1 = 21.4 Hz), 120.1, 114.7 (d, J1 = 24.3 Hz),
requires m/z 388.06191, found m/z 388.06161.
58.5 ppm. IR (neat): ν = 3277, 2927, 2874, 1708, 1447, 1151,
N-(9H-Fluoren-9-yl)-4-fluorobenzenesulfonamide (7). White 1058, 733 cm−1. HRMS (ESI): calculated for C19H13FNO2S [M −
solid (42 mg, 50%). M.p. 209–212 °C (hexanes : EtOAc 80 : 20). H]+ requires m/z 338.06510, found m/z 338.06534.
1
Rf = 0.40. H NMR (400 MHz, (CD3)2CO): δ = 8.19 (m, 2H), 7.75
2-Chloro-N-(9H-fluoren-9-yl)benzenesulfonamide (12). White
(d, J1 = 7.4 Hz, 2H), 7.49 (m, 2H), 7.38 (t, J1 = 6.7 × (2) Hz, 2H), solid (54 mg, 60%). M.p. 106–108 °C. Purification
7.25 (td, J1 = 7.4 × (2) Hz, J2 = 1.2 Hz, 3H), 7.19 (d, J1 = 7.4 Hz, (hexanes : EtOAc, 80 : 20). Rf = 0.34. 1H NMR (400 MHz, CDCl3):
2H), 5.45 (d, J1 = 8.6 Hz, 1H) ppm. 13C NMR (100 MHz, δ = 8.29 (dd, J1 = 7.6 Hz, J2 = 1.4 Hz, 1H), 7.64 (m, 4H), 7.51 (m,
(CD3)2CO): δ 165.8 (d, J1 = 252.8 Hz), 144.7, 140.9, 130.9, 130.8, 1H), 7.37 (td, J1 = 7.0 Hz, J2 = 1.4 Hz, 2H), 7.29 (m, 2H), 7.23
129.6, 128.5, 125.9, 120.8, 117.4, 117.2, 59.2 ppm. IR (neat): ν = (td, J1 = 7.4 Hz, J2 = 1.4 Hz, 2H), 5.44 (d, J1 = 9.0 Hz, 1H), 5.32
3268, 3065, 1590, 1495, 1329, 1169, 1161, 1092, 848, 738, (d, J1 = 9.0 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 142.9,
560 cm−1. HRMS (ESI): calculated for C19H13FNO2S [M − H]+ 140.1, 138.8, 133.9, 131.82, 131.8, 131.0, 129.1, 127.9, 127.4,
requires m/z 338.06510, found m/z 338.06516.
125.2, 120.0, 58.8 ppm. IR (neat): ν = 3348, 3293, 3066, 1707,
N-(9H-Fluoren-9-yl)benzenesulfonamide (8).20b White solid 1451, 1337, 1160, 1043, 742, 585, 558 cm−1. HRMS (ESI): calcu-
(36 mg, 44%). M.p. 214–218 °C. Purification (hexanes : EtOAc, lated for C19H13ClNO2S [M − H]+ requires m/z 354.03555,
1
80 : 20). Rf = 0.32. H NMR (400 MHz, CDCl3): δ = 8.07 (dt, J1 = found m/z 354.03610.
8.6 Hz, J2 = 2.7 Hz, 2H), 7.70 (m, 1H), 7.63 (m, 4H), 7.35 (td, J1
N-(9H-Fluoren-9-yl)-2-fluorobenzenesulfonamide (13). Off-
= 7.2 × (2) Hz, J2 = 1.2 Hz, 2H), 7.20 (m, 4H), 5.42 (d, J1 = 9.4 white solid (37 mg, 44%). M.p. 208–210 °C (hexanes : EtOAc
1
Hz, 1H), 4.79 (d, J1 = 9.4 Hz, 1H) ppm. 13C NMR (100 MHz, 80 : 20). Rf = 0.36. H NMR (400 MHz, CDCl3): δ = 8.09 (td, J1 =
CDCl3): δ 143.2, 141.4, 140.0, 133.0, 129.4, 129.0, 127.9, 127.3, 7.5 × (2) Hz, J2 = 1.8 Hz, 1H), 7.69 (m, 1H), 7.65 (d, J1 = 7.4 Hz,
125.2, 120.0, 58.5 ppm. IR (neat): ν = 3252, 3067, 1447, 1327, 2H), 7.38 (m, 4H), 7.33 (d, J1 = 7.4 Hz, 2H), 7.24 (dd, J1 = 7.4
1163, 1153, 739, 618, 559 cm−1. HRMS (ESI): calculated for Hz, J2 = 0.8 Hz, 2H), 5.52 (d, J1 = 9.4 Hz, 1H), 5.08 (d, J1 = 9.4
C19H15NO2SNa [M + Na]+ requires m/z 344.07212, found m/z Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 158.9 (d, J1
=
344.07611.
255.1 Hz), 143.0, 140.1, 135.2 (d, J1 = 8.2 Hz), 130.1, 129.1,
N-(9H-Fluoren-9-yl)-3-nitrobenzenesulfonamide (9). White 127.9, 125.2, 124.7, 117.2 (d, J1 = 20.9 Hz), 58.7 ppm. IR (neat):
solid (23 mg, 25%). M.p. 208–210 °C. Purification ν = 3264, 2920, 2850, 1474, 1334, 1168, 1076, 737 cm−1. HRMS
(hexanes : EtOAc, 80 : 20). Rf = 0.19. 1H NMR (400 MHz, CDCl3): (ESI): calculated for C19H13FNO2S [M − H]+ requires m/z
δ = 8.89 (t, J1 = 2.0 × (2) Hz, 1H), 8.53 (ddd, J1 = 8.2 Hz, J2 = 2.0 338.06510, found m/z 338.06570.
Hz, J3 = 1.0 Hz, 1H), 8.37 (dt, J1 = 7.8 Hz, J2 = 1.0 × (2) Hz, 1H),
N-(9H-Fluoren-9-yl)-2,4-difluorobenzenesulfonamide
(14).
7.84 (t, J1 = 8.0 × (2) Hz, 1H), 7.65 (dd, J1 = 7.4 Hz, J2 = 1.0 Hz, White solid (40 mg, 45%). M.p. 146–149 °C. Purification
2H), 7.38 (m, 2H), 7.24 (m, 4H), 5.47 (d, J1 = 9.0 Hz, 1H), 4.99 (hexanes : EtOAc, 90 : 10). Rf = 0.19. 1H NMR (400 MHz, CDCl3):
(d, J1 = 9.0 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 148.4, δ = 8.07 (q, J1 = 7.0 × (3) Hz, 1H), 7.62 (d, J1 = 7.4 Hz, 2H), 7.35
143.7, 142.4, 140.1, 132.6, 130.8, 129.4, 128.0, 127.4, 125.0, (m, 4H), 7.25 (m, 2H), 7.06 (m, 2H), 5.47 (d, J1 = 9.0 Hz, 1H),
122.5, 120.2, 58.7 ppm. IR (neat): ν = 3327, 3082, 2926, 1531, 5.06 (d, J1 = 9.0 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ
1355, 1169, 589 cm−1. HRMS (ESI): calculated for C19H13N2O4S 167.2 (dd, J1 = 257.3 Hz, J2 = 11.2 Hz), 159.7 (dd, J1 = 257.3 Hz,
[M − H]+ requires m/z 365.05961, found m/z 365.05981.
J2 = 12.7 Hz), 142.8, 140.1, 131.8 (d, J1 = 10.5 Hz), 129.2, 128.0,
3-Chloro-N-(9H-fluoren-9-yl)benzenesulfonamide (10). Off- 125.1, 120.1, 112.0 (dd, J1 = 20.9 Hz, J2 = 3.0 Hz), 105.8 (t, J1 =
white solid (46 mg, 52%). M.p. 165–168 °C. Purification 26.2 × (2) Hz), 58.7 ppm. IR (neat): ν = 3271, 2921, 2849, 1602,
1
(hexanes : EtOAc 80 : 20). Rf = 0.43. H NMR (400 MHz, CDCl3): 1340, 1167, 1148, 1075, 970, 851, 757 cm−1. HRMS (ESI): calcu-
δ = 8.05 (t, J1 = 1.8 × (2) Hz, 1H), 7.93 (dt, J1 = 7.8 Hz, 1H), 7.66 lated for C19H13F2NO2SNa [M + Na]+ requires m/z or 380.05328,
(ddd, J1 = 9.8 Hz, J2 = 7.8 Hz, J3 = 0.8 Hz, 1H), 7.61 (d, J1 = 7.4 found m/z 380.05356.
Hz, 2H), 7.57 (t, J1 = 7.8 × (2) Hz, 1H), 7.36 (m, 2H), 7.23 (m,
4H), 5.40 (d, J1 = 9.4 Hz, 1H), 4.90 (d, J1 = 9.4 Hz, 1H) ppm. 13
N-(9H-Fluoren-9-yl)-2,6-difluorobenzenesulfonamide
White solid (66 mg, 74%). M.p. 166–170 °C. Purification
(15).
C
NMR (100 MHz, CDCl3): δ 143.1, 142.8, 140.0, 135.5, 133.0, (hexanes : EtOAc, 80 : 20). Rf = 0.27. 1H NMR (400 MHz, CDCl3):
130.7, 129.2, 127.9, 127.3, 125.2, 125.1, 120.0, 58.5 ppm. IR δ = 7.61 (m, 3H), 7.36 (m, 4H), 7.24 (t, J1 = 7.4 × (2) Hz, 2H),
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7.13 (t, J1 = 8.6 Hz, 2H), 5.60 (d, J1 = 9.0 Hz, 1H), 5.27 (d, J1 = 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 145.0, 142.5, 139.8,
9.0 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 159.5 (dd, J1 = 139.7, 139.1, 139.0, 132.2, 129.8, 129.4, 128.7, 128.6, 128.4,
257.3 Hz, J2 = 3.8 Hz), 142.7, 140.1, 134.5 (t, J1 = 11.0 Hz), 125.1, 121.7, 121.3, 120.2, 58.2 ppm. IR (neat): ν = 3272, 2922,
129.2, 127.9, 125.1, 120.1, 119.8 (m), 113.3 (dd, J1 = 23.2 Hz, J2 2852, 1435, 1336, 1159, 1065, 757 cm−1. HRMS (ESI): calcu-
= 3.7 Hz), 58.8 ppm. IR (neat): ν = 3274, 3041, 1610, 1466, lated for C19H12BrClNO2S [M − H]+ requires m/z 432.95389,
1352, 1269, 1168, 1003, 735 cm−1. HRMS (ESI): calculated for found m/z 432.94989.
C19H13F2NO2SNa [M + Na]+ requires m/z or 380.05328, found
m/z 380.05588.
4-Chloro-N-(2-iodo-9H-fluoren-9-yl)benzenesulfonamide (21).
White solid (7 mg, 6%). M.p. 220–222 °C. Purification
N-(9H-Fluoren-9-yl)-3,5-difluorobenzenesulfonamide
(16). (hexanes : EtOAc, 90 : 10). Rf = 0.14. 1H NMR (400 MHz, CDCl3): δ
White solid (49 mg, 54%). M.p. 190–192 °C (hexanes : EtOAc = 7.98 (dt, J1 = 8.2 Hz, J2 = 2.3 × (2) Hz, 2H), 7.68 (d, J1 = 7.4 Hz,
1
90 : 10). Rf = 0.23. H NMR (400 MHz, CDCl3): δ = 7.58 (d, J1 = 1H), 7.61 (m, 3H), 7.37 (m, 3H), 7.29 (d, J1 = 7.4 Hz, 1H), 7.20 (d,
7.4 Hz, 2H), 7.53 (d, J1 = 3.9 Hz, 2H), 7.34 (td, J1 = 7.4 × (2) Hz, J1 = 7.4 Hz, 1H), 5.38 (d, J1 = 9.8 Hz, 1H), 4.83 (d, J1 = 9.8 Hz, 1H)
J2 = 1.2 Hz, 2H), 7.22 (m, 4H), 7.12 (tt, J1 = 8.2 × (2) Hz, J2 = 2.3 ppm. 13C NMR (100 MHz, CDCl3): δ 145.1, 142.3, 139.8, 139.6,
× (2) Hz, 1H), 5.36 (d, J1 = 9.8 Hz, 1H), 4.89 (d, J1 = 9.8 Hz, 1H) 139.1, 138.1, 134.5, 129.9, 129.4, 128.7, 128.6, 125.1, 121.6,
ppm. 13C NMR (100 MHz, CDCl3): δ 163.0 (dd, J1 = 253.8, J2 = 120.2, 92.9, 58.2 ppm. IR (neat): ν = 3283, 1586, 1335, 1159,
11.5 Hz), 144.8 (t, J1 = 8.3 Hz), 142.6, 140.0, 129.3, 128.0, 125.0, 1065, 772, 547 cm−1. HRMS (ESI): calculated for C19H12ClINO2S
120.1, 110.7 (m), 108.5 (t, J1 = 24.9 Hz), 58.6 ppm. IR (neat): ν = [M − H]− requires m/z 479.93221, found m/z 479.92819.
3288, 3084, 1605, 1436, 1337, 1297, 1159, 1061, 1003, 743,
4-Chloro-N-(9H-thioxanthen-9-yl)benzenesulfonamide (22).
611 cm−1. HRMS (ESI): calculated for C19H14F2NO2S [M + H]+ Performed on 0.125 mmol limiting reagent scale. Brown oil
requires m/z 380.05328, found m/z 380.05643.
(32 mg, 66%). Purification (hexanes : EtOAc, 85 : 15). Rf = 0.03.
N-(9H-Fluoren-9-yl)-2,3,4,5,6-pentafluorobenzenesulfonamide 1H NMR (400 MHz, CDCl3): δ = 7.94 (dt, J1 = 9.0 Hz, J2 = 2.7 × (2)
(17). White solid (59 mg, 58%). M.p. 144–148 °C. Purification Hz, 2H), 7.74 (d, J1 = 7.8 Hz, 2H), 7.45 (m, 8H), 4.36 (d, J1 = 17.2
(hexanes : EtOAc, 90 : 10 followed by 100% DCM). Rf = 0.74. H Hz, 1H), 3.92 (d, J1 = 17.2 Hz, 1H) ppm. 13C NMR (100 MHz,
1
NMR (400 MHz, CDCl3): δ = 7.61 (d, J1 = 7.8 Hz, 2H), 7.37 (m, CDCl3): δ 142.6, 137.7, 134.9, 132.1, 131.6, 129.0, 128.9, 128.1,
4H), 7.26 (t, J1 = 7.4 × (2) Hz, 2H), 5.58 (d, J1 = 9.0 Hz, 1H), 5.36 127.9, 126.4, 35.7 ppm. IR (neat): ν = 3057, 1709, 1145, 1088,
(d, J1 = 9.0 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 145.7 959, 731 cm−1. HRMS (ESI): calculated for C19H15ClNO2S2 [M +
(m), 143.2 (m), 142.0, 140.2, 136.7 (m), 129.5, 128.0, 125.0, H]+ requires m/z 388.02328, found m/z 388.02399.
120.2, 117.8 (m), 59.0 ppm. IR (neat): ν = 3312, 2923, 1641,
4-Methoxy-N-(9H-thioxanthen-9-yl)benzenesulfonamide (23).32
1494, 1362, 1170, 1096, 9991, 740 cm−1. HRMS (ESI): calcu- Performed on 0.125 mmol limiting reagent scale. White oil
lated for C19H10F5NO2SNa [M + Na]+ requires m/z or 434.02501, (6.7 mg, 14%). Purification (hexanes : EtOAc, 50 : 50). 1H NMR
found m/z 434.02670.
(400 MHz, CDCl3): δ = 7.98 (dt, J1 = 9.8 Hz, J2 = 2.7 × (2) Hz, 2H),
2,4,6-Trichloro-N-(9H-fluoren-9-yl)benzenesulfonamide (18). 7.79 (d, J1 = 7.8 Hz, 2H), 7.45 (m, 6H), 6.96 (dt, J1 = 9.8 Hz, J2 =
White solid (51 mg, 48%). M.p. 212–214 °C (hexanes : EtOAc 2.7 × (2) Hz, 2H), 4.30 (d, J1 = 17.2 Hz, 1H), 3.91 (d, J1 = 17.2 Hz,
90 : 10). Rf = 0.38. 1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J1 = 7.4 1H), 3.86 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 162.0,
Hz, 2H), 7.58 (s, 2H), 7.39 (t, J1 = 7.2 × (2) Hz, 2H), 7.28 (m, 4H), 136.2, 134.3, 132.9, 131.3, 128.7, 128.4, 128.1, 126.2, 113.9, 55.5,
5.60 (d, J1 = 9.0 Hz, 1H), 5.56 (d, J1 = 9.0 Hz, 1H) ppm. 13C NMR 35.8 ppm. IR (neat): ν = 2928, 1595, 1497, 1289, 1256, 1142,
(100 MHz, CDCl3): δ 142.6, 140.2, 138.2, 135.8, 135.7, 131.3, 129.3, 1088, 958, 755 cm−1. HRMS (ESI): calculated for C20H18NO3S2
128.0, 125.1, 120.1, 58.9 ppm. IR (neat): ν = 3275, 3057, 1560, [M + H]+ requires m/z 384.07281, found m/z 384.07327.
1364, 1171, 738 cm−1. HRMS (ESI): calculated for C19H11Cl3NO2S
[M − H]− requires m/z 421.95761, found m/z 421.95398.
N-(9H-Fluoren-9-yl)methanesulfonamide (19). White solid
Conflicts of interest
(27 mg, 40%). M.p. 180–182 °C. Purification (hexanes : EtOAc,
80 : 20). Rf = 0.13. 1H NMR (400 MHz, CDCl3): δ = 7.66 (dd, J1 = There are no conflicts to declare.
7.4 Hz, J2 = 1.2 Hz, 4H), 7.40 (td, J1 = 7.4 × (2) Hz, 2H), 7.33 (td,
J1 = 7.4 Hz, 2H), 5.50 (d, J1 = 9.8 Hz, 1H), 4.60 (d, J1 = 9.8 Hz,
1H), 3.24 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 143.3,
140.1, 129.2, 128.0, 125.2, 120.1, 58.7, 42.6 ppm. IR (neat): ν =
Acknowledgements
3277, 3020, 2927, 1450, 1322, 1150, 1068, 979, 743 cm−1
.
The research results discussed in this publication were made
HRMS (ESI): calculated for C14H13NO2SNa [M + Na]+ requires possible in part by funding through the award for project
m/z 282.05647, found m/z 282.05969. number HR18-013, from the Oklahoma Center for the
N-(2-Bromo-9H-fluoren-9-yl)-4-chlorobenzenesulfonamide (20). Advancement of Science and Technology. A. A. L. is grateful
Tan solid (17 mg, 16%). M.p. 197–200 °C. Purification for the financial support provided by the lab start-up contri-
(hexanes : EtOAc, 80 : 20). Rf = 0.45. 1H NMR (400 MHz, CDCl3): bution from The University of Tulsa. We would also like to
δ = 7.98 (dt, J1 = 9.4 Hz, J2 = 2.3 × (2) Hz, 2H), 7.60 (m, 3H), thank the Tulsa Undergraduate Research Challenge (TURC)
7.48 (s, 2H), 7.37 (t, J1 = 7.4 × (2) Hz, 1H), 7.27 (m, 2H), 7.18 (d, and Chemistry Summer Undergraduate Research Program
J1 = 7.0 Hz, 1H), 5.38 (d, J1 = 9.8 Hz, 1H), 4.87 (d, J1 = 9.8 Hz, (CSURP) for support. Finally, we acknowledge the critical
1142 | Org. Biomol. Chem., 2021, 19, 1133–1144
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