Design, Synthesis and Evaluation of Oxazaborine Inhibitors of the NLRP3 Inflammasome

Article abstract of DOI:10.1002/cmdc.201700731

The NLRP3 inflammasome is an important regulator of the sterile inflammatory response, and its activation by host-derived sterile molecules leads to the intracellular activation of caspase-1, processing of the pro-inflammatory cytokines interleukin-1β (IL-1β)/IL-18, and pyroptotic cell death. Inappropriate activation of NLRP3 drives a chronic inflammatory response and is implicated in several non-communicable diseases, including gout, atherosclerosis, type II diabetes and Alzheimer's disease. In this study, we report the design, synthesis and biological evaluation of novel boron compounds (NBCs) as NLRP3 inflammasome inhibitors. Structure–activity relationships (SAR) show that 4-fluoro substituents on the phenyl rings retain NLRP3 inhibitory activity, whereas more steric and lipophilic substituents diminish activity. Loss of inhibitory activity is also observed if the CCl₃ group on the oxazaborine ring is replaced by a CF₃ group. These findings provide additional understanding of the NBC series and will aid in the development of these NLRP3 inhibitors as tool compounds or therapeutic candidates for sterile inflammatory diseases.

Full text of DOI:10.1002/cmdc.201700731

Accepted Article
Title: Design, Synthesis and Evaluation of Novel Oxazaborine
Inhibitors of the NLRP3 Inflammasome
Authors: Alex George Baldwin, Victor S. Tapia, Tessa Swanton,
Claire S White, James A. Beswick, David Brough, and Sally
Freeman
This manuscript has been accepted after peer review and appears as an
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: ChemMedChem 10.1002/cmdc.201700731
Link to VoR: http://dx.doi.org/10.1002/cmdc.201700731
A Journal of
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10.1002/cmdc.201700731
ChemMedChem
FULL PAPER
Design, Synthesis and Evaluation of Novel Oxazaborine Inhibitors
of the NLRP3 Inflammasome
Alex G. Baldwin,[a] Victor S. Tapia,[b] Tessa Swanton,[b] Claire S. White,[b] James A. Beswick,[a] David
Brough,*[b] and Sally Freeman*[a]
[a]
[b]
Dr. A. G. Baldwin (ORCID: 0000-0002-7126-5220), James A. Beswick (ORCID: 0000-0002-3985-9141), Dr. S. Freeman (ORCID: 0000-0002-3831-9151)
Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre
The University of Manchester
Stopford Building, Oxford Road, Manchester, M13 9PT, U.K.
E-mail: sally.freeman@manchester.ac.uk
Victor S. Tapia, Tessa Swanton, Claire S. White, Dr. D. Brough (ORCID: 0000-0002-2250-2381)
Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic
Health Science Centre
The University of Manchester
AV Hill Building, Oxford Road, Manchester, M13 9PT, U.K.
E-mail: david.brough@manchester.ac.uk
Supporting information for this article is given via a link at the end of the document.
Abstract: The NLRP3 inflammasome is an important regulator of
the sterile inflammatory response and its activation by host-derived
sterile molecules leads to the intracellular activation of caspase-1,
processing of the pro-inflammatory cytokines interleukin-1β
(IL-1β)/IL-18, and pyroptotic cell death. Inappropriate activation of
NLRP3 drives a chronic inflammatory response and is implicated in
several non-communicable diseases, including gout, atherosclerosis,
type II diabetes and Alzheimer’s disease. In this study, we report the
design, synthesis and biological evaluation of novel boron
compounds (NBCs) as NLRP3 inflammasome inhibitors. Structure-
activity relationships (SAR) show that 4-F groups on the phenyl rings
retain NLRP3 inhibitory activity, whereas more steric and lipophilic
substituents diminish activity. Loss of inhibitory activity is also
observed when the CCl3 group on the oxazaborine ring is replaced
by a CF3 group. These findings provide additional understanding of
the NBC series and will aid in the development of these NLRP3
inhibitors as tool compounds or therapeutic candidates for sterile
inflammatory diseases.
requires the association of NLRP3 with the adaptor protein
apoptosis associated speck-like protein containing a CARD
(ASC). The inactive zymogen pro-caspase-1 is then recruited to
the NLRP3 inflammasome via CARD-CARD homotypic
interactions with ASC, resulting in its proximity-induced
autocleavage into active caspase-1. Caspase-1 then cleaves
pro-IL-1β/IL-18 into their biologically active mature forms IL-
1β/IL-18 which are subsequently released from the cell into the
extracellular space where they drive an inflammatory
response.[4-7] Activation of caspase-1 also leads to a form of cell
death termed pyroptosis.[4]
IL-1β and NLRP3 activation are well characterised in a
number of non-communicable diseases involving sterile
inflammation including gout,[8] atherosclerosis[9] and type II
diabetes (T2D).[10,11] Neuroinflammation caused by microglial
activation is also often dependent on NLRP3 and IL-1β and is
associated with depression[12] and Alzheimer’s disease
(AD).[13,14] Gain-of-function mutations in the NLRP3 gene causes
spontaneous IL-1β release in patients with cryopyrin-associated
periodic syndrome (CAPS) diseases that are characterised by
fever, rashes and extensive joint pain.[15]
Introduction
Given the critical role of NLRP3 and IL-1β in human
disease,[16] there has been great interest in the development of
pharmacological agents that target the NLRP3-IL-1β axis.
Although anti-IL-1β therapy using the biological IL-1β inhibitors
rilonacept (Arcalyst), canakinumab (Ilaris) and anakinra (Kineret)
are highly effective and are currently used clinically, blockade of
NLRP3 inflammasome activation would offer distinct advantages.
Firstly, biological IL-1β inhibitors are only able to target IL-1β
whereas small molecule NLRP3 inhibitors are likely to inhibit
both IL-1β and IL-18 release, block pyroptosis,[17] and prevent
the secretion of inflammasome components that are themselves
pro-inflammatory.[18,19] Secondly, biological IL-1β inhibitors are
protein-based therapeutics that are expensive, with anakinra
requiring high dosages and frequent administration.[20]
Additionally, they are unlikely to cross the blood-brain barrier
(BBB) easily and thus are limited to peripheral inflammatory
diseases. Therefore it would be preferable to develop small
Sterile inflammation is a host-driven immune response to injury
in the absence of infection.[1] A central regulator of the sterile
inflammatory response is the NOD-like receptor, pyrin domain-
containing protein 3 (NLRP3), a soluble pattern recognition
receptor (PRR) whose activation facilitates release of the pro-
inflammatory cytokines interleukin-1β (IL-1β) and IL-18 by
forming
a
multiprotein complex called the NLRP3
inflammasome.[2,3] NLRP3 is activated by various stimuli,
including host-derived endogenous molecules released by
necrosis termed damage-associated molecular patterns
(DAMPs).[2,3] Given the structural diversity of its known agonists,
it is unlikely that known DAMPs engage NLRP3 directly[4] and
there have been several proposed mechanisms for NLRP3
activation which converge on a two-step signalling process.[5,6]
The first step is referred to as priming, and an initial stimulus
(e.g. a TLR ligand) is required to upregulate the intracellular
levels of NLRP3 and pro-IL-1β. The second step is termed
activation in which the primed cell encounters a second stimulus
molecule
therapeutics
capable
of
blocking
NLRP3
inflammasome activation as they could be of use for CNS
indications, are able to be administered orally and are likely to
be more cost-effective alternatives.
(e.g.
a NLRP3 activating DAMP) that leads to NLRP3
inflammasome formation. This process is ATP-dependent and
1
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10.1002/cmdc.201700731
ChemMedChem
FULL PAPER
A number of small molecule inhibitors of the NLRP3
inflammasome have been previously described.[21] However,
many of the reported small molecule NLRP3 inhibitors have
potency in the micromolar range, show poor selectivity or
contain reactive functional groups, limiting their development as
potential drug candidates. A notable exception is MCC950
(formerly known as CRID3 or CP-456,773), the most potent and
selective inhibitor of the NLRP3 inflammasome to date,[22] and its
hybrids with known sulfonylurea drugs are being developed as
dual action insulin secretagogues and NLRP3 inhibitors for
T2D.[23] There is also commercial interest in the development of
sulfonylurea drugs as NLRP3 inflammasome inhibitors, with
recent patents in the sulfonylurea space highlighting the
significant current interest in the NLRP3 inhibitor area.[24,25]
Nevertheless, there is still a need for new NLRP3 inhibitors as
there are currently no approved small molecule inhibitors of the
NLRP3 inflammasome available clinically.
We recently reported on the discovery of new boron-based
small molecules as potent NLRP3 inhibitors.[26] Three of the
oxazaborine compounds screened, BC7 (1), BC23 (2) and
NBC6 (3, Figure 1) were particularly effective inhibitors of IL-1β
release. The pharmacophore for these molecules responsible for
NLRP3 inhibition is the oxazaborine ring and the highly electron-
withdrawing trichloromethyl (CCl3) group. However, the impact of
phenyl ring substitutions on IL-1β release was not assessed.
Additionally, the presence of the CCl3 group significantly
contributes to the high lipophilicity of these oxazaborine
inhibitors, limiting their drug-likeness.
synthesised by treating 4 (when X = MgBr), such as p-
tolylmagnesium bromide, with
a stoichiometric quantity of
phenylboronic acid pinacol ester (7) to give the asymmetric
borinic acid (6).
The synthesised borinic acids 5 and 6 were then reacted
with either (Z)-2-acetyl-3-amino-4,4,4-trichlorobut-2-enamide or
o
(Z)-4-amino-5,5,5-trichloropent-3-en-2-one[26] at 50 C in THF to
give substituted NBC6 (NBC32-33 and NBC40) or BC23
analogues (NBC35-39), respectively (Scheme 1).
AN0128, a known borinic acid picolinate ester prepared by
Anacor Pharmaceuticals, was also synthesised in a two-step
method according to the reported procedure (Scheme 1,
Method A).[29] The rationale for the synthesis of AN0128 was due
to its structural similarity with our oxazaborine inhibitors, in
addition to its known potent anti-bacterial and anti-inflammatory
activities. AN0128 showed 99% inhibition of IL-1β release and
100% inhibition of TNF-α release from human LPS-induced
PBMCs at a concentration of 10 µM,[29] and has since entered
Phase II clinical trials for the treatment of atopic dermatitis, acne
and periodontal disease.[30] Therefore it was of interest to
compare the inhibitory activity of the oxazaborine derivatives
with AN0128 in the IL-1β release assay.
Although the synthesis of oxazaborine derivatives containing
electron-donating substituents (R = R1 = 4-OMe, 4-NMe2,
Scheme 1) were attempted, we found that the bromine-
magnesium (Br-Mg) exchange reaction of aryl bromides with
B(OMe)3 was highly dependent on aromatic ring substitution.
Electron-withdrawing aryl halides (R = R1 = 4-F, 4-Cl, 4-CF3, 3,4-
Cl2, Scheme 1) generally reacted well with magnesium turnings
to give the corresponding borinic acids after aqueous work-up.
In contrast, electron-donating substituents (R = R1 = 4-CH3, 4-
OMe, 4-NMe2, Scheme 1) caused the aryl bromide to react very
slowly with magnesium turnings and, for 4- bromoanisole and 4-
bromo-N,N-dimethylaniline, led to a number of side-products.
The lack of significant reactivity observed for electron-rich aryl
bromides towards Br-Mg exchange is in line with previous
reports.[31,32]
Here we explored structure-activity relationships (SAR) of
phenyl ring substitutions based on the known NLRP3 inhibitors
BC23 (2) and NBC6 (3), in addition to seeking alternative
bioisosteres of the CCl3 group in the search for new NLRP3
inhibitors with improved potency and drug-like properties.
Analogues of BC23 (2) and NBC6 (3) were then designed
where the CCl3 group was replaced with the bioisosteric
trifluoromethyl (CF3) group (Scheme 2). We had previously
shown that only electron-withdrawing substituents at this
position were effective NLRP3 inhibitors,[26] thus the CF3 moiety
should retain similar electron-withdrawing properties to that of a
CCl3 group but is significantly less lipophilic. Additionally,
replacement of the polychlorinated centre would rule out its
potentially labile nature with regards to attack by nucleophiles or
radicals.
Figure 1. Boron-based NLRP3 inflammasome inhibitors.
Results and Discussion
CF3CN was prepared from trifluoroacetamide using
trifluoroacetic anhydride according to the method described by
Parker.[33] CF3CN was reacted with either acetylacetone or
acetoacetamide to give 8 and 9, respectively (Scheme 2).
Intermediate 8 was deacetylated under basic conditions using a
saturated solution of K2CO3 in EtOH to give deacetylated β-
trifluoroenaminone 10.[34] Subsequently, intermediates 9 and 10
were borylated with diphenylborinic anhydride (DPBA) to give
analogues NBC41 and NBC42 (Scheme 2).
Chemistry
Using the Topliss scheme for aromatic substituents,[27] a series
of mono- and di-substituted oxazaborine novel boron
compounds (NBCs) were synthesised by considering both
lipophilicity and electronic factors in order to determine the
optimal substituent as efficiently as possible. Borinic acids with
identical substituted phenyl rings (Scheme 1, Method A) were
first synthesised by reacting two molar equivalents of an aryl
halide (4, X = MgBr, Br or I) with magnesium turnings or
isopropylmagnesium chloride (iPrMgCl), followed by treatment
with one molar equivalent of trimethyl borate (B(OMe)3) to afford
symmetrical borinic acids (5).[28] Alternatively, mono-substituted
aryl(phenyl)borinic acids (Scheme 1, Method B) were
Inhibition of IL-1β release
We initially tested the effect of modifying the phenyl rings of
NBCs on their ability to inhibit NLRP3 inflammasome-dependent
2
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Compound
R
R1
R2
R3
Compound
R
R1
R2
R3
NBC32
NBC33
NBC35
NBC36
4-Me
4-Me
4-F
4-Me
H
NH2
NH2
Me
COMe
COMe
H
NBC37
NBC38
NBC39
NBC40
4-CF3
4-CF3
Me
H
H
4-Me
4-Me
Me
4-F
4-Cl
3,4-Cl2
3-Cl-4-Me
3,4-Cl2
3-Cl-4-Me
NH2
NH2
COMe
COMe
4-Cl
Me
H
Scheme 1. Synthesis of 2,2-diaryl-1,3,2-oxazaborines (NBC32-40) and AN0128. Reagents and conditions: a) B(OMe)3, THF, r.t., 3 h (when X = MgBr); b) Mg, I2,
i
B(OMe)3, THF, 40 oC, 3 h (when X = Br); c) PrMgCl, B(OMe)3, THF, 0 oC to r.t., 16 h (when X = I); d) 4 (X = MgBr), THF, r.t., 3 h; e) (Z)-4-Amino-5,5,5-
trichloropent-3-en-2-one or (Z)-2-acetyl-3-amino-4,4,4-trichlorobut-2-enamide, THF, 50 oC, 16 h; f) 3-Hydroxypicolinic acid, EtOH, reflux, 15 mins.
analysed by ELISA. Nigericin induced release of IL-1β and this
was inhibited by our parent molecule BC23 as expected
(Figure 2A). Addition of a small electron withdrawing fluorine at
the para position of each phenyl ring (NBC35) had minimal
effect on inhibitory activity (Figure 2A). However, inhibitory
activity was reduced when bulkier, more lipophilic substituents
were added (Figure 2A, NBC36-40). The electron-withdrawing
properties of aryl substituents were insignificant for inhibitory
activity as the bioisosteric 4-Cl (NBC36), 4-CF3 (NBC37) and 4-
CH3 (NBC38) derivatives all inhibited IL-1β release to a similar
extent. This observation is further supported by the significantly
reduced activities of 3,4-Cl2 (NBC39) and 3-Cl,4-Me (NBC40)
derivatives which possess additional substitutions around the
phenyl rings. In contrast, there was an observed correlation
between increasing lipophilicity and decreasing inhibitory activity
across the BC23 series (NBC35 < NBC36 ~ NBC37 ~ NBC38 <
Scheme 2. Synthesis of trifluoromethyl derivatives of BC23 (NBC41) and
NBC6 (NBC42). Reagents and conditions: a) CF3CN, Zn(acac)2, DCM, r.t.,
18 h; b) K2CO3, EtOH, 50 oC, 24 h (when R = Me); c) DPBA, THF, 50 oC, 16 h.
NBC39). These observations were also in agreement across the
NBC6 series, where the di-substituted-p-tolyl analogue NBC32
had slightly reduced IL-1β inhibitory activity compared to the
mono-substituted-p-tolyl analogue NBC33 and parent compound
NBC6 in THP-1 cells (Figure S1). These results suggest that aryl
ring substitution, particularly with more steric and lipophilic
substituents, is unlikely to enhance the activity of the NBCs.
It was surprising to note the lack of inhibitory activity of
AN0128 in the IL-1β release assay given its known anti-
inflammatory effects against IL-1β and TNF-α.[29] This could be
release of IL-1β from macrophages. Immortalized bone marrow
derived macrophages (iBMDMs) were treated with LPS (1 µg/ml,
4 h) to prime the cells and induce expression of pro-IL-1β. The
primed cells were then incubated with vehicle (0.5% DMSO) or
inhibitor (10 µM) for 15 minutes before the NLRP3
inflammasome activator nigericin (10 µM, 1 h) was added to
cells. Supernatants were removed and IL-1β levels were
3
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Figure 2: Effects of the new NBCs on IL-1β release. iBMDMs were treated with LPS (1 µg/ml, 4 h) followed by vehicle or drugs with ring substitutions (BC23 vs
NBC35-40, AN0128) (A), or drugs with CCl3 substituted for CF3 (BC23 vs NBC41; NBC6 vs NBC42) (B). Drugs were incubated at 10 µM 15 min before stimulation
with nigericin (10 µM, 1 h). IL-1β was measured by ELISA. Data are presented as the mean ± s.e.m. with a minimum of 3 experiments per group. Ns = non-
significant, *=P<0.05, ***=P<0.001, vs vehicle.
due to differences in cell type (iBMDMs vs PBMCs) or the two-
Conclusions
step priming and activating stimuli used in this study compared
to a single LPS stimulus used previously.[29] Nevertheless, the
The NLRP3 inflammasome is a multi-molecular protein
observation that AN0128 had little effect on IL-1β release in our
NLRP3 inflammasome-dependent assay is an important finding
and suggests that the anti-inflammatory action of AN0128 is
independent of blocking NLRP3 inflammasome activation.
We then tested the effects of BC23 and NBC6 analogues
where the CCl3 group had been replaced with the bioisosteric
trifluoromethyl (CF3) group (Scheme 2). As we had previously
reported that only electron-withdrawing substituents at this
position were effective NLRP3 inhibitors,[26] we proposed that
substituting CCl3 for a CF3 group would test the importance of
lipophilicity whilst retaining similar electron-withdrawing
properties. Using the iBMDM model as described, nigericin
induced a significant release of IL-1β and this was inhibited by
BC23 and NBC6 (Figure 2B). However, both NBC41 (the CF3
analogue of BC23) and NBC42 (the CF3 analogue of NBC6)
were ineffective under these conditions (Figure 2B). These
results, together with our previous observations, clearly
demonstrate that the CCl3 group fulfils both the lipophilic and
electron-withdrawing properties required at this position that is
critical for the inhibitory effects of the NBCs in the IL-1β release
assay (Figure 2B).
Given that the CCl3 group is essential for IL-1β inhibitory
activity, preliminary chemical studies on BC23 to determine the
potential lability of the CCl3 group to cysteine, amine-based and
oxygen-based nucleophiles were performed. However, no
evidence of CCl3 modification or loss was observed, except
fragmentation under mass spectrometry conditions (data not
shown). Therefore these initial studies suggest that the CCl3
group is not labile under these reaction conditions. It was noted
that during these experiments, nucleophiles were found to attack
the boron atom and undergo decomplexation. For example,
BC23 cleanly hydrolyses into diphenylborinic acid and (Z)-4-
amino-5,5,5-trichloropent-3-en-2-one in 9:1 DMSO-d6/D2O
solvent at 37 oC with a half-life of ~24 h, as monitored by 1H
NMR spectroscopy (Figure S2).
complex that is critical for inflammatory responses. Its formation
leads to activation of caspase-1, which cleaves and activates IL-
1β.[5] NLRP3 inflammasome activation is suggested to be
important in diseases such as Alzheimer’s disease,[13]
atherosclerosis,[9] and metabolic disease such as type II
diabetes.[10] The importance of IL-1β to disease was further
highlighted following the recent publication of the CANTOS trial,
where patients with a history of myocardial infarction were
treated with canakinumab, a monoclonal antibody targeting IL-
1β.[35] It was found that canakinumab treatment reduced the rate
of recurrent cardiovascular events, and cancer mortality, in
addition to many other clinical outcomes.[35] The CANTOS
findings have since led to several pharmaceutical companies
seeking to develop molecules that target NLRP3 directly.[36]
There is thus a growing interest in inhibitors of the NLRP3
inflammasome.[21]
We recently published the NBC series of NLRP3
inflammasome inhibitors reporting that key features required for
bioactivity were the oxazaborine ring and CCl3 group.[26] Here we
have further refined the SAR and shown that substitutions on the
aryl rings do not enhance inhibitory activity, and that the
lipophilicity of the CCl3 group is key to inhibitory activity. These
discoveries provide new insights into the activity of the NBC
series and will aid future development of the NBC molecules as
inflammasome inhibitors.
Experimental Section
Chemistry
General: (Z)-4-Amino-5,5,5-trichloropent-3-en-2-one and (Z)-2-acetyl-3-
amino-4,4,4-trichlorobut-2-enamide intermediates were prepared as
previously described.[26] All other chemicals, solvents and deuterated
solvents were purchased from Sigma-Aldrich, Alfa-Aesar or Fisher
4
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FULL PAPER
Scientific. 1H, 13C, 11B and 19F NMR spectra were recorded on a Bruker
Avance 400 or 300 MHz spectrometer. Chemical shifts (δ) are defined in
parts per million (ppm). 1H NMR spectra were referenced to
tetramethylsilane (TMS, δ = 0.0 ppm) or residual undeuterated solvent
(CDCl3, δ = 7.26 ppm; DMSO-d6, δ = 2.50 ppm). 13C NMR spectra were
referenced to residual undeuterated solvent (CDCl3, δ = 77.16 ppm,
DMSO-d6 = 39.52 ppm) as an internal reference. 11B NMR chemical
shifts were referenced to external reference BF3.OEt2 (δ = 0.0 ppm). 19F
NMR chemical shifts were referenced using the deuterium lock signal of
the solvent. ESI and APCI mass spectrometry was carried out on a
Waters Acquity UPLC system connected to a Waters SQD2 mass
spectrometer. Accurate mass determination was carried out on a Thermo
Exactive™ Plus EMR Orbitrap™ LC-MS system. Molecular ion peaks are
defined as mass/charge (m/z) ratios. Infrared spectroscopy was recorded
on a JASCO FT/IR-4100 spectrophotometer using the Spectra Manager
II (JASCO) software package. Melting points were measuring using a
Stuart SMP10 melting point apparatus. Lyophilisation was carried out
using a Christ alpha1-4 plus freeze dryer equipped with an Edwards
vacuum pump. Microwave irradiation was carried out on a Biotage®
Initiator Classic microwave using 2-5 mL Biotage® glass vials. Analytical
thin-layer chromatography (TLC) was performed using silica gel 60 on
aluminium sheets coated with F254 indicator. All spots were visualised
with KMnO4 or ultraviolet light using a MV Mineralight lamp (254/365)
UVGL-58. Flash column chromatography was performed using silica gel
with particle size 40-63 μm. Evaporation of solvents was conducted on a
Buchi Rotavapor R-200.
(Phenyl)(p-tolyl)borinic acid (6a): To an oven-dried Schlenk flask under
N2 was added p-tolylmagnesium bromide (1.0 M in THF, 2.02 mL,
2.02 mmol) in anhydrous THF (5 mL). Phenylboronic acid pinacol ester
(0.41 g, 2.00 mmol) in anhydrous THF (5 mL) was added dropwise to the
reaction mixture and stirred at room temperature for 3 h. 1M HCl (10 mL)
was then added and stirred for 30 mins to quench the reaction. The
reaction mixture was extracted with EtOAc (3 x 10 mL), washed with
brine (1 x 10 mL), dried over MgSO4, filtered and evaporated in vacuo.
The crude product was then purified by flash column chromatography
(EtOAc/n-hexane, 2:23) to give 6a as a colourless oil (0.18 g, 45%). 1H
NMR (300 MHz, CDCl3): δ = 7.72 (d, J = 7.8 Hz, 2H, B-Ph(o)), 7.64 (d, J
= 7.8 Hz, 2H, B-Ar(o)), 7.32-7.47 (m, 3H, B-Ph(m/p)), 7.19 (d, J = 7.8 Hz,
2H, B-Ar(m)), 5.74 (br s, 1H, OH), 2.33 ppm (s, 3H, CH3); 13C NMR
(75 MHz, CDCl3): δ = 141.4 (B-Ar(p)), 135.0 (B-Ph(o)), 134.6 (B-Ar(o)),
130.9 (B-Ph(p)), 128.8 (B-Ar(m)), 127.9 (B-Ph(m)), 21.7 ppm (CH3), B-
Ar(i) and B-Ph(i) quaternary signals not observed; MS(ES-) (m/z): 195.1
[M-H, 11B, 25%]-; HRMS(ES-) (m/z): [M-H]- calcd. for C13H1211BO,
195.0987; found, 195.0973, error: 7.2 ppm.
5-Acetyl-6-amino-2-(phenyl)-2-(p-tolyl)-4-(trichloromethyl)-2,3-
dihydro-1,3,2-oxazaborinin-1-ium-2-uide (NBC33): (Z)-2-Acetyl-3-
amino-4,4,4-trichlorobut-2-enamide (0.40 g, 1.65 mmol) was added to a
solution of 6a (0.13 g, 0.66 mmol) in anhydrous THF (5 mL). The mixture
o
was stirred at 50 C under N2 for 16 h. The mixture was concentrated in
vacuo and purified by flash column chromatography (EtOAc/n-hexane,
2:23). The collected fractions were combined, evaporated in vacuo and
stirred in cold n-hexane (15 mL) for 30 min. The precipitate was then
filtered and dried under vacuum to give NBC33 as a yellow solid (4.9 mg,
2%). mp: 141-143 oC; 1H NMR (300 MHz, CDCl3): δ = 9.25 (br s, 1H,
CONH2), 7.59 (br s, 1H, Cl3C(NH)C=C), 7.40 (d, J = 6.0 Hz, 2H, B-Ph(o)),
7.23-7.34 (m, 5H, B-Ph(m/p) & B-Ar(o)), 7.12 (d, J = 7.8 Hz, 2H, B-Ar(m)),
5.94 (br s, 1H, CONH2), 2.34 (s, 3H, CH3), 2.31 ppm (s, 3H, CH3); 13C
NMR (75 MHz, CDCl3): δ = 192.8 (CH3CO), 163.9 (Cl3C(NH)C=C), 160.3
(CONH2), 131.1 (B-Ar(p)), 126.8 (B-Ph(o)), 126.6 (B-Ar(o)), 123.0 (B-
Ar(m)), 122.1 (B-Ph(m)), 121.5 (B-Ph(p)), 92.7 (Cl3C(NH)C=C), 89.2
(CCl3), 28.7 (CH3CO), 16.0 ppm (CH3), B-Ar(i) and B-Ph(i) quaternary
signals not observed; MS(ES-) (m/z): 420.2 [M-H, 10B, 35Cl, 35Cl, 35Cl,
12%]-, 421.1 [M-H, 11B, 35Cl, 35Cl, 35Cl, 80%]-, 422.2 [M-H, 10B, 35Cl, 35Cl,
37Cl, 33%]-, 423.2 [M-H, 11B, 35Cl, 35Cl, 37Cl, 100%]-, 424.1 [M-H, 10B, 35Cl,
37Cl, 37Cl, 13%]-, 425.1 [M-H, 11B, 35Cl, 37Cl, 37Cl, 24%]-; HRMS(ES+)
(m/z): [M+H]+ calcd. for C19H1911B35Cl3N2O2, 423.0600; found, 423.0605,
error: 1.2 ppm.
Di-p-tolylborinic acid (5a): To an oven-dried Schlenk flask under N2
was added p-tolylmagnesium bromide (1.0 M in THF, 9.98 mL, 10 mmol)
in anhydrous THF (5 mL). B(OMe)3 (0.55 mL, 5 mmol) was added
dropwise to the reaction mixture and stirred at room temperature for 3 h.
1M HCl (10 mL) was then added and stirred for 30 mins to quench the
reaction. The reaction mixture was extracted with EtOAc (3 x 10 mL),
washed with brine (1
evaporated in vacuo. The crude product was then purified by flash
column chromatography (EtOAc/n-hexane, 1:19) to give 5a as
x 10 mL), dried over MgSO4, filtered and
a
colourless oil (0.61 g, 58%). 1H NMR (300 MHz, CDCl3): δ = 7.63 (d, J =
7.8 Hz, 4H, B-Ar(m)), 7.18 (d, J = 7.5 Hz, 4H, B-Ar(o)), 5.65 (br s, 1H,
OH), 2.33 ppm (s, 6H, CH3 x 2); 13C NMR (75 MHz, CDCl3): δ = 141.2 (B-
Ar(p)), 134.8 (B-Ar(o)), 128.7 (B-Ar(m)), 21.7 ppm (CH3), B-Ar(i)
quaternary signal not observed.
5-Acetyl-6-amino-2,2-bis(p-tolyl)-4-(trichloromethyl)-2,3-dihydro-
1,3,2-oxazaborinin-1-ium-2-uide (NBC32): (Z)-2-Acetyl-3-amino-4,4,4-
trichlorobut-2-enamide (1.46 g, 5.95 mmol) was added to a solution of 5a
(0.50 g, 2.38 mmol) in anhydrous THF (5 mL). The mixture was stirred at
50 oC under N2 for 16 h. The mixture was concentrated in vacuo and
purified by flash column chromatography (EtOAc/n-hexane, 2:23). The
collected fractions were combined, evaporated in vacuo and stirred in
cold n-hexane (15 mL) for 30 min. The precipitate was then filtered and
dried under vacuum to give NBC32 as a yellow solid (0.14 g, 14%). mp:
145-148 oC (dec); 1H NMR (300 MHz, CDCl3): δ = 9.23 (br s, 1H,
CONH2), 7.58 (br s, 1H, Cl3C(NH)C=C), 7.29 (d, J = 7.5 Hz, 4H, B-Ar(o)),
7.12 (d, 7.5 Hz, 4H, B-Ar(m)), 5.92 (br s, 1H, CONH2), 2.34 (s, 6H, CH3 x
2), 2.32 ppm (s, 3H, CH3CO); 13C NMR (75 MHz, CDCl3): δ = 198.1
(CH3CO), 169.2 (CONH2), 165.5 (Cl3C(NH)C=C), 156.1 (B-Ar(i)), 136.2
(B-Ar(p)), 132.0 (B-Ar(o)), 128.2 (B-Ar(m)), 97.9 (Cl3C(NH)C=C), 94.5
(CCl3), 34.0 (CH3CO), 21.3 ppm (CH3); IR (neat): 3388 (N-H), 3313 (N-H),
1644 (C=O), 1608 (C=C, conjugated), 1561 (C=C-NH) cm-1; MS(ES-)
(m/z): 434.2 [M-H, 10B, 35Cl, 35Cl, 35Cl, 12%]-, 435.2 [M-H, 11B, 35Cl, 35Cl,
35Cl, 100%]-, 436.2 [M-H, 10B, 35Cl, 35Cl, 37Cl, 24%]-, 437.2 [M-H, 11B, 35Cl,
35Cl, 37Cl, 50%]-, 438.2 [M-H, 10B, 35Cl, 37Cl, 37Cl, 11%]-, 439.2 [M-H, 11B,
35Cl, 37Cl, 37Cl, 10%]-; MS(ES+) (m/z): 344.1 [M-Tolyl, 10B, 35Cl, 35Cl, 35Cl,
10%]+, 345.0 [M-Tolyl, 11B, 35Cl, 35Cl, 35Cl, 27%]+, 346.0 [M-Tolyl, 10B,
35Cl, 35Cl, 37Cl, 12%]+, 347.0 [M-Tolyl, 11B, 35Cl, 35Cl, 37Cl, 36%]+, 349.1
[M-Tolyl, 11B, 35Cl, 37Cl, 37Cl, 21%]+, 439.1 [M+H, 11B, 35Cl, 35Cl, 37Cl,
10%]+; HRMS(ES+) (m/z): [M+H]+ calcd. for C20H2111B35Cl3N2O2,
437.0756; found, 437.0738, error: 4.1 ppm.
General procedure for synthesis of 2,2-bisaryl-1,3,2-oxazaborines:
Using an adapted procedure,[28] to an oven-dried Schlenk flask under N2
was added magnesium turnings (2.2 eq), anhydrous THF (5 mL) and a
small crystal of I2. The reaction was stirred at 40 oC for 30 mins until
complete decolourisation. A solution of aryl bromide (2 eq) and B(OMe)3
(1 eq) in anhydrous THF (5 mL) was then added dropwise to the reaction
mixture and then stirred for an additional 3 h at 40 oC. After cooling to
room temperature, 1M HCl (10 mL) was added and stirred for 30 mins to
quench the reaction. The reaction mixture was extracted with EtOAc (3 x
10 mL), washed with brine (1 x 10 mL), dried over MgSO4, filtered and
evaporated in vacuo to give the corresponding crude bisarylborinic acid,
typically as a solid. (Z)-4-Amino-5,5,5-trichloropent-3-en-2-one (1.5 eq)
was then added to crude bisarylborinic acid (1 eq) in anhydrous THF
(5 mL). The reaction was stirred at 50 oC for 16 h under N2. The reaction
mixture was concentrated and purified by flash column chromatography
using the indicated solvent system. Collected fractions were evaporated
in vacuo and stirred in the minimum amount of cold n-hexane for 30 mins
to induce precipitation. The precipitate was then filtered and dried under
vacuum to give the corresponding oxazaborine product. Percentage
yields are reported over two steps.
2,2-Bis(4-fluorophenyl)-6-methyl-4-(trichloromethyl)-2,3-dihydro-
1,3,2-oxazaborinin-1-ium-2-uide (NBC35): EtOAc/n-hexane, 1:9.
Reaction scale: B(OMe)3 (0.56 mL, 5.00 mmol), 1-bromo-4-
fluorobenzene (1.10 mL, 10 mmol) and magnesium turnings (0.27 g,
5
This article is protected by copyright. All rights reserved.

10.1002/cmdc.201700731
ChemMedChem
FULL PAPER
11 mmol) gives bis(4-fluorophenyl)borinic acid (1.20 g, quant.). Bis(4-
fluorophenyl)borinic acid (1.20 g, 5.50 mmol) and (Z)-4-amino-5,5,5-
trichloropent-3-en-2-one (0.89 g, 4.40 mmol) gives NBC35 as a yellow
(0.64 g, 3.16 mmol) gives NBC38 as a yellow solid (68.8 mg, 4% over
o
two steps). mp: 105-107 C; 1H NMR (400 MHz, CDCl3): δ = 7.41 (br s,
1H, NH), 7.28 (d, J = 7.2 Hz, 4H, B-Ar(o)), 7.13 (d, J = 7.2 Hz, 4H, B-
Ar(m)), 5.77 (s, 1H, Cl3C(NH)C=CH), 2.34 (s, 6H, CH3 x 2), 2.23 ppm (s,
3H, CH3CO); 13C NMR (100 MHz, CDCl3): δ = 186.2 (CH3CO), 136.3 (B-
Ar(p)), 131.9 (B-Ar(o)), 128.4 (B-Ar(m)), 91.5 (Cl3C(NH)C=CH), 24.9
(CH3CO), 21.5 ppm (CH3), B-Ar(i) and Cl3C(NH)C=CH quaternary signals
not observed; 11B{1H} NMR (128 MHz, CDCl3): δ = 4.61 ppm; MS(ES-)
(m/z): 392.1 [M-H, 11B, 35Cl, 35Cl, 35Cl, 100%]-, 393.1 [M-H, 10B, 35Cl, 35Cl,
37Cl, 20%]-, 394.1 [M-H, 11B, 35Cl, 35Cl, 37Cl, 88%]-, 395.1 [M-H, 10B, 35Cl,
37Cl, 37Cl, 21%]-, 396.1 [M-H, 11B, 35Cl, 37Cl, 37Cl, 22%]-; MS(ES+) (m/z):
301.2 [M-Tolyl, 10B, 35Cl, 35Cl, 35Cl, 75%]+, 302.1 [M-Tolyl, 11B, 35Cl, 35Cl,
35Cl, 90%]+, 303.1 [M-Tolyl, 10B, 35Cl, 35Cl, 37Cl, 28%]+, 304.1 [M-Tolyl,
11B, 35Cl, 35Cl, 37Cl, 100%]+, 305.1 [M-Tolyl, 10B, 35Cl, 37Cl, 37Cl, 16%]+,
306.0 [M-Tolyl, 11B, 35Cl, 37Cl, 37Cl, 25%]+; HRMS(ES-) (m/z): [M-H]- calcd.
for C19H1811B35Cl3NO, 392.0553; found, 392.0555, error: 0.6 ppm.
1
solid (0.22 g, 12% over two steps). mp: 130-131 oC; H NMR (400 MHz,
CDCl3): δ = 7.31 (dd ~ t, 3JHH ~ 4JHF = 6.6 Hz, 4H, B-Ar(o)), 7.00 (t, 3JHH
~
3JHF = 8.4 Hz, 4H, B-Ar(m)), 5.83 (s, 1H, Cl3C(NH)C=CH), 2.25 ppm (s,
3H, CH3CO), NH signal is overlapping with triplet at 7.31 ppm; 13C NMR
(100 MHz, CDCl3): δ = 186.5 (CH3CO), 166.1 (Cl3C(NH)C=CH), 162.6 (d,
3
1JCF = 242.6 Hz, B-Ar(p)), 133.4 (d, JCF = 27.6 Hz, B-Ar(o)), 114.4 (d,
2JCF = 77.2 Hz, B-Ar(m)), 92.8 (CCl3), 92.0 (Cl3C(NH)C=CH), 24.9 ppm
(CH3CO), B-Ar(i) quaternary signal not observed; 11B{1H} NMR (128 MHz,
CDCl3): δ = 4.11 ppm; 19F{1H} NMR (376 MHz, CDCl3): δ = -116.1 ppm;
MS(ES-) (m/z): 399.1 [M-H, 10B, 35Cl, 35Cl, 35Cl, 14%]-, 400.1 [M-H, 11B,
35Cl, 35Cl, 35Cl, 70%]-, 401.1 [M-H, 10B, 35Cl, 35Cl, 37Cl, 40%]-, 402.1 [M-H,
11B, 35Cl, 35Cl, 37Cl, 100%]-, 403.1 [M-H, 10B, 35Cl, 37Cl, 37Cl, 15%]-, 404.1
[M-H, 11B, 35Cl, 37Cl, 37Cl, 33%]-; HRMS(ES-) (m/z): [M-H]- calcd. for
C17H1211B35Cl319F2NO, 400.0051; found, 400.0048, error: 0.7 ppm.
2,2-Bis(3,4-dichlorophenyl)-6-methyl-4-(trichloromethyl)-2,3-
2,2-Bis(4-chlorophenyl)-6-methyl-4-(trichloromethyl)-2,3-dihydro-
1,3,2-oxazaborinin-1-ium-2-uide (NBC36): EtOAc/n-hexane, 1:9.
Reaction scale: B(OMe)3 (0.28 mL, 2.50 mmol), 1-bromo-4-
chlorobenzene (0.96 g, 5.00 mmol) and magnesium turnings (0.13 g,
5.50 mmol) gives bis(4-chlorophenyl)borinic acid (0.71 g, 57%). Bis(4-
chlorophenyl)borinic acid (0.71 g, 2.85 mmol) and (Z)-4-amino-5,5,5-
trichloropent-3-en-2-one (0.86 g, 4.27 mmol) gives NBC36 as a yellow
dihydro-1,3,2-oxazaborinin-1-ium-2-uide (NBC39): EtOAc/n-hexane,
1:19. Reaction scale: B(OMe)3 (0.28 mL, 2.50 mmol), 4-bromo-1,2-
dichlorobenzene (0.64 mL, 5.00 mmol) and magnesium turnings (0.13 g,
5.50 mmol) gives bis(3,4-dichlorophenyl)borinic acid (0.92 g, 58%).
Bis(3,4-dichlorophenyl)borinic acid (0.92 g, 2.88 mmol) and (Z)-4-amino-
5,5,5-trichloropent-3-en-2-one (0.87 g, 4.32 mmol) gives NBC39 as a
cream solid (0.71 g, 43% over two steps). mp: 109-110 oC; 1H NMR (400
MHz, CDCl3): δ = 7.37 (s, 2H, B-Ar-H2), 7.36 (d, J = 7.2 Hz, 2H, B-Ar-H5),
7.10 (d, J = 8.0 Hz, 2H, B-Ar-H6), 5.88 (s, 1H, Cl3C(NH)C=CH), 2.28 ppm
(s, 3H, CH3CO), NH signal is observed but overlapping with CHCl3 at
7.26 ppm; 13C NMR (100 MHz, CDCl3): δ = 187.1 (CH3CO), 166.7
(Cl3C(NH)C=CH), 133.5 (B-Ar-C6), 132.1 (B-Ar-C3), 131.1 (B-Ar-C4),
130.9 (B-Ar-C2), 129.9 (B-Ar-C5), 92.8 (Cl3C(NH)C=CH), 92.5 (CCl3),
24.9 ppm (CH3CO), B-Ar-C1 quaternary signal not observed; 11B{1H}
NMR (128 MHz, CDCl3): δ = 3.10 ppm; MS(ES-) (m/z): 499.9 [M-H, 11B,
35Cl, 35Cl, 35Cl, 35Cl, 35Cl, 35Cl, 35Cl, 45%]-, 500.9 [M-H, 10B, 35Cl, 35Cl, 35Cl,
35Cl, 35Cl, 35Cl, 37Cl, 22%]-, 501.9 [M-H, 11B, 35Cl, 35Cl, 35Cl, 35Cl, 35Cl, 35Cl,
37Cl, 100%]-, 502.9 [M-H, 10B, 35Cl, 35Cl, 35Cl, 35Cl, 35Cl, 37Cl, 37Cl, 50%]-,
503.9 [M-H, 11B, 35Cl, 35Cl, 35Cl, 35Cl, 35Cl, 37Cl, 37Cl, 98%]-, 504.9 [M-H,
10B, 35Cl, 35Cl, 35Cl, 35Cl, 37Cl, 37Cl, 37Cl, 23%]-, 505.9 [M-H, 11B, 35Cl, 35Cl,
35Cl, 35Cl, 37Cl, 37Cl, 37Cl, 63%]-, 506.9 [M-H, 10B, 35Cl, 35Cl, 35Cl, 37Cl, 37Cl,
37Cl, 37Cl, 10%]-, 507.9 [M-H, 11B, 35Cl, 35Cl, 35Cl, 37Cl, 37Cl, 37Cl, 37Cl,
21%]-; HRMS(ES-) (m/z): [M-H]- calcd. for C17H1011B35Cl7NO, 499.8681;
found, 499.8681, error: 0.0 ppm.
1
solid (0.38 g, 17% over two steps). mp: 106-107 oC; H NMR (400 MHz,
CDCl3): δ = 7.25 (br s, 1H, NH), 7.19 (br s, 8H, B-Ar(o/m)), 5.76 (s, 1H,
Cl3C(NH)C=CH), 2.18 ppm (s, 3H, CH3CO); 13C NMR (100 MHz, CDCl3):
δ = 186.7 (CH3CO), 166.3 (Cl3C(NH)C=CH), 133.2 (B-Ar(o)), 133.1 (B-
Ar(p)), 127.8 (B-Ar(m)), 92.7 (CCl3), 92.2 (Cl3C(NH)C=CH), 24.8 ppm
(CH3CO), B-Ar(i) quaternary signal not observed; 11B{1H} NMR (128 MHz,
CDCl3): δ = 3.82 ppm; MS(ES-) (m/z): 431.0 [M-H, 10B, 35Cl, 35Cl, 35Cl,
35Cl, 35Cl, 13%]-, 432.0 [M-H, 11B, 35Cl, 35Cl, 35Cl, 35Cl, 35Cl, 75%]-, 433.0
[M-H, 10B, 35Cl, 35Cl, 35Cl, 35Cl, 37Cl, 42%]-, 434.0 [M-H, 11B, 35Cl, 35Cl,
35Cl, 35Cl, 37Cl, 100%]-, 435.0 [M-H, 10B, 35Cl, 35Cl, 35Cl, 37Cl, 37Cl, 25%]-,
436.0 [M-H, 11B, 35Cl, 35Cl, 35Cl, 37Cl, 37Cl, 88%]-, 437.0 [M-H, 10B, 35Cl,
35Cl, 37Cl, 37Cl, 37Cl, 12%]-, 438.0 [M-H, 11B, 35Cl, 35Cl, 37Cl, 37Cl, 37Cl,
30%]-; HRMS(ES-) (m/z): [M-H]- calcd. for C17H1211B35Cl5NO, 431.9460;
found, 431.9460, error: 0.0 ppm.
6-Methyl-4-(trichloromethyl)-2,2-bis(4-(trifluoromethyl)phenyl)-2,3-
dihydro-1,3,2-oxazaborinin-1-ium-2-uide (NBC37): EtOAc/n-hexane,
1:19. Reaction scale: B(OMe)3 (0.28 mL, 2.50 mmol), 4-
bromobenzotrifluoride (0.70 mL, 5.00 mmol) and magnesium turnings
(0.13 g, 5.50 mmol) gives bis(4-trifluorophenyl)borinic acid (0.81 g,
quant.). Bis(4-trifluorophenyl)borinic acid (0.81 g, 2.55 mmol) and (Z)-4-
amino-5,5,5-trichloropent-3-en-2-one (0.77 g, 3.83 mmol) gives NBC37
as a yellow solid (0.43 g, 33% over two steps). mp: 103-105 oC; 1H NMR
(400 MHz, CDCl3): δ = 7.56 (d, J = 7.6 Hz, 4H, B-Ar(m)), 7.46 (d, J = 7.6
Hz, 4H, B-Ar(o)), 7.41 (br s, 1H, NH), 5.89 (s, 1H, Cl3C(NH)C=CH),
2.30 ppm (s, 3H, CH3CO); 13C NMR (100 MHz, CDCl3): δ = 187.1
5-Acetyl-6-amino-2,2-bis(3-chloro-4-methylphenyl)-4-
(trichloromethyl)-2,3-dihydro-1,3,2-oxazaborinin-1-ium-2-uide
(NBC40): Using an adapted procedure,[29] iPrMgCl (2.0 M in THF, 1.21
mL, 2.42 mmol) was added dropwise to a solution of 2-chloro-4-
iodotoluene (0.28 mL, 1.98 mmol) in anhydrous THF (5 mL) in an oven-
dried Schlenk flask under N2. The reaction was stirred at 0oC for 5h.
B(OMe)3 (0.10 mL, 0.92 mmol) was then added and the reaction mixture
was stirred overnight allowing to warm to room temperature. 3M HCl
(10 mL) was added and the reaction mixture was extracted with EtOAc
(3 x 10 mL), washed with brine (1 x 10 mL), dried over MgSO4, filtered
2
(CH3CO), 166.7 (Cl3C(NH)C=CH), 131.8 (B-Ar(o)), 129.2 (q, JCF = 31.3
1
3
Hz, B-Ar(p)), 124.7 (q, JCF = 270.2 Hz, CF3), 124.4 (q, JCF = 3.6 Hz, B-
Ar(m)), 92.7 (Cl3C(NH)C=CH), 24.8 ppm (CH3CO), B-Ar(i) and CCl3
quaternary signals not observed; 11B{1H} NMR (128 MHz, CDCl3): δ =
3.56 ppm; 19F{1H} NMR (376 MHz, CDCl3): δ = -62.4 ppm; MS(ES-)
(m/z): 499.1 [M-H, 10B, 35Cl, 35Cl, 35Cl, 22%]-, 500.1 [M-H, 11B, 35Cl, 35Cl,
35Cl, 75%]-, 501.1 [M-H, 10B, 35Cl, 35Cl, 37Cl, 45%]-, 502.1 [M-H, 11B, 35Cl,
35Cl, 37Cl, 100%]-, 503.1 [M-H, 10B, 35Cl, 37Cl, 37Cl, 12%]-, 504.1 [M-H, 11B,
35Cl, 37Cl, 37Cl, 22%]-; HRMS(ES-) (m/z): [M-H]- calcd. for
C19H1211B35Cl319F6NO, 499.9987; found, 499.9990, error: 0.6 ppm.
and
evaporated
in
vacuo
to
give
crude
bis(3-chloro-4-
methylphenyl)borinic acid as a cream solid in quantitative yield. To a
portion of this intermediate (0.20 g, 0.72 mmol) in anhydrous THF (5 mL)
was added (Z)-2-acetyl-3-amino-4,4,4-trichlorobut-2-enamide (0.26 g,
1.08 mmol). The reaction was stirred at 50 oC for 16 h under N2. The
reaction mixture was concentrated and purified by flash column
chromatography (EtOAc/n-hexane, 1:4). Collected fractions were
evaporated in vacuo and stirred in the minimum amount of cold n-hexane
for 30 mins to induce precipitation. The precipitate was then filtered and
dried under vacuum to give NBC40 as a white solid (41.4 mg, 11%). mp:
2,2-Bis(4-methylphenyl)-6-methyl-4-(trichloromethyl)-2,3-dihydro-
1,3,2-oxazaborinin-1-ium-2-uide (NBC38): EtOAc/n-hexane, 1:19.
Reaction scale: B(OMe)3 (0.28 mL, 2.50 mmol), 4-bromotoluene
(0.62 mL, 5.00 mmol) and magnesium turnings (0.13 g, 5.50 mmol) gives
bis(4-methylphenyl)borinic acid (0.44 g, 42%). Bis(4-methylphenyl)borinic
acid (0.44 g, 2.11 mmol) and (Z)-4-amino-5,5,5-trichloropent-3-en-2-one
147-148 oC; 1H NMR (300 MHz, CDCl3):
δ = 11.22 (br s, 1H,
Cl3C(NH)C=C), 7.38 (s, 2H, B-Ar-H2), 7.18 (d, J = 7.8 Hz, 2H, B-Ar-H6),
7.10 (d, J = 7.2 Hz, 2H, B-Ar-H5), 6.16 (br s, 1H, CONH2), 5.89 (br s, 1H,
CONH2), 2.32 (s, 6H, CH3 x 2), 2.26 ppm (s, 3H, CH3CO); MS(ES-) (m/z):
502.1 [M-H, 10B, 35Cl, 35Cl, 35Cl, 35Cl, 35Cl, 10%]-, 503.1 [M-H, 11B, 35Cl,
35Cl, 35Cl, 35Cl, 35Cl, 42%]-, 504.1 [M-H, 10B, 35Cl, 35Cl, 35Cl, 35Cl, 37Cl,
6
This article is protected by copyright. All rights reserved.

10.1002/cmdc.201700731
ChemMedChem
FULL PAPER
27%]-, 505.1 [M-H, 11B, 35Cl, 35Cl, 35Cl, 35Cl, 37Cl, 100%]-, 506.1 [M-H, 10B,
35Cl, 35Cl, 35Cl, 37Cl, 37Cl, 24%]-, 507.1 [M-H, 11B, 35Cl, 35Cl, 35Cl, 37Cl, 37Cl,
45%]-, 508.1 [M-H, 10B, 35Cl, 35Cl, 37Cl, 37Cl, 37Cl, 14%]-, 509.1 [M-H, 11B,
35Cl, 35Cl, 37Cl, 37Cl, 37Cl, 13%]-; HRMS(ES-) (m/z): [M-H]- calcd. for
C20H1711B35Cl5N2O2, 502.9831; found, 502.9833, error: 0.4 ppm.
solid (0.42 g, 27% over two steps). 1H NMR (400 MHz, CDCl3): δ = 5.52
(s, 1H, F3C(NH2)C=CH), 2.18 ppm (s, 3H, CH3CO); 13C NMR (100 MHz,
2
CDCl3): δ = 199.6 (CH3CO), 147.1 (q, JCF = 33.3 Hz, F3C(NH2)C=CH),
1
3
120.4 (q, JCF = 274 Hz, CF3), 94.1 (q, JCF = 3.7 Hz, F3C(NH2)C=CH),
30.5 ppm (CH3CO); 19F{1H} NMR (376 MHz, CDCl3): δ = -71.8 ppm. All
data were in agreement with literature values.[34]
3-Hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)
borane (AN0128): Prepared according to
a
previously published
6-Methyl-2,2-diphenyl-4-(trifluoromethyl)-2,3-dihydro-1,3,2-
method.[29] iPrMgCl (2.0 M in THF, 2.42 mL, 4.83 mmol) was added
dropwise to a solution of 2-chloro-4-iodotoluene (0.56 mL, 3.96 mmol) in
anhydrous THF (5 mL) in an oven-dried Schlenk flask under N2. The
oxazaborinin-1-ium-2-uide (NBC41): Using an adapted procedure,[37]
10 (0.29 g, 1.92 mmol) was added to a solution of DPBA (0.43 g, 1.23
mmol) in anhydrous THF (5 mL). The reaction mixture was stirred at
50 oC under Ar for 16 h. The reaction mixture was then concentrated and
purified by flash column chromatography (3:20, EtOAc/n-hexane) to give
o
reaction was stirred at 0 C for 5 h. B(OMe)3 (0.21 mL, 1.84 mmol) was
then added and the reaction mixture was stirred overnight allowing to
warm to room temperature. 3M HCl (10 mL) was then added and the
reaction mixture was extracted with EtOAc (3 x 10 mL), washed with
brine (1 x 10 mL), dried over MgSO4, filtered and evaporated in vacuo to
give crude bis(3-chloro-4-methylphenyl)borinic acid as a cream solid in
quantitative yield. A portion of this intermediate (0.50 g, 1.79 mmol) was
dissolved in EtOH (5 mL) and heated to reflux. 3-Hydroxypicolinic acid
(0.20 g, 1.43 mmol) was added in portions to the hot solution and after
the last addition, the reaction mixture was stirred at reflux for 15 mins.
The reaction was then cooled, resulting in the precipitation of product
from the solution. The reaction mixture was partially concentrated and
the precipitate was re-crystallised in EtOH to give AN0128 as a white
solid (0.30 g, 53%). mp: 166-167 oC (lit. 165.0-166.5 oC)[29]; 1H NMR (300
MHz, DMSO-d6): δ = 12.17 (br s, 1H, OH), 8.58 (t, J = 3.2 Hz, 1H, Py-
H12), 7.93 (d, J = 3.0 Hz, 2H, Py-H10,11), 7.22 (d, J = 7.5 Hz, 2H, B-Ar-
H6), 7.20 (s, 2H, B-Ar-H2), 7.11 (d, J = 7.5 Hz, 2H, B-Ar-H5), 2.27 ppm (s,
6H, CH3 x 2); 13C NMR (100 MHz, DMSO-d6): δ = 162.2 (COO), 156.2
(Py-C9), 134.2 (Py-C8), 134.0 (Py-C12), 133.0 (B-Ar-C4), 132.1 (B-Ar-
C3), 131.9 (B-Ar-C6), 131.5 (Py-C11), 130.7 (B-Ar-C5), 130.5 (B-Ar-C2),
127.5 (Py-C10), 19.4 ppm (CH3), B-Ar-C1 quaternary signal not
observed; 11B{1H} NMR (128 MHz, DMSO-d6): δ = 6.76 ppm; MS(ES-)
(m/z): 397.1 [M-H, 10B, 35Cl, 35Cl, 22%]-, 398.1 [M-H, 11B, 35Cl, 35Cl,
100%]-, 399.1 [M-H, 10B, 35Cl, 37Cl, 63%]-, 400.1 [M-H, 11B, 35Cl, 37Cl,
67%]-, 401.1 [M-H, 10B, 37Cl, 37Cl, 17%]-; HRMS(ES-) (m/z): [M-H]- calcd.
for C20H1511B35Cl2NO3, 398.0528; found, 398.0526, error: 0.5 ppm. All
data were in agreement with literature values.[29]
o
o
NBC41 as a yellow solid (0.34 g, 88%). mp: 96-97 C (lit. 99-100 C)[37]
;
1H NMR (400 MHz, CDCl3): δ = 7.14-7.31 (m, 10H, B-Ph x 2), 6.95 (br s,
4
1H, NH), 5.44 (d, JNH,H = 2.0 Hz, 1H, F3C(NH)C=CH), 2.17 ppm (s, 3H,
CH3CO); 13C NMR (100 MHz, CDCl3): δ = 188.3 (CH3CO), 156.7 (q, 2JCF
= 35.0 Hz, F3C(NH)C=CH), 131.8 (B-Ph(o)), 127.6 (B-Ph(m)), 127.1 (B-
1
Ph(p)), 118.8 (q, JCF = 276.7 Hz, CF3), 91.6 (F3C(NH)C=CH), 24.9 ppm
(CH3CO); 11B{1H} NMR (128 MHz, CDCl3): δ = 4.37 ppm; 19F{1H} NMR
(376 MHz, CDCl3): δ = -72.9 ppm; MS(ES-) (m/z): 316.11 [M-H, 98%]-;
MS(ES+) (m/z): 340.11 [M+Na, 100%]+; HRMS(ES-) (m/z): [M+Na]- calcd.
for C17H1511BF3NO, 340.1091; found, 340.1085, error: 1.8 ppm. All data
were in agreement with literature values.[37]
(Z)-2-Acetyl-3-amino-4,4,4-trifluorobut-2-enamide (9): CF3CN was
slowly generated by drop-wise addition of a solution of trifluoroacetic
anhydride (8.26 mL, 59.41 mmol) in anhydrous pyridine (40 mL) to a
solution of trifluoroacetamide (6.71 g, 59.41 mmol) in anhydrous pyridine
(20 mL) under N2 in a three-neck round-bottom flask equipped with a N2
gas inlet and gas outlet. The gas outlet was connected to a two-neck
round-bottom flask containing a solution of acetoacetamide (1.00 g, 9.90
mmol) and Zn(acac)2 (27.9 mg, 0.099 mmol) in anhydrous DCM (10 mL)
that was equipped with a dry ice condenser connected to a bubbler outlet.
CF3CN was bubbled into the stirring solution at room temperature for
several hours until complete consumption of the trifluoroacetic anhydride
solution. The reaction was further stirred at room temperature for 16 h.
The reaction mixture was extracted with EtOAc (5 x 50 mL), washed with
brine (3 x 50 mL), dried over MgSO4, filtered and evaporated in vacuo.
Et2O (10 mL) was added to induce precipitation and the precipitate was
filtered, washed with additional Et2O and dried to give 9 as a white solid
(1.52 g, 78%). mp: 192-193 oC; 1H NMR (400 MHz, CDCl3): δ = 9.06 (br s,
2H, NH2), 7.75 (br s, 1H, CONH2), 7.40 (br s, 1H, CONH2), 2.18 ppm (s,
3H, CH3CO); 13C NMR (100 MHz, CDCl3): δ = 196.5 (CH3CO), 168.3
(CONH2), 144.9 (q, 2JCF = 32.3 Hz, F3C(NH2)C=C), 120.3 (q, 1JCF = 277.7
Hz, CF3), 107.0 (F3C(NH2)C=C), 28.0 ppm (CH3CO); 19F{1H} NMR (376
MHz, CDCl3): δ = -65.4 ppm; MS(ES-) (m/z): 195.04 [M-H, 100%]-;
MS(ES+) (m/z): 219.03 [M+Na, 100%]+; HRMS(ES-) (m/z): [M+Na]- calcd.
for C6H7F3N2O2, 219.0352; found, 219.0346, error: 2.7 ppm.
3-(1-Amino-2,2,2-trifluoroethylidene)pentane-2,4-dione (8): Using a
previously reported procedure,[33] CF3CN was slowly generated by drop-
wise addition of a solution of trifluoroacetic anhydride (8.33 mL, 59.93
mmol) in anhydrous pyridine (40 mL) to a solution of trifluoroacetamide
(6.77 g, 59.93 mmol) in anhydrous pyridine (20 mL) under N2 in a three-
neck round-bottom flask equipped with a N2 gas inlet and gas outlet. The
gas outlet was connected to a two-neck round-bottom flask containing a
solution of acetylacetone (0.51 mL, 4.99 mmol) and Zn(acac)2 (14.1 mg,
0.050 mmol) in anhydrous DCM (10 mL) that was equipped with a dry ice
condenser connected to a bubbler outlet. CF3CN was bubbled into the
stirring solution at room temperature for several hours until complete
consumption of the trifluoroacetic anhydride solution. The reaction was
further stirred at room temperature for 16 h. The reaction mixture was
extracted with DCM (3 x 10 mL), washed with brine (1 x 10 mL), dried
over MgSO4, filtered and evaporated in vacuo to give 8 as a white solid
(0.86 g, 88%). 1H NMR (400 MHz, CDCl3): δ = 2.46 (s, 3H, CH3CO), 2.18
ppm (s, 3H, CH3CO); 13C NMR (100 MHz, CDCl3): δ = 202.1 (CH3CO),
5-Acetyl-6-amino-2,2-diphenyl-4-(trifluoromethyl)-2,3-dihydro-1,3,2-
oxazaborinin-1-ium-2-uide (NBC42): 9 (0.72 g, 3.69 mmol) was added
to a solution of DPBA (0.43 g, 1.23 mmol) in anhydrous THF (5 mL). The
reaction mixture was stirred at 50 oC under Ar for 16 h. The reaction
mixture was then concentrated and purified by flash column
chromatography (1:5, EtOAc/n-hexane). The collected fractions were
combined, evaporated in vacuo and precipitated in n-hexane (10 mL) to
give NBC42 as a white solid (0.28 g, 64%). mp: 118-120 oC; 1H NMR
(300 MHz, CDCl3): δ = 10.05 (br s, 1H, NH), 7.22-7.36 (m, 10H, B-Ph),
2
1
196.4 (CH3CO), 145.7 (q, JCF = 33 Hz, F3C(NH2)C=C), 120.2 (q, JCF
=
5
276 Hz, CF3), 112.8 (F3C(NH2)C=C), 32.2 (q, JCF = 4 Hz, CH3CO cis to
CF3), 29.2 ppm (CH3CO); 19F{1H} NMR (376 MHz, CDCl3): δ = -66.4 ppm.
All data were in agreement with literature values.[34]
6
6.17 (br s, 1H, NH), 2.26 ppm (q, JHF = 2.1 Hz, 3H, CH3CO); 13C NMR
2
(75 MHz, CDCl3): δ = 196.3 (CH3CO), 169.8 (CONH2), 156.7 (q, JCF
=
(Z)-4-Amino-5,5,5-trifluoropent-3-en-2-one (10): Using an adapted
procedure,[34] 8 (2.54 g, 13.02 mmol) was dissolved in EtOH (10 mL) and
a saturated solution of K2CO3 (20 mL) was added. The reaction was
stirred at 50 oC for 24 h. The reaction mixture was then extracted with
CHCl3 (3 x 10 mL), washed with brine (1 x 10 mL), dried over MgSO4,
filtered and evaporated in vacuo. The crude mixture was purified by flash
column chromatography (1:4, EtOAc/n-hexane) to give 10 as an orange
34.6 Hz, F3C(NH)C=C), 131.8 (B-Ar(o)), 127.5 (B-Ar(m)), 127.0 (B-Ar(p)),
1
119.4 (q, JCF = 280.0 Hz, CF3), 97.2 (F3C(NH)C=C), 30.5 ppm (q, 5JCF
=
5.5 Hz, CH3CO), B-Ar(i) quaternary signal not observed; 11B{1H} NMR
(128 MHz, CDCl3): δ = 2.55 ppm; 19F{1H} NMR (376 MHz, CDCl3):
δ = -65.1 ppm; MS(ES-) (m/z): 227.0 [M-(BPh2)-H, 50%]-, 359.1 [M-H,
100%]-, 523.3 [M+BPh2-H, 60%]-; MS(ES+) (m/z): 219.0 [M-BPh2+Na,
50%]+, 399.1 [M+K, 60%]+, 219.0 [M+BPh2+Na, 40%]+, 563.2
7
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10.1002/cmdc.201700731
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[M+BPh2+K, 100%]+; HRMS(ES+) (m/z): [M+H]+ calcd. for
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C18H1711BF3N2O2, 361.1330; found, 361.1338, error: 2.3 ppm.
Biology
Cell Culture
Immortalized murine bone marrow-derived macrophages (iBMDMs) were
cultured in DMEM, 10% fetal bovine serum (FBS), 100ꢀU/ml penicillin and
100ꢀμg/ml streptomycin (PenStrep). Cells were seeded overnight at
0.75 x 106 cells/ml and then stimulated with LPS (E.coli O26:B6, 1 µg/ml,
4 h), and then incubated with vehicle (0.5% DMSO) or drug as indicated
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60 min). IL-1β release was measured by a specific ELISA (R&D systems).
[15]
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[17]
Data presentation and statistical analysis
Data are presented as mean values+standard error of the mean (s.e.m)
of at least three separate experiments. Statistical analyses performed
were one-way analysis of variance (ANOVA) with Dunnett’s multiple
comparisons test post hoc. Accepted levels of significance were *P<0.05,
***P<0.001. Statistical analyses were carried out using GraphPad Prism.
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Acknowledgements
We thank the Mass Spectroscopy Service in the School of
Chemistry, University of Manchester. A.G.B. is funded by the
Division of Pharmacy and Optometry, University of Manchester
and the Presidential Doctoral Scholar award. T.S. is funded by
the Alzheimer’s Society (AS-PhD-16-002). V.S.T. is funded by
CONICYT (Doctorado Becas Chile 72170488) and J.A.B is
funded by a MRC Doctoral Training Fellowship.
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J. R. Hill, R. C. Coll, N. Sue, J. C. Reid, J. Dou, C. L.
Holley, R. Pelingon, J. B. Dickinson, T. J. Biden, K.
Schroder, M. A. Cooper, A. A. B. Robertson,
ChemMedChem 2017, 12, 1449-1457.
a) L. O’Neill, R. Coll, M. Cooper, A. Robertson, K.
Schroder, (The University of Queensland, Brisbane,
Australia, and The Provost, Fellows, Foundation Scholars,
and The Other Members of Board, of The College of The
Holy and Undivided Trinity of Queen Elizabeth near Dublin,
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Keywords: Inflammation • NLRP3 inflammasome • Oxazaborine
• Boron • SAR
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Entry for the Table of Contents
NLRP3 is a central regulator of sterile inflammation and its overactivation contributes to the progression of several important diseases,
thus representing a therapeutic target for the treatment of sterile inflammatory disease. SAR analysis of a series of oxazaborine small
molecules that inhibit NLRP3-dependent IL-1β release are reported, the results of which will aid the development of this new class of
boron-based NLRP3 inflammasome inhibitors.
10
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