Synthesis of multi-substituted pyridines from ylidenemalononitriles and their emission properties

Article abstract of DOI:10.1039/d0ob02591g

Numerous methodologies to obtain pyridines from ylidenemalononitriles are described in the literature. Nevertheless, they are limited to the use of microwave or conventional heat and few lead to 2,3,4 or 2,3,4,5-substituted pyridines as multi-proposal molecular scaffolds or evenuniversal pyridines. Herein, we present a mild and facile solvent-free methodology to obtain a scope of multi-substituted pyridines at room temperature. We also report an example where one of the resulting amino-nicotinonitriles exhibits a preliminary evidence of aggregation-induced emission (AIE).

Full text of DOI:10.1039/d0ob02591g

Organic &
Biomolecular Chemistry
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Synthesis of multi-substituted pyridines from
ylidenemalononitriles and their emission
properties†
Cite this: Org. Biomol. Chem., 2021,
19, 1991
c
Juliana M. de Souza,a,b Irini Abdiaj,a Jiaqi Chen,c Kenneth Hanson,
Kleber T. de Oliveira *b and D. Tyler McQuade*a
Numerous methodologies to obtain pyridines from ylidenemalononitriles are described in the literature.
Nevertheless, they are limited to the use of microwave or conventional heat and few lead to 2,3,4 or
2,3,4,5-substituted pyridines as multi-proposal molecular scaffolds or even universal pyridines. Herein, we
present a mild and facile solvent-free methodology to obtain a scope of multi-substituted pyridines at
room temperature. We also report an example where one of the resulting amino-nicotinonitriles exhibits
a preliminary evidence of aggregation-induced emission (AIE).
Received 29th December 2020,
Accepted 8th February 2021
DOI: 10.1039/d0ob02591g
rsc.li/obc
plated this unexpected result, we observed several reaction
conditions differences in the methodologies available in the
Introduction
Pyridine moieties play a key role in many bioactive substances, literature compared to the one used by our group; among
being nicotinonitriles common precursors in the synthesis of them, the employment of microwave/heat, long reaction times,
pyridine containing active pharmaceutical ingredients (APIs) and/or substrates containing different substituents.
such as nevirapine.1,2 In particular, amino-nicotinonitriles
We hypothesized that the fluorescent amidine which we
(3-cyano-2-aminopyridines) are very common, and two general observed when YMs were reacted with primary amines might
approaches are used to produce 3-cyano-2-aminopyridines: (1) be an intermediate on the reaction coordinate leading to the
methods that modify 3-cyano-2-halopyridines3 and (2) amino-nicotinonitrile. Our hypothesis was supported by
methods that build the pyridine from an acyclic precursor.4–6 experiments we performed using substrates such as those
Relevant examples are featured in Scheme 1 where acyclic pre- shown in Scheme 2B.8 Herein, we present these results in
cursors react to produce a variety of cyclic derivatives. detail showing examples with varying rates of transition from
Although numerous methodologies are available, few lead to the cyclic amidine to aminopyridine forms. Moreover, we
2,3,4 or 2,3,4,5-substituted pyridines, substitution patterns examine the scope for producing multi-substituted pyridines
that are prevalent in many pyridine containing species (i.e. universal pyridines) and provide one example where the
(Scheme 2B).
product exhibits preliminary evidence of aggregation-induced
Our group has explored ylidenemalononitriles (YMs) chem- emission (AIE), a peculiarity that can have its optoelectronic
istry for almost a decade.7 Our attempts to obtain amino-nico- and biological applications further explored.9
tinonitriles from YM substrates were unsuccessful6c as com-
bining primary amines and YMs under mild conditions only
yielded cyclic amidines (III) (Scheme 2A). When we contem-
Results and discussion
In our previous study,8 we showed that the reaction of sulfenyl
aDepartment of Chemical and Life Science Engineering, Virginia Commonwealth
University, Richmond, VA, 23284-3068, USA. E-mail: tylermcquade@gmail.com
chlorides (RSCl) and YMs (I) follows a pattern similar to enam-
ines where an addition followed by elimination provides a
regioselective β-substitution (Scheme 2A). We performed the
reaction of 17 different YMs (I) with sulfur electrophiles (RSCl)
and then cyclized the substituted YMs (II) with primary
amines in a click-like reaction to yield III. The resulting pro-
ducts were green or yellow fluorescent cyclic-amidines
(Scheme 2A).
bDepartamento de Química, Universidade Federal de São Carlos, São Carlos,
SP13565-905, Brazil. E-mail: kleber.oliveira@ufscar.br
cDepartment of Chemistry & Biochemistry, Florida State University, Tallahassee,
Florida 32306, USA
†Electronic supplementary information (ESI) available: Full characterizations
including NMR spectra, X-ray analysis, and photophysical studies. CCDC
1999801, 1999805, 1999806, 1999808, 1999809, 1999810 for 3, 35, 37, 33, 13 and
30 respectively. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/d0ob02591g
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We observed a different outcome when 1 reacted with an
excess of benzylamine (Scheme 4). In this case, the highly sub-
stituted YM produced the expected amidine 2, but as an
unstable intermediate that converted to amino-pyridine 3
reasonably fast (<2 h). Initially, we observed the formation of a
product that exhibited yellow fluorescence (2) and the emis-
sion spectra transitioned from yellow to blue (visual inspection
using 365 nm illumination). Monitoring the reaction by TLC
revealed that 2 transitioned to a single less polar product and
LC/MS analysis confirmed that the new product had the same
molecular mass as the amidine 2.
When monitored by 1H NMR the cyclic amidine chemical
shift for the C–H ring hydrogen shifted from 7.5 ppm to
8.3 ppm, a shift consistent with a pyridine (see ESI – Fig. S1†).
Furthermore, we were able to isolate this new product and
grow needle-shaped yellow crystals. X-ray crystallographic ana-
lysis of 3 confirmed that the new blue fluorescent species was
the amino-nicotinonitrile as suggested by the 1H NMR (see ESI
– Fig. S15†).
We propose that 2 yields 3 via a Dimroth rearrangement as
described by Odom and co-workers to similar amidine inter-
mediates.4k They proposed the amidine rearrangement occurs
in the presence of a DBU/phenol system. In our case, we
propose that benzylamine serves as both a base and proton
donor. Briefly, BnNH2 reacts with 2 and undergoes a ring-
opening followed by a 6-endo-trig cyclization step and benzyla-
mine elimination (Scheme 3).
As discussed before, not all amidines promptly transition-
ing to the amino-pyridine form and this observation encour-
aged us to determine what structural features favor the
Dimroth rearrangement. Subsequently, a series of YMs with
different substitution patterns was exposed to benzylamine (or
propylamine) in excess and the rate of conversion to the pyri-
dine was measured (formation of the amidine tends to be
from minutes to hours). We varied the substituents at R1 and
R2 because these two positions show the greatest impact on
controlling the rate of the Dimroth rearrangement. YMs pos-
sessing R1 = aryl and R2 = S-aryl (Scheme 4A), R1 = alkyl and R2
= S-aryl (Scheme 4B) and finally, R2 = H, Cl, Ph (Scheme 4C)
Scheme 1 Main methodologies described in the literature to produce
3-cyano-2-aminopyridines.
Scheme 2 A) Developed methodology for efficient functionalization of
YMs R2 position; (B) Facile synthesis of highly substituted pyridines from
YMs.
Scheme 3 The proposed mechanism to amino-pyridines formation –
Dimroth rearrangement mechanism.
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Scheme 4 Amino-pyridines obtained from YMs with varying R1 and R2 groups.
are shown as follows. Compounds 1, 4–9, 16, 18, and 20 react
We suggest that large groups in R1 and R2 produced allylic-
in a matter of 1–2 h to produce the corresponding amino-pyri- strains compared to small groups and that strain raises the
dines (Scheme 4A). Nevertheless, the substrates which are ground state of the cyclic amidine and increases the rate of
shown in Scheme 4B and C are slowly converted (cyclization/ addition of the benzylamine. Steric considerations are not the
aromatization).
only features that change the Dimroth rate. Electron withdraw-
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ing groups increase the rate as demonstrated by 33, 37, and 43 pyridyl core. This orthogonality reduces electronic communi-
(2–3 days versus 5–7 days). cation between the nitroaryl group and the fluorophore core,
Teasing out the mechanism for why each substrate in which could slow PET, resulting in emission in the solid-state.
Scheme 4 is faster or slower is difficult but we are confident In solution, there is greater rotational freedom and more favor-
that large groups in R1 and R2 increase the rate. Additionally, able electronic coupling resulting in PET quenching. In con-
attempts to perform the reaction with secondary amines were trast, for 29 where the 4-nitrothiophenol substituent cannot be
done, but with no success in the presented reaction orthogonal to the pyridyl core, PET quenching could still be
conditions.
active in the solid-state. Alternatively, the crystal of 13 may
We propose that these results are significant for three main inhibit non-radiative decay through the restriction of intra-
reasons: (1) YMs reacting with primary amines are a useful molecular rotation (RIR).9 However, if that is the case, it is not
turn-on fluorescent probe7c and understanding the design clear why RIR would not enhance the emission of 29 in the
principles that control the stability of the cyclic amidine vs. solid-state, nor why 13 is emissive in solution when a similar
formation of the pyridine will aid those who wish to exploit rotational deactivation mechanism would be active. It is worth
that application; (2) compounds in Scheme 4A and B are a rela- noting that in the crystal structure of 13 there is a hydrogen
tively rare class of amino-pyridine where the 5-position con- bond interaction between the amino group (NH) and nitrile
tains a sulfur substituent being an effective scope demon- (CN) forming a dimer and a π-stacking interaction between
stration; (3) members of this class of pyridines may have rele- aryl groups R1 and R2, which can support the inhibited
vant photophysical properties such as aggregation-induced rotation (Fig. 1).
emission.
It is unclear what role, if any, excited-state proton transfer
For further characterization of the new pyridine derivatives, may play in the unusual phase-dependent photophysics of 13.
we measured the photophysical properties for a cross-section To gain further insights into the photophysics of 13, we per-
of molecules in Scheme 4 and the data are presented in formed solvent dependent emission measurements (see ESI –
Table 1. In DCM, these compounds exhibit similar blue emis- Fig. S3†). Compound 13 is non-emissive in polar solvents (i.e.
sion (460–487 nm), excited-state lifetimes (2.6–3.1 ns), and EtOH, EtOAc, MeCN, DCM), but exhibited yellow-green emis-
fluorescence quantum yields (0.07–0.16) indicating that the sion in non-polar solvents (i.e. mesitylene, toluene, pentane,
photophysical properties are primarily dominated by the pyri- and hexanes). Interestingly, while the concentrations were
dine core with minimal influence from the aryl substituents similar, the solubility of 13 decreases from polar to non-polar
(i.e. Cl, OMe, H).
solvents with the obvious particulate formation in pentane
Additionally, compounds also exhibit a large Stokes shift and hexanes. The addition of EtOAc to the non-polar solutions
(∼6500 cm−1) that is similar to the cyclic amidine analogs.8 resulted in the disappearance of insoluble particles and a com-
Despite having a similar structure to those in Table 1, com- plete loss of fluorescence (see ESI – Fig. S3D†). The decreased
pound 13 (highlighted in grey in Scheme 4) was non-emissive solubility and increased emission in non-polar solvents
in DCM. It is common for nitroaromatics to quench the emis- further support an AIE mechanism. NMR experiments were
sion via a photoinduced electron transfer (PET).10
also carried out using a 25 mM solution of 13 in a deuterated
Given that nitroaromatic containing compound 29 was also solvent. Different samples were prepared where the ratio of
non-emissive, a similar mechanism may be active here. CDCl3 : toluene-d8 was varied from 100 : 0 to 0 : 100. An
Remarkably, in contrast to in solution, crystals of 13 exhibit increase in the fraction of the non-polar solvent resulted in an
yellow-green emission (see ESI – Fig. S2†). The lack of emission upfield chemical shift (Δδ = 0.4 ppm) for the hydrogen in the
in dilute solution and strong fluorescence in the solid-state is amino group (NH) (see ESI – Fig. S4†). This observation
typically described as aggregation-induced emission (AIE).11
From the X-ray crystal structure of 13 (see ESI – Fig. S16†),
the nitrobenzene group is nearly perpendicular (79°) to the
Table 1 Photophysical properties of 3, 10, 11, and 17 in DCM in
ambient conditions (∼10 μM)
Emission at rta
Absorbance
λmax
τ
kr (×107
(ns) ΦPL s−1 b
knr (×108
s−1 c
Compound λ (nm)
(nm)
)
)
3
358
354
358
360
474
460
486
487
3.0
3.1
2.6
3.0
0.09 3.0
0.16 5.2
0.07 2.8
0.08 2.5
3.0
2.7
3.6
3.1
10
11
17
Fig. 1 X-ray crystal structure of 13. (A) Hydrogen bond interaction
between amino group (NH) and nitrile (CN) groups are depicted with a
dashed red line. (B) π-Stacking interaction between aryl groups R1 and
R2.
a Emission data acquired using dilute solutions and lifetimes calcu-
lated from monoexponential fits. b kr = Φ/τ. c knr = (1 − Φ)/τ.
1994 | Org. Biomol. Chem., 2021, 19, 1991–1999
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reinforces the idea of aggregates formation and the chemical yellow-green fluorescence at the solid-state and when solubil-
shift is due to the prevalence of the hydrogen bonds in ized in non-polar solvents. Analysis of 13 in different solvents
toluene-d8.
and their emissions in different non-polar solvent concen-
For more quantitative insights into the solvent dependent trations, preliminarily support a molecule with AIE properties,
photophysics, we measured emission spectra for 13 in ratios of being 13 a promising compound for future studies and appli-
toluene : DCM ranging from 100 : 0 (100%) to 70 : 30 (70%) (see cations in optics, electronics, energy, and biosciences.
ESI – Fig. S12†). With a solution of <70% toluene, minimal
emission was observed. In contrast, from 70% to 90% toluene,
there was a subtle blue shift in emission from 610 to 605 nm
and a linear increase in emission intensity (see ESI –
Fig. S13†). At >90% toluene, there was an increase in intensity
Experimental section
General information
and a further blueshift to 570 nm. These results are consistent All commercially available reagents were purchased from Acros
with the above observations (i.e. increased aggregation and Organics, Sigma-Aldrich, TCI, or Alfa Aesar and used as
enhanced emission in non-polar solvents) further supporting received. Thin layered chromatography (TLC) was performed
an AIE mechanism. In this case, the AIE is likely accompanied using silica gel 60 F254 plates. Hydrogen nuclear magnetic
by polarity dependent solvatochromism.
resonance (1H NMR) spectra and carbon nuclear magnetic
While these observations are intriguing, we are yet to defini- resonance (13C NMR) spectra were recorded on a Bruker-
tively establish the mechanism of AIE in 13. Possible mecha- 600 MHz. Chemical shifts for protons are reported in parts per
nisms include RIR,12 restricted access to the dark state million downfield from tetramethylsilane. Chemical shifts for
(RADS),13 inhibited excited-state proton transfer,14 or as carbon are reported in parts per million (ppm) downfield from
suggested above, solid-state inhibition of PET. The latter is par- tetramethylsilane or referenced to residual solvent. Data are
ticularly intriguing in that, as far as we know, this would be represented as follows: chemical shift, multiplicity (br = broad,
the first example of AIE via inhibited PET. Ultrafast transient s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet,
absorption studies would be necessary to definitively establish sextet = sext, heptet = hept, octet = oct, dd = doublet of doub-
an AIE mechanism.
lets, dt = doublet of triplets, m = multiplet), coupling constants
It is important to acknowledge that the emission quantum in hertz (Hz), integration. HPLC chromatographs were
yield of these dyes (∼10%) is well below many commercially acquired either on an Agilent 1260 Infinity system using an
available probes used in fluorescent labeling and microscopy. Agilent Poroshell 120 EC-C18 column (2.7 μm, 4.6 mm ×
However, it is worth mentioning that no efforts have yet been 50 mm) applying a gradient of 5% ACN in H2O to 95% ACN in
made to optimize their photophysical properties which could H2O from 0.5 min to 6.5 min at a flow rate of 1.5 mL min−1
.
no doubt be improved with known fluorophore design strat- High-resolution mass spectra were obtained through the
egies (i.e. increased rigidity, inhibited deactivation modes, Virginia Commonwealth University Chemical and Proteomic
etc.). Regardless, this class of dyes exhibits a unique combi- Mass Spectrometry Core Facility using a Orbitrap Velos mass
nation of (1) readily tunable emission, (2) turn-on fluorescence spectrometer from Thermo Electron Corporation. For the
in the presents of primary amines, (3) high solvent sensitivity, crystal structure determination, single crystals were mounted
and in some cases (4) aggregate induced emission. This amal- on a MiTeGen Microloop and used for data collection on a
gamation of properties and stimuli responsiveness could open XtaLAB MM007-HF system (Cu Kα radiation, λ = 1.54184 Å)
door to a plethora of multiparameter sensing opportunities coupled with a Hybrid Photon Counting detector (Dectris
and applications including chiral recognition, ionic sensing, Eiger 4M). CrysAlis PRO software (Rigaku OD, 2015)16 was
biomolecule detection, and cell imaging.15
used for data collection, data processing, cell refinement, and
data reduction. The structures were solved with ShelXTL17
using Intrinsic Phasing and refined with the olex2-refine18
refinement package using Gauss–Newton minimization. H
atom positions were calculated geometrically and refined
Conclusions
In conclusion, we presented a solvent-free methodology devel- using a rigid model. The final difference Fourier maps showed
oped under mild conditions to obtain a scope of multi-substi- no peaks of chemical significance. The names of all com-
tuted pyridines from YMs. We demonstrated that the cycliza- pounds were generated using the PerkinElmer ChemDraw
tion time can be considerably reduced from days to hours by Ultra v.12.0.2 software package.
varying the YMs substituents. Such feature is especially
General procedure – synthesis of multi-substituted pyri-
observed in substrates possessing large steric groups in the R1 dines. 1 mmol of the enamine (1, 4–9, 16, 18, 20, 22–26, 32,
and R2 positions. Not only the stability/reactivity of the YMs 34, 36, 38–40) was dissolved in 2 mL of primary amine (ben-
can be tuned by varying the YM substituents, but also the fluo- zylamine or propylamine) at room temperature. The reaction
rescence λmax of the cyclic amidine intermediate, as discussed was left stirring vigorously until all the enamine was entirely
in our previous work.8 Photophysics studies showed that most consumed and a blue fluorescent spot was observed by TLC
of the amino-pyridines obtained in this present study exhibit when irradiated with a 254 nm UV-lamp. The reaction mixture
blue emission. Even so, amino-nicotinonitrile 13 presented was concentrated under vacuum in the rotatory evaporator and
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the product (3, 10–15, 17, 19, 21, 27–31, 33, 35, 37, 41–43) was (ESI-FTMS) m/z: [M + H]+ calcd for C27H24N3O2S 454.1589;
purified by column chromatography in EtOAc/hexanes. All found 454.1591.
enamines (1, 4–9, 16, 18, 20, 22–26, 32, 34, 36, 38–40) used in
5-((4-Methoxyphenyl)thio)-4-(4-nitrophenyl)-2-(propylamino)
this work to obtain the final aminopyridines were already nicotinonitrile (13). It was prepared following the general pro-
described in our previous publication. Their detailed experi- cedure. Purification by flash chromatography EtOAc/hexanes
mental procedures and full characterization are available.8
from 0 : 100 to 20 : 80 afforded the desired product in 84%
2-(Benzylamino)-5-((4-methoxyphenyl)thio)-4-phenylnicotino- yield (352 mg, 0.84 mmol). 1H NMR (600 MHz, CDCl3): δH 8.45
nitrile (3). It was prepared following the general procedure. (s, 1H), 8.27 (d, J = 7.7 Hz, 2H), 7.39 (d, J = 7.7 Hz, 2H), 6.92 (d,
Purification by flash chromatography EtOAc/hexanes from J = 7.9 Hz, 2H), 6.72 (d, J = 7.9 Hz, 2H), 5.43 (t, J = 4.8 Hz, 1H),
0 : 100 to 20 : 80 afforded the desired product in 91% yield 3.76 (s, 3H), 3.53 (q, J = 6.6 Hz, 2H), 1.70 (sext, J = 7.3 Hz, 2H),
1
(385 mg, 0.91 mmol). H NMR (600 MHz, CDCl3): δH 8.27 (s, 1.02 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (150 MHz, CDCl3): δC
1H), 7.38–7.34 (m, 3H), 7.32–7.28 (m, 4H), 7.27–7.21 (m, 1H), 159.2, 158.4, 157.8, 154.8, 148.1, 141.9, 132.1, 129.8, 126.0,
7.20–7.17 (m, 2H), 6.93 (d, J = 8.6 Hz, 2H), 6.65 (d, J = 8.6 Hz, 123.5, 118.0, 115.4, 114.8, 92.0, 55.4, 43.5, 22.6, 11.3. HRMS
2H), 5.56 (t, J = 5.5 Hz, 1H), 4.65 (d, J = 5.5 Hz, 2H), 3.68 (s, (ESI-FTMS) m/z: [M + H]+ calcd for C22H21N4O3S 421.1334;
3H). 13C{1H} NMR (150 MHz, CDCl3): δC 159.2, 158.0, 156.7, found 421.1336. X-ray available (Fig. S16†).
156.6, 138.1, 135.4, 132.9, 129.3, 128.8, 128.6, 128.3, 127.8,
2-(Benzylamino)-4-(4-chlorophenyl)-5-((2,2,2-trifluoroethyl)
127.7, 126.1, 119.9, 115.9, 114.7, 92.9, 55.3, 45.5. HRMS thio) nicotinonitrile (14). It was prepared following the
(ESI-FTMS) m/z: [M + H]+ calcd for C26H22N3OS 424.1483; general procedure. Purification by flash chromatography
found 424.1481. X-ray available (Fig. S15†).
EtOAc/hexanes from 0 : 100 to 20 : 80 afforded the desired
2-(Benzylamino)-4-phenyl-5-(phenylthio)nicotinonitrile (10). product in 88% yield (381 mg, 0.88 mmol). 1H NMR (600 MHz,
It was prepared following the general procedure. Purification CDCl3): δH 8.58 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.41–7.36 (m,
by flash chromatography EtOAc/hexanes from 0 : 100 to 20 : 80 4H), 7.36–7.30 (m, 3H), 5.77 (t, J = 5.5 Hz, 1H), 4.78 (d, J = 5.5
afforded the desired product in 83% yield (326 mg, Hz, 2H), 2.86 (q, J = 9.5 Hz, 2H). 19F{1H} NMR (565 MHz,
0.83 mmol). 1H NMR (600 MHz, CDCl3): δH 8.49 (s, 1H), CDCl3): δF −65.71. 13C{1H} NMR (150 MHz, CDCl3): δC 159.1,
7.44–7.38 (m, 7H), 7.35–7.31 (m, 1H), 7.26–7.23 (m, 2H), 158.7, 157.2, 139.3, 137.7, 136.0, 133.4, 130.2, 128.9, 128.8,
7.20–7.16 (m, 2H), 7.16–7.11 (m, 1H), 7.00 (d, J = 7.52 Hz, 2H), 127.8, 127.8, 127.8, 125.9, 124.1, 115.4, 115.1, 114.1, 92.8, 45.6,
5.73 (t, J = 5.5 Hz, 1H), 4.77 (d, J = 5.5 Hz, 2H). 13C{1H} NMR 38.2 (q, J = 32.1 Hz), 33.8, 31.9, 31.6, 29.7, 29.7, 29.6, 29.6,
(150 MHz, CDCl3): δC 158.6, 158.5, 158.3, 137.9, 137.1, 135.4, 29.5, 29.3, 29.1, 28.9, 22.7. HRMS (ESI-FTMS) m/z: [M + H]+
129.3, 128.9, 128.8, 128.8, 128.7, 128.5, 128.2, 127.8, 127.7, calcd for C21H16ClF3N3S 434.0706; found 434.0681.
126.3, 117.2, 115.8, 93.1, 45.6. HRMS (ESI-FTMS) m/z: [M + H]+
2-(Benzylamino)-4-(4-chlorophenyl)-5-(decylthio)nicotinoni-
calcd for C25H20N3S 394.1378; found 394.1379.
trile (15). It was prepared following the general procedure.
2-(Benzylamino)-4-(4-chlorophenyl)-5-((4-methoxyphenyl)thio) Purification by flash chromatography EtOAc/hexanes from
nicotinonitrile (11). It was prepared following the general pro- 0 : 100 to 20 : 80 afforded the desired product in 97% yield
1
cedure. Purification by flash chromatography EtOAc/hexanes (475 mg, 0.97 mmol). H NMR (600 MHz, CDCl3): δH 8.47 (s,
from 0 : 100 to 20 : 80 afforded the desired product in 89% 1H), 7.50–7.47 (m, 2H), 7.40–7.36 (m, 4H), 7.36–7.30 (m, 3H),
yield (406 mg, 0.89 mmol). 1H NMR (600 MHz, CDCl3): δH 8.39 5.65 (t, J = 5.5 Hz, 1H), 4.76 (d, J = 5.5 Hz, 2H), 2.43 (t, J = 7.1
(s, 1H), 7.43–7.39 (m, 2H), 7.39–7.35 (m, 4H), 7.35–7.30 (m, Hz, 2H), 1.39–1.12 (m, 20H), 0.90 (t, J = 7.1 Hz, 3H). 13C{1H}
1H), 7.22–7.19 (m, 2H), 7.02–6.99 (m, 2H), 6.77–6.73 (m, 2H), NMR (150 MHz, CDCl3): δC 158.0, 157.2, 156.1, 138.0, 135.6,
5.68 (t, J = 5.5 Hz, 1H), 4.75 (d, J = 5.5 Hz, 2H), 3.78 (s, 3H). 13
C
134.0, 130.3, 128.8, 128.7, 127.8, 127.7, 118.4, 115.9, 92.5, 45.5,
{1H} NMR (150 MHz, CDCl3): δC 159.2, 158.0, 156.9, 155.6, 36.1, 31.9, 29.6, 29.5, 29.4, 29.3, 29.0, 28.9, 28.4, 22.7, 14.1.
138.0, 135.5, 133.8, 132.7, 130.1, 129.7, 128.9, 128.8, 128.7, HRMS (ESI-FTMS) m/z: [M + H]+ calcd for C31H39ClN3S
128.6, 128.3, 127.8, 127.7, 125.9, 119.6, 115.7, 114.8, 92.7, 55.4, 520.2555; found 520.2556.
45.5. HRMS (ESI-FTMS) m/z: [M + H]+ calcd for C26H21ClN3OS
458.1094; found 458.1090.
2′-(Benzylamino)-5′-((4-methoxyphenyl)thio)-[3,4′-bipyridine]-
3′-carbonitrile (17). It was prepared following the general pro-
2-(Benzylamino)-4-(4-methoxyphenyl)-5-((4-methoxyphenyl) cedure. Purification by flash chromatography EtOAc/hexanes
thio) nicotinonitrile (12). It was prepared following the from 0 : 100 to 20 : 80 afforded the desired product in 70%
general procedure. Purification by flash chromatography yield (296 mg, 0.70 mmol). 1H NMR (600 MHz, CDCl3): δH 8.68
EtOAc/hexanes from 0 : 100 to 20 : 80 afforded the desired (dd, J = 4.9, 1.7 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.47 (s, 1H),
product in 85% yield (385 mg, 0.85 mmol). 1H NMR (600 MHz, 7.58 (dt, J = 7.9, 2.0 Hz, 1H), 7.40–7.29 (m, 6H), 6.95 (d, J = 8.8
CDCl3): δH 8.23 (s, 1H), 7.31–7.15 (m, 7H), 6.97 (d, J = 8.8 Hz, Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 5.80 (t, J = 5.5 Hz, 1H), 4.76
2H), 6.89 (d, J = 8.6 Hz, 2H), 6.68 (d, J = 8.8 Hz, 2H), 5.54 (t, J = (d, J = 5.5 Hz, 2H), 3.75 (s, 3H). 13C{1H} NMR (150 MHz,
5.5 Hz, 1H), 4.65 (d, J = 5.5 Hz, 2H), 3.78 (s, 3H), 3.69 (s, 3H). CDCl3): δC 159.1, 158.1, 157.4, 153.4, 150.2, 149.0, 137.8, 136.1,
13C{1H} NMR (150 MHz, CDCl3): δC 162.0, 160.4, 159.2, 158.1, 132.3, 131.5, 128.7, 127.8, 127.6, 125.8, 122.8, 119.5, 115.4,
156.5, 156.3, 138.1, 132.8, 130.3, 128.8, 127.8, 127.6, 127.6, 114.7, 92.8, 55.3, 45.5. HRMS (ESI-FTMS) m/z: [M + H]+ calcd
126.2, 120.0, 116.3, 114.7, 113.7, 92.9, 55.3, 45.5. HRMS for C25H21N4OS 425.1436; found 425.1437.
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1
2-(Benzylamino)-5-((4-methoxyphenyl)thio)-4-(quinolin-3-yl) (372.7 mg, 0.99 mmol). H NMR (600 MHz, CDCl3): δH 8.42 (s,
nicotinonitrile (19). It was prepared following the general pro- 1H), 8.11 (d, J = 8.8 Hz, 2H), 7.42–7.32 (m, 5H), 7.09 (d, J = 8.8
cedure. Purification by flash chromatography EtOAc/hexanes Hz, 2H), 5.78 (t, J = 5.5 Hz, 1H), 4.78 (d, J = 5.5 Hz, 2H), 2.49 (s,
from 0 : 100 to 20 : 80 afforded the desired product in 67% 3H). 13C{1H} NMR (150 MHz, CDCl3): δC 159.4, 159.2, 157.3,
yield (317 mg, 0.67 mmol). 1H NMR (600 MHz, CDCl3): δH 8.73 147.3, 145.5, 137.7, 128.9, 128.8, 127.7, 125.3, 124.3, 115.3,
(s, 1H), 8.37 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.85 (d, J = 1.8 Hz, 113.3, 93.9, 45.5, 19.4. HRMS (ESI-FTMS) m/z: [M + H]+ calcd
1H), 7.65–7.60 (m, 2H), 7.45–7.40 (m, 1H), 7.24–7.17 (m, 4H), for C20H17N4O2S 377.1072; found 377.1069.
7.16–7.11 (m, 1H), 6.76 (d, J = 8.6 Hz, 2H), 6.46 (d, J = 8.6 Hz,
2-(Benzylamino)-4-methyl-5-((2,2,2-trifluoroethyl)thio) nico-
2H), 5.84–5.75 (m, 1H), 4.61 (d, J = 5.5 Hz, 2H), 3.51 (d, J = 2.6 tinonitrile (30). It was prepared following the general pro-
Hz, 3H). 13C{1H} NMR (150 MHz, CDCl3): δC 158.9, 158.1, cedure. Purification by flash chromatography EtOAc/hexanes
157.3, 153.4, 149.1, 147.6, 137.8, 136.1, 132.2, 130.3, 129.1, from 0 : 100 to 20 : 80 afforded the desired product in 72%
128.6, 128.5, 128.5, 128.0, 127.6, 127.4, 127.4, 126.9, 126.7, yield (242.9 mg, 0.72 mmol). 1H NMR (600 MHz, CDCl3): δH
125.7, 119.5, 119.7, 115.4, 114.5, 92.8, 55.0, 45.2. HRMS 8.45 (s, 1H), 7.39–7.29 (m, 5H), 5.67 (t, J = 5.5 Hz, 1H), 4.73 (d,
(ESI-FTMS) m/z: [M + H]+ calcd for C29H23N4OS 475.1592; J = 5.5 Hz, 2H), 3.19 (q, J = 9.7 Hz, 2H), 2.63 (s, 3H). 19F{1H}
found 475.1594.
NMR (565 MHz, CDCl3): δF −66.1. 13C{1H} NMR (150 MHz,
2-(Benzylamino)-5-((4-methoxyphenyl)thio)-4-(naphthalen-2- CDCl3): δC 159.0, 158.7, 156.7, 137.9, 128.7, 127.7, 127.6, 126.1,
yl) nicotinonitrile (21). It was prepared following the general 124.3, 116.5, 115.6, 93.0, 45.3, 39.0 (q, J = 32.1 Hz), 19.4.
procedure. Purification by flash chromatography EtOAc/ HRMS (ESI-FTMS) m/z: [M + H]+ calcd for C16H15F3N3S
hexanes from 0 : 100 to 20 : 80 afforded the desired product in 338.0939; found 338.0939. X-ray available (Fig. S17†).
94% yield (444 mg, 0.94 mmol). 1H NMR (600 MHz, CDCl3): δH
2-(Benzylamino)-5-(decylthio)-4-methylnicotinonitrile (31). It
8.25 (s, 1H), 7.77–7.72 (m, 2H), 7.67 (d, J = 7.9 Hz, 1H), 7.55 (s, was prepared following the general procedure. Purification by
1H), 7.42–7.35 (m, 2H), 7.25–7.05 (m, 6H), 6.83 (d, J = 8.6 Hz, flash chromatography EtOAc/hexanes from 0 : 100 to 20 : 80
2H), 6.52 (d, J = 8.6 Hz, 2H), 5.59 (t, J = 5.5 Hz, 1H), 4.61 (d, J = afforded the desired product in 53% yield (224.5 mg,
5.5 Hz, 2H), 3.57 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3): δC 0.53 mmol). 1H NMR (600 MHz, CDCl3): δH 8.35 (s, 1H),
159.2, 158.1, 156.6, 143.3, 138.1, 133.4, 132.9, 132.8, 128.8, 7.38–7.28 (m, 5H), 5.52 (t, J = 5.5 Hz, 1H), 4.72 (d, J = 5.5 Hz,
128.7, 128.5, 128.4, 128.2, 128.0, 127.8, 127.7, 127.6, 127.0, 2H), 2.66 (t, J = 7.3 Hz, 2H), 2.60 (s, 3H), 1.53 (quint, J = 7.7 Hz,
126.9, 126.7, 126.4, 126.1, 125.9, 120.1, 116.0, 114.7, 93.1, 55.3, 2H), 1.42–1.24 (m, 18H), 0.90 (t, J = 7.1 Hz, 3H). 13C{1H} NMR
45.5. HRMS (ESI-FTMS) m/z: [M + H]+ calcd for C30H24N3OS (150 MHz, CDCl3): δC 158.1, 157.3, 155.6, 138.2, 128.7, 127.6,
474.1640; found 474.1603.
127.5, 119.3, 116.0, 93.0, 45.2, 36.3, 31.9, 29.6, 29.5, 29.4, 29.3,
2-(Benzylamino)-4-methyl-5-(phenylthio)nicotinonitrile (27). 29.2, 29.1, 28.6, 22.6, 19.5, 14.1. HRMS (ESI-FTMS) m/z: [M +
It was prepared following the general procedure. Purification H]+ calcd for C26H38N3S 424.2788; found 424.2788.
by flash chromatography EtOAc/hexanes from 0 : 100 to 20 : 80
2-(Benzylamino)-5-chloro-4-methylnicotinonitrile (33). It was
afforded the desired product in 93% yield (308.2 mg, prepared following the general procedure. Purification by flash
0.93 mmol). 1H NMR (600 MHz, CDCl3): δH 8.33 (s, 1H), chromatography EtOAc/hexanes from 0 : 100 to 20 : 80 afforded
7.30–7.26 (m, 4H), 7.25–7.20 (m, 1H), 7.19–7.14 (m, 2H), the desired product in 88% yield (226.8 mg, 0.88 mmol). 1H
7.09–7.05 (m, 1H), 7.00–6.96 (m, 2H), 5.56 (t, J = 5.5 Hz, 1H), NMR (600 MHz, CDCl3): δH 8.19 (s, 1H), 7.38–7.28 (m, 5H),
4.66 (d, J = 5.5 Hz, 2H), 2.40 (s, 3H). 13C{1H} NMR (150 MHz, 5.49 (br s, 1H), 4.69 (d, J = 5.7 Hz, 2H), 2.49 (s, 3H). 13C{1H}
CDCl3): δC 158.7, 158.6, 157.0, 138.0, 136.9, 129.1, 128.7, 127.6, NMR (150 MHz, CDCl3): δC 157.2, 150.8, 149.8, 138.2, 128.7,
127.7, 127.6, 126.9, 125.9, 116.5, 115.8, 93.5, 45.4, 19.5. HRMS 127.7, 127.6, 120.1, 115.5, 93.3, 45.4, 18.7. HRMS (ESI-FTMS)
(ESI-FTMS) m/z: [M + H]+ calcd for C20H18N3S 332.1221; found m/z: [M + H]+ calcd for C14H13ClN3 258.0800; found 258.0801.
332.1218.
X-ray available (Fig. S18†).
2-(Benzylamino)-5-((4-methoxyphenyl)thio)-4-methyl nicoti-
2-(Benzylamino)-4,5-diphenylnicotinonitrile (35). It was pre-
nonitrile (28). It was prepared following the general procedure. pared following the general procedure. Purification by flash
Purification by flash chromatography EtOAc/hexanes from chromatography EtOAc/hexanes from 0 : 100 to 20 : 80 afforded
0 : 100 to 20 : 80 afforded the desired product in 85% yield the desired product in 86% yield (310 mg, 0.86 mmol). 1H
1
(307.2 mg, 0.85 mmol). H NMR (600 MHz, CDCl3): δH 8.35 (s, NMR (600 MHz, CDCl3): δH 8.41 (s, 1H), 7.49–7.45 (m, 2H),
1H), 7.39–7.29 (m, 5H), 7.17–7.13 (m, 2H), 6.85–6.81 (m, 2H), 7.44–7.40 (m, 2H), 7.39–7.32 (m, 4H), 7.26–7.21 (m, 5H),
5.56 (t, J = 5.5 Hz, 1H), 4.73 (d, J = 5.5 Hz, 2H), 3.79 (s, 3H), 7.07–7.02 (m, 2H), 5.79 (t, J = 5.5 Hz, 1H), 4.85 (d, J = 5.5 Hz,
2.50 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3): δC 158.8, 158.4, 2H). 13C{1H} NMR (150 MHz, CDCl3): δC 158.0, 153.0, 152.8,
157.3, 155.8, 138.1, 130.8, 128.8, 127.7, 127.6, 126.5, 118.9, 138.4, 136.6, 135.7, 129.5, 129.3, 128.8, 128.7, 128.4, 128.3,
115.9, 114.9, 93.4, 55.4, 45.4, 19.5. HRMS (ESI-FTMS) m/z: [M + 128.1, 127.7, 127.5, 126.8, 126.1, 116.6, 91.9, 45.4. HRMS
H]+ calcd for C21H20N3OS 362.1327; found 362.1326.
(ESI-FTMS) m/z: [M + H]+ calcd for C25H20N3 362.1657; found
2-(Benzylamino)-4-methyl-5-((4-nitrophenyl)thio)nicotinoni- 362.1656. X-ray available (Fig. S19†).
trile (29). It was prepared following the general procedure.
2′-(Benzylamino)-[3,4′-bipyridine]-3′-carbonitrile (37). It was
Purification by flash chromatography EtOAc/hexanes from prepared following the general procedure. Purification by flash
0 : 100 to 20 : 80 afforded the desired product in 99% yield chromatography EtOAc/hexanes from 0 : 100 to 20 : 80 afforded
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the desired product in 96% yield (274 mg, 0.96 mmol).1H oration between M4ALL and the LQBO-UFSCar possible. This
NMR (600 MHz, CDCl3): δH 8.80 (d, J = 2.2 Hz, 1H), 8.73 (d, J = work was partially supported by Structural Biology resources
5.0 Hz, 1H), 8.36 (d, J = 5.1 Hz, 1H), 7.94 (dt, J = 8.0, 2.1 Hz, provided to VCU by the National Institutes of Health – Shared
1H), 7.44 (dd, J = 7.9, 4.8 Hz, 1H), 7.40–7.34 (m, 4H), 7.32–7.28 Instrumentation Grant S10OD021756 (MKS) – and Virginia
(m, 1H), 6.69 (d, J = 5.1 Hz, 1H), 5.81 (t, J = 5.1 Hz, 1H), 4.78 General Assembly Higher Education Equipment Trust Fund
(d, J = 5.7 Hz, 2H). 13C{1H} NMR (150 MHz, CDCl3): δC 159.2, (HEETF).
152.4, 150.8, 150.7, 149.7, 138.2, 135.4, 132.6, 128.7, 127.6,
127.5, 123.4, 116.3, 112.7, 90.0, 45.4. HRMS (ESI-FTMS) m/z:
[M + H]+ calcd for C18H15N4 287.1296; found 287.1292. X-ray
available (Fig. S20†).
Notes and references
2-(Benzylamino)-4-phenylnicotinonitrile (41). It was pre-
pared following the general procedure. Purification by flash
chromatography EtOAc/hexanes from 0 : 100 to 20 : 80 afforded
the desired product in 91% yield (259.7 mg, 0.91 mmol). 1H
NMR (600 MHz, CDCl3): δH 8.33 (d, J = 5.1 Hz, 1H), 7.62–7.58
(m, 2H), 7.55–7.48 (m, 3H), 7.44–7.36 (m, 4H), 7.35–7.30 (m,
1H), 6.72 (d, J = 5.1 Hz, 1H), 5.71 (t, J = 4.8 Hz, 1H), 4.79 (d, J =
5.5 Hz, 2H). 13C{1H} NMR (150 MHz, CDCl3): δC 159.2, 154.4,
152.0, 138.4, 136.7, 129.7, 128.8, 128.7, 128.1, 127.7, 127.5,
116.8, 113.1, 90.1, 45.5. HRMS (ESI-FTMS) m/z: [M + H]+ calcd
for C19H16N3 286.1344; found 286.1343.
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2013, 9, 2570–2578; (b) J. Verghese, C. J. Kong, D. Rivalti,
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2-(Benzylamino)-4-(4-methoxyphenyl)nicotinonitrile (42). It
was prepared following the general procedure. Purification by
flash chromatography EtOAc/hexanes from 0 : 100 to 20 : 80
afforded the desired product in 95% yield (299.6 mg,
1
0.95 mmol). H NMR (600 MHz, CDCl3): δH 8.29 (d, J = 5.3 Hz,
1H), 7.59–7.55 (m, 2H), 7.42–7.35 (m, 4H), 7.34–7.30 (m, 1H),
7.05–7.01 (m, 2H), 6.69 (d, J = 5.3 Hz, 1H), 5.67 (t, J = 5.3 Hz,
1H), 4.78 (d, J = 5.5 Hz, 2H), 3.88 (s, 3H). 13C{1H} NMR
(150 MHz, CDCl3): δC 160.9, 159.3, 154.0, 151.8, 138.5, 129.6,
128.9, 128.7, 127.7, 127.5, 117.2, 114.3, 112.8, 89.7, 55.3, 45.5.
HRMS (ESI-FTMS) m/z: [M + H]+ calcd for C20H18N3O 316.1450;
found 316.1446.
2-(Benzylamino)-4-(4-nitrophenyl)nicotinonitrile (43). It was
prepared following the general procedure. Purification by flash
chromatography EtOAc/hexanes from 0 : 100 to 20 : 80 afforded
the desired product in 99% yield (327.0 mg, 0.99 mmol). 1H
NMR (600 MHz, CDCl3): δH 8.42–8.35 (m, 3H), 7.75 (d, J = 8.6
Hz, 2H), 7.42–7.30 (m, 5H), 6.71 (d, J = 5.1 Hz, 1H), 5.73 (t, J =
5.0 Hz, 1H), 4.79 (d, J = 5.5 Hz, 2H). 13C{1H} NMR (150 MHz,
CDCl3): δC 159.1, 152.7, 151.9, 148.5, 142.9, 138.1, 129.3, 128.8,
127.8, 127.7, 124.1, 116.1, 112.6, 89.8, 45.6. HRMS (ESI-FTMS)
m/z: [M + H]+ calcd for C19H15N4O2 331.1197; found 331.1198.
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Conflicts of interest
The authors declare no competing financial interest.
Acknowledgements
The authors thank VCU and Bill and Melinda Gates
Foundation for supporting the Medicines for All Institute. We
also thank São Paulo Research Foundation (FAPESP/Brazil,
Grant 2018/14555-8 and 2018/00106-7) for making the collab-
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