Identification of the Side Products That Diminish the Yields of the Monoamidated Product in Metal-Catalyzed C-H Amidation of 2-Phenylpyridine with Arylisocyanates

Article abstract of DOI:10.1021/acs.joc.9b02831

The Ru(II)-catalyzed amidation of 2-Arylpyridines with aryl isocyanates via C-H bond activation is less efficient than described previously, due to the formation of a series of side products, which were readily identified using direct infusion electrospray mass spectrometry and high-performance liquid chromatography-mass spectrometry.

Full text of DOI:10.1021/acs.joc.9b02831

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Note
Identification of the Side Products That Diminish the Yields of the
Monoamidated Product in Metal-Catalyzed C−H Amidation of
2‑Phenylpyridine with Arylisocyanates
Alasdair I. McKay, Weam A. O. Altalhi, Lachlan E. McInnes, Milena L. Czyz, Allan J. Canty,
Paul S. Donnelly,* and Richard A. J. O’Hair*
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ABSTRACT: The Ru(II)-catalyzed amidation of 2-arylpyridines with aryl
isocyanates via C−H bond activation is less efficient than described previously,
due to the formation of a series of side products, which were readily identified using
direct infusion electrospray mass spectrometry and high-performance liquid
chromatography−mass spectrometry.
ven the most common and important reactions used in
Scheme 1. Approaches to the Synthesis of Amides via Metal-
Catalyzed “C−H Amidation” of (A) 2-Phenylpyridine15−18
and (B) N-Aryl Benzamide Substrates19
E
organic synthesis suffer from competing side reactions.1,2
Knowledge of such processes is important for the development
of new organic reaction methods, the design of efficient
syntheses, and advancing novel Artificial Intelligence methods
for predicting organic syntheses.3 Unfortunately, many reports
of new organic reaction methods focus on the isolation of the
desired product and pay less emphasis on the identification of
side products and mechanistic information. This is surprising
given the arsenal of modern mass spectrometry (MS) methods
that can rapidly be deployed to analyze crude reaction mixtures
for the presence of side products.4
In view of the exceptional importance of the amide group in
bio-organic and industrial applications,5,6 and our ongoing
studies in amide synthesis,7,8,53 we have explored this as our
first model system for MS studies of side products in metal-
catalyzed synthesis. The development of new efficient reactions
for the selective installation of functional groups, such as
amides, in complex molecules is an area of sustained efforts.5,6
Synthetic approaches that take advantage of transition metal-
catalyzed C−H bond functionalization have attracted consid-
erable interest.9 The functionalization of a C−H bond is
challenging, and often a directing group (DG) is used to
control the regioselectivity of the reaction via formation of a
cyclometalated intermediate.10−14 An example is the formation
of amides by transition metal-catalyzed C−H activation,
followed by the insertion of a substituted isocyanate (Scheme
1). In many of these studies, reaction mixtures are only
analyzed by NMR spectroscopy to optimize yields of products.
In this contribution, we demonstrate the insights provided by
the analysis of catalytic reaction mixtures using MS.
Received: October 17, 2019
https://dx.doi.org/10.1021/acs.joc.9b02831
© XXXX American Chemical Society
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Figure 1. 1H NMR spectrum (a) and 19F NMR spectrum (b) of reaction mixtures obtained upon removal of the solvent during the preparations of
3a and 3c, respectively.
Figure 2. Mass-spectrometry-based profiling of species present in the reaction mixture: (a) direct infusion ESI-HRMS; (b) extracted ion
chromatograms (EICs) derived from LC−MS data. The peak at m/z 182 is a fragment ion arising from an in-source collision-induced dissociation
(CID) of 275.28
We were attracted to the fact that many C−H functionaliza-
tion reactions have a DG that is either a base or an acid, and
thus, any species containing the DG will be readily ionized
during electrospray ionization (ESI), thereby allowing
qualitative20 identification of side products, which due to
both their low concentration and/or the complexity of the
reaction mixture renders them difficult to detect by NMR
spectroscopy. The ready ESI-MS based coidentification of
unreacted starting material, product, and side products1 in
reaction mixtures derived from directed C−H functionalization
reactions not only provides a powerful tool to rapidly screen an
array of additives, solvents, and reaction conditions but also
may offer a greater understanding of the reaction mechanism
and catalyst design, leading to improved procedures. Thus, we
turned our attention to the ruthenium-catalyzed C−H
amidation of 2-phenylpyridine (1) with phenyl isocyanate
(2a) (Scheme 1A).
(87%) was reported previously for the synthesis of 3b.17 The
presence of fluorine in 3c allows analysis of the crude reaction
mixtures by 19F NMR spectroscopy. To further understand the
relatively low isolated yields, the crude reaction mixture used
to prepare 3a was evaporated to dryness and the residue
analyzed by 1H NMR spectroscopy (CDCl3, Figure S12).
Examination of the low field region (δ 8−9 ppm, Figure 1a)
revealed doublets for the product 3a (δ 8.62 ppm, J = 4.6 Hz)
and starting material 1 (δ 8.70 ppm, J = 4.6 Hz) in a ca. 6:1
ratio.22 Surprisingly, five further small sets of doublets (J = 4.6
Hz) were also observed in this region, highlighting the
formation of several pyridyl containing side products. Further
examination of the aromatic region was uninformative due to
1
the numerous overlapping resonances. Similarly, the H NMR
spectra of crude 3b and 3c indicated the presence of several
pyridyl containing side products in moderate quantities
(Figures S13−S14). Likewise, several resonances were
observed in the 19F NMR spectrum as well as that attributed
to 3c (Figure 1b).23
Protonation of 1, 3, and the other pyridyl containing side
products would lead to compounds that are readily ionized
during ESI and permit their detection in the positive ion
mode.4 Analysis of the reaction mixture by direct infusion ESI-
HRMS24 (Figure 2a and Table S1) reveals the presence of [3a
+ H]+ at m/z 275 as the major ion together with an ion at m/z
156 corresponding to [1+H]+, consistent with the analysis by
TLC and the 1H NMR spectrum of the crude reaction mixture.
In our hands, 3a was isolated in a lower yield (42−55%)21
than the reported yield (90%),17 despite multiple attempts.
The isolation of 3a was confirmed by NMR spectroscopy and
analysis by single-crystal X-ray diffraction (Figures S1−S4). In
each instance, incomplete consumption of 1 was observed, as
indicated by TLC of the crude reaction mixture. Reactions
conducted with 4-tolyl isocyanate (2b) and 4-fluorophenyl
isocyanate (2c), maintaining the same stoichiometries, likewise
afforded amides 3b and 3c in moderate isolated yields (50 and
49%, respectively, Figures S5−S11). Notably, a high yield
B
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Scheme 2. Products and Side Products Formed in the C−H Amidation of 1 by 2a, as Indicated by Mass Spectrometry
Scheme 3. Suggested Pathways for the Formation of Products and Side Products in the Ruthenium-Catalyzed C−H Amidation
of 2-Phenylpyridine
Four other ions at m/z 309, 394, 428, and 547 are consistent
with [M + H]+ derived from the formation of 4 by oxidative
homocoupling of 2-phenylpyridine, 5a, a double insertion
product, as well as 6a and 7a formed by homocoupled 2-
phenylpyridine undergoing single or double insertion with the
substituted isocyanate (Scheme 2). In order to confirm that a
series of side products had formed, the crude reaction mixture
was also analyzed by LC−MS. An examination of extracted ion
chromatograms, confirmed the presence of 1 and 3a−7a,
which were readily separated using a gradient of CH3CN/H2O
containing 0.1% formic acid (Figure 2b). Other ions at m/z
213 and 332 provide evidence for the known phenyl isocyanate
decomposition products (Scheme 2), N,N′-diphenyl urea (8a),
and 1,3,5-triphenyl biuret (9a).25,26 Related products and side
products formed in the C−H amidation of 1 by 2b and 2c
were found in the crude reactions mixtures via ESI-HRMS and
LC−MS (Figures S16−S19 and Tables S2−S3).27
The formation of these side products was not reported
previously.17 We note that oxidative homocoupling of 1, to
afford 4, using the same Ru precatalyst, has been reported.29
The formation of the oxidatively coupled side products, 4, 6a,
and 7a, even only in minor quantities, highlights deactivation
C
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1
1
Figure 3. 2D NMR spectra of compound 5a isolated by HPLC: (a) H−13C HSQC NMR and (b) H−1H TOCSY NMR spectra
of the catalyst from the desired isohypsic cycle30 due to the
absence of an oxidant required to reoxidize the catalyst
(Scheme 3).31,32 To this end, a control experiment, conducted
in the absence of phenyl isocyanate 2a and any oxidant,
stoichiometries, likewise afforded poor yields of 3a. In both
instances, the formation of 5a was also observed by direct
infusion ESI-HRMS. Likewise, 5a was observed by direct
infusion ESI-HRMS when the amidation was catalyzed by a
Group 9 metal (Figures S31−S32).35
While the formation of bis-ortho-arylation side products have
been noted,36 reports of bis-ortho-amidated side products
isolated in metal-catalyzed C−H bond amidation with
isocyanates are sparse37−39 considering the wide substrate
scope that has been reported for this type of reaction.40 The
results presented herein may indicate sequentially amidated
and other side products to be more widely present in trace to
moderate yields in reaction mixtures. Indeed, few reports
specifically rule out the formation of bis-amidated side
products, and yet details are not given with regards to the
techniques employed.18,41
A range of different reaction conditions with different
solvents and additives was investigated, guided by literature on
related C−H bond activation.16,42 Analysis of the crude
reaction mixtures by ESI-MS allowed the identification of
conditions that minimized side product formation with the aim
of maximizing the yield of 3a (see Table S4 and Figures S33−
S82). Using 1,2-dichloroethane as a solvent, a reaction
temperature of 50 °C and the combination of o-nitrobenzoic
acid and silver hexafluoroantimonate appeared most promising
(Table S4, entries 6 and 19) as both the HRMS and 1H NMR
spectroscopy showed little side products with nearly complete
consumption of 1 (Figures S47−S49 and S82). These
conditions resulted in an increase in the isolated yield of 3a
to 78%. These additives and 1,2-dichloroethane likely aid the
complexation of both substrates by facilitating the availability
of low coordinate cationic ruthenium centers.43,44 The milder
reaction conditions enabled by these additives and solvent
selection likely prevent the dissociation of p-cymene from the
metal center, which prevents the formation of oxidatively
coupled side products.
In conclusion, we have demonstrated that, while Ru(II)-
catalyzed C−H amidation with aryl isocyanates presents an
attractive approach for the formation of amides, additional side
reactions, including sequential amidation, can compromise
isolated yields. Analysis of crude reaction mixtures by MS
allowed the identification of reaction conditions that gave
improved synthetic yields. Given the ease and speed of modern
MS-based methods, we recommend their use to identify and
1
afforded 4 in ca. 5% yield as shown by analysis by H NMR
spectroscopy (Figure S20). Furthermore, free p-cymene is
1
observed in the H NMR spectrum of crude 3a, providing
additional evidence of the decomposition of the catalyst over
the course of the reaction (Figure S12).
Our interest next turned to the identification of the doubly
amidated product 5a, since both the pyridine and newly
installed amide can potentially direct the second C−H
activation (Schemes 1 and 2).12 Alternatively, an N-aroylurea,
5a(III), may be formed by the interception of the metal
amidate intermediate with another equivalent of 2a (Scheme
2).33 Our attempts to separate 5a from the other pyridyl
containing side products using flash column chromatography
on silica were unsuccessful. Given that the LC−MS results
shown in Figure 2b indicate that 5a has a retention time quite
separate from the other side products, we next focused on
developing a preparative HPLC method. Indeed, 5a was
readily isolated using the same conditions and gradient
employed in the LC−MS study.34 Gratifyingly, 5a was isolated
with high purity (Figures S21−S24) and in sufficient quantity
1
to enable characterization by NMR spectroscopy. The H and
13C{1H} NMR spectrum (d6-acetone) displayed resonances
consistent with a highly symmetric product (Figures S25−
S27). Compound 5a was identified as the bis-ortho-amidated
1
isomer as the H−13C HSQC NMR spectrum (Figure 3a)
displayed 9 aromatic C−H resonances, which combined with
COSY and TOCSY (Figure 3b); NMR spectra enabled full
assignment (Figure S28).
Having shown the formation of 5a contributes to the poor
isolated yield of 3a on the isohypsic cycle (Scheme 3), we
utilized LC−MS to study the temporal evolution of the
products and side products. An examination of EICs revealed
the presence of 5a at 2 h of the reaction (Figures S29−S30),
indicating that the rate of the second amidation is competitive
with the first. We are reluctant to speculate any further on the
reaction kinetics given the number of competing reactions
involved. However, these data clearly explain why we were
unable to reproduce the relatively higher isolated yields of 3a
and 3b that were reported.17 It is noteworthy that reactions
conducted with 2a as the limiting reagent, or with 1:1
D
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Single-crystal X-ray diffraction data for all samples were collected as
follows: a typical crystal was mounted on a MiTeGen micromount,
using perfluoropolyether oil and cooled rapidly to 100(1) K in a
stream of nitrogen gas, using an Oxford Cryostream cooling device.
Diffraction data were collected (ω-scans) on a Rigaku XtaLAB
Synergy-S diffractometer equipped with a Hypix detector using Cu Kα
radiation (λ = 1.54184 Å). Raw frame data were reduced using
CrysAlisPro. The structures were solved with SHELXT50 and refined
with SHELXL51 using the interface OLEX2.52 All non-hydrogen
atoms were refined anisotropically. The hydrogen atoms were placed
in geometrically calculated positions and refined using a riding model.
A summary of crystallographic data can be found in Tables S5.
General Procedures for Ru-Catalyzed Amidation of 2-
Phenylpyridine with Arylisocyanates. Procedure A. [RuCl2(p-
cymene)]2 (31 mg, 0.05 mmol, 5 mol %) and NaOAc (25 mg, 0.30
mmol, 30 mol %) were added to a Schlenk flask. The flask was then
evacuated and purged with nitrogen three times. The glass stopper
was then replaced with a Suba-Seal under a flush of nitrogen. o-Xylene
(2 mL) was then added by syringe. 2-Phenylpyridine (142 μL, 1.0
mmol) and aryl isocyanate (1.8 mmol) were then added consecutively
by an Eppendorf pipet under a nitrogen flush. The flask was
thoroughly flushed with nitrogen and then sealed. The resultant red
reaction mixture was then transferred to a preheated oil bath (80 °C)
and stirred at that temperature for a further 24 h. After 2 h, the
reaction mixture began to darken. After 24 h, the reaction mixture was
a very dark purple-blue color. The flask was then removed from the oil
bath and permitted to cool to room temperature. The flask was then
open to the air and diluted with dichloromethane (10 mL). The
resultant dark mixture was filtered through a short pad of Celite and
eluted with dichloromethane (20 mL). A small amount of purple
residue was retained at the top of the column, while the eluent was
noticeably green in color. Dichloromethane and o-xylene were then
removed successively by rotary evaporation. The last traces of o-
xylene were removed under a high vacuum, affording a dark tar. The
crude was then analyzed by 1H NMR (CDCl3), ESI-HRMS (MeCN),
and TLC (petroleum ether/EtOAc = 7:3). The residue was purified
by column chromatography on silica (petroleum ether/EtOAc = 7:3
→ 0:10), unless otherwise stated. Amides were isolated as waxy off-
white solids.
report side product formation when developing new organic
reactions.
EXPERIMENTAL SECTION
■
General Synthetic Procedures. Unless noted, all catalytic
reactions were conducted using conventional Schlenk techniques
under an inert atmosphere (N2), utilizing glassware that was oven-
dried (120 °C) and evacuated while hot prior to use, whereas the
workup and isolation of the products from the catalytic reactions were
conducted on the benchtop using standard techniques. 2-Phenyl-
pyridine (1), phenyl isocyanate (2a), 4-tolyl isocyanate (2b), 4-
fluorophenyl isocyanate (2c), silver hexafluoroantimonate(V), o-
xylene (anhydrous, 97%), and 1,2-dichloroethane (anhydrous, 99.8%)
were purchased from Sigma-Aldrich and used without further
purification. NaOAc (anhydrous) was purchased from Chem-Supply
and used as received. Chloroform-d (Cambridge Isotopes) was
deacidified by eluting through a pipet packed with basic alumina prior
to use. All other reagents and materials were obtained from
commercial suppliers and used without further purification.
[RuCl2(p-cymene)]2,45 [Ru(OAc)2(p-cymene)]2,46 Cp*CoI2(CO),47
48
and [Cp*Rh(MeCN)3](SbF6)2 were synthesized according to
published procedures. Analytical TLC was performed on precoated
silica gel plates (0.20 mm thick, F-254, Silicycle, Canada) and
visualized under UV light (254 nm). Flash column chromatography
was carried out using P60 silica gel (40−63 μm, 230−400 mesh,
Silicycle, Canada) as the stationary phase.
Characterization Procedures. NMR spectroscopic character-
izations were recorded on Varian/Agilent or Bruker spectrometers
(see below for MHz) at 298 K unless otherwise stated, in the solvent
1
indicated. Chemical shifts (δ) are referenced to the residual H and
13C resonances of the solvent or TMS and are given in ppm.49
Coupling constants (J) are reported in hertz (Hz). Standard
abbreviations indicating multiplicity were used as follows: m =
multiplet, t = triplet, d = doublet, s = singlet, br = broad. Electrospray
ionization high-resolution mass spectra (ESI-HRMS) were collected
on a Thermo OrbiTrap Fusion Lumos mass spectrometer in the
positive ion mode. Collision-induced dissociation mass spectra (CID-
MS) were collected on a modified Finnigan LTQ linear ion trap mass
spectrometer (Bremen, Germany) in the positive ion mode. All LC−
MS experiments were performed on an Agilent 1200 liquid
chromatography system coupled with an Agilent 6520 quadrupole
time-of-flight (Q-TOF) mass spectrometer. A C18 reversed-phase
Agilent Eclipse XDB column (4.6 × 150 mm, 5 μm) was employed
for compound separation via gradient elution using 0.1% formic acid
in Milli-Q water as mobile phase A and acetonitrile with 0.1% formic
acid as mobile phase B. The injection volume of the sample is 5 μL,
and the flow rate of the solvent is 0.3 μL/min. The following solvent
gradient is used for all reaction analyses [time (min), %B solvent]: [0,
2], [2, 2], [20, 100], [23, 100], [24, 2], [30, 2]. Eluted analytes were
introduced into the gas phase via electrospray ionization (ESI).
Extracted ion chromatograms (EICs) were created by plotting the
integrated ion intensity for a selected m/z value versus retention time.
For a single run, all EICs that correspond to a different m/z value
were merged into one chromatogram. Mass spectral data were
acquired over the range 100−1000 m/z in positive ion mode. A
standard collision energy of 25 V was applied for the data-dependent
collision-induced dissociation experiment (CID). The drying gas flow
rate, nebulizer pressure, capillary, skimmer, and fragmentor voltages
were optimized in the positive ion mode. Analytical RP-HPLC traces
were acquired using an Agilent 1200 HPLC system equipped with an
Alltech Hypersil BDS C18 analytical HPLC column (4.6 × 150 mm, 5
μm) with a flow rate of 1 mL/min and UV absorbance detection at
254 nm. Retention times (tR/min) were recorded using a gradient
elution of 5−100% B in A (A = 0.1% trifluoroacetic acid (TFA), B =
acetonitrile with 0.1% trifluoroacetic acid) over 30 min. Preparative
HPLC was performed on an Agilent 1200 HPLC System using a
Phenomenex Luna 5μ 100 Å C18 column (21.2 × 250 mm) and
eluting with a gradient buffer of A = 0.1% formic acid and B = 0.1%
formic acid in MeCN over 40 min with UV detection at 214 nm.
Procedure B. [RuCl2(p-cymene)]2 (31 mg, 0.05 mmol, 5 mol %),
AgSbF6 (69 mg, 0.20 mmol, 20 mol %), and o-nitrobenzoic acid (50
mg, 0.30 mmol, 30 mol %) were added to a Schlenk flask. The flask
was then evacuated and purged with nitrogen three times. The glass
stopper was then replaced with a Suba-Seal under a flush of nitrogen.
2-Phenylpyridine (142 μL, 1.0 mmol) and phenyl isocyanate (196 μL,
1.8 mmol) were then added consecutively by an Eppendorf pipet
under a nitrogen flush. 1,2-Dichloroethane (2.0 mL) was then added
by syringe. The flask was thoroughly flushed with nitrogen and then
sealed. The resultant red reaction mixture was then transferred to a
preheated oil bath (50 °C) and stirred at that temperature for a
further 24 h. The reaction mixture was then cooled to room
temperature, and an aliquot was taken for HRMS analysis. The
volatiles were then removed under a vacuum. The residue was purified
by column chromatography on silica (petroleum ether/EtOAc = 7:3).
N-Phenyl-2-(pyridin-2-yl)benzamide (3a). Yield: 150 mg, 55%
(Procedure A). Yield: 213 mg, 78% (Procedure B). Rf = 0.1
(petroleum ether/EtOAc = 7:3). HRMS (ESI) m/z: [M + H]+ calcd
1
for C18H15N2O, 275.1179; found, 275.1178. H NMR (600 MHz,
CDCl3): δ 8.86 (br s, 1H), 8.60 (d, J = 4.4 Hz, 1H), 7.76 (d, J = 7.5
Hz, 1H), 7.72 (td, J = 7.8 Hz, J = 1.5 Hz, 1H), 7.51−7.49 (m, 3H),
7.46−7.43 (m, 3H), 7.26−7.23 (m, 3H), 7.06 (t, J = 7.6 Hz, 1H).
13C{1H} NMR (150 MHz, CDCl3): δ 167.8, 158.4, 148.9, 138.4,
138.3, 137.1, 136.4, 130.4, 130.4, 129.3, 129.0, 128.8, 124.3, 124.3,
122.7, 120.1. The NMR data for this compound is consistent with the
previously reported data.17
N-(p-Tolyl)-2-(pyridin-2-yl)benzamide (3b). Yield: 146 mg, 50%
(Procedure A). Rf = 0.1 (petroleum ether/EtOAc = 7:3). HRMS
(ESI) m/z: [M + H]+ calcd for C19H17N2O, 289.1335; found,
1
289.1335. H NMR (600 MHz, CDCl3): δ 8.66 (d, J = 4.7 Hz, 1H),
8.43 (s, 1H), 7.82 (d, J = 7.4 Hz, 1H), 7.73 (td, J = 7.7 Hz, J = 1.7 Hz,
E
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1H), 7.55−7.48 (m, 4H), 7.30 (d, J = 8.3 Hz, 2H), 7.26 (ddd, J = 7.5
Hz, J = 5.0 Hz, J = 1.0 Hz, 1H), 7.07 (d, J = 8.1 Hz, 2H), 2.29 (s, 3H).
13C{1H} NMR (150 MHz, CDCl3): δ 167.4, 158.4, 148.9, 138.3,
137.0, 136.4, 135.6, 133.9, 130.3, 130.3, 129.4, 129.3, 128.9, 124.3,
122.6, 119.9, 20.9. The NMR data for this compound is consistent
with the previously reported data.17
Authors
Alasdair I. McKay − School of Chemistry and Bio21 Institute of
Molecular Science and Biotechnology, The University of
Melbourne, Melbourne 3010, Australia
Weam A. O. Altalhi − School of Chemistry and Bio21 Institute
of Molecular Science and Biotechnology, The University of
Melbourne, Melbourne 3010, Australia
Lachlan E. McInnes − School of Chemistry and Bio21 Institute
of Molecular Science and Biotechnology, The University of
Melbourne, Melbourne 3010, Australia
Milena L. Czyz − School of Chemistry, The University of
Melbourne, Melbourne 3010, Australia
Allan J. Canty − School of Natural Sciences-Chemistry,
University of Tasmania, Hobart 7001, Australia; orcid.org/
0000-0003-4091-6040
N-(4-Fluorophenyl)-2-(pyridin-2-yl)benzamide (3c). Yield: 144
mg, 49% (Procedure A). Rf = 0.1 (petroleum ether/EtOAc = 7:3).
HRMS (ESI) m/z: [M + H]+ calcd for C18H14FN2O, 293.1085;
1
found, 293.1085. H NMR (600 MHz, CDCl3): δ 9.17 (s, 1H), 8.47
(d, J = 4.8 Hz, 1H), 7.75 (td, J = 7.7 Hz, J = 1.6 Hz, 1H), 7.70 (dd, J =
0.9 Hz, J = 7.6 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.47−7.36 (m, 5H),
7.25 (ddd, J = 7.6 Hz, J = 5.0 Hz, J = 1.0 Hz, 1H), 6.91 (t, J = 8.7 Hz,
2H). 13C{1H} NMR (150 MHz, CDCl3): δ 167.7, 159.3 (d, J = 245
Hz), 148.6, 138.3, 137.1, 136.0, 134.4 (d, J = 2.5 Hz), 130.4, 130.3,
129.2, 128.7, 124.2, 122.6, 121.8 (d, J = 7.9 Hz), 115.4 (d, J = 22.5
Hz). 19F NMR (470 MHz, CDCl3): δ −118.2.
N1,N3-Diphenyl-2-(pyridin-2-yl)isophthalamide (5a). One mg
was isolated by preparative HPLC from 10 mg of the crude reaction
mixture obtained from Procedure A. tR = 10.7 min. HRMS (ESI) m/z:
[M + H]+ calcd for C25H20N3O2, 394.1550; found, 394.1552. 1H
NMR (600 MHz, (CD3)2CO): δ 9.30 (br s, 2H), 8.52 (d, J = 4.8 Hz,
1H), 7.78 (d, J = 7.7 Hz, 2H), 7.77 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 7.6
Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 4H), 7.28−
7.23 (m, 5H), 7.05 (t, J = 7.4 Hz, 2H). 13C{1H} NMR (150 MHz,
(CD3)2CO): δ 167.5, 157.1, 148.9, 140.0, 139.5, 137.6, 130.1, 129.4,
129.3, 125.8, 124.5, 123.6, 120.4.
General Procedure for the Reaction Screening. [RuCl2(p-
cymene)]2 (6 mg, 0.01 mmol, 5 mol %) and additives were added to a
Schlenk flask. The flask was then evacuated and purged with nitrogen
three times. The glass stopper was then replaced with a Suba-Seal
under a flush of nitrogen. 2-Phenylpyridine (28 μL, 0.20 mmol) and
phenyl isocyanate (39 μL, 0.36 mmol) were then added consecutively
by an Eppendorf pipet under a nitrogen flush. The solvent (0.5 mL)
was then added by syringe. The flask was thoroughly flushed with
nitrogen and then sealed. The resultant red reaction mixture was then
transferred to a preheated oil bath and stirred at that temperature for
a further 24 h. The flask was then removed. An aliquot was taken for
HRMS analysis. The volatiles were then removed under a vacuum.
The crude dark solid was then extracted into CDCl3 (2 mL), eluted
through a plug of basic alumina, and then analyzed by 1H NMR
spectroscopy.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.9b02831
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Australian Research Council for financial support
(DP180101187 to R.A.J.O., P.S.D., and A.J.C.). We thank Dr.
Anastasios Polyzos for useful discussions. W.A. thanks Prince
Sattam Bin Abdulaziz University for the award of a scholarship,
while M.L.C. acknowledges the ARC for the award of an ITTC
Postdoctoral Fellowship.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
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well as ambident ionization methods that can be used to analyze
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.9b02831.
Copies of 1H, 13C{1H}, and 19F NMR, HRMS-ESI, MS/
MS spectra, LC−MS and HPLC chromatograms, and
crystallography data (PDF)
Crystal data (CIF)
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AUTHOR INFORMATION
■
Corresponding Authors
Paul S. Donnelly − School of Chemistry and Bio21 Institute of
Molecular Science and Biotechnology, The University of
Melbourne, Melbourne 3010, Australia; orcid.org/0000-
0001-5373-0080; Email: pauld@unimelb.edu.au
Richard A. J. O’Hair − School of Chemistry and Bio21 Institute
of Molecular Science and Biotechnology, The University of
Melbourne, Melbourne 3010, Australia; orcid.org/0000-
0002-8044-0502; Phone: +613-8344-2452; Email: rohair@
unimelb.edu.au; Fax: +613-9347-5180
F
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