Mapping the reactivity of the quinoline ring-system – Synthesis of the tetracyclic ring-system of isocryptolepine and regioisomers

Article abstract of DOI:10.1016/j.tet.2019.04.026

Bromoquinolines (2-bromoquinoline – 8-bromoquinoline and 5-bromo-3-methoxyquinoline) and 2-aminophenylboronic acid hydrochloride were subjected to Suzuki-Miyaura cross-coupling conditions resulting in formation of the desired biaryl systems in good yields. The resulting biaryls were then subjected to palladium catalyzed C–H activation/C–N bond formation utilizing PdCl₂(dppf). The reactions revealed large differences in reactivity depending on the attachment point for the 2-aminophenyl group on the quinoline. The variation in the reactivity was rationalized based on the electron distribution around the quinoline ring-system.

Full text of DOI:10.1016/j.tet.2019.04.026

Accepted Manuscript
Mapping the reactivity of the quinoline ring-system – Synthesis of the tetracyclic ring-
system of isocryptolepine and regioisomers
Katja S. Håheim, Ida T. Urdal Helgeland, Emil Lindbäck, Magne O. Sydnes
PII:
S0040-4020(19)30428-4
https://doi.org/10.1016/j.tet.2019.04.026
TET 30271
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 January 2019
Revised Date: 27 March 2019
Accepted Date: 11 April 2019
Please cite this article as: Håheim KS, Urdal Helgeland IT, Lindbäck E, Sydnes MO, Mapping the
reactivity of the quinoline ring-system – Synthesis of the tetracyclic ring-system of isocryptolepine and
regioisomers, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.04.026.
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ACCEPTED MANUSCRIPT
Mapping the Reactivity of the Quinoline Ring-System – Synthesis of the Tetracyclic
Ring-System of Isocryptolepine and Regioisomers
Katja S. Håheim,† Ida T. Urdal Helgeland,† Emil Lindbäck† and Magne O. Sydnes†*
†Faculty of Science and Technology, Department of Chemistry, Bioscience and
Environmental Engineering, University of Stavanger, NO-4036 Stavanger, Norway
Corresponding Author *E-mail: magne.o.sydnes@uis.no
Abstract Bromoquinolines (2-bromoquinoline – 8-bromoquinoline and 5-bromo-3-
methoxyquinoline) and 2-aminophenylboronic acid hydrochloride were subjected to Suzuki-
Miyaura cross-coupling conditions resulting in formation of the desired biaryl systems in
good yields. The resulting biaryls were then subjected to palladium catalyzed C-H
activation/C-N bond formation utilizing PdCl2(dppf). The reactions revealed large differences
in reactivity depending on the attachment point for the 2-aminophenyl group on the quinoline.
The variation in the reactivity was rationalized based on the electron distribution around the
quinoline ring-system.
Introduction
Nitrogen containing heterocycles are immensely important appearing in 59% of the Food and
Drug Administration (FDA) approved small-molecule drugs.1 Heterocycles containing one or
more nitrogen atoms are also commonly found in nature,2 with many of these compounds
being based on the quinoline core.2c,2d Cryptolepine, neocryptolepine, and isocryptolepine
belonging to the indoloquinoline family of natural products represents examples of such
compounds (Figure 1).3 The antimalarial activity of these three compounds has made them
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attractive synthetic targets.4 In particular isocryptolepine has been the focus of studies in
several research groups throughout the world resulting in a range of total syntheses,5,6
including our own synthesis.7 Lately it has also been found that neocryptolepine has activity
towards neglected topical diseases caused by trypanosomatid parasites, increasing the interest
for this natural product amongst medicinal chemists.8 The three mentioned natural products
have also been targeted for analogue synthesis with the aim to enhance the antimalarial and
anticancer activity.9
Figure 1. The structure of cryptolepine, neocryptolepine, and isocryptolepine.
As a continuation of our own synthesis of isocryptolepine,7 we became interested in mapping
the reactivity around the quinoline ring-system in terms of the ability to engage in the Suzuki-
Miyaura cross-coupling and the following C-H activation/C-N bond formation leading up to
the formation of the core structure of the natural products neocryptolepine and isocryptolepine
and regioisomers thereof. Although several of these compounds have been prepared
previously (compounds 4a,10,11 4b,7,11 4c,10,11 4d,12 4e,13 4f,14 and 4g15), in particular the
natural product precursors (compound 4a and 4b), it is the first time that the same reaction
conditions have been utilized in order to study the reactivity around the quinoline ring-system.
2

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Herein, we present the results of these studies highlighting the difference in reactivity around
the quinoline ring-system in particular towards ring formation.
Result and Discussion
In our reported synthesis of isocryptolepine, PdCl2(dppf) was utilized as catalyst in order to
facilitate the Suzuki-Miyaura cross-coupling reaction.7 Naturally, this catalyst was an obvious
starting point for our further studies. Treating 2-bromoquinoline (1a) and boronic acid 2 with
PdCl2(dppf) under our previously used reaction conditions gave quick conversion (1 h) to the
desired product 3a in 65% isolated yield (Table 1, Entry 1). Prolonging the reaction time only
resulted in the formation of unwanted byproducts. The drop in yield compared to the yield
obtained for the cross-coupling in C3,7a which gave compound 3b in 84% yield, prompted us
to try Pd(PPh3)4 as catalyst. Switching catalyst to Pd(PPh3)4 resulted in formation of
compound 3a in 94% yield (Table 1, Entry 1). The great difference in yields obtained with the
two catalysts in these two reactions prompted us to utilize both reaction conditions in the
continuation of the work.
Table 1. Suzuki-Miyaura cross-coupling of bromoquinoline 1 with 2-aminophenylboronic
acid hydrochloride (2).
b
Entry
Substrate
Catalyst PdCl2(dppf)a
(Reaction time)
Catalyst Pd(PPh3)4
(Reaction time)
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1
2
3
4
5
6
7
2-bromoquinoline (1a)
3a 65% (1 h)
3b 84%c (20 h)
3c 91% (21 h)
3a 94% (16 h)
3b 53% (20 h)
3-bromoquinoline (1b)
4-bromoquinoline (1c)
5-bromoquinoline (1d)
6-bromoquinoline (1e)
7-bromoquinoline (1f)
8-bromoquinoline (1g)
3c 96% (1.75 h)
3d 90% (overnight)
3e 82% (overnight)
3f 82% (20 h)
3d 54% (overnight)
3e 81% (overnight)
3f 30% (29 h)
3g 45% (22 h)
3g 87% (16 h)
aMethod A: PdCl2(dppf) (dppf = 1,1'-bis(diphenylphosphino)ferrocene) (5 mol%), K2CO3,
o
b
o
EtOH/H2O (5:1), 60 C; Method B: Pd(PPh3)4 (5 mol%), Cs2CO3, DME/H2O (5:1), 80 C;
cSlightly increased yield compared to our previously reported yield is due to optimization of
the purification of the crude material.
The remaining bromoquinolines were subjected to Suzuki-Miyaura cross-coupling reaction
using PdCl2(dppf) (Method A) and Pd(PPh3)4 (Method B). Both methods successfully yielded
all the desired Suzuki-Miyaura cross-coupling products 3b-g in predominantly good yields
(Table 1). Overall, tetrakis(triphenylphosphine)palladium(0) (Method B) generally resulted
in the best yields and the reaction times were mostly shorter (Table 1). In particular, the
coupling reaction with 4-bromoquinoline worked remarkably well resulting in the formation
of the desired cross-coupling product 3c in close to quantitative yield (96%) in less than 2 h
(Table 1, Entry 3).
Based on the results obtained for the Suzuki-Miyaura cross-coupling reactions it is obvious
that the reactivity around the quinoline ring varies. It has been known for some time that the
two least electron dense positions of the quinoline ring-system are the C2 and C4.16,17 This is
clearly demonstrated by electron density calculations by Coulson and Longuet-Higgins
(Figure 2a),18 however, other calculations suggest that the data for the C2 and C4 should be
reversed.10,18 Indeed, Brower et al.17 observed lower activation energies at the C2 of quinoline
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in the aromatic substitution with piperidine (Figure 2b) and PM3 calculations carried out by
Hostyn et al.10 revealed a significantly higher electron density at the C4 of quinoline.
Figure 2. (a) Electron densities of the quinoline ring-system;18 (b) Energies of activation (∆E)
for reactions of haloquinolines with piperidine.17
It was noted by Brower et al. that this deviation in electron density could be the result of the
chosen model employed by Coulson and Longuet-Higgins, as the calculations are based on
the occurrence of a certain substitution reaction being made.17,18 While there seems to be an
agreement that C3 is the least active of the pyridyl carbons,17,19 there is some debate regarding
which position is the most active between C2 and C4, as evident by the preceding discussion.
Schröter et al. argue that the annelated benzol ring in quinoline makes C2 the only carbon
with any significant electrophilicity,20 while Almond-Thynne et al. claims that in
dihalogenated quinolines, the electrophilicity is highest at C2, C4 and C3, in decreasing
order.19
In the Suzuki-Miyaura cross-coupling reactions of heteroaryl halides it has been remarked
that the oxidative addition step proceeds in a similar mechanistic fashion to SNAr reactions.19
From this, it can be inferred that the reaction occurs at the most electrophilic carbon given the
choice between multiple reaction sites.19-21 This trend was not quite representative for our
cross-couplings, with the reactions at C5 and C8 performing better than at C3 when Pd(PPh3)4
was used as catalyst (Table 1, Entries 2, 4, and 7). As can be seen from Table 1 the reactivity
was not only determined by the relative electron density, but also by the employed catalyst.
Keeping the previous discussion in mind, when it came to testing the reactivity of our Suzuki-
Miyaura cross-coupling products towards cyclization, we expected that when two positions
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were available to form a C-N bond it would selectively occur at the most electron deficient
carbon. This is based on the assumption that the cyclization proceeds via an oxidative
addition-type mechanism with the palladium species, which was proposed by Bjørsvik and
Elumalai as a likely reaction pathway for the cyclization of 2-aminobiphenyl to form the
carbazole scaffold under conditions similar to the ones used in this work.22
Rerunning the cyclization of compound 3b using our previously reported chemistry,7a
proceeded regiospecific to give indoloquinoline 4b in 73% yield (Table 2, Entry 2). The
increased yield (62% → 73%) for the cyclization reaction compared to our previous report7a is
due to the discovery of a better solvent combination for purification of the crude product by
flash chromatography.
Table 2. Summary of the C-H activation/C-N bond formation resulting in the formation of the
tetracyclic ring-systems 4b, 4e, 4f, 4g and 6c.a
Entry
1
Substrate
Cyclization product
Acetylation product
2
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3
4
5
6
7
aConditions: PdCl2(dppf) (20 mol%), 1,3-bis(2,4,6-trimethylphenyl)-imidazolium (IMes) (5
mol%), H2O2 (35 wt%, 29 mol%), AcOH, MW sealed reactor tube 118 ; bn. f. = not formed.
Upon cyclization of substrate 3b no trace of its regioisomer 6H-indolo[2,3-b]quinoline was
observed in the crude reaction mixture despite the resonance forms of compound 3b bearing a
negative charge at both the C2 and C4 as outlined in Scheme 3a. The observed
regioselectivity towards C-N bond formation at the C4 over C2 is presumably governed by
favorable relative electrostatic effects. Similar observations has also been reported for C-C
bond formations, although in those examples small amounts of the product resulting from
reaction at C2 was also isolated.10,17
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Much to our disappointment, subjecting biaryls 3a and 3c to our standard cyclization
conditions did not yield the expected products 7H-indolo[2,3-c]quinoline (4a) and 10H-
indolo[3,2-b]quinoline (4c), respectively. Instead, these reactions resulted in acetylation of the
starting materials to give 5a and 5c in 55% and 54% yield, respectively (Table 2, Entries 1
and 3). The resonance structures of 3a and 3c show that the C3 of the quinoline moiety can
bear a negative charge and additional inductive effects exhibited by the nuclear nitrogen may
make this position particularly unreactive.17 With the aid of ESI-MS, traces of a mass
corresponding to the expected mass of protonated species 4c was detected, however, 1H NMR
analysis on a minute amount of compound post purification by silica gel column
chromatography failed to provide evidence of its formation.
Acetic acid is known to act as an acetylating agent when employed in microwave-assisted
syntheses.23 Efforts were therefore made to avoid the formation of the acetylation product by
replacing acetic acid with a more sterically hindered acid, viz. pivalic acid. Attempts to carry
out the cyclization of 3a in pivalic acid unfortunately only lead to the formation of N-(2-
(quinolin-2-yl)phenyl)pivalamide (7a) in 65% yield, thus no further experiments were
conducted using this solvent (Scheme 1).
Scheme 1. Attempted formation of compound 4a utilizing pivalic acid as solvent.
Cyclization of compound 3d gave only phenanthridine 6d in 73% yield with no trace of
cyclization into C6 (Table 2, Entry 4). It can be seen from the resonance structures of
compound 3d that C6 of quinoline can have a negative charge while C4 cannot (Scheme 3b).
Formation of compound 6d is in agreement with cyclization into the most electron deficient
position.
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Despite the resonance structures for compound 3d favoring cyclization into C4 (Scheme 3b),
the kinetic preference is to form 5- over 6-membered rings24 and the regioselective formation
of phenanthridine 6d warranted further exploration. We became interested in altering the
electron distribution of biaryl 3d by introducing a methoxy group at C3 to examine if the
electron donating properties of the alkoxide would affect the regioselectivity (Scheme 3b).
Following the procedure outlined by Landagaray et al.25 5-bromo-3-methoxyquinoline (1h)
was synthesized starting from 3-bromoquinoline (1b) (Scheme 2). Subsequent Suzuki-
Miyaura cross-coupling of quinoline 1h with boronic acid 2 using methods A and B yielded
2-(3-methoxyquinolin-5-yl)aniline (3h) in poor yields (method A: 47%; method B: 34%).
Unreacted starting material (1h) (29%) and 19% of 2,2’-biphenyldiamine was also isolated
when method A was used. Method A could be further optimized by adjusting the equivalents
of boronic acid 2 from 1.5 eq. to 3 eq., which increased the yield of the desired coupling
product 3h from 47% → 88%. Finally, cyclization of biaryl 3h surprisingly yielded
phenanthridine 6h in 39% yield in addition to a small quantity of the acetylated product 5h (<
5%) together with several unidentified impurities. Analyzing the crude mixture by ESI-MS,
traces of a mass corresponding to the protonated mass of the 5-membered ring product 4h was
1
detected but this was not verifiable by H NMR. Consequently, it is clear that the inductive
effect exhibited by the methoxy moiety affects the system, however, it is not sufficient to
completely reverse the regioselectivity observed for the cyclization of biaryl 3d.
Scheme 2. Synthesis of 2-(3-methoxyquinolin-5-yl)aniline (3h) and subsequent ring closure
to yield 6-methoxy-7H-pyrido[4,3,2-gh]phenanthridine (6h). Conditions: a) (i) NaOMe
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(30%), CuI (5 mol%), DMF, reflux, overnight; (ii) NBS, H2SO4 (conc.), 0 to rt, overnight;
c
o
b) Method A: 2 (0.48 mmol), PdCl2(dppf) (5 mol%), K2CO3, EtOH/H2O (5:1), 60 C,
o
overnight; dMethod B: 2 (0.24 mmol), Pd(PPh3)4 (5 mol%), Cs2CO3, DME/H2O (5:1), 80 C,
overnight; e) PdCl2(dppf) (20 mol%), IMes (5 mol%), H2O2 (35 wt%, 29 mol%), AcOH, MW
118 ℃1 h.
A literature search revealed no synthetic strategies for the synthesis of systems such as
phenanthridines 6d and 6h at present time. Hostyn et al.10 describes the synthesis of 7H-
indolo[2,3-c]quinoline (4a) and 7H-pyrido[2,3,4-kl]acridine by thermal collapse of 4-(2-
azidophenyl)quinoline, where the indoloquinoline was the major product and only traces of
the acridine was observed. The authors rationalize the selectivity in terms of kinetics,
moreover, the cyclization is thought to be the result of a nitrene insertion which presumably
plays
a
role
in
determining
the
regioselectivity.
Turning to the cyclization of compounds 3e and 3f (Table 2, Entries 5 and 6), it did not seem
immediately obvious where the C-N bond would be formed. Unlike the resonance form of
compound 3b, there is no adjacent heteroatom to delocalize the negative charge in these cases
(Scheme 3c). Instead, we examined the chemical shifts for the protons adjacent to the tethered
aniline to see which of the two protons experienced the most deshielding, a method advocated
for by Handy and Zhang for the prediction of regioselectivity in cross-coupling reactions.21
However, it is noted that when ∆ꢀH < 0.03 ppm this technique should be used with caution as
they demonstrated that it failed to accurately predict the selectivity in such cases. In
compound 3e, H-5 has a shift of 7.91 ppm while H-7 is at 7.85 ppm (∆ꢀH = 0.06 ppm),
favoring cyclization into C5, which in fact was the outfall of the reaction resulting in a 65%
isolated yield of compound 4e (Table 2, Entry 5). No trace of the H-7 regioisomer, 10H-
pyrido[2,3-b]carbazole, was observed.
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Scheme 3. Resonance structures for compounds 3b, 3d/3h and 3e.
Similarly, cyclization of compound 3f occurred at H-8, which displayed a higher chemical
shift than H-6, to furnish 4f in 25% yield (Table 2, Entry 6). This reaction was also
regioselective towards cyclization at H-8, however, undesired acetylation product 5f was also
formed in 61% yield. The cyclization of biaryl 3g returned a similar outcome, with target
compound 4g formed in 29% yield while the acetylation product was furnished in 69% yield
(Table 2, Entry 7). It seems that acetylation of biaryls 3 is the outcome when the electron flow
of the quinoline ring-system is congested, i.e. it is energetically unfavorable to form the
tetracyclic ring-system due to high electron densities at the adjacent protons.
Conclusion
In conclusion, the reactivity of the quinoline ring-system has been mapped by subjecting
bromoquinolines 1a-h to
a
Suzuki-Miyaura cross-coupling reaction with 2-
aminophenylboronic acid hydrochloride (2). The resulting cross-coupling products were then
subjected to an intramolecular cyclization via tandem C-H activation and C-N bond formation
to furnish tetracyclic ring-systems 4b and 4e-4g and 6d and 6h. Our findings were congruent
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with earlier reports that C2 and C4 of the quinoline scaffold is the most active and it appears
that the electron densities at the various carbons determined the regioselectivity of the
cyclization. Our synthetic efforts also resulted in an improved yield for the formation of the
tetracyclic ring-system required for the formation of isocryptolepine.
Experimental
General experimental
Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AscendTM 400 series,
1
13
operating at 400 MHz for H and 100 MHz for C, respectively. Chemical shifts (δ) are
13
expressed in ppm relative to residual chloroform (1H, 7.26 ppm; C, 77.16 ppm), DMSO-d6
(1H, 2.50 ppm; 13C, 39.52 ppm) or methanol (1H, 3.31 ppm; 13C, 49.00 ppm). The assignments
of signals in various NMR spectra was often assisted by conducting correlation spectroscopy
(COSY), heteronuclear single-quantum correlation spectroscopy (HSQC) and/or
heteronuclear multiple bond correlation spectroscopy (HMBC).
Reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm silica
gel 60 F254 coated aluminium sheets using UV light as visualizing agent. Silica gel 60
(particle size 40-63 μm) was used for silica flash chromatography and alumina gel (particle
size 30-48 μm) was used for alumina flash chromatography. Automated flash chromatography
was carried out using an Interchim puriFlash 215 chromatography system. The sample was
evaporated onto celite and then dry-loaded onto a specialized column which was attached to
an SI-HP Interchim column filled with silica gel (particle size 40-50 μm). The appropriate
eluent was flushed through the columns using an applied pressure of 22-26 bar.
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In addition to TLC, low resolution mass spectrometry (LRMS) was routinely used to monitor
and identify the various components of reaction mixtures. The LRMS spectra were obtained
on an Advion expressions CMS mass spectrometer operating at 3.5 kV in electrospray
ionization (ESI) mode.
Infrared spectroscopy (IR) was performed on a Cary 360 FTIR spectrophotometer. Solids
were dissolved in CHCl3 or DCM and absorbed on a NaCl plate, or by placing the sample
directly onto the crystal of an attenuated total reflectance (ATR) module. Melting points were
measured using a Stuart Scientific SMP3 melting point apparatus and are uncorrected. High
resolution mass spectroscopy (HRMS) were conducted externally at the University of Bergen
or the University of Tromsø, using electron spray ionization (ESI). The microwave-assisted
experiments were performed in a CEM Focused MicrowaveTM Synthesis System, model type
Discover, operating at 0-300 W at a temperature of 118 ˚C, a pressure range of 0-290 psi, with
reactor vial volumes of either 10 or 35 mL. Commercially chemicals were used as delivered
from the supplier unless otherwise noted.
25
5-Bromo-3-methoxyquinoline (1h). Following the procedure reported by Landagaray et
al. the title compound 1h was obtained as off-white crystals (52%), mp 76-77 oC (lit.25 81-83
1
oC); IR (ATR): ѵmax 3067, 3004, 2995, 2964, 2853, 1599, 1407, 1161, 859 cm-1; H NMR
(400 MHz, CD3OD): δ 8.61 (d, J = 2.8 Hz, 1H), 7.99-7.96 (m, 1H), 7.87 (dd, J = 7.6 Hz, 1.0
13
Hz, 1H), 7.84 (d, J = 2.6 Hz, 1H), 7.48 (dd, J = 8.4 Hz, 7.6 Hz, 1H), 4.02 (s, 3H); C NMR
(100 MHz, CD3OD): δ 155.9, 146.2, 144.6, 132.3, 129.7, 129.3, 128.3, 121.5, 113.2, 56.3. In
accordance with previously reported data.25
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Method A: General method for Suzuki-Miyaura cross-coupling using [PdCl2(dppf)] as
catalyst. 2-Aminophenylboronic acid hydrochloride (2) (62.5 mg, 0.36 mmol), an aqueous
solution of potassium carbonate (116.1 mg, 0.84 mmol in 0.2 mL H2O), and PdCl2(dppf) (8.9
mg, 0.012 mmol, 5 mol%) was added to a stirred solution of bromoquinoline 1a-h (0.24
mmol) in EtOH (1 mL) under an argon atmosphere and the reaction mixture was stirred at 60
˚C until completion of the reaction as indicated by TLC analysis. The reaction mixture was
then allowed to cool to room temperature and the volatiles were removed under reduced
pressure. The concentrate was evaporated onto celite and purified by silica gel column
chromatography using the chromatographic technique and eluent as indicated for each
compound in order to give compound 3a-h.
Method B: General method for Suzuki-Miyaura cross-coupling using Pd(PPh3)4 as
catalyst. To a solution of bromoquinoline 1a-h (0.24 mmol) in dimethoxyethane (2 mL)
under an argon atmosphere was added 2-aminophenylboronic acid hydrochloride (2) (62.5
mg, 0.36 mmol), an aqueous solution of cesium carbonate (273.7 mg, 0.84 mmol in 0.4 mL
H2O), and tetrakis(triphenylphosphine)palladium(0) (13.9 mg, 0.012 mmol, 5 mol%). The
resulting reaction mixture was stirred at 80 ˚C until completion as indicated by TLC. The
reaction mixture was then allowed to cool to room temperature and the volatiles were
removed under reduced pressure. The concentrate was evaporated onto celite and purified by
silica gel column chromatography using the chromatographic technique and eluent as
indicated for each compound in order to give compound 3a-h.
2-(Quinolin-2-yl)aniline (3a). Following methods A and B; the crude was purified by silica
gel column chromatography (pet. ether/EtOAc, 9:1 v/v) and concentration of the relevant
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fractions [Rf = 0.17 (pet. ether/EtOAc, 9:1 v/v)] gave the title compound 3a as bright yellow
o
crystals (method A: 65%; method B: 94%), mp 152-155 C; IR (ATR): ѵmax 2922, 2852,
1
1718, 1465, 759 cm-1; H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 8.7 Hz, 1H), 8.06 (d, J =
8.4 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.82-7.80 (m, 1H), 7.73-7.69 (m, 2H), 7.54-7.49 (m,
13
1H), 7.24-7.19 (m, 1H), 6.85-6.82 (m, 2H); C NMR (100 MHz, CDCl3): δ 159.2, 147.2,
146.9, 136.9, 130.5, 129.9, 129.8, 128.9, 127.5, 126.4, 126.3, 121.8, 120.6, 117.9, 117.7. In
accordance with previously reported data.26
Utilizing method A, the desired product 3a had to undergo recrystallization (n-
heptane/EtOAc, 9:1 v/v) to remove overlapping impurities.
2-(Quinolin-3-yl)aniline (3b). Following methods A and B; the crude was purified by silica
gel column chromatography (pet. ether/EtOAc, 7:3 → 1:1 v/v) and concentration of the
relevant fractions [Rf = 0.27 (pet. ether/EtOAc, 7:3 v/v)] gave the title compound 3b as a
yellow crystalline solid (method A: 84%; method B: 53%), mp 132-135 ˚C (lit.7a 130-132 oC).
1
IR (NaCl): ѵmax 3438, 3331, 3208, 3061, 1619, 1575, 1497, 1452 cm-1; H NMR (400 MHz,
CDCl3) δ 9.03 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.83-
7.81 (m, 1H), 7.75-7-71 (m, 1H), 7.59-7.55 (m, 1H), 7.25-7.19 (m, 2H), 6.92-6.88 (m, 1H),
6.84-6.82 (m, 1H), 3.80 (bs, 2H); 13C NMR (100 MHz, CDCl3): δ 151.5, 147.1, 144.1, 135.5,
132.5, 130.9, 129.6, 129.5, 129.2, 127.9, 127.8, 127.1, 123.7, 119.1, 116.0. In accordance
with previously reported data.7a
2-(Quinolin-4-yl)aniline (3c). Following methods A and B; the crude was purified by an
Interchim puriFlash chromatography system (pet. ether/EtOAc, 95:5 → 55:45 v/v) and
concentration of the relevant fractions [Rf = 0.29 (pet. ether/EtOAc, 1:1 v/v)] gave the title
15

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compound 3c as a yellow solid (method A: 91%; method B: 96%), mp 128-129 oC (lit.13 119
1
oC). IR (NaCl): ѵmax 3454, 3328, 3210, 3061, 3033, 1617, 1494, 1451, 752 cm-1; H NMR
(400 MHz, CDCl3) δ 8.94 (d, J = 4.4 Hz, 1H), 8.18-8.15 (m, 1H), 7.74-7.69 (m, 2H), 7.50-
7.46 (m, 1H), 7.37 (d, J = 4.4 Hz, 1H), 7.28 (ddd, J = 7.5 Hz, 1.6 Hz, 0.6 Hz, 1H), 7.12 (dd, J
= 7.5 Hz, 1.5 Hz, 1H), 6.88 (td, J = 7.4 Hz, 1.0 Hz, 1H), 6.83 (dd, J = 8.1 Hz, 0.8 Hz, 1H),
3.83 (bs, 2H); 13C NMR (100 MHz, CDCl3) δ 150.4, 148.7, 146.2, 143.9, 130.6, 129.9, 129.8,
129.7, 126.9, 126.9, 126.1, 122.9, 122.3, 118.5, 115.8. In accordance with previously reported
data.13
2-(Quinolin-5-yl)aniline (3d). Following methods A and B; the crude was purified by silica
gel column chromatography (pet. ether/EtOAc, 7:3 → 6:4 v/v) and concentration of the
relevant fractions [Rf = 0.23 (pet. ether/EtOAc, 1:1 v/v)] gave the title compound 3d as light
o
brown crystals (method A: 54%; method B: 90%), mp 163-166 C. IR (ATR) ѵmax 3410,
3318, 3209, 2924, 1618, 1491, 959, 803, 754 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.93 (dd,
J = 4.1 Hz, 1.7 Hz, 1H), 8.16-8.14 (m, 1H), 8.02-7.99 (m, 1H), 7.81-7.77 (m, 1H), 7.53 (dd, J
= 6.9 Hz, 0.9 Hz, 1H), 7.35 (dd, J = 8.5 Hz, 4.2 Hz, 1H), 7.30-7.25 (m, 1H), 7.13 (dd, J = 7.5
Hz, 1.5 Hz, 1H), 6.88 (td, J = 7.5 Hz, 1.1 Hz, 1H), 6.84 (dd, J = 8.0 Hz, 0.7 Hz, 1H), 3.44 (bs,
13
2H) ; C NMR (100 MHz, CDCl3): δ 150.6, 148.7, 144.4, 137.5, 134.9, 131.4, 129.6, 129.5,
129.3, 128.2, 127.1, 124.4, 121.4, 118.56, 115.6; HRMS (ESI): calcd. for C15H12N2H+
221.1073, found 221.1071.
2-(Quinolin-6-yl)aniline (3e). Following methods A and B; the crude was purified by silica
gel column chromatography (pet. ether/EtOAc, 4:6 v/v) and concentration of the relevant
fractions [Rf = 0.16 (pet. ether/EtOAc, 6:4 v/v)] gave the title compound 3e as an off-white
16

ACCEPTED MANUSCRIPT
o
solid (method A: 81%; method B: 82%), mp 130-132 C. IR (NaCl) ѵmax 3462, 3327, 3203,
3020, 2925, 2854, 1618, 1570, 1490 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.93 (d, J = 2.4 Hz,
1H), 8.20-8.18 (m, 2H), 7.91(s, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.45-7.42 (m, 1H), 7.26-7.19
13
(m, 2H), 6.88-6.81 (m, 1H), 6.82 (d, J = 8.3 Hz, 1H), 3.62 (bs, 2H); C NMR (100 MHz,
CDCl3) δ 150.5, 147.4, 143.8, 138.1, 136.3, 131.3, 130.8, 129.9, 129.1, 128.6, 127.8, 126.7,
121.6, 119.0, 115.9; HRMS (ESI): calcd. for C15H12N2H+ 221.1073, found 221.1072.
2-(Quinolin-7-yl)aniline (3f). Following methods A and B; the crude was purified by silica
gel column chromatography (pet. ether/EtOAc, 6:4 v/v) and concentration of the relevant
fractions [Rf = 0.21 (pet. ether/EtOAc, 6:4 v/v] gave the title compound 3f as a pale yellow oil
(method A: 30%; method B: 82%). IR (ATR): ѵmax 3453, 3330, 3200, 3050, 3019, 2923,
1
2858, 1618, 1488, 1301, 839, 749 cm-1; H NMR (400 MHz, CDCl3): δ 8.93 (d, J = 3.1 Hz,
1H), 8.22 (s, 1H), 8.17 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.68 (dd, J = 8.4 Hz, 1.6
Hz, 1H), 7.40 (dd, J = 8.2 Hz, 4.2 Hz, 1H), 7.24 (dd, J = 7.6 Hz, 1.5 Hz, 1H), 7.20 (td, J = 7.9
Hz, 1.5 Hz, 1H), 6.87 (td, J = 7.4 Hz, 1.0 Hz, 1H), 6.80 (dd, J = 8.0 Hz, 0.8 Hz, 1H), 3.73 (bs,
13
2H); C NMR (100 MHz, CDCl3): δ 150.8, 148.5, 143.7, 141.2, 135.9, 130.7, 129.1, 129.0,
128.4, 128.3, 127.3, 126.6, 121.2, 118.9, 115.9; HRMS (ESI): calcd. for C15H12N2H+
221.1073, found 221.1073.
2-(Quinolin-8-yl)aniline (3g). Following methods A and B; the crude was purified by silica
gel column chromatography (pet. ether/EtOAc, 9:1 v/) and concentration of the relevant
fractions [Rf = 0.30 (pet. ether/EtOAc, 7:3 v/v)] gave the title compound 3g as an off-white
o
o
solid (method A: 45%; method B: 87%), mp 103-105 C (lit.27 100-102 C). IR (ATR): ѵmax
3424, 3330, 3206, 3026, 1615, 1491, 793, 743 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.93 (dd,
17

ACCEPTED MANUSCRIPT
J = 4.1 Hz, 1.8 Hz, 1H), 8.19 (dd, J = 8.3 Hz, 1.9 Hz, 1H), 7.83 (dd, J = 8.1 Hz, 1.5 Hz, 1H),
7.70 (dd, J = 7.1 Hz, 1.5 Hz, 1H), 7.62-7.58 (m, 1H), 7.39 (dd, J = 8.3 Hz, 4.2 Hz, 1H), 7.25-
13
7.21 (m, 2H), 6.90 (td, J = 7.5 Hz, 1.1 Hz, 1H), 6.85-6.82 (m, 1H), 3.67 (bs, 2H); C NMR
(100 MHz, CDCl3): δ 150.6, 146.2, 144.8, 139.4, 136.7, 131.7, 131.6, 128.9, 127.9, 126.8,
121.1, 118.8, 116.4. In accordance with previously reported data.27
2-(3-Methoxyquinolin-5-yl)aniline (3h). Following methods A and B; the crude was purified
by silica gel column chromatography (pet. ether/EtOAc, 1:1 v/v) followed by alumina gel
column chromatography (CH2Cl2/pet. ether, 8:2 v/v) and concentration of the relevant
fractions [Rf = 0.33 (CH2Cl2/pet. ether, 8:2 v/v)] gave the title compound 3h as an orange
solid (method A: 88%; method B: 34%) along with recovered starting material (1h) (method
B: 18%), mp 142-144 oC. IR (ATR): ѵmax 3059, 3018, 2957, 2933, 2857, 1604, 1249, 819 cm-
1; 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 2.9 Hz, 1H), 8.11-8.08 (m, 1H), 7.62 (dd, J = 8.4
Hz, 7.1 Hz, 1H), 7.49 (dd, J = 7.0 Hz, 1.2 Hz, 1H), 7.27 (ddd, J = 7.9 Hz, 7.5 Hz, 1.6 Hz, 1H),
7.21 (d, J = 2.8 Hz, 1H), 7.14 (dd, J = 7.5 Hz, 1.5 Hz, 1H), 6.88 (dt, J = 7.4 Hz, 1.1 Hz, 1H),
13
6.84 (dd, J = 8.0 Hz, 0.8 Hz, 1H), 3.79 (s, 3H), 3.58 (bs, 2H); C NMR (100 MHz, CDCl3):
δ153.4, 144.3, 143.6, 136.2, 131.3, 129.3, 128.9, 128.8, 127.6, 126.8, 124.6, 118.5, 115.6,
111.4, 55.6; HRMS (ESI): calcd. for C16H15N2OH+ 251.1179, found 251.1188.
Method C: General method for palladium-initiated intramolecular C-H activation/C-N
bond formation. The appropriate biaryl (3a-h) (0.23 mmol) in acetic acid (0.8 mL) was
added to a premixed solution of PdCl2(dppf) (33.6 mg, 0.046 mmol), 1,3-bis(2,4,6-
trimethylphenyl)-imidazolium (IMes) (3.5 mg, 0.011 mmol), H2O2 (35 wt%, 5.6 μL, 0.067
mmol) and acetic acid (0.2 mL). The reaction mixture was placed in a sealed reactor tube and
18

ACCEPTED MANUSCRIPT
immersed into the cavity of the microwave oven and heated at 118 ˚C until completion as
indicated by TLC. The reaction mixture was then transferred to a 25 mL round bottom flask
with the aid of EtOAc/CHCl3 and the volatiles were removed under reduced pressure. The
reaction mixture was evaporated onto celite and purified by silica gel column
chromatography, with the chromatographic technique and eluent gradient as indicated.
5H-Indolo[3,2-c]quinoline (4b). Following method C; the crude was purified by silica gel
column chromatography (CH2Cl2/EtOAc 8:2 → 6:4 v/v) to give the title compound 4b (Rf =
0.25 (CH2Cl2/EtOAc, 1:1 v/v)) as an off-white solid (73%), mp 333-336 ˚C (lit.7a 340-341
1
˚C). IR (NaCl): λmax 3060, 2958, 2854, 1682,1582, 1515, 1493 cm-1; H NMR (400 MHz,
DMSO-d6) δ 12.71 (bs, 1H), 9.59 (s, 1H), 8.52 (dd, J = 7.9 Hz, 1.1 Hz, 1H), 8. 32 (d, J = 7.9
Hz, 1H), 8.13 (dd, J = 8.0 Hz, 1.1 Hz, 1H), 7.77-7-67 (m, 3H), 7.52-7.48 (m, 1H), 7.36-7.33
13
(m, 1H); C NMR (100 MHz, DMSO-d6) δ 145.4, 144.8, 139.7, 138.7, 129.4, 128.0, 125.7,
125.5, 122.1, 121.8, 120.6, 120.1, 117.1, 114.3, 111.8. In accordance with previously reported
data.7a
11H-Pyrido[3,2-a]carbazole (4e). Following method C; the crude was purified by silica gel
column chromatography (CH2Cl2/EtOAc, 8:2 + 5% Et3N v/v) and concentration of the
relevant fractions [Rf = 0.06 (pet. ether/EtOAc, 6:4 v/v)] gave the title compound 4e as an off-
white solid (65%) along with recovered starting material (3e) (12%), mp 135-139 ˚C. IR
1
(NaCl): λmax 3133, 3075, 2923, 2852, 1731, 1574, 1372, 808, 776 cm-1; H NMR (400 MHz,
DMSO-d6): δ 12.48 (bs, 1H), 8.94 (ddd, J = 8.3 Hz, 1.6 Hz, 0.6 Hz, 1H), 8.91 (dd, J = 4.3 Hz,
1.7 Hz, 1H), 8.46 (d, J = 8.7 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 7.74 (dd, J = 8.7 Hz, 0.5 Hz,
1H), 7.68-7.63 (m, 2H), 7.46-7.42 (m, 1H), 7.29-7.25 (m, 1H); 13C NMR (100 MHz, DMSO-
19

ACCEPTED MANUSCRIPT
d6): δ 148.9, 147.2, 139.1, 134.6, 130.1, 124.9, 122.9, 122.7, 120.5, 119.9, 119.5, 117.3,
116.4, 111.5. In accordance with previously reported data.24
11H-Pyrido[2,3-a]carbazole (4f). Following method C; the crude was purified by silica gel
column chromatography (pet. ether/EtOAc, 1:1 + 0.2% Et3N → 2/8 v/v) and concentration of
the relevant fractions [Rf = 0.27 (pet. ether/ CH2Cl2, 1:1 v/v)] gave the title compound 4f as
pale yellow crystals (25%), mp 165-167 ˚C (lit.14 164-165 ˚C). IR (ATR): ѵmax 3263, 3043,
1
2923, 2854, 1523, 1369, 820, 734 cm-1; H NMR (400 MHz, CDCl3): δ 10.20 (bs, 1H), 8.92
(dd, J = 4.4 Hz, 1.5 Hz, 1H), 8.35 (dd, J = 8. 3 Hz, 1.5 Hz, 1H), 8.24 (d, J = 8.5 Hz, 1H),
13
8.19-8.17 (m, 1H), 7.62-7.60 (m, 2H), 7.51-7.47 (m, 2H), 7.35-7.31 (m, 1H); C NMR (100
MHz, CDCl3): δ 147.8, 139.2, 137.4, 136.8, 134.9, 127.3, 125.9, 123.8, 121.7, 120.8, 120.5,
120.4, 120.2, 118.8, 111.8. In accordance with previously reported data.14
7H-Pyrido[3,2-c]carbazole (4g). Following method C; the crude was purified by silica gel
column chromatography (pet. ether/EtOAc, 1:1 + 0.2% Et3N v/v) and concentration of the
relevant fractions [Rf = 0.06 (pet. ether/EtOAc, 6:4 v/v] gave the title compound 4g as a pale
yellow solid (29%), mp 150-152 ˚C (lit.15 173-174 ˚C). IR (ATR): ѵmax 3207, 2976, 2919,
2850, 2740, 2605, 2499 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 11.92 (bs, 1H), 9.02 (dd, J =
4.4 Hz, 1.8 Hz, 1H), 8.90-8.88 (m, 1H), 8.46 (dd, J = 8.1 Hz, 1.4 Hz, 1H), 7.92 (d, J = 8.8 Hz,
1H), 7.84 (d, J = 8.8 Hz, 1H), 7.66-7.64 (m, 1H), 7.49 (dd, J = 8.0 Hz, 4.3 Hz, 1H), 7.46-7.42
13
(m, 1H), 7.33-7.29 (m, 1H); C NMR (100 MHz, DMSO-d6): δ 149.8, 145.3, 139.6, 138.5,
136.5, 126.0, 124.5, 123.1, 122.9, 122.8, 119.7, 118.3, 115.3, 114.2, 111.4.
20

ACCEPTED MANUSCRIPT
N-(2-(Quinolin-2-yl)phenyl)acetamide (5a). Following method C; the crude was purified by
silica gel column chromatography (pet. ether/EtOAc, 9:1 → 7:3 v/v) and concentration of the
relevant fractions [Rf = 0.24 (pet. ether/EtOAc, 7:3 v/v)] gave the title compound 5a as orange
1
crystals (55%), mp 124-125 ˚C. IR (NaCl): ѵmax cm-1; H NMR (400 MHz, CDCl3): δ 12.97
(bs, 1H), 8.65 (d, J = 8.2 Hz, 1H), 8.28 (d, J = 8.7 Hz, 1H), 8.06-8.04 (m, 1H), 7.89 (d, J = 8.7
Hz, 1H), 7.86 (dd, J = 8.2 Hz, 1.0 Hz, 1H), 7.83 (dd, J = 7.9 Hz, 1.5 Hz, 1H), 7.80-7.76 (m,
1H), 7.48-7.43 (m, 1H), 7.20 (td, J = 7.9 Hz, 1.2 Hz, 1H), 2.26 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 168.8, 158.2, 146.2, 138.6, 137.7, 130.7, 130.5, 129.4, 128.4, 127.8, 127.1, 126.6,
124.9, 123.4, 121.8, 120.9, 25.5; HRMS (ESI): calcd. for C17H14N2OH+ 263.1179, found
263.1182.
N-(2-(Quinolin-4-yl)phenyl)acetamide (5c). Following method C; the crude was purified by
silica gel column chromatography (pet. ether/EtOAc, 6:4 → 3:7 v/v) and concentration of the
relevant fractions [Rf = 0.44 (pet. ether/EtOAc, 3:7 v/v)] gave the title compound 5c as a dark
yellow solid (54%), mp 183-185 ˚C. IR (NaCl): ѵmax 3253, 3033, 2925, 2853, 1685, 1526,
1
1295, 850 cm-1; H NMR (400 MHz, DMSO-d6): δ 9.08 (bs, 1H), 8.95 (d, J = 4.4 Hz, 1H),
8.09-8.07 (m, 1H), 7.78-7.74 (m, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.52-7.49 (m, 3H), 7.38 (d, J
13
= 4.4 Hz, 1H), 7.35-7.33 (m, 2H), 1.64 (s, 3H); C NMR (100 MHz, DMSO-d6): δ 168.5,
150.1, 148.0, 145.0, 135.8, 131.4, 130.7, 129.4, 129.2, 128.8, 126.4, 126.3, 126.2, 125.6,
125.2, 122.3, 22.3; HRMS (ESI): calcd. for C17H14N2OH+ 263.1179, found 263.1187.
N-(2-(Quinolin-7-yl)phenyl)acetamide (5f). Following method C; the crude was purified by
silica gel column chromatography (pet. ether/EtOAc, 1:1 + 0.2% Et3N v/v) and concentration
of the relevant fractions [Rf = 0.16 (pet. ether/EtOAc, 8:2 v/v)] gave the title compound 5f as
21

ACCEPTED MANUSCRIPT
a red oil (61%). IR (NaCl): ѵmax 3418, 3249, 3051, 2966, 2924, 2852, 1676, 1526, 1301, 840,
1
758 cm-1; H NMR (400 MHz, CD3OD/CDCl3): δ 8.85 (d, J = 3.3 Hz, 1H), 8.36 (d, J = 8.2
Hz, 1H), 8.04 ( s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.55-7.53 (m, 2H),
7.48-7.35 (m, 3H), 1.94 (s, 3H); 13C NMR (100 MHz, CD3OD/CDCl3): δ 172.1, 151.2, 148.4,
142.4, 138.0, 137.6, 135.3, 131.5, 129.5, 129.2, 128.9, 128.7, 128.5, 128.0, 127.7, 122.4, 22.9;
HRMS (ESI): calcd. for C17H14N2OH+ 263.1179, found 263.1181.
N-(2-(Quinolin-8-yl)phenyl)acetamide (5g). Following method C; the crude was purified by
silica gel column chromatography (pet. ether/EtOAc, 9:1 → 4:6 + 1% Et3N) and concentration
of the relevant fractions [Rf = 0.21 (pet. ether/EtOAc, 1:1 v/v)] gave the title compound 5f as
dark yellow crystals (69%), mp 128-130 ˚C. IR (ATR): ѵmax 3247, 3195, 3059, 3026, 2926,
1
2854, 1678, 1522, 1439, 1295, 789, 748 cm-1; H NMR (400 MHz, CDCl3): δ 8.97 (dd, J =
3.9 Hz, 1.4 Hz, 1H), 8.48 (bs, 1H), 8.31 (dd, J = 8.2 Hz, 1.3 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H),
7.92 (dd, J = 7.9 Hz, 1.3 Hz, 1H), 7.74-7.66 (m, 2H), 7.52-7.45 (m, 2H), 7.35 (dd, J = 7.7 Hz,
13
1.3 Hz, 1H), 7.29-7.25 (m, 1H), 1.77 (s, 3H); C NMR (100 MHz, CDCl3): δ 168.3, 150.7,
145.8, 138.8, 137.7, 135.7, 133.1, 132.9, 131.9, 128.9, 128.6, 128.6, 127.2, 125.3, 124.4,
121.4, 24.4; HRMS (ESI): calcd. for C17H14N2OH+ 263.1179, found 263.1183.
7H-Pyrido[4,3,2-gh]phenanthridine (6d). Following method C; the crude was purified by
silica gel column chromatography (EtOH/MeOH, 100:0 → 8:2 v/v) and concentration of the
relevant fractions [Rf = 0.19 (EtOH)] gave the title compound 6d as a yellow gel (73%). IR
1
(NaCl): ѵmax 3274, 3167, 3112, 3049, 2919, 2851, 2762, 1614, 1576, 1460, 669 cm-1; H
NMR (400 MHz, DMSO-d6): δ 8.33 (dd, J = 8.2 Hz, 0.8 Hz, 1H), 8.27 (d, J = 6.6 Hz, 1H),
8.16 (d, J = 7.8 Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.66 (dd, J = 8.4 Hz, 0.6 Hz, 1H), 7.59-7.55
22

ACCEPTED MANUSCRIPT
13
(m, 1H), 6.78-6.76 (m, 1H); C NMR (100 MHz, DMSO-d6): δ 149.2, 143.3, 141.1, 135.5,
134.1, 131.6, 130.9, 124.9, 123.8, 120.4, 118.1, 117.2, 115.9, 115.0, 99.7; HRMS (ESI):
calcd. for C15H10N2H+ 219.0917, found 219.0917.
6-Methoxy-7H-pyrido[4,3,2-gh]phenanthridine (6h). Following method C; the crude was
purified by silica gel column chromatography (CH2Cl2/EtOAc/EtOH, 1:1:0 → 1:0:1 → 0:0:1
v/v) followed by a second purification by silica gel (CH2Cl2/EtOH, 7:3 → 1:1 v/v) and
concentration of the relevant fractions [Rf = 0.33 (CH2Cl2/EtOH, 7:3 v/v)] gave the title
compound 6h as a bright yellow gel (39%). IR (ATR): ѵmax 2958, 2926, 2860, 1609, 1464,
1
1278, 764 cm-1; H NMR (400 MHz, DMSO-d6): δ 8.42 (bs, 1H), 8.30 (dd, J = 8.4 Hz, 1.0
Hz, 1H), 8.08 (d, J = 7.7 Hz, 1H), 7.88 (t, J = 8.0 Hz, 1H), 7.80 (dd, J = 8.2 Hz, 0.8 Hz, 1H),
13
7.71 (d, J = 8.4 Hz, 1H), 7.56-7.52 (m, 1H), 7.38-7.34 (m, 1H), 4.07 (s, 3H); C NMR (100
MHz, DMSO-d6): δ 140.2, 138.3, 135.5, 132.8, 131.0, 130.8, 127.0 (2C), 125.2, 123.6, 120.7,
118.8, 116.5, 115.7, 113.8, 57.8; HRMS (ESI): calcd. for C16H13N2OH+ 249.1028, found
249.1029.
N-(2-(Quinolin-2-yl)phenyl)pivalamide (7a). Following method C, take for the solvent
being pivalic acid; the crude was purified by silica gel column chromatography (pet.
ether/EtOAc, 9/1 v/v) and concentration of the relevant fractions [Rf = 0.25 (pet. ether/EtOAc,
9:1 v/v)] gave the title compound 7a as white crystals (65%), mp 107-108 ˚C (lit.28 99-100
˚C). IR (ATR): ѵmax 3181, 2954, 2928, 2865, 1676, 1582, 1501, 1297, 1158, 829, 757 cm-1; 1H
NMR (400 MHz, CDCl3): δ 12.28 (bs, 1H), 8.64 (dd, J = 8.4 Hz, 1.0 Hz, 1H), 8.28 (d, J = 8.6
Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.86 (dd, J = 8.2 Hz, 1.1 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H),
7.79-7.75 (m, 1H), 7.73 (dd, J = 7.9 Hz, 1.5 Hz, 1H), 7.60-7.56 (m, 1H), 7.47-7.43 (m, 1H),
23

ACCEPTED MANUSCRIPT
7.20 (td, J = 7.8 Hz, 1.2 Hz, 1H), 1.34 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 177.7, 158.5,
146.4, 138.1, 137.8, 130.4, 130.3, 129.9, 128.4, 127.9, 126.9, 126.8, 126.7, 123.4, 122.3,
121.5, 40.2, 27.9. In accordance with previously reported data.28
Corresponding Author
*E-mail: magne.o.sydnes@uis.no
Acknowledgments
The ToppForsk program and the research program Bioactive at the University of Stavanger is
gratefully acknowledged for funding. Dr. Holmelid, University of Bergen, and Dr. Johansen,
UiT The Arctic University of Norway, is also thanked for recording HRMS.
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24

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Supplementary Material
Supplementary material including 1H and 13C NMR charts can be found in the online version
at doi:…..
Graphical abstract
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