Photoreductive Removal of O-Benzyl Groups from Oxyarene N-Heterocycles Assisted by O-Pyridine-pyridone Tautomerism

Article abstract of DOI:10.1021/acs.joc.7b02775

Facile photoreductive protocols have been developed to remove benzyl O-protective groups from oxyarene N-heterocycles at positions capable for 2-/4-O-pyridine-2-/4-pyridone tautomerism. Blue light irradiation, a [Ru] or [Ir] photocatalyst, and ascorbic acid in a water-acetonitrile solution debenzylates a variety of aryl N-heterocycles cleanly and selectively. Ascorbic acid has two functions in the reaction. On the one hand, it protonates the N-heterocycles that reduces their reduction potentials notably and on the other hand it acts as a sacrificial reductant. Reduction potentials and free energy barriers calculated at the CPCM-B3LYP/6-31+G? level can predict the reactivities of the studied substrates.

Full text of DOI:10.1021/acs.joc.7b02775

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Note
Photoreductive removal of O-benzyl groups from oxyarene N-
heterocycles assisted by O-pyridine – pyridone tautomerism
Aleksandar R. Todorov, Tom Wirtanen, and Juho Helaja
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02775 • Publication Date (Web): 14 Nov 2017
Downloaded from http://pubs.acs.org on November 16, 2017
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Photoreductive removal of O-benzyl groups from oxyarene N-
heterocycles assisted by O-pyridine – pyridone tautomerism
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Aleksandar R. Todorov, Tom Wirtanen, and Juho Helaja*
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Department of Chemistry, A.I. Virtasen aukio 1, University of Helsinki, 00014, Finland.
ABSTRACT: Facile photoreductive protocols have been developed to remove benzyl Oꢀprotective groups
from oxyarene Nꢀheterocycles at positions capable for 2ꢀ/4ꢀOꢀpyridine – 2ꢀ/4ꢀpyridone tautomerism. Blue
light irradiation, a [Ru] or [Ir] photocatalyst and ascorbic acid in a waterꢀacetonitrile solution debenzylates a
variety of aryl Nꢀheterocycles cleanly and selectively. Ascorbic acid has two functions in the reaction. On the
one hand, it protonates the Nꢀheterocycles that reduces their reduction potentials notably and on the other
hand it acts as a sacrificial reductant. Reduction potentials and free energy barriers calculated at the CPCMꢀ
B3LYP/6ꢀ31+G** level can predict the reactivities of the studied substrates.
A variety of photoremovable protecting groups have been designed and developed for different
functionalities to optionally allow traceless, orthogonal, and functional group tolerant protections,
which are in some cases operable even in biological environments.1 Typically, the protecting group
chromophore absorbs an UV or a visible light photon that initiates the bond breaking processes and
ultimately the deprotection. However, some of the deprotections carried out with high energy UVꢀ
light may, in addition to the desired bond cleavages, lead to unwanted side reactions and unclean
deprotections.
The contemporary development of photoredox catalysis has conveyed a set of photocatalysts that
utilize visible light to induce single electron transfers to accomplish organic bond cleavages and
formations.2 Accordingly, Stephenson and coworkers have developed a visible lightꢀpromoted
catalytic method for deprotection of Oꢀbenzylꢀprotected aliphatic alcohols utilizing an [Ir]ꢀcatalyst
and CBrCl3 as a stoichiometric radical source that mediates the reaction (Scheme 1).3 Gryko and
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coworkers have recently shown that photoinduced deprotection of (allyloxy)arenes can be
conducted via a nucleophilic vitamin B12ꢀcatalysis.4 Moreover, Nꢀmethylꢀ4ꢀpicolinium esters5 and
carbamates6 have been practically photocleaved by reductive visible light [Ru] catalysis. Originally,
Sundararajan and Falvey introduced the concept of reductive photocleavage of Nꢀmethylꢀ4ꢀ
picolinium esters using Nꢀmethylcarbazole, laser dye or intramolecular electron donor
photosensitizers.7
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Conventionally, Oꢀbenzyl and ꢀallyl groups are removed via a reductive hydrogenation with number
of protocols.8 Frequentlyꢀused methods include Pd/C or Ni catalyzed hydrogenations and
stoichiometric reductions with NaBH4, DIBAL or LiAlH4. However, coordinative pyridineꢀtype
nitrogens tend to coordinate to catalytic metals inhibiting occasionally the catalytic reactions.9 Since
these are compounds of interest to us, i.e. aromatic hydroxyl functionalized Nꢀheterocycles that
have ability to hydroxyꢀoxo tautomerize,10 we envisioned that the tautomerization could be utilized
to promote the reductive protective group cleavage at the phenolic oxygen. Protonation of the
pyridineꢀtype nitrogen in the heterocycles would turn them into better electron acceptors that could
be in situ photoreduced followed by a radical cleavage of the Oꢀprotective group via a tautomeric
process.
Scheme 1
We initiated the study using 2ꢀ(benzyloxy)quinoline 1a as a model compound for the reaction development
(Table 1). Ascorbic acid was a rational choice for a sacrificial reductant as it can also protonate the
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quinoline. For example, in the case of 1i, protonation reduces its reduction potential by 1.13 V as measured
by cyclic voltammetry (SI). Also with other substrates, reduction potentials11 are reduced to appropriate
values for the commonly used photocatalysts. The photocatalysts for the reaction screening were selected
based on their adequate reduced state reduction potentials (RSRP) in MeCN.2a
9
Pleasingly, 2 equiv of ascorbic acid in MeCN:H2O (1:1) mixture, 0.5 mol % of Ru(bpy)3Cl2 photocatalyst,
with ꢀ1.33V (SCE)2a RSRP, removed the benzyl group cleanly after 1 h at rt under 455 nm irradiation (Table
1, entry 1); method A. In a similar fashion, Ir[dF(CF3)ppy]2(dtbbpy))PF6 catalyst with a slightly lower RSRP,
ꢀ1.37 V (SCE),2a worked neatly with 1.0 mol% loading (entry 4); method B. Moreover, under the same
conditions, the photocatalyst [Ir(dtbbpy)(ppy)2]PF6, with even lower RSRP (ꢀ1.51V, SCE),2a performed
soundly giving clean conversion with 0.5 mol % loading in 1 h (entry 5); method C. Meanwhile, the catalyst
facꢀIr(ppy)3 with a substantially negative reported RSRP, ꢀ2.19 V (SCE),2a showed only modest reactivity
(entry 6). Indicatively, a [Ru(bpz)3][PF6]2 catalyst with higher RSRP ꢀ0.80 V (SCE)2a did not give any
reactivity (entry 7). Apparently, the lack of reactivity relates to catalyst’s modest RSRP value, while its
reduced state formation should be smooth based on its high excited state via reduction potential, i.e. +1.45 V
(SCE).2a
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The catalysis with Ru(bpy)3Cl2 worked also moderately in MeOH; poorly in H2O; and gave no conversion in
MeCN or DMF (Table 1). The presence of the ascorbic acid was necessary for the reaction, while
substoichiometric amounts of it provided incomplete conversion, while generally an excess, 2.0 equiv, was
found to be beneficial for smooth reactions (cf. fluorescence quenching studies, SI). When a typical
photocatalytic sacrificial base reductant DIPEA was used as an additive together with ascorbic acid, the
reaction did not proceed. An inert atmosphere favored the progress of the reaction and, in the absence of
light irradiation, no conversion was observed.
Table 1. Effects of the reaction
parameters
entry
varied reaction parameters
time (h)
yield (%)c
Catalyst and loading [mol %]
Ru(bpy)3Cl2*6H2O [0.5]
Ru(bpy)3Cl2*6H2O [0.1]
Ir[dF(CF3)ppy]2(dtbbpy))PF6 [0.5]
Ir[dF(CF3)ppy]2(dtbbpy))PF6 [1.0]
[Ir(dtbbpy)(ppy)2]PF6 [0.5]
facꢀIr(ppy)3 [0.5]
[Ru(bpz)3][PF6]2[0.5]
no catalyst
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3
4
5
6
7
8
1
1
1
1
1
1
1
24
>99
41
76
>99
>99
32
NR
NR
Solvent
9
MeCN
H2O
MeOH
DMF
1
1
1
1
NR
24
79
10
11
12
NR
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other conditions
no ascorbic acid
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1
1
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1
1
NR
48
>99
NR
NR
58
0.5 equiv ascorbic acid
1.0 equiv ascorbic acid
no light irradiation
2.0 equiv DIPEA additived
ambient atmosphere
areactions were performed at [0.2 M] in a 10 mL Schlenk tube irradiated
with 455 nm LEDs (5*3W). bTautomeric form is media dependent –polar
and nonpolar media favours pyridone and pyridine isomers, respectively.
cIsolated yield after SiO2 chromatographic purification.d In the presence of
ascorbic acid. NR = No reaction
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Computational methods allow the estimation of the redox potentials of organic compounds conveniently and
we and others have used this approach previously.12ꢀ14 With the CPCMꢀB3LYP/6ꢀ31+G** method, Nicewicz
and coworkers have recently found a good correlation between a wide range of neutral organic redox
potentials and experimentally measured potentials.14 In our case, for the (Nꢀprotonated) quinolinium 1a, the
computational method gave a slightly lower value, ꢀ1.02V vs. the ꢀ0.86V experimental value (SCE). Since in
this study, we were interested in reduction potentials of protonated compounds, a set of aromatic Nꢀ
heterocycles were examined both experimentally and theoretically to justify the use of the method (SI). The
analysis showed that there is a high linear correlation (R2=0.97, SI) between calculated and experimental
values,15 but the latter were consistently ꢀ0.2 − ꢀ0.3V more negative (Figure S1, SI). The systematic deviation
likely arises from the facts that the protonated Nꢀaryls are calculated without counter ions and with implicit
solvation model, conductorꢀlike polarizable continuum model (CPCM), which is furthermore benchmarked
to have the largest solvation energy errors for cations and anions.16
With this information in hand, the scope of the reaction was then studied with various monoꢀ and biꢀ Oꢀ
benzyl substituted quinoline type compounds (Table 2). Prior to catalytic tests, reduction potentials were
calculated for all of the studied compounds to assess their reactivities. As expected, relying on the potentials,
for most of the quinolines method A delivered smooth reactivity excluding three substrates 1j, 1m and 1n
(entries 9, 12 and 13) having slightly more negative reduction potentials. They were, however, catalyzed in a
superior manner with method B; as clean conversions were obtained in 3 h. Evidently, the slightly more
negative reduction potential of the Irꢀcatalyst was critical to provide the facile reactivity in these cases.
Significantly, in the case of dibenzyloxy substituted quinolines 1j, 1k and 1n (entries 9, 10 and 13) a single
benzyl group was cleaved regioselectively, using methods A and B. The calculation of the cleavage energy
barriers for each benzyl group in the quinolinium radicals revealed that the removable benzyl exhibited
correspondingly significantly lower energy barriers (Table S1, SI). From a methodologic perspective, the
photoreduction catalysis provides a convenient access to pharma interest mono benzyloxy substituted
quinolines such as 4ꢀ(benzyloxy)quinolinꢀ2(1H)ꢀone, 2j.17
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Table 2. Scope of the reaction with OꢀBn protected quinolinesa
Eo b (V, SCE)
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entry
substrate
product
method time (h)
yield (%)c
>99
½
SM + H+
ꢀ1.11
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A
A
(ꢀ0.98)d
2
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>99
93
ꢀ1.18
ꢀ0.85e
(ꢀ0.56)d
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>99
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A,B
(ꢀ0.36)d
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>99
A
B
ꢀ1.32
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ꢀ1.22
ꢀ1.20
0.6
2
>99
>99
A
A
ꢀ1.07
4
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74
>99
A
B
(ꢀ0.79)d
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5.5
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A
B
ꢀ1.24
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aBenzyl ether 0.2 mmol, ascorbic acid 0.4 mmol, MeCN/H2O=1:1 10 mL. bCalculated with
B3LYP/6ꢀ31+G** CPCM model for MeCN (details in SI). cIsolated yield after SiO2
chromatographic purification. dexperimental values determined in 0.1 M NBu4PF6 in
MeCN using pꢀTSA to protonate the heterocycle. eCalculated with uwb97xd/def2ꢀTZVP
CPCM model for MeCN (details in SI). fIn addition to unreacted SM unidentified side
products were detected.
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As exceptions in the quinoline series, compound 1h (entry 7) having an ester functionality at the 8ꢀ
position gave an unclean reaction with a modest conversion, while the quinoline 1i (entry 8) failed
to show any reactivity under any studied conditions even though it has a more positive reduction
potential, which was rather baffling. Also, ester group substitution at the 3ꢀposition (1g, entry 6) did
not inhibit the reactivity. However, DFT calculations of the quinoliniꢀ1ꢀums (neutral radicals of the
protonated quinolines) showed two distinctive features for quinolinꢀ1ꢀium 1i+H• (Figure S3, SI). At
first, the comparison of the SOMOs morphologies of the 1g, 1h and 1i radicals showed distinctively
that for 1i the density was the most localized on the ester group, which might be the reason for the
observed inertness. Secondly, the free energy barrier for the benzyl group cleavage was higher for
1i (16.8 kcal/mol) than for the two other quinoliniums (9.6 and 13.3 kcal/mol for 1g and 1h,
respectively). We speculate that, due to a short lifetime of radical intermediates, low reaction
barriers are needed for the cleavage reactions to compete with other decay pathways.
Related to the above, the quinoline 1f having an electron donating acetal functionality at 8ꢀposition
reacted cleanly, while corresponding 8ꢀposition aldehyde decomposed fully under the reaction
conditions.18 Whereas, in the case of Brꢀsubstituted BnOꢀquinolines, 1d, 1e and 1g, the halogen
substituent remained intact, and the photoreduction catalysis yielded clean chemoselective benzyl
cleavages (entries 3, 4, and 6).
Next, we studied the scope of the reaction with monoꢀ and bifunctionalized Oꢀbenzyl substituted
pyridine and pyrimidine type compounds (Table 3). These compounds have inherently more
negative reduction potentials than the quinolines. Consequently, method A failed to give any
reactivity for these substrates, whereas method B delivered successful benzyl removal for the
pyridines with the least negative reduction potentials (entry 1 and 4). For the bi Oꢀbenzyl
substituted pyridine 3d, the DFT calculations gave strikingly dissimilar energy barriers for the
benzyl cleavages at the 2ꢀ and 3ꢀpositions (5.0 and 14.8 kcal/mol, respectively). The TS energies
agree perfectly with the observed regioselectivity, as monoprotected 3ꢀOꢀbenzyl 4d was received as
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the only product. Alternatively, one could predict that the regioselectivity is simply based on the
abilities of 2ꢀhydroxyl compounds to participate in pyridine/ꢀdone tautomerism, which is excluded
at the pyridine 3ꢀoxo position.
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Table 3. Scope of the reaction with mono and bi O-Bn protected pyridines and pyrimidinesa
Eo b (V, SCE)
½
entry
substrate product
time (h) yield (%)c
method
SM + H+
ꢀ1.31
18
3
NR
95
A
B
1
(ꢀ1.06)d
ꢀ1.54
24
21
NR
>99
A,B
C
2
(ꢀ1.31)d
3
4
ꢀ1.51
24
NR
A-C
ꢀ1.33
20
2
NR
95
A
B
(ꢀ1.20)d
ꢀ1.77
24
23
NR
59e
A,B
C
5
6
(ꢀ1.45)d
ꢀ1.11
24
NR
A,B
7
ꢀ1.18
23
85
B
aBenzyl ether 0.2 mmol, ascorbic acid 0.4 mmol, MeCN/H2O=1:1 10 mL. bCalculated
with B3LYP/6ꢀ31+G** CPCM acetonitrile (details in SI). cIsolated yield after SiO2
chromatographic purification. dexperimental values determined in 0.1 M NBu4PF6 in
MeCN using pꢀTSA to protonate the heterocycle. emixture of mono deprotected
regioisomers.
On the basis of the calculated reduction potential for 4ꢀOBnꢀpyridine 3b ꢀ1.54 V (SCE) it was
anticipated that methods A and B would only show borderline catalytic activity, but method C
should be effective. Indeed, the methods A and B did not yield any conversion after 24 h, while
method C cleaved benzyl from 3b quantitatively in 21 h. In contrast to this, for unknown reasons,
pyridine 3c did not show any reactivity under the studied conditions (entry 3) even though its
estimated reduction potential is less negative than that of 3b.19 Nevertheless, method C was also
able to cleave the benzyl from 3e with a rather low reduction potential of ꢀ1.45/ꢀ1.77 V (SCE)
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Exp./Cal. (entry 5). As a result, a mixture of monodeprotected compounds were obtained. This was
also in agreement with the similar calculated energy barriers found for benzyl cleavages at the 2ꢀ
and 4ꢀ positions, being 5.2 and 5.0 kcal/mol, respectively (Table S1, SI).
8
9
The pyrimidine compounds behaved somewhat unpredictably. On the one hand, NꢀBoc protected
cytosine 3f (entry 6) did not give any reactivity despite its high estimated reduction potential ꢀ1.11
V (SCE) and reasonably low energy barrier, 12.8 kcal/mol, for the benzyl cleavage. Pyridinium
radicals are known to have other possible reactive pathways that may compete herein.20 On the
other hand, with Oꢀdibenzyl protected uracil 3g (entry 7), the catalysis with method B cleaved off
both benzyls. The decrease of the amount of ascorbic acid resulted plainly in an incomplete
conversion. The observed performance can be explained computationally as the reduction potential
of the monodeprotected 2ꢀOBn uracil (3g-2, SI) is similar to 3g, while its radical has a negligible
energy barrier for benzyl cleavage, being only 1.3 kcal/mol (Table S1, SI).
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Finally, we were curious whether the benzyl, as removable group, could be replaced by some other
radical stabilizing groups (Scheme 2). For this purpose, 8ꢀtertꢀbutylꢀquinoline derivatives 5a – 5d
were studied. Gratifyingly, with method A, allyl, substituted allyl (Oꢀgeranyl) and methylene ester
could be cleaved off quantitatively in 1ꢀ1½ hour.
Scheme 2. Removal of other cleavable ethers
Our simplistic mechanistic proposal (Scheme 3) is similar to the one presented in a previous study
involving analogous photocatalyst and ascorbic acid:6 The cycle begins by ascorbic acid protonating
the Nꢀheterocycle and continues by reduction of the excited state of the photocatalyst with ascorbic
acid. Thereafter, the reduced state catalyst donates electron for the substrate, which is fragmented
into benzyl radical and neutral pyridone. This scenario is firmly supported by correlation of various
substrate reduction potentials vs. several catalyst RSRPs. Additionally, SternꢀVolmer plot indicate
that ascorbic acid acts as a primary fluorescence quencher of [Ru] catalyst (SI).
Scheme 3. Plausible mechanism
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In summary, we have discovered a mild, clean, regioꢀ and chemoselective photoreductive
methodology to remove selectively Oꢀbenzyl protections from oxyarene Nꢀheterocycles, which
have the ability to receive an electron from a photoreductant and are capable of 2ꢀ/4ꢀOꢀpyridine – 2ꢀ
/4ꢀpyridone tautomerism. From a methodological perspective, it was shown that useful predictive
information regarding the mode and scope of substrate reactivities could be straightforwardly
obtained by relatively simple, low computational cost DFT methods.
EXPERIMENTAL SECTION
General information. All commercial chemicals were used as received. Photocatalysts were purchased from
TCI
Europe
(Ru(bpy)3Cl2*6H2O)
and
SigmaꢀAldrich
((Ir[dF(CF3)ppy]2(dtbbpy))PF6
and
1
[Ir(dtbbpy)(ppy)2]PF6). H and 13C{1H} NMR spectra were recorded at 27 °C using Varian Mercury 300
[299.95 MHz] or Varian Inova 500 [499.82 MHz] spectrometers. 1H and 13C{1H} spectra were referenced to
the residual solvent signals (in CDCl3 7.26 and 77.2 ppm, respectively; in DMSOꢀd6 2.50 and 39.5 ppm,
respectively). No special notation was used for equivalent carbons. IR spectra were measured with FTIR
Bruker Alpha spectrometer. Cyclic voltammetry was performed with Gamry Interface 1000 potentiostat.
Fluorescence spectra were measured with Horiba Jobin Yvon Fluoromaxꢀ4 spectrofluorometer. High
resolution mass spectra were obtained with Bruker ESI microTOFLC instrument in positive ionisation mode.
Supelco silica gel TLCꢀcards with fluorescent indicator (254 nm) were used for TLC chromatography and Rfꢀ
value determinations. The melting points were determined in capillary tubes with Büchi 510 melting point
apparatus and are reported uncorrected. All photoreductive deprotections were performed in 10 mL Schlenkꢀ
tubes (ca. 110 x 10 mm) under an argon atmosphere. The distance from the light source was 5 cm. The 5 x
3W blue (455 nm) LEDs were positioned in a vertical row along the Schlenkꢀtube.
General procedures for photocatalytic benzyl deprotections:
Method A – using Ru(bpy)3Cl2*6H2O as photocatalyst. The corresponding benzyl ether (1 equiv)
and ascorbic acid (2 equiv) were weighted in a Schlenkꢀtube equipped with a stir bar. A 10 mL of degassed
MeCN/H2O (1:1) solvent mixture and a Ru(bpy)3Cl2*6H2O catalyst (0.5 mol %) were added to the tube
which was placed under a blue light irradiation (455 nm) on a magnetic stirrer plate for a reaction period at
rt. The reaction was monitored with TLC. After completion, the reaction mixture was quenched with aq.
NH4OH and evaporated to dryness. The crude was purified with SiO2 flash chromatography.
Method B – Using (Ir[dF(CF3)ppy]2(dtbbpy))PF6 as photocatalyst. Equivalent to Method A with an
exception that 1.0 mol % catalyst loading was used.
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Method C – Using [Ir(dtbbpy)(ppy)2]PF6 as photocatalyst. Equivalent to Method A with an
exception that 1.0 mol % catalyst loading was used.
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General procedure for the preparation of benzyl ethers:
Method AꢀBn. A roundꢀbottom flask equipped with a stirrer bar was charged with the corresponding
phenol (1 equiv) and K2CO3 (2 equiv). 55 mL of toluene/DMF (50:5) solvent mixture was then added to the
mixture followed by benzyl bromide (1.2 equiv). The reaction mixture was refluxed on a magnetic stirrer
plate for the corresponding time. The progress of the reaction was monitored with TLC. After completion,
the reaction mixture was partitioned between EtOAc and water. The organic layer was dried over Na2SO4
and evaporated to dryness. The crude product was purified with SiO2 flash chromatography.
Method BꢀBn. A roundꢀbottom flask equipped with a stirrer bar was charged with NaH (2 equiv) and
20 mL DMF. Benzyl alcohol (1.5 equiv) was added dropwise to the reaction mixture which was stirred 30
min at rt on a magnetic stirrer plate. The corresponding chloroꢀderivate (1 equiv) was then added to the
reaction mixture and it was further stirred at 80 °C for the corresponding time on a magnetic stirrer plate. The
progress of the reaction was monitored with TLC. After completion, the reaction mixture was partitioned
between EtOAc and water. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude
product was purified with SiO2 flash chromatography. Tip: If there are difficulties with the purification of the
product it can be salted out as the HCl salt. The salt can then be purified with SiO2 flash chromatography
eluting first with solvent that removes the impurities and then in situ neutralizing the salt by adding aq.
NH4OH to the eluent system of choice, thus providing pure and neutral product.
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General procedure for the preparation of quinolones:
Method AꢀQn – using biphenyl ether in the cyclization step. (Compounds 2e, 2h, 2k and 6) Step 1:
preparation of intermediate. A roundꢀbottom flask equipped with a stirrer bar was charged with Meldrum’s
acid (1.5 equiv) and trimethyl orthoformate (25 equiv). The reaction mixture was refluxed for 4 h on a
magnetic stirrer plate after which the corresponding aniline (1 equiv) was added and the refluxing was
continued for 20 h. After completion of the reaction, the excess of trimethyl orthoformate was evaporated
and the solids were suspended in Et2O. The solids were then filtrated off and washed with Et2O. Tip: If
needed, the crude intermediate can be purified, but usually it is sufficiently pure to be used without further
purification. Step 2: cyclization. A roundꢀbottom flask equipped with a stirrer bar was charged with the crude
intermediate, which was dissolved in PhOPh (2 mL/mmol) and refluxed for the corresponding time in a
heating mantle on magnetic stirrer plate. The progress of the reaction was monitored with TLC. After
completion, the reaction mixture was cooled down and diluted with Et2O. The precipitated solids were then
filtrated off and washed with Et2O. Tip: If the desired quinolone does not precipitate out of the reaction
mixture, the whole reaction mixture can be purified with SiO2 flash chromatography. First eluting with DCM
or Et2O to remove the PhOPh and then with the solvent of choice to eluate the desired quinolone.
Compound 2g. A roundꢀbottom flask equipped with a stirrer bar was charged with 2ꢀbromoaniline
°
(1 equiv) and diethyl ethoxymethylenemalonate (1.1 equiv). The reaction mixture was stirred at 100 C in
neat conditions for 2½ h on a magnetic stirrer. The progress of the reaction was monitored with TLC. After
the completion of the reaction, PhOPh (2 mL/mmol) was added to the mixture which was further refluxed for
4 h with the help of heating mantle. After cooling down, the reaction mixture was diluted with Et2O. The
precipitated solids were filtrated off and washed with Et2O.
Compound 2d. Step 1: preparation of intermediate. A roundꢀbottom flask equipped with a stirrer bar
was charged with 2ꢀbromoaniline (1 equiv) and diethyl oxalpropionate (1.1 equiv). Fifty milliliter of benzene
was added to the reaction mixture followed by a catalytic amount of acetic acid. The reaction mixture was
then refluxed for 96 h on a magnetic stirrer plate after which it was partitioned between Et2O and 1 M HCl.
The organic phase was washed with sat. K2CO3, dried over Na2SO4 and evaporated. The crude product was
purified with flash chromatography (SiO2) using nꢀhexane:EtOAc (5:1) as an eluent. Step 2: cyclization. A
roundꢀbottom flask equipped with a stirrer bar was charged with the purified intermediate, which was
refluxed for 4h in PhOPh (2 mL/mmol) with the help of a heating mantle on a magnetic stirrer plate. After
cooling down 50 mL 2 M NaOH was added to the reaction mixture, which was further refluxed for 2 h.
Upon cooling and addition of water the crude product precipitated out. The precipitated solids were filtrated
off and washed with water. The crude product was sufficiently pure to be used without further purifications.
Step 3: decarboxylation. A roundꢀbottom flask equipped with a stirrer bar was charged with the crude
product, which was dissolved in PhOPh (2 mL/mmol) and refluxed for 3 h with the help of a heating mantle
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on a magnetic stirrer plate. After completion of the reaction, the reaction mixture was cooled down and
diluted with Et2O. The precipitated solids were filtrated off and washed with
Method BꢀQn – using polyphosphoric acid (PPA) in the cyclization step. A roundꢀbottom flask fitted
with
a mechanical stirrer was charged with the corresponding aniline (1 equiv). Dimethyl
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acetylenedicarboxylate (1 equiv) was added dropwise to the reaction mixture which was stirred in neat
conditions at room temperature for 1 h. The reaction was monitored with TLC. After the completion of the
reaction, PPA was added and the reaction mixture was further stirred for 2 h at 140 C. After completion of
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the reaction, the reaction mixture was quenched with water and extracted with DCM. The organic phase was
dried over Na2SO4 and evaporated to dryness. The crude product was purified with SiO2 flash
chromatography.
Synthesis of target compounds.
2ꢀ(Benzyloxy)quinoline (1a). The title compound was synthesized following the general procedure
for benzyl ether preparation Method BꢀBn. Starting from 2ꢀchloroquinoline – 7 (0.818 g, 5 mmol), benzyl
alcohol (0.780 mL, 7.5 mmol) and sodium hydride 60% dispersion in mineral oil (0.336 g, 10 mmol).
Reaction time 22 h. Yield 90% (1.060 g, 4.50 mmol). Purification: Flash chromatography (SiO2) using nꢀ
hexane:EtOAc (10:1) as eluent. The characterization data of the obtained compound are in agreement with
°
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the literature values.21 White solid; Rf=0.35 (nꢀhexane:EtOAc=20:1); mp. 46ꢀ47 C; H NMR (300MHz;
CDCl3) δh 8.01 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.74 (dd, J = 8.0, 1.3 Hz, 1H), 7.65 (ddd, J =
8.4, 7.0, 1.5 Hz, 1H), 7.59 – 7.53 (m, 2H), 7.46 – 7.34 (m, 4H), 6.98 (d, J = 8.8 Hz, 1H), 5.59 (s, 2H); 13C
NMR (75MHz; CDCl3) δc 162.1, 146.8, 139.0, 137.6, 129.7, 128.7, 128.5, 128.1, 127.7, 127.5, 125.5, 124.3,
113.5, 67.9; FTIR(cmꢀ1) 2936(w), 2878(w).
Quinolinꢀ2ꢀol (2a). The title compound was synthesized following the general procedure for benzyl
ether removal Method A. Starting from 2ꢀ(benzyloxy)quinoline – 1a (0.0471 g, 0.2 mmol), ascorbic acid
(0.0704 g, 0.4 mmol) and [Ru] photocatalyst (0.75 mg, 0.001 mmol). Reaction time 1 h. Yield >99%
(0.0290g, 0.2mmol). Purification: Flash chromatography (SiO2) using DCM:MeOH (20:1) as eluent. Using
Method B: Reaction time 1 h. Yield >99% (0.0290 g, 0.2 mmol). Purification: Flash chromatography (SiO2)
using DCM:MeOH (20:1) as eluent. Using Method C: Catalyst loading 0.5 mol %. Reaction time 1 h. Yield
>99% (0.0290 g, 0.2 mmol). Purification: Flash chromatography (SiO2) using DCM:MeOH (20:1) as eluent.
The characterization data of the obtained compound are in agreement with the literature values.22 White
solid; Rf=0.35 (DCM:MeOH (20:1)); mp. 193ꢀ194 °C; 1H NMR (300 MHz; DMSO) δh 11.72 (s, 1H), 7.86 (d,
J = 9.6 Hz, 1H), 7.62 (dd, J = 7.8, 1.1 Hz, 1H), 7.46 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 7.29 (dd, J = 8.3, 0.5 Hz,
1H), 7.13 (ddd, J = 7.8, 7.2, 1.1 Hz, 1H), 6.48 (d, J = 9.5 Hz, 1H); 13C NMR (75 MHz; DMSO) δc 162.6,
140.9, 139.6, 131.0, 128.5, 122.6, 122.4, 119.9, 115.8; FTIR(cmꢀ1) 2987(m), 2885(m).
2ꢀChloroquinoline – (7). A roundꢀbottom flask equipped with a stirrer bar was charged with
quinolineꢀ2ꢀol (1.452 g, 10 mmol) dissolved in 100 mL of dry toluene. Phosphorous oxychloride (9.323 mL,
100 mmol) was then added and the reaction mixture was refluxed under argon for 21 h on a magnetic stirrer
plate. After completion of the reaction, the mixture was carefully quenched with water (NB! exothermic
reaction) and basified with aqueous NH4OH. The reaction mixture was extracted with EtOAc, dried over
Na2SO4 and evaporated to dryness. The crude was purified with SiO2 flash chromatography. Yield 99.1%
(1.621 g, 9.91 mmol). Purification: Flash chromatography (SiO2) using DCM as eluent. The characterization
data of the obtained compound are in agreement with the literature values.23 Light yellowish solid; Rf=0.25
(nꢀhexane:EtOAc (20:1)); mp. 36ꢀ37 °C; 1H NMR (300 MHz; CDCl3) δh 8.07 (d, J = 8.6 Hz, 1H), 8.00 (ddt, J
= 8.5, 1.3, 0.7 Hz, 1H), 7.79 (dd, J = 8.1, 1.3 Hz, 1H), 7.72 (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 7.53 (ddd, J = 8.2,
7.0, 1.2 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H); 13C NMR (75MHz; CDCl3) δc 150.8, 148.1, 139.1, 130.8, 128.8,
127.8, 127.8, 127.0, 122.5; FTIR(cmꢀ1) 813(s), 777(s), 741(s).
4ꢀ(Benzyloxy)quinoline (1b). The title compound was synthesized following the general procedure
for benzyl ether preparation Method AꢀBn. Starting from Quinolinꢀ4ꢀol (0.581 g, 4 mmol), benzyl bromide
(0.570 mL, 4.8 mmol) and potassium carbonate (1.106 g, 8 mmol). Reaction time 22 h. Yield 20.2% (0.190
g, 0.81 mmol). Purification: Flash chromatography (SiO2) using DCM:EtOAc (2:1→1:1) as eluent. The
characterization data of the obtained compound are in agreement with the literature values.24 White solid;
°
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Rf=0.20 (nꢀhexane:EtOAc (1:1)); mp. 75ꢀ76 C; H NMR (300 MHz; CDCl3) δh 8.74 (d, J = 5.2 Hz, 1H),
8.28 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.71 (dd, J = 11.1, 4.2 Hz, 1H), 7.55 – 7.37 (m, 5H), 6.79
(d, J = 5.2 Hz, 1H), 5.29 (s, 2H); 13C NMR (75MHz; CDCl3) δc 161.5, 151.6, 149.6, 136.0, 130.0, 129.2,
129.0, 128.6, 127.7, 125.9, 122.2, 121.7, 101.4, 70.5; FTIR(cmꢀ1) 3003(w), 2957(w), 2933(w), 2873(w).
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Quinolinꢀ4ꢀol – (2b). The title compound was synthesized following the general procedure for
benzyl ether removal Method A. Starting from 4ꢀ(benzyloxy)quinoline – 1b (0.0471 g, 0.2 mmol), ascorbic
acid (0.0704 g, 0.4 mmol) and [Ru] photocatalyst (0.75 mg, 0.001 mmol). Reaction time 1 h. Yield >99%
(0.0290 g, 0.2 mmol). Purification: Flash chromatography (SiO2) using DCM:MeOH (10:1) as eluent. The
characterization data of the obtained compound are in agreement with the literature values.25 White solid;
Rf=0.31 (DCM:MeOH=10:1); mp. 198ꢀ199 C; H NMR (300MHz; DMSO) δh 11.77 (s, 1H), 8.08 (dd, J =
8.1, 1.5 Hz, 1H), 7.88 (dd, J = 7.2, 5.4 Hz, 1H), 7.61 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.55 – 7.50 (m, 1H),
7.28 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 6.03 (d, J = 7.4 Hz, 1H); 13C NMR (75MHz; DMSO) δc 177.6, 140.7,
140.1, 132.3, 126.5, 125.6, 123.7, 118.9, 109.4; FTIR(cmꢀ1) 3062(w), 2972(w), 2901(w).
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4ꢀ(Benzyloxy)ꢀ2ꢀmethylquinoline (1c). The title compound was synthesized following the general
procedure for benzyl ether preparation Method AꢀBn. Starting from 2ꢀmethylquinolinꢀ4ꢀol (0.796 g, 5 mmol),
benzyl bromide (0.713 mL, 6 mmol) and potassium carbonate (1.382 g, 10 mmol). Reaction time 24 h. Yield
96% (1.197 g, 4.80 mmol). Purification: Flash chromatography (SiO2) using DCM→DCM:MeOH (40:1) as
eluent. Light yellowish solid; Rf=0.23 (DCM:MeOH (40:1)); mp. 105ꢀ106 C; H NMR (300 MHz; CDCl3)
δh 8.20 (dd, J = 8.3, 0.9 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.65 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.54 – 7.34
(m, 6H), 6.68 (s, 1H), 5.24 (s, 2H), 2.68 (s, 3H); 13C NMR (75 MHz; CDCl3) δc 161.5, 160.3, 149.2, 136.1,
130.0, 129.0, 128.6, 128.4, 127.7, 125.1, 122.0, 120.2, 101.8, 70.3, 26.2; FTIR(cmꢀ1) 3063(w), 3005(w),
2914(w), 2872(w); HRMS: calcd for C17H16NO 250.1226 (M+H); found 250.1224 (∆=0.99 ppm)
°
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2ꢀMethylquinolinꢀ4ꢀol (2c). The title compound was synthesized following the general procedure for
benzyl ether removal Method A. Starting from 4ꢀ(benzyloxy)ꢀ2ꢀmethylquinoline – 1c (0.0499 g, 0.2 mmol),
ascorbic acid (0.0704 g, 0.4 mmol) and [Ru] photocatalyst (0.75 mg, 0.001 mmol). Reaction time 1h. Yield
93.1% (0.0296 g, 0.19 mmol). Purification: Flash chromatography (SiO2) using acetone as eluent. The
characterization data of the obtained compound are in agreement with the literature values.26 White solid;
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Rf=0.33 (DCM:MeOH (10:1)); mp. 229ꢀ230 °C; H NMR (300MHz; DMSO) δh 11.58 (s, 1H), 8.05 (dd, J =
8.0, 1.3 Hz, 1H), 7.60 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.26 (ddd, J = 8.0, 7.0, 1.1
Hz, 1H), 5.91 (s, 1H), 2.33 (s, 3H); 13C NMR (75MHz; DMSO) δc 177.4, 150.3, 140.8, 132.1, 125.5, 125.2,
123.4, 118.4, 109.1, 20.1; FTIR(cmꢀ1) 3061(w), 2971(w), 2901(w), 2738(w), 2663(w).
4ꢀ(Benzyloxy)ꢀ8ꢀbromoꢀ3ꢀmethylquinoline (1d). The title compound was synthesized following the
general procedure for benzyl ether preparation Method AꢀBn. Starting from 8ꢀbromoꢀ3ꢀmethylquinolinꢀ4ꢀol
(0.238 g, 1 mmol), benzyl bromide (0.143 mL, 1.2 mmol) and potassium carbonate (0.276 g, 2 mmol).
Reaction time 24 h. Yield 84.8% (0.278 g, 0.85 mmol). Purification: Flash chromatography (SiO2) using nꢀ
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hexane:EtOAc (10:1) as eluent. Light yellowish solid; Rf=0.12 (nꢀhexane:EtOAc (10:1)); mp. 96ꢀ97 C; H
NMR (300 MHz; CDCl3) δh 8.86 (s, 1H), 8.04 (dd, J = 8.4, 1.3 Hz, 1H), 7.97 (dd, J = 7.4, 1.3 Hz, 1H), 7.49
– 7.37 (m, 5H), 7.33 (dd, J = 8.4, 7.5 Hz, 1H), 5.10 (s, 2H), 2.42 (s, 3H); 13C NMR (75 MHz; CDCl3) δc
160.2, 155.1, 146.1, 136.4, 132.7, 128.9, 128.7, 128.2, 126.8, 125.4, 124.9, 122.8, 121.9, 76.3, 14.0;
FTIR(cmꢀ1) 3089(w), 3066(w), 3033(w), 2953(w), 2917(w), 766(s), 747(s), 694(s)); HRMS: calcd for
C17H15BrNO 328.0332 (M+H); found 328.0.327 (∆=1.52 ppm)
8ꢀBromoꢀ3ꢀmethylquinolinꢀ4ꢀol (2d). By catalytic deprotection: The title compound was synthesized
following the general procedure for benzyl ether removal Method A. Starting from 4ꢀ(benzyloxy)ꢀ8ꢀbromoꢀ
3ꢀmethylquinoline – 1d (0.0656 g, 0.2 mmol), ascorbic acid (0.0704 g, 0.4 mmol) and [Ru] photocatalyst
(0.75 mg, 0.001 mmol). Reaction time 1 h. Yield 92.9% (0.0442 g, 0.19 mmol). Purification: Flash
chromatography (SiO2) using DCM:MeOH (40:1) as eluent.
By cyclization: The title compound was synthesized following the general procedure for preparation
of quinolones Method AꢀQn (compound 2d). The intermediate 1 was obtained from 2ꢀbromoaniline (5.161 g,
30 mmol) diethyl 2ꢀmethylꢀ3ꢀoxosuccinate (6.224 mL, 33 mmol) and catalytic amount of acetic acid. Yield
56% (6.0 g, 16.84 mmol). Purification: Flash chromatography (SiO2) using nꢀhexane:EtOAc (5:1) as eluent.
The intermediate 2 was obtained from intermediate 1 (6.0 g, 16.84 mmol), which was refluxed in PhOPh for
4 h. Then to the reaction mixture was added 50 mL 2 M NaOH and the reflux was continued for additional 2
h. Yield 15.3% (0.723 g, 2.56 mmol). The product was prepared from the intermediate 2 (0.600 g, 2.13
mmol), which was refluxed in PhOPh for 3 h. Yield 71.5% (0.326 g, 1.37 mmol). White solid; Rf=0.27
(DCM:MeOH (20:1)); mp. 224ꢀ225 °C; 1H NMR (300 MHz; DMSO) δh 10.99 (d, J = 4.6 Hz, 1H), 8.13 (dd,
J = 8.1, 1.3 Hz, 1H), 7.92 (dd, J = 7.6, 1.4 Hz, 1H), 7.81 (dd, J = 6.0, 0.6 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H),
1.99 (s, J = 0.5 Hz, 3H); 13C NMR (75 MHz; DMSO) δc 177.1, 138.1, 138.0, 135.3, 126.1, 125.7, 124.0,
118.1, 111.7, 14.1; FTIR(cmꢀ1) 3081(w), 2946(w), 2922(w), 2892(w), 746(s); HRMS: calcd for C10H9BrNO
237.9862 (M+H); found 237.9858 (∆=1.88 ppm)
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4ꢀ(benzyloxy)ꢀ8ꢀbromoquinoline (1e). The title compound was synthesized following the general
procedure for benzyl ether preparation Method AꢀBn. Starting from 8ꢀbromoquinolinꢀ4ꢀol (2.241 g, 10
mmol), benzyl bromide (1.523 mL, 12 mmol) and potassium carbonate (2.764 g, 20 mmol). Reaction time 25
h. Yield 61.1% (1.921 g, 6.11 mmol). Purification: Flash chromatography (SiO2) using DCM→DCM:MeOH
(100:1→50:1) as eluent. The characterization data of the obtained compound are in agreement with the
°
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literature values.10a light yellowish solid; Rf=0.30 (Hexane:EtOAc=2:1); mp. 125ꢀ126 C; H NMR (300
MHz; CDCl3) δh 8.86 (d, J = 5.2 Hz, 1H), 8.25 (dd, J = 8.4, 1.3 Hz, 1H), 8.03 (dd, J = 7.5, 1.3 Hz, 1H), 7.51
– 7.37 (m, 5H), 7.36 – 7.29 (m, 1H), 6.85 (d, J = 5.2 Hz, 1H), 5.28 (s, 2H); 13C NMR (75 MHz; CDCl3) δc
161.7, 152.3, 146.6, 135.6, 133.8, 129.0, 128.8, 127.7, 126.2, 124.5, 123.1, 122.2, 102.1, 70.9; FTIR(cmꢀ1)
3059(w), 3032(w), 2942(w), 2881(w), 746(s), 699(s).
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8ꢀBromoquinolinꢀ4ꢀol (2e). By catalytic deprotection: The title compound was synthesized following
the general procedure for benzyl ether removal Method A. Starting from 4ꢀ(benzyloxy)ꢀ8ꢀbromoquinoline –
1e (0.0628 g, 0.2 mmol), ascorbic acid (0.0704g, 0.4mmol) and [Ru] photocatalyst (0.00075g, 0.001mmol).
Reaction time 2h. Yield >99% (0.0448g, 0.2mmol). Purification: Flash chromatography (SiO2) using
DCM:MeOH (20:1) using as eluent.
By cyclization: The title compound was synthesized following the general procedure for preparation
of quinolones Method AꢀQn (compounds 2e, 2h, 2k and 6). The intermediate was obtained from 2ꢀ
bromoaniline (10.011 g, 58.2 mmol) Meldrum’s acid (12.160 g, 84.4 mmol) and trimethyl orthoformate
(159.027 mL, 1453.6 mmol). Yield 88.2% (16.739 g, 51.32 mmol). The product was prepared from the
intermediate (6.0 g, 18.39 mmol), which was refluxed in PhOPh for 4 h. Yield 88.4% (3.642 g, 16.25 mmol).
The characterization data of the obtained compound are in agreement with the literature values.10a White
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solid; Rf=0.22 (DCM:MeOH (20:1)); mp. 164ꢀ165 C; H NMR (300 MHz; DMSO) δh 11.09 (s, 1H), 8.10
(dd, J = 8.0, 1.0 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 6.10 (d,
J = 7.5 Hz, 1H); 13C NMR (75MHz; DMSO) δc 177.2, 141.0, 138.3, 135.9, 127.9, 125.7, 124.6, 112.0, 110.1;
FTIR(cmꢀ1) 3426 (br. w), 2988(w), 2901(w), 788(s), 742(s).
4ꢀ(Benzyloxy)quinolineꢀ8ꢀcarbaldehyde (8). A Schlenkꢀflask equipped with a stirrer bar was charged
with 4ꢀ(benzyloxy)ꢀ8ꢀbromoquinoline – 2e (0.730 g, 2.32 mmol) and 50 mL of dry THF under argon. The
reaction mixture was cooled down to ꢀ78 °C and 2.5 M nꢀbutyllithium (1.39 mL, 3.48 mmol) was added to it
°
under magnetic stirring. The reaction mixture was then stirred at ꢀ78 C for 30 min after which dry DMF
°
(0.268 mL, 3.48 mmol) was added to it. The mixture was further stirred 3½ h at ꢀ78 C. The reaction was
quenched with water and extracted with EtOAc. The organic phase was dried over Na2SO4 and evaporated to
dryness. The crude was purified with SiO2 flash chromatography. Yield 65.5% (0.400 g, 1.52 mmol).
Purification: Flash chromatography (SiO2) using DCM as eluent. The characterization data of the obtained
compound are in agreement with the literature values.10a Light yellowish solid; Rf=0.35
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(Hexane:EtOAc=3:1); mp. 118ꢀ119 C; H NMR (300MHz; CDCl3) δh 11.42 (s, 1H), 8.87 (d, J = 5.2 Hz,
1H), 8.56 (dd, J = 8.3, 1.6 Hz, 1H), 8.32 (dd, J = 7.2, 1.6 Hz, 1H), 7.63 (ddd, J = 8.1, 7.2, 0.7 Hz, 1H), 7.53 –
7.41 (m, 5H), 6.91 (d, J = 5.2 Hz, 1H), 5.33 (s, 2H); 13C NMR (75MHz; CDCl3) δc 193.1, 161.7, 152.5,
149.1, 135.5, 131.5, 129.8, 129.1, 128.8, 128.8, 127.8, 125.4, 122.1, 102.1, 70.8; FTIR(cmꢀ1) 2988(w),
2968(w), 2923(w), 2877 (w), 1678(s).
4ꢀ(Benzyloxy)ꢀ8ꢀ(5,5ꢀdimethylꢀ1,3ꢀdioxanꢀ2ꢀyl)quinoline – (1f). A roundꢀbottom flask equipped with
a stirrer bar was charged with 4ꢀ(benzyloxy)quinolineꢀ8ꢀcarbaldehyde – 8 (0.080 g, 0.3 mmol), 2,2ꢀ
dimethylpropaneꢀ1,3ꢀdiol (0.156 g, 1.5 mmol) and 30 mL benzene. pꢀTSA (0.003 g, 0.015 mmol) was added
to the mixture and it was refluxed in a DeanꢀStark apparatus for 24 h on a magnetic stirrer plate. The reaction
mixture was then quenched with 2N NaOH and extracted with EtOAc. Organic phase was dried over Na2SO4
and evaporated to dryness. The crude was purified with SiO2 flash chromatography. Yield 99% (0.104 g,
0.29 mmol). Purification: Flash chromatography (SiO2) using DCM→DCM:MeOH (100:1→50:1) as eluent.
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White solid; Rf=0.17 (Hexane:EtOAc=2:1); mp. 202ꢀ203 °C; H NMR (300MHz; CDCl3) δh 8.77 (d, J = 5.2
Hz, 1H), 8.31 (dd, J = 8.4, 1.5 Hz, 1H), 8.15 (dd, J = 7.2, 1.5 Hz, 1H), 7.57 (dd, J = 8.3, 7.3 Hz, 1H), 7.52 –
7.34 (m, 5H), 6.80 (d, J = 5.2 Hz, 1H), 6.71 (s, 1H), 5.28 (s, 2H), 3.89 (d, J = 10.6 Hz, 2H), 3.82 (d, J = 10.9
Hz, 2H), 1.40 (s, 3H), 0.84 (s, 3H); 13C NMR (75MHz; CDCl3) δc 161.5, 151.2, 146.6, 135.9, 135.8, 129.0,
128.6, 128.0, 127.6, 125.8, 123.1, 121.5, 101.4, 97.8, 78.2, 70.4, 30.6, 23.5, 22.2; FTIR(cmꢀ1) 2989(w),
2858(w); HRMS: calcd for C22H24NO3 350.1751 (M+H); found 350.1749 (∆=0.47 ppm)
8ꢀ(5,5ꢀDimethylꢀ1,3ꢀdioxanꢀ2ꢀyl)quinolinꢀ4ꢀol – (2f). The title compound was synthesized following
the general procedure for benzyl ether removal Method A. Starting from 4ꢀ(benzyloxy)ꢀ8ꢀ(5,5ꢀdimethylꢀ1,3ꢀ
dioxanꢀ2ꢀyl)quinoline – 1f (0.0349 g, 0.1 mmol), ascorbic acid (0.0352 g, 0.2 mmol) and [Ru] photocatalyst
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(0.375 mg, 0.0005 mmol). Reaction time 40 min. Yield 90% (0.0232 g, 0.09 mmol). Purification: Flash
chromatography (SiO2) using DCM:MeOH (20:1) as eluent. White solid; Rf=0.26 (DCM:MeOH (20:1)); mp.
°
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69ꢀ70 C; H NMR (300 MHz; CDCl3) δh 10.36 (s, 1H), 8.39 (dd, J = 8.2, 1.5 Hz, 1H), 7.64 (ddd, J = 7.4,
3.9, 2.3 Hz, 2H), 7.31 (dd, J = 8.1, 7.4 Hz, 1H), 6.29 (d, J = 7.5 Hz, 1H), 5.71 (s, 1H), 3.85 (d, J = 11.4 Hz,
2H), 3.74 (d, J = 10.7 Hz, 2H), 1.33 (s, 3H), 0.84 (s, 3H); 13C NMR (75MHz; CDCl3) δc 178.9, 138.2, 138.1,
131.6, 127.6, 127.3, 125.1, 123.2, 110.2, 102.9, 78.2, 30.6, 23.6, 22.1; FTIR(cmꢀ1) 3259(br. w), 3083(w),
2956(w), 2865(w), 1787(w); HRMS: calcd for C15H18NO3 260.1281 (M+H); found 260.1285 (∆=1.54 ppm)
Ethyl 4ꢀ(benzyloxy)ꢀ8ꢀbromoquinolineꢀ3ꢀcarboxylate – (1g). The title compound was synthesized
following the general procedure for benzyl ether preparation Method AꢀBn. Starting from ethyl 8ꢀbromoꢀ4ꢀ
hydroxyquinolineꢀ3ꢀcarboxylate (1.481 g, 5 mmol), benzyl bromide (0.761 mL, 6 mmol) and potassium
carbonate (1.381 g, 10 mmol). Reaction time 24 h. Yield 50.5% (0.975 g, 2.52 mmol). Purification: Flash
chromatography (SiO2) using DCM:MeOH (100:1) as eluent. Light yellowish solid; Rf=0.16 (nꢀ
hexane:EtOAc (10:1)); mp. 89ꢀ90 °C; 1H NMR (300 MHz; CDCl3) δh 9.34 (s, J = 3.4 Hz, 1H), 8.16 (dd, J =
8.4, 1.3 Hz, 1H), 8.08 (dd, J = 7.5, 1.3 Hz, 1H), 7.47 – 7.32 (m, 6H), 5.30 (s, 2H), 4.47 (q, J = 7.1 Hz, 2H),
1.42 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz; CDCl3) δc 165.0, 164.2, 153.0, 148.1, 136.1, 135.5, 128.9,
128.5, 127.4, 125.5, 124.9, 123.7, 115.0, 78.4, 62.0, 14.5; FTIR(cmꢀ1) 3065(w), 3036(w), 2979(w), 2928(w),
2904(w), 1719(s), 779(s), 741(s), 690(s); HRMS: calcd for C19H17BrNO3 386.0386 (M+H); found 386.0397
(∆=2.75 ppm)
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Ethyl 8ꢀbromoꢀ4ꢀhydroxyquinolineꢀ3ꢀcarboxylate (2g). By catalytic deprotection: The title
compound was synthesized following the general procedure for benzyl ether removal Method A. Starting
from ethyl 4ꢀ(benzyloxy)ꢀ8ꢀbromoquinolineꢀ3ꢀcarboxylate – 1g (0.0773 g, 0.2 mmol), ascorbic acid (0.0704
g, 0.4 mmol) and [Ru] photocatalyst (0.75 mg, 0.001 mmol). Reaction time 1 h. Yield >99% (0.0592 g, 0.2
mmol). Purification: Flash chromatography (SiO2) using DCM:MeOH (40:1) as eluent.
By cyclization: The title compound was synthesized following the general procedure for preparation
of quinolones Method AꢀQn (compound 2g). Starting from 2ꢀbromoaniline (8.601 g, 50 mmol) and diethyl
ethoxymethylenemalonate (11.115 mL, 55 mmol) Yield 93.2% (13.793 g, 46.56 mmol). The characterization
data of the obtained compound are in agreement with the literature values.27 White solid; Rf=0.32
(DCM:MeOH (20:1)); mp. 252ꢀ253 °C; 1H NMR (300 MHz; DMSO) δh 11.58 (s, 1H), 8.42 (s, 1H), 8.15 (dd,
J = 8.1, 1.4 Hz, 1H), 7.99 (dd, J = 7.7, 1.4 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 1.26 (t,
J = 7.1 Hz, 3H); 13C NMR (75 MHz; DMSO) δc 173.5, 165.0, 146.2, 137.3, 136.6, 129.5, 126.3, 126.3,
112.4, 111.0, 60.5, 14.9; FTIR(cmꢀ1) 3149(w), 3081(w), 2975(w), 2925(w), 2901(w), 1710(m), 743(s).
Ethyl 4ꢀ(benzyloxy)quinolineꢀ8ꢀcarboxylate – (1h). The title compound was synthesized following
the general procedure for benzyl ether preparation Method AꢀBn. Starting from ethyl 4ꢀhydroxyquinolineꢀ8ꢀ
carboxylate (0.652 g, 3 mmol), benzyl bromide (0.428 mL, 3.6 mmol) and potassium carbonate (0.829 g, 6
mmol). Reaction time 28 h. Yield 80.7% (0.744 g, 2.42 mmol). Purification: Flash chromatography (SiO2)
°
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using nꢀhexane:EtOAc (1:1) as eluent. Yellowish solid; Rf=0.24 (Hexane:EtOAc (1:1)); mp. 99ꢀ100 C; H
NMR (300 MHz; CDCl3) δh 8.86 (d, J = 5.2 Hz, 1H), 8.40 (dd, J = 8.4, 1.5 Hz, 1H), 7.98 (dd, J = 7.2, 1.5
Hz, 1H), 7.56 – 7.35 (m, 6H), 6.83 (d, J = 5.3 Hz, 1H), 5.28 (s, 2H), 4.52 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1
Hz, 3H); 13C NMR (75 MHz; CDCl3) δc 168.1, 161.4, 152.6, 146.8, 135.7, 131.8, 130.6, 129.0, 128.7, 127.7,
125.5, 124.8, 122.1, 101.9, 70.6, 61.6, 14.6; FTIR(cmꢀ1) 3061(w), 2985(w), 2943(w), 2903(w), 1724(s);
HRMS: calcd for C19H18NO3 308.1281 (M+H); found 308.1280 (∆=0.47 ppm)
Ethyl 4ꢀhydroxyquinolineꢀ8ꢀcarboxylate – (2h). By catalytic deprotection: The title compound was
synthesized following the general procedure for benzyl ether removal Method A. Starting from ethyl 4ꢀ
(benzyloxy)quinolineꢀ8ꢀcarboxylate – 1h (0.0615 g, 0.2 mmol), ascorbic acid (0.0704 g, 0.4 mmol) and [Ru]
photocatalyst (0.75 mg, 0.001 mmol). Reaction time 2 h. Yield 36.2% (0.0157 g, 0.07 mmol). Purification:
Flash chromatography (SiO2) using DCM:MeOH (40:1) as eluent.
By cyclization: The title compound was synthesized following the general procedure for preparation
of quinolones Method AꢀQn (compounds 2e, 2h, 2k and 6). The intermediate was obtained from ethyl 2ꢀ
aminobenzoate (8.599 mL, 58.2 mmol) Meldrum’s acid (12.160 g, 84.4 mmol) and trimethyl orthoformate
(159.027 mL, 1453.6 mmol). Yield 86.8% (16.128 g, 50.51 mmol). The product was prepared from the
intermediate (5.748 g, 18 mmol), which was refluxed in PhOPh for 3 h. Yield 73.7% (2.882 g, 13.27 mmol).
Light yellowish solid; Rf=0.27 (DCM:MeOH (20:1)); mp. 151ꢀ152 °C; 1H NMR (300 MHz; DMSO) δh 11.72
(s, 1H), 8.40 (dd, J = 8.0, 1.4 Hz, 1H), 8.31 (dd, J = 7.6, 1.6 Hz, 1H), 7.98 (dd, J = 7.5, 6.3 Hz, 1H), 7.40 (t, J
= 7.8 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); 13C NMR (75
MHz; DMSO) δc 177.1, 166.8, 141.2, 140.3, 135.4, 132.2, 127.3, 122.8, 116.7, 110.3, 62.1, 14.7; FTIR(cmꢀ1)
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3280(m), 2980(w), 2940(w), 2904(w), 1686(m); HRMS: calcd for C12H12NO3 218.0812 (M+H); found
218.0819 (∆=3.12 ppm)
Methyl 4ꢀ(benzyloxy)quinolineꢀ2ꢀcarboxylate (1i). The title compound was synthesized following the
general procedure for benzyl ether preparation Method AꢀBn. Starting from methyl 4ꢀhydroxyquinolineꢀ2ꢀ
carboxylate (0.610 g, 3 mmol), benzyl bromide (0.428 mL, 3.6 mmol) and potassium carbonate (0.829 g, 6
mmol). Reaction time 24 h. Yield 79% (0.693 g, 2.37 mmol). Purification: Flash chromatography (SiO2)
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using nꢀhexane:EtOAc (5:1→3:1) as eluent. White solid; Rf=0.19 (nꢀhexane:EtOAc (2:1)); mp. 128ꢀ129 C;
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1H NMR (300 MHz; CDCl3) δh 8.29 (ddd, J = 8.4, 1.5, 0.6 Hz, 1H), 8.24 (ddd, J = 8.5, 1.1, 0.6 Hz, 1H), 7.76
(ddd, J = 8.5, 5.5, 1.5 Hz, 1H), 7.68 (s, 1H), 7.59 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.55 – 7.50 (m, 2H), 7.48 –
7.37 (m, 3H), 5.35 (s, 2H), 4.07 (s, 3H); 13C NMR (75 MHz; CDCl3) δc 166.5, 162.6, 149.3, 148.8, 135.6,
130.7, 130.5, 129.0, 128.8, 127.9, 122.6, 122.2, 101.4, 70.9, 53.5; FTIR(cmꢀ1) 3109(w), 3074(w), 3035(w),
3009(w), 2954(w), 1744(m), 1721(m); HRMS: calcd for C18H16NO3 294.1125 (M+H); found 294.1115
(∆=3.33 ppm)
Methyl 4ꢀhydroxyquinolineꢀ2ꢀcarboxylate (2i). The title compound was synthesized following the
general procedure for preparation of quinolones Method BꢀQn. Starting from aniline (2.283 mL, 25 mmol)
and dimethyl acetylenedicarboxylate (3.073 mL, 25 mmol). PPA was used as a solvent. Yield 58.2% (2.958
g, 14.56 mmol). Purification: Flash chromatography (SiO2) using DCM:MeOH (40:1→20:1) as eluent. The
characterization data of the obtained compound are in agreement with the literature values.28 Light yellowish
solid; Rf=0.27 (DCM:MeOH (20:1)); mp. 224ꢀ225 °C; 1H NMR (300 MHz; DMSO) δh 12.05 (s, 1H), 8.08 (d,
J = 8.1 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 6.63 (s, 1H), 3.96
(s, 3H); 13C NMR (75 MHz; DMSO) δc 178.3, 163.3, 140.7, 138.3, 133.3, 126.6, 125.4, 124.7, 120.2, 110.9,
54.2; FTIR(cmꢀ1) 3072(w), 2954(w), 2875(w), 2761(w), 1738(m).
2,4ꢀBis(benzyloxy)quinoline (1j). The title compound was synthesized following the general
procedure for benzyl ether preparation Method BꢀBn. Starting from 2,4ꢀdichloroquinoline – 9 (0.990 g, 5
mmol), benzyl alcohol (1.560 mL, 15 mmol) and sodium hydride 60% dispersion in mineral oil (0.672 g, 20
mmol). Reaction time 18 h. Yield 86.4% (1.475 g, 4.32 mmol). Purification: Flash chromatography (SiO2)
using nꢀhexane:EtOAc (10:1) as eluent. The characterization data of the obtained compound are in
agreement with the literature values.29 White solid; Rf=0.27 (nꢀhexane:EtOAc=20:1); mp. 80ꢀ81 °C; 1H NMR
(300 MHz; CDCl3) δh 8.17 (dd, J = 8.2, 0.9 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.68 – 7.61 (m, 1H), 7.57 –
7.35 (m, 11H), 6.40 (s, 1H), 5.57 (s, 2H), 5.23 (s, 2H); 13C NMR (75 MHz; CDCl3) δc 163.4, 163.2, 147.3,
137.7, 136.0, 130.3, 129.0, 128.7, 128.6, 128.1, 127.7, 127.2, 123.6, 122.3, 119.7, 92.2, 70.5, 68.0; FTIR(cmꢀ
1) 3062(w), 3033(w), 2949(w), 2927(w), 2876(w).
4ꢀ(Benzyloxy)quinolinꢀ2ꢀol – (2j). The title compound was synthesized following the general
procedure for benzyl ether removal Method A. Starting from 2,4ꢀbis(benzyloxy)quinoline – 1j (0.0683 g, 0.2
mmol), ascorbic acid (0.0704g, 0.4mmol) and [Ru] photocatalyst (0.0015g, 0.002mmol). Reaction time 5 h.
Yield 76.5% (0.0385 g, 0.15 mmol). Purification: Flash chromatography (SiO2) using DCM→DCM:MeOH
(20:1) as eluent.
Using Method B: Reaction time 3 h. Yield 99% (0.0498 g, 0.19 mmol). Purification: Flash chromatography
(SiO2) using DCM→DCM:MeOH (20:1) as eluent. The characterization data of the obtained compound are
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in agreement with the literature values.17 White solid; Rf=0.31 (DCM:MeOH (20:1)); mp. 195ꢀ196 C; H
NMR (300 MHz; CDCl3) δh 12.52 (s, 1H), 7.96 (dd, J = 8.1, 1.0 Hz, 1H), 7.54 – 7.36 (m, 7H), 7.18 (ddd, J =
8.2, 5.5, 1.4 Hz, 1H), 6.11 (s, 1H), 5.20 (s, 2H); 13C NMR (75 MHz; CDCl3) δc 166.5, 164.1, 138.8, 135.5,
131.4, 129.0, 128.7, 127.8, 123.1, 122.3, 116.4, 115.8, 97.3, 70.8; FTIR(cmꢀ1) 3060(w), 2965(w), 2828(w),
2697(w).
2,4ꢀDichloroquinoline (9). A roundꢀbottom flask equipped with a stirrer bar was charged with
quinolineꢀ2,4ꢀdiol (1.612 g, 10 mmol) and 50 mL of dry toluene. Phosphorous oxychloride (9.323 mL, 100
mmol) was added to the reaction mixture which was then refluxed under argon for 21 h on a magnetic stirrer
plate. After completion of the reaction, the reaction mixture was carefully quenched with water (NB!
exothermic reaction) and basified with aqueous NH4OH. The reaction mixture was then extracted with
EtOAc, dried over Na2SO4 and evaporated to dryness. The crude was purified with SiO2 flash
chromatography. Yield 92.5% (1.833 g, 9.25 mmol). Purification: Flash chromatography (SiO2) using DCM
as eluent. The characterization data of the obtained compound are in agreement with the literature values.30
Light yellowish solid; Rf=0.30 (nꢀhexane:EtOAc (20:1)); mp. 64ꢀ65 °C; 1H NMR (300 MHz; CDCl3) δh 8.17
(ddd, J = 8.4, 1.4, 0.5 Hz, 1H), 8.02 (ddd, J = 8.5, 1.2, 0.6 Hz, 1H), 7.78 (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 7.63
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(ddd, J = 8.3, 5.8, 1.2 Hz, 1H), 7.49 (s, J = 1.8 Hz, 1H); 13C NMR (75 MHz; CDCl3) δc 150.0, 148.3, 144.6,
131.7, 129.2, 128.1, 125.4, 124.4, 122.2; FTIR(cmꢀ1) 854(m), 842(s), 755(s), 708(s).
4,8ꢀBis(benzyloxy)quinoline (1k). The title compound was synthesized following the general
procedure for benzyl ether preparation Method AꢀBn. Starting from 8ꢀ(benzyloxy)quinolinꢀ4ꢀol (0.754 g, 3
mmol), benzyl bromide (0.428 mL, 3.6 mmol) and potassium carbonate (0.829 g, 6 mmol). Reaction time 16
h. Yield 31.4% (0.322 g, 0.94 mmol). Purification: Flash chromatography (SiO2) using nꢀhexane:EtOAc
(1:1→EtOAc) as eluent. Light yellowish solid; Rf=0.34 (DCM:MeOH (40:1)); mp. 157ꢀ158 C; H NMR
(300 MHz; CDCl3) δh 8.80 (d, J = 5.2 Hz, 1H), 7.83 (dd, J = 8.4, 1.1 Hz, 1H), 7.55 – 7.46 (m, 4H), 7.45 –
7.28 (m, 7H), 7.03 (dd, J = 7.8, 1.0 Hz, 1H), 6.83 (d, J = 5.2 Hz, 1H), 5.44 (s, 2H), 5.27 (s, 2H); 13C NMR
(75 MHz; CDCl3) δc 161.4, 154.4, 150.5, 141.8, 137.3, 136.0, 129.0, 128.8, 128.6, 128.0, 127.6, 127.3,
125.8, 122.9, 114.2, 110.8, 102.0, 71.0, 70.5; FTIR(cmꢀ1) 3066(w), 3029(w), 2942(w), 2868(w); HRMS:
calcd for C23H20NO2 342.1489 (M+H); found 342.1490 (∆=0.36 ppm)
8ꢀ(Benzyloxy)quinolinꢀ4ꢀol (2k). By catalytic deprotection: The title compound was synthesized
following the general procedure for benzyl ether removal Method A. Starting from 4,8ꢀ
bis(benzyloxy)quinoline – 1k (0.0683 g, 0.2 mmol), ascorbic acid (0.0704 g, 0.4 mmol) and [Ru]
photocatalyst (0.75 mg, 0.001 mmol). Reaction time 40 min. Yield 98% (0.0490 g, 0.19 mmol). Purification:
Solids were filtrated off and washed with water.
By cyclization: The title compound was synthesized following the general procedure for preparation
of quinolones Method AꢀQn (compounds 2e, 2h, 2k and 6). The intermediate was obtained from 2ꢀ
benzyloxyaniline (3.985 g, 20 mmol) Meldrum’s acid (4.324 g, 30 mmol) and trimethyl orthoformate
(54.701 mL, 500 mmol). Yield 99% (6.996 g, 19.80 mmol). The product was prepared from the intermediate
(3.534 g, 10 mmol), which was refluxed in PhOPh for 15 min. Yield 76.6% (1.925 g, 7.66 mmol). Light
yellowish solid; Rf=0.22 (DCM:MeOH (20:1)); mp. 200ꢀ201 °C; 1H NMR (300 MHz; DMSO) δh 11.24 (d, J
= 4.6 Hz, 1H), 7.82 – 7.75 (m, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 7.0 Hz, 2H), 7.44 – 7.30 (m, 4H),
7.21 (t, J = 8.0 Hz, 1H), 6.07 (d, J = 7.4 Hz, 1H), 5.33 (s, 2H); 13C NMR (75 MHz; DMSO) δc 177.4, 148.0,
139.7, 137.1, 131.7, 129.1, 128.7, 128.6, 127.4, 123.4, 117.2, 113.0, 109.9, 70.8; FTIR(cmꢀ1) 3162(w),
3122(w), 3087(w), 3032(w), 2940(w), 2876(w); HRMS: calcd for C16H14NO2 252.1019 (M+H); found
252.1015 (∆=1.75 ppm)
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1ꢀ(Benzyloxy)isoquinoline (1l). The title compound was synthesized following the general procedure
for benzyl ether preparation Method BꢀBn. Starting from 1ꢀchloroisoquinoline (0.327 g, 2 mmol), benzyl
alcohol (0.312 mL, 3 mmol) and sodium hydride 60% dispersion in mineral oil (0.134 g, 4 mmol). Reaction
time 20 h. Yield 64.3% (0.326 g, 1.29 mmol). Purification: Flash chromatography (SiO2) using DCM as
eluent. The characterization data of the obtained compound are in agreement with the literature values.31
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Yellowish liquid; Rf=0.27 (nꢀhexane:EtOAc (20:1)); H NMR (300 MHz; CDCl3) δh 8.34 (ddt, J = 8.3, 1.4,
0.8 Hz, 1H), 8.04 (d, J = 5.9 Hz, 1H), 7.78 – 7.73 (m, 1H), 7.67 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.60 – 7.51
(m, 3H), 7.46 – 7.33 (m, 3H), 7.25 (dd, J = 5.9, 0.8 Hz, 1H), 5.61 (s, 2H); 13C NMR (75 MHz; CDCl3) δc
160.6, 139.9, 138.2, 137.7, 130.7, 128.7, 128.1, 126.9, 126.3, 124.5, 120.1, 115.4, 68.0; FTIR(cmꢀ1) 3055(w),
3032(w), 2944(w), 2886(w).
Isoquinolinꢀ1ꢀol (2l). The title compound was synthesized following the general procedure for
benzyl ether removal Method A. Starting from 1ꢀ(benzyloxy)isoquinoline – 1l (0.0507 g, 0.2 mmol),
ascorbic acid (0.0704 g, 0.4 mmol) and [Ru] photocatalyst (0. 75 mg, 0.001 mmol). Reaction time 2 h. Yield
>99% (0.0290 g, 0.2 mmol). Purification: Flash chromatography (SiO2) using DCM:MeOH (40:1) as eluent.
The characterization data of the obtained compound are in agreement with the literature values.32 White
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solid; Rf=0.29 (DCM:MeOH (20:1)); mp. 201ꢀ202 C; H NMR (300 MHz; DMSO) δh 11.20 (s, 1H), 8.17
(dd, J = 8.0, 0.6 Hz, 1H), 7.72 – 7.59 (m, 2H), 7.46 (ddd, J = 8.2, 6.7, 1.6 Hz, 1H), 7.15 (d, J = 6.8 Hz, 1H),
6.52 (d, J = 7.1 Hz, 1H); 13C NMR (75 MHz; DMSO) δc 162.5, 138.6, 133.0, 129.6, 127.3, 127.0, 126.9,
126.8, 105.3; FTIR(cmꢀ1) 3159(w), 3003(w), 2982(w), 2914(w), 2887(w), 2852(w),.
6ꢀ(Benzyloxy)phenanthridine (1m). The title compound was synthesized following the general
procedure for benzyl ether preparation Method BꢀBn. Starting from 6ꢀchlorophenanthridine – 10 (0.427 g, 2
mmol), benzyl alcohol (0.312 mL, 3 mmol) and sodium hydride 60% dispersion in mineral oil (0.134 g, 4
mmol). Reaction time 17 h. Yield 96.1% (0.549 g, 1.92 mmol). Purification: Flash chromatography (SiO2)
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using nꢀhexane:EtOAc (20:1) as eluent. White solid; Rf=0.38 (nꢀhexane:EtOAc (20:1)); mp. 75ꢀ76 C; H
NMR (300 MHz; CDCl3) δh 8.51 (d, J = 8.3 Hz, 1H), 8.48 – 8.41 (m, 2H), 7.96 (ddd, J = 8.2, 1.3, 0.4 Hz,
1H), 7.81 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.72 – 7.59 (m, 4H), 7.55 – 7.34 (m, 4H), 5.76 (s, 2H); 13C NMR
(75 MHz; CDCl3) δc 158.8, 143.5, 137.8, 135.1, 131.1, 129.0, 128.8, 128.4, 128.2, 128.1, 127.5, 125.4,
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124.7, 122.9, 122.4, 122.1, 120.3, 68.0; FTIR(cmꢀ1) 3066(w), 3035(w), 3020(w), 2930(w), 2876(w); HRMS:
calcd for C20H16NO 286.1226 (M+H); found 286.1235 (∆=3.06 ppm)
Phenanthridinꢀ6ꢀol (2m). The title compound was synthesized following the general procedure for
benzyl ether removal Method A. Starting from 6ꢀ(benzyloxy)phenanthridine – 1m (0.0571 g, 0.2 mmol),
ascorbic acid (0.0704 g, 0.4 mmol) and [Ru] photocatalyst (0.0015 g, 0.002 mmol). Reaction time 3 h. Yield
>99% (0.0390 g, 0.2 mmol). Purification: Flash chromatography (SiO2) using DCM→DCM:MeOH (40:1) as
eluent. Using Method B: Reaction time 3 h. Yield >99% (0.0390 g, 0.2 mmol). Purification: Flash
chromatography (SiO2) using DCM→DCM:MeOH (40:1) as eluent. The characterization data of the
obtained compound are in agreement with the literature values.33 Light yellowish solid; Rf=0.14
(DCM:MeOH (40:1)); mp. 286ꢀ287 C; H NMR (300 MHz; DMSO) δh 11.66 (s, 1H), 8.45 (d, J = 8.1 Hz,
1H), 8.38 – 8.29 (m, 2H), 7.88 – 7.78 (m, 1H), 7.66 – 7.58 (m, 1H), 7.46 (ddd, J = 8.2, 7.1, 1.3 Hz, 1H), 7.36
(dd, J = 8.2, 1.3 Hz, 1H), 7.23 (ddd, J = 8.2, 7.1, 1.4 Hz, 1H); 13C NMR (75 MHz; DMSO) δc 161.5, 137.3,
134.9, 133.4, 130.2, 128.6, 128.1, 126.4, 123.9, 123.2, 122.9, 118.2, 116.8; FTIR(cmꢀ1) 3288(w), 3156(w),
3100(w), 2997(w), 2975(w), 2887(w).
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6ꢀChlorophenanthridine (10). A roundꢀbottom flask equipped with a stirrer bar was charged with
phenanthridinꢀ6ꢀol (0.586 g, 3 mmol) and 30 mL of dry toluene. Phosphorous oxychloride (2.738 mL, 30
mmol) was added to the reaction mixture which was then refluxed under an argon for 19 h on a magnetic
stirrer plate. After completion of the reaction, the reaction mixture was carefully quenched with water (NB!
exothermic reaction) and basified with aqueous NH4OH. The reaction mixture was then extracted with
EtOAc. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude was purified with
SiO2 flash chromatography. Yield 96.3% (0.617 g, 2.89 mmol). Purification: Flash chromatography (SiO2)
using DCM as eluent. The characterization data of the obtained compound are in agreement with the
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literature values.34 Light yellowish solid; Rf=0.20 (nꢀhexane:EtOAc (20:1)); mp. 111ꢀ112 C; H NMR (300
MHz; CDCl3) δh 8.55 – 8.49 (m, 1H), 8.49 – 8.38 (m, 2H), 8.10 – 8.01 (m, 1H), 7.84 (ddd, J = 8.4, 7.1, 1.4
Hz, 1H), 7.75 – 7.59 (m, 3H); 13C NMR (75 MHz; CDCl3) δc 151.6, 143.5, 134.7, 131.9, 129.5, 128.4, 127.9,
127.7, 125.1, 124.2, 122.4; FTIR(cmꢀ1) 754(s), 719(s).
2,4ꢀbis(benzyloxy)ꢀ6,7ꢀdimethoxyquinazoline (1n). The title compound was synthesized following
the general procedure for benzyl ether preparation Method BꢀBn. Starting from 2,4ꢀdichloroꢀ6,7ꢀ
dimethoxyquinazoline (0.518 g, 2 mmol), benzyl alcohol (0.624 mL, 6 mmol) and sodium hydride 60%
dispersion in mineral oil (0.269 g, 8 mmol). Reaction was carried in THF at room temperature. Reaction time
22 h. Yield 88.6% (0.0713 g, 1.77 mmol). Purification: Flash chromatography (SiO2) using nꢀhexane:EtOAc
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(2:1) as eluent. White solid; Rf=0.34 (nꢀhexane:EtOAc (2:1)); mp. 137ꢀ138 C; H NMR (300MHz; CDCl3)
δh 7.56 – 7.48 (m, 4H), 7.44 – 7.33 (m, 6H), 7.31 (s, 1H), 7.11 (s, 1H), 5.61 (s, 2H), 5.52 (s, 2H), 4.01 (s,
3H), 3.94 (s, 3H); 13C NMR (75MHz; CDCl3) δc 167.6, 161.2, 156.0, 150.0, 147.9, 137.2, 136.5, 128.8,
128.6, 128.5, 128.1, 107.3, 106.0, 102.3, 69.1, 68.9, 56.4; FTIR(cmꢀ1) 3089(w), 3034(w), 3010(w), 2964(w),
2889(w); HRMS: calcd for C24H23N2O4 403.1652 (M+H); found 403.1666 (∆=3.34 ppm).
2ꢀ(Benzyloxy)ꢀ6,7ꢀdimethoxyquinazolinꢀ4ꢀol (2n). The title compound was synthesized following the
general procedure for benzyl ether removal Method A. Starting from 2,4ꢀbis(benzyloxy)ꢀ6,7ꢀ
dimethoxyquinazoline – 1n (0.0805 g, 0.2 mmol), ascorbic acid (0.0704g, 0.4 mmol) and [Ru] photocatalyst
(0.0015 g, 0.002 mmol). Reaction time 5½ h. Yield 57.6% (0.0360 g, 0.12 mmol). Purification: Flash
chromatography (SiO2) using DCM→DCM:MeOH (40:1) as eluent. Using Method B: Reaction time 2 h.
Yield 89.8% (0.0561 g, 0.18 mmol). Purification: Flash chromatography (SiO2) using DCM:MeOH (40:1) as
eluent.
White solid; Rf=0.30 (nꢀhexane:EtOAc (1:1)); mp. 224ꢀ225 °C; 1H NMR (300 MHz; CDCl3) δh 10.00 (s, 1H),
7.54 (s, 1H), 7.48 (dd, J = 7.8, 1.7 Hz, 2H), 7.43 – 7.34 (m, 3H), 6.97 (s, 1H), 5.49 (s, 2H), 4.00 (s, 3H), 3.96
(s, 3H); 13C NMR (75 MHz; CDCl3) δc 163.0, 155.7, 151.9, 147.7, 145.3, 135.6, 128.8, 128.8, 128.6, 112.1,
107.1, 106.3, 69.4, 56.5; FTIR(cmꢀ1) 3004(w), 2962(w), 2872(w), 2831(w), 2745(w); HRMS: calcd for
C17H17N2O4 313.1183 (M+H); found 313.1182 (∆=0.11 ppm).
2ꢀ(Benzyloxy)pyridine (3a). The title compound was synthesized following the general procedure for
benzyl ether preparation Method BꢀBn. Starting from 2ꢀbromopyridine (0.954 mL, 10 mmol), benzyl alcohol
(1.560 mL, 15 mmol) and sodium hydride 60% dispersion in mineral oil (0.672 g, 20 mmol). Reaction was
stirred at room temperature for 20 h. Yield 85.3% (1.580 g, 8.53 mmol). Purification: Flash chromatography
(SiO2) using nꢀhexane→ nꢀhexane:EtOAc (10:1) as eluent. The characterization data of the obtained
compound are in agreement with the literature values.21 Colorless liquid; Rf=0.45 (nꢀhexane:EtOAc (10:1));
1H NMR (300 MHz; CDCl3) δh 8.17 (ddd, J = 5.1, 2.0, 0.8 Hz, 1H), 7.56 (ddd, J = 8.4, 7.1, 2.0 Hz, 1H), 7.46
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(ddt, J = 3.7, 3.0, 1.5 Hz, 2H), 7.39 – 7.28 (m, 3H), 6.87 (ddd, J = 7.1, 5.1, 1.0 Hz, 1H), 6.80 (dt, J = 8.4, 0.9
Hz, 1H), 5.38 (s, 2H); 13C NMR (75 MHz; CDCl3) δc 163.8, 147.0, 138.7, 137.5, 128.6, 128.1, 127.9, 117.0,
111.5, 67.6; FTIR(cmꢀ1) 3064(w), 3032(w), 2944(w), 2884(w).
Pyridinꢀ2ꢀol – (4a). The title compound was synthesized following the general procedure for benzyl
ether removal Method B. Starting from 2ꢀ(benzyloxy)pyridine – 3a (0.0370 g, 0.2 mmol), ascorbic acid
(0.0704 g, 0.4 mmol) and [Ir] photocatalyst (0.0022 g, 0.002 mmol). Reaction time 3 h. Yield 95% (0.0180
g, 0.19 mmol). Purification: Flash chromatography (SiO2) using acetone as eluent. The characterization data
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of the obtained compound are in agreement with the literature values. Light brownish solid; Rf=0.42
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(DCM:MeOH (10:1)); mp. 105ꢀ106 °C; H NMR (300 MHz; CDCl3) δh 13.56 (s, 1H), 7.47 – 7.40 (m, 1H),
7.36 (ddd, J = 6.5, 2.1, 0.8 Hz, 1H), 6.59 – 6.51 (m, 1H), 6.25 (td, J = 6.6, 1.1 Hz, 1H); 13C NMR (75 MHz;
CDCl3) δc 165.8, 141.9, 134.9, 120.4, 107.2; FTIR(cmꢀ1) 3092(w), 3066(w), 2981(w), 2875(w), 2789(w).
4ꢀ(Benzyloxy)pyridine (3b). The title compound was synthesized following the general procedure for
benzyl ether preparation Method BꢀBn. Starting from 4ꢀchloropyridine hydrochloride (1.500 g, 10 mmol),
benzyl alcohol (3.119 mL, 30 mmol) and sodium hydride 60% dispersion in mineral oil (1.344 g, 40 mmol).
Reaction time 24 h. Yield 95% (1.760 g, 9.5 mmol). Purification: Flash chromatography (SiO2) using nꢀ
hexane:EtOAc (2:1→1:1) as eluent. The characterization data of the obtained compound are in agreement
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with the literature values.36 Yellowish solid; Rf=0.23 (DCM:MeOH (40:1)); mp. 51ꢀ52 C; H NMR (300
MHz; CDCl3) δh 8.43 (dd, J = 4.8, 1.6 Hz, 2H), 7.45 – 7.31 (m, 5H), 6.86 (dd, J = 4.8, 1.6 Hz, 2H), 5.09 (s,
2H); 13C NMR (75MHz; CDCl3) δc 164.9, 151.4, 135.9, 129.0, 128.6, 127.7, 110.8, 70.0; FTIR(cmꢀ1)
3064(w), 3036(w), 2938(w), 2875(w).
Pyridinꢀ4ꢀol – (4b). The title compound was synthesized following the general procedure for benzyl
ether removal Method C. Starting from 4ꢀ(benzyloxy)pyridine – 3b (0.0370 g, 0.2 mmol), ascorbic acid
(0.0704 g, 0.4 mmol) and [Ir] photocatalyst (0.0018 g, 0.002 mmol). Reaction time 21 h. Yield 98.9%
(0.0188 g, 0.198 mmol). Purification: Flash chromatography (SiO2) using CHCl3:MeOH:NH4OH (100:20:2)
as eluent. The characterization data of the obtained compound are in agreement with the literature values.37
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Light yellowish solid; Rf=0.14 (CHCl3:MeOH:NH4OH (100:20:2)); mp. 147ꢀ148 C; H NMR (300 MHz;
DMSO) δh 11.32 (br. s, 1H), 7.71 (d, J = 7.1 Hz, 2H), 6.18 (d, J = 7.2 Hz, 2H); 13C NMR (75 MHz; DMSO)
δc 176.6, 140.4, 116.8.; FTIR(cmꢀ1) 3198(w), 3109(w), 3034(w), 2936(w), 2903(w), 2853(w), 2806(w).
2,6ꢀBis(benzyloxy)pyridine – (3c). The title compound was synthesized following the general
procedure for benzyl ether preparation Method BꢀBn. Starting from 2,6ꢀdichloropyridine (0.740 g, 5 mmol),
benzyl alcohol (1.560 mL, 15 mmol) and sodium hydride 60% dispersion in mineral oil (0.672 g, 20 mmol).
Reaction time 25 h. Yield 99% (1.442 g, 4.95 mmol). Purification: After the reaction was quenched with
water, the precipitated solids were filtrated off and were washed with water. The characterization data of the
obtained compound are in agreement with the literature values.38 White solid; Rf=0.46 (Hexane:EtOAc
(20:1)); mp. 73ꢀ74 °C; 1H NMR (300 MHz; CDCl3) δh 7.52 (t, J = 7.9 Hz, 1H), 7.48 – 7.30 (m, 10H), 6.40 (d,
J = 7.9 Hz, 2H), 5.37 (s, 4H); 13C NMR (75 MHz; CDCl3) δc 162.5, 141.3, 137.8, 128.7, 128.0, 128.0, 102.2,
67.9; FTIR(cmꢀ1) 3062(w), 3037(w), 2942(w), 2885(w).
2,3ꢀbis(benzyloxy)pyridine (3d). The title compound was synthesized following the general
procedure for benzyl ether preparation Method AꢀBn. Starting from pyridineꢀ2,3ꢀdiol (0.556 g, 5 mmol),
benzyl bromide (1.425 mL, 12 mmol) and potassium carbonate (2.764 g, 20 mmol). Reaction time 18 h.
Yield 97% (1.414 g, 4.85 mmol). Purification: Flash chromatography (SiO2) using DCM→DCM:MeOH
(40:1) as eluent. The characterization data of the obtained compound are in agreement with the literature
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values.39 Light brown solid; Rf=0.31 (nꢀhexane:EtOAc (1:1)); mp. 104ꢀ105 °C; H NMR (300 MHz; CDCl3)
δh 7.43 (dq, J = 3.0, 2.0 Hz, 2H), 7.39 – 7.25 (m, 8H), 6.89 (dd, J = 6.9, 1.7 Hz, 1H), 6.62 (dd, J = 7.4, 1.7
Hz, 1H), 6.01 – 5.95 (m, 1H), 5.17 (s, 2H), 5.11 (s, 2H); 13C NMR (75 MHz; CDCl3) δc 158.5, 149.3, 136.7,
136.6, 129.0, 128.8, 128.7, 128.5, 128.2, 127.6, 115.7, 105.1, 71.0, 52.2; FTIR(cmꢀ1) 3079(w), 3063(w),
2941(w), 2907(w), 2873(w).
3ꢀ(Benzyloxy)pyridinꢀ2ꢀol – (4d). The title compound was synthesized following the general
procedure for benzyl ether removal Method B. Starting from 2,3ꢀbis(benzyloxy)pyridine – 3d (0.0583 g, 0.2
mmol), ascorbic acid (0.0704 g, 0.4 mmol) and [Ir] photocatalyst (0.0022 g, 0.002 mmol). Reaction time 2 h.
Yield 95% (0.0380 g, 0.18 mmol). Purification: Flash chromatography (SiO2) using DCM:MeOH (40:1) as
eluent. The characterization data of the obtained compound are in agreement with the literature values.40
Brownish solid; Rf=0.33 (DCM:MeOH (40:1)); mp. 127ꢀ128 °C; 1H NMR (500 MHz; CDCl3) δh 7.37 – 7.27
(m, 5H), 7.21 (s, 1H), 6.83 (dd, J = 7.0, 1.5 Hz, 1H), 6.80 (dd, J = 7.3, 1.4 Hz, 1H), 6.13 (t, J = 7.1 Hz, 1H),
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5.19 (s, 2H); 13C NMR (75 MHz; CDCl3) δc 159.0, 147.0, 136.1, 129.1, 128.4, 128.3, 126.9, 113.8, 107.2,
52.6; FTIR(cmꢀ1) 3211(w), 2988(w), 2902(w).
2,4ꢀBis(benzyloxy)ꢀ6ꢀmethylpyridine (3e). The title compound was synthesized following the general
procedure for benzyl ether preparation Method AꢀBn. Starting from 6ꢀmethylpyridineꢀ2,4ꢀdiol (0.626 g, 5
mmol), benzyl bromide (1.425 mL, 12 mmol) and potassium carbonate (2.764 g, 20 mmol). Reaction time 18
h. Yield 36.2% (0.553 g, 1.81 mmol). Purification: Salted out as HCl salt and then flash chromatography
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NMR (500 MHz; CDCl3) δh 7.47 (d, J = 7.3 Hz, 2H), 7.42 – 7.29 (m, 8H), 6.44 (d, J = 1.7 Hz, 1H), 6.18 (d, J
= 1.7 Hz, 1H), 5.37 (s, 2H), 5.05 (s, 2H), 2.43 (s, 3H); 13C NMR (75 MHz; CDCl3) δc 167.6, 165.1, 157.2,
137.8, 136.3, 128.9, 128.6, 128.4, 128.3, 128.0, 127.9, 127.7, 105.7, 92.4, 70.0, 67.9, 24.5; FTIR(cmꢀ1)
3090(w), 3065(w), 3033(w), 2943(w), 2881(w); HRMS: calcd for C20H20NO2 306.1489 (M+H); found
306.1485 (∆=1.25 ppm)
2ꢀ(Benzyloxy)ꢀ6ꢀmethylpyridinꢀ4ꢀol and 4ꢀ(benzyloxy)ꢀ6ꢀmethylpyridinꢀ2ꢀol – (4e and 4e’). The title
compounds were synthesized following the general procedure for benzyl ether preparation Method C.
Starting from 2,4ꢀbis(benzyloxy)ꢀ6ꢀmethylpyridine – 3e (0.0611 g, 0.2 mmol), ascorbic acid (0.0704 g, 0.4
mmol) and [Ir] photocatalyst (0.0018 g, 0.002 mmol). Reaction time 23 h. Yield 4e 20.9% (0.0090 g, 0.04
mmol) and 4e’ 38.1% (0.0164 g, 0.08 mmol). Total yield 59% (0.0254 g, 0.12 mmol). Purification: Flash
chromatography (SiO2) using nꢀhexane:EtOAc (5:1→1:1) → DCM:MeOH (20:1) as eluent.
2ꢀ(Benzyloxy)ꢀ6ꢀmethylpyridinꢀ4ꢀol (4e): white solid; Rf=0.28 (nꢀhexane:EtOAc (1:1)); mp. 45ꢀ46
°C; 1H NMR (300 MHz; CDCl3) δh δ 7.41 – 7.26 (m, 5H), 6.23 (d, J = 1.8 Hz, 1H), 6.00 (d, J = 1.9 Hz, 1H),
5.12 (s, 2H), 2.26 (s, 3H); 13C NMR (75 MHz; CDCl3) δc 173.5, 162.8, 152.4, 136.3, 128.7, 128.4, 128.1,
109.0, 93.9, 69.4, 22.1; FTIR(cmꢀ1) 3063(w), 3034(w), 2921(w), 2666(w), 2584(w); HRMS: calcd for
C13H14NO2 216.1019 (M+H); found 216.1014 (∆=2.54 ppm)
4ꢀ(Benzyloxy)ꢀ6ꢀmethylpyridinꢀ2ꢀol (4e’): white solid; Rf=0.28 (DCM:MeOH=20:1); mp. 174ꢀ175
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°C; H NMR (300 MHz; CDCl3) δh 12.94 (s, 1H), 7.46 – 7.30 (m, 5H), 5.87 – 5.79 (m, 2H), 4.99 (s, 2H),
2.29 (s, 3H); 13C NMR (75 MHz; CDCl3) δc 169.3, 167.8, 146.1, 135.7, 128.9, 128.6, 127.8, 100.4, 95.3,
70.2, 19.1; FTIR(cmꢀ1) 3118(w), 3025(w), 2915(w), 2842(w), 2727(w), 2688(w); HRMS: calcd for
C13H14NO2 216.1019 (M+H); found 216.1013 (∆=2.89 ppm)
Tertꢀbutyl (2ꢀ(benzyloxy)pyrimidinꢀ4ꢀyl)carbamate (3f). The title compound was synthesized
following the general procedure for benzyl ether preparation Method BꢀBn. Starting from tertꢀbutyl (2ꢀ
chloropyrimidinꢀ4ꢀyl)carbamate – 11 (0.115 g, 0.5 mmol), benzyl alcohol (0.078 mL, 0.75 mmol) and
sodium hydride 60% dispersion in mineral oil (0.024 g, 1 mmol). Reaction time 25 h. Yield 74.8% (0.113 g,
0.37 mmol). Purification: Flash chromatography (SiO2) using DCM→DCM:MeOH (20:1) as eluent. White
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solid; Rf=0.12 (nꢀhexane:EtOAc (10:1)); mp. 95ꢀ96 °C; H NMR (300 MHz; CDCl3) δh 8.35 (d, J = 5.7 Hz,
1H), 7.54 (d, J = 5.7 Hz, 1H), 7.48 – 7.41 (m, 2H), 7.39 – 7.27 (m, 3H), 7.23 (s, 1H), 5.38 (s, 2H), 1.52 (s,
9H); 13C NMR (75 MHz; CDCl3) δc 164.7, 160.2, 159.9, 151.6, 136.8, 128.6, 128.1, 128.0, 102.6, 82.5, 69.0,
28.3; FTIR(cmꢀ1) 3226(br. w), 3074(w), 2976(w), 1725(m); HRMS: calcd for C16H20N3O3 302.1499 (M+H);
found 302.1502 (∆=0.96 ppm).
Tertꢀbutyl (2ꢀchloropyrimidinꢀ4ꢀyl)carbamate (11). A roundꢀbottom flask equipped with a stirrer bar
was charged with 2ꢀchloropyrimidinꢀ4ꢀamine (0.259 g, 2 mmol) and Bocꢀanhydride (0.524 g, 2.4 mmol).
Then 20 mL of dry DCM was added followed by addition of DMAP (0.048 g, 0.4 mmol). The reaction
mixture was then stirred 24 h on a magnetic stirrer plate. The crude product was purified with SiO2 flash
chromatography. Yield 30.7% (0.141 g, 0.61 mmol). Purification: Flash chromatography (SiO2) using DCM
as eluent.
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White solid; Rf=0.37 (nꢀhexane:EtOAc (5:1)); mp. 145ꢀ146 °C; H NMR (300 MHz; CDCl3) δh 8.41 (d, J =
5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.59 (s, 1H), 1.51 (s, 9H); 13C NMR (75MHz; CDCl3) δc 160.3, 160.2,
160.0, 151.3, 107.0, 83.2, 28.7; FTIR(cmꢀ1) 3188(w), 3122(w), 3049(w), 2978(w), 2929(w), 1738(s),
771(m); HRMS: calcd for C9H13ClN3O2 230.0691 (M+H); found 230.0690 (∆=0.38 ppm)
2,4ꢀBis(benzyloxy)pyrimidine (3g). The title compound was synthesized following the general
procedure for benzyl ether preparation Method BꢀBn. Starting from 2,4ꢀdichloropyrimidine (0.745 g, 5
mmol), benzyl alcohol (1.560 mL, 15 mmol) and sodium hydride 60% dispersion in mineral oil (0.672 g, 20
mmol). THF was used as solvent and the reaction time was 4 h. Yield 86.6% (1.266 g, 4.33 mmol).
Purification: Flash chromatography (SiO2) using toluene:EtOAc (20:1) as eluent. The characterization data
of the obtained compound are in agreement with the literature values.41 Isolated as light yellowish liquid;
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Rf=0.30 (nꢀhexane:EtOAc (5:1)); H NMR (300 MHz; CDCl3) δh 8.23 (d, J = 5.7 Hz, 1H), 7.52 – 7.46 (m,
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2H), 7.45 – 7.32 (m, 8H), 6.43 (d, J = 5.7 Hz, 1H), 5.44 (s, 2H), 5.41 (s, 2H); 13C NMR (75 MHz; CDCl3) δc
171.1, 165.1, 158.9, 136.8, 136.3, 128.8, 128.7, 128.5, 128.4, 128.3, 128.2, 102.7, 69.3, 68.5; FTIR(cmꢀ1)
3090(w), 3064(w), 3033(w), 2953(w), 2893(w).
Pyrimidineꢀ2,4ꢀdiol (4g). The title compound was synthesized following the general procedure for
benzyl ether removal Method B. Starting from 2,4ꢀbis(benzyloxy)pyrimidine – 3g (0.0585 g, 0.2 mmol),
ascorbic acid (0.0704 g, 0.4 mmol) and [Ir] photocatalyst (0.0022 g, 0.002 mmol). Reaction time 18 h. Yield
84.8% (0.0190 g, 0.17 mmol). Purification: Flash chromatography (SiO2) using EtOAc as eluent. The
characterization data of the obtained compound are in agreement with the literature values.42 White solid;
Rf=0.11 (EtOAc); mp. >300 °C; 1H NMR (300 MHz; DMSO) δh 10.88 (s, 2H), 7.38 (d, J = 7.6 Hz, 1H), 5.44
(d, J = 7.6 Hz, 1H); 13C NMR (75MHz; DMSO) δc 165.0, 152.2, 142.8, 100.9; FTIR(cmꢀ1) 3082(m),
2986(m), 2931(m), 2857(m), 2804(m), 2735(m).
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4ꢀ(Benzyloxy)ꢀ8ꢀ(tertꢀbutyl)quinoline (5a). The title compound was synthesized following the
general procedure for benzyl ether preparation Method AꢀBn. Starting from 8ꢀ(tertꢀbutyl)quinolinꢀ4ꢀol – 6
(1.006 g, 5 mmol), benzyl bromide (0.713 mL, 6 mmol) and potassium carbonate (1.382 g, 10 mmol).
Reaction time 3 h. Yield 99% (1.442 g, 4.95 mmol). Purification: Flash chromatography (SiO2) using nꢀ
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hexane:EtOAc (20:1) as eluent. Isolated as a colorless liquid; Rf=0.29 (nꢀhexane:EtOAc (20:1)); H NMR
(300 MHz; CDCl3) δh 8.76 (d, J = 5.1 Hz, 1H), 8.22 (dd, J = 8.3, 1.5 Hz, 1H), 7.68 (dd, J = 7.4, 1.5 Hz, 1H),
7.55 – 7.48 (m, 2H), 7.48 – 7.34 (m, 3H), 6.77 (d, J = 5.1 Hz, 1H), 5.28 (s, 2H), 1.70 (s, 9H); 13C NMR (75
MHz; CDCl3) δc 161.5, 148.7, 148.3, 147.8, 136.3, 128.9, 128.5, 127.6, 126.7, 125.3, 122.6, 120.6, 100.6,
70.3, 36.8, 31.3; FTIR(cmꢀ1) 3067(w), 3033(w), 3001(w), 2949(w), 2908(w), 2864(w); HRMS: calcd for
C20H22NO 292.1696 (M+H); found 292.1707 (∆=3.88 ppm)
4ꢀ(Allyloxy)ꢀ8ꢀ(tertꢀbutyl)quinoline (5b). A roundꢀbottom flask equipped with a stirrer bar was
charged with 8ꢀ(tertꢀbutyl)quinolinꢀ4ꢀol – 6 (1.006 g, 5 mmol) and potassium carbonate (1.382 g, 10 mmol).
Then 55 mL of toluene:DMF (50:5) solvent mixture was added, followed by allyl bromide (0.508 mL, 6
°
mmol). The reaction mixture was then stirred at 90 C for 3 h on a magnetic stirrer plate after which it was
quenched with water and extracted with EtOAc. The organic phase was dried over Na2SO4, evaporated to
dryness and purified with SiO2 flash chromatography. Yield 95.9% (1.158 g, 4.80 mmol). Purification: Flash
chromatography (SiO2) using DCM as eluent. Light yellowish solid; Rf=0.39 (nꢀhexane:EtOAc (20:1)); mp.
46ꢀ47 °C; 1H NMR (300 MHz; CDCl3) δh 8.73 (d, J = 5.1 Hz, 1H), 8.16 (dd, J = 8.3, 1.5 Hz, 1H), 7.65 (dd, J
= 7.4, 1.5 Hz, 1H), 7.40 (dd, J = 8.3, 7.4 Hz, 1H), 6.67 (d, J = 5.1 Hz, 1H), 6.12 (ddt, J = 17.3, 10.5, 5.2 Hz,
1H), 5.50 (ddd, J = 17.3, 3.1, 1.6 Hz, 1H), 5.35 (dq, J = 10.6, 1.4 Hz, 1H), 4.72 (dt, J = 5.2, 1.5 Hz, 2H), 1.67
(s, 9H); 13C NMR (75 MHz; CDCl3) δc 161.4, 148.7, 148.3, 147.8, 132.5, 126.5, 125.2, 122.6, 120.5, 118.3,
100.4, 69.0, 36.8, 31.3; FTIR(cmꢀ1) 3084(w), 3004(w), 2965(w), 2949(m), 2917(w), 2862(w); HRMS: calcd
for C16H20NO 242.1539 (M+H); found 241.1538 (∆=0.67 ppm)
(E)ꢀ8ꢀ(Tertꢀbutyl)ꢀ4ꢀ((3,7ꢀdimethyloctaꢀ2,6ꢀdienꢀ1ꢀyl)oxy)quinoline (5c). A round bottom flask
equipped with a stirrer bar was charged with 8ꢀ(tertꢀbutyl)quinolinꢀ4ꢀol – 6 (1.006 g, 5 mmol) and potassium
carbonate (1.382 g, 10 mmol). Then 55 mL of toluene:DMF (50:5) solvent mixture was added, followed by
(E)ꢀ1ꢀbromoꢀ3,7ꢀdimethyloctaꢀ2,6ꢀdiene – 12 (1.303 g, 6 mmol). The reaction mixture was refluxed for 17 h
on a magnetic stirrer plate after which it was quenched with water and extracted with EtOAc. The organic
phase was dried over Na2SO4, evaporated and purified with SiO2 flash chromatography. Yield 87.7% (1.480
g, 4.39 mmol). Purification: Flash chromatography (SiO2) using nꢀhexane:EtOAc (20:1) as eluent. Yellowish
liquid; Rf=0.50 (nꢀhexane:EtOAc (20:1)); 1H NMR (300 MHz; CDCl3) δh 8.73 (d, J = 5.1 Hz, 1H), 8.14 (dd,
J = 8.3, 1.5 Hz, 1H), 7.64 (dd, J = 7.4, 1.5 Hz, 1H), 7.38 (dd, J = 8.3, 7.4 Hz, 1H), 6.68 (d, J = 5.1 Hz, 1H),
5.62 – 5.51 (m, 1H), 5.17 – 5.04 (m, 1H), 4.73 (d, J = 6.4 Hz, 2H), 2.21 – 2.07 (m, 4H), 1.77 (s, 3H), 1.67 (s,
12H), 1.61 (s, 3H); 13C NMR (75 MHz; CDCl3) δc 161.7, 148.6, 148.3, 147.7, 142.1, 132.1, 126.4, 125.1,
123.9, 122.8, 120.6, 119.1, 100.4, 65.4, 39.7, 36.8, 31.3, 26.5, 25.1, 18.0, 17.0; FTIR(cmꢀ1) 2947(m),
2913(m), 2860(w); HRMS: calcd for C23H32NO 338.2478 (M+H); found 338.2465 (∆=3.89 ppm).
Ethyl 2ꢀ((8ꢀ(tertꢀbutyl)quinolinꢀ4ꢀyl)oxy)acetate (5d). A roundꢀbottom flask equipped with a stirrer
bar was charged with 8ꢀ(tertꢀbutyl)quinolinꢀ4ꢀol ꢀ 6 (1.006 g, 5 mmol) and potassium carbonate (1.382 g, 10
mmol). Then 55 mL of toluene:DMF (50:5) solvent mixture was added, followed by ethyl 2ꢀchloroacetate
(0.642 mL, 6 mmol). The reaction mixture was refluxed for 5 h on a magnetic stirrer plate after which it was
quenched with water and extracted with EtOAc. The organic phase was dried over Na2SO4, evaporated and
purified with SiO2 flash chromatography. Yield 97% (1.394 g, 4.85 mmol). Purification: Flash
chromatography (SiO2) using nꢀhexane:EtOAc (10:1→5:1) as eluent. Isolated as a white solid; Rf=0.16 (nꢀ
hexane:EtOAc (20:1)); mp. 82ꢀ83 °C; 1H NMR (300 MHz; CDCl3) δh 8.74 (d, J = 5.1 Hz, 1H), 8.21 (dd, J =
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8.3, 1.5 Hz, 1H), 7.67 (dd, J = 7.4, 1.5 Hz, 1H), 7.43 (dd, J = 8.3, 7.4 Hz, 1H), 6.56 (d, J = 5.1 Hz, 1H), 4.81
(s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 1.67 (s, 9H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz; CDCl3) δc 168.2,
160.8, 148.7, 147.9, 147.8, 126.8, 125.6, 122.3, 120.5, 100.0, 65.4, 61.9, 36.8, 31.2, 14.4; FTIR(cmꢀ1)
3000(w), 2986(w), 2961(w), 2910(w), 2873(w), 1762(m); HRMS: calcd for C17H22NO3 288.1594 (M+H);
found 288.1604 (∆=3.46 ppm)
8ꢀ(Tertꢀbutyl)quinolinꢀ4ꢀol (6). By catalytic deprotection: From 4ꢀ(benzyloxy)ꢀ8ꢀ(tertꢀ
butyl)quinoline (5a). The title compound was synthesized following the general procedure for benzyl ether
removal Method A. Starting from 4ꢀ(benzyloxy)ꢀ8ꢀ(tertꢀbutyl)quinoline – 5a (0.0583 g, 0.2 mmol), ascorbic
acid (0.0704 g, 0.4 mmol) and [Ru] photocatalyst (0.75 mg, 0.001 mmol). Reaction time 1 h. Yield >99%
(0.0403 g, 0.2 mmol). Purification: Flash chromatography (SiO2) using DCM:MeOH (20:1→10:1) as eluent.
From 4ꢀ(allyloxy)ꢀ8ꢀ(tertꢀbutyl)quinoline (5b). The title compound 6 was synthesized following the
general procedure for benzyl ether removal Method A. Starting from the quinoline 5b (0.0483 g, 0.2 mmol),
ascorbic acid (0.0704 g, 0.4 mmol) and [Ru] photocatalyst (0.75 mg, 0.001 mmol). Reaction time 1 h. Yield
>99% (0.0442 g, 0.2 mmol). Purification: Flash chromatography (SiO2) using DCM:MeOH (20:1→10:1) as
eluent.
From (E)ꢀ8ꢀ(tertꢀbutyl)ꢀ4ꢀ((3,7ꢀdimethyloctaꢀ2,6ꢀdienꢀ1ꢀyl)oxy)quinoline (5c). The title compound 6
was synthesized following the general procedure for benzyl ether removal Method A. Starting from the
quinoline 5c (0.0675 g, 0.2 mmol), ascorbic acid (0.0704 g, 0.4 mmol) and [Ru] photocatalyst (0.75 mg,
0.001 mmol). Reaction time 1½ h. Yield >99% (0.0403 g, 0.2 mmol). Purification: Flash chromatography
(SiO2) using DCM:MeOH (20:1→10:1) as eluent.
From ethyl 2ꢀ((8ꢀ(tertꢀbutyl)quinolinꢀ4ꢀyl)oxy)acetate (5d). The title compound 6 was synthesized
following the general procedure for benzyl ether removal Method A. Starting from the compound 5d (0.0574
g, 0.2 mmol), ascorbic acid (0.0704 g, 0.4 mmol) and [Ru] photocatalyst (0.75 mg, 0.001 mmol). Reaction
time 1½ h. Yield 97% (0.0391 g, 0.19 mmol). Purification: Flash chromatography (SiO2) using DCM:MeOH
(20:1→10:1) as eluent.
By cyclization: The title compound was synthesized following the general procedure for the
preparation of quinolones Method AꢀQn (compounds 2e, 2h, 2k and 6). The intermediate was obtained from
2ꢀ(tertꢀbutyl)aniline (4.678 mL, 30 mmol) Meldrum’s acid (6.486 g, 45 mmol) and trimethyl orthoformate
(82.052 mL, 750 mmol). Yield 99% (9.010 g, 29.7 mmol). The product was prepared from the intermediate
(6.067 g, 20 mmol), which was refluxed in PhOPh for 2½ h. Yield 90.5% (3.641 g, 18.09 mmol).
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Purification: Flash chromatography (SiO2) using DCM (until PhOPh out)
→
DCM:MeOH
(40:1→20:1→10:1) as eluent. Offꢀwhite solid; Rf=0.44 (DCM:MeOH=10:1); mp. 210ꢀ211 °C; 1H NMR (300
MHz; CDCl3) δh 10.22 (s, 1H), 8.36 (dd, J = 8.1, 1.3 Hz, 1H), 8.08 – 7.98 (m, 1H), 7.65 (dd, J = 7.6, 1.5 Hz,
1H), 7.29 (dd, J = 9.8, 5.9 Hz, 1H), 6.34 (d, J = 7.4 Hz, 1H), 1.59 (s, 9H); 13C NMR (75 MHz; CDCl3) δc
179.8, 139.1, 138.4, 137.7, 129.3, 127.9, 124.8, 123.5, 109.1, 34.7, 30.8; FTIR(cmꢀ1) 3280(br. w), 3088(w),
2954(w), 2909(w), 2874(w); HRMS: calcd for C13H16NO 202.1226 (M+H); found 202.1224 (∆=1.36 ppm).
(E)ꢀ1ꢀbromoꢀ3,7ꢀdimethyloctaꢀ2,6ꢀdiene – (12). A roundꢀbottom flask equipped with a stirrer bar
was charged with ice cold solution of (E)ꢀ3,7ꢀdimethyloctaꢀ2,6ꢀdienꢀ1ꢀol (1.735 mL, 10 mmol) and 20 mL of
dry THF. Then phosphorus tribromide (0.475 mL, 5 mmol) was added dropwise and the reaction mixture
was stirred for 4 h at 0 °C on a magnetic stirrer plate. The reaction mixture was quenched with water and was
extracted with Et2O. Then the ethereal was dried over Na2SO4 and evaporated to dryness. The crude was
used without further purification. Yield 99% (2.150 g, 9.90 mmol). The characterization data of the obtained
compound are in agreement with the literature values.43
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website
1H, 13C, NMR spectra, CVꢀdata, SternꢀVolmer plot, computational details, XYZꢀparameters for TS
geometries (PDF)
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AUTHOR INFORMATION
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Corresponding Author
* Email: juho.helaja@helsinki.fi
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
Financial support from the Academy of Finland [project no. 129062] is acknowledged. The Finnish National
Centre for Scientific Computing (CSC) is recognized for computational resources.
REFERENCES
(1) Reviews: (a) Pelliccioli, A. P.; Wirz, J. Photochem. Photobiol. Sci. 2002, 1, 441ꢀ458. (b) Givens, R. S.;
Conrad, II, P. G.; Yousef, A. L.; Lee, J.ꢀI. ‘Photoremovable Proteting groups’ in CRC Handbook of Organic
Photochem. Photobiol., 2nd Ed., Chapter 69, CRD Press LLC, 2014, 1ꢀ45. (c) Klán, P.; Šolomek, T.; Bochet,
C. G.; Blanc, A.; Givens, R.; Rubina, M.; Popik, V.; Kostikov, A.; Wirz J. Chem. Rev. 2013, 113, 119ꢀ191.
(2) Selected photoreduction reviews: (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013,
113, 5322ꢀ5363. (b) Xi, Y.; Yia, H.; Lei, A. Org. Biomol. Chem. 2013, 11, 2387ꢀ2403. (c) Shaw, M. H.;
Twilton, J.; MacMillan, D. W. C. J. Org. Chem. 2016, 81, 6898ꢀ6926. (d) Majek, M.; Jacobi von Wangelin,
A. Acc. Chem. Res. 2016, 49, 2316ꢀ2327.
(3) Tucker, J. W.; Narayanam, J. M. R.; Shah, P. S.; Stephenson, C. R. J. Chem. Commun. 2011, 47, 5040ꢀ
5042.
(4) Giedyk, M.; Turkowska, J.; Lepak, S.; Marculewicz, M.; ó Proinsias, K.; Gryko D. Org. Lett. 2017, 19,
2070ꢀ2673.
(5) (a) DeClue, M. S.; Monnard, P.ꢀA.; Bailey, J. A.; Maurer, S. E.; Collis, G. E.; Ziock, H.ꢀJ.; Rasmussen,
S.; Boncella, J. M. J. Am. Chem. Soc. 2009, 131, 931ꢀ933. (b) Borak, J. B.; Lee, H.ꢀY.; Raghavan, S. R.;
Falvey, D. E. Chem. Commun. 2010, 46, 8983ꢀ8985. (c) Borak J. B.; Falvey D. E. J. Org. Chem. 2009, 74,
3894ꢀ3899.
(6) Edson, J. B.; Spencer, L. P.; Boncella, J. M. Org. Lett. 2011, 13, 6156ꢀ6159.
(7) (a) Falvey, D. E; Sundararajan, C. Photochem. Photobiol. Sci., 2004, 3, 831ꢀ838. (b) Sundararajan, C.;
Falvey, D. E. J. Org. Chem. 2004, 69, 5547ꢀ5554. (c) Sundararajan, C.; Falvey, D. E. J. Am. Chem. Soc.
2005, 127, 8000ꢀ8001. (c) Sundararajan, C.; Falvey, D. E. Org. Lett. 2005, 7, 2631ꢀ2634. (d) Sundararajan,
C.; Falvey, D. E. Photochem. Photobiol. Sci. 2006, 5, 116ꢀ121.
(8) Protective Groups in Organic Synthesis. 3rd Ed., Eds. Greene, T. W.; Wuts. P. G. M., John Wiley & Sons,
New York. 1999.
(9) Pd catalysis inhibition by Nꢀcoordination: Xiaojiao, S.; Yu, Z.; Wu, S.; Xiao, W.ꢀJ. Organometallics
2005, 24, 2959ꢀ2963
(10) (a) Todorov, A. R.; Nieger, M.; Helaja J. Chem. Eur. J. 2012, 18, 7269ꢀ7277. (b) Frank, J.; Katritzky, A.
R. J. Chem. Soc. Perkin Trans 2 1976, 12, 1428ꢀ1431.
(11) Groenenboom, M. C.; Saravanan, K.; Zhu, Y.; Carr, J. M.; Marjolin, A.; Faura, G. G.; Yu, E. C.;
Dominey, R. N.; Keith, J. A. J. Phys. Chem. A 2016, 120, 6888ꢀ6894.
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(12) Wirtanen T.; Muuronen, M.; Hurmalainen J., Tuononen, H. M.; Nieger, M.; Helaja, J. Org. Chem.
Front. 2016, 3, 1738ꢀ1745.
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6
7
8
(13) Davis, A. P.; Fry, A. J. J. Phys. Chem. A 2010, 114, 12299ꢀ12304.
(14) Roth, H.; Romero, N.; Nicewicz, D. Synlett 2016, 27, 714ꢀ723.
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(15) As it reported in ref. [14] that B3LYP/6ꢀ31+G** method did not provide good prediction for halogen
compounds, thus a more advanced DFT functional and basis set, uwb97xd/def2ꢀTZVP combined with
CPCM model for MeCN, was used for Brꢀcompounds compounds (see details in SI).
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60
(16) Takano, Y; Houk, K. N. J. Chem. Theory Comput. 2005, 1, 70ꢀ77.
(17) Chen, Y.F., Lin, Y.C., Morris Natschke, S.L., Wei, C.F., Shen, T.C., Lin, H.Y., Hsu, M.H., Chou, L.C.,
Zhao, Y., Kuo, S.C., Lee, K.H., Huang, L.J. Br. J. Pharmacol., 2015, 172, 1195ꢀ1221.
(18) Aldehyde is possibly converted into labile acyl radical: Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu,
I. Chem. Rev. 1999, 99, 1991ꢀ2070.
(19) For unknown reason ꢀWe speculate that the reduction could be possibly prevented due to steric
crowding around the pydine nitrogen.
(20) In electrocatalysis pyridium radicals has been reported to produce hydrogen: Baumgartel, H.; Retzlav,
K.ꢀJ. Heteroaromatic Compounds. In Encyclopedia of Electrochemistry of the Elements; Bard, A. J., Lund,
H., Eds.; Marcel Dekker: New York, 1984; Vol. XV, p 194.
(21) Lanni, E. L., Bosscher, M. A., Ooms, B. D., Shandro, C. A., Ellsworth, B. A., Anderson, C. E. J. Org.
Chem., 2008, 73, 6425–6428.
(22) Manikandan, R., Jeganmohan, M. Org. Lett., 2014, 16, 3568–3571.
(23) Malapit, C. A., Ichiishi, N., Sanford, M. S. Org. Lett., 2017, 19, 4142–4145.
(24) Wang, H., Ma, Y., Tian, H., Yu, A., Chang, J., Wu, Y. Tetrahedron, 2014, 70, 2669ꢀ2673.
(25) Cassis, R., Tapia, R., Valderrama, J. A. Synth. Commun., 1985, 15, 125ꢀ133
(26) Schulz, T., Torborg, C., Schäffner, B., Huang, J., Zapf, A., Kadyrov R., Börner, A., Beller, B. Angew.
Chem. Int. Ed., 2009, 48, 918 –921.
(27) Pasquini, S., De Rosa, M., Pedani, V., Mugnaini, C., Guida, F., Luongo, L., De Chiaro, M., Maione, S.,
Dragoni, S., Frosini, M., Ligresti, A., Di Marzo, V., Corelli, F. J. Med. Chem., 2011, 54, 5444–5453.
(28) Guillou, S., Janin, L. Y. J. Heterocycl. Chem., 2008, 45, 1377ꢀ1384.
(29) Morel, A. F., Larghi, E. L., Selvero, M. M. Synlett, 2005, 18, 2755ꢀ2758.
(30) Osborne, A. G., Buley, J. M., Clarke, H., Dakin, R. C. H., Price, P. I. J. Chem. Soc., Perkin Trans. 1,
1993, 22, 2747ꢀ2755.
(31) Ferrer, S., Naughton, D. P., Parveen, I., Threadgill, M. D. J. Chem. Soc., Perkin Trans. 1, 2002, 0, 335ꢀ
340.
(32) Chuang, TꢀH., Wu PꢀL. J. Chin. Chem. Soc., 2006, 53, 413ꢀ420.
(33) Thu, HꢀY., Yu, WꢀY., Che, CꢀM. J. Am. Chem. Soc., 2006, 128, 9048–9049.
(34) Nagesh H. N., Suresh N., Prakash G. V. S. B., Gupta S., Rao J. V., Sekhar K. V. G. C. Med. Chem. Res.,
2015, 24, 523–532.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 24
1
2
3
4
5
6
7
(35) Toganoh, M., Fujino, K., Ikeda, S., Furuta, H. Tetrahedron Lett., 2008, 49, 1488–1491.
(36) Ballesteros, P., Claramunt, R. M. Tetrahedron, 1987, 43, 2557ꢀ2564.
(37) Yang, D., Fu, H. Chem. Eur. J., 2010, 16, 2366 – 2370.
8
9
(38) Wasa, M., Chan, K. S. L., Zhang, Z.ꢀG., He, J., Miura, M., Yu, J.ꢀQ. J. Am. Chem. Soc., 2012, 134,
18570–18572.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(39) Yeung, C. S., Hsieh, T.H. H., Dong, V. M. Chem. Sci., 2011, 2, 544ꢀ551.
(40) Herdeis, C., Dimmerling, A. Heterocycles, 1984, 22, 2277 – 2283.
(41) Niedermann, HꢀP., Munro, D. Brit. UK Pat. Appl., 1995, GB 2285045 A 19950628.
(42) Ding, ZꢀG., Zhao, JꢀY., Yang, PꢀW., Li, MꢀG., Huang, R., Cui, XꢀL., Wen MꢀL. Magn. Reson. Chem.,
2009, 47, 366–370.
(43) Kobayashi, S., Ando, A., Kuroda, H., Ejima, S., Masuyama, A., Ryu, I. Tetrahedron, 2011, 67, 9087ꢀ
9092.
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