Photoredox Catalysis for Silyl-Mediated C–H Alkylation of Heterocycles with Non-Activated Alkyl Bromides

Article abstract of DOI:10.1002/ejoc.201900611

The development of a Minisci reaction of electron-deficient heteroarenes with non-activated alkyl bromides under visible-light photoredox catalysis is disclosed. Optimization of the reaction led to identification of mild, general, and practical reaction c

Full text of DOI:10.1002/ejoc.201900611

A Journal of
Accepted Article
Title: Photoredox Silyl-Mediated C-H Alkylation of Heterocycles with
Non-Activated Alkyl Bromides
Authors: James Perkins, Jeffrey W. Schubert, Eric C. Streckfuss,
Jaume Balsells, and Abdellatif El Marrouni
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900611
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900611
Supported by

10.1002/ejoc.201900611
European Journal of Organic Chemistry
FULL PAPER
Photoredox Silyl-Mediated C-H Alkylation of Heterocycles with
Non-Activated Alkyl Bromides
James J. Perkins,[a] Jeffrey W. Schubert,[a] Eric C. Streckfuss,[a] Jaume Balsells,[b] and Abdellatif
ElMarrouni*[a]
Abstract: The development of
a
Minisci reaction of electron-
several research groups have reported on Minisci-type
transformation by generation of carbon-centered radicals from a
diverse set of functional handles such as alkyl carboxylic acids,4
peroxides,5 boronic acids,6 trifluoroborate salts,7 iodides,8 1,4-
dihydropyridines,9 activated amines,10 or alcohols11 (Scheme 1).
Additionally, Barriault and co-workers described a protocol for
direct alkylation of heteroarenes with alkyl bromides mediated by
a gold photoredox catalyst under UVA irradiation.12
deficient heteroarenes with non-activated alkyl bromides under
visible-light photoredox catalysis is disclosed. Optimization of the
reaction led to identification of mild, general, and practical reaction
conditions compatible with sensitive functional groups. The scope of
this transformation allowed late-stage functionalization of
pharmaceutical products containing electron-deficient heteroarenes
in a parallel fashion.
While these synthetic methods allow access to a wide range of
substrates, there is still an opportunity to expand the scope of
this synthetic transformation by enabling the use of the large and
diverse pool of commercially available alkyl bromides. 13 We
sought to identify mild conditions to facilitate alkylation of
heteroarenes using nonactivated alkyl bromides at different
Introduction
Recent advances in photoredox catalysis have allowed the
generation of carbon-centered radicals under mild conditions,
enabling the development of general and modular synthetic
stages of
a synthetic campaign, including a late-stage
1
methods requiring minimal activating groups.
These
functionalization (LSF) approach. LSF strategies in medicinal
chemistry are highly desirable, as they provide a means to
rapidly diversify a complex scaffold and enable synthesis of
libraries of analogues to build structure-activity relationships
(SAR).2a
transformations have the potential to accelerate the discovery of
new therapeutics by expanding the medicinal chemist’s toolbox.2
Direct C-H bond alkylation of heteroaryl motifs is an important
reaction to rapidly install chemical diversity. To this end, the
Minisci reaction enables direct C-H alkylation of electron
deficient arenes.3 The classical Minisci reaction involves radical
decarboxylation of alkyl carboxylic acids catalyzed by Ag(I)
species at elevated temperatures with inorganic persulfates as
oxidants. These conditions limit the scope and efficiency of this
transformation.
Scheme 1. Photoredox-mediated Minisci reaction.
Scheme 2. Discovery of Minisci reactivity with (Me3Si)3SiH and alkyl bromides
under visible-light photoredox.
Recent work has focused on exploring alternative radical
precursors and/or mild experimental conditions. In this context,
Our group initially became interested in developing
a
photoredox-catalyzed Minisci alkylation of N-heteroarenes
following our recently reported work on silyl-mediated
photoredox-catalyzed Giese reaction with non-activated alkyl
bromides.14 During this campaign, we explored whether organic
bases such as 2,6-lutidine could promote the conjugate addition
of alkyl bromides, and interestingly, we observed the formation
of the desired product in 27% isolated yield along with significant
amounts of monoalkylated Minisci product 4 (Scheme 2). We
hypothesized that protonation of 2,6-lutidine by HBr generated
[a]
[b]
J. J. Perkins, J. W. Schubert, E. C. Streckfuss, Dr. A. ElMarrouni
Department of Discovery Chemistry
MRL, Merck & Co., Inc.,
770 Sumneytown Pike, West Point, Pennsylvania 19486 USA
E-mail: abdellatif.el.marrouni@merck.com
Dr. J. Balsells
Janssen Research & Development LLC
Spring House, Pennsylvania 19477 USA
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900611
European Journal of Organic Chemistry
FULL PAPER
during the reaction allowed activation of the heterocycle toward
attack by the alkyl radical.15
1 as a model system. These reactants were subjected to the
optimized silyl mediated photoredox catalysis reaction conditions
affording the alkylated product 6 in 81% isolated yield (Table 1,
entry 1). No difference was observed when 4CzIPN was used as
photocatalyst instead of Ir[dF(CF3)ppy]2(dtbbpy)PF6 as originally
employed in our previous work (Table 1, entry 2). We
hypothesized that an external oxidant was required to complete
the catalytic cycle and provide the final aromatic product;
therefore, we added K2S2O8, an inexpensive oxidant that has
shown utility since the discovery of the Minisci reaction. 17
Omission of K2S2O8 still provided the desired product in 41%
yield which most likely was due to the presence of oxygen as an
external oxidant (Table 1, entry 3). To further understand this
finding, an additional experiment without K2S2O8 under inert
atmosphere (in the glovebox) led to minimal conversion
demonstrating the role of oxygen as an oxidant when persulfate
is not present (Table 1, entry 4).
With these considerations in mind, we started a campaign to
convert this observation into a practical and efficient method of
alkylating heteroarenes using non-activated alkyl bromides and
mediated by (Me3Si)3SiH under photoredox conditions. During
the preparation of this manuscript, Wang and co-workers
reported
a protocol for direct C-H Minisci alkylation of
heteroaryls with alkyl halides using Ir photocatalyst, molecular
oxygen, and excess (Me3Si)3SiH mediated by visible light. 16
While this method provides a tool to make use of alkyl bromides,
we report here an alternative method that does not require any
metal photocatalyst. Even though oxygen is environmentally
benign, setting up parallel reactions bubbling oxygen
atmosphere may not be practical for library synthesis.
Additionally, a mixture of water and acetonitrile, which is ideal for
library purification under reverse-phase conditions, is preferred
as solvent.
We realized that our reaction conditions tolerated water and
found that a 2:1 ratio as co-solvent in acetonitrile facilitates
dissolution of persulfate and improved the yield of desired
product 6 (Table 1, entries 5 and 6). Importantly, this solvent
mixture is ideal for purification using reverse-phase techniques
and parallel workflows.
Results and Discussion
To evaluate this transformation, we first turned our attention to
the reaction of quinazolinone 5 and 4-bromopiperidine derivative
Next, we performed a series of control reactions to reinforce our
photoredox mechanistic hypothesis wherein we conducted
reactions in the absence of light and/or silane (Table 1, entries
7-8). In both cases, no reaction was observed and starting
materials were recovered. Interestingly, a test reaction without
photocatalyst resulted in the formation of the alkylated product 3
in 30% yield but with full consumption of starting material 1
(Table 1, entry 9). This observation is consistent with the ability
of persulfate to mediate single-electron transformations as
previously observed by others in the field of photoredox.4,18
Table 1. Optimization of C-H alkylation reaction.[a]
Entry
Conditions
Yield 6[b]
81%
70%
41%
<5%[c]
50%
70%
0%
Finally, we focused on the need of acid to activate the
heteroarene, and as speculated initially, TFA was not required to
afford the desired product (Table 1, entry 10). However, the
reaction was not homogeneous and lower conversions were
achieved. In addition, purification proved challenging when
employed in parallel fashion. The addition of TFA led to
homogeneous reactions that were easily manipulated for high
throughput purification protocols. Also, the control reactions
were run in parallel under uniform lighting conditions using an
Aldrich® SynLed parallel photoreactor.
1
2
3
4
5
6
7
8
9
10
As shown
Ir[dF(CF3)ppy]2(dtbbpy)PF6
No K2S2O8
No K2S2O8 (glovebox)
No water
MeCN: H2O [1:1]
No light
No (Me3Si)3SiH
No photocatalyst
No TFA
0%
30%
66%
[a] Optimized conditions: quinazolin-4(3H)-one (5) (1.0 equiv.), alkyl bromide 1
(1.5 equiv.), 4CzIPN (2 mol%), (Me3Si)3SiH (1.5 equiv.), K2S2O8 (1.5 equiv.)
and TFA (1.5 equiv.) in MeCN: water [2:1], blue LEDs. [b] Yields correspond to
isolated and analytically pure product. [c] Reaction conversion by LC-MS..
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900611
European Journal of Organic Chemistry
FULL PAPER
Scheme 4. Scope of heteroarenes.[a],[b] [a] Heteroaryl (1.0 equiv.), alkyl
bromide (1.5 equiv.), 4CzIPN (2 mol%), (Me3Si)3SiH (1.5 equiv.), K2S2O8 (1.5
equiv.) and TFA (1.5 equiv.) in MeCN: H2O [2:1], blue LEDs. [b] Yields
correspond to isolated and analytically pure products.
Scheme 3. Scope of alkyl bromides.[a],[b] [a] Quinazolin-4(3H)-one (5) (1.0
equiv.), alkyl bromide (1.5 equiv.), 4CzIPN (2 mol%), (Me3Si)3SiH (1.5 equiv.),
K2S2O8 (1.5 equiv.) and TFA (1.5 equiv.) in MeCN: H2O [2:1], blue LEDs. [b]
Yields correspond to isolated and analytically pure products.
Reaction scope was further explored by testing a variety of
heteroarenes (Scheme 4). Fused 5-membered rings, such as
benzothiazole or benzoimidazole, were successfully alkylated
with piperidine and/or tetrahydropyran bromides to access
products 18-20 (Scheme 4). Next, we turned our attention to the
functionalization of pyridine derivatives. Pyridine is a privileged
heteroarene in drug discovery and present in many therapeutics,
also found in pesticides and many natural products, such as
vitamins, coenzymes, and alkaloids.21 We were pleased to find
We explored the scope of the reaction using the optimized
conditions focusing on a set of primary, secondary and tertiary
alkyl bromides (Scheme 3). This transformation allowed access
to several quinazolinones, which represent an important class of
biologically active nitrogen-containing heterocyclic compounds
with vast therapeutic potential.19 We were satisfied to find that
primary alkyl bromides provided the desired products 7 and 8 in
synthetically useful yields, and that a labile phosphonate group
survived the reaction conditions. Several non-activated
secondary alkyl bromides, including unfunctionalized cyclic and
linear alkyls, were successfully installed to afford quinazolinone
derivatives 9-13, in addition to cyclic ethers such as
tetrahydrofuran 14 and tetrahydropyran 15 (Scheme 3). This
methodology also allowed access to quaternary centers when
using tertiary alkyl bromides. In this case, adamantane and its
ketone derivative gave alkylated quinazolinone analogs 16 and
17 in excellent yields (Scheme 3). Adamantyl groups are often
that
2,4-disubsituted
pyridines
were
alkylated
with
tetrahydropyran to provide the corresponding desired products
21-22 (Scheme 4). Fully substituted pyridine 23 was accessed in
moderate yield.
Hydroxymethylpyridine 24 was obtained in 25% yield, but pro-
vides access to a versatile compound with handles for further
functionalization. Alkylation of quinoline and isoquinoline, classic
examples in Minisci reactions, with secondary alkyl bromides
afforded C2-alkylated products 25 and 26 in synthetically useful
yield (Scheme 4).
used in medicinal chemistry as
a
strategy to modify
physicochemical or ADME properties of a lead compound.20
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900611
European Journal of Organic Chemistry
FULL PAPER
Scheme 6. Plausible reaction mechanism.
A plausible reaction mechanism for the visible light-mediated C-
H alkylation of alkyl bromides is proposed in Scheme 6. The
generation of an initial carbon-based radical A from an alkyl
bromide under photoredox conditions has been explained
23
previously by MacMillan
in the context of their cross-
electrophile coupling. Oxidation of bromide by the excited
photocatalyst generates an electrophilic bromine radical which is
capable of abstracting hydrogen from (Me3Si)3SiH,24 generating
the silyl radical species [(Me3Si)3Si]. 25 Subsequent halogen
abstraction from alkyl bromide
corresponding nucleophilic radical species
subsequent reaction of A with an activated heteroarene B to
generate radical C is also well established.3 Eventually, C could
undergo H atom abstraction or oxidation by SO4 to deliver the
desired product D.26
1
would provide the
and the
Scheme 5. Late-stage alkylation of therapeutic agents. [a], [b] [a] Heteroaryl (1.0
equiv.), alkyl bromide (1.5 equiv.), 4CzIPN (2 mol%), (Me3Si)3SiH (1.5 equiv.),
K2S2O8 (1.5 equiv.) and TFA (1.5 equiv.) in MeCN: H2O [2:1], blue LEDs. [b]
Yields correspond to isolated and analytically pure products.
A
To demonstrate the utility of this Minisci C-H alkylation method
as a late-stage functionalization tool, we focused on drug
scaffolds. Caffeine was successfully alkylated with primary and
secondary moieties to give 27 and 28 in 40% and 60% yields,
respectively. Fasudil, a potent vasodilator,22 reacted smoothly
with primary and secondary alkyl bromides to afford 29 and 30 in
60% and 90% yields, respectively, demonstrating the robustness
of this method in the presence of unprotected secondary amines.
More complex drugs such as antifungal Voriconazole, which
bears a tertiary alcohol, was selectively alkylated at the C2
position to give 31 in 30% yield. Moreover, antihistamine
Loratidine reacted with bromopiperidine derivative 1 leading to
the selective C2 product 32 in 30% yield in the presence of vinyl
and carbamate moieties (Scheme 5). The scope of these
examples demonstrates the robustness of this transformation
with a variety of alkyl bromides and heteroarenes. Finally, short
reaction times render this methodology highly useful for
synthetic chemists for single or parallel work.
Conclusions
In conclusion, we have developed a protocol for the Minisci C-H
alkylation of heteroarenes using the widely available and
structurally diverse pool of unactivated alkyl bromides mediated
by photoredox catalysis. Tolerability of functional groups on both
coupling partners, such as unprotected alcohols, esters, or
protected and unprotected amines make this a practical protocol
complementary to traditional methods. We have also
demonstrated that this transformation proceeds under mild
conditions to provide numerous primary, secondary and tertiary
products, including analogues of currently approved therapeutics.
Experimental Section
General Information: All commercially available reagents and
anhydrous acetonitrile (MeCN) were purchased from commercial
suppliers and used without further purification. All reactions were
performed under an inert nitrogen atmosphere unless otherwise stated.
All reactions were monitored by liquid chromatography-mass
spectrometry (LC-MS) using a Waters Acquity UPLC. High performance
liquid chromatography (HPLC) purification on Gilson PLC 2020 unit with
Waters SunFire C18 OBD 5 μm 30 x 150 mm prep column. Yields refer
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900611
European Journal of Organic Chemistry
FULL PAPER
to chromatographically and spectroscopically homogenous materials.
Infrared spectra (IR) were recorded on a PerkinElmer Spectrum 100
Optica FT-IR spectrometer. Only the strongest and/or structurally
important absorption of infrared (IR) spectra are reported in reciprocal
centimetres (, cm-1). 1H NMR spectra (500 MHz) and 13C{1H} NMR
spectra (126 MHz), and were recorded on a Bruker Avance NEO 500
MHz NMR spectrometer with a 5 mm iProbe in CD3OD. Chemical shift
(δ) values are reported in delta (δ) units, parts per million (ppm).
Chemical shifts for 1H NMR spectra are given relative to signals for
internal tetramethylsilane (0.00 ppm) and residual non-deuterated
methanol (3.31 ppm). Chemical shifts for 13C NMR spectra are given
relative to the signal of CD3OD (49.0 ppm). Multiples are reported by the
following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, dd
128.5, 121.0, 120.4, 44.1, 30.5, 26.6, 26.1 ppm. HRMS (ESI+): m/z
calculated. for C20H20N3O2 [M+H]+ 334.1550, found 334.1532.
General procedure for preparation of compounds 7 – 32:
In a 2-dram vial were added heteroarene (0.14 mmol, 1.0 equiv.), alkyl
bromide (0.21 mmol, 1.5 equiv.), K2S2O8 (55 mg, 0.21 mmol, 1.5 equiv.)
and 4CZIPN (2.2 mg, 2.7 µmol, 0.02 equiv.). MeCN (900 µL) and water
(450 µL) were added to the vial followed by tris(trimethylsilyl)silane (63
µL, 0.21 mmol, 1.5 equiv.). Then, TFA (16 µL, 0.21 mmol, 1.5 equiv.) was
added. The resulting vial was capped and set on the Aldrich® Syn LED
Parallel Reactor (4 h). After the reaction was completed, volatiles were
removed at reduced pressure. The resulting residue was dissolved in
DMSO (1 mL), filtered and purified by HPLC: eluted with a 15-minute
gradient of 90% water/MeCN (both 0.1% TFA) to 5% water/MeCN (both
0.1% TFA) with a flow rate of 25 ml/min. The fractions were concentrated
to provide the final products.
=
doublet of doublets, m = multiplet or overlap of nonequivalent
resonances. Coupling constants (J) are reported in Hertz (Hz). Products
containing the piperidine ring exhibited four unique methylenes in the
proton and carbon NMR spectra. These peaks were broad at room
temperature but sharpened significantly when cooled to 0 ⁰C. Taken
together, these data suggest there are conformational changes
associated with the piperidine ring. Variable-temperature 1H NMR
spectra for compound 6 are included. High resolution mass spectra
(HRMS) were recorded using a Waters Synapt G1 Quadrapole-Time of
Flight (Q-TOF) high definition mass spectrometer (HDMS).
2-(Cyclopentylmethyl)quinazolin-4(3H)-one
(7):
Synthesized
according to the general procedure using (bromomethyl)cyclopentane
(34 mg, 0.21 mmol, 1.5 equiv.). White solid. Yield: 56% (15 mg, 0.077
mmol). IR (neat) υ 2930, 2730, 2109, 1704, 1637, 1474, 1437 cm-1 1H
NMR (500 MHz, CD3OD) δ 8.30 (d, J = 7.9, 1H), 8.01 (m, 1H), 7.83 (d, J
= 7.9 Hz, 1H), 7.74 (m, 1H), 3.00 – 2.91 (m, 1H), 2.12 (m, 2H), 1.99 (m,
2H), 1.88 – 1.74 (m, 3H), 1.54 – 1.34 (m, 3H). 13C NMR (126 MHz,
CD3OD) δ 167.9, 160.4, 139.3, 137.7, 130.0, 128.5, 121.0, 120.4, 44.1,
30.5, 26.6, 26.1 ppm. HRMS (m/z) [M+H]+: calculated for C11H13N2O;
theoretical mass: 189.1022; found 189.1031.
Materials: All alkyl bromides, heteroarenes and catalysts
Ir[dF(CF3)ppy]2(dtbbpy)PF6 and 4CZIPN were purchased from Sigma
Aldrich, Strem Chemicals, or Frontier Scientific.
General procedure for screening (Table 1):
Diethyl (3-(4-oxo-3,4-dihydroquinazolin-2-yl)propyl)phosphonate (8):
synthesized according to the general procedure using diethyl (3-
bromopropyl)phosphonate (52 mg, 0.21 mmol, 1.5 equiv.). White solid.
Yield: 45% (20 mg, 0.062 mmol). IR (neat) υ 3383, 2636, 1717, 1599,
1573, 1477, 1446, 1373 cm-1 1H NMR (500 MHz, CD3OD) δ 8.24 (dd, J =
8.0, 1.1 Hz, 1H), 7.95 – 7.87 (m, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.66 –
7.57 (m, 1H), 4.22 – 3.98 (m, 4H), 2.92 (t, J = 7.6 Hz, 2H), 2.20 – 2.08 (m,
2H), 2.06 – 1.92 (m, 2H), 1.33 (t, J = 7.1 Hz, 6H) ppm. 13C NMR (126
MHz, CD3OD) δ 190.6, 189.1, 172.9, 164.9, 157.2, 155.9, 152.2, 149.7,
91.6 (d, J = 6.6 Hz), 63.2 (d, J = 16.9 Hz), 53.3 (d, J = 141.7 Hz), 49.7 (d,
J = 4.4 Hz), 44.9 (d, J = 6.0 Hz) ppm. HRMS (m/z) [M+H]+: calculated for
In a 2-dram vial were added quinazolin-4(3H)-one (5) (20 mg, 0.14 mmol,
1.0 equiv.), (4-bromopiperidin-1-yl)(phenyl)methanone (1) (55 mg, 0.21
mmol, 1.5 equiv.), and the appropriate photocatalyst (0.002 mmol, 0.02
equiv.). Solvent(s) was added to the vials (1500 µL) followed by
tris(trimethylsilyl)silane (63 µL, 0.21 mmol, 1.5 equiv.). Where noted,
K2S2O8 (55 mg, 0.21 mmol, 1.5 equiv.) and/or TFA (16 µL, 0.21 mmol,
1.5 equiv.) was added. Vials were sealed and then set on the Aldrich®
Syn LED Parallel Reactor overnight (16 h). After the reactions were
completed, volatiles were removed at reduced pressure. The resulting
residues were dissolved in DMSO (1 mL), filtered and purified by HPLC:
eluted with a 15-minute gradient of 90% water/MeCN (both 0.1% TFA) to
5% water/MeCN (both 0.1% TFA) with a flow rate of 25 ml/min. The
fractions were concentrated to provide the final products.
C15H22N2O4P; theoretical mass: 325.1312; found 325.1310.
2-Isopropylquinazolin-4(3H)-one (9): synthesized according to the
general procedure using 2-bromopropane (25 mg, 0.21 mmol, 1.5 equiv.).
White solid. Yield: 60% (16 mg, 0.082 mmol). IR (neat) υ 2647, 1717,
1650, 1589, 1562, 1478 cm-1 1H NMR (500 MHz, CD3OD) δ 8.30 (d, J =
7.9, 1H), 8.02 (m, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.75 (m, 1H), 3.35 – 3.23
(m, 1H), 1.53 (d, J = 7.0 Hz, 6H) ppm. 13C NMR (126 MHz, CD3OD) δ
169.3, 160.4, 139.2, 138.7, 130.3, 128.5, 121.0, 120.4, 34.5, 19.7 ppm.
HRMS (m/z) [M+H]+: calculated for C11H13N2O; theoretical mass:
189.1022; found 189.1031.
Synthesis of 2-(1-benzoylpiperidin-4-yl)quinazolin-4(3H)-one (6):
In a 2-dram vial were added quinazolin-4(3H)-one (5) (50 mg, 0.35 mmol,
1.0 equiv.), (4-bromopiperidin-1-yl)(phenyl)methanone (1) (138 mg, 0.53
mmol, 1.5 equiv.), K2S2O8 (138 mg, 0.53 mmol, 1.5 equiv.) and 4CZIPN
(5.5 mg, 6.8 µmol, 0.02 equiv.). MeCN (2250 µL) and water (1125 µL)
were added to the vial followed by tris(trimethylsilyl)silane (158 µL, 0.53
mmol, 1.5 equiv.). Then, TFA (40 µL, 0.53 mmol, 1.5 equiv.) was added.
The resulting vial was capped and set on the Aldrich® Syn LED Parallel
Reactor (4 h). After the reaction was completed, volatiles were removed
at reduced pressure. The resulting residue was dissolved in DMSO (1
mL), filtered and purified by HPLC: eluted with a 15-minute gradient of
90% water/MeCN (both 0.1% TFA) to 5% water/MeCN (both 0.1% TFA)
with a flow rate of 25 ml/min. The fractions were concentrated to provide
product 6 as a white solid (94 mg, 0.28 mmol, 81% yield). IR (neat) υ
3391, 2645, 1717, 1648, 1611, 1575, 1477, 1447, 1374 cm-1. 1H NMR
(500 MHz, CD3OD) δ 8.29 (d, J = 7.9, 1H), 8.02 (m, 1H), 7.82 (d, J = 7.9
Hz, 1H), 7.75 (m, 1H), 7.49 (m, 5H), 4.89 (m, 1H), 3.93 (m, 1H), 3.38 (m,
1H), 3.34 – 3.24 (m, 1H), 3.01 (m, 1H), 2.25 (m, 1H), 2.17 – 2.00 (m, 3H)
ppm. 13C NMR (126 MHz, CD3OD) δ 167.9, 160.4, 139.3, 137.7, 130.0,
2-(4-Phenylbutan-2-yl)quinazolin-4(3H)-one
(10):
synthesized
according to the general procedure using (3-bromobutyl)benzene (43 mg,
0.21 mmol, 1.5 equiv.). White solid. Yield: 40% (15 mg, 0.055 mmol). IR
(neat) υ 3026, 2631, 1717, 1648, 1587, 1562, 1477, 1454 cm-1 1H NMR
(500 MHz, CD3OD) δ 8.20 (d, J = 7.9 Hz, 1H), 7.99 (m, 1H), 7.77 – 7.70
(m, 2H), 7.18 (m, 2H), 7.08 (m, 2H), 6.93 (m, 1H), 3.21 – 3.11 (m, 1H),
2.99 – 2.90 (m, 1H), 2.74 – 2.65 (m, 1H), 2.43 – 2.31 (m, 1H), 2.26 –
2.16 (m, 1H), 1.54 (d, J = 7.2 Hz, 3H) ppm. 13C NMR (126 MHz, CD3OD)
δ 186.2, 160.0, 141.2, 138.8, 137.6, 130.4, 129.6, 129.5, 128.4, 127.3,
120.8, 120.3, 39.9, 36.3, 34.6, 18.5 ppm. HRMS (m/z) [M+H]+: calculated
for C18H19N2O; theoretical mass: 279.1492; found 279.1485.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900611
European Journal of Organic Chemistry
FULL PAPER
2-Cyclopentylquinazolin-4(3H)-one (11): synthesized according to the
general procedure using bromocyclopentane (30 mg, 0.21 mmol, 1.5
equiv.). White solid. Yield: 55% (16 mg, 0.075 mmol). IR (neat) υ 3445,
2927, 2526, 2159, 2029, 1977, 1717, 1647, 1494, 1452 cm-1 1H NMR
(500 MHz, CD3OD) δ 8.30 (d, J = 7.9, 1H), 8.01 (m, 1H), 7.85 (d, J = 7.9
Hz, 1H), 7.74 (m, 1H), 3.37 – 3.28 (m, 1H), 2.37 – 2.28 (m, 2H), 2.07 –
1.96 (m, 4H), 1.88 – 1.76 (m, 2H) ppm. 13C NMR (126 MHz, CD3OD) δ
168.2, 160.4, 139.3, 137.7, 130.2, 128.4, 120.9, 120.4, 44.8, 33.0, 27.8
ppm. HRMS (m/z) [M+H]+: calculated for C13H15N2O; theoretical mass:
215.1179; found 215.1172.
(150 MHz, CD3OD) δ 219.2, 135.7, 128.6, 127.7, 127.5, 126.95, 126.92,
47.5, 41.9, 40.1, 39.4, 37.4, 37.1, 33.6, 29.1, 28.4 ppm. HRMS (m/z)
[M+H]+: calculated for C18H19N2O2 ; theoretical mass: 295.1441; found
295.1436.
2-((3r,5r,7r)-Adamantan-1-yl)quinazolin-4(3H)-one (17): synthesized
according to the general procedure using rac-(3s,5s,7s)-1-
bromoadamantane (43 mg, 0.21 mmol, 1.5 equiv.). White solid. Yield:
91% (35 mg, 0.13 mmol). IR (neat) υ 2906, 1665, 1607 cm-1 1H NMR
(500 MHz, CD3OD) δ 8.30 (d, J = 7.9 Hz, 1H), 8.06 – 7.98 (m, 2H), 7.74
(m, 1H), 2.22 (m, 9H), 1.90 (m, 6H) ppm. 13C NMR (150 MHz, CD3OD) δ
169.9, 160.7, 139.9, 137.5, 130.3, 128.2, 121.3, 120.9, 41.0, 39.4, 36.6,
29.2 ppm. HRMS (m/z) [M+H]+: calculated for C18H21N2O; theoretical
mass: 281.1648; found 281.1642.
2-Cyclohexylquinazolin-4(3H)-one (12): synthesized according to the
general procedure using bromocyclohexane (33 mg, 0.21 mmol, 1.5
equiv.). White solid. Yield: 55% (17 mg, 0.075 mmol). IR (neat) υ 2929,
2106, 1700, 1635, 1618, 1436 cm-1 1H NMR (500 MHz, CD3OD) δ 8.30
(d, J = 7.9 Hz, 1H), 8.01 (m, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.74 (m, 1H),
2.97 (m, 1H), 2.18 – 2.08 (m, 2H), 2.03 – 1.94 (m, 2H), 1.88 – 1.73 (m
3H), 1.54 – 1.35 (m, 3H) ppm. 13C NMR (126 MHz, CD3OD) δ 167.9,
160.4, 139.2, 137.7, 130.3, 128.4, 121.0, 120.4, 44.1, 30.5, 26.6, 26.1
ppm. HRMS (m/z) [M+H]+: calculated for C14H17N2O; theoretical mass:
229.1335; found 229.1335.
(4-(Benzo[d]thiazol-2-yl)piperidin-1-yl)(phenyl)methanone
(18):
synthesized according to the general procedure using benzo[d]thiazole
(18 mg, 0.14 mmol, 1.0 equiv.) and (4-bromopiperidin-1-
yl)(phenyl)methanone (54 mg, 0.21 mmol, 1.5 equiv.). White solid. Yield:
55% (24 mg, 0.075 mmol). IR (neat) υ 2907, 1664, 1608 cm-1 1H NMR
(500 MHz, CD3OD) δ 7.94 (t, J = 8.6 Hz, 2H), 7.53 – 7.43 (m, 6H), 7.43 –
7.37 (m, 1H), 4.80 – 4.64 (m, 1H), 3.92 – 3.76 (m, 1H), 3.47 (tt, J = 11.4,
3.8 Hz, 1H), 3.36 – 3.23 (m, 1H), 3.15 – 3.05 (m, 1H), 2.33 – 2.22 (m,
1H), 2.19 – 2.05 (m, 1H), 2.01 – 1.80 (m, 2H) ppm. 13C NMR (150 MHz,
CD3OD) δ 176.9, 172.6, 153.9, 137.0, 135.6, 131.1, 129.8, 127.9, 127.4,
126.3, 123.2, 123.0, 43.0, 42.1, 33.6, 32.9 ppm. HRMS (m/z) [M+H]+:
calculated for C19H19N2OS; theoretical mass: 323.1213; found 323.1207.
2-Cyclohexylquinazolin-4(3H)-one (13): synthesized according to the
general procedure using bromocycloheptane (35 mg, 0.21 mmol, 1.5
equiv.). White solid. Yield: 56% (19 mg, 0.077 mmol). IR (neat) υ 3421,
2852, 2645, 1714, 1647 cm-1 1H NMR (500 MHz, CD3OD) δ 8.29 (d, J =
7.9 Hz, 1H), 7.99 (m, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.71 (m, 1H), 3.02 (m,
1H), 2.18 – 2.10 (m, 2H), 2.02 – 1.88 (m, 4H), 1.81 – 1.58 (m 6H) ppm.
13C NMR (126 MHz, CD3OD) δ 168.3, 160.9, 140.5, 137.5, 129.9, 128.3,
121.14, 121.07, 45.9, 32.8, 28.23, 28.21 ppm. HRMS (m/z) [M+H]+:
calculated for C15H19N2O; theoretical mass: 243.1492; found 243.1493.
2-(Tetrahydro-2H-pyran-4-yl)benzo[d]thiazole
(19):
synthesized
according to the general procedure using benzo[d]thiazole (18 mg, 0.14
mmol, 1.0 equiv.) and (4-bromotetrahydro-2H-pyran (33 mg, 0.21 mmol,
1.5 equiv.). White solid. Yield: 65% (20 mg, 0.089 mmol). IR (neat) υ
2952, 2854, 1508, 1439 cm-1 1H NMR (500 MHz, CD3OD) δ 8.16 (d, J =
7.9 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.63 (t, J =
7.9 Hz, 1H), 4.12 – 4.07 (m, 2H), 3.72 – 3.64 (m, 1H), 3.67 – 3.59 (m,
2H), 2.20 – 2.14 (m, 2H), 2.07 – 1.97 (m, 2H) ppm. 13C NMR (126 MHz,
CD3OD) δ 182.6, 146.9, 133.1, 129.5, 128.1, 124.2, 120.5, 68.1, 40.3,
33.5 ppm. HRMS (m/z) [M+H]+: calculated for C12H14NOS; theoretical
mass: 220.0791; found 220.0788.
2-(Tetrahydrofuran-3-yl)quinazolin-4(3H)-one
(14):
synthesized
according to the general procedure using 3-bromotetrahydrofuran (30 mg,
0.21 mmol, 1.5 equiv.). White solid. Yield: 65% (19 mg, 0.089 mmol). IR
(neat) υ 3375, 2650, 1717, 1651, 1561, 1478, 1305 cm-1 1H NMR (500
MHz, CD3OD) δ 8.30 (d, J = 7.9 Hz, 1H), 8.01 (m, 1H), 7.87 (d, J = 7.9
Hz, 1H), 7.75 (m, 1H), 4.21 (dt, J = 8.4 ,3.8 Hz, 1H), 4.16 (m, 2H), 3.87 (q,
J = 7.9 Hz, 1H), 3.78 (m, 1H), 2.65 – 2.56 (m, 1H), 2.43 – 2.33 (m, 1H)
ppm. 13C NMR (126 MHz, CD3OD) δ 165.8, 160.5, 139.6, 137.7, 130.3,
128.4, 121.0, 120.8, 72.1, 69.5, 44.1, 32.8 ppm. HRMS (m/z) [M+H]+:
calculated for C12H13N2O2; theoretical mass: 217.0972; found 217.0973.
(4-(1-Methyl-1H-benzo[d]imidazol-2-yl)piperidin-1-
yl)(phenyl)methanone (20): synthesized according to the general
procedure using 1-methyl-1H-benzo[d]imidazole (18 mg, 0.14 mmol, 1.0
equiv.) and (4-bromopiperidin-1-yl)(phenyl)methanone (54 mg, 0.21
mmol, 1.5 equiv.). White solid. Yield: 35% (15 mg, 0.048 mmol). IR (neat)
υ 3403, 1618, 1575, 1524, 1447 cm-1 1H NMR (500 MHz, CD3OD) δ 7.93
– 7.88 (m, 1H), 7.81 – 7.77 (m, 1H), 7.68 – 7.61 (m, 2H), 7.55 – 7.44 (m,
5H), 4.12 (s, 3H), 4.01 - 3.89 (m, 1H), 3.84 (tt, J = 12.2, 3.6 Hz, 1H), 3.35
– 3.23 (m, 1H), 3.52 – 3.35 (m, 1H), 3.22 – 3.04 (m, 1H), 2.37 – 2.22 (m,
1H), 2.20 – 2.07 (m, 1H), 2.05 – 1.87 (m, 2H) ppm. 13C NMR (126 MHz,
CD3OD) δ 172.7, 156.4, 136.7, 134.1, 131.6, 131.3, 129.9, 127.93,
127.91, 127.5, 114.9, 113.7, 42.7, 34.5, 31.9, 30.1 ppm. HRMS (m/z)
[M+H]+: calculated for C20H22N3O; theoretical mass: 320.1757; found
320.1744.
2-(Tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (15): synthesized
according to the general procedure using 4-bromotetrahydro-2H-pyran
(33 mg, 0.21 mmol, 1.5 equiv). White solid. Yield: 91% (30 mg, 0.13
mmol). IR (neat) υ 2855, 1718, 1651, 1478, 1448, 1304 cm-1 1H NMR
(500 MHz, CD3OD) δ 8.31 (d, J = 8.0 Hz, 1H), 8.02 (t, J = 7.8 Hz, 1H),
7.86 (d, J = 8.3 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 4.12 (dd, J = 11.7, 4.1
Hz, 2H), 3.64 – 3.51 (m, 2H), 3.29 – 3.21 (m, 1H), 2.11 (qd, J = 12.5, 4.4
Hz, 2H), 2.04 – 1.97 (m, 2H) ppm. 13C NMR (500 MHz, CD3OD) δ 166.1,
160.5, 139.5, 137.7, 130.4, 128.4, 121.1, 120.7, 67.9, 41.4, 30.1 ppm.
HRMS (m/z) [M+H]+: calculated for C13H15N2O2; theoretical mass:
231.1128; found 231.1131.
2-((1r,3R,5S,7s)-4-Oxoadamantan-1-yl)quinazolin-4(3H)-one
(16):
4-Methyl-2-phenyl-6-(tetrahydro-2H-pyran-4-yl)pyridine
(21):
synthesized according to the general procedure using rac-(5r,7s)-5-
bromoadamantan-2-one (46 mg, 0.21 mmol, 1.5 equiv.). White solid.
Yield: 82% (33 mg, 0.11 mmol). IR (neat) υ 2907, 2854, 1716, 1655,
1639, 1609 cm-1 1H NMR (500 MHz, CD3OD) δ 8.19 – 8.13 (m, 1H), 7.81
– 7.75 (m, 1H), 7.70 (t, J = 6.3 Hz, 1H), 7.48 (q, J = 7.4 Hz, 1H), 3.35 (s,
1H), 2.63 (s, 1H), 2.47 (d, J = 12.9 Hz, 1H), 2.37 (d, J = 12.9 Hz, 2H),
2.35 – 2.32 (m, 1H), 2.31 – 2.27 (m, 1H), 2.26 – 2.19 (m, 1H), 2.17 –
2.11 (m, 1H), 2.10 – 1.94 (m, 4H), 1.77 – 1.64 (m, 1H) ppm. 13C NMR
synthesized according to the general procedure using 4-methyl-2-
phenylpyridine (23 mg, 0.14 mmol, 1.0 equiv.) and (4-bromotetrahydro-
2H-pyran (33 mg, 0.21 mmol, 1.5 equiv.). White solid. Yield: 40% (14 mg,
0.055 mmol). IR (neat) υ 3393, 2952, 2848, 1629 cm-1 1H NMR (500 MHz,
CD3OD) δ 7.99 (s, 1H), 7.89 (d, J = 6.7 Hz, 2H), 7.85 (s, 1H), 7.73 – 7.63
(m, 3H), 4.15 – 4.07 (m, 2H), 3.65 – 3.57 (m, 2H), 3.46 – 3.37 (m, 1H),
2.72 (s, 3H), 2.06 – 1.93 (m, 4H) ppm. 13C NMR (126 MHz, CD3OD) δ
162.9, 160.5, 153.7, 133.2, 132.7, 130.7, 129.7, 126.3, 124.9, 68.4, 40.7,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900611
European Journal of Organic Chemistry
FULL PAPER
32.8, 22.5 ppm. HRMS (m/z) [M+H]+: calculated for C17H20NO; theoretical
mass: 254.1539; found 254.1532.
8.14 (t, J = 7.8 Hz, 1H), 8.04 (s, 1H), 7.96 (t, J = 7.7 Hz, 1H), 7.55 – 7.47
(m, 5H), 4.04 – 3.96 (m, 1H), 3.67 – 3.57 (m, 1H), 3.49 – 3.34 (m, 1H),
3.17 – 3.06 (m, 1H), 3.04 (s, 3H), 2.29 – 2.19 (m, 1H), 2.17 – 2.01 (m,
2H), 2.00 – 1.82 (m, 1H) ppm. 13C NMR (126 MHz, CD3OD) δ 172.7,
162.3, 160.9, 138.7, 136.6, 135.8, 131.3, 130.7, 129.8, 128.7, 127.98,
127.94, 126.8, 122.4, 121.6, 43.1, 42.9, 32.1, 31.5, 20.2 ppm. HRMS
(m/z) [M+H]+: calculated for C22H24N2O; theoretical mass: 331.1805;
found 331.1795.
2,4-diphenyl-6-(tetrahydro-2H-pyran-4-yl)pyridine (22): synthesized
according to the general procedure using 2,4-diphenylpyridine (32 mg,
0.14 mmol, 1.5 equiv.) and 4-bromotetrahydro-2H-pyran (33 mg, 0.21
mmol, 1.5 equiv.). White solid. Yield: 55% (24 mg, 0.075mmol). IR (neat)
υ 3400, 2850, 1623, 1443, 1384 cm-1 1H NMR (500 MHz, CD3OD) δ 8.37
(d, J = 1.2 Hz, 1H), 8.19 (d, J = 1.2 Hz, 1H), 8.07 (m, 2H), 8.00 (d, J = 7.9
Hz, 2H), 7.75 – 7.68 (m, 3H), 7.67 – 7.63 (m, 3H), 4.15 (dd, J = 11.7, 3.9
Hz, 2H), 3.64 (m, 2H), 3.52 (tt, J = 11.7, 3.9 Hz, 1H), 2.13 (qd, J = 12.4,
3.9 Hz, 2H), 2.07 – 2.01 (m, 2H) ppm. 13C NMR (126 MHz, CD3OD) δ
161.6, 160.0, 154.8, 136.4, 133.2, 133.1, 132.9, 130.8, 130.6, 130.0,
129.4, 122.9, 121.3, 68.5, 41.1, 32.8 ppm. HRMS (m/z) [M+H]+:
calculated for C22H22NO; theoretical mass: 316.1696; found 316.1697.
Diethyl
(3-(1,3,7-trimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-
yl)propyl)phosphonate (27): synthesized according to the general
procedure using caffeine (27 mg, 0.14 mmol, 1.0 equiv) and diethyl (3-
bromopropyl)phosphonate (52 mg, 0.21 mmol, 1.5 equiv.). White solid.
Yield: 40% (20 mg, 0.055 mmol). IR (neat) υ 3422, 2983, 1703, 1660,
1546, 1442 cm-1 1H NMR (500 MHz, CD3OD) δ 4.17 – 4.04 (m, 4H), 3.96
(s, 3H), 3.52 (s, 3H), 3.33 (s, 3H), 2.98 (t, J = 7.4 Hz, 2H), 2.13 – 2.02 (m,
2H), 2.01 – 1.91 (m, 2H), 1.33 (t, J = 7.1 Hz, 6H) ppm. 13C NMR (126
MHz, CD3OD) δ 156.2, 153.9, 152.7, 147.2, 108.5, 63.39, 63.34, 32.6,
30.5, 28.3, 27.2, 27.1, 25.7, 24.5, 21.3, 21.2, 16.8, 16.7 ppm. HRMS
(m/z) [M+H]+: calculated for C15H26N4O5P; theoretical mass: 373.1635;
found 373.1633.
Ethyl
cyclopenta[c]pyridine-4-carboxylate (23): synthesized according to the
general procedure using ethyl 3-methyl-6,7-dihydro-5H-
1-(1-benzoylpiperidin-4-yl)-3-methyl-6,7-dihydro-5H-
cyclopenta[c]pyridine-4-carboxylate (28 mg, 0.14 mmol, 1.0 equiv.) and
(4-bromopiperidin-1-yl)(phenyl)methanone (54 mg, 0.21 mmol, 1.5
equiv.). White solid. Yield: 55% (30 mg, 0.076 mmol). IR (neat) υ 2930,
1725, 1626, 1446 cm-1 1H NMR (500 MHz, CD3OD) δ 7.49 (s, 5H), 4.47
(q, J = 7.1 Hz, 2H), 4.01 – 3.84 (m, 1H), 3.48 (tt, J = 12.4, 3.5 Hz, 1H),
3.38 (t, J = 7.7 Hz, 2H), 3.34 – 3.26 (m, 2H), 3.23 (t, J = 7.6 Hz, 2H), 3.10
– 2.96 (m, 1H), 2.92 (s, 3H), 2.27 (p, J = 7.7 Hz, 2H), 2.18 – 1.99 (m, 3H),
1.94 – 1.80 (m, 1H), 1.42 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (126 MHz,
CD3OD) δ 172.6, 168.2, 164.9, 155.0, 154.4, 142.7, 136.8, 131.2, 129.8,
127.9, 127.1, 63.7, 43.2, 41.3, 36.3, 31.3, 30.4, 29.8, 25.2, 18.9, 14.4
ppm. HRMS (m/z) [M+H]+: calculated for C24H29N2O3; theoretical mass:
393.2173; found 393.2152.
1,3,7-Trimethyl-8-(tetrahydro-2H-pyran-4-yl)-3,7-dihydro-1H-purine-
2,6-dione (28): synthesized according to the general procedure using
caffeine (27 mg, 0.14 mmol, 1.0 equiv.) and (4-bromotetrahydro-2H-
pyran (33 mg, 0.21 mmol, 1.5 equiv.). White solid. Yield: 60% (23 mg,
0.084 mmol). IR (neat) υ 1701, 1658, 1544, 1437 cm-1 1H NMR (500 MHz,
CD3OD) δ 4.07 – 4.00 (m, 2H), 3.96 (s, 3H), 3.59 (td, J = 11.9, 1.9 Hz,
2H), 3.54 (s, 3H), 3.33 (s, 3H), 3.25 – 3.15 (m, 1H), 2.04 – 1.92 (m, 2H),
1.85 – 1.78 (m, 2H) ppm. 13C NMR (126 MHz, CD3OD) δ 158.2, 156.7,
153.3, 149.4, 108.4, 68.3, 33.8, 31.9, 31.6, 30.1, 28.2 ppm. HRMS (m/z)
[M+H]+: calculated for C13H19N4O3; theoretical mass: 279.1452; found
279.1440.
Methyl
2-(1-benzoylpiperidin-4-yl)-6-(hydroxymethyl)isonicotinate
(24): synthesized according to the general procedure using methyl 2-
(hydroxymethyl)isonicotinate (23 mg, 0.14 mmol, 1.0 equiv.) and (4-
bromopiperidin-1-yl)(phenyl)methanone (54 mg, 0.21 mmol, 1.5 equiv.).
White solid. Yield: 25% (12 mg, 0.034 mmol). IR (neat) υ 3272, 1736,
1630, 1445, 1250, 1086 cm-1 1H NMR (500 MHz, CD3OD) δ 8.36 (s, 1H),
8.29 (s,1H), 7.49 (m, 5H), 5.01 (s, 2H), 4.05 (s, 3H), 3.99 – 3.88 (m, 1H),
3.54 – 3.45 (m, 1H), 3.39 – 3.22 (m, 2H), 3.11 – 2.95 (m, 1H), 2.22 –
2.11 (m, 1H), 2.04 – 1.88 (m, 3H) ppm. 13C NMR (126 MHz, CD3OD) δ
172.6, 164.4, 161.8, 160.5, 147.3, 136.8, 131.2, 129.8, 127.9, 123.6,
123.0, 61.4, 61.2, 54.3, 43.1, 42.1, 32.3, 31.8 ppm. HRMS (m/z) [M+H]+:
calculated for C20H23N2O4; theoretical mass: 355.1652; found 355.1635.
Diethyl
(3-(5-((1,4-diazepan-1-yl)sulfonyl)isoquinolin-1-
yl)propyl)phosphonate (29): synthesized according to the general
procedure using fasudil (40 mg, 0.14 mmol, 1.0 equiv.) and diethyl (3-
bromopropyl)phosphonate (52 mg, 0.21 mmol, 1.5 equiv). White solid.
Yield: 60% (39 mg, 0.082 mmol). IR (neat) υ 3387, 2984, 2673, 1647,
1613, 1458 cm-1 1H NMR (500 MHz, CD3OD) δ 9.06 – 9.00 (m, 2H), 8.77
(d, J = 7.5 Hz, 1H), 8.66 (d, J = 7.5 Hz, 1H), 8.21 (t, J = 8.0 Hz, 1H), 4.20
– 4.05 (m, 4H), 3.87 – 3.78 (m, 4H), 3.65 (t, J = 6.1 Hz, 2H), 3.45 – 3.39
(m, 4H), 2.27 – 2.07 (m, 6H), 1.33 (t, J = 7.1 Hz, 6H) ppm. 13C NMR (126
MHz, CD3OD) δ 162.6, 138.8, 137.3, 136.5, 134.3, 133.7, 131.4, 129.3,
122.5, 63.6, 63.5, 48.0, 46.1, 45.6, 33.4 (d, J = 16.0 Hz), 27.1, 25.9, 24.8,
24.5 (d, J = 4.5 Hz), 16.76, 16.71 ppm. HRMS (m/z) [M+H]+: calculated
for C21H33N3O5PS; theoretical mass: 470.1873; found 470.1870.
Methyl 1-(tetrahydro-2H-pyran-4-yl)isoquinoline-3-carboxylate (25):
synthesized according to the general procedure using methyl
isoquinoline-3-carboxylate (26 mg, 0.14 mmol, 1.0 equiv.) and (4-
bromotetrahydro-2H-pyran (33 mg, 0.21 mmol, 1.5 equiv.). White solid.
Yield: 50% (19 mg, 0.069 mmol). IR (neat) υ 2952, 1736, 1237, 1086 cm-
(4-(5-((1,4-Diazepan-1-yl)sulfonyl)isoquinolin-1-yl)piperidin-1-
yl)(phenyl)methanone (30): synthesized according to the general
procedure using fasudil (40 mg, 0.14 mmol, 1.0 equiv.) and (4-
bromopiperidin-1-yl)(phenyl)methanone (54 mg, 0.21 mmol, 1.5 equiv.).
White solid. Yield: 90% (59 mg, 0.12 mmol). IR (neat) υ 3378, 2999,
1645, 1608, 1448, 1376 cm-1 1H NMR (500 MHz, CD3OD) δ 9.24 (d, J =
8.7 Hz, 1H), 9.06 (d, J = 7.0 Hz, 1H), 8.78 (d, J = 7.4 Hz, 1H), 8.68 (d, J =
7.0 Hz, 1H), 8.22 (t, J = 8.1 Hz, 1H), 7.59 – 7.47 (m, 5H), 4.97 – 4.86 (m,
1H), 4.68 – 4.56 (m, 1H), 4.05 – 3.92 (m, 1H), 3.86 – 3.78 (m, 2H), 3.65
(t, J = 6.1 Hz, 2H), 3.61 – 3.51 (m, 1H), 3.44 – 3.36 (m, 4H), 3.28 – 3.20
1H NMR (500 MHz, CD3OD) δ 8.96 (s, 1H), 8.94 (d, J = 8.6 Hz, 1H),
1
8.44 (d, J = 8.1 Hz, 1H), 8.31 – 8.26 (m, 1H), 8.22 – 8.16 (m, 1H), 4.44 –
4.34 (m, 1H), 4.26 – 4.16 (m, 2H), 4.15 (s, 3H), 3.83 – 3.74 (m, 2H), 2.50
– 2.37 (m, 2H), 2.05 – 1.98 (m, 2H) ppm.13C NMR (126 MHz, CD3OD) δ
166.5, 162.7, 139.4, 137.8, 134.1, 132.8, 131.5, 129.1, 128.5, 127.5,
68.5, 54.5, 39.9, 31.6 ppm. HRMS (m/z) [M+H]+: calculated for
C
16H18NO3; theoretical mass: 272.1281; found 272.1285.
(m, 1H), 2.69 (s, 1H), 2.32 – 2.15 (m, 5H), 2.15 – 2.04 (m, 1H) ppm.13
C
(4-(4-Methylquinolin-2-yl)piperidin-1-yl)(phenyl)methanone
(26):
NMR (126 MHz, CD3OD) δ 172.7, 164.7, 138.9, 137.2, 136.63, 136.61,
134.2, 133.9, 131.5, 131.3, 129.9, 128.8, 127.9, 122.5, 48.8, 48.0, 46.1,
45.6, 43.2, 40.3, 39.5, 32.2, 31.7, 27.1 ppm. HRMS (m/z) [M+H]+:
calculated for C26H31N4O3S; theoretical mass: 479.2111; found 479.2104.
synthesized according to the general procedure using 4-methylquinoline
(20 mg, 0.14 mmol, 1.0 equiv.) and (4-bromotetrahydro-2H-pyran (33 mg,
0.21 mmol, 1.5 equiv.). White solid. Yield: 65% (30 mg, 0.091 mmol). IR
(neat) υ 3342, 2642, 1602, 1574, 1525, 1498, 1445, 1414 cm-1 1H NMR
(500 MHz, CD3OD) δ 8.44 (d, J = 8.5 Hz, 1H), 8.32 (d, J = 8.6 Hz, 1H),
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900611
European Journal of Organic Chemistry
FULL PAPER
(4-(4-((2R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-
yl)butan-2-yl)-5-fluoropyrimidin-2-yl)piperidin-1-
Griesbeck, Adv. Synth. Catal. 2013, 355, 2727; f) Z. J. Garlets, J. D.
Nguyen, C. R. J. Stephenson, Isr. J. Chem. 2014, 54, 351; t) J. J.
Douglas, J. D. Nguyen, K. P. Cole, C. R. J. Stephenson, Aldrichimica
Acta 2014, 47, 15; g) D. A. Nicewicz, T. M. Nguyen, ACS Catal. 2014, 4,
355.
yl)(phenyl)methanone (31): synthesized according to the general
procedure using voriconazole (48 µL, 0.14 mmol, 1.0 equiv.) and (4-
bromopiperidin-1-yl)(phenyl)methanone (54 mg, 0.21 mmol, 1.5 equiv.).
White solid. Yield: 30% (22 mg, 0.041 mmol). IR (neat) υ 3370, 1618,
1595, 1500, 1448 cm-1 1H NMR (500 MHz, CD3OD) δ 9.75 (s, 1H), 8.87
(s, 1H), 8.45 (s, 1H), 7.39 – 7.25 (m, 6H), 6.90 (ddd, J = 11.6, 8.8, 2.1 Hz,
1H), 6.81 – 6.71 (m, 1H), 4.92 (d, J = 14.1 Hz, 1H), 4.70 – 4.60 (m, 1H),
4.47 (d, J = 14.1 Hz, 1H), 4.04 (q, J = 7.0 Hz, 1H), 3.86 – 3.70 (m, 1H),
3.51 – 3.35 (m, 1H), 3.31 – 3.18 (m, 1H), 3.04 – 2.91 (m, 1H), 2.55 (s,
1H), 1.99 – 1.64 (m, 4H), 1.02 (d, J = 7.0 Hz, 3H) ppm. 13C NMR (126
MHz, CD3OD) δ 172.6, 165.6 (d, J = 12.6 Hz), 163.6 (d, J = 12.6 Hz),
161.9 (d, J = 14.0 Hz), 161.6 (d, J = 12.0 Hz), 159.6 (d, J = 12.2 Hz),
158.4 (d, J = 14.6 Hz), 156.4, 154.4 (d, J = 9.6 Hz), 154.3, 143.6, 143.2,
136.6, 131.5 (dd, J = 9.6, 5.3 Hz), 129.9, 127.9, 124.2 (dd, J = 11.4, 3.7
Hz), 112.4 (d, J = 17.9 Hz), 105.3 (dd, J = 27.7, 26.4 Hz), 77.8 (d, J = 4.8
Hz), 59.9 (d, J = 5.7 Hz), 43.4, 40.2, 38.6 (d, J = 5.2 Hz), 38.0, 31.2, 30.5,
15.5 ppm. HRMS (m/z) [M+H]+: calculated for C28H28F3N6O2; theoretical
mass: 537.220; found 537.242.
[2]
[3]
a) T. Cernak, K. D. Dykstra, S. Tyagarajan, P. Vachal, S. W. Krska,
Chem. Soc. Rev. 2016, 45, 546; b) S. D. Roughley, A. M. Jordan, J.
Med. Chem. 2011, 54, 3451; c) A. M. Jordan, S. D. Roughley, Drug
Discovery Today 2009, 14, 731; d) J. S. Carey, D. Laffan, C. Thomson,
M. T. Williams, Org. Biomol. Chem. 2006, 2337.
For selected reviews on the Minisci reaction: a) R. S. J. Proctor, R. J.
Phipps, Angew. Chem., Int. Ed. 10.1002/anie.201900977; b) J. Tauber,
D. Imbr, T. Opatz, Molecules 2014, 19, 16190; c) C. Punta, F. Minisci,
Trends Heterocycl. Chem. 2008, 13, 1; d) F. Minisci, E. Vismara, F.
Fontana, Heterocycles 1989, 28, 489; e) F. Minisci, F. Fontana, E.
Vismara, J. Heterocycl. Chem. 1990, 27, 79; f) M. A. Duncton,
MedChemComm 2011, 2, 1135.
[4]
[5]
[6]
R. A. Garza-Sanchez, A. Tlahuext-Aca, G. Tavakoli, F. Glorius, ACS
Catal. 2017, 7, 4057.
D. A. DiRocco, K. Dykstra, S. Krska, P. Vachal, D. V. Conway, M.
Tudge, Angew. Chem., Int. Ed. 2014, 53, 4802.
Ethyl
4-(2-(1-benzoylpiperidin-4-yl)-8-chloro-5,6-dihydro-11H-
benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-
G.-X. Li, C. A. Morales-Rivera, Y. Wang, F. Gao, G. He, P. Liu, G.
Chen, Chem. Sci. 2016, 7, 6407.
carboxylate (32): synthesized according to the general procedure using
loratadine (52 mg, 0.14 mmol, 1.0 equiv.) and (4-bromopiperidin-1-
yl)(phenyl)methanone (54 mg, 0.21 mmol, 1.5 equiv.). White solid. Yield:
30% (23 mg, 0.041 mmol). IR (neat) υ 3421, 1692, 1622, 1437, 1233 cm-
1 Only major rotamer described: 1H NMR (500 MHz, CD3OD) δ 8.55 (d, J
= 6.2 Hz, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.48 (s, 5H), 7.37 (s, 1H), 7.30 –
7.25 (m, 1H), 7.19 (d, J = 8.2 Hz, 1H), 4.13 (q, J = 7.0 Hz, 2H), 4.10 –
4.02 (m, 1H), 4.01 – 3.85 (m, 2H), 3.61 – 3.44 (m, 3H), 3.42 – 3.33 (m,
1H), 3.22 – 2.88 (m, 5H), 2.56 – 2.36 (m, 3H), 2.28 – 2.12 (m, 1H), 2.03
(s, 1H), 1.97 – 1.66 (m, 4H), 1.25 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (126
MHz, CD3OD) δ 172.6, 166.5, 157.0, 151.8, 149.9, 146.9, 145.7, 140.7,
139.8, 137.9, 136.9, 135.8, 135.4, 131.8, 131.2, 130.9, 129.8, 127.9,
125.1, 62.9, 45.1, 44.9, 43.4, 41.3, 39.9, 32.1, 31.7, 31.6, 31.5, 31.2,
27.9, 14.9 ppm. HRMS (m/z) [M+H]+: calculated for C34H37ClN3O3;
theoretical mass: 570.2518; found 570.2526.
[7]
[8]
J. K. Matsui, D. N. Primer, G. A. Molander, Chem. Sci. 2017, 8, 3512-.
P. Nuhant, M. S. Oderinde, J. Genovino, A. Juneau, Y. Gagne, C. ́Allais,
G. M. Chinigo, C. Choi, N. W. Sach, L. Bernier, Y. M. Fobian, M. W.
Bundesmann, B. Khunte, M. Frenette, O. O. Fadeyi, Angew. Chem., Int.
Ed. 2017, 56, 15309.
[9]
A. Gutierrez-Bonet, C. Remeur, J. K. Matsui, G. A. Molander, J. Am.
Chem. Soc. 2017, 139, 12251.
[10] F. J. R. Klauck, M. J. James, F. Glorius, Angew. Chem., Int. Ed. 2017,
56, 12336.
[11] a) J. Jin, D. W. C. MacMillan, Nature 2015, 525, 87; b) C. A. Huff, R. D.
Cohen, K. D. Dykstra, E. Streckfuss, D. A. DiRocco, S. W. Krska, J. Org.
Chem. 2016, 81, 6980.
[12] T. McCallum, L. Barriault, Chem. Sci. 2016, 7, 4754.
[13] 1300 unique alkyl bromides are available in Merck building block
collection.
[14] A. ElMarrouni, C. B. Ritts, J. Balsells, Chem. Sci. 2018, 9, 6639.
[15] Oxidation may have been promoted by presence of oxygen as solvents
were not degassed.
Acknowledgments
[16] J. Dong, X. Lyu, Z. Wang, X. Wang, H. Song, Y. Liu, Q. Wang, Chem.
Sci. 2019, 10, 976.
We thank S. Bowen and J. Small for support with NMR
characterization and N. K. Jarrah and M. Roslawski for HRMS
support. We thank M. Jouffroy, A. Gutierrez and D. Schultz.
(Merck & Co., Inc., Kenilworth, NJ, USA) for reviewing the paper.
[17] S. Mandal, T. Bera, G. Dubey, J. Saha, J. K. Laha, ACS Catal. 2018, 8,
5085 – 5144.
[18] M. Jouffroy, J. Kong, Chem. Eur. J. 2019, 25, 2217.
[19] A. Hameed, M. Al-Rashida, M. Uroos, S. A. Ali, Arshia, M. Ishtiaq, K. M.
Expert. Opin. Ther. Pat. 2018, 28, 281.
[20] L. Wanka, K. Iqbal, P. R. Schreiner, Chem Rev. 2013, 113, 3516.
[21] M. Baumann, I. R. Baxendale, Beilstein J. Org. Chem. 2013, 9, 2265.
[22] H. Nagumo, Y. Sasaki, Y. Ono, H. Okamoto, M. Seto, Y. Takuwa, Am.
Keywords: Minisci • C-H alkylation • photoredox • visible-light •
alkyl bromides
J. Physicol. Cell Physiol. 2000, 278, C57.
[23]
[24]
P. Zhang, C. C. Le, D. W. C. MacMillan, J. Am. Chem. Soc. 2016, 138,
8084.
Oxygen can also act as initiatior capable of abstracting hydrogen from
(Me3Si)3SiH, see: J. J. Devery III, J. D. Nguyen, C. Dai, C. R. J.
Stephenson, ACS Catal. 2016, 6, 5962.
[1]
For selected reviews: a) D. M. Schultz, T. P. Yoon, Science 2014, 343,
941; b) C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev. 2013,
113, 5322; c) T. P. Yoon, ACS Catal. 2013, 3, 895; d) Y. Xi, H. Yi, A.
Lei, Org. Biomol. Chem. 2013, 11, 2387; e) M. Reckenthler, A. G.
[25] C. Chatgilialoglu, J. Lalevee, Molecules 2012, 17, 527.
[26] Y. Hu, L. Chen, B. Li, RSC Adv. 2016, 6, 65196.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900611
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Layout 2:
FULL PAPER
Photoredox C-H alkylation*
James J. Perkins, Jeffrey W. Schubert,
Eric C. Streckfuss, Jaume Balsells, and
Abdellatif ElMarrouni*
Page No. – Page No.
Text for Table of Contents (about 350 characters)
Photoredox Silyl-Mediated C-H
Alkylation of Heterocycles with Non-
Activated Alkyl Bromides
A new protocol for the Minisci C-H alkylation of heteroarenes using the widely available and
structurally diverse pool of unactivated alkyl bromides mediated by photoredox catalysis have been
developed. This transformation proceeds under mild conditions to provide numerous primary,
secondary and tertiary products, including analogues of currently approved therapeutics.
This article is protected by copyright. All rights reserved.