Synthesis of Arylated Nucleobases by Visible Light Photoredox Catalysis

Article abstract of DOI:10.1021/acs.joc.7b00088

Arylated nucleobases were synthesized by visible light photocatalysis using rhodamine 6G as photoredox catalyst and N,N-diisopropylethylamine as sacrificial electron donor. The high redox potential of this catalyst system is achieved by a consecutive photoinduced electron transfer process (conPET) and allows the room temperature conversion of brominated and chlorinated nucleobases or nucleobase precursors as starting materials. In contrast to many transition-metal-based syntheses, a direct C-H arylation of nitrogen-containing halogenated heterocycles is possible without protection of the N-H groups. The method provides a simple, metal-free alternative for the synthesis of biologically interesting arylated heterocycles under mild conditions.

Full text of DOI:10.1021/acs.joc.7b00088

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Article
Synthesis of arylated nucleobases by visible light photoredox catalysis
Andreas Graml, Indrajit Ghosh, and Burkhard König
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00088 • Publication Date (Web): 01 Mar 2017
Downloaded from http://pubs.acs.org on March 1, 2017
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Synthesis of arylated nucleobases by visible light
photoredox catalysis
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Andreas Graml, Indrajit Ghosh, and Burkhard König*
Institut für Organische Chemie, Universität Regensburg, Universitätsstraße 31, D-93053
Regensburg, Germany
*To whom correspondence should be addressed: Burkhard.König@ur.de
ABSTRACT: Arylated nucleobases were synthesized by visible light photocatalysis using
rhodamine-6G as photoredox catalyst and N,N-diisopropylethylamine as sacrificial electron donor.
The high redox potential of this catalyst system is achieved by a consecutive photoinduced electron
transfer process (conPET) and allows the room temperature conversion of brominated and
chlorinated nucleobases or nucleobase precursors as starting materials. In contrast to many
transition metal based syntheses, a direct C–H arylation of nitrogen containing halogenated
heterocycles is possible without protection of the N–H groups. The method provides a simple,
metal-free alternative for the synthesis of biologically interesting arylated heterocycles under mild
conditions.
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INTRODUCTION
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Nucleobases are well known molecular building blocks in living organisms whose presence and
function in the DNA or compounds like ATP is important to sustain life. Their structure is based
on pyrimidines and purines, which are common motifs in many natural products and biologically
active compounds.1 Among others, certain derivatives of uracil have gained enormous attention as
bactericides,2 insecticides,3 herbicides4 or fungicides,5 in addition to their use as privileged
structural unit in drug discovery.6 Many nucleobase-derived molecules have been investigated for
a potential use as cytostatic drugs in cancer treatment,7 as well as drugs against malaria8-9 or several
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viral diseases.10-13
A
bioanalytical application is the use as DNA labels.14-15
The abundance of nucleobases in many interesting compounds triggered the development of
efficient synthetic methods for their functionalization, especially functionalization of the uracil
moiety at the C5 and C6 positions.16-19 Several methods for the synthesis of substituted nucleobases
are reported, many based on transition metal catalyzed cross coupling protocols.20-21 While C – C
arylations are mostly realized by Suzuki Miyaura couplings,22-23 alkenylations and alkynylations
can be performed with Stille,24 Heck or Sonogashira couplings.25 As a more direct synthesis,
palladium-catalyzed C–H arylation strategies have emerged.26 In 2011, Hocek et al. reported a
direct arylation of N-protected uracils with aryl halides17 and recently Wnuk et al. developed a
method for the arylation of 5-iodouracil nucleosides with arenes and heteroarenes.19 Furthermore,
cross-dehydrogenative couplings without the need for halogenated starting materials are known.26-
27
Moreover, in 2010 Rossi et al. reported a photochemical arylation of 2,4-methoxyprotected
uracil28 and most recently Zhang et al. described in 2015 a direct photocatalytic arylation of
iodouracils.29 However all of the reported synthetic methods require transition metal catalysts,
auxiliary ligands, high temperatures, use of N-protected nucleobases, additional
prefunctionalization of the starting materials, or the use of UV-light.
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O
O
O
photoredox
catalysis
hydrolysis
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NH
+
R H
N
N
R
N
H
O
Cl
N
O
R
N
O
1a
2
3
4
trapping reagents
:
R H
R'
OMe
R
Cl
H
H
N
H
H
photoredox
catalysis
H
N
N
N
+
N
R H
Ph
Ph
MeO
R' = Me, R'' = H
pyrrole: R' = H, R'' = H, Me, Ph, Bz
OMe
N
R''
N
N
N
indole:
1b
2
3
Scheme 1: Photoredox catalytic synthetic strategy for the functionalization of nucleobases and
related structures (R = aryl, heteroaryl).
Transition metal free visible light photoredox catalysis may provide an attractive alternative
method for the functionalization of halogenated heteroarenes under very mild conditions. Not
surprisingly, its potential in organic synthesis has been investigated intensively.30-33 Of particular
interest are reactions using organic dye catalysts instead of commonly used Ru- or Ir-based
photocatalysts.34-35 Although these catalysts are less expensive and less toxic compared to
transition metal complexes, their use is limited to specific halogenated starting materials depending
on the redox potentials.36 However, organic dyes, such as PDI or Rh-6G give access to halogenated
heteroarenes as substrates for photoredox catalytic arylation reactions, as they exhibit very high
redox potentials under visible light irradiation, due to a consecutive photoinduced electron transfer
process (conPET).37-40 We report here a simple strategy for the functionalization of halogenated
nucleobases or nucleobase precursors utilizing blue LEDs as visible light source, the organic dye
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rhodamine 6G (Rh-6G) as photocatalyst and N,N-diisopropylethylamine (DIPEA) as a sacrificial
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electron donor.
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The photoredox arylation of uracil uses 6-chloro-2,4-dimethoxypyrimidine as the starting material,
as shown in Scheme 1. 6-Chloro-2,4-dimethoxypyrimidine (Ar–X) is activated by photoinduced
‒
electron transfer, yielding the corresponding radical anions (Ar–X• ) that fragments by releasing a
chloride anion to generate the corresponding 2,4-dimethoxypyrimidine radical that could be used
for subsequent arylation reactions with suitable trapping reagents. Finally, hydrolysis of the
functionalized 2,4-dimethoxypyrimidine provides uracil derivatives. The arylation of purine,
pyrimidine and other biologically relevant heterocycles, starts from their respective commercially
available bromides and chlorides. To achieve the one electron reduction of the halogenated
substrates initiating the substitution reaction, the previously reported high reduction power of
excited stable radical anions of rhodamine 6G is required.
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RESULT AND DISCUSSION
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Optimization of the photoredox reaction conditions was carried out by irradiation of a mixture of
6-chloro-2,4-dimethoxypyrimidine (1a), N-methylpyrrole (2a), rhodamine 6G (Rh-6G) and N,N-
diisopropylethylamine (DIPEA, sacrificial electron donor) with blue LEDs (455  15 nm) under
nitrogen atmosphere. With 10 mol% catalyst loading and 1.5 equiv. of DIPEA in DMSO a yield of
25% of the coupling product 3a was observed by gas chromatographic (GC) analysis after 24 h of
irradiation. While the yield was similar in EtOH, it dropped drastically when the reaction was
carried out in DMF (see supporting information). Excess amount of sacrificial electron donor (i.e.,
DIPEA) did not improve the reaction outcome. However, excess of trapping reagent (20 equiv.)
was important to suppress hydrogen abstraction from the solvent or the radical cation of DIPEA as
a competing reaction pathway giving the dehalogenated starting material as the product. The use
of only 5 or 10 equiv. of 2 resulted in significantly lower product yields (see supporting
information). Moreover, addition of H2O (DMSO/H2O, 12:1; v/v) to the reaction mixture enhanced
the yield significantly to 46%. The yield was further improved to 69% (isolated yield, see Table
1) when the reaction mixture was irradiated for 48 h. Control reactions without the catalyst, without
DIPEA and without visible light irradiation did not lead to any significant product formation (Table
1, entries 2–4). Only traces of the coupling product were observed when the reaction was carried
out in presence of air (Table 1, entry 5).
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Table 1. Optimization of reaction conditions
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Entry
1
Reaction conditions
Yield [%][a]
2a (20 equiv.), DIPEA (1.5 equiv.), Rh-6G (10 mol%), DMSO/H2O (12:1)
69[b]
2
3
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5
2a (20 equiv.), DIPEA (1.5 equiv.), Rh-6G (10 mol%), DMSO, no light
2a (20 equiv.), no DIPEA, Rh-6G (10 mol%), DMSO
0
trace
0
2a (20 equiv.), DIPEA (1.5 equiv.), no catalyst, DMSO
2a (20 equiv.), DIPEA (1.5 equiv.), Rh-6G (10 mol%), DMSO, air
trace
[a] Isolated yield, [b] reaction time 48 h.
Having the optimized reaction conditions in hand (entry 1, Table 1), we then explored the
scope of the photoredox catalytic arylation reaction of 1a with other pyrrole derivatives. These
reactions gave the C–H arylated products in moderate to good yields (see Table 2).Notably,
unprotected pyrrole could also be used with ease under this C–H arylation reaction protocol and
the reaction with N-benzylpyrrole as a trapping reagent gave exclusively the C–H arylated product
3e in 54% yield. In the case of N-benzylpyrrole, the 2 position of the pyrrole derivative was arylated
chemoselectively.
Other electron rich arenes and heteroarenes could also be used as the coupling partners of
the 2,4-dimethoxypyrimidine radical. Use of 1,3,5-trimethoxybenzene as a radical trapping reagent
gave 3g in 27% yield. The relatively low yield is due to the competing hydrogen abstraction
reactions of the 2,4-dimethoxypyrimidine radical either from the solvent or from the radical cation
of DIPEA (see below). The trapping with 3-methylindole provides coupling product 3f in
synthetically useful yield. 3-Methylindole was selectively functionalized at the 2 position. When
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1,1-diphenylethylene was employed as trapping reagent, product 3h and 3h’ were obtained in an
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excellent combined yield of 82%. .
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Subsequent to the coupling reactions, hydrolysis of the methoxy groups of the C–H arylated
products gave substituted uracils in almost quantitative yields. Thus, after two steps, compounds
4a, 4d, and 4e were obtained in 66%, 55%, and 54% yields respectively.
Table 2. Scope of trapping reagents (isolated yield).
C–H arylation reactions
O
O
O
N
N
O
N
N
N
N
O
N
N
O
N
O
N
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N
NH
3a: 69%
3c: 65%
3d: 58%
3e: 54%
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N
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NH
O
O
3g: 27%[b]
3f: 32%[b][c][d]
3h/3h': 82%[e]
Hydrolysis reactions
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[a] The reaction was started with 10 mol% catalyst loading, then 5 mol% catalyst were added after
20 h according to the general procedure A, [b] 15 equiv. of 2, [c] yield determined by quantitative
1H-NMR with 2,5-dimethylfurane as internal standard, [d] the reaction was started with 10 mol%
catalyst loading, then 10 mol% were added in two batches (5 + 5 mol%) after 20 h and 30 h, [e]
combined yield of saturated product 3h and unsaturated product 3h’ (3h:3h’ = 4.9:1). It is worth
mentioning here that bleaching of the photoredox catalyst organic dye Rh-6G was observed. The
bleaching rate differs depending on substrates and the trapping reagents. After complete
decomposition of the photocatalyst (as could be observed by naked eyes), the conversion of the
starting material to the respective C–H product stops. In cases of fast catalyst bleaching, the
addition of photocatalyst increased the yields (for more details and for the spectroscopic
investigations of the catalyst bleaching, see the supporting information).
Interestingly, the C–H arylated product 4a could also be obtained by using 6-chlorouracil
directly as the substrate with 22% isolated yield (see Table 3). However, due to the low yield, the
two-step synthesis including a simple hydrolysis step subsequent to the coupling reaction, is
preferable for the synthesis of arylated uracils. Note that the rate of the C–H arylation reactions is
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not only determined by the reduction potential of the substrates, but also by the carbon–halogen
bond cleavage kinetics that depends strongly on the substituents present in the substrates.41
Substitution at another position of the uracil moiety could be performed by using commercially
available 5-bromouracil (46% isolated yield), although a higher catalyst loading was needed in this
case (see supporting information). When 6-chloropurine was employed under the photoredox
protocol, the C–H arylated product 3b was obtained in moderate yield of 51%.
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Table 3. Scope of nucleobase derivatives (isolated yield).
Heteroarene bromide
Heteroarene chloride
[a] The reaction was started with 10 mol% catalyst loading, then 5 mol% catalyst were added after
20 h according to general procedure A, [b] the reaction was started with 10 mol% catalyst loading,
then 10 mol% were added in two batches (5 + 5 mol%) after 20 h and 30 h.
We then explored this photoredox protocol for the generation of biologically important pyrimidine
heteroaryl radicals from their respective bromides (see Table 4).42-43 The pyrimidine ring could be
functionalized at the 5 position with 74% isolated yield (3j) and the 2 position with 33% yield (3k).
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When 6-bromo-2-methylbenzoxazole was used as a substrate the coupling product 3l was obtained
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in 73% yield.
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Having realized that the redox power of the photoredox catalytic system could also exceed the
reduction potentials of chlorinated heteroaromatic substrates, we then used heteroaryl chlorides as
substrates for the C–H arylation reactions, giving access to biologically interesting heteroarenes.44-
46
Coupling reactions with 2-chlorobenzimidazole, 2-chlorobenzothiazole, and 2-chloro-
benzoxazole gave moderate to excellent yields of 3m (65%), 3n (96%), and 3o (55%)
respectively.47
Table 4. Scope of hetero aryl bromides and chlorides (isolated yield).
Heteroaryl bromides
Heteroaryl chlorides
[a] The reaction was started with 10 mol% catalyst loading, then 5 mol% catalyst were added
after 20 h according to general procedure A.
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MECHANISTIC PROPOSAL
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The proposed mechanism for the photoredox catalytic C–H arylation is depicted in Figure 1. Upon
blue light irradiation, the excited Rh-6G takes an electron from DIPEA to generate the radical anion
of rhodamine 6G and the radical cation of DIPEA.38 The radical anion, upon further photoexcitation
reduces the investigated substrates by an electron transfer, returning to its ground state and yielding
the nucleobase radical by scission of the C–Br or C–Cl bond. Finally, the radical is either trapped
by heteroarenes, double bonds, or substituted arenes present in the reaction media, yielding the C–
H arylated products after oxidation and rearomatization. In a competing pathway, also reported for
other photoredox catalytic C–H arylation reactions using aryl halides as substrates, the nucleobase
radical abstracts a hydrogen atom either from the solvent (in this case, DMSO) or from the radical
cation of DIPEA yielding the reduction product as observed in GC and GC–MS analysis of the
crude reaction mixtures.
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Figure 1. Proposed mechanism of the photocatalytic reductive cross-coupling reaction via a
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conPET type process.
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Experimental results, spectroscopic investigations, cyclic voltammetric results, and
literature reports support the proposed catalytic cycle. The results of the fluorescence titrations of
Rh-6G with substrate 1a and DIPEA are shown in Figure 2. The fluorescence intensity of Rh-6G
was not quenched upon titration with the substrate 1a. However, the fluorescence of Rh-6G was
quenched dramatically upon addition of DIPEA, which is due to the formation of the radical anion
of Rh-6G.38 The C–H arylation reaction did not proceed under green light (λEx = 530  15 nm)
irradiation of the reaction mixture. Note that the radical anion of rhodamine 6G is formed by
irradiation with green light, but it cannot be excited again by using green light. At the same time,
the radical anion of rhodamine 6G in the ground state is not capable of transferring an electron to
the investigated substrates, which have exceptionally high reduction potentials. The measured
reduction potentials for 1a, 1i, and 1b in DMSO are –2.32 V, –2.04 V, and –1.86 vs. SCE
respectively (see supporting information for the cyclic voltammograms). The reduction potential
of Rh-6G, upon blue light irradiation reaches or exceeds a value of ca. –2.4 V38 and thus, could
transfer an electron to the halogenated nucleobases or other halogenated heteroaromatic substrates
investigated herein. Additionally, formation of the products 3h and 3h’ with 1,1-diphenylethylene
(a radical scavenger that shows low reactivity towards nucleophiles or electrophiles),48 also
supports the proposed radical mechanism. After addition of 1a• to 1,1‐diphenylethylene product
3h’ is obtained by oxidation and deprotonation of the radical intermediate, while 3h is generated
by hydrogen atom abstraction either from the radical cation of DIPEA or from the solvent (see
supporting information). The role of water (present in 12:1 v/v) is not clear at the moment.
However, knowing that solvents play a crucial role in determining the stability and reactivity of
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radical intermediates, including the radical anion of rhodamine 6G, generated in situ, and the
photostability of the catalyst, we anticipate that water stabilizes the generated nucleobase radical
species and suppresses the degradation of the photocatalyst.
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Figure 2. Changes in the fluorescence spectra of Rh-6G (4.93µM in DMSO) upon successive
addition of 1a (i) and DIPEA (ii). The Stern-Volmer-quenching plot for the fluorescence titration
with Rh-6G in the presence of DIPEA is shown in the inset of Figure 2 (ii).
CONCLUSION
In conclusion, we report a mild metal-free photoredox catalytic method for the synthesis of arylated
nucleobases from commercially available halogenated heterocycles. Under blue light irradiation,
the strong reductive power of the excited radical anion of rhodamine 6G is used to reduce chloro-
or bromo-substituted nucleobases and heterocycles to their respective radical anions. Upon
elimination of a halide anion the corresponding aryl radicals are generated. These are trapped by
heteroarenes, 1,1-diphenylethylene and electron rich arenes present in the reaction mixture to
afford the targeted functionalized nucleobases in good isolated yields. The reported photoredox
catalytic protocol provides an alternative strategy to transition metal based cross coupling protocols
and C–H arylation protocols using halogenated nucleobases under UV-light irradiation.
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EXPERIMENTAL SECTION
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General information:
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Starting materials and reagents were purchased from commercial suppliers and were used without
further purification. Solvents were used as p.a. grade or dried and distilled according to literature
known procedures.49 Industrial grade of solvents was used for automated flash column
chromatography. All reactions with oxygen- or moisture-sensitive reagents were carried out in
glassware, which was dried before use by heating under vacuum. Dry nitrogen was used as inert
gas atmosphere. Liquids were added via syringe, needle and septum technique unless otherwise
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stated. All NMR spectra were measured at room temperature (300 or 400 MHz for H, 75 or
101 MHz for 13C).50 All chemical shifts are reported in δ-scale as parts per million [ppm]
(multiplicity, coupling constant J, number of protons) relative to the solvent residual peaks as the
internal standard.51 Coupling constants J are given in Hertz [Hz]. Abbreviations used for signal
multiplicity: 1H-NMR: b = broad, s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of
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doublets, dt = doublet of triplets, dq = doublet of quartets, and m = multiplet; C-NMR: (+) =
primary/tertiary, (–) = secondary, (Cq) = quaternary carbon). The mass spectrometric
measurements were performed at the Central Analytical Laboratory of the University of
Regensburg, using a TOF or Q-TOF mass analyzer. GC and GC-MS measurements were
performed at the university of Regensburg. A 30 m x 0.25 mm/0.25 μM film capillary was used
and helium served as carrier gas (flow rate of 1 mL/min). The injector temperature (split injection:
40:1 split) was 280 °C, detection temperature 300 °C (FID). GC measurements were made and
investigated via integration of the signal obtained. The GC oven temperature program was adjusted
as follows: initial temperature 40 °C was kept for 3 minutes, the temperature was increased at a
rate of 15 °C/min over a period of 16 minutes until 280 °C was reached and kept for 5 minutes, the
temperature was again increased at a rate of 25 °C/min over a period of 48 seconds until the final
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temperature (300 °C) was reached and kept for 5 minutes. Benzophenone was chosen as internal
standard. Analytical TLC was performed on silica gel coated alumina plates. Visualization was
done by UV light (254 or 366 nm). If necessary vanillin was used for chemical staining.
Purification by column chromatography was performed with silica gel 60 M (40-63 μm, 230-440
mesh). For irradiation blue LEDs (λmax = 455  15 nm, Imax = 1000 mA, 1.12 W) or green LEDs
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(λmax = 530  15 nm, Imax = 1000 mA, 1.12 W) were used. Absorption and fluorescence spectra
were performed with a quartz fluorescence cuvette at room temperature. CV measurements were
performed with the three-electrode potentiostat galvanostat using a glassy carbon working
electrode, a platinum wire counter electrode and a platinum wire reference electrode.
Tetrabutylammonium tetrafluoroborat (TBATFB) 0.1 M was used as supporting electrolyte. The
potentials are given relative to Fc/Fc+ redox couple with ferrocene as internal standard. The
measurements were carried out as follows: Prior to the measurement a 0.1 M solution of TBATFB
in DMSO was added to the measuring cell and the solution was degassed by argon purge for 5 min.
All experiments were performed under argon atmosphere. After recording the baseline, the
electroactive compound was added (0.01 M) and the solution was degassed again for 5 min. The
cyclic voltammogram was recorded with one scan. Afterwards ferrocene (2.20 mg, 12 µmol) was
added to the solution which was again degassed by argon purge for 5 min and the final measurement
was performed.
General procedure A: Photoredox catalytic cross coupling:
A 5 mL crimp vial was equipped with the aryl halide 1 (0.2 mmol, 1 equiv.), rhodamine-6G (10 mg,
0.02 mmol, 10 mol %), the respective trapping reagent 2 (4.0 mmol, 20 equiv.), DIPEA (52 µL,
0.3 mmol, 1.5 equiv.) and a stirring bar. After the addition of the solvent (1.5 ml) the vial was
capped and degassed using the freeze pump thaw (FPT) technique 3 times. The reaction mixture
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was stirred and irradiated using blue LEDs (455 +/- 15 nm) for 48 h. After 20 h, if necessary,
250 µL of a solution of the catalyst (c = 0.04 M) were added to the reaction mixture. This was done
with the help of a Hamilton syringe under exclusion of oxygen. To assure oxygen free conditions
for the remaining reaction time 1 FPT cycle was done subsequently. After the irradiation time the
reaction mixture was diluted with water and extracted with EtOAc (3 x 20 mL). The combined
organic layers were dried over MgSO4, and the solvent was removed under reduced pressure. The
crude product was purified by automated flash column chromatography (PE/EtOAc) and after
evaporation of the solvent the product was obtained.
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2,4-Dimethoxy-6-(1-methyl-1H-pyrrol-2-yl)pyrimidine (3a): The product was obtained
following general procedure A using 1a (34.9 mg, 0.2 mmol, 1.0 equiv.), Rh-6G (9.6 mg,
0.02 mmol, 10 mol%), 2a (355 µL, 4.0 mmol, 20 equiv.) and DIPEA (52 µL, 0.3 mmol,
1.5 equiv.). After 48 h automated column chromatography (PE/EtOAc, 5% EtOAc) gave product
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3a as a slightly brown solid in 69% yield.. H-NMR (400 MHz, CDCl3) δH [ppm] = 6.74 (d, J =
3.3 Hz, 2H), 6.55 (s, 1H), 6.16 (t, J = 3.2 Hz, 1H), 4.05 (s, 3H), 4.00 (s, 3H), 3.96 (s, 3H). 13C-
NMR (101 MHz, CDCl3) δC [ppm] = 172.0 (Cq), 165.1 (Cq), 160.6 (Cq), 129.7 (Cq), 128.3 (+),
113.3 (+), 108.3 (+), 96.0 (+), 54.7 (+), 53.7 (+), 37.9 (+). HRMS (ESI) (m/z): [M+H]+
(C11H14N3O2) calc.: 220.1081, found 220.1087.
6-(1-Methyl-1H-pyrrol-2-yl)-7H-purine (3b): The product was obtained following general
procedure A using 1h (30.9 mg, 0.2 mmol, 1.0 equiv.), Rh-6G (10.1 mg, 0.02 mmol, 10 mol%), 2a
(355 µL, 4.0 mmol, 20 equiv.) and DIPEA (52 µL, 0.3 mmol, 1.5 equiv.). After 20 h 250 µL of a
solution of the catalyst (c = 0.04 M, 5 mol%) were added with the help of a Hamilton syringe under
exclusion of air. Subsequent to one FPT cycle irradiation was continued. After 48 h automated
column chromatography (PE/EtOAc, 80% EtOAc) gave product 3b as a white solid in 51% yield.
1H-NMR (300 MHz, DMSO-d6) δH [ppm] = 13.39 (s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 7.75 (s, 1H),
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7.11 (t, J = 2.2 Hz, 1H), 6.24 (dd, J = 3.9, 2.5 Hz, 1H), 4.14 (s, 3H). 13C-NMR (101 MHz, DMSO-
d6) δC [ppm] = 151.9 (Cq), 151.3 (+), 148.4 (Cq), 143.1 (+), 129.6 (+), 127.8 (Cq), 126.6 (Cq), 118.9
(+), 108.4 (+), 38.0 (+). HRMS (ESI) (m/z): [M+H]+ (C10H10N5) calc.: 200.0931, found: 200.0934.
2,4-Dimethoxy-6-(1H-pyrrol-2-yl)pyrimidine (3c): The product was obtained following general
procedure A using 1a (34.9 mg, 0.2 mmol, 1.0 equiv.), Rh-6G (9.6 mg, 0.02 mmol, 10 mol%), 2c
(278 µL, 4.0 mmol, 20 equiv.) and DIPEA (25µL, 0.3 mmol, 1.5 equiv.). After 48 h automated
column chromatography (PE/EtOAc, 10% EtOAc) gave product 3c as a white solid in 65% yield.
1H-NMR (400 MHz, CDCl3) δH [ppm] = 9.62 (s, 1H), 6.92 (td, J = 2.6, 1.4 Hz, 1H), 6.79 (ddd, J
= 3.8, 2.5, 1.4 Hz, 1H), 6.51 (s, 1H), 6.30 (dt, J = 3.7, 2.6 Hz, 1H), 4.01 (s, 3H), 3.97 (s, 3H). 13C-
NMR (101 MHz, CDCl3) δC [ppm] = 172.2 (Cq), 165.4 (Cq), 158.7 (Cq), 129.5 (Cq), 121.0 (+),
110.9 (+), 110.0 (+), 93.6 (+), 54.7 (+), 53.9 (+). HRMS (ESI) (m/z): [M+H]+ (C10H12N3O2) calc.:
206.0924, found: 206.0928. mp = 103 – 108 °C
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2,4-Dimethoxy-6-(1-phenyl-1H-pyrrol-2-yl)pyrimidine (3d): The product was obtained
following general procedure A using 1a (34.9 mg, 0.2 mmol, 1.0 equiv.), Rh-6G (9.6 mg,
0.02 mmol, 10 mol%), 2d (572.8 mg, 4.0 mmol, 20 equiv.) and DIPEA (52 µL, 0.3 mmol,
1.5 equiv.). After 20 h 250 µL of a solution of the catalyst (c = 0.04 M, 5 mol%) were added with
the help of a Hamilton syringe under exclusion of air. Subsequent to one FPT cycle irradiation was
continued. After 48 h automated column chromatography (PE/EtOAc, 10% EtOAc) gave product
3d as an ochre brown solid in 58% yield. 1H-NMR (400 MHz, CDCl3) δH [ppm] = 7.42 – 7.31 (m,
3H), 7.28 – 7.22 (m, 2H), 6.97 – 6.92 (m, 2H), 6.35 (dd, J = 3.7, 2.8 Hz, 1H), 6.25 (s, 1H), 3.89 (s,
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3H), 3.44 (s, 3H). C-NMR (101 MHz, CDCl3) δC [ppm] = 171.9 (Cq), 164.7 (Cq), 159.3 (Cq),
141.6 (Cq), 130.8 (Cq), 128.9 (+), 128.3 (+), 127.2 (+), 126.3 (+), 114.7 (+), 109.7 (+), 97.0 (+),
54.2 (+), 53.8 (+). HRMS (ESI) (m/z): [M+H]+ (C16H16N3O2) calc.: 282.1237, found: 282.1243.
mp = 87 – 89 °C.
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4-(1-Benzyl-1H-pyrrol-2-yl)-2,6-dimethoxypyrimidine (3e): The product was obtained
following general procedure A using 1a (34.9 mg, 0.2 mmol, 1.0 equiv.), Rh-6G (9.6 mg,
0.02 mmol, 10 mol%), 2e (611 µL, 4.0 mmol, 20 equiv.) and DIPEA (52 µL, 0.3 mmol,
1.5 equiv.). After 20 h 250 µL of a solution of the catalyst (c = 0.04 M, 5 mol%) were added with
the help of a Hamilton syringe under exclusion of air. Subsequent to one FPT cycle irradiation was
continued. After 48 h automated column chromatography (PE/EtOAc, 10% EtOAc) gave product
3e as a brown oil in 54% yield. 1H-NMR (400 MHz, CDCl3) δH [ppm] = 7.31 – 7.18 (m, 3H), 7.05
– 6.98 (m, 2H), 6.82 (m, 2H), 6.58 (s, 1H), 6.26 (dd, J = 3.8, 2.7 Hz, 1H), 5.84 (s, 2H), 3.94 (s,
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3H), 3.77 (s, 3H). C-NMR (101 MHz, CDCl3) δC [ppm] = 172.0 (Cq), 165.1 (Cq), 160.5 (Cq),
139.3 (Cq), 129.7 (Cq), 128.6 (+), 127.8 (+), 127.2 (+), 126.4 (+), 113.7 (+), 109.2 (+), 96.5 (+),
54.6 (+), 53.8 (+), 52.5 (‒). HRMS (ESI) (m/z): [M+H]+ (C17H18N3O2) calc.: 296.1394,
found: 296.1398.
2-(2,6-Dimethoxypyrimidin-4-yl)-3-methyl-1H-indole (3f): The product was obtained following
general procedure A using 1a (34.9 mg, 0.2 mmol, 1.0 equiv.), Rh-6G (9.6 mg, 0.02 mmol,
10 mol%), 2f (393.5 mg, 3.0 mmol, 15 equiv.) and DIPEA (52 µL, 0.3 mmol, 1.5 equiv.). After
20 h and after 30 h 250 µL of a solution of the catalyst (c = 0.04 M, 5 mol%) were added with the
help of a Hamilton syringe under exclusion of air. Subsequent to one FPT cycle after the addition
of new catalyst, irradiation was continued. After 48 h automated column chromatography
(PE/EtOAc, 10% EtOAc) gave product 3f as a white solid in 32% yield (determined by quantitative
NMR analysis using 2,5-dimethylfurane as internal standard). 1H NMR (300 MHz, Chloroform-d)
δH [ppm] = 9.34 (s, 1H), 7.65 (dd, J = 8.0, 1.0 Hz, 1H), 7.40 (dt, J = 8.4, 1.0 Hz, 1H), 7.30 – 7.23
(m, 1H), 7.17 – 7.09 (m, 1H), 6.79 (s, 1H), 4.10 (s, 3H), 4.03 (s, 3H), 2.62 (s, 3H). 13C NMR (101
MHz, CDCl3) δC [ppm] = 172.4 (Cq), 165.2 (Cq), 159.0 (Cq), 135.5 (Cq), 130.1 (Cq), 129.9 (Cq),
124.5 (+), 119.8 (+), 119.8(+), 114.2 (Cq), 111.5 (+), 97.5 (+), 55.0 (+), 54.1 (+), 11.0 (+). HRMS
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(ESI): [M+Na]+ (C15H15N3NaO2) calc.: 292.1056, found: 292.1057
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2,4-Dimethoxy-6-(2,4,6-trimethoxyphenyl)pyrimidine (3g): The product was obtained
following general procedure A using 1a (34.9 mg, 0.2 mmol, 1.0 equiv.), Rh-6G (9.6 mg,
0.02 mmol, 10 mol%), 2g (504.6 mg, 3.0 mmol, 15 equiv.) and DIPEA (52 µL, 0.3 mmol,
1.5 equiv.). After 20 h 250 µL of a solution of the catalyst (c = 0.04 M, 5 mol%) were added with
the help of a Hamilton syringe under exclusion of air. Subsequent to one FPT cycle irradiation was
continued. After 48 h automated column chromatography (PE/EtOAc, 30% EtOAc) gave product
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3g as a white solid in 27% yield. H-NMR (400 MHz, CDCl3) δH [ppm] = 6.38 (s, 1H), 6.18 (s,
2H), 3.98 (d, J = 1.3 Hz, 6H), 3.84 (s, 3H), 3.73 (s, 6H). 13C-NMR (101 MHz, CDCl3) δC [ppm] =
171.6 (Cq), 165.3 (Cq), 164.3 (Cq), 161.9 (Cq), 158.9 (Cq), 110.6 (Cq), 104.0 (+), 91.2 (+), 56.1 (+),
55.5 (+), 54.8 (+), 53.8 (+). HRMS (ESI) (m/z): [M]+• (C15H17N2O5) calc.: 305.1132,
found: 305.1134. mp = 170 – 174 °C.
4-(2,2-Diphenylethyl)-2,6-dimethoxypyrimidine (3h): The product was obtained following
general procedure A using 1a (34.9 mg, 0.2 mmol, 1.0 equiv.), Rh-6G (9.6 mg, 0.02 mmol,
10 mol%), 2h (706 µL, 4.0 mmol, 20 equiv.) and DIPEA (52 µL, 0.3 mmol, 1.5 equiv.). After 20 h
250 µL of a solution of the catalyst (c = 0.04 M, 5 mol%) were added with the help of a Hamilton
syringe under exclusion of air. Subsequent to one FPT cycle irradiation was continued. After 48 h
automated column chromatography (PE/EtOAc, 10% EtOAc) gave product 3h as a white sold in
68% yield. 1H-NMR (400 MHz, acetone-d6) δH [ppm] = 7.39 – 7.31 (m, 4H), 7.28 – 7.21 (m, 4H),
7.17 – 7.10 (m, 2H), 6.24 (s, 1H), 4.74 (t, J = 8.0 Hz, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.41 (d, J =
8.0 Hz, 2H). 13C-NMR (101 MHz, acetone) δC [ppm] = 172.6 (Cq), 171.5 (Cq), 166.1 (Cq), 145.3
(Cq), 129.2 (Cq), 128.7 (+), 127.0 (+), 101.4 (+), 54.7 (+), 53.8 (+), 50.4 (+), 43.4 (‒). HRMS (ESI)
(m/z): [M]+• (C20H20N2O2) calc.: 320.1519 found: 320.1521. mp = 74 – 78°C.
4-(2,2-Diphenylvinyl)-2,6-dimethoxypyrimidine (3h’): The product was obtained following
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general procedure A using 1a (34.9 mg, 0.2 mmol, 1.0 equiv.), Rh-6G (9.6 mg, 0.02 mmol,
10 mol%), 2h (706 µL, 4.0 mmol, 20 equiv.) and DIPEA (52 µL, 0.3 mmol, 1.5 equiv.). After 20 h
250 µL of a solution of the catalyst (c = 0.04 M, 5 mol%) were added with the help of a Hamilton
syringe under exclusion of air. Subsequent to one FPT cycle irradiation was continued. After 48 h
automated column chromatography (PE/EtOH, 10% EtOAc) gave product 3h’ as a white solid in
14% yield. 1H-NMR (400 MHz, acetone-d6) δH [ppm] = 7.43 – 7.36 (m, 7H), 7.30 – 7.24 (m, 1H),
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7.22 – 7.19 (m, 2H), 6.95 (s, 1H), 5.98 (s, 1H), 3.80 (s, 3H), 3.57 (s, 3H). C-NMR (101 MHz,
acetone) δC [ppm] = 172.9 (Cq), 166.0 (Cq), 165.6 (Cq), 150.2 (Cq), 143.1 (Cq), 141.3 (Cq), 130.5
(+), 129.6 (+), 129.6 (+), 129.4 (+), 128.7 (+), 128.7 (+), 127.2 (+), 126.8 (+), 126.8 (+), 101.7 (+),
54.6 (+), 54.0 (+). HRMS (ESI) (m/z): [M]+• (C20H17N2O2) calc.: 318.1363, found: 318.1347.
5-(1-Methyl-1H-pyrrol-2-yl)pyrimidine-2,4(1H,3H)-dione (3i):52 The product was obtained
following general procedure A using 1i (38.2 mg, 0.2 mmol, 1.0 equiv.), Rh-6G (9.6 mg,
0.02 mmol, 10 mol%), 2a (355 µL, 4.0 mmol, 20 equiv.) and DIPEA (52 µL, 0.3 mmol,
1.5 equiv.). After 20 h and after 30 h 250 µL of a solution of the catalyst (c = 0.04 M, 5 mol%)
were added with the help of a Hamilton syringe under exclusion of air. Subsequent to one FPT
cycle after the addition of new catalyst, irradiation was continued. After 48 h automated column
chromatography (PE/EtOAc, 60% EtOAc) gave product 3i as a white, slightly brownish solid in
46% yield. 1H-NMR (400 MHz, DMSO-d6) δH [ppm] = 11.22 (s, 1H), 11.03 (s, 1H), 7.37 (d, J =
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3.9 Hz, 1H), 6.76 (t, J = 2.3 Hz, 1H), 5.96 – 5.93 (m, 2H), 3.43 (s, 3H). C-NMR (101 MHz,
DMSO-d6) δC [ppm] = 163.2 (Cq), 151.2 (Cq), 141.3 (+), 125.6 (Cq), 123.2 (+), 109.5 (+), 106.6
(+), 105.9 (Cq), 34.2 (+). HRMS (ESI) (m/z): [M+H] (C9H10N3O2) calc.: 192.0773,
found: 192.0773.
5-(1-Methyl-1H-pyrrol-2-yl)pyrimidine (3j): The product was obtained following general
procedure A using 1j (31.8 mg, 0.2 mmol, 1.0 equiv.), Rh-6G (9.6 mg, 0.02 mmol, 10 mol%), 2a
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(355 µL, 4.0 mmol, 20 equiv.) and DIPEA (52 µL, 0.3 mmol, 1.5 equiv.). After 20 h 250 µL of a
solution of the catalyst (c = 0.04 M, 5 mol%) were added with the help of a Hamilton syringe under
exclusion of air. Subsequent to one FPT cycle irradiation was continued. After 48 h automated
column chromatography (PE/EtOAc, 25% EtOAc) gave product 3j as a reddish oil in 74% yield.
1H-NMR (400 MHz, CDCl3) δH [ppm] = 9.09 (s, 1H), 8.77 (s, 2H), 6.80 (dd, J = 2.7, 1.8 Hz, 1H),
6.35 (dd, J = 3.7, 1.8 Hz, 1H), 6.23 (dd, J = 3.7, 2.7 Hz, 1H), 3.69 (s, 3H). 13C NMR (101 MHz,
CDCl3) δC [ppm] = 156.5 (+), 155.4 (+), 127.6 (Cq), 127.1 (Cq), 126.0 (+), 110.9 (+), 108.9 (+),
35.3 (+). HRMS (ESI) (m/z): [M]+• (C9H9N3) calc.: 159.0791, found: 159.0788.
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2-(1-Methyl-1H-pyrrol-2-yl)pyrimidine (3k): The product was obtained following general
procedure A using 1k (31.8 mg, 0.2 mmol, 1.0 equiv.), Rh-6G (9.6 mg, 0.02 mmol, 10 mol%), 2a
(355 µL, 4.0 mmol, 20 equiv.) and DIPEA (52 µL, 0.3 mmol, 1.5 equiv.). After 20 h 250 µL of a
solution of the catalyst (c = 0.04 M, 5 mol%) were added with the help of a Hamilton syringe under
exclusion of air. Subsequent to one FPT cycle irradiation was continued. After 48 h automated
column chromatography (PE/EtOAc, 10% EtOAc) gave product 3k as a reddish oil in 33% yield.
1H-NMR (400 MHz, CDCl3) δH [ppm] = 8.64 (d, J = 4.8 Hz, 2H), 7.16 (dd, J = 3.9, 1.9 Hz, 1H),
6.96 (t, J = 4.8 Hz, 1H), 6.78 (t, J = 2.2 Hz, 1H), 6.20 (dd, J = 3.9, 2.5 Hz, 1H), 4.08 (s, 3H). 13C
NMR (101 MHz, CDCl3) δC [ppm] = 160.7 (Cq), 156.8 (+), 131.1 (Cq), 128.7 (+), 116.9 (+), 115.3
(+), 108.2 (+), 38.2 (+). HRMS (ESI) (m/z): [M]+• (C9H8N3) calc.: 158.0713, found: 158.0708.
2-Methyl-6-(1-methyl-1H-pyrrol-2-yl)benzo[d]oxazole (3l): The product was obtained
following general procedure A using 1l (42.41 mg, 0.2 mmol, 1.0 equiv.), Rh-6G (9.6 mg,
0.02 mmol, 10 mol%), 2a (355 µL, 4.0 mmol, 20 equiv.) and DIPEA (52 µL, 0.3 mmol,
1.5 equiv.). After 20 h 250 µL of a solution of the catalyst (c = 0.04 M, 5 mol%) were added with
the help of a Hamilton syringe under exclusion of air. Subsequent to one FPT cycle irradiation was
continued. After 48 h automated column chromatography (PE/EtOAc, 10% EtOAc) gave product
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3l as a white solid in 72% yield. H-NMR (400 MHz, CDCl3) δH [ppm] = 7.66 (d, J = 8.2 Hz, 1H),
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7.49 (d, J = 1.0 Hz, 1H), 7.35 (dd, J = 8.2, 1.6 Hz, 1H), 6.74 (t, J = 2.2 Hz, 1H), 6.28 – 6.21 (m,
2H), 3.67 (s, 3H), 2.65 (s, 3H). 13C NMR (101 MHz, CDCl3) δC [ppm] = 164.2 (Cq), 151.2 (Cq),
140.5 (Cq), 134.2 (Cq), 130.2 (Cq), 125.3 (+), 123.9 (+), 119.0 (+), 110.3 (+), 109.2 (+), 108.0 (+),
35.1 (+), 14.6 (+). HRMS (ESI) (m/z): [M]+• (C13H12N2O) calc.: 212.0944, found: 212.0942.
2-(1-Methyl-1H-pyrrol-2-yl)-1H-benzo[d]imidazole (3m):39 The product was obtained
following general procedure A using 1m (30.5 mg, 0.2 mmol, 1.0 equiv.), Rh-6G (9.6 mg,
0.02 mmol, 10 mol%), 2a (355 µL, 4.0 mmol, 20 equiv.) and DIPEA (52 µL, 0.3 mmol,
1.5 equiv.). After 20 h 250 µL of a solution of the catalyst (c = 0.04 M, 5 mol%) were added with
the help of a Hamilton syringe under exclusion of air. Subsequent to one FPT cycle irradiation was
continued. After 48 h automated column chromatography (PE/EtOAc, 15% EtOAc) gave product
3m as a white solid in 65% yield. 1H-NMR (400 MHz, DMSO-d6) δH [ppm] = 12.45 (s, 1H), 7.62
(d, J = 7.0 Hz, 1H), 7.45 (d, J = 7.0 Hz, 1H), 7.15 (m, 2H), 6.99 (t, J = 2.2 Hz, 1H), 6.89 (dd, J =
3.8, 1.8 Hz, 1H), 6.17 (dd, J = 3.8, 2.6 Hz, 1H), 4.11 (s, 3H). 13C-NMR (101 MHz, DMSO-d6) δC
[ppm] = 146.6 (+), 143.9 (Cq), 134.0 (Cq), 127.1 (+), 122.9(+), 121.9 (+), 121.2 (+), 118.3 (Cq),
111.3 (+), 110.5 (Cq), 107.8 (+), 36.6 (+). HRMS (ESI) (m/z): [M+H]+ (C12H12N3) calc.: 198.1026,
found: 198.1031.
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2-(1-Methyl-1H-pyrrol-2-yl)benzo[d]thiazole (3n):53 The product was obtained following
general procedure A using 1n (33.9 mg, 0.2 mmol, 1.0 equiv.), Rh-6G (9.6 mg, 0.02 mmol,
10 mol%), 2a (355 µL, 4.0 mmol, 20 equiv.) and DIPEA (52 µL, 0.3 mmol, 1.5 equiv.). After 20 h
250 µL of a solution of the catalyst (c = 0.04 M, 5 mol%) were added with the help of a Hamilton
syringe under exclusion of air. Subsequent to one FPT cycle irradiation was continued. After 48 h
automated column chromatography (PE/EtOAc, 5% EtOAc) gave product 3n as a brown oil in
96% yield. 1H-NMR (400 MHz, CDCl3) δH [ppm] = 7.98 (dd, J = 8.2, 0.6 Hz, 1H), 7.84 (dd, J =
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8.0, 0.6 Hz, 1H), 7.46 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 7.33 (ddd, J = 8.3, 7.2, 1.2 Hz, 1H), 6.86 (dd,
J = 3.9, 1.7 Hz, 1H), 6.83 (t, J = 2.2 Hz, 1H), 6.24 (dd, J = 3.9, 2.6 Hz, 1H), 4.17 (s, 3H). 13C-NMR
(101 MHz, CDCl3) δC [ppm] = 160.5 (Cq), 154.4 (Cq), 134.0 (Cq), 128.1 (+), 126.6 (+), 126.0 (+),
124.5 (+), 122.5 (+), 121.2 (+), 114.9 (+), 108.8 (+), 37.2 (+). HRMS (ESI) (m/z): [M]+• (C12H9N2S)
calc.: 213.0481, found: 213.0480.
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2-(1-Methyl-1H-pyrrol-2-yl)benzo[d]oxazole (3o):53 The product was obtained following
general procedure A using 1o (34.9 mg, 0.2 mmol, 1.0 equiv.), Rh-6G (9.6 mg, 0.02 mmol,
10 mol%), 2a (355 µL, 4.0 mmol, 20 equiv.) and DIPEA (52 µL, 0.3 mmol, 1.5 equiv.). After 20 h
250 µL of a solution of the catalyst (c = 0.04 M, 5 mol%) were added with the help of a Hamilton
syringe under exclusion of air. Subsequent to one FPT cycle irradiation was continued. After 48 h
automated column chromatography (PE/EtOAc, 5% EtOAc) gave product 3o as a white solid in
55% yield. 1H-NMR (300 MHz, CDCl3) δH [ppm] = 7.76 – 7.64 (m, 1H), 7.56 – 7.45 (m, 1H), 7.24
(s, 2H), 7.11 (dd, J = 3.9, 1.8 Hz, 1H), 6.87 (t, J = 2.2 Hz, 1H), 6.26 (dd, J = 4.0, 2.5 Hz, 1H), 4.15
(s, 3H). 13C-NMR (75 MHz, CDCl3) δC [ppm] = 157.9 (Cq), 149.6 (Cq), 142.4 (Cq), 128.6 (+), 124.3
(+), 120.7 (Cq), 119.3 (+), 115.2 (+), 110.1 (+), 108.9 (+), 37.1 (+). HRMS (ESI) (m/z): [M+H]+
(C12H10N2O) calc.: 199.0866, found: 199.0867. mp = 85 – 90 °C.
6-(1-Methyl-1H-pyrrol-2-yl)pyrimidine-2,4(1H,3H)-dione (4a): The product was obtained
following general procedure A using unprotected 6-chlorouracil 1a’ (29.3 mg, 0.2 mmol, 1.0
equiv.), Rh-6G (9.6 mg, 0.02 mmol, 10 mol%), 2a (355 µL, 4.0 mmol, 20 equiv.) and DIPEA (52
µL, 0.3 mmol, 1.5 equiv.). After 20 h 250 µL of a solution of the catalyst (c = 0.04 M, 5 mol%)
were added with the help of a Hamilton syringe under exclusion of air. Subsequent to one FPT
cycle irradiation was continued. After 48 h automated column chromatography (PE/EtOAc, 80%
EtOAc) gave product 4a as a white solid in 22% yield. 1H-NMR (300 MHz, DMSO-d6) δH [ppm]
= 11.01 (s, 1H), 10.75 (s, 1H), 7.03 (dd, J = 2.6, 1.7 Hz, 1H), 6.67 (dd, J = 3.9, 1.8 Hz, 1H), 6.12
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(dd, J = 3.9, 2.6 Hz, 1H), 5.56 (t, J = 1.8 Hz, 1H), 3.73 (s, 3H). 13C NMR (75 MHz, DMSO-d6) δC
[ppm] = 164.1 (Cq), 151.7 (Cq), 144.6 (Cq), 129.0 (+), 124.2 (Cq), 113.4 (+), 108.0 (+), 96.6 (+),35.9
(+). HRMS (ESI) (m/z): [M+H]+ (C9H10N3O2) calc.: 192.0768, found: 192.0773.
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General procedure B: Hydrolysis of methoxy protected uracils
The hydrolysis of 3 was performed according to the procedure described in the reference. A round
bottom flask was charged with 3, which was then dissolved in a mixture of MeOH/HClconc. (25 mL,
1:1). The reaction mixture was heated to reflux and stirred for 24 h. Subsequently a saturated
solution of Na2CO3 (20 mL) was used to neutralize the acid, and water (10 mL) was added. After
the extraction with EtOAc (3  50 mL), the combined organic layers were dried over MgSO4. The
solvent was removed under reduced pressure, and evaporation of the remaining volatiles led to the
crude product. Purification was done by automated flash column chromatography (PE/EtOAc) and
the hydrolyzed product was obtained as a white powder.
6-(1-Methyl-1H-pyrrol-2-yl)pyrimidine-2,4(1H,3H)-dione (4a): The product was prepared
following general procedure B using 3a (53.0 mg, 0.24 mmol, 1.0 equiv.). After purification by
automated column chromatography (PE/EtOAc, 85% EtOAc) the product was obtained in 95%
yield. This compound has also been synthesized via the photoredox catalytic coupling reaction.
Due to the very similar work up and purification procedure, both methods provided this compound
with similar purity. Therefore see the photoredox catalytic coupling reaction in general procedure
A for the characterization.
6-(1-Phenyl-1H-pyrrol-2-yl)pyrimidine-2,4(1H,3H)-dione (4d): The product was prepared
following general procedure B using 3d (61.5 mg, 0.22 mmol, 1.0 equiv.). After purification by
automated column chromatography (PE/EtOAc, 80% EtOAc) the product was obtained as a white
solid in 99% yield. 1H-NMR (300 MHz, DMSO-d6) δH [ppm] = 10.96 (s, 1H), 10.90 (s, 1H), 7.55
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– 7.39 (m, 3H), 7.37 – 7.30 (m, 2H), 7.25 (dd, J = 2.8, 1.7 Hz, 1H), 6.96 (dd, J = 3.9, 1.7 Hz, 1H),
6.38 (dd, J = 3.9, 2.7 Hz, 1H), 4.68 (t, J = 1.8 Hz, 1H). 13C NMR (75 MHz, DMSO-d6) δC [ppm] =
163.6 (Cq), 151.6 (Cq), 144.4 (Cq), 139.2 (Cq), 129.6 (+), 129.3 (+), 127.9 (+), 125.6 (+), 123.6
(Cq), 115.6 (+), 109.8 (+), 97.37 (+). HRMS (ESI) (m/z): [M+H]+ (C14H12N3O2) calc.: 254.0924,
found: 254.0931.
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6-(1-Benzyl-1H-pyrrol-2-yl)pyrimidine-2,4(1H,3H)-dione (4e): The product was prepared
following general procedure B using 3e (60.6 mg, 0.21 mmol, 1.0 equiv.). After purification by
automated column chromatography (PE/EtOAc, 80% EtOAc) the product was obtained as a
slightly brownish solid in 95% yield. 1H-NMR (400 MHz, DMSO-d6) δH [ppm] = 10.94 (s, 1H),
10.80 (s, 1H), 7.35 – 7.28 (m, 2H), 7.28 – 7.21 (m, 1H), 7.17 (dd, J = 2.7, 1.8 Hz, 1H), 6.99 – 6.92
(m, 2H), 6.70 (dd, J = 3.9, 1.8 Hz, 1H), 6.23 (dd, J = 3.9, 2.7 Hz, 1H), 5.36 – 5.30 (m, 3H). 13C
NMR (101 MHz, DMSO-d6) δC [ppm] = 163.8 (Cq), 151.5 (Cq), 144.5 (Cq), 138.2 (Cq), 128.6 (+),
127.4 (+), 126.2 (+), 124.2 (Cq), 114.1 (+), 108.6 (+), 96.8 (+), 51.0 (-). HRMS (ESI) (m/z): [M+H]+
(C15H14N3O2) calc.: 268.1081, found: 268.1090. mp = 219 – 223 °C.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:.
Optimization of reaction condition and 1H and 13C NMR spectra of all compounds (PDF).
ACKNOWLEDGEMENTS
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This work was supported by the Deutsche Forschungsgemeinschaft DFG, (GRK 1626; Chemical
Photocatalysis). We thank Dr. Rudolf Vasold (University of Regensburg) for his assistance in
GC−MS measurements and Ms. Regina Hoheisel (University of Regensburg) for her assistance in
cyclic voltammetry measurements.
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NOTES
The authors declare no competing financial interest.
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