Article

pubs.acs.org/joc

Synthesis of Arylated Nucleobases by Visible Light Photoredox

Catalysis
Andreas Graml, Indrajit Ghosh, and Burkhard König*
Institut für Organische Chemie, Universität Regensburg, Universitätsstrasse 31, D-93053 Regensburg, Germany
*
S Supporting Information

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.

■ INTRODUCTION
Nucleobases are well-known molecular building blocks in
photocatalytic arylation of iodouracils.29 However, all of the
reported synthetic methods require transition metal catalysts,
living organisms whose presence and function in the DNA or auxiliary ligands, high temperatures, use of N-protected
compounds such as ATP is important to sustain life. Their nucleobases, additional prefunctionalization of the starting
structure is based on pyrimidines and purines, which are materials, or the use of UV-light.
common motifs in many natural products and biologically Transition-metal-free visible light photoredox catalysis may
active compounds.1 Among others, certain derivatives of uracil provide an attractive alternative method for the functionaliza-
have gained enormous attention as bactericides,2 insecticides,3 tion of halogenated heteroarenes under very mild conditions.
herbicides,4 or fungicides,5 in addition to their use as Not surprisingly, its potential in organic synthesis has been
privileged structural units in drug discovery. 6 Many investigated intensively.30−33 Of particular interest are
nucleobase-derived molecules have been investigated for reactions using organic dye catalysts instead of commonly
potential use as cytostatic drugs in cancer treatment,7 as used Ru- or Ir-based photocatalysts.34,35 Although these
well as drugs against malaria8,9 or several viral diseases.10−13 A catalysts are less expensive and less toxic compared to
bioanalytical application is the use as DNA labels.14,15 The transition metal complexes, their use is limited to specific
abundance of nucleobases in many interesting compounds halogenated starting materials depending on the redox
triggered the development of efficient synthetic methods for potentials.36 However, organic dyes, such as PDI or Rh-6G
their functionalization, especially functionalization of the uracil give access to halogenated heteroarenes as substrates for
moiety at the C5 and C6 positions.16−19 Several methods for photoredox catalytic arylation reactions, as they exhibit very
the synthesis of substituted nucleobases are reported, many high redox potentials under visible light irradiation, due to a
based on transition-metal-catalyzed cross-coupling proto- consecutive photoinduced electron transfer process (con-
cols.20,21 While C − C arylations are mostly realized by PET).37−40 We report here a simple strategy for the
Suzuki−Miyaura couplings,22,23 alkenylations and alkynyla- functionalization of halogenated nucleobases or nucleobase
tions can be performed with Stille,24 Heck, or Sonogashira precursors utilizing blue LEDs as visible light source, the
couplings.25 As a more direct synthesis, palladium-catalyzed organic dye rhodamine 6G (Rh-6G) as photocatalyst, and
C−H arylation strategies have emerged.26 In 2011, Hocek et N,N-diisopropylethylamine (DIPEA) as a sacrificial electron
al. reported a direct arylation of N-protected uracils with aryl donor.
halides,17 and recently Wnuk et al. developed a method for The photoredox arylation of uracil uses 6-chloro-2,4-
the arylation of 5-iodouracil nucleosides with arenes and dimethoxypyrimidine as the starting material, as shown in
heteroarenes.19 Furthermore, cross-dehydrogenative couplings Scheme 1. 6-Chloro-2,4-dimethoxypyrimidine (Ar−X) is
without the need for halogenated starting materials are activated by photoinduced electron transfer, yielding the
known.26,27 Moreover, in 2010 Rossi et al. reported a
photochemical arylation of 2,4-methoxyprotected uracil,28 Received: January 13, 2017
and most recently Zhang et al. described in 2015 a direct Published: March 1, 2017

© 2017 American Chemical Society 3552 DOI: 10.1021/acs.joc.7b00088

J. Org. Chem. 2017, 82, 3552−3560
The Journal of Organic Chemistry Article

Scheme 1. Photoredox Catalytic Synthetic Strategy for the Functionalization of Nucleobases and Related Structures (R = aryl,
heteroaryl)

Table 1. Control Reactions

entry reaction conditions yield [%]a

1 2a (20 equiv), DIPEA (1.5 equiv), Rh-6G (10 mol %), DMSO/H2O (12:1) 69b
2 2a (20 equiv), DIPEA (1.5 equiv), Rh-6G (10 mol %), DMSO, no light 0
3 2a (20 equiv), no DIPEA, Rh-6G (10 mol %), DMSO trace
4 2a (20 equiv), DIPEA (1.5 equiv), no catalyst, DMSO 0
5 2a (20 equiv), DIPEA (1.5 equiv), Rh-6G (10 mol %), DMSO, air trace
a
Isolated yield. bReaction time 48 h.

corresponding radical anions (Ar−X•−) that fragments by significantly lower product yields (see Supporting Informa-
releasing a chloride anion to generate the corresponding 2,4- tion). Moreover, addition of H2O (DMSO/H2O, 12:1; v/v)
dimethoxypyrimidine radical that could be used for sub- to the reaction mixture enhanced the yield significantly to
sequent arylation reactions with suitable trapping reagents. 46%. The yield was further improved to 69% (isolated yield,
Finally, hydrolysis of the functionalized 2,4-dimethoxypyr- see Table 1) when the reaction mixture was irradiated for 48
imidine provides uracil derivatives. The arylation of purine, h. Control reactions without the catalyst, without DIPEA, and
pyrimidine, and other biologically relevant heterocycles starts without visible light irradiation did not lead to any significant
from their respective commercially available bromides and product formation (Table 1, entries 2−4). Only traces of the
chlorides. To achieve the one-electron reduction of the coupling product were observed when the reaction was
halogenated substrates initiating the substitution reaction, the
carried out in the presence of air (Table 1, entry 5).
previously reported high reduction power of excited stable
Having the optimized reaction conditions in hand (entry 1,
radical anions of rhodamine 6G is required.

■
Table 1), we then explored the scope of the photoredox
catalytic arylation reaction of 1a with other pyrrole derivatives.
RESULTS AND DISCUSSION
These reactions gave the C−H arylated products in moderate
Optimization of the photoredox reaction conditions was to good yields (see Table 2). Notably, unprotected pyrrole
carried out by irradiation mixture of 6-chloro-2,4-dimethox- could also be used with ease under this C−H arylation
ypyrimidine (1a), N-methylpyrrole (2a), rhodamine 6G (Rh- reaction protocol, and the reaction with N-benzylpyrrole as a
6G), and N,N-diisopropylethylamine (DIPEA, sacrificial trapping reagent gave exclusively the C−H arylated product
electron donor) with blue LEDs (455 ± 15 nm) under
3e in 54% yield. In the case of N-benzylpyrrole, the 2 position
nitrogen atmosphere. With 10 mol % catalyst loading and 1.5
of the pyrrole derivative was arylated chemoselectively.
equiv of DIPEA in DMSO, a yield of 25% of the coupling
Other electron-rich arenes and heteroarenes could also be
product 3a was observed by gas chromatographic (GC)
analysis after 24 h of irradiation. While the yield was similar in used as the coupling partners of the 2,4-dimethoxypyrimidine
EtOH, it dropped drastically when the reaction was carried radical. Use of 1,3,5-trimethoxybenzene as a radical trapping
out in DMF (see Supporting Information). Excess amount of reagent gave 3g in 27% yield. The relatively low yield is due
sacrificial electron donor (i.e., DIPEA) did not improve the to the competing hydrogen abstraction reactions of the 2,4-
reaction outcome. However, excess of trapping reagent (20 dimethoxypyrimidine radical either from the solvent or from
equiv) was important to suppress hydrogen abstraction from the radical cation of DIPEA (see below). The trapping with 3-
the solvent or the radical cation of DIPEA as a competing methylindole provides coupling product 3f in synthetically
reaction pathway giving the dehalogenated starting material as useful yield. 3-Methylindole was selectively functionalized at
the product. The use of only 5 or 10 equiv of 2 resulted in the 2 position. When 1,1-diphenylethylene was employed as
3553 DOI: 10.1021/acs.joc.7b00088
J. Org. Chem. 2017, 82, 3552−3560
The Journal of Organic Chemistry Article

Table 2. Scope of Trapping Reagents (isolated yield)

a
The reaction was started with 10 mol % catalyst loading, and then 5 mol % catalyst was added after 20 h according to general procedure A. b15
equiv of 2. cYield determined by quantitative 1H NMR with 2,5-dimethylfuran as internal standard, dThe reaction was started with 10 mol % catalyst
loading, and then 10 mol % was added in two batches (5 + 5 mol %) after 20 and 30 h. eCombined 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 Supporting Information).

trapping reagent, product 3h and 3h′ were obtained in an substituents present in the substrates.41 Substitution at
excellent combined yield of 82%. another position of the uracil moiety could be performed
Subsequent to the coupling reactions, hydrolysis of the by using commercially available 5-bromouracil (46% isolated
methoxy groups of the C−H arylated products gave yield), although a higher catalyst loading was needed in this
substituted uracils in almost quantitative yields. Thus, after case (see Supporting Information). When 6-chloropurine was
two steps, compounds 4a, 4d, and 4e were obtained in 66%, employed under the photoredox protocol, the C−H arylated
57%, and 51% yields, respectively. product 3b was obtained in moderate yield of 51%.
Interestingly, the C−H arylated product 4a could also be We then explored this photoredox protocol for the
obtained by using 6-chlorouracil directly as the substrate with generation of biologically important pyrimidine heteroaryl
22% isolated yield (see Table 3). However, due to the low radicals from their respective bromides (see Table 4).42,43 The
yield, the two-step synthesis including a simple hydrolysis step pyrimidine ring could be functionalized at the 5 position with
subsequent to the coupling reaction, is preferable for the 74% isolated yield (3j) and the 2 position with 33% yield
synthesis of arylated uracils. Note that the rate of the C−H (3k). When 6-bromo-2-methylbenzoxazole was used as a
arylation reactions is not only determined by the reduction substrate, the coupling product 3l was obtained in 73% yield.
potential of the substrates but also by the carbon−halogen Having realized that the redox power of the photoredox
bond cleavage kinetics that depends strongly on the catalytic system could also exceed the reduction potentials of
3554 DOI: 10.1021/acs.joc.7b00088
J. Org. Chem. 2017, 82, 3552−3560
The Journal of Organic Chemistry Article

Table 3. Scope of Nucleobase Derivatives (isolated yield)

a
The reaction was started with 10 mol % catalyst loading, and then 5 mol % catalyst was added after 20 h according to general procedure A. bThe
reaction was started with 10 mol % catalyst loading, and then 10 mol % was added in two batches (5 + 5 mol %) after 20 and 30 h.

Table 4. Scope of Heteroaryl Bromides and Chlorides (isolated yield)

a
The reaction was started with 10 mol % catalyst loading, and then 5 mol % catalyst was added after 20 h according to general procedure A.

chlorinated heteroaromatic substrates, we then used heteroaryl substrates, the nucleobase radical abstracts a hydrogen atom
chlorides as substrates for the C−H arylation reactions, giving either from the solvent (in this case, DMSO) or from the
access to biologically interesting heteroarenes.44−46 Coupling radical cation of DIPEA, yielding the reduction product as
reactions with 2-chlorobenzimidazole, 2-chlorobenzothiazole, observed in GC and GC-MS analysis of the crude reaction
and 2-chlorobenzoxazole gave moderate to excellent yields of mixtures.
3m (65%), 3n (96%), and 3o (55%), respectively.47 Experimental results, spectroscopic investigations, cyclic

■
voltammetric results, and literature reports support the
MECHANISTIC PROPOSAL proposed catalytic cycle. The results of the fluorescence
titrations of Rh-6G with substrate 1a and DIPEA are shown
The proposed mechanism for the photoredox catalytic C−H in Figure 2. The fluorescence intensity of Rh-6G was not
arylation is depicted in Figure 1. Upon blue light irradiation, quenched upon titration with the substrate 1a. However, the
the excited Rh-6G takes an electron from DIPEA to generate fluorescence of Rh-6G was quenched dramatically upon
the radical anion of rhodamine 6G and the radical cation of addition of DIPEA, which is due to the formation of the
DIPEA.38 The radical anion, upon further photoexcitation, radical anion of Rh-6G.38 The C−H arylation reaction did not
reduces the investigated substrates by an electron transfer, proceed under green light (λEx = 530 ± 15 nm) irradiation of
returning to its ground state and yielding the nucleobase the reaction mixture. Note that the radical anion of
radical by scission of the C−Br or C−Cl bond. Finally, the rhodamine 6G is formed by irradiation with green light, but
radical is either trapped by heteroarenes, double bonds, or it cannot be excited again by using green light. At the same
substituted arenes present in the reaction media, yielding the time, the radical anion of rhodamine 6G in the ground state is
C−H arylated products after oxidation and rearomatization. In not capable of transferring an electron to the investigated
a competing pathway, also reported for other photoredox substrates, which have exceptionally high reduction potentials.
catalytic C−H arylation reactions using aryl halides as The measured reduction potentials for 1a, 1i, and 1b in
3555 DOI: 10.1021/acs.joc.7b00088
J. Org. Chem. 2017, 82, 3552−3560
The Journal of Organic Chemistry Article

Figure 1. Proposed mechanism of the photocatalytic reductive cross-coupling reaction via a conPET type process.

Figure 2. Changes in the fluorescence spectra of Rh-6G (4.93 μM 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 part ii.

DMSO are −2.32, −2.04, and −1.86 V vs SCE, respectively radical species and suppresses the degradation of the
(see Supporting Information for the cyclic voltammograms). photocatalyst.

■
The reduction potential of Rh-6G, upon blue light irradiation,
reaches or exceeds a value of ca. −2.4 V38 and thus could CONCLUSION
transfer an electron to the halogenated nucleobases or other
halogenated heteroaromatic substrates investigated herein. We report a mild metal-free photoredox catalytic method for
Additionally, formation of the products 3h and 3h′ with the synthesis of arylated nucleobases from commercially
1,1-diphenylethylene (a radical scavenger that shows low available halogenated heterocycles. Under blue light irradi-
reactivity toward nucleophiles or electrophiles)48 also supports ation, the strong reductive power of the excited radical anion
the proposed radical mechanism. After addition of 1a• to 1,1- of rhodamine 6G is used to reduce chloro- or bromo-
diphenylethylene, product 3h′ is obtained by oxidation and substituted nucleobases and heterocycles to their respective
deprotonation of the radical intermediate, while 3h is radical anions. Upon elimination of a halide anion, the
generated by hydrogen atom abstraction either from the corresponding aryl radicals are generated. These are trapped
radical cation of DIPEA or from the solvent (see Supporting by heteroarenes, 1,1-diphenylethylene, and electron-rich
Information). The role of water (present in 12:1 v/v) is not arenes present in the reaction mixture to afford the targeted
clear at the moment. However, knowing that solvents play a functionalized nucleobases in good isolated yields. The
crucial role in determining the stability and reactivity of reported photoredox catalytic protocol provides an alternative
radical intermediates, including the radical anion of rhodamine strategy to transition-metal-based cross-coupling protocols and
6G, generated in situ, and the photostability of the catalyst, C−H arylation protocols using halogenated nucleobases under
we anticipate that water stabilizes the generated nucleobase UV-light irradiation.
3556 DOI: 10.1021/acs.joc.7b00088
J. Org. Chem. 2017, 82, 3552−3560
The Journal of Organic Chemistry Article

■ EXPERIMENTAL SECTION
General Information. Starting materials and reagents were
for the remaining reaction time, one FPT cycle was performed
subsequently. After the irradiation time, the reaction mixture was
diluted with water and extracted with EtOAc (3 × 20 mL). The
purchased from commercial suppliers and were used without further combined organic layers were dried over MgSO4, and the solvent
purification. Solvents were used as p.a. grade or dried and distilled was removed under reduced pressure. The crude product was
according to known literature procedures.49 Industrial grade of purified by automated flash column chromatography (PE/EtOAc),
solvents was used for automated flash column chromatography. All and after evaporation of the solvent the product was obtained.
reactions with oxygen- or moisture-sensitive reagents were carried 2,4-Dimethoxy-6-(1-methyl-1H-pyrrol-2-yl)pyrimidine (3a). The
out in glassware that was dried before use by heating under vacuum. product was obtained following general procedure A using 1a (34.9
Dry nitrogen was used as an inert gas atmosphere. Liquids were mg, 0.2 mmol, 1.0 equiv), Rh-6G (9.6 mg, 0.02 mmol, 10 mol %),
added via syringe, needle, and septum technique unless stated 2a (355 μL, 4.0 mmol, 20 equiv), and DIPEA (52 μL, 0.3 mmol, 1.5
otherwise. All NMR spectra were measured at room temperature equiv). After 48 h, automated column chromatography (PE/EtOAc,
(300 or 400 MHz for 1H, 75 or 101 MHz for 13C).50 All chemical 5% EtOAc) gave product 3a as a slightly brown solid in 69% yield.
shifts are reported in δ-scale as parts per million [ppm] (multiplicity, 1
H NMR (400 MHz, CDCl3) δH [ppm] = 6.74 (d, J = 3.3 Hz, 2H),
coupling constant J, number of protons) relative to the solvent 6.55 (s, 1H), 6.16 (t, J = 3.2 Hz, 1H), 4.05 (s, 3H), 4.00 (s, 3H),
residual peaks as the internal standard.51 Coupling constants J are 3.96 (s, 3H). 13C NMR (101 MHz, CDCl3) δC [ppm] = 172.0 (Cq),
given in hertz [Hz]. Abbreviations used for signal multiplicity: 1H 165.1 (Cq), 160.6 (Cq), 129.7 (Cq), 128.3 (+), 113.3 (+), 108.3 (+),
NMR: b = broad, s = singlet, d = doublet, t = triplet, q = quartet, dd 96.0 (+), 54.7 (+), 53.7 (+), 37.9 (+). HRMS (ESI) (m/z): [M +
= doublet of doublets, dt = doublet of triplets, dq = doublet of H]+ (C11H14N3O2) calcd: 220.1081, found 220.1087.
quartets, and m = multiplet; 13C NMR: (+) = primary/tertiary, (−) 6-(1-Methyl-1H-pyrrol-2-yl)-7H-purine (3b). The product was
= secondary, (Cq) = quaternary carbon). The mass spectrometric obtained following general procedure A using 1h (30.9 mg, 0.2
measurements were performed at the Central Analytical Laboratory mmol, 1.0 equiv), Rh-6G (10.1 mg, 0.02 mmol, 10 mol %), 2a (355
of the University of Regensburg, using a TOF or Q-TOF mass μL, 4.0 mmol, 20 equiv), and DIPEA (52 μL, 0.3 mmol, 1.5 equiv).
analyzer. GC and GC-MS measurements were performed at the After 20 h, 250 μL of a solution of the catalyst (c = 0.04 M, 5 mol
University of Regensburg. A 30 m × 0.25 mm/0.25 μM film capillary %) was added with a Hamilton syringe under exclusion of air.
was used and helium served as carrier gas (flow rate of 1 mL/min). Subsequent to one FPT cycle, the irradiation was continued. After 48
The injector temperature (split injection: 40:1 split) was 280 °C, h, automated column chromatography (PE/EtOAc, 80% EtOAc)
detection temperature 300 °C (FID). GC measurements were made gave product 3b as a white solid in 51% yield. 1H NMR (300 MHz,
and investigated via integration of the signal obtained. The GC oven DMSO-d6) δH [ppm] = 13.39 (s, 1H), 8.78 (s, 1H), 8.50 (s, 1H),
temperature program was adjusted as follows: initial temperature 40 7.75 (s, 1H), 7.11 (t, J = 2.2 Hz, 1H), 6.24 (dd, J = 3.9, 2.5 Hz, 1H),
°C was kept for 3 min, the temperature was increased at a rate of 15 4.14 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δC [ppm] = 151.9
°C/min over a period of 16 min until 280 °C was reached and kept (Cq), 151.3 (+), 148.4 (Cq), 143.1 (+), 129.6 (+), 127.8 (Cq), 126.6
for 5 min, the temperature was again increased at a rate of 25 °C/ (Cq), 118.9 (+), 108.4 (+), 38.0 (+). HRMS (ESI) (m/z): [M + H]+
min over a period of 48 s until the final temperature (300 °C) was (C10H10N5) calcd: 200.0931, found: 200.0934.
reached and kept for 5 min. Benzophenone was chosen as internal 2,4-Dimethoxy-6-(1H-pyrrol-2-yl)pyrimidine (3c). The product
standard. Analytical TLC was performed on silica-gel-coated alumina was obtained following general procedure A using 1a (34.9 mg,
plates. Visualization was performed with UV light (254 or 366 nm). 0.2 mmol, 1.0 equiv), Rh-6G (9.6 mg, 0.02 mmol, 10 mol %), 2c
If necessary, vanillin was used for chemical staining. Purification by (278 μL, 4.0 mmol, 20 equiv) and DIPEA (25 μL, 0.3 mmol, 1.5
column chromatography was performed with silica gel 60 M (40−63 equiv). After 48 h automated column chromatography (PE/EtOAc,
μm, 230−440 mesh). For irradiation, blue LEDs (λmax = 455 ± 15 10% EtOAc) gave product 3c as a white solid in 65% yield. 1H NMR
nm, Imax = 1000 mA, 1.12 W) or green LEDs (λmax = 530 ± 15 nm, (400 MHz, CDCl3) δH [ppm] = 9.62 (s, 1H), 6.92 (td, J = 2.6, 1.4
Imax = 1000 mA, 1.12 W) were used. Absorption and fluorescence Hz, 1H), 6.79 (ddd, J = 3.8, 2.5, 1.4 Hz, 1H), 6.51 (s, 1H), 6.30 (dt,
spectra were performed with a quartz fluorescence cuvette at room J = 3.7, 2.6 Hz, 1H), 4.01 (s, 3H), 3.97 (s, 3H). 13C NMR (101
temperature. CV measurements were performed with a three- MHz, CDCl3) δC [ppm] = 172.2 (Cq), 165.4 (Cq), 158.7 (Cq), 129.5
electrode potentiostat galvanostat using a glassy carbon working (Cq), 121.0 (+), 110.9 (+), 110.0 (+), 93.6 (+), 54.7 (+), 53.9 (+).
electrode, a platinum wire counter electrode, and a platinum wire HRMS (ESI) (m/z): [M + H]+ (C10H12N3O2) calcd: 206.0924,
reference electrode. Tetrabutylammonium tetrafluoroborate found: 206.0928. mp = 103−108 °C
(TBATFB, 0.1 M) was used as supporting electrolyte. The potentials 2,4-Dimethoxy-6-(1-phenyl-1H-pyrrol-2-yl)pyrimidine (3d). The
are given relative to Fc/Fc+ redox couple with ferrocene as internal product was obtained following general procedure A using 1a (34.9
standard. The measurements were carried out as follows: Prior to the mg, 0.2 mmol, 1.0 equiv), Rh-6G (9.6 mg, 0.02 mmol, 10 mol %),
measurement, a 0.1 M solution of TBATFB in DMSO was added to 2d (572.8 mg, 4.0 mmol, 20 equiv) and DIPEA (52 μL, 0.3 mmol,
the measurement cell and the solution was degassed by argon purge 1.5 equiv). After 20 h 250 μL of a solution of the catalyst (c = 0.04
for 5 min. All experiments were performed under argon atmosphere. M, 5 mol %) was added with a Hamilton syringe under exclusion of
After the baseline was recorded, the electroactive compound was air. Subsequent to one FPT cycle, irradiation was continued. After 48
added (0.01 M) and the solution was degassed again for 5 min. The h automated column chromatography (PE/EtOAc, 10% EtOAc) gave
cyclic voltammogram was recorded with one scan. Afterward, product 3d as an ochre brown solid in 58% yield. 1H NMR (400
ferrocene (2.20 mg, 12 μmol) was added to the solution which MHz, CDCl3) δH [ppm] = 7.42−7.31 (m, 3H), 7.28−7.22 (m, 2H),
was again degassed by argon purge for 5 min and the final 6.97−6.92 (m, 2H), 6.35 (dd, J = 3.7, 2.8 Hz, 1H), 6.25 (s, 1H),
measurement was performed. 3.89 (s, 3H), 3.44 (s, 3H). 13C NMR (101 MHz, CDCl3) δC [ppm]
General Procedure A: Photoredox Catalytic Cross-Cou- = 171.9 (Cq), 164.7 (Cq), 159.3 (Cq), 141.6 (Cq), 130.8 (Cq), 128.9
pling. A 5 mL crimp vial was equipped with the aryl halide 1 (0.2 (+), 128.3 (+), 127.2 (+), 126.3 (+), 114.7 (+), 109.7 (+), 97.0 (+),
mmol, 1 equiv), rhodamine 6G (10 mg, 0.02 mmol, 10 mol %), the 54.2 (+), 53.8 (+). HRMS (ESI) (m/z): [M + H]+ (C16H16N3O2)
respective trapping reagent 2 (4.0 mmol, 20 equiv), DIPEA (52 μL, calcd: 282.1237, found: 282.1243. mp = 87−89 °C.
0.3 mmol, 1.5 equiv), and a stirring bar. After addition of the solvent 4-(1-Benzyl-1H-pyrrol-2-yl)-2,6-dimethoxypyrimidine (3e). The
(1.5 mL), the vial was capped and degassed using the freeze−pump− product was obtained following general procedure A using 1a
thaw (FPT) technique three times. The reaction mixture was stirred (34.9 mg, 0.2 mmol, 1.0 equiv), Rh-6G (9.6 mg, 0.02 mmol, 10 mol
and irradiated using blue LEDs (455 ± 15 nm) for 48 h. After 20 h, %), 2e (611 μL, 4.0 mmol, 20 equiv), and DIPEA (52 μL, 0.3 mmol,
if necessary, 250 μL of a solution of the catalyst (c = 0.04 M) was 1.5 equiv). After 20 h, 250 μL of a solution of the catalyst (c = 0.04
added to the reaction mixture. This was performed with a Hamilton M, 5 mol %) was added with a Hamilton syringe under exclusion of
syringe under exclusion of oxygen. To ensure oxygen-free conditions air. Subsequent to one FPT cycle, the irradiation was continued.

3557 DOI: 10.1021/acs.joc.7b00088

J. Org. Chem. 2017, 82, 3552−3560
The Journal of Organic Chemistry Article

After 48 h, automated column chromatography (PE/EtOAc, 10% 3H). 13C NMR (101 MHz, acetone) δC [ppm] = 172.9 (Cq), 166.0
EtOAc) gave product 3e as a brown oil in 54% yield. 1H NMR (400 (Cq), 165.6 (Cq), 150.2 (Cq), 143.1 (Cq), 141.3 (Cq), 130.5 (+),
MHz, CDCl3) δH [ppm] = 7.31−7.18 (m, 3H), 7.05−6.98 (m, 2H), 129.6 (+), 129.6 (+), 129.4 (+), 128.7 (+), 128.7 (+), 127.2 (+),
6.82 (m, 2H), 6.58 (s, 1H), 6.26 (dd, J = 3.8, 2.7 Hz, 1H), 5.84 (s, 126.8 (+), 126.8 (+), 101.7 (+), 54.6 (+), 54.0 (+). HRMS (ESI)
2H), 3.94 (s, 3H), 3.77 (s, 3H). 13C NMR (101 MHz, CDCl3) δC (m/z): [M]+• (C20H17N2O2) calcd: 318.1363, found: 318.1347.
[ppm] = 172.0 (Cq), 165.1 (Cq), 160.5 (Cq), 139.3 (Cq), 129.7 (Cq), 5-(1-Methyl-1H-pyrrol-2-yl)pyrimidine-2,4(1H,3H)-dione (3i): 52
128.6 (+), 127.8 (+), 127.2 (+), 126.4 (+), 113.7 (+), 109.2 (+), The product was obtained following general procedure A using 1i
96.5 (+), 54.6 (+), 53.8 (+), 52.5 (−). HRMS (ESI) (m/z): [M + (38.2 mg, 0.2 mmol, 1.0 equiv), Rh-6G (9.6 mg, 0.02 mmol, 10 mol
H]+ (C17H18N3O2) calcd: 296.1394, found: 296.1398. %), 2a (355 μL, 4.0 mmol, 20 equiv), and DIPEA (52 μL, 0.3 mmol,
2-(2,6-Dimethoxypyrimidin-4-yl)-3-methyl-1H-indole (3f). The 1.5 equiv). After 20 h and after 30 h, 250 μL of a solution of the
product was obtained following general procedure A using 1a catalyst (c = 0.04 M, 5 mol %) was added with a Hamilton syringe
(34.9 mg, 0.2 mmol, 1.0 equiv), Rh-6G (9.6 mg, 0.02 mmol, 10 mol under exclusion of air. Subsequent to one FPT cycle after the
%), 2f (393.5 mg, 3.0 mmol, 15 equiv), and DIPEA (52 μL, 0.3 addition of new catalyst, irradiation was continued. After 48 h,
mmol, 1.5 equiv). After 20 h and after 30 h 250 μL of a solution of automated column chromatography (PE/EtOAc, 60% EtOAc) gave
the catalyst (c = 0.04 M, 5 mol %) was added with a Hamilton product 3i as a white, slightly brownish solid in 46% yield. 1H NMR
syringe under exclusion of air. Subsequent to one FPT cycle after the (400 MHz, DMSO-d6) δH [ppm] = 11.22 (s, 1H), 11.03 (s, 1H),
addition of new catalyst, the irradiation was continued. After 48 h, 7.37 (d, J = 3.9 Hz, 1H), 6.76 (t, J = 2.3 Hz, 1H), 5.96−5.93 (m,
automated column chromatography (PE/EtOAc, 10% EtOAc) gave 2H), 3.43 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δC [ppm] =
product 3f as a white solid in 32% yield (determined by quantitative 163.2 (Cq), 151.2 (Cq), 141.3 (+), 125.6 (Cq), 123.2 (+), 109.5 (+),
NMR analysis using 2,5-dimethylfuran as internal standard). 1H 106.6 (+), 105.9 (Cq), 34.2 (+). HRMS (ESI) (m/z): [M + H]
NMR (300 MHz, chloroform-d) δH [ppm] = 9.34 (s, 1H), 7.65 (dd, (C9H10N3O2) calcd: 192.0773, found: 192.0773.
J = 8.0, 1.0 Hz, 1H), 7.40 (dt, J = 8.4, 1.0 Hz, 1H), 7.30−7.23 (m, 5-(1-Methyl-1H-pyrrol-2-yl)pyrimidine (3j). The product was
1H), 7.17−7.09 (m, 1H), 6.79 (s, 1H), 4.10 (s, 3H), 4.03 (s, 3H), obtained following general procedure A using 1j (31.8 mg, 0.2
2.62 (s, 3H). 13C NMR (101 MHz, CDCl3) δC [ppm] = 172.4 (Cq), mmol, 1.0 equiv), Rh-6G (9.6 mg, 0.02 mmol, 10 mol %), 2a (355
165.2 (Cq), 159.0 (Cq), 135.5 (Cq), 130.1 (Cq), 129.9 (Cq), 124.5 μL, 4.0 mmol, 20 equiv), and DIPEA (52 μL, 0.3 mmol, 1.5 equiv).
(+), 119.8 (+), 119.8(+), 114.2 (Cq), 111.5 (+), 97.5 (+), 55.0 (+), After 20 h, 250 μL of a solution of the catalyst (c = 0.04 M, 5 mol
54.1 (+), 11.0 (+). HRMS (ESI): [M + Na]+ (C15H15N3NaO2) %) was added with a Hamilton syringe under exclusion of air.
calcd: 292.1056, found: 292.1057 Subsequent to one FPT cycle, irradiation was continued. After 48 h,
2,4-Dimethoxy-6-(2,4,6-trimethoxyphenyl)pyrimidine (3g). The automated column chromatography (PE/EtOAc, 25% EtOAc) gave
product was obtained following general procedure A using 1a (34.9 product 3j as a reddish oil in 74% yield. 1H NMR (400 MHz,
mg, 0.2 mmol, 1.0 equiv), Rh-6G (9.6 mg, 0.02 mmol, 10 mol %), CDCl3) δH [ppm] = 9.09 (s, 1H), 8.77 (s, 2H), 6.80 (dd, J = 2.7, 1.8
2g (504.6 mg, 3.0 mmol, 15 equiv), and DIPEA (52 μL, 0.3 mmol, Hz, 1H), 6.35 (dd, J = 3.7, 1.8 Hz, 1H), 6.23 (dd, J = 3.7, 2.7 Hz,
1.5 equiv). After 20 h, 250 μL of a solution of the catalyst (c = 0.04 1H), 3.69 (s, 3H). 13C NMR (101 MHz, CDCl3) δC [ppm] = 156.5
M, 5 mol %) was added with a Hamilton syringe under exclusion of (+), 155.4 (+), 127.6 (Cq), 127.1 (Cq), 126.0 (+), 110.9 (+), 108.9
air. Subsequent to one FPT cycle, the irradiation was continued. (+), 35.3 (+). HRMS (ESI) (m/z): [M]+• (C9H9N3) calcd:
After 48 h, automated column chromatography (PE/EtOAc, 30% 159.0791, found: 159.0788.
EtOAc) gave product 3g as a white solid in 27% yield. 1H NMR 2-(1-Methyl-1H-pyrrol-2-yl)pyrimidine (3k). The product was
(400 MHz, CDCl3) δH [ppm] = 6.38 (s, 1H), 6.18 (s, 2H), 3.98 (d, obtained following general procedure A using 1k (31.8 mg, 0.2
J = 1.3 Hz, 6H), 3.84 (s, 3H), 3.73 (s, 6H). 13C NMR (101 MHz, mmol, 1.0 equiv), Rh-6G (9.6 mg, 0.02 mmol, 10 mol %), 2a (355
CDCl3) δC [ppm] = 171.6 (Cq), 165.3 (Cq), 164.3 (Cq), 161.9 (Cq), μL, 4.0 mmol, 20 equiv), and DIPEA (52 μL, 0.3 mmol, 1.5 equiv).
158.9 (Cq), 110.6 (Cq), 104.0 (+), 91.2 (+), 56.1 (+), 55.5 (+), 54.8 After 20 h, 250 μL of a solution of the catalyst (c = 0.04 M, 5 mol
(+), 53.8 (+). HRMS (ESI) (m/z): [M]+• (C15H17N2O5) calcd: %) was added with a Hamilton syringe under exclusion of air.
305.1132, found: 305.1134. mp = 170−174 °C. Subsequent to one FPT cycle, irradiation was continued. After 48 h,
4-(2,2-Diphenylethyl)-2,6-dimethoxypyrimidine (3h). The prod- automated column chromatography (PE/EtOAc, 10% EtOAc) gave
uct was obtained following general procedure A using 1a (34.9 mg, product 3k as a reddish oil in 33% yield. 1H NMR (400 MHz,
0.2 mmol, 1.0 equiv), Rh-6G (9.6 mg, 0.02 mmol, 10 mol %), 2h CDCl3) δH [ppm] = 8.64 (d, J = 4.8 Hz, 2H), 7.16 (dd, J = 3.9, 1.9
(706 μL, 4.0 mmol, 20 equiv), and DIPEA (52 μL, 0.3 mmol, 1.5 Hz, 1H), 6.96 (t, J = 4.8 Hz, 1H), 6.78 (t, J = 2.2 Hz, 1H), 6.20 (dd,
equiv). After 20 h, 250 μL of a solution of the catalyst (c = 0.04 M, J = 3.9, 2.5 Hz, 1H), 4.08 (s, 3H). 13C NMR (101 MHz, CDCl3) δC
5 mol %) was added with a Hamilton syringe under exclusion of air. [ppm] = 160.7 (Cq), 156.8 (+), 131.1 (Cq), 128.7 (+), 116.9 (+),
Subsequent to one FPT cycle, irradiation was continued. After 48 h, 115.3 (+), 108.2 (+), 38.2 (+). HRMS (ESI) (m/z): [M]+•
automated column chromatography (PE/EtOAc, 10% EtOAc) gave (C9H8N3) calcd: 158.0713, found: 158.0708.
product 3h as a white solid in 68% yield. 1H NMR (400 MHz, 2-Methyl-6-(1-methyl-1H-pyrrol-2-yl)benzo[d]oxazole (3l). The
acetone-d6) δH [ppm] = 7.39−7.31 (m, 4H), 7.28−7.21 (m, 4H), product was obtained following general procedure A using 1l
7.17−7.10 (m, 2H), 6.24 (s, 1H), 4.74 (t, J = 8.0 Hz, 1H), 3.90 (s, (42.41 mg, 0.2 mmol, 1.0 equiv), Rh-6G (9.6 mg, 0.02 mmol, 10 mol
3H), 3.82 (s, 3H), 3.41 (d, J = 8.0 Hz, 2H). 13C NMR (101 MHz, %), 2a (355 μL, 4.0 mmol, 20 equiv), and DIPEA (52 μL, 0.3 mmol,
acetone) δC [ppm] = 172.6 (Cq), 171.5 (Cq), 166.1 (Cq), 145.3 1.5 equiv). After 20 h, 250 μL of a solution of the catalyst (c = 0.04
(Cq), 129.2 (Cq), 128.7 (+), 127.0 (+), 101.4 (+), 54.7 (+), 53.8 M, 5 mol %) was added with a Hamilton syringe under exclusion of
(+), 50.4 (+), 43.4 (−). HRMS (ESI) (m/z): [M]+• (C20H20N2O2) air. Subsequent to one FPT cycle, irradiation was continued. After 48
calcd: 320.1519 found: 320.1521. mp = 74−78 °C. h, automated column chromatography (PE/EtOAc, 10% EtOAc)
4-(2,2-Diphenylvinyl)-2,6-dimethoxypyrimidine (3h′). The prod- gave product 3l as a white solid in 72% yield. 1H NMR (400 MHz,
uct was obtained following general procedure A using 1a (34.9 mg, CDCl3) δH [ppm] = 7.66 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 1.0 Hz,
0.2 mmol, 1.0 equiv), Rh-6G (9.6 mg, 0.02 mmol, 10 mol %), 2h 1H), 7.35 (dd, J = 8.2, 1.6 Hz, 1H), 6.74 (t, J = 2.2 Hz, 1H), 6.28−
(706 μL, 4.0 mmol, 20 equiv), and DIPEA (52 μL, 0.3 mmol, 1.5 6.21 (m, 2H), 3.67 (s, 3H), 2.65 (s, 3H). 13C NMR (101 MHz,
equiv). After 20 h, 250 μL of a solution of the catalyst (c = 0.04 M, CDCl3) δC [ppm] = 164.2 (Cq), 151.2 (Cq), 140.5 (Cq), 134.2 (Cq),
5 mol %) was added with a Hamilton syringe under exclusion of air. 130.2 (Cq), 125.3 (+), 123.9 (+), 119.0 (+), 110.3 (+), 109.2 (+),
Subsequent to one FPT cycle, irradiation was continued. After 48 h, 108.0 (+), 35.1 (+), 14.6 (+). HRMS (ESI) (m/z): [M]+•
automated column chromatography (PE/EtOH, 10% EtOAc) gave (C13H12N2O) calcd: 212.0944, found: 212.0942.
product 3h′ as a white solid in 14% yield. 1H NMR (400 MHz, 2-(1-Methyl-1H-pyrrol-2-yl)-1H-benzo[d]imidazole (3m): 39 The
acetone-d6) δH [ppm] = 7.43−7.36 (m, 7H), 7.30−7.24 (m, 1H), product was obtained following general procedure A using 1m
7.22−7.19 (m, 2H), 6.95 (s, 1H), 5.98 (s, 1H), 3.80 (s, 3H), 3.57 (s, (30.5 mg, 0.2 mmol, 1.0 equiv), Rh-6G (9.6 mg, 0.02 mmol, 10 mol

3558 DOI: 10.1021/acs.joc.7b00088

J. Org. Chem. 2017, 82, 3552−3560
The Journal of Organic Chemistry Article

%), 2a (355 μL, 4.0 mmol, 20 equiv), and DIPEA (52 μL, 0.3 mmol, organic layers were dried over MgSO4. The solvent was removed
1.5 equiv). After 20 h 250 μL of a solution of the catalyst (c = 0.04 under reduced pressure, and evaporation of the remaining volatiles
M, 5 mol %) was added with a Hamilton syringe under exclusion of led to the crude product. Purification was performed by automated
air. Subsequent to one FPT cycle, irradiation was continued. After 48 flash column chromatography (PE/EtOAc), and the hydrolyzed
h, automated column chromatography (PE/EtOAc, 15% EtOAc) product was obtained as a white powder.
gave product 3m as a white solid in 65% yield. 1H NMR (400 MHz, 6-(1-Methyl-1H-pyrrol-2-yl)pyrimidine-2,4(1H,3H)-dione (4a).
DMSO-d6) δH [ppm] = 12.45 (s, 1H), 7.62 (d, J = 7.0 Hz, 1H), 7.45 The product was prepared following general procedure B using 3a
(d, J = 7.0 Hz, 1H), 7.15 (m, 2H), 6.99 (t, J = 2.2 Hz, 1H), 6.89 (53.0 mg, 0.24 mmol, 1.0 equiv). After purification by automated
(dd, J = 3.8, 1.8 Hz, 1H), 6.17 (dd, J = 3.8, 2.6 Hz, 1H), 4.11 (s, column chromatography (PE/EtOAc, 85% EtOAc), the product was
3H). 13C NMR (101 MHz, DMSO-d6) δC [ppm] = 146.6 (+), 143.9 obtained in 95% yield. This compound has also been synthesized via
(Cq), 134.0 (Cq), 127.1 (+), 122.9(+), 121.9 (+), 121.2 (+), 118.3 the photoredox catalytic coupling reaction. Due to the very similar
(Cq), 111.3 (+), 110.5 (Cq), 107.8 (+), 36.6 (+). HRMS (ESI) (m/ work up and purification procedure, both methods provided this
z): [M + H]+ (C12H12N3) calcd: 198.1026, found: 198.1031. compound with similar purity. Therefore, see the photoredox
2-(1-Methyl-1H-pyrrol-2-yl)benzo[d]thiazole (3n): 53 The product catalytic coupling reaction in general procedure A for the
was obtained following general procedure A using 1n (33.9 mg, 0.2 characterization.
mmol, 1.0 equiv), Rh-6G (9.6 mg, 0.02 mmol, 10 mol %), 2a (355 6-(1-Phenyl-1H-pyrrol-2-yl)pyrimidine-2,4(1H,3H)-dione (4d).
μL, 4.0 mmol, 20 equiv), and DIPEA (52 μL, 0.3 mmol, 1.5 equiv). The product was prepared following general procedure B using 3d
After 20 h, 250 μL of a solution of the catalyst (c = 0.04 M, 5 mol (61.5 mg, 0.22 mmol, 1.0 equiv). After purification by automated
%) was added with a Hamilton syringe under exclusion of air. column chromatography (PE/EtOAc, 80% EtOAc), the product was
Subsequent to one FPT cycle, irradiation was continued. After 48 h, obtained as a white solid in 99% yield. 1H NMR (300 MHz, DMSO-
automated column chromatography (PE/EtOAc, 5% EtOAc) gave d6) δH [ppm] = 10.96 (s, 1H), 10.90 (s, 1H), 7.55−7.39 (m, 3H),
product 3n as a brown oil in 96% yield. 1H NMR (400 MHz, 7.37−7.30 (m, 2H), 7.25 (dd, J = 2.8, 1.7 Hz, 1H), 6.96 (dd, J = 3.9,
CDCl3) δH [ppm] = 7.98 (dd, J = 8.2, 0.6 Hz, 1H), 7.84 (dd, J = 1.7 Hz, 1H), 6.38 (dd, J = 3.9, 2.7 Hz, 1H), 4.68 (t, J = 1.8 Hz, 1H).
8.0, 0.6 Hz, 1H), 7.46 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 7.33 (ddd, J =
13
C NMR (75 MHz, DMSO-d6) δC [ppm] = 163.6 (Cq), 151.6 (Cq),
8.3, 7.2, 1.2 Hz, 1H), 6.86 (dd, J = 3.9, 1.7 Hz, 1H), 6.83 (t, J = 2.2 144.4 (Cq), 139.2 (Cq), 129.6 (+), 129.3 (+), 127.9 (+), 125.6 (+),
Hz, 1H), 6.24 (dd, J = 3.9, 2.6 Hz, 1H), 4.17 (s, 3H). 13C NMR 123.6 (Cq), 115.6 (+), 109.8 (+), 97.37 (+). HRMS (ESI) (m/z):
(101 MHz, CDCl3) δC [ppm] = 160.5 (Cq), 154.4 (Cq), 134.0 (Cq), [M + H]+ (C14H12N3O2) calcd: 254.0924, found: 254.0931.
128.1 (+), 126.6 (+), 126.0 (+), 124.5 (+), 122.5 (+), 121.2 (+), 6-(1-Benzyl-1H-pyrrol-2-yl)pyrimidine-2,4(1H,3H)-dione (4e). The
114.9 (+), 108.8 (+), 37.2 (+). HRMS (ESI) (m/z): [M]+• product was prepared following general procedure B using 3e (60.6
(C12H9N2S) calcd: 213.0481, found: 213.0480. mg, 0.21 mmol, 1.0 equiv). After purification by automated column
2-(1-Methyl-1H-pyrrol-2-yl)benzo[d]oxazole (3o): 53 The product chromatography (PE/EtOAc, 80% EtOAc), the product was obtained
was obtained following general procedure A using 1o (34.9 mg, 0.2 as a slightly brownish solid in 95% yield. 1H NMR (400 MHz,
mmol, 1.0 equiv), Rh-6G (9.6 mg, 0.02 mmol, 10 mol %), 2a (355 DMSO-d6) δH [ppm] = 10.94 (s, 1H), 10.80 (s, 1H), 7.35−7.28 (m,
μL, 4.0 mmol, 20 equiv), and DIPEA (52 μL, 0.3 mmol, 1.5 equiv). 2H), 7.28−7.21 (m, 1H), 7.17 (dd, J = 2.7, 1.8 Hz, 1H), 6.99−6.92
After 20 h, 250 μL of a solution of the catalyst (c = 0.04 M, 5 mol (m, 2H), 6.70 (dd, J = 3.9, 1.8 Hz, 1H), 6.23 (dd, J = 3.9, 2.7 Hz,
%) was added with a Hamilton syringe under exclusion of air. 1H), 5.36−5.30 (m, 3H). 13C NMR (101 MHz, DMSO-d6) δC
Subsequent to one FPT cycle, irradiation was continued. After 48 h, [ppm] = 163.8 (Cq), 151.5 (Cq), 144.5 (Cq), 138.2 (Cq), 128.6 (+),
automated column chromatography (PE/EtOAc, 5% EtOAc) gave 127.4 (+), 126.2 (+), 124.2 (Cq), 114.1 (+), 108.6 (+), 96.8 (+),
product 3o as a white solid in 55% yield. 1H NMR (300 MHz, 51.0 (−). HRMS (ESI) (m/z): [M + H]+ (C15H14N3O2) calcd:
CDCl3) δH [ppm] = 7.76−7.64 (m, 1H), 7.56−7.45 (m, 1H), 7.24 268.1081, found: 268.1090. mp = 219−223 °C.

■
(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) ASSOCIATED CONTENT
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 *
S Supporting Information
(+). HRMS (ESI) (m/z): [M + H]+ (C12H10N2O) calcd: 199.0866, The Supporting Information is available free of charge on the
found: 199.0867. mp = 85−90 °C. ACS Publications website at DOI: 10.1021/acs.joc.7b00088.
6-(1-Methyl-1H-pyrrol-2-yl)pyrimidine-2,4(1H,3H)-dione (4a).
The product was obtained following general procedure A using Optimization of reaction condition and 1H and 13
C
unprotected 6-chlorouracil 1a′ (29.3 mg, 0.2 mmol, 1.0 equiv), Rh- NMR spectra of all compounds (PDF)
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 %) was added with a
Hamilton syringe under exclusion of air. Subsequent to one FPT
■ AUTHOR INFORMATION
Corresponding Author
cycle, irradiation was continued. After 48 h, automated column
chromatography (PE/EtOAc, 80% EtOAc) gave product 4a as a *E-mail: Burkhard.König@ur.de.
white solid in 22% yield. 1H NMR (300 MHz, DMSO-d6) δH [ppm] ORCID
= 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 (dd, J = 3.9, 2.6 Hz, 1H), 5.56 (t, J = Burkhard König: 0000-0002-6131-4850
1.8 Hz, 1H), 3.73 (s, 3H). 13C NMR (75 MHz, DMSO-d6) δC Notes
[ppm] = 164.1 (Cq), 151.7 (Cq), 144.6 (Cq), 129.0 (+), 124.2 (Cq), The authors declare no competing financial interest.

■
113.4 (+), 108.0 (+), 96.6 (+),35.9 (+). HRMS (ESI) (m/z): [M +
H]+ (C9H10N3O2) calcd: 192.0768, found: 192.0773.
General Procedure B: Hydrolysis of Methoxy-Protected ACKNOWLEDGMENTS
Uracils. The hydrolysis of 3 was performed according to the
This work was supported by the Deutsche Forschungsge-
procedure described in the reference. A round-bottom flask was
charged with 3, which was then dissolved in a mixture of MeOH/ meinschaft DFG, (GRK 1626; Chemical Photocatalysis). We
HClconcd (25 mL, 1:1). The reaction mixture was heated to reflux thank Dr. Rudolf Vasold (University of Regensburg) for his
and stirred for 24 h. Subsequently, a saturated solution of Na2CO3 assistance in GC-MS measurements and Ms. Regina Hoheisel
(20 mL) was used to neutralize the acid, and water (10 mL) was (University of Regensburg) for her assistance in cyclic
added. After extraction with EtOAc (3 × 50 mL), the combined voltammetry measurements.
3559 DOI: 10.1021/acs.joc.7b00088
J. Org. Chem. 2017, 82, 3552−3560
The Journal of Organic Chemistry Article

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3560 DOI: 10.1021/acs.joc.7b00088

J. Org. Chem. 2017, 82, 3552−3560