Direct C-H photoarylation of diazines using aryldiazonium salts and visible-light

Article abstract of DOI:10.1039/d0ra06876d

In this study, direct C-H photoarylation of pyrazine with aryldiazonium salts under visible-light irradiation (blue-LEDs) is described, and additional examples including photoarylations of pyrimidine and pyridazine are also covered. The corresponding aryl-diazines were prepared in yields up to 84% only by mixing and irradiating the reaction with no need for an additional photocatalyst. We demonstrate the efficacy of this protocol by the scope with electron-donor, -neutral, and -withdrawing groups attached at the ortho, meta, and para positions of the aryldiazonium salts; the results are better than those reported for ruthenium-complex mediated photoarylations. Additionally, we demonstrate the robustness of this methodology with a 5 mmol scaled-up experiment. Mechanistic studies were carried out giving support to the proposal of a photocatalyzed approach by an electron donor-acceptor (EDA) complex, also highlighting the crucial role that solvents play in the formation of the EDA complex. This journal is

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Direct C–H photoarylation of diazines using
aryldiazonium salts and visible-light†
Cite this: RSC Adv., 2020, 10, 31115
Rodrigo C. Silva,
Lucas F. Villela,
Timothy J. Brocksom and Kleber T. de
*
Oliveira
In this study, direct C–H photoarylation of pyrazine with aryldiazonium salts under visible-light irradiation
(blue-LEDs) is described, and additional examples including photoarylations of pyrimidine and pyridazine
are also covered. The corresponding aryl-diazines were prepared in yields up to 84% only by mixing and
irradiating the reaction with no need for an additional photocatalyst. We demonstrate the efficacy of this
protocol by the scope with electron-donor, -neutral, and -withdrawing groups attached at the ortho,
meta, and para positions of the aryldiazonium salts; the results are better than those reported for
ruthenium-complex mediated photoarylations. Additionally, we demonstrate the robustness of this
methodology with a 5 mmol scaled-up experiment. Mechanistic studies were carried out giving support
to the proposal of a photocatalyzed approach by an electron donor–acceptor (EDA) complex, also
highlighting the crucial role that solvents play in the formation of the EDA complex.
Received 10th August 2020
Accepted 13th August 2020
DOI: 10.1039/d0ra06876d
rsc.li/rsc-advances
In 2006, Fagnou and co-workers reported a methodology for
the synthesis of a series of (N-hetero)bis-aryl scaffolds using
diazine N-oxides and aryl halides, catalyzed by palladium and
Introduction
The 1,n-diazines, such as pyridazines (n ¼ 2), pyrimidines (n ¼
3) and pyrazines (n ¼ 4), are six-membered aromatic rings
containing two nitrogen atoms. These building blocks are
electron-decient common N-heteroarenes present in natural
products,1–3 active pharmaceutical ingredients (APIs),4,5 agro-
chemicals,6 and functionalized materials.7,8 Arylated diazines
moieties can be found in many blockbuster drugs, such as
rosuvastatin (Crestor®), sildenal (Viagra®), and imatinib
(Gleevec®), besides others such as minaprine, gabazine, and
botryllazine (Fig. 1). Therefore, the development of methodol-
ogies for the formation of C–C bonds between aryl groups and
diazines is fundamental to the pharmaceutical industry, and
still a challenge for organic chemists.
Metal-catalyzed cross-coupling reactions have been widely
employed in the arylation of electron-decient N-heteroarenes,
mainly for the azines (pyridines and their derivatives).9–11 In
comparison with pyridines, the presence of a second N-atom in
the diazines decreases signicantly the electron density of these
compounds, which limits the use of such protocols.12 Typically,
metal-catalyzed protocols depend on either electrophilic
substitution or sequential metalation/deprotonation mecha-
nism, which restrict their application to only electron-rich
substrates or acidic C–H bond containing compounds,
respectively.13–15
copper complexes at high temperatures12 (Scheme 1, eqn (a)).
Other metals, including gold,16 nickel,13 and manganese17
were successfully applied to the cross-coupling between the aryl
halide or arylboronic acid and diazines. In 2010, Baran and co-
workers reported a silver-catalyzed Minisci-type reaction for the
arylation of azines and some diazines via radical coupling using
arylboronic acids, the silver salt, and potassium persulfate15
(Scheme 1, eqn (b)). Vishwakarma, Singh, and co-workers re-
ported a similar protocol for the arylation of pyrazines (1,4-
diazine) with a wide variety of arylboronic acids using an iron
complex18 (Scheme 1, eqn (c)). The same group, in 2016, also
reported a metal-free approach for this transformation, gener-
ꢀ
ating the aryl radical at 160 C (neat) in the presence of potas-
sium persulfate and the arylboronic acid (Scheme 1, eqn (d)).19
Xue and co-workers demonstrated that visible-light can be
employed in the arylation of diazines using a Ru(bpy)2Cl2
complex and aryldiazonium tetrauoroborate as the source of
aryl radicals (Scheme 1, eqn (e)).20
Herein, we report a protocol for the direct C–H photo-
arylation of pyrazine, pyrimidine, and pyridazine nuclei using
a variety of aryldiazonium salts substituted with electron-donor,
neutral and acceptor groups. Our methodology was developed
without additives such as strong oxidants nor additional pho-
tocatalysts; only the substrates, solvents, and visible-light irra-
diation (blue LEDs) were used. We postulate that the reaction
proceeds by a photoactive electron donor–acceptor (EDA)
complex between the diazines and the aryldiazonium salts, thus
´
˜
˜
Departamento de Quımica, Universidade Federal de Sao Carlos, Sao Carlos, SP,
13565-905, Brazil. E-mail: kleber.oliveira@ufscar.br
† Electronic supplementary information (ESI) available: 1H and 13C{1H} NMR
spectra, GC-MS and all the details of the homemade engineered batch
photoreactors. See DOI: 10.1039/d0ra06876d
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Fig. 1 Representative drugs containing diazine moieties.
allowing photocatalytic aryl radical generation and subsequent 3a in 43, 52, and 59%, respectively (Table 1, entries 3–5). Using
reaction with the diazines (Scheme 1, eqn (f)).
an excess of 2a instead of 1a allowed us to obtain 3a in only 2%
yield (Table 1, entry 6). Ruthenium-mediated photoarylation
reaction of diazines with aryldiazonium salts, reported by Xue
and co-workers,20 also required a relevant excess (10 equiv.) of
diazines for this transformation, suggesting that the use of
excesses of diazines are crucial in photoarylation protocols.
Consequently, further screenings of the reaction conditions
were performed with the use of 15 equiv. of 1a in comparison to
2a.
The increase of the irradiation time from 14 to 24 h did not
lead to better results (44% yield, Table 1, entry 7), while
a decrease of the yield (31%) was observed with 8 h of irradia-
tion (Table 1, entry 8). We have recently shown that protonated
pyridines can be efficiently employed in photoarylations by
EDA-complexes in water under visible-light irradiation.21
Therefore, we decided to test the use of pyrazine hydrochloride
(1b) (1.5 mmol) in water. In these conditions, 3a was obtained in
8% yield (14 h, Table 1, entry 9). However, an excellent result
was obtained using DMSO as the solvent, giving 3a in 81% yield
(78% isolated yield) under the same reaction conditions (Table
1, entry 10).
Results and discussion
Initially,
pyrazine
free
base
(1a)
and
p-methox-
ybenzenediazonium tetrauoroborate (2a) were selected as
model substrates. A homemade blue LED (120 W) photoreactor
was used and the setup was equipped with a control system
(Arduino) to monitor both irradiation time and the internal
temperature of the photoreactor (details of the photoreactor
and control system are shown in the ESI, Fig. S2–S4†). The
reaction between (1a) (0.75 mmol) and (2a) (0.1 mmol) in water
(0.6 mL) was tested under an oxygen atmosphere in the absence
ꢀ
of light at 40 C, thus furnishing 2-(4-methoxyphenyl)pyrazine
(3a) as traces (2% of yield) aer 14 h (Table 1, entry 1). Subse-
quently, the product (3a) was obtained in 20% yield under blue
ꢀ
LED irradiation (14 h) at 33 C (temperature controlled photo-
reactor), thus suggesting that this transformation is potentially
photoinduced (Table 1, entry 2).
Attempts to improve the protocol efficiency were tested using
15, 25, and 30 equiv. of 1a in comparison to 2a, thus obtaining
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literature such as N,N-dimethylaniline,24 triethylamine,25 1,3,5-
trimethoxybenzene (TMB),26 and pyridine.27 Thus, the photo-
arylation of pyrazine hydrochloride (1b) with p-methox-
ybenzenediazonium tetrauoroborate (2a) was carried out
using TMB or pyridine as sacricial donors. However, product
3a was obtained in 28 and 33% yields, respectively (Table 1,
entries 15 and 16).
Subsequently, the effect of the temperature was evaluated.
The photoarylation of 1b with 2a was carried out at ꢁ22 ꢀC
using a mixture of DMSO and acetonitrile to avoid the freezing
of DMSO. The yields were 51 and 54% for the mixtures of
DMSO/acetonitrile (1 : 1) and (3 : 1), respectively (Table 1,
entries 17 and 18). These results are superior to those per-
formed with DMSO/acetonitrile (1 : 1) at 33 ꢀC (44% yield, Table
1, entry 12), but not better than when pure DMSO at 33 ꢀC was
used (81%, Table 1, entry 10). The improvements in these
photoarylations at low temperatures have already been
demonstrated28 since this increases the excited-state lifetime of
the EDA complexes. However, a limitation of using only DMSO
(mp ¼ 19 ꢀC) as an optimal solvent in this protocol restricts the
use of low temperatures.
Since the mixture between molecular oxygen and DMSO has
been proved by Liu and co-workers29 to be an efficient radical
oxidative reagent under thermal conditions (high tempera-
tures), we decided to evaluate if DMSO + O2 exerts inuence and
can also justify the high efficiency of DMSO as solvent in our
photocatalyzed protocol. Therefore, the background reaction
was tested in the dark, maintaining all the optimized reaction
conditions between 1b and 2a at 40 ꢀC; in these conditions, the
product 3a was obtained in only 9% yield (Table 1, entry 19). The
requirement of an O2 atmosphere was also evaluated. The
DMSO solution was sonicated and purged with an argon
atmosphere for 30 min and the reaction was performed under
the optimized conditions, giving 3a in 66% yield (Table 1, entry
20). Additionally, the crude reaction product 3a obtained as
described in entry 10, Table 1 was carefully analysed by GC-MS
with no evidence of dimethylsulfone formation as veried in
Liu's protocol. With all these results in hand, we have no
evidence that the exceptional efficiency of DMSO as solvent is
due to the radical oxidant power of DMSO + O2. Thus, we have
proved the necessity of light to promote the reaction and
postulate that the inuence of DMSO is related to the formation
of photoactive intermediates or their excited states.
Finally, the robustness of the methodology was evaluated
under the optimized conditions (Table 1, entry 21) using 2a in
5 mmol scale, thus obtaining 3a in 74% yield (0.7 g).
Then, we used the optimized protocol (Table 1, entry 10) to
explore the scope and limitations of these photoarylations. A
variety of aryldiazonium salts with different substitution
patterns was evaluated, together with substituted pyrazines and
other diazines, such as pyrimidine (1,3-diazine) and pyridazine
(1,2-diazine) (Scheme 2).
Scheme 1 Representative protocols for C–H arylation of 1,n-diazines.
Continuing with our evaluation of solvents, the low solubility
of pyrazine hydrochloride limited the choice to DMF and
a mixture of DMSO with acetonitrile (1 : 1), thus giving 3a in 9
and 44% yields, respectively (Table 1, entries 11 and 12).
Attempts to generate the pyrazinium cation in situ starting from
1a were carried out using p-toluenesulfonic acid as the proton
source. However, a slight reduction in the yields was observed
when 15 and 20 equiv. of PTSA were used (65 and 66% yield,
Table 1, entries 13 and 14, respectively).
Considering the possibility of an EDA mechanism, the low
electron density of the diazines reduces their ability as donor
species. One strategy much employed to avoid this limitation is
to use sacricial donor compounds that promote the efficient
The protocol afforded yields between 71% (4-methyl-
benzenediazonium) and 75% (4-ethyl-benzenediazonium) for
alkyl electron-donor groups (Scheme 2, 3o and 3g, respectively)
and 72% for the neutral group H (benzenediazonium, Scheme
2, 3l), which are very close to the optimized reaction model (4-
formation of the EDA complex with the acceptor species.22,23
A
variety of sacricial donor compounds have been used in the
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Table 1 Screening of the reaction conditionsa
Entry
Pyrazine (mmol)
2a (mmol)
Solvent
Additive
Light
Temp. (ꢀC)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
1a (0.75)
1a (0.75)
1a (1.5)
1a (2.5)
1a (3.0)
1a (0.3)
1a (1.5)
1a (1.5)
1b (1.5)
1b (1.5)
1b (1.5)
1b (1.5)
1a (1.5)
1a (1.5)
1b (1.5)
1b (1.5)
1b (1.5)
1b (1.5)
1b (1.5)
1b (1.5)
1b (75)
0.1
0.1
0.1
0.1
0.1
0.6
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
5.0
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
—
—
—
—
—
—
—
—
—
—
—
—
Dark
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Dark
Blue
Blue
40
33
33
33
33
33
33
33
33
33
33
33
33
33
33
33
ꢁ22
ꢁ22
40
33
33
14
14
14
14
14
14
24
8
14
14
14
14
14
14
14
14
14
14
14
14
14
2
20
43
52
59
2
44
31
9
H2O
DMSO
DMF
DMSO : CH3CN (1 : 1)
DMSO
DMSO
DMSO
DMSO
DMSO : CH3CN (1 : 1)
DMSO : CH3CN (3 : 1)
DMSO
DMSO
DMSO
8
10
11
12
13
14
15
16
17d
18d
19
20e
21
81 (78)c
9
44
65
66
28
33
51
54
PTSA (15 equiv.)
PTSA (20 equiv.)
TMB (2 equiv.)
Pyridine (2 equiv.)
—
—
—
—
—
9
66
74 (0.7 g)
a
Reaction conditions: pyrazine free base (1a) (0.3, 0.75, 1.5, 2.5, 3.0 mmol), p-methoxybenzenediazonium tetrauoroborate (0.1, 0.2, 0.6 mmol), in
solvent (0.6 mL) at temperature (ꢁ22, 33, 40 ꢀC) under an O2 atmosphere for 14 or 24 h. Yield determined by 1H NMR using 1,3,5-
b
c
d
trimethoxybenzene as an internal standard. Isolated yield obtained in triplicate (average). Reaction performed inside a freezer at ꢁ22 ꢀC.
e
Solvent was previously deoxygenated and maintained under an argon atmosphere.
OMe-benzenediazonium, 3a, 78% isolated yield, Scheme 2). both C-6 and C-3 positions (1 : 1.4 ratio) and 41% overall yield.
Electron-withdrawing groups present in aryldiazonium salts at Pyrimidine 1d also afforded a regioisomeric mixture aer the
the 4-position (Cl, F, NO2) also gave the corresponding products photoarylation with 2a giving 3w in 69% overall yield (C-2 : C-4
(3p, 3d, and 3j) in similar yields (75, 72 and 60% yields, in 1 : 3.4 ratio), and pyridazine 1f yielded 3x (84% overall yield,
respectively). However, the expected product 3t was not ob- isomeric mixture, C3 : C4 in 1 : 1.8 ratio).
tained when the reaction was performed with 4-
Thus, we have established a protocol for photoarylations of
(dimethylamino)-benzenediazonium salt (2t). Similar results pyrazines with aryldiazonium salts. Reactions involving photo-
were observed for the photoarylation of azines using both arylations of pyrimidines, and pyridazines are also demon-
catalyst-free21 and metal-catalysis30 approaches, suggesting that strated making this protocol valuable. The reactions are all
the salt 2t is inappropriate for radical C–H arylation protocols. promoted by visible-light and do not require additional photo-
The s-acceptor group (CF3) in the meta-position of the diazo- catalysts, metals, additives or high temperatures, occurring via
nium salt 2m also gave the respective product 3m in a similar an electron donor–acceptor (EDA) complex, as evidenced below.
yield (74%), however, the CF3 group at ortho-position 2n gave
the corresponding product in only 15% yield. In general, all the
products from ortho-substituted diazonium salts were obtained
in very low to moderate yields (5–45% yields for 3c, 3f, 3i, 3n, 3r
and 3s) regardless of the electronic nature of the substituent in
the diazonium salts. These last results suggest that besides the
electronic effect, the steric effect is also important for this
protocol and, overall, the yields were superior for para-
substituted aryldiazonium salts followed by meta- and ortho-
positions. Finally, the substituted pyrazine 1c was also reacted
with 2a giving a regioisomeric mixture (3v) with arylation in
Mechanistic considerations
In our previous studies on direct C–H photoarylation of pyridine
hydrochlorides with aryldiazonium salts, an EDA complex was
proposed for the photocatalytic step.21 The crucial step involves
the formation of an aryl radical through a single-electron
transfer (SET) process in the excited state of a photoactive
EDA complex, which is formed between the pyridine free-base
and the aryldiazonium salt. Therefore, we propose that
a similar mechanism also operates for the direct C–H photo-
arylation of diazines.
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Scheme 2 Scope and limitation of the reaction. aReaction conditions: pyrazine hydrochloride (1b–1f, 7.5 mmol), aryldiazonium salt (2a–2u, 0.5
mmol) in DMSO (3 mL) at 33 ꢀC under an O2 atmosphere and blue LEDs (120 W) for 14 h. Isolated yield after column chromatography.
Initially, the reaction was performed in the presence of 2 the activated pyrazine (1b) is favored, similarly to the proposed
equiv. of the radical scavenger 2,2,6,6-tetramethyl-1- in our pyridine hydrochloride approach.21 On the other hand,
piperidinyloxy (TEMPO), using the optimized conditions. In for the EDA complex formation, an electron donor specie in
this case, the pyrazine free base 1a was used instead of its solution such as 1a is necessary, which is possible due to the
hydrochloride 1b (pKaH ¼ 0.6)31 to avoid the well-known acid- acid–base equilibrium between 1b and 1a.
promoted disproportionation reaction of TEMPO.32 In these
Intriguingly, the reaction between 2a and 1a (free base) or 2a
conditions, the TEMPO-trapped-O-aryl adduct was detected by and 1b (hydrochloride), using water as the solvent did not
GC-MS, supporting the photocatalyzed aryl radical generation furnish satisfactory yields (20–59%). However, excellent results
(Fig. S6, ESI†). Indeed, the use of pyrazine hydrochloride (1b) in were obtained when DMSO was used (up to 81%, Table 1, entry
the optimized protocol proved to be crucial for the efficiency of 10) which supports the idea and the importance of the equi-
the reaction, and we postulate that the aryl radical addition to librium between 1b and 1a depending on the solvent. In this
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Fig. 2 UV-Vis absorption spectra of 1b (1.5 mmol), 2a (0.1 mmol), the mixture of 1b with 2a, and the difference of the mixture with 1b and 2a in (A)
DMSO and (C) H2O. UV-Vis absorption spectra of 1a (1.5 mmol), 2a (0.1 mmol), the mixture of 1a with 2a, and the difference of the mixture with 1a
and 2a in (B) DMSO and (D) H2O.
case, the lower dielectric constant of DMSO probably reduces process. Thus, the last challenge on this mechanism would be
the ionization of 1b, and simultaneously allow an ideal to prove the EDA complex formation in solution.
concentration of protonated pyrazine 1b (radical addition step)
Typically, the EDA complex presents a strong colored solu-
and free base 1a (EDA complex formation step) to favor the role tion aer mixing two non-colored compounds, thus
Scheme 3 Proposed mechanism for the visible-light mediated C–H direct arylation of diazines with aryldiazonium salts.
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´
characterized by the appearance of a charge-transfer (CT) Aperfeiçoamento de Pessoal de Nıvel Superior – Brasil (CAPES) –
absorption band.21,22,27 The UV-Vis experiments were carried out Financial Code 001, for the nancial support. The authors also
in water and DMSO using p-methoxybenzenediazonium tetra- thank Prof. Dr Moacir R. Forim and Luciano da S. Pinto for
uoroborate (2a) with both pyrazine hydrochloride (1b) and HRMS measurements.
pyrazine free base (1a), respectively (Fig. 2). The UV-Vis spectra
obtained for 1b, 2a, and their mixtures in DMSO, showed that
no evident new CT band was observed in the tested concen-
trations (Fig. 2A). Conversely, a new band was clearly detected at
Notes and references
428 nm for the mixture between 1a and 2a in DMSO (Fig. 2B),
proving the formation of an EDA complex. In water, no CT band
was observed between 2a and 1a or 1b (Fig. 2C and D), sug-
gesting that the EDA concentration in water, even using 1a (free
base) is really low, thus justifying the lower efficiency of the
protocol in this solvent. Overall, these results corroborate with
the proposal of an equilibrium between the protonated pyrazine
1b and the free base form 1a, while both species are important
in the catalytic cycle, being 1a critical for the EDA complex
formation, and 1b a reactive starting material for the posterior
aryl radical attack (Scheme 3). To complete the catalytic cycle,
we suggest that the radical intermediate can be oxidized to the
corresponding arylated pyrazine by molecular oxygen (path a) or
by another aryldiazonium salt molecule (path b), as we have
shown that the removal of molecular oxygen from the reaction
mixture caused a slight reduction in yields, but did not
completely inhibit the reaction (Scheme 3).
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¨
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´
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Conflicts of interest
There are no conicts to declare.
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The authors would like to thank the Sao Paulo Research
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