Photoredox synthesis of functionalized quinazolinesviacopper-catalyzed aerobic oxidative Csp2-H annulation of amidines with terminal alkynes

Article abstract of DOI:10.1039/d1gc01493e

We have developed a visible light-induced photo-redox copper-catalyzed oxidative C_sp2-H annulation (Friedel-Crafts-type cyclization) of amidines with terminal alkynes at room temperature to synthesize functionalized quinazolines. We report copp

Full text of DOI:10.1039/d1gc01493e

Showcasing research from Prof. K. C. Hwang's laboratory,
Department of Chemistry, National Tsing Hua University,
Taiwan.
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Photoredox synthesis of functionalized quinazolines via
Chemistry
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copper-catalyzed aerobic oxidative Csp –H annulation of
Cutting-edge research for
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amidines with terminal alkynes
We are presenting a simple, inexpensive CuCl catalyzed
C–H annulation of amidines with terminal alkynes to form
functionalized quinazolines at room temperature. This
photochemical method is a mild process, highly efficient, and
practically applicable to the synthesis of anticancer agents.
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Photoredox synthesis of functionalized
quinazolines via copper-catalyzed aerobic
oxidative Csp2–H annulation of amidines with
terminal alkynes†
Cite this: Green Chem., 2021, 23,
5024
Received 29th April 2021,
Accepted 16th June 2021
DOI: 10.1039/d1gc01493e
Vaibhav Pramod Charpe, ‡ Ayyakkannu Ragupathi,‡ Arunachalam Sagadevan
rsc.li/greenchem
and Kuo Chu Hwang
*
We have developed a visible light-induced photo-redox copper- (with a high E-factor), and (d) harsh reaction conditions. Thus,
catalyzed oxidative Csp2–H annulation (Friedel–Crafts-type cycliza- the development of simple copper-catalyzed C–H annulation
tion) of amidines with terminal alkynes at room temperature to reactions using molecular oxygen as an oxidant at room temp-
synthesize functionalized quinazolines. We report copper(I)-phe- erature and under low energy visible light irradiation is highly
nylacetylide catalyzed photo-oxidative Csp2–H annulation of ami- desirable and very challenging.
dines at RT, which is very challenging and complementary to the
The use of visible light photo-redox catalysis (PRC) in
conventional transition metal-catalyzed thermal annulation reac- organic synthesis has dramatically upsurged in recent years.
tions. We have demonstrated the application of this method by Recently, copper complexes have emerged as an inexpensive
synthesizing anti-cancer compounds. Moreover, green chemistry and appealing complement to expensive conventional PRC
metrics (the E-factor is ∼1.9 times better than that of the reported (i.e., Ru or Ir-complexes)3 for various organic cross-couplings
thermal method) and Eco-Scale (scales 55.4, which shows an (C–C, C–N) and C–H functionalization reactions under visible
acceptable synthesis) evaluations show that this method is eco- light irradiation. In this regard, our group has demonstrated
friendly and environmentally feasible.
the visible light-induced and inexpensive Cu(I) phenylacetylide
(in situ generated photocatalyst)-catalyzed C–C, C–N/O coup-
ling reactions and C–H annulation reactions.4 Besides, copper
photocatalysis has been proven to follow the principles of
green chemistry.3b,d,4 Most of the literature reported that
photocatalysis reactions use expensive transition metal-con-
taining photocatalysts, along with specially designed ligands,
and an excess amount of organic oxidants, which leads to an
increase in the amount of waste and the cost of the reaction.
Thus, the use of all these reactants adversely affects the
ecology, the environment, or the ecosystem. Therefore, it is
important to develop an external photocatalyst-free green syn-
thetic process which follows the guidelines of green chemistry.
Herein, we report the visible light-initiated copper-catalyzed
oxidative Csp2–H annulation of amidines with terminal alkynes
to form 2,4-disubstituted quinazolines using molecular O2 as
an oxidant at RT (Scheme 2, eqn (b)). In the current discovery,
the copper ion forms a complex with the coupling partner
(terminal alkyne) rather than the substrate (amidines), which
is opposite to the traditional TMC thermal annulation reac-
tions (Scheme 1, eqn (1a) and (1b)).
Over the past few decades, transition metal-catalyzed (TMC) C–
H functionalization/C–H annulation has emerged as a sustain-
able and powerful method in organic synthesis, with extensive
applications in chemical biology, materials sciences and
pharmaceutical chemistry.1 In this instance, expensive noble
metal catalysts, such as palladium, ruthenium, and rhodium
complexes, have played major roles in C–H functionalization
via metal-chelated C–H insertion (activation).2 Owing to its
abundance on the Earth and inexpensiveness, copper catalysts
are particularly attractive for C–H alkenylation, alkynylation,
and amination of arenes via two-electron or single electron
processes (SET).2 Despite this, thermal TMC C–H annulation
reactions share some common drawbacks, such as; (a) the use
of expensive precious metal catalysts; (b) tedious processes
and the use of toxic reagents; (c) the use of excess amounts of
oxidants, such as peroxides, Selectfluor, PhI(OAc)2, MnO2, and
K2S2O8, thus leading to the generation of undesired waste
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan, Republic
of China. E-mail: kchwang@mx.nthu.edu.tw; Fax: (+886)35711082
†Electronic supplementary information (ESI) available. CCDC 2003605, 2003606,
2003609, 2003610, 2003611 and 2006219. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/d1gc01493e
Quinazolines are a vital class of fused heterocycles as they
are widely present in natural products and synthetic pharma-
ceutical compounds and thus have been extensively investi-
gated for therapeutic activities5 such as anticancer,5a,d,6 anti-
viral7 and antitubercular activities.8 Therefore, the synthesis of
‡These authors contributed equally to this work.
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quinazolines under visible light irradiation. The significant
features of our finding include: (a) the synthesis of 2,4-di-
substituted quinazolines at RT by simultaneous C–C and CvN
bond formation; (b) products are applicable for the further
synthesis of anticancer compounds in few steps; (c) the reac-
tion uses simple CuCl as a catalyst and O2 as an oxidant under
mild reaction conditions without the need for complicated
ligands; (d) a simple reaction setup, and water was produced
as the only by-product; (e) the green metrics and Eco-Scale
evaluations signify that the current photochemical process is
simple, cost-effective and environmentally benign.
In the initial experiment, 4-chloro-N-phenylbenzimidamide
(1a) and phenylacetylene (2a) were used as the standard sub-
strates (Table 1). Initially, the reaction of 1a with 2a in the pres-
ence of CuCl (5 mol%), K2CO3 (1.2 equiv.), and O2 in MeOH
afforded the product 3a in 64% yield upon 18 h irradiation
(entry 1, Table 1). Next, solvents such as ACN, DCM, DCE, and
THF were screened. However, only trace amounts of products
were formed in these solvents. Thus, mixed solvents were
employed for further optimization. Surprisingly, the reaction
in an ACN–MeOH (1 : 1) co-solvent formed the intermediate 3a′
and product 3a in 22% and 41% yield, respectively. The above
Scheme 1 Transition metal-catalyzed C–H annulation reactions.
Table 1 Optimization of reaction conditionsa
Entry [Cu] catalyst
Base
Solvent
Yieldb [%]
Scheme 2 Transition metal-catalyzed synthesis of quinazolines.
1
2
3
4
5
6
7
8
CuCl
CuCl
CuCl
CuCl
CuCl
CuBr
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
None
CuCl
CuCl
CuCl
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
tBuOK
K2CO3
K2CO3
K2CO3
K2CO3
None
MeOH
ACN : MeOH (1 : 1)
64 (18 h)
41 (22) (18 h)
DCM : MeOH (1 : 1) 58 (18) (18 h)
DCM : MeOH (1 : 1) 66
DCM : MeOH (2 : 1) 76
DCM : MeOH (2 : 1) 68
DCM : MeOH (2 : 1) 71
DCM : MeOH (2 : 1) 70
DCM : MeOH (2 : 1) 64
DCM : MeOH (2 : 1) 53
DCM : MeOH (2 : 1) 73
DCM : MeOH (2 : 1) 27 (14)
DCM : MeOH (2 : 1) n.r.
quinazolines has grabbed great attention for years, and
various powerful methods have been developed, including
transition metal9,10 and metal-free11 catalyzed thermal reac-
tions. Despite all these indisputable advances, thermal metal/
metal-free catalyzed methods have common drawbacks, such
as (a) the use of expensive metal catalysts; (b) high temperature
and harsh reaction conditions; (c) the use of excess ligands
and organic oxidants; (d) generation of toxic byproducts and
huge amounts of reaction waste, thus adding a heavy burden
to the environment.
9
10c
11d
12e
13f
14g
15h
16i
DCM : MeOH (2 : 1)
DCM : MeOH (2 : 1) n.r.
DCM : MeOH (2 : 1)
0
K2CO3
K2CO3
0
Given the fact that amidines have been widely used as start-
ing materials in metal-catalyzed thermal reactions to construct
heterocycles, Neuville’s group reported the thermal-mediated
copper(II)-catalyzed regioselective addition of terminal alkynes
to aniline nitrogen, followed by the 5-endo-dig cyclization
process to generate imidazoles12a (not quinazolines)
(Scheme 1c, A), while L. Ackerman’s group reported the syn-
thesis of isoquinolines from amidines and diazo12b com-
pounds, where only one NH was involved in the cyclisation12a,c
(Scheme 1c, B). In contrast, our work uses amidines to form
a Unless otherwise noted, reaction conditions are as follows; 1a
(0.2 mmol), 2a (0.4 mmol), [Cu] catalyst (5 mol%), base (1.2 equiv.),
and solvent (6 mL). The mixture was irradiated with blue LEDs (power
density: 40 mW cm−2 at 460 nm) for 22 h in O2 (1 atm). All light reac-
tions were conducted in an air-conditioned room with a cooling fan
around blue-LED’s to maintain the reaction temperature within
25–28 °C. b Yield of the isolated product. The value in brackets denotes
the yield of intermediate 3a′. c 0.5 mL of water was added. d In the pres-
ence of air (1 atm.). e Reaction irradiated with an ambient white light
bulb for 40 h (power density: 8 mW cm−2 at 460 nm). f In the absence
of the [Cu] catalyst. g In the absence of the base. h In the absence of O2.
i Reaction conducted in the dark at 60 °C. n.r. = no reaction.
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Table 3 Substrate scope of N-arylbenzimidamide with terminal
alkynesa
results indicate that the intermediate 3a′ upon further photo-
irradiation will be transformed to the product 3a.
Further investigation revealed that the solvent composition
and irradiation time played a crucial role in the formation of
product 3a in good yield (entries 3–5, Table 1). The product 3a
was obtained in a good yield of 76% in DCM : MeOH (2 : 1)
upon 22 h irradiation. Among the bases examined, K2CO3 was
found to be more efficient for the formation of 3a (entries
7–9). Further optimization investigations demonstrate that
CuCl, K2CO3, O2, and visible light are essential for the for-
mation of the product in good yield (entries 13–16, Table 1). In
all the above reactions, ∼10–15% of the alkyne homocoupling
product4g was observed.
Under the optimized conditions, we then investigated the
scope of amidine derivatives and terminal aromatic alkynes
(Tables 2 and 3). Various aryl/heteroaryl amidine and aryl/
hetero aryl alkyne derivatives with electron neutral, donating
and withdrawing groups, including halogen (I, Br, Cl, and F)
substituted groups, were all well tolerated by the current oxi-
dative annulation reaction to form quinazoline products (3a–
3p and 4a–4s) in moderate to good yields. Notably, substrate
(1p) selectively forms the product (3p) without forming other
Table 2 Substrate scope of N-arylbenzimidamidea
a Standard reaction conditions. Isolated yields after purification by
column chromatography on silica gel.
isomers. However, substrates, such as N-phenylpropionimi-
damide (1q) and N-(pyridin-2-yl) benzimidamide (1r), did not
work in the current protocol. The reason for these incompati-
ble substrates is not clear. The structures of 3e, 3i, 4c, 4i, and
4o were confirmed by single crystal X-ray diffraction.21
Subsequently, we turned our attention to the variation of
amidines with aliphatic terminal alkynes (Table 4). To our sur-
prise, when 1b reacted with 1-hexyne under standard reaction
conditions, we observed the product 4-pentyl-2-phenylquinazo-
line (5a) in a low yield of 31%, instead of oxidized product 5a′.
Also, other amidine derivatives (1a, 1f, and 1i) reacted with
long-chain aliphatic terminal alkynes to generate the products
5b–5d in low yields. Unfortunately, other aliphatic terminal
alkynes did not work well with the photo-oxidative annulation
reaction. The reason for the formation of unoxidized products
(5a–5d) could be well explained based on the Cu-superoxo
chemistry. CuCl reacts with O2 to form Cu-superoxo, which
a Standard reaction conditions. Isolated yields after purification by
column chromatography on silica gel.
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Table 4 Substrate scope of N-arylbenzimidamide with aliphatic term-
inal alkynesa
Table 5 Synthesis of anti-cancer compoundsa
a Standard reaction conditions. Isolated yields after purification by
column chromatography on silica gel.
a Standard reaction conditions. Isolated yields after purification by
column chromatography on silica gel.
further oxidizes the benzylic CH2 (intermediate 3a′) to form
the oxidized product.13 The C–H bond dissociation energy for
the benzylic CH2 (∼90.0 kcal mol−1) is less than that of the ali-
phatic chain –CH2 (∼100.0 kcal mol−1).14 Thus, the further oxi-
dation of benzylic CH2 is thermodynamically favored.
Table 6 Evaluation of green chemistry metrics for the synthesis of 3a
Furthermore, to demonstrate the application of this photo-
oxidative Csp2–H annulation reaction, some anti-cancer com-
pounds were prepared by late-stage functionalization of com-
pounds (3b, 3n, 4f, and 4s). Compounds 3b, 3n, 4f, and 4s
were subjected to further reaction with methyl magnesium
bromide to form the products 6, 7, 8, and 9, respectively, in
excellent yields (Table 5). Compounds 8 and 9 are known to
have excellent anti-proliferative (anti-cancer) activities.15 The
IC50 values15 are 0.40 μM and 0.035 μM for compounds 8 and
9, respectively. It is important to note that these anti-cancer
compounds were prepared in a total of 3 steps using the
current photoredox protocol (starting from commercially avail-
able substrates), which is far better than the reported 6-step
thermal reactions16 (see the ESI†).
Finally, to demonstrate the practicality and efficiency of this
photo-oxidative annulation reaction, a gram reaction was per-
formed. The reaction of 4-chloro-N-phenylbenzimidamide (1a,
1.15 g, 5.0 mmol) with 2a (9.8 mmol) in the presence of CuCl,
K2CO3, and O2 under photoirradiation for 24 h was performed
to generate 0.98 g of product 3a (56.8% yield). We have also
evaluated the green chemistry metrics,4c,f,h,13 and the Eco-
Scale13 value for this photo-oxidative annulation reaction on a
preparative scale for the synthesis of 3a. The green chemistry
metric evaluation for the current green process has an E-factor
of 20.18, 98.8% atom economy, 56.1% atom efficiency, 100% table green synthesis process (Table 7). In addition, we have
carbon efficiency and 45.6% reaction mass efficiency (Table 6). also calculated (3.0 mmol scale reaction) and compared the
The Eco-Scale value for the current photo-oxidative annulation green chemistry metrics of the current photochemical reaction
reaction is 55.4 on the scale of 100, which indicates an accep- and literature reported thermal method9a for the synthesis of
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Table 7 Eco Scale calculation for the synthesis of 3a
Scheme 3 Mechanistic investigations.
solid. This suggests that the in situ generated Cu(I)-phenylace-
tylide might be the key light-absorbing photocatalyst respon-
sible for this annulation reaction. When the above reaction
was carried out under an N2 atmosphere, no product (3a) was
obtained (Scheme 3, eqn (a)). Next, when the standard reaction
was conducted in the presence of a radical scavenger TEMPO
(2,2,6,6-tetramethylpiperidine1-oxyl) for 15 h, no product (3a)
was obtained, indicating that the current annulation reaction
is likely to proceed via a radical pathway (Scheme 3, eqn (b)).
compound 4e. Their green chemistry metrics values are tabu- Also, to detect the source of the O-atom in the product, reac-
lated in Table S3 (see detailed evaluation in the ESI†). The tions were carried out in the presence of 18O2 gas (instead of
results show that the green chemistry metrics values of the 16O2) (Scheme 3, eqn (c)) and in the presence of 0.2 mL of
current photochemical protocol are better than those for the H218O (Scheme 3, eqn (d)) for 14 h under standard reaction
literature reported thermal method, especially, the E-factor (an conditions. The results indicated that the O-atom in the
important physical parameter of green synthetic chemistry) of product is solely from the molecular oxygen (O2).
the current photochemical process is ∼1.9 times better than
Based on these above mechanistic investigations and our
that of the thermal method.9a Besides, we have also evaluated previous mechanistic studies,4 a possible reaction mechanism
the Eco-Scale for the current photochemical method and a lit- is depicted in Scheme 4. Under visible light irradiation, in situ
erature reported thermal method9a for the synthesis of com- generated Cu(I)-phenylacetylide (A) (λmax = 472 nm) absorbs
pound 4e. The Eco-Scale value of the current photochemical blue light and becomes photochemically excited triplet state B
method is within an acceptable level, and is better than that of (a long-lived triplet lifetime, τ = 15.95 μs).4,17 This photoexcited
the literature procedure, the Eco-Scale value of which is at an state B then undergoes a SET process by donating an electron
inadequate level (see detailed evaluation in the ESI†). Thus, to molecular O2 and generates a Cu(II) complex, C, as well as a
the current synthetic organic reaction is simple, ecofriendly, superoxide anion radical.18 EPR experiments19 confirm the for-
and highly efficient.
mation of the superoxide anionic radical (see the ESI†). Also,
To obtain mechanistic insights into the current photo-oxi- the formation of complexes A, B, and C was supported by
dative annulation reaction, various control reactions were per- theoretical calculation studies reported by W. Thiel et al.20
formed (Scheme 3). First, the reaction of 1a was carried out
In the next stage, the basic nature of the copper-superoxo
with pre-synthesized Cu(I)-phenylacetylide (2a′) powder in the radical anion has propensity to abstract acidic NH proton 1a to
absence of CuCl and in the presence of a base for 20 h under form a nitrogen-centered radical, which further reacts with Cu
photo-irradiation, which led to the formation of product 3a in (II)-phenylacetylide complex C and forms CuIII-complex species
56% yield. This decrease in yield is due to the polymeric form D. This intermediate CuIII-complex D undergoes reductive
(and thus poor dispersion) of the Cu(I)-phenylacetylide (2a′) elimination and generates Cu(I)-coordinated ynamine inter-
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reported thermal method. Eco-Scale evaluation for this syn-
thetic C–H annulation reaction scales 55.4 on the scale of
0–100 and indicates that it is an acceptable organic synthesis
from the safety, cost, and environmental points of view.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We are grateful to the Ministry of Science and Technology,
Taiwan for financial support. We also thank Dr Hsin-Ru Wu of
the Instrumentation Center of National Tsing Hua University
for HRMS measurements.
Notes and references
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Scheme 4 Proposed reaction mechanism.
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cyclization (6-exo-dig cyclization) to form cyclized intermediate
F and subsequent aromatization to form compound G, which
upon photo-oxidation by Cu(II) superoxo (λabs = 486 nm)13
forms product 3b.
Conclusions
In summary, we have developed a photo-oxidative copper-cata-
lyzed Csp2–H annulation of amidines with terminal alkynes to
form functionalized quinazolines at RT, which achieves simul-
taneously C–C and CvN bond formation and shows a totally
different reaction mechanism from conventional transition
metal-catalyzed thermal annulation reactions. Overall, 46
examples were presented. This reaction could achieve a gram
scale synthesis of functionalized quinazolines using a simple
reaction setup, commercially available substrates, low energy
visible light, inexpensive CuCl as a catalyst, and O2 as an
oxidant under mild reaction conditions. Water is the only
byproduct in the reactions. This method is also applicable for
the synthesis of anticancer compounds in overall 3 steps from
simple commercially available starting materials, far better
than a total of 6 steps in literature reported methods.
Moreover, the current protocol does not require the use of any
expensive, toxic external photocatalyst or organic oxidants, and
thus is simple and cost-efficient. In addition, the current
method does not produce any harmful byproducts which are
toxic to the environment or the ecosystem. Also, green chem-
istry metric calculation shows that the E-factor for the current
green organic reaction is ∼1.9 times better than that of the
3 Selected reviews on visible light induced C–C and C–N
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5030 | Green Chem., 2021, 23, 5024–5030
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