Copper-Catalyzed One-Pot Synthesis of 3-(N-Heteroarenyl)acrylonitriles through Radical Conjugated Addition of β-Nitrostyrene to Methylazaarenes

Article abstract of DOI:10.1002/ejoc.202000673

A simple procedure for the copper-catalyzed synthesis of 3-(N-heteroaryl)acrylonitriles was developed. Using a combination of Lewis and Br?nsted acids, this one-pot procedure undergoes via a radical conjugated addition and dehydration processes, without isolation of any intermediate, affording the acrylonitriles. This diastereoselective approach allowed the synthesis of a broad scope of quinazoline derivatives (22 examples) with moderate to good yields and good functional-group tolerance and could be extended to other N-heterocyles such as quinolines and isoquinolines. Based on control experiments, a mechanistic proposal for this new transformation is also presented.

Full text of DOI:10.1002/ejoc.202000673

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Copper-catalyzed one-pot synthesis of 3-(N-
heteroarenyl)acrylonitriles through radical conjugated addition of
β-nitrostyrene to methylazaarenes
Authors: Natália Menezes Moreira, Lorena S. R. Martelli, Kiyara I.R.
de Julio, Julio Zukerman-Schpector, Till Opatz, and Arlene
Correa
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000673
Link to VoR: https://doi.org/10.1002/ejoc.202000673
01/2020

10.1002/ejoc.202000673
European Journal of Organic Chemistry
Copper-catalyzed one-pot synthesis of 3-(N-heteroarenyl)acrylonitriles
through radical conjugated addition of β-nitrostyrene to methylazaarenes
Natália M. Moreira,[a] Lorena S. R. Martelli, [a] Kiyara I. R. de Julio, [a] Julio Zukerman-
Schpector, [b] Till Opatz,[c] and Arlene G. Corrêa* [a]
[a] Centre of Excellence for Research in Sustainable Chemistry, [b] Chemistry Department,
[c]
Federal University of São Carlos, 13565-905, São Carlos, SP, Brazil.
Institute of
Organic Chemistry, Johannes Gutenberg-University, Duesbergweg 10–14, 55128
Mainz, Germany. *e-mail: agcorrea@ufscar.br
Abstract
A
simple procedure for the copper-catalyzed synthesis of 3-(N-
heteroaryl)acrylonitriles was developed. Using a combination of Lewis and Brønsted
acids, this one-pot procedure undergoes via a radical conjugated addition and
dehydration processes, without isolation of any intermediate, affording the acrylonitriles.
This diastereoselective approach allowed the synthesis of a broad scope of quinazoline
derivatives (22 examples) with moderate to good yields and good functional-group
tolerance and could be extended to other N-heterocyles such as quinolines and
isoquinolines. Based on control experiments, a mechanistic proposal for this new
transformation is also presented.
Introduction
Aromatic nitrogen heterocycles are well known for their biological and
pharmacological properties and among this class of compounds, the quinazolines are of
great interest.[1] This scaffold is present in several compounds with anticancer,[2] anti-
inflammatory,[3] antiparasitary[4] and antibacterial[5] activities. Furthermore, this
heterocycle is present in commercial drugs, such as gefitinib, used in the treatment of
certain types of cancer,[6] or prazosin, indicated to control blood pressure.[7] Examples of
bioactive quinazoline derivatives are depicted in Figure 1. Due to the important role of
quinazoline derivatives, there is a need for robust, versatile, green and scalable
chemistry for the synthesis of this scaffold.
1
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10.1002/ejoc.202000673
European Journal of Organic Chemistry
Figure 1. Selected bioactive compounds containing quinazoline moiety.
The functionalization of activated alkyl azaarenes has been extensively reported
in the last years, especially for 2-methylazaarenes.[8] For example, there are reports of
functionalization of benzylic bonds in azaarenes using transition metals,[9] alkaline-earth
metals,[10] Brønsted acids[11] or bases.[12] These scaffolds have a privileged reactivity once
the acidic nature of benzylic hydrogens allows the facile deprotonation and
tautomerization to the corresponding enamine form. This tautomerization gives to the
azaarene a nucleophilic character, which allows the reaction with a variety of
electrophiles (Scheme 1).[13]
Scheme 1. General representation of functionalization of 2-alkyl azaarenes.
1,4-Addition reactions of 2-methylquinoline has also been explored. For example,
the Michael addition to -nitrostyrene using PEG-400 as a recyclable reaction medium
without the need of any additive or acid catalyst was described by Yeramanchi et al.[14]
Rao and Meshram reported the same reaction using water under microwave irradiation
(Scheme 2a).[15] Chatterjee et al. described the reaction of 2-methylquinoline and (E)-
1,4-diphenylbut-2-ene-1,4-dione in the presence of 10 mol % of InCl3 as catalyst in 1,4-
dioxane under microwave irradiation (Scheme 2b).[16] Moreover, Jamal et. al. described
the Michael addition of 2-methylquinolines to chalcones employing CoCl2 as catalyst
(Scheme 2c).[17] Besides the use of 2-methylquinolines, Lu and co-workers expanded
their methodology to the functionalization of methylpyridines with malononitrile-derived
Knoevenagel products, utilizing Bi(OTf)3 as catalyst (Scheme 2d).[18]
2
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10.1002/ejoc.202000673
European Journal of Organic Chemistry
Although these works are remarkable, most of them have not been applied to other
methylazaarenes. Thus, due to our ongoing interest in quinazoline derivatives, herein we
report a facile Cu-catalyzed 1,4-addition of 4-methylquinazolines to -nitrostyrene
followed by dehydration, which showed good functional group tolerance and
chemoselectivity.
Scheme 2. Selected reports of 1,4-addition to methylazaarenes.
Results and Discussion
We started our investigation using trans-β-nitrostyrene (1) and 4-
methylquinazoline (2) as model substrates. Initially, a wide variety of Lewis acids was
screened, using microwave irradiation as shown in Table 1. To our surprise, the Michael
adduct was not isolated; instead, only products 3a and 4 were obtained. The structure of
compound 3a was stablished by X-ray crystallography (Figure 2),[19] confirming the Z
configuration of the double bond, and it is probably produced by the direct transformation
3
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10.1002/ejoc.202000673
European Journal of Organic Chemistry
of the resulting nitroalkane or its salt to the corresponding nitrile, which has been
previously reported for different substrates.[20] On the other hand, compound 4 was fully
characterized by spectroscopic methods and may be obtained via cyclization of the
Michael adduct followed by elimination of HNO2 in an intramolecular Nef-process.[21]
Figure 2. X-ray structure of compound 3a.
Table 1. Screening of Lewis acids
Entrya
Catalyst
Co(NO3)2.6H2O
CoCl2.6H2O
CoCl2
Yield of 3a (%)b
Yield of 4 (%)b
1
2
traces
26
27
22
23
13
7
traces
3
16
4
FeCl3.6H2O
NiBr2
-
5
-
6
Ni(NO3)2
-
7
AgNO3
traces
13
11
32
20
8
SnCl2
-
13
-
9
Cu(OAc)2.2H2O
10
CuCl2.2H2O
[a] Reaction conditions: 1 (0.15 mmol), 2 (0.38 mmol, 2.5 eq.), catalyst (0.015 mmol, 10 mol%),
ethanol (0.5 mL). [b] Isolated yield.
Continuing the catalyst screening, when Co(NO3)2·6H2O or CoCl2·6H2O were used
(Table 1, entries 1-2), compound 4 was isolated in approximately 27% yield and with
CoCl2 (Table 1, entry 3) compound 3a was additionally obtained in 16% yield. With the
use of other Lewis acids, it was possible to isolate only product 4, but still in low yield
(Table 1, entries 4-8). When Cu(OAc)2·2H2O was employed as catalyst, we could isolate
4
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10.1002/ejoc.202000673
European Journal of Organic Chemistry
both products (Table 1, entry 9), but when we used CuCl2·2H2O (Table 1, entry 10), only
product 4 was observed.
Inspired by a previous report of Fan and coworkers,[22] in which the authors used a
combination of a copper salt and a Brønsted acid to perform oxygenation and cyclization
reactions, we then tried different combinations of Brønsted acids and copper salts using
DMF as the solvent under conventional heating. Initially, the same conditions of Table 1,
entry 9, were used in combination with hydrochloric acid and a slight increase in the yield
of 3a was observed, motivating us to continue the optimization with other copper salts.
The use of Cu(I) salts significantly increased the yield of 3a, and the best result was
obtained using CuI and HCl as catalysts (Table 2, entry 4). Then, other Brønsted acids
were used in combination with CuI (Table 2, entries 5-9), but none of them improved the
yield of product 3a.
Looking for greener conditions,[23] we carried out a large screening of solvents,
starting with ethanol (Table 2, entry 1). We then tested dimethyl carbonate (DMC),
acetonitrile, ethyl acetate, anisole, toluene, and N,N´-dimethylpropyleneurea (DMPU)
and traces of the desired product were obtained, while DMSO, THF or 1,3-dimethyl-2-
imidazolidinone (DMI) furnished low yields (10-26%) and N,N´-dimethylacetamide
(DMAc) gave 52% of compound 3a. Moreover, other parameters, such as temperature,
concentration, catalyst loading, ligands and reaction time were also evaluated without
success (see the S.I. for details). Finally, we tried to decrease the amount of HCl solution
and, to our delight, the yield of 3a slightly increased to 71% when we use 10 mol% of
HCl (Table 2, entry 10).
With the optimized condition, i.e., a combination of CuI (10 mol%) and HCl (10
mol%) in DMF at 140 ºC for 2 h, we turned our attention to investigate the scope and
limitations of this protocol (Scheme 3). Thus, we first evaluated the effect of substituents
on the quinazoline in different positions and observed that alkyl (3b-c), halogens (3d-f)
and methoxy (3g) groups were well tolerated, affording products with moderated to good
yields (47-68%). More importantly, the reaction is regioselective, as shown in 3b with the
methyl group at the 2-position.
Next, different substituents on the trans-β-nitrostyrene were evaluated and we
were pleased to find that the desired products containing electron-donor substituents
such as alkyl (3h-j), phenyl (3k), halogens (3l-n), methoxy (3o-p) and a dimethylamino
group (3q) were obtained in moderate to good isolated yields (40-68%).
5
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European Journal of Organic Chemistry
Table 2: Catalyst optimization
Entrya
Cat. 1
Cu(OAc)2
CuCl
CuBr
CuI
Cat. 2b
HCl
Yield of 3a (%)c
Yield of 4 (%)c
1d
26
53
56
62
33
34
32
43
30
71
44
44
25
38
2
HCl
3
HCl
10
4
HCl
22
5
CuI
H2SO4
AcOH
p-TSA
TFA
TfOH
HCl
14
6
CuI
12
7
CuI
12
8
CuI
13
9
CuI
13
10e
11f
12f
CuI
traces
traces
25
-
HCl
CuI
-
[a] Reaction conditions: 1 (0.15 mmol), 2 (0.38 mmol, 2.5 eq.), DMF (0.5 mL), sealed tube. [b]
substrate concentration = 0.5 mol·L-1. [c] Isolated yield. [d] EtOH instead of DMF. [e] 10 mol% of
CuI and 10 mol% of HCl 0.5 M for 2 h. [f] Control experiments using 10 mol% of catalyst for 2
h.
Concerning the trans-β-nitrostyrene containing electron-withdrawing groups,
product 3r was obtained in moderate yield (40%) when the reaction was carried out at
120ºC. However, the presence of cyano or nitro groups was not well tolerated and only
traces of the corresponding products 3s and 3t were observed. The use of
heteroaromatic nitroolefins afforded products 3u and 3v, albeit in low yields (18 and 19%,
respectively). Unfortunately, the methodology was not effective when alkyl nitroolefins
such as cyclohexyl and tert-butyl were used, for which only traces of the product 3w and
3x were observed, respectively.
Furthermore, other N-heterocycles such as quinoline (5) and isoquinoline (6) were
well tolerated and when the reactions were carried out at 120 ºC, the products were
obtained in moderate yields (45% and 28%, respectively).
6
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European Journal of Organic Chemistry
Scheme 3. Scope and limitations of the methodology.
In order to have a better understanding of the reaction mechanism, we performed
some control experiments. Thus, in the absence of CuI, product 3a was obtained in lower
yield than for the standard conditions (Table 2, entry 11) and without the HCl solution,
both products were obtained, albeit in lower yields (Table 2, entry 12). These results
indicate that, even though the formation of 3a is observed without any catalyst, both
catalysts play a crucial role to improve the yield of desired product. The use of an inert
atmosphere such as nitrogen instead of air did not afford product 3a, indicating that
oxygen is necessary to promote the reaction.
7
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European Journal of Organic Chemistry
We then performed the reaction in the presence of radical scavengers such as
TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) and BHT (3,5-di-tert-4-
butylhydroxytoluene). In both cases, only traces of product 3a were observed, which
suggested that this transformation involves a free radical mechanism. In order to detect
some key intermediates, we analyzed the crude products of these reactions by mass
spectrometry (See SI for more details). After 30 minutes reaction time, we were able to
detect TEMPO coupled with the Michael adduct (m/z = 449) as well as with starting
material 2 (m/z = 300), as shown in Figure 3. The observation of these intermediates
suggests that the conjugated addition might occur in a Giese-type radical pathway.[24]
Figure 3. MS analysis of radical scavenger experiment.
With the aim of isolating the Michael adduct formed by nucleophilic attack of
quinazoline 2 to β-nitrostyrene 1, we performed the reaction using conditions described
previously by Rao.[17] The reaction was carried out without catalyst in water at 102 ºC
under microwave irradiation, and after 35 minutes, the Michael adduct I was isolated in
43% yield (Scheme 4). The adduct I was then submitted to the reaction for the formation
of 3a, using 10 mol% of CuI, and after 2 hours at 140 ºC, the desired product was
obtained in 27% yield. These results are an indicative that the conjugated addition is the
first step of this transformation.
8
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10.1002/ejoc.202000673
European Journal of Organic Chemistry
Scheme 4. Formation of 3a from the isolated Michael adduct I.
There are reports where copper salts are used to promote radical reactions, and
in some cases, in combination with an oxidizing agent[25] or molecular oxygen from air.
Jie et al. described a copper-catalyzed dehydrogenation to generate chalcones, which
were used in a sequential conjugate addition. The authors proposed that the copper salt
reacts with ketone to form a metal-enolate complex, which promotes the formation of a
radical intermediate through homolysis of a Cu(II)-enolate.[26] Guo et al. described the
copper catalyzed synthesis of 3H-indol-3-ones through a copper superoxide complex.
Recently, Chatterjee and co-workers reported a Cu-catalyzed functionalization of 2-(2-
bromophenyl)quinazolin-4(3H)-ones in the presence of oxygen atmosphere.[27] The
combination of Cu(I) with molecular oxygen is a well-known method to promote the
oxidation to Cu(II),[28] with the latter copper species being able to perform oxidative
reactions in numerous types of substrates.[29]
Although the full reaction mechanism for the formation of 3a is still unclear and
other pathways cannot be discarded, on the basis of previous reports and in our
experimental results, we proposed a plausible mechanism for the formation of 3a and 4.
Thus, for product 3a (Scheme 5a), initially the Brønsted acid promotes the formation of
quinazoline enolate 2’. This intermediate is oxidized by Cu(II), produced in situ,[30]
furnishing benzylic radical 2’’, which undergoes a radical conjugated addition[31] with
trans-β-nitrostyrene, resulting in the α-nitro radical intermediate I that tautomerizes to II.
This intermediate might be capable of regenerate Cu(I) catalyst. Then, after protonation
and a vinylogous elimination of water the double bond is formed (V), followed by a
second elimination to afford product 3a.
In the other hand, for the formation of product 4, after the 1,4-addition, a
nucleophilic attack of the nitrogen at 3-position of the quinazoline to the -position of the
nitro group may occur, generating the cyclic intermediate IX (Scheme 5b). Then, in order
to form a conjugated system, elimination of HNO2 affords product 4. This elimination
could also be facilitated by the presence of a Brønsted acid, which protonates the oxygen
of the nitro group.
9
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10.1002/ejoc.202000673
European Journal of Organic Chemistry
Scheme 5. Mechanistic proposal for the synthesis of quinazoline derivatives 3a and 4.
Conclusion
In summary, we developed a unprecedent protocol for the one-pot synthesis of
new conjugated nitrile compounds, utilizing a combination of Lewis and Brønsted acid
catalysts. Based on control experiments, a mechanistic pathway was proposed via a
radical conjugated addition of β-nitrostyrenes to methylazaarenes followed by
dehydration processes. Using the optimized conditions, 22 derivatives were prepared in
18-71% overall yield. These new compounds can be used in subsequent conjugated
additions in order to create more complex molecules, besides the potential biological
activity of quinazoline derivatives scaffolds.
Experimental Section
General information
All commercially available reagents were purchased from Sigma-Aldrich. The
synthesized products were purified through chromatographic column using silica gel 60,
230–400 mesh. TLC were performed in silica gel 60 F254 supported in aluminum sheets.
1H and 13C NMR spectrum were recorded on a Bruker DRX 400 MHz
spectrometer. Chemical shifts (δ) were presented in ppm units and the coupling
constants (J) in Hertz (Hz). Signals multiplicity were expressed by the following
10
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10.1002/ejoc.202000673
European Journal of Organic Chemistry
abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). The IR
spectrum were recorded on a SHIMADZU (IR-Prestige-21).
UltraPerformance Convergence Chromatography™ was carried out using a
ACQUITY UPC2ꢀ™ system (Waters Corp., Milford, MA, USA), equipped with achiral
stationary phase Viridis HSS C18 SB and a mass spectrometer Waters (Xevo TQD Triple
Quadrupole Mass Spectrometry). The exact mass measurement was carried out using
a micrOTOF Q IITOF Mass Spectrometer (Bruker Daltonics, Billerica, MA, USA)
equipped with an ESI ion source (positive ionization mode).
General procedure for the synthesis of 3-(N-heteroarenyl)acrylonitriles
A mixture of β-nitrostyrene (0.15 mmol, 1.0 eq), 4-methylquinazoline (0.38 mmol,
2.5 eq), CuI (0.015 mmol, 10 mol%), HCl 0.5 M (0.015 mmol, 10 mol%) and DMF (0.50
mL) were added in a sealed tube equipped with a stir bar. The mixture was stirred for 2-
48 hours, at 120ºC or 140ºC. After completion of the reaction, the mixture was extracted
with ethyl acetate (3 x 10 mL) and the organic layers were combined and washed with
LiCl 5% (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The
residue was purified by flash chromatography using a solution of hexane: ethyl acetate
70-30% unless otherwise noted, affording the desired products 3a-3v, 5 and 6.
(Z )-2-phenyl-3-(quinazolin-4-yl)acrylonitrile (3a): The product was isolated in 71%
yield (27.5 mg, 0.11 mmol) as a brown solid. M.P.: 151ºC. 1H NMR (400 MHz, CDCl3) δ:
9.49 (s, 1H), 8.25 (s, 1H), 8.17 (dt, J= 8.6, 0.6 Hz, 1H), 8.13 (dt, J= 8.6, 0.6 Hz, 1H), 7.97
(ddd, J= 8.4, 6.9, 1.3 Hz, 1H), 7.87 – 7.86 (m, 1H), 7.85 – 7.84 (m, 1H), 7.72 (dt, J= 8.3,
6.9, 1.3 Hz, 1H), 7.54 – 7.50 (m, 3H). 13C NMR (100 MHz, CDCl3) δ: 159.1, 154.8, 151.3,
13
134.4, 133.8, 133.4, 131.0, 129.7, 129.5, 128.6, 127.1, 123.5, 123.2, 121.6, 116.7. C
NMR DEPT 135 (100 MHz, CDCl3) δ 154.7, 134.3, 133.3, 130.9, 129.6, 129.4, 128.5,
127.0, 123.4. IR (KBr, max) 3059, 3041, 2200, 1616, 1602, 1564, 1541, 1492, 1450,
1384, 760, 686 cm-1. HRMS (ESI): m/z calcd for C17H12N3 [(M+H)]+: 258.1026, found:
258.1028.
(Z)-3-(2-methylquinazolin-4-yl)-2-phenylacrylonitrile (3b): The product was isolated
in 42% yield (17.0 mg, 0.06 mmol), as a brown solid. M.P.: 123ºC. 1H NMR (400 MHz,
CDCl3) δ: 8.14 (s, 1H), 8.05-8.03 (d, J = 8.4 Hz, 1H), 7.97-7.95 (d, J = 8.4 Hz, 1H), 7.86-
7.84 (dd, J = 8.3, 7.3 Hz, 1H), 7.79-7.77 (dd, J = 6.2, 2.2 Hz, 1H), 7.57-7.54 (dd, J = 8.3,
7.3 Hz, 1H), 7.46-7.44 (dd, J = 6.2, 2.2 Hz, 1H), 2.92 (s, 3H). 13C NMR (100 MHz, CDCl3)
δ: 164.1, 158.9, 151.7, 134.2, 133.8, 133.6, 130.8, 129.3, 128.8, 127.4, 126.9, 123.3,
121.5, 120.9, 116.6, 26.1. HRMS (ESI): m/z calcd for C17H12N3 [(M+H)]+: 272.1188,
found: 272.1182.
11
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(Z)-3-(8-methylquinazolin-4-yl)-2-phenylacrylonitrile (3c): The product was isolated
in 52% yield (21.1 mg, 0.08 mmol) as a yellow solid. M.P.: 154ºC. 1H NMR (400 MHz,
CDCl3) δ: 9.53 (s, 1H), 8.26 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.87-7.85 (m, 2H), 7.81-
7.79 (m, 1H), 7.62-7.58 (t, J = 7.8 Hz, 1H), 7.55 – 7.49 (m, 3H), 2.83 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ: 159.1, 153.7, 150.4, 137.9, 134.1, 133.9, 130.8, 129.3, 128.7,
128.0, 126.9, 123.1, 122.4, 121.1, 116.7, 17.6. HRMS (ESI): m/z calcd for C18H14N3
[(M+H)]+: 272.1188, found: 272.1180.
(Z)-3-(6-fluoroquinazolin-4-yl)-2-phenylacrylonitrile (3d): The product was isolated in
1
54% yield (22.3 mg, 0.08 mmol), as a yellow solid. M.P.: 136ºC. H NMR (400 MHz,
CDCl3) δ: 9.50 (s, 1H), 8.18 (dd, J = 8.9, 5.1 Hz, 1H), 8.12 (s, 1H), 7.91 – 7.84 (m, 2H),
7.84 – 7.72 (m, 2H), 7.59 – 7.51 (m, 3H). 13C NMR (100 MHz, CDCl3) δ: 160.9 (d, J C-F
=
253.4 Hz), 158.6 (d, JC-C-C-C-F = 6.1 Hz), 154.1, 148.5, 133.5, 132.6, 132.5 (d, J c-c-c-F=
9.3 Hz), 131.1, 129.4, 127.0, 124.8 (d, JC-C-F = 25.8 Hz), 123.8 (d, JC-C-C-F = 9.1 Hz), 121.8,
116.5, 107.1 (d, JC-C-F= 22.8 Hz). HRMS (ESI): m/z calcd for C17H12FN3 [(M+H)]+:
276.0937, found: 276.0930.
(Z)-3-(6-bromoquinazolin-4-yl)-2-phenylacrylonitrile (3e): The product was isolated
1
in 57% yield (28.4 mg, 0.08 mmol) as a yellow solid. M.P.: 165.9 ºC. H NMR (400 MHz,
CDCl3) δ: 9.49 (s, 1H), 8.30 (s, 1H), 8.14 (s, 1H), 7.87 (dd, J = 6.3, 2.7 Hz, 2H), 7.54 (dd,
13
J = 6.3, 2.7 Hz, 3H). C NMR (100 MHz, CDCl3) δ: 158.1, 154.9, 149.9, 137.8, 133.5,
132.3, 131.3, 131.1, 129.4, 127.1, 125.8, 124.1, 122.5, 122.2, 116.5. HRMS (ESI): m/z
calcd for C17H12N3 [(M+H)]+: 336.0136, found: 336.0131.
(Z)-3-(7-bromoquinazolin-4-yl)-2-phenylacrylonitrile (3f): The product was isolated in
1
68% yield (34.1 mg, 0.10 mmol) as a green solid. M.P.: 184ºC. H NMR (400 MHz,
CDCl3) δ: 9.48 (s, 1H), 8.30 (sl, 1H), 8.13 (s, 1H), 8.00 (s, 2H), 7.86 (dd, J = 6.4, 2.8 Hz,
2H), 7.55 – 7.50 (m, 3H). 13C NMR (100 MHz, CDCl3) δ: 158.1, 154.8, 149.9, 137.8,
133.5, 132.3, 131.3, 131.1, 129.4, 127.1, 125.8, 124.0, 122.5, 122.1, 116.5. HRMS (ESI):
m/z calcd for C17H10N3 [(M+H)]+: 336.0136, found: 336.0131.
(Z)-3-(8-methoxyquinazolin-4-yl)-2-phenylacrylonitrile (3g): The product was
1
isolated in 54% yield (23.3 mg, 0.08 mmol) as a yellow solid. M.P.: 143.1ºC. H NMR
(400 MHz, CDCl3) δ: 9.53 (s, 1H), 8.22 (s, 1H), 7.86 (dd, J = 8.9, 4.0 Hz, 2H), 7.72 (d, J
= 8.1 Hz, 1H), 7.64 (t, J = 8.1 Hz, 1H), 7.56 – 7.48 (m, 3H), 7.28 (d, J = 7.7 Hz, 1H), 4.13
(s, 3H). 13C NMR (100 MHz, CDCl3) δ: 158.7, 155.5, 153.8, 143.6, 133.8, 133.6, 130.9,
129.3, 128.7, 127.0, 124.1, 121.4, 116.6, 114.6, 111.7, 56.3. HRMS (ESI): m/z calcd for
C17H14N3O[(M+H)]+: 288.1137, found: 288.1135.
(Z)-3-(quinazolin-4-yl)-2-(p-tolyl)acrylonitrile (3h): The product was isolated in 68%
yield (27.7 mg, 0.10 mmol) as a yellow solid. M.P.: 183ºC. 1H NMR (400 MHz, CDCl3) δ:
9.50 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.97 (dd, J = 8.1, 7.2 Hz,
12
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European Journal of Organic Chemistry
1H), 7.77 (d, J = 7.9 Hz, 2H), 7.72 (dd, J = 8.1, 7.2 Hz, 1H), 7.33 (d, J = 7.9 Hz, 2H), 2.45
(s, 3H). 13C NMR (100 MHz, CDCl3) δ: 159.2, 154.7, 151.2, 141.5, 134.2, 132.1, 130.9,
130.1, 129.6, 128.4, 126.9, 123.4, 123.2, 116.7, 21.4. HRMS (ESI): m/z calcd for
C18H14N3 [(M+H)]+: 272.1188, found: 272.1182.
(Z)-3-(quinazolin-4-yl)-2-(o-tolyl)acrylonitrile (3i): The product was isolated in 39%
yield (15.7 mg, 0.06 mmol) as a yellow solid. M.P.: 145.5ºC. 1H NMR (400 MHz, CDCl3)
δ: 9.52 (s, 1H), 8.14 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.97 (dd, J = 8.2, 7.2
Hz, 1H), 7.71 (dd, J = 8.2, 7.2 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H),
13
7.35 – 7.28 (m, 2H), 2.58 (s, 3H). C NMR (100 MHz, CDCl3) δ: 158.8, 154.7, 151.3,
138.4, 136.5, 134.8, 134.3, 131.3, 130.1, 129.6, 129.5, 128.5, 126.7, 123.3, 123.0, 121.7,
116.6, 20.33. HRMS (ESI): m/z calcd for C18H14N3 [(M+H)]+: 272.1182, found: 272.1183.
(Z)-2-(4-(tert-butyl)phenyl)-3-(quinazolin-4-yl)acrylonitrile (3j): The product was
isolated in 66% yield (30.9 mg, 0.10 mmol) as a brown solid. M.P.: 257 ºC. 1H NMR (400
MHz, CDCl3) δ: 9.50 (s, 1H), 8.23 (s, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.14 (d, J = 8.5 Hz,
1H), 7.97 (dd, J = 8.5, 7.31 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.72 (dd, J = 8.5, 7.3 Hz,
1H), 7.55 (d, J = 8.3 Hz, 2H), 1.38 (s, 9H). 13C NMR (100 MHz, CDCl3) δ: 159.2, 154.7,
151.2, 134.2, 132.24, 130.9, 129.6, 128.4, 126.8, 126.3, 123.4, 123.2, 121.4, 121.3,
116.7, 34.9, 31.2. HRMS (ESI): m/z calcd for C20H20N3 [(M+H)]+: 314.1657, found:
314.1653.
(Z)-2-([1,1'-biphenyl]-4-yl)-3-(quinazolin-4-yl)acrylonitrile (3k): The product was
isolated in 42% yield (21.1 mg) as a brown solid. M.P.: 210.7ºC. 1H NMR (400 MHz,
CDCl3) δ: 9.51 (s, 1H), 8.30 (s, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H),
7.99 (d, J = 7.4 Hz, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.76-7.73 (m, 3H), 7.67-7.65 (m, 2H),
7.50 (t, J = 7.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ: 159.0, 154.7, 151.3, 143.8, 139.6,
134.3, 132.7, 132.5, 129.6, 129.1, 128.5, 128.3, 127.9, 127.5, 127.2, 123.4, 123.2, 121.1,
116.6. HRMS (ESI): m/z calcd for C20H20N3 [(M+H)]+: 334.1339 found: 334.1339.
(Z)-2-(4-fluorophenyl)-3-(quinazolin-4-yl)acrylonitrile (3l): The product was isolated
1
in 65% yield (26.6 mg, 0.01 mmol) as a yellow solid. M.P.: 128ºC. H NMR (400 MHz,
CDCl3) δ 9.54 (s, 1H), 8.23 (s, 1H), 8.19 (t, J = 7.9 Hz, 2H), 8.02 (t, J = 7.7 Hz, 1H), 7.90
(dd, J = 8.5, 5.3 Hz, 2H), 7.77 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 6.5 Hz, 1H), 7.24 – 7.22
(m, 1H). 13C NMR (100 MHz, CDCl3) δ: 164.24 (d, JC-F= 253.0 Hz), 158.8, 154.6, 151.2,
134.3, 133.1, 129.9 (d, JC-C-C-C-F= 2.9 Hz), 129.6, 129.1 (d, JC-C-C-F = 8.7 Hz), 129.0, 128.5,
123.3, 123.1, 120.4, 116.6 (d, J = 22.2 Hz).HRMS (ESI): m/z calcd for C17H10FN3
[(M+H)]+: 276.0937, found: 276.0933.
(Z)-2-(4-chlorophenyl)-3-(quinazolin-4-yl)acrylonitrile (3m): The product was
isolated in 44% yield (19.1 mg, 0.07 mmol) as a yellow solid, M.P.: 198 ºC. 1H NMR (400
13
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10.1002/ejoc.202000673
European Journal of Organic Chemistry
MHz, CDCl3) δ: 9.49 (s, 1H), 8.23 (s, 1H), 8.18 – 8.12 (m, 2H), 8.00 – 7.95 (ddd, J = 8.3,
6.9, 1.1 Hz, 1H), 7.82 – 7.78 (dt, J = 9,3, 2,5 Hz, 2H), 7.73 (ddd, J = 8.3, 6.9, 1.1 Hz,
13
1H), 7.52 – 7.48 (dt, J = 9.3, 2.5 Hz, 2H). C NMR (100 MHz, CDCl3) δ: 158.7, 154.6,
151.3, 137.2, 134.4, 133.5, 132.1, 129.7, 129.6, 128.6, 128.3, 123.3, 123.1, 120.3, 116.3.
HRMS (ESI): m/z calcd for C17H12ClN3 [(M+H)]+: 292.0642, found: 292.0636.
(Z)-2-(4-bromophenyl)-3-(quinazolin-4-yl)acrylonitrile (3n): The product was isolated
in 56% yield (28.1 mg, 0.08 mmol) as a green solid. M.P.: 176ºC. 1H NMR (400 MHz,
CDCl3) δ: 9.44 (s, 1H), 8.18 (s, 1H), 8.11-8.09 (dd, J = 4.1, 0.6 Hz, 1H), 8.09 – 8.07 (dd,
J = 3.8, 1.3 Hz, 1H), 7.92 (ddd, J = 8.5, 6.9, 1.3 Hz, 1H), 7.69 – 7.67 (m, 1H), 7.67 – 7.64
(m, 2H), 7.62 – 7.57 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 158.7, 154.7, 151.3, 134.4,
133.6, 132.6, 129.7, 128.6, 128.4, 125.5, 123.2, 123.1, 120.4, 116.3. HRMS (ESI): m/z
calcd for C17H10BrN3 [(M+H)]+: 336.0136, found: 336.0132.
(Z)-2-(4-methoxyphenyl)-3-(quinazolin-4-yl)acrylonitrile (3o): The product was
isolated in 62% yield (26.9 mg, 0.09 mmol) as a yellow solid. M.P.: 184 ºC. 1H NMR (400
MHz, CDCl3) δ: 9.38 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 8.05 (s, 1H), 8.03 (d, J = 8.5 Hz,
1H), 7.87 (dd, J = 8.1, 7.3 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.62 (dd, J = 8.0, 7.3 Hz,
1H), 6.93 (d, J = 8.7 Hz, 2H), 3.81 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 162.0, 159.4,
154.8, 151.3, 134.3, 130.6, 129.7, 128.7, 128.4, 126.3, 123.5, 123.3, 121.1, 116.9, 114.9,
55.7. HRMS (ESI): m/z calcd for C18H14N3O [(M+H)]+: 288.1137, found: 288.1133.
(Z)-2-(3-methoxyphenyl)-3-(quinazolin-4-yl)acrylonitrile (3p): The product was
isolated in 64% yield (27.7 mg, 0.096 mmol ) as a yellow solid. M.P.: 157.3ºC. 1H NMR
(400 MHz, CDCl3) 9.51 (s, 1H), 8.25 (s, 1H), 8.16 (t, J = 8.7 Hz, 1H), 7.98 (t, J = 7.7 Hz,
1H), 7.73 (t, J = 7.7 Hz, 1H), 7.47 – 7.42 (m, 1H), 7.39 – 7.35 (m, 1H), 7.08 – 7.04 (m,
1H), 3.91 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 160.2, 159.0, 154.7, 151.2, 135.1, 134.3,
133.6, 130.4, 129.6, 128.5, 123.4, 123.2, 121.4, 119.3, 116.6, 116.4, 112.7, 55.6. HRMS
(ESI): m/z calcd for C18H14N3O [(M+H)]+ :288.1137 found: 288.1135.
(Z)-2-(4-(dimethylamino)phenyl)-3-(quinazolin-4-yl)acrylonitrile (3q): The product
was isolated in 21% yield (9.5 mg, 0.03 mmol) as a brown solid. M.P.: 195.9 ºC. 1H NMR
(400 MHz, CDCl3) δ 9.43 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.03
(s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.68 (t, J = 7.6 Hz, 1H), 6.75
13
(d, J = 8.5 Hz, 2H), 3.08 (s, 6H). C NMR (100 MHz, CDCl3) δ: 159.8, 154.6, 152.0,
150.9, 133.9, 129.3, 128.5, 128.0, 126.2, 123.5, 123.2, 121.3, 121.2, 117.1, 111.9, 40.2.
HRMS (ESI): m/z calcd for C19H16N4 [(M+H)]+: 301.1448, found: 301.1447.
(Z)-3-(quinazolin-4-yl)-2-(4-(trifluoromethyl)phenyl)acrylonitrile (3q): The product
was isolated in 40% yield (19.3 mg, 0.06 mmol) as a yellow solid. M.P.: 215 ºC. 1H NMR
(400 MHz, CDCl3) δ: 9.53 (s, 1H), 8.33 (s, 1H), 8.17 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 7.9
14
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10.1002/ejoc.202000673
European Journal of Organic Chemistry
Hz, 3H), 7.80 (d, J = 8.4 Hz, 2H), 7.75 (t, J = 7.9 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ:
158.4, 154.7, 151.4, 137.0, 135.5, 134.5, 129.8, 128.7, 127.4, 126.39, 126.36, 123.2,
123.1, 120.1, 116.1. HRMS (ESI): m/z calcd for C18H11N3F3 [(M+H)]+: 326.0905, found:
326.0896.
(E)-2-(furan-2-yl)-3-(quinazolin-4-yl)acrylonitrile (3u): The product was isolated in
1
19% yield (7.2 mg, 0.03 mmol) as a brown solid. M.P.: 211.3 ºC. H NMR (400 MHz,
CDCl3) δ: 9.53 (s, 1H), 8.14 (d, J = 4.8 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 7.9
Hz, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.24 – 7.21 (m, 1H). 13C NMR
(100 MHz, CDCl3) δ: 146.6, 141.9, 140.2, 136.7, 133.5, 130.8, 130.7, 129.0, 128.8,
127.7, 126.9, 125.3, 123.5, 119.9, 100.1. HRMS (ESI): m/z calcd for C15H9N3O[(M+H)]+:
248.0819, found: 248.0816.
(E)-3-(quinazolin-4-yl)-2-(thiophen-2-yl)acrylonitrile (3v): The product was isolated in
1
20% yield (7.9 mg, 0.30 mmol) as a brown solid. M.P.: 117.3ºC. H NMR (400 MHz,
CDCl3) δ: 9.48 (s, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.09 (s, 1H),
8.00 - 7.97 (m, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 3.8 Hz, 1H), 7.49 (d, J = 5.1
Hz, 1H), 7.18 (dd, J = 3.8, 5.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 154.6, 138.8,
138.3, 134.2, 133.7, 130.9, 129.6, 129.4, 128.9, 128.8, 128.4, 123.2, 123.0, 115.7, 115.2.
HRMS (ESI): m/z calcd for C15H9N3S[(M+H)]+: 264.0590, found: 264.0589.
2-phenylpyrrolo[1,2-c]quinazoline (4): The product was isolated in 34% yield (12.44
mg, 0.051 mmol) as a brown solid. 1H NMR: (400 MHz, CDCl3) δ: 8.67 (d, J= 0.30 Hz,
1H), 8.02-7.97 (m, 1H), 7.82-7.78 (m, 1H), 7.70 (m, 1H), 7.68 (m, 1H), 7.62 (d, J= 1.38
Hz, 1H), 7.50-7.49 (ddd, J= 1.81, 5.17, 7.62, 2H), 7.47-7.40 (ddd, J= 1.81, 5.17, 7.62,
2H), 7.34-7.29 (m, 1H), 7.21-7.19 (dd, J= 0.30,1.38 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ 138.08, 137.17, 130.53, 129.87, 128.95, 128.28, 127.91, 127.50, 127.57, 126.27,
121.79, 121.42, 109.67, 98.91. 13C DEPT 135 (100 MHz, CDCl3) δ 138.08, 128.95,
127.91, 127.27, 126.27, 121.79, 109.67. HRMS (ESI): m/z calcd for C17H12N2 [(M+H)]+:
245.1079, found: 257.1072.
(Z)-2-fenil-3-(quinolin-2-il)acrilonitrila (5): The product was isolated in 45% yield (17.4
mg, 0.07 mmol) as a yellow solid. M.P.: 94.8 ºC. 1H NMR (400 MHz, CDCl3) δ: 8.28 (d, J
= 8.6 Hz, 1H), 8.16 (dd, J = 15.5, 8.6 Hz, 2H), 7.53 – 7.44 (m, 2H), 7.83 – 7.74 (m, 3H),
7.61 (t, J = 7.6 Hz, 1H), 7.45 – 7.37 (m, 3H). 13C NMR (100 MHz, CDCl3) δ: 152.2, 148.1,
143.9, 141.4, 136.9, 135.9, 134.0, 129.2, 129.0, 127.8, 127.6, 126.5, 121.7, 120.8, 117.4,
116.1. HRMS (ESI): m/z calcd for C18H12N2 [(M+H)]+: 257.1073, found: 257.1073.
(Z)-3-(isoquinolin-1-yl)-2-phenylacrylonitrile (6): The product was isolated in 20%
yield (7.6 mg, 0.03 mmol) as a brown solid. M.P.: 144.2ºC. 1H NMR (400 MHz, CDCl3)
δ: 8.73 (d, J = 5.7 Hz, 1H), 8.32 (s, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H),
15
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000673
European Journal of Organic Chemistry
7.85 (d, J = 7.7 Hz, 2H), 7.77 – 7.71 (m, 2H), 7.70 – 7.62 (m, 1H), 7.54 – 7.45 (m, 3H).
13C NMR (101 MHz, CDCl3) δ 142.5, 140.4, 136.5, 136.5, 134.4, 130.4, 130.0, 129.2,
128.7, 128.1, 127.7, 126.7, 126.6, 125.2, 123.9, 122.3, 117.5. HRMS (ESI): m/z calcd
for C18H12N2 [(M+H)]+: 257.1073, found: 257.1070.
4-(3-nitro-2-phenylpropyl)quinazoline (I): The product was isolated in 43% yield (38
mg, 0.13 mmol) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 7.95 (t, J =
8.3 Hz, 2H), 7.81 (t, J = 7.7 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.25 – 7.20 (m, 3H), 7.18 –
7.12 (m, 2H), 4.87 (dd, J = 12.8, 6.3 Hz, 1H), 4.71 (dd, J = 12.7, 8.6 Hz, 1H), 4.39 – 4.26
(m, 1H), 3.61 (qd, J = 15.4, 7.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 167.3, 154.3,
149.9, 139.0, 133.9, 129.3, 129.1, 128.0, 127.9, 127.4, 124.01 (overlapping signal),
123.98, 79.5, 42.2, 37.3.
Acknowledgements
The authors gratefully acknowledge FAPESP (grants 2013/07600-3, 2014/50249-
8, 2017/19940-4 and 2018/23761-0), GlaxoSmithKline, CAPES (Finance Code 001), and
CNPq (grants 405330/2016-2, 303207/2017–5 and 302140/2019-0) for funding and
fellowships. We also thank Prof. Regina H. A. Santos from IQSC-USP for the X-ray data
collection.
Keywords: radical conjugated addition, copper-catalyzed reaction, acrylonitriles,
azaarenes, quinazolines
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