KOtBu-BF3.OEt2 mediated synthesis of quinazolin-4(3H)-ones from 2-substituted amides with nitriles and aldehydes

Article abstract of DOI:10.1080/00397911.2021.1928218

KO^tBu-BF₃.OEt₂ mediated synthesis of quinazolin-4(3H)-ones from 2-substituted amides with nitriles and aldehydes have been developed. In this protocol, a variety of nitriles as well as aldehydes react with 2-substituted benzamides to corresponding quinazolin-4(3H)-ones products in good to moderate yields, via the cleavage of C-X and C-N bonds and the formation of double C-N bonds simultaneously, in presence of potassium tert-butoxide.

Full text of DOI:10.1080/00397911.2021.1928218

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KOtBu-BF3.OEt2 mediated synthesis of
quinazolin-4(3H)-ones from 2-substituted amides
with nitriles and aldehydes
Vishnuvardhan Nomula & Sadu Nageswara Rao
To cite this article: Vishnuvardhan Nomula & Sadu Nageswara Rao (2021): KOtBu-BF3.OEt2
mediated synthesis of quinazolin-4(3H)-ones from 2-substituted amides with nitriles and aldehydes,
Synthetic Communications, DOI: 10.1080/00397911.2021.1928218
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https://doi.org/10.1080/00397911.2021.1928218
KOtBu-BF3.OEt2 mediated synthesis of quinazolin-4(3H)-
ones from 2-substituted amides with nitriles and aldehydes
a
Vishnuvardhan Nomulaa,b and Sadu Nageswara Rao
ꢀ
aDepartment of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology,
b
Hyderabad, India; Academy of scientific and innovative research(AcSIR), Ghaziabad, India
ABSTRACT
ARTICLE HISTORY
KOtBu-BF3.OEt2 mediated synthesis of quinazolin-4(3H)-ones from 2-
substituted amides with nitriles and aldehydes have been developed.
In this protocol, a variety of nitriles as well as aldehydes react with
2-substituted benzamides to corresponding quinazolin-4(3H)-ones
products in good to moderate yields, via the cleavage of C-X and
C-N bonds and the formation of double C-N bonds simultaneously,
in presence of potassium tert-butoxide.
Received 4 January 2021
KEYWORDS
Nitriles; aldehydes; KOtBu;
quinazolinones; metal-free
conditions
GRAPHICAL ABSTRACT
O
R
N
H
(x = halo, -NH2 etc.,)
X
KOtBu
N
BF3.OEt2
O
O
N
O
N
R
R
R1
R2
H
N
N
Δ
R1
Δ
R2
x = halo
x = amine
14 examples
9 examples
R = H, Me, Et, iPr, tBu etc,.
Transition metal free
Introduction
Nitrogen-containing heterocycles are back-bone of many bio-active natural products,
agro-chemicals as well as pharmaceutical industry; these are much in demand due to
their important physiological and biological activities (Figure 1).[1–2] In recent years
various groups have explored the newer and efficient methodologies to synthesize
CONTACT Sadu Nageswara Rao
snageswar85@gmail.com
Department of Organic Synthesis and Process
Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
ꢀ
Science and Engineering Research Board-National Post Doctoral Fellowship (SERB-NPDF), India
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

2
V. NOMULA AND S. N. RAO
Figure 1. Selected quinazolinone containing natural products and drug candidates.
Figure 2. Our novel approach.
molecules containing nitrogen atoms. One such preferred scaffold is phenylquinazolin-
4(3H)-one which has shown varying effects such as anti-cancer, anti-inflammatory,
anti-microbial, anti-allergetic etc.[3–5] In addition, a latest report highlights the role of
4-methyl quinazoline derivatives in the treatment of one of the rare disease idiopathic
pulmonary fibrosis through P13K inhibition.[6] During our efforts to develop new scaf-
folds for strengthening the drug discovery pipeline, we embarked on the synthesis of
quinazolin-4(3H)-one derivatives using very mild reagents. The results of our studies
are presented here.
Results and discussion
Synthesis of quinazolin-4(3H)-ones is traditionally being reported with the use of transi-
tion metal catalysts,[7–10] predominantly Cu(I) salts.[11–12] Our synthetic efforts are

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3
focused on the complete elimination of the transition metal (Figure 2). Thus 2-iodo N-
methyl benzamide 1a and benzonitrile 2a were reacted in presence of KOtBu, BF3.OEt2
t
in BuOH at 130 ꢁC where we observed the formation of 3-methyl-2-phenylquinazolin-
4(3H)-one 3a in 42% yield (Table 1, entry 1). This result enthused us to further explore
the conditions to synthesize 3a derivatives. In the first step we studied effect of solvents
where DMF, DMSO, toluene, nitrobenzene, N-methyl-pyrrolidone and Dimethyl
Table 1. Optimization of reaction conditions.
Reaction conditions: 1a (0.5 mmol), 2a (2.5 mmol), base (1.5 mmol, 3 equiv), BF3.OEt2 (0.5
a
b
equiv) in dioxane (3 mL) nd ¼ not detected. yields after column chromatography. reac-
c
d
tion performed in the presence of O2 atm. 0.1 equiv. of BF3.OEt2 was used. 0.2 equiv. of
BF3.OEt2 was used. 0.3 equiv. of BF3.OEt2 was used. 1.0 equiv. of BF3.OEt2 was used.
1.5 equiv of benzonitrile was used. 3.0 equiv of benzonitrile was used.
e
f
g
h

4
V. NOMULA AND S. N. RAO
Table 2. Screening of different Lewis acidsa.
O
N
KOtBu (3.0 equiv)
CN
O
CH3
Ph
CH3
Lewis acid (0.5 equiv)
N
N
H
Δ,
24 h
I
atmosphere
N2
1a
2a
3
product (3a)b
s.no.
solvent
lewis acid
InCl3
1
2
3
dioxane
dioxane
dioxane
35
nd
SnCl2
SnBr2
25
40
70
4
Sc(OTf)3
dioxane
.OEt
BF3
dioxane
5
2
TiCl4
AlCl3
6
7
8
dioxane
dioxane
dioxane
48
nd
nd
B(C6F5 3
)
aReaction conditions: 1a (0.5 mmol), 2a (2.5 mmol), base (1.5 mmol, 3 equiv), BF3.OEt2
(0.5 equiv) in dioxane (3 mL).b yields after column chromatography.
acetamide were explored, unfortunately none of these solvents could aid in increasing
the yield (Table 1, entries 2–8). The solvent of choice was 1,4-dioxane which resulted in
the increased yield of 3a (Table 1, entry 9). We then studied bases such as KOH,
t
K2CO3, Cs2CO3, BuONa and NaOH which resulted in poor yields or non-formation of
the products (Table 1, entries 10–14). The effect of temperature was also studied and it
was found that, the reaction could not take place at 100 ꢁC, under similar reaction con-
ditions (Table 1, entry 15). Further, the role of inert atmosphere was determined when
a reaction in optimized conditions open to air did not result in any product formation
(Table 1, entry 16), clearly indicating that inert atmosphere is essential for this reaction.
When the reaction was employed in the absence of the base no product formation was
observed (Table 1, entry 17). On varying the concentration of BF3.OEt2 from 0.1 equiv
to 1.0 equiv the yield ranged from 30% to 58% (Table 1, entries 18–21). And also we
checked the requirement of benzonitrile equivalents; when we used 1.5 equiv and 3.0
equiv of benzonitrile, the resulting yields were lower (Table 1, entries 22–23). Based on
the above observations, next we examined the reactivity of other Lewis acids like InCl3,
SnCl2, SnBr2, Sc(OTf)3, AlCl3 and B(C6F5)3 under the same optimal reaction conditions
(Table 2), lower yields of the final product 3a were observed compared to entry 5
(Table 2). It indicates that BF3.OEt2 may easily activate nitrile (2a) than the other Lewis
acids (Table 2). After establishment of the optimal reaction conditions, we then
explored the substrate scope (Table 3). Thus, 1a was treated with substituted benzoni-
triles 2a–2h under the optimized reaction conditions. The yields of 3a–3h were achieved
in the range of 35–70%. When N-Methyl group of 1a was substituted with N-ethyl, 57%
of the product formation (3i) was observed. Although, N-isopropyl and N-tert-butyl
substituents also tested, the reaction of N-isopropyl substituent, trace amount of
product (3j) was observed. Similarly, no product formation was observed in the case of
N-tert-butyl substituent (3k), due to steric hinderance.

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Table 3. Scope of 2-halo amide with various nitrilesa.
aReaction conditions: 1a (0.5 mmol), 2a (2.5 mmol), KOtBu (1.5 mmol, 3 equiv), BF3.OEt2 (0.5
equiv) in dioxane (3 mL), nd ¼ not detected.
We then varied the primary substrates, thus 2-halo benzamide 1 and benzonitrile 2
were replaced with 2-amino benzamide 4 and benzaldehyde 5. In recent years, various
groups have been developed elegant methods for synthesis of quinazolin-4(3H)-ones
using 2-amino benzamide with aldehyde under metal and metal free conditions.[13–14]
To our pleasure the same reaction conditions were applicable, 2-amino benzamide 4a
upon reaction with benzaldehyde 5a gave quinazoline-4(3H)-ones 6a in 60% yield. The
substituted aldehydes 5a–5i was reacted with 4a and respective quinazoline-4(3H)-ones
(6a–6i) were obtained in 45–67% yields (Table 4). We also explored the reaction of
2-bromo, 2-chloro, and 2-hydroxy-4-methoxy-N-methylbenzamides and found the
products 55% and no product formation in the case of 2-chloro benzamide and
2-hydroxy-4-methoxy-N-methylbenzamide (Table 5, 3a & 3l). We tested the reaction of
2-(bromo-methyl) benzonitrile 2b under optimal reaction conditions, where only a trace
amount of respective product was formed (Table 5, 3l) and no cyclized product was
observed (Table 5, 3m).

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V. NOMULA AND S. N. RAO
Table 4. Functional diversity of 2-amino benzamide with different aldehydesa.
aReaction conditions: 4 (0.5 mmol), 5 (1.0 mmol), KOtBu (1.5 mmol, 3 equiv), BF3.OEt2 (0.5
equiv) in dioxane (3 mL), 130 ꢁC, 24 h.
Based on the previous literature reports,[15] we proposed a plausible reaction mechan-
ism. Initially, nitrile 2, with BF3.OEt2 may form intermediate (I). Further the reaction
of 1 to the intermediate (I) may generate another intermediate (II) under basic condi-
tions, which upon elimination of halogen from intermediate (II), it forms the cyclized
product (III). Next, the subsequent oxidation of the intermediate (III) will give the
desired product (Table 6, 3).
Conclusion
In conclusion, we have developed an efficient method for the synthesis of quinazolin-
4(3H)-ones from easily available starting materials. This present methodology exhibits
good functional group tolerance with a variety of nitriles as well as aldehydes on the
aryl group into the corresponding quinazolin-4(3H)-ones in moderate to good yields.
Experimental
Unless otherwise noted, all reagents were used as received from commercial suppliers. All
non-aqueous reactions were performed under an atmosphere of nitrogen using oven-dried

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Table 5. Reactivity of the various benzonitriles and 2-halobenzamides.
Table 6. Plausible reaction mechanism for formation of quinazolin-4(3H)-ones.[15]
glassware. All solvents were dried before use, following the standard procedures. Reactions
were monitored using thin-layer chromatography (SiO2). TLC plates were visualized with
UV light (254 nm), Column chromatography was carried out using silica gel (100–200
mesh) packed in glass columns. NMR spectra were recorded at 300, 400, 500 MHz (H) and

8
V. NOMULA AND S. N. RAO
at 75, 101, 126 MHz (C), respectively. Chemical shifts (d) are reported in ppm, using the
residual solvent peak in CDCl3 (H: d ¼ 7.26 and C: d ¼ 77.16 ppm) as internal standard, and
coupling constants (J) are given in Hz. High-resolution mass spectrometry (HRMS) was
recorded using electro spray ionization (ESI)ꢂTime-off light techniques.
General procedure for the preparation of starting materials1
DMF (0.2 mL) was added to oxalyl chloride (1.5 mL, 17.74 mmol), and 2- iodobenzoic
acid (4.0 g, 16.12 mmol) in DCM (30 mL). The resulting mixture was stirred for 2 h. The
mixture was concentrated in vacuo and cooled to 0 ꢁC, the crude was directly used in
the next step; this was taken up in DCM (30 mL). To acid chloride, were added amine
2M methylamine in THF (60 mL, 120 mmol) and N, N’-di-isopropylethylamine
(3.09 mL, 17.74 mmol) added. This was stirred for 30 minutes, and a precipitate was
formed. The reaction was left standing overnight. The mixture was filtered; the filtrate
was washed with water. The crude reaction mixture was extracted with CH2Cl2, the
organic solvent was removed in vacuo and the residue purified by recrystallization (PE:
EA ¼ 5:1) 2-iodo-N-methylbenzamide (3.40 g, 81%) as a white solid.
General procedure for the synthesis of 3-Methyl-2-phenylquinazolin-4(3H)-
one (3a)
To a 25 mL round-bottom flask were added 2-iodo-N-methylbenzamide 1a (130.5 mg,
0.5 mmol), Benzonitrile (206 mg, 2.0 mmol), KOtBu (168 mg, 1.5 mmol) and BF3.OEt2
(35.2 mg, 0.25 mmol) in 3.0 mL of 1, 4-dioxane. The reaction mixture was heated in an
oil bath at 130 ꢁC for 24 hrs. After completion of the reaction; it was allowed to attain
room temperature. The reaction mixture was quenched by saturated NaHCO3 (20 ml,
PH ¼ 10.3) solution and extracted by ethyl acetate (15 mL ꢃ 3) dried over anhydrous
Na2SO4, and the solvent was removed under reduced pressure the residue was purified
by column chromatography using silica gel (30% EtOAc/hexane) to afford 3a (83.1 mg;
70% yield).
Full experimental detail, 1H and 13C NMR spectra can be found via the
“Supplementary Content” section of this article’s webpage.
Funding
CSIR-IICT Communication No. 432/2019. V. N. is thankful to CSIR and S.N.R thankful to
SERB-NPDF, New Delhi for their fellowship. We thank DST, Government of India [EMR/2016/
000010] and CSIR-IICT for financial support.

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