Preparation of Quinazolinoquinazolinones via a Cascade Approach

Article abstract of DOI:10.1021/acs.joc.8b02239

A one-pot synthesis of quinazolino[3,4-a]quinazolin-13-ones was realized from the direct reaction of o-(methoxycarbonyl)benzenediazonium salts, nitriles, and 2-cyanoanilines in moderate to good yields. This method utilizes the in situ generation of reactive N-arylnitrilium ion, which undergoes further amination/tandem cyclization/amidation to deliver the desired polycyclic scaffolds with consecutive formation of four N-C bonds. Flexibility in substitution patterns, mild reaction conditions, and operational simplicity are the salient features of this methodology.

Full text of DOI:10.1021/acs.joc.8b02239

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Note
Preparation of Quinazolinoquinazolinones via a Cascade Approach
Mani Ramanathan, and Shiuh-Tzung Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02239 • Publication Date (Web): 25 Oct 2018
Downloaded from http://pubs.acs.org on October 26, 2018
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Preparation of Quinazolinoquinazolinones via a
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Cascade Approach
Mani Ramanathan and Shiuh-Tzung Liu*
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan
Corresponding author. E-mail: stliu@ntu.edu.tw
TITLE RUNNING HEAD: Preparation of quinazolinoquinazolinones
Graphic Abstract (TOC)
___________________________________________________________________
O
N
R1
-
N2+BF4
NH2
CN
R-CN, 80 oC
R2
N
R1
R2
CO2Me
N
R
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ABSTRACT. A one-pot synthesis of quinazolino[3,4-a]quinazolin-13-ones has been realized
from the direct reaction of o-(methoxycarbonyl)benzenediazonium salts, nitriles and 2-
cyanoanilines in moderate to good yields. This method utilizes the in situ generation of reactive
N-arylnitrilium ion, which undergoes further amination/tandem cyclization/amidation to deliver
the desired polycyclic scaffolds with consecutive formation of four N-C bonds. Flexibility in
substitution patterns, mild reaction conditions and operational simplicity are the salient features
of this methodology.
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KEYWORDS. Quinazolinoquinazolinone, Diazonium, Cascade reaction, nitrilium.
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The polynuclear N-heterocyclic compounds with fused multi-ring skeletons are not only of
considerable interest to the drug and dye industry but also of great importance in the realm of
biological sciences.1 Especially, the combination of rigid scaffolds with unique installation of
functional groups, has evoked special interest in synthetic organic chemistry. Among the various
N-heterocycles, quinazolin-4(3H)-one fused polycyclic frameworks are privileged owing to their
prevalence in several natural products such as, Luotonin A,2 Rutaecarpine,3 Tryptanthrin,4
Cephalanthrin A,5 Phaitanthrin (A and B)6 and Cruciferane7 (Scheme 1). On the other hand,
quinazolino[3,4-a]quinazolin-13-one is particularly fascinating motif due to its ubiquitous
structural features.8 Yet, despite the inspiring skeletal diversity, synthetic efforts towards
quinazolino-quinazolinone remain largely underdeveloped.
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Scheme 1. Quinazolinone Fused Polycyclic Natural Products
O
N
O
N
O
N
N
N
N
N
HN
O
Tryptanthrin
O
Luotonin A
Rutaecarpine
O
N
O
N
N
H
N
N
OH
N
HO
HO
O
RO
O
O
Phaitanthrin A
Cruciferane
R = H Cephalanthrin A
R = Me Phaitanthrin B
In 1984, Yamada et al. described the synthesis of 13H-quinazolino[3,4-a]quinazolin-13-ones
from benzoxazine-4-ones and 2-cyanoanilines at elevated temperature (Scheme 2a).8a In this
preparation, 4-iminoquinazoline is believed to be the key intermediate. Venkateswarlu’s group
demonstrated a four step synthesis from 2-aminobenzamide and 2-nitrobenzoic acid (Scheme
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2b), in which the key intermediate dihydro-13H-quinazolino(3,4-a)quinazolin-13-one was
converted into quinazolino-quinazolinones upon the oxidative aromatization.8b In addition,
synthesis of 6-unsubstituted analogue was reported by Proença and co-workers involving the
acid mediated two step reaction of 2-cyanoanilines with triethylorthoformate (Scheme 2c), where
the title compound was obtained by the hydrolysis of the corresponding imine-acid salts.8c
Finally, Nanni’s group observed a minor formation of 6-unsubstituted 13H-quinazolino[3,4-
a]quinazolin-13-one in the multi-step reaction of 2-[4-imino-2-thioxa-1,4-dihydro-3(2H)-
quinazolinyl]benzonitrile with Mn(OAc)3.8d These existing synthetic routes require multi-step
procedures, complicated pre-functionalized sites and harsh conditions. Thus, development of a
strategically unique approach that can directly deliver fused quinazolino-quinazolinones from
readily available substrates in one-step remains elusive.
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Scheme 2. Various Approaches Towards Quinazolino-quinazolinones.
(c)
CN
ref. 8a
(a)
(b)
2 steps
ref. 8c
O
CN
HC(OEt)3
O
NH2
O
N
R = H
NH2
R
N
N
(d)
O
R
CONH2
NH2
+
-
N2 BF4
CN
NH2
OH
4 steps
ref. 8b
R = H
R-CN
one-pot
This report
NO2
CO2Me
Aryldiazonium salts are undoubtedly one of the most important precursors due to their
widespread applications in organic synthesis.9 Ease of preparation from a wide range of
commercially available anilines, excellent leaving group ability of N2 and inherent
electrophilicity render these compounds an attractive alternative to aromatic halides. Notably,
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synthetic applications involving in situ generation of nitrilium intermediate from aryldiazonium
salts and nitriles has gained extensive attention owing to their versatile reactivity and synthetic
flexibility.10 Based on our recent developments on aryldiazonium salts based tandem
annulations,11 we envisaged whether an in situ generation of suitably functionalized N-
arylnitrilium intermediate could be utilized to achieve a mild approach of quinazolino-
quinazolin-13-ones, via an intermolecular cascade/tandem cyclization process. Indeed, as a
proof-of-concept, recently we developed a synthesis of functionalized quinazolin-4(3H)-imines
via an annulation protocol.11b This strategy led us to envision that further advancements might be
plausible by utilizing aryldiazonium precursors. Herein, we disclose a convenient and mild
method for the preparation of substituted quinazolino-quinazolinone derivatives from o-ester
substituted aryldiazonium salts, nitriles and 2-cyanoanilines via in situ generation of N-
arylnitrilium intermediate I from the reaction of 2-(methoxycarbonyl)aryldiazonium salt and
nitrile followed by a tandem amination/cascade cyclization/amidation to afford the fused
quinazolino-quinazolinones (Scheme 3). Substitution reaction of aryldiazonium salts with nitrile
components is a known strategy to afford N-arylnitrilium intermediates with the loss of N2 and
this intermediate can further undergo reaction with various amino and carbon nucleophiles.10-11
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Scheme 3. Our Proposed Synthetic Approach
NC
+
-
R
MeO2C
N2 BF4
N
MeO2C
H2N
RCN
-N2
I
O
N
MeO2C
MeO2C
NH
N
N
N
N
N
R
N
R
N
R
H
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To explore the feasibility, we examined the reaction of 1a with 2-cyanoaniline (2a) in the
presence of anhydrous MeCN under various conditions (Table 1). It was observed that, at room
temperature, desired product was found only in trace amounts. Guided by our previous
9
o
learnings,11a-11d when the reaction was conducted at 80 C for 2h, 3a was isolated in 71% yield
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(Table 1, entry 2). To our delight, when the reaction was carried out at 80 C for 5 h, 6-methyl-
13H-quinazolino[3,4-a]quinazolin-13-one (3a) was isolated in 78% yield (Table 1, entry 3).
Lowering the reaction temperature with extended time resulted in a diminished yield (Table 1,
entry 4). Attempts to reduce the quantity of nitrile in the presence of other co-solvents such as,
DMSO, DMF and DCE were unfruitful and led to inferior results (Table 1, entries 5-7).
Table 1. Reaction Optimizationa
O
CO2Me
N2+BF4
CN
N
N
MeCN
-
N
NH2
1a
2a
3a
entry solvent
T (oC)
rt
t (h)
24
2
Yieldb
trace
71%
78%
56%
NDd
NDd
NDd
1
MeCN
MeCN
MeCN
MeCN
2
80
3
80
5
4
50
12
12
12
12
5c
6c
7c
MeCN/dmso
MeCN/DMF
MeCN/DCE
80
100
reflux
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a Reaction conditions: a mixture of 1a (0.40 mmol), 2a (0.48 mmol) and acetonitrile (2 mL) in a
sealed tube. b yields given refer to isolated yields. c MeCN (1 mL) in solvent (2 mL). d ND = not
detected.
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With these optimal conditions in hand, we then systematically studied the scope of this
reaction with varieties of substituted 2-cyanoanilines in combination with benzenediazonium salt
(1a) and acetonitrile (Table 2). Regardless of the position, various halogenated 2-cyanoanilines
were participated in the reaction and provided the corresponding products in good isolated yields
(Table 2, 3a-3d). Remarkably, anthralonitirle bearing ortho-chloro substituent readily reacted
(Table 2, 3g). All these halogenated quinazolino-quinazolinones could serve as potential
building blocks for further synthetic conversions. Substrates with phenyl and 1-naphthyl
substituents smoothly participated in the transformation and afforded the respective arylated
product in good yields (Table 2, 3e-3f). In particular, 2-amino-5-(naphthalen-1-yl)benzonitrile
reacted with 1a in acetonitrile, providing 6-methyl-10-(-naphthyl)quinazolino[3,4-
a]quinazolinones 3f in 73% yield. It is noted that, antharalonitrile with diketo functionality did
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not led to the desired product (Eq. 1).
Heteroaromatic counterparts such as, 2-
aminonicotinonitrile, 2-aminothiophene-3-carbonitrile and linear 3-aminocrotononitrile were
failed to give the corresponding products despite our extensive efforts.
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Table 2. Reaction of 1a with various 2-cyanoanilines in MeCNa
5
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7
8
O
N
80 oC
NH2
R2
N
1a
9
R2
MeCN
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CN
N
2
3
3a, R2 = H (78%)
3b, R2 = Cl (66%)
O
N
3c, R2 = Br (68%)
N
N
R2
3d, R2 = I (66%)
3e, R2 = o-MeC6H4 (76%)
3f, R2 = -naphthyl (73%)
O
N
N
3g (83%)
N
Cl
a Reaction conditions: 1a (0.40 mmol) and 2 (1.2 eq) in acetonitrile (2 mL) were heated to 80 oC
for 5 h; isolated yields are reported in brackets.
O
CH3CN
Ph
CN
(1)
complex mixture
1a
+
O
NH2
Next, we studied the scope and limitation of this method with various nitrile components
(Table 3). A series of aliphatic nitriles such as, 1o, 2o, 3o and cyclic nitriles were involved in the
reaction efficiently, leading to the formation of 4a-4d in moderate to excellent yields. Similarly,
profound flexibility can be exerted concerning aryl nitriles; thus, variously substituted
benzonitriles were utilized in this reaction to furnish 6-arylsubstituted quinazolino-
quinazolinones in yields ranging from 54%-63% (Table 3, 4e-4g). The sensitive cyano
functionality on the alkyl linkage remains intact, thus offering ample potential for further
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synthetic elaboration. To our delight, benzylnitrile was also amenable in this reaction to deliver
the corresponding 6-benzylated product in good yields (Table 3, 4i). Again, reaction of 1a with
2-amino-5-(naphthalen-1-yl)benzonitrile in various nitriles yielded the corresponding products in
good yields (Table 3, 4j-4k). Intriguingly, when 2-amino-5-(naphthalen-1-yl)benzonitrile was
treated with benzylnitrile, a mixture of isomers 4l and 4l’ were formed as an inseparable mixture,
presumably due to the similar stability of conjugation. Unfortunately, thiophene-2-carbonitrile
and α-chloroacetonitirle were failed to give the corresponding products.
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Table 3. Reaction of Various Nitriles with 1a and 2a
O
N
NH2
RCN
80 oC
R2
1a
N
R2
CN
N
R
2
4
4a
, R = Pr, (76%)
O
N
4b
, R = i-Pr, (47%)
, R = t-Bu, (42%)
N
N
4c
4d
4e
4f
, R = c-Pr, (69%)
, R = Ph, (63%)
, R = o-Tol, (57%)
R
4g
, R = p-Tol, (54%)
R2 = H
4h,
R = NC(CH2)4, (79%)
, R =PhCH2, (74%)
4i
O
N
4j
, R = Pr, (66%)
N
N
4k
, R = i-Pr, (62%)
R
R2 = -naphthyl
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O
N
O
N
N
N
N
Ph
N
Ph
H
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4l 4l'
+
(63%) (insepearable 1:0.47)
a Reaction conditions: 1a (0.40 mmol) and 2 (1.2 eq) in nitrile (2 mL) were heated to 80 oC for 5
h; isolated yields are reported in brackets.
Finally, we contemplated the scope of this tandem process with variously substituted o-
(methoxycarbonyl)benzenediazonium salts 1b-1e (Table 4). The efficiency was slightly affected
by variations of substituents on the aryl ring. A series of aryldiazonium salts bearing substituents
at para and meta positions underwent the reaction smoothly to provide the corresponding 13H-
quinazolino(3,4-a)quinazolin-13-ones in acceptable yields (Table 4, 5a-5c) with the exception of
3,4-dimethoxy substituted precursor 1f (Eq. 2). To further challenge, we also tested the reaction
in presence of a functionality of benzyl ester and found that the reaction proceeded smoothly to
give 5d in 44% yield (Table 4, 5d).
Table 4. Reaction Scope of Aryldiazonium Saltsa
O
+
-
NH2
CN
N
N
N2 BF4
MeCN
80 oC
R1
R1
N
CO2Me
1b-1e
2a
5
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O
N
O
N
O
O
N
O
I
N
N
N
N
N
N
N
O
N
Br
Ph
N
9
5b
(36%)
5d
(44%)
5a
5c
(33%)
(63%)
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a Reaction conditions: aryldiazonium salt 1 (1.0 eq) and 2 (1.2 eq) in acetonitrile (2 mL) were
heated to 80 oC for 5 h; isolated yields are given in brackets.
+
-
N2 BF4
MeO
MeO
MeCN
80 oC
complex mixture
(2)
2a
CO2Me
1f
Intriguingly, when 2-(methoxycarbonyl)-6-methylbenzenediazonium salt (1g) bearing an
adjacent methyl group was employed in this reaction, we observed the formation of quinazolin-
4-(3H)-imine (6) and N-arylquinazolin-3-(4H)-one (7), instead of the corresponding product, 4,6-
dimethyl-13H-quinazolino[3,4-a]quinazolin-13-one probably owing to the steric reason (Eq. 3).
O
NH
+
-
N
N2 BF4
2a
N
(3)
CN
N
CO2Me
MeCN,
CO2Me
N
1g
6
7
(73%)
(8%)
For a practical utility of this method, a gram scale synthesis of 3a was performed. Typically,
treatment of 1a (1 g) with anthralonitrile 2a (0.52 g) in acetonitrile (20 mL) furnished 3a (0.87 g,
84%) and 2-(2-methyl-4-oxo-quinazolin-3(4H)-yl)benzonitrile (8) in 4% yield (Eq. 4). (Caution:
Aryldiazonium salts are dangerously explosive upon heating, and reactions must be carried out
using necessary precautions).
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O
O
80 oC
N
(4)
N
2a
1a
+
N
MeCN
CN
N
N
8
(4%)
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3a
(84%)
In summary, we have developed a unique transition-metal free strategy for accessing diverse
polycyclic quinazolino-quinazolinones scaffolds from a simple set of readily available precursors
through an intermolecular amination/tandem cyclization/amidation of in situ generated N-
arylnitrilium intermediate from the reaction of diazonium salt with a nitrile functionality. The
salient features of this report include mild reaction condition, broad substrate scope,
experimental simplicity and consecutive formation of four C-N bonds, making this approach
with potential for further synthetic applications.
Experimental Section
General information. 1H and 13C NMR were recorded in a 400 MHZ spectrometer in CDCl3 and
CD3CN referenced to TMS. All the nitriles were dried over activated 4Ao molecular sieves and
solid nitriles were purchased and used without any further drying. All the anilines were
commercially purchased and used for diazotization without further purification. Other chemicals
were used as purchased. Flash chromatography was performed using silica gel 230-400 mesh.
Aryldiazonium salts were prepared according to the literature procedure. In cases of known
compounds, their spectral data were compared with the literature values. Melting points were
determined on a Fargo MP-1D instrument. Unless otherwise noted, all the reactions were
performed without any special precautions. Compounds 2b,12a 2c,12b 2d,12c, 2g,12d and 2h12e were
prepared according to the literature methods, whereas the preparation of 2e and 2f were achieved
by a Suzuki coupling.12b
General procedure for preparing aryldiazonium tetrafluoroborate.
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Methyl-2-aminobenzoate (1g, 6.61 mmol, 1.0 equiv.) was dissolved in a mixture of water (4 mL)
and 50% aqueous hydrofluroboric acid (2.4 mL, 13.23 mmol, 2.0 equiv.). The mixture was
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oC and a solution of NaNO2 (0.46 g, 6.68 mmol in 4 mL of water) was added
cooled to 0
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slowly. The
resulting reaction mixture was stirred at 0 C for 30 minutes and the precipitate
was collected by filtration. The solid product was dissolved in minimum acetone and re-
precipitated using diethyl ether to yield 2-(methoxycarbonyl)benzenediazonium tetrafluoroborate
which was dried under vacuum. (white solid, 1.45 g, 88%). The spectral data are in agreement
with the literature reported.13
2-(Methoxycarbonyl)-4-methylbenzenediazonium tetrafluoroborate (1b).
901 mg, 94%, pale pink solid: 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 8.4 Hz, 1H), 8.27
(s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 4.02 (s, 3H), 2.64 (s, 3H); C{1H} NMR (100 MHz, DMSO-
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d6) δ 161.5, 154.3, 135.5, 135.2, 133.0, 130.4, 111.8, 54.0, 22.1; HRMS (ESI-TOF) calcd. For
C9H9N2O2 (M-BF4)+ m/z = 177.0659, found 177.0667.
5-Bromo-2-(methoxycarbonyl)benzenediazonium tetrafluoroborate (1c).
630 mg, 74%, brown solid: 1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.61 (d, J = 8.4 Hz,
1H), 8.29 (d, J = 8.4 Hz, 1H), 4.02 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 160.9, 143.7,
136.8, 133.3, 129.5, 126.9, 117.3, 54.3; HRMS (ESI-TOF) calcd. For C8H6 BrN2O2 (M-BF4)+
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m/z = 240.9607, found 240.9612; HRMS (ESI-TOF) calcd. For C8H6 BrN2O2 (M-BF4)+ m/z =
81
242.9587, found 242.9595.
4-Iodo-2-(methoxycarbonyl)benzenediazonium tetrafluoroborate (1d).
569 mg, 84%, white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 8.4 Hz, 2H), 8.58 (d,
J = 8.0 Hz, 1H), 4.00 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 160.4, 143.9, 140.7, 135.0,
130.4, 114.6, 113.6, 54.2; HRMS (ESI-TOF) calcd. For C8H6IN2O2 (M-BF4)+ m/z = 288.9468,
found 288.9474.
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4-((Benzyloxy)carbonyl)-2-(methoxycarbonyl)benzenediazonium tetrafluoroborate (1e).
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770 mg, 72%, off-white solid: H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.81 (d, J = 7.6
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Hz, 1H), 8.50 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 6.8 Hz, 2H), 7.43 (d, J = 7.6 Hz, 3H), 5.46 (s, 2H),
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4.05 (s, 3H); C{1H} NMR (100 MHz, DMSO-d6) δ 161.8, 160.8, 140.8, 135.5, 135.0, 134.8,
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133.5, 132.8, 128.6 (2C), 128.5, 117.0, 68.0, 54.4; HRMS (ESI-TOF) calcd. For C16H13N2O4 (M-
BF4)+ m/z = 297.0870, found 297.0880.
4,5-Dimethoxy-2-(methoxycarbonyl)benzenediazonium tetrafluoroborate (1f).
677 mg, 77%, brown solid: 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.79 (s, 1H), 4.13 (s,
3H), 4.00 (s, 3H), 3.96 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 161.2, 158.2, 151.6,
127.5, 115.7, 114.4, 104.0, 57.9, 57.3, 53.9; HRMS (ESI-TOF) calcd. For C10H11N2O4 (M-BF4)+
m/z = 223.0713, found 223.0724.
2-(Methoxycarbonyl)-6-methylbenzenediazonium tetrafluoroborate (1g).
870 mg, 91%, white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 4.8 Hz, 2H), 8.13 (t, J
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= 4.8 Hz, 1H), 4.03 (s, 3H), 2.83 (s, 3H); C{1H} NMR (100 MHz, DMSO-d6) δ 161.6, 146.9,
140.2, 136.7, 130.4, 130.3, 115.0, 54.1, 18.4; HRMS (ESI-TOF) calcd. For C9H9N2O2 (M-BF4)+
m/z = 177.0659, found 177.0663.
General Procedure for the synthesis of 13H-quinazolino[3,4-a]quinazolin-13-ones.
In a dry 10 mL glass sealed tube, aryldiazonium salt (0.40 mmol) and 2-cyanoaniline (0.48
mmol) were suspended in 2 mL of anhydrous nitrile. The tube was sealed with a Teflon screw
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cap and heated in an oil bath (80 C) for 5h. After cooling to room temperature, the reaction
mixture was diluted with ethyl acetate (30 mL) and washed with saturated aq. NaHCO3 solution
(10 mL). Organic Layer was dried over anhydrous Na2SO4. Solvents removed and purified by
column chromatography (Eluent 40% to 70% EtOAc:Hexane) to obtain the desired compounds.
6-Methyl-13H-quinazolino[3,4-a]quinazolin-13-one (3a).8b
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81 mg, 78%, pale yellow solid: mp 227-229 oC: 1H NMR (400 MHz, CDCl3) δ 8.26 (dd, J = 8.0,
1.2 Hz, 1H), 8.32 (d, J = 7.6 Hz, 1H), 7.76 (ddd, J = 15.4, 7.6, 1.6 Hz, 1H), 7.72 (d, J = 3.2 Hz,
2H), 7.64 (d, J = 8.0 Hz, 1H), 7.61-7.57 (m, 1H), 7.51 (ddd, J = 15.2, 7.6, 0.8 Hz, 1H), 2.95 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.2, 153.2, 148.2, 143.3, 136.7, 134.8, 131.9, 128.2,
128.1, 128.0, 126.7, 126.1, 122.9, 120.4, 119.7, 26.0; HRMS (ESI-TOF) calcd. For C16H12N3O
(M+H)+ m/z = 262.0980, found 262.0984.
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10-Chloro-6-methyl-13H-quinazolino[3,4-a]quinazolin-13-one (3b).
94 mg, 81%, off-white solid: mp 228-229 oC: 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 2.4 Hz,
1H), 8.31 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 3.6 Hz, 2H), 7.68 (dd, J = 8.8, 2.4 Hz, 1H), 7.62-7.57
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(m, 2H), 2.95 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 166.9, 152.1, 148.5, 141.7, 136.5,
135.1, 133.9, 132.0, 128.4, 128.3, 127.8, 125.9, 122.9, 120.8, 120.4, 26.1; HRMS (ESI-TOF)
calcd. For C16H1135ClN3O (M+H)+ m/z = 296.0591, found 296.0599; HRMS (ESI-TOF) calcd.
For C16H1137ClN3O (M+H)+ m/z = 298.0561, found 298.0624.
10-Bromo-6-methyl-13H-quinazolino[3,4-a]quinazolin-13-one (3c).
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92 mg, 68%, white solid: mp 273-274 C: H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 2.0 Hz,
1H), 8.38 (d, J = 7.6 Hz, 1H), 7.86 (dd, J = 8.8, 2.4 Hz, 1H), 7.77-7.72 (m, 2H), 7.64 (ddd, J =
13.8, 6.6, 2.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 2.96 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 166.9, 152.0, 148.8, 141.9, 138.0, 136.5, 132.1, 129.2, 128.5 (2C), 127.8, 123.1, 121.9, 121.1,
120.4, 26.0; HRMS (ESI-TOF) calcd. For C16H1179BrN3O (M+H)+ m/z = 340.0085, found
340.0086; HRMS (ESI-TOF) calcd. For C16H1181BrN3O (M+H)+ m/z = 342.0065, found
342.0073.
10-Iodo-6-methyl-13H-quinazolino[3,4-a]quinazolin-13-one (3d).
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101 mg, 66%, white solid: mp 234-235 C: H NMR (400 MHz, CDCl3) δ 9.05 (d, J = 2.0 Hz,
1H), 8.38 (d, J = 8.0 Hz, 1H), 8.06 (dd, J = 8.4, 2.0 Hz, 1H), 7.77-7.71 (m, 2H), 7.67-7.63 (m,
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1H), 7.43-7.42 (m, 1H), 2.96 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 167.0, 151.8, 148.8,
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143.6, 142.6, 136.6, 135.4, 132.1, 128.5 (2C), 127.8, 123.1, 121.2, 120.4, 92.8, 26.1; HRMS
(ESI-TOF) calcd. For C16H11IN3O (M+H)+ m/z = 387.9947, found 387.9961.
6-Methyl-10-(o-tolyl)-13H-quinazolino[3,4-a]quinazolin-13-one (3e).
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106 mg, 76%, off-white solid: mp 119-120 C: H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 2.0
Hz, 1H), 8.36 (d, J = 8.0 Hz, 1H), 7.77 (dd, J = 8.4, 2.0 Hz, 1H), 7.74-7.70 (m, 3H), 7.65-7.59
(m, 1H), 7.27-7.23 (m, 4H), 2.99 (s, 3H), 2.26 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
167.2, 153.3, 148.0, 142.2, 140.0, 136.7, 136.1 (2C), 135.1, 131.9, 130.4, 129.8, 128.3, 128.1,
127.9, 126.8, 125.9 (2C), 123.0, 120.3, 119.6, 26.0, 20.4; HRMS (ESI-TOF) calcd. For
C23H18N3O (M+H)+ m/z = 352.1450, found 352.1457.
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6-Methyl-10-(naphthalen-1-yl)-13H-quinazolino[3,4-a]quinazolin-13-one (3f).
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113 mg, 73%, off-white solid: mp 283-284 C: H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 2.0
Hz, 1H), 8.37 (d, J = 8.0 Hz, 1H), 7.95 (dd, J = 8.4, 2.0 Hz, 1H), 7.89 (t, J = 8.4 Hz, 2H), 7.81-
7.71 (m, 4H), 7.62 (ddd, J = 13.4, 6.4, 2.4 Hz, 1H), 7.54-7.50 (m, 1H), 7.49-7.46 (m, 2H), 7.41
(t, J = 8.0 Hz, 1H), 3.01 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.2, 153.3, 148.2, 142.5,
141.0, 138.2, 136.9, 136.7, 133.7, 131.9, 131.2, 128.4 (2C), 128.3, 128.2, 127.6, 127.5, 126.4,
126.0, 125.9, 125.3 (2C), 123.0, 120.3, 119.9, 26.1; HRMS (ESI-TOF) calcd. For C26H18N3O
(M+H)+ m/z = 388.1450, found 388.1454.
8-Chloro-6-methyl-13H-quinazolino[3,4-a]quinazolin-13-one (3g).
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97 mg, 83%, off-white solid: mp 233-234 C: H NMR (400 MHz, CDCl3) δ 8.53 (dd, J = 8.0,
1.2 Hz, 1H), 8.33 (d, J = 7.6 Hz, 1H), 7.82 (dd, J = 8.0, 1.2 Hz, 1H), 7.75-7.72 (m, 2H), 7.64-
7.60 (m, 1H), 7.42 (t, J = 8.0 Hz, 1H), 3.01 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 167.0,
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152.6, 149.3, 140.1, 136.5, 134.9, 132.1, 130.9, 128.4, 128.3, 128.0, 125.4, 122.9, 121.5, 120.4,
26.2; HRMS (ESI-TOF) calcd. For C16H1135ClN3O (M+H)+ m/z = 296.0591, found 296.0599;
HRMS (ESI-TOF) calcd. For C16H1137ClN3O (M+H)+ m/z = 298.0561, found 298.0602.
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6-Propyl-13H-quinazolino[3,4-a]quinazolin-13-one (4a).
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87 mg, 76%, pale yellow solid: mp 238-239 oC: 1H NMR (400 MHz, CDCl3) δ 8.68 (dd, J = 8.0,
1.2 Hz, 1H), 8.36 (dd, J = 7.6, 1.6 Hz, 1H), 7.82-7.78 (m, 1H), 7.74-7.66 (m, 3H), 7.62 (ddd, J =
14.8, 7.4, 1.2 Hz, 1H), 7.55 (ddd, J = 15.2, 7.4, 1.2 Hz, 1H), 3.19 (t, J = 7.6 Hz, 2H), 1.91 (sex, J
= 7.6 Hz, 2H), 0.91 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.5, 153.3, 151.9,
143.5, 136.7, 134.8, 131.8, 128.3, 128.1, 128.0, 126.7, 126.5, 123.1, 120.4, 119.7, 39.0, 22.3,
13.6; HRMS (ESI-TOF) calcd. For C18H16N3O (M+H)+ m/z = 290.1293, found 290.1291.
6-Isopropyl-13H-quinazolino[3,4-a]quinazolin-13-one (4b).
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54 mg, 47%, brown solid: mp 178-179 oC: 1H NMR (400 MHz, CDCl3) δ 8.63 (dd, J = 8.0, 1.2
Hz, 1H), 8.32 (dd, J = 8.0, 1.6 Hz, 1H), 7.77 (ddd, J = 11.6, 7.4, 1.2 Hz, 1H), 7.75-7.67 (m, 2H),
7.60-7.55 (m, 2H), 7.51 (ddd, J = 14.4, 7.0, 1.2 Hz, 1H), 3.74 (hept, J = 6.4 Hz, 1H), 1.39 (d, J =
6.8 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.5, 157.2, 153.3, 143.7, 136.7, 134.7, 131.7,
128.1, 127.9, 127.8, 126.6, 126.5, 123.0, 120.2, 119.5, 33.5, 22.3; HRMS (ESI-TOF) calcd. For
C18H16N3O (M+H)+ m/z = 290.1293, found 290.1290.
6-(tert-Butyl)-13H-quinazolino[3,4-a]quinazolin-13-one (4c).
51 mg, 42%, brown sticky solid: 1H NMR (400 MHz, CDCl3) δ 8.57 (dd, J = 8.4, 1.2 Hz, 1H),
8.22 (dd, J = 7.2, 1.2 Hz, 1H), 7.77 (ddd, J = 15.2, 7.6, 1.6 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H),
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7.63-7.52 (m, 3H), 7.50-7.48 (m, 1H), 1.42 (s, 9H); C{1H} NMR (100 MHz, CDCl3) δ 167.7,
159.4, 154.3, 143.5, 138.5, 134.7, 130.7, 127.9, 127.7, 127.3, 126.5, 126.2, 122.3, 122.0, 119.2,
42.6, 32.0; HRMS (ESI-TOF) calcd. For C19H18N3O (M+H)+ m/z = 304.1450, found 304.1441.
6-Cyclopropyl-13H-quinazolino[3,4-a]quinazolin-13-one (4d).
81 mg, 69%, brown solid: mp 195-196 oC: 1H NMR (400 MHz, CDCl3) δ 8.66 (dd, J = 8.0, 0.8
Hz, 1H), 8.37 (dd, J = 8.0, 1.6 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.77-7.68 (m, 2H), 7.62-7.57
(m, 2H), 7.48 (t, J = 8.0 Hz, 1H), 2.34 (hept, J = 4.8 Hz, 1H), 1.68-1.64 (m, 2H), 1.30-1.26 (m,
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2H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.6, 153.2, 153.0, 143.8, 136.9, 134.7, 131.5, 128.2,
127.9, 127.3, 126.8, 126.2, 123.0, 120.7, 119.6, 17.4, 13.4; HRMS (ESI-TOF) calcd. For
C18H14N3O (M+H)+ m/z = 288.1137, found 288.1136.
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6-Phenyl-13H-quinazolino[3,4-a]quinazolin-13-one (4e).
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80 mg, 63%, off-white solid: mp 143-144 oC: 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 8.0 Hz,
1H), 8.29 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 3.6 Hz, 2H), 7.61-7.57 (m, 3H), 7.50-7.44 (m, 1H),
7.43-7.39 (m, 3H), 7.26-7.22 (m, 1H), 7.96 (d, J = 8.4 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 167.6, 153.6, 149.3, 143.7, 137.6, 135.5, 135.0, 131.1, 131.0, 129.1, 128.6, 128.5,
127.8, 127.5, 127.4, 126.8, 122.3, 121.9, 119.9; HRMS (ESI-TOF) calcd. For C21H14N3O
(M+H)+ m/z = 324.1137, found 324.1136.
6-(o-Tolyl)-13H-quinazolino[3,4-a]quinazolin-13-one (4f).
76 mg, 57%, off-white solid: mp 274-275 oC: 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J = 8.0, 0.8
Hz, 1H), 8.32 (dd, J = 7.6, 1.6 Hz, 1H), 7.87-7.81 (m, 2H), 7.62 (ddd, J = 11.2, 4.8, 2.0 Hz, 1H),
7.50 (dd, J = 7.6, 0.8 Hz, 1H), 7.45-7.37 (m, 2H), 7.30 (t, J = 7.6 Hz, 1H), 7.23-7.19 (m, 2H),
6.95 (d, J = 8.8 Hz, 1H), 2.12 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.4, 153.2, 149.4,
143.5, 137.3, 135.7, 135.0 (2C), 131.6, 131.4, 130.7, 129.3, 128.7, 127.9, 127.7, 127.3, 127.0
(2C), 122.3, 120.3, 120.0, 19.6; HRMS (ESI-TOF) calcd. For C22H16N3O (M+H)+ m/z =
338.1293, found 338.1292.
6-(p-Tolyl)-13H-quinazolino[3,4-a]quinazolin-13-one (4g).
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73 mg, 54%, pale yellow solid: mp 226-227 C: H NMR (400 MHz, CDCl3) δ 8.75-8.72 (m,
1H), 8.29-8.27 (m, 1H), 7.82-7.80 (m, 2H), 7.59-7.55 (m, 1H), 7.50-7.48 (m, 2H), 7.43 (ddd, J =
15.0, 7.4, 1.2 Hz, 1H), 7.28-7.24 (m, 1H), 7.21-7.19 (m, 2H), 7.01 (d, J = 8.4 Hz, 1H), 2.38 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.7, 153.7, 149.5, 143.8, 141.7, 137.7, 135.0, 132.7,
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130.9, 129.8, 128.5, 128.4, 127.7, 127.5, 127.3, 126.8, 122.2, 121.9, 119.9, 21.5; HRMS (ESI-
TOF) calcd. For C22H16N3O (M+H)+ m/z = 338.1293, found 338.1294.
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5-(13-Oxo-13H-quinazolino[3,4-a]quinazolin-6-yl)pentanenitrile (4h).
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104 mg, 79%, pale yellow sticky solid: 1H NMR (400 MHz, CDCl3) δ 8.64 (dd, J = 8.0, 0.8 Hz,
1H), 8.33 (dd, J = 8.0, 1.6 Hz, 1H), 7.81-7.77 (m, 1H), 7.72 (ddd, J = 15.6, 8.0, 1.6 Hz, 1H), 7.69
(dd, J = 8.0, 0.8 Hz, 1H), 7.65-7.59 (m, 2H), 7.54 (ddd, J = 15.2, 7.8, 1.2 Hz, 1H), 3.25 (t, J = 7.2
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Hz, 2H), 2.35 (t, J = 7.2 Hz, 2H), 2.12-2.04 (m, 2H), 1.73-1.66 (m, 2H); C{1H} NMR (100
MHz, CDCl3) δ 167.3, 153.1, 150.6, 143.2, 136.4, 134.9, 132.0, 128.3, 128.2 (2C), 126.6, 126.5,
123.1, 120.3, 119.6, 119.1, 36.2, 27.5, 24.7, 17.0; HRMS (ESI-TOF) calcd. For C20H17N4O
(M+H)+ m/z = 329.1402, found 329.1397.
6-Benzyl-13H-quinazolino[3,4-a]quinazolin-13-one (4i).
101 mg, 74%, pale yellow solid: mp 208-209 oC: 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 8.0
Hz, 1H), 8.32 (dd, J = 7.2, 1.2 Hz, 1H), 7.83-7.74 (m, 2H), 7.69 (d, J = 8.4 Hz, 1H), 7.65 (dd, J =
7.2, 1.6 Hz, 1H), 7.61-7.54 (m, 2H), 7.29-7.20 (m, 5H), 4.55 (s, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 167.3, 153.4, 149.9, 143.4, 136.7, 135.4, 134.8, 131.9, 128.9, 128.5, 128.4, 128.3,
128.2, 127.4, 126.8, 126.7, 122.9, 120.6, 119.8, 42.7; HRMS (ESI-TOF) calcd. For C22H15N3O
(M+H)+ m/z = 338.1293, found 338.1297.
10-(Naphthalen-1-yl)-6-propyl-13H-quinazolino[3,4-a]quinazolin-13-one (4j).
109 mg, 66%, pale yellow solid: mp 212-213 oC: 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 2.0
Hz, 1H), 8.33 (d, J = 7.2 Hz, 1H), 7.93 (dd, J = 8.4, 2.0 Hz, 1H), 7.88 (t, J = 8.4 Hz, 2H), 7.82-
7.79 (m, 2H), 7.71-7.67 (m, 2H), 7.61-7.58 (m, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.49-7.45 (m, 2H),
7.42-7.38 (m, 1H), 3.22 (t, J = 7.6 Hz, 2H), 1.92 (sex, J = 7.2 Hz, 2H), 0.92 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 167.4, 153.2, 152.0, 142.6, 140.8, 138.2, 136.8, 136.7,
133.7, 131.8, 131.1, 128.3 (2C), 128.2, 128.0, 127.5, 127.4, 126.4, 126.3, 125.9, 125.3, 125.2,
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123.0, 120.4, 119.7, 39.0, 22.3, 13.5; HRMS (ESI-TOF) calcd. For C28H22N3O (M+H)+ m/z =
416.1763, found 416.1761.
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6-Isopropyl-10-(naphthalen-1-yl)-13H-quinazolino[3,4-a]quinazolin-13-one (4k).
102 mg, 62%, pale brown solid: mp 126-127 oC: 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 2.0
Hz, 1H), 8.33 (dd, J = 8.4, 1.6 Hz, 1H), 7.93 (d, J = 8.0, 1.6 Hz, 1H), 7.83 (t, J = 8.8 Hz, 2H),
7.85-7.80 (m, 2H), 7.73-7.69 (m, 1H), 7.61-7.58 (m, 2H), 7.51 (t, J = 8.0 Hz, 1H), 7.47-7.44 (m,
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2H), 7.42-7.38 (m, 1H), 3.80 (hept, J = 6.8 Hz, 1H), 1.45 (d, J = 6.8 Hz, 6H); C{1H} NMR
(100 MHz, CDCl3) δ 167.5, 157.4, 153.3, 142.9, 140.8, 138.2, 136.8 (2C), 133.7, 131.8, 131.2,
128.3 (2C), 128.1, 127.9, 127.5, 127.4, 126.5, 126.4, 125.8, 125.3, 125.2, 123.1, 120.3, 119.6,
33.6, 22.4; HRMS (ESI-TOF) calcd. For C28H22N3O (M+H)+ m/z = 416.1763, found 416.1760.
6-Benzyl-10-(naphthalen-1-yl)-13H-quinazolino[3,4-a]quinazolin-13-one (4l) and 6-
benzylidene-10-(naphthalen-1-yl)-6,7-dihydro-13H-quinazolino[3,4-a]quinazolin-13-one
(4l’).
116 mg, 63% (4l : 4l’ = 1: 0.47), pale yellow solid: mp 132-133 oC; 1H NMR (400 MHz, CDCl3)
δ 8.79 (d, J = 2.0 Hz, 1H), 8.28 (dd, J = 8.0, 1.6 Hz, 1H), 7.95 (dd, J = 8.0, 2.0 Hz, 1.52 H), 7.89
(d, J = 8.4 Hz, 1.52 H), 7.87-7.85 (m, 2H), 7.82-7.79 (m, 2H), 7.77-7.72 (m, 1H), 7.74-7.70 (m,
0.90 H), 7.57 (ddd, J = 15.0, 7.2, 0.8 Hz, 1H), 7.53-7.45 (m, 2H), 7.44-7.41 (m, 2H), 7.40-7.37
(m, 2H), 7.35-7.31 (m, 1H), 7.29-7.26 (m, 3.5 H), 7.25-7.23 (m, 2.36H), 7.12 (t, J = 7.2 Hz, 0.47
H), 6.25 (brs, 0.79 H), 4.59 (s, 2H), 4.20 (s, 0.94 H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.2,
165.1, 161.8, 153.3, 150.0, 142.6, 141.2, 138.6, 138.4, 138.1, 136.9, 136.7, 135.6, 135.5, 133.7,
133.6, 131.9, 131.2, 131.1, 129.3, 128.9, 128.5, 128.4, 128.3, 128.2, 128.1, 127.5, 127.4, 127.2,
126.5, 126.46, 126.40, 126.3, 125.9, 125.4, 125.3, 123.0, 122.8, 120.6, 119.8, 112.4, 45.5, 42.8;
HRMS (ESI-TOF) calcd. For C32H22N3O (M+H)+ m/z = 464.1763, found 464.1766.
2,6-Dimethyl-13H-quinazolino[3,4-a]quinazolin-13-one (5a).
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65 mg, 63%, brown solid: mp 224-225 C: H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 8.0 Hz,
1H), 8.16 (s, 1H), 7.79-7.76 (m, 1H), 7.67-7.60 (m, 2H), 7.55-7.51 (m, 2H), 2.95 (s, 3H), 2.49 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.4, 153.0, 148.2, 143.3, 138.6, 134.7, 134.5, 132.9,
128.0 (2C), 126.7, 126.1, 122.8, 120.2, 119.8, 26.1, 20.9; HRMS (ESI-TOF) calcd. For
C17H14N3O (M+H)+ m/z = 276.1137, found 276.1144.
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3-Bromo-6-methyl-13H-quinazolino[3,4-a]quinazolin-13-one (5b).
37 mg, 36%, brown solid: mp 248-249 oC: 1H NMR (400 MHz, CDCl3) δ 8.66 (dd, J = 8.0, 0.8
Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H), 7.81 (ddd, J = 15.2, 7.4, 1.2 Hz, 1H),
7.80-7.75 (m, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 2.97 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 166.7, 153.5, 147.6, 143.2, 137.5, 135.2, 131.6, 129.9, 128.3, 126.8, 126.6,
126.4, 123.3, 121.7, 119.6, 26.0; HRMS (ESI-TOF) calcd. For C16H1179BrN3O (M+H)+ m/z =
340.0085, found 340.0086; HRMS (ESI-TOF) calcd. For C16H1181BrN3O (M+H)+ m/z =
342.0065, found 342.0081.
2-Iodo-6-methyl-13H-quinazolino[3,4-a]quinazolin-13-one (5c).
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34 mg, 33%, brown solid: mp 152-153 C: H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 2.0 Hz,
1H), 8.66 (d, J = 8.0 Hz, 1H), 8.01 (dd, J = 8.8, 1.6 Hz, 1H), 7.82 (t, J = 8.0 Hz, 1H), 7.68 (d, J =
8.0 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 2.95 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 165.8, 153.3, 147.6, 143.3, 140.6, 137.2, 136.2, 135.2, 128.3, 126.9, 126.3,
124.2, 121.9, 119.6, 93.0, 26.0; HRMS (ESI-TOF) calcd. For C16H11IN3O (M+H)+ m/z =
387.9947, found 387.9961.
Benzyl 6-methyl-13-oxo-13H-quinazolino[3,4-a]quinazoline-2-carboxylate (5d).
34 mg, 33%, brown sticky solid: 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 8.0 Hz, 1H), 8.49 (s,
1H), 8.41 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.69 (d, J = 8.0 Hz,
1H), 7.56 (t, J = 7.6 Hz, 1H), 7.45-7.41 (m, 2H), 7.39-7.33 (m, 3H), 5.41 (s, 2H), 2.98 (s, 3H);
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13C{1H} NMR (100 MHz, CDCl3) δ 166.6, 164.6, 153.8, 147.9, 143.4, 136.6, 135.2, 135.1,
133.2, 128.8, 128.7 (2C), 128.5, 128.4, 128.3, 126.8, 126.4, 125.7, 122.1, 119.5, 67.8, 26.0;
HRMS (ESI-TOF) calcd. For C24H18N3O3 (M+H)+ m/z = 396.1348, found 396.1362.
Methyl 2-(4-imino-2-methylquinazolin-3(4H)-yl)-3-methylbenzoate (6).
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85 mg, 73%, off-white solid: mp 95-96 C: H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 8.0 Hz,
1H), 8.07 (dd, J = 8.0, 1.2 Hz, 1H), 7.69 (ddd, J = 15.4, 7.6, 1.6 Hz, 1H), 7.66-7.64 (m, 1H),
7.61-7.53 (m, 2H), 7.45 (ddd, J = 15.0, 7.6, 0.8 Hz, 1H), 5.07 (brs, 1H), 3.68 (s, 3H), 2.18 (s,
3H), 2.05 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.6, 155.8, 152.4, 144.9, 137.5, 136.4,
135.4, 134.2, 130.9, 130.3, 128.0, 127.1, 127.0, 125.8, 117.7, 52.6, 23.3, 17.3; HRMS (ESI-
TOF) calcd. For C18H18N3O2 (M+H)+ m/z = 308.1399, found 308.1399.
2-(2,8-Dimethyl-4-oxoquinazolin-3(4H)-yl)benzonitrile (7).
9 mg, 8%%, pale yellow solid: mp 254-255 oC: 1H NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 7.6,
0.8 Hz, 1H), 7.87 (dd, J = 7.6, 1.2 Hz, 1H), 7.79 (td, J = 8.0, 1.6 Hz, 1H), 7.64-7.60 (m, 2H),
7.40 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 2.62 (s, 3H), 2.25 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 162.1, 150.8, 145.8, 140.7, 135.7, 134.2, 122.9 (2C), 129.8, 129.7, 126.5, 124.7,
120.2, 115.1, 113.2, 23.9, 17.3; HRMS (ESI-TOF) calcd. For C17H14N3O (M+H)+ m/z =
276.1137, found 276.1139.
2-(2-methyl-4-oxoquinazolin-3(4H)-yl)benzonitrile (8).14
42 mg, 4%, brown oil: 1H NMR (400 MHz, CDCl3) δ 8.24 (dd, J = 8.0, 0.8 Hz, 1H), 7.86 (dd, J
= 7.6, 0.4 Hz, 1H), 7.81-7.75 (m, 2H), 7.69 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.47 (t, J
= 7.6 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 2.24 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.5,
152.5, 147.0, 140.3, 135.1, 134.3, 133.9, 130.0, 129.6, 127.1, 126.9 (2C), 120.2, 114.9, 113.2,
23.5; HRMS (ESI-TOF) calcd. For C16H12N3O (M+H)+ m/z = 262.0980, found 262.0981.
ASSOCIATED CONTENT
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Supporting Information
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Spectra for all new compounds. The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.xxxxxx
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AUTHOR INFORMATION
Corresponding Author
*E-mail: stliu@ntu.edu.tw
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Ministry of Science and Technology, Taiwan (Grant No. MOST107-2113-M-002-
005) for the financial support. We also thank “National Taiwan University Mass Spectrometry-
based Proteomics Core Facility” for the measurement of ESI mass data.
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