Site-Selective C–H Amidation of 2-Aryl Quinazolinones Using Nitrene Surrogates

Article abstract of DOI:10.1002/ejoc.202001128

The site-selective modifications of quinazolinones constitute a pivotal topic in drug discovery and material science. Herein, we describe the rhodium(III)-catalyzed C–H amidation of 2-aryl quinazolin-4(3H)-ones with a range of nitrene surrogates including dioxazolones, organic azides, and N-methoxyamides. Complete site-selectivity and functional group tolerance are observed. Notably, the large-scale reaction and late-stage functionalization highlight the synthetic potential of the developed protocol. Combined mechanistic investigations elucidate a plausible reaction mechanism of this process.

Full text of DOI:10.1002/ejoc.202001128

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Site-Selective C–H Amidation of 2-Aryl Quinazolinones Using
Nitrene Surrogates
Authors: Saegun Kim, Daeun Jeoung, Kunyoung Kim, Seok Beom
Lee, Suk Hun Lee, Min Seo Park, Prithwish Ghosh, Neeraj
Kumar Mishra, Suckchang Hong, and In Su Kim
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001128
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1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202001128
FULL PAPER
Site-Selective C–H Amidation of 2-Aryl Quinazolinones Using
Nitrene Surrogates
Saegun Kim,[a,‡] Daeun Jeoung,[a,‡] Kunyoung Kim, Seok Beom Lee, Suk Hun Lee, Min Seo
[a]
[b]
[a]
[a]
[a]
[a]
[b]
[a]
Park, Prithwish Ghosh, Neeraj Kumar Mishra, Suckchang Hong,* and In Su Kim*
Dedicated to Prof. Pierre H. Dixneuf for his outstanding contribution to organometallic chemistry and catalysis
[a]
[b]
[‡]
S. Kim, D. Jeoung, K. Kim, Dr. S. H. Lee, M. S. Park, Dr. P. Ghosh, Dr. N. K. Mishra, Prof. Dr. I. S. Kim
School of Pharmacy
Sungkyunkwan University
Suwon 16419, Republic of Korea
E-mail: insukim@skku.edu (I.S.Kim)
http://pharmasyn.skku.edu/
S. B. Lee, Prof. Dr. S. Hong
College of Pharmacy
Seoul National University
Seoul 08826, Republic of Korea
E-mail: schong17@snu.ac.kr (S.Hong)
http://www.schong17.com
Theses authors equally contributed.
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: The site-selective modifications of quinazolinones
constitute a pivotal topic in drug discovery and material science.
Herein, we describe the rhodium(III)-catalyzed C–H amidation of 2-
inherent directing group capability and amide-iminol tautomerism.
Due to the biological importance and structural feasibility of 2-
aryl quinazolin-4(3H)-ones, recent efforts have been made
towards the transition-metal-catalyzed C−H functionalization of
2-aryl quinazolin-4(3H)-ones, leading to the C−X and C−C bond
forming reactions.[7]
aryl quinazolin-4(3H)-ones with
a range of nitrene surrogates
including dioxazolones, organic azides, and N-methoxyamides.
Complete site-selectivity and functional group tolerance are
observed. Notably, the large-scale reaction and late-stage
functionalization highlight the synthetic potential of the developed
protocol. Combined mechanistic investigations elucidate a plausible
reaction mechanism of this process.
Introduction
The carbon-nitrogen (C–N) bond is one of the most fundamental
links in various pharmaceuticals and biologically relevant
[1]
molecules. Representative approaches to realize the C–N
bond formation include the Ullmann[ and Buchwald-Hartwig[3]
cross-coupling reactions under transition-metal catalysis.
However, from a synthetic point of view, these approaches have
2]
intrinsic
drawbacks
including
the
requirement
for
prefunctionalized aryl(pseudo) halides as starting materials. In
the past decades, the transition-metal-catalyzed C–H amination
has been a central theme to realize the direct access of C–N
bonds.[4] In this context, various amidation agents such as
chloramines, organic azides, hydroxylamines, dioxazolones, and
anthranils have been employed for the generation of nitrene
intermediates.
Figure 1. Selected examples of bioactive and advanced organic molecules
containing 2-aryl quinazolinone motif.
For examples, the quinazolinone-directed C−H acetoxylation
and halogenation have been independently reported by Yadav[
and Dabiri (Scheme 1).[7b] Hong demonstrated the direct
construction of quinazolino-phenanthridinones through the
Pd(II)-catalyzed two-fold C–H functionalization of 2-aryl
quinazolin-4(3H)-ones.[ In addition, Cui described an elegant
literature for the synthesis of fused polyheterocycles through
sequential [4+2] and [3+2] cycloadditions between 2-aryl
7a]
2-Aryl quinazolin-4(3H)-one motif is among the ubiquitous core
found in natural products, pharmaceuticals, and advanced
organic materials such as bouchardatin, luotonin A,
7c]
[5]
methaqualone, and photoredox catalysts. Moreover, ortho-
aminated 2-aryl quinazolin-4(3H)-ones displayed interesting
[7d]
biological profiles including topoisomerase
I
inhibition and
antitumoral activity (Figure 1). The unmasked quinazolin-
(3H)-one framework possesses integral structural features with
quinazolinones and internal alkynes. However, the transition-
metal-catalyzed C−N bond forming reactions using 2-aryl
quinazolin-4(3H)-ones have been rarely explored.[8] In
[6]
4
1
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European Journal of Organic Chemistry
10.1002/ejoc.202001128
FULL PAPER
continuation of our recent works on the catalytic C−N bond
forming reactions,[9] we herein describe the Rh(III)- and Ir(III)-
catalyzed C–H amidation of a range of 2-aryl quinazolin-4(3H)-
ones with easily accessible nitrene surrogates such as
dioxazolones, organic azides, and N-methoxyamides. Notably,
the large-scale reaction and late-stage C–H amidations of
complex molecules demonstrate the synthetic utility of our
developed method.
unreactive under the optimized reaction conditions (data not
shown).
Table 1. Optimization of reaction conditions.[a]
previous works (C-X & C-C bond formations)
O
O
yield[b]
entry
catalyst (mol %)
additive (mol %)
solvent
NH
X
Ph
2
IOAc
or
NXS
NH
NH
H
H
Pd(II)
1
2
3
4
5
6
7
8
9
10
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
]
2 2
]
2 2
]
2 2
]
2 2
]
2 2
]
2 2
]
2 2
]
2 2
(2.5)
(2.5)
(2.5)
(2.5)
(2.5)
(2.5)
(2.5)
(2.5)
AgSbF
6
6
(10)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
57
93
81
93
99
76
58
85
91
13
97
51
+
+
N
N
O
AgSbF
(10), NaOAc (30)
X = OAc, halogens
O
NaOAc (30)
NaOAc (50)
NaOAc (100)
KOAc (100)
LiOAc (100)
NaOAc (100)
NaOAc (100)
NaOAc (100)
NaOAc (100)
NaOAc (100)
Pd(II)
N
N
2
Ph IOTf
oxidant
N
O
R
R
O
N
R
O
NH
H
Pd(II)
N
[Cp*RhCl2]2 (2.5)
toluene
MeOH
DCE
DCE
+
R
R
R
O
2
N
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
2
]
2
(2.5)
(1)
11
2 2
]
12[c]
]
2 2
(2.5)
this work (C-N bond formation)
O
O
X
FG
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.25 mmol), [RhCp*Cl
2
]
2
(quantity
NH
H
NH HN
o
Rh(III) or Ir(III)
noted), additive (quantity noted), solvent (1 mL) at 60 C for 14 h under air in
pressure tubes. [b] Yield isolated by flash column chromatography. [c] The
reaction was carried out at room temperature.
+
N
FG
X
X = N, C
for nitrene intermediates
O
O
O
O
O
O
O
S
O
HN
OMe
Ar
N
3
Ar N3
OR
N
Ar
3
N
R
Scheme 1. C–H functionalization of 2-aryl quinazolinones.
Results and Discussion
Optimization study was initiated by the coupling of 2-(o-
tolyl)quinazolin-4(3H)-one (1a) with 3-(m-tolyl)-1,4,2-dioxazol-5-
one (2a) under Rh(III) catalysis (Table 1). A cationic Rh(III)
catalyst afforded the desired product 3a in a moderate yield
(
57%), as shown in entry 1. Treatment of a cationic Rh(III)
catalyst in the presence of NaOAc displayed the significantly
improved formation of 3a (Table 1, entry 2). Notably, a neutral
Rh(III) species generated from [RhCp*Cl ] and NaOAc also
2 2
catalyzed the coupling reaction of 1a and 2a, furnishing the
desired product 3a in 81% yield (Table 1, entry 3). In addition,
the amidated adduct 3a was formed in an almost quantitative
yield (99%) in the presence of a stoichiometric amount of
NaOAc (Table 1, entry 5). However, exchanging NaOAc into
other acetate sources such as KOAc and LiOAc was less
effective in this transformation (Table 1, entries 6 and 7).
Screening of solvents indicated that DCE was a most effective
solvent in this reaction (Table 1, entries 8−10). Gratifyingly, this
reaction was comparable with 1 mol % of [RhCp*Cl
in 97% yield (Table 1, entry 11). Finally, it should be noted that
other transition-metal catalysts such as Pd(OAc) , [RuCl (p-
cymene)] , [Cp*Co(CO)I ], and [IrCp*Cl were found to be
2 2
] to give 3a
2
2
2
2
2 2
]
2
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European Journal of Organic Chemistry
10.1002/ejoc.202001128
FULL PAPER
Scheme 2. Scope of 2-aryl quinazolinones. [a] Reaction conditions: 1a−1t (0.2
benzothiadiazine dioxide can also undergo the C–H amidation
reaction. However, this reaction between 4b and 2a was found
to be unsuccessful to deliver 5b under the current reaction
conditions.
mmol), 2a (0.25 mmol), [RhCp*Cl
mL) at 60 C for 14 h under air in pressure tubes. [b] Yield isolated by flash
2
]
2
(1 mol %), NaOAc (100 mol %), DCE (1
o
column chromatography. [c] 2a (0.5 mmol, 2.5 equiv.) was used.
To evaluate the substrate scope of this reaction, a range of 2-
aryl quinazolinones 1b–1t were reacted with dioxazolone 2a
under the optimized reaction conditions (Scheme 2). 2-Aryl
quinazolinones 1b–1d with ortho- and meta-substituents on the
aryl ring were smoothly coupled with 2a to afford the
corresponding amidated products 3b–3d in good to high yields.
It is noted that the complete site-selectivity at less hindered
positions was detected in case of meta-substituted substrates.
However, a sterically congested 3,5-disubstituted compound 1e
led to no formation of amidated adduct 3e, and most of starting
material 1e was recovered under the current reaction conditions.
In addition, para-substituted 2-aryl quinazolinones 1f–1k
participated in the amidation reaction to afford bis-amidated
products 3f–3k in high yields under the slightly modified reaction
conditions. Meanwhile, the scope of quinazolinone motif has
been evaluated under the standard reaction conditions. To our
delight, the current protocol could be applied to the C5-, C6-,
C7-, and C8-substituted 2-aryl quinazolinones 1l–1r, providing
the desired products 3l–3r in good to high yields. The site-
selective C–H amidation of 2-aryl quinazolin-4(3H)-ones on the
ortho-position of aryl ring was confirmed by the X-ray
crystallographic data of product 3m (CCDC2002612, see the
Supporting Information for details). It is noteworthy that the
tolerance of iodo and bromo groups (3i, 3j, 3m and 3n) can
provide a versatile synthetic handle for further cross-coupling
reactions. Furthermore, we were pleased to observe the C–H
amidation reaction of heterocycle-containing substrates to afford
the corresponding products 3s (99%) and 3t (84%), respectively.
Scheme 4. Scope of dioxazolones. [a] Reaction conditions: 1a (0.2 mmol),
2
b−2n (0.25 mmol), [RhCp*Cl
]
2 2
(1 mol %), NaOAc (100 mol %), DCE (1 mL)
o
at 60 C for 14 h under air in pressure tubes. [b] Yield isolated by flash column
chromatography.
With successful screening data of quinazolinones in hand, the
scope of dioxazolones 2b–2n was examined (Scheme 4).
Regardless of electronic and steric effects on aromatic ring, a
range of dioxazolones 2b–2j were successfully coupled with 1a,
providing 6b–6j in good to high yields. Notably, dioxazolone 2j
2
with a NO group, which is often problematic in the C–H
functionalization event, was also tolerable in this transformation.
Additionally, heterocycle-containing dioxazolone 2k was also
compatible to afford 6k in 90% yield. Furthermore, this process
is not limited with (hetero)aryl-substituted dioxazolones. Alkyl-
substituted dioxazolones 2l–2n also reacted with 1a to furnish
the corresponding products 6l–6n in good to high yields.
Next, we envisioned that this protocol could be extended to the
C–H amidation reactions by using well-defined nitrene
surrogates. To our delight, tosyl azide 7a was smoothly coupled
with 1a at room temperature to provide 8a in 55% yield under
cationic Ir(III) catalysis (Scheme 5). It should be mentioned that
neutral or cationic Rh(III) catalysts was found to be ineffective in
this reaction, and the chemical yield of 8a can be improved by
further optimization of reaction conditions. Additionally, BOC
azide 7b also proved to be an amenable substrate under
cationic Ir(III) catalysis, furnishing the desired product 8b in 69%
yield. Moreover, C–H amidated adduct 8c was obtained from
acyl azide 7c and N-methoxyamide 7d, respectively, under
cationic Ir(III) or Rh(III) catalysis. It is noted that nitrene
surrogates 7a–7d were less reactive or unreactive with neutral
Scheme 3. C–H amidation of isoquinolone and benzothiadiazine dioxide.
Isoquinolone as a structural isostere of quinazolinone is a key
a
range of bioactive natural products.[
10]
motif found in
Consequently, the structural modifications of isoquinolones are
among recent intensive topic in organic and medicinal
chemistry.[ Thus, the reaction of isoquinolone 4a with 2a were
subjected under the standard reaction conditions (Scheme 3).
To our pleasure, our desired product 5a was formed in 64%
yield. It is mentioned that no formation of bis-amidated adduct
was observed. Given functional similarities between
11]
carboxamide
and
sulfonamide,
we
anticipated
that
3
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European Journal of Organic Chemistry
10.1002/ejoc.202001128
FULL PAPER
Ir(III) or Rh(III) catalysts under otherwise identical reaction
conditions.
To demonstrate the synthetic utility of the developed method,
the gram-scale experiment and late-stage functionalizations
were performed (Scheme 6). The reaction of 1a (1 g, 4.2 mmol)
with 2a was successfully carried out, providing 1.4 g of 3a in
nitrene surrogates
90% yield. The late-stage C–H amidation reactions of
O
O
O
O
O
quinazolinone derivatives 9a and 9b derived from estrone and
celecoxib afforded the corresponding adducts 10a (51%) and
S
MeO
N
3
N
N
H
3
t
N
3
O Bu
7b
Me
Me
Me
Ar
10b (46%), respectively. To highlight the synthetic applicability
7
a
7c
7d
of synthesized products, the deprotection of an N-aroyl group on
3a was performed under basic hydrolysis conditions, and aniline
adduct 11a was obtained in 89% yield.
O
N
O
amidated products
O
O
O
NH HN
Ts
t
NH HN
NH HN
O Bu
<
mechanistic investigation >
N
N
Me
Ar = p-tolyl
O
N
O
O
N
Me
Me
8b, 69%
from 7b by Ir(III)[a]
A (5 mol %)
NaOAc (100 mol %)
8
c
NH HN
Ar
N
Rh
8a, 55%
c by Ir(III)[a]
1a
53% from
7
from 7a by Ir(III)[a]
DCE, 60 oC, 14 h
3% from 7d by Rh(III)[b]
2
2a (1.25 equiv)
Me
a, 99% (Ar = m-tolyl)
3
A
Scheme 5. Amidation by other nitrene surrogates. [a] Reaction conditions: 1a
0.2 mmol), 7a−7c (0.25 mmol), [IrCp*Cl (2.5 mol %), AgNTf (10 mol %),
DCE (1 mL) at room temperature for 20 h under air in pressure tubes. [b]
Reaction conditions: 1a (0.2 mmol), 7d (0.25 mmol), [RhCp*Cl (2.5 mol %),
AgSbF
(10 mol %), NaOAc (30 mol %), DCE (1 mL) at 100 oC for 20 h under
air in pressure tubes.
<
KIE experiment >
O
(
]
2 2
2
O
2 2
]
NH
H
standard
conditions
standard
conditions
NH
D
6
N
3a
N
2
a
2a
KIE = 2.35
Me
Me
1a
deuterio-1a, 91% D
<
gram-scale experiment >
<
proposed reaction mechanism >
O
O
N
O
[
RhCp*Cl
2
]
2
(1 mol %)
2 2
[RhCp*Cl ]
NH
H
NH HN
NaOAc (100 mol %)
2NaOAc
N
DCE, 60 oC, 14 h
2
NaCl
2
a (5.25 mmol)
Me
3a
1a
Me
a (1 g, 4.2 mmol)
Me
2
2
[RhCp*(OAc) ]
HOAc
1
3a (1.4 g, 90% yield)
2
HOAc
O
N
protonation
<
late-stage functionalizations >
NH
Cp*
O
O
O
O
Rh OAc
Rh
N
H
H
H
NH
N
standard
conditions
N
N
Ar
HN
N
H
N
H
H
2a (1.25 equiv)
O
Me
Me
IV
H
O
Me
I
H
Me
10a, 51%
Me
O
nitrene
insertion
9
a from estrone
C-H activation
O
O
O
CO
2
NH
H
H
NH HN
m-tolyl
Ar
Cp*
O
N
N
O
O
N
standard
conditions
N
N
Rh
HN
O
O
N
Rh
CF
3
CF
3
N
N
N
coordination
N
N
2
a (2.5 equiv) m-tolyl
O
O
S
N
O
N
Me
O
Me
II
S
III
H
2
O
H
2
O
O
N
O
2
a (Ar = m-tolyl)
9
b from celecoxib
10b, 46%
Ar
<
synthetic transformation >
O
N
O
O
Scheme 7. Mechanistic investigation, KIE experiment, and proposed reaction
mechanism.
NH HN
NH NH
2
NaOH, EtOH
N
20 oC 20 h
,
1
Me
Me
Me
11a, 89%
To gain mechanistic insight, the reaction of 1a with 2a in the
presence of rhodacycle complex A was performed (Scheme 7).
We were pleased to observe the formation of 3a in an almost
quantitative yield (99%), suggesting that the catalytic cycle might
be initiated by the formation of rhodacycle complex. A kinetic
isotope effect (KIE) experiment between 1a and deuterio-1a
3
a
Scheme 6. Gram-scale experiment, late-stage functionalizations and synthetic
transformation.
H D
resulted in a k /k value of 2.35, thus revealing that C−H
4
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European Journal of Organic Chemistry
10.1002/ejoc.202001128
FULL PAPER
cleavage might be involved in the rate-limiting step of this
process. Based on preliminary mechanistic investigation and
reported literatures,[12] a plausible reaction pathway is depicted.
161.1, 157.9, 151.3, 147.3, 140.9, 138.4, 135.6, 134.7, 133.0, 132.7,
128.5, 127.9, 127.3, 126.7, 126.5, 124.8, 121.1, 115.4, 107.8, 160.5,
56.5, 21.4; IR (KBr) υ 2922, 2853, 1678, 1606, 1592, 1561, 1477, 1460,
-
1
20 3 3
H N O
[M+H]+
A monomeric [RhCp*(OAc)
2
] as an active catalyst can be
2 2
generated from [RhCp*Cl ] by the ligand exchange of
1234, 1137, 1014 cm ; HRMS (ESI) calcd for C23
386.1499, found 386.1499.
NaOAc.[ The formation of intermediate I assisted by NaOAc
followed by C–H activation can take place to deliver rhodacycle
II. In this stage, dioxazolone 2a can coordinate into II to give
intermediate III, which can undergo migratory insertion to afford
13]
3
-Methyl-N-(4-methyl-2-(4-oxo-3,4-dihydroquinazolin-2-
yl)phenyl)benzamide (3c): 65.1 mg (88%); yellow solid; mp = 255.4–
o
1
2
58.0 C; H NMR (400 MHz, CDCl
d, J = 8.4 Hz, 1H), 8.34 (d, J = 7.6 Hz, 1H), 7.87–7.72 (m, 5H), 7.55 (t, J
7.6 Hz, 1H), 7.43–7.37 (m, 3H), 2.46 (s, 2H), 2.45 (s, 3H); 13C NMR
100 MHz, CDCl ) δ 166.1, 162.7, 152.2, 147.4, 138.4, 137.2, 135.6,
3
) δ 12.88 (s, 1H), 10.95 (s, 1H), 8.80
2
N-Rh(III)-N species IV with release of CO gas. Protonation of IV
provides the desired product 3a and a recyclable [RhCp*(OAc) ]
2
catalyst.
(
=
(
3
1
1
1
35.2, 133.6, 133.2, 132.6, 128.5, 128.0, 127.6, 127.5, 126.7, 126.6,
24.7, 123.1, 122.1, 118.3, 21.4, 20.9; IR (KBr) υ 2922, 2853, 1674,
Conclusion
-1
613, 1586, 1523, 1477, 1408, 1282, 1189, 1038, 971, 808 cm ; HRMS
+
(ESI) calcd for C23
H N O
20 3 2
[M+H] 370.1550, found 370.1550.
In conclusion, we have described the site-selective modifications
of quinazolinones via the rhodium(III)-catalyzed C−H amidation
reactions of 2-aryl quinazolinones with dioxazolones, organic
azides, and N-methoxyamides as nitrene surrogates. This
method can be also applied into the C−N bond forming reactions
of isoquinolone as a quinazolinone isostere. Broad functional
group tolerance, large-scale reaction, and late-stage C−H
functionalizations demonstrate the synthetic potential of the
developed method. Preliminary mechanistic investigations
elucidate a plausible reaction mechanism of this process.
3
-Methyl-N-(2-(4-oxo-3,4-dihydroquinazolin-2-yl)-4-
(trifluoromethyl)phenyl)benzamide (3d): 59.5 mg (70%); white solid;
mp = 268.2–270.3 oC; 1H NMR (700 MHz, DMSO-d
6
) δ 8.97 (d, J = 9.1
Hz, 1H), 8.83 (s, 1H), 8.10–8.07 (m, 3H), 7.81 (d, J = 8.4 Hz, 1H), 7.66 (d,
J = 5.6 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.49–7.45 (m, 2H), 7.35 (s, 1H),
2
1
1
1
1
.47 (s, 3H); 13C NMR (175 MHz, DMSO-d
6
) δ 165.4, 153.6, 147.4, 143.1,
39.8, 138.2, 134.7, 132.6, 132.2, 131.7, 128.6, 128.0, 126.8, 125.9,
25.7, 125.1, 124.5 (q, JC-F = 268.9 Hz), 124.4, 124.1, 123.4, 121.6,
20.2, 20.8; IR (KBr) υ 2957, 2922, 2853, 1681, 1611, 1582, 1531, 1467,
-1
414, 1338, 1315, 1273, 1171, 1108, 960 cm ; HRMS (ESI) calcd for
+
23 17 3
C H F N
O
3 2
[M+H] 424.1268, found 424.1268.
Experimental Section
N,N'-(2-(4-Oxo-3,4-dihydroquinazolin-2-yl)-1,3-phenylene)bis(3-
methylbenzamide) (3f): 86.0 mg (88%); white solid; mp = 225.1–227.3
General procedure and characterization data for the amidation of 2-
aryl quinazolin-4(3H)-ones with dioxazolones (3a–3t, 5a and 6b–6n):
To an oven-dried sealed tube charged with 2-(o-tolyl)quinazolin-4(3H)-
oC; 1H NMR (400 MHz, CDCl
H), 7.83–7.72 (m, 4H), 7.59–7.56 (m, 4H), 7.47–7.43 (m, 2H), 7.24–7.19
m, 4H), 2.25 (s, 6H); 13C NMR (100 MHz, CDCl
/CD OD = 10:1 v/v) δ
66.6, 166.5, 162.3, 150.5, 138.4, 136.6, 136.5, 134.8, 133.9, 133.8,
3 3
/CD OD = 10:1 v/v) δ 8.14 (d, J = 7.6 Hz,
1
one (1a) (47.3 mg, 0.2 mmol, 100 mol %), [Cp*RhCl
mmol, 1 mol %) and NaOAc (16.4 mg, 0.2 mmol, 100 mol %) were added
-(m-tolyl)-1,4,2-dioxazol-5-one (2a) (44.3 mg, 0.25 mmol, 125 mol %)
2 2
] (1.2 mg, 0.002
(
3
3
1
1
1
1
3
32.8, 131.9, 128.5, 128.4, 127.7, 127.5, 126.9, 126.5, 124.3, 121.2,
21.1, 120.7, 118.3, 21.1; IR (KBr) υ 2957, 2922, 2853, 1678, 1657,
and DCE (1 mL) under air at room temperature. The reaction mixture
was allowed to stir at 60 oC for 14 h, and cooled to room temperature.
The reaction mixture was diluted with EtOAc (3 mL) and concentrated in
vacuo. The residue was purified by flash column chromatography (n-
hexanes/EtOAc = 1:1) to afford 3a (71.6 mg) in 97% yield.
-1
604, 1471, 1448, 1416, 1332, 1294, 1268, 1158, 925 cm ; HRMS (ESI)
+
calcd for C30H N O
25 4 3
[M+H] 489.1921, found 489.1922.
N,N'-(5-Methyl-2-(4-oxo-3,4-dihydroquinazolin-2-yl)-1,3-
phenylene)bis(3-methylbenzamide) (3g): 80.3 mg (80%); white solid;
3
-Methyl-N-(3-methyl-2-(4-oxo-3,4-dihydroquinazolin-2-
o
1
mp = 209.3–211.8 C; H NMR (400 MHz, CDCl
3
) δ 11.46 (s, 1H), 10.11
yl)phenyl)benzamide (3a): 71.6 mg (97%); white solid; mp = 235.9–
(s, 2H), 8.16 (d, J = 8.0 Hz, 1H), 7.72–7.69 (m, 2H), 7.58–7.52 (m, 6H),
o
1
2
36.8 C; H NMR (400 MHz, CDCl
d, J = 7.2 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.86–7.78 (m, 2H), 7.57–
.54 (m, 2H), 7.46 (s, 1H), 7.27–7.22 (m, 3H), 6.88 (d, J = 7.6 Hz, 1H),
.40 (s, 3H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl
) δ 165.2, 162.3,
3
) δ 11.31 (br, 1H), 10.14 (s, 1H), 8.31
7
.47–7.43 (m, 1H), 7.17–7.11 (m, 4H), 2.23 (s, 3H), 2.15 (s, 6H); 13C
) δ 166.2, 162.7, 150.5, 148.0, 142.9, 138.4,
36.3, 134.9, 133.9, 132.7, 128.5, 127.6, 127.4, 127.0, 126.5, 124.3,
22.2, 120.5, 115.8, 21.6, 21.1; IR (KBr) υ 3272, 2923, 2853, 1670, 1589,
(
NMR (100 MHz, CDCl
3
7
2
1
1
1
1
3
1
1
1
3
52.1, 148.1, 138.3, 136.8, 136.1, 134.9, 134.2, 132.7, 130.8, 128.5,
27.5, 127.4, 126.9 (two carbons overlap), 126.8, 124.4, 123.9, 121.0,
20.1, 21.2, 20.6; IR (KBr) υ 3068, 1675, 1601, 1529, 1466, 1296, 1267,
-1
565, 1515, 1466, 1438, 1276, 1199, 1132, 1039, 944, 821 cm ; HRMS
+
(ESI) calcd for C31H N O
27 4 3
[M+H] 503.2078, found 503.2078.
-1
20 3 2
H N O
[M+H]+
210, 1140, 941, 770 cm ; HRMS (ESI) calcd for C23
70.1550, found 370.1549.
N,N'-(5-Methoxy-2-(4-oxo-3,4-dihydroquinazolin-2-yl)-1,3-
phenylene)bis(3-methylbenzamide) (3h): 95.5 mg (92%); white solid;
o
1
mp = 233.8–234.2 C; H NMR (400 MHz, CDCl
3
) δ 11.44 (s, 1H), 10.24
N-(3-Methoxy-2-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-3-
methylbenzamide (3b): 67.9 mg (88%); brown solid; mp = 248.9–251.3
(
s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.71–7.70 (m, 2H), 7.56–7.53 (m, 4H),
7
6
1
1
1
.47 (s, 2H), 7.45–7.41 (m, 1H), 7.17–7.11 (m, 4H), 3.74 (s, 3H), 2.15 (s,
o
1
C; H NMR (400 MHz, CDCl
3
) δ 13.15 (s, 1H), 10.74 (s, 1H), 8.53 (d, J =
.4 Hz, 1H), 8.32 (dd, J = 8.0, 1.2 Hz, 1H), 7.81–7.76 (m, 3H), 7.71 (d, J
8.0 Hz, 1H), 7.52 (t, J = 8.4 Hz, 2H), 7.38–7.36 (m, 2H), 6.84 (d, J = 8.4
) δ 166.2,
H); 13C NMR (100 MHz, CDCl
3
) δ 166.3, 162.9, 162.0, 150.6, 148.0,
8
38.4, 138.1, 134.8, 134.0, 132.8, 128.4, 127.7, 127.2, 126.9, 126.5,
24.3, 120.4, 110.3, 106.8, 55.5, 21.1; IR (KBr) υ 3060, 2925, 1671,
604, 1589, 1536, 1467, 1278, 1206, 1161, 1085, 1049, 969, 946, 852,
=
Hz, 1H), 4.01 (s, 3H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl
3
5
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202001128
FULL PAPER
-
1
[M+H]+ 519.2027, found
8
07 cm ; HRMS (ESI) calcd for C31
H N O
27 4 4
N-(2-(6-Bromo-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methylphenyl)-3-
methylbenzamide (3n): 78.9 mg (88%); light yellow solid; mp = 224.8–
5
19.2027.
2
27.1 oC; 1H NMR (400 MHz, CDCl
3
) δ 11.62 (s, 1H), 9.91 (s, 1H), 8.41
N,N'-(5-Bromo-2-(4-oxo-3,4-dihydroquinazolin-2-yl)-1,3-
(d, J = 2.4 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.86 (dd, J = 8.8, 2.4 Hz, 1H),
7.59 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.43 (s, 1H), 7.28–7.21
(m, 2H), 7.12 (t, J = 8.0 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 2.33 (s, 3H),
phenylene)bis(3-methylbenzamide) (3i): 110.1 mg (97%); white solid;
mp = 269.8–272.3 oC; 1H NMR (400 MHz, CDCl
/CD
.18 (d, J = 8.0 Hz, 1H), 8.10–8.09 (m, 2H), 7.79–7.78 (m, 2H), 7.62–
.58 (m, 3H), 7.51–7.47 (m, 1H), 7.29–7.24 (m, 5H), 2.29 (s, 6H); 13C
/CD OD = 10:1 v/v) δ 166.5, 162.2, 150.2, 147.7,
38.6, 137.7, 137.6, 135., 133.6, 133.5, 133.1, 128.6, 128.5, 127.9,
27.8, 126.9, 126.7, 125.8, 124.4, 123.5, 12.9, 116.2, 21.2; IR (KBr) υ
3
3
OD = 10:1 v/v) δ
2.27 (s, 3H); 13C NMR (100 MHz, CDCl
8
7
3
) δ 165.4, 161.0, 152.5, 146.9,
138.4, 137.9, 137.0, 135.7, 133.8, 132.8, 130.7, 129.3, 128.6, 128.5,
127.5, 127.1, 124.3, 124.2, 122.4, 121.0, 120.4, 21.2, 20.5; IR (KBr) υ
3062, 2923, 2854, 1675, 1597, 1572, 1527, 1461, 1405, 1294, 1265,
NMR (100 MHz, CDCl
3
3
1
1
2
-1
3 2
1199, 1145, 1111, 941, 833 cm ; HRMS (ESI) calcd for C23H19BrN O
-1
+
920, 2852, 1672, 1599, 1563, 1509, 1462, 1376, 1268 cm ; HRMS
[M+H] 448.0655, found 448.0656.
+
(ESI) calcd for C30H24BrN O
4 3
[M+H] 567.1026, found 567.1027.
N-(2-(6-Chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methylphenyl)-3-
methylbenzamide (3o): 64.6 mg (80%); white solid; mp = 210.8–212.8
N,N'-(5-Iodo-2-(4-oxo-3,4-dihydroquinazolin-2-yl)-1,3-
o
1
phenylene)bis(3-methylbenzamide) (3j): 116.8 mg (95%); yellow solid;
3
C; H NMR (400 MHz, CDCl ) δ 11.47 (br, 1H), 9.91 (s, 1H), 8.26 (d, J =
o
1
mp = 243.2–244.8 C; H NMR (700 MHz, CDCl
3
) δ 9.97 (s, 1H), 8.15 (s,
H), 7.99 (s, 1H), 7.71–7.74 (m, 2H), 7.56–7.53 (m, 4H), 7.46 (s, 1H),
.20–7.19 (m, 2H), 7.18–7.16 (m, 2H), 2.19 (s, 6H); 13C NMR (175 MHz,
) δ 166.5, 160.3, 160.2, 156.0, 141.4, 138.7, 137.6, 135.2, 133.5,
33.2, 130.6, 128.7, 128.0, 127.8, 126.9, 124.4, 110.1, 105.7, 21.2; IR
KBr) υ 2954, 2921, 2853, 1665, 1591, 1560, 1524, 1466, 1419, 1295,
2.0 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.75–7.67 (m, 2H), 7.49 (d, J = 7.2
Hz, 1H), 7.44 (s, 1H), 7.29–7.22 (m, 2H), 7.17 (t, J = 8.0 Hz, 1H), 6.82 (d,
1
7
J = 7.6 Hz, 1H), 2.35 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl
3
) δ
CDCl
3
165.4, 161.2, 152.4, 146.6, 138.4, 136.9, 135.8, 135.2, 133.9, 133.3,
132.8, 130.8, 128.5, 128.4, 127.5, 127.1, 126.2, 124.2, 124.1, 122.1,
120.4, 21.2, 20.5; IR (KBr) υ 2922, 2853, 1678, 1602, 1572, 1532, 1463,
1
(
-1
-1
1
267, 1220, 1149, 944, 808 cm ; HRMS (ESI) calcd for C30
H24IN O
4 3
1410, 1328, 1295, 1202, 1146, 1119, 1073, 943, 879, 833 cm ; HRMS
+
+
[
M+H] 615.0888, found 615.0888.
(ESI) calcd for C23H19ClN O
3 2
[M+H] 404.1160, found 404.1160.
N,N'-(2-(4-Oxo-3,4-dihydroquinazolin-2-yl)-5-(trifluoromethyl)-1,3-
phenylene)bis(3-methylbenzamide) (3k): 100.2 mg (90%); white solid;
mp = 254.3–257.2 oC; 1H NMR (700 MHz, DMSO-d
) δ 12.68 (s, 1H),
0.98 (br, 2H), 8.35 (s, 2H), 8.14 (d, J = 9.1 Hz, 1H), 7.89 (t, J = 7.7 Hz,
H), 7.84 (d, J = 7.7 Hz, 1H), 7.67–7.64 (m, 4H), 7.57 (t, J = 7.7 Hz, 1H),
.39–7.36 (m, 4H), 2.32 (s, 3H); 13C NMR (175 MHz, DMSO-d
) δ 166.1,
62.2, 150.6, 148.6, 138.9, 138.3, 134.9, 134.8, 133.0, 131.1 (q, JC-F
1.6 Hz), 128.9, 128.4, 127.6, 127.4, 126.4, 125.3, 124.0 (q, JC-F = 270.5
3-Methyl-N-(3-methyl-2-(6-methyl-4-oxo-3,4-dihydroquinazolin-2-
yl)phenyl)benzamide (3p): 62.1 mg (81%); pale yellow solid; mp =
245.7–247.7 oC; 1H NMR (400 MHz, CDCl
6
3
) δ 11.36 (s, 1H), 10.16 (s,
1
1
7
1
3
1H), 8.15 (d, J = 8.4 Hz, 1H), 8.09 (s, 1H), 7.68–7.61 (m, 2H), 7.55 (d, J
= 6.4 Hz, 1H), 7.47 (s, 1H), 7.25–7.18 (m, 3H), 6.85 (d, J = 7.6 Hz, 1H),
2.52 (s, 3H), 2.37 (s, 3H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl
6
3
) δ
=
165.2, 162.3, 151.2, 146.1, 138.3, 137.8, 136.8, 136.3, 136.1, 134.2,
132.6, 130.6, 128.5, 127.5, 126.9, 126.7, 126.2, 124.3, 124.0, 120.7,
120.0, 21.3, 21.2, 20.6; IR (KBr) υ 3056, 2924, 1671, 1598, 1527, 1487,
Hz), 122.1, 120.6, 115.6, 21.3; IR (KBr) υ 3056, 2923, 2854, 1674, 1602,
-1
-1
1
577, 1505, 1434, 1355, 1290, 1268, 1165, 1128, 1105, 947, 875 cm ;
1463, 1414, 1295, 1266, 1198, 1141, 1085, 832 cm ; HRMS (ESI) calcd
+
+
HRMS (ESI) calcd for C31H F N O
24 3 4 3
[M+H] 557.1795, found 557.1796.
for C24H N O
22 3 2
[M+H] 384.1707, found 384.1707.
N-(2-(5-Chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methylphenyl)-3-
methylbenzamide (3l): 73.5 mg (91%); yellow solid; mp = 220.1–222.2
N-(2-(7-Methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methylphenyl)-
3-methylbenzamide (3q): 79.1 mg (99%); yellow solid; mp = 213.3–
oC; 1H NMR (400 MHz, CDCl
) δ 11.05 (br, 1H), 10.10 (s, 1H), 8.20 (d, J
8.4 Hz, 1H), 7.72–7.66 (m, 2H), 7.57–7.50 (m, 3H), 7.32 (t, J = 7.6 Hz,
H), 7.28–7.22 (m, 3H), 6.98 (d, J = 7.6 Hz, 1H), 2.44 (s, 3H), 2.28 (s,
H); 13C NMR (100 MHz, CDCl
) δ 165.3, 130.6, 152.8, 150.3, 138.4,
214.7 oC; 1H NMR (400 MHz, CDCl
3
3
) δ 11.48 (s, 1H), 10.26 (s, 1H),
=
1
3
1
1
2
8
8.33–8.28 (m, 2H), 7.71 (d, J = 6.8 Hz, 1H), 7.61 (s, 1H), 7.42–7.36 (m,
3H), 7.26–7.23 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 4.05 (s, 3H), 2.54 (s,
3H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl
3
3
) δ 165.3, 165.0, 162.0,
36.9, 136.2, 134.8, 134.4, 134.2, 132.7, 131.2, 130.2, 128.6, 127.5,
27.1, 126.1, 124.3, 123.1, 120.3, 118.2, 21.3, 20.7; IR (KBr) υ 3061,
923, 1672, 1592, 1536, 1463, 1410, 1296, 1267, 1197, 1129, 967, 894,
152.8, 150.3, 138.3, 136.8, 136.1, 134.3, 132.6, 130.8, 128.4, 128.3,
127.6, 126.9, 124.3, 124.1, 120.2, 117.1, 114.3, 107.9, 55.7, 21.2, 20.6;
IR (KBr) υ 2952, 2922, 2854, 1731, 1666, 1599, 1565, 1529, 1458, 1358,
-1
[M+H]+ 404.1160,
-1
16, 737 cm ; HRMS (ESI) calcd for C23
H19ClN O
3 2
1292, 1269, 1209, 1172, 1099, 1024, 940, 836 cm ; HRMS (ESI) calcd
+
found 404.1160.
for C24H N O
22 3 3
[M+H] 400.1656, found 400.1656.
N-(2-(6-Iodo-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methylphenyl)-3-
methylbenzamide (3m): 83.2 mg (84%); light yellow solid; mp = 139.8–
3-Methyl-N-(3-methyl-2-(8-methyl-4-oxo-3,4-dihydroquinazolin-2-
yl)phenyl)benzamide (3r): 55.2 mg (72%); yellow solid; mp = 169.1–
o
1
o
1
1
41.4 C; H NMR (400 MHz, CDCl
d, J = 2.0 Hz, 1H), 8.04–7.95 (m, 2H), 7.48–7.42 (m, 3H), 7.28–7.21 (m,
H), 7.10 (t, J = 7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 2.32 (s, 3H), 2.27
s, 3H); 13C NMR (100 MHz, CDCl
) δ 165.4, 160.7, 152.7, 147.3, 143.5,
38.3, 137.0, 135.7, 135.5, 133.8, 132.8, 130.6, 128.5 (two carbon
3
) δ 11.65 (br, 1H), 9.92 (s, 1H), 8.61
3
171.2 C; H NMR (400 MHz, CDCl ) δ 11.29 (s, 1H), 10.05 (s, 1H), 8.25
(
(d, J = 8.0 Hz, 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H),
7.50–7.43 (m, 2H), 7.33–7.26 (m, 2H), 7.25–7.20 (m, 2H), 6.93 (d, J =
7.6 Hz, 1H), 2.61 (s, 3H), 2.41 (s, 3H), 2.19 (s, 3H); 13C NMR (100 MHz,
2
(
3
1
3
CDCl ) δ 165.5, 162.8, 150.7, 146.7, 138.3, 136.7, 135.9, 135.7, 135.4,
overlap), 127.5, 127.1, 124.3, 124.2, 122.6, 120.4, 91.9, 21.2, 20.5; IR
134.5, 132.6, 130.6, 128.5, 127.3, 127.1, 126.9, 124.5, 124.4, 124.2,
121.0, 120.0, 21.0, 20.7, 17.6; IR (KBr) υ 2955, 1922, 1853, 1730, 1667,
1599, 1564, 1530, 1503, 1457, 1358, 1292, 1267, 1209, 1172, 1099, 941
(KBr) υ 3058, 2925, 1675, 1593, 1530, 1460, 1400, 1294, 1265, 1200,
-1
23 3 2
C H19IN O
[M+H]+
1
146, 1113, 941 cm ; HRMS (ESI) calcd for
96.0517, found 496.0518.
4
6
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202001128
FULL PAPER
-1
24 22 3 2
C H N O
[M+H]+ 384.1707, found
2925, 2854, 1675, 1605, 1524, 1466, 1296, 1266, 1137, 946, 739 cm-1;
cm ; HRMS (ESI) calcd for
+
384.1707.
HRMS (ESI) calcd for C23H N O
20 3 2
[M+H] 370.1550, found 370.1550.
3-Methyl-N-(3-methyl-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-
3-Bromo-N-(3-methyl-2-(4-oxo-3,4-dihydroquinazolin-2-
yl)phenyl)benzamide (3s): 74.4 mg (99%); white solid; mp = 220.1–
yl)phenyl)benzamide (6d): 80.0 mg (92%); white solid; mp = 228.7–
o
1
o
1
2
22.2 C; H NMR (400 MHz, CDCl
3
) δ 11.59 (br, 1H), 9.84 (s, 1H), 7.97
3
229.3 C; H NMR (400 MHz, CDCl ) δ 10.62 (s, 1H), 10.28 (s, 1H), 8.31
(
d, J = 8.4 Hz, 1H), 7.87 (d, J = 5.6 Hz, 1H), 7.52 (d, J = 6.8 Hz, 1H), 7.45
s, 1H), 7.36 (d, J = 5.6 Hz, 1H), 7.29–7.23 (m, 2H), 7.17 (t, J = 8.0 Hz,
(d, J = 8.8 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.88 (t, J = 8.4 Hz, 1H), 7.77
(d, J = 8.0 Hz, 1H), 7.63–7.56 (m, 3H), 7.49 (d, J = 8.4 Hz, 2H), 7.32 (t, J
= 8.0 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 2.43 (s, 3H); 13C NMR (100 MHz,
(
1
H), 6.84 (d, J = 7.6 Hz, 1H), 2.34 (s, 3H), 2.29 (s, 3H); 13C NMR (100
MHz, CDCl ) δ 165.6, 158.4, 156.6, 153.5, 138.4, 137.1, 135.8, 135.2,
33.9, 132.7, 130.8, 128.5, 127.6, 127.2, 124.4, 124.3, 124.3, 122.2,
20.8, 21.2, 20.5; IR (KBr) υ 3058, 2922, 1668, 1605, 1587, 1513, 1464,
3
3
CDCl ) δ 164.2, 161.9, 151.8, 148.0, 136.7, 136.1, 135.3, 133.1, 131.9,
1
1
1
131.1, 128.6, 127.8, 127.3, 126.9, 126.8, 126.7, 123.7, 121.0, 120.3,
20.8; IR (KBr) υ 3058, 2923, 1671, 1601, 1533, 1466, 1416, 1294, 1266,
-1
-1
418, 1294, 1269, 1132, 1088, 1043, 789 cm ; HRMS (ESI) calcd for
1139, 1070, 1009, 949, 840, 742 cm ; HRMS (ESI) calcd for
+
+
C
21
H
18
N
3
O
2
S [M+H] 376.1114, found 376.1114.
C H17BrN O
22 3 2
[M+H] 434.0499, found 434.0500.
3
-Methyl-N-(3-methyl-2-(4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-2-
yl)phenyl)benzamide (3t): 62.3 mg (84%); yellow solid; mp = 299.7–
01.3 oC; 1H NMR (400 MHz, CDCl
) δ 11.37 (br 1H), 9.79 (s, 1H), 9.20
s, 1H), 8.73 (d J = 4.8 Hz, 1H), 8.09 (d, J = 5.2 Hz, 1H), 8.01 (d, J = 8.0
Hz, 1H), 7.53–7.47 (m, 2H), 7.29–7.28 (m, 2H), 7.20 (t, J = 7.6 Hz, 1H),
.87 (d, J = 7.6 Hz, 1H), 2.38 (s, 3H), 2.30 (s, 3H); 13C NMR (100 MHz,
CDCl ) δ 165.7, 160.8, 154.0, 150.5, 147.0, 142.8, 138.7, 137.0, 135.8,
33.7, 133.1, 131.1, 128.7, 127.5, 127.4, 126.2, 124.4, 124.1, 120.9,
18.7, 21.3, 20.6; IR (KBr) υ 2922, 2853, 1679, 1602, 1511, 1460, 1423,
3-Chloro-N-(3-methyl-2-(4-oxo-3,4-dihydroquinazolin-2-
yl)phenyl)benzamide (6e): 76.5 mg (98%); yellow solid; mp = 233.8–
o
1
3
3
3
234.9 C; H NMR (400 MHz, CDCl ) δ 10.80 (br, 1H), 10.44 (s, 1H), 8.29
(
(d, J = 7.6 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.89–7.83 (m, 2H), 7.74 (s,
1H), 7.68 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 9.2 Hz,
1H), 7.36–7.29 (m, 2H), 7.02 (d, J = 7.6 Hz, 1H), 2.45 (s, 3H); 13C NMR
6
3
3
(100 MHz, CDCl ) δ 163.7, 162.2, 151.7, 147.9, 136.7, 136.2, 136.1,
1
1
1
135.3, 134.8, 132.0, 131.1, 130.0, 127.8, 127.4, 127.1 (two carbons
overlap), 126.8, 125.4, 123.5, 120.8, 120.2, 20.8; IR (KBr) υ 3064, 2920,
-1
320, 1293, 1263, 1196, 1169, 1142, 1078, 1033, 943 cm ; HRMS (ESI)
1673, 1601, 1567, 1534, 1466, 1419, 1294, 1258, 1134, 1071, 938, 776
+
-1
[M+H]+ 390.1004, found
calcd for C22H N O
19 4 2
[M+H] 371.1503, found 371.1503.
cm ; HRMS (ESI) calcd for C22
H17ClN O
3 2
390.1005.
3
-Methyl-N-(2-(1-oxo-1,2-dihydroisoquinolin-3-yl)phenyl)benzamide
5a): 45.4 mg (64%); yellow solid; mp = 134.1–135.3 oC; 1H NMR (400
MHz, CDCl ) δ 11.45 (s, 1H), 9.05 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.04
d, J = 8.0 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.59–7.51 (m, 5H), 7.46 (t, J
8.0 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.07–6.99 (m, 2H), 6.74 (s, 1H),
.96 (s, 3H); 13C NMR (100 MHz, CDCl
) δ 166.3, 164.3, 138.3, 138.0,
(
N-(3-Methyl-2-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-3-
3
(trifluoromethyl)benzamide (6f): 76.3 mg (90%); white solid; mp =
(
234.1–236.1 oC; 1H NMR (400 MHz, CDCl
3
) δ 11.18 (br, 1H), 10.39 (s,
=
1
1
1
3
1
3
1H), 8.27 (d, J = 7.2 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.00–7.98 (m, 2H),
7.84 (t, J = 8.0 Hz, 1H), 7.78–7.71 (m, 2H), 7.57–7.50 (m, 2H), 7.32 (t, J
= 8.0 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 2.43 (s, 3H); 13C NMR (100 MHz,
3
37.8, 135.3, 133.9, 133.1, 132.4, 130.6, 130.1, 129.3, 128.4, 127.5,
27.3, 127.2, 126.5, 126.4, 126.3, 124.4, 124.1, 107.8, 20.9; IR (KBr) υ
054, 2922, 2854, 1634, 1606, 1515, 1473, 1445, 1346, 1302, 1283,
3
CDCl ) δ 163.6, 162.4, 151.8, 147.9, 136.9, 135.9, 135.3, 135.2, 131.3,
131.0, 130.7, 129.4, 128.5 (q, JC-F = 3.4 Hz), 127.8, 127.5, 126.9, 126.7,
123.9, 123.6 (q, JC-F = 3.4 Hz), 123.5 (q, JC-F = 277.1 Hz), 120.7, 120.4,
20.7; IR (KBr) υ 3067, 2973, 2927, 1672, 1604, 1531, 1467, 1332, 1299,
-1
19 2 2
H N O
[M+H]+
150, 1022, 938, 837 cm ; HRMS (ESI) calcd for C23
55.1441, found 355.1440.
-1
1
253, 1168, 1127, 1073, 939, 810 cm ; HRMS (ESI) calcd for
+
2-Methyl-N-(3-methyl-2-(4-oxo-3,4-dihydroquinazolin-2-
23 17 3
C H F N
O
3 2
[M+H] 424.1267, found 424.1267.
yl)phenyl)benzamide (6b): 60.6 mg (82%); white solid; mp = 225.8–
o
1
2
27.1 C; H NMR (400 MHz, CDCl
3
) δ 10.59 (br, 1H), 9.35 (s, 1H), 8.27
4-Bromo-N-(3-methyl-2-(4-oxo-3,4-dihydroquinazolin-2-
(
(
(
d, J = 8.0 Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.77 (t, J =8.0 Hz, 1H), 7.63
d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.38–7.31 (m, 2H), 7.28–7.25
m, 2H), 7.16 (d, J = 7.6 Hz, 1H), 7.10–7.04 (m, 2H), 2.40 (s, 3H), 2.38 (s,
yl)phenyl)benzamide (6g): 67.8 mg (78%); white solid; mp = 227.3–
o
1
3
228.5 C; H NMR (400 MHz, CDCl ) δ 10.69 (s, 1H), 10.28 (s, 1H), 8.31
(d, J = 8.8 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.88 (t, J = 8.0 Hz, 1H), 7.76
(d, J = 8.0 Hz, 1H), 7.63–7.56 (m, 3H), 7.49 (d, J = 8.4 Hz, 1H), 7.31 (t, J
= 8.0 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 2.43 (s, 3H); 13C NMR (100 MHz,
3
1
1
2
H); 13C NMR (100 MHz, CDCl
3
) δ 168.0, 162.0, 151.6, 148.0, 137.1,
36.9, 136.1, 135.3, 135.0, 131.4, 131.0, 130.5, 127.6, 127.5, 127.1,
26.9, 126.7, 125.7, 124.9, 121.0, 120.9, 20.5, 20.0; IR (KBr) υ 2952,
3
CDCl ) δ 164.2, 162.0, 151.8, 148.0, 136.7, 136.1, 135.3, 133.1, 131.9,
-1
925, 2854, 1675, 1605, 1524, 1466, 1296, 1266, 1137, 946, 739 cm ;
131.1, 128.6, 127.8, 127.3, 126.9, 126.8, 126.7, 123.7, 120.9, 120.3,
20.8; IR (KBr) υ 3064, 2922, 1671, 1600, 1534, 1466, 1416, 1294, 1262,
+
HRMS (ESI) calcd for C23
H N O
20 3 2
[M+H] 370.1550, found 370.1550.
-1
1
3 2
139, 1070, 1009, 950, 841 cm ; HRMS (ESI) calcd for C22H17BrN O
+
2-Methyl-N-(3-methyl-2-(4-oxo-3,4-dihydroquinazolin-2-
[M+H] 434.0499, found 434.0499.
yl)phenyl)benzamide (6c): 74.2 mg (96%); white solid; mp = 225.8–
o
1
2
27.1 C; H NMR (400 MHz, CDCl
3
) δ 10.59 (br, 1H), 9.35 (s, 1H), 8.27
4-Chloro-N-(3-methyl-2-(4-oxo-3,4-dihydroquinazolin-2-
(
(
(
d, J = 8.0 Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.77 (t, J =8.0 Hz, 1H), 7.63
d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.38–7.31 (m, 2H), 7.28–7.25
m, 2H), 7.16 (d, J = 7.6 Hz, 1H), 7.10–7.04 (m, 2H), 2.40 (s, 3H), 2.38 (s,
yl)phenyl)benzamide (6h): 68.7 mg (88%); white solid; mp = 237.1–
o
1
3
238.7 C; H NMR (400 MHz, CDCl ) δ 10.89 (s, 1H), 10.27 (s, 1H), 8.30
(d, J = 7.6 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.89–7.85 (m, 1H), 7.76 (d, J
= 8.0 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.34–7.27
(m, 3H), 6.97 (d, J = 7.6 Hz, 1H), 2.42 (s, 3H); 13C NMR (100 MHz,
3
1
1
H); 13C NMR (100 MHz, CDCl
3
) δ 168.0, 162.0, 151.6, 148.0, 137.1,
36.9, 136.1, 135.3, 135.0, 131.4, 131.0, 130.5, 127.6, 127.5, 127.1,
26.9, 126.7, 125.7, 124.9, 121.0, 120.9, 20.5, 20.0; IR (KBr) υ 2952,
3
CDCl ) δ 164.1, 162.1, 151.9, 148.0, 138.3, 136.8, 136.1, 135.2, 132.7,
7
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202001128
FULL PAPER
-1
1
2
1
31.0, 128.9, 128.4, 127.7, 127.3, 126.9, 126.7, 123.8, 120.9, 120.3,
1525, 1466, 1416, 1328, 1294, 1265, 1163, 1135, 938, 777 cm ; HRMS
+
0.7; IR (KBr) υ 2957, 2923, 2854, 1671, 1598, 1565, 1534, 1465, 1293,
(ESI) calcd for C20H N O
22 3 2
[M+H] 336.1707, found 336.1706.
-1
262, 1210, 1137, 1092, 1013, 950, 844 cm ; HRMS (ESI) calcd for
+
C H17ClN O
22 3 2
[M+H] 390.1004, found 390.1005.
N-(3-Methyl-2-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-2-
phenylacetamide (6n): 54.0 mg (73%); white solid; mp = 220.5–223.4
N-(3-Methyl-2-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-4-
trifluoromethyl)benzamide (6i): 69.5 mg (82%); white solid; mp =
oC; 1H NMR (400 MHz, CDCl
3
) δ 10.59 (s, 1H), 8.29 (d, J = 8.8 Hz, 1H),
(
7.95 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.79 (t, J = 8.4 Hz, 1H), 7.57 (t, J =
7.2 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.01 (d, J =
7.6 Hz, 1H), 6.93 (d, J = 7.2 Hz, 2H), 6.83 (t, J = 7.2 Hz, 2H), 6.77–6.73
2
1
7
20.5–223.4 oC; 1H NMR (400 MHz, CDCl
3
) δ 11.08 (br, 1H), 10.39 (s,
H), 8.29 (d, J = 7.2 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.89–7.85 (m, 3H),
.77 (d, J = 8.4 Hz, 1H), 7.62–7.56 (m, 3H), 7.31 (t, J = 8.0 Hz, 1H), 7.01
(m, 1H), 3.51 (s, 2H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl
3
) δ 169.7,
(
d, J = 7.6 Hz, 1H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl
3
) δ 163.8,
62.3, 151.9, 147.8, 137.5, 137.0, 135.9, 135.3, 133.7, 133.4, 131.1,
27.8, 127.5 (two carbons overlap), 127.3, 126.9, 126.6, 125.7 (q, JC-F
162.0, 151.0, 148.2, 136.7, 135.0, 134.6, 133.4, 130.5, 128.9, 128.7,
127.8, 127.4, 127.3, 126.8, 126.5, 125.4, 121.1, 120.6, 44.6, 19.7; IR
(KBr) υ 3071, 2916, 1671, 1603, 1522, 1468, 1410, 1328, 1291, 1136,
1
1
3
3
1
=
-1
23 20 3 2
C H N O
[M+H]+
.4 Hz), 124.0, 123.5 (q, JC-F = 271.1 Hz), 120.5, 119.4, 20.7; IR (KBr) υ
1071, 1033, 943 cm ; HRMS (ESI) calcd for
370.1550, found 370.1551.
070, 2971, 2924, 1671, 1603, 1534, 1466, 1323, 1300, 1262, 1167,
-1
126, 1066, 1063, 951, 856, 766 cm ; HRMS (ESI) calcd for
+
23 17 3
C H F N
O
3 2
[M+H] 424.1267, found 424.1267.
General procedure and characterization data for the Ir(III)-catalyzed
C–H amidation (8a–8c): To an oven-dried sealed tube charged with 2-
(o-tolyl)quinazolin-4(3H)-one (1a) (47.3 mg, 0.2 mmol, 100 mol %),
N-(3-Methyl-2-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-4-
nitrobenzamide (6j): 48.8 mg (61%); light yellow solid; mp = 250.1–
2 2 2
[IrCp*Cl ] (4.0 mg, 0.005 mmol, 2.5 mol %) and AgNTf (7.8 mg, 0.02
o
1
2
1
7
2
1
1
1
51.6 C; H NMR (500 MHz, CDCl
3
) δ 10.56 (s, 1H), 8.30 (d, J = 7.5 Hz,
mmol, 10 mol %) were added nitrene surrogate (7a–7c) (0.25 mmol, 125
mol %) and DCE (1 mL) under air at room temperature. The reaction
mixture was allowed to stir at room temperature for 20 h under air, and
cooled to room temperature. The reaction mixture was diluted with EtOAc
(3 mL) and concentrated in vacuo. The residue was purified by flash
column chromatography (n-hexanes/EtOAc = 1:2) to afford 8a (44.7 mg)
in 55% yield.
H), 8.82 (d, J = 9.0 Hz, 2H), 7.95–7.89 (m, 3H), 7.79 (d, J = 8.0 Hz, 1H),
.60 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H),
.47 (s, 3H); 13C NMR (175 MHz, CDCl
3
) δ 163.0, 161.9, 161.8, 151.8,
49.8, 139.9, 136.8, 136.0, 135.5, 131.4, 128.2, 128.1, 127.9, 127.0,
26.5, 123.9, 123.6, 120.9, 120.5, 20.8; IR (KBr) υ 3066, 2923, 2854,
671, 1601, 1524, 1466, 1345, 1295, 1262, 1139, 1107, 1012, 951, 851
-1
22 17 4 4
C H N O
[M+H]+ 401.1244, found
cm ; HRMS (ESI) calcd for
01.1245.
4
General procedure and characterization data for the Rh(III)-
catalyzed C–H amidation (8c): To an oven-dried sealed tube charged
with 2-(o-tolyl)quinazolin-4(3H)-one (1a) (47.3 mg, 0.2 mmol, 100 mol %),
N-(3-Methyl-2-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)thiophene-2-
carboxamide (6k): 65.1 mg (90%); light yellow solid; mp = 232.1–233.6
[RhCp*Cl
2
]
2
(3.1 mg, 0.005 mmol, 2.5 mol %), NaOAc (5.0 mg, 0.005
(6.9 mg, 0.02 mmol, 10 mol %) were
oC; 1H NMR (400 MHz, CDCl
) δ 10.09 (s, 1H), 9.95 (s, 1H), 8.34 (d, J =
.6 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.88–7.85 (m, 2H), 7.61–7.57 (m,
H), 7.47–7.46 (m, 2H), 7.36 (t, J = 8.0 Hz, 1H), 7.05–7.01 (m, 2H), 2.45
) δ 183.8, 171.5, 159.7, 151.6, 139.1,
mmol, 2.5 mol %) and AgSbF
3
6
7
1
added N-methoxy-4-methylbenzamide (7d) (41.3 mg, 0.25 mmol, 125
mol %) and DCE (1 mL) under air at room temperature. The reaction
mixture was allowed to stir at 100 oC for 20 h under air, and cooled to
room temperature. The reaction mixture was diluted with EtOAc (3 mL)
and concentrated in vacuo. The residue was purified by flash column
chromatography (n-hexanes/EtOAc = 1:1) to afford 8c (17.0 mg) in 23%
yield.
(
s, 3H); 13C NMR (100 MHz, CDCl
3
1
1
1
36.3, 136.1, 135.2, 131.2, 130.9, 128.7, 127.8, 127.7, 127.2, 127.1,
26.9, 123.4, 121.0, 120.4, 20.8; IR (KBr) υ 2923, 2854, 1668, 1600,
-1
530, 1465, 1421, 1330, 1295, 1262, 1138, 1109, 946, 856 cm ; HRMS
+
(
ESI) calcd for C20
H
16
N
3
O
2
S [M+H] 362.0958, found 362.0958.
N-(3-Methyl-2-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)acetamide
4-Methyl-N-(3-methyl-2-(4-oxo-3,4-dihydroquinazolin-2-
(
6l): 58.1 mg (99%); light yellow solid; mp = 185.3–187.7 oC; 1H NMR
400 MHz, CDCl ) δ 10.99 (s, 1H), 8.86 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H),
.78–7.74 (m, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H),
.28–7.24 (m, 2H), 7.02 (d, J = 7.6 Hz, 1H), 2.30 (s, 3H), 1.97 (s, 3H);
) δ 168.9, 162.3, 151.7, 148.2, 136.9, 135.6,
34.9, 130.6, 127.1, 127.0, 126.7, 125.1, 121.3, 121.0, 24.3, 20.2; IR
KBr) υ 3055, 2963, 2933, 1681, 1603, 1521, 1461, 1416, 1328, 1294,
yl)phenyl)benzenesulfonamide (8a): 44.7 mg (55%); white solid; mp =
199.5–201.3 C; 1H NMR (400 MHz, CDCl
o
(
3
3
) δ 9.13 (s, 1H), 8.72 (s, 1H),
7
7
8.18 (d, J = 8.0 Hz, 1H), 7.84 (t, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H),
7.58–7.52 (m, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.22–7.16 (m, 3H), 6.93 (d, J
13C NMR (100 MHz, CDCl
= 8.0 Hz, 2H), 2.31 (s, 3H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl
3
3
) δ
1
161.4, 150.3, 147.7, 144.3, 136.5, 135.8, 135.3, 135.2, 131.2, 129.6 (two
carbons overlap), 129.1, 127.8, 127.5, 126.6, 126.5 (two carbons
overlap), 126.3, 124.3, 120.6, 21.5, 20.4; IR (KBr) υ 2922, 2853, 1671,
1600, 1464, 1386, 1331, 1293, 1265, 1161, 1090, 1021, 970, 940, 870,
(
-1
16 3 2
H N O
[M+H]+
1
262, 1163, 1114, 939 cm ; HRMS (ESI) calcd for C17
94.1237, found 294.1238.
2
-
1
20 3 3
12 cm ; HRMS (ESI) calcd for C22H N O
S [M+H]+ 406.1220, found
8
N-(3-Methyl-2-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)pivalamide
6m): 45.0 mg (67%); white solid; mp = 202.8–204.3 oC; 1H NMR (400
MHz, CDCl ) δ 10.43 (br, 1H), 9.19 (s, 1H), 8.33 (d, J = 8.0 Hz, 1H), 7.94
d, J = 8.0 Hz, 1H), 7.82 (t, J = 8.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.56
t, J = 8.0 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 2.38
s, 3H), 1.11 (s, 9H); 13C NMR (100 MHz, CDCl
) δ 177.2, 161.9, 151.7,
48.0, 136.5, 136.1, 135.0, 130.8, 127.5, 127.1, 127.0, 126.8, 124.9,
21.0, 120.9, 39.6, 27.4, 20.4; IR (KBr) υ 3057, 2964, 2932, 1677, 1603,
406.1221.
(
3
tert-Butyl
(3-methyl-2-(4-oxo-3,4-dihydroquinazolin-2-
(
(
(
yl)phenyl)carbamate (8b): 48.5 mg (69%); white solid; mp = 202.3–
o
1
3
204.0 C; H NMR (400 MHz, CDCl ) δ 9.93 (s, 1H), 8.29 (d, J = 7.6 Hz,
3
1H), 7.83–7.75 (m, 3H), 7.64 (s, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.33 (t, J =
8.0 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 2.33 (s, 3H), 1.42 (s, 9H); 13C NMR
1
1
3
(100 MHz, CDCl ) δ 161.9, 153.4, 151.4, 148.4, 136.7, 136.3, 134.9,
8
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202001128
FULL PAPER
1
30.8, 127.5, 127.4, 126.6, 126.3, 124.9, 121.0, 120.2, 80.9, 28.2, 20.4;
General procedure and characterization data for the removal of N-
aroyl group (11a): To an oven-dried sealed tube charged with 3-methyl-
N-(3-methyl-2-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)benzamide (3a)
(73.9mg, 0.2 mmol, 100 mol %) and EtOH (2 mL) and added NaOH
IR (KBr) υ 2975, 2925, 1729, 1672, 1603, 1520, 1469, 1366, 1294, 1246,
-1
22 3 3
H N O
[M+H]+
1
156, 1081, 945, 880 cm ; HRMS (ESI) calcd for C20
52.1656, found 352.1655.
3
(
448.0 mg, 11.2 mmol, 56 equiv.) under air at room temperature. The
reaction mixture was allowed to stir at 120 oC for 20 h, and cooled to
room temperature. The reaction was quenched with H O and the mixture
was extracted with EtOAc. The organic layer was dried over MgSO
4-Methyl-N-(3-methyl-2-(4-oxo-3,4-dihydroquinazolin-2-
yl)phenyl)benzamide (8c): 39.2 mg (53%) from 7c, 17.0 mg (23%) from
2
o
1
7
1
1
7
6
d; light yellow solid; mp = 241.4–243.9 C; H NMR (400 MHz, CDCl
3
) δ
4
,
0.32 (s, 1H), 10.15 (s, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.0 Hz,
H), 7.89–7.80 (m, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.57 (t, J = 8.0 Hz, 1H),
.33 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 7.6 Hz, 1H),
.93 (d, J = 7.2 Hz, 2H), 2.43 (s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz,
filtered and concentrated in vacuo. The residue was purified by flash
column chromatography (n-hexane/EtOAc = 2:1) to afford 44.8 mg of 11a
in 89% yield.
CDCl
3
) δ 165.2, 161.8, 151.8, 148.1, 142.6, 136.5, 136.4, 135.1, 131.4,
31.1, 129.3, 127.6, 127.1 (two carbons overlap), 127.0, 126.9, 123.7,
21.0, 120.4, 21.4, 20.7; IR (KBr) υ 3068, 2918, 1673, 1603, 1566, 1530,
2-(2-Amino-6-methylphenyl)quinazolin-4(3H)-one (11a): 44.8 mg
1
1
1
(89%); yellow solid; mp = 175.7–177.1 oC; 1H NMR (400 MHz, CDCl
3
) δ
10.54 (br, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.77–7.71 (m, 2H), 7.46 (t, J =
8.0 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.55 (d, J =
-1
466, 1416, 1295, 1263, 1187, 1138, 1021, 948, 839 cm ; HRMS (ESI)
+
8.0 Hz, 1H), 4.20 (br, 2H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl
62.8, 152.2, 148.8, 145.0, 136.9, 134.6, 130.8, 127.4, 127.0, 126.4,
120.9, 120.7, 119.6, 114.2, 20.0; IR (KBr) υ 3056, 2927, 2924, 1668,
calcd for C23H N O
20 3 2
[M+H] 370.1550, found 370.1550.
3
) δ
1
General procedure and characterization data for the late-stage
functionalizations (10a and 10b): To an oven-dried sealed tube
charged with 2-aryl quinazolinones derived from drug molecules (9a) (0.2
-1
1604, 1560, 1466, 1442, 1333, 1289, 1265, 1139, 940, 874 cm ; HRMS
+
(ESI) calcd for C15
H
14
N
3
O [M+H] 252.1131, found 252.1132.
2 2
mmol, 100 mol %), [Cp*RhCl ] (3.1 mg, 0.005 mmol, 2.5 mol %) and
NaOAc (16.4 mg, 0.2 mmol, 100 mol %) were added 3-(m-tolyl)-1,4,2-
dioxazol-5-one (2a) (44.3 mg, 0.25 mmol, 125 mol %) and DCE (1 mL)
under air at room temperature. The reaction mixture was allowed to stir
General procedure and characterization data for the synthesis of
rhodacycle A: A mixture of 2-phenylquinazolin-4(3H)-one (1f) (44.5 mg,
2 2
0.2 mmol, 100 mol %), [Cp*RhCl ] (61.8 mg, 0.1 mmol, 50 mol %),
o
at 60 C for 14 h, and cooled to room temperature. The reaction mixture
NaOAc (65.7 mg, 0.8 mmol, 400 mol %) and DCE (1 mL) were weighted
in a Schlenk tube equipped with a stir bar under nitrogen. The reaction
mixture was stirred at 60 °C under nitrogen for overnight, and
concentrated in vacuo. The residue was purified by flash column
chromatography (n-hexane/EtOAc = 1:1) to afford 38.8 mg of rhodacycle
A in 42% yield.
was diluted with EtOAc (3 mL) and concentrated in vacuo. The residue
was purified by flash column chromatography (n-hexanes/EtOAc = 1:2) to
afford 10a (54.3 mg) in 51% yield.
3
-Methyl-N-((8R,9S,13S,14S)-13-methyl-17-oxo-3-(4-oxo-3,4-
dihydroquinazolin-2-yl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-
o
cyclopenta[a]phenanthren-2-yl)benzamide (10a): 54.3 mg (51%);
Rhodacycle A: 38.8 mg (42%); dark brown solid; mp = 237.5–239.9 C;
o
1
1H NMR (500 MHz, CDCl
white solid; mp = 303.5–304.7 C; H NMR (500 MHz, CDCl
3
) δ 12.93 (s,
H), 11.40 (s, 1H), 8.87 (s, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.87–7.86 (m,
H), 7.80 (t, J = 7.5 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.52 (t,
3
) δ 8.36–8.31 (m, 2H), 8.00 (d, J = 7.5 Hz, 1H),
1
2
7.92 (d, J = 7.5 Hz, 1H), 7.85 (t, J = 7.0 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H),
7.32 (t, J = 7.5 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 1.55 (s, 15H); 13C NMR
J = 7.5 Hz, 1H), 7.42–7.37 (m, 2H), 2.91–2.88 (m, 2H), 2.55–2.48 (m,
3
(125 MHz, CDCl ) δ 162.4, 159.5, 159.4, 146.9, 138.1, 137.7, 135.4,
2
H), 2.44 (s, 3H), 2.29–2.25 (m, 1H), 2.18–2.11 (m, 1H), 2.07–1.96 (m,
H), 1.64–1.57 (m, 3H), 1.49–1.44 (m, 3H), 0.88 (s, 3H); 13C NMR (175
132.2, 127.7, 126.9, 126.8, 125.2, 123.2, 120.4, 96.5, 96.4, 9.5; IR (KBr)
υ 2920, 2852, 1698, 1666, 1606, 1586, 1536, 1509, 1468, 1454, 1376,
3
-1
MHz, CDCl
3
) δ 198.6, 166.1, 162.9, 152.3, 147.6, 145.3, 138.4, 137.4,
1324, 1292, 1163, 1127, 1023, 943, 862, 770 cm ; HRMS (ESI) calcd for
+
1
1
2
1
35.5, 135.1, 132.7, 131.8, 128.5, 128.0, 127.8, 127.2, 126.7, 126.6,
C
24
H
24
N
2
ORh [M+H] 459.0938, found 459.0938.
26.5, 124.7, 118.9, 116.1, 50.5, 47.9, 44.9, 37.8, 35.8, 31.5, 29.7, 28.8,
6.3, 25.6, 21.4, 13.8; IR (KBr) υ 3201, 3153, 3056, 2921, 1738, 1667,
-1
607, 1557, 1523, 1405, 1331, 1280, 1251, 1212, 1083, 956, 901 cm ;
Acknowledgements
+
HRMS (ESI) calcd for C34
H N O
34 3 3
[M+H] 532.2595, found 532.2595.
This work was supported by the National Research Foundation
of Korea (NRF) and funded by the Korea government (MSIFP)
N,N'-(2-(4-Oxo-3,4-dihydroquinazolin-2-yl)-5-(1-(4-sulfamoylphenyl)-
-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-phenylene)bis(3-
methylbenzamide) (10b): 71.6 mg (46%); white solid; mp = 281.5–283.4
oC; 1H NMR (500 MHz, CD
OD) δ 8.16 (d, J = 7.5 Hz, 1H), 7.99 (d, J =
.5 Hz, 2H), 7.91 (s, 2H), 7.82 (t, J = 7.5 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H),
.63–7.59 (m, 6H), 7.52 (t, J = 7.5 Hz, 1H), 7.35–7.29 (m, 4H), 7.11 (s,
H), 2.32 (s, 6H); 13C NMR (125 MHz, CD
OD) δ 168.6, 152.9, 149.6,
3
(
Nos.
2018R1C1B6005607,
2019R1A4A2001451
and
2020R1A2C3005357).
3
8
7
1
1
1
1
Keywords: Amidation • C–H functionalization • Dioxazolones •
Quinazolinoes • Rhodium
3
45.5, 145.3, 145.1, 144.8, 142.9, 139.8, 139.1, 135.8, 135.4, 134.0,
32.9, 129.6, 129.0, 128.6, 128.5, 128.0, 127.3, 127.1, 125.8, 123.7,
23.6 (q, JC-F = 280.6 Hz), 122.2, 121.5, 119.8, 107.9, 107.8, 21.3; IR
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European Journal of Organic Chemistry
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1
0
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European Journal of Organic Chemistry
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FULL PAPER
Entry for the Table of Contents
Key Topic: C–H Amidation
O
O
FG
R1
NH HN
R1
NH
H
N
FG Rh(III) or Ir(III)
+
X
R2
nitrene
X
R2 surrogates
X = N, C
40 examples
up to 99% yield
via late-stage C-H amidation
O
N
O
O
NH HN
m-tolyl
NH
N
H
H
HN
CF3
HN
N
N
H
m-tolyl
O
O
Me O
O
S
H2N
O
Me
The site-selective C–H amidation of 2-aryl quinazolin-4(3H)-ones with dioxazolones under rhodium(III) catalysis is described. Gram-
scale reaction, late-stage C–H functionalization, and synthetic transformations highlight the potential of the developed method.
1
1
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