Syntheses of 2-Iminoindolin-3-ones and 2-Alknyl-2,3-dihydroquinazolin-4(1 H)-ones from 3-Diazoindolin-2-imines

Article abstract of DOI:10.1021/acs.joc.0c01548

3-Diazoindolin-2-imines reacted with nitrones to furnish 2-iminoindolin-3-ones through a Au(I)-catalyzed cascade oxygen transfer/imine exchange process. The prepared 2-iminoindolin-3-ones could be further transformed into 2-Alknyl-2,3-dihydroquinazolin-4(1H)-ones through a Ag(I)-catalyzed reaction with terminal alkynes. A MeOH-Triggered ring expansion mechanism involving cyclic iminium formation and nucleophilic addition is proposed for this novel alkynylation reaction. This two-step procedure provides a general and convenient approach to 2-Alknyl-2,3-dihydroquinazolin-4(1H)-ones, which are privileged structures in medicinal chemistry.

Full text of DOI:10.1021/acs.joc.0c01548

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Article
Syntheses of 2-Iminoindolin-3-ones and 2-Alknyl-2,3-
dihydroquinazolin-4(1H)-ones from 3-Diazoindolin-2-imines
Zhenwei Lin, Jing Qian, Ping Lu, and Yanguang Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01548 • Publication Date (Web): 26 Aug 2020
Downloaded from pubs.acs.org on August 26, 2020
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Syntheses of 2-Iminoindolin-3-ones and 2-Alknyl-2,3-dihydroquinazolin
-4(1H)-ones from 3-Diazoindolin-2-imines
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Zhenwei Lin, Jing Qian, Ping Lu*, Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
E-mail: pinglu@zju.edu.cn; orgwyg@zju.edu.cn
O
O
N
Ar
R2
N2
O
Ar
R2
R4
AgOAc
MeOH
N
Ph
R2
X
N
X
N
X
N
N
R1
[Au], PhCl
AcOH, 4Å MS
R1
N
R1
SO2R3
Ar
R4
(X = CH or N)
28 examples
up to 93% yields
24 examples
up to 84% yields
ABSTRACT: 3-Diazoindolin-2-imines reacted with nitrones to furnish 2-iminoindolin-3-ones
through a Au(I)-catalyzed cascade oxygen transfer/imine exchange process. The prepared 2-
iminoindolin-3-ones could be further transformed into 2-alknyl-2,3-dihydroquinazolin-4(1H)-ones
through a Ag(I)-catalyzed reaction with terminal alkynes. A MeOH-triggered ring expansion
mechanism involving cyclic iminium formation and nucleophilic addition is proposed for this novel
alkynylation reaction. This two-step procedure provides a general and convenient approach to 2-
alknyl-2,3-dihydroquinazolin-4(1H)-ones, which are privileged structures in medicinal chemistry.
INTRODUCTION
2,3-Dihydroquinazolin-4(1H)-ones (DHQs) are important heterocycles in medicinal chemistry
because they possess a wide range of pharmacological properties and a panel of compounds with DHQ
core are currently used for treatment of various diseases.1 For examples, quinethazone and metolazone
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are antihypertensive and diuretic drugs, methaqualone is a sedative and hypnotic drug, and
VU0092145 is a neurotransmitter (Figure 1). Because of the importance of DHQs in medicinal
chemistry, the development of the synthetic strategies for the construction of DHQ core has attracted
much attention.1a,1f The classical and common synthetic protocol for DHQs is cyclocondensation of
anthranilamides with carbonyl compound.1a,2 Alternative methods include the reductive cyclization of
o-nitrobenzamides or o-azidobenzamides with carbonyl compounds,3 the cyclocondensation of o-
aminobenzonitriles with carbonyl compounds,4 and the three-commponent reaction of isatoic
anhydrides with primary amines (or ammonium salts) and aldehydes.5 More recently, Zhang and co-
workers reported a four-component synthesis of 1,2,3-trisubstituted 2,3-dihydroquinazolin-4(1H)-
ones via alkylamino-directed reaction of N-alkyl anilines with CO, primary amines and aldehydes.6
Thus, development of new methodologies for rapid construction of 1,2,3-trisubstituted DHQs is still
in a great demand.
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O
O
O
H2NO2S
Cl
H2NO2S
Cl
N
N
NH
Ph
N
H
N
H
N
H
Metolazone
antihypertensive,diuretic
Quinethazone
antihypertensive,diuretic
VU0092145
neurotransmitter
O
O
N
O2N
O
NH
N
N
N
H
N
N
N
N
antihistaminic
activity
Methaqualone
sedative,hypnotic
anticancer activity
Figure 1. Representative examples of marketed drugs and pharmacologically active compounds
containing DHQ core.
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Nitrones are easily prepared and highly useful synthons in organic synthesis. Various addition and
C−H functionalization reactions of nitrones provide powerful strategies for the construction of highly
selective and unique C-C bonds.7 For examples, the transition-metal-catalyzed [3+3] cycloadditions of
nitrones with electrophilic vinylcarbenes derived from vinyldiazoacetates or enoldiazoacetamides led
to asymmetric synthesis of 3,6-dihydro-1,2-oxazines.8 Besides of addition and C-H functionalization,
nitrones could also work as oxidants or oxygen-transfer reagents for the oxidative amination of some
alkynes.9
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Gold carbenes have been demonstrated to be chemically versatile intermediates, which can undergo
various important transformations, such as cycloaddition, cyclopropanation, cyclopropenation,
heteroatom−H insertion, C−H functionalization, and [2,3]-sigmatropic rearrangement reactions.10-12
Gold carbenes can be in situ generated from a number of precursors, such as diazo compounds,11
alkynes or cyclopropenes.12 Compared with other classical classes of metal carbenes, gold carbenes
present highly electrophilic character (i.e., a very weak electron donation from gold to the carbene
center).10b
Based on unique reactivities of nitrones and gold carbenes and encouraged by our success in the
chemistry of 3-diazoindolin-2-imine chemistry,13 we investigated the gold-catalyzed reaction between
3-diazoindolin-2-imines and nitrones. It was found that the reaction underwent a tandem oxygen
transfer/imine exchange process to furnish 2-iminoindolin-3-ones. Moreover, the synthesized 2-
iminoindolin-3-ones could be transformed to 2-alknyl-2,3-dihydroquinazolin-4(1H)-ones by treatment
with the silver acetylide in situ generated from silver catalysis and terminal alkynes. We herein report
this novel two-step approach to 2-alknyl-DHQs.
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RESULTS AND DISCUSSION
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Primarily, we examined the reaction of diazo compound 1a with nitrone 2a using 2.5 mol%
JohnPhosAu(CH3CN)SbF6 as catalyst. After the reaction was performed in toluene at 80 oC for 4 hours,
the unexpected 2-iminoindolin-3-one 3a instead of the [3+3] cycloaddition product was obtained
(Table 1, entry 1). Then, we optimized the reaction conditions of this modal reaction for getting the
satisfied yield of 2-iminoindolin-3-one. First, several other gold catalysts (e.g., (o-tosyl)3PAuCl,
Au(PPh3)Cl, (RO)3PAuCl and (t-BuXphos)PAuCl) were screened, but the yield of 3a was not
improved (Table 1, entries 2-5). Rh2(Oct)4, Rh2(CF3CO2H)4, CuCl, Cu(OTf)2, Fe(OTf)2 and Fe(OTf)3
were also tested. However, no reaction occurred in these cases (Table 1, entries 6-11). Then, we
screened several solvents (e.g., chlorobenzene, xylene, ethyl acetate, and 1,2-dichloroethane) and
chlorobenzene gave the best yield (Table 1, entries 12-15). Then, we fixed JohnPhosAu(CH3CN)SbF6
as catalyst and chlorobenzene as solvent to test some additives. Addition of 2 equivalent of acetic acid
significantly improved the yield (Table 1, entry 16), whereas the addition of CF3CO2H led to a decrease
in the yield (Table 1, entry 17) and AgSbF6 almost inhibited the reaction (Table 1, entry 18). The yield
was further improved to 83% by adding 25 mg of 4Å MS (Table 1, entry 19). Subsequently, the optimal
reaction temperature was determined to be 80 oC (Table 1, entries 20 and 21). Finally, the ratio of 1a
and 2a was optimized and the best result (91% yield) was obtained when 1.5 equivalent of 2a was used
(Table 1, entries 22 and 23).
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Table 1. Optimization of the Reaction Conditionsa
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N2
O
O
N
Ph
catalyst
N
+
N
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solvent, temp.
additives, 4 h
N
Ph
Ts
N
Ph
1a
2a
3a
entry catalyst system
solvent
Tol
temp(oC) yield (%)b
1
JohnPhosAu(CH3CN)SbF6
(o-tosyl)3PAuCl
Au(PPh3)Cl
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
31
2
Tol
24
3
Tol
17
4
(t-BuXphos)PAuCl
(RO)3PAuCl
Tol
21
5
Tol
16
6
Rh2(Oct)4
Tol
NR
NR
NR
NR
NR
NR
43
7
Rh2(CF3CO2H)4
CuCl
Tol
8
Tol
9
Cu(OTf)2
Tol
10
11
12
13
14
15
Fe(OTf)2
Tol
Fe(OTf)3
Tol
JohnPhosAu(CH3CN)SbF6
JohnPhosAu(CH3CN)SbF6
JohnPhosAu(CH3CN)SbF6
JohnPhosAu(CH3CN)SbF6
PhCl
xylene
EtOAc
DCE
37
37
19
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JohnPhosAu(CH3CN)SbF6/AcOH
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
80
80
80
80
60
100
80
80
77c
JohnPhosAu(CH3CN)SbF6/CF3CO2H
JohnPhosAu(CH3CN)SbF6/AgSbF6
32c
tracec
83d
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JohnPhosAu(CH3CN)SbF6 /AcOH/4Å MS
JohnPhosAu(CH3CN)SbF6 /AcOH/4Å MS
JohnPhosAu(CH3CN)SbF6/AcOH/4Å MS
JohnPhosAu(CH3CN)SbF6/AcOH/4Å MS
JohnPhosAu(CH3CN)SbF6/AcOH/4Å MS
67d
75d
91d,e
89d,f
aReaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), catalyst (0.005 mmol, 2.5 mol %), solvent (2
mL), sealed tube, 80 oC, 4 h. bIsolated yield. cAcid (0.4 mmol) was added. dAcOH (0.4 mmol) and 4Å
MS (25 mg) were added. e2a (0.3 mmol) was used. f2a (0.4 mmol) was used.
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Scheme 1. Preparation of Compounds 3a
4
5
6
7
8
O
R2
N2
R2
O
Ar
JohnPhosAu(CH3CN)SbF6
+
N
N
N
Ar
PhCl, AcOH,4Å MS
80 oC, 4 h
Ph
N
R1
9
N
R1
X
Ts
X
10
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3
1
2
O
Ph
N
O
O
R2
Ph
Ph
N
N
N
N
N
R1
2
1
3k
, 84%
3f
, R = F, 87%
3a,
R = Me, 91%
2
1
3g
3h
, R = Cl, 83%
3b
3c
3d
3e
, R = Et, 88%
2
1
, R = Br, 80%
, R = i-Pr, 86%
2
1
3i
3j
, R = Me, 83%
, R = Bn, 89%
2
1
, R = OMe, 74%
, R = Allyl, 88%
O
Br
O
Ph
N
O
Ph
N
R
N
N
N
N
N
3n
3o
, R = Me, 81%
, R = OBn,77%
3m
3l,
, 93%
82%
3p
3q
, R = F, 80%
, R = Cl, 87%
, R = Br, 85%
Ph
Ph
Ph
R
3r
3s
O
N
O
, R = I, 83%
3t
, R = Me, 86%
N
N
3u
3v
, R = OMe, 76%
, R = OEt, 74%
N
3w
,R = CO2Me, 71%
3z
, 83%
3x
3y
, R = CF3, 70%
, R = NPh2, 82%
aReaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), JohnPhosAu(CH3CN)SbF6 (0.005 mmol), AcOH
(0.4 mmol), 4Å MS (25 mg), PhCl (2 mL), 80 oC, 4 h; Isolated yield.
With the established reaction conditions (Table 1, entry 22), we investigated the substrate scope for
the preparation of 2-iminoindolin-3-ones 3 and the results are summarized in Scheme 1. A variety of
diazo compounds 1 were examined firstly. Good to excellent yields were obtained when the substituent
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(R1) on the 1-position of indole ring was alkyl (3a-c), benzyl (3d) or allyl (3e). The substituent (R2) at
the 5-position of indole ring could be fluoro, chloro, bromo, methyl or methoxy. In these cases, the
corresponding products 3f-j were obtained in 74-87% yields. Comparable yields of 3k and 3l were
obtained when methyl occupied on 7-position and bromo appeared on 4-position of indole ring,
respectively. In the case where 7-aza-3-diazoindolin-2-imine was used as diazo substrate, the
corresponding product 3m was isolated in 93% yield. Next, we examined the scope of nitrones 2. The
substituent (R) on the 2- or 4-position of aniline ring of nitrones could be electron-donating group
(e.g., Me, OBn, OMe, OEt and NPh2) and electron-withdrawing group (e.g., F, Cl, Br, I, CO2Me and
CF3). Thus, compounds 3n-y were obtained in 70-87% yields. Single crystal analysis of 3s confirmed
the skeleton of 2-iminoindolin-3-ones with the (E)-configuration of C=N bond.14 Moreover, R could
be 4-(1,2,2-triphenylvinyl). In this case, more conjugated system 3z was produced in 83% yield.
Altering the 4-methylbenzenesulfonyl group of diazo compound 1a to 4-chlorobenzenesulfonyl or
methanesulfonyl led to a slight decrease in the yield of 3a (Scheme 2).
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To explore the practical usage of this methodology, we carried out a gram-scale experiment. Thus,
the reaction of 8 mmol of 1a with 12 mmol of 2a under standard conditions afforded 1.16 g of 3a
(61.4% yield) (see Supporting Information).
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Scheme 2. Formation of 3a from Diazo Compounds with Different Sulfonyl
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O
N2
O
JohnPhosAu(CH3CN)SbF6
Ph
+
N
N
N
Ph
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Ph
SO2R3
PhCl, AcOH,4Å MS
80 oC, 4 h
N
N
3a
1
2a
R3 = p-C6H4Cl, 89% yield
R3 = Me, 84% yield
To have a good insight into the reaction mechanism, several control experiments were performed
(Scheme 3). We assumed that nitrone worked as oxygen transfer reagent at the beginning of the
reaction. Thus, the combination of N-oxide (e.g., 2,6-dichloropirydine N-oxide)15 and imine was used
instead of nitrone to react with 1a. The reaction was tested under standard conditions and 3a was
obtained in 71% yield (Scheme 3, eq 1). 3a could also be obtained in 57% yield when aniline was used
as nucleophile instead of imine (Scheme 3, eq 2). Finally, water was used as the nucleophile and
successfully trapped the oxygen transferred intermediate to afford 1-methylindoline-2,3-dione in 29%
yield (Scheme 3, eq 3) which indicated that oxygen transfer occurred before nucleophilic addition.
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Scheme 3. Controlled Experiments
6
7
O
Ph
8
9
JohnPhosAu(CH3CN)SbF6
Ph
(eq 1)
N
+
1a
+
N
Ph
PhCl, AcOH,4Å MS
80 oC, 4 h
Cl
N
O
Cl
N
10
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3a,
3a,
71%
O
(0.1 mmol)
(0.15 mmol) (0.15 mmol)
Ph
JohnPhosAu(CH3CN)SbF6
N
(eq 2)
+
PhNH2
+
1a
PhCl, AcOH,4Å MS
80 oC, 4 h
Cl
N
O
Cl
N
57%
O
(0.1 mmol)
(0.15 mmol)
(0.15 mmol)
JohnPhosAu(CH3CN)SbF6
(eq 3)
1a
H2O
+
O
+
Cl
N
O
Cl
PhCl, AcOH,4Å MS
80 oC, 4 h
N
29%
(0.1 mmol)
(0.15 mmol)
(0.15 mmol)
Based on the above results and LC-MS analysis of the reaction mixture, we propose a possible
mechanism for the formation of 3 as shown in Scheme 4. The cascade reaction is initiated by the
formation of gold carbene A with a release of nitrogen.10b,11a~11c The gold carbene intermediate acts as
electrophilic carbocation (resonance structure A), reacting with nitrone to form intermediate B.
Subsequently, B decomposes into 2-iminoindolin-3-one C and imine D (detected by LC-MS).15 Imine
D can be hydrolyzed into aniline and benzaldehyde (both were detected by LC-MS). C is very
unstable due to the presence of electron-withdrawing sulfonyl, and the adjacent newly formed carbonyl
group. It immediately reacts with aniline through a nucleophilic addition-elimination process,
providing stable 2-iminoindolin-3-one 3a with the release of TsNH2 that is isolable. In this process,
nitrone works as an oxygen-transfer reagent and aniline source.
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Scheme 4. Possible mechanism for the formation of 3a
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Ph
N
Ph
N
Au
Au
Au
Ph
O
[Au+]
Ph
O
1a
N
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N
N
 N2
N
Ts
N
Ts
N
Ts
B
A'
A
[Au+]
oxygen-transfer
O
H
O
O
N
Ph
N
N
NH
Ts
N
PhNH2
N
Ph
N
Ts
3a
C
E
TsNH2
+
PhCHO
Ph
Ph
N
D
H2O
As an expansion of our method, the transformation of synthesized 2-iminoindolin-3-ones 3 were
investigated. In consideration of widespread applications of the silver-catalyzed alkynylation via an
alkynyl silver intermediate16 and the transition-metal-catalyzed alkynylation of isatins16d,17 or isatin-
derived ketimines18 with terminal alkynes, we envisioned that the nucleophilic addition of alkynyl
silver to 2-iminoindolin-3-ones may furnish 3-alkynyl-3-hydroxyindolin-2-imines. We primarily
tested the reaction of 2-iminoindolin-3-one 3a with ethynylbenzene (4a) in methanol using 1 equiv of
AgOAc as catalyst. To our surprise, instead of obtaining 3-alkynyl-3-hydroxyindolin-2-imine, 1-
methyl-3-phenyl-2-(phenylethynyl)-2,3-dihydroquinazolin-4-(1H)-one (5a) was isolated in 40% yield
o
after the reaction proceeded at 80 C for 16 hours (Table 2, entry 1). A domino ring expansion and
alkynylation obviously occurred in this transformation. To the best of our knowledge, this type of ring
expansion followed by nucleophilic addition is rare in literature. Interested by the mechanism and the
importance of 2,3-dihydroquinazolin-4-(1H)-ones (DHQs) in medicinal chemistry,1 we optimized this
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reaction conditions. It was found that the yield could be improved to 56% by using extra dry methanol
as solvent (Table 2, entry 2). Ethanol and isopropanol work for this transformation but gave lower
yields in each case (Table 2, entries 3 and 4). However, no reaction was observed when acetonitrile,
ethyl acetate, 1,4-dioxane or toluene were used as solvent (Table 2, entries 5-8). The reaction did not
occur at all without the silver catalyst (Table 2, entry 9). The amount of catalyst could be reduced to
0.5 equivalent (Table 2, entries 10 and 11), but further reducing the catalyst amount led to a decrease
in the yield (Table 2, entries 12 and 13). Then, we optimized the ratio of 1a/2a (Table 2, entries 14-
16) as well as reaction temperature (Table 2, entry 17). The highest yield (73%) was obtained when
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o
the reaction was carried out with 1.5 equiv of 2a at 80 C (Table 2, entry 15). Finally, several other
silver salt catalysts were also tested for this transformation under similar conditions. AgNO3 and
AgOTf did not work (Table 2, entries 18 and 19), while Ag2CO3 gave 10% yield of 5a (Table 2, entry
20).
Table 2. Optimization of the Reaction Conditionsa
Ph
O
N
O
HO
N
Ph
Ph
AgOAc
N

Ph
N
Ph
solvent, temp
16 h
N
N
Ph
not observed
5a
3a
4a
entry
[Ag] (equiv)
AgOAc (1.0)
AgOAc (1.0)
AgOAc (1.0)
solvent
MeOH
3a/4a
1:1
temp (oC)
yieldb (%)
1
2
3
80
80
80
40
56
36
MeOH (extra dry)
EtOH
1:1
1:1
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4
AgOAc (1.0)
AgOAc (1.0)
AgOAc (1.0)
AgOAc (1.0)
AgOAc (1.0)
-
i-PrOH
1:1
80
80
80
80
80
80
80
80
80
80
80
80
80
60
80
80
80
17
5
MeCN
1:1
NR
NR
NR
NR
NR
61
6
EtOAc
1:1
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7
1,4-dioxane
1:1
8
Tol
1:1
9
MeOH (extra dry)
MeOH (extra dry)
MeOH (extra dry)
MeOH (extra dry)
MeOH (extra dry)
MeOH (extra dry)
MeOH (extra dry)
MeOH (extra dry)
MeOH (extra dry)
MeOH (extra dry)
MeOH (extra dry)
MeOH (extra dry)
1:1
10
11
12
13
14
15
16
17
18
19
20
AgOAc (0.6)
AgOAc (0.5)
AgOAc (0.4)
AgOAc (0.3)
AgOAc (0.5)
AgOAc (0.5)
AgOAc (0.5)
AgOAc (0.5)
AgNO3 (0.5)
AgOTf (0.5)
Ag2CO3 (0.5)
1:1
1:1
63
1:1
54
1:1
42
1:1.2
1:1.5
1:2.0
1:1.5
1:1.5
1:1.5
1:1.5
67
73
73
51
NR
NR
10
aReaction conditions: 3a (0.2 mmol), 4a (0.2 ~ 0.4 mmol), AgOAc (0.06 ~ 0.2 mmol), solvent (2 mL),
in sealed tube, 16 h. bIsolated yield.
To develop a general and practical approach to 2-alknyl-2,3-dihydroquinazolin-4(1H)-ones
because of the importance of this class of heterocycles, we investigated the substrate scope of this
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reaction (Scheme 5). Several 2-iminoindolin-3-ones with different substituents R1, R2 and R4 were
examined for their reaction with 1-bromo-4-ethynylbenzene under the optimized conditions and the
corresponding products 5b-h were isolated in moderate yields (55-67%). The structure of 5f was
unambiguously determined by X-ray analysis.14 No significant electronic effect was observed in these
cases. Then, we examined other terminal alkynes. Electron-donating group substituted 4-
ethynylbenzenes gave relatively higher yields (5i, 5j and 5o, 76-84%) than the electron-withdrawing
group substituted 4-ethynylbenzenes (5k-n, 41-51%). Heterocyclic aromatic alkynes, such as 2-
ethynylthiophene, 3-ethynylthiophene, 2-ethynylpyridine as well as 3-ethynylpyridine, reacted with
3a to give the corresponding products 5p-s in 41-62% yields. Aliphatic alkynes such as hex-1-yn, 3-
methylbut-1-yne, 3,3-dimethylbut-1-yne and ethynylcyclohexane provided the corresponding
products 5t-w in 37-57% yields. 3m originally derived from 1H-pyrrolo[2,3-b]pyridine could also
undergo this reaction to give the desired product 5x in 50% yield.
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Scheme 5. Preparation of 2-Alknyl-2,3-dihydroquinazolin-4(1H)-ones 5a
7
8
9
R
10
11
12
13
14
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R
O
O
R2
R2
AgOAc
N
R4

MeOH, 80 oC
16 h
N
N
R1
X
R
N
R1
5
X
R4
O
4
3
O
O
N
O
N
N
R2
N
N
N
OMe
N
R1
N
Br
Br
Br
1
2
5b
5c
, R = Me, 67%
5d
5e
, R = Cl, 55%
5g
5h
, R = Br, 63%
, R = I, 57%
5o
, 76%
1
2
, R = Et, 62%
, R = Br, 59%
2
5f
, R = Me, 60%
O
N
N
O
N
O
N
N
5i
5j
5k
5l
5m
5n
, R = OMe, 84%
, R = Me, 73%
, R = NO2, 44%
, R = CF3, 41%
, R = CN, 51%
, R = F, 48%
N
S
S
5p
5q
, 57%
, 41%
R
O
O
N
N
O
O
N
N
N
N
N
N
N
N
5r,
47%
5s
5t
5u
, 51%
, 62%
, 57%
O
O
N
N
O
N
N
N
N
N
Ph
5v
5w
5x
, 50%
, 37%
, 48%
aReaction conditions: 3 (0.2 mmol), 4 (0.3 mmol), AgOAc (0.1 mmol), extra dry MeOH (2 mL), 80
oC, 16 h; Isolated yield.
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To have a good insight into the mechanism of this transformation, we investigated the solvolysis of
compounds 3 in CH3OH and CD3OD, respectively. As shown in Scheme 6, refluxing 3a and 3e in
CH3OH for 12 h led to the formation of 6a and 6b, respectively. The structure of 6b was characterized
by X-ray analysis of its single crystal.14 A deuterated product D-6a was isolated when deuterated
solvent CD3OD was used instead of CH3OH (Scheme 7). The reaction between 3a and 4a using
CD3OD as solvent was also carried out under the standard conditions and D-5a was obtained (Scheme
6).
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Scheme 6. Controlled Experiments
Ph
HN
N
O
R2
R2
Ph
MeOH
O
N
reflux,12 h
N
O
H
2
2
6a
, R = H, 82%
3a
3e
, R = H
2
2
6b
, R = Br, 79%
, R = Br
Scheme 7. Deuterating Experiments
Ph
HN
O
Ph
CD3OD
reflux, 12 h
Ph
D
O
N
3a
AgOAc
CD3OD, 80 oC
16, h
N
N
Ph
O
D (100%)
, 80%
D-5a
, 56%
D-6a
Based on our observations and literature publications, we propose a possible mechanism for the
formation of 5 and 6 as shown in Scheme 8. First, the electrophilic carbonyl carbon atom at position 3
of 3a is attacked by MeOH to form hemiacetal G, which immediately undergoes a ring-opening to
form intermediate H. After H+/D+ transfer, intermediate I was generated. Then, an intramolecular
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nucleophilic substitution occurs to generate iminium-like intermediate J. Finally, the alkynyl silver in
situ formed from terminal alkyne 4 and silver salt attacks intermediate J to give addition product 5.16~19
If the nucleophilic reagent is altered to water from solvent, intermediate K is afforded. Subsequent
ring-opening provides diamide 6a.
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Scheme 8. Possible Mechanism for the Formation of 5 and 6
OH
O
HO Me
HO OMe
OMe
N
N
N
O
N
Ph
N
Ph
N Ph
OMe
3a
H
G
H
R
4
Ag+
H+
O
N
O
Ph
Ph
-
N

MeO
N
H
Ag
R
H
N
N
R
J
H
N
5
H+
Ph
H2O
I
O
N
O
Ph
N
Ph
N
H
H
N
OH
H
6a
O
K
CONCLUSIONS
In conclusion, we have developed a novel and efficient two-step synthesis of 2-alknyl-2,3-
dihydroquinazolin-4(1H)-ones from 3-diazoindolin-2-imines as the starting materials. The diazo
compounds reacted with nitrones to give 2-iminoindolin-3-ones through a Au(I)-catalyzed cascade
oxygen transfer and imine exchange process. The prepared 2-iminoindolin-3-ones could be further
transformed into 2-alknyl-2,3-dihydroquinazolin-4(1H)-ones through a Ag(I)-catalyzed reaction with
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terminal alkynes. A nucleophilic solvent (i.e., MeOH)-intrigued ring-opening mechanism involving a
cyclic iminium formation and subsequent nucleophilic addition with alkynyl silver is proposed for this
novel reaction based on our observations. The remarkable features of our method include: (1) practical
simplicity, (2) broad substrate scope, and (3) easy availability of starting materials. Furthermore, the
final products might be useful in medicinal chemistry. Further exploration of the chemistry of 3-
diazoindolin-2-imines is currently underway in our laboratory.
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EXPERIMENTAL SECTION
General Information. NMR spectra were recorded at 1H 400, 500 or 600 MHz and 13C 100, 125 or
1
150 MHz. H NMR chemical shifts were quoted in parts per million (ppm) and referenced to the
appropriate solvent peak or 0 ppm for TMS. 13C{1H} NMR chemical shifts were reported referenced
to the center line of a triplet at 77.00 ppm of CDCl3 or the center line of a heptet at 39.52 ppm of
DMSO-d6. The abbreviations s (singlet), d (doublet), t (triplet), m (multiplet) were used to describe
the peak splitting pattern. J values were reported in Hz. HRMS were recorded using EI or ESI
ionization source. Melting points were determined without temperature correction. Substrates 1 were
prepared according to our published methods.20,21 Substrates 2 were prepared by literature procedure.22
General procedure for the preparation of compounds 3. To an oven-dried 10 mL sealing tube
equipped with a magnetic stirring bar were added sequentially 1 (0.2 mmol), 2 (0.3 mmol), 4Å MS (25
mg), AcOH (0.4 mmol), JohnPhosAu(CH3CN)SbF6 (0.005 mmol, 2.5 mol %) and PhCl (2 mL). The
reaction mixture was stirred at 80 oC (oil bath) for about 4 h. The conversion of the starting materials
was monitored by TLC. Then, the reaction mixture was concentrated in vacuo to remove solvent. The
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crude product was purified by column chromatography on silica gel (eluent: petroleum ether / EtOAc
= 10:1 – 4:1, v/v).
8
9
Preparation of 3a in Gram Scale. To an oven-dried 100 mL roung-bottom flask equipped with a
magnetic stirring bar were added sequentially 1a (8 mmol), 2a (12 mmol), JohnPhosAu(CH3CN)SbF6
(0.08 mmol, 1 mol %), 4Å MS (100 mg), AcOH (16 mmol, 2 equiv) and PhCl (80 mL). The reaction
mixture was stirred at 80 oC (oil bath) for more than 12 h. The conversion of the starting materials was
monitored by TLC. After removal of solvent in vacuo, the crude product was purified by column
chromatography on silica gel (eluent: petroleum ether / EtOAc = 10:1) to give 1.16 g of pure 3a (61.4%
yield).
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General procedure for the preparation of compounds 5. To an oven-dried 10 mL sealing tube
equipped with a magnetic stirring bar were added sequentially 3 (0.2 mmol), 4 (0.3 mmol), AgOAc
(0.5 equiv, 0.1 mmol), and extra dry MeOH or CD3OD (2 mL). The reaction mixture was stirred at 80
oC (oil bath) for 16 h. The conversion of the starting materials was monitored by TLC. The solvent was
removed in vacuo and then the crude product was purified by column chromatography on silica gel
(eluent: petroleum ether / EtOAc = 20:1 – 10:1).
General procedure for the preparation of compounds 6. To an oven-dried 10 mL sealing tube
equipped with a magnetic stirring bar were added sequentially 3 (0.2 mmol) and MeOH or CD3OD (2
mL). The reaction mixture was stirred at 80 oC (oil bath) for 12 h. Then, the reaction was concentrated
in vacuo to remove solvent. The crude product was purified by column chromatography on silica gel
(eluent: petroleum ether / EtOAc = 4:1 – 1:1).
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(E)-1-Methyl-2-(phenylimino)indolin-3-one (3a). Red solid; column chromatography (PE/EtOAc
= 10:1); Yield: 43.0 mg, 91%; M.p. 129-130 oC; 1H NMR (400 MHz, CDCl3) δ 7.54 – 7.50 (m, 1H),
7.48 (d, J = 7.2 Hz, 1H), 7.31 (t, J = 8.0 Hz, 2H), 7.11 (t, J = 7.2 Hz, 1H), 6.95 – 6.90 (m, 3H), 6.86
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13
(d, J = 8.0 Hz, 1H), 3.33 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 179.8, 153.6, 147.7, 144.8,
137.6, 128.7, 125.2, 123.7, 121.1, 120.2, 118.9, 109.0, 27.3; HRMS (EI) m/z: [M]+ Calcd for
C15H12N2O 236.0950; Found 236.0952; IR (neat, cm-1): 2951, 2916, 2843,1871, 1472, 1373, 1332,
1199, 905, 746.
(E)-1-Ethyl-2-(phenylimino)indolin-3-one (3b）. Red solid; column chromatography (PE/EtOAc =
o
1
10:1); Yield: 44.0 mg, 88%; M.p. 129-130 C; H NMR (400 MHz, CDCl3) δ 7.53 – 7.48 (m, 2H),
7.31 (t, J = 8.0 Hz, 2H), 7.10 (t, J = 7.2 Hz, 1H), 6.95 – 6.89 (m, 3H), 6.88 (d, J = 8.0 Hz, 1H), 3.88
(q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 180.1 , 152.8 , 147.8
, 143.9, 137.6, 128.7, 125.5, 123.7, 120.9, 120.2, 119.0, 109.0, 35.7, 12.1; HRMS (EI) m/z: [M]+ Calcd
for C16H14N2O 250.1106; Found 250.1107; IR (neat, cm1): 2968, 2925, 2843, 1871, 1649, 1608, 1558,
1472, 1349, 1290, 1192, 1124, 1099, 930, 907, 875.
(E)-1-Isopropyl-2-(phenylimino)indolin-3-one (3c). Red solid; column chromatography
o
1
(PE/EtOAc = 10:1); Yield: 45.4 mg, 86%; M.p. 118-119 C; H NMR (500 MHz, CDCl3) δ 7.49 –
7.46 (m, 2H), 7.30 (t, J = 8.0 Hz, 2H), 7.09 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.91 – 6.88
(m, 3H), 4.79 (p, J = 7.5 Hz, 1H), 1.55 (d, J = 7.5 Hz, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 180.1,
152.4, 148.0, 144.0, 137.3, 128.7, 125.5, 123.5, 120.6, 119.9, 119.4, 110.8, 44.6, 19.2; HRMS (EI)
m/z: [M]+ Calcd for C17H16N2O 264.1263; Found 264.1264; IR (neat, cm-1): 2963, 2924, 2856, 1649,
1608, 1591, 1472, 1349,1183, 1098, 921.
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(E)-1-Benzyl-2-(phenylimino)indolin-3-one (3d). Red solid; column chromatography (PE/EtOAc
= 10:1); Yield: 55.6 mg, 89%; M.p. 124-125 oC; 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 7.5 Hz,
1H), 7.44 – 7.27 (m, 8H), 7.12 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 8.0 Hz, 2H), 6.91 (t, J = 7.5 Hz, 1H),
6.79 (d, J = 8.0 Hz, 1H), 5.05 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 179.7, 152.9, 147.4, 144.4,
137.6, 136.1, 128.8, 128.7, 127.6, 127.3, 125.4, 123.9, 121.3, 120.3, 119.1, 109.9, 44.7; HRMS (EI)
m/z: [M]+ Calcd for C21H16N2O 312.1263; Found 312.1261; IR (neat, cm-1): 2955, 2924, 2852, 1649,
1608, 1472, 1349, 1179, 1145, 868.
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(E)-1-Allyl-2-(phenylimino)indolin-3-one (3e). Red solid; column chromatography (PE/EtOAc =
10:1); Yield: 46.1mg, 88%; M.p. 127-128 oC; 1H NMR (400 MHz, CDCl3) δ 7.52 – 7.48 (m, 2H), 7.31
(t, J = 8.0 Hz, 2H), 7.12 (t, J = 7.2 Hz, 1H), 6.95 – 6.91 (m, 3H), 6.86 (d, J = 8.0 Hz, 1H), 5.98 – 5.89
13
(m, 1H), 5.33 – 5.25 (m, 2H), 4.47 (d, J = 5.6 Hz, 2H); C{1H} NMR (100 MHz, CDCl3) δ 179.7,
153.0, 147.5, 144.0, 137.6, 131.2, 128.7, 125.3, 123.8, 121.2, 120.2, 118.9, 117.3, 109.8, 43.3; HRMS
(EI) m/z: [M]+ Calcd for C17H14N2O 262.1106; Found 262.1108; IR (neat, cm-1): 2953, 2856, 2830,
1865, 1661, 1646, 1472, 1374, 1348, 1283, 1183, 1183, 1146, 1097, 986, 920, 874.
(E)-5-Fluoro-1-methyl-2-(phenylimino)indolin-3-one (3f). Red solid; column chromatography
o
1
(PE/EtOAc = 20:1 – 10:1); Yield: 44.2 mg, 87%; M.p. 148-149 C; H NMR (500 MHz, CDCl3) δ
7.32 (t, J = 8.0 Hz, 2H), 7.28 (dd, J = 8.5, 2.5 Hz, 1H), 7.19 (dd, J = 6.5, 2.5 Hz, 1H), 7.12 (t, J = 7.5
13
Hz, 1H), 6.94 (d, J = 7.5 Hz, 2H), 6.82 (dd, J = 8.5, 3.5 Hz, 1H), 3.33 (s, 3H); C{1H} NMR (125
MHz, CDCl3) δ 179.1, 157.9 (d, 1J C-F = 241.3 Hz), 150.0, 147.4, 144.8, 128.7, 124.5 (d, 2J C-F = 23.8
3
2
3
Hz), 124.0, 120.2, 119.2 (d, J
= 7.5 Hz), 111.7 (d, J
= 23.8 Hz), 109.9 (d, J
= 6.3 Hz),
C-F
C-F
C-F
19
27.5; F NMR (CDCl3, 376 MHz) δ -122.37 (s, 1F); HRMS (EI) m/z: [M]+ Calcd for C15H11FN2O
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254.0855; Found 254.0857; IR (neat, cm-1): 3062, 2955, 2908, 2843, 1748, 1649, 1558, 1448, 1319,
1257, 1198, 1105, 1046, 891, 817.
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8
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(E)-5-Chloro-1-methyl-2-(phenylimino)indolin-3-one (3g). Red solid; column chromatography
(PE/EtOAc = 10:1); Yield: 44.8 mg, 83%; M.p. 157-158 oC; 1H NMR (500 MHz, CDCl3) δ 7.48 (dd,
J = 8.5, 2.0 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.31 (t, J = 7.5 Hz, 2H), 7.12 (t, J = 7.5 Hz, 1H), 6.94
(d, J = 7.5 Hz, 2H), 6.82 (d, J = 8.5 Hz, 1H), 3.32 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 178.5,
151.9, 147.3, 144.4, 137.2, 128.7, 126.7, 124.9, 124.1, 120.2, 119.7, 110.3, 27.5; HRMS (EI) m/z: [M]+
Calcd for C15H11ClN2O 270.0560; Found 270.0558; IR (neat, cm-1): 2953, 2856, 2830, 1865, 1661,
1646, 1472, 1374, 1348, 1283, 1183, 1146, 1097, 986, 920, 874.
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(E)-5-Bromo-1-methyl-2-(phenylimino)indolin-3-one (3h). Red solid; column chromatography
(PE/EtOAc = 10:1); Yield: 50.2 mg, 80%; M.p. 171-172 oC; 1H NMR (500 MHz, CDCl3) δ 7.62 (dd,
J = 8.5, 2.0 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.32 (t, J = 7.5 Hz, 2H), 7.12 (t, J = 7.5 Hz, 1H), 6.95 –
6.93 (m, 2H), 6.78 (d, J = 8.0 Hz, 1H), 3.32 (s, 3H)); 13C{1H} NMR (125 MHz, CDCl3) δ 178.4, 152.3,
147.2, 144.2, 140.0, 128.7, 127.9, 124.1, 120.2, 120.1, 113.6, 110.7, 27.5; HRMS (EI) m/z: [M]+ Calcd
for C15H11BrN2O 314.0055; Found 314.0056; IR (neat, cm-1): 2955, 2832, 2768, 1831, 1667, 1606,
1372, 1281, 1183, 1043, 1091, 977, 874.
(E)-1,5-Dimethyl-2-(phenylimino)indolin-3-one (3i). Red solid; column chromatography
o
1
(PE/EtOAc = 10:1); Yield: 41.5 mg, 83%; M.p. 284-285 C; H NMR (500 MHz, CDCl3) δ 7.34 –
7.28 (m, 4H), 7.10 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 7.5 Hz, 2H), 6.76 (d, J = 8.5 Hz, 1H), 3.30 (s, 3H),
2.29 (s, 3H)；13C{1H} NMR (125 MHz, CDCl3) δ 180.0, 151.7, 147.8, 145.1, 138.4, 130.7, 128.7,
125.3, 123.6, 120.3, 118.9, 108.8, 27.4, 20.5; HRMS (EI) m/z: [M]+ Calcd for C16H14N2O 250.1106;
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Found 250.1107; IR (neat, cm-1): 2953, 2856, 2830, 1865, 1661, 1646, 1472, 1374, 1348, 1283, 1183,
1146, 1097, 986, 920, 874;
7
8
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(E)-5-Methoxy-1-methyl-2-(phenylimino)indolin-3-one (3j). Red solid; column chromatography
(PE/EtOAc = 10:1 – 6:1); Yield: 39.4 mg, 74%; M.p. 151-152 oC; 1H NMR (400 MHz, CDCl3) δ 7.31
(t, J = 7.6 Hz, 2H), 7.16 – 7.10 (m, 2H), 7.00 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 7.6 Hz, 2H), 6.80 (d, J
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= 8.8 Hz, 1H), 3.77 (s, 3H), 3.30 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 179.9, 154.7, 148.4,
147.8, 145.2, 128.7, 125.5, 123.7, 120.3, 119.0, 110.0, 108.3, 56.0, 27.4; HRMS (EI) m/z: [M]+ Calcd
for C16H14N2O2 266.1055; Found 266.1054; IR (neat, cm-1): 2953, 2856, 2830, 1865, 1661, 1646,
1472, 1374, 1348, 1283, 1183, 1146, 1097, 986, 920, 874.
(E)-1,7-Dimethyl-2-(phenylimino)indolin-3-one (3k). Red solid; column chromatography
o
1
(PE/EtOAc = 10:1); Yield: 42.0 mg, 84%; M.p. 132-133 C; H NMR (500 MHz, CDCl3) δ 7.35 –
7.29 (m, 3H), 7.26 – 7.25 (m, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.92 (d, J = 7.5 Hz, 2H), 6.81 (t, J = 7.5
Hz, 1H), 3.63 (s, 3H), 2.60 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 180.1, 151.8, 148.0, 146.0,
141.2, 128.7, 123.6, 123.3, 121.3, 120.9, 120.1, 120.0, 30.9, 19.4; HRMS (EI): calcd for C16H14N2O:
250.1106 (M+), Found: 250.1108; IR (neat, cm-1): 2957, 2854, 2831, 1863, 1661, 1646, 1472, 1374,
1348, 1283, 1183, 1151, 1099, 996, 923, 854.
(E)-4-Bromo-1-methyl-2-(phenylimino)indolin-3-one (3l). Red solid; column chromatography
(PE/EtOAc = 10:1); Yield: 51.5 mg, 82%; M.p. 158-159 oC; 1H NMR (400 MHz, CDCl3) δ 7.33 - 7.26
(m, 3H), 7.13 – 7.09 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 7.2 Hz, 2H), 6.81 (d, J = 8.0 Hz,
1H), 3.34 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 177.2, 155.3, 147.3, 143.9, 137.7, 128.8, 125.8,
123.9, 121.5, 120.0, 116.9, 107.9, 27.4; HRMS (EI) m/z: [M]+ Calcd for C15H11BrN2O 314.0055;
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Found 314.0054; IR (neat, cm-1): 2953, 2856, 2830, 1865, 1661, 1646, 1472, 1374, 1348, 1283, 1183,
1146, 1097, 986, 920, 874.
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8
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(E)-1-Methyl-2-(phenylimino)-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-one (3m). Red solid;
column chromatography (PE/EtOAc = 10:1); Yield: 44.1 mg, 93%; M.p. 123-124 oC; 1H NMR (400
MHz, CDCl3) δ 8.41 (dd, J = 4.8, 1.6 Hz, 1H), 7.72 (dd, J = 7.2, 1.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 2H),
7.14 (t, J = 6.8 Hz, 1H), 6.95 (d, J = 7.6 Hz, 2H), 6.89 (dd, J = 7.2, 5.2 Hz, 1H), 3.45 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 178.2, 164.4, 155.8, 147.3, 144.4, 133.0, 128.8, 124.2, 120.1, 117.0, 113.0,
26.0; HRMS (EI) m/z: [M]+ Calcd for C14H11N3O 237.0902; Found 237.0902; IR (neat, cm-1): 3001,
2866, 2811, 1874, 1650, 1612, 1473, 1411, 1368, 1284, 1043, 1149, 1100, 946, 910, 897.
(E)-1-Methyl-2-(o-tolylimino)indolin-3-one (3n). Red solid; column chromatography (PE/EtOAc
= 10:1); Yield: 40.5 mg, 81%; M.p. 124-125 oC; 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.48 (m, 2H),
7.19 (d, J = 7.2 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.02 (td, J = 7.6, 1.2 Hz, 1H), 6.93 (t, J = 7.6 Hz,
1H), 6.88 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 3.37 (s, 3H), 2.14 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 179.9, 153.8, 146.5, 144.5, 137.7, 130.2, 128.0, 126.1, 125.3, 123.7, 121.0, 119.2,
118.7, 109.0, 27.3, 18.0; HRMS (EI) m/z: [M]+ Calcd for C16H14N2O 250.1106; Found 250.1108; IR
(neat, cm-1): 3058, 3011, 2924, 2860, 1667, 1608, 1558, 1475, 1369, 1335, 1214, 1188, 1156, 1095.
(E)-2-((2-(Benzyloxy)phenyl)imino)-1-methylindolin-3-one (3o). Purple solid; column
chromatography (PE/EtOAc = 10:1–4:1); Yield: 52.7 mg, 77%; M.p. 130-131 oC; 1H NMR (400 MHz,
CDCl3) δ 7.52 – 7.46 (m, 2H), 7.27 – 7.25 (m, 2H), 7.22 – 7.17 (m, 3H), 7.05 – 7.01 (m, 1H), 6.96 –
6.89 (m, 4H), 6.83 (d, J = 8.0 Hz, 1H), 5.03 (s, 2H), 3.33 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
179.7, 153.5, 149.0, 146.4, 137.8, 137.42, 137.37, 128.2, 127.4, 127.0, 125.2, 124.3, 121.6, 121.4,
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120.9, 118.7, 113.5, 108.9, 70.7, 27.3; HRMS (EI) m/z: [M]+ Calcd for C22H18N2O2 342.1368; Found
342.1366; IR (neat, cm-1): 3061, 3019, 2926, 2869, 1660,1608, 1475, 1447, 1370, 1337, 1271, 1231,
1195, 1157, 1115, 1096, 1046, 1017, 962, 889.
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(E)-2-((4-Fluorophenyl)imino)-1-methylindolin-3-one (3p). Red solid; column chromatography
o
1
(PE/EtOAc = 10:1); Yield: 40.7 mg, 80%; M.p. 133-134 C; H NMR (400 MHz, CDCl3) δ 7.54 –
7.50 (m, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.01 – 6.96 (m, 2H), 6.94 – 6.90 (m, 3H), 6.85 (d, J = 8.0 Hz,
1H), 3.30 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 179.8, 159.7 (d, 1J C-F = 240 Hz), 153.5, 145.1,
143.4 (d, 4J C-F = 3.0 Hz), 137.8, 125.2, 121.8 (d, 3J C-F = 8.0 Hz), 121.1, 118.8, 115.3 (d, 2J C-F = 22.0
19
Hz), 109.0, 27.3; F NMR (CDCl3, 376 MHz) δ -120.19 (s, 1F); HRMS (EI) m/z: [M]+ Calcd for
C15H11FN2O 254.0855; Found 254.0854; IR (neat, cm-1): 2951, 2916, 2874, 1637, 1577, 1476, 1273,
1232, 1199, 935, 766.
(E)-2-((4-Chlorophenyl)imino)-1-methylindolin-3-one (3q). Red solid; column chromatography
o
1
(PE/EtOAc = 10:1); Yield: 47.0 mg, 87%; M.p. 118-119 C; H NMR (400 MHz, CDCl3) δ 7.57 –
7.52 (m, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.29 – 7.22 (m, 2H), 6.95 (t, J = 7.6 Hz, 1H), 6.89 – 6.87 (m,
3H), 3.32 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 179.8, 153.5, 146.2, 145.1, 137.8, 129.0, 128.8,
125.4, 121.8, 121.4, 118.8, 109.1, 27.4; HRMS (EI) m/z: [M]+ Calcd for C15H11ClN2O 270.0560;
Found 270.0561; IR (neat, cm-1): 2955, 2924, 2843, 1668, 1647, 1473, 1200, 1091, 888.
(E)-2-((4-Bromophenyl)imino)-1-methylindolin-3-one (3r). Red solid; column chromatography
(PE/EtOAc = 10:1); Yield: 53.4 mg, 85%; M.p. 135-136 oC; 1H NMR (400 MHz, CDCl3) δ 7.57-7.52
(m, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.42 – 7.39 (dt, J = 6.4, 2.4 Hz, 2H), 6.95 (t, J = 7.6 Hz, 1H), 6.87
(d, J = 8.0 Hz, 1H), 6.83(dd, J = 6.4, 2.0 Hz, 2H), 3.32 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
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179.8, 153.5, 146.7, 145.0, 137.8, 131.7, 125.4, 122.2, 121.4, 118.8, 116.7, 109.1, 27.4; HRMS (EI)
m/z: [M]+ Calcd for C15H11BrN2O 314.0055; Found 314.0053; IR (neat, cm-1): 2974, 2930, 2833, 1658,
1641,1614, 1452, 1366, 1092, 889.
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(E)-2-((4-Iodophenyl)imino)-1-methylindolin-3-one (3s). Red solid; column chromatography
(PE/EtOAc = 10:1); Yield: 60.1 mg, 83%; M.p. 142-143 oC; 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J
= 8.4 Hz, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.87 (d, J =
8.0 Hz, 1H), 6.71 (d, J = 8.4 Hz, 2H), 3.32 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 179.8, 153.5,
147.5, 144.9, 137.8, 137.6, 125.4, 122.6, 121.4, 118.8, 109.1, 87.3, 27.4; HRMS (EI) m/z: [M]+ Calcd
for C15H11IN2O 361.9916; Found 361.9918; IR (neat, cm-1): 2967, 2901, 2764, 1640, 1531, 1470,
1188, 1093, 871.
(E)-1-Methyl-2-(p-tolylimino)indolin-3-one (3t). Red solid; column chromatography (PE/EtOAc
= 10:1); Yield: 43.0 mg, 86%; M.p. 134-135 oC; 1H NMR (400 MHz, CDCl3) δ 7.54 – 7.48 (m, 2H),
7.12 (d, J = 8.0 Hz, 2H), 6.92 (t, J = 7.6 Hz, 1H), 6.88 – 6.85 (m, 3H) 3.33 (s, 3H), 2.34 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 179.7,153.5 ,144.9, 144.8, 137.6, 133.4, 129.3, 125.2, 121.0,
120.3, 118.9, 109.0, 27.4, 21.0; HRMS (EI) m/z: [M]+ Calcd for C16H14N2O 250.1106; Found
250.1108; IR (neat, cm-1): 3037, 2925, 2847, 1679,1644, 1503, 1373, 1199, 891.
(E)-2-((4-Methoxyphenyl)imino)-1-methylindolin-3-one (3u). Red solid; column chromatography
o
1
(PE/EtOAc = 10:1); Yield: 40.4 mg, 76%; M.p. 177-178 C; H NMR (400 MHz, CDCl3) δ 7.96 –
7.93 (m, 2H), 7.58 – 7.54 (m, 1H), 7.50 (d, J = 7.6 Hz, 1H), 6.99 - 6.96 (m, 3H), 6.90 (d, J = 8.0 Hz,
1H), 3.35 (s, 3H), 2.60 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.2, 153.6, 153.0, 144.6, 138.0,
132.6, 129.6, 125.5, 121.6, 120.1, 118.7, 109.2, 27.4, 26.5; HRMS (EI) m/z: [M]+ Calcd for
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C16H14N2O2 266.1055; Found 266.1056; IR (neat, cm-1): 2912, 2809, 1710, 1661, 1590, 1489, 1270,
1051, 812.
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(E)-2-((4-Ethoxyphenyl)imino)-1-methylindolin-3-one (3v). Red solid; column chromatography
(PE/EtOAc = 10:1);Yield: 41.5 mg, 74%; M.p. 168-169 oC; 1H NMR (400 MHz, CDCl3) δ 7.53 – 7.48
(m, 2H), 7.00 – 6.97 (m, 2H), 6.91 (t, J = 7.6 Hz, 1H), 6.86 – 6.83 (m, 3H), 4.03 (q, J = 6.8 Hz, 2H),
3.31 (s, 3H), 1.41 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 179.7, 156.0, 153.4, 144.8,
140.0, 137.5, 125.2, 122.2, 120.8, 119.0, 114.4, 108.9, 63.5, 27.3, 14.9; HRMS (EI) m/z: [M]+ Calcd
for C17H16N2O2 280.1212; Found 280.1215; IR (neat, cm-1): 2976, 2920, 1863, 1748, 1607, 1506,
1475, 1238, 1094, 888.
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Methyl (E)-4-((1-methyl-3-oxoindolin-2-ylidene)amino)benzoate (3w). Red solid; column
o
1
chromatography (PE/EtOAc = 10:1); Yield: 41.8 mg, 71%; M.p. 183-184 C; H NMR (400 MHz,
CDCl3) δ 8.00 (d, J = 8.4 Hz, 2H), 7.55 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 6.99 – 6.94 (m,
3H), 6.89 (d, J = 8.0 Hz, 1H), 3.90 (s, 3H), 3.34 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 179.8,
167.0, 153.6, 152.7, 137.9, 130.6, 125.4, 125.2, 121.5, 120.0, 118.7, 109.2, 99.9, 51.8, 27.4; HRMS
(EI) m/z: [M]+ Calcd for C17H14N2O3 294.1004; Found 294.1002; IR (neat, cm-1): 2951, 2924, 2843,
1682, 1668, 1593, 1472, 1273, 1095, 890.
(E)-1-Methyl-2-((4-(trifluoromethyl)phenyl)imino)indolin-3-one (3x). Red solid; column
o
1
chromatography (PE/EtOAc = 20:1 - 10:1); Yield: 42.6 mg, 70%; M.p. 127-128 C; H NMR (600
MHz, CDCl3) δ 7.56 – 7.54 (m, 3H), 7.49 (d, J = 7.2 Hz, 1H), 7.00 (d, J = 7.8 Hz, 2H), 6.96 (t, J = 7.2
13
Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 3.33 (s, 3H); C{1H} NMR (150 MHz, CDCl3) δ 179.9, 153.6,
3
2
1
151.3, 144.9, 137.9, 125.9 (q, J
= 3.8 Hz), 125.4 (q, J
= 32.3 Hz), 125.3, 124.6 (q, J
=
C-F
C-F
C-F
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269.9 Hz), 121.5, 120.3, 118.7, 109.2, 27.3; 19F NMR (CDCl3, 564 MHz) δ -61.71 (s, 3F); HRMS (EI)
m/z: [M]+ Calcd for C16H11F3N2O 304.0823; Found 304.0822; IR (neat, cm-1): 2955, 2923, 2839, 1682,
1601, 1475, 1338, 1105, 1070, 1049, 993, 890.
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(E)-2-((4-(Diphenylamino)phenyl)imino)-1-methylindolin-3-one (3y). Purple solid; column
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chromatography (PE/EtOAc = 8:1); Yield: 66.1 mg, 82%; M.p. 147-148 C; H NMR (400 MHz,
CDCl3) δ 7.55 – 7.51 (m, 2H), 7.24 – 7.17 (m, 4H), 7.12 (d, J = 7.6 Hz, 4H), 7.06 – 7.04 (m, 2H), 7.00
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- 6.94 (m, 5H), 6.87 (d, J = 8.4 Hz, 1H), 3.33 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 179.7,
153.4, 147.9, 144.1, 142.5, 137.6, 129.1, 125.3, 124.9, 123.7, 122.5, 122.3, 122.1, 121.0, 119.0, 109.0,
27.4; HRMS (EI) m/z: [M]+ Calcd for C27H21N3O 403.1685; Found 403.1686; IR (neat, cm-1): 3058,
3028, 2925, 2826, 1608, 1494, 1369, 1334, 1273, 1205, 1094, 1046, 866.
(E)-1-Methyl-2-((4-(1,2,2-triphenylvinyl)phenyl)imino)indolin-3-one (3z). Purple solid; column
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chromatography (PE/EtOAc = 10:1); Yield: 81.3 mg, 83%; M.p. 214-215 C; H NMR (400 MHz,
CDCl3) δ 7.53 – 7.49 (m, 2H), 7.17 – 7.14 (m, 2H), 7.11 – 7.08 (m, 11H), 7.05 – 7.02 (m, 2H), 6.97
(d, J = 8.4 Hz, 2H), 6.93 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.4 Hz, 2H), 3.29 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 179.6, 153.4, 146.0, 144.8, 144.1, 143.9, 140.9, 140.3, 139.3,
137.5, 131.8, 131.5, 131.4 (d, J = 2.0 Hz), 127.7, 127.6, 126.3, 126.2, 125.2, 121.1, 119.8, 118.9,
109.0, 27.3; HRMS (EI) m/z: [M]+ Calcd for C35H26N2O 490.2045; Found 490.2044; IR (neat, cm-1):
3080, 3054, 3015, 2925, 2856, 1772, 1661, 1610, 1476, 1443, 1369, 1336, 1206, 1173, 1156, 1117,
1095, 1075, 1046.
1-Methyl-3-phenyl-2-(phenylethynyl)-2,3-dihydroquinazolin-4(1H)-one (5a).Yellow solid; column
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chromatography (PE/EtOAc = 20:1); Yield: 49.4 mg, 73%; M.p. 83-84 C; H NMR (500 MHz,
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CDCl3) δ 8.11 (dd, J = 7.5, 1.5 Hz, 1H), 7.57 (dd, J = 8.5, 1.0 Hz, 2H), 7.50 – 7.43 (m, 3H), 7.33 –
7.28 (m, 4H), 7.26 – 7.23 (m, 2H), 7.00 (td, J = 7.5, 1.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 5.62 (s, 1H),
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3.02 (s, 3H); C{1H} NMR (125 MHz, CDCl3) δ 162.3, 147.2, 140.3, 133.9, 131.9, 129.3, 129.2,
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128.9, 128.2, 127.1, 126.0, 121.4, 119.8, 118.0, 113.1, 85.2, 83.7, 70.8, 35.8; HRMS (EI) m/z: [M]+
Calcd for C23H18N2O 338.1419; Found 338.1421; IR (neat, cm-1): 3064, 2952, 2903, 2867, 2194, 1652,
1591, 1488, 1377, 1304, 1282, 1253, 1126, 1060, 1004, 821, 767, 730.
1-methyl-3-phenyl-2-(phenylethynyl)-2,3-dihydroquinazolin-4(1H)-one-2-d (D-5a). Yellow oil;
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column chromatography (PE/EtOAc = 10:1); Yield: 37.6 mg, 56%; H NMR (400 MHz, CDCl3) δ
8.11 (dd, J = 7.6, 1.6 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.49 - 7.42 (m, 3H), 7.32 - 7.21 (m, 6H), 6.99
(t, J = 7.6 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 3.00 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.3,
147.1, 140.2, 133.9, 131.9, 129.3, 129.1, 128.8, 128.2, 127.0, 125.9, 121.4, 119.7, 118.0, 113.0, 85.2,
83.7, 70.4 (t, JC-D = 23.4 Hz), 35.6; HRMS (ESI) m/z: [M+H]+ Calcd for C23H18DN2O 340.1555; Found
340.1554; IR (neat, cm-1): 3063, 2962, 2924, 2878, 2816, 2221, 1739, 1663, 1606, 1489, 1476, 1454,
1429, 1371, 1309, 1183, 1129, 1079, 1053, 956, 909, 757, 692.
2-((4-Bromophenyl)ethynyl)-1-methyl-3-phenyl-2,3-dihydroquinazolin-4(1H)-one (5b). Yellow
solid; column chromatography (PE/EtOAc = 20:1); Yield: 55.8 mg, 67%; M.p. 154-155 oC; 1H NMR
(400 MHz, CDCl3) δ 8.10 (dd, J = 7.6, 1.6 Hz, 1H), 7.56 – 7.53 (m, 2H), 7.51 – 7.43 (m, 3H), 7.39 –
7.37 (m, 2H), 7.34 – 7.32 (m, 1H), 7.15-7.12 (m, 2H), 7.01 (td, J = 7.6, 0.8 Hz, 1H), 6.80 (d, J = 8.0
Hz, 1H), 5.61 (s, 1H), 3.01 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.3, 147.1, 140.3, 134.0,
133.3, 131.5, 129.4, 129.2, 127.2, 125.9, 123.3, 120.3, 119.9, 118.0, 113.1, 85.0, 84.2, 70.8, 35.8;
HRMS (ESI) m/z: [M+Na]+ calcd for C23H17BrN2ONa 439.0416; Found 439.0422; IR (neat, cm-1):
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