Synthesis of aroylguanidines by an unexpected demethylation-addition cascade

Article abstract of DOI:10.1055/s-0033-1338511

A simple and efficient method was developed for the synthesis of N-aroyl-N′-arylguanidines under mild conditions by an unexpected demethylation-addition cascade reaction of readily available N-cyanoimidates with aryl amines. Moreover, 1-aryl-2-aminoquinazolin-4(1H)-ones and 2-(arylamino)quinazolin-4(3H)-ones can also be prepared by selective cyclization reactions of (2-fluorobenzoyl)- or (2-nitrobenzoyl)guanidines, respectively. This method provided two attractive strategies for the preparation 2-aminoquinazolinones derivatives from inexpensive reactants.

Full text of DOI:10.1055/s-0033-1338511

PAPER
▌2533
paper
Synthesis of Aroylguanidines by an Unexpected Demethylation–Addition
Cascade
Aroylguanidines by a Demethylation–Addition Cascade
Ling Hui Gu, Zhen Guo,* Ling He, Qing Rong Qi*
Key Laboratory of Drug-Targeting and Drug-Delivery Systems of the Ministry of Education, Department of Medicinal Chemistry,
West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, P. R. of China
Fax +86(28)85501613; E-mail: qiqingronghh@yahoo.com.cn
Received: 06.05.2013; Accepted after revision: 30.06.2013
acylguanidines, the routes to N-acyl-N′-arylguanidines
are limited to several representative approaches, including
reactions of acylcyanamides with aniline hydrochloride in
refluxing toluene or xylenes,25 acylation of guanidines
Abstract: A simple and efficient method was developed for the
synthesis of N-aroyl-N′-arylguanidines under mild conditions by an
unexpected demethylation–addition cascade reaction of readily
available N-cyanoimidates with aryl amines. Moreover, 1-aryl-2-
aminoquinazolin-4(1H)-ones and 2-(arylamino)quinazolin-4(3H)- with carbonic acid in the presence of 1,1′-carbonyldimid-
azole,21 solid-phase synthesis of disubstituted acylguani-
ones can also be prepared by selective cyclization reactions of (2-
fluorobenzoyl)- or (2-nitrobenzoyl)guanidines, respectively. This
method provided two attractive strategies for the preparation 2-ami-
hexamethyldisilazane in the presence of 1-ethyl-3-[3-(di-
noquinazolinones derivatives from inexpensive reactants.
dines;26 and the reaction of acylthioureas with
methylamino)propyl]carbodiimide to give acylguani-
dines.27 Although these synthetic methods can be used to
Key words: heterocycles, cyclizations, cascade reactions, amines,
quinazolines, ketones
synthesize N-acyl-N′-arylguanidines, the poor selectivity
of the acylation reaction and the need to protect imino
groups represent considerable disadvantages. Other dis-
Acylguanidines have attracted a great deal of attention,
advantages include the multistep nature of the reactions,
not only because of the range of significant biological ac-
low efficiencies in the preparation of starting materials,
tivities that they have shown in medical studies,1 but also
and the need for extensive use of condensing agents.
because they are useful building blocks for several natural
Here we report a convenient method for the synthesis of
and therapeutic products of biological significance.2 De-
N-aroyl-N′-arylguanidines and its application in the prep-
aration of various 2-aminoquinazolinones; the method
does not entail any of the problems discussed above.
rivatives of acylguanidines are among the most potent in-
hibitors of Na+/H+ exchange3 and they also have shown
remarkable activities as potent αvβ3 antagonists,4 throm-
bin inhibitors,5 and histamine H2 receptors.6 The useful-
ness of acylguanidines is highlighted by the range of
marketed drugs of this class, which include the sympatho-
lytic guanfacine,7 the diuretic amiloride,8 and the Na+/H+
exchange inhibitors cariporide9 and eniporide.10 Addition-
ally, acylguanidines have also been reported to be poten-
tially useful in the treatment of glaucoma,11
osteoporosis,12 and cardiac ischemia and reperfusion,11,13
as well as acting as antihypertensives,14 antifungal
agents,15 and plant-protection agents.16 BMS-344577, an
aroylguanidine-based lactam derivative, has progressed to
the advanced preclinical development stage because of its
potent activity as an inhibitor of blood-coagulation factor
Xa.17 Besides their biological activities, N-aroyl-N′-aryl-
guanidines have also been used in syntheses of polysub-
stituted guanidines.18 Furthermore, several nitrogen-
containing heterocycles, including highly bioactive gua-
nosines,19 can be prepared by using acylguanidines as
starting materials.20–23
We have previously shown that oxidative cyanoimidation
is a direct and efficient method for the preparation of cya-
noimidates 2 (Scheme 1),28 a class of important organic
intermediates for the synthesis of heterocycle derivatives
containing several nitrogen atoms.29
R2OH
O
NCN
OR2
t-BuONa, NBS
+
R1
H
R1
r.t. to 50 °C
H2NCN
1
2
1,2,4-triazoles
2,4-diaminoquinazolines
tricyclic quinazolines
Scheme 1 Cyanoimidation of aldehydes as a route to nitrogen het-
erocycles
We recently described a one-pot process for the conver-
sion of methyl N-cyano-2-nitrobenzimidates into quinaz-
oline-2,4-diamines and tricyclic quinazolines by iron-
mediated reductive cyclization.30 However, the reactions
of aryl amines with cyanoimidates proved not to be an ide-
al route for the synthesis of N′-aryl-substituted quinazo-
linamines because of the low conversion of the starting
materials. To learn more about the scope of this reaction,
we chose methyl N-cyanonaphthalene-1-carboximidoate
(3k) as a model substrate, and we studied its condensation
with aniline (4a) in refluxing methanol. Unfortunately,
Because of the importance of acylguanidines in various
roles, several methods have been reported for their syn-
thesis.24 However, in comparison with N-polysubstituted
SYNTHESIS 2013, 45, 2533–2544
Advanced online publication: 01.08.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338511; Art ID: SS-2013-F0295-OP
© Georg Thieme Verlag Stuttgart · New York

2534
L. H. Gu et al.
PAPER
the yield of N′-cyano-N-phenylnaphthalene-1-carboximi- amount of 3k) favored the formation of product 5k, which
damide (6k) was only 24%. However, a second, unexpected, was obtained 71% and 86% yield, respectively (entries 11
product, N-[anilino(imino)methyl]-N'-cyanonaphthalene- and 12). No improvement in the yield occurred when 0.2
1-carboximidamide (5k) was obtained in 21% yield. We mmol of acetic acid or triethylamine was present as an ad-
then investigated the effect of various solvents on the re- ditive (entries 13 and 14). The optimal conditions are
action. N,N-Dimethylformamide at 70 °C was found to be therefore those shown in entry 12.
the most effective solvent for the condensation reaction to
give product 5k, whereas the reaction gave much lower
yields in refluxing chloroform or toluene (Table 1, entries
To test the scope of this reaction system, we examined the
reactions of various cyanoimidates under the optimized
conditions (Table 2). Almost all the substrates gave the
1–7). On prolonging the reaction time in N,N-dimethyl-
corresponding N-aroyl-N′-phenylguanidine products in
formamide to 48 hours, we obtained less of the aroylgua-
moderate to good yields. We concluded that the method
nidine 5k, and more of the expected amidine 6k (entry 8).
provides a convenient and efficient route for the prepara-
tion of N-aroylguanidines.
The temperature also affected the reaction. Increasing the
temperature to 90 °C led to a decrease in the yield of 5k
(entry 9). However, the yield of 5k did not increase and
Table 2 Synthesis of N-Aroyl-N′-Phenylguanidines
the conversion of the starting material was lower on re-
ducing the temperature to 50 °C (entry 10). The use of
three or five equivalents of aniline 4a (relative to the
O
NH
NCN
OMe
DMF
+
PhNH2
R1
N
NHPh
R1
3a–j
H
70 °C, 24 h
4a
5a–j
Table 1 Optimization of the Reaction for Selective Formation of
Aroylguanidine 5k
Entrya
Cyanoimidate reactant
Product Yieldb (%)
H
OMe
NCN
1
2
3
4
5
6
7
8
9
3a, X = H
3b, X = 4-Cl
5a
5b
51 (18)c
45 (23)c
54 (14)c
64
N
NHPh
O
NHPh
NCN
NH
+
PhNH2
+
3c, X = 4-MeO 5c
3k
5k
6k
4a
3d, X = 2-Cl
3e, X = 2-Br
3f, X = 2-TsO
3g, X = 2-Ph
5d
5e
5f
R1
X
=
Entrya
Solvent
Temp (°C) Time (h) Yield (%) Yield (%)
77
of 5kb
of 6kb
83d
1
2
3
4
5
6
7
MeOH
DMF
DMSO
CHCl3
toluene
–
reflux
70
24
24
24
24
24
24
24
21
52
46
31
36
27
42
24
12
16
14
26
19
23
5g
76
3h, X = 2-MeO 5h
3i, X = 2,6-Cl2 5i
55
70
91d
reflux
70
R1
=
O
10
3j
5j
71
O
70
Br
a Reaction conditions: cyanoimidate 3 (0.5 mmol), PhNH2 (2.5
mmol), DMF (10 mL), 70 °C, 24 h.
b Isolated yield.
DMF–H2O 70
(3:1)
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
70
90
50
70
70
70
70
48
24
24
24
24
24
24
46
18
c Yield of N-cyanobenzimidamide 6a–c.
d The reaction was performed at 90 °C.
9
34
21
10
trace
71
trace
trace
trace
trace
trace
11c
12d
13d,e
14d,f
The reactions of secondary aryl amines with cyanoimi-
dates showed better selectivities than those of primary
amines, giving moderate to high yields of the correspond-
ing N′,N′-disubstituted N-aroylguanidines 5l–z (Table 3).
To achieve complete conversion, it was necessary to use
slightly higher reaction temperatures and three equiva-
lents of the secondary aryl amine. Methyl N-cyanoben-
zenecarboximidoate (3a) reacted with several
nucleophiles, including N-methylaniline, indoline and
1,2,3,4-tetrahydroquinoline to give the corresponding
products in good yields (entries 1, 2, and 3). We were ex-
cited to find that substitution at the 4-position of the aryl
86
44
75
a Reaction conditions: cyanoimidate 3k (0.2 mmol), PhNH2 (0.4
mmol), solvent (2 mL).
b Isolated yield.
c 0.6 mmol PhNH2 was used.
d 1.0 mmol PhNH2 was used.
e AcOH (0.2 mmol) was used as an additive.
f Et3N (0.2 mmol) was used as an additive.
Synthesis 2013, 45, 2533–2544
© Georg Thieme Verlag Stuttgart · New York

PAPER
Aroylguanidines by a Demethylation–Addition Cascade
2535
Table 3 Reactions of Cyanoimidates with Secondary Aryl Amines
(continued)
rings was well tolerated (entries 4 and 6). Electron-rich
and electron-deficient benzene derivatives and heterocy-
cles participated well in the reaction (entries 4–15). How-
ever, the reactions of diphenylamine at 110 °C gave only
moderate yields of the desired products because of the low
nucleophilicity of this amine (entries 5, 11, and 13). The
reaction of imidate 3o with indoline gave the amidine
product 6o exclusively in 54% yield (entry 16).
O
NH
DMF
NCN
OMe
+
ArNHR2
Ar
R1
N
N
R2
R1
90 °C, 24 h
H
cyanoimidates
4
5l–z
Entrya Cyanoimidate
Product
Yieldb
(%)
Table 3 Reactions of Cyanoimidates with Secondary Aryl Amines
Ph
H
N
O
N
Bn
O
NH
DMF
NCN
OMe
10
3k
5u
80
NH
NH
Ar
+
ArNHR2
R1
N
N
R1
90 °C, 24 h
H
R2
cyanoimidates
4
5l–z
NO2
NO2 NCN
OMe
O
O
Entrya Cyanoimidate
Product
5l
Yieldb
(%)
11c 3l
5v
46
94
N
NPh2
H
NO2 NCN
OMe
NO2
O
NH
NH
Ph
1
3a
78
N
N
N
H
N
12
3l
5w
H
Me
NCN
O
NH
O
NH
13c 3m
OMe 5x
57
72
N
NPh2
N
N
2
3
4
5c
6
7
8
9
3a
3a
3b
3b
3c
3d
3d
3j
5m
84
74
80
53
84
79
89
76
H
H
O2N
O2N
O
NH
Ph
H
OMe
NCN
N
N
N
H
N
5n
S
14
3n
5y
S
S
Bn
O
O
NH
O
NH
Ph
N
H
N
OMe
NCN
N
H
N
S
5o
15
16
3n
3o
5z
6o
81
54
Me
Cl
NH
O
NH
NPh2
NCN
NCN
OMe
N
H
H
N
5p
H
Cl
a Reaction conditions: cyanoimidate 3 (0.5 mmol), aryl amine (1.5
mmol), DMF (2 mL), 90 °C, 24 h.
O
NH
N
N
b Isolated yield.
5q
H
c The reaction was performed at 110 °C.
MeO
Cl
O
O
NH
Ph
As part of an attempt to develop simple and efficient
methods for synthesizing various bioactive N-heterocy-
cles, we tested a novel one-pot approach to 1-aryl-2-ami-
N
N
5r
H
Me
Cl
NH
noquinazolin-4-ones by
a
tandem intramolecular
cyclization. The cascade one-pot reaction of several pri-
mary aryl amines with methyl N-cyano-2-fluorobenzene-
carboximidoate (3p) gave the corresponding 1-aryl-2-
aminoquinazolin-4-ones 7a–g in moderate to good yields,
showing that both electron-withdrawing and electron-
donating groups are tolerated in the cascade reaction (Ta-
ble 4, entries 1–6). However, with a secondary aryl amine,
this one-pot reaction did not give the expected cyclization
product 7g, but instead gave the aroylguanidine 5aa (entry
7).21
N
N
5s
H
O
NH
Ph
O
N
N
5t
H
O
Me
Br
© Georg Thieme Verlag Stuttgart · New York
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2536
L. H. Gu et al.
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Table 4 One-pot Synthesis of 2-Amino-1-Arylquinazolinonesa
(continued)
Table 4 One-pot Synthesis of 2-Amino-1-Arylquinazolinonesa
F
NCN
OMe
F
NCN
OMe
DMF, 90 °C
DMF, 90 °C
+ arylamine
+ arylamine
O
O
N
O
O
N
3p
4
3p
4
N
NH
N
NH
+
+
N
NH2
NHAr
N
NH2
NHAr
Ar
Ar
not observed
not observed
7a–g
7a–g
Yield (%)b
Entry Aryl amine
Product
Yield (%)b
Entry Aryl amine
Product
O
O
N
N
NH2
NH2
1
7a
7b
72
N
NH2
N
NH2
6
7f
76
O
N
N
O
NH2
NH2
NH
7
7g
–
2
43
45
71
64
N
Cl
N
O
N
H
F
NH
Cl
O
5aa
56c
N
N
H
N
NH2
a Reaction conditions: carboximidoate 3p (0.5 mmol), aryl amine 4
(2.5 mmol), DMF (10 mL), 90 °C, 24 h.
b Isolated yield.
N
NH2
3
7c
7d
7e
Br
Br
O
Moreover, in addition to 1-aryl-2-aminoquinazolin-4-
ones, 2-(arylamino)quinazolin-4-ones 8a–i could be read-
ily prepared through reductive cyclization of the (2-ni-
troaroyl)guanidines 5ab–aj formed by reaction of methyl
N-cyano-2-nitrobenzenecarboximidoate (3l) with various
aryl amines. Some compounds of type 8 have been the
subject of medicinal chemistry studies.31 Aryl amines
bearing electron-withdrawing groups such as 4-chloro, 4-
bromo, or 4-acetyl groups gave the corresponding aroyl-
guanidine intermediates 5 in moderate to good yields (Ta-
ble 5, entries 2, 3, and 7). Similar results were obtained
with aniline derivatives substituted with electron-donat-
ing groups or with 2-naphthylamine (Table 5, entries 4–6
and 8). N-Methylaniline also gave the desired product in
excellent yield when three equivalents of this secondary
amine were used (Table 5, entry 9). Much to our delight,
the resulting (2-nitroaroyl)guanidine derivatives 5ab–aj
underwent a selective reductive cyclization in the pres-
ence of an iron/hydrochloric acid system system30 to give
the corresponding (2-arylamino)quinazolin-4-ones 8a–i
(Table 5).
N
NH2
N
NH2
4
5
O
N
N
NH2
NH2
MeO
OMe
Synthesis 2013, 45, 2533–2544
© Georg Thieme Verlag Stuttgart · New York

PAPER
Aroylguanidines by a Demethylation–Addition Cascade
2537
Table 5 Synthesis of 2-Arylaminoquinazolinones by Cyclization with Iron–Hydrochloric Acid
O
O
NO2 NCN
OMe
NO2
O
NH
NH2
O
NH
Ar
Ar
NH
Fe/HCl
NH
DMF
N
N
R
N
N
R
+
+
ArNHR
H
H
Ar
70 °C
N
NH2
N
N
R
trace
3l
5ab–aj
8a–i
Entrya
ArNHR
Intermediate product
Yieldb (%) of 5 Final product
Yield (%) of 8
O
NO2
O
NH
NHPh
NH2
NH
1
5ab
82
8a
77
N
H
N
O
N
H
Cl
Br
NO2
O
NH
NH
NH2
Cl
Br
NH
NH
2
3
4
5
6
7e
8
5ac
5ad
5ae
5af
5ag
5ah
5ai
76
80
72
74
68
52
71
8b
8c
8d
8e
8f
70
76
84
81
78
65
75
N
N
H
H
Cl
Br
N
O
N
H
NO2
O
O
NH2
N
H
N
H
N
O
N
H
NO2
NH
NH2
NH
NH
NH
N
H
N
H
N
O
N
H
OMe
NO2
O
O
NH
NH2
OMe
N
H
N
H
MeO
N
O
N
H
NO2
NH
NH2
N
H
N
H
N
O
N
H
Ac
NO2
O
O
NH
NH
NH2
Ac
NH
NH
8g
8h
N
H
N
H
Ac
N
O
N
H
NO2
NH2
N
H
N
H
N
O
N
H
NO2
O
NH
NHMe
N
9c
5aj
90
8i
73
N
H
N
N
H
N
Me
Me
a Reaction conditions: (1st reaction) methyl N-cyano-2-nitrobenzenecarboximidoate (3l; 0.5 mmol), aryl amine 4 (2.5 mmol), DMF (10 mL),
70 °C, 24 h; (2nd reaction) aroylguanidine 5ab–5aj (0.1 mmol), Fe (1.8 mmol), concd HCl (0.2 mL), EtOH (10 mL), reflux.
b Isolated yield.
c The first reaction was performed at 90 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2533–2544

2538
L. H. Gu et al.
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1H NMR spectra were recorded in CDCl3 or DMSO-d6 on a Varian
Mercury 400-MHz spectrometer with TMS as the internal standard;
13C NMR spectra were recorded in CDCl3 or DMSO-d6 at 100 Hz.
High-resolution mass spectra (ESI) were recorded on an Agilent
LC/MSD spectrometer. IR spectra were recorded on a VECTOR22
spectrophotometer. Unless noted otherwise, all the solvents used in
the reactions were of analytical grade and were redistilled. Silica gel
F254 plates were used for TLC and visualized by UV irradiation at
254 nm. Column chromatography was performed on silica gel H
(HG/T2354–2010; Qingdao Haiyang Chemical Co., Ltd). The N-
cyanoimidates were prepared by the procedure described in our pre-
vious work.28
Because the transformation of cyanoimidates serves as a
unique route to N-aroyl-N′-arylguanidines, we were inter-
ested in its high selectivity and in the tandem demethyl-
ation–condensation process. One possible mechanism
involves the hydrolysis of the cyanoimidate, but our pre-
liminary results proved that the addition of water, acid, or
base did not promote the formation of the corresponding
aroylguanidine. To eliminate the effects of water and the
solvent, we examined the reaction of methyl N-cyanoben-
zenecarboximidoate (3a) with indoline in anhydrous tet-
rahydrofuran instead of N,N-dimethylformamide. The
yield of the desired aroylguanidine 5m was 75% com-
pared with 84% in N,N-dimethylformamide, and 1-meth-
ylindoline was isolated as a byproduct in 71% yield
(Scheme 2). We therefore surmised that the reaction
might involve demethylation of the cyanoimidate accom-
panied by methylation of indoline and generation of N-cy-
anobenzamide (I), which we were able to characterize by
1H NMR and high-resolution mass spectroscopy. The in-
termediate N-cyanobenzamide (I) is readily attacked by
the nucleophile indoline and smoothly converted into
N-[2,3-dihydro-1H-indol-1-yl(imino)methyl]benzamide
(5m).
N-Aroylguanidines 5a–k and 5ab–ai from Primary Amines;
General Procedure
The appropriate N-cyanoimidate 3 (0.5 mmol) and aryl amine 4 (2.5
mmol) were dissolved in DMF (10 mL), and the mixture was stirred
at 70 °C for 24 h. H2O (10 mL) was then added and the mixture was
extracted with EtOAc (2 × 10 mL). The organic phases were com-
bined, washed with H2O (3 × 10 mL), dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by flash column
chromatography (silica gel, PE–EtOAc).
N-[Anilino(imino)methyl]benzamide (5a)
Yellow powder; yield: 61 mg (51%); mp 108–110 °C.
1H NMR (400 MHz, DMSO-d6): δ = 9.36 (s, 1 H), 8.14 (d, J = 6.8
Hz, 2 H), 7.56 (d, J = 8.0 Hz, 2 H), 7.49–7.37 (m, 5 H), 7.12 (t,
J = 7.6 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 176.3, 159.4, 138.8, 138.5,
131.3, 129.1, 128.9, 128.1, 123.9, 122.1.
HRMS (ESI): m/z [M + H]+ calcd for C14H14N3O: 240.1137; found:
(71% yield based on 3a)
N
Me
240.1138.
O
NCN
CN
N
N′-Cyano-N-phenylbenzenecarboximidamide (6a)
OMe
H
+
THF, 90 °C, 24 h
White powder; yield: 20 mg (18%).
N
H
1H NMR (400 MHz, DMSO-d6): δ = 10.89 (s, 1 H), 7.76–7.74 (m,
4 H), 7.69–7.64 (m, 3 H), 7.43 (t, J = 7.6 Hz, 1 H), 7.24 (t, J = 7.6
Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C14H12N3: 222.1031; found:
222.1024.
I
3a
3 equiv
O
NH
N
N
N
H
H
5m 75%
N-[Anilino(imino)methyl]-4-chlorobenzamide (5b)
White powder; yield: 61 mg (45%); mp 178–181 °C.
Scheme 2 Proposed mechanism for the reaction
1H NMR (400 MHz, DMSO-d6): δ = 9.38 (s, 1 H), 8.08 (d, J = 8.4
Hz, 2 H), 7.51–7.48 (m, 4 H), 7.39 (t, J = 7.6 Hz, 2 H), 7.13 (t,
J = 7.6 Hz, 1 H).
In summary, we have demonstrated a simple method for
the synthesis of N-aroyl-N′-arylguanidines as an exten-
13C NMR (100 MHz, DMSO-d6): δ = 175.2, 159.6, 138.3, 137.7,
sion of our cyanoimidate research. This synthetic route in- 136.1, 130.7, 129.1, 128.2, 124.0, 122.3.
HRMS (ESI): m/z [M + H]+ calcd for C14H13ClN3O: 274.0747;
found: 274.0751.
volves an interesting transformation–condensation
cascade in the absence of a condensing agent (as required
in many other methods) and it provides a very simple
route for the preparation of aroylguanidines from readily
available starting materials. Furthermore, N-[aryl(imi-
no)methyl]-2-fluorobenzamide products underwent selec-
tive cyclization in a one-pot procedure to give the
corresponding 1-aryl-2-aminoquinazolin-4-ones. Further-
more, the reductive cyclization of N-[aryl(imino)methyl]-
2-nitrobenzamide products provides a practical method
for the synthesis of 2-(arylamino)quinazolin-4-ones. To
the best of our knowledge, these two intramolecular cycli-
zation reactions of ortho-substituted aroylguanidines have
not been reported before. Further exploration of the syn-
thetic utility of this methodology is currently underway
and will be reported in due course.
N-[Anilino(imino)methyl]-4-methoxybenzamide (5c)
Yellow powder; yield: 73 mg (54%); mp 152–154 °C.
1H NMR (400 MHz, DMSO-d6): δ = 9.33 (br s, 1 H), 8.08 (d,
J = 8.8 Hz, 2 H), 7.56 (d, J = 7.6 Hz, 2 H), 7.38 (t, J = 8.4 Hz, 2 H),
7.16–7.09 (m, 1 H), 6.97 (d, J = 8.8 Hz, 2 H), 3.80 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 176.1, 162.0, 159.2, 138.8,
131.3, 130.9, 129.1, 123.7, 122.0, 113.4, 55.5.
HRMS (ESI): m/z [M + H]+ calcd for C15H16N3O2: 270.1243; found:
270.1246.
N-[Anilino(imino)methyl]-2-chlorobenzamide (5d)
White powder; yield: 87 mg (64%); mp 186–188 °C.
1H NMR (400 MHz, DMSO-d6): δ = 9.48 (br s, 1 H), 7.63 (dd,
J = 6.8, 2.0 Hz, 1 H), 7.45–7.42 (m, 3 H), 7.37–7.31 (m, 4 H), 7.10
(t, J = 7.2 Hz, 1 H).
Synthesis 2013, 45, 2533–2544
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Aroylguanidines by a Demethylation–Addition Cascade
2539
13C NMR (100 MHz, DMSO-d6): δ = 177.4, 159.3, 140.1, 138.2,
130.4, 130.2, 129.8, 129.2, 126.9, 124.2, 122.4, 122.0.
HRMS (ESI): m/z [M + H]+ calcd for C14H13ClN3O: 274.0747;
found: 274.0752.
1H NMR (400 MHz, DMSO-d6): δ = 9.41 (s, 1 H), 7.44 (d, J = 8.0
Hz, 2 H), 7.33 (t, J = 7.8 Hz, 2 H), 7.23 (s, 1 H), 7.17 (s, 1 H), 7.10
(t, J = 7.4 Hz, 2 H), 6.21 (s, 1 H), 6.09 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 177.0, 159.2, 148.6, 146.8,
138.3, 135.0, 129.1, 124.1, 122.3, 113.1, 111.0, 109.8, 102.3.
HRMS (ESI): m/z [M + H]+ calcd for C15H13BrN3O3: 362.0140;
Anal. Calcd for C14H12ClN3O: C, 61.43; H, 4.42; Cl, 12.95; N,
15.35. Found: C, 61.48; H, 4.53; Cl, 13.08; N, 15.39.
found: 362.0145.
N-[Anilino(imino)methyl]-2-bromobenzamide (5e)
Yellow powder; yield: 122 mg (77%); mp 184–187 °C.
N-[Anilino(imino)methyl]-1-naphthamide (5k)
Yellow powder; yield: 124 mg (86%); mp 138–140 °C.
IR (KBr): 3449, 3244, 1587, 1551, 1455, 1408, 1331, 1305 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 9.46 (br s, 1 H), 8.84 (d, J =
9.2 Hz, 1 H), 8.07–7.94 (m, 3 H), 7.56–7.50 (m, 5 H), 7.34 (t,
J = 7.8 Hz, 2 H), 7.01 (t, J = 7.2 Hz, 1 H).
1H NMR (400 MHz, CDCl3): δ = 9.74 (br s, 1 H), 7.54 (dd, J = 7.6,
1.6 Hz, 1 H), 7.39 (d, J = 8.0 Hz, 1 H), 7.31–7.27 (m, 2 H), 7.21–
7.16 (m, 2 H), 7.07–7.03 (m, 1 H), 6.95 (d, J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 178.4, 159.9, 140.5, 135.6, 133.1,
130.1, 129.7, 129.3, 128.8, 126.7, 125.0, 119.7.
HRMS (ESI): m/z [M + H]+ calcd for C14H13BrN3O: 318.0242;
found: 318.0239.
13C NMR (100 MHz, DMSO-d6): δ = 179.0, 158.6, 136.7, 136.1,
133.1, 130.4, 130.2, 129.3, 129.0, 127.9, 126.7, 126.2, 126.0, 125.9,
124.4, 124.3, 114.9, 107.4.
HRMS (ESI): m/z [M + H]+ calcd for C18H16N3O: 290.1293; found:
290.1296.
2-({[Anilino(imino)methyl]amino}carbonyl)phenyl Tosylate
(5f)
Yellow powder; yield: 170 mg (83%); mp 166–168 °C.
1H NMR (400 MHz, CDCl3): δ = 7.86–7.84 (m, 1 H), 7.76 (d,
J = 8.4 Hz, 2 H), 7.43 (t, J = 7.8 Hz, 2 H), 7.38–7.20 (m, 8 H),
7.02–7.00 (m, 1 H), 3.41 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 175.5, 166.6, 159.0, 146.3, 145.4,
138.4, 134.9, 131.9, 130.9, 130.8, 130.0, 129.0, 128.4, 127.1, 123.6,
121.7, 21.3.
N-[Anilino(imino)methyl]-2-nitrobenzamide (5ab)
Light-yellow powder; yield: 116 mg (82%); mp 154–156 °C.
IR (KBr): 3437, 1614, 1564, 1520, 1450, 1394, 1346 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 9.40 (s, 1 H), 8.97 (br s, 1 H),
7.85–7.80 (m, 2 H), 7.71–7.59 (m, 2 H), 7.41–7.34 (m, 4 H), 7.14–
7.12 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 175.2, 159.5, 149.1, 137.8,
135.1, 132.5, 130.6, 130.0, 129.2, 124.4, 123.5, 122.6.
HRMS (ESI): m/z [M + H]+ calcd for C21H20N3O4S: 410.1175;
found: 410.1176.
HRMS (ESI): m/z [M + H]+ calcd for C14H13N4O3: 285.0988; found:
285.0939.
N-[Anilino(imino)methyl]biphenyl-2-carboxamide (5g)
White powder; yield: 120 mg (76%); mp 135–137 °C.
1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 7.2 Hz, 1 H), 7.44–
7.25 (m, 11 H), 7.15 (t, J = 7.2 Hz, 2 H), 6.92 (m, 1 H).
Anal. Calcd for C14H13N4O3: C, 59.15; H, 4.25; N, 19.71. Found: C,
59.23; H, 4.39; N, 19.72.
13C NMR (100 MHz, CDCl3): δ = 180.3, 158.6, 141.7, 141.0, 139.3,
138.5, 130.0, 129.0, 128.8, 128.6, 128.5, 128.2, 127.0, 126.9, 123.4,
121.7.
HRMS (ESI): m/z [M + H]+ calcd for C20H18N3O: 316.1450; found:
316.1447.
N-{[(4-Chlorophenyl)amino](imino)methyl}-2-nitrobenzamide
(5ac)
Light-yellow powder; yield: 121 mg (76%).
1H NMR (400 MHz, DMSO-d6): δ = 9.43 (s, 1 H), 9.03 (br s, 1 H),
7.82 (t, J = 8.6 Hz, 2 H), 7.70 (t, J = 7.4 Hz, 1 H), 7.64–7.60 (m, 1
H), 7.44–7.36 (m, 4 H).
N-[Anilino(imino)methyl]-2-methoxybenzamide (5h)
Yellow powder; yield: 74 mg (55%); mp 140–142 °C.
13C NMR (100 MHz, DMSO-d6): δ = 175.2, 159.3, 149.2, 137.1,
1H NMR (400 MHz, CDCl3): δ = 7.71–7.51 (m, 5 H), 7.41 (t,
J = 7.6 Hz, 2 H), 7.24 (t, J = 7.6 Hz, 1 H), 7.13–7.05 (m, 2 H), 3.93
(s, 3 H).
134.8, 132.5, 130.8, 130.0, 129.0, 128.1, 124.1, 123.5.
HRMS (ESI): m/z [M + H]+ calcd for C14H12ClN4O3: 319.0598;
found: 319.0595.
13C NMR (100 MHz, DMSO-d6): δ = 177.2, 157.1, 141.6, 131.7,
129.9, 129.2, 123.2, 122.0, 120.3, 115.8, 114.1, 112.3, 55.9.
HRMS (ESI): m/z [M + H]+ calcd for C15H16N3O2: 270.1243; found:
N-{(4-Bromophenyl)amino](imino)methyl}-2-nitrobenzamide
(5ad)
Yellow powder; yield: 145 mg (80%).
1H NMR (400 MHz, DMSO-d6): δ = 9.42 (s, 1 H), 9.03 (br s, 1 H),
7.84–7.80 (m, 2 H), 7.70 (t, J = 7.2 Hz, 1 H), 7.64–7.60 (m, 1 H),
7.50 (d, J = 8.8 Hz, 2 H), 7.37 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 175.1, 159.2, 149.2, 137.5,
134.8, 132.5, 131.8, 130.8, 130.0, 124.4, 123.5, 116.1.
270.1244.
N-[Anilino(imino)methyl]-2,6-dichlorobenzamide (5i)
Yellow powder; yield: 140 mg (91%); mp 158–160 °C.
1H NMR (400 MHz, DMSO-d6): δ = 9.65 (br s, 1 H), 9.06 (br s, 1
H), 7.45 (d, J = 8.4 Hz, 2 H), 7.37–7.31 (m, 6 H), 7.13 (t, J = 6.6
Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C14H12BrN4O3: 363.0093;
found: 363.0095.
13C NMR (100 MHz, DMSO-d6): δ = 175.2, 159.6, 140.4, 137.5,
130.3, 129.6, 129.3, 128.1, 124.7, 122.7.
N-{Imino[(4-tolyl)amino]methyl}-2-nitrobenzamide (5ae)
Light-green powder; yield: 107 mg (72%); mp 164–167 °C.
HRMS (ESI): m/z [M + H] calcd for C14H12Cl2N3O: 308.0357;
1H NMR (400 MHz, DMSO-d6): δ = 9.39 (s, 1 H), 7.83–7.78 (m, 2
H), 7.71–7.67 (m, 1 H), 7.63–7.58 (m, 1 H), 7.25 (t, J = 8.0 Hz, 2
H), 7.15 (t, J = 8.0 Hz, 2 H), 2.28 (s, 3 H).
found: 308.0361.
N-[Anilino(imino)methyl]-6-bromo-1,3-benzodioxole-5-car-
boxamide (5j)
Yellow powder; yield: 128 mg (71%); mp 198–200 °C.
13C NMR (100 MHz, DMSO-d6): δ = 175.1, 159.7, 149.1, 135.1,
133.8, 132.4, 130.6, 130.0, 129.7, 123.4, 123.0, 122.0, 20.7.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2533–2544

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L. H. Gu et al.
PAPER
HRMS (ESI): m/z [M + H]+ calcd for C15H15N4O3: 299.1144; found:
299.1149.
13C NMR (100 MHz, DMSO-d6): δ = 175.4, 160.6, 142.9, 139.2,
131.0, 129.8, 128.8, 128.0, 127.50, 127.46, 38.4.
HRMS (ESI): m/z [M + H]+ calcd for C15H16N3O: 254.1293; found:
254.1298.
N-{Imino[(4-methoxyphenyl)amino]methyl}-2-nitrobenzamide
(5af)
Yellow powder; yield: 116 mg (74%).
N-[2,3-Dihydro-1H-indol-1-yl(imino)methyl]benzamide (5m)
Yellow powder; yield: 111 mg (84%); mp 145–147 °C.
IR (KBr): 3499, 3310, 1620, 1590, 1550, 1511 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 10.04 (br s, 1 H), 8.46 (d,
J = 7.2 Hz, 1 H), 8.17 (m, 2 H), 7.68–7.48 (m, 3 H), 7.25 (m, 2 H),
6.99 (t, J = 6.6 Hz, 1 H), 4.04 (t, J = 7.6 Hz, 2 H), 3.18 (d, J = 7.4
Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 176.2, 158.7, 142.7, 139.3,
132.6, 131.2, 128.8, 128.3, 127.2, 125.1, 122.9, 117.4, 47.8, 26.9.
1H NMR (400 MHz, DMSO-d6): δ = 9.37 (br s, 1 H), 8.92 (br s, 1
H), 7.83–7.78 (m, 2 H), 7.70–7.66 (m, 1 H), 7.60 (dd, J = 7.6, 1.2
Hz, 1 H), 7.26 (d, J = 8.4 Hz, 2 H), 6.93 (d, J = 8.4 Hz, 2 H), 3.75
(s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 175.0, 160.0, 156.8, 149.1,
135.2, 134.1, 132.4, 130.5, 130.0, 125.2, 123.4, 114.5.
HRMS (ESI): m/z [M + H]+ calcd for C15H15N4O4: 315.1093; found:
315.1097.
HRMS (ESI): m/z [M + H]+ calcd for C16H16N3O: 266.1293; found:
266.1299.
N-[Imino(2-naphthylamino)methyl]-2-nitrobenzamide (5ag)
Light-yellow powder; yield: 114 mg (68%).
1H NMR (400 MHz, DMSO-d6): δ = 9.64 (s, 1 H), 9.07 (br s, 1 H),
7.97 (s, 1 H), 7.90–7.83 (m, 5 H), 7.72 (t, J = 7.2 Hz, 1 H), 7.65–
7.58 (m, 1 H), 7.52–7.42 (m, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 175.3, 159.6, 149.1, 135.5,
135.1, 133.6, 132.6, 130.7, 130.4, 130.0, 128.8, 127.7, 127.6, 126.7,
125.4, 123.5, 122.7, 119.2.
N-[3,4-Dihydroquinolin-1(2H)-yl(imino)methyl]benzamide
(5n)
Yellow powder; yield: 103 mg (74%); mp 104–107 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.19 (br s, 1 H), 8.11–8.09
(m, 2 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.49–7.39 (m, 3 H), 7.26–7.20
(m, 2 H), 7.13–7.09 (m, 1 H), 3.91 (t, J = 6.2 Hz, 2 H), 2.73 (t,
J = 6.4 Hz, 2 H), 1.95–1.89 (m, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C18H15N4O3: 335.1144; found:
335.1145.
13C NMR (100 MHz, DMSO-d6): δ = 175.9, 160.3, 153.8, 139.1,
138.0, 132.8, 131.1, 128.9, 128.0, 126.0, 125.4, 124.7, 44.7, 26.5,
23.9.
N-{[(4-Acetylphenyl)amino](imino)methyl}-2-nitrobenzamide
(5ah)
HRMS (ESI): m/z [M + H]+ calcd for C17H18N3O: 280.1450; found:
Yellow powder; yield: 85 mg (52%).
1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 8.4 Hz, 2 H), 7.75–
7.70 (m, 2 H), 7.56 (t, J = 7.4 Hz, 1 H), 7.45 (t, J = 7.6 Hz, 1 H),
7.19 (d, J = 8.4 Hz, 2 H), 2.57 (s, 3 H).
280.1451.
4-Chloro-N-[2,3-dihydro-1H-indol-1-yl(imino)methyl]benz-
amide (5o)
Gray powder; yield: 120 mg (80%); mp 163–165 °C.
13C NMR (100 MHz, DMSO-d6): δ = 196.6, 175.4, 159.0, 149.2,
143.1, 134.8, 132.6, 131.9, 130.8, 130.1, 129.6, 123.5, 120.6, 26.7.
HRMS (ESI): m/z [M + H]+ calcd for C16H15N4O4: 327.1093; found:
327.1102.
IR (KBr): 3448, 1611, 1589, 1522, 744 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.20–8.17 (m, 2 H), 8.10 (br s, 1
H), 7.41–7.83 (m, 2 H), 7.28–7.24 (m, 3 H), 7.04 (t, J = 7.2 Hz, 1
H), 4.14 (t, J = 8.4 Hz, 2 H), 3.22 (t, J = 8.4 Hz, 2 H).
N-{Imino[(2-tolyl)amino]methyl}-2-nitrobenzamide (5ai)
Yellow powder; yield: 106 mg (71%).
13C NMR (100 MHz, DMSO-d6): δ = 175.0, 158.6, 142.5, 138.1,
136.0, 132.6, 130.6, 128.4, 127.2, 125.1, 123.0, 117.3, 47.9, 26.9.
HRMS (ESI): m/z [M + H]+ calcd for C16H15ClN3O: 300.0904;
IR (KBr): 3455, 3222, 2923, 2744, 1656, 1609, 1568, 1528, 1480,
1360, 1303 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 9.31 (br s, 1 H), 8.87 (br s, 1
H), 7.78 (t, J = 6.4 Hz, 2 H), 7.66 (t, J = 7.4 Hz, 1 H), 7.61–7.58 (m,
1 H), 7.33–7.28 (m, 2 H), 7.24–7.16 (m, 2 H), 7.11 (br s, 1 H), 2.23
(s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 174.9, 160.4, 149.0, 135.2,
135.0, 133.7, 132.3, 130.9, 130.4, 129.9, 126.9, 126.8, 126.7, 123.3,
17.9.
found: 300.0910.
4-Chloro-N-[(diphenylamino)(imino)methyl]benzamide (5p)
White needle crystals; yield: 92 mg (53%); mp 168–171 °C.
1H NMR (400 MHz, CDCl3): δ = 10.29 (br s, 1 H), 7.89 (d, J = 8.4
Hz, 2 H), 7.45–7.25 (m, 12 H), 5.34 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 176.4, 160.2, 141.6, 137.2, 136.9,
130.6, 129.5, 128.1, 128.0, 127.3.
HRMS (ESI): m/z [M + H]+ calcd for C20H17ClN3O: 350.1060;
found: 350.1061.
HRMS (ESI): m/z [M + H]+ calcd for C15H15N4O3: 299.1144; found:
299.1146.
Aroylguanidines 5l–z and 5aj from Secondary Aryl Amines;
General Procedure
N-[2,3-Dihydro-1H-indol-1-yl(imino)methyl]-4-methoxybenz-
amide (5q)
The appropriate N-cyanoimidate 3 (0.5 mmol) and secondary aryl
amine 4 (1.5 mmol) were dissolved in DMF (2 mL) and the mixture
was stirred at 90 °C for 24 h. H2O (5 mL) was then added and the
mixture was extracted with EtOAc (3 × 10 mL). The organic phases
were combined, washed with H2O (3 × 10 mL), dried (Na2SO4), and
concentrated under reduced pressure. The residue was purified by
flash column chromatography (silica gel, PE–EtOAc).
Yellow powder; yield: 124 mg (84%); mp 166–169 °C.
IR (KBr): 3364, 1604, 1541, 1254, 1032 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 10.01 (br s, 1 H), 8.44 (d,
J = 7.2 Hz, 1 H), 8.12 (d, J = 8.0 Hz, 2 H), 7.25 (m, 2 H), 7.02–7.00
(m, 3 H), 4.03 (d, J = 7.6 Hz, 2 H), 3.82 (s, 3 H), 3.18 (d, J = 7.2
Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 176.0, 161.8, 158.5, 142.8,
132.6, 131.8, 130.6, 127.1, 125.1, 122.8, 117.3, 113.5, 55.5, 47.8,
26.9.
N-{Imino[methyl(phenyl)amino]methyl}benzamide (5l)
Dark-gray powder; yield: 99 mg (78%); mp 94–96 °C.
1H NMR (400 MHz, DMSO-d6): δ = 9.84 (br s, 1 H), 8.08 (d,
J = 7.2 Hz, 2 H), 7.51–7.33 (m, 9 H), 3.44 (s, 3 H).
Synthesis 2013, 45, 2533–2544
© Georg Thieme Verlag Stuttgart · New York

PAPER
Aroylguanidines by a Demethylation–Addition Cascade
IR (KBr): 3455, 1626, 1606, 1589, 1519, 1481, 1347 cm–1.
2541
HRMS (ESI): m/z [M + H]+ calcd for C17H18N3O2: 296.1399; found:
296.1396.
1H NMR (400 MHz, CDCl3): δ = 7.92 (dd, J = 7.6, 1.2 Hz, 2 H),
7.82 (br s, 1 H), 7.72 (d, J = 7.6 Hz, 1 H), 7.60 (t, J = 7.6 Hz, 1 H),
7.51 (t, J = 7.6 Hz, 1 H), 7.23–7.17 (m, 2 H), 7.02 (d, J = 7.6 Hz, 1
H), 4.09 (d, J = 8.4 Hz, 2 H), 3.18 (d, J = 8.4 Hz, 2 H).
2-Chloro-N-{imino[methyl(phenyl)amino]methyl}benzamide
(5r)
Yellow needle crystals; yield: 113 mg (79%); mp 183–185 °C.
13C NMR (100 MHz, DMSO-d6): δ = 174.7, 158.1, 149.2, 142.2,
135.4, 132.6, 130.6, 129.8, 127.1, 125.1, 123.6, 123.3, 117.6, 110.5,
47.8, 26.8.
HRMS (ESI): m/z [M + H]+ calcd for C16H15N4O3: 311.1144; found:
311.1142.
1H NMR (400 MHz, CDCl3): δ = 9.81 (br s, 1 H), 7.93–7.91 (m, 1
H), 7.50 (t, J = 7.8 Hz, 2 H), 7.42–7.39 (m, 2 H), 7.33–7.27 (m, 4
H), 3.49 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 177.7, 160.2, 141.1, 139.0,
132.1, 130.9, 130.4, 130.1, 128.5, 127.2, 126.2, 38.6, 29.6.
HRMS (ESI): m/z [M + H]+ calcd for C15H15ClN3O: 288.0904;
found: 288.0901.
N-[(Diphenylamino)(imino)methyl]-4-nitrobenzamide (5x)
White powder; yield: 103 mg (57%); mp 179–182 °C.
1H NMR (400 MHz, CDCl3): δ = 10.24 (br s, 1 H), 8.14–8.07 (m, 4
H), 7.48–7.44 (m, 4 H), 7.40–7.34 (m, 6 H), 5.44 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 173.6, 160.8, 142.3, 129.9,
129.7, 129.4, 128.6, 127.5, 123.3, 116.9.
HRMS (ESI): m/z [M + H]+ calcd for C20H17N4O3: 361.1301; found:
361.1306.
2-Chloro-N-[2,3-dihydro-1H-indol-1-yl(imino)methyl]benz-
amide (5s)
White powder; yield: 133 mg (89%); mp 144–146 °C.
1H NMR (400 MHz, CDCl3): δ = 8.13 (s, 1 H), 7.85–7.83 (m, 1 H),
7.42–7.39 (m, 1 H), 7.31–7.28 (m, 2 H), 7.21–7.16 (m, 2 H), 7.01
(m, 1 H), 4.09 (t, J = 8.2 Hz, 2 H), 3.20 (t, J = 8.4 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C16H15ClN3O: 300.0904;
found: 300.0906.
N-{[Benzyl(phenyl)amino](imino)methyl}thiophene-2-carbox-
amide (5y)
Yellow powder; yield: 121 mg (72%).
1H NMR (400 MHz, DMSO-d6): δ = 9.50 (br s, 1 H), 7.63–7.62 (m,
2 H), 7.49–7.21 (m, 10 H), 7.11–7.09 (m, 1 H), 6.77 (br s, 1 H), 5.20
(s, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 171.3, 160.0, 145.4, 140.1,
138.0, 131.1, 130.0, 129.9, 128.5, 128.4, 128.1, 127.93, 127.90,
127.4, 53.4.
Anal. Calcd for C16H15ClN3O: C, 64.11; H, 4.71, Cl, 11.83; N,
14.02. Found: C, 64.51; H, 4.85, Cl, 11.82; N, 14.00.
6-Bromo-N-{imino[methyl(phenyl)amino]methyl}-1,3-benzodi-
oxole-5-carboxamide (5t)
White powder; yield: 143 mg (76%); mp 187–190 °C.
IR (KBr): 3448, 3374, 2938, 1592, 1560, 1529, 1451, 1361 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 9.83 (s, 1 H), 7.52–7.48 (m, 2
H), 7.42–7.39 (m, 1 H), 7.33–7.28 (m, 2 H), 7.05 (s, 1 H), 6.00 (s, 2
H), 3.49 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C19H18N3OS: 336.1171;
found: 336.1177.
13C NMR (100 MHz, DMSO-d6): δ = 177.3, 160.1, 149.0, 146.7,
141.2, 130.4, 128.5, 127.3, 113.7, 112.7, 111.1, 101.8, 38.6, 29.6.
HRMS (ESI): m/z [M + H]+ calcd for C16H15BrN3O3: 376.0297;
found: 376.0295.
N-{Imino[methyl(phenyl)amino]methyl}thiophene-2-carbox-
amide (5z)
Yellow powder; yield: 105 mg (81%).
1H NMR (400 MHz, DMSO-d6): δ = 9.49 (br s, 1 H), 7.62–7.57 (m,
2 H), 7.49 (m, 2 H), 7.39–7.37 (m, 3 H), 7.08–7.06 (m, 2 H), 3.40
(s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 171.0, 160.0, 145.5, 142.5,
130.9, 129.8, 129.7, 127.8, 127.52, 127.46, 38.3.
HRMS (ESI): m/z [M + H]+ calcd for C13H14N3OS: 260.0858;
found: 260.082.
N-{[Benzyl(phenyl)amino](imino)methyl}-1-naphthamide (5u)
Yellow needle crystals; yield: 152 mg (80%); mp 151–153 °C.
IR (KBr): 3469, 2922, 2852, 1626, 1594, 1566, 1522, 1454, 1416,
1353, 1314 cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.19 (s, 1 H), 9.00 (t, J = 2.8 Hz,
1 H), 8.22 (d, J = 6.8 Hz, 1 H), 7.90–7.83 (m, 2 H), 7.54–7.14 (m,
12 H), 7.15 (d, J = 7.2 Hz, 2 H), 5.22 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 180.5, 160.3, 139.6, 137.7,
137.2, 133.9, 131.2, 130.6, 130.3, 129.2, 128.7, 128.6, 128.5, 128.4,
128.3, 128.1, 127.4, 127.1, 126.9, 126.3, 125.4, 124.7, 117.4, 112.7,
53.9.
(2,3-Dihydro-1H-indol-1-ylmethylene)cyanamide (6o)
Yellow powder; yield: 46 mg (54%).
1H NMR (400 MHz, CDCl3): δ = 8.94 (s, 1 H), 7.24 (m, 1 H), 7.17
(t, J = 6.0 Hz, 2 H), 7.08–7.06 (m, 1 H), 4.07 (t, J = 8.0 Hz, 2 H),
3.17 (t, J = 8.0 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C25H22N3O: 380.1763; found:
380.1769.
HRMS (ESI): m/z [M + H]+ calcd for C10H10N3: 172.0875; found:
172.0869.
N-[(Diphenylamino)(imino)methyl]-2-nitrobenzamide (5v)
N-{Imino[methyl(phenyl)amino]methyl}-2-nitrobenzamide
(5aj)
White powder; yield: 83 mg (46%); mp 178–181 °C.
Yellow powder; yield: 134 mg (90%); mp 155–158 °C.
1H NMR (400 MHz, CDCl3): δ = 10.08 (br s, 1 H), 7.71 (d, J = 8.0
Hz, 1 H), 7.58 (d, J = 7.6 Hz, 1 H), 7.46 (t, J = 7.2 Hz, 1 H), 7.43–
7.39 (m, 4 H), 7.33–7.29 (m, 6 H).
13C NMR (100 MHz, DMSO-d6): δ = 174.5, 160.5, 149.3, 142.1,
134.4, 131.9, 130.7, 130.1, 129.7, 128.4, 127.4, 123.2.
1H NMR (400 MHz, DMSO-d6): δ = 9.39 (s, 1 H), 7.85 (d, J = 7.6
Hz, 1 H), 7.73 (d, 7.2 Hz, 1 H), 7.67–7.58 (m, 2 H), 7.49 (t, J = 7.6
Hz, 2 H), 7.39–7.35 (m, 3 H), 7.07 (br s, 1 H), 3.30 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C15H15N4O3: 299.1144; found:
299.1150.
HRMS (ESI): m/z [M + H]+ calcd for C20H17N4O3: 361.1301; found:
361.1305.
1-Aryl-2-Aminoquinazolin-4(1H)-ones (7a–f) and N-[2,3-Di-
hydro-1H-indol-1-yl(imino)methyl]-2-fluorobenzamide (5aa);
General Procedure
The appropriate N-cyanoimidate 3 (0.5 mmol) and aryl amine 4 (2.5
mmol) were dissolved in DMF (10 mL) and the mixture was stirred
N-[2,3-Dihydro-1H-indol-1-yl(imino)methyl]-2-nitrobenz-
amide (5w)
Yellow powder; yield: 146 mg (94%); mp 148–151 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2533–2544

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L. H. Gu et al.
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at 90 °C for 24 h. The resulting mixture was purified by flash col-
umn chromatography (silica gel, CH2Cl2 then CH2Cl2–MeOH).
N-[2,3-Dihydro-1H-indol-1-yl(imino)methyl]-2-fluorobenza-
mide (5aa)
White powder; yield: 80 mg (56%).
2-Amino-1-phenylquinazolin-4(1H)-one (7a)
1H NMR (400 MHz, CDCl3): δ = 8.25 (br s, 1 H), 8.03 (t, J = 7.2
Hz, 1 H), 7.42–7.38 (br s, 1 H), 7.23–7.16 (m, 3 H), 7.13–7.08 (m,
1 H), 7.00 (t, J = 7.2 Hz, 1 H), 4.04 (t, J = 8.2 Hz, 2 H), 3.16 (t,
J = 8.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 176.2, 162.7, 158.1, 141.8, 132.0,
131.9, 131.6, 127.5, 124.9, 123.5, 123.4, 117.0, 116.7, 116.4, 47.6,
27.2.
Gray powder; yield: 85 mg (72%).
1H NMR (400 MHz, DMSO-d6): δ = 7.99 (dd, J = 7.8, 1.0 Hz, 1 H),
7.71–7.63 (m, 3 H), 7.49 (d, J = 6.8 Hz, 2 H), 7.46–7.42 (m, 1 H),
7.24 (t, J = 7.4 Hz, 1 H), 6.71 (br s, 2 H), 6.30 (d, J = 8.4 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 168.0, 155.9, 142.5, 135.7,
132.8, 131.4, 130.4, 129.5, 127.0, 123.3, 118.2, 115.1.
HRMS (ESI): m/z [M + H]+ calcd for C14H12N3O: 238.0980; found:
238.0988.
HRMS (ESI): m/z [M + H]+ calcd for C16H15FN3O: 284.1199;
found: 288.1196.
2-Amino-1-(4-chlorophenyl)quinazolin-4(1H)-one (7b)
2-(Arylamino)quinazolin-4-ones 8a–i; General Procedure
Fe (1.8 mmol) and concd HCl (0.2 mL) were added to a soln of ar-
oylguanidine 5 (0.1 mmol) in EtOH (10 mL). The resulting mixture
was refluxed for 2 h then filtered through kieselguhr. The solvent
was evaporated under reduced pressure and the residue was purified
by flash column chromatography (silica gel, CH2Cl2–MeOH).
White powder; yield: 58 mg (43%).
1H NMR (400 MHz, DMSO-d6): δ = 7.99–7.97 (m, 1 H), 7.74 (d,
J = 8.8 Hz, 2 H), 7.55 (d, J = 8.8 Hz, 2 H), 7.47–7.43 (m, 1 H),
7.26–7.22 (m, 1 H), 6.75 (br s, 2 H), 6.35 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 167.9, 155.8, 142.4, 135.0,
134.7, 132.9, 131.7, 131.5, 127.0, 123.3, 118.2, 115.1.
HRMS (ESI): m/z [M + H]+ calcd for C14H11ClN3O: 272.0591;
2-Anilinoquinazolin-4(3H)-one (8a)
White powder; yield: 18 mg (77%).
found: 272.0593.
1H NMR (400 MHz, DMSO-d6): δ = 10.83 (s, 1 H), 8.68 (s, 1 H),
7.88 (d, J = 8.0 Hz, 1 H), 7.76 (d, J = 8.4 Hz, 2 H), 7.66 (t, J = 7.6
Hz, 1 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.36 (t, J = 8.0 Hz, 2 H), 7.24
(t, J = 7.6 Hz, 1 H), 7.05 (t, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 161.9, 147.6, 139.2, 134.7,
129.1, 126.2, 125.6, 123.3, 122.8, 119.5, 118.6, 115.9.
2-Amino-1-(4-bromophenyl)quinazolin-4(1H)-one (7c)
White powder; yield: 71 mg (45%).
1H NMR (400 MHz, DMSO-d6): δ = 7.98 (d, J = 7.6 Hz, 1 H), 7.88
(d, J = 8.4 Hz, 2 H), 7.49–7.43 (m, 3 H), 7.25 (t, J = 7.4 Hz, 1 H),
6.84 (br s, 2 H), 6.36 (d, J = 8.4 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 167.9, 155.6, 142.3, 135.1,
134.4, 132.9, 131.9, 127.0, 123.8, 123.4, 118.1, 115.1.
HRMS (ESI): m/z [M + H]+ calcd for C14H12N3O: 238.0980; found:
238.0986.
HRMS (ESI): m/z [M + H]+ calcd for C14H11BrN3O: 316.0085;
found: 316.0086.
2-[(4-Chlorophenyl)amino]quinazolin-4(3H)-one (8b)
Light-yellow powder; yield: 19 mg (70%).
1H NMR (400 MHz, DMSO-d6): δ = 10.88 (s, 1 H), 8.82 (s, 1 H),
7.97 (dd, J = 8.0, 1.2 Hz, 1 H), 7.78 (d, J = 8.4 Hz, 2 H), 7.69–7.64
(m, 1 H), 7.42–7.39 (m, 3 H), 7.26–7.23 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.0, 150.0, 147.5, 138.2,
134.7, 128.9, 126.3, 126.2, 125.6, 123.5, 121.1, 118.7.
HRMS (ESI): m/z [M + H]+ calcd for C14H11ClN3O: 272.0591;
found: 272.0587.
2-Amino-1-(4-tolyl)quinazolin-4(1H)-one (7d)
White powder; yield: 89 mg (71%).
1H NMR (400 MHz, DMSO-d6): δ = 7.99 (d, J = 6.8 Hz, 1 H),
7.51–7.43 (m, 3 H), 7.36 (d, J = 8.0 Hz, 2 H), 7.24 (t, J = 7.4 Hz, 1
H), 6.34 (d, J = 8.4 Hz, 1 H), 2.45 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 167.7, 155.8, 142.6, 140.0,
133.0, 132.9, 131.8, 129.2, 127.0, 123.3, 118.1, 115.2, 21.1.
HRMS (ESI): m/z [M + H]+ calcd for C15H14N3O: 252.1137; found:
252.1132.
2-[(4-Bromophenyl)amino]quinazolin-4(3H)-one (8c)
Yellow powder; yield: 24 mg (76%).
1H NMR (400 MHz, DMSO-d6): δ = 10.88 (s, 1 H), 8.82 (s, 1 H),
7.98 (d, J = 7.6 Hz, 1 H), 7.73 (d, J = 8.0 Hz, 2 H), 7.67–7.63 (m,
1 H), 7.51 (d, J = 8.8 Hz, 2 H), 7.40 (d, J = 8.4 Hz, 1 H), 7.24 (t,
J = 7.4 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 161.8, 150.0, 147.4, 138.7,
134.7, 131.8, 126.2, 125.6, 123.5, 121.5, 118.7, 114.2.
2-Amino-1-(4-methoxyphenyl)quinazolin-4(1H)-one (7e)
White powder; yield: 85 mg (64%).
1H NMR (400 MHz, DMSO-d6): δ = 7.97 (dd, J = 7.6, 1.2 Hz, 1 H),
7.47–7.43 (m, 1 H), 7.40 (d, J = 8.8 Hz, 2 H), 7.25–7.20 (m, 3 H),
6.36 (d, J = 8.4 Hz, 1 H), 3.86 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C15H14N3O2: 268.1086; found:
268.1080.
HRMS (ESI): m/z [M + H]+ calcd for C14H11BrN3O: 316.0085;
found: 316.0086.
2-Amino-1-(2-naphthyl)quinazolin-4(1H)-one (7f)
Gray powder; yield: 109 mg (76%).
2-[(4-Tolyl)amino]quinazolin-4(3H)-one (8d)
Light-yellow powder; yield: 21 mg (84%).
1H NMR (400 MHz, DMSO-d6): δ = 8.24 (d, J = 8.8 Hz, 1 H), 8.16
(s, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 8.07–8.01 (m, 2 H), 7.71–7.64
(m, 2 H), 7.53 (dd, J = 8.4, 1.6 Hz, 1 H), 7.40 (t, J = 8.0 Hz, 1 H),
7.24 (t, J = 7.4 Hz, 1 H), 6.35 (d, J = 8.4 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 167.9, 156.0, 142.6, 134.2,
133.6, 133.0, 132.9, 131.5, 129.2, 128.6, 128.2, 127.7, 127.1, 127.0,
126.4, 123.4, 118.1, 115.3.
1H NMR (400 MHz, DMSO-d6): δ = 10.80 (s, 1 H), 8.58 (s, 1 H),
7.96 (dd, J = 7.6, 0.8 Hz, 1 H), 7.66–7.60 (m, 3 H), 7.38 (t, J = 8.0
Hz, 1 H), 7.16 (d, J = 8.0 Hz, 2 H), 2.28 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.0, 148.7, 148.2, 136.0,
134.8, 132.4, 129.6, 126.3, 124.4, 123.4, 120.5, 118.2, 20.7.
HRMS (ESI): m/z [M + H]+ calcd for C15H14N3O: 252.1137; found:
252.1136.
HRMS (ESI): m/z [M + H]+ calcd for C18H14N3O: 288.1137; found:
288.1142.
2-[(4-Methoxyphenyl)amino]quinazolin-4(3H)-one (8e)
White powder; yield: 22 mg (81%).
Synthesis 2013, 45, 2533–2544
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Aroylguanidines by a Demethylation–Addition Cascade
2543
1H NMR (400 MHz, DMSO-d6): δ = 10.82 (s, 1 H), 8.54 (s, 1 H),
7.95 (dd, J = 8.0, 1.2 Hz, 1 H), 7.64–7.60 (m, 3 H), 7.34 (d, J = 8.0
Hz, 1 H), 7.20 (t, J = 7.4 Hz, 1 H), 6.95–6.93 (m, 2 H), 3.75 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.3, 155.4, 149.8, 148.3,
134.6, 131.9, 126.2, 124.9, 123.0, 121.9, 118.3, 114.3, 55.5.
Methyl Cyanoimidoformate (3o)29e
Colorless oil; yield: 11.63g (85%).
1H NMR (400 MHz, CDCl3): δ = 8.66 (s, 1 H), 3.72 (s, 3 H).
MS (ESI): m/z [M + H]+ calcd for C3H5N2O: 85.0; found: 85.0.
HRMS (ESI): m/z [M + H]+ calcd for C15H14N3O2: 268.1086; found:
268.1080.
Acknowledgment
This work was financially supported by the National Science Foun-
dation of China (No. 21072131).
2-(2-Naphthylamino)quinazolin-4(3H)-one (8f)
White powder; yield: 22 mg (78%).
1H NMR (400 MHz, DMSO-d6): δ = 10.97 (s, 1 H), 8.95 (s, 1 H),
8.54 (s, 1 H), 8.01 (d, J = 8.0 Hz, 1 H), 7.91–7.85 (m, 3 H), 7.71–
7.66 (m, 2 H), 7.54–7.47 (m, 2 H), 7.40 (t, J = 7.4 Hz, 1 H), 7.26 (t,
J = 7.4 Hz, 1 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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13C NMR (100 MHz, DMSO-d6): δ = 161.9, 153.7, 150.2, 147.7,
136.8, 134.7, 133.9, 129.6, 128.7, 127.7, 127.5, 126.7, 126.2, 125.8,
124.6, 123.5, 120.7, 115.1.
References
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HRMS (ESI): m/z [M + H]+ calcd for C18H14N3O: 288.1137; found:
288.1140.
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C. E.; Wright, A. D.; Wiese, M.; König, G. M. J. Med. Chem.
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2-(4-Acetylphenylamino)quinazolin-4(3H)-one (8g)
Yellow powder; yield: 18 mg (65%).
1H NMR (400 MHz, DMSO-d6): δ = 10.95 (s, 1 H), 9.14 (s, 1 H),
8.00–7.86 (m, 5 H), 7.69 (t, J = 7.2 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1
H), 7.28 (t, J = 7.4 Hz, 1 H), 2.54 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 201.4, 166.6, 154.6, 151.9,
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Ngu, K.; Wu, S. C.; Yost, K. J.; Chen, B.-C.; Gougoutas, J.
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148.6, 139.6, 135.8, 134.7, 131.0, 130.7, 128.7, 123.2, 44.6, 31.5.
HRMS (ESI): m/z [M + H]+ calcd for C16H14N3O2: 280.1086; found:
280.1087.
2-(2-Tolylamino)quinazolin-4(3H)-one (8h)
Yellow powder; yield: 19 mg (75%).
1H NMR (400 MHz, DMSO-d6): δ = 11.27 (s, 1 H), 8.11 (s, 1 H),
7.97–7.95 (m, 2 H), 7.62 (t, J = 7.6 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1
H), 7.25–7.19 (m, 3 H), 7.05 (t, J = 7.2 Hz, 1 H), 2.27 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.1, 150.4, 148.2, 137.0,
134.6, 130.5, 129.2, 126.5, 126.1, 125.4, 123.8, 123.0, 122.7, 118.5,
18.1.
HRMS (ESI): m/z [M + H]+ calcd for C15H14N3O: 252.1137; found:
252.1136.
2-[Methyl(phenyl)amino]quinazolin-4(3H)-one (8i)
Yellow powder; yield: 18 mg (73%).
1H NMR (400 MHz, DMSO-d6): δ = 10.99 (s, 1 H), 7.94 (d, J = 7.6
Hz, 1 H), 7.61 (m, 1 H), 7.45–7.43 (m, 2 H), 7.35–7.34 (m, 4 H),
7.19 (t, J = 7.4 Hz, 1 H), 3.41 (s, 3 H).
(5) Adang, A. E. P.; Lucas, H.; de Man, A. P. A.; Engh, R. A.;
Grootenhuis, P. D. J. Bioorg. Med. Chem. Lett. 1998, 8,
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13C NMR (100 MHz, DMSO-d6): δ = 162.7, 150.7, 150.4, 144.2,
134.5, 131.4, 129.8, 126.6, 126.2, 125.3, 122.9, 117.9, 39.9.
HRMS (ESI): m/z [M + H]+ calcd for C15H14N3O: 252.1137; found:
252.1130.
1-Methylindoline32
Brown oil; yield: 95 mg (71%).
1H NMR (400 MHz, CDCl3): δ = 7.08–7.07 (m, 2 H), 6.67 (t,
J = 7.6 Hz, 1 H), 6.49 (t, J = 8.0 Hz, 1 H), 3.28 (t, J = 8.0 Hz, 2 H),
2.94 (t, J = 8.0 Hz, 2 H), 2.75 (s, 3 H).
MS (ESI): m/z [M + H]+ calcd for C9H12N: 134.1; found: 134.1.
N-Cyanobenzamide (I)33
White solid; yield: 34 mg (23%); mp 134–136 °C.
1H NMR (400 MHz, CDCl3): δ = 7.91 (d, 2 H, J = 7.6 Hz), 7.61 (t,
1 H, J = 7.6 Hz), 7.48 (t, 2 H, J = 7.6 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C8H7N2O: 147.0558; found:
147.0566.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2533–2544

2544
L. H. Gu et al.
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